WO2002089806A1 - Heterobicycles fkbp-ligands - Google Patents

Abstract

Diazabicyclo[3.3.1]nonane derivatives that inhibit the peptidyl-prolyl isomerase enzyme activity associated with FK-506 binding proteins (FKBP) are described for treating neurological disorders. Also described are compounds useful for preparing such inhibitors.

Description

HETEROBICYCLES FKBP-LIGANDS

TECHNICAL FIELD AND INDUSTRIAL APPLICABILITY OF THE INVENTION:

The present invention relates to methods and pharmaceutical compounds and compositions for stimulating neurite outgrowth in nerve cells leading to nerve regeneration. For example, the compositions comprise compounds that inhibit the peptidyl-prolyl isomerase (rotamase) enzyme activity associated with the FK-506 binding proteins (FKBP), such as FKBP- 12 and FKBP-52. The methods comprise treating nerve cells with compositions comprising the rotamase-inhibiting compound. The methods of the invention can be used to promote repair of neuronal damage caused by disease or physical trauma. BACKGROUND ART: Immunophilins are a family of soluble proteins that serve as receptors for important immunosuppressant drugs such as cyclosporin A, FK-506 and rapamycin. A class of immunophilins of particular interest are the FK-506 binding proteins (FKBP). For a review of the role of immunophilins in the nervous system, see Solomon et al., "Immunophilins and the Nervous System," Nature Med., 1(1), 32-37 (1995). The 12-kiloDalton FK-506 binding protein, FKBP-12, binds FK-506 with high affinity. Such binding has been directly measured using microcalorimetry and radiolabeled FK-506, e.g., [³H]dihydro-FK-506 (see Siekierka et al., Nature, 341, 755- 57 (1989); and U.S. Patent No. 5,696,135 to Steiner et al.) and 32-[l-¹⁴C]-benzoyl-FK- 506 (see Harding et al., Nαtwre, 341, 758-60 (1989)). Binding affinity of other compounds for FKBP can be determined directly by microcalorimetry or from competitive binding assays using either tritiated or ¹⁴C-labelled FK-506, as described by Siekierka et al. or Harding et al.

FK-506-binding protein FKBP-12 participates in a variety of significant cellular functions. FKBP-12 catalyzes cis-trans isomerization of peptidyl-prolyl linkages. This peptidyl-prolyl isomerase enzyme activity is also referred to as rotamase activity. Such activity is readily assayed by methods known in the art (see Fischer et al., Biochim. Biophys. Acta, 791, 87 (1984); Fischer et al., Biomed. Biochim. Acta, 43, 1101 (1984); and Fischer et al., Nature, 337, 476-478 (1989)). U.S. Patent Nos. 5,192,773 and 5,330,993 to Armistead et al. report FKBP binding affinities that were correlated with rotamase-inhibiting activities for many compounds.

FK-506 and compounds that bind FKBP competitively with FKBP stimulate outgrowth of neurites (axons) in nerve cells (see U.S. Patent No. 5,696,135 to Steiner et al.). Lyons et al. (Proc. Natl. Acad, Sci, USA, 91, 3191-95 (1994)) demonstrated that FK-506 acts to enhance or potentiate the effectiveness of nerve growth factor (NGF) in stimulating neurite outgrowth in a rat pheochromocytoma cell line. The mechanism of stimulation of such neurite outgrowth appears to be 10- to 100-fold potentiation of the action of nerve growth factor.

Potency for inhibition of the peptidyl-prolyl isomerase (rotamase) enzyme activity of FKBP by FK-506, and by compounds that competitively inhibit FK-506 binding to FKBP, empirically correlates with activity for stimulation of neurite outgrowth. Because of the close correlation between rotamase inhibition and neurotrophic action, it has been proposed that the rotamase may convert a protein substrate into a form that promotes neural growth (see U.S. Patent No. 5,696,135). For example, it has been found that FKBP-12 forms bound complexes with the intracellular calcium ion channels — the ryanodine receptor (RyR) and the inositol 1,4,5-triphosphate receptor (IP₃R) (Jayaraman et al., J. Biol. Chern., 267, 9474-9477 (1992); Cameron et al., Proc. Natl. Acad. Sci, USA, 92, 1784-1788 (1995)), helping to stabilize calcium release. For both the RyR and the IP₃R, it has been demonstrated that FK-506 and rapamycin are capable of dissociating FKBP-12 from these receptors. In both cases, the "stripping" off of FKBP-12 leads to increased leakiness of the calcium channels and lower intracellular calcium concentrations. In addition, FK-506--FKBP bound complexes bind to and inhibit calcineurin, a cytoplasmic phosphatase. The phosphatase activity of calcineurin is necessary for dephosphorylation and subsequent translocation into the nucleus of nuclear factor of activated T-cells (NF-AT) (see Flanagan et al., Nature, 352, 803-807 (1991)). NF-AT is a transcription factor that initiates interleukin-2 gene activation, which in turn mediates T-cell proliferation; these steps are important to the activation of an immune response. Calcineurin-inhibiting activity is correlated with the immunosuppressant activity of FK-506 and related compounds.

Calcineurin inhibition, however, does not correlate with the stimulation of neurite outgrowth. Therefore, compounds that are potent inhibitors of rotamase but not strong inhibitors of calcineurin are desired since they should be neurotrophic but non- immunosuppressive.

Such neurotrophic agents desirably find use in augmenting neurite outgrowth, and hence in promoting neuronal growth and regeneration in various pathological situations where neuronal repair can be facilitated, including peripheral nerve damage caused by injury or diseases such as diabetes, brain damage associated with stroke, and for the treatment of neurological disorders related to neurodegeneration, including Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis (ALS). Such neurotrophic agents should also be useful for the treatment of memory impairment, for the treatment of hair loss, for the treatment of hearing loss, and for the treatment of vision disorder. See International Publication Nos. WO 00/16603 and WO 00/32588. Further, such use is preferably without the associated effect of immunosuppression, since long-term use of immunosuppressants is associated with side effects such as kidney toxicity, neurological deficits, and vascular hypertension.

Various inhibitors of rotamase enzyme activity, FKBP-binding compounds, or immunomodulating compounds are known. See, e.g., U.S. Patent Nos. 5,192,773; 5,330,993; 5,516,797; 5,612,350; 5,614,547; 5,622,970; 5,654,332; 5,665,774;

5,696,135; 5,721,256; 5,798,355; 5,786,378; 5,846,979; 5,801,187; 5,801,197; and 6,080,753. See also EP 947,506 and International Publication Nos. WO 96/41609, WO 96/40633, WO 96/40140, WO 98/29116, WO 98/29117, WO 97/14439, WO 98/37882, WO 99/45006, WO 00/27811, WO 00/09102, WO 00/05232, WO 99/6251, WO 00/46181, and WO 00/32588. See also U.S. Serial No. 09/726,314, filed December 1, 2000.

In view of the variety of disorders that may be treated by stimulating neurite outgrowth and the relatively few neurotropic agents having an affinity for FKBP-type immunophilins, there remains a need for additional neurotrophic agents. In particular, there is a need for neurotropic agents that are potent inhibitors of the enzyme activity and especially of the cis-trans propyl isomerase (rotamase) activity of the FKBP-type immunophilins, particularly the immunophilin FKBP-12. Such compounds will preferably have physical and chemical properties suitable for use in pharmaceutical preparations, e.g., bioavailability, half-life, and efficient delivery to the active site. In view of the desired properties, small organic molecules are preferred over proteins. Furthermore, such compounds will not significantly inhibit the protein phosphatase calcineurin and therefore lack any significant immunosuppressive activity.

According to International Publication Nos. WO 00/46181 and WO 00/46222, binding to FKBP is not necessary for neuronal activity. DISCLOSURE OF INVENTION:

The invention relates to certain small-molecule neurotrophic compounds, such as those having affinity for FKBP-type immunophilins. Once bound to these proteins, the neurotrophic compounds are inhibitors of the enzyme activity associated with immunophilin proteins, preferably rotamase enzyme activity. Preferably the inhibitor compounds do not exert any significant immunosuppressive activity in addition to their neurotrophic activity. The invention also relates to effective processes for synthesizing such compounds as well as useful intermediates therefor. The invention further relates to methods for treating patients having neurological trauma or disorders as a result of, or associated with, conditions that include (but are not limited to) neuralgias, muscular dystrophy, Bell's palsy, myasthenia gravis, Parkinson's disease, Alzheimer's disease, multiple sclerosis, ALS, stroke and ischemia associated with stroke, neural parapathy, other neural degenerative diseases, motor neuron diseases, and nerve injuries including spinal cord injuries. The invention also relates to methods for treating patients with hair loss, vision disorder, memory impairment, or hearing loss.

The neurotrophic compounds of the present invention may be used to stimulate the growth and regeneration of neurons. The administration of these compounds to individuals requiring therapeutic stimulation of neuronal growth and regeneration provides effective therapies for treating various pathological situations where neuronal repair can be facilitated, including peripheral nerve damage caused by injury or disease such as diabetes, brain damage associated with stroke, and for the treatment of neurological disorders related to neurodegeneration, including Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis. In a first general aspect, the present invention relates to compounds of Formula (I):

and to pharmaceutically acceptable salts, solvates, prodrugs, pharmacologically active metabolites of such compounds, and pharmaceutically acceptable salts of said metabolites. In Formula (I):

R' R' I

QisR^-ORj, -^N-^Ri,or -^N-^NRi^R";

i i Ri— ^F

Q'R_L-OR^ -N-R^I. -N-NR^IR'OΓ F ;

R' R'

Q"is-OR_h - -Rι,_or-N-NRιR", wherein:

R_Ϊ is hydrogen; substituted or unsubstituted alkyl, alkenyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, or cycloalkenyl; or C (R^π)(R¹²)(R¹³), wherein R¹¹ and ¹² each independently is substituted or unsubstituted alkyl, or R¹¹ and R¹² together with the atom to which they are bound form a substituted or unsubstituted cycloalkyl, and R¹³ is H, OH, substituted or unsubstituted alkyl, aryl, heteroaryl, or heterocycloalkyl, or (CH^_n-O-L¹, where n is 0, 1, 2, or 3, L¹ is R² or C(O)R², and R² is substituted or unsubstituted alkyl; R' is hydrogen; or substituted or unsubstituted alkyl, hydroxyl or amino; or Ri and R' taken together with the adjacent nitrogen atom form a substituted or unsubstituted heterocycle (e.g., heterocycloalkyl, heteroaryl, etc.);

R" is hydrogen or substituted or unsubstituted alkyl; or Ri and R" taken together with the adjacent nitrogen atom form a substituted or unsubstituted heterocycle (e.g., heterocycloalkyl, heteroaryl, etc.);

A', B', C, and D" are independently carbon, oxygen, sulfur, or nitrogen;

E\ F', G', and H' are independently carbon or nitrogen; I' is hydrogen, a halide, alkyl, alkoxy, acyl, or amine; wherein there can be 1, 2, or 3 F groups, where F can be attached to one or more of E' , H' , F' , or G' ; J is hydrogen or substituted or unsubstituted alkyl, alkenyl, cycloalkyl, aryl, or heteroaryl; and

X is hydrogen, cyano, alkoxy, dimethoxymethyl, or oxygen, where when X is oxygen, the C-X bond is a double bond; or

X and J, taken together with the nitrogen heteroatom of the ring structure, form a substituted or unsubstituted heteroaryl or heterocycloalkyl.

In an additional general aspect, the present invention relates to compounds of Formula (H):

and pharmaceutically acceptable salts, solvates, prodrugs, and pharmacologically active metabolites thereof, and pharmaceutically acceptable salts of said metabolites. In Formula (II): R is hydrogen, or substituted or unsubstituted alkyl;

D' is C, O, or N; each X' is independently halogen, methoxy, amine wherein there can be 1, 2, or 3 X' groups, where X' can be attached to one or more of A, D, E, or the carbon atom of the ring; A, D, and E are each independently carbon, oxygen, or nitrogen; and

Z is as defined in Formula (I).

In another general aspect, the invention relates to pharmaceutical compositions comprising each: a therapeutically effective amount of a compound of Formula (I) or (II), or a pharmaceutically acceptable salt, solvate, prodrug, pharmacologically active metabolite thereof, or pharmaceutically acceptable salt of said metabolite; and a pharmaceutically acceptable carrier.

In a further general aspect, the invention relates to a method of treating a neurological disorder in an animal, comprising administering to the animal a therapeutically effective amount of a compound of Formula (I) or (II), or pharmaceutically acceptable salt, solvate, prodrug, pharmacologically active metabolite thereof, or pharmaceutically acceptable salt of said metabolite.

In another general aspect, the invention further relates to methods of treating neurological trauma or disorders as a result of, or associated with, conditions mediated by FKBP binding by administering a therapeutically effective amount of a compound of Formula (I) or (II), including neuralgias, muscular dystrophy, Bell's palsy, myasthenia gravis, Parkinson's disease, Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis (ALS), stroke and ischemia associated with stroke, neural parapathy, other neural degenerative diseases, motor neuron diseases, and nerve injuries including spinal cord injuries In a further general aspect, the invention relates to a method of treating hair loss, memory impairment, vision disorder, or hearing loss in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of Formula (I), or pharmaceutically acceptable salt, solvate, prodrug, or pharmacologically active metabolite thereof, or pharmaceutically acceptable salt of said metabolite. The inventive methods comprise administering a therapeutically effective amount of a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt, prodrug, or solvate, or pharmacologically active metabolite thereof, or a pharmaceutically acceptable salt of said metabolite, to a patient in need of such treatment. Optionally, a therapeutically effective amount of a neurotrophic factor selected from nerve growth factor, insulin growth factor and its active truncated derivatives, acidic and basic fibroblast growth factor, platelet-derived growth factors, brain-derived neurotrophic factor, ciliary neurotrophic factors, glial cell line-derived neurotrophic factor, neurotrophin-3, and neurotrophin 4/5, may be coadministered, separately or in a single pharmaceutical composition also containing an agent of the invention, to a patient in need of such treatment.

In another general aspect, the invention also relates to intermediates of Formulae (6), (10), (13), (17), L, and K which are described below and are useful for preparing the FKBP-modulating compounds of general structural Formula (I) and (II). The invention further relates to processes of making the compounds using such intermediates.

Other features, objects, and advantages of the invention will become apparent from the following detailed description of the invention. DETAILED DESCRIPTION AND PREFERRED EMBODIMENTS:

As used herein, the following terms have the defined meanings, unless indicated otherwise.

As used herein, the term "comprising" is used in the open sense. In accordance

with a convention used in the art,

is used in structural formulas herein to depict the bond that is the point of attachment of the moiety or substituent to the core or backbone structure.

Where chiral carbons are included in chemical structures, unless a particular orientation is depicted, both stereoisomeric forms are intended to be encompassed.

The term "alkyl " is intended to mean a straight- or branched-chain onovalent radical of saturated and/or unsaturated carbon and hydrogen atoms having one to twelve carbon atoms. A "lower alkyl" is intended to mean an alkyl group having from 1 to 4 carbon atoms in its chain. Illustrative alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, ethenyl, pentenyl, butenyl, propenyl, ethynyl, butynyl, propynyl, pentynl, hexynyl, and the like. The alkyl can be unsubstituted (i.e., containing only carbon and hydrogen) or substituted as specified. Suitable substituted alkyls include fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 3- fluoropropyl, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, and the like.

A "cycloalkyl " is intended to mean a non-aromatic monovalent monocyclic, bicyclic, or tricyclic radical containing from 3 to 14 carbon ring atoms, each of which may be saturated or unsaturated. Illustrative examples of cycloalkyl groups include the following moieties:

A "heterocycloalkyl " is intended to mean a non-aromatic monovalent monocyclic, bicyclic, or tricyclic radical, which is saturated or unsaturated, containing from 3 to 18 ring atoms, and which includes from 1 to 5 heteroatoms selected from nitrogen, oxygen, and sulfur. Illustrative examples of heterocycloalkyl groups include the following moieties:

An "aryl " is intended to mean an aromatic monovalent monocyclic, bicyclic, or tricyclic radical containing 6, 10, 14, or 18 carbon ring atoms. Examples of aromatic ring structures include phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, furyl, thienyl, pyrrolyl, pyridyl, pyridinyl, pyrazolyl, imidazolyl, pyrazinyl, pyridazinyl, 1,2,3- triazinyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, l-H-tetrazol-5-yl, indolyl, quinolinyl, benzofuranyl, benzothiophenyl (thianaphthenyl), and the like.

Illustrative examples of aryl groups include the following moieties:

A "heteroaryl " is intended to mean an aromatic monovalent monocyclic, bicyclic, or tricyclic radical containing from 4 to 18 ring atoms, including from 1 to 5 heteroatoms selected from nitrogen, oxygen, and sulfur. Illustrative examples of heteroaryl groups include the following moieties:

A "heterocycle" is intended to mean a heteroaryl or heterocycloalkyl group. As used herein, the term "carbonyl" refers to the -C (O)-R radical, where R is as defined below.

As used herein, the term "amide" refers to the - C (O)NR radical, where R is as defined below.

As used herein, the term "sulfonyl" refers to the -SO₂-R radical, where R is as defined below.

As used herein, the term "nitro" refers to the - C (NO₂)-R radical, where R is as defined below. The radical R is hydrogen or substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl or heteroaryl.

An "amino" group is intended to mean the radical -NH₂. An "alkoxy" group is intended to mean the radical -OR_a , where R_a is an alkyl group. Exemplary alkoxy group include methoxy, ethoxy, propoxy, and the like. A "hydroxy" group is intended to mean the radical -OH. Where indicated, the various moieties or functional groups for variables in the formulae may be substituted by one or more substituents. When a moiety is substituted, the substituent may be a: halogen (chloro, iodo, bromo, or fluoro); C_1-6- alkyl; C_1-6-alkenyl; Cι_-6-alkynyl; hydroxyl; C_1-6 alkoxyl; amino; nitro; inline; cyano; amido; phosphonato; phosphine; carboxyl; carbonyl; aminocarbonyl; sulfonyl; sulfonamine; sulfonamide; ketone; aldehyde; ester; oxygen (=O); haloalkyl (e.g., trifluoromethyl); carbocyclic cycloalkyl, which may be monocyclic or fused or non- fused polycyclic (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl); heterocycloalkyl, which may be monocyclic or fused or non-fused polycyclic (e.g., pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiazinyl); carbocyclic or heterocyclic, monocyclic or fused or non-fused polycyclic aryl (e.g., phenyl, naphthyl, pyrrolyl, indolyl, furanyl, thiophenyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolyl, pyridinyl, quinolinyl, isoquinohnyl, acridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, benzimidazolyl, benzothiophenyl, or benzofuranyl); amino (primary, secondary, or tertiary); nitro; O-lower alkyl; O-aryl; aryl; aryl-lower alkyl; CO₂CH₃; CONH₂; OCH₂CONH₂; NH₂; SO₂NH₂; OCHF₂; CF₃; or OCF₃. Such moieties may also be optionally substituted by a fused-ring structure or bridge, for example OCH -O. These substituents may optionally be further substituted with a substituent selected from such groups. Other examples of substituents are those reflected in the exemplary compounds that follow.

