MXPA06003639A - Spirocyclic heterocyclic derivatives and methods of their use - Google Patents

Abstract

Spirocyclic heterocyclic derivatives, pharmaceutical compositions containing these compounds, and methods for their pharmaceutical use are disclosed. In certain embodiments, the spirocyclic heterocyclic derivatives are ligands of the delta opioid receptor and may be useful, inter alia, for treating and/or preventing pain, anxiety, gastrointestinal disorders, and other delta opioid receptor-mediated conditions.

Description

HETEROCICLIC ESPIROCICLIC DERIVATIVES AND PROCEDURES FOR USE CROSS REFERENCES TO RELATED APPLICATIONS This application claims priority for the provisional US application. Serial No. 60 / 507,864, filed on October 1, 2003, the complete description of which is incorporated herein by reference in its entirety. FIELD OF THE INVENTION The invention relates to heterocyclic spirocyclic derivatives (including spiro derivatives (2 / - / - 1-benzopyran-2,4'-piperidines), to pharmaceutical compositions containing these compounds, and to methods for their use. In certain embodiments, the heterocyclic spirocyclic derivatives are opioid receptor ligands and are useful, inter alia, in the treatment and / or prevention of pain, anxiety, gastrointestinal disorders, and other conditions mediated by the opioid receptor. OF THE INVENTION There are at least three different opiate receptors (μ, d and K) which are present in both the central and peripheral nervous systems of numerous species, including humans, Lord, JAH, et al., Nature, 1977, 267, 495. The activation of opioid receptors d induces analgesia in various animal models, Moulin, et al., Pain, 1985, 23, 213. Some studies suggest that functional or analgesic in opioid receptors d do not exhibit the related side effects associated with the activation of the μ and K. opioid receptor. Galligan, et al., J. Pharm. Exp. Ther., 1985, 229, 641 It has also been identified that the opioid receptor d has a role in the circulatory systems. It has also been shown that the ligands for the receptor d possess immunomodulatory activity. Dondio, et al., Exp. Opin. Ther. Patents, 1997, 10, 1075. In addition, selective opioid receptor agonists d have been shown to promote organ and cell survival. Su, T-P, Journal of Biomedical Science, 2000, 9 (3), 195-199. The ligands for the opiate receptor d may therefore have a potential use as analgesics, as antihypertensive agents, as immunomodulatory agents and / or agents. Numerous selective ligands of the opioid receptor d are peptidic in nature and thus are not suitable for administration by systemic routes. Several ligands have been developed for the non-peptide opiate receptor d. See, for example, E. J. Bilsky, et al., Journal of Pharmacology and Experimental Therapeutics, 1995, 273 (1), 359-366; WO 93/15062, WO 95/04734, WO 95/31464, WO 96/22276, WO 97/10216, WO 01/46192, WO 02/094794, WO 02/094810, WO 02/094811, WO 02/094812, WO 02/48122, WO 03/029215, WO 03/033486, JP-4275288, EP-A-0,864,559, US-A-5,354,863, US-B-6,200,978, US-B-6,436,959 and US 2003/0069241 Although there are a large number of non-peptide opioid receptor modulators, there is still an unmet need for compounds with selective opioid receptor activity that can be used in methods to provide beneficial pharmaceutical characteristics while minimizing undesirable side effects.

The present invention relates to these, as well as to other important purposes. SUMMARY OF THE INVENTION In one aspect, the invention relates to compounds of formula I: I wherein: R1 and R3 are each independently H, alkyl, alkenyl, alkynyl, or aryl, or R1 and R3 when taken together with the atoms through which they are connected, form a heterocycloalkyl ring of 4 to 8 members; R2 is H, alkyl, alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl, aralkyl, or heteroarylalkyl, or R1 and R2 when taken together with the atoms through which they are connected, form a 4- to 8-membered heterocycloalkyl ring, or R2 and R3 when taken together with the atoms through which they are connected, form a 4 to 8 membered heterocycloalkyl ring; with the condition of each Ra is independently H or alkyl; each Rb is independently H, alkyl, or aryl; n is the integer 0, 1, 2 or 3; A and B are each independently H, fluoro, or alkyl, or together form a double bond between the carbon atoms to which they are attached; R4 is -Y-W; Y is a simple bond, C (Ra) (Rb), C (Ra) (Rb) C (Ra) (Rb), or C (Ra) (Rb) C (Ra) (Rb) C (Ra) (Rb) ); W is aryl or heteroaryl; X is -CHa-, -O-, -S-, -SO, -SO2, or -N (R5) -; R5 is H, alkyl, cycloalkyl, - (CH2) -alkenyl, - (CH2) -alkynyl, aryl, -CORb, or -SO2Rb; and J forms a 6-membered aryl ring or a 5- or 6-membered heteroaryl ring when taken together with the carbon atoms to which it is attached; with the proviso that when: (a) J is taken together with the carbon atoms to which it is attached it forms a phenyl ring substituted with 0-3 groups selected from the group consisting of: halogen, hydroxy, -S-C1- alkyl 4, CM alkyl, and C ^ alkoxy, the latter two optionally substituted with one or more halogens or with alkoxy W is unsubstituted naphthyl, or phenyl substituted with 0-3 groups selected from the group consisting of: halogen, C1-6 alkyl, C 1-6 alkoxy, phenyl, phenyloxy, 1,3-benzodioxazolyl or 2,2-difluoro-1,3-benzodioxazolyl, -NH 2, -IM (C 1-4 alkyl) 2, and pyrrolyl; n is 1, R1 and R3 are each H, A and B together form a double bond between the carbon atoms to which they are attached, and is a single bond; and X is -O-; then R2 is other than H or methyl; and with the proviso that when: (b) J is taken together with the carbon atoms to which it is attached it forms a phenyl ring, W is phenyl substituted with 0-3 groups selected from the group constituted by: fluorine, hydroxy, alkoxy C1-6 optionally substituted with one or more fluoros, C2-6 alkenyloxy, and -S-C1alkyl-, n is 1, R1 and R3 are each H, A and B together form a double bond between the carbon atoms at which are united, and it is a simple link; and X is -O-; then R2 is other than H or benzyl; and with the proviso that when: 6-membered aryl ring, it is not substituted with: or one of its stereoisomers, prodrugs, pharmaceutically acceptable salts, hydrates, solvates, acid salt hydrates, or N-oxides. In other aspects, the invention relates to compounds of formula IV: IV where: Y2 is a single bond or - [C (Rc) (Rd)] k-; each Rc, Re, and Rf is independently H or alkyl; each Rd is independently H, alkyl, or aryl; W2 is aryl, alkylaryl, heterocycloalkylaryl, heteroaryl, alkylheteroaryl, heteroarylaryl, or alkylheteroarylaryl; R23 and R24 are each independently H, alkyl, alkenyl, alkynyl, or aryl, or R23 and R24 when taken together with the atoms through which they are connected, form a cycloalkyl or heterocycloalkyl ring of 4 to 8 members; Z is -N (R25) -, -C (= O) -, -CH (OH) -, -CH (N (Rc) (Rd)) -, or -O-; R25 is H, alkyl, alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl, aralkyl, or heteroarylalkyl, or R23 and R25 when taken together with the atoms through which they are connected, form a 4- to 8-membered heterocycloalkyl ring, or R24 and R25 when taken together with the atoms through which they are connected, form a 4- to 8-membered heterocycloalkyl ring; each k is independently 1, 2, or 3; p is O, 1, 2 or 3; s is 0, 1, 2 or 3, with the proviso that the sum of p and s is 4; A2 and B2 are each independently H, fluoro, or alkyl, or together they form a double bond or -CH2-; G is H or alkyl; X2 is -C (R °) (Rd) -, -O-, -S-, -S (= O) -, -S (= O) 2-, -C (= O) -, -CH (OH ) - or -N (R26) -; R26 is H, alkyl, cycloalkyl, - (CH2) -alkenyl, - (CH2) -alkynyl, aryl, -C (= O) Rd, or -S (= O) 2Rd; and J2 forms a 6 to 10 membered aryl or a 5- to 10 membered heteroaryl ring when taken together with the carbon atoms to which it is attached; with the proviso that when: (a) J2 is taken together with the carbon atoms to which it is attached it forms a 6 to 10 membered aryl ring substituted with 0-3 groups selected from the group consisting of: halogen, hydroxy, - SH, -C (= O) -H -S-C 1-4 alkyl, -NHS (= O) 2-C 1-4 alkyl, -NHS (= O) 2-H, -N (C 1-4 alkyl) S (= O) 2-H, alkyl CM, and alkoxy C-, the last two optionally substituted with one or more halogens or with alkoxy CM; W 2 is phenyl substituted with 0-3 groups selected from the group consisting of: halogen, cyano, hydroxy, C 1-6 alkyl optionally substituted with one or more halogens, C 1-6 alkoxy optionally substituted with one or more halogens or with C 3-6 cycloalkyl , C 2-6 alkenyloxy, C 2-6 alkynyloxy, C 3-6 cycloalkyloxy, C 6-2 aryloxy, aralkoxy, heteroaryloxy, heteroaralkoxy, heterocycloalkyl substituted with alkoxy, -SH, -S-alkyl CM, -NH 2, -N = C (aryl) 2, -N (H) C 1-4 alkyl, -N (C 1-6 alkyl) 2, -OS (= O) 2-Cw alkyl optionally substituted with one or more halogens, -OS (= O) 2- C6-12 aryl optionally substituted with C1-4alkyl-NHS (= O) 2-C1alkyl, -N (C-alkyl) S (= O) 2-C1-4alkyl, -NHS (= O) 2-H, and -N (C1-4 alkyl) S (= O) 2-H; p and s are each 1, Re, Rf, R23, R24, and G are each H, A2 and B2 together form a double bond, Y2 is a single bond; and X2 is -O-; then Z is different from: , where t is an integer between 1 and 20; and with the proviso that when: (b) J2 is taken together with the carbon atoms to which it is attached it forms a phenyl ring substituted with 0-3 groups selected from the group consisting of: halogen, hydroxy, -S-alkyl CM , alkyl C, and alkoxy CM, the last two optionally substituted with one or more halogens or with C? -4 alkoxy; W2 is unsubstituted naphthyl, or phenyl substituted with 0-3 groups selected from the group consisting of: halogen, C1-6 alkyl, C1-6 alkoxy, phenyl, phenyloxy, 1,3-benzodioxazolyl, or 2,2-difluoro-1 , 3-benzodioxazoyl fluoro, -NH2, -N (C14 alkyl) 2, and pyrrolyl; p and s are each 1, Re, Rf, R23, R24, and G are each H, A2 and B2 together form a double bond, Y2 is a single bond; and X2 is -O-; then Z is different from: N «'N ^ 3 ^ ° ^; and with the proviso that when: (c) J2 is taken together with the carbon atoms to which unsubstituted phenyl form is attached, W2 is phenyl substituted with 0-3 groups selected from the group consisting of: fluoro, hydroxy, alkoxy C1-6 optionally substituted with one or more fluoros, C2-6 alkenyloxy, and -S-alkyl CM, pys are each 1, Re, Rf, R23, R24, and G are each H, A2 and B2 together form a double bond, Y2 is a simple link; and X2 is -O-; then Z is different from: with the proviso that when: (d) J2 is taken together with the carbon atoms to which it is attached it forms a 6-membered aryl ring substituted with: then Z is different from -N (R25) - or -CH (NH2) -; or one of its stereoisomers, prodrugs, pharmaceutically acceptable salts, hydrates, solvates, acid salt hydrates, or N-oxides. In another aspect, the invention relates to pharmaceutical compositions comprising a pharmaceutically acceptable carrier and an effective amount of a compound of the invention including, for example, a compound of formulas I, II, III, IV, V, VI, VII, VIII, IX, X, XI, Xll and / or Xlll. In certain embodiments, the pharmaceutical composition further comprises an effective amount of at least one opioid. In yet another aspect, the invention relates to methods of binding to opiate receptors, preferably opioid receptors d, in a patient in need thereof, comprising the step of administering to said patient an effective amount of a compound of the invention including, for example, a compound of formulas I, II, III, IV, V, VI, VII, VIII, IX, X, XI, Xll and / or Xlll. In preferred embodiments, the binding modulates the activity of the receptor. In certain other preferred embodiments, the binding has an agonistic effect on the activity of said opiate receptors. In other aspects, the invention relates to methods for the prevention or treatment of pain, comprising the step of administering to a patient in need thereof an effective amount of a compound of the invention including, for example, a compound of formulas I, II, III, IV, V, VI, VII, VII, IX, X, XI, Xll and / or Xlll. In another aspect, the invention relates to methods for the prevention or treatment of gastrointestinal dysfunction, comprising the step of administering to a patient in need of such treatment an effective amount of a compound of the invention including, for example, a composed of formulas I, II, III, IV, V, VI, VII, Vlll, IX, X, XI, Xll and / or Xlll. In another aspect, the invention relates to methods for the prevention or treatment of ileus, comprising the step of administering to a patient in need of such treatment an effective amount of a compound of the invention including, for example, a compound of formulas I, II, III, IV, V, VI, VII, VIII, IX, X, XI, Xll and / or Xlll. In another aspect, the invention relates to methods for the prevention or treatment of a disorder of the urogenital tract, comprising the step of administering to a patient in need of such treatment an effective amount of a compound of the invention including, example, a compound of formulas I, II, III, IV, V, VI, VII, VII, IX, X, XI, Xll and / or Xlll. In another aspect, the invention relates to methods for the prevention or treatment of an immunomodulatory disorder, comprising the step of administering to a patient in need thereof an effective amount of a compound of the invention including, for example, a compound of formulas I, II, III, IV, V, VI, VII, VII, IX, X, XI, XII and / or XIII. In another aspect, the invention relates to methods for the prevention or treatment of an inflammatory disorder, comprising the step of administering to a patient in need thereof an effective amount of a compound of the invention including, for example, a composed of formulas 1, II, III, IV, V, VI, VII, VII, IX, X, XI, Xll and / or Xlll. In another aspect, the invention relates to methods for the prevention or treatment of a respiratory function disorder, comprising the step of administering to a patient in need thereof an effective amount of a compound of the invention including, for example , a compound of formulas I, II, III, IV, V, VI, VII, Vlll, IX, X, XI, Xll and / or Xlll. In another aspect, the invention relates to methods for the prevention or treatment of anxiety, comprising the step of administering to a patient in need of such treatment an effective amount of a compound of the invention including, for example, a compound of formulas I, II, III, IV, V, VI, VII, VII, IX, X, XI, Xll and / or Xlll. In another aspect, the invention relates to methods for the prevention or treatment of a mood disorder, comprising the step of administering to a patient in need of such treatment an effective amount of a compound of the invention including, for example, a compound of formulas I, II, III, IV, V, VI, VII, Vlll, IX, X, XI, Xll and / or Xlll. In another aspect, the invention relates to methods for the prevention or treatment of a stress-related disorder, comprising the step of administering to a patient in need of such treatment an effective amount of a compound of the invention including, for example, a compound of formulas I, II, III, IV, V, VI, VII, VII, IX, X, XI, Xll and / or Xlll. In another aspect, the invention relates to methods for the prevention or treatment of attention deficit hyperactivity disorder, comprising the step of administering to a patient in need of such treatment an effective amount of a compound of the invention including , for example, a compound of formulas I, II, III, IV, V, VI, VII, VII, IX, X, XI, Xll and / or Xlll. In another aspect, the invention relates to methods for the prevention or treatment of disorders of the sympathetic nervous system, comprising the step of administering to a patient in need of such treatment an effective amount of a compound of the invention including, for example, a compound of formulas I, II, III, IV, V, VI, VII, VII, IX, X, XI, Xll and / or Xlll. In another aspect, the invention relates to methods for the prevention or treatment of cough, comprising the step of administering to a patient in need of such treatment an effective amount of a compound of the invention including, for example, a composed of formulas I, II, III, IV, V, VI, VII, VII, IX, X, XI, Xll and / or Xlll. In another aspect, the invention relates to methods for the prevention or treatment of a motor disorder, comprising the step of administering to a patient in need of such treatment an effective amount of a compound of the invention including, for example, a compound of formulas I, II, III, IV, V, VI, VII, Vlll, IX, X, XI, Xll and / or Xlll. In another aspect, the invention relates to methods for the treatment of a traumatic injury of the central nervous system, comprising the step of administration to a patient in need of such treatment of an effective amount of a compound of the invention including, for example, a compound of formulas I, II, III, IV, V, VI, VII, VII, IX, X, XI, Xll and / or Xlll. In another aspect, the invention relates to methods for the prevention or treatment of stroke, comprising the step of administering to a patient in need of such treatment an effective amount of a compound of the invention including, for example, a compound of formulas I, II, III, IV, V, VI, VII, VII, IX, X, XI, Xll and / or Xlll. In another aspect, the invention relates to methods for the prevention or treatment of cardiac arrhythmia, comprising the step of administering to a patient in need of such treatment an effective amount of a compound of the invention including, for example, a composed of formulas I, II, III, IV, V, VI, VII, VII, IX, X, XI, Xll and / or Xlll. In another aspect, the invention relates to methods for the prevention or treatment of glaucoma, comprising the step of administering to a patient in need of such treatment an effective amount of a compound of the invention including, for example, a compound of formulas I, II, III, IV, V, VI, VII, VII, IX, X, XI, Xll and / or Xlll. In another aspect, the invention relates to methods for the prevention or treatment of sexual dysfunctions, comprising the step of administering to a patient in need of such treatment an effective amount of a compound of the invention including, for example, a composed of formulas I, II, III, IV, V, VI, VII, Vlll, IX, X, XI, Xll and / or Xlll. In another aspect, the invention relates to methods for the treatment of a condition selected from the group consisting of concussion, cerebral edema, cerebral ischemia, cerebral deficits after cardiac bypass and graft surgery, systemic lupus erythematosus, Hodgkin's disease, Sjogren, epilepsy, and rejection in the transplantation of organs and in skin grafts, comprising the step of administration to a patient in need of such treatment of an effective amount of a compound of the invention including, for example, a compound of formulas I, II, III, IV, V, VI, VII, VII, IX, X, XI, Xll and / or Xlll. In another aspect, the invention relates to methods for the treatment of addiction to substances, comprising the step of administering to a patient in need of such treatment an effective amount of a compound of the invention including, for example, a compound of Formulas I, II, III, IV, V, VI, VII, VII, IX, X, XI, Xll and / or Xlll. In another aspect, the invention relates to methods for improving cellular and organic survival, comprising the step of administering to a patient in need of such treatment an effective amount of a compound of the invention including, for example, a compound of Formulas I, II, III, IV, V, VI, VII, VIII, IX, X, XI, Xll and / or Xlll. In another aspect, the invention relates to methods for providing cardioprotection after myocardial infarction, comprising the step of administering to a patient in need of such treatment an effective amount of a compound of the invention including, for example, a compound of formulas I, II, III, IV, V, VI, VII, Vlll, IX, X, XI, Xll and / or Xlll. In another aspect, the invention relates to methods for reducing the need for anesthesia, comprising the step of administering to a patient in need of such treatment an effective amount of a compound of the invention including, for example, a compound of formulas I, II, III, IV, V, VI, VII, VII, IX, X, XI, Xll and / or Xlll. In another aspect, the invention relates to methods for producing or maintaining an anesthetic state, comprising the step of administering to a patient in need of such treatment an effective amount of a compound of the invention including, for example, a compound of formulas 1, 11, III, IV, V, VI, VII, VII, IX, X, XI, Xll and / or Xlll. Preferably, the compound of the invention which includes, for example, a compound of formula I, II, III, IV, V, VI, VII, VII, X, XI, Xll, and / or Xlll is co-administered with an anesthetic agent selected from the group consisting of an inhaled anesthetic, a hypnotic, an anxiolytic, a neuromuscular blocker and an opiate. In certain aspects, the invention relates to radiolabelled derivatives and isotopically-labeled derivatives of the compounds of the invention including, for example, radiolabeled and isotopically-labeled derivatives of the compounds of formulas I, II, III, IV, V, VI, Vil, Vlll, IX, X, XI, Xll and / or Xlll. These and other aspects of the invention will become more apparent from the following detailed description. DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS The invention relates to heterocyclic spirocyclic derivatives, to pharmaceutical compositions containing these compounds, and to processes for their pharmaceutical use. In certain embodiments, the heterocyclic spirocyclic derivatives are opioid receptor ligands and d may be useful, inter alia, in methods for the treatment and / or prevention of diseases and conditions that may be mediated or modulated by the opiate receptor including, eg, example, pain, gastrointestinal disorders, disorders of the urogenital tract including incontinence and overactive bladder, immunomodulatory disorders, inflammatory disorders, respiratory function disorders, anxiety, mood disorders, stress-related disorders, hyperactivity disorders with anxiety deficit, sympathetic nervous system disorders, depression, cough, motor disorders, traumatic injuries, especially of the central nervous system, stroke, cardiac arrhythmias, glaucoma, dysfunctions disorders, concussion, cerebral edema, cerebral ischemia, cerebral deficits after cardiac bypass and graft surgery, systemic lupus erythematosus, Hodgkin's disease, Sjogren's disease, epilepsy, and rejection in organ transplantation and skin grafts, and addiction to substances. In certain other embodiments, heterocyclic spirocyclic derivatives are opioid receptor ligands and d may be useful in, among others, methods to improve organ and cell survival, methods of providing cardioprotection after myocardial infarction, methods to reduce the need for anesthesia, methods for producing and / or maintaining an anesthetic state, and methods for detecting, imaging or controlling the degeneration or dysfunction of opiate receptors in a patient. As used above and throughout the entire description, the following terms, unless otherwise indicated, are understood to have the following meanings. "Alkyl" refers to a linear, branched or cyclic saturated hydrocarbon, optionally substituted, having from about 1 to about 20 carbon atoms (and all combinations and subcombinations of ranges and specific numbers of carbon atoms contained therein), with about 1 to about 8 carbon atoms being preferred, referred to herein as "lower alkyl". Alkyl groups include, but are not limited to, methyl, ethyl, 7-propyl, isopropyl, 7-butyl, isobutyl, 1-butyl, n-pentyl, cyclopentyl, isopentyl, neopentyl, n-hexyl, isohexyl, 3-methylpentyl, 2,2-dimethylbutyl, and 2,3-dimethylbutyl. "Cycloalkyl" refers to an optionally substituted alkyl group having one or more rings in its structure and between about 3 and about 20 carbon atoms (and all combinations and subcombinations of ranges and specific numbers of carbon atoms contained therein) , with about 3 to about 10 carbon atoms being preferred. The multi-annular structures may be bridged or fused annular structures. Cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl, 2- [4-isopropyl-1-methyl-7-oxa-bicyclo [2.2.1] heptanyl], 2- [ 1, 2,3,4-tetrahydro-naphthalenyl], and adamantyl. "Alkylcycloalkyl" refers to an optionally substituted ring system comprising a cycloalkyl group having one or more alkyl substituents, wherein cycloalkyl and alkyl are each as previously defined. Examples of alkylcycloalkyl groups include, for example, 2-methylcyclohexyl, 3,3-dimethylcycline, trans-2,3-dimethylcyclooctyl, and 4-methyldehydcaphthalenyl. "Heterocycloalkyl" refers to an optionally substituted ring system composed of a cycloalkyl radical wherein in at least one of the rings, one or more of the carbon atoms of the ring members is independently replaced by a heteroatom group selected from the group constituted by O, S, N, and NH, wherein cycloalkyl is as previously defined. Preferred are heterocycloalkyl ring systems having a total of from about 5 to about 14 carbon atom ring members and about the ring heteroatom members (and all combinations and subcombinations of ranges and specific numbers of carbon and hetero atom ring members contained therein). In other preferred embodiments, the heterocyclic groups may be fused to one or more aromatic rings. Examples of heterocycloalkyl groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, piperazinyl, morpholinyl, piperadinyl, decahydroquinolyl, octahydrochromenyl, octahydro-cyclopenta [c] pyranyl, 1, 2,3,4 , -tetrahydroquinolyl, octahydro- [2] pyrindinyl, decahydro-cycloocta [c] furanyl, tetrahydroquinolyl, and imidazolidinyl. "Alkylheterocycloalkyl" refers to an optionally substituted ring system comprising a heterocycloalkyl group having one or more alkyl substituents, wherein heterocycloalkyl and alkyl are each as previously defined. Examples of alkylheterocycloalkyl groups include, for example, 2-methylpiperidinyl, 3,3-dimethylpyrrolidinyl, IraA7s-2,3-dimethylmorpholinyl, and 4-methyldehydroquinolinyl. "Alkenyl" refers to an optionally substituted alkyl group having between about 2 and about 10 carbon atoms and one or more double bonds (and all combinations and subcombinations of ranges and specific numbers of carbon atoms contained therein), wherein alkyl is as previously defined. "Alkynyl" refers to an optionally substituted alkyl group having between about 2 and about 10 carbon atoms and one or more triple bonds (and all combinations and subcombinations of ranges and specific numbers of carbon atoms contained therein), wherein alkyl is as previously defined. "Aryl" refers to a distinct mono-, di-, tri-, or multi-cyclic aromatic ring system, optionally substituted, having between about 50 and about 50 carbon atoms (and all combinations and subcombinations of ranges and numbers specific carbon atoms contained therein), with between about 6 and about 10 carbons being preferred. Non-limiting examples include, for example, phenyl, naphthyl, anthracenyl, and phenanthrenyl. "Aralkyl" refers to an optionally substituted moiety composed of an alkyl radical bearing an aryl substituent and having from about 6 to about 50 carbon atoms (and all combinations and subcombinations of ranges and specific numbers of carbon atoms contained in he), preferring between about 6 and about 10 carbons. Non-limiting examples include, for example, benzyl, diphenylmethyl, triphenylmethyl, phenylethyl, and diphenylethyl. "Halo" refers to a fluorine, chlorine, bromine, or iodine residue. "Heteroaryl" refers to an optionally substituted aryl ring system in which in at least one of the rings, one or more of the carbon atoms of the ring members is independently replaced by a heteroatom group selected from the group consisting of S, O , N, and NH, in which aryl is as previously defined. Heteroaryl groups having a total of from about 5 to about 14 carbon atom ring members and about ring hetero atom members are preferred (and all combinations and subcombinations of ranges and specific numbers of carbon and heteroatom ring members). Examples of heteroaryl groups include, but are not limited to, pyrryl, furyl, pyridyl, 1,4-thiadiazolyl, pyrimidyl, thienyl, isothiazolyl, imidazolyl, tetrazolyl, pyrazinyl, pyrimidyl, quinolyl, isoquinolyl, thiophenyl, benzothienyl, isobenzofuryl. , pyrazolyl, indolyl, purinyl, carbazolyl, benzimidazolyl, and isoxazolyl. The heteroaryl can be attached to the rest of the molecule through a carbon or a heteroatom. "Heteroarylalkyl" and "heteroaralkyl" each refers to an optionally substituted heteroaryl substituted alkyl radical, wherein heteroaryl and alkyl are as previously defined. Non-limiting examples include, for example, 2- (1 H -pyrrol-3-yl) ethyl, 3-pyridylmethyl, 5- (2H-tetrazolyl) methyl, and 3- (pyrimidin-2-yl) -2- methylcyclopentanyl. "Perhaloalkyl" refers to an alkyl group, wherein two or more hydrogen atoms have been replaced by halogen atoms (F, Cl, Br, I), and alkyl is as previously defined. Examples of perhaloalkyl groups include, for example, perhalomethyl, such as perfluoromethyl and difluoromethyl.

"Alkoxy" and "alkoxy" refer to an optionally substituted -O- alkyl group, wherein alkyl is as previously defined. Examples of alkoxy and alkoxy groups include, for example, methoxy, ethoxy, n-propoxy, / -propoxy, n-butoxy, and heptoxy. "Alkenyloxy" refers to an optionally substituted alkenyl-O- group, wherein alkenyl is as previously defined. Examples of alkenyloxy and alkenyloxy groups include, for example, allyloxy, butenyloxy, heptenyloxy, 2-methyl-3-buten-1-yloxy, and 2,2-dimethylalyloxy. "Alkynyloxy" refers to an optionally substituted alkynyl-O- group, in which alkynyl is as previously defined. Examples of alkynyloxy and alkynyloxy groups include, for example, propargyloxy, butynyloxy, heptynyloxy, 2-methyl-3-butyne-1-yloxy, and 2,2-dimethylpropargyloxy. "Aryloxy" and "aryloxy" refer to an optionally substituted aryl-O- group, wherein aryl is as previously defined. Examples of aryloxy and aryloxy groups include, for example, phenoxy and naphthoxy. "Aralkoxy" and "aralkoxy" refer to an optionally substituted aralkyl-O- group, wherein aralkyl is as previously defined. Examples of aralkoxy and aralkoxy groups include, for example, benzyloxy, 1-phenylethoxy, 2-phenylethoxy, and 3-naphtylheptoxy. "Cycloalkoxy" refers to an optionally substituted cycloalkyl-O- group, wherein cycloalkyl is as previously defined. Examples of cycloalkoxy and cycloalkoxy groups include, for example, cyclopropanoxy, cyclobutanoxy, cyclopentanoxy, cyclohexane, and cycloheptanoxy. "Heteroaryloxy" refers to an optionally substituted heteroaryl-O- group, wherein heteroaryl is as previously defined. Examples of heteroaryloxy groups include, but are not limited to, pyrryloxy, furyloxy, pyridyloxy-, 2,4-thiadiazolyoxi, pyrimidyloxy, thienyloxy, isothiazolyloxy, imidazolyloxy, tetrazolyloxy, pyrazinyloxy, pyrimidyloxy, quinolyloxy, isoquinolyloxy, thiophenyloxy, benzothienyloxy, isobenzofuryloxy, pyrazolinyloxy, indolyloxy, purinyloxy, carbazolyloxy, benzimidazolyloxy, and isoxazole-yloxy. "Heteroaralkoxy" refers to an optionally substituted heteroaralkyl-O- group, wherein heteroaralkyl is as previously defined. Examples of heteroaralkoxy groups include, but are not limited to, pyrrylethyloxy, furylethyloxy, pyridylmethyloxy, 1, 2,4-thiadiazolylpropyloxy, pyrimidylmethyloxy, thienylethyloxy, isothiazolylbutyloxy, and imidazolyl-2-methylpropyloxy. "Heterocycloalkylaryl" refers to an optionally substituted ring system composed of an aryl radical bearing a heterocycloalkyl substituent, wherein heterocycloalkyl and aryl are as previously defined. Examples of heterocycloalkylaryl groups include, but are not limited to, morpholinylphenyl, piperidinylnaphthyl, piperidinylphenyl, tetrahydrofuranylphenyl, and pyrrolidinylphenyl. "Alkylheteroaryl" refers to an optionally substituted ring system composed of a heteroaryl radical bearing an alkyl substituent, wherein heteroaryl and alkyl are as previously defined. Examples of alkylheteroaryl groups include, but are not limited to, methylpyrryl, ethylfuryl, 2,3-dimethylpyridyl, N-methyl-1,4-thiadiazolyl, propylpyrimidyl, 2-butylthienyl, methylisothiazolyl, 2-ethylimidazolyl, butyltetrazolyl, 5-ethylbenzothienyl, and N-methylindolyl. The alkylheteroaryl groups can be attached to the rest of the molecule through a carbon or a heteroatom. "Heteroarylaryl" refers to an optionally substituted ring system composed of an aryl radical bearing a heteroaryl substituent, wherein heteroaryl and aryl are as previously defined. Examples heteroarylaryl groups include, but are not limited to, pirrilfenilo, furiinaftilo, pyridylphenyl, 1, 2,4-tiadiazolilnaftilo, pirimidilfenilo, thienylphenyl, isotiazolilnaftilo, imidazolilfenilo, tetrazolylphenyl, piracinilnaftilo, pirimidilfenilo, quinolilfenilo, isoquinolilnaftilo, tiofenilfenilo, benzotienilfenilo, isobenzofurilnaftilo, pyrazolylphenyl, indolylnaphthyl, purinylphenyl, carbazolylnaphthyl, benzimidazolylphenyl, and isoxazolylphenyl. The heteroarylaryl can be attached to the rest of the molecule through a carbon or a heteroatom. "Alkylheteroarylaryl" refers to an optionally substituted ring system composed of an aryl radical bearing an alkylheteroaryl substituent and having between about 12 and about 50 carbon atoms (and all combinations and subcombinations of ranges and specific numbers of carbon atoms contained in it), with between about 12 and about 30 carbon atoms being preferred, wherein aryl and alkylheteroaryl are as previously defined. Examples of heteroarylaryl groups include, but are not limited to, methylpyrrilphenyl, ethylfurylnaphthyl, methylethylpyridylphenyl, dimethylethylpyrimidylphenyl, and dimethylthienylphenyl. Typically, the substituted chemical moieties include one or more substituents that replace hydrogen. Examples of substituents include, for example, halo (eg, F, Cl, Br, I), alkyl, cycloalkyl, alkylcycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, heteroaralkyl, spiroalkyl, heterocycloalkyl, hydroxyl (-OH ), oxo (= O), alkoxy, aryloxy, aralkoxy, nitro (-NO2), cyano (-CN), amino (-NH2), amino -N-substituted (-NHR "), amino -N, N-disubstituted (-N (R ") R"), carboxyl (-COOH), -C (= O) R ", -OR", -C (= O) OR ", -C (= O) NHSO2R", -NHC (= O) R ", aminocarbonyl (-C (= O) NH2), -N-substituted aminocarbonyl (-C (= O) NHR"), N, N-disubstituted aminocarbonyl (-C (= O) N ( R ") R"), thiol, thiolate (SR "), sulfonic acid and its esters (SO3R"), phosphonic acid and its mono-esters (P (= O) OR "OH) and di-esters (P (= O) OR "OR"), S (= O) 2R ", S (= O) 2NH2, S (= O) 2NHR", S (= O) 2NR "R", SO2NHC (= O) R ", NHS (= O) 2R ", NR" S (= O) 2R ", CF3, CF2CF3, NHC (= O) NHR", NHC (= O) NR "R", NR "C (= O) NHR", NR "C (= O) NR" R ", NR" C (= O) R ", NR" C (= N-CN) NR "R", and the like The aryl substituents can also include (CH2) pSO2NR " (CH 2) q and (CH2) pCO2NR "(CH2) q, where p and q are independently integers between 0 and 3, in which the methylene units are attached in position In relation to the aforementioned substituents, each residue R "can be, independently, any of H, alkyl, cycloalkyl, alkenyl, aryl, aralkyl, heteroaryl, or heterocycloalkyl, or when (R "(R")) is attached to a nitrogen atom, R "and R" can be taken together to form a heterocycloalkyl ring of nitrogen from 4 to 8 members, wherein said heterocycloalkyl ring is optionally interrupted by one or more groups -O-, -S-, -SO, -SO2-, -NH-, -N (alkyl) -, or -N ( arilo) - additional, for example. As used herein, a "*" denotes the presence of a chiral center in the molecule, in which a stereoisomeric form (R or S) predominates, more preferably is substantially enriched, and even more preferably is enantiomerically pure in a specific center of the molecule, but the absolute configuration of that center has not been established conclusively. This can be expressed, for example, in a compound identification number as 4 *, and indicates that the stereochemical configuration of at least one chiral center of the identified compound has not been established. The specific center is identified within a structure by placing the "*" next to the chiral center in question, as, for example, in the following structure.

In some compounds, several chiral centers may be present. The presence of two asterisks "*" in a single structure indicates that two racemic pairs may be present, but that each pair is diastereomeric relative to the other pair. As such, the first pair of enantiomers having two chiral centers can have the configurations, for example, (R, R) and (S, S). The second pair then has the configurations, for example, (R, S) and (S, R). For example, compounds 37A and 37B are diastereomeric to each other, but each is a racemic mixture of its two possible enantiomers. Their absolute stereochemistry has not been established conclusively. "Ligand" or "modulator" refers to a compound that binds to a receptor to form a complex, and includes agonists, partial agonists, antagonists, and inverse agonists. "Agonist" refers to a compound that can bind to a receptor to form a complex that can elicit a complete pharmacological response, which is normally peculiar to the nature of the receptor involved and which can alter the balance between the active and inactive receptor. "Partial agonist" refers to a compound that can bind to a receptor to form a complex that can only elicit a proportion of the complete pharmacological response, normally peculiar to the nature of the receptor involved, even if a high proportion of the receptors is occupied by the compound. "Antagonist" refers to a compound that is can bind a receiver to form a complex that can not elicit any response, usually in the same way as a receiver without occupying , and that preferably does not alter the balance between the active and inactive receptor. "Reverse agonist" refers to a compound that can bind to a receptor to form a complex that can preferentially stabilize the inactive conformation of the receptor. "Prodrug" refers to compounds specifically designed to maximize the amount of active species reaching the desired reaction site that are normally inactive or minly active by themselves for the desired activity, but not through biotransformation become biologically active metabolites. "Steroisomers" refers to compounds that have an identical chemical constitution, but differ with respect to the arrangement of atoms or groups in space. "N-oxide" refers to compounds in which the basic nitrogen atom of a heteroaromatic ring or of a tertiary amine is oxidized to a quaternary nitrogen having a positive formal charge and a bound oxygen atom having a formal charge negative. "Hydrate" refers to a compound of the present invention that is associated with water in molecular form, ie, in which the H-OH bond is not broken, and can be represented, for example, by the formula R? 2O, wherein R is a compound of the invention. A given compound can form more than one hydrate including, for example, monohydrates (R 2 O), dihydrates (R 2 H 2 O), trihydrates (R 3 H 2 O), and the like. "Pharmaceutically acceptable salts" refers to derivatives of the described compounds in which the parent compound is modified by producing its acid or basic salts. Examples of pharmaceutically acceptable salts include, but are not limited to, basic residues of salts of organic or mineral acids such as amines; acid residues of organic or alkaline salts such as carboxylic acids; and similar. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic organic or inorganic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric acid and the like; and salts prepared from organic acids such as acetic acid, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymalonic, phenylacetic, glutamic, benzoic, salicylic, sulfamic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, enedisulfonic, oxalic, isethionic , and similar. These physiologically acceptable salts are prepared by methods known in the art, for example, by dissolving the free amine bases with an excess of the acid in aqueous alcohol, or by neutralizing a free carboxylic acid with an alkali metal base such as a hydroxide, or with a amine. The compounds described throughout this document can be used or prepared in alternative ways. For example, numerous ring-containing compounds can be used or prepared in the form of an acid addition salt. Often such salts improve the isolation and handling properties of the compound. For example, depending on the reactants, the reaction conditions and the like, the compounds as described herein can be used or prepared, for example, in the form of their hydrochloride or tosylate salts. Crystalline somorphic forms, all racemic chiral forms, N-oxides, hydrates, solvates, and acid salt hydrates are also contemplated within the scope of the present invention. Certain acidic or basic compounds of the present invention can exist as bipolar ions. All forms of the compounds, including the free acid, the free base and the bipolar ions, are contemplated within the scope of the present invention. It is well known in the art that compounds containing a basic nitrogen atom and acid groups often exist in equilibrium with their bipolar forms. Thus, any of the compounds described throughout this document containing, for example, both basic nitrogens and acidic groups, also includes reference to their corresponding bipolar forms. "Effective amount" refers to an amount of a compound as described herein that may be therapeutically effective to inhibit, prevent or treat the symptoms of a particular disease, disorder, condition, or side effect. Such diseases, disorders, ailments, and side effects include, but are not limited to, those pathological conditions associated with the binding of the opioid receptor d (e.g., in relation to the treatment and / or prevention of pain), wherein the Treatment or prevention comprises, for example, an agonist effect on its activity by contacting the cells, tissues or receptors with the compounds of the present invention. Thus, for example, the term "effective amount", when used in connection with the compounds of the invention, opioids, or opioid substitutes, for example, for the treatment of pain, refers to the treatment and / or prevention of painful ailment The term "effective amount" when used in connection with active compounds against gastrointestinal dysfunctions, refers to the treatment and / or prevention of the symptoms, diseases, disorders, and ailments normally associated with gastrointestinal dysfunction. The term "effective amount" when used in connection with compounds useful in the treatment and / or prevention of disorders of the urogenital tract, refers to the treatment and / or prevention of the symptoms, diseases, disorders and ailments normally associated with disorders of the urogenital tract and other related ailments. The term "effective amount" when used in connection with compounds useful in the treatment and / or prevention of immunomodulatory disorders, refers to the treatment and / or prevention of the symptoms, diseases, disorders and ailments normally associated with immunomodulatory disorders and other conditions. related ailments. The term "effective amount" when used in connection with compounds useful in the treatment and / or prevention of inflammatory disorders, refers to the treatment and / or prevention of symptoms, diseases, disorders and ailments normally associated with inflammatory disorders and other related ailments. The term "effective amount" when used in connection with compounds useful in the treatment and / or prevention of respiratory function disorders, refers to the treatment and / or prevention of symptoms, diseases, disorders and ailments normally associated with disorders. of respiratory function and other related ailments. The term "effective amount" when used in connection with compounds useful in the treatment and / or prevention of anxiety, refers to the treatment and / or prevention of symptoms, diseases, disorders and ailments normally associated with anxiety, mood disorders , disorders related to stress, hyperactivity disorder with attention deficit and other related ailments. The term "effective amount" when used in connection with compounds useful in the treatment and / or prevention of disorders of the sympathetic nervous system, refers to the treatment and / or prevention of symptoms, diseases, disorders and ailments normally associated with disorders of the sympathetic nervous system and other related ailments. The term "effective amount" when used in connection with compounds useful in the treatment and / or prevention of cough, refers to the treatment and / or prevention of the symptoms, diseases, disorders and ailments normally associated with cough and other ailments. related The term "effective amount" when used in connection with compounds useful in the treatment and / or prevention of motor disorders, refers to the treatment and / or prevention of symptoms, diseases, disorders and ailments normally associated with motor disorders and other ailments. related The term "effective amount" when used in connection with compounds useful in the treatment of traumatic injuries of the central nervous system, refers to the treatment and / or prevention of symptoms, diseases, disorders and ailments normally associated with the central nervous system and others. related ailments. The term "effective amount" when used in connection with compounds useful in the treatment and / or prevention of stroke, cardiac arrhythmia or glaucoma, refers to the treatment and / or prevention of the symptoms, diseases, disorders and ailments normally associated with stroke. , cardiac arrhythmia, glaucoma and other related ailments. The term "effective amount" when used in connection with compounds useful in the treatment and / or prevention of sexual dysfunctions, refers to the treatment and / or prevention of the symptoms, diseases, disorders and ailments normally associated with sexual and other dysfunctions. related ailments. The term "effective amount" when used in connection with compounds useful in the improvement of organic and cellular survival, refers to the maintenance and / or increase of a minimally acceptable level of organic or cellular survival, including organic preservation. The term "effective amount" when used in connection with compounds useful in the treatment and / or prevention of myocardial infarction, refers to the level of minimum compound necessary to provide cardioprotection after a myocardial infarction. The term "effective amount" when used in connection with compounds useful in the treatment and / or prevention of concussion, cerebral edema, cerebral ischemia, cerebral deficits subsequent to cardiac bypass and graft surgery, systemic lupus erythematosus, Hodgkin's disease, disease of Sjogren, epilepsy, and rejection in the transplantation of organs and in skin grafts, refers to the treatment and / or prevention of symptoms, diseases, disorders and ailments normally associated with concussion, cerebral edema, cerebral ischemia, brain deficits subsequent to Cardiac bypass and graft surgery, systemic lupus erythematosus, Hodgkin's disease, Sjogren's disease, epilepsy, and rejection in the transplant of organs and in skin grafts, and other related ailments. The term "effective amount" when used in connection with compounds useful in the treatment of substance addiction, refers to the treatment of symptoms, diseases, disorders and ailments normally associated with addiction to substances and other related ailments. The term "effective amount" when used in connection with compounds useful in reducing the need for anesthesia or the production and / or maintenance of an anesthetic state, refers to the production and / or maintenance of a minimally acceptable anesthetic state. "Pharmaceutically acceptable" refers to those compounds, materials, compositions, and / or dosage forms that are, within the scope of medical assessment, suitable for contact with the tissues of humans and animals without toxicity, irritation, response excessive allergic, or other problems or complications in proportion to a reasonable benefit / risk ratio. The term specifically covers veterinary uses. "In combination with", "combination therapy", and "combination products" refer, in certain embodiments, to the concurrent administration to a patient of a compound of the invention including, for example, a compound of formulas I , II, III, IV, V, VI, VII, VII, IX, X, XI, Xll, and / or Xlll, and one or more additional agents including, for example, an opioid, an anesthetic agent (as, for example, inhaled anesthetic, a hypnotic, an anxiolytic, a neuromuscular blocker and an opioid), an anti-Parkinson's agent (for example, in the case of the treatment or prevention of a motor disorder, particularly Parkinson's disease), an antidepressant (e.g. , in the case of the treatment or prevention of mood disorders, particularly depression), an agent for the treatment of incontinence (for example, in the case of the treatment or prevention of a disorder of the urogenital tract), an agent for the treatment of pain , including or neuralgia or neuropathic pain, and / or other optional principles (including, for example, antibiotics, antivirals, antifungals, anti-inflammatories, anesthetics and their mixtures). When administered in combination, each component can be administered at the same time or sequentially in any order at different times. Thus, each component can be administered separately, but sufficiently close in time, so as to provide the desired therapeutic effect. "Dosing unit" refers to physically discrete units appropriate as unit dosages for the particular individual to be treated. Each unit may contain a predetermined quantity of active compound (s) calculated to produce the desired therapeutic effect (s) in association with the necessary pharmaceutical carrier. The specification for the dosage unit forms of the invention can be dictated by (a) the unique characteristics of the active compound (s) and the particular therapeutic effect (s) to be achieved, and (b) the limitations inherent in the compositional technique of such active compound (s). "Pain" refers to the perception or state of unpleasant sensory or emotional experience associated with actual or potential tissue damage or described in terms of such damage. "Pain" includes, but is not limited to, two general categories of pain: acute and chronic pain (Buschmann, H.; Christoph, T; Friderichs, E .; Maul, O; Sundermann, B; eds .; Analgesics, Wiley-VCH, Verlag GMbH and Co. KgaA, Weinheim; 2002; Jain, K. K. "A Guide to Drug Evaluation for Chronic Pain"; Emerging Drugs, 5 (2), 241-257 (2000)). Non-limiting examples of pain include, for example, nociceptive pain, inflammatory pain, visceral pain, somatic pain, neuralgia, neuropathic pain, pain from AIDS, pain from cancer, phantom pain, and psychogenic pain, and pain as a result of hyperalgesia, pain caused by rheumatoid arthritis, migraines, allodynia and the like. "Gastrointestinal dysfunction" refers collectively to diseases of the stomach, small intestine and large intestine. Non-limiting examples of gastrointestinal dysfunction include, for example, diarrhea, nausea, emesis, post-operative emesis, opiate-induced emesis, irritable bowel syndrome, narcotic bowel dysfunction, inflammatory bowel disease, colitis, increased gastric motility , increased gastric emptying, stimulation of the small intestine propulsion, stimulation of the propulsion of the large intestine, decrease in the amplitude of the contractions of non-propelling segments, disorders associated with the sphincter of Oddi, disorders associated with anal sphincter tone, deterioration of the reflex of relaxation with rectal distension, disorders associated with gastric, biliary, pancreatic or intestinal secretions, changes in the absorption of water from the contents of the intestine, gastroesophageal reflux, gastroparesis, cramps, swelling, distension, abdominal or epigastric pain and discomfort , not ulcerope dyspepsia nica, gastritis, or changes in the absorption of medications or orally administered nutrients. "Urogenital tract disorders" refers collectively to diseases of the urinary and genital tract. Non-limiting examples of disorders of the urogenital tract include incontinence (ie, involuntary loss of urine) such as stress urinary incontinence, imperious urinary incontinence and benign prostatic hyperplasia, overactive bladder disorder, urinary retention, renal colic, glomerulonephritis, and interstitial cystitis. "Overactive bladder disorder" refers to an ailment with symptoms of urgency with or without incontinence, and is usually associated with an increase in urinary frequency and nocturia. Overactive bladder disorders are usually associated with urodynamic findings of involuntary contractions of the bladder, generally referred to as bladder instability. "Immunomodulatory disorders" refers collectively to diseases characterized by a compromised or over-stimulated immune system. Non-limiting examples of immunomodulatory disorders include autoimmune diseases (such as arthritis, autoimmune disorders associated with skin transplantation, autoimmune disorders associated with organ transplantation, and autoimmune disorders associated with surgery), collagen diseases, allergies, side effects associated with the administration of an antitumor agent, side effects associated with the administration of an antiviral agent, multiple sclerosis and Guillain-Barre syndrome. "Inflammatory disorders" refers collectively to diseases characterized by cellular processes in injured tissues. Non-limiting examples of inflammatory diseases include arthritis, psoriasis, asthma, and inflammatory bowel disease. "Respiratory function disorders" refers to conditions in which breathing and / or air flow to the lungs are compromised. Non-limiting examples of disorders of respiratory function include asthma, apnea, cough, chronic lung disease, and lung edema. "Lung edema" refers to the presence of abnormally large amounts of fluid in the intercellular tissue spaces. "Anxiety" refers to the unpleasant emotional state constituted by psychophysiological responses in anticipation of real, unreal or imaginary damage, apparently as a result of unrecognized intrapsychic conflicts. "Mood disorders" refers to disorders that present a disturbance of mood as a predominant feature, including depression, bipolar manic depression, borderline personality disorder, and seasonal affective disorder.

"Depression" refers to a depressed mood state characterized by feelings of sadness, despair, and discouragement, including sadness, dysthymia, and severe depression. "Disorders related to stress" refers collectively to diseases characterized by a state of hyper- or hypo-excitation with hyper- or hypovigilance. Non-limiting examples of stress-related disorders include post-traumatic stress disorder, panic disorder, generalized anxiety disorder, social phobia, and obsessive-compulsive disorder. "Hyperactivity disorder with attention deficit" refers to an ailment characterized by an inability to control behavior due to difficulties in the processing of neural stimuli. "Disorders of the sympathetic nervous system" refers collectively to diseases characterized by disturbances of the autonomic nervous system. Non-limiting examples of disorders of the sympathetic nervous system include hypertension, and the like. "Cough" refers to a tusive ailment, and "antitussive" agents refer to those materials that modulate the tusive response. "Motor disorders" refers to involuntary manifestations of hyper or hypo activity and muscular coordination. Non-limiting examples of motor disorders include tremors, Parkinson's disease, Tourette's syndrome, parasomnias (sleep disorders) including restless legs syndrome, postoperative tremors and dyskinesia. "Traumatic injury to the central nervous system" refers to a wound or physical injury to the spinal cord or the brain. "Stroke" refers to an illness due to a lack of oxygen in the brain.

"Cardiac arrhythmia" refers to a condition characterized by a disturbance of the electrical activity of the heart that manifests itself in the form of an abnormality of heart rate or speed. Patients with a cardiac arrhythmia may experience a wide variety of symptoms ranging from palpitations to syncopes. "Glaucoma" refers collectively to eye diseases characterized by an increase in intraocular pressure that causes pathological changes in the optic disc and typical defects in the field of vision. "Sexual dysfunction" refers collectively to disturbances, impairments or abnormalities in the functioning of the male or female sexual organs, including, but not limited to, premature ejaculation and erectile dysfunction. "Cardioprotection" refers to conditions or agents that protect or restore the heart from dysfunction, cardiac co-management and reperfusion injury. "Myocardial infarction" refers to the irreversible injury of the heart muscle caused by a local absence of oxygen. "Addiction" refers to a pattern of compulsive substance abuse (alcohol, nicotine, or drugs) characterized by a continued craving for the substance and, in some cases, the need to use the substance for purposes other than those prescribed or its use legal. "Anesthetic state" refers to the state of loss of sensation or sensations, including not only the loss of tactile sensitivity or any other sense, but also the loss of sensation of pain, as induced to allow the performance of surgery or other procedures painful, and especially including amnesia, analgesia, muscle relaxation and sedation. "Improvement of the organic and cellular survival" refers to the maintenance and / or improvement of a minimally acceptable level of organic or cellular survival.

"Patient" refers to animals, including mammals, preferably humans. "Secondary effect" refers to a consequence other than that (s) by which an agent or quantity is used, such as the adverse effects produced by a drug, especially in an organ or in an organic system other than that provided for benefit by his administration. If, for example, of opiates, the term "side effect" may refer to conditions such as, for example, constipation, nausea, vomiting, dyspnea and pruritus. When any variable occurs more than once in any constituent or in any formula, its definition in each event is independent of its definition in any other event. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds. It is believed that the chemical forms and names used correctly and precisely in this document reflect the underlying chemical compounds. However, the nature and value of the present invention does not depend on the theoretical correction of these formulas, totally or partially. Thus it is understood that the formulas used herein, as well as the chemical names attributed to the correspondingly indicated compounds, are not intended to limit the invention in any way, including its restriction to any specific tautomeric form or to any optical isomer or specific geometric, except when such a stoichiometric is clearly defined. In certain preferred embodiments, the compounds, pharmaceutical compositions and methods of the present invention may involve a peripheral opioid modulator compound. The term "peripheral" means that the compound acts primarily on physiological systems and components external to the central nervous system. In a preferred form, the peripheral opioid modulator compounds used in the methods of the present invention exhibit high levels of activity with respect to peripheral tissue, such as gastrointestinal tissue, while exhibiting reduced activity, and preferably substantially no activity, about the SNC. The phrase "substantially without activity on the CNS", as used herein, means that less than about 50% of the pharmacological activity of the compounds employed in the present methods manifests in the CNS, preferably less than 25%. % approximately, more preferably less than about 10%, even more preferably less than about 5% and most preferably 0% of the pharmacological activity of the compounds employed in the present methods manifests in the CNS.

Furthermore, in certain embodiments of the invention it is preferred that the opioid modulator compound d not substantially cross the blood-brain barrier. The phrase "does not substantially cross", as used herein, means that less than about 20% by weight of the compound employed in the present methods passes through the blood-brain barrier, preferably less than about 15% by weight, more preferably less than 10% by weight approximately, even more preferably less than 5% by weight approximately and most preferably 0% by weight of the compound crosses the blood-brain barrier. The selected compounds can be evaluated for their penetration into the CNS, for example, by determining plasma and brain levels after i.v. administration. Accordingly, in one embodiment, the invention provides compounds of formula I: wherein: R1 and R3 are each independently H, alkyl, alkenyl, alkynyl, or aryl, or R1 and R3 when taken together with the atoms through which they are connected, form a 4 to 8 membered heterocycloalkyl ring; R2 is H, alkyl, alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl, aralkyl, or heteroarylalkyl, or R1 and R2 when taken together with the atoms through which they are connected, form a 4- to 8-membered heterocycloalkyl ring, or R2 and R3 when taken together with the atoms through which they are connected, form a 4- to 8-membered heterocycloalkyl ring; with the condition that R2 is not each Ra is independently H or alkyl; each Rb is independently H, alkyl, or aryl; n is the integer 0, 1, 2 or 3; A and B are each independently H, fluoro, or alkyl, or together form a double bond between the carbon atoms to which they are attached; R4 is -Y-W; And it is a simple bond, C (Ra) (Rb), C (Ra) (Rb) C (Ra) (Rb), or C (Ra) (Rb) C (Ra) (Rb) C (Ra) (R ); W is aryl or heteroaryl; X is -CH2-, -O-, -S-, -SO, -SO2, or -N (R5) -; R5 is H, alkyl, cycloalkyl, - (CH2) -alkenyl, - (CH2) -alkynyl, aryl, -COR, or -SO2Rb; and J forms a 6-membered aryl ring or a 5- or 6-membered heteroaryl ring when taken together with the carbon atoms to which it is attached; with the proviso that when: (a) J is taken together with the carbon atoms to which it is attached it forms a phenyl ring substituted with 0-3 groups selected from the group consisting of: halogen, hydroxy, -S-alkyl CM, C alkyl, and CM alkoxy, the last two optionally substituted with one or more halogens or with C1- alkoxy; W is unsubstituted naphthyl, or phenyl substituted with 0-3 groups selected from the group consisting of: halogen, C 1-6 alkyl, C 1-6 alkoxy, phenyl, phenyloxy, 1,3-benzodioxazolyl, or 2,2-difluoro- 1, 3-benzodioxazoliIo, -NH2, -N (C) alkyl, and pyrrolyl; n is 1, R1 and R3 are each H, A and B together form a double bond between the carbon atoms to which they are attached, and is a single bond; and X is -O-; then R2 is other than H or methyl; and with the proviso that when: (b) J is taken together with the carbon atoms to which it is attached it forms a phenyl ring, W is phenyl substituted with 0-3 groups selected from the group consisting of: fluoro, hydroxy, alkoxy C? _? Optionally substituted with one or more fluoros, C2-6 alkenyloxy, and -S-C alkyl, n is 1, R1 and R3 are each H, A and B together form a double bond between the carbon atoms at the which are united, and it is a simple link; and X is -O-; then R2 is other than H or benzyl; and with the proviso that when: 6-membered aryl ring, it is not substituted with: or one of its stereoisomers, prodrugs, pharmaceutically acceptable salts, hydrates, solvates, acid salt hydrates, or N-oxides. In certain preferred embodiments of compounds of formula I, J is -C-D-E- or -C-D-E-F-; wherein C, D, E and F are each independently -O-, -S-, -SO-, -SO2-, = N-, = CH- or -NH-; wherein the last two residues are each optionally substituted independently; with the proviso that each atom -O- of the ring within J is directly attached only to carbon or nitrogen atoms; with the proviso that each atom -S- of the ring within J is directly attached only to carbon or nitrogen atoms; and with the proviso that when J is -C-D-E-F-, at least one of C, D, E and F is = CH-. In certain preferred embodiments of compounds of formula I, X is -CH2-, -O-, -S-, -SO, or -SO2, more preferably -CH2- or -O-, even more preferably -O-. In other preferred embodiments of compounds of formula I, J, In other preferred embodiments of compounds of formula I, J, taken together with the carbon atoms to which it is attached, forms an optionally substituted 6-membered aryl ring , preferably, optionally substituted phenyl, or an optionally substituted 5 or 6-membered heteroaryl ring. Preferably, J is optionally substituted, including phenyl, 3-pyridinyl, 4-pyridinyl, 5-pyridinyl, 6-pyridinyl, thienyl, oxazolyl, 1, 2,5-oxadiazolyl, imidazolyl, N-methylimidazolyl or indolyl completely substituted. In certain preferred embodiments of compounds of formula I, at least one of R1 and R3 is H. In other preferred embodiments of formula I, R1 and R3 are each independently H, alkyl, alkenyl, or alkynyl; more preferably R1 and R3 are each independently H, C? -C3 alkyl, C2-C3 alkenyl, or C2-C3 alkynyl; even more preferably R1 and R3 are each independently H, C? -C3 alkyl, or C2-C3 alkenyl. In certain preferred embodiments of compounds of formula I, R 2 is H, alkyl, alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl, aralkyl, or heteroarylalkyl, more preferably H or alkyl, more preferably alkyl, even more preferably lower alkyl. In certain preferred embodiments of compounds of formula I, n is the integer 1. In certain preferred embodiments of compounds of formula I, A and B are taken together to form a double bond between the carbon atoms to which They are united. More preferably, A and B are taken together to form a double bond between the carbon atoms to which they are attached and n is the integer 1 Even more preferably, A and B are taken together to form a double bond between the carbon atoms to which they are attached, n is the integer 1 and at least one of R1 and R3 is H. In certain preferred embodiments of compounds of formula I, A and B are each H. Most preferably, A and B are each H and n is the integer 1. Even more preferably, A and B are each H, n is the integer 1 and at least one of R1 and R3 is H. In certain preferred embodiments of compounds of formula I , R 4 is aryl substituted with -C (= O) NR 11 R 12, wherein: R 11 is H, alkyl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, alkylheterocycloalkyl, aryl, heteroaryl, aralkyl, heteroarylalkyl, or COR 12; R12 is H, alkyl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, alkylheterocycloalkyl, aryl, heteroaryl, aralkyl, or heteroarylalkyl, or R11 and R12 are taken together with the nitrogen atom to which they are attached to form a 4 to 8 membered heterocycloalkyl ring, wherein 1 or 2 of the carbon atoms of the heterocycloalkyl ring can optionally be independently replaced by -O-, -S-, -SO-, -SO2-, -NH-, -N (alkyl) -, groups, or -N (aryl) -. In other embodiments, the invention provides compounds of formula II: p wherein: R6, R7, R8 and R9 are each independently H or - (CH2) mR10; m is the integer 0, 1, 2, 3, or 4; each R10 is independently alkyl, halo, perhaloalkyl, -OR5, -OCF2H, OCF3, -CN, -CO2R5, -C (= O) NR11R12, -S (= O) 2R13, -S (= O) 2NR11R12, -NR11R12 , NR14C (= O) R15, -NR14S (= O) 2R15, aryl, or heteroaryl; each R 1 is independently H, alkyl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, alkylheterocycloalkyl, aryl, heteroaryl, aralkyl, heteroarylalkyl, or COR 12; each R12 is independently H, alkyl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, alkylheterocycloalkyl, aryl, heteroaryl, aralkyl, or heteroarylalkyl, or R11 and R12 taken together with the nitrogen atom to which they are attached form a 4 to 8 membered heterocycloalkyl ring, wherein 1 or 2 of the carbon atoms of the heterocycloalkyl ring can optionally be independently replaced by -O-, -S-, -SO-, -SO2-, -NH-, -N (alkyl) -, groups, or -N (aryl) -; each R 3 is independently -OH, alkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, cycloalkyl, or alkylcycloalkyl; each R14 is independently H, alkyl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, aryl, heteroaryl, alkylheterocycloalkyl, aralkyl, or heteroarylalkyl; and each R15 is independently alkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, cycloalkyl, alkylcycloalkyl, heterocycloalkyl, or alkylheterocycloalkyl. In certain preferred embodiments of the compounds of formula II, R1 and R3 are each H. In certain preferred embodiments of formula II, R4 is aryl substituted with -C (= O) NR11R12. In still other embodiments of the compounds of formula I, the invention provides compounds of formula III: m wherein: R6, R7, R8 and R9 are each independently H or - (CH2) mR10; m is the integer 0, 1, 2, 3 or 4; each R10 is independently alkyl, halo, perhaloalkyl, -OR5, -OCF2H, -OCF3, -CN, -CO2R5, -C (= O) NR11R12, -S (= O) 2R13, -S (= O) 2NR11R12, - NR1 R12, -NR 4C (= O) R15, -NR14S (= O) 2R15, aryl, or heteroaryl; each R 11 is independently H, alkyl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, alkylheterocycloalkyl, aryl, heteroaryl, aralkyl, heteroarylalkyl, or COR 12; each R12 is independently H, alkyl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, alkylheterocycloalkyl, aryl, heteroaryl, aralkyl, or heteroarylalkyl, or R11 and R12 taken together with the nitrogen atom to which they are attached form a 4 to 8 membered heterocycloalkyl ring, wherein 1 or 2 of the carbon atoms of the heterocycloalkyl ring can optionally be independently replaced by -O-, -S-, -SO-, -SO2-, -NH-, -N (alkyl) -, groups, or -N (aryl) -; each R13 is independently -OH, alkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, cycloalkyl, or alkylcycloalkyl; each R14 is independently H, alkyl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, aryl, heteroaryl, alkylheterocycloalkyl, aralkyl, or heteroarylalkyl; and each R15 is independently alkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, cycloalkyl, alkylcycloalkyl, heterocycloalkyl, or alkylheterocycloalkyl. In certain preferred embodiments of the compounds of formula II, R1 and R3 are each H. In certain preferred embodiments of the compounds of formula II, R4 is aryl substituted with -C (= O) NR11R12. In certain preferred embodiments of the invention, the compound is selected from the group consisting of: 4 - [(4-N / V-diethylaminocarbonyl) phenyl] -spiro [2 H, 1-benzopyran-2,4'-piperidine]; 4 - [(4-?,? / - diethylaminocarbonyl) phenyl] -6-fluoro-spiro [2 H, 1-benzopyran-2,4'-piperidine] hydrochloride; 4 - [(4 -? /,? / - diethylaminocarbonyl) phenyl] -6-hydroxyspiro [2 H, 1-benzopyran-2,4'-piperidine]; 4 - [(4 -? / J? / - diethylaminocarbonyl) phenyl] -3,4-dihydrospiro hydrochloride [2 H, 1-benzopyran-2,4'-piperidine]; 4 - [(4- / V, V-diethylaminocarbonyl) phenyl] -? / - methyl-spiro [2 H, 1-benzopyran-2,4'-piperidine]; 4 - [(4- / V-ethylaminocarbonyl) phenyl] spiro [2 H, 1-benzopyran-2,4'-piperidine]; 4 - [(4- / V-propyl- / V-cyclopropylmethylaminocarbonyl) phenyl] -spiro [2 H, 1-benzopyran-2,4'-piperidine]; 4- [4- (isoindoleminocarbonyl) phenyl] -spiro [2 H, 1-benzopyran-2,4'-pperiodine]; 4- [4- (4-carboxypiperidinaminocarbonyl) phenyl] -spiro [2 H, 1-benzopyran-2,4'-piperidine]; 4- [4- (2H-tetrazole) phenyl] -spiro [2 H, 1-benzopyran-2,4'-piperidine]; 4- [4- (4-carboxypropyl-tetrazol-2-yl) phenyl] -spiro [2 H, 1-benzopyran-2,4'-pperiodine]; 4- (3-pyridyl) -spiro [2 H, 1-benzopyran-2,4 '-piperidine]; 4- [4- (methanesulfonyl) -phenyl] -spiro [2 H, 1-benzopyran-2,4'-piperidine]; and 4 - [(4 -? /,? / - diethylaminocarbonyl) phenyl] spiro [2 H, 1-benzopyran-2,4'-nortropine]; or one of its stereoisomers, prodrugs, pharmaceutically acceptable salts, hydrates, solvates, acid salt hydrates, or N-oxides. In other aspects, the invention relates to compounds of formula IV: IV where: Y2 is a single bond or - [C (Rc) (Rd)] k-; each Rc, Re, and Rf is independently H or alkyl; each Rd is independently H, alkyl, or aryl; W2 is aryl, alkylaryl, heterocycloalkylaryl, heteroaryl, alkylheteroaryl, heteroarylaryl, or alkylheteroarylaryl; R23 and R24 are each independently H, alkyl, alkenyl, alkynyl, or aryl, or R23 and R24 when taken together with the atoms through which they are connected, form a cycloalkyl or heterocycloalkyl ring of 4 to 8 members; Z is -N (R25) -, -C (= O) -, -CH (OH) -, -CH (N (Rc) (Rd)) -, or -O-; R25 is H, alkyl, alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl, aralkyl, or heteroarylalkyl, or R23 and R25 when taken together with the atoms through which they are connected, form a 4- to 8-membered heterocycloalkyl ring, or R24 and R25 when taken together with the atoms through which they are connected, form a 4- to 8-membered heterocycloalkyl ring; each k is independently 1, 2, or 3; p is O, 1, 2 or 3; s is 0, 1, 2 or 3, with the proviso that the sum of p and s is 4; A2 and B2 are each independently H, fluoro, or alkyl, or together they form a double bond or -CH2-; G is H or alkyl; X2 is -C (Rc) (Rd) -, -O-, -S-, -S (= O) -, -S (= O) 2-, -C (= O) -, -CH (OH) - or -N (R26) -; R26 is H, alkyl, cycloalkyl, - (CH2) -alkenyl, - (CH2) -alkynyl, aryl, -C (= O) Rd, or -S (= O) 2Rd; and J2 forms a 6 to 10 membered aryl or a 5- to 10 membered heteroaryl ring when taken together with the carbon atoms to which it is attached; with the proviso that when: (a) J2 is taken together with the carbon atoms to which it is attached it forms a 6 to 10 membered aryl ring substituted with 0-3 groups selected from the group consisting of: halogen, hydroxy, - SH, -C (= O) -H -S-alkyl CM, -NHS (= O) 2-alkyl CM, -NHS (= O) 2-H, -N (alkylC) S (= O) 2-H, alkyl CM, and alkoxy CM, the latter two optionally substituted with one or more halogens or with C-alkoxy; W2 is phenyl substituted with 0-3 groups selected from the group consisting of: halogen, cyano, hydroxy, C6_6 alkyl optionally substituted with one or more halogens, C6_6 alkoxy optionally substituted with one or more halogens or with C3 cycloalkyl 6, C2-6 alkenyloxy, C2-6 alkynyloxy, C3-6 cycloalkyloxy, C6-? 2 aryloxy, aralkoxy, heteroaryloxy, heteroaralkoxy, heterocycloalkyl substituted with alkoxy, -SH, -S-alkyl CM, -NH2, -N = C (aryl) 2, -N (H) alkyl CM, -N (C1 alkyl) 2, -OS (= O) 2 -alkyl optionally substituted with one or more halogens, -OS (= O) 2-aryl C6- 2 optionally substituted with alkyl CM, -NHS (= O) 2-alkyl CM, -N (alkyl CM) S (= O) 2-alkyl C, -NHS (= O) 2-H, and -N (alkyl CM) S (= O) 2-H; p and s are each 1, Re, Rf, R23, R24, and G are each H, A2 and B2 together form a double bond, Y2 is a single bond; and X ^ is -O-; then Z is different from: , where t is an integer between 1 and 20; and with the proviso that when: (b) J2 is taken together with the carbon atoms to which it is attached it forms a phenyl ring substituted with 0-3 groups selected from the group consisting of: halogen, hydroxy, -S-alkyl C , alkyl CM, and alkoxy C, the latter two optionally substituted with one or more halogens or with alkoxy C; W2 is unsubstituted naphthyl, or phenyl substituted with 0-3 groups selected from the group consisting of: halogen, C1-6 alkyl, C6.6 alkoxy, phenyl, phenyloxy, 1,3-benzodioxazolyl, or 2,2-difluoro- 1,3-benzodioxazolyl fluoro, -NH2, -N (alkylCM) 2, and pyrrolyl; p and s are each 1, Re, Rf, R23, R24, and G are each H, A2 and B2 together form a double bond, Y2 is a single bond; and X2 is -O-; then Z is different from: with the proviso that when: (c) J2 is taken together with the carbon atoms to which unsubstituted phenyl form is attached, W2 is phenyl substituted with 0-3 groups selected from the group consisting of: fluorine, hydroxy, C1-alkoxy -6 optionally substituted with one or more fluoros, C2-6 alkenyloxy, and -S-alkyl CM, pys are each 1, Re, Rf, R23, R24, and G are each H, A2 and B2 together form a double link, Y2 is a simple link; and X2 is -O-; then Z is different from: with the proviso that when: (d) J2 is taken together with the carbon atoms to which it is attached it forms a 6-membered aryl ring substituted with: then Z is different from -N (R25) - or -CH (NH2) -; or one of its stereoisomers, prodrugs, pharmaceutically acceptable salts, hydrates, solvates, acid salt hydrates, or N-oxides. In certain preferred embodiments of the compounds of formula IV, Y2 is a single bond. In some preferred embodiments of the compounds of formula IV, Rc, Re, and Rf are each independently H or lower alkyl; more preferably H or CrC3 alkyl; even more preferably H or methyl; still more preferably, each is H. In some alternative preferred embodiments, at least one of Rc, Re, and Rf is H. In other preferred embodiments of the compounds of formula IV, each Rd is independently H, alkyl , or phenyl, the last two optionally substituted; more preferably H, alkyl, or unsubstituted phenyl; even more preferably H or alkyl; still more preferably H or methyl; most preferably H. In certain preferred embodiments of the compounds of formula IV, W2 is aryl, alkylaryl, heteroaryl, alkylheteroaryl, heteroarylaryl, or alkylheteroarylaryl, each of which is optionally substituted. More preferably W2 is aryl, alkylaryl, heteroaryl, or heteroarylaryl, each of which is optionally substituted. Even more preferably, W2 is phenyl, pyridyl, tetrazolylphenyl, benzothienyl, benzofuranyl, thienyl, furanyl, indolyl, thiazolyl, pyrimidinyl, or diazolyl, each of which is optionally substituted; still more preferred is optionally substituted phenyl or optionally substituted pyridyl. As indicated above, the annular systems in W2 are optionally substituted. In preferred embodiments, the ring systems in W2 are optionally substituted with at least one of alkyl, aryl, hydroxyl, carboxyl,? /,? / - dialkylaminocarbonyl, -S (= O) 2-N (alkyl) 2, - N (H) S (= O) 2-alkyl, and -N (alkyl) C (= O) -alkyl. In particularly preferred embodiments, W2 is: wherein W2 is optionally substituted with at least one of alkyl, aryl, hydroxyl, carboxyl,? /,? / - dialkylaminocarbonyl, -S (= O) 2-N (alkyl) 2, -N (H) S (= O) 2-alkyl, and -N (alkyl) C (= O) -alkyl; and L is H or alkyl. In other preferred embodiments of the compounds of formula IV, R23 and R24 are each independently H or alkyl, alkenyl, alkynyl, or aryl, each of the last four groups being optionally substituted. More preferably, R23 and R24 are each independently H, alkyl, alkenyl, or alkynyl; H or alkyl being still more preferred and H or methyl being still more preferred. In particularly preferred embodiments, R23 and R24 are H. In alternative preferred embodiments of the compounds of formula IV, R23 and R24 are each independently H, alkyl, alkenyl, or alkynyl; more preferably R23 and R24 are each independently H, C1-C3 alkyl, C2-C3 alkenyl, or C2-C3 alkynyl; still more preferably R23 and R24 are each independently H, C3 alkyl, or C2-C3 alkenyl. In still other preferred embodiments, at least one of R23 and R24 is H. In certain preferred embodiments of the compounds of formula IV, Z is -N (R25) -, -CH (N (Rc) (Rd) ) -, or -O-; more preferably -N (R25) - or -O-; even more preferably -N (R25) -. In other preferred embodiments of the compounds of formula IV, Z is -N (R25) -, -CH (OH) -, or -CH (N (Rc) (Rd)). In preferred embodiments of the compounds of formula IV, R 25 is H, alkyl, alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl, aralkyl, or heteroarylalkyl, each of the last seven groups optionally substituted. More preferably, R 25 is H, alkyl, or aralkyl, still more preferably H or alkyl, even more preferably H or lower alkyl, even more preferably H or methyl, most preferably H. In certain preferred embodiments of the compounds of formula IV, k is 1 In certain preferred embodiments of the compounds of formula IV, p is 0, 1 or 2, with 1 or 2 being more preferred, and 1 being even more preferred.

In certain preferred embodiments of the compounds of formula IV, s is 0, 1, or 2, with 1 or 2 being more preferred, and 1 being even more preferred. In preferred embodiments of the compounds of formula IV, the sum of p and s is 2 or 3, with 2 being more preferred. In some preferred embodiments of the compounds of formula IV, A2 and B2 are each independently H, fluoro, or alkyl, or together they form a double bond; more preferably each is independently H or alkyl, or together they form a double bond; still more preferably each is independently H or lower alkyl, or together they form a double bond; even more preferably H or methyl, or together they form a double bond; even more preferably together they form a double bond. In other preferred embodiments of the compounds of formula IV, A2 and B2 are each independently H, fluoro, or alkyl. Alternatively, A2 and B2 together form ~ CH2-.

In other preferred embodiments of the compounds of formula IV, G is H or lower alkyl; more preferably H or methyl; still more preferably G is H. In certain preferred embodiments of the compounds of formula IV, X2 is -C (Rc) (Rd) -, -O-, -S-, -S (= O) -, -S (= O) 2-, or -N (R26) -; more preferably -C (Rc) (Rd) -, -O-, or -S (= O) 2-; still more preferably -C (Rc) (Rd) - or -O-; even more preferably -O-.

In some preferred embodiments of the compounds of formula IV, R 26 is H or alkyl; more preferably H or lower alkyl; still more preferably H or methyl; even more preferably H. In preferred embodiments of the compounds of formula IV, J2 forms a 6- to 10-membered aryl ring optionally substituted when taken together with the carbon atoms to which it is attached; more preferably optionally substituted phenyl or optionally substituted naphthyl; still more preferably optionally substituted phenyl.

In certain preferred embodiments, the compounds of formula IV have the structure according to formula V: In certain preferred embodiments, the compounds of formula IV have the structure according to formula VI: vi where A v2 and D B2 are each independently H, fluoro or alkyl. In certain preferred embodiments, the compounds of formula IV have the structure according to formula VII: vp In certain preferred embodiments, the compounds of formula IV have the structure according to formula Vlll: vm wherein A2 and B2 are each independently H, fluoro or alkyl. In certain preferred embodiments, the compounds of formula IV have the structure according to formula IX: IX In certain preferred embodiments, the compounds of formula IV have the structure according to formula X: X In certain preferred embodiments, the compounds of formula X have the structure according to formula XI: In certain preferred embodiments, the compounds of formula X have the structure according to formula Xll: xp wherein: Q1 and Q2 are each independently H, halo, alkyl, hydroxyl, alkoxy, substituted cycloalkylalkoxy, aminocarbonyl, -S (= O) 2 -alkyl, -S (= O) 2-N (H) alkyl , -S (= O) 2-N (H) cycloalkylalkyl, or -N (H) S (= O) 2-a-alkyl. In certain other more preferred embodiments, the compounds of formula Xll have the structure according to the formula In certain preferred embodiments of the compounds of formula IV, the compound is selected from the group consisting of: 4 - [(4 -? /,? / - diethyl-aminocarbonyl) phenyl] -spiro [2H, 1-benzopyran-2, 4'-piperidine]; 4 - [(2 -? /,? / - diethylaminocarbonyl) pyrid-5-yl] -spiro [6-fluoro-2H, 1-benzopyran-2,4'-piperidine]; 4 - [(2 -? /,? / - diethylaminocarbonyl) pyrid-5-yl] -spiro [5-methoxy-2H, 1-benzopyran-2,4 * -piperidine]; 4 - [(4 -? /,? / - diethylaminocarbonyl) phenyl] -spiro [5-hydroxy-2H, 1-benzopyran-2,4'-piperidine]; 4 - [(4- / V,? / - diethylaminocarbonyl) phenyl] -spiro [2H, 1-benzopyran-2,4'-azepane]; 4 - [(4 -? /, -diethylaminocarbonyl) phenyl] -spiro [6-cyclopropylmethylaminosulfonyl-2H, 1-benzopyran-2,4'-azepane]; 4 - [(4 -? /,? / - diethylaminocarbonyl) phenyl] -spiro [3,4-dihydro-2H, 1-benzopyran-2,4"-piperidine]; 4 - [(4 -? /,? / -diethylaminocarbonyl) phenyl] -spiro [1,2-dihydronaphthalen-2,4'-piperidine]; 4 - [(4- / V,? / - diethylaminocarbonyl-2-hydroxy) phenyl] -spiro [2H, 1 -benzopyran-2,4'-piperidine]; 4 - [(4-?,? / - diethylaminocarbonyl-3-hydroxy) phenyl] -spiro [2H, 1-benzopyran-2,4'-piperidine]; 4- [ (4 -? /,? - diethylaminocarbonyl) phenyl] -3-methyl-spiro [2 H, 1-benzopyran-2,4'-piperidine]; 4 - [(2 -? /, / V-diethylaminocarbonyl) pyrid-5-yl] -spiro [2 H, 1-benzopyran-2,4'-piperidine]; 4 - [(4-?,? / - diethylaminocarbonyl) phenyl] -spiro [6-cyclopropy-methoxy-2H, 1-benzopyran-2,4'-piperidine]; 4 - [(2 -? /,? / - diethylaminocarbonyl) pyrid-5-yl] -spiro [-6-cyclopropylmethoxy-2H, 1-benzopyran-2,4'-piperidine]; 4 - [(4- / V,? / - diethylaminocarbonyl) phenyl] -spiro [6-aminocarbonyl-2H, 1-benzopyran-2,4'-piperidine]; 4 - [(4- / V,? / - diethylaminocarbonyl) phenyl] -spiro [6-propylaminosulfonyl-2H, 1-benzopyran-2,4'-azepane]; 4 - [(4-N,? / -d-ethylaminocarbonyl) phenyl] -spiro [6-methanesulfonyl-2H, 1-benzopyran-2,4'-azepane]; 4 - [(2 -? /,? / - diethylaminocarbonyl) pyrid-5-yl] -spiro [3,4-dihydro-2H, 1-benzopyran-2,4'-piperidine]; 4 - [(2- / V,? / - diethylaminocarbonyl) pyrid-5-yl] -spiro [6-fluoro-3,4-dihydro-2H, 1-benzopyran-2,4'-piperidine]; 4 - [(5 -? /,? - diisopropylaminocarbonyl) pyrid-2-yl] -spiro [2 H, 1-benzopyran-2,4'-piperidine] 4 - [(4 -? /, W-diethylaminocarbonyl) phenyl] -spiro [6-ethylsulphonylamino-2H, 1-benzopyran-2,4'-piperidine]; 4 - [(4-N,? / - diethylaminocarbonyl) phenyl] -espyrro [6-methylsulfonylamino-2H, 1-benzopyran-2,4'-piperidine]; 4 - [(4-?,? / - diethylaminocarbonyl) phenyl] -espyrro [5-methyl-2H, 1-benzopyran-2,4'-piperidine]; 4- [4- (2H-tetrazol-5-yl) phenyl] -spiro [2 H, 1-benzopyran-2,4'-piperidine]; 4- [4- (2-methyl-tetrazol-5-yl) phenyl] -spiro [2 H, 1-benzopyran-2,4'-piperidine]; 4- [3- (2- (3-carboxyprop-1-yl) -tetrazol-5-yl) phenyl] -spiro [2 H, 1-benzopyran-2,4'-piperidine]; 4- [4- (5-Methyl- [1, 2,4] oxadiazol-3-yl) phenyl] -spiro [2 H, 1-benzopyran-2,4'-piperidine]; 4 - [(4-N -diethylaminocarbonyl) phenyl] -spiro [2 H, 1-benzopyran-2,4 '- (1'-methyl-piperidine)]; 4 - [(4 -? /,? / - diethylaminosulfonyl) pheny] -spiro [2 H, 1-benzopyran-2,4'-piperidine]; and 4 - [(4 - (? / - methyl -? / - (3-methylbutanoyl) -amino) phenyl] -spiro [2H, 1-benzopyran-2,4'-piperidine]; or one of its stereoisomers, prodrugs , pharmaceutically acceptable salts, hydrates, solvates, acid salt hydrates, or N-oxides In certain preferred embodiments of the compounds of formula IV, the compound is selected from the group consisting of: 4 - [(4 -? /, Vd-ethylaminocarbonyl) phenyl] -spiro [2 H, 1-benzopyran-2,4'-piperidine]; 4 - [(2 -? /, / V-diethylaminocarbonyl) pyrid-5-yl] -spiro [6-fluoro] -2H, 1-benzopyran-2,4'-piperidine]; 4 - [(2 -? /,? / - diethylaminocarbonyl) pyrid-5-yl] -spiro [5-methoxy-2H, 1-benzopyran-2, 4'-piperidine]; 4 - [(4 -? /, / V-diethylaminocarbonyl) phenyl] -spiro [5-hydroxy-2H, 1-benzopyran-2,4'-piperidine]; 4 - [(4-? /,? / - diethylaminocarbonyl) phenyl] -spiro [2H, 1-benzopyran-2,4'-azepane]; 4 - [(4- / V, / V-diethylaminocarbonyl) phenyl] -spiro [6-cyclopropylmethylaminosulfonyl-2H] , 1-benzopyran-2,4'-azepane]; 4 - [(4 -? /,? / - diethylaminocarbonyl) phenyl] -spiro [3,4-dihydro-2H, 1-benzopyran-2,4'-pip eridina]; 4 - [(4 -? /,? / - diethylaminocarbonyl) phenyl] -spiro [1,2-dihydronaphthalen-2,4'-piperidine]; 4 - [(4-A /,? / - diethylaminocarbonyl-2-hydroxy) phenyl] -spiro [2 H, 1-benzopyran-2,4'-piperidine]; 4 - [(4 -? /,? / - diethylaminocarbonyl-3-hydroxy) phenyl] -spiro [2 H, 1-benzopyran-2,4'-piperidine]; 4 - [(4-?,? / - d-ethylaminocarbonyl) phenyl] -3-methyl-spiro [2 H, 1-benzopyran-2,4'-piperidine]; 4 - [(2 -? /,? / - diethylaminocarbonyl) pyrid-5-yl] -spiro [2 H, 1-benzopyran-2,4'-piperidine]; 4 - [(4- / V,? / - diethylaminocarbonyl) phenyl] -spiro [6-cyclopropylmethoxy-2H, 1-benzopyran-2,4'-piperidine]; 4 - [(2- / V,? / - diethylaminocarbonyl) pyrid-5-yl] -spiro [-6-cyclopropylmethoxy-2H, 1-benzopyran-2,4'-piperidine]; 4 - [(4- / V,? / - diethylaminocarbonyl) phenyl] -spiro [6-aminocarbonyl-2H, 1-benzopyran-2,4'-piperidine]; 4 - [(4 -? /, / V-diethylaminocarbonyl) phenyl] -spiro [6-propylaminosulfonyl-2H, 1-benzopyran-2,4'-azepane]; 4 - [(4 -? /, V-diethyl-aminocarbonyl) phenyl] -spiro [6-methanesulfonyl-2H, 1-benzopyran-2,4 * -azepane]; 4 - [(2 -? /,? / - diethylaminocarbonyl) pyrid-5-yl] -spiro [3,4-dihydro-2H, 1-benzopyran-2,4'-piperidine]; 4 - [(2- / V,? / - diethylaminocarbonyl) pyrid-5-yl] -spiro [6-fluoro-3,4-dihydro-2H, 1-benzopyran-2,4'-piperidine]; and 4 - [(5 -? /,? / - diisopropylaminocarbonyl) pyrid-2-yl] -spiro [2 H, 1 -benzopyran-2,4'-piperidine]; or one of its stereoisomers, prodrugs, pharmaceutically acceptable salts, hydrates, solvates, acid salt hydrates, or N-oxides. In certain preferred embodiments of the compounds of formula IV, the compound is selected from the group consisting of: 4 - [(4 -? /,? / - diethylaminocarbonyl) phenyl] -spiro [2H, 1-benzopyran-2,4 '-piperidine]; 4 - [(2 -? /,? / -d-ethylaminocarbonyl) pyrid-5-yl] -spiro [6-fluoro-2 H, 1-benzopyran-2,4'-piperidine]; 4 - [(2 -? /,? / - diethylaminocarbonyl) pyrid-5-yl] -spiro [5-methoxy-2H, 1-benzopyran-2,4'-piperidine]; 4 - [(4 -? /,? / - diethylaminocarbonyl) phenyl] -spiro [5-hydroxy-2H, 1-benzopyran-2,4'-piperidine]; 4 - [(4 -? /,? / - diethylaminocarbonyl) phenyl] -spiro [2 H, 1-benzopyran-2,4'-azepane]; 4 - [(4 -? /,? / - diethylaminocarbonyl) phenyl] -spiro [6-cyclopropylmethylaminosulfonyl-2H, 1-benzopyran-2,4'-azepane]; 4 - [(4 -? /,? / - diethylaminocarbonyl) phenyl] -spiro [3,4-dihydro-2H, 1-benzopyran-2,4'-piperidine]; 4 - [(4 -? /,? / - diethylaminocarbonyl) phenyl] -spiro [1,2-dihydronaphthalen-2,4'-piperidine]; 4 - [(2-N, N-diethylaminocarbonyl) pyrid-5-yl] -spiro [6-cyclopropylmethoxy-2H, 1-benzopyran-2,4'-piperidine]; 4 - [(4-N, N-d-ethylaminocarbonyl) phenyl] -spiro [6-methanesulfonyl-2H, 1-benzopyran-2,4'-azepane]; 4 - [(4 -? /, / V-diethylaminocarbonyl-2-hydroxy) phenyl] -spiro [2 H, 1-benzopyran-2,4'-piperidine]; and 4 - [(4- / V, / V-diethylaminocarbonyl-3-hydroxy) phenyl] -spiro [2 H, 1-benzopyran-2,4'-piperidine]; or one of its stereoisomers, prodrugs, pharmaceutically acceptable salts, hydrates, solvates, acid salt hydrates, or N-oxides. In certain preferred embodiments of the compounds of formula IV, the compound is selected from the group consisting of: 4 * - [(4 -? /, / V-diethylaminocarbonyl) phenyl] -spiro [3,4-dihydro-2H, 1-benzopyran-2,4'-piperidine]; and 4 * - [(2 -? /,? / - diethylaminocarbonyl) pyrid-5-yl] -spiro [3,4-dihydro-2H, 1-benzopyran-2,4'-piperidine]; or one of its partial steroisomers, prodrugs, pharmaceutically acceptable salts, hydrates, solvates, acid salt hydrates, or N-oxides.

In certain preferred embodiments of the compounds of formula IV, the compound is selected from the group consisting of: 4 - [(4 -? /, A / -diethylaminocarbonyl) phenyl] -spiro * [2H, 1-benzopyran-2, 4'-azepane]; 4 - [(4 -? /,? - diethylaminocarbonyl) phenyl] -spiro * [6-cyclopropylmethylaminosulfonyl-2H, 1-benzopyran-2,4'-azepane]; 4 - [(4 -? /,? / - diethylaminocarbonyl) phenyl] -spiro * [6-propylaminosulfonyl-2H, 1-benzopyran-2,4'-azepane]; and 4 - [(4- / V,? / - diethylaminocarbonyl) phenyl] -spiro * [6-methanesulfonyl-2H, 1-benzopyran-2,4'-azepane]; or one of its partial steroisomers, prodrugs, pharmaceutically acceptable salts, hydrates, solvates, acid salt hydrates, or N-oxides. In an alternative preferred embodiment, the present invention relates to compounds selected from the group consisting of: - [(4-methoxyphenyl) -spiro [2 H, 1-benzopyran-2,4'-piperidine]; 4 - [(4-methylphenyl) -spiro [2 H, 1-benzopyran-2,4'-piperidine]; -phenyi-spiro [2 H, 1-benzopyran-2,4'-piperidine]; 4 - [(3-methoxyphenyl) -spiro [2 H, 1-benzopyran-2,4'-piperidine]; and 4- [ (2-methoxyphenyl) -espyrro [2H, 1-benzopyran-2,4'-piperidine]; or one of its stereoisomers, prodrugs, pharmaceutically acceptable salts, hydrates, solvates, acid salt hydrates, or N-oxides. In another aspect, the invention relates to pharmaceutical compositions, comprising: a pharmaceutically acceptable carrier, and an effective amount of a compound of the invention including, for example, a compound of formulas I, II, III, IV, V, VI , Vil, Vlll, IX , X, XI, Xll, and / or Xlll. In certain embodiments, the pharmaceutical composition additionally comprises an effective amount of at least one opioid. In some preferred aspects, the invention relates to pharmaceutical compositions comprising a pharmaceutically acceptable carrier; and a compound of formula IV: IV? wherein: Y2 is a single bond or - [C (Rc) (Rd)] k-; each Rc, Re, and Rf is independently H or alkyl; each Rd is independently H, alkyl, or aryl; W2 is aryl, alkylaryl, heterocycloalkylaryl, heteroaryl, alkylheteroaryl, heteroarylaryl, or alkylheteroarylaryl; R23 and R24 are each independently H, alkyl, alkenyl, alkynyl, or aryl, or R23 and R24 when taken together with the atoms through which they are connected, form a cycloalkyl or heterocycloalkyl ring of 4 to 8 members; Z is -N (R25) -, -C (= O) -, -CH (OH) -, -CH (N (Rc) (Rd)) -, or -O-; R25 is H, alkyl, alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl, aralkyl, or heteroarylalkyl, or R23 and R25 when taken together with the atoms through which they are connected, form a 4- to 8-membered heterocycloalkyl ring, or R24 and R25 when taken together with the atoms through which they are connected, form a 4 to 8 membered heterocycloalkyl ring; each k is independently 1, 2, or 3; p is 0, 1, 2 or 3; s is 0, 1, 2 or 3, with the proviso that the sum of p and s is 4; A2 and B2 are each independently H, fluoro, or alkyl, or together they form a double bond or -CH2-; G is H or alkyl; X2 is -C (Rc) (Rd) -, -O-, -S-, -S (= O) -, -S (= O) 2-, -C (= O) -, -CH (OH) - or -N (R26) -; R26 is H, alkyl, cycloalkyl, - (CH2) -alkenyl, - (CH2) -alkynyl, aryl, -C (= O) Rd, or -S (= O) 2Rd; and J2 forms a 6 to 10 membered aryl or a 5- to 10 membered heteroaryl ring when taken together with the carbon atoms to which it is attached; with the proviso that when: (a) J2 is taken together with the carbon atoms to which it is attached it forms a 6 to 10 membered aryl ring substituted with 0-3 groups selected from the group consisting of: halogen, hydroxy, - SH, -C (= O) -H -S-alkyl CM, -NHS (= O) 2-alkyl CM, -NHS (= O) 2-H, -N (alkyl CM) S (= O) 2- H, alkyl CM, and alkoxy CM, the last two optionally substituted with one or more halogens or with alkoxy CM; W 2 is phenyl substituted with 0-3 groups selected from the group consisting of: halogen, cyano, hydroxy, C 1-6 alkyl optionally substituted with one or more halogens, C 1-6 alkoxy optionally substituted with one or more halogens or with C 3-6 cycloalkyl , C2-6 alkenyloxy, C2-6 alkynyloxy > C3-6 cycloalkyloxy, C6-? 2 aryloxy, aralkoxy, heteroaryloxy, heteroaralkoxy, heterocycloalkyl substituted with alkoxy, -SH, -S-alkyl CM, -NH2, -N = C (aryl) 2, -N (H) alkyl CM , -N (alkyl CM) 2, -OS (= O) 2 -alkyl CM optionally substituted with one or more halogens, -OS (= O) 2-aryl C6-12 optionally substituted with alkyl CM, -NHS (= O ) 2-alkyl CM, -N (alkyl CM) S (= O) 2-alkyl CM, -NHS (= O) 2-H, and -N (alkyl CM) S (= O) 2-H; p and s are each 1, Re, Rf, R23, R24, and G are each H, A2 and B2 together form a double bond, Y2 is a single bond; and X2 is -O-; then Z is different from: where t is an integer between 1 and 20; and with the proviso that when: (b) J2 is taken together with the carbon atoms to which it is attached it forms a phenyl ring substituted with 0-3 groups selected from the group consisting of: halogen, hydroxy, -S-alkyl CM , alkyl CM, and alkoxy C, the last two optionally substituted with one or more halogens or with C-alkoxy; W2 is unsubstituted naphthyl, or phenyl substituted with 0-3 groups selected from the group consisting of: halogen, C1-6 alkyl, C6-6 alkoxy, phenyl, phenyloxy, 1,3-benzodioxazolyl, or 2,2-difluoro -1, 3-benzodioxazolyl fluoro, -NH2, -N (C14 alkyl) 2, and pyrrolyl; p and s are each 1, Re, Rf, R23, R24, and G are each H, A2 and B2 together form a double bond, Y2 is a single bond; and X2 is -O-; then Z is different from: VH VCH5 with the proviso that when: (c) J2 is taken together with the carbon atoms to which unsubstituted phenyl form is attached, W2 is phenyl substituted with 0-3 groups selected from the group constituted by: fluorine, hydroxy, C1-6 alkoxy optionally substituted with one or more fluoros, C2-6 alkenyloxy, and -S-alkyl CM, pys are each 1, Re, Rf, R23, R24, and G are each H , A2 and B2 together form a double bond, Y2 is a single bond; and X2 is -O-; then Z is different from: with the proviso that when: (d) J2 is taken together with the carbon atoms to which it is attached it forms a 6-membered aryl ring substituted with: then Z is different from -N (R25) - or -CH (NH2) -; or one of its stereoisomers, prodrugs, pharmaceutically acceptable salts, hydrates, solvates, acid salt hydrates, or N-oxides. The compounds of the invention may be useful as anesthetic agents for use during general anesthesia and supervised anesthesia. Combinations of agents with different properties are often used to achieve a balance of the effects necessary to maintain the anesthetic state (for example, amnesia, analgesia, muscle relaxation and sedation). This combination includes inhaled anesthetics, hypnotics, anxiolytics, neuromuscular blockers and opiates. In any of the above teachings, a compound of the invention can be a compound of one of the formulas described herein, or one of its stereoisomers, prodrugs, pharmaceutically acceptable salts, hydrates, solvates, acid salt hydrates, N- oxides or isomorphic crystalline forms. The compounds used in the methods and compositions of the present invention may exist in the form of a prodrug. As used herein, "prodrug" is intended to include any covalently linked vehicle that releases the active parental drug, for example, according to formula I or other formulas or compounds as described herein, in vivo when such a prodrug is administered to a mammal. Since it is known that prodrugs enhance numerous desirable qualities of pharmaceutical compositions (eg, solubility, bioavailability, manufacture, etc.), the compounds described herein can be administered, if desired, in the form of a prodrug. Thus, the present invention contemplates compositions and methods that include prodrugs. The prodrugs of the compounds used in the present invention, for example of formula I, can be prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either during routine manipulation or in vivo, to give the parent compound . Accordingly, prodrugs include, for example, compounds described herein in which a hydroxyl, amino or carboxylic acid group is attached to any group such that, when the prodrug is administered to a mammal, it extends to form a hydroxy free, free amino, or carboxylic acid, respectively. Examples include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups; and alkyl, carbocycle, aryl and alkylaryl esters such as methyl, ethyl, propyl, de / so-propyl, butyl, isobutyl, sec-butyl, fer-butyl, cyclopropyl esters, phenyl, benzyl, and phenethyl, and the like. The compounds described herein may contain one or more asymmetrically substituted carbon atoms, and may be isolated in optically active or racemic forms. Thus, all chiral, diastereomeric, racemic forms and all forms of geometric isomers are provided, unless the specific stereochemical or isomeric form is specifically indicated. It is well known in the art how to prepare and isolate such optically active forms. For example, mixtures of stereoisomers can be separated by standard techniques including, but not limited to, resolution of racemic forms, normal phase, reverse phase and chiral chromatography, preferential salt formation, recrystallization, and the like, or by chiral synthesis to starting from chiral starting materials or by deliberate synthesis of final chiral centers. The compounds of the present invention can be prepared in a variety of ways well known to those led in the art. The compounds can be synthesized, for example, by the methods described below, or variations on them as will be appreciated by the led person. All the methods described in conjunction with the present invention are contemplated to be performed at any scale, including milligrams, grams, multigrams, kilograms, multikilograms or commercial industrial scale. As will be readily understood, the present functional groups may contain protecting groups during the course of the synthesis. Protecting groups are known per se as functional chemical groups that can be selectively bound to and removed from functions, such as hydroxyl groups and carboxyl groups. These groups are present in a chemical compound to give an inert function to the chemical reaction conditions to which the compound is exposed. Any of a variety of protecting groups can be employed with the present invention. Preferred protecting groups include the benzyloxycarbonyl group and the tert-butyloxycarbonyl group. Other preferred protecting groups that can be employed according to the present invention can be described in Greene, T.W. and Wuts, P.G.M., Protective Groups in Organic Synthesis 2nd Ed., Wiley and Sons, 1991, whose descriptions are incorporated herein by reference, in their entirety. The agonist compounds d of the present invention can be administered by any means that results in contact of the active agent with the site of action of the agent in the patient's body. The compounds can be administered by any conventional means available for use in conjunction with pharmaceutical compositions, as individual therapeutic agents or in a combination of therapeutic agents. For example, they can be administered as the active agent alone in a pharmaceutical composition, or they can be used in combination with other therapeutically active ingredients including, for example, opioid analgesic agents. In such combinations, the selected compounds of the invention can provide equivalent therapeutic activity, or even improved, such as pain improvement, while providing a reduction in side effects associated with opioids, such as addiction or pruritus, decreasing the amount of opiate necessary to achieve the therapeutic effect. The compounds are preferably combined with a pharmaceutical carrier selected according to the chosen route of administration and usual pharmaceutical practice, described, for example, in Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, PA, 1980), the descriptions of which are incorporated herein by reference. in this document by reference, In its whole. In addition to the pharmaceutical carrier, the compounds of formulas I, II, III, IV, V, VI, VII, VII, IX, X, XI, Xll, and / or Xlll can be co-administered with at least one opioid, preferably a opioid receptor modulator compound μ. In certain embodiments, the combination of the compounds of formula I, II, III, IV, V, VI, VII, VII, IX, X, XI, Xll, and / or Xlll with at least one opioid, preferably a compound μ-opioid receptor modulator, provides a synergistic analgesic effect. The utility of the present combination product can be determined by those skilled in the art using established animal models. Suitable opioids include, without limitation, alfentanil, allylprodine, alphaprodin, anileridin, benzylmorphine, becitramide, buprenorphine, butorphanol, clonitazene, codeine, cyclazocine, desomorphine, dextromoramide, dezocin, diampromide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol, dimetheptanol, dimethylthiambutene, dioafethylbutyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, fentanyl, heroin, hydrocodone, hydromorphone, hydroxypetidine, isomethadone, ketobemidone, eevalorfan, levorphanol, levofenacylmorphan, lofentanil, loperamide, meperidine (pethidine), meptacinol, metazocine, methadone , metopon, morphine, mirofin, nalbuphine, narcein, nicomorphine, norievorphanol, normetadone, nalorphine, normorphine, norpinanone, opium, oxycodone, oxymorphone, papaveretum, pentazocine, fenadoxone, fenomorfan, fanazocine, phenoperidine, piminodine, piritramide, profeptacin, promedol, properidin propiram, propoxyphene, sulfentanil, tilidine, tram adol, its diastereomers, its pharmaceutically acceptable salts, its complexes; and its mixtures. The combination pain and / or opiate enhancement products of the present compositions may additionally include one or more other active ingredients that can be conventionally employed in analgesic and / or cough-cold-antitussive combination products. Such conventional principles include, for example, aspirin, acetaminophen, phenylpropanolamine, phenylephrine, chlorpheniramine, caffeine, and / or guaifenesin. Typical or conventional principles that may be included in the opiate component are written, for example, in the Physicians' Desk Reference, 1999, the disclosure of which is hereby incorporated by reference in its entirety. In addition, the opioid component may additionally include one or more compounds designed to increase the analgesic potency of the opiate and / or reduce the development of tolerance to the analgesic. Such compounds include, for example, dextromethorphan or other NMDA antagonists (Mao, MJ et al., Pain 1996, 67, 361), L-364,718 and other CCK antagonists (Dourish, CT et al., Eur J Pharmacol 1988 , 147, 469), NOS inhibitors (Bhargava, HN et al., Neuropeptides 1996, 30, 219), inhibitors of PKC (Bilsky, EJ et al., J Pharmacol Exp Ther 1996, 277, 484), and antagonists of dynorphin or antiserum (Nichols, ML et al., Pain 1997, 69, 317). The descriptions of each of the above documents are incorporated herein by reference, in their entirety. Other opioids, optional conventional opioid components, and optional compounds for increasing the analgesic potency of the opiate and / or for reducing the development of analgesic tolerance, which may be employed in the methods and compositions of the present invention, in addition to those exemplified above, they will be immediately apparent to someone with ordinary knowledge in the field, once provided with the teachings of the present description. The compounds of the present invention can be administered to a mammalian host in a variety of forms adapted for the chosen route of administration, for example, orally or parenterally. In this regard parenteral administration includes administration via the following routes: intravenous, intramuscular, subcutaneous, rectal, intraocular, intrasynovial, transepithelial including transdermal, ophthalmic, sublingual and buccal; topically including ophthalmic, dermal, ocular, rectal, and nasal inhalation through an insufflation aerosol. The active compound can be administered orally, for example, with an inert diluent or with an edible assimilable carrier, or it can be introduced into hard or soft gelatin capsules, or it can be compressed into tablets, or it can be incorporated directly into foodstuffs. the diet. For oral therapeutic administration, the active compound can be incorporated into excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like. Such compositions and preparations should preferably contain at least 0.1% of the active compound. Of course, as a percentage of the compositions and preparations, it can be varied and can conveniently be, for example, between about 2 and about 6% by weight of the unit. The amount of active compound in such therapeutically useful compositions is preferably such that adequate dosage will be obtained. Preferred compositions or preparations according to the present invention can be prepared so that a unit dosage form oral contains between about 0.1 and about 1000 mg of active compound. The tablets, troches, pills, capsules and the like may also contain one or more of the following compounds: a binding agent, such as gum tragacanth, gum arabic, corn starch or gelatin; an excipient, such as dicalcium phosphate; a disaggregating agent, such as corn starch, potato starch, cynic acid and the like; a lubricant, such as magnesium stear; a sweetening agent, such as sucrose, lactose or saccharin; or a flavoring agent, such as peppermint oil, wintergreen oil or cherry flavor. When the unit dosage form is a capsule, it may contain, in addition to the materials of the above type, a liquid carrier. Various other materials may be present in the form of coatings or to otherwise modify the physical form of the dosage unit. For example, tablets, pills, or capsules may be coated with gum, sugar, or both. A syrup or elixir may contain the active compound, sucrose as a sweetening agent, methyl and propylparabens as preserving agents, a dye and a flavoring agent, such as cherry or orange flavor. Of course, any material used in the preparation of any unit dosage form is preferably pharmaceutically pure and substantially non-toxic in the amounts employed. In addition, the active compound can be incorporated into sustained release preparations and formulations. The active compound can also be administered parenterally or intraperitoneally. Solutions of the active compound in the form of a free base or a pharmacologically acceptable salt can be prepared in water conveniently mixed with a surfactant, such as hydroxypropylcellulose. A dispersion can also be prepared in glycerol, liquid polyethylene glycols and their mixtures and in oils. Under conditions of ordinary storage and use, these preparations may contain a preserving agent to prevent the growth of microorganisms. Pharmaceutical forms suitable for injectable use include, for example, sterile aqueous solutions or dispersions and sterile powders for the improvised preparation of sterile injectable solutions or dispersions. In all cases, the shape is preferably sterile and fluid to provide a good syringeability. It is preferably stable under the conditions of manufacture and storage and is preferably preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier may be a solvent or a dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils. Proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of a dispersion, and by the use of surfactants. The prevention of the action of microorganisms can be carried out by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars or sodium chloride. The prolonged absorption of the injectable compositions can be carried out by the use of absorption retarding agents, for example, aluminum monostearate and gelatin. Sterile injectable solutions can be prepared by incorporating the active compound in the necessary amount, in the appropriate solvent, with several of the other principles enumerated above, as necessary, followed by sterilization by filtration. Generally, dispersions can be prepared by incorporating the sterilized active ingredient into a sterile vehicle containing the basic dispersion medium and the other necessary principles from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred preparation methods including can include vacuum drying and the freeze-drying technique that gives a powder of the active principle, plus any additional desired principle from the previously filtered solution to sterility. The therapeutic compounds of this invention can be administered to a patient alone or in combination with a pharmaceutically acceptable carrier. As indicated above, the relative proportions of the active principle and the vehicle can be determined, for example, by the solubility and chemical nature of the compound, the route of administration chosen and the usual pharmaceutical practice.

The dosage of the compounds of the present invention which will be more suitable for prophylaxis or treatment will vary with the form of administration, the particular compound chosen and the physiological characteristics of the particular patient under treatment. Generally, small dosages can be used initially and, if necessary, increased in small increments until the desired effect is achieved under those circumstances. The therapeutic dosage in humans, based on physiological studies using rats, can generally encompass between about 0.01 mg and about 100 mg / kg of body weight and day, and all combinations and subcombinations of specific ranges and dosages contained therein. . Alternatively, the therapeutic dosage in humans may be between about 0.4 mg and about 10 g or more, and may be administered in several different dosage units between one and several times a day. Generally speaking, oral administration may require higher dosages. It will further be appreciated that the amount of compound, or of one of its active salts or derivatives, necessary for its use in the treatment will vary, not only with the particular salt selected, but also with the route of administration, the nature of the condition being treated. and the age and physical condition of the patient, and will ultimately depend on the criterion of the physician or the attending physician. The desired dose can be conveniently presented in a unit dose or in the form of divided doses administered at appropriate intervals, for example, in the form of two, three, four or more sub-doses per day. The sub-dose itself may be further divided, for example, into a series of discrete administrations freely spaced; as multiple inhalations of an insufflator or by applying a plurality of drops in the eye. The dose can also be delivered for controlled release of the compound, by techniques well known to those skilled in the art. The compounds of the invention can also be formulated with other optional active ingredients, in addition to or in place of the optional opioids, and in addition to the optional pharmaceutically acceptable carriers. Other active ingredients include, but are not limited to, antibiotics, antivirals, antifungals, anti-inflammatories, including steroidal and nonsteroidal anti-inflammatory drugs, anesthetics and mixtures thereof. Such additional principles include any of the following: a. Antibacterial agents Aminoglycosides, such as Amicacin, Apramycin, Arbecacine, Bambermycins, Butirosin, Dibecacin, Dihydrostreptomycin, Fortimycin (s), Fradiomycin, Gentamicin, Ispamycin, Canamycin, Micronomycin, Neomycin, Neomycin Undecylenate, Netilmicin, Paromomycin, Ribostamycin, Sisomycin, Spectinomycin, Streptomycin, Streptonicozid and Tobramycin; Amphenicols, such as Acidanfenicol, Chloramphenicol, Chloramphenicol Palmirate, Chloramphenicol Pantothenate, Florphenicol, Tianfenicol; Ansamicins, such as Rifamide, Rifampin, Rifamycin and Rifaximin; /? - Lactams; Carbapenomes, such as Imipenem; Cephalosporins, such as 1-Carba (detia) Cephalosporin, Cefactor, Cefadroxil, Cefamandol, Cefatricin, Cefazedone, Cefazolin, Cefixime, Cefmenoxim, Cephodicima, Cefonicid, Cefoperazone, Ceforanide, Cefotaxime, Cefotiam, Cefpimizole, Cefpirimide, Cefpodoxime Proxetil, Cefroxadine, Cefsulodin, Ceftacidima, Cefteram, Ceftezole, Ceftibutene, Ceftizoxime, Ceftriaxone, Cefuroxime, Cefuzonam, Sodium Cefacetril, Cephalexin, Cephaloglycine, Cefaloridine, Cephalosporin, Cefalotin, Sodium Cephapirin, Cephradine and Pivzefalexin; Cefamycins such as Cefbuperazone, Cefmetazole, Cefminox, Cefetan and Cefoxitin; Monobactams such as Aztreonam, Carumonam and Tigemonan; Oxacefemos such as Flomoxef and Moxolactama; Penicillins such as Amidinocillin, Amdinocillin, Pivoxil, Amoxicillin, Ampicillin, Apaccilin, Aspoxycillin, Azidocilan, Azlocilan, Bacampicillin, Benzylpenicillinic Acid, Benzylpenicillin, Carbenicillin, Carfecillin, Carindacillin, Clometocillin, Cloxacillin, Cyclacillin, Dicloxacillin, Diphenicillin, Epicillin, Fenbenicillin, Floxicillin, Hetacycline, Lenampicillin, Metampicillin, Methicillin, Mezlocillin, Nafcillin, Oxacillin, Penamecillin, Penetamate Yodhidrate, Penicillin G Benetamine, Penicillin G Benzathine, Penicillin G Benzohydrilamine, Calcium Penicillin G, Penicillin G Hydragamine, Potassium Penicillin G, Penicillin G Procaine, Penicillin N, Penicillin O, Penicillin V, Penicillin V Benzathine, Penicillin V Hydrylamide, Penimapicycline, Feneticilin, Piperacillin, Pivapicillin, Propicillin, Quinacillin, Sulbenicillin, Talampicillin, Temocillin and Ticarcillin; Lincosamides such as Clindamycin and Lincomycin; Macrolides such as Acythromycin, Carbomycin, Clarithromycin, Erythromycin (s) and their derivatives, Josamycin, Leucomycins, Midacamycins, Miocamycin, Oleandomycin, Primicin, Roquitamycin, Rosaramycin, Roxithromycin, Spiramycin and Troleandomycin; Polypeptides such as Anphomycin, Bacitracin, Capreomycin, Colistin, Enduracidin, Enviomycin, Fusafungin, Gramicidin (s), Gramicidin S, Micamycin, Polymyxin, Polymyxin of β-methanesulfonic acid, Pristinamycin, Ristocetin, Teicoplanin, Tiostrepton, Tuberactinomycin, Tirocidin, Thyrothricin, Vancomycin, Viomycin (s), Virginiamicin and Zinc Bacitracin; Tetracyclines such as Spicycline, Chlorothetracycline, Clomocycline, Demeclocycline, Doxycycline, Guamecycline, Limecycline, Meclocycline, Metacycline, Minocycline, Oxytetracycline, Penimepicycline, Pipacycline, Rolitetracycline, Sancycline, Senocycline and Tetracycline; and others such as Cicloserina, Mupirocina, Tuberina. b. Synthetic antibacterials 2,4-Diaminopyrimidines such as Brodimoprim, Tetroxoprim and Trimatoprim; Nitrofurans such as Furaltadone, Furazolium, Nifuradene, Nifuratel, Nifurfolina, Nifurpirinol, Nifurpracina, Nifurtoinol and Nitrofurantoína; Quinolones and their analogues, such as Amifloxacin, Cinoxacin, Ciprofloxacin, Difloxacin, Enoxacin, Fleroxacin, Flumequine, Lomefloxacin, Miloxacin, Nalidixic Acid, Norfloxacin, Ofloxacin, Oxolinic Acid, Perfloxacin, Pipemidic Acid, Pyromidic Acid, Rosoxacin, Temafloxacin and Tosufloxacin; Sulfonamides such as Acetyl Sulfamethoxypiracine, Acetyl Sulfisoxazole, Azosulfamide, Benzylsulfamide, Chloramine-β, Chloramine-T, Dicloramine-T, Formosulfatiazole, N2 -Formyl-sulfisomidine, N4-β-D-Glucosylsulfanilamide, Mafenide, 4 '- (Methyl-sulfamoyl) sulfanilanilida, p-Nitrosulfatiazol, Noprilsulfamida, Ftalilsulfacetamida, phthalylsulfathiazole, Salazosulfadimidina, succinylsulfathiazole, sulfabenzamide, sulfacetamide, Sulfaclorpiridacina, sulfachrysoidine, sulfacytine, sulfadiazine, Sulfadicramida, Sulfadimethoxine, Sulfadoxine, Sulfaetidol, sulfaguanidine, Sulfaguanol, sulfalene, Sulfalóxico acid, sulfamerazine, Sulfameter, sulfamethazine , Sulfamethizole, Sulfametomidina, sulfamethoxazole, sulfamethoxypyridazine, sulfametrole, Sulfamidocrisoidina, sulfamoxole, sulfanilamide, acid Triethanolamine Salt Sulfanilamidometanosulfónico, 4-SulfanilamidosalicícIico, N4 Sulfanililsulfanilamida, Sulfanililurea, N-ylsulfanyl-3,4-xilamida, Sulfanitran, Sulfaperina, sulfaphenazole, Sulfaproxyline, Su lfapiracin, Sulphopyridine, Sulfasomizol, Sulfasimazine, Sulfathiazole, Sulfatiourea, Sulfatolamide, Sulfisomidine and Sulfisoxazole; Sulfones, such as Acedapsone, Acetylsulfone, Acetosulfone, Dapsone, Diatimosulfone, Glucosulfone, Solasulfone, Succisulfone, Sulfanilic Acid, p-Sulfanilylbenzylamine, p, p'-sulfonyldianilin-N, N'-digalactoside, Sulfoxone and Thiazolsulfone; Others such as Clofoctol, Hexedine, Magainins, Metenamine, Anhydromethylene-Metenamine Citrate, Metenamine Hippurate, Metenamine Mandelate, Metenamine Sulfosalicylate, Nitroxoline, Esqualamin and Xibomol. c. Antifungals (antibiotics) Polyenes such as Amphotericin-B, Candicidin, Dermostatin, Philippine, Fungicromin, Hachymycin, Hamicin, Lucensomycin, Meparticin, Natamycin, Nystatin, Pecillin, Perimycin; and others, such as Azaserin, Griseofulvin, Oligomycins, Pyrrolnitrin, Siccanin, Tubercidin and Viridine. d. Antifungals (synthetic) Allylamines such as Naftifine and terbinafine; Imidazoles such as Bifonazole, Butoconazole, Chlordantoin, Clormidazole, Cloconazole, Clotrimazole, Econazole, Enilconazole, Finticonazole, Isoconazole, Ketoconazole, Miconazole, Omoconazole, Oxiconazole Nitrate, Sulconazole and Tioconazole; Triazoles such as Fluconazole, Itraconazole, Terconazole; Others like Acrisorcin, Amorolfine, Bifenamina, Bromosalicilcloranilida, Buclosamide, Clofenesin, Cyclopirox, Cloxyquin, Coparafinate, Diamtazole, Dihydrochloride, Exalamide, flucytosine, halethazole, hexetidine, Loflucarban, Nifuratel, Potassium Iodide, Propionic Acid, Pyrithione, Salicylanilide, sulbentine, Tenonitrozol, tolciclate, Tolindato, Tolnaftate, Tricetine, Ujotion, and Undecylenic Acid. and. Antiglaucoma agents Antiglaucoma agents, such as Dapiprazoke, Dichlorphenamide, Dipivefrine and Pilocarpine. F. Anti-inflammatory agents Corticosteroids, Aminoarilcarboxylic Acid Derivatives such as Etofenamate, Meclofenamic Acid, Mefanamic Acid, Niflumic Acid; Derivatives of the Arylactatic Acid such as Acemetacin, Amfenac Cinmetacin, Clopirac, Diclofenac, Fenclofenac, Fenclorac, Fenclic Acid, Fentiazac, Glucametacin, Isozepac, Lonazolac, Methiacinic Acid, Oxametacin, Proglumetacin, Sulindac, Tiaramide and Tolmetin; Derivatives of Arylbutyric Acid such as Butibufen and Fenbufen; Arylcarboxylic acids such as Clidanac, Cetorolac and Tinoridine; Arylpropionic acid derivatives such as bucloxic acid, carprofen, fenoprofen, flunoxaprofen, ibuprofen, ibuproxam, oxaprozin, Picetoprofeno, pirprofen, pranoprofen, tiaprofenic acid and Proticínico acid; Pyrazoles such as Mepirizol; Pyrazolones such as clofezone, feprazone, mofebutazone, oxyphenbutazone, phenylbutazone, Phenyl Pirazolidininonas, Suxibuzone and thiazolinobutazone; Derivatives of Salicylic Acid such as Bromosaligenin, Fendosal, Glycol Salicylate, Mesalamine, 1-Naltyl Salicylate, Olsalazine and Sulfasalazine; Thiacincarboxamides such as Droxicam, Isoxicam and Piroxicam; Others such as e-Acetamidocaproic Acid, S-Adenosylmethionine, 3-Amino-4-hydroxybutyric acid, Amixetrin, Bendazac, Bucoloma, Carbazonas, Difenpyramide, Ditazole, Guaiazulene, Heterocyclic Aminoalkyl Esters of Mycophenolic Acid and its Derivatives, Nabumetone, Nimasulide, Orgotein, Oxaceprol, Oxazole, Paraniline, Pifoxime, 4,6-di-tert-butyl-s-hydroxy-1,3-pyrimidine 2-substituted derivatives, Proquazona and Tenipdap. g. Antiseptics Guanidines such as Alexidine, Ambazone, Chlorhexidine and Picloxidine; Halogen / halogen compounds as chloride Bomilo, calcium iodate, iodine, iodine monochloride, iodine trichloride, Iodoform, povidone-iodine, sodium hypochlorite, sodium iodate Simcloseno Iodide Thymol, Triclocarban, Triclosan and troclosene Potassium; Nitrofurans such as Furazolidone, 2- (Methoxymethyl) -5-Nitrofuran, Nidroxizone, Nifuroxime, Nifurcide and Nitrofurazone; Phenols as Acetomeroctol, Chloroxylenol, Hexachlorophene, 1-naphthyl salicylate, 2,4,6-tribromo-cresol and 3 \ 4 ', 5-Triclorosalicilan¡lida; Quinolines such as Aminoquinuride, Cloroxin, Chlorquinaldol, Cloxiquine, Ethylhydrocuprein, Halquinol, Hydrastine, 8-Hydroxyquinoline and Sulfate; and others, such as Boric Acid, Chlorozodine, m-Cresyl Acetate, Cupric Sulfate and Ictamol. h. Purine / Pyrimidinone antivirals, such as 2-Acetyl-Pyridin 5 - ((2-pyridylamino) thiocarbonyl) thiocarbonohydrazone, Acyclovir, Dideoxydenosine, Dideoxycytidine, Dideoxyinosine, Edoxudin, Floxuridine, Ganciclovir, Idoxuridine, MADU, Pyridinone, Trifluridine, Vidrarbine and Zidovudline; others such as Acetyleucine Monoethanolamine, Acridinamine, Alkylisoxazoles, Amantadine, Amidinomycin, Tiosemicarbazone Cuminaldehyde, Sodium Foscamet, Cetoxal, Lysozyme, Methisazone, Moroxidine, Podofilotoxin, Ribavirin, Rimantadine, Stathylmycin, Estatolon, Thymosins, Tromantadine and Xenazoic Acid. i. Agents for neuralgia / neuropathic pain OTC soft analgesics (without prescription), such as aspirin, acetaminophen, and ibuprofen.

