Aryl substituted imidazoquinolines

FIELD OF THE INVENTION

[0002] This invention relates to derivatives of imidazoquinoline compounds and to pharmaceutical compositions containing the compounds. A further aspect of this invention relates to the use of these compounds as immunomodulators, for inducing cytokine biosynthesis in animals and in the treatment of diseases including viral and neoplastic diseases.

BACKGROUND OF THE INVENTION

[0003] The first reliable report on the 1H-imidazo[4,5-c]quinoline ring system, Backman et al., J. Org. Chem., 15, 1278-1284 (1950) describes the synthesis of 1-(6-methoxy-8-quinolinyl)-2-methyl-1H-imidazo[4,5-c]quinoline for possible use as an antimalarial agent. Subsequently, syntheses of various substituted 1H-imidazo[4,5-c]quinolines were reported. For example, Jain et al., J. Med. Chem., 11, 87-92 (1968), synthesized the compound 1-[2-(4-piperidyl)ethyl]-1H-imidazo[4,5-c]quinoline as a possible anticonvulsant and cardiovascular agent. Also, Baranov et al., Chem. Abs., 85, 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-c]quinolines.

[0004] Certain 1H-imidazo[4,5-c]quinolin-4-amines and 1- and 2-substituted derivatives thereof were later found to be useful as antiviral agents, bronchodilators and immunomodulators. These are described in, inter alia, U.S. Pat. Nos. 4,689,338; 4,698,348; 4,929,624; 5,037,986; 5,268,376; 5,346,905; and 5,389,640.

[0005] There continues to be interest in the imidazoquinoline ring system and there is a continuing need for compounds that have the ability to modulate the immune response, by induction of cytokine biosynthesis or other mechanisms.

SUMMARY

[0006] The present invention provides a new class of compounds that are useful in inducing cytokine biosynthesis in animals. Such compounds are of the following Formula (I):

[0007] and more specifically of the following Formula (II):

[0008] wherein: R, n, R′, R″, R1, R2, and R3 are as defined below.

[0009] The compounds of Formulas I and II are useful as immune response modifiers (IRMs) due to their ability to modulate cytokine biosynthesis (e.g., induce or inhibit the biosynthesis or production of one or more cytokines) and otherwise modulate the immune response when administered to animals. Compounds can be tested per the test procedures described in the Examples Section. Compounds can be tested for induction of cytokine biosynthesis by incubating human PBMC in a culture with the compound(s) at a concentration range of 30 to 0.014 μM and analyzing for interferon (a) or tumor necrosis factor (a) in the culture supernatant. Compounds can be tested for inhibition of cytokine biosynthesis by incubating mouse macrophage cell line Raw 264.7 in a culture with the compound(s) at a single concentration of, for example, 5 μM and analyzing for tumor necrosis factor (α) in the culture supernatant. Compounds can be further tested for dose response by running the test at several compound concentrations, for example, 0.03, 0.1, 0.3, 1, 3, 5, and 10 μM. The ability to modulate cytokine biosynthesis makes the compounds useful in the treatment of a variety of conditions such as viral diseases, neoplastic diseases, and autoimmune diseases that are responsive to such changes in the immune response.

[0010] In another aspect, the present invention provides pharmaceutical compositions containing the immune response modifier compounds, and methods of modulating (e.g., inducing or inhibiting) cytokine biosynthesis in an animal, treating a viral disease in an animal, and treating a neoplastic disease in an animal, by administering an effective amount of one or more compounds of Formula I (and more specifically, of Formula II) and/or pharmaceutically acceptable salts thereof to the animal.

[0011] In another aspect, the invention provides methods of synthesizing compounds of Formulas I and II and intermediates useful in the synthesis of these compounds.

[0012] As used herein, “a,” “an,” “the,” “at least one,” and “one or more” are used interchangeably.

[0013] The terms “comprising” and variations thereof do not have a limiting meaning where these terms appear in the description and claims.

[0014] The above summary of the present invention is not intended to describe each disclosed embodiment or every implementation of the present invention. The description that follows more particularly exemplifies illustrative embodiments. Guidance is also provided herein through lists of examples, which can be used in various combinations. In each instance, the recited list serves only as a representative group and should not be interpreted as an exclusive list.

DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS OF THE INVENTION

[0015] The present invention provides compounds of the following Formula (I):

[0016] wherein:

[0017] R is selected from the group consisting of alkyl, alkoxy, hydroxy, and trifluoromethyl;

[0018] n is 0 or 1;

[0019] R′ and R″ are independently selected from the group consisting of hydrogen and non-interfering substitutents;

[0020] R3 is selected from the group consisting of:

[0021] —Z—Ar,

[0022] —Z—Ar′—Y—R4,

[0023] —Z—Ar′—X—Y—R4,

[0024] —Z—Ar′—R5, and

[0025] —Z—Ar′—X—R5;

[0026] Ar is selected from the group consisting of aryl and heteroaryl both of which can be unsubstituted or can be substituted by one or more substituents independently selected from the group consisting of alkyl, alkenyl, alkoxy, methylenedioxy, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, hydroxyalkyl, mercapto, cyano, carboxy, formyl, aryl, aryloxy, arylalkoxy, heteroaryl, heteroaryloxy, heteroarylalkoxy, heterocyclyl, heterocyclylalkyl, amino, alkylamino, and dialkylamino;

[0027] Ar′ is selected from the group consisting of arylene and heteroarylene both of which can be unsubstituted or can be substituted by one or more substituents independently selected from the group consisting of alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, hydroxyalkyl, mercapto, cyano, carboxy, formyl, aryl, aryloxy, arylalkoxy, heteroaryl, heteroaryloxy, heteroarylalkoxy, heterocyclyl, heterocyclylalkyl, amino, alkylamino, and dialkylamino;

[0028] X is selected from the group consisting of alkylene, alkenylene, alkynylene, arylene, heteroarylene, and heterocyclylene wherein the alkylene, alkenylene, and alkynylene groups can be optionally interrupted or terminated with arylene, heteroarylene, or heterocyclylene, and optionally interrupted by one or more —O— groups;

[0029] Y is selected from the group consisting of:

[0030] Z is selected from the group consisting of a bond, alkylene, alkenylene, and alkynylene;

[0031] R4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl wherein the alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl groups can be unsubstituted or substituted by one or more substituents independently selected from the group consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, mercapto, cyano, aryl, aryloxy, arylalkyleneoxy, heteroaryl, heteroaryloxy, heteroarylalkyleneoxy, heterocyclyl, amino, alkylamino, dialkylamino, (dialkylamino)alkyleneoxy, and in the case of alkyl, alkenyl, alkynyl, and heterocyclyl, oxo;

[0032] R5 is selected from the group consisting of:

[0033] R6 is selected from the group consisting of ═O and ═S;

[0034] each R7 is independently C2-7 alkylene;

[0035] R8 is selected from the group consisting of hydrogen, alkyl, alkoxyalkylenyl, and arylalkylenyl;

[0036] R9 is selected from the group consisting of hydrogen and alkyl;

[0037] each R10 is independently C3-8 alkylene;

[0038] A is selected from the group consisting of —O—, —C(O)—, —S(O)0-2—, —CH2—, and —N(R4)—;

[0039] Q is selected from the group consisting of a bond, —C(R6)—, —C(R6)—C(R6), —S(O)2—, —C(R6)—N(R8)—W—, —S(O)2—N(R8)—, —C(R6)—O—, and —C(R6)—N(OR9)—;

[0040] V is selected from the group consisting of —C(R6)—, —O—C(R6)—, —N(R8)—C(R6)—, and —S(O)2—;

[0041] W is selected from the group consisting of a bond, —C(O)—, and —S(O)2—; and

[0042] a and b are independently integers from 1 to 6 with the proviso that a +b is ≦7;

[0043] or a pharmaceutically acceptable salt thereof.

[0044] For certain embodiments of Formula I, n is 0 and —Z— is a bond. For certain embodiments of Formula I, R3 is —Z—Ar, and for certain other embodiments, R3 is

[0045] —Z—Ar′—Y—R4 or —Z—Ar′—X—Y—R4.

[0046] For some embodiments of Formula I, R′ is selected from the group consisting of:

[0047] —R4,

[0048] —X—R4,

[0049] —X—Y—R4,

[0050] —X—Y—X—Y—R4, and

[0051] —X—R5;

[0052] wherein each X is independently selected, each Y is independently selected, each R4 is independently selected, and each R5 is independently selected.

[0053] For some embodiments of Formula I, R″ is selected from the group consisting of:

[0054] —R4,

[0055] —X—R4,

[0056] —X—Y—R4, and

[0057] —X—R5;

[0058] wherein each X is independently selected, each Y is independently selected, each R4 is independently selected, and each R5 is independently selected.

[0059] The present invention also provides compounds of the following Formula (II):

[0060] wherein:

[0061] R is selected from the group consisting of alkyl, alkoxy, hydroxy, and trifluoromethyl;

[0062] n is 0 or 1;

[0063] R1 is selected from the group consisting of:

[0064] —R4,

[0065] —X—R4,

[0066] —X—Y—R4,

[0067] —X-Y—X—Y—R4, and

[0068] —X—R5;

[0069] R2 is selected from the group consisting of:

[0070] —R4,

[0071] —X—R4,

[0072] —X—Y—R4, and

[0073] —X—R5;

[0074] R3 is selected from the group consisting of:

[0075] —Z—Ar,

[0076] —Z—Ar′—Y—R4,

[0077] —Z—Ar′—X—Y—R4,

[0078] —Z—Ar′—R5, and

[0079] —Z—Ar′—X—R5;

[0080] Ar is selected from the group consisting of aryl and heteroaryl both of which can be unsubstituted or can be substituted by one or more substituents independently selected from the group consisting of alkyl, alkenyl, alkoxy, methylenedioxy, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, hydroxyalkyl, mercapto, cyano, carboxy, formyl, aryl, aryloxy, arylalkoxy, heteroaryl, heteroaryloxy, heteroarylalkoxy, heterocyclyl, heterocyclylalkyl, amino, alkylamino, and dialkylamino;

[0081] Ar′ is selected from the group consisting of arylene and heteroarylene both of which can be unsubstituted or can be substituted by one or more substituents independently selected from the group consisting of alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, hydroxyalkyl, mercapto, cyano, carboxy, formyl, aryl, aryloxy, arylalkoxy, heteroaryl, heteroaryloxy, heteroarylalkoxy, heterocyclyl, heterocyclylalkyl, amino, alkylamino, and dialkylamino;

[0082] each X is independently selected from the group consisting of alkylene, alkenylene, alkynylene, arylene, heteroarylene, and heterocyclylene wherein the alkylene, alkenylene, and alkynylene groups can be optionally interrupted or terminated with arylene, heteroarylene, or heterocyclylene, and optionally interrupted by one or more -0- groups;

[0083] each Y is independently selected from the group consisting of:

[0084] Z is selected from the group consisting of a bond, alkylene, alkenylene, and alkynylene;

[0085] each R4 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl wherein the alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl groups can be unsubstituted or substituted by one or more substituents independently selected from the group consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, mercapto, cyano, aryl, aryloxy, arylalkyleneoxy, heteroaryl, heteroaryloxy, heteroarylalkyleneoxy, heterocyclyl, amino, alkylamino, dialkylamino, (dialkylamino)alkyleneoxy, and in the case of alkyl, alkenyl, alkynyl, and heterocyclyl, oxo;

[0086] each R5 is independently selected from the group consisting of:

[0087] each R6 is independently selected from the group consisting of ═O and ═S;

[0088] each R7 is independently C2-7 alkylene;

[0089] R8 is selected from the group consisting of hydrogen, alkyl, alkoxyalkylenyl, and arylalkylenyl;

[0090] R9 is selected from the group consisting of hydrogen and alkyl;

[0091] each R10 is independently C3-8 alkylene;

[0092] A is selected from the group consisting of —O—, —C(O)—, —S(O)0-2—, —CH2—, and —N(R4)—;

[0093] Q is selected from the group consisting of a bond, —C(R6)—, —C(R6)—C(R6), —S(O)2—, —C(R6)—N(R8)—W—, —S(O)2—N(R8)—, —C(R6)—O—, and —C(R6)—N(OR9)—;

[0094] V is selected from the group consisting of —C(R6)—, —O—C(R6)—, —N(R8)—C(R6)—, and —S(O)2—;

[0095] W is selected from the group consisting of a bond, —C(O)—, and —S(O)2—; and

[0096] a and b are independently integers from 1 to 6 with the proviso that a +b is ≦7;

[0097] or a pharmaceutically acceptable salt thereof.

[0098] In some embodiments of Formula II, R1 is selected from the group consisting of alkyl, arylalkylenyl, aryloxyalkylenyl, hydroxyalkyl, alkylsulfonylalkylenyl, —X—Y—R4, and —X—R5; wherein X is alkylene; Y is selected from the group consisting of —N(R8)—C(O)—, —N(R8)—S(O)2—, —N(R8)—C(O)—N(R8)—,

[0099] and

[0100] R4is selected from the group consisting of alkyl, aryl, and heteroaryl; and R5 is selected from the group consisting of

[0101] In some embodiments of Formula II, R2 is selected from the group consisting of hydrogen, alkyl, and alkoxyalkylenyl.

[0102] For some embodiments of Formula II, n is 0 and —Z— is a bond. For some embodiments of Formula II, R3 is —Z—Ar, and for certain of these embodiments, R3 is selected from the group consisting of phenyl, pyridyl, pyrrolyl, thienyl, and furyl; each of which can be unsubstituted or can be substituted by one or more substituents selected from the group consisting of halogen, alkyl, hydroxy, hydroxyalkyl, alkoxy, carboxy, and cyano.

[0103] For some embodiments of Formula II, R3 is —Z—Ar′—Y—R4, —Z—Ar′—X—Y—R4, or —Z—Ar′—R5, and for certain of these embodiments, Ar′ is phenyl or pyridyl;

[0104] Y is selected from the group consisting of:

[0105] —S(O)0-2—

[0106] —C(O)—,

[0107] —N(R8)—Q—,

[0108] —C(R6)—N(R8)—, and

[0109] —C(R6)—N(OR9)—;

[0110] wherein Q is selected from the group consisting of a bond, —C(O)—, and —S(O)2—; R8 is selected from the group consisting of hydrogen, C1-4 alkyl, and alkoxyalkylenyl;

[0111] X is C1-4 alkylene;

[0112] R4 is selected from the group consisting of alkyl, aryl, heteroaryl, and heterocyclyl; and

[0113] R5 is

[0114] The present invention also provides compounds of the following Formula (IIa):

[0115] wherein:

[0116] R is selected from the group consisting of alkyl, alkoxy, hydroxy, and trifluoromethyl;

[0117] n is 0 or 1;

[0118] R1 is selected from the group consisting of:

[0119] —R4,

[0120] —X—R4,

[0121] —X—Y—R4,

[0122] —X—Y—X—Y—R4, and

[0123] —X—R5;

[0124] R2 is selected from the group consisting of:

[0125] —R4,

[0126] —X—R4,

[0127] —X—Y—R4, and

[0128] —X—R5;

[0129] R3 is selected from the group consisting of:

[0130] —Z—Ar and

[0131] —Z—Ar′—Y—R4;

[0132] each X is independently selected from the group consisting of alkylene, alkenylene, alkynylene, arylene, heteroarylene, and heterocyclylene wherein the alkylene, alkenylene, and alkynylene groups can be optionally interrupted by arylene, heteroarylene or heterocyclylene or by one or more —O— groups;

[0133] each Y is independently selected from the group consisting of:

[0134] Z is selected from the group consisting of a bond, alkylene, alkenylene, and alkynylene;

[0135] Ar is selected from the group consisting of aryl and heteroaryl both of which can be unsubstituted or can be substituted by one or more substituents independently selected from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, mercapto, cyano, carboxy, formyl, aryl, aryloxy, arylalkoxy, heteroaryl, heteroaryloxy, heteroarylalkoxy, heterocyclyl, heterocyclylalkyl, amino, alkylamino, and dialkylamino;

[0136] Ar′ is selected from the group consisting of arylene and heteroarylene both of which can be unsubstituted or can be substituted by one or more substituents independently selected from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, mercapto, cyano, carboxy, formyl, aryl, aryloxy, arylalkoxy, heteroaryl, heteroaryloxy, heteroarylalkoxy, heterocyclyl, heterocyclylalkyl, amino, alkylamino, and dialkylamino;

[0137] each R4 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl groups can be unsubstituted or substituted by one or more substituents independently selected from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, mercapto, cyano, carboxy, formyl, aryl, aryloxy, arylalkoxy, heteroaryl, heteroaryloxy, heteroarylalkoxy, heterocyclyl, heterocyclylalkyl, amino, alkylamino, dialkylamino, and in the case of alkyl, alkenyl, alkynyl, and heterocyclyl, oxo;

[0138] each R5 is independently selected from the group consisting of:

[0139] R6 is selected from the group consisting of ═O and ═S;

[0140] R7 is C2-7 alkylene;

[0141] each R8 present is independently selected from the group consisting of hydrogen, alkyl, and arylalkyl;

[0142] R9 is selected from the group consisting of hydrogen and alkyl;

[0143] A is selected from the group consisting of —O—, —S(O)0-2—, —NR4—, and —CH2—;

[0144] Q is selected from the group consisting of—CR6—, —SO2—, —CR6—NR8—W—, —SO2—NR8—, —CR6—O—, and —CR6—N(OR9)—;

[0145] V is selected from the group consisting of —CR6—, —O—CR6—, and —NR8—CR6—;

[0146] W is selected from the group consisting of a bond, —C(O)—, and —SO2—; and

[0147] a and b are independently integers from 1 to 6 with the proviso that a +b is ≦7;

[0148] or a pharmaceutically acceptable salt thereof.

[0149] For certain embodiments of Formula Ia, n is 0 and the R1, R2, and R3 groups are defined as follows: R1 is R4 or —X—Y—R4, R1 is alkyl or hydroxyalkyl, —X— is C2-6 alkylene, and —Y— is —S(O)0-2— or —NR8—Q—; R2 is R4 or R2 is alkyl or alkoxyalkyl; R3 is —Z—Ar, —Z— is a bond, —Ar is unsubstituted aryl or heteroaryl, and more particularly —Ar is phenyl, thienyl or pyridyl; and R3 is attached at the 7-position or 8-position per the following numbering scheme.

[0150] The present invention also provides compounds of the following Formula (III), which include a sulfonamide functional group:

[0151] wherein:

[0152] R2 is selected from the group consisting of:

[0153] —R4,

[0154] —X—R4,

[0155] —X—Y—R4, and

[0156] —X—R5;

[0157] R3 is selected from the group consisting of:

[0158] —Z—Ar,

[0159] —Z—Ar′—Y—R4,

[0160] —Z—Ar′—X—Y—R4,

[0161] —Z—Ar′—R5, and

[0162] —Z—Ar′—X—R5;

[0163] Ar is selected from the group consisting of aryl and heteroaryl both of which can be unsubstituted or can be substituted by one or more substituents independently selected from the group consisting of alkyl, alkenyl, alkoxy, methylenedioxy, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, hydroxyalkyl, mercapto, cyano, carboxy, formyl, aryl, aryloxy, arylalkoxy, heteroaryl, heteroaryloxy, heteroarylalkoxy, heterocyclyl, heterocyclylalkyl, amino, alkylamino, and dialkylamino;

[0164] Ar′ is selected from the group consisting of arylene and heteroarylene both of which can be unsubstituted or can be substituted by one or more substituents independently selected from the group consisting of alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, hydroxyalkyl, mercapto, cyano, carboxy, formyl, aryl, aryloxy, arylalkoxy, heteroaryl, heteroaryloxy, heteroarylalkoxy, heterocyclyl, heterocyclylalkyl, amino, alkylamino, and dialkylamino;

[0165] each X is independently selected from the group consisting of alkylene, alkenylene, alkynylene, arylene, heteroarylene, and heterocyclylene wherein the alkylene, alkenylene, and alkynylene groups can be optionally interrupted or terminated with arylene, heteroarylene, or heterocyclylene, and optionally interrupted by one or more —O— groups;

[0166] X′ is C2-8 alkylene;

[0167] each Y is independently selected from the group consisting of:

[0168] Z is selected from the group consisting of a bond, alkylene, alkenylene, and alkynylene;

[0169] each R4 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl wherein the alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl groups can be unsubstituted or substituted by one or more substituents independently selected from the group consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, mercapto, cyano, aryl, aryloxy, arylalkyleneoxy, heteroaryl, heteroaryloxy, heteroarylalkyleneoxy, heterocyclyl, amino, alkylamino, dialkylamino, (dialkylamino)alkyleneoxy, and in the case of alkyl, alkenyl, alkynyl, and heterocyclyl, oxo;

[0170] each R5 is independently selected from the group consisting of:

[0171] each R6 is independently selected from the group consisting of ═O and ═S;

[0172] each R7 is independently C2-7 alkylene;

[0173] R8 is selected from the group consisting of hydrogen, alkyl, alkoxyalkylenyl, and arylalkylenyl;

[0174] R9 is selected from the group consisting of hydrogen and alkyl;

[0175] each R10 is independently C3-8 alkylene;

[0176] A is selected from the group consisting of —O—, —C(O)—, —S(O)0-2—, —CH2—, and —N(R4)—;

[0177] Q is selected from the group consisting of a bond, —C(R6)—, —C(R6)—C(R6), —S(O)2—, —C(R6)—N(R8)—W—, —S(O)2—N(R8)—, —C(R6)—O—, and —C(R6)—N(OR9)—;

[0178] V is selected from the group consisting of—C(R6)—, —O—C(R6)—, —N(R8)—C(R6)—, and —S(O)2—;

[0179] W is selected from the group consisting of a bond, —C(O)—, and —S(O)2—; and

[0180] a and b are independently integers from 1 to 6 with the proviso that a +b is ≦7;

[0181] or a pharmaceutically acceptable salt thereof.

[0182] For certain embodiments of Formula III, X′ is —CH2—C(CH3)2—.

[0183] For certain embodiments of Formula III, R2 is selected from the group consisting of hydrogen, C1-4 alkyl, and C1-4 alkyl-O—C1-4 alkylenyl.

[0184] For certain embodiments of Formula III, R4 is selected from the group consisting of alkyl, aryl, and heteroaryl.

[0185] For certain embodiments of Formula III, R3 is phenyl or pyridyl, either of which can be unsubstituted or can be substituted by one or more substituents selected from the group consisting of halogen, alkyl, hydroxy, hydroxyalkyl, alkoxy, alkylsulfonylamino, arylsulfonylamino, alkylcarbonylanino, arylcarbonylamino, alkylsulfonylaminoalkylenyl, arylsulfonylaminoalkylenyl, alkylcarbonylaminoalkylenyl, and arylcarbonylaminoalkylenyl.

[0186] The present invention also provides compounds of the following Formula (IV), which include an amide functional group:

[0187] wherein R2, R3, R4, and X′ are the same as that for Formula III listed above; or a pharmaceutically acceptable salt thereof.

[0188] For certain embodiments of Formula IV, X′ is —CH2—C(CH3)2—.

[0189] For certain embodiments of Formula IV, R2 is selected from the group consisting of hydrogen, C1-4 alkyl, and C1-4 alkyl-O—C1-4 alkylenyl.

[0190] For certain embodiments of Formula IV, R4 is selected from the group consisting of alkyl, aryl, and heteroaryl.

[0191] For certain embodiments of Formula IV, R3 is phenyl or pyridyl, either of which can be unsubstituted or can be substituted by one or more substituents selected from the group consisting of halogen, alkyl, hydroxy, hydroxyalkyl, alkoxy, alkylsulfonylamino, arylsulfonylamino, alkylcarbonylamino, arylcarbonylamino, alkylsulfonylaminoalkylenyl, arylsulfonylaminoalkylenyl, alkylcarbonylaminoalkylenyl, and arylcarbonylaminoalkylenyl.

[0192] The present invention also provides compounds of the following Formula (V), which include a urea functional group:

[0193] wherein R2, R3, R4, and X′ are the same as that for Formula III listed above; or a pharmaceutically acceptable salt thereof.

[0194] For certain embodiments of Formula V, X′ is —CH2—C(CH3)2—.

[0195] For certain embodiments of Formula V, R2 is selected from the group consisting of hydrogen, C1-4 alkyl, and C1-4 alkyl-O—C1-4 alkylenyl.

[0196] For certain embodiments of Formula V, R4 is selected from the group consisting of alkyl, aryl, and heteroaryl.

[0197] For certain embodiments of Formula V, R3 is phenyl or pyridyl, either of which can be unsubstituted or can be substituted by one or more substituents selected from the group consisting of halogen, alkyl, hydroxy, hydroxyalkyl, alkoxy, alkylsulfonylamino, arylsulfonylamino, alkylcarbonylamino, arylcarbonylamino, alkylsulfonylaminoalkylenyl, arylsulfonylaminoalkylenyl, alkylcarbonylaminoalkylenyl, and arylcarbonylaminoalkylenyl.

[0198] The present invention also provides compounds of the following Formula (VI), which include a piperidine moiety:

[0199] wherein R2, R3, R4, Q, and X′ are the same as that for Formula III listed above; or a pharmaceutically acceptable salt thereof.

[0200] For certain embodiments of Formula VI, Q is selected from the group consisting of —C(O)—, —S(O)2—, and —C(O)—NH—.

[0201] For certain embodiments of Formula VI, R2 is selected from the group consisting of hydrogen, C1-4 alkyl, and C1-4 alkyl-O—C1-4 alkylenyl.

[0202] For certain embodiments of Formula VI, R4 is selected from the group consisting of alkyl, aryl, and heteroaryl.

[0203] For certain embodiments of Formula VI, R3 is phenyl or pyridyl, either of which can be unsubstituted or can be substituted by one or more substituents selected from the group consisting of halogen, alkyl, hydroxy, hydroxyalkyl, alkoxy, alkylsulfonylamino, arylsulfonylamino, alkylcarbonylamino, arylcarbonylamino, alkylsulfonylaminoalkylenyl, arylsulfonylaminoalkylenyl, alkylcarbonylaminoalkylenyl, and arylcarbonylaminoalkylenyl.

[0204] The present invention also provides compounds of the following Formula (VII):

[0205] wherein R2, R3, R5, and X′ are the same as that for Formula III listed above; or a pharmaceutically acceptable salt thereof.

[0206] For certain embodiments of Formula VII, R2 is selected from the group consisting of hydrogen, C1-4 alkyl, and C1-4 alkyl-O—C1-4 alkylenyl.

[0207] For certain embodiments of Formula VII, R3 is phenyl or pyridyl, either of which can be unsubstituted or can be substituted by one or more substituents selected from the group consisting of halogen, alkyl, hydroxy, hydroxyalkyl, alkoxy, alkylsulfonylamino, arylsulfonylamino, alkylcarbonylamino, arylcarbonylamino, alkylsulfonylaminoalkylenyl, arylsulfonylaminoalkylenyl, alkylcarbonylaminoalkylenyl, and arylcarbonylaminoalkylenyl.

[0208] For certain embodiments of Formula VII, R5 is selected from the group consisting of:

[0209] The present invention also provides compounds of the following Formula (VIII):

[0210] wherein R2, R3, and R4 are the same as that for Formula III listed above; or a pharmaceutically acceptable salt thereof.

[0211] For certain embodiments of Formula VIII, R2 is selected from the group consisting of hydrogen, C1-4 alkyl, and C1-4 alkyl-O—C1-4 alkylenyl.

[0212] For certain embodiments of Formula VIII, R3 is phenyl or pyridyl, either of which can be unsubstituted or can be substituted by one or more substituents selected from the group consisting of halogen, alkyl, hydroxy, hydroxyalkyl, alkoxy, alkylsulfonylamino, arylsulfonylamino, alkylcarbonylamino, arylcarbonylamino, alkylsulfonylaminoalkylenyl, arylsulfonylaminoalkylenyl, alkylcarbonylaminoalkylenyl, and arylcarbonylaminoalkylenyl.

[0213] For certain embodiments of Formula VIII, R4 is selected from the group consisting of C1-6 alkyl, C1-6 hydroxyalkyl, C1-4 alkyl-O—C1-4 alkylenyl, and aryl-O—C1-4 alkylenyl.

[0214] For certain embodiments of Formula VIII, R4 is selected from the group consisting of 2-methylpropyl, 2-hydroxy-2-methylpropyl, 3-methoxypropyl, and phenoxyethyl.

[0215] The present invention also provides a compound of the following Formula (XLVI):

[0216] wherein:

[0217] R1 is selected from the group consisting of:

[0218] —R4,

[0219] —X—R4,

[0220] —X—Y—R4,

[0221] —X-Y—X—Y—R4, and

[0222] —X—R5;

[0223] R2 is selected from the group consisting of:

[0224] —R4,

[0225] —X—R4,

[0226] —X—Y—R4, and

[0227] —X—R5;

[0228] Ar′ is selected from the group consisting of arylene and heteroarylene both of which can be unsubstituted or can be substituted by one or more substituents independently selected from the group consisting of alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, hydroxyalkyl, mercapto, cyano, carboxy, formyl, aryl, aryloxy, arylalkoxy, heteroaryl, heteroaryloxy, heteroarylalkoxy, heterocyclyl, heterocyclylalkyl, amino, alkylamino, and dialkylamino;

[0229] each X is independently selected from the group consisting of alkylene, alkenylene, alkynylene, arylene, heteroarylene, and heterocyclylene wherein the alkylene, alkenylene, and alkynylene groups can be optionally interrupted or terminated with arylene, heteroarylene, or heterocyclylene, and optionally interrupted by one or more —O— groups;

[0230] each Y is independently selected from the group consisting of:

[0231] each Z is independently selected from the group consisting of a bond, alkylene, alkenylene, and alkynylene;

[0232] each R4 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl wherein the alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkytheteroarylenyl, and heterocyclyl groups can be unsubstituted or substituted by one or more substituents independently selected from the group consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, mercapto, cyano, aryl, aryloxy, arylalkyleneoxy, heteroaryl, heteroaryloxy, heteroarylalkyleneoxy, heterocyclyl, amino, alkylamino, dialkylamino, (dialkylamino)alkyleneoxy, and in the case of alkyl, alkenyl, alkynyl, and heterocyclyl, oxo;

[0233] each R5 is independently selected from the group consisting of:

[0234] each R6 is independently selected from the group consisting of ═O and ═S;

[0235] each R7 is independently C2-7 alkylene;

[0236] R8 is selected from the group consisting of hydrogen, alkyl, alkoxyalkylenyl, and arylalkylenyl;

[0237] R9 is selected from the group consisting of hydrogen and alkyl;

[0238] each R10 is independently C3-8 alkylene;

[0239] A is selected from the group consisting of —O—, —C(O)—, —S(O)0-2—, —CH2—, and —N(R4)—;

[0240] Q is selected from the group consisting of a bond, —C(R6)—, —C(R6)—C(R6), —S(O)2—, —C(R6)—N(R8)—W—, —S(O)2—N(R8)—, —C(R6)—O—, and —C(R6)—N(OR9)—;

[0241] V is selected from the group consisting of —C(R6)—, —O—C(R6)—, —N(R8)—C(R6)—, and —S(O)2—;

[0242] W is selected from the group consisting of a bond, —C(O)—, and —S(O)2—; and

[0243] a and b are independently integers from 1 to 6 with the proviso that a +b is ≦7;

[0244] or a pharmaceutically acceptable salt thereof.

[0245] For certain embodiments of Formula XLVI, Z is a bond and Ar′ is phenylene. For certain embodiments of Formula XLVI, R1 is selected from the group consisting of alkyl, hydroxyalkyl, and —X—Y—R4 wherein X is alkylene, Y is selected from the group consisting of —N(R8)—C(O)—, —N(R8)—S(O)2—, and —N(R8)—C(O)—N(R8)—, and R4 is alkyl. For certain embodiments of Formula XLVI, R2 is selected from the group consisting of hydrogen, alkyl, and alkoxyalkylenyl.

[0246] The present invention also provides compounds of the following Formulas XLVII and XLVIII, which are intermediates in the preparation of certain compounds of the present invention:

[0247] wherein:

[0248] R is selected from the group consisting of alkyl, alkoxy, hydroxy, and trifluoromethyl;

[0249] n is 0 or 1;

[0250] R1 is selected from the group consisting of:

[0251] —R4,

[0252] —X—R4,

[0253] —X—Y—R4,

[0254] —X—Y—X—Y—R4, and

[0255] —X—R5;

[0256] R2 is selected from the group consisting of:

[0257] —R4,

[0258] —X—R4,

[0259] —X—Y—R4, and

[0260] —X—R5;

[0261] R3 is selected from the group consisting of:

[0262] —Z—Ar,

[0263] —Z—Ar′—Y—R4,

[0264] —Z—Ar′—X—Y—R4,

[0265] —Z—Ar′—R5, and

[0266] —Z—Ar′—X—R5;

[0267] Ar is selected from the group consisting of aryl and heteroaryl both of which can be unsubstituted or can be substituted by one or more substituents independently selected from the group consisting of alkyl, alkenyl, alkoxy, methylenedioxy, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, hydroxyalkyl, mercapto, cyano, carboxy, formyl, aryl, aryloxy, arylalkoxy, heteroaryl, heteroaryloxy, heteroarylalkoxy, heterocyclyl, heterocyclylalkyl, amino, alkylamino, and dialkylamino;

[0268] Ar′ is selected from the group consisting of arylene and heteroarylene both of which can be unsubstituted or can be substituted by one or more substituents independently selected from the group consisting of alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, hydroxyalkyl, mercapto, cyano, carboxy, formyl, aryl, aryloxy, arylalkoxy, heteroaryl, heteroaryloxy, heteroarylalkoxy, heterocyclyl, heterocyclylalkyl, amino, alkylamino, and dialkylamino;

[0269] each X is independently selected from the group consisting of alkylene, alkenylene, alkynylene, arylene, heteroarylene, and heterocyclylene wherein the alkylene, alkenylene, and alkynylene groups can be optionally interrupted or terminated with arylene, heteroarylene, or heterocyclylene, and optionally interrupted by one or more —O— groups;

[0270] each Y is independently selected from the group consisting of:

[0271] Z is selected from the group consisting of a bond, alkylene, alkenylene, and alkynylene;

[0272] each R4 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl wherein the alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl groups can be unsubstituted or substituted by one or more substituents independently selected from the group consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, mercapto, cyano, aryl, aryloxy, arylalkyleneoxy, heteroaryl, heteroaryloxy, heteroarylalkyleneoxy, heterocyclyl, amino, alkylamino, dialkylamino, (dialkylamino)alkyleneoxy, and in the case of alkyl, alkenyl, alkynyl, and heterocyclyl, oxo;

[0273] each R5 is independently selected from the group consisting of:

[0274] each R6 is independently selected from the group consisting of ═O and ═S;

[0275] each R7 is independently C2-7 alkylene;

[0276] R8 is selected from the group consisting of hydrogen, alkyl, alkoxyalkylenyl, and arylalkylenyl;

[0277] R9 is selected from the group consisting of hydrogen and alkyl;

[0278] each R10 is independently C3-8 alkylene;

[0279] A is selected from the group consisting of —O—, —C(O)—, —S(O)0-2—, —CH2—, and —N(R4)—;

[0280] Q is selected from the group consisting of a bond, —C(R6)—, —C(R6)—C(R6), —S(O)2—, —C(R6)—N(R8)—W—, —S(O)2—N(R8)—, —C(R6)—O—, and —C(R6)—N(OR9)—;

[0281] V is selected from the group consisting of —C(R6)—, —O—C(R6)—, —N(R8)—C(R6)—, and —S(O)2—;

[0282] W is selected from the group consisting of a bond, —C(O)—, and —S(O)2—; and

[0283] a and b are independently integers from 1 to 6 with the proviso that a +b is ≦7;

[0284] or a pharmaceutically acceptable salt thereof.

[0285] Herein, “non-interfering” means that the ability of the compound or salt to modulate (e.g., induce or inhibit) the biosynthesis of one or more cytokines is not destroyed by the non-interfering substitutent. Illustrative non-interfering R′ groups include those described above for R1 in Formula II. Illustrative non-interfering R″ groups include those described above for R2 in Formula II.

[0286] As used herein, the terms “alkyl,” “alkenyl,” “alkynyl” and the prefix “alk-” are inclusive of both straight chain and branched chain groups and of cyclic groups, i.e. cycloalkyl and cycloalkenyl. Unless otherwise specified, these groups contain from 1 to 20 carbon atoms, with alkenyl groups containing from 2 to 20 carbon atoms, and alkynyl groups containing from 2 to 20 carbon atoms. In some embodiments, these groups have a total of up to 10 carbon atoms, up to 8 carbon atoms, up to 6 carbon atoms, or up to 4 carbon atoms. Cyclic groups can be monocyclic or polycyclic and preferably have from 3 to 10 ring carbon atoms. Exemplary cyclic groups include cyclopropyl, cyclopropylmethyl, cyclopentyl, cyclohexyl, adamantyl, and substituted and unsubstituted bornyl, norbornyl, and norbornenyl.

[0287] Unless otherwise specified, “alkylene,” “alkenylene,” and “alkynylene” are the divalent forms of the “alkyl,” “alkenyl,” and “alkynyl” groups defined above. Likewise, “alkylenyl,” “alkenylenyl,” and “alkynylenyl” are the divalent forms of the “alkyl,” “alkenyl,” and “alkynyl” groups defined above. For example, an arylalkylenyl group comprises an alkylene moiety to which an aryl group is attached.

[0288] The term “haloalkyl” is inclusive of groups that are substituted by one or more halogen atoms, including perfluorinated groups. This is also true of other groups that include the prefix “halo-”. Examples of suitable haloalkyl groups are chloromethyl, trifluoromethyl, and the like.

[0289] The term “aryl” as used herein includes carbocyclic aromatic rings or ring systems. Examples of aryl groups include phenyl, naphthyl, biphenyl, fluorenyl and indenyl.

[0290] The term “heteroatom” refers to the atoms O, S, or N.

[0291] The term “heteroaryl” includes aromatic rings or ring systems that contain at least one ring heteroatom (e.g., O, S, N). Suitable heteroaryl groups include furyl, thienyl, pyridyl, quinolinyl, isoquinolinyl, indolyl, isoindolyl, triazolyl, pyrrolyl, tetrazolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, benzofuranyl, benzothiophenyl, carbazolyl, benzoxazolyl, pyrimidinyl, benzimidazolyl, quinoxalinyl, benzothiazolyl, naphthyridinyl, isoxazolyl, isothiazolyl, purinyl, quinazolinyl, pyrazinyl, 1-oxidopyridyl, pyridazinyl, triazinyl, tetrazinyl, oxadiazolyl, thiadiazolyl, and so on.

[0292] The term “heterocyclyl” includes non-aromatic rings or ring systems that contain at least one ring heteroatom (e.g., O, S, N) and includes all of the fully saturated and partially unsaturated derivatives of the above mentioned heteroaryl groups. Exemplary heterocyclic groups include pyrrolidinyl, tetrahydrofuranyl, morpholinyl, thiomorpholinyl, piperidinyl, piperazinyl, thiazolidinyl, imidazolidinyl, isothiazolidinyl, tetrahydropyranyl, quinuclidinyl, homopiperidinyl, homopiperazinyl, and the like.

[0293] The terms “arylene,” “heteroarylene,” and “heterocyclylene” are the divalent forms of the “aryl,” “heteroaryl,” and “heterocyclyl” groups defined above. Likewise, “arylenyl,” “heteroarylenyl,” and “heterocyclylenyl” are the divalent forms of the “aryl,” “heteroaryl,” and “heterocyclyl” groups defined above. For example, an alkylarylenyl group comprises an arylene moiety to which an alkyl group is attached.

[0294] When a group is present more that once in a Formula I-VIII or XLVI-XLVIII described herein, each group is independently selected, whether specifically stated or not. For example, when more than one Y group is present in a Formula, each Y group is independently selected. Furthermore, subgroups contained within these groups are also independently selected. For example, when each Y group contains an R6, each R6 is also independently selected.

[0295] The invention is inclusive of the compounds and salts thereof, described herein in any of their pharmaceutically acceptable forms, including isomers (e.g., diastereomers and enantiomers), solvates, polymorphs, and the like. In particular, if a compound is optically active, the invention specifically includes each of the compound's enantiomers as well as racemic mixtures of the enantiomers.

[0296] In some embodiments, compounds of Formulas I-VIII and XLVI induce the biosynthesis of one or more cytokines.

[0297] In some embodiments, compounds of Formulas I-VIII and XLVI inhibit the biosynthesis of one or more cytokines.

[0298] Preparation of the Compounds

[0299] Compounds of the invention can be prepared using known palladium catalyzed coupling reactions such as Suzuki coupling, Stille coupling, Sonogashira coupling, and the Heck reaction.

[0300] Suzuki coupling is used in Reaction Scheme I where R1, R2, and R are as defined above, R3a is —Za—Ar, —Za—Ar′—Y—R4, or —Za—Ar′—X—Y—R4 where Za is a bond, alkylene or alkenylene, and Hal is bromo, chloro or iodo.

[0301] In Reaction Scheme I a halogen substituted imidazoquinoline of Formula IX is coupled with a boronic acid of Formula X to provide an imidazoquinoline of Formula XI which is a subgenus of Formula II. A compound of Formula IX is combined with a boronic acid of Formula X in the presence of palladium (II) acetate, triphenylphosphine and a base such as sodium carbonate in a suitable solvent such as n-propanol. The reaction can be carried out at an elevated temperature (e.g., 80-100° C).

[0302] Many compounds of Formula IX are known. See, for example, U.S. Pat. Nos. 4,689,338; 4,929,624; 5,268,376; 5,346,905; 5,389,640; 5,756,747; 6,331,539; and 6,451,810; PCT Publications WO 00/76518; WO 02/46188, WO 02/46189; WO 02/46190; WO 02/46191; WO 02/46192; and WO 02/46193; European Patent Application 1 104 764; and Japanese Patent Application 9- 255926. Others can be readily prepared using known synthetic methods. See, for example, U.S. Patent Nos. 4,988,815; 5,175,296; 5,367,076; 5,395,937; and 5,741,908.

[0303] Many boronic acids of Formula X are commercially available; others can be readily prepared using known synthetic methods. See, for example, Li, W. et al, J Org. Chem., 67, 5394-5397 (2002). The Suzuki coupling reaction can also be carried out using boronic acid esters of Formula R3a-B(O-alkyl)2 and anhydrides of boronic acids of Formula X.

[0304] Compounds of the invention where Z is alkynylene can be prepared using Stille coupling to couple a halogen substituted imidazoquinoline of Formula IX with a terminal alkyne of the formula —C≡C—Ar.

[0305] Compounds of the invention can be prepared according to Reaction Scheme II wherein Rb is selected from alkyl, and alkoxy; R1b and R2b are subsets of R1 and R2 as defined above, which subsets do not include those substituents which one skilled in the art would recognize as being susceptible to oxidation in step (9), examples include substituents containing an —S— or a heteroaryl group; R3b is aryl which may be unsubstituted or substituted by one or more substituents independently selected from alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, nitro, cyano, carboxy, formyl, aryl, aryloxy, arylalkoxy, heterocyclyl, heterocyclylalkyl, amino, alkylamino, and dialkylamino; and n is 0 or 1.

[0306] In step (1) of Reaction Scheme II a bromoaniline of Formula XII is coupled with a boronic acid of formula R3b—B(OH)2, an anhydride thereof, or a boronic acid ester of Formula R3a-B(O-alkyl)2 using the method described in Reaction Scheme I to provide an aryl substituted aniline of Formula XIII. Many bromoanilines of Formula XII are commercially available; others can be readily prepared using known synthetic methods.

[0307] In step (2) of Reaction Scheme II an aryl substituted aniline of Formula XIII is reacted with a mixture of triethyl orthoformate and Meldrum's Acid (2,2-dimethyl-1,3-dioxane-4,6-dione) at an elevated temperature (50-55° C.) to provide a compound of Formula XIV.

[0308] In step (3) of Reaction Scheme II a quinolin-4-ol of Formula XV is prepared by thermolysis of a compound of Formula XIV. The reaction can be carried out by heating (approximately 215° C.) a solution of the compound of Formula XIV in a heat transfer fluid.

[0309] In step (4) of Reaction Scheme II a quinolin-4-ol of Formula XV is nitrated using conventional nitration methods to provide a 3-nitroquinolin-4-ol of Formula XVI. The reaction can be carried out by combining the compound of Formula XV with nitric acid in a suitable solvent such as propionic acid at an elevated temperature (approximately 130° C.).

[0310] In step (5) of Reaction Scheme II a 3-nitroquinolin-4-ol of Formula XVI is chlorinated using conventional chlorinating methods to provide a 4-chloro-3-nitroquinoline of Formula XVII. The reaction can be carried out by combining the compound of Formula XVI with phosphorous oxychloride in a suitable solvent such as toluene. The reaction can be carried out at ambient temperature.

[0311] In step (6) of Reaction Scheme II a 4-chloro-3-nitroquinoline of Formula XVII is reacted with an amine of Formula R1b—NH2 to provide a 3-nitroquinolin-4-amine of Formula XVIII. The reaction can be carried out by adding the amine to a solution of the compound of Formula XVII in a suitable solvent such as N,N-dimethylformamide (DMF) in the presence of a tertiary amine such as triethylamine. The addition can be carried out at a reduced temperature (0° C.) or at ambient temperature.

[0312] In step (7) of Reaction Scheme II a 3-nitroquinolin-4-amine of Formula XVIII is reduced to provide a quinoline-3,4-diamine of Formula XIX. The reaction can be carried out using a conventional heterogeneous hydrogenation catalyst such as platinum on carbon or palladium on carbon. The reaction can conveniently be carried out on a Parr apparatus in a suitable solvent such as toluene, isopropanol, or mixtures thereof.

[0313] Alternatively the reduction in step (7) can be carried out using sodium dithionite. A solution or suspension of the compound of Formula XVIII in a suitable solvent such as ethanol or isopropanol is treated with an aqueous solution of sodium dithionite. The reaction can be carried out at an elevated temperature (reflux) or at ambient temperature.

[0314] In step (8) of Reaction Scheme II a quinoline-3,4-diamine of Formula XIX is reacted with a carboxylic acid or an equivalent thereof to provide a 1H-imidazo[4,5-c]quinoline of Formula XX. Suitable equivalents to carboxylic acid include orthoesters, and 1,1-dialkoxyalkyl alkanoates. The carboxylic acid or equivalent is selected such that it will provide the desired R2b substituent in a compound of Formula XX. For example, triethyl orthoformate will provide a compound where R2b is hydrogen and trimethyl orthovalerate will provide a compound where R2b is butyl. The reaction can be run in the absence of solvent or in an inert solvent such as toluene. The reaction is run with sufficient heating to drive off any alcohol or water formed as a byproduct of the reaction. Optionally a catalyst such as pyridine hydrochloride can be included.

[0315] Alternatively, step (8) can be carried out by (i) reacting a compound of Formula XIX with an acyl halide of formula R2bC(O)Cl or R2bC(O)Br and then (ii) cyclizing. In part (i) the acyl halide is added to a solution of a compound of Formula XIX in an inert solvent such as acetonitrile, pyridine or dichloromethane. The reaction can be carried out at ambient temperature. Optionally a catalyst such as pyridine hydrochloride can be included. In part (ii) the product of part (i) is heated in pyridine. If step (i) is run in pyridine, then the two steps can be combined into a single step.

[0316] In step (9) of Reaction Scheme II a 1H-imidazo[4,5-c]quinoline of Formula XX is oxidized to provide an N-oxide of Formula XXI using a conventional oxidizing agent that is capable of forming N-oxides. The reaction can be carried out by treating a solution of a compound of Formula XX in a suitable solvent such as chloroform or dichloromethane with 3-chloroperoxybenzoic acid at ambient temperature.

[0317] In step (10) of Reaction Scheme II an N-oxide of Formula XXI is aminated to provide a 1H-imidazo[4,5-c]quinoline-4-amine of Formula XXII which is a subgenus of Formula II. The reaction is carried out in two parts. In part (i) a compound of Formula XXI is reacted with an acylating agent. Suitable acylating agents include alkyl- or arylsulfonyl chorides (e.g., benzenesulfonyl choride, methanesulfonyl choride, and p-toluenesulfonyl chloride). In part (ii) the product of part (i) is reacted 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). The reaction can be carried out by dissolving a compound of Formula XXI in a suitable solvent such as dichloromethane or chloroform, adding ammonium hydroxide to the solution, and then adding p-toluenesulfonyl chloride. The product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.

[0318] For some embodiments, compounds shown in Reaction Scheme II can be further elaborated using conventional synthetic methods. For example, an amine of Formula R1b—NH2, where R1b is R4b and R4b is a subset of R4 that does not include those substitutents which one skilled in the art would recognize as being susceptible to oxidation in step (9), may be substituted by a hydroxy or second amino group, which can be further functionalized before step (7) of Reaction Scheme II. For example, a 3-nitroquinolin-4-amine of Formula XVIII, in which R1b is R4b having an amino substituent, can react with an acid chloride of Formula R4bC(O)Cl, a sulfonyl chloride of Formula R4bS(O)2Cl, or a sulfonic anhydride of Formula (R4bS(O)2)2O to provide a compound of Formula XVIII in which R1b is —X—Y—R4b, where Y is —N(R8)—Q—, R8 is as defined above, and Q is —C(O)— or —SO2—. Numerous acid chlorides, sulfonyl chlorides, and sulfonic anhydrides are commercially available; others can be readily prepared using known synthetic methods. The reaction can be conveniently carried out by adding an acid chloride of Formula R4bC(O)Cl, a sulfonyl chloride of Formula R4bS(O)2Cl, or a sulfonic anhydride of Formula (R4bS(O)2)2O to a solution of a 3-nitroquinolin-4-amine of Formula XVIII, in which R1b is R4b having an amino substituent, and a base such as triethylamine in a suitable solvent such as dichloromethane. The reaction can be carried out at ambient temperature.

[0319] A 3-nitroquinolin-4-amine of Formula XVIII, in which R1b is R4b having an amino substituent, can also react with isocyanates of Formula R4bN═C═O to provide a compound of Formula XVIII in which R1b is —X—Y—R4b, where Y is —N(R8)—Q—, R8 is as defined above, and Q is —C(R6)—N(R8)—W—, R6 is ═O, and W is a bond. Numerous isocyanates of Formula R4bN═C═O are commercially available; others can be readily prepared using known synthetic methods. The reaction can be conveniently carried out by adding the isocyanate of Formula R4bN═C═O to a solution of the 3-nitroquinolin-4-amine of Formula XVIII, in which R1b is R4b having an amino substituent, in a suitable solvent such as dichloromethane. The reaction can be carried out at ambient temperature. Alternatively, a compound of Formula XVIII can be treated with an isocyanate of Formula R4b(CO)N═C═O, a thioisocyanate of Formula R4bN═C═S, a sulfonyl isocyanate of Formula R4bS(O)2N═C═O, or a carbamoyl chloride of Formula R4bN—(R8)—C(O)Cl or

[0320] to provide a compound of Formula XVIII, where Rib is —X—N(R8)—Q—R4b or

[0321] Q is —C(R6)—N(R8)—W—, and R6, R8, and W are as defined above. The product can then be treated according to steps (7) through (10) of Reaction Scheme II to provide 1H-imidazo[4,5-c]quinolin-4-amine of Formula XXII.

[0322] Compounds of the invention, where R1c is —X—Y—R4b or —X—R5; Y is —N(R8)—Q—; R5 is

[0323] and X, Q, R, R2, R3a, R4b, and n are as defined above can be prepared according to Reaction Scheme III. Steps (1) through (4) of Reaction Scheme III are carried out as described for steps (2) through (5) of Reaction Scheme II.

[0324] In step (5) of Reaction Scheme III, a 4-chloro-3-nitroquinoline of Formula XXVII is treated with a Boc-protected diamine of Formula (CH3)3CO—C(O)—NH—X—NH2 to provide a protected 3-nitroquinolin-4-amine of Formula XXVIII. Several Boc-protected diamines of Formula (CH3)3CO—C(O)—NH—X—NH2 are commercially available; others can be prepared by known synthetic methods. The reaction is conveniently carried out by adding a solution of the Boc-protected diamine of Formula (CH3)3CO—C(O)—NH—X—NH2 to a cooled solution of a 4-chloro-3-nitroquinoline of Formula XXVII in a suitable solvent such as dichloromethane in the presence of a tertiary amine such as triethylamine. The reaction can be carried out at ambient temperature, and the product can be isolated using conventional methods.

[0325] In steps (6) and (7) of Reaction Scheme III, a 3-nitroquinolin-4-amine of Formula XXVIII is first reduced to provide a quinoline-3,4-diamine of Formula XXIX, which is converted to 1H-imidazo[4,5-c]quinoline of Formula XXX by reaction with a carboxylic acid equivalent. Steps (6) and (7) of Reaction Scheme III can be carried out as described for steps (7) and (8) of Reaction Scheme II. The sodium dithionite reduction in step (6) can also be conveniently carried out in a mixture of dichloromethane and water at ambient temperature in the presence of potassium carbonate and 1,1′-di-n-octyl-4,4′-bipyridinium dibromide. In part (ii) of step (7), the cyclization can also be carried out in ethanol while heated at reflux.

[0326] In step (8) of Reaction Scheme III, the Boc-protecting group of a 1H-imidazo[4,5-c]quinoline of Formula XXX is removed to provide a 1H-imidazo[4,5-c]quinoline of Formula XXXI. The reaction is conveniently carried out by adding hydrochloric acid or a solution of hydrochloric acid in ethanol to a solution of a 1H-imidazo[4,5-c]quinoline of Formula XXX in a suitable solvent such as ethanol. The reaction can be carried out at an elevated temperature, for example, the reflux temperature of the solvent. The product or pharmaceutically acceptable salt thereof can be isolated by conventional methods.

[0327] In step (9) of Reaction Scheme III, an amino-substituted 1H-imidazo[4,5-c]quinoline of Formula XXXI is converted to a 1H-imidazo[4,5-c]quinolin-1-yl compound of Formula XXXII, where R1c is as defined above, using conventional methods. For example, a 1H-imidazo[4,5-c]quinoline of Formula XXXI can react with an acid chloride of Formula R4bC(O)Cl to provide a compound of Formula XXXII in which R1c is —X—Y—R4b, Y is —N(R8)—Q—, and Q is —C(O)—. In addition, a 1H-imidazo[4,5-c]quinoline of Formula XXXI can react with sulfonyl chloride of Formula R4bS(O)2Cl or a sulfonic anhydride of Formula (R4bS(O)2)2O to provide a compound of Formula XXXII in which R1c is —X—Y—R4b, Y is —N(R8)—Q—, and Q is —S(O)2—. Numerous acid chlorides of Formula R4bC(O)Cl, sulfonyl chlorides of Formula R4bS(O)2Cl, and sulfonic anhydrides of Formula (R4bS(O)2)2O are commercially available; others can be readily prepared using known synthetic methods. The reaction can be carried out as described above for a compound of Formula XVIII.

[0328] Ureas of Formula XXXII, where R1c is —X—Y—R4b, Y is —N(R8)—Q—, Q is —C(R6)—N(R8)—W—, and W and R8 are as defined above can be prepared by reacting a 1H-imidazo[4,5-c]quinoline of Formula XXXI with isocyanates of Formula R4N═C═O or Formula R4(CO)N═C═O, thioisocyanates of Formula F4N═C═S, sulfonyl isocyanates of Formula R4S(O)2N═C═O, or carbamoyl chlorides of Formula R4N—(R8)—C(O)Cl. Numerous compounds of these types are commercially available; others can be readily prepared using known synthetic methods. The reaction can be carried out as described above for a compound of Formula XVIII.

[0329] Compounds of Formula XXXII where R1c is —X—R5 and R5 is

[0330] can be prepared by treating an amino-substituted 1H-imidazo[4,5-c]quinoline of Formula XXXI with a chloroalkanesulfonyl chloride of Formula Cl—R7S(O)2Cl. The reaction is conveniently carried out by adding the chloroalkanesulfonyl chloride to a solution of the amino-substituted 1H-imidazo[4,5-c]quinoline of Formula XXXI in a suitable solvent such as chloroform at ambient temperature. The isolable intermediate chloroalkanesulfonamide can then be treated with a base such as 1,8-diazabicyclo[5.4.0]undec-7-ene at ambient temperature in a suitable solvent such as DMF to effect the cyclization. The product can be isolated using conventional methods.

[0331] In steps (10) and (11) of Reaction Scheme III, a 1H-imidazo[4,5-c]quinoline of Formula XXXII is oxidized to afford a 1H-imidazo[4,5-c]quinoline-5N-oxide of Formula XXXIII, which is aminated to provide a 1H-imidazo[4,5-c]quinolin-4-amine of Formula XXXIV. Steps (10) and (11) of Reaction Scheme III can be carried out as described for steps (9) and (10), respectively, of Reaction Scheme II.

[0332] In step (12) of Reaction Scheme III, a 1H-imidazo[4,5-c]quinolin-4-amine of Formula XXXIV undergoes a coupling reaction with boronic acid of Formula X, an anhydride thereof, or a boronic acid ester of Formula R3a—B(O-alkyl)2. The Suzuki coupling reaction can be carried out as described in Reaction Scheme I to provide a 1H-imidazo[4,5-c]quinolin-4-amine of Formula XXXV, which is a subgenus of Formula II. The product or pharmaceutically acceptable salt thereof can be isolated using conventional methods.

[0333] Compounds of the invention can also be prepared according to Reaction Scheme IV, where R, R2, R3a, R4, R10, X, and Q are as defined above. In step (1) of Reaction Scheme IV, a 4-chloro-3-nitroquinoline of Formula XXVII is treated with a Boc-protected diamine of Formula XXXVI to provide a 3-nitroquinolin-4-amine of Formula XXXVII. Boc-protected diamines of Formula XXXVII are available from the method described by Carceller, E. et al, J. Med. Chem., 39, 487-493 (1996). The reaction can be carried out as described for step (5) of Reaction Scheme III.

[0334] In steps (2)-(5) of Reaction Scheme IV, a 3-nitroquinolin-4-amine of Formula XXXVII is first reduced to provide a quinoline-3,4-diamine of Formula XXXVIII, which is converted to 1H-imidazo[4,5-c]quinoline of Formula XXXIX by reaction with a carboxylic acid equivalent. The 1H-imidazo[4,5-c]quinoline of Formula XXXIX is then oxidized to afford a 1H-imidazo[4,5-c]quinoline-5N-oxide of Formula XL, which is aminated to provide a 1H-imidazo[4,5-c]quinolin-4-amine of Formula XLI. Steps (2), (3), (4), and (5) of Reaction Scheme IV can be carried out as described for steps (7), (8), (9), and (10), respectively, of Reaction Scheme II.

[0335] In steps (6) of Reaction Scheme IV, the Boc protecting group of a 1H-imidazo[4,5-c]quinolin-4-amine of Formula XLI is removed to provide a 1H-imidazo[4,5-c]quinolin-4-amine of Formula XLII, which is converted to a 1H-imidazo[4,5-c]quinolinyl compound of Formula XLIII in step (7). Steps (6) and (7) of Reaction Scheme IV can be carried out as described for steps (8) and (9) of Reaction Scheme III.

[0336] In step (8), the compound of Formula XLIII is then coupled with a boronic acid of Formula X, an anhydride thereof, or boronic acid ester of Formula R3a—B(O-alkyl)2 to provide a 1H-imidazo[4,5-c]quinolin-4-amine of Formula XLIV, which is a subgenus of Formula II. The Suzuki coupling reaction can be carried out as described in Reaction Scheme I. In some embodiments, the coupling reaction shown in step (8) is carried out prior to the deprotection and functionalization reactions shown in steps (6) and (7) to provide a compound of Formula XLIV. The product or pharmaceutically acceptable salt thereof can be isolated using conventional methods.

[0337] The Heck reaction can be used to prepare compounds of the invention as shown in step (1) of Reaction Scheme V, wherein R1,R2, R, Hal, and n are as defined above and Ara is —Ar, —Ar′—Y—R4, or —Ar′—X—Y—R4. In step (1) of Reaction Scheme V, a halogen-substituted imidazoquinolin-4-amine of Formula IX is coupled with a vinyl-substituted compound of Formula L to provide an imidazoquinolin-4-amine of Formula LI, which is a subgenus of Formula II. Alternatively, a compound of Formula L can be coupled with a trifluoromethanesulfonate-substituted imidazoquinolin-4-amine, in which Hal in Formula IX is replaced by —OSO2CF3. Several compounds of Formula L are commercially available; others can be prepared by known methods. The reaction is conveniently carried out by combining the imidazoquinolin-4-amine of Formula IX and the vinyl-substituted compound of Formula L in the presence of palladium (II) acetate, triphenylphosphine or tri-ortho-tolylphosphine, and a base such as triethylamine in a suitable solvent such as acetonitrile or toluene. The reaction can be carried out at an elevated temperature such as 100-120° C. under an inert atmosphere. The compound or pharmaceutically acceptable salt thereof can be isolated using conventional methods.

[0338] In step (2) of Reaction Scheme V, the vinyl group of an imidazoquinolin-4-amine of Formula LI is reduced to provide an imidazoquinolin-4-amine of Formula LII, which is also a subgenus of Formula II. The reduction can be carried out by hydrogenation using a conventional heterogeneous hydrogenation catalyst such as palladium on carbon. The reaction can conveniently be carried out on a Parr apparatus in a suitable solvent such as ethanol, methanol, or mixtures thereof. The compound or pharmaceutically acceptable salt thereof can be isolated using conventional methods.

[0339] Palladium-catalyzed coupling reactions can also be used to prepare compounds of the invention according to Reaction Scheme VI, wherein R1, R2, R9, R, Hal, Ara, and n are as defined above. In step (1) of Reaction Scheme VI, a halogen-substituted imidazoquinolin-4-amine of Formula IX undergoes a Suzuki-type coupling with a potassium alkenyltrifluoroborate of Formula LIII to provide an imidazoquinolin-4-amine of Formula XLVII. The reaction is conveniently carried out by combining the imidazoquinolin-4-amine of Formula IX and a compound of Formula LIII, such as potassium vinyltrifluoroborate, in the presence of dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct and a base such as triethylamine in a suitable solvent such as n-propanol. The reaction can be carried out at an elevated temperature such as the reflux temperature of the solvent under an inert atmosphere. The compound or pharmaceutically acceptable salt thereof can be isolated using conventional methods.

[0340] In step (2) of Reaction Scheme VI, the Heck reaction is used to couple a vinylated imidazoquinolin-4-amine of Formula XLVII with an aryl or hetereoaryl halide of Formula Ara-Hal or a trifluoromethanesulfonate of Formula Ara—OSO2CF3. Numerous compounds of Formula Ara-Hal are commercially available; others can be prepared using known synthetic methods. The reaction is conveniently carried out under the conditions described in step (1) of Reaction Scheme V to provide an imidazoquinolin-4-amine of Formula LI. The product or pharmaceutically acceptable salt thereof can be isolated using conventional methods.

[0341] In step (3) of Reaction Scheme VI, the vinyl group of an imidazoquinolin-4-amine of Formula LI is reduced to provide an imidazoquinolin-4-amine of Formula LII. The reaction is conveniently carried out by hydrogenation under the conditions described in step (2) of Reaction Scheme V.

[0342] Dimers of the invention can be prepared according to Reaction Scheme VII, wherein R1, R2, Z, Hal, and Ar′ are as defined above. In Reaction Scheme VII, a Suzuki coupling is carried out with an imidazoquinolin-4-amine of Formula LIV and a difunctional boronic acid of Formula LV, or an ester or anhydride thereof. Some boronic acids of Formula LV are commercially available; others can be prepared by known synthetic methods. The coupling can be carried out as described in Reaction Scheme I to provide a dimer of Formula XLVI. The compound or pharmaceutically acceptable salt thereof can be isolated using conventional methods.

[0343] Compounds of the invention can also be prepared according to Reaction Scheme VIII, wherein R, R3a, n, and Hal are as defined above, and R1d and R2d are subsets of R1 and R2 that do not include substituents that one skilled in the art would recognize as being susceptible to nucleophilic attack in step (5). These groups include, for example, esters and ureas. In step (1) of Reaction Scheme VIII, a nitro-substituted quinoline-2,4-diol of Formula LVI is chlorinated to provide a 2,4-dichloroquinoline of Formula LVII. Nitro-substituted quinoline-2,4-diols of Formula LVI can be prepared from substituted anilines according to the methods described in Buckle et al, J. Med. Chem., 18, 726-732 (1975). The chlorination is conveniently carried out by heating the compound of Formula LVI and phenylphosphonic dichloride at an elevated temperature such as 140° C. The reaction can be carried out without solvent, and the product can be isolated using conventional methods.

