MX2008004012A

MX2008004012A - METHOD FOR 1H-IMIDAZO[4,5-c]PYRIDINES AND ANALOGS THEREOF

Info

Publication number: MX2008004012A
Application number: MXMX/A/2008/004012A
Authority: MX
Inventors: Sonja S Mackey; Larry R Krepski; Gregory J Marszalek; John F Gerster
Original assignee: 3M Innovative Properties Company; John F Gerster; Larry R Krepski; Sonja S Mackey; Gregory J Marszalek
Priority date: 2005-09-23
Filing date: 2008-03-24
Publication date: 2008-09-02

Abstract

Methods and intermediates for preparing compounds of the Formulas:(I and X) are disclosed. The methods include a method providing a compound of the Formula:(IV) and converting a compound of Formula IV to a compound of Formula I, a method providing a compound of the Formula:(VIII) and converting a compound of Formula VIII to a compound of Formula I, and a method providing a compound of the Formula:(XI) and converting a compound of Formula XI to a compound of Formula I.

Description

METHOD FOR IH-IMIDAZO d-cIPIRIDINAS AND ANALOGS OF THE SAME INTERREFERENCE WITH RELATED REQUESTS This request claims the priority of the provisional application of EE. UU Serial No. 60/720171, filed on September 23, 2005, and the provisional application of EE. UU Serial No. 60/743505, filed March 16, 2006, both incorporated herein by reference.

BACKGROUND OF THE INVENTION It has been found that some compounds are useful as modifiers of the immune response (MRI's), making them useful in the treatment of a variety of disorders. However, the interest and need for compounds that have the ability to modulate the immune response, by induction of cytokine biosynthesis or other mechanisms, continues. Thus, there is a need for methods and intermediates to prepare said compounds.

BRIEF DESCRIPTION OF THE INVENTION It has now been found that some 1H-imidazo [4,5-c] pyridines and analogs thereof, or pharmaceutically acceptable salts thereof, can be prepared by a method comprising: providing a compound of formula IV: IV and reacting the compound of formula IV with an amine of the formula R- | NH 2 to provide a 1H-imidazo [4,5-c] pyridine or analogue thereof of the formula I: RA "i I or a pharmaceutically acceptable salt thereof; where E, L, R-i, R2, RA, and B are as defined below. In another embodiment, some 1H-.midazo [4,5-c] pyridines and analogs thereof, or pharmaceutically acceptable salts thereof, may be prepared by a method comprising: providing a compound of formula VIII: VIII and reacting the compound of formula VIII with an amine of the formula R-? NH2 to provide a 1 / - / - imidazo [4,5-c] pyridine or analogue thereof of the formula I: I or a pharmaceutically acceptable salt thereof; where E, L, R-i, R2, R-11, R-? 2, RA and B are as defined below. In another embodiment, some 1 / - / - imidazo [4,5-c] pyridines and analogs thereof, or pharmaceutically acceptable salts thereof, can be prepared by a method comprising: providing a compound of formula XI : XI and forming a 1H-imidazo [4,5-c] pyridine or analogue thereof of formula I: I or a pharmaceutically acceptable salt thereof; where E, L, RL R2, RA and RB are as defined below. The compounds and salts of formula I are useful for preparing immune modifier compounds of the following formula X: X or pharmaceutically acceptable salts thereof, wherein Ri, R2, RA, and RB are as defined below. It is known that the compounds and salts of formula X are useful as modifiers of the immune response due to their ability to induce or inhibit cytokine biosynthesis (for example it induces or inhibits the biosynthesis of at least one cytokine), or modulate another way the immune response when administered to animals. This makes these compounds and salts useful in the treatment of a variety of conditions such as viral diseases and tumors that are sensitive to such changes in the immune response. In one embodiment, a method is provided that includes: providing a compound of formula IV: IV reacting the compound of formula IV with an amine of formula R- | NH 2 to provide a 1 - / - imidazo [4,5-c] pyridine or analogue thereof of formula I: I or a pharmaceutically acceptable salt thereof; and converting E to an amino group in the compound of formula I, to provide a compound (1 / - / - midazo [4,5-c] pyridin-4-amine or analog thereof) of formula X: X or a pharmaceutically acceptable salt thereof; where E, L, R-i, R2, RA, and RB are as defined below. In another aspect, the invention provides intermediates useful in the preparation of immune response modifiers. In one modality, provides a compound of formula XI: where E, L, Ri, RA, and RB are as defined below. As used herein, "a", "an", "the", or "the", "at least one", and "one or more", are used interchangeably. The term "comprises" and its variations do not have a limiting meaning when these terms appear in the description and the claims. The above brief description of the present invention does not describe each disclosed embodiment or each embodiment of the present invention. The description that follows exemplifies more particularly illustrative modalities. In several parts throughout the description a guide is given by lists of examples; These examples can be used in various combinations. In each case, the aforementioned list serves only as a representative group and should not be considered as an exclusive list.

DETAILED DESCRIPTION OF THE ILLUSTRATIVE MODALITIES OF THE INVENTION The present invention provides methods and intermediates for preparing some 1H-imidazo [4,5-c] pyridines and analogues thereof of the formula I: or pharmaceutically acceptable salts thereof; which are useful for preparing 1 / - / - imidazo [4,5-c] pyridin-4-amine compounds or analogs thereof of formula X: X or pharmaceutically acceptable salts thereof; where E, R-i, R2, RA, and RB are as defined below. In one embodiment, a method (i) is provided comprising: providing a compound of formula IV: IV and reacting the compound of formula IV with an amine of the formula R1NH2 to provide a 1 / - / - imidazo [4,5-c] pyridine or analogue of the same formula I or a pharmaceutically acceptable salt thereof; wherein: E is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, iodine, hydroxy, phenoxy, -OS (O) 2 -R 'and -N (Bn) 2, wherein R' is selected from the group which consists of alkyl, haloalkyl and aryl optionally substituted with alkyl, halogen or nitro, and Bn is selected from the group consisting of benzyl, p-methoxybenzyl, p-methylbenzyl, and 2-furanylmethyl; or E is attached to the adjacent nitrogen atom of pyridine of formulas I and IV to form the fused tetrazolo ring of formulas 1-1 and IV-1: 1-1 IV-1 L is selected from the group consisting of fluorine, chlorine, bromine, iodine, phenoxy, and -OS (O) 2-R ', wherein R' is selected from the group consisting of alkyl, haloalkyl and aryl optionally substituted with alkyl, halogen or nitro; RA and RB are independently selected from the group consisting of: hydrogen, halogen, alkyl, alkenyl, alkoxy, alkylthio, and -N (R9) 2; or RA and RB taken together form a fused benzene ring or a fused pyridine ring, wherein the benzene ring or the pyridine ring is unsubstituted or substituted with a group R, or is substituted with a group R3, or is substituted with a group R and a group R3; or RA and RB taken together form a 5 to 7 membered fused saturated ring optionally containing a nitrogen atom, wherein the fused ring is unsubstituted or is substituted with one or more groups R; R is selected from the group consisting of: halogen, hydroxy, alkyl, alkenyl, haloalkyl, alkoxy, alkylthio, and -N (R9) 2; Ri is selected from the group consisting of: -R4, -X-R4, -XY-R4, -XYXY-R4, -X-Rs, -N (R1 ') - Q-R4, -NYR ^ JX YR ,, and -NÍR JX Rsb; R2 is selected from the group consisting of: -R, -X-R4, -X-Y-R4, and -X-R5; R3 is selected from the group consisting of: -Z-R4, -Z-X-R4, -Z-X-Y-R4, -Z-X-Y-X-Y-R4, and -Z-X-R5; X is selected from the group consisting of alkylene, alkenylene, alkynylene, arylene, heteroarylene, and heterocyclylene, wherein optionally the alkylene, alkenylene and alkynylene groups may be interrupted or terminated with arylene, heteroarylene or heterocyclylene, and optionally may be interrupted with one or more groups -O-; Xi is C2-20 alkylene; Y is selected from the group consisting of: -O-, -S (O) 0-2-, -S (O) 2-N (R8) -, -C (R6) -, -OC (R6) -, -OC (O) -O-, -N (R8) -Q-, -OC (R6) -N (R8) -, -C (R6) -N (OR9) -, -ON (R8) -Q- , -ON = C (R4) -, -C (= NO-R8) -, -CH (-N (-0-R8) -Q-R4) -, f N-Q - YI is selected from the group consisting of: -O-, -S (O) 0-2-, -S (O) 2-N (R8) -, -N (R8) -Q-, -C (R6) -N (R8) -, -OC (R6) -N (R8) -, and Z is a bond u -O-; Ri 'is selected from the group consisting of hydrogen, alkyl CL20, C2-20 hydroxy-alkylenyl and C2-2alkoxy-alkylenyl; R 4 is selected from the group consisting of: hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl, wherein the alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, Aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl and heterocyclyl can be unsubstituted or can be 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, arylalkyloxy, heteroaryl, heteroaryloxy, heteroaplaylealkyloxy, heterocyclyl, amino, alkylamino, dialkylamino, (dialkylamino) alkylenoxy, and in the case of alkyl, alkenyl, alkynyl and heterocyclyl, oxo; R5 is selected from the group consisting of: R5 is selected from the group consisting of: R6 is selected from the group consisting of: = O y = S; R7 is C2-7 'alkylene, R8 is selected from the group consisting of hydrogen, alkyl, alkoxyalkylenyl, hydroxyalkylenyl, arylalkylenyl and heteroarylalkylenyl; Rg is selected from the group consisting of hydrogen and alkyl; R-io is C3-8 alkylene; A is selected from the group consisting of -O-, -C (O) -S (O) 0-2-, and -N (R4) -; A 'is selected from the group consisting of -O-, -S (O) 0-2-, -N (-Q-R4) -y -CH2-; 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-, -C (R6) -S-, and -C (R6) -N (OR9) -; V is selected from the group consisting of: -C (Re) -, -O-, C (R6) -, -N (R8) -C (R6) -, and -S (O) 2-; V is selected from the group consisting of: -O-C (R6) -, -N (R8) -C (R6) -, and -S (O) 2-; W is selected from the group consisting of a bond, -C (O) -, and - S (O) 2-; and a and b are independently integers from 1 to 6, with the proviso that a + b < 7. This ring-forming reaction is unexpected, since group L is displaced without a strong electron-attracting group adjacent to group L. In another embodiment, a method (ii) is provided wherein method (i) above comprises, In addition, the steps of: providing a compound of formula III: and reacting the compound of formula III with a halogenide of carboxylic acid of the formula hal-C (0) -R2, wherein hal is chloro or bromo, or a mixed anhydride or anhydride of the formula O (-C (O) -R2) 2, to provide a compound of formula IV. In another embodiment, a method (iii) is provided, wherein method (ii) above further comprises the steps of: providing a compound of formula II:? II and reducing the compound of formula II to give a compound of formula III. In another embodiment, a method (iv) is provided, wherein method (ii) further comprises the steps of: providing a compound of formula VI: and converting the hydroxy group from position 4 of formula VI into a group L to provide a compound of formula III. In another embodiment, a method (v) is provided, wherein the method (i) further comprises the steps of: providing a compound of the formula VII: VII and converting the hydroxy group from position 4 of formula VII into a group L to provide a compound of formula IV. In another embodiment, a method (vi) is provided, wherein method (v) also comprises the steps of: providing a compound of formula VI: E VI and reacting the compound of formula VI with a carboxylic acid halide of the formula hal-C (O) -R2, wherein hal is chloro or bromo, or a mixed anhydride or anhydride of the formula O (-C (O) -R2) 2, to give a compound of Formula VII. In other embodiments, a method (vii) or (viii) is provided, wherein method (iv) or (vi), respectively, also comprises the steps of: providing a compound of formula V: V and reducing the compound of formula V to provide a compound of formula VI. In one embodiment, a method (ix) is provided which includes: providing a compound of formula VIII: VIII and reacting the compound of formula VIII with an amine of the formula R- | NH2 to give a 1 / - / - imidazo [4,5-c] pyridine or analogue thereof of the formula I: I or a pharmaceutically acceptable salt thereof; wherein: E is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, iodine, hydroxy, phenoxy, -OS (O) 2 -R 'and -N (Bn) 2, wherein R' is selected from the group which consists of alkyl, haloalkyl and aryl optionally substituted with alkyl, halogen or nitro, and Bn is selected from the group consisting of benzyl, p-methoxybenzyl, p-methylbenzyl, and 2-furanylmethyl; or E is attached to the adjacent nitrogen atom of pyridine of formulas I and VIII to form the fused tetrazolo ring of formulas 1-1 and IX: L is selected from the group consisting of fluorine, chlorine, bromine, iodine, phenoxy, and -OS (0) 2-R ', wherein R' is selected from the group consisting of alkyl, haloalkyl, and aryl optionally substituted with alkyl , halogen or nitro; RA and RB are independently selected from the group that it consists of: hydrogen, halogen, alkyl, alkenyl, alkoxy, alkylthio and -N (R9) 2; or RA and RB taken together form a fused benzene ring or a fused pyridine ring, wherein the benzene ring or the pyridine ring is unsubstituted or substituted with a group R, or is substituted with a group R3, or is substituted with a group R and a group R3; or RA and RB taken together form a saturated fused ring of to 7 members optionally containing a nitrogen atom, wherein the fused ring is unsubstituted or is substituted with one or more groups R; R is selected from the group consisting of: halogen, hydroxy, alkyl, alkenyl, haloalkyl, alkoxy, alkylthio and -N (R9) 2; Ri is selected from the group consisting of: -R4, -X-R4, -X-Y-R4, -X-Y-X-Y-R4, -X-R5, -NYR ^ -Q-R, -NYR ^ -X and R ^ y R2 is hydrogen; R3 is selected from the group consisting of: -Z-R4, -Z-X-R4, -Z-X-Y-R4, -Z-X-Y-X-Y-R4, and -Z-X-R5; X is selected from the group consisting of alkylene, alkenylene, alkynylene, arylene, heteroarylene, and heterocyclylene, wherein optionally the alkylene, alkenylene and alkynylene groups may be interrupted or terminated with arylene, heteroarylene or heterocyclylene, and optionally may be interrupted with one or more groups -O-; X-i is C2.2o alkylene and Y is selected from the group consisting of: -O-, -S (O) o.2", -S (O) 2-N (R8) -, -C (R6) -, -OC (R6) -, -OC (O) -O-, -N (R8) -Q-, -OC (R6) -N (R8) -, -C (R6) -N (OR9) -, -ON (R8) -Q-, -ON = C (R4) - , -C (= NO-R8) -, -CH (-N (-O-R8) -Q-R4) -, Yi is selected from the group consisting of: -O-, -S (O) or-2-, S (O) 2-N (R8) -, -N (R8) -Q-, -C (R6) - N (R8) -, -OC (R6) -N (R8) -, and Z is a bond u -O-; R-i 'is selected from the group consisting of hydrogen, C? 2o alkyl, C2.2o hydroxy-alkylenyl and C2-2alkoxy-alkylenyl; R 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 may be unsubstituted or may be substituted with one or more substituent groups independently selected from the group consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, mercapto, cyano, aryl, aryloxy, arylalkylenoxy, heteroaryl, heteroaryloxy, heteroaplaylealkyloxy, heterocyclyl, amino, alkylamino, dialkylamino, (dialkylamino) alkyleneoxy, and in the case of alkyl, alkenyl, alkynyl, and heterocyclyl, oxo; R is selected from the group consisting of: R5b is selected from the group consisting of: Re is selected from the group consisting of: = 0 y = S; R7 is C2.7 alkylene; R8 is selected from the group consisting of hydrogen, alkyl, alkoxyalkylenyl, hydroxyalkylenyl, arylalkylenyl and heteroarylalkylenyl; R9 is selected from the group consisting of hydrogen and alkyl; R-io is C3.8 alkylene; R11 and R12 are independently C? -4 alkyl, or Rn and R12 together with the nitrogen atom to which they are attached form a 5- or 6-membered ring optionally containing -O-, -N (C1- alkyl) - , or -S-; A is selected from the group consisting of -O-, -C (O) -, -S (O) 0-2- and -N (R4) -; A 'is selected from the group consisting of -O-, -S (O) 0-2-, -N (-Q-R4) - and -CH2-; 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-, -C (R6) -S-, and C (R6) -N (OR9) -; V is selected from the group consisting of -C (R6) -, -O-C (R6) -, -N (R8) -C (R6) -, and S (O) 2-; V is selected from the group consisting of -O-C (R6) -, -N (R8) -C (R6) -, and S (0) 2-; W is selected from the group consisting of a bond, -C (O) -, and -S (O) 2-; and a and b are independently integers from 1 to 6, with the proviso that a + b < 7. This ring-forming reaction is also unexpected, since group L is displaced without a strong electron-attracting group adjacent to group L. In another embodiment, a method (x) is provided where method (ix) above also includes: forming an intermediate of formula XI: XI and then reacting the compound of formula VIII with an amine of the formula R-? NH2. In another modality, a method (xi) is provided where the intermediate of formula (XI) in the above method (x) is isolated after reacting the compound of formula VIII with an amine of the formula R ^ Hz. In other embodiments, a method (xii) or (xiii) is provided wherein the method (ix) or (x) above, respectively, also comprises: providing a compound of the formula VI: VI convert the hydroxy group from position 4 to a group L, and react the amino group from position 3 with a formamide of formula H-C (O) -N (Rn) R? 2 to give a compound of formula VIII. In other embodiments, a method (xiv) or (xv) is provided wherein the compound of formula VIII of method (xii) or (xiii) above, respectively, is provided without being isolated before reacting with an amine of formula R- | NH2. In one embodiment, a method (xvi) is provided which includes: providing a compound of formula XI: XI and form a 1H-imidazo [4,5-c] pyridine or analogue thereof of formula I: or a pharmaceutically acceptable salt thereof; wherein: E is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, iodine, hydroxy, phenoxy, -OS (O) 2 -R 'and -N (Bn) 2, wherein R' is selected from the group which consists of alkyl, haloalkyl, and aryl optionally substituted with alkyl, halogen, or nitro, and Bn is selected from the group consisting of benzyl, p-methoxybenzyl, p-methylbenzyl, and 2-furanylmethyl; or E is linked to the adjacent nitrogen atom of pyridine of formulas I and XI to form the fused tetrazolo ring of formulas 1-1 and XIII: 1-1 XIII L is selected from the group consisting of fluorine, chlorine, bromine, iodine, phenoxy and -OS (O) 2 -R ', wherein R' is selected from the group consisting of alkyl, haloalkyl, and substituted aryl optionally with alkyl, halogen, or nitro; RA and RB are independently selected from the group consisting of: hydrogen, halogen, alkyl, alkenyl, alkoxy, alkylthio, and -N (R9) 2; or RA and RB taken together form a fused benzene ring or a fused pyridine ring, wherein the benzene ring or the pyridine ring is unsubstituted or substituted with a group R, or is substituted with a group R3, or is substituted with a group R and a group R3; or RA and RB taken together form a saturated fused ring of to 7 members which optionally contains a nitrogen atom, wherein the fused ring is unsubstituted or is substituted with one or more groups R; R is selected from the group consisting of: halogen, hydroxy, alkyl, alkenyl, haloalkyl, alkoxy, alkylthio, and -N (R9) 2; R-i is selected from the group consisting of: -R4, -X-R, -X-Y-R4, -X-Y-X-Y-R4, -X-R5, -NKR -Q-R ,, -NKR ^ -X YrR ,, and -NÍR -XrRsb; R2 is hydrogen; R3 is selected from the group consisting of: -Z-R4, -Z-X-R4, -Z-X-Y-R4, -Z-X-Y-X-Y-R4, and -Z-X-R5; X is selected from the group consisting of alkylene, alkenylene, alkynylene, arylene, heteroarylene and heterocyclylene, wherein optionally the alkylene, alkenylene and alkynylene groups may be interrupted or terminated by arylene, heteroarylene or heterocyclylene, and optionally interrupted by one or more groups -OR-; X1 is C2.20 alkylene; Y is selected from the group consisting of: -O-, -S (O) 0-2-, -S (O) 2-N (R8) -, -C (R6) -, -0-C (R6) -, -0-C (O) -0-, -N (R8) -Q-, -0-C (R6) -N (R8) -, -C (R6) -N (OR9) -, -0 -N (R8) -Q-, -0-N = C (R4) -, -C (= N-0-R8) -, -CH (-N (-O-R8) -Q-R4) -, -N-C (Re) -N "- Yi is selected from the group consisting of -O-, -S (O) 0-2-, -S (O) 2-N (R8) -, -N (R8) -Q-, -C (R6) - N (R8) -, -OC (R6) -N (R8) -, and Z is a bond u -O-; R ^ is selected from the group consisting of hydrogen, C1.20 alkyl, C2-22 hydroxy-alkylenyl, and C2-20 alkyloxynyl; R 4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl, wherein the alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl groups , alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl may not be substituted or may be substituted with one or more substituents independently selected from the group consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, mercapto, cyano, aryl, aryloxy, arylalkyloxy, heteroaryl, heteroaryloxy, heteroarylalkylenoxy, heterocyclyl , amino, alkylamino, dialkylamino, (dialkylamino) alkyleneoxy, and in the case of alkyl, alkenyl, alkynyl and heterocyclyl, oxo; R5 is selected from the group consisting of: R5 is selected from the group consisting of: Re is selected from the group consisting of = O y = S; R7 is C2.7 alkylene; R8 is selected from the group consisting of hydrogen, alkyl, alkoxyalkylenyl, hydroxyalkylenyl, arylalkylenyl and heteroarylalkylenyl; Rg is selected from the group consisting of hydrogen and alkyl; R-io is C3-8 alkylene; A is selected from the group consisting of -O-, -C (O) -, -S (O) 0-2-, and -N (R4) -; A 'is selected from the group consisting of -O-, -S (O) 0-2-, -N (-Q-R4) -, and -CH2-; 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-, -C (R6) -S-, and -C (R6) -N (OR9) -; V is selected from the group consisting of -C (R6) -, -O-C (R6) -, -N (R8) -C (R6) -, and -S (O) 2-; V is selected from the group consisting of -O-C (R6) -, -N (R8) -C (R6) -, and -S (O) 2-; W is selected from the group consisting of a bond, -C (O) -, and -S (O) 2-; and a and b are, independently, integers from 1 to 6, with the proviso that a + b < 7. Also, this ring formation reaction is unexpected, since the L group is displaced without a strong electron attractant group adjacent to the group L. In another embodiment a method is provided (xvii) where the method (xvi) above further comprises: providing a compound of formula VI: VI convert the hydroxy group from position 4 to a group L, and react the amino group of position 3 with a formamide of formula H-C (O) -NH (R?), To provide a compound of formula XI. In another embodiment, a method (xviii) is provided wherein the compound of formula XI of method (xvii) above is provided without being isolated, before forming a compound of formula I. In other embodiments, a method (xix) is provided, ( xx), (xxi), (xxii), (xxiii), or (xxiv), where the methods (xii), (xiii), (xiv), (xv), (xvii), or (xviii) above comprise , additionally, providing a compound of formula V: V and reducing the compound of formula V to give a compound of formula VI. In other modalities, a method is provided (i-1), (¡i-1), (¡ii-1), (iv-1), (v-1), (vi-1), (vii-1) ), (viii-1), (ix-1), (x-1), (xi-1), (xii-1), (xiii-1), (xiv-1), (xv-1), (xvi-1), (xvii-1), (xviii-1), (xix-1), (xx-1), (xxi-1), (xxii-1), (xxiii-1), or ( xxiv-1), where methods (i), (ii), (iii), (iv), (v), (vi), (vii), (viii), (ix), (x), ( xi), (xii), (xiii), (xiv), (xv), (xvi), (xvii), (xviii), (xix), (xx), (xxi), (xxii), (xxiii), or (xxiv), respectively, additionally comprise the step of converting E to an amino group in the compound of formula I, to give a compound of formula X: X or a pharmaceutically acceptable salt thereof. In other modalities, a method is provided (i-2), (ii-2), (iii-2), (iv-2), (v-2), (vi-2), (vii-2), (viii-2), (ix-2), (x-2), (xi-2), (xii-2), (xiii-2), (xiv-2), (xv-2), (xvi -2), (xvii-2), (xviii-2), (xix-2), (xx-2), (xxi-2), (xxii-2), (xxiii-2), or (xxiv-) 2), where E in the method (i-1), (¡i-1), (iii-1), (iv-1), (v-1), (vi-1), (vii-1) ), (viii-1), (ix-1), (x-1), (xi-1), (xii-1), (xii¡-1), (xiv-1), (xv-1) , (xvi-1), (xvii-1), (xviii-1), (xix-1), (xx-1), (xxi-1), (xxii-1), (xxiii- 1), or (xxiv-1), is hydrogen, the compound of formula I is of formula I-2: I-2 and the step of converting the hydrogen to an amino group in the compound of formula I-2 comprises: oxidizing the compound of formula I-2 to give the 5A / -oxide of Formula XX: XX and amine the compound of formula XX to give the compound of formula X, or a pharmaceutically acceptable salt thereof. In other modalities, a method is provided (i-3), (ii-3), (iii-3), (iv-3), (v-3), (vi-3), (vii-3), (viii-3), (ix-3), (x-3), (xi-3), (xii-3), (xiii-3), (xiv-3), (xv-3), (xvi -3), (xvi-3), (xviii-3), (xix-3), (xx-3), (xxi-3), (xx¡¡-3), (xx¡¡¡-3) , or (xxiv-3), where E in the method (i-1), (¡i-1), (iii-1), (iv-1), (v-1), (v-1) , (vii-1), (viii-1), (ix-1), (x-1), (xi-1), (xii-1), (xiii-1), (xiv-1), (xv-1), (xvi-1), (xvii-1), (xviii-1), (xix-1), (xx-1), (xxi-1), (xxii-1), (xxiii -1), or (xxiv-1), is halogen, the compound of formula I is of the formula I-3: I-3 wherein Hal is fluorine, chlorine, bromine, or iodine, and the step of converting the group Hal to an amino group in the compound of formula I-3, comprises aminating the compound of formula I-3 to give the compound of formula X, or a pharmaceutically acceptable salt thereof. In other modalities, a method is provided (i-4), (ü-4), (iü-4), (v- 4), (v-4), (vi-4), (vii-4), (viii-4), (ix-4), (x-4), (xi-4), (xii-4) , (xiii-4), (xiv-4), (xv-4), (xvi-4), (xvii- 4), (xviii-4), (xix-4), (xx-4), ( xxi-4), (xxii-4), (xxüi-4), or (xxiv-4), where E in the method (i-1), (ii-1), (iii-l), (iv -1), (v-1), (vi-1), (vii-1), (viii-1), (ix-1), (x-1), (xi-1), (xii-1) ), (xiii-1), (xiv-1), (xv-1), (xvi-1), (xvii-1), (xviii-1), (xix-1), (xx-1), (xxi-1), (xxii-1), (xxiii-1), or (xxiv-1), is hydroxy, the compound of formula I is of the formula I-4: I-4 and the step of converting the hydroxy group to an amino group in the compound of formula I-4 comprises: converting the hydroxy group in the 4-position of formula I-4 to a halogen group, to give a compound of formula I-3, or a salt thereof: I-3 wherein Hal is fluorine, chlorine, bromine, or iodine; and amending the compound of formula I-3 to give the compound of formula X, or a pharmaceutically acceptable salt thereof. In other modalities, a method is provided (i-5), (ii-5), (iii-5), (iv-5), (v-5), (vi-5), (vi-5) , (viii-5), (ix-5), (x-5), (xi-5), (xii-5), (xiii-5), (xiv-5), (xv-5), (xv¡-5), (xvii-5), (xviii-5), (xix-5), (xx-5), (xxi-5), (xxi¡-5), (xxiii-5), or (xxiv-5), where E in the method (i-1), (¡i-1), (iii-1), (iv-1), (v-1), (vi-1), (vii-1), (viii-1), (ix-1), (x-1), (xi-1), (xü-1), (xiü-1), (xiv-1), (xv -1), (xvi-1), (xvii-1), (xviii-1), (xix-1), (xx-1), (xxi-1), (xxii-1), (xxiii- 1 ), or (xxiv-1), is hydroxy, the compound of formula I is of formula I-4: and the step of converting the hydroxy group to an amino group in the compound of formula I-4 comprises: sulfonating the compound of formula I-4 by reaction with a compound of formula hal-S (O) 2-R ', wherein hal is chlorine or bromine, or of the formula O (-S (0) 2-R ') 2, to give a compound of formula I-5: displace the -O-S (O) 2 -R 'group in the formula I-5 with an amino group of the formula -N (Bn) 2, to give a compound of the formula I-6: 1-6 remove the Bn protecting groups of formula 1-6 to give the compound of formula X, or a pharmaceutically acceptable salt thereof. In other modalities, a method is provided (i-6), (ii-6), (iii-6), (v-6), (v-6), (vi-6), (vii-6) , (viii-6), (ix-6), (x-6), (xi-6), (xi-6), (xiii-6), (xiv-6), (xv-6), (xv¡-6), (xvii-6), (xviü-6), (xix-6), (xx-6), (xxi-6), (xxii-6), (xxiii-6), or (xxiv-6), where E in the method (i-1), (ii-1), (iii-1), (iv-1), (v-1), (vi-1), (vii -1), (viii-1), (ix-1), (x-1), (xi-1), (xü-1), (xüi-1), (x¡v-1), (xv -1), (xv¡-1), (xvii-1), (xviii-1), (xix-1), (xx-1), (xxi-1), (xxii-1), (xxiii- 1), or (xxiv-1) is phenoxy, the compound of formula I is of formula I-7: 1-7 wherein Ph is phenyl, and the step of converting the phenoxy group to an amino group in the compound of formula 1-7 comprises aminating the compound of formula 1-7 to give the compound of formula X, or a pharmaceutically salt acceptable of it. In other modalities, a method is provided (i-7), (ii-7), (iii-7), (iv- 7), (v-7), (vi-7), (vü-7), (vüi-7), (ix-7), (x-7), (xi-7), (xii-7), (xiii-7), (xiv-7), (xv-7), (xvi-7), (xvii- 7), (xviii-7), (xix-7), (xx-7), (xxi-7), (xxii-7), (xxiii-7), or ( xxiv-7), where E in the method (i-1), (¡i-1), (iii-1), (iv-1), (v-1), (vi-1), (vü -1), (vüi-1), (ix-1), (x-1), (xi-1), (xü-1), (xiii-1), (xiv-1), (xv-1) ), (xvi-1), (xv¡¡-1), (xviii-1), (xix-1), (xx-1), (xx¡-1), (xxü-1), (xxiii- 1), or (xxxiv-1), is -OS (O) 2 -R \ the compound of formula I is of formula I-5: I-5 and the step of converting the group -OS (O) 2 -R 'to an amino group in the compound of formula I-5, comprises: displacing the group -OS (O) 2 -R' with an amino group of formula -N (Bn) 2, to give a compound of formula I-6: I-6 and removing the protecting groups Bn in the formula I-6 to give the compound of the formula X, or a pharmaceutically acceptable salt thereof. In other modalities, a method is provided (i-8), (i-8), (iii-8), (iv-8), (v-8), (v-8), (vii-8) ), (viii-8), (ix-8), (x-8), (xi-8), (xii-8), (xi¡¡-8), (xiv-8), (xv- 8), (xvi-8), (xvü-8), (xvüi-8), (xix-8), (xx-8), (xx¡-8), (xx¡¡-8), (xxiii -8), or (xxiv-8), where E in the method (i-1), (¡i-1), (¡ü-1), (iv-1), (v-1), ( v-1), (vii-1), (viii-1), (ix-1), (x-1), (xi-1), (xü-1), (xiü-1), (xiv-1), (xv-1), (xvi-1), (xvii-1), (xvii -1), (xix-1), (xx-1), (xx¡-1), (xxü-1), (xxüi-1), or (xxiv-1), is -N (Bn) 2 , the compound of formula I is of formula I-6: I-6 and the step of converting the group -N (Bn) 2 to an amino group in the compound of formula I-6 comprises removing the protecting groups Bn to give the compound of formula X, or a pharmaceutically acceptable salt thereof. In other modalities, a method is provided (i-9), (¡i-9), (iii-9), (iv-9), (v-9), (vi-9), (vii-9) , (viii-9), (ix-9), (x-9), (x¡-9), (xii-9), (xiii-9), (xiv-9), (xv-9), (xvi-9), (xvü-9), (xviü-9), (xix-9), (xx-9), (xxi-9), (xxi¡-9), (xxiii-9), or (xxiv-9), where E in the method (i-1), (ii-1), (ii-1), (iv-1), (v-1), (vi-1), ( vii-1), (viii-1), (ix-1), (x-1), (x¡-1), (xii-1), (xiü-1), (x¡v-1), (xv-1), (xvi-1), (xvii-1), (xviii-1), (xix-1), (xx-1), (xxi-1), (xxii-1), (xxiii -1), or (xxiv-1), is bonded to the adjacent nitrogen atom of pyridine of formula I to form the fused tetrazolo ring of formula 1-1: 1-1 and the step of converting the fused tetrazolo ring to an amino group in the compound of formula 1-1 comprises the steps of: reacting the compound of formula 1-1 with tpphenylphosphine to give a compound of formula XXI: XXI and hydrolyze the compound of formula XXI to give the compound of formula X, or a pharmaceutically acceptable salt thereof. In other modalities, a method is provided (i-10), (ü-10), (iü-10), (iv-10), (v-10), (vi-10), (vii-10), (viii-10), (ix-10), (x-10), (xi-10), (xü-10), (xii¡-10), (xiv-10), (xv-10), ( xvi-10), (xvii-10), (xvüi-10), (xix-10), (xx-10), (xxi-10), (xxü-10), (xxiü-10), or (xxiv) -10), where E in the method (i-1), (ii-1), (iü-1), (iv-1), (v-1), (vi-1), (vii-1) ), (vüi-1), (ix-1), (x-1), (x¡-1), (xi¡-1), (xiü-1), (x¡v-1), (xv -1), (xvi-1), (xvü-1), (xviü-1), (xix-1), (xx-1), (xxi-1), (xxii-1), (xxiii-1) ), or (xxiv-1), is bonded with the adjacent nitrogen atom of pyridine of the formula I to form the fused tetrazolo ring of formula 1-1: 1-1 and the step of converting the fused tetrazolo ring to a group amino in the compound of formula 1-1 comprises the step of: reductively removing the tetrazolo ring of the compound of formula 1-1 to give the compound of formula X, or a pharmaceutically acceptable salt thereof. In another embodiment, the invention provides an intermediate compound of formula XI: XI wherein: E is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, iodine, hydroxy, phenoxy, -OS (O) 2 -R ', and -N (Bn) 2, wherein R' is selected from the group consisting of alkyl, haloalkyl, and aryl optionally substituted with alkyl, halogen, or nitro, and Bn is selected from the group consisting of benzyl, p-methoxybenzyl, p-methylbenzyl, and 2-furanylmethyl; or E is linked with the adjacent nitrogen atom of pyridine of formula XI to form the fused tetrazolo ring of formula XIII: XIII L is selected from the group consisting of fluorine, chlorine, bromine, iodine, phenoxy, and -0-S (O) 2-R ', wherein R' is selected from the group consisting of alkyl, haloalkyl, and aryl optionally substituted with alkyl, halogen, or nitro; RA and RB are independently selected from the group consisting of: hydrogen, halogen, alkyl, alkenyl, alkoxy, alkylthio, and -N (R9) 2; or RA and RB taken together form a fused benzene ring or a fused pyridine ring, wherein the benzene ring or the pyridine ring is unsubstituted or substituted with a group R, or is substituted with a group R3, or is substituted with a group R and a group R3; or RA and RB taken together form a 5 to 7 membered fused saturated ring optionally containing a nitrogen atom, wherein the fused ring is unsubstituted or substituted with one or more R groups; R is selected from the group consisting of: halogen, hydroxy, alkyl, alkenyl, haloalkyl, alkoxy, alkylthio, and -N (R9) 2; Ri is selected from the group consisting of: -R, -X-R4, -X-Y-R4, -X-Y-X-Y-R4, -X-R5, -NÍR ^ Í-Q-R ,, -N (R, ') -? R4, and -N (R, ') - X, -R5b; R3 is selected from the group consisting of: -Z-R4, -Z-X-R4, -Z-X-Y-R4, -Z-X-Y-X-Y-R4, and -Z-X-R5; X is selected from the group consisting of alkylene, alkenylene, alkynylene, arylene, heteroarylene, and heterocyclylene, wherein the alkylene, alkenylene, and alkynylene groups may optionally be interrupted with arylene, heteroarylene or heterocyclylene, and optionally interrupted by one or more -O- groups; Xi is C2-20 alkylene; Y is selected from the group consisting of: -O-, -S (O) or-2-, -S (0) 2-N (R8) -, -C (R6) -, -OC (R6) -, -OC (O) -0-, -N (R8) -Q-, -OC (R6) -N (R8) -, -C (R6) -N (OR9) -, -0-N (R8) - Q-, -ON = C (R4) -, -C (= NO-R8) -, -CH (-N (-O-R8) -Q-R4) -, Yi is selected from the group consisting of -O-, -S (O) 0.2-, -S (O) 2- N (R8) -, -N (R8) -Q-, -C (R6) -N ( R8) -, -OC (R6) -N (R8) -, and Z is a bond u -O-; Ri 'is selected from the group consisting of hydrogen, alkyl C-20 20, C2-2o hydroxy-alkylenyl, and C2-20 alkyloxynyl; R 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 groups , alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl and heterocyclyl may be unsubstituted or may be substituted with one or more substituents independently selected from the group consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, mercapto, cyano, aryl, aryloxy, arylalkyloxy, heteroaryl, heteroaryloxy, heteroaplaylealkyloxy, heterocyclyl, amino, alkylamino, dialkylamino, (dialkylamino) alkylenoxy, and in the case of alkyl, alkenyl, alkynyl and heterocyclyl, oxo; R5 is selected from the group consisting of: Rd is selected from the group consisting of: -N A R6 is selected from the group consisting of = 0 y = S; R7 is C2.7 alkylene; R8 is selected from the group consisting of hydrogen, alkyl, alkoxyalkylenyl, hydroxyalkylenyl, arylalkylenyl, and heteroarylalkylenyl; R9 is selected from the group consisting of hydrogen and alkyl; R-io is C3-8 alkylene; A is selected from the group consisting of -O-, -C (O) -, -S (O) 0-2-, and -N (R4) -; A 'is selected from the group consisting of -O-, -S (O) 0-2-, -N (-Q-R4) -, and -CH2-; Q is selected from the group consisting of a bond, -C (Re) -, -C (R6) -C (R6) -, -S (0) 2-, -C (R6) -N (R8) -W -, -S (O) 2-N (R8) -, -C (R6) -O-, -C (R6) S-, and -C (R6) -N (OR9) -; V is selected from the group consisting of -C (Re) -, -O-C (R6) -, -N (R8) -C (R6) -, and -S (O) 2-; V is selected from the group consisting of -O-C (Re) -, -N (R8) -C (R6) -, and -S (O) 2-; W is selected from the group consisting of a bond, -C (O) -, and - S (O) 2-; and a and b are, independently, integers from 1 to 6, with the proviso that a + b < 7; or a pharmaceutically acceptable salt thereof. For some embodiments, which include any of the above embodiments, Ri is selected from the group consisting of -R4, -X-R4, -XY-R4, -XYXY-R4, -X-R5, -N (R1 ') - Q-R4, -N (R1,) - X1-YrR4, and -NKR ^ -X Rdb- For some embodiments, including any of the foregoing embodiments, R-i is selected from the group consisting of -R 4, -X-R 4, -X-Y-R 4, -X-Y-X-Y-R 4, and -X-R 5. For some embodiments, which include any of the above modalities, R ^ is -R4 or -X-R4. For some of these embodiments, -R4 is selected from the group consisting of 2-methylpropyl, 2-hydroxy-2-methylpropyl, 2,2-dimethyl-4-oxopentyl, and (1-hydroxycyclobutyl) methyl.

