MXPA06005807A - Substituted 1h-pyrrolo[3,2-b, 3,2-c, and 2,3-c]pyridine-2-carboxamides and related analogs as inhibitors of casein kinase i epsilon - Google Patents

Abstract

The present invention discloses and claims substituted 1H-pyrrolo[3,2-b]pyridine-2-carboxamides, 1H-pyrrolo[3,2-c]pyridine-2-carboxamides and 1H-pyrrolo[2,3-c]pyridine-2-carboxamides (compounds of formula (I)) as inhibitors of human casein kinase I Epsilon, and methods of using said compounds of formula (I) for treating central nervous system diseases and disorders including mood disorders and sleep disorders. Pharmaceutical compositions comprising compounds of formula (I) and methods for the preparation of compounds of formula (I) are also disclosed and claimed.

Description

1H-PIRROL? R3.2-b, 3,2-c, and 2,3-c1PIRIDIN-2-CARBOXAMIDAS SUBSTITUTED AND ANALOGUE RELATED AS INHIBITORS OF CASEINA QUINASA BACKGROUND OF THE INVENTION 1. FIELD OF THE INVENTION This present invention relates to a series of 1 H-pyrrolo [3,2-b] pyridine-2-carboxamides, 1 H-pyrrolo [3,2-c] pyridine-2-carboxamides and 1 H- pyrro-lo [2,3-c] pyridine-2-carboxamides substituted. More specifically the invention relates to 1 H-pyrrolo [3,2-b] pyridine-2-carboxamides, 1 H-pyrrolo [3,2-c] pyridine-2-carboxamides and 1 H-pyrrolo [2,3-c] ] pyridine-2-carboxamides substituted with 3-arylthio and 3-heterocyclothio and related analogues. The invention also relates to processes for preparing these compounds. The compounds of the invention are inhibitors of the phosphorylation activity of human casein kinase and therefore are useful as pharmaceutical agents, especially in the treatment and / or prevention of diseases and disorders associated with the central nervous system. 2. Description of the technique Many organisms present rhythmic variations of behavior, from unicellular organisms to human beings. When the rhythm persists under constant conditions and has a period of approximately one day, depending little on the temperature, the rhythm is called "circadian" (Konopka, RJ and Benzer, S. (1971) Proc. Nat. Acad. Sci. USA 68, 2112-2116). Circadian rhythms are generated by endogenous biological pacemakers (circadian clocks) and are present in most living organisms including humans, fungi, insects and bacteria (Dunlap, JC (1999) Cell 96, 271-290; Hastings, JW et al., circadian rhythms, The Physiology of Biological Timing, in: Prosser, CL editors, Neural and Integrative Animal Physiology, New York: Wiley-Liss (1991) 435-546, Aliada, R. et al. (1998) Cell 93, 791-804; Kondo et al. (1994) Science 266, 1233-1236; Crosthwaite, SK et al. (1997) Science 276, 763-769; Shearman, LP et al. (1997) Neuron, 19, 1261-1269 ). Circadian rhythms are self-sustaining and constant even in conditions of total darkness, but can be synchronized (adjusted) to a new day / night pattern by environmental cues such as light and temperature cycles (Pittendrigh, CS (1993) Annu. Rev. Physioi., 55, 16-54; Takahashi, JS (1995) Annu., Rev. Neurosci 18, 531-553; Albrecht, U. et al. (1997) Cell, 91, 1055-1064). Circadian clocks are essential to maintain biological rhythms and regulate a variety of circadian behaviors such as daily fluctuations of behavior, food intake and sleep / wake cycle, as well as physiological changes such as hormonal secretion and fluctuations in body temperature ( Hastings, M. (1997) Trends Neurosci 20, 459-464; Reppert, SM and Weaver, DR (1997) Cell 89, 487-490). Genetic and molecular studies in the fly of the vinegar Drosophila melanogaster led to the elucidation of some of the genes involved in the circadian rhythm. These studies led to the recognition of a closely self-regulatory pathway composed of a negative transcription / translation feedback loop (Dunlap, JC (1999) Cell, 96, 271-290; Dunlap, JC (1996) Annu. Genet 30, 579-601; Hall, JC (1996) Neuron, 17, 799-802). The main elements of the circadian oscillator in Drosophila consist of two stimulator proteins dCLOCK / dBMAL (CYCLE) and two inhibitor proteins dPERlOD (dPER) and dTIMELESS (dTIM). dCLOCK and dBMAL form a heterodimer giving rise to the transcription factor dCLOCK / dBMAL that promotes the expression of two genes called Drosophila Period (dper) and Drosophila Timeless (dtim). Finally, the mRNAs of these genes are transcribed providing the dPER and dTIM proteins, respectively. For several hours, the protein products dPER and dTIM are synthesized and phosphorylated in the cytoplasm, reach a critical level and form heterodimers that are translocated to the interior of the nucleus. Once in the core dPER and dTIM function as negative regulators of their own transcription, the accumulation of dPER and dTIM decreases and the activation of dper and dtim begins again by dCLOCK dBMAL (Zylka, MJ et al. (1998) Neuron 20, 1103-1110; Lowrey, P.L. and you (2000) 288, 483-491). It has been shown that the dper gene is a necessary element in the control of circadian rhythms in adult hatching (the emergence of the adult fly from the pupa) in its behavior and locomotor activity (Konopka, RJ, &Benzer , S. (1971) Proc. Nati. Acad.

Sci. USA, 68, 2112-2116). Antisense mutations of the per gene may shorten (per8) or lengthen. { pei) the period of circadian rhythms, while nonsense mutations (per0) cause arrhythmia in their behaviors (Hall, J.C. (1995) Trends Neurosci., 18, 230-240). In mammals, the suprachiasmatic nuclei (SCN) of the anterior hypothalamus are the seat of a master biological clock (for a review see Panda et al., (2002) Nature 417, 329 - 335; Reppert, SM and Weaver, DR (1997). ) Cell, 89, 487-490). The clock of the SCN is adjusted to the 24-hour day by the light and dark cycle, with light acting both by direct and indirect routes from the retina to the SCN (Klein, DC et al. (1991) Suprachiasmatic Nuclei: The Mind's Clock, Oxford Univeristy Press, New York). In the SCN of rodents, three Per genes have been identified and cloned and are called Perl (mPerl), mPer2 and mouse mPer3. The protein products of these mammalian genes (mPER1, mPER2, mPER3) share several regions of homology with each other and each mammalian Per gene encodes a protein with a protein dimerization domain called PAS (PAS is the acronym of the three first proteins PER, ARNT and SIM that were observed that shared this important dimerization domain) that presents great homology with the PAS domain of the PER insects. All Per messenger RNAs (mRNAs) and protein levels oscillate during the circadian day and are intimately involved in both positive and negative regulation of the biological clock, but only mPER1 and mPER2 oscillate in response to light (Zylka, MJ and cois. (1998) Neuron 20, 1103-1110, Albrecht, U. et al., (1997) Cell 91, 1055-1064, Shearman, LP et al. (1997) Neuron 19, 1261-1269). The mammal homolog of the Drosophila tim gene was cloned and named mTim. However, no evidence of mPER-mTIM interactions analogous to those observed in Drosophila was found and it was suggested that PER-PER interactions may have replaced the function of PER-TIM dimers in the molecular functioning of the mammalian circadian clock. (Zylka, MJ et al., (1998) Neuron 21, 1115-1122). Another possibility is that the rhythms in PER1 and PER2 form a negative feedback loop that regulates the transcription activity of the Clock protein (through its PAS domains), which, in turn, directs the expression of either or both Per genes (Shearman, LP et al. (1997) Neuron 19, 1261-1269). The understanding of the roles of the three mPer genes in the machinery of the mammalian clock has been the subject of much research. The structural homology between the mPER and dPER proteins led to the expectation that the mPER proteins would function as negative elements in the feedback loop in mammals. It is believed that PER1 is involved in the negative regulation of its own transcription in the feedback loop, but recent indications suggest that it is involved in the delivery path (Hastings, MH et al. (1999) Proc. Nati. Acad. Sci. USA 26, 15211-15216). PER2 is the best characterized protein and mutant mice for mPER2 (m er2Brdm1), which lack 87 residues in the carboxylic portion of the PAS dimerization domain, have a shortened circadian cycle in normal light and dark environments, but show arrhythmia in darkness complete The mutation also decreases the oscillating expression of Peri and mPer2 in the SCNs, which indicates that mPer2 can regulate mPerl in vivo (Zheng, B. et al. (1999) Nature 400, 169-173). It has been shown that PER2 has a dual function in the regulation of the "clock" of the central clock (Shearman, L.P. et al. (2000) Science 288, 1013-1018). In that study, it was shown that PER2 binds to cryptochrome (CRY) proteins and translocates to the nucleus in which the negatively regulated transcript of CRY directs the positive transcription complexes CLOCK and BMAL1. Upon entering the nucleus, PER2 initiated the positive branch of the clock by positively regulating the transcription of BMAL1 by a mechanism not yet identified. The PER3 function is poorly understood; however, a subtle effect on circadian activity is observed in mice with non-functional mPer3 gene and therefore it has been suggested that PER3 is involved in the circadian controlled exit routes (Shearman, LP et al. (2000) Mol Cell Biol. 17, 6269-6275). It has been reported that mPER proteins interact with each other and that mPER3 can serve as a transporter of mPER1 and mPER2 to carry them to the nucleus, which is critical for the generation of circadian signals in SCNs (Kume, K. and cois. (1999) Cell 98, 193-205; Takano, A. et al. (2000), FEBS Letters, 477, 106-112). It has been postulated that the phosphorylation of the components of the circadian clock regulates the duration of the cycle. The first genetic clue that a specific protein kinase regulates the circadian rhythm of Drosophila was the discovery of the novel doubletime gene (dbt), which encodes a serine / threonine protein kinase (Price JL et al. (1998) Cell 94, 83- 95; Kloss B. et al. (1998) Cell 94, 97-107). The antisense mutations in dbt produce an altered circadian rhythm. The null alleles of dbt produce the hypophosphorylation of dPER and arrhythmia. The mammalian kinases most similar to DBT are casein kinase le (CKle) and casein kinase [d] (CKI <5). Both kinases have been shown to bind to mPER1 and several studies have shown that CKle phosphorylates both mouse and human PER1 (Price JL et al. (1998) Cell 94, 83-95; Kloss B. et al. (1998) Cell 94, 97-107). In a study with 293T embryonic kidney cells cotransfected with wild-type hCKIe, hPERI demonstrated a significant increase in phosphorylation (evidenced by a change in molecular mass). In this study, phosphorylated hPER1 had a half-life of approximately twelve hours while unphosphorylated hPER1 remained stable in the cell for more than 24 hours, suggesting that phosphorylation of hPER1 causes a decrease in protein stability (Kessler , GA et al. (2000) NeuroReport, 11, 951-955). Another study also demonstrated that the consequence of the phosphorylation of PER1 by hCKIe includes cytoplasmic retention, translocation to the nucleus and protein instability (Vielhaber, E. et al. (2000) Mol. Cell. Biol. 13, 4888-4899; Takano; , A. et al. (2000) FEBS Letters 477, 106-112). There has been no biochemical reason to choose between CKle or CKld as a potential regulator in mammals until Lowery et al. [(2000) Science 288, 483-491] observed that in the Syrian golden hamster, semidominant mutations in CKle (Mutation tau, Ralph, MR and Menaker, M. (1988) Science 241, 1225-1227) caused a circadian day shortened in heterozygous animals (22 hours) and homozygotes (20 hours). In this case, reduced levels of CKle activity caused a lower phosphorylation of PER presumably with higher levels of cytoplasmic PER protein that produced an enhanced nuclear input and altered circadian cycles. More recently, it has been suggested that CKI < 5 may also be involved in the regulation of circadian rhythm by posttranslational modification of mammalian clock proteins hPER1 and hPER2 [Camacho, F. et al., (2001) FEBS Letters 489 (2,3), 159-165]. In this way, the small molecule inhibitors of CKle and / or CKI¿ > they provide a novel means of altering the circadian rhythm. As described below, altered circadian rhythm may find utility in the treatment of sleep or mood disorders. U.S. Patent 6,555,328 B1 discloses selection methods in cells to identify compounds that alter circadian rhythms based on an experimental compound that alters the ability of human casein kinase 1e and / or human casein kinase to phosphorylate clock proteins Human hPER1, hPER2 and hPER3. For example, HEK293T cells are cotransfected with hCKIe and Perl or Per2. In order to evaluate the relevance of inhibition of CKle and CKle inhibitors in circadian biology, a high throughput cell assay was developed (33rd Annual Meeting, Soc. for Neurosci., November 8-12, 2003, Numbers of abstracts 284.1, 284.2, and 284.3) in which the circadian rhythm could be routinely monitored . The assay consists of Rat-1 fibroblasts expressing a Mper1-luc construct stably, thus allowing the determination of the rhythmic activation of the Mperi promoter in living cells by repeatedly estimating the luciferase activity by controlling the light production during several days. The repeated measurement format of the assay allows the exact and reproducible evaluation of the concentration-dependent effects of CKle inhibitors on the circadian rhythm and provides the link to relate CKle inhibition with the alteration of the circadian period. Sleep disorders have been classified into four main categories that include primary sleep disorders (disomnios and parasomnios), sleep disorders associated with medical / psychiatric disorders and a category of sleep disorders proposed for sleep disorders that can not be classified due to sleep disorders. insufficient data. It is believed that primary sleep disorders arise from abnormalities in the intrinsic systems responsible for the generation of sleep and wakefulness (homeostatic system) or synchronization (circadian system). Disomnios are disorders in the onset or maintenance of sleep and include primary insomnia, hypersomnia (excessive sleepiness), narcolepsy, sleep disorder related to breathing, sleep disturbance due to circadian rhythm and unspecified disomnios. Primary insomnia is characterized by persistence (>1 month) of the difficulty of initiating and maintaining sleep or non-restorative sleep. Sleep difficulties associated with primary insomnia produce significant fatigue or disability, including irritability during the day, loss of attention and concentration, fatigue and discomfort, and deterioration of mood and motivation. Sleep disorders related to circadian rhythm include jet lag syndrome, shift sleep disorder at work, advanced phase sleep syndrome and late phase sleep syndrome (J. Wagner, ML Wagner and WA Hening, Annals of Pharmacotherapy (1998) 32, 680-691). Individuals who undergo a paradigm of forced sleep demonstrate greater wakefulness, in percentage of sleep time, at certain periods of the circadian day (Dijk and Lockley, J. Appl. Physioi. (2002) 92, 852-862). It has generally been accepted that with advancing age our circadian rhythm for sleep and often produces a lower quality sleep (Am J Physiol Endocrinol Metab. (2002) 282, E297-E303). In this way, the dream that takes place outside the circadian phase can suffer in qualitative and quantitative terms, as they further exemplify sleep disturbances due to changes in work shift and jet lag. Alterations of the human circadian clock may cause sleep disturbances and agents that modulate the circadian rhythm, such as a CKle inhibitor and / or CKI, may be useful for the treatment of sleep disorders and in particular sleep disorders related to the circadian rhythm. Mood disorders are divided into depressive disorders ("unipolar depression"), bipolar disorders and two disorders based on the etiology that include mood disorder due to a general medical condition and substance-induced mood disorder. Depressive disorders are subclassified into major depressive disorder, dysthymic disorder and unspecified depressive disorder. Bipolar disorders are subclassified into bipolar I disorder and bipolar II disorder. It has been observed that the "seasonal pattern" specification can be applied to major depressive disorders that are recurrent and to the pattern of major depressive episodes in bipolar I disorder and bipolar II disorder. Prominent anergy, hypersomnia, excessive food intake, weight gain and uncontrolled desire for carbohydrates often characterize major depressive episodes that occur with a seasonal pattern. It is not clear if a seasonal pattern is more likely in a major depressive disorder that is recurrent or in bipolar disorders. However, within bipolar disorders, a seasonal pattern appears to be more likely in bipolar II than in bipolar I disorder. In some individuals, the onset of manic or hypomanic episodes may also be linked to a particular season. The seasonal winter pattern seems to vary with latitude, age and sex. The frequency increases in higher latitudes, younger people have a higher risk of winter depressive episodes and women comprise 60% to 90% of people with a seasonal pattern. Seasonal affective disorder (SAD), a term commonly used in the literature, is a subtype of mood disorders in the Diagnostic and Statistical Manual of Mental Disorders IV (DSM-IV) (American Psychiatric Association: "Diagnostic and Statistical Manual of Mental Disorders, "Fourth Edition, Revision of the Text, Washington, DC, American Psychiatrics Association, 2000) the expression" seasonal pattern "is used when describing a seasonal pattern of major depressive episodes in bipolar I disorder, bipolar II disorder or recurrent major depressive disorder (EM Tam et al., Can. J. Psychiatry (1995) 40, 457-466). The characteristics and diagnoses of depressive disorders, major depressive disorder, major depressive episode, bipolar I disorder, bipolar disorder 11 and seasonal effects are described in DSM-IV. It has been shown that patients suffering from major depressive disorders, including SAD that is characterized by recurrent depressive episodes, typically in winter, respond positively to phototherapy (Kripke, Journal of Affective Disorders (1998) 49 (2), 109-117) . The success of bright light treatment for patients with SAD and major depression led to the hypothesis of several hypotheses to explain the mechanism of action underlying the therapeutic effect of light. These hypotheses included the "circadian rhythm hypothesis" which suggests that the antidepressant effect of bright light could be associated with a change in the phases of the circadian pacemaker with respect to sleep (EM Tam et al., Can J. Psychiatry (1995). ) 40, 457-466). Supporting the relationship between phototherapy and circadian rhythm, clinically effective phototherapy in major depressive disorders causes a concomitant change in the circadian phase and the clinical effectiveness of phototherapy seems to depend on the ability of phototherapy to change phases (Czeisler and cois., The Journal of Physiology (2000) 526 (Part 3), 683-694; Terman et al., Arch. Gen. Psychiatry (2001) 58, 69-75). Furthermore, it has been shown that phototherapy accelerates and increases the effectiveness of pharmacological treatment of major depressive disorders (Benedetti et al., J. Clin. Psychiatry (2003) 64, 648-653). Thus, it would be expected that the inhibition of casein kinase le and / or casein kinase would cause a change in the circadian phases and said inhibition represents a potential clinically effective monotherapy or polytherapy for mood disorders. It should be emphasized that sleep disturbance is a criterion symptom of many psychiatric disorders (W.V. McCall, J. Clin. Psychiatry (2001) 62 (supl.10), 27-32). Sleep disturbances are a common feature of depressive disorders and insomnia is the sleep disorder that is frequently reported in depression, which occurs in more than 90% of depressed patients (ME Thase, J. Clin. Psychiatry ( 1999) 60 (suppl 17), 28-31). Increasing indications support a common pathogenesis for primary insomnia and major depressive disorder. It has been hypothesized that the hyperactivity of corticotropin-releasing factor (CRF) (due to genetic predisposition or possibly early stress) and stress induce a process that causes exaggerated and dilated sleep disturbances over time and, eventually, primary insomnia. The characteristic of circadian rhythmicity in the secretion of CRF under stress-free conditions may play a role in the normal expression of sleep and wakefulness (GS Richardson and T. Roth, J. Clin Psychiatry (2001) 62 (Suppl 10), 39- Four. Five). Thus, agents that modulate the circadian rhythm, for example by inhibiting casein kinase le and / or casein kinase δ, may be useful for the treatment of depressive disorders due to effects on CRF secretion. All references cited above are incorporated herein by reference in their entirety. Thus, it is an object of this invention to provide a series of 1 H-pyrrolo [3,2-b] pyridine-2-carboxamides, 1 H-pyrrolo [3,2-c] pyridine-2-carboxamides and 1 H - substituted pyrrolo [2,3-c] pyridine-2-carboxamides which are inhibitors of casein kinase le. This object and other objects of this invention will be apparent from the following detailed description of the invention. SUMMARY OF THE INVENTION The present invention provides 1 H-pyrrolo [3,2-b] pyridine-2-carboxamides, 1 H-pyrrolo [3,2-c] pyridine-2-carboxamides, 1 H-pyrrolo [2,3 -c] substituted pyridine-2-carboxamides and related analogs, and their pharmaceutically acceptable salts or stereoisomers, of the formula (I) as inhibitors of human casein kinase phosphorylation activity and to methods for using the compounds of the formula (I) ) for the treatment of diseases and disorders of the central nervous system, such as for example mood disorders which include major depressive disorder, bipolar I disorder and bipolar II disorder and sleep disorders which include sleep disorders related to circadian rhythm such as for example shift sleep at work, jet lag syndrome, advanced phase of sleep syndrome and late phase sleep syndrome. Accordingly, a broad embodiment of the invention relates to a compound of the formula (I) wherein: R-i is H or C 1-6 alkyl; R2 is NR5R6; R3 is aryl or heterocycle; R is H, C-? 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, CF 3, halogen, SH, S-C 1-6 alkyl, NO 2, NH 2 or NR 5 R 6; R5 is H or C-? -6 alkyl; R6 is H or C6-C6 alkyl; X is S or S (0) n; one of K, L or M is N and the other two members of K, L or M are each C in which R4 is attached only to K, L, M or to another ring atom that is C; m is 1, 2 or 3; and n is 1 or 2; or a pharmaceutically acceptable salt or stereoisomer thereof. One embodiment of the present invention relates to a pharmaceutical composition comprising a pharmaceutical carrier and a therapeutically effective amount of a compound of the formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof. Another embodiment of the present invention relates to a method for inhibiting casein kinase, by administering to a patient a therapeutically effective amount of a compound of the formula (I). Another embodiment of the present invention relates to a method of treating a patient suffering from a disease or disorder that is improved by the inhibition of casein kinase which comprises administering to said patient a therapeutically effective amount of a compound of the formula (I) . Another embodiment of the present invention relates to a process for preparing a compound of the formula (I). A further embodiment of the present invention relates to a compound of the formula (I) prepared by a process of this invention as described herein. DETAILED DESCRIPTION OF THE INVENTION As used herein, 'stereoisomer' is a general term that is used for all isomers of individual molecules that differ only in the orientation of their atoms in space. The term stereoisomer includes mirror isomers (enantiomers), mixtures of the mirror isomers (racemates, racemic mixtures), geometric isomers (cis / trans or E / Z) and isomers of compounds with more than one chiral center that are not mirror images and one of the other (diastereoisomers). As used herein, 'R' and 'S' are used as they are commonly used in organic chemistry to denote the specific configuration of a chiral center. The term 'R' (rectus) refers to the configuration of a chiral center with a clockwise relation between the priorities of the groups (from the largest to the smallest) when viewed from the link to the group with the lowest priority. The term 'S' (sinister) refers to the configuration of a chiral center with a counter-clockwise relationship between the priorities of the groups (from the largest to the second smallest) when viewed from the link towards the group with the lowest priority. The priority of the groups is based on sequence rules in which the priority is based first on the atomic number (in order of decreasing atomic number). In Stereochemistry of Organic Compounds, Ernest L. Eliel, Samuel H. Wilen and Lewis N. Mander, editors, Wiley-lnterscience, John Wiley & Sons, Inc., New York, 1994 is a list and description of priorities. In addition to the (R) - (S) system, the more archaic D-L system may also be used herein to denote the absolute configuration, especially in reference to amino acids. In this system a formula according to the Fischer projection is oriented so that the carbon number 1 of the main chain is at the top. The prefix 'D' is used to represent the absolute configuration of the isomer in which the functional group (determinant) is to the right of the carbon of the chiral center and 'L' of the isomer in which it is on the left. As used herein, "tautomer" or "Tautomerism" refers to the coexistence of two (or more) compounds that differ from each other only in the position of one (or more) mobile atoms and in the distribution of electrons, for example, tautomers or tautomerism of ketoenol. As used herein, "alkyl" means a straight or branched saturated aliphatic chain hydrocarbon group having from one to six carbon atoms and includes methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tere -butyl and similar groups. As used herein "alkenyl" means a linear or branched monovalent nonsaturated aliphatic chain having from two to six carbon atoms and includes ethenium (also known as vinyl), 1-methyletenyl, 1-methyl-1 -propenyl, 1-butenyl, 1-hexenyl, 2-methyl-2-propenyl, 2,4-hexadienyl, 1-propenyl, 2-propenyl, 2-butenyl, 2-pentenyl and similar groups. As used herein "alkynyl" means a linear or branched monovalent nonsaturated aliphatic chain having from two to six carbon atoms with at least one triple bond and includes ethynyl, 1-propynyl, 1-butynyl, 1-hexynyl, 2-propynyl, 2-butynyl, 2-pentynyl and similar groups. As used herein, "alkoxy" means a monovalent substituent consisting of a linear or branched alkyl chain having from one to six carbon atoms bonded through an ether oxygen atom and having its free valence bond in ether oxygen and includes methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, tert-butoxy and similar groups. As used herein the term "cycloalkyl" C3-C8 means a saturated hydrocarbon ring structure containing from three to eight carbon atoms and includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. As used herein, "aryl" or "Ar" means any stable monocyclic, bicyclic or tricyclic carbon ring of up to seven members in each ring, wherein at least one ring is aromatic and is unsubstituted or is substituted with from one to three substituents which are selected from the group consisting of methylenedioxy, hydroxy, C-? 6 -alkoxy, halogen, C-? 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, trifluoromethyl, trifluoromethoxy, -N02, -NH2, -NH (C? -6 alkyl), -N (C1-6 alkyl) 2, -NH-acyl, and -N (C? -6) alkyl acyl. Examples of "aryl" or "Ar" include phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-aminophenyl, 3-aminophenyl, 4-aminophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2- nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 2,4-dichlorophenyl, 2,3-dichlorophenyl, 3,5-dimethylphenyl, 2-trifluoromethoxyphenyl, 3-trifluoromethoxyphenyl, 4-trifluoromethoxyphenyl, naphthyl, tetrahydronaphthyl and biphenyl. The term "aryl- (C 1-6 alkyl)" includes 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, phenyimethyl (benzyl), phenylethyl, p-methoxybenzyl, p-fluorobenzyl and p-chlorobenzyl. As used herein, the term "acyl" means saturated aliphatic hydrocarbon groups of both branched and straight chain having from one to six carbon atoms attached to a carbonyl moiety and includes acetyl, propionyl, butyryl, isobutyryl, and similar. As used herein, "heterocycle" or "heterocyclic" means a stable monocyclic 5- to 7-membered heterocyclic ring or a stable 8 to 11 membered bicyclic ring which is saturated or unsaturated and which is formed by carbon atoms and from one to three heteroatoms selected from the group which consists of N, O and S and in which the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatom may optionally be quatemized and which includes any bicyclic group in which any of the heterocyclic rings defined above is fused with a benzene ring. The heterocyclic ring can be attached to any heteroatom or carbon atom that causes the creation of a stable structure. The heterocyclic ring may be unsubstituted or substituted with from one to three substituents selected from the group consisting of C 1 --6 alkoxy, hydroxy, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, trifluoromethyl, trifluoromethoxy, -N02, -NH2, -NH (Ci-β alkyl), -N (C 1-6 alkyl) 2, -NH-aciio, and -N (alkyl Citale) Examples of such heterocyclic elements include piperidinyl, piperazinyl , 2-oxopiperazinyl, 2-oxopiperidinium, 2-oxopyrrolidinyl, 2-oxoazepinyl, acepinyl, pyrrolyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl thiazolyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, quinolinyl, isoquinoliniio, benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, benzoxazolyl, furyl, tetrahydrofuryl, benzofuranyl, tetrahydropyranyl, thienyl, benzothienyl, thiamorpholinyl, and oxadiazolyl. As used herein, "halogen", "hal" or "halo" means a member of the family of fluorine, chlorine, bromine or iodine. When any variable (eg, aryl, heterocycle, R f R2, R3, R, etc.) appears more than once in any constituent or in a compound of formula (I) of this invention, its definition each time it appears it is independent of its definition each of the other times it appears. Also, combinations of substituents and / or variables are allowed only if such combinations produce stable compounds. Tai as used herein, 'treating,' treating 'or' treatment 'means: (i) preventing the onset of a disease, disorder or condition in a patient who may be predisposed to the disease, disorder and / or condition, but not yet diagnosed as having it; (ii) inhibit a disease, disorder or condition, that is, stop its development; and (iii) alleviating a disease, disorder or condition, i.e., causing the regression of the disease, disorder and / or condition. As used herein, the term "patient" means a warm-blooded animal such as a mammal suffering from a particular disease, disorder or condition. It is explicitly understood that guinea pigs, dogs, cats, rats, mice, horses, cattle, sheep and humans are examples of animals within the scope of the meaning of the term. As used herein, "disease" means an ailment or malaise or an interruption, cessation or disorder of bodily functions, systems or organs. As used herein, "disorder" means an alteration of a function, structure or both caused by a genetic or embryological failure in development or by exogenous factors such as poison, injury or disease. As used herein, "condition" refers to a state of being, health or fitness. As used herein, 'prophylaxis' means the prevention of disease. As used herein, the term "sleep disorder", "sleep disorders" or "sleep disturbance" means insomnia. As used herein, the term "insomnia" means the inability to sleep in the absence of external impediments such as noise, bright light, etc., during the period in which sleep should normally occur and the inability to sleep. Sleep can vary in degree from agitation or altered slumber to a shortening of normal sleep duration or an absolute wakefulness. The term 'insomnia' includes primary insomnia, insomnia related to a mental disorder, insomnia induced by substances and insomnia due to the circadian rm ie insomnia due to a change in the normal schedule of sleep and wakefulness (shift changes, sleep disturbance by change of shifts, jet lag or jet lag syndrome, etc.). As used herein the term 'primary insomnia' means difficulty to initiate sleep, to maintain sleep or to conciliate a restful sleep that is not caused by a mental disorder nor is it due to physiological effects by taking or leaving of taking certain substances (insomnia induced by substances). As used herein the term 'sleep disorder due to circadian rm' includes jet lag or jet lag syndrome, shift shift sleep disorder, late phase sleep syndrome and late phase sleep syndrome. As used herein the term 'effective amount of inhibition of a compound' or 'effective amount of inhibition of casein kinase' of a compound 'means the sufficient amount of a compound that is made bioavailable via the route of appropriate administration to treat a patient suffering from the disease, disorder or condition that can be treated with such treatment. As used herein, the term "a therapeutically effective amount" means an amount of a compound that is effective to treat the named disease, disorder or condition. As used herein, the term "pharmaceutically acceptable salt" is intended to be applied to any salt, whether known previously or discovered in the future, used by a person skilled in the art who is an addition salt organic or non-toxic inorganic that is suitable for use as a drug. Illustrative bases which form suitable salts include alkali metal or alkaline earth metal hydroxides such as sodium, potassium, calcium, magnesium hydroxides; ammonia and cyclic or aromatic aliphatic amines such as methylamine, dimethylamine, triethylamine, diethylamine, isopropyldiethylamine, pyridine and picoline. Illustrative acids which form suitable salts include inorganic acids such as, for example, hydrochloric, hydrobromic, sulfuric, phosphoric acids and the like and organic carboxylic acids such as, for example, acetic, propionic, glycolic, lactic, pyruvic, malonic, succinic, fumaric , mellic, tartaric, citric, ascorbic, maleic, hydroximic and dihydroxymethic, benzoic, phenylacetic, 4-aminobenzoic, 4-hydroxybenzoic, anthranilic, cinnamic, salicylic, 4-aminosalicylic, 2-phenoxybenzoic, 2-acetoxybenzoic, mandelic and the like and acids organic sulfonic acids such as methanesulfonic and p-toluenesulfonic. As used herein, "Pharmaceutical vehicle" refers to pharmaceutical excipients known to be useful in the formulation of pharmaceutically active compounds for administration and which are substantially non-toxic and do not cause sensitization under the conditions of use. The exact proportion of these excipients is determined by the solubility and chemical properties of the active compound, the chosen route of administration as well as standard pharmaceutical practice. In practicing the methods of this invention, the active ingredient is preferably incorporated into a composition containing a pharmaceutical carrier, although the compounds are effective and can be administered alone. Having said that, the proportion of active ingredient may vary from about 1% to about 90% by weight.