[0344] In step (2) of Reaction Scheme VIII, a 2,4-dichloroquinoline of Formula LVII is reacted with an amine of Formula R1—NH2 to provide a 2-chloro-3-nitroquinolin-4-amine of Formula LVIII. The reaction can be carried out as described in step (6) of Reaction Scheme II.

[0345] In step (3) of Reaction Scheme VIII, the nitro group of a 2-chloro-3-nitroquinolin-4-amine of Formula LVIII is reduced to provide a 2-chloroquinoline-3,4-diamine of Formula LIX. The reduction is conveniently carried out with sodium dithionite according to the method described in step (7) of Reaction Scheme II.

[0346] In step (4) of Reaction Scheme VIII, a 2-chloroquinoline-3,4-diamine of Formula LIX is treated with a carboxylic acid or an equivalent thereof to provide a 4-chloro-1H-imidazo[4,5-c]quinoline of Formula LX. The reaction can be carried out as described in step (8) of Reaction Scheme II.

[0347] In step (5) of Reaction Scheme VIII, a 4-chloro-1H-imidazo[4,5-c]quinoline of Formula LX is aminated to provide a 1H-imidazo[4,5-c]quinolin-4-amine of Formula LXI. The reaction is conveniently carried out by combining the compound of Formula LX with a solution of ammonia in methanol in a bomb reactor and heating at an elevated temperature, such as 120° C. The product or pharmaceutically acceptable salt thereof can be isolated using conventional methods.

[0348] In step (6) of Reaction Scheme VIII, a 1H-imidazo[4,5-c]quinolin-4-amine of Formula LXI undergoes a coupling reaction with a boronic acid of Formula X, an anhydride thereof, or a boronic acid ester of Formula R3a—B(O-alkyl)2. The Suzuki coupling reaction can be carried out as described in Reaction Scheme I to provide a 1H-imidazo[4,5-c]quinolin-4-amine of Formula LXII, which is a subgenus of Formula II. The product or pharmaceutically acceptable salt thereof can be isolated using conventional methods.

[0349] For some embodiments, compounds of the invention are prepared according to Reaction Scheme IX, where R, R2, R3a, R4, X, Q, and n are as defined above. In step (1) of Reaction Scheme IX, a 4-chloro-3-nitroquinoline of Formula XXVII is treated with a Boc-protected piperazine of Formula LXIII to provide a 3-nitroquinolin-4-amine of Formula LXIV. The reaction can be carried out as described for step (5) of Reaction Scheme III.

[0350] In steps (2) and (3) of Reaction Scheme IX, a 3-nitroquinolin-4-amine of Formula LXIV is first reduced to provide a quinoline-3,4-diamine of Formula LXV, which is converted to 1H-imidazo[4,5-c]quinoline of Formula LXVI by reaction with a carboxylic acid equivalent. Step (2) of Reaction Scheme IX can be carried out as described for step (7) of Reaction Scheme II or step (8) of Reaction Scheme III. Step (3) of Reaction Scheme IX can be carried out as described for step (8) of Reaction Scheme II.

[0351] The 1H-imidazo[4,5-c]quinoline of Formula LXVI is then oxidized in step (4) of Reaction Scheme IX to afford a dioxido-1H-imidazo[4,5-c]quinoline of Formula LXVII. The oxidation reaction is conveniently carried out in a similar manner to step (9) of Reaction Scheme II but with additional equivalents of 3-chloroperoxybenzoic acid. The product can be isolated using conventional methods.

[0352] In step (5) of Reaction Scheme IX, a dioxido-1H-imidazo[4,5-c]quinoline of Formula LXVII is aminated to provide a 1H-imidazo[4,5-c]quinolin-4-amine of Formula LXVIII. Step (5) of Reaction Scheme IX can be carried out as described for step (10) of Reaction Scheme II.

[0353] In step (6) of Reaction Scheme IX, the piperazine N-oxide of the 1H-imidazo[4,5-c]quinolin-4-amine of Formula LXVIII is reduced to provide a 1H-imidazo[4,5-c]quinolin-4-amine of Formula LXIX. The reaction is conveniently carried out by adding phosphorous trichloride to an N-oxide of Formula LXVIII in a suitable solvent such as chloroform. The reaction can be carried out at a subambient temperature, such as 4° C. The product can be isolated using conventional methods.

[0354] In step (7) of Reaction Scheme IX, the Boc protecting group of a 1H-imidazo[4,5-c]quinolin-4-amine of Formula LXIX is removed to provide a 1H-imidazo[4,5-c]quinolin-4-amine of Formula LXX. The deprotection can be carried out as described in step (8) of Reaction Scheme III.

[0355] In step (8) of Reaction Scheme IX, a 1H-imidazo[4,5-c]quinolin-4-amine of Formula LXX is coupled with a boronic acid of Formula X, an anhydride thereof, or boronic acid ester of Formula R3a—B(O-alkyl)2 to provide a 1H-imidazo[4,5-c]quinolin-4-amine of Formula LXXI, which is a subgenus of Formula II. The Suzuki coupling reaction can be carried out as described in Reaction Scheme I. The product or pharmaceutically acceptable salt thereof can be isolated using conventional methods.

[0356] In step (9) of Reaction Scheme IX, a 1H-imidazo[4,5-c]quinolin-4-amine of Formula LXXI is converted to a 1H-imidazo[4,5-c]quinolinyl compound of Formula LXXII. Step (9) can be carried out as described for step (9) of Reaction Scheme III, and the product or pharmaceutically acceptable salt thereof can be isolated using conventional methods.

[0357] For certain embodiments, compounds of the invention can be prepared according to Reaction Scheme X, where R, R2, R4, Hal, and n are as defined above and X1-1 is selected from the group consisting of C1-10alkylene, C4-10alkenylene, and C4-10alkynylene, wherein the terminal carbon atoms of alkenylene and alkynylene are tetrahedral. In step (1) a 3-nitroquinolin-4-amine of Formula LXXIII is reduced to provide a quinoline-3,4-diamine of Formula LXXIV. The reaction can be carried out as in step (7) of Reaction Scheme II. The product or a pharmaceutically acceptable salt thereof can be isolated by conventional methods. Many 3-nitroquinolin-4-amines of Formula LXXIII are known or can be prepared using known synthetic methods, see for exarnple, U.S. Pat. Nos. 4,689,338; 5,175,296; and 5,389,640; and the references cited therein.

[0358] In step (2) of Reaction Scheme X, a quinoline-3,4-diamine of Formula LXXIV is reacted with a carboxylic acid or an equivalent thereof to provide a 1H-imidazo[4,5-c]quinoline of Formula LXXV. The reaction can be conveniently carried out as described in step (8) of Reaction Scheme II. The product or a pharmaceutically acceptable salt thereof can be isolated by conventional methods.

[0359] In step (3) of Reaction Scheme X, a 1H-imidazo[4,5-c]quinoline of Formula LXXV is reacted with sodium hydride to form an alkoxide, which is reacted with a vinyl sulfone to provide a 1H-imidazo[4,5-c]quinoline of Formula LXXVI. The reaction can be carried out by adding catalytic sodium hydride dispersed in mineral oil to a solution of a 1H-imidazo[4,5-c]quinoline of Formula LXXV and a vinyl sulfone of the formula CH2═CH—S(O)2—R4 in a suitable solvent such DMF or tetrahydrofuran. The reaction can be run at ambient temperature. The product or a pharmaceutically acceptable salt thereof can be isolated by conventional methods.

[0360] In step (4) of Reaction Scheme X, a 1H-imidazo[4,5-c]quinoline of Formula LXXVI is oxidized to provide an N-oxide of Formula LXXVII. The reaction can be conveniently carried out as in step (9) of Reaction Scheme II.

[0361] In step (5) an N-oxide of Formula LXXVII is aminated to provide a 1H-imidazo[4,5-c]quinoline-4-amine of Formula LXXVIII. The reaction is carried as in step (10) of Reaction Scheme II. The product or a pharmaceutically acceptable salt thereof can be isolated by conventional methods.

[0362] In step (6) of Reaction Scheme X, a halogen-substituted 1H-imidazo[4,5-c]quinoline-4-amine of Formula LXXVIII undergoes a coupling reaction with a boronic acid of Formula X, an anhydride thereof, or a boronic acid ester of Formula R3a—B(O-alkyl)2. The Suzuki coupling reaction can be carried out as described in Reaction Scheme I to provide a 1H-imidazo[4,5-c]quinolin-4-amine of Formula LXXIX, which is a subgenus of Formula II. The product or pharmaceutically acceptable salt thereof can be isolated using conventional methods.

[0363] For other embodiments, compounds of the invention can be prepared according to Reaction Scheme XI, where R, R2, R4, R8, X, Hal, and n are as defined above. In step (1) of Reaction Scheme XI, the hydroxy group of a 3-nitroquinolin-4-amine of Formula LXXX is chlorinated using conventional methods to provide a 3-nitroquinolin-4-amine of Formula LXXXI. Many 3-nitroquinolin-4-amines of Formula LXXIII are known or can be prepared using known synthetic methods, see for example, U.S. Pat. Nos. 4,689,338; 5,175,296; and 5,389,640; and the references cited therein. The chlorination is conveniently carried out by adding thionyl chloride to a solution of the 3-nitroquinolin-4-amine of Formula LXXX in a suitable solvent such as dichloromethane. The reaction can be carried out at ambient temperature, and the product can be isolated using conventional methods.

[0364] In step (2) of Reaction Scheme XI, a 3-nitroquinolin-4-amine of Formula LXXXI is reduced to provide a quinoline-3,4-diamine of Formula LXXXII. The reduction can be carried out with sodium dithionite as described in step (7) of Reaction Scheme II. The product can be isolated by conventional methods.

[0365] In step (3) of Reaction Scheme XI, a quinoline-3,4-diamine of Formula LXXXII is reacted with a carboxylic acid or an equivalent thereof to provide a 1H-imidazo[4,5-c]quinoline of Formula LXXXIII. The reaction can be conveniently carried out as described in step (8) of Reaction Scheme II; the product can be isolated by conventional methods.

[0366] In step (4) of Reaction Scheme XI, the chloro group of a 1H-imidazo[4,5-c]quinoline of Formula LXXXIII is displaced with potassium thioacetate to provide a 1H-imidazo[4,5-c]quinoline of Formula LXXXIV. The reaction is conveniently carried out by adding potassium thioacetate to a solution of a 1H-imidazo[4,5-c]quinoline of Formula LXXXIII in a suitable solvent such as DMF. The reaction can be carried out at ambient temperature, and the product can be isolated using conventional methods.

[0367] In step (5) of Reaction Scheme XI, the thioacetate group of a 1H-imidazo[4,5-c]quinoline of Formula LXXXIV is hydrolyzed under basic conditions to provide a thiol-substituted 1H-imidazo[4,5-c]quinoline of Formula LXXXV. The reaction is conveniently carried out by adding a solution of sodium methoxide in methanol to a solution of a 1H-imidazo[4,5-c]quinoline of Formula LXXXIV in methanol. The reaction can be carried out at ambient temperature, and the product can be isolated using conventional methods.

[0368] In step (6) of Reaction Scheme XI, the thiol group of a 1H-imidazo[4,5-c]quinoline of Formula LXXXV is oxidized to a sulfonyl chloride of Formula LXXXVI. The reaction is conveniently carried out by adding a solution of sodium chlorate in a suitable solvent such as water to a solution of a thiol-substituted 1H-imidazo[4,5-c]quinoline of Formula LXXXV in hydrochloric acid. The reaction can be carried out at a subambient temperature such as 0° C., and the product can be isolated using conventional methods.

[0369] Alternatively, steps (4), (5), and (6) can be replaced with steps (4a) and (5a) of Reaction Scheme XI. In step (4a), the chloro group of a 1H-imidazo[4,5-c]quinoline of Formula LXXXIII is displaced with thiourea to provide a 1H-imidazo[4,5-c]quinoline of Formula LXXXVII. The reaction is conveniently carried out by adding thiourea and a catalytic amount of potassium iodide to a solution of a 1H-imidazo[4,5-c]quinoline of Formula LXXXIII in a suitable solvent such as DMF. The reaction can be carried out at an elevated temperature, such as 110° C., and the product can be isolated using conventional methods.

[0370] In step (5a) of Reaction Scheme XI, the thiourea group of a 1H-imidazo[4,5-c]quinoline of Formula LXXXVII is converted to a sulfonyl chloride of Formula LXXXVI under the conditions described in step (6).

[0371] In step (7) of Reaction Scheme XI, the sulfonyl chloride of Formula LXXXVI is treated with an amine or an amine salt to provide a sulfonamide of Formula LXXXVIII. The reaction is conveniently carried out by adding an amine of Formula NH(R4)(R8) to a sulfonyl chloride of Formula LXXXVI in a suitable solvent such as dichloromethane. The reaction can be carried out at ambient temperature, and the product can be isolated using conventional methods. Alternatively, step (7) can be carried out by adding an amine hydrochloride of Formula (R4)(R8)NH.HCl followed by aqueous potassium carbonate to a solution of a sulfonyl chloride of Formula LXXXVI in a suitable solvent such as dichloromethane. The reaction can be carried out at ambient temperature, and the product can be isolated using conventional methods.

[0372] In steps (8) and (9) of Reaction Scheme XI, a sulfonamide-substituted 1H-imidazo[4,5-c]quinoline of Formula LXXXVIII is oxidized in step (8) to afford a 1H-imidazo[4,5-c]quinoline-5N-oxide of Formula LXXXIX, which is aminated in step (9) to provide a 1H-imidazo[4,5-c]quinolin-4-amine of Formula XC. Steps (8) and (9) of Reaction Scheme XI can be carried out as described in steps (9) and (10) of Reaction Scheme II.

[0373] In step (10) of Reaction Scheme XI, a 1H-imidazo[4,5-c]quinolin-4-amine of Formula XC is coupled with a boronic acid of Formula X, an anhydride thereof, or boronic acid ester of Formula R3a—B(O-alkyl)2 to provide a 1H-imidazo[4,5-c]quinolin-4-amine of Formula XCI, which is a subgenus of Formula II. Step (10) can be carried out as described in Reaction Scheme I. The product or pharmaceutically acceptable salt thereof can be isolated using conventional methods.

[0374] For other embodiments, compounds of the invention can be prepared according to Reaction Scheme XII, wherein R, R1, R2, Hal, and n are as defined above, and HA is a heteroaryl group attached at a nitrogen atom. In Reaction Scheme XII, a halogen-substituted imidazoquinolin-4-amine of Formula IX undergoes a copper-catalyzed amination with a nitrogen-containing heteroaryl compound to provide an imidazoquinolin-4-amine of Formula XClI, which is a subgenus of Formula II. Several nitrogen-containing heteroaryl compounds, such as imidazole and pyrazole, are commercially available; others can be prepared by known methods. The reaction is conveniently carried out by combining the imidazoquinolin-4-amine of Formula IX and the nitrogen-containing heteroaryl compound in the presence of copper (I) iodide, potassium phosphate, and trans-1,2-diaminocyclohexane in a suitable solvent such as 1,4-dioxane. The reaction can be carried out at an elevated temperature such as 110° C. The compound or pharmaceutically acceptable salt thereof can be isolated using conventional methods.

[0375] Pharmaceutical Compositions and Biological Activity

[0376] Pharmaceutical compositions of the invention contain a therapeutically effective amount of a compound of the invention as described above in combination with a pharmaceutically acceptable carrier.

[0377] The term “therapeutically effective amount” or “effective amount” means an amount of the compound sufficient to induce a therapeutic or prophylactic effect, such as cytokine induction, cytokine inhibition, immunomodulation, antitumor activity, and/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 compound, the nature of the carrier, and the intended dosing regimen, it is anticipated that the compositions of the invention will contain sufficient active ingredient to provide a dose of about 100 ng/kg to about 50 mg/kg, preferably about 10 μg/kg to about 5 mg/kg, of the compound to the subject. A variety of dosage forms may be used, such as tablets, lozenges, capsules, parenteral formulations, syrups, creams, ointments, aerosol formulations, transderrnal patches, transmucosal patches and the like.

[0378] The compounds of the invention can be administered as the single therapeutic agent in the treatment regimen, or the compounds of the invention may be administered in combination with one another or with other active agents, including additional immune response modifiers, antivirals, antibiotics, antibodies, proteins, peptides, oligonucleotides, etc.

[0379] Compounds of the invention have been shown to modulate (e.g., induce or inhibit) the production of certain cytokines in experiments performed according to the tests set forth below. These results indicate that compounds of the invention are useful as immune response modifiers that can modulate the immune response in a number of different ways, rendering them useful in the treatment of a variety of disorders.

[0380] Cytokines whose production may be induced by the administration of certain compounds according to the invention generally include interferon-a (IFN-α) and/or tumor necrosis factor-α (TNF-α) as well as certain interleukins (IL). Cytokines whose biosynthesis may be induced by certain compounds of the invention include IFN-α, TNF-α, IL-1, IL-6, IL-10 and IL-12, and a variety of other cytokines. Among other effects, these and other cytokines can inhibit virus production and tumor cell growth, making the compounds useful in the treatment of viral diseases and neoplastic diseases. Accordingly, the invention provides a method of inducing cytokine biosynthesis in an animal comprising administering an effective amount of a compound or composition of the invention to the animal. The animal to which the compound or composition is administered for induction of cytokine biosynthesis may have a disease as described infra, for example a viral disease or a neoplastic disease, and administration of the compound may provide therapeutic treatment. Alternatively, the compound may be administered to the animal prior to the animal aquiring the disease so that administration of the compound may provide a prophylactic treatment.

[0381] In addition to the ability to induce the production of cytokines, certain compounds of the invention affect other aspects of the innate immune response. For example, natural killer cell activity may be stimulated, an effect that may be due to cytokine induction. Certain compounds may also activate macrophages, which in turn stimulate secretion of nitric oxide and the production of additional cytokines. Further, certain compounds may cause proliferation and differentiation of B-lymphocytes.

[0382] Certain compounds of the invention also have an effect on the acquired immune response. For example, the production of the T helper type 1 (TH1) cytokine IFN-γ is induced indirectly and the production of the T helper type 2 (TH2) cytokines IL-4, IL-5 and IL-13 are inhibited upon administration of compounds of the invention.

[0383] Other cytokines whose production is inhibited by the administration of certain compounds according to the invention include tumor necrosis factor-α (TNF-α). Among other effects, inhibition of TNF-α production can provide prophylaxis or therapeutic treatment of diseases in animals in which TNF is mediated, making the compounds useful in the treatment of, for example, autoimmune diseases. Accordingly, the invention provides a method of inhibiting TNF-α biosynthesis in an animal comprising administering an effective amount of a compound or composition of the invention to the animal. The animal to which the compound or composition is administered for inhibition of TNF-α biosynthesis may have a disease as described infra, for example an autoimmune disease, and administration of the compound may provide therapeutic treatment. Alternatively, the compound may be administered to the animal prior to the animal aquiring the disease so that administration of the compound may provide a prophylactic treatment.

[0384] Whether for prophylaxis or therapeutic treatment of a disease, and whether for effecting innate or acquired immunity, the compound or composition may be administered alone or in combination with one or more active components as in, for example, a vaccine adjuvant. When administered with other components, the compound and other component or components may be administered separately; together but independently such as in a solution; or together and associated with one another such as (a) covalently linked or (b) non-covalently associated, e.g., in a colloidal suspension.

[0385] Conditions for which IRMs identified herein may be used as treatments include, but are not limited to:

[0386] (a) viral diseases such as, for example, diseases resulting from infection by an adenovirus, a herpesvirus (e.g., HSV-I, HSV-II, CMV, or VZV), a poxvirus (e.g., an orthopoxvirus such as variola or vaccinia, or molluscum contagiosum), a picomavirus (e.g., rhinovirus or enterovirus), an orthomyxovirus (e.g., influenzavirus), a paramyxovirus (e.g., parainfluenzavirus, mumps virus, measles virus, and respiratory syncytial virus (RSV)), a coronavirus (e.g., SARS), a papovavirus (e.g., papillomaviruses, such as those that cause genital warts, common warts, or plantar warts), a hepadnavirus (e.g., hepatitis B virus), a flavivirus (e.g., hepatitis C virus or Dengue virus), or a retrovirus (e.g., a lentivirus such as HIV);

[0387] (b) bacterial diseases such as, for example, diseases resulting from infection by bacteria of, for example, the genus Escherichia, Enterobacter, Salmonella, Staphylococcus, Shigella, Listeria, Aerobacter, Helicobacter, Klebsiella, Proteus, Pseudomonas, Streptococcus, Chlamydia, Mycoplasma, Pneumococcus, Neisseria, Clostridium, Bacillus, Corynebacterium, Mycobacterium, Campylobacter, Vibrio, Serratia, Providencia, Chromobacterium, Brucella, Yersinia, Haemophilus, or Bordetella;

[0388] (c) other infectious diseases, such chlamydia, fungal diseases including but not limited to candidiasis, aspergillosis, histoplasmosis, cryptococcal meningitis, or parasitic diseases including but not limited to malaria, pneumocystis camii pneumonia, leishmaniasis, cryptosporidiosis, toxoplasmosis, and trypanosome infection; and

[0389] (d) neoplastic diseases, such as intraepithelial neoplasias, cervical dysplasia, actinic keratosis, basal cell carcinoma, squamous cell carcinoma, renal cell carcinoma, Kaposi's sarcoma, melanoma, renal cell carcinoma, leukemias including but not limited to myelogeous leukemia, chronic lymphocytic leukemia, multiple myeloma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, B-cell lymphoma, and hairy cell leukemia, and other cancers; and

[0390] (e) TH2-mediated, atopic, and autoimmune diseases, such as atopic dermatitis or eczema, eosinophilia, asthma, allergy, allergic rhinitis, systemic lupus erythematosus, essential thrombocythaemia, multiple sclerosis, Ommen's syndrome, discoid lupus, alopecia areata, inhibition of keloid formation and other types of scarring, and enhancing would healing, including chronic wounds.

[0391] IRMs identified herein also may be useful as a vaccine adjuvant for use in conjunction with any material that raises either humoral and/or cell mediated immune response, such as, for example, live viral, bacterial, or parasitic immunogens; inactivated viral, tumor-derived, protozoal, organism-derived, fungal, or bacterial immunogens, toxoids, toxins; self-antigens; polysaccharides; proteins; glycoproteins; peptides; cellular vaccines; DNA vaccines; recombinant proteins; glycoproteins; peptides; and the like, for use in connection with, for example, BCG, cholera, plague, typhoid, hepatitis A, hepatitis B, hepatitis C, influenza A, influenza B, parainfluenza, polio, rabies, measles, mumps, rubella, yellow fever, tetanus, diphtheria, hemophilus influenza b, tuberculosis, meningococcal and pneumococcal vaccines, adenovirus, HIV, chicken pox, cytomegalovirus, dengue, feline leukemia, fowl plague, HSV-1 and HSV-2, hog cholera, Japanese encephalitis, respiratory syncytial virus, rotavirus, papilloma virus, yellow fever, and Alzheimer's Disease.

[0392] IRMs may also be particularly helpful in individuals having compromised immune function. For example, IRM compounds may be used for treating the opportunistic infections and tumors that occur after suppression of cell mediated immunity in, for example, transplant patients, cancer patients and HIV patients.

[0393] Thus, one or more of the above diseases or types of diseases, for example, a viral disease, a neoplastic disease, may be treated in an animal in need there of (having the disease) by administering a therapeutically effective amount of a compound or salt of Formula I, II, III, IV, V, VI, VII, VIII, XLVI, or a combination thereof to the animal.

[0394] An amount of a compound effective to induce or inhibit cytokine biosynthesis is an amount sufficient to cause one or more cell types, such as monocytes, macrophages, dendritic cells and B-cells to produce an amount of one or more cytokines such as, for example, IFN-α, TNF-α, IL-1, IL-6, IL-10 and IL-12 that is increased (induced) or decreased (inhibited) over a background level of such cytokines. The precise amount will vary according to factors known in the art but is expected to be a dose of about 100 ng/kg to about 50 mg/kg, preferably about 10 μg/kg to about 5 mg/kg. The invention also provides a method of treating a viral infection in an animal and a method of treating a neoplastic disease in an animal comprising administering an effective amount of a compound or composition of the invention to the animal. An amount effective to treat or inhibit a viral infection is an amount that will cause a reduction in one or more of the manifestations of viral infection, such as viral lesions, viral load, rate of virus production, and mortality as compared to untreated control animals. The precise amount that is effective for such treatment will vary according to factors known in the art but is expected to be a dose of about 100 ng/kg to about 50 mg/kg, preferably about 10 μg/kg to about 5 mg/kg. An amount of a compound effective to treat a neoplastic condition is an amount that will cause a reduction in tumor size or in the number of tumor foci. Again, the precise amount will vary according to factors known in the art but is expected to be a dose of about 100 ng/kg to about 50 mg/kg, preferably about 10 μg/kg to about 5 mg/kg.

[0395] In addition to the formulations and uses described specifically herein, other formulations, uses, and administration devices suitable for compounds of the present invention are described in, for example, International Publication Nos. WO 03/077944, WO 03/080114, WO 03/045494, WO 02/024225, WO 02/036592, U.S. Pat. No. 6,245,776, and U.S. Publication Nos. 2002/0193729 and 2003/0139364.

[0396] Objects and advantages of this invention are further illustrated by the following examples, but the particular materials and amounts thereof recited in these examples, as well as other conditions and details, should not be construed to unduly limit this invention.

EXAMPLES

[0397] In the examples below some of the compounds were purified by preparative high performance liquid chromatography (prep HPLC) using a Waters Fraction Lynx automated purification system. The prep HPLC fractions were analyzed using a Micromass LC-TOFMS and the appropriate fractions were combined and centrifuge evaporated to provide the trifluoroacetate salt of the desired compound. In order to maximize purity, the compounds were sent through the purification process twice. Column: Phenomenex Luna C18(2), 21.2×50 millimeters (mm), 10 micron particle size, 100 Angstrom (Å) pore; flow rate: 25 milliliters per minutes (mL/min); non-linear gradient elution from 5-95% B in 9 min (first purification run) and from 5-65% B in 16 min (second purification run), then hold at 95% B for 2 min, where A is 0.05% trifluoroacetic acid/water and B is 0.05% trifluoroactic acid/acetonitrile; fraction collection by mass-selective triggering.

[0398] A variety of chromatographic conditions were used for the prep HPLC purification of other compounds shown in the examples below using either the Phenomenex Luna C18(2) column (21.2×50 millimeters (mm), 10 micron particle size) or a Waters Xterra C18 column (19×50 mm, 5 micron particle size). Elution was carried out in a non-linear gradient from 95:5 to 5:95 A:B, where A is 0.05% trifluoroacetic acid/water and B is 0.05% trifluoroactic acid/acetonitrile; fraction collection was performed by mass-selective triggering.

[0399] Some of the compounds prepared by Suzuki coupling were passed through a Waters Oasis Sample Extractions Cartridge MCX (6 cc) prior to prep HPLC purification. The following procedure was used. The product from the coupling reaction was dissolved in 1N hydrochloric acid (3 mL) to adjust to pH 5-7 and passed through the cartridge optionally using light nitrogen pressure. The cartridge was washed with methanol (5 mL) optionally using light nitrogen pressure and transferred to a clean test tube. A solution of 1% ammonia in methanol (2×5 mL) was then passed through the cartridge optionally using light nitrogen pressure, and the basic solution was collected and concentrated.

Example 1

2-Butyl-1-isobutyl-7-(thiophen-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine

[0400]

[0401] Part A

[0402] A mixture of triethyl orthoformate (154 grams (g), 1.04 moles (mol) and Meldrum's acid (142 g, 0.983 mol) was heated to 55° C. for 4 hours (h). After cooling to 50° C., a solution of 3-bromoaniline (162.6 g, 0.945 mol) in ethanol (300 mL) was added such that the temperature of the reaction was maintained between 50-55° C. After half of the 3-bromoaniline had been added, stirring became difficult due to the formation of solids, so more ethanol (1 liter (L)) was added to facilitate stirring. Upon complete addition, the reaction was cooled to room temperature (RT), and the solids were collected by filtration. The filter cake was washed with ice cold ethanol until the washings were nearly colorless, and the product was dried at 65° C. under vacuum to afford 287 g of 5-[(3-bromophenylamino)methylene]-2,2-dimethyl-[1,3]dioxane-4,6-dione as an off-white solid.

[0403]

1
H NMR (300 MHz, CDCl3) δ 11.19 (brd, J=12.8 Hz, 1H), 8.60 (d, J=14.0 Hz, 1H), 7.44-7.38 (m, 2H), 7.30 (t, J=8.0 Hz, 1H), 7.18 (ddd, J=8.0, 2.2, 0.9 Hz, 1H), 1.75 (s, 6H).

[0404] Part B

[0405] 7-Bromoquinolin-4-ol was prepared in accordance with the literature procedure (D. Dibyendu et al., J. Med. Chem., 41, 4918-4926 (1998)) or by thermolysis of 5-[(3-bromophenylamino)methylene] -2,2-dimethyl-[1,3]dioxane-4,6-dione in DOWTHERM A heat transfer fluid and had the following spectral properties: 1H NMR (300 MHz, d6-DMSO) δ 11.70 (brs, 1H), 8.00 (d, J=8.7 Hz, 1H), 7.92 (d, J=7.5 Hz, 1H), 7.74 (d, J=1.9 Hz, 1H), 7.44 (dd, J=8.7, 1.9 Hz, 1H), 6.05 (d, J=7.5 Hz, 1H).

[0406] Part C

[0407] A stirred suspension of 7-bromoquinolin-4-ol (162 g, 0.723 mol) in propionic acid (1500 mL) was brought to 110° C. 70% Nitric acid (85 g) was added dropwise over 1 h such that the temperature was maintained between 110-115° C. After half of the nitric acid had been added, stirring became difficult due to the formation of solids and an additional 200 mL of propionic acid was added. Upon complete addition, the reaction was stirred for 1 h at 110° C., cooled to room temperature, and the solid was collected by filtration. The filter cake was washed with ice cold ethanol until the washings were nearly colorless (800 mL), and the product was dried at 60° C. under vacuum to afford 152 g of 7-bromo-3-nitro-quinolin-4-ol as a pale yellow solid.

[0408]

1
H NMR (300 MHz, d6-DMSO) δ 13.0 (brs, 1H), 9.22 (s, 1H), 8.15 (d, J=8.4 Hz, 1H), 7.90 (d, J=1.6 Hz, 1H), 7.66 (dd, J=8.7, 1.9 Hz, 1H).

[0409] Part D

[0410] 7-Bromo-3-nitroquinolin-4-ol (42 g, 156 millimoles (mmol)) was suspended in POCl3 (130 mL) and brought to 102° C. under an atmosphere of N2. After 45 min, all of the solids had dissolved, so the reaction was cooled to room temperature (RT). The resulting solids were collected by filtration, washed with H2O, and then partitioned with CH2Cl2 (3 L) and 2M Na2CO3 (500 mL). The organic layer was separated, washed with H2O (1×), dried over Na2SO4, filtered, and concentrated to afford 33.7 g of 7-bromo-4-chloro-3-nitroquinoline as a beige solid.

[0411]

1
H NMR (300 MHz, CDCl3) δ 9.26 (s, 1H), 8.41 (d, J=1.8 Hz, 1H), 8.30 (d, J=9.0 Hz, 1H), 7.90 (dd, J=8.9, 2.1 Hz, 1H).

[0412] Part E

[0413] 7-Bromo-4-chloro-3-nitroquinoline (33.5 g, 117 mmol) and Et3N (13.0 g, 128 mmol) were dissolved in CH2Cl2 (500 mL) and cooled on an ice bath. Isobutylamine (9.36 g, 128 mmol) was added in one portion and then the reaction was allowed to warm to room temperature. After 2 h, the reaction mixture was washed with water (500 mL), and the aqueous layer was extracted with CH2Cl2 (2×100 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated to afford 38.0 g of a yellow solid. Recrystallization from refluxing isopropanol (1.1 L) afforded 34.0 g of (7-bromo-3-nitroquinolin-4-yl)isobutylamine as yellow needles.

[0414]

1
H NMR (300 MHz, CDCl3) δ 9.79 (brs, 1H), 9.35 (s, 1H), 8.16 (d, J=9.1 Hz, 1H), 8.16 (d, J=2.2 Hz, 1H), 7.57 (dd, J=9.1, 2.2 Hz, 1H), 3.75 (dd, J=6.6, 5.0 Hz, 2H), 2.14-2.01 (m, 1H), 1.10 (d, J=6.9 Hz, 6H).

[0415] Part F

[0416] A solution of Na2S2O4 (193 g) in H2O (1 L) was added to a boiling solution of (7-bromo-3-nitroquinolin-4-yl)isobutylamine (32.0 g, 99 mmol) in isopropanol (1 L). Upon complete addition, the reaction mixture was cooled to room temperature and the bulk of the isopropanol was removed on a rotary evaporator. The resulting mixture was extracted with CH2Cl2 (3×), and the combined organic layers were dried over Na2SO4, filtered, and concentrated to afford 39.5 g of the crude 7-bromo—N4-isobutylquinoline-3,4-diamine as a yellow solid.

[0417] Part G

[0418] 7-Bromo-N4-isobutylquinoline-3,4-diamine (39.4 g of crude material), trimethyl orthovalerate (32 g, 0.20 mol), and pyridine hydrochloride (0.31 g, 2.7 mmol) were combined with anhydrous toluene (500 mL) and heated to reflux for 30 min. The reaction was cooled to room temperature, concentrated, and the residue was purified by chromatography on silica gel (75% ethyl acetate in hexane to 100% ethyl acetate gradient) to afford 21.2 g of 7-bromo-2-butyl-1-isobutyl-1H-imidazo[4,5-c]quinoline as a yellow solid.

[0419]

1
H NMR (300 MHz, CDCl3) δ 9.28 (s, 1H), 8.43 (d, J=2.2 Hz, 1H), 7.95 (d, J=8.7 Hz, 1H), 7.70 (dd, J=9.1, 2.2 Hz, 1H), 4.29 (d, J=7.5 Hz, 2H), 2.97-2.91 (m, 2H), 2.40-2.26 (m, 1H), 2.01-1.90 (m, 2H), 1.52 (sextet, J=7.5 Hz, 2H), 1.02 (d, J=6.9 Hz, 6H), 1.01 (t, J=7.3 Hz, 3H);

[0420] MS m/z (M+1+) calcd 362.1, obsd 362.1.

[0421] Part H

[0422] To a solution of 7-bromo-2-butyl-1-isobutyl-1H-imidazo[4,5-c]quinoline (10.8 g, 30.0 mmol) in CH2Cl2 (300 mL) was added 3-chloroperoxybenzoic acid (10.4 g of approximately 77% purity). The reaction was allowed to stir overnight and was washed with 2M Na2CO3 (200 mL). The aqueous layer was extracted with CH2Cl2 (2×200 mL), and the combined organic layers were dried (MgSO4), filtered, and concentrated to afford 13.6 g orange solid. Recrystallization from boiling ethyl acetate (300 mL) afforded 8.25 g of 7-bromo-2-butyl-1-isobutyl-1H-imidazo[4,5-c]quinoline 5-oxide as a yellow powder.

[0423]

1
H NMR (300 MHz, CDCl3) δ 9.24 (d, J=1.9 Hz, 1H), 9.00 (s, 1H), 7.93 (d, J=8.7 Hz, 1H), 7.81 (dd, J=9.1, 2.2 Hz, 1H), 4.26 (d, J=7.5 Hz, 2H), 2.94-2.89 (m, 2H), 2.37-2.23 (m, 1H), 1.97-1.87 (m, 2H), 1.51 (sextet, J=7.4 Hz, 2H), 1.03 (d, J=6.6 Hz, 6H), 1.01 (t, J=7.3 Hz, 3H);

[0424] MS m/z (M+1+) calcd 378.1, obsd 378.1.

[0425] Part I

[0426] To a vigorously stirred mixture of 7-bromo-2-butyl-1-isobutyl-1H-imidazo[4,5-c]quinoline 5-oxide (345 mg, 0.92 mmol) in CH2Cl2 (7 mL) and NH4OH (0.50 mL of 30%) was added p-toluenesulfonyl chloride (175 mg, 0.92 mmol) in one portion. After 15 h, the reaction mixture was diluted with CH2Cl2 and washed with 2 M Na2CO3. The aqueous layer was extracted with CH2Cl2 (2×), and the combined organic layers were dried (Na2SO4), filtered, and concentrated to afford 331 mg of a yellow solid. Recrystallization from boiling isopropanol (3 mL) followed by purification on silica gel (40% acetone in toluene to 50% acetone in toluene gradient) afforded 208 mg of 7-bromo-2-butyl-1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine as a white solid, m.p. 198-200° C.

[0427]

1
H NMR (300 MHz, CDCl3) δ 7.98 (d, J=2.2 Hz, 1H), 7.73 (d, J=8.7 Hz, 1H), 7.40 (dd, J=8.7, 1.9 Hz, 1H), 5.44 (s, 2H), 4.22 (d, J=7.8 Hz, 2H), 2.92-2.86 (m, 2H), 2.38-2.24 (m, 1H), 1.93-1.83 (m, 2H), 1.50 (sextet, J=7.5 Hz, 2H), 1.00 (d, J=6.9 Hz, 6H), 1.00 (t, J=7.3 Hz, 3H);

[0428]

13
C NMR (75 MHz, CDCl3) δ 154.4, 152.0, 146.2, 133.3, 129.9, 127.2, 125.2, 121.1, 120.5, 114.6, 52.8, 30.3, 29.4, 27.7, 22.8, 20.0, 14.1;

[0429] MS m/z (M+1+) calcd 375.1, obsd 375.2;

[0430] Anal. Calcd for C18H23BrN4: C, 57.60; H, 6.18; N, 14.93. Found: C, 57.54; H, 6.17; N, 14.98.

[0431] Part J

[0432] 7-Bromo-2-butyl-1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine (751 mg, 2.00 mmol), thiophene-3-boronic acid (269 mg, 2.10 mmol), and n-propanol (3.6 mL) were combined in a reaction vessel and placed under an atmosphere of N2. Pd(OAc)2 (1.3 mg, 0.0060 mmol), triphenylphosphine (4.7 mg, 0.018 mmol), Na2CO3 (1.2 mL of a 2 M solution, 2.4 mmol), and H2O (0.7 mL) were added, and the reaction mixture was heated to reflux in an oil bath for 2.5 h. Upon cooling to RT, the solid product was collected by filtration and washed with H2O and ethanol. Purification on silica gel (5%-6% methanol (MeOH) in CH2Cl2 gradient) afforded 700 mg of product which was recrystallized from boiling isopropanol (20 mL) to yield 535 mg of 2-butyl-1-isobutyl-7-(thiophen-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine as an off-white powder, m.p. 229-230° C.

[0433]

1
H NMR (300 MHz, CDCl3) δ 8.08 (d, J=1.9 Hz, 1H), 7.91 (d, J=8.7 Hz, 1H), 7.61-7.58 (m, 2H), 7.55 (dd, J=5.2, 1.4 Hz, 1H), 7.42 (dd, J=5.2, 3.0 Hz, 1H), 5.39 (s, 2H), 4.26 (d, J=7.5 Hz, 2H), 2.93-2.88 (m, 2H), 2.46-2.32 (m, 1H), 1.94-1.84 (m, 2H), 1.51 (sextet, J=7.4 Hz, 2H), 1.03 (d, J=6.6 Hz, 6H), 1.01 (t, J=7.5 Hz, 3H);

[0434]

13
C NMR (75 MHz, CDCl3) δ 154.1, 151.7, 145.5, 142.3, 134.3, 133.6, 127.2, 126.53, 126.47, 124.6, 121.0, 120.6, 120.4, 114.8, 52.8, 30.4, 29.5, 27.8, 22.9, 20.0, 14.1;

[0435] MS m/z (M+1+) calcd 379.1956, obsd 379.1943;

[0436] Anal. Calcd for C22H26N4S: C, 69.80; H, 6.92; N, 14.80; S, 8.47. Found: C, 69.45; H, 7.10; N, 14.90; S, 8.44.

Example 2

2-Butyl-1-isobutyl-7-phenyl-1H-imidazo[4,5-c]quinolin-4-amine

[0437]

[0438] 7-Bromo-2-butyl-1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine and benzeneboronic acid were coupled according to the general procedure described in Part J of Example 1. Purification by chromatography on silica gel (20% acetone in toluene to 60% acetone in toluene gradient) afforded 2-butyl-1-isobutyl-7-phenyl-1H-imidazo[4,5-c]quinolin-4-amine as a white solid, m.p. >250° C.

[0439]

1
H NMR (300 MHz, CDCl3) δ 8.09 (d, J=1.9 Hz, 1H), 7.96 (d, J=8.7 Hz, 1H), 7.77-7.74 (m, 2H), 7.61 (dd, J=8.4, 1.9 Hz, 1H), 7.50-7.45 (m, 2H), 7.36 (tt, J=7.3, 1.5 Hz, 1H), 5.40 (s, 2H), 4.28 (d, J=7.5 Hz, 2H), 2.94-2.89 (m, 2H), 2.48-2.34 (m, 1H), 1.95-1.84 (m, 2H), 1.52 (sextet, J=7.4 Hz, 2H), 1.04 (d, J=6.6 Hz, 6H), 1.01 (t, J=7.3 Hz, 3H);

[0440]

13
C NMR (75 MHz, CDCl3) δ 154.2, 151.7, 145.3, 141.0, 139.6, 133.6, 129.1, 127.6, 127.4, 127.2, 125.4, 121.6, 120.4, 114.9, 52.9, 30.4, 29.5, 27.8, 22.9, 20.0, 14.1;

[0441] MS m/z (M+1+) calcd 373.2, obsd 373.2;

[0442] Anal. Calcd for C24H28N4: C, 77.38; H, 7.58; N, 15.04. Found: C, 77.16; H, 7.62; N, 14.95.

Example 3

2-Butyl-7-(2,4-dimethoxyphenyl)-1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine

[0443]

[0444] 7-Bromo-2-butyl-1-isobutyl-1H-imidazo[4,5-c]quinoline and 2,4-dimethoxybenzeneboronic acid were coupled according to the general procedure described in Part J of Example 1. The resulting 2-butyl-7-(2,4-dimethoxyphenyl)-1-isobutyl-1H-imidazo[4,5-c]quinoline was oxidized and then aminated according to the general procedures described in Parts H and I of Example 1 and purified by chromatography on silica gel (8% methanol in CH2Cl2 to 10% methanol in CH2Cl2 gradient) followed by recrystallization from 1/1 ethyl acetate/hexane to afford 2-butyl-7-(2,4-dimethoxyphenyl)-1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine as apale orange solid, m.p. 187-189° C.

[0445]

1
H NMR (300 MHz, CDCl3) δ 7.96 (d, J=1.6 Hz, 1H), 7.89 (d, J=8.7 Hz, 1H), 7.53 (dd, J=8.4, 1.9 Hz, 1H), 7.40-7.37 (m, 1H), 6.62-6.58 (m, 2H), 5.38 (s, 2H), 4.25 (d, J=7.5 Hz, 2H), 3.87 (s, 3H), 3.83 (s, 3H), 2.93-2.88 (m, 2H), 2.50-2.36 (m, 1H), 1.94-1.84 (m, 2H), 1.51 (sextet, J=7.4 Hz, 2H), 1.02 (d, J=6.6 Hz, 6H), 1.01 (t, J=7.2 Hz, 3H);

[0446]

13
C NMR (75 MHz, CDCl3) δ 160.6, 157.8, 152.9, 151.4, 145.0, 137.2, 133.6, 131.7, 127.7, 127.1, 124.3, 123.5, 119.3, 114.3, 105.0, 99.3, 55.8, 55.6, 52.8, 30.3, 29.4, 27.7, 22.9, 20.0, 14.1;

[0447] MS m/z (M+1+) calcd 433.2604, obsd 433.2600;

[0448] Anal. Calcd for C26H32N4O2.0.17H2O: C, 71.67; H, 7.48; N, 12.86. Found: C, 71.25; H, 7.46; N, 12.81. Water content determined by Karl-Fischer analysis.

Example 4

2-Butyl-7-(4-tert-butylphenyl)-1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine

[0449]

[0450] 7-Bromo-2-butyl-1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine and 4-tert-butylbenzeneboronic were coupled according to the general procedure described in Part J of Example 1. Purification by chromatography on silica gel (5% methanol in CH2Cl2 to 6% methanol in CH2Cl2 gradient) followed by recrystallization from ethyl acetate afforded 2-butyl-7-(4-tert-butylphenyl)-1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine as a white solid, m.p. 219-220° C.

[0451]

1
H NMR (300 MHz, CDCl3) δ 8.09 (d, J=1.9 Hz, 1H), 7.94 (d, J =8.7 Hz, 1H), 7.71 (dm, J=8.4 Hz, 2H), 7.60 (dd, J =8.6, 2.1 Hz, 1H), 7.51 (dm, J=8.7 Hz, 2H), 5.38 (s, 2H), 4.27 (d, J=7.5 Hz, 2H), 2.94-2.89 (m, 2H), 2.48-2.35 (m, 1H), 1.92-1.84 (m, 2H), 1.51 (sextet, J=7.4 Hz, 2H), 1.38 (s, 9H), 1.03 (d, J=6.6 Hz, 6H), 1.01 (t, J=7.3 Hz, 3H);

[0452]

13
C NMR (100 MHz, CDCl3) δ 154.1, 151.6, 150.6, 145.4, 139.4, 138.0, 133.6, 127.1, 127.0, 126.0, 125.1, 121.5, 120.3, 114.8, 52.8, 34.8, 31.6, 30.4, 29.4, 27.8, 22.9, 20.0, 14.1;

[0453] MS m/z (M+1+) calcd 429.3, obsd 429.5;

[0454] Anal. Calcd for C28H36N4: C, 78.46; H, 8.47; N, 13.07. Found: C, 78.10; H, 8.45; N, 13.02.

Example 5

2-Butyl-1-isobutyl-7-(4-propoxyphenyl)-1H-imidazo[4,5-c]quinolin-4-amine

[0455]

[0456] 7-Bromo-2-butyl-1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine and 4-propoxybenzeneboronic acid were coupled according to the general procedure described in Part J of Example 1. The product was recrystallized from isopropanol, collected by filtration, dissolved in CH2Cl2, and then precipitated with hexanes to afford 2-butyl-1-isobutyl-7-(4-propoxyphenyl)-1H-imidazo[4,5-c]quinolin-4-amine as a pale yellow solid, m.p. 194-197° C.

[0457]

1
H NMR (300 MHz, CDCl3) δ 8.03 (d, J=1.9 Hz, 1H), 7.92 (d, J=8.4 Hz, 1H), 7.69 (dm, J=8.7 Hz, 2H), 7.55 (dd, J=8.4, 1.9 Hz, 1H), 7.01 (dm, J=9.0 Hz, 2H), 5.42 (s, 2H), 4.25 (d, J=7.5 Hz, 2H), 3.98 (t, J=6.7 Hz, 2H), 2.93-2.88 (m, 2H), 2.40 (septet, J=6.9 Hz, 1H), 1.94-1.79 (m, 4H), 1.51 (sextet, J=7.4 Hz, 2H), 1.06 (t, J=7.5 Hz, 3H), 1.02 (d, J=7.2 Hz, 6H), 1.01 (t, J=7.5 Hz, 3H);

[0458]

13
C NMR (75 MHz, CDCl3) δ 159.0, 154.0, 151.6, 145.5, 139.3, 133.6, 133.3, 128.3, 127.1, 124.8, 121.2, 120.3, 115.1, 114.5, 69.8, 52.8, 30.4, 29.4, 27.7, 22.87, 22.84, 20.0, 14.1, 10.8;

[0459] MS m/z (M+1+) calcd 431.2811, obsd 431.2821;

[0460] Anal. Calcd for C27H34N4O: C, 75.31; H, 7.96; N, 13.01. Found: C, 75.20; H, 8.18; N, 12.96.

Example 6

2-Butyl-1-isobutyl-7-(2-propoxyphenyl)-1H-imidazo[4,5-c]quinolin-4-amine

[0461]

[0462] 7-Bromo-2-butyl-1-isobutyl-1 H-imidazo[4,5-c]quinolin-4-amine and 2-propoxybenzeneboronic acid were coupled according to the general procedure described in Part J of Example 1. The product was recrystallized from isopropanol, collected by filtration, dissolved in CH2Cl2, and then precipitated with hexanes to afford 2-butyl-1-isobutyl-7-(2-propoxyphenyl)-1H-imidazo[4,5-c]quinolin-4-amine as a white powder, m.p. 174.5-176.0° C.

[0463]

1
H NMR (300 MHz, CDCl3) δ 7.98 (d, J=1.9 Hz, 1H), 7.89 (d, J=8.7 Hz, 1H), 7.61 (dd, J=8.7, 1.9 Hz, 1H), 7.47 (dd, J=7.5, 1.9 Hz, 1H), 7.34-7.29 (m, 1H), 7.07-7.00 (m, 2H), 5.46 (s, 2H), 4.27 (d, J=7.5 Hz, 2H), 3.96 (t, J=6.6 Hz, 2H), 2.94-2.88 (m, 2H), 2.41 (septet, J=6.8 Hz, 1H), 1.94-1.84 (m, 2H), 1.76 (sextet, J=7.1 Hz, 2H), 1.51 (sextet, J=7.4 Hz, 2H), 1.03-0.93 (m, 12H);

[0464]

13
C NMR (75 MHz, CDCl3) δ 156.4, 153.9, 151.4, 145.1, 137.6,133.6, 131.3, 131.0, 128.8, 127.9, 127.2, 124.5, 121.1, 118.9, 114.5, 113.0, 70.4, 52.8, 30.4, 29.4, 27.8, 22.9, 22.8, 20.0, 14.1, 10.9;

[0465] MS m/z (M+1+) calcd 431.2811, obsd 431.2809;

[0466] Anal. Calcd for C27H34N4O.0.16H2O: C, 74.82; H, 7.98; N, 12.93. Found: C, 74.64; H, 7.99; N, 12.78. Water content determined by Karl-Fischer titration.

Example 7

2-Butyl-1-isobutyl-7-[(E)-2-phenylethenyl]-1H-imidazo[4,5-c]quinolin-4-amine

[0467]

[0468] 7-Bromo-2-butyl-1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine and trans-2-phenylvinylboronic acid were coupled according to the general procedure described in Part J of Example 1. Recrystallization from toluene followed by chromatography on silica gel (8% methanol in CH2Cl2) afforded 2-butyl-1-isobutyl-7-[(E)-2-phenylethenyl]-1H-imidazo[4,5-c]quinolin-4-amine, m.p. 215-216° C.

[0469]

1
H NMR (300 MHz, CDCl3) δ 7.92 (d, J=1.6 Hz, 1H), 7.87 (d, J =8.7 Hz, 1H), 7.57-7.52 (m, 3H), 7.40-7.35 (m, 2H), 7.30-7.24 (m, 3H), 5.44 (s, 2H), 4.24 (d, J=7.5 Hz, 2H), 2.93-2.87 (m, 2H), 2.37 (septet, J=6.9 Hz, 1H), 1.94-1.83 (m, 2H), 1.51 (sextet, J=7.4 Hz, 2H), 1.02 (d, J=7.2 Hz, 6H), 1.00 (t, J=7.5 Hz, 3H);

[0470]

1
H NMR (500 MHz, CDCl3) δ 7.24 (center of AB pattern, J=16.4 Hz);

[0471]

13
C NMR (100 MHz, CDCl3) δ 154.2, 151.6, 145.1, 137.6, 136.0, 133.6, 129.2, 128.9, 128.8, 127.9, 127.1, 126.8, 125.6, 120.5, 120.2, 115.1, 52.8, 30.4, 29.4, 27.7, 22.9, 20.0, 14.1;

[0472] MS m/z (M+1+) calcd 399.3, obsd 399.2;

[0473] Anal. Calcd for C26H30N4: C, 78.36; H, 7.59; N, 14.06. Found: C, 78.05; H, 7.61; N, 14.01.

Example 8

2-Butyl-1-isobutyl-7-phenethyl-1H-imidazo[4,5-c]quinolin-4-amine

[0474]

[0475] 2-Butyl-1-isobutyl-7-[(E)-2-phenylethenyl]-1H-imidazo[4,5-c]quinolin-4-amine (562 mg, 1.41 mmol) was hydrogenated in a Parr bottle over palladium on carbon (10%) until the starting material was consumed as judged by high performance liquid chromatography (HPLC) and thin layer chromatography (TLC) analyses. Purification on silica (5% to 10% methanol in CH2Cl2 gradient) followed by recrystallization from boiling CH3CN afforded 150 mg of 2-butyl-1-isobutyl-7-phenethyl-1H-imidazo[4,5-c]quinolin-4-amine, m.p. 181-182° C.

[0476]

1
H NMR (300 MHz, CDCl3) δ 7.80 (d, J=8.4 Hz, 1H), 7.70 (d, J=1.6 Hz, 1H), 7.32-7.14 (m, 6H), 5.44 (s, 2H), 4.23 (d, J =7.5 Hz, 2H), 3.11-3.00 (m, 4H), 2.92-2.87 (m, 2H), 2.43-2.30 (m, 1H), 1.93-1.83 (m, 2H), 1.50 (sextet, J=7.4Hz, 2H), 1.00 (d, J =6.6 Hz, 6H), 1.00 (t, J=7.3 Hz, 3H);

[0477]

13
C NMR (75 MHz, CDCl3) δ 153.9, 151.4, 145.1, 142.1, 140.8, 133.7, 128.7, 128.6, 126.8, 126.5, 126.1, 123.4, 119.8, 114.0, 52.8, 38.1, 38.0,30.4, 29.4,27.7, 22.9, 20.0, 14.1;

[0478] MS m/z (M+1+) calcd 401.2705, obsd 401.2705;

[0479] Anal. Calcd for C26H32N4: C, 77.96; H, 8.05; N, 13.99. Found: C, 77.95; H, 8.02; N, 14.04.

Example 9

2-Ethoxymethyl-1-isobutyl-7-(thiophen-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine

[0480]

[0481] Part A

[0482] A solution of 7-bromo—N4-isobutylquinoline-3,4-diamine (85 g, prepared according to Part F of Example 1) in anhydrous pyridine (413 mL) was immersed in an ice bath, and ethoxyacetyl chloride (36.9 g, 300 mmol) was added. The reaction was allowed to warm to room temperature and was then heated in an oil bath held at 85° C. for 3.5 h. The reaction mixture was concentrated under vacuum, and the residue was taken up in diethyl ether and washed with 2M Na2CO3 (2×) followed by H2O (1×). The organic layer was dried (MgSO4), filtered, and concentrated. Recrystallization of the resulting solid from boiling 15% ethyl acetate in hexanes afforded 43.0 g of 7-bromo-2-ethoxymethyl-1-isobutyl-1H-imidazo[4,5-c]quinoline as brown crystals.

[0483]

1
H NMR (300 MHz, CDCl3) δ 9.28 (s, 1H), 8.45 (d, J=1.9 Hz, 1H), 7.99 (d, J=9.1 Hz, 1H), 7.74 (dd, J=8.7, 2.2 Hz, 1H), 4.88 (s, 2H), 4.49 (d, J=7.5 Hz, 2H), 3.61 (q, J=7.1 Hz, 2H), 2.45-2.31 (m, 1H), 1.24 (t, J=7.0 Hz, 3H), 1.01 (d, J=6.6 Hz, 6H);

[0484] MS m/z (M+1+) calcd 364.1, obsd 364.1.

[0485] Part B

[0486] 7-Bromo-2-ethoxymethyl-1-isobutyl-1H-imidazo[4,5-c]quinoline was oxidized and then aminated according to the general procedures described in Parts H and I of Example 1. Purification by recrystallization from isopropanol afforded 7-bromo-2-ethoxymethyl-1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine as yellow needles.

[0487]

1
H NMR (300 MHz, CDCl3) δ 7.96 (d, J =2.2 Hz, 1H), 7.73 (d, J=8.7 Hz, 1H), 7.39 (dd, J=8.7, 2.2 Hz, 1H), 5.80 (s, 2H), 4.80 (s, 2H), 4.38 (d, J=7.5 Hz, 2H), 3.60 (q, J=7.1 Hz, 2H), 2.42-2.28 (m, 1H), 1.24 (t, J=6.9 Hz, 3H), 0.99 (d, J=6.6 Hz, 6H);

[0488]

13
C NMR (75 MHz, CDCl3) δ 152.4, 149.9, 146.5, 134.1, 129.8, 127.1, 125.3, 121.5, 121.1, 114.5, 66.5, 65.5, 53.1, 29.2, 20.0, 15.2;

[0489] Anal. Calcd for C17H21BrN4O: C, 54.12; H, 5.61; N, 14.85. Found: C, 54.16; H, 5.61; N, 14.67.

[0490] Part C

[0491] 7-Bromo-2-ethoxymethyl-1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine and thiophene-3-boronic acid were coupled according to the general procedure described in Part J of Example 1. Recrystallization from isopropanol followed by purification on silica gel (5% methanol in CH2Cl2 to 7% methanol in CH2Cl2 gradient) afforded 2-ethoxymethyl-1-isobutyl-7-(thiophen-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine as a pale yellow solid, m.p. 187-189° C.

[0492]

1
H NMR (300 MHz, CDCl3) δ 8.08 (d, J=1.9 Hz, 1H), 7.94 (d, J=8.4 Hz, 1H), 7.63-7.60 (m, 2H), 7.55 (dd, J=5.2,1.4 Hz, 1H), 7.43 (dd, J=5.2, 3.0 Hz, 1H), 5.44 (s, 2H), 4.83 (s, 2H), 4.45 (d, J =7.5 Hz, 2H), 3.61 (q, J=7.1 Hz, 2H), 2.44 (septet, J=6.8 Hz, 1H), 1.25 (t, J =7.0 Hz, 3H), 1.04 (d, J =6.9 Hz, 6H);

[0493]

13
C NMR (125 MHz, CDCl3) δ 152.0,149.7, 145.8, 142.2, 134.9, 134.5, 127.1, 126.5, 124.6, 121.1, 120.84, 120.82, 114.8, 66.5, 65.6, 53.1, 29.3, 20.1, 15.3;

[0494] MS m/z (M+1+) calcd 381.1749, obsd 381.1763;

[0495] Anal. Calcd for C21H24N4OS: C, 66.29; H, 6.36; N, 14.72. Found: C, 66.54; H, 6.37; N, 14.73.

Example 10

2-Butyl-1-(3-methanesulfonylpropyl)-7-phenyl-1H-imidazo[4,5-c]quinolin-4-amine

[0496]

[0497] Part A

[0498] A solution of 3-bromoaniline (344 g, 2.00 mol) and phenyl boronic acid (268 g, 2.2 mol) in n-propanol (3.5 L) was sparged with N2 for 10 min. To this solution was added Pd(OAc)2 (1.35 g, 6.0 mmol), triphenylphosphine (4.72 g, 18.0 mmol), Na2CO3 (1.2 L of a 2 M solution, 2.4 mol), and H2O (700 mL). The reaction was brought to reflux under a N2 atmosphere over a period of 45 min and then cooled to RT and transferred to a separatory funnel. The clear aqueous layer was drawn off (1.1 L), and the organic layer was washed with brine (3×500 mL). The organic layer was treated with charcoal (90 g of Darco G-60) and MgSO4 (160 g) and was filtered through CELITE filter agent, washing with ethyl acetate. The filtrate was concentrated (420 g of an orange oil), dissolved in 1.1 L of 1/1 hexane/isopropanol, filtered to remove insoluble solid and then diluted with an additional 1.9 L of 1/1 hexane/isopropanol. The resulting solution was cooled in an ice bath and then anhydrous HCl in ether (1.05 L of a 2 M solution, 2.1 mol) was added. The solid was collected by filtration, washed with 700 mL diethyl ether (Et2O), and dried at RT in a vacuum oven to obtain 345 g of the HCl salt of biphenyl-3-ylamine as yellow crystals. The free base was obtained by shaking the solid with tert-butyl methyl ether and 1 N NaOH followed by isolation in the usual fashion.

[0499]

1
H NMR (300 MHz, CDCl3): consistent with literature data (C. N. Carrigan et al., J. Med. Chem., 45, 2260-2276 (2002)).

[0500] Part B

[0501] Triethyl orthoformate (148 g, 1.00 mol), Meldrum's acid (137 g, 0.95 mol), and biphenyl-3-ylamine (155 g, 0.916 mol) were combined and treated according to the general procedure described in Part A of Example 1 to obtain 283 g of 5-(biphenyl-3-ylaminomethylene)-2,2-dimethyl-[1,3]dioxane-4,6-dione as a yellow solid.

[0502]

1
H NMR (300 MHz, CDCl3) δ 11.33 (brd, J=14.0 Hz, 1H), 8.72 (d, J=15.0 Hz, 1H), 7.60-7.56 (m, 2H), 7.51-7.37 (m, 6H), 7.25-7.21 (m, 1H), 1.77 (s, 6H).

[0503] Part C

[0504] 5-(Biphenyl-3-ylaminomethylene)-2,2-dimethyl-[1,3]dioxane-4,6-dione (160.2 g, 496 mmol) was dissolved in 800 mL of DOWTHERM A heat transfer fluid at 100° C. and added over 40 min by way of a cannula line to 1.3 L of preheated DOWTHERM A heat transfer fluid to 215° C. After complete addition, the reaction was held at 215° C. for 90 min and then cooled to RT. The resulting solid was collected by filtration, sequentially washed with diethyl ether (1.7 L) and acetone (500 mL), and then dried in a vacuum oven at 70° C. overnight. The resulting product (74.5 g) contained approximately 5% of the undesired isomer. This product was combined with material from a separate run (51.4 g) and slurried in 440 mL of refluxing ethanol. Filtration of the slurry while hot followed by sequential ethanol and diethyl ether rinses afforded 106.1 g of 7-phenylquinolin-4-ol as a tan solid.

[0505]

1
H NMR (300 MHz, d6-DMSO) δ 11.77 (brs, 1H), 8.16 (d, J=8.4 Hz, 1H), 7.95-7.91 (m, 1H), 7.75-7.70 (m, 3H), 7.61 (dd, J=8.4, 1.6 Hz, 1H), 7.56-7.50 (m, 2H), 7.47-7.42 (m, 1H), 6.05 (d, J=7.5 Hz, 1H).

[0506] Part D

[0507] A stirred suspension of 7-phenylquinolin-4-ol (84.9 g, 384 mmol) in propionic acid (850 mL) was heated to 129° C. Nitric acid (70%, 45.0 g) was added dropwise over 25 min, during which the temperature dropped to 124° C. The reaction was stirred an additional 3 h at that temperature and then cooled to 5° C. on an ice bath. The resulting solid was collected by filtration, washed with ice cold ethanol (until washings were nearly colorless) and dried at 70° C. in a vacuum oven overnight to obtain 83.2 g of 3-nitro-7-phenylquinolin-4-ol as a beige powder.

[0508]

1
H NMR (300 MHz, d6-DMSO) δ 13.00 (brs, 1H), 9.23 (s, 1H), 8.33 (d, J =8.4 Hz, 1H), 7.94 (d, J =1.3 Hz, 1H), 7.83 (dd, J =8.4, 1.9 Hz, 1H), 7.77-7.74 (m, 2H), 7.59-7.53 (m, 2H), 7.51-7.45 (m, 1H);

[0509] MS m/z (M+1+) calcd 267.1, obsd 267.1.

[0510] Part E

[0511] A solution of phosphorous oxychloride (3.1 g, 20 mmol) in anhydrous N,N-dimethylformamide (DMF, 14 mL) was added to a suspension of 3-nitro-7-phenylquinolin-4-ol (5.0 g, 18.8 mmol) in 80 mL of DMF over 3 min. The reaction was allowed to stir for 1.5 h and then poured into 250 mL crushed ice. The resulting precipitate was collected by filtration, washed with H2O, and dried under vacuum for 2 h. The crude 4-chloro-3-nitro-7-phenylquinoline thus obtained was used without further purification.