Narcotic analgesics, such as codeine. Anti-seizure medications, such as carbamazepine, gabapentin, lamotrigine and phenytoin.

Anti-depressants, such as amitriptyline. j. Agents for the treatment of depression Selective serotonin reuptake inhibitors (SSRIs), such as Fluoxetine, Paroxetine, Fluvoxamine, Citaprolam, and Sertraline. Tricyclics, such as Imipramine, Amitriptyline, Desipramine, Nortriptyline, Protriptyline, Trimipramine, Doxepin, Amoxapine, and Clomipramine. Monoamine Oxidase inhibitors (MAOls), such as Tranylcypromine, Fenelcin, and Isocarboxazide. Heterocyclics, such as Amoxipin, Maprotiline and Trazodone. others such as Venlafaxine, Nefazodone and Mirtazapine. k. Agents for the treatment of incontinence Anticholinergic agents such as propantheline. Antispasmodic medications such as oxybutynin, tolterodine, and flavoxate. Tricyclic antidepressants such as imipramine, and doxepin. Blockers of calcium channels such as tolterodine. Beta-agonists such as terbutaline. I. Agents aníiParkinason Deprenilo, Amantadina, Levodopa, and Carbidopa. In yet another aspect, the invention relates to methods of binding to opioid receptors, preferably opioid receptors d, in patients in need thereof, comprising the step of administering to said patient an effective amount of a compound of the invention including, for example, a compound of formulas I, II, III, IV, V, VI, VII, VII, IX, X, XI, Xll, and / or Xlll. The opioid receptors d may be localized in the central nervous system or peripherally located to the central nervous system. In certain preferred embodiments, the binding of the present compounds modulates the activity, preferably as an agonist, of said opiate receptors. In certain preferred embodiments, the compound of formula I, II, III, IV, V, VI, VII, VII, IX, X, XI, Xll, and / or Xlll is not aviary substantially the blood-brain barrier. Preferably, the compounds of the present invention are peripherally selective. In certain preferred aspects, the methods comprise the step of administering to said patient an effective amount of a compound of formula IV: IV where: Y2 is a single bond or - [C (Rc) (Rd)] k-; each Rc, Re, and Rf is independently H or alkyl; each Rd is independently H, alkyl, or aryl; W2 is aryl, alkylaryl, heterocycloalkylaryl, heteroaryl, alkylheteroaryl, heteroarylaryl, or alkylheteroarylaryl; R23 and R24 are each independently H, alkyl, alkenyl, alkynyl, or aryl, or R23 and R24 when taken together with the atoms through which they are connected, form a cycloalkyl or heterocycloalkyl ring of 4 to 8 members; Z is -N (R25) -, -C (= O) -, -CH (OH) -, -CH (N (Rc) (Rd)) -, or -O-; R25 is H, alkyl, alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl, aralkyl, or heteroarylalkyl, or R23 and R25 when taken together with the atoms through which they are connected, form a 4- to 8-membered heterocycloalkyl ring, or R24 and R25 when taken together with the atoms through which they are connected, form a 4- to 8-membered heterocycloalkyl ring; each k is independently 1, 2, or 3; p is O, 1, 2 or 3; s is 0, 1, 2 or 3, with the proviso that the sum of p and s is 4; A2 and B2 are each independently H, fluoro, or alkyl, or together they form a double bond or -CH2-; G is H or alkyl; X2 is -C (Rc) (Rd) -, -O-, -S-, -S (= O) -, -S (= O) 2-, -C (= O) -, -CH (OH) - or -N (R26) -; R26 is H, alkyl, cycloalkyl, - (CH2) -alkenyl, - (CH2) -alkyl, aryl, -C (= O) Rd, or -S (= O) 2Rd; and J2 forms a 6 to 10 membered aryl or a 5- to 10 membered heteroaryl ring when taken together with the carbon atoms to which it is attached; or one of its stereoisomers, prodrugs, pharmaceutically acceptable salts, hydrates, solvates, acid salt hydrates, or N-oxides. The heterocyclic spirocyclic derivatives of the present invention and the pharmaceutical compositions containing these compounds can be used in different ways. In certain embodiments, the heterocyclic spirocyclic derivatives are opioid receptor ligands and are useful, inter alia, in methods for the treatment and / or prevention of pain, gastrointestinal disorders, disorders of the urogenital tract including incontinence, eg, urinary incontinence. stress, imperious urinary incontinence and benign prostatic hyperplasia, and overactive bladder disorders (see, for example, RB Moreland et al., Perspectives in Pharmacology, Vol. 308 (3), pp. 797-804 (2004) and MO Fraser, Annual Reports in Medicinal Chemistry, chapter 6, pp. 51-60 (2003), whose descriptions are incorporated herein by reference, in their entirety), immunomodulatory disorders, inflammatory disorders, respiratory function disorders, depression, anxiety, disorders mood disorders, stress-related disorders, sympathetic nervous system disorders, cough, motor disorders, traumatic injury, stroke, cardiac arrhythmia, glaucoma, sexual dysfunction, concussion, cerebral edema, cerebral ischemia, cerebral deficits after cardiac bypass and graft surgery , systemic lupus erythematosus, Hodgkin's disease, Sjogren's disease, epilepsy, and rejection in the transplantation of organs and skin grafts, and addiction n substances. In certain other embodiments, the heterocyclic spirocyclic derivatives are opioid receptor ligands and are useful, inter alia, in methods for providing cardioprotection after myocardial infarction, in procedures for producing and maintaining an anesthetic state, and in methods for detecting, obtain images or control the degeneration or dysfunction of opiate receptors in a patient. Thus, according to preferred aspects of the invention, pain prevention or treatment methods are provided, comprising the step of administering to said patient an effective amount of a compound of the invention including, for example, a compound of formulas I , II, III, IV, V, VI, VII, VII, IX, X, XI, Xll and / or Xlll. More preferably, methods of preventing or treating pain are provided, comprising the step of administering to said patient an effective amount of a compound of formula IV: IV where: Y2 is a single bond or - [C (Rc) (Rd)] k-; each Rc, Re, and Rf is independently H or alkyl; each Rd is independently H, alkyl, or aryl; W2 is aryl, alkylaryl, heterocycloalkylaryl, heteroaryl, alkylheteroaryl, heteroarylaryl, or alkylheteroarylaryl; R23 and R24 are each independently H, alkyl, alkenyl, alkynyl, or aryl, or R23 and R24 when taken together with the atoms through which they are connected, form a cycloalkyl or heterocycloalkyl ring of 4 to 8 members; Z is -N (R25) -, -C (= O) -, -CH (OH) -, -CH (N (Rc) (Rd)) -, or -O-; R25 is H, alkyl, alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl, aralkyl, or heteroarylalkyl, or R23 and R25 when taken together with the atoms through which they are connected, form a 4- to 8-membered heterocycloalkyl ring, or R24 and R25 when taken together with the atoms through which they are connected, form a 4- to 8-membered heterocycloalkyl ring; each k is independently 1, 2, or 3; p is O, 1, 2 or 3; s is 0, 1, 2 or 3, with the proviso that the sum of p and s is 4; A2 and B2 are each independently H, fluoro, or alkyl, or together they form a double bond or -CH2-; G is H or alkyl; X2 is -C (Rc) (Rd) -, -O-, -S-, -S (= O) -, -S (= O) 2-, -C (= O) -, -CH (OH) - or -N (R26) -; R26 is H, alkyl, cycloalkyl, - (CH2) -alkenyl, - (CH2) -a -quinyl, aryl, -C (= O) Rd, or -S (= O) 2Rd; and J2 forms a 6 to 10 membered aryl or a 5- to 10 membered heteroaryl ring when taken together with the carbon atoms to which it is attached; or one of its stereoisomers, prodrugs, pharmaceutically acceptable salts, hydrates, solvates, acid salt hydrates, or N-oxides. In certain preferred embodiments, the present methods of preventing or treating pain may further comprise administering to a patient an effective amount of an agent for the treatment of neuralgia and / or neuropathic pain. In another aspect, the invention relates to methods for the prevention or treatment of gastrointestinal dysfunctions, comprising the step of administration to a patient in need of such treatment of an effective amount of a compound of the invention including, for example, a composed of formulas I, II, III, IV, V, VI, VII, VII, IX, X, XI, Xll, and / or Xlll. In certain preferred aspects, the methods comprise the step of administering to said patient an effective amount of a compound of formula IV: rv in which: Y2 is a simple bond or - [C (Rc) (Rd)] k-; each Rc, Re, and Rf is independently H or alkyl; each Rd is independently H, alkyl, or aryl; W2 is aryl, alkylaryl, heterocycloalkylaryl, heteroaryl, alkylheteroaryl, heteroarylaryl, or alkylheteroarylaryl; R23 and R24 are each independently H, alkyl, alkenyl, alkynyl, or aryl, or R23 and R24 when taken together with the atoms through which they are connected, form a cycloalkyl or heterocycloalkyl ring of 4 to 8 members; Z is -N (R25) -, -C (= O) -, -CH (OH) -, -CH (N (Rc) (Rd)) -, or -O-; R25 is H, alkyl, alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl, aralkyl, or heteroarylalkyl, or R23 and R25 when taken together with the atoms through which they are connected, form a 4- to 8-membered heterocycloalkyl ring, or R24 and R25 when taken together with the atoms through which they are connected, form a 4- to 8-membered heterocycloalkyl ring; each k is independently 1, 2, or 3; p is O, 1, 2 or 3; s is 0, 1, 2 or 3, with the proviso that the sum of p and s is 4; A2 and B2 are each independently H, fluoro, or alkyl, or together they form a double bond or -CH2-; G is H or alkyl; X2 is -C (Rc) (Rd) -, -O-, -S-, -S (= O) -, -S (= O) 2-, -C (= O) -, -CH (OH) - or -N (R26) -; R26 is H, alkyl, cycloalkyl, - (CH2) -alkenyl, - (CH2) -alkyne, aryl, -C (= O) Rd, or -S (= O) 2Rd; and J2 forms a 6 to 10 membered aryl or a 5- to 10 membered heteroaryl ring when taken together with the carbon atoms to which it is attached; or one of its stereoisomers, prodrugs, pharmaceutically acceptable salts, hydrates, solvates, acid salt hydrates, or N-oxides. In another aspect, the invention relates to methods for the prevention or treatment of a disorder of the urogenital tract, such as incontinence (including, for example, stress urinary incontinence and imperious urinary incontinence, and overactive bladder), which comprise the step of administration to a patient in need of such treatment of an effective amount of a compound of the invention including, for example, a compound of formulas I, II, III, IV, V, VI, VII, VII, X, XI, Xll, and / or Xlll. In certain preferred aspects, the methods comprise the step of administering to said patient an effective amount of a compound of formula IV: TV where: Y2 is a simple bond or - [C (Rc) (Rd)] k-; each R c, R b, and R f is independently H or alkyl; each Rd is independently H, alkyl, or aryl; W2 is aryl, alkylaryl, heterocycloalkylaryl, heteroaryl, alkylheteroaryl, heteroarylaryl, or alkylheteroarylaryl; R23 and R24 are each independently H, alkyl, alkenyl, alkynyl, or aryl, or R23 and R24 when taken together with the atoms through which they are connected, form a cycloalkyl or heterocycloalkyl ring of 4 to 8 members; Z is -N (R25) -, -C (= O) -, -CH (OH) -, -CH (N (Rc) (Rd)) -, or -O-; R25 is H, alkyl, alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl, aralkyl, or heteroarylalkyl, or R23 and R25 when taken together with the atoms through which they are connected, form a 4- to 8-membered heterocycloalkyl ring, or R24 and R25 when taken together with the atoms through which they are connected, form a 4- to 8-membered heterocycloalkyl ring; each k is independently 1, 2, or 3; p is 0, 1, 2 or 3; s is 0, 1, 2 or 3, with the proviso that the sum of p and s is 4; A2 and B2 are each independently H, fluoro, or alkyl, or together they form a double bond or -CH2-; G is H or alkyl; X2 is -C (Rc) (Rd) -, -O-, -S-, -S (= O) -, -S (= O) 2-, -C (= O) -, -CH (OH) - or -N (R26) -; R26 is H, alkyl, cycloalkyl, - (CH2) -alkenyl, - (CH2) -aquinquin, aryl, -C (= O) Rd, or -S (= O) 2Rd; and J2 forms a 6 to 10 membered aryl or a 5- to 10 membered heteroaryl ring when taken together with the carbon atoms to which it is attached; or one of its stereoisomers, prodrugs, pharmaceutically acceptable salts, hydrates, solvates, acid salt hydrates, or N-oxides. In certain preferred embodiments, the present methods of preventing or treating a disorder of the urogenital tract may further comprise administering to a patient an effective amount of an agent for the treatment of incontinence. In another aspect, the invention relates to methods for the prevention or treatment of an immunomodulatory disorder, comprising the step of administering to a patient in need thereof an effective amount of a compound of the invention including, for example, a compound of formulas I, II, III, IV, V, VI, VII, VII, IX, X, XI, Xll, and / or Xlll. Immunomodulatory disorders include, but are not limited to, autoimmune diseases, collagen diseases, allergies, side effects associated with the administration of an antitumor agent, and side effects associated with the administration of an antiviral agent. Autoimmune diseases include, but are not limited to, arthritis, autoimmune disorders associated with skin transplantation, autoimmune disorders associated with organ transplantation, and autoimmune disorders associated with surgery. In certain preferred aspects, the methods comprise the step of administering to said patient an effective amount of a compound of formula IV: IV where: Y2 is a single bond or - [C (Rc) (Rd)] k-; each Rc, Re, and Rf is independently H or alkyl; each Rd is independently H, alkyl, or aryl; W2 is aryl, alkylaryl, heterocycloalkylaryl, heteroaryl, alkylheteroaryl, heteroarylaryl, or alkylheteroarylaryl; R23 and R24 are each independently H, alkyl, alkenyl, alkynyl, or aryl, or R23 and R24 when taken together with the atoms through which they are connected, form a cycloalkyl or heterocycloalkyl ring of 4 to 8 members; Z is -N (R25) -, -C (= O) -, -CH (OH) -, -CH (N (Rc) (Rd)) -, or -O-; R25 is H, alkyl, alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl, aralkyl, or heteroarylalkyl, or R23 and R25 when taken together with the atoms through which they are connected, form a 4- to 8-membered heterocycloalkyl ring, or R24 and R25 when taken together with the atoms through which they are connected, form a 4- to 8-membered heterocycloalkyl ring; each k is independently 1, 2, or 3; p is O, 1, 2 or 3; s is 0, 1, 2 or 3, with the proviso that the sum of p and s is 4; A2 and B2 are each independently H, fluoro, or alkyl, or together they form a double bond or -CH2-; G is H or alkyl; X2 is -C (Rc) (Rd) -, -O-, -S-, -S (= O) -, -S (= O) 2-, -C (= O) -, -CH (OH) - or -N (R26) -; R26 is H, alkyl, cycloalkyl, - (CH2) -alkenyl, - (CH2) -a -quinyl, aryl, -C (= O) Rd, or -S (= O) 2Rd; and J2 forms a 6 to 10 membered aryl or a 5- to 10 membered heteroaryl ring when taken together with the carbon atoms to which it is attached; or one of its stereoisomers, prodrugs, pharmaceutically acceptable salts, hydrates, solvates, acid salt hydrates, or N-oxides. In another aspect, the invention relates to methods for the prevention or treatment of an inflammatory disorder, comprising the step of administering to a patient in need thereof an effective amount of a compound of the invention including, for example, a compound of formulas I, II, III, IV, V, VI, VII, VII, IX, X, XI, Xll, and / or Xlll. Inflammatory disorders include, but are not limited to, arthritis, psoriasis, asthma, or inflammatory bowel disease. In certain preferred aspects, the methods comprise the step of administering to said patient an effective amount of a compound of formula IV: TV where: Y2 is a simple bond or - [C (RG) (Rd)] k-; each R c, Re, and R f is independently H or alkyl; each Rd is independently H, alkyl, or aryl; W2 is aryl, alkylaryl, heterocycloalkylaryl, heteroaryl, alkylheteroaryl, heteroarylaryl, or alkylheteroarylaryl; R23 and R24 are each independently H, alkyl, alkenyl, alkynyl, or aryl, or R23 and R24 when taken together with the atoms through which they are connected, form a cycloalkyl or heterocycloalkyl ring of 4 to 8 members; Z is -N (R25) -, -C (= O) -, -CH (OH) -, -CH (N (Rc) (Rd)) -, or -O-; R25 is H, alkyl, alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl, aralkyl, or heteroarylalkyl, or R23 and R25 when taken together with the atoms through which they are connected, form a 4- to 8-membered heterocycloalkyl ring, or R24 and R25 when taken together with the atoms through which they are connected, form a 4- to 8-membered heterocycloalkyl ring; each k is independently 1, 2, or 3; p is O, 1, 2 or 3; s is 0, 1, 2 or 3, with the proviso that the sum of p and s is 4; A2 and B2 are each independently H, fluoro, or alkyl, or together they form a double bond or -CH2-; G is H or alkyl; X2 is -C (Rc) (Rd) -, -O-, -S-, -S (= O) -, -S (= O) 2-, -C (= O) -, -CH (OH) - or -N (R26) -; R26 is H, alkyl, cycloalkyl, - (CH2) -akenyl, - (CH2) -aClinium, aryl, -C (= O) Rd, or -S (= O) 2Rd; and J2 forms a 6 to 10 membered aryl or a 5- to 10 membered heteroaryl ring when taken together with the carbon atoms to which it is attached; or one of its stereoisomers, prodrugs, pharmaceutically acceptable salts, hydrates, solvates, acid salt hydrates, or N-oxides. In another aspect, the invention relates to methods for the prevention or treatment of a respiratory function disorder, comprising the step of administering to a patient in need thereof an effective amount of a compound of the invention including, for example , a compound of formulas I, II, III, IV, V, VI, VII, VII, IX, X, XI, Xll, and / or Xlll. Disorders of respiratory function include, but are not limited to, asthma or pulmonary edema. In certain preferred aspects, the methods comprise the step of administering to said patient an effective amount of a compound of formula IV: IV) in which: Y2 is a single bond or - [C (Rc) (Rd)] k-; each R °, Re, and Rf is independently H or alkyl; each Rd is independently H, alkyl, or aryl; W2 is aryl, alkylaryl, heterocycloalkylaryl, heteroaryl, alkylheteroaryl, heteroarylaryl, or alkylheteroarylaryl; R23 and R24 are each independently H, alkyl, alkenyl, alkynyl, or aryl, or R23 and R24 when taken together with the atoms through which they are connected, form a cycloalkyl or heterocycloalkyl ring of 4 to 8 members; Z is -N (R25) -, -C (= O) -, -CH (OH) -, -CH (N (Rc) (Rd)) -, or -O-; R25 is H, alkyl, alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl, aralkyl, or heteroarylalkyl, or R23 and R25 when taken together with the atoms through which they are connected, form a 4- to 8-membered heterocycloalkyl ring, or R24 and R25 when taken together with the atoms through which they are connected, form a 4- to 8-membered heterocycloalkyl ring; each k is independently 1, 2, or 3; p is O, 1, 2 or 3; s is 0, 1, 2 or 3, with the proviso that the sum of p and s is 4; A2 and B2 are each independently H, fluoro, or alkyl, or together they form a double bond or -CH2-; G is H or alkyl; X2 is -C (Rc) (Rd) -, -O-, -S-, -S (= O) -, -S (= O) 2-, -C (= O) -, -CH (OH) - or -N (R26) -; R26 is H, alkyl, cycloalkyl, - (CH2) -alkenyl, - (CH2) -alkynyl, aryl, -C (= O) Rd, or -S (= O) 2Rd; and J2 forms a 6 to 10 membered aryl or a 5- to 10 membered heteroaryl ring when taken together with the carbon atoms to which it is attached; or one of its stereoisomers, prodrugs, pharmaceutically acceptable salts, hydrates, solvates, acid salt hydrates, or N-oxides. In another aspect, the invention relates to methods for the prevention or treatment of anxiety, comprising the step of administering to a patient in need of such treatment an effective amount of a compound of the invention including, for example, a composed of formulas I, II, III, IV, V, VI, VII, VII, IX, X, XI, Xll, and / or Xlll. In certain preferred aspects, the methods comprise the step of administering to said patient an effective amount of a compound of formula IV: IV where: Y2 is a single bond or - [C (Rc) (Rd)] k-; each Rc, Re, and Rf is independently H or alkyl; each Rd is independently H, alkyl, or aryl; W2 is aryl, alkylaryl, heterocycloalkylaryl, heteroaryl, alkylheteroaryl, heteroarylaryl, or alkylheteroarylaryl; R23 and R24 are each independently H, alkyl, alkenyl, alkynyl, or aryl, or R23 and R24 when taken together with the atoms through which they are connected, form a cycloalkyl or heterocycloalkyl ring of 4 to 8 members; Z is -N (R25) -, -C (= O) -, -CH (OH) -, -CH (N (Rc) (Rd)) -, or -O-; R25 is H, alkyl, alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl, aralkyl, or heteroarylalkyl, or R23 and R25 when taken together with the atoms through which they are connected, form a 4- to 8-membered heterocycloalkyl ring, or R24 and R25 when taken together with the atoms through which they are connected, form a 4- to 8-membered heterocycloalkyl ring; each k is independently 1, 2, or 3; p is O, 1, 2 or 3; s is 0, 1, 2 or 3, with the proviso that the sum of p and s is 4; A2 and B2 are each independently H, fluoro, or alkyl, or together they form a double bond or -CH2-; G is H or alkyl; X2 is -C (Rc) (Rd) -, -O-, -S-, -S (= O) -, -S (= O) 2-, -C (= O) -, -CH (OH) - or -N (R26) -; R26 is H, alkyl, cycloalkyl, - (CH2) -alkenyl, - (CH2) -alkynyl, aryl, -C (= O) Rd, or -S (= O) 2Rd; and J2 forms a 6 to 10 membered aryl or a 5- to 10 membered heteroaryl ring when taken together with the carbon atoms to which it is attached; or one of its stereoisomers, prodrugs, pharmaceutically acceptable salts, hydrates, solvates, acid salt hydrates, or N-oxides. In another aspect, the invention relates to methods for the prevention or treatment of a mood disorder, comprising the step of administering to a patient in need of such treatment an effective amount of a compound of the invention including, for example, a compound of formulas I, II, III, IV, V, VI, VII, VII, IX, X, XI, Xll, and Xlll. Mood disorders include, but are not limited to, depression, bipolar manic depression, and seasonal affective disorder. In certain preferred aspects, the methods comprise the step of administering to said patient an effective amount of a compound of formula IV: IV where: Y2 is a single bond or - [C (Rc) (Rd)] k-; each R °, Re, and Rf is independently H or alkyl; each Rd is independently H, alkyl, or aryl; W2 is aryl, alkylaryl, heterocycloalkylaryl, heteroaryl, alkylheteroaryl, heteroarylaryl, or alkylheteroarylaryl; R23 and R24 are each independently H, alkyl, alkenyl, alkynyl, or aryl, or R23 and R24 when taken together with the atoms through which they are connected, form a cycloalkyl or heterocycloalkyl ring of 4 to 8 members; Z is -N (R25) -, -C (= O) -, -CH (OH) -, -CH (N (Rc) (Rd)) -, or -O-; R25 is H, alkyl, alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl, aralkyl, or heteroarylalkyl, or R23 and R25 when taken together with the atoms through which they are connected, form a 4- to 8-membered heterocycloalkyl ring, or R24 and R25 when taken together with the atoms through which they are connected, form a 4- to 8-membered heterocycloalkyl ring; each k is independently 1, 2, or 3; p is O, 1, 2 or 3; s is 0, 1, 2 or 3, with the proviso that the sum of p and s is 4; A2 and B2 are each independently H, fluoro, or alkyl, or together they form a double bond or -CH2-; G is H or alkyl; X2 is -C (Rc) (Rd) -, -O-, -S-, -S (= O) -, -S (= O) 2-, -C (= O) -, -CH (OH) - or -N (R26) -; R26 is H, alkyl, cycloalkyl, - (CH2) -alkenyl, - (CH2) -alkynyl, aryl, -C (= O) Rd, or -S (= O) 2Rd; and J2 forms a 6 to 10 membered aryl or a 5- to 10 membered heteroaryl ring when taken together with the carbon atoms to which it is attached; or one of its stereoisomers, prodrugs, pharmaceutically acceptable salts, hydrates, solvates, acid salt hydrates, or N-oxides. In certain preferred embodiments, the present methods of preventing or treating a mood disorder may further comprise administering to a patient an effective amount of an agent for the treatment of depression. In another aspect, the invention relates to methods for the prevention or treatment of a stress-related disorder, comprising the step of administering to a patient in need of such treatment an effective amount of a compound of the invention including, for example, a compound of formulas I, II, III, IV, V, VI, VII, VII, IX, X, XI, Xll, and / or Xlll. Stress-related disorders include, but are not limited to, post-traumatic stress disorder, panic disorders, generalized anxiety disorder, social phobia, and obsessive-compulsive disorder. In certain preferred aspects, the methods comprise the step of administering to said patient an effective amount of a compound of formula IV: IV where: Y2 is a single bond or - [C (Rc) (Rd)] k-; each Rc, Re, and Rf is independently H or alkyl; each Rd is independently H, alkyl, or aryl; W2 is aryl, alkylaryl, heterocycloalkylaryl, heteroaryl, alkylheteroaryl, heteroarylaryl, or alkylheteroarylaryl; R23 and R24 are each independently H, alkyl, alkenyl, alkynyl, or aryl, or R23 and R24 when taken together with the atoms through which they are connected, form a cycloalkyl or heterocycloalkyl ring of 4 to 8 members; Z is -N (R25) -, -C (= O) -, -CH (OH) -, -CH (N (Rc) (Rd)) -, or -O-; R25 is H, alkyl, alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl, aralkyl, or heteroarylalkyl, or R23 and R25 when taken together with the atoms through which they are connected, form a 4- to 8-membered heterocycloalkyl ring, or R24 and R25 when taken together with the atoms through which they are connected, form a 4- to 8-membered heterocycloalkyl ring; each k is independently 1, 2, or 3; p is O, 1, 2 or 3; s is 0, 1, 2 6 3, with the proviso that the sum of p and s is 4; A2 and B2 are each independently H, fluoro, or alkyl, or together they form a double bond or -CH2-; G is H or alkyl; X2 is -C (Rc) (Rd) -, -O-, -S-, -S (= O) -, -S (= O) 2-, -C (= O) -, -CH (OH) - or -N (R26) -; R26 is H, alkyl, cycloalkyl, - (CH2) -alkenyl, - (CH2) -alkynyl, aryl, -C (= O) Rd, or -S (= O) 2Rd; and J2 forms a 6 to 10 membered aryl or a 5- to 10 membered heteroaryl ring when taken together with the carbon atoms to which it is attached; or one of its stereoisomers, prodrugs, pharmaceutically acceptable salts, hydrates, solvates, acid salt hydrates, or N-oxides. In another aspect, the invention relates to methods for the prevention or treatment of attention deficit hyperactivity disorder, comprising the step of administering to a patient in need of such treatment an effective amount of a compound of the invention including , for example, a compound of formulas I, II, III, IV, V, VI, VII, VII, IX, X, XI, Xll, and / or Xlll. In certain preferred aspects, the methods comprise the step of administering to said patient an effective amount of a compound of formula IV: TV in which: Y2 is a simple bond or - [C (Rc) (Rd)] k-; each Rc, Rβ, and Rf is independently H or alkyl; each Rd is independently H, alkyl, or aryl; W2 is aryl, alkylaryl, heterocycloalkylaryl, heteroaryl, alkylheteroaryl, heteroarylaryl, or alkylheteroarylaryl; R23 and R24 are each independently H, alkyl, alkenyl, alkynyl, or aryl, or R23 and R24 when taken together with the atoms through which they are connected, form a cycloalkyl or heterocycloalkyl ring of 4 to 8 members; Z is -N (R25) -, -C (= O) -, -CH (OH) -, -CH (N (Rc) (Rd)) -, or -O-; R25 is H, alkyl, alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl, aralkyl, or heteroarylalkyl, or R23 and R25 when taken together with the atoms through which they are connected, form a 4- to 8-membered heterocycloalkyl ring, or R24 and R25 when taken together with the atoms through which they are connected, form a 4- to 8-membered heterocycloalkyl ring; each k is independently 1, 2, or 3; p is 0, 1, 2 or 3; s is 0, 1, 2 or 3, with the proviso that the sum of p and s is 4; A2 and B2 are each independently H, fluoro, or alkyl, or together they form a double bond or -CH2-; G is H or alkyl; X2 is -C (Rc) (Rd) -, -O-, -S-, -S (= O) -, -S (= O) 2-, -C (= O) -, -CH (OH) - or -N (R26) -; R26 is H, alkyl, cycloalkyl, - (CH2) -alkenyl, - (CH2) -a -quinyl, aryl, -C (= O) Rd, or -S (= O) 2Rd; and J2 forms a 6 to 10 membered aryl or a 5- to 10 membered heteroaryl ring when taken together with the carbon atoms to which it is attached; or one of its stereoisomers, prodrugs, pharmaceutically acceptable salts, hydrates, solvates, acid salt hydrates, or N-oxides. In another aspect, the invention relates to methods for the prevention or treatment of disorders of the sympathetic nervous system, including hypertension, comprising the step of administering to a patient in need of such treatment an effective amount of a compound of the invention including, example, a compound of formulas I, II, III, IV, V, VI, VII, VII, IX, X, XI, Xll, and / or Xlll. In certain preferred aspects, the methods comprise the step of administering to said patient an effective amount of a compound of formula IV: IV where: Y2 is a single bond or - [C (Rc) (Rd)] k-; each Rc, Re, and Rf is independently H or alkyl; each Rd is independently H, alkyl, or aryl; W2 is aryl, alkylaryl, heterocycloalkylaryl, heteroaryl, alkylheteroaryl, heteroarylaryl, or alkylheteroarylaryl; R23 and R24 are each independently H, alkyl, alkenyl, alkynyl, or aryl, or R23 and R24 when taken together with the atoms through which they are connected, form a cycloalkyl or heterocycloalkyl ring of 4 to 8 members; Z is -N (R25) -, -C (= O) -, -CH (OH) -, -CH (N (Rc) (Rd)) -, or -O-; R25 is H, alkyl, alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl, aralkyl, or heteroarylalkyl, or R23 and R25 when taken together with the atoms through which they are connected, form a 4- to 8-membered heterocycloalkyl ring, or R24 and R25 when taken together with the atoms through which they are connected, form a 4- to 8-membered heterocycloalkyl ring; each k is independently 1, 2, or 3; p is O, 1, 2 or 3; s is 0, 1, 2 or 3, with the proviso that the sum of p and s is 4; A2 and B2 are each independently H, fluoro, or alkyl, or together they form a double bond or -CH2-; G is H or alkyl; X2 is -C (Rc) (Rd) -, -O-, -S-, -S (= O) -, -S (= O) 2-, -C (= O) -, -CH (OH) - or -N (R26) -; R26 is H, alkyl, cycloalkyl, - (CH2) -alkenyl, - (CH2) -alkynyl, aryl, -C (= O) Rd, or -S (= O) 2Rd; and J2 forms a 6 to 10 membered aryl or a 5- to 10 membered heteroaryl ring when taken together with the carbon atoms to which it is attached; or one of its stereoisomers, prodrugs, pharmaceutically acceptable salts, hydrates, solvates, acid salt hydrates, or N-oxides. In another aspect, the invention relates to methods for the prevention or treatment of cough, comprising the step of administering to a patient in need of such treatment an effective amount of a compound of the invention including, for example, a compound of formulas I, II, III, IV, V, VI, VII, VII, IX, X, XI, Xll, and / or Xlll. In certain preferred aspects, the methods comprise the step of administering to said patient an effective amount of a compound of formula IV: IV where: Y2 is a single bond or - [C (Rc) (Rd)] k-; each R c, Re, and R f is independently H or alkyl; each Rd is independently H, alkyl, or aryl; W2 is aryl, alkylaryl, heterocycloalkylaryl, heteroaryl, alkylheteroaryl, heteroarylaryl, or alkylheteroarylaryl; R23 and R24 are each independently H, alkyl, alkenyl, alkynyl, or aryl, or R23 and R24 when taken together with the atoms through which they are connected, form a cycloalkyl or heterocycloalkyl ring of 4 to 8 members; Z is -N (R25) -, -C (= O) -, -CH (OH) -, -CH (N (Rc) (Rd)) -, or -O-; R25 is H, alkyl, alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl, aralkyl, or heteroarylalkyl, or R23 and R25 when taken together with the atoms through which they are connected, form a 4- to 8-membered heterocycloalkyl ring, or R24 and R25 when taken together with the atoms through which they are connected, form a 4- to 8-membered heterocycloalkyl ring; each k is independently 1, 2, or 3; p is 0, 1, 2 or 3; s is 0, 1, 2 or 3, with the proviso that the sum of p and s is 4; A2 and B2 are each independently H, fluoro, or alkyl, or together they form a double bond or -CH2-; G is H or alkyl; X2 is -C (Rc) (Rd) -, -O-, -S-, -S (= O) -, -S (= O) 2-, -C (= O) -, -CH (OH) - or -N (R26) -; R26 is H, alkyl, cycloalkyl, - (CH2) -alkenyl, - (CH2) -alkynyl, aryl, -C (= O) Rd, or -S (= O) 2Rd; and J2 forms a 6 to 10 membered aryl or a 5- to 10 membered heteroaryl ring when taken together with the carbon atoms to which it is attached; or one of its stereoisomers, prodrugs, pharmaceutically acceptable salts, hydrates, solvates, acid salt hydrates, or N-oxides. In another aspect, the invention relates to methods for the prevention or treatment of a motor disorder, including tremors, Parkinson's disease, Tourette's syndrome and dyskinesia, comprising the step of administering to a patient in need of such treatment an effective amount of a compound of the invention including, for example, a compound of formulas I, ll, III, IV, V, VI, VII, VII, IX, X, XI, Xll, and / or Xlll. In certain preferred aspects, the methods comprise the step of administering to said patient an effective amount of a compound of formula IV: IV where: Y2 is a single bond or - [C (Rc) (Rd)] k-; each Rc, Re, and Rf is independently H or alkyl; each Rd is independently H, alkyl, or aryl; W2 is aryl, alkylaryl, heterocycloalkylaryl, heteroaryl, alkylheteroaryl, heteroarylaryl, or alkylheteroarylaryl; R23 and R24 are each independently H, alkyl, alkenyl, alkynyl, or aryl, or R23 and R24 when taken together with the atoms through which they are connected, form a cycloalkyl or heterocycloalkyl ring of 4 to 8 members; Z is -N (R25) -, -C (= O) -, -CH (OH) -, -CH (N (Rc) (Rd)) -, or -O-; R25 is H, alkyl, alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl, aralkyl, or heteroarylalkyl, or R23 and R25 when taken together with the atoms through which they are connected, form a 4- to 8-membered heterocycloalkyl ring, or R24 and R25 when taken together with the atoms through which they are connected, form a 4- to 8-membered heterocycloalkyl ring; each k is independently 1, 2, or 3; p is O, 1, 2 or 3; s is 0, 1, 2 or 3, with the proviso that the sum of p and s is 4; A2 and B2 are each independently H, fluoro, or alkyl, or together they form a double bond or -CH2-; G is H or alkyl; X2 is -C (Rc) (Rd) -, -O-, -S-, -S (= O) -, -S (= O) 2-, -C (= O) -, -CH (OH) - or -N (R26) -; R26 is H, alkyl, cycloalkyl, - (CH2) -akenyl, - (CH2) -alkynyl, aryl, -C (= O) Rd, or -S (= O) 2Rd; and J2 forms a 6 to 10 membered aryl or a 5- to 10 membered heteroaryl ring when taken together with the carbon atoms to which it is attached; or one of its stereoisomers, prodrugs, pharmaceutically acceptable salts, hydrates, solvates, acid salt hydrates, or N-oxides. In certain preferred embodiments, the present methods of preventing or treating a motor disorder may further comprise administering to a patient an effective amount of an agent for the treatment of Parkinson's disease. In another aspect, the invention relates to methods for the treatment of a traumatic injury of the central nervous system, including the spinal cord or the brain, comprising the step of administering to a patient in need of treatment of an effective amount of a compound of the invention including, for example, a compound of formulas I, II, III, IV, V, VI, VII, VII, IX, X, XI, Xll, and / or Xlll. In certain preferred aspects, the methods comprise the step of administering to said patient an effective amount of a compound of formula IV: IV where: Y2 is a single bond or - [C (Rc) (Rd)] k-; each Rc, RT, and Rf is independently H or alkyl; each Rd is independently H, alkyl, or aryl; W2 is aryl, alkylaryl, heterocycloalkylaryl, heteroaryl, alkylheteroaryl, heteroarylaryl, or alkylheteroarylaryl; R23 and R24 are each independently H, alkyl, alkenyl, alkynyl, or aryl, or R23 and R24 when taken together with the atoms through which they are connected, form a cycloalkyl or heterocycloalkyl ring of 4 to 8 members; Z is -N (R25) -, -C (= O) -, -CH (OH) -, -CH (N (Rc) (Rd)) -, or -O-; R25 is H, alkyl, alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl, aralkyl, or heteroarylalkyl, or R23 and R25 when taken together with the atoms through which they are connected, form a 4- to 8-membered heterocycloalkyl ring, or R24 and R25 when taken together with the atoms through which they are connected, form a 4- to 8-membered heterocycloalkyl ring; each k is independently 1, 2, or 3; p is O, 1, 2 6 3; s is 0, 1, 2 or 3, with the proviso that the sum of p and s is 4; A2 and B2 are each independently H, fluoro, or alkyl, or together they form a double bond or -CH2-; G is H or alkyl; X2 is -C (Rc) (Rd) -, -O-, -S-, -S (= O) -, -S (= O) 2-, -C (= O) -, -CH (OH) - or -N (R26) -; R26 is H, alkyl, cycloalkyl, - (CH2) -akenyl, - (CH2) -alkyne, aryl, -C (= O) Rd, or -S (= O) 2Rd; and J2 forms a 6 to 10 membered aryl or a 5- to 10 membered heteroaryl ring when taken together with the carbon atoms to which it is attached; or one of its stereoisomers, prodrugs, pharmaceutically acceptable salts, hydrates, solvates, acid salt hydrates, or N-oxides. In another aspect, the invention relates to methods for the prevention or treatment of stroke, comprising the step of administering to a patient in need of such treatment an effective amount of a compound of the invention including, for example, a compound of formulas I, II, III, IV, V, VI, VII, VII, IX, X, XI, Xll, and / or Xlll. In certain preferred aspects, the methods comprise the step of administering to said patient an effective amount of a compound of formula IV: IV; wherein: Y2 is a single bond or - [C (Rc) (Rd)] k-; each Rc, Re, and Rf is independently H or alkyl; each Rd is independently H, alkyl, or aryl; W2 is aryl, alkylaryl, heterocycloalkylaryl, heteroaryl, alkylheteroaryl, heteroarylaryl, or alkylheteroarylaryl; R23 and R24 are each independently H, alkyl, alkenyl, alkynyl, or aryl, or R23 and R24 when taken together with the atoms through which they are connected, form a cycloalkyl or heterocycloalkyl ring of 4 to 8 members; Z is -N (R25) -, -C (= O) -, -CH (OH) -, -CH (N (Rc) (Rd)) -, or -O-; R25 is H, alkyl, alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl, aralkyl, or heteroarylalkyl, or R23 and R25 when taken together with the atoms through which they are connected, form a 4- to 8-membered heterocycloalkyl ring, or R24 and R25 when taken together with the atoms through which they are connected, form a 4- to 8-membered heterocycloalkyl ring; each k is independently 1, 2, or 3; p is 0, 1, 2 or 3; s is 0, 1, 2 or 3, with the proviso that the sum of p and s is 4; A2 and B2 are each independently H, fluoro, or alkyl, or together they form a double bond or -CH2-; G is H or alkyl; X2 is -C (Rc) (Rd) -, -O-, -S-, -S (= O) -, -S (= O) 2-, -C (= O) -, -CH (OH) - or -N (R26) -; R26 is H, alkyl, cycloalkyl, - (CH2) -akenyl, - (CH2) -aquinyl, aryl, -C (= O) Rd, or -S (= O) 2Rd; and J2 forms a 6 to 10 membered aryl or a 5- to 10 membered heteroaryl ring when taken together with the carbon atoms to which it is attached; or one of its stereoisomers, prodrugs, pharmaceutically acceptable salts, hydrates, solvates, acid salt hydrates, or N-oxides. In another aspect, the invention relates to methods for the prevention or treatment of cardiac arrhythmia, comprising the step of administering to a patient in need of such treatment an effective amount of a compound of the invention including, for example, a compound of formulas I, II, III, IV, V, VI, VII, VII, IX, X, XI, Xll, and / or Xlll. In certain preferred aspects, the methods comprise the step of administering to said patient an effective amount of a compound of formula IV: IV; wherein: Y2 is a single bond or - [C (Rc) (Rd)] k-; each Rc, Re, and Rf is independently H or alkyl; each Rd is independently H, alkyl, or aryl; W2 is aryl, alkylaryl, heterocycloalkylaryl, heteroaryl, alkylheteroaryl, heteroarylaryl, or alkylheteroarylaryl; R23 and R24 are each independently H, alkyl, alkenyl, alkynyl, or aryl, or R23 and R24 when taken together with the atoms through which they are connected, form a cycloalkyl or heterocycloalkyl ring of 4 to 8 members; Z is -N (R25) -, -C (= O) -, -CH (OH) -, -CH (N (Rc) (Rd)) -, or -O-; R25 is H, alkyl, alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl, aralkyl, or heteroarylalkyl, or R23 and R25 when taken together with the atoms through which they are connected, form a 4- to 8-membered heterocycloalkyl ring, or R24 and R25 when taken together with the atoms through which they are connected, form a 4- to 8-membered heterocycloalkyl ring; each k is independently 1, 2, or 3; p is O, 1, 2 6 3; s is 0, 1, 2 or 3, with the proviso that the sum of p and s is 4; A2 and B2 are each independently H, fluoro, or alkyl, or together they form a double bond or -CH2-; G is H or alkyl; X2 is -C (Rc) (Rd) -, -O-, -S-, -S (= O) -, -S (= O) 2-, -C (= O) -, -CH (OH) - or -N (R26) -; R26 is H, alkyl, cycloalkyl, - (CH2) -alkenyl, - (CH2) -alkynyl, aryl, -C (= O) Rd, or -S (= O) 2Rd; and J2 forms a 6 to 10 membered aryl or a 5- to 10 membered heteroaryl ring when taken together with the carbon atoms to which it is attached; or one of its stereoisomers, prodrugs, pharmaceutically acceptable salts, hydrates, solvates, acid salt hydrates, or N-oxides. In another aspect, the invention relates to methods for the prevention or treatment of glaucoma, comprising the step of administering to a patient in need of such treatment an effective amount of a compound of the invention including, for example, a compound of formulas I, II, III, IV, V, VI, VII, VII, IX, X, XI, Xll, and / or Xlll. In certain preferred aspects, the methods comprise the step of administering to said patient an effective amount of a compound of formula IV: IV where: Y2 is a single bond or - [C (Rc) (Rd)] k-; each Rc, Re, and Rf is independently H or alkyl; each Rd is independently H, alkyl, or aryl; W2 is aryl, alkylaryl, heterocycloalkylaryl, heteroaryl, alkylheteroaryl, heteroarylaryl, or alkylheteroarylaryl; R23 and R24 are each independently H, alkyl, alkenyl, alkynyl, or aryl, or R23 and R24 when taken together with the atoms through which they are connected, form a cycloalkyl or heterocycloalkyl ring of 4 to 8 members; Z is -N (R25) -, -C (= O) -, -CH (OH) -, -CH (N (Rc) (Rd)) -, or -O-; R25 is H, alkyl, alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl, aralkyl, or heteroarylalkyl, or R23 and R25 when taken together with the atoms through which they are connected, form a 4- to 8-membered heterocycloalkyl ring, or R24 and R25 when taken together with the atoms through which they are connected, form a 4- to 8-membered heterocycloalkyl ring; each k is independently 1, 2, or 3; p is O, 1, 2 or 3; s is 0, 1, 2 or 3, with the proviso that the sum of p and s is 4; A2 and B2 are each independently H, fluoro, or alkyl, or together they form a double bond or -CH2-; G is H or alkyl; X2 is -C (Rc) (Rd) -, -O-, -S-, -S (= O) -, -S (= O) 2-, -C (= O) -, -CH (OH) - or -N (R26) -; R 26 is H, alkyl, cycloalkyl, - (CH 2) -alkenyl, - (CH 2) -alkynyl, aryl, -C (= O) R d, or -S (= O) 2 R d; and J2 forms a 6 to 10 membered aryl or a 5- to 10 membered heteroaryl ring when taken together with the carbon atoms to which it is attached; or one of its stereoisomers, prodrugs, pharmaceutically acceptable salts, hydrates, solvates, acid salt hydrates, or N-oxides. In another aspect, the invention relates to methods for the prevention or treatment of sexual dysfunction, including premature ejaculation, comprising the step of administering to a patient in need of such treatment an effective amount of a compound of the invention including , for example, a compound of formulas I, II, III, IV, V, VI, VII, VII, IX, X, XI, Xll, and / or Xlll. In certain preferred aspects, the methods comprise the step of administering to said patient an effective amount of a compound of formula IV: TV where: Y2 is a simple bond or - [C (Rc) (Rd)] k-; each R c, Re, and R f is independently H or alkyl; each Rd is independently H, alkyl, or aryl; W2 is aryl, alkylaryl, heterocycloalkylaryl, heteroaryl, alkylheteroaryl, heteroarylaryl, or alkylheteroarylaryl; R23 and R24 are each independently H, alkyl, alkenyl, alkynyl, or aryl, or R23 and R24 when taken together with the atoms through which they are connected, form a cycloalkyl or heterocycloalkyl ring of 4 to 8 members; Z is -N (R25) -, -C (= O) -, -CH (OH) -, -CH (N (Rc) (R)) -, or -O-; R25 is H, alkyl, alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl, aralkyl, or heteroarylalkyl, or R23 and R25 when taken together with the atoms through which they are connected, form a 4- to 8-membered heterocycloalkyl ring, or R24 and R25 when taken together with the atoms through which they are connected, form a 4- to 8-membered heterocycloalkyl ring; each k is independently 1, 2, or 3; p is O, 1, 2 or 3; s is 0, 1, 2 or 3, with the proviso that the sum of p and s is 4; A2 and B2 are each independently H, fluoro, or alkyl, or together they form a double bond or -CH2-; G is H or alkyl; X2 is -C (Rc) (Rd) -, -O-, -S-, -S (= O) -, -S (= O) 2-, -C (= O) -, -CH (OH) - or -N (R26) -; R26 is H, alkyl, cycloalkyl, - (CH2) -alkenyl, - (CH2) -alkynyl, aryl, -C (= O) Rd, or -S (= O) 2Rd; and J2 forms a 6 to 10 membered aryl or a 5- to 10 membered heteroaryl ring when taken together with the carbon atoms to which it is attached; or one of its stereoisomers, prodrugs, pharmaceutically acceptable salts, hydrates, solvates, acid salt hydrates, or N-oxides. In another aspect, the invention relates to methods for the treatment of a condition selected from the group consisting of concussion, cerebral edema, cerebral ischemia, cerebral deficits after cardiac bypass and graft surgery, systemic lupus erythematosus, Hodgkin's disease, Sjogren's disease, epilepsy , and rejection in transplantation of organs and skin grafts, comprising the step of administration to a patient in need of such treatment of an effective amount of a compound of the invention including, for example, a compound of formulas I, II , III, IV, V, VI, VII, VII, IX, X, XI, Xll, and / or Xlll. In certain preferred aspects, the methods comprise the step of administering to said patient an effective amount of a compound of formula IV: TV where: Y2 is a simple bond or - [C (Rc) (Rd)] k-; each Rc, Re, and Rf is independently H or alkyl; each Rd is independently H, alkyl, or aryl; W2 is aryl, alkylaryl, heterocycloalkylaryl, heteroaryl, alkylheteroaryl, heteroarylaryl, or alkylheteroarylaryl; R23 and R24 are each independently H, alkyl, alkenyl, alkynyl, or aryl, or R23 and R24 when taken together with the atoms through which they are connected, form a cycloalkyl or heterocycloalkyl ring of 4 to 8 members; Z is -N (R25) -, -C (= O) -, -CH (OH) -, -CH (N (Rc) (Rd)) -, or -O-; R25 is H, alkyl, alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl, aralkyl, or heteroarylalkyl, or R23 and R25 when taken together with the atoms through which they are connected, form a 4- to 8-membered heterocycloalkyl ring, or R24 and R25 when taken together with the atoms through which they are connected, form a 4- to 8-membered heterocycloalkyl ring; each k is independently 1, 2, or 3; p is 0, 1, 2 or 3; s is O, 1, 2 or 3, with the proviso that the sum of p and s is 4; A2 and B2 are each independently H, fluoro, or alkyl, or together they form a double bond or -CH2-; G is H or alkyl; X2 is -C (Rc) (Rd) -, -O-, -S-, -S (= O) -, -S (= O) 2-, -C (= O) -, -CH (OH) - or -N (R26) -; R26 is H, alkyl, cycloalkyl, - (CH2) -alkenyl, - (CH2) -alkynyl, aryl, -C (= O) Rd, or -S (= O) 2Rd; and J2 forms a 6 to 10 membered aryl or a 5- to 10 membered heteroaryl ring when taken together with the carbon atoms to which it is attached; or one of its stereoisomers, prodrugs, pharmaceutically acceptable salts, hydrates, solvates, acid salt hydrates, or N-oxides. In another aspect, the invention relates to methods for the treatment of addiction to substances, including addictions to alcohol, nicotine or drugs such as opiates, which comprises the step of administration to a patient in need of such treatment of an effective amount of a compound of the invention including, for example, a compound of formulas I, II, III, IV, V, VI, VII, VII, IX, X, XI, Xll, and / or Xlll. In certain preferred aspects, the methods comprise the step of administering to said patient an effective amount of a compound of formula IV: IV where: Y2 is a single bond or - [C (Rc) (Rd)] k-; each Rc, Re, and Rf is independently H or alkyl; each Rd is independently H, alkyl, or aryl; W2 is aryl, alkylaryl, heterocycloalkylaryl, heteroaryl, alkylheteroaryl, heteroarylaryl, or alkylheteroarylaryl; R23 and R24 are each independently H, alkyl, alkenyl, alkynyl, or aryl, or R23 and R24 when taken together with the atoms through which they are connected, form a cycloalkyl or heterocycloalkyl ring of 4 to 8 members; Z is -N (R25) -, -C (= O) -, -CH (OH) -, -CH (N (Rc) (Rd)) -, or -O-; R25 is H, alkyl, alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl, aralkyl, or heteroarylalkyl, or R23 and R25 when taken together with the atoms through which they are connected, form a 4- to 8-membered heterocycloalkyl ring, or R24 and R25 when taken together with the atoms through which they are connected, form a 4- to 8-membered heterocycloalkyl ring; each k is independently 1, 2, or 3; p is O, 1, 2 or 3; s is 0, 1, 2 or 3, with the proviso that the sum of p and s is 4; A2 and B2 are each independently H, fluoro, or alkyl, or together they form a double bond or -CH2-; G is H or alkyl; X2 is -C (Rc) (Rd) -, -O-, -S-, -S (= O) -, -S (= O) 2-, -C (= O) -, -CH (OH) - or -N (R26) -; R26 is H, alkyl, cycloalkyl, - (CH2) -akenyl, - (CH2) -alkynyl, aryl, -C (= O) Rd, or -S (= O) 2Rd; and J2 forms a 6 to 10 membered aryl or a 5- to 10 membered heteroaryl ring when taken together with the carbon atoms to which it is attached; or one of its stereoisomers, prodrugs, pharmaceutically acceptable salts, hydrates, solvates, acid salt hydrates, or N-oxides. In another aspect, the invention relates to methods for improving cellular and organic survival, comprising the step of administering to a patient in need of such treatment an effective amount of a compound of the invention including, for example, a compound of Formulas I, II, III, IV, V, VI, VII, VII, IX, X, XI, Xll, and / or Xlll. In certain preferred aspects, the methods comprise the step of administering to said patient an effective amount of a compound of formula IV: IV in which: Y2 is a simple bond or - [C (R °) (Rd)] k-; each Rc, Re, and Rf is independently H or alkyl; each Rd is independently H, alkyl, or aryl; W2 is aryl, alkylaryl, heterocycloalkylaryl, heteroaryl, alkylheteroaryl, heteroarylaryl, or alkylheteroarylaryl; R23 and R24 are each independently H, alkyl, alkenyl, alkynyl, or aryl, or R23 and R24 when taken together with the atoms through which they are connected, form a cycloalkyl or heterocycloalkyl ring of 4 to 8 members; Z is -N (R25) -, -C (= O) -, -CH (OH) -, -CH (N (Rc) (Rd)) -, or -O-; R25 is H, alkyl, alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl, aralkyl, or heteroarylalkyl, or R23 and R25 when taken together with the atoms through which they are connected, form a 4- to 8-membered heterocycloalkyl ring, or R24 and R25 when taken together with the atoms through which they are connected, form a 4- to 8-membered heterocycloalkyl ring; each k is independently 1, 2, or 3; p is 0, 1, 2 0 3; s is 0, 1, 2 or 3, with the proviso that the sum of p and s is 4; A2 and B2 are each independently H, fluoro, or alkyl, or together they form a double bond or -CH2-; G is H or alkyl; X2 is -C (Rc) (Rd) -, -O-, -S-, -S (= O) -, -S (= O) 2-, -C (= O) -, -CH (OH) - or -N (R26) -; R26 is H, alkyl, cycloalkyl, - (CH2) -alkenyl, - (CH2) -a -quinyl, aryl, -C (= O) Rd, or -S (= O) 2Rd; and J2 forms a 6 to 10 membered aryl or a 5- to 10 membered heteroaryl ring when taken together with the carbon atoms to which it is attached; or one of its stereoisomers, prodrugs, pharmaceutically acceptable salts, hydrates, solvates, acid salt hydrates, or N-oxides. Techniques for the evaluation and / or use of the present compounds in processes for improving organ and cell survival and organ preservation are described, for example, in C.V. Borlongan et al., Frontiers in Bioscience (2004), 9 (Suppl.), 3392-3398, Su, Journal of Biomedical Science (Basel) (2000), 7 (3), 195-199, and U.S. Pat. No. 5,656,420, each of whose descriptions is incorporated herein by reference in its entirety. In another aspect, the invention relates to methods for providing cardioprotection after myocardial infarction, comprising the step of administering to a patient in need of such treatment an effective amount of a compound of the invention including, for example, a composed of formulas I, II, III, IV, V, VI, VII, VII, IX, X, XI, Xll, and / or Xlll. In certain preferred aspects, the methods comprise the step of administering to said patient an effective amount of a compound of formula IV: TV where: Y2 is a simple bond or - [C (Rc) (Rd)] k-; each Rc, Re, and Rf is independently H or alkyl; each Rd is independently H, alkyl, or aryl; W2 is aryl, alkylaryl, heterocycloalkylaryl, heteroaryl, alkylheteroaryl, heteroarylaryl, or alkylheteroarylaryl; R23 and R24 are each independently H, alkyl, alkenyl, alkynyl, or aryl, or R23 and R24 when taken together with the atoms through which they are connected, form a cycloalkyl or heterocycloalkyl ring of 4 to 8 members; Z is -N (R25) -, -C (= O) -, -CH (OH) -, -CH (N (Rc) (Rd)) -, or -O-; R25 is H, alkyl, alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl, aralkyl, or heteroarylalkyl, or R23 and R25 when taken together with the atoms through which they are connected, form a 4- to 8-membered heterocycloalkyl ring, or R24 and R25 when taken together with the atoms through which they are connected, form a 4- to 8-membered heterocycloalkyl ring; each k is independently 1, 2, or 3; p is 0, 1, 2 or 3; s is 0, 1, 2 or 3, with the proviso that the sum of p and s is 4; A2 and B2 are each independently H, fluoro, or alkyl, or together they form a double bond or -CH2-; G is H or alkyl; X2 is -C (Rc) (Rd) -, -O-, -S-, -S (= O) -, -S (= O) 2-, -C (= O) -, -CH (OH) - or -N (R26) -; R26 is H, alkyl, cycloalkyl, - (CH2) -alkenyl, - (CH2) -alkynyl, aryl, -C (= O) Rd, or -S (= O) 2Rd; and J2 forms a 6 to 10 membered aryl or a 5- to 10 membered heteroaryl ring when taken together with the carbon atoms to which it is attached; or one of its stereoisomers, prodrugs, pharmaceutically acceptable salts, hydrates, solvates, acid salt hydrates, or N-oxides. In another aspect, the invention relates to methods for reducing the need for anesthesia, comprising the step of administering to a patient in need of such treatment an effective amount of a compound of the invention including, for example, a compound of formulas I, II, III, IV, V, VI, VII, VII, IX, X, XI, Xll, and / or Xlll. In certain preferred aspects, the methods comprise the step of administering to said patient an effective amount of a compound of formula IV: IV where: Y2 is a single bond or - [C (Rc) (Rd)] k-; each Rc, Re, and Rf is independently H or alkyl; each Rd is independently H, alkyl, or aryl; W2 is aryl, alkylaryl, heterocycloalkylaryl, heteroaryl, alkylheteroaryl, heteroarylaryl, or alkylheteroarylaryl; R23 and R24 are each independently H, alkyl, alkenyl, alkynyl, or aryl, or R23 and R24 when taken together with the atoms through which they are connected, form a cycloalkyl or heterocycloalkyl ring of 4 to 8 members; Z is -N (R25) -, -C (= O) -, -CH (OH) -, -CH (N (Rc) (Rd)) -, or -O-; R25 is H, alkyl, alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl, aralkyl, or heteroarylalkyl, or R23 and R25 when taken together with the atoms through which they are connected, form a 4- to 8-membered heterocycloalkyl ring, or R24 and R25 when taken together with the atoms through which they are connected, form a 4- to 8-membered heterocycloalkyl ring; each k is independently 1, 2, or 3; p is 0, 1, 2 or 3; s is 0, 1, 2 or 3, with the proviso that the sum of p and s is 4; A2 and B2 are each independently H, fluoro, or alkyl, or together they form a double bond or -CH2-; G is H or alkyl; X2 is -C (Rc) (Rd) -, -O-, -S-, -S (= O) -, -S (= O) 2-, -C (= O) -, -CH (OH) - or -N (R26) -; R26 is H, alkyl, cycloalkyl, - (CH2) -alkenyl, - (CH2) -alkynyl, aryl, -C (= O) Rd, or -S (= O) 2Rd; and J2 forms a 6 to 10 membered aryl or a 5- to 10 membered heteroaryl ring when taken together with the carbon atoms to which it is attached; or one of its stereoisomers, prodrugs, pharmaceutically acceptable salts, hydrates, solvates, acid salt hydrates, or N-oxides. In another aspect, the invention relates to methods for producing or maintaining an anesthetic state, comprising the step of administering to a patient in need of such treatment an effective amount of a compound of the invention including, for example, a compound of formulas I, II, III, IV, V, VI, VII, VII, IX, X, XI, Xll, and / or Xlll. The method may further comprise the step of administering to said patient an anesthetic agent, which may be co-administered with the compound (s) of the invention. Suitable anesthetic agents include, for example, an inhaled anesthetic, a hypnotic, an anxiolytic, a neuromuscular blocker and an opioid. Thus, in the present embodiment, the compounds of the invention may be useful as anesthetic agents for use during general anesthesia and supervised anesthesia. The combinations of agents with different properties can be used to achieve a balance of the effects necessary to maintain the anesthetic state. In certain preferred aspects, the methods comprise the step of administering to said patient an effective amount of a compound of formula IV: IV where: Y2 is a single bond or - [C (Rc) (Rd)] k-; each R c, Re, and R f is independently H or alkyl; each Rd is independently H, alkyl, or aryl; W2 is aryl, alkylaryl, heterocycloalkylaryl, heteroaryl, alkylheteroaryl, heteroarylaryl, or alkylheteroarylaryl; R23 and R24 are each independently H, alkyl, alkenyl, alkynyl, or aryl, or R23 and R24 when taken together with the atoms through which they are connected, form a cycloalkyl or heterocycloalkyl ring of 4 to 8 members; Z is -N (R25) -, -C (= O) -, -CH (OH) -, -CH (N (Rc) (Rd)) -, or -O-; R25 is H, alkyl, alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl, aralkyl, or heteroarylalkyl, or R23 and R25 when taken together with the atoms through which they are connected, form a 4- to 8-membered heterocycloalkyl ring, or R24 and R25 when taken together with the atoms through which they are connected, form a 4- to 8-membered heterocycloalkyl ring; each k is independently 1, 2, or 3; p is O, 1, 2 0 3; s is 0, 1, 2 or 3, with the proviso that the sum of p and s is 4; A2 and B2 are each independently H, fluoro, or alkyl, or together they form a double bond or -CH2-; G is H or alkyl; X2 is -C (Rc) (Rd) -, -O-, -S-, -S (= O) -, -S (= O) 2-, -C (= O) -, -CH (OH) - or -N (R26) -; R26 is H, alkyl, cycloalkyl, - (CH2) -alkenyl, - (CH2) -alkynyl, aryl, -C (= O) Rd, or -S (= O) 2Rd; and J2 forms a 6 to 10 membered aryl or a 5- to 10 membered heteroaryl ring when taken together with the carbon atoms to which it is attached; or one of its stereoisomers, prodrugs, pharmaceutically acceptable salts, hydrates, solvates, acid salt hydrates, or N-oxides. Additional diseases and / or disorders that can be treated and / or prevented with the compounds and pharmaceutical compositions of the present invention include those described, for example, in WO2004 / 062562 A2, WO 2004/063157 A1, WO 2004/063193 A1, WO 2004/041801 A1, WO 2004/041784 A1, WO 2004/041800 A1, WO 2004/060321 A2, WO 2004/035541 A1, WO 2004/035574 A2, WO 2004041802 A1, US 2004082612 A1, WO 2004026819 A2, WO 2003057223 A1, WO 2003037342 A1, WO 2002094812 A1, WO 2002094810 A1, WO 2002094794 A1, WO 2002094786 A1, WO 2002094785 A1, WO 2002094784 A1, WO 2002094782 A1, WO 2002094783 A1, WO 2002094811 A1, each of which descriptions are incorporated in this document by reference in its entirety.

In certain aspects, the present invention relates to radiolabelled derivatives and isotopically-labeled derivatives of the compounds of the invention including, for example, the compounds of formulas I, II, III, IV, V, VI, VII, VII, IX, X, XI, Xll, and / or Xlll. Suitable labels include, for example, 2H, 3H, C, 13C, 13N, 15N, 150, 180, 18F, and S. Such labeled derivatives may be useful for biological studies, for example, using positron emission tomography, for metabolite identification studies and the like. Such diagnostic imaging methods may comprise, for example, the administration to a patient of a radiolabelled derivative or an isotopically-labeled derivative of a compound of the invention, and the obtaining of the patient's image, for example, by application of the appropriate energy, as in the positron emission tomography. Radiolabelled and isotopically labeled derivatives can be prepared using techniques well known to one of ordinary skill in the art. In certain preferred aspects, the radiolabelled derivatives and the isotopically-labeled derivatives of the invention are compounds of formula IV: IV; wherein: Y2 is a single bond or - [C (Rc) (Rd)] k-; each Rc, Re, and Rf is independently H or alkyl; each Rd is independently H, alkyl, or aryl; W2 is aryl, alkylaryl, heterocycloalkylaryl, heteroaryl, alkylheteroaryl, heteroarylaryl, or alkylheteroarylaryl; R23 and R24 are each independently H, alkyl, alkenyl, alkynyl, or aryl, or R23 and R24 when taken together with the atoms through which they are connected, form a cycloalkyl or heterocycloalkyl ring of 4 to 8 members; Z is -N (R25) -, -C (= O) -, -CH (OH) -, -CH (N (Rc) (Rd)) -, or -O-; R25 is H, alkyl, alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl, aralkyl, or heteroarylalkyl, or R23 and R25 when taken together with the atoms through which they are connected, form a 4- to 8-membered heterocycloalkyl ring, or R24 and R25 when taken together with the atoms through which they are connected, form a 4- to 8-membered heterocycloalkyl ring; each k is independently 1, 2, or 3; p is O, 1, 2 6 3; s is 0, 1, 2 or 3, with the proviso that the sum of p and s is 4; A2 and B2 are each independently H, fluoro, or alkyl, or together they form a double bond or -CH2-; G is H or alkyl; X2 is -C (Rc) (Rd) -, -O-, -S-, -S (= O) -, -S (= O) 2-, -C (= O) -, -CH (OH) - or -N (R26) -; R26 is H, alkyl, cycloalkyl, - (CH2) -alkenyl, - (CH2) -alkynyl, aryl, -C (= O) Rd, or -S (= O) 2Rd; and J2 forms an aryl of 6 to 10 members or a heteroaryl ring of 5 to 10 members when taken together with the carbon atoms to which it is attached; with the proviso that when: (a) J2 is taken together with the carbon atoms to which it is attached it forms a 6 to 10 membered aryl ring substituted with 0-3 groups selected from the group consisting of: halogen, hydroxy, - SH, -C (= O) -H -S-alkyl CM, -NHS (= O) 2-alkyl CM, -NHS (= O) 2-H, -N (alkyl CM) S (= O) 2- H, alkyl CM, and alkoxy C, the last two optionally substituted with one or more halogens or with alkoxy CM; W 2 is phenyl substituted with 0-3 groups selected from the group consisting of: halogen, cyano, hydroxy, C 1-6 alkyl optionally substituted with one or more halogens, C 1-6 alkoxy optionally substituted with one or more halogens or with C 3-6 cycloalkyl , C 2-6 alkenyloxy, C 2-6 alkynyloxy, C 3-6 cycloalkyloxy, C 6-12 aryloxy, aralkoxy, heteroaryloxy, heteroaralkoxy, heterocycloalkyl substituted with alkoxy, -SH, -S-alkyl CM, -NH 2, -N = C (aryl ) 2, -N (H) alkylCM, -N (alkylCM) 2, -OS (= O) 2-C-alkyl optionally substituted with one or more halogens, -OS (= O) 2-aryl C6-? 2 optionally substituted by alkyl CM, -NHS (= O) 2-alkylated CM, -N (alkyl CM) S (= O) 2-alkyl CM, -NHS (= O) 2-H, and -N (alkyl CM) S (= O) 2-H; p and s are each 1, Re, Rf, R23, R24, and G are each H, A2 and B2 together form a double bond that incorporates the atoms to which they are attached, Y2 is a single bond; and X2 is -O-; then Z is different from: , where t is an integer between 1 and 20; and with the proviso that when: (b) J2 is taken together with the carbon atoms to which it is attached it forms a phenyl ring substituted with 0-3 groups selected from the group consisting of: halogen, hydroxy, -S-alkyl C , alkyl CM, and alkoxy CM, the last two optionally substituted with one or more halogens or with alkoxy CM; W2 is unsubstituted naphthyl, or phenyl substituted with 0-3 groups selected from the group consisting of: halogen, C6 alkyl, C2 alkoxy, phenyl, phenyloxy, 1,3-benzodioxazolyl, or 2,2-difluoro-1, 3 -benzodioxazolyl fluoro, -NH2, -N (alkyl CM) 2, and pyrrolyl; p and s are each 1, Re, Rf, R23, R24, and G are each H, A2 and B2 together form a double bond that incorporates the atoms to which they are attached, Y2 is a single bond; and X2 is -O-; then Z is different from: with the proviso that when: (c) J2 is taken together with the carbon atoms to which unsubstituted phenyl form is attached, W2 is phenyl substituted with 0-3 groups selected from the group consisting of: fluorine, hydroxy, alkoxy C optionally substituted with one or more fluoros, C2-6 alkenyloxy, and -S-C alkyl, pys are each 1, Re, Rf, R23, R24, and G are each H, A2 and B2 together form a double bond that incorporates the atoms to which they are attached, Y2 is a simple link; and X2 is -O-; then Z is different from: with the proviso that when: (d) J2 is taken together with the carbon atoms to which it is attached it forms a 6-membered aryl ring substituted with: then Z is other than -N (R25) - or -CH (NH2 ) -; or one of its stereoisomers, prodrugs, pharmaceutically acceptable salts, hydrates, solvates, acid salt hydrates, or N-oxides. Now the present invention will be illustrated by reference to the following specific non-limiting examples. Those skilled in the art of organic synthesis may be aware of yet other synthetic routes for the compounds of the invention. The reagents and intermediates used in the present document are commercially available or can be prepared according to procedures customary in the literature. Methods of Preparation The examples listed in Table 1 were prepared according to Schemes 1-37.

The synthesis of the compounds 1A-1U is described in Scheme 1. The 2'-hydroxyacetophenone derivatives 1.1a-1.1m were condensed with 1-Boc-4-piperidone 1.2 in pure pyrolidine (method 1A) at room temperature, or in reflux meianol in the presence of pyrrolidine (method 1B) to provide derivatives? / - Boc-spiro [2H-1-benzopyran-2,4'-piperidine] -4 (3H) -one 1.3. The conversion of the ketones 1.3 to the triflate-enol derivatives 1.5 was achieved using? / -phenylbis (trifluoromethanesulfonimide) 1.4 as a triflactant reagent. The type of Suzuki coupling of enol triflate derivatives 1.5 with either 4 - (? /,? / - diethylaminocarbonyl) phenyl boron acid 1.6 (commercially available from Combi-Blocks Inc.) or 2 - (? /? / -diethylaminocarbonyl) -5- (4,4,5,5-tetramethyl-1, 3,2-dioxoborolan-2-yl) pyridine 1.7 in ethylene glycol dimethyl ether in the presence of tetrakis triphenylphosphine palladium (0) (method 1C) or palladium, 10 weight.% (Dry basis) on activated carbon (1D method), lithium chloride, and an aqueous solution of compounds provided with sodium carbonate 1.8 that were converted to the final products (compounds 1A-1T) under acidic conditions (method 1E: anhydrous HCl, diethylene ether, room temperature or 1F method: pure trifluoroacetate acid, room temperature). Demethylation of compound 1G using boron tribromide gave the corresponding phenolic derivative (compound 1U). The boron derivative 1.7 was prepared in 4 steps of 2, 5-dibromopyridine 1.9. Treatment of 2,5-dibromopyridine with n-butyllithium gave the corresponding lithium derivative, which reacted with carbon dioxide to provide 5-bromopyridin-2-carboxylic acid 1.10. Treatment of the carboxylic acid derivative 1.10 with oxalyl chloride gave acyl chloride 1.11, which reacted with diethylamine 1.12 to provide 5-bromo-2 - (/ V,? / - diethylaminocarbonyl) -pyridine 1.13. The conversion of aryl bromide 1.13 to the corresponding boron derivative 1.7 was achieved using 4,4,5,5-tetramethyl-2- (4,4 I5,5-tetramethyl-1,2,2-dioxaborlane-2-yl) -1 , 3,2-dioxaborolane 1.14 and dicIoro [1,1'-bis (diphenylphosphine) ferrocene] palladium (II) dichloromethane adduct, abbreviated as [Pd (dppf) CI2-CH2Cy. The synthesis of compounds 2A-2F is described in Scheme 2. The derivative 2'-5'-dihydroxyacetophenone 2.1 was condensed with 1-Boc-4-piperidone 1.2 in refluxing methanol in the presence of pyrolidine to provide the derivative α / - Boc-spiro [2H-1-benzopyran-2,4'- piperidine] -4 (3H) -one 2.2 which was converted to the silyl ether derivative 2.4 using ferc-butyldimethylsilyl chloride 2.3. The conversion of the ketone 2.4 to the enol triflate 2.5 derivative was achieved using / V-phenylbis (trifluoromethanesulfonimide) 1.4 as a triflactant reagent. The type of suzuki coupling of the enol derivative of triflate 2.5, either with boron acid 4 - (? /,? / - diethylaminocarbonyl) -phenyl-1,6, or with 2- (N, N-diethylaminocarbonyl) -5- (4, 4,5,5-tetramethyl-1, 3,2-dioxoborlane-2-yl) pyridine 1.7 in dimethyl ether glycol ethylene in the presence of palladium tetrakis triphenylphosphine (0) (method 1 C) or palladium, weight. % (dry base) on activated carbon (1D method), lithium chloride, and an aqueous sodium carbonate solution provided compounds 2.6. Removal of the 2.6 silyl protecting group, using a solution of tetrabutylammonium floride (TBAF) in tetrahydrofuran gave the phenolic derivatives 2.7 that were converted to the compounds of the final products 2A and 2B under acidic conditions. The preparation of each of the 2.9 ether derivatives of the phenols 2.7 was achieved by the alkylation reaction using the appropriate alkyl bromide (2.8a, 2.8b) (method 2A) or the iodide alkyl reagent (2.8c) (method 2C). In some cases, ether 2.9 derivatives were also obtained from phenols 2.7 using the Mitsunobu conditions, ie the condensation of phenols 2.7 with the appropriate alcohol (2.8d, 2.8e) in the presence of triphenylphosphine and diodisopropylazodicarboxylate ( DIAD) (method 2B). Treatment of the Boc 2.9 derivatives with hydrochloric acid provided the final compounds 2C-F. The synthesis of the compounds 3A-AC is described in Scheme 3. The conversion of the phenols 2.7 to the triflate 3.1 derivatives was achieved by using the triflactant reagent? / -phenylbis (trifluoromethanesulfonimide) 1.4. The catalysed carbonization of palladium 3.1, made in methanol or in a mixture of dimethylsulfoxide / methanol using palladium (II) acetate, 1,1'-bis (diphenylphosphine) ferrocene (dppf) and carbon monoxide, provided the methylene esters 3.2 that were hydrolyzed under basic conditions to offer carboxylic acid derivatives 3.3. The coupling of carboxylic acids 3.3 with several amines (3.4a-3.4q) using O-benzotriazole-1-yl-? ,? /,? / ', N-tetramethyluronium tetrafluoroborate (TBTU) as cosolvent provided the primary, secondary and tertiary amides 3.5. The treatment of the Boc 3.2, 3.3 and 3.5 derivatives with the hydrochloric acid provided the final compounds 3A-3Y. The Suzuki-type coupling of the triflate derivative 3.1a (X = CH) with various organoboron reagents (3.6a-3.6d) in ethylene glycol dimethyl ether in the presence of palladium tetrakis triphenylphosphine (0), and / or dichloro [ 1, 1'-bis (diphenylphosphine) ferrocene] palladium (ll) dichloromethane, [Pd (dppf) CI2 CH2Cl2], lithium chloride, and an aqueous solution of sodium carbonate provided compounds 3.7 that were converted to the final products (3Z compounds) -3AC) under acidic conditions. The synthesis of compounds 4A-4I is described in Scheme 4. The treatment of compound 1A with trifluoroacetic anhydride in tetrahydrofuran in the presence of triethylamine was provided by the trifluoroacetamide derivative 4.2 which was converted to sulfonyl chloride 4.4 using the sulfuric trioxide complex, W -dimethylformamide (4.3) as a sulfation agent. The condensation of 4.4 with several primary and secondary amines (3.4, 4.5) provided the sulfonamide derivatives 4.6 that were converted to compounds 4A-4G under basic conditions. Treatment of sulfonic chloride 4.4 with ammonium hydroxide in acetonitrile gave the sulfonamide compound 4H, which was additionally protected as its tert-butyloxycarbonyl derivative (Boc) 4.8 with the treatment with tert-butyloxycarbonyl anhydride (4.7). Acetylation of 4.8 using acetic anhydride (4.9) afforded the acetylsulfonamide derivative 4.10 which was converted to compound 41 with the iodotrimethylsilane treatment. The synthesis of compound 5A is described in Scheme 5. The condensation of the hydrazine hydrate (5.1) with the sulfonic chloride derivative 4.4 gave the sulphonic hydrazide 5.2, which was converted to sulfate 5.3 by the treatment with methyl iodide (2.8c) in the presence of sodium acetate. Deprotection of the trifluoroacetamide protecting group of 5.3 under basic conditions (potassium carbonate, methanol / tetrahydrofuran / water) provided the final compound 5A. The synthesis of compounds 6A-6E is described in Scheme 6. The nitration of trifluoroacetamide 4.2 using the nitronium tetrafluoroborate complex (6.1) as the nitrurant provided predominantly the mono-nitric isomer 6.2. The reduction of nitric functionality of 6.2 using tin (II) chloride dihydrate (6.3) provided the aniline derivative 6.4, which reacted with the derivatives of the sulfonyl chloride 6.5 or with the acetyl chloride (6.7) to provide sulfonamides 6.6 or acetamides 6.8, respectively. Deprotection of the protective group trifluoroacetamide 6.2, 6.4, 6.6 and 6.8 under basic conditions (potassium carbonate, methanol / tetrahydrofuran / water) provided the final compounds (compounds 6A-6E). The synthesis of the compounds 7A-7C is described in Scheme 7. The Buchwaid type coupling of the triflate derivative 3.1a with diphenylmethanimine (7.1) in toluene in the presence of dipalladium (dibenzylideneacetone) dipalladium (0) [Pd2 (dba ) 3], 1,1'-bis (diphenylphosphine) ferrocene (dppf) and sodium tert-butoxide provided the benzophenone imine7.2 derivative, which was converted to 7.3 aniline by treatment with hydroxylamine hydrochloride in the presence of acetate sodium Treatment of 7.3 with methanesulfonyl chloride (7.4) in dichloromethane in the presence of triethylamine gave the j / s-methanesulfonamide 7.5, which was hydrolyzed to the mono-methanesulfonamide derivative 7.6 under basic conditions. Deprotection of the urea-butyloxycarbonyl protecting group of 7.6 under acidic conditions afforded the final compound 7A. Compound 7B was obtained in two steps of 7.6. Alkylation of 7.6 with methyl iodide (2.8c) in tetrahydrofuran in the presence of sodium hydride provided the N-methylsulfonamide 7.7, which was converted to compound 7B under acidic conditions. Treatment of the 6.4-aniline derivative with methanesulfonyl chloride (7.4) in dichloromethane in the presence of triethylamine gave the jb / s-methanesulfonamide7.8, which was hydrolyzed to the mono-methanesulfonamide derivative 7A under basic conditions. During the course of this reaction, the compound of / V-methyl piperidine 7C was identified as a secondary product. Separation of the mixture containing the compounds 7A and 7C was achieved by first treating the mixture of the compounds 7A / 7C with tert-butyloxycarbonylahydrate (4.7) which gave the Boc7.6 derivative and de-reacted the 7C compound, followed by purification of compound 7C using "flash colum" chromatography. The synthesis of the compounds 8A-8F is described in Scheme 8. The derivative of 2'-3'-dihydroxyacetophenone 8.1 was condensed with 1-Boc-4-piperidone 1.2 in refluxing methanol in the presence of pyrolidine to provide the derivative of? / - Boc-spiro [2H-1-benzopyran-2,4'-piperidine] -4 (3 / - /) - one 8.2 which was converted to the 8.3 silyl ether derivative using tert-butyldimethylsilyl chloride 2.3 . The ketone 8.3 was converted to the triflate-enol derivative 8.4 using the triflactant reagent N-phenylbis (trifluoromethanesulfonimide) 1.4. The Suzuki type coupling of the enol triflate derivative 8.4 well with boron acid 4 - (/ V,? / - diethylaminocarbonyl) phenyl 1,6 or 2- (N, Nd-ethylaminocarbonyl) -5- (4,4,5,5-tetramethyl-1,2,2-dioxoborlane-2-yl) pyridine 1.7 in ethylene ether dimethyl glycol in the presence of palladium, 10. weight% (dry base) on activated carbon, lithium chloride, and an aqueous sodium carbonate solution provided compounds 8.5. Removal of the silyl protecting group of 8.5 using a solution of tetrabutylammonium fluoride (TBAF) in tetrahydrofuran provided the phenolic derivatives 8.6 that were converted to the final product (compounds 8A and 8B) under acidic conditions. The preparation of the ether derivatives 8.7 of the phenols 8.6 was achieved by alkylation using the appropriate alkyl bromide (2.8a) or the reactive methyl iodide (2.8c). Treatment of the Boc 8.7 derivatives with hydrochloric acid provided the final compounds 8C-8F. The synthesis of compounds 9A-9B is described in Scheme 9. The derivative 2 * 4'-dihydroxyacetophenone 9.1 was condensed with 1-Boc-4-piperidone 1.2 in refluxing methanol in the presence of pyrolidine to provide the derivative? / -Boc-spiro [2H-1-benzopyran-2,4'-piperidine] -4 (3H) -one 9.2 which was converted to the silyl ether derivative 9.3 using tert-butyldimethylsilyl chloride 2.3. The conversion of the ketone 9.3 to the triflate enol 9.4 derivative was achieved by using N-phenylbis (trifluoromethanesulfonimide) 1.4 as a triflate reagent. The Suzuki type coupling of the enol triflate derivative 9.4 with boron acid 4- (N, N-diethylaminocarbonyl) phenyl 1.6 in dimethyl glycol ethylene ether in the presence of palladium tetrakis triphenylphosphine (0), lithium chloride, and a solution aqueous sodium carbonate provided the phenolic derivative 9.5 (simultaneous removal of the silyl protecting group occurred under Suzuki coupling conditions). Alkylation of phenol 9.5 with (bromomethyl) cyclopropane (2.8a) in acetone in the presence of potassium carbonate gave the ether derivative 9.6 which was converted to compound 9A under acidic conditions. The treatment of phenol 9.5 with methyl chlorodifluoroacetate (9.7) in? /,? / - dimethylformamide in the presence of cesium carbonate gave the ether derivative 9.8 which was converted to compound 9B under acidic conditions. The synthesis of the compounds 10A-10J is summarized in Scheme 10. The conversion of the phenol 9.5 to the triflate derivative 10.1 was carried out using N-phenylbis (trifluoromethanesulfonimide) 1.4 as a triflate reagent. Palladium catalyzed carbonylation of 10.1, carried out in a mixture of A /,? / - dimethylformamide / methanol using palladium (II) acetate, 1,1'-bis (diphenylphosphino) ferrocene (dppf), and carbon monoxide, gave the methyl ester 10.2 which was hydrolyzed under basic conditions to give the carboxylic acid derivative 10.3. The coupling of carboxylic acid 10.3 with various amines (3.4a, c, j, k, p; 1.12) using O- (7-azabenzotriazol-1-yl) -N,? /,? / ', / V-tetramethiuronium hexafluorophosphate (HATU) (method 10B) or O-benzotriazol-1-yl-tetrafluoroborate. I,? /,? / ', / \ / -tetramethyluronium (TBTU) (procedure 10A) as coupling agents gave the primary, secondary, and tertiary amides 10.4. The dimethylamide derivative 10.4b (R- | = H, R2 = CH3) was obtained by heating a mixture of ester 10.2 with methylamine (3.4b) in methanol in a sealed tube. Treatment of the Boc derivatives 10.2, 10.3 and 10.4 with hydrochloric acid gave the final compounds 10A-10I. Treatment of ester 10.2 with lithium borohydride in tetrahydrofuran gave the primary alcohol 10.5 which was converted to compound 10J under acidic conditions. The synthesis of the compounds 11A-11F is summarized in Scheme 11 The 2'-6'-dihydroxyacetophenone derivative 11.1 was condensed with 1-Boc-4-piperidone 1.2 in methanol at reflux temperature in the presence of pyrrolidine to give the derivative of N-Boc-spiro [2H-1-benzopyran-2,4'-piperidine] -4 (3H) -one 11.2 which was converted to the methoxymethyl ether derivative (MOM) 11.4 using chloro (methoxy) methane ( 11.3). The conversion of the ketone 11.4 to the enol triflate 11.5 derivative was carried out using N-phenylbis (trifluoromethanesulfonimide) 1.4 as triflate reagent. The Suzuki-type coupling of the enol triflate 11.5 derivative with 4- (N, N-diethylaminocarbonyl) phenylboronic acid 1.6 or 2 - (/ V, / V-diethylaminocarbonyl) -5- (4,4,5, 5-tetramethyl-1, 3,2-dioxoborolan-2-yl) pyridine 1.7 in dimethylether ethylene glycol in the presence of tetrakistriphenylphosphine of palladium (0), lithium chloride, and an aqueous solution of sodium carbonate gave compounds 11.6. Removal of the MOM and Boc protecting groups of 11.6 in methanol at room temperature in the presence of hydrochloric acid (anhydrous solution in dioxane) gave the phenolic compounds 11A and 11B which were converted to the corresponding Boc derivatives 11.7 by treatment with tertiary anhydride. -butyloxycarbonyl (4.7). The preparation of ether derivatives 11.9a [X = CH; R = CH2C (C3H5)], 11.9b [X = N; R = CH2c (C3H5)] and 11.9d [X = N; R = c ^ Hg)] from the corresponding phenols 11.7a [X = CH] or 11.7b [X = N] was carried out using the conditions of Mitsunobu, that is, the condensation of phenols 11.7a or 11.7b with cyclopropylmethanol (2.8e) or cyclopentanol (11.10) in dichloromethane in the presence of triphenylphosphine and diethyl azodicarboxylate (DEAD). The cyclobutyl ether 11.9c [X = CH; R = c (C4H7)] was obtained by alkylation of the corresponding phenol 11.7a [X = CH] with bromocyclobutane in acetone in the presence of potassium carbonate. Treatment of the Boc 11.9 derivatives with hydrochloric acid gave the final compounds 11C-11F. The synthesis of compounds 12A-12L is summarized in Scheme 12. The conversion of phenol 11.2 to triflate derivative 12.1 was carried out using N-phenylbis (trifluoromethanesulfonimide) 1.4 as a triflate reagent. The palladium-catalyzed Negishi-type coupling of 12.1 with methylcinc chloride (12.2a), propylcinc bromide (12.2b), or butylcinc bromide (12.2c), carried out in tetrahydrofuran using palladium (0) tetrakistriphenylphosphine as catalyst, gave the ketones 12.3. The conversion of the ketones 12.3 to the enol triflate 12.4 derivatives was carried out using N-phenylbis (trifluoromethanesulfonimide) 1.4 as a triflate reagent. The Suzuki type coupling of enol triflate 12.4 derivative with 4 - (? /, / V-diethylaminocarbonyl) phenylboronic acid 1.6 or 2 - (? /,? / - diethylaminocarbonyl) -5- (4,4,5, 5-tetramethi-1,3,2-dioxoborolan-2-yl) pyridine 1.7 using the procedure 1C (palladium tetrakistriphenylphosphine (0), lithium chloride, an aqueous solution of sodium carbonate, dimethylether ethylene glycol) or the process 12A (tetrakistriphenylphosphine of palladium (0), potassium bromide, potassium phosphate, dioxane) gave compounds 12.5. Removal of the Boc protecting group of 12.5 in dichloromethane at room temperature in the presence of hydrochloric acid (anhydrous solution in diethylether) gave compounds 12A and 12H-12L. Palladium catalyzed carbonylation of 12.1, made in a mixture of N, N-dimethylformamide / methanol using palladium (II) acetate, 1,3-bis (diphenylphosphino) propane (dppp) and carbon monoxide, gave the methyl ester 12.6 which was hydrolyzed under basic conditions (lithium hydroxide, methanol / tetrahydrofuran) to give the carboxylic acid derivative 12.7. Coupling of the carboxylic acid 12.7 with dimethylamine (3.4j) using O-benzotriazole-1-yl-γ-γ /, / V ', γ-tetramethyluronium (TBTU) tetrafluoroborate as the coupling agent gave the dimethylaminocarbonyl derivative 12.8. The conversion of 12.8 to the enol triflate 12.9 derivative was carried out using? / -phenylbis (trifluoromethanesulfonimide) 1. 4 as triflate reagent. The Suzuki-type coupling of the enol triflate derivative 12. 9 with 4 - (? /, N-diethylaminocarbonyl) phenylboronic acid 1.6 in dimethylether ethylene glycol in the presence of tetrakistriphenylphosphine of palladium (0), lithium chloride, and an aqueous solution of sodium carbonate gave compound 12.10. Removal of the Boc protecting group of 12.10 in dichloromethane at room temperature in the presence of hydrochloric acid (anhydrous solution in diethylether) gave the compound 12G (R <1 = R2 = CH3). The conversion of 12.6 to the enol triflate 12.11 derivative was carried out using N-phenylbis (trifluoromethanesulfonimide) 1.4 as a triflate reagent. The Suzuki-type coupling of the enol triflate 12.11 derivative with 4- (N, N-diethylaminocarbonyl) phenylboronic acid 1.6 in dimethylether ethylene glycol in the presence of tetrakistriphenylphosphine of palladium (0), lithium chloride, and an aqueous solution of sodium carbonate gave the ester 12.12 which was hydrolyzed under basic conditions (potassium tert-butoxide, diethyl ether, water) to give the carboxylic acid 12.13. The coupling of carboxylic acid 12.13 with various amines (12.15 or 3.4b-3.4d) using O-benzotriazole-1-yl-α /, V, / /,, / / -tetramethyluronium tetrafluoroborate (TBTU) as the coupling agent gave the primary and secondary aminocarbonyl derivatives 12.14. Treatment of the Boc 12.13 and 12.14 derivatives with hydrochloric acid gave the final compounds 12B-12F. The synthesis of compounds 13A-13S is summarized in Scheme 13. The 2'-hydroxyacetophenone derivative 1.1a was condensed with 1-Boc-4-piperidone 1.2 in methanol at reflux temperature in the presence of pyrrolidine to give / V- Boc-spiro [2H-1-benzopyran-2, 4'-piperidine] -4 (3 -) -one 1.3a. The conversion of 1.3a to the enol triflate 1.5a derivative was carried out using / V-phenylbis (trifluoromethanesulfonimide) 1.4 as a triflate reagent. The Suzuki-type coupling of the enol triflate derivative 1.5a with 4- (methoxycarbonyl) phenylboronic acid (13.1) in dimethylether ethylene glycol in the presence of tetrakistriphenylphosphine of palladium (0), lithium chloride, and an aqueous solution of sodium carbonate gave the ester 13.2 which was hydrolyzed under basic conditions (lithium hydroxide, methanol / tetrahydrofuran / water) to give the carboxylic acid 13.3. The coupling of carboxylic acid 13.3 with various amines (3.4a-3.4c, 3.4e, 3.4j-3.4k, 3.4o-3.4q; 13.4a-13.4h) using O-benzotriazol-1-yl-? / Tetrafluoroborate, A /,? / ', N-tetramethyluronium (TBTU) as the coupling agent gave the primary, secondary, and tertiary aminocarbonyl derivatives 13.5. Treatment of the Boc 13.3 and 13.5 derivatives with hydrochloric acid gave the final compounds 13A-13R. Hydrolysis of compound 130 under basic conditions (sodium hydroxide, ethanol / tetrahydrofuran) gave the 13S carboxylic acid compound.

The synthesis of the compounds 14A-14C is summarized in Scheme 14. The Suzuki-type coupling of the enol triflate derivative 1.5a with 4-cyanophenylboronic acid (14.1) in dimethylether ethylene glycol in the presence of tetrakistriphenylphosphine of palladium (0), lithium, and an aqueous solution of sodium carbonate gave cyanide 14.2 which was converted to tetrazole 14.4 using sodium azide (14.3) and zinc bromide in a solution of isopropanol / water. Alkylation of 14.4 with methyl iodide (2.8c) in N, N-dimethylformamide in the presence of triethylamine gave the two regioisomers 14.5 (major isomer) and 14.6 (secondary isomer) separated by column chromatography on silica gel. The Boc protecting group of 14.4, 14.5, and 14.6 was removed using hydrochloric acid to generate compounds 14A-14C. Alternatively, the Boc protecting group of 14.4 was also removed using trifluoroacetic acid to give 14A. The synthesis of compounds 15A-15N is summarized in Scheme 15. The alkylation of 14.4 with the alkyl bromide derivatives 15.1a-15.1e in N, N-dimethylformamide in the presence of triethylamine gave the regioisomers 15.2 (major isomers) and 15.3 (secondary isomers) separated by column chromatography on silica gel. The Boc protecting group of 15.2 and 15.3 was removed using hydrochloric acid to generate compounds 15A-15J. Hydrolysis of compounds 15A or 15C-15E under basic conditions (sodium hydroxide, methanol (or ethanol) / tetrahydrofuran / water) gave the corresponding carboxylic acid compounds 15K-15N, respectively. In some cases, the 15K-15N compounds were also obtained in two steps from 15.2, that is, by basic hydrolysis of the ester function of 15.2 followed by deprotection of the Boc 15.4 derivatives under acidic conditions. The synthesis of the compounds 16A-16C is summarized in Scheme 16. The Suzuki-type coupling of the enol triflate derivative 1.5a with 3-cyanophenylboronic acid (16.1) in dimethylether ethylene glycol in the presence of tetrakistriphenylphosphine of palladium (0), lithium, and an aqueous sodium carbonate solution gave cyanide 16.2 which was converted to tetrazole 16.3 using sodium azide (14.3) and zinc bromide in a solution of isopropanol / water. Alkylation of 16.3 with methyl iodide (2.8c) in N / V-dimethylformamide in the presence of triethylamine gave the two regioisomers 16.4 (major isomer) and 16.5 (secondary isomer) separated by column chromatography on silica gel. The Boc protecting group of 16.3, 16.4, and 16.5 was removed using hydrochloric acid to generate compounds 16A-16C. The synthesis of compounds 17A-17F is summarized in Scheme 17. The alkylation of 16.3 with the alkyl bromide derivatives 15.1a or 15.1c in N, N-dimethylformamide in the presence of triethylamine gave the regioisomers 17.1 (major isomers) and 17.2 (secondary isomers) separated by column chromatography on silica gel. Alkylation of 16.3 with 4- (2-bromoethyl) morpholine (17.3) in N, N-dimethylformamide in the presence of triethylamine gave isomer 17.4. The Boc protecting group of 17.1, 17.2, and 17.4 was removed using hydrochloric acid to generate compounds 17A-17D. Hydrolysis of compounds 17A and 17B under basic conditions (sodium hydroxide, methanol / tetrahydrofuran / water) gave the corresponding carboxylic acids, compound 17E and compound 17F, respectively. In some cases compounds 17E and 17F could also be obtained in two steps from 17.1, ie, by basic hydrolysis of the ester function of 17.1 followed by deprotection of the Boc 17.5 derivatives under acidic conditions. The synthesis of compounds 18A-18C is summarized in Scheme 18. The coupling of carboxylic acid 13.3 with ammonium chloride (3.4a) in acetonitrile in the presence of diisopropylethylamine using O-benzotriazole-1-yl- / V, tetrafluoroborate. ,? / ',? -tetramethyluronium (TBTU) as a coupling agent gave the primary aminocarbonyl derivative 13.5a which was converted to thioamide 18.2 using Lawesson's reagent (18.1) [2], 4-bis (4-methoxyphenyl) -1,3-dithia-2,4-diphosphetane-2,4-disulfide]. The condensation of thioamide 18.2 with 1-bromo-3,3-dimethylbutan-2-one (18.3a) or 2-bromo-1-phenyletanone (18.3b) of the thiazole derivatives 18.4 which were converted to the final compounds ( compounds 18A and 18B) under acidic conditions. The condensation of the nitrile derivative 14.2 with hydroxylamine hydrochloride (18.5) in ethanol in the presence of triethylamine gave the? / -hydroxybenzamidine derivative 18.6 which was reacted with acetyl chloride (6.7) in pyridine at reflux temperature to give the derivative of 1, 2,4-oxadiazole 18.7. Deprotection of the Boc function of 18.7 under acidic conditions gave compound 18C. The synthesis of compound 19A-19D is summarized in Scheme 19. The 2'-hydroxyacetophenone 1.1a was condensed with benzyl 4-oxopiperidine-1-carboxylate (19.1) in methanol at reflux temperature in the presence of pyrrolidine to give? -Cbz-spiro [2H-1-benzopyran-2,4'-piperidine] -4 (3H) -one (19.2). The conversion of the ketone 19.2 to the enol triflate 19.3 derivative was carried out using? / -phenylbis (trifluoromethanesulfonimide) 1.4 as a triflate reagent. The conversion of enol triflate 19.3 to the corresponding boron derivative 19.4 was carried out using 4,4,5,5-tetramethyl-2- (4,4,5,5-tetramethyl-1,3,2-dioxaboroIan- 2-yl) -1,3,2-dioxaborolane 1.14 and the dichloromethane [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) adduct dichloromethane, aviated as [Pd dppfJCI ^ C ^ CIJ. Suzuki-type coupling of boronate derivative 19.4 with tert-butyl 4-bromophenylcarbamate 19.5 in dimethylether ethylene glycol in the presence of tetrakistriphenylphosphine of palladium (0), lithium chloride, and an aqueous solution of sodium carbonate gave the aniline derivative ferc-butyloxycarbonyl (Boc) protected 19.6. The acid hydrolysis of 19.6 gave the aniline derivative 19.7 which was reacted with the acyl chlorides 19.8a, 19.8b, the / sopropylsulfonyl chloride (6.5b) or the ethyl isocyanate (19.11) to give the corresponding amide derivatives 19.9, the sulfonamide derivative 19.10 or the urea derivative 19.12, respectively. Derivatives 19.9, 19.10 and 19.12 were converted to compounds 19A-19D by treatment with iodotrimethylsilane. The synthesis of compounds 20A-20R is summarized in Scheme 20. Compounds derived from the tertiary amine 20A-20R were obtained from the secondary amines of general formula 20I, by reductive amination procedures (procedures 20A or 20B) using aldehydes 20.1a-20.1d and sodium cyanoborohydride as a reducing agent or by an alkylation process (method 20C) using bromides 2.8a, 20.2ae as alkylating reagent. The synthesis of compounds 21A-21F is summarized in Scheme 21. Condensation of 1-Boc-4-piperidone 1.2 with ethyl diazoacetate (21.1) in the presence of diethyl ether boron trifluoride gave 4-ethyl 3-oxoazepan-1, 4-dicarboxylate of 1-tert-butyl in equilibrium with its enol form (21.2). Ester hydrolysis followed by decarboxylation of 21.2 under acidic conditions gave azepan-3-one (21.3), which was protected in the form of its Boc 21.4 derivative by treatment with tert-butyloxycarbonyl anhydride (4.7). The 2'-hydroxyacetophenone 1.1a was condensed with 21.4 in methanol at reflux temperature in the presence of pyrrolidine to give the racemic ketone 21.5. The conversion of 21.5 to the enol triflate 21.6 derivative was carried out using triflate reagent? / - phenylbis (trifluoromethanesulfonimide) 1.4. The Suzuki-type coupling of the enol triflate 21.6 derivative with 4 - (? /,? / - diethylaminocarbonyl) phenylboronic acid (1.6) in dimethylether ethylene glycol in the presence of tetrakistriphenylphosphine of palladium (0), lithium chloride, and an aqueous solution of Sodium carbonate gave racemic derivative 21.7, which was hydrolyzed under acidic conditions to give compound 21A (racemic mixture). The two enantiomers derived from 21.7, ie, compounds 21.7a and 21.7b, were separated by chiral HPLC. The pure enantiomers 21.7a and 21.7b were converted to compounds 21 B and 21 C, respectively, in acidic conditions. Palladium-catalyzed hydrogenation of compounds 21 B and 21 C gave compounds 21 D (diastereoisomeric mixture) and 21 E (diastereoisomeric mixture), respectively. Treatment of compound 21 A with benzyl chloroformate (21.8) in dichloromethane in the presence of triethylamine gave the Cbz-protected derivative 21.9, which was converted to sulfonyl chloride 21.10 using the complex sulfur trioxide? /,? / - dimethylformamide (4.3 ) as a sulfating agent. Condensation of 21.10 with ethylamine (3.4c) in dichloromethane in the presence of triethylamine gave the ethyl sulfonamide derivative 21.11 which was converted to compound 21 F by treatment with iodotrimethylsilane. The synthesis of compounds 22A-22E is summarized in Scheme 22. Treatment of compound 21 B (most active enantiomer) with trifluoroacetic anhydride (4.1) in tetrahydrofuran in the presence of triethylamine gave the trifluoroacetamide derivative 22.1 which was converted to the sulphonyl 22.2 using the complex sulfur trioxide / V,? - dimethylformamide (4.3) as a sulfating agent. The condensation of 22.2 with various primary amines (3.4b, 3.4c, 3.4d, 3.4g) gave the sulfonamide derivatives 22.3 which were converted to the compounds 22A-22D under basic conditions. The condensation of hydrazine hydrate (5.1) with the sulfonyl chloride derivative 22.2 gave the sulfonyl hydrazide 22.4, which was converted to sulfone 22.5 by treatment with methyl iodide (2.8c) in the presence of sodium acetate. Deprotection of the trifluoroacetamide protecting group of 22.5 under basic conditions (potassium carbonate, methanol / tetrahydrofuran / water) gave the methylsulfonyl analog (compound 22E). The synthesis of compounds 23A-23C is summarized in Scheme 23. The 2'-hydroxyacetophenone 1.1a was condensed with tert-butyl 3-oxopyrrolidin-1-carboxylate (23.1a) or tert-3-oxopiperidin-1-carboxylate. -butyl (23.1b) in methanol at reflux temperature in the presence of pyrrolidine to give the racemic ketones 23.2a (n = 0) and 23.2b (n = 1), respectively. The conversion of the ketones 23.2 to the enol triflate 23.3 derivatives was carried out using? / -phenylbis (trifluoromethanesulfonimide) 1.4 as the triflate reagent. The Suzuki-type coupling of enol triflate 23.3 derivatives with 4 - (? /,? / - diethylaminocarbonyl) phenylboronic acid 1.6 in dimethylether ethylene glycol in the presence of tetrakistriphenylphosphine of palladium (0), lithium chloride, and an aqueous solution of carbonate Sodium of the Boc 23.4 derivatives that were converted to the final products, compounds 23A and 23B (racemic mixtures) under acidic conditions. The 2'-hydroxyacetophenone 1.1a was also condensed with 1-Boc-4-nortropinone (23.5) in methanol at reflux temperature in the presence of pyrrolidine to give the ketone 23.6. The conversion of the ketone 23.6 to the enol triflate 23.7 derivative was carried out using N-phenylbis (trifluoromethanesulfonimide) 1.4 as a triflate reagent. The Suzuki type coupling of the enol triflate 23.7 derivative with 4 - (? /,? / - diethylaminocarbonyl) phenylboronic acid 1.6 in dimethylether ethylene glycol in the presence of tetrakistriphenylphosphine of palladium (0), lithium chloride, and an aqueous solution of sodium carbonate gave the Boc derivative 23.8 which was converted to the final product compound 23C under acidic conditions. The synthesis of the compounds 24A-24G is summarized in Scheme 24. The 2'-hydroxyacetophenone 1.1a was condensed with 1,4-cyclohexanedione mono-ethylene ketal (24.1) in methanol at reflux temperature in the presence of pyrrolidine to give the Ketone 24.2. The conversion of the ketone 24.2 to the enol triflate 24.3 derivative was carried out using N-phenylbisftrifluoromethanesulfonimide) 1.4 as a triflate reagent. The Suzuki-type coupling of the enol triflate derivative 24.3 with 4 - (? /,? / - diethylaminocarbonyl) phenylboronic acid 1.6 in dimethylether ethylene glycol in the presence of tetrakistriphenylphosphine of palladium (0), lithium chloride, and an aqueous solution of sodium carbonate gave the derivative 24.4 which was converted to the ketone compound 24A under acidic conditions. The reduction of the ketone compound 24A, made in tetrahydrofuran in the presence of sodium borohydride, gave the corresponding alcohol derivative compounds 24B and 24C. Treatment of the ketone compound 24A with propylamine (3.4d) or dimethylamine (3.4j) under reductive amination conditions using sodium cyanoborohydride as a reducing agent, gave the amine compounds 24D-24G. The synthesis of compound 25A is summarized in Scheme 25. The 2'-hydroxyacetophenone 1.1a was also condensed with tetrahydropyran-4-one (25.1) in methanol at reflux temperature in the presence of pyrrolidine to give the ketone 25.2. The conversion of the ketone 25.2 to the enol triflate 25.3 derivative was carried out using N-phenylbis (trifluoromethanesulfonimide) 1.4 as a triflate reagent. The Suzuki type coupling of the enol triflate 25.3 derivative with 4 - (? /,? / - diethylaminocarbonyl) phenylboronic acid 1.6 in dimethylether ethylene glycol in the presence of tetrakistriphenylphosphine of palladium (0), lithium chloride, and an aqueous solution of sodium carbonate gave compound 25A. The synthesis of compounds 26A-26B is summarized in Scheme 26. Palladium-catalyzed Negishi-type coupling of 1.5a with zinc 4-cyanobenzylbromide (26.1) was carried out in tetrahydrofuran using palladium (0) tetrakistriphenylphosphine as catalyst , giving the nitrile 26.2. Acid hydrolysis of nitrile 26.2 gave the carboxylic acid derivatives 26.3a and 26.3b (compounds 26.3a and 26.3b were separated by column chromatography).; however, the next step was carried out using mixture 26.3a / 26.3b). Treatment of mixture 26.3a / 26.3b with methanol in the presence of hydrochloric acid gave the piperidine esters 26.4a / 26.4b which were converted to the corresponding Boc derivatives 26.5a / 26.5b by treatment with fer-butyloxycarbonyl anhydride ( 4.7). Hydrolysis of the esters 26.5a / 26.5b under basic conditions gave the carboxylic acid derivatives 26.6a / 26.6b. The coupling of the carboxylic acid derivatives 26.6a / 26.6b with diethylamine (1.12) using O-benzotriazole-1-yl-α /, V, / V ', / /' - tetramethyluronium tetrafluoroborate (TBTU) as a coupling agent gave the dimethylaminocarbonyl derivatives 26.7a / 26.7b. Removal of the Boc protecting group from 26.7a / 26.7b in dichloromethane at room temperature in the presence of hydrochloric acid (anhydrous solution in dioxane) gave compounds 26A and 26.8 which were separated by column chromatography. Palladium-catalyzed hydrogenation of compound 26.8 gave compound 26B. The synthesis of compounds 27A-27W is summarized in Scheme 27. The saturated derivatives (compounds 27A, 27D, 27G, 27H, 27K, 27N, and 27W, in the form of their racemic mixtures) were obtained by hydrogenation of the unsaturated analogs (compounds 1A, 1D, 2C, 1N, 10, 1S, and 1E), respectively, in methanol in the presence of palladium, 10% by weight (dry basis) on activated carbon (process 27A) or palladium hydroxide, 20% in weight of Pd (dry basis) on carbon (Pearlman catalyst (method 27B)). Hydrogenation of 11.6a in methanol in the presence of palladium hydroxide, 20% by weight of Pd (dry base) on carbon (Pearlman's catalyst) gave the saturated derivative 27.1. The acid hydrolysis of 27.1 gave compound 27T. Hydrolysis of 2.7a in methanol in the presence of palladium, 10% by weight (dry base) on activated carbon, gave the saturated derivative 27.6. The acid hydrolysis of 27.6 gave compound 27Q. Chiral separation of the enantiomers derived from 27.1 gave compounds 27.4 and 27.5. The enantiomers 27.4 and 27.5 were converted to compounds 27U and 27V, respectively under acidic conditions. The chiral separation of the enantiomers derived from each of the racemic compounds (compounds 27A, 27 D, 27G, 27H, 27K, 27N, 27Q and 27W) gave compounds 27B, 27E, 27I, 27L, 270, 27R (pure enantiomer ) and compounds 27C, 27F, 27J, 27M, 27P, 27S (pure enantiomer). Condensation of compound 27B with (1S) - (+) - 10 -sulfonyl camphorchloride (27.2) (used as a chiral resolving agent) in dichloromethane in the presence of triethylamine gave the chiral sulfonamide derivative 27.3. The absolute configuration of 27.3 was determined by X-ray crystallography, thus establishing the absolute configuration of compound 27B, and by deduction, that of its enantiomer, compound 29C. The synthesis of the compounds 28A-28E is summarized in Scheme 28. The condensation of benzyl 4-oxopiperidin-1-carboxylate (19.1) with ethyl cyanoacetate (28.1) in the presence of acetic acid and ammonium acetate gave the unsaturated ester 28.2 . Compound 28.2 was subjected to conjugate addition by reaction with organo-cuprate reagents derived from benzyl- or methoxybenzyl magnesium chloride (28.3a and 28.3b, respectively) and copper cyanide (I) to give the cyanoesters 28.4. Treatment of the conjugate addition product 28.4a (Rv = H) with concentrated sulfuric acid at 90 ° C gave the amino ketone 28.5. Treatment of 28.5 with benzyl chloroformate (21.8) in dichloromethane in the presence of triethylamine gave the corresponding Cbz-protected derivative 28.6a (Rv = H). Decarboxylation of 28.4b (Rv = OCH3) by treatment with sodium chloride in dimethylsulfoxide containing a small amoof water at 160 ° C gave the nitrile 28.9. Hydrolysis of the nitrile function from 28.9 to the methyl ester group by treatment with methanol in the presence of sulfuric acid gave the corresponding piperidine derivative ( Cbz protective group break of 28.9 occurred during the course of hydrolysis). Treatment of the piperidine derivative with benzyl chloroformate gave compound 28.10. The ester 28.10 was hydrolyzed with lithium hydroxide to give the carboxylic acid 28.11. Treatment of the acid 28.11 with oxalyl chloride followed by the reaction of the resulting acyl chloride with aluminum chloride gave the corresponding spiro piperidine derivative which was subsequently protected in the form of its CBz derivative 28.6b (Rv = OCH3) by treatment with benzyl chloroformate. The conversion of the ketones 28.6 to the enol triflate 28.7 derivatives was carried out using N-phenylbis (trifluoromethanesulfonimide) 1.4 as a triflate reagent. The Suzuki type coupling of the enol triflate 28.7 derivatives with 4- (N, N-diethylaminocarbonyl) phenylboronic 1.6 in dimethylether ethylene glycol in the presence of tetrakistriphenylphosphine of palladium (0), lithium chloride, and an aqueous solution of sodium carbonate gave the derivatives 28.8 which were converted to compounds 28A and 28B by treatment with iodotrimethylsilane. Compounds 28C and 28D (racemic mixtures) were obtained by hydrogenation of the unsaturated derivatives 28.8 in methanol in the presence of palladium, 10% by weight (dry basis) on activated carbon. The Suzuki-type coupling of the enol triflate derivative 28.7a (Rv = H) with 2 - (/ V,? / - diethylaminocarbonyl) -5- (4,4,5,5-tetramethyl-1,3I2-dioxoborolan-2 -il) pyridine 1.7 in dimethylether ethylene glycol in the presence of tetrakistriphenylphosphine of palladium (0), lithium chloride, and an aqueous solution of sodium carbonate gave the derivative 28.12 which was converted to compound 28E by treatment with iodotrimethylsilane. The synthesis of compounds 29A-29D is summarized in Scheme 29. The Negishí coupling of enol triflate 28.7a with 4- (ethoxycarbonyl) phenylcinc iodide (29.1) in tetrahydrofuran in the presence of palladium teirachiriphenylphosphine (0) gave the ester 29.2, which was hydrolyzed with lithium hydroxide to give the carboxylic acid 29.3. Coupling of the carboxylic acid 29.3 with / sopropylamine (3.4h) or 1-eti-propylamine (29.4) using 2-chloro-1-methylpyridinium iodide (Mukaiyama acylating reagent) as a coupling agent gave the secondary aminocarbonyl derivatives 29.5, which were converted to compounds 29A and 29B by treatment with iodotrimethylsilane. The Curtius rearrangement of the carboxylic acid 29.3 by reaction with diphenylphosphoryl azide (29.6) in the presence of tert-butyl alcohol gave the protected aniline derivative ferc-butyloxycarbonyl (Boc) 29.7. The acid hydrolysis of 29.7 gave the aniline derivative 29.8 which was reacted with propionyl chloride 29.9 or sulfonyl methanochloride (7.4) to give the corresponding amide derivative 29.10 or the sulfonamide derivative 29.11, respectively. Derivatives 29.10 and 29.11 were converted to compounds 29C and 29D, respectively, by treatment with iodotrimethylsilane. The synthesis of compound 30A is summarized in Scheme 30. Wittig-type condensation of 1-benzoyl-4-piperidone (30.1) with methyl (triphenylphosphoranylidene) acetate (30.2) in toluene gave the unsaturated ester 30.3. Compound 30.3 was subjected to the conjugate addition by reaction with benzenethiol (30.4) to give thioether 30.5. Treatment of conjugate addition product 30.5 with concentrated sulfuric acid gave the cyclized product 30.6, which was converted to sulfone 30.7 by oxidation using a solution of hydrogen peroxide in glacial acetic acid. Acid hydrolysis of 30.7 gave the amine 30.8, which was treated with tert-butyloxycarbonyl anhydride (4.7) to give the Boc-protected derivative 30.9. The conversion of the ketone 30.9 to the enol triflate 30.10 derivative was carried out using? / -phenylbis (trifluoromethanesulfonimide) 1.4 as a triflate reagent. The Suzuki-type coupling of the enol triflate 30.10 derivative with 4 - (/ V,? / - diethylaminocarbonyl) phenylboronic acid 1.6 in dimethylether ethylene glycol in the presence of tetrakistriphenylphosphine of palladium (0), lithium chloride, and an aqueous solution of sodium carbonate gave derivative 30.11 which was converted to compound 30A under acidic conditions. The synthesis of the compounds 31A-31AA is summarized in Scheme 31 The Suzuki-type coupling of the enol triflate derivative 1.5a with the commercially available boronic acid derivatives 13.1, 14.1, 16.1 or 31.1a-31.1u in dimethylether ethylene glycol in the presence of tetrakistriphenylphosphine of palladium (0), lithium chloride, and an aqueous solution of sodium carbonate gave compounds 13.2, 14.2, 16.2 and 31.2, respectively. Compounds 13.2, 14.2, 16.2 and 31.2 were converted to the final products, compounds 31A-31X, under acidic conditions (procedure 1E: anhydrous HCl), diethyl ether, room temperature or 1F method: pure trifluoroacetic acid (with optional dichloromethane), room temperature or process 31A: anhydrous HCl, methanol, dioxane, reflux). Treatment of nitrile 16.2 with lithium aluminum hydride in tetrahydrofuran gave the compound diamine 31 Y, which was reacted with acetyl chloride (6.7) or sulfonyl methanochloride (7.4) to give the corresponding amide derivative compounds 31Z or the compound sulfonamide derivative 31AA, respectively. The synthesis of compounds 32A-32Z is summarized in Scheme 32. The conversion of enol triflate 1.5a to the corresponding boron derivative 32.1 was carried out using 4,4,5,5-tetramethyl-2- (4.4, 5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1,3,2-dioxaborolane 1.14 and the dichloromethane dichloro [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) adduct, abbreviated as [PdídppfJCI ^ CH ^ y. The Suzuki-type coupling of boronate derivative 32.1 with various derivatives of aryl bromide 32.2 under different conditions [1C procedure: dimethylether ethylene glycol, palladium tetrakistriphenophosphine (0), lithium chloride, an aqueous solution of sodium carbonate; 1D method: dimethylether ethylene glycol, palladium, 10% by weight (dry basis) on activated carbon, lithium chloride, an aqueous solution of sodium carbonate; Process 12A: tetrakistriphenylphosphine of palladium (0), potassium bromide, potassium phosphate, dioxane] gave derivatives 32.3, which were converted to compounds 32A-32I or 32K-32Z under acidic conditions. The tert-butyl sulfonamide derivative 32.3b was converted to the sulfonamide compound 32J by treatment with trifluoroacetic acid. The derivatives 32.2 used in the Suzuki coupling stage were prepared in the following manner. Coupling of carboxylic acid 32.4 with diethylamine (1.12) using 2-chloro-1-methylpyridinium iodide (Mukaiyama acylating reagent) as a coupling agent gave 2- (4-bromophenyl) -? /, / V-diethylacetamide (32.2a) . The sulfone derivatives 32.2j-32.2p were obtained in two steps from 4-bromobenzenethiol (32.7). Alkylation of 32.7 with the alkyl bromide derivatives 20.2, 2.8 or 32.8 in acetonitrile in the presence of triethylamine (process 32A) or in A,? / - dimethylformamide in the presence of sodium hydride (method 32B) gave the thioether derivatives 32.9, which were oxidized to the sulfone derivatives 32.2j-32.2p in glacial acetic acid in the presence of an aqueous solution of hydrogen peroxide. The coupling of 4-bromobenzene-1-sulfonyl chloride (32.5) with various amines (3.4, 1.12, 13.4 or 32.6) in tetrahydrofuran in the presence of triethylamine gave the sulfonamides 32.2b-32.2i. Acylation of α / - methyl-4-bromoaniline (32.10) with various acyl chloride derivatives (19.8, 32.11 or 6.7) in dichloromethane in the presence of triethylamine gave the amides 32.2q-32.2u, 32.2x, 32.2y. The aryl bromides 32.2v and 32.2w are commercially available. The synthesis of compounds 33A-33L is summarized in Scheme 33. The Suzuki-type coupling of boronate derivative 32.1 with various derivatives of aryl bromide 33.1 under different conditions [process 1C: dimethylether ethylene glycol, tetrakistriphenylphosphine palladium (0), chloride lithium, an aqueous solution of sodium carbonate; 1 D procedure: ethylene glycol dimethyl ether, palladium, 10% by weight (dry basis) on activated carbon, lithium chloride, an aqueous solution of sodium carbonate; procedure 33A: dimethylether ethylene glycol, dichloromethane [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) dichloromethane adduct, abbreviated as [Pd (dppf) CI2 »CH2Cl2], lithium chloride, potassium phosphate] gave the derivatives 33.2, which were converted to compounds 33A-33K under acidic conditions. Derivatives 33.1 used in the Suzuki coupling stage were obtained from commercial sources (33.1 a-e) or prepared in the following manner. The coupling of 5-bromopyridine-3-carboxylic acid (33.3) or 6-bromopyridine-2-carboxylic acid (33.4) with diethylamine (1.12) using O-benzotriazol-1-yl -? / Tetrafluoroborate,? /,? / ', / -tetramethyluronium (TBTU) as a coupling agent gave the diethylaminocarbonyl derivatives 33.1f and 33.1g, respectively. Treatment of 2,5-dibromopyridine (1.9) with n-butyllithium gave the corresponding lithiated derivative, which was reacted with carbon dioxide to give 5-bromopyridine-2-carboxylic acid 1.10. The carboxylic acid 1.10 was also obtained by acid hydrolysis of commercially available 5-bromopyridine-2-carbonitrile (33.1 e). Treatment of the carboxylic acid derivative 1.10 with oxalyl chloride gave the acyl chloride 1.11, which was reacted with dimethylamine (3.4j), ethylamine (3.4c) or methylamine (3.4b) to give the corresponding aminocarbonyl derivatives 33.1 h , 33.1 i and 33.1 j, respectively. Treatment of 5-bromo-2-iodopyrimidine (33.5) commercially available with n-butyllithium gave the corresponding lithiated derivative, which was reacted with carbon dioxide to give 5-bromopyrimidine-2-carboxylic acid (33.6). The treatment of the 33.6 carboxylic acid derivative with oxalyl chloride gave the acyl chloride 33.7, which was reacted with diethylamine 1.12 to give 5-bromo-2 - (? /,? / - diethylaminoarbonyl) -pyrimidine 33.1 k. Hydrolysis of the nitrile derivative 33.2a under acidic conditions gave the carboxylic acid derivative 33E and compound 33L. Compound 33E and compound 33L were easily separated by column chromatography. The synthesis of compounds 34A-34P is summarized in Scheme 34. The Suzuki-type coupling of boronate derivative 32.1 with various derivatives of aryl bromide 34.1 in dimethylether ethylene glycol in the presence of palladium (0) tetrakistriphenylphosphine, lithium chloride, and an aqueous solution of sodium carbonate gave the compounds 34.2 which were converted to the final products, compounds 34A-34P under acidic conditions. The derivatives 34.1 used in the Suzuki coupling stage were prepared in the following manner. The coupling of 6-bromopyridine-3-carboxylic acid (34.3), 5-bromothiophen-2-carboxylic acid (34.4), 4-bromothiophen-2-carboxylic acid (34.7) or 5-bromofuran-2-carboxylic acid (34.6) with diethylamine (1.12) or diisopropylamine (3.4o) using O-benzotriazoi-1-yl-? /, tetrahydrofoborate, F,? / - tetramethyluronium (TBTU) as the coupling agent gave the diethylaminocarbonyl derivatives 34.1 ad, fi . Coupling of 5-bromothiophen-2-sulfonyl chloride (34.5) with diethylamine (1.12) in acetonitrile in the presence of triethylamine gave sulfonamide 34.1 e. Coupling of the commercially available carboxylic acid derivatives 34.8a-34.8f and 34.9 with diethylamine (1.12) using O-benzotriazol-1-yl-α /, tetrahydrofoborate, / V,? / ',? / - tetramethiuronium (TBTU) as coupling agent gave the corresponding diethylaminocarbonyl derivatives 34.1j-34.1 and 34.1 p. The synthesis of compounds 35A and 35B is summarized in Scheme 35. Iodination of 3-hydroxybenzoic acid (35.1) gave 3-hydroxy-4-iodobenzoic acid (35.2), which was converted to methyl ester 35.3 under esterification conditions usual. Alkylation of the phenolic derivative 35.3 with methyl iodide (2.8c) in acetone in the presence of potassium carbonate gave methyl ether 35.4, which was converted to carboxylic acid 35.5 in the presence of lithium hydroxide. Coupling of carboxylic acid derivatives 35.5 with diethylamine (1.12) using O-benzotrazole-1-yl-W,? /,? / ',? / - tetramethyluronium tetrafluoroborate (TBTU) as the coupling agent gave the diethylaminocarbonyl derivative corresponding 35.6. Demethylation of 35.6 using boron tribromide gave the phenolic derivative 35.7 which was converted to the methyloxymethyl ether derivative (MOM) 35.8 using chlorine (methoxy) methane 11.3. Suzuki-type coupling of boronate derivative 32.1 with 35.6 in dimethylether ethylene glycol in the presence of tetrakistriphenylphosphine of palladium (0), lithium chloride, and an aqueous solution of sodium carbonate gave compound 35.9 which was converted to the final product compound 35A under acidic conditions . The Suzuki-type coupling of boronate derivative 32.1 with 35.8 in dimethylether ethylene glycol in the presence of palladium, 10% by weight (dry base) on activated carbon, lithium chloride, and an aqueous sodium carbonate solution gave compound 35.10 which was converted to Final product compound 35B under acidic conditions. The synthesis of compounds 36A and 36B is summarized in Scheme 36. The coupling of 4-bromo-2-hydroxybenzoic acid (36.3) [obtained from 4-amino-2-hydroxybenzoic acid (36.1) under Sandmeyer conditions] with diethylamine (1.12) using O- (7-azabenzotriazole-1-yl) - / V,? /, / V ',? / - tetramethyluronium (HATU) as the coupling agent gave the corresponding diethylaminocarbonyl derivative 36.4 . Suzuki-type coupling of boronate derivative 32.1 with 36.4 in ethylene glycol dimethyl ether in the presence of palladium tetrakistriphenylphosphine (0), lithium chloride, and an aqueous solution of sodium carbonate gave compound 36.5 which was converted to the final product (compound 36A) in acid conditions. Compound 36B was obtained in 7 steps from 2- (3-methoxyphenyl) ethanamine (36.6). Coupling of 36.6 with ethyl chloroformate (36.7) gave the ethyl carbamate derivative 36.8 which was cyclized to 3., 4-dihydro-6-methoxyisoquinolin-1- (2H) -one (36.9) in the presence of polyphosphoric acid. Alkylation of 36.9 with ethyl iodide (36.10) in tetrahydrofuran in the presence of sodium hydride gave methyl ether 36.11, which was converted to phenolic derivative 36.12 by treatment with boron tribromide. Condensation of 36.12 with trifluoromethanesulfonic anhydride (36.13) in dichloromethane in the presence of pyridine gave the triflate derivative 36.14. The Suzuki-type coupling of boronate derivative 32.1 with 36.14 in? ,? / - dimethylformamide in the presence of the dichloro [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) dichloromethane adduct, abbreviated as [PdídppfjCI ^ CH ^ y, and potassium acetate gave compound 36.15 which was converted to the product final (compound 36B) under acidic conditions. The synthesis of compounds 37A-37B is summarized in Scheme 37. The 2'-hydroxyacetophenone 1.1a was condensed with 1-benzyl-3-methylpiperidin-4-one (37.1) (racemic mixture) in methanol at reflux temperature in presence of pyrrolidine to give the racemic ketones 37.2 and 37.3. The diastereomers 37.2 and 37.3 were separated by column chromatography. Palladium-catalyzed hydrogenation of 37.2 gave the piperidine derivative 37.4, which was converted to 37.5 by treatment with tert-butyloxycarbonyl anhydride (4.7). The conversion of the ketone 37.5 to the enol triflate derivative 37.6 was carried out using? / -phenylbis (trifluoromethanesulfonamide) 1.4 as triflate reagent. The Suzuki-type coupling of the enol triflate derivative 37.6 with 4- (N, N-diethylaminocarbonyl) phenylboronic acid 1.6 in dimethylether ethylene glycol in the presence of tetrakistriphenylphosphine of palladium (0), lithium chloride, and an aqueous solution of sodium carbonate gave the Boc derivative 37.7, which was converted to the final product compound 37A (racemic mixture) under acidic conditions. Similarly, the palladium-catalyzed hydrogenation of 37.3 gave the piperidine derivative 37.8, which was converted to 37.9 by treatment with tert-butyloxycarbonyl anhydride (4.7). The conversion of the ketone 37.9 to the enol triflate derivative 37.10 was carried out using N-phenylbis (trifluoromethanesulfonimide) 1.4 as a triflate reagent. Suzuki-type coupling of the enol triflate derivative 37.10 with 4- (N, N-diethylaminocarbonyl) phenylboronic acid 1.6 in dimethylether ethylene glycol in the presence of tetrakistriphenylphosphine of palladium (0), lithium chloride, and an aqueous solution of sodium carbonate gave the Boc derivative 37.11, which was converted to the final product compound 37B (racemic mixture) under acidic conditions.