Pharmaceutical compositions according to the invention comprise, as an active ingredient, a compound of the Formula I or II, or a pharmaceutically acceptable salt, prodrug, solvate, or a pharmaceutically active metabolite of such compound, or a pharmaceutically acceptable salt of such a metabolite. Such compounds, salts, prodrugs, solvates and metabolites are sometimes referred to herein collectively as "neurotrophic agents".

A "pharmaceutically acceptable salt" is intended to mean a salt that retains substantially the biological effectiveness of the free acid or base form of the specified compound and that is biologically suitable for pharmaceutical use. A compound of the invention may possess a sufficiently acidic group, a sufficiently basic group, or both functional groups, and accordingly react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form pharmaceutically acceptable salts. Exemplary pharmaceutically acceptable salts include those salts prepared by reaction of the compounds of the present invention with a mineral or organic acid or an inorganic base, such as salts including sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-1,4- dioates, hexyne-l,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, γ-hydroxybutyrates, glycollates, tartrates, methane sulfonates, propanesulfonates, naphthalene- 1 -sulfonates, naphthalene-2-sulfonates, and mandelates. If the inventive compound is a base, the desired pharmaceutically acceptable salt may be prepared by any suitable method available in the art, for example, by treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, or with an organic acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyrovic acid, oxalic acid, glycolic acid, salicylic acid, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alpha-hydroxy acid, such as citric acid or tartaric acid, an amino acid, such as aspartic acid or glutamic acid, an aromatic acid, such as benzoic acid or cinnamic acid, a sulfonic acid, such as p-toluenesulfonic acid or ethanesulfonic acid, or the like. If the inventive compound is an acid, the desired pharmaceutically acceptable salt may be prepared by any suitable method, for example, treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary or tertiary), an alkali metal hydroxide or alkaline earth metal hydroxide, or the like. Illustrative examples of suitable salts include organic salts derived from amino acids, such as glycine and arginine, ammonia, primary, secondary, and tertiary amines, and cyclic amines, such as piperidine, morpholine and piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.

In the case of agents that are solids, it is understood by those skilled in the art that the inventive compounds and salts may exist in different crystal or polymorphic forms, all of which are intended to be within the scope of the present invention. "A pharmaceutically acceptable prodrug" is intended to mean a compound that may be converted under physiological conditions or by solvolysis in the body to the specified compound.

"A pharmaceutically active metabolite" is intended to mean a pharmacologically active product of a specified compound produced through metabolism in the body.

Prodrugs and active metabolites of a compound may be identified using routine techniques known in the art. See, e.g., Bertolini et al., J. Med. Chern., 40, 2011-2016

(1997); Shan et al., J. Pharm. Sci., 86 (7), 765-767; Bagshawe, Drug Dev. Res., 34,

220-230 (1995); Bodor, Advances in Drug Res., 13, 224-331 (1984); Bundgaard, Design of Prodrugs (Elsevier Press 1985); and Larsen, "Design and_Application of

Prodrugs, Drug Design and Development" (Krogsgaard-Larsen et al., eds., Harwood

Academic Publishers, 1991).

The inventive compounds having one or more chiral centers may exist as single stereoisomers (i.e., essentially free of other stereoisomers), racemates, and/or mixtures of enantiomers and/or diastereomers. All such single stereoisomers, racemates and mixtures thereof are intended to be within the scope of the present invention.

Preferably, the inventive compounds that are optically active are used in optically pure form.

As generally understood by those skilled in the art, an optically pure compound having one chiral center (i.e., one asymmetric carbon atom) is one that consists essentially of one of the two possible enantiomers (i.e., is enantiomerically pure), and an optically pure compound having more than one chiral center is one that is both diastereomerically pure and enantiomerically pure. Preferably, the compounds of the present invention are used in a form that is at least 90% optically pure, that is, a form that contains at least 90% of a single isomer (80% enantiomeric excess ("e.e.") or diastereomeric excess ("d.e.")), more preferably at least 95% (90% e.e. or d.e.), even more preferably at least 97.5% (95% e.e. or d.e.), and even more preferably at least 99% (98% e.e. or d.e.).

Additionally, the formulas are intended to cover solvated as well as unsolvated forms of the identified structures. For example, Formula (I) or (II) includes compounds of the indicated structure in both hydrated and non-hydrated forms. Other examples of solvates include the structures in combination with isopropanol, ethanol, methanol, DMSO.

Neurotrophic compounds of the invention are represented by the general structural Formulae (I) and (II) defined above. Preferably, these compounds inhibit the rotamase (peptidyl-prolyl isomerase) enzyme activity of FKBP, in particular, FKBP-12. Particularly preferred are compounds of the Formula (Ila):

wherein:

R, D', X', A, D, E, and Q are as previously defined for the compound of Formula (II).

Preferably, Q is phenylmethyl, 3-methylphenyl, 1-naphthalenyl, 4-(4- pyridinyloxy)-phenyl, 4-methylphenyl, 4-(l,l-dimethylethyl)phenyl, 4-(l- methylethyl)phenyl, 4-ethylphenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 2,4-dinitroρhenyl, 2-(l-naphthalenyl)ethyl, l,l'-biphenyl, 3-[(3,4,5- trimethoxyphenyl)amino]phenyl, 3',4'-dichloro[l,l'-biphenyl]-4-yl, 3',4'- dichloro[l,l'-biphenyl]-3-yl, 4-cyanophenyl, 6-chloro-3-pyridinyl, cis-2,6-dimethyl-4- morpholinyl, 1-piperidinyl, 4-morpholinyl, 3-(2-ethoxycarbonyl-phenylamino)-phenyl, or -NHR , where R2is 3,4-difluorophenyl, 3,4,5-trimethoxyphenyl, 6-chloro-3- pyridinyl, 6-methoxy-3-pyridinyl, 3,4-difluorophenyl, 2,3,4- trifluorophenyl, 3,4,5- trifluorophenyl, 2,4,5-trifluorophenyl, 6-(4-morpholinyl)-3-pyridinyl, 3-pyridinyl, or 6- fluoro-3-pyridine.

Preferably, X' is 3-methoxy, 1,3-dimethoxy, 4-methoxy, or l,3-dimethoxy-4- chloro.

Preferably, D' is carbon. R is preferably hydrogen.

Particularly preferred are compounds of the Formula (lib):

wherein:

R, D', X', A, D, E, and Q' are as previously defined for the compound of Formula (II).

Preferably, Q' is l-lH-indozol-3-yl-methanoyl, difluoro(3,4,5- trimethoxyphenyl), difluoro(4-chlorophenyl), 3,4-dimethoxybenzoyl, or NHR₄, where R₄ is phenyl, 3-methoxyphenyl, phenylmethyl, 3-methylphenyl, or 4-nitrophenyl.

Preferably, X' is 4-methoxy, 3-methoxy, or 1,3-dimethoxy.

Preferably, D' is carbon.

Preferably, R is hydrogen.

Particularly preferred are also compounds of the Formula (He):

wherein:

R, D', X', A, D, E, and Q" are as previously defined for the compound of Formula (II).

Preferably, Q"is (2,5-dihydro-lH-pyrrol-l-yl)-oxo, or oxo-1-piperidinyl. Preferably, X' is 3-methoxy.

Preferably, D' is carbon.

R is preferably hydrogen. EXAMPLES:

The following examples are illustrative of the present invention. Abbreviations that are used in the description of the invention include the following: EDC is l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; DCC is 1,3-dicyclohexylcarbodiimide; DMAP is 4-dimethylaminopyridine; DMF is N, N-dimethylformamide; HATU is O-(7-azabenzotriazol-l-yl)-N,N,N',N'- tetramethyluronium hexafluorophosphate; HRMS is high resolution mass spectrum; DEAD is diethyl azodicarboxylate; MS is mass spectrum; THF is tetrahydrofuran; DIEA is diisopropylethylamine; HOBt is 1-hydroxybenzotiazole hydrate; Pd-C is palladium on carbon; atm is (atmosphere); MOPS is (4-morpholinepropanesulfonic acid, sodium salt); Boc is t-butoxycarbonyl; DMSO is dimethyl sulfoxide; DAST is (diethylamino)sulfur triflouride; FMOC is 9-Fluorenylmethoxy-carbonyl; TEA is triethyl amine; BOC is Butoxy- carbonyl; LCMS is liquid chromatography/mass spectrometry; and TLC is thin layer chromatography.

The compounds of the present invention may be readily prepared by standard techniques of organic chemistry, utilizing the following synthetic pathways depicted below. Unless otherwise indicated, the starting materials are either commercially available or can be prepared by conventional techniques. In the schemes and examples below, Z is benzyloxycarbonyl. As an alternative to benzyloxycarbonyl, other moieties suitable for use as protecting groups for the bridgehead nitrogen may be employed, such as FMOC and BOC.

Scheme 1, which is depicted below, is useful for preparing Compound 6 (Compound D):

Scheme 1

EXAMPLE 1

Svnmesis of 9,13-Imino-8H-azocinor2,l-a1isoquinolin-8-one,5,6,9,10,l 1,12,13, 13a- octahvdro-6-methyl-,(6S ,9S , 13R, 13aR)-(9CT>- (Compound 6) Step 1: Synthesis of Compound 1:

2,6-Pyridine dicarboxylic acid (25 g, 0.15 mol) was dissolved in 2.0M NaOH (154 mL) and H2O (30 mL) at room temperature, and placed in a 500-mL Parr bottle. Rhodium on alumina powder (5%, 1.87 g) was added and the mixture was purged with argon for 15 minutes. The reaction mixture was shaken under 55 psi of hydrogen for 48 hours. The suspension was filtered through compacted Celite, and the clear filtrate was cooled to 0°C. Benzyl chloroformate (30.62 g, 0.18 mol) was added from the top to the cooled filtrate in three portions during a period of 30 minutes, and the solution was allowed to reach room temperature and stirred for an additional 5 hours. The remaining benzyl chloroformate was extracted from the mixture with diethyl ether. The aqueous layer was acidified with 2N HCI and extracted with ethyl acetate (EtOAc). The EtOAc was passed over a short plug of Na2SO4 and evaporated. The residue was titrated with EtOAc (20 mL), and the resulting white solid was collected by vacuum filtration, washed with EtOAc (3 x 20 mL), and air-dried to give Compound 1 (38.3 g, 83% yield). Spectral analysis of the product was consistent with Compound 1:

R_f = 0.06 (10% MeOH7CHCl3).

⁺¹H NMR: δ 1.49 - 1.73 (m, 4H), 1.96 - 2.03 (m, 2H), 4.48 - 4.65 (m, 2H), 5.10 (s, 2H), 7.26 - 7.35 (m, 5H). The preceding synthesis of Compound 1 is further described in WO 00/04020. Step 2: Synthesis of Compound 2:

Compound 2

Piperidine-1, 2, 6-tricarboxylic acid 1-benzyl ester (Compound 1, 19.7 g, 64.11 mmol) was suspended in acetic anhydride (80 mL, 848 mmol) in a dry 250-mL round- bottom flask. The mixture was stirred at 70°C for 30 minutes until a clear solution formed. The remaining acetic anhydride was removed in vacuo, to afford Compound 2 (18.5 g, 100%) as a clear oil. The material was of sufficiently good quality to be used in the next reaction without purification. The product was sensitive to water, so it was prepared for immediate use in the next step.

Spectral analysis of the product was consistent with Compound 2: 1H NMR: δ 1.57 - 2.01 (cm, 6H), 5.14 (s, 2H), 5.17 (s, 2H), 7.32 - 7. 37 (m, 5H). The preceding synthesis of Compound 2 is further described in WO 00/04020. Step 3: Synthesis of Compound 3:

Compound 3

A suspension of piperidine-1, 2, 6-tricarboxylic acid 1-benzyl ester (Compound 1, 8.8 g, 28.7 mmol) in acetic anhydride (50 mL) was heated at 70°C for 2.5 hours. The resulting clear solution was diluted with toluene and concentrated to minimum volume.

The residue (Compound 2) was azeotropically evaporated with toluene (4x) until 1H

NMR showed the absence of acetic anhydride. The resulting residue (cyclic anhydride,

Compound 2) was dissolved in dioxane (50 mL), to which was added L-amphetamine

(3.88 g, 28.7 mmol). After the solution was stirred at room temperature for 18 hours, acetic anhydride (5 mL) was added and the mixture was stirred at 110°C for 70 hours.

The mixture was cooled down, diluted with toluene and concentrated to minimum volume. The resulted residue was partitioned between ethyl acetate and sodium bicarbonate solution. The aqueous layer was extracted with ethyl acetate (2x80 mL).

The combined organic layers were washed with brine (1x80), dried over sodium sulfate and reduced to minimum volume. The residue was purified by flash chromatography on silica gel (ethyl acetate/hexanes 1:3) to give the desired imide (Compound 3, 7.5 g) in 65% yield.

Spectral analysis of the product was consistent with Compound 3:

MS (ESP): 407 (M*).

¹HNMR (CDCI₃): δ 7.40 - 7.12 (10H, m), 5.18 - 5.08 (3H, m), 4.82 (IH, br s), 4.74

(IH, br s), 3.29 (IH, dd, J = 13.7, 10 Hz), 3.03 (IH, dd, J = 13.69, 6.8 Hz), 1.81-1.48

(6H, m), 1.43 (3H, d, J = 6.9 Hz).

Step 4: Synthesis of Compound 5:

To a solution of the imide (Compound 3, 7.4 g, 18.2 mmol) in THF/MeOH (1:1, 80 mL) was added sodium borohydride (690 mg, 18.2 mmol) at -5°C. After stirring at - 5°C for 55 minutes, the mixture was added carefully to citrate buffer (pH 4.5) and extracted with ethyl acetate (3x30 mL). The combined extracts were washed with brine, dried over sodium sulfate and concentrated to dryness. The crude residue (4a/4b) was dissolved in dichloromethane/TFA (2:1, 30 mL) and stirred at room temperature for 19 hours. The mixture was diluted with toluene and reduced to minimum volume. The oily residue was purified by flash chromatography on silica gel (ethyl acetate in chloroform 0 -10%) to afford two compounds. The more polar compound was found to be the unreacted hydroxyamide (4b) as a single diastereomer. The less polar compound was found to be the desired cyclized product as an oil which solidified upon standing. The solid residue was titrated with MTBE/hexanes and collected by filtration to give the title compound (5, 2.35 g) as a single enantiomer in 35% yield. Spectral analysis of the product was consistent with Compound 5:

MS (electrospray): 391 (M⁺).

1H NMR (CDC1₃, mixture of rotamers): δ 7.54 - 7.51 (IH, m), 7.39 - 7.12 (8H, m), 5.30 -5.03 (3H, m), 4.73 - 4.45 (2H, m), 4.36 (IH, s), 3.10 (IH, dd, J = 15.5, 6. 7 Hz), 2.63 - 2.55 (IH, m), 2.09 - 1.69 (6H, m), 1.40 and 1.34 (3H, two set d, J = 6.4 Hz). Step 5: Synthesis of 9,13-Imino-8H-azocino[2,l-a]isoquinolin-8- one,5,6,9,10,ll,12,13,13a-octahydro-6-methyl-,(6S,9S,13R,13aR)-(9Cl) (Compound

Compound 6 (Core D)

The cyclized product (Compound 5, 0.7 g, 1.8 mmol) and Palladium on Carbon (10%, 225 mg) in 20 mL ethanol/ethyl acetate (1:1) was stirred under H atmosphere at room temperature for 18 hours. The mixture was filtered through a 0.45 μ PFTE membrane and the filtrate was concentrated to dryness to give the Compound 6 (Compound D) in quantitative yield which was carried on without further purification.

Spectral analysis of the product was consistent with Compound 6: ¹HNMR (CDC1₃): δ 7.29-7.16 (4H, m), 4.89 (IH, q, J = 6.5 Hz), 4.37 (IH, s), 4.01 (IH, s), 3.46 (IH, br s), 3.15 (IH, dd, J = 15.8, 6. 5 Hz), 2.55 (IH, dd, J = 15.8, 6.4 Hz), 2.15 -1.69 (6H, m), 1.31 (3H, d, J = 6.6 Hz).

Scheme 2, which is depicted below, is useful for preparing Compound 10 (Compound E):

Scheme 2

diastereomeric H₂/Pd-C mixture

EXAMPLE 2

Synthesis of 9,13-Imino-8H-azocino T2,l-al isoquinolin-8-one, 5,6,9,10,11,12,13,13a- octahvdro-6-methyl-, (6R, 9R, 13S, 13aS)-(9CD (Compound 10) Step 1: Synthesis of Compound 7:

Compound 7

Compound 7 was prepared from piperidine- 1,2, 6-tricarboxylic acid 1-benzyl ester (6.3 g, 24 mmol) and D-amphetamine (3.24 g, 24 mmol) according to a procedure similar to Compound 3 synthesis (Example 1— Step 3). The title compound (7, 3.66 g) was obtained in 38% yield. Spectral analysis of the product was consistent with Compound 7:

MS (ESP): 407 (M⁺).

¹HNMR (CDC1₃): δ 7.39-7.12 (10H, m), 5.16 - 5.09 (3H, m), 4.82 (IH, br s), 4.74 (IH, br s), 3.29 (IH, dd, J = 13.7, 10 Hz), 3.03 (IH, dd, J = 13.6, 6.8 Hz), 1.82 - 1.48 (6H, m), 1.43 (3H, d, J = 6.9 Hz). Step 2: Synthesis of Compound 9: Compound 9

The imide (Compound 7, 3.6 g, 8.9 mmol) was reduced and cyclized according to a procedure similar to Compound 5 synthesis (Example 1— Step 4). The title compound (1.22 g) was obtained as a single enantiomer in 35% yield.