[0512] Part F

[0513] 4—Chloro-3-nitro-7-phenylquinoline (5.3 g, 18.8 mmol) and 3-methylsulfanyl-propylamine (2.17 g, 20.6 mmol) were combined and treated according to the general procedure described in Part E of Example 1. Recrystallization from isopropanol afforded 6.2 g of (3-methylsulfanylpropyl)- (3-nitro-7-phenylquinolin-4-yl)amine as gold plates.

[0514] Part G

[0515] (3-Methylsulfanylpropyl)-(3-nitro-7-phenylquinolin-4-yl)amine (3.0 g, 8.5 mmol) was hydrogenated in a Parr bottle over Pt/C (0.3 g of 5%) in 42 mL of toluene for 1 h. The reaction mixture was filtered through CELITE filter agent, washed with methanol (100 mL) and CHCl3 (50 mL), and then concentrated to afford 2.75 g of N4-(3-methylsulfanylpropyl)-7-phenylquinoline-3,4-diamine as a brown oil.

[0516] Part H

[0517] N4-(3-Methylsulfanylpropyl)-7-phenylquinoline-3,4-diamine (2.75 g, 8.49 mmol), trimethyl orthovalerate (1.7 g, 10 mmol), and pyridine hydrochloride (0.3 g) were dissolved in toluene (28 mL) and heated to reflux for 1.5 h, collecting the volatiles in a Dean—Stark trap. Upon cooling to room temperature, the solvent was removed under vacuum. The resulting solid was slurried in hexanes (100 mL) for 1 h and then collected by filtration to afford 3.0 g of 2-butyl-1-(3-methylsulfanylpropyl)-7-phenyl-1H-imidazo[4,5-c]quinoline.

[0518] Part I

[0519] To a solution of 2-butyl-1-(3-methylsulfanylpropyl)-7-phenyl-1H-imidazo[4,5-c]quinoline (3.0 g, 7.70 mmol) in CHCl3 (39 mL) was added 3-chloroperoxybenzoic acid (6.74 g of approximately 77% purity) over 20 min. Aqueous NH4OH (39 mL, 30%) was added, and to the resulting rapidly stirred biphasic suspension was addedp-toluenesulfonyl chloride (1.8 g, 9.44 mmol) in one portion. After monitoring by thin layer chromatography indicated that no starting material remained, the reaction mixture was sequentially washed with 1% Na2CO3 (2×50 mL) and brine (50 mL); then dried (Na2SO4); filtered; and concentrated to a brown solid. Purification on silica (5% methanol in CH2Cl2) followed by recrystallization from CH3CN afforded 0.50 g of 2-butyl-1-(3-methanesulfonylpropyl)-7-phenyl-1H-imidazo[4,5-c]quinolin-4-amine as colorless needles, m.p. 214-216° C.

[0520]

1
H NMR (300 MHz, d6-DMSO) δ 8.21 (d, J=8.7 Hz, 1H), 7.87 (d, J=1.9 Hz, 1H), 7.78-7.75 (m, 2H), 7.57-7.48 (m, 3H), 7.41-7.36 (m, 1H), 6.52 (s, 2H), 4.69 (t, J=7.5 Hz, 2H), 3.41 (t, J=7.6 Hz, 2H), 3.02 (s, 3H), 2.95 (t, J=7.8 Hz, 2H), 2.30-2.20 (m, 2H), 1.82 (pentet, J=7.6 Hz, 2H), 1.47 (sextet, J=7.5 Hz, 2H), 0.97 (t, J=7.3 Hz, 3H);

[0521] MS m/z (M+1+) calcd 437.2, obsd 437.3;

[0522] Anal. Calcd for C24H28N4O2S: C, 66.03; H, 6.46; N, 12.86. Found: C, 66.09; H, 6.43; N, 12.57.

Example 11

8-(4-tert-Butylphenyl)-1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine

[0523]

[0524] Part A

[0525] To a solution of 1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine (10.0 g, 41.6 mmol) in acetic acid (150 mL) was added Br2 (10.0 g, 62.6 mmol), and after 24 h, the resulting solid was collected by filtration and washed with H2O. The orange solid was suspended in a saturated aqueous solution of NaHSO3, after which it was again collected and stirred with a 2 M solution of Na2CO3 for 18 h. The solid was collected by filtration, washed with H2O, and azeotropically dried with toluene on a rotary evaporator. Purification on silica gel (7%-10% methanol in CH2Cl2 gradient) afforded 3.4 g of 8-bromo-1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine.

[0526]

1
H NMR (400 MHz, CDCl3) 6 8.00 (d, J=2.2 Hz, 1H), 7.79 (s, 1H), 7.69 (d, J=9.0 Hz, 1H), 7.59 (dd, J=8.8, 2.2 Hz, 1H), 5.60 (s, 2H), 4.26 (d, J=7.4 Hz, 2H), 2.37-2.27 (m, 1H), 1.05 (d, J=6.6 Hz, 6H).

[0527] Part B

[0528] 8-Bromo-1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine and 4-tert-butylbenzeneboronic acid were coupled according to the general procedure described in Part J of Example 1. Recrystallization from isopropanol followed by chromatography on silica gel (7% methanol in CH2Cl2) afforded 8-(4-tert-butylphenyl)-1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine as a white solid, m.p. >250° C.

[0529]

1
H NMR (400 MHz, d6-DMSO) δ 8.21 (s, 1H), 8.16 (d, J=2.0 Hz, 1H), 7.75 (dd, J=8.8, 2.1 Hz, 1H), 7.70-7.67 (m, 3H), 7.52 (dt, J=8.6, 2.1 Hz, 2H), 6.68 (s, 2H), 4.49 (d, J=7.2 Hz, 2H), 2.28 (septet, J=6.8 Hz, 1H), 1.33 (s, 9H), 0.97 (d, J=6.6 Hz, 6H);

[0530]

13
C NMR (125 MHz, d6-DMSO) δ 152.2,149.4, 144.3, 143.4, 137.6, 132.7, 131.7, 128.5, 126.7, 126.2, 125.8, 125.5, 118.0, 115.1, 53.5,34.2,31.1, 28.5, 19.4;

[0531] Anal. Calcd for C24H28N4: C, 77.38; H, 7.58; N, 15.04. Found: C, 77.17; H, 7.57; N, 14.99.

Example 12

1-Isobutyl-8-(thiophen-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine

[0532]

[0533] 8-Bromo-1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine and thiophene-3-boronic acid were coupled according to the general procedure described in Part J of Example 1. Recrystallization from isopropanol followed by chromatography on silica gel (7% methanol in CH2Cl2) afforded 1-isobutyl-8-(thiophen-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine as a white solid, m.p. 235-236° C.

[0534]

1
H NMR (400 MHz, d6-DMSO) δ 8.20 (s, 1H), 8.19 (d, J=2.0 Hz, 1H), 7.88 (dd, J=3.0, 1.4 Hz, 1H), 7.81 (dd, J=8.7, 2.0 Hz, 1H), 7.70 (dd, J=5.1, 3.0 Hz, 1H), 7.64-7.62 (m, 2H), 6.66 (s, 2H), 4.51 (d, J=7.4 Hz, 2H), 2.23 (septet, J=6.9 Hz, 1H), 0.96 (d, J=6.6 Hz, 6H);

[0535]

13
C NMR (125 MHz, d6-DMSO) δ 152.1, 144.2, 143.4, 141.8, 131.7, 128.5, 128.1, 127.2, 126.6, 126.1, 125.3, 119.9, 117.5, 115.0, 53.5, 28.4, 19.4;

[0536] Anal. Calcd for C18H18N4S: C, 67.05; H, 5.63; N, 17.38. Found: C, 66.74; H, 5.46; N, 17.32.

Example 13

8-(2,4-Dimethoxyphenyl)-1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine

[0537]

[0538] 8-Bromo-1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine and 2,4-dimethoxybenzeneboronic acid were coupled according to the general procedure described in Part J of Example 1. Purification by chromatography on silica gel (7% methanol in CH2Cl2) afforded 8-(2,4-dimethoxyphenyl)-1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine as a white solid, m.p. 223-227° C.

[0539]

1
H NMR (400 MHz, d6-DMSO) δ 8.18 (s, 1H), 8.08 (d, J=2.0 Hz, 1H), 7.62 (d, J=8.6 Hz, 1H), 7.52 (dd, J=8.6, 2.0 Hz, 1H), 7.34 (d, J=8.4 Hz, 1H), 6.71 (d, J=2.4 Hz, 1H), 6.66 (dd, J=8.3, 2.4 Hz, 1H), 6.61 (s, 2H), 4.36 (d, J=7.5 Hz, 2H), 3.82 (s, 3H), 3.80 (s, 3H), 2.34-2.24 (m, 1H), 0.93 (d, J=6.6 Hz, 6H);

[0540]

13
C NMR (100 MHz, d6-DMSO) δ 159.8, 157.1, 152.0, 143.6, 143.2, 131.7, 130.9, 130.5, 128.3, 128.1, 125.7, 122.5, 120.8, 114.4, 105.4, 99.0, 55.6, 55.3, 55.4, 28.2, 19.3;

[0541] Anal. Calcd for C22H24N4O2: C, 70.19; H, 6.43; N, 14.88. Found: C, 69.92; H, 6.41; N, 14.67.

Example 14

1-Isobutyl-8-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine

[0542]

[0543] 8-Bromo-1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine and pyridine-3-boronic acid were coupled according to the general procedure described in Part J of Example 1. Purification by chromatography on silica gel (7%-10% methanol in CH2Cl2 gradient) afforded 1-isobutyl-8-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine as a white solid, m.p. 244-246° C.

[0544]

1
H NMR (400 MHz, d6-DMSO) δ 9.01 (dd, J=2.3,0.8 Hz, 1H), 8.57 (dd, J=4.7, 1.6 Hz, 1H), 8.22 (s, 1H), 8.22 (d, J=2.0 Hz, 1H), 8.18 (ddd, J=8.0, 2.5, 1.6 Hz, 1H), 7.82 (dd, J=8.7, 2.1 Hz, 1H), 7.72 (d, J=8.6 Hz, 1H), 7.52 (ddd, J=8.0, 4.7, 0.8 Hz, 1H), 6.76 (s, 2H), 4.52 (d, J=7.2 Hz, 2H), 2.29-2.22 (m, 1H), 0.95 (d, J=6.6 Hz, 6H);

[0545]

13
C NMR (125 MHz, d6-DMSO) δ 152.5, 147.9, 147.6, 144.8, 143.5, 135.9, 133.8, 131.7, 129.5, 128.5, 126.9, 125.5, 123.9, 118.7, 115.2, 53.4, 28.4, 19.4;

[0546] Anal. Calcd for C19H19N5: C, 71.90; H, 6.03; N, 22.07. Found: C, 71.73; H, 5.91; N, 21.86.

Example 15

1-Isobutyl-8-phenyl-1H-imidazo[4,5-c]quinolin-4-amine

[0547]

[0548] 8-Bromo-1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine and benzeneboronic acid were coupled according to the general procedure described in Part J of Example 1. Recrystallization from isopropanol followed by recrystallization from methanol afforded 1-isobutyl-8-phenyl-1H-imidazo[4,5-c]quinolin-4-amine as a beige solid, m.p. 203-204° C.

[0549]

1
H NMR (400 MHz, d6-DMSO) δ 8.21 (s, 1H), 8.17 (d, J=2.0 Hz, 1H), 7.78-7.76 (m, 3H), 7.69 (d, J=8.6 Hz, 1H), 7.52-7.48 (m, 2H), 7.36 (tt, J=7.4, 1.2 Hz, 1H), 6.71 (s, 2H), 4.49 (d, J=7.4 Hz, 2H), 2.32-2.21 (m, 1H), 0.96 (d, J=6.6 Hz, 6H);

[0550]

13
C NMR (100 MHz, d6-DMSO) δ 152.3, 144.4, 143.4, 140.5, 132.8, 131.8, 129.0, 128.5, 126.9, 126.7, 126.5, 125.6, 118.4, 115.1, 53.6, 28.5, 19.4;

[0551] Anal. Calcd for C20H20N4: C, 75.92; H, 6.37; N, 17.71. Found: C, 75.80; H, 6.26; N, 17.68.

Example 16

2-Ethyl-1-isobutyl-8-phenyl-1H-imidazo[4,5-c]quinolin-4-amine

[0552]

[0553] Part A

[0554] To a solution of 2-ethyl-1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine (805 mg, 3.00 mmol) in acetic acid (10 mL) was added Br2 (719 mg, 4.50 mmol), and after 20 h, the resulting solid was collected by filtration and washed with H2O. The orange solid was suspended in NaHSO3 (25 mL of a saturated solution) and stirred for 23 h, after which it was again collected and stirred with NaHCO3 (20 mL of a saturated solution) and CH2Cl2. The organic layer was drawn off, washed with H2O, dried (Na2SO4), filtered, and concentrated to afford 858 mg of a yellow solid. Purification on silica gel (5%-7% MeOH in CH2Cl2 gradient) afforded 450 mg of 8-bromo-2-ethyl-1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine as a yellow solid. Additional purification on silica as before followed by recrystallization from boiling isopropanol (10 mL) afforded 316 mg of white needles, m.p. 222-223° C.

[0555]

1
H NMR (400 MHz, d6-DMSO) δ 8.02 (s, 1H), 7.52 (s, 2H), 6.65 (s, 2H), 4.33 (d, J=7.0 Hz, 2H), 2.94 (q, J=7.5 Hz, 2H), 2.18-2.07 (m, 1H), 1.37 (t, J=7.5 Hz, 3H), 0.94 (d, J=6.8 Hz, 6H);

[0556]

13
C NMR (100 MHz, d6-DMSO) δ 155.1, 152.1, 143.6, 131.4, 128.9, 128.3, 127.0, 122.3, 116.2, 112.8, 51.3, 28.9, 20.2, 19.2, 12.1;

[0557] Anal. Calcd for C16H19BrN4: C, 55.34; H, 5.52; N, 16.13. Found: C, 55.26; H, 5.36; N, 16.14.

[0558] Part B

[0559] 8-Bromo-2-ethyl-1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine and benzeneboronic acid were coupled according to the general procedure described in Part J of Example 1. Chromatography on silica gel (5%-7% methanol in CH2Cl2 gradient) afforded 2-ethyl-1-isobutyl-8-phenyl-1H-imidazo[4,5-c]quinolin-4-amine as a white solid, m.p. 233-235° C.

[0560]

1
H NMR (400 MHz, d6-DMSO) δ 8.15 (d, J=1.8 Hz, 1H), 7.77-7.72 (m, 3H), 7.68 (d, J=8.6 Hz, 1H), 7.52-7.48 (m, 2H), 7.36 (tt, J=7.4, 1.1 Hz, 1H), 6.57 (s, 2H), 4.42 (d, J=6.6 Hz, 2H), 2.96 (q, J=7.5 Hz, 2H), 2.35-2.24 (m, 1H), 1.39 (t, J=7.5 Hz, 3H), 0.98 (d, J=6.6 Hz, 6H);

[0561]

13
C NMR (100 MHz, d6-DMSO) δ 154.6, 151.9, 144.2, 140.7, 132.7, 132.5, 129.0, 126.9, 126.8, 126.6, 125.1, 118.2, 115.1, 51.5, 28.9, 20.2, 19.3, 12.1;

[0562] Anal. Calcd for C22H24N4: C, 76.71; H, 7.02; N, 16.27. Found: C, 76.52; H, 6.89; N, 16.30.

Example 17

2-Ethyl-1-isobutyl-8-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine

[0563]

[0564] 8-Bromo-2-ethyl-1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine and pyridine-3-boronic acid were coupled according to the general procedure described in Part J of Example 1. Chromatography on silica gel (5%-7% methanol in CH2Cl2 gradient) followed by recrystallization from isopropanol afforded 2-ethyl-1-isobutyl-8-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine as white crystals, m.p. >250° C.

[0565]

1
H NMR (400 MHz, d6-DMSO) δ 9.00 (d, J=2.4 Hz, 1H), 8.57 (dd, J=4.8, 1.5 Hz, 1H), 8.19 (d, J=2.0 Hz, 1H), 8.16 (dt, J=7.9, 1.7 Hz, 1H), 7.78 (dd, J=8.6, 2.0 Hz, 1H), 7.71 (d, J=8.6 Hz, 1H), 7.53 (dd, J=7.9, 4.8 Hz, 1H), 6.63 (s, 2H), 4.45 (d, J=6.8 Hz, 2H), 2.96 (q, J=7.5 Hz, 2H), 2.33-2.23 (m, 1H), 1.39 (t, J=7.5 Hz, 3H), 0.96 (d, J=6.4 Hz, 6H);

[0566]

13
C NMR (100 MHz, d6-DMSO) δ 154.7, 152.2, 147.9, 147.6, 144.7, 136.1, 133.9, 132.4, 129.4, 127.0, 126.9, 125.1, 124.0, 118.6, 115.2, 51.4, 28.9, 20.3, 19.3, 12.1;

[0567] Anal. Calcd for C21H23N5: C, 73.02; H, 6.71; N, 20.27. Found: C, 73.24; H, 6.77; N, 20.65.

Example 18

1-Butyl-2-ethoxymethyl-8-phenyl-1H-imidazo[4,5-c]quinolin-4-amine

[0568]

[0569] Part A

[0570] 1-Butyl-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-4-amine was brominated according to the general procedure described in Part A of Example 11. Purification on silica gel (6%-10% methanol in CH2Cl2) followed by recrystallization from isopropanol afforded 8-bromo-1-butyl-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-4-amine as yellow needles, m.p. 182-183° C.

[0571]

1
H NMR (300 MHz, CDCl3) δ 8.07 (d, J=2.2 Hz, 1H), 7.68 (d, J=8.7 Hz, 1H), 7.58 (dd, J=8.7, 2.2 Hz, 1H), 5.44 (s, 2H), 4.80 (s, 2H), 4.56-4.51 (m, 2H), 3.61 (q, J=7.0 Hz, 2H), 2.02-1.93 (m, 2H), 1.57 (sextet, J=7.4 Hz, 2H), 1.25 (t, J=6.9 Hz, 3H), 1.07 (t, J=7.3 Hz, 3H);

[0572]

13
C NMR (75 MHz, CDCl3) δ 151.8, 149.7, 144.0, 133.3, 130.6, 129.1, 127.3, 122.7, 117.0, 115.5, 66.6, 65.4, 46.2, 32.3, 20.3, 15.3, 13.9;

[0573] MS m/z (M+1+) calcd 379.1, obsd 379.0;

[0574] Anal. Calcd for C17H21BrN4O: C, 54.12; H, 5.61; N, 14.85. Found: C, 54.01; H, 5.50; N, 14.83.

[0575] Part B

[0576] 8-Bromo-1-butyl-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-4-amine and benzeneboronic acid were coupled according to the general procedure described in Part J of Example 1. Chromatography on silica gel (10% methanol in CH2Cl2) followed by recrystallization from isopropanol afforded 1-butyl-2-ethoxymethyl-8-phenyl-1H-imidazo[4,5-c]quinolin-4-amine as an off-white solid, m.p. 186-187° C.

[0577]

1
H NMR (300 MHz, CDCl3) δ 8.17 (d, J=1.9 Hz, 1H), 7.89 (d, J=8.7 Hz, 1H), 7.79 (dd, J=8.7, 1.9 Hz, 1H), 7.69-7.66 (m, 2H), 7.52-7.47 (m, 2H), 7.37 (tt, J=7.3, 1.3 Hz, 1H), 5.46 (s, 2H), 4.82 (s, 2H), 4.64-4.58 (m, 2H), 3.62 (q, J=7.0 Hz, 2H), 2.11-2.01 (m, 2H), 1.58 (sextet, J=7.5 Hz, 2H), 1.26 (t, J=7.0 Hz, 3H), 1.05 (t, J=7.3 Hz, 3H);

[0578]

13
C NMR (75 MHz, CDCl3) δ 151.7, 149.2, 144.7, 141.5, 135.4, 134.5, 129.1, 127.8, 127.3, 127.2, 126.9, 118.5, 115.9, 66.5, 65.4, 46.4, 32.5, 20.4, 15.3, 13.9;

[0579] MS m/z (M+1+) calcd 375.2, obsd 375.2;

[0580] Anal. Calcd for C23H26N4O: C, 73.77; H, 7.00; N, 14.96. Found: C, 73.76; H, 7.15; N, 14.95.

Example 19

1-Butyl-2-ethoxymethyl-8-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine

[0581]

[0582] 8-Bromo-1-butyl-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-4-amine and pyridine-3-boronic acid were coupled according to the general procedure described in Part J of Example 1. Chromatography on silica gel (8%-10% methanol in CH2Cl2 gradient) followed by recrystallization from isopropanol (3×) and chromatography as above afforded 1-butyl-2-ethoxymethyl-8-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine as a white solid, m.p. 220-222° C.

[0583]

1
H NMR (300 MHz, CDCl3) δ 8.95 (dd, J=2.3, 0.8 Hz, 1H), 8.63 (dd, J=4.7, 1.6 Hz, 1H), 8.17 (d, J=2.2 Hz, 1H), 7.96 (ddd, J=7.8, 2.5, 1.6 Hz, 1H), 7.92 (d, J=8.7 Hz, 1H), 7.76 (dd, J=8.7, 1.9 Hz, 1H), 7.42 (ddd, J=8.0, 4.8, 0.8 Hz, 1H), 5.47 (s, 2H), 4.83 (s, 2H), 4.65-4.60 (m, 2H), 3.63 (q, J=7.0 Hz, 2H), 2.10-1.99 (m, 2H), 1.57 (sextet, J=7.5 Hz, 2H), 1.26 (t, J=7.0 Hz, 3H), 1.04 (t, J=7.3 Hz, 3H);

[0584]

13
C NMR (125 MHz, CDCl3) δ 152.0, 149.5, 148.49, 148.51, 145.2, 137.0, 134.4, 134.3, 131.8, 128.3, 127.4, 126.6, 123.9, 118.7, 116.2, 66.6, 65.4, 46.5, 32.5, 20.4, 15.3, 14.0;

[0585] MS m/z (M+1+) calcd 376.2, obsd 376.2;

[0586] Anal. Calcd for C22H25N5O: C, 70.37; H, 6.71; N, 18.66. Found: C, 70.00; H, 6.49; N, 18.64.

Examples 20-65

[0587] The compounds in the table below were prepared according to the following method. 8-Bromo-1-isobutyl-1H-imidazo[4,5-c]quinoline-4-amine (25 mg) was dissolved in 1:1 volume:volume (v:v) dichloromethane:methanol. An aliquot (2 mL, 1.0 equivalents (eq.)) was placed in a 2 dram (7.4 mL) vial. The solvent was removed by vacuum centrifugation. The vial was charged with the appropriate boronic acid (1.25 eq.), palladium (II) acetate (0.1 eq.), and n-propanol (900 μL) and then sonicated for 30 seconds. The vial was then charged with 2M aqueous sodium carbonate solution (313 μL), deionized water (63 μL), and a solution of triphenylphosphine in n-propanol (63 μL, 0.15 eq.). The vial was capped and then heated to 80° C. for 5 hours in a sand bath. The vial was allowed to cool to room temperature and then the solvent was removed by vacuum centrifugation. The residue was purified by preparative high performance liquid chromatography using the method described above to provide the trifluoroacetate salt of the desired compound. The table below shows the structure of the free base and the measured mass (M+H).

Measured MassExample NumberR3(M + H)20

317.177421

323.133022

331.192023

331.190524

331.194525

332.187726

335.166127

335.167828

335.167729

343.192130

345.209531

345.209332

345.209933

347.188834

347.187435

347.189236

347.186537

351.136738

351.137539

351.137540

353.159441

353.157742

353.157943

353.158744

357.173145

359.187346

361.167047

361.163948

363.165249

367.193250

367.194251

369.128852

373.148453

100

373.149454

101

374.196555

102

377.198556

103

377.200057

104

381.150758

105

385.165859

106

385.097460

107

385.099861

108

385.098262

109

389.198063

110

393.205764

111

401.159665

112

409.2036

Examples 66-105

[0588] The compounds in the table below were prepared according to the method of Examples 20-65 above using 7-bromo-2-butyl-1-isobutyl-1H-imidazo[4,5c]quinoline-4-amine as the starting material. The table below shows the structure of the free base and the measured mass (M+H).

113

Measured MassExample NumberR3(M + H)66

114

373.238567

115

379.197868

116

387.258269

117

387.255070

118

387.254571

119

388.253672

120

399.257773

121

401.271274

122

401.268675

123

401.271976

124

403.248377

125

403.250778

126

403.251679

127

403.250580

128

407.202181

129

407.202482

130

407.200883

131

409.221484

132

409.222785

133

409.224186

134

413.237687

135

417.231388

136

418.226889

137

419.229990

138

419.228391

139

423.255292

140

423.255993

141

425.191594

142

429.212595

143

429.214296

144

433.263397

145

433.261398

146

437.212299

147

441.2265100

148

441.1620101

149

441.1646102

150

441.1586103

151

449.2728104

152

457.2203105

153

465.2656

Examples 106-116

[0589] 7-Bromo-2-ethoxymethyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine and the boronic acid or boronic acid ester from the table below were coupled according to the general procedure described in Part J of Example 1. The reaction was heated at reflux overnight unless otherwise indicated below the table. The solid collected from the reaction was washed with hexanes. Samples that were recrystallized from isopropanol and then dichloromethane:hexanes were dried under high vacuum overnight. Samples that were recrystallized from acetonitrile were then washed with hexanes and dried overnight in a vacuum oven at 75-80° C. The purification for Examples 115 and 1 16 is described below the table.

154

RecrystallizationExampleBoronic Acid or EsterSolventR31063-Propoxyphenylboronic acidIsopropanol then dichloromethane: hexanes

155

1074-Propoxyphenylboronic acidIsopropanol then dichloromethane: hexanes

156

108Phenylboronic acidIsopropanol then dichloromethane: hexanes

157

1092-Propoxyphenylboronic acidIsopropanol, then acetonitrile

158

1104-Cyanophenylboronic acidAcetonitrile

159

1113-Cyanophenylboronic acidAcetonitrile

160

112trans-2-[4- (Trifluoromethyl)phenyl]vinylboronic acidAcetonitrile

161

113Pyridine-3-boronic acid 1,3- propanediol cyclic esterAcetonitrile

162

1144-(Dimethylamino)phenyl boronic acidAcetonitrile

163

1155-(tert-Butyldimethylsilanyloxymethyl) pyridine-3-boronic acidNot used

164

116Pyridine-4-boronic acid pinacol esterAcetonitrile

165

Example 106

2-Ethoxymethyl-1-(2-methylpropyl)-7-(3-propoxyphenyl)-1H-imidazo[4,5-c]quinolin-4-amine

[0590] The product was obtained as an off-white powder, mp 140.0-141.0° C.

[0591] Anal. Calcd for C26H32N4O2: C, 72.19; H, 7.46; N, 12.95. Found: C, 71.88; H, 7.36; N, 12.72.

Example 107

2-Ethoxymethyl-1-(2-methylpropyl)-7-(4-propoxyphenyl)-1H-imidazo[4,5-c]quinolin-4-amine

[0592] The product was obtained as a white solid, mp 209.0-210.0° C.

[0593] Anal. Calcd for C26H32N4O2: C, 72.19; H, 7.46; N, 12.95. Found: C, 71.93; H, 7.41; N, 12.76.

Example 108

2-Ethoxymethyl-1-(2-methylpropyl)-7-phenyl-1H-imidazo[4,5-c]quinolin-4-amine

[0594] The product was obtained as a white solid, mp 176.5-178.0° C.

[0595] Anal. Calcd for C23H26N4O: C, 73.77; H, 7.00; N, 14.96. Found: C, 73.65; H, 6.90; N, 14.80.

Example 109

2-Ethoxymethyl-1-(2-methylpropyl)-7-(2-propoxyphenyl)-1H-imidazo[4,5-c]quinolin-4-amine

[0596] The product was obtained as light-yellow needles, mp 168.0-169.0° C.

[0597] Anal. Calcd for C26H32N4O2: C, 72.19; H, 7.46; N, 12.95. Found: C, 71.96; H, 7.40; N, 13.13.

Example 110

4-(4-Amino-2-ethoxymethyl-1-(2-methylpropyl)- I H-imidazo[4,5-c]quinolin-7-yl)benzonitrile

[0598] The product was obtained as an off-white solid, mp 211.0-212.0° C.

[0599] Anal. Calcd for C24H25N5O: C, 72.16; H, 6.31; N, 17.53. Found: C, 71.87; H, 6.22; N, 17.40.

Example 111

3-(4-Amino-2-ethoxymethyl-1-(2-methylpropyl)-1H-imidazo[4,5-c] quinolin-7-yl)benzonitrile

[0600] The product was obtained as light-brown crystals, mp 210.0-211.0° C.

[0601] Anal. Calcd for C24H25N5O: C, 72.16; H, 6.31; N, 17.53. Found: C, 71.88; H, 6.06; N, 17.63.

Example 112

2-Ethoxymethyl-1-(2-methylpropyl)-7- {(E)-2-[(4-trifluoromethyl)phenyl]vinyl}-1H-imidazo[4,5-c]quinolin-4-amine

[0602] The product was obtained as light-yellow needles, mp 193.0-194.0° C.

[0603] Anal. Calcd for C26H27F3N4O: C, 66.65; H, 5.81; N, 11.96. Found: C, 66.51; H, 5.76; N, 11.96.

Example 113

2-Ethoxymethyl-1-(2-methylpropyl)-7-(pyridin-3-yl)- I H-imidazo[4,5-c]quinolin-4-amine

[0604] Following recrystallization from acetonitrile, the crystals were purified by flash column chromatography on silica gel. The polar component of the eluent was a mixture of chloroform:methanol:ammonium hydroxide 80:18:2 (CMA). The chromatographic separation was carried out eluting sequentially with 95:5, 90:10, 85:15, 80:20, and 75:25 chloroform:CMA. The fractions containing the product were combined, dried over magnesium sulfate, filtered, and concentrated under reduced pressure until a precipitate began to form. Hexanes were added, and the resulting solid was isolated by filtration to provide 2-ethoxymethyl-1-(2-methylpropyl)-7-pyridin-3-yl-1H-imidazo[4,5-c]quinolin-4-amine as a white solid, mp 179.5-181.5° C.

[0605] Anal. Calcd for C22H25N5O: C, 70.38; H, 6.71; N, 18.65. Found: C, 70.07; H, 6.87; N, 18.57.

Example 114

7-(4-Dimethylaminophenyl)-2-ethoxymethyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine

[0606] The product was obtained as a yellow solid, mp 214.5-215.5° C.

[0607] Anal. Calcd for C25H31N5O: C, 71.91; H, 7.48; N, 16.77. Found: C, 71.66; H, 7.40; N, 16.71.

Example 115

{5-[4-Amino-2-ethoxyrnethyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]pyridin-3-yl}methanol

[0608] Part A

[0609] 3-Bromo-5-(tert-butyldimethylsilanyloxymethyl)pyridine was prepared according to the published procedure (Zhang, N. et al, J. Med. Chem., 45, 2832-2840 (2002)). Under a nitrogen atmosphere, a solution of 3-bromo-5-(tert-butyldimethylsilanyloxymethyl)pyridine (28.70 g, 94.94 mmol) and triisopropyl borate (26.3 mL, 114 mmol) in dry THF was cooled to −70° C. n-Butyllithium (45.6 mL, 114 mmol) was added dropwise over a period of 1.5 hours. The reaction was stirred for an additional 30 minutes and then allowed to warm to −20° C. Dilute aqueous ammonium chloride was added, and the mixture was allowed to warm to ambient temperature. The aqueous layer was separated and extracted with diethyl ether. The combined organic fractions were concentrated under reduced pressure, and methanol was added to the resulting oil. A solid formed, which was stirred with water for two days, isolated by filtration, and dried under reduced pressure to provide 18.19 g of 5-(tert-butyldimethylsilanyloxymethyl)pyridine-3-boronic acid as a white solid.

[0610] Part B

[0611] The coupling reaction was heated at reflux for four days, and the product was purified on a Biotage HORIZON High-Performance Flash Chromatography instrument (HPFC) (eluting with chloroform:CMA in a gradient from 100:0 to 55:45.) The fractions containing the product were combined and concentrated under reduced pressure until a precipitate began to form. Hexanes were added, and the resulting solid was isolated by filtration and dried overnight in an oven at 70° C. to provide [5-(4-amino-2-ethoxymethyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl)pyridin-3-yl]methanol as an off-white powder, mp 211.0-212.0° C.

[0612] Anal. Calcd for C23H27N5O2: C, 68.13; H, 6.71; N, 17.27. Found: C, 68.04; H, 7.07; N, 17.21.

Example 116

2-Ethoxymethyl-1-(2-methylpropyl)-(7-pyridin-4-yl)-1H-imidazo [4,5-c]quinolin-4-amine

[0613] The reaction was heated at reflux for 48 hours, and the reaction mixture was partitioned between aqueous sodium chloride and dichloromethane. The aqueous layer was extracted twice with dichloromethane, and the combined organic fractions were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluting with chloroform:CMA in a gradient from 95:5 to 80:20) followed by recrystallization from acetonitrile to provide 2-ethoxymethyl-1-(2-methylpropyl)-(7-pyridin-4-yl)-1H-imidazo[4,5-c]quinolin-4-amine as a white solid, mp 211-213° C.

[0614] Anal. Calcd for C22H25N5O: C, 70.38; H, 6.71; N, 18.65. Found: C, 70.33; H, 6.76; N, 18.69.

Example 117

2-Ethoxymethyl-1-(2-methylpropyl)-7-{2-[(trifluoromethyl)phenyl]ethyl}-1H-imidazo[4,5-c]quinolin-4-amine

[0615]

166

[0616] A solution of 2-ethoxymethyl-1-(2-methylpropyl)-7-{(E)-2-[(4-trifluoromethyl)phenyl]vinyl}-1H-imidazo[4,5-c]quinolin-4-amine (0.47 g, 1.0 mmol) in ethyl acetate (200 mL) was added to a Parr vessel charged with 10% palladium on carbon (0.30 g). The reaction was placed under hydrogen pressure (50 psi, 3.4×105 Pa) for seven days. The reaction mixture was filtered, and the filter cake was washed with ethyl acetate. The filtrate was concentrated under reduced pressure to provide 0.22 g of 2-ethoxymethyl-1-(2-methylpropyl)-7-{2-[(4-trifluoromethyl)phenyl]ethyl}-1H-imidazo[4,5-c]quinolin-4-amine as a white powder, mp 175.5-178° C.

[0617] Anal. Calcd for C26H29F3N4O: C, 66.37; H, 6.21; N, 11.91. Found: C, 66.09; H, 6.39; N, 11.53.

Examples 118-122

[0618] For Examples 118-121, triphenylphosphine (31 mg, 0.12 mmol) and palladium (II) acetate (9 mg, 0.04 mmol) were added to a mixture of 8-bromo-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine (1.28 g, 4.00 mmol), the boronic acid from the table below (6.00 mmol, 1.5 equivalents), n-propanol (7 mL), aqueous sodium carbonate (5.0 mL of 2 M), and water (1.4 mL). The reaction was purged with nitrogen and heated at reflux under a nitrogen atmosphere for one to two hours. Upon cooling to ambient temperature, a solid formed and was isolated by filtration and washed with water. The crude product was recrystallized from methanol and dried overnight at 1.33 Pa and 98° C. to provide the products listed below the table.

[0619] For Example 122, 8-bromo-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine and the boronic acid from the table below were coupled according to the general procedure described in Part J of Example 1. The reaction was heated at reflux overnight. The crude product was recrystallized from methanol.

Examples 118-122

[0620]

167

Example
Boronic acid or ester
R3

118
4-Ethylphenylboronic acid

168

119
3,4-Dimethylphenylboronic acid

169

120
3-Acetylphenylboronic acid

170

121
Thianaphthene-3-boronic acid

171

122
trans-2-Phenylvinylboronic acid

172

Example 118

8-(4-Ethylphenyl)-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine

[0621] The product was obtained as pale yellow needles, mp 238-240° C.

[0622] Anal. Calcd for C22H24N4: C, 76.71; H, 7.02; N, 16.26. Found: C, 76.67; H, 7.00N; 16.31.

Example 119

8-(3,4-Dimethylphenyl)-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine

[0623] The product was obtained as pale yellow needles, mp 204-205° C.

[0624] Anal. Calcd for C22H24N4: C, 76.71; H, 7.02; N, 16.26. Found: C, 76.33; H, 7.28; N, 16.21.

Example 120

1-{3-[4-Amino-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-8-yl]phenyl}ethanone

[0625] The product was obtained as a white solid, mp 217-218° C.

[0626] Anal. Calcd for C22H22N4O: C, 73.72; H, 6.19; N, 15.63. Found: C, 73.87; H, 6.24; N, 15.75.

Example 121

8-Benzo[b]thiophen-3-yl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine

[0627] The product was obtained as pale yellow needles, mp 247-248° C.

[0628] Anal. Calcd for C22H20N4S.0.14H2O: C, 70.46; H, 5.45; N, 14.94. Found: C, 70.28; H, 5.26; N, 14.91.

Example 122

1-(2-Methylpropyl)-8-styryl-1H-imidazo[4,5-c]quinolin-4-amine

[0629] The product was obtained as pale yellow crystals, mp 228-230° C.

[0630] Anal. Calcd for C22H22N4.1.5H20: C, 71.52; H, 6.82; N, 15.16. Found: C, 71.34; H, 6.63; N, 15.20.

Example 123

1-(2-Methylpropyl)-8-phenethyl-1H-imidazo[4,5-c]quinolin-4-amine

[0631]

173

[0632] A solution of 1-(2-methylpropyl)-8-styryl-1H-imidazo[4,5-c]quinolin-4-amine (1.37 g, 4.00 mmol) in ethanol (40 mL) was added to a Parr vessel charged with 10% palladium on carbon (137 mg). The reaction was placed under hydrogen pressure (40 psi, 2.8×105 Pa) for six days. The reaction mixture was filtered through a layer of CELITE filter aid, and the filter cake was washed with ethanol. The filtrate was concentrated under reduced pressure, and the residue was recrystallized from methanol to provide 0.300 g of 1-(2-methylpropyl)-8-phenethyl-1H-imidazo[4,5-c]quinolin-4-amine as a white solid, mp 175-178° C.

[0633] Anal. Calcd for C22H24N4.0.75H20: C, 73.82; H, 7.18; N, 15.65. Found: C, 73.45; H, 7.32; N, 15.33.

Example 124

2-Methyl-1-(3-methanesulfonylpropyl)-7-phenyl-1H-imidazo[4,5-c]quinolin-4-amine

[0634]

174

[0635] Part A

[0636] N4-(3-Methylsulfanylpropyl)-7-phenylquinoline-3,4-diamine and trimethyl orthoacetate were reacted according to the general method described in Part H of Example 10. The crude product was purified by column chromatography on silica gel (eluting with 95:5 dichloromethane:methanol) to provide 2-methyl-1-(3-methanesulfanylpropyl)-7-phenyl-1H-imidazo[4,5-c]quinolin-4-amine as a light brown solid.

[0637] Part B

[0638] The method described in Part I of Example 10 was followed. The crude product was recrystallized from acetonitrile (67 mL/g) and then from methanol (106 mL/g). The crystals were purified by column chromatography on silica gel (eluting with 90:10 dichloromethane:methanol), and the resulting solid was recrystallized from acetonitrile (220 mL/g) and dried for 17 hours under vacuum at 85° C. to provide 2-methyl-1-(3-methanesulfonylpropyl)-7-phenyl-1H-imidazo[4,5-c]quinolin-4-amine as a white powder, mp mp 203-205° C.

[0639] Anal. Calcd for C21H22N4O2S: C, 63.94; H, 5.62: N, 14.20. Found: C, 63.81; H, 5.47; N, 14.14.

Examples 125-135

[0640] Part A

[0641] Triethylamine (17.35 mL, 124 mmol) was added to a solution of 7-bromo-4-chloro-3-nitroquinoline (29.84 g, 104 mmol) in dichloromethane (253 mL), and the reaction was cooled to 0° C. 1-Amino-2-methylpropan-2-ol (10.17 g, 114 mmol) was added dropwise, and then the reaction was allowed to warm to ambient temperature and stirred overnight. A precipitate formed and was isolated by filtration and washed with water. The crude solid was recrystallized from a mixture of isopropanol and acetonitrile to provide 27.78 g of 1-(7-bromo-3-nitroquinolin-4-ylamino)-2-methylpropan-2-ol as a solid.

[0642] Part B

[0643] A solution of 1-(7-bromo-3-nitroquinolin-4-ylamino)-2-methylpropan-2-ol (27.78 g, 81.66 mmol) in acetonitrile (1.2 L) was added to a Parr vessel charged with 5% platinum on carbon (0.84 g), and the reaction was placed under hydrogen pressure (50 psi, 3.4×105 Pa) for two days. The reaction mixture was filtered through a layer of CELITE filter aid, and the filter cake was washed with ethanol (1 L). The filtrate was concentrated under reduced pressure to provide 21.70 g of 1-(3-amino-7-bromoquinolin-4-ylamino)-2-methylpropan-2-ol as a yellow oil.

[0644] Part C

[0645] A solution of 1-(3-amino-7-bromoquinolin-4-ylamino)-2-methylpropan-2-ol (158.19 g, 0.510 mol) in dichloromethane (1.2 L) was cooled to 0° C. Ethoxyacetyl chloride (62.50 g, 0.510 mol) was added dropwise, and then the reaction was allowed to warm to ambient temperature and stirred overnight. A precipitate formed and was isolated by filtration to provide N-[7-bromo-4-(2-hydroxy-2-methylpropylamino)quinolin-3-yl]-2-ethoxyacetamide as a solid.

[0646] Part D

[0647] A solution of sodium hydroxide (25 g, 0.625 mol) in water (205 mL) was added to a solution of N-[7-bromo-4-(2-hydroxy-2-methylpropylamino)quinolin-3-yl]-2-ethoxyacetamide (170.88 g, 0.431 mol) in ethanol (700 mL), and the reaction was heated at reflux under a nitrogen atmosphere for two hours. Upon cooling the reaction, a precipitate formed and was isolated by filtration. The solid was purified by flash column chromatography on silica gel (eluting sequentially with chloroform, 99:1 chloroform:methanol, and 97:3 chloroform:methanol) to provide 80.31 g of 1-(7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol as a tan solid.

[0648] Part E

[0649] 3-Chloroperoxybenzoic acid (73.27 g of 50% pure material, 0.212 mol) was added in four portions over a period of 30 minutes to a solution of 1-(7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c] quinolin-1-yl)-2-methylpropan-2-ol (80.31 g, 0.212 mol) in dichloromethane (950 mL), and the reaction was stirred overnight at ambient temperature. The reaction mixture was washed twice with aqueous sodium carbonate (2 M) and then diluted with additional dichloromethane (1.5 L total volume). The solution was cooled to 0° C., and concentrated ammonium hydroxide (83 mL) was added. p-Toluenesulfonyl chloride (48.56 g, 0.254 mol) was then added over a period of 20 minutes, and the reaction was allowed to warm to ambient temperature and stirred overnight. A precipitate formed and was isolated by filtration and washed sequentially with 2 M aqueous sodium carbonate and water. The crude product was recrystallized from 2:1 isopropanol:acetonitrile and collected in two crops to provide 58.4 g of 1-(4-amino-7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol as a solid.

[0650] Part F

[0651] 1-(4-Amino-7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol and the boronic acid or boronic acid ester from the table below were coupled according to the general procedure described in Part J of Example 1. The reaction was heated at reflux for between 1.5 and 27 hours. The reaction mixture was partitioned between brine and chloroform. The aqueous layer was extracted twice with chloroform, and the combined organic fractions were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The purification and characterization of each compound is given below the table.

Examples 125-135

[0652]

175

Example
Boronic acid or ester
R3

125
Thiophene-3-boronic acid

176

126
Pyridine-3-boronic acid 1,3-propanediol cyclic ester

177

127
Pyridine-4-boronic acid pinacol ester

178

128
1H-Pyrazole-4-boronic acid pinacol ester

179

129
3-(Pyrrolidine-1-carbonyl)phenylboronic acid

180

130
3-(Morpholine-4- carbonyl)phenylboronic acid

181

131
Phenylboronic acid

182

132
4-(N,O- Dimethylhydroxylaminocarbonyl)phenyl boronic acid

183

133
5-(tert-Butyldimethylsilanyloxymethyl) pyridine-3-boronic acid

184

134
5-Ethoxymethylpyridin-3-ylboronic acid

185

135
3-Carboxyphenylboronic acid

186

Example 125

1-[4-Amino-2-ethoxymethyl-7-(thiophen-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol

[0653] The crude product was recrystallized from 2-butanone and then purified by flash column chromatography on silica gel (eluting with chloroform:CMA in a gradient from 90:10 to 65:35). The resulting solid was recrystallized from acetonitrile to provide 1-[4-amino-2-ethoxymethyl-7-(thiophen-3-yl)-1H-imidazol[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol as white crystals, mp 204-205° C.

[0654] Anal Calcd for C21H24N4O2S: C, 63.61; H, 6.10; N, 14.13. Found: C, 63.71; H, 6.23N; 4.31.

Example 126

1-[4-Amino-2-ethoxymethyl-7-(pyridin-3-yl)- H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol

[0655] The crude product was purified three times by HPFC (eluting with chloroform:CMA in a gradient from 90:10 to 70:30). The resulting solid was recrystallized from acetonitrile and dried overnight at 1.33 Pa and 98° C. to provide 1-[4-amino-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol as a white solid, mp 197-199° C.

[0656] Anal. Calcd for C22H25N5O2.0.28H2O: C, 66.63; H, 6.50; N, 17.66. Found: C, 66.63; H, 6.55; N, 17.88.

Example 127

1-[4-Amino-2-ethoxymethyl-7-(pyridin-4-yl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol

[0657] The crude product was purified twice by HPFC (eluting with chloroform:CMA in a gradient from 100:0 to 55:45). The fractions containing the pure product were concentrated under reduced pressure until a precipitate formed. Hexanes were added, and the resulting solid was isolated by filtration and dried overnight under vacuum to provide 1-[4-amino-2-ethoxymethyl-7-(pyridin-4-yl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol as a pale yellow solid, mp 220-221° C.

[0658] Anal. Calcd for C22H25N5O2.0.39H2O: C, 66.31; H, 6.52; N, 17.57. Found: C, 65.95; H, 6.32; N, 17.44.

Example 128

1-[4-Amino-2-ethoxymethyl-7-(1H-pyrazol-4-yl)-1H-imidazo[4,5-c]quinolin 1-yl]-2-methylpropan-2-ol

[0659] The crude product was purified by HPFC (eluting with chloroform:CMA in a gradient from 100:0 to 40:60) followed by recrystallization from methanol to provide 1-[4-amino-2-ethoxymethyl-7-(1H-pyrazol-4-yl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol as white, granular crystals, mp >250° C.

[0660] Anal. Calcd for C20H24N6O2: C, 63.14; H, 6.36; N, 22.09. Found: C, 62.89; H, 6.35; N, 21.94.

Example 129

{3-[4-Amino-2-ethoxymethyl-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]phenyl}pyrrolidin-1-ylmethanone

[0661] The crude product was purified by HPFC (eluting with chloroform:CMA in a gradient from 100:0 to 65:35) followed by recrystallizations from isopropanol and acetonitrile to provide {3-[4-amino-2-ethoxymethyl-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]phenyl}pyrrolidin-1-ylmethanone as a white powder, mp 216.5-217.5° C.

[0662] Anal. Calcd for C28H33N5O3: C, 68.97; H, 6.82; N, 14.36. Found: C, 68.67; H, 7.01; N, 14.42.

Example 130

{3-[4-Amino-2-ethoxymethyl-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]phenyl}morpholin-4-ylmethanone

[0663] The crude product was purified by HPFC (eluting with chloroform:CMA in a gradient from 100:0 to 70:30) followed by recrystallizations from isopropanol, dichloromethane:hexanes, and isopropanol. The crystals were dried under vacuum with heating to provide {3-[4-amino-2-ethoxymethyl-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]phenyl}morpholin-4-ylmethanone as a white powder, mp 152.0-154.0° C.

[0664] Anal. Calcd for C28H33N5O4.0.5H2O: C, 65.61; H, 6.69; N, 13.66. Found: C, 65.67; H, 7.09; N, 13.72.

Example 131

1-(4-Amino-2-ethoxymethyl-7-phenyl-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol

[0665] The crude product was recrystallized from methanol:water and then 30 purified by HPFC (eluting with chloroform:CMA in a gradient from 100:0 to 70:30) to provide 1-(4-amino-2-ethoxymethyl-7-phenyl-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol as a white solid, mp 211-212° C.

[0666]

1
H NMR (500 mHz, DMSO-d6) δ 8.34 (d, J=8.5 Hz, 1H), 7.83 (d, J=2 Hz, 1H), 7.76-7.73 (m, 2H), 7.52-7.46 (m, 3H), 7.38-7.35 (m, 1H), 6.58 (br s, 2H), 4.88 (s, 3H), 4.68 (br s, 2H), 3.52 (q, J=7 Hz, 2H), 1.19 (br s, 6H), 1.13 (t, J=7 Hz, 3H);

[0667] HRMS (ESI) m/z 391.2124 (391.2134 calcd for C23H26N4O2, (M+H).

Example 132

4-[4-Amino-2-ethoxymethyl-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]-N-methoxy-N-methylbenzamide

[0668] The crude product was purified three times by HPFC (eluting with chloroform:CMA in gradients from 100:0 to 70:30). The fractions containing the pure product were concentrated under reduced pressure until a precipitate formed. Hexanes were added, and the resulting solid was isolated by filtration and dried overnight in a vacuum oven at 80° C. and then heated to melting under vacuum to provide 4-[4-amino-2-ethoxymethyl-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]-N-methoxy-N-methylbenzamide as a light green solid.

[0669]

13
C NMR (75 MHz, DMSO-d6) δ 168.7, 152.3, 151.0, 145.5, 141.9, 137.0, 133.9, 133.0, 128.5, 126.2, 123.7, 122.2, 119.1, 114.8, 70.6, 65.2, 64.8, 60.7, 54.8, 33.2, 27.6, 14.9;

[0670] HRMS (El) m/z 478.2446 (478.2454 calcd for C26H31N5O4).

Example 133

1-[4-Amino-2-ethoxymethyl-7-(5-hydroxymethylpyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol

[0671] The reaction was heated at reflux for three hours and then allowed to cool and stand at ambient temperature for several days. The crude product was purified by HPFC (eluting with chloroform:CMA in a gradient from 100:0 to 65:35). The solid (3.73 g) was dissolved in tetrahydrofuran (THF) (5 mL), water (5 mL), and acetic acid (15 mL). The solution was allowed to stand at room temperature for three days, and then the solvents were removed under reduced pressure. The residue was partitioned between chloroform and 2 M aqueous sodium carbonate:brine, and the aqueous layer was extracted with chloroform (7×). The combined organic fractions were concentrated under reduced pressure. The residue was then purified by HPFC (eluting with chloroform:CMA in a gradient from 100:0 to 35:65) followed by recrystallization from acetonitrile to provide 1-[4-amino-2-ethoxymethyl-7-(5-hydroxymethylpyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol as a white powder, mp 188-190° C.

[0672] Anal. Calcd for C23H27N5O3: C, 65.54; H, 6.46; N, 16.62. Found: C, 65.22; H, 6.66; N, 16.56.

Example 134

1-[4-Amino-2-ethoxymethyl-7-(5-ethoxymethylpyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol

[0673] Part A

[0674] (5-Bromopyridin-3-yl)methanol was prepared according to the published procedure (Zhang, N. et al, J. Med. Chem., 45, 2832-2840 (2002)). A solution of (5-bromopyridin-3-yl)methanol (7.39 g, 39.3 mmol) in THF was cooled to 0° C. Sodium bis(trimethylsilyl)amide (39.3 mL of a 1.0 M solution in THF) was added, and the reaction was stirred for 20 minutes. lodoethane (3.46 mL, 43.2 mmol) and DMF were added, and the reaction was allowed to warm to ambient temperature and stirred overnight. Brine was added, and the aqueous layer was extracted twice with hexanes. The combined organic fractions were concentrated under reduced pressure, and the residue was purified by HPFC (eluting with hexanes:ethyl acetate in a gradient from 100:0 to 70:30) to provide 5.11 g of 3-bromo-5-ethoxymethylpyridine as a colorless oil.

[0675] Part B

[0676] The method described in Part A of Example 115 was used to convert 3-bromo-5-ethoxymethylpyridine (5.11 g, 23.6 mmol) to 5-ethoxymethylpyridin-3-ylboronic acid, which was obtained as a white solid.

[0677] Part C

[0678] The crude product from the coupling reaction was recrystallized from dichloromethane:hexanes and then purified twice by HPFC (eluting with chloroform:CMA in a gradient from 100:0 to 70:30). The resulting solid was recrystallized from dichloromethane:hexanes to provide 1-[4-amino-2-ethoxymethyl-7-(5-ethoxymethylpyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol as a white powder, mp 156.0-156.5° C.

[0679] Anal. Calcd for C25H31N5O3: C, 66.79; H, 6.95; N, 15.58. Found: C, 66.46; H, 6.98; N, 15.51.

Example 135

3-[4-Amino-2-ethoxymethyl-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]benzoic acid

[0680] The crude product was isolated as a solid from the reaction mixture, recrystallized from dimethyl sulfoxide, stirred with methanol:water, and isolated by filtration to provide 3-[4-amino-2-ethoxymethyl-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]benzoic acid as a white powder, mp >250° C.

[0681] HRMS (ESI) m/z 435.2016 (435.2032 calcd for C24H26N4O4, (M+H).

Examples 136-141

[0682] Part A

[0683] The method described in Part A of Example 9 was used to react 1-(3-amino-7-bromoquinolin-4-ylamino)-2-methylpropan-2-ol (29.0 g, 93.5 mmol) with 3-methoxypropionyl chloride (11.5 g, 93.5 mmol). The crude product was recrystallized from 2:1 ethyl acetate:hexane and then purified by flash column chromatography on silica gel (eluting sequentially with 60:40 acetone:toluene and acetone). The resulting solid was recystallized from 3:1 ethyl acetate hexane to provide 13.3 g of 1-[7-bromo-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol as translucent crystals.

[0684] Part B

[0685] 1-[7-Bromo-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol was oxidized and then aminated according to the methods described in Parts H and I of Example 1. After recrystallization from ethanol, 1-[4-amino-7-bromo-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol was obtained as a pale orange solid.

[0686] Part C

[0687] 1-[4-Amino-7-bromo-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol and the boronic acid or boronic acid ester from the table below were coupled according to the general procedure described in Part J of Example 1. The reaction was heated at reflux for between three hours and overnight. For Example 136, a solid formed upon cooling to room temperature aqnd was isolated by filtration and washed with hexanes. For Examples 137-141, the reaction mixture was partitioned between brine and chloroform. The aqueous layer was extracted twice with chloroform, and the combined organic fractions were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The purification and characterization of each compound is given below the table.

Examples 136-141

[0688]

187

Example
Boronic acid or ester
R3

136
Phenylboronic acid

188

137
Thiophene-3-boronic acid

189

138
Pyridine-3-boronic acid 1,3-propanediol cyclic ester

190

139
3-(Methylsulfonylamino)phenylboronic acid

191

140
3-(Hydroxymethyl)phenylboronic acid

192

141
5-(tert-Butyldimethylsilanyloxymethyl pyridine-3-boronic acid

193

Example 136

1-[4-Amino-2-(2-methoxyethyl)-7-phenyl-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol

[0689] The crude product was recrystallized twice from isopropanol and then from dichloromethane:hexanes and dried overnight under vacuum to provide 1-[4-amino-2-(2-methoxyethyl)-7-phenyl-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol as a white solid, mp 226-227° C.

[0690] Anal. Calcd for C23H26N4O2: C, 70.75; H, 6.71; N, 14.35. Found: C, 70.49; H, 6.56; N, 14.28.

Example 137

1-[4-Amino-2-(2-methoxyethyl)-7-(thiophen-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol

[0691] The crude product purified by flash column chromatography on silica gel (eluting with chloroform:CMA in a gradient from 85:15 to 70:30). The resulting solid was recrystallized from ethanol to provide 1-[4-amino-2-(2-methoxyethyl)-7-(thiophen-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol as white crystals, mp 233-234° C.

[0692] Anal. Calcd for C21H24N4O2S: C, 63.61; H, 6.10; N, 14.13. Found: C, 63.45; H, 6.21; N, 14.07.

Example 138

1-[4-Amino-2-(2-methoxyethyl)-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol

[0693] The crude product was purified by flash column chromatography on silica gel (eluting with chloroform:CMA in a gradient from 90:10 to 70:30). The resulting solid was recrystallized from methanol to provide 1-[4-amino-2-(2-methoxyethyl)-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol as white needles, mp 158-160° C.

[0694] Anal. Calcd for C22H25N5O2.1.10H2O: C, 64.26; H, 6.67; N, 17.03. Found: C, 64.12; H, 7.02; N, 17.27.

Example 139

N-{3-[4-Amino-1-(2-hydroxy-2-methylpropyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-7-yl]phenyl}methanesulfamide

[0695] The crude product was purified by flash column chromatography on silica gel (eluting with chloroform:CMA in a gradient from 90:10 to 80:20) to provide N-{3-[4-amino-1-(2-hydroxy-2-methylpropyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-7-yl]phenyl}methanesulfamide as a white powder, mp 156-158° C.

[0696] Anal. Calcd for C24H29N5O4S.3.0H2O: C, 53.62; H, 6.56; N, 13.03. Found: C, 53.50; H, 6.49; N, 12.95.

Example 140

1-[4-Amino-7-(3-hydroxymethylphenyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol

[0697] The crude product was purified by flash column chromatography on silica gel (eluting with chloroform:CMA in a gradient from 90:10 to 80:20) to provide 1-[4-amino-7-(3-hydroxymethylphenyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol as a white powder, mp 212-213° C.

[0698] Anal. Calcd for C24H28N4O3.0.17H2O: C, 68.06; H, 6.74; N, 13.22. Found: C, 67.73; H, 6.63; N, 13.04.

Example 141

1-[4-Amino-7-(5-hydroxymethylpyridin-3-yl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol

[0699] The crude product was purified by flash column chromatography on silica gel (eluting with chloroform:CMA in a gradient from 90:10 to 80:20) to provide 1-[4-amino-7-(5-hydroxymethylpyridin-3-yl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol as a yellow solid, mp 210-211° C.

[0700] Anal. Calcd for C23H27N5O3.1.0H2O: C, 62.85; H, 6.65; N, 15.93. Found: C, 62.47; H, 6.33; N, 15.83.

Examples 142-144

[0701] Part A

[0702] Triethyl orthopropionate (12.9 g, 73.2 mmol) and pyridine hydrochloride (220 mg) were added to a solution of 1-(3-amino-7-bromoquinolin-4-ylamino)-2-methylpropan-2-ol (22.1 g, 70.6 mmol) in anhydrous toluene (300 mL), and the reaction was heated at reflux for three hours. The reaction was allowed to cool to ambient temperature and stand overnight; a precipitate formed. The precipitate was isolated by filtration, washed with toluene, and air-dried to provide 18.42 g of 1-(7-bromo-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol as beige crystals.

[0703] Part B

[0704] 1-(7-Bromo-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol was oxidized and then aminated according to the methods described in Parts H and I of Example 1. The product from amination was isolated by filtration from the reaction mixture and stirred with 2 M aqueous sodium carbonate and chloroform for ten minutes. The resulting solid was isolated by filtration and washed with water to provide 1-(4-amino-7-bromo-2-methoxyethyl-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol as a white solid, which was used without further purification.

[0705] Part C

[0706] 1-(4-Amino-7-bromo-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol and the boronic acid or boronic acid ester from the table below were coupled according to the general procedure described in Part J of Example 1. The reaction was heated at reflux between 12 and 54 hours. The work-up procedure described in Part F of Examples 125-131 was followed, and the purification and characterization of each compound is described below the table.

Examples 142-144

[0707]

194

Example
Boronic acid or ester
R3

142
Pyridine-3-boronic acid 1,3- propanediol cyclic ester

195

143
Pyridine-4-boronic acid pinacol ester

196

144
5-(tert- Butyldimethylsilanyloxymethyl) pyridine-3-boronic acid

197

Example 142

1-[4-Amino-2-ethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol

[0708] The crude product was purified by HPFC (eluting with chloroform:CMA in a gradient from 100:0 to 55:45). The resulting solid was dissolved in chloroform and precipitated with hexane, recrystallized twice from acetonitrile, and finally recystallized from 3:1 acetonitrile:methanol and dried at 1.33 Pa and 80° C. to provide 1-[4-amino-2-ethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol as white needles, mp 245-247° C.

[0709] Anal. Calcd for C21H23N5O: C, 69.78; H, 6.41; N, 19.38. Found: C, 69.60; H, 6.53; N, 19.58.

Example 143

1-[4-Amino-2-ethyl-7-(pyridin-4-yl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol

[0710] The crude product was purified by HPFC (eluting with chloroform:CMA in a gradient from 100:0 to 65:35) The resulting solid was recrystallized from acetonitrile:methanol and air-dried to provide 1-[4-amino-2-ethyl-7-(pyridin-4-yl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol as a white solid, mp >250° C.

[0711] Anal. Calcd for C21H23N5O: C, 69.78; H, 6.41; N, 19.38. Found: C, 69.68; H, 6.54; N, 19.43.

Example 144

1-[4-Amino-2-ethyl-7-(5-hydroxymethylpyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol

[0712] The crude product was purified by HPFC, and the resulting solid was dissolved in THF (5 mL), water (5 mL), and acetic acid (15 mL). The solution was allowed to stand at room temperature for three days, and 5 M aqueous sodium hydroxide and 2 M aqueous sodium carbonate were added to adjust to pH 11. A solid was present and was isolated by filtration and purified by HPFC™ (eluting with chloroform:CMA in a gradient from 100:0 to 35:65). The resulting solid was recrystallized from 3:1 methanol:acetonitrile and dried overnight at 1.33 Pa and 80° C. to provide 1-[4-amino-2-ethyl-7-(5-hydroxymethylpyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol as white crystals, mp >250° C.

[0713] Anal. Calcd for C22H25N5O2: C, 67.50; H, 6.44; N, 17.89. Found: C, 67.28; H, 6.71; N, 18.06.

Example 145

2-(2-Methoxyethyl)-1-(2-methylpropyl)-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine

[0714]

198

[0715] 7-Bromo-2-(2-methoxyethyl)-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine was prepared according to the procedures described in Parts A and B of Example 9 using methoxypropanoyl chloride instead of ethoxyacetyl chloride. 7-Bromo-2-(2-methoxyethyl)-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine was coupled with pyridine-3-boronic acid 1,3-propanediol cyclic ester according to the method described in Examples 118-121. The reaction was heated at reflux overnight, and the work-up procedure described in Part F of Examples 125-131 was followed. The crude product was purified by flash column chromatography on silica gel (eluting with chloroform:CMA in a gradient from 90:10 to 76:24) followed by recrystallization from methanol. The crystals were dried at 1.33 Pa and 98° C. to provide 2-(2-methoxyethyl)-1-(2-methylpropyl)-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine as white needles, mp 207-208° C.

[0716] Anal. Calcd for C22H25N5O: C, 70.38; H, 6.71; N, 18.65. Found: C, 70.31; H, 6.76; N, 18.76.

Example 146

{5-[4-Amino-2-(2-methoxyethyl)-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]pyridin-3-yl }methanol

[0717]

199

[0718] 7-Bromo-2-(2-methoxyethyl)-1-(2-methylpropyl)-1H-imidazo[4,5- c]quinolin-4-amine was coupled with 5-(tert-butyldimethylsilanyloxymethyl)pyridine-3-boronic acid according to the method described in Examples 118-121. The reaction was heated at reflux for 2.25 hours, and the work-up procedure described in Part F of Examples 125-131 was followed. The crude product was purified and deprotected according to the procedure described in Example 144. The resulting solid was purified by HPFC (eluting with chloroform:CMA in a gradient from 100:0 to 55:45) followed by recrystallization from acetonitrile to provide {5-[4-amino-2-(2-methoxyethyl)-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]pyridin-3-yl}methanol as white needles, mp 202-204° C.

[0719] Anal. Calcd for C23H27N5O2: C, 68.13; H, 6.71; N, 17.27. Found: C, 67.89; H, 6.62; N, 17.26.