For some of these embodiments, R-i is -R, and -R4 is 2- methylpropyl or 2-hydroxy-2-methylpropyl. For some of these embodiments, R- \ is -R4 and -R4 is 2-methylpropyl. Alternatively, for some of these embodiments, Ri is -X-R4 and -X-R4 is 2,2-dimethyl-3- (2-methyl-1,3-dioxolan-2-yl) propyl. For some modalities that include any of the previous modalities, except the modalities where R-i is -R4 or -X-R4, R-i is -X-Y-R4. For some of these embodiments, X is C2-4 alkylene, and Y is -S (O) 2- or -N (R8) -Q-. For some of these embodiments, -XY-R4 is selected from the group consisting of 2- (propylsulfonyl) ethyl, 2-methyl-2- [(methylsulfonyl) amino] propyl, 4-methylsulfonylaminobutyl, and 2- (acetylamino) -2 -methylpropyl. For some modalities that include any of the above modalities, except the modalities where Ri is -R, -X-R4, or -X-Y-R4, R-i is -X-R5. For some of these embodiments, -X-R5 is 4- [(morpholin-4-ylcarbonyl) amino] butyl. For some embodiments including any of the foregoing modalities, except for embodiments wherein R1 is -R4, -XR, -XYR, -XYXY-R4, or -X-R5, R1 is selected from the group consisting of -N (R ? ') - Q-R4. -N (R1 ') - X? -Y1-R4, and -NIR ^ d-Rs ,,. For some modalities that include any of the above modalities, except the embodiments wherein R2 is hydrogen, R2 is selected from the group consisting of -R4, -X-R4, -X-Y-R4, and -X-R5. For some modalities that include any of the above modalities, except the modalities where it is excluded, R2 is -R4. For some of these embodiments, R 2 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, butyl, 2-methoxyethyl, 2-hydroxyethyl, ethoxymethyl, and hydroxymethyl. For some of these embodiments, R 2 is selected from the group consisting of hydrogen, methyl, ethyl and ethoxymethyl. For some modalities, R2 is hydrogen. For some embodiments including any of the above embodiments, RA and RB are each independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkoxy, alkylthio, and -N (R9) 2; or RA and RB taken together form a fused benzene ring or a fused pyridine ring, wherein the benzene ring or the pyridine ring is unsubstituted or substituted with an R group, or is substituted with a group R3, or are substituted with a group R and a group R3; or RA and RB taken together form a saturated fused ring of to 7 members optionally containing a nitrogen atom, wherein the fused ring is unsubstituted or is substituted with one or more R groups. For some embodiments including any of the above embodiments, RA and RB are selected, each independently , of the group consisting of hydrogen, halogen, alkyl, alkenyl, alkoxy, alkylthio, and -N (R9) 2. For some of these modalities, RA and R8 are, each methyl. For some embodiments including any of the above embodiments wherein RA and RB taken together can form a fused benzene ring, RA and RB taken together form a fused benzene ring wherein the benzene ring is unsubstituted, or is substituted with a group R, or is substituted with a group R3, or is substituted with a group R and a group R3. For some of these embodiments, R is hydroxy or bromine, and R3 is methoxy, phenoxy, or benzyloxy. For some of these embodiments, the fused benzene ring is substituted with a group R selected from the group consisting of hydroxy and bromine. Alternatively, for some of these embodiments, the fused benzene ring is substituted with a group R3, wherein R3 is methoxy, phenoxy, or benzyloxy. For some embodiments, RA and RB taken together form a fused benzene ring, wherein the benzene ring is not substituted. For some embodiments that include any of the above embodiments wherein RA and RB taken together can form a fused pyridine ring, RA and RB taken together form a fused pyridine ring wherein the fused pyridine ring is unsubstituted, or is substituted with a group R, or is substituted with a group R3, or is substituted with a group R and a group R3; and wherein the fused pyridine ring is: where the highlighted link indicates the position where the ring is fused. For some of these embodiments, R is hydroxy or bromine, and R3 is methoxy, phenoxy, or benzyloxy. For some of these embodiments, the fused pyridine ring is substituted with a group R selected from the group consisting of hydroxy and bromine. Alternatively, for some of these embodiments, the fused pyridine ring is substituted with a group R3, wherein R3 is methoxy, phenoxy, or benzyloxy. For some embodiments, RA and RB taken together form a fused pyridine ring wherein the fused pyridine ring is unsubstituted, and wherein the fused pyridine ring is: where the highlighted link indicates the position where the ring is fused. For some embodiments including any of the above embodiments wherein RA and RB taken together can form a fused saturated ring of 5 to 7 members, RA and RB taken together form a 5 to 7 membered fused saturated ring optionally containing a hydrogen atom. nitrogen, wherein the fused ring is unsubstituted or is substituted with one or more R groups. For some of these embodiments, R and RB taken together form a fused carbocyclic ring of 5-7 members wherein the fused ring is unsubstituted or substituted by one or more R groups. For some of these embodiments, the fused ring is a 6-membered carbocyclic ring that is unsubstituted. Alternatively, for some of these embodiments, RA and RB taken together form a 5 to 7 membered fused saturated ring containing a nitrogen atom, wherein the fused ring is unsubstituted or is substituted with one or more R groups. For some of these embodiments, the fused ring is a 6-membered fused ring that is unsubstituted, or is substituted on a carbon atom with one or more R groups. For some of these embodiments, the 6-membered fused ring is: where the ring is not substituted; and where the highlighted link indicates the position where the ring is fused. For some modalities that include any of the above modalities of methods (i) to (viii), methods (i-1) to (viii-1), methods (i-2) to (viii-2), methods (i-3) to (viii-3), methods (i-4) a (viii-4), methods (i-5) to (viii-5), methods (i-6) to (viii-6), methods (i-7) to (viii-7), methods (i-8) to (viii-8), methods (i-9) to (viii-9), and methods (i-10) to (viii-10), RA is RA- ?, RB is RB ?, Ri is R? A, and R2 is R2a, where: RAI and RBI are independently selected from the group consisting of: hydrogen, halogen, alkyl, alkenyl, alkoxy, alkylthio, and -N (R9) 2; or RA? and RBI taken together form a fused benzene ring or a fused pyridine ring, wherein the benzene ring or the pyridine ring is unsubstituted or substituted with a group Ra, or is substituted with a group R3a, or is substituted with a group Ra and a group R3a; or RA? and RBI taken together form a saturated 5 to 7 membered fused ring optionally containing a nitrogen atom, wherein the fused ring is unsubstituted or substituted with one or more Ra groups; Ra is selected from the group consisting of: halogen, hydroxy, alkyl, alkenyl, trifluoromethyl, alkoxy, alkylthio, and -N (R9) 2; R1a is selected from the group consisting of: -X-R a, -X-Rda, -N (R? ') - Q-R4a. -N (R1 ') - X1-Y? -R4a, and R2a is selected from the group consisting of: -R a, -X-R4a, R3a is selected from the group consisting of: -Z-R4a, -Z-X-R4a, -Z-X-Ya-R4a, -Z-X-Ya-X-Ya-R4a, and -Z-X-R5a; It is already selected from the group consisting of: -OR-, -S (O) or-2-, S (O) 2-N (R8) -, N (R8) -Q- O-C (R6) -N (R8) -, C (R6) -N (OR9) -, J R 4a 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 may be unsubstituted or may be substituted with one or more substituents independently selected from the group consisting of alkyl, alkoxy, hydroxyalkyl, trifluoromethyl, trifluoromethoxy, nitro, hydroxy, mercapto, cyano , aryl, aryloxy, arylalkylenoxy, heteroaryl, heteroaryloxy, heteroarylalkylenoxy, heterocyclyl, amino, alkylamino, dialkylamino and (dialkylamino) alkyleneoxy; and Rda is selected from the group consisting of: -N For each of the resulting modalities, where it is present: Formula I is the formula l £ The formula 1-1 is the formula la-1: la-1 Formula I-2 is the formula la-2: la-2 The formula I-3 is the formula la-3: la-3 The formula I-4 is the formula la-4: la-4 Formula I-5 is la-5: la-5 Formula I-6 is la-6: la-6 The formula I-7 is la-7: -7 Formula II is the formula lia: Formula III is the formula llla: E Formula IV is the formula IVa ?goes Formula IV-1 is formula IVa-1: IVa-1 Formula V is the formula Va Goes Formula VI is the formula Vla: VL The formula V is the formula Vlla: VI For some of the resulting modalities, where present: Formula X is formula Xa: Xa The formula XX is the formula XXa: XXa and formula XXI is formula XXIa: XX1a For some modalities that include any of the previous modalities of methods (ix) to (xxiv), methods (ix-1) to (xxiv- 1), the methods (ix-2) to (xxiv-2), the methods (ix-3) to (xxiv-3), the methods (ix-4) to (xxiv-4), the methods (ix- 5) a (xxiv-5), methods (ix-6) a (xxiv-6), methods (ix-7) a (xxiv-7), methods (ix-8) a (xxiv-8) , the methods (ix-9) to (xxiv-9), and the methods (ix-10) to (xxiv-10), RA is RA ?, RB is RB ?, Ri is R? a, and R2 is hydrogen , where RA ?, RBI and Ría are as defined above for the modalities where RA is RA? , RB is RBI, RI is R? A, and R2 is R2a- For the resulting modalities of formula la, la-2, la-3, la-4, la-5, la-6, and la-7, R2a It is hydrogen. For the resulting embodiments of formula Xa, XXa, and XXIa, R2a is hydrogen. For some embodiments including any of the above modalities of formula XI, RA is RAI, RB is RBI, and R1 is R? A, where RAI, RBI and Ria are as defined above for the modalities in which RA is RA? , RB is RBI, RI is R1 a, and R2 is R2a- For each resulting modality, where it is present: Formula VIII is the formula Vllla: VIIL Formula IX is formula IXa IXa Formula XI is the formula Xla: Xla and formula XIII is the formula Xllla: For each resulting modality, where it is present: R is Ra, R3 is R3a, R4 is R4a, R5 is R5a, and Y is Ya. For some modalities that include any of the above modalities where RA is RA ?, RB is RB ?, Ri is R? And R2 is R2a, the modalities where RA is RAI, RB is RBI, RI is R1a and R2 is hydrogen , and the modalities of Xla, Ria is selected from the group consisting of -R4a, -X-R4a, -X-Ya-R4a, -X-Ya-X-Ya-R4a, -X-R5a, -NKR -QR ^, -N (R? ') - X? -YrR4b, and - For some modalities that include any of the previous modalities where RA is RA ?, RB is RB ?, Ri is R1a and R2 is R2a, the modalities where RA is RA ?, RB is RB ?, Ri is R? a, and R2 is hydrogen, and the modalities of Xla, R1a is selected from the group consisting of -R4a, -X "R4a," X "and" R4a, -X-Ya "X-Ya-4a and" X'Rda- For some embodiments including any of the previous modalities where RA is RA ?, RB is RB ?, Ri is R? a, and R2 is R2a, the modalities where RA is RA ?, RB is RB ?, Ri is R1a and R2 is hydrogen, and Xla modalities, Ría is -R ao -X-R4a. For some of these embodiments, -R a is selected from the group consisting of 2-methylpropyl, 2-hydroxy-2-methylpropyl and (l-hydroxycyclobutyl) methyl, and -X-R 4a is 2,2-dimethyl-3- ( 2-methyl-1,3-dioxolan-2-yl) propyl. For some of these embodiments, R1a is -R4a and -R4a is 2-methylpropyl or 2-hydroxy-2-methylpropyl. For some of these embodiments, R1a is -R4a, and -R4a is 2-methylpropyl. Alternatively, for some of these embodiments, R a is -X-R 4a, and -X-R 4a is 2,2-dimethyl-3- (2-methyl-1,3-dioxolan-2-yl) propyl. For some modalities that include any of the above modalities where RA is RA ?, RB is RBI, RI is R-? A, and R2 is R2a, the modalities where RA is RA ?, RB is RB ?, Ri is R ? a, and R2 is hydrogen, and the modalities of Xla, except the modalities where R? a is -R4a or -XR- a, R ^ is -X-Ya-R4a. For some of these embodiments, X is alkylene of C2- and Ya is -S (0) 2- or -N (R8) -Q-. For some of these embodiments, -X-Ya-R4a is selected from the group consisting of 2- (propylsulfonyl) ethyl, 2-methyl-2 - [(methylsulfonyl) amino] propyl, 4-methylsulfonylaminobutyl, and 2- (acetylamino) -2- methylpropyl. For some modalities that include any of the above modalities where RA is RA ?, RB is RB ?, R? is R and R2 is R2a, the modes where RA is RA, RB is RBI, R1 is R and R2 is hydrogen, and the modalities of Xla, except the modalities where R a is -R4a, -X- R4a, or -X-Ya-R4a, Ria is -X-Rsa. For some of these embodiments, -X-Rsa is 4 - [(morpholin-4-ylcarbonyl) amino] butyl. For some modalities that include any of the above modalities where RA is RA ?, RB is RB ?, Ri is R? And R2 is R2a, the modalities where RA is RA ?, RB is RB ?, Ri is R? Ay R2 is hydrogen, and the modalities of Xla, except the modalities where R? A is -R a, -X-R4a, -X-Ya-R4a, -X-Ya-X-Ya-R4a, or -X- Rsa, R? A is selected from the group consisting of -N (R? ') - Q-R4a, -N (R-, X? -Y? -R4a, and -NKR d-Rsb- For some embodiments including any of the above embodiments wherein RA is RA, RB is RB ?, Ri is R1a, and R2 is R2a, R2a is selected from the group consisting of -R4a, -X-R4a, -X-Ya-R and a -X -Rsa For some embodiments including any of the above embodiments wherein RA is RA ?, RB is RB1, Ri is R and R2 is R2a, R2a is -R4a For some of these embodiments, R2a is selected from the group consisting of in hydrogen, methyl, ethyl, propyl, butyl, 2-methoxyethyl, 2-hydroxyethyl, ethoxymethyl and hydroxymethyl For some of these embodiments, R2a s e is selected from the group consisting of hydrogen, methyl, ethyl and ethoxymethyl.