Additional abbreviations that may appear in this patent application will have the following meanings: Me (methyl), Et (ethyl), Ph (phenyl), Et3N (triethylamine), p-TsOH (para-toluenesulfonic acid), TsCI (para -toluenesulfonyl), hept (heptane), DMF (dimethylformamide), NMP (1-methyl-2-pyrrolidinone or N-methyl-2-pyrrolidinone), IPA (isopropanol or isopropyl alcohol), TFA (trifluoroacetic acid), DBU ( 1, 8-diazabicyclo [5.4.0] undec-7-ene), DBN (1, 5-diazabicyclo [4.3.0] non-5-ene), ta o ta (room temperature), min or min. (minutes), h (hour or hours), UV (ultraviolet), EMCL (mass spectrometry by liquid chromatography), t-Boc or Boc (tert-butoxycarbonyl), Bn (benzyl), t-Bu (tertiary butyl), i-Pr (isopropyl), HOAc (acetic acid), EtOAc (ethyl acetate), Et20 (diethyl ether), EtOH (ethanol), g (gram), mg (milligram), μg (microgram), ng (nanogram), mi (milliliter), μl (microliter), L (liter), HPLC (high performance liquid chromatography), TLC, Tic or tic (thin layer chromatography), g / L (grams per liter), Si02 (silica gel) ), L / minute (liters per minute), ml / minute (milliliters per minute), mmol (millimole), M (molar), mM (millimolar), μM (micromolar), nM (nanomolar), // Ci (microCurie ), CPM (pulses per minute), rpm (revolutions per minute), mm (millimeter), μm (micrometer), μ (miera), nm (nanometer), ppm (parts per million), psi (pounds per square inch) , eq. or equiv. (equivalent), Rt (retention time), ° C (degrees Celsius) and K (Kelvin). Accordingly, a broad embodiment of the invention relates to a compound of the formula (I) wherein R-i is H or C-? 6 alkyl; R2 is NR5R6; R3 is aryl or heterocycle; R4 is H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-6 alkoxy, CF3, halogen, SH, S-C-? -6 alkyl, NO2, NH2 or NRsRβ; R5 is H or C1-6 alkyl; RG is H or C1-6 alkyl; X is S or S (O) n; one of K, L or M is N and the other two members of K, L or M are each C, where R4 is attached only to K, L, M or to another ring atom that is C; m is 1, 2 or 3; and n is 1 or 2. One embodiment of this invention relates to compounds wherein L is N, and K and M are each C. A further embodiment of this invention relates to compounds wherein L is N, K and M are each C, Ri, R4, R5 and Re are each H, and R3 is aryl. The following compounds are representative examples within the scope of this embodiment: 3-phenylsulfanyl-1H-pyrrolo [3,2-c] pyridine-2-carboxylic acid amide, 3- (3-fluorophenylsulfanyl-1H-) acid amide pyrrolo [3,2-c] pyridine-2-carboxylic acid and 3- (4-chlorophenylsulfanyl-1 H -pyrrolo [3,2-c] pyridine-2-carboxylic acid amide.

Another embodiment of this invention relates to compounds wherein M is N, and K and L are each C. A further embodiment of this invention relates to compounds wherein M is N, K and L are each C, Ri, R4, R5 and RT are each H, and R3 is aryl or heterocycle. The following compounds are representative examples within the scope of this embodiment: 3-phenylsulfanyl-1 H -pyrrolo [2,3-c] pyridin-2-carboxylic acid amide, 3- (3-fluorophenylsulfanyl) amide ) -1 H -pyrrolo [2,3-c] pyridine-2-carboxylic acid, 3- (3-methoxyphenylsulfanyl) -1 H -pyrrolo [2,3-c] pyridin-2-carboxylic acid amide , 3- (3-chlorophenylsulfanii) -1 H -pyrrolo [2,3-c] pyridine-2-carboxylic acid amide, 3- (2-trifluoromethylphenylsulfani) -1 H -pyrroic acid amide [2,3-c] ] pyridine-2-carboxylic acid, 3- (2-trifluoromethoxyphenylsulfanyl) -1 H -pyrrolo [2,3-c] pyridin-2-carboxylic acid amide, 3- (2-aminide) -methoxyphenylsulfanyl) -1Hrrrolo [2,3-c] pyridine-2-carboxylic acid, and 3- (pyridine-2-sulfanyl) -1H-pyrrolo [2,3-c] pyridine- 2-carboxylic acid Another embodiment of this invention relates to compounds wherein K is N and L and M are each C. A further embodiment of this invention relates to compounds wherein K is N, L and M are each C, Ri is C-? -6 alkyl, R5 is H, Rd is H or C? -6 alkyl, and R3 is aryl. The following compounds are representative examples within the scope of this embodiment: 1-methyl-3-phenylsulfanyl-1 H -pyrrolo [3,2-b] pyridine-2-carboxylic acid methylamide, 1-methyl-3-amide phenylsulfanyl-1 H -pyrrolo [3,2-b] pyridine-2-carboxylic acid, and 3-phenylsulfanyl-1-propyl-1 H -pyrrolo [3,2-b] pyridine-2-carboxylic acid amide. A further embodiment of this invention relates to compounds wherein K is N, L and M are each C, R-i, R4 and R5 are each H, R3 is aryl and R6 is C1-6 alkyl. The following compounds are representative examples within the scope of this embodiment: 3- (3-trifluoromethyloxyphenylsuifanyl-1H-pyrrolo [3,2-b] pyridine-2-carboxylic acid methylamide, 3- (3-chlorophenylsulfanyl-1-methylamide Hr¡rrolo [3,2-b] pyridine-2-carboxylic acid, 3- (3-fluorophenylsulfanyl-1 H -pyrrolo [3,2-b] pyridine-2-carboxylic acid methylamide, and 3-phenylsulfanyl-methylamide -1 H -pyrrolo [3,2-b] pyridine-2-carboxylic acid.

A further embodiment of this invention relates to compounds wherein K is N, L and M are each C, R-i, R4, R5 and Re are each H and R3 is heterocycle. The following compounds are representative examples within the scope of this embodiment: 3- (quinolin-8-ylsulfanyl) -1 H -pyrrolo [3,2-b] pyridine-2-carboxylic acid amide, 3- (pyridine) amide -2-sulfanyl) -1 H -pyrrolo [3,2-b] pyridine-2-carboxylic acid, 3- (pyridine-4-sulfanyl) -1 H -pyrrolo [3,2-b] pyridin-3-amide -carboxylic acid amide of 3- (thiophen-2-ylsulfanyl) -1H-pyrrolo [3,2-b] pyridine-2-carboxylic acid. A further embodiment of this invention relates to compounds wherein K is N, L and M are each C, R-i, R5 and Re are each H and R3 is aryl. The following compounds are representative examples within the scope of this embodiment: 3-phenylsulfanyl-1 H -pyrrolo [3,2-b] pyridine-2-carboxylic acid amide, 3- (3-fluorophenylsulfanyl) -1 H acid amide -pyrrolo [3,2-b] pyridine-2-carboxylic acid, 3- (3-chlorophenylsulfanyl) -1 H -pyrrolo [3,2-b] pyridine-2-carboxylic acid amide, 3- (3-amide -bromophenylsufanyl) -1 H -pyrrolo [3,2-b] pyridine-2-carboxylic acid, 3- (2-chlorophenylsulfanyl) -1 H -pyrrolo [3,2-b] pyridine-2-carboxylic acid amide , 3- (4-chlorophenylsulfanyl) -1 H -pyrrolo [3,2-b] pyridine-2-carboxylic acid amide, 3- (2,4-dichlorophenylsulfanyl) -1 H -pyrrolo [3,2] -b] pyridine-2-carboxylic acid, 3- (2-fluorophenylsulfanyl) -1H-pyrrolo [3,2-b] pyridine-2-carboxylic acid amide, 3- (2,3-dichlorophenylsulfanyl) amide ) -1 H -pyrrolo [3,2-b] pyridine-2-carboxylic acid, 3- (2-trifluoromethylphenylsulfanyl) -1 H -pyrrolo [3,2-b] pyridine-2-carboxylic acid amide, acid amide 3- (3-trifluoromethylphenylsu lffil) -1 H-pyrro! or [3, 2-b] pyridine-2-carboxylic acid, 3- (2-aminophenylsulfanyl) -1H-pyrrolo [3,2-b] pyridine-2-carboxylic acid amide, 3- (2,5-dichlorophenylsulfanyl) -amide -1 H -pyrrolo [3,2-b] pyridine-2-carboxylic acid, 3- (2-methoxyphenylsulfanyl) -1 H -pyrrolo [3,2-b] pyridine-2-carboxylic acid amide, 3- (3-methoxyphenylsulfanyl) -1 H -pyrrolo [3,2-b] pyridine-2-carboxylic acid, 3- (3-aminophenylsulfanyl) -1 H -pyrrolo [3,2-b] pyridine- 2-carboxylic acid 3- (4-nitrophenyl sulfanyl) -1 H -pyrrolo [3,2-b] pyridine-2-carboxylic acid amide 3- (3-nitrophenylsulfanyl) -1 H- pyrrolo [3,2-b] pyridine-2-carboxylic acid, 3-o-tolylsulfanyl-1 H-pyrrolo [3,2-b] pyridine-2-carboxylic acid amide, 3-p-tolylsulfanyl acid amide -1 H-pyrroyl [3,2-b] pyridine-2-carboxylic acid, 3- (3,5-dimethylphenylsulfanyl) -1 H -pyrrolo [3,2-b] pyridine-2-carboxylic acid amide, 3-m-tolylsulfanyl-1 H -pyrrolo [3,2-b] pyridine-2-carboxylic acid, 3- (2-ethylphenylsulfanyl) -amide -1 H -pyrrolo [3,2-b] pyridine-2-carboxylic acid, 3- (3-trifluoromethoxyphenylsulfanyl) -1 H -pyrrolo [3,2-b] pyridine-2-carboxylic acid amide, 3-carboxylic acid amide - (3-fluorophenylisulfanyl) -5-methoxy-1 H -pyrrolo [3,2-b] pyridine-2-carboxylic acid, and 3- (3-methoxyphenylsulfanyl) -5-methoxy-1 H -pyrroloamide [3] , 2-b] pyridine-2-carboxylic acid. The compounds of the present invention can be prepared by methods analogous to those known in the art. Reaction Schemes 1, 2 and 3 and the corresponding descriptive text describe the preparation of the various compounds of the invention. The methods and examples described are provided by way of illustration and in no way limit the scope of the present invention. Alternative reactants and reaction conditions and other combinations and permutations of the steps described herein to arrive at the individual compounds are readily apparent to one of ordinary skill in the art. Tables 1, 2 and 3 provide summaries of the exemplary compounds and Table 4 summarizes biological data for exemplary compounds of the invention.

CHEMICAL SYNTHESIS Scheme 1 Scheme 1 Scheme 1 describes a synthesis of the compounds of this invention from commercially available 2-chloro-3-nitropyridine (1a-1 in which K is N and L and M are each C), 3-chloro- 4-nitropyridine (1b-1 in which L is N and K and M are each C) or 4-chloro-3-nitropyridine (1c-1 in which M is N and K and L are each C), or an optionally substituted chloronitropyridine 1.