Examples 147-150

[0720] Part A

[0721] 6-Bromo-4-chloro-3-nitroquinoline, prepared from 4-bromoaniline according to the methods described in Parts A-D of Example 1, was treated according to the methods described in Parts A and B of Examples 125-135 to provide 1-(3-amino-6-bromoquinolin-4-ylamino)-2-methylpropan-2-ol.

[0722] Part B

[0723] 1-(3-Amino-6-bromoquinolin-4-ylamino)-2-methylpropan-2-ol was treated according to the method described in Parts A and B of Example 9 to provide 1-(4-amino-8-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol.

[0724] Part C

[0725] 1-(4-Amino-8-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol and the boronic acid or boronic acid ester from the table below were coupled according to the general procedure described in Part J of Example 1. The reaction was stirred overnight. The crude product was purified by flash column chromatography on silica gel (eluting sequentially with 95:5 and 90:10 dichloromethane:methanol) followed by recrystallization from methanol to provide the products shown in the table below.

[0726] For Example 150, the product from the coupling reaction (1.5 g, 2.8 mmol) was dissolved in THF (25 mL). Tetrabutylammonium fluoride (3.64 mL of a 1.0 M solution in THF) was added, and the reaction was stirred for one hour at ambient temperature. Saturated ammonium chloride (20 mL) was added, and the aqueous layer was separated and extracted with dichloromethane (3×50 mL). The combined organic fractions were dried over sodium sulfate and filtered. A precipitate formed in the filtrate and was isolated by filtration. The solid was washed with dichloromethane, stirred with methanol, isolated by filtration, and washed with methanol to provide the product shown in the table below.

Examples 147-150

[0727]

200

Example
Boronic Acid or Ester
R3

147
trans-2-Phenylvinylboronic acid

201

148
Pyridine-3-boronic acid

202

149
3-(Methylsulfonylamino)phenylboronic acid

203

150
5-(tert-Butyldimethylsilanyloxymethyl) pyridine-3-boronic acid

204

Examples 147-150

[0728]

9

mp

Example
Name
Form
(° C.)
Anal.

147
1-(4-Amino-2-
Pale
217-218
Calcd for C25H28N4O2:

ethoxymethyl-8-styryl-1H-
yellow

C, 72.09; H, 6.78; N,

imidazo[4,5-c]quinolin-1-
powder

13.45. Found: C,

yl)-2-methylpropan-2-ol

71.71; H, 6.97; N,

13.46.

148
1-[4-Amino-2-
White
222-223
Calcd for C22H25N5O2:

ethoxymethyl-8-(pyridin-3-
crystals

C, 67.50; H, 6.44; N,

yl)-1H-imidazo[4,5-

17.89. Found: C,

c]quinolin-1-yl]-2-

67.23; H, 6.55; N,

methylpropan-2-ol

17.85.

149
N-{3-[4-Amino-2-
Off-
221-222
Calcd for

ethoxymethyl-1-(2-hydroxy-
white

C24H29N5O4S.0.33H2O:

2-methylpropyl)-1H-
crystals

C, 58.89; H, 6.11; N,

imidazo[4,5-c]quinolin-8-

14.31. Found: C,

yl]phenyl}methanesulfamide

58.81; H, 5.80; N,

14.30.

150
1-[4-Amino-2-
White
230-232
Calcd for C23H27N5O3:

ethoxymethyl-8-(5-
powder

C, 65.54; H, 6.46; N,

hydroxymethylpyridin-3-yl)-

16.62. Found: C,

1H-imidazo[4,5-c]quinolin-

65.25; H, 6.24; N,

1-yl]-2-methylpropan-2-ol

16.65.

Example 151

1-(4-Amino-2-ethoxymethyl-8-phenethyl-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol

[0729]

205

[0730] 1-(4-Amino-2-ethoxymethyl-8-styryl-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol (1.0 g, 2.4 mmol) was treated according to the method described in Example 123. The crude product was purified by flash column chromatography on silica gel (eluting with 95:5 dichloromethane:methanol) prior to recrystallization from methanol to provide 0.500 g of 1-(4-amino-2-ethoxymethyl-8-phenethyl-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol as white crystals, mp 175-176° C.

[0731] Anal. Calcd for C25H30N4O2: C, 70.38; H, 7.30; N, 13.13. Found: C, 70.27; H, 7.26; N, 13.11.

Examples 152-156

[0732] Part A

[0733] A solution of tert-butoxy N-(4-aminobutyl)carbamate (15.38 g, 81.7 mmol) in dichloromethane (100 mL) was added dropwise over a period of 30 minutes to a solution of 7-bromo-4-chloro-3-nitroquinoline (74.3 mmol) and triethylamine (20.6 mL, 149 mmol) in dichloromethane (400 mL), and the reaction was stirred overnight at ambient temperature. The reaction was diluted with dichloromethane (500 mL), washed sequentially with water and brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was recrystallized from isopropanol to provide tert-butyl [4-(7-bromo-3-nitroquinolin-4-ylamino)butyl]carbamate as a yellow solid.

[0734] Part B

[0735] A solution of sodium hydrosulfite (43.35 g, 249 mmol) and potassium carbonate (38.28 g, 277 mmol) in water (300 mL) was added to a mixture of tert-butyl [4-(7-bromo-3-nitroquinolin-4-ylamino)butyl]carbamate (24.3 g, 55.3 mmol) and 1,1′-diethyl-4,4′-bipyridinium dibromide (1.03 g, 2.76 mmol) in dichloromethane (368 mL) and water (40 mL), and the reaction was stirred overnight at ambient temperature. The reaction mixture was filtered through a layer of CELITE filter aid. The aqueous filtrate was extracted with dichloromethane, and the combined organic fractions were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide 22.4 g of tert-butyl [4-(3-amino-7-bromoquinolin-4-ylamino)butyl]carbamate as a brown powder.

[0736] Part C

[0737] tert-Butyl [4-(3-amino-7-bromoquinolin-4-ylamino)butyl]carbamate (24.3 g, 59.4 mmol) was treated with ethoxyacetyl chloride (7.28 g, 59.4 mmol) according to the method described in Part C of Examples 125-135.

[0738] Part D

[0739] A solution of the material from Part C and triethylamine (33.1 mL, 238 mmol) in ethanol (295 mL) was heated at reflux for two hours. The reaction was then allowed to cool to ambient temperature, and the solvent was removed under reduced pressure. The residue was dissolved in dichloromethane, and the resulting solution was washed sequentially with water and brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel (eluting sequentially with 90:10 and 85:15 chloroform:CMA) to provide 23.6 g of tert-butyl [4-(7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]carbamate as a tan solid.

[0740] Part E

[0741] Concentrated hydrochloric acid (15.6 mL, 0.194 mol) was added to a solution of tert-butyl [4-(7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]carbamate (23.2 g, 48 mmol) in ethanol, and the reaction was heated at reflux for 20 minutes. A precipitate formed, and the reaction was allowed to cool to ambient temperature overnight. The solid was isolated by filtration, washed with ethanol, and dissolved in water. The solution was washed with dichloromethane and then made basic with the addition of 50% aqueous sodium hydroxide. The basic solution was extracted with dichloromethane (3×300 mL), and the combined extracts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide 17 g of 4-(7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)butylamine as an off-white solid.

[0742] Part F

[0743] 3-Chloropropanesulfonyl chloride (5.45 mL, 44.8 mmol) was added dropwise over a period of four minutes to a solution of 4-(7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)butylamine (16.9 g, 44.8 mmoL) and triethylamine (9.42 mL, 67.6 mmol) in dichloromethane (300 mL), and the reaction was stirred at ambient temperature for 30 minutes. The reaction was poured into water, and the organic layer was washed with brine and dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting solid was dissolved in N,N-dimethylformamide (DMF) (300 mL), and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (10.1 mL, 67.6 mmol) was added. The reaction was stirred overnight at ambient temperature under a nitrogen atmosphere. Additional DBU (5 mL) was added, and the reaction was stirred for an additional four hours. The solvent was removed under reduced pressure, and the residue was dissolved in dichloromethane. The resulting solution was washed with water (2×200 mL) and brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide 7-bromo-1-[4-(1,1-dioxidoisothiazolidin-2-yl)-2-ethoxymethyl-1H-imidazo[4,5-c]quinoline as an oil.

[0744] Part G

[0745] 7-Bromo-1-[4-(1,1-dioxidoisothiazolidin-2-yl)-2-ethoxymethyl-1H-imidazo[4,5-c]quinoline was oxidized and then aminated according to the methods described in Parts H and I of Example 1. The oxidation was carried out in chloroform, and several equivalents of 3-chloroperoxybenzoic acid were used. The product from amination was purified by column chromatography on silica gel (eluting with chloroform:CMA in a gradient from 98:2 to 85:15) followed by recrystallization from acetonitrile to provide 7-bromo-1-[4-(1,1-dioxidoisothiazolidin-2-yl)-2-ethoxymethyl-1H-imidazo [4,5-c] quinolin-4-amine ethyl-1H-imidazo[4,5-c]quinolin-4-amine

[0746] Part H

[0747] 7-Bromo-1-[4-(1,1-dioxidoisothiazolidin-2-yl)-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-4-amine and the boronic acid or boronic acid ester from the table below were coupled according to the general procedure described in Part J of Example 1. The reaction was heated at reflux until an analysis by HPLC indicated the reaction was complete. The work-up procedure described in Part F of Examples 125-135 was followed, and the crude product was purified by column chromatography on silica gel (eluting with a gradient of chloroform:CMA) followed by recrystallization using the solvent indicated in the table below.

[0748] For Example 155, the reaction was heated at reflux for three hours. Following chromatographic purification, the residue was deprotected according to the method described in Example 144, purified by column chromatography, and recrystallized from acetonitrile.

[0749] For Example 156, the coupling was carried out using tri(ortho-tolyl)phosphine instead of triphenylphosphine.

Examples 152-156

[0750]

206

Recrystallization

Example
Boronic acid or ester
solvent
R3

152
Phenylboronic acid
Acetonitrile

207

153
Pyridine-3-boronic acid 1,3- propanediol cyclic ester
Isopropanol

208

154
Pyridine-4-boronic acid pinacol ester
Methanol then Isopropanol

209

155
5-(tert- Butyldimethylsilanyloxymethyl) pyridine-3-boronic acid
Acetonitrile

210

156
3-(Hydroxymethyl)phenylboronic acid
Acetonitrile (twice)

211

Example 152

1-[4-(1,1-Dioxidoisothiazolidin-2-yl)butyl]-2-ethoxymethyl-7-phenyl-1H-imidazo[4,5-c]quinolin-4-amine

[0751] The product was obtained as white crystals, mp 167-168.5° C.

[0752]

13
C NMR (75MHz, DMSO-d6) δ 152.3, 148.9, 145.6, 140.1, 138.5, 132.8, 129.0, 127.4, 126.7, 126.4, 123.8, 121.0, 120.1, 113.8, 65.4, 64.1, 46.5, 46.1, 45.1, 43.8, 27.2, 24.3, 18.3, 14.9;

[0753] MS (APCl) m/z 494.2213 (494.2226 calcd for C26H31N5O3S, M+H);

[0754] Anal. Calcd for C26H31N5O3S: C, 63.26; H, 6.33; N, 14.19; S, 6.50. Found: C, 62.66; H, 6.34; N, 14.10; S, 6.45.

Example 153

1-[4-(1,1-Dioxidoisothiazolidin-2-yl)-butyl]-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine

[0755] The product was obtained as white, flocculent crystals, mp 171-173° C.

[0756] Anal. Calcd for C25H30N6O3S: C, 60.71; H, 6.11; N, 16.99. Found: C, 60.56; H, 6.18; N, 16.92.

Example 154

1-[4-(1,1-Dioxidoisothiazolidin-2-yl)-butyl]-2-ethoxymethyl-7-(pyridin-4-yl)-1H-imidazo[4,5-c]quinolin-4-amine

[0757] The product was obtained as a white, crystalline solid, mp 186-187.5° C.

[0758] Anal. Calcd for C25H30N6O3S: C, 60.71; H, 6.11; N, 16.99; S, 6.48. Found: C, 60.36; H, 6.38; N, 16.88; S, 6.42.

Example 155

(5-{4-Amino-1-[4-(1,1-dioxidoisothiazolidin-2-yl)butyl]-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-7-yl}pyridin-3-yl)methanol

[0759] The product was obtained as a white, powdery solid, mp 184.5-186° C.

[0760] Anal. Calcd for C26H32N6O4S: C, 59.52; H, 6.15; N, 16.02; S, 6.11. Found: C, 59.53; H, 6.01; N, 16.06; S, 6.04.

Example 156

(5-{4-Amino-1-[4-(1,1-dioxidoisothiazolidin-2-yl)butyl]-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-7-yl}phenyl)methanol

[0761] The product was obtained as a white powder, mp 158-161° C.

[0762]

13
C NMR (75MHz, DMSO-d6) δ 152.3, 148.9, 145.4, 143.3, 139.9, 138.7, 132.9, 46.5, 46.1, 45.1, 43.8, 27.2, 24.3, 18.3, 14.9; 46.5, 46.1, 45.1, 43.8, 27.2, 24.3, 18.3, 14.9;

[0763] MS (APCl) m/z 524.2 (524.2 calcd for C27H33N5O4S, M+H);

[0764] Anal. Calcd for C27H33N5O4S.0.3H2O: C, 61.93; H, 6.35; N, 13.37; S, 6.12.

[0765] Found: C, 61.51; H, 6.78; N, 13.24; S, 6.12.

Example 157

tert-Butyl {4-[4-amino-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazol[4,5-c]quinolin-1-yl]butyl}carbamate

[0766]

212

[0767] tert-Butyl [4-(7-bromo-2-ethoxymethyl-1H-imidazo [4,5-c]quinolin-1-yl)butyl]carbamate was oxidized and aminated according to the methods described in Parts H and I of Example 1 to afford tert-butyl [4-(4-amino-7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]carbamate, which was coupled with 3-pyridylboronic acid according to the method described in Part J of Example 1. The reaction was heated at reflux for four hours, and the work-up procedure described in Part F of Examples 125-135 was followed. The crude product was recrystallized from acetonitrile (1 mL/g) to provide tert-butyl {4-[4-amino-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]butyl}carbamate as a white solid, mp 117-119° C.

[0768] Anal. Calcd for C27H34N6O3: C, 64.33; H, 7.10; N, 16.67. Found: C, 64.35; H, 7.42; N, 16.71.

Example 158

tert-Butyl {4-[4-amino-2-propyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]butyl}carbamate

[0769]

213

[0770] tert-Butyl [4-(3-amino-7-bromoquinolin-4-ylamino)butyl]carbamate was treated with butyryl chloride and cyclized according to the methods described in Part C and D of Examples 125-135. The resulting product, tert-butyl [4-(7-bromo-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]carbamate was oxidized and aminated according to the methods described in Parts H and I of Example 1 to afford tert-butyl [4-(4-amino-7-bromo-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]carbamate, which was coupled with 3-pyridylboronic acid according to the method described in Part J of Example 1. The reaction was heated at reflux for four hours, and the work-up procedure described in Part F of Examples 125-135 was followed. The crude product was recrystallized from toluene (1 mL/g) to provide tert-butyl {4-[4-amino-2-propyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]butyl}carbamate as a tan powder, mp 136-138° C.

[0771] Anal. Calcd for C27H34N6O2: C, 65.83; H, 7.37; N, 17.06. Found: C, 65.92; H, 7.61; N, 16.92.

Examples 159-161

[0772] Part A

[0773] 7-Bromo-4-chloro-3-nitroquinoline (39.85 g, 138.6 mmol) was reacted with 2,2-dimethyl-1,3-dioxolane-4-methanamine (20.0 g, 152 mmol) according to the method described in Part A of Examples 125-135 to provide 48.35 g of (7-bromo-3-nitroquinolin-4-yl)-2,2-dimethyl-1,3-dioxolan-4-ylmethyl)amine as a yellow solid. The product was not recrystallized.

[0774] Part B

[0775] The methods described in Parts B, C, and D of Examples 152-156 were used to convert (7-bromo-3-nitroquinolin-4-yl)-2,2-dimethyl-1,3-dioxolan-4-ylmethyl)amine to 7-bromo-1-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]-2-ethoxymethyl-1H-imidazo[4,5-c]quinoline, which was obtained as an off-white solid, mp 138-140° C. In Part B, 1,1′-di-n-octyl-4,4′-bipyridinium dibromide was used instead of 1,1′-diethyl-4,4′-bipyridinium dibromide. Triethylamine (1.1 equivalents) was added in Part C.

[0776] Anal. Calcd for C19H22BrN3O3: C, 54.30; H, 5.28; N, 10.00. Found: C, 54.07; H, 5.25; N, 9.90.

[0777] Part C

[0778] 7-Bromo-1-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]-2-ethoxymethyl-1H-imidazo[4,5-c]quinoline was oxidized and then aminated according to the methods described in Parts H and I of Example 1. The oxidation product was not recrystallized. The product from amination was purified by column chromatography on silica gel (eluting with chloroform:CMA in a gradient from 95:5 to 85:15) followed by recrystallization from acetonitrile to provide 7- bromo-1-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-4-amine as a white solid, mp 174-175° C.

[0779] Anal. Calcd for C19H23BrN4O3: C, 52.42; H, 5.33; N, 12.87. Found: C, 52.41; H, 5.25; N, 12.81.

[0780] Part D

[0781] 7-Bromo-1-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-4-amine and the boronic acid or ester from the table below were coupled according to the method described in Examples 118-121. The work-up procedure described in Part F of Examples 125-135 was followed. For Examples 159 and 160, the crude product was purified by flash chromatography (eluting with a gradient of chloroform:CMA) followed by recrystallization from the solvent indicated in the table below. For Example 161, the crude product was dissolved in hot methanol, filtered, concentrated under reduced pressure, triturated with ethyl acetate, isolated by filtration, and then recrystallized from methanol.

Examples 159-161

[0782]

214

Recrystallization

Example
Boronic acid or ester
solvent
R3

159
Pyridine-3-boronic acid 1,3- propanediol cyclic ester
Acetonitrile (twice)

215

160
4- (Hydroxymethyl)phenylboronic acid
Ethanol

216

161
Phenylboronic acid
Methanol

217

Example
Name
Form
mp
Anal.

159
1-[(2,2-Dimethyl-1,3- dioxolan-4-yl)methyl]-2- ethoxymethyl-7-(pyridin-3- yl)-1H-imidazo[4,5- c]quinolin-4-amine
White crystals
181-182° C.
Calcd for C24H27N5O3: C, 65.65; H, 6.33; N, 15.95. Found: C, 65.77; H, 6.33; N, 15.96.

160
1-[(2,2-Dimethyl-1,3- dioxolan-4-yl)methyl]-2- ethoxymethyl-7-(4- hydroxymethyiphenyl)-1H- imidazo[4,5-c]quinolin-4- amine
Off- white crystals
219-220° C.
Calcd for C26H30N4O4: C, 67.51; H, 6.54; N, 12.11. Found: C, 67.47; H, 6.21; N, 11.98.

161
1-[(2,2-Dimethyl-1,3- dioxolan-4-yl)methyl]-2- ethoxymethyl-7-phenyl-1H- imidazo[4,5-c]quinolin-4- amine
Light yellow crystals
168-170° C.
Calcd for C25H28N4O3: C, 69.42; H, 6.53; N, 12.95. Found: C, 69.37; H, 6.62; N, 13.04.

Example 162

3-[4-Amino-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]propane-1,2-diol

[0783]

218

[0784] Hydrochloric acid (12 mL of 1 N) was added to a solution of 1-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine (0.75 g, 1.73 mmol) in THF, and the reaction was stirred overnight at ambient temperature. The THF was removed under reduced pressure, and 1% aqueous sodium hydroxide was added to the remaining solution to adjust to pH 9. A precipitate formed, was isolated by filtration, washed with water, and dried in an oven at 60° C. to provide 0.61 g of 3-[4-amino-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]propane-1,2-diol as a white solid, mp 218-220° C.

[0785] Anal. Calcd for C21H23N5O3: C, 62.68; H, 6.01; N, 17.40. Found: C, 62.58; H, 5.99; N, 17.29.

Examples 163-175

[0786] Part A

[0787] 7-Bromo-4-chloro-3-nitroquinoline (29.54 g, 102.7 mmol) was reacted with 3-methoxy propyl amine (10.07 g, 113.0 mmol) according to the method described in Part A of Examples 125-135 to provide 32.9 g of (7-bromo-3-nitroquinolin-4-yl)-(3-methoxypropyl)amine as a yellow solid. The product was not recrystallized.

[0788] Part B

[0789] The methods described in Parts B, C, and D of Examples 152-156 were used to convert (7-bromo-3-nitroquinolin-4-yl)-(3-methoxypropyl)amine to 7-bromo-2-ethoxymethyl-1-(3-methoxypropyl)-1H-imidazo[4,5-c]quinoline, which was obtained as a white solid. In Part B, 1,1′-di-n-octyl-4,4′-bipyridinium dibromide was used instead of 1,1′-diethyl-4,4′-bipyridinium dibromide. Triethylamine (1.1 equivalents) was added in Part C. The chromatographic purification in Part D was carried out using ethyl acetate:acetone as the eluent.

[0790] Part C

[0791] 7-Bromo-2-ethoxymethyl-1-(3-methoxypropyl)-1H-imidazo[4,5-c]quinoline was oxidized and then aminated according to the methods described in Parts H and I of Example 1. The oxidation product was not recrystallized. The product from amination was purified as described in Part C of Examples 159-161 to provide 7-bromo-2-ethoxymethyl-1-(3-methoxypropyl)-1H-imidazo[4,5-c]quinolin-4-amine as off-white crystals.

[0792] Part D

[0793] 7-Bromo-2-ethoxymethyl-1-(3-methoxypropyl)-1H-imidazo[4,5-c]quinolin-4-amine and the boronic acid or ester from the table below were coupled according to the method described in Examples 118-121 or in Part J of Example 1. For Example 159, the product was isolated as a solid and recrystallized from ethanol. For the remaining examples, the crude product was purified by flash chromatography (eluting with a gradient of chloroform:CMA) followed by recrystallization from the solvent indicated in the table below.

[0794] For Example 167, following chromatographic purification the product was deprotected according to the method described in Example 144. The crude deprotected product was recrystallized from isopropanol and then from acetonitrile to provide the product shown in the table below.

Examples 163-175

[0795]

219

Recrystallization

Ex.
Boronic acid or ester
solvent
R3

163
Phenylboronic acid
Isopropanol then acetonitrile

220

164
Pyridine-3-boronic acid 1,3-propanediol cyclic ester
Acetonitrile (twice)

221

165
Pyridine-4-boronic acid pinacol ester
Ethanol (twice)

222

166
4-(Hydroxymethyl)phenylboronic acid
Ethanol

223

167
5-(tert- butyldimethylsilanyloxymethyl)pyridine- 3-boronic acid
Isopropanol then Acetonitrile

224

168
Furan-2-boronic acid
Acetonitrile

225

169
4-Chlorophenylboronic acid
Ethanol (twice)

226

170
4-(Morpholine-4- carbonyl)phenylboronic acid
Ethanol

227

171
3-(iso-Butylaminocarbonyl) phenylboronic acid
Ethanol (twice)

228

172
4-(Ethylsulfonyl)phenylboronic acid
Ethanol

229

173
4-(iso-Propoxyphenyl)boronic acid
Acetonitrile

230

174
3-(Morpholine-4- carbonyl)phenylboronic acid
Acetonitrile

231

175
3-(Pyrrolidine-1-carbonyl)phenylboronic acid
Ethyl acetate

232

Examples 163-175

[0796]

13

Example
Name
Form
Mp (° C.)
Anal.

163
2-Ethoxymethyl-1-(3-methoxypropyl)-7-
White
146-147
Calcd for C23H26N4O2: C, 70.75; H,

phenyl-1H-imidazo[4,5-c]quinolin-4-amine
crystals

6.71; N, 14.35. Found: C, 70.73; H,

6.70; N, 14.34.

164
2-Ethoxymethyl-1-(3-methoxypropyl)-7-
White
151-152
Calcd for C22H25N5O2: C, 67.50; H,

(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-
crystals

6.44; N, 17.89. Found: C, 67.21; H,

4-amine

6.46; N, 17.97.

165
2-Ethoxymethyl-1-(3-methoxypropyl)-7-
White,
225-226
Calcd for C22H25N5O2: C, 67.50; H,

(pyridin-4-yl)-1H-imidazo[4,5-c]quinolin-
crystalline

6.44; N, 17.89. Found: C, 67.29; H,

4-amine
solid

6.37; N, 17.64.

166
2-Ethoxymethyl-1-(3-methoxypropyl)-7-(4-
White,
228-229
Calcd for C24H28N4O3: C, 68.55; H,

hydroxymethylphenyl)-1H-imidazo[4,5-
crystalline

6.71; N, 13.32. Found: C, 68.36; H,

c]quinolin-4-amine
solid

6.86; N, 13.06.

167
2-Ethoxymethyl-1-(3-methoxypropyl)-7-(5-
White solid
198-199
Calcd for C23H27N5O3: C, 65.54; H,

hydroxymethylpyridin-3-yl)-1H-

6.46; N, 16.62. Found: C, 65.41; H,

imidazo[4,5-c]quinolin-4-amine

6.40; N, 16.63.

168
2-Ethoxymethyl-7-(furan-2-yl)-1-(3-
Off-white
144-145
Calcd for C21H24N4O3: C, 66.30; H,

methoxypropyl)-1H-imidazo[4,5-
solid

6.36; N, 14.73. Found: C, 65.96; H,

c]quinolin-4-amine

6.16; N, 14.56.

169
7-(4-Chlorophenyl)-2-ethoxymethyl-1-(3-
White solid
188-190
Calcd for C23H25ClN4O2: C, 65.01;

methoxypropyl)-1H-imidazo[4,5-

H, 5.93; N, 13.18. Found: C, 64.72;

c]quinolin-4-amine

H, 5.93; N, 13.04.

170
{4-[4-Amino-2-ethoxymethyl-1-(3-
White solid
163-165
Calcd for C28H33N5O4: C, 66.78; H,

methoxypropyl)-1H-imidazo[4,5-

6.61; N, 13.91. Found: C, 66.52; H,

c]quinolin-7-yl]phenyl}morpholin-4-

6.59; N, 13.71.

ylmethanone

171
3-[4-Amino-2-ethoxymethyl-1-(3-
Off-white
209-210
Calcd for C28H35N5O3: C, 68.69; H,

methoxypropyl)-1H-imidazo[4,5-
solid

7.21; N, 14.30. Found: C, 68.52; H,

c]quinolin-7-yl]-N-(2-

7.44; N, 14.23.

methylpropyl)benzamide

172
7-[(4-Ethanesulfonyl)phenyl]-2-
White solid
156-158
Calcd for C25H30N4O4S: C, 62.22;

ethoxymethyl-1-(3-methoxypropyl)-1H-

H, 6.27; N, 11.61. Found: C, 61.99;

imidazo[4,5-c]quinolin-4-amine

H, 5.98; N, 11.47.

173
2-Ethoxymethyl-7-[4-(2-propoxy)phenyl]-
Off-white
175-177
Calcd for C26H32N4O3: C, 69.62; H,

1-(3-methoxypropyl)-1H-imidazo[4,5-
crystals

7.19; N, 12.49. Found: C, 69.70; H,

c]quinolin-4-amine

7.45; N, 12.60.

174
{3-[4-Amino-2-ethoxymethyl-1-(3-
Off-white
174-176
Calcd for C28H33N5O4: C, 66.78; H,

methoxypropyl)-1H-imidazo[4,5-
crystals

6.61; N, 13.91. Found: C, 66.55; H,

c]quinolin-7-yl]phenyl}morpholin-4-

6.53; N, 13.97.

ylmethanone

175
{3-[4-Amino-2-ethoxymethyl-1-(3-
White solid
145-146
Calcd for C28H33N5O3.0.85HCl: C,

methoxypropyl)-1H-imidazo[4,5-

64.85; H, 5.81; N, 6.58. Found: C,

c]quinolin-7-yl]phenyl}pyrrolidin-1-

64.90; H, 5.74; N, 6.61.

ylmethanone

Example 176

tert-Butyl 4-{[4-amino-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}piperidine-1-carboxylate

[0797]

233

[0798] Part A

[0799] 7-Bromo-4-chloro-3-nitroquinoline was treated according to the methods described in Parts A through D of Examples 152-156 using 1-(tert-butoxycarbonyl)-4-(aminomethyl)piperidine (Carceller, E. et al, J. Med. Chem., 39, 487-493 (1996)) in Part A. In Part B, 1,1′-di-n-octyl-4,4′-bipyridinium dibromide was used instead of 1,1′-diethyl-4,4′-bipyridinium dibromide. Triethylamine (1.1 equivalents) was added to the reaction in Part C. Following chromatographic purification in Part D (eluting with 95:5 chloroform:CMA), tert-butyl 4-[(7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]piperidine-1-carboxylate was obtained as an off-white solid. A small portion of the product was recrystallized from acetonitrile to provide a white solid, mp 169-170° C.

[0800] Anal. Calcd for C24H31BrN4O3: C, 57.26; H, 6.21; N, 11.13. Found: C, 57.31; H, 6.29; N, 11.07.

[0801] Part B

[0802] tert-Butyl 4-[(7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]piperidine-1-carboxylate was oxidized and then aminated according to the methods described in Parts H and I of Example 1. The oxidation product was not recrystallized. The product from amination was purified as described in Part C of Examples 159-161 to provide tert-butyl 4-[(4-amino-7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]piperidine-1-carboxylate as a tan solid.

[0803] Part C

[0804] tert-Butyl 4-[(4-amino-7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]piperidine-1-carboxylate (12.79 g, 24.67 mmol) and pyrdine-3-boronic acid 1,3-propanediol cyclic ester (4.42 g, 27.14 mmol) were coupled according to the method described in Examples 118-121. The work-up procedure described in Part F of Examples 125-135 was followed. The crude product was recrystallized twice from ethyl acetate to provide 10.89 g of tert-butyl 4-{[4-amino-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}piperidine-1-carboxylate as an off-white solid, mp 197-198° C.

[0805] Anal. Calcd for C29H36N6O3.0.5H2O: C, 66.26; H, 7.10; N, 15.99. Found: C, 66.47; H, 7.47; N, 16.00.

Example 177

2-Ethoxymethyl- -(piperidin-4-ylmethyl)-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine trihydrochloride

[0806]

234

[0807] Ethanolic hydrochloric acid (17.68 mL of 4.25 M) was added to a solution of tert-butyl 4-{[4-amino-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}piperidine-1-carboxylate (9.71 g, 18.8 mmol) in anhydrous ethanol, and the reaction was heated at reflux for two hours. A precipitate formed, and the reaction was allowed to cool to ambient temperature. The solid was isolated by filtration, washed with a small volume of cold ethanol, and dried under reduced pressure to provide 7.1 g of 2-ethoxymethyl-1-(piperidin-4-ylmethyl)-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine trihydrochloride as an off-white solid, mp >250° C.

[0808] Anal. Calcd for C24H28N6O.3HCl.1.17H2O: C, 52.70; H, 6.14; N, 15.36. Found: C, 53.11; H, 6.48; N, 15.07.

Examples 178-181

[0809] A 0.02-0.03 M solution of 2-ethoxymethyl-1-(piperidin-4-ylmethyl)-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine trihydrochloride (1 equivalent) and triethylamine (5 equivalents) in the solvent indicated in the table below was cooled to 4° C. The reagent from the table below (1 equivalent) was added dropwise, and the reaction was allowed to warm to ambient temperature and stirred for between two and 24 hours. The reaction mixture was diluted with chloroform, and the resulting solution was washed sequentially with water, 4% aqueous sodium carbonate (2×), water, and brine and then concentrated under reduced pressure. For Examples 178, 179, and 181, the residue was purified by flash column chromatography on silica gel (eluting with chloroform:CMA) followed by recrystallization from the solvent indicated in the table below. For Example 180, the crude product was recystallized from ethyl acetate. The structures of the products are shown in the table.

Examples 178-181

[0810]

14

Reaction
Recrystallization

Example
Reagent
solvent
solvent
R

178
Methanesulfonyl chloride
Chloroform
Acetonitrile then ethyl acetate

235

179
Isobutyryl chloride
1-Methyl-2- pyrrolidinone
Ethyl Acetate

236

180
4- Morpholinecarbonyl chloride
Chloroform
Ethyl acetate

237

181
Palmitoyl chloride
Chloroform
Chloroform:hexanes

238

Examples 178-181

[0811]

15

Mp

Example
Name
Form
(° C.)
Anal.

178
2-Ethoxymethyl-1-{[1-
Off-white
254-255
Calcd for

(methanesulfonyl)piperidin-
powder

C25H30N6O3S.

4-yl]methyl}-7-(pyridin-3-

0.4 HCl: C,

yl)-1H-imidazo[4,5-

58.97; H, 6.02; N,

c]quinolin-4-amine

16.50; Cl, 2.78.

Found: C, 58.94;

H, 5.78; N, 16.34;

Cl, 3.06.

179
2-Ethoxymethyl-1-[(1-
Beige
130-132
Calcd for

isobutyrylpiperidin-4-
powder

C28H34N6O2.

yl)methyl]-7-(pyridin-3-yl)-

0.375 H2O: C,

1H-imidazo[4,5-c]quinolin-

68.16; H, 7.10; N,

4-amine

17.03. Found: C,

67.84; H, 7.14; N,

16.82.

180
2-Ethoxymethyl-1-{[1-
Tan solid
224-225
Calcd for

(morpholin-4-

C29H35N7O3.

ylcarbonyl)piperidin-4-

0.125 H2O: C,

yl]methyl}-7-(pyridin-3-yl)-

65.49; H, 6.68; N,

1H-imidazo[4,5-c]quinolin-

18.43. Found: C,

4-amine

65.12; H, 6.40; N,

18.19.

181
2-Ethoxymethyl-1-[(1-
Off-white
72-75
Calcd for

palmitoylpiperidin-4-
crystalline

C40H58N6O2.0.1

yl)methyl]-7-(pyridin-3-yl)-
solid

H2O: C, 73.15;

1H-imidazo[4,5-c]quinolin-

H, 8.93; N, 12.80.

4-amine

Found: C, 72.83;

H, 8.84; N, 12.75

Example 182

2-Ethoxymethyl-7-(pyridin-3-yl)-1-{[1-(tetrahydrofuran-2-ylcarbonyl)piperidin-4-yl]methyl}-1H-imidazo[4,5-c]quinolin-4-amine

[0812]

239

[0813] A solution of 2-ethoxymethyl-1-(piperidin-4-ylmethyl)-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine trihydrochloride (1.0 g, 1.90 mmol) and triethylamine (1.35 mL, 9.50 mmol) in chloroform (80 mL) was cooled to 4° C. 2-Tetrahydrofuroic acid (0.243 g, 2.09 mmol) and 1-(3-dimethoxyaminopropyl)-3-ethylcarbodiimide hydrochloride (0.401 g, 2.09 mmol) were sequentially added, and the reaction was stirred for two hours. The reaction was incomplete as determined by thin layer chromatography (TLC) analysis. The reaction was cooled to 4° C., and 1-hydroxybenzotriazole (0.283 g, 2.09 mmol) was added. The reaction was allowed to warm to ambient temperature, stirred for 16 hours, and then diluted with chloroform (100 mL). The resulting solution was washed sequentially with water (100 mL), 4% aqueous sodium carbonate (2×100 mL), water (200 mL), and brine (150 mL); dried over sodium sulfate; filtered; and concentrated under reduced pressure. The residue was purified by HPFC followed by recrystallization from ethyl acetate to provide 0.68 g of 2-ethoxyrnethyl-7-(pyridin-3-yl)-1-{[1-(tetrahydrofuran-2-ylcarbonyl)piperidin-4-yl]methyl}-1H-imidazo[4,5-c]quinolin-4-amine as a white, crystalline solid, mp 191-192° C.

[0814] Anal. Calcd for C29H34N6O3.0.3H2O: C, 66.98; H, 6.71; N, 16.16. Found: C, 66.87; H, 6.70; N, 15.77.

Example 183-186

[0815] Part A

[0816] 7-Bromo-4-chloro-3-nitroquinoline (35.26 g, 123.8 mmol) was treated with 1-(3-aminopropyl)pyrrolidin-2-one (19.1 mL, 136.2 mmol) according to the method described in Part E of Example 1 to provide 40.87 g of 1-[3-(7-bromo-3-nitroquinolin-4-ylamino)propyl]pyrrolidin-2-one as a yellow solid.

[0817] Part B

[0818] 1-[3-(7-Bromo3-nitroquinolin-4-ylamino)propyl]pyrrolidin-2-one was treated according to the methods described in Parts B, C, and D of Examples 152-156. 3-Methoxypropionyl chloride was used in Part C, and triethylamine (1.3 equivalents) was added to the reaction mixture. The crude product obtained in Part D was purified by flash chromatography on silica gel (eluting sequentially with 100:0 and 92.5:7.5 chloroform:methanol) followed by recrystallization from acetonitrile. The crystals were washed with acetonitrile and diethyl ether and dried in a vacuum oven at 60° C. to provide 1-{3-[7-bromo-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}pyrrolidin-2-one as a light grey solid.

[0819] Part C

[0820] 1-{3-[7-Bromo-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}pyrrolidin-2-one was oxidized and then aminated according to the methods described in Parts H and I of Example 1. The product from amination was recrystallized from isopropanol and then from ethanol. The crystals were washed with cold ethanol and diethyl ether and dried overnight in a vacuum oven at 60° C. to provide 1-{3-[4-amino-7-bromo-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}pyrrolidin-2-one as a white solid, mp 228-231° C.

[0821] Anal. Calcd for C20H24N5O2Br: C, 53.82; H, 5.42; N, 15.69. Found: C, 53.48; H, 5.37; N, 15.45.

[0822] Part D

[0823] 1-{3-[4-Amino-7-bromo-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}pyrrolidin-2-one and the boronic acid or ester from the table below were coupled according to the method described in Examples 118-121. The work-up procedure described in Part F of Examples 125-135 was followed. The crude product was purified by HPFC (eluting with chloroform:CMA in a gradient from 100:00 to 70:30) followed by recrystallization from the solvent listed in the table below to provide the product shown in the table.

Examples 183-186

[0824]

240

Recrystallization

Example
Boronic acid or ester
solvent
R3

183
3-Pyridine boronic acid
Ethanol

241

184
Pyridine-4-boronic acid pinacol ester
Acetonitrile

242

185
3-(Hydroxymethyl)phenylboronic acid
Ethanol

243

186
[3- (Methylsulfonyl)aminophenyl]boronic acid
Not used

244

Examples 183-186

[0825]

17

Exam-

Mp

ple
Name
Form
(° C.)
Anal.

183
1-{3-[4-Amino-2-(2-
White
218-
Calcd for

methoxyethyl)-7-(pyridin-
solid
221
C25H28N6O2: C,

3-yl)-1H-imidazo[4,5-

67.55; H, 6.35;

c]quinolin-1-yl]propyl}

N, 18.91. Found:

pyrrolidin-2-one

C, 67.30; H,

6.37; N, 18.79.

184
1-{3-[4-Amino-2-(2-
Off-
232-
Calcd for

methoxyethyl)-7-
white
235
C25H28N6O2: C,

(pyridin-4-yl)-1H-
solid

67.55; H, 6.35;

imidazo[4,5-c]quinolin-1-

N, 18.91. Found:

yl]propyl}pyrrolidin-2-one

C, 67.18; H,

6.49; N, 18.77.

185
1-{3-[4-Amino-7-(3-
Off-
184-
Calcd for

hydroxymethylphenyl)-
white
187
C27H31N5O3.1.2

2-(2-methoxyethyl)-1H-
needles

H2O: C, 65.49;

imidazo[4,5-

H, 6.80; N,

c]quinolin-1-yl]propyl}

14.14. Found:

pyrrolidin-2-one

C, 65.46; H,

6.82; N, 14.14.

186
N-(3-{4-Amino-2-(2-
White
210-
Calcd for

methoxyethyl)-1-[3-(2-
powder
213
C27H32N6O4S: C,

oxopyrrolidin-1-

60.43; H, 6.01;

yl)propyl]-1H-imidazo[4,5-

N, 15.66. Found:

c]quinolin-7-yl}

C, 60.17; H,

phenyl)methanesulfonamide

6.15; N, 15.66.

Examples 187-190

[0826] Part A

[0827] 6-Bromo-4-chloro-3-nitroquinoline (50.62 g, 177.8 mmol), prepared from 4-bromoaniline according to the methods described in Parts A-D of Example 1, was treated with 1-(3-aminopropyl)pyrrolidin-2-one (27.5 mL, 196 mmol) according to the method described in Part E of Example 1 to provide 61.41 g of 1-[3-(6-bromo-3-nitroquinolin-4-ylamino)propyl]pyrrolidin-2-one as a solid.

[0828] Part B

[0829] 1-[3-(6-Bromo3-nitroquinolin-4-ylamino)propyl]pyrrolidin-2-one was treated according to the methods described in Parts B, C, and D of Examples 152-156. 3-Methoxypropionyl chloride was used in Part C. The crude product obtained in Part D was recrystallized from acetonitrile. The crystals were washed with cold acetonitrile and diethyl ether and dried in a vacuum oven at 60° C. to provide 1-{3-[8-bromo-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}pyrrolidin-2-one as a light grey solid.

[0830] Part C

[0831] 1-{3-[8-Bromo-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}pyrrolidin-2-one was oxidized and then aminated according to the methods described in Parts H and I of Example 1. The product from amination was recrystallized twice from isopropanol. The crystals were washed with cold isopropanol and dried in a vacuum oven at 60° C. to provide 1-{3-[4-amino-8-bromo-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}pyrrolidin-2-one as a white solid, mp 185-188° C.

[0832] Anal. Calcd for C20H24N5O2Br: C, 53.82; H, 5.42; N, 15.69. Found: C, 53.67; H, 5.28; N, 15.45.

[0833] Part D

[0834] 1-{3-[4-Amino-8-bromo-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}pyrrolidin-2-one and the boronic acid or ester from the table below were coupled according to the method described in Examples 118-121. The reaction was heated at reflux overnight. The work-up procedure described in Part F of Examples 125-135 was followed. For Examples 1-3, the crude product was recrystallized from the solvent indicated in the table below. For Example 4, the crude product was purified by HPFCTM (eluting with chloroform:CMA in a gradient from 100:00 to 75:25) followed by recrystallization from the solvents listed in the table below to provide the product shown in the table.

Examples 187-190

[0835]

245

Recrystallization

Example
Boronic acid or ester
solvent
R3

187
Phenylboronic acid
Isopropanol

246

188
3-Pyridine boronic acid
Ethanol (twice)

247

189
3-Acetylphenyl boronic acid
Acetonitrile

248

190
Thianaphthene-3-boronic acid
Propyl acetate then toluene

249

Examples 187-190

[0836]

19

Mp

Example
Name
Form
(° C.)
Anal.

187
1-{3-[4-Amino-2-(2-
Off-
207-210
Calcd for

methoxyethyl)-8-phenyl-
white

C26H29N5O2.0.2H2O:

1H-imidazo[4,5-
solid

C, 69.85; H, 6.63; N,

c]quinolin-1-

15.67. Found: C, 69.51;

yl]propyl}pyrrolidin-2-

H, 7.00; N, 15.42.

one

188
1-{3-[4-Amino-2-(2-
Yellow
221-224
Calcd for C25H28N6O2:

methoxyethyl)-8-(pyridin-
solid

C, 67.55; H, 6.35; N,

3-yl)-1H-imidazo[4,5-

18.91. Found: C, 67.30;

c]quinolin-1-

H, 5.99; N, 18.91.

yl]propyl}pyrrolidin-2-

one

189
1-{3-[8-(3-Acetylphenyl)-
Yellow
164-167
Calcd for

4-amino-2-(2-
solid

C28H31N5O3.0.3H2O:

methoxyethyl)-1H-

C, 68.50; H, 6.49; N,

imidazo[4,5-c]quinolin-1-

14.27. Found: C, 68.16;

yl]propyl}pyrrolidin-2-

H, 6.43; N, 14.37.

one

190
1-{3-[4-amino-8-
White
202-205
Calcd for C28H29N5O2S:

(benzo[b]thiophen-3-yl)-
solid

C, 67.31; H, 5.85; N,

2-(2-methoxyethyl)-1H-

14.02. Found: C, 67.07;

imidazo[4,5-c]quinolin-1-

H, 5.66; N, 13.88.

yl]propyl}pyrrolidin-2-

one

Example 191

tert-Butyl 4-[(4-amino-2-ethoxymethyl-7-phenyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]piperidine-1-carboxylate

[0837]

250

[0838] Part A

[0839] 4—Chloro-3-nitro-7-phenylquinoline (8.35 g, 29.3 mmol) was treated with 1-(tert-butoxycarbonyl)-4-(aminomethyl)piperidine (7.54 g, 35.2 mmol) according to the method described in Part A of Examples 152-156. The crude solid was triturated with water, isolated by filtration, sonicated with diethyl ether, isolated by filtration, and dried for four hours in a vacuum oven at 40° C. to provide 12.78 g of tert-butyl 4-[(3-nitro-7-phenylquinolin-4-ylamino)methyl]piperidine-1-carboxylate as a yellow solid, mp 153-154° C.

[0840] Part B

[0841] tert-Butyl 4-[(3-nitro-7-phenylquinolin-4-ylamino)methyl]piperidine-1-carboxylate was treated according to the methods described in Parts B-D of Example 152-156. In Part B, 1,1′-di-n-octyl-4,4′-bipyridinium dibromide was used instead of 1,1′-diethyl-4,4′-bipyridinium dibromide. Triethylamine (1.1 equivalents) was added to the reaction in Part C. The crude product from Part D was purified by flash column chromatography on silica gel (eluting with 95:5 chloroform:CMA) followed by recrystallization from dichloromethane:diethyl ether to provide tert-butyl 4-[(2-ethoxymethyl-7-phenyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]piperidine-1-carboxylate as a white powder, mp 166-167° C.

[0842] Anal. Calcd for C30H36N4O3: C, 71.97; H, 7.25; N, 11.19. Found: C, 71.86; H, 7.20; N, 11.11.

[0843] Part C

[0844] tert-Butyl 4-[(2-ethoxymethyl-7-phenyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]piperidine-1-carboxylate was oxidized and then aminated according to the methods described in Parts H and I of Example 1. The oxidation product was not recrystallized. The product from amination was purified by column chromatography on silica gel (eluting with 90:10 chloroform:CMA) followed by recrystallization from ethyl acetate to provide tert-butyl 4-[(4-amino-2-ethoxymethyl-7-phenyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]piperidine-1-carboxylate as a white powder, mp 194-195° C.

[0845] Anal. Calcd for C30H37N5O3: C, 69.88; H, 7.23; N, 13.58. Found: C, 69.85; H, 7.16; N, 13.43.

Example 192

2-Ethoxymethyl-7-phenyl-1-(piperidin-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-4-amine

[0846]

251

[0847] tert-Butyl 4-[(4-amino-2-ethoxymethyl-7-phenyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]piperidine-1-carboxylate (0.64 g) was deprotected according to the method described in Example 177. The crude solid was dissolved in water (10 mL), and ammonium hydroxide was added until the solution was basic. The mixture was then extracted with chloroform (2×10 mL), and the combined extracts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was recrystallized from acetonitrile and dried for 16 hours in a vacuum oven at 60° C. to provide 0.28 g of 2-ethoxymethyl-7-phenyl-1-(piperidin-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-4-amine as a white, crystalline solid, mp 142-143° C.

[0848] Anal. Calcd for C25H29N5O.0.5H2O: C, 70.73; H, 7.12; N, 16.50. Found: C, 70.58; H, 7.24; N, 16.61.

Examples 193-195

[0849] 2-Ethoxymethyl-7-phenyl-1-(piperidin-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-4-amine dihydrochloride was prepared according to the method described in Example 177. A solution of 2-ethoxymethyl-7-phenyl-1-(piperidin- 4-ylmethyl)-1H-imidazo[4,5-c]quinolin-4-amine dihydrochloride (1.0 g, 2.05 mmol) and triethylamine (1.14 mL, 8.20 mmol) in dichloromethane (35 mL) was cooled to 4° C. The reagent from the table below (2.05 mmol) was added dropwise, and the reaction was allowed to warm to ambient temperature and stirred for between one and three hours. The reaction mixture was diluted with chloroform, and the resulting solution was washed sequentially with water, 4% aqueous sodium carbonate (2×), water, and brine and then concentrated under reduced pressure. The crude product was recystallized from the solvent listed in the table below to provide the compound shown in the table.

Example 193-195

[0850]

252

Recrystallization

Example
Reagent
solvent
R

193
Methanesulfonyl chloride
Ethyl acetate

253

194
Isobutyryl chloride
Ethyl acetate then acetonitrile

254

195
4- Morpholinecarbonyl chloride
Ethyl acetate

255

Examples 193-195

[0851]

21

Exam-

Mp

ple
Name
Form
(° C.)
Anal.

193
2-Ethoxymethyl-1-{[1-
White
224-
Calcd for

(methanesulfonyl)piperidin-
solid
225
C26H31N5O3S:

4-yl]methyl}-7-

C, 63.26; H,

phenyl-1H-imidazo[4,5-

6.33; N, 14.19.

c]quinolin-4-amine

Found: C, 62.99;

H, 6.49; N,

14.05.

194
2-Ethoxymethyl-1-[(1-
White,
156-
Calcd for

isobutyrylpiperidin-4-
crys-
158
C29H35N5O2.0.5.

yl)methyl]-7-phenyl-1H-
talline

H2O: C,

imidazo[4,5-c]quinolin-4-
solid

70.42; H, 7.34;

amine

N, 14.16.

Found: C, 70.17;

H, 7.49; N,

14.13.

195
2-Ethoxymethyl-1-{[1-
White
208-
Calcd for

(morpholin-4-
solid
209
C30H36N6O3: C,

ylcarbonyl)piperidin-4-

68.16; H, 6.86;

yl]methyl}-7-phenyl-1H-

N, 15.90.

imidazo[4,5-c]quinolin-4-

Found: C, 67.82;

amine

H, 6.99; N,

15.71.

Examples 196-198

[0852] Part A

[0853] 4-Chloro-3-nitro-7-phenylquinoline (6.0 g, 21 mmol) was treated with 2- phenoxyethylamine (3.18 g, 23.2 mmol) according to the method described in Part A of Examples 125-135. The crude solid was triturated with water (100 mL), isolated by filtration, sonicated with diethyl ether, isolated by filtration, and dried for two hours in a vacuum oven at 40° C. to provide 8.12 g of (3-nitro-7- phenylquinolin-4-yl)-(2-phenoxyethyl)amine as a yellow solid. Part B A solution of (3-nitro-7-phenylquinolin-4-yl)-(2-phenoxyethyl)amine (7.25 g, 18.8 mmol) in methanol (150 mL) was added to a Parr vessel charged with 5% platinum on carbon (0.84 g), and the reaction was placed under hydrogen pressure (50 psi, 3.4×105 Pa) for three hours. The reaction mixture was filtered through a layer of CELITE filter aid, and the filtrate was concentrated under reduced pressure, dissolved in toluene (2×25 mL), and concentrated under reduced pressure to provide N4-(2-phenoxyethyl)-7- phenylquinoline-3,4-diamine as a yellow semi-solid. Part C A modification of the method described in Part C of Examples 125-135 was followed. A 0.2 M solution of the material from Part B and triethylamine (1 equivalent) in dichloromethane was treated with the acid chloride (1 equivalent) indicated in the table below. Part D The material from Part C was cyclized according to the method described in Part D of Examples 152-156. The crude product was purified by flash chromatography on silica gel (eluting with 95:5 chloroform:CMA) followed by recrystallization from ethyl acetate or ethyl acetate:diethyl ether to provide the following products. Example 196: 2-Cyclopropylmethyl-1-(2-phenoxyethyl)-7-phenyl-1H- imidazo[4,5-c]quinoline was obtained as a white powder, mp 175-176° C. Anal. Calcd for C28H25N3O: C, 80.16; H, 6.01; N, 10.02. Found: C, 79.87; H, 5.92; N, 9.85.

[0854] Example 197: 2-Ethoxymethyl-1-(2-phenoxyethyl)-7-phenyl-1H-imidazo[4,5-c]quinoline was obtained as a yellow, crystalline solid, mp 137-138° C. Anal. Calcd for C27H25N3O2: C, 76.57; H, 5.95; N, 9.92. Found: C, 76.60; H, 6.10; N, 9.66.

[0855] Example 198: 2-(4-Methoxybenzyl)-1-(2-phenoxyethyl)-7-phenyl-1H-imidazo[4,5-c]quinoline was obtained as a white, crystalline powder, mp 205-206° C. Anal. Calcd for C32H27N3O2: C, 79.15; H, 5.60; N, 8.65. Found: C, 78.87; H, 5.65; N, 8.60.

[0856] Part E

[0857] The material from Part D was oxidized and then aminated according to the methods described in Parts H and I of Example 1. The oxidation product was not recrystallized. The product from amination was purified by column chromatography on silica gel (eluting with 95:5 or 90:10 chloroform:CMA) followed by recrystallization from ethyl acetate to provide the products shown in the table below.

Examples 196-198

[0858]

256

Example
Acid Chloride
R2

196
Cyclopropylacetyl chloride

257

197
Ethoxyacetyl chloride

258

198
4-Methoxyphenylacetyl chloride

259

Examples 196-198

[0859]

23

Exam-

Mp

ple
Name
Form
(° C.)
Anal.

196
2-Cyclopropylmethyl-1-
White
188-
Calcd for

(2-phenoxyethyl)-7-
solid
189
C28H26N4O: C,

phenyl-1H-imidazo[4,5-

77.39; H, 6.03; N,

c]quinolin-4-amine

12.89. Found: C,

77.10; H, 6.03; N,

12.85.

197
2-Ethoxymethyl-1-(2-
White,
159-
Calcd for

phenoxyethyl)-7-phenyl-
crys-
160
C27H26N4O2: C,

1H-imidazo[4,5-
talline

73.95; H, 5.98; N,

c]quinolin-4-amine
solid

12.78. Found: C,

73.72; H, 5.94; N,

12.78.

198
2-(4-Methoxybenzyl)-1-
Fluffy,
197-
Calcd for

(2-phenoxyethyl)-7-
white
198
C32H28N4O2: C,

phenyl-1H-imidazo[4,5-
powder

76.78; H, 5.64; N,

c]quinolin-4-amine

11.19. Found: C,

76.55; H, 5.75; N,

11.12.

Example 199

N-{4-[4-Amino-2-(2-methoxyethyl)-7-phenyl-1H-imidazo[4,5-c]quinolin-1-yl]butyl}methanesulfonamide

[0860]

260

[0861] Part A

[0862] Under a nitrogen atmosphere, a solution of tert-butyl N-(4-aminobutyl)carbamate (13.8 g, 73.4 mmol) and triethylamine (15.3 mL, 110 mmol) was cooled to 0° C. Methanesulfonyl chloride (6.3 mL, 81 mmol) was added, and the reaction was allowed to warm to ambient temperature and stirred overnight. Aqueous acetic acid (200 mL of 10%) was added. The organic layer was then separated and washed with water (200 mL), saturated aqueous sodium bicarbonate (200 mL), water (200 mL), and brine; dried over sodium sulfate; filtered; and concentrated under reduced pressure to provide 18.9 g of tert-butyl [4-(methanesulfonylamino)butyl]carbamate as an off-white solid.

[0863] Part B

[0864] A solution of hydrochloric acid in ethanol was added to a solution of tert-butyl [4-(methanesulfonylamino)butyl]carbamate (18.9 g, 71.1 mmol) in ethanol (100 mL), and the reaction was heated at 100° C. for two hours. The solvent was removed under reduced pressure. A mixture of dichloromethane:hexanes was added to the resulting oil and removed under reduced pressure; this process was repeated several times. The residue was dried for three days under vacuum to provide 14.3 g of N-(4-aminobutyl)methanesulfonamide hydrochloride as a tan solid.

[0865] Part C

[0866] N-(4-aminobutyl)methanesulfonamide hydrochloride (7.8 g, 39 mmol) was added to a suspension of 4-chloro-3-nitro-7-phenylquinoline (35 mmol) and triethylamine (8.0 g, 79 mmol) in NMP (80 mL), and the reaction was stirred at ambient temperature overnight. The resulting solution was poured into water (350 mL) to form a solid, which was isolated by filtration, washed with water, air-dried, and recrystallized from acetonitrile to provide 12.0 g of N-[4-(3-nitro-7-phenylquinolin-4-ylamino)butyl]methanesulfonamide as yellow plates.

[0867] Part D

[0868] The method described in Part B of Examples 125-135 was used to convert N-[4-(3-nitro-7-phenylquinolin-4-ylamino)butyl]methanesulfonamide (12.0 g, 29.0 mmol) to N-[4-(3-amino-7-phenylquinolin-4-ylamino)butyl]methanesulfonamide, which was isolated as a brown solid.

[0869] Part E

[0870] The material from Part D was treated according to the method described in Part A of Example 9. The crude product was recrystallized from methyl ethyl ketone and then purified twice by flash column chromatography on silica gel (eluting with chloroform:CMA in a gradient from 95:5 to 75:25 and eluting with acetone:methanol in a gradient from 100:0 to 95:5).

[0871] Part F

[0872] N-{4-[2-(2-methoxyethyl)-7-phenyl-1H-imidazo[4,5-c]quinolin-1-yl]butyl}methanesulfonamide was oxidized and then aminated according to the methods described in Parts H and I of Example 1. Both reactions were carried out in chloroform. The oxidation product was recrystallized from 5:1 acetonitrile:ethyl acetate and dried under vacuum overnight at 45° C. The amination product was recrystallized from acetonitrile and dried in a vacuum oven at 70° C. to provide N-{4-[4-amino-2-(2-methoxyethyl)-7-phenyl-1H-imidazo[4,5-c]quinolin-1-yl]butyl}methanesulfonamide as a white solid, mp 201-202° C.

[0873] Anal. Calcd for C24H29N5O3S: C, 61.65; H, 6.25; N, 14.98. Found: C, 61.55; H, 6.11; N, 15.01.

Example 200

N-[2-(4-Amino-7-phenyl-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)-1,1-dimethylethyl]methanesulfonamide

[0874]

261

[0875] Part A

[0876] A solution of 1,2-diamino-2-methylpropane (9.3 mL, 88.9 mmol) and triethylamine (5.0 mL, 35.5 mmol) in dichloromethane (100 mL) was cooled to 0° C. A solution of 4-chloro-3-nitro-7-phenylquinoline (5.06 g, 17.8 mmol) in dichloromethane (50 mL) was added over a period of 45 minutes, and then the reaction was allowed to warm to ambient temperature. The solution was washed sequentially with water (2×100 mL) and brine (150 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide N1-(3-nitro-7-phenylquinolin-4-yl)-2-methylpropane-1,2-diamine as an orange solid.

[0877] Part B

[0878] A solution of N1-(3-nitro-7-phenylquinolin-4-yl)-2-methylpropane-1,2-diamine (5.85 g, 17.4 mmol) in dichloromethane (200 mL) was cooled to 0° C.

[0879] Triethylamine (3.6 mL, 26 mmol) and methanesulfonic anhydride (3.03, 17.4 mmol) were sequentially added. The reaction was allowed to warn to ambient temperature and stirred for two hours. Additional methanesulfonic anhydride (0.76 g, 4.4 mmol) was added, and the reaction was stirred overnight. A precipitate was present and was isolated by filtration, washed with water, and dried for two hours under high vacuum at 75° C. The filtrate was washed sequentially with water (2×100 mL) and brine (100 mL), dried over sodium sulfate, filtered, concentrated under reduced pressure, and recrystallized from dichloroethane. The two solids were combined to provide 5.26 g of N-[1,1-dimethyl-2-(3-nitro-7-phenylquinolin-4-ylamino)ethyl]methanesulfonamide as a yellow powder.

[0880] Part C

[0881] The method described in Part B of Examples 125-135 was used to convert N-[1,1-dimethyl-2-(3-nitro-7-phenylquinolin-4-ylamino)ethyl]methanesulfonamide (5.26 g, 12.6 mmol) to 4.53 g of N-[2-(3-amino-7-phenylquinolin-4-ylamino)-1,1-dimethylethyl]methanesulfonamide, which was isolated as a yellow-orange solid.

[0882] Part D

[0883] N-[2-(3-Amino-7-phenylquinolin-4-ylamino)-1,1-dimethylethyl]methanesulfonamide (2.20 g, 5.04 mmol) was treated with trimethyl orthobutyrate (0.90 mL, 5.5 mmol) according to the method described in Part G of Example 1. The chromatographic purification was carried out eluting with 92.5:7.5 dichloromethane:methanol to provide 1.8 g of N-[2-(7-phenyl-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)-1,1-dimethylethyl]methanesulfonamide as a tan solid.

[0884] Part E

[0885] N-[2-(7-Phenyl-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)-1,1-dimethylethyl]methanesulfonamide was oxidized and then aminated according to the methods described in Parts H and I of Example 1. The oxidation reaction was carried out in chloroform, and the product was not recrystallized. The product from amination was recrystallized from ethanol, and isolated by filtration. The solid was recrystallized from acetonitrile, and the crystals were dissolved in dichloromethane:methanol, concentrated under reduced pressure, and dried under high vacuum at 60° C. to provide N-[2-(4-amino-7-phenyl-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)-1,1-dimethylethyl]methanesulfonamide as a white, crystalline solid, mp 135-141° C.

[0886] Anal. Calcd for C24H29N5O2S: C, 63.83; H, 6.47; N, 15.51. Found: C, 63.48; H, 6.80; N, 15.34.

Example 201

N-[2-(4-Amino-2-ethoxymethyl-7-phenyl-1H-imidazo[4,5-c]quinolin-1-yl)-1,1-dimethylethyl]methanesulfonamide

[0887]

262

[0888] Part A

[0889] A modification of the method described in Part C of Examples 125-135 was used to treat N-[1,1-dimethyl-2-(3-amino-7-phenylquinolin-4-ylamino)ethyl]methanesulfonamide (2.33 g, 5.33 mmol) with ethoxyacetyl chloride (0.72 g, 5.87 mmol). Triethylamine (1.5 mL, 11 mmol) was added to the reaction, which was stirred overnight.

[0890] Part B

[0891] A solution of the material from Part A and triethylamine (1.5 mL, 11 mmol) in anhydrous toluene (100 mL) was heated at reflux overnight. The solvent was then removed under reduced pressure, and the residue was dissolved in dichloromethane (100 mL). The resulting solution was washed sequentially with 1% aqueous sodium carbonate (2×100 mL) and brine (100 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (eluting with 95:5 dichloromethane:methanol) to provide 2.07 g of N-[2-(2-ethoxymethyl-7-phenyl-1H-imidazo[4,5-c]quinolin-1-yl)-1,1-dimethylethyl]methanesulfonamide as a yellow solid.

[0892] Part C

[0893] N-[2-(2-Ethoxymethyl-7-phenyl-1H-imidazo[4,5-c]quinolin-1-yl)-1,1-dimethylethyl]methanesulnamide was oxidized and then aminated according to the methods described in Parts H and I or Example 1. The oxidation reaction was carried out in chloroform, and the product was not recrystallized. The product from amination was recrystallized from acetonitrile, and the crystals were dissolved in dichloromethane:methanol, concentrated under reduced pressure, and dried in a vacuum oven to provide N-[2-(4-amino-2-ethoxymethyl- 7-phenyl-1H-imidazo[4,5-c]quinolin-1-yl)-1,1-dimethylethyl]methanesulfonamide as a white powder, mp 239-242° C.

[0894] Anal. Calcd for C24H29N5O2S.0.3H2O: C, 60.94; H, 6.31; N, 14.81. Found: C, 60.91; H, 6.03; N, 14.71.

Example 202

Cyclohexane N-[2-(4-amino-2-ethoxymethyl-7-phenyl-1H-imidazo[4,5-c]quinolin-1-yl)-1,1-dimethylethyl]carboxamide

[0895]

263

[0896] Part A

[0897] A solution of N1-(3-nitro-7-phenylquinolin-4-yl)-2-methylpropane-1,2-diamine (3.56 g, 10.6 mmol) in dichloromethane (100 mL) was cooled to 0° C. Triethylamine (3.0 mL, 21 mmol) and cyclohexanecarbonyl chloride (1.55 mL, 11.6 mmol) were sequentially added. The reaction was allowed to warm to ambient temperature and stirred for two hours. The reaction was washed sequentially with water (2×100 mL) and brine (100 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (eluting with 65:35 hexanes:ethyl acetate) to provide 3.33 g of cyclohexane N-[1,1-dimethyl-2-(3-nitro-7-phenylquinolin-4-ylamino)ethyl]carboxamide as a yellow solid.