For some modalities that include any of the above modalities where RA is RA ?, RB is RB ?, Ri is R1a and R2 is R2a, the modalities where RA is RA ?, RB is RB ?, Ri is R1a, and R2 is hydrogen, and the Xla, RAI and RBI modalities are each independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkoxy, alkylthio and -N (R9) 2; or RAI and RBI taken together form a fused benzene ring or a fused pyridine ring, wherein the benzene ring or the pyridine ring is unsubstituted or substituted with a group Ra, or is substituted with a group R3a, or is substituted with a group Ra and a group R3a; or RA? and RBI taken together form a saturated 5 to 7 membered fused ring optionally containing a nitrogen atom, wherein the fused ring is unsubstituted or substituted with one or more Ra groups. For some modalities that include any of the above modalities where RA is RA ?, RB is RBL RI is R? And R2 is R2a, the modalities where RA is RA ?, RB is RB ?, Ri is R1a and R2 is hydrogen , and the Xla, RAI and RBI modalities are each independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkoxy, alkylthio and -N (R9) 2. For some of these modalities, RA? and RBI are, each, methyl. For some modalities that include any of the previous modalities where RA is RA? , RB is RB ?, Ri is R? A and R2 is R2a, the modalities in which RA is RAI, RB is RBI, I is R? a and R2 is hydrogen, and the modalities of Xla, and where RA? and RBI taken together can form a fused benzene ring, RA? and RB? taken together they form a fused benzene ring wherein the benzene ring is unsubstituted or substituted with a group Ra, or is substituted with a group R3a, or is substituted with a group Ra and a group R3a. For some of these embodiments, Ra is hydroxy or bromine, and R3a is methoxy, phenoxy, or benzyloxy. For some of these embodiments, the fused benzene ring is substituted with a group Ra selected from the group consisting of hydroxy and bromine. Alternatively, for some of these embodiments, the fused benzene ring is substituted with a group R3a wherein R3a is methoxy, phenoxy, or benzyloxy. For some modalities, RAI and RBI taken together form a fused benzene ring that is not substituted. For some modalities that include any of the above modalities where RA is RA ?, RB is RBI, RI is R? And R2 is R2a, the modalities where RA is RA ?, RB is RB ?, Ri is R1a and R2 is hydrogen, and the Xla modalities, and where RAI and RBI taken together can form a fused pyridine ring, RA? and RB? taken together they form a fused pyridine ring wherein the fused pyridine ring is unsubstituted or substituted with a group Ra, or is substituted with a group R3a, is or is substituted with a group Ra and a group R3a; and wherein the fused pyridine ring is: where the highlighted link indicates the position where the ring is fused. For some of these embodiments, Ra is hydroxy or bromine, and R3a is methoxy, phenoxy, or benzyloxy. For some of these embodiments, the fused pyridine ring is substituted with a group Ra selected from the group consisting of hydroxy and bromine. Alternatively, for some of these embodiments, the fused pyridine ring is substituted with a group R3a wherein R3a is methoxy, phenoxy, or benzyloxy. Alternatively, for some of these embodiments, the fused pyridine ring is unsubstituted. For some modalities that include any of the above modalities where RA is RA ?, RB is RB ?, Ri is R? A, and R2 is R2a, the modalities where RA is RA? RB is RB ?, is R? a and R2 is hydrogen, and the modalities of Xla, and where RA? and RB? taken together can form a saturated ring fused from 5 to 7 members, RA? and RBI taken together form a saturated 5 to 7 membered fused ring optionally containing a nitrogen atom, wherein the fused ring is unsubstituted or substituted with one or more Ra groups. For some of these modalities, RA? and RBI taken together form a 5 to 7 membered fused carbocyclic ring, wherein the fused ring is unsubstituted or substituted with one or more Ra groups. For some of these modalities, the fused ring is a 6-membered carbocyclic ring that it is not substituted. Alternatively, for some of these modalities, RA? and RBI taken together form a 5 to 7 membered fused saturated ring containing a nitrogen atom, wherein the fused ring is unsubstituted or substituted with one or more Ra groups. For some of these embodiments, the fused ring is a 6-membered fused ring that is unsubstituted or substituted on a carbon atom with one or more Ra groups. For some of these modalities, the 6 member merged ring is: where the ring is not substituted; and where the highlighted link indicates the position where the ring is fused. For some embodiments including any of the above embodiments, which include a step of reacting the compound of formula IV with an amine of formula R? NH2, said step is carried out with the reagents alone and at an elevated temperature. For some embodiments that include any of the above embodiments wherein formula IV is formula IVa: IVa and including a step of reacting the compound of IVa formula with an amine of the formula R1aNH2, said step is carried out with the reactants alone at an elevated temperature. For some embodiments including any of the above embodiments, which include a step of reacting the compound of formula IV with an amine of the formula R1NH2, the step is carried out in a solvent and at an elevated temperature, except for the embodiments wherein step is carried out with the reagents alone. For some of these embodiments, the solvent is selected from the group consisting of methanol, ethanol, trifluoroethanol, isopropanol, fer-butanol, water, acetonitrile, 1-methyl-2-pyrrolidinone, and toluene. For some of these embodiments, the solvent is selected from the group consisting of trifluoroethanol, isopropanol and fer-b-tanol. For some embodiments that include any of the above embodiments wherein formula IV is formula IVa: These steps include the step of reacting the compound of formula IVa with an amine of formula R1aNH2, said step being carried out in a solvent and at an elevated temperature, except for the embodiments wherein said step is carried out with the reagents alone. For some of these embodiments, the solvent is selected from the group consisting of methanol, IV where RA, RB, R2, E and L are as defined above in method (i). For some of these embodiments, RA, RB, R2, E and L are as defined in any of the foregoing modalities of method (i). In another embodiment, the present invention provides a compound of formula IVa: IVa where RAI, RBI, R2a, E and L are as defined above in method (i), where RA is RA ?, RB is RB? and R2 is R2a- For some of these modalities, RAI, RBI, R2a, E and L are as defined in any of the above modalities of the method (i) where RA is RA ?, RB is RB? and R2 is For some modalities that include any of the above modalities of method (i), (ii), (iii), (iv), (v), (vi), (vii), (viii) of formula IV or IVa, E is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, iodine, hydroxy, phenoxy, -OS (O) 2 -R ', and -N (Bn) 2, wherein R' is selected from the group consisting of in alkyl, haloalkyl and substituted aryl ethanol, tpfluoroethanol, isopropanol, re-butanol, water, acetonitrile, 1-methyl-2-pyrrolidinone and toluene. For some of these embodiments, the solvent is selected from the group consisting of trifluoroethanol, isopropanol and fer-butanol. For some embodiments including any of the above embodiments, which include the step of reacting the compound of formula VIII with an amine of the formula R1NH2, said step is carried out with the reagents alone. For some of these embodiments, the amine is of the formula R? ANH2. For some of these embodiments, said step is carried out at an elevated temperature. For some of these embodiments, the compound of formula VIII is of formula Vllla. For some embodiments including any of the above embodiments, which include a step of reacting the compound of formula VIII with an amine of formula R NH 2, the step is carried out in a solvent. For some of these embodiments, the solvent is selected from the group consisting of methanol, ethanol, trifluoroethanol, isopropanol, rer-butanol, water, acetonitrile, 1-methyl-2-pyrrolidinone, toluene and tetrahydrofuran. For some of these embodiments, the solvent is selected from the group consisting of trifluoroethanol, isopropanol, tert-butanol and acetonitrile. For some of these embodiments, the amine is of the formula R? ANH2. For some of these embodiments, said step is carried out at an elevated temperature. For other of these modalities, said step is carried out at room temperature. For some of these embodiments, the compound of formula VIII is of formula Vllla.

For some modalities that include any of the above modalities that include an elevated temperature, the elevated temperature is higher than 80 ° C. For some embodiments including any of the above embodiments that include a high temperature, the elevated temperature is greater than 110 ° C. For some embodiments including any of the above embodiments that include a high temperature, the elevated temperature is less than 200 ° C. For some embodiments including any of the above embodiments that include an elevated temperature, the elevated temperature is less than 180 ° C. For some embodiments including any of the above embodiments that include a high temperature, the elevated temperature is less than 165 ° C. For some embodiments including any of the above embodiments that include a high temperature, the elevated temperature is less than 150 ° C. For some embodiments including any of the above embodiments that include an elevated temperature, the elevated temperature is less than 135 ° C. In one embodiment, the present invention provides a compound of formula IV: optionally with alkyl, halogen, or nitro, and Bn is selected from the group consisting of benzyl, p-methoxybenzyl, p-methylbenzyl and 2-furanylmethyl; or E is attached to the adjacent nitrogen atom of pyridine to form the fused tetrazolo ring shown in formulas 1-1 and IV-1: 1-1 IV- 1 For some modalities that include any of the above modalities of method (ix), (x), (xi), (xii), (xiii), (xiv), (xv), (xix), (xx), (xxi), or (xxii), E is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, iodine, hydroxy, phenoxy, -OS (O) 2 -R 'and -N (Bn) 2, wherein R 'is selected from the group consisting of alkyl, haloalkyl and aryl optionally substituted with alkyl, halogen, or nitro, and Bn is selected from the group consisting of benzyl, p-methoxybenzyl, p-methylbenzyl and 2-furanylmethyl; or E is attached to the adjacent nitrogen atom of pyridine of formulas I and VIII to form the fused tetrazolo ring of formulas 1-1 and IX: For some modalities that include any of the previous embodiments of the method (xvi), (xvii), (xviii), (xxiii) and (xxiv), E is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, iodine, hydroxy, phenoxy, -OS (O ) 2-R ', and -N (Bn) 2, wherein R' is selected from the group consisting of alkyl, haloalkyl and aryl optionally substituted with alkyl, halogen, or nitro, and Bn is selected from the group consisting of benzyl , p-methoxybenzyl, p-methylbenzyl and 2-furanylmethyl; or E is attached to the adjacent nitrogen atom of pyridine of formulas I and XI to form the fused tetrazolo ring of formulas 1-1 and XIII: For some embodiments including any of the above embodiments of formula XI or Xla, E is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, iodine, hydroxy, phenoxy, -0-S (O) 2-R ', and -N (Bn) 2, wherein R 'is selected from the group consisting of alkyl, haloalkyl and aryl optionally substituted with alkyl, halogen, or nitro, and Bn is selected from the group consisting of benzyl, p-methoxybenzyl, p -methylbenzyl and 2-furanylmethyl; or E is attached to the adjacent nitrogen atom of pyridine of formula XI to form the fused tetrazolo ring of formula XIII: XIII For some of these modalities, E is hydrogen.

Alternatively, for some of these embodiments, E is fluorine, chlorine, bromine, or iodine, and for some of these embodiments, E is chlorine. Alternatively, for some of these embodiments, E is hydroxy. Alternatively, for some of these embodiments, E is phenoxy (OPh). Alternatively, for some of these embodiments, E is -O-S (0) 2-R 'wherein R' is selected from the group consisting of alkyl, haloalkyl, and aryl optionally substituted with alkyl, halogen, or nitro. Alternatively, for some of these embodiments, E is -N (Bn) 2 wherein Bn is selected from the group consisting of benzyl, p-methoxybenzyl, p-methylbenzyl, and 2-furanylmethyl. Alternatively, for some of these embodiments, E is bonded to the adjacent nitrogen atom of pyridine to form the fused tetrazolo ring. For some embodiments including any of the above embodiments, L is selected from the group consisting of fluorine, chlorine, bromine, iodine, phenoxy, and -OS (O) 2 -R ', wherein R' is selected from the group consisting of in alkyl, haloalkyl, and aryl optionally substituted with alkyl, halogen, or nitro. For some embodiments including any of the above embodiments, L is selected from the group consisting of fluorine, chlorine, bromine, iodine, phenoxy, and -O-S (O) 2-R ', wherein R' is selected from the group consisting of alkyl, haloalkyl, and aryl optionally substituted with alkyl or halogen. For some of these embodiments, L is fluorine, chlorine, bromine, or iodine, and for some of these embodiments, L is chlorine. Alternatively, for some of these embodiments, L is phenoxy. Alternatively, for some of these modalities, L is -0-S (0) 2-R ', wherein R' is selected from the group consisting of alkyl, haloalkyl, and aryl optionally substituted with alkyl, halogen, or nitro. For some of these embodiments, L is -O-S (0) 2-R ', wherein R' is selected from the group consisting of alkyl, haloalkyl, and aryl optionally substituted with alkyl or halogen. For some embodiments including any of the above embodiments wherein R 'is present, R' is selected from the group consisting of alkyl, haloalkyl, and aryl optionally substituted with alkyl, halogen, or nitro. For some embodiments, R 'is selected from the group consisting of alkyl, haloalkyl, and aryl optionally substituted with alkyl or halogen. For some of these embodiments, R 'is alkyl, and for some of these embodiments, R' is methyl. Alternatively, for some of these embodiments, R 'is haloalkyl, and for some of these embodiments, R' is trifluoromethyl. Alternatively, for some of these embodiments, R 'is aryl optionally substituted with alkyl or halogen, and for some of these embodiments, R' is phenyl, p-bromophenyl, or p-tolyl. For some of these embodiments, R 'is aryl optionally substituted with alkyl, halogen, or nitro, and for some of these embodiments, R' is phenyl, p-bromophenyl, p-tolyl, 2-nitrophenyl, or 4-nitrophenyl. For some embodiments including any of the above embodiments wherein R is present, R is selected from the group consisting of halogen, hydroxy, alkyl, alkenyl, haloalkyl, alkoxy, alkylthio, and -N (R9) 2. For some of these embodiments, R is selected from the group consisting of hydroxy and bromine. For some of these modalities, R is in the 7 or 8 position. For some of these modalities, R is in the 7 position. Alternatively, for some of these modalities, R is in the 8 position. For some modalities that include either the above embodiments wherein R is present, except where R is selected from the group consisting of hydroxy and bromine, R is Ra. For some embodiments including any of the above embodiments wherein Ra is present, Ra is selected from the group consisting of halogen, hydroxy, alkyl, alkenyl, trifluoromethyl, alkoxy, alkylthio and -N (R9) 2. For some of these embodiments, Ra is selected from the group consisting of hydroxy and bromine. For some of these modalities, Ra is in the 7 or 8 position. For some of these modalities, Ra is in the 7 position. Alternatively, for some of these modalities, Ra is in the 8 position. For some modalities that include any of the above embodiments wherein R3 is present, R3 is selected from the group consisting of -Z-R4, -ZXR, -ZXY-R4, -ZXYXY-R4, and -ZX-R5.

For some of these embodiments, R3 is -Z-R or -Z-X-R4. For some of these modalities, R3 is -Z-R. Alternatively, for some of these embodiments, R3 is -Z-X-R4. For some of these modalities, Z is -O-. For some of these embodiments, R3 is methoxy, phenoxy, or benzyloxy. For some of these modalities, R3 is in the 7 or 8 position. For some of these modalities, R3 is in the 7 position. For some of these modalities, R3 is a benzyloxy group in the 7 position. Alternatively, for some of these embodiments, R3 is in the 8-position. For some embodiments including any of the above embodiments wherein R3 is present, except where R3 is -Z-R4, -ZX-R4, methoxy, phenoxy, or benzyloxy, R3 is R3a . For some embodiments including any of the above embodiments wherein R3a is present, R3a is selected from the group consisting of -ZR a, -ZX-R4a, -ZX-Ya-R4a, -ZX-Ya-X-Ya-R4a , and -ZX-R5a. For some of these embodiments, R3a is -Z-R4a or -Z-X-R a. For some of these modalities, R3a is -Z-R4a. Alternatively, for some of these embodiments, R3a is -Z-X-R4a. For some of these modalities, Z is -O-. For some of these embodiments, R3a is methoxy, phenoxy, or benzyloxy. For some of these embodiments, R3a is in the 7 or 8 position. For some of these embodiments, R3a is in the 7 position. For some of these embodiments, R3a is a benzyloxy group in the 7 position. Alternatively, for some of these modalities, R3a is in position 8.