Spectral analysis of the product was consistent with Compound 9: MS (ESP): 391 (M⁺).

1H NMR (CDC1₃, mixture of rotamers): δ 7.54 - 7.51 (IH, m), 7.35 - 7.16 (8H, m), 5.30 -5.04 (3H, m), 4.67 - 4.47 (2H, m), 4.36 (IH, s), 3.10 (IH, dd, J = 15.4, 6.6 Hz), 2.63 - 2.55 (IH, m), 2.10 - 1.68 (6H, m), 1.40 and 1.34 (3H, two set d, J = 6.3 Hz). Step 3: Synthesis of 9,13-Imino-8H-azocino [2,1-a] isoquinolin-8-one, 5,6,9,10,11, 12,13, 13a-octahydro-6-methyl-, (6R, 9R, 13S, 13aS)-(9Cl) (Compound 10):

Compound 10 (Core E)

The cyclized product 9 was deprotected in a fashion similar to that used in the Compound 6 synthesis (Example l~Step 5). The title compound was obtained in quantitative yield. Spectral analysis of the product was consistent with Compound 10:

1H NMR (CDC1₃): δ 7.27 - 7.16 (4H, m), 4.90 (IH, q, J = 6.5 Hz), 4.37 (IH, s), 4.02 (IH, s), 3.47 (IH, br s), 3.15 (IH, dd, J = 15.8, 6.5 Hz), 2.55 (IH, dd, J = 15.8, 6.3 Hz), 2.17-1.72 (6H, m), 1.31 (3H, d, J = 6.62 Hz).

Scheme 3, which is depicted below, is useful for preparing Compound 13 (Compound C):

Scheme 3

EXAMPLE 3

Synthesis of 9,13-Imino-8H-azocino T2,l-al isoquinolin-8-one, 5,6,9,10,11,12,13,13a- octahydro-1, 3-dimethoxy- (9C1) (Compound 13) Step 1: Synthesis of Compound 11:

Compound 11

Compound 11 was prepared from piperidine-1, 2, 6-tricarboxylic acid 1-benzyl ester (2.11 g, 6.86 mmol) and 3,5-dimethoxyphenethyl amine (1.16 mL, 6.9 mmol) according to a procedure similar to the Compound 3 synthesis (Example l~Step 3). The title compound (11, 2.29 g) was obtained in 74% yield.

Spectral analysis of the product was consistent with Compound 11 : MS (ESP): 453 (M⁺).

1H NMR (CDC1₃): δ 7.39 - 7.32 (5H, m), 6.39 (2H, d, J = 2.2 Hz), 6.32 (IH, t, J = 2.2 Hz), 5.19 (2H, s), 4.96 (2H, br s), 4.01 (2H, t, J = 7.9 Hz), 3.77 (6H, s), 2.79 (2H, t, J = 7.9 Hz), 1.99 - 1.76 (6H, m). Step 2: Synthesis of Compound 12: Compound 12

The imide (Compound 11, 2.24 g, 4.95 mmol) was reduced and cyclized according to a procedure similar to the Compound 5 synthesis (Example l~Step 4). The title compound (12, 1.51 g) was obtained as a mixture of enantiomers in 70% yield.

Spectral analysis of the product was consistent with Compound 12: MS (ESP): 437 (M⁺).

1H NMR (CDC1₃, mixture of rotamers): δ 7.30 - 7.19 (4H, m), 6.90 - 6.89 (IH, m), 6.36 and 6.21 (IH, two s), 6.24 (IH, s), 5.17 (IH, s), 5.09 - 4.70 (4H, m), 4.59 and 4.58 (IH, two s), 3.85, 3.80, 3.78 and 3.64 (6H, four s), 2.96 - 2.87 (IH, m), 2.79 - 2.64 (IH, m), 2.50 (IH, d, J = 5.9 Hz), 2.09 - 1.90 (2H, m), 1.80 - 1.60 (4H, m). Step 3: Synthesis of 9,13-Irnino-8H-azocino [2,1-a] isoquinolin-8-one, 5,6,9,10,11, 12,13,13a-octahydro-l, 3-dimethoxy- (9C1) (Compound 13):

The cyclized product 12 was deprotected in a fashion similar to that of the Compound 6 synthesis (Example l~Step 5). The title compound was obtained in quantitative yield.

Spectral analysis of the product was consistent with Compound 13: 1H NMR (CDC1₃): δ 6.35 (IH, d, J = 2.2 Hz), 6.27 (IH, d, J = 1.9 Hz), 4.97 (IH, m), 3.80 (6H, s), 3.74 (IH, s), 3.52 (IH, s), 3.03-2.92 (IH, m), 2.68 (IH, dt, J = 7.4, 2.8 Hz), 2.57 (IH, d, J = 16.2 Hz), 2.00 - 1.59 (6H, m).

Scheme 4, which is depicted below, is useful for preparing Compound 17 (Compound G): Scheme 4

EXAMPLE 4

Synthesis of 9,13-Imino-oxa-6-8H-azocino F2,l-a^"l isoquinolin-8- one,5,9,10,ll,12,13,13a-heptahvdro-3-methoxy-(9Cl) (Compound 17) Step 1: Synthesis of Compound 14:

Compound 14

A suspension of piperidine-1, 2, 6-tricarboxylic acid 1-benzyl ester (2 g, 6.5 mmol) in acetic anhydride (15 mL) was heated at 80°C for 2 hours. The resulting clear solution was diluted with toluene and reduced to minimum volume. The residue was azeotrophically evaporated with toluene (4x) until 1H NMR showed absence of acetic anhydride. The cyclic anhydride (Compound 2) was dissolved in THF (20 mL) and added dropwise to a solution of hydroxylamine (50% solution in water, 4 mL, 65 mmol) in THF (20 mL) at 5°C. After the solution was stirred at ambient temperature for 1 hour, Rexyn 101H ion exchange resin (prewashed, 80 mL) was added to the mixture. The mixture was diluted with THF and then stirred at room temperature for 1 hour. The resin was removed by filtration and rinsed with THF. The combined filtrates were concentrated to dryness. To a solution of the residue in acetonitrile at 0°C was added DCC (1.3 g, 6.3 mmol) as a solution in acetonitrile. After allowing the mixture to warm slowly to room temperature for over 18 hours with stirring, the mixture was cooled to 0°C and filtered. The solids were washed with acetonitrile and the combined filtrates were concentrated to dryness. The residue was purified by flash chromatography on silica gel using ethyl acetate/hexanes (1:1) to give the desired imide (Compound 14, 1.26 g) in 64% yield.

Spectral analysis of the product was consistent with Compound 17: 1H NMR (DMSO-d₆): δ 10.43 (IH, s), 7.40 - 7.29 (5H, m), 5.13 (2H, s), 4.89 (2H, s), 1.98 -1.73 (5H, m), 1.40 - 1.29 (IH, m).

Step 2: Synthesis of Compound 15:

To a solution of the imide (Compound 14, 1.2 g, 3.94 mmol) in acetone (10 mL) were added 3-methoxy benzyl bromide (0.6 mL, 4.23 mmol), potassium carbonate (0.545 g, 3.94 mmol) and 18-crown-6 (52 mg, 0.2 mmol). After stirring at 50 °C for 2.5 hours, the mixture was partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate (2x). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated to dryness. The oily residue was titrated with hexanes (3x) to give the product (Compound 15, 1.49 g) as an oil (89% yield), which was used without further purification.

Spectral analysis of the product was consistent with Compound 15: 1H NMR (CDC1₃): δ 7.40 - 7.22 (6H, m), 7.06-7.01 (2H, m), 6.91 - 6.87 (IH, m), 5.14 (2H, s), 5.00 (4H, s), 3.81(3H, s), 2.04 - 1.99 (2H, m), 1.87 - 1.77 (3H, m), 1.57 - 1.48 (lH, m). Step 3: Synthesis of Compound 16:

The imide (Compound 15, 1.42 g, 3.34 mmol) was reduced and cyclized according to a procedure similar to the Compound 5 synthesis (Example l~Step 4). The title Compound (0.63 g) was obtained as a mixture of enantiomers in 46% yield.

Spectral analysis of the product was consistent with Compound 16: MS (ESP): 409 (M⁺).

1H NMR (CDCI₃, mixture of rotamers): δ 7.35 - 7.08 (6H, m), 6.87 - 6.85 and 6.65 - 6.61 (IH, two sets of m), 6.55 (IH, s), 5.39 - 4.76 (7H, m), 3.79 (3H, s), 2.08 - 1.70 (6H, m).

Step 4: Synthesis of 9,13-Imino-oxa-6-8H-azocino [2,1-a] isoquinolin-8-one, 5,9,10,ll,12,13,13a-heptahydro-3-methoxy-(9Cl) (Compound 17):

The cyclized product was deprotected in a fashion similar to the Compound 6 synthesis (Example 1— Step 5). The title Compound (Compound G) was obtained in quantitative yield.

Spectral analysis of the product was consistent with Compound 17: MS (ESP): 275 (M^1").

1H NMR (CDC1₃): δ 7.14 (IH, d, J = 8.7 Hz), 6.85 (IH, dd, J = 8.6, 2.5 Hz), 6.59 (IH, d, J = 2.5 Hz), 5.43 (IH, d, J = 14.5 Hz), 4.83 (IH, d, J = 14.5 Hz), 4.94 (IH, s), 3.86 (IH, s), 3.80 (3H, s), 3.58 (IH, s), 2.06 -1.67 (6H, m).

General Scheme 5, which is depicted below, is useful for preparing Compounds K, and L:

Scheme 5

127

Step 1: Synthesis of the precursors 3K-3L:

The N-z protected 2,6-dicarboxylic acid 1 (1.0 eq) was suspended in acetic anhydride (0.08 M) and heated at 65 °C for 30 minutes, during which time the solution became clear and colorless. The mixture was cooled to room temperature and concentrated to an oil which was dissolved in 20 ml toluene and concentrated again. The toluene treatment was repeated 3 additional times to remove all traces of acetic anhydride. The residual oil was dissolved in toluene (0.45 M) and the desired phenethyl amine (1.1 eq.) was added and the mixture was stirred for 1.5 hours at room temperature. At this time, acetic anhydride (5 M with respect to phenethyl amine) was added and the resultant solution was stirred at room temperature for 16 hours. The reaction mixture was then concentrated to an oil and purified by MPLC (hexane/ethyl acetate gradient 90:10 to 40:60). Fractions containing the desired product were combined and concentrated to give the precursor 3 as an oil. Step 2: General Procedure for Conversion of precursor 3K-3L to 127K-127L:

The precursor (3K-3L) was dissolved in THF (0.2 M) and the solution was cooled to -78 °C for the addition of Li(HBEt₃) (1.7 eq.). After 30 minutes at -78 °C, methanol was added and the reaction mixture was warmed to O °C. After 10 minutes, NaHCO₃ (saturated aqueous) and 30% H₂O₂ were added and the mixture was stirred for 30 minutes at room temperature. The solution was then concentrated, diluted with water, extracted with CH₂C1₂ , organics combined, dried over MgSO₄/Na₂SO₄, filtered and concentrated. The residual oil was taken up in dry CH₂C1 and TFA (0.02 M) was added. After stirring at room temperature for 15 hours, BF₃:OEt₂ was added and the mixture was stirred at room temperature until ring closure and deprotection were complete as determined by mass spec. The reaction mixture was then neutralized with NaHCO₃ (saturated aqueous), extracted with CH₂C1₂, dried over MgSO /Na₂SO₄, filtered and concentrated onto silica and purified by MPLC (CH₂Cl₂/MeOH 99:1 to 70:30). Concentration of the fractions containing the desired product gave the desired tetracyclic compound 127K-127L. EXAMPLE 5

Synthesis of Compound K

Compound K Step 1: Synthesis of Compound 3K:

Compound 3K was prepared according to Scheme 5— Step 1, using diacid 1 (2.0 g, 6.8 mmol) acetic anhydride (10.0 ml), and 2-(4-fluoro)phenylethyl amine (1.0 g, 7.18 mmol). Concentration of the fractions containing the desired product gave 2.24 g of 3K (80% yield from 1). Spectral analysis of the product was consistent with Compound 3K:

MS (APCI) m/z 411.1 (M⁺+l). Step 2: Synthesis of Compound K (Compound 127K):

This compound was prepared according to Scheme 5— Step 2, using 3K (1.2 g, 2.9 mmol), Li(HBEt₃) (4.9 ml, 4.9 mmol) THF (15 ml), TFA (2 ml), CH₂C1₂ (15 ml) and BF₃:OEt₂ (1.0 ml). Concentration of the fractions containing the desired product gave 0.5193 g of 127K (69% yield from 3K).

Spectral analysis of the product was consistent with Compound 127K: MS (APCI) m/z 261.0 (M⁺+1).

EXAMPLE 6 Synthesis of Compound L

Compound L Step 1: Synthesis of Compound 3L:

Compound 3L was prepared according to Scheme 5~Step 1, using diacid 1 (2.0 g, 6.8 mmol) acetic anhydride (10.0 ml), and 2-(4-methyl)phenylethyl amine (1.01 g, 7.18 mmol). Concentration of the fractions containing the desired product gave 2.16 g of 3L (78% yield from 1).

Spectral analysis of the product was consistent with Compound 3L: MS (APCI) m/z 407.1 (M⁺+1). Step 2: Synthesis of Compound L (Compound 127L): Compound 127L was prepared according to Scheme5--Step 2, using 3L (1.48 g,

3.64 mmol), Li(HBEt₃) (6.19 ml, 6.19 mmol) THF (18 ml), TFA (5 ml), CH₂C1₂ (20 ml) and BF₃:OEt (2.0 ml). Concentration of the fractions containing the desired product gave 0.550 g of 127L (60 % yield from 3D.

Spectral analysis of the product was consistent with Compound 127L: MS (APCI) m/z 257.0 (M⁺+l).

Scheme 6, which is depicted below, is useful for preparing ,α-difluoro acids:

Scheme 6

EXAMPLE 7

Synthesis of ,α-difluoro-3, 4,5-trimethoxy-phenylacetic acid (Compound 18)

To a stirred solution of 2-oxo-3, 4, 5-trimethoxy-phenylacetic acid (2.00 g, 8.32 mmol) in anhydrous methylene chloride (16 mL) under nitrogen at room temperature was added diethylaminosulfurtrifluoride (DAST, 8.8 mL, 66.6 mmol) dropwise. The reaction was stirred overnight. The reaction was cooled in an ice bath and water was carefully added to quench excess DAST. The mixture was extracted with ethyl acetate (2x50 mL) and the organic layer was washed with saturated aqueous sodium bicarbonate and water. The organic layer was dried over magnesium sulfate, filtered, and concentrated. The crude material was purified by MPLC (hexanes/ethyl acetate 90:10 to 30:70). Concentration afforded 1.19 g of the N, N-diethylamide derivative

(45% yield). The basic aqueous layer was acidified with concentrated hydrochloric acid prior to extraction with ethyl acetate and drying over magnesium sulfate.

Concentration afforded the title acid. The N, N-diethylamide derivative (Compound 19) was hydrolyzed by heating a solution in ethanol with 10% NaOH at reflux for 4 hours. The mixture was concentrated, acidified and extracted with ethyl acetate (2x50 mL). After removal of solvent, the two crops were combined to give 1.21g (55% yield) of the title acid 18.

Spectral analysis of the product was consistent with Compound 18: 1H NMR (CDC1₃): δ 6.85 (2H, s), 3.90 (6H, s), 3.89 (3H, s). MS (APCI) 260.9 (M+H⁺).

Spectral analysis of the product was consistent with N, N-diethylamide derivative (Compound 19):

1H NMR (CDCI₃): δ 6.77 (2H, s), 3.88 (9H, s), 3.45 (2H, q, J = 7.0 Hz), 3.25 (2H, q, J = 7.0 Hz), 1.20 (3H, t, J = 7.0 Hz), 1.10 (3H, t, J = 7.0 Hz). MS (APCI) 318.1 (M+H⁺).

EXAMPLE 8 Synthesis of α, -Difluoro-4-choro-phenylacetic acid (Compound 20)

mpound 20 Compound 21

Compound 20 was prepared by a synthetic method analogous to Compound 18 synthesis, using 2-oxo-4-chloro-phenylacetic acid (2.00 g, 10.8 mmol) and DAST (11.5 mL, 86.7 mmol). Purification afforded 1.17 g of the N, N-diethylamide derivative (Compound 21, 41%). Hydrolysis afforded 1.11 g of the title acid (20, 49% overall). Spectral analysis of the product was consistent with Compound 20: 1H NMR (CDCI3): δ 9.25 (IH, br s), 7.52 (2H, d, J = 8.4 Hz), 7.40 (2H, d, J = 8.4 Hz). MS (APCI) 204.9 (M+H⁺).

Spectral analysis of the product was consistent with N, N-diethylamide derivative (Compound 21):

¹ H NMR (CDCI3): δ 7.46 (2H, m), 7.40 (2H, m), 3.36 (2H, m), 3.25 (2H, m), 1.14 (2H, m), 1.10 (2H, m).

MS (APCI) 261.9 (M+H⁺). Compounds A, B, C, D, E, F, G, K, L, and Compounds 18-21 were used to prepare sulfonamides, sulfamides, sulfamates, ureas, amides, oxalyl diamides, α, - difluoroarylacyl heterobicycles derivatives of the present invention:

Compound A Compound B Compound C (Compound ( O0004020) (WO0004020) 13)

Compound D Compound E (Compound 6) (Compound 10)

Compound G (Compound 17) Compound K Compound L (Compound 128) (Compound 129)

The sulfonamides compounds of the present invention may be prepared in the manner depicted in Scheme A below:

Scheme A

wherein:

X and Y are as defined in Compound (I); R_a is selected from substituted or unsubstituted aryl, alkyl, heteroaryl, and heterocycloalkyl .