[0898] Part B

[0899] The method described in Part B of Examples 125-135 was used to convert cyclohexane N-[1,1-dimethyl-2-(3-nitro-7-phenylquinolin-4-ylamino)ethyl]carboxamide (3.33 g, 7.46 mmol) to 3.06 g of cyclohexane N-[2-(3-amino-7-phenylquinolin-4-ylamino)-1,1-dimethylethyl]carboxamide, which was isolated as an orange solid.

[0900] Part C

[0901] Cyclohexane N-[2-(3-amino-7-phenylquinolin-4-ylamino)-1,1-dimethylethyl]carboxamide was treated according to the methods described in Parts A—C Example 201. The product from amination was purified by column chromatography on silica gel (eluting with 92.5:7.5 dichloromethane:methanol) followed by recrystallization from isopropanol. The crystals were dissolved in dichloromethane:methanol, concentrated under reduced pressure, and dried for two days under high vacuum at 65° C. to provide cyclohexane N-[2-(4-amino-2-ethoxymethyl-7-phenyl-1H-imidazo[4,5-c]quinolin-1-yl)-1,1-dimethylethyl]carboxamide as a white powder, mp 195-198° C.

[0902] Anal. Calcd for C30H37N5O2.0.25H2O: C, 71.47; H, 7.50; N, 13.89. Found: C, 71.49; H, 7.54; N, 13.88.

Example 203

N-[2-(4-Amino-2-ethoxymethyl-7-phenyl-1H-imidazo[4,5-c]quinolin-1-yl)-1,1-dimethylethyl]-N′-cyclohexylurea

[0903]

264

[0904] Part A

[0905] A solution of N1-(3-nitro-7-phenylquinolin-4-yl)-2-methylpropane-1,2-diamine (3.56 g, 10.6 mmol) in dichloromethane (100 mL) was cooled to 0° C. Cyclohexyl isocyanate (3.00 mL, 23.5 mmol) was added over the course of a day, and the reaction was stirred at ambient temperature for three days. The solvent was removed under reduced pressure. Xylenes (3 cx 100 mL) were added and removed under reduced pressure to provide N-cyclohexyl-N′-[1,1-dimethyl-2-(3-nitro-7-phenylquinolin-4-ylamino)ethyl]urea as a yellow solid.

[0906] Part B

[0907] The method described in Part B of Examples 125-135 was used to convert N-cyclohexyl—N′-[1,1-dimethyl-2-(3-nitro-7-phenylquinolin-4-ylamino)ethyl]urea (4.88 g, 10.6 mmol) to 4.35 g of N-[2-(3-amino-7-phenylquinolin-4-ylamino)-1,1-dimethylethyl]-N′-cyclohexylurea, which was isolated as an orange powder.

[0908] Part C

[0909] N-cyclohexyl—N′-[2-(3-amino-7-phenylquinolin-4-ylamino)-1,1-dimethylethyl]urea was treated according to the methods described in Parts A-C Example 201. The product from amination was recrystallized twice from ethanol. The crystals were dissolved in dichloromethane, and the resulting solution was washed sequentially with water (2×) and brine, dried over sodium sulfate, filtered, concentrated under reduced pressure, and dried for two days under high vacuum at 65° C. to provide N-[2-(4-amino-2-ethoxymethyl-7-phenyl-1H-imidazo[4,5-c]quinolin-1-yl)-1,1-dimethylethyl]-N′-cyclohexylurea as an off-white powder, mp 152-156° C.

[0910] Anal. Calcd for C30H38N6O2: C, 70.01; H, 7.44; N, 16.33. Found: C, 69.78; H, 7.63; N, 16.24.

Examples 204

1-[3-(4-Amino-7-phenyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]pyrrolidin-2-one

[0911]

265

[0912] Part A

[0913] 4-Chloro-3-nitro-7-phenylquinoline (3.51 g, 12.3 mmol) was treated with 1-(3-aminopropyl)pyrrolidin-2-one (2.3 mL, 16 mmol) according to the method described in Part E of Example I to provide 4.23 g of 1-[3-(3-nitro-7-phenylquinolin-4-ylamino)propyl]pyrrolidin-2-one as a yellow solid.

[0914] Part B

[0915] The method described in Part B of Examples 152-156 was used to convert 1-[3-(3-nitro-7-phenylquinolin-4-ylamino)propyl]pyrrolidin-2-one (4.25 g, 10.9 mmol) to 3.66 g of 1-[3-(3-amino-7-phenylquinolin-4-ylamino)propyl]pyrrolidin-2-one, which was obtained as a brown solid. In Part B, 1,1′-di-n-octyl-4,4′-bipyridinium dibromide was used instead of 1,1′-diethyl-4,4′-bipyridinium dibromide.

[0916] Part C

[0917] Triethyl orthoformate (2.50 mL, 15.0 mmol) was added to a solution of 1-[3-(3-amino-7-phenylquinolin-4-ylamino)propyl]pyrrolidin-2-one (3.59 g, 9.96 mmol) and pyridine hydrochloride (50 mg, 0.43 mmol) in anhydrous toluene (65 mL) and 1,2-dichloroethane (35 mL), and the reaction was heated at reflux overnight under a nitrogen atmosphere. The solution was then washed with saturated aqueous sodium carbonate (150 mL). The aqueous layer was extracted with dichloromethane (2×150 mL), and the combined organic fractions were washed with brine (150 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting solid was dissolved in dichloromethane (5 mL), and diethyl ether (100 mL) was added to form a solid, which was isolated by filtration and dried in a vacuum oven at 60° C. to provide 2.51 g of a light brown solid. A portion of the product was recrystallized from 25:75 ethyl acetate:heptane and dried in a vacuum oven at 60° C. to provide 1-[3-(7-phenyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]pyrrolidin-2-one as a light brown solid, mp 138-141° C.

[0918] Anal. Calcd. for C23H22N4O: C, 74.57; H, 5.99; N, 15.12. Found: C, 74.45; H, 6.17; N, 15.06.

[0919] Part D

[0920] 1-[3-(7-Phenyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]pyrrolidin-2-one was oxidized and then aminated according to the methods described in Parts H and I of Example 1. The product from amination was purified twice by column chromatography on silica gel (eluting with chloroform:CMA in gradients from 100:0 to 70:30). The resulting solid was washed with diethyl ether, recrystallized from acetonitrile, and dried in a vacuum oven at 60° C. to provide 1-[3-(4-amino-7-phenyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]pyrrolidin-2-one as a light brown solid, mp 201-204° C.

[0921] Anal. Calcd. for C23H23N5O: C, 71.67; H, 6.01; N, 18.17. Found: C, 71.64; H, 5.95; N, 18.48.

Example 205

1-[3-(4-Amino-2-ethoxymethyl-7-phenyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]pyrrolidin-2-one

[0922]

266

[0923] Part A

[0924] 1-[3-(3-Amino-7-phenylquinolin-4-ylamino)propyl]pyrrolidin-2-one (2.21 g, 6.13 mmol) was treated with ethoxyacetyl chloride (0.95 mL, 8.76 mmol) according to the methods described in Parts C and D of Examples 152-156. Triethylamine (8.6 mmol) was added in Part C. The product from Part D was purified by column chromatography on silica gel (eluting with acetone and then chloroform:methanol in a gradient from 95:5 to 90:10) to provide 1.49 g of 1-[3-(2-ethoxymethyl-7-phenyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]pyrrolidin-2-one as a brown solid.

[0925] Part B

[0926] 1-[3-(2-Ethoxymethyl-7-phenyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]pyrrolidin-2-one was oxidized and then aminated according to the methods described in Parts H and I of Example 1. The product from amination was purified by column chromatography on silica gel (eluting with chloroform:CMA in a gradient from 100:0 to 75:25) followed by recrystallization from acetonitrile and drying in a vacuum oven at 60° C. to provide 1-[3-(4-amino-2-ethoxymethyl-7-phenyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]pyrrolidin-2-one as a light brown solid, mp 199-203° C.

[0927] Anal. Calcd. for C26H29N5O2: C, 70.41; H, 6.59; N, 15.79. Found: C, 70.04; H, 6.55; N, 15.55.

Example 206

1-{3-[4-Amino-2-(2-methoxyethyl)-7-phenyl-1H-imidazo[4,5-c]quinolin-1-yl]propyl}pyrrolidin-2-one

[0928]

267

[0929] The methods described in Parts A of Example 204 were used to treat 1-[3-(3-amino-7-phenylquinolin-4-ylamino)propyl]pyrrolidin-2-one (1.19 g, 3.30 mmol) with 3-methoxypropionyl chloride (0.45 mL, 4.1 mmol) to afford 1-{3-[2-(2-methoxyethyl)-7-phenyl-1H-imidazo[4,5-c]quinolin-1-yl]propyl}pyrrolidin-2-one, which was oxidized and then aminated according to the methods described in Parts H and I of Example 1. The product from amination was recrystallized twice from acetonitrile and dried in a vacuum oven at 60° C. to provide 1-{3-[4-amino-2-(2-methoxyethyl)-7-phenyl-1H-imidazo[4,5-c]quinolin-1-yl]propyl}pyrrolidin-2-one as a light brown solid, mp 187-191° C.

[0930] Anal. Calcd. for C26H29N5O2.0.13H2O: C, 70.05; H, 6.61; N, 15.71. Found: C, 69.66; H, 6.73; N, 15.82.

Examples 207-243

[0931] 7-Bromo-2-ethoxymethyl-1-(3-methoxypropyl)-1H-imidazo[4,5-c]quinolin-4-amine was coupled with the appropriate boronic acid or boronic acid ester according to the procedure described in Examples 20-65 and then purified by prep HPLC according to procedures described above. The table below shows the structure of the compound obtained in each example and the observed accurate mass for the isolated trifluoroacetate salt. Examples 207-243

268

MeasuredMassExampleR(M + H)207

269

381.1920208

270

397.1703209

271

397.1696210

272

405.2279211

273

407.2063212

274

407.2091213

275

416.2078214

276

416.2076215

277

419.2453216

278

419.2456217

279

421.2240218

280

421.2233219

281

427.1955220

282

433.2238221

283

433.2244222

284

433.2226223

285

434.2203224

286

435.2425225

287

448.2346226

288

449.2544227

289

449.2560228

290

451.2355229

291

420.2405230

292

381.2043231

293

481.2441232

294

484.1996233

295

488.2650234

296

490.2800235

297

448.2330236

298

420.2382237

299

459.1323238

300

421.2232239

301

490.2826240

302

435.2045241

303

437.2012242

304

451.2355243

305

437.2174

Examples 244-323

[0932] A reagent from the table below, (0.064 mmol, 1.1 equivalents) was added to a test tube containing a solution of 2-ethoxymethyl-1-(piperidin-4-ylmethyl)-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine trihydrochloride (30 mg, 0.057 mmol) and N,N-diisopropylethylamine (0.048 mL, 0.27 mmol, 4.8 equivalents) in chloroform (2 mL). The test tube was capped placed on a shaker at ambient temperature overnight. One drop of deionized water was then added to each test tube, and the solvent was removed by vacuum centrifugation. For Example 323, the capped test tube was heated at 60° C. overnight in a sand bath, and then lithium trifluoromethanesulfonimide (3 mg) was added followed by shaking for an additional four hours. The products were purified by prep HPLC according to the methods described above. The table below shows the reagent used for each example, the structure of the resulting compound, and the observed accurate mass for the isolated trifluoroacetate salt.

Examples 244-323

[0933]

306

Measured

Mass

Example
Reagent
R
(M + H)

244
Acetyl chloride

307

459.2510

250
Isobutyryl chloride

308

487.2840

245
Isovaleryl chloride

309

501.2990

246
Pentanoyl chloride

310

501.2957

247
Isoxazole-5-carbonyl chloride

311

512.2435

248
Benzoyl chloride

312

521.2667

249
Cyclohexanecarbonyl chloride

313

527.3166

250
m-Toluoyl chloride

314

535.2848

251
Phenylacetyl chloride

315

535.2853

252
Thiophene-2-acetyl chloride

316

541.2407

253
3-Cyclopentylpropionyl chloride

317

541.3304

254
Cinnamoyl chloride

318

547.2837

255
Hydrocinnamoyl chloride

319

549.3021

256
2-Methoxybenzoyl chloride

320

551.2809

257
m-Anisoyl chloride

321

551.2786

258
2-Chlorobenzoyl chloride

322

555.2264

259
3-Chlorobenzoyl chloride

323

555.2272

260
4-Chlorobenzoyl chloride

324

555.2281

261
trans-2-Phenyl-1- cyclopropanecarbonyl chloride

325

561.2970

262
Benzyloxyacetyl chloride

326

565.2938

263
1-Naphthoyl chloride

327

571.2817

264
2-Naphthoyl chloride

328

571.2817

265
Methyl 4-chlorocarbonylbenzoate

329

579.2716

266
3-(Trifluoromethyl)benzoyl chloride

330

589.2557

267
4-(Trifluoromethyl)benzoyl chloride

331

589.2585

268
2,4-Dichlorobenzoyl chloride

332

589.1870

269
3,4-Dichlorobenzoyl chloride

333

589.1912

270
4-(Trifluoromethoxy)benzoyl chloride

334

605.2531

271
Ethanesulfonyl chloride

335

509.2364

272
Isopropylsulfonyl chloride

336

523.2523

273
Dimethylsulfamoyl chloride

337

524.2463

274
Benzenesulfonyl chloride

338

557.2380

275
2-Thiophenesulfonyl chloride

339

563.1921

276
α-Toluenesulfonyl chloride

340

571.2524

277
m-Toluenesulfonyl chloride

341

571.2509

278
2-Cyanobenzenesulfonyl chloride

342

582.2325

279
3-Cyanobenzenesulfonyl chloride

343

582.2301

280
4-Cyanobenzenesulfonyl chloride

344

582.2322

281
trans-β-Styrenesulfonyl chloride

345

583.2543

282
4-Methoxybenzenesulfonyl chloride

346

587.2435

283
2-Chlorobenzenesulfonyl chloride

347

591.1967

284
3-Chlorobenzenesulfonyl chloride

348

591.1970

285
2,4-Difluorobenzenesulfonyl chloride

349

593.2180

286
2,6-Difluorobenzenesulfonyl chloride

350

593.2167

287
3-Nitrobenzenesulfonyl chloride

351

602.2214

288
8-Quinolinesulfonyl chloride

352

608.2483

289
3,4-Dimethoxybenzenesulfonyl chloride

353

617.2534

290
2- (Trifluoromethyl)benzenesulfonyl chloride

354

625.2228

291
3- (Trifluoromethyl)benzenesulfonyl chloride

355

625.2214

292
2,4-Dichlorobenzenesulfonyl chloride

356

625.1567

293
(1R)-(-)-10-Camphorsulfonyl chloride

357

631.3110

294
(1S)-(-)-10-Camphorsulfonyl chloride

358

631.3090

295
4-Biphenylsulfonyl chloride

359

633.2662

296
4- (Trifluoromethoxy)benzenesulfonyl chloride

360

641.2178

297
Isopropyl isocyanate

361

502.2964

298
n-Propyl isocyanate

362

502.2924

299
tert-Butyl isocyanate

363

516.3080

300
Dimethylcarbamyl chloride

364

488.2809

301
Phenyl isocyanate

365

536.2817

302
Cyclohexyl isocyanate

366

542.3281

303
Benzyl isocyanate

367

550.2914

304
m-Tolyl isocyanate

368

550.2971

305
o-Tolyl isocyanate

369

550.2964

306
p-Tolyl isocyanate

370

550.2953

307
3-Fluorophenyl isocyanate

371

554.2717

308
3-Cyanophenyl isocyanate

372

561.2725

309
4-Cyanophenyl isocyanate

373

561.2756

310
Phenethyl isocyanate

374

564.3129

311
1-Piperidinecarbonyl chloride

375

528.3115

312
3-Methoxyphenyl isocyanate

376

566.2924

313
4-Methoxyphenyl isocyanate

377

566.2906

314
2-Chlorophenyl isocyanate

378

570.2419

315
trans-2-Phenylcyclopropyl isocyanate

379

576.3120

316
3-Acetylphenyl isocyanate

380

578.2910

317
Benzoyl Isothiocyanate

381

580.2478

318
N-Methyl-N-phenylcarbamoyl chloride

382

550.2927

319
Methyl 3-Isocyanatobenzoate

383

594.2820

320
2-(Trifluoromethyl)phenyl isocyante

384

604.2616

321
3-(Trifluoromethyl)phenyl isocyante

385

604.2638

322
4-(Trifluoromethyl)phenyl isocyante

386

604.2658

323
Benzyl glycidyl ether

387

581.3278

Examples 323-331

[0934] 1-(2-Amino-2-methylpropyl)-2-ethoxymethyl-7-phenyl-1H-imidazo[4,5-c]quinolin-4-amine was prepared from N1-(3-nitro-7-phenylquinolin-4-yl)-2-methylpropane-1,2-diamine according to the methods described in Part C of Example 200 and Parts A—C of Example 201. A reagent from the table below, (0.051-0.058 mrnmol, 1.1 equivalents) was added to a test tube containing a solution of 1-(2-amino-2-methylpropyl)-2-ethoxymethyl-7-phenyl-1H-imidazo[4,5-c]quinolin-4-amine (20 mg, 0.051 mmol) and N,N-diisopropylethylamine (0.018 mL, 0.10 mmol, 2 equivalents) in chloroform (2 mL). The test tube was capped placed on a shaker at ambient temperature overnight. For Examples 324 and 327, the test tubes were then heated on a sand bath for two hours at 50° C. Ammonium hydroxide (2 drops) was added to the other reactions, and they were placed back on the shaker. The solvent was removed by vacuum centrifugation, and the products were purified by prep 15HPLC according to the methods described above. The table below shows the reagent used for each example, the structure of the resulting compound, and the observed accurate mass for the isolated trifluoroacetate salt.

Examples 324-331

[0935]

388

Measured

Exam-

Mass

ple
Reagent
R
(M + H)

324
Dimethylcarbamyl chloride

389

475.2825

325
Cyclohexyl isocyanate

390

515.3126

326
Methyl malonyl chloride

391

490.2459

327
Dimethylsulfamoyl chloride

392

497.2338

328
Phenylacetyl chloride

393

508.2685

329
3-Cyclopentylpropionyl chloride

394

514.3140

330
m-Anisolyl chloride

395

524.2621

331
3-Chlorobenzoyl chloride

396

528.2164

Examples 332-362

[0936] Part A

[0937] tert-Butyl 4-[(4-amino-7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]piperidine-1-carboxylate (11.83 g, 22.82 mmol) was treated according to the method described in Example 177 to provide 9.73 g of 7-bromo-2-ethoxymethyl-1-(piperidin-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-4-amine dihydrochloride as a white, crystalline solid, mp >300° C.

[0938] Part B

[0939] The method described in Examples 178-181 was used to treat 7-bromo-2-ethoxymethyl-1-(piperidin-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-4-amine dihydrochloride (4.95 g, 10.1 mmol) with methanesulfonic anhydride (1.76 g, 10.1 mmol). The reaction was carried out in dichloromethane (150 mL). Following chromatographic purification (eluting with chloroform:CMA in a gradient from 100:0 to 90:10), the product was recrystallized from ethyl acetate to provide 2.37 g of 7-bromo-2-ethoxymethyl-1-{[1-(methanesulfonyl)piperidin-4-yl]methyl}-1H-imidazol[4,5-c]quinolin-4-amine as a white, crystalline solid, mp 233-234° C.

[0940] Anal. Calcd for C20H26BrN5O3 S: C, 47.87; H, 5.34; N, 13.96. Found: C, 48.14; H, 5.28; N, 13.56.

[0941] Part C

[0942] 7-Bromo-2-ethoxymethyl-1-{[1-(methanesulfonyl)piperidin-4-yl]methyl}-1H-imidazo[4,5-c]quinolin-4-amine was coupled with the appropriate boronic acid or boronic acid ester according to the procedure described in Examples 20-65. The preoducts were purifed by prep HPLC according to the methods described above. The table below shows the structure of the compound obtained in each example and the observed accurate mass for the isolated trifluoroacetate salt.

Examples 332-362

[0943]

397

Measured Mass

Example
R
(M + H)

332

398

494.2178

333

399

500.1795

334

400

500.1746

335

401

524.2994

336

402

508.2383

337

403

508.2341

338

404

510.2195

339

405

510.2144

340

406

519.2164

341

407

524.2298

342

408

528.1834

343

409

530.1990

344

410

536.2293

345

411

536.2316

346

412

536.2313

347

413

538.2466

348

414

538.2468

349

415

593.2872

350

416

554.2466

351

417

566.2402

352

418

572.1982

353

419

584.2515

354

420

586.2136

355

421

587.2072

356

422

587.2101

357

423

591.2743

358

424

593.2916

359

425

618.2496

360

426

523.2438

361

427

591.2751

362

428

538.2087

Example 363

2-Ethoxymethyl-1-{2-[2-(methanesulfonyl)ethoxy]-2-methylpropyl}-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine

[0944]

429

[0945] Part A

[0946] A solution of methyl vinyl sulfone (3.0 g, 29 mmol) and 1-(7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol (5.4 g, 14 mmol) in anhydrous THF (57 mL) was purged with nitrogen; solid sodium hydride (available as a 60% dispersion in mineral oil, 57 mg, 1.4 mmol) was added. The reaction was stirred for 70 minutes at ambient temperature, at which time an analysis by HPLC indicated a ratio of product to starting material of 3:1. The reaction mixture was combined with material from another run, and water (100 mL) was added. The aqueous layer was separated and extracted with ethyl acetate (100 mL, 50 mL). The combined organic fractions were washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluting with 95:5 dichloromethane:methanol) to provide 7-bromo-2-ethoxymethyl-1-{2-[2-(methanesulfonyl)ethoxy]-2-methylpropyl}-1H-imidazo[4,5-c]quinoline.

[0947] Part B

[0948] A modification of the method described in Example 1 Part H was used to oxidize 7-bromo-2-ethoxymethyl-1-{2-[2-(methanesulfonyl)ethoxy]-2-methylpropyl}-1H-imidazo[4,5-c]quinoline (3.65 g, 7.53 mmol) with 3-chloroperoxybenzoic acid (2.2 g of 60% pure material, 7.53 mmol). The reaction was carried out in chloroform (38 mL) and allowed to proceed for one hour. The crude product was used without purification.

[0949] Part C

[0950] The material from Part B was aminated according to the method described in Part I of Example 1. The crude product was recrystallized from acetonitrile (35 mL), and the crystals were isolated by filtration, washed with acetonitrile, and dried for four hours under vacuum at 65° C. to provide 7-bromo-2-ethoxymethyl-1-{2-[2-(methanesulfonyl)ethoxy]-2-methylpropyl}-1H-imidazo[4,5-c]quinolin-4-amine as gold, crystalline plates, mp 198-201° C.

[0951] Anal. Calcd for C20H27BrN4O4S: C, 48.10; H15.45; N, 11.22. Found: C, 47.96; H, 5.34; N, 11.20.

[0952] Part D

[0953] 7-Bromo-2-ethoxymethyl-1-{2-[2-(methanesulfonyl)ethoxy]-2-methylpropyl}-1H-imidazo[4,5-c]quinolin-4-amine (1.2 g, 2.4 mmol) and pyridine-3-boronic acid 1,3-propanediol cyclic ester (0.47 g, 2.9 mmol) were coupled according to the method described in Part J of Example 1. The work-up procedure used in Part F of Examples 125-135 was followed. The crude product was purified by column chromatography on silica gel (eluting sequentially with 95:5 and 90:10 dichloromethane:methanol) followed by recrystallization from acetonitrile (52 mL/g). The crystals were isolated by filtration, washed with acetonitrile, and dried for four hours under vacuum at 65° C. to provide 0.70 g of 2-ethoxymethyl- -{2-[2-(methanesulfonyl)ethoxy]-2-methylpropyl }-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine as white, crystalline plates, mp 202-204° C.

[0954] Anal. Calcd for C25H31N5O4S: C, 60.34; H, 6.28; N, 14.07. Found: C, 60.19; H, 6.45; N, 14.02.

Example 364

2-Ethoxymethyl-1-{2-[2-(methanesulfonyl)ethoxy]-2-methylpropyl}-7-(5-methoxypyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine

[0955]

430

[0956] 7-Bromo-2-ethoxymethyl-1-{2-[2-(methanesulfonyl)ethoxy]-2-methylpropyl}-1H-imidazo[4,5-c]quinolin-4-amine (1.1 g, 2.2 mmol) and pyridine-5-methoxy-3-boronic acid pinacol ester (0.63 g, 2.7 mmol) were coupled according to the method described in Part J of Example 1. The work-up procedure used in Part F of Examples 125-135 was followed. The crude product was purified by HPFC (eluting with dichloromethane:methanol in a gradient from 99:1 to 85:15) followed by trituration with ethyl acetate. The crystals were isolated by filtration and dried for four hours under vacuum at 65° C. to provide 0.1 g of 2-ethoxymethyl-1-{2-[2-(methanesulfonyl)ethoxy]-2-methylpropyl}-7-(5-methoxypyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine as a white powder, mp 186-188° C.

[0957] Anal. Calcd for C26H33N5O5S: C, 59.18; H, 6.30; N, 13.27. Found: C, 58.96; H, 6.64; N, 13.09.

Example 365

Dimethyl 4-[4-amino-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]butane-1-sulfonamide

[0958]

431

[0959] Part A

[0960] A modification of the method described in Part E of Example 1 was used to treat 7-bromo-4-chloro-3-nitroquinoline (20.0 g, 69.6 mmol) with 4-amino-1-butanol (6.9 mL, 76.5 mmol). The addition of 4-amino-1-butanol was carried out at ambient temperature. The product, 4-(7-bromo-3-nitroquinolin-4-ylamino)butan-1-ol (21.1 g) was isolated as a yellow solid and used without purification.

[0961] Part B

[0962] A suspension of 4-(7-bromo-3-nitroquinolin-4-ylamino)butan-1-ol (20.75 g, 61.0 mmol) in dichloromethane (220 mL) was cooled to 0° C.; thionyl chloride (4.90 mL, 67.1 mmol) was added dropwise over a period of ten minutes. The reaction was stirred at 0° C. for five minutes, allowed to warm to ambient temperature, and stirred overnight. Aqueous sodium bicarbonate (500 mL of 50%) was slowly added. The aqueous layer was separated and extracted with dichloromethane (3×100 mL). The combined organic fractions were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to yield an orange semi-solid. An analysis by LCMS indicated the presence of starting material, and the semi-solid was dissolved in dichloromethane (150 mL) and treated with thionyl chloride (3.0 mL) as described above. Following the work-up procedure, the crude product was purified by column chromatography on silica gel (eluting with dichloromethane:methanol in a gradient from 100:0 to 95:5) to provide 8.3 g of (7-bromo-3-nitroquinolin-4-yl)-(4-chlorobutyl)amine as a yellow solid.

[0963] Part C

[0964] A suspension of (7-bromo-3-nitroquinolin-4-yl)-(4-chlorobutyl)amine (8.05 g, 22.5 mmol) in methanol (250 mL) was cooled to 0° C.; a solution of sodium hydrosulfite (19.5 g, 112 mmol) in water (80 mL) was added dropwise over a period of 30 minutes. The reaction was stirred at ambient temperature for two hours and then concentrated under reduced pressure. The residue was partitioned between dichloromethane (300 mL) and aqueous sodium bicarbonate (150 mL of 50%). The aqueous layer was separated and extracted with dichloromethane (2×50 mL). The combined organic fractions were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide 7.25 g of crude 7-bromo-N4-(4-chlorobutyl)quinoline-3,4-diamine as a light brown semi-solid.

[0965] Part D

[0966] A modification of the method described in Part C of Examples 125-135 was used to treat 7-bromo-N4-(4-chlorobutyl)quinoline-3,4-diamine (7.25 g, 22.1 mmol) with ethoxyacetyl chloride (2.76 mL, 24.3 mmol). After the reaction was stirred for one hour, it was concentrated under reduced pressure to provide N-[7-bromo-4-(4-chlorobutylamino)quinolin-3-yl]-2-eth6xyacetamide hydrochloride as a yellow solid.

[0967] Part E

[0968] Aqueous sodium hydroxide (16.6 mL of 2 M, 33.2 mmol) was added to a suspension of the material from Part D in ethanol (100 mL), and the reaction was heated to 60° C. over a period of 30 minutes and stirred at 60° C. for one hour. The reaction was allowed to cool to ambient temperature and then concentrated under reduced pressure. The residue was partitioned between water (150 mL) and dichloromethane (300 mL). The aqueous layer was separated and extracted with dichloromethane (2×75 mL). The combined organic fractions were washed with brine (100 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (eluting with ethyl acetate:chloroforn in a gradient from 20:80 to 100:0) to provide 4.46 g of 7-bromo-1-(4-chlorobutyl)-2-ethoxymethyl-1H-imidazo[4,5-c]quinoline as a tan solid.

[0969] Part F

[0970] Potassium thioacetate (1.70 g, 14.9 mmol) was added in one portion to a stirred solution of 7-bromo-1-(4-chlorobutyl)-2-ethoxymethyl-1H-imidazo[4,5-c]quinoline (5.37 g, 13.5 mmol) in DMF (65 mL), and the reaction was stirred at ambient temperature for 21 hours. The DMF was removed under reduced pressure, and the residue was partitioned between dichloromethane (300 mL) and water (150 mL). The organic layer was separated, washed with brine (120 mL), dried over magnesium sulfate, filtered, and concentrated to provide 6.09 g of thioacetic acid S-[4-(7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]ester as a brown solid.

[0971] Part G

[0972] Nitrogen was bubbled through a solution of thioacetic acid S-[4-(7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]ester (1.93 g, 4.42 mmol) in methanol (45 mL), and then sodium methoxide (2.5 mL of 25% by weight in methanol, 11.1 mmol) was added dropwise over a period of three minutes. The yellow solution was stirred at ambient temperature for one hour and then concentrated under reduced pressure. The residue was partitioned between dichloromethane (250 mL) and water (125 mL), and hydrochloric acid (˜3 mL of 2 M) was added to adjust the mixture to pH 7. The aqueous layer was separated and extracted with dichloromethane (50 mL); the combined organic fractions were washed with brine (100 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide 1.73 g of 4-(7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)butane-1-thiol as a tan solid.

[0973] Part H

[0974] A solution of 4-(7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)butane-1-thiol (1.73 g, 4.39 mmol) in concentrated hydrochloric acid (7.5 mL) and water (5 mL) was cooled to 0° C. A solution of sodium chlorate (0.61 g, 5.7 mmol) in water (2.5 mL) was added dropwise with vigourous stirring over a period of three minutes. The reaction was stirred at 0° C. for 90 minutes then diluted with dichloromethane (50 mL). Aqueous potassium carbonate (8 mL of 6M) was slowly added to adjust the mixture to pH 5. Dichloromethane (100 mL) and water (75 mL) were added, and the reaction was allowed to warm to ambient temperature with stirring. The aqueous layer was separated and extracted with dichloromethane (3×40 mL). The combined organic fractions were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide 1.61 g of 4-(7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)butane-1-sulfonyl chloride as a tan solid.

[0975] Part I

[0976] Dimethylamine hydrochloride (0.60 g, 7.3 mmol) and aqueous potassium carbonate (1.46 mL of 6 M, 8.7 mmol) were sequentially added to a stirred solution of 4-(7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)butane- 1-sulfonyl chloride (1.61 g, 3.49 mmol) in dichloromethane (35 mL), and the reaction was stirred at ambient temperature for 80 minutes. Dichloromethane (180 mL) and aqueous sodium bicarbonate (60 mL) were added. The aqueous layer was separated and extracted with dichloromethane (2×40 mL); the combined organic fractions were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide 1.49 g of dimethyl 4-(7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)butane-1-sulfonamide as a tan solid.

[0977] Part J

[0978] 3-Chloroperoxybenzoic acid (0.126 g of 70% pure material, 0.73 mmol) was added in one portion to a stirred solution of dimethyl 4-(7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)butane-1-sulfonamide (0.30 g, 0.63 mmol) in chloroform (7 mL), and the solution was stirred for two hours at ambient temperature. Ammonium hydroxide (2 mL) and p-toluenesulfonyl chloride (0.15 g, 0.76 mmol) were sequentially added, and the mixture was stirred at ambient temperature for one hour. Dichloromethane (100 mL) was added, and the mixture was washed sequentially with 2 M aqueous sodium hydroxide (2×30 mL), saturated aqueous sodium bicarbonate (2×30 mL), and brine (30 mL); dried over magnesium sulfate; filtered; and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (eluting with ethyl acetate:ethanol in a gradient from 100:0 to 80:20) followed by recrystallization from dichloromethane:heptane. The crystals were dried for two hours under vacuum at 40° C. to provide 0.185 g of dimethyl 4-(4-amino-7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)butane-1-sulfonamide as a white solid, mp 193° C.

[0979] Anal. Calcd for Cl9H26BrN5O3S: C, 47.11; H, 5.41; N, 14.46. Found: C, 46.85; H, 5.48; N, 14.14.

[0980] Part K

[0981] Dimethyl 4-(4-amino-7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)butane-1-sulfonamide (1.00 g, 2.06 mmol), which was prepared in a separate run, and pyridine-3-boronic acid 1,3-propanediol ester (0.40 g, 2.5 mmol) were coupled according to the method described in Part J of Example 1. The reaction was heated at reflux for 14 hours, and the work-up procedure used in Part F of Examples 125-135 was followed. The crude product was purified by column chromatography on silica gel (eluting with chloroform:CMA in a gradient from 95:5 to 80:20) and then triturated sequentially with dichloromethane and methanol, isolated by filtration, and dried for two days under high vacuum at 140° C. to provide 0.695 g of dimethyl 4-[4-amino-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]butane-1-sulfonamide as yellow needles, mp 205-206° C.

[0982] Anal. Calcd for C24H30N6O3S: C, 59.73; H, 6.27; N, 17.41. Found: C, 59.49; H, 6.24; N, 17.36.

Example 366

Dimethyl 4-[4-amino-2-ethoxymethyl-7-phenyl-1H-imidazo[4,5-c]quinolin-1-yl]butane-1-sulfonamide

[0983]

432

[0984] Dimethyl 4-(4-amino-7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)butane-1-sulfonamide (0.66 g, 1.4 mmol) and phenyl boronic acid (0.20 g, 1.6 mmol) were coupled according to the method described in Part J of Example 1. The reaction was heated at reflux for 14 hours, and the work-up procedure used in Part F of Examples 125-135 was followed. The crude product was recrystallized from methanol and then purified by column chromatography on silica gel (eluting with chloroform:CMA in a gradient from 100:0 to 90:10). The solid was then purified by HPFC to provide 0.14 g of dimethyl 4-[4-amino-2-ethoxymethyl-7-phenyl-1H-imidazo[4,5-c]quinolin-1-yl]butane-1-sulfonamide as Off-white needles, mp 207-208° C.

[0985] Anal. Calcd for C25H31N5O3S: C, 61.56; H, 6.55; N, 14.36. Found: C, 61.65; H, 6.67; N, 14.30.

Example 367

4-Methoxybenzyl 4-[4-amino-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]butane-1-sulfonamide

[0986]

433

[0987] Part A

[0988] Over a period of three minutes, p-methoxybenzylamine (1.9 mL, 15 mmol) was added dropwise to a stirred solution of 4-(7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)butane-1-sulfonyl chloride (2.9 g, 6.1 mmol), prepared according to the methods described in Parts A-H of Example 365, in dichloromethane (60 mL). The reaction was stirred at ambient temperature for 90 minutes then diluted with dichloromethane (150 mL) and brine (100 mL). The aqueous layer was separated and extracted with dichloromethane (2×30 mL); the combined organic fractions were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was triturated with dichloromethane (30 mL) to provide a white solid, which was isolated by filtration. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluting with chloroform:CMA in a gradient from 90:10 to 20:80) to provide a white solid, which was triturated with dichloromethane and isolated by filtration. The solids were combined to yield 1.92 g of 4-methoxybenzyl 4-(7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)butane-1-sulfonamide as a white solid.

[0989] Part B

[0990] 4-Methoxybenzyl 4-(7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)butane-1-sulfonamide was oxidized and then aminated according to the general method described in Part J of Example 365. The oxidation reaction was stirred for five hours, and the amination reaction was stirred overnight. The crude product was purified twice by column chromatography on silica gel (eluting with chloroform:CMA in a gradient from 95:5 to 80:20) to provide 0.80 g of 4-methoxybenzyl 4-(4-amino-7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)butane-1-sulfonamide. This material was mixed with material from another run.

[0991] Part C

[0992] 4-Methoxybenzyl 4-(4-amino-7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)butane-1-sulfonamide (1.16 g, 2.0 mmol) and pyridine-3-boronic acid (0.30 g, 2.4 mmol) were coupled according to the method described in Part J of Example 1. The reaction was heated at reflux for 14 hours, at which time additional pyridine-3-boronic acid (0.3 equivalent) was added and the reaction was heated for an additional five hours. The work-up procedure used in Part F of Examples 125-135 was followed. The crude product was purified by column chromatography on silica gel (eluting with chloroform:CMA in a gradient from 100:0 to 80:20) and then triturated with methanol, isolated by filtration, and dried for 20 hours under high vacuum at 140° C. to provide 0.62 g of 4-methoxybenzyl 4-[4-amino-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]butane-1-sulfonamide as a beige powder, mp 230-231.5° C.

[0993] Anal. Calcd for C30H34N6O4S: C, 62.70; H, 5.96; N, 14.62. Found: C, 62.39; H, 6.06; N, 14.56.

Example 368

4-[4-Amino-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]butane-1-sulfonamide

[0994]

434

[0995] A solution of 4-methoxybenzyl 4-[4-amino-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]butane-1-sulfonamide (0.50 g, 0.88 mmol) in trifluoroacetic acid (5 mL) was stirred at ambient temperature for four hours and then concentrated under reduced pressure. The residue was dissolved in methanol and concentrated under reduced pressure; this process was repeated three times. The residue was then suspended in water, and 2 M aqueous sodium hydroxide was added to adjust to pH 7. The mixture was stirred for 30 minutes, and the resulting solid was isolated by filtration, washed with water, and purified by HPFC (eluting with chloroform:CMA in a gradient from 100:0 to 30:70). The purified product was dried overnight under high vacuum at 80° C. to provide 0.31 g of 4-[4-amino-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]butane-1-sulfonamide as tan needles, mp 250-251.5° C.

[0996] Anal. Calcd for C22H26N6O3S: C, 58.13; H, 5.77; N, 18.49. Found: C, 57.89; H, 5.44; N, 18.16.

Example 369

Methyl 4-[4-amino-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]butane-1-sulfonamide

[0997]

435

[0998] Part A

[0999] The method described in Part I of Example 365 was used to treat 4-(7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)butane-1-sulfonyl chloride (1.61 g, 3.49 mmol), prepared according to the methods described in Parts A-H of Example 365, with methylamine hydrochloride (0.50 g, 7.3 mmol) and aqueous potassium carbonate (1.3 mL of 6 M, 7.7 mmol) to provide 1.4 g of methyl 4-[7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl]butane-1-sulfonamide as a tan solid.

[1000] Part B

[1001] Methyl 4-(7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)butane-1-sulfonamide was oxidized and then aminated according to the general method described in Part J of Example 365. The oxidation reaction was stirred for three hours, and the amination reaction was stirred for 90 minutes. The crude product was recrystallized from a mixture of dichloromethane, heptane, and a trace of methanol and isolated by filtration. The mother liquor was concentrated and purified by column chromatography on silica gel (eluting with chloroform:CMA in a gradient from 95:5 to 80:20) and then triturated with dichloromethane and isolated by filtration. The products were dried overnight under high vacuum at 140° C. to provide a total of 0.86 g of methyl 4-(4-amino-7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)butane-1-sulfonamide as a white solid, mp 199-200° C.

[1002] Anal. Calcd for C18H24BrN5O3S: C, 45.96; H, 5.14; N, 14.89. Found: C, 46.02; H, 4.85; N, 14.65.

[1003] Part C

[1004] Methyl 4-(4-amino-7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)butane-1-sulfonamide (0.78 g, 1.7 mmol) and pyridine-3-boronic acid 1,3-propanediol cyclic ester (0.33 g, 2.0 mmol) were coupled according to the method described in Part J of Example 1. The reaction was heated at reflux for 15 hours, at which time additional pyridine-3-boronic acid 1,3-propanediol cyclic ester, palladium acetate, and triphenylphosphine were added, and the reaction was heated for an additional three hours. The work-up procedure used in Part F of Examples 125-135 was followed. The crude product was purified twice by column chromatography on silica gel (eluting with chloroform:CMA in a gradient from 95:5 to 70:30) and then triturated with methanol, isolated by filtration, and dried for eight hours under high vacuum at 100° C. to provide 0.78 g of methyl 4-[4-amino-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]butane-1-sulfonamide as off-white needles, mp 216-218° C.

[1005] Anal. Calcd for C23H28N6O3S.0.23H2O: C, 58.44; H, 6.07; N, 17.78. Found: C, 58.08; H, 5.97; N, 17.71.

Example 370

Dimethyl 5-[4-amino-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]pentane-1-sulfonamide

[1006]

436

[1007] Part A

[1008] The method described in Part A of Example 365 was used to treat 7-bromo-4-chloro-3-nitroquinoline (20.0 g, 69.5 mmol) with 4-amino-1-pentanol (7.9 g, 76 mmol) to provide 24.0 g of 5-(7-bromo-3-nitroquinolin-4-ylamino)pentan-1-ol as a yellow solid.

[1009] Part B

[1010] A suspension of 5-(7-bromo-3-nitroquinolin-4-ylamino)pentan-1-ol (0.92 g, 2.6 mmol) in dichloromethane (13 mL) was cooled to 0° C.; thionyl chloride was added dropwise. The reaction was stirred for five minutes at 0° C. then allowed to warm to ambient temperature and stirred overnight. Saturated aqueous sodium bicarbonate (25 mL) was slowly added followed by water (25 mL). The aqueous layer was separated and extracted with dichloromethane (3×50 mL), and the combined organic fractions were dried over magnesium sulfate and concentrated under reduced pressure to provide 0.91 g of (7-bromo-3-nitroquinolin-4-yl)-(5-chloropentyl)amine as a yellow semisolid.

[1011] Part C

[1012] The methods described in Parts C-E of Example 365 were used to convert (7-bromo-3-nitroquinolin-4-yl)-(5-chloropentyl)amine to 7-bromo-1-(5-chloropentyl)-2-ethoxymethyl-1H-imidazo[4,5-c]quinoline. The crude product was purified twice by column chromatography on silica gel (eluting with chloroform:methanol in a gradient from 100:0 to 90:10).

[1013] Part D

[1014] Thiourea (0.29 g, 3.8 mmol) and potassium iodide (0.052 g, 3.1 mmol) were sequentially added to a suspension of 7-bromo-1-(5-chloropentyl)-2-ethoxymethyl-1H-imidazo[4,5-c]quinoline (1.3 g, 3.2 mmol) in DMF (15 mL), and the reaction was heated at 110° C. for 24 hours. The DMF was removed under reduced pressure, and the residue was partitioned between saturated aqueous sodium bicarbonate (40 mL) and dichloromethane (50 mL). The mixture was adjusted to pH 7 with the addition of 10% hydrochloric acid. Product remained on the walls of the reaction flask and was dissolved with methanol. The resulting solution was concentrated under reduced pressure to provide a solid. The aqueous layer was concentrated under reduced pressure, and the resulting solid was triturated with methanol and isolated by filtration. The filtrate was concentrated under reduced pressure, and the residue was triturated and isolated as described above. The isolated solids were combined and dried under high vacuum to provide 1.49 g of 2-[5-(7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)pentyl]isothiourea hydrochloride as a yellow solid.

[1015] Part E

[1016] A solution of 2-[5-(7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)pentyl]isothiourea hydrochloride (1.49 g, 3.16 mmol) in 7 M hydrochloric acid (8 mL) was cooled to 0° C. A solution of sodium chlorate (0.44 g, 4.1 mmol) in water (1.0 mL) was added dropwise with stirring, and the reaction was stirred at 0° C. for one hour. A precipitate formed and was isolated by filtration, washed with ice-cold water (4×4 mL), and dried under high vacuum to provide 0.92 g of 5-(7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)pentane-1-sulfonyl chloride as a yellow solid.

[1017] Part F

[1018] The method described in Part I of Example 365 was used to treat 5-(7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)pentane-1-sulfonyl chloride (0.91 g, 1.9 mmol) with dimethylamine hydrochloride (0.33 g, 4.0 mmol). The crude product was purified by HPFC (eluting with ethyl acetate:methanol in a gradient from 100:0 to 90:10) to provide 0.57 g of dimethyl 5-(7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)pentane-1-sulfonamide as a yellow solid.

[1019] Part G

[1020] Dimethyl 5-(7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)pentane-1-sulfonamide was oxidized and aminated according to the methods described in Part J of Example 365. The crude product was purified twice by HPFC (eluting with chloroform:CMA in a gradient from 100:0 to 90:10) and then triturated with ethyl acetate, isolated by filtration, washed with ethyl acetate (2×1 mL), and dried for several hours under high vacuum at 150° C. to provide dimethyl 5-(4-amino-7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)pentane-1-sulfonamide as a yellow solid.

[1021] Part H

[1022] Dimethyl 5-(4-amino-7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)pentane-1-sulfonamide (0.26 g, 0.53 mmol) and pyridine-3-boronic acid (0.78 g, 0.63 mmol) were coupled according to the method described in Part J of Example 1. The reaction was heated at 100° C. for 31 hours, at which time additional palladium acetate (0.002 equivalent) was added. Heating was resumed for 14 hours, and then additional pyridine-3-boronic acid (0.3 equivalent) was added. The reaction was heated for another 22 hours. The work-up procedure used in Part F of Examples 125-135 was followed. The crude product was purified twice by HPFC (eluting with chloroform:CMA in a gradient from 100:0 to 80:20) and then triturated with ethyl acetate and isolated by filtration. The product was finally recrystallized from isopropanol, isolated by filtration, and dried for eight hours under high vacuum at 100° C. to provide 0.090 g of dimethyl 5-[4-amino-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]pentane-1-sulfonamide as a white powder, mp 159-160° C.

[1023] Anal. Calcd for C25H32N6O3S: C, 60.46; H, 6.49; N, 16.92. Found: C, 60.33; H, 6.56; N, 16.81.

Example 371

Methyl 5-[4-amino-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]pentane-1-sulfonamide

[1024]

437

[1025] Part A

[1026] The method described in Part I of Example 365 was used to treat 5-(7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)pentane-1-sulfonyl chloride (1.11 g, 2.33 mmol) with methylamine hydrochloride (0.33 g, 4.9 mmol). The reaction was stirred overnight, and additional methylamine hydrochloride (0.3 equivalent) and 6 M potassium carbonate (0.4 equivalent) were added. The reaction was stirred for an additional four hours. The crude product was purified by HPFC (eluting with chloroform:CMA in a gradient from 100:0 to 80:20) to provide 0.80 g of methyl 5-(7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)pentane-1-sulfonamide as a white solid.

[1027] Part B

[1028] Methyl 5-(7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)pentane-1-sulfonamide was oxidized and aminated according to the methods described in Part J of Example 365. The oxidation reaction was stirred for three hours, and the amination reaction was stirred for 90 minutes. The product precipitated from the reaction mixture and was isolated by filtration. The crude product was purified by HPFC (eluting with chloroform:CMA in a gradient from 100:0 to 80:20) to provide methyl 5-(4-amino-7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)pentane-1-sulfonamide as a white solid.

[1029] Part C

[1030] Methyl 5-(4-amino-7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)pentane-1-sulfonamide (0.47 g, 0.97 mmol) was coupled with pyridine-3-boronic acid (0.14 g, 1.2 mmol) according to the methods described in Part J of Example 1 and Part H of Example 370. The crude product was purified twice by HPFC (eluting with chloroform:CMA in a gradient from 100:0 to 70:30) and then recrystallized from methanol, isolated by filtration, and dried for 5 days under high vacuum at 100-140° C. to provide 0.13 g of methyl 5-[4-amino-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]pentane-1-sulfonamide as a white powder, mp 191-192° C.

[1031] Anal. Calcd for C24H30N6O3S: C, 59.73; H, 6.27; N, 17.41. Found: C, 59.48; H, 6.58; N, 17.56.

Examples 372-376

[1032] Part A

[1033] A solution of tert-butyl {4-[4-amino-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]butyl}carbamate (40.35 g, 82.24 mmol) in concentrated hydrochloric acid (400 mL) was stirred for one hour, filtered, and concentrated under reduced pressure. The residue was dissolved in a minimal amount of water, and 50% aqueous sodium hydroxide was added to adjust the solution to pH 14. Chloroform (1.2 L) and a mixture of saturated aqueous sodium bicarbonate and 1% aqueous sodium carbonate (600 mL) were added; the mixture was stirred for 30 minutes. The organic layer was separated, dried over sodium sulfate, and concentrated under reduced pressure to provide 36.48 g of 1-(4-aminobutyl)-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine as a light yellow solid.

[1034] Part B

[1035] Triethylamine (1.39 mL, 10.0 mmol) was added to a solution of 1-(4-aminobutyl)-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine (3.00 g, 7.70 mmol) in chloroform (150 mL); the reagent (1.1 equivalents) listed in the table below was then added. The reaction was stirred for one hour or until completion; additional triethylamine and the indicated reagent were added as need until the reaction was complete. Deionized water (15-20 mL) was added, and the mixture was stirred for five minutes. The organic layer was separated, washed with 1% aqueous sodium carbonate, optionally dried with sodium sulfate and filtered, and concentrated under reduced pressure. The crude product was recrystallized from the solvent listed in the table below and dried overnight in a drying oven to provide the compound with the structure shown below.

438

RecrystallizationExampleReagentsolventR372Butyryl chlorideAcetonitrile:water 83:17

439

373Isobutyryl chlorideIsopropanol then acetonitrile:water

440

374Cyclopentanecarbonyl chlorideAcetonitrile:water, isopropanol, methyl acetate, then isopropanol

441

375Methanesulfonic anhydridePrecipitated during work-up, no recrystallization done

442

3761-Propanesulfonyl chlorideIsopropanol then acetonitrile:water 75:25

443

mpExampleNameForm(°C.)Anal.372N-{4-[4-Amino-2-ethoxymethyl- 7-(pyridin-3-yl)-1H-imidazo[4,5- c]quinolin-1-yl]butyl}butyramideWhite soid150-152Calcd for C26H32N6O2: C, 67.80; H, 7.00; N, 18.25. Found: C, 67.51; H, 7.29; N, 18.18.373N-{4-[4-Amino-2-ethoxymethyl- 7-(pyridin-3-yl)-1H-imidazo[4,5- c]quinolin-1-yl]butyl}-2- methylpropanamideWhite solid200-202Calcd for C26H32N6O2: C, 67.80; H, 7.00; N, 18.25. Found: C, 67.47; H, 7.09; N, 18.16.374N-{4-[4-Amino-2-ethoxymethyl- 7-(pyridin-3-yl)-1H-imidazo[4,5- c]quinolin-1- yl]butyl}cyclopentanecarboxamideWhite solid196-198Calcd for C28H34N6•O20.25 H2O: C, 68.48; H, 7.08; N, 17.11. Found: C, 68.28; H, 7.36; N, 17.00.375N-{4-[4-Amino-2-ethoxymethyl- 7-(pyridin-3-yl)-1H-imidazo[4,5- c]quinolin-1- yl]butyl}methanesulfonamideWhite solid186-188Calcd for C23H28N6O3S•0.25 H2O: C, 58.39; H, 6.07; N, 17.76. Found: C, 58.31; H, 5.75; N, 17.72.376N-{4-[4-Amino-2-ethoxymethyl- 7-(pyridin-3-yl)-1H-imidazo[4,5- c]quinolin-1-yl]butyl}propane-1- sulfonamideOff- white solid178-180Calcd for C25H32N6O3S: C, 60.46; H, 6.49; N, 16.92. Found: C, 60.22; H, 6.42; N, 16.77.

Examples 377-379

[1036] The isocyanate indicated in the table below was added slowly to a solution of 1-(4-aminobutyl)-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine (1 equivalent) in chloroform (20-50 mL/g). A precipitate formed within five minutes or formed upon cooling the reaction mixture to ˜0° C. after 15 minutes. The precipitate was isolated by filtration and dried overnight in an oven. The solid was slurried with the solvent(s) listed in the table below, isolated by filtration, and dried overnight in an oven to provide the product with the structure shown in the table below.

Examples 377-379

[1037]

444

Example
Isocyanate
Purification solvent
R

377
Cyclopentyl isocyante
Acetonitrile:water 75:25

445

378
Propyl isocyanate
Not used

446

379
Isopropyl isocyanate
Hot isopropanol

447

mp

Example
Name
Form
(° C.)
Anal.

377
N-{4-[4-Amino-2- ethoxymethyl-7-(pyridin- 3-yl)-1H-imidazo[4,5- c]quinolin-1-yl]butyl}-N′- cyclopentylurea
White solid
190-192
Calcd for C28H35N7O2: C, 67.04; H, 7.03; N, 19.55. Found: C, 66.76; H, 7.01; N, 19.46.

378
N-{4-[4-Amino-2- ethoxymethyl-7-(pyridin- 3-yl)-1H-imidazo[4,5- c]quinolin-1-yl]butyl}-N′- propylurea
White solid
191-193
Calcd for C26H33N7O2: C, 65.66; H, 6.99; N, 20.62. Found: C, 65.84; H, 7.43; N, 20.66.

379
N-{4-[4-Amino-2- ethoxymethyl-7-(pyridin- 3-yl)-1H-imidazo[4,5- c]quinolin-1-yl]butyl}-N′- (1-methylethyl)urea
White solid
192-194
Calcd for C26H33N7O2: C, 65.66; H, 6.99; N, 20.62. Found: C, 65.83; H, 7.39; N, 20.52.

Examples 380-382

[1038] A solution of tert-butyl {4-[4-amino-2-propyl-7-(pyridin-3-yl)-1H-imidazol[4,5-c]quinolin-1-yl]butyl}carbamate (41.92 g, 88.32 mmol) in concentrated hydrochloric acid (210 mL) was stirred for ten minutes, and 50% aqueous sodium hydroxide was added to adjust the solution to pH 14. Cloroform (2.0 L) and a mixture of saturated aqueous sodium bicarbonate and 1% aqueous sodium carbonate (300 mL) were added. The organic layer was separated, dried over sodium sulfate, and concentrated under reduced pressure to provide a yellow solid. The aqueous phase was treated with sodium chloride and chloroform (400 mL), and the mixture was stirred overnight. The organic layer was separated, dried over sodium sulfate, and concentrated under reduced pressure to provide a yellow solid. The two solids were combined to yield 28.77 g of 1-(4-aminobutyl)-2-propyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine as a light yellow solid.

[1039] Triethylamine (1.34 mL, 9.61 mmol) was added to a solution of 1-(4-aminobutyl)-2-propyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine (3.00 g, 8.01 mmol) in chloroform (141 mL); the solution was then cooled to 0° C. A cold solution of the reagent (1.0 equivalent) listed in the table below in chloroform (9 mL) was then added. The reaction was stirred for 15 or 90 minutes, and deionized water (25 mL) was added. A precipitate formed and was isolated by filtration and dried overnight in a drying oven. The crude product was triturated with the solvent(s) listed in the table below, isolated by filtration, and dried overnight in a drying oven to provide the compound with the structure shown below.

Examples 380-382

[1040]

448

Example
Reagent
Purification solvent
R

380
Butyryl chloride
Chloroform (10 mL/g) and 1% aqueous sodium carbonate (3 mL/g)

449

381
Isobutyryl chloride
Not used

450

382
Cyclopentanecarbonyl chloride
Chloroform (10 mL/g) then recrystallized from isopropanol (6 mL/g)

451

mp

Example
Name
Form
(° C.)
Anal.

380
N-{4-[4-Amino-2-propyl-7- (pyridin-3-yl)-1H-imidazo[4,5- c]quinolin-1-yl]butyl}butyramide
White solid
144-146
Calcd for C26H32N6O•2 H2O: C, 64.98; H, 7.55; N, 17.49. Found: C, 64.53; H, 7.08; N, 17.44.

381
N-{4-[4-Amino-2-propyl-7- (pyridin-3-yl)-1H-imidazo[4,5- c]quinolin-1-yl]butyl}-2- methylpropanamide
White solid
168-170
Calcd for C26H32N6O•0.25 H2O: C, 69.54; H, 7.29; N, 18.71. Found: C, 69.45; H, 7.67; N, 18.65.

382
N-{4-[4-Amino-2-propyl-7- (pyridin-3-yl)-1H-imidazo[4,5- c]quinolin-1- yl]butyl}cyclopentanecarboxamide
White solid
180-182
Calcd for C28H34N6O•1.5 H2O: C, 67.58; H, 7.49; N, 16.89. Found: C, 67.51; H, 7.72; N, 17.09.

Examples 383-385

[1041] A solution of 1-(4-aminobutyl)-2-propyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine (1 equivalent) in chloroform (18 mL/g) was cooled to 0° C.; a cold solution of the isocyanate indicated in the table below (1.05 equivalents) in chloroform (2 mL/g) was added. A precipitate formed within ten minutes or formed upon cooling the reaction mixture to ˜0° C. for 30 minutes. The precipitate was isolated by filtration and dried overnight in an oven. The solid was from 1:1 acetonitrile:water, isolated by filtration, and dried for five days in an oven at 63° C. to provide the product with the structure shown in the table below.

Examples 383-385

[1042]

452

Example
Isocyanate
R

383
Cyclopentyl isocyanate

453

384
Propyl isocyanate

454

385
Isopropyl isocyanate

455

mp

Example
Name
Form
(° C.)
Anal.

383
N-{4-[4-Amino-2-propyl- 7-(pyridin-3-yl)-1H- imidazo[4,5-c]quinolin-1- yl]butyl}-N′- cyclopentylurea
White solid
181-183
Calcd for C28H35N7O•1.5 H2O: C, 65.60; H, 7.47; N, 19.13. Found: C, 65.44; H, 7.61; N, 19.09.

384
N-{4-[4-Amino-2-propyl- 7-(pyridin-3-yl)-1H- imidazo[4,5-c]quinolin-1- yl]butyl}-N′-propylurea
White solid
184-185
Calcd for C26H33N7O•0.25 H2O: C, 67.29; H, 7.28; N, 21.13. Found: C, 67.15; H, 7.56; N, 21.41.

385
N-{4-[4-Amino-2-propyl- 7-(pyridin-3-yl)-1H- imidazo[4,5-c]quinolin-1- yl]butyl}-N′-(1- methylethyl)urea
White solid
173-175
Calcd for C26H33N7O•1.25 H2O: C, 64.77; H, 7.42; N, 20.34. Found: C, 64.36; H, 7.78; N, 20.21.

Example 386

N-{2-[4-Amino-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]ethyl}-2-methylpropanamide

[1043]

456

[1044] Part A

[1045] A solution of 7-bromo-4-chloro-3-nitroquinoline (140.00 g, 486.96 mmol) in chloroform (2.8 L) was cooled to 0° C. Triethylamine (82.0 mL, 588 mol) and ethylenediamine (35.75 mL, 535.6 rnrnol) were sequentially added; the resulting mixture was stirred for one hour at 0° C. then allowed to warm to ambient temperature and stirred for two hours. Additional ethylenediamine (0.1 equivalent) was added, and the reaction was stirred for an additional 1.75 hours. Additional triethylamine (88.0 mL, 631 mmol) followed by a solution of di-tert-butyl dicarbonate (180.0 mL, 779.1 mmol) in chloroform (320 mL) were added, and the reaction was stirred overnight at ambient temperature. Water (750 mL) was added, and the mixture was stirred for 15 minutes. The organic layer was separated and washed with 1% aqueous sodium carbonate (2×750 mL), dried over sodium sulfate, filtered through a layer of CELITE filter aid, and concentrated under reduced pressure. The resulting solid was triturated with hot acetonitrile (5 mL/g at 95° C.), cooled in an ice bath, and isolated by filtration to provide 165.0 g of tert-butyl [2-(7-bromo-3-nitroquinolin-4-ylamino)ethyl]carbamate as a light yellow solid.

[1046] Part B

[1047] A solution of tert-butyl [2-(7-bromo-3-nitroquinolin-4-ylamino)ethyl]carbamate (165.0 g, 401.2 mmol) in acetonitrile (3.3 L) and, isopropanol (990 mL) and 5% platinum on carbon (13.2 g) were added to a Parr vessel, which was placed under hydrogen pressure (50 psi, 3.4×105 Pa) overnight. The mixture was filtered through a layer of CELITE filter aid, and the filtrate was concentrated under reduced pressure to provide 139.29 g of tert-butyl [2-(3-amino-7-bromoquinolin-4-ylamino)ethyl]carbamate as a yellow solid. The product was suspended in a mixture of dichloromethane (4 mL/g) and chloroform (8 mL/g), and the suspension was divided into two equal portions.

[1048] Part C

[1049] Ethoxyacetyl chloride (25.44 g, 182.7 mmol) in chloroform (50 mL) was added to one portion of the suspension from Part B. The resulting brown solution was stirred for 30 minutes and then concentrated under reduced pressure.

[1050] Part D

[1051] Triethylamine (101.85 mL, 730.7 mmol) was added to a suspension of the material from Part C in ethanol (1.1 L); the mixture was heated at reflux for two hours, allowed to stand over three days, and concentrated under reduced pressure. The residue was partitioned between chloroform (1.2 L) and water (400 mL). The organic layer was separated, washed with brine (2×400 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was triturated with acetonitrile (10 mL/g) at 95° C., isolated by filtration, and dried for three days to provide 51.48 g of tert-butyl [2-(7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]carbamate as a white solid.

[1052] Part E

[1053] A modification of the method described in Example 1 Part H was used to oxidize tert-butyl [2-(7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]carbamate (36.48 g, 81.18 mmol) with 3-chloroperoxybenzoic acid (36.31 g of 77% pure material, 105.5 mmol). The reaction was carried out in chloroform (370 mL) and allowed to proceed for 30 minutes. The crude product was used without purification.

[1054] Part F

[1055] The material from Part E was aminated according to the method described in Part I of Example 1; the reaction was complete after one hour. The crude product was triturated with acetonitrile (7 mL/g) at 95° C., and the resulting solid was isolated by filtration to provide 26.89 g of tert-butyl [2-(4-amino-7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]carbamate as a fluffy, white solid.

[1056] Part G

[1057] tert-Butyl [2-(4-amino-7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]carbamate (21.80 g, 46.94 mmol) and 3-pyridylboronic acid (6.64 g, 54.0 mrnmol) were coupled according to the method described in Part J of Example 1. Palladium (II) acetate was added as a 5 mg/mL solution in toluene. The reaction was terminated after 4.5 hours, and the work-up procedure described in Part F of Examples 125-135 was followed. The crude product was recrystallized from acetonitrile (12 mUg) to provide 10.80 g of tert-butyl {2-[2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]ethyl}carbamate as a white solid.

[1058] Part H

[1059] The method described in Part A of Examples 372-376 was used to convert tert-butyl {2-[2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]ethyl}carbamate (10.80 g, 23.34 mmol) to 8.38 g of 1-(2-aminoethyl)-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine as a white solid.

[1060] Part I

[1061] 1-(2-Aminoethyl)-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine (2.00 g, 5.50 mmol) was treated with triethylamine (1.00 mL, 7.20 mmol) and isobutyryl chloride (0.64 mL, 6.10 mmol) according to the method described in Part B of Examples 372-376. The crude product was recrystallized from 93:7 acetonitrile:water and then from isopropanol (7.3 mL/g) and dried for two hours in a drying oven to provide 0.78 g of N-{2-[4-amino-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]ethyl}-2-methylpropanamide as a white solid, mp 213-215° C.

[1062] Anal. Calcd for C24H28N6O2.0.75H2O: C, 64.63; H, 6.67; N, 18.84. Found: C, 64.66; H, 6.54; N, 18.71.