J CttXOH., CH £ l0H, I = CHBG 3 = CH, H List of amines used in Step 3.5 List of organoboron derivatives used in Stage 3.8 S y__J? BSHJ2 < ? BßHi. P M- Uta Us U.

Scheme 6: Stage 6.6 CH3C0C1 (6.T), pyridine, DCE Scheme 8: K = CH, N Scheme 9: 11 D Stage 11.7 What are the steps in Step 15.1 BrCy * BrtCEijljCDyiife BitCBysCQj ?. 15.1 to 1511? 15.lt 1514? Le Scheme 20: Fó 2ÜA-R List of alkyl aldehydes and bromides used in Step 20.1 HCHO HO ^ XCHO | ^ CH0 20.1a 20.1b 8-lc 2aid Ru = H, OH Rv = H, OH, CONH2, CONHCH3, C0NHC H5 S02NH2 ? d? ^ Scheme 25 Scheme 26: 132. 142.M2o 31.2 Commercially available boronic acid derivatives used in Step 31.2: Description and preparation of the aryl bromides (32.2) used in Step 322: Scheme 33: Stage 33.2 R'Br commercially available used in Step 33.2: Preparation of the RzBr used in Step 33.2: ? BH_ T »H_ 3 * 3.? Scheme 34: Preparation of the R'Br used in Stage 34.2 BG B R, Eí¡H? P..l!) B B, -VT1"^ • IDI? -. JS" '«O O Stage 34.9 OO ^ Br B * B * l i-f 14 lj-- EtNHUl!) ^ ¡¡^ At¡E «; ipiir, (f ^ = Ü C ^. D OH BG Stage 34.10 ^ X * 14 J 1 Jp 3510 37A and 37B are diastereomeric with respect to the other, but each is a racemic mixture of its two possible enantiomers. Their absolute stereochemistry has not been established conclusively.

INVENTION 21 B and 21 C are enantiomeric with respect to the other, but their absolute stereochemistry has not been established conclusively. 21 D and 21 E are diastereomeric with respect to the other, but their absolute stereochemistry has not been established conclusively. 24B and 24C are geometric isomers with respect to each other (in which the hydroxyl is either equatorial or axial), but the conformation of each has not been established conclusively. 24D and 24E are geometric isomers with respect to each other (in which the hydroxyl is either equatorial or axial), but the conformation of each has not been established conclusively. 24F and 24G are geometric isomers with respect to each other (in which the hydroxyl is either equatorial or axial), but the conformation of each has not been established conclusively. 27B and 27C are enantiomeric with respect to each other, and their absolute stereochemistries have been established conclusively using X-ray crystallography. 27E and 27F are enantiomeric with respect to each other, but their absolute stereochemistry has not been conclusively established. 271 and 27 J are enantiomeric with respect to each other, but their absolute stereochemistry has not been established conclusively. 27L and 27M are enantiomeric with respect to the other, but their absolute stereochemistry has not been established conclusively. 270 and 27P are enantiomeric with respect to each other, but their absolute stereochemistry has not been established conclusively. 27R and 27S are enantiomeric with respect to the other, but their absolute stereochemistry has not been established conclusively. 27U and 27V are enantiomeric with respect to the other, but their absolute stereochemistry has not been established conclusively. 37A and 37B are diastereomeric with respect to the other, but each is a racemic mixture of its two possible enantiomers. Their absolute stereochemistry has not been established conclusively. Biological procedures In vitro assays The potencies of the compounds listed in Table 1 were determined by testing the ability of a range of concentrations of each compound to inhibit the binding of the non-selective opioid antagonist, [3 H] diprenorphine, to the opiate receptors μ,? .and d cloned humans, expressed in different cell lines. Cl50 values were obtained by non-linear analysis of the data using GraphPad Prism version 3.00 for Windows (GraphPad Software, San Diego). The values of K, were obtained by the Cheng-Prusoff corrections of the Cl 50 values. Binding to the receptor The receptor binding procedure (DeHaven and DeHaven-Hudkins, 1998) was a modification of the procedure of Raynor et al. (1994). After dilution in buffer A and homogenization as above, the membrane proteins (10-80 μg) in 250 μL were added to mixtures containing the test compound and [3 H] diprenorphine (0.5 to 1.0 nM). , 40,000 to 50,000 dpm) in 250 μL of buffer A in 96 deep well polystyrene (Beckman) titration plates. After incubation at room temperature for one hour, the samples were filtered through GF / B filters previously soaked in a solution of 0.5% polyethyleneimine (w / v) and 0.1% bovine serum albumin (w / o). v) in water. The filters were rinsed 4 times with 1 mL of 50 mM cold Tris HCl, pH 7.8 and the radioactivity remaining on the filters was determined by scintillation spectroscopy. The non-specific binding was determined by the minimum values of the titration curves and confirmed by wells with a different assay containing 10 μM naloxone. The values of K i were determined by the Cheng-Prusoff corrections of the Cl 50 values derived from the linear regression adjustments of 12-point titration curves using GraphPad Prism® version 3.00 for Windows (GraphPad Software, San Diego, CA ). To determine the dissociation equilibrium constant for the inhibitors (K), the bound radioligand (cpm) was measured in the presence of various concentrations of the test compounds. The concentration to give the semi-maximal inhibition (CE50) of radioligand binding was determined from a better fit of the non-linear regression to the following equation, r Y = where Y is the amount of radioligand bound to each concentration of the test compound, Bottom is the calculated amount of radioligand bound in the presence of an infinite concentration of the test compound, Top is the calculated amount of radioligand bound in the absence of the test compound, X is the logarithm of the concentration of the test compound , and LogCE50 is the log of the concentration of the test compound in which the amount of radioligand bound is halfway between Top and Bottom. The adjustment of the non-linear regression was performed using the program Prism® (GraphPad Software, San Diego, CA). The values of Kj were then determined from the EC50 values by the following equation, where [ligand] is the concentration of radioligand and Kd is the equilibrium constant of dissociation for the radioligand. [35 S] GTPDS-mediated receptor binding The potency and efficacy of the compounds in each of the receptors were assessed by modifications of the procedures of Selley et al., 1997 and Traynor and Nahorski, 1995 using receptor-mediated receptor binding. [35S] GTP? S in the same membrane preparations used to measure receptor binding. The assays were carried out in 96-well FlashPlates® (Perkin? Lmer Life Sciences, Inc., Boston, MA). Membranes prepared from CHO cells expressing the appropriate receptor (50-100 μg protein) were added to assay mixtures containing agonist with or without antagonists, [35 S] GTPDS 100 pM (ca. 100,000 dpm), GDP 3.0 μM, 75 mM NaCl, 15 mM MgCl 2, ethylene glycol-bis-f-aminoethyl ether) -? /,? / ,? '? / - 1.0 mM tetraacetic, 1.1 mM dithiothreitol, 10 μg / mL leupeptin, 10 μg / mL pepstatin A, 200 μg / mL bacitracin, and 0.5 μg / mL aprotinin in Tris buffer 50 mM -HCl, pH 7.8. After incubation at room temperature for one hour, the plates were sealed, centrifuged at 800 xg in a swinging bucket rotor for 5 min and the bound radioactivity was determined with a scintillation counter for TopCount microplates (Packard Instrument Co., Merlden, CT). The EC50 values for the agonists were determined from non-linear regression adjustments of titration curves of 8 or 12 points to the 4-parameter equation for a sigmoidal dose-response with a slope factor of 1.0 using GraphPad Prism® version 3.00 for Windows (GraphPad Software, San Diego, CA). The potencies of the compounds were determined by testing the ability of a range of concentrations of each compound to inhibit the binding of the non-selective opioid antagonist, [3 H] diprenorphine, to the μ opiate receptors. j? and d cloned humans, expressed in different cell lines. All compounds tested (compounds included in Table 1) bind with an affinity to the cloned human opiate receptor d less than 2 μM (K i values). These compounds present a high selectivity per dl? and i / μ at least 10 times. The potencies of the agonists were assessed for their abilities for [35 S] GTP? S-stimulated binding to membranes containing the cloned human opiate receptors. All the compounds listed in Table 1 were agonists at the opioid receptor < * > . As an example, 1A (Table 1) binds to opiate receptors delta, mu, and kappa with an affinity (expressed as the value of K) of 0.93 nM, 980 nM and > 1000 nM, respectively). In addition, 1A exhibited potent in vitro agonist activity (EC50 = 9.1 nM). In vivo assays Hyperalgesia induced by Freund's complete adjuvant (FCA) Rats were injected intraplantarly with ACF and 24h later treated with test compounds administered orally. Paw pressure thresholds (UPP) were evaluated 30, 60, 120, and 240 minutes after treatment with the drug. 1A significantly increased the UPP by 170-180% in the inflamed paw 1-2h after oral administration (ED50 = 2.5 mg / kg p.o.). 1A produced a similar increase in UPP in the non-inflamed paw at 2 o'clock, a change that is generally associated with mid-effects within the central nervous system. Acetic acid-induced seizures Male ICR mice weighing 20-25g were injected s.c. with the vehicle or with the test compound 15 min before being injected intraperitoneally with 0.6% acetic acid. At 5 minutes after treatment with acetic acid, the number of convulsions was counted for 10 minutes. The dose response curves are expressed as the percentage of inhibition of seizures induced by acetic acid, when compared to the average number of seizures observed in mice treated with the vehicle. The percentage of average inhibition (% l) of acetic acid-induced seizures for mice treated with the drug is calculated according to the following formula:% l = (Average vehicle response - Average individual response) x 100 (Average vehicle response) The average individual response is the average number of seizures in mice treated with the test compound. The response to the mean vehicle is the average number of seizures in mice treated with the vehicle. 1 A produces a 69% inhibition of convulsions Induced by acetic acid at 30 mg / kg (s.c.) Castor oil-induced diarrhea The mice were fasted overnight with water ad libitum. The mice were weighed, 0.6 mL of castor oil was orally administered and placed in individual cubicles (11 cm x 10 cm) covered with a sheet of pre-weighed absorbent paper. Thirty min after receiving the castor oil, the mice were injected s.c. with the test compound. 75 min after dosing with the castor oil, the mice and the absorbent paper were reweighed and the number of mice with diarrhea (defined as a wet and reportable deposition) was determined. The percentage of inhibition by the test compounds in the diarrhea test induced by castor oil was determined by the following formula: 1 - (response to the agonist) x 100 (response to the vehicle) 1A reduced the incidence of diarrhea in a dependent manner of time: SD50 (sc) = 8.7 mg / kg. Forced swimming test Male Sprague-Dawley rats (approximately 200g) were placed in a water tank at room temperature during a 15-minute swim test. Every 5 seconds during the first 5 minutes of the swim test, the rats were classified as motionless (floating with the movements necessary to keep the head above the water), swimming (movement through the tank), or climbing (trying to actively climb out of the water tank, with movements of the front legs in ascending direction). The percentage of time the rats spent in each of these phases was calculated. 24 h after the swimming test approximately, the rats were treated with the vehicle or with the test compound and placed in the tank to swim for 5 min. As in the case of the swimming test, the rats were classified as motionless, swimming, or climbing during the test swim and the percentage of time spent in each of these phases was calculated. The data were analyzed using the one-way ANOVA with post-hoc analysis to compare the behavioral response after vehicle treatment with the behavioral response after drug treatment for each of the three behavioral responses. The level of importance was adjusted to p <; 0.05. Data for 1 A (presented as a percentage change ± SEM, in relation to the rats treated with the vehicle) Significantly different values (p <0.05) to the rats treated with the vehicle Experimental section Introduction Materials: All the chemicals were of reagent quality and were used without further purification. Analytical: Thin layer chromatography (TLC) was performed on plates coated with flexible silica gel (250 microns) from Alltech and visualized by UV irradiation at 254 and iodine. Flash chromatography was carried out using the ISCO CombiFlash with RediSep silica gel cartridges (4 g, 12 g, 40 g, 120 g). Flash chromatography was also carried out with silica gel (network 200-400, 60Á, Aldrich). The chromatographic elution solvent systems are presented in the form of volume: volume ratios. All the 1 H NMR spectra were obtained at room temperature on a Bruker-400 MHz spectrometer. They are presented in ppm on the scale d, from the TMS. The LC-MS data were obtained using a Thermo-Finnigan Surveyor HPLC and a Thermo-Finnigan AQA MS using positive or negative electrospray ionization. Program (positive) Solvent A: 10 mM ammonium acetate, pH 4.5, 1% acetonitrile; solvent B: acetonitrile; column: Michrom Bioresources Magic C18 Macro Bullet, detector: PDA? = 220-300 nm. Gradient: 96% A-100% B in 3.2 minutes, maintain 100% B for 0.4 minutes. Program (negative) Solvent A: 1 mM ammonium acetate, pH 4.5, 1% acetonitrile; solvent B: acetonitrile; column: Michrom Bioresources Magic C18 Macro Bullet, detector: PDA? = 220-300 nm. Gradient: 96% A-100% B in 3.2 minutes, maintain 100% B for 0.4 minutes. EXAMPLE 1 A Preparation of 1.3a: Procedure 1A: Pyrrolidine (6.12 mL, 73.38 mmol, 2.0 eq) was added at room temperature to 1.2 (7.31 g, 36.69 mmol, 1.0). eq) and 1.1a (5.00 g, 36.69 mmol, 1.0 eq). The solution was stirred overnight at room temperature and then concentrated under reduced pressure. Diethyl ether (500 mL) was added. The organic mixture was washed with an aqueous solution of 1N hydrochloric acid, an aqueous solution of 1 N sodium hydroxide, brine and dried over sodium sulfate. Hexane (300 mL) was added to the mixture. The resulting precipitate was collected by filtration, washed with hexane and used for the next step without further purification. Yield: 68% Procedure 1B: Pyrrolidine (42 mL, 73.38, 2.0 eq) was added dropwise at room temperature to a solution of 1.2 (49.8 g, 0.249 mol, 1.0 eq) and 1.1a (34 g, 0.184 mol, 1.0 eq) in anhydrous methanol (400 mL). The solution was heated to reflux temperature overnight and then concentrated under reduced pressure. Diethyl ether (500 mL) was added. The organic mixture was washed with an aqueous solution of 1N hydrochloric acid, an aqueous solution of 1N sodium hydroxide, brine and dried over sodium sulfate. Hexane (300 mL) was added to the mixture. The resulting precipitate was collected by filtration, washed with hexane, and used for the next step without further purification. Yield: 72% 1 H NMR (400MHz, CDCl 3) d 7.86 (d, 1H), 7.50 (t, 1H), 7.00 (m, 2H), 3.87 (m, 2H), 3, 22 (m, 2H), 2.72 (s, 2H), 2.05 (d, 2H), 1.61 (m, 2H), 1.46 (s, 9H) Analysis of the mass spectrum m / z = 318.0 (M + H) + Preparation of 1.5a: To a solution of 1.3a (25 g, 0.078 mol, 1.0 eq) in tetrahydrofuran (250 mL) at -78 ° C under nitrogen was added dropwise to drop a solution of 1.0M lithium bis (trimethylsilyl) amide in tetrahydrofuran (94.5 mL, 0.095 mol, 1.2 eq). The mixture was stirred for 1 h at -78 ° C. A solution of 1.4 (33.8 g, 0.095 mol, 1.2 eq) in tetrahydrofuran (150 mL) was added dropwise. The mixture was heated slowly to room temperature and stirring was continued for 12 h more. The mixture was then poured into ice water and the two phases separated. The organic phase was washed with an aqueous solution of 1 N hydrochloric acid, an aqueous solution of 1N sodium hydroxide, brine and dried over sodium sulfate. The crude product was purified by column chromatography (eluent: mixtures of hexane / ethyl acetate of increasing polarity). Performance: 70% 1H NMR (400MHz, DMSO d6) d 7.45-7.20 (m, 2H), 7.00 (m, 2H), 6.15 (s, 1H), 3.70 (m, 2H), 3.20 (m , 2H), 1.90 (m, 2H), 1.75 (m, 2H), 1.40 (s, 9H) Analysis of the mass spectrum m / z = 450.1 (M + H) + Preparation of 1.8a: Procedure 1C: To a solution of 1.5a (15 g, 33.37 mmol, 1.0 eq) in dimethoxyethane (100 mL) was added sequentially an aqueous 2N sodium carbonate solution (50.06 mL, 100 mL). , 12 mmol, 3.0 eq), lithium chloride (4.24 g, 100.12 mmol, 3.0 eq), 1.6 (8.12 g, 36.71 mmol, 1.1 eq) and tetrakis ( triphenylphosphine) of palladium (0) (0.77 g, 0.67 mmol, 0.02 eq). The mixture was heated to reflux temperature for 10 h under nitrogen. The mixture was then cooled to room temperature and water (250 mL) was added. The mixture was extracted with ethyl acetate. The organic phase was further washed with brine and dried over sodium sulfate. The crude product was purified by column chromatography (eluent: mixtures of hexane / ethyl acetate of increasing polarity). Yield: 73% Procedure 1D: To a solution of 1.5a (10 g, 22.25 mmol, 1.0 eq) in dimethoxyethane (67 mL) was added sequentially an aqueous 2N sodium carbonate solution (33.37 mL, 66.75 mmol, 3.0 eq), lithium chloride (2.83 g, 66.75 mmol, 3.0 eq), 1.6 (4.40 g, 24.47 mmol, 1.1 eq) and palladium , 10% by weight (dry basis) on activated carbon, wet, type Degussa E101 NE / W (0.24 g, 0.11 mmol, 0.005 eq). The mixture was heated at reflux temperature for 2 h under nitrogen. The mixture was then cooled to room temperature and diluted with dichloromethane (350 mL). The mixture was filtered through a plug of Celite and dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was triturated with diethyl ether. The precipitate was collected by filtration.

Yield: 60% 1 H NMR (400MHz, CDCl 3) d 7.35 (m, 4H), 7.15 (t, 1H), 7.00-6.80 (m, 3H), 5.55 (s, 1H) ), 3.85 (m, 2H), 3.55 (m, 2H), 3.30 (m, 4H), 2.00 (m, 2H), 1.65 (m, 2H), 1.40 (s, 9H); 1.20 (m, 6H) Analysis of the mass spectrum m / z = 477.2 (M + H) + Preparation of 1A: Procedure 1E: A solution of 2.0M hydrochloric acid in diethylether (34.6 mL, 69 , 24 mmol, 5.5 eq) was added dropwise to a cooled (0 ° C) solution of 1.8a (6.00 g, 12.59 mmol, 1.0 eq) in anhydrous dichloromethane (70 mL). The mixture was warmed to room temperature and stirring was continued for a further 10 h. Diethyl ether (100 mL) was added to the solution and the resulting precipitate was collected by filtration and washed with diethyl ether. Yield: 99% Procedure 1 F: Trifluoroacetic acid (10.33 mL, 134.09 mmol, 5.5 eq) was added dropwise to a cold (0 ° C) solution of 1.8a (11.62 g, 24.38 mmol, 1.0 eq) in anhydrous dichloromethane (50 mL). The mixture was warmed to room temperature and stirring was continued for a further 10 h. The mixture was then concentrated under reduced pressure. A saturated solution of sodium bicarbonate (100 mL) was added to the mixture, which was extracted with dichloromethane. The organic phase was separated, washed with brine, dried over sodium sulfate and concentrated under reduced pressure. To a cold solution (0 ° C) of the resulting oil in anhydrous dichloromethane was added dropwise a solution of anhydrous hydrochloric acid 2.0M in diethyl ether (36.5 mL, 0.073 mol, 3.0 eq). The mixture was then stirred for 1 h at room temperature and concentrated under reduced pressure. Diethylether was added. The resulting precipitate was collected by filtration in vacuo and washed with diethyl ether.

Yield: 99% 1 H NMR (400MHz, DMSO d6) d 9.06 (m, 2H), 7.43 (s, 4H), 7.27 (t, 1H), 7.00 (m, 3H), 5 , 95 (s, 1H), 3.45 (m, 2H), 3.23 (m, 6H), 2.00 (m, 4H), 1.12 (m, 6H) Analysis of the mass spectrum m / z = 377.4 (M + H) + Elemental analysis: C 24 H 28 N 2 O 2, 1 HCl Theory:% C 69.80; % H 7.08; % N 6.78 Found:% C 69.73; % H 7.04; % N 6.81 EXAMPLE 1B 1B was obtained according to a procedure similar to that described for 1A, with the following exceptions: Step 1.1: 1.1a was replaced by 1.1b and Procedure 1B was used. Step 1.3: Procedure 10 Step 1.4 was used: Procedure 1 was used E. 1H NMR (400MHz, DMSO d6) d 8.97 (m, 2H), 7.42 (m, 4H), 6.98 (m , 1 HOUR), 6.86 (m, 1H), 6.49 (m, 1H), 5.99 (s, 1 H), 3.62 (m, 3H), 3.50 (m, 2H), 3.21 ( m, 6H), 2.06 (m, 4H), 1, 11 (m, 6H) Mass spectrum analysis m / z = 407.1 (M + H) + Elemental analysis: C25H30N2O3, HCl, 1, 25H2O Theoretical:% C 64.51; % H 7.25; % N 6.02 Found:% C 64.53; % H 7.11; % N 5.89 EXAMPLE 1C 1C was obtained according to a procedure similar to that described for 1A, with the following exceptions: Step 1.1: 1.1a was replaced by 1.1c and Procedure 1A was used. Step 1.3: Procedure 1C was used. Step 1.4: Procedure 1 was used E. 1 H NMR (400MHz, DMSO d 6) d 9.05 (m, 1.5H), 7.45 (s, 4H), 7.30 (d, 1H), 7, 10 (d, 1H), 6.90 (s, 1H), 6.00 (s, 1 H), 3.1-3.55 (m, 8H), 2.05 (m, 4H), 1, 10 (m, 6H) Analysis of the mass spectrum m / z = 411, 2 (M + H) + EXAMPLE 1D 1D was obtained according to a procedure similar to that described for 1A, with the following exceptions: Stage 1.1: 1.1 a was replaced by 1.1 d and was used Procedure 1 B. Stage 1.3: Procedure 1 D was used. Step 1.4: Procedure 1 was used E. 1 H NMR (400 MHz, DMSO d 6) d 8.95 (m, 1 H), 7.40 (s, 4H), 7.10 (m, 2H), 6.70 (m, 1H), 6.05 (s, 1H), 3.10-3.50 (m, 8H), 2.00 (m, 4H), 1.10 (m, 6H) Analysis of the mass spectrum m / z = 395.2 (M + H) + EXAMPLE 1E 1E was obtained according to a procedure similar to that described for 1A, with the following exceptions: Stage 1.1: 1.1a was replaced by 1.1 e and the procedure was used 1A. Step 1.3: Procedure 1 D was used. Step 1.4: Procedure 1 was used E. 1 H NMR (400MHz, DMSO d6) d 8.92 (ma, 1H), 7.42 (s, 4H), 7.07 (dd, 1H), 6.94 (d, 1H), 6.79 (d, 1 H), 5.92 (s, 1 H), 3.45 (sa, 2H), 3.22 (ma, 6H), 2.18 (s, 3H), 2.08 (m, 2H), 1, 97 (m, 2H), 1, 2 (day, 6H) Analysis of the mass spectrum m / z = 391, 3 (M + H) + Elemental analysis: C25H30 2O2. 1 HCl, 1.5H2O Theory:% C 66.13; % H 7.55; % N 6.17 Found:% C 65.73; % H 7.38; % N 6.05 EXAMPLE 1F 1F was obtained according to a procedure similar to that described for 1A, with the following exceptions: Step 1.1: 1.1a was replaced by 1.1f and Procedure 1B was used. Step 1.3: Procedure 1C was used. Step 1.4: Procedure 1F was used. 1 H NMR (400MHz, DMSO d6) d 8.90 (m, 2H), 7.25 (m, 5H), 6.71 (m, 1H), 6.64 ( m, 1 H), 5.81 (s, 1 H), 3.45 (m, 2H), 3.39 (m, 3H), 3.20 (m, 6H), 2.00 (m, 4H) ), 1, 09 (m, 6H) Mass spectrum analysis m / z = 407.2 (M + H) + Elemental analysis: Theoretical:% C 62.69; % H 7.36; % N 5.85 Found:% C 62.78; % H 6.90; % N 5.61 EXAMPLE 1G 1G was obtained according to a procedure similar to that described for 1A, with the following exceptions: Step 1.1: 1.1a was replaced by 1.1 g and Procedure 1B was used. Step 1.3: Procedure 10 Step 1.4 was used: Procedure 1E was used. H-NMR (400MHz, DMSO d6) d 8.95 (m, 1 H), 8.85 (m, 1H), 7.38 (m, 4H), 6.89 (m, 1H), 6.68 ( m, 1H), 6.54 (m, 1H), 5.78 (s, 1 H), 3.76 (m, 3H), 3.45 (m, 2H), 3.21 (m, 6H), 2.09 (m, 2H), 1.98 (m, 2H), 1.11 (m, 6H) Mass spectrum analysis m / z = 407.1 (M + H) + Elemental analysis: C25H30N2O3, 1 HCl, 0.5H2O Theoretical:% C 66.43; % H 7.14; % N 6.20 Found:% C 66.25; % H 7.19; % N 6.11 EXAMPLE 1H 1H was obtained according to a procedure similar to that described for 1A, with the following exceptions: Step 1.1: 1.1a was replaced by 1.1 h and Procedure 1B was used. Step 1.3: Procedure 1 D was used. Step 1.4: Procedure 1 was used E. 1 H NMR (400MHz, DMSO d6) d 8.80 (ma, 1H), 8.33 (d, 1H), 7.90 (m, 1H), 7.58 (m, 2H), 7.51 (d, 1H), 7.46 (d, 4H), 7.16 (d, 1H), 5.97 (s, 1H) , 3.46 (sa, 2H), 3.30 (ma, 6H), 2.25 (d, 2H), 2.05 (m, 2H), 1.13 (day, 6H) Mass spectrum analysis m / z = 427.4 (M + H) + Elemental Analysis: C28H30 2O2, 1HCI, 1.5H2O Theoretical:% C 68.63; % H 6.99; % N 5.72 Found:% C 68.96; % H 6.82; % N 5.75 EXAMPLE 11 was obtained according to a procedure similar to that described for 1A, with the following exceptions: Step 1.1: 1.1a was replaced by 1.1 i and Procedure 1B was used.

Step 1.3: Procedure 1 D was used. Step 1.4: Procedure 1 was used E. 1 H NMR (400MHz, DMSO d6) d 8.90 (ma, 1H), 7.94 (d, 1H), 7.87 (d, 1H), 7.37 (m, 3H), 7.28 (t, 1H), 7.24 (d, 2H), 7.10 (t, 1H), 6.96 (d, 1H) , 6.04 (s, 1H), 3.44 (sa, 2H), 3.23 (sa, 6H), 2.09 (ma, 4H), 1, 12 (day, 6H) Mass spectrum analysis m / z = 427.4 (M + H) + Elemental Analysis: C2dH3? N2O2, 1HCI, 0.67H2O Theoretical:% C 70.80; % H 6.86; % N 5.90 Found:% C 70.57; % H 6.72; % N 5.83 EXAMPLE 1 J 1 J was obtained according to a procedure similar to that described for 1A, with the following exceptions: Step 1.1: 1.1a was replaced by 1.1j and Procedure 1A was used. Step 1.3: Procedure 1D was used. Step 1.4: Procedure 1 was used E. 1 H NMR (400MHz, DMSO d 6) d 9.09 (ma, 1H), 7.41 (s, 4H), 6.87 (s, 1H), 6.75 ( s, 1 H), 5.84 (s, 1H), 3.45 (sa, 2H), 3.20 (ma, 6H), 2.19 (s, 3H), 2.08 (s, 3H) , 2.05 (m, 2H), 1.97 (m, 2H), 1.12 (da, 6H) Mass spectrum analysis m / z = 405.4 (M + H) + Elemental analysis: C26H32N2? 2, 1HCl, 0.5H2O Theory:% C 69.39; % H 7.62; % N 6.22 Found:% C 69.22; % H 7.49; % N 6.24 EXAMPLE 1K 1K was obtained according to a procedure similar to that described for 1A, with the following exceptions: Stage 1.1: 1.1 a was replaced by 1.1 k and Process 1B was used. Step 1.3: Procedure 1 was used C. Stage 1.4: Procedure 1 F. 1 H NMR (400MHz, DMSO d6) d 9.25 (m, 1 H), 7.40 (m, 4H), 7.35 (m, 1H), 6 was used. , 61 (s, 1H), 3.25 (, 8H), 2.06 (m, 4H), 1.02 (m, 6H) Analysis of the mass spectrum m / z = 413.2 (M + H) EXAMPLE 1L 1L was obtained according to a procedure similar to that described for 1A, with the following exceptions: Stage 1.1: 1.1a was replaced by 1.11 and Procedure 1B was used. Step 1.3: Procedure 1 D was used. Step 1.4: Procedure 1E was used. 1 H NMR (400MHz, DMSO d6) d 8.84 (br s, 1H), 7.41 (d, 4H), 6.96 (s, 1H), 6.61 (s, 1H), 5.86 (s, 1 H), 3.45 (sa, 2H), 3.20 (ma, 6H), 2.23 (s, 3H), 2.13 ( s, 3H), 2.08 (m, 2H), 1.96 (m, 2H), 1.12 (da, 6H) Mass spectrum analysis m / z = 405.4 (M + H) + Analysis Elemental: C26H32N2? 2, 1HCI, 0.5H2O Theoretical:% C 69.39; % H 7.62; % N 6.22 Found:% C 69.69; % H 7.56; % N 6.28 EXAMPLE 1M 1M was obtained according to a procedure similar to that described for 1A, with the following exceptions: Step 1.1: 1.1a was replaced by 1.1m and Procedure 1B was used. Step 1.3: Procedure 1C was used. Step 1.4: Procedure 1 was used E. 1 H NMR (400MHz, DMSO d 6) d 9.05 (m, 2H), 7.46 (m, 2H), 7.20 (m, 3H), 7.01 ( m, 1H), 6.82 (m, 1H), 6.48 (m, 1H), 3.45 (m, 2H), 3.28 (m, 6H), 2.24 (m, 2H), 2.06 (m, 2H), 1.60 (m, 3H), 1.12 (m, 6H) Mass spectrum analysis m / z = 391, 0 (M + H) + Elemental analysis: C25H30N2O2, 1HCI , 0.25H2O Theory:% C 69.59; % H 7.36; % N 6.49 Found:% C 69.25; % H 7.29; % N 6.58 EXAMPLE 1N Preparation of 1.10: To a 500 mL 2-neck flask dried in an oven charged with anhydrous toluene (90 mL) at -78 ° C was added n-butyllithium (2.5 M solution in hexane, 40 mL, 0.1 mol, 1.0 eq). A solution of 2,5-dibromo-pyridine (1.9) (23.69 g, 0.1 mol, 1.0 eq) in anhydrous toluene (50 mL) was added dropwise. The reaction mixture was stirred at -78 ° C for 2 h and then poured onto freshly chopped dry ice (~ 500 g). The dry ice mixture was then left at room temperature for 10 h. The volatiles were removed under reduced pressure and the residue was dissolved in water. The insoluble solids were filtered and the filtrate acidified to pH 2, at which time a light brown solid precipitated. The solids were collected by filtration and recrystallized from acetic acid (500 mL). This gave 1.10 isolated as its acetic acid salt. Yield: 74% 1 H NMR (400MHz, DMSO d6) d 8.84 (d, 1 H), 8.25 (dd, 1H), 7.98 (d, 1 H) Mass spectrum analysis m / z = 202.06 (M + H) + Preparation of 1.11: To a suspension of 5-bromo-pyridine-2-carboxylic acid (1.10) (808 mg, 3.01 mmol, 1.0 eq) in dry dichloromethane (5 mL ) oxalyl chloride (0.34 mL, 3.96 mmol, 1.3 eq) was added followed by 2 drops of? /,? / - dimethylformamide. The reaction mixture was heated to reflux temperature for 1 h. After cooling to room temperature, the mixture was concentrated under reduced pressure to give the crude product 1.11, which was used in the next step without further purification. Preparation of 1.13: To a suspension of 1.11 (crude, from 3.01 mmol, 1.0 eq) in dry tetrahydrofuran (5 mL) was added v *,? / - diethylamine (1.12) (1.56) mL, 15.08 mmol, 5.0 eq) dropwise. The reaction mixture was stirred at room temperature for 2 h. Ethyl acetate (20 mL) was added and the mixture was washed with water (20 mL), saturated aqueous sodium bicarbonate (30 mL), 1M aqueous hydrochloric acid (20 mL) and brine. The organic extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure to give a red / brown crystalline solid. Yield: 88% in two steps 1 H NMR (400MHz, CDCl 3) d 8.64 (d, 1H), 7.91 (dd, 1H), 7.53 (d, 1H), 3.56 (c, 2H) , 3.39 (c, 2H), 1.27 (t, 3H), 1, 17 (t, 3H) Analysis of the mass spectrum m / z = 257.15 (M + H) + Preparation of 1.7: A a solution of bis (pinacolato) diboro (1.14) (2.18 g, 8.6 mmol, 1.2 eq) in ? /,? / - dimethylformamide (10 mL) at 0 ° C was added potassium acetate (2.3 g, 23.4 mmol, 3.0 eq), the 1,1'-bis (diphenylphosphino) chloride complex ferrocene palladium (II) with dichloromethane (171 mg, 0.23 mmol, 0.03 eq). The reaction mixture was heated to 80 ° C at which time a solution of 1.13 (2.0 g, 7.8 mmol, 1.0 eq) in N, N -dimethylformamide (10 mL) was added dropwise. . The reaction mixture was stirred at 80 ° C for another 10 h. Ethyl acetate (75 mL) and water (50 mL) were added and the two phases were separated. The organic phase was washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a dark brown oil., which solidified into needles. The crude product was triturated with hexane. The resulting solid was collected by filtration. Yield: 52% 1 H NMR (400MHz, CDCl 3) d 8.92 (d, 1 H), 8.14 (dd, 1 H), 7.53 (d, 1 H), 3.55 (c, 2H) , 3.32 (c, 2H), 1.36 (s, 12H), 1.27 (t, 3H), 1.12 (t, 3H) Preparation of 1.8b: To a solution of 1.5a (1, 48 g, 3.29 mmol, 1.0 eq) in dimethoxyethane (DME) (20 mL) under nitrogen was added sequentially with an aqueous 2M sodium carbonate solution (4.94 mL, 9.87 mmol, 3.0 eq). ), lithium chloride (0.42 g, 9.87 mmol, 3.0 eq), palladium (70 mg, 10% by weight (dry basis) on activated charcoal (0.033 mmol, 0.01 eq), and 1.7 (1.0 g, 3.29 mmol, 1.0 eq) The mixture was heated to reflux temperature for 10 h, dichloromethane (200 mL) was added to dilute the reaction mixture and palladium (0) on carbon was added. The filter was washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure.The crude product was purified by column chromatography (eluent: hexane / ethyl acetate mixtures. polarity Yield: 76% 1 H NMR (400MHz, CDCl 3) d 8.56 (dd, 1H), 7.75 (dd, 1 H), 7.64 (dd, 1H), 7.22 (m, 1H ), 6.99-6.85 (m, 3H), 5.62 (s, 1H), 3.88 (m, 2H), 3.59 (c, 2H), 3.45 (c, 2H) , 3.34 (m, 2H), 2.06 (m, 2H), 1.69 (m, 2H), 1.48 (s, 9H), 1.29 (t, 3H), 1.20 ( t, 3H) Analysis of the mass spectrum m / z = 478.0 (M + H) + Preparation of 1N: To a cold (0 ° C) solution of 1.8b (2 g, 4.18 mmol, 1.0 eq) in anhydrous dichloromethane (20 mL) was slowly added a solution of 4.0M hydrogen chloride in dioxane (5%). , 2 mL, 20.8 mmol, 5.0 eq). The reaction mixture was stirred at room temperature for 10 h and then concentrated under reduced pressure. The resulting foam solids were soaked in diethyl ether to give fine powders, which were collected by filtration and washed sequentially with ethyl acetate and diethyl ether. Yield: 95% 1H NMR (400MHz, DMSO d6) d 8.99 (m, 2H), 8.60 (d, 1H), 7.90 (dd, 1H), 7.61 (d, 1H), 7 , 29 (m, 1 H), 7.06 (d, 1 H), 6.98 (m, 2H), 6.09 (s, 1H), 3.47 (c, 2H), 3.35- 3.13 (m, 6H), 2.06 (m, 4H), 1.17 (t, 3H), 1.11 (t, 3H) Analysis of the mass spectrum m / z = 378.4 (M + H) + Elemental analysis: C23H27N3O2, 2HCI, 0.5H2O Theory:% C 60.13; % H 6.58; % N 9.15 Found:% C 60.34; % H 6.60; % N 9.10 EXAMPLE 1O 1O was obtained according to a procedure similar to that described for 1N, with the following exception: Stage 1.1: 1.1a was replaced by 1.1 d. 1 H NMR (400MHz, DMSO d6) d 8.96 (m, 1H), 8.62 (d, 1 H), 7.92 (dd, 1H), 7.61 (d, 1 H), 7.12 (m, 2H), 6.78 (dd, 1 H), 6.20 (s, 1H), 3.47 (c, 2H), 3.30 (c, 2H), 3.24 (m, 4H), 2.05 (m, 4H), 1, 17 (t, 3H), 1.11 (t, 3H) Mass spectrum analysis m / z = 396.3 (M + H) + Elemental Analysis: C23H26FN3O2, 1.05HCI, 1 Theoretical H2O:% C 61, 15; % H 6.48; % N 9.30; % Cl 8.24 Found:% C 61.11; % H 6.44; % N 9.18; % CI 8.28 EXAMPLE 1P 1P was obtained according to a procedure similar to that described for 1N, with the following exception: Stage 1.1: 1.1a was replaced by 1.1e. 1 H NMR (400MHz, DMSO d6) d 8.93 (ma, 1 H), 8.60 (d, 1H), 7.89 (dd, 1 H), 7.61 (d, 1H), 7.09 (dd, 1H), 6.96 (d, 1H), 6.77 (s, 1H), 6.07 (s, 1H), 3.47 (c, 2H), 3.30 (c, 2H) , 2.21 (ma, 4H), 2.18 (s, 3H), 2.04 (ma, 4H), 1.17 (t, 3H), 1.11 (t, 3H) Mass spectrum analysis m / z = 392.3 (M + H) + Elemental Analysis: C24H29N3O2, 2HCI Theory:% C 62.07; % H 6.73; % N 9.05; % C1 15.27 Found:% C 61.81; % H 6.69; % N 8.95; % C1 15.42 EXAMPLE 1Q 1Q was obtained according to a procedure similar to that described for 1N, with the following exceptions: Step 1.1: 1.1a was replaced by 1.1f and Procedure 1A was used. 1 H NMR (400MHz, DMSO d6) d 9.20 (m, 2H), 8.38 (m, 1H), 7.69 (m, 1H), 7.48 (m, 1 H), 7.28 ( m, 1 H), 6.75 (, 1 H), 6.69 (, 1 H), 5.99 (s, 1 H), 3.40 (, 5H), 3.26 (m, 6H) , 2.08 (m, 4H), 1.20 (m, 3H), 1.10 (m, 3H) Mass spectrum analysis m / z = 408.3 (M + H) + Elemental analysis: C24H29N3O3, 1 HCI, 0.25H2O Theoretical:% C 64.28; % H 6.85; % N 9.37; % CI 7.91 Found:% C 64.07; % H 6.84; % N 9.23; % CI 8.18 EXAMPLE 1R 1R was obtained according to a procedure similar to that described for 1N, with the following exception: Stage 1.1: 1.1 a was replaced by 1.1 h. 1 H NMR (400MHz, DMSO d6) d 9.06 (br s, 0.5H), 8.90 (br s, 0.5H), 8.65 (d, 1H), 8.33 (d, 1H), 7 , 95 (dd, 1H), 7.91 (m, 1H), 7.64 (d, 1 H), 7.59 (m, 2H), 7.53 (d, 1H), 7.14 (d , 1H), 6.11 (s, 1H), 3.48 (c, 2H), 3.32 (ma, 6H), 2.26 (d, 2H), 2.10 (m, 2H), 1 , 18 (t, 3H), 1.12 (t, 3H) Analysis of the mass spectrum m / z = 428.3 (M + H) + Elemental analysis: C27H29N3O2, 1.8HCI, 1H2O Theoretical:% C 63.44; % H 6.47; % N 8.22; % C1 12.48 Found:% C 63.36; % H 6.22; % N 8.14; % C1 12.87 EXAMPLE 1S 1S was obtained according to a procedure similar to that described for 1N, with the following exception: Stage 1.1: 1.1a was replaced by 1.1j. 1 H NMR (400MHz, DMSO d6) d 8.89 (ma, 2H), 8.59 (d, 1H), 7.88 (dd, 1H), 7.61 (d, 1H), 6.89 (s) , 1H), 6.73 (s, 1H), 5.99 (s, 1H), 3.47 (c, 2H), 3.30 (c, 2H), 3.20 (ma, 4H), 2 , 20 (s, 3H), 2.09 (s, 3H), 2.06 (m, 2H), 1.97 (m, 2H), 1, 17 (t, 3H), 1, 11 (t, 3H) Analysis of the mass spectrum m / z = 406.3 (M + H) + Elemental analysis: C25H3lN3? 2, 2HCI, 2H2? Theoretical:% C 58.36; % H, 7.25; % N 8.17% Cl 13.78 Found:% C 58.45; % H 7.16; % N 8.16; % C1 13.68 EXAMPLE 1T 1T was obtained according to a procedure similar to that described for 1N, with the following exception: Stage 1.1: 1.1 a was replaced by 1.11. 1H NMR (400MHz, DMSO d6) d 9.02 (ma, 1 H), 8.56 (d, 1 H), 7.87 (dd, 1 H), 7.61 (d, 1H), 6, 98 (s, 1H), 6.59 (s, 1 H), 6.01 (s, 1H), 3.47 (c, 2H), 3.30 (c, 2H), 3.25 (m, 2H), 3.14 (sa, 2H), 2.24 (s, 3H), 2.15 (s, 3H), 2.09 (m, 2H), 2.02 (m, 2H), 1, 17 (t, 3H), 1, 11 (t, 3H) Analysis of the mass spectrum m / z = 406.4 (M + H) + Elemental analysis: C25H31N3O2, 1, 9HCI, 0.5H2O Theoretical:% C 62 , 06; % H 7.06; % N 8.69; % C1 13.92 Found:% C 61, 90; % H 7.03; % N 8.45; % C1 13.85 EXAMPLE 1U Preparation of 1U: A solution of 1G (1.00 g, 2.46 mmol, 1.0 eq) in dichloromethane (12 mL) was added dropwise to a cold solution (-78) ° C) of boron tribromide, 1.0M, in anhydrous dichloromethane (13.53 mL, 13.53 mmol, 5.5 eq). The mixture was warmed to room temperature and stirring was continued for 1 h more. Water (1.2 mL) was added dropwise to the cooled reaction mixture (0 ° C) and then a saturated solution of sodium bicarbonate (3.7 mL) was added thereto. The resulting mixture was stirred for 1 h at room temperature. A saturated solution of sodium bicarbonate was added to the mixture until the solution became basic when checked with pH paper. The phases were separated and the aqueous phase was extracted with dichloromethane.

The organic phases were combined and washed with brine. A gummy residue stuck to the walls of the separatory funnel. It was dissolved in methanol and combined with the dichloromethane extracts. The combined organic phases were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (eluent: mixtures of dichloromethane / methanol of increasing polarity). Yield: 79% 1 H NMR (400MHz, DMSO d6) d 9.66 (m, 1H), 7.37 (m, 4H), 6.77 (m, 1H), 6.32 (m, 2H), 5 , 62 (s, 1 H), 3.32 (m, 5H), 2.89 (m, 2H), 2.76 (m, 2H), 1.78 (m, 2H), 1.67 (m , 2H), 1.11 (m, 6H) Mass spectrum analysis m / z = 393.2 (M + H) + Elemental analysis: C24H28N2O3, 0.5H2O Theoretical:% C 71.80; % H 7.28; % N 6.98 Found:% C 71.79; % H 7.13; % N 6.94 EXAMPLE 2A Preparation of 2.2: Pyrrolidine (104 mL, 1.256 mol, 2.0 eq) was added at room temperature to 1.2 (125.2 g, 0.628 mol, 1.0 eq) and 2.1 (95 , 6 g, 0.628 mol, 1.0 eq). The solution was stirred at 70 ° C for 30 min and then cooled to room temperature and stirred for 48 h. The mixture was then concentrated under reduced pressure and ethyl acetate (800 mL) was added. The organic mixture was washed with an aqueous solution of 1 N hydrochloric acid, water, brine and dried over sodium sulfate. Diethyl ether (500 mL) was added to the organic extracts and the mixture was stirred overnight at room temperature. The resulting precipitate was collected by filtration, washed with hexane and used for the next step without further purification. Yield: 75% 1 H NMR (400MHz, CDCl 3) d 7.31 (d, 1H), 7.08 (m, 1 H), 6.87 (d, 1H), 6.06 (s, 1H), 3 , 86 (sa, 2H), 3.19 (sa, 2H), 2.69 (s, 2H), 2.02 (m, 2H), 1.58 (m, 2H), 1.47 (s, 9H) Analysis of the mass spectrum m / z = 332.4 (MH) "Preparation of 2.4: To a solution of 2.3 (2.17 g, 14.4 mmol, 1.2 eq) and imidazole (2.04 g) , 30.03 mmol, 2.5 eq) in dimethylformamide (20 mL) at room temperature under nitrogen was added dropwise a solution of 2.2 (4 g, 12.01 mmol, 1.0 eq) in dimethylformamide. The mixture was stirred overnight at room temperature and then diluted with ethyl acetate.The organic extracts were washed with water, dried over sodium sulfate, filtered and concentrated under reduced pressure. it was triturated with methanol and then isolated using vacuum filtration and used without further purification Yield: 76% H-NMR (400MHz, DMSO d6) d 7.10 (m, 2H), 6.99 (d, 1H), 3.70 (m, 2H) , 3.11 (sa, 2H), 2.81 (s, 2H), 1.84 (m, 2H), 1.60 (m, 2H), 1.40 (s, 9H), 0.94 ( s, 9H), 0.17 (s, 6H) Preparation of 2.5: To a solution of 2.4 (4 g, 8.94 mmol, 1.0 eq) in tetrahydrofuran (20 mL) a -78 ° C in nitrogen was added dropwise a solution of 1.0M lithium bis (trimethylsilyl) amide in tetrahydrofuran (6.2 mL, 10.72 mmol, 1.2 eq). The mixture was stirred for 1 h at -78 ° C. A solution of 1.4 (3.83 g, 10.72 mmol, 1.2 eq) in tetrahydrofuran (20 mL) was added dropwise. The mixture was stirred and allowed to slowly warm to room temperature. The reaction was concentrated under reduced pressure. The crude product was purified by column chromatography (eluent: mixtures of hexane / ethyl acetate of increasing polarity). Yield: 90.5% 1 H NMR (400MHz, CDCl 3) d 6.76 (m, 3H), 5.56 (s, 1H), 3.85 (sa, 2H), 3.26 (m, 2H), 2.05 (m, 2H), 1.65 (m, 2H), 1.47 (s, 9H), 0.97 (s, 9H), 0.18 (s, 6H) Preparation of 2.6a: A a solution of 2.5 (4.47 g, 7.71 mmol, 1.0 eq) in dimethoxyethane (35 mL) was added sequentially to an aqueous 2N sodium carbonate solution (11.6 mL, 23.13 mmol, 3, 0 eq), lithium chloride (0.98 g, 23.13 mmol, 3.0 eq), 1.6 (1.87 g, 8.48 mmol, 1.1 eq) and palladium tetrakis (triphenylphosphine) (0) (0.18 g, 0.15 mmol, 0.02 eq). The mixture was heated at reflux temperature for 4 h under nitrogen. The mixture was then cooled to room temperature and water was added thereto. The mixture was extracted with ethyl acetate. The organic phase was further washed with an aqueous 2N sodium hydroxide solution, brine and dried over sodium sulfate. The crude product was triturated with hexanes and used without further purification. Yield: 84% 1 H NMR (400MHz, DMSO d6) d 7.39 (m, 4H), 6.87 (d, 1H), 6.69 (m, 1H), 6.37 (d, 1H), 5.89 (s, 1H), 3.71 (m, 2H), 3.45 (sa, 2H), 3.23 (m, 4H), 1.85 (m , 2H), 1, 70 (m, 2H), 1.41 (s, 9H); 1, 10 (m, 6H), 0.87 (s, 9H), 0.08 (s, 6H) Analysis of the mass spectrum m / z = 607.0 (M + H) + Preparation of 2.7a: A a solution of 2.6a (0.50 g, 0.82 mmol, 1.0 eq) in tetrahydrofuran (10 mL) was added a solution of 1 N tetrabutylammonium fluoride (2.5 mL, 2.47 mmol, 3%). , 0 eq) in tetrahydrofuran at 0 ° C. The mixture was stirred for 1 h at room temperature under nitrogen. The mixture was diluted with ethyl acetate. The organic phase was washed with a saturated solution of aqueous sodium bicarbonate, brine, a 1 N hydrochloric acid solution and brine. The solution was then dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was triturated with a mixture of diethyl ether / hexanes (3: 7) and used without further purification. Yield: 74% 1 H NMR (400MHz, CDCl 3) d 7.34 (s, 4H), 6.80 (d, 1H), 6.67 (m, 1H), 6.49 (d, 1H), 5, 87 (s, 1H), 5.57 (s, 1H), 3.84 (sa, 2H), 3.56 (sa, 2H), 3.30 (sa, 4H), 2.00 (m, 2H) ), 1.64 (m, 2H), 1.47 (s, 9H), 1.20 (m, 6H) Mass spectrum analysis m / z = 493.0 (M + H) + Preparation of 2A: A solution of 2.0M hydrochloric acid in diethylether (1.7 mL, 3.35 mmol, 5.5 eq) was added dropwise to a cooled (0 ° C) solution of 2.7a (0.30 g, 0.degree. , 61 mmol, 1.0 eq) in anhydrous dichloromethane (5 mL). The mixture was warmed to room temperature and stirring was continued for a further 10 h. Diethyl ether (100 mL) was added to the solution. The resulting precipitate was collected by filtration and washed with diethyl ether. The crude product was purified by column chromatography (eluent: mixtures of dichloromethane / methanol of increasing polarity). Yield: 50% or 1 H NMR (400MHz, DMSO d6) d 9.03 (m, 2H), 7.42 (s, 4H), 6.85 (d, 1H), 6.64 (m, 1H), 6.42 (d, 1H), 5.91 (s, 1H), 3.49 (m, 4H), 3.21 (m, 5H), 2.08 (m, 2H), 1.96 (m , 2H), 1.13 (m, 6H) Mass spectrum analysis / z = 393.3 (M + H) + Elemental analysis: C24H28N2O2, 1HCl, 1H2O Theoretical:% C 64.49; % H 6.99; % N 6.27 Found:% C 64.59; % H 6.67; % N 6.26 EXAMPLE 2B 2B was obtained according to a procedure similar to that described for 2A, with the following exception: Stage 2.4: 1.6 was replaced by 1.7. 1 H NMR (400MHz, DMSO d6) d 8.94 (ma, 2H), 8.59 (s, 1H), 7.90 (dd, 1H), 7.62 (d, 1 H), 6.88 (d, 1H), 6.67 (dd, 1 H), 6.38 (d, 1H), 6.06 (s, 1 H), 3, 47 (c, 2H), 3.22 (m, 6H), 2.07 (m, 2H), 1.97 (m, 2H), 1.17 (t, 3H), 1, 11 (t, 3H) Mass spectrum analysis m / z = 394 (M + H) + Elemental analysis: C23H27N3O3, 2HCI, 1, 25H2O Theoretical:% C 56.50; % H 6.49; % N 8.59; % C1 14.50 Found:% C 56.55; % H 6.46; % N 8.39; % C1 14.49 EXAMPLE 2C Preparation of 2.9a A mixture of 2.7a (0.210 g, 0.00042 mol, 1.0 eq), cyclopropylmethyl bromide (2.8a) (0.12 mL, 0.0012 mol, 2 , 95 eq) and potassium carbonate (0.350 g, 0.0025 mol, 6.0 eq) in? /, / V-dimethylformamide (5 mL) was stirred for 48 h at 80 ° C. The mixture was cooled to room temperature, poured into water (50 mL) and extracted with ethyl acetate. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (eluent: mixtures of hexane / ethyl acetate of increasing polarity). Yield: 96% Analysis of the mass spectrum m / z = 547.12 (M + H) + Preparation of 20 A cold solution (0 ° C) of 2.9a (0.200 g, 0.00036 mol, 1.0 eq ) in anhydrous dichloromethane (10 mL) was added dropwise a solution of 2.0M anhydrous hydrochloric acid in diethylether (1.8 mL, 0.0036 mol, 10.0 eq). The mixture was heated slowly to room temperature and stirring was continued for 12 h at room temperature. The mixture was concentrated under reduced pressure. Diethyl ether was then added to the mixture, which was stirred for 1 h at room temperature. The precipitate was collected by filtration, washed with diethyl ether and dried under vacuum. Performance: 63% 1H NMR (400MHz, DMSO d6) d 8.85 (m, 1 H), 7.40 (s, 4H), 6.97 (d, 1H), 6.80 (m, 1H), 6.45 (d, 1H) , 5.95 (s, 1H), 3.65 (d, 2H), 3.10-3.50 (m, 8H), 2.00 (m, 4H), 1.10 (m, 7H), 0.50 (m, 2H), 0.20 (m, 2H) Analysis of the mass spectrum m / z = 447.1 (M + H) + 2D EXAMPLE 2D was obtained according to a procedure similar to that described for 2C, with the following exception: Stage 2.7: 2.8a was replaced by 2.8b (procedure 2A). 1 H NMR (400MHz, DMSO d6) d 9.00 (s, 1H), 7.45 (s, 4H), 7.00 (m, 1H), 6.80 (m, 1 H), 6.45 ( m, 1H), 6.00 (s, 1H), 4.55 (m, 1H), 3.10-3.55 (m, 8H), 2.00 (m, 4H), 1.80 (m , 2H), 1.60 (m, 4H), 1.50 (m, 2H), 1.10 (m, 6H) Mass spectrum analysis m / z = 461, 1 (M + H) + EXAMPLE 2E Preparation of 2.7b: Intermediate 2.7b was obtained according to a procedure similar to that described for 2.7a (see 2A), except that 1.6 was replaced by 1.7 in Stage 2.4. Preparation of 2.9b: To a solution of 2.7b (1.0 g, 2.03 mmol, 1.0 eq), 2.8e (0.29 g, 4.06 mmol, 2.0 eq), triphenylphosphine (1.06 g, , 06 mmol, 2.0 eq) and triethylamine (0.82 g, 8.12 mmol, 4.0 eq) in tetrahydrofuran (50 mL) at 0 ° C was added diisopropyl azodicarboxylate (DIAD) (0.82). g, 4.06 mmol, 2.0 eq). The mixture was warmed to room temperature and stirred for 48 h at room temperature. Methylene chloride was added and the crude mixture was washed with water, concentrated under reduced pressure and purified by column chromatography (eluent: mixtures of hexane / ethyl acetate of increasing polarity). Yield: 45% 1 H NMR (400MHz, CDCl 3) d 8.56 (s, 1H), 7.76 (dd, 1H), 7.64 (d, 1H), 6.89 (d, 1H), 6, 78 (m, 1H), 6.50 (d, 1H), 5.65 (s, 1 H), 3.86 (ma, 2H), 3.62 (m, 4H), 3.45 (c, 2H), 3.32 (ma, 2H), 2.05 (ma, 2H), 1.67 (ma, 2H), 1.48 (s, 9H), 1, 30 (m, 4H), 1, 21 (t, 3H), 0.60 (m, 2H), 0.30 (m, 2H) Analysis of the mass spectrum m / z = 548.4 (M + H) + Preparation of 2E: To a solution of 2.9b (0.50 g, 0.913 mmol, 1.0 eq) in methylene chloride (3 mL) was slowly added an excess of a 1.0M anhydrous hydrochloric acid solution in diethyl ether. The mixture was stirred for 16 h at room temperature and then concentrated under reduced pressure. This mixture (0.41 g) was purified by HPLC using a 20x150 mm column XTerra Reversed Phase-HPLC (eluent: 95: 5 A: B to 1: 99 A: B wherein A is 0.1% ammonia in water Milli-Q and B is acetonitrile). After purification by HPLC, the pure product (0.10 g, 0.22 mmol, 1.0 eq) was obtained as the free amine, which was dissolved in methanol (10 mL) at 0 ° C under nitrogen and treated with a solution of 1.0M anhydrous hydrochloric acid in diethylether (0.47 mL, 0.47 mmol, 2.1 eq). The mixture was stirred at 0 ° C for 30 min. The mixture was concentrated under reduced pressure and dried under vacuum.

Yield: 26% 1H NMR (400MHz, CDCl 3) d 9.75 (br s, 1H), 9.33 (br, 1H), 9.18 (s, 1H), 8.45 (da, 1H), 7, 96 (da, 1H), 6.94 (d, 1H), 6.80 (m, 1 H), 6.42 (ma, 2H), 3.66 (ma, 4H), 3.46 (ma, 6H), 2.30 (ma, 4H), 1, 35 (t, 3H), 1.22 (ma, 4H), 0.62 (m, 2H), 0.31 (m, 2H) Spectrum analysis mass m / z = 448.3 (M + H) + Elemental analysis: C27H33 3O3, 1.75HCl, 1, 5H2O Theoretical:% C 60.23; % H 7.07; % N 7.80; % C1 11, 52 Found:% C 60.50; % H 6.99; % N 7.77; % C1 11, 38 EXAMPLE 2F 2F was obtained according to a procedure similar to that described for 2E, with the following exception: Stage 2.7: 2.8e was replaced by 2.8d. 1 H NMR (400MHz, DMSO d6) d 9.10 (br s, 2H), 8.62 (d, 1 H), 7.93 (dd, 1H), 7.61 (d, 1H), 7.03 ( d, 1 H), 6.89 (dd, 1H), 6.47 (d, 1 H), 6.13 (s, 1 H), 3.64 (s, 3H), 3.47 (c, 2H), 3.24 (m, 6H), 2.05 (ma, 4H), 1, 17 (t, 3H), 1, 11 (t, 3H) Analysis of the mass spectrum m / z = 408.3 (M + H) + Elemental analysis: C 24 H 29 N 3 O 3, 1.25 HCl, 1.25 H 2 O Theory:% C 60.61; % H 6.94; % N 8.84% CI 9.32 Found:% C 60.69; % H 6.87; % N 8.66; % CI 9.35 Note: 2F was also obtained according to a procedure similar to that described for 20 with the following exceptions: Stage 2.7: 2.8a was replaced by 2.8c and Procedure 2C was used (alkylation reaction performed in acetone instead of ? /, / V-dimethylformamide).

EXAMPLE 3A Preparation of 3.1a: To a cold (0 ° C) solution of 2.7a (2.5g, 0.0050 mol, 1.0 eq) in anhydrous dichloromethane (100 mL),? / - triphenyltrifluoromethane sulfonimide was added. (1.4) (2 g, 0.0055 mol, 1.1 eq) followed by the addition of triethylamine (0.85 mL, 0.060 mol, 1.2 eq). The mixture was allowed to slowly warm to room temperature and stirring was continued for 12h The mixture was diluted with ethyl acetate and washed successively with water, 1 N aqueous NaOH, water, and brine. The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography (eluent: mixtures of hexane / ethyl acetate of increasing polarity). Yield: 78% Analysis of the mass spectrum m / z = 666.06 (M + H + CH3CN) "" Preparation of 3.2a: To a stirred solution of 3.1a (2), 5 g, 0.040 mol, 1.0 eq) in a mixture of methanol (30 mL) and dimethyl sulfoxide (40 mL) was added triethylamine (1.23 mL, 0.088 mol, 2.2 eq). Gaseous carbon monoxide was bubbled through the mixture for 5 min. To the mixture was added palladium (II) acetate (0.090 g, 0.00040 mol, 0.1 eq) followed by 1, 1'-bis (diphenylphosphino) ferrocene (0.443 g, 0.00080 mol, 0.2 eq). Gaseous carbon monoxide was bubbled through the mixture for 15 min and the mixture was then stirred under carbon monoxide atmosphere and heated at 65 ° C overnight. The mixture was cooled to room temperature and poured into water. The mixture was extracted with ethyl acetate. The combined organic extracts were washed with water, brine, dried over sodium sulfate and filtered. Evaporation of the solvent under reduced pressure gave a dark oil. The crude product was purified by column chromatography (eluent: mixtures of hexane / ethyl acetate of increasing polarity).

Yield: 75% Analysis of the mass spectrum m / z = 576.08 (M + H + CH3CN) * 1"Preparation of 3A: To a cold solution (0 ° C) of 3.2a (0.140 g, 0.00026 mol , 1.0 eq) in anhydrous dichloromethane (10 mL) was added dropwise a solution of anhydrous hydrochloric acid 2.0M in diethylether (2.6 mL, 0.0026 mol, 10.0 eq). The mixture was heated slowly to room temperature and the stirring was continued for 12 h at room temperature, and an additional 1.0 mL of anhydrous hydrochloric acid solution 2.0 M in diethylether was added to the reaction mixture, which was allowed to stir for 12 h. The mixture was concentrated under reduced pressure, then diethyl ether was added to the mixture, which was stirred for 2 h at room temperature The resulting precipitate was collected by filtration, washed with diethyl ether and dried under vacuum. Yield: 53% 1 H NMR (400MHz, DMSO d6) d 9.08 (m, 2H), 7.90 (d, 1 H), 7.60 (s, 1H), 7.40 (s, 4H), 7.15 (d, 1H), 6.00 (s, 1 H), 3.70 (s, 3H), 3.10-3.50 (m, 8H), 2.1 (m, 4H), 1, 10 (m, 6H) Analysis of the mass spectrum m / z = 435.0 (M + H) + EXAMPLE 3B Preparation of 3.3a: To a cold solution (0 ° C) ) of 3.2a (1.41 g, 0.0026 mol, 1.0 eq) in tetrahydrofuran (20 mL), a solution of lithium hydroxide monohydrate (0.332 g, 0.0079 mol, 3.0 eq. ) in water (3mL). Then methanol (6 mL) was added to the reaction mixture, which was stirred at room temperature for 12 h. To the reaction mixture was added a solution of lithium hydroxide monohydrate (0.165 g, 0.0058 mol, 1.5 eq) in water (3mL), which was stirred for 12h more at room temperature. The mixture was concentrated under reduced pressure and the residue was dissolved in ethyl acetate. The organic solution was dried over sodium sulfate and filtered. Evaporation of the filtrate gave a solid, which was triturated in hexane. The precipitate was collected by filtration. Yield: 85% Mass spectrum analysis / z = 562.08 (M + H + CH3CN) + Preparation of 3B: To a cold (0 ° C) solution of 3.3a (0.200 g, 0.00038 mol, 1.0 eq) in anhydrous dichloromethane (10 mL) was added dropwise a solution of anhydrous hydrochloric acid 2 , 0M in diethylether (1.9 mL, 0.0038 mol, 10 eq). The mixture was heated slowly to room temperature and stirring was continued for 12 h at room temperature. The desired product precipitated in the reaction mixture. The precipitate was collected by filtration, washed with diethyl ether and dried under vacuum. Yield: 60% 1 H NMR (400MHz, DMSO d6) d 9.10 (m, 1.5H), 7.85 (d, 1H), 7.60 (s, 1H), 7.40 (s, 4H), 7.10 (d, 1 H), 6.00 (s, 1H), 3.10-3.55 (m, 8H), 2.10 (m, 4H), 1.10 (m, 6H) Analysis of the mass spectrum m / z = 421, 0 (M + H) + EXAMPLE 30 3C was obtained according to a procedure similar to that described for 3B, with the following exception: Stage 3.1: 2.7 a (X = H) was replaced by 2.7b (X = N). 1 H NMR (400MHz, DMSO d6) d 9.02 (ma, 2H), 8.64 (d, 1 H), 7.94 (dd, 1H), 7.87 (dd, 1 H), 7.66 (d, 1H), 7.52 (d, 1H), 7.16 (d, 1H), 6.19 (s, 1H), 3.48 ( c, 2H), 3.25 (ma, 6H), 2.10 (ma, 4H), 1, 18 (t, 3H), 1.11 (t, 3H) Analysis of the mass spectrum m / z = 422.2 (M + H) + 3D 3D EXAMPLE it was obtained according to a procedure similar to that described for 3E, with the following exception: Stage 3.5: 3.4b was replaced by 3.4a. 1 H NMR (400MHz, DMSO d6) d 9.33 (m, 2H), 7.83 (m, 2H), 7.54 (m, 1H), 7.42 (m, 4H), 7.22 (, 1H), 7.10 (m, 1H), 6.01 (s, 1H), 5.60 (m, 2H), 3.42 (m, 2H), 3.25 (m, 4H), 2.11 (m, 4H), 1.10 (m, 6H) Analysis of the mass spectrum m / z = 420.0 (M + H) + Elemental analysis: C25H29N3? 3, 1 HCl, 3H2O Theoretical :% C 58.87; % H 7.11; % N 8.24 Found:% C 58.85; % H 6.74; % N 8.03 EXAMPLE 3E Preparation of 3.5a: O-Benzotriazol-1-yl -? /, A /,? / ',? / -tetramethyluronium tetrafluoroborate (TBTU) (244.2 mg, 0.76 mmol , 1.1 eq) was added to a cooled (0 ° C) solution of 3.3a (360.0 mg, 0.69 mmol, 1.0 eq), 3.4b (256.8 mg, 3.80 mmol, 5.5 eq), and / V,? / - diisopropyethylamine (1.06 mL, 6.08 mmol7.7 eq) in acetonitrile (8 mL). The solution was stirred overnight at room temperature and then concentrated under reduced pressure. Ethyl acetate (10 mL) and a saturated aqueous solution of sodium bicarbonate (10 mL) were added to the crude product and the mixture was stirred for 20 min. The phases were separated and the organic phase was washed with a saturated aqueous solution of sodium bicarbonate and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (eluent: mixtures of hexane / ethyl acetate of increasing polarity).

