MX2007016409A

MX2007016409A - Process for preparing benzimidazole compounds

Info

Publication number: MX2007016409A
Application number: MXMX/A/2007/016409A
Authority: MX
Inventors: Gair Ford James; Mark Pointon Simon; Leonard John; Demattei John; Shakya Sagar; P Hache Bruno; Charles Evans Matthew; D Piscopio Anthony; Peeters Koen; John Lilley Timothy
Original assignee: Array Biopharma Inc; Astrazeneca Ab; Demattei John; Charles Evans Matthew; Gair Ford James; P Hache Bruno; Leonard John; John Lilley Timothy; Peeters Koen; D Piscopio Anthony; Mark Pointon Simon; Shakya Sagar
Priority date: 2005-06-23
Filing date: 2007-12-18
Publication date: 2008-09-02

Abstract

Provided are methods for the synthesis of heterocyclic compounds such as benzimidazole carboxylic acid core structures having Formula Ia-1 and their synthetic intermediates:wherein Z, X1, X2, X5, R2and R10are as defined herein. Compounds of Formula Ia-1 and their synthetic intermediates can be used to prepare heterocyclic derivatives such as benzimidazole derivatives.

Description

PROCESS FOR PREPARING BENZYM DAZOL COMPOUNDS BACKGROUND OF THE INVENTION Field of the Invention This invention relates to processes for the preparation of heterocyclic compounds. More specifically, this invention relates to the synthesis of compounds that can be used to prepare pharmaceutical agents such as benzimidazole derivatives. This invention also includes intermediary compounds obtained during the synthesis of heterocyclic compounds according to this invention and methods of preparation thereof. Description of the state of the art Benzimidazole derivatives have been investigated as therapeutics for treating cancers, viral infections and diseases and pathological conditions involving inflammation and have been disclosed in a number of patents and publications in the past several years, including publications. of Patents Nos. 2003/0232869, 2004/0116710 and 2003/0216460; U.S. Patent Nos. 5,525,625; WO 98/43960; WO 99/01421; WO 99/01426; WO 00/41505; WO 00/42002; WO 00/42003; WO 00/41994; WO 00/42022; WO 00/42029; WO 00/68201; WO 01/68619; WO 02/06213; WO 03/077914; and WO 03/077855.

In particular, WO 03/077914 describes the synthesis of the sodium salt of a benzimidazole derivative of 2,3-trifluorobenzoic acid in 11 linear steps as illustrated in Scheme 1. This route is not only very large in terms of the number of stages, but also include a number of chemical transformations that could be dangerous to carry out on a manufacturing scale, and / or produced levels of by-products that would not be acceptable in a final active pharmaceutical ingredient (API ). It will be appreciated by those skilled in the art that for a process that is suitable for industrial application, it should be (i) handled that is performed on a large scale, (ii) have minimal environmental impact (for example in terms of quantity of raw materials required). and / or the amount of waste produced), (iii) safe (eg, use materials of low toxicity that do not produce toxic waste) and (iv) low cost as possible (eg, being a higher yield and synthesis more convergent). Since heterocyclic compounds such as benzimidazoles are potentially useful as therapeutic products, there is an ongoing need for a more efficient synthetic route for the production of benzimidazole derivatives which is more manageable to or suitable for large-scale manufacture. 4 Scheme 1 BRIEF DESCRIPTION OF THE INVENTION In general, the present invention provides methods for preparing the heterocyclic compounds and their synthetic intermediates, which are useful for the production of therapeutic compounds such as benzimidazole derivatives. According to one aspect of the present invention, the methods are provided for the preparation of compounds, of general Formulas Ia-1, Ia-2, Ib-1, Ib-2 and Ic-1 and their synthetic intermediates Ic-1 and salts and solvates thereof, wherein Z is -CAOOR1, -C (= 0) NR6R7, CN, -C (= 0) H, or , or a portion that can be transformed into any of the Z groups, for example through hydrolysis; R1 is hydrogen, C1-C10alkyl, C2-C2alkenyl, C2-C2alkynyl, C3-cycloalkyl, C3-C10 cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, trialkylsilyl or dialkylarylsilyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl portions are optionally substituted with one or more groups independently selected from halogen, hydroxyl, C? -C4 alkyl , C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl and C3-C6 heterocycloalkyl; R2 and R2b are independently hydrogen, Ci-Cio alkyl, C2-C? Alkenyl, C2-C? Alkynyl, arylalkyl, trialkylsilyl, dialkylarylsilyl, -COR6, C (0) OR6 or -C (0) NR6R7 , wherein the alkyl, alkenyl, alkynyl and arylalkyl portions are optionally substituted with one or more groups independently selected from halogen, hydroxyl, C 1 -C 4 alkyl, C2-C4 alkenyl and C2-C4 alkyl, wherein for Formula Ic-1, R2 is not hydrogen; X1 and X2 are independently selected from hydrogen, F, Cl, Br, I, OR8, A-Cio alkyl, C2-C? Alkenyl, C2-C? Alkynyl, C3-C? Cycloalkyl, cycloalkylalkyl of C3-C10 and C1-C10 thioalkyl, wherein the alkyl, alkenyl, alkyl, cycloalkyl, cycloalkylalkyl and thioalkyl portions are optionally substituted with one or more groups independently selected from oxo, halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy and azido; X5 is H, F, Cl, Br, I or C? -C6 alkyl; R6 and R7 are independently hydrogen, trifluoromethyl, -OR8, C1-C10 alkyl, C2-C20 alkenyl, C2-C20 alkyl, C3-C3 cycloalkyl, C3-C10 cycloalkylalkyl, aryl, lactyl, heteroaryl, heteroalalkyl, heterocyclyl or heterocyclylalkyl, or R6 and R7 together with the atom to which they are attached form a heteroacyl or heterocyclic ring of 4 to 10 mrs, wherein the heteroaryl and heterocyclic rings are optionally substituted with one or more groups independently selected from halogen, trifluoromethyl, difluoromethoxy, trifluoromethoxy and OR8; R8 is hydrogen, alkyl of A-Cio, alkenyl of C2-Cio, aplo or aplaxyl, wherein the alkyl, alkenyl, aryl and arylalkyl are optionally substituted with one or more groups independently selected from OH, -0- (C? -C? alkyl) and -0- (C1-C10 alkenyl); R10 is hydrogen, alkyl of A-Cio, cycloalkylalkyl of C3-C10, arylalkyl, heteroarylalkyl or heterocyclylalkyl, wherein the alkyl, cycloalkylalkyl, arylalkyl, heteroalalkyl and heterocyclylalkyl portions are optionally substituted with one or more groups independently selected from halogen, hydroxyl, cyano, nitro, azido, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 heterocycloalkyl, -NR 6 R 7 and -OR 8; and R12a and R12b are independently selected from hydrogen, C1-C10 alkyl, C2-C2 alkenyl, C2-C2 alkynyl, C3-C3 cycloalkyl, C3-C10 cycloalkylalkyl, aryl, aplakyl, heteropole and heteroaplakyl, or R12a and R12 together with the atom to which they are attached form a carbocyclic, heteroaryl or heterocyclic ring of 4 to 10 mrs. More specifically, one diment of the present invention provides a process, referred to herein as Method 1, to prepare benzimidazole N-3 compounds represented by Formula Ia-1 and its synthetic intermediates.

Ia-1 and salts and solvates thereof, wherein Z, R2, R10, X1, X2 and X5 are as defined herein, the method comprising: nitrating a compound having the Formula wherein X and X are independently F, Cl, Br, I or a sulfonate ester, and Z and X5 are as defined herein, to provide a compound of Formula II wherein X, X4, X5 and Z are as defined herein; treating the compound of Formula II, optionally at elevated temperature and / or pressure, with two or more equivalents of (i) a reagent that contains or generates ammonia, (ii) a primary or secondary amine other than an aromatic amine or (iii) a reagent that supplies a group that can be subsequently converted to an amine to provide a compound of Formula VI-11, or treat the compound of Formula II with (iv) two or more equivalents of a metal azide, optionally at elevated temperatures and / or pressure, to provide a compound of Formula VI-12 VI-11: A NR2R2a VI-12: A = U-. wherein X5, R2 and Z are as defined herein, and R2a is hydrogen, C? -C? alkyl, C2-C? alkenyl, C2-C? alkynyl, benzyl, allyl, arylalkyl , trialkylsilyl, dialkylarylsilyl, -COR6, -C (0) OR6, C (0) NR6R7, -OR1 or -NHR1, wherein the alkyl, alkenyl, alkynyl, benzyl, allyl and arylalkyl portions are optionally substituted with one or more groups independently selected from halogen, hydroxyl, C 1 -C 4 alkyl, C 2 -C 4 alkenyl and C 2 -C 4 alkynyl; reducing the compound of Formula VI-11 or VI-12 to provide a compound of Formula VIIa-1 VIIa-1 wherein X5, R2, R2a and Z are as defined herein, and wherein when A of Formula VI-11 or VI-12 is -NH-benzyl, -NHOR1, -NHNHR1 or N3, then R2 and R2a of Formula VIIa-1 are hydrogen; when R2a is hydrogen, cyclize the compound of Formula VIIa-1 to provide a compound of Formula VIIIa-1 wherein Z, R2, R2a, R10 and X5 are as defined herein; and when R2a is hydrogen, coupling the compound of Formula VIIIa-1 with a reagent having the formula wherein X1 and X2 are as defined herein and X6 is F, Cl, Br, I, -OS02CF3, alkyl sulfonate, aryl sulfonate, alkylaryl sulfonate, -B (0R8) 2, -BF3 or -Bi (R1) 2, optionally either (i) at elevated temperature and optionally in the presence of a base, or (ii) in the presence of a catalyst based on metal and a base, to provide the compound of Formula Ia-1. In a particular embodiment of Method 1, a process for preparing a compound of Formula Ia-1 is provided ? a-1 and salts and solvates thereof, wherein: Z is -C (= 0) 0R1, R1 is C? -C? 0 alkyl, and R2, R10, X1, X2 and X5 are as defined herein, process comprising: i) nitrating a compound having the Formula wherein XJ and X "are independently F, Cl, Br, I, or a sulfonate ester and X5 is as defined herein, to provide a compound of Formula II wherein X3, X4 and X5 are as defined herein; ii) reacting the compound of the Formula II with a compound of the formula R 1 OH, wherein R 1 is C 1 -C 10 alkyl, to form the corresponding ester having the formula wherein R1 is C? -C? alkyl and X3, X4 and X5 are as defined herein; iii) reacting the ester of step (ii) with two or more equivalents of a reactant that generates ammonia to form a compound of Formula VI-11 VI-ll: A = NR2R2a wherein R2a is hydrogen, R1 is Ci-Cio alkyl and R2 and X5 are as defined herein; iv) reducing the compound of Formula VX-11 to provide a compound of Formula VIIa-1 VIIa-1 wherein R2a is hydrogen, R1 is Ci-Cio alkyl and R2 and X5 are as defined herein; v) cyclizing the compound of Formula VIIa-1 to provide a compound of Formula VIIIa-1 VIIIa-1 wherein R2a is hydrogen, R1 is C? -C? 0 alkyl, and R2, R10 and X5 are as defined herein; and vi) coupling the compound of Formula VIIIa-1 with a reagent having the Formula wherein X1 and X2 are as defined herein and X6 is F, Cl, Br, I, -OS02CF3, alkyl sulfonate, aryl sulfonate, alkylaryl sulfonate, -B (0R8) 2, -BF3 or -Bi (R8) 2, to provide the compound of Formula Ia-1. The coupling step of this process is optionally carried out at either i) elevated temperature and optionally in the presence of a base or ii) in the presence of a catalyst based on metal and a base. In another particular embodiment of Method 1, a process for preparing a compound of Formula Ia-1 is provided. and salts and solvates thereof, wherein R1, R2, R10, X1, X2 and X5 are as defined herein, the method comprising: coupling a compound of Formula VIIIa-1, VIIIa-1 wherein R, 2a is hydrogen, with a reagent having Formula X wherein X1 and X2 are as defined herein and X6 is F, Cl, Br, I, -OS02CF3, alkyl sulfonate, aryl sulfonate, alkylaryl sulfonate, -B (0-R8) 2, -BF3 or -Bi (R1) 2, in the presence of a catalyst based on suitable metal and a base in a suitable solvent. In one embodiment the reagent of Formula X has the Formula where X1 is Br, X2 is alkyl or halogen and X6 is iodine. In one embodiment of the compound for Formula Ia-1 it is isolated as esterified form (ie, where Z is COOR1). In another embodiment the ester group COOR1 is hydrolyzed and the compound is isolated as a free acid (where Z is COOH) or a salt thereof, for example a sodium salt. In another embodiment, the present invention provides a method, referred to herein as Method 2, for preparing benzimidazole N-3 compounds represented by Formula Ia-2 and their synthetic intermediates.

Ia-2 and salts and solvates of the mimes, wherein R1, R2, R10, X1, X2 and X5 are as defined herein, the method comprising: nitrating a compound having the Formula wherein X3, X4, X5 and Z are as defined herein, to provide a compound of Formula II II wherein Z, X3, X4 and X5 are as defined herein; treating the compound of Formula II optionally at an elevated temperature and / or pressure with two or more equivalents of (i) a reagent that contains or generates ammonia, (ii) a primary or secondary amine other than an aromatic amine or (iii) a reagent that supplies a group that can be subsequently converted to an amine to provide a compound of Formula VI-11 wherein R2a is as defined herein; or treating the compound of Formula II with (iv) two or more equivalents of a metal azide optionally at an elevated temperature and / or pressure to provide a compound of Formula VI-12 VI-11: A = NR2R2a VI-12: A = N3 wherein Z, X5, R2 and R2a are as defined herein; reacting the compound of Formula VI-11 or VI-12 with a compound having the Formula R x H, wherein R 1 is as defined herein, optionally in the presence of an activating agent that activates the group Z toward reaction with the compound having the Formula R 1 OH, provide a compound of the Formula Va-11 or Va-12 Va-11: A > NR2R2a Va-12: A = N3 wherein R1, R2, R2a, and X5 are as defined herein; reducing the compound of Formula Va-11 or Va-12 to provide a compound of Formula VIIa-2 VIIa-2 wherein R1, R2, R2a and X5 are as defined herein, and wherein when A of the Formula Va-11 or Va-12 is -NH-benzyl, -NHOR1, -NHNHR1 or N3, then R2 and R2d of Formula VIIa-2 are hydrogen; when R2a is hydrogen, cyclize the compound of Formula VIIa-2 to provide a compound of the Formula VIIIa-2 wherein R1, R2, R2a, R10 and X5 are as defined herein; and when R2a is hydrogen, coupling the compound of Formula VIIIa-2 with a reagent having the Formula optionally either (i) at elevated temperature and optionally in the presence of a base, or (ii) in the presence of a catalyst based on metal and a base, wherein X1, X2 and X6 are as defined herein, to provide the compound of Formula Ia-2. Still another embodiment of the present invention provides a method, referred to herein as Method 3, to prepare benzimidazole N-3 compounds represented by Formula Ib-1 and its synthetic intermediates Ib-1 and salts and solvates thereof, wherein Z, R 2b, R 1, X, X 2, and X 5 are as defined herein, the method comprising: nitrating a compound having the Formula where X3, X4, X5 and Z are as defined in the present, to provide a compound of Formula II wherein X3, X4, X5 and Z are as defined herein; reacting the compound of Formula II with (i) a reagent that contains or generates ammonia, (ii) a primary or secondary amine other than an aromatic amine or (iii) a reagent that supplies a group that can be subsequently converted to an amine under conditions that allow selective displacement of X4 to provide a compound of Formula III-ll; or reacting the compound of Formula II with (iv) a metal azide under conditions that allow selective displacement of X4 to provide a compound of Formula 111-12 ? II-11: A = NR2R2a wherein X3, X5, R2, R2a and Z are as defined herein; reacting the compound of Formula III-ll or 111-12, optionally at elevated temperatures, with (i) a reagent that contains or generates ammonia, (ii) a primary or secondary amine other than an aromatic amine or (iii) a reagent that supplies a group that can be subsequently converted in an amine to provide a compound having the Formula Vb-11 wherein B is -NR2bR2c and A is -NRR2a or N3; or reacting the compound of Formula III-ll or 111-12 with (iv) a metal azide, optionally at elevated temperatures, to provide a compound of Formula Vb-12 wherein B is N3 and A is -NR2R2a or N3, Vb-ll: B = NR2bR2c; A = NR2R2a or N3 Vb-12: B = N3, A = NR2R a or N3 wherein Z, X 5, R 2, R 2a and R 2b are as defined herein and R 2c is hydrogen, C 1 -C 6 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, benzyl, allyl, arylalkyl , trialkylsilyl, dialkylarylsilyl, -COR6, -C (0) 0R6, C (0) NR6R7, -OR1 or -NHR1, wherein the alkyl, alkenyl, alkynyl, benzyl, allyl and arylalkyl portions are optionally substituted with one or more groups independently selected from halogen, hydroxyl, C? -C4 alkyl, alkenyl of C2-C4 and C2-C4 alkynyl; 2? reducing the compound of Formula Vb-11 or Vb-12 to provide a compound of Formula VIIb-1 VIIfo-1 wherein Z, R2, R2a, R2b, R2c and X5 are as defined herein, and wherein when A and / or B of Formula Vb-11 or Vb-12 is -NH-benzyl, N3 , -NHOR1 or -NHNHR1, then R2 and R2a and / or R2b and R2c, respectively, of Formula VIIb-1 are hydrogen; When R2a is hydrogen, cyclize the compound of the Formula Vllb-l to provide a compound of Formula VI I Ib- 1 vpib-i wherein Z, R2b, R2c, R10 and X5 are as defined herein; and when R2c is hydrogen, coupling the compound of Formula VIIIb-1 with a reagent having the formula optionally either (i) at elevated temperature and optionally in the presence of a base, or (ii) in the presence of a catalyst based on metal and a base, wherein X1, X2 and X6 are as defined herein, to provide the compound of Formula Ib-1. In another embodiment, the present invention provides a process, referred to herein as the Method 4, to prepare benzimidazole N-3 compounds represented by Formula Ib-2 and their synthetic intermediates Ib-2 and salts and solvates thereof, wherein R1, Rb, R10, X1, X2 and X5 are as defined herein, the method comprising: nitrating a compound having the formula where X, X4, X5 and Z are as defined in the present, to provide a compound of Formula II wherein X3, X4, X5 and Z are as defined herein; reacting the compound of Formula II with (i) a reagent that contains or generates ammonia, (ii) a primary or secondary amine other than an aromatic amine, or (iii) a reagent that supplies a group that can subsequently be converted to a amine, under conditions that allow selective displacement of X4, to provide a compound of Formula III-ll, or react the compound of Formula II with (iv) a metal azide under conditions that allow selective displacement of X4 to provide a compound of Formula 111-12 III-ll: A = NR2R2a 111-12: A = N3 wherein Z, R2, R2a, X3 and X5 are as defined herein; reacting the compound of Formula III-ll or 111-12 with a compound having the formula R 1 OH wherein R 1 is as defined herein, optionally in the presence of an activating agent that activates group Z to the reaction with the compound of the formula R1OH, to provide a compound of the Formula IV-21 or IV-22 IV-22: A = N3 wherein R1, R2, R2a, X3 and X5 are as defined herein; reacting the compound of Formula IV-21 or IV-22, optionally at elevated temperatures, with (i) a reagent that contains or generates ammonia, (ii) a primary or secondary amine other than an aromatic amine or (iii) a reagent that supplies a group that can be subsequently converted to an amine to provide a compound of Formula Vb-21 wherein B is -NR2bR2c and A is -NR2R2a or N3, or reacting the compound of Formula IV-21 or IV -22 with (iv) a metal azide, optionally at elevated temperatures, to provide a compound of Formula Vb-22 wherein B is N3 and A is -NRR2a or N3, Vb-21: B = NR2bR2c Vb-22: B = N3 wherein R1, R2, R2a, R2b, R2c and X5 are as defined herein; reducing the compound of Formula Vb-21 or Vb-22 to provide a compound of Formula VIIb-2 wherein R1, R2, R2a, R2b, Rc and X5 are as defined herein, and wherein when A and / or B of Formula Vb-21 or Vb-22 is -NH-benzyl, N3, -NHOR1 or -NHNHR1, then R2 and R2a and / or R2b and R2c, respectively, of Formula VIIb-2 are hydrogen; when R2a is hydrogen, cyclize the compound of Formula VIIb-2 to provide a compound of Formula VIIIb-2 wherein R, R, R, R and X are as defined herein; and when R2c is hydrogen, coupling the compound of Formula VIIIb-2 with a compound having the formula optionally either (i) at elevated temperature and optionally in the presence of a base, or (ii) in the presence of a catalyst based on metal and a base, wherein X1, X2 and X6 are as defined herein, to provide the compound of Formula Ib-2. Yet another embodiment of the present invention provides a method, referred to herein as Method 5, to prepare N-1 benzimidazole compounds represented by Formula Ib-1 and its synthetic intermediates Ic-1 and salts and solvates thereof, wherein Z, R, 2b, X1, X2 and X5 are as defined herein, the method comprising: cyclizing a compound of Formula VIIb-1 prepared as described in Method 3, wherein R2 is not hydrogen and Z, R2a, R2b, R2c and X5 are as defined herein to provide a compound of Formula XIb-1 XIb-1 wherein Z, R2, R2c, R10 and X are as defined herein and R2 is not hydrogen; and coupling the compound of Formula XIb-1 with a reagent having the formula optionally either (i) at elevated temperatures and optionally in the presence of a base, or (ii) in the presence of a metal-based catalyst and a base, wherein X1, X2 and X6 are as defined herein, to provide the compound of Formula Ib-1. The step of cyclizing a compound of Formula VIIa-1, VIIa-2, VIIb-1 or VIIb-2 to provide benzimidazole core structures in any of Methods 1-5 described above can be performed in several ways. Various methods of cyclization, specifically Methods A-E, are generally described below with respect to the cyclization of a compound of Formula VIIb-1 for easy explanation; however, it is to be understood that Methods A-E is applied equal to the cyclization of the compounds of Formulas VIIa-1, VIIa-2 and VIIb-2. Cyclization methods will provide either N-3 benzimidazole derivatives or N-1 benzimidazole derivatives, depending on the reagents used and the substituents of the compounds of Formulas VIIa-1, VIIa-2, VIIb-1 and VIIb-2. Method A: According to Method A, a compound of Formula VIIb-1, wherein R2 and R2a are hydrogen, can be cyclized to the corresponding benzimidazole represented by Formula VIIIb-1, wherein R10 is hydrogen, by a method of "a container" in the treatment with (i) formic acid, optionally in the presence of an additional acid or (ii) a formic acid derivative in the presence of an acid. The compound of Formula VIIIb-1 can then be carried out in a compound of Formula Ib as described in detail below. Method B: According to Method B, a compound of Formula VIIb-1, wherein R2a is hydrogen and R2 is not hydrogen, the corresponding N-3 benzimidazole represented by Formula VIIIb-1 can be cyclized by a method of multi-stage in the treatment with (i) formic acid, optionally in the presence of an additional acid, (ii) a formic acid derivative in the presence of an acid, or (iii) formaldehyde or a formaldehyde derivative in the presence of an acid, to provide an intermediate N-benzimidazole compound by Formula XIb-1. The compound of Formula XIb-1 can then be carried out in Formula Ib-1 of the benzimidazole derivative N-3 by alkylating the N-3 position, then by removing it from the R2 group in the N-1 position. Method C: According to Method C, a compound of Formula VIIb-1, wherein R2 and R2a are hydrogen, can be cyclized to the corresponding N-3 benzimidazole represented by Formula VIIIb-1 wherein R10 is methyl, by a "one vessel" method in the treatment with two or more equivalents of formaldehyde or a formaldehyde derivative in the presence of an acid. The compound of Formula VIIIb-1 can then be carried out to the benzimidazole compound N-3 represented by Formula Ib-1 as described in detail below. Method D: According to Method D, a compound of Formula VIIb-1, wherein R2 and R2a are hydrogen, can be cyclized to the corresponding benzimidazole represented by Formula VIIIb-1, wherein R10 is not hydrogen, by a stepped process comprising: (a) reacting a compound of Formula VIIb-1 with a suitable acylating agent to provide a compound of Formula IXb wherein Z, R2, R2a and X5 are as defined herein and R10a is H, C? -C? alkyl, C3-C10 cycloalkylalkyl, arylalkyl, heteroarylalkyl or heterocyclylalkyl, wherein the alkyl, cycloalkylalkyl, Arylalkyl, heteroarylalkyl and heterocyclylalkyl are optionally substituted with one or more groups independently selected from halogen, hydroxyl, cyano, nitro, azido, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 3 -C 6 cycloalkyl, C 3 -C 6 heterocycloalkyl , -NR6R7 and -OR8; (b) reducing the amide group of the compound of Formula IXb to provide a compound of Formula Xb wherein Z, R2, R2a, R10a and X5 are as defined herein; and (c) reacting the compound of Formula Xb with (i) formic acid optionally in the presence of an additional acid or (ii) a formic acid derivative in the presence of an acid to provide the compound of Formula VIIIb- 1. Alternatively, according to another embodiment of Method D, the compound of Formula Xb can be obtained by reacting the compound of Formula VIIb-1 with an alkylating agent of formula R10aCH2L, wherein L is a leaving group, such such as Cl, Br, I, OMs, OTs, OTf, etc. Method E: According to Method E, a compound of Formula VIIb-1, wherein R2a is hydrogen and R2 is not hydrogen, the corresponding benzimidazole compound of Formula VIIIb-1, wherein R10 is not hydrogen, can be cyclized by a stepped method comprising: (a) reacting a compound of Formula VIIb-1 VIIb-1 with a suitable acylating agent to provide a compound of Formula IXb wherein Z, R2, R2a and X5 are as defined herein and R, 10a is H, y-Cio alkyl, C3-C ?cycloalkylalkyl, arylalkyl, heteroarylalkyl or heterocyclylalkyl, wherein the alkyl, cycloalkylalkyl , arylalkyl, heteroarylalkyl and heterocyclylalkyl are optionally substituted with one or more groups independently selected from halogen, hydroxyl, cyano, nitro, azido, C? -C alkyl, C2-C alkenyl, C2-C4 alkynyl, C3-Cd cycloalkyl, C3-C6 heterocycloalkyl, -NR6R7 and -OR8; (b) reducing the amide group of the compound of Formula IXb to provide a compound of Formula Xb wherein Z, R2, R2a, R2b, R2c, R10a and X5 are as defined herein; (c) reacting the compound of Formula Xb with (i) formic acid optionally in the presence of an additional acid or (ii) a formic acid derivative in the presence of an acid to provide the compound of Formula XIIb-1 wherein Z, R2, R2b, R2c, R10a and X5 are as defined herein; and removing the R2 group to provide the benzimidazole compound N-3 of the Formula Ib-1. Alternatively, from According to another embodiment of Method E, a compound of Formula Xb can be obtained by reacting a compound of Formula VIIb-1 with an alkylating agent of formula R10aCH2L, wherein L is a leaving group, such as Cl , Br, I, OMs, OTs, OTf, etc. In additional aspect, the present invention provides compounds of Formulas III, Va-1, Vb-1, Vlla-1, VIIb-1, VIIIa-1, VIIIb-1 and XIb-1 and salts and solvates thereof. The compounds having Formulas III, Va-1, Vb-1, VIIa-1, VIIb-1, VIIIa-1, VIIIb-1 and XIb-1 are useful for the synthesis of the heterocyclic compounds that include, but are not limited to, benzimidazoles, benzimidazolones, pyrazmas and piperazines. Additional advantages and novel features of this invention will be set forth in part in the description that follows, and in part will become apparent to those skilled in the art in the examination of the following specification or may be understood by the practice of the invention. The advantages of the invention can be realized and achieved by means of the instrumentalities, combinations, compositions and methods particularly pointed out in the detailed description and the appended claims. BRIEF DESCRIPTION OF THE FIGURES The accompanying drawings, which are incorporated herein and form part of the specification, illustrate Non-limiting embodiments of the present invention, and together with the description, serve to explain the principles of the invention. In the Figures: Figure 1 shows a Reaction Scheme (Method 1) for the synthesis of the compounds of Formula Ia-1. Figure 2 shows a reaction scheme (Method 2) for the synthesis of the compounds having the Formula Ia-2. Figure 3 shows a Reaction Scheme (Method 3) for the synthesis of the compounds having the Formula Ib-1. Figure 4 shows a Reaction Scheme (Method 4) for the synthesis of the compounds having the Formula Ib-2. Figure 5 shows the structures of organometallic ligands used in certain aplo halide coupling reactions of the present invention. Figure 6 shows a "one vessel" cyclization method (Method A) using formic acid or a formic acid derivative for the preparation of benzimidazole core structures represented by Formula Ib-1. Figure 7 shows a multi-step cyclization method (Method B) using formic acid or a derivative of formic acid for the preparation of benzimidazole core structures represented by Formula Ib-1. Figure 8 shows a "one vessel" cyclization method (Method C) using formaldehyde or a formaldehyde derivative for the preparation of benzimidazole core structures represented by the Formula Ib-1. Figure 9 shows an alternative multi-step cyclization method (Method D) for the preparation of benzimidazole core structures represented by Formula Ib-1. Figure 10 shows yet another multi-step cyclization method (Method E) for the preparation of benzimidazole core structures represented by Formula Ib-1. DETAILED DESCRIPTION OF THE INVENTION One aspect of the present invention provides methods for the preparation of the compounds of the general formulas Ia-1, Ia-2, Ib-1, Ib-2 and Ib-1 and their synthetic intermediates Ic-1 and salts and solvates thereof, wherein: Z is -CC = 0) OR1, -C (= 0) NR6R7, CN, -C (= 0) H, or > or a portion that can be transformed into any of the Z groups, for example through hydrolysis; R 1 is hydrogen, C 1 -C 6 alkyl, C 2 -C 20 alkenyl, C 2 -C 8 alkynyl, C 3 -C 10 cycloalkyl, C 3 -C 10 cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, trialkylsilyl or dialkylarylsilyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl are optionally substituted with one or more groups independently selected from halogen, hydroxyl, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 3 -C 6 cycloalkyl and C 3 -C 6 heterocycloalkyl; R 2 is hydrogen, C 1 -C 6 alkyl, C 2 -C 10 alkenyl, C 2 -C 8 alkynyl, arylalkyl, trialkylsilyl, dialkylarylsilyl, -COR 6, -C (0) OR 6 or -C (0) NR 6 R 7, wherein the alkyl, alkenyl, alkyl, and arylalkyl portions are optionally substituted with one or more groups independently selected from halogen, hydroxyl, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, and C 2 -C 4 alkyl, where for Formula Ib-1, R2 is not hydrogen; R 2b is hydrogen, C 1 -C 10 alkyl, C 2 -C 0 alkenyl, C 2 -C 8 alkynyl, arylalkyl, trialkylsilyl, dialkylarylsilyl, -COR 6, -C (0) OR 6 or -C (0) NR 6 R 7, wherein the alkyl, alkenyl, alkyl and arylalkyl portions are optionally substituted with one or more groups independently selected from halogen, hydroxyl, C 1 -C 4 alkyl, C 2 -C 4 alkenyl and C 2 -C 4 alkynyl; X and X2 are independently selected from hydrogen, F, Cl, Br, I, OR8, C1-C10 alkyl, 2-C10 alkenyl, C2-C10 alkyl, C3-C10 cycloalkyl, C3-C10 cycloalkylalkyl or thioalkyl. of C1-C10, wherein the alkyl, alkenyl, alkyl, cycloalkyl, cycloalkylalkyl and thioalkyl are optionally substituted with one or more groups independently selected from oxo, halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy and azido; X5 is H, F, Cl, Br, I or C? -C6 alkyl; R6 and R7 are independently hydrogen, trifluoromethyl, -OR8, C1-C10 alkyl, C2-C2 alkenyl, C2-C3 alkynyl, C3-C10 cycloalkyl, C3-C10 cycloalkylalkyl, aryl, aryl-alkyl, heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl, or R6 and R7 together with the atom to which they are attached form a heteroaryl or heterocyclic ring of 4 to 10 members, wherein the heteroaryl and heterocyclic rings are optionally substituted with one or more groups independently selected from halogen, trifluoromethyl, difluoromethoxy, trifluoromethoxy and OR8; R8 is hydrogen, C1-C10 alkyl, C2-C10 alkenyl, aryl or arylalkyl, wherein the alkyl, alkenyl, aryl and arylalkyl are optionally substituted with one or more groups independently selected from OH, -0- (C1 alkyl) -C10) and -O- (C1-C10 alkenyl); R10 is hydrogen, C1-C10 alkyl, C3-C10 cycloalkylalkyl, arylalkyl, heteroarylalkyl or heterocyclylalkyl, wherein the alkyl, cycloalkylalkyl, arylalkyl, heteroarylalkyl and heterocyclylalkyl are optionally substituted with one or more groups independently selected from halogen, hydroxyl, cyano, nitro, azido, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 3 -C 6 cycloalkyl, C 3 heterocycloalkyl -C6, -NR6R7 and -OR8; and R12a and R12b are independently selected from hydrogen, C? -C10 alkyl, C2-C? alkenyl, C2-C? alkynyl, C3-C10 cycloalkyl, C3-C10 cycloalkylalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl, or R12a and R12b together with the atom to which they are attached form a carbocyclic, heteroaryl or heterocyclic ring of 4 to 10 members. The methods for preparing the benzimidazole N-3 compounds of the general formulas la-1, Ia-2, Ib-1 and Ib-2 can be carried out in several ways. Four methods, specifically Methods 1-4, are shown in Figures 1-4, respectively, and are described below. Method 5 describes the synthesis of the benzimidazole derivative N-l represented by Formula Ib-1. In certain modalities of Methods 1-5, Z is -C (= 0) NR6R7. In certain embodiments, R6 is OR8 and R7 is H. In certain embodiments, R6 is C1-C10 alkyl optionally substituted with OH, O- (C? -C6 alkyl) or -O- (C? ~10 alkenyl) . In certain embodiments, R8 is - (CH2) 2-OH. In particular embodiments, Z is -C (= 0) NH (CH2) 2-OH.