For some embodiments including any of the above embodiments wherein R4 is present, 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 may be unsubstituted or may be substituted with one or more substituent groups independently selected from the group consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, mercapto, cyano, aryl, aryloxy, arylalkyloxy, heteroaryl, heteroaryloxy, heteroarylalkylenoxy, heterocyclyl, amino, alkylamino, dialkylamino, (dialkylamino) alkyleneoxy, and in the case of alkyl, alkenyl, alkynyl and heterocyclyl, oxo. For some of these embodiments, R is alkyl optionally substituted with hydroxy or oxo. For some of these embodiments, R is selected from the group consisting of 2-methylpropyl, 2-hydroxy-2-methylpropyl, 2,2-dimethyl-4-oxopentyl, and (1-hydroxycyclobutyl) methyl. For some of these embodiments, R is 2-methylpropyl or 2-hydroxy-2-methylpropyl. For some of these embodiments, R 4 is 2-methylpropyl. For some embodiments including any of the above embodiments wherein R 4 is present in -X-Y-R, R is C 1-4 alkyl. For some of these modalities, R4 is methyl.

For some embodiments including any of the above embodiments wherein R 4a is present, R 4a 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 may be unsubstituted or may be substituted with one or more substituent groups independently selected from the group consisting of alkyl , alkoxy, hydroxyalkyl, trifluoromethyl, trifluoromethoxy, nitro, hydroxy, mercapto, cyano, aryl, aryloxy, arylalkyloxy, heteroaryl, heteroaryloxy, heteroalalkylenoxy, heterocyclyl, amino, alkylamino, dialkylamino, and (dialkylamino) alkyleneoxy. For some of these embodiments, R a is alkyl optionally substituted with hydroxy. For some of these embodiments, R 4a is selected from the group consisting of 2-methylpropyl, 2-hydroxy-2-methylpropyl and (1-hydroxycyclobutyl) methyl. For some of these embodiments, R 4a is 2-methylpropyl or 2-hydroxy-2-methylpropyl. For some of these embodiments, R 4a is 2-methylpropyl. For some embodiments including any of the above embodiments wherein R a is present in -X-Y-R 4a > R 4a is C 4 alkyl. For some of these modalities, R4a is methyl. For some embodiments including any of the above embodiments wherein R5 is present, R5 is selected from group consisting of: For some of these modalities, R5 is: For some of these modalities, V is -NH-C (O) -. For some of these modalities, A is -O-. For some of these embodiments, a and b are each, 2. For some embodiments including any of the above embodiments where R5 is present, R5 is Rsa. For some embodiments including any of the above embodiments wherein R5a is present, Rsa is selected from the group consisting of: -N- C (R5) For some of these modalities, R5a is: ^ (CH2) to N -V '- N A For some of these modalities, V is -NH-C (O) -. For some of these modalities, A is -O-. For some of these embodiments, a and b are each, 2. For some embodiments, R n and R 2 are, independently, C 4 alkyl, or R n and R 2 together with the nitrogen atom to which they are attached , form a 5 or 6 member ring optionally containing -O-, -N (C? -) -, or -S- alkyl. For some modalities, R-H and R? 2 are, each, methyl. For some embodiments including any of the above embodiments wherein X is present, X is selected from the group consisting of alkylene, alkenylene, alkynylene, arylene, heteroarylene, and heterocyclylene, wherein optionally the alkylene, alkenylene and alkynylene groups may be interrupted or terminated with arylene, heteroarylene or heterocyclylene, and optionally they may be interrupted with one or more -O- groups. For some of these embodiments, X is C2-6 alkylene. For some of these embodiments, X is C2-4 alkylene. For some embodiments including any of the above embodiments wherein Y is present, Y is selected from the group consisting of -O-, -S (O) 0.2-, -S (O) 2-N (R8) -, - C (R6) -, -OC (R6) -, -OC (0) -O-, -N (R8) -Q-, -OC (R6) -N (R8) -, -C (R6) -N (OR9) -, -ON (R8) -Q-, -ON = C (R4) -, -C (= N- O-R8) -, -CH (-N (-O-R8) -Q-R4) - For some of these modalities, Y is -S (O) 2- or -N (R8) -Q-. For some modalities that include any of the previous modalities where Y is present, and it is already. For some embodiments including any of the above embodiments wherein Ya is already present, it is already selected from the group consisting of -O-, -S (O) 0-2-, -S (O) 2-N (R8) - , -N (R8) -Q-, -OC (R6) -N (R8) -, -C (R6) -N (OR9) -, N For some of these modalities, it is already -S (0) 2- or -N (R8) -Q-. As used herein, the terms "alkyl", "alkylene", "alkynyl", and the prefix "ale", are inclusive of straight chain and branched chain groups and cyclic groups, for example, cycloalkyl and cycloalkenyl. TO unless otherwise specified, these groups contain from 1 to 20 carbon atoms; the alkenyl groups containing from 2 to 20 carbon atoms, and the 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. The cyclic groups can be monocyclic or polycyclic, and preferably have from 3 to 10 ring carbon atoms. Exemplary cyclic groups include cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclobutylmethyl, cyclopentyl, cyclopentylmethyl, cyclohexyl, cyclohexylmethyl, adamantyl, and substituted and unsubstituted bornyl, norbornyl, and norbornenyl. Unless otherwise specified, "alkylene", "alkenylene" and "alkynylene" refer to a divalent form of the "alkyl", "alkenyl" and "alkynyl" groups defined above. The terms, "alkylenyl", "alkenylenyl", and "alkynynyl" are used when the "alkylene", "alkenylene", "alkynylene", respectively, are substituted. For example, an arylalkylenyl group comprises an alkylene moiety to which an aryl group is attached. The term "haloalkyl" includes groups that are substituted with one or more halogen atoms, including perfluorinated groups. This is also valid for other groups that include the prefix "halo". Examples of suitable haloalkyl groups are chloromethyl, trifluoromethyl, and the like.

The term "aryl", as used herein, includes rings or carbocyclic aromatic ring systems. Examples of aryl groups include phenyl, naphthyl, biphenyl, fyluorenyl, and indenyl. Unless otherwise indicated, the term "heteroatom" refers to the O, S, or N atoms. The term "heteroaryl" includes rings or aromatic ring systems containing at least one ring heteroatom (e.g. , O, S, N). In some embodiments, the term "heteroaryl" includes a ring or ring system containing 2-12 carbon atoms, 1-3 rings, 1-4 heteroatoms, and O, S and N as the heteroatoms. 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, naphthipdinyl, isoxazolyl, isothiazolyl, purinyl, quinazolinyl, pyrazinyl, 1-oxidopyridyl, pyridazinyl, triazinyl, tetrazinyl, oxadiazolyl, thiadiazolyl, and the like. The term "heterocyclyl" includes non-aromatic ring systems or systems containing at least one heteroatom (for example O, S, N) and includes all fully saturated or partially saturated derivatives of the aforementioned heteroalyl groups. In some embodiments, the term "heterocyclyl" includes a ring or ring system containing 2-12 carbon atoms, 1-3 rings, 1-4 heteroatoms, and O, S and N as the heteroatoms. Exemplary heterocyclyl groups include pyrrolidinyl, tetrahydrofuranyl, morpholinyl, thiomorpholinyl, 1,1-dioxothiomorpholinyl, piperidinyl, piperazinyl, thiazolidinyl, imidazolidinyl, isothiazolidinyl, tetrahydropyranyl, quinuclidinyl, homopiperidinyl (azepanyl), 1,4-oxazepanyl, homopiperazinyl (diazepanyl), 1,3-dioxolanyl, aziridinyl, azetidinyl, dihydroisoquinolin- (1 / - /) -yl, octahydroisoquinolin- (1H) -yl, dihydroquinolin- (2H) -yl, octahydroquinolin- (2 / - /) -yl, dihydro-1H-imidazolyl, 3- azabicyclo [3.2.2] non-3-yl, etcetera. The term "heterocyclyl" includes bicyclic and tricyclic heterocyclic ring systems. Such ring systems include fused or bridge rings and spiro rings. Fused rings can include, in addition to a saturated or partially saturated ring, an aromatic ring, for example a benzene ring. The spiro rings include two rings joined by a spiro atom and three rings joined by two spiro atoms. When the "heterocyclyl" contains a nitrogen atom, the point of attachment of the heterocyclyl can be the nitrogen atom. The terms "arylene", "heteroarylene" and "heterocyclylene" refer to a divalent form of the "aryl", "heteroaryl" and "heterocyclyl" groups defined above. The terms "arylenyl", "heteroarylenyl" and "heterocyclylenyl" are used when "arylene", "heteroarylene" and "heterocyclylene", respectively, are substituted. For example, an alkylarylenyl group comprises an arylene moiety to which an alkyl group is attached. The term "fused saturated ring of 5 to 7 members" includes rings that are completely saturated except for the link where the ring is fused. When a group (or substituent or variable) is present more than once in any formula described here, each group (or substituent or variable) is independently selected, whether explicitly stated or not. For example, when more than one group R 'is present, then each group R' is independently selected. In another example, in the formula O (-C (O) -R2) 2, each group R2 is independently selected. The invention includes the compounds described herein in any of their pharmaceutically acceptable forms, including isomers (e.g., diastereomers and enantiomers), salts, solvates, polymorphs, prodrugs and the like. In particular, if a compound is optically active, the invention specifically includes each of the enantiomers of the compound as well as racemic mixtures of the enantiomers. It should be understood that the term "compound" includes any or all of these forms, whether or not explicitly indicated (although "salts" is sometimes explicitly indicated).

Preparation of the compounds More specific details of the reactions described herein are set forth in the context of the following schemes. Some embodiments of the invention are described below in the reaction schemes I to IX. For a more detailed description of the individual reaction steps, see the examples section below. The starting materials are generally available from commercial sources such as Aldrich Chemicals (Milwaukee, Wisconsin, USA), or are readily prepared using the methods known to those skilled in the art (eg, they are prepared by the methods described by Louis F. Fieser and Mary Fieser, "Reagents for Organic Synthesis", v. 1-19, Wiley, New York, (1967-1999 ed.), Alan R. Katritsky, Otto Met-Cohn, Charles W. Rees, "Comprehensive Organic Functional Group Transformations ", v. 1-6, Pergamon Press, Oxford, England, (1995), Barry M. Trost and Ian Fleming," Comprehensive Organic Synthesis ", v. 1-8, Pergamon Press, Oxford, England, (1991), or "Beilsteins Handbuch der organischen Chemie", 4, Aufl Ed. Springer-Verlag, Berlin, Germany, including supplements (also available through Beilstein's online database)). Although the starting materials and reagents are represented in the reaction schemes and are discussed below, they can be substituted with other starting materials and known reagents to provide a variety of derivatives or reaction conditions. In addition, many of the methods described below can be further modified in light of this description using conventional methods known to those skilled in the art. To perform the methods of the invention, it may sometimes be necessary to protect a particular functional group while reacting other functional groups of an intermediate. The need for such protection it varies depending on the nature of the particular functional group and the conditions of the reaction step. Suitable amino protecting groups include acetyl, trifluoroacetyl, fer-butoxycarbonyl (Boc), benzyloxycarbonyl, and 9-fluorenylmethoxycarbonyl (Fmoc). Suitable hydroxy protecting groups include the acetyl and silyl groups, such as the tert-butyl-dimethylsilyl group. For a general description of protecting groups and their use see T. W. Greene and P. G. M. Wuts, "Protective Groups in Organic Synthesis", 3rd edition, John Wiley & Sons, New York, USA UU., 1999. Conventional separation and purification methods and techniques can be used to isolate the compounds shown in the following reaction schemes. Such techniques may include, for example, all types of chromatography (high performance liquid chromatography (HPLC), column chromatography with common absorbents such as silica gel, and thin layer chromatography), recrystallization and differential extraction techniques (ie, liquid-liquid). The methods of the invention are shown in reaction scheme I, wherein RA, RB, RI, R2, E, and L are as defined above. In step (1) or (1 a) of reaction scheme I, a 3-nitropyridine, 3-nitroquinoline, or 3-nitronaphthyridine of formula V or II is reduced to a 3-aminopyridine, 3-aminoquinoline, or 3- aminonaphthyridine of formula VI or III, respectively. The reduction can be effected by several conventional methods. For example, the reaction can be carried out by hydrogenation using a heterogeneous hydrogenation catalyst, such as platinum on carbon or Raney nickel. The hydrogenation can be conveniently carried out at room temperature in a Parr apparatus, in a suitable solvent such as? /,? / - dimethylformamide (DMF). The reduction can also be carried out using nickel boride, prepared in situ from sodium borohydride and nickel (II) chloride. The reduction of nickel boride is conveniently effected by adding a solution of a compound of formula V or II in a solvent or mixture of suitable solvents, such as dichloromethane / methanol, to a mixture of excess sodium borohydride and nickel chloride (II). ) catalytic or stoichiometric in methanol. The reaction can be carried out at room temperature. Alternatively, the reduction can be effected using a reduction of sodium dithionite in one or two phases. The reduction of sodium dithionite can be conveniently effected using the conditions described by Park K. K .; Oh, C. H .; and Joung, W. K .; Tetrahedron Lett, 34, p. 7445-7446 (1993), adding sodium dithionite to a compound of formula V or II in a mixture of dichloromethane and water, at room temperature in the presence of potassium carbonate and ethylviologen dibromide, or ethylvilógeno diiodide, or dibromide of 1 , 1'-di-rj-octyl-4,4'-bipyridinium. Many compounds of formula V and II are known; others can be prepared by known methods. For quinolines and [1,5] naphthyridines of formula V and II wherein E is hydrogen and L is chlorine, see U.S. Pat. UU Nos. 4,689,338 (Gerster) and 6,194,425 (Gerster et al.), And references cited therein. The quinolines, tetrahydroquinolines and pyridines of formula II wherein E and L are chloro or -O-S (O) 2-R ', can be prepared from the compounds of formula V wherein E is hydroxy; see, for example, U.S. Pat. UU Nos. 4,988,815 (Andre et al.), 5,395,937 (Nikolaides et al.), 5,352,784 (Nikolaides et al.), 5,446,153 (Lindstrom et al.), And 6,743,920 (Lindstrom et al.), And references cited therein. For quinolines and naphthyridines of formula V or II wherein E is part of a tetrazolo ring and L is chloro or -O-S (O) 2-R ', see US Pat. UU Nos. 6,194,425 (Gerster et al.) And 5,741, 908 (Gerster et al.), And references cited therein. The compounds of formula II wherein E or L are phenoxy can be prepared from the compounds of formula II wherein E or L is chloro, using the methods described in 6,743,920 (Lindstrom et al.). The compounds of formula II wherein E is -N (Bn) 2 can be prepared from the compounds of formula II wherein E is -OS (O) 2 -R according to the methods described in 5,395,937 (Nikolaides and others) and 5,352,784 (Nikolaides and others). Various compounds of formula VI wherein E is hydrogen are known compounds, including substituted and unsubstituted pyridines, quinolines and naphthyridines, of each isomeric variation. See, for example, US Pat. UU No. 6,110,929 (Gerster et al.) And references cited therein. Also, some compounds of formula III are known. For example, 3-amino-4-chloroquinoline, 3-amino-4,5-dichloroquinoline and 3-amino-4,7-dichloroquinoline have been prepared by Surrey et al., Journal of the American Chemical Society, 73, p. 2413-2416 (1951).

In step (2) or (3a) of reaction scheme I, a 3-aminopyridine, 3-aminoquinoline or 3-aminonaphthyridine of formula VI or III is reacted with a carboxylic acid or an equivalent thereof, to provide a compound of formula VII or IV, respectively, substituted with amide. Suitable equivalents for carboxylic acids include acid anhydrides and acid halides. The selection of the carboxylic acid equivalent is determined by the desired substituent on R2. For example, the use of butyryl chloride provides a compound in which R2 is a propyl group; the use of ethoxyacetyl chloride provides a compound wherein R2 is an ethoxymethyl group. The reaction can be conveniently carried out by combining an acid halide of formula R2C (O) CI or R2C (O) Br with a compound of formula VI or III in a suitable solvent such as dichloromethane, acetonitrile or 1,2-dichloroethane, optionally in the presence of a tertiary amine such as triethylamine, pyridine, or 4-dimethylaminopyridine (DMAP). The reaction can be carried out at a reduced temperature, for example at 0 ° C, at room temperature, or at an elevated temperature such as 40 ° C to 90 ° C. For compounds wherein R2 is hydrogen, a compound of formula VI or III can be reacted with a formylating agent such as for example dietoxymethyl acetate or formic acetic anhydride. Some compounds of formula VII are known; see, for example, US Pat. UU No. 6,110,929 (Gerster et al.). In step (3) of reaction scheme I, the hydroxy group in a compound of formula VII is converted to a leaving group using conventional activation methods to provide a compound of formula IV. For example, the conversion of the hydroxy group to a chloro group can be conveniently carried out by combining a compound of formula VII with phosphorus oxychloride (III). The chlorination reaction can be carried out with the reagents alone or in a suitable solvent such as? /,? / - dimethylformamide (DMF), dichloromethane, acetonitrile, 1-methyl-2-pyrrolidinone (NMP), and 1,2-dichloroethane . The reaction can be carried out at room temperature or at an elevated temperature up to the reflux temperature, for example at a temperature of 25 ° C to 120 ° C. Other examples of chlorinating agents include, for example, thionyl chloride, phosgene, oxalyl chloride and phosphorus pentachloride. Other halogenating agents include phosphorus oxybromide (III), phosphorus pentabromide, diphenylphosphinic chloride, and triphenylphosphine, in the presence of bromine. The hydroxy group in a compound of formula VII can also be converted to a sulfonate ester by reaction with, for example, a sulfonyl halide or sulfonic anhydride. Suitable sulphonation agents include methanesulfonyl chloride, methanesulfonic anhydride, trifluoromethanesulfonyl chloride, trifluoromethanesulfonic anhydride,? / -phenylbis (trifluoromethanesulfonimide), benzenesulfonyl chloride, benzenesulfonic anhydride, p-bromobenzenesulfonyl chloride, p-bromobenzenesulfonic anhydride, p-toluenesulfonyl, p-toluenesulfonic anhydride, 2-nitrobenzenesulfonyl chloride and 4-nitrobenzenesulfonyl chloride. The reaction with a sulfonating agent is usually carried out in the presence of a base.

Preferably, the base is a tertiary amine such as triethylamine. The reaction can be carried out in a suitable solvent such as 1,2-dichloroethane, acetonitrile, tetrahydrofuran (THF), DMF, and NMP. The reaction can also be carried out in pyridine, which can be used as the base and as the solvent for the reaction. The reaction can be carried out at room temperature or at elevated temperature, such as the reflux temperature of the solvent. Preferably, the reaction temperature is from about room temperature to no more than 90 ° C. These methods described for step (3) of reaction scheme I can also be used to convert a 3-aminopyridine, 3-aminoquinoline, or 3-aminonaphthyridine of formula VI to a compound of formula III, as shown in step ( 2a) of reaction scheme I. In step (4) of reaction scheme I, an amide of formula IV is reacted with an amine of formula R? NH2, or a suitable salt thereof, to give a compound 1H -imidazo of formula I. The reaction can be carried out with reagents alone at an elevated temperature such as the temperature required to melt the mixture. The reaction can also be carried out in a suitable solvent at a suitable temperature. Suitable solvents include alcohols such as methanol, ethanol, trifluoroethanol, isopropanol and re-butanol; Water; acetonitrile; NMP; and toluene. Preferred solvents include trifluoroethanol, isopropanol, and fer-butanol. Preferably, the reaction temperature is higher than 80 ° C and lower than 200 ° C. Preferably, the reaction temperature is less than 180 ° C. From Preferably, the reaction temperature is 110 ° C to 165 ° C. Optionally, a base can be used in the reaction. Suitable bases include triethylamine. Optionally, a catalyst such as pyridine hydrochloride, pyridinium p-toluenesulfonate, or p-toluenesulfonic acid can be added. For some amines of the formula R? NH2 under certain conditions, an unclimed 3-amido-4-amino intermediate can be isolated. Then, the intermediate can be cyclized in a subsequent step by heating it in a solvent such as toluene, optionally in the presence of a catalyst such as pyridine hydrochloride or pyridinium p-toluenesulfonate. The cyclization can be carried out at an elevated temperature, such as the reflux temperature of the solvent. Many primary amines of the formula R? NH2 or salts thereof are commercially available, suitable for this reaction; others can be prepared by known methods. See for example the methods of the US patents. UU Nos. 6,451, 810 (Coleman et al.), 6,660,747 (Crooks et al.), 6,683,088 (Crooks et al.), And 6,656,938 (Crooks et al.); the US patent application publication UU No. 2004/0147543 (Hays et al.); and the international publication No. WO2005 / 051317 (Krepski et al.). Some amines of the formula R? NH2 can be made according to the following method. For some embodiments, Ri is a 1-hydroxycycloalkylmethyl group. The corresponding amine of formula R-? NH can be prepared by combining a cyclic ketone, such as cyclopentanone or cyclobutanone, with an excess of nitromethane, in a suitable solvent such as ethanol or methanol, in the presence of a catalytic amount of a base such as sodium ethoxide or sodium hydroxide, and reducing the resulting nitromethyl-substituted compound using heterogeneous hydrogenation conditions conventional Normally the hydrogenation is carried out in the presence of a catalyst such as palladium hydroxide on carbon, palladium on carbon, or Raney nickel, in a suitable solvent such as ethanol. Both the reaction with nitromethane and the reduction can be carried out at room temperature. A wide variety of cyclic ketones can be obtained from commercial sources, others can be synthesized using the known synthetic methods.

REACTION SCHEME I A compound of formula I can be converted to a compound of formula X using a variety of methods, depending on the identity of E.

Examples of these methods are shown in Reaction Schemes II to V. For some embodiments, the amination of a compound of Formula I is shown in Reaction Scheme II where Ei is a halogen, phenoxy, or -OS ( 0) 2-R ', and RA, RB, RI, R2 are as defined above. Step (1) of reaction scheme II can be used to convert a compound of formula I-4, wherein E is a hydroxy, to a compound of formula. Any of the methods described in step (3) and step (2a) of reaction scheme I can be used. The amination of step (2) of reaction scheme II is it can conveniently be carried out by heating a combination of a compound of formula h and a solution of ammonia in a suitable solvent such as methanol. The amination may be carried out using ammonium acetate or ammonium hydroxide in combination with a compound of formula and heating. The amination is preferably carried out at a temperature of less than 100 ° C, preferably not lower than 25 ° C, preferably not lower than 140 ° C. Preferably, the reaction is carried out at a temperature of less than 200 ° C, preferably less than 170 ° C.

REACTION SCHEME II l X Alternatively, a compound of formula li can be converted in two steps to a compound of formula X as shown in reaction scheme III, wherein RA > RB, RI, R2, ET and Bn are as defined above. Step (1) of reaction scheme III can be used to displace the group E1 in a compound of formula -¡ with an amine of formula HN (Bn) 2 to provide a compound of formula I-6. The displacement can be conveniently carried out by combining an amine of formula HN (Bn) 2 and a compound of formula [delta] in a suitable solvent, such as toluene or xylene, in the presence of a base such as triethylamine, and heating to a elevated temperature, such as the reflux temperature of the solvent. In step (2) of reaction scheme III, the protecting groups are removed from the 4-amine of a compound of formula I-6 to provide a compound of formula X. For some embodiments, the deprotection can be conveniently carried out in a Parr apparatus under hydrogenolysis conditions using a suitable heterogeneous catalyst, such as palladium on carbon in a solvent such as ethanol. Alternatively, when Bn is p-methoxybenzyl, step (2) can be carried out by combining trifluoroacetic acid and a compound of formula I-6 and stirring at room temperature or heated at an elevated temperature, such as 50 ° C to 70 ° C.