The following examples are illustrative of the present invention:

EXAMPLE IA Synthesis of 9,13-Imino-8H-azocino F2,l-a^"l isoquinolin-8-one, 5,6,9,10,11,12,13,13a- octahvdro-4-methoxy-14-r(3-methylphenyl)sulfonyll-(Compound 63)

The amine (Compound A, 0.0363 g, 0.126 mmol), which was synthesized according to a published procedure (Katoh, S. and et al. WO 00/04020), was dissolved in DMF (1 mL) and o-tolylsulfonyl chloride (0.0260 g, 0.1259 mmol) was added followed by ethyl diisopropyl amine (0.0219 mL, 0.125 mmol). The mixture was stirred at room temperature for 12 hours with product formation monitored by TLC and/or mass spec. Upon disappearance of the starting compound, the reaction mixture was added to 5 mL brine. Filtration of the precipitate gave 0.0185 g of Compound 63 (34% yield). Spectral analysis of the product was consistent with Compound 63:

MS (APCI) 427.1 (M+H⁺).

Elemental analysis for (C₂₃H₂₆N₂O₄S 0.10C₃H₇NO 0.05H₂O) calculated: C 64.37, H 6.21, N 6.77; found: C 64.05, H 6.06, N 6.42.

EXAMPLE 2A Synthesis of 9,13-Imino-8H-azocino [2,1-al isoquinolin-8-one, 5,6,9,10,11,12,13,13a- octahvdro-4-methoxy-14-r(4-methylpheny0 sulfonyll-CCompound 36)

This compound was prepared similar to Example 1 A, using Compound A (0.0326 g, 0.1189 mmol), which was synthesized according to a published procedure (Katoh, S. and et al. WO0004020), DMF (1 mL), p-tolylsulfonyl chloride (0.0256 g, 0.1342 mmol) and ethyl diisopropyl amine (0.0205 mL, 0.116 mmol). Filtration of the final precipitate gave 0.0248 g of Compound 36 (49% yield).

Spectral analysis of the product was consistent with Compound 36: MS (APCI) 427.1 (M+H⁺).

Elemental analysis for (C₂₃H₂₆N₂O₄S 0.15C₃H₇NOO.15H₂O) calculated: C 63.98, H 6.26, N 6.84; found: C 63.7, H 6.05, N 6.45.

EXAMPLE 3A Synthesis of 9,13-Imino-8H-azocino T2,l-a^"| isoquinolin-8-one, 5,6,9,10,11,12,13,13a- octahvdro-3-methoxy-14-r(4-methylphenyl) sulfonyl1-(Comρound 37)

This compound was prepared similar to Example 1 A, using Compound B (0.0339 g, 0.126 mmol, synthesized according to a published procedure [Katoh, S. and et al. WO 00/04020]), DMF (1 mL), p-tolylsulfonyl chloride (0.0237 g, 0.126 mmol) and ethyl diisopropyl amine (0.021 mL, 0.126 mmol). Filtration of the final precipitate gave 0.0255 g of Compound 37 (47% yield).

Spectral analysis of the product was consistent with Compound 37: MS (APCI) 427.1 (M+H⁺). Elemental analysis for (C₂₃H₂₆N₂O₄SO.10C₃H₇NOO.4H₂O) calculated: C 63.45, H

6.28, N 6.67; found: C 63.11, H 6.00, N 6.30. EXAMPLE 4A

Synthesis of 9,13-Imino-8H-azocino T2,l-al isoquinolin-8-one, 14-rr4-(l,l- dimethylethyl phenyll sulf onyll -5,6,9,10,11,12,13,13 a-octahydro-3 -methoxy- (Compound 38)

This compound was prepared similar to Example 1 A, using Compound B (0.0532 g, 0.1954 mmol, synthesized according to a published procedure [Katoh, S. and et al. WO 0004020]), DMF (1 mL), p-t-butyl phenylsulfonyl chloride (0.0680 g, 0.293 mmol) and ethyl diisopropyl amine (0.0339 mL, 0.195 mmol). Filtration of the final precipitate gave 0.0691 g of Compound 38 (75% yield).

Spectral analysis of the product was consistent with Compound 38: MS (APCI) 469.1 (M+H*).

Elemental analysis for (C₂₆H₃2N₂O₄SO.05C₃H₇NOO.65H₂O) calculated: C 64.90, H 7.01, N 5.93; found: C 64.5, H 6.78, N 5.63.

EXAMPLE 5A Synthesis of 9,13-Imino-8H-azocino [2,1-a] isoquinolin-8-one, 5,6,9,10,11,12,13,13a- octahydro-3 -methoxy- 14- [ [4-( 1 -methylethyl) phenyl] sulfonyl] -(Compound 39)

This compound was prepared similar to Example 1 A using Compound B (0.0521 g, 0.191 mmol), DMF (1 mL), p-i-propyl phenylsulfonyl chloride (0.0626 g, 0.286 mmol) and ethyl diisopropyl amine (0.033 mL, 0.191 mmol). Filtration of the final precipitate gave 0.0539 g of Compound 39 (62% yield).

Spectral analysis of the product was consistent with Compound 39: MS (APCI) 455.2 (M+H⁴). Elemental analysis for (C₂₄H₃oN₂O₄S l .45H₂O) calculated: C 62.46, H 6.90, N 5.83; found: C 62.18, H 6.28, N 5.60.

EXAMPLE 6A Synthesis of 9,13-Imino-8H-azocino[2,l-a] isoquinolin-8-one, 5,6,9,10,11,12,13,13a- octahydro-l,3-dimethoxy-14-[(4-methylphenyl sulfonvn-(Compound 40)

Compound 40

This compound was prepared similar to Example 1 A using Compound C (0.1060 g, 0.350 mmol), DMF (2 mL), p-tolyl sulfonyl chloride (0.200 g, 1.05 mmol), and ethyl diisopropyl amine (0.060 mL, 0.350 mmol). Filtration of the final precipitate gave the product in the water layer. The water layer was extracted with CH₂C1₂ (3 10 mL). The organic layers were combined, dried over MgSO₄, filtered, concentrated onto silica and purified by MPLC (hexane/ethyl acetate gradient 90:10 to 40:60). Concentration of the fractions containing the desired product gave 0.1409 g of Compound 40 (88% yield).

Spectral analysis of the product was consistent with Compound 40: MS (APCI) 457.2 (M+H⁺).

Elemental analysis for (C₂₄H₂₈N₂O₅SO.15C₆H₁₄) calculated: C 63.70, H 6.46, N 5.97; found: C 64.03, H 6.65, N 5.68.

EXAMPLE 7A Synthesis of 9,13-Imino-8H-azocino [2,1-a] isoquinolin-8-one, 5,6,9,10,11,12,13,13a- octahvdro- 1 ,3 -dimethox v- 14- [(phenylmethyl)sulf onyll -(Compound 41)

Compound 41

This compound was prepared similar to Example 1 A, using Compound C

(0.1070 g, 0.354 mmol), DMF (2 mL), benzylsulfonyl chloride (0.2025 g, 1.06 mmol) and ethyl diisopropyl amine (0.061 mL, 0.354 mmol). Filtration of the final precipitate gave the product in the water layer. The water layer was extracted with 3x10 mL CH₂C1₂. The organic layers were combined, dried over MgSO₄, filtered, concentrated onto silica and purified by MPLC (hexane/ethyl acetate gradient 90:10 to 40:60). Concentration of the fractions containing the desired product gave 0.059 g of Compound 41 (37% yield).

Spectral analysis of the product was consistent with Compound 41: MS (APCI) 457.2 (M+H⁺). Elemental analysis for (C₂ H₂₈N₂O₅SO.15C₄H₈O₂) calculated: C 62.90, H 6.27, N 5.96; found: C 62.83, H 6.54, N 5.64.

EXAMPLE 8A Synthesis of 9,13-Imino-8H-azocino [2,1-a] isoquinolin-8-one, 14-[[4-(l,l- dimethylethyl) phenyl]sulfonyl1-5,6,9, 10,11, 12,13, 13a-octahydro-l,3-dimethoxy- (Compound 42)

This compound was prepared similar to Example 1 A using Compound C (0.1021 g, 0.337 mmol), DMF (1 mL), p-t-butylphenylsulfonyl chloride (0.2303 g, 0.993 mmol) and ethyl diisopropyl amine (0.058 mL, 0.337 mmol). Filtration of the final precipitate gave the product which was dissolved in CH₂C1₂, concentrated onto silica and purified by MPLC (hexane/ethyl acetate gradient 90:10 to 40:60). Concentration of the fractions containing the desired product gave 0.1396 g of Compound 42 (83% yield).

Spectral analysis of the product was consistent with Compound 42: MS (APCI) 499.1 (M+H⁺). Elemental analysis for (C₂₇H₃₄N₂O₅S) calculated: C 65.04, H 6.87, N 5.62; found: C 65.19, H 7.02, N 5.24.

EXAMPLE 9A Synthesis of 9,13-Imino-8H-azocino T2,l-a1 isoquinolin-8-one, 5,6,9,10,11,12,13,13a- octahydro-l,3-dimethoxy-14-rr4-(l-methylethyl)phenyl]sulfonyl]-(Compound 43)

This compound was prepared similar to Example 1 A using Compound C (0.1056 g, 0.349 mmol), DMF (1 mL), p-i-propylphenylsulfonyl chloride (0.2171 g, 0.993 mmol) and ethyl diisopropyl amine (0.0576 L, 0.369 mmol). Filtration of the final precipitate gave the product which was dissolved in CEΪ2C1₂, concentrated onto silica and purified by MPLC (hexane/ethyl acetate gradient 90:10 to 40:60). Concentration of the fractions containing the desired product gave 0.142 g of Compound 43 (84% yield).

Spectral analysis of the product was consistent with Compound 43: MS (APCI) 485.1 (M+H⁴).

Elemental analysis for (C₂₆H3₂N2O₅S) calculated: C 64.44, H 6.66, N 5.78; found: C 64.50, H 6.94, N 5.52.

EXAMPLE 10A Synthesis of 9,13-Imino-8H-azocino [2,1-a] isoquinolin-8-one, 14-[(4- ethylphenvDsulf onyl] -5,6,9,10,11,12,13,13 a-octahydro- 1 ,3 -dimethoxy (Compound 44)

This compound was prepared similar to Example 1 A using Compound C

(0.1049 g, 0.347 mmol), DMF (1 mL), p-ethylphenylsulfonyl chloride (0.2031 g, 0.993 mmol) and ethyl diisopropyl amine (0.0576 mL, 0.369 mmol). Filtration of the final precipitate gave the product which was dissolved in CH₂Cl₂, concentrated onto silica and purified by MPLC (hexane/ethyl acetate gradient 90:10 to 40:60). Concentration of the fractions containing the desired product gave 0.1311 g of Compound 44 (80% yield).

Spectral analysis of the product was consistent with Compound 44: MS (APCI) 471.2 (M+H⁺). Elemental analysis for (C₂₅H₃oN₂O₅SO.3C₆H₁₄) calculated: C 64.84, H 6.94, N 5.64; found: C 64.85, H 7.08, N 5.47.

EXAMPLE HA Synthesis of 9,13-Imino-8H-azocino [2,1-a] isoquinolin-8-one, 14-[(2-bromophenyl) sulfonyll-5,6,9,10,11, 12,13, 13a-octahydro-l, 3-dimethoxy (Compound 47)

Compound 47

This compound was prepared similar to Example 1 A using Compound C

(0.1003 g, 0.331 mmol), DMF (1 mL), o-bromophenylsulfonyl chloride (0.2695 g, 1.05 mmol) and ethyl diisopropyl amine (0.056 mL, 0.331 mmol). Filtration of the final precipitate gave very little product so the water layer was extracted with 3x10 mL CH₂C1₂. The organic layers were combined, dried (MgSO₄), filtered and concentrated onto silica and purified by MPLC (hexane/ethyl acetate gradient 90:10 to 40:60). Concentration of the fractions containing the desired product gave 0.1173 g of Compound 47 (68% yield).

Spectral analysis of the product was consistent with Compound 47: MS (APCI) 523.0 (M+H*^"). Elemental analysis for (C₂3H₂5BrN₂O5SO.15C6H₁₄) calculated: C 53.72, H 5.11, N 5.24; found: C 54.09, H 4.98, N 4.91. EXAMPLE 12A

Synthesis of 9,13-Imino-8H-azocino [2,1-a] isoquinolin-8-one, 14-[(3-bromophenyl) sulfonyl]-5,6,9,10,ll, 12,13, 13 a-octahydro- 1, 3-dimethoxy (Compound 48)

Compound 48

This compound was prepared similar to Example 1 A, using Compound C (0.1053 g, 0.348 mmol), DMF (1 mL), m-bromophenylsulfonyl chloride (0.2739 g, 1.07 mmol) and ethyl diisopropyl amine (0.057 mL, 0.348 mmol). Filtration of the final precipitate gave very little product so the water layer was extracted with 3x10 mL CH₂Cl₂. The organic layers were combined, dried over MgSO , filtered and concentrated onto silica and purified by MPLC (hexane/ethyl acetate gradient 90:10 to 40:60). Concentration of the fractions containing the desired product gave 0.1472 g of Compound 48 (81% yield).

Spectral analysis of the product was consistent with Compound 48: MS (APCI) 523.0 (M+H⁺).

Elemental analysis for (C₂₃H₂₅BrN₂O₅SO.3C₆H₁₄O. I5OH_J3O₂) calculated: C 54.43, H 5.47, N 5.00; found: C 54.57, H 5.34, N 4.61.

EXAMPLE 13A Synthesis of 9,13-Imino-8H-azocino [2,1-a] isoquinolin-8-one, 14-[(4-bromophenyl) sulfonvn-5,6,9,10,ll,12,13,13a-octahvdro-l, 3-dimethoxy (Compound 49)

This compound was prepared similar to Example 1 A using Compound C (0.1103 g, 0.365 mmol), DMF (1 mL), p-bromophenylsulfonyl chloride (0.2800 g, 1.10 mmol), and ethyl diisopropyl amine (0.061 mL, 0.365 mmol). Filtration of the final precipitate gave very little product so the water layer was extracted with 3x10 mL CH₂C1₂. The organic layers were combined, dried over MgSO , filtered and concentrated onto silica and purified by MPLC (hexane/ethyl acetate gradient 90:10 to 40:60). Concentration of the fractions containing the desired product gave 0.1472 g of Compound 49 (75% yield). Spectral analysis of the product was consistent with Compound 49:

MS (APCI) 523.0 (M+H⁺).

Elemental analysis for (C₂₃H2₅BrN2θ₅SO.5C₄H8θ₂) calculated: C 56.10, H 5.17, N 4.95; found: C 56.49, H 4.89, N 5.03.

EXAMPLE 14A Synthesis of 9,13-Imino-8H-azocino [2,1-a] isoquinolin-8-one, 14-[(2,4-dinitrophenyl) sulfonyll-5,6,9, 10,11, 12,13, 13 a-octahydro- 1, 3-dimethoxy (Compound 50)

This compound was prepared similar to Example 1 A, using Compound C (0.1024 g, 0.338 mmol), DMF (1 mL), 2,4-Dinitrophenylsulfonyl chloride (0.271 g, 1.02 mmol) and ethyl diisopropyl amine (0.059 mL, 0.338 mmol). Filtration of the final precipitate gave very little product so the water layer was extracted with 3x10 mL CH₂Ci₂. The organic layers were combined, dried over MgSO₄, filtered and concentrated onto silica and purified by MPLC (hexane/ethyl acetate gradient 90:10 to 40:60). Concentration of the fractions containing the desired product gave 0.0481 g of Compound 50 (27% yield).

Spectral analysis of the product was consistent with Compound 50: MS (APCI) 533.1 (M+H^4").

Elemental analysis for (C₂₃H25BrN₂O₅SO.25C₆H₁₄) calculated: C 53.11, H 5.00, N 10.11; found: C 53.12, H4.76, N 9.72. EXAMPLE 15A

Synthesis of 9,13-Imino-8H-azocino [2,1-a] isoquinolin-8-one, 5,6,9,10,11,12,13,13a- octahydro-1, 3-dimethoxy-14-[[2-(l-naphthalenyl)ethyl]sulfonyl] (Compound 51)

Compound 51

This compound was prepared similar to Example 1 A, using Compound C (0.1028 g, 0.340 mmol), DMF (1 mL), 2-(l-naphthyl)ethanesulfonyl chloride (0.259 g, 1.02 mmol) and ethyl diisopropyl amine (0.059 mL, 0.338 mmol). Filtration of the final precipitate gave very little product so the water layer was extracted with 3x10 mL CH₂C1₂. The organic layers were combined, dried over MgSO , filtered and concentrated onto silica and purified by MPLC (hexane/ethyl acetate gradient 90:10 to 40:60). Concentration of the fractions containing the desired product gave 0.0203 g of Compound 51 (17% yield).

Spectral analysis of the product was consistent with Compound 51: MS (APCI) 521.1 (M+H⁺).

Elemental analysis for (C₂₉H32N2θ5SO.15C₆Hι₄O.3C₄H₈O₂) calculated: C 66.70, H 6.57, N 5.00; found: C 66.91, H 6.48, N 4.71.

EXAMPLE 16A Synthesis of 9,13-Imino-8H-azocino [2,1-a] isoquinolin-8-one, 14-([l, -biphenyl]-4- ylsulfonyD-5,6,9,10,11, 12,13, 13a-octahydro-l, 3-dimethoxy (Compound 52)

This compound was prepared similar to Example 1 A, using Compound C (0.1076 g, 0.356 mmol), DMF (1 mL), 4-biphenylsulfonyl chloride (0.275 g, 1.07 mmol) and ethyl diisopropyl amine (0.062 mL, 0.356 mmol). Filtration of the final precipitate gave very little product so the water layer was extracted with 3x10 mL CH₂CI₂. The organic layers were combined, dried over MgSO₄, filtered and concentrated onto silica and purified by MPLC (hexane/ethyl acetate gradient 90:10 to 40:60). Concentration of the fractions containing the desired product gave 0.1351 g of Compound 52 (73% yield). Spectral analysis of the product was consistent with Compound 52:

MS (APCI) 519.1 (M+H⁺).

Elemental analysis for (C₂₉H₃oN₂O₅SO.3C₄H₈O₂) calculated: C 66.55, H 5.99, N 5.14; found: C 66.42, H 5.87, N 5.20.