In certain modalities of Methods 1-5, Z is COOR1. In certain embodiments, R1 is Ci-Cio alkyl- In particular embodiments, R1 is methyl. In certain embodiments of Methods 1-5, X5 is halogen. In particular embodiments, X5 is F. In certain embodiments of Methods 1-5, X1 and X2 are H or halogen, and X6 is halogen. In other embodiments, X2 is alkyl. In certain modalities, X1 is Br. In certain modalities, X2 is Cl. In certain modalities, X6 is iodine. In certain embodiments of Methods 1-5, R10 is Ci-Cio alkyl- In particular embodiments, R10 is methyl. In other embodiments of Methods 1-5, R2 and R2b are hydrogen. In certain embodiments, Methods 1-5 provide the methods for preparing the compounds of Ia-1, Ia-2, Ib-1, Ib-2 and Ib-1 wherein Z is -C (= 0) NR6R7, X5 is halogen, X1 and X2 are H or halogen, and R10 is C? -C? 0 alkyl. In certain embodiments, R6 is OR8, R7 is H, X5 is F, X2 is Cl and R10 is methyl. In particular embodiments, Z is -C (0) NH- (CH2CH2OH), X5 is F, X2 is Cl and R10 is methyl. In certain embodiments, Methods 1-5 provide methods for preparing the compounds of la- 1, Ia-2, Ib-1, Ib-2 and Ib-1 wherein Z is COOR1, X5 is halogen, X1 and X2 are H or halogen, and R10 is C? -C? 0 alkyl. In certain embodiments, R1 is alkyl of A-Cio, X5 is F, X2 is Cl and R10 is methyl. In particular embodiments, Z is COOCH2, X5 is F, X2 is Cl and R10 is methyl. Method 1: One embodiment of the present invention provides a method, referred to herein as Method 1 and shown schematically in Figure 1, to prepare the compounds of Formula Ia-1 and their synthetic intermediates and salts and solvates thereof, wherein X1, X2, X3, R2 and R10 are as defined herein, and Z is -CC = 0) OR1, -C (= 0) NR6R7, CN, -C ( = 0) H, or i or a portion that can be transformed into any of the Z groups, for example through hydrolysis. Examples of portions that can be transformed into the Z groups defined through hydrolysis include, but are not limited to, orthoesters having the formula C (OR *) 3 and acetals having the formula CH (OR 1) 2. More specifically, Method 1 comprises nitrating a compound having the Formula wherein X3 and X4 are independently F, Cl, Br, I, or a sulfonate ester such as, but not limited to, trifluoromethanesulfonate, methanesulfonate, benzenesulfonate or p-toluenesulfonate, and X5 and Z are as defined herein, to provide a compound of Formula II wherein X3, X4 and X5 are as defined herein. In one embodiment of a compound of Formula II, X3, X4 and are F. The nitration reaction conditions, which are well known to those skilled in the art, can include reacting an aromatic system with nitric acid in the presence of an activating agent such as concentrated sulfuric acid. For example, in a embodiment a 2, 3, 4-trihalobenzoic acid can be treated with smoking nitric acid in H3S04 to provide a 2,3-trihalo-5-nitrobenzoic acid, such as 2, 3, 4-trifluoro- 5-nitrobenzoic, in high yield.

The compound of Formula II is then subjected to a bis-amination reaction comprising a nucleophilic shift of X3 and X4. Nucleophilic substitution of a leaving group (such as a halide, or sulfonate ester) ortho- or para- to a nitro group in an aromatic ring is a method well known in the art for the introduction of an amino group into an aromatic ring . In the case of the compounds of Formula II, the leaving groups in the ortho- and para- positions to the nitro group can be replaced in an individual process under suitable conditions. Examples of bisaminations are illustrated herein by Method 1 as well as Method 2 below. More specifically, according to Method 1 a compound of Formula II is optionally treated at elevated temperatures with two or more equivalents of (i) a reagent that contains or generates ammonia, (ii) a primary or secondary amine other than an amine aromatic or (iii) a reagent that supplies a group that can be subsequently converted to an amine to provide a compound of Formula VI-11 wherein A is NR2R2a, or the compound of Formula II is treated with (iv) two or more equivalents of a metal azide optionally at elevated temperatures and / or pressure to provide a compound of Formula VI-12 wherein A is N3 VI-11: A = NR2R2a VI-12 A = N3 wherein X5, R and Z are as defined herein, and R2a is hydrogen, C? -C? Alkyl, C2-C? Alkenyl, C2-C? alkynyl, benzyl, allyl, arylalkyl, trialkylsilyl, dialkylarylsilyl, -COR6, -C (0) OR6, -C (0) NR6R7, -OR1 or -NHR1, wherein the alkyl, alkenyl, alkynyl moieties , benzyl, allyl, or arylalkyl are optionally substituted with one or more groups independently selected from halogen, hydroxyl, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, and C 2 -C 4 alkynyl. In certain embodiments, R2a is a nitrogen protecting group such as hydrogen, substituted or unsubstituted benzyl, allyl or -C (0) OR6. In a particular embodiment, R2a is hydrogen. In a particular embodiment of Method 1, the compound of Formula II, wherein Z is COOH, can be subjected to an esterification of group Z and a bis-amination in one step. This can be achieved by reacting the compound of Formula II, where Z is COOH, with a compound of the formula R1OH wherein R1 is Ci-Cio alkyl, optionally in the presence of an activating agent, to form the ester corresponding in-si tu, followed by the reaction of the ester with two or more equivalents of (i) a reactant that generates ammonia, for example ammonium hydroxide or (ii) a primary or secondary amine other than an aromatic amine to provide a compound of Formula VI-11, wherein Z is COOR1, R1 is C? -C10 alkyl, and R2 and R2a are as defined herein. Examples of activating agents include, but are not limited to, (a) mineral and organic acids; (b) reagents capable of converting a carboxylic acid to an acid chloride including, but not limited to, halogenating agents such as S0C12 or (C0C1) 2, alkyl chloroformates, aryl chloroformates and chlorides (such as trimethylacetyl); (c) carbodiimides, including, but not limited to, dicyclohexylcarbodiimide (DCC); (d) trialkylsilyl halides including, but not limited to, trimethylsilyl chloride (Me 3 SiCl); (e) chloroformates such as alkyl chloroformates (eg, isobutyl chloroformate) and ethyl chloroformates (phenyl chloroformate) and (f) dialkylazodicarboxylates such as, but not limited to, diethylazodicarboxylate (DEAD), which is typically used in conjunction with a phosphino reagent such as, but not limited to, Ph3P. In one embodiment, the activating agent is trimethylsilyl chloride. Examples of reagents that contain or generate Ammonia include, but are not limited to, NH3 and NH4OH. Examples of primary and secondary amines suitable for purposes of this invention include amines having the formula HNR2R2a, wherein R2 and Ra are as defined herein. Specific examples of primary and secondary amines include, but are not limited to methylamine, benzylamine, dibenzylamine, allylamine, diallylamine and hexamethyldisilazane. Examples of reagents that provide a group that can be subsequently converted to an amine include, but are not limited to, (1) metal amides such as sodium, potassium and lithium amide, or alkylating derivatives thereof, (2) ammonia. protected or amide equivalents such as, but not limited to, hydroxylamines and hydrazines, (3) nitrogen nucleophiles having the Formula MNR2R2a wherein M is a metal such as Na, K, Li, Cs, Mg or Al and (4) metal silylamides such as lithium (bis) (trimethylsilyl) amide, sodium (bis) (trimethyl silyl) -amidea or potassium (bis) (trimethylsilyl) amide. Examples of azide metal azides include, but are not limited to, sodium azide (NaN3), potassium azide (KN3) and lithium azide (LiN3). The bis-amination reaction can be carried out in any suitable organic or aqueous solvent, including but not limited to N-methyl pyrrolidine, THF, dioxane, at temperatures ranging from -20 ° C to 200 ° C. In certain The reaction is carried out at elevated temperatures in a range of approximately 50 and 100 ° C. An example of a method for preparing a compound of Formula VI-11 comprises reacting a compound of Formula II with ammonium hydroxide at a temperature between 50 and 100 ° C, in particular between 80 and 90 ° C. Another example of a method for preparing a compound of Formula VI-11 of a compound of Formula II comprises reacting, for example, a compound of Formula II, wherein Z = C02H and X3 and X4 = F, with excess of ammonium hydroxide solution in N-methyl pyrrolidine at an elevated temperature, for example between 80-90 ° C, in a sealed reactor, ba or a light pressure of ammonia, for example 0-5 bar, to provide a compound of Formula VI-11 wherein Z = C02H, R2 = H, and R2a = H in high yield. This invention also provides compounds of Formulas VI-11 and VI-12 and salts and solvates thereof, wherein Z, X5, A, R2 and R2a are as defined herein. In some embodiments of the compounds of Formula VI-11 and VI-12, Z is -COOR1 or -C (= 0) NR6R7. In certain embodiments, R6 is -OR8 and R7 is H. In particular embodiments, R8 is - (CH2) 2-OH. In some embodiments, X5 is halogen. In particular embodiments, X5 is F. In some embodiments of the compounds of Formula VI-11, A is NH2. The compound of Formula VI-11 or VI-12 is then reduces to provide the compound of the Formula VXIa-1 wherein X5, R2, R2a and Z are as defined herein, wherein when A of the compound of Formula VI-11 or Formula VI-12 is -NH-benzyl, -NHOR1, -NHNHR1 or N3, then R2 and R2a of the compound of Formula VIIa-1 are hydrogen. The reduction step can be carried out using the reaction conditions and reagents well known to those skilled in the art. Examples of suitable methods for reducing an aromatic nitro group include, but are not limited to, dissolving metal reductions, cytic hydrogenations and enzymatic reactions. More specific examples of dissolved metal reductions include the use of a metal in a suitable solvent under acidic conditions. Examples of metals suitable for dissolving metal reductions include, but are not limited to, Zn, Fe and Sn. Suitable solvent systems include water and / or organic solvents such as, but not limited to, alcohols, carboxylic acids, ethers or a mixture thereof. For example, in one embodiment a compound of Formula VI-11 or VI-12 can be converted to a compound of Formula VIIa-1 using zinc powder and HCl concentrated in a mixture of methanol and water, at temperatures between 0-100 ° C, more typically at 50-70 ° C. Cytic hydrogenations can be carried out with hydrogen in the presence of a metal cyst in a suitable solvent system under hydrogen (eg, 1-20 atm.H2) typically at temperatures between 0-100 ° C. Metal cysts suitable for use in cytic hydrogenations include, but are not limited to, Pd, Pt, Rh and Ni. Examples of suitable solvent systems include, but are not limited to, alcohols (e.g., methanol, ethanol, isopropanol), acetic acid, esters (e.g., ethyl acetate) and ethers (e.g., THF). Mixed solvents, which include aqueous mixtures are also commonly used for hydrogenations. Cytic hydrogenation was found to be particularly effective for the conversion of a compound of Formula VI-11 or VI-12 into a compound of Formula VIIa-1. In one embodiment, platinum oxide was found to be an effective and convenient cyst, to provide a compound of VIIa-1 free of carbon residue. In another embodiment, Pd (OH) 2 was a cyst for suitable hydrogenation. In a particular embodiment the palladium supported on carbon was found to be effective. The reaction can be carried out in a range of organic solvents, and a mixture of methanol and THF was found to be both effective and convenient. The Hydrogen pressure in a range between 2-10 bar was effective and the temperature was typically between 20-80 ° C. This invention further provides the compounds of Formula VIIa-1 and salts and solvates thereof wherein Z, X5, R2 and R2a are as defined herein. In some embodiments of the compounds of Formula VIIa-1, Z is -COOR1 or -C (= 0) NR6R7. In certain embodiments, R6 is OR8 and R7 is H. In particular embodiments, R8 is - (CH2) 2-OH. In some embodiments, X5 is halogen. In particular embodiments, X5 is F. In other embodiments, R2 and R2a are hydrogen. With continued reference to Figure 1, the compound of Formula VIIa-1 can be cyclized to the benzimidazole derivative represented by Formula VIIIa-1 when R2a of the compound of Formula VIIa-1 is hydrogen.