Yield: 68% 1 H NMR (400MHz, DMSO d6) d 8.28 (m, 1 H), 7.70 (m, 1 H), 7.50 (m, 1H), 7.42 (m, 4H) , 7.04 (d, 1H), 5.94 (s, 1 H), 3.72 (m, 2H), 3.45 (sa, 2H), 3.25 (m, 4H), 2.70 (d, 3H), 1.89 (m, 2H), 1.74 (m, 2H), 1.42 (s, 9H), 1.12 (m, 6H) Analysis of the mass spectrum m / z = 534.3 (M + H) + Preparation of 3E: A solution of 2.0M hydrochloric acid in diethyl ether (1.30 mL, 2.57 mmol, .5 eq) was added dropwise to a cooled (0 ° C) solution of 3.5a (0.25 g, 0.47 mmol, 1.0 eq) in anhydrous dichloromethane (5 mL). The mixture was warmed to room temperature and stirring was continued for a further 10 h. Diethyl ether (100 mL) was added to the solution. The resulting precipitate was collected by filtration and washed with diethyl ether. Yield: 99% 1 H NMR (400MHz, DMSO d6) d 9.14 (m, 2H), 8.34 (m, 1H), 7.77 (d, 1H), 7.54 (s, 1 H), 7.44 (s, 4H), 7.12 (d, 1 H), 6.01 (s, 1H), 3.63 (sa, 2H), 3.45 (sa, 2H), 3.24 ( m, 4H), 2.69 (d, 3H), 2.09 (m, 4H), 1.11 (m, 6H) Analysis of the mass spectrum m / z = 434.3 (M + H) + Analysis Elemental: C26H31N3O3, 1HC1, 1, 25H2O Theoretical:% C 63.40; % H 7.06; % N 8.53 Found:% C 63.13; % H 6.94; % N 8.39 EXAMPLE 3F 3F was obtained according to a procedure similar to that described for 3E, with the following exception: Step 3.5: 3.4b was replaced by 3.4c. 1 H NMR (400MHz, DMSO d6) 59.20 (m, 2H), 8.37 (m, 1H), 7.79 (m, 1H), 7.55 (m, 1H), 7.44 (m, 4H), 7.10 (m, 1H), 6.01 (s, 1 H), 3.61 (m, 2H), 3.45 (m, 2H), 3.22 (m, 6H), 2.10 (m, 4H), 1, 10 (m, 9H) Analysis of the mass spectrum m / z - 448.4 (M + H) + Elemental analysis: C27H33N3? 3, 1 HCl, 1 H2O Theoretical:% C 64.59; % H 7.23; % N 8.37 Found:% C 64.70; % H 7.16; % N 8.30 EXAMPLE 3G 3G was obtained according to a procedure similar to that described for 3E, with the following exception: Stage 3.5: 3.4b was replaced by 3.4d. 1 H NMR (400MHz, DMSO d6) d 9.16 (m, 2H), 8.36 (m, 1H), 7.78 (m, 1 H), 7.55 (m, 1H), 7.44 (m, 4H), 7.10 (m, 1H), 6.00 (s, 1H), 3.44 (m, 2H), 3.20 (m , 8H), 2.10 (m, 4H), 1.45 (m, 2H), 1.12 (m, 6H), 0.80 (m, 3H) Mass spectrum analysis m / z = 462.4 (M + H) + Elemental analysis: C28H35N3O3. IHCU .5H2O Theoretical:% C 64.05; % H 7.49; % N 8.00 Found:% C 63.76; % H 7.41; % N 7.76 EXAMPLE 3H 3H was obtained according to a procedure similar to that described for 3E, with the following exception: Step 3.5: 3.4b was replaced by 3.4e. 1 H NMR (400MHz, DMSO d6) d 9.23 (m, 2H), 8.36 (m, 1H), 7.79 (m, 1 H), 7.55 (m, 1H), 7.45 ( m, 4H), 7.12 (m, 1H), 6.01 (s, 1H), 3.45 (m, 2H), 3.24 (m, 6H), 3.01 (m, 2H), 2.06 (m, 4H), 1.76 (m, 1 H), 1, 11 (m, 6H), 0.81 (m, 6H) Analysis of the mass spectrum m / z - 476.5 (M + H) + Elemental analysis: C29H37N3O3, 1HCl, 1, 5H2O Theoretical:% C 64.61; % H 7.67; % N 7.79 Found:% C 64.94; % H 7.39; % N 7.77 EXAMPLE 31 31 was obtained according to a procedure similar to that described for 3E, with the following exception: Stage 3.5: 3.4b was replaced by 3.4f. 1 H NMR (400MHz, DMSO d 6) 9.14 (sa, 2H), 8.23 (m, 1H), 7.80 (m, 1H), 7.54 (m, 1H), 7.44 (m, 4H), 7.11 (m, 1H), 6.02 (s, 1H), 3.45 (m, 2H), 3.23 (m, 6H), 3.01 (m, 2H), 2, 10 (m, 4H), 1.12 (m, 6H), 0.83 (m, 9H) Analysis of the mass spectrum m / z - 490.6 (M + H) + Elemental analysis: C30H39N3O3, 1HCI, 0 , 75H2O Theory:% C 66.77; % H 7.75; % N 7.79 Found:% C 66.63; % H 7.64; % N 7.77 EXAMPLE 3J 3J was obtained according to a procedure similar to that described for 3E, with the following exception: Stage 3.5: 3.4b was replaced by 3.4g. 1 H NMR (400MHz, DMSO d6) d 9.21 (m, 2H), 8.45 (m, 1H), 7.80 (m, 1H), 7.54 (m, 1 H), 7.44 ( m, 4H), 7.11 (m, 1H), 6.01 (s, 1H), 3.45 (m, 2H), 3.24 (m, 6H), 3.09 (m, 2H), 2.11 (m, 4H), 1.12 (m, 6H), 0.96 (m, 1H), 0.36 (m, 2H), 0.16 (m, 2H) Analysis of the mass spectrum m / z = 474.4 (M + H) + Elemental Analysis: C29H35N3? 3, 1HCl, 1.75H2O Theoretical:% C 64.31; % H 7.35; % N 7.76 Found:% C 64.69; % H 7.17; % N 7.66 EXAMPLE 3K 3K was obtained according to a procedure similar to that described for 3E, with the following exception: Stage 3.5: 3.4b was replaced by 3.4h. 1 H NMR (400MHz, DMSO d6) d 9.36 (m, 2H), 8.13 (m, 1H), 7.82 (m, 1H), 7.54 (m, 1H), 7.44 (m, 4H), 7.11 (m, 1 H), 6.00 (s, 1H), 4.01 (m, 1H), 3.45 ( m, 2H), 3.22 (m, 6H), 2.10 (m, 4H), 1.15 (m, 12H) Analysis of the mass spectrum m / z = 462.5 (M + H) + Analysis elemental: C28H35N3O3, 1 HCl, 2.25H2O Theory:% C 62.44; % H 7.58; % N 7.80 Found:% C 62.42; % H 7.58; % N 8.08 EXAMPLE 3L 3L was obtained according to a procedure similar to that described for 3E, with the following exception: Stage 3.5: 3.4b was replaced by 3.4i. 1 H NMR (400MHz, DMSO d6) d 9.20 (m, 2H), 8.34 (m, 1H), 7.78 (m, 1 H), 7.54 (m, 1H), 7.44 ( m, 4H), 7.11 (m, 1H), 6.00 (s, 1H), 3.45 (m, 2H), 3.20 (m, 8H), 2.08 (m, 4H), 1.45 (m, 2H), 1.25 (m, 4H), 1.11 (m, 6H), 0.84 (m, 3H) Analysis of the mass spectrum m / z = 490.5 (M + H) + Elemental analysis: C30H39N3O3, 1HCl, 1, 5H2O Theoretical:% C 65.14; % H 7.84; % N 7.60 Found:% C 65.38; % H 7.60; % N 7.64 EXAMPLE 3M 3M was obtained according to a procedure similar to that described for 3E, with the following exception: Stage 3.5: 3.4b was replaced by 3.4j. 1 H NMR (400MHz, DMSO d6) d 9.11 (m, 2H), 7.41 (m, 4H), 7.30 (m, 1 H), 7.09 (m, 1 H), 6.99 (m, 1H), 6.00 (s, 1H), 3.45 (m, 2H), 3.20 (m, 6H), 2.91 (m, 6H), 2.10 (m, 4H) , 1.12 (m, 6H) Mass spectrum analysis m / z = 448.4 (M + H) + Elemental analysis: C27H33N3? 3, 1HCl, 1, 25H2O Theoretical:% C 64.02; % H 7.26; % N 8.30 Found:% C 64.03; % H 7.21; % N 8.23 EXAMPLE 3N 3N was obtained according to a procedure similar to that described for 3E, with the following exception: Stage 3.5: 3.4b was replaced by 3.4k. 1 H NMR (400MHz, DMSO d6) d 9.21 (m, 2H), 7.44 (m, 5H), 7.09 (m, 2H), 5.99 (s, 1 H), 3.41 ( m, 2H), 3.36 (m, 4H), 3.21 (m, 6H), 2.10 (m, 4H), 1.78 (m, 4H), 1.10 (m, 6H) Analysis of the mass spectrum m / z = 474.5 (M + H) + Elemental analysis: 29H35N3? 3, 1HCl, 1, 25H2O Theoretical:% C 65.40; % H 7.29; % N 7.89 Found:% C 65.48; % H 7.08; % N 7.90 EXAMPLE 30 30 was obtained according to a procedure similar to that described for 3E, with the following exception: Stage 3.5: 3.4b was replaced by 3.4I. 1 H NMR (400MHz, DMSO d) 9.03 (sa, 2H), 7.44 (m, 5H), 7.13 (m, 2H), 6.01 (s, 1H), 4.96 (m, 1H), 4.24 (m, 1H), 3.44 (m, 6H), 3.22 (m, 6H), 2.09 (m, 4H), 1.86 (m, 1 H), 1 , 75 (m, 1H), 1, 12 (m, 6H) Analysis of the mass spectrum m / z = 490.3 (M + H) + EXAMPLE 3P 3P was obtained according to a procedure similar to that described for 3E, with the following exception: Stage 3.5: 3.4b was replaced by 3.4m. H NMR (400MHz, DMSO d6) d 9.25 (m, 2H), 7.44 (m, 5H), 7.10 (m, 2H), 6.00 (s, 1H), 4.93 (m , 1 H), 4.24 (m, 1H), 3.45 (m, 6H), 3.21 (m, 6H), 2.11 (m, 4H), 1.88 (m, 1H), 1, 76 (m, 1 H), 1, 11 (m, 6H) Mass spectrum analysis m / z = 490.5 (M + H) + Elemental analysis: C29H35 3O4, 1HCl, 1, 5H2O Theoretical:% C, 62.98; % H 7.11; % N 7.60 Found:% C 62.79; % H 6.98; % N 7.58 EXAMPLE 3Q 3Q was obtained according to a procedure similar to that described for 3E, with the following exception: Stage 3.5: 3.4b was replaced by 3.4n. 1 H NMR (400MHz, DMSO d6) d 9.25 (m, 2H), 7.40 (m, 5H), 7.09 (m, 1 H), 6.99 (m, 1H), 6.01 ( s, 1H), 4.10 (m, 2H), 3.45 (m, 2H), 3.25 (m, 6H), 2.11 (m, 6H), 2.51 (m, 2H), 1.19 (m, 9H), 0.80 (m, 3H) Mass spectrum analysis m / z = 502.5 (M + H) + Elemental analysis: C31 H39N3O3, 1HCl, 2H2O Theoretical:% C 64.85; % H 7.72; % N 7.32 Found:% C 64.54; % H 7.37; % N 7.35 EXAMPLE 3R 3R was obtained according to a procedure similar to that described for 3E, with the following exception: Stage 3.5: 3.4b was replaced by 1.12. 1 H NMR (400MHz, DMSO d6) d 9.21 (m, 2H), 7.41 (m, 4H), 7.29 (m, 1H), 7.08 (m, 1 H), 6.89 (m, 1H), 5.98 (s, 1 H), 3.41 (m, 2H), 3.22 (m, 10H), 2.10 (m, 4H), 1, 02 (m, 12H) Analysis of the mass spectrum m / z = 476.5 (M + H) + Elemental analysis: C29H37N3O3, 1 HCl, 1, 25H2O Theoretical:% C 65.15; % H 7.64; % N 7.86 Found:% C64.85; % H 7.26; % N 7.79 EXAMPLE 3S 3S was obtained according to a procedure similar to that described for 3E, with the following exception: Stage 3.5: 3.4b was replaced by 3.4o. 1 H NMR (400MHz, DMSO d6) 58.67 (m, 1H), 8.55 (m, 1H), 7.43 (m, 4H), 7.22 (m, 1 H), 7.09 (m, 1H), 6.82 (m, 1H), 6.01 (s, 1 H), 3.66 (m, 2H), 3.44 (m, 2H), 3.23 (m, 6H), 2.10 (m, 2H), 1.98 (m, 2H), 1.16 (m, 18H) Analysis of the mass spectrum miz-504.4 (M + H) + EXAMPLE 3T 3T was obtained according to a procedure similar to that described for 3E, with the following exception: Stage 3.5: 3.4b was replaced by 3.4p. 1 H NMR (400MHz, DMSO d6) d 9.00 (m, 1.3H), 7.45 (s, 4H), 7.32 (d, 1H), 7.10 (d, 1H), 7.00 (s, 1H), 6.00 (s, 1H), 4.10 (m, 4H), 3.35-3.60 (m, 8H), 3 , 20 (m, 4H), 2.10 (m, 4H), 1, 10 (m, 6H) Analysis of the mass spectrum m / z = 490.1 (M + H) + EXAMPLE 3U 3U was obtained according to a procedure similar to that described for 3E, with the following exception: Stage 3.5: 3.4b was replaced by 3.4q. 1 H NMR (400MHz, DMSO d 6) 59.23 (sa, 2H), 7.44 (m, 4H), 7.30 (m, 1H), 7.12 (m, 1H), 6.96 (m, 1H), 6.01 (s, 1H), 3.40 (m, 6H), 3.22 (m, 6H), 2.11 (m , 4H), 1.56 (m, 2H), 1, 43 (m, 4H), 1, 12 (m, 6H) Mass spectrum analysis m / z = 488.4 (M + H) + Elemental analysis : C30H37N3O3, 1 HCl, 1.75H2O Theory:% C 64.85; % H 7.53; % N 7.56 Found:% C 64.99; % H 7.37; % N 7.46 EXAMPLE 3V 3V was obtained according to a procedure similar to that described for 3E, with the following exceptions: Stage 3.5: 3.3a (X = CH) was replaced by 3.3b (X = N). Stage 3.5: 3.4b was replaced by 3.4a. 1 H NMR (400MHz, DMSO d6) d 9.20 (ma, 2H), 8.63 (d, 1H), 7.92 (m, 2H), 7.83 (dd, 1 H), 7.64 ( d, 1 H), 7.53 (d, 1H), 7.25 (sa, 1 H), 7.12 (d, 1H), 6.16 (s, 1H), 3.48 (c, 2H) ), 3.31 (c, 2H), 3.22 (ma, 4H), 2.10 (ma, 4H), 1, 18 (t, 3H), 1, 12 (t, 3H) Analysis of the spectrum of masses m / z = 421, 3 (M + H) + Elemental analysis: C24H28N4? 3, 1.6HCI, 1, 4H2O Theoretical:% C 57.19; % H 6.48; % N 11,12; % C1 11.25 Found:% C 57.14; % H 6.41; % N 10.98; % C1 11.00 EXAMPLE 3W 3W was obtained according to a procedure similar to that described for 3E, with the following exception: Stage 3.5: 3.3a was replaced by 3.3b. 1 H NMR (400MHz, DMSO d6) d 9.21 (ma, 2H), 8.63 (d, 1H), 8.36 (m, 1H), 7.93 (dd, 1 H), 7.79 ( dd, 1H), 7.64 (d, 1H), 7.49 (d, 1H), 7.13 (d, 1H), 6.16 (s, 1H), 3.48 (c, 2H), 3.25 (m, 6H), 2.71 (d, 3H), 2.10 (m, 4H), 1, 18 (t, 3H), 1, 12 (t, 3H) Analysis of the mass spectrum m / z = 435.3 (M + H) + Elemental Analysis: C25H30N4O3, 1, 8HCI, 2H2O Theoretical:% C 56.00; % H 6.73; % N 10.45; % C1 11, 90 Found:% C 56.16; % H 6.72; % N 10.47; % C1 12.23 EXAMPLE 3X 3X was obtained according to a procedure similar to that described for 3E, with the following exceptions: Stage 3.5: 3.3a was replaced by 3.3b. Stage 3.5: 3.4b was replaced by 3.4c. 1 H NMR (400MHz, DMSO d6) d 9.23 (ma, 2H), 8.63 (d, 1H), 8.40 (t, 1H), 7.93 (dd, 1H), 7.81 (dd) , 1 H), 7.64 (d, 1H), 7.49 (d, 1H), 7.13 (d, 1H), 6.16 (s, 1 H), 3.48 (c, 2H) , 3.25 (ma, 8H), 2.10 (ma, 4H), 1, 18 (t, 3H), 1.12 (t, 3H), 1.05 (t, 3H) Mass spectrum analysis m / z = 449.3 (M + H) + Elemental Analysis: C26H32N4? 3, 2HCl, 1, 5H2O Theory:% C 56.93; % H 6.80; % N 10.21; % C1 12.93 Found:% C 56.64; % H 6.86; % N 10.13; % CI 12.59 EXAMPLE 3Y and 3Y was obtained according to a procedure similar to that described for 3E, with the following exceptions: Stage 3.5: 3.3a was replaced by 3.3b. Stage 3.5: 3.4b was replaced by 3.4j. 1 H NMR (400MHz, DMSO d6) d 9.06 (sa, 2H), 8.62 (d, 1H), 7.92 (dd, 1H), 7.63 (d, 1H), 7.36 (dd) , 1H), 7.11 (d, 1H), 6.98 (d, 1H), 6.16 (s, 1H), 3.47 (c, 2H), 3.25 (ma, 6H) , 2.91 (s, 6H), 2.10 (ma, 4H), 1.17 (t, 3H), 1, 11 (t, 3H) Analysis of the mass spectrum m / z = 449.3 (M + H) + Elemental analysis: C26H32N4O3, 1, 75HCI, 1, 25H2O Theoretical:% C 58.38; % H 6.83; % N 10.47; % C1 11, 60 Found:% C 58.37; % H 6.94; % N 10.21; % C1 11, 35 EXAMPLE 3Z 3Z was obtained according to a procedure similar to that described for 3AC, with the following exception: Stage 3.8: 3.6d was replaced by 3.6a; palladium (0) tetrakis (triphenylphosphine) was used. 1 H NMR (400MHz, DMSO d6) 59.21 (ma, 2H), 9.01 (s, 1H), 8.73 (d, 1H), 8.47 (d, 1 H), 7.87 (m , 1H), 7.76 (dd, 1H), 7.53 (d, 2H), 7.44 (d, 2H), 7.38 (d, 1H), 7.28 (d, 1H), 6 , 07 (s, 1H), 3.44 (m, 2H), 3.23 (ma, 6H), 2.11 (ma, 4H), 1.12 (da, 6H) Analysis of the mass spectrum m / z = 454.0 (M + H) + EXAMPLE 3AA 3AA was obtained according to a procedure similar to that described for 3AC, with the following exception: Stage 3.8: 3.6d was replaced by 3.6b; tetrakis (triphenylphosphine) palladium (0) was used. 1 H NMR (400MHz, DMSO d6) d 8.84 (ma, 2H), 7.58 (dd, 1H), 7.46 (m, 5H), 7.27 (d, 1H), 7.18 ( d, 1H), 7.12 (d, 1H), 7.06 (m, 1H), 6.04 (s, 1H), 3.46 (m, 2H), 3.23 (ma, 6H), 2.13 (m, 2H), 2.01 (m, 2H), 1.12 (da, 6H) Analysis of the mass spectrum m / z = 459.3 (M + H) + Elemental analysis: C28H30 2O2S, 1 HCl, 0.5H2O Theory:% C 66.71; % H 6.40; % N 5.56; % Cl 7.03 Found:% C 66.76; % H 6.27; % N 5.50; % Cl 7.34 EXAMPLE 3AB 3AB was obtained according to a procedure similar to that described for 3AC, with the following exception: Stage 3.8: 3.6d was replaced by 3.6c; tetrakis (triphenylphosphine) of palladium (0) was used. 1 H NMR (400MHz, DMSO-d 6) d 9.39 (a, 1H), 9.32 (a, 1H), 8.83 (d, 2H), 8.16 (d, 2H), 7.98 ( d, 1 H), 7.49 (m, 3H), 7.46 (d, 2H), 7.34 (d, 1 H), 6.14 (s, 1H), 3.3-3.7 (m, 8H), 2.12 (m, 4H), 1, 05-1, 2 (a, 6H) Analysis of the mass spectrum m / z = 454.4 (M + H) + Elemental analysis: C29H33CI2N3O2, 2HCl, 2.75H2O Theory:% C 60.47; % H 6.74; % N 7.29 Found:% C 60.35; % H 6.46; % N 7.32 EXAMPLE 3AC Preparation of 3.7a: To a solution of 3.1a (1.50 g, 2.40 mmol, 1.0 eq) in dimethoxyethane (DME) (20 mL) was added sequentially an aqueous solution of 2N sodium carbonate (3.6 mL, 7.20 mmol, 3.0 eq), lithium chloride (0.305 g, 7.20 mmol, 3.0 eq), 3.6d (0.357 g, 2.88 mmol, 1, 2 eq) and tetrakis (triphenylphosphine) of palladium (0) (0.277 g, 0.24 mmol, 0.10 eq). The mixture was heated at 120 ° C for 16 h. After this time, only the starting material 3.1a was observed by LC / MS. Therefore, additional amounts of 3.6d (0.10 g, 0.81 mmol, 0.34 eq), tetrakis (triphenylphosphine) of palladium (0) (0.10 g, 0.087 mmol, 0.036 eq) and chloride were added. of palladium [1, 1'-bis (diphenylphosphino) ferrocene), complexed with dichloromethane] (0.50 g, 0.68 mmol, 0.28 eq) to the reaction mixture, which was heated to 120 °. C for 5h. The crude mixture was cooled to room temperature, dissolved in ethyl acetate and the mixture was washed with water. The organic extract was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (eluent: hexane / ethyl acetate mixtures of increasing polarity), and the product was used without further purification. Yield: 20% Analysis of the mass spectrum m / z = 555.5 (M + H) + Preparation of 3AC: To a solution of 3.7a (0.3 g, purity: 90%, 0.489 mmol, 1.0 eq ) in methylene chloride (10 mL) was added an excess of a solution of 1.0M anhydrous hydrochloric acid in diethylether (10 mL). The mixture was stirred for 16 h at room temperature, concentrated under reduced pressure and purified by column chromatography (eluent: mixtures of methylene chloride / methanol of increasing polarity). Yield: 90% 1 H NMR (400MHz, DMSO d6) d 9.26 (sa, 2H), 9.13 (s, 1 H), 8.99 (s, 2H), 7.72 (d, 1H), 7.53 (d, 2H), 7.44 (d, 2H), 7.34 (s, 1 H), 7.25 (d, 1 H), 6.07 (s, 1 H), 3, 44 (sa, 2H), 3.23 (ma, 6H), 2.12 (ma, 4H), 1, 12 (day, 6H) Analysis of the mass spectrum m / z = 455.4 (M + H) + Elemental analysis: C28H30N4O2, 2HCI, 2.75H2O Theory:% C 58.28; % H 6.55; % N 9.71 Found:% C 58.53; % H 6.27; % N 9.74 EXAMPLE 4A Preparation of 4.2: To a suspension of 1A (21.9 g, 52.45 mmol, 1.0 eq) in tetrahydrofuran (200 mL) at 0 ° C was added triethylamine (18.3 mL, 131 mmol, 2.5 eq), followed by trifluoroacetic anhydride (4.1) (8.75 mL, 63 mmol, 1.2 eq) dropwise. The reaction mixture was slowly heated and stirred at room temperature for 10 h. Ethyl acetate (500 mL) was added and the organic phase was washed with a 1M aqueous hydrochloric acid solution (5 x 100 mL) and brine, dried over sodium sulfate and filtered. The crude product was concentrated under reduced pressure and purified by column chromatography (eluent: mixtures of hexane / ethyl acetate of increasing polarity). Yield: 93% 1 H NMR (400MHz, CDCl 3) d 7.42 (m, 2H), 7.36 (m, 2H), 7.22 (m, 1H), 7.02 (m, 1H), 6, 96 (m, 1H), 6.90 (, 1H), 5.54 (s, 1H), 4.39 (m, 1H), 3.87 (m, 1H), 3.71 (m, 1H) , 3.58 (m, 2H), 3.35 (m, 3H), 2.22 (m, 2H), 1.74 (m, 2H), 1.22 (m, 6H) Mass spectrum analysis m / z = 473.3 (M + H) + Preparation of 4.4: To a solution of 4.2 (4.0 g, 8.47 mmol, 1.0 eq) in dry dichloroethane (100 mL) was added the complex Sulfur trioxide? /,? / - dimethylformamide (4.3) (1.98 g, 12.9 mmol, 1.5 eq) fractionally. The reaction mixture was heated to reflux temperature for 10 h and then cooled to 0-10 ° C, at which point oxalyl chloride (1.2 mL, 13.55 mmol, 1.6 eq) was added dropwise. ). Then the reaction mixture was stirred at 70 ° C for another 3h. The reaction was quenched with ice / water (100 mL). Dichloromethane (100 mL) was added and the two phases were separated. The aqueous phase was extracted with dichloromethane (3 x 50 mL) and the combined organic phases were dried over sodium sulfate., filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (eluent: mixtures of hexane / ethyl acetate of increasing polarity). Yield: 79% 1 H NMR (400MHz, CDCl 3) d 7.90 (dd, 1 H), 7.72 (d, 1H), 7.49 (m, 2H), 7.36 (m, 2H), 7 , 13 (d, 1H), 5.68 (s, 1 H), 4.44 (m, 1H), 3.92 (m, 1H), 3.70 (m, 1 H), 3.58 ( m, 2H), 3.35 (m, 3H), 2.25 (m, 2H), 1.83 (m, 2H), 1.22 (m, 6H) Mass spectrum analysis m / z = 571 , 2 (M + H) + Preparation of 4.6a: To a solution of 4.4 (0.7 g, 1.22 mmol, 1.0 eq) in dry dichloromethane (30 mL) at 0 ° C was added triethylamine (0.85 mL, 6.10 mmol, 5.0 eq) and the methylamine hydrochloride salt (3.4b) (0.25 g, 3.66 mmol, 3.0 eq) in one portion. The reaction mixture was slowly warmed to room temperature and stirred at room temperature for 10 h. Water (50 mL) and chloroform (50 mL) were added and the two phases separated. The aqueous phase was extracted with chloroform (3 x 50 mL) and the combined organic phases were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (eluent: mixtures of hexane / ethyl acetate of increasing polarity). Yield: 86% 1 H NMR (400MHz, CDCl 3) d 7.73 (dd, 1H), 7.53 (d, 1H), 7.45 (m, 2H), 7.35 (m, 2H), 7, 07 (d, 1H), 5.63 (s, 1 H), 4.42 (m, 1 H), 4.29 (c, 1H), 3.90 (m, 1H), 3.69 (m , 1 H), 3.58 (m, 2H), 3.35 (m, 3H), 2.63 (d, 3H), 2.22 (m, 2H), 1.79 (m, 2H), 1.22 (m, 6H) Analysis of the mass spectrum m / z = 566.2 (M + H) + Preparation of 4A: To a solution of 4.6a (0.63 g, 1.11 mmol, 1.0 eq) in a mixture of methanol (20 mL) and water (5 mL) at 0 ° C was added potassium carbonate (0.92 g, 6.66 mmol, 6.0 eq) fractionally. The reaction mixture was warmed to room temperature and stirred at room temperature for 10 h. Brine (50 mL) and chloroform (50 mL) were added and the two phases separated. The aqueous phase was extracted with chloroform (3 x 50 mL). The combined organic phases were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (eluent: mixtures of dichloromethane / methanol of increasing polarity). The desired fractions were combined and concentrated under reduced pressure. To a cold solution (0 ° C) of the resulting oil in anhydrous dichloromethane was added a solution of 2.0M hydrogen chloride in diethylether (1.11 mL, 2.22 mmol, 2 eq) dropwise. The mixture was then stirred for 1 h at room temperature, concentrated under reduced pressure, and dried under reduced pressure. Yield: 85% H NMR (400MHz, DMSO d6) d 8.99 (m, 2H), 7.66 (dd, 1H), 7.49-7.37 (m, 6H), 7.25 (d, 1H), 6.10 (s, 1H), 3.45 (m, 2H), 3.22 (m, 6H), 2.36 (d, 3H), 2, 01 (m, 4H), 1.12 (m, 6H) Analysis of the mass spectrum m / z = 470.2 (M + H) + Elemental analysis: C25H31 N3O4S, 1 HCl, 1.5H2O Theoretical:% C 56.33; % H 6.62; % N 7.88 Found:% C 56.06; % H 6.50; % N 8.18 EXAMPLE 4B 4B was obtained according to a procedure similar to that described for 4A, with the following exception: Stage 4.3: 3.4b was replaced by 3.4c. 1 H NMR (400MHz, DMSO d6) d 8.88 (sa, 1 H), 7.67 (dd, 1H), 7.46 (m, 4H), 7.39 (d, 1H), 7.23 (d, 1 H), 6.10 (s, 1 H), 3.52-3.15 (m, 9H), 2.71 (m, 2H) 2.08 (m, 4H), 1.42 (m, 6H), 0.94 (t, 3H) Analysis of the mass spectrum m / z = 484.3 (M + H) + Elemental analysis: C26H33N3O4S, 1 HCl, 1.25H2O Theoretical:% C 57,55; % H 6.78; % N 7.74 Found:% C 57,61; % H 6.75; % N 7.60 EXAMPLE 40 was obtained according to a procedure similar to that described for 4A, with the following exception: Stage 4.3: 3.4b was replaced by 3.4d. 1 H NMR (400MHz, DMSO d6) d 8.85 (m, 2H), 7.67 (dd, 1H), 7.51 (t, 1H), 7.45 (m, 3H), 7.39 (d , 1H), 7.23 (d, 1H), 6.10 (s, 1H), 3.45 (m, 2H), 3.24 (m, 7H), 2.63 (m, 2H), 2 , 08 (m, 4H), 1.34 (m, 2H), 1, 12 (m, 6H), 0.77 (t, 3H) Analysis of the mass spectrum m / z = 498.3 (M + H ) + Elemental analysis: C27H35N3O4S, 1 HCI, 1H2O Theoretical:% C 58.74; % H 6.94; % N 7.61 Found:% C 58.82; % H 6.78; % N 7.56 EXAMPLE 4D 4D was obtained according to a procedure similar to that described for 4A, with the following exception: Stage 4.3: 3.4b was replaced by 3.4g. 1 H NMR (400MHz, DMSO d6) d 8.90 (m, 2H), 7.68 (m, 2H), 7.45 (m, 3H), 7.40 (d, 1H), 7.22 (d , 1H), 6.09 (s, 1H), 3.45 (m, 2H), 3.24 (m, 7H), 2.59 (t, 2H), 2.07 (m, 4H), 1 , 12 (m, 6H), 0.75 (m, 1H), 0.32 (m, 2H), 0.04 (m, 2H) Analysis of the mass spectrum m / z = 510.3 (M + H ) + Elemental Analysis: C28H33 3O4S, 1HCI, 1H2O Theoretical:% C 59.61; % H 6.79; % N 7.45 Found:% C 59.55; % H 6.75; % N 7.40 EXAMPLE 4E 4E was obtained according to a procedure similar to that described for 4A, with the following exception: Stage 4.3: 3.4b was replaced by 3.4h. 1 H NMR (400MHz, DMSO dβ) d 8.79 (m, 2H), 7.69 (dd, 1H), 7.54 (d, 1H), 7.44 (m, 4H), 7.22 (d , 1H), 6.10 (s, 1H), 3.51-3.09 (m, 10H), 2.07 (m, 4H), 1.12 (m, 6H), 0.92 (d, 6H) Mass spectrum analysis m / z = 498.3 (M + H) + Elemental analysis: C27H35 3O4S, 1 HCl, 1.4H2O Theoretical:% C 57.98; % H 6.99; % N 7.51 Found:% C 57.99; % H 7.04; % N 7.38 EXAMPLE 4F 4F was obtained according to a procedure similar to that described for 4A, with the following exception: Stage 4.3: 3.4b was replaced by 3.4j. 1 H NMR (400MHz, DMSO d6) d 9.11 (m, 2H), 7.64 (dd, 1H), 7.46 (m, 4H), 7.29 (d, 1 H), 7.24 ( d, 1H), 6.13 (s, 1 H), 3.45 (m, 2H), 3.23 (m, 6H), 2.56 (s, 6H), 2.11 (m, 4H) , 1.12 (m, 6H) Analysis of the mass spectrum m / z = 484.1 (M + H) + Elemental analysis: C26H33 3O4S, 1 HCl, 2.75H2O Theory:% C 54.82; % H 6.99; % N 7.38 Found:% C 54.66; % H 6.89; % N 7.30 EXAMPLE 4G 4G was obtained according to a procedure similar to that described for 4A, with the following exception: Stage 4.3: 3.4b was replaced by 4.5. 1 H NMR (400MHz, DMSO d6) d 8.85 (m, 2H), 7.83 (d, 1H), 7.69 (dd, 1H), 7.45 (, 3H), 7.41 (d, 1 H), 7.25 (d, 1 H), 6.11 (s, 1 H), 3.45 (m, 2H), 3.25 (, 7H), 2.09 (m 5H), 1 , 12 (m, 6H), 0.45 (m, 2H), 0.34 (m, 2H) Analysis of the mass spectrum m / z = 496.2 (M + H) + Elemental analysis: C27H33N3O4S, 1 HCI , 0.75H2O Theory:% C 59.44; % H 6.56; % N 7.70 Found:% C 59.37; % H 6.46; % N 7.60 EXAMPLE 4H Preparation of 4H: To a solution of 4.4 (1.5 g, 2.82 mmol) in acetonitrile (20 mL) was added a concentrated aqueous solution of ammonium hydroxide (28-35%, 20 mL). The reaction mixture was heated to reflux temperature for 10 h. Brine (100 mL) was added and the aqueous phase was adjusted to pH = 10 with a 1M aqueous sodium hydroxide solution. Chloroform (150 mL) was added and the two phases separated. The aqueous phase was extracted with chloroform (3 x 50 mL). The combined organic phases were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (eluent: mixtures of dichloromethane / methanol of increasing polarity). The desired fractions were combined and concentrated under reduced pressure. To a cold (0 ° C) solution of the resulting oil (0.32 g, 0.70 mmol, 1.0 eq) in dichloromethane / methanol was added dropwise a 2.0M hydrogen chloride solution in diethyl ether ( 0.7 mL, 1.4 mmol, 2.0 eq). The mixture was then stirred for 1 h at room temperature, concentrated under reduced pressure, and dried under vacuum. Yield: 80% 1 H NMR (400MHz, DMSO d6) d 8.98 (m, 1.5H), 7.71 (dd, 1 H), 7.45 (m, 5H), 7.27 (s, 2H) , 7.22 (d, 1 H), 6.09 (s, 1 H), 3.46 (m, 2H), 3.23 (m, 6H), 2.07 (m, 4H), 1, 12 (m, 6H) Analysis of the mass spectrum m / z = 456.0 (M + H) + Elemental analysis: C24H29N3O4S, 1HCl, 2H2O Theory:% C 54.59; % H 6.49; % N 7.96 Found:% C 54.50; % H 6.49; % N 7.82 EXAMPLE 41 Preparation of 4.8: To a suspension of 4H (1.12 g, 2.45 mmol, 1.0 eq) in a mixture of dichloromethane (50 mL) and methanol (5 mL) at 0 ° C was added sequentially triethylamine (0.85 mL, 6.12 mmol, 2.5 eq), and di-fer-butyl dicarbonate 4.7 (0.80 g, 3.67 mmol, 1.5 eq) fractionated The reaction mixture was slowly warmed to room temperature and stirred at room temperature for 10 h. The solvents were removed under reduced pressure. The crude product was purified by column chromatography (eluent: mixtures of hexane / ethyl acetate of increasing polarity). Yield: 92% 1 H NMR (400MHz, CDCl 3) d 7.75 (dd, 1H), 7.57 (d, 1 H), 7.43 (m, 2H), 7.35 (m, 2H), 7.03 (d, 1H), 5.65 (s, 1 H), 4.83 (s, 2H), 3.89 (m, 2H), 3.57 (m, 2H) ), 3.32 (m, 4H), 2.04 (m, 2H), 1.71 (m, 2H), 1.47 (s, 9H), 1.21 (m, 6H) Analysis of the mass spectrum m / z = 556.3 (M + H) + Preparation of 4.10: To a solution of 4.8 (1.25 g, 2.25 mmol, 1.0 eq) in dichloromethane (40 mL) was added triethylamine (0.94 mL, 6.75 mmol, 3%). , 0 eq), and acetic anhydride (4.9) (0.64 mL, 6.75 mmol, 3.0 eq) dropwise. The mixture was stirred at room temperature for 10 h. Dichloromethane (100 mL) and water (100 mL) were added to the reaction mixture and the two phases were separated. The aqueous phase was extracted with dichloromethane (3 x 50 mL) and the combined organic phases were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (eluent: mixtures of hexane / ethyl acetate of increasing polarity). Yield: 70% Analysis of the mass spectrum m / z = 598.3 (M + H) + Preparation of 41: To a solution of 4.10 (0.6 g, 0.27 mmol, 1.0 eq) in dichloromethane ( 5 mL) was added iodotrimethylsilane (0.06 mL, 0.43 mmol, 1.6 eq) dropwise. The mixture was stirred at room temperature for 30 min. The mixture was diluted in chloroform (100 mL) and methanol (5 mL), washed with an aqueous solution of 20% sodium thiosulfate (2 x 30 mL) and an aqueous solution of 1 M sodium carbonate (2 x 30 mL) , dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (eluent: mixtures of dichloromethane / methanol of increasing polarity). Yield: 60% 1 H NMR (400MHz, DMSO d6) d 7.73 (dd, 1H), 7.51 (d, 1 H), 7.45 (s, 4H), 7.17 (d, 1H), 6.01 (s, 1 H), 3.45 (sa, 2H), 3.38-3.15 (m, 7H), 2.07 (m, 4H), 1.79 (s, 3H), 1.12 (m, 6H) Analysis of the mass spectrum m / z = 498.3 (M + H) + EXAMPLE 5A Preparation of 5.2: To a solution of 4.4 (1.4 g, 2.45 mmol, 1, 0 eq) in a mixture of tetrahydrofuran (5 mL) and dichloromethane (1 mL) at 0 ° C was added a solution of 1.0M hydrazine (5.1) in tetrahydrofuran (24.5 mL, 24.5 mmol, 10%). 0 eq) in one portion. The reaction mixture was stirred at 0 ° C for 30 min. Water (50 mL) and chloroform (100 mL) were added and the two phases separated. The aqueous phase was extracted with chloroform (3 x 50 mL) and the combined organic phases were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (eluent: mixtures of hexane / ethyl acetate of increasing polarity). Yield: 70% 1 H NMR (400MHz, CDCl 3) d 7.78 (dd, 1H), 7.59 (d, 1H), 7.46 (d, 2H), 7.35 (d, 2H), 7, 10 (d, 1 H), 5.64 (s, 1H), 4.42 (m, 1H), 3.91 (m, 1H), 3.69 (m, 1H), 3.57 (m, 2H), 3.35 (m, 4H), 2.23 (m, 2H), 1.80 (m, 2H), 1.22 (m, 6H) Analysis of the mass spectrum m / z = 567.4 (M + H) + Preparation 5.3: To a suspension of 5.2 (0.9 g, 1.59 mmol, 1.0 eq) in ethanol (10 mL) was added sodium acetate (0.87 g, 10, 8 mmol, 6.65 eq) and iodomethane (2.8c) (0.54 mL, 8.85 mmol, 5.45 eq). The mixture was heated to reflux temperature for 10 h. Water (100 mL) and dichloromethane (100 mL) were added and the two phases were separated. The aqueous phase was extracted with dichloromethane (3 x 50 mL) and the combined organic phases were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (eluent: mixtures of hexane / ethyl acetate of increasing polarity). Yield: 74% 1 H NMR (400MHz, CDCl 3) d 7.81 (dd, 1H), 7.64 (d, 1H), 7.46 (d, 2H), 7.35 (d, 2H), 7, 11 (d, 1H), 5.64 (s, 1 H), 4.42 (m, 1H), 3.91 (m, 1H), 3.69 (m, 1H), 3.57 (m, 2H), 3.35 (m, 3H), 3.00 (s, 3H), 2.23 (m, 2H), 1.80 (m, 2H), 1.22 (m, 6H) Spectrum Analysis mass m / z = 551.2 (M + H) + Preparation of 5A: To a solution of 5.3 (0.65 g, 1.18 mmol, 1.0 eq) in a mixture of methanol (20 mL) and Water (5 mL) at 0 ° C was added potassium carbonate (0.98 g, 7.08 mmol, 6.0 eq) fractionally. The mixture was heated and stirred at room temperature for 10 h. Brine (50 mL) and chloroform (50 mL) were added and the two phases separated. The aqueous phase was extracted with chloroform (3 x 50 mL). The combined organic phases were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (eluent: mixtures of dichloromethane / methanol of increasing polarity). The desired fractions were combined and concentrated under reduced pressure. To a cold (0 ° C) solution of the resulting oil in anhydrous dichloromethane was added dropwise a 2.0M hydrogen chloride solution in diethylether (1.18 mL, 2.36 mmol, 2.0 eq). The mixture was then stirred at room temperature for 1 h, concentrated under reduced pressure, and dried under vacuum. Yield: 88% 1 H NMR (400MHz, DMSO d6) d 9.07 (m, 2H), 7.83 (dd, 1 H), 7.47 (m, 5H), 7.30 (d, 1 H), 6.12 (s, 1H), 3.63-3.10 (m, 11H), 2.10 (m, 4H), 1.12 (m, 6H) Analysis of the mass spectrum m / z = 455.2 (M + H) + Elemental analysis: C25H30N2O4S, 1 HCI, 1.33H2O Theoretical:% C 58.30; % H 6.59; % N 5.44 Found:% C 58.35; % H 6.56; % N 5.37 EXAMPLE 6A Preparation of 6.2: To a cold (0 ° C) solution of 4.2 (0.23 g, 0.48 mmol, 1.0 eq) in dry acetonitrile (3 L) in nitrogen was added the nitronium tetrafluoroborate complex (6.1) (78.5 mg, 0.576 mmol, 1.2 eq) in one portion with rapid stirring. The reaction mixture was kept at 0 ° C for 1 h and then quenched with ice / water (1: 1) (15 mL). Dichloromethane (50 mL) was added and the two phases were separated. The aqueous phase was extracted with dichloromethane (3 x 30 mL) and the combined organic phases were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (eluent: mixtures of hexane / ethyl acetate of increasing polarity). Yield: 38% 1 H NMR (400MHz, CDCl 3) d 8.14 (dd, 1 H), 7.97 (d, 1H), 7.48 (m, 2H), 7.36 (m, 2H), 7 , 06 (d, 1H), 5.66 (s, 1H), 4.43 (m, 1H), 3.92 (m, 1H), 3.70 (m, 1H), 3.58 (m, 2H), 3.36 (m, 3H), 2.23 (m, 2H), 1.82 (m, 2H), 1, 23 (m, 6H) Analysis of the mass spectrum m / z = 518.3 (M + H) + Preparation of 6A: To a solution of 6.2 (0.2 g, 0.386 mmol, 1.0 eq) in a mixture of methanol (15 mL) and water (5 mL) at 0 ° C was added potassium carbonate (0.32 g, 2.32 mmol, 6.0 eq) fractionally. The mixture was warmed to room temperature and stirred at room temperature for 10 h. Brine (50 mL) and chloroform (50 mL) were added and the two phases separated. The aqueous phase was extracted with chloroform (3 x 30 mL). The combined organic phases were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative liquid chromatography (mobile phase: acetonitrile / water / trifluoroacetic acid). The desired fractions were combined and concentrated under reduced pressure. The product was dissolved in chloroform (100 mL), washed with an aqueous 1M sodium carbonate solution (2 x 30 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. To a cold solution (0 ° C) of the resulting oil in anhydrous dichloromethane was added dropwise a solution of 1.0M hydrogen chloride in diethylether (0.8 mL, 0.8 mmol, 2.0 eq). The mixture was then stirred for 1 h at room temperature, concentrated under reduced pressure, and dried under vacuum. Yield: 50% 1 H NMR (400MHz, DMSO dβ) d 9.01 (m, 2H), 8.19 (dd, 1H), 7.79 (d, 1H), 7.49 (m, 4H), 7.29 (d, 1H), 6.19 (s, 1 H), 3.56-3.14 (m, 8H), 2.11 (m, 4H), 1.13 (m, 6H) Analysis of the mass spectrum m / z = 422.3 (M + H) + EXAMPLE 6B Preparation of 6.4: To a cold (0 ° C) solution of 6.2 (1.92 g, 3 , 71 mmol, 1.0 eq) in ethanol (50 mL) was added tin chloride (II) dihydrate (6.3) (2.51 g, 11.13 mmol, 3.0 eq) in one portion. The reaction mixture was heated to reflux temperature for 10 h and then concentrated under reduced pressure to give the crude product, which was used in the next step without further purification. Analysis of the mass spectrum m / z = 488.2 (M + H) + Preparation of 6B: To a suspension of 6.4 (1.3 g, crude, from 0.91 mmol, 1.0 eq) in a mixture of methanol (30 mL) and water (10 mL) at 0 ° C was added potassium carbonate (0.75 g, 5.46 mmol, 6.0 eq) fractionally. The reaction mixture was warmed to room temperature and stirred at room temperature for 10 h. Brine (50 mL) and chloroform (50 mL) were added and the two phases separated. The aqueous phase was extracted with chloroform (3 x 30 mL). The combined organic phases were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative liquid chromatography (mobile phase: acetonitrile / water / trifluoroacetic acid). The desired fractions were combined, concentrated under reduced pressure, and dried in vacuo. Yield: 27% in two stages 1 H NMR (400MHz, DMSO d 6) d 9,98 (sa, 2.5H), 9.11 (m, 2H), 7.44 (m, 4H), 7.23 (dd, 1H), 7.15 (d, 1H), 7.00 (d, 1H), 6.06 (s, 1 H), 3.78-3.10 (m, 8H), 2.06 (m, 4H), 1.12 (m, 6H) Analysis of the mass spectrum m / z = 392.2 (M + H) + EXAMPLE 60 Preparation of 6.6a: To a suspension of 6.4 (1.5 g, crude, from 1.05 mmol, 1.0 eq) in dichloroethane (50 mL) at 0 ° C was added pyridine (0.42 g, 5.25 mmol, 5 eq) followed by the dropwise addition of ethylchloride of sulfonyl (6.5a) (0.30 mL, 3.15 mmol, 3.0 eq). The mixture was stirred at 0 ° C for another 2h. An aqueous solution of 1 M hydrochloric acid (100 mL) and chloroform (100 mL) was added and the two phases were separated. The aqueous phase was extracted with chloroform (3 x 50 mL). The combined organic phases were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (eluent: mixtures of hexane / ethyl acetate of increasing polarity). Yield: 90% Analysis of the mass spectrum m / z = 580.3 (M + H) + Preparation of 6C: To a solution of 6.6a (0.55 g, 0.9 mmol, 1.0 eq) in a mixture of methanol (20 mL) and water (5 mL) at 0 ° C was added potassium carbonate (0, 78 g, 5.4 mmol, 6.0 eq) fractionally. The mixture was warmed to room temperature and stirred at room temperature for 10 h. Brine (100 mL) and chloroform (100 mL) were added and the two phases separated. The aqueous phase was extracted with chloroform (3 x 50 mL). The combined organic phases were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (eluent: dichloromethane / methanol mixture of increasing polarity). The desired fractions were combined and concentrated under reduced pressure. To a cold solution (0 ° C) of the resulting oil in anhydrous dichloromethane was added dropwise a solution of 1.0M hydrogen chloride in diethylether (1.8 mL, 1.8 mmol, 2.0 eq). The mixture was then stirred for 1 h at room temperature, concentrated under reduced pressure, and dried under vacuum. Yield: 80% 1 H NMR (400MHz, DMSO d6) d 9.49 (s, 1H), 8.91 (m, 2H), 7.43 (m, 4H), 7.11 (dd, 1 H), 7.02 (d, 1H), 6.93 (d, 1H), 6.00 (s, 1H), 3.45 (sa, 2H), 3.21 (d. m, 6H), 2.97 (c, 2H), 2.03 (m, 4H), 1.20-1.00 (m, 9H) Analysis of the mass spectrum m / z = 484.2 (M + H) + Elemental analysis: C26H33N3O4S, 1 HCl, 1,25H2O Theoretical:% C 57,55; % H 6.78; % N 7.74 Found:% C 57,52; % H 6.67; % N 7.73 EXAMPLE 6D 6D was obtained according to a procedure similar to that described for 6C, with the following exception: Stage 6.5: 6.5a was replaced by 6.5b. 1 H NMR (400MHz, DMSO d6) d 9.48 (s, 1H), 8.66 (ma, 1H), 7.43 (s, 4H), 7.12 (dd, 1H), 7.01 (d , 1H), 6.95 (d, 1H), 6.00 (s, 1H), 3.46 (sa, 4H), 3.23 (ma, 4H), 3.12 (m, 1H), 2 , 06 (m, 2H), 1, 95 (m, 2H), 1.20 (d, 6H), 1, 12 (day, 6H) Analysis of the mass spectrum m / z = 498.2 (M + H ) + EXAMPLE 6E Preparation of 6.8: To a suspension of 6.4 (1.0 g, crude, from 0.58 mmol, 1.0 eq) in dichloroethane (30 mL) at 0 ° C was added pyridine ( 0.23 mL, 2.9 mmol, 5.0 eq) followed by the dropwise addition of acetyl chloride (6.7) (0.16 mL, 2.32 mmol, 4.0 eq). The reaction mixture was slowly warmed to room temperature and stirred at room temperature for 10 h. An aqueous solution of 1 M hydrochloric acid (50 mL) and chloroform (50 mL) was added and the two phases were separated. The aqueous phase was extracted with chloroform (3 x 50 mL). The combined organic phases were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (eluent: hexane / ethyl acetate mixture of increasing polarity). Yield: 88% Analysis of the mass spectrum m / z = 530.2 (M + H) + Preparation of 6E: To a solution of 6.8 (0.27 g, 0.5 mmol, 1.0 eq) in a mixture of methanol (20 mL) and water (5 mL) at 0 ° C was added potassium carbonate (0.42 g, 3.0 mmol, 6.0 eq) fractionally. The reaction mixture was warmed to room temperature and stirred at room temperature for 10 h. Brine (100 mL) and chloroform (100 mL) were added and the two phases separated. The aqueous phase was extracted with chloroform (3 x 30 mL). The combined organic phases were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was first purified by column chromatography (eluent: dichloromethane / methanol mixture of increasing polarity) and then re-purified by preparative liquid chromatography (mobile phase: acetonitrile / water / trifluoroacetic acid). The desired fractions were combined and concentrated under reduced pressure. The product was dissolved in chloroform (100 mL) and washed with a 1 M sodium carbonate solution (2 x 30 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. To a cold solution (0 ° C) of the resulting oil in anhydrous dichloromethane was added dropwise 1.0M hydrogen chloride in diethyl ether (1, 0 mL, 1.0 mmol, 2 eq). The mixture was then stirred for 1 h at room temperature, concentrated under reduced pressure, and dried under reduced pressure. Yield: 73% 1 H NMR (400MHz, DMSO d6) d 9.34 (s, 1 H), 8.80 (sa, 2H), 7.68 (d, 1H), 7.42 (s, 4H), 6.90 (t, 1H), 6.77 (d, 1 H), 5.95 (s, 1H), 3.45 (sa, 2H), 3.25 (m, 6H), 2.15 ( s, 3H), 2.04 (m, 4H), 1.12 (m, 6H) Analysis of the mass spectrum m / z = 434.2 (M + H) + Elemental analysis: C26H31 3O3, 1HCI, 1, 7H2O Theoretical:% C 62.38; % H 7.13; % N 8.39 Found:% C 62.26; % H 6.81; % N 8.29 EXAMPLE 7A Preparation of 7.2: To a solution of 3.1a (3 g, 4.80 mmol, 1.0 eq), sodium urea-butoxide (0.55 g, 5.67 mmol, 1.18 eq), dipalladium (0) tris (dibenzylideneacetone) (0.22 g, 0.24 mmol, 0.05 eq) and 1,1'-bis (diphenylphosphino) ferrocene (dppf) (0.39 g, 0, 70 mmol, 0.145 eq) in anhydrous toluene (48 mL) was added 7.1 (0.95 mL, 5.67 mmol, 1.18 eq) at room temperature. The solution was stirred at 80 ° C overnight and then cooled to room temperature. The mixture was diluted with ethyl acetate and filtered under vacuum through a plug of Celite. The filtrate was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (eluent: mixtures of hexane / ethyl acetate of increasing polarity). Yield: 33% Analysis of the mass spectrum m / z - 656.6 (M + H) + Preparation of 7.3: To a solution of 7.2 (1.00 g, 1.52 mmol, 1.0 eq) in anhydrous methanol (5 mL) at room temperature under nitrogen was added hydroxylamine hydrochloride (0.21 g, 2.97 mmol, 1.95 eq) and sodium acetate (0.64 g, 7.78 mmol, 5.1 eq). . The mixture was stirred overnight at room temperature. The mixture was then diluted with ethyl acetate, washed with a saturated aqueous sodium bicarbonate solution and brine, dried over sodium sulfate and filtered. The organic extracts were concentrated under reduced pressure and the crude product was purified by column chromatography (eluent: mixtures of hexane / ethyl acetate of increasing polarity). Yield: 99% Analysis of the mass spectrum m / z = 492.5 (M + H) + Preparation of 7.5: To a solution of 7.3 (0.75 g, 1.53 mmol, 1.0 eq) and triethylamine ( 1.06 mL, 7.63 mmol, 5.0 eq) in dichloromethane (10 mL) at 0 ° C under nitrogen was added dropwise 7.4 (0.35 mL, 4.58 mmol, 3.0 eq) . The mixture was stirred overnight at room temperature. An aqueous solution of sodium bicarbonate was added and the mixture was stirred for 20 min. The phases were separated and the organic phase was washed with an aqueous solution of sodium bicarbonate, brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was used in the next step without further purification. Yield: 83% Analysis of the mass spectrum m / z - 648.5 (M + H) + Preparation of 7.6: To a solution of 7.5 (0.82 g, 1.27 mmol, 1.0 eq) in tetrahydrofuran ( 5 mL) and methanol (5 mL) was added an aqueous solution of 1 N sodium hydroxide (5 mL, 5 mmol, 4.0 eq). The mixture was stirred at room temperature for 3 h under nitrogen. The mixture was then neutralized with an aqueous solution of 1N hydrochloric acid (50 mL). The mixture was extracted with ethyl acetate and the organic phase was further washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (eluent: mixtures of hexane / ethyl acetate of increasing polarity). Yield: 40% 1H NMR (400MHz, DMSO d6) d 9.35 (m, 1 H), 7.41 (s, 4H), 7.09 (m, 1H), 6.97 (d, 1 H) , 6.91 (d, 1H), 5.92 (s, 1 H), 3.72 (m, 2H), 3.44 (m, 2H), 3.23 (m, 4H), 2.87 (s, 3H), 1.86 (m, 2H), 1.71 (m, 2H), 1.42 (s, 9H), 1.11 (m, 6H) Analysis of the mass spectrum m / z = 570.4 (M + H) + Preparation of 7A: A solution of 2.0M hydrochloric acid in diethylether (1.4 mL, 2.78 mmol, 5.5 eq) was added dropwise to a cooled solution (0.degree. ° C) of 7.6 (0.29 g, 0.51 mmol, 1.0 eq) in anhydrous dichloromethane (5 mL). The mixture was warmed to room temperature and stirring was continued for a further 10 h at room temperature. Diethyl ether (100 mL) was added to the solution and the resulting precipitate was collected by filtration and washed with diethyl ether. The crude product was purified by column chromatography (eluent: mixtures of dichloromethane / methanol of increasing polarity). Yield: 25% 1 H NMR (400MHz, DMSO d6) d 9.42 (s, 1H), 8.85 (m, 2H), 7.43 (m, 4H), 7.12 (m, 1H), 7 , 05 (m, 1H), 6.93 (m, 1H), 6.00 (s, 1H), 3.45 (m, 2H), 3.37 (m, 2H), 3.24 (m, 4H), 2.88 (s, 3H), 2.07 (m, 2H), 1.98 (m, 2H), 1, 11 (m, 6H) Analysis of the mass spectrum m / z - 470.4 (M + H) + Elemental Analysis: C25H31 N3O4S, 1HCI, 2H2O Theoretical:% C 55.39; % H 6.69; % N 7.75 Found:% C 55.03; % H 6.33; % N 7.36 EXAMPLE 7B Preparation of 7.7: To a solution of 7.6 (0.5 g, 0.88 mmol, 1.0 eq) in dry tetrahydrofuran (20 mL) at 0 ° C was added sodium hydride (dispersion 60% in mineral oil, 70 mg, 1.76 mmol, 2.0 eq) in one portion. The reaction mixture was kept at 0 ° C for 1 h and methyl iodide (2.8c) (0.08 mL, 1.1 mmol, 1.3 eq) was added dropwise. The mixture was kept at 0 ° C for another 30 min, heated to room temperature, and then heated at 80 ° C for 10 h. Water (50 mL) and chloroform (100 mL) were added and the two phases separated. The aqueous phase was extracted with chloroform (3 x 50 mL). The combined organic phases were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (eluent: mixtures of hexane / ethyl acetate of increasing polarity). Yield: 83% 1 H NMR (400MHz, CDCl 3) d 7.43 (m, 2H), 7.36 (m, 2H), 7.19 (dd, 1H), 7.01 (d, 1 H), 6 , 95 (d, 1 H), 5.61 (s, 1 H), 3.87 (sa, 2H), 3.57 (sa, 2H), 3.32 (m, 4H), 3.21 ( s, 3H), 2.81 (s 3H), 2.05 (m, 2H), 1.68 (m, 2H), 1.48 (s, 9H), 1.20 (m, 6H) Analysis of the mass spectrum m / z = 584.3 (M + H) + Preparation of 7B To a cold (0 ° C) solution of 7.7 (0.43 g, 0.73 mmol, 1.0 eq) in anhydrous dichloromethane (20 mL) was added dropwise a 1.0 M sodium chloride solution. hydrogen in diethylether (4.38 L, 4.38 mmol, 6.0 eq). The reaction mixture was stirred at room temperature for 10 h and then concentrated under reduced pressure. The crude product was purified by preparative liquid chromatography (mobile phase: acetonitrile / water / trifluoroacetic acid). The desired fractions were combined and concentrated under reduced pressure. The product was dissolved in chloroform (100 mL) and washed with a 1 M sodium carbonate solution (2 x 30 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. To a cold (0 ° C) solution of the resulting oil in anhydrous dichloromethane was added dropwise 1.0 M hydrogen chloride in diethylether (1.46 mL, 1.46 mmol, 2.0 eq). The mixture was then stirred for 1 h at room temperature, concentrated under reduced pressure, and dried under vacuum. Yield: 60% 1 H NMR (400MHz, DMSO d6) d 8.79 (m, 2H), 7.44 (m, 4H), 7.34 (dd, 1H), 7.10 (d, 1 H), 7.00 (d, 1 H), 6.03 (s, 1H), 3.23 (m, 8H), 3.14 (s, 3H), 2.89 (s, 3H), 2.04 (m, 4H), 1, 11 (m, 6H) Analysis of the mass spectrum m / z = 484.2 (M + H) + Elemental analysis: C26H33N3O4S, 1HCl, 1, 3H2O Theory:% C 57.46; % H 6.79; % N 7.73 Found:% C 57.46; % H 6.86; % N 7.80 EXAMPLE 7C Preparation of 7.8: To a suspension of 6.4 (2 g, crude, from 1.4 mmol, 1.0 eq) in dichloromethane (50 mL) at 0 ° C was added triethylamine (0.98 mL, 7.0 mmol, 5 eq) followed by the dropwise addition of sulfonyl methyl chloride (7.4) (0.33 mL, 4.2 mmol, 3.0 eq). The reaction mixture was stirred at 0 ° C for 1 h. An aqueous solution of 1 M hydrochloric acid (100 mL) and chloroform (100 mL) was added and the two phases were separated. The aqueous phase was extracted with chloroform (3 x 50 mL). The combined organic phases were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product, which were used in the next step without further purification. Analysis of the mass spectrum m / z - 644.2 (M + H) + Preparation of the mixture of 7A and 7C: To a suspension of 7.8 (1.57 g, crude, from 1.4 mmol, 1 , 0 eq) in a mixture of methanol (20 mL), tetrahydrofuran (20 mL) and water (20 mL) was added lithium hydroxide hydrate (0.98 mL, 7.0 mmol, 5.0 eq). The reaction mixture was stirred at room temperature for 10 h and then concentrated under reduced pressure to give the crude product as a mixture of 7A and 70, which was carried to the next step without further purification. Analysis of the mass spectrum m / z = 470.2 (M + H) + (7 A) Analysis of the mass spectrum m / z = 484, 2 (M + H) + (70) Preparation of 7C To a suspension of the mixture of 7A and 7C (2.2 g, crude, from 1.4 mmol, 1.0 eq) in dry dichloroethane ( 50 mL) at 0 ° C was added pyridine (0.34 mL, 4.2 mmol, 3 eq) followed by di-ert-butyl dicarbonate (4.7) (0.46 g, 2.1 mmol, 1, 5 eq) fractionally. The reaction mixture was slowly warmed to room temperature and stirred at room temperature for 10 h. Water (50 mL) and chloroform (100 mL) were added. The two phases were separated and the aqueous phase was further extracted with chloroform (3 x 50 mL). The combined organic phases were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (eluent: mixtures of hexane / ethyl acetate of increasing polarity to obtain 7.6 as the pure compound; eluent: dichloromethane / methanol mixture of increasing polarity to obtain crude 7C). Yield: 62% for 7.6 in three steps The crude 7C (100 mg) was further purified by preparative liquid chromatography (mobile phase: acetonitrile / water / trifluoroacetic acid). The desired fractions were combined and concentrated under reduced pressure. The product was dissolved in chloroform (100 mL) and washed with an aqueous solution of sodium carbonate 1 (2 x 30 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. To a cold solution (0 ° C) of the resulting oil in anhydrous dichloromethane was added dropwise a solution of 1.0M hydrogen chloride in diethylether (0.41 mL, 0.41 mmol, 2.0 eq). The mixture was then stirred for 1 h at room temperature, concentrated under reduced pressure, and dried under vacuum. 1 H NMR (400MHz, DMSO d6) d 10.47 (m, 1H), 9.435 and 9.422 (2s, 1H), 7.51-6.92 (m, 7H), 6.31 and 5.90 (2s, 1 H), 3.50-3.17 (m, 8H), 2.88 and 2.87 (2s, 3H), 2.82 (d, 3H), 2.12 (m, 4H), 1, 12 (m, 6H) Analysis of the mass spectrum m / z = 484.2 (M + H) + Elemental analysis: C26H33N3O4S, 1HCl, 0.9H2O Theoretical:% C 58.23; % H 6.73; % N 7.84 Found:% C 58,02; % H 6.68; % N 8.20 EXAMPLE 8A 8A was obtained according to a procedure similar to that described for 2A, with the following exception: Stage 2.1: 2.1 was replaced by 8.1 (see also step 8.1). 1 H NMR (400MHz, DMSO d6) d 9.16 (s, 1H), 8.92 (sa, 1H), 8.73 (sa, 1H), 7.40 (s, 4H), 6.78 (m, 2H), 6.43 (dd, 1 H), 5.86 (s, 1H), 3.43 (ma, 4H), 3.20 ( ma, 4H), 2.09 (m, 2H), 1.93 (m, 2H), 1.11 (day, 6H) Mass spectrum analysis m / z = 393.4 (M + H) + Elemental analysis: C24H28N2O3, 1 HCI, 0 , 33H2O Theory:% C 66.27; % H 6.87; % N 6.44 Found:% C 66.24; % H 6.77; % N 6.44 EXAMPLE 8B 8B was obtained according to a procedure similar to that described for 2A, with the following exceptions: Stage 2.1: 2.1 was replaced by 8.1 (see also step 8.1). Stage 2.4: 1.6 was replaced by 1.7 (see also step 8.4). 1 H NMR (400MHz, DMSO d6) d 9.12 (ma, 1H), 8.99 (ma, 1H), 8.57 (d, 1H), 7.88 (dd, 1 H), 7.59 (d, 1H), 6.84 (m, 1 H), 6.78 (t, 1H), 6.40 (dd, 1H), 6.00 (s, 1 H), 3.47 (c, 2H), 3.40 (m, 2H), 3.29 (c, 2H), 3.19 (m, 2H), 2.10 (m, 2H) ), 1.97 (m, 2H), 1.17 (t, 3H), 1, 10 (t, 3H) Mass spectrum analysis m / z = 394.2 (M + H) + Elemental analysis: C24H27N3 ° 3 ,. 2HC |. 0.67H2O Theoretical:% C 57.74; % H 6.39; % N 8.78; % C1 14.82 HaUado:% C 57.70; % H 6.28; % N 8.73; % C1 14.47 EXAMPLE 8C 80 was obtained according to a procedure similar to that described for 20, with the following exception: Stage 2.1: 2.1 was replaced by 8.1 (see also step 8.1). 1 H NMR (400MHz, DMSO d6) d 8.88 (ma, 2H), 7.42 (s, 4H), 7.00 (d, 1H), 6.86 (t, 1H), 6.58 (d , 1H), 5.97 (s, 1H), 3.90 (d, 2H), 3.44 (m, 2H), 3.23 (ma, 6H), 2.09 (, 2H), 1, 98 (m, 2H), 1, 26 (m, 1 H), 1, 12 (day, 6H), 0.59 (m, 2H), 0.37 (m, 2H) Analysis of the mass spectrum m / z = 447.3 (M + H) + Elemental analysis: C2dH34 2O3, 1 HCl, 1.5H2O Theoretical:% C 65.93; % H 7.51; % N 5.49 HaUado:% C 65.64; % H 7.29; % N 5.41 EXAMPLE 8D 8D was obtained according to a procedure similar to that described for 2C, with the following exceptions: Stage 2.1: 2.1 was replaced by 8.1 (see also step 8.1). Step 2.7: 2.8a was replaced by 2.8c (Procedure 2A was used) (see also step 8.7). 1 H NMR (400MHz, DMSO d6) d 8.78 (br s, 2H), 7.41 (s, 4H), 7.04 (d, 1H), 6.90 (t, 1 H), 6.58 (d, 1H), 5.97 (s, 1H), 3.83 (s, 3H), 3.44 (sa, 2H), 3.20 ( ma, 6H), 2.08 (m, 2H), 1.97 (m, 2H), 1.12 (da, 6H) Analysis of the mass spectrum m / z = 407.3 (M + H) + Elemental analysis: C25H30N2O3. 1 HCl, 1H2O Theory:% C 65.14; % H 7.22; % N 6.08 HaUado:% C 65.22; % H 6.85; % N 6.02 EXAMPLE 8E 8E was obtained according to a procedure similar to that described for 2C, with the following exceptions: Stage 2.1: 2.1 was replaced by 8.1 (see also step 8.1). Stage 2.4: 1.6 was replaced by 1.7 (see also step 8.4). 1 H NMR (400MHz, DMSO d6) d 8.94 (ma, 2H), 8.59 (d, 1 H), 7.88 (dd, 1H), 7.60 (d, 1H), 7.03 (d, 1H), 6.88 (t, 1 H), 6.56 (d, 1H), 6.11 (s, 1 H), 3.91 (d, 2H), 3.47 (c, 2H), 3.29 (m, 4H), 3.17 (m, 2H), 2.10 (m, 2H), 2.01 (m, 2H) , 1, 26 (m, 1H), 1, 17 (t, 3H), 1, 11 (t, 3H), 0.59 (m, 2H), 0.37 (m, 2H) Mass spectrum analysis m / z = 448.3 (M + H) + Elemental Analysis: C27H33N3O3. 1.2 HCl, 0.8H2O Theoretical:% C 64.12,% H 7.14; % N 8.31; % Cl 8.41 HaUado:% C 64.09; % H 7.20; % N 8.18; % C18.15 EXAMPLE 8F 8F was obtained according to a procedure similar to that described for 20, with the following exceptions: Stage 2.1: 2.1 was replaced by 8.1 (see also step 8.1). Stage 2.4: 1.6 was replaced by 1.7 (see also step 8.4). Stage 2.7: 2.8a was replaced by 2.8c (see also stage 8.7). 1 H NMR (400MHz, DMSO d) 58.96 (ma, 2H), 8.59 (d, 1H), 7.88 (dd, 1H), 7.60 (d, 1 H), 7.06 (d , 1H), 6.92 (t, 1 H), 6.56 (d, 1 H), 6.12 (s, 1 H), 3.84 (S, 3H), 3.47 (c, 2H) ), 3.28 (m, 4H), 3.14 (m, 2H), 2.09 (m, 2H), 2.02 (m, 2H), 1.17 (t, 3H), 1, 11 (t, 3H) Analysis of the mass spectrum m / z = 408.4 (M + H) + Elemental analysis: C24H29N3O3, 2HCU, 5H2? Theoretical:% C 56.81; % H 6.75; % N 8.28; % C1 13.97 Found:% C 56.80; % H 6.48; % N 8.24; % C113.89 EXAMPLE 9A 9A was obtained according to a procedure similar to that described for 20, with the following exception: Stage 2.1: 2.1 was replaced by 9.1 (see also step 9.1). 1 H NMR (400MHz, DMSO d6) 59.68 (da, 2H), 7.41 (d, 2H), 7.35 (d, 2H), 6.92 (d, 1H), 6.43 (s, 1H), 6.37 (d, 1 H), 5.44 (s, 1H), 3.80 (d, 2H), 3.56 (sa, 2H), 3.40 (sa, 4H), 3 , 30 (sa, 2H), 2.30 (m, 2H), 2.19 (m, 2H), 1, 27 (m, 4H), 1.17 (sa, 3H), 0.66 (m, 2H), 0.36 (m, 2H) Analysis of the mass spectrum m / z = 447.3 (M + H) + Elemental analysis: C28H34N2O3, 1.0HCI, 1, 3H2O Theoretical:% C 66.40; % H 7.48; % N 5.53 HaUado:% C 66.28; % H 7.48; % N 5.48 EXAMPLE 9B Preparation of 9.5: 9.5 was obtained according to a procedure similar to that described for 2.7a except that 2.1 was replaced by 9.1 in step 2.1 (see also step 9.1).

Preparation of 9.8: To a solution of 9.5 (1.00 g, 2.02 mmol, 1.0 eq) in dimethylformamide (10 mL) was added sequentially cesium carbonate (3.30 g, 10.1 mmol, , 0 eq) and methyl chlorodifluoroacetate (9.7) (1.47 g, 10.1 mmol, 5.0 eq.). The reaction mixture was heated at 90 ° C for 48 h, poured into water (100 mL) and extracted with ethyl acetate. The organic extracts were washed with an aqueous solution of 1 N sodium hydroxide and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (eluent: mixtures of hexane: ethyl acetate of increasing polarity). Yield: 79% 1 H NMR (400MHz, CDCl 3) d 7.41 (d, 2H), 7.36 (d, 2H), 6.98 (d, 1 H), 6.73 (d, 1H), 6 , 61 (dd, 1 H), 6.52 (ts, 1 H, J = 73.8 Hz), 5.54 (s, 1 H), 3.86 (sa, 2H), 3.57 (ma , 2H), 3.32 (ma, 4H), 2.03 (d, 2H), 1.68 (m, 2H), 1.47 (s, 9H) 1, 20 (day, 6H) Spectrum analysis mass m / z = 543.4 (M + H) + Preparation of 9B: To a solution of 9.8 (860 mg, 1.58 mmol, 1.0 eq) in anhydrous methanol (15 mL) was added drop to drop a solution of 4.0M hydrochloric acid in dioxane (4.0 mL, 15.8 mmol, 10.0 eq). The mixture was stirred at room temperature for 16 h and the solvent was evaporated in vacuo. The crude oil was purified by reverse phase HPLC chromatography (eluent: mixtures of acetonitrile / water (0.1% trifluoroacetic acid) of decreasing polarity). The solvent was evaporated in vacuo and a solution of 1N HCl in diethylether (25 mL) was added. The resulting solid was filtered and washed with diethyl ether. Yield: 23% 1 H NMR (400MHz, CDCl 3) d 7.42 (d, 2H), 7.35 (d, 2H), 7.02 (d, 1H), 6.75 (m, 1H), 6, 66 (dd, 1 H), 6.54 (ts, 1 H, J = 73.4 Hz), 5.59 (s, 1H), 3.57 (sa, 2H), 3.41 (day, 4H) ), 3.31 (sa, 2H), 2.26 (m, 4H), 1, 21 (day, 6H) Mass spectrum analysis m / z = 443.4 (M + H) + Elemental analysis: C28H34N2O3 , 1.0 HCl, 1.2 H2O Theoretical:% C 59.99; % H 6.32; % N 5.60 Found:% C 60.01; % H 6.25; % N 5.54 EXAMPLE 10A 10A was obtained from 9.5 according to a procedure similar to that described for 3A, with the following exception: Stage 3.1: 2.7a was replaced by 9.5 (see also step 10.1). 1 H NMR (400MHz, DMSO d 6) 59.80 (br s, 1 H), 7.60 (s, 1H), 7.58 (d, 1H), 7.42 (d, 2H), 7.36 (d , 2H), 7.09 (d, 1H), 5.75 (s, 1H), 3.91 (s, 3H), 3.61 (sa, 2H), 3.40 (m, 4H), 3.30 (sa, 2H), 2.27 (m, 4H), 1, 20 (day, 6H) Mass spectrum analysis m / z = 435.3 (M + H) + Elemental analysis: C26H3? N2O4 , 1HCl, 1, 1H2O Theory:% C 63.63; % H 6.82; % N 5.71 Found:% C 63.64; % H 6.75; % N 5.72 EXAMPLE 10B 10B was obtained according to a procedure similar to that described for 3B, with the following exception: Step 3.1: 2.7a was replaced by 9.5 (see also step 10.1). 1 H NMR (400MHz, DMSO-d 6) d 13.10 (sa, 1H), 9.10 (ma, 2H), 7.57 (d, 1H), 7.52 (dd, 1H), 7.44 (s, 4H), 7.12 (d, 1 H), 6.09 (s, 1H), 3.45 (sa, 2H), 3.35 ( ma, 2H), 3.23 (ma, 4H), 2.08 (m, 4H), 1.10 (day, 6H) Analysis of the mass spectrum m / z = 421.3 (M + H) + EXAMPLE 10C 10C was obtained according to a similar procedure to that described for 3E, with the following exceptions: Stage 3.5: 3.3a was replaced by 10.3 and 3.4b was replaced by 3.4a (see also stage . 5). 1 H NMR (400MHz, CDCl 3) d 9.50 (da, 2H), 7.64 (ma, 2H), 7.32 (ma, 5H), 7.00 (sa, 2H), 5.68 (s, 1H), 3.50 (ma, 4H), 3.27 (ma, 4H), 2.62 (sa, 2H), 2.19 (sa , 2H), 1, 17 (da, 6H) Analysis of the mass spectrum m / z = 420.3 (M + H) + EXAMPLE 10D Preparation of 10.2: Compound 10.2 was obtained according to a procedure similar to that described for 3.2a except that 2.7a was replaced by 9.5 in stage 3.1 (see also step 10.1).

Preparation of 10.4: To a solution of methylamine 2N (3.4b) in methanol (10.0 mL, 20.0 mmol, 11.0 eq) was added fractionally at room temperature 10.2 (1.00 g, 1, 86 mmol) in a sealed tube. The mixture was heated at 60 ° C for 20 h until a homogeneous solution was formed. The mixture was poured into water (25 mL), extracted with methylene chloride, washed with brine, dried over sodium sulfate, filtered and the solvent was evaporated to an off-white solid. The crude product was purified by column chromatography (eluent: mixtures of hexane / ethyl acetate of increasing polarity).

Yield: 80% 1 H NMR (400MHz, CDCl 3) d 7.53 (s, 1 H), 7.47 (s, 1H), 7.45 (d, 2H), 7.23 (d, 1H), 7 , 04 (d, 1H), 6.20 (sa, 1H), 5.64 (s, 1H), 3.88 (sa, 2H), 3.57 (ma, 2H), 3.33 (ma, 4H), 3.00 (d, 3H), 2.03 (d, 2H), 1.68 (ma, 2H), 1.45 (s, 9H) 1, 21 (day, 6H) Analysis of the spectrum of masses m / z = 534.4 (M + H) + Preparation of 10D: To a solution of 10.4a (790mg, 1.48 mmol, 1.0 eq) in anhydrous methanol (20 mL) was added dropwise a solution of 4M hydrochloric acid in dioxane (3.7 mL, 14.8 mmol, 0.0 eq). The mixture was stirred at room temperature for 16 h and the solvent was evaporated in vacuo to a white solid. The white solid was triturated in diethyl ether (50 mL). The resulting solid was collected by filtration and washed with diethyl ether. Yield: 85% 1 H NMR (400MHz, CDCl 3) d 7.43 (m, 3H), 7.34 (m, 3H), 7.05 (d, 1 H), 6.90 (da, 1H), 5 , 69, (s, 1H), 3.57 (ma, 2H), 3.35 (ma, 6H), 3.00 (d, 3H), 2.20 (sa, 4H), 1.19 (da , 6H) Analysis of the mass spectrum m / z = 434.3 (M + H) + Elemental analysis: C26H31 N3? 3, 1.0 HCl, 1.5 H2O Theoretical:% C 62.83; % H 7.10; % N 8.45 Found:% C 62.74; % H 6.95; % N 8.29 EXAMPLE 10E 10E was obtained according to a procedure similar to that described for 3E, with the following exceptions: Stage 3.5: 3.3a was replaced by 10.3 and 3.4b was replaced by 3.4c (see also step 10.5) ( Procedure 10A was used). 1 H NMR (400MHz, CDCl 3) d 9.68 (sa, 2H), 7.43 (m, 3H), 7.34 (m, 3H), 7.06 (d, 1H), 6.61 (sa, 1 H), 5.68 (s, 1 H), 3.57 (sa, 2H), 3.50 (ma, 2H), 3.40 (sa, 2H), 3.32 (sa, 2H), 2.25 (sa, 4H), 1, 28 (ma, 6H), 1, 15 (sa, 3H) Analysis of the mass spectrum m / z = 448.3 (M + H) + EXAMPLE 10F 10F was obtained according to a procedure similar to that described for 3E, with the following exceptions: Stage 3.5: 3.3a was replaced by 10.3 and 3.4b was replaced by 3.4j (see also step 10.5) and the TBTU was replaced by the HATU (the Procedure 10B). 1 H NMR (400MHz, DMSO d6) 59.77 (ma, 2H), 7.42 (d, 2H), 7.36 (d, 2H), 7.08 (d, 1 H), 7.03 (s, 1H), 6.97 (d, 1 H), 5.66 (s, 1H), 3.59 (sa, 2H), 3.40 (sa, 4H), 3.32 (sa, 2H), 3.12 (s, 3H), 3.04 (s, 3H), 2.28 (m, 4H), 1, 20 (day, 6H) Mass spectrum analysis m / z = 448.3 (M + H) + Elemental analysis: C27H33N3O3, 1 HCl, 1.7H2O Theoretical:% C 63.01; % H 7.32; % N 8,16 HaUado:% C 63.06; % H 7.18; % N 8.09 EXAMPLE 10G 10G was obtained according to a procedure similar to that described for 3E, with the following exceptions: Stage 3.5: 3.3a was replaced by 10.3 and 3.4b was replaced by 1.12 (see also step . 5) (Procedure 10A was used). 1 H NMR (400MHz, DMSO d ") 59.73 (sa, 2H), 7.43 (d, 2H), 7.36 (d, 2H), 7.07 (d, 1 H), 6.98 (s, 1 H), 6.92 (d, 1H), 5.67 (s, 1H), 3.56 (sa, 4H), 3.40 (sa, 4H), 3.31 (sa, 4H), 2.26 (sa, 4H), 1, 22 (day, 12H) Analysis of the mass spectrum m / z = 476.2 (M + H) + Elemental analysis: C29H37N3O3, 1 HCl, 1.7H2O Theory:% C 64.18; % H 7.69; % N 7.74 Found:% C 64.08; % H 7.45; % N 7.60 EXAMPLE 10H 10H was obtained according to a procedure similar to that described for 3E, with the following exception: Stage 3.5: 3.3a was replaced by 10.3 and 3.4b was replaced by 3.4k (see also step 10.5) ( Procedure 10A was used). 1 H NMR (400MHz, DMSO d) 59.77 (sa, 2H), 7.43 (d, 2H), 7.37 (d, 2H), 7.12 (s, 1H), 7.09 (s, 2H), 5.68 (s, 1 H), 3.64 (m, 2H), 3.60 (ma, 2H), 3.47 (m, 2H), 3.40 (ma, 4H), 3 , 30 (sa, 2H), 2.30 (sa, 4H), 2.00 (m, 2H), 1, 93 (m, 2H), 1, 24 (day, 6H) Analysis of the mass spectrum m / z = 474.3 (M + H) + Elemental Analysis: C29H35N3? 3, 1 HCl, 0.7 H2O Theory:% C 66.64; % H 7.21; % N 8.04 Found:% C 66.56; % H 7.07; % N 7.91 EXAMPLE 101 101 was obtained according to a procedure similar to that described for 3E, with the following exception: Stage 3.5: 3.3a was replaced by 10.3 and 3.4b was replaced by 3.4c (see also step 10.5) ( Procedure 10A was used). 1 H NMR (400MHz, CDCl 3) d 9.70 (br s, 2 H), 7.44 (d, 2 H), 7.35 (d, 2 H), 7.09 (d, 1 H), 7.02 (s) , 1 H), 6.96 (dd, 1 H), 5.68 (s, 1H), 3.73 (ma, 6H), 3.58 (sa, 4H), 3.41 (ma, 4H), 3.31 (sa, 2H), 2.28 (m, 4H), 1, 21 (m, 6H) Analysis of the mass spectrum m / z = 490.2 (M + H) + EXAMPLE 10J Preparation of 10.5: To a suspension of LiBH4 (82.0 mg, 3.75 mmol, 2.0 eq.) in tetrahydrofuran (20 mL) After cooling to 0 ° C under a nitrogen atmosphere, a solution of 10.2 (1.00 g, 1.87 mmol, 1.0 eq) in tetrahydrofuran (10 mL) was added dropwise. The reaction mixture was warmed to room temperature and stirred for 16 h at room temperature. The reaction mixture was quenched with water (0.54 mL, 8 eq.), Extracted with ethyl acetate, washed with brine, dried over sodium sulfate and filtered. The solvent was removed in vacuo and the crude product was purified by column chromatography (eluent: mixtures of hexane / ethyl acetate of increasing polarity). Yield: 49% 1 H NMR (400MHz, CDCl 3) d 7.40 (d, 2H), 7.36 (d, 2H), 6.98 (m, 2H), 6.85 (d, 1H), 5, 56 (s, 1H), 4.65 (s, 2H), 3.87 (sa, 2H), 3.57 (sa, 2H), 3.32 (ma, 4H), 2.05 (d, 2H) ), 1, 91 (ta, 1H), 1, 66 (m, 2H), 1, 48 (s, 9H) 1, 21 (day, 6H) Analysis of the mass spectrum m / z = 507.3 (M + H) + Preparation of 10J: To a solution of 10.5 (460mg, 0.91 mmol, 1.0 eq) in anhydrous methanol (30 mL) was added dropwise a solution of 4M hydrochloric acid in dioxane (2, 3 mL, 9.1 mmol, 10.0 eq.). The mixture was stirred at room temperature for 16 h and the solvent was evaporated in vacuo. The residue was triturated in ethyl ether (50 mL); the solid was collected by filtration and washed with diethyl ether. The crude product was purified by column chromatography (eluent: mixtures of methylene chloride / methanol of increasing polarity). Yield: 46% 1 H NMR (400MHz, CDCl 3) d 9.62 (sa, 2H), 7.38 (da, 4H), 7.00 (m, 2H), 6.90 (da, 1H), 5, 60 (sa, 1H), 4.66 (sa, 2H), 3.58 (ma, 2H), 3.40 (ma, 4H), 3.31 (ma, 2H), 2.50 (sa, 1H) ), 2.25 (sa, 4H), 1, 21 (day, 6H) Analysis of the mass spectrum m / z = 407.4 (M + H) + Elemental analysis: C26H31 N3O3, 1 HCI, 0.7H2O Theoretical :% C 65.91; % H 7.17; % N 6.15 Found:% C 65.93; % H 6.99; % N 6.08 EXAMPLE 11 A Preparation of 11.2: The 2S6'-hydroxyacetophenone (11.1) (200.0 g, 1.31 mol, 1.0 eq) was added fractionally at room temperature to pyrrolidine (220 mL, 2.0 eq) followed by the addition of fractionated form of 1-Boc-4-piperidone (1.2) (262.0 g, 1.31 mol, 1.0 eq). Then anhydrous methanol (100 mL) was added and the red suspension was heated to reflux temperature to dissolve all solids. After dissolution, the reaction was cooled to room temperature overnight with stirring to form a solid mass. This solid mass was dissolved in ethyl acetate, washed with an aqueous solution of 1N hydrochloric acid, an aqueous solution of 1N sodium hydroxide and brine, dried over sodium sulfate and filtered. The solvent was evaporated in vacuo. A mixture of hexane and diethylether (80:20) (400 mL) was added to the mixture and the resulting precipitate was collected by filtration, washed with hexane and used for the next step without further purification.

Performance: 74%. 1 H NMR (400MHz, CDCl 3) 11, 61 (s, 1H), 7.37 (t, 1H), 6.49 (d, 1H), 6.44 (d, 1H), 3.89 (sa, 2H), 3.20 (ma, 2H), 2.73 (s, 2H), 2.02 (d, 2H), 1.64 (m, 2H), 1.46 (s, 9H) Spectrum analysis mass m / z = 334.0 (M + H) + Preparation of 11.4: To a solution of 11.2 (140.0 g, 0.420 mol, 1.0 eq) in dichloromethane (700 mL) at room temperature under nitrogen He added dropwise diisopropylethylamine (294.0 mL, 1.68 mol, 4.0 eq). Gold (methoxy) methane (11.3) (100.0 g, 1.26 mol, 3.0 eq) was added dropwise to this solution. The mixture was heated to reflux temperature for 16 h, cooled to room temperature and the solvent removed in vacuo to give a brown oil. This oil was dissolved in ethyl acetate (700 mL) and washed with an aqueous solution of 1 N hydrochloric acid, a saturated aqueous solution of sodium bicarbonate and brine. The organic extracts were dried over sodium sulfate, filtered and the solvent was removed in vacuo to give a brown oil. Diethyl ether (400 mL) was added and the resulting white precipitate was filtered and used for the next step without further purification. Yield: 83% 1 H NMR (400MHz, CDCl 3) d 7.36 (t, 1H), 6.74 (d, 1H), 6.65 (d, 1H), 5.27 (s, 2H), 3, 86 (br s, 2H), 3.52 (s, 3H), 3.22 (m, 2H), 2.69 (s, 2H), 2.02 (d, 2H), 1.60 (m, 2H) ), 1.46 (s, 9H) Analysis of the mass spectrum m / z = 378.2 (M + H) + Preparation of 11.5: To a solution of 11.4 (131.2 g, 0.348 mol) in tetrahydrofuran (600 mL) at -78 ° C under nitrogen atmosphere was added dropwise a solution of 1.0M LiHMDS in tetrahydrofuran (420.0 mL, 1.2 eq). The mixture was stirred for 1 h at -78 ° C. A solution of 1.4 (149.4 g, 0.418 mol, 1.2 eq) in tetrahydrofuran (200 mL) was added dropwise. The mixture was heated slowly to room temperature and stirring was continued for 12h more at room temperature. The mixture was then poured into ice water and the two phases separated. The organic phase was washed with an aqueous solution of 1 N hydrochloric acid, an aqueous solution of 1N sodium hydroxide and brine, dried over sodium sulfate and filtered. The solvent was removed in vacuo and the roasted oily residue was used in the next step without further purification. Yield: 100% 1 H NMR (400MHz, CDCl 3) d 6.98 (t, 1 H), 6.62 (d, 1 H), 6.39 (d, 1 H), 5.24 (s, 1 H ), 5.03 (s, 2H), 3.62 (sa, 2H), 3.30 (s, 3H), 3.07 (m, 2H), 1.84 (d, 2H), 1, 46 (m, 2H), 1, 26 (s, 9H) Analysis of the mass spectrum m / z = 510.0 (M + H) + Preparation of 11.6a: To a solution of 11.5 (100 g, 196 mmol, 1 , 0 eq) in dimethoxyethane (DME) (600 mL) was added sequentially an aqueous solution of 2N sodium carbonate (294 mL, 588 mmol, 3.0 eq), lithium chloride (25.0 g, 588 mmol, 3%). , 0 eq), 4- (N, N-diethylaminocarbonyl) phenylboronic acid (1.6) (36.9 g, 166 mmol, 1.1 eq) and tetrakis (triphenylphosphine) palladium (0) (4.54 g, 3 , 92 mmol, 0.02 eq). The mixture was heated to reflux temperature for 10 h under nitrogen. The mixture was then cooled to room temperature, filtered through a pad of Celite and the filter cake was washed with DME (100 mL) and water (750 mL). The aqueous mixture was extracted with ethyl acetate. The organic phase was further washed with brine and dried over sodium sulfate. The crude product was purified by chromatography (eluent: mixtures of hexane / ethyl acetate of increasing polarity). Yield: 62% 1 H NMR (400MHz, CDCl 3) d 7.21 (d, 2H), 7.17 (d, 2H), 7.05 (t, 1H), 6.60 (m, 2H), 5, 45 (s, 1H), 4.58 (s, 2H), 3.71 (sa, 2H), 3.45 (ma, 2H), 3.22 (ma, 4H), 3.06 (s, 3H) ), 1, 90 (d, 2H), 1.56 (m, 2H), 1.38 (s, 9H), 1, 09 (day, 6H) Mass spectrum analysis m / z - 537.4 ( M + H) + Preparation of 11 A: To a solution of 11.6a (25.0 g, 46.6 mmol, 1.0 eq) in anhydrous methanol (250 mL) was added a solution of hydrochloric acid dropwise 4M in dioxane (58.2 mL, 233 mmol, 5.0 eq). The mixture was stirred at room temperature for 16 h and the solvent was evaporated in vacuo to give a brown oil. Brown oil was added to methanol (20 mL) followed by diethyl ether (300 mL) and the resulting precipitate was collected by filtration and washed with diethyl ether. The solid was used in the next step without further purification. Performance: 100% 1H NMR (400MHz, DMSO dβ) d 9.55 (s, 1H), 9.07 (sa, 2H), 7.27 (m, 4H), 7.06 (t, 1 H), 6.52 (d, 1H) , 6.47 (d, 1H), 5.76 (s, 1 H), 3.42 (ma, 2H), 3.35 (s, 4H), 3.19, (ma, 6H), 2, 03 (m, 4H), 1, 11 (ma, 6H) Analysis of the mass spectrum m / z = 393.0 (M + H) + Elemental analysis: C24H28N2O3, 1HCI, 0.67H2O Theoretical:% C 65.37; % H 6.93; % N 6.35 Found:% C 65.41; % H 6.98; % N 6.31 EXAMPLE 11B 11B was obtained according to a procedure similar to that described for 11 A, with the following exception: Stage 11.4: 1.6 was replaced by 1.7. 1 H NMR (400MHz, DMSO d6) 9.67 (sa, 1H), 9.23 (da, 2H), 8.50 (s, 1 H), 7.79 (d, 1H), 7.52 (d , 1H), 7.09 (t, 1 H), 6.57 (d, 1H), 6.50 (d, 1H), 5.93 (s, 1H), 3.43 (c, 2H), 3.26 (c, 2H), 3.21 (m, 2H), 3.14 (m, 2H), 2.05 (m, 4H), 1.18 (t, 3H), 1.11 (t , 3H) Analysis of the mass spectrum m / z = 394.3 (M + H) + Elemental analysis: C23H27N3? 3, 2HCI, 1.5H2O Theoretical:% C 55.99; % H 6.54; % N 8.52 Found:% C 56.11; % H 6.54; % N 8.53 EXAMPLE 11C Preparation of 11.7a: To a suspension of 11A (10.0 g, 23.3 mmol, 1.0 eq) in tetrahydrofuran (200 mL) under a nitrogen atmosphere was added triethylamine (9, 75 mL, 69.9 mmol, 3.0 eq). The reaction mixture was cooled to 0 ° C. A solution of di-fer-butyl dicarbonate (4.7) (4.58 g, 21.0 mmol, 0.9 eq) in tetrahydrofuran (50 mL) was added dropwise to the reaction mixture, which was stirred for 3 h at room temperature. The solvent was evaporated in vacuo and the residue was dissolved in ethyl acetate (500 mL), washed with water and brine, and dried over sodium sulfate and filtered. The solvent was evaporated in vacuo. The residue was subjected to sonication and triturated in a mixture of ethyl acetate / methanol 95: 5 (75 mL). The solid was collected by filtration and washed with ethyl acetate. Yield: 100% 1 H NMR (400MHz, DMSO d6) d 9.49 (s, 1 H), 7.31 (s, 4H), 7.08 (t, 1H), 6.54 (d, 1H), 6.47 (d, 1 H), 5.77 (s, 1 H), 3.70 (m, 2H), 3.48 (ma, 2H), 3.30 (ma, 4H), 1.87 (d, 2H), 1.74 (m, 2H), 1.47 (s, 9H) 1, 16 (sa, 6H) Analysis of the mass spectrum m / z = 493.4 (M + H) + Preparation of 11.9a: To a solution of 11.7a (1.00 g, 2.02 mmol, 1.0 eq) in dichloromethane (4 mL) under a nitrogen atmosphere was added sequentially cyclopropylmethanol (2.8e) (189 mg, 2.63 mmol, 1.3 eq) and triphenylphosphine (690 mg, 2.63 mmol, 1.3 eq). The reaction mixture was stirred for 5 min at room temperature and a solution of diethyl azodicarboxylate (460 mg, 2.63 mmol, 1.3 eq) was added dropwise. The reaction was stirred an additional 30 min at room temperature and the solvent was evaporated in vacuo. The crude product was purified by chromatography (eluent: mixtures of hexane / ethyl acetate of increasing polarity). Yield: 42% 1 H NMR (400MHz, CDCl 3) d 7.31 (d, 2H), 7.27 (d, 2H), 7.13 (t, 1 H), 6.64 (d, 1H), 6.42 (d, 1H), 5.50 (s, 1 H), 3.78 (da, 2H), 3.54 (ma, 2H), 3.49 (d, 2H), 3 , 35 (ta, 4H), 2.02 (d, 2H), 1.69 (m, 2H), 1.47 (s, 9H) 1, 26 (day, 6H), 0.53 (m, 1H) ), 0.29 (m, 2H), -0.07 (m, 2H) Analysis of the mass spectrum m / z = 547.5 (M + H) + Preparation of 11 C: To a solution of 11.9a ( 460 mg, 0.84 mmol, 1.0 eq) in anhydrous methanol (15 mL) was added dropwise a solution of 4M hydrochloric acid in dioxane (2.0 mL, 8.4 mmol, 10.0 eq) . The mixture was stirred at room temperature for 16 h and the solvent was evaporated in vacuo. The residue was triturated in diethyl ether (50 mL). The resulting solid was collected by filtration and washed with diethyl ether. Yield: 97% 1 H NMR (400MHz, CDCl 3) d 9.67 (sa, 2H), 7.32 (d, 2H), 7.26 (d, 2H), 7.16 (t, 1 H), 6 , 64 (d, 1H), 6.46 (d, 1 H), 5.50 (s, 1 H), 3.54 (ma, 2H), 3.49 (d, 2H), 3.36 ( ma, 6H), 2.28 (d, 2H), 2.18 (m, 2H), 1.19 (da, 6H), 0.53 (m, 1H), 0.30 (m, 2H), -0.07 (m, 2H) Analysis of the mass spectrum m / z = 447.4 (M + H) + Elemental analysis: C28H34N2O3, 1.0 HCl, 0.7 H2O Theoretical:% C 67.73; % H 7.41; % N 5.64 Found:% C 67.73; % H 7.24; % N 5.59 EXAMPLE 11D 11D was obtained according to a procedure similar to that described for 11C, with the following exceptions: Stage 11.4: 1.6 was replaced by 1.7. 1 H NMR (400MHz, CDCl 3) d 9.67 (sa, 1 H), 8.44 (m, 1 H), 7.61 (dd, 1H), 7.55 (d, 1H), 7.19 ( t, 1 H), 6.64 (d, 1 H), 6.43 (d, 1 H), 5.55 (s, 1 H), 3.56 (c, 2 H), 3.50 (d, 2 H) ), 3.46 (c, 2H), 3.38 (m, 4H), 2.29 (m, 2H), 2.21 (m, 2H), 1, 28 (t, 3H), 1.17 (t, 3H), 0.54 (m, 1 H), 0.33 (m, 2H), -0.05 (m, 2H) Mass spectrum analysis m / z = 448.4 (M + H) + EXAMPLE 11 E Preparation of 11.9b: To a solution of 11.7a (1.00 g, 2.02 mmol, 1.0 eq) in acetone (20 mL) was he added sequentially potassium carbonate (1.70 g, 12.1 mmol, 6.0 eq) and bromocyclobutane (11.8) (1.66 g, 12.1 mmol, 6.0 eq). The reaction mixture was heated to reflux temperature for 90 h, poured into water (100 mL) and extracted with ethyl acetate. The organic extracts were washed with an aqueous solution of 1 N sodium hydroxide and brine, dried over sodium sulfate and filtered. The solvent was evaporated and the crude product was first purified by column chromatography (eluent: mixtures of hexane / ethyl acetate of increasing polarity) and then further purified by reverse phase HPLC chromatography (eluent: acetonitrile / water mixtures (0.1% trifluoroacetic acid) of decreasing polarity).

Yield: 18% 1 H NMR (400MHz, CDCl 3) 7.31 (d, 2H), 7.27 (d, 2H), 7.11 (t, 1 H), 6.64 (d, 1H), 6 , 26 (d, 1H), 4.36 (m, 1 H), 5.50 (s, 1H), 3.79 (da, 2H), 3.54 (ma, 2H), 3.48 (d , 2H), 3.34 (ma, 4H), 2.12 (m, 2H), 2.02 (d, 2H), 1.67 (m, 2H), 1.55 (m, 2H), 1 , 47 (s, 9H) 1.19 (day, 6H) Analysis of the mass spectrum m / z = 547.5 (M + H) + Preparation of 11 E: To a solution of 11.9b (200 mg, 0, 37 mmol, 1.0 eq) in anhydrous methanol (25 mL) was added dropwise a solution of 2M hydrochloric acid in diethylether (0.73 mL, 1.44 mmol, 4.0 eq). The mixture was stirred at room temperature for 16 h and the solvent was evaporated in vacuo. The residue was triturated in diethyl ether (50 mL). The solid was collected by filtration and washed with diethyl ether. Yield: 96"% 1 H NMR (400MHz, DMSO d6) 9.14 (sa, 2H), 7.29 (d, 2H), 7.24 (d, 2H), 7.19 (t, 1H), 6.68 (d, 1H), 6.42 (d, 1 H), 5.79 (s, 1H), 4.43 (m, 1H), 3.40 (ma, 4H), 3.35 ( sa, 4H), 3.17 (ma, 4H), 2.10 (m, 2H), 2.03 (m, 2H), 1.45 (m, 2H), 1, 11 (m, 6H) Analysis of the mass spectrum m / z = 447.3 (M + H) + EXAMPLE 11 F 11 F was obtained according to a procedure similar to that described for 11C, with the following exceptions: Stage 11.4: 1.6 was replaced by 1.7. : 2.8e was replaced by 11.10, 1 H NMR (400MHz, CDCl 3) d 9.71 (da, 2H), 8.40 (s, 1H), 7.56 (m, 2H), 7.18 (t, 1H). ), 6.62 (d, 1H), 6.48 (d, 1 H), 5.50 (s, 1 H), 4.50 (m, 1H), 3.58 (m, 2H), 3 , 48 (m, 2H), 3.38 (sa, 4H), 2.30 (d, 2H), 2.22 (sa, 2H), 1.64 (m, 2H), 1.36 (m, 2H), 1.30 (m, 5H), 1.19 (m, 5H) Analysis of the mass spectrum m / z = 462.4 (M + H) + EXAMPLE 12A Preparation of 12.1: To a solution of compound 11.2 (3.33 g, 10 mmol) in anhydrous methylene chloride (100 mL) was added sequentially triethylamine (3.48 mL, 25 mmol, 2.5 eq), 4-dimethylaminopyridine (122 mg, 1 mmol, 0.1 eq) and? / - phenyltrifluoromethanesulfonimide (1.4) (4.48 g, 12.5 mmol, 1, 25 eq). The reaction mixture was stirred at room temperature for 24 h, washed with a saturated aqueous sodium bicarbonate solution, dried over sodium sulfate and filtered. The solvent was evaporated in vacuo and the residue was purified by column chromatography (eluent: hexane / ethyl acetate, 3: 1). Yield: 92.5% 1 H NMR (400MHz, DMSO d6) d 7.52 (t, 1 H), 7.09 (d, 1H), 6.88 (d, 1H), 3.90 (m, 2H) ), 3.21 (m, 2H), 2.80 (s, 2H), 2.03 (m, 2H), 1.63 (m, 2H), 1.48 (s, 9H) Preparation of 12.3: To a solution of 12.1 (5.4 g, 11.6 mmol) in tetrahydrofuran (100 mL) at room temperature was added tetrakis (triphenylphosphine) palladium (0) (670 mg, 0.58 mmol, 0.05 eq. ) followed by the dropwise addition of a solution of methylene chloride 2.0 M (12.2a) in tetrahydrofuran (10 mL, 20 mmol, 1.72 eq). The mixture was stirred at room temperature for 2 days. The reaction mixture was then quenched with a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The organic phase was washed with brine and dried over sodium sulfate. The solvent was evaporated in vacuo and the crude product was purified by column chromatography (eluent: hexane / ethyl acetate, 4: 1).

Yield: 80.6% 1 H NMR (400MHz, CDCl 3) 7.30 (t, 1 H), 6.86 (d, 1 H), 6.80 (d, 1H), 3.88 (m, 2H ), 2.70 (s, 2H), 2.60 (s, 3H), 2.00 (m, 2H), 1.60 (m, 2H), 1.45 (s, 9H) Preparation of 12.4: To a solution of 12.3 (2.8 g, 8.46 mmol) in anhydrous tetrahydrofuran (80 mL) at -78 ° C under nitrogen was added dropwise a solution of 1.0M LiHMDS in tetrahydrofuran (11 mL, mmol, 1, 1 eq). The reaction mixture was stirred for 45 min at -78 ° C. To the reaction mixture was added dropwise a solution of N-phenyltrifluoromethanesulfonimide (1.4) (3.95 g, 11 mmol, 1.1 eq) in tetrahydrofuran (15 mL). The mixture was heated slowly to room temperature and stirring was continued for a further 3 h at room temperature. The mixture was then poured into ice water and extracted with a mixture of hexane and diethylether (1: 1). The organic phase was washed with water and brine, and dried over sodium sulfate and filtered. The organic extracts were concentrated in vacuo and the crude product was purified by column chromatography (eluent: hexane / ethyl acetate, 6: 1). Yield: 61.3% 1H NMR (400MHz, CDCl3) 7.11 (t, 1H), 6.80 (m, 2H), 3.82 (m, 2H), 3.29 (m, 2H), 2.50 (s, 3H), 2.03 (m, 2H), 1.68 (m, 2H), 1.48 (s, 9H) Preparation of 12.5: To a solution of 12.4 (848 mg, 1, 83 mmol) in dimethoxyethane (DME) (16 mL) was added sequentially an aqueous solution of 2N sodium carbonate (3.1 mL, 6.2 mmol, 3.4 eq), lithium chloride (259 mg, 6.1 mmol, 3.3 eq), 4- (N, N-diethylaminocarbonyl) phenylboronic acid (1.6) (486 mg, 2.2 mmol, 1.2 eq) and tetrakis (triphenylphosphine) of palladium (0) (64 mg, 0.055 mmol, 0.03 eq). The mixture was heated at reflux temperature overnight under nitrogen. The mixture was then cooled to room temperature and water (20 mL) was added. The mixture was extracted with ethyl acetate. The organic phase was further washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography (eluent: hexane / ethyl acetate, 1: 1). Yield: 96.9% 1 H NMR (400MHz, CDCl 3) d 7.36 (d, 2H), 7.26 (d, 2H), 7.10 (t, 1H), 6.86 (d, 1H), 6.70 (d, 1H), 5.60 (s, 1H), 3.80 (m, 2H), 3.55 (m, 2H), 3.30 (, 4H), 2.00 (m, 2H), 1.74 (s, 3H), 1.65 (m, 2H), 1.49 (s, 9H), 1, 20 (m, 6H) Preparation of 12A: To a solution of 12.5 (860 mg, 1, 76 mmol) in methylene chloride (10 mL) was added a solution of anhydrous hydrochloric acid 2.0 M in diethyl ether (30 mL). The mixture was stirred at room temperature for 24 h and diethyl ether was added. The resulting precipitate was collected by filtration and washed with diethyl ether. Yield: 97.8%) 1 H NMR (400MHz, DMSO dβ) d 8.99 (m, 2H), 7.38 (d, 2H), 7.29 (d, 2H), 7.18 (t, 1H), 6.93 (d, 1H), 6.80 (d, 1 H), 5.95 (s, 1H), 3.45 (m, 2H), 3.20 ( m, 6H), 2.00 (m, 4H), 1.70 (s, 3H), 1.10 (m, 6H) Mass spectrum analysis m / z = 391.4 (M + H) + Elemental analysis: C24H28 2O2, 1 HCl, 1 / 2H2O Theoretical:% C 68.87; % H 7.40; % N 6.43 Found:% C 68.99; % H 7.33; % N 6.39 EXAMPLE 12B Preparation of 12.6: To a solution of 12.1 (14.4 g, 31 mmol) in? /,? / - dimethylformamide was added sequentially methanol (50 mL), triethylamine (7 mL, 50 mmol, 1.6 eq), 1-3. o / s (diphenylphosphino) propane (dppp) (1.04 g, 2.5 mmol, 0.08 eq) and palladium (II) acetate (565 mg, 2.5 mmol, 0.08 eq). Carbon monoxide was then bubbled through the reaction solution while the mixture was heated at 65-70 ° C for 3.5h. The reaction mixture was cooled to room temperature, diluted with diethyl ether and washed with water and brine. The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography (eluent: hexane / ethyl acetate, 4: 1). Yield: 87.9% 1 H NMR (400MHz, CDCl 3) 7.50 (t, 1 H), 7.10 (d, 1H), 6.99 (d, 1 H), 3.94 (s, 3H) ), 3.90 (m, 2H), 3.21 (m, 2H), 2.73 (s, 2H), 2.05 (m, 2H), 1.63 (m, 2H), 1.48 (s, 9H) Preparation of 12.11 : To a solution of 12.6 (13.2 g, 35.2 mmol) in anhydrous tetrahydrofuran (300 mL) at -78 ° C, a solution of 1.0M LiHMDS in tetrahydrofuran (42 mL, 42 mmol) was added dropwise. , 1, 2 eq) in nitrogen. The reaction mixture was stirred for 45 min at -78 ° C. To the reaction mixture was added dropwise a solution of N-phenyltrifluoromethanesulfonimide (1.4) (15.1 g, 42 mmol, 1.2 eq) in tetrahydrofuran (60 mL). The mixture was slowly warmed to room temperature and stirred for 3 h. The mixture was then poured into ice water and extracted with a mixture of hexane and diethylether (1: 1). The organic phase was washed with water and brine, dried over sodium sulfate and filtered. The organic extracts were concentrated in vacuo and the crude product was purified by column chromatography (eluent: hexane / ethyl acetate, 4: 1). Yield: 90.2% 1 H NMR (400MHz, CDCl 3) 7.32 (d, 1H), 7.26 (t, 1H), 7.10 (d, 1H), 5.70 (s, 1H), 3.90 (s, 3H), 3.83 (m, 2H), 3.30 (m, 2H), 2.10 (m, 2H), 1.77 (m, 2H), 1.48 (s) , 9H) Preparation of 12.12: To a solution of 12.11 (16 g, 31.6 mmol) in dimethoxyethane (DME) (260 mL) was added sequentially an aqueous 2N sodium carbonate solution (53 mL, 106 mmol, 3, 4 eq), lithium chloride (4.5 mg, 106 mmol, 3.4 eq.), 4- (N, N-diethylaminocarbonyl) phenylboronic acid (1.6) (8.4 g, 38 mmol, 1.2 eq. ) and tetrakis (triphenylphosphine) of palladium (0) (1.1 g, 0.95 mmol, 0.03 eq). The mixture was heated at reflux temperature overnight under nitrogen and then cooled to room temperature. Water (300 mL) was added to the mixture and the crude product was extracted with ethyl acetate. The organic phase was further washed with brine, dried over sodium sulfate and filtered. The organic extracts were concentrated in vacuo and the crude product was purified by column chromatography (eluent: hexane / ethyl acetate, 1: 1). Yield: 98.5% 1 H NMR (400MHz, CDCl 3) d 7.33 (d, 2H), 7.25 (m, 4H), 7.15 (d, 1H), 5.72 (s, 1H), 3.85 (m, 2H), 3.53 (m, 2H), 3.32 (m, 4H), 3.10 (s, 3H), 2.06 (m, 2H), 1.76 (m , 2H), 1, 50 (s, 9H), 1, 20 (m, 6H) Preparation of 12.13: A suspension of potassium ferc-butoxide (9 g, 80 mmol, 8.0 eq) in diethyl ether (200 mL) was added water (0.72 mL, 40 mmol, 4.0 eq) dropwise at 0 ° C. The suspension was stirred for 30 min. To this mixture was added 12.12 (5.34 g, 10 mmol). The ice bath was removed and the reaction mixture was stirred at room temperature overnight and quenched by the addition of ice water. The aqueous phase was separated, acidified to pH 2-3 with an aqueous solution of 1 N hydrochloric acid and extracted with methylene chloride. The organic phases were combined, dried over sodium sulfate and concentrated in vacuo. The crude product was used in the next step without further purification. Yield: 86.9% 1 H NMR (400MHz, DMSO d6) d 12.55 (sa, 1 H), 7.23 (m, 7H), 5.98 (s, 1H), 3.68 (m, 2H) ), 3.42-3.20 (m, 6H), 1.80 (m, 4H), 1, 42 (s, 9H), 1, 10 (m, 6H) Preparation of 12B: A solution of 12.13 (300 mg, 0.58 mmol) in methylene chloride (4 mL) was added a solution of anhydrous hydrochloric acid 2.0M in diethylether (15 mL). The mixture was stirred at room temperature for 24 h and diluted with diethyl ether. The resulting precipitate was collected by filtration and washed with diethyl ether. Yield: 95% 1 H NMR (400MHz, DMSO d6) 12.61 (sa, 1 H), 8.69 (m, 6H), 7.38-7.25 (m, 7H), 6.06 (s) , 1 H), 3.41 (m, 2H), 3.25 (m, 6H), 2.06 (m, 4H), 1, 11 (m, 6H) Analysis of the mass spectrum m / z = 421, 3 (M + H) + EXAMPLE 12C Preparation of 12.14a To a solution of 12.13 (780 mg, 1.5 mmol) in acetonitrile (50 mL) was added sequentially diisopropylethylamine (1.75 mL, 10 mmol, 6.7 eq), a 0.5M ammonia solution (12.15) in dioxane (30 mL, 15 mmol, 10 eq) and TBTU (580 mg, 1.8 mmol, 1.2 eq). The reaction mixture was stirred at room temperature for 3 days and then concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with a saturated aqueous solution of sodium bicarbonate. The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography (eluent: hexane / acetone, 1: 1). Yield: 60.4% 1 H NMR (400MHz, DMSO d6) 7.51 (s, 1 H), 7.29 (t, 1H), 7.22 (s, 4H), 7.10 (d, 1) H), 7.05 (d, 1H), 6.97 (s, 1 H), 5.90 (s, 1 H), 3.63 (m, 2H), 3.41 (m, 2H), 3.32 (m, 2H), 3.20 (m, 2H), 1.80 (m, 4H), 1.42 (s, 9H), 1.10 (m, 6H) Preparation of 12C: A 12.14a solution (420 mg, 0.81 mmol) in methylene chloride (6 mL) was added a solution of anhydrous hydrochloric acid 2.0M in diethylether (20 mL). The mixture was stirred at room temperature for 2 days and diluted with diethyl ether. The resulting precipitate was collected by filtration and washed with diethyl ether. Yield: 87.5% 1 H NMR (400MHz, DMSO d6) 59.21 (m, 2H), 7.54 (s, 1 H), 7.32-7.10 (m, 7H), 6.88 (s, 1H), 5.98 (s, 1 H), 3.42 (m, 2H), 3.20 (m, 6H), 2.10 (m, 4H), 1 , 10 (m, 6H) Analysis of the mass spectrum m / z = 420.3 (M + H) + EXAMPLE 12D 12D was obtained according to a procedure similar to that described for 12C, with the following exception: Stage 12.16: 12.15 replaced by 3.4b. 1 H NMR (400MHz, DMSO d6) d 9.19 (m, 2H), 7.83 (m, 1 H), 7.30-7.20 (m, 6H), 7.00 (d, 1H), 5.96 (s, 1 H), 3.41 (m, 2H), 3.20 (m, 6H), 2.11 (m, 4H), 2.06 (d, 3H), 1.10 ( m, 6H) Analysis of the mass spectrum m / z = 434.3 (M + H) + EXAMPLE 12E 12E was obtained according to a procedure similar to that described for 12C, with the following exception: Stage 12.16: 12.15 was replaced by 3.4 c. 1 H NMR (400MHz, DMSO d 6) d 9.18 (m, 2H), 7.90 (t, 1H), 7.30-7.20 (m, 6H), 7.00 (d, 1 H), 5.96 (s, 1 H), 3.40 (m, 2H), 3.20 (m, 6H), 2.50 (m, 2H), 2.10 (m, 4H), 1, 10 ( m, 6H), 0.78 (t, 3H) Analysis of the mass spectrum m / z = 448.4 (M + H) + Elemental analysis: C27H33 3O3, 5 / 4H2O Theoretical:% C 68.99; % H 7.61; % N 8.94 Found:% C 69.27; % H 7.43; % N 8.93 EXAMPLE 12F 12 F was obtained according to a procedure similar to that described for 12C, with the following exception: Stage 12.16: 12.15 was replaced by 3.4d. 1 H NMR (400MHz, DMSO d6) d 8.98 (m, 2H), 7.91 (t, 1H), 7.31 (m, 1H), 7.20 (m, 5H), 7.00 (m , 1H), 5.96 (s, 1 H), 3.45 (m, 4H), 3.20 (m, 6H), 2.40 (m, 2H), 2.08 (m, 4H), 1, 10 (m, 6H), 0.70 (t, 3H) Analysis of the mass spectrum m / z = 462.4 (M + H) + Elemental analysis: C28H35N3? 3. 1 HCl, 7 / 3H2O Theory:% C 62.27; % H 7.59; % N 7.78 Found:% C 62.37; % H 7.23; % N 7.74 EXAMPLE 12G Preparation of 12.7: To a solution of 12.6 (2.25 g, 6 mmol) in a solvent mixture of methanol (40 mL), tetrahydrofuran (40 mL) and water (40 mL) were added. added lithium hydroxide (1.52 g, 36.2 mmol, 6.0 eq) in one portion. The reaction mixture was stirred at room temperature overnight. The mixture was concentrated in vacuo and extracted with diethyl ether. The aqueous phase was acidified to pH 2-3 using an aqueous solution of 1N hydrochloric acid. The acidified solution was extracted with methylene chloride. The organic extracts were combined, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was used in the next step without further purification. Performance: 100%. 1 H NMR (400MHz, DMSO dβ) d 12.93 (br s, 1 H), 7.59 (t, 1H), 7.15 (d, 1H), 6.97 (d, 1H), 3.71 ( m, 2H), 3.12 (m, 2H), 1.90 (m, 2H), 1.65 (m, 2H), 1.40 (s, 9H) Preparation of 12.8: To a solution of 12.7 ( 1, 63 g, 4.5 mmol) in acetonitrile (100 mL) was added sequentially diisopropylethylamine (5.23, 30 mmol, 6.7 eq), dimethylamine hydrochloride (3.4j) (1.14 g, 14 mmol, 3.0 eq) and TBTU (1.74 g, 5.4 mmol, 1.2 eq). The reaction mixture was stirred at room temperature for 3 days and then concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with a saturated aqueous solution of sodium bicarbonate. The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography (eluent: hexane / acetone, 2: 1). Yield: 60% 1 H NMR (400MHz, DMSO dβ) 7.50 (t, 1H), 7.00 (d, 1H), 6.85 (d, 1H), 3.89 (m, 2H), 3 , 22 (m, 2H), 3.14 (s, 3H), 2.74 (s, 3H), 2.03 (m, 2H), 1.62 (m, 2H), 1.48 (s, 6H) Preparation of 12.9: To a solution of 12.8 (950 mg, 2.45 mmol) in anhydrous tetrahydrofuran (20 mL) at -78 ° C under nitrogen was added dropwise a solution of 1.0M LiHMDS in tetrahydrofuran ( 3.2 mL, 3.2 mmol, 1.3 eq). The reaction mixture was stirred for 45 min at -78 ° C. To the reaction mixture was added dropwise a solution of N-phenyltrifluoromethanesulfonimide (1.4) (1.15 g, 3.2 mmol, 1.3 eq) in tetrahydrofuran (8 mL). The mixture was heated slowly at ambient temperature and the stirring was continued for an additional 2.5 h at room temperature. The mixture was then poured into ice water and extracted with a mixture of hexane and diethylether (1: 1). The organic phase was washed with water and brine, and dried over sodium sulfate and filtered. The organic extracts were concentrated in vacuo and the crude product was purified by column chromatography (eluyenie: methylene chloride / ethyl ether, 3: 1). Yield: 78.6% 1 H NMR (400MHz, CDCl 3) d 7.28 (t, 1 H), 6.96 (d, 1H), 6.83 (d, 1 H), 5.65 (s, 1H) ), 3.80 (m, 2H), 3.38 (m, 1H), 3.20 (m, 1 H), 3.10 (s, 3H), 2.92 (s, 3H), 2, 09 (m, 2H), 1, 70 (m, 2H), 1, 48 (s, 9H) Preparation of 12.10: To a solution of 12.9 (950 mg, 1.83 mmol) in dimethoxyethane (DME) (16 mL ) was added sequentially an aqueous 2N sodium carbonate solution (3.1 mL, 6.2 mmol, 3.4 eq), lithium chloride (259 mg, 6.1 mmol, 3.3 eq. - (N, N-dieylaminocarbonyl) phenylboronic acid (1.6) (486 mg, 2.2 mmol, 1.2 eq) and palladium (triphenyl) phosphoryl (triphenylphosphine) (64 mg, 0.055 mmol, 0.03 eq). The mixture was heated at reflux temperature for overnight in nihologen and then cooled to ambient temperature. Water (20 mL) was added to this mixture and the crude product was extracted with ethyl acetate. The organic phase was washed with brine, dried over sodium sulfate and filtered. The organic extracts were concentrated in vacuo and the crude product was purified by column chromatography (eluyenie: hexane / aceilone, 2: 1). Yield: 88% 1 H NMR (400MHz, CDCl 3) d 7.35 (d, 2H), 7.25 (m, 3H), 7.05 (d, 1H), 6.91 (d, 1H), 5, 62 (s, 1 H), 3.86 (m, 2H), 3.55 (m, 2H), 3.30 (m, 4H), 2.69 (s, 3H), 2.30 (s, 3H), 2 , 10 (m, 1H), 1.98 (m, 1H), 1.70 (m, 2H), 1.49 (s, 6H), 1.20 (m, 6H) Preparation of 12G: To a solution of 12.10 (840 mg, 1.54 mmol) in methylene chloride (10 mL) was added a solution of anhydrous hydrochloric acid 2.0 M in dieyl ether (30 mL). The mixture was stirred at ambient temperature for 2 days and diluted with diethyl ether. The resulting precipitate was collected by filtration and washed with diethyl ether. Performance: 100%. 1 H NMR (400MHz, DMSO d 6) 59.28 (m, 2H), 7.35-7.19 (m, 6H), 6.90 (d, 1H), 5.96 (s, 1H), 3.43 (m, 2H), 3.22 (m, 6H), 2.66 (s, 3H), 2.18 (s, 3H), 2.18 (s, 3H), 2.09 (m , 4H), 1.11 (m, 6H) Analysis of the mass spectra m / z = 448.4 (M + H) + EXAMPLE 12H 12H was done according to a procedure similar to that described for 12A, with the following exception: Eíapa 12.4: 1.6 was replaced by 1.7. 1 H NMR (400MHz, DMSO d6) 9.20 (m, 2H), 8.48 (s, 1H), 7.73 (d, 1H), 7.58 (d, 1H), 7.20 (t, 1H), 6.98 (d, 1 H), 6.82 (d, 1 H), 6.10 (s, 1H), 3.42-3, 12 (m, 8H), 2.02 (m, 4H), 1.70 (s, 3H), 1, 18 (1, 3H), 1, 10 (1, 3H) Mass spectral analysis m / z = 392.4 (M + H) + Elemental analysis: C 24 H 29 N 3 O 3, 7/5 HCl, 7/5 H 2 O Theory:% C 61, 60; % H 7.15; % N 8.98; % C1 10.61 Found:% C 61, 70; % H 6.78; % N 8.86; % C1 10.73 EXAMPLE 121 121 was made according to a procedure similar to that described for 12A, with the following exception: Stage 12.2: 12.2a was substituted by 12.2b. H NMR (400MHz, DMSO d6) 8.89 (sa, 2H), 7.12 (d, 2H), 7.04 (d, 2H), 6.95 (,, 1H), 6.71 (d, 1H), 6.58 (d, 1H), 5.66 (s, 1H), 3.20 (sa, 2H), 2.92 (ma, 6H ), 1.75 (ma, 6H), 0.86 (ma, 8H), 0.22 (i, 3H) Analysis of the mass spectrum m / z = 419.4 (M + H) + Elemenfal analysis: Theoretical :% C 68.55; % H 7.88; % N 5.92 Found:% C 68.42; % H 7.73; % N 5.92 EXAMPLE 12J 12J was worked up according to a procedure similar to that described for 12A, with the following exception: Eiapa 12.2: 12.2a was subsumed by 12.2c. 1 H NMR (400MHz, DMSO d 6) 9,12 (sa, 1, 5H), 7.54 (d, 2H), 7.47 (d, 2H), 7.38 (1, 1 H), 7.13 (d, 1 H), 7.02 (d, 1 H), 6.09 (s, 1 H), 3.62 (sa, 2H), 3 36 (ma, 5H), 2.18 (ma, 6H), 1, 30 (ma, 8H), 1, 00 (m, 2H), 0.81 (í, 3H) Analysis of the mass spectrum m / z = 433.4 (M + H) + Elemental analysis: C28H36N2O2, 1 HCI, 2H2O Theoretical:% C 66.58; % H 8.18; % N 5.55 Found:% C 66.82; % H 7.88; % N 5.59 EXAMPLE 12K 12K was made according to a procedure similar to that described for 12A, with the following exceptions: Stage 12.2: 12.2a was replaced by 12.2b. Stage 12.4: 1.6 was replaced by 1.7 and Proceedings 12A was used. 1 H-NMR (400MHz, DMSO-d) 9.73 (sa, 1H), 9.61 (sa, 1H), 8.47 (s, 1H), 7.65 (m, 2H), 7.20 (m, 1H), 6.90 (d, 1H), 6.82 (d, 1 H), 5.66 (s, 1H), 3.59 ( c, 2H), 3.41 (ma, 6H), 2.24 (sa, 4H), 2.01 (ma, 2H), 1.25 (ma, 8H), 0.54 (i, 3H) Analysis of the mass spectra m / z = 420.4 (M + H) + EXAMPLE 12L 12L was made according to a procedure similar to that described for 12A, with the following exceptions: Eíapa 12.2: 12.2a was subsumed by 12.2c. Step 12.4: 1.6 was replaced by 1.7 and Procedure 12A was used. 1 H NMR (400MHz, DMSO d6) 8.86 (da, 1.5H), 8.43 (d, 1 H), 7.66 (dd, 1 H), 7.48 (d, 1 H), 7, 16 (1, 1H), 6.91 (d, 1 H), 6.79 (d, 1 H), 5.98 (s, 1H), 3.40 (c, 2H), 3.12 (ma , 5H), 1.94 (m, 6H), 1.10 (m, 5H), 1, 01 (f, 3H), 0.76 (m, 2H), 0.56 (t, 3H) Analysis of the spectra mass m / z = 434.3 (M + H) + EXAMPLE 13A Preparation of 13.2: To a solution of 1.5a (7.80 g, 17.35 mmol, 1.0 eq) in dimethoxy manganese (75 mL) was he added sequentially an aqueous solution of 2N sodium carbonate (26.03 mL, 52.06 mmol, 3.0 eq), lithium chloride (2.21 g, 52.06 mmol, 3.0 eq), 13.1 (3 , 44 g, 19.09 mmol, 1.1 eq) and palladium tetra (pyridylphosphine) (0) (0.40 g, 0.35 mmol, 0.02 eq). The mixture was heated to reflux temperature overnight in nitrogen. The mixture was then cooled to ambient temperature and water (250 mL) was added. The mixture was extracted with ethyl acetate. The organic phase was further washed with brine and dried over sodium sulfate. The crude product was purified by column chromatography (eluyenie: mixtures of hexane / acetyl ether of increasing polarity). Yield: 64% 1 H NMR (400MHz, DMSO dβ) d 8.02 (d, 2H), 7.49 (d, 2H), 7.23 (m, 1H), 6.99 (d, 1 H), 6.92 (m, 2H), 5.92 (s, 1 H), 3.88 (s, 3H), 3.70 (m, 2H), 3.27 (m, 2H), 1, 89 (m, 2H), 1, 71 (m, 2H), 1, 42 (s, 9H) Mass spectral analysis m / z = 436.0 (M + H) + Preparation of 13.3: A solution of 13.2 (4.71) g, 10.81 mmol, 1.0 eq) in urea-hydrofuran (30 mL) at 0 ° C in nihologen was added dropwise to a solution of monohydric acid hydroxide (0.54 g, 12.98 mmol, 1%). 2 eq) in water (30 mL). The mixture was stirred during the night at ambient temperature. The mixture was then concentrated under reduced pressure and redissolved in water. The mixture was then acidified to pH 2 using concentrated hydrochloric acid. The resulting precipitate was collected by filtration and the crude product was used in the next step without further purification. Yield: 98% 1 H NMR (400MHz, DMSO d6) d 13.03 (br s, 1 H), 8.01 (d, 2H), 7.47 (d, 2H), 7.23 (m, 1H), 6.98 (d, 1H), 6.92 (m, 2H), 5.91 (s, 1 H), 3.70 (m, 2H), 3.28 ( m, 2H), 1.86 (m, 2H), 1.72 (m, 2H), 1.42 (s, 9H) Mass spectrum analysis m / z = 420.1 (MH) "Preparation of 13A : Trifluoroacetic acid (0.15 mL, 1.96 mmol, 5.5 eq) was added drop wise to a cold (0 ° C) solution of 13.3 (0.15 g, 0.36 mmol, 1.0 eq) in anhydrous dichloromethane (5 mL) The mixture was heated to room temperature and stirred overnight at ambient temperature, then the mixture was concentrated under reduced pressure, the crude product was rinsed with diethyl ether. it was collected by filtration Yield: 87% 1H NMR (400MHz, DMSO d6) 13.05 (sa, 1H), 8.67 (m, 2H), 8.02 (d, 2H), 7.49 (d , 2H), 7.27 (m, 1H), 7.05 (d, 1H), 6.96 (m, 2H), 5.98 (s, 1H), 3.26 (m, 4H), 2 , 08 (m, 2H), 1.97 (m, 2H) Mass spectral analysis m / z = 322.1 (M + H) + Elemental analysis: C2? H19NO3, CF3CO2H, 0.2H2O Theoretical:% C 60.19; % H 4.68; % N 3.19 Found:% C 60.18; % H 4.61; % N 3.24 EXAMPLE 13B Preparation of 13.5a: The O-benzotriazol-1-yl-γ-γ-γ-κ-γ-y-yl-methyl-urea ester (150.8 mg, 0.47 mmol, 1.1 eq) was added to a cooled (0 ° C) solution of 13.3 (180.0 mg, 0.43 mmol, 1.0 eq), 3.4a (50.3 mg, 0.94 mmol, 2.2 eq), and ?,? - diisopropylethylamine (0.25 L, 0.94 mmol, 2.2 eq) in acetoniiril (5 mL). The solution was stirred overnight at room temperature and then concentrated under reduced pressure. Acetyl ether (10 mL) and a saturated aqueous solution of sodium bicarbonate (10 mL) were added to the product, and the mixture was stirred for 20 minutes at ambient temperature. The phases were separated and the organic phase was washed with a saturated aqueous solution of sodium bicarbonate, brine, dried over sodium sulfate and filtered. The organic extracts were concentrated under reduced pressure and the crude product was purified by column chromatography (eluyenie: mixtures of hexane / acetyl ether of increasing polarity).

Yield: 10% Analysis of the mass spectrum m / z = 421, 2 (M + H) + Preparation of 13B: A solution of 2.0M hydrochloric acid in diethylether (0.12 mL, 0.24 mmol, 5.5 eq) was added dropwise to a cooled (0 ° C) solution of 13.5a (18 mg, 0.04 mmol, 1.0 eq) in anhydrous meianol (5 mL). The mixture was stirred during the night at ambient temperature and then concentrated under reduced pressure. The crude product was triturated with ethyl acetate. The resulting precipitate was collected by filtration. Yield: 70% 1 H NMR (400MHz, DMSO d6) d 8.99 (m, 2H), 8.06 (m, 1H), 7.95 (m, 2H), 7.46 (m, 3H), 7.27 (m, 1H), 7.06 (m, 1 H), 6.96 (m, 2H), 5.95 (s, 1H), 3.24 ( m, 4H), 2.08 (m, 4H) Analysis of the mass spectra m / z = 321, 1 (M + H) + EXAMPLE 13C 13C was done according to a procedure similar to that described for 13B, with the following exception : Eíapa 13.6: 3.4a was subsumed by 3.4b. 1 H NMR (400MHz, DMSO d6) d 9.05 (m, 2H), 8.55 (m, 1H), 7.92 (m, 2H), 7.41 (m, 2H), 7.26 (m , 1H), 7.06 (m, 1 H), 6.95 (m, 2H), 5.95 (s, 1H), 3.20 (m, 4H), 2.81 (m, 3H), 2.08 (m, 4H) Analysis of the mass spectra m / z = 335.2 (M + H) + EXAMPLE 13D 13D was done according to a procedure similar to that described for 13B, with the following exception: Eíapa 13.6: 3.4 a was subsumed by 3.4c. 1 H NMR (400MHz, DMSO d 6) d 8.50 (m, 1 H), 7.90 (d, 2H), 7.40 (d, 2H), 7.20 (m, 1H), 6.90 ( m, 3H), 5.85 (s, 1 H), 3.30 (m, 2H), 2.90 (m, 2H), 2.70 (m, 2H), 1.85-1.70 (m m, 4H), 1.10 (f, 3H) Mass spectrum analysis m / z = 349.2 (M + H) + Elemental analysis: C22H24N2O2, 0.25 (CH3) 2CO, 0.25H2O Theoretical:% C, 70.89; % H 7.32; % N 7.27 Found:% C 71, 13; % H 7.04; % N 7.07 EXAMPLE 13E 13E was obtained according to a procedure similar to that described for 13B, with the following exception: Eíapa 13.6: 3.4a was subsumed by 3.4e. 1 H-NMR (400MHz, CDCl 3) 9.75 (sa, 1 H), 9.31 (sa, 1H), 7.81 (d, 2H), 7.39 (d, 2H), 7.21 (m) , 1H), 6.98 (m, 2H), 6.90 (m, 1H), 6.25 (m, 1 H), 5.56 (s, 1H), 3.46 (m, 2H), 3.33 (m, 4H), 2.30 (m, 2H), 2.12 (m, 2H), 1.94 (m, 1H), 1, 04 (d, 6H) Mass spectral analysis / z = 377.2 (M + H) + EXAMPLE 13F 13F was made according to a procedure similar to that described for 13B, with the following exception: Eíapa 13.6: 3.4a was subsumed by 3.4j. 1 H NMR (400MHz, DMSO d6) d 9.08 (m, 2H), 7.42 (m, 4H), 7.24 (m, 1H), 7.00 (m, 3H), 5.91 (s) , 1H), 3.25 (m, 4H), 2.96 (m, 6H), 2.07 (m, 4H) Mass spectral analysis m / z = 349.1 (M + H) + EXAMPLE 13G 13G was made according to a procedure similar to that described for 13B, with the following exception: Eíapa 13.6: 3.4a was subsumed by 3.4k. 1 H NMR (400MHz, DMSO dβ) d 8.91 (m, 2H), 7.58 (d, 2H), 7.41 (d, 2H), 7.25 (m, 1 H), 7.00 ( m, 3H), 5.92 (s, 1 H), 3.49 (m, 2H), 3.41 (m, 2H), 3.24 (m, 4H), 2.09 (m, 2H) , 2.00 (m, 2H), 1.84 (m, 4H) Analysis of the mass spectra m / z = 375.1 (M + H) + EXAMPLE 13H 13H was obtained according to a procedure similar to that described for 13B , with the following exception: Stage 13.6: 3.4a was subsituted by 3.4o. 1 H NMR (400MHz, DMSO d6) d 8.98 (m, 2H), 7.39 (dd, 4H), 7.24 (m, 1H), 6.95 (m, 3H), 5.91 (s) , 1H), 3.66 (sa, 2H), 3.22 (m, 4H), 2.10 (m, 4H), 1.30 (m, 12H) Analysis of the mass spectrum m / z = 405, 3 (M + H) + Elemental analysis: C 26 H 32 N 2 O 2, 1 HCl, 0.5 H 2 O Theory:% C 69.39; % H 7.62; % N 6.22 Found:% C 69.31; % H 7.64; % N 6.19 EXAMPLE 131 131 was obtained according to a procedure similar to that described for 13B, with the following exception: Stage 13.6: 3.4a was subsumed by 3.4p. 1 H NMR (400MHz, DMSO d6) d 8.91 (m, 2H), 7.46 (m, 4H), 7.26 (m, 1 H), 7.01 (m, 3H), 5.94 ( s, 1H), 3.61 (m, 6H), 3.35 (m, 2H), 3.21 (m, 4H), 2.09 (m, 2H), 1.98 (m, 2H) Analysis of the mass spectra m / z = 391, 1 (M + H) + EXAMPLE 13J 13J was made according to a procedure similar to that described for 13B, with the following exception: Eíapa 13.6: 3.4a was subsumed by 3.4q. 1 H NMR (400MHz, DMSO d6) 8.90 (m, 2H), 7.44 (m, 4H), 7.26 (m, 1H), 7.00 (m, 3H), 5.91 (s) , 1H), 3.59 (m, 2H), 3.21 (m, 6H), 2.09 (m, 2H), 1.99 (m, 2H), 1.55 (m, 6H) Analysis of the Mass spectra m / z = 389.1 (M + H) + EXAMPLE 13K 13K was obtained according to a procedure similar to that described for 13B, with the following exception: Eíapa 13.6: 3.4a was subsumed by 13.4a. 1 H NMR (400MHz, DMSO d6) 8.75 (m, 2H), 7.49 (m, 2H), 7.41 (m, 2H), 7.26 (m, 1H), 7.05 (m , 1 H), 6.97 (m, 2H), 5.95 (s, 1 H), 4.00 (m, 4H), 3.23 (m, 4H), 2.10 (m, 2H) , 1, 97 (m, 2H), 1, 64 (m, 2H), 1, 15 (m, 6H) Mass spectral analysis m / z = 403.3 (M + H) + Elemental analysis: C26H3? N 2 O 2, 1 HCl, 0.3 H 2 O Theory:% C 70.27; % H 7.17; % N 6.30 Found:% C 70.02; % H 7.04; % N 6.27 EXAMPLE 13L 13L was worked out according to a procedure similar to that described for 13B, with the following exception: Eíapa 13.6: 3.4a was subsumed by 13.4b. 1 H NMR (400MHz, DMSO d6) d 8.90 (m, 2H), 7.70 (d, 2H), 7.50 (d, 2H), 7.40 (m, 1H), 7.30 (m , 4H), 7.00 (m, 3H), 5.95 (s, 1 H), 4.90 (s, 2H), 4.80 (s, 2H), 3.30 (ma, 4H), 2.05 (m, 4H) Analysis of the mass spectra m / z = 423.1 (M + H) + Elemental Analysis: C28H26 2O2, 1 HCI, IH2O Theoretical:% C 70.50; % H 6.13; % N 5.87 Found:% C 70.58; % H 5.95; % N 5.89 EXAMPLE 13M 13M was made according to a procedure similar to that described for 13B, with the following exception: Eíapa 13.6: 3.4a was subsumed by 13.4c. 1 H NMR (400MHz, DMSO d6) d 9.00 (m, 1H), 7.40 (m, 4H), 7.25 (m, 1H), 7.00 (m, 3H), .90 (s, 1H), 3.55-3.05 (m, 8H), 2.05 (m, 4H), 1.60 (m, 2H), 1.10 (m, 1H), 0 , 90 (m, 2H), 0.65 (m, 1H), 0.40 (m, 2H), 0.15 (m, 1H), 0.10 (m, 1 H) Analysis of the mass spectrum m / z = 417.2 (M + H) + Elemental analysis: C27H32N2O2, 1 HCI, 0.4H2O Theoretical:% C 70.46; % H 7.40; % N 6.09 Found:% C 70.54; % H 7.30; % N 6.15 EXAMPLE 13N 13N was obtained according to a procedure similar to that described for 13B, with the following exception: Eíapa 13.6: 3.4a was subsumed by 13.4d. 1 H NMR (400MHz, DMSO d6) 8.88 (m, 2H), 7.40 (m, 10H), 7.00 (m, 3H), 5.94 (s, 1 H), 4.70 ( m, 1 H), 4.52 (m, 1 H), 3.21 (m, 4H), 2.88 (m, 3H), 2.02 (m, 4H) Mass spectral analysis m / z = 425.2 (M + H) + Elemental analysis: C28H28N2O2, 1HC1, 0.6H2O Theoretical:% C 71, 28; % H 6.45; % N 5.94 Found:% C 71, 13; % H 6.51; % N 5.97 EXAMPLE 130 130 was obtained according to a procedure similar to that described for 13B, with the following exception: Eíapa 13.6: 3.4a was subsumed by 13.4e. 1 H NMR (400MHz, DMSO d6) 8.65 (m, 2H), 7.45 (m, 4H), 7.26 (m, 1H), 7.00 (m, 3H), 5.95 (s, 1 H), 4.36 (m, 2H), 4.11 (m, 2H), 3.88 (m, 2H), 3.60 ( m, 2H), 3.00 (m, 2H), 2.65 (m, 1H), 2.09 (m, 2H), 1.99 (m, 4H), 1.52 (m, 2H), 1.19 (m, 3H) Analysis of the specimen of masses m / z = 461, 2 (M + H) + EXAMPLE 13P 13P was made according to a procedure similar to that described for 13B, with the following exception: Eíapa 13.6: 3.4a was subsumed by 13.4f. 1 H NMR (400MHz, DMSO dβ) 8.60 (m, 2H), 7.47 (m, 4H), 7.25 (m, 1H), 7.00 (m, 3H), 5.95 (s, 1 H), 4.18 (m, 2H), 3.80 (sa, 4H), 3.24 (m, 2H), 3.00 ( s, 3H), 2.10 (m, 2H), 1.94 (m, 2H), 1, 20 (m, 3H) Mass spectral analysis m / z = 421, 2 (M + H) + EXAMPLE 13Q 13Q was done according to a procedure similar to that described for 13B, with the following exception: Eíapa 13.6: 3.4a was subsumed by 13.4g. 1 H NMR (400MHz, DMSO d6) 10.32 (sa, 1H), 8.80 (m, 2H), 7.54 (m, 2H), 7.46 (m, 2H), 7.27 (m, 1H), 7.00 (m, 3H), 5.92 (s, 1 H), 4.54 (sa, 2H), 3.84 ( sa, 2H), 3.45 (m, 2H), 3.24 (m, 4H), 3.12 (m, 2H), 2.83 (s, 3H), 2.10 (m, 2H), 1.97 (m, 2H) Analysis of the mass spectra m / z = 404.3 (M + H) + EXAMPLE 13R 13R was done according to a procedure similar to that described for 13B, with the following exception: Eíapa 13.6: 3.4a was suspended for 13.4h. 1 H NMR (400MHz, DMSO d6) 9.55 (m, 1 H), 8.95 (m, 1H), 7.55 (m, 5H), 7.30 (m, 10H), 7.04 ( m, 1 H), 6.95 (m, 2H), 5.93 (s, 1H), 4.62 (s, 2H), 4.46 (s, 2H), 3.20 (m, 4H), 2.02 (m, 4H) Analysis of mass spectra m / z = 501, 2 (M + H) + EXAMPLE 13S Preparation of 13S: An aqueous solution of 2N sodium hydroxide (1.0 mL) , 2 mmol, 9.2 eq) was added to a solution of 130 (0.10 g, 0.22 mmol, 1.0 eq) in tetrahydrofuran (5 mL) and anhydrous pure ethanol (1 mL). The mixture was stirred for 10 h at ambient temperature and acidified to pH 6 using an aqueous solution of 2N hydrochloric acid. The mixture was concentrated under reduced pressure. The production in bruise was dissolved in dichloromean. The mixture was filtered and the filtrate was concentrated under reduced pressure. Yield: 60% 1 H NMR (400MHz, DMSO d6) 7.43 (m, 4H), 7.25 (m, 1H), 7.01 (m, 2H), 6.94 (m, 1H), 5.93 (s, 1H), 4.33 (sa, 2H), 3.65-2.90 (m, 9H), 1.91 (m, 6H), 1 , 52 (m, 2H) Analysis of the mass spectra m / z = 433.1 (M + H) + EXAMPLE 14A Preparation of 14.2: To a solution of 1.5a (5.00 g, 11, 12 mmol, 1.0 eq) in dimethoxy manganese (17 mL) was added sequentially a 2N sodium carbonate aqueous solution (16.69 mL, 33.37 mmol, 3.0 eq), lithium chloride (1.41 g, 33.37 mmol, 3.0 eq), 14.1 (1.80 g, 12.24 mmol, 1.1 eq) and palladium (pyridine) urea (pyridylphosphine) (0.26 g, 0.22 mmol, 0.02 eq). The mixture was heated at reflux for 10 hours in nihologen. The mixture was then cooled to ambient temperature and an aqueous 1N sodium hydroxide solution was added. The mixture was extracted with dichloromethane. The organic phase was further washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was triturated with diethyl ether. The resulting solid was collected by filtration. Performance: 78% 1H NMR (400MHz, DMSO d6) 7.90 (d, 2H), 7.50 (d, 2H), 7.20 (m, 1H), 7.00 (m, 1 H), 6.90 (m, 2H) , 5.95 (s, 1 H), 3.70 (m, 2H), 3.25 (m, 2H), 1.85 (m, 2H), 1.70 (m, 2H), 1.40 (s, 9H) Analysis of the mass spectrum m / z = 403.1 (M + H) + Preparation of 14.4: A mixture of 14.2 (3.49 g, 8.67 mmol, 1.0 eq), 14.3 ( 1.13 g, 17.34 mmol, 2.0 eq.) And zinc bromide (0.98 g, 4.34 mmol, 0.5 eq) in isopropanol (70 mL) and water (50 mL) was heated to Reflux temperature for 3 days. The reaction mixture was then cooled to 0 ° C and acidified to pH 1 using an aqueous 3N hydrochloric acid solution. The mixture was extracted with acetyl ether. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. Diethyl ether (30 mL) was added. The resulting precipitate was collected by filtration and washed with diethyl ether. The bruise compound was used in the next step without further purification. Yield: 89% 1 H NMR (400MHz, DMSO dβ) 8.10 (d, 2H), 7.55 (d, 2H), 7.20 (m, 1H), 7.00 (m, 2H), 6 , 90 (m, 1H), 5.90 (s, 1H), 3.70 (m, 2H), 3.30 (m, 2H), 1.90 (m, 2H), 1.70 (m, 2H), 1.40 (s, 9H) Analysis of the mass spectra m / z = 446.0 (M + H) + Preparation of 14A: A solution of 2.0M hydrochloric acid in dieryl ether (21.3 mL, 42 , 58 mmol, 5.5 eq) was added in vacuo to a cooled (0 ° C) solution of 14.4 (3.71 g, 7.74 mmol, 1.0 eq) in anhydrous dichloromethane (25 mL). The mixture was heated to ambient temperature and the stirring continued for 10 hours at room temperature. Diethyl ether (100 mL) was added to the solution. The resulfanie precipitate was collected by filtration and washed with diethyl ether. The crude product was purified by column chromatography (eluyenie: dichloromean / melanol mixtures of increasing polarity). Yield: 20% 1 H NMR (400MHz, DMSO d6) 9.08 (sa, 2H), 8.16 (d, 2H), 7.61 (d, 2H), 7.28 (m, 1 H), 7.02 (m, 3H), 6.02 (s, 1 H), 3.59 (sa, 1 H), 3.24 (m, 4H), 2.06 (m, 4H) Analysis of the spectra of masses m / z = 346.1 (M + H) + Elemenfal analysis: C20H19N5O, 1 HCl, 0.5H2O Theory:% C 61, 46; % H 5.42; % N 17.92 Found:% C 61, 52; % H 5.23; % N 17.63 EXAMPLE 14B Preparation of 14.5 and 14.6 Methyl iodide (2.8c) (0.35 mL, 0.0056 mol, 5.0 eq) was added dropwise to a solution of 14.4 (0.500 g, 0.0011 mol, 1.0 eq) and eryrylamine (0.80 mL, 0.0056 mol, 5.0 eq) in anhydrous dimethylformamide (5 mL) and the mixture was stirred at ambient temperature for 3 days. The mixture was poured into water (50 mL) and extracted with acetone. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude production was purified by column chromatography (eluyenie: mixtures of hexane / acetyl ether oil of increasing polarity). Yield of 14.5 (main regioisomer): 65% Mass spectrum analysis m / z = 460.1 (M + H) + Yield of 14.6 (secondary regioisomer): 17% Mass spectral analysis m / z = 460.2 (M + H) + Preparation of 14B Anhydrous solution of 2.0M hydrochloric acid in diethylether (10 mL) was added drop wise to a cold (0 ° C) solution of 14.5 (0.330 g, 0.00071 mol, 1 , 0 eq) in anhydrous dichloromethane (10 mL). The mixture was heated at ambient temperature and the agitation continued for 16 hours at ambient temperature. The mixture was concentrated under reduced pressure and to the residue was added dieylene. The resulting precipitate was collected by filtration and washed with diethyl ether. Yield: 90% 1 H NMR (400MHz, DMSO dβ) d 8.80 (m, 1H), 8.10 (d, 2H), 7.55 (d, 2H), 7.25 (1, 1 H), 6.90-7.10 (m, 3H), 6.00 (s, 1 H), 4.45 (s, 3H), 3.15-3.40 (m, 4H), 1.95-2 , 15 (m, 4H) Analysis of the mass spectra m / z = 360.1 (M + H) + EXAMPLE 14C Preparation of 14C An anhydrous solution of 2.0M hydrochloric acid in diethyl ether (5 mL) was added. to a cold (0 ° C) solution of 14.6 (0.090 g, 0.00019 mol, 1.0 eq) in anhydrous dichloromethane (10 mL). The mixture was heated to ambient temperature and the agitation continued for 10 more hours at ambient temperature. The mixture was concentrated under reduced pressure and to the residue was added dieylene. The resulting precipitate was collected by filtration and washed with diethyl ether. Yield: 88% 1 H NMR (400MHz, DMSO d ") d 8.80 (m, 1.5H), 7.90 (d, 2H), 7.60 (d, 2H), 7.25 (t, 1H) , 6.90-7.10 (m, 3H), 6.00 (s, 1H), 4.20 (s, 3H), 3.20 (m, 4H), 1, 95-2.15 (m , 4H) Analysis of the mass spectrum m / z = 360.2 (M + H) + EXAMPLE 15A 15A was done according to a procedure similar to that described for 15C, with the following exception: Eíapa 15.1: 15.1 c was subsumed by 15.1 to. 1 H NMR (400MHz, DMSO dβ) d 8.87ma, 1 H), 8.16 (d, 2H), 7.59 (d, 2H), 7.29 (m, 1H), 7.06 (m, 2H), 6.97 (m, 1H), 6.02 (s, 1 H), 5.96 (s, 2H), 3.77 ( s, 3H), 3.23 (ma, 4H), 2.11 (ma, 2H), 2.00 (ma, 2H) Analysis of the mass spectra m / z = 418.1 (M + H) + EXAMPLE 15B 15B was made according to a procedure similar to that described for 15C, with the following exception: Eíapa 15.1: 15.1c was subsumed by 15.1b. 1 H NMR (400MHz, DMSO d6) 8.75 (m, 1 H), 8.15 (d, 2H), 7.57 (d, 2H), 7.25 (t, 1 H), 7.00 (m, 3H), 6.00 (s, 1 H), 5.00 (t, 2H), 3.60 (s, 3H), 3.10-3.40 (m, 6H), 1.95 - 2.18 (m, 4H) Mass spectral analysis m / z = 432.2 (M + H) + EXAMPLE 15C Preparation of 15.2a and 15.3a: Ethyl bromobufira (15.1c) (0.40 mL, 0.0028 mol, 2.5 eq) was added in a go to a solution of 14.4 (0.500 g, 0.0011 mol, 1.0 eq) and eryrylamine (0.40 mL, 0.0028 mol, 2.5 eq) in anhydrous? /, / V-dimethylformamide and the mixture was stirred at ambient temperature for 3 days. The mixture was poured into water (50 mL) and extracted with ethyl acetate. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (eluent: mixtures of hexane / ethyl acetyl of increasing polarity). Yield of 15.2a (main regioisomer): 82%. (15.2a) 1 H NMR (400MHz, DMSO d6) 8.10 (d, 2H), 7.50 (d, 2H), 7.20 (m, 1H), 7.00 (m, 2H), 6 90 (m, 1 H), 5.90 (s), 1 H), 4.70 (1, 2H), 4.00 (c, 2H), 3.70 (m, 2H), 3.30 (m, 2H), 2.40 (m, 2H), 2.10 (m, 2H), 1.90 (m, 2H), 1.70 (m, 2H), 1, 40 (s, 9H), 1, 15 (1, 3H) Analysis of the mass speci / z = 560.2 (M + H) + Yield of 15.3a (secondary regioisomer): 6%. (15.3a) 1 H NMR (400MHz, DMSO d6) d 7.90 (d, 2H), 7.60 (d, 2H), 7.20 (m, 1H), 7.00 (m, 2H), 6 , 90 (m, 1 H), 5.95 (s, 1 H), 4.55 (i, 2H), 4.00 (c, 2H), 3.70 (m, 2H), 3.30 ( m, 2H), 2.40 (m, 2H), 2.10 (m, 2H), 1.90 (m, 2H), 1.70 (m, 2H), 1.40 (s, 9H), 1, 10 (t, 3H) Analysis of the mass spectrum m / z = 560.2 (M + H) + Preparation of 15C: An anhydrous solution of 2.0M hydrochloric acid in dieyl ether (10 mL) was added to gola to a cold (0 ° C) solution of 15.2a (0.520 g, 0.00092 mol, 1.0 eq) in anhydrous dichloromethane (10 mL). The mixture was heated to room temperature and stirring was continued for a further 10 h at room temperature. An additional amount of an anhydrous solution of 2.0 M hydrochloric acid in diethyl ether (10 mL) was added to the mixture, which was stirred for an additional 6 hours at room temperature. The mixture was concentrated under reduced pressure and dieyl ether added. The resulting precipitate was collected by filtration and washed with diethyl ether. Yield: 70% 1 H NMR (400MHz, DMSO d6) 8.80 (m, 1 H), 8.15 (d, 2H), 7.60 (d, 2H), 7.25 (m, 1H), 7.00 (m, 3H), 6.00 (s, 1 H), 4.80 (t, 2H), 4.00 (c, 2H), 3.35 (m, 2H), 3.20 ( m, 2H), 2.40 (m, 2H), 2.20 (m, 2H), 2.10 (m, 2H), 1.95 (m, 2H), 1, 15 (1, 3H) Analysis of the mass spectra m / z = 460.2 (M + H) + EXAMPLE 15D 15D was prepared according to a procedure similar to that described for 15C, with the following exception: Stage 15.1: 15.1 c was replaced by 15.1 d. 1 H NMR (400MHz, DMSO d6) 8.90 (ma, 1.5H), 8.14 (d, 2H), 7.57 (d, 2H), 7.28 (t, 1 H), 7.04 (m, 2H), 6.96 (m, 1 H), 6.00 (s, 1H), 4.78 (t, 2H), 4.04 (c, 2H), 3.22 (ma, 4H), 2.37 (1, 2H), 2.11 (ma, 2H), 2.01 (ma, 4H), 1.57 (m, 2H), 1.16 (t, 3H) Spectrum analysis of masses m / z = 474.2 (M + H) + EXAMPLE 15E 15E was obtained according to a procedure similar to that described for 15C, with the following exception: Eíapa 15.1: 15.1c was subsumed by 15.1e. 1 H NMR (400MHz, DMSO d6) d 8.88 (ma, 1.5H), 8.14 (d, 2H), 7.57 (d, 2H), 7.28 (t, 1 H), 7.05 (m, 2H), 6.96 (m, 1 H), 6.00 (s, 1H), 4.76 (t, 2H), 4.02 (c, 2H), 3.22 (ma, 4H), 2.29 (1, 2H), 2.10 (ma, 2H), 2.00 (ma, 4H), 1.57 (m, 2H), 1.30 (m, 2H), 1, 14 (í, 3H) Analysis of the mass spectra m / z = 488.2 (M + H) + EXAMPLE 15F 15F was done according to a procedure similar to that described for 15H, with the following exception: Eíapa 15.1: 15.1c was subsumed by 15.1a. 1 H NMR (400MHz, DMSO d6) d 8.86 (m, 1 H), 7.84 (d, 2H), 7.62 (d, 2H), 7.29 (m, 1H), 7.07 ( d, 1H), 6.99 (m, 2H), 6.03 (s, 1H), 5.71 (s, 2H), 3.70 (s, 3H), 3.23 (m, 4H), 2.11 (ma, 2H), 2.00 (ma, 2H) Analysis of the mass spectra m / z = 418.2 (M + H) + EXAMPLE 15G 15G was done according to a procedure similar to that described. for 15H, with the following exception: Stage 15.1: 15.1c was replaced by 15.1b. 1 H NMR (400MHz, DMSO d6) d 8.78 (ma, 1H), 7.91 (d, 2H), 7.64 (d, 2H), 7.29 (m, 1H), 7.05 (m, 2H), 6.98 (m, 1 H), 6.04 (s, 1H), 4.71 (t, 2H), 3.56 ( s, 3H), 3.23 (m, 4H), 3.11 (t, 2H), 2.12 (ma, 2H), 2.00 (ma, 2H) Analysis of the mass spectrum m / z = 432.1 (M + H) + EXAMPLE 15H Preparation of 15H An anhydrous solution of 2.0M hydrochloric acid in diethyl ether (10 mL) was added as desired to a cold solution (0 ° C) of 15.3a (0.030 g, 0.000053 mol, 1.0 eq) in dichloromethane anhydrous (10 mL). The mixture was warmed to room temperature and stirring was continued for 10 more hours at room temperature. An additional amount of an anhydrous solution of 2.0M hydrochloric acid in diethyl ether (10 mL) was added to the mixture, which was stirred for a further 6h at room temperature. The mixture was concentrated under reduced pressure and diethyl ether was added. The resulting precipitate was collected by filtration and washed with diethyl ether.