The first digit of the number of a compound refers to the number of the corresponding compound or structure as shown in any of Schemes 1-3, for example, the first digit 1 in 1a-1 refers to the compound or structure 1 in Scheme 1. The subsequent designation with the letters "a", "b" or "c" identifies a compound as a precursor or member of the 1 H-pyrrolo [3,2-b] pyridine-2-carboxamide series ("a" , also known as the 4-azaindole series), the series of 1H-pyrrolo [3,2-c] pyridine-2-carboxamide ("b", also known as the 5-azaindole series) and the series of 1 H-pyrrolo [2,3-c] pyridine-2-carboxamide ("c", also known as the 6-azaindole series), respectively. The digit or digits after the hyphen in a number of a compound identify the specific compound in that series of structures. When a compound is uniquely identified by a number, the number refers to the corresponding compound or structure as shown in any one of Schemes 1-3 and it is understood that the description generally includes the three series of structures identified by "a" , '"b" and "c" as described above. In Scheme 1, step a, chloronitropyridine 1 is added in portions to an alkali metal salt of a malonic acid diester in an excess of malonic diester, such as for example the sodium, potassium or lithium salt of the malonic acid diester. in an excess of the malonic acid diester, such as for example diethyl malonate or dimethyl malonate, at a temperature of about 50 ° C to about 70 ° C. The alkali metal salt of the malonic acid diester can be prepared, for example, by adding an alkali metal, such as for example sodium metal, to an excess of the malonic acid diester as is known to one skilled in the art. After about three hours from about 50 ° C to about 70 ° C, the mixture is allowed to stand at room temperature for about 12 to about 24 hours. If the reaction is incomplete, the mixture is heated to about 80 ° C from about 2 hours to about 4 hours, then concentrated to remove excess diester of malonic acid and then treated with a concentrated mineral acid such as for example acid hydrochloric or sulfuric acid and water. The mixture is heated from about 100 ° C to about 110 ° C from about 5 hours to about 9 hours to effect decarboxylation. After standing for about 12 to about 24 hours at room temperature the mixture is washed with a suitable solvent, such as for example ethyl ether and ethyl acetate, basified from about pH 8 to about pH 9 with an alkali metal hydroxide, such as, for example, sodium hydroxide or potassium hydroxide and extracted with a suitable organic solvent, such as, for example, ethyl acetate. The organic extract is filtered and concentrated under reduced pressure to provide the desired methylnitropyridine 2. The preparation of 2 by this process of "step a" is called "two-step synthesis and a vessel". Alternatively, in Scheme 1, step a, methylnitropyridine 2 can be prepared by Suzuki coupling of 1 with methylboronic acid. Thus, a mixture of chloronitropyridine 1, methylboronic acid, potassium carbonate and tetrakis (triphenylphosphine) palladium (0) [Pd (PPh 3) 4] in a suitable aprotic solvent, such as for example dioxane, is heated to about 110 ° C at about 120 ° C from about 12 hours to about 16 hours. The reaction mixture is cooled to room temperature, concentrate and purify by chromatography to give methiinitropyridine 2. Advantageously it has now been observed that compound 2 can also be prepared in a two-stage vessel according to Scheme 1, step a. Accordingly, to a polar solvent, such as for example dimethylformamide or N-methyl-2-pyrrolidinone, from about 2 to about 2.5 equivalents of a base, such as for example potassium t-butoxide, sodium ethoxide, hydride, are added. Sodium, sodium t-butoxide or sodium hexamethyldisilazide, at a temperature of about 16 ° C and stirring for about 30 minutes. The mixture is then treated with from about one to about four equivalents of a malonic acid diester, such as, for example, malonate, at a temperature of about 20 ° C to about 35 ° C. After about 20 minutes, the mixture is treated from about 29 ° C to about 44 ° C with a solution of about one equivalent of compound 1 and a polar solvent such as for example dimethylformamide or N-methylpyrrolidone. The mixture is heated to about 50 ° C until the reaction is complete, as indicated by HPLC analysis or other chromatographic analysis as is known to one skilled in the art. Most advantageously, compound 1 is condensed with approximately 2.0 equivalents of malonate in which N-methyl-2-pyrrolidinone is the preferred solvent, wherein from about 2.2 to about 2.5 equivalents of t- Sodium butoxide is the preferred base and in which the order of additions, temperatures and reaction times described above are employed for this part of the most advantageous synthesis in "one vessel, two stages" (step a) of compound 2. When the reaction is completed, the mixture is treated with a mineral acid and water, preferably about 4.2 equivalents of 6 M sulfuric acid, at about 100 ° C for about 12 hours to effect decarboxylation. The reaction is quenched with ice water and extracted with a suitable solvent such as toluene to provide compound 2. Synthesis of compound 2a-1 (2-methyl-3-nitropyridine) by this advantageous "step a" process as a result a surprisingly significant reduction of the reaction time (approximately 2 hours compared to about 3 days) for the condensation of 1a-1 with diethyl malonate and provided 2a-1 with a significantly improved overall yield (approximately 80% compared to 30- 68%) and significantly improved purity (>96%) without the need for chromatographic purification. The process is advantageously reproducible with respect to yield and isolated purity. This process, also advantageously, avoids the use of sodium metal and relatively expensive reagents such as for example tetrakis (triphenylphosphine) palladium (0) which would be necessary for the preparation of compound 2 by other methods described above. As shown in Scheme 1, step b, the ethyl ester of 2-hydroxy-3- (nitropyridinyl) acrylic acid 3 can be prepared by treating methylnitropyridine 2 with a suitable base, such as for example sodium ethoxide, ethoxide lithium, lithium t-butoxide, sodium t-butoxide, potassium t-butoxide or lithium hexamethyldisilazide, in a suitable solvent, such as for example ethanol or t-butanol, and then treating the reaction mixture with an oxalate diester such such as, for example, dimethyl oxalate or diethyl oxalate at room temperature and allowing the reaction mixture to stand for about 12 hours to about 48 hours at room temperature. The reaction mixture is then treated with a mineral acid, such as for example hydrochloric acid or sulfuric acid, at about pH 1. The precipitate is collected by filtration, washed sequentially with a suitable solvent, such as for example ethanol and isopropyl ether, respectively, providing 2-hydroxy-3- (nitropyridinyl) acrylic acid ethyl ester 3 or its tautomeric ketoester. Advantageously it has been found that compound 3 can also be synthesized by another process according to Scheme 1, step b, by slowly adding compound 2 to a premixed solution of diethyl oxalate and a suitable base, in a suitable solvent, of about 2 ° C at about room temperature. Accordingly a suitable base such as for example sodium ethoxide, lithium ethoxide, lithium t-butoxide, sodium t-butoxide, potassium t-butoxide or lithium hexamethyldisilazide is added to a suitable solvent such as for example tetrahydrofuran, at about 2. ° C. The mixture is stirred for about 20 minutes and then about 3 equivalents of diethyl oxalate of about -0.3 ° C to about 4 ° C are added. After about 10 minutes, a solution of about one equivalent of compound 2 and a suitable solvent, such as for example tetrahydrofuran, is added from about 4 ° C to about 9 ° C. The mixture is allowed to warm to room temperature. When the reaction has been completed, as indicated by HPLC analysis or other chromatographic analysis as is known to one skilled in the art, the reaction mixture is cooled to about 1 ° C and treated with saturated ammonium chloride solution of about 1 ° C to about 9 ° C. Compound 3 is isolated by further dilution with water and / or a cosolvent, such as for example isopropanol. Most advantageously, compound 2 is condensed with diethyl oxalate in which sodium ethoxide is the preferred base and tetrahydrofuran is the preferred solvent in the order of additions and times and reaction conditions described above. The synthesis of compound 3a-1 (2-hydroxy-3- (3-nitropyridin-2-yl) acrylic acid ethyl ester) by this more advantageous "step b" procedure resulted in a surprisingly significant reduction of reaction time (about 2 hours compared to about 2 to 3 days) and provided compound 3a-1 with significantly improved performance (approximately 88% compared to 32-68%). As shown in Scheme 1, step c, the intermediates of 1 H-pyrrolo [3,2-b] pyridine-2-carboxylic acid ester, 1 H-pyrrolo [3,2-c] p-acid ester Ridin-2-carboxylic acid or 1 H -pyrrolo [2,3-c] pyridine-2-carboxylic acid ester 4 can be prepared by catalytic or chemical reduction of the nitro group of a 2-hydroxy-3-acid ester (nitropyridine) acrylic 3 substituted appropriately, or its tautomeric ketoester, with concomitant pyrrole ring formation giving compound 4. In this way, a mixture of compound 3 and a suitable catalyst, such as for example palladium on carbon, in a suitable solvent, such as for example ethanol or methanol, is hydrogenated in a manner notorious to one skilled in the art from about one to about three hours at a pressure of about 45 psi to about 1200 psi providing, after purification, intermediate 4. Advantageously the compound 4 is prepared by this process in which absolute ethanol is the preferred solvent and palladium on carbon is the preferred catalyst. Under these conditions, an advantageously reduced catalyst loading of 10 weight percent is achieved. Alternatively, the ethyl ester of 2-hydroxy-3- (nitropyridinyl) acrylic acid 3, or its tautomeric ketoester can be chemically reduced to provide intermediate compound 4. For example, a mixture of compound 3, SnCl 2 and T¡Cl 4 in a suitable solvent, such as for example ethanol, is heated to reflux for about 4 hours providing, after purification by means of procedures well known to one skilled in the art, intermediate 4. When diethyl oxalate is used for the preparation of compound 3, the subsequent reduction of compound 3 gives intermediate 4 in the form of the ethyl ester. The ethyl ester of intermediate 4 can optionally be converted to other suitable esters by well-known transesterification procedures for one skilled in the art. As shown in Scheme 1, step d, the methyl ester 5 can be prepared by treating a methanol solution of ethyl ester 4 in the presence of a base, such as for example potassium carbonate or sodium carbonate, by heating the mixture of about 50 °. C at about 80 ° C for about one hour or until the reaction is completed, as determined by thin layer chromatography or other suitable chromatographic analysis as is known to one skilled in the art. Dilution of the reaction with water and isolation of the methyl ester 5 by filtration or extraction procedures well known to one skilled in the art provide the methyl ester 5. As shown in Scheme 1, step e, the intermediate esters 4 or 5 can be converted to amide 6 by methods known to a person skilled in the art. Thus, by treating a solution of ester 4 or 5 in a suitable polar solvent, such as for example methanol or ethanol, with ammonium hydroxide solution from about 5 N to about 7 N from about a day to about three days at room temperature At room temperature or upon heating the solution to about 55 ° C for about 10 hours, the primary amide 6 is provided after isolation by procedures well known to one skilled in the art. Alternatively, ester 4 or 5 can be suspended in a mixture of concentrated solution of ammonium hydroxide and lithium chloride at room temperature from about three to about five days until the thin-layer chromatographic analysis or other suitable chromatographic analysis as is well known for one skilled in the art, indicate that the reaction has been substantially completed. Amide 6 is isolated from the reaction mixture by procedures known to one skilled in the art. The N-C 6 -6 alkyl substituted amides are prepared by treating the azaindole ester intermediate 4 or 5 with an alkyl by procedures well known to the person skilled in the art, for example, the azaindole ester intermediate 4 or 5 can be treated. with an (C 1 -C 6 alkyl) amine, such as for example methylamine in the form of a concentrated or pure aqueous solution with excess of one (C 1 -C 6 alkyl) amine and controlling the reaction to determine that it has been completed by chromatography in thin layer or other well-known chromatographic procedures for a person skilled in the art The desired N- (C 1-6 alkyl) amide-6 is collected after diluting the reaction with water or by means of extraction procedures well known to one skilled in the art. Similar treatment of the intermediate azaindole ester 4 or 5 with a (dialkyl) cyanolamine provides the corresponding N- (dialkyl) amide 6 amide., the primary amide 6 is prepared according to Scheme 1, step e, by adding the azaindoletyl ester 4 to a solution of ammonia in methanol and heating under pressure until the reaction is complete. The use of methanol as a solvent provides significantly greater solubility of the starting material and a significantly faster reaction time. The azaindoletyl ester 4 is also transesterified under these conditions to the corresponding azaindolmethyl ester 5, but both esters 4 and 5 are converted to the desired primary amide 6 under the reaction conditions. The reaction is preferably carried out using 7 N ammonia in methanol, at a reaction temperature of about 50 ° C and an initial pressure of about 35 psi for about 49 hours. During this time the pressure in the reaction vessel drops to approximately 16 psi. The determination that the reaction is completed is performed by chromatographic analysis by HPLC or other chromatographic analysis as is known to one skilled in the art. As shown in Scheme 1, step f, the intermediate amide 6 is thioarylated at the 3-position of the pyrrole ring by procedures well-known to one skilled in the art. For example, a suspension of the intermediate amide 6 in a suitable solvent, such as for example dimethylformamide or NMP, is treated with a suitable base, such as for example sodium hydride or lithium hydride, at room temperature, followed by treatment with a suitable diaryl disulfide and then the mixture is heated from about 90 ° C to about 100 ° C from about 12 hours to about 20 hours. The progress of the reaction is monitored by thin layer chromatographic analysis or other well-known chromatographic procedures for one skilled in the art. The reaction is then concentrated, diluted with water and the desired compound of the formula (I) is isolated and purified chromatographically by procedures well known to one skilled in the art. Alternatively, a mixture of the intermediate amide 6 and about 1.5 equivalents of cesium carbonate in a suitable solvent, such as for example dimethylformamide or NMP, are treated with a suitable diaryl disulfide (approximately 1.1 equivalents) and then the mixture is heated from about 90 ° C to about 100 ° C from about 12 hours to about 20 hours. The reaction is monitored by thin layer chromatography or other known chromatographic procedures for one skilled in the art. The compound of the formula (I) is isolated and purified chromatographically by procedures well known to one skilled in the art. The compounds of the formula (I) wherein R3-X is heterocycle-S are prepared in a similar manner using suitably substituted diheterocyclic disulfide. Advantageously, a compound of the formula (I) is synthesized according to Scheme 1, step f, by adding to the preferred solvent NMP in a single portion, about 1.5 equivalents of the diaryl disulfide, about two equivalents of carbonate of cesium and about one equivalent of the amide 6. The mixture is heated to about 120 ° C for about 21 hours and the reaction is monitored by HPLC or other chromatographic procedures well-known to one skilled in the art. If it is necessary for the reaction to be completed, approximately 0.5 equivalents of cesium carbonate is optionally added and it is continuously heated for about four hours. When complete, as determined by chromatographic analysis, the reaction is cooled, quenched by pouring into water and the desired compound of the formula (!) Is isolated and purified by procedures well known to one skilled in the art. When a compound of formula (I) is prepared in this way, the reaction time surprisingly shortens significantly and the compound of formula (I) is advantageously obtained with a higher yield (85% compared to 59% ) and with sufficient purity that the additional chromatographic purification of the product is unnecessary. As shown in Scheme 1, step g, the nitrogen of the pyrrole ring of a compound of the formula (I) can be alkylated in N by treating a solution of a compound of the formula (!) in which Ri is H and a suitable solvent, such as for example 1,3-dimethyl-3,4,5,6-tetrahydro-2 (1 H) -pyrimidinone with a (dialkyl-C-6) sulfate and a suitable base, such as, for example, cesium carbonate, at room temperature from about 12 hours to about 20 hours. It is determined whether the reaction has been completed by thin layer chromatographic analysis or other well-known chromatographic procedures for one skilled in the art. When complete, the reaction mixture is diluted with water and the compound of the formula (I) wherein R-i is C-? 6 alkyl is isolated and purified by procedures well known to one skilled in the art. The nitrogen of the pyrrole ring of a compound of the formula (I) can also be alkylated by treating a pyridine solution of a compound of the formula (1) in which R ^ is H with a C1-6 alkyl halide in the presence of a suitable base such as for example cesium carbonate heating from about 0.25 hours to about 3 hours. The reaction mixture is cooled, diluted with water or concentrated to dryness and extracted with ethyl acetate. Concentration and purification by means of chromatographic procedures well known to a person skilled in the art provide the compound of the formula (1) in which Ri is C 1 - alkyl. Other methods for the N-alkylation of the pyrro ring nitrogen may be employed! of a compound of the formula (I) in which Ri is H that are well known to one skilled in the art, for example by treatment of a compound of the formula (!) in which Ri is H in a suitable polar solvent such such as for example dimethylformamide or NMP, with a suitable base, such as for example sodium hydride or potassium t-butoxide and then adding a C1-S alkyl halide such as, for example, propyl iodide. It is determined whether the reaction has been completed by thin layer chromatographic analysis or other well-known chromatographic procedures for one skilled in the art. When complete, the reaction mixture is diluted with water and the compound of the formula (I) is isolated in which R-i is C-? 6 alkyl and is purified by procedures well known to one skilled in the art.

Scheme 2 As shown in Scheme 2, the diary disulfides are prepared by treating a solution of the appropriate arylsulfide in a suitable organic solvent, such as for example methanol, with an aqueous solution of sodium perborate and letting the mixture stand at about 12 to about 24 hours at room temperature. The diaryl disulfide can be isolated and purified by procedures well known to one skilled in the art. Diheterocyclic disulfides such as for example bis (2-thienyl) disulfide are prepared in a similar manner. Scheme 3 Scheme 3 7b-l Scheme 3 describes a synthesis of 1 H-pyrrolo [3,2-c] pyridine-2-carboxylic acid methyl ester 5b-1. In Scheme 3, step h, a mixture of (3-iodo-pyridin-4-yl) -carbamic acid-1, 1-dimethylethyl ester (7b-1), 3,3-diethoxy-1-propino, a base such as Example triethylamine or Hunig's base (N, N-diisopropylethylamine), dichlorobis (triphenylphosphine) palladium (ll) and copper iodide is heated in a suitable solvent such as for example DMF dried under inert atmosphere at about 90 ° C for about three hours . The reaction mixture is cooled to about 70 ° C and treated with a suitable base such as for example 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) or 1,5-diazabicyclo [4]. , 3.0] non-5-ene (DBN), followed by stirring for about three hours at about 70 ° C and then stirring at room temperature for about twelve hours. The reaction mixture is poured into ethyl acetate, washed with water and brine and the organic phase is dried, filtered and concentrated to give 2- (diethoxymethyl) -1H-pyrrolo-1-dimethylethyl ester [3]. , 2-c] pyridin-1-carboxylic acid (8b-1) which is purified by chromatography or other procedures well known to one skilled in the art. As shown in Scheme 3, step i, hydrolysis of compound 8b-1 is carried out under acidic conditions to give 1 H-pyrrolo [3,2-c] pyridine-2-carboxaldehyde. Treatment of 8b-1 with a mineral acid such as for example hydrochloric acid for a suitable period of time such as about 20 hours at room temperature provides a mixture of 1 H-pyrrolo [3,2-c] pyridin-2. -carboxaIdehyde (9b-1) and 2-formyl-1H-pyrrolo [3,2-c] pyridine-1-carboxylic acid 1,1-dimethylethyl ester after isolating and separating by chromatography the product mixture by means of well-known procedures for a person skilled in the art. The acid hydrolysis of 1-1-dimethylethyl ester of 2-formyl-1H-pyrrolo [3,2-c] pyridin-1-carboxylic acid by refluxing it with a suitable acid such as, for example, , trifluoroacetic acid and a suitable solvent such as for example dichloromethane provides 1H-pyrrolo [3,2-c] pyridine-2-carboxaldehyde, 9b-1. As shown in Scheme 3, step j, the treatment of 1 H-pyrrolo [3,2-c] pyridine-2-carboxaldehyde (9b-1) in a suitable solvent such as methanol with sodium cyanide and manganese dioxide cooling to about 0 ° C and stirring for about five hours provides 1 H-pyrrolo [3,2-c] pyridine-2-carboxylic acid methyl ester 5b-1 after filtering, washing with water and isolating by well-known procedures for a skilled in the art. All the various embodiments of the compounds that are used in the methods of this invention as described herein can be used in the process of treating various diseases and disorders as described herein. As reflected herein, the compounds that are used in the method of this invention are capable of inhibiting the effects of casein kinase le. One embodiment of this invention provides a method for treating a mood disorder and a sleep disorder. In another embodiment of the present invention, the mood disorder may be a depressive disorder or a bipolar disorder. One modality Further of the present invention relates to the treatment of a depressive disorder in which the depressive disorder is major depressive disorder. Another embodiment of the present invention relates to the treatment of bipolar disorder in which the bipolar disorder is bipolar I disorder or bipolar II disorder. Another embodiment of the present invention relates to the treatment of a sleep disorder. A further embodiment of the present invention relates to the treatment of a sleep disorder in which the sleep disorder is a sleep disorder due to the circadian rhythm. A further embodiment of the present invention relates to the treatment of a sleep disorder due to the circadian rhythm in which the sleep disorder due to the circadian rhythm is sleep disorder by shift change, jet lag syndrome, advanced phase of sleep syndrome and late phase sleep syndrome. One skilled in the art readily appreciates that the diseases and disorders expressly mentioned herein are not intended to be limiting but rather illustrative of the efficacy of the compounds of the present invention. Thus, it should be understood that the compounds of the invention can be used to treat any disease or disorder that is improved by the inhibition of casein kinase. In another embodiment of the present invention, the pharmaceutical compositions of the compounds of the formula (I) of the invention are well-known to a person skilled in the pharmaceutical art. The carrier or excipients may be a solid, semi-solid or liquid material that can serve as a vehicle or medium for the active ingredient. Suitable carriers or excipients are well known in the art. The pharmaceutical composition can be adapted for use orally, by inhalation, parenterally or topically and can be administered to the patient in the form of tablets, capsules, suspensions, syrups, aerosols, inhalers, suppositories, salves, powders, solutions and the like. As used herein, the term "pharmaceutical carrier" means one or more excipients. As described herein, the pharmaceutical compositions of the invention provide the inhibition of casein kinase and thus are useful for the treatment of diseases or disorders that are improved by the inhibition of casein kinase in order to prepare the formulations of the compounds of the invention. In the invention, precautions must be taken to ensure the bioavailability of an effective amount of the active compound or compounds by the selected route, including the oral, parenteral and subcutaneous route. For example, effective routes of administration may include subcutaneous, intravenous, transdermal, intranasal, rectal, vaginal and the like including delivery from implants as well as injection of the active ingredient and / or composition directly into the tissue. For oral administration, the compounds can be formulated in solid or liquid preparations with or without inert diluents or edible carriers, such as capsules, pills, tablets, pills, powders, solutions, suspensions or emulsions. Capsules, pills, tablets, troches and the like may also contain one or more of the following adjuvants: binders such as microcrystalline cellulose, tragacanth; excipients such as starch or lactose, disintegrating agents such as alginic acid, corn starch and the like; lubricants such as stearic acid, magnesium stearate or Sterotex®, (Stokely-Van Camp Inc., Indinapolis, Indiana) glidants such as colloidal silicon dioxide; sweetening agents such as sucrose or saccharin; and flavoring agents such as peppermint, methyl salicylate or fruit flavoring. When the dosage form is a capsule, it may also contain a tai liquid vehicle such as polyethylene glycol or a fatty oil. The materials used must be pharmaceutically pure and non-toxic in the amounts in which they are used. Alternatively, the pharmaceutical compositions may be prepared in a manner suitable for prolonged release by providing a therapeutic amount of a compound of the formula (I) of the invention in a suitable form once a day, twice a week or a once a month using well-known procedures for a person skilled in the art. For example, an erodible polymer containing the active ingredient can be provided. For parenteral administration, the compound can be administered in the form of injectable doses of a solution or suspension of the compound in a physiologically acceptable diluent with a pharmaceutical carrier which can be a sterile liquid such as water in oil or without the addition of a surfactant or other pharmaceutically acceptable excipients. Illustrative oils which may be employed in the preparations are those of petrochemical, animal, vegetable or synthetic origin such as, for example, peanut oil, soybean oil and mineral oil. In general, preferred liquid carriers are water, saline, dextrose and related sugar solutions, ethanol and glycols, such as propylene glycol, in particular for injectable solutions. The parenteral preparation can be included in ampules, disposable syringes or multiple dose vials of inert plastic or glass. The solutions or suspensions described above may also include one or more of the following adjuvants: sterile diluents such as water for injection, saline, non-volatile oils, polyethylene glycols, glycerin, propylene glycol or other synthetic solvents, antibacterial agents such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and tonicity adjusting agents such as sodium chloride or dextrose. The compounds can be administered in the form of a skin patch, a depot injection or an implant preparation that can be formulated in such a way as to allow a sustained release of the active ingredient. The active ingredient can be compressed in the form of granules or small cylinders and implanted subcutaneously or intramuscularly in the form of injections or depot implants. The implants can use inert materials such as biodegradable polymers and synthetic silicones. Pharmaceutical vehicles and suitable formulation techniques are found in standard texts such as Remington: The Science and Practice of Pharmacy, 19th edition, Volumes 1 and 2, 1995, Mack Publishing Co., Easton, Pennsylvania, USA, which is incorporated to the present report as reference. In the treatment of various disease states such as those described herein, a suitable dose level is from about 0.01 mg / kg per day to about 250 mg / kg per day, preferably about 0.05 mg / kg per day at approximately 100 mg / kg per day and especially from approximately 0.05 mg / kg per day to approximately 40 mg / kg per day. The compounds can be administered at a dosage of 1 to 4 times a day and depending on the nature of the disease or disorder being treated. EXAMPLES It is intended that the following examples serve as an illustration of the invention in greater detail, without restricting the scope of the invention in any way. Tables 1, 2 and 3 provide summaries of the exemplary compounds that are prepared herein. The nitro compounds as described herein were handled with caution due to the potential perceived potential detonation of such compounds.