The cyclization step to provide the benzimidazole core structure can be carried out in various ways, such as any of Methods A-E as described herein. Compounds are also provided herein of Formula VIIIa-1 and salts and solvates thereof wherein Z, X5, R2, R2a and R10 are as defined herein. In some embodiments of the compounds of Formula VlIIa-1, Z is COOR1 or -C (= 0) NR6R7. In certain modalities, R6 is OR8 and R7 is H. In particular modalities, R8 is - (CH2) 2-OH. In some embodiments of the compounds of Formula VIIIa-1, R1 is C? -C? 0 alkyl. In particular embodiments, R1 is methyl. In some embodiments of the compounds of Formula VIIIa-1, X5 is halogen. In particular embodiments, X is F. In some embodiments of the compounds of Formula VIIIa-1, R2 and R2a are hydrogen. In other embodiments, R10 is methyl. When R2a is hydrogen, the compound of Formula VIIIa-1 can be directly converted to the compound of Formula Ia-1 as shown in Figure 1. Various methods are known in the literature for the preparation of diarylamines by coupling an aromatic amine with a halobenzene (see, for example, PCT Publication No. WO 02/083622). Nucleophilic aromatic substitutions and transition metal catalyst processes are particularly common coupling methods. On the other hand, there are very few examples of efficient catalysed transition metal coupling processes that provide diarylamines that are highly substituted in both rings, as is the case for the compounds of Formula Ia-1. In addition, very few of the catalysts that have been reported in the literature for a coupling reaction between a tphalobenzene and an aromatic amine to provide the desired product in high yield. However, particular catalyst systems have been identified herein that can be employed to give high yields for the coupling of the compounds of Formula VIIIa-1 with aplo halides. More specifically, one embodiment for the preparation of the compounds of Formula Ia-1, as n in Figure 1, comprises a coupling reaction between a compound of Formula VIIIa-1, wherein R2a is hydrogen, and a halide of aplo in the presence of a catalyst based on suitable metal and a base in a suitable solvent. In one embodiment, the aryl halide has the Formula 1 wherein X and X are as defined herein and X6 is F, Cl, Br, I, -OS02CF3, alkyl sulfonate, aryl sulfonate, alkylamp sulfonate, -B (0-R8) 2, -BF3 or -B? (Rx) 2. In another embodiment, the aryl halide has the Formula In certain embodiments, X 1 is F, Cl, Br or I, X 2 is C 1 -C 10 alkyl, F, Cl, Br or I, and X 6 is F, Cl, Br or I. In certain embodiments, X 1 is Br. certain modalities, X2 is Cl. In another modality, X6 is iodine. In a particular embodiment, 4-bromo-2-chloroiodobenzene was found to be an effective and regioselective partner for the coupling reaction in the conversion of the compounds of Formula VIIIa-1 to the compounds of Formula Ia-1, wherein the iodine group of 4-bromo-2-chloroiodobenzene is selectively displaced. Bases suitable for use in the coupling reactions of this invention include, but are not limited to, metal bases of Group I and Group II such as Na 2 CO 3, K 2 CO 3, Cs 2 CO 3, NaOH and NaOtBu, and organic bases such as triethylamine. . Suitable solvents for the coupling reaction include, but are not limited to, toluene, anisole, 2-methyltetrahydrofuran, and dioxane. Metal-based catalysts suitable for this coupling reaction include, but are not limited to, organometallic catalysts. The phrase "organometallic catalyst" means a catalyst that it comprises a metal and an organic ligand. Examples of metals include, but are not limited to, palladium, copper, nickel and platinum. Preferred ligands for copper include those containing heteroatoms such as oxygen, sulfur, nitrogen or phosphorus. Ligands containing oxygen groups are generally inexpensive and readily available, and ethylene glycol is a particular example of a convenient ligand that is effective in the process. For palladium-catalyzed coupling reactions, phosphine ligands have been n to be effective, and in certain cases bidentate ligands containing either two phosphine groups or a phosphine group and a second heteroatom-containing group have been n to It is effective. Examples of such ligands include, but are not limited to, DPE-fos and Xantfos. Illustrative examples of suitable organopalladium catalysts include, but are not limited to, Pd (OAc) 2 and Xantfos, Pd (OAc) 2 and DPE-fos, Pd2 (dba) 3 and Xantphos, Pd2 (dba) 3 and DPE-fos, tetrakis- (triphenylphosphine) palladium and palladium dichloride [bis (difm-nylphosphino) ferrocene]. Other organopalladium catalysts are known, and can be found in Comprehensive Organic Transformations, 2- edition, by Richard C. Laroc, VCH Publishers, Inc., New York, 1999. Preferred catalysts include, but are not limited to, Pd ( 0Ac) 2 and Pd2 (dba) 3 in combination with Xantfos or DPE-fos. One modality Particular of the present invention comprises heating to reflux a compound of Formula VIIIa-1, wherein Ra is hydrogen, and a benzene substituted with halo in toluene in the presence of a catalytic amount of Pd (OAc) 2, Xanthos, and a excess amount of a suitable base such as Cs2C03. Another embodiment of the present invention comprises refluxing a compound of Formula VIIIa-1, wherein R2a is hydrogen, and a benzene substituted with halo in toluene in the presence of a catalytic amount of Pd (OAc) 2 and DPE-fos in the presence of a suitable base. A particular embodiment of the present invention comprises heating a compound of Formula VIIIa-1 and a substituted halobenzene (for example 2-chloro-4-iodobromobenzene) at a temperature between 40-140 ° C in anisole in the presence of a catalytic amount of Pd2 (dba) 3 and Xantphos and an excess amount of a suitable base such as CS2CO3. Table 1 summarizes a selection of ligands, bases and solvents that have been evaluated for the metal-catalyzed coupling reaction of the present invention. Figure 5 illustrates several ligands evaluated in organometallic coupling reactions to convert the compounds of Formula VIIIa-1 to the compound of Formula Ia-1, and the chemical names for the ligands are given in Table 2. Table 1 Table 2 S Fos 2-cyclohexylphosphino-2 ', 6'-dimethoxy-1,1' biphenyl Cyclo B 2- (dicyclohexylphosphino-2 '- (N, N- In a Pd debugger embodiment, for example Silicycle Siliabond Si-Thiourea can be used to reduce the Pd content of the compounds produced by the process of the invention. Alternatively, the metal catalyzed coupling reaction can be carried out using a copper catalyst (see F. Y. Kwong, A. Klaparsy SX, Buchwald, Organi c Letters 2002, 4, 581-584). Examples of suitable copper-based catalysts include, but are not limited to, Cul / ethylene glycol. In one modality, the The reaction is carried out in an alcohol solvent, such as isopropanol or 2-butanol, with a simple chelating diol catalyst, such as ethylene glycol. In an alternative embodiment, the coupling of a compound of Formula VIIIa-1 with an aryl halide to provide a compound of Formula Ia-1 may proceed by direct nucleophilic displacement, optionally in the presence of a base such as an amide of lithium, at either ambient or elevated temperature. Method 2: In yet another embodiment, the present invention provides a method, referred to herein as Method 2, for preparing the compounds of Formula Ia-2 and their synthetic intermediates Ia-2 and salts and solvates thereof, wherein R1, R2, R10, X1, X2 and X5 are as defined herein. Method 2, as illustrated in Figure 2, after the route of diamination of Method 1, with the exception that the group Z is converted to a -COOR1 group at some point during the synthesis of the compounds of Formula Ia -2. For example, as shown in Figure 2, the group Z of a compound of Formula VI-11 or VI-12 (prepared as described in Method 1) VI-11: A = NR2R20 VÍ-12: A = N3 it can be converted to the corresponding ester derivative represented by Formula Va-11 or Va-12 Va-ll: A = NR2R2a Va-12: A = N3 wherein R1, R2, R2a and X5 are as defined herein, by reacting a compound of Formula VI-11 or VI-12 with a compound having the formula R10H, optionally in the presence of an activating agent which activates the group Z towards the reaction with the compound of the formula R1OH, wherein R1 is as defined herein. Examples of activation suitable for purposes of this invention include, but are not limited to, the activation agents listed in the foregoing for Method 1, which includes (a) mineral and organic acids; (b) reactive capable of converting a carboxylic acid to an acid chloride including, but not limited to, halogenating agents; (c) carbodiimides; (d) trialkylsilyl halides; (e) chloroformates and (f) dialkylazodicarboxylates alone or in conjunction with a phosphine reagent. The compounds of Formulas Va-11 and Va-12 can be converted to a compound of Formula Ia-2 in a manner similar to that described in Method 1. More specifically, as shown in Figure 2, a modality for the conversion of a compound of Formula Va-11 or Va-12 to a compound of Formula Ia-2 comprises: (i) reducing the compound of Formula Va-11 or Va-12 to provide a compound of Formula VIIa -2 wherein R1, R2, R2a and X5 are as defined herein, and wherein when A of the compound of the Formula Vali or Va-12 is -NH-benzyl, -NHOR1, -NHNHR1 or N3, then R2 and R2a of Formula VIIa-2 are hydrogen; (ii) when R2a is hydrogen, cyclize the compound of Formula VIIa-2 using methods such as, but not limited to, any of the Cyclization Methods A-E described herein, to provide a compound of Formula VIIIa-2 wherein R1, R2, R2, R10 and X5 are as defined herein; and when FAa is hydrogen, coupling the benzimidazole represented by Formula VIIIa-2 with a compound having the Formula wherein X1, X2 and X6 are as defined herein, optionally either (i) at elevated temperature and optionally in the presence of a base, or (ii) in the presence of a catalyst based on metal and a base, to provide the compound of Formula Ia-2. In certain embodiments, X1, X2 and X6 are independently F, Cl, Br or I. In certain modalities, X1 is Br. In certain modalities, X2 is Cl. In another modality, X6 is iodine. In a particular embodiment, the compound of Formula VIIIa-2 is reacted with is 4-bromo-2-chloroiodobenzene.

In one embodiment, the synthesis of the compounds of VIIIa-2 of the compounds of the Formula Va-11 or Va-12 is carried out without isolation of the intermediate compound VIIa-2. In another embodiment, the intermediate compound of Formula VIIa-2 is isolated. While Method 2 as illustrated in Figure 2 shows the conversion of group Z to a group COOR1 during the preparation of a compound of Formula Va-11 or Va-12 of a compound of Formula VI-11 or VI- 12, it will be understood that Figure 2 shows only one of several modalities of Method 2 for easy explanation. That is, the group Z can be converted to COOR1 at any point during the process of Method 2. Method 3: In yet another embodiment, the present invention provides a method of stepped amination, referred to herein as Method 3 and generally shown in Figure 3, for the preparation of the compounds of Formula Ib and their synthetic intermediates Ib-1 and salts and solvates thereof, wherein Z, X1, X, X, R > 2b and R, 10 are as defined herein. In In general, according to one embodiment of the invention, a method for preparing a compound of Formula Ib-1 according to Method 3 comprises nitrizing a compound having the Formula wherein X3, X4, X5 and Z are as defined herein, to provide a compound of Formula II II Nitration reaction conditions are well known to those skilled in the art. For example, in one embodiment a trihalobenzoic acid can be treated with smoking nitric acid in H2SO4 to provide a 2,3-trihalo-5-nitrobenzoic acid. The compounds of Formula II are then converted to the compounds of Formula III-ll or 111-12 by a stepped amination process. A useful discovery was that the X3 and X4 groups of the compounds represented by Formula II can be independently replaced. That is, the outgoing group in the ortho- position to the nitro group in the The compound of Formula II can be selectively replaced by a nitrogen nucleophile, in high yield, under carefully controlled conditions. The leaving group in the para- position to the nitro group can then be displaced by a second nucleophile in a last convenient step in the synthetic pathway. Examples of selective staggered mono-aminations are illustrated herein by Method 3 as well as in Method 4. More specifically, in one embodiment a compound of Formula II is reacted with (i) a reagent that contains or generates ammonia, (ii) a primary or secondary amine other than an aromatic amine or (iii) a reagent that supplies a group that can be subsequently converted to an amine, under conditions that allow selective displacement of X4, to provide a compound of Formula III -ll, or the compound of Formula II is reacted with (iv) a metal azide under conditions that allow selective displacement of X4 to provide a compound of Formula 111-12 111-11: A = NR2R2a 111-12: A = N3 where X3, X5, R2, R2a and Z are as defined in the present. In certain embodiments, R2a is a nitrogen protecting group such as substituted or unsubstituted benzyl, allyl or -C (0) OR6. In another embodiment, R2 and / or R2a is hydrogen. The nucleophilic substitution of a halide or sulfonate ester ortho- or para- to a nitro group in an aromatic ring is a method well known in the art for the introduction of an amino group into an aromatic ring. The reaction conditions need to achieve selective mono-amination in the para- position to the Z group depending on the type of nucleophile used in the mono-amination reaction. For example, if a strong nucleophile is used, the reaction can proceed easily at or below room temperature and at atmospheric pressure using an equivalent of the nucleophile to provide the desired mono-amination product. Examples of strong nucleophiles include, but are not limited to, aqueous ammonia (30% vol / vol) and metal amides such as sodium, potassium and lithium amide. Alternatively, if a weak nucleophile is used, further forcing conditions such as elevated temperatures and / or high pressure and / or an excess amount of the nucleophile may be required to achieve the monoamination. Examples of weak nucleophiles include, but are not limited to, a primary or secondary amine substituted with a spherically coarse group such as t-butyl. The introduction of an amino group ortho- to nitro groups cause the substitution product represented by Formula III-ll or 111-12 which is less reactive to the additional nucleophilic attack in the para- position to the nitro group, so the reaction can be carried out with a high level of selectivity. For example, according to one embodiment a compound of Formula 111-11 can be prepared by reacting a compound of Formula II with NH4OH at temperatures between 0 ° C and room temperature in water (with or without an organic co-solvent ) after acidification at pH between 0 and 7. Examples of suitable organic co-solvents include THF, 1,4-dioxane and N-methyl pyrrolidine. In certain embodiments, a compound of Formula III-ll is prepared by reacting a compound of Formula II with excess NH 4 OH in water at room temperature. The acidification can be carried out by the addition of an acid such as, but not limited to, a diluent or concentrated mineral acid or a carboxylic acid such as acetic acid. In one embodiment, the above-described preparation of a compound of Formula III-11 or 111-12 is carried out without isolation of the intermediate compound. In another embodiment, the intermediate compound represented by Formula II is isolated. Examples of reagents that contain or generate ammonia to prepare a compound of Formula II-11 or 111-12 include, but are not limited to, NH 3 and NH 4 OH.

Examples of primary and secondary amines suitable for purposes of this invention include amines having the formula HNR2R2a, wherein R2 and R2a are as defined herein. Specific examples of primary and secondary amines include, but are not limited to methylamine, benzylamine, dibenzylamine, allylamine, diallylamine and hexamethyldisilazane. Examples of reagents that provide a group that can be subsequently converted to an amine include, but are not limited to, (1) metal amides such as sodium, potassium and lithium amide, or alkylating derivatives thereof, (2) ammonia. protected or amide equivalents such as, but not limited to, hydroxylamines and hydrazines, (3) nitrogen nucleophiles having the Formula MNR2R2a wherein M is a metal such as Na, K, Li, Cs, Mg or Al, and ( 4) metal silylamides such as lithium (bis) (trimethylsilyl) amide, sodium (bis) (trimethylsilyl) amide or potassium (bis) (trimethylsilyl) amide. Examples of metal azides include, but are not limited to, sodium azide (NaN3), potassium azide (KN3) and lithium azide (LiN3). This invention also provides compounds of the Formula III and salts and solvates thereof. In some embodiments of the compounds of Formula III, Z is COOR1 or -C (= 0) NR6R7. In certain embodiments, R6 is -OR8 and R7 is H. In particular embodiments, R8 is - (CH2) 2-OH. In some embodiments, X5 is halogen. In particular modalities, X5 is F. In certain modalities, A is -NH2. With continued reference to Figure 3, the compound of Formula III-ll or 111-12 is reacted, optionally at elevated temperatures, with (i) a reagent that contains or generates ammonia, (ii) a different primary or secondary amine to an aromatic amine or (iii) a reagent that supplies a group that can be subsequently converted to an amine to provide a compound having the Formula Vb-11 wherein B is -NR2bR2c and A is -NR2R2a or N3, or the compound of Formula III-ll or III-12 is reacted with (iv) a metal azide, optionally at elevated temperatures, to provide a compound of Formula Vb-12 wherein B is N3 and A is -NR2R2a or N3, Vb-ll: B = NR2bR2c Vb-12: B = N3 wherein Z, X 5, R 2, R 2a and R 2b are as defined herein and R 2c is hydrogen, C 1 -C 6 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, benzyl, allyl, arylalkyl , trialkylsilyl, dialkylarylsilyl, -COR6, -C (0) OR6, C (0) NR6R7, -OR1 or -NHR1, wherein the alkyl, alkenyl, alkynyl, benzyl, allyl and arylalkyl portions are optionally substituted with one or more groups independently selected from halogen, hydroxyl, C 1 -C 4 alkyl, C 2 -C 4 alkenyl and C 2 -C 4 alkynyl. In a particular embodiment, X5 is F. According to one embodiment, the animation reaction is performed by reacting a compound of Formula III with a suitable nitrogen nucleophile using methods well known to those skilled in the art. Suitable nitrogen nucleophiles for the purposes of this invention include, but are not limited to, (i) reagents that contain or generate ammonia (including, but not limited to, NH3 and NH4OH); (ii) primary and secondary amines having the formula HNR2taR2c, wherein R2 and R2a are as defined herein; (iii) metal azides including, but not limited to, (NaN3), potassium azide (KN3) and lithium azide (LiN3) and (iv) reagents that provide a group that can be subsequently converted to an amine include, but are not limited to, protected ammonia or amide equivalents such as, but not limited to, hydroxylamines and hydrazines, (3) nitrogen nucleophiles having the Formula MNR2bR2c wherein M is a metal such as Na, K, Li, Cs , Mg or Al; and metal silylamides such as lithium (bis) (trimethylsilyl) amide, sodium (bis) (trimethylsilyl) amide or potassium (bis) (trimethylsilyl) amide. The reaction can be Perform in any suitable organic or inorganic solvent at temperatures ranging from -20 ° C to 200 ° C. Typically the reaction is carried out at elevated temperatures in the range of about 30 and 130 ° C, more preferably at temperatures between 50 and 95 ° C. For example, in one embodiment a compound of Formula Vb-11 wherein A = B-NH 2 can be obtained by reacting a compound of Formula III with aqueous ammonia in an organic solvent such as, but not limited to, tetrahydrofuran. , dioxane or N-methyl pyrrolidinone, at elevated temperature, for example, between 30 and 130 ° C, and as an additional example between 55-90 ° C under a light pressure of ammonia (for example between 1 to 5 bar). The nitro group of the compound of Formula Vb-11 or Vb-12 is then reduced to provide a compound of Formula VIIb-1 wherein Z, R2, R2a, R2b, R2c and X5 are as defined herein. In embodiments of Method 3 wherein A and / or B is N3, -NH-benzyl, -NHOR1 or -NHNHR1, then the group NR2R2a and / or NR2bR2c of the compound of Formula VIIb-1 is -NH2. The reduction stage can be carried out using conditions of reaction and reagents known to those skilled in the art. Examples of suitable methods for reducing an aromatic nitro group include, but are not limited to, dissolving metal reductions, catalytic hydrogenations and enzymatic reactions as described above. This invention further provides the compounds of Formula VIIb-1 and salts and solvates thereof. When R2a is hydrogen, the compounds of Formula VIIb-1 can be cyclized to provide the benzimidazole derivative represented by Formula VIIIb-1 VIIIb-1 wherein Z, R2b, R2c, 210 and X5 are as defined herein. The cyclisation step to provide the benzimidazole core structure can be carried out in various ways, such as any of the Cyclization Methods A-E as described herein. This invention further provides the compounds of Formula VIIIb-1 and salts and solvates thereof. When R2c is hydrogen, the benzimidazole represented by Formula VIIIb-1 is optionally isolated or directly converted to the compound of Formula Ib-1 without isolation by reacting the compound of Formula VIIIb-1 with a compound having the formula optionally either (i) at elevated temperature and optionally in the presence of a base, or (ii) in the presence of a catalyst based on metal and a base, wherein X1, X2 and X6 are as defined herein, to provide the compound of Formula Ib-1. the coupling reaction can generally be performed as described by Method 1, using any suitable metal-based catalyst. Suitable catalysts include, but are not limited to, copper-based and palladium-based catalysts. Illustrative examples of suitable organopalladium catalysts include, but are not limited to, Pd (OAc) 2 and Xantphos, Pd (OAc) 2 and DPE-fos, Pd2 (dba) 3 and Xantphos, Pd2 (dba) 3 and DPE-fos , tetrakis (triphenylphosphine) palladium and palladium bichloride [bis (diphenylphosphino) ferrocene]. Preferred catalysts include organopalladium catalysts such as Pd2 (dba) 3 in combination with Xantfos or DPE-fos, and Pd (OAc) 2 in combination with Xantfos or DPE-fos. Method 4: In still another embodiment, the present invention provides a method, referred to herein as Method 4, to prepare the compounds of Formula Ib-2 and their synthetic intermediates Ib-2 and salts and solvates thereof, wherein R1, R2b, R10, X1, X2 and X5 are as defined herein. Method 4, which is illustrated in Figure 4, after the stepped amination path of Method 3, with the exception that group Z is converted to a group COOR1 at some point during the synthesis. For example, as shown in Figure 4, the group Z of a compound of Formula III-ll or 111-12 (prepared as described in Method 3) II? -11: A = NRR / 111-12: A = N3 it can be converted to the corresponding ester derivative represented by Formula IV-21 or IV-22 IV-21.A = NR2R2a IV-22: A = N by reacting the compound of Formula III-11 or 111-12 with a compound having the formula R ^ H, wherein R1 is as defined herein , optionally in the presence of an activating agent that activates the Z group towards the reaction with the compound of the formula R1OH, under reaction conditions well known to those skilled in the art. Examples of suitable activating agents for purposes of this invention include, but are not limited to, (a) mineral and organic acids; (b) reagents capable of converting a carboxylic acid to an acid chloride including, but not limited to, halogenating agents such as S0C12 or (C0C1) 2, alkyl chloroformates, aryl chloroformates and acid chlorides (such as chloride) trimethylacetyl); (c) carbodiimides including, but not limited to, dicyclohexylcarbodiimide (DCC); (d) trialkylsilyl halides including, but not limited to, trimethylsilyl chloride (Me 3 SiCl); and (e) dialkylazodicarboxylates such as, but not limited to, diethylazodicarboxylate (DEAD), typically in conjunction with a phosphine reagent such as, but not limited to, Ph3P. In a particular embodiment, a compound of Formula III-11 or 111-12 wherein Z is COOH can be converted to a methyl ester derivative represented by Formula IV-21 or IV-22 by reaction with methanol in the presence of chloride of trimethylsilyl. A compound of Formula IV-21 or IV-22 is then reacted, optionally at elevated temperatures, with (i) a reagent that contains or generates ammonia, (ii) a primary or secondary amine other than an aromatic amine or (iii) ) a reagent that supplies a group that can be subsequently converted to an amine to provide a compound of Formula Vb-21 wherein A is -NR2bR2c or N3, or the compound of Formula IV-21 or IV-22 is reacted with (iv) a metal azide, optionally at elevated temperatures, to provide a compound of Formula Vb-22 wherein A is -NR2bR2c or N3, Vb-21; B = NR2bR2c Vb-22: B = N3 wherein R1, R2b, R2c, R20, X1, X2 and X5 are as defined herein. The reaction can be carried out in any suitable organic or inorganic solvent at temperatures ranging from -20 ° C to 200 ° C. Typically the The reaction is carried out at elevated temperatures in the range of about 30 and 130 ° C, more preferably at temperatures between 50 and 95 ° C. For example, in one embodiment a compound of Formula Vb-21 can be obtained by reacting a compound of Formula IV-21 or IV-22 with aqueous ammonia in an organic solvent such as, but not limited to, tetrahydrofuran, dioxane or N-methyl pyrrolidinone at elevated temperature and under a slight pressure of ammonia (for example between 1 to 5 bar). This invention also includes the compound of Formula Vb-21 and Vb-22. In a particular embodiment, R1 is C? -C? In another embodiment, R1 is methyl. According to one embodiment, the compound of Formula Vb-21 is an ester of 2, -d? Am? No-3-fluoro-5-n? Trobenzoic acid. In a particular embodiment, the compound of Formula Vb-21 is methyl 2,4-d? Ammo-3-fluoro-5-n-trobenzoate. With continuous reference to Figure 4, the carboxylic acid esters represented by Formula Vb-21 or Vb-22 can be used to prepare the compounds of Formula Ib-2 by the method comprising: (i) reducing the compound of Formula Vb-21 or Vb-22 using reaction conditions known in the art, such as those described by Method 1, to provide a compound represented by Formula VIIb-2 VIIb-2 wherein when A and / or B of Formula Vb-21 or Vb-22 is -NH-benzyl, -NHOR1, -NHNHR1 or N3, then R2 and R2a and / or R2b and R2b, respectively, of the Formula VIIb-2 are hydrogen; (ii) when R2a is hydrogen, cyclize the compound of Formula VIIb-2 using methods such as, but not limited to, any of Methods A-E described herein, to provide a compound of Formula VlIIb- wherein R1, R2, R2b, R2c, R10 and X5 are as defined herein; and (iii) when R2c is hydrogen, coupling the compound of Formula VIIIb-2 with a reagent having the Formula optionally either (i) at elevated temperature and optionally in the presence of a base, or (ii) in the presence of a catalyst based on metal and a base, wherein X1, X2 and X6 are as defined herein, using reaction conditions such as those described by Method 1, to provide the compound of Formula Ib-2. According to one embodiment of the present invention, a process for the conversion of a compound of Formula VIIIb-2 into a compound of Formula Ib-2 comprises a coupling reaction between the compound of Formula VIIIb-2 and a halide of aryl in the presence of a catalyst based on suitable metal and a base in a suitable solvent. In one embodiment, the aryl halide has the Formula wherein X1, X2 and X6 are as defined herein. The coupling reaction can be performed generally as described by Method 1. The preparation of the compounds of Formula VIIIb-2 of the compounds of Formula Vb-2 as described in Method 4 can be prepared in a container or in a staggered way. While Method 4 as illustrated in Figure 4 shows the conversion of group Z to a group -COOR1 during the preparation of a compound of Formula IV-21 or IV-22 of a compound of Formula III-ll or 111 -12, it's going to understand that Figure 4 shows only one of several modalities of Method 4 for easy explanation. That is, the group Z can be converted to -COOR1 at any point during the process of Method 4. This invention further provides the compounds of Formula VIIb-2 and VIIIb-2 and salts and solvates thereof. Still another embodiment of the present invention provides a method, referred to herein as the Method , to prepare the benzimidazole N-1 compounds represented by Formula Ib-1 and their synthetic intermediates Ic-1 and salts and solvates thereof, wherein Z, R2b, X1, X2 and X5 are as defined herein and R '? is not hydrogen, the method comprising: cyclizing a compound of Formula VIIb-1 prepared as described in Method 3, where R2a is hydrogen and Z, R2b, R2c and X5 are as defined herein, to provide a compound of Formula XIb-1 XIb-1 wherein Z, R2, R2, R2c, R10 and X5 are as defined herein; and when R2c is hydrogen, coupling the compound of Formula XIb-1 with a reagent having the formula optionally either (i) at elevated temperatures and optionally in the presence of a base, or (ii) in the presence of a metal-based catalyst and a base, wherein X1, X2 and X6 are as defined herein, to provide the compound of Formula Ib-1. Methods 1-5 of the present invention provide a number of distinct advantages over conventional processes for preparing the compounds of general Formulas Ia-1, Ib-1 and Ib-1. For example, the processes of the present invention provide the compounds of the General formulas Ia-1, Ib-1 and Ib-1 in high yields compared with conventional processes. In addition, the invention provides methods for the regioselective and chemoselective cyclization of the compounds of Formulas VIIa-1 and VIIb-1 to provide benzimidazoles of Formulas VIIIa-1 and VIIIb-1, respectively. In addition, the process of the present invention is more reliable and suitable for the large-scale synthesis of benzimidazoles than conventional processes. For example, the conversion of a compound of Formula VIIa-1 or VIIb-1, to a compound of Formula VIIIa-1 or VIIIb-1, respectively, according to the methods of the present invention produces far less toxic byproducts that the methods used in the prior art for the synthesis of benzimidazole ring systems, and it is a more efficient process. The synthetic methods of the present invention are selective and the preparation of the compounds of this invention can be carried out in high yield, thus providing industrial value. In addition, the benzimidazole derivatives represented by Formulas VIIIa-1, VIIIb-1, Ia-1, Ib-1 and Ic-1 can be synthesized from trihalobenzoic acids in a relatively short number of steps. Benzimidazole cyclizations As established, the cyclization of the compounds of Formula VIIa-1 or VIIa-2, VIIb-1 and VIIb-2 in any of Methods 1-5 of the present invention to provide benzimidazole core structures can be performed in several ways. Several methods, mainly Methods A-E, are described below and are illustrated in Figures 6-10. While Methods AE are specifically described with respect to the cyclization of a compound of Formula VIIb-1 for easy explanation, it is to be understood that Methods AE also apply equally to the cyclization of compounds of Formulas VIIa-1. , VIIa-2 and VIIb-2. Cyclization methods will provide either benzimidazole N-3 derivatives or benzimidazole N-1 derivatives, depending on the reagents used and the particular substituents R 2 and R 2a in the compounds of Formulas VIIa-1, VIIa-2, VIIb-1 and VIIb-2 Method A: According to the method's cyclization As shown in Figure 6, a compound of Formula VIIb-1, wherein R2 and R2a are hydrogen, can be cyclized to the corresponding benzimidazole tautomer represented by Formula VIIIb-1 VHlb-1 (ie, where R, 10 is hydrogen) according to a "one vessel" process comprising reacting a compound of Formula VIIb-1 with (i) formic acid optionally in the presence of an additional acid, or (ii) a formic acid derivative in the presence of a low acid appropriate conditions known to those skilled in the art. As used herein, the term "formic acid derivative" includes, but is not limited to, formic acid esters such as, but not limited to, trimethylortoformate, triethyl orthoformate and formamidine acetate. For example, in one embodiment, a compound of Formula VIIb-1 (wherein Z is C02Me, and R2 and R2a are H) was converted to a compound of Formula VIIIb-1 (wherein Z is C02Me) at very high performance in the reaction with methyl orthoformate and sulfuric acid in THF solution. Method B: According to Method B, as illustrated in Figure 7, the compound of Formula Vllb-1, wherein R 2a is hydrogen and R 2 is not hydrogen, can be cyclized to the corresponding N-3 benzimidazole represented by the Formula VIIIb-1 by a multi-step method in treatment with (i) formic acid, optionally in the presence of an additional acid, (ii) a formic acid derivative (e.g., a formic acid ester such as trimethylorthoformate, triethyl orthoformate, or formamidine acetate) in the presence of an acid, or (iii) formaldehyde or a formaldehyde derivative in the presence of an acid, to provide an intermediate N-1 benzimidazole compound represented by Formula XIb-1. As used herein, the term "formaldehyde derivative" includes, but is not limited to, dialkoxy ethanes such as diethoxymethane and dimethoxymethane. Alqualation of the compound of Formula XIb-1 provides the benzimidazolium ion represented by the compound of Formula XIIb-1. Remove the N-l substituent (i.e., the substituent R2) of the compound of Formula XIIb-1 provides the benzimidazole compound N-3 represented by Formula VIIIb-1, which can be subjected to an arylation reaction as described in Method 1 for provide the benzimidazole compound N-3 represented by Formula Ib-1. Methods for removing benzimidazole substituents from N-1 are well known to those skilled in the art, and the reactants and reaction conditions required depending on the nature of the group R 2. For example, when the R2 group of a compound of Formula XIIb-1 is substituted or unsubstituted benzyl, aillo or COOR wherein R is benzyl, the removal of the R2 group can be achieved by hydrogenation. An N-1 ring substituent can also be removed by heating a compound of Formula XIIb-1 in the presence of an organometallic catalyst such as Rh (PPh3) 3Cl (also known as ilkinson catalyst). Method C: Cyclization of Method C, as shown in Figure 8, provides a "one vessel" method of selectively and directly converting a compound of Formula VIIb-1, wherein R2 and R2a are hydrogen, to a derivative of N-3 benzimidazole represented by the Formula VIIIb-1 wherein R10 is methyl. Method C comprises treating a compound of Formula VIIb-1 with (i) two or more equivalents of formaldehyde or a formaldehyde derivative in the presence of an acid. Suitable formaldehyde derivatives include, but are not limited to, dialkoxymethanes such as diethoxymethane and dimethoxymethane. Suitable acids for purposes of this invention include mineral acids (eg, sulfuric acid, HCl, HBr), sulfonic acids (methanesulfonic acid, toluene sulfonic acid, etc.) or carboxylic acids such as formic acid or acetic acid. In a non-limiting mode, the reaction is carried out in acetonitrile which contains some water and diethoxymethane or dimethoxymethane in the presence of an acid such as toluene sulfonic acid. This reaction advantageously proceeds with complete regioselectivity to provide methyl N-3 benzimidazoles represented by Formula VIIIb-1. Other advantageous features of this process is that formaldehyde does not appear to react with the amino group ortho to the group Z of the compounds represented by Formula VIIIb-1. In addition, the reaction conditions allow the production of ether. > is-chloromethyl as a by-product. This by-product is a carcinogen, and its production on an industrial scale is highly undesirable. Method D: According to another embodiment, a N-3 benzimidazole derivative represented by Formula VIIIb-1, wherein R 10 is not hydrogen, can be prepared from a compound of Formula VIIb-1 in a staggered manner as shown in Figure 9. More specifically, Method D comprises treating a compound of Formula VIIb-1 wherein R2 and R2a is hydrogen, with a suitable acylating agent such as, but not limited to, formic acid, an acid anhydride (for example acetic anhydride), an acid halide (for example acetyl chloride) or an ester (for example trifluoroethyl formate) to provide the intermediate compound represented by Formula IX-b wherein Z, R2, R2a and X5 are as defined herein and R10a is H, C1-C10 alkyl, C3-C6 cycloalkylalkyl, arylalkyl, heteroarylalkyl or bieterocyclylalkyl, wherein the alkyl, cycloalkylalkyl, arylalkyl , heteroarylalkyl and heterocyclylalkyl are optionally substituted with one or more groups independently selected from halogen, hydroxyl, cyano, nitro, azido, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 3 -C 5 cycloalkyl, C3-C6 heterocycloalkyl, -NR6R7 and -OR8. The amide group of the compound of Formula IXb is then reduced to provide an intermediate compound represented by Formula Xb Suitable reducing agents include, but are not limited to, borane-type reducing agents (for example, BH3-THF) in an appropriate solvent such as THF.