EXAMPLE 17A Synthesis of 9,13-Imino-8H-azocino [2,1-a] isoquinolin-8-one, 5,6,9,10,11,12,13,13a- octahydro-1, 3-dimethoxy-14-[[3-[(3,4,5-trimethoxyphenyl)amino]phenynsulfonyl] (Compound 55)

Compound 48 (0.050 g, 0.0985 mmol) was combined with 3,5,5-trimethoxy aniline (0.0189 g, 0.114 mmol), Pd₂(dba)₃ (0.0024 g, 0.00249 mmol), Cs₂CO₃ (0.0436 g, 0.134 mmol), and (S)-tol-BINAP (0.0072 g, 0.0105 mmol) in toluene (0.5 mL) at room temperature. The mixture was heated at reflux for 18 hours, and then allowed to cool to room temperature. Et₂O (1.0 mL) was added to the mixture, and the mixture was filtered through celite, concentrated, dissolved in 10 mL CH₂CI₂, re-concentrated onto silica and purified by MPLC (hexane/ethyl acetate gradient 90: 10 to 40:60). Concentration of the fractions containing the desired product gave 0.023 g of Compound 55 (38% yield).

Spectral analysis of the product was consistent with Compound 55: MS (APCI) 624.2 (M+H⁺). Elemental analysis for (CsΛNsOsSO.SGJTsO O.lSCβHu) calculated: C 61.77, H 6.31, N 6.34; found: C 62.14, H 6.28, N 6.03. EXAMPLE 18A

Synthesis of Benzoic acid, 2-[r3-[(5,8,9,10,ll,12,13,13a-octahydro-l, 3 -dimethoxy- 8- oxo-9, 13-imino-6H-azocino[2,l-a]isoquinolin-14-yl)sulfonyl]phenyl1amino1-,ethyl ester (Compound 56)

Compound 48 (0.050 g, 0.0985 mmol) was combined with anthranilic acid ethyl ester (0.0189 g, 0.114 mmol), Pd₂(dba)₃ (0.0023 g, 0.00249 mmol), Cs₂CO₃ (0.0436 g, 0.134 mmol), and (S)-tol-BINAP (0.0072 g, 0.0105 mmol) in toluene (0.5 mL) at room temperature. The mixture was heated at reflux for 18 hours, and then allowed to cool to room temperature. Et₂O (1.0 mL) was added to the mixture, and the mixture was filtered through celite, concentrated, dissolved in 10 mL CH₂CI₂, re-concentrated onto silica and purified by MPLC (hexane/ethyl acetate gradient 90:10 to 40:60). Concentration of the fractions containing the desired product gave 0.023 g of Compound 56 (76% yield).

Spectral analysis of the product was consistent with Compound 56: MS (APCI) 606.2 (M+H^4").

Elemental analysis for (C32H35N3O7SO.15CH2CI₂O.9CH3OH) calculated: C 61.33, H 6.06, N 6.49; found: C 61.51, H 6.04, N 6.12.

EXAMPLE 19A Synthesis of 9,13-Imino-8H-azocino [2,1-a] isoquinolin-8-one, 14-[(3',4'- dichloror r-biphenyll^-vDsulfonvn-S^^JOΛl.^αS.lSa-octahvdro- S-dimethoxy (Compound 57)

Compound 49 (0.050 g, 0.0985 mmol) was combined with Pd(PPh₃)₄ (0.0033 g, 0.0029 mmol) in toluene (1.0 mL) at room temperature and stirred for 15 minutes. 3,4- Dichlorophenyl boronic acid (0.027 g), 0.1437 mmol) was then added followed by aqueous Na2CO₃ (0.0203 g, 0.1916 mmol in 0.9 mL water) to the mixture. The mixture was heated at reflux for 18 hours, and then allowed to cool to room temperature. Ethyl acetate (5 mL) was added, and the mixture was filtered through celite, concentrated, dissolved in 10 mL CH₂CI₂, re-concentrated onto silica and purified by MPLC (hexane/ethyl acetate gradient 90:10 to 40:60). Concentration of the fractions containing the desired product gave 0.0318 g of Compound 57 (56% yield). Spectral analysis of the product was consistent with Compound 57:

MS (APCI) 587.1 (M+H^4").

Elemental analysis for (C₂₉H₂₈Ci₂N₂O₅SO.45C₆H₁₄) calculated: C 60.79, H 5.52, N 4.47; found: C 60.91, H 5.60, N 4.08.

EXAMPLE 20A Synthesis of 9,13-Imino-8H-azocino [2,1-a] isoquinolin-8-one, 14-[(3', 4'- dichloror r-biphenvn-S-vDsulfonvn-S^^JOqiJΣJS Sa-octahvdro-l.S-dimethoxy (Compound 58 )

Compound 48 (0.050 g, 0.0985 mmol) was combined with Pd(PPh₃)₄ (0.0033 g,

0.0029 mmol) in toluene (1.0 mL) at room temperature and stirred for 15 minutes. 3,4- Dichlorophenyl boronic acid (0.027 g), 0.1437 mmol) was then added followed by aqueous Na₂CO₃ (0.0203 g, 0.1916 mmol in 0.9 mL water) to the mixture. The mixture was heated at reflux for 18 hours, and then allowed to cool to room temperature. Ethyl acetate (5 mL) was added to the mixture, and the mixture was filtered through celite, concentrated, dissolved in 10 mL CH₂CI₂, re-concentrated onto silica and purified by MPLC (hexane/ethyl acetate gradient 90:10 to 40:60). Concentration of the fractions containing the desired product gave 0.0479 g of Compound 58 (85% yield). Spectral analysis of the product was consistent with Compound 58: MS (APCI) 587.1 (M+H⁺).

Elemental analysis for (C₂₉H2₈Cl₂N₂O₅SO.45C₆H₁₄O.3C₄H8θ2) calculated: C 59.59, H 5.23, N 4.47; found: C 59.23, H 5.33, N 4.11. EXAMPLE 21A

Synthesis of 9,13-Imino-8H-azocino [2,1-a] isoquinolin-8-one, 14-[(4-cyanophenyl) sulfonyll-5,6,9, 10,11, 12,13, 13a-octahydro-l,3-dimethoxy (Compound 59)

Compound 59

This compound was prepared similar to Example 1 A using Compound C

(0.1069 g, 0.353 mmol), DMF (1 mL), 4-cyanobenzene chloride (0.2169 g, 1.07 mmol) and ethyl diisopropyl amine (0.066 mL, 0.356 mmol). Filtration of the final precipitate gave very little product so the water layer was extracted with 3x10 mL CH₂CI₂. The organic layers were combined, dried over MgSO₄, filtered and concentrated onto silica and purified by MPLC (hexane/ethyl acetate gradient 90: 10 to 40:60). Concentration of the fractions containing the desired product gave 0.1271 g of Compound 59 (88% yield).

Spectral analysis of the product was consistent with Compound 59: MS (APCI) 468.1 (M+H⁴). Elemental analysis for ^sNsOsSO.S Hu) calculated: C 62.81, H 5.97, N 8.52; found: C 62.98, H 5.94, N 8.12. EXAMPLE 22A

Synthesis of 9, 13-Lmino-8H-azocino[2,l-a]isoquinolin-8-one,5,6,9,10,l 1,12,13, 13a- octahydro- 1 ,3 -dimethoxy- 14- [(3 -methylphenyPsulf onyl] (Compound 64)

Compound 64

This compound was prepared similar to Example 1 A, using Compound C (0.103 g, 0.340 mmol), DMF (2 mL), m-tolyl sulfonyl chloride (0.194 g, 1.02 mmol), and ethyl diisopropyl amine (0.059 mL, 0.340 mmol). Filtration of the final precipitate gave the product in the water layer. The water layer was extracted with 3x10 mL CH₂CI₂. The organic layers were combined, dried over MgSO₄, filtered, concentrated onto silica and purified by MPLC (hexane/ethyl acetate gradient 90:10 to 40:60). Concentration of the fractions containing the desired product gave 0.1244 g of Compound 64 (80% yield).

Spectral analysis of the product was consistent with Compound 64: MS (APCI) 457.2 (M+H⁴).

Elemental analysis for (C₂₄H₂₈N₂O₅S 0.3C₆H₁₄) calculated: C 63.70, H 6.46, N 5.97; found: C 64.20, H 6.75, N 5.62.

EXAMPLE 23A Synthesis of 7,ll-Imino-2H-pyrazino [1,2-a] azocine-3, 6(4H,7H)-dione,2-(3,5- dimethoxyphen yl)-8 ,9, 10,11 -tetrahydro- 12- [(phenylmethyl)sulf onyl] (Compound 23)

The amine (Compound F, 50 mg, 0.145) which was prepared according to a published procedure (Guo, C. and et al. Tetrahedron Lett. 2000, 41, 5307-5311) was dissolved in CH2CI₂ (1 mL). Triethylamine (0.1 mL) was added to the solution followed by benzylsulfonyl chloride (42 mg, 0.22 mmol). After 1 hour, the solution was diluted with CH₂CI₂ (50 mL), washed with brine (2x30 mL), dried and concentrated. The residue was purified with flash column chromatography (35% EtOAc in hexanes), affording 60 mg of the title Compound (83% yield). Spectral analysis of the product was consistent with Compound 23:

1H NMR (CDCI₃): δ 7.37 (5H, m), 6.43 (3H, m), 5.49 (IH, s), 4.48 (2H, AB), 4.39 (IH, s), 4.25 (3H, s), 3.80 (6H, s).

HRMS (FAB): calculated for C₂₅H₂₈N₃O₆S (M+H^1") 498.1699; found 498.1712.

EXAMPLE 24A Synthesis of 9,13-Imino-8H-azocino [2,1-a] isoquinolin-8-one, 14-[(6-chloro-3- pyridinyl) sulfonyl]-5,6,9,10,l 1,12,13, 13 a-octahydro-3 -methoxy (Compound 60)

This compound was prepared by a synthetic method analogous to Example 23A from Compound B and 2-chloro-pyridin-5 -sulfonyl chloride, which was synthesized according to a published procedure (Naegeli, C. and et al. Helv. Chim. Acta. 1939, 21,

1746 -1756). A 55% yield was obtained.

Spectral analysis of the product was consistent with Compound 60:

1H NMR (CDCI3): δ 8.12 (IH, d, J = 2.4 Hz), 7.28 (IH, dd, J = 8.2, 2.3 Hz), 6.95 (IH, d, J = 8.5 Hz), 6.90 (IH, d, J = 8.1 Hz), 6.70 (IH, dd, J = 8.5, 2.3 Hz), 6.38 (IH, d, J = 3.0 Hz), 4.81 (IH, br s), 4.74 - 4.66 (IH, m), 4.49 (IH, br s), 4.40 (IH, s), 3.78 (3H, s),

2.73-2.61 (IH, m), 2.44-1.66 (7H, m).

MS (ESP) 448 (M+H^4").

Elemental analysis for (C₂₁H₂₂ClN₃O₄S): C 56.31 H 4.95 N 9.38; found C 56.28 H 4.92

N 9.35. EXAMPLE 25A

Synthesis of 9,13-Imino-8H-azocino [2,1-a] isoquinolin-8-one, 5,6.9,10,11,12,13,13a- octahvdro-6-methyl-14-r(3-methylphenvD sulfonyll-,(6S,9S.13R,13aR) (Compound 26)

The amine (Compound D, 1.1 mmol) was dissolved in 10 mL dichloromethane at room temperature and m-toluenesulphonyl chloride (220 mg, 1.16 mmol) and N- methylmorpholine (140 mL, 1.3 mmol) were added to the mixture. After stirring at room temperature for 1 hour, the mixture was partitioned between ethyl acetate and aqueous sodium bicarbonate. The aqueous layer was extracted with ethyl acetate (2x). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated to dryness. The residue was purified on silica gel using ethyl acetate/hexanes (1:1) to give the product as a pale yellow solid which was titrated with t-butylmethyl ether/Hexanes and collected by filtration to give the title compound in 46% yield.

Spectral analysis of the product was consistent with Compound 26: ¹HNMR (CDC1₃): δ 7.29 - 7.03 (7H, m), 6.93 (IH, d, J = 6.9 Hz), 5.11 (IH, s), 5.01 - 4.96 (IH, s), 4.39 (2H, s), 2.38 (IH, dd, J = 16.1, 6.2 Hz), 2.25 (IH, dd, J = 16.6, 3.9 Hz), 2.16 (3H, s), 2.05 - 1.63 (6H, m), 1.14 (3H, d, J = 6.9 Hz). Elemental analysis for (C₂₃H₂₆N₂O₃S 0. lH₂O) calculated: C 66.99, H: 6.41 , N 6.79, S 7.78; found: C 66.94, H 6.33, N 6.79, S 7.63.

EXAMPLE 26A Synthesis of 9,13-Imino-8H-azocino [2,1-a] isoquinolin-8-one, 5.6.9,10,11,12,13,13a- octahydro-6-methyl-14-[f3-methylphenvnsulfonvn-,(6R,9R.13S.13aS^") (Compound 25) Compound 25

This compound was prepared similar to Example 24A from Compound E (54 mg, 0.2 mmol), m-toluenesulphonylchloride (45 mg, 0.24 mmol), and N- methylmorpholine (0.03 mL, 0.28 mmol) to give 15 mg of the title compound (18% yield).

Spectral analysis of the product was consistent with Compound 25: ¹HNMR (CDCI₃): δ 7.28 - 7.03 (7H, m), 6.93 (IH, d, J = 6.9 Hz), 5.11 (IH, s), 5.01 - 4.95 (IH, m), 4.39 (2H, s), 2.38 (IH, dd, J = 16.1, 6.1 Hz), 2.25 (IH, dd, J = 16.6, 3.8 Hz), 2.16 (3H, s), 2.05 -1.63 (6H, m), 1.14 (3H, d, J = 6.9 Hz). Elemental analysis for (C₂₃H₂₆N₂O₃S 0.3H₂O) calculated: C 66.41, H 6.45, N 6.74, S 7.71; found: C 66.22, H 6.39, N 6.70, S 7.50.

EXAMPLE 27A Synthesis of 9,13-Imino-8H-azocino [2,1-a] isoquinolin-8-one, 5,6,9,10,11,12,13,13a- octahydro-6-methyl- 14-( 1 -naphthalenylsulf onyl)-, (6S ,9S , 13R, 13 aR) (Compound 27)

Compound 27

This compound was prepared similar to Example 24A, using Compound D (68 mg, 0.26 mmol), 1-naphthalenelsulfonylchloride (70 mg, 0.31 mmol), and N- methylmorpholine (0.04 mL, 0.38 mmol) in 5 mL dichloromethane. The crude product was purified on silica gel using ethyl acetate/hexanes (1:1) as eluent to give 25mg of the title compound (21% yield).

Spectral analysis of the product was consistent with Compound 27: ¹HNMR (CDC1₃, mixture of rotamers, major rotamer reported): δ 8.07 (2H, d, J = 7.3 Hz), 7.82 (IH, d, J = 8.3 Hz), 7.71 (IH, d, J = 7.6 Hz), 7.43 (IH, t, J = 7.2 Hz), 7.35 - 6.89 (5H, m), 6.72 (IH, d, J = 7.3 Hz), 5.11 - 5.03 (IH, m), 4.89 (IH, s), 4.54 (IH, s), 4.40 (IH, s), 2.46 -1.60 (8H, m), 1.08 (3H, d, J = 7.0 Hz).

Elemental analysis for (C₂₆H₂₆N₂O₃S 0.6H₂O): calculated: C 68.28 H 5.99, N 6.13, S 7.01; found: C 68.27, H 6.02, N 6.14, S 6.93.

EXAMPLE 28A Synthesis of 9,13-Imino-8H-azocino [2,1-a] isoquinolin-8-one, 5,6,9,10,11,12,13,13a- octahvdro-l,3-dimethoxy-14-[(3-methylphenyl)sulfonyl]-,(9S,13R,13aR) (Compound 24)

Compound 24

The racemic dimethoxyisoquinoline compound (502 mg, 1.66 mmol) was reacted with (R)-Mandelic acid (190 mg, 1.25 mmol), HATU (1.49 g, 3.92 mmol), and N-methylmorpholine (0.5 mL, 4.5 mmol) in 10 mL DMF at room temperature for 2 hours. The mixture was dropped into a cold solution of aqueous sodium bicarbonate. The resulting precipitate was collected by filtration. The filtrate was extracted with ethyl acetate (2x). The extracts and the solid were combined and set aside. The aqueous layer was basified with IN NaOH to ~pH 11 and extracted with ethyl acetate (2x). The extracts were combined with the earlier organics and were washed with 0.5N HCI (3x), brine (lx), dried over sodium sulfate, concentrated to dryness and set aside. The acidic aqueous washings were basified with ION NaOH to ~pH 11 and extracted with ethyl acetate (3x). These extracts were washed with brine, dried over sodium sulfate and concentrated to dryness to yield recovered isoquinoline compound (140 mg, 0.46 mmol, 28%) as predominantly one enantiomer(~80ee approx). A portion of this crude residue (77 mg, 0.25 mmol) was reacted with m-toluenesulfonyl chloride (57 mg, 0.3 mmol), and N-methylmorpholine (0.036 mL, 0.33 mmol) in 5 mL dichloromethane at room temperature for I hour. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulfate and concentrated to dryness. The crude residue crystallized from ethyl acetate/t- butylmethyl ether. The crystalline product was titrated with ethyl acetate/t-butylmethyl ether/hexanes and collected by filtration to afford 33 mg of the title compound (29% yield).

Spectral analysis of the product was consistent with Compound 24: 1HNMR (CDC1₃): δ 7.21 - 7.09 (4H, m), 6.32 (IH, d, J = 2.3 Hz), 6.00 (IH, d, J = 2.3 Hz), 4.94 (IH, s), 4.73 - 4.68 (IH, m), 4.50 - 4.47 (2H, m), 3.84 (3H, s), 3.80 (3H, s), 2.50 (IH, dt, J = 12.9, 3.0 Hz), 2.23 (3H, s), 2.23 - 1.63 (8H, m). Elemental analysis for

calculated: C 63.14, H 6.18, N 6.14, S 7.02; found: C 62.92, H 6.20, N 6.07, S 6.94.