Unless otherwise specified, all initial materials, reagents and solvents were obtained from commercial suppliers and used without further purification. All reactions were carried out in an inert atmosphere with reagents and dry solvents. Flash chromatography was carried out using silica gel 60 (40-63 mm) of EM Science according to the literature using solvent systems such as those described in Still, W. C; Kahn, M .; Mitra, A. Rapid Cromatographic Technique for Preparative Separations with Modérate Resolution. J. Org. Chem., 1978, 43, 2923-2925). Thin layer chromatography was performed using 60F-254 (EM) plates coated with 0.25 mm silica gel and visualized using iodine vapor, ultraviolet light or a staining reagent such as KMn04 solution (the other solutions of staining, when mentioned, were prepared as described in "Thin-Layer Cromatography, A Laboratory Handbook," Egon Stahl, Editors, Springer-Verlag Berlin-Heidelberg-New York, 1969). The infrared (IR) spectra were recorded on a Nexus 670 FTIR (Nicolet) spectrometer by preparing the samples as indicated and expressed in wave numbers (cm "1). The 1 H NMR spectra were recorded on Gemini Varian spectrometers and / or mercury 300, Unity 400, or Unity plus and / or Inova of 500 MHz expressing the chemical deviations (d) in ppm taking as reference tetramethylsilane (0.0 ppm) or chloroform (CDCI3, 7.26 ppm). 13 C NMR were recorded on a Varian Unity instrument (100.57 MHz, 13 C frequency) expressing the chemical deviations (d) ppm relative to CDCI3 (77.0 ppm), unless otherwise indicated. Mass spectrometry (MS) were obtained in a Finnigan MAT Model TSQ 700 mass spectrometry system by chemical ionization at 120 eV using methane (Cl, 120 eV). Mass chromatography by liquid chromatography (EMCL) was performed in a Micromass LCT in interface with a Gilson 215 liquid manipulator The high-resolution mass spectrometry analysis (exact mass spectrum) was performed in the IES mode with a mass resolution of 10,000 using a Micromass QTOF mass spectrometer. The exact mass values for the protonated molecular ions (M + 1) in which M refers to the molecular ion were determined. Preparation of Pyrrolof3,2-bindole (4-Azaindoles) 2-Methyl-3-nitropyridine, 2a-1 (Scheme 1, step a) Add sodium metal (3.5 g) in portions over 1 hour to a 3-neck flask containing 79 ml of diethyl malonate heated to 90 ° C under a nitrogen atmosphere. Reduce the temperature to 60 ° C and add 2-chloro-3-nitropyridine (1a-1, 25.0 g) in portions for 15 minutes. The color of the reaction turns dark red. Keep the solution for 3 hours at 60 ° C and then let stand at room temperature until the next morning. The FTA indicates that there is still initial material. Heat the solution at 80 ° C for 3 more hours (until the reaction is complete). Remove the diethyl malonate under reduced pressure and dissolve the dark brown residue in a mixture of concentrated H2SO4 (18 ml) and H20 (32 ml). Heat the mixture for 7 hours at 105 ° C (decarboxylation) and then let stand at room temperature until the next morning. Wash the mixture with 3 x 150 ml of Et20 and 2 x 200 ml of EtOAc and discard the washings. Basify the aqueous phase to pH 8-9 with NaOH and extract with 3 x 200 ml of EtOAc. Filter the combined organic extracts with Celite® (diatomaceous earth) (Celite Corporation, 137 West Central Avenue, Lompor, California 93436) and remove the solvent under reduced pressure. The residue crystallizes to give 2a-1 (15.0 g, 68%), mp 29-31 ° C. 2-Methyl-3-nitropyridine, 2a-1 (Scheme 1, step a) Heat a mixture of 2-chloro-3-n -tropyridine (1a-1, 7.9 g, 49.8 mmol), methylboronic acid ( 1.10 equiv. 54.8 mmol, 3.30 g), K2CO3 (3.0 equiv., 150 mmol, 20.7 g) and Pd (PPh3) (1.2 g, 1.2 mmol) at 110 ° C in dioxane (250 ml) for 16 hours. Allow the reaction to cool to room temperature, concentrate to a dark oil and perform a flash chromatography on Si02 (heptane / Et20 3: 1, dilute the oil with limited amounts of CH2CI to apply to the column) to provide compound 2a-1 (Niu , C; Li, J .; Doile, T. W .; Chen, S-H. Tetrahedron, 1998, 6311-6318). 2-Methyl-3-nitropyridine, 2a-1 (Scheme 1, step a) Add NMP (2.0 I) to a 12 l 3-neck flask equipped with a stirrer, a temperature probe and a reflux condenser provided of a gas adapter for N2 and cool to 16 ° C. Add sodium tert-butoxide (0.675 kg, 6.81 mol, 2.2 equiv., Corrected for a purity of 97%) in a portion at which moment an immediate exothermic effect is observed up to 29 ° C. Stir the mixture for 30 minutes to partially dissolve the NaOt-Bu and then add diethyl malonate (0.943 i, 6.19 mol, 2.0 equiv.) From 20 ° C to 35 ° C for 70 minutes with continuous cooling, moment a in which a homogeneous solution is formed. Stir for 20 minutes and add a solution of 2-chloro-3-nitropyridine (1a-1, 0.491 kg, 3.09 mol, 1.0 equiv.) And NMP (1.0 I) to the reaction mixture of 29 ° C at 44 ° C for 70 minutes. Heat the reaction mixture to 50 ° C. Control the progress of the reaction by HPLC (Agilent series 1100; Waters Symmetry C8 column (5 μ) (3.9 x 150 mm), flow rate of 1.0 ml / minute) Isocratic: CH3CN / 0.1% aqueous TFA , 50/50;? = 220 nm TR: diethyl malonate = 2.6 minutes, 2-chloro-3-nitropyridine = 2.7 minutes, 2- (3-nitropyridin-2-yl) diethyl ester ) malonic = 3.9 minutes). Typically a conversion occurs > 99% in 1-2 hours. Stop heating and add 6 M H2S04 (2.17 I) from 50 ° C to 59 ° C for 45 minutes. A thick solid precipitate forms during the addition. Heat the mixture to 100 ° C. Gas evolution occurs. Control the progress of the reaction by HPLC as described above (TR: 2-methyl-3-nitropyridine 2a-1 = 2.0 minutes, 2- (3-nitropyridin-2-yl) malonic acid diethyl ester = 3 9 minutes). Typically a conversion is observed > 99% in 12 hours. Allow the mixture to cool to 40 ° C and pour into ice water (20 kg, pH 1, 5). Add 25% aqueous NaOH (2.65 I) from -11 ° C to -6 ° C for 20 minutes at pH 11. Add toluene (4.0 L) and stir the mixture for 10 minutes. Filter the mixture with Celite® to remove the inorganic solids and wash the filter cake with toluene (6.0 I). Separate the phases and extract the aqueous phase twice with toluene (6.0 I and 4.0 I). Filter the toluene phases combined with Celite® and wash the filter cake with toluene (1.0 I). Combine the toluene filtrates and wash with water (2 x 3.0 I). Dry (MgSO4) the toluene phase, filter and concentrate to give 2-methyl-3-nitropyridine 2a-1 (0.34 kg, 80% yield, corrected for residual NMP and toluene) as an oil. HPLC analysis shows that the material is 96% pure. 1 H NMR (CDCl 3) 2.87 (s, 3 hours), 7.35 (dd, 1 H, J = 4.8, 8.1 Hz), 8.27 (dd, 1 H, J = 1 , 4, 8.1 Hz), d 8.72 (dd, 1 H, J = 1, 4, 4.8 Hz). 2-Hydroxy-3- (3-nitropyridin-2-yl) acrylic acid ester 3a-1 (Scheme 1, step b) To a 3-neck flask containing 500 ml of absolute ethanol under N 2 atmosphere , add 2.2g (0.0956 g-atom) of sodium. After all the sodium reacts, add diethyl oxalate (98 ml) dropwise and then add compound 2a-1 (one equivalent). The color changes from pale yellow to brown after the addition. Let the resulting solution stand for two days at room temperature. Treat the orange mixture with 5 N HCl (pH = 1), collect the precipitate by filtration and wash the filter cake with 100 ml of EtOH and 200 ml of diisopropylether to give 3a-1 in the form of the 2-hydroxyethyl ethyl ester. 3- (3-nitropyridin-2-yl) acrylic acid (R = H, 20 g, 86%) or its tautomeric ketoester or in the form of a mixture of ketoenol tautomers. 1 H NMR (DMSO-c / 6) d 8.83 (dd, 1 H, J = 1, 1, 5.0 Hz), 8.65 (dd, 1 H, J = 1, 5, 8.4 Hz), 7.56 (dd, 1 H, J = 5.0, 8.4 Hz), 7.11 (s, 1 H), 3.47 (bs, 1 H), 4.28 (q, 2H, J = 7.1 Hz), 1.30 (t, 3H, J = 7.0 Hz). 2-Hydroxy-3- (3-nitropyridin-2-yl) acrylic acid ethyl ester, 3a-1 (Scheme 1, step b) Add tetrahydrofuran (2.7 I) to a 22-liter three-neck flask equipped with a stirrer, temperature probe and an addition funnel equipped with a gas inlet adapter for N2, and cooled to approximately 2 ° C. Add sodium ethoxide (0.409 kg, 6.02 mol, 2.0 equiv.) In one portion. A slightly exothermic effect is observed up to 2.7 ° C. Stir the mixture for 20 minutes, add diethyl oxalate (1.22 I, 9.03 mol, 3.0 equiv.) At -0.3-4 ° C for 50 minutes (slightly exothermic) and then stir the mixture for 10 minutes. Add a solution of 2-methyl-3-nitropyridine (2a-1, 0.415 kg, 3.01 mol, 1.0 equiv.) And THF (0.625 I) at 4-9 ° C for 22 minutes without cooling. Allow the mixture to warm to room temperature for 1 hour. Control the progress of the reaction by HPLC (Agilent 1100 series using the following conditions: Waters Symmetry C8 column (5 μ) (3.9 x 150 mm), flow rate of 1.0 ml / minute; CH3CN / 0.1% TFA aqueous, 55/45;? = 210 nm; TR: 2-methyl-3-nitropyridine 2a-1 = 1.8 minutes, 3a-1 = 2.7 minutes). Typically a conversion to the product is observed > 99% in 2-3 hours. During the reaction, a thick red precipitate forms. Cool the reaction mixture to approximately 1 ° C and add saturated solution of NH4Cl (2.0 I) from 1 ° C to 9 ° C. Add water (5.9 I) (at pH 7.4) and then add IPA (3.5 I). Stir the mixture for 1 hour and collect the red solid by filtration. Wash the filter cake with IPA H20 (1: 4, 8.0 I), H20 (15 I) and air dry. Dry the filter cake (40 ° C / 0.1 mm Hg) to provide 3a-1 (0.635 kg, 89%). 1 H NMR (CDCl 3) d 1, 40 (t, 3 H, J = 7 Hz), 4.38 (q, 2 H, J = 7 Hz), 7.36 (m, 2 H), 8.42 (dd, 1 HJ = 1, 5, 8.4 Hz), 8.66 (dd, 1 H, J = 1.5, 4.8 Hz), 14.52 (2, 1 H, OH). 1 H-Pyrrolof3,2-b1pyridin-2-carboxylic acid ethyl ester, 4a-1 (Scheme 1, step c) Hydrogenated 3a-1 (20 g) with 10% palladium on carbon (5.5 g) in EtOH (350 ml) at room temperature for 3 hours at 1200 psi. Filter the reaction mixture with Celite® and concentrate the filtrate to give ester 4a-1 (R4 = H) in a yield of 39%. Alternatively, reduce 3a-1 with SnCl2 (5.0 equiv.), TCII (2.5 equiv.) In EtOH at reflux for 4 hours, cool to room temperature, concentrate and purify by silica gel chromatography to provide ester 4a-1 (R4 = H) in 81% yield. 1 H NMR (DMSO-ue) d 13.48 (bs, 1 H), 8.80 (dd, 1 H, J = 0.7, 5.4 Hz), 8.56 (dd, 1 H, J = 0.7, 8.4 Hz), 7.80 (dd, 1 H, J = 5.5, 8.4 Hz), 7.37 (s, 1 H), 4.40 (q, 2H, J = 7.0 Hz), 1.38 (t, 3H, J = 7.0 Hz). 1H-Pyrrolor3,2-b1pyridine-2-carboxylic acid ethyl ester, 4a-1 (Scheme 1, step c) To a thick-walled 2 I Parr reactor add compound 3a-1 (56.8 g, 0, 24 mol), ethanol (200 proof, 850 ml, 15 parts) and 10% Pd / C (5.7 g, 10% by weight). Connect the reaction vessel to a Parr hydrogenator, clean with hydrogen and pressurize the orange suspension to 45 psi. Stir at room temperature for 1 hour, during this time the temperature increases to 57 ° C. When the temperature of the reaction mixture is stabilized at 35 ° C, heat the reaction slowly to 40 ° C for 3 hours. When the reaction is complete, as determined by TLC, (silica gel, 1% MeOH in CH 2 Cl 2), cool the reaction mixture to room temperature, filter the suspension with Celite® and wash the filter cake with EtOH ( 4 x 200 mi). Concentrate the yellow filtrate to give a solid (41.6 g), add ethyl acetate (302 ml) and heat in a steam bath. Cool the mixture to room temperature and add heptane (600 ml) to the precipitated product. Stir the mixture in an ice bath for 1 hour, filter and wash the filter cake with heptane (100 ml). Dry the filter cake (50 ° C / 0.1 mm Hg) for 24 hours giving 4a-1 as a light gray solid (36, 6 g, yield of 81%). 1 H NMR (DMSO-d 6) 1, 36 (t, 3 H, J = 7.0 Hz), 4.36 (q, 2 H, J = 7.0 Hz), 7.19 (s, 1 H), 7.25 (dd, 1 H, J = 4.5, 8.1 Hz), 7.82 (d, 1 H, J = 8.1 Hz), 8.44 (d, 1 H, J = 4 , 5 Hz), d 12.11 (s, 1 H). Amide of 1H-pyrrolor3,2-b1pyridin-2-carboxylic acid, 6a-1 (Scheme 1, step e) Dissolve the ester 4a-1 in 5N ammonia solution in MeOH and heat at 55 ° C for 10 hours providing, after processing, amide 6a-1 (R2 = NH2, R4 = H) in 44% yield, mp 332 ° C (cent). 1 H NMR (DMSO-d 6) d 11, 72 (bs, 1 H), 8.36 (dd, 1 H, J = 1, 5, 4.5 Hz), 8.10 (bs, 1 H), 7.76 (dd, 1 H, J = 2.2, 8.2 Hz), 7.52 (bs, 1 H), 7.24 (s, 1 H), 7.17 (dd, 1 H, J = 4.5, 8.2 Hz).