Alternatively, the compounds of Formula Xb can be formed directly from a compound of Formula VIIb-1 by reaction with an alkylating agent of the formula R10aCH2X, wherein X is a leaving group such as Cl, Br, I, OMs, OTs, OTf, etc. Examples of alkylating agents include alkyl halides such as ethyl iodide. Cyclization of the compound of Formula Xb to provide the benzimidazole represented by Formula VIIIb-1 wherein R10 is not hydrogen, is performed by reacting the compound of Formula Xb with (i) formic acid optionally in the presence of an additional acid or (ii) a formic acid derivative (e.g., formic acid esters such as, but not limited to, trimethylortoformate, triethyl orthoformate and formamidine acetate) in the presence of an acid under appropriate conditions known to those skilled in the art to provide a compound of Formula VIIIb-1. The compound of Formula Vlllb-1 can be reacted with an aryl halide as described in Method 1 to provide a benzimidazole compound N-3 of Formula Ib-1. Method E: In an alternative multi-stage cyclization method, referred to herein as Method E as shown in Figure 10, a compound of Formula VIIb-1, wherein R2a is hydrogen and R2 is not hydrogen, HE can cyclize the corresponding benzimidazole compound of Formula VIIIb-1, wherein R10 is not hydrogen, by a stepped method comprising: (a) reacting a compound of Formula VIIb-1 with a suitable acylating agent to provide a compound of Formula IXb wherein Z, R 2, R 2a and X 5 are as defined herein and R 10a is H, C 1 -C 0 alkyl, C 3 -C 0 cycloalkylamino, arylalkyl, heteroarylalkyl or heterocyclylalkyl, wherein the alkyl, cycloalkylalkyl, arylalkyl , heteroarylalkyl and heterocyclylalkyl are optionally substituted with one or more groups independently selected from halogen, hydroxyl, cyano, nitro, azido, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 3 -C 6 cycloalkyl, C3-C6 heterocycloalkyl, -NR 6 ° R7 'and -OR ° (b) reducing the amide group of the compound of the Formula IXb to provide a compound of Formula Xb wherein Z, R2, R2a, R2, R2c, R10a and X5 are as defined herein; (c) reacting the compound of Formula Xb with (i) formic acid optionally in the presence of an additional acid or (ii) a formic acid derivative (eg, formic acid esters such as, but not limited to, trimethylortoformate, triethyl orthoformate and formamidine acetate) in the presence of an acid to provide the compound of Formula XIIb-1 wherein Z, R2, R2c, R10 and X5 are as defined herein; and removing the R2 group using methods such as those described in Method B to provide the benzimidazole compound N-3 of Formula VIIIb-1. He The compound of Formula VIIIb-1 can be reacted with an aplo halide as described in Method 1 to provide a benzimidazole compound N-3 of Formula Ib-1. Alternatively, according to another embodiment of Method E, a compound of Formula Xb can be obtained by the reaction of VIIb-1 with an alkylating agent of the formula R10aCH2L, wherein L is a leaving group, such as Cl, Br , I, OMs, OTs, OTf, etc. The above-described cyclization of Methods A-E of the present invention offers several advantages over conventional methods for the preparation of benzimidazole derivatives. First, there is only a small literature of examples of the conversion of a diamino aryl compound to a benzimidazole (see, for example, GP Ellis, RT Jones, J. Chem. Soc, Perkin 1, 191 A, 903, GT Morgan, WAP Challenor, J. Chem. Soc. Trans., 1921, 1537; NS Zefirov et al., Zyk, ECHET98: Electroni c Conference on Heterocycli c Chemistry, (1988) 406-408; V. Milata, D. Ilavsky, Organic Proc And Prep. In t., (1993), 25: 703-704), however, none of the reported examples involve highly substituted substrates such as those involved in the process of the present invention. Moreover, in many of the literature examples regioselectivity is inaccurate (G. T. Morgan, W.A.P. Challenor, J. Chem. Soc. Trans., 1921, 1537), and none of the methods before the present invention utilizes a substrate having a third amino substituent on the aromatic ring, which has the potential to react with formaldehyde, allowing the formation of alternative products. In addition, the methods of this invention are more suitable for industrial applications, since the uses of reagents that are less toxic than the HC1 / HCH0 reagent mixture used in conventional methods, and therefore do not generate toxic byproducts such as dichloromethyl ester. The terms "C? -C? Alkyl" and "alkyl" as used herein refer to a straight or branched saturated monovalent hydrocarbon radical having one to ten carbon atoms, wherein the alkyl radical may be optionally being independently substituted with one or more substituents described below. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, ter-pentyl, hexyl, 2-hexyl, 3-hex It, 3-metpentol, heptyl, octium and the like. The terms "C2-C10 alkenyl" and "alken lo" refer to the straight or branched chain monovalent hydrocarbon radical having two to 10 carbon atoms and at least one double bond, and includes, but is not limited to, ethenyl, propenyl, l-but-3-enyl, l-pent-3-enyl, l-hex-5- enyl and the like, wherein the alkenyl radical can be optionally substituted independently with one or more substituents described herein, and include radicals having "cis" and "trans" orientations, or alternatively, "E" and "Z" orientations . The terms "C 2 -C 8 alkynyl" and "alkylo" refer to a linear or branched monovalent hydrocarbon radical of two to twelve carbon atoms containing at least one triple bond. Examples include, but are not limited to, ethynyl, propyme, butynyl, pentm-2-? Lo and the like, wherein the alkynyl radical can be optionally substituted independently with one or more substituents described herein. The terms "carbocycle", "carbocyclyl", "cycloalkyl" or "C3-C10 cycloalkyl" refer to the saturated or partially unsaturated cyclic hydrocarbon radical having from three to ten carbon atoms. The term "cycloalkyl" includes monocyclic and polycyclic cycloalkyl structures (for example, bicyclic and cyclic), wherein the polycyclic structures optionally include a saturated or partially unsaturated cycloalkyl fused to a saturated or partially unsaturated cycloalkyl or heterocycloalkyl ring or a ring of aryl or heteroaryl. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, c-clobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. The cycloalkyl can be optionally substituted independently in one or more positions substitutable with several groups. For example, such cycloalkyl groups may be optionally substituted with, for example, C?-C6 alkyl, Ci-Cd alkoxy, halogen, hydroxy, cyano, nitro, amino, mono-alkylammo of (C?-Ce), di -alkylamine of (Ci-Cß), C2-Cβ alkenyl, C2-C6 alkynyl, haloalkyl of A-Ce, haloalkoxy of C? -C6, ammoalkyl of (C? -C6), monoalkylamino (C? -C6) -alkyl of (C? -C6) and di-alkylamine of (C? -C6) -alkyl of (Ci-Cß). The term "heteroalkyl" refers to the monovalent straight or branched chain saturated hydrocarbon radical of one or twelve carbon atoms, wherein at least one of the carbon atoms is replaced with a heteroatom selected from N, O, or S, and wherein the radical can be a carbon radical or heteroatom radical (ie, the heteroatom can occur in the middle or at the end of the radical). The heteroalkyl radical can be optionally substituted independently with one or more substituents described herein. The term "heteroalkyl" embraces alkoxy and heteroalkoxy radicals. The terms "heterocycloalkyl", "heterocycle" or "heterocyclyl" refer to a saturated or partially unsaturated carbocyclic radical of 3 to 8 atoms in the ring in which at least one atom in the ring is a heteroatom selected from nitrogen, oxygen and sulfur, the remaining ring atoms which are C, wherein one or more atoms in the ring can be optionally substituted independently with one or more substituents described below. The radical can be a carbon radical or heteroatom radical. The term also includes bicyclic and tricyclic fused ring systems, which includes a fused heterocycle one or more carbocyclic or heterocyclic rings. "Heterocycloalkyl" also includes radicals wherein the heterocycle radicals are fused with aromatic or heteroaromatic rings. Examples of heterocycloalkyl rings include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydrophemeral, tetrahydrothiopyranyl, piperidino, morpholmo, thiomorpholino, thioxanyl, piperazinyl, homopiperazinyl, azetidmyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, tiepanyl. , oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolonol, 3-pyrrolone, indolinyl, 2H-pranillole, 4H-p? ranol, dioxanyl, 1,3-dioxolanyl, pyrazolyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidylimidazolinyl, imidazolidinyl, 3-azabicico [3.1.0] hexanil, 3-azab? c? clo [4.1.0] heptanil, azabicyclo [2.2.2] hexanyl, 3H-indolyl and quinolizinyl. Spiro portions are also included within the scope of this definition. The above groups, as derivatives of the groups listed above, can be linked to C or linked to N where this is possible. For example, a pyrrole derivative group can be pyrrol-1-yl (attached to N) or pyrrole-3-yl (attached to C). In addition, a derivative group of imidazole can be imidazol-1-yl (attached to N) or imidazol-3-yl (attached to C). An example of a heterocyclic group wherein 2 carbon atoms in the ring are substituted with oxo moieties (= 0) is 1,1-dioxo-thiomorpholinyl. The heterocyclo groups in the present are not substituted or, as specified, substituted in one or more substitutable positions with several groups. For example, such heterocycle groups may be optionally substituted with, for example, Ci-Ce alkyl, C 1 -C 6 alkoxy, halogen, hydroxy, cyano, nitro, amino, (Ci-Ce) monoalkylamino, di-alkylamino of ( C? -C6), C2-C6 alkenyl, C2-C6 alkynyl, C? -C6 haloalkyl, C? -C6 haloalkoxy, amino (C? -C6) alkyl, monoalkylamino (CI) Cß) -alkyl of (C? -C6) and di-alkylamino of (C? -C6) -alkyl of (C? ~ C6) • The term "aryl" refers to a monovalent aromatic carbocyclic radical having an individual ring (for example, phenyl), multiple rings (for example, biphenyl), or multiple condensed rings in the which at least one is aromatic, (eg, 1,2,3,4-tetrahydronaphthyl, naphthyl), which is optionally mono-, di-, or tp-substituted with, for example, halogen, lower alkyl, lower alkoxy , trifluoromethyl, aryl, heteroaryl and hydroxy. The term "heteroaryl" refers to a monovalent aromatic radical of 5-, 6- or 7-membered rings that include fused ring systems (at least one of which is aromatic) of 5-10 atoms containing at least one and up to four heteroatoms selected from nitrogen, oxygen or sulfur. Examples of heteroaryl groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolium, isothiazolyl, pyrrolyl, quinolinyl, isoquinolyl, indolyl, benzimidazolyl, benzofuranyl, cinolinyl, indazolyl, indolomile, phthalazinyl, pyridazinyl, triazinyl, isomodolyl, pteridyl, pupnyl, oxadiazolyl, triazolyl, thiadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolyl, quinoxalmyl, naphthyridinyl and furopyridyl. Spiro portions are also included within the scope of this definition. Heteroaryl groups are optionally mono-, di-, or tri-substituted with, for example, halogen, hydroxyl, cyano, nitro, azido, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl and C3-C6 heterocycloalkyl. The term "arylalkyl" means an alkyl moiety (as defined above) substituted with an aryl moiety (also as defined above). The most preferred arylalkyl radicals are aryl-alkyl of A-C3. Examples include benzyl, phenylethyl and the like. The term "heteroarylalkyl" means an alkyl moiety (as defined above) substituted with a heteroaryl moiety (also as defined above). The most preferred heteroarylalkyl radicals are 5- or 6-membered heteroaryl-C 1-3 alkyl. Examples include oxazolylmethyl, pyridylethyl and the like. The term "heterocyclylalkyl" means an alkyl portion (as defined above) substituted with a heterocyclyl portion (also as defined above). The most preferred heterocyclylalkyl radicals are 5- or 6-membered C 1 - heterocyclylkyls. Examples include tetrahydropyranylmethyl. The term "cycloalkylalkyl" means an alkyl moiety (as defined above) substituted with a cycloalkyl moiety (also as defined above). The most preferred heterocyclyl radicals they are 5 or 6 membered cycloalkyl-alkyls of C? _3. Examples include cyclopropylmethyl. The term "Me" means methyl, "Et" means ethyl, "Bu" means butyl, and "Ac" means acetyl. The term "halogen" represents fluorine, bromine, chlorine and iodine. In general, the various functional group portions of any of the compounds of the present invention may be optionally substituted by one or more substituents. Examples of substituents suitable for purposes of this invention include, but are not limited to, oxo (with the proviso that it is not an aryl or heteroaryl), halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, -OR ', -NR 'S02R "" S02NR'R ", -C (0) R', -C (0) OR ', -OC (0) R', -NR 'C (O) OR" ", NR'C (0) R ", -C (0) NR'R", -SR ', -S (0) R "", -S02R "", -NR'R ", -NR'C (0) NR "R" ', -NR'C (NCN) NR "R'", aryl, heteroaryl, arylalkyl, heteroaplalkyl, heterocyclyl and heterocyclylalkyl, where R ', R ", R"' and R "" are independently lower alkyl, Lower alkenyl or lower alkyl It will be understood that in cases where two or more radicals are used in succession to define a substituent attached to a structure, the first called radical is considered to be terminal and the last one called radical is considered to be attached to the structure in question. Thus, for example, the arylalkyl radical is attached to the structure in question by the alkyl group. Certain compounds prepared according to a process of the present invention can exist as two or more tautomeric forms. The tautomeric forms of the compounds can be interchangeably, for example, via enolization / de-enolization and the like. Accordingly, the present invention includes the preparation of all tautomeric forms of the compounds of Formulas Ia-1, Ib-1, VIIIa-1 and VIIIb-1 wherein R 10 is hydrogen. This invention also encompasses the compounds of Formulas Ia-1, Ib-1, Ic-1, III, VI, VIIIa-1, VIIIb-1, Xla and Xlb Ia-1 lb-1 Ic-1 III VI wherein Z, R1, R2, R2a, R2b, R2c, R10, X1, X2, X3, X5, A, and B are as defined herein. In certain embodiments, Z is -C (= 0) NR6R7. In certain embodiments, R 8 is C 1 -C 10 alkyl optionally substituted with OH, O- (C 1 -C 6 alkyl) or -O- (C 1 -C 10 alkenyl). In certain embodiments, R8 is - (CBb) 2-OH. In particular embodiments, Z is C (= 0) NH (CH2) -OH. In other embodiments, Z is -COOR1 and R1 is Ci-Cio alkyl. In particular embodiments, R1 is methyl. In certain embodiments, X5 is halogen. In particular embodiments, X5 is F. In certain embodiments, X1 is H or halogen and X2 is alkyl or halogen. In certain modalities, X1 is Br and X2 is Cl. In certain embodiments, R10 is C? -C10 alkyl. In particular embodiments, R10 is methyl. In certain embodiments, R2, R2a, R2b and R2c are hydrogen. This invention also includes solvates the compound of Formula Ia-1, Ib-1, Ic-1, III, VI, VIIa-1, VIIb-1, VIIIa-I, VIIIb-1, Xla and Xlb. The term "solvate" refers to an aggregate of a compound of this invention with one or more solvent molecules. This invention also encompasses salts of the compounds of Formula Ia-1, Ib-1, Ic-1, III, VI, VIIa-1, VIIb-1, VIIIa-1, VIIIb-1, Xla and Xlb. That is, a compound of the invention can possess a sufficiently acidic group, a sufficiently basic group, or both functional groups, and therefore react with any of a number of inorganic and organic bases, and inorganic and organic acids, to form a salt . Examples of salts include those salts prepared by the reaction of the compounds of the present invention with a mineral or organic acid or an inorganic base, such salts including sulfites, bisulfites, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, capplates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succmates, suberates, sebacates, fumarates, maleates, but? n-1, 4-d? oates, hex? n-1, 6-dianates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, xylene sulphonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates,? -hydroxybutyrates, glycolates, tartrates, methanesulfonates, propanesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates and mandelates. Since a single compound of the present invention may include more than one acidic or basic portion, the compounds of the present invention may include mono, di or tri-salts in a single compound. If the inventive compound is a base, the desired salt can be prepared by any suitable method available in the art, for example, the treatment of the free base with an acidic compound, particularly an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, or with an organic acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, masonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alpha hydroxy acid, such as citric acid or tartaric acid, an amino acid, such as aspartic acid or glutamic acid, an aromatic acid, such as benzoic acid or cinnamic acid, an sulfonic acid, such as p-toluenesulfonic acid or ethanesulfonic acid, or the like. If the inventive compound is an acid, the desired salt can be prepared by any suitable method, for example, the treatment of the free acid with a base inorganic or organic Preferred inorganic salts are those formed with alkali and alkaline earth metals such as lithium, sodium, potassium, barium and calcium. Preferred organic base salts include, for example, ammonium, dibenzylammonium, benzylammonium, 2-hydroxyethylammonium, bis (2-hydroxyethyl) ammonium, phenylethylbenzylamine, dibenzyl-ethylenediamine salts and the like. Other salts of acidic portions may include, for example, those salts formed with procaine, quinine and N-methylglucosamine, plus salts formed with basic amino acids such as glycine, ornithine, histidine, phenylglycine, lysine and arginine. The inventive compounds can be prepared using the reaction routes and synthetic schemes as described herein, which employ techniques available in the art using starting materials that are readily available or can be synthesized using methods known in the art. Representative compounds of the present invention, which are encompassed by the present invention include, but are not limited to, the compounds of the examples and the acid or base addition salts thereof. The examples presented below are proposed to illustrate particular embodiments of the invention, and are not intended to limit the scope of the specification or the claims in any way.