REACTION SCHEME III I, 1-6 X For some embodiments, a compound of formula I wherein E is hydrogen, can be converted to a compound of formula X2 by oxidation and amination, as shown in reaction scheme IV, wherein RA2, and RB2 taken together form a fused benzene ring or a fused pyridine ring, wherein the benzene ring or the pyridine ring is unsubstituted or substituted with a group R, or is substituted with a group R3, or is substituted with a group R and a group R3, and Ri and R2 are as defined above. In step (1) of reaction scheme IV, a compound of formula 1-22 is oxidized to a 5? / -oxide of formula XX2 using a conventional oxidizing agent capable of forming? / - oxides. The reaction is conveniently carried out by combining 3-chloroperoxybenzoic acid with a compound of formula l-22 in a suitable solvent, such as dichloromethane or chloroform. The reaction can be carried out at room temperature. Alternatively, other percents such as peracetic acid may be used as the oxidizing agent. The reaction with peracetic acid can be carried out in a suitable solvent such as ethanol, at an elevated temperature such as 50 ° C to 60 ° C. Then, the 5? / - oxide of formula XX2 is aminated in step (2) of reaction scheme IV to provide a compound of formula X2. The amination can be effected by activating the 5? / -oxide by conversion to an ester, and then reacting the ester with an amination agent. Suitable activating agents include alkyl- or arylsulfonyl chlorides such as benzenesulfonyl chloride, methanesulfonyl chloride, or p-toluenesulfonyl chloride. Suitable amination agents include ammonia in the form of ammonium hydroxide, for example, and ammonium salts such as ammonium carbonate, ammonium bicarbonate and ammonium phosphate. The reaction is conveniently carried out by adding p-toluenesulfonyl chloride to a mixture of ammonium hydroxide and a solution of the 5? / -oxide in a suitable solvent such as dichloromethane or chloroform. The reaction can be carried out at room temperature. The oxidation and amination steps can be carried out as a procedure in a container, without isolating the 5? / - oxide of formula XX2. Alternatively, the 5? / -oxide can be treated in step (2) with an isocyanate, wherein the isocyanate group is attached to a hydrolytically active functional group; subsequent hydrolysis of the resulting intermediate gives a compound of formula X2. The reaction can be conveniently carried out in two steps, (i) combining an isocyanate such as trichloroacetyl isocyanate and a solution of the 5? / -oxide in a solvent such as dichloromethane and stirring at room temperature to provide an insulatable amide intermediate. In step (ii), a solution of the intermediate in methanol can be treated with a base such as sodium methoxide at room temperature. Alternatively, a 5? / - oxide of formula XX can be converted to a compound of formula wherein E < It is chlorine, using one of the methods described in step (3) of reaction scheme I. The resulting 4-chloro compound can then be aminated according to the methods described in reaction scheme II.

REACTION SCHEME IV 1_22 xx2 X2 For the embodiments wherein E is attached to the pyridine nitrogen atom in a compound of formula I to form a ring of fused tetrazolo, the tetrazolo ring can be removed to form a compound of formula X as shown in reaction scheme V, wherein, RA, RB, RI, and R2, are as defined above, and Ph is phenyl. In step (1) of reaction scheme V, a compound of formula 1-1 is combined with triphenylphosphine to form an intermediate of? Rifenylphosphinyl of formula XXI. The reaction with triphenylphosphine can be carried out in a suitable solvent such as toluene or 1,2-dichlorobenzene, under a nitrogen atmosphere with heating, for example at reflux temperature. In step (2) of reaction scheme V, a? / - triphenylphosphinyl intermediate of formula XXI is hydrolyzed to provide a compound of formula X. The hydrolysis can be carried out by known general methods, for example, by heating in an alkanol or an alkanol / water solution in the presence of an acid such as trifluoroacetic acid, acetic acid, or hydrochloric acid. A compound of formula X can also be obtained by an alternative route as shown in step (1 a) of reaction scheme V. In step (1 a), the tetrazolo ring is reductively removed from a compound of formula 1-1 to provide a compound of formula X. The reaction can be carried out by reacting the compound of formula 1-1 with hydrogen in the presence of a catalyst and an acid. The hydrogenation can conveniently be carried out at room temperature in a Parr apparatus, with a suitable catalyst such as platinum IV oxide, and a suitable acid such as trifluoroacetic acid or hydrochloric acid. Optionally, the reaction can be carried out in the presence of a solvent, such as for example ethanol. If step (1a) is used, a compound of formula 1-1 wherein RA, and RB, taken together form a fused benzene ring or a fused pyridine ring, can be converted to a compound of formula X, wherein RA and RB taken together form a saturated 5 to 7 membered fused ring optionally containing a nitrogen atom. The person skilled in the art will understand that other groups susceptible to reduction, such as the alkenyl, alkynyl and aryl groups, would be reduced in step (1a).

REACTION SCHEME V For some embodiments, the compounds of formula XB can be reduced according to reaction scheme VI, wherein RA3 and RB3 taken together form a fused benzene ring or a fused pyridine ring, wherein the benzene ring or ring of pyridine is unsubstituted or substituted with a group Rb, or is substituted with a group R3b; or is substituted with a group R and a group R3b; RA, and RB4 taken together form a saturated 5 to 7 membered fused ring optionally containing a nitrogen atom, wherein the fused ring is not substituted or substituted with one or more Rb groups; and Rib, R 2b, R 3b and Rb are subgroups of R-i, R 2, R 3, and R as defined above, and do not include substituents that the person skilled in the art would recognize as susceptible to reduction under the acid hydrogenation conditions of the reaction. These susceptible groups include, for example, the alkenyl, alkynyl and aryl groups, and groups bearing nitro substituents. As shown in reaction scheme VI, a 1 H-imidazo [4,5-c] quinolin-4-amine or 1 H-midazo [4,5-c] [1,5] naphthipid -4-amino of formula Xb can be reduced to a 6,7,8,9-tetrahydroquinoline or tetrahydronaphthyridine of formula Xc. The compounds of formula Xb can be prepared according to the methods described in reaction schemes II, III, IV, or V. The reaction is conveniently carried out under heterogeneous hydrogenation conditions by adding platinum (IV) oxide to a solution of the compound of formula Xb in trifluoroacetic acid, and placing the reaction under hydrogen pressure. The reaction can be carried out in a Parr apparatus at room temperature.

REACTION SCHEME VI For some embodiments, the compounds shown in the Reaction schemes I to VI can be further modified using conventional synthetic methods. Amines of formula R? NH2 used in step (4) of reaction scheme I may contain a protected functional group, such as an amino group protected with fer-butoxycarbonyl. For example, protected diamines of formula Bco-N (R8) -X-NH2, they are commercially available or can be prepared by known methods; see, for example, U.S. Pat. UU Nos. 6,660,747 (Crooks et al.), 6,683,088 (Crooks et al.), And 6,656,938 (Crooks et al.), And Carceller, E. et al., J Med. Chem., 39, p. 487-493 (1996).

The protecting group can be removed after the cyclization step shown in step (4) of reaction scheme I, or after the steps shown in reaction scheme II to VI, to reveal for example an amino substituent on the group Ri An amino group introduced in this manner can be reacted with an acid chloride of the formula R 4 C (O) CI, a sulfonyl chloride of the formula R 4 S (O) 2 Cl, a sulfonic anhydride of the formula (R4S (? 2)) 2O, or an isocyanate of formula R4N = C = 0, to give a compound of formula X wherein Ri is: -X-N (R8) -Q-R4, wherein X, R4, R7, Rβ and Rio are as defined above and Q is -C (O) -, -SO2-, or -C (O) -NH-. Many acid chlorides, sulfonyl chlorides, sulfonic anhydrides and isocyanates are commercially available; others can be easily prepared using known synthetic methods. The reaction can be conveniently carried out by combining the acid chloride, sulfonyl chloride, sulfonic anhydride or isocyanate, and a solution of an amino substituted compound, and a base such as triethylamine in a suitable solvent such as dichloromethane. The reaction can be carried out at room temperature. Amines of formula RtNH2 may also contain other protected functional groups such as ketal protected ketones. For example, 2,2-dimethyl-3- (2-methyl-1,3-dioxolan-2-yl) propylamine prepared in Example 22 of International Publication No. WO 2005/051317 (Krepski et al.) Can be used in step (4) of reaction scheme I. The ketal protecting group can then be removed by conventional methods to give a compound of formula I or X wherein Ri is 2,2-dimethyl-4-oxopentyl. The aminoalcohols of the formula H2N-X-OH can be used in step (4) of reaction scheme I, and the hydroxy functional group can convert in subsequent steps to a compound of formula I or X having a group XS (O) 0.2-R4, -XS (O) 2-N (R8) -R4, -XON (R8) -QR, -XON = C (R4) -R4, -X-CH (-N (-O-R8) - Q-R4) -R4 in the Ri position, using the methods described in U.S. Pat. UU No. 6,664,264 (Dellaria et al.), And publications International Nos. WO 2005/066169 (Bonk and Dellaria), WO 2005/018551 (Kshirsagar and others), WO 2005/018556 (Kshirsagar and others), and WO 2005/051324 (Krepski and others), respectively. The amine used in step (1) may be fer-butyl carbazate, and the resulting compound of formula I or the subsequently converted compound of formula X wherein Ri is an amino group protected with Boc may be deprotected to provide a compound 1 -amino or a salt thereof (for example a hydrochloride salt). The deprotection can be effected by refluxing a solution of a compound of formula I or X in ethanolic hydrogen chloride. The resulting compound of formula I or X wherein Ri is an amino group can be treated with a corresponding ketone, aldehyde, or ketal or acetal, acidic conditions. For example, a ketone can be added to a solution of the hydrochloride salt of a compound of formula I or X wherein Ri is an amino group, in a suitable solvent such as isopropanol or acetonitrile, in the presence of an acid such as p- pyridinium toluene sulfonate or acetic acid, or an acid resin, for example as the DOWEX W50-X1 acid resin. The reaction can be carried out at an elevated temperature. The resulting imine can be reduced to provide a compound of formula I or X wherein R-i is -N (R '?) - QR4, where Q is a bond. The reduction can be carried out at room temperature with sodium borohydride in a suitable solvent, for example methanol. A rer-butyl hydrazinecarboxylate can also be manipulated in subsequent steps using the methods of the publication of the patent application. from USA UU No. 2005/0054640, to give other compounds of formula I or X wherein Ri is -N (R? ') - Q-R4, -N (R?') - X? -Y-R4, or -N (R ? ') - XrR5b. Other transformations can be made in the R- | position. See, for example, U.S. Pat. UU Nos. 5,389,640 (Gerster et al.), 6,33, 539 (Crooks et al.), 6,451, 810 (Coleman et al.), 6,541, 485 (Crooks et al.), 6,660,747 (Crooks et al.), 6,670,372 (Charles et al. ), 6,683,088 (Crooks et al.), 6,656,938 (Crooks et al.), 6,664,264 (Dellaria et al.), 6,677,349 (Griesgraber), and 6,664,260 (Charles et al.). For some embodiments synthetic transformations can be made at the position R2 in a compound of the formula I or X, if for example the carboxylic equivalent used in step (2) or (3a) of the reaction scheme I contains a protected hydroxy group or unprotected or a protected amino group. Some carboxylic acid equivalents of this type are commercially available; others can be prepared by known synthetic methods. A protected hydroxy or amino group installed in the R2 position can be deprotected by a variety of well-known methods. For example, a hydroxyalkylenyl group is conveniently introduced at the R 2 position by dealkylation of a methoxy- or ethoxyalkylenyl group, which can be installed using an equivalent carboxylic acid substituted with methoxy or ethoxy in step (2) or (3a) of the reaction scheme I. The dealkylation can be carried out by treating a compound of formula I or formula X wherein R2 is an alkoxyalkylenyl group with boron tribromide in a suitable solvent such as dichloromethane a a temperature lower than room temperature, such as 0 ° C. Then, the resulting hydroxy group can be oxidized to an aldehyde or carboxylic acid, or can be converted to a leaving group such as for example a chloro group, using thionyl chloride or a trifluoromethanesulfonate group using trifluoromethanesulfonic anhydride. Then, the resulting leaving group can be displaced with a variety of nucleophiles. Sodium azide can be used as the nucleophile to install an azide group, which can then be reduced to an amino group using heterogeneous hydrogenation conditions. An amino group at the R 2 position can be converted to an amide, sulfonamide, sulfamide, or urea, using conventional methods. A leaving group in R2, such as a chloro or trifluoromethanesulfonate group, can also be displaced with a secondary amine, a substituted phenol, or a mercaptan, in the presence of a base such as potassium carbonate. For examples of these and other methods used to install a variety of groups in the R2 position, see U.S. Pat. UU 5,389,640 (Gerster et al.). These synthetic transformations can be conveniently carried out as the last steps of the synthesis, or before the steps shown in reaction schemes II to VI. The 1 / - / - imidazo [4,5-c] quinolines of formulas II and V wherein the quinoline ring is substituted with a bromo, benzyloxy, or methoxy substituent, and E is hydrogen, are known, or can be prepare according to the methods described in the publication of the US patent application. UU No. 2004/0147543 (Hays et al.), And the international publication No. WO 2005/020999 (Lindstrom et al.). These compounds can be subjected to the methods of reaction scheme I to give the 1 / - / - imidazo [4,5-c] quinolines of formula I-22, which can then be oxidized and aminated according to the methods of the scheme of reaction IV. Compounds in which the quinoline ring is substituted with a benzyloxy or methoxy group can then be converted to a hydroxy-substituted 1 / - / - imidazo [4,5-c] quinolin-4-amine of formula XXII, shown further below in the VIL reaction scheme The demethylation of a methoxy-substituted compound can be carried out with boron tribromide as described in the previous paragraph. Alternatively, the demethylation can be effected by heating the methoxy-substituted compound with anhydrous pyridinium chloride at an elevated temperature, such as 210 ° C. The removal of a benzyloxy group can be carried out as described in International Publication No. WO 2005/020999 (Lindstrom et al.). Then further synthetic work up of the 1H-imidazo [4,5-c] quinolin-4-amines can be done as shown in reaction scheme VII, where R3c is -R4, -X-R4, -XY-R4 , -XYXY-R4, or -X-R5; R3d is -0-R4, -O-X-R4, -O-X-Y-R, -O-X-Y-X-Y-R, or -O-X-R5, Rd is selected from the group consisting of halogen, alkyl, alkenyl, trifluoromethyl and dialkylamino; n is 0 or 1; and R1 and R2 are as defined above. In step (1) of reaction scheme VII, the hydroxy group of a 1H-imidazo [4,5-c] quinolin-4-amine of formula XXII is activated by conversion to a trifluoromethanesulfonate (triflate) group according to any of the methods described in step (2a) or (3) of reaction scheme I, to give a compound of formula XXIII.

Step (2) of reaction scheme VII can be carried out using known reactions of palladium catalyzed coupling, such as Suzuki coupling, Heck reaction, Stille coupling, and Sonogashira coupling according to any of the methods described in the publication of the US patent application. UU No. 2004/0147543 (Hays et al.), To give a compound of formula XXIV. Alternatively, in this transformation, compounds can be used in which a bromo substituent is used in place of a triflate group in a compound of formula XXIII. The Suzuki coupling is carried out with an aryl or vinyl boronic acid, an anhydride thereof, or a boronic acid ester. The Heck reaction is carried out with a vinyl-substituted compound. The coupling reactions of Sonogashira and Stille can be carried out with alkynes, and any of the unsaturated compounds prepared by these couplings can be subjected to reduction of the alkenylene or alkynylene group. In step (1a) of reaction scheme VII, a hydroxy-substituted 1H-imidazo [4,5-c] quinolin-4-amine of formula XXII is converted to a compound of formula XXV using a Williamson-type ether synthesis . The methods described in international publications Nos. WO 2005/020999 (Lindstrom et al.) And WO 2005/032484 (Lindstrom et al.) Can be used.

REACTION SCHEME Vil For some embodiments, the methods of the invention are shown in reaction scheme VIII, wherein RA, RB, RI, Rn R? 2, E and L are as defined above. In step (1) of reaction scheme VIII, a 3-aminopyridine, 3-aminoquinoline, or 3-aminonaphthyridine of formula VI is converted to an imidoformamide of formula VIII. The reaction can be carried out by combining a 3-aminopyridine, 3-aminoquinoline, or 3-aminonaphthyridine of formula VI, or a suitable salt thereof, with a halogenating agent or a sulfonating agent described in step (3) or ( 2a) of reaction scheme I, in the presence of a formamide of formula HC (O) -N (Rn) R12. Several formamides of formula HC (0) -N (Rn) R? 2 are commercially available, such as for example DMF, N, N-diethylformamide, and 1-formylpiperidine. Other formamides of this formula can be prepared by known methods; for example, an amine can be combined with a mixture of formic acid and acetic anhydride in a suitable solvent such as THF, acetone, acetonitrile, ethyl acetate, tert-butyl methyl ether, DMF, NMP, dichloromethane, toluene, xylene methanol and ethanol. The reaction can be carried out at room temperature, below room temperature, or at a temperature of about 0 ° C to room temperature, or at a temperature raised to the reflux temperature of the solvent. Step (1) of reaction scheme VIII can be carried out in a solvent such as dichloromethane, 1,2-dichloroethane, acetonitrile, THF, toluene, and NMP, or in some embodiments the reaction can be carried out in excess of DMF. The reaction can be carried out at room temperature, below room temperature, such as a temperature higher than 0 ° C, or a high temperature, such as at a temperature lower than the reflux temperature of the solvent. For some embodiments, the reaction temperature is less than 40 ° C. For some embodiments, step (1) of reaction scheme VIII can be performed by combining a compound of formula VI with phosphorus oxychloride (III) in excess of DMF, at an ambient temperature or at an elevated temperature such as a temperature of less than 150X. . For some embodiments, DMF can be used as the solvent. For some modalities, the reaction temperature is 15 ° C to 30 ° C. For some modalities, the conversion of a 3-aminopyridine, 3-aminoquinoline, or 3-aminonaphthyridine of formula VI to an imidoformamide of formula VIII can be carried out in two steps, such as steps (la) and (2a), or (Ib) and (2b) of reaction scheme VIII. Steps (1a) and (2b) can be Carry out in accordance with the methods described in step (3) or (2a) in reaction scheme (1), in a solvent different from DMF. Steps (1a) and (2b) can be performed as described in step (1) of reaction scheme VIII, but in the absence of a halogenating or sulfonation agent. In step (3) of reaction scheme VIII, an imidoformamide of formula VIII is reacted with an amine of formula R1NH2, or a suitable salt thereof, to provide a 1H-imidazo compound of formula I-H. The reaction can be carried out with the reagents alone at an elevated temperature, such as the temperature required to melt the mixture. The reaction can also be carried out in a suitable solvent at room temperature or at an elevated temperature. Suitable solvents include alcohols such as methanol, ethanol, trifluoroethanol, isopropanol and re-butanol; Water; acetonitrile; NMP; toluene and tetrahydrofuran. Preferred solvents include trifluoroethanol, isopropanol, tert-butanol and acetonitrile. Preferably, the reaction temperature is less than 250 ° C. The reaction can be carried out at a temperature lower than 200 ° C or at a temperature below 180 ° C Optionally, a base can be used in the reaction Suitable bases include triethylamine Optionally a catalyst such as pyridine hydrochloride can be added. pyridinium toluene sulfonate, or p-toluenesulfonic acid Under certain conditions, an intermediate of imideoformamide of formula XI can be formed, XI during step (3) of the reaction scheme (VIII). For some embodiments, the intermediate of formula XI is isolated from the reaction mixture. The intermediary can then be cyclized in a subsequent step. Cyclization can optionally be carried out by heating in a solvent such as those described in the preceding paragraph, and optionally in the presence of a catalyst such as pyridine hydrochloride, pyridinium p-toluenesulfonate, or p-toluenesulfonic acid. Preferably, the cyclization reaction temperature is less than 200 ° C. The cyclization can be carried out at a temperature lower than 200 ° C or at a temperature lower than 180 ° C. For some embodiments, steps (1) and (3) of the reaction scheme VIII are carried out as a procedure in a container, without isolating the compound of formula VIII The method can be carried out by adding an amine of formula R? NH2, or a suitable salt thereof, directly to the reaction mixture of step (1) of reaction scheme VIII. The reaction mixture can be filtered before adding the amine of the formula R? NH2 The resulting mixture can then be subjected to the conditions of step (3) to give a compound of formula 1-H.

REACTION SCHEME VIII For some embodiments, the methods of the invention are shown in reaction scheme IX, wherein RA, RB, RI, E and L are as defined above. In step (1) of reaction scheme IX, a 3-aminopyridine, 3-aminoquinoline, or 3-aminonaphthyridine of formula VI is converted to an imidoformamide of formula XI. Step (1) of reaction scheme IX can be carried out under the conditions described for step (1) of reaction scheme VIII, using a formamide of formula, HC (O) -NHR- ?, instead of HC (0) ) -N (Rn) R12. Some formamides of formula HC (O) -NHR? They are commercially available. Others may be prepared by known methods; for example, an amine of formula R? NH2 can be combined with a mixture of formic acid and acetic anhydride, using any of the solvents and conditions described in step (1) of reaction scheme VIII with respect to the preparation of HC ( O) -N (Rn) R? 2. Alternatively, an amine of formula R? NH 2 can be combined with another formylating agent such as methyl formate, formamide, and chloroform, in the presence of sodium hydroxide, under conditions known to the person skilled in the art. See, for example, J. Org. Chem., 23, p. 1032 (1958), J. Am. Chem. Soc. 78, p. 2467 (1956), J. Chem. Soc, p. 858 (1957), J. Am. Chem. Soc. 74, p. 5619 (1952), and Tetrahedron Lett, 7, p. 5 (1959). The compound of formula XI can be isolated from the reaction mixture before step (2) of reaction scheme IX, or steps (1) and (2) can be carried out without isolating the compound of formula XI. If an imidoformamide of formula XI is isolated, step (2) of reaction scheme IX can be used to cyclize a compound of formula XI to a compound of formula l-H. The reaction can be carried out with reagents alone at an elevated temperature, such as the temperature required to melt the compound of formula XI. The reaction can also be carried out in a suitable solvent at room temperature or at an elevated temperature. Suitable solvents include alcohols such as methanol, ethanol, trifluoroethanol, isopropanol and tert-butanol; water, acetonitrile; NMP; and toluene. Preferred solvents include trifluoroethanol, isopropanol and tert-butanol; and acetonitrile. Preferably, the temperature of the cyclization reaction is less than 250 ° C. The cyclization can be carried out at a temperature lower than 200 ° C, or at a temperature lower than 180 ° C. Optionally, a base can be used in the reaction. Suitable bases include triethylamine. Optionally, a catalyst such as pyridine hydrochloride, pyridinium p-toluenesulfonate, or p-toluenesulfonic acid can be added.