EXAMPLE 29A Synthesis of 9,13-Imino-8H-azocino [2,1-a] isoquinolin-8-one, 5,6,9,10,11,12,13,13a- octahvdro-6-methyl-14-[[4-(4-ρyridinyloxy phenyll sulfonyl1-,(6S,9S,13R,13aR^') (Compound 35)

This compound was prepared similar to Example 25 A, using Compound A (145 mg, 0.37 mmol), Palladium on Carbon (10%, 50 mg) in 5 mL ethyl acetate/ethanol, then 4'-pyridyloxy-4-phenylsulfonylchloride hydrochloride (100 mg, 0.33 mmol), and N-methylmorpholine (100 mg, 0.99 mmol) in 5 mL dichloromethane. Compound was purified by flash column chromatography (0-5% methanol in chloroform) to give 65 mg of the title compound (36% yield).

Spectral analysis of the product was consistent with Compound 35: 1H NMR (CDCI3): δ 8.54 (2H, d, J = 4.5 Hz), 7.32 - 7.19 (5H, m), 6.98 (IH, d, J = 7.5 Hz), 6.83 (2H, d, J = 6.2 Hz), 6.79 (2H, d, J = 8.9 Hz), 5.14 (IH, s), 5.07 - 5.02 (IH, m), 4.44 (IH, m), 4.38 (IH, m), 2.48 (IH, dd, J = 15.7, 6.3 Hz), 2.34 (IH, dd, J = 16.1,

3.2 Hz), 2.27 -1.60 (6H, m), 1.17 (3H, d, J = 7.4 Hz).

Elemental analysis for (C₂₇H₂₇N₃O₄S) calculated: C 66.24, H 5.56, N 8.58, S 6.55; found: C 66.05, H 5.81, N 8.34, S 6.44.

EXAMPLE 30A Synthesis of Compound 130

Compound 130

This compound was prepared according to Scheme A, using Compound L (0.100 g, 0.39 mmol) DMF (3.3 ml), 3-methyl sulfonyl chloride (0.16 g, 0.89 mmol), and ethyl diisopropyl amine (0.07 ml, 0.39 mmol). Filtration of the final precipitate gave very little product so the water layer was extracted with 3x10 ml CH₂Cl₂. The organics were combined, dried (MgSO ), filtered and concentrated onto silica and purified by MPLC (hexane/ethyl acetate gradient 90: 10 to 40:60). Concentration of the fractions containing the desired product gave 0.067 g of Compound 130 (42% yield). Spectral analysis of the product was consistent with Compound 130:

MS (APCI) m/z 411.2 (MM).

CHN for (C₂₃H₂₆N₃O₅SO.2C₄H₈O:0.25C₆H₁₈) calculated: C 67.29, H 6.38, N 6.82; found: C 67.97, H 6.62, N 5.88.

EXAMPLE 31A Synthesis of Compound 145

This compound prepared as described in Scheme A, using Compound A (0.100 g, 0.330 mmol) DMF (3 ml), phenylsulfonyl chloride (0.088 g, 0.496 mmol) and ethyl diisopropyl amine (0.064 ml, 0.496 mmol). Filtration of the final preciptate gave 0.133 g of compound 145 (91% yield).

Spectral analysis of the product was consistent with Compound 145: MS (APCI) m/z 443.2 (M⁺+l).

CHN for (C23H2.5N2O₅SO.i5 H₂O) calculated: C 62.05, H 5.95, N 6.29; found: C 62.02, H 6.06, N 6.19.

EXAMPLE 32A Synthesis of Compound 154

A mixture of Compound A (0.2 g, 0.73mmol), 1 -methyl- lH-imidazole-4- sulfonyl chloride (0.325 g, 1.8mmol) and potassium carbonate (0.255 g, 1.83mmol) in 25 mL of acetonitrile was stirred under N₂ for 15 hours. The sample was concentrated, then partitioned between EtOAc and sat. NaΗCO₃ solution. The organic extract was washed with brine solution, dried (MgSO₄), filtered and concentrated. The crude sample was chromatographed (MPLC, silica gel, 70% ethyl acetate and 5% methanol in hexanes) to give 0.2 g (66%) of the title compound as a white solid. M+l = 417.1; mp >230 °C.

Spectral analysis of the product was consistent with Compound 154: Calculated for C20H24N4O4S₁ (416.503): C, 57.68; H, 5.81; N, 13.45; S, 7.70; found: C, 57.35; H, 5.83; N, 13.19; S, 7.85.

EXAMPLE 33A Synthesis of Compound 155

Compound 155

This compound was prepared analogous to Compound 154, using appropriate starting materials. A cream solid was produced; melting point = 202-203 °C, M+1 = 419.1

Spectral analysis of the product was consistent with Compound 155: Calculated for C₂₀H₂₂N₂O₄S₂ (418.532): C, 57.22; H, 5.32; N, 6.67; S, 15.28; H₂O, 0.30, found: C, 56.83; H, 5.18; N, 6.43; S, 15.07; H₂O, 0.18.

EXAMPLE 34A Synthesis of Compound 156

This compound was prepared analogous to Compound 154, using appropriate starting materials. A cream solid was produced; mp 230-231 °C, M+1 = 414.1.

Spectral analysis of the product was consistent with Compound 156: Calculated for C₂oH22N₂O₄S₂ (413.496): C, 61.00; H, 5.61; N, 10.16; S, 7.75, found: C, 60.75; H, 5.78; N, 9.98; S, 7.88.

The sulfamides & sulfamates compounds of the present invention may be prepared in the manner depicted in Schemes B and C respectively below: Scheme B

wherein:

R' and R" are selected from hydrogen, substituted or unsubstituted alkyl, aryl, heteroaryl, or R' and R" together taken with an adjacent nitrogen atom form a substituted or unsubstituted heterocycle.

Scheme C

Sulfamoyl Chlorides wherein:

R is selected from hydrogen, substituted or unsubstituted alkyl and aryl.

The following examples are illustrative of the present invention:

EXAMPLE IB Synthesis of Sulfomoyl Chloride A

To a CH₂C1₂ solution (10 mL) of Compound B (1.1 g, 4.04 mmol) which was prepared according to a

published procedure (Katoh, S. and et al. WO 0004020) was added triethylamine (3 mL) and ClSO₃H (0.565 g, 4.85 mmol) slowly. The mixture was allowed to warm to about 25°C and stirred at that temperature for about 2 hours. The solution was then concentrated in vacuo after which benzene (2x20 mL) was added and evaporated to remove trace amount of Et₃N and water. Benzene (30 mL) and PC1₅ (1.26 g, 6.06 mmol) were added to the residue. The suspension was heated at reflux for about 30 minutes, then cooled to about 25°C and poured into an ice- cold NaOH solution (60 mL). The aqueous mixture was extracted with CH₂CI₂ (3x35 mL), dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography (35-50% EtOAc in hexanes) affording 1.25 g (83% yield) of the title compound as an off-white solid.

Spectral analysis of the product was consistent with sulfamoyl chloride A: 1H NMR (CDCI₃): δ 7.19 (IH, d, J = 8.7 Hz), 6.82 (IH, dd, J = 8.7, 2.8 Hz), 6.64 (IH, d, J = 8.6 Hz), 5.12 (IH, m), 4.84 (IH, m), 4.64 (IH, s), 4.58 (IH, m), 3.79 (3H, s), 3.16 - 2.95 (2H, m), 2.72 (IH, m), 2.35 (IH, m).

EXAMPLE 2B Synthesis of sulfamoyl chloride B

Sulfamoyl Chloride B Sulfamoyl Chloride C

Sulfamoyl chloride B was prepared from Compound C by a synthetic method analogous to sulfamoyl chloride A synthesis. The title compound was obtained in 35% yield which contains -25% (mol/mol) of inseparable chloride as a side product (sulfamoyl chloride C).

Spectral analysis of the product was consistent with sulfamoyl chloride B: 1H NMR (CDCI₃): δ 6.38 (IH, d, J = 2.1 Hz), 6.23 (IH, d, J = 2.3 Hz), 5.18 (IH, m), 4.99 (IH, m), 4.66 (IH, br s), 4.59 (IH, m), 3.85 (3H, s), 3.78 (3H, s), 3.63 (IH, m), 2.77 (IH, m), 2.56 (IH, d, J = 16.2 Hz).

EXAMPLE 3B Synthesis of sulfamoyl chloride D Sulfamoyl Chloride D

This compound was prepared from Compound D (Compound 6) by synthetic method analogous to sulfamoyl chloride A. synthesis. The title compound was obtained in 42% yield.

Spectral analysis of the product was consistent with sulfamoyl chloride D: 1H NMR (CDC1₃): δ 7.38 (IH, br d), 7.35 - 7.22 (2H, m), 7.14 (IH, br d), 5.23 (IH, br s), 5.03 (IH, s, J = 6.3 Hz), 4.58 (IH, br s), 4.54 (IH, s), 3.19 (IH, dd, J = 16.2, 6 Hz), 2.56 (IH, dd, J = 16.8, 5.4 Hz), 2.45 (IH, m), 2.25 (IH, m), 1.32 (3H, d, J = 6.6 Hz).

EXAMPLE 4B Synthesis of 9,13-Imino-6H-azocino [2,1-a] isoquinoline-14- sulfonamide,5, 8,9,10,11,12,13, 13a-octahvdro-3-methoxy-8-oxo-N-(3,4,5- trimethoxyphenyl) (Compound 28)

To a 3,5-lutidine solution (2 mL) of 3,4,5-trimethoxyaniline (150 mg, 0.82 mmol) was added sulfamoyl chloride A (200 mg, 0.54 mmol) in CH₂C1₂ (2 mL) at 25°C. After 20 hours, the mixture was diluted with CH₂C1₂ (50 mL) and washed with 5% HCI solution (ice-cold, 2x40 mL) and brine (1x50 mL). The solution was dried over MgSO and concentrated. The residue was purified by column chromatography (30-35% EtOAc in hexanes) to provide 190 mg (68% yield) of the title compound as a white solid.

Spectral analysis of the product was consistent Compound 28: 1HNMR (CDCI3): δ 7.09 (IH, d, J = 8.5 Hz), 6.73 (IH, dd, J = 8.6, 2.6 Hz), 6.49 (IH, d, J = 2.8 Hz), 6.12 (IH, br s), 5.94 (2H, s), 4.8 - 4.69 (2H, m), 4.50 (IH, br s), 4.44 (IH, m), 3.79 (3H, s), 3.76 (3H, s), 3.70 (6H, s), 2.85 (IH, td, J = 11.7, 4.0 Hz), 2.65 (IH, m), 2.51 (IH, dt, J = 16.0, 3.6 Hz), 2.17 (IH, m). MS (ESP) positive 518 (M+Na⁺) negative 516 (M-H^4").

EXAMPLE 5B Synthesis of 9,13-Imino-6H-azocino [2,1-a] isoquinoline-14-sulfonamide,N-(6-chloro- 3-pyridinyl)- 5, 8,9,10,11, 12,13, 13a-octahvdro-3-methoxy-8-oxo-(Compound 29)

To a 3,5-lutidine solution (2 mL) of 6-chloro-pyridin-3-ylamine (150 mg, 1.17 mmol) was added sulfamoyl chloride A (110 mg, 0.297 mmol) in CH₂C1₂ (2 mL) at 25°C. After 20 hours, the mixture was diluted with EtOAc (50 mL) and washed with concentrated CuSO₄ solution (2x40 mL). The solution was dried over Na₂SO₄ and concentrated. The residue was purified by column chromatography (35% EtOAc in hexanes) to provide 109.5 mg (80% yield) of the title compound as a white solid.

Spectral analysis of the product was consistent with Compound 29: 1H NMR (CDC1₃): δ 8.48 (IH, br s), 7.94 (1, d, J = 2.8 Hz), 7.20 (IH, dd, J = 8.7, 2.8 Hz), 7.10 (IH, d, J = 8.7 Hz), 6.92 (IH, d, I = 8.7 Hz), 6.75 (IH, dd, J = 8.7, 2.6 Hz), 6.57 (IH, d, J = 2.8 Hz), 4.73 - 4.85 (2H, m), 4.55 (IH, s), 4.36 (IH, m), 3.82 (3H, s), 2.96 - 2.76 (2H, m), 2.59 (IH, m).

HRMS (MALDI) calculated for C₂₁H₂ ClN₄O₄S (M+H^4") 463.1201; found 463.1184.

EXAMPLE 6B Synthesis of 9,13-Imino-6H-azocino [2,1-a] isoquinoline-14-sulfonamide, N-(3,4- difluorophenyl)- 5,8,9, 10, 11 , 12, 13, 13a-octahydro-3-methoxy-8-oxo(Compound 22)

This compound was prepared from sulfamoyl chloride A by a synthetic method analogous to Example 4B. A 49% yield was obtained.

Spectral analysis of the product was consistent with Compound 22:

1H NMR (CDC1₃): δ 7.13 (IH, d, J = 8.9 Hz), 6.86 (IH, t, J = 8.5 Hz), 6.81 - 6.74 (IH, m), 6.48 - 6.64 (4H, m), 4.86 - 4.74 (2H, m), 4.54 (IH, s), 4.36 (IH, s), 3.82 (3H, s), 2.98 - 2.75 (2H, m), 2.66 - 2.56 (IH, m), 2.11 - 2.26 (IH, m), 2.05 -1.75 (5H, m).

HRMS (MALDI) calculated for C₂₂H₂₃F₂N₃O₄SNa (M+Na⁺) 486.1270; found

486.1255.

EXAMPLE 7B

Synthesis of 9,13-Imino-8H-azocino [2,1-a] isoquinolin-8-one, 5,6,9,10,11,12,13,13a- octahydro-3-methoxy-14-(l-piperidinylsulfonyl)-(Compound 30)

Compound 30

This compound was prepared from sulfamoyl chloride A by a synthetic method analogous to Example 4B. A 59% yield was obtained. Spectral analysis of the product was consistent with Compound 30:

1H NMR (CDCI₃): δ 7.20 (IH, d, J = 8.9 Hz), 6.80 (IH, dd, J = 8.9, 2.6 Hz), 6.65 (IH, d, J = 2.8 Hz), 4.88 - 4.79 (IH, m), 4.71 (IH, m), 4.57 (IH, br s), 4.18 (IH, m), 3.78

(3H, s), 3.15 - 2.90 (2H, m), 2.81 - 2.64 (5H, m)

HRMS (MALDI) calculated for C₂ιH₃₀N₃O₄S (M+H⁴) 420.1952; found 420.1970. EXAMPLE 8B

Synthesis of 9,13-Imino-8H-azocino [2,1-a] isoquinolin-8-one, 5,6,9,10,11,12,13,13a- octahvdro-3-methoxy-14-(4-morpholinylsulfonyl)-(Compound 31)

This compound was prepared from sulfamoyl chloride A by a synthetic method analogous to Example 4B. A 59% yield was obtained.

Spectral analysis of the product was consistent with Compound 31: 1H NMR (CDC1₃): δ 7.20 (IH, d, J = 8.7 Hz), 6.81 (IH, dd, J = 8.7, 2.7 Hz), 6.66 (IH, d, J = 2.7 Hz), 4.90 - 4.80 (IH, m), 4.72 (IH, m), 4.59 (IH, br s), 4.22 (IH, m), 3.78 (3H, s), 3.38 (4H, m), 3.13 - 2.9 (2H, m), 2.8 - 2.65 (5H, m), 2.20 (IH, ). HRMS (MALDI) calculated for C₂₀H₂₈N₃O₅S (M+H⁴) 422.1744; found 422.1761.

EXAMPLE 9B Synthesis of 9,13-Imino-6H-azocino [2,1-a] isoquinoline-14-sulfanomide, 5,8,9,10,ll,12,13,13a-octahydro-3-methoxy-N-(6-methoxy-3-pyridinyl)-8-oxo- (Compound 32)

This compound was prepared from sulfamoyl chloride A by a synthetic method analogous to Example 4B. A 31% yield was obtained.

Spectral analysis of the product was consistent with Compound 32: 1H NMR (CDCI₃): δ 7.28 (IH, s), 7.06-7.14 (2H, m), 6.72 (IH, dd, I = 8.7, 2.6 Hz), 6.58 (IH, d, J = 2.8 Hz), 6.38 (IH, d, J = 8.5 Hz), 6.32 (IH, s), 4.85-4.80 (IH, m), 4.79 - 4.72 (IH, m), 4.51 (IH, s), 4.36 (IH, s), 3.88 (3H, s), 3.82 (3H, s), 3.03-2.87 (2H, m), 2.69 -2.57 (IH, m), 2.23 - 2.09 (IH, m), 2.08 - 1.99 (2H, m), 1.97 - 1.77 (3H, m). HRMS (MALDI) calculated for C₂₂H₂₇N₄O₅S (M+H^4") 459.1697; found 459.1701.

EXAMPLE 10B Synthesis of 9,13-Imino-8H-azocino [2,1-a] isoquinolin-8-one, 14-[(cis-2,6-dimethyl-4- morpholinyl)sulfonvn-5,6,9,10,ll, 12,13, 13a-octahydro-3-methoxy-(Compound 33)

Compound 33

This compound was prepared from sulfamoyl chloride A by a synthetic method analogous to Example 4B. A 96% yield was obtained.

Spectral analysis of the product was consistent with Compound 33:

1H NMR (CDCI₃): δ 7.45 (IH, d, J=8.9 Hz), 7.05 (IH, dd, J = 8.6, 2.6 Hz), 6.91 (IH, d,

J = 2.6 Hz), 5.17 - 5.08 (IH, m), 4.97 (IH, br s), 4.84 (IH, s), 4.43 (IH, br s), 4.02 (3H, s), 3.54 - 3.66 (IH, m), 3.46 - 3.06 (5H, m), 2.99-2.90 (IH, m), 2.53 - 2.02 (8H, m),

1.22 (3H, d, J = 6.4 Hz), 1.13 (3H, d, I = 6.4 Hz).

MS (ESP) 450 (M+H^4").

Elemental analysis for (C₂₂H₃₁N₃O₅S) calculated: C 58.78, H 6.95, N 9.35; found C

58.92, H 7.00, N 9.22. EXAMPLE 11B

Synthesis of 9,13-Imino-6H-azocino [2,1-a] isoquinoline-14-sulfonamide, N-(3,4- difluorophenvD-5,8,9, 10,11, 12,13, 13a-octahydro-l,3-dimethoxy-8-oxo-(Compound 34)

This compound was prepared from sulfamoyl chloride B (containing 25% mol/mol sulfamoyl chloride C) by a synthetic method analogous to Example 4B. A 53% yield was obtained.