Amide of 1H-pyrrolor3,2-b1pyridine-2-carboxylic acid, 6a-1 (Scheme 1, step e) Dissolve the ester 4a-1 in 7N ammonia solution in MeOH and stir at room temperature for several days controlling by TLC (10% MeOH / CH2Cl2). When complete, concentrate the reaction to the minimum volume, dilute with excess H20, collect the precipitate by filtration and dry to give the amide 6a-1 (R = NH2, R4 = H) in approximately quantitative yield. Amide of 1H-pyrrolor3,2-b1pyridine-2-carboxylic acid, 6a-1 (Scheme 1, step e) Suspend ester 4a-1 in concentrated NH4OH and stir at room temperature for several days controlling by TLC (10% MeOH) / CH2Cl2). When complete, concentrate the reaction to the minimum volume, dilute with excess H20, collect the precipitate by filtration and dry to give the amide 6a-1 (R2 = NH2, R4 = H) in approximately quantitative yield. Amide of 1H-pyrrolor3,2-b1pyridine-2-carboxylic acid, 6a-1 (Scheme 1, step e) Add a solution of 7N NH3 in MeOH (1.5 I, 10.5 mol, 20 equiv.) To a pressure reactor of 3 I at room temperature and then adding azaindol ester 4a-1 (100 g, 0.53 mol) as a solid. Slowly heat the suspension to 50 ° C providing a clear solution. It is observed that the initial pressure of 35 psi drops to 16 psi in 4 hours. Maintain the reaction at 50 ° C for 49 hours. A final pressure of 10 psi is observed. Control the progress of the reaction by HPLC (Agilent 1100 series using the following conditions: Waters Symmetry C8 column (5 μ) (3.9 x 150 mm), flow rate of 1.0 ml / minute, gradient elution conditions: time (minutes), relationship between water and acetonitrile-methanol (acetonitrile-methanol used in the form of a 1: 1 solution) 0 minutes, 70:30, 10 minutes, 20:80, 15 minutes, 70:30, 20 minutes, 70 : 30;? -, = 210 nm,? 2 = 220 nm, flow rate 1.0 ml / minute, TR: ethyl ester 4a-1 = 5.6 minutes, methyl ester 5a-1 = 4.2 minutes, amide 6a -1 = 2.2 minutes). The formation of the corresponding methyl ester 5a-1 is observed in the reaction and 5a-1 also serves as an intermediate in the reaction. Cool the reaction to 4 ° C and isolate the resulting precipitate by vacuum filtration. Wash the filter cake with methyl tert-butyl ether (2 x 100 mL) and dry (40 ° C / 0.1 mm Hg) for 20 hours to give 6a-1 as a gray solid (78.6 g) , 93%). 1 H NMR (DMSO-c / 6) d 7.17 (dd, 1 H, J = 4.5, 8.4 Hz), 7.53, 8.11 (2s, 2H, NH2), 7.76 (d, 1 H, J = 8.1 Hz), 8.37 (d, 1 H, J = 1.5 Hz), 11, 72 (s, 1 H, NH). 1 H-Pyrrolor3,2-b1pyridine-2-carboxylic acid methylamide, 6a-2 Agitate 4-azaindole ester 4a-1 (R = Et, R4 = H) pure in methylamine (solution in H20 at 40% by weight) at room temperature for 16 hours monitored by TLC (10% MeOH / CH2Cl2). When complete, dilute the reaction in excess of H20, collect the precipitate by filtration and dry to give 6a-2 (R2 = NHCH3, R4 = H) as an ivory solid (see General Synthetic Procedure VI). EM Obs. 176.07 (M + 1). General preparation of diaryl disulphide starting materials and diheterocycle disulfide (Scheme 2) To a solution of unsubstituted or unsubstituted phenylthiol (17.2 mmol, 1.0 equivalent) and MeOH (30 mL), add a solution of sodium perborate (22 millimoles) and water (20 ml) stirring and then let the reaction stand at room temperature until the next morning. Collect the solid by filtration and wash with methanol to provide the desired diaryl disulfide. Other disulfides, including diheterocyclyl disubide (eg, bis (2-thienyl) disulfide), can be prepared in a similar manner, as described for the preparation of the desired diaryls disulfide. General synthetic procedure I (transesterification, Scheme 1, step di A 4-azaindole-2-carboxylic acid ethyl ester 4a (42.3 mmol) in MeOH (50 ml), add K2CO3 (1.20 equiv., 50.7 mmol) and stir the suspension by heating at 55 ° C for 1 hour. Control the reaction by TLC (Et20 / hept). When complete, concentrate the reaction in vacuo, dilute with H2O and stir for 15 minutes. Collect the solid by filtration and dry in a vacuum oven at 65 ° C for 3 hours providing from about 90% to about 100% of the desired methyl 4-azaindole-2-carboxylate 5a. General synthetic procedure II (amidation using NH4OH, Scheme 1, step e) Agitate ester of 4-azaindole carboxylate 4a or 5a (40.0 mmol) as a suspension in concentrated NH OH (100 ml) and LiCl (1.0 equiv. .) at room temperature for 16 hours. Collect the ivory solid by filtration, wash with H20 and air dry to provide the primary amide 6a (60-75%). Synthetic procedure qeneral lll (amidation using NH3 / MeOH, Scheme 1, step e) Agitate 4-aza-2-indole ethyl carboxylate 4a (4.67 mmol) in NH37 N / MeOH (20 mL) and add LiCl (1, 0 equiv., 4.67 mmol). Stir the reaction at room temperature for 5 days by monitoring by TLC (10% MeOH / CH2Cl2) during which time a precipitate forms. Concentrate the mixture to the minimum volume, dilute with H20 and collect the solid by filtration. Wash the filter cake with H20 and dry under vacuum at 60 ° C to provide the primary amide 6a (>90%). General synthetic procedure IVa (3-thioarylation using NaH as base, Scheme 1, step f) To a stirred suspension of NaH (60% dispersion in oil, 1.2 equiv., 9.8 mmol) in DMF (75 ml ) under N2 at room temperature add 4-azaindole-2-carboxyamide 6a (8.18 mmol) as a solution in DMF (5 ml). After 5 minutes add the diaryl disulfide (1.0 equiv., 8.18 mmol) in one portion and then heat the reaction by stirring at 95 ° C for 16 hours. Continue the reaction by fractionating an aliquot of the reaction mixture between EtOAc / H20 and control by TLC (10% MeOH / CH2Cl2). When complete, concentrate the reaction mixture in vacuo, dilute with H20, stir for 30 minutes, filter and air-dry the filter cake. Chromatograph the crude solid in Si02 eluting with CH 2 Cl 2 / MeOH 9: 1 to give the 3-arylthioether (Ri = H). Synthetic procedure IVb (3-thioarylation using Cs CO3, Scheme 1, step f) A 4-azaindole-2-carboxyamide 6a (0.42 mmol) dissolved in dry DMF (10 ml) add Cs2CO3 (100 mg, 0.31 mmol) and then add the diaryl disulfide (1.1 equiv., 0.46 mmol). Heat the reaction under N2 at 95 ° C for 16 hours (control by TLC / EMCL to determine that it is complete). Allow the reaction to cool to room temperature and then pour by stirring in ice-cooled H20. Collect the precipitate by filtration and dry in a vacuum oven at 40 ° C providing the crude product as a tan crystalline solid. Purification by chromatography on Si02 gives the 3-arylthioether (R-i = H). Synthetic procedure general V (N-methylation of the pyrrole ring, Scheme 1, step g) To the 4-azaindole-2-carboxylic acid amide substituted on 3 (Ri = H, 0.24 mmol) and 1, 3- dimethyl-3,4,5,6-tetrahydro-2 (1H) -pyrimidinone (5.0 ml), add stirring dimethyl sulphate (1.5 equiv., 0.36 mmol) and Cs2CO3 (2.0 equiv. , 0.48 mmol). Stir the reaction at room temperature for 16 hours under control by TLC (10% MeOH / CH 2 Cl 2). When complete, concentrate the reaction mixture to the minimum volume, dilute with H20 and collect the precipitate by filtration. Wash the filter cake with more H20 and dry under vacuum at 40 ° C to provide 1-methyl-3-substituted-4-azaindole-2-carboxylic acid amide (R-i = CH3, 65%). Other methods for the N-alkylation of the pyrrole ring nitrogen of a compound of the formula (I) which are notorious to one skilled in the art may be employed. For example, by treating a compound of the formula (I) in which Ri is H in a suitable polar solvent, such as for example dimethylformamide or NMP, with a suitable base, such as for example sodium hydride or potassium t-butoxide and adding then an alkyl halide, such as for example propyl iodide, to provide the compound of the formula (I) in which Ri is propyl. SYNTHETIC PROCEDURE VI GENERAL: General preparation of indole-2-methylamide and other secondary amides (Scheme 1, step e) Shake the ester of 4-azaindole 4 or 5 with a (C 1 -C 6 alkyl) amine (for example 40% by weight methylamine in H20 or pure) at room temperature for 16 hours monitored by TLC (10% MeOH / CH2C12). When complete, dilute the reaction with excess H20, collect the precipitated solid by filtration and dry to give the secondary amide 6 (R2 = NH-C 1-6 alkyl) in approximately quantitative yield. 3-Phenylsulfanyl-1H-pyrrolor3,2-b1pyridin-2-carboxylic acid amide, la-1. To 1 H-pyrrolo [3,2-b] pyridine-2-carboxylic acid amide (6a-1, R4 = H; 1.0 equiv.) In DMF (100 ml) add diphenyl disulfide (1.0 equiv. .) as described in General Synthetic Procedure IVb providing la-1 as a tan crystalline solid (81%), mp 251 ° C, TLC Rf = 0.49. 1 H NMR (DMSO-6) d 12.48 (bs, 1 H), 8.45 (dd, 1 H, J = 1, 5, 4.4 Hz), 8.11 (bs, 1 H), 7.89 (dd, 1 H, J = 1, 5, 4.0 Hz superimposed on a bs, 1 H), 7.31 (dd, 1 H, J = 1, 4, 4.5 Hz), 7 , 28 (dd, J = 1, 5, 4.5 Hz, 1 H) 7.21 (m, 2H), 7.13-7.05 (m, 3H); m / z = 270.06 (M + H). Anal. cale, for C 14 HnN 3 SO: C, 62.44; H, 4.12; N, 15.6. Found: C, 62.31; H, 4.08; N, 15.39. 3-Phenylsulfanyl-1H-pyrrolor3,2-b1pyridine-2-carboxylic acid amide, la-1 using excess Cs CO3 Add NMP (1.20 I) to a 3-neck 3-necked flask equipped with a mechanical stirrer, a temperature probe and a reflux condenser in a nitrogen atmosphere. Add diphenyl disulfide in one portion (177.8 g, 1.5 equiv.), Cs2CO3 (351, 9 g, 2.0 equiv.) And amide 6a-1 (87.5 g, 0.54 mol). Heat the reaction mixture at 120 ° C for 21 hours. Control the progress of the reaction by HPLC (Agilent 1100 series using the following conditions: Waters Symmetry C8 column (5 μ) (3.9 x 150 mm), flow rate of 1.0 ml / minute, gradient elution conditions: time (minutes), relationship between water and acetonitrile-methanol (acetonitrile-methanol used in the form of a 1: 1 solution) 0 minutes, 70:30, 10 minutes, 30:70, 15 minutes, 30:70, 20 minutes, 70 : 30; 25 minutes, 70:30; X = 210 nm,? 2 = 300 nm, flow rate: 1.0 ml / minute. (TR: amide 6a-1 = 2.1 minutes, product la-1 = 5, 7 minutes, PhSSPh = 14.0 minutes, NMP = 1, 9 minutes) If the reaction has not been completed, add more Cs2C03 (87.97 g, 0.5 equiv.) And maintain the reaction at 120 ° C during Another 4 hours Cool the reaction mixture to room temperature, pour into ice water and stir for 1 hour Collect the brown solid by filtration, wash the filter cake twice with water and air dry for 6 hours. the solid twice in 20% EtOAc / heptane at room temperature to remove the PhSSPh. Decolor the crude product in THF with activated carbon at reflux for 1 hour, filter and process to give la-1 as a light brown solid. Suspend la-1 in ethanol (12 parts), reflux for one hour and cool in an ice bath shaking. Collect the solid by filtration, wash with cold EtOH and dry (40 ° C / 0.1 mm Hg) to yield la-1. 1 H NMR (DMSO-6) d 7.05-7.32 (m, 6H), 7.91 (m, 2H), 8.12 (s, 1 H, NH2), 8.45 (dd, 1 H, J = 4.5, 0.9 Hz), 12.50 (s, 1 H, NH). Analysis: Calculated for C-, 2H ?? N3OS: 62.44% C, 4.12% H, 15.60% N; Found: 62.31% C, 4.08% H, 15.39% N. Amide of 3- (3-fluorophenylsulfanyl) -1H-pyrrolor3.2-b1pyridine-2-carboxylic acid, la-2 Treat 1 H -pyrrolo [3,2-b] pyridine-2-carboxylic acid amide 6a-1 (1.20 g, 74.4 mmol) in DMF (100 mL) with bis- (3-fluorophenyl) disulfide ( 1.90 g, 1.0 equiv.) As described in General Synthetic Procedure IVb providing la-2 in the form of an ivory solid (1.73 g, 80.8%), mp 235-237 °. C, TLC Rf = 0.49. 1 H NMR (DMSO-d 6) d 12.52 (bs, 1 H), 8.45 (dd, 1 H, J = 1, 2, 4.5 Hz), 8.10 (bs, 1 H), 7.90 (dd, 1 H, J = 1, 2, 8.2 Hz), 7.83 (bs, 1 H), 7.27 (superimposed on dd, 1 H, J = 4.5, 8, 2 Hz and dd, J = 7.8, 14.0 Hz, 1 H), 6.97-6.82 (m, 3H); EM Obs. 288 (M + 1); LC / MS: a = 100%. Analysis: Calc. For C 14 H? 0 FN 3 SO: C, 58.53; H, 3.51; N, 14.62. Found: C, 57.95; H, 3.54; N, 14.25. 3- (3-Chlorophenylsulfanyl) -1H-pyrrolor3,2-b1pyridine-2-carboxylic acid amide. la-3 Treat 1 H-pyrrolo [3,2-b] pyridine-2-carboxylic acid amide 6a-1 (1.20 g, 74.4 mmol) in DMF (100 ml) with bis- (3-chlorophenyl) disulfide (2.13 g, 1.0 equiv.) As described in General Synthetic Procedure IVb providing la-3 in the form of an ivory solid (1.95 g, 86.3%), mp 246.5-248 ° C, TLC Rf = 0.49. 1 H NMR (DMSO-d 6) d 12.54 (bs, 1 H), 8.45 (dd, 1 H, J = 1, 2, 4.5 Hz), 8.11 (bs, 1 H), 7.90 (dd, 1 H, J = 1, 3, 8.3 Hz) superimposed on 7.84 (bs, 1 H), 7.31 (dd, 1 H, J = 4.5, 8.2 Hz) 7.22 (m, 2H), 7.06-6.99 (m, 2H). Analysis: Cale, for C? 4H10CIN3SO: C, 55.36; H, 3.32; N, 13.83. Found: C, 54.94; H, 3.26; N, 13.62. 3- (3-Bromophenylsulfanyl) -1H-pyrrolor3,2-b1pyridine-2-carboxylic acid amide, 4-Treated 1 H -pyrrolo [3,2-b] pyridine-2-carboxylic acid amide 6a-1 ( 1.0 equiv.) In DMF with bis- (3-bromophenyl) disulfide (1.1 equiv.) As described in General Synthetic Procedure IVb providing la-4 as an ivory solid. 1 H NMR (DMSO-d 6) d 12.55 (bs, 1 H), 8.46 (dd, 1 H, J = 1, 2, 4.5 Hz), 8.10 (bs, 1 H), 7.91 (dd, 1 H, J = 1, 2, 8.2 Hz) superimposed on 7.85 (bs, 1 H), 7.33 (dd, 1 H, J = 4.7, 8.5 Hz), 7.20 (m, 2H), 7.05-7.00 (m, 2H). EM Obs. 348.1 (M + 1). 3- (2-Chlorophenylsulfanyl) -1 H -pyrroloyl-3,2-b1-pyridine-2-carboxylic acid amide. la-5 Treat 1 H-pyrrolo [3,2-b] pyridine-2-carboxylic acid amide 6a-1 (1.0 equiv.) in DMF with bis- (2-chlorophenyl) disulfide (1.1 equiv. .) as described in General Synthetic Procedure IVb providing la-5 in the form of an ivory solid. 1 H NMR (DMSO-d 6) d 12.61 (bs, 1 H), 8.46 (dd, 1 H, J = 1, 0, 4.5 Hz), 8.09 (bs, 1 H), 7.95 (d, 1 H, J = 8.0 Hz), 7.76 (bs, 1 H), 7.49 (dd, 1 H, J = 1, 5, 7.5 Hz), 7, 34 (dd, 1 H, J = 4.5, 8.0 Hz), 7.14 (dt, 1 H, J = 1.5, 7.5 Hz), 7.08 (dt, 1 H, J = 1, 5, 7.5 Hz), 6.49 (dd, 1 H, J = 1, 5, 7.5 Hz). EM Obs. 304.7 (M + 1). 3- (4-Chlorophenylsulfanyl) -1 H-pyrrolor3,2-b1pyridine-2-carboxylic acid amide, 1-6 Treating 1 H -pyrrolo [3,2-b] pyridine-2-carboxylic acid amide 6a-1 (1.0 equiv.) In DMF with bis- (4-chlorophenyl) disulfide (1.1 equiv.) As described in General Synthetic Procedure IVb providing la-6 as an ivory solid, mp. = 266 ° C, MS Obs. 304.7 (M + 1). 3- (2,4-Dichlorophenylsulfanyl) -1H-pyrrolor3,2-b1pyridine-2-carboxylic acid amide. Treating 1H-pyrroloß ^ -bJpyridine-carboxylic acid amide 6a-1 (1.0) equiv.) in DMF with bis- (2,4-dichlorophenyl) disulfide (1.1 equiv.) as described in General Synthetic Procedure IVb providing la-7 as an ivory solid, mp = 266 ° C, MS Obs. 339.2 (M + 1). 3- (2-Fluorophenylsulfanyl) -1H-pyrrolor-3,2-b-1-pyridine-2-carboxylic acid amide. Treating 1 H -pyrrolo [3,2-b] pyridine-2-carboxylic acid amide 6a-1 ( 1.0 equiv.) In DMF with bis- (2-fluorophenyl) disulfide (1.1 equiv.) As described in General Synthetic Procedure IVb providing la-8 as an ivory solid. 1 H NMR (DMSO-d 6) d 12.57 (bs, 1 H), 8.45 (dd, 1 H, J = 1, 2, 4.2 Hz), 8.15 (bs, 1 H), 7.90 (dd, 1 H, J = 1, 2, 8.1 Hz) superimposed on 7.84 (bs, 1 H), 7.31 (dd, 1 H, J = 4.5, 8.2 Hz), 7.20 (m, 2H), 6.98 (m, 1 H), 6.69 (m, 1 H). EM Obs. 288.2 (M + 1). 3- (2,3-Dichlorophenylsulfanyl) -1 H -pyrrolof3,2-blpyridine-2-carboxylic acid amide, la-9 Treating 1 H -pyrrolo [3,2-b] pyridine-2-carboxylic acid amide 6a -1 (1.0 equiv.) In DMF with bis- (2,3-dichlorophene) disulfide (1.1 equiv.) As described in General Synthetic Procedure IVb providing la-9 as an ivory solid . 1 H NMR (DMSO-d 6) d 12.62 (bs, 1 H), 8.44 (dd, 1 H, J = 1, 2, 4.5 Hz), 8.10 (bs, 1 H), 7 , 93 (dd, 1 H, J = 1, 2, 8.3 Hz), 7.75 (bs, 1 H), 7.35 (m, 2H), 7.07 (t, 1 H, J = 8.1 Hz), 6.40 (dd, 1 H, J = 1, 4, 8.1 Hz). EM Obs. 338.1 (M + 1). 3- (2-Trifluoromethylphenylsulfanyl) -1H-pyrrolor3,2-b1pyridine-2-carboxylic acid amide, 1-H-pyrrolo [3,2-b] pyridine-2-carboxylic acid amide 6a-1 (1.0 equiv.) In DMF with bis- (2-trifluoromethylphenium disulphide) (1.1 equiv.) As described in General Synthetic Procedure IVb to give la-10 as an ivory solid. 1 H NMR (DMSO-d 6) d 12.65 (bs, 1 H), 8.47 (dd, 1 H, J = 1, 5, 4.5 Hz), 8.15 (bs, 1 H), 7.92 (dd, 1 H, J = 1, 2, 8.2 Hz), 7.75 (bs, superimposed on dd, 2H), 7.34 (m, 3H), 6.75 (d, 1 H, J = 7.8 Hz); EM Obs. 338.2 (M + 1). 3- (3-trifluoromethylphenylsulfanp-1H-pyrrolor3,2-b1pyridine-2-carboxylic acid amide 1-H-pyrrolo [3,2-b] pyridine-2-carboxylic acid amide 6a -1 (1.0 equiv.) In DMF with bis- (3-trifluoromethylfenyl) disulphide (1.1 equiv.) As described in General Synthetic Procedure lVb providing la-11 as an ivory solid . EM Obs. 338.06 (M + 1). 3- (2-aminophenylsulfanyl) -1H-pyrrolor3,2-b1pyridine-2-carboxylic acid amide, 12H-pyrrolo [3,2-b] pyridine-2-carboxylic acid amide (1.0 equiv. .) 6a-1 in DMF with bis- (2-aminophenyl) disulfide (1.1 equiv.) As described in General Synthetic Procedure IVb providing la-12 in the form of an ivory solid. 1H NMR (DMSO-d6) d 12.29 (bs, 1 H), 8.49 (dd, 1H, J = 1, 3, 4.5 Hz), 8.18 and 8.15 (superimposed on bs , 2H), 7.83 (dd, 1 H, J = 1, 4, 8.2 Hz), 7.28 (dd, 1 H, J = 4.5, 8.3 Hz), 7.15 ( dd, 1 H, J = 1, 4, 7.8 Hz), 6.93 (m, 1 H), 6.62 (d, 1 H, J = 6.9 Hz), 6.39 (m, 1 H), 5.74 (superimposed on bs, 2H); EM Obs. 288.2 (M + 1). 3- (2,5-dichlorophenylsulfanyl) -1H-pyrrolor3,2-b1pyridine-2-carboxylic acid amide, 13-Treating 1 H -pyrrolo [3,2-b] pyridine-2-amide -carboxylic acid 6a-1 (1.0 equiv.) in DMF with bis- (2,5-dichlorophenyl) disulfide (1.1 equiv.) as described in General Synthetic Procedure IVb providing la-13 in the form of an ivory solid. 1 H NMR (DMSO-d 6) d 12.68 (bs, 1 H), 8.46 (dd, 1 H, J = 1, 3, 4.5 Hz), 8.10 (bs, 1 H), 7.94 (dd, 1 H, J = 1, 2, 8.2 Hz), 7.77 (bs, 1 H), 7.52 (apparent d, 1 H, J = 8.5 Hz), 7 , 35 (dd, 1 H, J = 4.5, 8.4 Hz), 7.20 (dd, 1 H, J = 2.5, 8.5 Hz), 6.37 (apparent d, 1 H , J = 2.5 Hz); EM Obs. 338.1 (M + 1). 3- (2-Methoxyphenylsulfanyl) -1H-pyrrolor3,2-b1pyridine-2-carboxylic acid amide. Treat 1-H-pyrrolo [3,2-b] pyridine-2-carboxylic acid amide 6a-1 ( 1.0 equiv.) In DMF with bis- (2-methoxyphenyl) disulfide (1.1 equiv.) As described in General Synthetic Procedure IVb providing la-14 in the form of an ivory solid. 1 H NMR (DMSO-d 6) d 12.48 (bs, 1 H), 8.44 (dd, 1 H, J = 1, 5, 4.5 Hz), 8.10 (bs, 1 H), 7.90 (dd, 1 H, J = 1, 2, 8.0 Hz), 7.60 (bs, 1 H), 7.30 (m, 3H), 6.71 (apparent t, 1 H) , 6.50 (apparent d, 1 H), 3.91 (s, 3H); EM Obs. 300.3 (M + 1). 3- (3-Methoxyphenylsulfanyl) -1H-pyrrolof3,2-b1pyridine-2-carboxylic acid amide. Treating 1 H-pyrrolo [3,2-b] pyridin-2-acid amide carboxylic acid 6a-1 (1.0 equiv.) in DMF with bis- (3-methoxyphenyl) disulfide (1.1 equiv.) as described in General Synthetic Procedure IVb providing la-15 in the form of a Ivory color. 