Yield: 57% 1 H NMR (400MHz, DMSO d6) d 9.00 (m, 1.5H), 7.90 (d, 2H), 7.62 (d, 2H), 7.30 (m, 1H) , 7.05 (m, 2H), 6.95 (m, 1H), 6.00 (s, 1 H), 4.60 (i, 2H), 4.00 (c, 2H), 3.25 ( m, 4H), 2.40 (m, 2H), 2.10 (m, 6H), 1, 15 (t, 3H) Analysis of the mass spectrum m / z = 460.2 (M + H) + EXAMPLE 151 151 was obtained according to a procedure similar to that described. for 15H, with the following exception: Eíapa 15.1: 15.1c was subsumed by 15.1d. 1 H NMR (400MHz, DMSO d6) 8.96 (ma, 1.5H), 7.89 (d, 2H), 7.63 (d, 2H), 7.29 (1, 1 H), 7.06 (m, 2H), 6.97 (m, 1 H), 6.03 (s, 1H), 4.55 (t, 2H), 4.01 (c, 2H), 3.22 (ma, 4H), 2.29 (t, 2H), 2.12 (ma, 2H), 2.02 (ma, 2H), 1.85 (m, 2H), 1.49 (m, 2H), 1, 13 (í, 3H) Analysis of the mass spectra m / z = 474.3 (M + H) + EXAMPLE 15J 15J was obtained according to a procedure similar to that described for 15H, with the following exception: Stage 15.1: 15.1c was suspended by 15.1 e. 1 H NMR (400MHz, DMSO d6) 8.93 (ma, 1 H), 7.87 (d, 2H), 7.62 (d, 2H), 7.29 (t, 1H), 7.05 (m, 2H), 6.97 (m, 1 H), 6.03 (s, 1H), 4.52 (t, 2H), 4.01 ( c, 2H), 3.23 (ma, 4H), 2.22 (1, 2H), 2.11 (ma, 2H), 2.02 (ma, 2H), 1.83 (m, 2H), 1.47 (m, 2H), 1, 23 (m, 2H), 1, 14 (1, 3H) Analysis of the mass spectra m / z = 488.3 (M + H) + EXAMPLE 15K 15K was done according to a procedure similar to that described for 15L, with the following exception: Stage 15.6: 150 was replaced by 15A. 1 H NMR (400MHz, DMSO d6) 8.18 (d, 2H), 7.60 (d, 2H), 7.29 (t, 1 H), 7.06 (í, 2H), 6.97 (m, 1H), 6.02 (s, 1 H), 5.80 (s, 2H), 3.27 (ma, 4H), 2.13 (ma, 2H) ), 2.00 (ma, 2H) Analysis of mass spectra m / z = 404.1 (M + H) + EXAMPLE 15L Preparation of 15L An aqueous solution of 2N sodium hydroxide (1.8 mL, 0.0036 mol, 5.5 eq) was added to a solution of 15 C (0.300 g, 0.00060 mol, 1.0 eq) in tetrahydrofuran (10 mL) and pure ethanol (1 mL). The mixture was stirred for 10 h at ambient temperature and acidified to pH 6 using an aqueous 2N hydrochloric acid solution. The mixture was concentrated under reduced pressure and dieyl ether added. Then the mixture was stirred for 1 hour at ambient temperature. The resulting precipitate was collected by filtration and washed several times with water and diethyl ether. Yield: 98% 1H NMR (400MHz, DMSO d6 + CF3CO2D) 8.80 (m, 1 H), 8.20 (m, 2H), 7.70 (m, 2H), 7.30 (m, 1H), 7.00 (m, 3H), 6.00 (s, H), 4.80 (m, 2H), 3.30 (m, 4H), 2.60-1, 95 ( m, 8H) Analysis of the mass spectra m / z = 432.1 (M + H) + EXAMPLE 15M 15M was obtained according to a procedure similar to that described for 15L, with the following exception: Stage 15.6: 15C was replaced by 15D . 1 H NMR (400MHz, DMSO d6) 8.76 (ma, 1H), 8.16 (d, 2H), 7.58 (d, 2H), 7.29 (,, 1 H), 7.06 (,, 2H), 6.97 (m, 1 H), 6.00 (s, 1 H), 4.78 (,, 2H), 3, 24 (m, 4H), 2.31 (t, 2H), 2.13 (ma, 2H), 2.01 (ma, 4H), 1.56 (m, 2H) Mass spectral analysis m / z = 446.2 (M + H) + EXAMPLE 15N 15N was worked up according to a procedure similar to that described for 15L, with the following exception: Step 15.6: 15C was replaced by 15E. 1 H NMR (400MHz, DMSO d6) d 8.62 (ma, 1.5H), 8.15 (d, 2H), 7.57 (d, 2H), 7.28 (m, 1H), 7.05 (m, 2H), 6.97 (m, 1 H), 6.00 (s, 1H), 4.76 (t, 2H), 3.25 ( ma, 4H), 2.21 (t, 2H), 2.11 (ma, 2H), 1.98 (ma, 4H), 1.55 (m, 2H), 1.31 (m, 2H) Analysis of the mass spectrum m / z = 460.2 (M + H) + EXAMPLE 16A 16A was obtained according to a procedure similar to that described for 14A, with the following exception: Eíapa 14.1: 14.1 was suspended by 16.1 (see also clause 16.1). 1H NMR (400MHz, DMSO d6) 9.00 (sa, 2H), 8.12 (1, 2H), 7.70 (1, 1H), 7.60 (t, 1H), 7.25 (t, 1 H), 7.00 (m, 3H), 6.00 (s, 1 H), 3.30 (m, 4H), 2.05 (m, 4H) Analysis of the mass spectrum m / z = 346.1 (M + H) + EXAMPLE 16B 16B was obtained according to a procedure similar to that described for 14B, with the following exception: Eíapa 14.1: 14.1 was subsumed by 16.1 (see also tab 16.1). 1 H NMR (400MHz, DMSO d6) 8.66 (ma, 2H), 8.11 (m, 1H), 8.01 (m, 1H), 7.66 (1, 1H), 7.54 (m, 1H), 7.28 (m, 1 H), 7.06 (d, 1H), 6.97 (m, 2H), 6.00 (m, 1H), s, 1H), 4.43 (s, 3H), 3.23 (ma, 4H), 2.12 (ma, 2H), 2.00 (ma, 2H) Analysis of the mass spectra m / z = 360.1 (M + H) + EXAMPLE 16C 160 it was made according to a procedure similar to that described for 140, with the following exception: Stage 14.1: 14.1 was replaced by 16.1 (see also clause 16.1). 1 H NMR (400MHz, DMSO d6) 8.73 (ma, 2H), 7.91 (m, 1H), 7.83 (1, 1H), 7.72 (1, 1H), 7.03 ( m, 1 H), 7.28 (m, 1 H), 7.05 (m, 2H), 6.96 (m, 1 H), 6.02 (s, 1 H), 4.20 (s) , 3H), 3.23 (ma, 4H), 2.11 (ma, 2H), 1, 99 (ma, 2H) Mass spectral analysis m / z = 360.1 (M + H) + EXAMPLE 17A 17A it was made according to a procedure similar to that described for 15A, with the following exception: Eíapa 15.1: 14.4 was subsumed by 16.3 (see also paragraph 17.1). 1 H NMR (400MHz, DMSO d6) 8.93 (ss, 1.5H), 8.13 (m, 1H), 8.03 (s, 1H), 7.68 (t, 1H), 7.56 (m, 1H), 7.28 (m, 1 H), 7.07 (m, 1H), 6.97 (m, 2H), 6.01 ( s, 1H), 5.94 (s, 2H), 3.75 (s, 3H), 3.22 (ma, 4H), 2.12 (ma, 2H), 2.02 (ma, 2H) Analysis of the mass spectrum m / z = 418.1 (M + H) + EXAMPLE 17B 17B was worked up according to a procedure similar to that described for 15C, with the following exception: Ephapa 15.1: 14.4 was suspended by 16.3 (see also tab 17.1). 1 H NMR (400MHz, DMSO d6) 9.07 (sa, 2H), 8.11 (m, 1 H), 8.01 (1, 1 H), 7.66 (,, 1H), 7.54 (m, 1 H), 7.28 (m, 1 H), 7.07 (dd, 1H), 6.96 (m, 2H), 5.99 (s, 1H), 4.79 (í, 2H), 4.03 (c, 2H), 3.22 (ma, 4H), 2.42 (1, 2H), 2.21 (m, 2H), 2.09 (ma, 4H), 1, 16 (í, 3H) Analysis of the mass spectra m / z = 460.2 (M + H) + EXAMPLE 17C 170 was obtained according to a procedure similar to that described for 15F, with the following exceptions: Eíapa 15.1: 14.4 was subsumed by 16.3 (see also Step 17.1). 1 H NMR (400MHz, DMSO dβ) d 8.95 (br s, 2H), 7.80 (m, 1H), 7.69 (m, 3H), 7.28 (m, 1 H), 7.06 ( d, 1 H), 6.97 (m, 2H), 5.99 (s, 1 H), 5.70 (s, 2H), 3.64 (s, 3H), 3.23 (ma, 4H), 2.10 (ma, 2H), 2.01 (ma, 2H) Analysis of the mass spectra m / z = 418.1 (M + H) + EXAMPLE 17D 17D was done according to a procedure similar to that described. for 15C, with the following exceptions: Eíapa 15.1: 14.4 was subsumed by 16.3 (see also paragraph 17.1). 1 H NMR (400MHz, DMSO d ") d 8.37 (dí, 1H), 8.30 (í, 1 H), 7.81 (í, 1H), 7.71 (say, 1H), 7.44 (m, 1 H), 7.22 (m, 2H), 7.10 (m, 1 H), 5.98 (s, 1H), 5.47 (i, 2H), 4.22 (sa, 2H), 4.15 (1, 2H), 4.02-3.46 (ma, 10H), 2.48 (ma, 2H), 2.22 (ma, 2H) Analysis of the mass spectra m / z = 459, 2 (M + H) + EXAMPLE 17E 17E was made according to a procedure similar to that described for 15K, with the following exceptions: Eíapa 15.1: 14.4 was subsumed by 16.3 (see also paragraph 17.1). 1 H NMR (400MHz, DMSO d6) d 8.87 (ma, 2H), 8.13 (d1, 1H), 8.03 (1, 1H), 7.68 (t, 1H), 7.56 (m, 1H), 7.28 (m, 1 H), 7.07 (d, 1H), 6.98 (m, 2H), 6.01 ( s, 1H), 5.77 (s, 2H), 3.24 (ma, 4H), 2.12 (ma, 2H), 2.02 (ma, 2H) Analysis of the mass spectrum m / z = 404.1 (M + H) + EXAMPLE 17F 17F it was worked out according to a procedure similar to that described for 15L, with the following exception: Eíapa 15.1: 14.4 was subsumed by 16.3 (see also paragraph 17.1). 1 H NMR (400 MHz, DMSO d 6) 8.11 (d, 1 H), 8.01 (m, 1H), 7.66 (1, 1H), 7.54 (df, 1H), 7.28 ( m, 1H), 7.07 (d, 1H), 6.97 (m, 2H), 5.99 (s, 1H), 4.78 (f, 2H), 3.21 (ma, 4H), 2.34 (t, 2H), 2.18 (m, 2H), 2.10 (ma, 4H) Mass spectral analysis m / z = 432.1 (M + H) + EXAMPLE 18A Preparation of 18.2: A mixture of 13.5a (0.300 g, 0.00071 mol, 1.0 eq), and the reactive of Lawesson (18.1) (0.288 g, 0.00071 mol, 1 eq) in toluene (10 mL) was heated at reflux temperature for 6 h. The mixture was cooled to room temperature, poured into a saturated aqueous solution of sodium bicarbonate (50 mL) and extracted with ethyl acetate. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. Diethyl ether was added to the mixture, which was stirred at ambient temperature for 1 h. The resulting precipitate was collected by filtration, washed with diethyl ether and used for the next step without further purification. Yield: 64% Analysis of the mass spectrum m / z = 434.93 (MH) "Preparation of 18.4a: A mixture of 18.2 (1 g, 0.0022 mol, 1.0 eq) and 1-bromopinacoIone (18.3a) ) (0.30 mL, 0.0022 mol, 1.0 eq) in? /,? / - dimethylformamide (5 mL) was stirred at ambient temperature for 48 h.The mixture was poured into a saturated aqueous solution of sodium bicarbonate and The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure.The crude product was purified by column chromatography (eluyenie: hexane / acetyl mixtures). of ethyl of increasing polarity.) Yield: 55% 1 H NMR (400MHz, DMSO d6) 8.00 (d, 2H), 7.45 (d, 2H), 7.35 (s, 1 H), 7, 20 (f, 1H), 7.00 (d, 2H), 6.90 (1, 1H), 5.90 (s, 1H), 3.70 (m, 2H), 3.30 (m, 2H) ), 1.90 (m, 2H), 1.70 (m, 2H), 1.30 (s, 9H), 1.35 (s, 9H) Mass spectral analysis m / z - 517.2 ( M + H) + Preparation of 18A: To a cold solution (0 ° C) of 18.4a (0.600 g, 0.0011 mol, 1.0 eq) in anhydrous dichloromethane (20 mL) was added dropwise a solution of anhydrous hydrochloric acid 2.0M in diethylether (5.8 g). mL, 0.0011 mol, 10.0 eq). The mixture was heated slowly at ambient temperature and the stirring was continued for 12 h. The mixture was concentrated under reduced pressure. Subsequently, diethyl ether was added to the mixture, which was stirred for 1 h at ambient temperature. The precipitate was collected by filtration, washed with diethyl ether and dried in vacuo. Yield: 80% H NMR (400MHz, DMSO d6) d 9.00 (s, 2H), 8.00 (d, 2H), 7.50 (d, 2H), 7.40 (s, 1 H), 7.25 (í, 1 H), 7.00 (m, 3H), 6.00 (s, 1 H), 3.20 (m, 4H), 2.00 (m, 4H), 1.30 (s, 9H) Analysis of the mass spectra m / z = 417.3 (M + H) + EXAMPLE 18B 18B was done according to a procedure similar to that described for 18A, with the following exception: Eíapa 18.3: 18.3a was subsumed by 18.3b. 1 H NMR (400MHz, DMSO d6) 8.93 (sa, 2H), 8.24 (s, 1H), 8.10 (m, 4H), 7.52 (m, 4H), 7.40 (m , 1H), 7.29 (m, 1 H), 7.06 (t, 2H), 6.97 (m, 1H), 6.00 (s, 1 H), 3.22 (m, 4H) , 2.07 (m, 4H) Analysis of the mass spectra m / z = 437.1 (M + H) + EXAMPLE 18C Preparation of 18.6: A mixture of 14.2 (1 g, 0.00248 mol, 1.0 eq ), hydroxylamine hydrochloride (18.5) (0.260 g, 0.0037 mol, 1.5 eq.) and íriethylamine (0.70 mL, 0.0049 mol, 2.0 eq) in pure ethanol (15 mL) was heated at reflux temperature for 6 hours. The mixture was cooled to room temperature and poured into water. The resulting precipitate was collected by filtration, washed with water, dried over high vacuum and used for the next step without further purification. Yield: 75% Analysis of the mass spectra m / z = 436.2 (M + H) + Preparation of 18.7 Acetyl chloride (6.7) (0.07 mL, 0.00097 mol, 2.0 eq) was added went to a solution at reflux temperature of 18.6 (0.212 g, 0.00048 mol, 1.0 eq) in pyridine (2 mL). The mixture was heated at reflux temperature for 3 h. The mixture was cooled to room temperature, poured into a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate. The organic phase was washed with an aqueous solution of 1 N hydrochloric acid and brine, dried over sodium sulfate and filtered. The organic extracts were concentrated under reduced pressure and the production in witch was purified by column chromatography (eluyenie: mixtures of hexane / ethyl acetate of increasing polarity). Yield: 35% 1 H NMR (400MHz, CDCl 3) 8.10 (d, 2H), 7.45 (d, 2H), 7.20 (m, 1H), 7.00 (m, 1H), 6, 95 (m, 1H), 6.85 (m, 1 H), 5.60 (s, 1 H), 3.90 (m, 2H), 3.35 (m, 2H), 2.65 (s) , 3H), 2.05 (d, 2H), 1.70 (m, 2H), 1.55 (s, 4H), 1.40 (s, 5H) Analysis of the mass spectra m / z = 460, 1 (M + H) + Preparation of 18 C To a cold (0 ° C) solution of 18.7 (0.300 g, 0.00065 mol, 1.0 eq) in anhydrous dichloromelan (20 mL) was added a solution to the solution. of anhydrous hydrochloric acid 2.0M in dieyl ether (3.2 mL, 0.0065 mol, 10.0 eq). The mixture was heated at ambient temperature and the stirring was continued for 12 h. The mixture was concentrated under reduced pressure. Subsequently, diethyl ether was added to the mixture, which was stirred for 1 hour at room temperature. The precipitate was collected by filtration, washed with diethyl ether and dried in vacuo. Yield: 60% 1 H NMR (400MHz, DMSO d6) d 9.00 (m, 2H), 8.10 (m, 2H), 7.60 (m, 2H), 7.30 (m, 1H), 7 , 05 (m, 3H), 6.00 (s, 1H), 3.30 (m, 4H), 2.45-2.80 (m, 3H), 2.10 (m, 4H) Analysis of the specie mass m / z = 360.3 (M + H) + EXAMPLE 19A Preparation of 19.2: To a solution of 19.1 (29.75 g, 127.5 mmol, 1.2 eq) in dry meianol (200 mL) was he added pyrrolidine (17.6 mL, 212.6 mmol, 2.0 eq) followed by 2'-hydroxyaceophenone (1.1a) (12.8 mL, 106.3 mmol, 1.0 eq). The mixture was heated to reflux temperature for 10 h. The volatiles were removed under reduced pressure and the residue was dissolved in ethyl acetate (500 mL), washed with an aqueous solution of 1 M hydrochloric acid (3 x 200 mL), a 1 M aqueous sodium hydroxide solution x 200 mL) and brine. The organic extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure to give the crude production, which were used in the following step without further purification. 1 H NMR (400MHz, CDCl 3) 7.86 (dd, 1H), 7.50 (m, 1H), 7.42-7.29 (m, 5H), 7.00 (m, 2H), 5.14 (s, 2H), 3.97 (sa, 2H), 3.29 (sa, 2H), 2.71 (s, 2H), 2.04 (m , 2H), 1.61 (m, 2H) Analysis of the mass spectra m / z = 352.1 (M + H) + Preparation of 19.3: In nihologen, to a 1 L and 2 mouths dried in an oven with a dissolution of 19.2 (45.4 g, from 106.3 mmol, 1.0 eq) in dry tetrahydrofuran (350 mL) at -78 ° C was added a solution of 1.0M bis (rlymethylsilyl) amide in teirahydrofuran ( 127.6 mL, 127.6 mmol, 1.2 eq) for a period of 45 minutes. The reaction mixture was maintained at -78 ° C for 1 h and a solution of N-phenylis (trifluoromethanesulfonamide) (1.4) (45.57 g, 127.6 mmol, 1.2 eq) in leirahydrofuran (150 mL) was added. ) lasts for a period of 45 minutes. The reaction mixture was maintained at -78 ° C for 1 h, then slowly warmed to ambient temperature and was stirred for 10 h more at room temperature. Ice water added (300 mL) to inactivate the reaction and the production was extracted with diethyl ether (500 mL). The organic phase was then washed with an aqueous solution of 1 M hydrochloric acid (3 x 150 mL), an aqueous solution of 1M sodium hydroxide (3 x 150 mL), and brine, dried over sodium sulfate and filtered. The organic extractions were concentrated under reduced pressure to give the crude product, which was used in the next step without further purification. Analysis of the mass spectra m / z = 484.0 (M + H) + Preparation of 19.4: To a solution of 1.14 (53.58 g, 212.6 mmol, 2.0 eq) in N, N-dimethyi-formamide (200 mL) at 0 ° C was added poiasium acetylation (31.3 g, 318.9 mmol, 3.0 eq), the palladium (II) 1,1-bis (diphenylphosphino) ferrocene chloride complex with dichloromethane (2.33 g, 3.19 mmol, 0.03 eq). The reaction mixture was heated to 80 ° C, at which point a solution of 19.3 (60 g, crude, from 106.3 mmol, 1.0 eq) in N was added to the reaction mixture. N -dimethylformamide (100 mL) lasted for a period of 30 min. Then the reaction mixture was stirred at 80 ° C for 10 h. Diethyl ether (500 mL) and water (300 mL) were added and the two phases separated. The organic phase was washed with an aqueous solution of 1M hydrochloric acid (2 x 150 mL) and brine, dried over sodium sulfate and filtered. The organic extractions were concentrated under reduced pressure and the crude production was purified by column chromatography (eluyenie: hexane / ethyl acid mixtures of increasing polarity). Yield: 75% in RM countries? 1 H (400MHz, CDCl 3) d 7.71 (dd, 1 H), 7.43-7.28 (m, 5H), 7.11 (m, 1H), 6.90 (m, 1 H), 6 , 82 (dd, 1H), 6.27 (s, 1 H), 5.14 (s, 2H), 3.94 (sa, 2H), 3.34 (sa, 2H), 1.96 (m , 2H), 1, 61 (m, 2H), 1.33 (s, 12H) Analysis of the mass spectra m / z = 462.2 (M + H) + Preparation of 19.6: To a solution of 4-bromophenylcarbamazole of fer-butyl (19.5) (20.7 g, 76 mmol, 1.04 eq) in dimethoxy manganese (200 mL) was added sequentially with an aqueous solution of 2M sodium carbonate (109.5 mL, 210 mmol, 3.0 eq), chlidium chloride (9.28 g, 210 mmol, 3.0 eq), palladium (triphenylphosphine) -eleraquls (0) (1.69 g, 1.46 mmol, 0.02 eq), and 19.4 ( 33.7 g, 73 mmol, 1.0 eq) in nihirogen. The reaction mixture was heated at reflux temperature for 10 h. Water (500 mL) and diethyl ether (300 mL) were added and the two phases separated. The organic phase was washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting foamed solids were soaked with hexane and the fine powders were collected by filtration. Yield: 91% 1 H NMR (400MHz, CDCl 3) d 7.43-7.30 (m, 7H), 7.28-7.23 (m, 2H), 7.17 (m, 1H), 7.02 (m, 1H), 6.92 (m, 1H), 6.85 (m, 1H), 6.53 (s, 1H), 5.50 (s, 1H), 5.15 (s, 2H) , 3.96 (ss, 2H), 3.40 (ss, 2H), 2.06 (m, 2H), 1.67 (m, 2H), 1 53 (s, 9H) Analysis of the mass spectrum m / z = 527.4 (M + H) + Preparation of 19.7: To a cold (0 ° C) solution of 19.6 (35.5 g, 67 mmol, 1.0 eq) in anhydrous dichloromethane (150 mL) was a solution of 2.0M hydrogen chloride in diethyl ether (167.5 mL, 335 mmol, 5.0 eq) was added slowly. The reaction mixture was stirred at ambient temperature for 10 h and then concentrated under reduced pressure. The resulting foam solids were soaked in diethyl ether and the fine powders were collected by filtration. This production in witch was used in the following stages without further purification. Analysis of the mass spectrum m / z = 427.3 (M + H) + Preparation of 19.9a: To a suspension of 19.7 (1.28 g, crude, from 3 mmol, 1.0 eq) in dichloromethane Dry (80 mL) at 0 ° C was slowly added with rhipidylamine (2.1 mL, 15 mmol, 5.0 eq) followed by dropwise addition of isobutyryl chloride (19.8a) (0.48 mL, 4 mL). , 5 mmol, 1.5 eq). The mixture was heated slowly at room temperature and stirred for 10 hours at ambient temperature. Dichloromean (100 mL) was added and the mixture was washed with an aqueous solution of 1 N hydrochloric acid (3 x 50 mL), a saturated aqueous solution of sodium bicarbonate (2 x 50 mL) and brine, dried over sodium sulfate and filtered. The crude product was concentrated under reduced pressure and purified by column chromatography (eluent: mixtures of hexane / ethyl acetate of increasing polarity). Yield: 81% in two stages 1 H NMR (400MHz, CDCl 3) 7.57 (d, 2H), 7.40-7.27 (m, 8H), 7.17 (m, 1H), 7.01 ( d, 1H), 6.93 (d, 1H), 6.85 (m, 1H), 5.50 (s, 1H), 5.15 (s, 2H), 3.96 (sa, 2H), 3.41 (sa, 2H), 2.53 (m, 1H), 2.06 (m, 2H), 1.67 (m, 2H), 1, 28 (d, 6H) Mass Spectrum Analysis m / z-467.3 (M + H) + Preparation of 19A To a stirred solution of 19.9a (1.2 g, 2.44 mmol, 1.0 eq) in dry dichloromethane (20 mL) was added iodotrimethylsilane ( 0.66 mL, 4.89 mmol, 2.0 eq.). After stirring at ambient temperature for 1 h, the mixture was concentrated to dryness under reduced pressure. To the residue was added an aqueous solution of 1 N hydrochloric acid (300 mL) and diethyl ether (200 mL). The resulting solid was collected by filtration, washed with diethyl ether, and dried under vacuum. Yield: 92% 1 H NMR (400MHz, DMSO d6) 10.02 (s, 1 H), 8.98 (sa, 2H), 7.70 (d, 2H), 7.36-7.22 (m , 3H), 7.02 (m, 2H), 6.94 (m, 1H), 5.82 (s, 1 H), 3.21 (m, 4H), 2.63 (m, 1H), 2.03 (m, 4H), 1, 11 (d, 6H) Analysis of the mass spectra m / z - 363.4 (M + H) + EXAMPLE 19B 19B was done according to a procedure similar to that described for 19A, with the following exception: Eíapa 19.6: 19.8a was suspended by 19.8b. 1 H NMR (400MHz, DMSO d6) d 10.04 (s, 1 H), 8.90 (m, 2H), 7.71 (m, 2H), 7.29 (m, 2H), 7.25 ( m, 1H), 7.03 (m, 2H), 6.94 (m, 1H), 5.82 (s, 1H), 3.44-3.11 (m, 4H), 2.25 (m , 1H), 2.02 (m, 4H), 1.51 (m, 4H), 0.86 (i, 6H) Mass spectral analysis m / z = 391, 4 (M + H) + EXAMPLE 19C Preparation of 19.10: To a solution of 19.7 (4.63 g, crude, from 10 mmol, 1.0 eq) in dry pyridine (10 mL) at 0 ° C was added leniamenium isopropylsulfonyl chloride (6.5b ) (1.68 mL, 15 mmol, 1.5 eq). The reaction mixture was stirred at ambient temperature for 10 hours. The pyridine was reduced under reduced pressure and the residue was dissolved in ethyl acetate (200 mL). The solution was washed with an aqueous solution of 1 M hydrochloric acid (5 x 50 mL) and brine, dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the production underwent purification by column chromatography (eluent: mixtures of hexane / acetyl ether oil of increasing polarity). Yield: 55% in two layers NMR 1H (400MHz, CDCI3) d 7.43-7.16 (m, 10H), 6.99 (dd, 1H), 6.94 (dd, 1H), 6.86 (m, 1H), 6.60 (s, 1H), 5.51 (s, 1 H), 5.15 (s, 2H), 3.96 (sa, 2H), 3.49-3.30 (m, 3H), 2.06 (m, 2H), 1.67 (m, 2H), 1.43 (d, 6H) Mass spectral analysis m / z = 533.3 (M + H) + Preparation of 19 C: To a stirred solution of 19.9a (1.37 g, 2.57 mmol, 1.0 eq) in dry dichloromean (20 mL) was added iodophyrylsilane (0.70 mL, 5.14 mmol, 2%). , 0 eq) went to goía. The mixture was stirred at ambient temperature for 1 h and then concentrated under reduced pressure. To the residue was added an aqueous solution of 1 M hydrochloric acid (300 mL) and diethyl ether (200 mL). The resulting solid was collected by filtration and washed with diethyl ether. The compound in bruise was further purified by preparative liquid chromatography (mobile phase: acetyliron / water / urea fluoride). The desired fractions were combined, concentrated under reduced pressure, and dried in vacuo. Yield: 66% 1 H NMR (400MHz, DMSO d ") d 9.93 (ss, 1 H), 8.67 (ss, 2H), 7.36-7.22 (m, 5H), 7.05-6.91 (m, 3H), 5.83 (s, 1H), 3.32-3.14 (m, 5H), 2.06 (m, 2H), 1.93. (m, 2H), 1, 26 (d, 6H) Analysis of the mass spectrum m / z = 399.3 (M + H) + EXAMPLE 19D Preparation of 19.12: To a solution of 19.7 (1.28 g, in crude, from 2.67 mmol, 1.0 eq) in dry pyridine (15 mL) at 0 ° C was added leniamenie isocyanate ethyl (19.11) (0.33 mL, 4.15 mmol, 1.5 eq). The reaction mixture was stirred at ambient temperature for 10 h. The pyridine was reduced under reduced pressure and the residue was partitioned between water (100 mL) and dichloromelan (200 mL). The organic phase was washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (eluyenie: hexane / acetyl mixtures of increasing polarity). Yield: 78% in two layers NMR 1H (400MHz, CDCI3) d 7.44-7.12 (m, 10H), 7.05-6.79 (m, 4H), 5.45 (s, 1H), 5.16 (m, 3H), 3.95 (br s, 2H), 3.50-3.26 (m, 4H), 2.04 (m, 2H), 1.65 (m, 2H), 1 , 16 (1, 3H) Analysis of the mass spectra m / z = 498.4 (M + H) + Preparation of 19D: To an agitated solution of 19.12 (1.03 g, 2.09 mmol, 1.0 eq ) in dichloromethane (20 mL) was added iodotrimethylsilane (0.57 mL, 4.18 mmol, 2.0 eq), dropwise. The reaction mixture was stirred at room temperature for 1 h and then concentrated under reduced pressure. The residue was suspended in meianol (50 mL) and stirred for a further hour at ambient temperature. The resulting solid was collected by filtration and washed with meianol. The solid was further washed with an aqueous solution of 1 M sodium hydroxide (3 x 10 mL) and water (2 x 10 mL), and then dried under vacuum. Yield: 60% 1 H NMR (400MHz, DMSO d6) d 8.54 (s, 1 H), 7.44 (d, 2H), 7.18 (m, 3H), 6.98 (m, 1H), 6.91 (m, 1H), 6.86 (m, 1H), 6.13 (t, 1H), 5.72 (s, 1H), 3.11 (m, 2H), 2.89 (m , 2H), 2.74 (m, 2H), 1.77 (m, 2H), 1.67 (m, 2H), 1, 06 (1, 3H) Mass spectral analysis m / z = 364, 4 (M + H) + EXAMPLE 20A Preparation of 20A: The aryl amylamine (0.37 mL, 2.66 mmol, 2.2 eq) was added to a solution of 1A (0.50 g, 1.21 mmol, 1.0 eq) in anhydrous hydrohydrofuran (4 mL). Then anhydrous meianol (4 mL) was added followed by 20.1a (0.20 mL, 2.42 mmol, 2.0 eq). Sodium cyanoborohydride (0.09 g, 1.45 mmol, 1.2 eq) was added to the reaction mixture, which was stirred for 30 min at ambient temperature in nihologen. The mixture was concentrated under reduced pressure. Dichloromethane (30 mL) and water (10 mL) were added and the suspension was stirred at ambient temperature for 10 min. The phases separated. The organic phase was further washed with water and brine, dried over sodium sulfate, filled and concentrated under reduced pressure. To a cold solution (0 ° C) of the resulting oil in anhydrous dichloromethane was added a solution of 2.0 M anhydrous hydrochloric acid in diethyl ether (5 mL). The mixture was then stirred for 1 h at room temperature and concentrated under reduced pressure. Diethylether was added. The resulfanie precipitate was collected by filtration and washed with diethyl ether. Yield: 65% 1 H NMR (400MHz, DMSO d6) d 10.63 (sa, 0.25H), 10.50 (sa, 0.75H), 7.42 (m, 4H), 7.28 (m, 1 H), 7.08 (d, 1 H), 6.98 (m, 2H), 6.27 (s, 0.25H), 5.85 (s, 0.75H), 3.37 (ma, 8H) , 2.82 (s, 3H), 2.11 (m, 4H), 1.12 (m, 6H) Analysis of the mass spectrum m / z = 391, 2 (M + H) + Elemental analysis: C25H3oN2O2, 1HCl, 0.9H2O Theoretical:% C 67.75; % H 7.46; % N 6.32 Found:% C 67.89; % H 7.32; % IM 6.26 EXAMPLE 20B 20B was worked up according to a procedure similar to that described for 20A, with the following exception: Step 20.1: 1A was replaced by 11 A. 1H NMR (400MHz, DMSO d6) 510.42 (sa, 1H), 9.47 (s, 1 H), 7.30 (m, 4H), 7.08 (t, 1 H), 6.60 (d, 1 H), 6.46 (d, 1 H) ), 5.68 (s, 1 H), 3.40 (m, 4H), 3.30 (s, 3H), 3.20 (m, 2H), 2.81 (s, 2H), 2, 15 (m, 2H), 2.05 (m, 2H), 1, 10 (m, 6H) Mass spectrum analysis m / z = 407.3 (M + H) + Elemental analysis: C25H30N2O3, 1 HCl, 0.5H2O Theory:% C 66.43; % H 7.14; % N 6.20 Found:% C 66.53; % H 7.06; % N 6.24 EXAMPLE 20C 20C was worked up according to a procedure similar to that described for 20A, with the following exception: Eíapa 20.1: 1A was suspended by 11 B. 1 H NMR (400MHz, DMSO d6) d 10.79 (sa, 1H), 9.74 (d, 1H), 8.41 (s, 1H), 7.69 (dd, 1H), 7.45 (d, 1H), 7.09 (1, 1H) , 6.62 (d, 1 H), 6.49 (d, 2H), 5.81 (s, 1 H), 3.42 (m, 4H), 3.30 (m, 4H), 2.79 (d, 3H), 2.12 (m, 4H), 1.16 (m, 3H), 1.08 (m, 3H) Analysis of the specimen of masses m / z = 408.3 (M + H) + EXAMPLE 20D 20D was worked up according to a procedure similar to that described for 20A, with the following exception: Eíapa 20.1: 1A was suspended by 3D. 1 H NMR (400MHz, DMSO dβ) 11.00 (m, 0.25H), 10.85 (m, 0.75H), 7.80 (m, 2H), 7.54 (m, 1 H), 7.40 (m, 4H), 7.22 (m, 1 H), 7.10 (m, 0.75H), 7.02 (m 0.25H), 6.32 (s, 0.25H), 5.91 (s, 0.75H), 3.33 (m, 10H), 2.80 (m, 2H), 2.20 (m, 3H), 1, 11 (m, 6H) Analysis of the mass spectra m / z = 434.4 (M + H) + Elemental analysis: C26H3l N3O3, 1 HCl, 1 H2O Theoretical:% C 63.99; % H 7.02; % N 8.61 Found:% C 64.11; % H 6.70; % N 8.49 EXAMPLE 20E 20E was obtained according to a procedure similar to that described for 20A, with the following exception: Eíapa 20.1: 1A was subsumed by 3E. 1 H NMR (400MHz, DMSO d6) d 10.84 (m, 1 H), 8.31 (m, 1H), 7.78 (m, 1H), 7.52 (m, 1H), 7.42 ( m, 3H), 7.10 (m, 1 H), 5.90 (s, 1H), 3.46 (m, 2H), 3.31 (m, 10H), 2.82 (m, 2H) , 2.72 (m, 2H), 2.12 (m, 3H), 1.16 (m, 6H), Mass spectrum analysis m / z = 448.5 (M + H) + Elemental analysis: C27H33N3O3 , 1HCl, 1H2O Theory:% C 64.59; % H 7.23; % N 8.37 Found:% C 64.77; % H 7.27; % N 8.40 EXAMPLE 20F 20F was worked up according to a procedure similar to that described for 20A, with the following exception: Eíapa 20.1: 1 A was subsumed by 3F. 1 H NMR (400MHz, DMSO d6) d 10.80 (br s, 1 H), 8.35 (m, 1H), 7.78 (m, 1H), 7.50 (m, 1 H), 7.40 (m, 3H), 7.09 (m, 1 H), 5.93 (s, 1H), 3.41 (m, 2H), 3.20 (m, 10H), 2.72 (m, 2H), 2.10 (m, 3H), 1, 10 (m, 9H) Analysis of the mass spectra m / z = 462.5 (M + H) + Elemental analysis: C28H35 3O3. I HCU H2O Theoretical:% C 65.17; % H 7.42; % N 8,14 Found:% C 65.28; % H 7.37; % N 8.21 EXAMPLE 20G 20G was worked up according to a procedure similar to that described for 20A, with the following exception: Step 20.1: 1 A was subsumed by 3V. 1 H NMR (400MHz, CDCl 3) 8.57 (s, 1H), 7.70 (m, 2H), 7.66 (d, 1H), 7.38 (s, 1H), 7.02 (d, 1 H), 5.70 (s, 1H), 3.61 (m, 2H), 3.46 (m, 2H), 2.62 (m, 2H), 2.52 (m 2H), 2, 12 (m, 2H), 2.78 (m, 2H), 1, 30 (1, 3H), 1, 23 (1, 3H) Mass spectral analysis m / z = 435.4 (M + H) EXAMPLE 20H 20H was done according to a procedure similar to that described for 20L, with the following exception: Stage 20.1: 21 A was replaced by 4H and 20.1 d was suspended by 20.1a. 1 H NMR (400MHz, DMSO dβ) d 10.44-10.12 (m, 1H), 7.74 (dd, 0.7H), 7.67 (dd, 0.7H), 7.45 (m, 5H) , 7.27 (m, 3H), 6.38 (s, 0.3H), 6.00 (s, 0.7H), 3.53-3.16 (m, 8H), 2.84 (m, 3H) ), 2.35-2.03 (m, 4H), 1, 12 (day, 6H) Mass spectral analysis m / z = 470.3 (M + H) + Elemental analysis: C25H31 N3O4S, 1 HCl, 1H2O Theoretical:% C 57.30% H 6.54% N 8.02 Found:% C 57.46% H 6.44% N 7.96 EXAMPLE 20I 20I was obtained according to a procedure similar to that described for 20L, with the following exception: Eíapa 20.1: 20.1 d was subsumed by 20.1a. 1 H NMR (400MHz, DMSO d6) d 10.62 (br s, 1H), 7.41 (m, 4H), 7.24 (m, 1H), 6.97 (m, 2H), 6.93 (m, 1 H), 5.92 and 5.86 (2s, 1 H, roimer), 3.55-2.92 (m, 8H), 2, 80 and 2.77 (d, 3H), 2.56-1.76 (m, 6H), 1.12 (m, 6H) Mass spectral analysis m / z = 405.4 (M + H) + EXAMPLE 20J 20J was obtained according to a procedure similar to that described for 20L, with the following exception: Efapa 20.1: 20.1d was susfiíuyó by 20.1b. 1 H NMR (400MHz, DMSO d6) d 10.72 (m, 1H), 7.41 (m, 4H), 7.24 (m, 1H), 6.95 (m, 3H), 5.91 and 5 , 84 (2s, 1 H, rotamer), 3.56-2.94 (m, 10H), 2.57-1, 77 (m, 6H), 1.27 (m, 3H), 1, 12 (m, 6H) Analysis of the mass spectrum m / z = 419.4 (M + H) + EXAMPLE 20K 20K was obtained according to a procedure similar to that described for 20L, with the following exception: Stage 20.1: 20.1 d was suspended by 20.1c. 1 H NMR (400MHz, DMSO d6) d 9.99 (m, 1 H), 7.41 (m, 4H), 7.25 (m, 1H), 6.95 (m, 3H), 5.88 and 5.86 (2s, 1 H ropymer), 3.70-2.93 (m, 10H), 2.57-1, 76 (m, 7H), 1.12 (m, 6H), 0.99 (m, 6H) Mass spectral analysis m / z = 447.5 (M + H) + EXAMPLE 20L Preparation of 20L: To an agitated solution of cyclopropanecarbaldehyde (20.1 d) (0 , 22 mL, 3.0 mmol, 2.0 eq) in dry dichloromethane (25 mL) was sequentially added 21 A (0.64 g, 1.5 mmol, 1.0 eq), acetic acid (0.10 mL, 1, 8 mmol, 1, 2 eq), and sodium cyanoborohydride (0.14 g, 2.25 mmol, 1.5 eq). The reaction mixture was stirred at ambient temperature for 10 h. Water (40 mL) was added and the aqueous phase was basified to pH = 10 with an aqueous solution of 1 M sodium hydroxide. The two phases were separated and the aqueous phase was saturated with sodium chloride and exsolved with dichloromean (3 x 50). mL). The combined organic phases were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The production in bruise was purified by column chromatography (eluyenie: mixtures of dichloromethane / meianol of increasing polarity). The desired fractions were combined and concentrated under reduced pressure. To a cold (0 ° C) solution of the oil resulting in dichloromethane was added a solution of 2.0M hydrogen chloride in diethyl ether (1.0 mL, 2.0 mmol, 2.0 eq). The mixture was then stirred for 1 h at ambient temperature, concentrated under reduced pressure, and dried under vacuum. Yield: 65% 1 H NMR (400MHz, DMSO d6) d 10.66 (br s, 1H), 7.41 (m, 4H), 7.25 (m, 1H), 7.03-6.89 (m, 3H), 5.91 and 5.86 (2s, 1H, roimer), 3.80-2.95 (m, 10H), 2.44-1, 78 (m, 6H), 1.12 (m , 7H), 0.64 (m, 2H), 0.42 (m, 2H) Analysis of the mass spectrum m / z = 445.4 (M + H) + EXAMPLE 20M Preparation of 20M: Triethylamine (0, 98 mL, 7.00 mmol, 3.3 eq) was added to a solution of 1A (0.80 g, 2.12 mmol, 1.0 eq) in anhydrous dichloromean (5 mL). Compound 2.8a (0.68 mL, 7.00 mmol, 3.3 eq) was then added to the reaction mixture, which was stirred overnight at room temperature in nilrogen. The mixture was concentrated under reduced pressure. The crude product was purified by column chromatography (eluent: mixtures of dichloromethane / methanol of increasing polarity). To a solution of the product purified in dichloromethane (5 mL) was added at 0 ° C a solution of 2.0M hydrochloric acid in dieryl ether (3.2 mL, 1.16 mmol, 5.5 eq). Diethylether was added to the mixture. The resulting precipitate was collected by filtration and washed with diethyl ether. Yield: 46% 1 H NMR (400MHz, DMSO d6) d 10.83 (m, 0.25H), 10.71 (m, 0.75H), 7.45 (m, 4H), 7.28 (m, 1H), 7.08 (m, 1 H), 7.00 (m, 2H), 6.24 (s, 0.25H), 5.85 (s, 0.75H), 3.47 (m, 5H), 3.25 (m, 4H), 3.06 (m, 2H), 2.18 (m, 4H), 1.12 (m, 6H), 0.65 (m, 2H), 0, 43 (m, 2H) Analysis of the mass spectrum m / z = 431, 0 (M + H) + EXAMPLE 20N 20N was obtained according to a procedure similar to that described for 20M, with the following exception: Step 20.1: 2.8a was replaced by 20.2a. 1 H NMR (400MHz, DMSO d6) d 10.10 (m, 1H), 7.43 (m, 4H), 7.28 (m, 1H), 7.09 (m, 1H), 6.98 (m , 2H), 6.28 (s, 0.25H), 5.85 (s, 0.75H), 3.35 (ma, 10H), 2.15 (m, 4H), 1, 28 (m, 3H) , 1, 11 (m, 6H) Analysis of the mass spectrum m / z = 405.0 (M + H) + EXAMPLE 20O 20O was obtained according to a procedure similar to that described for 20M, with the following exception: Eíapa 20.1: 2.8a was subsumed by 20.2b. 1 H NMR (400MHz, DMSO d6) 10.18 (m, 1H), 7.45 (m, 4H), 7.29 (m, 1H), 7.09 (m, 1 H), 6.98 ( m, 2H), 6.25 (m, 0.25H), 5.84 (m, 0.75H), 3.41 (m, 4H), 3.21 (m, 4H), 3.09 (m, 2H) ), 2.16 (m, 4H), 1.75 (m, 2H), 1, 11 (m, 6H), 0.91 (m, 3H) Analysis of the mass spectra m / z = 419.1 ( M + H) + EXAMPLE 20P 20P was prepared according to a procedure similar to that described for 20M, with the following exception: Eíapa 20.1: 2.8a was suspended by 20.2c. 1 H NMR (400MHz, CDCl 3) d 7.35 (m, 9H), 7.17 (m, 1H), 6.98 (dd, 1H), 6.94 (dd, 1H), 6.84 (m, 1H), 5.61 (s, 1 H), 3.58 (sa, 4H), 3.32 (sa, 2H), 2.60 (ma, 4H ), 2.08 (ma, 2H), 1.81 (ma, 2H), 1.20 (da, 6H) Analysis of the mass spectrum m / z = 467.3 (M + H) + EXAMPLE 20Q 20Q was obluvored according to a procedure similar to that described for 20M, with the following exception: Stage 20.1: 2.8a was replaced by 20.2d. 1 H NMR (400MHz, DMSO dβ) d 10.95 (br s, 0.5H) 7.44 (m, 4H), 7.33 (m, 6H), 7.04 (d, 1H), 6.99 ( m, 2H), 6.24 (s, 0.3H), 5.87 (s, 0.7H), 3.40 (ma, 10H), 3.12 (m, 2H), 2.18 (ma, 4H), 1, 13 (day, 6H) Analysis of mass spectra m / z = 481, 3 (M + H) + EXAMPLE 20R 20R was obtained according to a procedure similar to that described for 20M, with the following exception: Stage 20.1: 2.8a was replaced by 20.2e. 1 H NMR (400MHz, DMSO dβ) d 10.70 (ma, 0.50H), 7.43 (m, 4H), 7.28 (m, 6H), 7.08 (d, 1H), 6.97 (m, 2H), 6.36 (s, 0.3H), 5.83 (s, 0.7H), 3.44 (m, 4H) ), 3.18 (ma, 6H), 2.67 (1, 2H), 2.12 (ma, 6H), 1.12 (da, 6H) Analysis of the mass spectra m / z = 495.3 (M + H) + EXAMPLE 21A Preparation of 21.2: To a stirred solution of N-boc 4- piperidone (1.2) (2.0 g, 10 mmol, 1.0 eq) in dry diethyl ether (15 mL) at -25 ° C was added simultaneously, but independently diazoaceia of ethyl (21.1) (1.35 mL, 13 mmol, 1.3 eq) and the diethyl ether boron chloride complex (1.33 mL, 10.5 mmol, 1.05 eq) in nihinogen aminosphere over a period of time of 20 min. The reaction mixture was stirred for another hour at -25 ° C. To the stirred reaction mixture, an aqueous solution of carbonate of potassium 1 was added until the evolution of gases ceased. The two phases were separated and the organic phase was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was used in the next step without further purification. Preparation of 21.3: A mixture of crude 21.2 (3 g, to give 10 mmol) in an aqueous solution of 4M hydrochloric acid (50 mL) was heated at reflux temperature for 6 h. The water was reduced under reduced pressure and the resulting solid was washed with diethyl ether and dried under vacuum. Yield: 90% in two layers NMR 1H (400MHz, DMSO dβ) d 9.41 (sa, 2H), 3.30 (m, 2H), 3.21 (m, 2H), 2.77 (m, 2H) ), 2.62 (m, 2H), 1.94 (m, 2H) Preparation of 21.4: To a suspension of 21.3 (4.98 g, 33.3 mmol, 1.0 eq) in dry dichloromean (100 mL) at 0 ° C was added leniamenie-rhipidylamine (11 mL, 79.92 mmol, 2.4 eq) followed by a dicarbonate solution of di-ert-butyl (4.7) (8.72 g, 39.96 mmol, 1.2 eq) in dichloromean (30 mL) for a period of time of 20 min . The reaction mixture was stirred at ambient temperature for 10 h and was washed with an aqueous solution of 1 M hydrochloric acid (3 x 100 mL), brine, dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the crude product was used in the next layer without further purification. 1 H NMR (400MHz, CDCl 3) 53.58 (m, 4H), 2.65 (m, 4H), 1.78 (m, 2H), 1.45 (s, 9H) Preparation of 21.5: To a solution of 21.4 (2.56 g, 12 mmol, 1.0 eq) in dry meianol (30 mL) was added pyrrolidine (2 mL, 24 mmol, 2.0 eq) followed by 2'-hydroxyaceophenone (1.1a) (1 , 44 mL, 12 mmol, 1.0 eq). The mixture was heated at reflux temperature for 10 h. The volatiles were removed under reduced pressure and the residue was dissolved in ethyl acetate (200 mL) and washed with an aqueous solution of 1 M hydrochloric acid (3 x 50 mL), an aqueous solution of 1 M sodium hydroxide (3 mL). x 50 mL) and brine, dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the production in shale was purified by column chromatography (eluyenie: hexane / acetyl mixtures of etiyl of increasing polarity). Yield: 72% in two layers NMR 1H (400MHz, CDCI3) 7.85 (dd, 1 H), 7.49 (m, 1 H), 6.99 (m, 2H), 3.78-3, 49 (m, 2H), 3.32 (m, 2H), 2.83-2.63 (m, 2H), 2.19 (m, 2H), 2.00-1.55 (m, 4H) , 1.47 (s, 9H) Analysis of the mass spectra m / z = 331, 9 (M + H) + Preparation of 21.6: To a 250 mL and 2-mouth macerata dried in a furnace loaded with a solution of 21.5 (2.86 g, 8.6 mmol, 1.0 eq) in dry hydrofuran (40 mL) at -78 ° C in nihologen was added a solution of 1.0M bis (lyrimethyl silyl) amide in tetrahydrofuran (10M). , 3 mL, 10.3 mmol, 1.2 eq) for a period of 10 min. The mixture was maintained at -78 ° C for 1 h and a solution of N-phenylbis (trifluoromethanesulfonamide) (1.4) (3.68 g, 10.3 mmol, 1.2 eq) in tetrahydrofuran (20 mL) was added to the mixture. ) lasts a period of 10 min. The mixture was kept at -78 ° C for another hour, then the lenghmeny was heated to ambient temperature and it was stirred for 10 h more at room temperature. Ice water (50 mL) was added to inactivate the reaction and the product was extracted with diethyl ether (200 mL). The organic phase was then washed with an aqueous solution of 1N hydrochloric acid (3 x 50 mL), an aqueous solution of 1 N sodium hydroxide (3 x 50 mL) and brine, dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the crude product was purified by column chromatography (eluyenie: hexane / ethyl alcohol mixtures of increasing polarity). Yield: 85% 1 H NMR (400MHz, CDCl 3) d 7.30-7.23 (m, 2H), 6.97 (m, 1H), 6.89 (m, 1H), 5.60 (s, 1H ), 3.80-3.53 (m, 2H), 3.36-3.24 (m, 2H), 2.30-2.06 (m, 3H), 1.90-1.64 (m , 3H), 1.47 (s, 9H) Preparation of 21.7: To a solution of 21.6 (3.38 g, 7.3 mmol, 1.0 eq) in dimethoxyethane (50 mL) was added sequentially an aqueous solution of 2M sodium carbonate (11 mL, 22 mmol, 3.0 eq), lithium chloride (0.93 g, 22 mmol, 3.0 eq), palladium (ρ) (0.17 g 0.15 mmol, 0.02 eq), and 4 -? /,? / - diethylphenylboronic acid (1.6) (1.77 g, 8.02 mmol, 1.1 eq) in niimogen aminosphere. The reaction mixture was heated at reflux for 10 h and then cooled to room temperature. Water (200 mL) and diethyl ether (300 mL) were added and the two phases separated. The organic phase was washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (eluyenie: mixtures of hexane / acetyl ether of increasing polarity). Yield: 81% 1 H NMR (400MHz, CDCl 3) d 7.39 (m, 4H), 7.18 (m, 1H), 6.99 (d, 1H), 6.92 (d, 1 H), 6 , 85 (m, 1H), 5.60 (s, 1 H), 3.86-3.50 (m, 4H), 3.42-3.24 (m, 4H), 2.27-1, 68 (m, 6H), 1 48 (s, 9H), 1, 21 (m, 6H) Analysis of the mass spectrum m / z = 491, 0 (M + H) + Preparation of 21 A: A cold solution (0 ° C) of 21.7 (1.15 g, 2.34 mmol, 1.0 eq) in anhydrous dichloromethane (20 mL) was added with a 4.0M solution of hydrogen chloride in dioxane (3, 51 mL, 14.04 mmol, 6.0 eq). The mixture was stirred at ambient temperature for 10 h and concentrated under reduced pressure. The resulting foamed solids were soaked in water. The fine powder was collected by filtration and washed with diethyl ether. Yield: 98% 1 H NMR (400MHz, CDCl 3) d 9.76 (m, 2H), 7.41 (m, 2H), 7.36 (m, 2H), 7.20 (m, 1H), 7.00 (dd, 1H), 6.97 (dd, 1 H), 6.88 (m, 1 H), 5.63 (s, 1H), 3.68-3, 23 (m, 8H), 2.50-2.23 (m, 4H), 2.02-1.82 (m, 2H), 1.35-1.07 (m, 6H) Mass spectrum analysis m / z = 391, 2 (M + H) + Elemental Analysis: C25H30N2O2, 1 HCI Theoretical:% C 70.32; % H 7.32; % N 6.56 Found:% C 70.14; % H 7.23; % N 6.55 EXAMPLE 21 B Preparation of 21.7a and 21.7b: The racemic compound 21.7 (15 g) was resolved by chiral HPLC to give 21. 7a (6.7 g) and 21.7b (6.0 g) as the pure enaniomers. Chiral separation conditions: Column: Chiralcel OJ, 4.6 x 250 mm Flow rate: 1.0 mL / min Temperaure: Ambient temperature Detection: 335 nm Mobile phase: Methanol 21.7a: 1H NMR (400MHz, CDCI3) d 7, 38 (m, 4H), 7.18 (m, 1H), 6.99 (dd, 1H), 6.92 (dd, 1H), 6.85 (m, 1 H), 5.60 (s, 1H), 3.84-3.49 (m, 4H), 3.31 (m, 4H), 2.25-1.65 (m, 6H), 1.48 (s, 9H), 1.21 (m, 6H) Analysis of the mass spectrum m / z = 491, 3 (M + H) + MD25 = - 1, 04 (c.1, 14 mg / mL, MeOH) Chiral purity: ee = 99%; IR = 4.6 min 21.7b: 1 H NMR (400MHz, CDCl 3) 7.39 (m, 4H), 7.18 (m, 1H), 6.99 (dd, 1H), 6.92 (dd, 1 H), 6.85 (m, 1 H), 5.60 (s, 1 H), 3.85-3.48 (m, 4H), 3.31 (m, 4H), 2.25- 1, 66 (m, 6H), 1, 48 (s, 9H), 1, 21 (m, 6H) Analysis of the mass spectrum m / z = 491, 3 (M + H) + ND25 = + 1, 07 (c.1.16 mg / mL, MeOH) Chiral purity: ee = 99%; R = 5.2 min Preparation of 21 B: To a cold (0 ° C) solution of 21.7a (1.3 g, 2.65 mmol, 1.0 eq) in anhydrous dichloromethane (20 mL) was added The solution was admixed with 4.0M hydrogen chloride in dioxane (3.31 mL, 13.25 mmol, 5.0 eq). The reaction mixture was stirred at ambient temperature for 10 h and then concentrated under reduced pressure. The foamed solids were soaked in diethyl ether and the resulting fine powder was collected by filtration and washed with diethyl ether. Yield: 87% 1 H NMR (400MHz, DMSO d6) d 8.97 (ss, 2H), 7.41 (m, 4H), 7.24 (m, 1 H), 7.00-6.89 (m , 3H), 5.89 (s, 1H), 3.54-3.01 (m, 8H), 2.30-2.10 (m, 3H), 2.03-1, 88 (m, 2H) ), 1.78 (m, 1 H), 1, 23-0.99 (m, 6H) Mass spectrum analysis m / z = 391, 3 (M + H) + Elemental analysis: C25H30N2O2, 1 HCl, 1/6 Theoretical H2O:% C 69.83; % H 7.35; % N 6.51 Found:% C 69.84; % H 7.27; % N 6.46 [D] D25 = + 0.18 (c.10.0 mg / mL, MeOH) EXAMPLE 210 Preparation of 21C: To a cold (0 ° C) solution of 21.7b (1.3 g, 2.65 mmol, 1.0 eq) in anhydrous dichloromethane (20 mL) was added dropwise a solution of 4.0M hydrogen chloride in dioxane (3.31 mL, 13.25 mmol, 5.0 eq) . The reaction mixture was stirred at ambient temperature for 10 h and then concentrated under reduced pressure. The foamed solids were soaked in diethyl ether and the resulting fine powder was collected by filtration and washed with diethyl ether. Yield: 89% 1H NMR (400MHz, DMSO d6) d 9.00 (ss, 2H), 7.41 (m, 4H), 7.24 (m, 1H), 7.02-6.89 (m, 3H), 5.89 (s, 1 H), 3.52-3.02 (m, 8H), 2.35-2.10 (m, 3H), 2.04-1, 88 (m, 2H) ), 1.78 (m, 1 H), 1.23-0.99 (m, 6H) Analysis of the mass spectra m / z = 391, 3 (M + H) + Elemental analysis: C25H30N2 ° 2. HCI > 1 6 H2? Theoretical:% C 69.83; % H 7.35; % N 6.51 Found:% C 69.84; % H 7.32; % N 6.47 [D] D25 = -0.18 (c.10.25 mg / mL, MeOH) EXAMPLE 21 D Preparation of 21 D: To an agitated solution of 21 B (0.47 g, 1.1) mmol, 1.0 eq) in meianol (20 mL) was added palladium [90 mg, 10% by weight (dry base) on acyival charcoal, 20% by weight eq.]. The reaction mixture was stirred in a hydrogen atmosphere using a hydrogen balloon at ambient temperature for 10 hours. The palladium on charcoal was filtered on a Celite bed and the filtrate was concentrated under reduced pressure. The bruise production was purified by column chromatography (eluyenie: mixtures of dichloromean / meianol / ammonium hydroxide of increasing polarity). The desired fractions were combined and concentrated under reduced pressure. To a cold (0 ° C) solution of the resulting oil in dichloromethane, a solution of 2.0M hydrogen chloride in diethyl ether (1.1 mL, 2.2 mmol, 2.0 eq) was added dropwise. The mixture was then stirred for 1 h at ambient temperature, concentrated under reduced pressure, and dried under vacuum. Yield: 89% 1 H NMR (400MHz, DMSO d6) 8.88 (ss, 2H), 7.30 (m, 4H), 7.12 (m, 1 H), 6.86 (m, 1H), 6.78 (m, 1H), 6.62 (m, 1H), 4.20 (m, 1 H), 3.50-2.96 (m, 8H), 2.29-1.66 (m , 8H), 1.10 (m, 6H) Analysis of the mass spectrum m / z = 393.3 (M + H) + EXAMPLE 21 E Preparation of 21 E: To a stirred solution of 21C (0.49 g, 1.14 mmol, 1.0 eq) in methanol (20 mL) was added palladium [98 mg, 10% by weight (dry base) on activated charcoal, 20%) by weight eq. The reaction mixture was stirred in hydrogen using a hydrogen balloon at ambient temperature for 10 hours. The palladium on acivated carbon was filtered on a Celiie bed and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (eluyenie: mixtures of dichloromethane / methanol / ammonium hydroxide of increasing polarity). The desired fractions were combined and concentrated under reduced pressure. To a cold (0 ° C) solution of the resulting dichloromethane oil was added dropwise a solution of 2.0M hydrogen chloride in diethyl ether (1.14 mL, 2.28 mmol, 2.0 eq). After cooling, the mixture was stirred for 1 h at ambient temperature, concentrated under reduced pressure, and dried under vacuum. Yield: 93% 1 H NMR (400MHz, DMSO d6) d 8.80 (br s, 2H), 7.29 (m, 4H), 7.12 (m, 1H), 6.85 (m, 1 H), 6.77 (m, 1 H), 6.62 (m, 1 H), 4.20 (m, 1 H), 3.52-2.96 (m, 8H), 2.22-1.66 (m, 8H), 1, 10 (m, 6H) Analysis of the mass spectra m / z = 393.3 (M + H) + EXAMPLE 21 F Preparation of 21.9: To an agitated solution of 21 A (1, 93 g, 4.52 mmol, 1.0 eq) in dry dichloromethane (30 mL) at 0 ° C was added triethylamine (1.51 mL, 10.85 mmol, 2.4 eq) followed by dropwise addition. of benzyl chloroformate (21.8) (0.76 mL, 5.42 mmol, 1.2 eq). The reaction mixture was heated slowly to room temperature and stirred for 10 h at ambient temperature. The volatile compounds were re-treated under reduced pressure and the residue was partitioned between diethyl ether (200 mL) and water (100 mL). The organic phase was washed with an aqueous solution of 1N hydrochloric acid (3 x 50 mL) and brine, dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give the crude product, which was used in the following step without further purification. Analysis of the mass spectra m / z = 525.0 (M + H) + Preparation of 21.10: To a solution of 21.9 (0.9 g, in bruise, from 1.71 mmol, 1.0 eq) in dry dichloroean (10 mL) was added the sulfur dioxide complex N, N-dimethylformamide (4.3) (315 mg, 2.06 mmol, 1.2 eq) fractionally. The reaction mixture was heated at 75 ° C for 10 h and then cooled to 0-10 ° C, at which point oxalyl chloride (0.2 mL, 2.22 mmol, 1.3 eq) was added in addition. ). The mixture was then stirred at 65 ° C for a further 3 h and then quenched with ice water (50 mL) at room temperature. Dichloromethane (100 mL) was added and the two phases were separated. The aqueous phase was extracted with dichloromethane (3 x 50 mL) and the combined organic phases were dried over sodium sulphamide, filtered, and concentrated under reduced pressure to give the crude product, which were used in the next step without further purification. . Analysis of the mass spectra m / z = 622.9 (M + H) + Preparation of 21.11: To a solution of 21.10 (0.9 g, in bruise, from 1.4 mmol, 1.0 eq) in dry dichloromethane (50 mL) at 0 ° C was added lemanimenia-rhyethylamine (0.4 mL, 2.8 mmol, 2.0 eq) and a solution of 2.0M eylamine (3.4c) in hydrofuran (7 mL, 14 mL). mmol, 10.0 eq) was a goya. The mixture was heated slowly to room temperature and stirred for 10 hours at room temperature. Water (50 mL) and chloroform (50 mL) were added and the two phases separated. The aqueous phase was extracted with chloroform (3 x 50 mL) and the combined organic phases were dried over sodium sulphamide, filled, and concentrated under reduced pressure. The bruise production was purified by column chromatography (eluyenie: hexane / acetyl mixtures of increasing polarity). Performance: 34% in eyelids 1H NMR (400MHz, CDCl3) d 7.68 (m, 1 H), 7.50 (m, 1H), 7.43 (m, 2H), 7.40-7.30 (m, 7H), 6.98 (d , 1 H), 5.66 and 5.44 (2s, 1 H), 5,18 and 5,16 (2s, 2H), 4,21 (í, 1H), 3,89-3,23 (m , 8H), 2.97 (m, 2H), 2.32-1, 66 (m, 6H), 1.35-1, 05 (m, 9H) Analysis of the mass spectrum m / z = 631, 95 (M + H) + 21 F Preparation: To a solution of 21.11 (0.35 g, 0.55 mmol, 1.0 eq) in dichloromethane (10 mL) was added iodotrimethylsilane (0.15 mL, 1, 1 mmol, 2.0 eq) drop by drop. The mixture was stirred at ambient temperature for 2 hours. The mixture was diluted with chloroform 9100 mL) and meianol (5 mL). The solution was washed with an aqueous solution of 20% sodium ethosulfonate >; (2 x 30 mL), with an aqueous solution of 1M sodium carbonate (2 x 30 mL), dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the crude product was purified by preparative liquid chromatography (mobile phase: acetylonitrile / water / urea-trifluoroacetic acid). The desired fractions were combined and concentrated under reduced pressure. The product was dissolved in dichloromean (50 mL); The organic phase was washed with an aqueous solution of 1 N sodium hydroxide (2 x 20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. To a cold (0 ° C) solution of the oil resulting in anhydrous dichloromethane was added a solution of 1.0M hydrogen chloride in diethyl ether (1.1 mL, 1.1 mmol, 2.0 eq). The mixture was then stirred for 1 h at ambient temperature, concentrated under reduced pressure, and dried under vacuum. Yield: 56% 1H NMR (400MHz, DMSO d6) d 9.03 (br s, 2H), 7.65 (dd, 1H), 7.54-7.36 (m, 6H), 7.16 (d, 1H), 6.04 (s, 1 H), 3.54-3.02 (m, 8H), 2.71 (m, 2H), 2.37-2.13 (m, 3H), 2, 06-1.72 (m, 3H), 1.22-1.03 (m, 6H), 0.94 (l, 3H) Mass spectrum analysis m / z = 498.5 (M + H) + Elemental analysis: C27H35N3O4S, 1 HC1, 0.33H2O Theoretical:% C 60.04; % H 6.84; % N 7.78 Found:% C 59.93; % H 6.81; % N 7.80 EXAMPLE 22A Preparation of 22.1: To a suspension of 21 B (4.06 g, 9.5 mmol, 1.0 eq) in teirahydrofuran (50 mL) at 0 ° C was added aryl amylamine (3, 3 mL, 23.75 mmol, 2.5 eq) followed by the addition was aided with urea fluoride (4.1) (1.6 mL, 11.4 mmol, 1.2 eq). The reaction mixture was heated slowly to ambient temperature and stirred for 10 h at room temperature. To the reaction mixture was added ethyl acetyl (200 mL) and the organic phase was washed with a 1 M aqueous hydrochloric acid solution (3 x 50 mL) and brine, dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give the production in witch, which was used in the following stage without further purification. Analysis of the mass spectrum m / z = 487.2 (M + H) + Preparation of 22.2: To a solution of 22.1 (5.0 g, from 9.5 mmol, 1.0 eq) in dry dichloroethane ( 100 mL) was added the sulfur trioxide complex N, N-dimethylylformamide (4.3) (2.18 g, 14.25 mmol, 1.5 eq) fractionally. The mixture was heated to reflux temperature for 10 h and then cooled to 0-10 ° C, at which point oxalyl chloride (1.33 mL, 15.2 mmol, 1.6 eq) was added in addition. The mixture was then stirred at 70 ° C for a further 3 h and quenched with ice water (1: 1) (150 mL) at room temperature. Dichloromethane (100 mL) was added to the reaction mixture and the two phases were separated. The aqueous phase was further extracted with dichloromethane (3 x 50 mL) and the combined organic phases were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (eluyenie: mixtures of hexane / ethyl acetate of increasing polarity). Yield: 84% in two stages 1 H NMR (400MHz, CDCI3) 7.88 (m, 1H), 7.70 (m, 1 H), 7.48 (m, 2H), 7.35 (m, 2H), 7.08 (d, 1H), 5.716 and 5.706 (2s, 1 H), 4.03-3.26 (m, 8H), 2.49-2.21 (m, 3H) , 2.03-1, 72 (m, 3H), 1, 33-1, 11 (m, 6H) Analysis of the mass spectrum m / z = 585.2 (M + H) + Preparation of 22.3a: A a solution of 22.2 (0.6 g, 1.02 mmol, 1.0 eq) in dry dichloromethane (30 mL) at 0 ° C was added iarythylamine (0.71 mL, 5.10 mmol, 5.0 eq) and the methylamine hydrochloride salt (3.4b) (0.21 g, 3.06 mmol, 3%). , 0 eq) in one portion. The reaction mixture was warmed slowly to ambient temperature and stirred for 10 h at ambient temperature. Water (50 mL) and dichloromethane (50 mL) were added to the mixture and the two phases were separated. The aqueous phase was further extracted with dichloromethane (3 x 50 mL) and the combined organic phases were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (eluyenie: hexane / ethyl acetate mixtures of increasing polarity). Yield: 89% 1 H NMR (400MHz, CDCl 3) d 7.71 (dd, 1H), 7.51 (t, 1H), 7.45 (m, 2H), 7.34 (m, 2H), 7, 02 (d, 1H), 5,665 and 5,657 (2s, 1 H), 4.29 (m, 1 H), 4.02-3.25 (m, 8H), 2.63 (d, 3H), 2 , 47-2.19 (m, 3H), 1, 99-1, 68 (m, 3H), 1, 22 (m, 6H) Analysis of the mass spectrum m / z = 580.3 (M + H) + Preparation of 22A: To a solution of 22.3a (0.53 g, 0.91 mmol, 1.0 eq) in a mixture of methanol (20 mL) and water (5 mL) at 0 ° C was added carbonation of poiasium (0.75 g, 5.46 mmol, 6.0 eq) fractionally. The reaction mixture was heated to ambient temperature and stirred for 10 h at room temperature. Brine (50 mL) and chloroform (50 mL) were added to the reaction mixture and the two phases were separated. The aqueous phase was extracted with chloroform (3 x 50 mL) and the combined organic phases were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude production was purified by column chromatography (eluyenie: mixtures of dichloromean / meianol of increasing polarity). The desired fractions were combined and concentrated under reduced pressure. To a cold solution (0 ° C) of the oil resulting in anhydrous dichloromethane was added a solution of 2.0M hydrogen chloride in diethyl ether (0.91 mL, 1.82 mmol, 2.0 eq). The mixture was stirred for 1 h at room temperature, concentrated under reduced pressure, and dried under vacuum. Yield: 82% 1 H NMR (400MHz, DMSO d6) d 9.04 (sa, 2H), 7.64 (dd, 1H), 7.49-7.34 (m, 6H), 7.17 (d, 1H), 6.04 (s, 1 H), 3.45 (m, 2H), 3.31-3.15 (m, 5H), 3.09 (m, 1H), 2.35 (d, 3H), 2.28 (m, 2H), 2.18 (m, 1H), 1.99 (m, 2H), 1.80 (m, 1 H), 1 , 12 (m, 6H) Analysis of the mass spectrum m / z = 484.2 (M + H) + Elemental analysis: C26H33N3O4S, 1 HCl, 1, 2H2O Theoretical:% C 57,65; % H 6.77; % N 7.76 Found:% C 57,69; % H 6.62; % N 7.71 [G] D25 = -0.42 (c.9.4 mg / mL, MeOH) EXAMPLE 22B 22B was prepared according to a procedure similar to that described for 22A, with the following exception: Efapa 22.3: 3.4 b was subsumed by 3.4c. 1 H NMR (400MHz, DMSO d6) d 8.98 (br s, 1H), 7.65 (dd, 1H), 7.44 (m, 5H), 7.37 (d, 1H), 7.16 (d , 1 H), 6.04 (s, 1 H), 3.45 (m, 2H), 3.32-3.05 (m, 6H), 2.71 (m, 2H), 2.35- 1.75 (m, 6H), 1.12 (m, 6H), 0.94 (t, 3H) Analysis of the mass spectrum m / z = 498.3 (M + H) + Elemental Analysis: C27H35N3O4S, 1 HCl, 1, 1 Theoretical H2O:% C 58.54; % H 6.95; % N 7.59 Found:% C 58.55; % H 6.82; % N 7.55 [D] D25 = _0 > 51 (c = 9.25 mg / mL, MeOH) EXAMPLE 22C 22C was obtained according to a procedure similar to that described for 22A, with the following exception: Eíapa 22.3: 3.4b was subsituted by 3.4d. 1 H-NMR (400MHz, DMSO-d) 9.05 (sa, 2H), 7.65 (dd, 1 H), 7.56 (t, 1H), 7.43 (m, 4H), 7.37 ( d, 1 H), 7.16 (d, 1 H), 6.04 (s, 1 H), 3.53-3.04 (m, 8H), 2.63 (m, 2H), 2, 35-1, 75 (m, 6H), 1, 33 (m, 2H), 1, 12 (m, 6H), 0.77 (t, 3H) Analysis of the mass spectrum m / z = 512.4 ( M + H) + Elemental Analysis: C28 37N3 ° 4S. HCl, 0.5H2O Theory:% C 60.36; % H 7.06; % N 7.54 Found:% C 60.28; % H 7.10; % N 7.53 [D] D25 = -0.60 (c = 9.55 mg / mL, MeOH) EXAMPLE 22D 22D was made according to a procedure similar to that described for 22A, with the following exception: Stage 22.3: 3.4b was subsituted by 3.4g. 1 H NMR (400MHz, DMSO d6) d 9.0 (br s, 2H), 7.66 (m, 2H), 7.42 (m, 5H), 7.16 (d, 1H), 6.04 (s) , 1H), 3.45 (m, 2H), 3.22 (m, 6H), 2.59 (m, 2H), 2.35-1.75 (m, 6H), 1.12 (m, 6H), 0.75 (m, 1H), 0.32 (m, 2H), 0.03 (m, 2H) Analysis of the mass spectrum m / z = 524.3 (M + H) + Elemental Analysis: C29H37N3O4S, 1 HCl, 0.66H2O Theoretical:% C 60.88; % H 6.93; % N 7.34 Found:% C 60.92; % H 6.96; % N 7.37 [D] D25 = .0.59 (C = 9.35 mg / mL, MeOH) EXAMPLE 22E Preparation of 22.4: To a solution of 22.2 (0.86 g, 1.47 mmol, 1.0 eq) in teirahydrofuran (5 mL) at 0 ° C was added a solution of 1.0 M hydrazine in teirahydrofuran ( 5.1) (15 mL, 15 mmol, 15.0 eq) in one portion. The reaction mixture was stirred at 0 ° C for 30 min. Water (50 mL) and dichloromethane (100 mL) were added and the two phases were separated. The aqueous phase was extracted with dichloromethane (3 x 50 mL) and the combined organic phases were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (eluent: hexane / acetyl mixtures of increasing polarity). Yield: 72% Analysis of the mass spectrum m / z = 581, 2 (M + H) + Preparation of 22.5: To a suspension of 22.4 (0.62 g, 1.06 mmol, 1.0 eq) in ethanol ( 10 mL) was added sodium acetate (0.58 g, 7.1 mmol, 6.7 eq) and iodomean (2.8c) (0.37 mL, 5.8 mmol, 5.5 eq). The reaction mixture was heated at reflux temperature for 10 h. Water (100 mL) and dichloromethane (100 mL) were added and the two phases were separated. The aqueous phase was extracted with dichloromethane (3 x 50 mL) and the combined organic phases were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (eluyenie: hexane / acetyl mixtures of increasing polarity). Yield: 78% 1 H NMR (400MHz, CDCl 3) d 7.78 (m, 1 H), 7.61 (t, 1 H), 7.45 (m, 2H), 7.35 (m, 2H), 7.06 (d, 1 H), 5.685 and 5.675 (2s, 1 H), 4.01-3.42 (m, 6H), 3.33 (sa, 2H), 3, 00 (s, 3H), 2.46-2.22 (m, 3H), 2.00-1, 69 (m, 3H), 1.22 (m, 6H) Mass spectral analysis m / z = 565.3 (M + H) + Preparation of 22E: To a solution of 22.5 (0.45 g, 0.8 mmol, 1.0 eq) in a mixture of methanol (20 mL) and water (5 mL) at 0 ° C was added potassium carbonate (0, 86 g, 4.8 mmol, 6.0 eq) fractionally. The reaction mixture was heated to room temperature and stirred for 10 h at ambient temperature. Brine (50 mL) and chloroform (50 mL) were added and the two phases separated. The aqueous phase was extracted with chloroform (3 x 50 mL) and the combined organic phases were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude production was purified by column chromatography (eluyenie: mixtures of dichloromethane / methanol of increasing polarity). The desired fractions were combined and concentrated under reduced pressure. To a cold solution (0 ° C) of the resulting oil in anhydrous dichloromethane was added a solution of 2.0M hydrogen chloride in diethyl ether (0.8 mL, 1.6 mmol, 2.0 eq). The mixture was then stirred for 1 hour at ambient temperature, concentrated under reduced pressure, and dried under vacuum. Yield: 86% 1 H NMR (400MHz, DMSO dβ) d 9.01 (br s, 2H), 7.80 (dd, 1H), 7.46 (m, 5H), 7.22 (d, 1 H), 6.06 (s, 1H), 3.45 (m, 2H), 3.32-3.03 (m, 9H), 2.29 (m, 2H), 2.18 (m, 1H), 1 , 99 (m, 2H), 1.81 (m, 1H), 1.12 (m, 6H) Mass spectrum analysis m / z = 469.2 (M + H) + Elemental analysis: C26H32N2O4S, 1 HCl Theoretical:% C 61, 83; % H 6.59; % N 5.55 Found:% C 61, 82; % H 6.60; % N 5.51 [D] D25 = _ o, 45 (c.10.3 mg / mL, MeOH) EXAMPLE 23A 23A was obtained according to a procedure similar to that described for 1A, with the following exceptions: EIApa 1.1: Procedure 1 B was used and 1.2 was replaced by 23.1a (see also step 23.1). Stage 1.3: Procedure 1 C was used (see also paragraph 23.3). Step 1.4: Procedure 1 E was used (see also step 23.4). 1 H NMR (400MHz, CDCl 3) d 10.20 (m, 2H), 7.40 (m, 4H), 7.22 (m, 1H), 7.04 (m, 2H), 6.91 (m, 1 H), 5.66 (s, 1 H), 3.85-3.50 (m, 5H), 3.31 (m, 3H), 2, 60 (m, 1H), 2.13 (m, 1 H), 1.27 (m, 3H), 1, 16 (m, 3H) Mass spectral analysis m / z = 363.2 (M + H) + EXAMPLE 23B 23B was made according to a procedure similar to that described for 1 A, with the following exceptions: Eíapa 1.1: Procedure 1 B was used and 1.2 was subsumed by 23.1b (see also paragraph 23.1). Step 1.3: Procedure 1 C was used (see also clause 23.3). Step 1.4: Procedure 1 E was used (see also paragraph 23.4). 1 H NMR (400MHz, CDCl 3) d 10.33 (m, 1H), 9.21 (m, 1H), 7.39 (m, 5H), 7.21 (m, 1H), 6.98 (m, 1H), 6.87 (m, 1 H), 5.50 (s, 1 H), 3.55 (m, 4H), 3.34 (m, 2H), 2.93 (m, 2H), 2.44 (m, 1 H), 2.33 (m, 1H), 1.83 (m, 1 H), 1.70 (m, 1 H), 1.26 (m, 3H), 1, 16 (m, 3H) Analysis of the mass spectra m / z- 377.0 (M + H) + EXAMPLE 23C 23C was done according to a procedure similar to that described for 1A, with the following exceptions: EIAP 1.1: The Procedure 1 B and 1.2 was subsumed by 23.5 (see also step 23.5). Step 1.3: Procedure 1C was used (see also step 23.7). Step 1.4: Procedure 1 E was used (see also step 23.8). 1 H NMR (400MHz, DMSO d6) 9.28 (ma, 2H), 7.43 (d, 2H), 7.35 (d, 2H), 7.27 (m, 1 H), 7.01 (d, 1 H), 6.97 (m, 2H), 5.57 (s, 1 H), 4.01 (sa, 2H), 3, 44 (sa, 2H), 3.22 (sa, 2H), 2.36 (m, 2H), 2.27 (m, 4H), 2.04 (m, 2H), 1.12 (da, 6H) ) Analysis of the mass spectra m / z = 403.2 (M + H) + EXAMPLE 24A Preparation of 24.2: To a solution of 24.1 (9.37 g, 60 mmol, 1.0 eq) in dry meianol (100 mL ) pyrrolidine (10 mL, 120 mmol, 2.0 eq) was added followed by 2'-hydroxyacetophenone (1.1a) (7.22 mL, 60 mmol, 1.0 eq). The reaction mixture was heated to reflux temperature for 10 h. The volatiles were removed under reduced pressure and the residue was dissolved in ethyl ether (200 mL). The mixture was washed with an aqueous solution of 1 M hydrochloric acid (3 x 50 mL), with an aqueous solution of 1 M sodium hydroxide (3 x 50 mL) and brine. The organic extracts were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The production in witch was purified by column chromatography (eluyenie: mixtures of hexane / ethyl acetate of increasing polarity). Yield: 100% 1 H NMR (400MHz, CDCl 3) 7.86 (dd, 1 H), 7.48 (m, 1H), 6.98 (m, 2H), 3.96 (m, 4H), 2 , 71 (s, 2H), 2.12 (m, 2H), 1.99 (m, 2H), 1.74 (m, 2H), 1.61 (m, 2H) Preparation of 24.3: To a mary of 500 mL and 2 mouths dried in an oven loaded with a solution of 24.2 (16.46 g, 60 mmol, 1.0 eq) in dry hydrofuran (100 mL) at -78 ° C in nihologen was added a solution of 1.0 M lithium bis (trimethylsilyl) amide in hydrofuran (72 mL, 72 mmol, 1.2 eq) for a period of 30 min. The mixture was maintained at -78 ° C for 1 h and a solution of N-phenylbis (trifluoromethanesulfonamide) (1.4) (25.72 g, 72 mmol, 1.2 eq) in diethylhydrofuran (100 mL) was added to the mixture. a period of 30 min. The reaction mixture was maintained at -78 ° C for 1 h, and it was slowly heated to room temperature and stirred for 10 h at ambient temperature. Ice water (100 mL) was added to inactivate the reaction and the product was extracted with diethyl ether (200 mL). The organic phase was then washed with an aqueous solution of 1 M hydrochloric acid (3 x 100 mL), with an aqueous solution of 1 M sodium hydroxide (3 x 100 mL) and brine., dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the crude production was purified by column chromatography (eluent: mixtures of hexane / ethyl ether oil of increasing polarity). Yield: 90% 1 H NMR (400MHz, CDCl 3) 7.34-7.19 (m, 2H), 6.97 (m, 1 H), 6.89 (m, 1H), 5.60 (s, 1H), 4.03-3.91 (m, 4H), 2.20 (m, 2H), 2.09-1, 97 (m, 2H), 1.81 (m, 2H), 1.62. (m, 2H) Preparation of 24.4: To a solution of 24.3 (22 g, 54.14 mmol, 1.0 eq) in dimethoxy manganese (200 mL) in nihologen was added sequentially a 2M aqueous sodium carbonate solution (81, 2 mL, 162.42 mmol, 3.0 eq.), Lithium chloride (6.88 g, 162.42 mmol, 3.0 eq.), Palladium (ρ) (1,15 g, 1-yl) esters (triphenylphosphine). , 08 mmol, 0.02 eq), and 4-N, N-dierylphenylboronic acid (1.6) (13.16 g, 59.55 mmol, 1.1 eq). The reaction mixture was heated to reflux temperature for 10 h. Water (200 mL) and diethyl ether (300 mL) were added and the two phases separated. The aqueous phase was further extracted with diethyl ether (2 x 100 mL) and the combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The production in witch was purified by column chromatography (eluyenie: mixtures of hexane / ethyl acetate of increasing polarity). Yield: 95% 1 H NMR (400MHz, CDCl 3) d 7.38 (m, 4H), 7.18 (m, 1H), 6.99 (m, 1H), 6.93 (m, 1 H), 6 , 85 (m, 1 H), 5.62 (s, 1 H), 3.99 (m, 4H), 3.57 (sa, 2H), 3.32 (sa, 2H), 2.24- 2.02 (m, 4H), 1.80 (m, 2H), 1.65 (m, 2H), 1.21 (m, 6H) Preparation of 24A: To a cold (0 ° C) solution of 24.4 (22.32 g, 51.48 mmol, 1.0 eq) in hydrohydrofuran (200 mL) was added an aqueous solution of 1.0M hydrochloric acid (155 mL, 155 mmol, 3.0 eq). The mixture was stirred at ambient temperature for 10 h and then concentrated under reduced pressure. The resulting solid was collected by filtration, washed with hexane / ethyl acetate mixture (20: 1), and dried under vacuum. Yield: 85% 1 H NMR (400MHz, CDCl 3) d 7.40 (m, 4H), 7.23 (m, 1H), 7.04 (d, 1H), 7.00 (d, 1H), 6, 91 (m, 1H), 5.62 (s, 1 H), 3.57 (sa, 2H), 3.32 (sa, 2H), 2.87 (m, 2H), 2.50 (m, 2H), 2.33 (m, 2H), 1.94 (m, 2H), 1.21 (m, 6H) Mass spectral analysis m / z = 390.2 (M + H) + EXAMPLE 24B / EXAMPLE 24C Preparation of 24B / 24C: To a solution of 24A (0.51 g, 1.3 mmol, 1.0 eq) in dry hydrofuran (30 mL) at 0 ° C was added sodium borohydride (50 mg, 1 mg). , 3 mmol, 1, 0 eq) in a portion in nihosogen aminosphere. The reaction mixture was stirred at room temperature for 1 h. Water (50 mL) and diethyl ether (100 mL) were added and the two phases separated. The aqueous phase was further extracted with diethyl ether (2 x 50 mL) and the combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated to give the mixture of two isomers. The bruise production was purified by preparative liquid chromatography giving 24B and 24C. (24B) H NMR (400MHz, CDCl 3) d 7.39 (m, 4H), 7.18 (m, 1H), 6.97 (m, 2H), 6.85 (m, 1 H), 5, 55 (s, 1H), 3.73 (m, 1 H), 3.58 (sa, 2H), 3.33 (sa, 2H), 2.51 (sa, 4H), 2.21 (m, 2H), 1, 52 (m, 2H), 1, 22 (day, 6H) Analysis of the mass spectra m / z = 392.2 (M + H) + (240) 1H NMR (400MHz, CDCI3) d 7 , 39 (m, 4H), 7.18 (m, 1H), 7.01-6.81 (m, 3H), 5.73 and 5.55 (2s, 1H), 4.07 and 3.74 (2m, 1H), 3.59 (sa, 2H), 3.34 (sa, 2H), 3 , 16 (sa, 4H), 2.31-1.89 (m, 2H), 1, 68-1, 46 (m, 2H), 1, 22 (m, 6H) Analysis of the mass spectrum m / z = 392.2 (M + H) + EXAMPLE 24D / EXAMPLE 24E Preparation of 24D / 24E: To a stirred solution of 24A (0.63 mL, 1.62 mmol, 2.0 eq) in dry dichloromethane (20 mL) sequentially n-propylamine (3.4d) (0.16 g, 1.94 mmol, 1.2 eq), acetic acid (0.11 mL, 1.94 mmol, 1.2 eq), and sodium cyanoborohydride were added sequentially. (0.153 g, 2.43 mmol, 1.5 eq). The reaction mixture was stirred at ambient temperature for 10 hours. Water (40 mL) was added and the aqueous phase was basified to pH = 10 with an aqueous solution of 1 M sodium hydroxide. The two phases were separated and the aqueous phase was saturated with sodium chloride and extracted with dichloromethane (3 x 50 mL). The combined organic extractions were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the crude mixture, which was purified by column chromatography (eluent: mixtures of dichloromethane / methanol of increasing polarity). (24D) 1 H NMR (400MHz, CDCl 3) d 7.38 (m, 4H), 7.17 (m, 1 H), 6.99 (dd, 1 H), 6.90 (dd, 1 H), 6.84 (m, 1 H), 5.91 (s, 1 H), 3.57 (sa, 2H), 3.31 (sa, 2H), 2.75 (sa, 1H), 2.65 (t, 2H), 2.11 (m, 2H), 1.98 (m, 2H), 1, 82-1, 46 (m, 7H), 1.21 (m, 6H), 0.95 ( 1, 3H) Analysis of the mass spectrum m / z = 433.2 (M + H) + (24E) 1 H NMR (400MHz, CDCl 3) d 7.38 (m, 4H), 7.16 (m, 1 H) ), 6.98 (dd, 1H), 6.93 (dd, 1 H), 6.83 (m, 1 H), 5.54 (s, 1 H), 3.57 (sa, 2H), 3.31 (br s, 2H), 2.64 (t, 2H), 2.53 (m, 1 H), 2.20 (m, 2H), 1, 83-1, 42 (m, 7H), 1.21 (m, 6H), 0.94 (t, 3H) Analysis of the mass spectrum m / z = 433.2 (M + H) + EXAMPLE 24F 24F was obtained according to a procedure similar to that described for 24D, with the following exception: Eíapa 24.6: 3.4d was subsumed by 3.4j. 1 H NMR (400MHz, CDCl 3) d 7.38 (m, 4H), 7.17 (m, 1H), 6.96 (m, 2H), 6.84 (m, 1H), 5.54 (s, 1H), 3.57 (m, 2H), 3.32 (m, 2H), 2.35 (s, 6H), 2.25 (m, 3H), 1.79 (m, 4H), 1, 46 (m, 2H), 1, 26 (m, 3H), 1, 16 (m, 3H) Analysis of the mass spectra m / z = 419.2 (M + H) + EXAMPLE 24G 24G was made according to a procedure similar to that described for 24E, with the following exception: Eíapa 24.6: 3.4d was subsumed by 3.4j. 1 H NMR (400MHz, CDCl 3) 7.40 (m, 4H), 7.18 (m, 1H), 7.00 (m, 1 H), 6.91 (m, 1H), 6.85 (m , 1H), 5.89 (s, 1 H), 3.57 (m, 2H), 3.32 (m, 2H), 2.51 (m, 7H), 2.20 (m, 2H), 2.06 (m, 2H), 1.76 (m, 4H), 1.26 (m, 3H), 1.16 (m, 3H) Analysis of the mass spectra m / z = 419.2 (M + H) + EXAMPLE 25A 25A was done according to a procedure similar to that described for compound 1.8a with the following exception: EIApa 1.1: 1.2 was subsumed by 25.1 (see also paragraph 25.1). 1 H NMR (400MHz, DMSO d6) d 7.42 (d, 2H), 7.38 (d, 2H), 7.19 (m, 1H), 6.97 (m, 2H), 6.86 (m , 1 H), 5.62 (s, 1 H), 3.96 (m, 2H), 3.79 (m, 2H), 3.57 (sa, 2H), 3.32 (sa, 2H) , 2.03 (d, 2H), 1.84 (m, 2H), 1, 21 (day, 6H) Mass spectral analysis m / z = 378.2 (M + H) + EXAMPLE 26A Preparation of 26.2 : To a solution of 1.5a (2.08 g, 4.63 mmol, 1 eq) in dry tetrahydrofuran (40 mL) was added palladium (pyridine) (palladium) 0-free fatty acid (0.535 g, 0.463 mmol, 0.1 eq), followed by zinc 4-cyanobenzylbromide (26.1) (0.5M solution in hydrohydrofuran, 23.16 mL, 11.58 mmol, 2.5 eq) was a goya in aosphere of nihologen. The reaction mixture was stirred at ambient temperature for 10 hours. A saturated aqueous solution of ammonium chloride (40 mL) was added to inactivate the reaction and diethyl ether (50 mL) was added to partition the two phases. The aqueous phase was extracted with diethyl ether (3 x 50 mL) and the combined organic phases were washed with brine.were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (eluent: hexane / ethyl acetate mixture of increasing polarity). Yield: 62% 1 H NMR (400MHz, CDCl 3) d 7.59 (d, 2H), 7.34 (d, 2H), 7.14 (m, 1H), 7.00 (dd, 1 H), 6 , 88 (dd, 1 H), 6.82 (m, 1 H), 5.28 (s, 1 H), 3.95-3.75 (m, 4H), 3.28 (m, 2H) , 1, 99 (m, 2H), 1, 59 (m, 2H), 1, 46 (s, 9H) Analysis of the mass spectrum m / z = 417 (M + H) + Preparation of 26.3a and 26.3b: A mixture of 26.2 (1.2 g, 2.88 mmol) in concentrated hydrochloric acid (30 mL) was heated at reflux temperature for 10 h and then concentrated under reduced pressure to give the crude mixture of 26.3 a and 26.3 b. An amount of 80 mg of the mixture was purified by preparative liquid chromatography. The remaining mixture (26.3a / 26.3b) was used in the next efapa without further purification. 26.3a: 1 H NMR (400MHz, DMSO-d 6) d 12.87 (br s, 1 H), 8.58 (m, 2H), 7.86 (m, 2H), 7.41 (m, 2H), 7.21-7.12 (m, 2H), 6.92 (dd, 1H), 6.86 (m, 1H), 5.70 (s, 1H), 3.85 (s, 2H), 3 , 19 (m, 4H), 2.06 (m, 2H), 1.86 (m, 2H) Analysis of the mass spectrum m / z = 336.2 (M + H) + 26.3b: 1H NMR (400MHz) , DMSO-d6) d 13.00 (br s, 1H), 8.68 (m, 1 H), 8.29 (m, 1 H), 7.97 (m, 2H), 7.84 (dd, 1 H), 7.50 (m, 2H), 7.41 (s, 1 H), 7.27 (m, 1H), 7.03-6.94 (m, 2H), 3.19-3 , 00 (m, 4H), 2.82 (s, 2H), 1.91 (m, 2H), 1.63 (m, 2H) Mass spectrum analysis m / z = 336.2 (M + H ) + Preparation of 26.4a and 26.4b: To a solution of the mixture of 26.3a and 26.3b (1g, 2.69 mmol) in methanol (50 mL) was added leniamenie a solution of 4.0M hydrogen chloride in dioxane (20 mL). The reaction mixture was stirred at ambient temperature for 10 h and concentrated under reduced pressure. The residue was dissolved in ethyl ether (100 mL), washed with an aqueous solution of 1 M sodium carbonate (4 x 50 mL), brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the crude mixture of 26.4a and 26.4b. A small amount (150 mg) of the crude mixture was purified by column chromatography (eluyenie: hexane / acetyl ether oil mixture of increasing polarity) and re-purified by preparative liquid chromatography. The resin mixture (26.4a / 26.4b) was used in the next step without further purification. Yield: 90% 26.4a: 1 H NMR (400MHz, CDCl 3) d 9.05 (sa, 1H), 8.72 (sa, 1H), 7.98 (d, 2H), 7.29 (d, 2H) , 7.17 (m, 1 H), 7.11 (m, 1H), 6.93-6.85 (m, 2H), 5.29 (s, 1H), 3.91 (s, 3H) , 3.80 (s, 2H), 3.37 (m, 4H), 2.24 (m, 2H), 1.95 (m, 2H) Analysis of the mass spectra m / z = 350.2 (M + H) + 26.4b: 1 H NMR (400MHz, CDCl 3) d 9.42 (sa, 1H), 8.95 (sa, 1H), 8.05 (d, 2H), 7.66 (d, 1 H), 7.40-7.22 (m, 4H), 7.00 (m, 1 H), 6.92 (d, 1H), 3.94 (s) , 3H), 3.25 (m, 4H), 2.78 (s, 2H), 2.04 (m, 2H), 1.75 (m, 2H) Analysis of the mass spectrum m / z = 350, 2 (M + H) + Preparation of 26.5a and 26.5b: To a solution of the mixture of 26.4a and 26.4b (0.5 g, 1.5 mmol, 1 eq) in dry dichloromethane (30 mL) at 0 ° C there was added lemanimenia, rhenylamine (0.42 mL, 3 mmol, 2 eq) and a solution of dicarbonate of di-ert-buíilo 4.7 (0.38 g, 1.74 mmol, 1.2 eq) in dichloromethane (10 mL). ) I went to goya. The reaction mixture was heated slowly to ambient temperature and stirred at ambient temperature for 10 hours. Dichloromean (50 mL) was added and the mixture was washed with an aqueous solution of 1 N hydrochloric acid (3 x 50 mL), brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the mixture in vacuo. gross from 26.5a and 26.5b, which was used in the next stage without further purification. Preparation of 26.6a and 26.6b: To a solution of the mixture of 26.5a and 26.5b (0.57 g, 1.26 mmol, 1 eq) in a mixture of methanol (15 mL), hydrohydrofuran (15 mL) and water ( 15 mL) was added monohydric acid hydroxide (0.21 g, 5 mmol, 4 eq) in one portion. The reaction mixture was stirred at ambient temperature for 10 h. The volatiles were removed under reduced pressure and the aqueous solution was acidified to pH = 3 with an aqueous solution of 1 N hydrochloric acid while stirring. The mixture was stirred for 1 h at ambient temperature and left at ambient temperature for 10 hours. The resulting solid was collected by filtration, washed with water, and dried in vacuo to give the mixture of 26.6a and 26.6b, which was used in the next step without further purification. Preparation of 26.7a and 26.7b: To a stirred solution of the mixture of 26.6a and 26.6b (0.49 g, 1.12 mmol, 1 eq) in acetylnyl (20 mL) was added leniamenie diisopropileilamine (0.46 mL, 2.69 mmol, 2.4 eq), diethylamine 1.12 (0.24 g, 3.36 mmol, 3 eq) at room temperature . The mixture was stirred for 10 minutes at ambient temperature. The mixture was cooled to 0 ° C and O-benzofriazol-1-yl- / V, NJ? / ', / V'-fetramethyluron (TBTU) (0.43 g, 1.34 mmol) was added. , 1,2 eq) fractionally. The reaction mixture was heated slowly to room temperature and stirred at room temperature for a further 10 h. The volatiles were re-treated under reduced pressure and the residue was partitioned between ethyl acetate (100 mL) and aqueous 1M sodium bicarbonate solution (100 mL). The organic phase was washed with an aqueous solution of 1M sodium bicarbonate (2 x 50 mL), an aqueous solution of 1 M hydrochloric acid (3 x 50 mL), brine, dried over sodium sulfate, filtered, and concentrated to a reduced pressure to give the mixture in bruise of 26.7a and 26.7b. The crude mixture was purified by column chromatography (eluyenie: hexane / ethyl alcohol mixture of increasing polarity). A small amount (85 mg) of the purified mixture was separated by preparative liquid chromatography. The slurry mixture (26.7a / 26.7b) was used in the next step without further purification. Yield: 81% in patients 26.7a: 1H NMR (400MHz, CDCl3) d 7.33-7.24 (m, 4H), 7.15-7.07 (m, 2H), 6.89-6, 80 (m, 2H), 5.25 (s, 1 H), 3.84 (m, 2H), 3.74 (s, 2H), 3.55 (m, 2H), 3.28 (m, 4H), 1.98 (m, 2H), 1.57 (m, 2H), 1, 46 (s, 9H), 1, 18 (m, 6H) Mass spectral analysis m / z = 491, 1 (M + H) + 26.7b: 1 H NMR (400MHz, CDCl 3) d 7.63 (dd, 1H), 7.39 (m, 2H), 7.31 (m, 2H), 7.22 (m, 1H), 7.17 (s, 1 H), 6.95 (m, 1 H), 6.90 (dd, 1H), 3.81 (m, 2H), 3.58 (m, 2H), 3.34 (m, 2H), 3.17 (m, 2H), 2.71 (s, 2H), 1.82 (m, 2H), 1, 43 (s, 9H), 1.38 (m , 2H), 1.22 (m, 6H) Analysis of the mass spectrum m / z = 491, 1 (M + H) + Preparation of 26A To a cold, stirred solution (0 ° C) of the mixture of 26.7a 26.7b (0.36 g, 0.73 mmol, 1 eq) in dry dichloromethane (20 mL) was added dropwise a solution of 4.0M hydrogen chloride in dioxane (1.8 mL, 7.2 mmol, 10 eq). The mixture was stirred at room temperature for 10 h and concentrated under reduced pressure to give the crude mixture of 26A and 26.8. The bruison mixture was purified by preparative liquid chromatography. Yield: 85% 26A: 1 H NMR (400MHz, CDCl 3) d 9.35 (sa, 1H), 9.00 (sa, 1H), 7.30 (m, 4H), 7.14 (m, 2H), 6.87 (m, 2H), 5.28 (s, 1 H), 3.76 (s, 2H), 3.55 (m, 2H), 3.24 (m, 6H), 2.11 ( m, 2H), 1.93 (m, 2H), 1, 20 (m, 6H) Mass spectrum analysis m / z = 391, 0 (M + H) + 26.8: 1 H NMR (400MHz, CDCl 3) 9,12 (sa, 1 H), 8,71 (sa, 1H), 7,65 (d, 1H), 7,39 (d, 2H), 7,31 (d, 2H), 7,28- 7.19 (m, 2H), 7.00 (m, 1H), 6.92 (d, 1H), 3.59 (m, 2H), 3.29 (m, 6H), 2.78 (s) , 2H), 2.05 (m, 2H), 1.78 (m, 2H), 1, 23 (m, 6H) Mass spectrum analysis m / z = 391, 0 (M + H) + EXAMPLE 26B Preparation of 26B: To an agitated solution of 26.8 (0.12 g, 0.26 mmol, 1 eq) in meianol (10 mL) was added palladium [24 mg, 10% by weight (dry basis) on charcoal, 20% by weight eq]. The reaction mixture was stirred in a hydrogen atmosphere using a hydrogen balloon at room temperature for 10 h. The palladium on activated charcoal was filtered on a Celiie bed and the filtrate was concentrated under reduced pressure. The crude production was purified by column chromatography (eluent: dichloromean / meianol / ammonium hydroxide mixture of increasing polarity). The desired fractions were combined and concentrated under reduced pressure. To a cold solution (0 ° C) of the oil resulting in dichloromethane was added dropwise a 2.0M hydrogen chloride solution in diethyl ether (0.26 mL, 0.52 mmol, 2 eq). The mixture was then stirred for 1 hour at room temperature, concentrated under reduced pressure, and dried under vacuum. Yield: 88% 1 H NMR (400MHz, CDCl 3) d 9.41 (sa, 1 H), 8.95 (sa, 1H), 7.40 (m, 1 H), 7.33 (m, 2H), 7.25-7.14 (m, 3H), 6.97 (m, 1 H), 6.86 (m, 1 H), 3.62-3.04 (m, 10H), 2.63 ( m, 1H), 2.03-1.49 (m, 6H), 1.20 (m, 6H) Mass spectrum analysis m / z = 393.0 (M + H) + EXAMPLE 27A Preparation of 27A: A solution of 1A (0.66 g, 1.75 mmol, 1.0 eq) in anhydrous methanol (13 mL) was hydrogenated at atmospheric pressure in the presence of palladium hydroxide [Pd (OH) 2: Pearlman's catalyst] ( 0.120 g, 0.09 mmol, 0.05 eq) lasts 10 h. The mixture was then filtered through Celiie. The filtrate was concentrated and hydrogenated at atmospheric pressure in the presence of palladium hydroxide (0.120 g) for a further 10 h. The mixture was filtered through Celite and the filtrate was concentrated to dryness under reduced pressure. To a cold solution (0 ° C) of the resulting oil in anhydrous dichloromethane was added dropwise a solution of anhydrous hydrochloric acid 2.0M in diethyl ether (5 mL). The mixture was then stirred for 1 h at ambient temperature and concentrated under reduced pressure. Diethyl ether was added. The resulting precipitate was collected by filtration and washed with diethyl ether and ethyl acetate. Yield: 63% 1 H NMR (400MHz, DMSO d6) d 9.15 (m, 2H), 7.30 (m, 4H), 7.10 (m, 1H), 6.90 (m, 1 H), 6.75 (m, 1H), 6.60 (m, 1H), 4.20 (m, 1H), 3.40 (m, 3H), 3.20 ( m, 4H), 3.00 (m, 1 H), 2.15 (m, 1 H), 1.95 (m, 5H), 1.05 (m, 6H) Analysis of the mass spectrum m / z = 379.1 (M + H) + Elemental analysis: C24H30N2O2, 1 HCl, 0.75H2O Theoretical:% C 67.28; % H 7.65; % N 6.54 Found:% C 67.32; % H 7.63; % N 6.37 EXAMPLE 27B Preparation of 27B: 27A (racemic mixture) (10 g, 24.10 mmol, 1.0 eq) was resolved using the procedure by chiral HPLC: Column: Chiralpak AD-H, 4.6 x 250 mm, 5μ, Chiral Technologies PN # 19325 Column temperature: ambient temperature Detection: UV photodiode diode network, 200 to 300 nm, obtained at 275 nm Injection volume: 40 μL of a 2 mg / mL sample in EIOH : MeOH (80: 20) Flow: 1 mL / minute Mobile phase: Dissolution A 85%, Solution B 15% Solution A: Diisopropylethylamine in 0.1% hexane (HPLC grade) Solution B: 80% ethanol, 20% of methanol (both HPLC grade) Note: Meianol is only miscible in hexane if it first dissolves in ethanol. Solution B must be mixed beforehand. Race time: 25 min. HPLC: Wafers Alliance 2695 (the system delay volume is -350 μL) Detector: Waters 996 (resolution: 4.8 nm, scanning speed: 1 Hz) Performance: 40% 1H NMR (400MHz, DMSO dß) 9 , 10 (m, 2H), 7.28 (m, 4H), 7.14 (m, 1H), 6.90 (d, 1H), 6.80 (m, 1H), 6.63 (d, 1H), 4.25 (m, 1H), 3.42 (m, 3H), 3.24 (m , 4H), 2.97 (m, 1H), 2.20 (m, 1 H), 1.97 (m, 5H), 1, 10 (m, 6H) Mass spectrum analysis m / z = 379 , 4 (M + H) + Chiral HPLC procedure: tR = 8.64 min. (ee = 97%) Elemental analysis: C24H30N2O2, 1 HCl, 0.25H2O Theoretical:% C 68.72; % H 7.57; % N 6.68 Found:% C 68.87; % H 7.52; % N 6.68 [D] D25 = +58.40 (c.0.01, MeOH) DETERMINATION OF THE ABSOLUTE CONFIGURATION OF EXAMPLE 27B Preparation of 27.3: Compound 27.2 (0.45 g, 1.78 mmol, 1 , 1 eq) was added at 0 ° C to a solution of 27B (0.67 g, 1.61 mmol, 1 eq) and triethylamine (0.74 mL, 5.33 mmol, 3.3 eq) in dichloromethane ( 6 mL). The reaction was heated to ambient air and it went on during the night at ambient air. The mixture was washed with a saturated aqueous solution of sodium hydrogencarbonate and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The production in bruise was purified by column chromatography (eluyenie: mixtures of hexane / acetyl ether of increasing polarity). Yield: 64% 1 H NMR (400MHz, DMSO d6) d 7.30 (m, 4H), 7.11 (1, 1 H), 6.90 (d, 1 H), 6.77 (,, 1 H), 6.61 (d, 1H), 4.23 (m, 1 H), 3.39 (m, 9H), 2.93 (d, 1 H), 2.37 (m , 2H), 2.24 (m, 1H), 2.06 (m, 2H), 1.93 (m, 6H), 1.53 (m, 1H), 1.41 (m, 1 H), 1.10 (m, 6H), 1, 03 (s, 3H), 0.83 (s, 3H) Analysis of the mass spectra m / z = 593.4 (M + H) + Elemental Analysis: Theoretical:% C 68.37; % H 7.51; % N 4.69 Theoretical:% C 68.38; % H 7.50; % N 4.55 X-ray crystallography data: Isolated crystals were formed in the form of needles by dissolving 27.3 (10 mg, 0.017 mmol, 1 eq) in isopropanol (1 mL) and allowing them to sediment at ambient temperature for 72 h. Damage of the chrysalis and refinement of the structure for 27.3: Identification code: ptut001 Empirical formula: C34H 4N2O5S Molecular weight: 592.77 Temperature: 120 (2) K Wave length: 0.71073 Á Chrysalis system, space group: Monoclinic, P2 (1) Dimensions of the unit cell: a = 15.135 (2) A, alpha = 90 ° b = 6.1924 (10) A, beta = 91, 802 (2) ° c = 16,602 (3) A, gamma = 90 ° Volume: 1555.2 (4) A3 Z, calculated density: 2, 1, 266 mg / m3 Absorption coefficient: 0.148 mm "1 F (000): 636 Chrysalis size: 0.30 x 0.08 x 0.04 mm Data interval for data acquisition: 1.79 to 27.79 ° interval index: -18 < = h < = 19, -7 < = k < = 7, -20 < = l < = 21 Reflections collected / unique: 12166/6251 [R (iní) = 0.0168] Complement for íheía = 27.79: 91, 9% Correction of absorption: Semi-empirical from the equivalents Max transmission and min .: 0.9941 and 0.9569 Refinement period: Mairiz completes least squares in F2 Dafos / resíringidos / parameíros: 6251/1/383 Goodness of fit in F2: 1, 040 final R index [l > 2sigma (l)]: R1 = 0.0392, wR2 = 0.1030 R index (all damage): R1 = 0.0401, wR2 = 0.1041 Parametric of the absolute structure: -0.03 (6) Difference largest of the ridge and valley: 0.365 and -0.200 eA "3 EXAMPLE 27C Preparation of 27C: 27A (racemic mixture) (10 g, 24.10 mmol, 1 eq) was resolved using the method by chiral HPLC: Column: Chiralpak AD-H, 4.6 x 250 mm, 5 μ, Chiral Technologies PN # 19325 Column temperature: ambient temperature Detection: UV photodiode diode array, 200 to 300 nm, obtained at 275 nm Injection volume: 40 μL of a sample of 2 mg / mL in EOH: MeOH (80: 20 ) Flow: 1 mL / minute Mobile phase: Dissolution A 85%, Dissolution B 15% Solution A: Diisopropylethylamine in 0.1% hexane (HPLC quality) Solution B: 80% ethanol, 20% methanol (both of quality HPLC) Running time: 25 min HPLC: Waters Alliance 2695 (the system delay volume is -350 μL.) Detector: Wais 996 (Resolution: 4.8 nm, Scanning speed: 1 Hz) Yield: 40% NMR 1H (400MHz, DMSO d6) d 9.12 (m, 2H), 7.28 (m, 4H), 7.14 (m, 1H), 6.90 (d, 1 H), 6.79 (m , 1 H), 6.63 (d, 1 H), 4.25 (m, 1 H), 3.44 (m, 3 H), 3.24 (m, 4 H), 2.96 (m, 1 H), 2.18 (m, 1H), 1.97 (m, 5H), 1, 10 (m, 6H) Mass spectral analysis m / z = 379.4 (M + H) + Procedure by Chiral HPLC: tR = 11, 914 min. (ee = 100%) Elemental analysis: C24H30N2O2, 1 HCl, 0.25H2O Theoretical:% C 68.72; % H 7.57; % N 6.68 Found:% C 68.79; % H 7.55; % N 6.68 [D] D25 = -63.59 (c.0.01, MeOH) EXAMPLE 27D 27D was obtained according to a procedure similar to that described for 27A, with the following exception: Step 27.3: The procedure was used 27A and 1A was subsumed by 10. 1 H NMR (400MHz, DMSO d6) 9.05 (m, 2H), 7.31 (c, 4H), 6.98 (m, 2H), 6.36 (dd, 1H), 6.47 (dd, 1 H), 3.51-3.33 (m, 2H), 3.29-3.11 (m, 5H), 2.96 (m, 1H), 2, 19 (m, 1 H), 2.05-1, 82 (m, 5H), 1, 20-1, 00 (m, 6H) Analysis of the mass spectrum m / z = 397.3 (M + H) EXAMPLE 27E 27E was obtained from 27D by chiral HPLC chromatography 1 H NMR (400MHz, DMSO d6) 8.82 (m, 2H), 7.31 (m, 4H), 6.97 (m, 2H), 6.37 (m, 1 H), 4.27 (m, 1 H), 3.42 (m, 2 H), 3.23 (m, 5 H), 2.97 (m, 1 H), 2, 20 (m, 1 H), 1.94 (m, 5H), 1, 11 (m, 6H) Mass spectrum analysis m / z = 397.4 (M + H) + Elemental analysis: C24H29FN2O2, 1 HCl , 0.33H2O Theory:% C 65.71; % H 7.09; % N 6.36 Found:% C 65.68; % H 7.07; % N 6.41 [D] D25 = + 6j53 (C = 9.85 mg / mL, MeOH) EXAMPLE 27F 27F was obtained from 27D by chiral HPLC chromatography 1H NMR (400MHz, DMSO d6) d 8.92 (m, 2H), 7.32 (m, 4H), 6.98 (m, 2H), 6.37 (m, 1 H), 4.27 (m, 1H), 3.42 (m, 2H), 3.24 (m, 5H), 2.97 (m, 1H), 2.20 ( m, 1H), 1, 95 (m, 5H), 1, 11 (m, 6H) Mass spectral analysis m / z = 397.3 (M + H) + Elemental analysis: C24H29FN2O2, 1 HCl, 0.2H2O Theoretical:% C 66.03; % H 7.02; % N 6.42 Found:% C 66.07; % H 6.99; % N 6.34 [D] D25 = _6? 54 (C = 9 75 mg / m [_, MeOH) EXAMPLE 27G 27G was worked out according to a procedure similar to that described for 27A, with the following exception: Step 27.3: Procedure 27A was used and 1A was subsumed by 2C. 1H-NMR (400MHz, DMSO d6) ¿9.12 (sa, 1H), 8.97 (sa, 1H), 7.32 (d, 2H), 7.27 (d, 2H), 6.84 ( d, 1 H), 6.73 (dd, 1 H), 6.12 (d, 1H), 4.21 (m, 1 H), 3.55 (m, 3H), 3.42 (sa, 1H), 3.20 (m, 5H), 2.94 (m, 1 H), 2.16 (m, 1H), 1.92 (m, 5H), 1.09 (m, 7H), 0 , 46 (m, 2H), 0.18 (m, 2H) Mass spectral analysis m / z = 449.3 (M + H) + Elemental analysis: C28H36N2O3, 1 HCl, 1 Theoretical H2O:% C 66, 85; % H 7.81; % N 5.57; % CI 7.05 Found:% C 67.02; % H 7.51; % N 5.54; % CI 7.25 EXAMPLE 27H 27H was worked out according to a procedure similar to that described for 27A, with the following exception: Step 27.3: Procedure 27A was used and 1A was subsumed by 1N. 1 H NMR (400MHz, DMSO d 6) d 9.07 (m, 1.5H), 8.53 (d, 1H), 7.70 (dd, 1H), 7.52 (d, 1H), 7.16 (m, 1H), 6.93 (dd, 1H), 6.82 (m, 1H), 6.63 (d, 1H), 4.36 (dd, 1H), 3.45 (c, 2H) , 3, 33-3.15 (m, 5H), 2.98 (m, 1H), 2.22 (m, 1H), 2.07-1.85 (m, 5H), 1.15 (t, 3H) ), 1.09 (t, 3H) Analysis of the mass spectra m / z = 380.2 (M + H) + EXAMPLE 271 271 was obtained from 27H by chiral HPLC chromatography 1H NMR (400MHz, DMSO dβ) d 8.89 (m, 2H), 8.52 (d, 1H), 7.68 (dd, 1H), 7.51 (d, 1H), 7.16 (m, 1H), 6.94 (m , 1H), 6.82 (m, 1H), 6.62 (m, 1H), 4.35 (m, 1H), 3.44 (c, 2H), 3.26 (m, 5H), 2 , 98 (m, 1H), 2.23 (m, 1H), 1.95 (m, 5H), 1.15 (t, 3H), 1.09 (t, 3H) Mass spectrum analysis m / z = 380.2 (M + H) + Elemental analysis: C23H29N3O2, 1.3HCI, 1.4H2O Theoretical:% C 61.10; % H 7.38; % N 9.29; % C110.19 Found:% C 61.01; % H 7.35; % N 9.21; % C110.41 [D] D25 = +4.46 (c = 9.65 mg / mL, MeOH) EXAMPLE 27J 27J was obtained from 27H by chiral HPLC chromatography 1H NMR (400MHz, DMSO dβ) d 9.08 (m, 2H), 8.53 (d, 1H), 7.70 (dd, 1H), 7.52 (d, 1H), 7.16 (m, 1H), 6.93 (m, 1H), 6.82 (m, 1H), 6.63 (m, 1H), 4.36 (m , 1H), 3.45 (c, 2H), 3.25 (m, 5H), 2.97 (m, 1H), 2.22 (m, 1H), 1.97 (m, 5H), 1 , 15 (t, 3H), 1.09 (í, 3H) Analysis of the mass spectra m / z = 380.2 (M + H) + Elemental analysis: C23H29N3O2, 2HCI, 1, 75H2O Theoretical:% C 57, 08; % H 7.19; % N 8.68; % C1 14.65 Found:% C 56.92; % H 7.15; % N 8.58; % C1 15.02 [G] D25 = _3 > 55 (C =? O, 3 mg / mL, MeOH) EXAMPLE 27K 27K was obtained according to a procedure similar to that described for 27A, with the following exception: EIAP 27.3: Procedure 27A was used and 1A was replaced by 10. 1H NMR (400MHz, DMSO d6) ¿9.17-8, 85 (m, 2H), 8.53 (d, 1H), 7.70 (dd, 1H), 7.52 (d, 1H), 7.06-6.94 (m, 2H), 6.41 (dd, 1 H), 4.37 (dd, 1 H), 3.49-3 , 35 (m, 2H), 3.32-3.14 (m, 5H), 2.97 (m, 1 H), 2.23 (m, 1 H), 2.05-1, 82 (m , 5H), 1, 15 (1, 3H), 1.09 (1, 3H) Analysis of the mass spectra m / z = 398.3 (M + H) + EXAMPLE 27L 27L was obtained from 27K by chiral HPLC chromatography 1 H NMR (400MHz, DMSO d6) d 9.15 (m, 2H), 8 , 54 (d, 1 H), 7.72 (dd, 1H), 7.54 (d, 1H), 7.00 (m, 2H), 6.42 (dd, 1 H), 4.38 ( m, 1 H), 3.45 (c, 2H), 3.25 (m, 5H), 2.96 (m, 1 H), 2.22 (m, 1H), 1, 96 (m, 5H), 1.15 (1, 2H), 1, 09 (1, 3H) Mass spectral analysis m / z = 398, 3 (M + H) + Elemental analysis: C23H28FN3O2, 2HCI, 1.75H2O Theoretical:% C 55.04; % H 6.73; % C1 14,13; % N 8.37 Found:% C 54.85; % H 6.53; % C1 14.28; % N 8.45 [D] D25 = +4.19 (C = 10.2 mg / mL, MeOH) EXAMPLE 27M 27M was obtained from 27K by chiral HPLC chromatography 1H NMR (400MHz, DMSO d6) d 9.14 (m, 2H), 8.54 (d, 1 H), 7.79 (dd, 1H), 7.54 (d, 1H), 7.00 (m, 2H), 6.42 (dd, 1 H), 4.38 (m, 1 H), 3.45 (c, 2H), 3.25 (m, 5H), 2.96 (m, 1H), 2.23 (m, 1 H), 1.96 (m, 5H), 1, 15 (1, 3H), 1, 09 (1, 3H) ) Analysis of the mass spectra m / z = 398.3 (M + H) + Elemental analysis: C23H28FN3 ° 2, 2HC1, 1.75H2O Theoretical:% C 55.04; % H 6.73; % N 8.37; % CI 14,13 Found:% C 54.85; % H 6.66; % N 8.37; % CI 14.31 [D] D25 = .4.09 (C = 10.25 mg / mL, MeOH) EXAMPLE 27N 27N was obtained according to a procedure similar to that described for 27A, with the following exception: Step 27.3: 1A was replaced by 1S. Analysis of the mass spectra m / z = 408.3 (M + H) + EXAMPLE 270 270 was obtained from 27N by chiral HPLC chromatography 1 H NMR (400MHz, DMSO dβ) d 8.93 (br s, 1 H), 8.75 (sa, 1 H), 8.50 (d, 1H), 7.65 (dd, 1H), 7.50 (d, 1H), 6.74 (s, 1 H), 6.37 (s, 1H), 4.26 (m, 1H), 3.45 (c, 2H), 3.24 (m, 5H), 2.94 (m, 1H), 2.18 (m, 1 H) ), 2.14 (s, 3H), 1, 99 (s, 3H), 1, 90 (m, 5H), 1.15 (t, 3H), 1.08 (1, 3H) Analysis of the spectra of masses m / z = 408.3 (M + H) + Elemental analysis: C25H33 3O2, 1.25HCl, 1, 63H2O Theory:% C 62.25; % H 7.84; % N 8.70; % CI 9.19 Found:% C 62.52; % H 7.64; % N 8.30; % CI 8.80 EXAMPLE 27P 27P was obtained from 27N by chiral HPLC chromatography 1 H NMR (400MHz, DMSO dβ) 9.00 (sa, 1H), 8.82 (sa, 1H), 8.50 (d , 1 H), 7.65 (dd, 1H), 7.50 (d, 1H), 6.74 (s, 1 H), 6.37 (s, 1 H), 4.26 (m, 1 H), 3.45 (c, 2H), 3.24 (m, 5H), 2.94 (m, 1H), 2.18 (m, 1H), 2.13 (s, 3H), 1, 99 (s, 3H), 1.88 (m, 5H), 1.15 (t, 3H), 1, 09 (1, 3H) Mass spectral analysis m / z = 408.3 (M + H) + Elemental analysis: C25H33 3O2, 1.2HCI, 1, 6H2O Theoretical:% C 62.54; % H 7.85; % N 8.75; % CI 8.86 Found:% C 62.61; % H 7.73; % N 8.44; % CI 8.52 EXAMPLE 27Q Preparation of 27.6: A solution of 2.7a (15.00 g, 30.45 mmol, 1 eq) in anhydrous dichloromethane (50 mL) and anhydrous melanol (100 mL) was hydrogenated at 1 aím ( 101.3 kPa), in the presence of palladium, 10% by weight (dry basis) on activated carbon, wet, type Degussa E101 NE / W (3.24 g, 1.52 mmol, 0.05 eq) for 10 h . The mixture was then filtered through Celiie and the filtrate was concentrated to dryness under reduced pressure. The production was used without further purification. Yield: 99% Mass spectral analysis m / z = 495, 4 (M + H) + Preparation of 27Q: A solution of 4.0M hydrochloric acid in dioxane (41.9 mL, 167.46 mmol, 5.5 eq) was added dropwise to a cooled solution (0 ° C). C) of 27.6 (15.06 g, 30.45 mmol, 1 eq) in anhydrous methanol (50 mL). The mixture was heated to room temperature and stirring continued for 10 hours at room temperature. The mixture was concentrated under reduced pressure. Diethyl ether (100 mL) was added to the solution. The resulting precipitate was collected by filtration and washed with diethyl ether. Yield: 85% 1 H NMR (400MHz, DMSO d ") d 9.03 (m, 1 H), 8.90 (m, 1H), 8.80 (s, 1H), 7.28 (m, 4H), 6.71 (d, 1H), 6.53 (m, 1 H), 6.05 (d, 1 H), 4.16 (m, 1H), 3.43 (m, 3H), 3.21 (m, 5H), 2.92 (m, 1H), 2.11 (m, 1 H), 1.98 (m, 1 H), 1.90 (m, 4H), 1.11 (m, 6H) Analysis of the mass spectra m / z = 395.4 (M + H) + Elemental analysis: C24H30N2O2, 1HCI, 0.75H2O Theoretical:% C 64.85,% H 7 , 37,% N 6.30 Found:% C 65.12,% H 7.43,% N 6.18 EXAMPLE 27R Preparation of 27R: 27R was obtained from 27Q by chiral HPLC chromatography 27Q (racemic mixture) ( 10 g, 23.20 mmol, 1 eq) was resolved using the procedure by chiral HPLC: Column: Chiralpak AD-H, 4.4 x 250 mm Column temperature: 25 ° C Defection: UV at 230 nm Flow: 2 , 0 mL / minute Mobile phase: 80% carbon dioxide, 20% ethanol, 0.1% ethane sulfonic acid Running time: 24 min.