Spectral analysis of the product was consistent with Compound 34: 1H NMR (CDCI₃): δ 7.91 (IH, br s), 6.94 (IH, q, d = 8.7 Hz), 6.81 (IH, m), 6.70 (IH, m), 6.34 (IH, d, J = 2.3 Hz), 6.17 (IH, d< J=2.4 Hz), 4.9-4.75 (2H, m), 4.59 (IH, br s), 4.34 (IH, m), 3.84 (3H, s), 3.78 (3H, s), 2.84 - 2.59 (2H, m), 2.42 (IH, d, J = 15.6 Hz). HRMS (MALDI) calculated for C₂₃H₂₆F₂N₃O₅S (M+H⁴) 494.1556; found 494.1575.

EXAMPLE 12B Synthesis of 9,13-Imino-6H-azocino [2,1-a] isoquinoline-14-sulfonamide, 5, 8, 9.10,11, 12, 13, 13a-octahvdro-3-methoxy-8-oxo-N- (2,3 ,4-trifluorophenyl -(Compound 45)

This compound was prepared from sulfamoyl chloride A by a synthetic method analogous to Example 4B. A 51% yield was obtained.

Spectral analysis of the product was consistent with Compound 45: 1H NMR (CDC1₃): δ 6.97 (IH, d, J = 9.4 Hz), 6.65 - 6.47 (3H, m), 6.43 (IH, d, J = 2.6 Hz), 6.18 (IH, s), 4.77 - 4.64 (2H, m), 4.44 (IH, s), 4.37 (IH, s), 3.72 (3H, s), 2.86 - 2.63 (2H, m), 2.54 - 2.44 (IH, m), 2.22 - 2.08 (IH, m), 2.02 - 1.93 (2H, m), 1.89 - 1.7 (3H, m).

MS (ESP) 482 (M+H^4").

Elemental analysis for (C₂₂H₂₂F₃N₃O₄S 0.35H2O) calculated: C 54.17, H 4.69, N 8.61; found: C 54.40, H 4.89, N 8.22.

EXAMPLE 13B Synthesis of 9,13-Imino~6H-azocino T2,l-a] isoquinoline-14-sulfonamide, 5, 8,9,10,11, 12,13, 13a-octahydro-3-methoxy-8-oxo-N-(3,4,5-trifluorophenyl)-

(Compound 46)

This compound was prepared from sulfamoyl chloride A by a synthetic method analogous to Example 4B. A 58% yield was obtained.

Spectral analysis of the product was consistent with Compound 46:

1H NMR (CDCI₃): δ 7.23 (IH, s), 6.93 (IH, d, J = 8.7 Hz), 6.59 (IH, dd, J = 8.9, 2.6

Hz), 6.42 (IH, d, I = 2.8 Hz), 6.31 (2H, dd, J = 8.9, 5.8 Hz), 4.67 - 4.58 (2H, m), 4.38

(IH, s), 4.17 (IH, s), 3.63 (3H, s), 2.81 - 2.64 (2H, m), 2.52 - 2.39 (IH, m), 2.05 - 1.89

(lH, m), 1.88 - 1.55 (5H, m). MS (ESP) 482 (M+H⁴).

Elemental analysis for (C₂₂H₂₂F₃N₃O₄S) calculated: C 54.88, H 4.61, N 8.73; found C

54.93, H 4.64, N 8.56.

EXAMPLE 14B

Synthesis of 9,13-Imino-6H-azocino [2,1-a] isoquinoline-14-sulfonamide, 5.8.9.10.11.12.13.13a-octahvdro-3-methoxy-8-oxo-N-(2.4,5-trifluorophenvD-

(Compound 53)

This compound was prepared from sulfamoyl chloride A by a synthetic method analogous to Example 4B. A 42% yield was obtained. Spectral analysis of the product was consistent with Compound 53:

1H NMR (CDC1₃): δ 7.06 (IH, d, J = 8.3 Hz), 6.84 - 6.65 (3H, m), 6.52 (IH, d, J = 2.6

Hz), 6.25 (IH, s), 4.85 - 4.74 (2H, m), 4.53 (IH, s), 4.40 (IH, s), 3.78 (3H, s), 2.96 -

2.80 (2H, m), 2.66 - 2.55 (IH, m), 2.30 - 2.15 (IH, m), 2.09 - 2.0 (2H, m), 1.97 - 1.80

(3H, m). MS (ESP) 482 (M+H^4").

Elemental analysis for (C₂₂H₂2F₃N₃O₄S) calculated: C 54.88, H 4.61, N 8.73; found C

54.71, H 4.73, N 8.54.

EXAMPLE 15B

Synthesis of 9.13-Imino-6H-azocino [2,1-a] isoquinoline-14-sulfonamide, 5,8,9,10,11, 12,13,13a-octahvdro-3-methoxy-N-[6-(4-morpholinylV3-pyridinyl1-8-oxo-

(Compound 54)

This compound was prepared from sulfamoyl chloride A by a synthetic method analogous to Example 5B. A 50% yield was obtained.

Spectral analysis of the product was consistent with Compound 54:

1H NMR (CDC1₃): δ 7.67 (IH, d, J = 2.4 Hz), 7.14 (IH, d, J = 9.2 Hz), 7.09 (IH, dd, J = 8.9, 3.2 Hz), 6.75 (IH, dd, J = 8.7, 2.3 Hz), 6.60 (IH, d, J = 2.6 Hz), 6.29 (IH, d, J =

8.9 Hz), 4.87 - 4.82 (IH, m), 4.80 - 4.73 (IH, m), 4.53 (IH, s), 4.36 (IH, br s), 3.83

(4H, t, J = 4.9 Hz), 3.81 (3H, s), 3.45 (4H, t, J = 5.1 Hz), 3.04 - 2.89 (2H, m), 2.71 -

2.59 (IH, m), 2.25 - 2.10 (IH, m), 2.09 - 1.79 (6H, m).

MS (ESP) 514 (M+H^4"). Elemental analysis for (C₂₅H₃₁N₅O₅S) calculated: C 58.21, H 6.28, N 12.76; found C

58.22, H 6.26, N 12.67.

EXAMPLE 16B

Synthesis of 9,13-Imino-8H-azocino [2,1-a] isoquinolin-8-one, 14-[(cis-2,6-dimethyl-4- morpholinyl) sulfonyl]-5,6,9,10,ll, 12,13, 13a-octahydro-l,3-dimethoxy- (Compound 61) and 9,13-Imino-8H-azocino [2,l-a]isoqumolin-8-one,14-[(cis-2,6-dimethyl-4- morphoiinvDsulf onyl] -5,6,9,10,11,12,13,13 a-octahydro- 1 ,3-dimethoxy-4-chloro-

(Compound 62)

Compound 62

These compounds were prepared from sulfamoyl chloride B (containing 25% mol/mol sulfamoyl chloride C) by a synthetic method analogous to Example 4B. Three fractions were collected from flash column chromatography (3.5% THF in CH₂C1₂): 30 mg of Compound 62, 70 mg of Compound 61and 180 mg mixture of Compound 62 and

Compound 61 (1:4).

Spectral analysis of the product was consistent with Compound 61:

R_f = 0.25 (3% THF in CH₂C1₂). 1H NMR (CDC1₃): δ 6.36 (IH, d, I = 2.4 Hz), 6.27 (IH, d, J = 2.3 Hz), 4.95 (IH, m),

4.67 (IH, m), 4.62 IH, br s), 4.23 (IH, m), 3.84 (3H, s), 3.77 (3H, s), 3.22 - 3.07 (2H, m), 3.05 - 2.9 (2H, m), 2.72 (IH, td, I = 12.4, 2.6 Hz), 2.58 (IH, d, J = 16 Hz), 1.06

(3H, d, J = 6.2 Hz), 0.94 (3H, d, J = 6.2 Hz).

HRMS (MALDI) calculated for C₂₃H₃₄N₃O₆S (M+H⁴) 480.2163; found 480.2174. Spectral analysis of the product was consistent with Compound 62:

R_f = 0.27 (3% THF in CH₂C1₂).

1HNMR (CDC13): d 6.47 (IH, s), 5.00 (IH, m), 4.63 (2H, s), 4.20 (IH, m), 3.91 (3H, s), 3.90 (3H, s), 3.38 (IH, m), 3.22 - 3.09 (2H, m), 3.01 (IH, dt, I = 11.9, 2.3 Hz), 2.94

- 2.60 (3H, m). LCMS: 515 (M+H^4"). The structure shown was confirmed by single crystal X-ray analysis.

EXAMPLE 17B

Synthesis of 9, 13-Imino-6H-azocino[2, 1 -a]isoquinoline- 14-sulf onamide,N-(pyrrol- 1 - yl)-5,8,9, 10,11 , 12, 13 ,13a-octahvdro-3-methoxy-8-oxo-(Compound 66)

This compound was prepared from sulfamoyl chloride A by a synthetic method analogous to Example 4B. An 80% yield was obtained.

Spectral analysis of the product was consistent with Compound 66: 1H NMR (CDCI₃): δ 7.10 (IH, d, J = 9 Hz), 6.75 (IH, dd, J = 9, 3 Hz), 6.64 (IH, d, J = 3.1 Hz), 6.38 (2H, t, J = 2.1 Hz), 5.87 (2H, t, I = 2.1 Hz), 4.81 - 4.71 (2H, m), 4.54 (IH, s), 4.26 (IH, m), 3.79 (3H, s), 3.15 - 2.92 (2H, m), 2.67 (IH, m). LCMS 417 (M+H^4"). EXAMPLE 18B

Synthesis of 9,13-lmino-6H-azocino[2,l-a]isoquinoline-14- sulfonamide,5, 8,9, 10,11, 12,13, 13a-octahydro-3-methoxy-8-oxo-(Compound 65)

Compound 65

This compound was prepared from sulfamoyl chloride A by a synthetic method analogous to Example 4B. A 55% yield was obtained.

Spectral analysis of the product was consistent with Compound 65: 1H NMR (CDC1₃): δ 7.28 (IH, d, I = 9 Hz), 6.84 (IH, dd, = 9, 2.8 Hz), 6.66 (IH, d, J = 2.9 Hz), 4.91 - 4.79 (2H, m), 4.59 (IH, s), 4.31 (IH, m), 4.18 (2H, br s), 3.79 (3H, s), 3.10 (IH, m), 2.96 (IH, td, J = 12, 3 Hz), 2.71 (IH, dt, J = 15, 3 Hz), 2.18 (IH, m). LCMS 352 (M+H⁴).

EXAMPLE 19B Synthesis of 9,13-lmino-6H-azocino[2,l-a1isoquinoline-14-sulfonamide,N-(6-fluoro-3- pyridinyl)-5,8,9,10,ll, 12,13, 13a-octahydro-3-methoxy-8-oxo-(Compound 118)

This compound was prepared from sulfamoyl chloride A by a synthetic method analogous to Example 5B. A 68% yield was obtained.

Spectral analysis of the product was consistent with Compound 118: 1H NMR (CDC1₃): δ 7.63 (IH, br s), 7.38 - 7.30 (2H, m), 7.08 (IH, d, J = 8.7 Hz), 6.74 (IH, m), 6.61 - 6.52 (2H, m), 4.84 - 4.72 (2H, m), 4.53 (IH, s), 4.36 (IH, br s), 3.81 (3H, s), 2.98 - 2.80 (2H, m), 2.67 - 2.53 (IH, m), 2.12 (IH, m). LCMS 447 (M+H^4").

Elemental analysis for (C₂₁H₂₃FN₄O₄S) calculated: C 56.49, H 5.19, N 12.55; found C 56.72, H 5.38, N 12.30. EXAMPLE 20B

Synthesis of 9,13-lmino-6H-azocino[2,l-a1isoquinoline-14-sulfonamide,N-(3- pyridinyD-5,8,9,10,11, 12,13, 13a-octahydro-3-methoxy-8-oxo-(Compoundl 19)

This compound was prepared from sulfamoyl chloride A by a synthetic method analogous to Example 5B. A 7% yield was obtained.

Spectral analysis of the product was consistent with Compound 119: 1H NMR (CDCI₃): δ 8.19 (IH, br s), 8.08 (IH, br s), 7.29 (IH, d), 7.15 (IH, d, J = 9.3 Hz), 7.03 (IH, m), 6.75 (IH, dd, J = 9, 3 Hz), 6.53 (IH, d, J = 3 Hz), 4.87 - 4.74 (2H, m), 4.57 (IH, s), 4.40 (IH, m), 3.79 (3H, s), 2.96 - 2.74 (2H, m), 2.59 (IH, m), 2.17 (IH, m).

LCMS 429 (M+H^4").

EXAMPLE 21B

Synthesis of (Compound 120)

This compound was prepared from sulfamoyl chloride D by a synthetic method analogous to Example 5B. A 72% yield was obtained.

Spectral analysis of the product was consistent with Compound 120:

1H NMR (CDCI₃): δ 8.09 (IH, s), 7.73 (IH, s), 7.30 (IH, m), 7.24 - 7.08 (3H, m), 7.04

(IH, d, J = 8.1 Hz), 6.46 (IH, dd, I = 9.3, 3.9 Hz), 4.99 - 4.85 (2H, m), 4.46 - 4.38 (2H, m), 2.92 (IH, dd, J = 16.5, 6 Hz), 2.41 (IH, dd, J = 16.5, 4.5 Hz), 1.23 (3H, d, I = 6.6

Hz).

HRMS calculated for C₂₁H₂₄FN O₃S (M+H⁴) 431.1553; 431.1554 EXAMPLE 1C

Synthesis of 9,13-lmino-6H-azocino[2,l-a]isoquinoline-14-sulfate,O-phenyl- 5,8,9,10,11, 12,13, 13a-octahydro-3-methoxy-8-oxo-(Compound 67)

To an ethylene glycol dimethyl ether solution (2.5 mL) of phenol (160 mg, 1.68 mmol) was added NaH (90% pure, 30 mg, 1.17 mmol) at 25°C. The solution was stirred for 2 minutes, after which sulfamide A (101 mg, 0.272 mmol) was added in one portion. The mixture was heated at 70°C for 4 hours, diluted with CH₂CI₂ (25 mL) and washed with ice-cold saturated Na₂CO₃ solution (3x30 mL). The solution was then dried over MgSO₄ and concentrated. The residue was purified by flash column chromatography (35% EtOAc in hexanes) to afford 95 mg (81% yield) of the title compound.

Spectral analysis of the product was consistent with Compound 67: 1H NMR (CDCI₃): δ 7.21-7.1 (4H, m), 6.81 (IH, dd, J = 9.3 Hz), 6.73 - 6.69 (2H, m), 4.62 (IH, s), 4.43 (IH, m), 3.78 (3H, s), 3.03 - 2.82 (2H, m), 2.61 (IH, m), 2.23 (IH, m). LCMS 429 (M+H⁴).

EXAMPLE 2C Synthesis of 9,13-Imino-6H-azocino[2,l-a]isoquinoline-14-sulfate,O-(2-propyl)- 5,8,9,10,11.12,13, 13a-octahvdro-3-methoxy-8-oxo-(Comρound 68)

Compound 68

This compound was prepared from sulfamoyl chloride A by a synthetic method analogous to Example lC. A 61% yield was obtained.

Spectral analysis of the product was consistent with Compound 68: 1H NMR (CDCI3): δ 7.22 (IH, d, J = 9 Hz), 6.80 (IH, dd, J = 9, 3 Hz), 6.65 (IH, d, J = 3 Hz), 4.88 - 4.74 (2H, ), 4.57 (IH, s), 4.37 - 4.21 (2H, m), 3.79 (3H, s), 3.13 - 2.93 (2H, m), 2.70 (IH, m), 2.19 (IH, m), 1.09 (3H, d, J = 6.3 Hz), 0.92 (3H, d, J = 6.3 Hz). LCMS 395 (M+H^4").

The ureas compounds of the present invention may be prepared in the manner depicted in Scheme D below:

Scheme D

wherein: R_c is selected from hydrogen, substituted or unsubstituted aryl, alkyl, heteroaryl or heterocycloalkyl.

The following examples are illustrative of the present invention:

EXAMPLE ID Synthesis of 9,13-Imino-6H-azocino [2,1-a] isoquinoline-14-carboxamide, N-ethyl-5, 8,9, 10, 11 ,12,13, 13a-octahvdro-4-methoxy-8-oxo-(Comρound 69)

Compound 69

The amine (Compound A, 0.0311 g, 0.114 mmol), which was synthesized according to a published procedure (Katoh, S. and et al. WO 0004020), was dissolved in DMF (0.5 mL). Ethyl isocyanate (0.009 mL, 0.114 mmol) was added to the solution. The mixture was stirred at room temperature for 12 hours with product formation monitored by TLC and/or mass spectrum. Upon completion of the reaction as judged by disappearance of the starting compound, the reaction mixture was added to 5 mL brine with stirring. Filtration of the precipitate gave 0.009 g of Compound 69 (22% yield).

Spectral analysis of the product was consistent with Compound 69: MS (APCI) 344.1 (M+H⁴).

Elemental analysis for (C₁₉H₂₅N₃O₃.1.35H₂O) calculated: C 62.06, H 7.59, N 11.43; found: C 61.69, H 7.17, N 11.62.

EXAMPLE 2D Synthesis of 9,13-Imino-6H-azocino [2,1-a] isoquinoline-14-carboxamide,N-ethyl- 5.8,9,10,11, 12,13,13a-octahydro-3-methoxy-8-oxo-(Comρound 70)

This compound was prepared similar to Example ID, using Compound B (0.0313 g, 0.114 mmol, synthesized according to a published procedure [Katoh, S. and et al. WO 00/04020]), DMF (0.5 mL), ethyl isocyanate (0.010 mL, 0.114 mmol). Filtration of the final precipitate gave 0.0174 g of Compound 70 (44% yield).

Spectral analysis of the product was consistent with Compound 70: MS (APCI) 344.1 (M+H⁴).