Example 387

N-{2-[4-Amino-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]ethyl}methanesulfonamide

[1063]

457

[1064] A solution of 1-(2-aminoethyl)-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine (2.00 g, 5.50 mmol) in chloroform (40 mL) was treated with triethylamine (1.62 mL, 11.6 mmol) and methanesulfonyl chloride (0.47 mL, 6.05 mmol). The reaction was stirred for 1.5 hours, and additional methanesulfonyl chloride (2 equivalents) was added. The reaction was stirred for 30 minutes, and then deionized water (15 mL) was added. A precipitate formed and was isolated by filtration, triturated once with methanol and twice with chloroform and 1% aqueous sodium carbonate, isolated by filtration, and dried overnight in an oven to provide 0.65 g of N-{2-[4-amino-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]ethyl}methanesulfonamide as a white solid, mp 233-235° C.

[1065] Anal. Calcd for C21H24N6O3S.0.5H2O: C, 56.1 1; H, 5.61; N, 18.69. Found: C,

[1066] Anal. Calcd for C21H24N6O3S.0.5H2O: C, 56.1 1; H, 5.61; N, 18.69. Found: C,

Example 388

N-{2-[4-Amino-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]ethyl}-N′-(1-methylethyl)urea

[1067]

458

[1068] A solution of 1-(2-aminoethyl)-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine (2.50 g, 6.90 mmol) in chloroform (50 mL) was treated with isopropyl isocyanate (0.65 mL, 6.9 mmol) according to the method described in Examples 377-379. The crude product was purified by column chromatography on silica gel (eluting with 94:6 chloroform:methanol) followed by trituration with acetonitrile (15 mL/g) at 95° C. The mixture was cooled in an ice bath, isolated by filtration, and dried for one hour in a vacuum oven at 100° C. to provide 0.88 g of N-{2-[4-amino-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]ethyl}-N′-(1-methylethyl)urea as a white solid, mp 194-196° C.

[1069] Anal. Calcd for C24H29N7O2: C, 64.41; H, 6.53; N, 21.91. Found: C, 64.34; H, 6.82; N, 22.05.

Example 389

1-[2-(1,1-Dioxo-1-isothiazolidin-2-yl)ethyl]-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine

[1070]

459

[1071] 3-Chloropropanesulfonyl chloride (2.52 mL, 20.7 mmol) was added to a solution of 1-(2-aminoethyl)-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine (2.50 g, 6.90 mmol) in chloroform (50 mL) in two portions over a period of two hours, and the reaction was stirred overnight at ambient temperature. Additional 3-chloropropanesulfonyl chloride (1.72 mL, 14.1 mmol) was added followed by triethylamine (2.02 mL, 14.9 mmol) to drive the reaction to completion. Chloroform (50 mL) and water (30 mL) were added, and the mixture was stirred for five minutes. A precipitate formed, was isolated by filtration, and was mixed with DMF (66 mL) and DBU (2.06 mL, 13.8 mmol). The resulting solution was stirred for three days at ambient temperature and then combined with water (660 mL) and chloroform (400 mL). The organic layer was separated and dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (eluting with 95:5 chloroform:methanol). The resulting solid was triturated with methanol at 80° C., cooled in an ice bath, isolated by filtration, and dried overnight in a vacuum oven to provide 0.28 g of 1-[2-(1,1-dioxo-1-isothiazolidin-2-yl)ethyl]-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine as a white solid, mp 244-246° C.

[1072] Anal. Calcd for C23H26N6O3S.0.11H2O: C, 58.96; H, 5.64; N, 17.94. Found: C, 58.86; H, 5.69; N, 17.90.

Example 390

N-{2-[4-Amino-2-butyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]ethyl}-2-methylpropanamide

[1073]

460

[1074] Part A

[1075] Valeryl chloride (21.68 mL, 182.6 mmol) in chloroform (50 mL) was added to one portion of the suspension from Part B of Example 386. The resulting brown solution was stirred for 30 minutes and then concentrated under reduced pressure.

[1076] Part B

[1077] A solution of sodium hydroxide (21.92 g, 274.0 mmol) in water (110 mL) was added to a suspension of the material from Part A in ethanol (640 mL); the mixture was heated at reflux for four hours and then concentrated under reduced pressure. The residue was partitioned between chloroform (1.2 L) and deionized water (400 mL). The mixture was stirred for 30 minutes. The organic fraction was separated, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting solid was triturated with isopropanol at 95° C., isolated by filtration, and dried on the filter funnel to provide 39.78 g of tert-butyl [2-(7-bromo-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]carbamate as a pinkish-gray solid.

[1078] Part C

[1079] tert-Butyl [2-(7-bromo-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]carbamate (24.78 g, 55.4 mmol) was oxidized and then aminated according to the methods described in Parts E and F of Example 386. After purification 19.13 g of tert-butyl [2-(4-amino-7-bromo-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]carbamate was obtained as a gray solid.

[1080] Part D

[1081] tert-Butyl [2-(4-amino-7-bromo-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]carbamate (14.09 g, 30.5 mmol) and 3-pyridylboronic acid (4.31 g, 35.0 mmol) were coupled according to the method described in Part G of Example 386. The reaction was heated for 2.5 hours. The crude product was triturated with toluene (15 mL/g) at 123° C. and isolated by filtration to provide 11.31 g of tert-butyl {2-[2-butyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]ethyl}carbamate as a white solid.

[1082] Part E

[1083] The method described in Part A of Examples 372-376 was used to convert tert-butyl {2-[2-butyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]ethyl}carbamate (11.31 g, 24.56 mmol) to 1-(2-aminoethyl)-2-butyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine.

[1084] Part F

[1085] 1-(2-Aminoethyl)-2-butyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine (2.00 g, 5.50 mmol) was treated with triethylamine (1.01 mL, 7.26 mmol) and isobutyryl chloride (0.64 mL, 6.10 mmol) according to the method described in Part B of Examples 372-376. The crude product was recrystallized from isopropanol (4 mL/g) and then triturated with acetonitrile (12.5 mL/g), isolated by filtration, and dried overnight in a drying oven to provide 0.61 g of N-{2-[4-amino-2-butyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]ethyl}-2-methylpropanamide as a white solid, mp 228-230° C.

[1086] Anal. Calcd for C25H30N6O: C, 69.74; H, 7.02; N, 19.52. Found: C, 69.37; H, 6.97; N, 19.60.

Example 391

N-{2-[4-Amino-2-butyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]ethyl}methanesulfonamide

[1087]

461

[1088] The method described in Example 387 was used to convert 1-(2-aminoethyl)-2-butyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine to N-{2-[4-amino-2-butyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]ethyl}methanesulfonamide.

Example 392

N-{2-[4-Amino-2-butyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]ethyl}-N′-(1-methylethyl)urea

[1089]

462

[1090] Isopropyl isocyanate (0.29 mL, 3.1 mmol) was added slowly to a suspension of 1-(2-aminoethyl)-2-butyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine (1.13 g, 3.1 mmol) in chloroform (113 mL). A precipitate formed within 15 minutes, was isolated by filtration, and was dried overnight in an oven to provide 0.66 g of N-{2-[4-amino-2-butyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]ethyl}—N′-(1-methylethyl)urea as a white solid, mp 240-241° C.

[1091] Anal. Calcd for C25H31N7O: C, 67.39; H, 7.01; N, 22.00. Found: C, 67.24; H, 7.08; N, 21.90.

Example 393

1-[2-(1,1-Dioxo-1-isothiazolidin-2-yl)ethyl]-2-butyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine

[1092]

463

[1093] The method described in Example 389 was used to convert 1-(2-aminoethyl)-2-butyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine (4.00 g, 11.1 mmol) to 1.05 g of 1-[2-(1,1-dioxo-1-isothiazolidin-2-yl)ethyl]-2-butyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine, which was isolated as a white solid, mp 290-292° C.

[1094] Anal. Calcd for C24H28N6O2S.0.06H2O: C, 61.90; H, 6.09; N, 18.05. Found: C, 61.52; H, 6.03; N, 18.05.

Examples 394-403

[1095] The methods described in Parts C, D, and E of Examples 125-135 were used to convert 1-(3-amino-7-bromoquinolin-4-ylamino)-2-methylpropan-2-ol to 1-(4-amino-7-bromo-2-methoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol. Methoxyacetyl chloride was used in lieu of ethoxyacetyl chloride in Part C.

[1096] 1-(4-Amino-7-bromo-2-methoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol and the boronic acid or boronic acid ester from the table below were coupled according to the procedure described in Part F of Examples 125-135. After the work-up procedure, the crude product was purified by HPFC (eluting with chloroform:methanol in a gradient from 100:0 to 70:30). The resulting product was dissolved in dichloromethane and concentrated under reduced pressure until a precipitate began to form. Hexanes were added, and the resulting solid was isolated by filtration and dried overnight under vacuum at 70° C. to provide the compound shown in the table below. For Example 399, the solid isolated by filtration was triturated with hot acetonitrile, isolated by filtration, and dried under vacuum. For Example 402, the product from the coupling reaction was deprotected according to the method described in Part C of Example 150 to provide the product shown in the table below. The purification and characterization of Example 403 is given below the following tables.

Examples 394-403

[1097]

464

Example
Boronic acid
R

394
2-Ethoxyphenylboronic acid

465

395
Pyrimidine-5-boronic acid

466

396
Pyridine-3-boronic acid

467

397
2-Methoxypyrimidine-5-boronic acid

468

398
2-Methoxy-5-pyridineboronic acid

469

399
4-Methoxy-3-pyridineboronic acid

470

400
3-Methoxypyridine-5-boronic acid pinacol ester

471

401
3-(Morpholine-4- carbonyl)phenylboronic acid

472

402
5-(tert-Butyldimethylsilanyloxymethyl) pyridine-3-boronic acid

473

403
5-Ethoxymethylpyridin-3-ylboronic acid

474

[1098] The characterization data for Examples 394-402 are shown in the table below.

Examples 394-403

[1099]

33

mp

Example
Name
Form
(° C.)
Anal.

394
1-[4-Amino-7-(2-
White
173-175
Calcd for C24H28N4O3:

ethoxyphenyl)-2-
solid

C, 68.55; H, 6.71; N,

methoxymethyl-1H-

13.32. Found: C,

imidazo[4,5-c]quinolin-1-

68.38; H, 6.92; N,

yl]-2-methylpropan-2-ol

13.47.

395
1-[4-Amino-2-
White
220-220.5
Calcd for C20H22N6O2:

methoxymethyl-7-
powder

C, 63.48; H, 5.86; N,

(pyrimidin-5-yl)-1H-

22.21. Found: C,

imidazo[4,5-c]quinolin-1-

63.30; H, 5.72; N,

yl]-2-methylpropan-2-ol

22.21.

396
1-[4-Amino-2-
White
225-225.5
Calcd for C21H23N5O2:

methoxymethyl-7-
solid

C, 65.70; H, 6.23; N,

(pyridin-3-yl)-1H-

18.24. Found: C,

imidazo[4,5-c]quinolin-1-

65.30; H, 5.57; N,

yl]-2-methylpropan-2-ol

17.99.

397
1-[4-Amino-2-
White
241-242
Calcd for C21H24N6O3:

methoxymethyl-7-(2-
solid

C, 59.17; H, 6.14; N,

methoxypyrimidin-5-yl)-

19.71. Found: C,

1H-imidazo[4,5-

59.33; H, 6.12; N,

c]quinolin-1-yl]-2-

19.73.

methylpropan-2-ol

398
1-[4-Amino-2-
White
190-190.5
Calcd for C22H25N5O3:

methoxymethyl-7-(6-
powder

C, 64.85; H, 6.18; N,

methoxypyridin-3-yl)-

17.19. Found: C,

1H-imidazo[4,5-

64.61; H, 5.97; N,

c]quinolin-1-yl]-2-

17.13.

methylpropan-2-ol

399
1-[4-Amino-2-
White
220.5-222
Calcd for C22H25N5O3:

methoxymethyl-7-(4-
powder

C, 64.85; H, 6.18; N,

methoxypyridin-3-yl)-

17.19. Found: C,

1H-imidazo[4,5-

64.54; H, 5.90; N,

c]quinolin-1-yl]-2-

17.11.

methylpropan-2-ol

400
1-[4-Amino-2-
Yellow
234-236
Calcd for

methoxymethyl-7-(5-
powder

C22H25N5O3.0.13

methoxypyridin-3-yl)-

CH2Cl2: C, 63.51; H,

1H-imidazo[4,5-

6.08; N, 16.73.

c]quinolin-1-yl]-2-

Found: C, 63.26; H,

methylpropan-2-ol

5.83; N, 16.61.

401
{3-[4-Amino-1-(2-
White
176-177
Calcd for

hydroxy-2-
solid

C27H31N5O4.1.0H2O:

methylpropyl)-2-

C, 63.89; H, 6.55; N,

methoxymethyl-1H-

13.80. Found: C,

imidazo[4,5-c]quinolin-7-

63.50; H, 6.44; N,

yl]phenyl}morpholin-4-

13.64.

ylmethanone

402
1-[4-Amino-7-(5-
White
224-225
Calcd for

hydroxymethylpyridin-3-
powder

C22H25N5O3.1.5H2O:

yl)-2-methoxymethyl-1H-

C, 60.82; H, 6.50; N,

imidazo[4,5-c]quinolin-1-

16.12. Found: C,

yl]-2-methylpropan-2-ol

60.81; H, 6.51; N,

16.14.

Example 403

1-[4-Amino-7-(5-ethoxymethylpyridin-3-yl)-2-methoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol

[1100] The product from the coupling reaction was further purified by recrystallizing twice from acetonitrile:isopropanol followed by a second chromatographic purification on silica gel (eluting with chloroform:CMA in a gradient from 99:1 to 70:30) to provide the product as a white powder.

[1101]

1
H NMR (300mHz, DMSO-d6 @ 45° C.) δ 8.90 (d, J=2.2 Hz, 1H), 8.54 (d, J=1.9 Hz, 1H), 8.40 (d, J=8.6 Hz, 1H), 8.07 (t, J=2.1 Hz, 1H), 7.91 (d, J=2.0 Hz, 1H), 7.57 (dd, J=8.6, 2.0 Hz, 1H), 6.54 (br s, 2H), 4.89 (br s, 2H), 4.83 (br s, 1H), 4.69 (br s, 2H), 4.60 (br s, 2H), 3.58 (q, J=7.0 Hz, 2H), 3.34 (s, 3H), 1.22-1.17 (m, 9H);

[1102] MS (ESI) m/z 436.2361 (436.2349 calcd for C24H29N5O3, M+H).

Example 404

tert-Butyl 4-{[4-amino-2-ethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}piperidine-1-carboxylate

[1103]

475

[1104] Part A

[1105] The method described in Part A of Examples 142-144 was used to treat tert-butyl 4-[(3-amino-7-bromoquinolin-4-ylamino)methyl]piperidine-1-carboxylate (15.0 g, 34.5 mmol) with triethyl orthopropionate (6.68 g, 37.9 mmol). After completion, the reaction mixture was concentrated under reduced pressure, and the residue was purified by flash column chromatography on silica gel (eluting with 95:5 chloroform:CMA) followed by recrystallization from ethyl acetate to provide 12.6 g of tert-butyl 4-[(7-bromo-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]piperidine-1-carboxylate as a white powder, mp 208-209° C.

[1106] Anal. Calcd for C23H29BrN4O2: C, 58.35; H, 6.17; N, 11.83. Found: C, 58.13; H, 5.85; N, 11.69.

[1107] Part B

[1108] tert-Butyl 4-[(7-bromo-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]piperidine-1-carboxylate was oxidized and then aminated according to the methods described in Parts H and I of Example 1. The oxidation product was not recrystallized; the amination reaction was stirred for 16 hours. The product from amination was purified by column chromatography on silica gel (eluting with 90:10 chloroform:CMA) followed by recrystallization from ethyl acetate to provide tert-butyl 4-[(4-amino-7-bromo-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]piperidine-1-carboxylate as an off-white powder, mp 131-132° C.

[1109] Anal. Calcd for C23H30BrN5O2: C, 56.56; H, 6.19; N, 14.34. Found: C, 56.30; H, 6.14; N, 14.06.

[1110] Part C

[1111] tert-Butyl 4-[(4-amino-7-bromo-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]piperidine-1-carboxylate (9.24 g, 18.9 mmol) and pyridine-3-boronic acid 1,3-propanediol cyclic ester (3.39 g, 20.8 mmol) were coupled according to the method described in Examples 118-121. Additional reagents were added after the reaction was heated for 16 hours, and the reaction was continued for 16 hours. Water (20 mL) was added, and the n-propanol was removed under reduced pressure. The remaining mixture was extracted with chloroform (2×200 mL), and the combined organic fractions were purified by column chromatography on silica gel (eluting with chloroform and chloroform:CMA). The resulting solid was recrystallized from acetonitrile to provide 5.44 g of tert-butyl 4-{[4-amino-2-ethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}piperidine-1-carboxylate as a white, fluffy solid, mp 229-231° C.

[1112] Anal. Calcd for C28H34N6O2: C, 69.11; H, 7.04; N, 17.27. Found: C, 69.18; H, 7.07; N, 17.36.

Example 405

2-Ethyl-1-(piperidin-4-ylmethyl)-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine trihydrochloride

[1113]

476

[1114] The method described in Example 177 was used to convert tert-butyl 4-{[4-anino-2-ethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}piperidine-1-carboxylate (5.22 g, 10.7 mmol) to 5.15 g of 2-ethyl-1-(piperidin-4-ylmethyl)-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine trihydrochloride, which was obtained as a white solid, mp >250° C.

[1115] Anal. Calcd for C23H26N6.3HCl.1.4H2O: C, 53.01; H, 6.15; N, 16.13. Found: C, 53.40; H, 6.53; N, 16.15.

Examples 406-408

[1116] A solution of 2-ethyl-1-(piperidin-4-ylmethyl)-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine trihydrochloride (1.50 g, 2.88 mmol) and triethylamine (5 or 10 equivalents) in chloroform (100 mL for Example 406 and 250 mL for Examples 407 and 408) and pyridine (60 mL for Example 406 and 100 mL for Examples 407 and 408) was cooled to 4° C. The reagent from the table below (1 equivalent) was added dropwise, and the reaction was allowed to warm to ambient temperature and stirred for between 12 and 48 hours, with additional reagents added in Example 406. For Example 406, the reaction mixture was diluted with chloroform, and the resulting solution was washed sequentially with water (100 mL), 4% aqueous sodium carbonate (2×50 mL), water (50 mL), and brine (50 mL) and then concentrated under reduced pressure. For Examples 407 and 408, the reaction mixture was concentrated under reduced pressure and then triturated with 5 N aqueous sodium hydroxide to afford a solid that was isolated by filtration. The crude products were purified by flash column chromatography on silica gel (eluting with chloroform and chloroform:CMA) followed by recrystallization from acetonitrile to provide the products shown in the table below. The following table contains characterization data for these compounds.

Examples 406-408

[1117]

477

Example
Reagent
R

406
Methanesulfonyl chloride

478

407
Isobutyryl chloride

479

408
Isopropyl isocyanate

480

Examples 406-408

[1118]

35

Ex-

am-

mp

ple
Name
Form
(° C.)
Anal.

406
2-Ethyl-1-{[1-
White
228-
Calcd for

(methanesulfonyl)piperidin-
crys-
229
C24H28N6O2S.

4-yl]methyl}-7-(pyridin-3-
talline

0.86 H2O: C,

yl)-1H-imidazo[4,5-
solid

60.04; H, 6.24; N,

c]quinolin-4-amine

17.50. Found: C,

60.21; H, 6.51; N,

17.43.

407
1-{4-[4-Amino-2-ethyl-7-
White
189-
Calcd for

(pyridin-3-yl)-1H-
crys-
191
C27H32N6O.0.5

imidazo[4,5-c]quinolin-1-
talline

H2O: C, 69.65; H,

ylmethyl]piperidin-1-yl}-2-
solid

7.14; N, 18.05.

methylpropan-1-one

Found: C, 69.58;

H, 7.26; N, 18.11.

408
4-[4-Amino-2-ethyl-7-
White
255-
Calcd for

(pyridin-3-yl)-1H-
solid
256
C27H33N7O.1.25

imidazo[4,5-c]quinolin-1-

H2O: C, 65.63; H,

ylmethyl]piperidin-1-

7.24; N, 19.84.

carboxylic acid

Found: C, 65.58;

isopropylamide

H, 7.03; N, 19.85.

Example 409

tert-Butyl 4-{[4-amino-2-propyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}piperidine-1-carboxylate

[1119]

481

[1120] Part A

[1121] The method described in Part A of Examples 142-144 was used to treat tert-butyl 4-[(3-amino-7-bromoquinolin-4-ylamino)methyl]piperidine-1-carboxylate (15.0 g, 34.5 mmol) with trimethyl orthobutyrate (5.62 g, 37.9 mmol). After completion, the reaction mixture was concentrated under reduced pressure, and the residue was purified by flash column chromatography on silica gel (eluting with 95:5 chloroform:CMA) followed by recrystallization from ethyl acetate to provide 13.1 g of tert-butyl 4-[(7-bromo-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]piperidine-1-carboxylate as a white solid, mp 215-216° C.

[1122] Anal. Calcd for C24H31BrN4O2: C, 59.14; H, 6.41; N, 11.49. Found: C, 59.06; H, 6.24; N, 11.42.

[1123] Part B

[1124] tert-Butyl 4-[(7-bromo-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]piperidine-1-carboxylate was oxidized and then aminated according to the methods described in Parts H and I of Example 1. The oxidation product was not recrystallized; the amination reaction was stirred for 16 hours. The product from amination was purified by column chromatography on silica gel (eluting with 90:10 chloroform:CMA) followed by recrystallization from ethyl acetate to provide tert-butyl 4-[(4-amino-7-bromo-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]piperidine-1-carboxylate as off-white needles, mp 134-137° C.

[1125] Anal. Calcd for C24H32BrN5O2: C, 57.37; H, 6.42; N, 13.94. Found: C, 57.14; H, 6.41; N, 13.52.

[1126] Part C

[1127] tert-Butyl 4-[(4-amino-7-bromo-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]piperidine-1-carboxylate (8.02 g, 15.9 mmol) and pyridine-3-boronic acid 1,3-propanediol cyclic ester (2.86 g, 17.6 mmol) were coupled according to the method described in Part C of Example 404 to provide, after purification, 4.12 g of tert-butyl 4-{[4-amino-2-propyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}piperidine-1-carboxylate as an off-white solid, mp 209-211° C.

[1128] Anal. Calcd for C29H36N6O2.0.6H2O: C, 68.10; H, 7.33; N, 16.43. Found: C, 67.72; H, 7.26; N, 16.31.

Example 410

1-(Piperidin-4-ylmethyl)-2-propyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine trihydrochloride

[1129]

482

[1130] The method described in Example 177 was used to convert tert-butyl 4-{[4-amino-2-propyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}piperidine-1-carboxylate (4.00 g, 7.99 mmol) to 3.84 g of 1-(piperidin-4-ylmethyl)-2-propyl-7-(pyridin-3-yl)-1H-imidazo [4,5-c]quinolin-4-amine trihydrochloride, which was obtained as a white solid, mp >250° C.

[1131] Anal. Calcd for C24H28N6.3HCl.0.59H2O: C, 55.39; H, 6.23; N, 16.15. Found: C, 55.35; H, 6.52; N, 16.08.

Examples 411-413

[1132] The methods described for Examples 406, 407, and 408 were carried out for Examples 411, 412, and 413 respectively to provide the products shown in the table below.

Examples 411-413

[1133]

483

Example
Reagent
R

411
Methanesulfonyl chloride

484

412
Isobutyryl chloride

485

413
Isopropyl isocyanate

486

[1134] Characterization data for Examples 411-413 are shown in the table below.

Examples 411-413

[1135]

37

Ex-

am-

mp

ple
Name
Form
(° C.)
Anal.

411
1-{[1-
White
>250
Calcd for

(Methanesulfonyl)piperidin-
solid

C25H30N6O2S.0.8

4-yl]methyl}-2-propyl-7-

HCl.1.0 H2O: C,

(pyridin-3-yl)-1H-

57.11; H, 6.29; N,

imidazo[4,5-c]quinolin-4-

15.98; Cl, 5.39.

amine

Found: C, 56.87; H,

6.68; N, 15.77; Cl,

5.02.

412
1-{4-[4-Amino-2-propyl-7-
White
248-
Calcd for

(pyridin-3-yl)-1H-
solid
249
C28H34N6O: C,

imidazo[4,5-c]quinolin-1-

71.46; H, 7.28; N,

ylmethyl]piperidin-1-yl}-2-

17.86. Found: C,

methylpropan-1-one

71.21; H, 7.33; N,

17.55.

413
4-[4-Amino-2-ethyl-7-
Off-
240-
Calcd for

(pyridin-3-yl)-1H-
white
242
C28H35N7O: C,

imidazo[4,5-c]quinolin-1-
solid

69.25; H, 7.26; N,

ylmethyl]piperidin-1-

20.19. Found: C,

carboxylic acid

68.98; H, 7.20; N,

isopropylamide

20.35.

Example 414

2-Ethoxymethyl-1-(2-piperazin-1-ylethyl)-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine

[1136]

487

[1137] Part A

[1138] 7-Bromo-4-chloro-3-nitroquinoline (33.0 g, 115 mmol) was treated with 4-(2-aminoethyl)-1-(tert-butoxycarbonyl)piperazine (26.4 mL, 115 mmol) according to the method described in Part E of Example 1. The reaction was stirred overnight. The crude product was triturated with diethyl ether and isolated by filtration to provide 33.05 g of tert-butyl 4-[2-(7-bromo-3-nitroquinolin-4-ylamino)ethyl]piperazine-1-carboxylate as a yellow solid.

[1139] Part B

[1140] tert-Butyl 4-[2-(7-bromo-3-nitroquinolin-4-ylamino)ethyl]piperazine-1-carboxylate was treated according to the methods described in Parts B through D of Examples 152-156. Triethylamine (1.1 equivalents) was added to the reaction in Part C, and the reaction in Part D was heated at reflux overnight. Following chromatographic purification in Part D (eluting with chloroform:CMA in a gradient from 100:0 to 94:6), tert-butyl 4-[2-(7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]piperazine-1-carboxylate was obtained as a white solid, mp 140-143° C.

[1141] Anal. Calcd for C24H32BrN5O3: C, 55.60; H, 6.22; N, 13.51. Found: C, 55.62; H, 6.31; N, 13.40.

[1142] Part C

[1143] tert-Butyl 4-[2-(7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]piperazine-1-carboxylate (21.5 g, 41.5 mmol) was oxidized with three equivalents of 3-chloroperoxybenzoic acid (28.63 g of 75% pure material, 124.4 mmol) according to the method described Part H of Example 1 to provide tert-butyl 4-[2-(7-bromo-2-ethoxymethyl-5-oxido-1H-imidazo[4,5-c]quinolin 1-yl)ethyl]-4-oxidopiperazine-1-carboxylate, which was used without purification.

[1144] Part D

[1145] tert-Butyl 4-[2-(7-bromo-2-ethoxymethyl-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]-4-oxidopiperazine-1-carboxylate was aminated according to the method described in Part I of Example 1. The reaction was stirred overnight, and the crude product was purified by flash column chromatography on silica gel (eluting with chloroform:CMA in a gradient from 95:5 to 70:30) to provide 10.84 g of tert-butyl 4-[2-(4-amino-7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]-4-oxidopiperazine-1-carboxylate as a white solid.

[1146] Part E

[1147] A solution of tert-butyl 4-[2-(4-amino-7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]-4-oxidopiperazine-1-carboxylate (8.84 g, 16.1 mmol) in chloroform (400 mL) was cooled to 4° C. Phosphorous trichloride (9.82 mL, 113 mmol) was added dropwise, and the reaction was stirred for 45 minutes at 4° C. Water (one drop) was added to the reaction, which was allowed to warm to ambient temperature. The chloroform was removed under reduced pressure, and the residue was dissolved in ethanol (150 mL). Hydrogen chloride (21.5 mL of a 3 M solution in ethanol) was added, and the reaction was heated at reflux for 25 minutes. The reaction was allowed to cool to room temperature; a precipitate formed and was isolated by filtration to provide 6.86 g of 7-bromo-2-ethoxymethyl-1-(2-piperazin-1-ylethyl)-1H-imidazo[4,5-c]quinolin-4-amine dihydrochloride as a light yellow solid.

[1148] Part F

[1149] Under a nitrogen atmosphere, triphenylphosphine (0.0409 g, 0.156 mmol), 2 M aqueous sodium carbonate (18.3 mL, 36.5 mmol) and a solution of palladium (II) acetate (0.0117 g, 0.52 mmol) in warm toluene were added to a solution of 7-bromo-2-ethoxymethyl-1-(2-piperazin-1-ylethyl)-1H-imidazo[4,5-c]quinolin-4-amine dihydrochloride (5.28 g, 10.4 mmol) and pyridine-3-boronic acid 1,3-propanediol cyclic ester (1.87 g, 11.5 mmol) in n-propanol (8 mL). The reaction was heated at reflux under nitrogen for three hours then allowed to cool to ambient temperature. Deionized water was added, and organic solvent was removed under reduced pressure. The aqueous mixture was extracted with ethyl acetate (3×), and the combined organic fractions were washed sequentially with 2 M aqueous sodium carbonate and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was combined with material from another run and purified by flash column chromatography on silica gel (eluting with chloroform:methanol in a gradient from 90:10 to 50:50 and 50:50 chloroform:CMA) to provide 3.54 g of 2-ethoxymethyl-1-(2-piperazin-1-ylethyl)-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine as a white solid, mp 208-211° C.

[1150] Anal. Calcd for C24H29N7O.0.5H2O: C, 65.43; H, 6.86; N, 22.26. Found: C, 65.59; H, 7.09; N, 22.53.

Examples 415-417

[1151] A 0.015 M solution of 2-ethoxymethyl-1-(2-piperazin-1-ylethyl)-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine (1.00 g, 2.32 mmol) and triethylamine (1.3-1.4 equivalents) in chloroform was cooled to 4° C. The reagent from the table below (1.1-1.2 equivalents) was added dropwise, and the reaction was allowed to warm to ambient temperature and stirred for two or three hours. In Examples 415 and 417, additional triethylamine and the reagent indicated in the table were added at 4° C., and the reaction was stirred overnight. The work-up procedure described in Examples 178 to 181 was carried out. The crude product was purified by flash column chromatography on silica gel or by HPFC (eluting with chloroform:CMA in a gradient from about 100:0 to 75:25) followed by recrystallization from acetonitrile to provide the products shown in the table below.

Examples 415-417

[1152]

488

Example
Reagent
R

415
Methanesulfonyl chloride

489

416
Isobutyryl chloride

490

417
4-Morpholinecarbonyl chloride

491

[1153] The characterization data for Examples 415-417 are provided in the table below.

Examples 415-417

[1154]

39

Ex-

am-

mp

ple
Name
Form
(° C.)
Anal.

415
2-Ethoxymethyl-1-{2-[4-
White
205-
Calcd for

(methanesulfonyl)piperazin-
solid
207
C25H31N7O3S.0.65

1-yl]ethyl}-7-(pyridin-

H2O: C, 57.60; H,

3-yl)-1H-imidazo[4,5-

6.25; N, 18.81.

c]quinolin-

Found: C, 57.51; H,

4-amine

6.22; N, 18.79.

416
1-(4-{2-[4-Amino-2-
White
190-
Calcd for

ethoxymethyl-7-(pyridin-3-
solid
192
C28H35N7O2.0.5

yl)-1H-imidazo[4,5-

H2O: C, 65.86; H,

c]quinolin-1-

7.11; N, 19.20.

yl]ethyl}piperazin-1-yl)-2-

Found: C, 65.90; H,

methylpropan-1-one

7.07; N, 19.34.

417
1-(4-{2-[4-Amino-2-
Light
212-
C29H36N8O3.0.5

ethoxymethyl-7-(pyridin-3-
yellow
214
H2O: C, 62.91; H,

yl)-1H-imidazo[4,5-
solid

6.74; N, 20.24.

c]quinolin-1-

Found: C, 63.02; H,

yl]ethyl}piperazin-1-

6.69; N, 20.26.

yl)morpholin-4-

ylmethanone

Examples 418-420

[1155] Part A

[1156] Trimethyl orthobutyrate (11.61 mL, 72.6 mmol) and catalytic pyridine hydrochloride were added to a solution of 1-(3-amino-7-bromoquinolin-4-ylamino)-2-methylpropan-2-ol (22.51 g, 72.6 mmol) in anhydrous toluene (120 mL), and the reaction was heated at reflux for two hours. The solvent was removed under reduced pressure, and the residue was dissolved in dichloromethane and washed with water. The dichloromethane was removed under reduced pressure until a precipitate began to form. Hexanes were added, and the precipitate was isolated by filtration to provide 20.17 g of 1-(7-bromo-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol.

[1157] Part B

[1158] 1-(7-Bromo-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol was oxidized and then aminated according to the methods described in Part E of Examples 125-135 to provide 14.6 g of 1-(4-amino-7-bromo-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol as a white solid, which was used without purification.

[1159] Part C

[1160] 1-(4-Amino-7-bromo-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol and the boronic acid from the table below were coupled according to the general procedure described in Part J of Example 1. Example 420 was heated at reflux overnight. The purification and characterization of each compound is described below the table.

Examples 418-420

[1161]

492

Example
Boronic acid or ester
R3

418
Pyridine-3-boronic acid

493

419
Phenylboronic acid

494

420
5-(tert- Butyldimethylsilanyloxymethyl) pyridine-3-boronic acid

495

Example 418

1-[4-Amino-2-propyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol

[1162] The reaction mixture was concentrated under reduced pressure, and hexanes were added to form a precipitate. The precipitate was isolated by filtration and purified by HPFC (eluting with chloroform:CMA in a gradient from 100:0 to 70:30) to provide the product as an off-white solid, mp 238.5-241° C.

[1163]

1
H NMR (300 MHz, DMSO-d6) δ 8.97 (s, 1H), 8.57 (d, J=3.6 Hz, 1H), 8.38 (d, J=8.7 Hz, 1H), 8.14 (d, J=7.8 Hz, 1H), 7.9 (s, 1H), 7.55-7.47 (m, 2H), 6.39 (s, 2H), 4.71 (s, 1H), 4.56 (br s, 2H), 3.01 (t, J=7.2 Hz, 2H), 1.86 (sextet, J=7.5 Hz, 2H), 1.2 (s, 6H), 1.01 (t, J=7.5 Hz, 3H);

[1164] MS (APCl) m/z 376 (M+H)+;

[1165] Anal. Calcd for C22H25N5O.0.33H2O: C, 69.28; H, 6.78; N, 18.36. Found: C, 69.68; H, 7.24; N, 18.58.

Example 419

1-[4-Amino-7-phenyl-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol

[1166] The isolated solid was recrystallized from methanol:water and then purified by HPFC (eluting with chloroform:CMA in a gradient from 100:0 to 70:30). A second recrystallization was carried out with acetonitrile:isopropanol to provide the product as a white solid.

[1167]

1
H NMR (300mHz, DMSO-d6) δ 8.35 (d, J=8.7 Hz, 1H), 7.85 (d, J=2.0 Hz, 1H), 7.77-7.74 (m, 2H), 7.52-7.47 (m, 3H), 7.39-7.34 (m, 1H), 6.32 (br s, 2H), 4.71 (s, 1H), 4.57 (br s, 2H), 3.02 (t, J=7.4 Hz, 2H), 1.86 (sextet, J=7.6 Hz, 2H), 1.21 (br s, 6H), 1.02 (t, J=7.3 Hz, 3H);

[1168] MS (ESI) 375.2180 (375.2185 calcd for C23H26N4O).

Example 420

1-[4-Amino-7-(5-hydroxymethylpyridin-3-yl)-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol

[1169] The crude product was purified by HPFC (eluting with ethyl acetate and then chloroform:CMA in a gradient from 90:10 to 70:30) and then deprotected according to the method described in Part C of Example 150. The product from the deprotection was purified by HPFC (eluting with chloroform:CMA in a gradient from 100:0 to 60:40). The resulting product was mixed with dichloromethane and concentrated under reduced pressure until a solid began to form. The solid was isolated by filtration and dried under vacuum to provide 1-[4-amino-7-(5-hydroxymethylpyridin-3-yl)-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol as a white solid, mp 225-226° C.

[1170] Anal. Calcd for C23H27N5O2.0.67H2O: C, 66.17; H, 6.84; N, 16.78. Found: C, 65.86; H, 6.85; N, 16.66.

Example 421-424

[1171] Part A

[1172] The method described in Part A of Example 200 was used to treat 7-bromo-4-chloro-3-nitroquinoline (50.0 g, 174 mmol) with 1,2-diamino-2-methylpropane (36.5 mL, 348 mmol) and triethylamine (45 mL, 260 mmol). Following the work-up procedure, the solution of N-(3-nitro-7-bromoquinolin-4-yl)-2-methylpropane-1,2-diamine in dichloromethane was concentrated to a volume of 1 L.

[1173] Part B

[1174] The solution from Part A was cooled to 0° C. under a nitrogen atmosphere. Triethylamine (48.5 mL, 348 mmol) was added followed by a solution of di-tert-butyl dicarbonate (41.8 g, 191 mmol) in dichloromethane (200 mL) over a period of 30 minutes. The reaction was allowed to warm to ambient temperature and stirred for three days. The reaction was washed with deionized water (2×500 mL) and brine (500 mL), dried over sodium sulfate and magnesium sulfate, filtered through a layer of CELITE filter aid, and concentrated under reduced pressure to provide 58 g of tert-butyl [2-(7-bromo-3-nitroquinolin-4-ylamino)-1,1-dimethylethyl]carbamate as a yellow solid.

[1175] Part C

[1176] The method described in Part B of Examples 125-135 was used to reduce tert-butyl [2-(7-bromo-3-nitroquinolin-4-ylamino)-1,1-dimethylethyl]carbamate (58.05 g, 132 mmol) to 23.74 g of tert-butyl [2-(3-amino-7-bromoquinolin-4-ylamino)-1,1-dimethylethyl]carbamate as an orange solid.

[1177] Part D

[1178] A modification of the method described in Part C of Examples 125-135 was used to treat tert-butyl [2-(3-amino-7-bromoquinolin-4-ylamino)-1,1-dimethylethyl]carbamate (23.7 g, 58.0 mmol) with ethoxyacetyl chloride (6.4 mL, 58 mmol). Triethylamine (12.1 mL, 87.0 mmol) was added to the reaction, which was stirred overnight. The reaction was washed with deionized water (2×) and brine, dried over sodium sulfate and magnesium sulfate, filtered, and concentrated under reduced pressure to provide 26.25 g of an orange solid.

[1179] Part E

[1180] The method described in Part D of Examples 152-156 was followed. The reaction was heated at reflux for four days. The crude product was purified first by HPFC (eluting with chloroform:CMA in a gradient from 85:15 to 80:20) and then by column chromatography on silica gel (eluting with 85:15 chloroform:CMA) to provide 15.94 g of tert-butyl [2-(7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)-1,1-dimethylethyl]carbamate as a brown solid.

[1181] Part F

[1182] tert-Butyl [2-(7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)-1,1-dimethylethyl]carbamate (15.94 g, 33.39 mmol) was oxidized and then aminated according to the methods described in Parts H and I of Example 1. The oxidation reaction was carried out in chloroform and stirred overnight. The product was not recrystallized. The product from amination, tert-butyl [2-(4-amino-7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)-1,1-dimethylethyl]carbamate, was obtained as a brown solid after the work-up procedure and used without purification.

[1183] Part G

[1184] The material from Part F was deprotected according to the method described in Example 177. The work-up procedure described in Example 192 was followed with the exception that the aqueous solution was washed with twice dichloromethane before ammonium hydroxide was added. The crude product was purified by column chromatography on silica gel (eluting with dichloromethane:methanol in a gradient from 95:5 to 90:10) to provide 7.27 g of 1-(2-amino-2-methylpropyl)-7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-4-amine as a tan solid.

[1185] Part H

[1186] A solution of 1-(2-amino-2-methylpropyl)-7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-4-amine (lequivalent, 4.5-5 mmol) in the solvent shown in the table below was cooled to −20° C. or 0° C.; triethylamine (2 equivalents) was added. The reagent shown in the table below (1.1 equivalents) was added slowly, and the reaction was stirred for between one hour and overnight. The reaction was washed with deionized water (2×) and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by HPFC (eluting with chloroform:CMA in a gradient from 100:0 to 70:30 for Examples 422 and 424 and with 90:10 dichloromethane:methanol for Example 423).

[1187] Part I

[1188] Under a nitrogen atmosphere, triphenylphosphine (0.015 equivalents), 2 M aqueous sodium carbonate (1.2 equivalents) and a solution of palladium (II) acetate in warm toluene (0.005 equivalents) were added to a solution of the material from Part G (Example 421) or Part H (Examples 422-424) (1 equivalent) and pyridine-3-boronic acid 1,3-propanediol cyclic ester (1.1 equivalents) in n-propanol (0.05-0.15 M). The reaction was heated at reflux under nitrogen for 1.5 to 3.5 hours. Deionized water was added, and organic solvent was removed under reduced pressure. The aqueous mixture was extracted twice with ethyl acetate, and the combined organic fractions were washed with 2 M aqueous sodium carbonate, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by HPFC (eluting with chloroform:CMA in a gradient from 100:0 to 70:30) to provide the product shown in the table below. Characterization data are shown after the table.

496

Solvent for Part HExample(concentration)Reagent for Part HR421Not usedNot usedH422NMP (0.17 M)Isobutyryl chloride

497

423Dichloromethane (0.1 M)Methanesulfonic anhydride

498

424Dichloromethane (0.1 M)4-Morpholinecarbonyl chloride

499

Example 421

1-(2-Amino-2-methylpropyl)-2-ethoxyrnethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine

[1189] The product was obtained as an off-white powder. Anal. Calcd for C22H26N6O.0.25H2O: C, 66.90; H, 6.76; N, 21.28. Found: C, 66.62; H, 7.05, 21.34.

Example 422

N-{2-[4-Amino-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]-1,1-dimethylethyl}-2-methylpropamide

[1190] The product was obtained as a yellow powder. Anal. Calcd for C26H32N6O2.0.40H2O: C, 67.02; H, 7.05; N, 18.04. Found: C, 66.81; H, 7.25, N, 18.06.

Example 423

N-{2-[4-Amino-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]-1,1-dimethylethyl}methanesulfonamide

[1191] The product was obtained as a white powder. 1H NMR (300 MHz, DMSO-d6) δ 8.99 (d, J=1.8 Hz, 1H), 8.59 (dd, J=4.7, 1.5 Hz, 1H), 8.41 (d, J=8.6 Hz, 1H), 8.19 (m, 1H), 7.91 (d, J=2.0 Hz, 1H), 7.59-7.50 (m, 2H), 7.33 (s, 1H), 6.73 (s, 2H), 4.90 (s, 4H), 3.57 (q, J=7.0 Hz, 2H), 3.01 (s, 3H), 1.32 (br s, 6H), 1.15 (t, J=7.0 Hz, 3H); MS (ESI) m/z 469.2018 (469.2022 calcd for C23H28N6O3S, M+H+).

Example 424

N-{2-[4-Amino-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]-1,1-dimethylethyl}morpholine-4-carboxamide

[1192] The product was obtained as an off-white powder; 1H NMR (300 MHz, CDCl3) δ 9.00 (d, J=2.1 Hz, 1H), 8.62 (m, 1H), 8.34 (d, J=8.6 Hz, 1H), 8.06-8.01 (m, 2H), 7.57 (m, 1H), 7.41 (m, 1H), 5.49 (s, 2H), 5.14 (s, 2H), 4.82 (br s, 3H); MS (ESI) m/z 504.2734 (504.2723 calcd for C27H33N7O3, M+H+).

Example 425

1-(2-Methylpropyl)-8-(2-pyridin-4-ylethyl)-1H-imidazo[4,5-c]quinolin-4-amine

[1193]

500

[1194] Part A

[1195] A solution of 1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine (30.0 g, 125 mmol) in chloroform (620 mL) was heated to 50° C., and N-bromosuccinimide (28.8 g, 162 mmol) was added in five portions over a period of five minutes. The resulting dark red solution was heated at reflux for 45 minutes, allowed to cool to ambient temperature, and stirred for one hour. A precipitate formed, was isolated by filtration, and was washed with water and diethyl ether to provide 9.0 g of 8-bromo-1-(2-methylpropyl)-1H-imidazo[4,5-c]-quinolin-4-amine as a solid.

[1196] Part B

[1197] Nitrogen was bubbled through a solution of 8-bromo-1-(2-methylpropyl)-1H-imidazo[4,5-c]-quinolin-4-amine (3.0 g, 9.4 mmol), 4-vinylpyridine (2.0 mL, 19 mmol), triphenylphosphine (246 mg, 0.94 mmol), and triethylamine (2.7 mL, 19 mmol) in acetonitrile (50 mL) for 15 minutes. Palladium (II) acetate (105 mg, 0.47 mmol) was added, and the reaction was heated at 100° C. for three days. The solvent was removed under reduced pressure, and the residue was adjusted to pH 2 with the addition of concentrated hydrochloric acid. Water was added, and the mixture was filtered through a layer of CELITE filter aid. Aqueous sodium carbonate (2 N) was added to the filtrate to adjust the solution to pH 10. The solution was then extracted with dichloromethane, and the combined extracts were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (eluting with chloroform:CMA in a gradient from 95:5 to 80:20) to provide 2.1 g of 1-(2-methylpropyl)-8-(2-pyridin-4-ylvinyl)-1H-imidazo[4,5-c]-quinolin-4-amine as a yellow solid.

[1198] Part C

[1199] 1-(2-Methylpropyl)-8-(2-pyridin-4-ylvinyl)-1H-imidazo[4,5-c]-quinolin-4-amine (2.1 g, 6.1 mmol) was treated according to the method described in Example 123; the reaction was allowed to run for seven days. An analysis by proton nuclear magnetic resonance spectroscopy indicated the presence of starting material in the purified product. The product mixture was dissolved in methanol (100 mL), and 10% palladium on carbon (200 mg) was added. The reaction was placed under hydrogen pressure (40 psi, 2.8×105 Pa) for four days, and the product was isolated as described in Example 123. The crude product was purified by flash column chromatography on silica gel (eluting with 90:10 chloroform:CMA) followed by recrystallization from acetonitrile to provide 380 mg of 1-(2-methylpropyl)-8-(2-pyridin-4-ylethyl)-1H-imidazo[4,5-c]-quinolin-4-amine as pale, yellow crystals, mp 221-224° C.

[1200] Anal. Calcd for C21H23N5: C, 73.02; H, 6.71; N, 20.27. Found: C, 72.77; H, 6.39; N, 20.23.

Example 426

1-(2-Methylpropyl)-8-(4-phenylbutyl)-1H-imidazo[4,5-c]quinolin-4-amine

[1201]

501

[1202] Part A

[1203] 8-Bromo-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine (3.0 g, 9.4 mmol) was treated with 4-phenyl butene (4.2 mL, 28.2 mmol) according to the method described in Part B of Example 425. The reaction was heated overnight. Following chromatographic purification (eluting with 95:5 chloroform:methanol), 1.8 g of 1-(2-methylpropyl)-8-(4-phenylbut-1-enyl)-1H-imidazo[4,5-c]quinolin-4-amine were obtained as an off-white solid.

[1204] Part B

[1205] 1-(2-Methylpropyl)-8-(4-phenylbut-1-enyl)-1H-imidazo[4,5-c]quinolin-4-amine (1.8 g, 4.8 mmol) was treated according to the method described in Example 123. The crude product was recrystallized from acetonitrile and then from methanol to provide 700 mg of 1-(2-methylpropyl)-8-(4-phenylbutyl)-1H-imidazo[4,5-c]quinolin-4-amine as white crystals, mp 176-177° C.

[1206] Anal. Calcd for C24H28N4: C, 77.38; H, 7.58; N, 15.04. Found: C, 76.99; H, 7.45; N, 14.97.

Examples 427-429

[1207] Part A

[1208] A solution of (7-bromo-3-nitroquinolin-4-yl)-(2-methylpropyl)amine (30.9 g, 105 mmol) in acetonitrile (1.8 L) and isopropanol (200 mL) was added to a Parr vessel. A mixture of 5% platinum on carbon (3.0 g) and acetonitrile:isopropanol (20 mL) was added, and the vessel was purged with nitrogen. The vessel was placed under hydrogen pressure (40 psi, 2.8×105 Pa) for two hours. After one hour, the pressure had decreased to 20 psi (1.4×105 Pa) and was readjusted to 40 psi (2.8×105 Pa). The reaction mixture was filtered through a layer of CELITE filter aid, and the filter cake was washed with acetonitrile. The filtrate was concentrated under reduced pressure to provide 7-bromo-N4-(2-methylpropyl)quinoline-3,4-diamine as an oil.

[1209] Part B

[1210] Under a nitrogen atmosphere, a mixture of the material from Part A,. triethyl orthoformate (20.9 mL, 126 mmol), and pyridine hydrochloride (3.1 g, 27 mmol) in acetonitrile was heated at reflux for 20 minutes. A Dean—Stark trap was used to collect the volatiles. The reaction mixture was concentrated under reduced pressure to provide 18.7 g of 7-bromo-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline as a gold solid.

[1211] Part C

[1212] The method described in Part J of Example 365 was used to oxidize and aminate 7-bromo-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline (18.7 g, 58.4 mmol). 3-Chloroperoxybenzoic acid (22.1 g of 50% pure material, 129 mmol) was added in five portions during the oxidation step, and the amination with ammonium hydroxide (146 mL) and p-toluenesulfonyl chloride (16.6 g, 87.6 mmol) proceeded overnight. The crude product was obtained as an oil, which was treated with acetonitrile to form a precipitate. The precipitate was isolated by filtration, washed with a small amount of acetonitrile, and recrystallized from acetonitrile to provide 4 g of 7-bromo-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine as off-white needeles, mp 218-220° C.

[1213] Anal. Calcd for C14H15BrN4: C, 52.68; H, 4.74; N, 17.55. Found: C, 52.55; H, 4.99; N, 17.44.

[1214] Part D

[1215] 7-Bromo-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine and the boronic acid indicated in the table below were coupled according to the general methods described in Part J of Example I and Part F of Examples 125-135. Palladium (II) acetate was added as a 5 mg/mL solution in toluene, and the reaction was heated overnight. The crude product was purified by flash column chromatography on silica gel (eluting with 90:10 chloroform:CMA for Examples 428 and 429 and chloroform:methanol in a gradient from 95:5 to 90:10 for Example 427). Examples 427 and 428 were recrystallized from the solvents shown in the table below, isolated by filtration, and dried under high vacuum.

[1216] Example 429 was dissolved in THF (20 mL), and tetrabutylammonium fluoride (4.0 mL of a 1.0 M solution in THF) was added. The reaction was stirred for 15 minutes and concentrated under reduced pressure. The resulting black oil was purified by flash column chromatography on silica gel (eluting with methanol:CMA in a gradient from 90:10 to 75:25) to provide an oil that was stirred with acetonitrile at 0° C. to provide a solid, which was recrystallized from acetonitrile/methanol to provide the compound shown in the following table.

502

RecrystallizationExampleBoronic Acidsolvent(s)R427trans-2-Phenylvinylboronic acidMethanol

503

4283-Pyridine boronic acidAcetonitrile

504

4295-(tert- Butyldimethylsilanyloxymethyl) pyridine-3-boronic acidAcetonitrile/methanol

505

Examples 427-429

[1217]

43

mp

Example
Name
Form
(° C.)
Anal.

427
1-(2-Methylpropyl)-7-styryl-
Light
257-258
Calcd for C22H22N4:

1H-imidazo[4,5-c]quinolin-
brown

C, 77.16; H, 6.48; N,

4-amine
needles

16.36. Found: C,

76.86; H, 6.40; N,

16.44.

428
1-(2-Methylpropyl)-7-
Gray
125
Calcd for C19H19N5:

(pyridin-3-yl)-1H-
needles

C, 71.90; H, 6.03; N,

imidazo[4,5-c]quinolin-4-

22.07. Found: C,

amine

70.99; H, 6.20; N,

21.88.

429
1-(2-Methylpropyl)-7-(5-
Yellow
210-211
Calcd for

hydroxymethylpyridin-3-yl)-
crystals

C20H21N5O: C,

1H-imidazo[4,5-c]quinolin-

69.14; H, 6.09; N,

4-amine

20.16. Found: C,

68.96; H, 6.26; N,

20.22.

Example 430

1-(2-Methylpropyl)-7-phenethyl-1H-imidazo[4,5-c]quinolin-4-amine

[1218]

506

[1219] A modification of the method described in Example 123 was used to reduce 1-(2-methylpropyl)-7-styryl-1H-imidazo[4,5-c]quinolin-4-amine (1.2 g, 3.5 mmol). The reaction was carried out in methanol (100 mL) for seven days. The crude product was purified by flash column chromatography on silica gel (eluting with 90:10 chloroform:CMA) followed by recrystallization from acetonitrile to provide 1-(2-methylpropyl)-7-phenethyl-1H-imidazo[4,5-c]quinolin-4-amine as white crystals, mp 172-173° C.

[1220] Anal. Calcd for C22H24N4: C, 76.71; H, 7.02; N, 16.27. Found: C, 76.56; H, 7.15; N, 16.24.

Examples 431-436

[1221] Part A

[1222] Triethyl orthoformate (10.0 mL, 60.1 mmol), Meldrum's acid (8.2 g, 57 mmol), and either 3-benzyl aniline or 4-benzyl aniline (10.0 g, 54.6 mmol) as indicated in the table below in methanol (303 mL) were combined and treated according to the method described in Part A of Example 1 to provide 5-[(3-benzylphenylamino)methylene]-2,2-dimethyl-[1,3]dioxane-4,6-dione (15.5 g) or 5-[(4-benzylphenylamino)methylene]-2,2-dimethyl-[1,3]dioxane-4,6-dione (15.2 g), respectively.

[1223] Part B

[1224] 5-[(3-Benzylphenylamino)methylene]-2,2-dimethyl-[1,3]dioxane-4,6-dione (15.5 g, 46.0 mmol, Examples 431-433) or 5-[(4-benzylphenylamino)methylene]-2,2-dimethyl-[1,3]dioxane-4,6-dione (15.2 g, 45.0 mmol, Examples 434-436) was heated at 230° C. in DOWTHERM A heat transfer fluid for one hour, and then the reaction was allowed to cool to ambient temperature overnight.

[1225] For Examples 431-433, a 4.0 M solution of hydrogen chloride in 1,4-dioxane followed by diethyl ether were added to the reaction to precipitate a salt, which adhered to the sides of the reaction flask. The salt was washed with diethyl ether (3×) and dissolved in dichloromethane. Sodium carbonate (2 M) was added to adjust the solution to pH 11, and water was added. The aqueous layer was separated and extracted with dichloromethane, and the combined organic fractions were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by HPFC (eluting with chloroform:CMA in a gradient from 97:3 to 40:60) to provide 4.0 g of 7-benzylquinolin-4-ol and 4.75 g of 5-benzylquinolin-4-ol.

[1226] For Examples 434-436, a precipitate formed upon cooling and was isolated by filtration and washed with diethyl ether to provide 6-benzylquinolin-4-ol as a light brown solid.

[1227] Part C

[1228] The method described in Part D of Example 10 was used to treat 7-benzylquinolin-4-ol or 6-benzylquinolin-4-ol with nitric acid to provide 7-benzyl-3-nitroquinolin-4-ol or 6-benzyl-3-nitroquinolin-4-ol, respectively, as solids.

[1229] Part D

[1230] The method described in Part E of Example 10 was used to treat 7-benzyl-3-nitroquinolin-4-ol or 6-benzyl-3-nitroquinolin-4-ol with phosphorous oxychloride to provide 7-benzyl-4-chloro-3-nitroquinoline as a light yellow powder or 6-benzyl-4-chloro-3-nitroquinoline as a tan powder, respectively.

[1231] Part E

[1232] Under a nitrogen atmosphere, 1-amino-2-methylpropan-2-ol (1.2 equivalents) was added to a 0.2 M solution of 7-benzyl-4-chloro-3-nitroquinoline or 6-benzyl-4-chloro-3-nitroquinoline (1 equivalent) and triethylamine (3 equivalents) in dichloromethane, and the reaction was stirred overnight at ambient temperature. The volatiles were removed under reduced pressure, and the residue was stirred with water (50 mL) for one hour. The resulting yellow solid was isolated by filtration and washed with water to provide 1-(7-benzyl-3-nitroquinolin-4-ylamino)-2-methylpropan-2-ol or 1-(6-benzyl-3-nitroquinolin-4-ylamino)-2-methylpropan-2-ol, respectively.

[1233] Part F

[1234] A modification of the method described in Part A of Examples 427-429 was used to reduce 1-(7-benzyl-3-nitroquinolin-4-ylamino)-2-methylpropan-2-ol or 1-(6-benzyl-3-nitroquinolin-4-ylamino)-2-methylpropan-2-ol. The reaction was shaken for one or two days to provide 1-(3-amino-7-benzylquinolin-4- ylamino)-2-methylpropan-2-ol or 1-(3-amino-6-benzylquinolin-4-ylamino)-2-methylpropan-2-ol.

[1235] Part G

[1236] For Examples 431 and 434, a modification of the method described in Part B of Examples 427-429 was used to treat 1-(3-amino-7-benzylquinolin-4-ylamino)-2-methylpropan-2-ol or 1-(3-amino-6-benzylquinolin-4-ylamino)-2-methylpropan-2-ol with triethyl orthoformate, as indicated in the table below. The reaction was heated at reflux for one hour and then stirred overnight at ambient temperature. A precipitate formed, which was isolated by filtration to provide 1-(7-benzyl-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol or 1-(8-benzyl-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol.

[1237] For Examples 432, 433, 435, and 436, 1-(3-amino-7-benzylquinolin-4-ylamino)-2-methylpropan-2-ol or 1-(3-amino-6-benzylquinolin-4-ylamino)-2-methylpropan-2-ol was treated with the acid chloride shown in the table below according to the method described in Part A of Example 9. The reaction was heated overnight, and after the work-up procedure, the crude product was purified by HPFC (eluting with chloroform:CMA in a gradient from 99:1 to 70:30).

[1238] Part H

[1239] The method described in Part J of Example 365 was used to oxidize and aminate the material from Part G. 3-Chloroperoxybenzoic acid (1-1.5 equivalents of 50% pure material) was added in two portions over a period of 30 minutes during the oxidation step. After the work-up procedure, the crude product was purified by HPFC (eluting with chloroform:CMA in a gradient from about 100:0 to about 60:40) followed by recrystallization from acetonitrile to provide the product shown in the table below. For Example 434, no chromatographic purification was carried out, and the product was recrystallized from acetonitrile:methanol.

Examples 431-436

[1240]

507

Ex.
Starting material
Reagent in Part G
Product
R

431
3-Benzyl aniline
Triethyl orthoformate
7-Benzyl
—H

432
3-Benzyl aniline
Butyryl chloride
7-Benzyl
—CH2CH2CH3

433
3-Benzyl aniline
Ethoxyacetyl chloride
7-Benzyl
—CH2OCH2CH3

434
4-Benzyl aniline
Triethyl orthoformate
8-Benzyl
—H

435
4-Benzyl aniline
Butyryl chloride
8-Benzyl
—CH2CH2CH3

436
4-Benzyl aniline
Ethoxyacetyl chloride
8-Benzyl
—CH2OCH2CH3

Examples 431-436

mp

Example
Name
Form
(° C.)
Anal.

431
1-(4-Amino-7-benzyl-1H-
Brown
228-
Calcd for C21H22N4O:

imidazo[4,5-c]quinolin-1-
crystals
229
C, 72.81; H, 6.40; N,

yl)-2-methylpropan-2-ol

16.17. Found. C,

72.66; H, 6.37; N,

16.14.

432
1-(4-Amino-7-benzyl-2-
Tan
130-
Calcd for

propyl-1H-imidazo[4,5-
crystals
131
C24H28N4O · 0.25 H2O:

c]quinolin-1-yl)-2-

C, 73.35; H, 7.31; N,

methylpropan-2-ol

14.26. Found: C,

73.04; H, 7.46; N,

14.30.

433
1-(4-Amino-7-benzyl-2-
Light
166-
Calcd for C24H28N4O2:

ethoxymethyl-1H-
brown
167
C, 71.26; H, 6.98; N,

imidazo[4,5-c]quinolin-1-
crystals

13.85. Found: C,

yl)-2-methylpropan-2-ol

70.92; H, 7.30; N,

14.05.

434
1-(4-Amino-8-benzyl-1H-
Pale
256-
Calcd for C21H22N4O:

imidazo[4,5-c]quinolin-1-
yellow
257
C, 72.81; H, 6.40; N,

yl)-2-methylpropan-2-ol
crystals

16.17. Found: C,

72.56; H, 6.21; N,

16.13.

435
1-(4-Amino-8-benzyl-2-
Tan
191-
Calcd for C24H28N4O:

propyl-1H-imidazo[4,5-
powder
192
C, 74.20; H, 7.26; N,

c]quinolin-1-yl)-2-

14.42. Found: C,

methylpropan-2-ol

73.93; H, 7.47; N,

14.26.

436
1-(4-Amino-8-benzyl-2-
Yellow
209-
Calcd for C24H28N4O2:

ethoxymethyl-1H-
crystlas
210
C, 71.26; H, 6.98; N,

imidazo[4,5-c]quinolin-1-

13.85. Found: C,

yl)-2-methylpropan-2-ol

70.89; H, 6.87; N,

13.84.

Examples 437-439

[1241] Part A

[1242] Under a nitrogen atmosphere, cyclohexylmethylamine (40.9 mL, 315 mmol) was added dropwise to a solution of 7-bromo-4-chloro-3-nitroquinoline (30.0 g, 105 mmol) in dichloromethane (524 mL). The reaction was stirred for 18 hours at ambient temperature and then concentrated under reduced pressure. Water (200 mL) was added to the residue, and the mixture was stirred for three hours. Acetonitrile was added; a precipitate formed. The solid was isolated by filtration, dried under a flow of air for two hours, and recrystallized from acetonitrile to provide 24.0 g of (7-bromo-3-nitroquinolin-4-yl)cyclohexylmethylamine as a yellow solid.

[1243] Part B

[1244] The method described in Part A of Examples 427-429 was used to reduce (7-bromo-3-nitroquinolin-4-yl)cyclohexylmethylamine (24.0 g, 65.9 mmol) to 21.0 g of 7-bromo-N4-(cyclohexylmethyl)quinoline-3,4-diamine, obtained as a greenish solid.

[1245] Part C

[1246] A modification of the method described in Part A of Example 9 was used to treat 7-bromo-N4-(cyclohexylmethyl)quinoline-3,4-diamine (7.3 g, 22 mmol) with ethoxyacetyl chloride (2.75 mL, 24.0 mmol). The reaction was heated overnight at 90° C. and then concentrated under reduced pressure to provide 7-bromo-1-cylcohexylmethyl-2-ethoxymethyl-1H-imidazo[4,5-c]quinoline as a dark brown semi-solid.

[1247] Part D

[1248] The method described in Part J of Example 365 was used to oxidize and aminate 7-bromo-1-cylcohexylmethyl-2-ethoxymethyl-1H-imidazo[4,5-c]quinoline (7.58 g, 22.0 mmol). 3-Chloroperoxybenzoic acid (9.1 g of 50% pure material, 26.4 mmol) was added in five portions during the oxidation step, and the amination with ammonium hydroxide (55 mL) and p-toluenesulfonyl chloride (6.3 g, 33 mmol) proceeded overnight. The crude product was obtained as an oil, which was treated with acetonitrile to form a precipitate. The precipitate was isolated by filtration and washed with a small amount of acetonitrile. A portion of the brown solid was purified by flash column chromatography on silica gel (eluting with chloroform:CMA in a gradient from 95:5 to 85:15) to provide 7-bromo-1-cylcohexylmethyl-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-4-amine as a brown solid, mp 215-216° C.

[1249] Anal. Calcd for C20H25BrN4O: C, 57.56; H, 6.04; N, 13.42. Found: C, 57.57; H, 5.93; N, 13.44.