The pertinent fractions were combined and concentrated under reduced pressure. To the resulting oil was added an aqueous solution of 1 N sodium hydroxide until the solution was made basic using pH paper. The aqueous mixture was extracted with dichloromethane. The organic exiphats were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure. A solution of 4M anhydrous hydrochloric acid in dioxane (5.5 eq) was added to a cold (0 ° C) solution of the oil resulting in anhydrous meganol. The mixture was then stirred for 1 hour at ambient temperature and concentrated under reduced pressure. The crude product was purified by column chromatography (eluyenie: mixtures of dichloromean / meianol of increasing polarity). Yield: 30% 1 H NMR (400MHz, DMSO d6) d 9.19 (m, 1H), 9.05 (m, 1 H), 7.31 (m, 4H), 6.73 (d, 1 H) , 6.54 (m, 1 H), 6.05 (d, 1 H), 4.16 (m, 1 H), 3.42 (sa, 2H), 3.17 (ma, 6H), 2 , 91 (m, 1H), 2.11 (m, 1 H), 1.98 (m, 1 H), 1.90 (m, 4H), 1, 10 (m, 6H) Mass spectrum analysis m / z = 395.1 (M + H) + Purity of chiral HPLC: tR = 9.932 min. (ee => 99%) [D] D24'2 = +21, 49 (c.0.01, MeOH) EXAMPLE 27S Preparation of 27S: 27S was obtained from 27Q by chiral HPLC chromatography 27Q (racemic mixture) (10 g, 23.20 mmol, 1 eq) was resolved using the procedure by chiral HPLC: Column: Chiralpak AD-H, 4.4 x 250 mm Column temperature: 25 ° C Detection: UV at 230 nm Flow: 2.0 mL / min. Mobile phase: 80% carbon dioxide, 20% ethanol, 0.1% ethanesulfonic acid Running time: 24 min. The pertinent fractions were combined and concentrated under reduced pressure. Upon the reaction, an aqueous solution of 1N sodium hydroxide was added until the solution was made basic using pH paper. The aqueous mixture was extracted with dichloromethane. The organic exiphats were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure. A solution of 4M anhydrous hydrochloric acid in dioxane (5.5 eq) was added dropwise to a cold solution (0 ° C) of the resulting oil in anhydrous meianol. The mixture was then stirred for 1 h at ambient temperature and concentrated under reduced pressure. The crude production was purified by column chromatography (eluyenie: mixtures of dichloromean / meianol of increasing polarity). Yield: 18% 1 H NMR (400MHz, DMSO dβ) d 9.03 (m, 1 H), 8.87 (m, 1H), 8.80 (s, 1H), 7.31 (m, 4H), 6.71 (d, 1 H), 6.55 (d, 1 H), 6.05 (m, 1 H), 4.18 (m, 1 H), 3.36 (m, 2H), 3 , 18 (m, 5H), 2.93 (m, 1H), 2.11 (m, 1 H), 1.98 (m, 1 H), 1.87 (m, 4H), 1, 10 ( m, 6H) Mass spectral analysis m / z = 395.1 (M + H) + Purity of chiral HPLC: IR = 13.371 min. (ee = 98.1%) [G] D24'2 = -25.96 (c.0.01, MeOH) EXAMPLE 27T Preparation of 27.1: A solution of 11.6a (15.00 g, 27.95 mmol, 1 eq) in anhydrous melanol (100 mL) was hydrogenated at 70 psi (482.6 kPa) in the presence of palladium hydroxide [Pd (OH) 2: Pearlman's cayallizer] (1.96 g, 1.40 mmol, 0 , 05 eq) lasts 10 h. The mixture was filtered through Celite. The filtrate was concentrated under reduced pressure and hydrogenated at 70 psi (482.6 kPa) in the presence of palladium hydroxide (1, 96 g) lasts 10 more hours. The mixture was filtered through Celile and the filtrate was concentrated to dryness under reduced pressure. The product in bruise was used without further purification. Yield: 84% 1 H NMR (400MHz, DMSO d6) d 7.23 (d, 2H), 7.11 (m, 3H), 6.60 (d, 1H), 6.52 (d, 1H), 4 , 85 (d, 1H), 4.74 (d, 1 H), 4.16 (m, 1H), 3.61 (m, 2H), 3.30 (ma, 6H), 2.83 (s) , 3H), 2.24 (m, 1H), 1.75 (m, 2H), 1.64 (m, 1 H), 1.52 (m, 2H), 1, 39 (s, 9H), 1.06 (m, 6H) Analysis of the mass spectra m / z = 539.5 (M + H) + Preparation of 27T: To a cold solution (0 ° C) of 27.1 (2.00 g, 3.71 mmol, 1.0 eq) in anhydrous meianol (40 mL) was added dropwise a solution of 4M anhydrous hydrochloric acid in dioxane (9.3 mL, 37.20 mmol, 10.0 eq). The mixture was then stirred for 10 h at ambient temperature and concentrated under reduced pressure. Diethylether was added. The resulting precipitate was collected by filtration and washed with diethyl ether. Yield: 99% 1 H NMR (400MHz, DMSO d6) d 9.30 (br s, 1 H), 9.03 (br s, 1 H), 8.96 (br s, 1H), 7.21 (d, 2H) , 7.14 (d, 2H), 6.99 (t, 1 H), 6.43 (d, 1H), 6.35 (d, 1 H), 4.15 (m, 1H), 3, 87 (br s, 3H), 3.39 (m, 2H), 3.15 (m, 5H), 2.90 (m, 1H), 2.25 (m, 1H), 1.83 (ma, 5H) ), 1.09 (m, 6H) Analysis of the mass spectrum m / z = 395.3 (M + H) + EXAMPLE 27U Preparation of 27.4: Compound 27.1 (racemic mixture) (10 g, 18.56 mmol, 1 eq) was resolved using the procedure by chiral HPLC: Column: Chiralpak AD-H, 4.4 x 250 mm Column temperature: 25 ° C Detection : UV at 280 nm Flow: 2.0 mL / minute Mobile phase: 75% carbon dioxide, 25% isopropanol Career time: 10 minutes. The pertinent fractions were combined and concentrated under reduced pressure. The production in bruise was used without further purification. Yield: 79% H NMR (400MHz, DMSO d6) 7.21 (d, 2H), 7.11 (m, 3H), 6.60 (d, 1H), 6.55 (d, 1H), 4 , 83 (d, 1H), 4.74 (d, 1 H), 4.16 (m, 1H), 3.62 (m, 2H), 3.15 (ma, 6H), 2.83 (s) , 3H), 2.24 (m, 1 H), 1.75 (m, 2H), 1.61 (m, 1 H), 1.50 (m, 2H), 1.39 (s, 9H) , 1.06 (m, 6H) Mass spectrum analysis m / z = 539.1 (M + H) + Purity of chiral HPLC: IR = 4.728 min. (ee => 99%) [0] D24'1 = -32.97 (c.0.01, MeOH) Preparation of 27U: To a cold solution (0 ° C) of 27.4 (1.00 g, 1 , 86 mmol, 1 eq) in anhydrous meannol was added a solution of 4M anhydrous hydrochloric acid in dioxane (2.5 mL, 10.21 mmol, 5.5 eq). The mixture was stirred for 10 hours at ambient temperature and concentrated under reduced pressure. The bruise production was purified by column chromatography (eluyenie: mixtures of dichloromean / meianol of increasing polarity). Yield: 88% 1 H NMR (400MHz, DMSO d6) d 9.30 (s, 1 H), 9.00 (m, 2H), 7.21 (d, 2H), 7.14 (d, 2H), 6.99 (1, 1 H), 6.41 (d, 1 H), 6.35 (d, 1 H), 4.15 (m, 1 H), 3.42 (sa, 5H), 3 , 12 (m, 2H), 2.90 (m, 1H), 2.24 (m, 1 H), 1.83 (m, 4H), 1.72 (m, 1 H), 1.09 ( m, 6H) Analysis of the mass spectrum m / z = 395.1 (M + H) + [D] D24.2 = +3.24 (c.0.0, MeOH) EXAMPLE 27V Preparation of 27.5: 27.1 ( racemic mixture) (10 g, 18.56 mmol, 1 eq) was resolved using the procedure by chiral HPLC: Column: Chiralpak AD-H, 4.4 x 250 mm Column temperature: 25 ° C Defection: UV to 280 nm Flow: 2.0 mL / min. Mobile phase: 75% carbon dioxide, 25% of sopropanol Career time: 10 minutes. The pertinent fractions were combined and concentrated under reduced pressure. The production in bruise was used without further purification. Yield: 83% 1 H NMR (400MHz, DMSO dβ) d 7.23 (d, 2H), 7.11 (m, 3H), 6.58 (d, 1H), 6.54 (d, 1H), 4 , 85 (d, 1H), 4.73 (d, 1 H), 4.16 (m, 1H), 3.63 (m, 2H), 3.16 (ma, 6H), 2.83 (s) , 3H), 2.24 (m, 1H), 1.75 (m, 2H), 1.61 (m, 1 H), 1.52 (m, 2H), 1.39 (s, 9H), 1.05 (m, 6H) Mass spectral analysis / z-539.1 (M + H) + Chiral HPLC procedure: IR = 5.943 min. (ee = 98.7%) [D] D24 '° = +29.88 (c.0.01, MeOH) 27V preparation: To a cold (0 ° C) solution of 27.5 (1.00 g, 1.86 mmol, 1 eq) in anhydrous methanol was added dropwise a solution of 4M anhydrous hydrochloric acid in dioxane (2.5 mL, 10 mL). , 21 mmol, 5.5 eq). The mixture was then stirred for 10 h at ambient temperature and concentrated under reduced pressure. The crude product was purified by column chromatography (eluyenie: mixtures of dichloromean / meianol of increasing polarity). Yield: 92% H NMR (400MHz, DMSO dβ) d 9.32 (s, 1 H), 9.09 (sa, 2H), 7.21 (d, 2H), 7.12 (d, 2H), 6.99 (t, 1H), 6.41 (d, 1 H), 6.38 (d, 1 H), 4.16 (m, 1 H), 3.36 (m, 5H), 3, 13 (ma, 2H), 2.90 (m, 1 H), 2.24 (m, 1 H), 1.81 (ma, 5H), 1, 09 (m, 6H) Mass spectral analysis / z = 395.1 (M + H) + [D] D24'3 = -6.35 (c.0.01, MeOH) EXAMPLE 27W 27W was made according to a procedure similar to that described for 27A, with the following exception: Eíapa 27.3: 1A was subsumed by 1E. 1 H NMR (400MHz, CDCl 3) d 7.34 (d, 2H), 7.18 (d, 2H), 6.96 (d, 1H), 6.78 (d, 1H), 6.54 (s, 1H), 4.06 (m, 1 H), 3.72 (c, 1 H), 3.55 (m, 3H), 3.28 (m, 3H), 3.17 (m, 1 H) , 3.03 (m, 1 H), 2.14 (m, 5H), 1.97 (m, 2H), 1, 49 (1, 1 H), 1, 20 (day, 6H) Analysis of the specie mass m / z = 393.4 (M + H) + EXAMPLE 28A Preparation of 28.2: To a solution of 4-oxopiperidine-1-carboxylic acid benzyl (19.1) (37.26 g, 160 mmol) in toluene (450 mL) was added cyanoacety of ethylene (28.1) (18, 8 g, 166 mmol, 1.04 eq), acetic acid (2 mL) and ammonium acetyl (1.24 g, 16 mmol, 0.1 eq). The reaction mixture was heated at reflux for 2 hours with the azero-isopic water reagent formed during the reaction using a Dean-Siark roller. Cyanoacety of ethylene (10 g, 88.4 mmol, 0.55 eq), acetic acid (2 mL) and additional ammonium acetyl (1.24 g, 6 mmol, 0.0375 eq) were added to the reaction mixture, which was then heated to reflux temperature for 1.5 h. Cyanoacety of ethylene (10 g, 88.4 mmol, 0.55 eq), acetic acid (2 mL) and additional ammonium acetic acid (1.24 g, 6 mmol, 0.0375 eq) were added and heated to íemperature. of reflux last 1 hour more. The reaction mixture was cooled to ambient temperature and washed with a saturated aqueous solution of sodium bicarbonate, and dried over sodium sulfate. The mixture was filtered and the filtrate was concentrated in vacuo. To the residue was added hexane (300 mL) and ethyl acetate (20 mL). The mixture was kept at ambient temperature throughout the night. The solid was collected by filtration, washed with hexane and dried under vacuum. Yield: 87.7% 1 H NMR (400MHz, CDCl 3) d 7.35 (m, 5H), 5.19 (s, 2H), 4.30 (c, 2H), 3.70 (m, 2H), 3.63 (m, 2H), 3.18 (m, 2H), 2.80 (m, 2H), 1, 39 (i, 3H) Preparation of 28.4a: To a suspension of copper cyanide (I) (17.3 g, 193.2 mmol, 2.0 eq) in anhydrous hydrohydrofuran (400 mL) was added a solution of 2.0 M benzylmagnesium chloride (28.3a) (192 mL, 384 mmol, 4 g). , 0 eq) in hydrofuran in niimogen atmosphere at 0 ° C. After stirring the reaction mixture at ambient temperature for 2 hours, a solution of compound 28.2 (31.5 g, 96 mmol) in tetrahydrofuran (100 mL) was added dropwise at -30 ° C. After the addition, the reaction mixture was stirred at ambient temperature overnight, and then quenched with a saturated aqueous ammonium chloride solution, and filtered. The filtrate was excreted with diethyl ether and the combined organic exiphases were dried over sodium sulfate. The organic exfracts were concentrated under reduced pressure and the residue was purified by column chromatography (eluent: hexane / methylene chloride / ethyl ether, 4: 1: 1). Yield: 100% 1 H NMR (400MHz, CDCl 3) d 7.35-7.20 (m, 10H), 5.11 (s, 2H), 4.25 (c, 2H), 3.72-3.50 (m, 5H), 3.06 (d, 1 H), 2.91 (d, 1 H), 1, 90-1, 65 (m, 4H), 1.32 (t, 3H) Preparation of 28.6 a: Concentrated sulfuric acid (210 mL) was added leniamenie at 28.4a (38 g, 90.5 mmol) at 0 ° C. The mixture was heated to ambient temperature, stirred for 30 min at room temperature, and then heated to 90 ° C overnight. The reaction mixture was cooled in an ice bath and basified carefully to pH = 9-10 with an aqueous solution of 6N sodium hydroxide. The mixture was extracted with methylene chloride, and the organic exíractos were combined, dried over sodium sulfate and concentrated in vacuo. The residue was dissolved in methylene chloride (500 mL). To this solution was added triethylamine (30 mL, 215.6 mmol, 2.4 eq) followed by the dropwise addition of benzyl chloroformate (21.8) (16 mL, 106.5 mmol, 1.2 eq) to 0 ° C. The reaction mixture was stirred at 0 ° C for 1 h and then washed with a saturated aqueous solution of sodium bicarbonate. The organic phase was dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (eluent: hexane / methylene chloride / ethyl ether, 4: 1: 1). Yield: 41.2% 1 H NMR (400MHz, CDCl 3) d 8.00 (d, 1 H), 7.50 (t, 1H), 7.33-7.23 (m, 7H), 5.11 ( s, 2H), 2.98 (s, 2H), 2.62 (s, 2H), 1.50 (m, 4H) Preparation of 28.7a: A solution of bis (frimethylsilyl) amide 1.0M in 1,1-hydrohydrofuran , 6 mL, 3.6 mmol, 1.2 eq) was added at -78 ° C to a solution of 28.6a (1.047 g, 3.0 mmol) in telrahydrofuran (30 mL). After 45 min, a solution of 1.4 (1.3 g, 3.6 mmol, 1.2 eq) in ureahydrofuran (8 mL) was added to the reaction mixture. The reaction mixture was then heated to ambient temperature and stirred for 2.5 h, quenched by the addition of water (40 mL), and extracted with a mixture of hexane and diethylether (1: 1). The organic extracts were combined and washed with water, brine and dried over sodium sulfate. Evaporation of the solvent gave the production in witch, which was used in the next step without further purification. Yield: 100% 1 H NMR (400MHz, CDCl 3) 57.35-7.18 (m, 9H), 5.98 (s, 1H), 5.11 (s, 2H), 3.70 (m, 2H) , 3.40 (m, 2H), 2.83 (s, 2H), 1, 66-1, 56 (m, 4H) Preparation of 28.8a: A solution of 28.7a in bruison (3 mmol) in dimethoxy manganese (25 mL) was added sequentially a 2N sodium carbonate aqueous solution (5 mL, 10 mmol, 3.3 eq), lithium chloride (424 mg, 10 mmol, 3.3 eq), 4 - (? ,? -? - dieylaminocarbonyl) phenylboronic acid (796 mg, 3.6 mmol, 1.2 eq) and palladium (pyridine) (104 mg, 0.09 mmol, 0.03 eq). The reaction mixture was heated to reflux temperature overnight, cooled to room temperature, diluted with water (30 mL) and extracted with diethyl ether. The combined organic extracts were dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (eluyenie: hexane / methylene chloride / ethyl acetate, 2: 1: 1). Yield: 91.9% 1 H NMR (400MHz, CDCl 3) 7.36-7.12 (m, 12H), 7.00 (d, 1 H), 6.00 (s, 1H), 5.13 ( s, 2H), 3.70 (m, 2H), 3.58 (m, 2H), 3.45 (m, 2H), 3.30 (m, 2H), 2.82 (s, 2H), 1, 65-1, 52 (m, 4H), 1, 21 (m, 6H) Preparation of 28A: The iodoimethylsilane (0.29 mL, 2 mmol, 2 eq) was added to a solution of 28.8a (508 mg, 1 mmol) in anhydrous methylene chloride (10 mL) in niimogen's atmosphere. The reaction mixture was stirred at ambient temperature for 2 hours and quenched with an aqueous solution of 1 N hydrochloric acid (30 mL) and extracted with diethyl ether. The aqueous phase was basified to pH = 9-10 with an aqueous solution of 3N sodium hydroxide, and extracted with methylene chloride. The organic extracts were combined, dried over sodium sulfate and concentrated in vacuo. The residue was dissolved in methylene chloride (3 mL) and diluted with diethyl ether (15 mL). To this solution was added a solution of anhydrous hydrochloric acid 2.0 M in diethylether (1.5 mL, 3 mmol, 3.0 eq) and the reaction was stirred at ambient temperature for 30 min. The solid was collected by filtration, washed with diethyl ether and dried under vacuum. Yield: 92.7% 1 H NMR (400MHz, CDCl 3) 58.90 (m, 2H), 7.40-7.20 (m, 7H), 6.97 (d, 1H), 6.20 (s, 1H), 3.42 (m, 2H), 3.20 (m, 6H), 2.82 (s, 2H), 1.70 (m, 4H), 1, 10 (m, 6H) Analysis of the spectra mass m / z = 375.1 (M + H) + EXAMPLE 28B Preparation of 28.4b: Compound 28.4b was prepared as described for 28.4a except that 28.3a was subsumed by 23.8b. Preparation of 28.9: To a solution of compound 28.4b (29 g, 64.4 mmol) in dimethylsulfoxide (200 mL) was added sodium chloride (1.5 g, 25.6 mmol, 0.4 eq) and water ( 3.0 mL, 167 mmol, 2.6 eq). The reaction mixture was heated to 160 ° C for 2 hours and then cooled to ambient temperature. Water (600 mL) was added to the mixture and the crude product was extracted with diethyl ether. The organic extracts were combined, washed with water and brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by column chromatography (eluent: hexane / methylene chloride / ethyl ether, 4: 1: 1). Yield: 94.8% 1 H NMR (400MHz, CDCl 3) d 7.35 (m, 5H), 7.08 (d, 2H), 6.83 (d, 2H), 5.12 (s, 2H), 3.80 (s, 3H), 3.68 (m, 2H), 3.40 (m, 2H), 2.74 (s, 2H), 2.21 ( s, 2H), 1, 60-1, 52 (m, 4H) Preparation of 28.10: To a solution of compound 28.9 (7.56 g, 20 mmol) in meianol (200 mL) was added concentrated sulfuric acid (40 mL). mL). The mixture was heated at reflux temperature for 2 days. The reaction mixture was cooled to 0 ° C, basified to pH = 9 by the slow addition of an aqueous solution of 6N sodium hydroxide, and then concentrated in vacuo to re stream the methanol. The mixture was extracted with methylene chloride. The organic extractions were combined, dried over sodium sulphated, filtered and concentrated in vacuo. The residue was dissolved in methylene chloride (80 mL) and cooled to 0 ° C. To this solution was added eryrylamine (9.6 mL, 69 mmol, 3.5 eq), followed by the dropwise addition of benzyl chloroformate (21.8) (6.4 mL, 95%, 42.7 mmol, 2.1 eq). The reaction mixture was stirred at 0 ° C for 1 h, washed with a saturated aqueous solution of sodium bicarbonate, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (eluyenie: hexane / methylene chloride / ethyl aceia, 4: 1: 1). Yield: 94.8% 1 H NMR (400MHz, CDCl 3) 57.38 (m, 5H), 7.10 (d, 2H), 6.80 (d, 2H), 5.12 (s, 2H), 3 , 80 (s, 3H), 3.75 (m, 2H), 3.70 (s, 3H), 3.32 (m, 2H), 2.73 (s, 2H), 2.30 (s, 2H), 1.50 (m, 4H) Preparation of 28.11: Compound 28.10 (2.06 g, 5 mmol) was dissolved in a mixture of meianol (40 mL), teirahydrofuran (40 mL) and water (40 mL). To this solution was added lithium hydroxide (1.52 g, 36 mmol, 7.2 eq) in one portion. The reaction mixture was stirred at room temperature overnight, concentrated in vacuo, acidified with an aqueous 3N hydrochloric acid solution and extracted with methylene chloride. The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The production in bruise was used in the following step without further purification. Yield: 100% 1 H NMR (400MHz, DMSO d6) 512.22 (sa, 1H), 7.33 (m, 5H), 7.10 (d, 2H), 6.86 (d, 2H), 5, 06 (s, 2H), 3.73 (s, 3H), 3.60 (m, 2H), 3.32 (m, 2H), 2.69 (s, 2H), 2.17 (s, 2H) ), 1.45-1.35 (m, 4H) Preparation of 28.6b: To a solution of 28.11 (1.98 g, 5 mmol) in anhydrous methylene chloride (10 mL) was added a solution of oxalyl 2.0M in methylene chloride (20 mL, 40 mmol, 8.0 eq) followed by 2 drops of anhydrous / V / d-dimethylformamide. The reaction mixture was stirred at room temperature for 4 h and then concentrated in vacuo. The acyl chloride was dissolved in anhydrous methylene chloride (100 mL) and aluminum chloride (1.35 g, 10 mmol, 2.0 eq) was added in one portion. The reaction mixture was stirred at room temperature overnight and then quenched with water (60 mL) followed by the addition of concentrated ammonium hydroxide to basify the aqueous phase. The organic phase was separated and the aqueous phase was further extracted with methylene chloride. The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. Then the residue was dissolved in methylene chloride (60 mL) and cooled to 0 ° C. To this solution was added triethylamine (3.0 mL, 21.6 mmol, 4.3 eq), followed by benzyl chloroformate (21.8) (2.0 mL, 13.3 mmol, 2.7 eq). The reaction mixture was stirred at 0 ° C for 1 h and then washed with a saturated aqueous solution of sodium bicarbonate, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (eluyenie: hexane / methylene chloride / ethyl ether, 4: 1: 1). Yield: 89.7% 1 H NMR (400MHz, CDCl 3) 57.48 (d, 1 H), 7.35 (m, 5H), 7.16 (d, 1H), 7.10 (dd, 1H), 5,11 (s, 2H), 3.81 (s, 3H), 3.50 (m, 4H), 2.90 (s, 2H), 2.60 (s, 2H), 1.50 (m, 4H) Preparation of 28B : 28B was obtained from 28.6b according to a procedure similar to that described for 28A. 1 H NMR (DMSO d6) 8.90 (m, 2H), 7.48 (d, 2H), 7.40 (d, 2H), 7.26 (d, 1H), 6.85 (dd, 1) H), 6.45 (d, 1H), 6.20 (s, 1H), 3.64 (s, 3H), 3.42 (m, 4H), 3.18 (m, 4H), 2, 78 (s, 2H), 1.70 (m, 4H), 1, 11 (m, 6H) Analysis of the mass spectra m / z = 405.1 (M + H) + EXAMPLE 28C Preparation of 28C: The compound 28.8a (800 mg, 1.58 mmol) was dissolved in a mixture of methylene chloride (5 mL) and methanol (50 mL), and the reaction mixture was hydrogenated in the presence of 10% Pd / C (240 mg ) using a hydrogen balloon. After 2 days at room temperature, the reaction mixture was filtered through Celite and the filtrate was concentrated in vacuo. The residue was dissolved in methylene chloride (10 mL) and a solution of anhydrous hydrochloric acid 2.0M in diethyl ether (2 mL, 4 mmol, 2.5 eq) was added. The mixture was stirred for 1 h at ambient temperature and then concentrated in vacuo. Yield: 100% 1 H NMR (400MHz, DMSO d6) 59.12 (sa, 2H), 7.28-7.03 (m, 7H), 6.66 (d, 1H), 4.10 (m, 1H), 3.40 (m, 2H), 3.20-3.08 (m, 6H), 2.85 (d, 1H), 2.78 (d, 1 H), 2.10 (m, 1H), 1.60 (m, 5H), 1, 10 (m, 6H). Analysis of the mass spectrum m / z = 377.1 (M + H) + EXAMPLE 28D 28D was done according to a procedure similar to that described for 28C, with the following exception: Stage 28.12: 28.8a was replaced by 28.8b. 1 H NMR (400MHz, DMSO d6) 8.77 (m, 2H), 7.28 (m, 4H), 7.89 (d, 1H), 6.75 (dd, 1H), 6.16 (d) , 1H), 4.09 (m, 1H), 3.55 (s, 3H), 3.49-3.00 (m, 8H), 2.73 (m, 2H), 2.10 (m, 1H), 1.59 (m, 5H), 1, 10 (m, 6H) Analysis of the mass spectra m / z = 407.3 (M + H) + EXAMPLE 28E 28E was obtained according to a procedure similar to that described for 28A, with the following exception: Eypa 28.10: 1.6 was subsumed by 1.7 (see also paragraph 28.13). 1 H NMR (400MHz, DMSO d6) 8.91 (m, 2H), 8.61 (s, 1 H), 7.89 (d, 1H), 760 (d, 1H), 7.31-7.20 (m, 3H), 6.90 (d, 1 H), 6.33 (s, 1 H), 3.45-3.15 (m, 8H) ), 2.83 (s, 2H), 1, 70 (m, 4H), 1, 12 (m, 6H) Mass spectral analysis m / z = 376.4 (M + H) + Elemenfal analysis: C24H29N30, 4 / 3HCI, 1 Theoretical H2:% C 65.20; % H 7.37; % N 9.50; % C 10.69 Found:% C 64.94; % H 7.06; % N 9.36; % CI 10.56 EXAMPLE 29A Preparation of 29.2: A solution of 4- (eioxycarbonyl) phenyl-zinc 0 iodide solution was added to a solution of compound 28.7a in dimethyl ether (12 mmol) in anhydrous etherhydrofuran (200 mL) at room temperature. 5M (29.1) in hydrohydrofuran (60 mL, 30 mmol, 2.5 eq) followed by teiraks (triphenylphosphine) of palladium (0) (833 mg, 0.72 mmol, 0.06 eq). The reaction mixture was heated at 40 ° C for 2 days and then cooled to ambient temperature. The reaction was quenched by the addition of a saturated aqueous solution of ammonium chloride and extracted with ethyl ether. The organic extracts were combined, dried over sodium sulfate and filtered. The organic extracts were concentrated under reduced pressure and the residue was purified by column chromatography (eluent: hexane / ethyl ether, 5: 1). Yield: 86.6% 1 H NMR (400MHz, CDCl 3) 58.05 (d, 2H), 7.40-7.10 (m, 10H), 6.96 (d, 1H), 6.00 (s, 1 H), 5.13 (s, 2H), 4.40 (c, 2H), 3.70 (m, 2H), 3.48 (m, 2H), 2.82 (s, 2H), 1 , 66-1.53 (m, 6H), 1, 40 (1, 3H) Preparation of 29.3: Lithium hydroxide (3.36 g, 80 mmol, 8.0 eq) was added to a solution of 29.2 ( 4.81 g, 10 mmol) in a mixture of methanol (100 mL), teirahydrofuran (100 mL) and water (100 mL). The reaction mixture was stirred at ambient temperature for overnight, concentrated in vacuo and acidified to pH = 1-2 with an aqueous 3N hydrochloric acid solution. The acidified solution was extracted with methylene chloride and the organic extracts were combined, dried over sodium sulfate, filtered and concentrated in vacuo. The production in bruise was used in the following step without further purification. Yield: 100% 1 H NMR (400MHz, DMSO d6) 513.00 (sa, 1 H), 7.99 (d, 2H), 7.48 (d, 2H), 7.38-7.15 (m, 8H), 6.91 (d, 1H), 6.18 (s, 1 H), 5.10 (s, 2H), 3.60-3.46 (m, 4H), 2.82 (s, 2H), 1.53 (m, 2H), 1.42 (m, 2H) Preparation of 29.5a: To a solution of 29.3 (680 mg, 1.5 mmol, 1.0 eq)) in methylene chloride ( 40 mL) was added / sopropylamine (3.4h) (0.26 mL, 3 mmol, 2.0 eq) followed by eryrylamine (0.84 mL, 6 mmol, 4.0 eq) and the Mukaiyama acylating reagent ( 2-Chloro-1-meilypyridinium iodide) (461 mg, 1.8 mmol, 1.2 eq). The reaction mixture was stirred at room temperature overnight, washed with a saturated aqueous sodium bicarbonate solution, dried over sodium sulfate, and filtered. The organic extracts were concentrated under reduced pressure and the residue was purified by column chromatography (eluent: hexane / methylene chloride / ethyl ether, 2: 1: 1). Yield: 95.8% 1 H NMR (400MHz, CDCl 3) 57.78 (d, 2H), 7.40-7.10 (m, 10H), 6.94 (d, 1 H), 6.00 (s) , 1H), 5.95 (d, 1 H), 5.12 (s, 2H), 4.31 (m, 1 H), 3.70 (m, 2H), 3.46 (m, 2H) , 2.81 (s, 2H), 1, 62-1, 52 (m, 6H), 1, 30 (d, 6H) Preparation of 29A: The iodoimethylsilane (0.37 mL, 2.6 mmol, 2, 0 eq) was added to a solution of 29.5 (620 mg, 1.26 mmol) in anhydrous meiylene chloride (20 mL) in a niosogenic atmosphere. The reaction mixture was stirred at ambient temperature for 2 hours, quenched with an aqueous solution of 1 N hydrochloric acid (40 mL), and the mixture exfoliated with diethyl ether. The aqueous phase was basified to pH = 9-10 with an aqueous solution of 3N sodium hydroxide and was extracted with methylene chloride. The organic extracts were combined, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was dissolved in methylene chloride (4 mL) and diluted with diethyl ether (20 mL). To this solution was added a solution of anhydrous hydrochloric acid 2.0M in diethylether (2.0 mL, 4 mmol, 3.2 eq) and the mixture was stirred at ambient temperature for 30 min. The precipitated resulfanie was collected by filtration, washed with diethyl ether and dried under vacuum. Yield: 100% H NMR (400MHz, DMSO d6) 58.90 (da, 2H), 8.29 (d, 1H), 7.90 (d, 2H), 7.43 (d, 2H), 7 , 31-7.16 (m, 3H), 6.90 (d, 1 H), 6.18 (s, 1 H), 4.11 (m, 1 H), 3.16 (m, 4H) , 2.86 (s, 2H), 1.70 (m, 4H), 1, 20 (d, 6H) Analysis of the mass spectrum m / z = 361, 0 (M + H) + EXAMPLE 29B 29B was obtained according to a procedure similar to that described for 29A, with the following exception: Eiapa 29.3: 3.4h was subsumed by 29.4. 1 H NMR (400MHz, DMSO d6) 8.89 (m, 2H), 8.10 (d, 1H), 7.92 (d, 2H), 7.45 (d, 2H), 7.31 (d, 1 H), 7.25 (t, 1 H), 7.20 (t, 1H), 6.90 (d, 1 H), 6, 18 (s, 1H), 3.80 (m, 1 H), 3.20 (m, 4H), 2.88 (s, 2H), 1.60 (m, 8H), 0.90 (i, 6H) Analysis of the mass spectra m / z = 389.1 (M + H) + EXAMPLE 29C Preparation of 29.7: To a solution of the carboxylic acid 29.3 (1.82 g, 4 mmol) in a dioxane mixture (18 mL ) and urea-builic alcohol (18 mL) was added triethylamine (0.78 mL, 5.6 mmol, 1.4 eq) and diphenylphosphorylazide (29.6) (1.12 mL, 5.2 mmol, 1.3 eq). ). The reaction mixture was heated at reflux temperature overnight and concentrated in vacuo. The residue was purified by column chromatography (eluyenie: hexane / methylene chloride / ethyl acetate, 5: 1: 1) to give the desired crude carbamate 29.7, which was used in the next step without further purification.

Yield: 33.4% Preparation of 29.8: To a solution of carbamate in crude 29.7 (700 mg) in methylene chloride (15 mL) was added a solution of anhydrous hydrochloric acid 2.0M in dieyly ether (15 mL, 30 mmol ). The reaction mixture was stirred at ambient temperature throughout the night and then diethyl ether was added to the reaction mixture, which was stirred for an additional 2 hours at room temperature. The resulting precipitate was collected by filtration and used for the next step without further purification. Yield: 57% 1 H NMR (400MHz, DMSO d6) 510.15 (sa, 3H), 7.40-7.15 (12H), 6.89 (d, 1H), 6.10 (s, 1 H) , .10 (s, 2H), 3.59 (m, 2H), 3.46 (m, 2H), 2.81 (s, 2H), 1.54 (m, 2H), 1.41 (m , 2H) Preparation of 29.10: Triethyl amine (0.42 mL, 3 mmol) was added to a suspension of 29.8 (300 mg, 0.65 mmol) in methylene chloride (20 mL) at 0 ° C, followed by add dropwise to propionyl chloride (29.9) (0.12 mL, 1.3 mmol, 2.0 eq). The reaction mixture was stirred at ambient temperature for 6 h and was washed with a saturated aqueous solution of sodium bicarbonate. The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (eluent: hexane / methylene chloride / ethyl acetate, 2: 1: 1). Yield: 89.5% 1 H NMR (400MHz, CDCl 3) 57.54 (d, 2H), 7.38-7.10 (m, 11H), 7.00 (d, 1H), 5.95 (s, 1 HOUR), .12 (s, 2H), 3.70 (m, 2H), 3.44 (m, 2H), 2.80 (s, 2H), 2.42 (c, 2H), 1.60 (m , 2H), 1.50 (m, 2H), 1.28 (t, 3H) Preparation of 29C: The iodotrlmethylsilane (0.21 mL, 1.47 mmol, 2.0 eq) was added to a solution of compound 29.10 (220 mg, 0.46 mmol) in anhydrous methylene chloride (8 mL) in aminosphere of nihologen. The reaction mixture was stirred at room temperature for 2 h and quenched with an aqueous solution of 1 N hydrochloric acid (15 mL). The crude product was extracted with diethyl ether. The aqueous phase was basified to pH = 9-10 with a 3M aqueous sodium hydroxide solution and the mixture was extracted with methylene chloride. The organic extracts were combined, dried over sodium sulfate and concentrated in vacuo. The residue was dissolved in methylene chloride (3 mL) and diluted with diethyl ether (10 mL). To this solution was added a solution of anhydrous hydrochloric acid 2.0 M in diethyl ether (0.7 mL, 1.4 mmol, 3.0 eq) and the mixture was stirred at room temperature for 30 min. The solid was collected by filtration, washed with diethyl ether and dried under vacuum. Yield: 83.9% 1 H NMR (400 MHz, DMSO d6) d 10.05 (s, 1 H), 8.94 (da, 2H), 7.66 (d, 2H), 7.30-7, 20 (m, 5H), 6.96 (d, 1H), 6.08 (s, 1H), 3.15 (m, 4H), 2.82 (s, 2H), 2.34 (c, 2H) ), 1.68 (m, 4H), 1.10 (t, 3H) Mass spectral analysis m / z = 347.0 (M + H) + EXAMPLE 29D Preparation of 29.11: Menesosulfonyl chloride (7.4) (0.051 mL, 0.66 mmol, 2.0 eq) was added to a solution of 29.8 (150 mg, 0.326 mmol) in pyridine (6 mL) at 0 ° C. The reaction mixture was stirred at room temperature overnight, diluted with methylene chloride (40 mL) and washed with an aqueous 1N hydrochloric acid solution and brine. The organic phase was dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (eluent: hexane / acetyl ether, 1: 1).

Yield: 97.7% H NMR (400MHz, CDCI3) 57.38-7.13 (m, 12H), 6.99 (d, 1H), 6.50 (s, 1 H), 5.96 (s) , 1H), 5.12 (s, 2H), 3.70 (m, 2H), 3.46 (m, 2H), 3.08 (s, 3H), 2.81 (s, 2H), 1 , 62-1, 52 (m, 4H) Preparation of 29D: The iodotrimethylsilane (0.14 mL, 0.98 mmol, 3.5 eq) was added to a solution of 29.11 (140 mg, 0.28 mmol) in anhydrous meiylene chloride (6 mL) in niimogen atmosphere. The reaction mixture was stirred at room temperature for 2 h and quenched with an aqueous solution of 1 N hydrochloric acid (10 mL). The crude product was extracted with diethyl ether. The aqueous phase was basified to pH = 9-10 with an aqueous 3N sodium hydroxide solution and extracted with methylene chloride. The organic extractions were combined, dried over sodium sulphated, filtered and concentrated in vacuo. The residue was dissolved in methylene chloride (3 mL) and diluted with diethyl ether (10 mL). To this solution was added a solution of anhydrous hydrochloric acid 2.0M in diethyl ether (0.42 mL, 0.84 mmol, 3.0 eq) and the mixture was stirred at room temperature for 30 min. The solid was collected by filtration, washed with diethyl ether and dried under vacuum. Yield: 90.5% 1 H NMR (400MHz, DMSO d) 5RMN 1H (400 MHz, DMSO-d6) d 9.88 (s, 1H), 8.91 (da, 2H), 7.35-7.18 (m, 7H), 6.96 (d, 1 H), 6.09 (s, 1 H), 3.12 (m, 4H), 3.02 (s, 3H), 2.82 (s, 2H), 1.68 (m, 4H) Analysis of the mass spectrum m / z = 368.9 (M + H) + EXAMPLE 30A Preparation of 30.3: A mixture of 30.1 (10.2 g, 0.050 mol, 1, 0 eq) and 30.2 (25 g, 0.075 mol, 1.5 eq) in toluene (100 mL) in nihologen was heated to reflux temperature for 2 h. The mixture was concentrated under reduced pressure and the crude product was purified by column chromatography (eluyenie: hexane / ethyl acetate, 1: 1). Yield: 92% 1H NMR (400MHz, CDCl 3) d 7.42 (s, 5H), 5.78 (s, 3H), 3.83 (s, 2H), 3.70 (s, 3H), 3, 49 (sa, 2H), 3.02 (ma, 2H), 2.37 (ma, 2H) Analysis of the mass spectrum m / z = 259.9 (M + H) + Preparation of 30.5: A solution of 30.3 (5.0 g, 19.3 mmol, 1.0 eq), 30.4 (16.39 g, 149 mmol, 7.7 eq), and triethylamine (3.90 g, 38.6 mmol, 2.0 eq. ) in tetrahydrofuran (100 mL) was heated at reflux temperature for 12 h. The mixture was concentrated under reduced pressure and the crude production was purified by column chromatography (eluyenie: hexane / ethyl ether, 60:40). Yield: 98% 1 H NMR (400MHz, CDCl 3) d 7.56 (m, 2H), 7.37 (m, 8H), 4.40 (sa, 1H), 3.72 (s, 3H), 3, 58 (ma, 3H), 2.56 (s, 2H), 1, 76 (ma, 4H) Analysis of the mass spectrum m / z = 369.9 (M + H) + Preparation of 30.6: A solution of 30.5 (10.0 g, 27.07 mmol, 1.0 eq) and concentrated sulfuric acid (50 mL) was stirred at ambient temperature for 18 h. The mixture was poured into ice water (1: 1) (200 mL) and the crude product was extracted with acetyl ether. The combined organic extracts were dried over magnesium sulfate, concentrated under reduced pressure and the crude product was purified by column chromatography (eluent: hexane / ethyl acetate, 70:30). Yield: 22% 1 H NMR (400MHz, CDCl 3) d 8.08 (dd, 1 H), 7.40 (m, 7H), 7.20 (m, 1H), 4.47 (sa, 1H), 3 , 44 (ma, 3H), 2.97 (da, 2H), 1, 92 (ma, 4H) Analysis of the mass spectrum m / z = 337.9 (M + H) + Preparation of 30.7: To a solution of 30.6 (, 2 g, 3.56 mmol,, 0 eq) in acetic acid (5 mL) was added at room temperature an aqueous solution of 30% hydrogen peroxide (2 mL). The solution was heated at 90 ° C for 2 h and then cooled to ambient temperature. The mixture was concentrated to 1/3 of its volume under reduced pressure. Water was added and the crude product was extracted with methylene chloride. The combined organic extracts were then washed with a saturated solution of sodium salicylate, brine, dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (eluent: hexane / ethyl acetate, 1: 1). Yield: 84% 1 H NMR (400MHz, CDCl 3) d 8.10 (m, 2H), 7.87 (m, 1H), 7.77 (m, 1H), 7.41 (m, 5H), 4.34 (sa, 1 H), 3.90 (ma, 1 H), 3.50 (ma, 4H), 2.36 (sa, 2H), 1.80 (ma, 2H) Analysis of the mass spectra m / z = 369.8 (M + H) + Preparation of 30.8: A mixture of 30.7 (1.1 g, 2.98 mmol, 1.0 eq) and an aqueous solution of acid 6N hydrochloric acid (5 mL) in ethylene (20 mL) was heated at 90 ° C for 12 hours. The mixture was conceted under reduced pressure and used for the next step without further purification. Yield: 100% Analysis of the mass spectrum m / z = 265.8 (M + H) + Preparation of 30.9: To a solution of 30.8 (0.9 g, 2.98 mmol, 1.0 eq) in hydrofuran (10 mL) at 0 ° C was added eryrylamine (1.2 g, 11.22 mmol, 4.0 eq). and 4.7 (0.78 g, 3.58 mmol, 1.2 eq). The mixture was stirred at 0 ° C for 1 h and at ambient temperature it lasted 1 h. Water (20 mL) was added and the crude mixture was extracted with acetone. The combined organic extracts were washed with water, brine, dried over magnesium sulfate and filtered. The filtrate was conceted under reduced pressure. The crude product was purified by column chromatography (eluent: eluent: hexane / ethyl acetate, 1: 1). Yield: 79% 1 H NMR (400MHz, CDCl 3) d 8.09 (m, 2H), 7.86 (m, 1 H), 7.76 (m, 1 H), 3.97 (sa, 2H), 3.39 (s, 2H), 3.20 (ma, 2H), 2.29 (m, 2H), 1.76 (ma, 2H), 1.46 (s, 9H) Preparation of 30.10: A 30.9 solution (0.84 g, 2.30 mmol, 1.0 eq) in tetrahydrofuran (10 mL) at -78 ° C in nihorogen atmosphere was added dropwise a solution of 1.0M LiHMDS in teirahydrofuran ( 2.76 mL, 2.76 mmol, 1.2 eq). The mixture was stirred for 45 min at -78 ° C. To the reaction mixture was added a solution of 1.4 (0.986 g, 2.76 mmol, 1.2 eq) in tetrahydrofuran (3 mL). The mixture was stirred for 3 h at 0 ° C and at room temperature for 16 h. The mixture was poured into ice water (20 mL) and the crude product was extracted with ethyl alcohol. The combined organic extracts were washed with water, brine, dried over magnesium sulfate and filtered. The crude product was purified by column chromatography (eluent: hexane / ethyl acetate 85/15 mixture). Yield: 52% 1 H NMR (400MHz, CDCl 3) d 8.09 (dd, 1 H), 7.76 (m, 1 H), 7.69 (m, 1H), 7.61 (d, 1H), 6.36 (s, 1H), 4.17 (sa, 2H), 3.06 (sa, 2H), 2.24 (m, 2H), 1.82 (m, 2H), 1.47 (s) , 9H) Preparation of 30.11: To a solution of 30.10 (0.15 g, 0.30 mmol, 1.0 eq) in dimethoxy manganese (DME) (30 mL) was added sequentially an aqueous 2N sodium carbonate solution (0.45 mL, 0.90 mmol, 3.0 eq), lithium chloride (0.038 g, 0.90 mmol, 3.0 eq), 1.6 (0.106 g, 0.33 mmol, 1.1 eq) and palladium teirak (triphenylphosphine) ( ) (0.007 g, 0.006 mmol, 0.02 eq). The mixture was heated to reflux temperature for 16 h under a nitrogen atmosphere. The mixture was then cooled to ambient temperature and ice water (20 mL) was added. The mixture was extracted with acetone. The combined organic extracts were washed further with water, brine, dried over magnesium sulfate and filmed. The filtrate was conceted under reduced pressure. The bruise production was purified by column chromatography (eluyenie: hexane / acetyl ether, 70:30). Yield: 86% 1 H NMR (400MHz, CDCl 3) 8.09 (m, 1 H), 7.56 (m, 2H), 7.44 (d, 2H), 7.38 (d, 2H), 7 , 15 (m, 1 H), 6.22 (s, 1 H), 4.16 (sa, 2H), 3.58 (sa, 2H), 3.30 (sa, 2H), 3.14 ( sa, 2H), 2.23 (m, 2H), 1.88 (m, 2H), 1.47 (s, 9H), 1.23 (day, 6H) Analysis of the mass spectrum m / z = 525 , 9 (M + H) + 30A Preparation: To a solution of 30.11 (0.440 g, 0.84 mmol, 1.0 eq) in anhydrous methylene chloride (20 mL) was added a solution of anhydrous hydrochloric acid 2 , 0M in dieryl ether (8.0 mL, 16 mmol, 19 eq). The mixture was stirred for 48 hours at ambient temperature. The mixture was conceted under reduced pressure and dried with diethyl ether. The resulting precipitate was collected by filtration. Yield: 100% 1H NMR (400MHz, DMSO d6) 9.37 (ma, 1H), 8.80 (ma, 1H), 8.05 (d, 1H), 7.73 (m, 2H), 7.53 (d, 2H), 7.44 (d, 2H), 7, 21 (d, 1 H), 6.58 (s, 1 H), 3.36 (ma, 8H), 2.26 (ma, 2H), 1, 95 (day, 2H), 1, 13 ( da, 6H) Analysis of the mass spectrum m / z = 425.3 (M + H) + EXAMPLE 31A Preparation of 13.2a: To a solution of 1.5a (7.80 g, 17.35 mmol, 1.0 eq ) in dimethoxylation (75 mL) was added sequentially an aqueous 2N sodium carbonate solution (26.03 mL, 52.06 mmol, 3.0 eq), lithium chloride (2.21 g, 52.06 mmol, 3%), , 0 eq), 13.1 (3.44 g, 19.09 mmol, 1.1 eq) and teiraks (phenyl) phosphine (0) (0.40 g, 0.35 mmol, 0.02 eq). The mixture was heated at reflux temperature overnight under nitrogen. The mixture was then cooled to ambient temperature and water (250 mL) was added. The mixture was extracted with acetyl ether. The organic phase was further washed with brine and dried over sodium sulfate. The mixture was filtered and the filtrate was concentrated under reduced pressure. The crude production was purified by column chromatography (eluent: hexane / acetyl mixtures of increasing polarity). Yield: 64% 1 H NMR (400MHz, DMSO d6) d 8.02 (d, 2H), 7.49 (d, 2H), 7.23 (m, 1H), 6.99 (d, 1H), 6.92 (m, 2H), 5.92 (s, 1 H), 3.88 (s, 3H), 3.70 (m, 2H), 3.27 ( m, 2H), 1.89 (m, 2H), 1.71 (m, 2H), 1.42 (s, 9H) Analysis of the mass spectra m / z = 436.0 (M + H) + Preparation of 31 A: 31A was done according to a similar procedure to that described for 1A, with the following exceptions: Eíapa 1.4: Procedimento 1 E was used; 1.8a was replaced by 13.2a (see also step 31.2). 1 H NMR (DMSO d6) d 8.81 (m, 2H), 8.00 (m, 2H), 7.45 (m, 2H), 7.24 (m, 1H), 7.03 (m, 1) H), 6.91 (m, 2H), 5.99 (s, 1 H), 3.90 (s, 3H), 3.22 (m, 4H), 2.06 (m, 2H), 1 , 98 (m, 2H), Mass spectral analysis m / z = 336.0 (M + H) + Elemenfal analysis: C21H21NO3, 1 HCl, 0.2H2O Theoretical:% C 67.18; % H 6.01; % N 3.73 Found:% C 67.32; % H 5.98; % N 3.77 EXAMPLE 31 B 31 B was done according to a procedure similar to that described for 31 A, with the following exceptions: Eíapa 31.1: 13.1 was subsumed by 14.1. Step 31.2: Procedure 1F was used. 1H NMR (400MHz, DMSO d6) 8.92 (m, 2H), 7.94 (d, 2H), 7.59 (d, 2H), 7.29 ( m, 1 H), 7.06 (m, 1 H), 6.94 (m, 2H), 6.02 (s, 1 H), 3.22 (m, 4H), 2.05 (m, 4H) Analysis of the mass spectrum m / z = 303.1 (M + H) + Elemental analysis: C2oHi8N2O, 1HC1, 0.8H2O Theoretical:% C 68.00; % H 5.88; % N 7.93 Found:% C 67.89; % H 5.59; % N 7.79 EXAMPLE 31C 31C was obtained according to a procedure similar to that described for 31A, with the following exceptions: Eíapa 31.1: 13.1 was replaced by 16.1. Stage 31.2: Procedure 1 F was used. 1 H NMR (400MHz, DMSO dβ) 9.10 (sa, 1 H), 7.90 (s, 2H), 7.65 (m, 2H), 7.25 (,, 1H), 7.10 (d, 1 H), 6.00 (s, 1 H), 3.20 (m, 4H), 2.00 (m, 4H) Mass spectral analysis m / z = 303.1 (M + H) + EXAMPLE 31 D 31 D was obtained according to a procedure similar to that described for 31 A, with the following exceptions: Stage 31.1: 13.1 was subsumed by 31.1a. Step 31.2: Procedure 1 was used E. 1 H NMR (400MHz, DMSO d6) d 9.18 (m, 2H), 7.51 (m, 1 H), 7.41 (m, 2H), 7.26 (m, 2H), 7.05 (m, 1H), 6.94 (m, 2H), 5.92 (s, 1 H), 3.46 (m, 2H), 3.20 (m, 6H) ), 2.06 (m, 4H), 1, 11 (m, 6H) Analysis of the mass spectrum m / z = 377.4 (M + H) + EXAMPLE 31 E 31 E was obtained according to a procedure similar to that described for 31 A, with the following Exceptions: Stage 31.1: 13.1 was replaced by 31.1b. Step 31.2: Procedure 1F was used. 1H NMR (DMSO d6) See provisional example 13 Analysis of the mass spectrum m / z = 356.1 (M + H) + EXAMPLE 31 F 31 F was prepared according to a procedure similar to that described for 31 A, with the following exceptions: Eíapa 31.1: 13.1 was replaced by 31.1c. Step 31.2: Procedure 1 F. Was used. 1 H NMR (400MHz, DMSO d6) d 8.60 (m, 2H), 7.41 (m, 4H), 7.26 (m, 1H), 7.03 (m, 1 H), 6.95 (m, 2H), 5.89 (s, 1 H), 4.11 (s, 2H), 3.23 (m, 4H), 2.09 (m, 2H), 1.94 (m, 2H) Analysis of the mass spectra m / z = 317.0 (M + H) + EXAMPLE 31 G 31 G was made according to a procedure similar to that described for 31 A, with the following exceptions: Eíapa 31.1: 13.1 was subsumed by 31.1 d. Step 31.2: Procedure 31A was used. 1 H NMR (400MHz, DMSO dβ) 9.16 (sa, 2H), 7.30 (d, 2H), 7.24 (m, 1H), 7.02 (m, 4H), 6.93 (m, 1H), 5.80 (s, 1 H), 3.80 (s, 3H), 3.20 (ma, 4H), 2.03 ( ma, 4H) Analysis of the mass spectrum m / z = 308.0 (M + H) + EXAMPLE 31 H 31 H was obtained according to a procedure similar to that described for 31 A, with the following exceptions: Eíapa 31.1: 13.1 was replaced by 31.1 e . Step 31.2: Procedure 1 F was used. 1 H NMR (400MHz, DMSO dβ) 9.07 (m, 2H), 7.26 (m, 5H), 6.98 (m, 3H), .82 (s, 1H), 3.21 (m, 4H), 2.35 (s, 3H), 2.03 (m, 4H) Analysis of the mass spectrum m / z = 292.1 (M + H) + EXAMPLE 311: 311 was made according to a procedure similar to that described for 31 A, with the following exceptions: Eíapa 31.1: 13.1 was subsumed by 31.1 f. Step 31.2: Procedure 1 F. Was used. 1 H NMR (400MHz, CDCl 3) 9.76 (m, 1 H), 9.29 (m, 1 H), 7.69 (m, 1H), 7.46 (m, 1H), 7.27 (ma, 4H), 6.96 (m, 2H), 5.64 (m, 1 H), 3.44 (m, 2H), 3.30 (m, 2H) ), 2.29 (m, 2H), 2.11 (m, 2H) Analysis of the mass spectra m / z = 346.1 (M + H) + EXAMPLE 31 J 31 J was done according to a procedure similar to that described for 31A, with the following exceptions : Eíapa 31.1: 13.1 was subscribed by 31.1g. Step 31.2: Procedure 31A was used. 1H NMR (400MHz, DMSO d6) d 8.92 (ss, 1.5H), 7.44 (m, 3H), 7.36 (m, 2H), 7.25 (m, 1 H), 7.04 (d, 1 H), 6.95 (m, 2H), 5.87 (s, 1 H), 3.22 (m, 4H), 2, 09 (ma, 2H), 1.97 (ma, 2H) Analysis of the mass spectra m / z = 278.1 (M + H) + EXAMPLE 31 K 31 K was done according to a procedure similar to that described for 31 A, with the following exceptions: Eíapa 31.1: 13.1 It was suspended for 31.1h. Ephapa 31.2: Procedure 31A was used. 1H NMR (400MHz, DMSO dβ) 9.66 (sa, 1 H), 8.96 (sa, 2H), 7.50 (ma, 1 H), 7, 18 (ma, 3H), 6.97 (ma, 3H), 6.82 (ma, 1 H), 5.67 (s, 1 H), 3.18 (ma, 4H) 2.02 (ma, 4H) Analysis of the mass spectrum m / z = 294.0 (M + H) + EXAMPLE 31 L 31 L was done according to a procedure similar to that described for 31 A, with the following exceptions: Eíapa 31.1: 13.1 was subsumed by 31.1 i .

Step 31.2: Procedure 31A was used. 1H NMR (400MHz, DMSO d6) d 8.93 (sa, 2H), 7.37 (t, 1H), 7.25 (t, 1H), 6.97 (ma, 6H), 5.89 (s, 1H), 3.79 (s, 3H), 3.21 (ma, 4H), 2.03 (ma, 4H) Analysis of the mass spectrum m / z = 308.0 (M + H) + EXAMPLE 31 31 M was made according to a procedure similar to that described for 31 A, with the following exceptions: Stage 31.1: 13.1 was replaced by 31.1 j. Step 31.2: Procedure 31A was used. 1 H NMR (400MHz, DMSO d6) d 9.60 (s, 1 H), 9.05 (sa, 2H), 7.24 (m, 2H), 7.02 (m, 2H), 6.94 (m, 1H), 6.82 (d, 1 H), 6.76 (m, 2H), 5.82 (s, 1 H), 3.20 (ma, 4H), 2.03 (ma, 4H) Analysis of the mass spectrum m / z = 294.0 (M + H) + EXAMPLE 31 N 31 N was obtained according to a procedure similar to that described for 31 A, with the following exceptions: Stage 31.1: 13.1 it was replaced by 31.1k. Step 31.2: Procedure 1 F. H NMR (400MHz, DMSO d6) d 9.10 (ma, 1.5H), 8.20 (s, 1H), 8.05 (s, 2H), 7.29 was used. (m, 1H), 7.08 (d, 1H), 6.97 (t, 1 H), 6.90 (dd, 1H), 6.16 (s, 1H), 3.23 (ma, 4H ), 2.08 (ma, 4H) Analysis of the mass spectra m / z = 414.1 (M + H) + EXAMPLE 31O 31O was done according to a procedure similar to that described for 31 A, with the following exceptions: Eíapa 31.1: 13.1 was subsumed by 31.11. Step 31.2: Procedure 31A was used. 1H NMR (400MHz, DMSO d6) d 8.88 (sa, 2H), 7.42 (m, 1 H), 7.07 (ma, 5H), 6.83 (1, 1 H), 6.60 (d, 1 H), 5.73 (s, 1H), 3.65 (s, 3H), 3.18 (ma, 4H), 2.08 (ma, 2H), 1.96 (m, 2H) Analysis of the mass spectra m / z = 308.0 (M + H) + EXAMPLE 31 P 31 P was done according to a procedure similar to that described for 31 A, with the following exceptions: Eíapa 31.1: 13.1 was subscribed by 31.1m. Step 31.2: Procedure 31A was used. 1H NMR (400MHz, DMSO d ") d 9.46 (s, 1H), 9.02 (sa, 2H), 7.22 (t, 1H), 7.16 (t, 1H), 7.10 (d, 1 H), 6.93 (m, 2H), 6.84 (m, 2H), 6.70 (d, 1H), 5.71 ( s, 1H), 3.20 (ma, 4H), 2.11 (ma, 2H), 1.97 (ma, 2H) Analysis of the mass spectrum m / z = 294.0 (M + H) + EXAMPLE 31 Q 31 Q was obtained according to a procedure similar to that described for 31 A, with the following exceptions: Efapa 31.1: 13.1 was subscribed by 31.1 n. Step 31.2: Procedure 1 was used E. 1 H NMR (400MHz, CDCl 3) 9.75 (m, 2H), 7.85 (m, 1H), 7.78 (m, 1H), 7.49 (m, 1 H), 7.37 (m, 3H), 7.28 (m, 1 H), 6.99 (m, 2H), 5.88 (s, 1H), 3.42 (m, 4H), 2.27 (m, 4H) Analysis of the mass spectra m / z = 333.9 (M + H) + EXAMPLE 31 R 31 R was done according to a procedure similar to that described for 31 A, with the following exceptions: Eíapa 31.1: 13.1 was subsumed by 31.1o . Step 31.2: Procedure 1 F. H NMR (400MHz, DMSO d6) d 9.04 (m, 2H), 7.66 (m, 3H), 7.34 (m, 4H), was used. 7.10 (m, 2H), 6.48 (m, 1H), 3.23 (m, 4H), 2.09 (m, 4H) Analysis of the mass spectrum m / z = 318.1 (M + H) + EXAMPLE 31 S 31S was obtained according to a procedure similar to that described for 31A, with the following exceptions: Eíapa 31.1: 13.1 was replaced by 31.1p. Step 31.2: Procedure 31A was used. 1H NMR (400MHz, CDCI3) d 9.81 (sa, 1H), 9.40 (sa, 1H), 8.76 (sa, 2H), 7.98 (d, 1H), 7.67 (sa, 1 H), 7.29 (m, 1H), 7.01 (d, 1 H), 6.95 (t, 1 H), 6.91 (d, 1 H), 5.70 ( s, 1H), 3.43 (m, 2H), 3.34 (m, 2H), 2.29 (m, 2H), 2.15 (m, 2H) Mass spectral analysis m / z = 279 , 1 (M + H) + EXAMPLE 31T 31T was made according to a procedure similar to that described for 31A, with the following exceptions: Eíapa 31.1: 13.1 was replaced by 31.1 q. Step 31.2: Procedure 1 was used E. 1 H NMR (400MHz, CDCl 3) 59.71 (m, 2H), 7.44-7.21 (m, 3H), 7.11 (m, 2H), 6, 96 (m, 2H), .75 (s, 1H), 3.39 (m, 4H), 2.24 (m, 4H) Analysis of the mass spectrum m / z = 283.9 (M + H) + EXAMPLE 31 U 31 U It worked according to a procedure similar to that described for 31 A, with the following exceptions: Eíapa 31.1: 13.1 was replaced by 31.1 r. Step 31.2: Procedure 1F was used. 1 H NMR (400MHz, DMSO d6) d 9.04 (ma, 1.5H), 7.66 (m, 1H), 7.62 (m, 1H), 7.26 (m, 1H), 7.20 (m, 2H), 7.03 (d, 1 H), 6.97 (t, 1H), 5.96 (s, 1 H), 3.20 (ma, 4H), 2.07 (ma, 2H), 1, 98 (ma, 2H) Analysis of the mass spectrum m / z = 284.1 (M + H) + EXAMPLE 31V 31 V was obtained according to a procedure similar to that described for 31 A, with The following exceptions: Eíapa 31.1: 13.1 was replaced by 31.1 s. Step 31.2: Procedure 1 F. 1 H NMR (400MHz, CDCl 3) 59.71 (sa, 1 H), 9.29 (sa, 1 H), 7.52 (m, 3H), 6.99 ( m, 2H), 6.59 (m, 1 H), 6.49 (m, 1H), 5.95 (s, 1 H), 3.42 (m, 2H), 3.32 (m, 2H) ), 2.25 (m, 2H), 2.10 (m, 2H) Analysis of the mass spectrum m / z = 268.1 (M + H) + EXAMPLE 31W 31W was obtained according to a procedure similar to that described for 31A, with the following exceptions: Stage 31.1: 13.1 it was replaced by 31.1t. Step 31.2: Procedure 1 F was used. 1 H NMR (400MHz, DMSO dβ) d 9.34 (ma, 1.5H), 8.12 (d, 1H), 7.60 (m, 6H), 7.42 (,, 1H), 7.32 (,, 1H), 7.22 (,, 1H), 7.02 (d, 1H), 6.89 (m, 2H), 6, 81 (d, 1H), 5.98 (s, 1H), 3.41 (sa, 2H), 2.20 (ma, 6H) Analysis of the mass spectra m / z = 457.1 (M + H) EXAMPLE 31X 31X was made according to a procedure similar to that described for 31A, with the following exceptions: Stage 31.1: 13.1 was replaced by 31.1 u. Step 31.2: Procedure 1 was used E. 1 H NMR (400MHz, DMSO dβ) d 8.93 (m, 2H), 8.03 (d, 1H), 7.42 (d, 1 H), 7.32 (m, 2H), 7.05 (m, 2H), 6.25 (s, 1 H), 3.22 (m, 4H), 2.03 (m, 4H) Analysis of the mass spectrum m / z = 308.8 (M + H) + EXAMPLE 31Y Preparation of 31Y: A solution of 16.2 (0.200 g, 0.0046 mol, 1.0 eq) in tetrahydrofuran (50 mL) was added dropwise to a cold suspension ( 0 ° C) of lithium aluminum hydride (1.05 g, 0.027 mol, 6.0 eq) in hydrofuran (50 mL). The mixture was allowed to warm to ambient temperature and heated to reflux temperature for 12 h in a niosogenic atmosphere. The reaction was cooled to ambient temperature and quenched by the careful addition of water (3 mL). The mixture was stirred for 1 h at room temperature and filtered at iovés de Cellie. The Celiie was further rinsed with acetone heat. Evaporation of the filtrate gave an oil which was dissolved in diethyl ether (20 mL). To the mixture was added a solution of 2.0M hydrochloric acid in anhydrous diethyl ether (6.9 mL, 0.0138 mol, 3.0 eq). The resulting precipitate was collected by filtration and washed with diethyl ether. Yield: 70% 1 H NMR (400MHz, DMSO d6) d 8.60 (m, 1 H), 8.40 (m, 2H), 7.50 (m, 3H), 7.35 (m, 1H), 7.25 (m, 1H), 6.90-7.10 (m, 3H), 5.80 (s, 1 H), 4.10 (m, 2H), 3.30 (m, 7H), 2.10 (m, 4H) Analysis of the mass spectra m / z = 321, 1 (M + H) + EXAMPLE 31Z Preparation of 31 Z: Acetyl chloride (0.14 mL, 0.0019 mol, 1, 5 eq) was added drop wise to a cold solution of 31Y (salt of dihydric acid) (0.500 g, 0.0012 mol, 1.0 eq) and triethylamine (0.90 mL, 0.006 mol, 5.0 eq) in dichloromethane (10 mL). The mixture was allowed to warm to room temperature and stirring was continued for 12 hours at ambient temperature. The mixture was poured into water and ethyl acetate (30 mL) was added. The organic phase was separated, washed with brine, dried over sodium sulfate, filtered and evaporated. The crude production was purified by column chromatography (eluent: dichloromethane / methanol, mixtures of increasing polarity). The purified compound was dissolved in diethyl ether (20 mL). To the mixture was added a solution of anhydrous hydrochloric acid 2.0M in diethyl ether (1.8 mL, 0.0036 mol, 3.0 eq). The precipitate resulfanfe was collected by filtration and washed with diethyl ether. Yield: 31% 1 H NMR (400MHz, DMSO dβ) d 10.70 (m, 1 H), 8.35 (m, 1 H), 7.35 (m, 1 H), 7.20-7.30 (m) m, 3H), 7.05 (m, 1H), 6.90 (m, 3H), 5.75 (s, 1 H), 4.20 (s, 2H), 3.30 (m, 4H) , 2.80 (s, 3H), 2.15 (m, 4H), 1.85 (s, 3H) Mass spectral analysis m / z = 363.1 (M + H) + EXAMPLE 31AA Preparation of 31 AA Meyenosulfonyl chloride (0.15 mL, 0.0019 mol, 1.5 eq) was added as desired to a cold solution of 31Y (dihydrochloric acid salt) (0.500 g, 0.0012 mol, 1.0). eq) and eryrylamine (0.90 mL, 0.006 mol, 5.0 eq) in dichloromethane (10 mL). The mixture was allowed to cool to ambient temperature and the stirring was continued for 12 hours at room temperature. The mixture was poured into water and ethyl acetate (30 mL) was added.

The organic phase was separated, washed with brine, dried over sodium sulfate, filtered and evaporated. The crude production was purified by column chromatography (eluent: mixtures of dichloromean / meianol of increasing polarity). The purified compound was dissolved in diethyl ether (20 mL). To the mixture was added a solution of anhydrous hydrochloric acid 2.0M in diethyl ether (1.8 mL, 0.0036 mol, 3.0 eq). The resulting precipitate was collected by filtration and washed with diethyl ether. Yield: 30% 1H NMR (400MHz, DMSO d6) d 10.90 (m, 1 H), 7.40 (m, 2H), 7.35 (m, 1 H), 7.30 (m, 2H) , 7.10 (m, 1 H), 7.00 (m, 2H), 5.75 (s, 1 H), 4.20 (d, 2H), 3.30 (m, 4H), 2, 90 (s, 3H), 2.80 (s, 3H), 2.10 (m, 4H) Analysis of the mass spectrum m / z = 399.1 (M + H) + EXAMPLE 32A Preparation of 32.1: A Dissolution of bis (pinacolato) of diborium 1.14 (14.7g, 57.8 mmol, 2.0 eq) in N -dimethylformamide (200 mL) at room temperature under nihorogen was added to the chloride complex of 1.1. Palladium (II) -bis (diphenylphosphino) ferrocene with dichloromethane (710 mg, 0.867 mmol, 0.03 eq) followed by the addition of polasium acephalous (8.58 g, 86.7 mmol, 3.0 eq. ) The mixture was heated at 80 ° C followed by the gola-drop addition of a solution of enol triflate 1.5a (13.0 g, 28.9 mmol, 1.0 eq) in N, N-dimethylformamide (100 mL) . After the addition was complete, the reaction mixture was heated at 80 ° C for a further 16h. The solvent was evaporated in vacuo and the residue was added to an aqueous 1N hydrochloric acid solution. The aqueous residue was extracted with ethyl acetate. The organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give a brown semi-solid. The crude product was purified by column chromatography (eluyenie: hexane / ethyl acetate mixtures of increasing polarity). Yield: 96.0% 1 H NMR (400MHz, CDCl 3) 7.71 (d, 1 H), 7.11 (1, 1 H), 6.90 (t, 1H), 6.83 (d, 1) H), 6.28 (s, 1 H), 3.84 (sa, 2H), 3.27 (ma, 2H), 1, 96 (d, 2H), 1, 60 (m, 2H), 1 , 34 (s, 9H), 1, 26 (s, 12H) Analysis of the mass spectrum m / z - 428.0 (M + H) + Preparation of 32.2a: To a solution of 4-bromophenylacetic acid (32.4) (3.21 g, 15 mmol) in methylene chloride (300 mL) was added diethylamine (1.12) (3.2 mL, 30 mmol, 2.0 eq) followed by triethylamine (8.4 mL, 60 mmol, 4.0 eq) and the Mukaiyama acylase reactive (2-chloro-1-methyl-pyridinium iodide) (4.61 mg, 18 mmol, 1.2 eq). The reaction mixture was stirred at room temperature overnight and the mixture was washed with a saturated aqueous sodium bicarbonate solution, dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (eluent: hexane / methylene chloride / ethyl acetate, 2: 1: 1). Yield: 89.2% 1 H NMR (400MHz, CDCl 3) 57.43 (d, 2H), 7.15 (d, 2H), 3.63 (s, 2H), 3.40 (c, 2H), 3 , 30 (c, 2H), 1, 10 (1, 3H) Preparation of 32.3a: To a solution of 32.1 (2.14 g, 5 mmol) in dimethoxyethane (DME) (40 mL) was added sequentially a solution aqueous 2N sodium carbonate (8 mL, 16 mmol, 3.2 eq), lithium chloride (679 mg, 16 mmol, 3.2 eq.), 32.2a (1.62 mg, 6 mmol, 1.2 eq) ) and palladium (0) tetrakis (triphenylphosphine) (174 mg, 0.15 mmol, 0.03 eq). The mixture was heated to reflux temperature overnight under a nitrogen atmosphere. The mixture was then cooled to ambient temperature and water (50 mL) was added. The mixture was extracted with ethyl acetate. The organic phase was further washed with brine, dried over sodium sulfate and concentrated in vacuo. The crude product was purified by column chromatography (eluent: hexane / ethyl acetate, 1: 1). Yield: 61% 1 H NMR (400MHz, CDCl 3) d 7.29 (s, 4H), 7.18 (t, 1 H), 7.03 (d, 1H), 6.95 (d, 1H), 5.86 (1, 1H), 5.53 (s, 1H), 3.86 (m, 2H), 3.72 (s, 2H), 3.39 (m, 6H), 2 , 05 (m, 2H), 1, 68 (m, 2H), 1.49 (s, 9H), 1.16 (m, 6H) Preparation of 32A: To a solution of 32.3a (1.4 g, 3.38 mmol) in methylene chloride (15 g). mL) was added a solution of anhydrous hydrochloric acid 2.0M in diethyl ether (50 mL). The mixture was stirred at ambient temperature for 24 h and diluted by the addition of diethyl ether. The resulting precipitate was collected by filtration and washed with diethyl ether. Yield: 92% 1 H NMR (400MHz, DMSO d6) d 9.20 (m, 2H), 7.20 (s, 4H), 7.24 (m, 1H), 7.00 (m, 3H), 5.83 (s, 1H), 3.40-3.20 (m, 8H), 2.03 (m, 4H), 1, 08 (m, 6H) Analysis of the mass spectra m / z = 391, 3 (M + H) + EXAMPLE 32B 32B was made according to a procedure similar to that described for 32A, with the following exceptions: Stage 32.2: 32.2a was suspended by 32.2b and the procedure was used. 10 Noia: 32.2b was done according to a procedure similar to that described for 32.2e (see 32E) except that 13.4b was subsumed by 1.12 in step 32.8. 1 H NMR (400MHz, DMSO d6) d 9.02 (br s, 2H), 8.88 (s, 2H), 8.57 (s, 2H), 7.23 (s, 1 H), 7.05 ( s, 1 H), 6.91 (s, 2H), 6.00 (s, 1 H), 3.32 (s, 4H), 3.12 (sa, 4H), 2.08 (m, 4H) ), 1, 02 (day, 6H) Mass spectral analysis m / z = 454.0 (M + H) + Elemental analysis: C23H28N2O3S, 1 HCI, 1 / 3H2O Theoretical:% C 60.71; % H 6.57; % N 6.16 Found:% C 60.64; % H 6.36; % N 6.16 EXAMPLE 320 32C was obfuscated according to a procedure similar to that described for 32A, with the following exceptions: Eiapa 32.2: 32.2a was replaced by 32.2c and Procedure 1D was used. Noia: 32.2c was worked out according to a procedure similar to that described for 32.2e (see 32E) except that 13.4b was subsumed by 3.4c in step 32.8. 1 H NMR (400MHz, DMSO d6) d 9.00 (br s, 2H), 7.86 (d, 2H), 7.68 (l, 1 H), 7.60 (d, 2H), 7.28 (m, 1 H), 7.06 (d, 1 H), 6.96 (d, 2H), 6.01 (s, 1 H), 3, 21 (ma, 4H), 2.81 (m, 2H), 2.10 (ma, 2H), 2.01 (ma, 2H), 1, 00 (i, 3H) Analysis of the mass spectrum m / z = 385.3 (M + H) + Elemental analysis: C21H24N2O3S, 1 HCI, 0.25H2O Theoretical:% C 59.28; % H 6.04; % N 6.58 Found:% C 59.06; % H 5.92; % N 6.44 EXAMPLE 32D 32D was obtained according to a procedure similar to that described for 32A, with the following exceptions: Eíapa 32.2: 32.2a was replaced by 32.2d. Note: 32.2d was obtained according to a procedure similar to that described for 32.2e (see 32E) except that 13.4b was subsumed by 32.6 in step 32.8. 1 H NMR (400MHz, DMSO d ") d 9.13 (br s, 2H), 7.90 (d, 2H), 7.64 (s, 1H), 7.56 (d, 2H), 7.27 ( m, 1H), 7.06 (d, 1 H), 6.95 (m, 2H), 6.01 (s, 1H), 3.22 (m, 4H), 2.07 (ma, 4H), 1.12 (s, 9H) Analysis of the mass spectrum m / z = 413.3 (M + H) + EXAMPLE 32E Preparation of 32.2e: 13.4b (7.33 mL, 64.58 mmol, 3.3 eq) was added at ambient temperature to a solution of 32.5 (5 g, 19.57 mmol, 1 eq) in tetrahydrofuran (20 mL). The reaction was stirred a. Ambience throughout the night. The mixture was concentrated under reduced pressure and dichloromethane was added. The mixture was washed with water, a saturated aqueous solution of sodium bicarbonate and brine, and then dried over sodium sulfate and filtered. The organic exiphats were concentrated under reduced pressure and the crude product was used in the next step without further purification. Yield: 40% 1 H NMR (400MHz, DMSO dβ) d 7.82 (s, 4H), 7.25 (s, 4H), 4.58 (s, 4H) Mass spectral analysis m / z = 337, 9 (M + H) + Preparation of 32E: 32E was made according to a procedure similar to that described for 32A, with the following exceptions: Eíapa 32.2: 32.2a was subsituted by 32.2e.

H-NMR (400MHz, DMSO dβ) d 9.06 (br s, 2H), 7.94 (d, 2H), 7.60 (d, 2H), 7.26 (m, 5H), 7.04 (d , 1 H), 6.90 (m, 2H), 5.97 (s, 1 H), 4.62 (s, 4H), 3.19 (ma, 4H), 2.03 (ma, 4H) Analysis of the mass spectrum m / z = 459.3 (M + H) + EXAMPLE 32F 32F was done according to a procedure similar to that described for 32A, with the following exceptions: Stage 32.2: 32.2a was subsituted by 32.2f. Note: 32.2f was obtained according to a procedure similar to that described for 32.2e except that 13.4b was replaced by 3.4e in step 32.8. 1 H NMR (400MHz, DMSO d6) d 9.04 (sa, 2H), 7.86 (d, 2H), 7.72 (t, 1H), 7.59 (d, 2H), 7.28 (m , 1 H), 7.06 (d, 1 H), 6.95 (d, 2H), 6.01 (s, 1 H), 3.22 (ma, 4H), 2.57 (t, 2H) ), 2.10 (ma, 2H), 2.02 (ma, 2H), 1.65 (m, 1 H), 0.83 (d, 6H) Analysis of the mass spectrum m / z = 413.3 (M + H) + Elemental Analysis: C23H28N2O3S, 1 HCl, 0.5H2O Theoretical:% C 60.31; % H 6.60; % N 6.12 Found:% C 60.67; % H 6.33; % N 6.10 EXAMPLE 32G 32G was obtained according to a procedure similar to that described for 32A, with the following exceptions: Eiapa 32.2: 32.2a was subsituted for 32.2g and Procedure 1 D was used. 32.2g was done according to a similar procedure to that description for 32.2e exception that 13.4b was subsumed by 3.4h in stage 32.8. 1 H NMR (400MHz, DMSO dB) 9.16 (sa, 2H), 7.87 (d, 2H), 7.70 (d, 1H), 7.59 (d, 2H), 7.28 (m) , 1 H), 7.06 (d, 1 H), 6.95 (m, 2H), 6.01 (s, 1 H), 3.24 (m, 5H), 2.07 (m, 4H ), 0.98 (d, 6H) Analysis of the mass spectra m / z = 399.4 (M + H) + Elemenfal analysis: C22H26N2? 3S, 1 HCI Theory:% C 60.75; % H 6.26; % N 6.44 Found:% C 60.58; % H 6.29; % N 6.36 EXAMPLE 32H 32H was done according to a procedure similar to that described for 32A, with the following exceptions: Efapa 32.2: 32.2a was subscribed for 32.2h. 32.2h was obtained according to a procedure similar to that described for 32.2e except that 13. 4b was subsumed by 3.4o in step 32.8. 1 H NMR (400MHz, DMSO dß) d 9.09 (br s, 2 H), 7.89 (d, 2 H), 7.58 (d, 2 H), 7.28 (m, 1 H), 7.06 (d, 1 H), 6.94 (m, 2H), 6.02 (s, 1 H), 3.76 (m, 2H), 3, 22 (ma, 4H), 2.05 (ma, 4H), 1, 20 (d, 12H) Analysis of the mass spectra m / z = 441, 4 (M + H) + EXAMPLE 32I 32I was done according to a procedure similar to that described for 32A, with the following Exceptions: Eíapa 32.2: 32.2a was subsumed by 32.2i. 32.2i was done according to a procedure similar to that described for 32.2e, except that 13. 4b was subsumed by 13.4c in step 32.8. 1 H NMR (400MHz, DMSO dβ) 9.03 (br s, 2H), 7.66 (d, 2H), 7.38 (d, 2H), 7.08 (m, 1 H), 6.86 ( d, 1 H), 6.74 (m, 2H), 5.81 (s, 1 H), 3.00 (m, 6H), 2.82 (d, 2H), 1.87 (m, 4H ), 1.37 (m, 2H), 0.71 (m, 1 H), 0.65 (t, 3H), 0.27 (m, 2H), 0.01 (m, 2H) Spectrum analysis mass m / z = 453.3 (M + H) + EXAMPLE 32J Preparation of 32 J: Trifluoroacetic acid (5 mL, 64.90 mmol, 10.0 eq) was added dropwise to 32.3 b (3, 83 g, 7.47 mmol, 1.0 eq) at 0 ° C. The mixture was warmed to room temperature and stirring was continued for a further 10 h at room temperature. The mixture was concentrated under reduced pressure. A saturated solution of sodium bicarbonate (50 mL) was added to the mixture, which was then extracted with dichloromethane. The organic phase was separated, washed with brine, dried over sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. To a cold solution (0 ° C) of the resulting oil in anhydrous dichloromethane (35 mL) was added dropwise a solution of anhydrous hydrochloric acid 2.0M in diethylether (17 mL, 35.70 mmol, 5.5 eq) . The mixture was then stirred for 1 h at room temperature and concentrated under reduced pressure. Diethyl ether was added. The resulting precipitate was collected by filtration and washed with diethyl ether. The crude product was purified by column chromatography (eluent: mixtures of dichloromethane / methanol of increasing polarity). Yield: 10% 1 H NMR (400MHz, DMSO dβ) d 9.08 (m, 2H), 7.90 (m, 2H), 7.56 (m, 2H), 7.46 (m, 2H), 7 , 28 (m, 1 H), 7.07 (m, 1 H), 6.94 (m, 2H), 5.98 (s, 1 H), 3.46 (m, 2H), 3.17 (m, 2H), 2.05 (m, 4H) Analysis of the mass spectrum m / z = 357.4 (M + H) + Elemental analysis: C19H20N2O3S, 1 HCl, 1 H 2 O Theory:% C 55.54; % H 5.64; % N 6.82 Found:% C 55.30; % H 5.28; % N 6.55 EXAMPLE 32K Preparation of 32.9a: The iris (0.96 mL, 6.88 mmol, 1.3 eq) was added to a solution of 20.2a (0.40 mL, 5.29 mmol, 1 , 0 eq) and 32.7 (1.0 g, 5.29 mmol, 1.0 eq) in acetoniiril (60 mL). The solution was heated at reflux temperature for 1 h and then concentrated under reduced pressure. Methylene chloride was added and the organic mixture was washed with water. The organic mixture was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was used in the next step without further purification. Yield: 93% 1 H NMR (400MHz, CDCl 3) 7.40 (d, 2H), 7.18 (d, 2H), 2.92 (c, 2H), 1.31 (1, 3H) Preparation of 32.2 j: To a solution of 32.9a (1.07 g, 4.93 mmol, 1.0 eq) in acetic acid (7 mL) was added an aqueous solution of 30% hydrogen peroxide (3 mL). The mixture was heated at 90 ° C for 2 h. The mixture was cooled to room temperature. Water was added and the mixture was extracted with methylene chloride. The organic mixture was then washed with a saturated aqueous solution of sodium thiosulfate and brine. The organic mixture was dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The crude product was used in the next step without further purification. Performance: 92% 1H NMR (400MHz, CDCl3) 7.78 (d, 2H), 7.72 (d, 2H), 3.11 (c, 2H), 1, 28 (t, 3H) Preparation of 32K: 32K was obtained according to a similar procedure to that described for 32A, with the following exceptions: Stage 32.2: 32.2a was subsumed by 32.2j and Procedure 1 D was used. 1 H NMR (400MHz, DMSO dB) d 8.86 (sa, 1H), 7.96 (d, 2H), 7.66 (d, 2H), 7.29 (m, 1 H), 7.07 (d, 1H), 6.96 (d, 2H), 6.04 (s, 1 H), 3.37 (m, 2H), 3.22 (m, 4H), 2.10 (m, 2H), 2.00 (m, 2H), 1, 13 (1, 3H) Mass spectral analysis m / z 370.2 (M + H) + Elemental analysis: C21 H23NO3S, 1 HCl, 0.33H2O Theoretical :% C 61, 23; % H 6.04; % N 3.40; % S 7.78 Found:% C 61.15; % H 5.92; % N 3.39; % S 7.68 EXAMPLE 32L 32L was made according to a procedure similar to that described for 32A, with the following exceptions: Eíapa 32.2: 32.2a was subsumed by 32.2k and Procedure 12A was used. Noia: 32.2k was worked according to a procedure similar to that described for 32.2j except that 20.2a was subsumed by 20.2b in step 32.6. 1 H NMR (400MHz, DMSO d6) d 8.92 (br s, 1H), 7.96 (d, 2H), 7.66 (d, 2H), 7.29 (m, 1 H), 7.07 ( d, 1 H), 6.96 (d, 2H), 6.04 (s, 1 H), 3.31 (m, 2H), 3.22 (m, 4H), 2.10 (m, 2H) ), 2.00 (m, 2H), 1.58 (m, 2H), 0.94 (t, 3H) Mass spectral analysis m / z = 384.2 (M + H) + Elemental analysis: C22H25N 3S, IHCl, 0.5H2O Theory:% C 61, 60; % H 6.34; % N 3.27; % S 7.47 Found:% C 61, 88; % H 6.28; % N 3.36; % S 7.36 EXAMPLE 32M 32M was worked up according to a procedure similar to that described for 32A, with the following exceptions: Step 32.2: 32.2a was replaced by 32.21 and Procedure 12A was used. Note: 32.21 was obtained according to a procedure similar to that described for 32.2J except that 20.2a was subscribed for 2.8a in stage 32.6. 1 H NMR (400MHz, DMSO d6) 8.93 (sa, 1 H), 7.97 (d, 2H), 7.65 (d, 2H), 7.29 (m, 1H), 7.07 ( d, 1 H), 6.95 (m, 2H), 6.04 (s, 1 H), 3.32 (m, 2H), 3.22 (m, 4H), 2.10 (m, 2H) ), 2.01 (m, 2H), 0.87 (m, 1 H), 0.47 (m, 2H), 0.13 (m, 2H) Analysis of the mass spectrum m / z = 396.2 (M + H) + Elemental Analysis: C23H25NO3S, 1 HCI Theoretical:% C 63.95; % H 6.07; % N 3.24; % S 7.42 Found:% C 63.94; % H 6.03; % N 3.32; % S 7.32 EXAMPLE 32N 32N was obtained according to a procedure similar to that described for 32A, with the following exceptions: Step 32.2: 32.2a was replaced by 32.2m and Procedure 12A was used. Note: 32.2m was obtained according to a procedure similar to that described for 32.2j except that 20.2a was subsituted by 32.8a in step 32.6. 1 H NMR (400MHz, DMSO d6) 8.91 (br s, 1 H), 7.98 (d, 2H), 7.66 (d, 2H), 7.29 (m, 1 H), 7.07 (d, 1 H), 6.96 (m, 2H), 6.04 (s, 1 H), 3.32 (m, 2H), 3, 22 (m, 4H), 2.10 (m, 2H), 2.02 (m, 2H), 1.62 (m, 1H), 1.46 (m, 2H), 0.84 (d, 6H) Analysis of the mass spectrum m / z = 412.2 (M + H) + Elemental analysis: C24H29NO3S, 1 HCI, 0.33H2O Theoretical:% C 63.49; % H 6.81; % N 3.08 Found:% C 63.45; % H 6.71; % N 3.39 EXAMPLE 320 320 was obtained according to a procedure similar to that described for 32A, with the following exceptions: Eiapa 32.2: 32.2a was suspended by 32.2n and Procedure 12A was used. Noia: 32.2n was worked according to a procedure similar to that described for 32.2p (see 32Q) except that 32.8d was subscribed by 32.8b in step 32.6. 1 H NMR (400MHz, DMSO dβ) d 8.93 (ma, 1 H), 7.98 (d, 2 H), 7.64 (d, 2 H), 7.29 (m, 1 H), 7.07 (d, 1 H), 6.94 (m, 2H), 6.02 (s, 1 H), 3.32 (m, 2H), 3.22 (m, 4H), 2.10 (m, 2H), 2.01 (m, 2H), 1, 10 (s, 9H) Mass spectrum analysis m / z = 412.2 (M + H) + Elemental analysis: C24H29NO3S, 1 HCI, 0.33H2O Theoretical:% C 63.49; % H 6.81; % N 3.08; % S 7.06 Found:% C 63.49; % H 6.70; % N 3.25; % S 6.78 EXAMPLE 32P 32P was obtained according to a procedure similar to that described for 32A, with the following exceptions: Step 32.2: 32.2a was replaced by 32.2o and Procedure 12A was used. Noia: 32.2o was done according to a procedure similar to that described for 32.2p (see 32Q) except that 32.8d was subsituted by 32.8c in step 32.6. 1 H NMR (400MHz, DMSO dB) d 8.82 (br s, 2H), 7.93 (d, 2H), 7.66 (d, 2H), 7.29 (m, 1H), 7.07 (d , 1H), 6.96 (m, 2H), 6.05 (s, 1H), 3.47 (m, 1H), 3.23 (m, 4H), 2.10 (m, 2H), 2 , 00 (m, 2H), 1, 19 (d, 6H) Mass spectral analysis m / z = 384.2 (M + H) + Elemental analysis: C22H25NO3S, 1 HCI Theoretical:% C 62.92; % H 6.24; % N 3.34; % S 7.63 Found:% C 63.18; % H 6.26; % N 3.46; % S 7.54 EXAMPLE 32Q Preparation of 32.9b: To a suspension of sodium hydride (0.33 g, 13.75 mmol, 1.3 eq) in? /,? -dimeiiformamide (10 mL) at 0 ° C in Nitrogen was added dropwise to a solution of 32.7 (2.0 g, 10.58 mmol, 1.0 eq) in / V,? / - dimethylformamide (5 mL). The mixture was stirred for 10 min at 0 ° C and 32.8d (1.48 mL, 10.58 mmol, 1.0 eq) was added drop wise. The mixture was allowed to warm up at ambient temperature and the stirring was continued for an additional 16 hours at ambient temperature. The reaction was carefully quenched with water and the mixture was extracted with diethyl ether. The organic extracts were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was used in the next layer without further purification. Yield: 87% 1 H NMR (400MHz, CDCl 3) 7.38 (d, 2H), 7.18 (d, 2H), 2.87 (d, 2H), 1.45 (m, 5H), 0, 88 (í, 6H) Preparation of 32.2p: To a solution of 32.9b (2.53 g, 9.26 mmol, 1.0 eq) in acetic acid (14 mL) was added an aqueous solution of 30% hydrogen peroxide ( 6 mL). The mixture was heated at 90 ° C for 2 h. The mixture was cooled to room temperature. Water was added and the crude product was extracted with methylene chloride. The organic mixture was washed with a saline aqueous solution of sodium oliosulfate and brine. The mixture was dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The crude product was used in the next step without further purification. Yield: 80% H NMR (400MHz, CDCl 3) d 7.78 (d, 2H), 7.71 (d, 2H), 3.00 (d, 2H), 1.88 (m, 1H), 1, 46 (m, 4H), 0.82 (t, 6H) Preparation of 32Q: 32Q was obtained according to a procedure similar to that described for 32A, with the following exceptions: Step 32.2: 32.2a was suspended by 32.2p and Procedure 12A was used. (32Q) 1 H NMR (400MHz, DMSO d6) d 8.97 (sa, 2H), 7.99 (d, 2H), 7.65 (d, 2H), 7.29 (m, 1 H), 7.07 (d, 1 H), 6.94 (m, 2H), 6.03 (s, 1 H), 3.23 (m, 6H) , 2.10 (m, 2H), 2.02 (m, 2H), 1.73 (m, 1 H), 1.40 (m, 4H), 0.77 (t, 6H) Analysis of the spectrum of masses m / z = 426.2 (M + H) + Elemental analysis: C25H31 NO3S, 1HCI, 0.33H2O Theoretical:% C 64.15; % H 7.03; % N 2.99; % S 6.85 Found:% C 64.26; % H 6.91; % N 3.20; % S 6.35 EXAMPLE 32R Preparation of 32.2q: To a solution of 4-bromo-? / - methylaniline of (32.0) (0.74 g, 4 mmol, 1.0 eq) in dry dichloromethane (50 mL ) at 0 ° C triethylamine (2.23 mL, 8 mmol, 2.0 eq) was added slowly. The mixture was stirred for 10 min at ambient temperature and 19.8a (0.63 mL, 6 mmol, 1.5 eq) was added dropwise to the reaction mixture. The reaction mixture was slowly warmed to room temperature and stirred for 10 h at room temperature. Dichloromethane (100 mL) was added to the mixture, which was washed with an aqueous solution of hydrochloric acid 1 (3 x 50 mL), a saturated aqueous solution of sodium bicarbonate (2 x 50 mL) and brine. The organic extracts were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product, which were used in the next step without purification. 1 H NMR (400MHz, CDCl 3) d 7.56 (m, 2H), 7.08 (m, 2H), 3.23 (s, 3H), 2.49 (m, 1H), 1.02 (d, 6H) Analysis of the mass spectrum m / z = 256.15 (M + H) + Preparation of 32R: 32R was obtained according to a procedure similar to that described for 32A, with the following exceptions: Eíapa 32.2: 32.2a it was subsumed by 32.2q and Procedure 1D was used. 1 H NMR (400MHz, DMSO dβ) d 8.91 (br s, 2H), 7.43 (m, 4H), 7.27 (m, 1H), 7.01 (m, 3H), 5.96 (s, 1 H), 3.40-3.14 (m, 8H), 2.04 (m, 4H), 0.96 (m, 6H) Analysis of the mass spectrum m / z = 377.3 (M + H) + Elemental analysis: C24H28N2O3, 1 HCl, 2 / 3H2O Theoretical:% C 67.83; % H 7.19; % N 6.59 Found:% C 67.78; % H 7.19; % N 6.50 EXAMPLE 32S 32S was done according to a procedure similar to that described for 32A, with the following exceptions: Eíapa 32.2: 32.2a was subsumed by 32.2r and Procedimento 1 D was used. Ñola: 32.2r was made according to a procedure similar to that described for 32.2q except that 19.8a was subsumed by 19.8b in step 32.9. 1 H NMR (400MHz, DMSO d6) d 8.98 (br s, 2H), 7.47 (m, 2H), 7.33 (m, 2H), 7.27 (m, 1H), 7.00 (m , 3H), 5.96 (s, 1 H), 3.40-3.12 (m, 7H), 2.25-1, 94 (m, 5H), 1.48 (m, 2H), 1 , 30 (m, 2H), 0.76 (m, 6H) Mass spectrum analysis m / z = 405.4 (M + H) + Elemental analysis: C26H32N2O2, 1 HCl, 1 / 5H2O Theoretical:% C 70 , 24; % H 7.57; % N 6.30 Found:% C 70.20; % H 7.50; % N 6,19 EXAMPLE 32T 32T was obtained according to a procedure similar to that described for 32A, with the following exceptions: Eíapa 32.2: 32.2a was subsumed by 32.2s and Procedure 1 D was used. Note: 32.2s was obtained according to a procedure similar to that described for 32.2q except that 19.8a was subsumed by 32.11a in step 32.9. 1 H NMR (400MHz, DMSO dβ) d 8.95 (br s, 2H), 7.44 (br, 2H), 7.37 (br, 2H), 7.27 (br, 1H), 7.00 (br , 3H), 5.96 (s, 1 H), 3.21 (m, 7H), 2.03 (m, 7H), 0.81 (m, 6H) Mass spectrum analysis m / z - 391 , 3 (M + H) + Elemental Analysis: C25H30 2O2, 1 HCl, 0.1H2O Theoretical:% C 70.03; % H 7.33; % N 6.53 Found:% C 69.97; % H 7.33; % N 6.57 EXAMPLE 32U 32U was obtained according to a procedure similar to that described for 32A, with the following exceptions: Eíapa 32.2: 32.2a was subsumed by 32.2t and Procedure 1 D was used. Noia: 32.2t was produced according to a procedure similar to that described for 32.2q except that 19.8a was subsumed by 6.7 in stage 32.9. 1 H NMR (400MHz, DMSO d6) d 8.95 (m, 2H), 7.42 (m, 4H), 7.26 (m, 1H), 7.00 (m, 3H), 5.93 (s) , 1 H), 3.20 (m, 7H), 2.04 (m, 4H), 1.83 (s, 3H) Mass spectrum analysis / z = 349.2 (M + H) + Elemental analysis : C2 H2 N2O2, 1 HCl, 1, 4H2O Theoretical:% C 64.43; % H 6.83; % N 6.83 Found:% C 64.49; % H 6.87; % N 6.89 EXAMPLE 32V 32V was obtained according to a procedure similar to that described for 32A, with the following exceptions: Stage 32.2: 32.2a was replaced by 32.2u and Procedure 1D was used. Noia: 32.2u was obtained according to a procedure similar to that described for 32.2q except that 19.8a was subsumed by 32.11b in step 32.9. 1 H NMR (400MHz, DMSO dβ) d 8.95 (m, 2H), 7.42 (m, 4H), 7.26 (m, 1 H), 7.05 (m, 1H), 6.96 ( m, 2H), 5.94 (s, 1 H), 3.20 (m, 7H), 2.05 (m, 6H), 1.38 (m, 3H), 0.74 (m, 6H) Mass spectrum analysis m / z = 405.3 (M + H) + Elemental analysis: C26H32N2O2, 1 HCl, 1.5H2O Theoretical:% C 66.72; % H 7.75; % N 5.99 Found:% C 66.57; % H 7.67; % N 5.93 EXAMPLE 32W 32W was made according to a procedure similar to that described for 32A, with the following exceptions: EIApa 32.2: 32.2a was subsumed by 32.2v and Procedure 1 D. Noia was used: 32.2v is commercially available. 1 H NMR (400MHz, DMSO d6) 8.91 (sa, 2H), 7.74 (m, 2H), 7.37 (m, 2H), 7.25 (m, 1 H), 7.02 (m, 2H), 6.94 (m, 1 H), 5.86 (s, 1 H), 3.87 (I, 2H), 3, 20 (m, 4H), 2.52 (t, 2H), 2.08 (m, 4H), 1.99 (m, 2H) Mass spectrum analysis m / z = 361, 2 (M + H) + Elemental analysis: C23H2 N2O2, 1 HCl, 0.5H2O Theoretical:% C 68.06; % H 6.46; % N 6.90 Found:% C 68.10; % H 6.42; % N 6.96 EXAMPLE 32X 32X was obtained according to a procedure similar to that described for 32A, with the following exceptions: Eiapa 32.2: 32.2a was suspended by 32.2w and Procedure 1D was used. Note: 32.2w is commercially available. 1 H NMR (400MHz, DMSO d6) 8.82 (sa, 2H), 8.07 (d, 1H), 7.24 (m, 2H), 7.14 (d, 1 H), 7.02 (m, 2H), 6.94 (m, 1 H), 5.82 (s, 1 H), 4.13 (I, 2H), 3, 19 (m, 6H), 2.18 (s, 3H), 2.06 (m, 2H), 1.96 (m, 2H) Mass spectral analysis m / z - 361, 3 (M + H) + Elemental analysis: C23H24N2O2, 1 HC1, 0.4H2O Theoretical:% C 68.36% H 6.44% N 6.93 Found:% C 68.41% H 6.23% N 6.93 EXAMPLE 32Y 32Y obtained according to a procedure similar to that described for 32A, with the following exceptions: Eíapa 32.2: 32.2a was replaced by 32.2x and Procedure 1 D was used. Note: 32.2x was obtained according to a procedure similar to that described for 32.2q that 19.8a was subsumed by 32.11c in stage 32.9. 1 H NMR (400MHz, DMSO d6) d 9.04 (sa, 2H), 7.41 (m, 4H), 7.26 (m, 1 H), 7.00 (m, 3H), 5.94 ( s, 1 H), 3.20 (m, 7H), 2.05 (m, 6H), 1.49 (m, 2H), 3.79 (m, 3H) Analysis of the mass spectrum m / z = 377.4 (M + H) + Elemental Analysis: C24H28N2O2, 1 HCl, 1, 1 H2O Theoretical:% C 66.61; % H 7.27; % N 6.47 Found:% C 66.51; % H 7.20; % N 6.39 EXAMPLE 32Z 32Z was obtained according to a procedure similar to that described for 32A, with the following exceptions: Eíapa 32.2: 32.2a was replaced by 32.2y and Procedure 1D was used. Noia: 32.2y was worked out according to a procedure similar to that described for 32.2q except that 19.8a was replaced by 32.11d in step 32.9. 1 H NMR (400MHz, DMSO dβ) d 8.98 (br s, 2 H), 7.41 (m, 4 H), 7.26 (m, 1 H), 7.00 (m, 3H), 5.94 (s, 1H), 3.20 (m, 7H), 2.05 (m, 6H), 1.46 (m, 2H), 1.18 (m , 2H), 3.79 (m, 3H) Analysis of the mass spectrum m / z = 391, 4 (M + H) + Elemental analysis: C25H3oN2O2, 1 HCl, 0.9H2O Theoretical:% C 67.75; % H 7.46; % N 6.32 Found:% C 67.71; % H 7.45; % N 6.30 EXAMPLE 33A 33A was made according to a procedure similar to that described for 32A, with the following exception: Eíapa 32.2: 32.2a was replaced by 33.1a (see also step 33.2). Noia: 33.1a is commercially available. 1 H NMR (400MHz, DMSO d6) 7.98 (d, 1 H), 7.89 (dd, 1 H), 7.84 (d, 1 H), 7.29 (m, 1 H), 7.01 (m, 2H), 6.42 (s, 1 H), 3.07 (m, 4H), 1.95 (m, 4H) Analysis of the spectrum of masses / z = 284.9 (M + H) + EXAMPLE 33B 33B was obtained according to a procedure similar to that described for 32A, with the following exceptions: Step 32.2: 32.2a was replaced by 33.1 b and Method 33A was used (see also the tab 33.2). Noia: 33.1b is commercially available. H NMR (400MHz, DMSO d6) 9.19 (m, 3H), 8.86 (m, 2H), 7.29 (m, 1H), 7.07 (m, 1 H), 6.97 ( m, 2H), 6.15 (s, 1 H), 3.22 (m, 4H), 2.08 (m, 4H) Analysis of the mass spectra m / z = 279.9 (M + H) + EXAMPLE 33C 33C was obtained according to a procedure similar to that described for 32A, with the following exceptions: Step 32.2: 32.2a was replaced by 33.1 c and Procedure 33A was used (see also step 33.2). Noia: 33.1c is commercially available. 1 H NMR (400MHz, DMSO d6) d 7.73 (m, 1 H), 7.21 (m, 1H), 6.90 (m, 5H), 5.94 and 5.88 (2s, 1 H rotamer ), 3.6-2.7 (m, 7H), 1.91 (m, 4H) Analysis of the mass spectra m / z = 282.0 (M + H) + EXAMPLE 33D 33D was done according to a similar procedure to that described for 32A, with the following exceptions: Stage 32.2: 32.2a was replaced by 33.1 d and Procedure 33A was used (see also paragraph 33.2). Noia: 33.1 d is available commercially. 1 H NMR (400MHz, DMSO dB) 58.87 (m, 2H), 7.80 (s, 2H), 7.56 (m, 1H), 7.32 (m, 2H), 7.26 (m, 1 H), 7.15 (m, 2H), 6.18 (s, 1 H), 3.30-3.07 (m, 4H) , 2.03 (m, 4H) Analysis of the mass spectra m / z = 362.9 (M + H) + EXAMPLE 33E 33E was done according to a procedure similar to that described for 32A, with the following exceptions: Eíapa 32.2: 32.2a was replaced by 33.1 e and Method 33A was used (see also tab 33.2). Note: 33.1 e is commercially available. 1 H NMR (400MHz, DMSO d6) d 8.99 (sa, 2H), 8.80 (s, 1H), 8.15 (m, 1H), 8.08 (m, 1H), 7.30 (m, 1H), 7.07 (m, 1 H), 6.96 (m, 2H), 6.17 (s, 1H), 3.23 ( m, 4H), 2.08 (m, 4H) Analysis of the mass spectrum m / z = 303.9 (M + H) + EXAMPLE 33F Preparation of 33.1f: To an agitated solution of 33.3 (3 g, 14.85 mmol, 1.0 eq) in acetyloiryl ( 20 mL) was added diisopropylethylamine (6.2 mL, 35.64 mmol, 2.4 eq) and diethylamine (1.12) (3.1 mL, 29.70 mmol, 2 eq) at ambient temperature. The mixture was stirred for 10 min at ambient temperature, cooled to 0 ° C and added with O-benzoyriazole-1-yl -? /, / V,? / ',? /' - tetramethyluronium tetrafluoroborate (TBTU). ) (5.72 g, 17.82 mmol, 1.2 eq) fractionally. The reaction mixture was heated slowly to room temperature and stirred for 10 h at room temperature. The volatiles were re-treated under reduced pressure and the residue was partitioned between ethyl acetate (200 mL) and an aqueous 1M sodium bicarbonate solution (100 mL). The organic phase was washed with an aqueous solution of 1M sodium bicarbonate (2 x 50 mL), an aqueous solution of 1M hydrochloric acid (3 x 50 mL) and brine. The organic phase was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (eluent: mixtures of hexane / ethyl acetate of increasing polarity). Yield: 100% 1 H NMR (400MHz, CDCl 3) 8.72 (d, 1H), 8.55 (d, 1 H), 7.87 (m, 1H), 3.56 (c, 2H), 3 , 27 (c, 2H), 1, 26 (t, 3H), 1, 16 (t, 3H) Analysis of the mass spectrum m / z = 256.81 (M + H) + Preparation of 33F: 33F was obtained according to a procedure similar to that described for 32A, with the following exceptions: Eíapa 32.2: 32.2a was replaced by 33.1f and Procedure 33A was used (see also paragraph 33.2). 1 H NMR (400MHz, DMSO d6) d 9.07 (br s, 2H), 8.65 (m, 2H), 7.80 (m, 1H), 7.29 (m, 1 H), 7.07 ( m, 1 H), 6.96 (m, 2H), 6.09 (s, 1H), 3.52-3.10 (m, 8H), 2.05 (m, 4H), 1.12 ( m, 6H) Analysis of the mass spectrum m / z = 378.3 (M + H) + EXAMPLE 33G Preparation of 33.1 g: To a stirred solution of 33.4 (3 g, 14.85 mmol, 1.0 eq) in Acrylonitrile (20 mL) was slowly added diisopropylethylamine (6.2 mL, 35.64 mmol, 2.4 eq) and dilerylamine (1.12) (3.1 mL, 29.70 mmol, 2 eq) at room temperature. The mixture was stirred for 10 min, cooled to 0 ° C and added with O-benzotriazole-1-yl- / V, / V, / V ', γ / -l-erylamyluronium tetrafluoroborate (TBTU) (5.72 g). 17.82 mmol, 1.2 eq) fractionally. The reaction mixture was heated slowly to room temperature and stirred for 10 hours at room temperature. The volatiles were re-treated under reduced pressure and the residue was partitioned between ethyl acetate (200 mL) and an aqueous solution of 1 M sodium bicarbonate (100 mL). The organic phase was washed with an aqueous solution of 1 M sodium bicarbonate (2 x 50 mL), an aqueous solution of 1M hydrochloric acid (3 x 50 mL) and brine. The organic phase was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (eluyenie: hexane / ethyl acetate mixtures of increasing polarity). Yield: 100% 1 H NMR (400MHz, CDCl 3) 7.64 (d, 1 H), 7.59 (dd, 1H), 7.52 (dd, 1H), 3.54 (c, 2H), 3 , 38 (c, 2H), 1, 25 (m, 6H) Analysis of the mass spectrum m / z = 256.7 (M + H) + Preparation of 33G: 33G was made according to a procedure similar to that described for 32A , with the following exceptions: Eíapa 32.2: 32.2a was replaced by 33.1 g and Procedure 33A was used (see also step 33.2). (33G) 1 H NMR (400MHz, DMSO d6) d 9.01 (m, 2H), 8.01 (m, 1H), 7.59 (m, 2H), 7.26 (m, 1 H), 7.13 (m, 1 H), 7.04 (m, 1H), 6.93 (m, 1 H), 6.11 (s, 1H) , 3.51-3.11 (m, 8H), 2.05 (m, 4H), 1.15 (t, 3H), 1, 06 (t, 3H) Mass spectrum analysis m / z = 378 , 2 (M + H) + EXAMPLE 33H 33H was worked up according to a procedure similar to that described for 32A, with the following exceptions: Eíapa 32.2: 32.2a was replaced by 33.1 h and Procedure 1D was used (see also paragraph 33.2) . Noia: 33.1 h was done according to a procedure similar to that described for 1.13 (see 1) except that 1.12 was replaced by 3.4j in stage 1.8 (see also paragraph 33.9). 1 H NMR (400MHz, DMSO d6) d 8.99 (sa, 1 H), 8.61 (d, 1 H), 7.91 (dd, 1H), 7.64 (d, 1 H), 7, 29 (m, 1 H), 7.06 (d, 1 H), 6.97 (m, 2H), 6.09 (s, 1H), 3.23 (m, 4H), 3.04 (s) , 3H), 2.99 (s, 3H), 2.11 (m, 2H), 2.02 (m, 2H) Analysis of the mass spectrum m / z = 350.2 (M + H) + Elemental Analysis : C2 H23N3O2, 1.35HCI, 0.8H2O Theory:% C 61, 06; % H 6.33; % N 10.17; % CI 11, 59 Found:% C 60.72; % H 6.23; % N 10.05; % C1 11,26 EXAMPLE 33! 331 was made according to a procedure similar to that described for 32A, with the following exceptions: Step 32.2: 32.2a was replaced by 33.1 i and Procedure 1D was used (see also step 33.2). Noia: 33.1 i was done according to a procedure similar to that described for 1.13 (see 1) except that 1.12 was subscribed by 3.4c in stage 1.8 (see also paragraph 33.9). 1 H NMR (400MHz, DMSO d6) 8.87 (m, 2H), 8.62 (d, 1H), 8.11 (d, 1H), 7.99 (dd, 1 H), 7.30 (m, 1 H), 7.08 (d, 1 H), 6.96 (m, 2H), 6.10 (s, 1 H), 3 , 35 (m, 2H), 3.24 (m, 4H), 2.11 (m, 2H), 2.02 (m, 2H), 1, 14 (1, 3H) Mass spectrum analysis m / z = 350.2 (M + H) + Elemental analysis: C2i H23N302, 1.4HCI, 1, 8H2O Theoretical:% C 58.26; % H 6.52; % N 9.71; % CI 11, 47 Found:% C 58,26; % H 6.23; % N 9.59; % C1 11, 83 EXAMPLE 33J 33J was obtained according to a procedure similar to that described for 32A, with the following exceptions: Step 32.2: 32.2a was replaced by 33.1 j and Procedure 1 D was used (see also step 33.2). Noia: 33.1j was worked out according to a procedure similar to that described for 1.13 (see 1N) except that 1.12 was replaced by 3.4b in step 1.8 (see also paragraph 33.9). 1 H NMR (400MHz, DMSO d6) 8.94 (sa, 1 H), 8.83 (m, 1 H), 8.62 (d, 1H), 8.11 (d, 1H), 7.98 (dd, 1H), 7.30 (m, 1 H), 7.08 (d, 1 H), 6.96 (m, 2H), 6.10 (s, 1H), 3.22 (m, 4H), 2.84 (d, 3H), 2.11 (m, 2H), 2.02 (m, 2H) Analysis of the mass spectrum m / z = 336.2 (M + H) + Elemental analysis: C20 21 N3 ° 2, 1, 1 HCl, 0.8H2O Theory:% C 61, 61; % H 6.13; % N 10.78; % CI 10.00 Found:% C 61, 84; % H 5.90; % N 10.75; % CI 10.01 EXAMPLE 33K Preparation of 33.6: To a mixture of a solution of n-butyl-lithium 2.5M in hexanes (0.84 mL, 2.1 mmol, 1.05 eq) and ileol (4 mL) At -78 ° C a solution of 33.5 (0.57 g, 2.0 mmol, 1.0 eq) in toluene (2 mL) was added. The reaction was stirred for 1 h at -78 ° C. The reaction was quenched with freshly chopped dry ice. The mixture was slowly warmed to room temperature and stirred for 2 h at room temperature. The mixture was concentrated under reduced pressure and the resulting solid was treated with acetic acid. The solid was collected by filtration, dried under vacuum and used for the next layer without further purification. Yield: 62% 1H NMR (400MHz, CD3OD) d 8.90 (s, 2H) Preparation of 33.7: To a solution of 33.6 (0.055 g, 0.27 mmol, 1.0 eq) in methylene chloride (5 mL) oxalyl chloride (0.050 mL, 0.58 mmol, 2.1 eq) was added. The mixture was heated to reflux temperature for 1 h and concentrated under reduced pressure. The crude acyl chloride was used in the next step without further purification. Preparation of 33.1 k: To a solution of 33.7 (0.060 g, 0.27 mmol, 1.0 eq) in tetrahydrofuran (2.5 mL) was added 1.12 (0.11 mL, 1.06 mmol, 4.0 eq). The mixture was stirred for 16 h and then diluted with ethyl acetate. The organic mixture was washed with water, with a saturated aqueous solution of sodium bicarbonate, an aqueous solution of 1N hydrochloric acid and brine. The organic mixture was dried over sodium sulfate, filtered, concentrated under reduced pressure and the crude product was used in the next step without further purification. Note: the product was isolated with a 17% impurity corresponding to the? /,? / - diethyl-2-iodopyrimidine-5-carboxamide. Yield: 86% H NMR (400MHz, CDCl 3) d 8.82 (s, 2H), 3.56 (c, 2H), 3.20 (c, 2H), 1, 28 (t, 3H), 1.18 (t, 3H) Preparation of 33K: 33K was obtained according to a procedure similar to that described for 32A, with the following exceptions: Step 32.2: 32.2a was replaced by 33.1k and Procedure 12A was used (see also stage 33.2). 1 H NMR (400MHz, DMSO d6) 58.81 (m, 2H), 7.18 (m, 1 H), 6.92 (m, 2H), 6.85 (m, 1H), 6.06 (s, 0.8H), 6.04 (s, 0.2H), 3.41 (c, 2H), 3.06 (c, 2H), 2, 86 (m, 2H), 2.76 (m, 2H), 1.73 (ma, 4H), 1, 10 (t, 3H), 1.00 (t, 3H) Analysis of the mass spectrum m / z = 379.3 (M + H) + EXAMPLE 33L Preparation of 33 L: To a solution of 33.2a (0.27 g, 0.67 mmol, 1 eq) in dry dichloromethane (15 mL) was added dropwise a solution of 4.0M hydrogen chloride in dioxane (1.34 mL, 5.35 mmol, 8 eq). The reaction mixture was stirred at room temperature for 10 h and concentrated under reduced pressure. The crude mixture (containing a mixture of 33E and 33L) was purified by column chromatography (eluyenie: mixture of dichloromethane / methanol / ammonium hydroxide of increasing polarity), giving 33L in pure form.