EXAMPLES The example and the preparations provided below further illustrate and exemplify the compounds of the present invention and methods for preparing such compounds. It is to be understood that the scope of the present invention is not limited in any way to the scope of the following examples and preparations. Those skilled in the art will recognize that the described chemical reactions can be readily adapted to prepare a number of other MEK inhibitors of the invention, and alternative methods for preparing the compounds of this invention are considered to be within the scope of this invention. For example, the synthesis of the non-exemplified compounds according to the invention can be completely accomplished by modifications apparent to those skilled in the art, for example, by appropriately protecting the interfering groups, by using other suitable reagents known in the art. different from those described, and / or by marking routine modifications of the reaction conditions. Alternatively, other reactions disclosed herein or known in the art will be recognized as having applicability to prepare other compounds of the invention. In the example described below, unless otherwise indicated all temperatures are exposed in degrees Celsius. Reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Lancaster, TCI or Maybridge, and were used without further purification unless otherwise indicated. Tetrahydrofuran (THF), N, N-dimethylformamide (DMF), dichloromethane, toluene, dioxane and 1,2-d? -fluoroethane were purchased from Aldrich in sealed sealed bottles and used as received. The reactions set forth below were generally terminated under a positive nitrogen or argon pressure or with a drying tube (unless otherwise stated) in anhydrous solvents, and the reaction flasks were typically equipped with septum rubber for introduction of substrates and reagents via the syringe. The glassware was dried in an oven and / or dried with heat. The 1H-NMR spectra were recorded on a Vanan or Buker instrument operating at 400 or 500 MHz. The 1 H-NMR spectrums were obtained as CDC13 or DMSOdd solutions (reported in ppm). Other NMR solvents were used as needed. When peak multiplicities are reported, the following abbreviations are used: (singlet), d (doublet), t (tpplete), m (multiplet), br (broad), dd (doublet of doublets), dt (doublet of triplets). The constant couplings, when they occur, are report in Hertz (Hz). Example 1 Synthesis of 6- (4-bromo-2-chloro-phenylamino) -7-fluoro-3-methyl-3H-benzoimidazo-5-carboxylic acid 1 2 Stage 1: 2, 3, 4-trifluoro-5-nitrobe acid, nzoic acid (2): 90% HN03 (549.0 g, 7.84 mol corrected for 90% by weight, 1.26 equiv.) Was added to 2.0 L (3.35 kg) of concentrated HS04 for 18 minutes with stirring. The HNO3 solution was then added to a mixture of 2,3,4-trifluorobenzoic acid (1094 g, 6.21 mol, 1 equiv.) In 3.3 L (5.85 kg) of concentrated H2SO in a second flask with an ice-water bath cooled for one hour. In the complete addition, the reaction mixture was allowed to warm to room temperature. After 5 hours, the reaction was completed by HPLC and the reaction mixture (brown solution) was emptied for 10 minutes in a mechanically stirred mixture of 10.6 kg of distilled water and 11.8 kg of ice. The yellow suspension was cooled to 14 ° C, stirred for 2 hours and then filtered. The cake was rinsed with 4.0 L of distilled water and then with 5 L of heptane. The wet cake will dried in an oven overnight. The crude solids (1791 kg) were then stirred in 16 L distilled water (9 vol.), Filtered and dried in an oven at 55 ° C under high vacuum overnight to yield 1035.9 g (75%) of the compound 2 as a yellowish solid. HPLC was 98 at% (220 nm) and 100% (254 nm). lH NMR (400 MHz, d6 DMSO) d 8.44 (1H, apparent dt, J 1.9, 7, Ar-H). 19F NMR (376 MHz, d5 DMSO) d -153.9, -131.5, -120.9. 13 C NMR (100 MHz, d 6 DMSO) d 117 (C, m), 124 (CH, bs), 134 (C, s), 141 (CF, dt, 7251, 10), 148 (CF, dd, J265, 13), 154 (CF, dd, J265, 10), 163 (COOH). IR vmax / cnA 3108 (br), 1712, 1555, 1345, 1082. MS APCI (-) m / z 220 (M-1) detected.

Step 2: 4-Amino-2, 3-difluoro-5-nitrobenzoic acid (3): To a mixture of 2,3-trifluoro-5-nitrobenzoic acid (2) (167.2 g, 0.756 mol, 1 equiv) in 400 mL of distilled water was added concentrated ammonium hydroxide (28% NH3 solution, 340 g, 380 mL, 4.23 mol, 5.6 equiv.) Ensuring that the internal temperature was below 6.0 ° C for 2-2.5 hours. The mixture was stirred for 50 minutes and then warmed to room temperature for 3-4 hours. When the reaction was > 90% complete by HPLC, the mixture of lll The reaction was cooled in an ice-water bath and concentrated HCl (350 mL) then added dropwise to adjust the pH = 2. The suspension was stirred for 1 hour with a cooled ice bath and filtered. The cake was rinsed with 1 L of distilled water and then with 350 mL of MTBE. The cake was dried in an oven at 48 ° C overnight to give 134.9 g of a yellow solid. HPLC was 83.6% (220 nm) and 96.96% (254 nm). The MTBE filtrate was concentrated on a rotary evaporator and pumped overnight to give 9.9 g of a second culture as a yellow solid: HPLC was 81.1% (220 nm) and 95.40% (254 nm). The combined yield of 4-amino-2 acid, 3-difluoro-5-nitrobenzoic acid (3) was 144.8 g (88%). NMR (400 MHz, d6 DMSO) d 8.0 (2H, br s, NH 2) 8.42 (1H, dd, J 1.5, 7.6, Ar-H). 19F NMR (376 MHz, d6 DMSO) d -153.9, -129.0. 13 C NMR (100 MHz, d 6 DMSO) d 106 (C, d, J 10), 126 (CH), 128 (C), 140 (CF, dd, J 241, 16), 140.8 (C, dd, J 12 , 4), 153 (CF, dd, J 263, 11), 164 (COOH). IR vraax / crrA 3494, 3383, 1697, 1641, 1280. MS APCI (-) m / z 217 (M-l) detected.

Step 4 Methyl 4-amino-2, 3-difluoro-5-nitrobenzoate (4): TMSC1 (132 g, 1.21 mol, 2.0 equiv) was added. for 5 minutes to a suspension of 4-am.ino-2,3-difluoro-5-nitrobenzoic acid (3) (132.3 g, 0.607 mol, 1 equiv) in 325 mL of MeOH. The mixture was refluxed for 15 hours. Once the reaction was complete by HPLC, the reaction mixture was cooled in an ice-water bath for 45 minutes. Then the reaction mixture was filtered and the cake was washed with 65 L of MeOH. The wet cake was dried overnight at 55 ° C under high vacuum to provide 128.8 g (92%) of 4-amino-2,3-difluoro-5-nitrobenzoic acid methyl ester (4). The HPLC was 97.9 to% (220 nm) and 99. 2 to% (254 nm). ? H NMR (400 MHz, d6 DMSO) d 3.84 (3H, s, OMe), 8.1 (2H, br s, NH2), 8.43 (1H, apparent dd, J 1.9, 7.2, Ar-H). 19F NMR (376 MHz, d6 DMSO) d -153.6, -129.2. 13C NMR (100 MHz, d6 DMSO) d 52 (CH30), 105 (C, d, J 10), 125 (CH, t, 2.7), 128 (CH, d, J 5), 140 (CF, dd, J244, 15,), 141 (C, dd, J 14, 5), 152 (CF, dd, J263, 11), 162 (COO, t, J 3). IR vmax / c '1 3433, 3322, 1699, 1637, 1548, 1342, 1234. MS APCI (-) m / z 231 (M-1) detected. 4 5 Stage 5: 2, 4-Diamino-3-f luoro-5-nitrobenzoate methyl (5): To a stirred solution of 4-amino-2, 3-dif luoro-5- Methyl nitrobenzoate (4) (33.0 g, 142.15 mmol) in 1,4-dioxane (165 mL, 1.93 mol), in a 250 L glass pressure vessel, an aqueous solution of ammonia (39 g, 711) was added mmol, 42.9 mL, 16.5 M). The vessel was then heated in an immersion bath at a bath temperature between 79 and 105 ° C, for 80 minutes, during which time the internal pressure varies between 0.2 and 2.7 bar. The pressure was then released slowly to the mixture was treated with water (330 mL, 10 vol). The resulting suspension was stirred for 20 minutes and then filtered under vacuum, and the solid was washed with water (33 mL, 1 vol). The sucked solid was dried, then dried in a vacuum oven at 50 ° C to provide methyl 2, 4-diamino-3-fluoro-5-nitrobenzoate (5) (32.6 g, 92% yield) as a solid. yellow. A NMR (500 MHz, d6 DMSO) d 3.83, (3H, s, OMe), 7.20 (2H, br, NH2), 7.37 (2H, br, NH2), 8.47 (1H, s, Ar-H). 13C NMR (100 MHz, d6 DMSO) 6 52 (CH3), 101 (C), 122 (C), 126 (CH), 134 (C), 137 (C), 142 (C), 166 (C = 0 ). vmax / cm '1 3474, 3358, 1697, 1633, 1528, 1435, 1317, 1285.

Step 6: 6-Amino-7-fluoro-3-methyl-3-yl-benzo-m? Dazol-5-carboxylic acid methyl ester (6): A hydrogenating vessel purged with nitrogen charged with palladium on carbon (5.53 g, 1.30 mmol) and to this was added a solution of 2,4-d? am? no-3-fluoro-5-n? trobenzoate methyl (5) (100 g, 419 mmol) in tetrahydrofuran (1.3 L) 15.98, followed by methanol (700 mL). The mixture was then stirred, purged with nitrogen and heated to 55 ° C. The stirring was then paused while the system was purged with hydrogen (4 bar), and the stirring was then restarted at 750 rpm. After 6.75 hours the observed hydrogen uptake had ceased and 29.1 L of hydrogen had been taken. The system was then purged with nitrogen and allowed to cool to 20 ° C. HPLC analysis indicated that all of the starting materials had been reacted and that the yield of the desired solution of the desired product was about 96%. The mixture was then filtered using a Whatman 1 μ in a linear filter to remove the catalyst and the system was washed with tetrahydrofuran (400 mL). The solvent was then distilled until a total of 1400 mL had been collected and the mixture was cooled to room temperature. Acetonitoplo (1.0 L) was added to the mixture, after removal of the solvent (1 L) by distillation, then two additional 500 mL aliquots of acetonitrile were added, after each time the solvent was removed (2 x 500 mL) through distillation After the above solvent swing procedure, the stirred mixture was cooled to 60 ° C and a solution of p-toluenesulfonic acid monohydrate (87.7 g), 461 mmol) in acetonitrile (175 mL) and water (7.6 mL, 419 mmol) was added slowly, after diethoxymethane (95.98 g, 921.59 mmol). After 3 hours, HPLC analysis indicated the complete reaction and the temperature was raised to 65 ° C for an additional 1 hour, after which the reaction time was completed by HPLC analysis. Pyridine (66.3 g, 838 mmol) was added over 10 minutes and the reaction mixture was cooled to 20 ° C for about 30 minutes and kept at this temperature for 2.5 hours. The resulting suspension was then filtered and the solid was washed with acetonitoplo (2 x 200 mL), and then dried at 45 ° C in a vacuum oven, to provide 73.65 g of 6-amino-7-methyl acid methyl ester. -fluoro-3-met? l -3 / í-benzo? m? dazol-5-carboxylic acid (6) as a pale brown solid (95.3% assay), yield at 100%, 75%. X NMR (400 MHz, d6 DMSO) d 3.79 (3H, s, NMe), 3.87, (3H, s, OMe), 6.04 (2H, br, NH2), 7.82 (1H, s, ArH), 8.23 (1H, s, Ar-H). 13C NMR (100 MHz, d6 DMSO) d 33 (NCH3), 52 (OMe), 110 (CH, d J 5), 111 (C, d JA), 124 (C, d J5), 125 (C, d J 14), 136 (C, d J 11), 137 (CF, d J 242), 145 (CH), 167 (C = 0). V "/ cm" 1 3455, 3283, 3166, 3096, 2950, 2361, 2342, 1689, 1608, 1228. MS APCI (+) m / z 224 (M + l) detected.

Step Acid 6- (4-bromo-2-chlorophenylamino) -7-fluoro-3-met? -1 -3 / f-benzo m? Dazole-5-carboxyl? Co (Na salt) (7): A mixture of Xantphos (1.20 g, 2.05 mmol) and tris (dibenzylideneacetone) dipalladium (0) (1.26 g, 1.37 mmol) in anhydrous anisole (76 mL) was stirred under nitrogen, at 50 ° C for 30 minutes to provide an orange-brown solution. of the catalyst. To a stirred mixture of 6-amino-7-fluoro-3-methyl-3-t-benzo-m? Dazo-5-carboxylic acid methyl ester (6) (8.00 g, 34.16 mmol) and cesium carbonate (22.48 g, 68.31 mmol) in anhydrous anisole (76 mL) under nitrogen was added 4-bromo-2-chloroiodobenzene (1.60 g, 1.10 equiv, 4.88 mmol). The preformed catalyst, as prepared above, was then added to the mixture to provide a dark brown suspension, which was heated to 100 ± 2 ° C, with stirring at 350 rpm. The reaction was monitored by HPLC analysis. After 41 hours, none of the 6-amino-7-fluoro-3-methyl-3H-benzoim-dazole-5-carboxylic acid methyl ester (6) remained. The reaction mixture was cooled to about 80 ° C and 1M sulfuric acid was added (40.99) mL 40.99 mmol). The evolution of the gas was observed after 10 minutes and the proportion of addition was controlled to moderate the effervescence. At the end point of the addition the pH was between 7 and 8. Additional sulfuric acid (1M, 10.25 mL, 10.25 mmol) was then added to give the mobile suspension with a pH of 0. The mixture was diluted with anisole (20 mL ) and the Celatom FW-1 filter agent was added. It was then filtered at about 80 ° C through a damp pad with Celatom FW-14 filter agent water and the cake was washed with anisole (1 x 40 mL + 3 x 20 mL), then water (10 mL) . The lower aqueous layer was separated and discarded and the organic layer was washed with 10% aqueous NaCl solution (2 x 40 mL). This was added to a sodium hydroxide (5.46 g, 68.3 mmol) in methanol (24 mL) and the mixture was heated to 65 ° C with stirring. After 17.5 hours the HPLC analysis indicated that the hydrolysis of the ester was complete and the suspension was cooled to 15 ° C, then filtered over a sinter. The solid was washed with water (4 x 24 mL), MTBE (24 mL) and acetonitrile (2 x 25 mL) and then dried at 45 ° C in a vacuum oven to provide 11.07 g of 6- (4-) acid. Bromo-2-chlorophenyl-amino) -7-fluoro-3-metha1-benzo-m-dazole-5-carboxylic acid (7) as a fine pale brown solid (93.7% by 1H NMR), actual weight 10.37 g ( 72.2% yield). X H NMR (400 MHz, d 6 DMSO) d 3.85 (3 H, s, NMe), 6.53 (1 H, dd, J 9, 7, Ar-H), 7.27 (1 H, dd, J 9, 2.5, Ar-H) 7.56 (1H, d, J 9, Ar-H), 7.97 (1H, s, Ar-H), 8.20 (1H, s, Ar-H), 11.5 (1H, s, C02H). 13 C NMR (100 MHz, d 6 DMSO) d 31 (CH 3), 108 (CH, d, J 2), 109 (CH), 117 (C, d, J 6), 122 (C), 124 (C, d, Jl), 127 (C), 130 (C), 131 (C), 132 (C, d, J9), 133 (C, d, J 11), 141 (C), 145 (CF, d, J 252 ), 146 (CH), 170 (C = 0). Example IA Synthesis of 6- (4-bromo-2-chlorophenylamino) -7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid, Na salt 1 2 Stage 1: 2, 3, 4-Trifluoro-5-nitrobenzoic acid (2): To a stirred solution of 2, 3, 4-Trifluorobenzoic acid (70 Kg, 398 Mol) in sulfuric acid (96% by weight, 194 L) and hexamethyldisiloxane (6.5 Kg, 40 Mol), at 23 ° C, added a 1: 1 mixture of sulfuric acid (96% by weight) and nitric acid (98% by weight) (total 70.1 Kg), for 75 min. The temperature of the reaction mixture was maintained between 15 and 25 ° C during the addition. The mixture was stirred for an additional 5 hours and then run on ice (700 Kg), keeping the temperature of the ice mixture below 0 ° C. Water (35 L) was used to rinse the nitration reactor in the cooled reactor and the obtained mixture was stirred for 2 hours at 0 ° C, then isolated in a centrifuge. The resulting wet cake was washed with ice water (350 L), and the solid was then suspended in water (280 L) and stirred for 2 hours at 0 ° C. This suspension was then centrifuged and the cake was washed with ice water (210 L), then dried in a vacuum oven at 45 ° C for 2 days, to provide acid 2, 3, -tr? Fluoro-5-n? trobenzo? co (69.4 Kg, yield of 74.3%). ^ i NMR (400 MHz, d6 DMSO) d 8.44 (1H, apparent dt, J 2, 7, Ar-H). 19F NMR (376 MHz, d6 DMSO) d -153.9, -131.5, -120.9. 13C NMR (100 MHz, d6 DMSO) d 117 (C, m), 124 (CH, bs), 134 (C, s), 141 (CF, dt, J251, 10), 148 (CF, dd, J265, 13), 154 (CF, dd, J265, 10), 163 (COOH). IR VmaAcpf1 3108 (br), 1712, 1555, 1345, 1082. MS APCI (-) m / z 220 (M-l) detected.

Step 2: 2,4-D? Am? No-3-fluoro-5-n? Trobensnzoate methyl (5): 2,3,4-trifluoro-5-n-trobenzoic acid (100 g, 0.452 Mol) was dissolved in methanol (60 mL) at 25-30 ° C. To the resulting stirred solution, at 10 ° C, chlorotpmethylsilane (98.3 g, 0.91 Mol, 2 equiv.) Was added, maintaining the temperature between 10 and 20 ° C. Upon completion of the addition, The mixture was heated to reflux for 5 hours. At this point 99% (area) of conversion to 2, 3, 4-trifluoro-5-n-trobenzoate methyl (2) was indicated by HPLC analysis. After cooling the mixture at room temperature was diluted with N-methylpyrrolidone (NMP, 380 mL) and the reaction vessel was placed in an ice bath. Ammonium hydroxide solution (33% by weight [d 0.88], 164 mL, 144 g, 2.7 Mol) was added to the stirred mixture vigorously, keeping the temperature below 15 ° C. A yellow precipitate formed during the addition. The reactor was then closed and heated to 80 ° C, with an internal pressure of 2.5 barg. After 5 hours the reaction mixture was cooled to 60 ° C and the pressure released. The temperature was then increased to 75 ° C, after the addition of ammonium hydroxide (33% by weight [d 0.88] in water, 53 mL, 47 g, 1.0 Mol). The mixture was then cooled to 50 ° for 90 min. a yellow precipitate formed during the time. After an additional 1 hour at 50 ° C, water (400 mL) was added over 1 hour and the resulting suspension was cooled to 25 ° C and filtered. The filter cake was washed once with NMP / water 1: 1 (540 mL), once with water (540 mL) or then dried in a vacuum oven at 50 ° C for 24 hours, to provide 2, 4 -d? am? no-3-fluoro-5-n-trobenzoate methyl 4) (91 g, 88% yield).

Step 3: Methyl ester of 6-amino-7-fluoro-S-methyl-JH-benzoimidazole-S-carboxylic acid (6): A hydrogen purge vessel purged with nitrogen was charged with palladium on carbon (5.53 g, 1.30 mmol) , and to this was added a solution of methyl 2,4-diamino-3-fluoro-5-nitrobenzoate (5) (100 g, 419 mmol) in tetrahydrofuran (1.3 L) 15.98, then methanol (700 mL). The mixture was then stirred, purged with nitrogen and heated to 55 ° C. The stirring was then paused while the system was purged with hydrogen (4 bar), and the stirring was then restarted at 750 rpm. After 6.75 hours the observable hydrogen uptake had ceased and 29.1 L of hydrogen had been taken. The system was then purged with nitrogen and allowed to cool to 20 ° C. HPLC analysis indicated that all the stirred material had been reacted and that the solution yield of the desired triamine product was about 96%. The mixture was then filtered using a 1 μ Whatman line filter to remove the catalyst and the system was washed with tetrahydrofuran (400 mL). The solvent was then distilled until a total of 1400 mL had been collected and the mixture was allowed to cool to. room temperature. Acetonitrile (1.0 L) was added to the mixture, after removal of the solvent (1 L) by distillation, then two aliquots of additional 500 mL of acetonitrile were added, after each time the solvent was removed (2 x 500 mL) by distillation. After the oscillation step of the above solvent, the stirred mixture was cooled to 60 ° C and a solution of p-toluenesulfonic acid monohydrate (87.7 g), 461 mmol) in acetonitrile (175 mL) and water (7.6 mL, 419 mmol) was added slowly, followed by diethoxymethane (95.98 g, 921.59 mmol). After 3 hours, HPLC analysis indicated incomplete reaction and the temperature was raised to 65 ° C for an additional 1 hour, after which the reaction time was completed by HPLC analysis. Pyridine (66.3 g, 838 mmol) was added over 10 minutes and the reaction mixture was cooled to 20 ° C for about 30 minutes and kept at this temperature for 2.5 hours. The resulting suspension was then filtered and the solid was washed with acetonitrile (2 x 200 mL), and then dried at 45 ° in a vacuum oven, to provide 73.65 g of 6-ammo-7-fluoro-6-methyl ester. 3-met? L-3tf-benzoim? Dazol-5-carboxylic acid (6) as a pale brown solid (95.3% assay), yield 100%, 75%. X NMR (400 MHz, d6 DMSO) d 3.79 (3H, S, NMe), 3.87, (3H, s, OMe), 6.04 (2H, br, NH2), 7.82 (1H, s, ArH), 8. 23 (1H, s, Ar-H). 13C NMR (100 MHz, d6 DMSO) d 33 (NCH3), 52 (OMe), 110 (CH, d J 5), 111 (C, d J4), 124 (C, d J 5), 125 (C, d J 14), 136 (C, d J 11), 137 (CF, d J 242), 145 (CH), 167 (C = 0). Vma / cm1"3455, 3283, 3166, 3096, 2950, 2361, 2342, 1689, 1608, 1228. MS APCI (+) m / z 224 (M + l) detected.