1 H NMR (DMSO-d 6) d 12.51 (bs, 1 H), 8.46 (dd, 1 H, J = 1, 5, 4.5 Hz), 8.10 (bs, 1 H), 7.89 (dd, 1 H, J = 1, 5, 8.3 Hz superimposed on bs, 1 H), 7.32 (dd, 1 H, J = 4.5, 8.2 Hz), 7, 13 (apparent t, 1 H, J = 8.0 Hz) 6.62 (m, 3H), 3.64 (s, 3H); EM Obs. 300.3 (M + 1). 3- (3-Aminophenylsulfanyl) -1H-pyrrolor3,2-b1pyridine-2-carboxylic acid amide. la-16 Treat 1 H-pyrrolo [3,2-b] pyridine-2-carboxylic acid amide 6a-1 (1.0 equiv.) in DMF with bis- (3-aminophenyl) disulfide (1.1 equiv. .) as described in General Synthetic Procedure IVb providing la-16 in the form of an ivory-colored solid.- 1 H NMR (DMSO-d 6) d 12.40 (bs, 1 H), 8.44 (dd) , 1 H, J = 1, 5, 4.5 Hz), 8.10 (bs, - 1 H), 7.86 (dd, 1 H, J = 1, 5, 8.3 Hz superimposed on bs, 1 H), 7.28 (dd, 1 H, J = 4.5, 8.2 Hz), 7.13 (apparent t, 1 H, J = 7.8 Hz) 6.28 (m, 3H) 5.08 (bs, 2H); EM Obs. 288.08 (M + 1). 3- (4-Nitrophenylsulfanyl) -1H-pyrrolor3,2-b1pyridine-2-carboxylic acid amide, Treating 1 H -pyrrolo [3,2-b] pyridine-2-carboxylic acid amide 6a-1 ( 1.0 equiv.) In DMF with bis- (4-nitrophenyl) disulfide (1.1 equiv.) As described in General Synthetic Procedure IVb providing la-17 as an ivory solid. 1 H NMR (DMSO-d 6) d 12.63 (bs, 1 H), 8.43 (dd, 1 H, J = 1, 5, 4.5 Hz), 8.05 (m, 3H), 7 , 91 (m, 1 H), 7.50 (bs, 1 H), 7.32 (dd, 1 H, J = 4.5, 8.1 Hz), 7.18 (apparent d, 2H, J = 9.0 Hz); EM Obs. 315.05 (M + 1). 3- (3-Nitrophenylsulfanyl) -1H-pyrrolof3.2-b1pyridine-2-carboxylic acid amide, 1-H-pyrrolo [3,2-b] pyridine-2-carboxylic acid amide 6a- 1 (1.0 equiv.) In DMF with bis- (3-nitrophenyl) disulfide (1.1 equiv.) As described in General Synthetic Procedure IVb providing la-18 as an ivory solid. 1 H NMR (DMSO-d 6) d 12.59 (bs, 1 H), 8.45 (dd, 1 H, J = 1, 5, 4.6 Hz), 8.11 (bs, 1 H), 7.96-7.81 (m, 4H), 7.50 (m, 2H), 7.33 (dd, 1 H, J = 4.5, 8.4 Hz); Obs. 315.1 (M + 1). 3-O-tolylsulfanyl-1 H-pyrrolor3,2-b1pyridine-2-carboxylic acid amide, la-19. Treating 1 H-pyrrolo [3,2-b] pyridine-2-carboxylic acid amide 6a-1 (1.0 equiv.) In DMF with bis- (o-tolyl) disulfide (1.1 equiv.) as described in General Synthetic Procedure IVb providing la-19 in the form of an ivory solid. 1 H NMR (DMSO-d 6) d 12.5 (bs, 1 H), 8.41 (dd, 1 H, J = 1, 5, 4.5 Hz), 8.05 (bs, 1 H), 7.90 (dd, 1 H, J = 1.5, 8.3 Hz) superposed on 7.87 (bs, 1 H), 7.31 (m, 1 H), 7.29 (m, 1 H ), 7.00 (m, 2H), 6.4 (m, 1 H), 3.3 (s, 3H). EM Obs. 284.3 (M + 1). Amide of 3-p-tolylsulfanyl-1H-pyrrolof3,2-b1pyridine-2-carboxylic acid, la-20 Treating 1 H -pyrrolo [3,2-b] pyridine-2-carboxylic acid amide 6a-1 (1.0 equiv.) In DMF with bis- (p-tolyl) disulfide (1.1 equiv.) As described in General Synthetic Procedure IVb to give la-20 as an ivory solid. 1 H NMR (DMSO-d 6) d 12.42 (bs, 1 H), 8.44 (dd, 1 H, J = 1, 5, 4.5 Hz), 8.10 (bs, 1 H), 7.91 (bs, 1 H) superimposed on 7.86 (dd, 1 H, J = 1, 5, 7.9 Hz), 7.28 (dd, 1 H, J = 3.7, 8.3 Hz), 7.00 (superimposed on ds, 4H, J = 12.5 Hz), 3.31 (s, 3H); EM Obs. 284 (M + 1). 3- (3,5-Dimethylphenylsulfanyl) -1H-pyrrolor3,2-b1pyridine-2-carboxylic acid amide, 1-H-pyrrolo [3,2-b] pyridine-2-carboxylic acid amide 6a- 1 (1.0 equiv.) In DMF with bis- (3,5-dimethylphenyl) disulfide (1.1 equiv.) As described in General Synthetic Procedure IVb providing la-21 as a solid colored ivory. 1 H NMR (DMSO-d 6) d 12.45 (bs, 1 H), 8.45 (dd, 1 H, J = 1, 2, 4.5 Hz), 8.12 (bs, 1 H), 7.90 (dd, 1 H, J = 1, 2, 8.0 Hz) superimposed on (bs, 1 H), 7.3 (dd, 1 H, J = 4.5, 8.2 Hz), 6.76 (s, 1 H), 6.7 (s, 2H), 2.05 (s, 6H). EM Obs. 298.3 (M + 1). 3-M-Tolylsulfanyl-1 H-pyrrolor-3-b-pyridine-2-carboxylic acid amide, 1-H-1-pyrrolo [3,2-b] pyridine-2-carboxylic acid amide 6a-1 (1.0 equiv.) In DMF with bis- (m-tolyl) disulphide (1.1 equiv.) As described in General Synthetic Procedure IVb providing la-22 as an ivory solid. 1 H NMR (DMSO-d 6) d 10.2 (bs, 1 H), 8.62 (dd, 1 H, J = 1, 0.4, 4.4 Hz), 8.19 (bs, 1 H), 7.85 (dd, 1 H, J = 1, 3, 8.4 Hz), 7.28 (superimposed on dd, 1 H, J = 4.5, 8.3 Hz and 7.24 (s, 1 H), 7.1-6.9 (m, 4H), 2.22 (s, 3H), EM Obs 284 (M + 1), 3- (2-ethylphenylsulfanyl) -1H-pyrroloF3 acid amide, 2-b1pyridine-2-carboxylic acid, la-23 Treat 1H-pyrrolo [3,2-b] pyridine-2-carboxylic acid amide 6a-1 (1.0 equiv.) In DMF with bis- (2-) disulfide ethylphenyl) (1.1 equiv.) as described in General Synthetic Procedure IVb affording la-23 as an ivory solid.1 H-NMR (DMSO-d6) d 12.5 (bs, 1 H) , 8.42 (dd, 1 H, J = 1, 5, 4.4 Hz), 8.1 (bs, 1 H), 7.91 (dd, 1 H, J = 1, 5, 8.1 Hz), 7.82 (bs, 1 H), 7.30 (m, 1 H), 7.2 (m, 1 H), 7.05 (m, 1 H), 6.95 (m, 1 H), 6.5 (m, 1 H), 2.9 (q, 2H), 1.3, (t, 3H) EM Obs. 298.3 (M + 1). -trifl? oromethoxyphenylsulfanyl) -1H-pyrrolor3,2-b1pyridine-2-carboxylic acid, la-24 • Treating 1 H -pyrrolo acid amide [3, 2-b] pyridine-2-carboxylic acid 6a-1 (1.0 equiv.) In DMF with bis- (3-trifluoromethoxyphenyl) disulfide (1.1 equiv.) As described in General Synthetic Procedure IVb providing la-24 as an ivory solid. 1 H NMR (DMSO-d 6) d 12.56 (bs, 1 H), 8.45 (dd, 1 H, J = 1, 5, 4.5 Hz), 8.12 (bs, 1 H), 7.92 (dd, 1H, J = 1, 5, 8.3 Hz), 7.85 (bs, 1 H), 7.33 (dd, 1 H, J = 4.4, 8.3 Hz) superimposed over 7.32 (m, 1 H), 7.1 (m, 1H) superimposed over 7.03 (m, 2H). EM Obs. 354.1 (M + 1). 3- (Quinolin-8-i.sulfanyl) -1H-pyrrolof3,2-b1pyridine-2-carboxylic acid amide. Treating 1 H -pyrrolo [3,2-b] pyridine-2-carboxylic acid amide io 6a-1 (1.0 equiv.) in DMF with bis- (8-quinolyl) disulfide (1.1 equiv.) as described in General Synthetic Procedure IVb providing la-25 as a solid Ivory, EM Obs. 321, 1 (M + 1). 3- (Pyridin-2-sulfanip-1H-pyrrolof3,2-b1pyridine-2-carboxylic acid amide, -26 Treating 1H-pyrrolo [3,2-b] pyridine-2-carboxylic acid amide 6a-1 (1.0 eq.) In DMF with 2,2'-dipyridyl disulfide (1.1 equiv.) As described in General Synthetic Procedure IVb to give la-26 as an ivory solid. 1 H NMR (DMSO-d6) d 12.51 (bs, 1 H), 8.42 (dd, 1H, J = 1.4, 4.5 Hz), 8.34 (dd, 1H, J = 1 , 4 Hz) 8.06 (bs, 1H), 7.89 (dd, 1H, J = 1.4, 8.3 Hz) superposed on 7.82 (bs, 1H), 7.53 (dd, 1H , J = 1.8, 7.5 Hz), 7.30 (dd, 1H, J = 4.3, 8.2 Hz), 7.10 (dd, 1H, J = 4.9, 7.4 Hz), 6.74 (d, 1 H, J = 8.1 Hz). MS Obs.271, 1 (M + 1). 3- (pyridin-4-su.fanyl) -1H-pyrrolor3 acid amide, 2-b1pyridine-2-carboxylic acid, la-27 Treat 1H-pyrrolo [3,2-b] pyridine-2-carboxylic acid amide 6a-1 (1.0 equiv.) In DMF with disulfide of 4, 4'-dipyridyl (Aldrithiol 4) (1.1 equiv.) As described in General synthetic procedure IVb providing la-27 in the form of an ivory solid. 1 H NMR (DMSO-d 6) d 12.5 (bs, 1H), 8.44 (dd, 1H, J = 1.5, 4.5 Hz), 8.27 (dd, 2H, J = 1, 5, 4.5 Hz), 8.07 (bs, 1H), 7.93 (dd, 1H, J = 1.4, 8.3 Hz), 7.73 (bs, 1H), 7.33 ( dd, 1H, J = 4.5, 8.2 Hz), 6.94 (dd, 2H, J = 1.5, 4.5 Hz). MS Obs.271, 07 (M + 1). 3- (Thiophene-2-ylsulfanyl) -1H-pyrrolor3,2-bluprin-2-carboxylic acid amide, la-28 Treating 1H-pyrrolo [3,2-b] pyridin-2-acid amide carboxylic acid 6a-1 (1.0 equiv.) in DMF with 2,2'-bis- (thienyl) disulfide (1.1 equiv.) as described in General Synthetic Procedure IVb providing la-28 in the form of an ivory solid. 1 H NMR (DMSO-d6) d 12.34 (bs, 1H), 8.50 (d, 1 H, J = 4.4 Hz), 8.21 (bs, 1 H), 8.00 (bs) , 1 H), 7.83 (d, 1 H, J = 8.3 Hz), 7.42 (d, 1H, J = 5.3 Hz), 7.26 (dd, 2H, J = 4, 5, 8.2 Hz), 6.92 (dd, 1H, J = 3.6, 5.2 Hz). MS Obs.276.01 (M + 1). 1-Methyl-3-phenylsulfanyl-1H-pyrrolof3,2-blpyridine-2-carboxylic acid methylamide To treat 3-phenylsulfanyl-1 H -pyrrolo [3,2-b] pyridin-2-methylamide -carboxylic la-33 (1.0 equiv.) in DMF with dimethyl sulfate (1.5 equiv.) as described in General Synthetic Procedure V providing la-29 in the form of an ivory solid, EM Obs. . 298.09 (M + 1). 1-Methyl-3-phenylsulfanyl-1H-pyrroIof3,2-b1pyridine-2-carboxylic acid methylamide Add methyl iodide (20 mg, 0.164 mmol) at room temperature to a mixture of 3-phenylsulfanyl methylamide -1 H -pyrrolo [3,2-b] pyridine-2-carboxylic acid (la-33, 47 mg, 0.166 mmol), Cs2CO3 (65 mg, 0.2 mmol) and pyridine (1.5 mL). Heat the reaction at 60 ° C in a sealed container for 3 hours. Add more methyl iodide (20 mg) and monitor the progress of the reaction by chromatography. When complete, cool the mixture, concentrate to dryness and extract into ethyl acetate from brine. Separate the organic phase and concentrate. Purify the residue by flash chromatography twice (Si02, 3 g, elute with 0-4% MeOH in DCM; and SiO2, 1 g, eluting with heptane: DCM, 1: 1) to afford the title compound (10 mg) as a white solid, 1 H NMR (CDCl 3) and EMCL (m / e = 297) were consistent with the structure of the title compound. 3- (3-Trifluoromethoxyphenylsulfanyl-1H-pyrrolor3,2-blpyridine-2-carboxylic acid methylamide.) Treat 1 H -pyrrolo [3,2-b] pyridin-2-carboxylic acid methylamide 6a -2 (1.0 equiv.) In DMF with bis- (3-trifluoromethoxyphenyl) disulfide (1.1 equiv.) As described in General Synthetic Procedure IVb providing la-30 as an ivory solid , EM Obs. 368.03 (M + 1) 3- (3-Chlorophenylsulfanyl-1H-pyrrolof3,2-b1pyridine-2-carboxylic acid methylamide, la-31 Treating 1 H-pyrrolo methylamide [3.2 -b] pyridine-2-carboxylic acid 6a-2 (1.0 equiv.) in DMF with bis- (3-chlorophenyl) disulfide (1.1 equiv.) as described in General Synthetic Procedure IVb providing the 31 in the form of an ivory solid, EM Obs. 318.03 (M + 1). 3- (3-Fluorophenylsulfanyl-1H-pyrrolor3,2-b1pyridine-2-carboxylic acid methylamide, la-32) Treat methylamide of i-pyrrolo [3,2-b] pyridine-2-carboxylic acid 6a-2 (1.0 equiv.) in DMF with bis- (3-fluorophenyl) disulfide (1.1 equiv.) as described in General synthetic procedure IVb providing la-32 as an ivory solid, MS Obs. 305.05 (M + 1). 3-Phenylsulfanyl-1H-pyrrolor3,2-blpyridin-2-carboxylic acid methylamide. Treating 1 H-pyrrolo [3,2-b] pyridine-2-carboxylic acid methylamide 6a-2 (1.0 equiv.) In DMF with bis- (phenyl) disulfide (1.1 equiv.) As described in General Synthetic Procedure IVb providing la-33 as an ivory solid. 1 H NMR (DMSO-d 6) d 12.48 (bs, 1 H), 8.45 (dd, 1 H, J = 1, 5, 4.4 Hz), 8.11 (bs, 1 H), 7.89 (dd, 1 H, J = 1, 5, 4.0 Hz superimposed on a bs, 1 H), 7.31 (dd, 1 H, J = 1, 4, 4.5 Hz), 7 , 28 (dd, J = 1, 5, 4.5 Hz, 1 H) 7.21 (m, 2H), 7.13-7.05 (m, 3H), 2.9 (d, 3H, J = 4.2 Hz); EM Obs. 284.06 (M + 1). Amide of 1-methyl-3-phenylsulfanyl-1H-pyrrolor3,2-b1pyridine-2-carboxylic acid, la-34 Treating 3-phenylsuifanii-1 H-pyrrolo [3,2-b] pyridine amide -2-carboxylic acid la-1 (1.0 equiv.) In DMF with dimethisulfate (1.5 equiv.) As described in General Synthetic Procedure V providing la-34 in the form of an ivory solid, EM Obs. . 284.06 (M + 1). Amide of 1-methyl-3-phenylsulfanyl-1H-pyrrolor3,2-b1pyridine-2-carboxylic acid, la-34 (Scheme I, step q) Add methyl iodide (20 mg, 0.14 mmol) at temperature environment to a mixture of 3-phenylsulfanyl-1H-pyrrolo [3,2-b] pyridine-2-carboxylic acid amide (la-1, 27 mg, 0.1 mmol), Cs2C03 (43 mg, 0.13 mmoi) in pyridine (0.5 ml). Heat the reaction to 80 ° C in a sealed container for 15 minutes. Cool the mixture and extract in ethyl acetate from water. Separate the organic solution and evaporate. Purify the residue (33 mg) by flash chromatography (silica gel, 3 g, elute with 0-4% MeOH in dichloromethane) to provide the title compound (11 mg) as a white solid, 1 H NMR (CDCl 3) and the EMCL (rale = 283) are consistent with the structure of the title compound. 3- (3-Fluorophenylsulfanyl) -5-methoxy-1H-pyrrolor3,2-b1pyridine-2-carboxylic acid amide. Treating 5-methoxy-1H-pyrrolo [3,2-b] acid amide pyridine-2-carboxylic acid (1.0 equiv., prepared from the corresponding ethyl ester, Frydman, B .; Reil, SJ; Boned, J .; Rapoport, HJ Org. Chem. 1968, 33, 3762-6) in DMF with bis- (3-fluorophenyl) disulfide (1.1 equiv.) As described in General synthetic procedure IVb providing la-35 in the form of an ivory solid, MS Obs. 318.03 (M + 1). 3- (3-Methoxyphenylsulfanyl) -5-methoxy-1H-pyrrolor3,2-blpyridine-2-carboxylic acid amide, 36- Treating 5-methoxy-1H-pyrrolo [3,2-b] pyridine -2-carboxylic acid (1.0 equiv., Prepared from the corresponding ethyl ester, Frydman, B.; Reil, S. J .; Boned, J .; Rapoport, H. J. Org. Chem. 1968, 33, 3762-6) in DMF with bis- (3-methoxyphenyl) disulfide (1.1 equiv.) As described in General Synthetic Procedure IVb providing la-36 as a solid colored Ivory, EM Obs. 330.01 (M + 1). 3-Phenylsulfanyl-1-propyl-1H-pyrrolor3,2-b1pyridine-2-carboxylic acid amide, 3-phenylsulfanyl-1H-pyrrolo [3,2-b] pyridin-2 carboxylic acid la-1 (1.0 equiv.) in DMF with propyl iodide (1.5 equiv.) in the presence of Cs2CO3 (1.5 equiv.) according to General Procedure V providing la-37 in the form of a solid of ivory color after chromatography, EM Obs. 312.06 (M + 1). 3-Phenylsulfanyl-1-propyl-1H-pyrrolor3,2-b1pyridine-2-carboxylic acid amide, la-37 (Scheme I, step g) Add 1-bromopropane (19 mg, 0.154 mmol) at room temperature to a 3-phenylsulfanyl-1H-pyrrolo [3,2- b] pyridine-2-carboxylic acid amide mixture (la-1, 31.5 mg, 0.12 mmol), Cs2CO3 (60 mg, 0.185 mmol) in pyridine (0.5 ml). Heat the reaction at 80 ° C in a sealed container for 1 hour. Cool the mixture and extract in ethyl acetate from water. 'Separate the organic phase and evaporate. Purify the residue (33 mg) by flash chromatography (Si02, 2 g, elute with heptane: DCM then 0-4% MeOH in DCM) to give the title compound (11.5 mg) as a white solid, NMR 1H (CDCl3) and EMCL (m / e = 311) are consistent with the structure of the title compound. Preparation of Pirrolor3,2-clindoles (5-Azaindoles) 2- (diethoxymethyl) -1H-pyrrolor3,2-c1pyridin-1-carboxylic acid 1,1-dimethylethyl ester, 8b-1 (Scheme 3, step h) Heat a solution of (3-iodopyridin-4-yl) -carbamic acid 1, 1-dimethylethyl ester (13.3 g, 41.56 mmol, Darnbrough, Shelley, Mervic, Miljenko, Condon, Stefen M., Burns, Christopher J. Synthetic Communications (2001) 31 (21), 3273-3280), 3,3-diethoxy-1-propyne (5.96 mL, 41.56 mmol), triethylamine (23 mL, 166 mmol), dichlorob (triphenylphosphine) ) paired (II) (1.46 g, 2.08 mmol) and copper iodide (237 mg, 1.25 mmol) in dry DMF under an argon atmosphere at 90 ° C for 3 hours. Allow the reaction mixture to cool to 70 ° C and add DBU (12.5 ml, 83.12 mmol). Stir the reaction at 70 ° C for 3 hours and then stir at room temperature until the next morning. Pour the reaction mixture into EtOAc, wash with water (2x) and brine, dry over MgSO 4, filter and concentrate to provide the title compound as an oil. Purify the oil by flash chromatography (silica, elute with 10-20% EtOAc / n-heptane) to give 9.8 g of the title compound as a clear oil, TLC (silica, 30% EtOAc / heptane, Rf = 0.30). 1H-pyrrolor3,2-c1pyridine-2-carboxaldehyde, 9b-1 (Scheme 3, step i) To a solution of 2- (dimethoxymethyl) -1H-pyrrolo1,2-dimethylethyl ester [3.2] -c] pyridine-1-carboxylic acid (8b-1, 9.8 g, 30.6 mmol) in 100 ml of THF, add 6 ml of concentrated HCl. Stir the reaction mixture at room temperature for 20 hours, basify with saturated sodium bicarbonate solution, pour into EtOAc, wash with saturated sodium bicarbonate and brine, dry the organic phase over MgSO 4, filter and concentrate to give a mixture of ester 1.1. 2-formyl-1Hrrrolo [3,2-c] pyridin-1-carboxylic acid dimethylethyl and 1 H -pyrrolo [3,2-c] pyridine-2-carboxaidehyde 9b-1 as a solid. Separate the mixture by flash chromatography (silica, 1-3% MeOH / CH2Cl2) to give 2-formyl-1 H -pyrrolo [3,2-c] pyridine-1-carboxylic acid 1, 1-dimethylethyl ester (5, 0 g) in the form of an oil and 1 H-pyrrolo [3,2-c] pyridine-2-carboxaldehyde 9b-1 (1.0 g) as a tan solid. Add TFA (5.0 ml) dropwise to a solution of 2-formyl-1 H -pyrrolo [3,2-c] pyridine-1-carboxylic acid 1,1-dimethylethyl ester (5.0 g, , 3 mmol) in 250 ml of dichloromethane. Heat the reaction mixture to reflux for 3 hours, concentrate, dilute the residue with 300 mL of EtOAc, wash with saturated sodium bicarbonate solution (3x) and brine, dry the organic phase (MgSO), filter and concentrate to give 1 H- pyrrolo [3,2-c] pyridine-2-carboxaldehyde 9b-1 (2.24 g) as a pure solid. 1H-Pyrrolor3,2-Clpyridine-2-carboxylic acid methyl ester, 5b-1 (Scheme 3, step i) To a solution of 1 H-pyrrolo [3,2-c] pyridine-2-carboxaldehyde (9b-1) , 3.24 g, 22.19 mmol) at 0 ° C in methanol under an argon atmosphere, add sodium cyanide (5.44 g, 111 mmol) and manganese dioxide (9.65 g, 111 mmol). Stir the reaction mixture for 5 hours, filter with Celite® and dilute with 500 ml of EtOAc. Wash the organic phase with water (2x) and brine, dry over sodium carbonate, filter and concentrate to provide the title compound (3.27 g) as a pure tan solid. Prepare 1 H-pyrrolo [3,2-c] pyridine-2-carboxylic acid 6b-1 amide from 5b-1 by any of the procedures described above for the synthesis of compound 6a-1 from ethyl ester 4a -1. Amide of 1 H-pyrrolor3,2-c1pyridine-2-carboxylic acid, 6b-1 (R4 = H, Scheme 1, steps ac, e) Prepare 3-methyl-4-nitropyridine (2b-1) from 3- chloro-4-nitropyridine 1b-1 as described above for the synthesis of the isomeric 2-methyl-3-nitropyridine analog 2a-1 from compound 1a-1. Prepare 2-hydroxy-3- (4-nitropyridin-3-yl) acrylic acid ester (3b-1) from compound 2b-1 by any of the procedures described above for the preparation of compound 3a-1 a from compound 2a-1. Prepare 1 H-pyrrolo [3,2-c] pyridine-2-carboxylic acid ethyl ester, 4b-1, from compound 3b-1 by any of the procedures described above for the preparation of compound 4a-1 from of compound 3a-1. Prepare 1 H-pyrrolo [3,2-c] pyridin-2-carboxylic acid amide 6b-1 from compound 4b-1 by any of the procedures described above for the synthesis of compound 6a-1 from compound 4a-1. 3-Phenylsulfanyl-1H-pyrrolof3,2-c1pyridine-2-carboxylic acid amide, lb-1 Treating 1 H-pyrrolo [3,2-c] pyridine-2-carboxylic acid amide 6b-1 (1.0 equiv. .) in DMF (100 ml) with diphenyl disulfide (1.1 equiv.) as described above in General Procedure IVb providing lb-1 as an ivory solid: 1 H NMR (DMSO-d6) d 12.48 (bs, 1 H), 8.70 (s, 1 H), 8.29 (d, J = 5.8 Hz, 1 H), 8.04 (bs, 1 H), 7, 76 (bs, 1 H), 7.44 (dd, J = 1, 1, 5.7 Hz, 1 H), 7.26 (m, 2H), 7.14 (m, 3H); m / z = 270.1 (M + H). 