REACTION SCHEME IX A compound of formula IH can be converted to a compound of formula X wherein R2 is hydrogen, using a variety of methods depending on the identity of E. Examples of these methods are shown in reaction schemes II to V, wherein R2 It is hydrogen. The synthetic methods of reaction schemes VI and VII can also be carried out using the starting materials Xb and XXII wherein R2b and R2, respectively, are hydrogen.

EXAMPLES The objects and advantages of this invention are further illustrated by the following examples, but the particular materials and amounts cited in these examples, as well as other conditions and details, are not considered to be limiting of this invention.

EXAMPLE 1 Preparation of 1 - [4-amino-2- (ethoxymethyl) -1 H-imidazof4,5-c1quinolin-1 -ill-2-methylpropan-2-ol Part AA a solution of 3-amino-4-chloroquinoline (see Surrey et al., Journal of the American Chemical Society, 73, p 2413-2416 (1951)) (11.2 g, 62.7 mmol) in dichloromethane (125 mL) was he added triethylamine (13.1 mL, 94.1 mmol) with shaking. Then a solution of ethoxyacetyl chloride (9.2 g, 75 mmol) in dichloromethane (35 mL) was added dropwise, and the reaction was stirred at room temperature overnight. An analysis by liquid chromatography / mass spectrometry (LC / MS) indicated the presence of initial material, and a solution of more ethoxyacetyl chloride (2.3 g, 19 mmol) in dichloromethane (10 mL) was added dropwise. The reaction was stirred at room temperature overnight. A saturated aqueous solution of sodium bicarbonate (100 mL) was added and the resulting mixture was stirred at room temperature for 30 minutes. The organic layer was separated and washed sequentially with a saturated aqueous solution of sodium bicarbonate (50 mL) and water (2 x 50 mL).; dried over potassium carbonate, filtered and concentrated under reduced pressure, to give 17.0 g of? / - (4-chloroquinolin-3-yl) -2-ethoxy-acetamide as a dark oil which crystallized at room temperature. rest. Part B A mixture of? / - (4-chloroquinolin-3-yl) -2-ethoxyacetamide (4.5 g, 17 mmol), 1-amino-2-methylpropan-2-ol (2.3 g, 26 mmol), and acid p-toluenesulfonic monohydrate (150 mg, 0.79 mmol), put in a pressure vessel lined with TEFLON, heated at 125 ° C for 15 hours, and allowed to cool to room temperature. Dichloromethane (150 mL) and a saturated aqueous solution of sodium bicarbonate (25 mL) were added; the mixture was stirred for 15 minutes. The organic layer was separated and washed sequentially with a saturated aqueous solution of sodium bicarbonate (2 x 35 mL) and water (25 mL), dried over potassium carbonate, filtered and concentrated under reduced pressure to yield 4.6. g of 1- [2- (ethoxymethyl) -1H-imidazo [4,5-c] quinolin-1-yl] -2-methylpropan-2-ol as a dark brown oil. HRMS (ESI) cale, for C17H21N3O2 M + H +: 300.1712, found 300.1713. Part C A solution of 1- [2- (ethoxymethyl) -1 / - / - imidazo [4,5-c) quinolin-1-yl] -2-methylpropan-2-ol (0.98 g, 3.3 mmol) in dichloromethane (35 mL) was cooled to about 0 ° C and 3-chloroperoxybenzoic acid (1.1 g of approximately 77% pure material, 5 mmol) was added. The reaction was stirred for 10 minutes at 0 ° C, stirred for 3 hours at room temperature, diluted with dichloromethane (50 mL) and saturated aqueous sodium bicarbonate solution (35 mL), and stirred for 15 minutes. The aqueous layer was separated and extracted with dichloromethane (3 x 25 mL), and the combined organic fraction was dried over potassium carbonate, filtered and concentrated under reduced pressure to give 0.96 g of 1- [2- (ethoxymethyl) -5-oxido-1 H-imidazo [4,5-c] quinolin-1-yl] - 2-methylpropan-2-ol as a brown oil. HRMS (ESI) cale, for C? H2? N303 M + H +: 316.1661, found 316.1664. Part D A solution of 1- [2- (ethoxymethyl) -5-oxido-1 / - / - imidazo [4,5-c] quinolin-1-yl] -2-methylpropan-2-ol (0.96 g, 3.0 mmol) in dichloromethane (35 mL) was cooled to 0 ° C and trichloroacetyl isocyanate (0.60 mL, 5.0 mmol) was added with stirring. The reaction was stirred for 15 minutes at 0 ° C and then stirred overnight at room temperature. Methanol (10 mL) was added and the mixture was stirred 20 minutes and concentrated under reduced pressure. The residue was dissolved in methanol (10 mL) and sodium methoxide (0.25 mL of a 25% w / w solution in methanol) was added. The mixture was stirred at room temperature for 3 hours. An LC / MS analysis indicated that the reaction was incomplete, and more sodium methoxide solution (1.0 mL) was added. The reaction was stirred overnight at room temperature and determined to be incomplete. Hydrochloric acid (5 mL of a 10% w / w solution) was added, and the mixture was stirred for 1 hour. A saturated aqueous solution of sodium bicarbonate (15 mL) and aqueous sodium hydroxide (10 drops of 50% w / w solution) was added, and the reaction was stirred overnight at room temperature. An analysis by LC / MS again showed that the reaction is incomplete. Potassium hydroxide (5 mL of a 0.5 N solution in methanol) was added, and the reaction mixture was heated to reflux for four hours, it was allowed to cool to room temperature, and concentrated under reduced pressure. The residue was dissolved in dichloromethane (75 mL), and the solution was washed with water (2 x 50 mL), dried over potassium carbonate, filtered and concentrated under reduced pressure. The residue (0.64 g) was purified by column chromatography on silica gel (eluting with 5% methanol in dichloromethane containing 2 mL of aqueous ammonium hydroxide per liter of eluent). The resulting solid was recrystallized from methanol / water, recrystallized from methanol three times, and dried overnight under vacuum at 70 ° C to give 1- [4-amino-2- (ethoxymethyl) -1 / - / - imidazole. [4,5-c] quinolin-1-yl] -2-methylpropan-2-ol as cinnamon needles, mp 192-194 ° C. MS (APCI) m / z 315 (M + H +); HRMS (ESI) cale, for C? 7H22N4O2M + H +: 315.1821, found 315.1819. Anal, cale, for C? 7H22N4O2: C.64.95; H.7.05; N, 17.82. Found C.64.94; H, 6.94; N, 17.74.

EXAMPLE 2 Preparation of V-f4- (4-amino-2-ethyl-1 H-imidazo [4,5-c] quinolin-1-yl) butyl] methanesulfonamide Part A A solution of 3-amino-4-chloroquinoline (5.0 g, 28 mmol) and triethylamine (5.8 mL, 42 mmol) in dichloromethane (100 mL) was cooled to about 0 ° C. Then a solution of propionyl chloride (2.8 g, 31 mmol) in dichloromethane (15 mL) was added dropwise over a period of 15 minutes, and the reaction was allowed to warm to room temperature and stirred overnight. An analysis by high performance liquid chromatography (HPLC) indicated the presence of initial material, and added more triethylamine (1.95 mL, 14.0 mmol) and propionyl chloride (0.85 g, 9.2 mmol) in dichloromethane (5 mL). The reaction was stirred at room temperature overnight; it was diluted with dichloromethane (100 mL); it was washed sequentially with water, saturated aqueous sodium carbonate solution, 10% w / w aqueous sodium hydroxide solution, saturated aqueous sodium carbonate solution, and brine. It was dried over magnesium sulfate and sodium sulfate, filtered and concentrated under reduced pressure. The resulting brown solid (8.1 g) was recrystallized from toluene to give 4.5 g of? / - (4-chloroquinolin-3-yl) propanamide as beige platelets, m.p. 151-152 ° C. Part B In a glass-lined pressure vessel, a solution of N- (4-chloroquinolin-3-yl) propanamide (3.3 g, 14 mmol),? / - (4-aminobutyl) methanesulfonamide hydrochloride (see example 199) from the publication of US Patent Application No. 2004/0147543; 3.14 g, 15.5 mmol), and triethylamine (3.9 mL, 28 mmol) in trifluoroethanol (35 mL), was heated at 150 ° C for 16 hours. hours and allowed to cool to room temperature. The volatile material was removed under reduced pressure and the resulting amber paste dissolved in dichloromethane. The solution was washed sequentially with dilute aqueous ammonium chloride, saturated aqueous sodium carbonate solution (2 x), and brine; dried over magnesium sulfate and sodium sulfate; it leaked; and concentrated under reduced pressure. The resulting amber syrup (4.8 g) was recrystallized from hot propyl acetate. The crystals were washed with propyl acetate to give 3.8 g of? / - [4- (2-ethyl-1 / - / - imidazo [4,5-c] quinolin-1-yl) butyl] methanesulfonamide as color granules light amber, mp 166-168 ° C. Part CA a solution of? / - [4- (2-ethyl-1 / - / - imidazo [4,5-c] quinolin-1-yl) butyl] methanesulfonamide (3.8 g, 11 mmol) in dichloromethane (75 mi) was added in portions solid 3-chloroperoxybenzoic acid (2.7 g of approximately 77% pure material, 13 mmol). The reaction was stirred for 5 hours at room temperature. An HPLC analysis indicated the presence of initial material and more 3-chloroperoxybenzoic acid (0.5 g) was added. The reaction was stirred one hour at room temperature and ammonium hydroxide (50 mL) was added thereto. The resulting mixture was stirred vigorously at room temperature for 15 minutes and then p-toluenesulfonyl chloride (2.5 g, 0.013 mol) was added in one portion. The mixture was stirred vigorously at room temperature overnight. A fine solid was present and was collected by vacuum filtration (3.4 g) and recrystallized from ethanol (100 mL). The crystals were dried in a vacuum oven at 60 ° C for four hours to give 3.0 g of? / - [4- (4-amino-2-ethyl-1 / - / - imidazo [4,5-c] quinolin -1-il) butyl] - methanesulfonamide as straw-colored feathery crystals, m.p. 198-200 ° C. MS (APCI) m / z 362 (M + H) +; Anal. cale, for C17H23N502S: C, 56.49; H.6.41; N, 19.37. Found C.56.31; H, 6.49; N, 19.13.

EXAMPLE 3 Preparation of V-. { 2-r4-amino-2- (ethoxymethyl) -1H-imidazo [4,5-c1quinolin-1-H -1,1 -dimethylethyl) methanesulfonamide monohydrate Part A A solution of 1,2-diamino-2-methylpropane (11.9 mL, 113 mmol), tert-butyl-phenyl carbonate (42.1 mL, 227 mmol) and absolute ethanol (500 mL) was heated to reflux under one atmosphere of nitrogen for 20.5 hours. The volatile material was removed under reduced pressure and the residue was dissolved in water (560 mL). The solution was adjusted to a pH of about 3 by adding hydrochloric acid (140 mL of 1 N) and washed with dichloromethane (2 x 1 L). The pH of the aqueous solution was adjusted to approximately 12, adding an aqueous solution of sodium hydroxide (70 mL of 2 N solution), and extracted with dichloromethane (5 x 800 mL). The combined extract was dried over sodium sulfate, filtered, concentrated under reduced pressure and further dried under vacuum to give 13.05 g of 2-amino-2- tert-butyl methylpropylcarbamate, which was combined with material from other runs. Part B A solution of tert-butyl 2-amino-2-methylpropylcarbamate (20.8 g, 111 mmol) and triethylamine (23.2 mL, 167 mmol) in dichloromethane (125 mL) was cooled to -9 ° C. A solution was added of methanesulfonic anhydride (21.25 g, 122 mmol) in dichloromethane (106 mL) over a period of 50 minutes, keeping the reaction temperature at -4 ° C or less. After the addition, the reaction was stirred 30 minutes; it was diluted with dichloromethane (80 mL); washed sequentially with brine (30 mL), saturated aqueous solution of ammonium chloride (30 mL), hydrochloric acid % w / w (20 mL), brine (10 mL), saturated aqueous sodium carbonate solution (20 mL), and brine (10 mL); dried over magnesium sulfate, filtered, concentrated under reduced pressure and dried in vacuo, to give tert-butyl 2-methyl-2 - [(methylsulfonyl) amino] propylcarbamate. Part C Hydrogen chloride (153 mL of a 4 N solution in 1,4-dioxane) was cooled to 0 ° C and stirred. The material from part B was added in portions followed by a rinse with ethanol. The reaction was allowed to warm to room temperature and stirred overnight. The solvent was removed under reduced pressure and the residue was concentrated twice from ethanol and dried under vacuum to give? / - (2-amino-1,1-dimethylethyl) methanesulfonamide hydrochloride.

Part D In a pressurized glass lined container, a solution of N- (4-chloroquinolin-3-yl) -2-ethoxyacetamide (2.0 g, 7.6 mmol),? / - hydrochloride (2-amino-1, 1) -dimethylethyl) methanesulfonamide (2.16 g, 10.7 mmol), and triethylamine (2.6 mL, 19 mmol) in trifluoroethanol (30 mL), was heated at 150 ° C for 16 hours. An HPLC analysis indicated the presence of initial material and more γ / - (2-amino-1,1-dimethylethyl) methanesulfonamide hydrochloride (0.5 g) and triethylamine (0.3 mL) were added. The heating is continuous 16 hours more. The volatile material was removed under reduced pressure and the resulting amber paste was dissolved in dichloromethane. The solution was washed sequentially with dilute aqueous ammonium chloride, saturated aqueous sodium carbonate solution (2x), and brine; dried over magnesium sulfate and sodium sulfate; it leaked; and concentrated under reduced pressure. The resulting amber syrup (4 g) was purified by column chromatography on silica gel to give 1.6 g of? / -. { 2- (Ethoxymethyl) -1H-imidazo [4,5-c] quinolin-1-yl] -1, 1-dimethylethyl} -methanesulfonamide as an amber syrup. Part E To a solution of? / -. { 2- (Ethoxymethyl) -1 / - / - imidazo [4,5-c] quinolin-1-yl] -1, 1-dimethylethyl} methanesulfonamide (1.6 g, 4.2 mmol) in dichloromethane (30 mL) was added in portions solid 3-chloroperoxybenzoic acid (1.1 g of approximately 77% pure material, 5 mmol). The reaction was stirred for three hours at room temperature. An HPLC analysis indicated the presence of a small amount of starting material, and more acid was added. chloroperoxybenzoic acid (0.2 g). The reaction was stirred one hour at room temperature and ammonium hydroxide (30 mL) was added. The resulting mixture was stirred vigorously at room temperature for 15 minutes and then p-toluenesulfonyl chloride (0.97 g, 0.0051 mol) was added in one portion. The reaction mixture was stirred vigorously at room temperature for two hours, diluted with dichloromethane, washed sequentially with a saturated aqueous solution of sodium carbonate (2 x) and brine (1 x), dried over sodium sulfate and sulfate of magnesium, filtered and concentrated under reduced pressure to give an amber syrup. The syrup was purified by column chromatography on silica gel (eluting with dichloromethane), followed by recrystallization of propyl acetate (10 mL / g) to give 0.8 g of a tan solid. The solid was recrystallized from ethanol (4 mL) and water (two drops), and the crystals were dried in a vacuum oven at 60 ° C for 4 hours, to give 0.55 g of / -. { 2- [4-amino-2- (ethoxymethyl) -1H-imidazo [4,5-c] quinolin-1-yl] -1, 1-dimethylethyl} methanesulfonamide monohydrate as light yellow crystals, m.p. 161-163 ° C. MS (ESI) m / z 392 (M + H) +; Anal. cale, for d8H25N5O3S-1.0 H2O: C, 52.79; H, 6.65; N.17.10. Found: C.52.69; H.6.56; N, 16.87.

EXAMPLE 4 Preparation of W- [4- (2-ethyl-1H- '- midazo [4,5-c1quinolin-1-yl] butyl] methanesulfonamide A mixture of? / - (4-chloroquinolin-3-yl) propanamide (0.1 g, 0.4 mmol) and? / - (4-aminobutyl) methanesulfonamide hydrochloride (0.095 g, 0.5 mmol) was sealed in a flask, heated at 125 ° C for 16 hours and allowed to cool to room temperature. Water was added and the pH of the solution was adjusted to approximately 10, adding sodium carbonate. The aqueous solution was extracted twice with dichloromethane (50 mL), and the combined extract was washed with brine, dried over magnesium sulfate and sodium sulfate, filtered and concentrated under reduced pressure. An HPLC analysis and mass spectrometry gave evidence that? / - 4- (2-ethyl-1H-imidazo [4,5-c] quinolin-1-yl) butyl] methanesulfonamide was the main product. MS (APCI) m / z 347 (M + H) +.

EXAMPLES 5 and 6 Preparation of M-f4- (2-ethyl-1H-imidazof4,5-c1quinolin-1-i-butymethanesulfonamide A solution of? / - (4-chloroquinolin-3-yl) propanamide (0.05 g, 0.2 mmol),? / - (4-aminobutyl) methanesulfonamide hydrochloride (0.047 g, 0.2 mmol), and triethylamine (0.059 mL, 0.40 mmol) in the solvent indicated below, sealed in a flask and heated at 128 ° C for 48 hours. Below is an HPLC analysis indicating the ratio of? / - [4- (2-ethyl-1H-imidazo [4,5-c] quinolin-1-yl) butyl] methanesulfonamide to? / - (4- chloroquinolin-3-yl) propanamide.

EXAMPLE 7 Preparation of 2-methyl-1- (2-methylpropyl) -1H-imidazor4.S-cip, 51-naphthyridin-4-amine Part A A Parr vessel was flushed with nitrogen and loaded with 5% platinum on carbon (1.1 g) and water (5 mL). A solution of 3-nitro [1, 5] naphthyridin-4-ol (22.0 g, 0.115 mol) in triethylamine (23.3 g, 0.230 mol) and water (1.1 L) was added, and the mixture was placed under pressure. hydrogen (2.45 kg / cm2, 2.4 x 105 Pa) for three hours and then filtered through a layer of the CELITE filter agent. The filtrate was concentrated to a volume of 400 mL by flash evaporation at 75 ° C and allowed to cool. A solid formed and was collected by vacuum filtration to give 3-amino [1,5] naphthyridin-4-ol (16.4g) as a mustard-colored fine powder, m.p. 315-320 ° C. MS (ESI) m / z 162 (M + H) +. Part B Phosphorus (III) oxychloride (47.0 g 0.304 mol) was added over a period of 30 minutes to a mixture of 3-amino [1, 5] naphthyridin-4-ol (20.0 g, 0.124 mol) in N , N-dimethylformamide (DMF) (200 mL). The reaction temperature was maintained between 10 ° C and 20 ° C during the addition. Upon completion of the addition, the reaction was stirred at room temperature for 3 hours, heated at 90 ° C for 15 minutes, and allowed to cool to room temperature. Water (150 mL) and ice were added, keeping the temperature below 55 ° C. The mixture was stirred at room temperature for 30 minutes, heated at 100 ° C for three hours, and allowed to cool to room temperature overnight. The resulting black solution was made basic by slowly adding solid sodium carbonate and saturated aqueous sodium carbonate. The basic solution was extracted three times with dichloromethane. The combined extract was washed with brine, dried over sodium sulfate and magnesium sulfate, and concentrated under reduced pressure to give an amber sticky paste. The pulp was triturated with hot diethyl ether for 30 minutes, and the resulting solid was collected by vacuum filtration to give 4-chloro [1,5] naphthyridin-3-amine (11 g) as brown granules, m.p. 188-190 ° C. MS (ESI) m / z 180 (M + H) +. Part C A solution of 4-chloro [1, 5] naphthyridin-3-amine (4.0 g, 0.022 mol) and triethylamine (4.6 mL, 0.033 mol) in 1,2-dichloroethane (80 mL) was cooled to 3 ° C. . A solution of acetyl chloride (4.4 g, 0.056 mol) in 1,2-dichloroethane (5 mL) was added dropwise over a period of 5 minutes. Then, the reaction was heated to reflux for 5 hours; it was allowed to cool to room temperature; it was diluted with dichloromethane (100 mL); was washed sequentially with a saturated aqueous solution of sodium carbonate (2 x), water (1 x), and brine (1 x); dried over sodium sulfate and magnesium sulfate; it leaked; it was concentrated under reduced pressure to give 4.7 g of a dark brown solid.

The solid was recrystallized from acetonitrile (20 mL) and collected in two crops to give? / - (4-chloro [1, 5] naphthyridin-3-yl) acetamide (3.0 g) as a dark brown solid. MS (ESI) m / z 222 (M + H) +. Part D A mixture of? / - (4-chloro [1,5] naphthyridin-3-yl) acetamide (1.6 g, 0. 073 mol) and isobutylamine (7.3 mL, 0.0722 mol) was heated in a sealed vessel at 120 ° C overnight, allowed to cool to room temperature and added to a solution of water (100 mL) and saturated aqueous carbonate solution of sodium (20 mL). A precipitate formed. The mixture was stirred at room temperature for 1.5 hours and the precipitate was collected by vacuum filtration and dried in a filtration funnel, to give 2-methyl-1- (2-methylpropyl) -1H-imidazo [4.5- c) [1, 5] naphthyridine (1.45 g) as a gray powder, mp. 110-111 ° C. MS (APCI) m / z 241 (M + H) +. Part EA a solution of 2-methyl-l- (2-methylpropyl) -1H-imidazo [4,5-c] [1,5] naphthyridine (1.45 g, 0.0060 mol) in dichloromethane (30 mL) was added in portions solid 3-chloroperoxybenzoic acid (1.8 g of approximately 77% pure material, 0.0078 mol). The reaction was stirred at room temperature for three hours and washed with a saturated aqueous sodium carbonate solution (100 mL). The aqueous fraction was extracted three times with dichloromethane. The combined organic fraction was washed with brine, dried over sodium sulfate and magnesium sulfate, filtered and concentrated under reduced pressure to give 2-methyl-1- (2-methylpropyl) -5-oxido-1H-imidazole. [4,5- c] [1, 5] naphthyridine (1.3 g) as a yellow solid. MS (APCI) m / z 257 (M + H) +. Part F p-Toluenesulfonyl chloride (1.2 g, 0.0061 mol) was added to a vigorously stirred mixture of 2-methyl-1- (2-methylpropyl) -5-oxido-1H-imidazo [4,5-c] [1 , 5] naphthyridine (1.3 g, 0.0051 mol), dichloromethane (25 mL), and ammonium hydroxide (17 mL). The reaction was stirred vigorously at room temperature for two hours and then the stirring was stopped and the layers allowed to separate for two hours. A precipitate formed and was collected by vacuum filtration to give 0.9 g of ivory needles. The needles were recrystallized from isopropanol (12 mL) and the collected crystals were dried in a vacuum oven at 60 ° C for 5 hours, to give 2-methyl-1- (2-methylpropyl) -IH-imidazo [4.5 -c] [1, 5] naphthyridin-4-amine (0.7 g) as colorless needles, mp 227-229 ° C. MS (ESI) m / z 256 (M + H) +; anal. cale, for C14H17N5: C.65.86; H.6.71; N.27.43. Found: C.65.53; H.6.68; N.27.35.