Step 4: 6- (4-Bromo-2-chlorophenylamino) -7-fluoro-3-methyl-3-fluoro-benzo-m-dazole-5-carboxylic acid (Na salt) (7): A Mixture of Xantphos (1.95 g, 3.36 mmol) and tris (dibenzylidene ketone) dipalladium (0) (1.23 g, 1.34 mmol) in anisole (135 niL) was stirred under nitrogen at 50 ° C for 30 minutes to provide a brown solution of the solution. catalyst. To a stirred mixture of 6-ammo-7-fluoro-3-methyl-H-benzo-m? Dazole-5-carboxylic acid methyl ester (6) (15.01 g, 67.2 mmol) and cesium carbonate (43.79) g, 134.4 mmol) in anisole (150 mL) under nitrogen was added 4-bromo-2-chloroiodobenzene (23.5 g, 1.10 equiv., 74.0 mmol). The preformed catalyst, as prepared above, was then added to the mixture, followed by an anisole (15 mL) washed in line, to provide a dark brown suspension, which was heated to 90 ° C, with stirring at 400 rpm. The reaction it was monitored by HPLC analysis. After 14 hours, no 6-amino-7-fluoro-3-methyl-3-yl-benzoamidazole-5-carboxylic acid methyl ester (6) remained. The reaction mixture was diluted with anisole (75 mL) and cooled to about 80 ° C. 1M aqueous sulfuric acid (108 mL 108 mmol) was added, evaluation of gas and an endotherm was observed and the addition rate controlled to moderate the effervescence and maintain the temperature above 75 ° C. At the end of the addition, the pH was 0. The harbolite filter agent (3.75 g) was added to the biphasic mixture and the mixture was stirred for 20 minutes. It was then filtered at about 80 ° C through a Harbolite filter agent pad and the cake was washed with hot anisole (80 ° C) (2 x 75 mL). The lower aqueous layer was separated and discarded and the organic layer was washed with 10% aqueous NaCl solution (2 x 75 mL). Si-Thiourea Silicone Silicone (5.00 g) was added to the organic layer to provide a fine suspension, which was stirred at 80 ° C. After 2 hours the mixture was filtered through a glass fiber filter paper (GF / C) at 80 ° C, to provide a light orange-brown solution, which was cooled to 55 ° C. To the solution, methanol (45 mL) and water (2.7 mL 2.2 equiv.) Were added. A mixture of methanol (15 mL) and sodium methoxide in 30% methanol w / w (24.22 g 2.0 equiv.) Was added to the organic solution for a period of 1 hour, to provide a beige suspension. After 2 hours the HPLC analysis indicated that the hydrolysis of the ester was completed and water (75 mL) was added to the mixture over a period of 2 hours. The resulting suspension was then filtered and the solid washed with water (3 x 45 mL) then dried at 45 ° C in a vacuum oven to provide 6- (4-bromo-2-chlorophenylamino) -7-fluoro acid. 3-methyl-3H-benzoimidazole-5-carboxylic acid Na Na (7) as a beige solid (22.9 g, [assay 95.0% by H1 NMR, present by weight 21.8 g], yield of 77.0%). A NMR (400 MHz, d6 DMSO) d 3.85 (3H, s, NMe), 6.53 (1H, dd, J 9, 7, Ar-H), 7.27 (1H, dd, J 9, 2.5, Ar-H), 7.56 (1H , d, J 9, Ar-H), 7. 97 (1H, s, Ar-H), 8.20 (1H, s, Ar-H), 11.5 (1H, s, C02H). 13 C NMR (100 MHz, d 6 DMSO) d 31 (CH 3), 108 (CH, d, J 2), 109 (CH), 117 (C, d, 6), 122 (C), 124 (C, d, l), 127 (C), 130 (C), 131 (C), 132 (C, d, J9), 133 (C, d, J 11), 141 (C), 145 (CF, d, J252), 146 (CH), 170 (C = 0). Example 2 Synthesis of 6- (4-bromo-2-chlorophenylamino) -7-fluoro-3-methyl-A-benzoimidazole-S-carboxylic acid methyl ester (11; A solution of Pd (OAc) 2 (0.777 g, 3.46 mmol, 0.04 equiv.) And Xantphos (3.0 g, 5.19 mmol, 0.06 equiv.) In toluene (300 mL), under N2 was stirred for 20 minutes and then added to a suspension of 6-amino-7-fluoro-3-metho-3H-benzoamidazole-5-carboxylic acid methyl ester (6) (19.3 g, 86.5 mmol, 1 equiv. ), bromochloroiodobenzene (30.2 g, 95.1 mmol, 1.1 equiv.) and Cs2C0 (particle size = 20 microns or less; 51 g, 156 mmol, 1.8 equiv.) In toluene (200 mL), for 15 minutes at about 50 ° C. The mixture was then heated to reflux for 29 hours, after which no starting material remained by HPLC analysis. After allowing the mixture to cool to ambient it was filtered through a frit M and the solid was washed with toluene (95 mL), then dried in a vacuum oven at 50 ° C overnight. The solid was then suspended in water (784 mL) and 2N aqueous HCl (174 mL) was added slowly, for about 15 minutes to the control bubbling. The resulting suspension was stirred at room temperature for 2 hours, then filtered through a frit funnel M (150 mL). The solid product was washed with water (3 x 87 mL) and dried in a vacuum oven at 45 ° C, to provide 6- (4-bromo-2-chlorophenylamino) -7-fluoro-3- methyl acid ester. methanol-3H-benzo-m-dazole-5-carboxyl? co (11) 25.6 g (92% by weight by HPLC, corrected mass = 23.6 g, 66% yield). 1 H NMR (400 MHz, d 6 DMSO) d 3.84 (3 H, s, NMe), 3.93 (3 H, s, OMe), 6.44 (1H, dd, J 8.8, 5.1, Ar-H), 7.28 (1H, dd, J 2, 9. 8, Ar-H), 7.64 (1H, d J2.1, Ar-H), 8.1 (1H, s, NH) 8.14 (1H, s, Ar-H), 8.5 (1H, s, Ar-H); d 19F (376 MHz, d6 DMSO) -133; 13C NMR (100 MHz, d6 DMSO) d 32 (MeN), 52 (MeO), 109.4 (C), 109.7 (CH), 115.7 (CH), 119.1 (C), 120.7 (C), 122.5 (C, d, J 10), 130.4 (CH), 131.0 (CH), 133.4 (C, d, J 10), 135.5 (C, d, J 16), 140.8 (C), 146.0 (C-F, d, J 252), 148.6 (CH), 166. 7 (COO); vma / cm_1 3401, 1700, 1506, 1274; m / z 412 and 414 (M + and M + 2) detected with MS APCI (+). Example 3, methyl 2, 5-Tr? Am? No-3-fluorobenzoate (9) 9 A mixture of methyl 2, 4-d? Amino-3-fluoro-5-n-trobenzoate (5) (40.0 g, 173.7 mmol) and 5% Pd / C (3.0 g, Type 487; 0.4% in mol of Pd relative to the starting material), in methanol (300.0 mL) and tetrahydrofuran (300.0 mL) was stirred at 2000 RPM, ba or hydrogen (-3.5 bar), at 50 ° C in a hydrogenation vessel 1.5 L. After 6 hours the vessel was purged with nitrogen and HPLC analysis indicated that no starting material remained. The mixture was then filtered under nitrogen pressure and the filter was washed through with THF (160 mL), to give a clear yellow solution. The solvent was removed by rotary evaporation, to give methyl 2,4,5-triam? No-3-fluorobenzoate (9) 37.5 g (93.3% w / w by NMR) as a solid, yield -100%. X NMR (400 MHz, d6 DMSO) d 3.69 (3 H, s, NMe), 4.20 (2 H, br s, NH 2), 5.24 (2 H, br s, NH 2), 5.70 (2 H, br s, NH 2), 6.83. (1H, d, J 1, Ar-H). 13 C NMR (100 MHz, d 6 DMSO) d 51 (CH 3), 98 (C, d, J 5), 110 (CH, d, J 2), 125 (C, d, J 6), 131 (C, d , J 12), 133 (C, d, J 12), 139 (CF, d, J 225), 166 (C = 0). vma / cm "1 3480, 3461, 3373, 3356, 3280, 3163, 1679, 1655, 1314. MS APCI (+) m / z 200 (M + l) detected Example 4 Synthesis of 6- (4-bromo) acid -2-chlorophen-lamino) -7-fluoro-3-methyl-3-fluoro-benzo-m-dazole-5-carboxylic acid (10) (coupling method of copper-catalyzed aplo) 6 1 ° A mixture of 6-amino-7-fluoro-3-methyl-JI-benzoimidazole-5-carboxylic acid methyl ester (6) (1.0 g5 4.4 mmol), copper iodide (85.3 mg, 443.5 μmol) and isopropanol (10.0 mL, 130.8 mmol) was stirred at 40 ° C for 15 minutes. Potassium carbonate (1.2 g, 8.9 mmol) and ethylene glycol (551 mg, 8.9 mmol) then they were added and the mixture was heated to reflux for 1 hour in a Dean-Stark trap. An additional charge of isopropanol (1.5 mL) was added, after 4-bromo-2-chloroiodobenzene (1.5 g, 4.4 mmol) in isopropanol (2 mL) for 1 hour. After 26 hours, HPLC analysis was shown to be 81% of the benzimidazole substrate and has been converted to 6- (4-Bromo-2-chlorophenylammo) -7-fluoro-3-methyl-3f / -benzoic acid ? m? dazol-5-carbox? l? co (10). Example 5 Synthesis of 6-amino-7-f-3H-benzo-m-dazole-5-carboxylic acid methyl ester (12) To a stirred solution of methyl 2, 4, 5-tristamine-3-fluorobenzoate (9) (7.58 g, 38.1 mmol) in THF (152 mL, 20 vol) was added triethyl orthoformate (20.3 g, 22.8 mL, 137.0 mmol), after the dropwise addition of H2SO4 (9.33 g, 18 M, 94.1 mmol). The mixture was then heated at 60 ° C for 6 hours, at which point no starting material was detected by HPLC analysis. The solid product was filtered and rinsed with THF (150 mL, 20 vol), then transferred to a reaction vessel, suspended in water (150 mL) and the resulting mixture was neutralized to about pH 7.5 with 2 N NaOH. After stirring for 30 minutes, the suspension was filtered and the solid product was dried in a vacuum oven at 55 ° C, during the overnight to provide 6-amino-7-fluoro-3i-benzoimidazole-5-carboxylic acid methyl ester (12) 7.5 g, 94% yield (100% area by HPLC). X NMR (400 Hz, d6 DMSO) d 3.53 (1 H, br s, NH), 3.85, (3 H, s, OMe), 6.10 (2 H, br s, NH 2), 7.90 (1 H, s, Ar-H) 7.20 (1H, s, Ar-H). MS APCI (+) m / z 210 (M + l) detected with MS APCI (+). Example 6 Synthesis of 2,4-diamino-3-fluoro-5-nitrobenzoic acid (13) 1 2 A suspension of 2, 3, 4-trifluoro-5-nitrobenzoic acid (1) (5 g) and ammonium hydroxide (7.7 grams, 25% by weight of NH3 in H20, 4.9 equivalents) in N-methyl pyrrolidinone ( 12.5 mL) was heated to 80-90 ° C in a sealed reactor. During the reaction the mixture became homogeneous and the pressure rose to 0.4 bar. After 1.75 hours, the HPLC analysis showed incomplete conversion and an additional charge of ammonium hydroxide was added (2 g, 25% by weight NH3 in H20), followed by heating to 80-90 ° C in the sealed reactor for an additional 1.5 hours. After this time the HPLC analysis indicated > 99% conversion and the mixture was allowed to cool to room temperature overnight. The contents of the reactor were then added to water (100 mL), producing a homogenous coffee solution, with a pH of 9.4. Then acetic acid was added to the mixture until the pH was 6. After cooling to 0 ° C the product was isolated by filtration and washed with a water mixture. (10 mL) and MeOH (10 mL), then dried in a vacuum oven at 50 ° C, to provide 4.4 g (86% yield) of 2, 4-d? Ammo-3-fluoro-5- acid n? trobenzo? co (2) (HPLC purity 99.7%). A NMR (400 MHz, d6 DMSO) d 7.27 (2H, br s, NHA 7.31 (2H, br s, NH2), 8.46, (1H, s, Ar-H), 13.10 (1H, br, C02H). 13 C NMR (100 MHz, d 6 DMSO) d 102 (C), 123 (C), 127 (CH), 136 (d, J 229, CF), 138 (C), 143 (CF), 168 (C = 0). Example 7 Synthesis of methyl 2, 4-d? Am? No-3-fluoro-5-n-trobenzoate (5) Stage 1: 4 -am? No-2, 3-d f luoro-5-n? Trobenzoic acid (3) To a mixture of 2, 3, 4-tpf luoro-5-n? Trobenzoic acid (2) (167.2 g, 0.756 mol, 1 equiv) in 400 mL of distilled water was added concentrated ammonium hydroxide (28% solution of NH3, 340 g, 380 mL, 4.23 mol, 5.6 equiv.) Ensuring that the temperature internal temperature was below 6.0 ° C for 2-2.5 hours. The mixture was stirred for 50 minutes and then warmed to room temperature for 3-4 hours. When the reaction was > 90% complete by HPLC, the reaction mixture was cooled in an ice-water bath and concentrated HCl (350 mL) then added dropwise to adjust the pH = 2. The suspension was stirred for 1 hour with a Ice bath cooled and filtered. The cake was rinsed with 1 L of distilled water and then with 350 mL of MTBE. The cake was dried in an oven at 48 ° C overnight to give 134.9 g of a yellow solid. HPLC was 83.6% (220 nm) and 96.96% (254 nm). The MTBE filtrate was concentrated on a rotary evaporator and pumped overnight to give 9.9 g of a second culture as a yellow solid: HPLC was 81.1% (220 nm) and 95.40% (254 nm). The combined yield of 4-amino-2,3-difluoro-5-nitrobenzoic acid (3) was 144.8 g (88%). X NMR (400 MHz, d6 DMSO) d 8.0 (2H, br s, NH 2) 8.42 (1 H, dd, J 1.5, 7.6, Ar-H). 19F. NMR (376 MHz, d6 DMSO) d -153.9, -129.0. 13 C NMR (100 MHz, d 6 DMSO) d 106 (C, d, J 10), 126 (CH), 128 (C), 140 (CF, dd, J 241, 16), 140.8 (C, dd, J 12, 4), 153 (CF, dd, J 263, 11), 164 (COOH). IR vmax / cm_1 3494, 3383, 1697, 1641, 1280. MS APCI (-) m / z 217 (M- 1) detected, Step 2: Methyl 4-amino-2,3-difluoro-5-nitrobenzoate (4): TMSC1 (132 g, 1.21 mol, 2.0 equiv) was added over 5 minutes to a suspension of 4-amino-2,3-difluoro acid. -5-nitrobenzoic acid (3) (132.3 g, 0.607 mol, 1 equiv) in 325 mL of MeOH. The mixture was refluxed for 15 hours. Once the reaction was complete by HPLC, the reaction mixture was cooled in an ice-water bath for 45 minutes. Then the reaction mixture was filtered and the cake was washed with 65 mL of MeOH. The wet cake was dried overnight at 55 ° C under high vacuum to provide 128.8 g (92%) of 4-amino-2,3-difluoro-5-nitrobenzoic acid methyl ester (4). HPLC was 97.9% (220 nm) and 99.2% (254 nm). X H NMR (400 MHz, d 6 DMSO) d 3.84 (3 H, s, OMe), 8.1 (2 H, br s, NH 2), 8.43 (1 H, apparent dd, J 1.9, 7.2, Ar-H). 19F NMR (376 MHz, d6 DMSO) d -153.6, -129.2. 13C NMR (100 MHz, d6 DMSO) d 52 (CH30), 105 (C, d, J 10), 125 (CH, t, J2.7,), 128 (CH, d, Jb), 140 (CF, dd, J244, 15,), 141 (C, dd, J 14, 5), 152 (CF, dd, J263, 11), 162 (COO, t, J 3). IR v ^ / cm "1 3433, 3322, 1699, 1637, .1548, 1342, 1234. MS APCI (-) m / z 231 (M-l) detected .

Step 3: Methyl 2, 4-diamino-3-fluoro-5-nitrobenzoate (5): To a stirred solution of methyl 4-amino-2,3-difluoro-5-nitrobenzoate (4) (33.0 g, 142.15 mmol ) in 1,4-dioxane (165 mL, 1.93 moles), in a 250 mL glass pressure vessel, an aqueous solution of ammonia (39 g, 711 mmol, 42.9 mL, 16.5 M) was added. The vessel was then heated in an immersion bath at a bath temperature between 79 and 105 ° C, for 80 minutes, during which time the internal pressure varied between 0.2 and 2.7 bar. The pressure was then released slowly and the mixture was treated with water (330 mL, 10 vol). The resulting suspension was stirred for 20 minutes and then filtered under vacuum, and the solid was washed with water (33 mL, 1 vol). The solid was sucked dry, then dried in a vacuum oven at 50 ° C to provide methyl 2-diamino-3-fluoro-5-nitrobenzoate (5) (32.6 g, 92% yield) as a yellow solid . 1H NMR (500 MHz, d6 DMSO) d 3.83, (3H, s, OMe), 7.20 (2H, br, NH2), 7.37 (2H, br, NH2), 8.47 (1H, s, Ar-H). 13 C NMR (100 MHz, d 6 DMSO) d 52 (CH 3), 101 (C), 122 (C), 126 (CH), 134 (C), 137 (C), 142 (C), 166 (C = 0 ). vma;: / cnA 3474, 3358, 1697, 1633, 1528, 1435, 1317, 1285. The foregoing description is considered as illustrative only of the principles of the invention. In addition, since numerous modifications and changes will be readily apparent to those skilled in the art, it is not desired to limit the invention to the exact construction and process shown as described above. Accordingly, all suitable and equivalent modifications may be frequent to fall within the scope of the invention as defined by the claims that follow. The words "comprises", "comprising", "includes", "including" and "include" when used in this specification and in the following claims are proposed to specify the presence of established characteristics, integers, components, or stages, but does not avoid the presence or addition of one or more other characteristics, integers, components, stages, or groups thereof.