[1250] Part E

[1251] 7-Bromo-1-cylcohexylmethyl-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-4-amine and the boronic acid indicated in the table below were coupled according to the general methods described in Part J of Example 1 and Part F of Examples 125-135. Palladium (II) acetate was added as a 5 mg/mL solution in toluene, and the reaction was heated overnight. The crude product was purified by HPFC (eluting with chloroform:CMA in a gradient from 90:10 to 55:45 for Examples 437 and 438 and 95:5 to 85:15 for Example 439) followed by recrystallization from acetonitrile to provide the product shown in the table below.

[1252] Example 439 was treated as described in Example 429. The crude product was purified twice by flash column chromatography on silica gel (eluting with chloroform:CMA in a gradient from 90:10 to 70:30) followed by recrystallization from methanol to provide the compound shown in the following table.

Examples 437-439

[1253]

508

Example
Boronic Acid
R

437
3-(Morpholine-4- carbonyl)phenylboronic acid

509

438
3-Pyridine boronic acid

510

439
5-(tert-Butyldimethylsilanyloxymethyl) pyridine-3-boronic acid

511

Examples 437-439

[1254]

46

mp

Example
Name
Form
(° C.)
Anal.

437
1-[3-(4-Amino-1-
Tan
186-187
Calcd for

cyclohexylmethyl-2-
needles

C31H37N5O3: C,

ethoxymethyl-1H-

70.56; H, 7.07; N,

imidazo[4,5-c]quinolin-7-

13.27. Found: C,

yl)phenyl]morpholin-4-

70.16; H, 7.24; N,

ylmethanone

13.40.

438
1-Cyclohexylmethyl-2-
Tan
146-148
Calcd for

ethoxymethyl-7-(pyridin-3-
crystals

C25H29N5O: C,

yl)-1H-imidazo[4,5-

71.95; H, 7.05; N,

c]quinolin-4-amine

16.78. Found: C,

71.60; H, 6.83; N,

16.65.

439
1-Cyclohexylmethyl-2-
Off-
240-241
Calcd for

ethoxymethyl-7-(5-
white

C26H31N5O2: C,

hydroxymethylpyridin-3-yl)-1H-
crystals

70.09; H, 7.01; N,

imidazo[4,5-c]quinolin-

15.72. Found: C,

4-amine

69.92; H, 6.97; N,

15.61.

Examples 440-463

[1255] Part A

[1256] (7-Bromo-3-nitroquinolin-4-yl)-(2-methylpropyl)amine (117 g) was dissolved in hot toluene (2 L) and poured into stainless steel Parr vessel. Additional toluene (2 L) and 5% platinum on carbon (12.5 g) were added. The vessel was evacuated, charged with hydrogen (54 psi, 3.7×105 Pa), and shaken overnight at room temperature. The reaction mixture evacuated, filtered through a layer of CELITE filter aid, and concentrated under reduced pressure to provide 7-bromo-N4-(2-methylpropyl)quinoline-3,4-diamine, which was used without purification.

[1257] Part B

[1258] Butyryl chloride (1.1 equivalent) was slowly added to a stirred solution of 7-bromo-N4-(2-methylpropyl)quinoline-3,4-diamine (52.9 g, 0.18 mol.) in pyridine (700 mL) at room temperature. A pale yellow precipitate formed and then went into solution. The reaction mixture was heated at reflux for eight hours, and then allowed to slowly cool to room temperature over the weekend. The dark gold, turbid reaction mixture was concentrated under reduced pressure. The residue was dissolved in 1 N hydrochloric acid and then adjusted to pH 14 with the addition of 10% aqueous sodium hydroxide. A precipitate formed, was isolated by filtration, washed with water (3×100 mL), and dried overnight on the filter funnel to provide 7-bromo-1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c]quinoline as an off-white solid.

[1259] Part C

[1260] To a stirred solution of 7-bromo-1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c]quinoline (51.1 g, 0.148 mol) in dichloromethane (1 L) was slowly added 3-chloroperoxybenzoic acid (1.0 equivalent of 50% pure material) in small portions. The reaction was maintained at room temperature for one hour. Concentrated ammonium hydroxide (600 mL) was added with stirring. After 15 minutes, p-toluenesulfonyl chloride (1.1 equivalents.) was added in small portions. The reaction was stirred at room temperature overnight. The reaction was quenched by adding water (1 L) and stirred for an additional hour. A solid was present and was isolated by filtration to provide 7-bromo-1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c]quinolin-4-amine as an off-white solid.

[1261] Part D

[1262] Triethylamine (3.0 equivalents), potassium vinyltrifluoroborate (1.0 equivalent) and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct (0.2 equivalent) were added to a solution of 7-bromo-1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c]quinolin-4-amine (1.0 equivalent) in n-propanol (30 ml/g). The reaction mixture was heated at reflux under a nitrogen atmosphere until it was complete (between four and 18 hours) and then poured into water (3 volumes). The pH of the mixture was monitored and adjusted to pH 12 with the addition of 10% aqueous sodium hydroxide if needed. The mixture was extracted with ethyl acetate, and the combined organic fractions were filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (eluting with chloroform:methanol in a gradient from 100:0 to 90:10), followed by recrystallization from acetonitrile to provide 1-(2-methylpropyl)-2-propyl-7-vinyl-1H-imidazo[4,5-c]quinolin-4-amine as an off-white solid.

[1263] Part E

[1264] A thick-walled glass tube, equipped with magnetic stir-bar, was charged with acetonitrile (20 mL/g), palladium (II) acetate (0.1 equivalent), tri-ortho-tolylphosphine (0.3 equivalent), triethylamine (3.0 equivalent), 1-(2-methylpropyl)-2-propyl-7-vinyl-1H-imidazo[4,5-c]quinolin-4-amine (1.0 equivalent), and the aryl- or heteroaryl-halide (1.5 equivalents) shown in the table below. The tube was purged with nitrogen and sealed. The reaction mixture was heated at 120° C. for between 24 and 48 hours and then allowed to cool to ambient temperature. The solvent was removed under reduced pressure. The solid was then partitioned between dichloromethane and water; the mixture was adjusted to pH 12 with the addition of 10% aqueous sodium hydroxide if needed. The organic layer was separated and was purified by flash column chromatography on silica gel (eluting with chloroform:methanol in a gradient from 100:0 to 90:10) followed by recrystallization from acetonitrile to provide the compound shown in the table below.

Examples 440-455

[1265]

512

Example
Aryl- or Heteroaryl halide
R

440
3-Bromobenzenesulfonamide

513

441
5-Bromo-2-methylbenzothiazole

514

442
2-Iodo-5-methylthiophene

515

443
3-Bromoanisole

516

444
4-Bromoanisole

517

445
2-Bromoanisole

518

446
3-Bromopyridine

519

447
4-Bromobenzenesulfonamide

520

448
2-Bromopyridine

521

449
2-Chlorobenzothiazole

522

450
5-Bromonicotinonitrile

523

451
5-Bromonicotinamide

524

452
2-Bromobenzamide

525

453
2-Acetyl-5-bromothiophene

526

454
4-Bromotoluene

527

455
Ethyl 3-bromobenzoate

528

[1266] tHE characterization data for Examples 440-446 and Example 452 are shown in the table below.

Examples 440-446, 450, 452

[1267]

48

Mp

Ex.
Name
Form
(° C.)
Anal.

440
(E)-3-{2-[4-Amino-1-(2-
White
>250
Calcd for C25H29N5O2S: C,

methylpropyl)-2-propyl-1H-
solid

54.69; H, 5.60; N, 12.77.

imidazo[4,5-c]quinolin-7-

Found: C, 54.62; H, 5.44;

yl]vinyl}benzenesulfonamide

N, 12.65.

441
(E)-7-[2-(2-Methylbenzothiazol-
Off-
210-212
Calcd for C27H29N5S.1.8

5-yl)vinyl]-1-(2-methylpropyl)-
white

CH4O: C, 67.22; H, 7.46:

2-propyl-1H-imidazo[4,5-
solid

N, 13.63. Found: C, 67.07;

c]quinolin-4-amine

H, 7.18; N, 13.91.

442
(E)-1-(2-Methylpropyl)-7-[2-(5-
Light
182-185
Calcd for C24H28N4S: C,

methylthiophen-2-yl)vinyl]-2-
tan

71.25; H, 6.98; N, 13.85.

propyl-1H-imidazo[4,5-
crystals

Found: C, 71.01; H, 6.80;

c]quinolin-4-amine

N, 13.81.

443
(E)-7-[2-(3-
Pale
181-183
Calcd for C26H30N4O: C,

Methoxyphenyl)vinyl]-1-(2-
yellow

75.33; H, 7.29; N, 13.51.

methylpropyl)-2-propyl-1H-
crystals

Found: C, 75.28; H, 7.52;

imidazo[4,5-c]quinolin-4-amine

N, 13.77.

444
(E)-7-[2-(4-
Off-
201-202
Calcd for C26H30N4O: C,

Methoxyphenyl)vinyl]-1-(2-
white

75.33; H, 7.29; N, 13.51.

methylpropyl)-2-propyl-1H-
solid

Found: C, 75.06; H, 7.44;

imidazo[4,5-c]quinolin-4-amine

N, 13.63.

445
(E)-7-[2-(2-
Tan
214-216
Calcd for C26H30N4O: C,

Methoxyphenyl)vinyl]-1-(2-
needles

75.33; H, 7.29; N, 13.51.

methylpropyl)-2-propyl-1H-

Found: C, 75.12; H, 7.68;

imidazo[4,5-c]quinolin-4-amine

N, 13.53.

446
(E)-1-(2-Methylpropyl)-2-
Yellow
190-192
Calcd for C24H27N5.0.5

propyl-7-[2-(pyridin-3-yl)vinyl]-
crystals

H2O: C, 73.07; H, 7.15: N,

1H-imidazo[4,5-c]quinolin-4-

17.75. Found: C, 73.13; H,

amine

7.33; N, 17.88.

450
(E)-3-{2-[4-Amino-1-(2-
Yellow
246-248
Calcd for C25H26N6: C,

methylpropyl)-2-propyl-1H-
solid

73.14; H, 6.38: N, 20.47.

imidazo[4,5-c]quinolin-7-

Found: C, 73.15; H, 6.11;

yl]vinyl}nicotinonitrile

N, 20.42.

452
(E)-2-{2-[4-Amino-(2-
Tan
Not
Calcd for C26H29N5O: C,

methylpropyl)-2-propyl-1H-
crystals
measured
73.04; H, 6.84: N, 16.38.

imidazo[4,5-c]quinolin-7-

Found: C, 72.80; H, 6.79;

yl]vinyl}benzamide

N, 16.26.

Examples 447-449, 451, 453-455

[1268]

49

MS (APCI) m/z

Example
Name
(M + H)+

447
(E)-4-{2-[4-Amino-1-(2-
464

methylpropyl)-2-propyl-1H-

imidazo[4,5-c]quinolin-7-

yl]vinyl}benzenesulfonamide

448
(E)-1-(2-Methylpropyl)-2-propyl-7-[2-
386

(pyridin-2-yl)vinyl]-1H-imidazo[4,5-

c]quinolin-4-amine

449
(E)-7-[2-(Benzothiazol-2-yl)vinyl]-1-
442

(2-methylpropyl)-2-propyl-1H-

imidazo[4,5-c]quinolin-4-amine

451
(E)-3-{2-[4-Amino-1-(2-
429.3

methylpropyl)-2-propyl-1H-

imidazo[4,5-c]quinolin-7-

yl]vinyl}nicotinamide

453
(E)-7-[2-(2-Acetylthiophen-5-yl)vinyl]-
433.3

1-(2-methylpropyl)-2-propyl-1H-

imidazo[4,5-c]quinolin-4-amine

454
(E)-1-(2-Methylpropyl)-2-propyl-7-[2-
399.1

(p-tolyl)vinyl]-1H-imidazo[4,5-

c]quinolin-4-amine

455
(E)-Ethyl 3-{2-[4-amino-(2-
457.3

methylpropyl)-2-propyl-1H-

imidazo[4,5-c]quinolin-7-

yl]vinyl}benzoate

Examples 456-461

[1269] A Parr hydrogenation vessel was charged with the starting material indicated in the table below, a 1:1 mixture of methanol:ethanol (30 mL/g), and 10% palladium on carbon (50% wt./wt.). The reaction vessel was evacuated, charged with hydrogen (45 psi, 3.1×105 Pa), and shaken until the reaction was complete (24-48 hours). The reaction mixture was filtered through CELITE filter agent, concentrated under reduced pressure, and purified by flash column chromatography on silica gel (eluting with dichloromethane:methanol in a gradient from 100:0 to 90:10) followed by recrystallization from acetonitrile to provide the product shown in the table below.

Examples 456-461

[1270]

529

Example
Starting Material
R

456
Example 440

530

457
Example 441

531

458
Example 443

532

459
Example 444

533

460
Example 445

534

461
Example 442

535

[1271] The characterization data for Examples 456-461 are shown in the table below.

Examples 456-461

[1272]

51

mp

Example
Name
Form
(° C.)
Anal.

456
3-{2-[4-Amino-1-(2-
Off-
250-251
Calcd for C25H31N5O2S: C,

methylpropyl)-2-propyl-1H-
white

64.49; H, 6.71; N, 15.04.

imidazo[4,5-c]quinolin-7-
solid

Found: C, 64.28; H, 6.76;

yl]ethyl}benzenesulfonamide

N, 14.88.

457
7-[2-(2-Methylbenzothiazol-5-
White
>250
Calcd for C27H31N5S.HCl:

yl)ethyl]-1-(2-methylpropyl)-2-
solid

C, 65.63; H, 6.53: N,

propyl-1H-imidazo[4,5-

14.17. Found: C, 65.68; H,

c]quinolin-4-amine

6.73; N, 13.96.

458
7-[2-(3-Methoxyphenyl)ethyl]-1-
White
155-157
Calcd for C26H32N4O: C,

(2-methylpropyl)-2-propyl-1H-
crystals

74.97; H, 7.74; N, 13.45.

imidazo[4,5-c]quinolin-4-amine

Found: C, 74.57; H, 7.65;

N, 13.52.

459
7-[2-(4-Methoxyphenyl)ethyl]-1-
White
>250
Calcd for C26H32N4O.HCl:

(2-methylpropyl)-2-propyl-1H-
solid

C, 68.93; H, 7.34: N,

imidazo[4,5-c]quinolin-4-amine

12.37. Found: C, 68.67; H,

7.82; N, 12.33.

460
7-[2-(2-Methoxyphenyl)ethyl]-1-
White
>250
Calcd for C26H32N4O.HCl:

(2-methylpropyl)-2-propyl-1H-
solid

C, 68.93; H, 7.34: N,

imidazo[4,5-c]quinolin-4-amine

12.37. Found: C, 68.76; H,

7.69; N, 12.29.

461
1-(2-Methylpropyl)-7-[2-(5-
Off-
150-152
Calcd for C24H30N4S: C,

methylthiophen-2-yl)ethyl]-2-
white

70.90; H, 7.44; N, 13.78.

propyl-1H-imidazo[4,5-
solid

Found: C, 71.28; H, 7.70;

c]quinolin-4-amine

N, 13.80.

Examples 462-471

[1273] The procedure described in Examples 456-461 can also be used to hydrogenate the following compounds to provide the products shown in the table below.

Examples 462-471

[1274]

536

Example
Starting Material
R

462
Example 446

537

463
Example 454

538

464
Example 447

539

465
Example 448

540

466
Example 449

541

467
Example 450

542

468
Example 451

543

469
Example 452

544

470
Example 453

545

471
Example 455

546

Example 472

2-Ethoxymethyl-1-(3-methoxypropyl)-7-(pyrazol-1-yl)-1H-imidazo[4,5-c]quinolin-4-amine

[1275]

547

[1276] A 4 dram vial containing a stir bar was charged sequentially with copper(I) iodide (0.038 g), potassium phosphate (0.890 g), pyrazole (0.164 g), 7-bromo-2-ethoxymethyl-1-(3-methoxypropyl)-1H-imidazo[4,5-c]quinolin-4-amine (0.786 g), (±)-trans-1,2-diaminocyclohexane (0.030 mL), and anhydrous 1,4-dioxane (2 mL). The vial was flushed with nitrogen, capped, and placed in an oil bath at 110° C. After 15.5 hours, the reaction was cooled to room temperature and purified by flash column chromatography using a gradient of CMA/chloroform as the eluent. Subsequent recrystallization from acetonitrile yielded 0.190 g of 2-ethoxymethyl-1-(3-methoxypropyl)-7-(pyrazol-1-yl)-1H-imidazo[4,5-c]quinolin-4-amine as a white solid, mp 159.0-160.0° C.

[1277] Anal Calcd. for C20H24N6O2: % C, 63.14; % H, 6.36; % N, 22.09. Found: % C, 62.91; % H, 6.32; % N, 22.06.

Example 473

2-Ethoxymethyl-7-(imidazol-1-yl)-1-(3-methoxypropyl)-1H-imidazo[4,5-c]quinolin-4-amine

[1278]

548

[1279] The general method described in Example 452 was followed with imidazole replacing pyrazole as a reactant. After cooling to room temperature, the reaction mixture was poured into water and diluted with dichloromethane. The mixture was stirred for 10 minutes, followed by separation of the layers. The aqueous fraction was extracted with dichloromethane and the combined organic fractions were concentrated. The residue was initially purified by HPFC eluting with a linear gradient of 1-30% CMA in chloroform. A final recrystallization from acetonitrile provided 0.070 g of 2-ethoxymethyl-7-(imidazol-1-yl)-1-(3-methoxypropyl)-1H-imidazo [4,5-c]quinolin-4-amine as an off-white solid, mp 167.5-169.0° C.

[1280] Anal Calcd. for C20H24N6O2: % C, 63.14; % H, 6.36; % N, 22.09. Found: % C, 63.11; % H, 6.30; % N, 22.16.

Example 474

1-(4-Amino-7-{4-[4-amino-2-ethoxymethyl-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]phenyl}-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol

[1281]

549

[1282] A mixture of 1-(4-amino-7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol (2.18 g, 5.54 mmol), 1,4-phenylenebisboronic acid (0.44 g, 2.65 mmol), triphenylphosphine (42 mg, 0.16 mmol), n-propanol (36 mL), 2 M aqueous sodium carbonate (3.2 mL, 6.4 mmol), and water was degassed three times and placed under a nitrogen atmosphere. Palladium (II) acetate (12 mg, 0.050 mmol) in 250 μL of warm toluene was added, and reaction was degassed twice and placed under a nitrogen atmosphere. The reaction was heated at 100° C. for one hour and then allowed to cool to ambient temperature. A precipitate formed and was isolated by filtration, recrystallized from ethanol (300 mL), isolated by filtration, washed with ethanol, and dried in a vacuum oven at 60° C. to provide 286 mg of 1-(4-amino-7-{4-[4-amino-2-ethoxymethyl-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]phenyl}-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol as off-white needles, mp 325-328° C.

[1283] Anal. Calcd for C40H46N8O4.1.4H2O: C, 65.99; H, 6.76; N, 15.39. Found: C, 65.86; H, 6.80; N, 15.39.

Example 475

1-(4-Amino-7-{7-[4-amino-2-ethoxymethyl-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]-9,9-dihexyl-9H-fluoren-2-yl}-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol

[1284]

550

[1285] 1-(4-Amino-7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol (2.18 g, 5.54 mmol) and 9,9-dihexylfluorene-2,7-diboronic acid (1.12 g, 2.65 mmol) were coupled according to the method described in Example 474. At the completion of the reaction, the n-propanol was removed under reduced pressure, and the residue was dissolved in dichloromethane (150 mL). The resulting solution was washed sequentially with 2 M aqueous sodium carbonate (50 mL) and brine (50 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by HPFC (eluting with chloroform:CMA in a gradient from 100:0 to 75:25) followed by recrystallization from dichloromethane (I5 mL) and heptane (30 mL). The solid was isolated by filtration, washed with heptane, and dried overnight in a vacuum oven at 60° C. to provide 0.68 g of 1-(4-amino-7-{7-[4-amino-2-ethoxymethyl-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]-9,9-dihexyl-9H-fluoren-2-yl}-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol as off-white needles, mp 261-265° C.

[1286] Anal. Calcd for C59H74N8O4.1.1H2O: C, 72.35; H, 7.85; N, 11.44. Found: C, 72.24; H, 7.99; N, 11.47.

Example 476

1-[4-Amino-7-(7-{4-amino-2-(2-methoxyethyl)-1-[3-(pyrrolidin-2-one)propyl]-1H-imidazo[4,5-c]quinolin-7-yl}-9,9-dihexyl-9H-fluoren-2-yl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}pyrrolidin-2-one

[1287]

551

[1288] 1-{3-[4-Amino-7-bromo-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}pyrrolidin-2-one (0.91 g, 2.0 mmol) and 9,9-dihexylfluorene-2,7-diboronic acid (0.41 g, 0.97 mmol) were coupled according to the method described in Example 474; the work-up procedure described in Example 475 was followed. The crude product was purified by HPFC (eluting with chloroform:CMA in a gradient from 90:10 to 65:35) followed by recrystallization from isopropanol (40 mL). The solid was isolated by filtration, washed with isopropanol, and dried over three days in a vacuum oven at 60° C. to provide 0.45 g of 1-[4-amino-7-(7-{4-amino-2-(2-methoxyethyl)-1-[3-(pyrrolidin-2-one)propyl]-1H-imidazo[4,5-c]quinolin-7-yl}-9,9-dihexyl-9H-fluoren-2-yl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}pyrrolidin-2-one as off-white needles, mp 251-254° C.

[1289] Anal. calcd for C65H80N10O4.0.8H2O: C, 72.27; H, 7.62; N, 12.97. Found: C, 72.07; H, 7.84; N, 12.99.

Examples 477-480

[1290] Part A

[1291] Ammonium hydroxide (1 L) was added to a solution of methyl tetrahydropyranyl acetate (20 mL, 150 mmol) in methanol (500 mL), and the reaction was stirred overnight at ambient temperature. Additional ammonium hydroxide (500 mL) was added, and the reaction was stirred for four additional days. The methanol was removed under reduced pressure. Solid sodium chloride was added to the aqueous layer, which was extracted with chloroform (3×150 mL). The combined extracts were dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide 11.4 g of tetrahydropyran-4-carboxamide as a white solid.

[1292] Part B

[1293] A solution of tetrahydropyran-4-carboxamide (11.4 g, 88.3 mmol) in THF (441 mL) was cooled to 0° C. Lithium aluminum hydride (10.0 g, 265 mmol) was added in six portions over a period of ten minutes. The reaction flask was purged with nitrogen between the additions. When the reaction mixture was no longer bubbling, it was heated at reflux for six hours. The reaction was then cooled to 0° C., and ethyl acetate was added dropwise until bubbling ceased. Methanol was then added dropwise until bubbling ceased. Water (10 mL), 15% aqueous sodium hydroxide (10 mL), and water (30 mL) were sequentially added. The organic fraction was decanted off, and the remaining gray solid was washed with chloroform. The combined organic fractions were dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide C-(tetrahydropyran-4-yl)methylamine.

[1294] Part C

[1295] The method described in Part E of Examples 431-436 was used to treat 7-bromo-4-chloro-3-nitroquinoline (12.43 g, 43.45 mmol) with C-(tetrahydropyran-4-yl)methylamine (10 g, 87 mmol) to provide 15.0 g of (7-bromo-3-nitroquinolin-4-yl)(tetrahydropyran-4-ylmethyl)amine as a bright yellow solid.

[1296] Part D

[1297] The method described in Part A of Examples 427-429 was used to reduce (7-bromo-3-nitroquinolin-4-yl)(tetrahydropyran-4-ylmethyl)amine (15.0 g, 44.0 mmol) to 7-bromo-N4-(tetrahydropyran-4-ylmethyl)quinoline-3,4-diamine, obtained as a greenish solid.

[1298] Part E

[1299] The material from Part D was treated with ethoxyacetyl chloride (5.5 mL, 48 mmol) according to the method described in Part A of Example 9. The reaction was heated overnight, and after the work-up procedure, the crude product was purified by HPFC (eluting with chloroform:CMA in a gradient from 100:0 to 80:20) to provide 9.3 g of 7-bromo-2-ethoxymethyl-1-(tetrahydropyran-4-ylmethyl)-1H-imidazo[4,5-c]quinoline as an oil.

[1300] Part F

[1301] The method described in Part J of Example 365 was used to oxidize and aminate 7-bromo-2-ethoxymethyl-1-(tetrahydropyran-4-ylmethyl)-1H-imidazo[4,5-c]quinoline (9.3 g, 23.0 mmol). 3-Chloroperoxybenzoic acid (7.9 g of 50% pure material, 23 mmol) was added in five portions during the oxidation step, which was stirred overnight. Additional 3-chloroperoxybenzoic acid (200 mg) was added, and the reaction was stirred for 20 mintues before ammonium hydroxide (60 mL) and p-toluenesulfonyl chloride (6.58 g, 34.5 mmol) were added. The crude product was obtained as an oil, which was treated with acetonitrile to form a precipitate. The precipitate was isolated by filtration and purified by HPFC (eluting with chloroform:CMA in a gradient from 100:0 to 80:20) to provide 6.0 g of 7-bromo-2-ethoxymethyl-1-(tetrahydropyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-4-amine as a white solid, mp 186-188° C.

[1302] Part G

[1303] 7-Bromo-2-ethoxymethyl-1-(tetrahydropyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-4-amine and the boronic acid indicated in the table below were coupled according to the general methods described in Part J of Example 1 and Part F of Examples 125-135. Palladium (II) acetate was added as a 5 mg/mL solution in toluene, and the reaction was heated overnight. The crude product was purified by HPFC (eluting with chloroform:CMA in a gradient from 100:0 to 70:30). The resulting oil was stirred with a small amount of acetonitrile to provide a solid, which was isolated by filtration. For Examples 477 and 478, the solid was recrystallized twice from acetonitrile to provide the product shown in the table below. For Examples 479 and 480, the solid was allowed to dry in the filter funnel to provide the product shown in the table below.

Examples 477-480

[1304]

552

Example
Boronic Acid
R

477
3-(Morpholine-4-carbonyl)phenylboronic acid

553

478
2-Ethoxyphenylboronic acid

554

479
3-Pyridine boronic acid

555

480
3-(Methylsulfonylamino)phenylboronic acid

556

[1305] The characterization data for Examples 477-480 are provide in the table below.

Examples 477-480

[1306]

54

mp

Example
Name
Form
(° C.)
Anal.

477
{3-[4-Amino-2-ethoxymethyl-
White
125-128
Calcd for

1-(tetrahydropyran-4-
crystals

C30H35N5O4.0.2

ylmethyl)-1H-imidazo[4,5-

H2O: C, 66.67; H,

c]quinolin-7-

6.75; N, 12.96.

yl]phenyl}morpholin-4-

Found: C, 66.34;

ylmethanone

H, 6.75; N, 12.99.

478
2-Ethoxymethyl-7-(2-
Yellow
192-193
Calcd for

ethoxyphenyl)-1-
crystals

C27H32N4O3.0.06

(tetrahydropyran-4-ylmethyl)-

H2O: C, 70.25; H,

1H-imidazo[4,5-c]quinolin-4-

7.01; N, 12.14.

amine

Found: C, 69.85;

H, 7.37; N, 12.32.

479
2-Ethoxymethyl-7-(pyridin-3-
White
116-121
Calcd for

yl)-1-(tetrahydropyran-4-
powder

C24H27N5O2.0.09

ylmethyl)-1H-imidazo[4,5-

H2O: C, 68.78; H,

c]quinolin-4-amine

6.54; N, 16.71.

Found: C, 68.89;

H, 6.94; N, 16.73.

480
{3-[4-Amino-2-ethoxymethyl-
White
254-255
Calcd for

1-(tetrahydropyran-4-
powder

C26H31N5O4S: C,

ylmethyl)-1H-imidazo[4,5-

61.28; H, 6.13; N,

c]quinolin-7-

13.74. Found: C,

yl]phenyl}methanesulfonamide

60.96; H, 6.46; N,

13.99.

Example 481

1-(2-Methylpropyl)-8-(1-pyrrolyl)-1H-imidazo[4,5-c]quinolin-4-amine

[1307]

557

[1308] Part A

[1309] A solution of 1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine (28.3 g, 0.118 mol) in concentrated sulfuric acid (150 mL) was cooled to 5° C. A solution of 70% nitric acid (8.4 mL, 0.130 mol) in sulfuric acid (30 mL) was added in portions over a period of one hour. The reaction temperature was maintained below 10° C. The solution was allowed to warm to ambient temperature, stirred for two hours, and then poured into 500 g of ice. The resulting solution was made basic with the addition of ammonium hydroxide while keeping the solution cold. A precipitate formed, was isolated by filtration, washed with water, and dried to provide 1-(2-methylpropyl)-8-nitro-1H-imidazo[4,5-c]quinolin-4-amine as a yellow solid.

[1310] Part B

[1311] The material from Part A was added slowly with stirring to a solution of 98% tin (II) chloride (114 g, 0.589 mmol) in concentrated hydrochloric acid (500 mL), and the reaction was heated at 100° C. for 15 minutes, allowed to cool to ambient temperature, and cooled to 0° C. A precipitate formed and was isolated by filtration, washed with a small amount of ethanol, and suspended in water. The suspension was adjusted to pH 13-14, and the resulting precipitate was isolated by filtration, washed with water, and mixed with water. The resulting suspension was made acidic with the addition of 6 N aqueous hydrochloric acid and then filtered. The filtrate was adjusted to pH 13-14 to form a precipitate, which was isolated by filtration, washed with water, and dried to provide 21.8 g of 8-amino-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine as a solid.

[1312] Part C

[1313] 2,5-Dimethoxytetrahydrofuran (1.6 mL of 95%, 12 mmol) was added to a suspension of 8-amino-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine (3.0 g, 12 mmol) in acetic acid (60 mL), and the reaction was heated at reflux for one hour. The resulting dark brown solution was concentrated under reduced pressure, and the residue was mixed with water. The resulting mixture was made basic with the addition of ammonium hydroxide and stirred for 30 minutes. The resulting precipitate was isolated by filtration, washed with water, dried, and recrystallized from ethanol (100 mL). The crystals were collected in three crops. The first crop was dried for a day in a vacuum oven at 100° C. to provide 2.1 g of 1-(2-methylpropyl)-8-(1-pyrrolyl)-1H-imidazo[4,5-c]quinolin-4-amine as a solid, mp 227.5-231.5° C.

[1314] Anal. Calcd for C18H19N5: C, 70.8; H, 6.3; N, 22.9. Found: C, 70.6; H, 6.3; N, 23.1.

Example 482

1-(2-Methylpropyl)-9-phenyl-1H-imidazo[4,5-c]quinolin-4-amine

[1315]

558

[1316] Part A

[1317] 5-[(3-Bromophenylamino)methylene]-2,2-dimethyl-[1,3]dioxane-4,6-dione (32.6 g, 0.100 mol) was heated at 250° C. in DOWTHERM A heat transfer fluid for one hour, and then the reaction was allowed to cool to ambient temperature. A precipitate formed upon cooling and was isolated by filtration and washed with diethyl ether to provide 7-bromoquinolin-4-ol and 5-bromoquinolin-4-ol in a 2:1 ratio.

[1318] Part C

[1319] The method described in Part D of Example 10 was used to treat the material from Part A with nitric acid (10.3 mL of 11.74 M, 0.121 mmol) to provide 18.0 g of a 2:1 mixture of 7-bromo-3-nitroquinolin-4-ol and 5-bromo-3-nitroquinolin-4-ol.

[1320] Part D

[1321] The method described in Part D of Example 1 was used to treat 7-bromo-3-nitroquinolin-4-ol and 5-bromo-3-nitroquinolin-4-ol (10.0 g, 37.0 mmol) with phosphorous oxychloride (32.0 mL of 1.16 M) to provide a 2:1 mixture of 7-bromo-4-chloro-3-nitroquinoline and 5-bromo-4-chloro-3-nitroquinoline.

[1322] Part E

[1323] Under a nitrogen atmosphere, isobutylamine (11.0 mL, 0.111 mol) was added to the material from Part D and triethylamine (11.0 mL, 0.111 mol) in dichloromethane (15 mL). The reaction was stirred for 30 minutes at ambient temperature, and the volatiles were removed under reduced pressure to provide a 2:1 mixture of (7-bromo-3-nitroquinolin-4-yl)isobutylamine and (5-bromo-3-nitroquinolin-4-yl)isobutylamine containing some triethylamine.

[1324] Part F

[1325] A solution of sodium hydrosulfite (3.2 g, 185 mmol) in water (8 mL) was added to a solution of the material from Part E in 1:1 ethanol:acetonitrile (300 mL), and the reaction was stirred at ambient temperature for one hour. The solvents were removed under reduced pressure, and the resulting mixture was diluted with water. The aqueous mixture was extracted with chloroform (3×). The combined extracts were purified by HPFC (eluting with chloroform:CMA in a gradient from 100:0 to 80:20); the first compound to elute was 5-bromo-N4-(2-methylpropyl)quinoline-3,4-diamine. Following the purification 2.2 g of this compound were isolated.

[1326] Part G

[1327] A mixture of 5-bromo-N4-(2-methylpropyl)quinoline-3,4-diamine (1.0 g, 3.4 mmol), triethyl orthoformate (0.9 mL, 5 mmol), and pyridine hydrochloride (117 mg, 1.0 mmol) in acetonitrile (17 mL) was heated at reflux overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by HPFC (eluting with chloroform:CMA in a gradient from 100:0 to 70:30) to provide 9-bromo-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline as a dark oil.

[1328] Part H

[1329] 9-Bromo-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline (0.34 mmol) and benzene boronic acid (62 mg, 0.51 mmol) were coupled according to Part J of Example 1. The work-up procedure described in Parts 125-135 was followed. The crude product was purified by HPFC (eluting with chloroform:CMA in a gradient from 100:0 to 85:15) to provide 1-(2-methylpropyl)-9-phenyl-1H-imidazo[4,5-c]quinoline.

[1330] Part I

[1331] The method described in Part J of Example 365 was used to oxidize and aminate 1-(2-methylpropyl)-9-phenyl-1H-imidazo[4,5-c]quinoline (0.34 mmol). The crude product was purified by HPFC (eluting with chloroform:CMA in a gradient from 100:0 to 85:15) to provide 40 mg of 1-(2-methylpropyl)-9-phenyl-1H-imidazo[4,5-c]quinolin-4-amine as a pale yellow powder, mp 263-265° C.

[1332]

1
H NMR (300 MHz, DMSO-d6) δ 7.98 (s, 1H), 7.57 (d, J=8.1 Hz, 1H), 7.55-7.39 (m, 6H), 7.12 (d, J=7.2 Hz, 1H), 6.65 (broad s, 2H), 2.57 (d, J=7.6 Hz, 2H), 1.48 (m, 1H), 0.22 (d, J=6.7 Hz, 6H);

[1333] MS (ESI) m/z 317.1770 (calcd for C20H20N4 317.1766, M+H+).

Example 483

1-(2-Methylpropyl)-9-(4-propoxyphenyl)-1H-imidazo[4,5-c]quinolin-4-amine

[1334]

559

[1335] Part A

[1336] 9-Bromo-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline (1.0 g, 3.4 mmol) and 4-propoxyphenylboronic acid (1.0 g, 5.5 mmol) were coupled according to Part J of Example 1. The palladium (II) acetate (2.5 mg, 0.011 mmol) was added as a 5 mg/mL solution in toluene. The work-up procedure described in Parts 125-135 was followed. The crude product was purified by HPFC (eluting with chloroform:CMA in a gradient from 100:0 to 70:30) to provide 1.1 g of 1-(2-methylpropyl)-9-(4-propoxyphenyl)-1H-imidazo[4,5-c]quinoline as a dark brown oil.

[1337] Part I

[1338] The method described in Part J of Example 365 was used to oxidize and aminate 1-(2-methylpropyl)-9-(4-propoxyphenyl)-1H-imidazo[4,5-c]quinoline (1.1 g, 3.1 mmol). The amination reaction was stirred for 36 hours. The crude product was purified by HPFC (eluting with chloroform:CMA in a gradient from 100:0 to 70:30) to provide an oil, which was stirred with acetonitrile to provide a solid. The solid was isolated by filtration and recrystallized from acetonitrile to provide 165 mg of 1-(2-methylpropyl)-9-(4-propoxyphenyl)-1H-imidazo[4,5-c]quinolin-4-amine as light tan needles, mp 181-182° C.

[1339] Anal. Calcd for C23H26N4O.0.2H2O: C, 73.07; H, 7.04; N, 14.82. Found: C, 72.70; H, 6.90; N, 14.87.

Examples 484-486

[1340] Part A

[1341] Diethyl malonate (101 mL, 0.989 mol) and 2-bromoaniline (50.g, 0.291 mol) were combined and heated at 180° C. for six hours. A Dean—Stark trap was used to collect the volatiles. The reaction was allowed to cool to ambient temperature overnight; a precipitate formed. The precipitate was isolated by filtration and combined with methanol (160 mL), water (800 mL), and solid sodium carbonate (105 g). The mixture was heated at reflux for two hours, allowed to cool to ambient temperature, and then cooled to 0° C. The mixture was adjusted to pH 2 with the addition of 3 N hydrochloric acid; a white precipitate formed. The precipitate was isolated by filtration, washed with water, and dried overnight on the filter funnel to provide 43 g of N-(2-bromophenyl)malonamic acid as a white solid.

[1342] Part B

[1343] N-(2-Bromophenyl)malonamic acid (43 g, 170 mmol), polyphosphoric acid (334 mL of 0.5 M), and hydrochloric acid (444 mL of 1 N) were combined and heated at 140° C. for three hours. The solution was allowed to cool to ambient temperature, and additional hydrochloric acid (603 mL of 1 N) was added. The reaction was stirred for four hours and then adjusted to pH 4 with the addition of 20% aqueous sodium hydroxide. A precipitate formed and was isolated by filtration, washed with water, and dried to provide 37.4 g of 8-bromoquinoline-2,4-diol as a solid.

[1344] Part C

[1345] A modification of the method described in Part D of Example 10 was used to treat 8-bromoquinoline-2,4-diol (10.Og, 41.6 mmol) with nitric acid (3.6 mL of 11.74 M, 54 mrnol). The nitric acid was added at ambient temperature, and then the reaction was heated at 100° C. for one hour, at which time an exotherm occurred. The reaction was allowed to cool to ambient temperature; a precipitate formed and was isolated by filtration and washed with a small volume of water to provide 7.58 g of 8-bromo-3-nitroquinoline-2,4-diol as a yellow solid.

[1346] Part D

[1347] A mixture of phenylphosphonic dichloride (14.1 mL of 90% pure material, 99.3 mmol) and 8-bromo-3-nitroquinoline-2,4-diol (7.08 g, 24.8 mmol) was heated at 140° C. for three hours and then allowed to cool to ambient temperature. Ice water was added, and the mixture was stirred for 20 minutes to form a precipitate. The precipitate was isolated by filtration to provide 8-bromo-2,4-dichloro-3-nitroquinoline as a solid.

[1348] Part E

[1349] 1-Amino-2-methylpropan-2-ol (2.08 g, 24.8 mmol) and triethylamine (10.4 mL, 74.4 mmol) were added to a solution of the material from Part D in dichloromethane (73 mL), and the reaction was stirred for 30 minutes. The solvent and some of the amines were removed under reduced pressure, and the residue was diluted with water. The aqueous layer was separated and extracted with chloroform, and the combined organic fractions were purified by HPFC (eluting with chloroform:CMA in a gradient from 100:0 to 80:20) to provide 1-(8-bromo-2-chloro-3-nitroquinolin-4-ylamino)-2-methylpropan-2-ol as a yellow solid.

[1350] Part F

[1351] The method described in Part F of Example 482 was used to reduce the material from Part E with sodium hydrosulfite (25.4 g, 124 mmol) to provide 5.15 g of 1-(3-amino-8-bromo-2-chloroquinolin-4-ylamino)-2-methylpropan-2-ol as a brown oil.

[1352] Part G

[1353] A solution of 1-(3-amino-8-bromo-2-chloroquinolin-4-ylamino)-2-methylpropan-2-ol (4.65 g, 14.4 mmol) and ethoxyacetyl chloride (1.9 mL, 15.8 mmol) in dichloromethane (72 mL) was stirred for one hour at ambient temperature. The solvent was removed under reduced pressure, and ethanol (43 mL), water (29 mL), and potassium carbonate (3.98 g, 28.8 mmol) were added. The reaction was stirred at 40° C. for 36 hours. The solvent was removed under reduce pressure, and the residue was diluted with water. The aqueous solution was extracted with chloroform, and the combined extracts were dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide 4.4 g of 1-(6-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)-2- methylpropan-2-ol as an orange solid.

[1354] Part H

[1355] Ammonia (50 mL of a 7 N solution in methanol) and 1-(6-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol (4.4 g, 11 mmol) were heated at 120° C. for 72 hours in a high-pressure vessel. The solvent was removed under reduced pressure to provide 3.5 g of a tan powder. The powder was dissolved in chloroform, washed with water, dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide 1-(4-amino-6-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol as a tan solid.

[1356] Part I 1-(4-Amino-6-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol (842 mg, 2.14 mmol) and the boronic acid indicated in the table below (2.56 mmol) were coupled according to the procedure described in Part J of Example 1. Palladium (II) acetate was added as a 5 mg/mL solution in toluene. The reaction was heated for 15-17 hours at which time additional palladium (II) acetate (1.5 mg) and optionally additional boronic acid were added, and the reaction was heated for an additional 16 hours. The work-up procedure described in Examples 125-135 was followed. The crude product was purified by HPFC (eluting with chloroform:CMA in a gradient from 100:0 to 70:30) followed by recrystallization from the solvent indicated in the table below. For Example 484, a second purification by HPFC, and the resulting oil was triturated with acetonitrile to provide a solid. The structures of the products are shown in the table below.

Examples 484-486

[1357]

560

Recrystallization

Example
Boronic Acid
Solvent
R

484
3- (Methylsulfonylamino)phenylboronic acid
Acetonitrile

561

485
3-Pyridine boronic acid
Methanol

562

486
3-(Morpholine-4- carbonyl)phenylboronic acid
Acetonitrile

563

[1358] The characterization data for Examples 484-486 are shown in the table below.

Examples 484-486

[1359]

56

mp

Example
Name
Form
(° C.)
Anal.

484
{3-[4-Amino-2-ethoxymethyl-
White
234-235
Calcd for

1-(2-hydroxy-2-methylpropyl)-
powder

C24H29N5O4S: C,

1H-imidazo[4,5-c]quinolin-6-

59.61; H, 6.04; N,

yl]phenyl}methanesulfonamide

14.48. Found: C,

59.56; H, 6.30; N,

14.55.

485
1-[4-Amino-2-ethoxymethyl-6-
Tan
199-201
Calcd for

(pyridin-3-yl)-1H-imidazo[4,5-
crystals

C22H25N5O2: C,

c]quinolin-1-yl]-2-

67.50; H, 6.44; N,

methylpropan-2-ol

17.89. Found: C,

67.38; H, 6.49; N,

17.92.

486
{3-[4-Amino-2-ethoxymethyl-
Tan
164-166
Calcd for

1-(2-hydroxy-2-methylpropyl)-
crystals

C28H33N5O4: C,

1H-imidazo[4,5-c]quinolin-6-

66.78; H, 6.60; N,

yl]phenyl}morpholin-4-

13.91. Found: C,

ylmethanone

66.61; H, 6.58; N,

13.91.

Example 487

(R)-1-[(2,2-Dimethyl-1,3-dioxolan-4-yl)methyl]-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine

[1360]

564

[1361] Part A

[1362] 7-Bromo-4-chloro-3-nitroquinoline (22.00 g, 76.52 mmol) was treated with (R)-2,2-dimethyl-1,3-dioxolane-4-methanamine (11.61 g, 114.8 mmol) according to the method described in Part A of Examples 152-156. The crude product was triturated with water (200 mL), isolated by filtration, washed with water, dried, and suspended in diethyl ether (100 mL). The suspension was sonicated, and the resulting solid was isolated by filtration, and dried for four hours in a vacuum oven at 40° C. to provide 25.84 g of (R)-(7-bromo-3-nitroquinolin-4-yl)-(2,2-dimethyl-1,3-dioxolan-4-ylmethyl)amine as a yellow solid, mp 136-137° C.

[1363] Anal. Calcd for C15Hl6BrN3O4: C, 47.14; H, 4.22; N, 10.99. Found: C, 46.78; H, 3.93; N, 10.90.

[1364] Part B

[1365] The methods described in Parts B, C, and D of Examples 152-156 were used to treat (R)-(7-bromo-3-nitroquinolin-4-yl)-(2,2-dimethyl-1,3-dioxolan-4-ylmethyl)amine (25.8 g, 67.5 mmol). Triethylamine (11.3 mL, 81.2 mmol) was added in Part C, and after the reaction was stirred for four hours, it was concentrated under reduced pressure and used in Part D. Following chromatographic purification in Part D (eluting with 95:5 chloroform:CMA), the resulting white solid was recrystallized from acetonitrile to provide 17.37 g of (R)-7-bromo-1-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]-2-ethoxymethyl-1H-imidazo[4,5-c]quinoline as a white, crystalline solid, mp 90-91° C.

[1366] Anal. Calcd for C19H22BrN3O3: C, 54.30; H, 5.28; N, 10.00. Found: C, 54.37; H, 5.06; N, 9.94.

[1367] Part C

[1368] (R)-7-Bromo-1-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]-2-ethoxymethyl-1H-imidazo[4,5-c]quinoline (17.37 g, 41.22 mmol) was oxidized and then aminated according to the methods described in Parts H and I of Example 1. The oxidation product was not recrystallized. The product from amination was purified by flash column chromatography on silica gel (eluting with chloroform:CMA in a gradient from 100:0 to 90:10) followed by recrystallization from acetonitrile to provide 7.48 g of (R)-7-bromo-1-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-4-amine as a white solid, mp 176-177° C.

[1369] Anal. Calcd for C19H23BrN4O3.0.25H2O: C, 51.89; H, 5.39; N, 12.74. Found: C, 52.10; H, 5.31; N, 12.88.

[1370] Part D

[1371] (R)-7-Bromo-1-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-4-amine (3.0 g, 6.9 mmol) and pyridine-3-boronic acid (1.02 g, 8.27 mmol) were coupled according to the method described in Examples 118-121. The work-up procedure described in Part F of Examples 125-135 was followed. The crude product was purified by HPFC (eluting with chloroform:CMA in a gradient from 100:0 to 80:20) followed by recrystallization from acetonitrile to provide 1.96 g of (R)-1-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine as a white, crystalline solid, mp 155-156° C.

[1372] Anal. Calcd for C24H27N5O3: C, 66.50; H, 6.28; N, 16.15. Found: C, 66.37; H, 6.22; N, 16.37.

Example 488

(R)-3-[4-Amino-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]propane-1,2-diol

[1373]

565

[1374] (R)-1-[(2,2-Dimethyl-1,3-dioxolan-4-yl)methyl]-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine (1.0 g, 2.3 mmol) was treated according to the method Example 162. The product was recrystallized from methanol to provide 0.60 g of (R)-3-[4-amino-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]propane-1,2-diol as a white, crystalline solid, mp 202-204° C.

[1375] Anal. Calcd for C21H23N5O3.0.5H2O: C, 62.67; H, 6.01; N, 17.40. Found: C, 62.58; H, 5.99; N, 17.29.

Example 489

(S)-1-[(2,2-Dimethyl-1,3-dioxolan-4-yl)methyl]-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine

[1376]

566

[1377] Part A

[1378] 7-Bromo-4-chloro-3-nitroquinoline (11.00 g, 38.26 mmol) was reacted with (S)-2,2-dimethyl-[1,3]dioxolane-4-methanamine (5.81 g, 57.4 mmol) according to the method described in Part A of Examples 125-135. When the reaction was complete, it was concentrated under reduced pressure, and the residue was stirred with water (100 mL). The resulting solid was isolated by filtration, mixed twice with ethanol and concentrated under reduced pressure. The solid was then triturated with diethyl ether, isolated by filtration, and dissolved in dichloromethane. An insoluble impurity was removed by filtration, and the filtrate was concentrated under reduced pressure to provide 14.05 g of (S)-(7-bromo-3-nitroquinolin-4-yl)-(2,2-dimethyl-1,3-dioxolan-4-ylmethyl)amine as a yellow solid.

[1379] Part B

[1380] The methods described in Parts B, C, and D of Examples 152-156 were used to treat (S)-(7-bromo-3-nitroquinolin-4-yl)-(2,2-dimethyl-1,3-dioxolan-4-ylmethyl)amine (10.7 g, 30.4 mmol). Triethylamine (4.67 mL, 33.5 mmol) was added in Part C, and after the reaction was stirred for 1.5 hours, additional reagents were added. The reaction was stirred for an additional four hours before it was concentrated under reduced pressure and used in Part D. Following purification in Part D by HPFC (eluting with chloroform:CMA in a gradient from 100:0 to 78:22), the resulting white solid was mixed with diethyl ether to form a solid. The solid was isolated by filtration to provide 8.88 g of (S)-7-bromo-1-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]-2-ethoxymethyl-1H-imidazo[4,5-c]quinoline as a white solid, mp 89-90° C.

[1381] Anal. Calcd for C19H22BrN3O3: C, 54.30; H, 5.28; N, 10.00. Found: C, 54.31; H, 5.25; N, 10.00.

[1382] Part C

[1383] (S)-7-Bromo-1-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]-2-ethoxymethyl-1H-imidazo[4,5-c]quinoline (8.74 g, 20.8 mmol) was oxidized and then aminated according to the methods described in Parts H and I of Example 1. The oxidation product was not recrystallized. The product from amination was purified by HPFC (eluting with chloroform:CMA in a gradient from 100:0 to 80:20) followed by recrystallization from acetonitrile to provide 4.28 g of (S)-7-bromo-1-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-4-amine as a white solid, mp 184-185° C.

[1384] Anal. Calcd for C19H23BrN4O3: C, 52.42; H, 5.33; N, 12.87. Found: C, 52.41; H, 5.13; N, 12.91.

[1385] Part D

[1386] (S)-7-Bromo-1-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-4-amine (2.65 g, 6.09 mmol) and pyridine-3-boronic acid 1,3-propanediol cyclic ester (1.19 g, 7.30 mmol) were coupled according to the method described in Examples 118-121. The work-up procedure described in Part F of Examples 125-135 was followed. The crude product was purified by HPFC (eluting with chloroform:CMA in a gradient from 100:0 to 80:20) followed by recrystallization from acetonitriled to provide 1.43 g of (S)-1-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine as a white solid, mp 157-158° C.

[1387] Anal. Calcd for C24H27N5O3.0.3H2O: C, 65.68; H, 6.34; N, 15.96. Found: C, 65.76; H, 6.24; N, 16.05.

Example 490

(S)-3-[4-Amino-2-ethoxymethyl-7-pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]propane-1,2-diol

[1388]

567

[1389] (S)-1-[(2,2-Dimethyl-1,3-dioxolan-4-yl)methyl]-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine (0.72 g, 1.66 mmol) was treated according to the method Example 162. The product was recrystallized from methanol to provide 0.38 g of (S)-3-[4-amino-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]propane-1,2-diol as a white, crystalline solid, mp 203-204° C.

[1390] Anal. Calcd for C21H23N5O3.0.25H2O: C, 63.38; H, 5.95; N, 17.60. Found: C, 63.41; H, 6.02; N, 17.61.

Example 491

2-Ethoxymethyl-1-(piperidin-2-ylmethyl)-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine trihydrochloride

[1391]

568

[1392] Part A

[1393] 7-Bromo-4-chloro-3-nitroquinoline (12.08 g, 42.0 mmol) was treated according to the methods described in Parts A through D of Examples 152-156 using 1-(tert-butoxycarbonyl)-2-(aminomethyl)piperidine (10.0 g, 46.7 mmol) in Part A. The product from Part A was triturated with diethyl ether and isolated by filtration. Triethylamine (1.1 equivalents) was added to the reaction in Part C. At the completion of the reaction in Part C, the solvent was removed under reduced pressure, and the residue was used in Part D. Following chromatographic purification in Part D (eluting with chloroform:CMA in a gradient from 100:0 to 98:2), tert-butyl 2-[(7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]piperidine-1-carboxylate was obtained as a light yellow solid.

[1394] Part B

[1395] tert-Butyl 2-[(7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]piperidine-1-carboxylate (8.68 g, 17.24 mmol) was oxidized and then aminated according to the methods described in Parts H and I of Example 1. The oxidation product was not recrystallized. The product from amination was purified by flash column chromatography on silica gel (eluting with chloroform:CMA in a gradient from 100:0 to 90:10) to provide tert-butyl 2-[(4-amino-7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]piperidine-1-carboxylate as a white solid, mp 190-192° C.

[1396] Anal. Calcd for C24H32BrN5O3: C, 55.60; H, 6.22; N, 13.51. Found: C, 55.52; H, 6.20; N, 13.31.

[1397] Part C

[1398] tert-Butyl 2-[(4-amino-7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]piperidine-1-carboxylate (4.82 g, 9.30 mmol) and pyridine-3-boronic acid 1,3-propanediol cyclic ester (1.67 g, 10.2 mmol) were coupled according to the method described in Part F of Example 414. Palladium (II) acetate (0.0103 f, 0.046 mmol) was added as a solid. The reaction was heated for 15 hours. The crude product was purified by HPFC (eluting with chloroform:CMA in a gradient from 100:0 to 72:28) to provide 3.4 g of tert-butyl 2-{[4-amino-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}piperidine-1-carboxylate as an off-white, crystalline solid.

[1399] Part D

[1400] tert-Butyl 2-{[4-amino-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}piperidine-1-carboxylate (3.15 g, 6.10 mmol) was deprotected according to the method described in Example 177 to provide 2.54 g of 2-ethoxymethyl-1-(piperidin-2-ylmethyl)-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine trihydrochloride as an off-white solid, mp >250° C.

[1401] Anal. Calcd for C24H28N6O.3HCl.2H2O: C, 51.30; H, 6.28; N, 14.96. Found: C, 50.95; H, 6.38; N, 15.10.

Example 492

2-Ethoxymethyl-1-{[1-(methanesulfonyl)piperidin-2-yl]methyl}-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine

[1402]

569

[1403] A solution of 2-ethoxymethyl-1-(piperidin-2-ylmethyl)-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine trihydrochloride (0.60 g, 1.1 mmol) and triethylamine (0.79 mL, 5.7 mmol) in chloroform (50 mL) was cooled to 4° C. Methanesulfonyl chloride (0.12 mL, 1.5 mmol) was added, and the reaction was allowed to warm to ambient temperature and stirred overnight. Additional methanesulfonyl chloride (2.5 equivalents) was added at 4° C. over the course of several days. The work-up procedure described in Examples 178 to 181 was carried out. The crude product was purified by HPFC (eluting with chloroform:CMA in a gradient from about 100:0 to 70:30) followed by recrystallization from acetonitrile to provide 0.19 g of 2-ethoxymethyl-1-{[1-(methanesulfonyl)piperidin-2-yl]methyl}-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine as a white solid, mp 152-154° C.

[1404] Anal. Calcd for C25H30N6O3S.0.5H2O: C, 59.62; H, 6.20; N, 16.69. Found: C, 59.62; H, 6.44; N, 16.78.

Example 493

N-{4-[4-Amino-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-ylmethyl]benzyl}methanesulfonamide

[1405]

570

[1406] Part A

[1407] 1-(N-BOC-aminomethyl)-4-(aminomethyl)benzene (5.0 g, 21 mmol) in dichloromethane (50 mL) was added dropwise to a mixture of 7-bromo-4-chloro-3-nitroquinoline (5.81 g, 20 mmol) and triethylamine (5.63 mL) in dichloromethane (60 mL). The reaction was stirred for 16 hours and then washed sequentially with water and saturated aqueous sodium chloride. The organic fraction was dried over sodium sulfate, filtered and concentrated to provide a yellow crystalline solid. Recrystallization from 2-propanol yielded 9.1 g of tert-butyl {4-[(7-bromo-3-nitroquinolin-4-ylamino)methyl]benzyl}carbamate as a yellow powder.

[1408] Part B

[1409] Ethyl viologen dibromide (0.069 g, 0.18 mmol), potassium carbonate (12.76 g, 92 mmol) in water (55mL), and sodium hydrosulfite (11.25 g, 65 mmol) in water (55mL) were added sequentially to a solution of tert-butyl {4-[(7-bromo-3-nitroquinolin-4-ylamino)methyl]benzyl}carbamate (9.0 g, 18.5 mmol) in dichloromethane (110 mL). The resulting biphasic mixture was stirred for 20 hours. The reaction was diluted with water (600 mL) and dichloromethane (500 mL). The layers were separated and the aqueous fraction was extracted with dichloromethane. The organic fractions were combined and washed sequentially with water and saturated aqueous sodium chloride. The organic fraction was dried over sodium sulfate, filtered, and concentrated under reduced pressure to yield 8.5 g of tert-butyl {4-[(3-amino-7-bromoquinolin-4-ylamino)methyl]benzyl}carbamate as a yellow-brown amorphous solid.

[1410] Part C.

[1411] tert-Butyl {4-[(3-amino-7-bromoquinolin-4-ylamino)methyl]benzyl}carbamate (8.46 g, 18.5 mmol), triethylamine (2.25 mL) and dichloromethane (92 mL) were combined. Ethoxyacetyl chloride (2.92 g, 24 mmol) was added dropwise to the mixture. The reaction was stirred for an additional 1.5 hours and then concentrated under reduced pressure. Ethanol (92 mL) and triethylamine (10.31 mL) were added to the residue and the reaction was heated at reflux temperature for 1.5 hours. A precipitate formed. The reaction was cooled to room temperature and then concentrated under reduced pressure. The residue was dissolved in dichloromethane and washed sequentially with water and saturated aqueous sodium chloride. The organic fraction was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. An initial purification by flash column chromatography eluting with a gradient of CMA in chloroform (2-10%) was followed by recrystallization from acetonitrile to provide 3.4 g of tert-butyl [4-(7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-ylmethyl)benzyl]carbamate as yellow-orange crystals.

[1412] Part D

[1413] 3-Chloroperoxybenzoic acid (2.91 g, 9.3 mmol, 55% pure) was added to a solution of tert-butyl [4-(7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-ylmethyl)benzyl]carbamate (3.2 g, 6.1 mmol) in chloroform (60 mL). The reaction was stirred for 1 hour and then cooled with an ice bath. Ammonium hydroxide (40 mL) was added and the reaction was stirred for 10 minutes. p-Toluenesulfonyl chloride (1.16 g, 6.1 mmol) was added in two portions. The cooling bath was removed and the mixture was stirred for an additional 16 hours. The layers were separated and the aqueous fraction was extracted with dichloromethane. The combined organic fractions were washed sequentially with water and saturated aqueous sodium chloride, dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification of the residue by flash column chromatography (CMA/chloroform) and subsequent recrystallization from acetonitrile yielded 1.15 g of tert-butyl [4-(4-amino-7-bromo-2-ethoxymethyl-1H-imidazo [4,5-c]quinolin-1-ylmethyl)benzyl]carbamate as a tan solid.

[1414] Part E.

[1415] tert-Butyl [4-(4-amino-7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-ylmethyl)benzyl]carbamate (1.15 g, 2.1 mmol), triphenylphosphine (0.005 g), pyridine-3-boronic acid 1,3-propanediol cyclic ester (0.365 g, 2.2 mmol), and n-propanol (3.67 mL) were combined. Aqueous sodium carbonate (2M, 1.12 mL) and water (0.6 mL) were added to the mixture and the flask was flushed with nitrogen. Palladium(II) acetate (0.0013 g) in toluene (0.200 mL) was added, and the flask was again flushed with nitrogen. The flask was sealed and heated in an oil bath at a temperature of 105° C. for 16 hours. The reaction was allowed to cool to room temperature and the mixture was diluted with dichloromethane and water. The layers were separated and the aqueous fraction was extracted with dichloromethane. The organic fractions were combined, washed sequentially with water and saturated aqueous sodium chloride, dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification of the residue by flash column chromatography eluting with a gradient of CMA/chloroform and subsequent recrystallization from acetonitrile yielded 0.725 g of tert-butyl {4-[4-amino-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-ylmethyl]benzyl}carbamate as flocculent white crystals, m.p. 195.5-197.0° C.

[1416] Anal Calcd. for C31H34N6O3: % C, 69.13; % H, 6.36; % N, 15.60. Found: % C, 68.85; % H, 6.34; % N, 15.63.

[1417] Part F

[1418] tert-Butyl {4-[4-amino-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-ylmethyl]benzyl}carbamate (0.660 g) was added to ethanolic hydrogen chloride (4M, 10 mL) and the solution was heated at reflux temperature for 30 minutes. The reaction was cooled to room temperature and concentrated under reduced pressure. Diethyl ether and water were added to the oily residue and the layers were separated. The aqueous fraction was brought to pH 13 with 10% aqueous sodium hydroxide and then extracted sequentially with dichloromethane and dichloromethane containing 5% methanol. The organic fractions were combined, washed sequentially with water and saturated aqueous sodium chloride, dried over sodium sulfate, filtered, and concentrated under reduced pressure to yield 0.526 g of 1-(4-aminomethylbenzyl)-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine as an off-white solid, mp 211.0-213.5° C.

[1419] Anal Calcd. for C26H26N6O: % C, 71.21; % H, 5.98; % N, 19.16. Found: % C, 70.85; % H, 5.98; % N, 19.22.

[1420] Part G.

[1421] Methanesulfonyl chloride (0.13 mL, 1.7 mmol) was added dropwise to a mixture of 1-(4-aminomethylbenzyl)-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine (0.520 g, 1.2 mmol) in dichloromethane (10 mL). The reaction was stirred for 16 hours and then saturated aqueous sodium carbonate was added. The layers were separated and the aqueous fraction was extracted with 95:5 chloroform/methanol. The organic fractions were combined and washed sequentially with water and saturated aqueous sodium chloride, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting solid was purified by flash column chromatography with a gradient of CMA (2%-10%) in chloroform as the eluent. A final recrystallization from 2-propanol provided 0.240 g of N-{4-[4-amino-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-ylmethyl]benzyl}methanesulfonamide as white granular crystals, mp 228.0-229.0° C.

[1422] Anal Calcd. for C27H28N6O3S: % C, 62.77; % H, 5.46; % N, 16.27; % S, 6.21.

[1423] Found: % C, 62.55; % H, 5.13; % N, 16.15; % S, 6.11.

Example 494

N-[4-(4-Amino-2-ethoxymethyl-7-(pyridin-3-yl)imidazo[4,5-c]quinolin-1-yl)butyl]-4-[(2-dimethylaminoethoxy)phenylmethyl]benzamide

[1424]

571

[1425] A mixture of 4-[(2-dimethylaminoethoxy)phenylmethyl]benzoic acid (0.433 g) and 1-hydroxybenzotriazole (0.196 g) in chloroform (7 mL) was cooled to 0° C. and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.277 g) was added in small portions over a 2 minute period. The mixture was stirred for 1 hour and then added dropwise to a chilled (0° C.) solution of 1-(4-aminobutyl)-2-ethoxymethyl-7-(pyridin-3-yl)-]H-imidazo[4,5-c]quinolin-4-amine (0.400 g) in anhydrous dimethylacetamide (7 mL). The cooling bath was removed and the reaction was stirred for an additional 16 hours. Water was added and the mixture was made acidic by the addition of 4N hydrochloric acid. The aqueous fraction was extracted with diethyl ether (3X) to remove the dimethylacetamide. Sodium hydroxide (10% in water) was added to make the aqueous fraction basic and the aqueous fraction was subsequently extracted with multiple portions of dichloromethane. The organic fractions were combined, washed sequentially with water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography using a gradient of CMA/chloroform as the eluent. A final recrystallization from acetonitrile provided 0.426 g of N-[4-(4-amino-2-ethoxymethyl-7-(pyridin-3-yl)imidazo[4,5-c]quinolin-1-yl)butyl]-4-[(2-dimethylaminoethoxy)phenylmethyl]benzamide as a white crystalline solid, mp 157.0-161.0° C.

[1426] Anal Calcd. for C40H45N7O3.1.0H2O: % C, 69.64; % H, 6.87; % N, 14.21. Found: % C, 69.81; % H, 7.07; % N, 14.25.