EXAMPLE 8 Preparation of 1- (2-methylpropyl) -1H-imidazof4.5-c1quinoline Part A Formic acid (0.36 mL) was added slowly with stirring to acetic anhydride (0.8 mL), and the reaction was stirred at room temperature. for 2.75 hours; then it was added to a solution of 3-amino-4-chloroquinoline (0.50 g, 2.8 mmol) in tetrahydrofuran (5 mL). The resulting mixture was stirred one hour at room temperature. A solid was present which was collected by filtration and washed with diethyl ether to give 0.48 g of 4-chloroquinolin-3-ylformamide as a beige solid, m.p. 175-177 ° C. Part B A mixture of 4-chloroquinolin-3-ylformamide (0.050 g, 0.24 mol) and isobutylamine (0.25 mL, 2.4 mmol) was heated in a sealed flask at 1 10 ° C overnight, and allowed to cool to room temperature . Dichloromethane (1 mL) and aqueous ammonium chloride (1 mL of 10% w / w solution) were added. The organic layer was separated and washed with an aqueous solution of 10% w / w ammonium chloride, dried over sodium sulfate, concentrated under reduced pressure, and dried overnight in a 35 ° vacuum oven. C, to give 41 mg of a brown crystalline solid that was analyzed by LC / MS and found to be a mixture of 1- (2-methylpropyl) -1 / - / - imidazo [4,5-c] quinoline and 3 -amino-4-chloroquinoline.

EXAMPLE 9 Preparation of 1- (2-methylpropyl) -1H-imidazo [4,5-clquinoline] Part A To a stirred suspension of 3-aminoquinolin-4-ol hydrochloride (150 g, 0.76 mol) in 500 ml of DMF was added dropwise phosphorus oxychloride (90 mL, 0.97 mol). The temperature of the mixture increased to about 100 ° C during the addition. The reaction mixture was allowed to cool to room temperature and then about 2/3 of the DMF were removed under reduced pressure. Then, the mixture was filtered and the solid was dried to give? / '- (4-chloroquinolin-3-yl) -? /,? / - dimethylimidoformamide (118 g), MS (ESI) m / z 234 (M + H) +. Part B A glass vial was loaded with? / '- (4-chloroquinolin-3-yl) -? /,? / - dimethylimidoformamide (0.10 g, 0.40 mmol), isobutylamine (0.50 mL, 5.4 mmol), and p- pyridinium toluenesulfonate (5 mg, 0.02 mmol). The flask was placed inside a pressurized steel reactor and the flask was heated in an oven at 150 ° C for 15 hours. After cooling to room temperature, an examination of the reaction mixture by liquid chromatography / mass spectrometry indicated that the reaction was incomplete, such that the vessel was put back into the oven and heated to 175 ° C during fifteen hours. After cooling to room temperature, examination of the reaction mixture by liquid chromatography / mass spectrometry indicated that the main product of the reaction was 1- (2-methylpropyl) -1 / - / - imidazo [4,5- cjquinoline, MS (ESI) m / z 226 (M + H) +.

EXAMPLE 10 Preparation of 1- (2-methylpropyl) -1H-imidazo [4.5-c] quinoline A flask was charged with 3-aminoquinolin-4-ol hydrochloride (1.0 g, 5.1 mmol), 20 mL of acetonitrile and 1.5 mL of DMF. To the stirred suspension was added phosphorus oxychloride (0.7 mL, 7.5 mmol). The mixture was stirred at room temperature for 21 hours. The mixture was filtered to remove the solids, rinsing with acetonitrile. Isobutylamine (2.5 mL, 25.5 mmol) was added to the filtrate. An exotherm was observed after the addition and the solution became a suspension; The mixture was placed in a glass pressure vessel and heated in an oven at 120 ° C for 3 hours. After cooling to room temperature, an examination of the reaction mixture by liquid chromatography / mass spectrometry indicated that the reaction was almost complete. The suspension was taken in 50 mL of water and 50 mL of dichloromethane. The layers separated. The aqueous phase was extracted with 25 mL of dichloromethane, which was combined with the dichloromethane layer separated. Examination of the combined dichloromethane layers by liquid chromatography / mass spectrometry indicated that the main product was 1- (2-methylpropyl) -1 / - / - imidazo [455-c] quinoline, MS (ESI) m / z 226 (M + H) +. The layers were dried with magnesium sulfate; it was filtered and concentrated to give 0.17 g (15%) of a sticky amber residue. 1 H NMR (300 MHz, DMSO-d 6) d 9.24 (s, 1 H), 8.43 (s, 1 H), 8.35 (m, 1 H), 8.18 (m, 1 H), 7.74 (m, 2H), 4.53 (d, J = 7.5 Hz, 2H), 2.22 (m, 1 H), 0.93 (d, J = 6.6 Hz, 6H); HRMS (ESI) cale, for C 14 H 15 N 3 [M + H] +: 226.1344, found 226.1352. The full descriptions of the patents, patent documents and publications cited herein are incorporated by reference in their entirety as if each were incorporated individually. Various modifications and alterations of this invention will be apparent to the person skilled in the art without departing from the scope and spirit of this invention. It should be understood that this invention is not considered to be unduly limited by the illustrative embodiments and examples set forth herein, and that said examples and embodiments are presented by way of example only, since the scope of the invention is limited only by the claims that are exposed in the following way.