H NMR (400MHz, DMSO dB) d 8.59 (d, 1H), 8.17 (s, 1H), 8.09 (d, 1H), 7.95 (dd, 1H), 7.71 (s) , 1H), 7.23 (m, 1 H), 6.97 (d, 1 H), 6.91 (m, 2H), 6.02 (s, 1 H), 2.91 (m, 2H) ), 2.77 (m, 2H), 1.82 (m, 2H), 1.73 (m, 2H) Mass spectral analysis m / z = 321, 9 EXAMPLE 34A Preparation of 34.1a: To a solution agitation of 34.3 (2.5 g, 12.38 mmol, 1.0 eq) in acetoniiril (20 mL) was slowly added diisopropylethylamine (4.74 mL, 27.24 mmol, 2.2 eq) and diethylamine (1.12). ) (2.56 mL, 24.76 mmol, 2.0 eq) at room temperature. The mixture was stirred for 10 min at ambient temperature, cooled to 0 ° C and added with O-benzoyriazo-1-yl-yl, -alkyl, -l, -l'-yl-yl-methyluronium (TBTU). , 37 g, 13.62 mmol, 1.1 eq) fractionally to the reaction mixture. The reaction mixture was heated slowly to room temperature and stirred for 10 h at room temperature. The volatiles were refracted under reduced pressure and the residue was partitioned between ethyl acetate (200 mL) and 1 M aqueous sodium bicarbonate (100 mL). The organic phase was washed with an aqueous solution of 1 M sodium bicarbonate (2 x 50 mL), with an aqueous solution of 1 M hydrochloric acid (3 x 50 mL) and brine. The organic phase was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (eluyenie: mixtures of hexane / ethyl acetate of increasing polarity). Yield: 78% 1 H NMR (400MHz, CDCl 3) d 8.41 (m, 1 H), 7.59 (m, 1H), 7.55 (m, 1H), 3.55 (c, 2H), 3 , 27 (c, 2H), 1, 25 (t, 3H), 1, 15 (t, 3H) Analysis of the mass spectra m / z = 257.04 (M + H) + Preparation of 34A: 34A was achieved according to a procedure similar to that described for 32A, with the following exceptions: Stage 32.2: 32.2a was replaced by 34.1a (see also step 34.2). 1 H NMR (400MHz, DMSO dB) d 8.94 (ma, 2H), 8.64 (s, 1 H), 7.92 (dd, 1H), 7.65 (d, 1 H), 7.29 (m, 2H), 7.05 (d, 1 H), 6.96 (t, 1 H), 6.22 (s, 1 H), 3.48 (m, 2H), 3.24 (m) , 6H), 2.05 (ma, 4H), 1, 14 (day, 6H) Analysis of the mass spectrum m / z = 378.4 (M + H) + Elemental analysis: C23H27N302, 1 HCI, 1, 3H2O Theoretical :% C 63.16; % H 7.05; % N 9.61 Found:% C 63.05; % H 6.75; % N 9.50 EXAMPLE 34B 34B was obtained according to a procedure similar to that described for 32A, with the following exceptions: Eíapa 32.2: 32.2a was replaced by 34.1 b (see also step 34.2). Note: 34.1b was obtained according to a procedure similar to that described for 34.1a except that 1.12 was replaced by 3.4o in step 34.4. 1 H NMR (400MHz, DMSO dB) d 9.04 (sa, 2H), 8.59 (d, 1H), 7.85 (dd, 1H), 7.64 (d, 1 H), 7.28 (m, 2H), 7.05 (d, 1 H), 6.96 (t, 1H), 6.21 (s, 1H), 3.67 (m, 2H), 3.22 (ma, 4H), 2.06 (ma, 4H), 1.45 (sa, 6H), 1, 15 (sa, 6H) Analysis of the mass spectrum m / z = 406.4 (M + H) + Elemental analysis: C25H3? N302, 1.5HCI, 0.66H2O Theory:% C 63.59; % H 7.22; % N 8.90; % CI 11, 26 Found:% C 63.68; % H 7.21; % N 8.99; % CI 11, 28 EXAMPLE 34C Preparation of 34.1c: To a stirred solution of 34.4 (2.1 g, 10 mmol, 1.0 eq) in aceton'frile (20 mL) was added loosely diisopropylethylamine (4.2 mL) , 24 mmol, 2.4 eq) and diethylamine (1.12) (2.1 mL, 20 mmol, 2 eq) at room temperature. The mixture was stirred for 10 min at room temperature, cooled to 0 ° C and teirafluoroboralo of O-benzoyriazoI-1 -yl-N, N, N ', N'-feframefiluronium (TBTU) (3.85 g, 12 mmol, 1, 2 eq) fractionally. The reaction mixture was heated slowly to room temperature and stirred for 10 h at room temperature. The volatiles were removed under reduced pressure and the residue partitioned between ethyl acetate (200 mL) and an aqueous 1M sodium bicarbonate solution (100 mL). The organic phase was washed with an aqueous solution of 1 M sodium bicarbonate (2 x 50 mL), with an aqueous solution of hydrochloric acid 1? (3 x 50 mL) and brine, dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The crude product was used in the next step without further purification. Mass spectrum analysis m / z = 262.1 (M + H) + 34C preparation: 34C was obtained according to a procedure similar to that described for 32A, with the following exceptions: Elapa 32.2: 32.2a was replaced by 34.1c (see also step 34.2). RM? H (400MHz, DMSO d6) d 9.07 (br s, 2H), 7.41 (d, 1 H), 7.37 (d, 1H), 7.31 (t, 1 H), 7.22 (d, 1 H), 7.07 (d, 1 H), 7.02 (t, 1 H), 6.12 (s, 1 H), 3.50 (ma, 4H), 3.21 (ma, 4H), 2.03 (ma, 4H), 1, 18 (ta, 6H) Analysis of the mass spectrum m / z - 383.3 (M + H) + Elemental Analysis: C22H26? 2O2S, 1 Theoretical HCl:% C 63.07; % H 6.50; % N 6.69 Found:% C 63.03; % H 6.52; % N 6.61 EXAMPLE 34D 34D was prepared according to a procedure similar to that described for 32A, with the following exceptions: Stage 32.2: 32.2a was replaced by 34.1 d (see also step 34.2). Note: 34.1d was obtained according to a procedure similar to that described for 34.1c except that 1.12 was subsumed by 3.4o in stage 34.5. 1 H NMR (400MHz, DMSO dB) 8.93 (sa, 2H), 7.38 (d, 1H), 7.31 (t, 1H), 7.26 (d, 1H), 7.19 (d) , 1 H), 7.07 (d, 1 H), 7.02 (i, 1H), 6.10 (s, 1H), 3.97 (sa, 2H), 3.21 (ma, 4H) , 2.07 (ma, 2H), 1, 97 (ma, 2H), 1, 31 (day, 12H) Analysis of the mass spectrum miz = 411, 4 (M + H) + Elemental analysis: C24H30N2O2S, 1 HCI , Theoretical:% C 64.48; % H 6.99; % N 6.27 Found:% C 64.25; % H 7.01; % N 6.22 EXAMPLE 34E Preparation of 34.1 e: To a stirred solution of 34.5 (4.58 g, 17.5 mmol, 1.0 eq) in dichloromethane (100 mL) at 0 ° C was slowly added triethylamine ( 7.32 mL, 52.5 mmol, 3 eq) followed by the dropwise addition of diethylamine (1.12) (3.64 mL, 35.0 mmol, 2.0 eq). The reaction mixture was maintained at 0 ° C for 30 min and then stirred at room temperature for 3 h. The mixture was washed with an aqueous solution of 1 N hydrochloric acid (3 x 50 mL) and brine. The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure to give the crude product, which was used in the next step without further purification. Yield: 100% 1 H NMR (400MHz, CDCl 3) d 7.30 (d, 1 H), 7.05 (d, 1H), 3.24 (c, 4H), 1, 19 (1, 6H) Analysis of the mass spectra m / z = 297.92 (M + H) + Preparation of 34E: 34E was obluded according to a procedure similar to that described for 32A, with the following exceptions: Stage 32.2: 32.2a was replaced by 34.1 e (see also tab 34.2). (34E) H NMR (400MHz, DMSO d6) d 8.98 (sa, 2H), 7.68 (d, 1H), 7.34 (ma, 3H), 7.06 (m, 2H), 6, 23 (s, 1 H), 3.22 (ma, 8H), 2.03 (ma, 4H), 1, 12 (m, 6H) Mass spectral analysis / z - 419.2 (M + H) EXAMPLE 34F Preparation of 34.1 f: To a stirred solution of 34.6 (2 g, 10.47 mmol, 1.0 eq) in acetonitrile (20 mL) was slowly added diisopropylethylamine (4 mL, 23.03 mmol, 2, 2 eq) and diethylamine (1.12) (2.1 mL, 20.94 mmol, 2.0 eq) at room temperature. The mixture was stirred for 10 min at ambient temperature, cooled to 0 ° C, and O-benzoyriazole-1-yl- / V,? /,? / ',? /' -elimelliluronium (TBTU) was added (3). , 7 g, 11, 52 mmol, 1.1 eq) fractionally. The reaction mixture was slowly warmed to room temperature and stirred for 10 h at room temperature. The volatiles were re-treated under reduced pressure and the residue was partitioned between ethyl acetate (200 mL) and an aqueous 1M sodium bicarbonate solution (100 mL). The organic phase was washed with an aqueous solution of 1M sodium bicarbonate (2 x 50 mL), an aqueous solution of 1M hydrochloric acid (3 x 50 mL) and brine. The organic phase was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (eluyenie: hexane / ethyl acetate mixtures of increasing polarity). Yield: 91% 1 H NMR (400MHz, CDCl 3) d 6.99 (d, 1H), 6.41 (d, 1H), 3.54 (sa, 4H), 1.26 (sa, 6H) Analysis of the mass spectrum m / z = 246.0 (M + H) + Preparation of 34F: 34F was obtained according to a procedure similar to that described for 32A, with the following exceptions: Eíapa 32.2: 32.2a it was subscribed by 34.1f (see also step 34.2). 1 H NMR (400MHz, DMSO dß) d 9.05 (br s, 2 H), 7.52 (d, 1 H), 7.32 (t, 1 H), 7.07 (ma, 3H), 6.91 (d, 1H), 6.26 (s, 1H), 3.50 (sa, 4H), 3.20 (ma, 4H), 2.05 ( ma, 4H), 1.17 (sa, 6H) Analysis of the mass spectrum m / z = 367.3 (M + H) + EXAMPLE 34G 34G was done according to a procedure similar to that described for 32A, with the following exceptions: Eíapa 32.2: 32.2a subscribed by 34.1 g (see also step 34.2). Note: 34.1 g was obtained according to a procedure similar to that described for 34.1f except that 1.12 was subsumed by 3.4o in stage 34.8. 1 H NMR (400MHz, DMSO dB) d 8.89 (sa, 2H), 7.52 (d, 1 H), 7.32 (t, 1 H), 7.07 (m, 2H), 6.92 (d, 1 H), 6.87 (d, 1 H), 6.24 (s, 1H), 4.02 (sa, 2H), 3.20 (ma, 4H), 2.03 (ma, 4H), 1, 31 (sa, 12H), Mass spectrum analysis m / z - 395.5 (M + H) + EXAMPLE 34H Preparation of 34.1 h: To a stirred solution of 34.7 (2.1 g, 10 mmol, 1.0 eq) in acetonitrile (20 mL) was slowly added diisopropylethylamine (4.2 mL, 24 mmol, 2.4 eq) and diethylamine (1.12) (2.1 mL, 20 mmol, 2 mmol). eq) at ambient temperature. The mixture was stirred for 10 min at ambient temperature, cooled to 0 ° C and O-benzotriazoI-1-i-N, N, N ', N'-tetramethyloride (TBTU) (3T) was added. , 85 g, 12 mmol, 1, 2 eq) fractionally. The reaction mixture was slowly warmed to room temperature and stirred for 10 h at ambient temperature. The volatiles were re-treated under reduced pressure and the residue was partitioned between ethyl acetate (200 mL) and an aqueous 1M sodium bicarbonate solution (100 mL). The organic phase was washed with an aqueous solution of 1 M sodium bicarbonate (2 x 50 mL), an aqueous solution of 1M hydrochloric acid (3 x 50 mL) and brine. The organic phase was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (eluent: mixtures of hexane / ethyl acetate of increasing polarity). Yield: 87% Analysis of the mass spectrum m / z = 262.15 (M + H) + Preparation of 34H: 34H was obtained according to a procedure similar to that described for 32A, with the following exceptions: Stage 32.2: 32.2a replaced by 34.1 h (see also step 34.2). 1 H NMR (400MHz, DMSO dβ) d 9.01 (br s, 2 H), 7.80 (s, 1 H), 7.41 (s, 1 H), 7.27 (t, 1 H), 7.19 ( d, 1 H), 7.04 (d, 1 H), 6.99 (t, 1 H), 6.04 (s, 1 H), 3.48 (m, 4 H), 3.21 (m) , 4H), 2.02 (ma, 4H), 1, 16 (ta, 6H) Analysis of the mass spectrum m / z = 383.4 (M + H) + EXAMPLE 341 341 was obtained according to a procedure similar to that description for 32A, with the following exceptions: Eiapa 32.2: 32.2a was subscribed by 34.1 i (see also paragraph 34.2). 34.1 i worked according to a procedure similar to that described for 34.1 h except that 1. 12 was subscribed by 3.4o in stage 34.7. 1 H NMR (400MHz, DMSO d6) 8.99 (sa, 2H), 7.73 (d, 1 H), 7.27 (m, 2H), 7.21 (dd, 1H), 7.04 (d, 1H), 6.99 (t, 1 H), 6.04 (s, 1 H), 3.90 (sa, 2H), 3.21 (ma, 4H), 2.07 (ma, 2H), 1, 98 (ma, 2H), 1, 30 (day, 12H) Analysis of the mass spectrum m / z = 411, 4 (M + H) + EXAMPLE 34J 34J was obtained according to a similar procedure to that described for 32A, with the following exceptions: Eíapa 32.2: 32.2a was subsumed by 34.1j (see also stage 34.2). Note: 34.1j was made according to a procedure similar to that described for 34.1 k (see 34K) except that 34.8b was replaced by 34.8a in step 34.9. 1 H NMR (400MHz, DMSO dβ) d 8.85 (br s, 2 H), 7.43 (br 1 H), 7.35 (d, 1 H), 7.27 (m, 2H), 7.04 (m, 2H), 6.97 (m, 1 H), 6.03 (s, 1 H), 3.48 (c, 2H), 3.22 (ma, 6H), 2.04 (ma, 4H), 1.16 (1, 3H), 1, 04 (1, 3H) Mass spectrum analysis m / z = 395.0 (M + H) + Elemental analysis: c24H27FN2? 2, 1HCl, 0,25H2O Theoretical:% C 66.20; % H 6.60; % N 6.43 Found:% C 65.97; % H 6.48; % N 6.21 EXAMPLE 34K Preparation of 34.1 k: To a stirred solution of 34.8b (5.0 g, 22.83 mmol, 1.0 eq) in acetonitrile (50 mL) was added? /,? / - diisopropylethylamine (8.35 mL, 47.94 mmol, 2.1 eq), 1.12 (2.6 mL, 25.11 mmol, 1.1 eq) and teirafluoroborate of 0-benzotriazol-1-yl -? /, / \ /,? / ',? /' - íeírameíiIuronio (TBTU) (8.06 g, 25.11 mmol, 1.1 eq). The reaction mixture was stirred at room temperature for 16 h. The mixture was concentrated under reduced pressure and the residue was dissolved in ethyl acetate. The mixture was washed with a saturated aqueous solution of sodium bicarbonate, dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the crude product was purified by column chromatography (eluyenie: hexane / ethyl acid mixtures of increasing polarity). Yield: 91% 1 H NMR (400MHz, CDCl 3) 7.30 (m, 2H), 7.03 (m, 1 H), 3.53 (c, 2H), 3.24 (c, 2H), 1.27 (t, 3H), 1, 13 (t, 3H) Preparation of 34K: 34K was obtained according to a procedure similar to that described for 32A, with the following exceptions: Eíapa 32.2: 32.2a was subsituted by 34.1k (see also step 34.2). 1 H NMR (400MHz, DMSO d6) 8.92 (br s, 2H), 7.29 (m, 3H), 7.13 (s, 1H), 7.05 (d, 1H), 6.98 (m , 2H), 6.01 (s, 1 H), 3.43 (ma, 2H), 3.23 (ma, 6H), 2.04 (ma, 4H), 1.10 (day, 6H) Analysis of the mass spectrum m / z = 395.0 (M + H) + Elemental analysis: C24H27FN2O2, 1 HCI, 0.25H2O Theoretical:% C 66.20; % H 6.60; % N 6.43 Found:% C 66.17; % H 6.57; % N 6.32 EXAMPLE 34L 34L was obtained according to a procedure similar to that described for 32A, with the following exceptions: Eíapa 32.2: 32.2a was subsumed by 34.11 (see also step 34.2). Note: 34.11 was obtained according to a procedure similar to that described for 34.1 k except that 34.8b was replaced by 34.8c in step 34.9. 1 H NMR (400MHz, CDCl 3) d 9.76 (br s, 1 H), 9.63 (br s, 1H), 7.20 (br, 4H), 7.05 (dd, 1 H), 6.93 (m, 2H), 5.60 (s, 1 H), 3.76 (sa, 2H), 3.42 (ma, 4H), 3.18 (c, 2H), 2.32 (s, 3H), 2.21 (ma, 4H), 1, 28 (t, 3H), 1, 08 (t, 3H) Analysis of the mass spectrum m / z = 391, 0 (M + H) + Elemental analysis: C25H3? N2O2, 1 HCI Theoretical:% C 70.32; % H 7.32; % N 6.56 Found:% C 69.92; % H 7.27; % N 6.49 EXAMPLE 34M 34M was obtained according to a procedure similar to that described for 32A, with the following exceptions: Stage 32.2: 32.2a was replaced by 34.1 m (see also tab 34.2). Noia: 34.1 m was obtained according to a procedure similar to that described for 34.1 k except that 34.8 b was subsumed by 34.8 d in step 34.9. 1 H NMR (400MHz, CDCl 3) d 9.78 (br s, 1H), 9.62 (br, 1 H), 7.22 (m, 3H), 7.13 (d, 1 H), 6.92 ( d, 1 H), 6.84 (t, 1 H), 6.63 (dd, 1 H), 5.48 (s, 1 H), 3.42 (ma, 8 H), 2.36 (m , 2H), 2.21 (m, 2H), 2.13 (s, 3H), 1, 21 (day, 6H) Analysis of the mass spectrum m / z = 391, 0 (M + H) + Elemental Analysis : C25H3? N2O2, 1 HCl Theory:% C 70.32; % H 7.32; % N 6.56 Found:% C 70.01; % H 7.30; % N 6.57 EXAMPLE 34N 34N was obtained according to a procedure similar to that described for 32A, with the following exceptions: Eíapa 32.2: 32.2a was subsumed by 34.1 n (see also paragraph 34.2). Noia: 34.1n was obtained according to a procedure similar to that described for 34.1k except that 34.8b was subsumed by 34.8e in step 34.9. 1 H NMR (400MHz, CDCl 3) 59.78 (sa, 1H), 9.68 (sa, 1H), 7.28 (m, 1H), 7.03 (dd, 1H), 6.95 (m, 4H), 5.64 (s, 1 H), 3.62 (c, 2H), 3.41 (ma, 4H), 3.28 (c, 2H) ), 2.26 (ma, 4H), 1.28 (1, 3H), 1, 05 (t, 3H) Analysis of the mass spectrum m / z = 413.0 (M + H) + Elemental analysis: C24H26F2N202 , 1 HCl, 0.25H2O Theory:% C 63.57; % H 6.11; % N 6.18 Found:% C 63.54; % H 6.09; % N 6.20 EXAMPLE 340 340 was obtained according to a procedure similar to that described for 32A, with the following exceptions: Eíapa 32.2: 32.2a was subsituted by 34.1o (see also clause 34.2). Noia: 34.1o was done according to a procedure similar to that described for 34.1k except that 34.8b was replaced by 34.8f in stage 34.9. 1 H NMR (400MHz, CDCl 3) 59.78 (sa, 1H), 9.66 (sa, 1H), 7.38 (s, 1H), 7.33 (d 1 H), 7.25 (m, 2H) ), 7.02 (d, 1 H), 6.95 (m, 2H), 5.63 (s, 1 H), 3.81 (sa, 1H), 3.42 (ma, 5H), 3 , 21 (ma, 2H), 2.26 (ma, 4H), 1, 28 (í, 3H), 1, 12 (t, 3H Analysis of the mass spectrum m / z = 411, 0 (M + H) + Elemental analysis: C24H27CIN2O2, 1 HCI Theoretical:% C 64.43; % H 6.31; % N 6.26 Found:% C 64.34; % H 6.35; % N 6.28 EXAMPLE 34P 34P was obtained according to a procedure similar to that described for 32A, with the following exceptions: Stage 32.2: 32.2a was replaced by 34.1 p (see also step 34.2). Noia: 34.1p was obtained according to a procedure similar to that described for 34.1k except that 34.8b was subsituted by 34.9p in step 34.9 (see also clause 34.10). 1 H NMR (400MHz, DMSO dB) 59.10 (sa, 2H), 7.47 (m, 2H), 7.34 (m, 1H), 7.27 (m, 1 H), 7.20 (m, 1 H), 6.98 (m, 1 H), 6.87 (m, 1H), 6.76 (m, 1H), 5, 69 (s, 1H), 3.29 (m, 2H), 3.18 (m, 4H), 3.01 (m, 2H), 2.04 (m, 2H), 1.93 (m, 2H) ), 0.96 (m, 6H) Analysis of the mass spectrum m / z = 377.4 (M + H) + EXAMPLE 35A Preparation of 35.2: To a solution of 35.1 (41.44 g, 0.3 mol, 1.0 eq) in ammonium hydroxide (105 mL, solution in 30% H 2 O) was added dropwise a solution of 12 (61.23 g, 0.24 mol, 0.8 eq) and Kl (47 , 71 g, 0.287 mol, 0.96 eq) in water (300 mL) for a period of 20 min. The mixture was stirred at room temperature for 1 h, and the mixture was concentrated under reduced pressure up to the volume. The pH was adjusted to 3-4 with an aqueous solution of 6N hydrochloric acid. The white solid was collected by filtration and washed with a small amount of water. The solid was recrystallized from water / EtOH (2: 1), and dried over high vacuum. Yield: 22% 1H NMR (400MHz, DMSO-d6) d 12.96 (a, 1H), 10.70 (s, 1H), 7.80 (d, 1H), 7.42 (s, 1H), 7.12 (d, 1H) Preparation of 35.3: To an acid methanolic solution, prepared by the dropwise addition of acetyl chloride (0.5 mL) to anhydrous meganol (75 mL) was added 35.2 (20.0 g, 75.8 mmol). The mixture was heated at reflux temperature for 18 h. The reaction mixture was allowed to cool to room temperature, and concentrated under reduced pressure. The residue was diluted in ethyl ether (100 mL), washed with water (100 mL), brine (100 mL), and dried over Na2SO4. The solution was filtered and the filtrate was concentrated under reduced pressure. The crude product was dried under vacuum. Yield: 92% 1 H NMR (400MHz, DMSO-d 6) 510.79 (s, 1 H), 7.85 (d, 1 H), 7.46 (s, 1 H), 7.15 (d, 1H) ), 3.84 (s, 3H) Preparation of 35.4: A mixture of 35.3 (2.0 g, 7.19 mmol, 1.0 eq), 2.8c (4.08 g, 28.8 mmol, 4.0 eq) and carbonation of poasium (9.94 g, 71.9 mmol, 10.0 eq) in acetone (100 mL) was heated to reflux temperature for 16 h. The reaction was cooled to room temperature and the solid was collected by filtration. The volume of the filtrate was reduced to 15 mL and this solution was taken to the next stage without further purification. Preparation of 35.5: To a solution of 35.4 (2.10 g, 7.19 mmol, 1.0 eq) in acetone (15 mL) was added lithium hydroxide (1.2 g, 28.8 mmol, 4.0 eq) and a 1: 1 solution of water / hydrofuran / water (30 mL). The mixture was stirred at room temperature for 16 h. The mixture was reduced to half its volume under reduced pressure and acidified with an aqueous solution of 6N hydrochloric acid (5 mL). The crude mixture was extracted with ethyl ether. The organic phase was washed with brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The crude product was used in the next layer without further purification. 1 H NMR (400MHz, CDCl 3) d 7.91 (d, 1 H), 7.49 (d, 1 H), 7.45 (dd, 1H), 3.96 (s, 3H) Preparation of 35.6: A a mixture of 35.5 (2.0 g, 7.19 mmol, 1.0 eq) and O-benzotriazole-1-yl-? /,? /,? / ',? / - tetramethyluronium hydroxyurea (TBTU) (2) , 54 g, 7.91 mmol, 1.1 eq) in acetyloiryl (75 mL) at 0 ° C was added 1.12 (0.58 g, 7.91 mmol, 1.1 eq) and? /, A / -diisopropylethylamine (1.95 g, 15.1 mmol, 2.1 eq). The mixture was heated to ambient temperature, stirred for 16 h at ambient temperature and concentrated under reduced pressure. The crude mixture was dissolved in ethyl acetate. The mixture was washed with a saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (eluent: hexane / ethyl acetate mixture, 60:40). Yield: 96% 1 H NMR (400MHz, CDCl 3) 7.78 (d, 1 H), 6.84 (d, 1 H), 6.70 (dd, 1H), 3.90 (s, 3H), 3,54 (sa, 2H), 3.26 (sa, 2H), 1, 19 (day, 6H) Analysis of the mass spectra m / z = 334.1 (M + H) + Preparation of 35.9 To a solution of 35.6 (1.34) g, 4.02 mmol, 1.0 eq) in dimethoxyethane (DME) (20 mL) was added sequentially an aqueous 2N sodium carbonate solution (6.03 mL, 12.06 mmol, 3.0 eq), chloride lithium (0.511 g, 12.06 mmol, 3.0 eq), 32.1 (2.06 g, 4.83 mmol, 1.2 eq) and palladium (pyridine) teiraki (pyridylphosphine) (0.232 g, 0, 20 mmol, 0.05 eq). The Suzuki coupling reaction was carried out under microwave conditions (A. 25 ° C at 170 ° C for 10 min, B. 170 ° C for 7 min). The crude mixture was dissolved in ethyl ether, washed with water, dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (eluent: mixtures of hexane / ethyl acetate of increasing polarity). Yield: 74% 1 H NMR (400MHz, CDCl 3) 7.18 (d, 1 H), 7.13 (m, 1 H), 6.98 (m, 2H), 6.90 (d, 1H), 6.79 (m, 1H), 6.70 (dd, 1H), 5.53 (s, 1 H), 3.84 (sa, 2H), 3.72 (s, 3H), 3.56 (s) sa, 2H), 3.33 (sa, 4H), 2.07 (ma, 2H), 1.67 (ma, 2H), 1.47 (s, 9H), 1, 22 (day, 6H) Analysis of the mass spectra m / z = 507.3 (M + H) + Preparation of 35A: The compound 35.9 (1.50 g, 2.96 mmol, 1.0 eq) was dissolved in an anhydrous solution of hydrochloric acid 4 , 0M in dioxane (15 mL, 60 mmol, 20 eq) and the mixture was stirred at room temperature for 16 h. The mixture was concentrated under reduced pressure. The residue was dissolved in the minimum amount (until complete dissolution of the product) of methylene chloride, and ethyl acetate was added until the solution became cloudy. The mixture was stirred for 2 h at room temperature. The resulting precipitate was collected by filtration. Yield: 77% 1 H NMR (400MHz, CDCl 3) d 9.75 (br s, 1 H), 9.58 (br s, 1 H), 7.16 (m, 2H), 6.98 (m, 2H), 6.90 (d, 1H), 6.83 (m, 1 H), 6.72 (dd, 1 H), 5.56 (s, 1 H), 3.72 (s, 3H), 3.50 (m) , 8H), 2.35 (ma, 2H), 2.16 (ma, 2H), 1, 23 (day, 6H) Analysis of the mass spectrum m / z = 407.0 (M + H) + Elemental analysis: C25H30 2O3. 1 HCl, 0.5H2O Theory:% C 66.43; % H 7.14; % N 6.20 Found:% C 66.28; % H 7.10; % N 5.94 EXAMPLE 35B Preparation of 35.7: To a solution of 35.6 (1.10 g, 3.30 mmol, 1.0 eq) in methylene chloride (30 mL) at 0 ° C was added a solution of 1.0 M boronibromide in methylene chloride (5.0 mL, 5.0 mmol, 1.5 eq). The reaction was heated to ambient air and it lasted for 16 hours at ambient air. To the mixture was added a saturated aqueous solution of sodium bicarbonate and the crude product was extracted with methylene chloride. The combined organic extracts were dried over sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The production in bruise was used in the following step without further purification. Yield: 87% 1 H NMR (400MHz, CDCl 3) d 8.28 (sa, 1 H), 7.64 (d, 1 H), 6.95 (d, 1 H), 6.56 (dd, 1 H), 3.54 (c, 2H), 3.25 (c, 2H), 1, 24 (1, 3H), 1, 10 (1, 3H) Mass spectral analysis m / z = 320.0 (M + H) + Preparation of 35.8: To a solution of 35.7 (0.90 g, 2.82 mmol, 1.0 eq) and N, N-diisopropylethylamine (2.91 g, 22.6 mmol, 8.0 eq) in methylene chloride (25 mL) at 0 ° C under nitrogen was added dropwise 11.3 (0.86 mL, 11.3 mmol, 4.0 eq). The mixture was warmed to room temperature and stirred for 48 hours at room temperature. The mixture was concentrated under reduced pressure, dissolved in ethyl acetate and the solution was washed with a saturated aqueous solution of sodium bicarbonate. The organic phase was dried over sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The crude product was used in the next step without further purification. Analysis of the mass spectrum m / z = 364.1 (M + H) + Preparation of 35.10: To a solution of 35.8 (1.02 g, 2.82 mmol, 1.0 eq) in dimethoxyethane (DME) (20) mL) was added sequentially a 2N sodium carbonate aqueous solution (4.23 mL, 8.46 mmol, 3.0 eq), lithium chloride (0.359 g, 8.46 mmol, 3.0 eq), 32.1 ( 1.44 g, 3.38 mmol, 1.2 eq) and palladium on carbon (10%, 50% water) (0.038 g, 0.007 mmol, 0.0025 eq). The reaction was carried out under microwave conditions (A. 25 ° C to 170 ° C for 10 min; B. 170 ° C for 7 min). The mixture was dissolved in ethyl acetate, washed with water, and dried over sodium sulfate. The mixture was filtered and the filtrate was concentrated under reduced pressure.

The crude product was purified by column chromatography (eluent: mixtures of hexane / acetyl ether oil of increasing polarity). Yield: 50% 1 H NMR (400MHz, CDCl 3) 7.21 (m, 2H), 7.13 (m, 1 H), 7.06 (dd, 1 H), 6.90 (d, 1H), 6.76 (m, 2H), 5.53 (s, 1 H), 5.04 (s, 2H), 3.87 (sa, 2H), 3.55 (sa, 2H), 3.34 ( sa, 4H), 3.30 (s, 3H), 2.08 (ma, 2H), 1, 67 (ma, 2H), 1, 48 (s, 9H), 1, 24 (ma, 6H) Analysis of the mass spectra m / z = 537.3 (M + H) + Preparation of 35B: To a solution of 35.10 (0.647 g, 1.21 mmol, 1 eq) in meianol (3 mL) was added an excess of a 4.0M anhydrous hydrochloric acid solution in dioxane (20 mL) ). The mixture was stirred at room temperature for 16 h. The mixture was concentrated under reduced pressure and evaporated with a mixture of methylene chloride (15 mL) and ethyl acetate (25 mL). The resulting precipitate was collected by filtration and dried under vacuum. Yield: 77% 1 H NMR (400MHz, DMSO dB) d 9.75 (s, 1 H), 8.84 (m, 2H), 7.16 (m, 2H), 6.96 (d, 1H), 6.84 (m, 3H), 6.72 (d, 1 H), 5.78 (s, 1 H), 3.42 (sa, 2H), 3.22 (sa, 6H), 2.10 (ma, 2H), 1, 96 (ma, 2H), 1, 12 (sa, 6H) Mass spectrum analysis m / z = 393.3 (M + H) + EXAMPLE 36A Preparation of 36.3: To a mixture of copper (II) bromide (8.8 g, 39.4 mmol, 1.2 eq) in acetyloiryl (50 mL) in nitrogen atmosphere was added 36.2 (5.1 g, 49.5 mmol, 1, 5 eq). The mixture was cooled to 0 ° C and 36.1 (5.0 g, 32.6 mmol, 1.0 eq) was added in small portions. An additional amount of acetoniiril (25 mL) was added to the mixture, which was stirred at 0 ° C for 2 hours. The mixture was poured into an aqueous solution of 20% hydrochloric acid (200 mL) and extracted with diethyl ether. The combined organic extractions were washed with an aqueous solution of 20% hydrochloric acid, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was dissolved in dieyl ether. The mixture was extracted with an aqueous solution of 15% sodium hydroxide. The aqueous fraction was washed with diethyl ether, acidified to pH 1 with an aqueous solution of 6N hydrochloric acid, and the mixture was extracted with diethyl ether. The combined organic extractions were washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was treated with chloroform and the resulting precipitate was collected by filtration. The product was used in the next step without further purification.

Analysis of the mass spectrum m / z = 215.1 (MH) "Preparation of 36.4: To a mixture of 1.12 (0.85 g, 11.58 mmol, 2.5 eq), O-benzotriazole-1-α-fluoroborate L -? /,? /,? / ', / V-erylamyluronium (TBTU) (1, 93 g, 6.02 mmol, 1, 3 eq) and? /,? / - di-orpropi-eylamine (1, 25) g, 9.72 mmol, 2.1 eq) in acetyloiryl (50 mL) at 0 ° C was added a solution of 36.3 (1.0 g, 4.63 mmol, 1.0 eq) in acetyloilyl. (10 mL) The mixture was heated to ambient temperature and stirred for 48 hours at room temperature An additional portion of TBTU (1.04 g, 3.24 mmol, 0.7 eq) was added to the mixture which was heated. The mixture was concentrated under reduced pressure at 60 ° C. and the residue was dissolved in ethyl acetate, the mixture was washed with water, brine, dried over magnesium sulfate and filtered. The crude product was purified by column chromatography (eluent: hexane / acetamide mixtures). lime of increasing polarity) Yield: 63% 1 H NMR (400MHz, CDCl 3) d 10.08 (s, 1 H), 7.17 (d, 1 H), 7.12 (d, 1H), 6.98 ( dd, 1H), 3.50 (c, 4H), 1, 27 (t, 6H) Analysis of the mass spectrum m / z = 270.1 (MH) "Preparation of 36.5: To a solution of 36.4 (0, 30 g, 1.11 mmol, 1.0 eq) in dimethoxiefan (DME) (10 mL) was added sequentially a 2N aqueous sodium carbonate solution (1.66 mL, 3.32 mmol, 3.0 eq), liioium chloride (0.141 g, 3.32 mmol, 3.0 eq), 32.1 (0.57 g, 1.33 mmol, 1.2 eq) and palladium (0) (0.128 g 0.11 mmol, 0.1 eq). The reaction was carried out under microwave conditions (A. 25 ° C. at 170 ° C. for 10 minutes, B. 170 ° C. for 10 minutes). The crude mixture was dissolved in ethyl acetate. The mixture was washed with an aqueous solution of 0.5 N hydrochloric acid, brine, and dried over magnesium sulfate. The mixture was filtered and the filtrate was concentrated under reduced pressure. The production in bruise was purified by column chromatography (eluyenie: mixtures of hexane / acetyl ether of increasing polarity). Yield: 37% 1 H NMR (400MHz, CDCl 3) d 9.94 (s, 1H), 7.29 (d, 1 H), 7.18 (m, 1H), 7.06 (dd, 1H), 7 , 00 (d, 1 H), 6.94 (d, 1 H), 6.85 (m, 2H), 5.59 (s, 1 H), 3.85 (sa, 2H), 3.55 (c , 4H), 3.34 (sa, 2H), 2.04 (ma, 2H), 1, 66 (m, 2H), 1, 48 (s, 9H), 1, 30 (i, 6H) Analysis of the mass spectrum m / z = 493.2 (M + H) + Preparation of 36A: To a solution of 36.5 (0.20 g, 0.406 mmol, 1.0 eq) in methylene chloride (2 mL) was added a solution of 1.0 M anhydrous hydrochloric acid in diethylether (10 g). mL, 10 mmol, 25 eq). The mixture was stirred at room temperature for 16 h. The mixture was concentrated under reduced pressure and evaporated with diethyl ether. The resulting precipitate was collected by filtration.

It was checked by LC / MS that some of the starting material remained; so that the precipitate was fused with an excess of a 4.0M anhydrous hydrochloric acid solution in dioxane. The mixture was stirred at room temperature for 16 h. The mixture was concentrated under reduced pressure and the crude product was purified by column chromatography (eluent: mixtures of methylene chloride / methanol of increasing polarity). Yield: 66% 1H NMR (400MHz, DMSO d6) d 9.91 (br s, 1H), 9.08 (br, 2H), 7.26 (m, 1H), 7.13 (d, 1H), 7.04 (m, 2H), 6.95 (m, 1 H), 6.84 (m, 2H), 5.87 (s, 1 H), 3.66 (sa, 4H), 3.20 (ma, 4H), 2.05 (ma, 4H), 1, 08 (day, 6H) Analysis of the mass spectra m / z = 393.4 (M + H) + Elemental analysis: C24H28N2O3, 1 HCU, 5H2O Theoretical:% C 63.22; % H 7.07; % N 6,14 Found:% C 63,45; % H 6.88; % N 6.09 EXAMPLE 36B Preparation of 36.8: To a solution of 36.6 (13.0 mL, 89.41 mmol, 1.0 eq) and triethylamine (13.71 mL, 98.35 mmol, 1.1 eq) in methylene chloride (100 mL) at 0 ° C in nihonogen atmosphere were added ethyl chloroformate (9.40 mL, 98.35 mmol, 1.1 eq). The mixture was heated to ambient temperature and stirred for 1 h at ambient temperature. Water and methylene chloride were added to the reaction mixture and the phases were separated. The organic phase was dried over sodium sulphamide, filtered and concentrated under reduced pressure. The production in bruise was used in the next stage without further purification. Yield: 100% 1 H NMR (400MHz, CDCl 3) 7.22 (t, 1 H), 6.76 (m, 3H), 4.66 (sa, 1H), 4.11 (c, 2H), 3 , 80 (s, 3H), 3.43 (m, 2H), 2.78 (m, 2H), 1, 23 (1, 3H) Analysis of the mass spectra m / z = 224.1 (M + H ) + Preparation of 36.9: A mixture of 36.8 (20 g, 89.58 mmol, 1.0 eq) and polyphosphoric acid (90 g) was heated to 120 ° C in nihonogen atmosphere for 1.5 h. The mixture was cooled to ambient temperature. Water (200 mL) was added to the mixture, which was extracted with ethyl acetate. The organic extractions were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (eluent: ethyl acetate). Polyphosphoric acid remained in the purified sample; The residue was then dissolved in ethyl ether and the solution was washed with a saturated aqueous solution of sodium bicarbonate. The mixture was dried over sodium sulfate, filtered and concentrated under reduced pressure. Acetyl ether (15 mL) was added to the mixture. The resulting precipitate was collected by filtration and used in the next step without further purification. Yield: 30% 1 H NMR (400MHz, CDCl 3) 8.02 (d, 1 H), 6.86 (dd, 1H), 6.71 (d, 1H), 6.22 (sa, 1 H), 3.85 (s, 3H), 3.55 (m, 2H), 2.97 (i, 2H) Analysis of the mass spectra m / z = 178.1 (M + H) + Preparation of 36.11: A NaH suspension (0.81 g, 33.86 mmol, 6.0 eq) in tetrahydrofuran (30 mL) under nitrogen was added dropwise a solution of 36.9 (1.0 g, 5.64 mmol, 1.0 eq) in teirahydrofuran (15 mL). To this mixture, 36.10 (2.28 mL, 28.22 mmol, 5.0 eq) was added to goya and the agitation was continued for 16 hours at ambient temperature. A dense precipitate formed; an additional amount of tetrahydrofuran (15 mL) and 36.10 (1.0 mL, 12.39 mmol, 2.2 eq) was added and the stirring was continued for 24 hours at room temperature. The reaction was quenched by the addition of an aqueous solution of 1 N hydrochloric acid followed by ethyl acetate and water. The phases separated. The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (eluent: mixtures of hexane / ethyl acetate of increasing polarity). Performance: 83%. 1 H NMR (400MHz, CDCl 3) d 8.03 (d, 1 H), 6.84 (dd, 1H), 6.65 (d, 1H), 3.84 (s, 3H), 3.61 (c, 2H), 3.53 (,, 2H), 2.95 (,, 2H), 1, 21 (,, 3H) Mass spectral analysis m / z = 206.1 (M + H) + Preparation of 36.12: To a solution of 36.11 (0.96 g, 4.68 mmol, 1.0 eq) in anhydrous methylene chloride (30 mL) at -78 ° C in amosphere of nitrogen was added dropwise a solution of 1.0 M boronibromide in methylene chloride (9.35 mL, 9.35 mmol, 2.0 eq). The reaction was heated to room temperature and stirred for 16 h at ambient temperature. The mixture was cooled in an ice bath, quenched with methanol (10 mL) and concentrated under reduced pressure. The crude mixture was dissolved in ethyl alcohol and the solution was washed with an aqueous solution of hydrochloric acid 1 and then with brine. The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude solid was dissolved in a solution of ethyl acetate / hexane (1: 1). The precipitate was collected by filtration. Performance: 74%. 1 H NMR (400MHz, CDCl 3) 7.89 (d, 1H), 6.82 (dd, 1 H), 6.68 (d, 1H), 3.63 (c, 2H), 3.54 (t, 2H), 2.91 (t, 2H), 1, 22 (t, 3H) Analysis of the mass spectra m / z = 192.1 (M + H) + Preparation of 36.14: To a solution of 36.12 (0.38 g, 1.99 mmol, 1.0 eq) and pyridine (0.32 mL, 3.98 mmol, 2.0 eq) in methylene chloride (10 mL) ) at 0 ° C in amosphere of nihologen was added 36.13 (0.40 mL, 2.38 mmol, 1.2 eq). The reaction was heated to room temperature and stirred for 2 h at ambient temperature. Methylene chloride was added to the mixture, which was washed with an aqueous solution of hydrochloric acid 1, and with an aqueous solution of 1 N sodium hydroxide. The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. The production in willow was purified by column chromatography (eluent: hexane / acetyl ether, 1: 1). Performance: 45%. 1 H NMR (400MHz, CDCl 3) 8.18 (d, 1 H), 7.23 (dd, 1 H), 7.11 (d, 1 H), 3.62 (m, 4H), 3.04 (t, 2H), 1, 23 (i, 3H) Mass spectral analysis m / z = 324.1 (M + H) + Preparation of 36.15: To a solution of 36.14 (0.100 g, 0.309 mmol, 1, 0 eq) in? /,? / - dimethylformamide (5 mL) in nitrogen atmosphere was added 32.1 (0.145 g, 0.340 mmol, 1.1 eq), potassium acetate (0.091 g, 0.928 mmol, 3.0 eq). ) and [1, 1'-bis (diphenylphosphino) ferrocene] palladium (II), complexed with dichloromethane (0.005 g, 0.006 mmol, 0.02 eq). The reaction was stirred at 65 ° C for 16 h. The mixture was cooled to room temperature. Water was added and the mixture was extracted with acetyl ether. The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (eluent: hexane / acetone mixtures of increasing polarity). Performance: 45%. 1 H NMR (400MHz, CDCl 3) 8.11 (d, 1 H), 7.31 (d, 1 H), 7.19 (m, 1 H), 7.15 (s, 1 H), 6, 96 (m, 2H), 6.86 (m, 1 H), 5.58 (s, 1 H), 3.86 (m, 2H), 3.65 (c, 2H), 3.59 (m) , 2H), 3.34 (m, 2H), 3.01 (t, 2H), 2.05 (m, 2H), 1.67 (m, 2H), 1.48 (s, 9H), 1 , 26 (1, 3H) Analysis of the mass spectra m / z = 475.3 (M + H) + Preparation of 36B: To a solution of 36.15 (0.150 g, 0.316 mmol, 1.0 eq) in methylene chloride Anhydrous (5 mL) at 0 ° C in nitrogen atmosphere was added with a solution of 1.0M anhydrous hydrochloric acid in diethyl ether (1.26 mL, 1.26 mmol, 4.0 eq). The reaction was heated to ambient temperature and stirred for 4 days at ambient temperature. Diethyl ether (5 mL) was added and the resulting precipitate was collected by filtration. Yield: 27%. 1 H NMR (400MHz, DMSO d6) 8.80 (sa, 2H), 7.92 (d, 1 H), 7.29 (m, 3H), 7.05 (d, 1 H), 6.97 (m, 2H), 5.94 (s, 1 H), 3.54 (m, 4H), 3.23 (ma, 4H), 3.00 (1, 2H), 2.08 (ma, 2H) ), 1, 97 (ma, 2H), 1, 13 (1, 3H) Mass spectral analysis m / z = 375.3 (M + H) + Elemental analysis: C 4H26N2O2, 1 HCl, 1 Theoretical H2O: % C 67.20; % H 6.81; % N 6.53 Found:% C 67.52; % H 6.46; % N 6.54 EXAMPLE 37A Preparation of 37.2 and 37.3: To a solution of 37.1 (5.0 g, 24.60 mmol, 1.0 eq) and 1.1a (2), 56 mL, 24.60 mmol, 1.0 eq) in methanol (100 mL) was added pyrrolidine (5.53 mL, 66.90 mmol, 2.72 eq). The mixture was heated at reflux temperature for 16 h. The mixture was concentrated under reduced pressure, dissolved in ethyl acetate and the mixture was washed with a 1N aqueous sodium hydroxide solution and brine. The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude mixture was purified by column chromatography (eluent: hexane / ethyl acetate mixtures of increasing polarity) to give a mixture of 37.2 / 37.3 (1/1, 7). Yield: 80% (37.2) 1 H NMR (400MHz, CDCl 3) d 7.82 (dd, 1H), 7.47 (m, 1H), 7.28 (m, 5H), 6.96 (m, 2H) , 3.50 (c, 2H), 2.76 (c, 2H), 2.64 (ma, 1H), 2.40 (ma, 1 H), 2.18 (ma, 2H), 2.00 (ma, 1 H), 1, 82 (ma, 1 H), 1, 70 (ma, 1 H), 1, 07 (da, 3H) Analysis of the mass spectra m / z = 322.3 (M + H) + (37.3) 1 H NMR (400MHz, CDCl 3) d 7.84 (dd, 1 H), 7.48 (m, 1 H), 7.29 (m, 5H), 6.98 (m, 2H), 3.51 (m, 2H), 3.15 (d, 1 H), 2.65 (m, 1H), 2.55 (m, 1 H), 2.34 (m, 2H), 2.24 (m, 1 H), 2.15 (m, 1H), 1.91 (m, 1 H), 1.56 (m, 1 H), 1, 02 (d, 3H) Analysis of the mass spectra m / z = 322.3 (M + H) + Preparation of 37.4: To a solution of 37.2 (2.30 g, 7.16 mmol, 1.0 eq) in meianol (25 mL) was added 10% Pd / C (0.50 g). The mixture was stirred for 6 h at 55 psi (379.2 kPa) of hydrogen. The mixture was filtered through Celite, and concentrated under reduced pressure. The production in bruise was used in the following stage without further purification. Yield: 99% 1 H NMR (400MHz, CDCl 3) 7.83 (dd, 1H), 7.48 (m, 1 H), 6.97 (m, 2H), 3.18 (dd, 1 H), 3.02 (m, 1H), 2.77 (m, 2H), 2.55 (m, 1 H), 2.06 (m, 1 H), 1.80 (m, 3H), 1, 06 (d, 3H) Analysis of the mass spectrum m / z = 232.3 (M + H) + Preparation of 37.5: To a solution of 37.4 (1.65 g, 7.13 mmol, 1.0 eq) in hydrofuran (50 mL) was added eryrylamine (2.98 mL, 21, 40 mmol, 3.0 eq) and 4.7 (1.87 g, 8.56 mmol, 1.2 eq). The mixture was stirred for 2 hours at room temperature. Water (100 mL) was added and the crude mixture was extracted with ethyl acetate and washed with brine. The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. The production in bruise was purified by column chromatography (eluyenie: hexane / ethyl acetate, 70/30). Yield: 100% 1 H NMR (400MHz, CDCl 3) 7.85 (dd, 1 H), 7.50 (m, 1 H), 6.99 (m, 2H), 3.80 (sa, 1 H) , 3.56 (ma, 2H), 3.30 (sa, 1 H), 2.73 (m, 2H), 2.12 (sa, 1H), 1.82 (ma, 2H), 1, 46 (s, 9H), 1.03 (d, 3H) Analysis of the mass spectrum m / z = 332.3 (M + H) + Preparation of 37.6: To a solution of 37.5 (2.70 g, 8.15 mmol, 1.0 eq) in teirahydrofuran (20 mL) at -78 ° C in nitrogen atmosphere was added dropwise a solution of 1.0M LiHMDS in tetrahydrofuran (9.78 mL, 9.78 mmol, 1, 2 eq). The mixture was stirred for 45 min at -78 ° C. To the mixture was added a solution of 1.4 (3.49 g, 9.78 mmol, 1.2 eq) in tetrahydrofuran (10 mL), which was slowly warmed to room temperature and stirred for 16 h at the same time. ambienie. Then the mixture was poured into ice water. An aqueous 1N hydrochloric solution was added and the crude mixture was extracted with ethyl acetate. The organic extracts were washed with an aqueous solution of 1 N sodium hydroxide, brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (eluyenie: mixtures of hexane / ethyl acetate of increasing polarity). Yield: 62% 1 H NMR (400MHz, DMSO d6) 7.31 (m, 1 H), 7.15 (m, 1 H), 6.95 (m, 1 H), 6.85 (m, 1) H), 6.25 (s, 0.6H), 5.83 (s, 0.4H), 3.54 (sa, 2H), 3.19 (ma, 2H), 1.96 (ma, 2H) , 1, 55 (ma, 1 H), 1, 33 (s, 9H), 0.83 (d, 3H) Analysis of the mass spectra m / z = 464.2 (M + H) + Preparation of 37.7: To a solution of 37.6 (1.17 g, 2.52 mmol, 1.0 eq) in dioxane (20 mL) was added sequentially 1.6 (0.61 g, 2.78 mmol, 1.1 eq), phosphate of poasium (0.80 g, 3.79 mmol, 1.5 eq) and potassium bromide (0.33 g, 2.78 mmol, 1.1 eq). The mixture was placed under vacuum, bubbled with nitrogen and then the process was repeated. Palladium (0) tetrakis (triphenylphosphine) (0.146 g, 0.13 mmol, 0.05 eq) was added and the mixture was heated at 100 ° C for 16 h in a niosogenic atmosphere. The mixture was cooled to ambient temperature, dissolved in ethyl acetate and the mixture was washed with water. The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (eluent: mixtures of hexane / ethyl acetate of increasing polarity). Yield: 53% 1 H NMR (400MHz, CDCl 3) 7.42 (d, 2H), 7.37 (d, 2H), 7.18 (m, 1H), 6.99 (d, 1H), 6 , 92 (d, 1H), 6.84 (m, 1 H), 5.70 (s, 1 H), 3.65 (ma, 5H), 3.32 (sa, 3H), 2.15 ( sa, 1 H), 2.04 (m, 1 H), 1, 77 (sa, 1 H), 1, 48 (s, 9H), 1, 22 (day, 6H), 1, 02 (d, 3H) Analysis of the mass spectrum m / z = 491, 5 (M + H) + 37 A Preparation: To a solution of 37.7 (0.65 g, 1.33 mmol, 1.0 eq) in anhydrous methylene chloride (10 mL) at 0 ° C in aminosphere of Nihydrogen was added a solution of anhydrous hydrochloric acid 1.0M in diethyl ether (5.31 mL, 5.31 mmol, 4.0 eq). The mixture was heated to ambient temperature and stirred for 5 days at ambient temperature. The mixture was concentrated under reduced pressure and dissolved in methylene chloride (5 mL). Diethyl ether (10 mL) was added to the blended mixture, which was stirred for 1 h at ambient temperature. The resulting precipitate was collected by filtration and dried under vacuum. Yield: 82% 1H NMR (400MHz, DMSO d6) 9.46 (ma, 1.5H), 7.71 (d, 2H), 7.67 (d, 2H), 7.48 (m, 1H) , 7.21 (m, 2H), 7.15 (m, 1 H), 6.44 (s, 1 H), 3.70 (sa, 2H), 3.42 (ma, 6H), 2, 52 (ma, 1 H), 2.44 (ma, 1 H), 2.13 (ma, 1 H), 1, 36 (day, 6H), 1, 22 (d, 3H) Mass spectral analysis m / z = 391, 3 (M + H) + Elemental Analysis: C25H30N2O2, 1HCI, 0.25H2O Theoretical:% C 69.59; % H 7.36; % N 6.49 Found:% C 69.29; % H 7.28; % N 6.40 EXAMPLE 37B 37B was done according to a procedure similar to that described for 37A, with the following exceptions: Eíapa 37.2: 37.2 was suspended by 37.3 (see also paragraph 37.5). 1 H NMR (400MHz, DMSO d ") d 9.40 (ma, 1.5H), 7.66 (s, 4H) 7.48 (m, 1 H), 7.27 (d, 1 H), 7, 21 (m, 1 H), 7.15 (m, 1 H), 6.03 (s, 1H), 3.69 (sa, 2H), 3.43 (ma, 4H), 3.24 (ma) , 2H), 2.47 (ma, 1 H), 2.35 (ma, 1 H), 2.08 (ma, 1 H), 1.37 (day, 6H), 1, 20 (d, 3H) ) Analysis of the mass spectra m / z = 391, 3 (M + H) + Elemental analysis: C25H30N2O2, 1HCI, 0.25H2O Theoretical:% C 69.59; % H 7.36; % N 6.49 Found:% C 69.69; % H 7.18; % N 6.49 Preparation procedures for the final compounds found in Examples Z1-Z14 The compounds prepared in Examples Z1-Z14 and represented in Table Z1 were prepared according to Schemes Z1-Z6. The preparation of the spiro derivatives [2H-1-benzopyran-2,4'-piperidine] 15 (Example Z1), 16 (Example Z2) and 18 (Example Z3) is summarized in Scheme Z1. The 2'-hydroxyaceophenone derivatives 1, 2 and 3 (commercially available from the Aldrich Chemical Company) were condensed with 1-Boc-4-piperidone 4 in meianol in the presence of pyrrolidine to give the N-Boc-spiro derivatives [2]. - -1-benzopyran-2,4'-piperidine] -4 (3H) -one 5-7 respecíivamenie. The compues 12-14 were prepared by converting the ceiones 5-7 to the enol triflate derivatives 8-10 and the subsequent coupling reaction of Suzuki with the 4- (N, N-dieylaminocarbonyl) phenylboronic acid M. The Boc proiecuous groups of 12-14 were then reacted using uro-fluoroacetic acid to generate the spiro derivatives [2H-1-benzopyran-2,4'-piperidine] 15 (Example Z1), 16 (Example Z2) and 17 corresponding ones. Demethylation of methyl ether 17 using boron tribromide in anhydrous dichloromean gave the phenolic derivative 18 (Example Z3). Hydrogenation of 15 in meianol in the presence of palladium hydroxide (Pearlman's caylator) gave the 3,4-dihydrospiro derivative [2 H, 1-benzopyran-2,4'-piperidine] 19 (Example Z4) (Scheme Z2). The fractionation of 15 with formaldehyde in the presence of sodium cyanoborohydride gave the A / -methyl derivative 20 (Example Z5) (Scheme Z2). 12: R = H 15: R = H (Example Z1) 13: R = F 16: R = F (Example Z2) 14: R = OCH3 17: R = 0CH3 18 (Example Z3) The compounds prepared in Examples Z6-Z9 were prepared according to Scheme Z3. The Suzuki-type coupling of the enol triflate derivative 8 (Scheme Z1) with 4- (methoxycarbonyl) phenylboronic acid 21_ in dimethoxyether in the presence of palladium-1-kerachiriphenylphosphine (0), lithium chloride and an aqueous solution of sodium carbonate gave the ester meylic acid 22 which was hydrolyzed under basic conditions to give the carboxylic acid derivative 23. The coupling of the carboxylic acid 23 with the primary amine (24) or the secondary amine derivatives (25-27) using TBTU as an agent for the coupling of the peptides gave the amides 28-31 which were converted to the spiro derivatives [2H-1-benzopyran-2,4'-pipridine] 32-34 (Examples Z6-Z8) and in acidic conditions. Hydrolysis of the ethyl ester 35 in the presence of sodium hydroxide gave the carboxylic acid 36 (Example Z9). Scheme 2: 19 (Example Z4) (Example Z5) The coupling of the Suzuki type of the enol frilide derivative 8 (Scheme Z1) with the 4-cyanophenylboronic acid 37 in dimethoxyether in the presence of palladium-3-keraphenylphenylphosphine (0), lithium chloride and an aqueous solution of sodium carbonate gave cyanide 38 which was converted to tefrazol 39 using sodium azide and zinc bromide in a 1: 1 isopropanol / water solution (Scheme Z4). The Boc group of 39 was subsequently referred to using urea-fluoroacetic acid to generate the corresponding spiro derivative [2 / - / - 1-benzopyran-2,4'-piperidine] 40 (Example Z10). Alkylation of 39 with ethyl bromopropionium in dimethylylformamide in the presence of triethylamine gave the two regioisomers 42 (secondary isomer) and 43 (major isomer) separated by column chromatography on silica gel. The Boc protecting group of 43 was then cautiously fused using uro-fluoroacetic acid to generate the corresponding spiro derivative [2H-1-benzopyran-2,4'-piperidine] 44. Hydrolysis of the eyl ester 44 in the presence of sodium hydroxide gave the carboxylic acid 45 (Example Z11) (Scheme Z4). what Z7) 36 (Example Z9) The coupling of the Suzuki type of the crude metal derivative 8 (Scheme Z1) with the 3-pyridylboronic acid 46 in dimethoxyether in the presence of palladium (0) -alkyriphenylphosphine, lithium chloride and an aqueous solution of sodium carbonate gave the compound 47 which was converted to the corresponding spiro derivative [2 / - 1-benzopyran-2,4'-piperidine] 48 (Example Z12) under acidic conditions (Scheme Z5). The Suzuki coupling of the enyl chloride derivative 8 (Scheme Z1) with the 4-methanesulfonylphenylboronic acid 49 in dimethoxyether in the presence of palladium tetrastriphenylphosphine (0), lithium chloride and an aqueous solution of sodium carbonate gave the compound 50 converted to the spiro derivative [2W-1-benzopyran-2,4'-piperidine] 51 (Example Z13) corresponding to acid conditions (Scheme Z5). Scheme 40 (Example Z10) 43 44 5 (Example Z11) The preparation of the spiro derivative [2H-1-benzopyran-2,4'-nortropine] 56 (Example Z14) is summarized in Scheme 6. The 2'-hydroxyaceiophenone (1) was condensed with 1-Boc-4-nortropinone (52) in meianol in the presence of pyrrolidine to give the derivatives of? / - Boc-spiro [2 - / - 1-benzopyran-2,4'-nortropin] -4 (3H) -one 53. Compound 55 was prepared by the conversion of the ceinone 53 to the enol trifluoride derivative 54 and the subsequent Suzuki coupling reaction with the 4- (N, N-dieylaminocarbonyl) phenylboronic acid 11_. The Boc group of 55 was briefly referred to using urea-fluoroacetic acid to generate the spiro derivatives [2A / -1-benzopyran-2,4'-noryropin] 56 (Example Z14) corresponding.

Scheme 5: (Example Z13) 50 56 (Example Z14) 5d Materials: All chemical products were of reactive quality and were used without further purification. Analííica: Thin layer chromatography (TLC) was carried out on recessed plates of flexible silica gel (250 micrometers) from Hayech and visualized by UV irradiation at 254 and iodine. The sudden chromathography was carried out using the ISCO CombiFlash with RediSep silica gel cartridges (4 g, 12 g, 40 g, 120 g). All 1 H NMR specimens were obtained at ambient temperature in a Bruker-400 MHz spectrometer. They are presented in ppm on the ¿scale, from the TMS. Damage to LC-MS was achieved using a Thermo-Finnigan Surveyor HPLC and a Thermo-Finnigan AQA MS using positive or negative evaporative ionization. Program (posiíivo) Solvent A: 10 mM ammonium acetamide, pH 4.5, 1% acetylironyl; Solvent B: Aceophylloyl; column: Michrom Bioresources Magic C18 Macro Bulleí, detector: PDA? = 220-300 nm. Gradient: 96% A-100% B in 3.2 minutes, maintain 100% B for 0.4 minutes. Program (negafive) Solvent A: 1 mM ammonium acetyl, pH 4.5, 1% acetylironyl; solvent B: acetoniiril; column: Michrom Bioresources Magic C18 Macro Bulleí, detector: PDA? = 220-300 nm. Gradient: 96% A-100% B in 3.2 minutes, maintain 100% B for 0.4 minutes. Example Z1 Preparation of the hydrochloride of 4 - [(4-A /, A / -diemylaminocarbonyl) phenyl-spiro-2H, 1-benzopyran-2,4'-piperidine1 (15) Step 1: The pyrrolidine (42 mL, 2 eq) was added to go ahead in ambience to a dissolution of 1-Boc-4-piperidone (4) (49.8 g, 0.249 mol) and 2'-hydroxyaceiophenone (1) (34 g, 0.184 mol, 1 eq) in anhydrous meianol (400 mL). The solution was heated at reflux temperature overnight and then concentrated under reduced pressure. Diethyl ether (500 mL) was added. The organic mixture was washed with an aqueous solution of 1N hydrochloric acid, an aqueous solution of 1 N sodium hydroxide, brine and dried over sodium sulfate. Hexane (300 mL) was added to the mixture. The resulting precipitate was collected by filtration, washed with hexane, and used for the next step without further purification (56.6 g, 72%). 5: 1 H NMR (400MHz, CDCl 3) 7.85 (d, 1 H), 7.45 (1, 1H), 7.00 (m, 2H), 3.85 (m, 2H), 3.20 (m, 2H), 2.70 (s, 1 H), 2.00 (d, 2H), 1.60 (m, 2H), 1.40 (s, 9H); Analysis of the mass spectra m / z = 318.0 (M + H) + IR = 2.42 minima. Step 2: To a solution of 5 (25 g, 0.078 mol) in diethylhydrofuran (250 mL) at -78 ° C in nihologen was added to a solution of 1.0 M LiHMDS in tetrahydrofuran (94.5 mL). The mixture was stirred for 1 hour at -78 ° C. A solution of N-phenyltrifluoromethanesulfonimide (33.8 g, 1.2 eq) in diethylhydrofuran (150 mL) was added to leave. The mixture was heated slowly at room temperature and the stirring was continued for a further 12 hours at ambient temperature. The mixture was then poured into ice water and the 2 phases separated. The organic phase was washed with an aqueous solution of 1 N hydrochloric acid, an aqueous solution of sodium hydroxide tN, brine and dried over sodium sulfate. The crude product was purified by column chromatography (eluyenie: mixtures of hexane / acetyl ether oil of increasing polarity) (25 g, 70%) 8: 1 H NMR (400MHz, DMSO dβ) d 7.45-7.20 ( m, 2H), 7.00 (m, 2H), 6.15 (s, 1H), 3.70 (m, 2H), 3.20 (m, 2H), 1.90 (m, 2H), 1.75 (m, 2H), 1, 40 (s, 9H); Analysis of the mass spectra m / z = 450.1 (M + H) + tR = 2.95 minutes. Step 3: To a solution of 8 (15 g, 33.37 mmol, 1 eq) in dimethoxy manganese (DME) (100 mL) was added sequentially a 2N sodium carbonate aqueous solution (50.06 mL, 100.12 mmol , 3 eq), lithium chloride (4.24 g, 100.12 mmol, 3 eq.), 4- (N, N-dieylaminocarbonyl) phenyl boronic acid 11_ (8.12 g, 36.71 mmol, 1.1) eq) and palladium (pyridylphosphine) (0) (0.77 g, 0.67 mmol, 0.02 eq). The mixture was heated at reflux temperature for 10 hours in nihologen. The mixture was then cooled to room temperature and water (250 mL) was added. The mixture was extracted with ethyl acetate. The organic phase was further washed with brine and dried over sodium sulfate. The crude product was purified by column chromatography (eluyenie: mixtures of hexane / acetyl ether oil of increasing polarity) (11.5 g, 73%). 12: 1 H NMR (400MHz, CDCl 3) d 7.35 (m, 4H), 7.15 (1, 1 H), 7.00-6.80 (m, 3H), 5.55 (s, 1 H ), 3.85 (m, 2H), 3.55 (m, 2H), 3.30 (m, 4H), 2.00 (m, 2H), 1.65 (m, 2H), 1.40 (s, 9H); 1.20 (m, 6H); Analysis of the mass spectra m / z = 477.2 (M + H) + tR = 2.82 minima. Step 4: The trifluoroacetic acid (10.33 mL, 134.09 mmol, 5.5 eq) was added drop by drop to a cold (0 ° C) solution of 12 (11, 62 g, 24.38 mmol, 1 eq) in anhydrous dichloromethane (50 mL). The mixture was heated to ambient temperature and the agitation continued for 10 more hours at ambient temperature. The mixture was then concentrated under reduced pressure. To the mixture was added a saturated solution of sodium bicarbonate (100 mL), which was extracted with dichloromethane. The organic phase was separated, washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. To a cold solution (0 ° C) of the oil resulting in anhydrous dichloromethane was added a solution of 2M anhydrous hydrochloric acid in diethyl ether (3 eq. 0.073 mol, 36.5 mL). The mixture was then stirred for 1 hour at ambient temperature and concentrated under reduced pressure. Diethyl ether was added. The resulting precipitate was collected by filtration and washed with diethyl ether (9.9 g, 99%). 15 (Example Z1): 1H NMR (400MHz, DMSO d6) d 9.1 (m, 2H), 7.40 (s, 4H), 7.20 (i, 1 H), 7.00 (m, 3H), 5.95 (s, 1H), 3.45 (m, 2H), 3.20 (m, 6H), 2.00 (m, 4H), 1 , 10 (m, 6H); Analysis of the mass spectra m / z = 377.2 (M + H) + IR = 1, 77 minutiae. Example Z2 Preparation of the hydrochloride of 4-α (4-A /,? / - dieylaminocarbonyl) phenyl-6-fluoro-spiro [2H, 1-benzopyran-2,4'-piperidine1 (16) Step 1: The compound 6 is prepared using the same procedure as described for the preparation of 5 (5 * -fluoro-2'-hydroxyacetophenone was used as starting material) (71% yield). 6: 1 H NMR (400MHz, DMSO d ") d 7.45 (m, 2H), 7.15 (d, 1 H), 3.70 (m, 2H), 3.10 (m, 2H), 2.85 (s, 1 H), 1.85 (m, 2H), 1.60 (m, 2H), 1.40 (s, 9H); Analysis of the mass spectra m / z = 377.0 (M + H + CH3CN) + IR = 2.42 minutes.

Stage 2: Compound 9 was prepared using the same procedure as described for the preparation of 8 from 5 (83% yield). 9: Analysis of the mass spectra m / z = 509.0 (M + H + CH3CN) + IR = 2.93 minutes.

Step 3: Compound 13 was prepared using the same procedure as described for the preparation of 12 from 8 (66% yield). 13: 1 H NMR (400MHz, DMSO d6) 7.40 (s, 4H), 7.05 (m, 2H), 6.70 (m, 1 H), 5.95 (s, 1 H), 3 , 70 (m, 2H), 3.45 (m, 2H), 3.20 (m, 4H), 1.85 (m, 2H), 1.60 (m, 2H), 1.40 (s, 9H); 1, 10 (m, 6H); Analysis of the mass spectrum m / z = 495.2 (M + H) + tR = 2.83 minutes. Step 4: Compound 16 was prepared using the same procedure as described for the preparation of 15 from 12 (37% yield). 16 (Example Z2): 1 H NMR (400MHz, DMSO d6) 8.95 (m, 2H), 7.40 (s, 4H), 7.10 (m, 1 H), 6.70 (m, 1 H), 6.00 (s, 1H), 3.40 (m, 2H), 3.30 (m, 2H), 3.20 (m, 4H), 2.00 (m, 4H), 1, 10 (m, 6H); Analysis of the mass spectra m / z = 395.2 (M + H) + R = 1.87 min. EXAMPLE Z3 Preparation of the hydrochloride of 4 - [(4-? / -d-epilaminocarbonyl) phenyl-1-6-hydroxyspiroyl-2H, 1-benzopyran-2,4'-piperidine1 (18) Step 1: The compound 7 was prepared using the same procedure as it has been described for the preparation of 5 (5'-meioxy-2'-hydroxyaceiophenone was used as starting material) (75% yield). 7: 1 H-NMR (400MHz, CDCl 3) 7.30 (s, 1H), 7.10 (m, 1H), 6.90 (m, 1H), 3.85 (m, 2H), 3.75 (s, 3H), 3.20 (m, 2H), 2.70 (s, 2H), 2.00 (d, 2H), 1.55 (m, 2H), 1, 40 (s, 9H); Analysis of the mass spectrum m / z = 348.0 (M + H) + tR = 2.43 min.

Step 2: Compound 10 was prepared using the same procedure as described for the preparation of 8 from 5 (96% yield). 10: 1 H NMR (400MHz, DMSO dβ) 6.95 (m, 2H), 6.70 (s, 1 H), 6.15 (s, 1 H), 3.70 (m, 5H), 3 , 15 (m, 2H), 1.85 (m, 2H), 1.70 (m, 2H), 1.40 (s, 9H); Mass spectrum analysis m / z = 480.0 (M + H) + IR = 3.01 min. Step 3: Compound 14 was prepared using the same procedure as described for the preparation of 12 from 8 (96% yield). 14: 1 H NMR (400MHz, DMSO d ") d 7.40 (s, 4H), 6.90 (d, 1H), 6.80 (m, 1H), 6.45 (s, 1H), 5.90 (s, 1H), 3.70 (m, 2H), 3.60 (s, 3H), 3.55 (m, 2H), 3.40 (m , 2H), 3.20 (m, 4H), 1.80 (m, 2H), 1.65 (m, 2H), 1.40 (s, 9H); 1.10 (m, 6H); Analysis of the mass spectra m / z = 507.1 (M + H) + IR = 2.86 minutiae. Step 4: Compound 17 was prepared using the same procedure as described for the preparation of 15 from 12 (98% yield). 17: 1H NMR (400MHz, DMSO d6) d 8.80 (m, 2H), 7.40 (m, 4H), 7.00 (d, 1H), 6.85 (m, 1H), 6.45 (s, 1 H), 5.95 (s, 1H), 3.60 (m, 5H), 3.40 (m, 2H), 3.20 (m, 4H), 2.00 (m, 4H) ), 1, 10 (m, 6H); Mass spectrum analysis m / z = 407.2 (M + H) + tR = 1, 74 min. Step 5: A solution of 17 (1 g, 2.46 mmol, 1 eq) in anhydrous dichloromethane (40 mL) was added dropwise at -78 ° C to a solution of 1M boronibromide in anhydrous dichloromean (13)., 53 mL, 13.53 mmol, 5.5 eq). The mixture was slowly heated to ambient temperature and the stirring was continued for 1 hour. The mixture was cooled to 0 ° C, water was added to water followed by a saturated aqueous solution of sodium bicarbonate. The mixture was stirred for 1 hour at ambient temperature and made basic using an additional quantity of a saturated aqueous solution of sodium bicarbonate. The phases were separated and the aqueous phase was further extracted with dichloromethane. The combined organic extracts were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (eluent: mixtures of dichloromethane / meianol of increasing polarity (0.21 g, 22%) .18 (Example Z3): H NMR (400MHz, DMSO d6) d 9.05 (FIG. s, 1 H), 8.60 (m, 2H), 7.40 (m, 4H), 6.80 (d, 1 H), 6.60 (m, 1 H), 6.40 (s, 1 H), 5.90 (s, 1 H), 3.40 (m, 4H), 3.20 (m, 4H), 2.05 (m, 2H), 1.90 (m, 2H), 1, 10 (m, 6H); Analysis of the mass spectra m / z = 393.2 (M + H) + tR = 1, 54 min. Example Z4 Preparation of the hydrochloride of 4 - [(4 -? /, A / -diemylaminocarbonyl) phenin-3,4-dihydrospirof2H, 1-benzopyran-2,4'-piperidinal (19) A solution of 15 (0.66 g) in Anhydrous melanol was hydrogenated at atmospheric pressure in the presence of palladium hydroxide [Pd (OH) 2: Pearlman cayalizer] (0.120 g) lasts 10 hours. The mixture was then filtered through Celite. The filtrate was concentrated and hydrogenated at atmospheric pressure in the presence of palladium hydroxide (0.120 g) for a further 10 hours. The mixture was filtered through Celine and the filtrate was concentrated to dryness under reduced pressure. To a cold solution (0 ° C) of the resulting oil in anhydrous dichloromethane was added dropwise a solution of 2M anhydrous hydrochloric acid in diethyl ether (5 mL). The mixture was then stirred for 1 hour at ambient temperature and concentrated under reduced pressure. Diethylether was added. The resulting precipitate was collected by filtration and washed with diethyl ether and ethyl acetate (0.457 g, 63%). 19 (Example Z4): 1 H NMR (400MHz, DMSO d6) d 9.15 (s, 1H), 8.60 (m, 2H), 7.30 (m, 4H), 7.10 (m, 1 H) ), 6.90 (m, 1 H), 6.75 (m, 1H), 6.60 (m, 1 H), 4.20 (m, 1 H), 3.40 (m, 2H), 3.20 (m, 5H), 3.00 (m, 1 H), 2.15 (m, 2H), 1.95 (m, 5H), 1. 05 (m, 6H); Analysis of the mass spectra m / z = 379.1 (M + H) + IR = 1.74 minutes. EXAMPLE Z5 Preparation of 4 - [(4- / V, / V-dieylaminocarbonyl) phenin - / / -methyl-spiro [2 H, 1-benzopyran-2,4'-piperidinal hydrochloride (20) The amyrylamine ( 0.37 mL, 2.66 mmol, 2.2 eq.) Was added to a solution of 15 (HCl salt, 0.500 g, 1.21 mmol, 1 eq.) In anhydrous hydrohydrofuran (4 mL). Then anhydrous meianol (4 g) was added, followed by formaldehyde (0.20 mL, 2.42 mmol, 2 eq). Next to the reaction mixture was added sodium cyanoborohydride (0.090 g, 1.45 mmol, 1.2 eq), which was stirred for 30 min at ambient temperature in nihologen. The mixture was concentrated under reduced pressure. Dichloromethane (30 mL) and water (10 mL) were added and the suspension was stirred at ambient temperature for 10 minutes. The phases separated. The organic phase was further washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure. To a cold solution (0 ° C) of the oil resulting in anhydrous dichloromethane was added a solution of 2M anhydrous hydrochloric acid in diethyl ether (5 mL). The mixture was then stirred for 1 hour at ambient temperature and concentrated under reduced pressure. Diethyl ether was added. The resulting precipitate was collected by filtration and washed with diethyl ether. (0.340 g, 65%). 20 (Example Z5): 1 H NMR (400MHz, DMSO d6) 10.5 (m, 1H), 7.40 (m, 4H), 7.25 (m, 1H), 7.10 (m, 1 H) ), 6.95 (m, 2H), 5.85 (s, 1 H), 3.60-3.10 (m, 8H), 2.80 (s, 3H), 2.10 (m, 4H) ), 1.10 (m, 6H); Analysis of the mass spectrum m / z = 391, 2 (M + H) + IR = 1, 82 min. Example Z6 Preparation of the hydrochloride of 4-f (4-N-ethylaminocarbonyl) phenylarspiro [2H, 1-benzopyran-2,4'-piperidinal (32) Steps 1.2: See the preparation of 8 from 1,. Step 3: Compound 22 was prepared using the same procedure as described for the preparation of 12 from 8 (64% yield). The [4- (mexoxycarbonyl) phenylboronic acid 21 was used in place of 4- (N, N-dieylaminocarboniphenylboronic acid 111. 22: 1 H NMR (400MHz, DMSO d6) d 8.00 (d, 2H), 7.45 ( d, 2H), 7.20 (m, 1H), 7.00 (m, 1 H), 6.90 (m, 2H), 5.90 (s, 1 H), 3.90 (s, 3H), 3.70 (m, 2H), 3.25 (m, 2H), 1.85 (m, 2H), 1.70 (m, 2H), 1.40 (s, 9H); Analysis of the mass spectra m / z = 436.0 (M + H) + tR = 3.12 minutes. Step 4: The lithium hydroxide (0.54 g, 12.98 mmol, 1.2 eq) was added to a solution of (4.71 g, 10.81 mmol, 1 eq) in hydrofuran (30 mL) and water (30 mL). The mixture was stirred for 10 hours at ambient temperature and acidified to pH 1 using an aqueous solution of 2N hydrochloric acid. The mixture was concentrated under reduced pressure. Acetyl ether was added and the phases were separated. The aqueous phase is further extracted with ethyl acetate. The combined organic extracts were washed with water, brine, dried over sodium sulfate and evaporated to give the carboxylic acid 23 which was used for the next step without further purification. (99%) 23: 1H NMR (400MHz, DMSO d6) 13.00 (s, 1 H), 8.00 (d, 2H), 7.50 (d, 2H), 7.20 (m, 1 H), 7.00-6.85 (m, 3H), 5.90 (s, 1 H), 3.70 (m, 2H), 3.30 (m, 2H), 1, 85 (m, 2H), 1.70 (m, 2H), 1.40 (s, 9H); Analysis of the mass spectra m / z = 420, 1 (M-H) + tR = 2, 10 min.

Stages 5-6: < To a solution of 23 (0.18 g, 0.43 mmol, 1 eq.) In acetoniiril (5 mL) was added diisopropylethylamine (0.17 mL, 0.94 mmol, 2.2 eq), hydrochloride ethylamine (0.08 g, 0.94 mmol, 2.2 eq.) and TBTU (0.15 g, 0.47 mmol, 1.1 eq.). The mixture was stirred at room temperature under nitrogen for 10 hours. The mixture was then poured into a saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic extracts were washed with brine, dried over sodium sulfate and concentrated under reduced pressure to give the amide 28 in which was used for the next step without further purification. The trifluoroacetic acid (1.20 mL, 5.5 eq) was added in a goi ve manner to a cold (0 ° C) solution of the compound 28 obtained previously in anhydrous dichloromethane (10 mL). The mixture was heated to ambient temperature and the stirring continued for 10 more hours. The mixture was then concentrated under reduced pressure. A saturated solution of sodium bicarbonate (100 mL) was added to the mixture, which was extracted with dichloromethane. The organic phase was separated, washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. To a cold solution (0 ° C) of the oil resulting in anhydrous dichloromethane was added a solution of 2M anhydrous hydrochloric acid in diethyl ether (3 eq., 0.073 mol, 36.5 mL). The mixture was then stirred for 1 hour at room temperature and concentrated under reduced pressure. Diethyl ether was added. The precipice Result was collected by filtration and washed with diethyl ether. (0.033 g, 21%). 32 (Example Z6): 1 H NMR (400MHz, DMSO d6) d 8.50 (m, 1H), 7.90 (d, 2H), 7.40 (d, 2H), 7.20 (m, 1 H) ), 6.90 (m, 3H), 5.85 (s, 1H), 3.30 (m, 2H), 2.90 (m, 2H), 2.70 (m, 2H), 1.85 -1, 70 (m, 4H), 1, 10 (t, 3H); Analysis of the mass spectra m / z = 349.2 (M + H) + IR = 1, 56 min. EXAMPLE Z7 Preparation of the hydrochloride of 4 - [(4-A / -propyl-β-cyclopropylmethylaminocarbonyl) phenin-2-pyridine, 1-benzopyran-2,4'-piperidine1 (33) Steps 1-2: See the preparation of 8 a from JL Steps 3-4: See preparation of 23 from 8. Steps 5-6: Compound 33 was prepared using the same procedure described for the preparation of 32 from 23 (30% yield). [? / - Propyl -? / - cyclopropyl amine 25 was used in place of 241 erylamine. 33 (Example Z7): 1 H NMR (400MHz, DMSO dβ) d 9.00 (m, 1 H), 7.40 (m, 4H), 7.25 (m, 1 H), 7.00 (m, 3H), 5.90 (s, 1 H), 3.55-3.05 (m, 8H), 2, 05 (m, 4H), 1, 60 (m, 2H), 1, 10 (m, 1 H), 0.90 (m, 2H), 0.65 (m, 1 H), 0.40 (m , 2H), 0.15 (m, 1 H), 0.10 (m, 1 H); Analysis of the mass spectra m / z = 417.2 (M + H) + IR = 2.03 minima. Example Z8 Preparation of the hydrochloride of 4-r4- (isoindolinaminocarbonyl) phenin-2-spiro, 1-benzopyran-2,4'-piperidinal (34) Steps 1-2: See the preparation of 8 from. Steps 3-4: See the preparation of 23 from 8. Steps 5-6: Compound 34 was prepared using the same procedure as described for the preparation of 32 from 23 (44% yield). [Isoindoline 26 was used in place of eiylamine 24]. 34 (Example Z8): 1 H NMR (400MHz, DMSO d6) d 8.90 (m, 2H), 7.70 (d, 2H), 7.50 (d, 2H), 7.40 (m, 1 H) ), 7.30 (m, 4H), 7.00 (m, 3H), 5.95 (s, 1 H), 4.90 (s, 2H), 4.80 (s, 2H), 3, 30 (s, 4H), 2.05 (m, 4H); Analysis of the mass spectra m / z = 423.2 (M + H) + IR = 1, 94 min. Example Z9 Preparation of the hydrochloride of 4-r4- (4-carboxypiperidinaminocarbonyl) phenyl "l-spirof2H, 1-benzopyran-2,4'-piperidine1 (36) Steps 1-2: See the preparation of 8 from 1 Steps 3-4: See the preparation of 23 from 8. Steps 5-6: The compound 35 was prepared using the same procedure as described for the preparation of 32 from 23 (63% yield). [4-Eioxycarbonylpiperidine 27 was used in place of the erylamine 24] .35: 1H NMR (400MHz, DMSO d6) d 8.65 (m, 2H), 7.45 (m, 4H), 7.25 ( , 1 H), 7.00 (m, 3H), 5.95 (s, 1 H), 4.35 (m, 1 H), 4.10 (c, 2H), 3.95-3.55 (m, 3H), 3.25 (m, 4H), 2.65 (m, 1 H), 2.15-1, 75 (m, 6H), 1.50 (m, 2H), 1, 20 (í, 3H); Analysis of the mass spectra m / z = 461, 2 (M + H) + IR = 1.86 minutes. Step 7: An aqueous solution of 2N sodium hydroxide (1.0 mL, 2 mmol, 9.2 eq.) Was added to a solution of 35 (0.100 g, 0.22 mmol, 1 eq.) In tetrahydrofuran (5 mL). ) and pure anhydrous alcohol (5 mL). The mixture was stirred for 10 hours at ambient temperature and acidified to pH 6 using an aqueous solution of 2N hydrochloric acid. The mixture was concentrated under reduced pressure. The mixture was then stirred for 1 hour at room temperature. The resulting precipitate was collected by filtration, and washed several times with water and diethyl ether (0.054 mg, 60%). 36 (Example Z9): 1 H NMR (400MHz, DMSO d6) d 7.40 (m, 4H), 7.20 (m, 1H), 6.95 (m, 3H), 5.90 (s, 1 H) ), 4.30 (m, 1 H), 3.65-2.90 (m, 8H), 2.10-1, 70 (m, 6H), 1.50 (m, 2H); Analysis of the mass spectra m / z = 433.1 (M + H) + IR = 1, 39 min. Example Z10 Preparation of the trifluoroacetic acid salt of 4- [4- (2H-tetrazoli-pheyp-spiro-2H, 1-benzopyran-2,4'-piperidine1 (40) Steps 1-2: See preparation of 8 from 1. Stage 3 : To a solution of 8 (7.80 g, 17.35 mmol, 1 eq) in dimethoxyethane (DME) (75 mL) was added sequentially an aqueous 2N sodium carbonate solution (26.03 mL, 52.06 mmol , 3 eq.), Lithium chloride (2.21 g, 52.06 mmol, 3 eq), 4-cyanophenylboronic acid 37 (2.81 g, 19.09 mmol, 1.1 eq) and tetrakis (urea) The mixture was heated at reflux for 10 h under nitrogen, then the mixture was cooled to room temperature and water (250 mL) was added. The mixture was extracted with ethyl acetate, the organic phase was further washed with brine and dried over sodium sulfate.The crude product was purified by column chromatography (eluent: hexane / acetone mixtures of ethyl acetate). increasing rate) (5.20 g, 74%) 38: 1 H NMR (400MHz, DMSO d6) 7.90 (d, 2H), 7.50 (d, 2H), 7.20 (m, 1 H) ), 7.00 (m, 1 H), 6.90 (m, 2H), 5.95 (s, 1 H), 3.70 (m, 2H), 3.25 (m, 2H), 1 , 85 (m, 2H), 1.70 (m, 2H), 1.40 (s, 9H); Analysis of the mass spectrum m / z = 403.1 (M + H) + IR = 2.98 min. Stage 4: A mixture of 38 (4.95 g, 0.0122 mol, 1 eq), sodium azide (1, 60 g, 0.024 mol, 2 eq) and zinc bromide (1.38 g, 0.0061 mol, 0, 5 eq) in isopropanol (100 mL) and water (80 mL) was heated at reflux temperature for 3 days. The reaction mixture was then cooled to 0 ° C and acidified to pH 1 using an aqueous 3N hydrochloric acid solution. The mixture was extracted with acetone. The organic phase was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. Diethyl ether (30 mL) was added. The resulting precipitate was collected by filtration and washed with diethyl ether. The crude compound was used in the next step without further purification (3.25 g, 59%). 39: 1 H NMR (400MHz, DMSO d6) d 8.10 (d, 2H), 7.55 (d, 2H), 7.20 (m, 1 H), 7.00 (m, 2H), 6.90 (m, 1 H), 5.90 (s, 1 H), 3.70 (m, 2H), 3.30 (m, 2H), 1.90 (m, 2H), 1.70 (m, 2H), 1.40 (s, 9H); Analysis of the mass spectra m / z = 446.1 (M + H) + tR = 2.22 minima. Step 5: The trifluoroacetic acid (0.18 mL, 0.0023 mol, 5 eq) was added drop wise to a cold (0 ° C) solution of 39 (0.206 g, 0.00046 mol, 1 eq) in dichloromean anhydrous (10 mL). The mixture was heated at ambient temperature and the stirring continued for 10 h at room temperature. The precipitate was collected by filtration and washed with diethyl ether (0.112 g, 52%). 40 (Example Z10): 1 H NMR (400MHz, DMSO d6) d 8.60 (m, 1H), 8.10 (d, 2H), 7.60 (d, 2H), 7.25 (m, 1 H) ), 7.00 (m, 3H), 6.00 (s, 1 H), 3.40 (m, 2H), 3.25 (m, 2H), 2.10 (m, 2H), 1, 95 (m, 2H); Analysis of the mass spectrum m / z = 346.1 (M + H) + tR = 1, 33 min. Example Z11 Preparation of 4-r4- (4-carboxypropyl-fefrazol-2-yl) phenyl '| -spiror2H, 1-benzopyran-2,4'-piperidine] (45) Steps 1-2: See the preparation of 8 a Starting from 1. Stages 3-4: See the preparation of 39 from 8. Stage 5: Ethyl bromobuyral (41.) (0.40 mL, 0.0028 mol, 2.5 eq) was added to The solution was diluted to 39 (0.500 g, 0.0011 mol, 1 eq) and eryrylamine (0.40 mL, 0.0028 mol, 2.5 eq) in anhydrous dimethylformamide and the mixture was stirred at ambient temperature for 3 days . The mixture was poured into water (50 mL) and extracted with ethyl acetate. The organic phase was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The bruise production was purified by sudden column chromatography (eluyenie: mixtures of hexane / oil effile of increasing polarity). The secondary regioisomer 42 was isolated with a yield of 6% (40 mg); the major regioisomer 43 was isolated with 82% (0.520 g). 42: 1 H NMR (400MHz, DMSO d6) 7.90 (d, 2H), 7.60 (d, 2H), 7.20 (m, 1 H), 7.00 (m, 2H), 6.90 (m, 1 H), 5.95 (s, 1 H), 4.55 (t, 2H), 4.00 (c, 2H), 3.70 (m, 2H), 3.30 (m, 2H), 2.40 (m, 2H), 2.10 (m, 2H), 1.90 (m, 2H), 1.70 (m, 2H), 1, 40 (s, 9H), 1, 10 (1, 3H); Analysis of the mass spectra m / z = 560.2 (M + H) + IR = 2.83 min. 43: 1 H NMR (400MHz, DMSO d6) 8.10 (d, 2H), 7.50 (d, 2H), 7.20 (m, 1H), 7.00 (m, 2H), 6.90 (m, 1 H), 5.90 (s, 1 H), 4.70 (t, 2H), 4.00 (c, 2H), 3.70 (m, 2H), 3.30 (m, 2H), 2.40 (m, 2H), 2.10 (m, 2H), 1.90 (m, 2H), 1.70 (m, 2H), 1.40 (s, 9H), 1, 15 (t, 3H); Analysis of the mass spectra m / z = 560.3 (M + H) + IR = 3.09 min. Step 6: An anhydrous solution of 2M hydrochloric acid in diethyl ether (10 mL) was added as desired to a cold (0 ° C) solution of 43 (0.520 g, 0.00092 mol, 1 eq) in anhydrous dichloromethane (10 mL). ). The mixture was heated to ambient temperature and the stirring was continued for a further 10 hours at room temperature. An adonal amount (10 mL) of an anhydrous 2M hydrochloric acid solution in diethylether was added to the mixture, which was stirred for a further 6 hours at ambient temperature. The mixture was concentrated under reduced pressure. Diethyl ether was added. The resulting precipitate was collected by filtration and washed with diethyl ether. (0.321 g, 70%). 44: 1H NMR (400MHz, DMSO d6) d 8.80 (m, 1H), 8.15 (d, 2H), 7.60 (d, 2H), 7.25 (m, 1 H), 7, 00 (m, 3H), 6.00 (s, 1H), 4.80 (i, 2H), 4.00 (c, 2H), 3.35 (m, 2H), 3.20 (m, 2H) ), 2.40 (m, 2H), 2.20 (m, 2H), 2.10 (m, 2H), 1.95 (m, 2H), 1.15 (t, 3H); Analysis of the mass spectrum m / z = 460.2 (M + H) + tR = 2.08 minima. Step 7: An aqueous solution of 2N sodium hydroxide (1.8 mL, 0.0036 mol, 5.5 eq.) Was added to a solution of 44 (0.300 g, 0.00060 mol, 1 eq) in tetrahydrofuran (10 g). mL) and pure ethanol (1 mL). The mixture was stirred for 10 hours at ambient temperature and acidified to pH 6 using an aqueous solution of 2N hydrochloric acid. The mixture was concentrated under reduced pressure. The mixture was then stirred for 1 hour at ambient temperature. The resulting precipitate was collected by filtration, washed several times with water and dieyl ether (0.258 mg, 98%). 45 (Example Z11): 1 H NMR (400MHz, DMSO d6 + CF3CO2d) 8.80 (m, 1 H), 8.20 (m, 2H), 7.70 (m, 2H), 7.30 (m , 1H), 7.00 (m, 3H), 6.00 (s, 1H), 4.80 (m, 2H), 3.30 (m, 4H), 2.60-1, 95 (m, 8H); Analysis of the mass spectra m / z = 432.1 (M + H) + IR = 1.65 minutes. Example Z12 Preparation of the hydrochloride of 4- (3-pyridyl) -spiroyl-2H, 1-benzopyran-2,4'-piperidine1 (48) Steps 1-2: See the preparation of 8 from?.

Steps 3-4: To a solution of 8 (0.5 g, 1 eq.) In dimethoxy manganese (DME) (3.5 mL) was added sequentially an aqueous 2N sodium carbonate solution (1.67 mL, 3 eq.). .), lithium chloride (0.141 g, 3 eq), 3-pyridiomeric acid 46 (0.199 g, 1.1 eq) and teirac (triphenylphosphine) palladium (0) (0.025 g, 0.02 eq). The reaction mixture was heated using a MicroSynfh Microwave Lab Station (Milestone), with the following temperature conditions: the temperature increased from 25 ° C to 160 ° C during 15 min; The temperature was stabilized at 160 ° C for 15 minutes; The temperature was reduced from 160 ° C to 25 ° C during 15 minutes. Dichloromethane (10 mL) and an aqueous solution of 1 N sodium hydroxide (10 mL) were added to the reaction mixture. The phases separated. The organic phase was dried over sodium sulfate and filtered. Trifluoroacetic acid (3 mL) was added to the filtrate and the mixture was stirred at room temperature for 10 hours. The mixture is then concentrated under reduced pressure. A saturated solution of sodium bicarbonate (100 mL) was added to the mixture, which was extracted with dichloromethane. The organic phase was separated, washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography [eluent: dichloromethane / meianol (containing 1% ammonium hydroxide) using solvent mixtures of increasing polarity. To a cold (0 ° C) solution of the oil resulting in anhydrous dichloro-nitrogen was added dropwise a solution of 2M anhydrous hydrochloric acid in diethyl ether (3 eq., 1.67 mL). The mixture was then stirred for 1 hour at ambient temperature and concentrated under reduced pressure. Diethylether was added. The resulting precipitate was collected by filtration and washed with diethyl ether. (0.189 g, '61%). 48 (Example Z12): 1 H NMR (400MHz, DMSO d6) 9.50 (m, 2H), 8.90 (m, 2H), 8.40 (m, 1 H), 8.00 (m, 1 H), 7.25 (m, 1 H), 7.10 (m, 1 H), 6.95 (m, 2H), 6.20 (s, 1H), 3.20 (m, 4H), 2.10 (m, 4H); Analysis of the mass spectra m / z = 279.1 (M + H) + IR = 1.42 minutes.

Example Z13 Preparation of the hydrochloride of 4-β4- (menesosulfonyl) -pheni'1-spiro [2H, 1-benzopyran-2,4'-piperidinal (51) Steps 1-2: See the preparation of 8 from 1_. Steps 3-4: To a solution of 8 (0.5 g, 1 eq.) In dimethoxy manganese (DME) (3.5 mL) was added sequentially a 2N aqueous sodium carbonate solution (1.67 mL, 3 eq). .), lithium chloride (0.141 g, 3 eq), 4-methandosulfonyl-phenyl boronic acid 49 (0.244 g, 1.1 eq) and palladium (0) (palladium (pyridylphosphine)) (0.025 g, 0.02 eq). The reaction mixture was heated using a MicroSyníh Microwave Lab Síaíion (Milestone), with the following temperature conditions: the temperature was increased from 25 ° C to 160 ° C for 15 min; the temperature stabilized at 160 ° C for 15 minutes; The temperature decreased from 160 ° C to 25 ° C during 15 min. Dichloromean (10 mL) and an aqueous solution of 1 N sodium hydroxide (10 mL) were added to the reaction mixture. The phases separated. The organic phase was dried over sodium sulfate and filtered. Trifluoroacetic acid (3 mL) was added to the filtrate and the mixture was stirred at ambient temperature for 10 h. The mixture was subsequently concentrated under reduced pressure. A saturated solution of sodium bicarbonate (100 mL) was added to the mixture, which was extracted with dichloromethane. The organic phase was separated, washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude production was purified by column chromatography [eluent: dichloromethane / meianol (containing 1% ammonium hydroxide) using solvent mixtures of increasing polarity. A solution of 2M anhydrous hydrochloric acid in dieryl ether (3 eq. The mixture was then stirred for 1 hour at ambient temperature and concentrated under reduced pressure. Diethylether was added. The resulting precipitate was collected by filtration and washed with diethyl ether. (0.269 g, 68%). 51 (Example Z13): 1 H NMR (400MHz, DMSO d6) d 8.95 (m, 2H), 8.00 (d, 2H), 7.65 (d, 2H), 7.25 (m, 1 H) ), 7.05 (m, 2H), 6.95 (m, 1 H), 6.00 (s, 1 H), 3.30 (s, 3H), 3.20 (m, 4H), 2 , 10 (m, 4H); Analysis of the mass spectra m / z = 356.1 (M + H) + IR = 1, 54 minutes. Example Z14 Preparation of the hydrochloride of 4 - [(4 -? /, And V-dieylaminocarbonyl) phenyl-spiro [2H-1-benzopyran-2,4'-nortropin-1 (56) Step 1: The pyrrolidine (1, 83 mL, 0.022 mol, 2 eq ) was added to the ambient atmosphere with a solution of 1-Boc-4-norfropinone (52) (2.5 g, 0.011 mol, 1 eq) and 2'-hydroxyaceiophenone (1.51 g, 0.011 mol, 1 eq) in anhydrous meianol (15 mL). The solution was heated at reflux temperature for 3 days and then concentrated under reduced pressure. Diethyl ether (200 mL) was added. The organic mixture was washed with an aqueous solution of 1 N hydrochloric acid, an aqueous solution of 1 N sodium hydroxide, brine and dried over sodium sulfate. The crude product was purified by column chromatography using solvent mixtures of increasing polarity (eluyenie: hexane / effile acetyl, 0.80 g, 30%). 53: 1H NMR (400MHz, DMSO d6) d 7.70 (m, 1 H), 7.60 (m, 1 H), 7.00 (m, 2H), 4.10 (s, 2H), 2.65 (s, 2H), 2.00 (m, 4H), 1.90 (m, 2H), 1.75 (m, 2H), 1.40 (s, 9H); Analysis of the mass spectra m / z = 385.0 (M + H + CH3CN) + IR = 2.51 minima.

Step 2: To a solution of 53 (0.75 g, 0.00218 mol) in diethylhydrofuran (10 mL) at -78 ° C in nihologen was added a solution of 1.0 M LiHMDS in hydrofuran (2, 62 mL, 0.00262 mol, 1.2 eq). The mixture was stirred for 1 hour at -78 ° C. A solution of? / - phenyl-trifluoromethanesulfonimide (0.936 g, 0.00262 mol, 1.2 eq) in diethylhydrofuran (10 mL) was added as desired. The mixture was heated slowly to ambient temperature and the agitation continued for 12 hours at ambient temperature. The mixture was then poured into ice water and the 2 phases separated. The organic phase was washed with an aqueous solution of 1 N hydrochloric acid, an aqueous solution of 1 N sodium hydroxide, brine and dried over sodium sulfate. The crude product was purified by column chromatography using solvent mixtures of increasing polarity (eluent: hexane / acetyl acetate 0.76 g, 69%). 54: Analysis of the mass spectra m / z - 517.0 (M + H + CH3CN) + IR = 3.05 min.