3- (3-Fluorophenylsulfanyl-1H-pyrrolor3,2-c1pyridin-2-carboxylic acid amide, lb-2 Treating 1 H -pyrrolo [3,2-c] pyridine-2-carboxylic acid amide 6b -1 (1.0 equiv.) In DMF (100 ml) with bis- (3-fluorophenyl) disulfide (1.1 equiv.) As described above in General Procedure IVb providing lb-2 in the form of a ivory solid: NMR of 1H (DMSO-d6) d 12.63 (bs, 1 H), 8.71 (s, 1 H), 8.31 (d, J = 5.8 Hz, 1H), 8.06 (bs, 1 H), 7.74 (bs, 1 H), 7.46 (d, J = 5.8 Hz, 1 H), 7.3 (m, 1 H), 6.99 -6.89 (superimposed on m, 3H); m / z = 288.06 (M + 1) 3- (4-chlorophenylsulfanyl-1 H -pyrrolor3,2-clpyridine-2-carboxylic acid amide, lb- 3 Treat 1 H-pyrrolo [3,2-c] pyridine-2-carboxylic acid 6b-1 amide (1.0 eq.) In DMF (100 ml) with bis- (4-chlorophenyl) disulfide (1, 1 equiv.) As described above in General Procedure IVb providing lb-2 as an ivory solid: 1 H NMR (DMSO-d 6) d 12.61 (bs, 1 H), 8.71 ( bs, 1 H), 8.30 (d, 1 H, J = 4.5 Hz), 8.07 (bs, 1 H), 7.76 (bs, 1 H), 7.45 (d, 1 H, J = 5.7 Hz), 7.32 (d, 2H, J = 8.7 Hz), 7.12 (d, 2H, J = 8.5 Hz), m / z = 304 (M + 1) . Preparation of Pyrrolof2,3-clindoles (6-Azaindoles) 1H-pyrrolor-2,3-c1pyridin-2-carboxylic acid amide, 6c-1 (R4 = H, Scheme 1, steps ac, e) Prepare 4-methyl-3- nitropyridine (2c-1) from 4-chloro-3-nitropyridine 1c-1 as described above for the synthesis of the isomeric 2-methyl-3-nitropyridine analog 2a-1 from compound 1a-1 . Prepare 2-hydroxy-3- (3-nitropyridin-4-yl) acrylic acid ester (3c-1) from compound 2c-1 by any of the procedures described above for the preparation of compound 3a-1 from compound 2a-1. Prepare ethyl ester of 1 H-pyrrolo acid [2, 3-c] pyridine-2-carboxylic acid (4c-1) from compound 3c-1 by any of the methods described above for the preparation of compound 4a-1 from compound 3a-1. Prepare 1 H-pyrrolo [2,3-c] pyridine-2-carboxylic acid amide 6c-1 from compound 4c-1 by any of the procedures described above for the synthesis of compound 6a-1 from compound 4a -1. Amide of 3-phenylsulfanyl-1H-pyrrolof2,3-c1pyridin-2-carboxylic acid, lc-1 A i-pyrrolo [2,3-c] pyridine-2-carboxylic acid amide 6c-1 (1.0 equiv .) in DMF (100 ml), add (diphenyl) disulfide (1.0 equiv.) as described above in General Procedure IVb to provide lc-1 as a tan crystalline solid: 1H NMR (DMSO-d6) ) d 12.4 (bs, 1 H), 8.86 (s, 1H), 8.18 (m, 2H), 7.84 (bs, 1H), 7.42 (d, J = 5.5 Hz, 1H), 7.24 (m, 2H), 7.14 (m, 1 H), 7.03 (d, 8.3 Hz, 2H); m / z = 270.1 (M + H). 3-Benzenesulfonyl-1H-pyrrolor-2,3-clpiridin-2-carboxylic acid amide, lc-2 Treat 3-phenylsulfanyl-1H-pyrrolo [2,3-c] pyridine-2-carboxylic acid amide 6c 1 (1.0 mmol) with H202 (30% w / v, 131 μL, 2.5 mmol) and Na 2 CO 3 (212 mg, 2.0 mmol). Stir at room temperature for 16 hours, quench the reaction with H20 and extract with EtOAc. Wash the extract with brine, dry the organic phase (MgSO4) and concentrate to give lc-2 as an ivory solid; EM Obs. 303 (M + 1). 3- (3-Fluorophenylsulfanyl) -MH-pyrrolof2,3-clpyridine-2-carboxylic acid amide, 1C-3 Treating 1 H -pyrrolo [2,3-c] pyridine-2-carboxylic acid amide 6c-1 (1.0 equiv.) in DMF (100 ml) with bis- (3-fluorophenyl) disulfide (1.0 equiv.) as described above in General Procedure IVb to provide lc-3 as a tan solid: 1H NMR ( DMSO-d6) d 12.77 (bs, 1 H), 8.87 (s, 1 H), 8.2 (d, J = 5.2 Hz, 1 H) partially superimposed on 8.13 (bs, 1 H), 7.81 (bs, 1 H), 7.42 (d, J = 5.5 Hz, 1 H), 7.26 (m, 1 H), 6.96 (m, 1 H) 6.84 (m, 2H); m / z = 288.04 (M + H). 3- (3-Methoxyphenylsulfanyl) -1H-pyrrolof2,3-c1pSridin-2-carboxylic acid amide, 1C-4 Treat 1 H -pyrrolo [2,3-c] pyridine-2-carboxylic acid amide 6c-1 (1.0 equiv.) In DMF (100 ml) with bis- (3-methoxyphenyl) disulfide (1.0 equiv.) As described above in General Procedure IVb providing lc-4 in the form of Roasted solid: 1H NMR (DMSO-d6) d 12.8 (bs, 1 H), 8.89 (s, 1 H), 8.2 (d, J = 5.3 Hz, 1 H) superimposed on 8.19 (bs, 1H), 7.81 (bs, 1 H), 7.41 (d, J = 5.4 Hz, 1 H), 7.19 (m, 1 H), 6.61 (b). s, 1 H), partially superimposed on 6.56 (m, 2H), 3.65 (s, 3H); m / z = 300.1 (M + H). 3- (3-Chlorophenylsulfanyl) -1H-pyrrolof2,3-c1pyridine-2-carboxylic acid amide, lc-5 Treat 1 H -pyrrolo [2,3-c] pyridine-2-carboxylic acid amide 6c-1 ( 1.0 equiv.) In DMF (100 ml) with bis- (3-chlorophenyl) disulfide (1.0 equiv.) As described above in General Procedure IVb to provide lc-5 as an ivory solid: 1 H NMR (DMSO-d6) d 12.8 (bs, 1 H), 8.87 (s, 1 H), 8.2 (d, J = 5.3 Hz, 1 H) superimposed over 8.17 (bs, 1 H), 7.82 (bs, 1 H), 7.41 (d, J = 5.4 Hz, 1 H), 7.2 (m, 2H), 7.05 (s, 1 H), 6.95 (d, J = 7.3 Hz, 1 H); m / z = 304 (M + H). 3- (2-Trifluoromethylphenylsulfanyl) -1H-pyrrolor-2,3-clpyridine-2-carboxylic acid amide, 1C-6 Treat 1 H -pyrrolo [2,3-c] pyridine-2-carboxylic acid amide 6c-1 ( 1.0 equiv.) In DMF (100 ml) with bis- (2-trifluoromethyldiphenyl) disulfide (1.0 equiv.) As described above in General Procedure IVb providing lc-6 in the form of ivory solid: NMR of 1H (DMSO-d6) d 12.9 (bs, 1 H), 8.9 (bs, 1 H), 8.19 (m, 2H), 7.79 (m, 1 H), 7.33 (m, 2H), 7.46 (d, J = 5.5 Hz, 1 H), 7.14 (m, 1 H), 6.75 (dd, J = 1, 3 7.5 Hz, 1 H); m / z = 338 (M + H). 3- (2-trifluoromethoxyphenylsulfanyl) -1H-pyrrolor-2,3-clpyridine-2-carboxylic acid amide, 1-pyridine-2-carboxylic acid 1-pyrrolo [2,3-c] pyridine-2-carboxylic acid amide 1 (1.0 equiv.) In DMF (100 ml) with bis- (2-trifluoromethoxyphenyl) disulfide (1.0 equiv.) As described above in General Procedure IVb to provide lc-7 as a tan solid. : 1 H NMR (DMSO-d6) d 12.8 (bs, 1 H), 8.89 (s, 1 H), 8.2 (d, J = 5.3 Hz, 1 H) superimposed on 8, 14 (bs, 1H), 7.8 (bs, 1 H), 7.36 (m, 2H), 7.1 (dd, J = 1, 0, 8.3 Hz, 1 H), 6.98 (m, 2H); m / z = 354 (M + H). 3- (2-Methoxyphenylsulfanyl) -1H-pyrrolor2,3-c]? Iridin-2-carboxylic acid amide, lc-8 Treating 1-Hyrrolo [2,3-c] pyridine-2-cardehyde carboxycocid 6c-1 (1.0 equiv.) in DMF (100 ml) with (2-methoxydiphenyl) disulfide (1.0 equiv.) as described above in General Procedure IVb providing lc-8 in form of an ivory solid: NMR of 1H (DMSO-d6) d 12.40 (bs, 1 H), 8.89 (bs, 1 H), 8.3-8.16 (m, 1 H) , 7.86 (s, 1 H) superposed on 7.77 (m, 1 H), 7.46 (d, J = 5.5 Hz, 1 H), 7.14 (m, 1 H), 7 , 03 (dd, J = 1, 0, 8.3 Hz, 1 H), 6.75 (dd, J = 1, 3, 7.5 Hz, 1 H), 6.50 (dd, J = 1 , 5, 7.8 Hz, 1 H), 3.89 (s, 3H); m / z = 300.1 (M + H). 3- (Pyridin-2-sulfaniO-1H-pyrrolor2,3-c1pyridine-2-carboxylic acid amide, lc-9 A i-pyrrolo [2,3-c] pyridine-2-carboxylic acid amide (1.0 equiv.) in DMF (100 ml), add 2,2'-dipyridium disulfide (Aldrithiol 2, 1.1 equiv.) as described in General Procedure IVb to provide lc-9 as an ivory solid: NMR of 1 (DMSO-d6) d 12.75 (bs, i), 8.86 (s, 1H), 8.35 (dd, 1H, J = 14, 4.5 Hz), 8.19 (dd) , 1H, J = 1.4 Hz), 8.1 (bs, 1H), 7.85 (bs, 1H), 7.54 (dd, 1H, J = 1.8, 7.5 Hz), 7 , 42 (d, J = 5.5 Hz, 1H), 7.10 (dd, 1 H, J = 4.9, 7.4 Hz), 6.74 (d, 1 H, J = 8.1 Hz), m / z = 271, 1 (M + H) Table 1 1H-pyrrolo [3,2-b] pyridine-2-carboxylic acid amides substituted at 3 Table 2 1 H -pyrrolo [3,2-c] pyridine-2-carboxylic acid amides substituted in 3 Ib Table 3 1H-pyrrolo [2,3-c] pyridine-2-carboxylic acid amides substituted in 3 I Biological examples Assay with casein filtrate plates guinea-epsilon with 33P-ATP for the Selection of CK1e Inhibitors Objective: This assay measures the effect of compounds to inhibit the phosphorylation of the casein substrate by the enzyme casein kinase 1 e using a 33P-ATP in vitro filtration assay. The compounds are analyzed in five concentrations in duplicate to generate CI or% inhibition values at a 10 micromolar concentration summarized in Table 4. Materials: Apparatus: Beckman Biomek 2000 liquid manipulator robot Beckman Multimek 96-channel automatic pipettor 96 Millipore Multi-Vacuum Basic Kit No. MAVM0960R Titertek Multidrop Liquid Dispenser Packard TopCount NXT Esciquiometer Plates: Costar EIA / RIA Plate n ° 9018 96-well U-Bottom Polystyrene Plate Falcon n ° 353910 Millipore 96-well Filtration Plates Multiscreen n ° MAPHNOB50Millipore Multiscreen TopCount Adapter plates n ° SE3M203V6 Chemical products: EGTA of SIGMA n ° E-3889 Casein (dephosphorylated) of SIGMA n ° C-4032 ATP of SIGMA n ° A-7699 DTT of Fisher Biotech n ° BP1725 Trichloroacetic acid of SIGMA n ° T-6399? -33P-ATP of 1 mCi / 37 MBq of Perkin Elmer Life Sciences No. NEG- 602H Enzyme: Casein Kinase 1. at a final concentration of 0.58 mg / ml obtained by fermentation and purification procedures made by Aventis Pharmaceuticals Inc., France. This is stored in 100 μl aliquots at minus 80 ° C. Compounds: Compounds for the experiments are provided in the form of 10 mM stock solution of the frozen compound dissolved in 100% DMSO. Test conditions: The final total assay volume per well is equal to 50 μl prepared as follows: 5 μl of diluted compound stock solution (10, 1, 0.1, 0.01 or 0.001 μM), 5 μl of dephosphorylated casein to a final concentration of 0.2 μg / μl, 20 μl of CK1 at a final concentration of 3 ng / μl, and 20 μl of? -33P-ATP at a final concentration of 0.02 μCi / μl mixed with cold ATP (final 10 M). Methodology: 1. 500 ml of fresh assay buffer are prepared: 50 mM Tris pH 7.5, 10 mM MgCl2, 2 mM DTT and 1 mM EGTA. 2. The compounds to be evaluated are obtained in the form of 10 μl of 10 mM stock solution dissolved in 100% DMSO. Using a Biomek 2000 liquid handling robot, serial dilutions are made by providing final dilutions of the compound of 10, 1, 0.1, 0.01 and 0.001 μM that are added in the form of 5 μl additions to Falcon plates with background in U. Typically, 8 compounds are analyzed for each 96-well plate with columns 1 and 12 being the control wells. A routine selection test will consist of 32 compounds which is equivalent to 4 test plates. 3. Maps of the test plates are made according to the following pattern CK1 ePlateMap.xls 4. Once 5 μl of compound has been added as indicated, add 5 μl of dephosphorylated casein (dissolved in distilled H20) (0.2 μg / μl) and 20 μi of CK1e (3 ng / μl) to the appropriate wells . 5. Finally, 20 μl of? -33 P-ATP (0.02 μCi / μl) / cold 10 μM ATP (equivalent to approximately 2 x 106 CPM per well) is added. 6. The Falcon U-bottom assay plate containing the above reaction volume of 50 μl is stirred in a vortex and then incubated at room temperature for 2 hours. 7. At the end of 2 hours, the reaction is terminated by the addition of 65 μl of ice cold 2 mM ATP (dissolved in assay buffer) to the test plates using a Beckman Multimek 8. At the same time 25 μl of 100% frozen TCA dissolved in H20 distilled to an equal number of Millipore MAPH filtration plates. 9. Using an 8 channel manual pipettor, transfer 100 μl of the reaction mixture of the Falcon plate with U-bottom to the Millipore MAPH filtration plates previously embedded in TCA. 10. Millipore MAPH filter plates are mixed carefully and allowed to stand at room temperature for at least 30 minutes to precipitate the proteins. 11. After 30 minutes the filtration plates are placed in a Millipore multiple vacuum apparatus and filtered at no more than 8 mm Hg since the MAPH filters tend to block with air bubbles at higher voids. 12. Filtration plates are washed and sequentially filtered with 2 x 150 μl of 20% TCA, 2 x 150 μl of 10% TCA and 2 x 150 μl of 5% TCA (total of 6 washes per plate / 900 μl per well). 13. Let the plates dry until the next morning at room temperature. The next day, 40 μl of Packard Microscint-20 scintillation fluid per well was added using a Titertek Multidrop dispenser; the plates are sealed and counted for 2 minutes / well on a Packard Topcount NXT scintillometer (CPM / well values are obtained). Calculation: 1. The Impulses Per Minute (CPM) data is obtained and imported into a commercial database of calculation and data file (Activity Base of IDBS version 5.0). 2. Column 1 for each plate reflects the total phosphorylation activity of the enzyme in the absence of any inhibitory compound and, in this way, it represents 100%. Column 12 reflects any phosphorylation / radioactivity activity maintained in the absence of inhibition compound and enzyme. Typically it is observed that approximately 1% of the total CPMs are "non-specific". 3. In determining the "total" and "non-specific" CPMs for each plate, the percentage inhibition of the ability of the enzyme to phosphorylate the substrate for each concentration of test compound can be determined. These percentage inhibition data are used to calculate a Cl50 value (concentration at which a compound is capable of inhibiting the activity of the enzyme by 50%) for a compound using a non-linear curve fitting program contained in the protocol of calculation Activitybase (DG0027-CK1-D-BL) (Study: RESR0290). 4. Kinetic studies have determined that the Km value for ATP is 21 μM in this test system. Assay with casein guinasa 1? in membrane plates with affinity of streptavidin for CKId inhibitors Objective: To evaluate the experimental compounds to determine their activity of CKI¿ > in biotin capture plates with streptavidin affinity membrane (SAM) (Promega V7542) Materials and reagents HEPES Sigma n ° H3375 MW = 238.3; ß-Sigma glycerol phosphate n ° G-9891 MW = 216.0; 0.5 M EDTA, at pH 8.0 GibcoBRL; ACROS sodium orthovanadate n ° 205330500 MW = 183.9; DTT (DL-dithiothreitol) Sigma n ° D-5545 PM = 154.2; Magnesium chloride ACROS n ° 41341-5000 MW = 203.3; ATP Sigma No. A-7699 MW = 551, 1; ? 33P ATP NEN n ° NEG602H; Casein kinase 1d Sigma No. C4455; Casein kinase 1 substrate New England Peptide Biotin- RRKDLHDDEEDEAMSITA PM = 2470 Prepare kinase buffer (KB, 100 ml) as follows: 50 mM HEPES, pH 8.0 5 ml of 1 M stock solution 10 mM MgCl 1 ml of 1 M ß-glycerophosphate 10 mM stock solution 1 ml of 1 M stock solution 2.5 mM EDTA 500 μl of stock solution 500 mM sodium orthovanadate 1 mM 100 / I of 1 M stock solution 1 mM DTT 100 μl of 1 M stock solution water 92.3 ml Prepare the master ATP mixture as follows: Prepare 1 ml of a 1 M ATP solution in water (stock solution of ATP 1 M). To 12 ml of KB: Add 12 μl of 1 M ATP solution, then Add 12 μl of 33P ATP (10 μCi / μl), NEG602H, Perkin Elmer Prepare the reaction plate and perform the assay as follows: Add 10 μl of KB per well with or without the inhibitor test compound to the wells of the reaction plate. 2. Add 60 μl of KB per well. 3. Add 10 μl of 500 μM substrate peptide per well. 4. Bring the plate to 37 ° C. 5. Add 10 μl of 1: 10 dilution of CK1d per well = 0.42 μg or 0.68 units. 6. Start the reaction with 10 μl of master ATP mix per well. • 7. Introduce the reaction plate in an incubator at 37 ° C for 10 minutes. 8. Finish the reaction with 10 μl of 1 M ATP. Transfer 20 μl to the SAM plate and let stand 10 minutes at room temperature. 9. Wash three times with 100 μl of 2 M NaCl solution, then three times with 100 μl of 2 M NaCl and 1% H3P0 solutions and then three times with 100 μl of water in a multiple vacuum apparatus. 10. Dry the filter plate with a lamp for 30 minutes. 11. Seal the bottom of the plate and add 20 μl of MicroScint 20. 12. Take the reading in TOPCOUNT. Experimental procedures of circadian assays in cells Cell culture: Mper1-luc Rat-1 (P2C4) fibroblast cultures were distributed every 3-4 days (confluence of -10-20%) in 150 cm2 ventilated tissue culture flasks ( Falcon No. 35-5001) and were maintained in growth medium [EMEM (Cellgro No. 10-010-CV); 10% fetal bovine serum (FBS, Gibco n ° 16000-044); and 50 U./ml of penicillin-streptomycin (Cellgro No. 30-001 -C1)] at 37 ° C and 5% C02. Stable transfection: Rat-1 fibroblast cultures with 30-50% confluency were co-transfected with vectors containing the selectable Zeocin resistance marker for stable transfection and a control luciferase gene controlled by the mPer-1 promoter. After 24-48 hours, the cultures were distributed in 96-well plates and maintained in growth medium supplemented with 50-100 μg / ml Zeocin (Invitrogen No. 45-0430) for 10-14 days. Stably transfected cells with Zeocin resistance were analyzed for control expression by supplementing the growth medium with 100 μM luciferin (Promega # E1603) and analyzing the luciferase activity in a TopCount scintillometer (Packard Model # C384V00) . Rat-1 clones expressing both Zeocin resistance and mPerl-controlled luciferase activity were synchronized by shock with 50% horse serum [HS (Gibco n ° 16050-122)] and analyzed to determine the circadian activity of the control. The P2C4 clone of the Mperl-luc Rat-1 fibroblasts was selected for the experimentation of the compounds. Synchronization protocol: Mper1-luc Rat-1 (P2C4) fibroblasts were plated (40-50% confluency) in 96-well opaque tissue culture plates (PerkinElmer No. 6005680) and maintained in growth medium supplemented with 100 μg / ml Zeocin (Invitrogen No. 45-0430) until the cultures reached a confluence of 100% (48-72 hours). The cultures were synchronized with 100 μl of synchronization medium [EMEM (Cellgro n ° 10-010-CV); 100 U./ml of penicillin-streptomycin (Cellgro No. 30-001 -C1); 50% HS (Gibco No. 16050-122)] for 2 hours at 37 ° C and 5% C02. After synchronization, the cultures were rinsed with 100 μl of EMEM (Cellgro # 10-010-CV) for 10 minutes at room temperature. After rinsing, the media was replaced with 300 μl of C02-independent medium [C02I (Gibco n ° 18045-088); 2 mM L-glutamine (Cellgro No. 25-005-C1); 100 U. I.ml penicillin-streptomycin (Cellgro No. 30-001-C1); 100 μM luciferin (Promega No. E1603)]. Compounds that were being analyzed for circadian effects were added to a C02-independent medium in 0.3% DMSO (final concentration). The cultures were immediately sealed with a TopSeal-A coating (Packard No. 6005185) and transferred to measure the luciferase activity. Automated circadian control measurement: After synchronization, the assay plates were maintained at 37 ° C in a tissue culture incubator (Forma Scientific Model No. 3914). Luciferase activity was estimated in vivo by measuring the relative light production in a TopCount scintillometer (Packard Model No. C384V00). The plates were transferred from the incubator to the scintillometer using an ORCA robotic arm (Beckman Instruments) and an automated organization program SAMI-NT (Version 3.3, SAGIAN / Beckman Instruments). Data analysis: Microsoft Excel and XLfit were used (Version 2. 0.9; IDBS) to import, manipulate and represent the data. The analysis of the periods was carried out by determining the interval between the minimums of light production during several days or by Fourier transform. Both procedures produced identical estimates of the periods for a range of circadian periods. The power is expressed in terms of CE? T + ih, which is presented as the effective micromolar concentration that induced 1 hour of elongation of the periods. The data were analyzed by fitting a hyperbolic curve to the data expressed in terms of change in the period (y axis) as a function of the concentration of experimental compound (x-axis) in XLfit and the CE? T + -ih was interpolated from this curve. Table 4 Biological data denotes the average of 2 or more determinations