Claims

CLAIMS 1. A process for preparing a compound of Formula Ia-1 la-1 and salts and solvates thereof, characterized in that: Z is -C (= 0) ORJ -C (= 0 NRdR7, CN, -C (= 0) H, or 'or a portion that can be transformed into any of the Z groups; R1 is hydrogen, C? -C? Alkyl, C2-C? Alkenyl, C2-C10 alkynyl, C3-C? Cycloalkyl, C3-C10 cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl , heterocyclylalkyl, trialkylsilyl or dialkylarylsilyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl portions are optionally substituted with one or more groups independently selected from halogen, hydroxyl, C1 alkyl -C4, C2-C4 alkenyl, C2-C4 alkyl, C3-C6 cycloalkyl and C3-C6 heterocycloalkyl, R2 is hydrogen, C? -C? 0 alkyl, C2-C10 alkenyl, C2-C? alkynyl, arylalkyl, trialkylsilyl, dialkylansilyl, -COR6, - C (0) OR6 or -C (0) NR6R7, wherein the alkyl, alkenyl, alkynyl or aplalqualo portions are optionally substituted with one or more groups independently selected from halogen, hydroxyl, C? -C4 alkyl, C2 alkenyl C4 and C2-C4 alkynyl; X1 and X "are independently selected from hydrogen, F, Cl, Br, I, OR8, alkyl of A-Cio, alkenyl of C2-C? Or, alkynyl of C2-C? Or, cycloalkyl of C3-C10, cycloalkylalkyl of C3-C10 and C1-C10 thioalkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl and thioalkyl portions are optionally substituted with one or more groups independently selected from oxo, halogen, cyano, nitro, azido, trifluoromethyl, difluoromethoxy and tnfluoromethoxy; X5 is H, F, Cl, Br, I or C? -C6 alkyl; R6 and R7 are independently hydrogen, trifluoromethyl, -OR8, C1-C10 alkyl, C2-C? 0 alkenyl, C2 alkynyl -C?, C3-C10 cycloalkyl, C3-C10 cycloalkyl, ring, aplakyl, heteroaryl, heteroaplalkyl, heterocyclyl or heterocyclylalkyl, or R6 and R7 together with the atom to which they are attached form a heteroaryl or heterocyclic ring of 4? to 10 members, wherein the heteroaryl and heterocyclic rings are optionally substituted with one or more groups independently selected from halogen, trifluoromethyl, d-fluoromethoxy, trifluoromethoxy and OR8; R8 is hydrogen, C1-C10alkyl, C2-C3alkenyl, aryl or aplakyl, wherein the alkyl, alkenyl, aryl and arylalkyl are optionally substituted with one or more groups independently selected from OH, -0- (alkyl of C? -C? o) and 0- (Ci-Cio alkenyl); R10 is hydrogen, alkyl of A-Cio, cycloalkylalkyl of C3-C10, arylalkyl, heteroarylalkyl or heterocyclylalkyl, wherein the alkyl, cycloalkylalkyl, aplakyl, heteroalalkyl and heterocyclylalkyl portions are optionally substituted with one or more groups independently selected from halogen, hydroxyl , cyano, n-tro, azido, C 1 -C alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 3 -C 6 cycloalkyl, C 3 -C 6 heterocycloalkyl, -NR 6 R 7 and -OR 8; and R12a and R12b are independently selected from hydrogen, y-Cio alkyl, C2-C? alkenyl, C2-C alqu alkynyl, C3-C10 cycloalkyl, C3-C10 cycloalkylalkyl, aryl, aplakyl, heteroaryl and heteroaplakyl, or R12a and R12 together with the atom to which they are attached form a carbocyclic, heteroaryl or heterocyclic ring of 4 to 10 members; the method comprising: nitrating a compound having the Formula wherein X and X are independently F, Cl, Br, I, or a sulfonate ester, to provide a compound of Formula II treating the compound of Formula II optionally at elevated temperatures and / or pressure with two or more equivalents of (i) a reactant that contains or generates ammonia, (ii) a primary or secondary amine other than an aromatic amine or (ii) a reagent that supplies a group that can be subsequently converted to an amine to provide a compound of Formula VI-11 wherein A is -NR2R2a, or treat the compound of Formula II with (iv) two or more equivalents of an azide of metal optionally at elevated temperatures and / or pressure to provide a compound of Formula VI-12 wherein A is N3 wherein R2a is hydrogen, C? -C? alkyl, C2-C? alkenyl, C2-C? alkynyl, benzyl, allyl, arylalkyl, trialkylsilyl, dialkylarylsilyl, -COR, C (O) OR6, -C (0) NR6R7, -OR1, or -NHR1, wherein the alkyl, alkenyl, alkynyl, benzyl, allyl and arylalkyl portions are optionally substituted with one or more groups independently selected from halogen, hydroxyl, alkyl of C] _- C4, C2-C4 alkenyl and C2-C4 alkynyl; reducing the compound of Formula VI-11 or VI-12 to provide a compound of Formula VIIa-1 wherein when A of Formula VI-11 or VI-12 is -NH-benzyl, -NHOR1 or -NHNHR1 or N3, then R2 and R2d of Formula VIIa-1 are hydrogen; when R2a of Formula VIIa-1 is hydrogen, cyclize the compound of Formula VIIa-1 to provide a compound of Formula VIIIa-1 when R ~ a of Formula VIIIa-1 is hydrogen, coupling the compound of Formula VIIIa-1 with a reagent having the Formula wherein Xd is F, Cl, Br, I, -OS02CF3, alkyl sulfonate, aplo sulfonate, alkylaryl sulfonate, B (OR8y, -BF3 or -B? (Rx) 2, optionally either (i) at temperature elevated and optionally in the presence of a base, or (? i) in the presence of a catalyst based on metal and a base, to provide the compound of the Formula Ia-1.
2. The process in accordance with the claim 1, characterized in that it further comprises: reacting the compound of Formula VI-11 or VI-12 with a compound having the formula R ^ H, optionally in the presence of an activating agent that activates the group Z towards the reaction with the compound of the formula R1OH, to provide a compound of Formula Va-11 wherein A is -NR2R2a or a compound of Formula Va-12 wherein A is N3 Va-11: A = NR2R to Va-12: A = N3 reducing the compound of Formula Va-11 or Va-12 to provide the compound of Formula VIIa-1 wherein Z is -COOR1; when R ^ a of Formula VIIa-1 is hydrogen, cyclize the compound of Formula VIIa-1 to provide the compound of Formula VIIIa-1 wherein Z is -COOR1; and coupling the compound of Formula VIIIa-1 with the reagent having the Formula optionally either (i) at elevated temperature and optionally in the presence of a base, or (ii) in the presence of a metal-based catalyst and a base, to provide the compound of Formula Ia-1 wherein Z is COOR1 .
3. A process for the preparation of a compound of Formula Ib-1 Ib-1 and salts and solvates thereof, characterized in that: Z is -C (= 0) 0R1, -C (= 0) NR6R7, CN, -C (= 0) H, or or a portion that can be transformed into any of the Z groups; R1 is hydrogen, alkyl of A-Cio, alkenyl of C2-C? Or, alkynyl of C2-C? Or, cycloalkyl of C3-C10, cycloalkylalkyl of C3-C10, aplo, arylalkyl, heteropole, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, tpalkylsilyl or dialkylarylsilyl, wherein the alkyl, alkenyl, alkyl, chloroalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl portions are optionally substituted with one or more groups independently selected from halogen, hydroxy, C1-C4 alkyl , C2-C4 alkenyl, C2-C4 alkyl, C3-C6 cycloalkyl and C3-C6 heterocycloalkyl; R, 2b is hydrogen, C? -C10 alkyl, C2- alkenyl Cι, C 2 -C 0 alkynyl, arylalkyl, trialkylsilyl, dialkylarylsilyl, -COR 6, -C (0) OR 6 or -C (0) NR 5 R 7, wherein the alkyl, alkenyl, alkynyl and arylalkyl portions are optionally substituted with one or more groups independently selected from halogen, hydroxyl, C1-C4 alkyl, C2-C4 alkyl, or C2-C5 alkyl; X1 and X2 are independently selected from hydrogen, F, Cl, Br, I, OR8, C 1 -C 6 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 10 cycloalkyl, C 3 cycloalkylalkyl -C10 and C1-C10 thioalkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl and thioalkyl portions are optionally their isomers with one or more groups independently selected from oxo, halogen, cyano, nitro, trifluoromethate, difluoromethoxy, trifluoro ethoxy and azido; X5 is H, F, Cl, Br, I or alkyl of A-A; R6 and R7 are independently hydrogen, trifluoromethyl, -OR8, C? -C? Alkyl, C2-C? Alkenyl, C2-C? Alkyl, C3-C10 cycloalkyl, C3-C1-cycloalkyl. 0, aryl, anlalkyl, heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl, or R6 and R7 together with the atom at which L are attached form a heteroaryl or heterocyclic ring of 4 to 10 members, wherein the heteroaryl or heterocyclic rings are optionally substituted with one or more groups independently selected from halogen, trifluoromethyl, difluoromethoxy, trifluoromethoxy and -OR8; R8 is hydrogen, C1-C10alkyl, C2-C3alkenyl, aryl or arylalkyl, wherein the alkyl, alkenyl, aryl and arylalkyl are optionally substituted with one or more groups independently selected from OH, -0- (alkyl) Ci-Cio) and 0- (C? -C10 alkenyl); R10 is hydrogen, Ci-Cio alkyl, C3-C? Cycloalkylalkyl, arylalkyl, heteroarylalkyl or heterocyclylalkyl, wherein the alkyl, cycloalkylalkyl, arylalkyl, heteroarylalkyl and heterocyclylalkyl portions are optionally substituted with one or more groups independently selected from halogen, hydroxyl, cyano, nitro, azido, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C alkynyl, C 3 -C 6 cycloalkyl, C 3 -C 6 heterocycloalkyl, -NR 6 R 7 and -OR 8; and R 1"" 3 and R 12 are independently selected from hydrogen, C 1 -C 6 alkyl, C 2 -C 0 alkenyl, C 2 -C 10 alkynyl, C 3 -C 10 cycloalkyl, C 3 -C 10 cycloalkylalkyl, aryl, arylalkyl , heteroaryl and heteroarylalkyl, or R12a and R12b together with the atom to which they are attached form a carbocyclic, heteroaryl or heterocyclic ring of 4 to 10 members; The method comprising: nitrate a compound that has the Formula wherein X and X are independently F, Cl, Br, I, or a sulfonate ester, to provide a compound of Formula II reacting the compound of Formula II with (i) a reagent that contains or generates ammonia, (ii) a primary or secondary amine other than an aromatic amine, or (m) a reagent that supplies a group that can be subsequently converted into a amine, ba or conditions permitting selective displacement of X4, to provide a compound of Formula III-ll wherein A is NR2R2a, or reacting the compound of Formula II with (iv) a metal azide under conditions that allow the selective displacement of X4 to provide a compound of Formula 111-12 wherein A is N3 OI-ll A = NR2R2a 111-12 A = N3 and R 2 and R 2a are independently hydrogen, C 1 -C 10 alkyl, C 2 -C 0 alkenyl, C 2 -C 8 alkynyl, benzyl, halo, arylalkyl, trialkylsilyl, dialkylarylsilyl, COR 6, -C (0) OR 6, - C (0) NR6R7, -OR1 or -NHR1, wherein the alkyl, alkenyl, alkyl, benzyl, aryl and arylalkyl portions are optionally substituted with one or more groups independently selected from halogen, hydroxyl, C1-C alkyl, alkenyl C2 - I, and C2-C4 alkyl; reacting the compound of Formula III-ll or 111-12, optionally at elevated temperatures, with (i) a reagent that contains or generates ammonia, (n) a primary or secondary amine other than an aromatic amine or (m) a reagent that supplies a group that can be subsequently converted to an amine to provide a compound having Formula Vb-11 wherein B is -NR2bR2c and A is -NR2R2a or N3, or reacting the compound of Formula III-ll or 111-12 with (iv) a metal azide, optionally at elevated temperatures, to provide a compound of Formula Vb-12 wherein B is N3 and A is -NR2R2a Vb-11: B = NR2bR c, A = NR2R2a or N3 Vb-12: B = N3, A = NR 2ztR > 2aa or, N3 wherein R 2c is hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 8 alkynyl, benzyl, allyl, arylalkyl, trialkylsilyl, dialkylarylsilyl, -COR 6, C (0) OR 6, -C ( 0) NR6R7, -OR1 or -NHR1, wherein the alkyl, alkenyl, alkynyl, benzyl, allyl and arylalkyl portions are optionally substituted with one or more groups independently selected from halogen, hydroxyl, C 1 -C 4 alkyl, C 2 alkenyl -C4 and C2-C4 alkynyl; reducing the compound of Formula Vb-11 or Vb-12 to provide a compound of Formula VIIb-1 wherein when A and / or B of Formula Vb-11 or Vb-12 is -NH-benzyl, N3, -NHOR1 or -NHNHR1, then R2 and R2a and / or R2b and R2c, respectively, of Formula VIIb- 1 are hydrogen; when R2a of Formula VIIb-1 is hydrogen, cyclizing the compound of Formula VIIb-1 to provide a compound of Formula VIIIb-1 when R ~ c of Formula VIIIb-1 is hydrogen, coupling the compound of Formula VIIIb-1 with a compound having the formula wherein X6 is F, Cl, Br, I, -OS02CF3, alkyl sulfonate, aplo sulfonate, alkylamp sulfonate, B (OR8) 2, -BF3 or -BAR1) 2 optionally either (i) at elevated temperature and optionally in the presence of a base, or (n) in the presence of a catalyst based on metal and a base, to provide the compound of Formula Ib-1.
4. The process according to claim 3, characterized in that it further comprises: reacting the compound of the Formula III with a compound having the formula R1OH, optionally in the presence of an activating agent that activates the group Z towards the reaction with the compound of the formula R OH, to provide a compound of the Formula IV-21 or IV-22 IV-21: A = NR R2a IV-22: A = N reacting the compound of Formula IV-21 or IV-22 at elevated temperatures with (i) a reagent that contains or generates ammonia, (ii) a primary or secondary amine other than an aromatic amine or (iii) a reagent that supplies a group that can be subsequently converted to an amine to provide a compound of Formula Vb-11 wherein Z is -COOR1, or reacting the compound of Formula IV-21 or IV-22 with (iv) a metal azide at elevated temperatures to provide a compound of Formula Vb-12 wherein Z is -COOR1; reducing the compound of Formula Vb-21 or Vb-22 to provide the compound of Formula VIIb-1 wherein Z is -COOR1; when R ~ a is hydrogen, cyclize the compound of Formula VIIb-1 to provide the compound of Formula VIIIb-1 wherein Z is -COOR1; and coupling the compound of Formula VIIIb-1 with the compound having the formula optionally either (i) at elevated temperature and optionally in the presence of a base, or (ii) in the presence of a metal-based catalyst and a base, to provide the compound of Formula Ib-1 wherein Z is COOR1 .
5. A process for the preparation of a compound of Formula VIIIb-1 and solvate salts thereof, characterized in that: , or a portion that can be transformed into any of the Z groups; X5 is H, F, Cl, Br, I or Cj-Ce alkyl; R 1 is hydrogen, C 1 -C 0 alkyl, C 2 alkenyl Cio, C2-C? Alkynyl, C3-C10 cycloalkyl, C3-C10 cycloalkylalkyl, aplo, aplakyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, trialkyl silyl or di to chrylarylsilyl, wherein the alkyl, alkenyl, alkynyl moieties , cycloalkyl or, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl are optionally substituted with one or more groups independently selected from halogen, hydroxy, C1-C4 alkyl, C2-C alkenyl, C2-C alkyl, C3-C6 cycloalkyl and C3-C6 heterocycloalkyl, R2 and R2c are independently hydrogen, C1-C10 alkyl, C2-C3 alkenyl, C2-C alkynyl, benzyl, halo, aplakyl, trialkylsilyl, dialkylarylsilyl, COR6, -C (0) OR6 or -C (0) NR6R7, wherein the alkyl, alkenyl, alkynyl, benzyl, allyl and arylalkyl portions are optionally substituted with one or more groups independently selected from halogen, hydroxyl, C1-C4, C2-C4 alkenyl and C-C4 alkynyl; R6 and R7 are independently hydrogen, trifluoromethyl, -OR8, alkyl of A-Cio, alkenyl of C2-C? 0, alkyl of C2-C? Or, cycloalkyl of C3-C10, cycloalkylalkyl of C3-C10, aryl, arylCalkyl, heteropole, heteroaryl, Ikyl, heterocyclyl or heterocyclylalkyl, or R6 and R7 together with the atom to which they are \ 5j linked form a heterolate or heterocyclic ring of 4 to 10 members, wherein the heteroaryl and heterocyclic rings are optionally substituted with one or more groups independently selected from halogen, trifluoromethyl, difluoromethoxy, trifluoromethoxy and OR8; R8 is hydrogen, alkyl, C2-C2 alkenyl, aryl or arylalkyl, wherein alkyl, alkenyl, aplo and arylalkyl are optionally substituted with one or more groups independently selected from OH, -0- (alkyl) of A-CA and 0- (C 1 -C 10 alkenyl) R 10 is hydrogen, Ci-Cι alkyl, C 3 -C 10 cycloalkylalkyl, aplaxyl, heteroarylalkyl or heterocyclylalkyl, wherein the alkyl, cycloalkylalkyl, arylalkyl , heteroarylalkyl and heterocyclylalkyl are optionally substituted with one or more groups independently selected from halogen, hydroxyl, cyano, nitro, azido, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 3 -C 6 cycloalkyl, C3-C6 heterocycloalkyl, -NR6R7 and -OR8, and R a and X ~ b are independently selected from hydrogen, C10-alkyl, C2-C20 alkenyl, C2-C20 alkyl, C3-cycloalkyl C10, C3-C10 cycloalkylalkyl, aplo, aplaxyl, heteroaryl and heteroarylalkyl, or R1"3 and R1b with together with the atom to which they are attached they form a carbocyclic, heteroaryl or heterocyclic of 4 to 10 members; the method comprising cyclizing a compound of Formula VIIb-1 wherein R "hydrogen, Ci-Cio alkyl, C2-C? alkenyl, C2-C? alkynyl, benzyl, halo, arylalkyl, trialkylsilyl, dialkylarylsilyl, -COR6, -C (0) OR6 or C ( 0) NR6R7, wherein the alkyl, alkenyl, alkynyl, benzyl, allyl and arylalkyl portions are optionally substituted with one or more groups independently selected from halogen, hydroxyl, C 1 -C 4 alkyl, C 2 -C 4 alkenyl and C 2 alkynyl -C4, and R a is hydrogen, to provide the compound of Formula VIIIb-1
6. A process for the preparation of a compound of Formula VIIIb-1 and salts and solvates thereof, characterized in that: Z is -C (= 0) ORx, -C (= 0) NR6R
7, CN, -C (= 0) H, or > or a portion that can be transformed into any of the Z groups; X5 is H, T, Cl, Br, I or C? -C6 alkyl; R 1 is hydrogen, C 1 -C 0 alkyl, C 2 -C 0 alkenyl, C 2 -C 8 alkynyl, C 3 -C 6 cycloalkyl, C 3 -C 10 cycloalkylalkyl, aryl, aplaxyl, heteroaryl, heteroaplakyl, heterocyclyl , heterocyclylalkyl, trialkylsilyl or dialkylarylsilyl, wherein the alkyl, alkenyl, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl groups are optionally substituted with one or more groups independently selected from halogen, hydroxyl, C1-C4, C2-C4 alkenyl, C2-C4 alkyl, C3-C6 cycloalkyl and C3-C6 heterocycloalkyl; R 2b is hydrogen, C 1 -C 0 alkyl, C 2 -C 6 alkenyl, C 2 -C 8 alkynyl, benzyl, halo, arylalkyl, trialkylsilyl, dialkylarylsilyl, -COR 6, -C (0) 0R 6 or C (0) NR6R7, wherein the alkyl, alkenyl, alkynyl, benzyl, aryl and arylalkyl portions are optionally substituted with one or more groups independently selected from halogen, hydroxyl, C1-C4 alkyl, C2-C4 alkenyl, and C2-C alkyl; R2c is hydrogen, alkyl of A-C10, alkenyl of C2-Cio, alkynyl of C2-C10, benzyl, halo, arylalkyl, trialkylsilyl, dialkylarylsilyl, -COR6, -C (0) OR6, C (0) NR6R7, -OR1 or -NHR1, wherein the alkyl, alkenyl, alkyl, benzyl, halo and arylalkyl portions are optionally substituted with one or more groups independently selected from halogen, hydroxyl, C1-C4 alkyl, C2-C4 alkenyl and C2-alkyl C; R6 and R7 are independently hydrogen, trifluoromethyl, -OR
8, C1-C10 alkyl, C2-C3 alkenyl, C2-C? Alkyl, C3-C10 cycloalkyl, C3-C10 cycloalkylalkyl, aplo, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl, or R and R together with the atom to which they are attached form a heteroaryl or heterocyclic ring of 4 to 10 members, wherein the heteroaryl and heterocyclic rings are optionally substituted with one or more groups independently selected from halogen, trifluoromethyl, di fluoromethoxy, trifloromethoxy and OR8; R8 is hydrogen, y-Cio alkyl, C2- alkenyl Cι, aryl or arylalkyl, wherein the alkyl, alkenyl, aryl and aplakyl are optionally substituted with one or more groups independently selected from OH, -0- (C 1 -C 10 alkyl) and 0- (Ci-Cι alkenyl); R 10 is hydrogen, C 1 -C 4 alkyl, C 3 -C 0 cycloalkylalkyl, arylalkyl, heteroarylalkyl or heterocyclylalkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, arylalkyl, heteroarabyl and heterocyclylalkyl portions are optionally substituted with one or more groups independently selected from halogen, hydroxyl, cyano, nitro, azido, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, -NR6R7 and -OR8; and R12a and R12b are independently selected from hydrogen, C? -C10 alkyl, C2-C? alkenyl, C2? C? alkynyl, C3-C10 cycloalkyl, C3-C10 cycloalkylalkyl, aryl, arylalkyl, heteroaryl and heteroaplalkyl, or R12a and lAb together with the atom to which they are attached form a carbocyclic, heteroaryl or heterocyclic ring of 4 to 10 members; the method comprising: providing a compound of Formula Vb-11 wherein B is NR2bR2L and A is NR2R2a or N3, or a compound of Formula Vb-12 wherein B is N3 and A is NR2R2a or N3, Vb-ll: B = NR bR2c, A = NR2R2a or N3 Vb-12: B = N3, A = NR2R2a or N3 wherein R 'is hydrogen, substituted or unsubstituted benzyl, allyl or -C (0) OR6 and R2a is hydrogen; reducing the compound of Formula Vb-11 or Vb-12 to provide a compound of Formula VIIb-1 wherein when A and / or B of Formula Vb-11 or Vb-12 is N3, then R2 and R2a and / or R2b and R2c, respectively, of Formula VIIb-1 are hydrogen; and when R2a is hydrogen, cyclize the compound of Formula VIIb-1 to provide the compound of Formula VIIIb-1. The process according to any of claims 1 to 6, characterized in that the cyclization comprises reacting the compound of Formula VIIa-1 or VIIb-1, wherein R2 and R2a are H, with (i) formic acid, optionally in the presence of an additional acid, or (ii) a formic acid derivative in the presence of an acid, to provide the. Compound of Formula VIIIa-1 or VlIIb-1 wherein R10 is H. The process according to any of claims 1 to 6, characterized in that the cyclization comprises (a) reacting the compound of the Formula VIIa-1 or VIIb-1, wherein R2a is hydrogen and R2 is not hydrogen, with (i) formic acid, optionally in the presence of an additional acid, (ii) a formic acid derivative in the presence of an acid, or (iii) formaldehyde or a formaldehyde derivative in the presence of an acid, to provide a compound of Formula XIa-1 or XIb-1 XIa-1 Xlb-1 (b) alkylating the compound of Formula XIa-1 or XIb-1 with a reagent having the formula R10-Y wherein R10 is not hydrogen and Y is Cl, Br, I, or a sulfonate ester, to provide a compound of Formula XIIa-1 or XIIb-1 Xlla-l Xllb-l (c) removing the R group from the N-1 position to provide the compound of the Formula VIIIa-1 or VIXIb-1 wherein R10 is not hydrogen.
9. The process according to any of claims 1 to 6, characterized in that the cyclization comprises treating the compound of Formula VIIa-1 or VIIb-1, wherein R2 and Ra are H, with two or more equivalents of formaldehyde or a formaldehyde derivative in the presence of an acid to provide the compound of Formula VIIIa-1 or VIIIb-1 wherein R10 is methyl.
The process according to any of claims 1 to 6, characterized in that the cyclization comprises: (a) reacting the compound of Formula VIIa-1 or VIIb-1, wherein R2 and R2a are hydrogen, with an agent of acylation to provide a compound of Formula IXa or IXb wherein R, 10Wad is H, alkyl of A-Cio, cycloalkylalkyl of C3-C10, arylalkyl, heteroarylalkyl or heterocyclylalkyl, wherein the alkyl, cycloalkylalkyl, arylalkyl, heteroarylalkyl and heterocyclylalkyl are optionally substituted with one or more groups independently selected from halogen, hydroxyl, cyano, nitro, azido, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 3 -C 6 cycloalkyl, C 3 heterocycloalkyl -C6, -NR6R7 and -OR8; (b) reducing the amide group of the compound of Formula IXa or IXb to provide a compound of Formula Xa or Xb Xa Xb (c) reacting the compound of Formula Xa or Xb with (1) formic acid optionally in the presence of an additional acid or (11) a formic acid derivative in the presence of an acid to provide the compound of the Formula VIIIa-1 or Vlllb-l wherein R10 is not hydrogen.
11. The process according to any of claims 1 to 6, characterized in that the cyclization comprises: (a) reacting the compound of Formula VIIa-1 or Vllb-l, wherein R2a is hydrogen and R2 is not hydrogen, with an acylating agent to provide a compound of Formula IXa or IXb wherein R10a is H, alkyl of A-Cio, cycloalkylalkyl of C3-C? 0, arylalkyl, heteroarylalkyl or heterocyclylalkyl, wherein the alkyl, cycloalkylalkyl, arylalkyl, heteroarylalkyl and heterocyclylalkyl portions are optionally substituted with one or more groups independently selected from halogen, hydroxyl, cyano, nitro, azido, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 3 -C 6 cycloalkyl, C 3 -C 6 heterocycloalkyl, -NR 6 R 7 and -OR 8; (b) reducing the amide group of the compound of Formula IXa or IXb to provide a compound of Formula Xa or Xb (c) reacting the compound of Formula Xa or Xb with (i) formic acid optionally in the presence of an additional acid or (ii) a formic acid derivative in the presence of an acid to provide a compound of Formula XIIa -1 or XIIb-1 (d) removing the R group from the N-1 position to provide the compound of the Formula VIIIa-1 or VIIIb-1 wherein R10 is not hydrogen.