Example 495

N-[2-(4-Amino-2-butyl-7-vinyl-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]methanesulfonamide

[1427]

572

[1428] Part A

[1429] A solution of 7-bromo-4-chloro-3-nitroquinoline (143.8 g, 0.5 mol) in 800 mL warm DMF was added to a stirred solution of ethylenediamine in 200 mL DMF at room temperature; the reaction was stirred at room temperature overnight. The reaction was quenched with 2 L water and stirred for an additional hour. Additional water was added, and the mixture was stirred overnight. A precipitate formed and was isolated by filtration and air-dried overnight on the filter funnel to provide N1-(7-bromo-3-nitroquinolin-4-yl)ethane-1,2-diamine as a yellow solid.

[1430] Part B

[1431] To a stirred solution of NI-(7-bromo-3-nitroquinolin-4-yl)ethane-1,2-diamine (50 g, 0.167 mol) and triethylamine (2 equivalents) in 1500 mL dichloromethane, was slowly added methanesulfonic anhydride (1.2 equivalents), and the reaction was stirred overnight at room temperature. Water (1 L) was added, and the mixture was stirred vigorously for one hour. The organic layer was separated and concentrated under reduced pressure to provide N-[2-(7-bromo-3-nitroquinolin-4-ylamino)ethyl]methanesulfonamide.

[1432] Part C

[1433] An 8 L stainless steel Parr vessel was charged with N-[2-(7-bromo-3-nitroquinolin-4-ylamino)ethyl]methanesulfonamide (61 g), 5% Pt/C catalyst (6.0 g) and acetonitrile (3 L). The vessel was evacuated, filled with hydrogen (45 psi, 3.1×105 Pa), and shaken at ambient temperature overnight. The reaction mixture was filtered through CELITE filter agent and concentrated under reduced pressure to provide N-[2-(3-amino-7-bromoquinolin-4-ylamino)ethyl]methanesulfonamide.

[1434] Part D

[1435] To a stirred solution of N-[2-(3-amino-7-bromoquinolin-4-ylamino)ethyl]methanesulfonamide (46.4 g, 0.129 mol) in 1000 mL pyridine was slowly added valeryl chloride (1.1 equivalents). After 1.5 hours the mixture was yellow and turbid. The reaction mixture was then heated at reflux for 12 hours, allowed to cool to ambient temperature and concentrated under reduced pressure. The residue was mostly dissolved in 10% HCl to adjust to pH 1. The resulting suspension was adjusted to pH 12 with the addition of 50% aqueous sodium hydroxide and stirred overnight. A precipitate formed and was isolated by filtration and air-dried to provide 45 g of N-[2-(7-bromo-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]methanesulfonamide as a pale gray/green solid.

[1436] Part E

[1437] 3-Chloroperoxybenzoic acid (1.0 equivalent of 50% pure material) was added to a solution of N-[2-(7-bromo-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]methanesulfonamide (44 g, 103.4 mmol) in 1000 mL dichloromethane. After 2 hours, concentrated ammonium hydroxide solution (600 mL) was added. The reaction was stirred for 15 minutes before p-toluenesulfonyl chloride (1.1 equivalents) was slowly added in small portions. The reaction was stirred overnight at room temperature and then water and potassium carbonate were added with vigorous stirring. A precipitate formed and was isolated by filtration to provide N-[2-(4-amino-7-bromo-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)-ethyl]methanesulfonamide.

[1438] Part F

[1439] N-[2-(4-Amino-7-bromo-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]methanesulfonamide was coupled with potassium vinyltrifluoroborate according to the procedure described in Part D of Examples 440-455 and recrystallized from acetonitrile to provide N-[2-(4-amino-2-butyl-7-vinyl-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]methanesulfonamide as an off-white solid.

Example 496

1-[2-(4-Amino-2-ethoxymethyl-7-vinyl-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]-3-(2-methylethyl)urea

[1440]

573

[1441] Part A

[1442] A mixture of N1-(7-bromo-3-nitroquinolin-4-yl)ethane-1,2-diamine (40 g, 0.129 mol), triethylamine (3.0 equivalents) and IL dichloromethane was stirred vigorously as isopropyl isocyante (1.1 equivalents) was added dropwise. As the reaction progressed it became more homogeneous, and then a yellow precipitate formed. After 4 hours the volume of dichloromethane was reduced under reduced pressure. The yellow solid was isolated by filtration and air-dried overnight to provide 43 g 1-(2-methylethyl)-3-[2-(3-nitroquinolin-4- ylamino)ethyl]urea.

[1443] Part B

[1444] An 8 L stainless steel Parr vessel was charged with 1-(2-methylethyl)-3-[2-(3-nitroquinolin-4-ylamino)ethyl]urea (44 g, 0.111 mol), 5% platinum on carbon (5 g) and acetonitrile (4000 mL). The vessel was evacuated, charged with hydrogen, and shaken vigorously for six hours. An analysis by HPLC and TLC indicated the reaction was not complete. Additional catalyst (5 g) was added, and the vessel was placed under hydrogen pressure and shaken overnight. The reaction mixture was filtered and concentrated under reduced pressure to provide 1-[2-(3-amino-7-bromoquinolin-4-ylamino)ethyl]-3-(2-methylethyl)urea.

[1445] Part C

[1446] To a stirred solution of 1-[2-(3-amino-7-bromoquinolin-4-ylamino)ethyl]-3-(2-methylethyl)urea (27.2 g, 0.0743 mol) in 600 mL pyridine was slowly added ethoxyacetyl chloride (1.1 equivalents). After 1.5 hours the mixture was yellow and turbid. The reaction mixture was then heated at 80° C. for 12 hours and then concentrated under reduced pressure. The residue was dissolved in water and saturated aqueous potassium carbonate and stirred vigorously for three hours. A precipitate was present, was isolated by filtration, and air-dried for 48 hours to provide 32 g of 1-[2-(7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]-3-(2-methylethyl)urea.

[1447] Part D

[1448] The method described in Part E of Example 495 was used to oxidize and aminate 1-[2-(7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]-3-(2-methylethyl)urea (31 g, 71.4 mmol). The isolated product was recrystallized from acetonitrile to provide 1-[2-(4-amino-7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]-3-(2-methylethyl)urea.

[1449] Part E

[1450] 1-[2-(4-Amino-7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]-3-(2-methylethyl)urea was coupled with potassium vinyltrifluoroborate according to the procedure described in Part D of Examples 440-455 to provide N-[2-(4-amino-2-butyl-7-vinyl-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]-3-(2-methylethyl)urea as an off-white solid.

[1451] MS (APCl) m/z 397.2 (M+H)+.

Examples 497-500

[1452] The bromide starting material indicated in the table below was coupled with potassium vinyltrifluoroborate according to the procedure described in Part D of Examples 440-463 and recrystallized from acetonitrile to provide the products shown in the table below.

Examples 497-500

[1453]

57

Example
Starting Material
Product Structure

497
7-Bromo-2-ethoxymethyl-1- (2-methylpropyl)-1H- imidazo[4,5-c]quinolin-4- amine

574

498
1-[4-Amino-7-bromo-2- ethoxymethyl-1H- imidazo[4,5-c]quinolin-1-yl]- 2-methylpropan-2-ol

575

499
8-Bromo-1-(2-methylpropyl)- 1H-imidazo[4,5-c]quinolin-4- amine

576

500
7-Bromo-2-ethoxymethyl-1- (3-methoxypropyl)-1H- imidazo[4,5-c]quinolin-4- amine

577

MS

(APCI)

m/z

Example
Product Name
Form
(M + H)+
Anal.

497
2-Ethoxymethyl-1-(2-
Off-
325.1
Calcd for C19H24N4O:

methylpropyl)-7-vinyl-1H-
white

C, 70.34; H, 7.46; N,

imidazo[4,5-c]quinolin-4-
solid

17.27. Found: C,

amine

69.99; H, 7.60; N,

17.36.

498
1-[4-Amino-2-ethoxymethyl-
Off-
341.1
Calcd for

7-vinyl-1H-imidazo[4,5-
white

C19H24N4O2: C,

c]quinolin-1-yl]-2-
solid

67.04; H, 7.11; N,

methylpropan-2-ol

16.46. Found: C,

66.09; H, 7.41; N,

16.16.

499
1-(2-Methylpropyl)-8-vinyl-
Off-
267.2
Not measured

1H-imidazo[4,5-c]quinolin-4-
white

amine
solid

500
2-Ethoxymethyl-1-(3-
Off-
341.1
Not measured

methoxypropyl)-7-vinyl-1H-
white

imidazo[4,5-c]quinolin-4-
solid

amine

Examples 501-506

[1454] The method described in Part E of Example 440-455 was used to couple the vinyl compound indicated in the table below with 3-bromopyridine to provide the product shown and named in the table below.

Example 501-506

[1455]

58

MS

Starting

(APCI)

Vinyl

m/z

Example
Compound
Product Structure
Product Name
Form
(M + H)+

501
Example 495

578

(E)-N-{2-[4-Amino-2- butyl-7-(2-pyridin-3- ylvinyl)-1H-imidazo[4,5- c]quinolin-1- yl]ethyl}methanesulfona mide
Off- White solid
465.0

502
Example 496

579

(E)-N-{2-[4-Amino-2- ethoxymethyl-7-(2- pyridin-3-ylvinyl)-1H- imidazo[4,5-c]quinolin- 1-yl]ethyl}-N′-(2- methylethyl)urea
Off- White solid
474.1

503
Example 497

580

(E)-2-Ethoxymethyl-1- (2-methylpropyl)-7-(2- pyridin-3-ylvinyl)-1H- imidazo[4,5-c]quinolin- 4-amine
Off- White solid
402.2

504
Example 498

581

(E)-1-[4-Amino-2- ethoxymethyl-7-(2- pyridin-3-ylvinyl)-1H- imidazo[4,5-c]quinolin- 1-yl]-2-methylpropan-2- ol
Off- White solid
418.1

505
Example 499

582

(E)-1-(2-Methylpropyl)- 8-(2-pyridin-3-ylvinyl)- 1H-imidazo[4,5- c]quinolin-4-amine
Off- White solid
344.0

506
Example 500

583

(E)-2-Ethoxymethyl-1- (3-methoxypropyl)-7-(2- pyridin-3-ylvinyl)-1H- imidazo[4,5-c]quinolin- 4-amine
Not reported
418.0

Example 507

(E)-2-Ethoxymethyl-1-(3-methoxypropyl)-7-(2-pyridin-2-ylvinyl)-1H-imidazo[4,5-c]quinolin-4-amine

[1456]

584

[1457] A thick walled glass tube, equipped with magnetic stir-bar, was charged with toluene (20 mL/g), palladium (II) acetate (0.1 equivalents), tri-ortho-tolylphosphine (0.3 equivalents), triethylamine (3.0 equivalents), 2-vinylpyridine (1.0 equivalent), and 7-bromo-2-ethoxymethyl-1-(3-methoxypropyl)-1H-imidazo[4,5-c]quinolin-4-amine (1.0 eq.). The tube was purged with nitrogen and sealed. The reaction mixture was heated at 120° C. for 24-48 hours. The reaction mixture was allowed to cool and then concentrated under reduced pressure. The solid residue was partitioned between dichloromethane and water, and the mixture was adjusted to pH 12 with the addition of 10% aqueous sodium hydroxide. The organic layer was separated and purified by flash chromatography on silica gel (eluting with chloroform:methanol in a gradient from 100:0 to 90:10) followed by recrystallization from acetonitrile to provide (E)-2-ethoxymethyl-1-(3-methoxypropyl)-7-(2-pyridin-2-ylvinyl)-1H-imidazo[4,5-c]quinolin-4-amine as an off-white solid.

[1458] MS (APCl) m/z 418.2 (M+H)+.

Examples 508-557

[1459] Part A

[1460] Concentrated hydrochloric acid (˜15 mL) was added to a suspension of tert-butyl [4-(4-amino-7-bromo-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]carbamate (3.19 g, 6.7 mmol) in ethanol (6.4 mL), and the reaction was stirred for 30 minutes. The reaction was adjusted to pH 13 with the addition of 50% aqueous sodium hydroxide. A precipitate formed, was isolated by filtration, washed with 1% sodium carbonate, and dried overnight on the filter funnel to provide 1-(4-aminobutyl)-7-bromo-2-propyl-1H-imidazo[4,5-c]quinolin-4-amine, which contained some water.

[1461] Part B

[1462] A suspension of 1-(4-aminobutyl)-7-bromo-2-propyl-1H-imidazo[4,5-c]quinolin-4-amine (2.00 g, 5.3 mmol) in chloroform (20 mL) was cooled to 0° C., and a solution of isopropyl isocyanate (5.3 mmol) in chloroform (3 mL/g) was added slowly over a period of eight minutes. After one hour, additional isopropyl isocyanate (0.53 mmol) in chloroform was added. Additional isopropyl isocyanate (2.15 mmol) was added again after an additional 2.5 hours. A precipitate was present and was isolated by filtration, washed with cold chloroform, and dried overnight on the filter funnel to provide 1.99 g of N-{4-[4-amino-7-bromo-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl]butyl}-N′-(1-methylethyl)urea as a white solid.

[1463] Part C

[1464] N-{4-[4-Amino-7-bromo-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl]butyl}-N′-(1-methylethyl)urea was coupled with the appropriate boronic acid or boronic acid ester according to the procedure described in Examples 20-65. The products were purified by prep HPLC according to the methods described above. The table below shows the structure of the compound obtained in each example and the observed accurate mass for the isolated trifluoroacetate salt.

Examples 508-557

[1465]

585

Measured Mass

Example
R
(M + H)

508

586

449.2651

509

587

459.2888

510

588

460.2821

511

589

460.2820

512

590

465.2428

513

591

465.2402

514

592

489.3017

515

593

473.3035

516

594

473.3037

517

595

473.3009

518

596

475.2831

519

597

475.2809

520

598

475.2786

521

599

484.2824

522

600

484.2817

523

601

485.3011

524

602

487.3150

525

603

490.2932

526

604

489.2955

527

605

489.2944

528

606

493.2472

529

607

493.2459

530

608

493.2487

531

609

495.2691

532

610

501.2973

533

611

501.2957

534

612

501.2982

535

613

502.2921

536

614

502.3275

537

615

503.3109

538

616

474.2977

539

617

505.2754

540

618

516.3057

541

619

517.3257

542

620

517.3261

543

621

519.3101

544

622

519.3092

545

623

488.3139

546

624

531.3060

547

625

537.2693

548

626

549.3190

549

627

551.2814

550

628

552.2754

551

629

552.2759

552

630

556.3423

553

631

558.3538

554

632

572.3351

555

633

516.3045

556

634

488.3117

557

635

489.2997

Examples 558-582

[1466] Part A

[1467] A suspension of 1-(4-aminobutyl)-7-bromo-2-propyl-1H-imidazo[4,5-c]quinolin-4-amine (2.42 g, 6.4 mmol) and triethylamine (0.99 mL, 7.1 mmol) in chloroform (240 mL) was cooled to 0° C., and cyclopentanecarbonyl chloride (0.78 mL, 6.4 mmol) was added dropwise over a period of five minutes. The reaction was stirred for ten minutes, washed sequentially with water (50 mL) and 1% aqueous sodium carbonate (100 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was triturated with isopropanol:water (10 mL/g and 1.7 mL/g) and isolated by filtration. The filtrate was concentrated under reduced pressure and recrystallized from isopropanol (5 mL/g). The two solids were combined and dried overnight in a vacuum oven to provide 1.51 g of N-{4-[4-amino-7-bromo-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl]butyl}cyclopentanecarboxamide as a light yellow solid.

[1468] Part B

[1469] N-{4-[4-Amino-7-bromo-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl]butyl}-cyclopentanecarboxamide was coupled with the appropriate boronic acid or boronic acid ester according to the procedure described in Examples 20-65. The products were purified by prep HPLC according to the methods described above. The table below shows the structure of the compound obtained in each example and the observed accurate mass for the isolated trifluoroacetate salt.

Examples 558-582

[1470]

636

Measured Mass

Example
R
(M + H)

558

637

470.2917

559

638

471.2877

560

639

476.2485

561

640

476.2503

562

641

500.3024

563

642

484.3093

564

643

486.2841

565

644

495.2852

566

645

496.3090

567

646

498.3227

568

647

501.2946

569

648

500.3015

570

649

506.2754

571

650

512.3023

572

651

512.2994

573

652

512.3024

574

653

485.3015

575

654

530.3084

576

655

530.3101

577

656

499.3166

578

657

542.3149

579

658

460.2821

580

659

548.2672

581

660

562.2844

582

661

563.2784

Examples 583-611

[1471] Part A

[1472] A solution of 7-bromo-2-ethoxymethyl-1-(piperidin-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-4-amine dihydrochloride (4.0 g, 8.1 mmol) and triethylamine (5.67 mL, 40.7 mmol) in chloroform (300 mL) was cooled to 0° C., and 4-morpholinecarbonyl chloride (0.95 mL, 8.1 mmol) was added dropwise. The reaction was allowed to warm to ambient temperature and stirred overnight before it was diluted with chloroform (200 mL); washed sequentially with water (200 mL), 2 M sodium carbonate (2×200 mL), water (200 mL), and brine (200 mL); and concentrated under reduced pressure. The residue was triturated with ethyl acetate and subsequently recrystallized from acetonitrile to provide 3.64 g of 7-bromo-2-ethoxymethyl-1-{[1-(morpholin-4-ylcarbonyl)piperidin-4-yl]methyl }-1H-imidazo[4,5-c]quinolin-4-amine as a white solid, mp 198-199° C.

[1473] Anal. Calcd for C24H31BrN6O3: C, 54.24; H, 5.88; N, 15.81. Found: C, 54.27; H, 5.64; N, 15.87.

[1474] Part B

[1475] 7-Bromo-2- ethoxymethyl-1-{[1-(morpholin-4-ylcarbonyl)piperidin-4-yl]methyl}-1H-imidazo[4,5-c]quinolin-4-amine was coupled with the appropriate boronic acid or boronic acid ester according to the procedure described in Examples 20-65. The products were purified by prep HPLC according to the methods described above. The table below shows the structure of the compound obtained in each example and the observed accurate mass for the isolated trifluoroacetate salt.

Examples 583-611

[1476]

662

Measured Mass

Example
R
(M + H)

583

663

529.2931

584

664

530.2852

585

665

530.2841

586

666

535.2465

587

667

535.2465

588

668

543.3043

589

669

543.3057

590

670

543.3105

591

671

545.2865

592

672

545.2874

593

673

554.2842

594

674

554.2849

595

675

555.3068

596

676

559.3006

597

677

563.2570

598

678

563.2519

599

679

563.2496

600

680

565.2722

601

681

571.3003

602

682

571.3016

603

683

571.3063

604

684

572.2994

605

685

628.3633

606

686

586.3104

607

687

558.3211

608

688

601.3146

609

689

607.2709

610

690

621.2830

611

691

622.2778

Examples 612-642

[1477] Part A

[1478] Hydrogen chloride (100 mL of a 4 M solution in 1,4-dioxane) was added to tert-butyl [4-(4-amino-7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]carbamate (10.0 g, 20.3 mmol), and the reaction was stirred for one hour. The reaction was adjusted to pH 11 with the addition of sodium hydroxide pellets in a small amount of water. Chloroform (300 mL) was added followed by saturated aqueous sodium bicarbonate (50 mL). The organic layer was separated, dried over sodium sulfate, filtered, concentrated under reduced pressure, and dried overnight in a drying oven to provide 5.60 g of 1-(4-aminobutyl)-7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-4-amine as a light yellow solid.

[1479] Part B

[1480] Methanesulfonyl chloride (0.44 mL, 5.7 mmol) was added to a suspension of 1-(4-aminobutyl)-7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-4-amine (2.04 g, 5.2 mmol) and triethylamine (0.94 mL, 6.8 mmol) in chloroform (100 mL), and the reaction was stirred for four hours. Water was added; a precipitate formed. The aqueous layer was adjusted to pH 10 with the addition of 50% aqueous sodium hydroxide. The precipitate was isolated by filtration, washed with cold chloroform, and dried overnight on the filter funnel. Material from another run was added, and entire procedure was repeated to eliminate unreacted starting material. N-{4-[4-Amino-7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl]butyl}methanesulfonamide (2.95 g) was obtained as a white solid.

[1481] Part C

[1482] N-{4-[4-Amino-7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl]butyl}methanesulfonamide was coupled with the appropriate boronic acid or boronic acid ester according to the procedure described in Examples 20-65. The products were purified by prep HPLC according to the methods described above. The table below shows the structure of the compound obtained in each example and the observed accurate mass for the isolated trifluoroacetate salt.

Examples 612-642

[1483]

692

Measured Mass

Example
R
(M + H)

612

693

468.2072

613

694

482.2245

614

695

482.2243

615

696

484.2014

616

697

484.2051

617

698

493.2035

618

699

494.2239

619

700

496.2400

620

701

496.2396

621

702

499.2145

622

703

498.2190

623

704

498.2167

624

705

502.1650

625

706

502.1717

626

707

504.1894

627

708

510.2177

628

709

510.2184

629

710

512.2349

630

711

512.2345

631

712

567.2750

632

713

525.2305

633

714

526.2516

634

715

526.2512

635

716

528.2282

636

717

528.2320

637

718

540.2274

638

719

561.1957

639

720

561.1987

640

721

565.2621

641

722

567.2791

642

723

581.2590

Example 643-663

[1484] Part A

[1485] A solution of 1-(4-aminobutyl)-7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-4-amine (2.00 g, 5.1 mmol) in chloroform (36 mL) was cooled to 0° C., and a cold solution of isopropyl isocyanate (0.50 mL, 5.4 mmol) in chloroform (4 mL) was added slowly. A precipitate formed, and the reaction was stirred for 45 minutes. The reaction mixture was triturated with ethyl acetate (200 mL), and the precipitate was isolated by filtration and dried for three days in a drying oven to provide 1.86 g of N-{4-[4-amino-7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl]butyl}—N′-(1-methylethyl)urea as a white solid, mp 211° C.

[1486] Anal. Calcd for C21H29BrN6O2: C, 52.83; H, 6.12; N, 17.60. Found: C, 52.52; H, 6.13; N, 17.29.

[1487] Part B

[1488] N-{4-[4-Amino-7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1- yl]butyl}-N′-(1-methylethyl)urea was coupled with the appropriate boronic acid or boronic acid ester according to the procedure described in Examples 20-65. The products were purified by prep HPLC according to the methods described above. The table below shows the structure of the compound obtained in each example and the observed accurate mass for the isolated trifluoroacetate salt.

Example 643-663

[1489]

724

Measured Mass

Example
R
(M + H)

643

725

475.2793

644

726

476.2749

645

727

481.2385

646

728

481.2366

647

729

505.2915

648

730

489.2940

649

731

489.2956

650

732

491.2746

651

733

491.2772

652

734

491.2758

653

735

505.2906

654

736

517.2902

655

737

518.2886

656

738

518.3214

657

739

574.3497

658

740

465.2721

659

741

568.2730

660

742

568.2715

661

743

572.3354

662

744

574.3502

663

745

588.3318

Examples 664-703

[1490] 1-{3-[4-Amino-7-bromo-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}pyrrolidin-2-one was coupled with the appropriate boronic acid or boronic acid ester according to the procedure described in Examples 20-65. The products were purified by prep HPLC according to the methods described above. The table below shows the structure of the compound obtained in each example and the observed accurate mass for the isolated trifluoroacetate salt.

Examples 664-703

[1491]

746

Measured Mass

Example
R
(M + H)

664

747

444.2367

665

748

445.2348

666

749

445.2376

667

750

450.1961

668

751

450.1949

669

752

474.2487

670

753

458.2561

671

754

458.2533

672

755

458.2528

673

756

460.2343

674

757

460.2322

675

758

469.2308

676

759

469.2344

677

760

474.2486

678

761

474.2510

679

762

478.1996

680

763

486.2490

681

764

486.2463

682

765

486.2488

683

766

487.2797

684

767

488.2299

685

768

543.3068

686

769

459.2486

687

770

501.2592

688

771

502.2805

689

772

473.2643

690

773

516.2563

691

774

522.2159

692

775

537.2263

693

776

537.2266

694

777

541.2872

695

778

543.3067

696

779

557.2853

697

780

473.2643

698

781

474.2495

699

782

569.2845

700

783

502.2812

701

784

487.2454

702

785

567.2703

703

786

483.2511

Examples 704-738

[1492] 1-{3-[4-Amino-8-bromo-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}pyrrolidin -2-one was coupled with the appropriate boronic acid or boronic acid ester according to the procedure described in Examples 20-65. The products were purified by prep HPLC according to the methods described above. The table below shows the structure of the compound obtained in each example and the observed accurate mass for the isolated trifluoroacetate salt.

Examples 704-738

[1493]

787

Measured Mass

Example
R
(M + H)

704

788

434.2216

705

789

444.2412

706

790

445.2380

707

791

450.1968

708

792

450.1963

709

793

458.2571

710

794

458.2547

711

795

458.2563

712

796

460.2370

713

797

460.2324

714

798

460.2359

715

799

470.2581

716

800

475.2460

717

801

474.2530

718

802

474.2484

719

803

478.2023

720

804

478.2005

721

805

478.1989

722

806

486.2513

723

807

486.2530

724

808

486.2545

725

809

487.2502

726

810

459.2529

727

811

490.2287

728

812

501.2592

729

813

473.2639

730

814

522.2183

731

815

537.2275

732

816

537.2269

733

817

541.2952

734

818

543.3086

735

819

557.2878

736

820

501.2599

737

821

473.2668

738

822

474.2533

Example 739-762

[1494] Part A

[1495] A solution of 7-bromo-2-ethoxymethyl-1-(piperidin-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-4-amine dihydrochloride (4.0 g, 8.1 mmol) and triethylamine (5.67 mL, 40.7 mmol) in chloroform (300 mL) was treated with isobutyryl chloride (0.85 mL, 8.1 mmol) according to the method described in Part A of Examples 583-611. The reaction was complete after one hour. Following trituration with ethyl acetate, the solid was recrystallized from ethyl acetate and then triturated with hot acetonitrile and isolated by filtration to provide 3.63 g of 7-bromo-2-ethoxymethyl-1-{[1-(2-methylpropylcarbonyl)piperidin-4-yl]methyl}-1H-imidazo[4,5-c]quinolin-4-amine as a white solid, mp 199-200° C.

[1496] Anal. Calcd for C23H30BrN5O2: C, 56.56; H, 6.19; N, 14.34. Found: C, 56.49; H, 6.33; N, 14.12.

[1497] Part B

[1498] 7-Bromo-2-ethoxymethyl-1-{[1-(2-methylpropylcarbonyl)piperidin-4-yl]methyl}-1H-imidazo[4,5-c]quinolin-4-amine was coupled with the appropriate boronic acid or boronic acid ester according to the procedure described in Examples 20-65. The products were purified by prep HPLC according to the methods described above. The table below shows the structure of the compound obtained in each example and the observed accurate mass for the isolated trifluoroacetate salt.

Example 739-762

[1499]

823

Measured Mass

Example
R
(M + H)

739

824

486.2873

740

825

487.2845

741

826

487.2839

742

827

492.2446

743

828

492.2407

744

829

500.3025

745

830

500.3015

746

831

500.3022

747

832

502.2812

748

833

502.2826

749

834

511.2816

750

835

511.2824

751

836

516.3008

752

837

520.2502

753

838

520.2512

754

839

520.2506

755

840

522.2695

756

841

528.2963

757

842

528.2943

758

843

585.3572

759

844

564.2650

760

845

578.2791

761

846

579.2740

762

847

599.3309

Examples 763-785

[1500] Part A

[1501] Cyclopentanecarbonyl chloride (0.80 mL, 6.6 mmol) was added dropwise over a period of five minutes to a suspension of 1-(4-aminobutyl)-7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-4-amine (2.00 g, 5.1 mmol) and triethylamine (0.78 mL, 5.6 mmol) in chloroform (200 mL). The reaction was stirred for 2.5 hours and then stored for three days in a refrigerator. Additional cyclopentanecarbonyl chloride (0.18 mL) was added, and the reaction was stirred for 30 minutes and treated as described for Examples 558-583. The crude product was recrystallized from isopropanol (13 mL/g), isolated by filtration, and dried overnight on the filter funnel to provide 1.60 g of N-{4-[4-amino-7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl]butyl}cyclopentanecarboxamide as a white solid.

[1502] Part B

[1503] N-{4-[4-Amino-7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl]butyl}-cyclopentanecarboxamide was coupled with the appropriate boronic acid or boronic acid ester according to the procedure described in Examples 20-65. The products were purified by prep HPLC according to the methods described above. The table below shows the structure of the compound obtained in each example and the observed accurate mass for the isolated trifluoroacetate salt.

Examples 763-785

[1504]

848

Measured Mass

Example
R
(M + H)

763

849

487.2841

764

850

487.2839

765

851

492.2468

766

852

492.2411

767

853

516.3013

768

854

500.3054

769

855

500.3050

770

856

502.2824

771

857

502.2812

772

858

511.2804

773

859

511.2807

774

860

517.2941

775

861

516.3018

776

862

516.2982

777

863

520.2447

778

864

520.2510

779

865

520.2469

780

866

585.3587

781

867

515.3151

782

868

564.2663

783

869

579.2753

784

870

579.2776

785

871

599.3339

Example 786-806

[1505] Part A

[1506] A suspension of 1-(4-aminobutyl)-7-bromo-2-propyl-1H-imidazo[4,5- c]quinolin-4-amine (3.27 g, 8.7 mmol) and triethylamine (3.82 mL, 11.3 mmol) in chloroform (165 mL) was cooled to 0° C. A cold solution of methanesulfonyl chloride (1.37 mL, 9.6 mmol) in chloroform (10 mL) was slowly added. The reaction was allowed to warm to ambient temperature after 15 minutes. Additional triethylamine (3.74 mL) and methanesulfonyl chloride (2.12 mL) were added over the course of several days to drive the reaction to completion. The reaction was concentrated under reduced pressure, and the residue was partitioned between 1% aqueous sodium carbonate and chloroform. The aqueous layer was adjusted to pH 13 with the addition of saturated aqueous sodium bicarbonate and 50% aqueous sodium hydroxide. The precipitate was isolated by filtration, air-dried, and combined with material from another run. The crude product was recrystallized from isopropanol:water (15 mL/g:1.5 mUg) and dried in a drying oven for several days to provide 1.48 g of N-{4-[4-amino-7-bromo-2-propyl-1H-imidazo[4,5- c]quinolin-1-yl]butyl}methanesulfonamide as a white solid.

[1507] Part B

[1508] N-{4-[4-Amino-7-bromo-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl]butyl}methanesulfonamide was coupled with the appropriate boronic acid or boronic acid ester according to the procedure described in Examples 20-65. The products were purified by prep HPLC according to the methods described above. The table shows the structure of the compound obtained in each example and the observed accurate mass for the isolated trifluoroacetate salt.

Examples 786-806

[1509]

872

Measured Mass

Example
R
(M + H)

786

873

452.2107

787

874

453.2040

788

875

453.2061

789

876

466.2274

790

877

466.2247

791

878

466.2280

792

879

468.2050

793

880

477.2056

794

881

483.2149

795

882

482.2186

796

883

486.1711

797

884

486.1713

798

885

486.1720

799

886

495.2148

800

887

551.2762

801

888

510.2527

802

889

481.2388

803

890

530.1874

804

891

545.1954

805

892

549.2600

806

893

551.2773

Examples 807-860

[1510] 1-(4-Amino-8-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol was coupled with the appropriate boronic acid or boronic acid ester according to the procedure described in Examples 20-65. The products were purified by prep HPLC according to the methods described above. The table below shows the structure of the compound obtained in each example and the observed accurate mass for the isolated trifluoroacetate salt.

Example 807-860

[1511]

894

Measured Mass

Example
R
(M + H)

807

895

391.2158

808

896

392.2117

809

897

392.2101

810

898

397.1702

811

899

397.1716

812

900

421.2254

813

901

405.2313

814

902

405.2303

815

903

405.2323

816

904

407.2123

817

905

407.2115

818

906

407.2117

819

907

416.2117

820

908

416.2068

821

909

417.2311

822

910

419.2468

823

911

422.2206

824

912

421.2281

825

913

421.2275

826

914

425.1750

827

915

425.1758

828

916

425.1772

829

917

433.2227

830

918

433.2268

831

919

433.2265

832

920

434.2209

833

921

434.2561

834

922

490.2814

835

923

406.2247

836

924

448.2364

837

925

449.2564

838

926

449.2574

839

927

420.2432

840

928

381.2046

841

929

478.2410

842

930

483.2058

843

931

484.2024

844

932

484.2026

845

933

488.2686

846

934

504.2607

847

935

420.2394

848

936

421.2247

849

937

488.2662

850

938

474.2520

851

939

490.2816

852

940

504.2585

853

941

464.2324

854

942

478.2449

855

943

502.2843

856

944

462.2492

857

945

524.2639

858

946

476.2647

859

947

502.2809

860

948

476.2672

Examples 861-921

[1512] 1-(4-Amino-7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol was coupled with the appropriate boronic acid or boronic acid ester according to the procedure described in Examples 20-65. The products were purified by prep HPLC according to the methods described above. The table below shows the structure of the compound obtained in each example and the observed accurate mass for the isolated trifluoroacetate salt.

Examples 861-921

[1513]

949

Measured Mass

Example
R
(M + H)

861

950

381.1925

862

951

391.2139

863

952

392.2069

864

953

392.2050

865

954

397.1667

866

955

397.1695

867

956

405.2259

868

957

405.2269

869

958

405.2283

870

959

407.2066

871

960

407.2051

872

961

407.2068

873

962

416.2070

874

963

416.2066

875

964

417.2247

876

965

419.2472

877

966

419.2413

878

967

421.2206

879

968

425.1762

880

969

425.1763

881

970

425.1725

882

971

427.1958

883

972

433.2243

884

973

433.2263

885

974

433.2231

886

975

434.2170

887

976

435.2352

888

977

435.2393

889

978

490.2780

890

979

437.1983

891

980

449.2522

892

981

449.2562

893

982

449.2521

894

983

451.2303

895

984

451.2195

896

985

381.2039

897

986

469.1895

898

987

478.2435

899

988

481.2317

900

989

483.2026

901

990

484.2015

902

991

488.2650

903

992

490.2784

904

993

448.2361

905

994

420.2409

906

995

421.2241

907

996

488.2619

908

997

490.2794

909

998

504.2563

910

999

464.2296

911

1000

502.2782

912

1001

462.2493

913

1002

524.2609

914

1003

476.2669

915

1004

502.2786

916

1005

487.2453

917

1006

449.2572

918

1007

434.2215

919

1008

419.2444

920

1009

514.2440

921

1010

430.2249

Example 922-955

[1514] A reagent from the table below, (0.11 mmol, 1.1 equivalents) was added to a test tube containing a solution of 1-(4-aminobutyl)-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine (39 mg, 0.10 mmol) and N,N-diisopropylethylamine (0.024 mL, 0.14 mmol, 1.4 equivalents) in chloroform (2 mL). The test tube was capped and placed on a shaker at ambient temperature overnight. One drop of deionized water was then added to each test tube, and the solvent was removed by vacuum centrifugation. The products were purified by prep HPLC according to the methods described above. The table below shows the reagent used for each example, the structure of the resulting compound, and the observed accurate mass for the isolated trifluoroacetate salt.

Examples 922-955

[1515]

1011

Measured

Example
Reagent
R
Mass (M + H)

922
Acetyl chloride

1012

433.2328

923
Cyclopropanecarbonyl chloride

1013

459.2498

924
Butyryl chloride

1014

461.2625

925
Methoxyacetyl chloride

1015

463.2431

926
Cyclobutanecarbonyl chloride

1016

473.2641

927
2-Furoyl chloride

1017

485.2261

928
3-Furoyl chloride

1018

485.2284

929
Hexanoyl chloride

1019

489.2979

930
Methyl malonyl chloride

1020

491.2390

931
Benzoyl chloride

1021

495.2462

932
Thiophene-2-carbonyl chloride

1022

501.2066

933
Isonicotinoyl chloride hydrochloride

1023

496.2431

934
Nicotinoyl chloride hydrochloride

1024

496.2466

935
Picolinoyl chloride hydrochloride

1025

496.2476

936
Methanesulfonyl chloride

1026

469.2018

937
Ethanesulfonyl chloride

1027

483.2137

938
Isopropylsulfonyl chloride

1028

497.2370

939
Dimethylsulfamoyl chloride

1029

498.2243

940
Benzenesulfonyl chloride

1030

531.2141

941
1-Methylimidazole-4-sulfonyl chloride

1031

535.2206

942
3-Methylbenzenesulfonyl chloride

1032

545.2297

943
3,5-Dimethylisooxazole-4- sulfonyl chloride

1033

550.2181

944
3-Methoxybenzenesulfonyl chloride

1034

561.2244

945
4-Methoxybenzenesulfonyl chloride

1035

561.2260

946
3,4- Dimethoxybenzenesulfonyl chloride

1036

591.2353

947
Ethyl isothiocyanate

1037

478.2372

948
Pentyl isocyanate

1038

504.3038

949
Phenyl isocyanate

1039

510.2595

950
Phenyl isothiocyanate

1040

526.2362

951
3-Pyridyl isothiocyanate

1041

527.2310

952
Cyclohexyl isothiocyanate

1042

532.2814

953
2-Oxo-1- imidazolidinecarbonyl chloride

1043

503.2503

954
1-Naphthyl isocyanate

1044

560.2722

955
2-Morpholinoethyl isothiocyanate

1045

563.2881

Examples 956-981

[1516] Part A

[1517] 1-(4-Amino-7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol (2.62 g, 6.67 mmol) and 3-(N-tert-butoxycarbonylaminomethyl)phenylboronic acid (2.0 g, 8.0 mmol) were coupled according to the procedure described in Part J of Example 1. Palladium (II) acetate was added as a 5 mg/mL solution in toluene. The reaction was heated for four hours, and the work-up procedure described in Examples 125-135 was followed. The crude product was purified by HPFC (eluting with chloroform:CMA in a gradient from 100:0 to 80:20) to provide 2.94 g of tert-butyl {3-[4-amino-2-ethoxymethyl-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]benzyl}carbamate as a white solid.

[1518] Part B

[1519] Hydrogen chloride (30 mL of a 3 M solution in ethanol) was added to the material from Part A, and the reaction was heated at reflux for 30 minutes. A precipitate formed. Diethyl ether was added, and the precipitate was isolated by filtration, washed with diethyl ether, and air-dried to provide an off-white solid. The solid was partitioned between 2 M aqueous sodium carbonate, brine, and chloroform. The aqueous layer was extracted with chloroform. The combined organic fractions were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by HPFC (eluting with chloroform:CMA in a gradient from 100:0 to 50:50). The resulting white solid was recrystallized from acetonitrile, isolated by filtration, washed with cold acetonitrile, and air-dried to provide 1.7 g of 1-[4-amino-7-(3-aminomethylphenyl)-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol as a white solid.

[1520] Part C

[1521] A reagent from the table below, (0.11 mmol, 1.1 equivalents) was added to a test tube containing a solution of 1-[4-amino-7-(3-aminomethylphenyl)-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol (40 mg, 0.097 mmol) and N,N-diisopropylethylamine (0.022 mL, 0.12 mmol, 1.25 equivalents) in chloroform (2 mL). The test tube was capped and placed on a shaker at ambient temperature overnight. The solvent was removed by vacuum centrifugation. The products were purified by prep HPLC according to the methods described above. The table below shows the reagent used for each example, the structure of the resulting compound, and the observed accurate mass for the isolated trifluoroacetate salt.

Examples 956-981

[1522]

1046

Measured

Example
Reagent
R
Mass (M + H)

956
None

1047

420.2386

957
Acetyl chloride

1048

462.2499

958
Cyclopropanecarbonyl chloride

1049

488.2661

959
3-Furoyl chloride

1050

514.2431

960
Benzoyl chloride

1051

524.2619

961
Cyclopentylacetyl

1052

530.3090

962
Hydrocinnamoyl chloride

1053

552.2921

963
3-Methoxybenzoyl chloride

1054

554.2740

964
Ethanesulfonyl chloride

1055

512.2318

965
Isopropylsulfonyl chloride

1056

526.2449

966
Dimethylsulfamoyl chloride

1057

527.2409

967
Trifluoromethanesulfonyl chloride

1058

552.1876

968
Benzenesulfonyl chloride

1059

560.2306

969
1-Methylimidazole-4- sulfonyl chloride

1060

564.2360

970
3-Methylbenzenesulfonyl chloride

1061

574.2455

971
3-Fluorobenzenesulfonyl chloride

1062

578.2197

972
3-Cyanobenzenesulfonyl chloride

1063

585.2266

973
3- Methoxybenzenesulfonyl chloride

1064

590.2421

974
8-Quinolinesulfonyl chloride

1065

611.2408

975
Ethyl isocyanate

1066

491.2751

976
N,N-Dimethylcarbamoyl chloride

1067

491.2740

977
Benzyl isocyanate

1068

553.2889

978
m-Tolyl isocyanate

1069

553.2903

979
2-Tetrahydrofurfuryl isothiocyanate

1070

563.2772

980
2-Oxo-1- imidazolidinecarbonyl chloride

1071

532.2656

981
3-Methoxyphenyl isocyanate

1072

569.2869

Examples 982-1020

[1523] 7-Bromo-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine was coupled with the appropriate boronic acid or boronic acid ester according to the procedure described in Examples 20-65. The products were purified by prep HPLC according to the methods described above. The table below shows the structure of the compound obtained in each example and the observed accurate mass for the isolated trifluoroacetate salt.

Examples 982-1020

[1524]

1073

Measured Mass

Example
R
(M + H)

982

1074

317.1781

983

1075

318.1737

984

1076

323.1358

985

1077

323.1355

986

1078

331.1947

987

1079

331.1948

988

1080

331.1940

989

1081

333.1740

990

1082

333.1720

991

1083

342.1749

992

1084

343.1926

993

1085

345.2101

994

1086

345.2080

995

1087

347.1886

996

1088

351.1398

997

1089

351.1399

998

1090

353.1572

999

1091

359.1885

1000

1092

359.1897

1001

1093

359.1907

1002

1094

360.1859

1003

1095

361.2050

1004

1096

416.2472

1005

1097

363.1660

1006

1098

375.2195

1007

1099

375.2171

1008

1100

377.2009

1009

1101

377.2013

1010

1102

410.1660

1011

1103

410.1689

1012

1104

374.2006

1013

1105

346.2040

1014

1106

414.2326

1015

1107

416.2472

1016

1108

390.1950

1017

1109

402.2324

1018

1110

428.2479

1019

1111

413.2098

1020

1112

402.2303

CYTOKINE INDUCTION IN HUMAN CELLS

[1525] Many compounds of the invention have been found to modulate cytokine biosynthesis by inducing the production of interferon a and/or tumor necrosis factor a when tested using the method described below. Particular examples include but are not limited to the compounds of Examples 1-10, 12, 16, 18-21, 24-31, 43, 44, 51, 54, 55, 63, 66-101, 103-117, 119, 121-203, 205-390, 392-400, 403-407, 409-412, 414-418, 420, 425, 426, 428, 430-440, 442-446, 464-466, 468, 472-474, 476, 493, 494, 508-663, 807-830, 832-837, 839-841, 843, 844, 847-849, 852, 856, 858, 860-916, and 922-955.

[1526] An in vitro human blood cell system is used to assess cytokine induction. Activity is based on the measurement of interferon and tumor necrosis factor (α) (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 ofLeukocyte Biology, 58, 365-372 (September, 1995).

[1527] Blood Cell Preparation for Culture

[1528] Whole blood from healthy human donors is collected by venipuncture into EDTA vacutainer tubes. Peripheral blood mononuclear cells (PBMC) are separated from whole blood by density gradient centrifugation using HISTOPAQUE-1077. Blood is diluted 1:1 with Dulbecco's Phosphate Buffered Saline (DPBS) or Hank's Balanced Salts Solution (HBSS). The PBMC layer is collected and washed twice with DPBS or HBSS and resuspended at 4×106 cells/mL in RPMI complete. The PBMC suspension is added to 48 well flat bottom sterile tissue culture plates (Costar, Cambridge, Mass. or Becton Dickinson Labware, Lincoln Park, N.J.) containing an equal volume of RPMI complete media containing test compound.

[1529] Compound Preparation

[1530] The compounds are solubilized in dimethyl sulfoxide (DMSO). The DMSO concentration should not exceed a final concentration of 1% for addition to the culture wells. The compounds are generally tested at concentrations ranging from 30-0.014 μM.

[1531] Incubation

[1532] The solution of test compound is added at 60 μM to the first well containing RPMI complete and serial 3 fold dilutions are made in the wells. The PBMC suspension is then added to the wells in an equal volume, bringing the test compound concentrations to the desired range (30-0.014 μM). The final concentration of PBMC suspension is 2×106 cells/mL. The plates are covered with sterile plastic lids, mixed gently and then incubated for 18 to 24 hours at 37° C. in a 5% carbon dioxide atmosphere.

[1533] Separation

[1534] Following incubation the plates are centrifuged for 10 minutes at 1000 rpm (approximately 200×g) at 4° C. The cell-free culture supernatant is removed with a sterile polypropylene pipet and transferred to sterile polypropylene tubes. Samples are maintained at −30 to −70° C. until analysis. The samples are analyzed for interferon (α) by ELISA and for tumor necrosis factor (α) by ELISA or IGEN Assay.

[1535] Interferon (α) and Tumor Necrosis Factor (α) Analysis by ELISA

[1536] Interferon (α) concentration is determined by ELISA using a Human Multi-Species kit from PBL Biomedical Laboratories, New Brunswick, N.J. Results are expressed in pg/mL.

[1537] Tumor necrosis factor (α) (TNF) concentration is determined using ELISA kits available from Biosource International, Camarillo, Calif. Alternately, the TNF concentration can be determined by ORIGEN M-Series Immunoassay and read on an IGEN M-8 analyzer from IGEN International, Gaithersburg, Md. The immunoassay uses a human TNF capture and detection antibody pair from Biosource International, Camarillo, Calif. Results are expressed in pg/mL.

TNF-α INHIBITION IN MOUSE CELLS

[1538] Certain compounds of the invention have been found to modulate cytokine biosynthesis by inhibiting production of tumor necrosis factor α (TNF-α) when tested using the method described below. Particular examples include but are not limited to the compounds of Examples 14, 15, and 481.

[1539] The mouse macrophage cell line Raw 264.7 is used to assess the ability of compounds to inhibit tumor necrosis factor-α (TNF-α) production upon stimulation by lipopolysaccharide (LPS).

[1540] Single Concentration Assay:

[1541] Blood Cell Preparation for Culture

[1542] Raw cells (ATCC) are harvested by gentle scraping and then counted. The cell suspension is brought to 3×105 cells/mL in RPMI with 10% fetal bovine serum (FBS). Cell suspension (100 μL) is added to 96-well flat bottom sterile tissues culture plates (Becton Dickinson Labware, Lincoln Park, N.J.). The final concentration of cells is 3×104 cells/well. The plates are incubated for 3 hours. Prior to the addition of test compound the medium is replaced with colorless RPMI medium with 3% FBS.

[1543] Compound Preparation

[1544] The compounds are solubilized in dimethyl sulfoxide (DMSO). The DMSO concentration should not exceed a final concentration of 1% for addition to the culture wells. Compounds are tested at 5 μM. LPS (Lipopolysaccaride from Salmonella typhimurium, Sigma-Aldrich) is diluted with colorless RPMI to the EC70 concentration as measured by a dose response assay.

[1545] Incubation

[1546] A solution of test compound (1 μl) is added to each well. The plates are mixed on a microtiter plate shaker for 1 minute and then placed in an incubator. Twenty minutes later the solution of LPS (1 μL, EC70 concentration ˜10 ng/ml) is added and the plates are mixed for 1 minute on a shaker. The plates are incubated for 18 to 24 hours at 37° C. in a 5% carbon dioxide atmosphere.

[1547] TNF-α Analysis

[1548] Following the incubation the supernatant is removed with a pipet. TNF-α concentration is determined by ELISA using a mouse TNF-α kit (from Biosource International, Camarillo, Calif.). Results are expressed in pg/mL. TNF-α expression upon LPS stimulation alone is considered a 100% response.

[1549] Dose Response Assay:

[1550] Blood Cell Preparation for Culture

[1551] Raw cells (ATCC) are harvested by gentle scraping and then counted. The cell suspension is brought to 4×105 cells/mL in RPMI with 10% FBS. Cell suspension (250 μL) is added to 48-well flat bottom sterile tissues culture plates (Costar, Cambridge, Mass.). The final concentration of cells is 1×105 cells/well. The plates are incubated for 3 hours. Prior to the addition of test compound the medium is replaced with colorless RPMI medium with 3% FBS.

[1552] Compound Preparation

[1553] The compounds are solubilized in dimethyl sulfoxide (DMSO). The DMSO concentration should not exceed a final concentration of 1% for addition to the culture wells. Compounds are tested at 0.03, 0.1, 0.3, 1, 3, 5 and 10 μM. LPS (Lipopolysaccaride from Salmonella typhimurium, Sigma-Aldrich) is diluted with colorless RPMI to the EC70 concentration as measured by dose response assay.

[1554] Incubation

[1555] A solution of test compound (200 μl) is added to each well. The plates are mixed on a microtiter plate shaker for 1 minute and then placed in an incubator. Twenty minutes later the solution of LPS (200 μL, EC70 concentration ˜10 ng/ml) is added and the plates are mixed for 1 minute on a shaker. The plates are incubated for 18 to 24 hours at 37° C. in a 5% carbon dioxide atmosphere.

[1556] TNF-α Analysis

[1557] Following the incubation the supernatant is removed with a pipet. TNF-α concentration is determined by ELISA using a mouse TNF-α kit (from Biosource International, Camarillo, Calif.). Results are expressed in pg/mL. TNF-α expression upon LPS stimulation alone is considered a 100% response.

[1558] Exemplary Compounds

[1559] Certain exemplary compounds, including some of those described above in the Examples, have the following Formula (XLV) wherein R1, R2, and R3 are defined immediately below.

1113

[1560] R1 substituents:

[1561] 4-methanesulfonylaminobutyl (as shown with only a portion of the ring system)

1114

[1562] 2-hydroxy-2-methylpropyl (as shown with only a portion of the ring system)

1115

[1563] 2-methylpropyl (as shown with only a portion of the ring system)

1116

[1564] 2-methanesulfonylamino-2-methylpropyl (as shown with only a portion of the ring system)

1117

[1565] 3-methoxypropyl (as shown with only a portion of the ring system)

1118

[1566] 2-[3-(1-methylethyl)ureido]ethyl (as shown with only a portion of the ring system)

1119

[1567] R2 substituents:

[1568] ethoxymethyl (as shown with only a portion of the ring system)

1120

[1569] methoxymethyl (as shown with only a portion of the ring system)

1121

[1570] ethyl (as shown with only a portion of the ring system)

1122

[1571] hydrogen (as shown with only a portion of the ring system)

1123

[1572] 2-methoxyethyl (as shown with only a portion of the ring system)

1124

[1573] R3 substituents:

[1574] pyridin-3-yl (as shown attached to the ring system)

1125

[1575] 5-hydroxymethylpyridin-3-yl (as shown attached to the ring system)

1126

[1576] pyridin-4-yl (as shown attached to the ring system)

1127

[1577] 2-ethoxyphenyl (as shown attached to the ring system)

1128

[1578] 3-(morpholine-4-carbonyl)phenyl (as shown attached to the ring system)

1129

[1579] Certain exemplary compounds have the above Formula (XLV) and the following substituents, wherein each line of the table represents a specific compound.

74R1R2R34-methanesulfonylaminobutylethoxymethylpyridin-3-yl4-methanesulfonylaminobutylethoxymethyl5-hydroxymethylpyridin-3-yl4-methanesulfonylaminobutylethoxymethylpyridin-4-yl4-methanesulfonylaminobutylethoxymethyl2-ethoxyphenyl4-methanesulfonylaminobutylethoxymethyl3-(morpholine-4-carbonyl)phenyl4-methanesulfonylaminobutylmethoxymethylpyridin-3-yl4-methanesulfonylaminobutylmethoxymethyl5-hydroxymethylpyridin-3-yl4-methanesulfonylaminobutylmethoxymethylpyridin-4-yl4-methanesulfonylaminobutylmethoxymethyl2-ethoxyphenyl4-methanesulfonylaminobutylmethoxymethyl3-(morpholine-4-carbonyl)phenyl4-methanesulfonylaminobutylethylpyridin-3-yl4-methanesulfonylaminobutylethyl5-hydroxymethylpyridin-3-yl4-methanesulfonylaminobutylethylpyridin-4-yl4-methanesulfonylaminobutylethyl2-ethoxyphenyl4-methanesulfonylaminobutylethyl3-(morpholine-4-carbonyl)phenyl4-methanesulfonylaminobutylhydrogenpyridin-3-yl4-methanesulfonylaminobutylhydrogen5-hydroxymethylpyridin-3-yl4-methanesulfonylaminobutylhydrogenpyridin-4-yl4-methanesulfonylaminobutylhydrogen2-ethoxyphenyl4-methanesulfonylaminobutylhydrogen3-(morpholine-4-carbonyl)phenyl4-methanesulfonylaminobutyl2-methoxyethylpyridin-3-yl4-methanesulfonylaminobutyl2-methoxyethyl5-hydroxymethylpyridin-3-yl4-methanesulfonylaminobutyl2-methoxyethylpyridin-4-yl4-methanesulfonylaminobutyl2-methoxyethyl2-ethoxyphenyl4-methanesulfonylaminobutyl2-methoxyethyl3-(morpholine-4-carbonyl)phenyl2-hydroxy-2-methylpropylethoxymethylpyridin-3-yl2-hydroxy-2-methylpropylethoxymethyl5-hydroxymethylpyridin-3-yl2-hydroxy-2-methylpropylethoxymethylpyridin-4-yl2-hydroxy-2-methylpropylethoxymethyl2-ethoxyphenyl2-hydroxy-2-methylpropylethoxymethyl3-(morpholine-4-carbonyl)phenyl2-hydroxy-2-methylpropylmethoxymethylpyridin-3-yl2-hydroxy-2-methylpropylmethoxymethyl5-hydroxymethylpyridin-3-yl2-hydroxy-2-methylpropylmethoxymethylpyridin-4-yl2-hydroxy-2-methylpropylmethoxymethyl2-ethoxyphenyl2-hydroxy-2-methylpropylmethoxymethyl3-(morpholine-4-carbonyl)phenyl2-hydroxy-2-methylpropylethylpyridin-3-yl2-hydroxy-2-methylpropylethyl5-hydroxymethylpyridin-3-yl2-hydroxy-2-methylpropylethylpyridin-4-yl2-hydroxy-2-methylpropylethyl2-ethoxyphenyl2-hydroxy-2-methylpropylethyl3-(morpholine-4-carbonyl)phenyl2-hydroxy-2-methylpropylhydrogenpyridin-3-yl2-hydroxy-2-methylpropylhydrogen5-hydroxymethylpyridin-3-yl2-hydroxy-2-methylpropylhydrogenpyridin-4-yl2-hydroxy-2-methylpropylhydrogen2-ethoxyphenyl2-hydroxy-2-methylpropylhydrogen3-(morpholine-4-carbonyl)phenyl2-hydroxy-2-methylpropyl2-methoxyethylpyridin-3-yl2-hydroxy-2-methylpropyl2-methoxyethyl5-hydroxymethylpyridin-3-yl2-hydroxy-2-methylpropyl2-methoxyethylpyridin-4-yl2-hydroxy-2-methylpropyl2-methoxyethyl2-ethoxyphenyl2-hydroxy-2-methylpropyl2-methoxyethyl3-(morpholine-4-carbonyl)phenyl2-methylpropylethoxymethylpyridin-3-yl2-methylpropylethoxymethyl5-hydroxymethylpyridin-3-yl2-methylpropylethoxymethylpyridin-4-yl2-methylpropylethoxymethyl2-ethoxyphenyl2-methylpropylethoxymethyl3-(morpholine-4-carbonyl)phenyl2-methylpropylmethoxymethylpyridin-3-yl2-methylpropylmethoxymethyl5-hydroxymethylpyridin-3-yl2-methylpropylmethoxymethylpyridin-4-yl2-methylpropylmethoxymethyl2-ethoxyphenyl2-methylpropylmethoxymethyl3-(morpholine-4-carbonyl)phenyl2-methylpropylethylpyridin-3-yl2-methylpropylethyl5-hydroxymethylpyridin-3-yl2-methylpropylethylpyridin-4-yl2-methylpropylethyl2-ethoxyphenyl2-methylpropylethyl3-(morpholine-4-carbonyl)phenyl2-methylpropylhydrogenpyridin-3-yl2-methylpropylhydrogen5-hydroxymethylpyridin-3-yl2-methylpropylhydrogenpyridin-4-yl2-methylpropylhydrogen2-ethoxyphenyl2-methylpropylhydrogen3-(morpholine-4-carbonyl)phenyl2-methylpropyl2-methoxyethylpyridin-3-yl2-methylpropyl2-methoxyethyl5-hydroxymethylpyridin-3-yl2-methylpropyl2-methoxyethylpyridin-4-yl2-methylpropyl2-methoxyethyl2-ethoxyphenyl2-methylpropyl2-methoxyethyl3-(morpholine-4-carbonyl)phenyl2-methanesulfonylamino-2-ethoxymethylpyridin-3-ylmethylpropyl2-methanesulfonylamino-2-ethoxymethyl5-hydroxymethylpyridin-methylpropyl3-yl2-methanesulfonylamino-2-ethoxymethylpyridin-4-ylmethylpropyl2-methanesulfonylamino-2-ethoxymethyl2-ethoxyphenylmethylpropyl2-methanesulfonylamino-2-ethoxymethyl3-(morpholine-4-methylpropylcarbonyl)phenyl2-methanesulfonylamino-2-methoxymethylpyridin-3-ylmethylpropyl2-methanesulfonylamino-2-methoxymethyl5-hydroxymethylpyridin-methylpropyl3-yl2-methanesulfonylamino-2-methoxymethylpyridin-4-ylmethylpropyl2-methanesulfonylamino-2-methoxymethyl2-ethoxyphenylmethylpropyl2-methanesulfonylamino-2-methoxymethyl3-(morpholine-4-methylpropylcarbonyl)phenyl2-methanesulfonylamino-2-ethylpyridin-3-ylmethylpropyl2-methanesulfonylamino-2-ethyl5-hydroxymethylpyridin-methylpropyl3-yl2-methanesulfonylamino-2-ethylpyridin-4-ylmethylpropyl2-methanesulfonylamino-2-ethyl2-ethoxyphenylmethylpropyl2-methanesulfonylamino-2-ethyl3-(morpholine-4-methylpropylcarbonyl)phenyl2-methanesulfonylamino-2-hydrogenpyridin-3-ylmethylpropyl2-methanesulfonylamino-2-hydrogen5-hydroxymethylpyridin-methylpropyl3-yl2-methanesulfonylamino-2-hydrogenpyridin-4-ylmethylpropyl2-methanesulfonylamino-2-hydrogen2-ethoxyphenylmethylpropyl2-methanesulfonylamino-2-hydrogen3-(morpholine-4-methylpropylcarbonyl)phenyl2-methanesulfonylamino-2-2-methoxyethylpyridin-3-ylmethylpropyl2-methanesulfonylamino-2-2-methoxyethyl5-hydroxymethylpyridin-methylpropyl3-yl2-methanesulfonylamino-2-2-methoxyethylpyridin-4-ylmethylpropyl2-methanesulfonylamino-2-2-methoxyethyl2-ethoxyphenylmethylpropyl2-methanesulfonylamino-2-2-methoxyethyl3-(morpholine-4-methylpropylcarbonyl)phenyl3-methoxypropylethoxymethylpyridin-3-yl3-methoxypropylethoxymethyl5-hydroxymethylpyridin-3-yl3-methoxypropylethoxymethylpyridin-4-yl3-methoxypropylethoxymethyl2-ethoxyphenyl3-methoxypropylethoxymethyl3-(morpholine-4-carbonyl)phenyl3-methoxypropylmethoxymethylpyridin-3-yl3-methoxypropylmethoxymethyl5-hydroxymethylpyridin-3-yl3-methoxypropylmethoxymethylpyridin-4-yl3-methoxypropylmethoxymethyl2-ethoxyphenyl3-methoxypropylmethoxymethyl3-(morpholine-4-carbonyl)phenyl3-methoxypropylethylpyridin-3-yl3-methoxypropylethyl5-hydroxymethylpyridin-3-yl3-methoxypropylethylpyridin-4-yl3-methoxypropylethyl2-ethoxyphenyl3-methoxypropylethyl3-(morpholine-4-carbonyl)phenyl3-methoxypropylhydrogenpyridin-3-yl3-methoxypropylhydrogen5-hydroxymethylpyridin-3-yl3-methoxypropylhydrogenpyridin-4-yl3-methoxypropylhydrogen2-ethoxyphenyl3-methoxypropylhydrogen3-(morpholine-4-carbonyl)phenyl3-methoxypropyl2-methoxyethylpyridin-3-yl3-methoxypropyl2-methoxyethyl5-hydroxymethylpyridin-3-yl3-methoxypropyl2-methoxyethylpyridin-4-yl3-methoxypropyl2-methoxyethyl2-ethoxyphenyl3-methoxypropyl2-methoxyethyl3-(morpholine-4-carbonyl)phenyl2-[3-(1-ethoxymethylpyridin-3-ylmethylethyl)ureido]ethyl2-[3-(1-ethoxymethyl5-hydroxymethylpyridin-methylethyl)ureido]ethyl3-yl2-[3-(1-ethoxymethylpyridin-4-ylmethylethyl)ureido]ethyl2-[3-(1-ethoxymethyl2-ethoxyphenylmethylethyl)ureido]ethyl2-[3-(1-ethoxymethyl3-(morpholine-4-methylethyl)ureido]ethylcarbonyl)phenyl2-[3-(1-methoxymethylpyridin-3-ylmethylethyl)ureido]ethyl2-[3-(1-methoxymethyl5-hydroxymethylpyridin-methylethyl)ureido]ethyl3-yl2-[3-(1-methoxymethylpyridin-4-ylmethylethyl)ureido]ethyl2-[3-(1-methoxymethyl2-ethoxyphenylmethylethyl)ureido]ethyl2-[3-(1-methoxymethyl3-(morpholine-4-methylethyl)ureido]ethylcarbonyl)phenyl2-[3-(1-ethylpyridin-3-ylmethylethyl)ureido]ethyl2-[3-(1-ethyl5-hydroxymethylpyridin-methylethyl)ureido]ethyl3-yl2-[3-(1-ethylpyridin-4-ylmethylethyl)ureido]ethyl2-[3-(1-ethyl2-ethoxyphenylmethylethyl)ureido]ethyl2-[3-(1-ethyl3-(morpholine-4-methylethyl)ureido]ethylcarbonyl)phenyl2-[3-(1-hydrogenpyridin-3-ylmethylethyl)ureido]ethyl2-[3-(1-hydrogen5-hydroxymethylpyridin-methylethyl)ureido]ethyl3-yl2-[3-(1-hydrogenpyridin-4-ylmethylethyl)ureido]ethyl2-[3-(1-hydrogen2-ethoxyphenylmethylethyl)ureido]ethyl2-[3-(1-hydrogen3-(morpholine-4-methylethyl)ureido]ethylcarbonyl)phenyl2-[3-(1-2-methoxyethylpyridin-3-ylmethylethyl)ureido]ethyl2-[3-(1-2-methoxyethyl5-hydroxymethylpyridin-methylethyl)ureido]ethyl3-yl2-[3-(1-2-methoxyethylpyridin-4-ylmethylethyl)ureido]ethyl2-[3-(1-2-methoxyethyl2-ethoxyphenylmethylethyl)ureido]ethyl2-[3-(1-2-methoxyethyl3-(morpholine-4-methylethyl)ureido]ethylcarbonyl)phenyl

[1580] The complete disclosures of the patents, patent documents, and publications cited herein are incorporated by reference in their entirety as if each were individually incorporated. Various modifications and alterations to this invention will become apparent to those skilled in the art without departing from the scope and spirit of this invention. It should be understood that this invention is not intended to be unduly limited by the illustrative embodiments and examples set forth herein and that such examples and embodiments are presented by way of example only with the scope of the invention intended to be limited only by the claims set forth herein as follows.

	Number	Date	Country
	60435889	Dec 2002	US
	60516331	Oct 2003	US

Aryl substituted imidazoquinolines

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