Claims (44)

1. A compound of the formula (I) wherein: R-i is H or alkyl R2 is NR5R6; R3 is aryl or heterocycle; R is H, C-? -6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C-? 6 alkoxy, CF3, halogen, SH, S-C6-alkyl, N02, NH2 or NR5R6; R5 is H or C1-6 alkyl; R6 is H or C-? -6 alkyl; X is S or S (0) n; one of K, L or M is N and the other two members of K, L or M are each C in which R4 is attached only to one K, L, M or to another ring atom that is C; m is 1, 2 or 3; and n is 1 or 2; or a pharmaceutically acceptable salt or stereoisomer thereof.
2. 2. - The compound according to claim 1 wherein L is N, and K and M are each C.
3. 3. - The compound according to claim 2 wherein R-i, R4, Rs and RT are each H and R3 is aryl.
4. 4. The compound according to claim 3 which is selected from the group consisting of: 3-phenylsulfanyl-1 H -pyrrolo [3,2-c] pyridine-2-carboxylic acid amide, 3- (3-) -3-amide fluorophenylsulfanyl-1Hrrrolo [3,2-c] pyridine-2-carboxylic acid and 3- (4-chlorophenylsulfanyl-1H-pyrrolo [3,2-c] pyridin-2-carboxylic acid) amide.
5. 5. - The compound according to claim 1 wherein M is N, and K and L are each C.
6. 6. - The compound according to claim 5 wherein R-i, R, R5 and R6 are each H and R3 is aryl or heterocycle.
7. 7. The compound according to claim 6 which is selected from the group consisting of: 3-phenylsulfanyl-1 H -pyrrolo [2,3-c] pyridine-2-carboxylic acid amide, 3- (3-) -3-amide fluorophenylsulfanyl) -1 H -pyrrolo [2,3-c] pyridine-2-carboxylic acid, 3- (3-methoxyphenylsulfanyl) -1 H -pyrrolo [2,3-c] pyridine-2-carboxylic acid amide, 3- (3-Chlorophenylsulfanyl) -1 H -pyrrolo [2,3-c] pyridine-2-carboxylic acid amide, 3- (2-trifluoromethylphenylsulfanyl) -1 H -pyrrolo [2,3-c] pyridine-2-carboxylic acid, 3- (2-trifluoromethoxyphenylsulfanyl) -1 H -pyrrolo [2,3-c] pyridine-2-carboxylic acid amide, 3- (2-methoxyphenylsulfanyl) -1 Hp rrolo [2,3-c] pyridine-2-carboxylic acid, and 3- (pyridin-2-sulfanyl) -1 H -pyrro! or [2,3-c] pyridine-2-carboxylic acid amide.
8. 8. - The compound according to claim 1 wherein K is N and L and M are each C.
9. 9. The compound according to claim 8 wherein R-i is C6 alkyl, R5 is H, R6 is H or C6-alkyl, and R3 is aryl.
10. 10. The compound according to claim 9 which is selected from the group consisting of: 1-methyl-3-phenylsulfanyl-1 H -pyrrolo [3,2-b] pyridine-2-carboxylic acid methylamide, acid amide 1 -methyl-3-phenylsulfanyl-1 H -pyrrolo [3,2-b] pyridin-2-carboxylic acid, and 3-phenylsulfanyl-1-propyl-1 H -pyrrolo [3,2-b] pyridinamide -2-carboxylic acid.
11. 11. - The compound according to claim 8 wherein R-i, R and R5 are each H, R3 is aryl and Re is C-? -6 alkyl.
12. 12. The compound according to claim 11 which is selected from the group consisting of: 3- (3-trifluoromethyloxyphenylsulfanyl-1H-pyroolo [3,2-b] pyridine-2-carboxylic acid methylamide, 3-methylamide (3-chlorophenylsulfanyl-1H-pyrrolo [3,2-b] pyridine-2-carboxylic acid, 3- (3-fluorophenesulfanyl-1H-pyrrolo [3,2-b] pyridine-2-carboxylic acid methylamide, and 3-phenylsulfanyl-1 H -pyrrolo [3,2-b] pyridine-2-carboxylic acid methylamide.
13. 13. - The compound according to claim 8 wherein R-i, R4, Rs and Re are each H and R3 is heterocycle.
14. 14. The compound according to claim 13 is selected from the group consisting of: 3- (quinolin-8-ylsulfanyl) -1 H -pyrrolo [3,2-b] pyridine-2-carboxylic acid amide, acid amide 3- (pyridin-2-sulfanyl) -1 H -pyrrolo [3,2-b] pyridine-2-carboxylic acid amide of 3- (pyridin-4-sulfanyl) -1 H -pyrrolo [3,2] -b] pyridine-2-carboxylic acid, and 3- (tiophen-2-ylsulfanyl) -1 H -pyrrolo [3,2-b] pyridin-2-carboxylic acid amide.
15. 15. - The compound according to claim 8 wherein R-t, R5 and R6 are each H and R3 is aryl.
16. 16. - The compound according to claim 15 which is selected from the group consisting of: 3-phenylsulfanyl-1 H -pyrrolo acid amide [3, 2-b] pyridine-2-carboxylic acid, 3- (3-fluorophenylsulfanyl) -1 H -pyrrolo [3,2-b] pyridine-2-carboxylic acid amide, 3- (3-chlorophenylsulfanyl) -amide 1 H-Pyrrolo [3,2-b] pyridine-2-carboxylic acid, 3- (3-bromophenylsulfanyl) -1 H -pyrrolo [3,2-b] pyridin-2-carboxylic acid amide, acid amide 3- (2-Chlorophenylsulfanyl) -1 H -pyrrolo [3,2-b] pyridine-2-carboxylic acid amide of 3- (4-chlorophenylsulfanyl) -1 H -pyrrolo [3,2-b] pyridine -2-carboxylic acid, 3- (2,4-dichlorophenylsulfanyl) -1 H -pyrrolo [3,2-b] pyridine-2-carboxylic acid amide, 3- (2-fluorophenylsulfanyl) -1 Hyrroloic acid amide [3,2-b] pyridine-2-carboxylic acid, 3- (2,3-dichlorophenylsulfanyl) -1 H -pyrrolo [3,2-b] pyridin-2-carboxylic acid amide, amide 3- (2-Trifluoromethylphenylsulfanyl) -1H-pyrrolo [3,2-b] pyridine-2-carboxylic acid, 3- (3-trifluoromethyl-phenylsulfanyl) -1H-pyrrolo [3,2-b] pyridine- 2-carboxylic acid 3- (2-aminophenylsulfanyl) -1 H -pyrrolo [3,2-b] pyridine-2-carboxylic acid amide, 3- (2,5-Dichlorophenylsulfanyl) -1 H -pyrrolo [3,2- b] pyridine-2-carboxylic acid amide, 3- (2-methoxyphenylsulfanyl) -1H-pyrrolo [3,2-] b) pyridine-2-carboxylic acid, 3- (3-methoxyphenylsulfanyl) -1 H -pyrrolo [3,2-b] pyridine-2-carboxylic acid amide, 3- (3-aminophenylsulfanyl) -1H-pyrroloic acid amide [3,2-b] pyridine-2-carboxylic acid, 3- (4-nitrophenylsulfanyl) -1 H -pyrrolo [3,2-b] pyridine-2-carboxylic acid amide, 3- (3-nitrophenylsulfanyl) amide ) -1 H -pyrrolo [3,2-b] pyridine-2-carboxylic acid, 3-o-tolylsulfanyl-1 H -pyrrolo [3,2-b] pyridine-2-carboxylic acid amide, 3-aminide p -tolysulfanyl-1 H -pyrrolo [3,2-b] pyridine-2-carboxylic acid, 3- (3,5-dimethylphenylsulfanyl) -1 H -pyrrolo [3,2-b] pyridine-2-carboxylic acid amide , 3-m-Tolylsulfanyl-1 H -pyrrolo [3,2-b] pyridine-2-carboxylic acid amide, 3- (2-ethylphenylisulfanyl) -1 H -pyrrolo [3,2-b] pyridine -2-carboxylic acid, 3- (3-trifluoromethoxyphenylsulfanyl) -1 H -pyrrolo [3,2-b] pyridi amide n-2-carboxylic acid, 3- (3-fluorophenylsulfanyl) -5-methoxy-1 H -pyrrolo [3,2-b] pyridine-2-carboxylic acid amide, and 3- (3-methoxyphenylsulfanyl) amide - 5-methoxy-1 H -pyrrolo [3,2-b] pyridine-2-carboxylic acid.
17. 17. - A pharmaceutical composition comprising a pharmaceutical carrier and a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt or a stereoisomer thereof, of the formula (I) wherein: R-i is H or C-6 alkyl; R2 is NR5R6; R3 is aryl or heterocyclic; R is H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, CF 3, halogen, SH, S-C 1-6 alkyl, N 0 2, NH 2 or NR 5 R 6; R5 is H or C1-6 alkyl; R6 is H or C-6-alkyl; X is S or S (0) n; one of K, L or M is N and the other two members of K, L or M are each C in which R4 is attached only to one K, L, M or to another ring atom that is C; m is 1, 2 or 3; and n is 1 or 2.
18. 18. A method for inhibiting casein kinase activity in a patient comprising administering to said patient a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt or stereoisomer thereof, of the formula (I) wherein: R-i is H or C-i-β alkyl; R2 is NR5R6; R3 is aryl or heterocycle; R4 is H, C6-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, CF3, halogen, SH, S-C1-6 alkyl, N02l NH2 or NR5RT; Rs is H or C? _6 alkyl; Re is H or C-I-T alkyl; X is S or S (0) n; one of K, L or M is N and the other two members of K, L or M are each C in which R is attached only to one K, L, M or to another ring atom that is C; m is 1, 2 or 3; and n is 1 or 2.
19. 19. A method for treating a patient suffering from a disease or disorder that is improved by inhibiting casein kinase comprising administering to said patient a therapeutically effective amount of a compound or a pharmaceutically acceptable salt or stereoisomer thereof of the formula (I). ) wherein: R-i is H or C 1-6 alkyl; R2 is NR5R6; R3 is aryl or heterocycle; R 4 is H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, CF 3, halogen, SH, S-C 1-6 alkyl, N 0 2, NH 2 or NR 5 R 6; R5 is H or C1-6 alkyl; R6 is H or C1-6 alkyl; X is S or S (0) n; one of K, L or M is N and the other two members of K, L or M are each C in which R4 is attached only to one K, L, M or to another ring atom that is C; m is 1, 2 or 3; and n is 1 or 2.
20. 20. - The method according to claim 19 wherein the disease or disorder is a mood disorder or a sleep disorder.
21. 21. - The method according to claim 20 wherein the disorder is mood disorder.
22. 22. - The method according to claim 21 wherein the mood disorder is selected from a depressive disorder or a bipolar disorder.
23. 23. - The method according to claim 22 wherein the depressive disorder is major depressive disorder.
24. 24. - The method according to claim 22 wherein the bipolar disorder is selected from the group consisting of bipolar I disorder and bipolar II disorder.
25. 25. - The method according to claim 20 wherein the disorder is a sleep disorder.
26. 26. - The method according to claim 25 wherein the sleep disorder is a sleep disorder due to the circadian rhythm.
27. 27. - The method according to claim 26 wherein the sleep disorder due to circadian rhythm is selected from the group consisting of sleep disorder by change of work shift, jet lag syndrome, advanced phase sleep syndrome and syndrome of late phase of sleep.
28. 28. - A process for the preparation of a compound of the formula (I) wherein: Ri is H; R2 is NH2; R3 is aryl or heterocycle; R 4 is H, C 1-4 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, CF 3, halogen, SH, S-C 1-6 alkyl, N 0 2, NH 2 or NR 5 R 6; R5 is H or C1-6 alkyl; R6 is H or C1-6 alkyl; X is S; one of K, L or M is N and the other two members of K, L or M are each C in which R4 is attached only to one K, L, M or to another ring atom that is C; and m is 1, 2 or 3; comprising the step of treating a malonic diester with a suitable base in a suitable solvent, adding a 2-chloro-3-nitropyridine, 3-chloro-4-nitropyridine or unsubstituted or substituted 4-chloro-3-nitropyridine, heating the reaction mixture until the reaction is complete, treat the reaction mixture with a mineral acid and heat the reaction mixture until the decarboxylation is complete providing a 2-methyl-3-nitropyridine, 3-methyl-4-nitrofyridine or unsubstituted or substituted 4-methyl-3-nitropyridine.
29. 29. The process of claim 28 wherein the malonic diester is diethyl malonate, the base is sodium t-butoxide, the solvent is N-methyl-2-pyrrolidinone and the mineral acid is sulfuric acid.
30. 30. - The method of claim 29 wherein 2-methyl-3-nitropyridine is prepared.
31. 31. - The method of claim 28 further comprising the step of adding a 2-methyl-3-nitropyridine, 3-methyl-4-nitropyridine or 4-methyl-3-nitropyridine unsubstituted or substituted to a mixture of a suitable solvent, a suitable base and an oxalate diester providing a 2-hydroxy-3- (3-nitropyridin-2-yl) acrylic acid ester, 2-hydroxy-3- (4-nitropyridin-3-yl) ester acrylic or ester of unsubstituted or substituted 2-hydroxy-3- (3-n -tropyridin-4-yl) acrylic acid or its corresponding tautomeric ketone.
32. 32. - The process of claim 31 wherein the oxalate diester is diethyl oxalate, the solvent is tetrahydrofuran and the base is sodium ethoxide.
33. 33. - The method of claim 32 wherein 2-hydroxy-3- (3-nithropyridin-2-yl) acrylic acid ethyl ester is prepared.
34. 34. - The method of claim 28 further comprising the step of reducing an ester of 2-hydroxy-3- (3-nitropyridin-2-yl) acrylic acid ester of 2-hydroxy-3- (4-n) tropirdin-3-yl) acrylic or ester of 2-hydroxy-3- (3-nitropyridin-4-yl) acrylic acid unsubstituted or substituted in a suitable solvent with a suitable catalyst to give an ester of 1 H-pyrrolo acid [3,2-b] pyridine-2-carboxylic acid, 1 H-pyrrolo [3,2-c] pyridine-2-carboxylic acid ester or 1 H-pyrrolo [2,3-c] pyridin ester -2-carboxylic acid unsubstituted or substituted.
35. 35. - The process of claim 34 wherein the solvent is absolute ethanol and the catalyst is palladium on carbon.
36. 36. - The process of claim 35 wherein 1 H-pyrrolo [3,2-b] pyridine-2-carboxylic acid ethyl ester is prepared.
37. 37. - The process of claim 28 further comprising the step of adding an ester of 1 H-pyrrolo [3,2-b] pyridine-2-carboxylic acid ester of 1 H-pyrrolo [3,2-c] pyrid N-2-carboxylic acid or 1 H -pyrrolo [2,3-c] pyridine-2-carboxylic acid ester unsubstituted or substituted by ammonia in a suitable solvent to give an amide of 1 H-pyrrolo acid [3,2- b) pyridine-2-carboxylic acid, 1 H-pyrrolo [3,2-c] pyridine-2-carboxylic acid amide or 1 H -pyrrolo [2,3-c] pyridine-2-carboxylic acid amide replaced or replaced.
38. 38. - The method of claim 37 wherein the solvent is methanol.
39. 39. - The process of claim 38 wherein 1 H-pyrrolo [3,2-b] pyridine-2-carboxylic acid amide is prepared.
40. 40. - The process of claim 28 further comprising the step of adding an amide of 1 H-pyrrolo [3,2-b] pyridine-2-carboxylic acid amide, 1 H-pyrrolo [3,2-c] pyridin amide -2-carboxylic or unsubstituted or substituted 1 H-pyrrolo [2,3-c] pyridine-2-carboxylic acid amide, an excess amount of a suitable base and a diaryl disulfide or a diheterocycle disulfide to a solvent and heating to give a compound of the formula (I) in which Ri is hydrogen.
41. 41. The process according to claim 40 wherein the excess amount of base is from about 2.0 to about 2.5 equivalents, the base is cesium carbonate and the diaryl disuifide is diphenium disulfide or bis disulfide. - (3-fluorophenyl).
42. 42. - The process according to claim 41 wherein 3-phenylsulfanyl-1 H -pyrrolo [3,2-b] pyridine-2-carboxylic acid amide is prepared.
43. 43. - The process according to claim 41 wherein 3- (3-fluorophenylsulfanyl) -1 H -pyrrolo [3,2-b] pyridine-2-carboxylic acid amide is prepared.
44. 44. - A compound of the formula (I) prepared by a process comprising the steps of: a. Treat a malonic diester with a suitable base in a suitable solvent, add a 2-chloro-3-nitropyridine, 3-chloro-4-nitropyridine or unsubstituted or substituted 4-chloro-3-nitropyridine, heat the reaction mixture until the reaction is complete, treat the reaction mixture with a mineral acid and heating the reaction mixture until the decarboxylation is complete to give a 2-methyl-3-n -tropyridine, 3-methyl-4-nitropyridine or 4-methyl-3-nitropyridine unsubstituted or substituted, b. add a 2-methyl-3-nitropyridine, 3-methyl-4-nitropyridine or 4-methyl-3-nitropyridine unsubstituted or substituted to a mixture of a suitable solvent, a suitable base and an oxalate diester to provide an ester of 2-hydroxy-3- (3-nitropyridin-2-yl) acrylic acid ester, 2-hydroxy-3- (4-nitropyridin-3-yl) acrylic acid ester or 2-hydroxy acid ester 3- (3-Nitropyridin-4-yl) acrylic unsubstituted or substituted, or its corresponding tautomeric ketone, c. reduce a 2-hydroxy-3- (3-nitropyridin-2-yl) acrylic acid ester, 2-hydroxy-3- (4-n -tropyridin-3-yl) acrylic acid ester or 2-h acid ester Droxi-3- (3-nitropyridin-4-yl) acrylic unsubstituted or substituted in a suitable solvent with a suitable catalyst to give an ester of 1 H-pyrrolo [3,2-b] pyridine-2-carboxylic acid, ester of 1 H-pyrrolo [3,2-c] pyridine-2-carboxylic acid or 1 H-pyrrolo [2,3-c] pyridine-2-carboxylic acid unsubstituted or substituted ester, d. add a 1 H -pyrrolo [3,2-b] pyridine-2-carboxylic acid ester, 1 H -pyrrolo [3,2-c] pyridine-2-carboxylic acid ester or 1 H -pyrrolo acid ester [ 2,3-c] pyridine-2-carboxylic acid unsubstituted or substituted by ammonia in a suitable solvent to give a 1H-pyrrolo [3,2-b] pyridine-2-carboxylic acid amide, 1 H-pyrrolo acid amide [ 3,2-c] pyridine-2-carboxylic acid or unsubstituted or substituted 1 H-pyrrolo [2,3-c] pyridine-2-carboxylic acid amide, and e. add 1 H-pyrrolo [3,2-b] pyridine-2-carboxylic acid amide, 1 H-pyrrolo [3,2-c] pyridine-2-carboxylic acid amide or 1 H-pyrrolo acid amide [ 2,3-c] unsubstituted or substituted pyridine-2-carboxylic acid, an excess amount of a suitable base and a diaryl disulfide or a diheterocycle disulfide to a suitable solvent to provide a compound of the formula (I) in which R is H; R2 is NH2; R3 is aryl or heterocycle; R is H, C - ?. alquilo alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C alco _ alkoxy, CF 3, halogen, SH, S-C 1-6 alkyl, NO 2, NH 2 or NR 5 R 6; Rs is H or C? -6 alkyl; R6 is H or C1-6 alkyl; X is S or S (0) n; one of K, L or M is N and the other two members of K, L or M are each C in which R4 is attached only to one K, L, M or to another ring atom that is C; and m is 1, 2 or 3.