12. A compound, including salts and solvates thereof, having the Formula VIIb-1 characterized in that: Z is -C (= 0) OR1, -C (= 0) NR6R7, CN, -C (= 0) H, or > 'or a portion that can be transformed into any of the Z groups; R 1 is hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 0 alkynyl, cycloalkyl, C 3 -C 10 cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, trialkylsilyl or dialkylarylsilyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl portions are optionally substituted with one or more groups independently selected from halogen, hydroxyl, alkyl of C1-C, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl and heterocycloalkyl or C3-C6; R 2 and R 2b are independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 8 alkynyl, benzyl, halo, arylalkyl, trialkylsilyl, dialkylaryl io, COR 6, -C (0) OR 6 or - C (0) NR6R7, wherein the alkyl, alkenyl, alkyl, benzyl, halo and lozenge portions are optionally substituted with one or more groups independently selected from halogen, hydroxyl, C1-C4 alkyl, C2-C4 alkenyl and alkyl of C2-C; R 2a and R 2c are independently hydrogen, C 1 -C 10 alkyl, C 2 -C 0 alkenyl, C 2 -C 8 alkynyl, benzyl, halo, aplakyl, trialkylsilyl, dialkylalkyl, COR6, -C (0) 0R6, -C (0) NR6R7, -OR1 or -NHR1, wherein the alkyl, alkenyl, alkynyl, benzyl, aryl and arylalkyl portions are optionally substituted with one or more groups independently selected from halogen, hydroxyl, C 1 -C 4 alkyl, C 2 -C 4 alkenyl and alkynyl C2-C4, "or -NR2R2a and / or -NR2bR2c is N3; X5 is H, T, Cl, Br, I or C? -C6 alkyl; R6 and R7 are independently hydrogen, trifluoromethyl, -OR8, C1 alkyl -C10, C2-C? Alkenyl, C2-C alqu alkynyl, C3-C10 cycloalkyl, C3-C10 cycloalkylalkyl, aplo, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl, or R6 and R7 together with the atom to which they are attached form a 4 to 10 membered heterocyclic or heterocyclic ring, wherein hetero- and heterocyclic rings are optionally substituted with one or more groups independently selected from halogen, trifluoromethyl, difluoromethoxy, trifluoromethoxy and OR8; R8 is hydrogen, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, aryl or arylalkyl, wherein the alkyl, alkenyl, aryl and arylalkyl are optionally substituted with one or more groups independently selected from OH, -0- (C 1 -C 10 alkyl) and -O- (C1-C10 alkenyl), R10 is hydrogen, alkyl of A-C10, CI C3-C10-chloralkylalkyl, aplaxyl, heteroarylalkyl or heterocyclylalkyl, wherein the alkyl, cycloalkyl, alkyl, arylalkyl, heteroarylalkyl and heterocyclylalkyl portions are optionally substituted with one or more groups independently selected from halogen, hydroxyl, cyano, nitro, azido, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, 3-C6 cycloalkyl, C3-C6 heterocycloalkyl, -NR6R7 and -OR8; and R12a and R12 are independently selected from hydrogen, C1-C10 alkyl, C2-C3 alkenyl, aryl or arylalkyl, or R1 a and R1"13 together with the atom to which they are attached form a carbocyclic, heteroaryl or heterocyclic ring from 4 to 10 members
13. A compound having Formula VIIIa-1 and salts and solvates thereof, characterized in that Z is -CAOAR1, -C (= 0) NR6R7, CN, -C (= 0) H, or , or a portion that can be transformed into any of the Z groups; R 1 is hydrogen, C 1 -C 6 alkyl, C 2 -C 10 alkenyl, C 2 -C 8 alkynyl, C 3 -C 10 cycloalkyl, C 3 -C 10 cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl , trialkylsilyl or dialkylarylsilyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl portions are optionally substituted with one or more groups independently selected from halogen, hydroxyl, C 1 -C 4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl and C3-C6 heterocycloalkyl; R 2 and R 2a are independently hydrogen, C 1 -C 10 alkyl, C 2 -C 0 alkenyl, C 2 -C 8 alkynyl, benzyl, allyl, arylalkyl, trialkylsilyl, dialkylarylsilyl, COR 6, -C (0) OR 6 or -C (0) NR6R7, wherein the alkyl, alkenyl, alkynyl, benzyl, allyl and arylalkyl portions are optionally substituted with one or more groups independently selected from halogen, hydroxyl, C1-C4 alkyl, C2-C4 alkenyl and C2 alkynyl -C4; X5 is H, F, Cl, Br, I or C? -C6 alkyl; R6 and R7 are independently hydrogen, trifluoromethyl, -OR8, alkyl of A-Cio, alkenyl of C2-C? Or, alkynyl of C2-C? Or, cycloalkyl of C3-C10, cycloalkylalkyl of C3-C10, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl, or R6 and R7 together with the atom to which they are attached form a heteroaryl or heterocyclic ring of 4 to 10 members, wherein the heteroaryl and heterocyclic rings they are optionally substituted with one or more groups independently selected from halogen, trifluoromethyl or, difluoromethoxy, trifluoromethoxy and 0R !; R8 is hydrogen, alkyl, C2-Cio alkenyl, aplo or arylalkyl, wherein the alkyl, alkenyl, aplo and arylalkyl portions are optionally substituted with one or more groups independently selected from OH, -0- (alkyl) C? -C10) and -0- (Ci-Cio alkenyl); R10 is hydrogen, alkyl of A-Cio, cycloalkylalkyl of C3-C? 0, aplaxyl, heteroarylalkyl or heterocyclylalkyl, wherein the alkyl, cycloalkylalkyl, arylalkyl, heteroarylalkyl and heterocyclylalkyl portions are optionally substituted with one or more groups independently selected from halogen, hydroxyl, cyano, nitro, azido, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 3 -C 6 cycloalkyl, C 3 -C 6 heterocycloalkyl, -NR 6 R 7 and -OR 8; and R12a and R12 are independently selected from hydrogen, C? -C10 alkyl, C2-C? alkenyl, C2-C? alkynyl, C3-C10 cycloalkyl, C3-C10 cycloalkylalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl, or R12a and R12 together with the atom to which they are attached form a carbocyclic, heteroaryl or heterocyclic ring of 4 to 10 members.
14. A compound that has Formula VI characterized because: Z is -C (= 0) OR1, -C (= 0) NR6R7, CN, -C (= 0) H, or , or a portion that can be transformed into any of the Z groups; A is N3 or NR2R2; B is N3 or NR2bR2c; R 1 is hydrogen, C 1 -C 0 alkyl, C 2 -C y alkenyl, C 2 -C 8 alkynyl, C 3 -C 10 cycloalkyl, C 3 -C 10 cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, trialkylsilyl or dialkylarylsilyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl portions are optionally substituted with one or more groups independently selected from halogen, hydroxyl, C 1 -C 4 alkyl, alkenyl C2-C4, C2-C4 alkynyl, C3-Ce cycloalkyl and C3-C6 heterocycloalkyl; R2 and R2 are independently hydrogen, C1-C10 alkyl, C2-C? Alkenyl, C2-C alqu alkynyl, benzyl, halo, arylalkyl, trialkylsilyl, dialkylarylsilyl, COR6, -C (0) OR6 or -C (0) NR6R7, wherein the alkyl, alkenyl, alkynyl, benzyl, aryl and arylalkyl portions are optionally substituted with one or more groups independently selected from halogen, hydroxyl, C? -C4 alkyl, C2-C4 alkenyl and alkynyl of C2-C4, - R 2a and R 2c are independently hydrogen, C 1 -C 10 alkyl, C -C 8 alkenyl, C 2 -C 8 alkynyl, benzyl, halo, arylalkyl, trialkylsilyl, dialkylaryl silyl, COR 6, -C (0) OR 6, - C (0) NR6R7, -OR1 or -NHR1, wherein the alkyl, alkenyl, alkyl, benzyl, allyl and arylalkyl portions are optionally substituted with one or more groups independently selected from halogen, hydroxyl, C1-C4 alkyl, alkenyl C2-C4 and C2_C4 alkynyl; X5 is H, F, Cl, Br, I, or C? -C6 alkyl; R and R are independently hydrogen, trifluoromethyl, -OR8, C? -C10 alkyl, C2-C? Alkenyl, C2-C? Alkyl, C3-C10 cycloalkyl, C3-C10 cycloalkylalkyl, aryl, arylalkyl , heteroaryl, heteroaryl, L-alkyl, heterocyclyl, heterocyclyl, or R6 and R7 together with the atom to which they are attached form a heteroaryl or heterocyclic ring of 4 to 10. members, wherein the heteroaryl and heterocyclic rings are optionally substituted with one or more groups independently selected from halogen, trifluoromethyl, difluoromethoxy, trifluoromethoxy and OR8; R8 is hydrogen, Ci-Cio alkyl, C2-C? Alkenyl, aryl or arylalkyl, wherein the alkyl, alkenyl, aryl and arylalkyl are optionally substituted with one or more groups independently selected from OH, -0- (alkyl) of A-CA and R12a and R12b are independently selected from hydrogen, Ci-Cio alkyl, C2-C? alkenyl, aryl or arylalkyl, or R12a and R12b together with the atom to which they are attached form a carbocyclic ring, heteroaryl or heterocyclic from 4 to 10 members
15. A compound having Formula XIb-1 -1 character because Z is -C (-C (= 0) NR6R7, CN, -C (= 0) H, or or a portion that can be transformed into any of the Z groups; R 1 is hydrogen, C 1 -C 10 alkyl, C 2 -C 6 alkenyl, C 2 -C 10 alkyl, C 3 -C 10 cycloalkyl, C 3 -C 10 cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, trialkylsilyl or dialkylarylsilyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl portions are optionally substituted with one or more groups independently selected from halogen, hydroxyl, C 1 -C 4 alkyl, alkenyl of C2-C4, C2-C4 alkynyl, C3-C6 cycloalkyl and C3-C6 heterocycloalkyl; R 2 and R 2c are independently hydrogen, C 1 -C 0 alkyl, C 2 -C 0 alkenyl, C 2 -C 8 alkynyl, benzyl, halo, arylalkyl, trialkylsilyl, dialkylalkyl, COR 6, -C (0 ) OR6 or -C (0) NR6R7, wherein the alkyl, alkenyl, alkynyl, benzyl, alAo and arylalkyl portions are optionally substituted with one or more groups independently selected from halogen, hydroxyl, CX-C4 alkyl, C2 alkenyl C4 and C2-C alkynyl ,; R2 is C? -C10 alkyl, C2-C? 0 alkenyl, C2-C10 alkynyl, benzyl, aryl, arylalkyl, trialkylsilyl, dialkylarylsilyl, -COR6, -C (0) OR6 or C (0) NR6R7, wherein the alkyl, alkenyl, alkynyl, benzyl, aryl and arylalkyl portions are optionally substituted with one or more groups independently selected from halogen, hydroxyl, C 1 -C 4 alkyl, C 2 -C 4 alkenyl and C 2 -C 4 alkynyl; X5 is H, F, Cl, Br, I or C? -C6 alkyl; R6 and R7 are independently hydrogen, trifluoromethyl, -OR8, alkyl of A-C10, alkenyl of C2-C or, alkynyl of C2-C? Or, cycloalkyl of C3-C10, cycloalkylalkyl of C3-C10, aryl, arylalkyl, heteroaryl , heteroarylalkyl, heterocyclyl or heterocyclylalkyl, or R ° and R together with the atom to which they are attached form a heteroaryl or heterocyclic ring of 4 to 10 members, wherein the heteroaryl and heterocyclic rings are optionally substituted with one or more groups independently selected from halogen, trifluoromethyl, difluoromethoxy, trifluoromethoxy and OR8; R8 is hydrogen, alkyl of A-C10, alkenyl of C2-C10, aryl or arylalkyl, wherein the alkyl, alkenyl, aplo and arylalkyl are optionally substituted with one or more groups independently selected from OH, -0- (C1 alkyl) -C10) and -0- (C1-C10 alkenyl); and R1_a and R1_b are independently selected from hydrogen, Ci-Cio alkyl, C2-C? alkenyl, aryl or arylalkyl, or R12a and R12 together with the atom to which they are attached form a carbocyclic, heteroaryl or heterocyclic ring of 4 to 10 members.
16. A compound of Formula III characterized in that: A is N3 or NR2R2a; Z is -C (= 0) ORx, -C (= 0) NR6R7, CN, -C (D) H, or , or a portion that can be transformed into any of the Z groups; X3 is F, Cl, Br, I, N0 or a sulfonate ester; X5 is H, F, Cl, Br, I or C? -C6 alkyl; R1 is hydrogen, alkyl of A-Ao, C2-C2 alkenyl, C2-C10 alkynyl, C3-C3 cycloalkyl, C3-C6 cycloalkylalkyl, aryl, aplakyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, trialkylsilyl or dialkylarylsilyl, wherein the portions alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl are optionally substituted with one or more groups independently selected from halogen, hydroxyl, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, alkynyl, C2-C4, C3-C6 cycloalkyl and C3-C6 heterocycloalkyl; R 2 is hydrogen, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 8 alkynyl, arylalkyl, trialkylsilyl, dialkylarylsilyl, -COR 6, -C (0) OR 6 or -C (0) NR 6 R 7, wherein alkyl, alkenyl, alkynyl and arylalkyl portions are optionally substituted with one or more groups independently selected from halogen, hydroxyl, C 1 -C 4 alkyl, C 2 -C 4 alkenyl and C 2 - C 4 alkynyl; R 2a is hydrogen, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 8 alkynyl, benzyl, allyl, arylalkyl, trialkylsilyl, dialkylarylsilyl, -COR 6, -C (0) OR 6, C (0) NR 6 R 7, -OR1 or -NHR1, wherein the alkyl, alkenyl, alkynyl, benzyl, allyl and arylalkyl portions are optionally substituted with one or more groups independently selected from halogen, hydroxyl, C? -C4 alkyl, C2-C4 alkenyl and alkynyl of C2-C4; R and R are independently hydrogen, trifluoromethyl, -OR8, C1-C10 alkyl, C2-C10 alkenyl, C2-C20 alkynyl, C3-C10 cycloalkyl, cycloalkylalkyl of C3-C10, aryl, aplaxyl, heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl, or R6 and R7 together with the atom to which they are attached form a heteroaryl or heterocyclic ring of 4 to 10 members, wherein the heteroaryl and heterocyclic rings are optionally substituted with one or more groups independently selected from halogen, trifluoromethyl, difluoromethoxy, t-trifluoromethoxy and OR8; R 8 is hydrogen, C 1 -C 0 alkyl, C 2 -C 0 alkenyl, aryl or arylalkyl, wherein the alkyl, alkenyl, aryl and arylalkyl are optionally substituted with one or more groups independently selected from OH, -0- (C 1 -C 10 alkyl) and -0- (C 1 -C 10 alkenyl); R10 is hydrogen, alkyl of A-C10, cycloalkylalkyl of C3-C10, aplaxyl, heteroaplalkyl or heterocyclylalkyl or, wherein the alkyl, cycloalkylalkyl, arylalkyl, heteroanlalkyl, and heterocyclylalkyl portions optionally substituted with one or more groups independently selected from halogen, hydroxyl , cyano, nitro, azido, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, -NR6R7 and -OR8; and R 1 a and R 1 '13 are independently selected from hydrogen, C 1 -C 10 alkyl, C 2 -C 0 alkenyl, C 2 -C 8 alkynyl, C 3 -C 10 cycloalkyl, C 3 -C 10 cycloalkylalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl, or R12a and R12 together with the atom to which they are attached form a carbocyclic, heteroaryl or heterocyclic ring of 4 to 10 members.
17. The use of a compound according to any of claims 12, 13, 14, 15 or 16, characterized in that it is in the manufacture of the heterocyclic compounds.
18. A method for preparing a compound of Formula XIb-1 characterized in that: Z is -C (= 0) OR1, -C (= 0) NR6R7, CN, -C (= 0) H, or , or a portion that can be transformed into any of the Z groups; R 1 is hydrogen, C 1 -C 6 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 10 cycloalkyl, C 3 -C 10 cycloalkyl, aplo, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclyl Quilo trialkylsilyl or dialkylarylsilyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroaryl, heterocyclyl, and heterocyclylalkyl portions are optionally substituted with one or more groups independently selected from halogen, hydroxyl, C? C4, C2-C4 alkenyl, C2-C4 alkynyl, C3-A cycloalkyl and C3-C5 heterocycloalkyl; R 2 is C 1 -C 10 alkyl, C 2 -C 6 alkenyl, C 2 -C 10 alkynyl, benzyl, halo, arylalkyl, trialkylsilyl, dialkylarylsilyl, -COR 6, -C (0) OR 6 or C (0) NR 6 R 7, wherein the alkyl, alkenyl, alkyl, benzyl, aryl and arylalkyl portions are optionally substituted with one or more groups independently selected from halogen, hydroxyl, C 1 -C 4 alkyl, C 2 -C 4 alkenyl and C 2 -C 4 alkynyl; R 2 and R 2c are independently hydrogen, C 1 -C 10 alkyl, C 2 -C 0 alkenyl, C 2 -C 8 alkynyl, benzyl, halo, aplakyl, tr to L-alkylsilo 1, dialkylarylsilyl, COR 6, -C (0 ) OR6 or -C (0) NR6R7, wherein the alkyl, alkenyl, alkynyl, benzyl, aryl and arylalkyl moieties are optionally substituted with one or more groups independently selected from halogen, hydroxyl, C 1 -C 4 alkyl, C 2 alkenyl -C4 and C2-Cj alkynyl; X5 is H, F, Cl, Br, I or C? -C6 alkyl; R6 and R7 are independently hydrogen, trifluoromethyl, -OR8, C1-C10 alkyl, C2-C2 alkenyl, C2-C6 alkyl, C3-C10 cycloalkyl, cycloalkyl C3-C3 alkyl, , arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl, or R and R together with the atom to which they are attached form a heteroaryl or heterocyclic ring of 4 to 10 members, wherein the heteroaryl and heterocyclic rings are optionally substituted with one or more groups independently selected from halogen, trifluoromethyl, difluoromethoxy, trifluoromethoxy and OR8; R8 is hydrogen, alkyl of A-Cio, C2-C10 alkenyl, aryl or arylalkyl, wherein alkyl, alkenyl, aplo and arylalkyl are optionally substituted with one or more groups independently selected from OH, -0- (C-alkyl) -C10) and -O- (C? -C10 alkenyl); and R1a and R12b are independently selected from hydrogen, C1-C10alkyl, C2-C2alkenyl, aryl or arylalkyl, or R12a and R12b together with the atom to which they are attached form a carbocyclic, heteroaryl or heterocyclic 4-ring. to 10 members, the method comprising: (a) providing a compound of Formula VIIb-1 where R ~ a is hydrogen; and (b) reacting the compound of Formula VIIb-1 with (i) formic acid, optionally in the presence of an additional acid, (ii) a formic acid derivative in the presence of an acid, or (iii) two or more equivalents of formaldehyde or a formaldehyde derivative in the presence of an acid, to provide the compound of Formula XIb-1.
19. A method for preparing a compound of Formula Ib-1 lc-1 characterized in that: Z is -C (= 0) OR1, -C (= 0) NR6R7, CN, -C (= 0)) H, or , or a portion that can be transformed into any of the Z groups; R 1 is hydrogen, C 1 -C 6 alkyl, C 2 alkenyl Cι, C2-C? Alkyl, C3-C10 cycloalkyl, C3-C10 cycloalkylalkyl, aryl, arylalkyl, heterolalkyl, heteroacylalkyl, heterocyclyl, heterocyclylalkyl, trialkylsilyl or dialkylarylsilyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, Cycloalkylalkyl, aplo, aplakyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclic are optionally substituted with one or more groups independently selected from halogen, hydroxyl, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, cycloalkyl of C -C6 and C3-C6 heterocycloalkyl; R 2 is C 1 -C 10 alkyl, C 2 -C 6 alkenyl, 2-C 1 alkyls, benzyl, allyl, arylalkyl, trialkylsilyl, dialqua laplsyl IOL, -COR 6, -C (0) OR 6 or C (0) NR6R7, wherein the alkyl, alkenyl, alkynyl, benZlo, aryl and arylalkyl portions are optionally substituted with one or more groups independently selected from halogen, hydroxyl, C1-C4 alkyl, C2-C4 alkenyl and C2-C4 alkynyl; R 2b is hydrogen, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 0 alkyl, benzyl, aryl, arylalkyl, trialkylsilyl, di a 1-alkylsilyl, -COR 6, -C (0) OR 6 or C ( 0) NR6R7, wherein the alkyl, alkenyl, alkyl, benzyl, alane and arylalkyl portions are optionally substituted with one or more groups independently selected from halogen, hydroxyl, C 1 -C 4 alkyl, C 2 -C 4 alkenyl and C 2 -C 4 alkynyl; X1 and X2 are independently selected from hydrogen, F, Cl, Br, I, OR8, alkyl of A-C10, alkenyl of C2-C? Or, alkynyl of C2-C? 0, cycloalkyl of C3-C10, cycloalkylalkyl of C3 -C10 and C1-C10 thioalkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl thioalkyl portions are optionally substituted with one or more groups independently selected from oxo, halogen, cyano, n-tr, trifluoromethyl, difluoromethoxy, trifluoromethoxy and azido; X5 is H, F, Cl, Br, I or C? -C6 alkyl; R 6 and R 7 are independently hydrogen, trifluoromethyl, -OR 8, C 1 -C 10 alkyl, C 2 -C 0 alkenyl, C 2 -C 0 alkyl, C 3 -C 10 cycloalkyl, C 3 -C 10 cycloalkyl, aryl, lalkyl, heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl, or R6 and R7 together with the atom to which they are attached form a heteroaryl or heterocyclic ring of 4 to 10 members, wherein the heteroaryl and heterocyclic rings are optionally substituted with one or more groups independently selected from halogen, trifluoromethyl, difluoromethoxy, trifluoromethoxy and OR8; R 8 is hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, aryl or arylalkyl, wherein the alkyl, alkenyl, aryl and arylalkyl are optionally substituted with one or more groups independently selected from OH, -0- (alkyl of A-CA and -0- (alkenyl of y-CA, and R12a and R12b are independently selected from hydrogen, Ci-Cio alkyl, C2-C10 alkenyl, aryl or arylalkyl, or R12a and R1b together with the atom to which they are attached form a carbocyclic, heteroaryl or heterocyclic ring of 4 to 10 members, the method comprising: (a) providing a compound of Formula VIIb-1 wherein Ra and Rc are hydrogen; (b) reacting the compound of Formula VIb-1 with (i) formic acid optionally in the presence of an additional acid, (ii) a formic acid derivative in the presence of an acid, or (iii) two or more equivalents of formaldehyde or a formaldehyde derivative in the presence of an acid, to provide a compound of Formula XIb-1 XI b-1 (c) coupling the compound of Formula XIb-1 with a reagent that has the Formula wherein X is F, Cl, Br, I, -OSO2CF3, alkyl sulfonate, aryl sulfonate, alkylaryl sulfonate, -B (OR8) 2, -BF3 or -BAR1) 2, optionally either (i) at temperature elevated and optionally in the presence of a base; or (ii) in the presence of a metal-based catalyst and a base, to provide the compound of Formula Ib-1.
20. A process for preparing a compound of Formula Ia-1 Ia-1 and salts and solvates thereof, characterized in that: Z is -CC = 0) OR1; R1 is C1-C10 alkyl; R 2 is hydrogen, C 1 -C 10 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, arylalkyl, trialkylsilyl, dialkylarylsilyl, -COR 6, -C (0) OR 5 or -C (0) NR 6 R 7, wherein the alkyl, alkenyl, alkyl or arylalkyl portions are optionally substituted with one or more groups independently selected from halogen, hydroxyl, C 1 -C 4 alkyl, C 2 -C 4 alkenyl and C 2 -C 4 alkynyl; X1 and X2 are independently selected from hydrogen, F, Cl, Br, I, OR8, y-Cioalkyl, C2-C6alkynyl, C2-Calkylalkyl, C3-C10cycloalkyl, cycloalkylalkyl of C3-C10 and C?-C10 thioalkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl and thioalkyl portions are optionally substituted with one or more groups independently selected from oxo, halogen, cyano, nitro, azido, trifluoromethyl, difluoromethoxy and tri fluoromethoxy; X5 is H, F, Cl, Br, 1 or C? -C6 alkyl; R6 and R7 are independently hydrogen, trifluoromethyl, -OR8, y-Cio alkyl, C2-C? Alkenyl, C2-C? Alkyl or C3-C10 cycloalkyl, C3-C10 cycloalkyl, aplo, aplakyl, heteroacyl, heteroaplalkyl, heterocyclyl or heterocyclylalkyl, or R6 and R7 together with the atom to which they are attached form a heteroaryl or heterocyclic ring of 4 to 10 members, wherein the hetero-halo and heterocyclic are optionally substituted with one or more groups independently selected from halogen, tnfluoromethyl, difluoromethoxy, trifluoromethoxy and OR8; R8 is hydrogen, C1-C10alkyl, C2-C2alkenyl, aryl or arylalkyl, wherein the alkyl, alkenyl, aryl and arylalkyl are optionally substituted with one or more groups independently selected from OH, -0- (alkyl of C? -C? 0) and 0- (alken? lo of Ci-Cio); and R 10 is hydrogen, C 1 -C 0 alkyl, C 3 -C 0 cycloalkylalkyl, aplakyl, heteroarylalkyl or heterocyclylalkyl, wherein the alkyl, cycloalkylalkyl, aplakyl, heteroarylalkyl and heterocyclylalkyl portions are optionally substituted with one or more independently selected groups halogen, hydroxyl, cyano, nitro, azido, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 3 -C 6 cycloalkyl, C 3 -C 6 heterocycloalkyl, -NR 6 R 7 and -OR 8; the method comprising: i) nitrating a compound having the Formula wherein X3 and X4 are independently F, Cl, Br, I, or a sulfonate ester to provide a compound of Formula II II ii) reacting the compound of the Formula II with a compound of the formula RAH, to form the corresponding ester having the formula iii) reacting the ester with two or more equivalents of a reactant that generates ammonia to form a compound of Formula VI-11 V-ll: A = NR R2a wherein R, 2a is hydrogen; iv) reducing the compound of Formula VI-11 to provide a compound of Formula V Ia-1 v) cyclizing the compound of Formula VIIa-1 to provide a compound of Formula VIIIa-1 VIOa-1 vi) coupling the compound of Formula VIIIa-1 with a reagent having the Formula wherein X6 is F, Cl, Br, I, -OS02CF3, alkyl sulfonate, aryl sulfonate, alkylaryl sulfonate, -B (OR8) 2, -BF3 or -BAR1) 2 to provide the compound of Formula Ia- 1.
21. A process for preparing a compound of Formula Ia-1 Ia-1 and salts and solvates thereof, characterized in that: R1 is hydrogen, C? -C? alkyl, C2-C10 alkenyl, C2-C? alkynyl, C3-C10 cycloalkyl, C3-C10 cycloalkylalkyl, aryl , aplaxyl, heteroaryl, heteroacylalkyl, heterocyclyl, heterocyclylalkyl, trialkylsilyl or L-alkylaryl day, wherein the alkyl, alkenyl, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclyalkyl portions are optionally substituted with one or more groups independently selected from halogen, hydroxyl, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkyl, C3-Cg cycloalkyl and C3-C6 heterocycloalkyl; R2 is hydrogen, alkyl of A-C10, alkenyl of C2-Cio, alkynyl of C2-C10, arylalkyl, tpalqui-silyl, dialkylarylsilyl, -COR6, -C (0) OR6 or -C (0) NR6R7, wherein the alkyl, alkenyl, alkynyl or arylalkyl portions are optionally substituted with one or more groups independently selected from halogen, hydroxyl, C 1 -C 4 alkyl, C 2 -C 4 alkenyl and C 2 -C 4 alkyl; X1 and X2 are independently selected from hydrogen, F, Cl, Br, I, OR8, alkyl of A-C10, alkenyl of C2-C10, alkynyl of C2-C? Or, cycloalkyl of C3-C10, cycloalkylalkyl of C3-C10 and C1-C10 thioalkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl and thioalkyl are optionally substituted with one or more groups independently selected from oxo, halogen, cyano, nitro, azido, trifluoromethyl, difluoromethoxa and trafloromethoxy; X5 is H, F, Cl, Br, I or C? -C6 alkyl; R6 and R7 are independently hydrogen, trifluoromethyl or, -OR8, alkyl of A-Cio, alkenyl of C2-C10, alkylic of C2-C? Or, cycloalkyl of C3-C10, cycloalkylalkyl of C3-C10, aplo, aplalquilo, heteroaryl , heteroarylalkyl, heterocyclyl or heterocyclylalkyl, or Rd and R7 together with the atom to which they are attached form a heteroacyl or heterocyclic ring of 4 to 10 members, wherein the heteroaryl and heterocyclic rings are optionally substituted with one or more groups independently selected from halogen , trifluoromethyl, difluoromethoxy, trifluoromethoxy and OR8; or R is hydrogen, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, aryl or arylalkyl, wherein the alkyl, alkenyl, aryl and arylalkyl are optionally substituted with one or more groups independently selected from OH, -0- (alkyl C1-C10) and 0- (alkenyl of A-CA and R10 is hydrogen, alkyl of A-Cio, cycloalkyl C3-C10 alkyl, arylalkyl, heteroarylalkyl or heterocyclylalkyl, wherein the alkyl, cycloalkylalkyl, arylalkyl, heteroarylalkyl Y heterocyclylalkyl are optionally substituted with one or more groups independently selected from halogen, hydroxyl, cyano, nitro, azido, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 3 -C 6 cycloaicyl, C 3 heterocycloalkyl -C6, -NR6R7 and -OR8; the method comprising: coupling a compound of Formula VIIIa-1, VIIIa-1 where R, ¿2da is hydrogen, with a reagent that has Formula X X wherein X6 is F, Cl, Br, I, -OS02CF3, alkyl sulfonate, aryl sulfonate, alkylaryl sulfonate, - B (0-R8) 2, -BF3 or -Bi (R1) 2, in the presence of a catalyst based on suitable metal and a base in a suitable solvent.
22. The compound according to claim 12 or 13, characterized in that Z is -C (= 0) NR6R7, wherein Rβ is -OR8, R7 is H and R8 is - (CH2) 2-OH.
23. The compound according to claim 12 or 13, characterized in that Z e -COOR1 and R1 is C? -C? 0 alkyl.
24. The compound according to claim 23, characterized in that R1 is methyl.