Step 3: To a solution of 54 (0.760 g, 0.001598, 1 eq) in dimethoxy manganese (DME) (10 mL) was added sequentially an aqueous solution of 2N sodium carbonate (2.4 mL, 0.00479 mol, 3 eq), lithium chloride (0.203 g, 0.00479 mol, 3 eq), 4- (N, N-diethylaminocarbonyl) phenylboronic acid 1 (0.388 g, 0.00175 mol, 1.1 eq) and irrake (iriphenylphosphine) ) of palladium (0) (0.037 g, 0.0000319 mol, 0.02 eq). The mixture was heated to reflux temperature for 10 hours under nitrogen. The mixture was then cooled to ambient temperature and water (250 mL) was added. The mixture was extracted with acetone. The organic phase was further washed with brine and dried over sodium sulfate. The crude product was dissolved in hexane. The resulting precipitate was collected by filtration and washed with hexane (0.5 g, 62%). 55: 1H NMR (400MHz, DMSO d6) 7.40 (m, 4H), 7.20 (1, 1 H), 7.00 (m, 3H), 5.60 (s, 1 H), 4 , 10 (m, 2H), 3.45 (m, 2H), 3.20 (m, 2H), 2.15 (m, 4H), 1.90 (m, 4H), 1.40 (s, 9H); 1, 10 (m, 6H); Analysis of the mass spectra m / z = 503.2 (M + H) + IR = 2.96 minima. Stage 4: The trifluoroacetic acid (0.19 mL, 0.00248 mol, 5 eq.) Was added in a goi solution to a cold (0 ° C) solution of 55 (0.250 g, 0.00049 mol, 1 eq.) In anhydrous dichloromethane. (10 mL). The mixture was heated to room temperature and stirring continued for 10 more hours. The mixture was then concentrated under reduced pressure. To the mixture was added a saturated solution of sodium bicarbonate (20 mL), which was extracted with dichloromethane. The organic phase was separated, washed with brine, dried over sodium sulfate and concentrated under reduced pressure. To a cold solution (0 ° C) of the resulting oil in anhydrous dichloromethane was added a solution of 2M anhydrous hydrochloric acid in diethyl ether (3 eq., 0.00149 mol, 0.75 mL). The mixture was then stirred for 1 hour at ambient temperature and concentrated under reduced pressure. Diethyl ether was added. The resulting precipitate was collected by filtration and washed with diethyl ether (0.125 g, 57%). 56 (Example Z14): 1 H NMR (400MHz, DMSO d6) 9.4 (m, 2H), 7.40 (d, 2H), 7.30 (d, 2H), 7.20 (t, 1 H) ), 6.95 (m, 3H), 5.55 (s, 1 H), 4.00 (s, 2H), 3.40 (m, 2H), 3.20 (m, 2H), 2, 25 (m, 6H), 2.00 (m, 2H), 1, 10 (m, 6H); Analysis of the mass spectra m / z = 403.2 (M + H) + fR = 1, 91 minima. Table Z1 Biological Activity The potencies of the final compounds found in Examples Z1-Z14 and Cripples in Table Z1 were determined by testing the ability of a range of concentrations of each compound to inhibit the binding of the non-selective opioid antagonist, [3H] diprenorphine, to opioid receptors μ ,. ,? and cloned humans, expressed in different cell lines. The Cl50 values were obtained by means of non-linear damage analysis using GraphPad Prism version 3.00 for Windows (GraphPad Software, San Diego). The values of K, were obtained by means of the Cheng-Prusoff corrections of the Cl 50 values. Union to the Receptor The Receptor Binding Procedure (DeHaven and DeHaven-Hudkins, 1998) was a modification of the procedure of Raynor et al. (1994). After dilution in buffer A and homogenization as above, the membrane proteins (10-80 μg) in 250 μL were added to mixtures containing the test compound and [3 H] diprenorphine (0.5 to 1.0 nM). , 40,000 to 50,000 dpm) in 250 μL of buffer A in 96-well deep polysyrene toll plates (Beckman). After incubation at ambient temperature for one hour, the samples were filtered through GF / B filters previously soaked in a 0.5% (w / v) polyethylenimine solution and 0.1% bovine serum albumin (p / v). v) in water. The filters were rinsed 4 times with 1 mL of 50 mM cold Tris HCl, pH 7.8 and the remaining radioactivity on the filiras was determined by scintillation spectroscopy. The non-specific binding was determined by the minimum values of the expression curves and confirmed by wells with a different assay containing 10 μM naloxone. The values of K i were determined by the Cheng-Prusoff corrections of the Cl 50 values derived from the linear regression fits of 12-point curve curves using GraphPad Prism® version 3.00 for Windows (GraphPad Software, San Diego, CA ). To determine the dissociation equilibrium constant for the inhibitors (K), the bound radioligand (cpm) was measured in the presence of various concentrations of the test compounds. The concentration to give the semi-maximal inhibition (CE50) of radioligand binding was determined from a better fit of the non-linear regression to the following equation, Y where Y is the amount of radioligand bound to each concentration of the compound test, Bottom is the calculated amount of bound radioligand in the presence of an infinite concentration of the test compound, Top is the calculated amount of radioligand bound in the absence of the test compound, X is the logarithm of the concentration of the test compound, and LogCE5o is the log of the concentration of the test compound in which the amount of radioligand bound is halfway between Top and Bottom. The adjustment of the non-linear regression was performed using the Prism® program (GraphPad Software, San Diego, CA). The Ki values were then determined from the EC50 values by the following equation, where [ligand] is the concentration of radioligand and Kd is the balance of the dissociation equilibrium for the radioligand. Receptor binding mediated by [35S1GTPDS] The potency and efficacy of the compounds in each of the receptors were assessed by modifications of the procedures of Selley et al., 1997 and Traynor and Nahorski, 1995 using receptor binding mediated by [35S] ] GTP? S in the same membrane preparations used to measure receptor binding. The assays were carried out in 96-well FlashPlaies® (Perkin? Lmer Life Sciences, Inc., Boston, MA). Membranes prepared from CHO cells expressing the appropriate receptor (50-100 μg proiein) were added to assay mixtures containing agonisia with or without antagonists, [35S] GTPDS 100 pM (approx 100,000 dpm), GDP 3.0 μM, 75 mM NaCl, 15 mM MgCl 2, ethylene glycol-bis (-aminoeiyléfer) -N,? /, / V ', 1 / 0mM feyracemic acid, 1.1 mM diolino-glycol, 10 μg / mL of leupepin, 10 μg / mL of pepsifaina A, 200 μg / mL of baciiracin, and 0.5 μg / mL of aproinin in 50 mM Tris-HCl buffer, pH 7.8. After incubation at ambient temperature for one hour, the plates were sealed, centrifuged at 800 xg in a Swinging Buckey tilting rotor for 5 min and the bound radioactivity was determined with a scintillation counter for TopCount microplates (Packard Instrument Co., Meriden, CT). The EC50 values for the agonists were determined from adjustments of the non-linear regression of 8 or 12-point induction curves to the equation of 4 parameters for a sigmoid dose-response with a slope factor of 1.0 using GraphPad. Prism® version 3.00 for Windows (GraphPad Software, San Diego, CA). To determine the IC50 values, the concentration was measured to give the semi-maximal inhibition of binding of [35S] GTP [beta] S stimulated by the agonist, the amount of [35S] GTP [beta] S bound in the presence of a fixed agonist concentration and of various concentrations of antagonist. The fixed concentration of agonist was CE8o, the concentration to give 80% of the maximum relative stimulation of binding of [35S] GTP? S. The agonists loperamide (100 nM), U50.488 (50 nM), and BW373U86 (2.0 nM) were used to stimulate the binding of [35S] GTP? S to the opiate receptors β, y and d respectively. The Cl50 value was determined from a better adjustment of the damae of the non-linear regression to the equation of 4 parameters for a sigmoidal dose-response with a slope factor of 1.0 using GraphPad Prism® version 3.00 for Windows. In vivo assays Diarrhea induced by castor oil The mice were fasted overnight with water ad libitum. The mice were weighed, 0.6 mL of castor oil was orally administered and placed in individual cubicles (11 cm x 10 cm) covered with a sheet of preweighed absorbent paper. Thirty minutes after receiving the castor oil, the mice were injected s.c. with the test compound. 75 min after dosing with the castor oil, the mice and the absorbent paper were reweighed and the number of mice with diarrhea (defined as a wet and reportable deposition) was determined. The percent inhibition by the test compounds in the diarrhea test induced by castor oil was determined by the following formula: 1 - . 1 - (response to the agonist) x 100 (response to the vehicle) Example Z1 reduced the incidence of diarrhea in a time-dependent manner: SD50 (s.c.) = 8.7 mg / kg. Hyperalgesia induced by Freund's complete adjuvant (FCA). The rats were injected intraplantaly with FCA and 24 hours later they were irradiated with the test compounds administered orally. The leg pressure thresholds (UPP) were evaluated 30, 60, 120, and 240 minutes after the treatment with the drug. Example Z1 significantly increased the UPP by 170-180% in the inflamed paw 1-2h after oral administration (ED50 = 2.5 mg / kg p.o.). Example Z1 produced a similar increase in UPP in the non-inflamed country at 2 o'clock, a change that is generally associated with mid-erythroidal effects of the central nervous system. Acetic acid-induced seizures Male ICR mice weighing 20-25 g were injected s.c. with the vehicle or with the test compound 15 minutes before being injected intraperitoneally with 0.6% acetic acid. At 5 minutes after the treatment with acidic acid, the number of seizures was counted for 10 minutes. The response dose curves are expressed as the percentage of inhibition of seizures induced by acetic acid, when compared to the mean number of seizures observed in mice irradiated with the vehicle. The average inhibition percentage (% I) of acetic acid-induced seizures for mice irradiated with the drug is calculated according to the following formula:% l = (Average vehicle response - Average individual response) x 100 (Average vehicle response ) The mean individual response is the mean number of convulsions in mice irradiated with the test compound. The average response to the vehicle is the average number of seizures in mice treated with the vehicle. Example Z1 produces a 69% inhibition of seizures induced by acetic acid at 30 mg / kg (sc). Results and descriptions The potencies of the compounds were determined by testing the ability of a range of concentrations of each compound to inhibit binding of the compound. non-selective opiate antagonist, [3 H] diprenorphine, to cloned human opiate receptors μ, K and d, expressed in different cell lines. All tested compounds (Examples Z1-Z14, Table Z2) bind with high affinity to the cloned human opioid receptor. These compounds have a high selectivity for 6? and dμ. The potencies of the ligands were evaluated by their capacities for the binding stimulated by [35 S] GTP? S to membranes that condense the cloned human opiate receptors. All the compounds tested were opioid receptor agonisias with EC50 values in the nanomolar inervator (Table Z2). Table Z2 The descriptions of each country, patent application and publications cited or described in this document are incorporated in the present document by reference, in its entirety.

Those skilled in the art will appreciate that numerous changes and modifications can be made to the preferred embodiments of the invention and that changes and modifications can be made without departing from the spirit of the invention. It is foreseeable, therefore, that the appended claims cover all those equivalent variations that fall within the true spirit and scope of the invention.

Claims (148)

1. CLAIMS: A compound of formula I: I wherein: R1 and R3 are each independently H, alkyl, alkenyl, alkynyl, or aryl, or R1 and R3 when taken together with the atoms to which they are connected, form a heterocycloalkyl ring of 4 to 8 members; R 2 is H, alkyl, alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl, aralkyl, or heteroarylalkyl, or R 1 and R 2 when taken together with the atoms through which they are connected, form a 4 to 8 membered heterocycloalkyl ring, or R 2 and R3 when taken together with the atoms to which they are connected, form a ring of 4 to 8 membered heteroaryloalkyl; with the condition that each Ra is independently H or alkyl; each Rb is independently H, alkyl, or aryl; n is the integer 0, 1, 2 or 3; A and B are each independently H, fluoro, or alkyl, or together they form a double bond between the carbon atoms to which they are attached; R4 is -Y-W; Y is a single bond, C (Ra) (Rb), C (Ra) (Rb) C (Ra) (Rb), or C (Ra) (Rb) C (Ra) (Rb) C (Ra) (Rb) ); W is aryl or heeroaryl; X is -CH2-, -O-, -S-, -SO, -SO2, or -N (R5) -; R5 is H, alkyl, cycloalkyl, - (CH2) -alkenyl, - (CH2) -alkynyl, aryl, -CORb, or -SO2Rb; and J forms a 6-membered aryl ring or a 5- or 6-membered heteroaryl ring when taken June with the carbon atoms to which it is attached; with the proviso that when: (a) J is taken with the carbon atoms to which it is attached it forms a phenyl ring subsituted with 0-3 groups selected from the group consisting of: halogen, hydroxy, -S-C1- alkyl 4, C1-4 alkyl, and C1- alkoxy, the latter two optionally substituted with one or more halogens or with C1-4 alkoxy; W is unsubstituted naphthyl, or phenyl unsubstituted with 0-3 groups selected from the group consisting of: halogen, C1-6 alkyl, C6 alkoxy, phenyl, phenoxy, 1,3-benzodioxazolyl, or 2,2-difluoro-1 , 3-benzodioxazolyl, -NH 2, -N (C 1-4 alkyl) 2, and pyrrolyl; n is 1, R1 and R3 are each H, A and B together form a double bond between the carbon atoms to which they are attached, and is a single bond; and X is -O-; then R2 is other than H or methyl; and with the proviso that when: (b) J is taken together with the carbon atoms to which it is attached it forms a phenyl ring, W is phenyl substituted with 0-3 groups selected from the group consisting of: fluorine, hydroxy, alkoxy C1-6 optionally substituted with one or more fluoros, C2.6 alkenyloxy, and -S-C1-4alkyl, n is 1, R1 and R3 are each H, A and B together form a double bond between the carbon atoms to which they are united, and it is a simple link; and X is -O-; then R2 is different from H or benzyl; and with the proviso that when: (c) J forms a 6-membered aryl ring, it is not substituted with: or one of its stereoisomers, prodrugs, pharmaceutically acceptable salts, hydrates, solvates, acid salt hydrates, or N-oxides.
2. 2. A compound according to claim 1, wherein J is -C-D-E- or -C-D-E-F-; wherein C, D, E, and F are each independently -O-, -S-, -SO-, -S02-, = N-, = CH-, or -NH-; wherein the last two residues are optionally substituted each independently; with the proviso that each atom -O- of the denitrium ring of J is joined directly only to carbon or nihologen atoms; with the proviso that each atom -S- of the denitrium ring of J is joined directly only to carbon or nihologen atoms; and with the proviso that when J is -C-D-E-F-, at least one of C, D, E, and F is = CH-.
3. 3. A compound according to claim 1, wherein X is -CH2-, -O-, -S-, -SO, or -SO2.
4. 4. A compound according to claim 1, wherein said X is -O-.
5. 5. A compound according to claim 1, wherein said J, taken in June with the carbon atoms to which it is attached, forms a 6-membered aryl ring optionally substituted.
6. 6. A compound according to claim 5, wherein said 6-membered aryl ring is phenyl optionally susíifuido.
7. 7. A compound according to claim 1, wherein said J, taken in June with the carbon atoms to which it is attached, forms a 5- or 6-membered heteroaryl ring optionally substituted.
8. 8. A compound according to claim 1, wherein R1 and R3 are each independently H, alkyl, alkenyl, or alkynyl.
9. 9. A compound according to claim 8, wherein R1 and R3 are each independently H, CtC3 alkyl, C2-C3 alkenyl, or C2-C3 alkynyl. A compound according to claim 1, wherein at least one of R1 and R3 is H. 11. A compound according to claim 1, wherein R2 is H, alkyl, alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl, aralkyl, or heeroarylalkyl. 12. A compound according to claim 1, wherein R2 is H or alkyl. 13. A compound according to claim 12, wherein R2 is alkyl. 14. A compound according to claim 13, wherein R2 is lower alkyl. 15. A compound according to claim 1, wherein n is the integer 1. 16. A compound according to claim 1, wherein R and R3 are each independently H, alkyl, or alkenyl. 17. A compound according to claim 1, wherein A and B taken together form a double bond between the carbon atoms to which they are attached. 18. A compound according to claim 17, wherein n is the integer 1. 19. A compound according to claim 18, wherein at least one of R1 and R3 is H. 20. A compound according to claim 1, wherein A and B are each H. 21. A compound according to claim 20, wherein n is the integer 1. 22. A compound according to claim 21, wherein at least one of R1 and R3 is H. 23. A compound according to claim 1, wherein: R4 is aryl substituted with -C (= O) NR11R12; R11 is H, alkyl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, alkylheterocycloalkyl, aryl, heleroaryl, aralkyl, heteroarylalkyl, or COR12; and each R12 is independently H, alkyl, cycloalkyl, helerocycloalkyl, alkylcycloalkyl, alkylheylocycloalkyl, aryl, heleroaryl, aralkyl, or heteroarylalkyl, or R11 and Re taken in June with the nitrogen atom to which they are attached form a 4 to 8 membered ring, in which 1 or 2 of the carbon atoms of the heterocycloalkyl ring may be optionally subsituted independently by -O- groups , -S-, -SO-, -SO2-, -NH-, -N (alkyl) -, or -N (aryl) -. 24. A compound according to claim 1, of formula II: p wherein: R6, R7, R8 and R9 are each independently H or - (CH2) mR10; m is the integer 0, 1, 2, 3, or 4; each R10 is independently alkyl, halo, perhaloalkyl, -OR5, -OCF2H, -OCF3, -CN, -CO2R5, -C (= O) NR11R12, -S (= O) 2R13, -S (= O) 2NR11R12, - NR 11 R 12, -NR 14 C (= O) R 15, -NR 1 S (= O) 2 R 15, aryl, or heteroaryl; each R 11 is independently H, alkyl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, alkylheterocycloalkyl, aryl, heteroaryl, aralkyl, heteroarylalkyl, or COR 12; each R12 is independently H, alkyl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, alkylheylocycloalkyl, aryl, heteroaryl, aralkyl, or heteroarylalkyl, or R11 and R12 taken together with the nihogen atom to which they are attached form a 4 to 8 membered heterocycloalkyl ring, wherein 1 or 2 of the carbon atoms of the ring-ether ring may optionally be substituted independently by -O-, -S-, -SO-, -SO2-, -NH-, -N (alkyl) -, groups, or -N (aryl) -; each R13 is independently -OH, alkyl, aryl, aralkyl, heeroaryl, heteroarylalkyl, cycloalkyl, or alkylcycloalkyl; each R14 is independently H, alkyl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, aryl, heteroaryl, alkylheterocycloalkyl, aralkyl, or heteroarylalkyl; and each R15 is independently alkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, cycloalkyl, alkylcycloalkyl, heterocycloalkyl, or alkylheterocycloalkyl. 25. A compound according to claim 24, wherein R1 and R3 are each H. 26. A compound according to claim 24, wherein R4 is aryl substituted with -C (= O) NR11R12. 27. A compound according to claim 1, of formula III: III wherein: R6, R7, R8 and R9 are each independently H or - (CH2) mR10; m is the integer 0, 1, 2, 3 or 4; each R10 is independently alkyl, halo, perhaloalkyl, -OR5, OCF2H, -OCF3, -CN, -CO2R5, -C (= O) NR11R12, -S (= O) 2R13, -S (= O) 2NR1 R12, - NR 11 R 12, NR 14 C (= O) R 15, -NR 14 S (= O) 2 R 15, aryl, or heteroaryl; each R 1 is independently H, alkyl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, alkylheterocycloalkyl, aryl, hepheroaryl, aralkyl, heteroarylalkyl, or COR12; each R12 is independently H, alkyl, cycloalkyl, heyerocycloalkyl, alkylcycloalkyl, alkylheylocycloalkyl, aryl, heeroaryl, aralkyl, or heeroarylalkyl, or R11 and R12 taken in June with the niologen atom to which they are attached form a 4 to 8 membered ring, cycloalkyl, wherein 1 or 2 of the carbon atoms of the ring-ether ring may optionally be substituted independently by groups -O-, -S-, -SO-, -SO2-, -NH-, -N (alky) -, or -N (aryl) -; each R 13 is independently -OH, alkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, cycloalkyl, or alkylcycloalkyl; each R14 is independently H, alkyl, cycloalkyl, heyerocycloalkyl, alkylcycloalkyl, aryl, heeroaryl, alkylheylocycloalkyl, aralkyl, or heteroarylalkyl; and each R15 is independently alkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, cycloalkyl, alkylcycloalkyl, heterocycloalkyl, or alkylheterocycloalkyl. 28. A compound according to claim 27, wherein R1 and R3 are each H. 29. A compound according to claim 27, wherein R4 is aryl susii- uid with -C (= O) NR11R12. 30. A compound selected from the group consisting of: 4 - [(4 -? /,? / - diethylaminocarbonyl) phenyl] -spiro [2 H, 1-benzopyran-2,4'-piperidine]; 4 - [(4 -? /,? / - dieylaminocarbonyl) phenyl] -6-fluoro-spiro [2 H, 1-benzopyran-2,4'-piperidine] hydrochloride; 4 - [(4 -? /, / V-diethylaminocarbonyl) phenyl] -6-hydroxyspiro [2 H, 1-benzopyran-2,4'-piperidine]; 4 - [(4 -? /,? / - diethylaminocarbonyl) phenyl] -3,4-dihydrospiro hydrochloride [2 H, 1-benzopyran-2,4'-piperidine]; 4 - [(4 -? /, / V-diethylaminocarbonyl) phenyl] -? / - methyl-spiro [2 H, 1-benzopyran-2,4'-piperidine]; 4 - [(4 -? / - ethylaminocarbonyl) phenyl] spiro [2 H, 1-benzopyran-2,4'-piperidine]; 4 - [(4 -? / - propyl -? / - cyclopropylmethylaminocarbonyl) phenyl] -spiro [2 H, 1-benzopyran-2,4'-piperidine]; 4- [4- (isoindolinaminocarbonyl) phenyl] -espro [2 H, 1-benzopyran-2,4'-piperidine]; 4- [4- (4-carboxypiperidinaminocarbonyl) phenyl] -spiro [2 H, 1-benzopyran-2,4'-piperidine]; 4- [4- (2 / - / - teryrazolyl) phenyl] -spiro [2 H, 1-benzopyran-2,4'-piperidine]; 4- [4- (4-carboxypropyl-idiorazol-2-yl) phenyl] -spiro [2 H, 1-benzopyran-2,4'-piperidine]; 4- (3-pyridyl) -spiro [2 H, 1-benzopyran-2,4'-piperidine]; 4- [4- (methanesulfonyl) -phenyl] -spiro [2 H, 1-benzopyran-2,4'-piperidine]; and 4 - [(4 -? /, / V-dieylaminocarbonyl) phenyl] spiro [2 H, 1-benzopyran-2,4'-nortropine]; or one of its stereoisomers, prodrugs, pharmaceutically acceptable salts, hydrates, solvates, acid salt hydrates, or N-oxides. 31. A compound of formula IV: IV where: Y2 is a single bond or - [C (Rc) (Rd)] k-; each Rc, R e, and R f is independently H or alkyl; each Rd is independently H, alkyl, or aryl; W2 is aryl, alkylaryl, heteroarylcarbaryl, heteroaryl, alkylheorylaryl, heteroarylaryl, or alkylheteroarylaryl; R23 and R24 are each independently H, alkyl, alkenyl, alkynyl, or aryl, or R23 and R24 when they are in June with the atoms to which they are connected, form a cycloalkyl or heterocycloalkyl ring of 4 to 8 members; Z is -N (R25) -, -C (= O) -, -CH (OH) -, -CH (N (Rc) (Rd)) -, or -O-; R25 is H, alkyl, alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl, aralkyl, or heteroarylalkyl, or R23 and R25 when taken together with the atoms through which they are connected, form a 4- to 8-membered heterocycloalkyl ring, or R24 and R25 when taken together with the atoms through which they are connected, form a 4 to 8 membered ring-cycloalkyl ring; each k is independently 1, 2, or 3; p is 0, 1, 2 or 3; s is 0, 1, 2 or 3, with the proviso that the sum of p and s is 4; A2 and B2 are each independently H, fluoro, or alkyl, or together they form a double bond or -CH2-; G is H or alkyl; X2 is -C (Rc) (Rd) -, -O-, -S-, -S (= O) -, -S (= O) 2-, -C (= O) -, -CH (OH) - or -N (R26) -; R26 is H, alkyl, cycloalkyl, - (CH2) -alkenyl, - (CH2) -alkynyl, aryl, -C (= O) Rd, or -S (= O) 2Rd; and J2 forms a 6 to 10 membered aryl ring or a 5- to 10 membered heteroaryl ring when taken together with the carbon atoms to which it is attached; with the proviso that when: (a) J2 is taken June with the carbon atoms to which it is attached it forms a 6 to 10 membered aryl ring substituted with 0-3 groups selected from the group consisting of: halogen, hydroxy, - SH, -C (= O) -H -S-C1-4alkyl, -NHS (= O) 2-C1-4alkyl, -NHS (= O) 2-H, -N (C1-4alkyl) S (= O) 2-H, C 1-4 alkyl, and C 1-4 alkoxy, the last two optionally substituted with one or more halogens or with C 1-4 alkoxy; W2 is phenyl substituted with 0-3 groups selected from the group consisting of: halogen, cyano, hydroxy, C6 alkyl optionally substituted with one or more halogens, C1-6 alkoxy optionally susiiuuido with one or more halogens or with C3-6 cycloalkyl , C2.6 alkenyloxy, C2-6 alkynyloxy, C3-6 cycloalkyloxy, C6-? 2 aryloxy, aralkoxy, hephenoaryloxy, heteroarylalkoxy, heterocyclic alkyl with alkoxy, -SH, -S-C1- alkyl, -NH2, -N = C (aryl) 2, -N (H) C 1-4 alkyl, -N (C 1-4 alkyl) 2, -OS (= O) 2-C 1-4 alkyl optionally susíiuuido with one or more halogens, -OS (= O) 2-aryl C6-? 2 optionally subsituted with C- ^ alkyl, -NHS (= O) 2-C1-4 alkyl, -N (C1-alkyl) S (= O) 2-C1 alkyl -4, -NHS (= O) 2-H, and -N (C 1-4 alkyl) S (= O) 2-H; p and s are each 1, Re, Rf, R23, R24, and G are each H, A2 and B2 juni form a double bond, Y2 is a single bond; and X2 is -O-; then Z is different from: where i is an integer between 1 and 20; and with the condition that when: (b) J2 is omited together with the carbon atoms to which it is attached, forming a phenyl ring substituted with 0-3 groups selected from the group consiifuted by: halogen, hydroxy, -S-C1-4alkyl, C1-4alkyl, and C 1-4 alkoxy, the latter two optionally substituted with one or more halogens or with C 1-4 alkoxy; W 2 is unsubstituted naphthyl, or phenyl substituted with 0-3 groups selected from the group consisting of: halogen, C 1-6 alkyl, C 1-6 alkoxy, phenyl, phenoxy, 1,3-benzodioxazolyl, or 2,2-difluoro- 1,3-benzodioxazolyl fluoro, -NH 2, -N (C 1-4 alkyl) 2, and pyrrolyl; p and s are each 1, Re, Rf, R23, R24, and G are each H, A2 and B2 juni form a double bond, Y2 is a single bond; and X2 is -O-; then Z is different from: with the proviso that when: (c) J2 is taken together with the carbon atoms to which the unsubstituted phenyl form is attached, W2 is phenyl substituted with 0-3 groups selected from the group considred by: fluorine, hydroxy, C1-alkoxy Optionally optionally with one or more fluoros, C2-6 alkenyloxy, and -S-C1-4alkyl, pys are each 1, Re, Rf, R23, R24, and G are each H, A2 and B2 together form a double bond, Y2 is a simple link; and X2 is -O-; then Z is different from: with the proviso that when: (d) J2 is taken together with the carbon atoms to which it is attached it forms a 6-membered aryl ring substituted with: then Z is different from -N (R25) - or -CH (NH2) -; or one of its stereoisomers, prodrugs, pharmaceutically acceptable salts, hydrates, solvates, acid salt hydrates, or N-oxides. 32. A compound according to claim 31, wherein Z is -N (R25) -, -CH (OH) -, or -CH (NRcRd)) -. 33. A compound according to claim 31 of formula V: 34. A compound according to claim 31, wherein Y2 is a single bond. 35. A compound according to claim 31, wherein W2 is aryl, alkylaryl, heteroaryl, alkylheorylaryl, heteroarylaryl, or alkylhearyarylaryl. 36. A compound according to claim 31, wherein R23 and R24 are each independently H, alkyl, alkenyl, or alkynyl. 37. A compound according to claim 36, wherein R23 and R24 are each independently H, C3 alkyl, C2-C3 alkenyl, or C2-C3 alkynyl. 38. A compound according to claim 31, wherein at least one of R23 and R24 is H. 39. A compound according to claim 31, wherein R25 is H, alkyl, alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl, aralkyl, or heteroarylalkyl. 40. A compound according to claim 31 wherein R25 is H or alkyl. 41. A compound according to claim 31, wherein p is 1 or 2. 42. A compound according to claim 41, wherein s is 1. 43. A compound according to claim 31, wherein s is 1. 44. A compound according to claim 31, wherein A2 and B2 are each independently H, fluoro, or alkyl. 45. A compound according to claim 31, wherein A2 and B2 are each H. 46. A compound according to claim 31, wherein A2 and B2 taken together form a double bond between the carbon atoms to which they are linked. United. 47. A compound according to claim 31, wherein G is H. 48. A compound according to claim 31, wherein X2 is -CH2-, -O-, -S-, -S (= O) -, -S (= O) 2-, or -N (R26) -. 49. A compound according to claim 48, wherein X2 is -CH2-, -O-, or -S (= O) 2. 50. A compound according to claim 49, wherein X2 is -CH2- or -O-. 51. A compound according to claim 50, wherein X2 is -O-. 52. A compound according to claim 31, wherein J2 forms an aryl ring of 6 to 10 members when Jun is taken with the carbon atoms to which it is attached. 53. A compound according to claim 52, wherein J2 forms a 6-membered aryl ring when Jun is taken with the carbon atoms to which it is attached. 54. A compound according to claim 44 of formula VI: VI 55. A compound according to claim 31 of formula VII: vp 56. A compound according to claim 44 of formula Vlll: vm 57. A compound according to claim 32, wherein Y2 is a single bond. 58. A compound according to claim 57, wherein X is -CH2- or O. 59. A compound according to claim 58, wherein p is 1 or 2 and s is 1. 60. A compound according to claim 59 of formula IX: IX 61. A compound according to claim 59 of formula X: X wherein A2 and B2 are each independently H, fluoro, or alkyl. 62. A compound according to claim 61 of formula XI: XI 63. A compound according to claim 60, wherein Z is -N (R25) -. 64. A compound according to claim 63, wherein W2 is aryl, alkylaryl, heteroaryl, alkylheorylaryl, heteroarylaryl, or alkylheyaryarrylaryl. 65. A compound according to claim 64, wherein said aryl, alkylaryl, heteroaryl, alkylheteroaryl, heteroarylaryl or alkylheyaryariaryl in W2 is optionally substituted with at least one of alkyl, aryl, hydroxyl, carboxyl, N, N-dialkylaminocarbonyl, -S (= O) 2-N (alkyl) 2, -N (H) S (= O) 2 -alkyl, and -N (alkyl) C (= O) -alkyl. 66. A compound according to claim 65, wherein J2 forms a 6-membered aryl ring when taken together with the carbon atoms to which it is attached. 67. A compound according to claim 66 of formula Xll: wherein: Q1 and Q2 are each independently H, halo, alkyl, hydroxyl, alkoxy, substituted cycloalkyl-alkoxy, aminocarbonyl, -S (= O) 2-alkyl, -S (= O) 2-N (H) alkyl, -S (= O) 2-N (H) cycloalkylalkyl, or -N (H) S (= O) 2-alkyl. 68. A compound according to claim 67 of formula Xlll: XIII wherein: A2 and B2 are each independently H, fluoro, or alkyl. wherein W2 is optionally susíifuido with at least one of alkyl, aryl, hydroxyl, carboxyl,? /, / V-dialkylaminocarbonyl, -S (= O) 2-N (alkyl) 2, -N (H) S (= O) 2-alkyl, and -N (alkyl) C (= O) -alkyl; and L is H or alkyl. 70. A compound according to claim 31, selected from the group consisting of: 4 -? /,? / - dieylaminocarbonyl) phenyl] - spiro [2H, 1-benzopyran-2,4'-piperidine]; 2 -? /,? / - dieylaminocarbonyl) pyrid-5-yl] -spiro [6-fluoro-2H, 1-benzopyran-2,4'-piperidine]; 2 -? /,? / - dieylaminocarbonyl) pyrid-5-yl] -spiro [5-meioxy-2H, 1-benzopyran-2,4'-piperidine]; 4-1 4 -? /,? / - dieylaminocarbonyl) phenyl] -spiro [5-hydroxy-2H, 1-benzopyran-2,4'-piperidine]; 4- | 4 -? /,? / - dieylaminocarbonyl) phenyl] -spiro [2 H, 1-benzopyran-2,4'-azepane]; 4-1 4 -? /,? / - diethylaminocarbonyl) phenyl] -spiro [6-cyclopropylmethylaminosulfonyl-2H, 1-benzopyran 2,4'-azepane]; 4- 4 -? /,? / - dieylaminocarbonyl) phenyl] -spiro [3,4-dihydro-2H, 1-benzopyran-2,4'-piperidine]; 4- 4 -? /,? / - dieylaminocarbonyl) phenyl] -spiro [1,2-dihydronaphthalen-2,4'-piperidine]; 4- 4 -? /, / V-dieylaminocarbonyl-2-hydroxy) phenyl] -spiro [2 H, 1-benzopyran-2,4'-piperidine]; 4- | 4 -? /,? / - diethylaminocarbonyl-3-hydroxy) phenyl] -spiro [2 H, 1-benzopyran-2,4'-piperidine]; 4- | 4- / V,? / - dieylaminocarbonyl) phenyl] -3-meityl-spiro [2 H, 1-benzopyran-2,4'-piperidine]; 4- | 2 -? /,? / - dieylaminocarbonyl) pyrid-5-yl] -spiro [2 H, 1-benzopyran-2,4'-piperidine]; 4- 4 -? /,? / - dieylaminocarbonyl) phenyl] -spiro [6-cyclopropylmethioxy-2H, 1-benzopyran-2,4'-piperidine]; 4 - [(2 -? /,? / - dieylaminocarbonyl) pyrid-5-yl] -spiro [-6-cyclopropylmethioxy-2H, 1-benzopyran-2,4'-piperidine]; 4 - [(4-N,? / - diethylaminocarbonyl) phenyl] -spiro [6-aminocarbonyl-2HJ1-benzopyran-2,4'-piperidine]; 4 - [(4 -? /,? / - diethylaminocarbonyl) phenyl] -spiro [6-propylaminosulfonyl-2H, 1-benzopyran-2,4'-azepane]; 4 - [(4 -? /, / V-diethylaminocarbonyl) phenyl] -spiro [6-methanesulfonyl-2H, 1-benzopyran-2,4'-azepane]; 4 - [(2 -? /,? / - diethyl! Aminocarbonyl) pyrid-5-yl] -spiro [3,4-dihydro-2H, 1-benzopyran-2,4'-p-peridine]; 4 - [(2 -? /, / V-diylaminocarbonyl) pyrid-5-yl] -spiro [6-fluoro-3,4-dihydro-2H, 1-benzopyran-2,4'-piperidine]; 4 - [(5 -? /,? - diisopropylaminocarbonyl) pyrid-2-yl] -espyrro [2H, 1-benzopyran-2,4'-piperidine 4 - [(4 -? /,? / - diethyl! aminocarbonyl) phenyl] -spiro [6-ylsulfonylamino-2H, 1-benzopyran-2,4'-pi? eridine]; 4 - [(4 -? /,? / - dieylaminocarbonyl) phenyl] -spiro [6-methylsulfonylamino-2H, 1-benzopyran-2,4'-piperidine]; 4 - [(4 -? /,? / - diethylaminocarbonyl) phenyl] -spiro [5-meityl-2H, 1-benzopyran-2,4'-piperidine]; 4- [4- (2H-tetrazol-5-yl) phenyl] -spiro [2 H, 1-benzopyran-2,4'-piperidine]; 4- [4- (2-methyl-idiorazol-5-yl) phenyl] -spiro [2 H, 1-benzopyran-2,4'-piperidine]; 4- [3- (2- (3-carboxyprop-1-yl) -icyrazol-5-yl) phenyl] -spiro [2 H, 1-benzopyran-2,4'-piperidine]; 4- [4- (5-methyl- [1, 2,4] oxadiazol-3-yl) phenyl] -spiro [2 H, 1-benzopyran-2,4'-piperidine]; 4 - [(4 -? /,? / - diethylaminocarbonyl) phenyl] -spiro [2 H, 1-benzopyran-2,4 '- (1'-meityl-piperidine)]; 4 - [(4 -? /,? / - dieylaminosulfonyl) pheny] -espros [2 H, 1-benzopyran-2,4'-piperidine]; Y 4 - [(4 - (? / - mephyl-? / - (3-meilyylbuanyl) -amino) phenyl] -spiro [2H, 1-benzopyran-2,4 * -piperidine]; or one of its stereoisomers, prodrugs, pharmaceutically acceptable salts, hydrates, solvates, acid salt hydrates, or N-oxides. 71. A compound according to claim 70, selected from the group consisting of: 4 - [(4-A /,? / - dieylaminocarbonyl) phenyl] -spiro [2 H, 1-benzopyran-2,4'-piperidine]; 4 - [(2 -? /,? / - dieylaminocarbonyl) pyrid-5-yl] -spiro [6-fluoro-2 H, 1-benzopyran-2,4'-piperidine]; 4 - [(2-A /,? / - dieylaminocarbonyl) pyrid-5-yl] -spiro [5-methioxy-2H, 1-benzopyran-2,4'-piperidine]; 4 - [(4 -? /, N-dieylaminocarbonyl) phenyl] -spiro [5-hydroxy-2H, 1-benzopyran-2,4'-piperidine]; 4 - [(4-,? / - dieylaminocarbonyl) phenyl] -spiro [2 H, 1-benzopyran-2,4'-azepane]; 4 - [(4 -? /,? / - diethylaminocarbonyl) phenyl] -spiro [6-cyclopropylmethylaminosulfonyl-2H, 1-benzopyran-2,4'-azepane]; 4 - [(4 -? /,? / - diethylaminocarbonyl) phenyl] -spiro [3,4-dihydro-2H, 1-benzopyran-2,4'-piperidine]; 4 - [(4 -? /,? / - diethylaminocarbonyl) phenyl] -spiro [1,2-dihydronaphoria-2,4'-piperidine]; 4 - [(4 -? /,? / - dieylaminocarbonyl-2-hydroxy) phenyl] -spiro [2 H, 1-benzopyran-2,4'-piperidine]; 4 - [(4 -? /,? / - dieylaminocarbonyl-3-hydroxy) phenyl] -spiro [2 H, 1-benzopyran-2,4'-piperidine]; 4 - [(4 -? /,? / - diethylaminocarbonyl) phenyl] -3-meityl-spiro [2 H, 1-benzopyran-2,4'-piperidine]; 4 - [(2 -? /,? / - dieylaminocarbonyl) pyrid-5-yl] -spiro [2 H, 1-benzopyran-2,4'-piperidine]; 4 - [(4 -? /,? / - diethylaminocarbonyl) phenyl] -spiro [6-cyclopropylmethioxy-2H, 1-benzopyran-2,4'-piperidine]; 4 - [(2 -? /,? / - dieylaminocarbonyl) pyrid-5-yl] -spiro [-6-cyclopropylmethioxy-2H, 1-benzopyran-2,4'-piperidine]; 4 - [(4- / V,? / - dieylaminocarbonyl) phenyl] -spiro [6-aminocarbonyl-2H, 1-benzopyran-2,4'-piperidine]; 4 - [(4 -? /,? / - dieylaminocarbonyl) phenyl] -spiro [6-propylaminosulfonyl-2H, 1-benzopyran-2,4'-azepane]; 4 - [(4 -? /,? / - diethylaminocarbonyl) phenyl] -spiro [6-methandosulfonyl-2H, 1-benzopyran-2,4'-azepane]; 4 - [(2 -? /,? / - diethylaminocarbonyl) pyrid-5-yl] -spiro [3,4-dihydro-2H, 1-benzopyran-2,4'-piperidine]; 4 - [(2-?,? - dieylaminocarbonyl) pyrid-5-yl] -spiro [6-fluoro-3,4-dihydro-2H, 1-benzopyran-2,4'-piperidine]; and 4 - [(5-,? / - dilsopropylaminocarbonyl) pyrid-2-yl] -spiro [2 H, 1-benzopyran-2,4'-piperidine]; or one of its stereoisomers, prodrugs, pharmaceutically acceptable salts, hydrates, solvates, acid salt hydrates, or N-oxides. 72. A compound according to claim 71, selected from the group consisting of: 4 - [(4 -? /, / V-dieylaminocarbonyl) phenyl] -spiro [2H, 1-benzopyran-2,4'-piperidine ]; 4 - [(2 -? /,? / - dieylaminocarbonyl) pyrid-5-yl] -spiro [6-fluoro-2 H, 1-benzopyran-2,4'-piperidine]; 4 - [(2-N,? / - dι-eylaminocarbonyl) pyrid-5-yl] -spiro [5-methoxy-2 H, 1-benzopyran-2,4'-piperidine]; 4 - [(4 -? /,? / - d-eylaminocarbonyl) phenyl] -spiro [5-hydroxy-2H, 1-benzopyran-2,4'-piperidine]; 4 - [(4- / V, / V-dieylaminocarbonyl) phenyl] -spiro [2 H, 1-benzopyran-2,4'-azepane]; 4 - [(4 -? /,? / - dieylaminocarbonyl) phenyl] -spiro [6-cyclopropylmethylaminosulfonyl-2H, 1-benzopyran-2,4'-azepane]; 4 - [(4 -? /,? / - dieylaminocarbonyl) phenyl] -spiro [3,4-dihydro-2H, 1-benzopyran-2,4'-piperidine]; 4 - [(4-A /, / V-dieylaminocarbonyl) phenyl] -spiro [1,2-dihydronaphthalen-2,4'-piperidine]; 4 - [(2-N, N-dieylaminocarbonyl) pyrid-5-yl] -spiro [6-cyclopropylmethioxy-2H, 1-benzopyran-2,4'-piperidine]; 4 - [(4-N, N-dieylaminocarbonyl) phenyl] -spiro [6-methanesulfonyl-2H, 1-benzopyran-2,4'-azepane]; 4 - [(4 -? /, / V-diethylaminocarbonyl-2-hydroxy) phenyl] -spiro [2 H, 1-benzopyran-2,4'-piperidine]; and 4 - [(4 -? /,? / - dieylaminocarbonyl-3-hydroxy) phenyl] -spiro [2 H, 1-benzopyran-2,4'-piperidine]; or one of its stereoisomers, prodrugs, pharmaceutically acceptable salts, hydrates, solvates, acid salt hydrates, or N-oxides. 73. A compound according to claim 54, selected from the group consisting of: 4 * - [(4 -? /,? / - d, yylaminocarbonyl) phenyl] - spiro [3,4-dihydro-2H, 1-benzopyran -2,4'-piperidine]; and 4 * - [(2 -? /,? / - dieylaminocarbonyl) pyrid-5-yl] -spiro [3,4-dihydro-2H, 1-benzopyran-2,4'-piperidine]; or one of its partial esioisomers, prodrugs, pharmaceutically acceptable salts, hydranes, solvates, hydraids of acidic salt, or N-oxides. 74. A compound according to claim 55, selected from the group consisting of: 4 - [(4 -? /,? / - d, yylaminocarbonyl) phenyl] - spiro * [2H, 1-benzopyran-2,4'-azepane]; 4 - [(4 -? /,? / - dieylaminocarbonyl) phenyl] -spyro [6-cyclopropylmethylaminosulfonyl-2H, 1-benzopyran-2,4'-azepane]; 4 - [(4 -? /,? / - diethylaminocarbonyl) phenyl] -spiro * [6-propylaminosulfonyl-2H, 1-benzopyran-2,4'-azepane]; and 4 - [(4 -? /, A / -diethylaminocarbonyl) phenyl] -spiro * [6-methandosulfonyl-2H, 1-benzopyran-2,4'-azepane]; or one of its partial esioisomers, prodrugs, pharmaceutically acceptable salts, hydrates, solvates, hydrates of acidic salt, or N-oxides. 75. A compound according to claim 31, wherein Re and Rf are each independently H or CtC3 alkyl. 76. A compound according to claim 75, wherein Re and Rf are each independently H or meyloyl. 77. A compound according to claim 76, wherein at least one of Re and Rf is H. 78. A compound according to claim 77, wherein Re and Rf are each H. 79. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier; and a compound of formula IV: IV where: Y2 is a single bond or - [C (Rc) (Rd)] k-; each Rc, Re, and Rf is independently H or alkyl; each Rd is independently H, alkyl, or aryl; W2 is aryl, alkylaryl, heteroaryloalkylaryl, heteroaryl, alkylheorylaryl, heteroarylaryl, or alkylheteroarylaryl; R23 and R24 are each independently H, alkyl, alkenyl, alkynyl, or aryl, or R23 and R24 when taken together with the atoms through which they are connected, form a cycloalkyl or heyerocycloalkyl ring of 4 to 8 members; Z is -N (R25) -, -C (= O) -, -CH (OH) -, -CH (N (Rc) (Rd)) -, or -O-; R25 is H, alkyl, alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl, aralkyl, or heeroarylalkyl, or R23 and R25 when they are in June with the atoms to which they are connected, form a 4 to 8 membered ring, or R24 ring and R25 when june June with the atoms through which they are connected, form a 4 to 8 membered heterocycloalkyl ring; each k is independently 1, 2, or 3; p is 0, 1, 2 0 3; s is 0, 1, 2 or 3, with the proviso that the sum of p and s is 4; A2 and B2 are each independently H, fluoro, or alkyl, or together they form a double bond or -CH2-; G is H or alkyl; X2 is -C (Rc) (Rd) -, -O-, -S-, -S (= O) -, -S (= O) 2-, -C (= O) -, -CH (OH) - or -N (R26) -; R26 is H, alkyl, cycloalkyl, - (CH2) -alkenyl, - (CH2) -alkynyl, aryl, -C (= O) Rd, or -S (= O) 2Rd; and J2 forms a 6 to 10 membered aryl ring or a 5- to 10 membered heteroaryl ring when taken together with the carbon atoms to which it is attached; with the proviso that when: (a) J2 is taken together with the carbon atoms to which it is attached it forms an aryl ring of 6 to 10 members suspended with 0-3 groups selected from the group consisting of: halogen, hydroxy, - SH, -C (= O) -H -S-C 1-4 alkyl, -NHS (= O) 2-C 1-4 alkyl, -NHS (= O) 2-H, -N (C 1-4 alkyl) S (= O) 2-H, C 1-4 alkyl, and C 1-4 alkoxy, the two optionally substituted with one or more halogens or with C 1-4 alkoxy; W2 is substituted phenyl with 0-3 groups selected from the group consisting of: halogen, cyano, hydroxy, optionally substituted C 1-6 alkyl with one or more halogens, optionally substituted C 1-6 alkoxy with one or more halogens or with C 3- cycloalkyl 6, C 2-6 alkenyloxy, C 2-6 alkynyloxy, C 3-6 cycloalkyloxy, C 6-2 aryloxy, aralkoxy, heteroaryloxy, heteroaralkoxy, heterocycloalkyl substituted with alkoxy, -SH, -S-C 1-4 alkyl, -NH 2, -N = C (aryl) 2, -N (H) C 1-4 alkyl, -N (C 1-6 alkyl) 2, -OS (= O) 2-C 1 -alkyl optionally substituted with one or more halogens, -OS (= O) 2-aryl C6-12 optionally substituted with C1-alkyl, -NHS (= O) 2-C1-4 alkyl, -N (C1-4 alkyl) S (= O) 2-C1- alkyl , -NHS (= O) 2-H, and -N (C 1-4 alkyl) S (= O) 2-H; p and s are each 1, Re, Rf, R23, R24, and G are each H, A2 and B2 together form a double bond that incorporates the atoms to which they are attached, Y2 is a single bond; and X2 is -O-; then Z is different from: where t is an integer number between 1 and 20; and with the proviso that when: (b) J2 is formed June with the carbon atoms to which it is attached it forms a phenyl ring suspended with 0-3 groups selected from the group consisting of: halogen, hydroxy, -S-C1 alkyl -4, C alkyl, and C- alkoxy, the two optionally substituted with one or more halogens or with C 1-4 alkoxy; W2 is unsubstituted naphthyl, or phenyl substituted with 0-3 groups selected from the group consisting of: halogen, C1-6 alkyl, C1-6 alkoxy, phenyl, phenoxy, 1,3-benzodioxazolyl, or 2,2-d-fluoro-1 , 3-benzodioxazolyl fluoro, -NH2, -N (alkylCM) 2, and pyrrolyl; p and s are each 1, Re, Rf, R23, R24, and G are each H, A2 and B2 together form a double bond that incorporates the atoms to which they are bound, Y2 is a single bond; and X2 is -O-; then Z is different from: with the proviso that when: (c) J2 taken together with the carbon atoms to which it is attached is unsubstituted phenyl, W2 is phenyl substituted with 0-3 groups selected from the group consisting of: fluorine, hydroxy, C1-6 alkoxy; Optionally susiiuid with one or more fluoros, C2-6 alkenyloxy, and -S-C alkyl, pys are each 1, Re, Rf, R23, R24, and G are each H, A2 and B2 together form a double bond that incorporates the atoms to which they are united, Y2 is a simple link; and X2 is -O-; then Z is different from: with the proviso that when: (d) J2 is taken June with the carbon atoms to which it is attached it forms a 6-membered aryl ring substituted with: then Z is other than -N (R25) - or -CH (NH2 ) -; or one of its stereoisomers, prodrugs, pharmaceutically acceptable salts, hydrates, solvates, hydrates of acid salt, or N-oxides. 80. A pharmaceutical composition according to claim 79, which further comprises an opioid, an agent for the trava- liation of neuropathic pain / pain, an agent for the treatment of depression, an agent for the traumatization of incontinence, or an anti-Parkinson agent. . 81. A pharmaceutical composition according to claim 80, wherein said opioid is alfentanil, allylprodine, alphaprodin, anileridin, benzylmorphine, becitramide, buprenorphine, butorphanol, clonitazene, codeine, cyclazocine, desomorphine, dextromoramide, dezocin, diampromide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimetilíiambuteno, dioafeíilbuíiraío, dipipanone, epíazocina, eíohepíacina, etilmefiltiambuteno, eíilmorfina, eíonifazeno, feníanilo, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomeíadona, ketobemidone, levallorphan, levorphanol, levophenacylmorphan, lofentanil, loperamide, meperidine, mepíacinol, metazocina, meiadona, meíopon, morphine, mirofina, nalbufina, narceína, nicomorfina, norlevorfanol, normeíadona, nalorfina, normorfina, norpinanona, opium, oxycodone, oxymorphone, papaveretum, peniazocina, fenadoxona, fenomorfan, fanazocina, fenoperidina, piminodina, piriíramida, profepiacin, promedol, properidin, propiram, propoxyphene, sulfenanil, tilidine, tramadol, one of its diasyrosomers, one of its pharmaceutically acceptable salts, one of its complexes; or one of its mixtures. 82. A pharmaceutical composition according to claim 80, wherein said agent for the treatment of neuropathic pain / neuralgia is a mild SR analgesic, a narcotic analgesic, an ani-seizure medication or an ani-depressant. 83. A pharmaceutical composition according to claim 80, wherein said agent for the eradication of the depression is a selective inhibitor of the reuptake of seroïonin, an irricyl compound, an inhibitor of the monoamine oxidase, or an ani-depressant compound belonging to the class of the heero-cycles. 84. A pharmaceutical composition according to claim 80, wherein said agent for the treatment of urge incontinence is an anticholinergic agent, an anispaspasmodic medicament, an antichlideric, a calcium channel blocker or a beta agonist. 85. A pharmaceutical composition according to claim 80, further comprising: an antibiotic, antiviral, antifungal, anti-inflammatory, anesthetic or mixtures thereof. 86. A method of binding to opioid receptors in a patient in need thereof, comprising the step of: administering to said patient an effective canine of a compound of formula IV: IV where: Y2 is a single bond or - [C (Rc) (Rd)] k-; each Rc, Re, and Rf is independently H or alkyl; each Rd is independently H, alkyl, or aryl; W2 is aryl, alkylaryl, heteroaryloalkylaryl, heteroaryl, alkylheorylaryl, heteroarylaryl, or alkylheyaryarrylaryl; R23 and R24 are each independently H, alkyl, alkenyl, alkynyl, or aryl, or R23 and R24 when taken June with the atoms through which they are connected, form a cycloalkyl or heterocycloalkyl ring of 4 to 8 members; Z is -N (R25) -, -C (= O) -, -CH (OH) -, -CH (N (Rc) (Rd)) -, or -O-; R25 is H, alkyl, alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl, aralkyl, or heteroarylalkyl, or R23 and R25 when they are in June with the atoms through which they are connected, form a 4- to 8-membered heterocycloalkyl ring, or R24 and R25 when taken together with the atoms through which they are connected, form a 4- to 8-membered heterocycloalkyl ring; each k is independently 1, 2, or 3; p is O, 1, 2 6 3; s is 0, 1, 2 or 3, with the proviso that the sum of p and s is 4; A2 and B2 are each independently H, fluoro, or alkyl, or together they form a double bond or -CH2-; G is H or alkyl; X2 is -C (Rc) (Rd) -, -O-, -S-, -S (= O) -, -S (= O) 2-, -C (= O) -, -CH (OH) - or -N (R26) -; R26 is H, alkyl, cycloalkyl, - (CH2) -alkenyl, - (CH2) -alkynyl, aryl, -C (= O) Rd, or -S (= O) 2Rd; and J2 forms a 6 to 10 membered aryl ring or a 5- to 10 membered heteroaryl ring when taken together with the carbon atoms to which it is attached; or one of its stereoisomers, prodrugs, pharmaceutically acceptable salts, hydrates, solvates, hydrates of acid salt, or N-oxides. 87. A method according to claim 86, wherein said compound is attached to the opioid receptors. 88. A method according to claim 87, wherein said opioid receptors are located in the central nervous system. 89. A method according to claim 87, wherein said opioid receptors are located peripherally to the central nervous system. 90. A method according to claim 86, wherein said binding modulates the activity of said opiate receptors. 91. A method according to claim 90, wherein said binding has an agonistic effect on the activity of said opiate receptors. 92. A method according to claim 88, wherein said compound does not substantially ameliorate the blood-brain barrier. 93. A method of preventing or treating pain, comprising the step of: administering to a patient in need thereof an effective amount of a compound of formula IV: rv > wherein: Y2 is a single bond or - [C (Rc) (Rd)] k-; each R c, Re, and R f is independently H or alkyl; each Rd is independently H, alkyl, or aryl; W2 is aryl, alkylaryl, heterocycloalkylaryl, heteroaryl, alkylheteroaryl, heteroarylaryl, or alkylheyaryarylaryl; R23 and R24 are each independently H, alkyl, alkenyl, alkynyl, or aryl, or R23 and R24 when combined with the atoms to which they are connected, form a cycloalkyl or heterocycloalkyl ring of 4 to 8 members; Z is -N (R25) -, -C (= O) -, -CH (OH) -, -CH (N (Rc) (Rd)) -, or -O-; R25 is H, alkyl, alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl, aralkyl, or heteroarylalkyl, or R23 and R25 when joined June with the atoms to which they are connected, form a 4- to 8-membered heterocycloalkyl ring, or R24 and R25 when they are taken June with the atoms through which they are connected, they form a heterocycloalkyl ring of 4 to 8 members; each k is independently 1, 2, or 3; p is 0, 1, 2 or 3; s is 0, 1, 2 or 3, with the proviso that the sum of p and s is 4; A2 and B2 are each independently H, fluoro, or alkyl, or junios form a double bond or -CH2-; G is H or alkyl; X2 is -C (Rc) (Rd) -, -O-, -S-, -S (= O) -, -S (= O) 2-, -C (= O) -, -CH (OH) - or -N (R26) -; R26 is H, alkyl, cycloalkyl, - (CH2) -alkenyl, - (CH2) -alkynyl, aryl, -C (= O) Rds or -S (= O) 2Rd; and J2 forms an aryl ring of 6 to 10 members or a heteroaryl ring of 5 to 10 members when Jun is taken with the carbon atoms to which it is attached; or one of its stereoisomers, prodrugs, pharmaceutically acceptable salts, hydrates, solvates, acid salt hydrates, or N-oxides. 94. A method according to claim 93, further comprising the step of: administering to said patient an effective amount of an opioid. 95. A method according to claim 94, wherein said opioid is alfentanil, allylprodin, alphaprodin, anileridin, benzylmorphine, beciiramide, buprenorphine, buorphanol, clononyne, codeine, cyclazocine, desomorphine, dextromoramide, dezocin, diampromide, diamorphone, dihydrocodeine , dihydromorphine, dimenoxadol, dimefepianoi, dimethylaminobenzyl, dioafeyiibuíirate, dipipanone, epiazocine, ethoheptazine, ethylmethyl diamine, ethylmorphine, eichoniazene, fentanyl, heroin, hydrocodone, hydromorphone, hydroxypeidine, isomeadone, ceiobemidone, levalorfan, levorphanol, levofenacilmorphan, lofenanil, loperamide, meperidine, mepiacinol, metazocine, meiadone, meopon, morphine, mirofin, nalbuphine, narcein, nicomorphine, norievorphanol, normetadone, nalorphine, normorphine, norpinanone, opium, oxycodone , oxymorphone, papaveretum, peniazocine, fenadoxone, fenomorfan, fanazocine, phenoperidine, piminodine, pyriramide, profeptacin, promedol, properidin, propiram, propoxyphene, sulfentanil, tilidine, uradol, one of its diasyrosomers, one of its pharmaceutically acceptable salts, one of its complex; or one of its mixtures. 96. A procedure for the prevention or elimination of gastrointestinal dysfunction, comprising the step of: administering to a patient in need of an effective canine of a compound of formula IV: IV where: Y2 is a single bond or - [C (Rc) (Rd)] k-; each R c, Re, and R f is independently H or alkyl; each Rd is independently H, alkyl, or aryl; W2 is aryl, alkylaryl, heteroaryloalkylaryl, heteroaryl, alkylheorylaryl, heteroarylaryl, or alkylheyrylarylaryl; R23 and R24 are each independently H, alkyl, alkenyl, alkynyl, or aryl, or R23 and R24 when taken June with the atoms through which they are connected, form a cycloalkyl or heyerocycloalkyl ring of 4 to 8 members; Z is -N (R25) -, -C (= O) -, -CH (OH) -, -CH (N (Rc) (Rd)) -, or -O-; R25 is H, alkyl, alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl, aralkyl, or heeroarylalkyl, or R23 and R25 when june with the atoms through which they are connected, form a 4- to 8-membered heteroaryloalkyl ring, or R24 and R25 when they are taken in June with the atoms through which they are connected, they form a 4 to 8 membered heterocycloalkyl ring; each k is independently 1, 2, or 3; p is O, 1, 2 or 3; s is 0, 1, 2 or 3, with the proviso that the sum of p and s is 4; A2 and B2 are each independently H, fluoro, or alkyl, or together they form a double bond or -CH2-; G is H or alkyl; X2 is -C (Rc) (Rd) -, -O-, -S-, -S (= O) -, -S (= O) 2-, -C (= O) -, -CH (OH) - or -N (R26) -; R26 is H, alkyl, cycloalkyl, - (CH2) -alkenyl, - (CH2) -alkynyl, aryl, -C (= O) Rd, or -S (= O) 2Rd; and J2 forms a 6 to 10 membered aryl ring or a 5- to 10 membered heteroaryl ring when taken together with the carbon atoms to which it is attached; or one of its steroisomers, prodrugs, pharmaceutically acceptable salts, hydrates, solvates, hydrates of acid salt, or N-oxides. 97. A procedure for the prevention or treatment of an urogenital artery disease, comprising the step of: administering to a patient in need thereof an effective amount of a compound of formula IV: IV where: Y2 is a single bond or - [C (Rc) (Rd)] k-; each R c, Re, and R f is independently H or alkyl; each Rd is independently H, alkyl, or aryl; W2 is aryl, alkylaryl, heterocycloalkylaryl, heteroaryl, alkylheorylaryl, heteroarylaryl, or alkylheyaryarylaryl; R23 and R24 are each independently H, alkyl, alkenyl, alkynyl, or aryl, or R23 and R24 when taken together with the atoms through which they are connected, form a cycloalkyl or heterocycloalkyl ring of 4 to 8 members; Z is -N (R25) -, -C (= O) -, -CH (OH) -, -CH (N (Rc) (Rd)) -, or -O-; R25 is H, alkyl, alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl, aralkyl, or heteroarylalkyl, or R23 and R25 when taken together with the atoms to which they are connected, form a 4- to 8-membered heterocycloalkyl ring, or R24 and R25, when taken together with the atoms through which they are connected, form a 4 to 8 membered ring-cycloalkyl ring; each k is independently 1, 2, or 3; p is O, 1, 2 or 3; s is 0, 1, 2 or 3, with the proviso that the sum of p and s is 4; A2 and B2 are each independently H, fluoro, or alkyl, or together they form a double bond or -CH2-; G is H or alkyl; X2 is -C (Rc) (Rd) -, -O-, -S-, -S (= O) -, -S (= O) 2-, -C (= O) -, -CH (OH) - or -N (R26) -; R26 is H, alkyl, cycloalkyl, - (CH2) -alkenyl, - (CH2) -a -quinyl, aryl, -C (= O) Rd, or -S (= O) 2Rd; and J2 forms a 6 to 10 membered aryl ring or a 5- to 10 membered heteroaryl ring when taken together with the carbon atoms to which it is attached; or one of its stereoisomers, prodrugs, pharmaceutically acceptable salts, hydrates, solvates, hydrates of acidic salt, or N-oxides. 98. A method according to claim 97, wherein said urogenital uranium is overactive or bladder overactive. 99. A method according to claim 98, wherein said incontinence is urinary stress incontinence or imperious urinary incontinence. 100. A method according to claim 98, in which said urogenital artery is overactive bladder. 101. A method according to claim 98 further comprising the step of: administering to said patient an effective canine of an agent for the delivery of incontinence. 102. A method for the prevention or treatment of an immunomodulatory disorder, comprising the step of administering to a patient in need of an effective canineity of a compound of formula IV: IV where: Y2 is a single bond or - [C (Rc) (Rd)] k-; each R c, Re, and R f is independently H or alkyl; each Rd is independently H, alkyl, or aryl; W2 is aryl, alkylaryl, heterocycloalkylaryl, heteroaryl, alkylheteroaryl, heteroarylaryl, or alkylheyryarylaryl; R23 and R24 are each independently H, alkyl, alkenyl, alkynyl, or aryl, or R23 and R24 when they are in June with the atoms from which they are connected, form a cycloalkyl or heyerocycloalkyl ring of 4 to 8 members; Z is -N (R25) -, -C (= O) -, -CH (OH) -, -CH (N (Rc) (Rd)) -, or -O-; R25 is H, alkyl, alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl, aralkyl, or heteroarylalkyl, or R23 and R25 when taken together with the atoms to which they are connected, form a 4- to 8-membered heterocycloalkyl ring, or R24 and R25 when taken June with the atoms to which they are connected, form a 4 to 8 membered heterocycloalkyl ring; each k is independently 1, 2, or 3; p is O, 1, 2 or 3; s is O, 1, 2 0 3, with the proviso that the sum of p and s is 4; A2 and B2 are each independently H, fluoro, or alkyl, or junios form a double bond or -CH2-; G is H or alkyl; X2 is -C (Rc) (Rd) -, -O-, -S-, -S (= O) -, -S (= O) 2-, -C (= O) -, -CH (OH) - or -N (R26) -; R26 is H, alkyl, cycloalkyl, - (CH2) -alkenyl, - (CH2) -alkynyl, aryl, -C (= O) Rd, or -S (= O) 2Rd; and J2 forms an aryl ring of 6 to 10 members or a heeroaryl ring of 5 to 10 members when it is formed together with the carbon atoms to which it is attached; or one of its stereoisomers, prodrugs, pharmaceutically acceptable salts, hydrates, solvates, hydrates of acid salt, or N-oxides. 103. A method according to claim 102, wherein said immunomodulatory immunosorbent is selected from the group consisting of: an autoimmune disease, a collagen disease, an allergy, a side effect associated with the administration of an anilimic agent, and a side effect associated with the administration of an animistic agency. 104. A method according to claim 103, wherein said immune-diseased disease is selected from the group consisting of: arthritis, an immunoimmune disorder associated with the skin flap, an autoimmune disease associated with the organism, and an urodynamic disease associated with surgery. 105. A method for the prevention or treatment of an inflammatory disorder, comprising the step of: administering to a patient in need thereof an effective amount of a compound of formula IV IV where: Y2 is a single bond or - [C (Rc) (Rd)] k-; each Rc, Re, and Rf is independently H or alkyl; each Rd is independently H, alkyl, or aryl; W2 is aryl, alkylaryl, heterocycloalkylaryl, heteroaryl, alkylheorylaryl, heteroarylaryl, or alkylheteroarylaryl; R23 and R24 are each independently H, alkyl, alkenyl, alkynyl, or aryl, or R23 and R24 when taken June with the atoms to which they are connected, form a cycloalkyl or heterocycloalkyl ring of 4 to 8 members; Z is -N (R25) -, -C (= O) -, -CH (OH) -, -CH (N (Rc) (Rd)) -, or -O-; R25 is H, alkyl, alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl, aralkyl, or heteroarylalkyl, or R23 and R25 when taken June with the atoms to which they are connected, form a 4- to 8-membered heterocycloalkyl ring, or R 24 and R25 when taken together with the atoms to which they are connected, form a 4 to 8 membered heterocycloalkyl ring; each k is independently 1, 2, or 3; p is O, 1, 2 0 3; s is 0, 1, 2 or 3, with the proviso that the sum of p and s is 4; A2 and B2 are each independently H, fluoro, or alkyl, or together they form a double bond or -CH2-; G is H or alkyl; X2 is -C (Rc) (Rd) -, -O-, -S-, -S (= O) -, -S (= O) 2-, -C (= O) -, -CH (OH) - or -N (R26) -; R26 is H, alkyl, cycloalkyl, - (CH2) -alkenyl, - (CH2) -alkynyl, aryl, -C (= O) Rd, or -S (= O) 2Rd; and J2 forms an aryl ring of 6 to 10 members or a heteroaryl ring of 5 to 10 members when Jun is taken with the carbon atoms to which it is attached; or one of its stereoisomers, prodrugs, pharmaceutically acceptable salts, hydrates, solvates, hydrates of acidic salt, or N-oxides. 106. A method according to claim 105, wherein said inflammatory disorder is arthritis, psoriasis, asthma, or inflammatory disease of the intestine. 107. A procedure for the prevention or protection of respiratory function, comprising the step of: administering to a patient in need of an effective amount of a compound of formula IV: rv in which: Y2 is a single bond or - [C (Rc) (Rd)] k-; each R c, Re, and R f is independently H or alkyl; each Rd is independently H, alkyl, or aryl; W2 is aryl, alkylaryl, heterocycloalkylaryl, heteroaryl, alkylheteroaryl, heteroarylaryl, or alkylheteroarylaryl; R23 and R24 are each independently H, alkyl, alkenyl, alkynyl, or aryl, or R23 and R24 when taken together with the atoms to which they are connected, form a cycloalkyl or heterocycloalkyl ring of 4 to 8 members; Z is -N (R25) -, -C (= O) -, -CH (OH) -, -CH (N (Rc) (Rd)) -, or -O-; R25 is H, alkyl, alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl, aralkyl, or heteroarylalkyl, or R23 and R25 when they are joined in June with the atoms through which they are connected, form a 4- to 8-membered ring-alkyl ring, or R24. and R25 when june June with the atoms through which they are connected, form a heterocycloalkyl ring of 4 to 8 members; each k is independently 1, 2, or 3; p is 0, 1, 2 or 3; s is 0, 1, 2 or 3, with the proviso that the sum of p and s is 4; A and B2 are each independently H, fluoro, or alkyl, or together form a double bond or -CH2-; G is H or alkyl; X2 is -C (Rc) (Rd) -, -O-, -S-, -S (= O) -, -S (= O) 2-, -C (= O) -, -CH (OH) - or -N (R26) -; R26 is H, alkyl, cycloalkyl, - (CH2) -alkenyl, - (CH2) -alkynyl, aryl, -C (= O) Rd, or -S (= O) 2Rd; and J2 forms an aryl ring of 6 to 10 members or a heteroaryl ring of 5 to 10 members when Jun is taken with the carbon atoms to which it is attached; or one of its stereoisomers, prodrugs, pharmaceutically acceptable salts, hydrates, solvates, acid salt hydrates, or N-oxides. 108. A method according to claim 107, wherein said respiratory function disorder is asthma or pulmonary edema. 109. A procedure for the prevention or treatment of anxiety, which comprises the step of administering to a patient in need of an effective canine of a compound of formula IV: rv in which: Y2 is a single bond or - [C (Rc) (Rd)] k-; each Rc, Re, and Rf is independently H or alkyl; each Rd is independently H, alkyl, or aryl; W2 is aryl, alkylaryl, heterocycloalkylaryl, heteroaryl, alkylheteroaryl, heteroarylaryl, or alkylheteroarylaryl; R23 and R24 are each independently H, alkyl, alkenyl, alkynyl, or aryl, or R23 and R24 when taken together with the atoms to which they are connected, form a cycloalkyl or heterocycloalkyl ring of 4 to 8 members; Z is -N (R25) -, -C (= O) -, -CH (OH) -, -CH (N (Rc) (Rd)) -, or -O-; R25 is H, alkyl, alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl, aralkyl, or heteroarylalkyl, or R23 and R25 when taken June with the atoms through which they are connected, form a 4- to 8-membered heterocycloalkyl ring, or R24 and R25 when they are taken in June with the atoms through which they are connected, they form a 4 to 8 membered heterocycloalkyl ring; each k is independently 1, 2, or 3; p is O, 1, 2 or 3; s is 0, 1, 2 or 3, with the proviso that the sum of p and s is 4; A2 and B2 are each independently H, fluoro, or alkyl, or together they form a double bond or -CH2-; G is H or alkyl; X2 is -C (Rc) (Rd) -, -O-, -S-, -S (= O) -, -S (= O) 2-, -C (= O) -, -CH (OH) - or -N (R26) -; R26 is H, alkyl, cycloalkyl, - (CH2) -alkenyl, - (CH2) -alkynyl, aryl, -C (= O) Rd, or -S (= O) 2Rd; and J2 forms a 6- to 10-membered aryl ring or a 5- to 10-membered heteroaryl ring when it is formed June with the carbon atoms to which it is attached; or one of its stereoisomers, prodrugs, pharmaceutically acceptable salts, hydrates, solvates, acid salt hydrates, or N-oxides. 110. A method for the prevention or treatment of a mood transient, comprising the step of: administering to a patient in need thereof an effective amount of a compound of formula IV: IV; wherein: Y2 is a single bond or - [C (Rc) (Rd)] k-; each Rc, Re, and Rf is independently H or alkyl; each Rd is independently H, alkyl, or aryl; W2 is aryl, alkylaryl, heterocycloalkylaryl, heteroaryl, alkylheteroaryl, heteroarylaryl, or alkylheteroarylaryl; R23 and R24 are each independently H, alkyl, alkenyl, alkynyl, or aryl, or R23 and R24 when taken together with the atoms to which they are connected, form a cycloalkyl or heterocycloalkyl ring of 4 to 8 members; Z is -N (R25) -, -C (= O) -, -CH (OH) -, -CH (N (Rc) (Rd)) -, or -O-; R25 is H, alkyl, alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl, aralkyl, or heteroarylalkyl, or R23 and R25 when combined with the atoms through which they are connected, form a 4- to 8-membered heterocycloalkyl ring, or R24 and R25 when taken together with the atoms through which they are connected, form a 4 to 8 membered heterocycloalkyl ring; each k is independently 1, 2, or 3; p is 0, 1, 2 0 3; s is 0, 1, 2 or 3, with the proviso that the sum of p and s is 4; A2 and B2 are each independently H, fluoro, or alkyl, or together they form a double bond or -CH2-; G is H or alkyl; X2 is -C (Rc) (Rd) -, -O-, -S-, -S (= O) -, -S (= O) 2-, -C (= O) -, -CH (OH) - or -N (R26) -; R26 is H, alkyl, cycloalkyl, - (CH2) -alkenyl, - (CH2) -alkynyl, aryl, -C (= O) Rd, or -S (= O) 2Rd; and J2 forms a 6 to 10 membered aryl ring or a 5- to 10 membered heteroaryl ring when taken together with the carbon atoms to which it is attached; or one of its stereoisomers, prodrugs, pharmaceutically acceptable salts, hydrates, solvates, acid salt hydrations, or N-oxides. 111. A method according to claim 110, wherein said mood disorder is selected from the group consisting of depression, bipolar manic depression, and seasonal affective disorder. 112. A method according to claim 110 further comprising the step of: administering to said patient an effective canine of an agent for the treatment of the depression. 113. A method for preventing or delaying a stress-related disorder, comprising the step of: administering to a patient in need thereof an effective amount of a compound of formula IV: IV where: Y2 is a single bond or - [C (Rc) (Rd)] k-; each R c, R 8, and R f is independently H or alkyl; each Rd is independently H, alkyl, or aryl; W2 is aryl, alkylaryl, heterocycloalkylaryl, heteroaryl, alkylheteroaryl, heteroarylaryl, or alkylheteroarylaryl; R23 and R24 are each independently H, alkyl, alkenyl, alkynyl, or aryl, or R23 and R24 when they are branched with the atoms through which they are connected, form a cycloalkyl or heterocycloalkyl ring of 4 to 8 members; Z is -N (R25) -, -C (= O) -, -CH (OH) -, -CH (N (Rc) (Rd)) -, or -O-; R25 is H, alkyl, alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl, aralkyl, or heteroarylalkyl, or R23 and R25 when branched in June with the atoms through which they are connected, form a 4- to 8-membered heterocycloalkyl ring, or R24 and R25, when taken together with the atoms through which they are connected, form a 4 to 8 membered ring-cycloalkyl ring; each k is independently 1, 2, or 3; p is O, 1, 2 0 3; s is O, 1, 2 or 3, with the proviso that the sum of p and s is 4; A2 and B2 are each independently H, fluoro, or alkyl, or together they form a double bond or -CH2-; G is H or alkyl; X2 is -C (Rc) (Rd) -, -O-, -S-, -S (= O) -, -S (= O) 2-, -C (= O) -, -CH (OH) - or -N (R26) -; R26 is H, alkyl, cycloalkyl, - (CH2) -alkenyl, - (CH2) -alkynyl, aryl, -C (= O) Rd, or -S (= O) 2Rd; and J2 forms an aryl ring of 6 to 10 members or a heteroaryl ring of 5 to 10 members when taken together with the carbon atoms to which it is attached; or one of its esioerosomers, prodrugs, pharmaceutically acceptable salts, hydrates, solvates, acid salt hydrates, or N-oxides. 114. A method according to claim 113, wherein said transi- tion related to the esírés is an írasíorno selected from the group constituted by postra-traumatic stress disorder, panic disorder, generalized anxiety disorder, social phobia, and obsessive-compulsive disorder . 115. A method for the prevention or treatment of an attention deficit hyperactivity disorder, comprising the step of: administering to a patient in need thereof an effective amount of a compound of formula IV: rv in which: Y2 is a single bond or - [C (Rc) (Rd)] k-; each Rc, Re, and Rf is independently H or alkyl; each Rd is independently H, alkyl, or aryl; W2 is aryl, alkylaryl, heterocycloalkylaryl, heteroaryl, alkylheteroaryl, heteroarylaryl, or alkylheteroarylaryl; R23 and R24 are each independently H, alkyl, alkenyl, alkynyl, or aryl, or R23 and R24 when taken together with the atoms through which they are connected, form a cycloalkyl or heterocycloalkyl ring of 4 to 8 members; Z is -N (R25) -, -C (= O) -, -CH (OH) -, -CH (N (Rc) (Rd)) -, or -O-; R25 is H, alkyl, alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl, aralkyl, or heteroarylalkyl, or R23 and R25 when taken together with the atoms through which they are connected, form a 4- to 8-membered heterocycloalkyl ring, or R24 and R25 when taken together with the atoms through which they are connected, form a 4- to 8-membered heterocycloalkyl ring; each k is independently 1, 2, or 3; p is 0, 1, 2 or 3; s is 0, 1, 2 6 3, with the proviso that the sum of p and s is 4; A2 and B2 are each independently H, fluoro, or alkyl, or together they form a double bond or -CH2-; G is H or alkyl; X2 is -C (Rc) (Rd) -, -O-, -S-, -S (= O) -, -S (= O) 2-, -C (= O) -, -CH (OH) - or -N (R26) -; R26 is H, alkyl, cycloalkyl, - (CH2) -alkenyl, - (CH2) -alkynyl, aryl, -C (= O) Rd, or -S (= O) 2Rd; and J2 forms a 6 to 10 membered aryl ring or a 5- to 10 membered heteroaryl ring when taken together with the carbon atoms to which it is attached; or one of its stereoisomers, prodrugs, pharmaceutically acceptable salts, hydrates, solvates, acid salt hydrates, or N-oxides. 116. A method for the prevention or treatment of a sympathetic nervous system disorder, comprising the step of: administering to a patient in need thereof an effective amount of a compound of formula IV: IV where: Y2 is a single bond or - [C (Rc) (Rd)] k-; each R c, R b, and R f is independently H or alkyl; each Rd is independently H, alkyl, or aryl; W2 is aryl, alkylaryl, heterocycloalkylaryl, heteroaryl, alkylheteroaryl, heteroarylaryl, or alkylheteroarylaryl; R23 and R24 are each independently H, alkyl, alkenyl, alkynyl, or aryl, or R23 and R24 when taken June with the atoms through which they are connected, form a cycloalkyl or heterocycloalkyl ring of 4 to 8 members; Z is -N (R25) -, -C (= O) -, -CH (OH) -, -CH (N (Rc) (Rd)) -, or -O-; R25 is H, alkyl, alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl, aralkyl, or heteroarylalkyl, or R23 and R25 when taken together with the atoms through which they are connected, form a 4- to 8-membered heteroaryloalkyl ring, or R24 and R25 when june June with the atoms through which they are connected form a heterocycloalkyl ring of 4 to 8 members; each k is independently 1, 2, or 3; p is 0, 1, 2 or 3; s is 0, 1, 2 or 3, with the proviso that the sum of p and s is 4; A2 and B2 are each independently H, fluoro, or alkyl, or junios form a double bond or -CH2-; G is H or alkyl; X2 is -C (R °) (Rd) -, -O-, -S-, -S (= O) -, -S (= O) 2-, -C (= O) -, -CH (OH ) - or -N (R26) -; R26 is H, alkyl, cycloalkyl, - (CH2) -alkenyl, - (CH2) -alkynyl, aryl, -C (= O) Rd, or -S (= O) 2Rd; and J2 forms an aryl ring of 6 to 10 members or a heteroaryl ring of 5 to 10 members when taken together with the carbon atoms to which it is attached; or one of its stereoisomers, prodrugs, pharmaceutically acceptable salts, hydrates, solvates, acid salt hydrates, or N-oxides. 117. A method according to claim 116, wherein said insult of the sympathetic nervous system is hypertension. 118. A procedure for the prevention or treatment of cough, comprising the step of: administering to a patient in need thereof an effective amount of a compound of formula IV: IV where: Y2 is a single bond or - [C (Rc) (Rd)] k-; each Rc, Re, and Rf is independently H or alkyl; each Rd is independently H, alkyl, or aryl; W2 is aryl, alkylaryl, heterocycloalkylaryl, heteroaryl, alkylheteroaryl, heteroarylaryl, or alkylheteroarylaryl; R23 and R24 are each independently H, alkyl, alkenyl, alkynyl, or aryl, or R23 and R24 when taken June with the atoms from which they are connected, form a cycloalkyl or heyerocycloalkyl ring of 4 to 8 members; Z is -N (R25) -, -C (= O) -, -CH (OH) -, -CH (N (Rc) (Rd)) -, or -O-; R25 is H, alkyl, alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl, aralkyl, or heeroarylalkyl, or R23 and R25 when they are joined in June with the atoms of 24 which are connected, form a 4- to 8-membered heterocycloalkyl ring, or R and R25, when taken together with the atoms from which they are connected, form a 4 to 8 membered ring-cycloalkyl ring; each k is independently 1, 2, or 3; p is 0, 1, 2 0 3; s is 0, 1, 2 or 3, with the proviso that the sum of p and s is 4; A2 and B2 are each independently H, fluoro, or alkyl, or together they form a double bond or -CH2-; G is H or alkyl; X2 is -C (Rc) (Rd) -, -O-, -S-, -S (= O) -, -S (= O) 2-, -C (= O) -, -CH (OH) - or -N (R26) -; R26 is H, alkyl, cycloalkyl, - (CH2) -alkenyl, - (CH2) -alkynyl, aryl, -C (= O) Rd, or -S (= O) 2Rd; and J2 forms a 6 to 10 membered aryl ring or a 5- to 10 membered heteroaryl ring when taken together with the carbon atoms to which it is attached; or one of its stereoisomers, prodrugs, pharmaceutically acceptable salts, hydrates, solvates, acid salt hydrates, or N-oxides. 119. A method for the prevention or treatment of a motor disorder, comprising the step of: administering a patient in need of an effective canine of a compound of formula IV: IV where: Y2 is a single bond or - [C (Rc) (Rd)] k-; each Rc, Re, and Rf is independently H or alkyl; each Rd is independently H, alkyl, or aryl; W2 is aryl, alkylaryl, heterocycloalkylaryl, heteroaryl, alkylheteroaryl, heteroarylaryl, or alkylheyaryarylaryl; R23 and R24 are each independently H, alkyl, alkenyl, alkynyl, or aryl, or R23 and R24 when taken together with the atoms to which they are connected, form a cycloalkyl or heterocycloalkyl ring of 4 to 8 members; Z is -N (R25) -, -C (= O) -, -CH (OH) -, -CH (N (Rc) (Rd)) -, or -O-; R25 is H, alkyl, alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl, aralkyl, or heteroarylalkyl, or R23 and R25 when branched in June with the atoms through which they are connected, form a 4- to 8-membered heterocycloalkyl ring, or R24 and R25 when taken together with the atoms to which they are connected, form a ring heyerocyclocycle of 4 to 8 members; each k is independently 1, 2, or 3; p is O, 1, 2 or 3; s is 0, 1, 2 or 3, with the proviso that the sum of p and s is 4; A2 and B2 are each independently H, fluoro, or alkyl, or together they form a double bond or -CH2-; G is H or alkyl; X2 is -C (Rc) (Rd) -, -O-, -S-, -S (= O) -, -S (= O) 2-, -C (= O) -, -CH (OH) - or -N (R26) -; R26 is H, alkyl, cycloalkyl, - (CH2) -alkenyl, - (CH2) -alkynyl, aryl, -C (= O) Rd, or -S (= O) 2Rd; and J2 forms an aryl ring of 6 to 10 members or a heteroaryl ring of 5 to 10 members when taken together with the carbon atoms to which it is attached; or one of its stereoisomers, prodrugs, pharmaceutically acceptable salts, hydrates, solvates, acid salt hydrates, or N-oxides. 120. A method according to claim 119, wherein said moiriz transi- tion is tremor, Parkinson's disease, Touretie's syndrome or dyskinesia. 121. A method according to claim 120 wherein said motor disorder is tremor. 122. A method according to claim 121, further comprising the step of: administering to said patient an effective amount of an anti-Parkinson's agent. 123. A method for the treatment of a traumatic injury of the central nervous system, comprising the step of: administering to a patient in need thereof an effective amount of a compound of formula IV: rv in which: Y2 is a single bond or - [C (Rc) (Rd)] k-; each R c, R e, and R f is independently H or alkyl; each Rd is independently H, alkyl, or aryl; W2 is aryl, alkylaryl, heterocycloalkylaryl, heteroaryl, alkylheteroaryl, heteroarylaryl, or alkylheteroarylaryl; R23 and R24 are each independently H, alkyl, alkenyl, alkynyl, or aryl, or R23 and R24 when taken June with the atoms through which they are connected, form a cycloalkyl or heterocycloalkyl ring of 4 to 8 members; Z is -N (R25) -, -C (= O) -, -CH (OH) -, -CH (N (Rc) (Rd)) -, or -O-; R25 is H, alkyl, alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl, aralkyl, or heteroarylalkyl, or R23 and R25 when branched in June with the atoms through which they are connected, form a 4- to 8-membered heterocycloalkyl ring, or R24 and R25 when taken June with the atoms through which they are connected, form a 4 to 8 membered heterocycloalkyl ring; each k is independently 1, 2, or 3; p is 0, 1, 2 0 3; s is 0, 1, 2 or 3, with the proviso that the sum of p and s is 4; A and B are each independently H, fluoro, or alkyl, or together they form a double bond or -CH2-; G is H or alkyl; X2 is -C (Rc) (Rd) -, -O-, -S-, -S (= O) -, -S (= O) 2-, -C (= O) -, -CH (OH) - or -N (R26) -; R26 is H, alkyl, cycloalkyl, - (CH2) -alkenyl, - (CH2) -alkynyl, aryl, -C (= O) Rd, or -S (= O) 2Rd; and J2 forms a 6 to 10 membered aryl ring or a 5- to 10 membered heteroaryl ring when taken together with the carbon atoms to which it is attached; or one of its stereoisomers, prodrugs, pharmaceutically acceptable salts, hydrates, solvates, acid salt hydrates, or N-oxides. 124. A method according to claim 123, wherein said traumatic injury is a traumatic injury of the spine or brain. 125. A procedure for the prevention or delay of stroke, comprising the step of: administering to a patient in need thereof an effective amount of a compound of formula IV: rv in which: Y2 is a single bond or - [C (Rc) (Rd)] k-; each Rc, Re, and Rf is independently H or alkyl; each Rd is independently H, alkyl, or aryl; . W2 is aryl, alkylaryl, heterocycloalkylaryl, heteroaryl, alkylheteroaryl, heteroarylaryl, or alkylheyaryarylaryl; R23 and R24 are each independently H, alkyl, alkenyl, alkynyl, or aryl, or R23 and R24 when taken together with the atoms from which they are connected, form a cycloalkyl or heterocycloalkyl ring of 4 to 3 members; Z is -N (R25) -, -C (= O) -, -CH (OH) -, -CH (N (Rc) (Rd)) -, or -O-; R 25 is H, alkyl, alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl, aralkyl, or heteroaplalkyl, or R 25 and R 25 when they are branched in June with the atoms through which they are connected, form a 4- to 8-membered heterocycloalkyl ring, or R24 and R25, when conjugated with the atoms through which they are connected, form a 4 to 8 membered heterocycloalkyl ring; each k is independently 1, 2, or 3; p is O, 1, 2 or 3; s is 0, 1, 2 or 3, with the proviso that the sum of p'y s is 4; A2 and B2 are each independently H, fluoro, or alkyl, or together they form a double bond or -CH2-; G is H or alkyl; X2 is -C (Rc) (Rd) -, -O-, -S-, -S (= O) -, -S (= O) 2-, -C (= O) -, -CH (OH) - or -N (R26) -; R26 is H, alkyl, cycloalkyl, - (CH2) -alkenyl, - (CH2) -alkynyl, aryl, -C (= O) Rd, or -S (= O) 2Rd; and J2 forms a 6 to 10 membered aryl ring or a 5- to 10 membered heteroaryl ring when taken together with the carbon atoms to which it is attached; or one of its stereoisomers, prodrugs, pharmaceutically acceptable salts, hydrates, solvates, acid salt hydrates, or N-oxides. 126. A method for the prevention or treatment of cardiac arrhythmia, comprising the step of: administering to a patient in need thereof an effective amount of a compound of formula IV: IV wherein: X is a single bond each R c, Re, and R f is independently H or alkyl; each Rd is independently H, alkyl, or aryl; W2 is aryl, alkylaryl, heterocycloalkylaryl, heteroaryl, alkylheteroaryl, heteroarylaryl, or alkylheteroarylaryl; R23 and R24 are each independently H, alkyl, alkenyl, alkynyl, or aryl, or R23 and R24 when taken together with the atoms through which they are connected, form a cycloalkyl or heterocycloalkyl ring of 4 to 8 members; Z is -N (R25) -, -C (= O) -, -CH (OH) -, -CH (N (Rc) (Rd)) -, or -O-; R25 is H, alkyl, alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl, aralkyl, or heteroarylalkyl, or R23 and R25 when they are in June with the atoms through which they are connected, form a 4- to 8-membered heterocycloalkyl ring, or R24 and R25 when they are taken in June with the atoms through which they are connected, they form a 4 to 8 membered heterocycloalkyl ring; each k is independently 1, 2, or 3; p is O, 1, 2 or 3; s is 0, 1, 2 or 3, with the proviso that the sum of p and s is 4; A2 and B2 are each independently H, fluoro, or alkyl, or together they form a double bond or -CH2-; G is H or alkyl; X2 is -C (Rc) (Rd) -, -O-, -S-, -S (= O) -, -S (= O) 2-, -C (= O) -, -CH (OH) - or -N (R26) -; R26 is H, alkyl, cycloalkio, - (CH2) -alkenyl, - (CH2) -alkynyl, aryl, -C (= O) Rd, or -S (= O) 2Rd; and J2 forms a 6 to 10 membered aryl ring or a 5- to 10 membered heteroaryl ring when taken together with the carbon atoms to which it is attached; or one of its stereoisomers, prodrugs, pharmaceutically acceptable salts, hydrates, solvates, hydrates of acid salt, or N-oxides. 127. A method for the prevention or treatment of glaucoma, comprising the step of: administering to a patient in need thereof an effective amount of a compound of formula IV: rv in which: Y2 is a single bond or - [C (Rc) (Rd)] k-; each Rc, Re, and Rf is independently H or alkyl; each Rd is independently H, alkyl, or aryl; W2 is aryl, alkylaryl, heterocycloalkylaryl, heteroaryl, alkylheteroaryl, heteroarylaryl, or alkylheteroarylaryl; R23 and R24 are each independently H, alkyl, alkenyl, alkynyl, or aryl, or R23 and R24 when taken together with the atoms through which they are connected, form a cycloalkyl or heterocycloalkyl ring of 4 to 8 members; Z is -N (R25) -, -C (= O) -, -CH (OH) -, -CH (N (Rc) (Rd)) -, or -O-; R25 is H, alkyl, alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl, aralkyl, or heteroarylalkyl, or R23 and R25 when taken together with the atoms through which they are connected, form a 4- to 8-membered heterocycloalkyl ring, or R24 and R25 when they are taken in June with the atoms through which they are connected, they form a 4 to 8 membered heterocycloalkyl ring; each k is independently 1, 2, or 3; p is 0, 1, 2 or 3; s is 0, 1, 2 or 3, with the proviso that the sum of p and s is 4; A2 and B2 are each independently H, fluoro, or alkyl, or together they form a double bond or -CH2-; G is H or alkyl; X2 is -C (Rc) (Rd) -, -O-, -S-, -S (= O) -, -S (= O) 2-, -C (= O) -, -CH (OH) - or -N (R26) -; R26 is H, alkyl, cycloalkyl, - (CH2) -alkenyl, - (CH2) -alkynyl, aryl, -C (= O) Rd, or -S (= O) 2Rd; and J2 forms an aryl ring of 6 to 10 members or a heteroaryl ring of 5 to 10 members when it is formed June with the carbon atoms to which it is attached; or one of its stereoisomers, prodrugs, pharmaceutically acceptable salts, hydrates, solvates, hydrates of acidic salt, or N-oxides. 128. A method for the prevention or treatment of sexual dysfunction, comprising the step of: administering to a patient in need thereof an effective amount of a compound of formula IV: IV where: Y2 is a single bond or - [C (Rc) (Rd)] k-; each Rc, Re, and Rf is independently H or alkyl; each Rd is independently H, alkyl, or aryl; W2 is aryl, alkylaryl, heterocycloalkylaryl, heteroaryl, alkylheorylaryl, heteroarylaryl, or alkylheteroarylaryl; R23 and R24 are each independently H, alkyl, alkenyl, alkynyl, or aryl, or R23 and R24 when taken together with the atoms through which they are connected, form a cycloalkyl or heterocycloalkyl ring of 4 to 8 members; Z is -N (R25) -, -C (= O) -, -CH (OH) -, -CH (N (Rc) (Rd)) -, or -O-; R25 is H, alkyl, alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl, aralkyl, or heteroarylalkyl, or R23 and R25 when branched in June with the atoms through which they are connected, form a 4- to 8-membered heterocycloalkyl ring, or R24 and R25 when they are taken in June with the atoms through which they are connected, they form a 4 to 8 membered heterocycloalkyl ring; each k is independently 1, 2, or 3; p is 0, 1, 2 or 3; s is 0, 1, 2 or 3, with the proviso that the sum of p and s is 4; A2 and B2 are each independently H, fluoro, or alkyl, or together they form a double bond or -CH2-; G is H or alkyl; X2 is -C (Rc) (Rd) -, -O-, -S-, -S (= O) -, -S (= O) 2-, -C (= O) -, -CH (OH) - or -N (R26) -; R26 is H, alkyl, cycloalkyl, - (CH2) -alkenyl, - (CH2) -alkynyl, aryl, -C (= O) Rd, or -S (= O) 2Rd; and J2 forms a 6 to 10 membered aryl ring or a 5- to 10 membered heteroaryl ring when taken together with the carbon atoms to which it is attached; or one of its stereoisomers, prodrugs, pharmaceutically acceptable salts, hydrates, solvates, acid salt hydrates, or N-oxides. 129. A method according to claim 128, wherein said sexual dysfunction is premature ejaculation. 130. A procedure for the treatment of a condition selected from the group consisting of concussion, cerebral edema, cerebral ischemia, cerebral deficits after cardiac bypass and graft surgery, systemic lupus erythematosus, Hodgkin's disease, Sjogren's disease, epilepsy, and rejection in the transplantation of organs and skin grafts, which comprises the step of administering to a patient in need of an effective canine of a compound of formula IV: rv in which: Y2 is a single bond or - [C (Rc) (Rd)] k-; each Rc, Re, and Rf is independently H or alkyl; each Rd is independently H, alkyl, or aryl; W2 is aryl, alkylaryl, heterocycloalkylaryl, heteroaryl, alkylheteroaryl, heteroarylaryl, or alkylheteroarylaryl; R23 and R24 are each independently H, alkyl, alkenyl, alkynyl, or aryl, or R23 and R24 when taken together with the atoms through which they are connected, form a cycloalkyl or heterocycloalkyl ring of 4 to 8 members; Z is -N (R25) -, -C (= O) -, -CH (OH) -, -CH (N (R °) (Rd)) -, or -O-; R25 is H, alkyl, alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl, aralkyl, or heteroarylalkyl, or R23 and R25 when taken together with the atoms through which they are connected, form a 4- to 8-membered heterocycloalkyl ring, or R24 and R25 when taken together with the atoms through which they are connected, form a 4- to 8-membered heterocycloalkyl ring; each k is independently 1, 2, or 3; p is O, 1, 2 0 3; s is 0, 1, 2 or 3, with the proviso that the sum of p and s is 4; A2 and B2 are each independently H, fluoro, or alkyl, or together they form a double bond or -CH2-; G is H or alkyl; X2 is -C (Rc) (Rd) -, -O-, -S-, -S (= O) -, -S (= O) 2-, -C (= O) -, -CH (OH) - or -N (R26) -; R26 is H, alkyl, cycloalkyl, - (CH2) -alkenyl, - (CH2) -alkynyl, aryl, -C (= O) Rd, or -S (= O) 2Rd; and J2 forms an aryl ring of 6 to 10 members or a heeroaryl ring of 5 to 10 members when it is formed June with the carbon atoms to which it is attached; or one of its stereoisomers, prodrugs, pharmaceutically acceptable salts, hydrates, solvates, hydrates of acid salt, or N-oxides. 131. A procedure for the eradication of substance addiction, comprising the step of: administering to a patient in need thereof an effective canine of a compound of formula IV: rv in which: Y2 is a single bond or - [C (Rc) (Rd)] k-; each Rc, Re, and Rf is independently H or alkyl; each Rd is independently H, alkyl, or aryl; W2 is aryl, alkylaryl, heterocycloalkylaryl, heteroaryl, alkylheteroaryl, heteroarylaryl, or alkylheteroarylaryl; R23 and R24 are each independently H, alkyl, alkenyl, alkenyl, or aryl, or R23 and R24 when taken together with the atoms through which they are connected, form a cycloalkyl or heterocycloalkyl ring of 4 to 8 members; Z is -N (R25) -, -C (= O) -, -CH (OH) -, -CH (N (Rc) (Rd)) -, or -O-; R25 is H, alkyl, alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl, aralkyl, or heteroarylalkyl, or R23 and R25 when taken together with the atoms through which they are connected, form a 4- to 8-membered heterocycloalkyl ring, or R24 and R25 when taken June with the atoms to which they are connected, form a heterocycloalkyl ring of 4 to 8 members; each k is independently 1, 2, or 3; p is 0, 1, 2 or 3; s is 0, 1, 2 6 3, with the proviso that the sum of p and s is 4; A2 and B2 are each independently H, fluoro, or alkyl, or together they form a double bond or -CH2-; G is H or alkyl; X2 is -C (Rc) (Rd) -, -O-, -S-, -S (= O) -, -S (= O) 2-, -C (= O) -, -CH (OH) - or -N (R26) -; R26 is H, alkyl, cycloalkyl, - (CH2) -alkenyl, - (CH2) -alkynyl, aryl, -C (= O) Rd, or -S (= O) 2Rd; and J2 forms a 6 to 10 membered aryl ring or a 5- to 10 membered heteroaryl ring when taken together with the carbon atoms to which it is attached; or one of its stereoisomers, prodrugs, pharmaceutically acceptable salts, hydrates, solvates, acid salt hydrates, or N-oxides. 132. A method according to claim 131, wherein said addiction to addictions is alcohol addiction, nicotine addiction, or drug addiction. 133. A method according to claim 132, wherein said drug addiction is opioid addiction. 134. A method for improving cell and organ survival, comprising the step of: administering to a patient in need of an effective amount of a compound of formula IV: TV where: Y2 is a single bond or - [C (Rc) (Rd)] k-; each Rc, Re, and Rf is independently H or alkyl; each Rd is independently H, alkyl, or aryl; W2 is aryl, alkylaryl, heterocycloalkylaryl, heteroaryl, alkylheorylaryl, heteroarylaryl, or alkylheyaryarylaryl; R23 and R24 are each independently H, alkyl, alkenyl, alkynyl, or aryl, or R23 and R24 when taken together with the atoms through which they are connected, form a cycloalkyl or heterocycloalkyl ring of 4 to 8 members; Z is -N (R25) -, -C (= O) -, -CH (OH) -, -CH (N (Rc) (Rd)) -, or -O-; R25 is H, alkyl, aikenyl, alkynyl, cycloalkyl, alkylcycloalkyl, aralkyl, or heteroarylalkyl, or R3 and R25 when taken together with the atoms through which they are connected, form a 4- to 8-membered heterocycloalkyl ring, or R24 and R25 when taken together with the atoms to which they are connected, form a 4- to 8-membered heterocycloalkyl ring; each k is independently 1, 2, or 3; p is 0, 1, 2 0 3; s is 0, 1, 2 or 3, with the proviso that the sum of p and s is 4; A and B2 are each independently H, fluoro, or alkyl, or together form a double bond or -CH2-; G is H or alkyl; X2 is -C (Rc) (Rd) -, -O-, -S-, -S (= O) -, -S (= O) 2-, -C (= O) -, -CH (OH) - or -N (R26) -; R26 is H, alkyl, cycloalkyl, - (CH2) -alkenyl, - (CH2) -alkynyl, aryl, -C (= O) Rd, or -S (= O) 2Rd; and J2 forms an aryl ring of 6 to 10 members or a heteroaryl ring of 5 to 10 members when Jun is taken with the carbon atoms to which it is attached; or one of its stereoisomers, prodrugs, pharmaceutically acceptable salts, hydrates, solvates, acid salt hydrates, or N-oxides. 135. A method for providing cardioprotection after myocardial infarction, comprising the step of: administering to a patient in need thereof an effective amount of a compound of formula IV: IV where: Y2 is a single bond or - [C (Rc) (Rd)] k-; each Rc, Re, and Rf is independently H or alkyl; each Rd is independently H, alkyl, or aryl; W2 is aryl, alkylaryl, heteroaryloalkylaryl, heteroaryl, alkylheteroaryl, heteroarylaryl, or alkylheyryarylaryl; R23 and R24 are each independently H, alkyl, alkenyl, alkynyl, or aryl, or R23 and R24 when taken together with the atoms through which they are connected, form a cycloalkyl or heterocycloalkyl ring of 4 to 8 members; Z is -N (R25) -, -C (= O) -, -CH (OH) -, -CH (N (Rc) (Rd)) -, or -O-; R25 is H, alkyl, alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl, aralkyl, or heteroarylalkyl, or R23 and R25 when branched in June with the atoms through which they are connected, form a 4- to 8-membered heteroaryloalkyl ring, or R24. and R25 when june June with the atoms through which they are connected, form a heterocycloalkyl ring of 4 to 8 members; each k is independently 1, 2, or 3; p is O, 1, 2 0 3; s is 0, 1, 2 or 3, with the proviso that the sum of p and s is 4; A2 and B2 are each independently H, fluoro, or alkyl, or together they form a double bond or -CH2-; G is H or alkyl; X2 is -C (Rc) (Rd) -, -O-, -S-, -S (= O) -, -S (= O) 2-, -C (= O) -, -CH (OH) - or -N (R26) -; R26 is H, alkyl, cycloalkyl, - (CH2) -alkenyl, - (CH2) -alkynyl, aryl, -C (= O) Rd, or -S (= O) 2Rd; and J2 forms an aryl ring of 6 to 10 members or a heteroaryl ring of 5 to 10 members when Jun is taken with the carbon atoms to which it is attached; or one of its stereoisomers, prodrugs, pharmaceutically acceptable salts, hydrates, solvates, hydrates of acid salt, or N-oxides. 136. A method for reducing the need for anesthesia, comprising the step of: administering to a patient in need thereof an effective amount of a compound of formula IV: rv in which: Y2 is a single bond or - [C (Rc) (Rd)] k-; each Rc, R ß, and Rf is independently H or alkyl; each Rd is independently H, alkyl, or aryl; W2 is aryl, alkylaryl, heterocycloalkylaryl, heteroaryl, alkenheteroaryl, heteroarylaryl, or alkylheteroarylaryl; R23 and R24 are each independently H, alkyl, alkenyl, alkynyl, or aryl, or R23 and R24 when taken together with the atoms through which they are connected, form a cycloalkyl or heterocycloalkyl ring of 4 to 8 members; Z is -N (R25) -, -C (= O) -, -CH (OH) -, -CH (N (Rc) (Rd)) -, or -O-; R25 is H, alkyl, alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl, aralkyl, or heteroarylalkyl, or R23 and R25 when taken together with the atoms through which they are connected, form a 4- to 8-membered heterocycloalkyl ring, or R24 and R25 when taken together with the atoms through which they are connected, form a heterocycloalkyl ring of 4 to 8 members; each k is independently 1, 2, or 3; p is O, 1, 2 6 3; s is 0, 1, 2 or 3, with the proviso that the sum of p and s is 4; A2 and B2 are each independently H, fluoro, or alkyl, or together they form a double bond or -CH2-; G is H or alkyl; X2 is -C (Rc) (Rd) -, -O-, -S-, -S (= O) -, -S (= O) 2-, -C (= O) -, -CH (OH) - or -N (R26) -; R26 is H, alkyl, cycloalkyl, - (CH2) -alkenyl, - (CH2) -alkynyl, aryl, -C (= O) Rd, or -S (= O) 2Rd; and J2 forms a 6 to 10 membered aryl ring or a 5- to 10 membered heteroaryl ring when taken together with the carbon atoms to which it is attached; or one of its stereoisomers, prodrugs, pharmaceutically acceptable salts, hydrates, solvates, acid salt hydrates, or N-oxides. 137. A method for producing or maintaining an anesthetic state, comprising the step of: administering to a patient in need thereof an effective canine of a compound of formula IV: IV where: Y2 is a single bond or - [C (Rc) (Rd)] k-; each R c, Re, and R f is independently H or alkyl; each Rd is independently H, alkyl, or aryl; W2 is aryl, alkylaryl, heterocycloalkylaryl, heteroaryl, alkylheteroaryl, heteroarylaryl, or alkylheteroarylaryl; R23 and R24 are each independently H, alkyl, alkenyl, alkynyl, or aryl, or R23 and R24 when taken together with the atoms through which they are connected, form a cycloalkyl or heterocycloalkyl ring of 4 to 8 members; Z is -N (R25) -, -C (= O) -, -CH (OH) -, -CH (N (Rc) (Rd)) -, or -O-; R25 is H, alkyl, alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl, aralkyl, or heeroarylalkyl, or R23 and R25 when taken June with the atoms through which they are connected, form a 4- to 8-membered heterocycloalkyl ring, or R24 and R25 when they are taken in June with the atoms through which they are connected, they form a 4 to 8 membered heterocycloalkyl ring; each k is independently 1, 2, or 3; p is 0, 1, 2 or 3; s is 0, 1, 2 or 3, with the proviso that the sum of p and s is 4; A2 and B2 are each independently H, fluoro, or alkyl, or together they form a double bond or -CH2-; G is H or alkyl; X2 is -C (Rc) (Rd) -, -O-, -S-, -S (= O) -, -S (= O) 2-, -C (= O) -, -CH (OH) - or -N (R26) -; R 26 is H, alkyl, cycloalkyl, - (CH 2) -alkenyl, - (CH 2) -alkynyl, aryl, -C (= O) R d, or -S (= O) 2 R d; and J2 forms a 6 to 10 membered aryl ring or a 5- to 10 membered heteroaryl ring when taken together with the carbon atoms to which it is attached; or one of its stereoisomers, prodrugs, pharmaceutically acceptable salts, hydrates, solvates, acid salt hydrates, or N-oxides. 138. A method according to claim 137, further comprising the step of: administering to said patient an anesthetic agent selected from the group consisting of an inhaled anesthetic, a hypnotic, an anxiolytic, a neuromuscular blocker and an opioid. 139. A method according to claim 138, wherein said compound and said anesthetic agent are co-administered. 140. A radiolabeled derivative of a compound of formula IV: IV where: Y2 is a single bond or - [C (Rc) (Rd)] k-; each Rc, Re, and Rf is independently H or alkyl; each Rd is independently H, alkyl, or aryl; W2 is aryl, alkylaryl, heterocycloalkylaryl, heteroaryl, alkylheteroaryl, heteroarylaryl, or alkylheteroarylaryl; R23 and R24 are each independently H, alkyl, alkenyl, alkynyl, or aryl, or R23 and R24 when taken together with the atoms from which they are connected, form a cycloalkyl or heyerocycloalkyl ring of 4 to 8 members; Z is -N (R25) -, -C (= O) -, -CH (OH) -, -CH (N (Rc) (Rd)) -, or -O-; R25 is H, alkyl, alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl, aralkyl, or heeroarylalkyl, or R23 and R25 when taken together with the atoms through which they are connected, form a 4- to 8-membered heterocycloalkyl ring, or R24 and R25 when they are taken June with the atoms to which they are connected, they form a ring of 4 to 8 membered heteroaryloalkyl; each k is independently 1, 2, or 3; p is O, 1, 2 or 3; s is 0, 1, 2 or 3, with the proviso that the sum of p and s is 4; A2 and B2 are each independently H, fluoro, or alkyl, or together they form a double bond or -CH2-; G is H or alkyl; X2 is -C (Rc) (Rd) -, -O-, -S-, -S (= O) -, -S (= O) 2-, -C (= O) -, -CH (OH) - or -N (R26) -; R26 is H, alkyl, cycloalkyl, - (CH2) -alkenyl, - (CH2) -alkynyl, aryl, -C (= O) Rd, or -S (= O) 2Rd; and J2 forms an aryl ring of 6 to 10 members or a heteroaryl ring of 5 to 10 members when it is formed together with the carbon atoms to which it is attached; with the proviso that when: (a) J2 is formed June with the carbon atoms to which it is attached it forms a 6 to 10 membered aryl ring substituted with 0-3 groups selected from the group consisting of: halogen, hydroxy, - SH, -C (= O) -H -S-alkyl CM, -NHS (= O) 2-alkyl C, -NHS (= O) 2-H, -N (alkyl CM) S (= O) 2- H, alkyl CM, and alkoxy CM, the last two optionally substituted with one or more halogens or with C1-4 alkoxy; W2 is substituted phenyl with 0-3 groups selected from the group taken up by: halogen, cyano, hydroxy, optionally C1-6alkyl sus- pended with one or more halogens, C1-6 alkoxy optionally susii- uid with one or more halogens or with C3-6 cycloalkyl , C 2-6 alkenyloxy, C 2-6 alkynyloxy, C 3-6 cycloalkyloxy, C 6-2 aryloxy, aralkoxy, heteroaryloxy, heteroaralkoxy, heterocycloalkyl susi-substituted with alkoxy, -SH, -S-alkyl CM, -NH 2, -N = C ( aryl) 2, -N (H) alkyl CM, -N (C 14 alkyl) 2, -OS (= O) 2 -alkyl optionally substituted with one or more halogens, -OS (= O) 2-aryl C6-? 2 optionally susiiuuido with alkyl CM, -NHS (= O) 2-alkyl CM, -N (alkyl CM) S (= O) 2-alkyl CM, -NHS (= O) 2-H, and -N (alkyl CM) S (= O) 2-H; pys are each 1, Re, Rf, R23, R24, and G are each H, A2 and B2 together form a double bond that incorporates the atoms to which they are attached, Y2 is a single bond; and X2 is -O-; then Z is different from: , where t is an integer between 1 and 20; and with the proviso that when: (b) J2 is taken together with the carbon atoms to which it is attached it forms a substituted phenyl ring with 0-3 groups selected from the group consisting of: halogen, hydroxy, -S-alkyl CM , alkyl C, and alkoxy C, the two last optionally substituted with one or more halogens or with C-alkoxy; W 2 is unsubstituted naphthyl, or phenyl substituted with 0-3 groups selected from the group consisting of: halogen, C 1-6 alkyl, C 1-6 alkoxy, phenyl, phenoxy, 1,3-benzodioxazolyl, or 2,2-difluoro-1 , 3-benzodioxazolyl fluoro, -NH2, -N (alkylCM) 2, and pyrrolyl; p and s are each 1, Re, Rf, R23, R24, and G are each H, A2 and B2 together form a double bond that incorporates the atoms to which they are attached, Y2 is a single bond; and X2 is -O-; then Z is different from: with the proviso that when: (c) J2 is taken together with the carbon atoms to which unsubstituted phenyl form is attached, W2 is phenyl substituted with 0-3 groups selected from the group consisting of: fluorine, hydroxy, alkoxy C ? -6 optionally substituted with one or more fluoros, C2-6 alkenyloxy, and -S-alkyl CM, pys are each 1, Re, Rf, R23, R24, and G are each H, A2 and B2 together form a double bond that incorporates the atoms to which they are attached, Y2 is a simple link; and X2 is -O-; then Z is different from:; and with the proviso that when: (d) J2 is taken together with the carbon atoms to which it is attached it forms a 6-membered aryl ring substituted with: then Z is different from -N (R25) - or -CH (NH2) -; or one of its stereoisomers, prodrugs, pharmaceutically acceptable salts, hydrates, solvates, acid salt hydrates, or N-oxides. 141. An isotopically-labeled derivative of a compound of formula IV) in which: Y2 is a single bond or - [C (Rc) (Rd)] k-; each Rc, R e, and R f is independently H or alkyl; each Rd is independently H, alkyl, or aryl; W2 is aryl, alkylaryl, heterocycloalkylaryl, heteroaryl, alkylheorylaryl, heteroarylaryl, or alkylheyaryarylaryl; R23 and R24 are each independently H, alkyl, alkenyl, alkynyl, or aryl, or R23 and R24 when taken together with the atoms through which they are connected, form a cycloalkyl or heterocycloalkyl ring of 4 to 8 members; Z is -N (R25) -, -C (= O) -, -CH (OH) -, -CH (N (Rc) (Rd)) -, or -O-; R25 is H, alkyl, alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl, aralkyl, or heteroarylalkyl, or R23 and R25 when taken together with the atoms through which they are connected, form a 4- to 8-membered heterocycloalkyl ring, or R24 and R25 when taken together with the atoms through which they are connected, form a 4- to 8-membered heterocycloalkyl ring; each k is independently 1, 2, or 3; p is O, 1, 2 or 3; s is 0, 1, 2 or 3, with the proviso that the sum of p and s is 4; A2 and B2 are each independently H, fluoro, or alkyl, or together they form a double bond or -CH2-; G is H or alkyl; X2 is -C (Rc) (Rd) -, -O-, -S-, -S (= O) -, -S (= O) 2-, -C (= O) -, -CH (OH) - or -N (R26) -; R26 is H, alkyl, cycloalkyl, - (CH2) -alkenyl, - (CH2) -alkynyl, aryl, -C (= O) Rd, or -S (= O) 2Rd; and J2 forms an aryl ring of 6 to 10 members or a heteroaryl ring of 5 to 10 members when Jun is taken with the carbon atoms to which it is attached; with the proviso that when: (a) J2 is taken June with the carbon atoms to which it is attached it forms an aryl ring of 6 to 10 members substituted with 0-3 groups selected from the group constituted by: halogen, hydroxy, - SH, -C (= O) -H -S-alkyl C, -NHS (= O) 2-alkyl CM, -NHS (= O) 2-H, -N (C 1-4 alkyl) S (= O) 2-H, C-alkyl, and C-alkoxy, the last two optionally substituted with one or more halogens or with C? -4 alkoxy; W 2 is phenyl substituted with 0-3 groups selected from the group consisting of: halogen, cyano, hydroxy, C 1-6 alkyl optionally susiiuuido with one or more halogens, C-6 alkoxy optionally susíiuuido with one or more halogens or with C3-6 cycloalkyl , C 2-6 alkenyloxy, C 2-6 alkynyloxy, C 3-6 cycloalkyloxy, C 6-2 aryloxy, aralkoxy, heteroaryloxy, heteroaralkoxy, heteroaryloalkyl additionally substituted with alkoxy, -SH, -S-alkyl CM, -NH 2, -N = C (aryl) 2, -N (H) alkyl CM, -N (C1 alkyl) 2, -OS (= O) 2 -alkyl optionally substituted with one or more halogens, -OS (= O) 2-aryl C6-? 2 optionally susíiuuido with alkyl CM, -NHS (= O) 2-alkyl CM, -N (alkyl CM) S (= O) 2-alkyl CM, -NHS (= O) 2-H, and -N (alkyl CM) S (= O) 2-H; p and s are each 1, Re, Rf, R23, R24, and G are each H, A2 and B2 together form a double bond that incorporates the atoms to which they are linked, Y2 is a single bond; and X2 is -O-; then Z is disíinío of: , where i is an integer in the range of 1 to 20; and with the proviso that when: (b) J2 is omited together with the carbon atoms to which it is attached it forms a substituted phenyl ring with 0-3 groups selected from the group consisting of: halogen, hydroxy, -S-alkyl CM , alkyl CM, and alkoxy CM, the two last optionally substituted with one or more halogens or with C1-4 alkoxy; W2 is unsubstituted naphtyl, or phenyl substituted with 0-3 groups selected from the group consisting of: halogen, C1-6 alkyl, C6-6 alkoxy, phenyl, phenoxy, 1,3-benzodioxazolyl, or 2,2-difluoro- 1,3-benzodioxazolyl fluoro, -NH2, -N (alkylCM) 2, and pyrrolyl; p and s are each 1, Re, Rf, R23, R24, and G are each H, A2 and B2 together form a double bond that incorporates the atoms to which they are attached, Y2 is a single bond; and X2 is -O-; r '? , r: rhnno 3 the ri ialo.K is joined form one with the proviso that when: (e) J2 is taken together with the carbon atoms to which it is attached i '• unsubstituted phenyl form, W2 is phenyl substituted with 0-3 groups selected from the group consisting of: fluorine, hydroxy, C 1-6 alkoxy optionally substituted with one or more fluoros, C 2-6 alkenyloxy, and -S-C alkyl, pys are each 1, Re, Rf , R23, R24, and G are each H, A2 and B2 together form a double bond that incorporates the atoms to which they are bound, Y2 is a single bond; and X2 is -O-; then Z is different from: with the proviso that when: (d) J2 is taken together with the carbon atoms to which it is attached it forms a 6-membered aryl ring substituted with: then Z is other than -N (R25) - or -CH (NH2 ) -; or one of its stereoisomers, prodrugs, pharmaceutically acceptable salts, hydrates, solvates, acid salt hydrates, or N-oxides. 142. A compound selected from the group consisting of: 4 - [(4-methoxyphenyl) -spiro [2 H, 1-benzopyran-2,4'-piperidine]; 4 - [(4-methylphenyl) -spiro [2H, 1- benzopyran-2,4'-piperidine]; 4-phenyl-spiro [2H, 1-benzopyran-2,4'-piperidine]; 4 - [(3-methoxyphenyl) -spiro [2H, 1-benzopyran-2 , 4'-piperidine], and 4 - [(2-methoxyphenyl) -spiro [2H, 1-benzopyran-2,4'-piperidine]; or one of its stereoisomers, prodrugs, pharmaceutically acceptable salts, hydrates, solvates, hydrates of acid salt, or N-oxides 143. A compound according to claim 1, wherein J2 forms a 6 to 10 membered aryl ring or a 5- to 10 membered heteroaryl ring when taken together with the carbon atoms which is attached 144. A pharmaceutical composition according to claim 80 wherein said agent for the treatment of Parkinson's disease is selected from deprenyl, amantadine, levodopa and carbidopa 145. A method of obtaining a diagnostic image comprising the adm insisting on a patient of a compound according to claim 140, and obtaining the patient's image. 146. A method according to claim 145 wherein said obtaining an image comprises the emission tomography of posiírones. 147. A procedure for obtaining a diagnostic image comprising the administration to a patient of a compound according to claim 141, and the obtaining of the patient's image. 148. A method according to claim 147, wherein said obtaining an image comprises positron emission tomography.