Claims

NOVELTY OF THE INVENTION CLAIMS 1. - A method for preparing a 1 / - / - imidazo [4,5-c] pyridine or an analog thereof, or a pharmaceutically acceptable salt thereof, comprising: providing a compound of formula IV: IV and reacting the compound of formula IV with an amine of the formula R-? NH2 to give a 1H-imidazo [4,5-c] pyridine, or analog thereof, of formula I: or a pharmaceutically acceptable salt thereof; wherein: E is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, iodine, hydroxy, phenoxy, -OS (O) 2 -R 'and -N (Bn) 2, wherein R' is selected from the group which consists of alkyl, haloalkyl and aryl optionally substituted with alkyl, halogen or nitro, and Bn is selected from the group consisting of benzyl, p-methoxybenzyl, p-methylbenzyl, and 2-furanylmethyl; or E is attached to the adjacent nitrogen atom of pyridine of formulas I and IV to form the fused tetrazolo ring of formulas 1-1 and IV-1: 1-1 IV-1 L is selected from the group consisting of fluorine, chlorine, bromine, iodine, phenoxy and -OS (0) 2-R ', wherein R' is selected from the group consisting of alkyl, haloalkyl and aryl optionally substituted with alkyl, halogen or nitro; RA and RB are independently selected from the group consisting of: hydrogen, halogen, alkyl, alkenyl, alkoxy, alkylthio, and -N (R9) 2; or RA and RB taken together form a fused benzene ring or a fused pyridine ring, wherein the benzene ring or the pyridine ring is unsubstituted or substituted with a group R, or is substituted with a group R3, or is substituted with a group R and a group R3; or RA and RB taken together form a 5 to 7 membered fused saturated ring optionally containing a nitrogen atom, wherein the fused ring is unsubstituted or substituted with one or more R groups; R is selected from the group consisting of: halogen, hydroxy, alkyl, alkenyl, haloalkyl, alkoxy, alkylthio, and -N (R9) 2; Ri is selected from the group consisting of: -R4, -XR, -XY-R4, -XYXY-R4, -X-R5, -NYR -QR ,, -N (R1 ') - X1-YrR4, and -N (R? ') - X? -R5b; R2 is selected from the group consisting of: -R4, -X-R4, -X-Y-R4, and -X-R5; R3 selects from the group consisting of: -Z-R4, -Z-X-R4, -Z-X-Y-R4, -Z-X-Y-X-Y-R4, and -Z-X-R5; X is selected from the group consisting of alkylene, alkenylene, alkynylene, arylene, heteroarylene, and heterocyclylene, wherein optionally the alkylene, alkenylene and alkynylene groups may be interrupted or terminated with arylene, heteroarylene or heterocyclylene, and optionally may be interrupted with one or more groups -O-; Xi is C2.20 alkylene; Y is selected from the group consisting of: -O-, -S (O) 0-2-, -S (O) 2-N (R8) -, -C (R6) -, -OC (R6) -, -OC (O) -O-, -N (R8) -Q-, -OC (R6) -N (R8) -, -C (R6) -N (OR9) -, -ON (R8) -Q- , -ON = C (R4) -, -C (= NO-R8) -, -CH (-N (-O-R8) -Q-R4) -, Y1 is selected from the group consisting of: -O-, -S (O) 0.2-, -S (O) 2- N (R8) -, -N (R8) -Q-, -C (R6) -N (R8) -, -OC (R6) -N (R8) -, and -V »N ^ R" r Z is a bond u -O-; Ri "is selected from the group consisting of hydrogen, C1.20 alkyl, C2-2o hydroxy-alkylenyl and C2-20 alkyloxynyl ', R 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 may not are substituted or may be substituted with one or more substituents independently selected from the group consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, mercapto, cyano, aryl, aryloxy, arylalkyloxy, heteroaryl, heteroaryloxy, heteroarylalkylenoxy, heterocyclyl, amino, alkylamino, dialkylamino, (dialkylamino) alkylene oxy, and in the case of alkyl, alkenyl, alkynyl and heterocyclyl, oxo; R5 is selected from the group consisting of: Y Rdb is selected from the group consisting of: - R6 is selected from the group consisting of: = O y = S; R7 is C2-7alkylene; R8 is selected from the group consisting of hydrogen, alkyl, alkoxyalkylenyl, hydroxyalkylenyl, arylalkylenyl and heteroarylalkylenyl; Rg is selected from the group consisting of hydrogen and alkyl; R? 0 is C3-8 alkylene; A is selected from the group consisting of -O-, -C (O) -S (O) 0-2-, and -N (R4) -; A 'is selected from the group consisting of -O-, -S (O) 0.2-, -N (-Q-R4) -y -CH2-; 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 (0) 2-N (R8) -, -C (R6) -0-, -C (R6) -S-, and -C (R6) -N (OR9) -; V is selected from the group consisting of: -C (R6) -, -O-, C (R6) -, -N (R8) -C (R6) -, and -S (O) 2-; V is selected from the group consisting of: -O-C (R6) -, -N (R8) -C (R6) -, and -S (O) 2-; W is selected from the group consisting of a bond, -C (O) -, and -S (O) 2-; and a and b are independently integers from 1 to 6, with the proviso that a + b < 7. The method according to claim 1, further characterized in that it comprises the steps of: providing a compound of the formula III: III and reacting the compound of formula III with a carboxylic acid halogenide of the formula hal-C (0) -R2, wherein hal is chlorine or bromine, or a mixed anhydride or anhydride of the formula O (-C (O) -R2) 2, to provide a compound of formula IV. 3. The method according to claim 2, further characterized in that it comprises the steps of: providing a compound of the formula II: E II and reducing the compound of formula II to give a compound of formula III. 4. The method according to claim 2, further characterized in that it comprises the steps of: providing a compound of the formula VI: VI and converting the hydroxy group from position 4 of formula VI to a group L to give a compound of formula III. 5. The method according to claim 1, further characterized in that it comprises the steps of: providing a compound of the formula VII: VII and converting the hydroxy group from position 4 of formula VII to group L to give a compound of formula IV. 6. The method according to claim 5, further characterized in that it comprises the steps of: providing a compound of formula VI: E VI and reacting the compound of formula VI with a halogenide of carboxylic acid of the formula hal-C (0) -R2, wherein hal is chloro or bromo, or a mixed anhydride or anhydride of the formula O (-C (0 ) -R2) 2, to give a compound of formula VII. 7. The method according to claim 4 or 6, further characterized in that it comprises the steps of: providing a compound of the formula V: V and reducing the compound of formula V to give a compound of formula VI. 8. A method for preparing a 1H-imidazo [4,5-c] pyridine, or an analogue thereof, or a pharmaceutically acceptable salt thereof, comprising: providing a compound of formula VIII: VIII and reacting the compound of formula VIII with an amine of formula R? NH2 to give a 1H-imidazo [4,5-c] pyridine or analogue thereof of formula I: or a pharmaceutically acceptable salt thereof; wherein: E is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, iodine, hydroxy, phenoxy, -O-S (0) 2-R 'and -N (Bn) 2, wherein R' is selected from a group consisting of alkyl, haloalkyl and aryl optionally substituted with alkyl, halogen or nitro, and Bn is selected from the group consisting of benzyl, p-methoxybenzyl, p-methylbenzyl, and 2-furanylmethyl; or E is attached to the adjacent nitrogen atom of pyridine of formulas I and VIII to form the fused tetrazolo ring of formulas 1-1 and IX: L is selected from the group consisting of fluorine, chlorine, bromine, iodine, phenoxy, and -OS (O) 2-R ', wherein R' is selected from the group consisting of alkyl, haloalkyl, and aryl optionally substituted with alkyl , halogen or nitro; RA and RB are independently selected from the group consisting of: hydrogen, halogen, alkyl, alkenyl, alkoxy, alkylthio and -N (R9) 2; or RA and RB taken together form a fused benzene ring or a fused pyridine ring, wherein the benzene ring or the pyridine ring is unsubstituted or substituted with a group R, or is substituted with a group R3, or is substituted with a group R and a group R3; or RA and RB taken together form a 5 to 7 membered fused saturated ring optionally containing a nitrogen atom, wherein the fused ring is unsubstituted or substituted with one or more R groups; R is selected from the group consisting of: halogen, hydroxy, alkyl, alkenyl, haloalkyl, alkoxy, alkylthio and -N (R9) 2; Rn is selected from the group consisting of: -R4l -X-R4, -X- Y-R4, -X-Y-X-Y-R4, -X-R5, -N (R1 ') - Q-R4I-NfR -X and F and -N (R?') - X? -R5b; R2 is hydrogen; R3 is selected from the group consisting of: -Z-R4, -Z-X-R4, -Z-X-Y-R4I -Z-X-Y-X-Y-R, and -Z-X-R5; X is selected from the group consisting of alkylene, alkenylene, alkynylene, arylene, heteroarylene, and heterocyclylene, wherein optionally the alkylene, alkenylene and alkynylene groups may be interrupted or terminated with arylene, heteroarylene or heterocyclylene, and optionally may be interrupted with one or more groups -O-; Xi is C2-2alkylene, and is selected from the group consisting of: -O-, -S (O) 0-2", -S (O) 2-N (R8) -, -C (R6) - , -OC (R6) -, -OC (O) -O-, -N (R8) -Q-, -0-C (R6) -N (R8) -, -C (R6) -N (OR9) -, -ON (R8) -Q-, -ON = C (R4) -, -C (= N-0-R8) -, -CH (-N (-O-R8) -Q-R4) -, N-Q -, R 10) is selected from the group consisting of: -O-, -S (0) or-2-, S (O) 2-N (R8) -, -N (R8) -Q-, -C (R6) -N (R8) -, -OC (R6) -N (R8) -, and Z is a bond u -0-; R is selected from the group consisting of hydrogen, C? -2 alquilooalkyl, C2-2o hidro hydroxy-alkylenyl, and C2-20 alco alkylalkyl-N;-20;; R 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 may be unsubstituted or may be substituted with one or more substituent groups independently selected from the group consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, mercapto, cyano, aryl, aryloxy, arylalkylenoxy, heteroaryl, heteroaryloxy, heteroaplaylealkyloxy, heterocyclyl, amino, alkylamino, dialkylamino, (dialkylamino) alkyleneoxy, and in the case of alkyl, alkenyl, alkynyl, and heterocyclyl, oxo; R5 is selected from the group consisting of: .W ^ ^ (CH2) a? -N-- C (RG) -N- S (ü) 2 _v, _ < _o-N = ,, (CH2.}. B- '- u R5 is selected from the group consisting of: R6 is selected from the group consisting of: = O y = S; R7 is C2-7alkylene; R8 is selected from the group consisting of hydrogen, alkyl, alkoxyalkylenyl, hydroxyalkylenyl, arylalkylenyl and heteroarylalkylenyl; Rg is selected from the group consisting of hydrogen and alkyl; R10 is C3-8 alkylene; Rn and R? 2 are independently C? -4 alkyl, or Rn and R? 2 together with the nitrogen atom to which they are attached form a 5-6 membered ring optionally containing -O-, -N ( C? _4) -, or -S-; A is selected from the group consisting of -O-, -C (O) -, -S (O) 0.2- and -N (R4) -; A 'is selected from the group consisting of -O-, -S (O) or-2-, -N (-Q-R4) - and -CH2-; Q is selected from the group consisting of a bond, -C (Re) -, -C (R6) -C (Re) -, -S (O) 2-, -C (R6) -N (R8) -W -, -S (0) 2-N (Rβ) -, C (R 6) -O-, -C (R 6) -S-, and C (R 6) -N (OR 9) -; V is selected from the group consisting of -C (R6) -, -0-C (R6) -, -N (R8) -C (R6) -, and S (O) 2-; V is selected from the group consisting of -O-C (R6) -, -N (R8) -C (R6) -, and S (0) 2-; W is selected from the group consisting of a bond, -C (O) -, and -S (O) 2-; and a and b are independently integers from 1 to 6, with the proviso that a + b < 7. The method according to claim 8, further characterized in that it comprises forming an intermediate of formula XI: XI and then reacting the compound of formula VIII with an amine of the formula R? NH2. 10. The method according to claim 9, further characterized in that the intermediate of formula XI is isolated after reacting the compound of formula VIII with an amine of the formula R! NH2. 1. The method according to claim 8 or claim 9, further characterized in that it comprises providing a compound of the formula VI: E VI convert the hydroxy group from position 4 to a group L, and react the amino group from position 3 with a formamide of formula H-C (O) -N (Rn) R? 2 to give a compound of formula VIII. 12. The method according to claim 1, further characterized in that the compound of formula VIII is provided without being isolated before reacting with an amine of formula RtNH2. 13. - A method for preparing a 1H-imidazo [4,5-c] pyridine, or analog thereof, or a pharmaceutically acceptable salt thereof, which comprises providing a compound of formula XI: XI and forming a 1H-imidazo [4,5-c] p-pdine or analogue thereof of formula I: E or a pharmaceutically acceptable salt thereof; wherein: E is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, iodine, hydroxy, phenoxy, -OS (O) 2 -R 'and -N (Bn) 2, wherein R' is selected from the group which consists of alkyl, haloalkyl, and aryl optionally substituted with alkyl, halogen, or nitro, and Bn is selected from the group consisting of benzyl, p-methoxybenzyl, p-methylbenzyl, and 2-furanylmethyl; or E is attached to the adjacent nitrogen atom of pyridine of formulas I and XI to form the fused tetrazolo ring of formulas 1-1 and XIII: 1-1 XIII L is selected from the group consisting of fluorine, chlorine, bromine, iodine, phenoxy and -OS (0) 2-R ', wherein R' is selected from the group consisting of alkyl, haloalkyl, and substituted aryl optionally with alkyl, halogen, or nitro; RA and RB are independently selected from the group consisting of: hydrogen, halogen, alkyl, alkenyl, alkoxy, alkylthio, and -N (R9) 2; or RA and RB taken together form a fused benzene ring or a fused pyridine ring, wherein the benzene ring or the pyridine ring is unsubstituted or substituted with a group R, or is substituted with a group R3, or is substituted with a group R and a group R3; or RA and RB taken together form a 5 to 7 membered fused saturated ring optionally containing a nitrogen atom, wherein the fused ring is unsubstituted or substituted with one or more R groups; R is selected from the group consisting of: halogen, hydroxy, alkyl, alkenyl, haloalkyl, alkoxy, alkylthio, and -N (R9) 2; Ri is selected from the group consisting of: -R4, -X-R4, -XY-R4, -XYXY-R4, -X-R5, -N (R? ') - Q-R4, -N (R?' -XY? -R4, and -N (R? ') - XrR5b; R2 is hydrogen; R3 is selected from the group consisting of: -Z-R, -Z-X-R, -Z-X-Y-R4, -Z-X-Y-X-Y-R4, and -Z-X-R5; X is selected from the group consisting of alkylene, alkenylene, alkynylene, arylene, heteroarylene and heterocyclylene, wherein optionally the alkylene, alkenylene and alkynylene groups may be interrupted or terminated by arylene, heteroarylene or heterocyclylene, and optionally interrupted by one or more -O- groups; Xi is C2-20 alkylene; Y is selected from the group consisting of: -O-, -S (O) 0.2-, -S (O) 2-N (R8) -, -C (R6) -, -OC (R6) -, -OC (O) -O-, -N (R8) -Q-, -OC (R6) -N (R8) -, -C (R6) -N (OR9) -, -0-N (R8) -Q- , -0-N = C (R4) -, -C (= N-0-R8) -, -CH (-N (-O-R8) -QR) -, - N-CÍRe) -N-W- V -N- R? - -N-Q- Yi is selected from the group consisting of -O-, -S (O) 0.2-, -S (O) 2- N (R8) -, -N (R8) -Q-, -C (R6) -N ( R8) -, -0-C (R6) -N (R8) -, and Z is a bond u -O-; R is selected from the group consisting of hydrogen, C? -20 alkyl, C2-2o hydroxy-alkylenyl, and C2.2 alkoxy-alkylenyl, 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 may be unsubstituted or may be substituted with one or more substituents independently selected from the group consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, mercapto, cyano, aryl, aryloxy, arylalkyloxy, heteroaryl, heteroaryloxy, heteroarylalkylenoxy, heterocyclyl, amino, alkylamino, dialkylamino, (dialkylamino) alkyleneoxy, and in the case of alkyl, alkenyl, alkynyl and heterocyclyl, oxo; R5 is selected from the group consisting of: R5b is selected from the group consisting of: -N- C (R - - SÍO) 2 R6 is selected from the group consisting of = 0 y = S; R7 is C2-7alkylene; R8 is selected from the group consisting of hydrogen, alkyl, alkoxyalkylenyl, hydroxyalkylenyl, arylalkylenyl and heteroarylalkylenyl; Rg is selected from the group consisting of hydrogen and alkyl; R10 is C3-8 alkylene; A is selected from the group consisting of -O-, -C (O) -, -S (O) or-2-, and -N (R4) -; A 'is selected from the group consisting of -O-, -S (O) 0-2-, -N (-Q-R4) -, and -CH2-; 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) -0-, -C (Re) -S-, and -C (R8) -N (ORg) -; V is selected from the group consisting of -C (R6) -, -O-C (R6) -, -N (R8) -C (R6) -, and -S (0) 2-; V is selected from the group consisting of -O-C (Re) -, -N (R8) -C (Re) -, and -S (O) 2-; W is selected from the group consisting of a bond, -C (O) -, and -S (O) -; and a and b are, independently, integers from 1 to 6, with the proviso that a + b 7. 14. The method according to claim 13, further characterized in that it comprises: providing a compound of the formula VI: E VI convert the hydroxy group from position 4 to a group L, and react the amino group of position 3 with a formamide of formula H-C (O) -NH (R?), To give a compound of formula XI. 15. The method according to claim 14, further characterized in that the compound of formula XI is provided without being isolated before forming a compound of formula I. 16. The method according to any of the claims 11, 12, 14 and 15, further characterized in that it comprises providing a compound of formula V: V and reducing the compound of formula V to give a compound of formula VI. 17. The method according to any of claims 1 to 16, further characterized in that it comprises the step of converting E to an amino group in the compound of formula I, to give a compound of formula X: X or a pharmaceutically acceptable salt thereof. 18. The method according to claim 17, further characterized in that E is hydrogen, the compound of formula I is of the formula I-2: and the step of converting the hydrogen to an amino group in the compound of formula I-2 comprises: oxidizing the compound of formula I-2 to give the 5? / -oxide of formula XX: XX and amine the compound of formula XX to give the compound of formula X, or a pharmaceutically acceptable salt thereof. 19. The method according to claim 17, further characterized in that E is halogen, the compound of formula I is of the formula I-3: 1-3 wherein Hal is fluorine, chlorine, bromine, or iodine, and the step of converting the group Hal to an amino group in the compound of formula 1-3, comprises aminating the compound of formula 1-3 to give the compound from Formula X, or a pharmaceutically acceptable salt thereof. 20. The method according to claim 17, further characterized in that E is hydroxy, the compound of formula I is of formula I-4: and the step of converting the hydroxy group to an amino group in the compound of formula I-4 comprises: converting the hydroxy group from the 4-position of the formula I-4 to a halogen group, to give a compound of the formula I-3 , or a salt thereof: I-3 wherein Hal is fluorine, chlorine, bromine, or iodine; and amending the compound of formula I-3 to give the compound of formula X, or a pharmaceutically acceptable salt thereof. 21. The method according to claim 17, further characterized in that E is hydroxy, the compound of formula I is of formula I-4: I-4 and the step of converting the hydroxy group to an amino group in the compound of formula I-4 comprises: sulfonating the compound of formula I-4 by reaction with a compound of formula hal-S (O) 2-R ' , wherein hal is chloro or bromo, or of the formula O (-S (O) 2 -R ') 2, to give a compound of formula I-5: I-5 displace the -O-S (O) 2 -R 'group in the formula I-5 with an amino group of the formula -N (Bn) 2, to give a compound of the formula I-6: I-6 remove the protecting groups Bn of the formula I-6 to give the compound of formula X, or a pharmaceutically acceptable salt thereof. 22. The method according to claim 17, further characterized in that E is phenoxy and the compound of formula I is of the formula I-7: I-7 wherein Ph is phenyl, and the step of converting the phenoxy group to an amino group in the compound of formula I-7 comprises aminating the compound of formula I-7 to give the compound of formula X, or a pharmaceutically salt acceptable of it. 23. The method according to claim 17, further characterized in that E is -O-S (O) 2-R ', the compound of formula I is of the formula I-5: I-5 and the step of converting the group -OS (O) 2 -R 'to an amino group in the compound of formula I-5, comprises: displacing the group -OS (O) 2 -R' with an amino group of formula -N (Bn) 2, to give a compound of formula I-6: I-6 and remove the protective groups Bn in the formula I-6 to give the compound of formula X, or a pharmaceutically acceptable salt thereof. 24. The method according to claim 17, further characterized in that E is -N (Bn) 2, the compound of formula I is of the formula I-6: and the step of converting the group -N (Bn) 2 to an amino group in the compound of formula I-6 comprises removing the protecting groups Bn to give the compound of formula X, or a pharmaceutically acceptable salt thereof. 25. The method according to claim 17, further characterized in that E is linked to the adjacent nitrogen atom of pyridine of formula I to form the fused tetrazolo ring of formula 1-1: 1-1 and the step of converting the fused tetrazolo ring to an amino group in the compound of formula 1-1 comprises the steps of: reacting the compound of formula 1-1 with triphenylphosphine to give a composed of formula XXI: XXI and hydrolyzing the compound of formula XXI to give the compound of formula X, or a pharmaceutically acceptable salt thereof. 26. The method according to claim 17, further characterized in that E is linked to the adjacent nitrogen atom of pyridine of the formula I to form the fused tetrazolo ring of formula 1-1: 1-1 and the step of converting the fused tetrazolo ring to an amino group in the compound of formula 1-1 comprises the step of: reductively removing the tetrazolo ring of the compound of formula 1-1 to give the compound of formula X , or a pharmaceutically acceptable salt thereof. 27. The method according to any of claims 1 to 7, or any of claims 17 to 26 dependent on any of claims 1 to 7, further characterized in that R2 is -R. 28. The method according to claim 27, further characterized in that R 2 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, butyl, 2-methoxyethyl, 2-hydroxyethyl, ethoxymethyl, and hydroxymethyl. 29. The method according to any of claims 1 to 28, further characterized in that Ri is -R4 or -X-R. 30. The method according to claim 29, further characterized in that -R is selected from the group consisting of 2-methylpropyl, 2-hydroxy-2-methylpropyl, 2,2-dimethyl-4-oxopentyl and (1-hydroxycyclobutyl) ) methyl, and -X-R 4 is 2,2-dimethyl-3- (2-methyl-1,3-dioxolan-2-yl) propyl. 31. The method according to claim 30, further characterized in that -R4 is 2-methylpropyl. 32. The method according to any of claims 1 to 28, further characterized in that Ri is -X-Y-R. 33. The method according to claim 32, further characterized in that X is alkylene of C2- and Y is -S (O) 2- or -N (R8) -Q-. 34 - The method according to claim 33, further characterized in that -XYR is selected from the group consisting of 2- (propylsulfonyl) ethyl, 2-methyl-2 - [(methylsulfonyl) amino] propyl, 4-methylsulfonylaminobutyl, and - (acetylamino) -2-methylpropyl. 35.- The method of compliance with any of the claims 1 to 28, further characterized in that R-i is -X-R5. 36. The method according to claim 35, further characterized in that -X-R5 is 4 - [(morpholin-4-ylcarbonyl) amino] butyl. 37. - The method according to any of claims 1 to 36, further characterized in that RA and RB are independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkoxy, alkylthio and -N (R9) 2. 38. The method according to claim 37, further characterized in that RA and RB are each methyl. 39.- The method according to any of claims 1 to 36, further characterized in that RA and RB taken together form a fused benzene ring wherein the benzene ring is unsubstituted, or is substituted with an R group, or is substituted with a group R3, or is substituted with a group R and a group R3. The method according to claim 39, further characterized in that the fused benzene ring is substituted with a group R selected from the group consisting of hydroxy or bromine. 41. The method according to claim 39, further characterized in that the fused benzene ring is substituted with a group R3 wherein R3 is methoxy, phenoxy, or benzyloxy. 42 - The method according to any of claims 1 to 36, further characterized in that RA and RB taken together they can form a fused pyridine ring, wherein the fused pyridine ring is unsubstituted, or is substituted with a group R, or is substituted with a group R3, or is substituted with a group R and a group R3; and wherein the fused pyridine ring is: where the highlighted link indicates the position where the ring is fused. 43. The method according to claim 39 or 42, further characterized in that R is hydroxy or bromine, and R3 is methoxy, phenoxy, or benzyloxy. 44. The method according to claim 42, further characterized in that the fused pyridine ring is substituted with a group R selected from the group consisting of hydroxy and bromine. 45. The method according to claim 42, further characterized in that the fused pyridine ring is substituted with a group R3, wherein R3 is methoxy, phenoxy, or benzyloxy. 46. The method according to any of claims 1 to 7, or any of claims 17 to 26 dependent on any of claims 1 to 7, further characterized in that RA is RA? , RB is RB ?, Ri is R? A, and R2 is R2a, where: RA? and RBI are independently selected from the group consisting of: hydrogen, halogen, alkyl, alkenyl, alkoxy, alkylthio, and -N (Rg) 2; or RAÍ and RBI taken together they form a fused benzene ring or a fused pyridine ring, wherein the benzene ring or the pyridine ring is unsubstituted or substituted with a group Ra, or is substituted with a group R3a, or is substituted with a group Ra and a group R3a; or RA? and RBI taken together form a saturated 5 to 7 membered fused ring optionally containing a nitrogen atom, wherein the fused ring is unsubstituted or substituted with one or more Ra groups; Ra is selected from the group consisting of: halogen, hydroxy, alkyl, alkenyl, trifluoromethyl, alkoxy, alkylthio, and -N (Rg) 2; R a is selected from the group consisting of: -R 4a, -X-R 4a, -X-Ya-R a, -X-Ya-X-Ya-R 4a, -X-R 5a, -N (R 1,) - Q-R4a, -N (R? ') - X? -Y? -R4a, and -N (R1') - X1-R5b; R2a is selected from the group consisting of: -R a, -X-R4a, -X-Ya-R4a, and -X-Rsa; ßa is selected from the group consisting of: -Z-R a, -Z-X-R 4a, -Z-X-Ya-R 4a, -Z-X-Ya-X-Ya-R 4a, and -Z-X-R 5a; It is already selected from the group consisting of: -O-, -S (O) 0-2-, -S (O) 2-N (R8) -, -N (R8) -Q-, -OC (R6) -N (R8) -, -C (R6) -N (OR9) -, N- R7 -N, -Q- R 4a 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 may be unsubstituted or may be substituted with one or more substituents independently selected from the group consisting of alkyl, alkoxy, hydroxyalkyl, trifluoromethyl, trifluoromethoxy, nitro, hydroxy, mercapto, cyano, aryl, aryloxy, arylalkyloxy, heteroaryl, heteroaryloxy, heteroarylalkylenoxy, heterocyclyl, amino, alkylamino, dialkylamino and ( dialkylamino) alkylenoxy; Y Rsa is selected from the group consisting of: -N- C (R6) - 47. - The method according to claim 46, further characterized in that R2a is -R4a. 48. The method according to claim 47, further characterized in that R2a is selected from the group consisting of hydrogen, methyl, ethyl, propyl, butyl, 2-methoxyethyl, 2-hydroxyethyl, ethoxymethyl, and hydroxymethyl. 49.- The method according to any of claims 8 to 16, or any of claims 17 to 26 depending on any of claims 8 to 16, further characterized in that RA is RA ?, RB is Rei, RI is R? a, and R2 is hydrogen, where: RAI and RBI are independently selected from the group consisting of: hydrogen, halogen, alkyl, alkenyl, alkoxy, alkylthio, and -N (R9) 2; or RA? and RBI taken together form a fused benzene ring or a fused pyridine ring, wherein the benzene ring or the pyridine ring is unsubstituted or substituted with a group Ra, or is substituted with a group R3a, or is substituted with a group Ra and a group R3a; or RA? and RBI taken together form a saturated 5 to 7 membered fused ring optionally containing a nitrogen atom, wherein the fused ring is unsubstituted or substituted with one or more Ra groups; Ra is selected from the group consisting of: halogen, hydroxy, alkyl, alkenyl, trifluoromethyl, alkoxy, alkylthio, and -N (R9) 2; R Ra is selected from the group consisting of: -R 4a, -X-R 4a, -X-Ya-R 4a, -X-Ya-X-Ya-R 4a, -X-R 5a, -N (R 1 ') - Q -R4a -N (R? ') - X? -And R4a, and -N (R1') -X? -R5b; R3a is selected from the group consisting of: -Z-R4a, -Z-X-R a, -Z-X-R a, -Z-X-Ya-X-Ya-R4a, and -Z-X-R5a; It is already selected from the group consisting of: -O-, -S (O) 0-2-, -S (O) 2-N (R8) -, -N (R8) -Q-, -0-C ( R6) -N (R8) -, -C (R6) -N (OR9) -, - - R7-, -Q- R7- R 4a 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 groups , alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl and heterocyclyl may be unsubstituted or may be substituted with one or more substituents independently selected from the group consisting of alkyl, alkoxy, hydroxyalkyl, trifluoromethyl, trifluoromethoxy, nitro, hydroxy, mercapto, cyano, aryl, aryloxy, arylalkylenoxy, heteroaryl, heteroaryloxy, heteroarylalkylenoxy, heterocyclyl, amino, alkylamino, dialkylamino and (dialkylamino) alkyleneoxy; and Rsa is selected from the group consisting of: 50. - The method according to any of claims 46 to 49, further characterized in that R? A is -R a or -X-R a. 51. The method according to claim 50, further characterized in that -R a is selected from the group consisting of 2-methylpropyl, 2-hydroxy-2-methylpropyl and (l-hydroxycyclobutyl) methyl, and -X-R4a is 2,2-Dimethyl-3- (2-methyl-1,3-dioxolan-2-yl) propyl. 52. The method according to claim 51, further characterized in that -R4a is 2-methylpropyl. 53. The method according to any of claims 46 to 49, further characterized in that R1a is -X-Ya-R a. 54. The method according to claim 53, further characterized in that X is alkylene of C2-, and Ya is -S (0) 2- or N (R8) -Q-. The method according to claim 54, further characterized in that -X-Ya-R a is selected from the group consisting of 2- (propylsulfonyl) ethyl, 2-methyl-2 - [(methylsulfonyl) amino] propyl, 4-methylsulfonylaminobutyl, and 2- (acetylamino) -2-methylpropyl. 56.- The method according to any of claims 46 to 49, further characterized in that R? A is -X-R5a. 57.- The method according to claim 56, further characterized in that -X-Rsa is 4 - [(morpholin-4-ylcarbonyl) amino] butyl. 58.- The method according to any of claims 46 to 57, further characterized because RA? and Ri are independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkoxy, alkylthio and -N (R9) 2. 59.- The method according to claim 58, further characterized in that RA? and BI are, each, methyl. 60.- The method according to any of claims 46 to 57, further characterized in that RA? and RBI taken together form a fused benzene ring wherein the benzene ring is unsubstituted, or is substituted with a group Ra, or is substituted with a group R3a, or is substituted with a group Ra and a group R3a. 61. The method according to claim 60, further characterized in that the fused benzene ring is substituted with a group Ra selected from the group consisting of hydroxy and bromine. 62. The method according to claim 60, further characterized in that the fused benzene ring is substituted with a group R3a wherein R3a is methoxy, phenoxy, or benzyloxy. 63. The method according to any of claims 39 or 60, further characterized in that the fused benzene ring is not substituted. 64.- The method according to any of claims 46 to 57, further characterized by RAI and RBI taken together they form a fused pyridine ring, wherein the fused pyridine ring is unsubstituted, or is substituted with a group Ra, or is substituted with a group R3a, or is substituted with a group Ra and a group R3a; and wherein the fused pyridine ring is: where the highlighted link indicates the position where the ring is fused. The method according to claim 60 or 64, further characterized in that Ra is hydroxy or bromine, and R3a is methoxy, phenoxy, or benzyloxy. 66 - The method according to claim 64, further characterized in that the fused pyridine ring is substituted with a group Ra selected from the group consisting of hydroxy and bromine. 67. The method according to claim 64, further characterized in that the fused pyridine ring is substituted with a group R3a, wherein R3a is methoxy, phenoxy, or benzyloxy. 68.- The method according to claim 42 or 64, further characterized in that the fused pyridine ring is not substituted. 69. The method according to any of claims 1 to 7, or any of claims 17 to 45 dependent on any of claims 1 to 7, further characterized in that the reaction of the compound of formula IV with an amine of Formula R ^ H2 is carried out with the reagents alone and at an elevated temperature. The method according to any of claims 46 to 48, and 50 to 68 dependent on any of claims 1 to 7, further characterized in that formula IV is formula IVa: I Va and wherein the reaction of the compound of formula IVa with an amine of the formula R? ANH2 is carried out with the reagents alone and at an elevated temperature. 71.- The method according to any of claims 1 to 7, or any of claims 17 to 45 dependent on any of claims 1 to 7, further characterized in that the reaction of the compound of formula IV with an amine of the formula R? NH2 is carried out in a solvent and at an elevated temperature. The method according to any of claims 46 to 48, and 50 to 68 dependent on any of claims 1 to 7, further characterized in that formula IV is formula IVa: Where and where the reaction of the compound of formula IVa with an amine of formula R? to NH2, said step is carried out in a solvent and at an elevated temperature. 73.- The method according to claim 71 or 72, further characterized in that the solvent is selected from the group consisting of methanol, ethanol, trifluoroethanol, isopropanol, rer-butanol, water, acetonitrile, 1-methyl-2-pyrrolidinone and toluene The method according to claim 73, further characterized in that the solvent is selected from the group consisting of trifluoroethanol, isopropanol and fer-butanol. 75.- The method according to any of claims 69 to 74, further characterized in that the elevated temperature is greater than 80 ° C. The method according to any of claims 69 to 75, further characterized in that the elevated temperature is greater than 110 ° C. 77. The method according to any of claims 69 to 76, further characterized in that the elevated temperature is less than 180 ° C. 78. - The method according to any of claims 69 to 77, further characterized in that the elevated temperature is less than 165 ° C. 79.- The method according to any of claims 8 to 12, claim 16 dependent on the claim 11 or claim 12, or any of claims 17 to 26 and 29 a 45 dependent on any of claims 8 to 12, further characterized in that the reaction of the compound of formula VIII with an amine of formula R1NH2 is carried out with the reagents alone. 80.- The method according to any of claims 8 to 12, claim 16 dependent on the claim 11 or claim 12, or any of claims 17 to 26 and 29 a 45 dependent on any of claims 8 to 12, further characterized in that the reaction of the compound of formula VIII with an amine of formula R? NH2 is carried out in a solvent. 81. The method according to claim 80, further characterized in that the solvent is selected from the group consisting of methanol, ethanol, trifluoroethanol, isopropanol, fer-butanol, water, acetonitrile, 1-metit-2-pyrrolidinone, toluene and tetrahydrofuran. 82. The method according to claim 81, further characterized in that the solvent is selected from the group consisting of trifluoroethanol, isopropanol, fer-butanol, and acetonitrile. 83.- A compound of the formula XI: XI wherein: E is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, iodine, hydroxy, phenoxy, -0-S (0) 2-R ', and -N (Bn) 2l wherein R' is selects from the group consisting of alkyl, haloalkyl, and aryl optionally substituted with alkyl, halogen, or nitro, and Bn is selected from the group consisting of benzyl, p-methoxybenzyl, p-methylbenzyl, and 2-furanylmethyl; or E is linked with the adjacent nitrogen atom of pyridine of formula XI to form the fused tetrazolo ring of formula XIII: XIII L is selected from the group consisting of fluorine, chlorine, bromine, iodine, phenoxy, and -OS (O) 2-R ', wherein R' is selected from the group consisting of alkyl, haloalkyl, and aryl optionally substituted with alkyl, halogen, or nitro; RA and RB are independently selected from the group consisting of: hydrogen, halogen, alkyl, alkenyl, alkoxy, alkylthio, and -N (R9) 2i or RA and RB taken together form a fused benzene ring or a fused pyridine ring , wherein the benzene ring or the pyridine ring is unsubstituted or substituted with a group R, or is substituted with a group R3, or is substituted with a group R and a group R3; or RA and RB taken together form a 5 to 7 membered fused saturated ring optionally containing a nitrogen atom, wherein the fused ring is unsubstituted or substituted with one or more R groups; R is selected from the group consisting of: halogen, hydroxy, alkyl, alkenyl, haloalkyl, alkoxy, alkylthio, and -N (R9) 2; Ri is selected from the group consisting of: -R, -XR, -XY-R4, -XYXY-R4, -X-R5, -N (R? ') - Q-R4, -N (R?') - XY? -R4, and -N (R? ') - X R5b; R3 is selected from the group consisting of: -Z-R4, -Z-X-R4, -Z-X-Y-R4, -Z-X-Y-X-Y-R4, and -Z-X-R5; X is selected from the group consisting of alkylene, alkenylene, alkynylene, arylene, heteroarylene, and heterocyclylene, wherein the alkylene, alkenylene, and alkynylene groups may optionally be interrupted with arylene, heteroarylene or heterocyclylene, and optionally may be interrupted by one or more groups -O-; Xi is C2-20 alkylene; Y is selected from the group consisting of: -O-, -S (O) 0-2-, -S (O) 2-N (R8) -, -C (R6) -, -0-C (R6) -, -OC (O) -0-, -N (R8) -Q-, -OC (R6) -N (R8) -, -C (R6) -N (OR9) -, -0-N (R8) ) -Q-, -0-N = C (R4) -, -C (= N-O'-R8) -, -CH (-N (-0-R8) -Q-R4) -, -v * • N V R, Yi is selected from the group consisting of -O-, -S (0) or-2-, -S (0) 2-N (R8) -, -N (R8) -Q-, -C (R6) - N (R8) -, -OC (R6) -N (R8) -, and Z is a bond u -O-; Ri 'is selected from the group consisting of hydrogen, C? _2oalkyl, C2.2o-hydroxy-alkylenyl, and C2.2alkoxy-alkylenyl; R 4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl, wherein the alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl groups , alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl and heterocyclyl may be unsubstituted or may be substituted with one or more substituents independently selected from the group consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, mercapto, cyano, aryl, aryloxy, arylalkylenoxy, heteroaryl, heteroaryloxy, heteroarylalkylenoxy, heterocyclyl, amino, alkylamino, dialkylamino, (dialkylamino) alkyleneoxy, and in the case of alkyl, alkenyl, alkynyl and heterocyclyl, oxo; R5 is selected from group consisting of: R5b is selected from the group consisting of: -N- C <; R6) - Re is selected from the group consisting of = O y = S; R7 is C2- alkylene; R8 is selected from the group consisting of hydrogen, alkyl, alkoxyalkylenyl, hydroxyalkylenyl, arylalkylenyl, and heteroarylalkylenyl; R9 is selected from the group consisting of hydrogen and alkyl; River is C3-8 alkylene; A is selected from the group consisting of -O-, -C (O) -, -S (O) 0-2-, and -N (R4) -; A 'is selected from the group consisting of -O-, -S (O) or-2-, -N (-Q-R4) -, and -CH2-; 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-, -C (Re) S-, and -C (R6) -N (OR9) -; V is selected from the group consisting of -C (R6) -, -OC (R6) - (-N (R8) -C (R6) -, and -S (O) 2-; V is selected from the group consisting of in -OC (R6) -, -N (R8) -C (R6) -, and -S (O) 2-; W is selected from the group consisting of a bond, -C (O) -, and -S (O) 2-; and a and b are, independently, integers from 1 to 6, with the proviso that a + b <7; pharmaceutically acceptable thereof. 84. The compound or salt according to claim 83, further characterized in that Ri is -R4 or -X-R. The compound or salt according to claim 84, further characterized in that -R4 is selected from the group consisting of 2-methylpropyl, 2-hydroxy-2-methylpropyl, 2,2-dimethyl-4-oxopentyl, and ( 1-hydroxycyclobutyl) methyl, and -X-R4 is 2,2-dimethyl-3- (2-methyl-1,3-dioxolan-2-yl) propyl. 86.- The compound or salt according to claim 85, further characterized in that -R4 is 2-methylpropyl. 87. The compound or salt according to claim 83, further characterized in that R is -X-Y-R4. 88. The compound or salt according to claim 87, further characterized in that X is alkylene of C2-, and Y is -S (0) 2- or N (R8) -Q-. 89. The compound or salt according to claim 88, further characterized in that -XY-R4 is selected from the group consisting of 2- (propylsulfonyl) ethyl, 2-methyl-2 - [(methylsulfonyl) amino] propyl, -methylsulfonylaminobutyl, and 2- (acetylamino) -2-methylpropyl. 90.- The compound or salt according to claim 83, further characterized in that Ri is -X-R5. 91.- The compound or salt according to claim 90, further characterized in that -X-R5 is 4 - [(morpholin-4-ylcarbonyl) amino] butyl. 92. The compound or salt according to any of claims 83 to 91, further characterized in that RA and RB taken together form a fused benzene ring, wherein the benzene ring is not substituted. 93.- The compound or salt according to any of claims 83 to 91, further characterized in that RA and RB taken together form a fused pyridine ring, wherein the fused pyridine ring is unsubstituted, and wherein the ring of Fused pyridine is: where the highlighted link indicates the position where the ring is fused.