Elemental analysis for (C₁₉H₂₅N₃O₃ 0.4H₂O 0.15C₃H₇NO) calculated: C 64.61, H 7.48, N 12.20; found: C 64.36, H 7.11, N 11.83.

EXAMPLE 3D Synthesis of 9,13-Imino-6H-azocino [2,1-a] isoquinoline-14-carboxamide, 5,8,9,10,11, 12.13,13a-octahvdro-3-methoxy-N-(2-methylρhenyl^')- 8-oxo-(Compound 71) Compound 71

This compound was prepared similar to Example ID, using Compound B (0.0549 g, 0.2017 mmol), DMF (1.0 mL), 2-methylphenyl isocyanate (0.062 mL, 0.504 mmol). The reaction was quenched with 3 mL 1.0 M HCI, and the solution was extracted with 3x5 mL CH₂CI₂. The organic layers were combined, dried over MgSO₄, filtered and concentrated onto silica. The crude material was purified by MPLC (hexane/ethyl acetate gradient 90: 10 to 40:60). Concentration of the fractions containing the desired product gave 0.0369 g of Compound 71 (45% yield).

Spectral analysis of the product was consistent with Compound 71: MS (APCI) 406.3 (M+H⁺).

Elemental analysis for (C₂ H2₇N3O₃ 0.15CH₃OH 0.45C₄H₈O₂) calculated: C 69.27, H 6.99, N 9.34; found: C 69.02, H 6.76, N 9.63.

EXAMPLE 4D Synthesis of 9,13-Imino-6H-azocino [2,1-a] isoquinoline-14-carboxamide, 5,8,9,10,11, 12,13, 13a-octahydro-4-methoxy-N-(4-methylphenyl)- 8-oxo-(Compound 72)

This compound was prepared similar to Example ID, using Compound A (0.0705 g, 0.2509 mmol), DMF (1.0 mL), 4-methylphenyl isocyanate (0.065 mL, 0.518 mmol). After stirring for 12 hours at room temperature, an additional 0.065 mL isocyanate was added and stirring was continued for 48 hours. The reaction was quenched with 3 mL 1.0 M HCI, and the solution was extracted with 3x5 mL CH₂CI₂.

The organic layers were combined, dried over MgSO₄, filtered and concentrated onto silica. The crude material was purified by MPLC (hexane/ethyl acetate gradient 90:10 to 40:60). Concentration of the fractions containing the desired product gave 0.0354 g of Compound 72 (35% yield). Spectral analysis of the product was consistent with Compound 72:

MS (APCI) 406.1 (M+H^4").

Elemental analysis for (C₂₄H₂₇N₃O₃ 0.15C₆H₁₄ 0.30C₄H₈O₂) calculated: C 70.47, H

7.17, N 9.45; found: C 70.54, H 7.02, N 9.30.

EXAMPLE 5D Synthesis of 9,13-Imino-6H-azocino T2,l-a1 isoquinoline-14-carboxamide,

5,8,9,10,11, 12,13, 13a-octahvdro-3-methoxy-N-(4-methylphenyl)-8-oxo-(Compound

73)

This compound was prepared similar to Example ID, using Compound B

(0.0912 g, 0.335 mmol), DMF (1.0 mL), 4-methylphenyl isocyanate (0.0842 mL, 0.670 mmol). After stirring for 12 hours at room temperature, an additional 0.080 mL isocyanate was added and stirring was continued for 48 hours. The reaction was quenched with 3 mL 1.0 M HCI, and the solution was extracted with 3x5 mL CH₂CI₂. The organic layers were combined, dried over MgSO , filtered and concentrated onto silica. The crude material was purified by MPLC (hexane/ethyl acetate gradient 90:10 to 40:60). Concentration of the fractions containing the desired product gave 0.0635 g of Compound 73 (47% yield).

Spectral analysis of the product was consistent with Compound 73: MS (APCI) 406.1 (M+H^4"). Elemental analysis for (C₂₄H₂₇N₃O₃ O.3OG₁H₈O₂) calculated: C 70.08, H 6.86, N 9.73; found: C 70.04, H 7.00, N 10.01.

EXAMPLE 6D Synthesis of 9,13-Imino-6H-azocino [2,1-al isoquinoline-14-carboxamide, N-(2,4- difluorophenyl)- 5, 8,9,10,11, 12,13, 13 a-octahydro- 4-methoxy- 8-oxo-(Compound 74)

This compound was prepared similar to Example ID, using Compound A (0.0912 g, 0.335 mmol), DMF (1.0 mL), 2,4-difluorophenyl isocyanate (0.0796 mL, 0.670 mmol). After stirring for 12 hours at room temperature, an additional 0.07 mL isocyanate was added and stirring was continued for 48 hours. The reaction was quenched with 3 mL 1.0 M HCI, and the solution was extracted with 3x5 mL CH₂CI₂. The organic layers were combined, dried over MgSO₄, filtered and concentrated onto silica. The crude material was purified by MPLC (hexane/ethyl acetate gradient 90:10 to 40:60). Concentration of the fractions containing the desired product gave 0.0464 g of Compound 74 (32% yield).

Spectral analysis of the product was consistent with Compound 74: MS (APCI) 428.1 (M+H⁴).

Elemental analysis for (C₂₃H₂₃F₂N₃O₃ 0.450^0^ calculated: C 63.77, H 5.74, N 9.00; found: C 63.60, H 5.4, N 9.1.

EXAMPLE 7D Synthesis of 9,13-Imino-6H-azocino [2,1-a] isoquinoline-14-carboxamide, 5,8,9,10,11, 12,13, 13a-octahvdro-4-methoxy-8-oxo-N-phenyl-(Compound 75) Compound 75

This compound was prepared similar to Example ID, using Compound A (0.0573 g, 0.210 mmol), DMF (1.0 mL), phenyl isocyanate (1.2 mL, 1.1 mmol). The reaction was quenched with 3 mL 1.0 M HCI, and the solution was extracted with 3x5 mL CH₂C1₂. The organic layers were combined, dried over MgSO₄, filtered and concentrated onto silica. The crude material was purified by MPLC (hexane/ethyl acetate gradient 90:10 to 40:60). Concentration of the fractions containing the desired product gave 0.0222 g of Compound 75 (27% yield).

Spectral analysis of the product was consistent with Compound 75: MS (APCI) 392.3 (M+H⁴).

Elemental analysis for (C23H25N3O3 0.15C_jH8O₂ 0.4C₆H₁₄) calculated: C 71.11, H 7.30, N 9.57; found: C 71.28, H 7.20, N 9.24.

EXAMPLE 8D Synthesis of 9,13-Imino-6H-azocino [2,1-a] isoquinoline-14-carboxamide, 5,8,9,10,11, 12,13, 13a-octahydro-3-methoxy-8-oxo-N-phenyl-(Compound 76)

This compound was prepared similar to Example ID, using Compound B (0.0576 g, 0.211 mmol), DMF (1.0 mL), phenyl isocyanate (O.lmL, 0.920 mmol). The reaction was quenched with 3 mL 1.0 M HCI, and the solution was extracted with 3x5 mL CH2C1₂. The organic layers were combined, dried over MgSO , filtered and concentrated onto silica. The crude material was purified by MPLC (hexane/ethyl acetate gradient 90:10 to 40:60). Concentration of the fractions containing the desired product gave 0.0864 g of Compound 76 (100% yield).

Spectral analysis of the product was consistent with Compound 76: MS (APCI) 392.3 (M+H^4"). Elemental analysis for (C₂₃H₂₅N₃O₃ 0.35C₄H₈O₂) calculated: C 69.40, H 6.64, N 9.95; found: C 69.15, H 6.75, N 10.22.

EXAMPLE 9D Synthesis of 9,13-Imino-6H-azocino [2,1-a] isoquinoline-14-carboxamide, N-(2,6- dimethylphen yl)-5 ,8,9,10,11,12,13,13 a-octahydro-3 -methoxy-8 -oxo-(Comρound 77)

This compound was prepared similar to Example ID, using Compound B (0.0569 g, 0.201 mmol), DMF (1.0 mL), 2,6-dimethylphenyl isocyanate (0.09 mL, 0.646 mmol). The reaction was quenched with 3 mL 1.0 M HCI, and the solution was extracted with 3x5 mL CH₂CI₂. The organic layers were combined, dried over MgSO₄, filtered and concentrated onto silica. The crude material was purified by MPLC (hexane/ethyl acetate gradient 90: 10 to 40:60). Concentration of the fractions containing the desired product gave 0.100 g of Compound 77 (100% yield). Spectral analysis of the product was consistent with Compound 77: MS (APCI) 420.3 (M+H*). Elemental analysis for (C₂₅H₂₉N₃O₃) calculated: C 71.57, H 6.97, N 10.02; found: C 71.31, H 7.21, N 9.66.

EXAMPLE 10D Synthesis of 9,13-Imino-6H-azocino [2,1-a] isoquinoline-14- carboxamide,5,8,9, 10, 11 , 12, 13.13a-octahvdro-3-methoxy-N-(3-methoxyphenyl)-8-oxo- (Compound 78)

This compound was prepared similar to Example ID, using Compound B (0.0829 g, 0.304 mmol), DMF (1.0 mL), 2-methoxyphenyl isocyanate (0.079 mL, 0.609 mmol). The reaction was quenched with 3 mL 1.0 M HCI, and the solution was extracted with 3x5 mL CH₂θ₂. The organic layers were combined, dried over MgSO₄, filtered and concentrated onto silica. The crude material was purified by MPLC (hexane/ethyl acetate gradient 90:10 to 40:60). Concentration of the fractions containing the desired product gave 0.1138 g of Compound 78 (89% yield).

Spectral analysis of the product was consistent with Compound 78: MS (APCI) 422.2 (M+H⁺).

Elemental analysis for (C₂₄H₂₇N₃O₄0.15CH₂C1₂) calculated: C 66.80, H 6.34, N 9.68; found: C 67.15, H 6.60, N 9.42.

EXAMPLE 11D Synthesis of 9,13-Imino-6H-azocino [2,1-a] isoquinoline-14-carboxamide,5, 8,9, 10, 11 , 12, 13, 13a-octahvdro-l ,3-dimethoxy-N-(3-methoxyphenylV 8-oxo- (Compound 79)

This compound was prepared similar to Example ID, using Compound C (0.0867 g, 0.286 mmol), DMF (1.0 mL), 3-methoxyphenyl isocyanate (0.074 mL, 0.573 mmol). The reaction was quenched with 3 mL 1.0 M HCI, and the solution was extracted with 3x5 mL CH₂C1₂. The organic layers were combined, dried over MgSO₄, filtered and concentrated onto silica. The crude material was purified by MPLC (hexane/ethyl acetate gradient 90:10 to 40:60). Concentration of the fractions containing the desired product gave 0.0418 g of Compound 79 (32% yield). Spectral analysis of the product was consistent with Compound 79: MS (APCI) 452.2 (M+H⁺).

Elemental analysis for (C₂₅H₂₉N₃O₅

calculated: C 66.16, H 6.55, N 9.04; found: C 66.34, H 6.58, N 8.76.

EXAMPLE 12D Synthesis of 9,13-Imino-6H-azocino [2,1-a] isoquinoline-14-carboxamide, 5,8,9,10,11,12,13,13 a-octahydro-4-methoxy-8 -oxo-N-(phenylmethyl)-(Compound 80)

This compound was prepared similar to Example ID, using Compound A (0.0893 g, 0.328 mmol), DMF (1.0 mL), benzyl isocyanate (0.0804 mL, 0.656 mmol). The reaction was quenched with 3 mL 1.0 M HCI, and the solution was extracted with 3x5 mL CH₂CI₂. The organic layers were combined, dried over MgSO₄, filtered and concentrated onto silica. The crude material was purified by MPLC (hexane/ethyl acetate gradient 90:10 to 40:60). Concentration of the fractions containing the desired product gave 0.085 g of Compound 80 (64% yield).

Spectral analysis of the product was consistent with Compound 80: MS (APCI) 406.1 (M+H⁴).

Elemental analysis for (C₂₄H₂₇N₃O₃ 0.15C₄H₈O₂) calculated: C 70.57, H 6.79, N 10.04; found: C 70.33, H 6.87, N 9.94.

EXAMPLE 13D Synthesis of 9,13-Imino-6H-azocino [2,1-a] isoquinoline-14-carboxamide, 5,8.9.10.11,12,13,13a-octahvdiO-3-methoxy-8-oxo-N-(phenylmethvD-(Compound 81) O 02/089

This compound was prepared similar to Example ID, using Compound B (0.0818 g, 0.300 mmol), DMF (1.0 mL), benzyl isocyanate (0.0737 mL, 0.601 mmol). The reaction was quenched with 3 mL 1.0 M HCI, and the solution was extracted with 3x5 mL CH₂CI₂. The organic layers were combined, dried over MgSO , filtered and concentrated onto silica. The crude material was purified by MPLC (hexane/ethyl acetate gradient 90: 10 to 40:60). Concentration of the fractions containing the desired product gave 0.0676 g of Compound 81 (56% yield).

Spectral analysis of the product was consistent with Compound 81: MS (APCI) 406.1 (M+H*).

Elemental analysis for (C₂₄H₂₇N₃O₃ 0.3C₄H₈O₂) calculated: C 70.08, H 6.86, N 9.73; found: C 70.06, H 6.85, N 9.87.

EXAMPLE 14D Synthesis of 9,13-Lmino-6H-azocino [2,1-al isoquinoline-14-carboxamide, 5,8,9,10,11, 12,13, 13 a-octahydro- 1, 3-dimethoxy-8-oxo-N-(phenylmethyl)-(Compound 82)

This compound was prepared similar to Example ID, using Compound C (0.0822 g, 0.272 mmol), DMF (1.0 mL), benzyl isocyanate (0.0667 mL, 0.544 mmol). The reaction was quenched with 3 mL 1.0 M HCI, and the solution was extracted with 3x5 mL CH2CI2. The organic layers were combined, dried over MgSO₄, filtered and concentrated onto silica. The crude material was purified by MPLC (hexane/ethyl acetate gradient 90:10 to 40:60). Concentration of the fractions containing the desired product gave 0.085 g of Compound 82 (72% yield).

Spectral analysis of the product was consistent with Compound 82: MS (APCI) 436.2 (M+H⁺).

Elemental analysis for (C₂₅H₂₉N₃O₄ O.3C₄H₈O₂) calculated: C 68.12, H 6.85, N 9.10; found: C 68.01, H 6.69, N 9.25.

EXAMPLE 15D Synthesis of 9,13-Imino-6H-azocino [2,1-a] isoquinoline-14-carboxamide, 5,8,9,10,11, 12,13,13a-octahvdro-4-methoxy-N-(4-nitrophenyl)-8-oxo-(Compound 83)

This compound was prepared similar to Example ID, using Compound A (0.0823 g, 0.302 mmol), DMF (1.0 mL), 4-nitrophenyl isocyanate (0.1093 g, 0.604 mmol). The reaction was quenched with 3 mL 1.0 M HCI, and the solution was extracted with 3x5 mL CH₂CI2. The organic layers were combined, dried over MgSO₄, filtered and concentrated onto silica. The crude material was purified by MPLC (hexane/ethyl acetate gradient 90:10 to 40:60). Concentration of the fractions containing the desired product gave 0.0568 g of Compound 83 (56% yield).

Spectral analysis of the product was consistent with Compound 83: MS (APCI) 437.3 (M+H^4").

Elemental analysis for (C₂₃H₂₄N₄O₅ 0.1500^0: calculated: C 61.90, H 5.45, N 12.47; found: C 61.56, H 5.38, N 12.42.

EXAMPLE 16D Synthesis of 9,13-Imino-6H-azocino [2,1-al isoquinoline-14-carboxamide, 5,8,9,10,ll,12.13.13a-octahvdro-3-methoxy-N-(4-nitrophenyl)-8-oxo-(Compound 84)

This compound was prepared as described in Example ID, using Compound B (0.0855 g, 0.314 mmol), DMF (1.0 mL), 4-nitrophenyl isocyanate (0.1089 g, 0.628 mmol). The reaction was quenched with 3 mL 1.0 M HCI, and the solution was extracted with 3x5 mL CH₂CI₂. The organic layers were combined, dried over MgSO₄, filtered and concentrated onto silica. The crude material was purified by MPLC (hexane/ethyl acetate gradient 90:10 to 40:60). Concentration of the fractions containing the desired product gave 0.0709 g of Compound 84 (52% yield).

Spectral analysis of the product was consistent with Compound 84: MS (APCI) 437.3 (M+H⁴).

Elemental analysis for (C₂₃H24N4O5 O.I5C4H-₃O2) calculated: C 61.90, H 5.45, N 12.47; found: C 62.24, H 5.51, N 12.08.

EXAMPLE 17D Synthesis of 9.13-Imino-6H-azocino [2,1-a] isoquinoline-14-carboxamide, 5,8,9,10,11, 12,13, 13a-octahydro-3-methoxy-N-(3-methylphenyl)-8-oxo-(Compound 85)

This compound was prepared similar to Example ID, using Compound B (0.0866 g, 0.318 mmol), DMF (1.0 mL), 3 -methylphenyl isocyanate (0.1197 mL, 0.954 mmol). The reaction was added to 5 mL brine, filtered and the solids were dissolved in CH₂C1₂ concentrated onto silica, and purified by MPLC (hexane/ethyl acetate gradient 90:10 to 40:60). Concentration of the fractions containing the desired product gave 0.0785 g of Compound 85 (60% yield). Spectral analysis of the product was consistent with Compound 85: MS (APCI) 406.1 (M+H⁴).

Elemental analysis for (C₂₄H₂₇N₃O₃ 0.15C₄H₈O₂) calculated: C 70.57, H 6.79, N 10.04; found: C 70.65, H 6.87, N 9.78.

EXAMPLE 18D Synthesis of 9,13-Imino-6H-azocino [2,1-a] isoquinoline-14-carboxamide, 5.8.9.10.11.12.13,13a-octahvdro-l, 3-dimethoxy-8-oxo-N- (3-methylρhenylV (Compound 86)

This compound was prepared similar to Example ID, using Compound C

(0.0889 g, 0.296 mmol), DMF (1.0 mL), 3-methylphenyl isocyanate (0.1106 mL, 0.882 mmol). The reaction was added to 5 mL brine, filtered and the solids were dissolved in CH₂CI₂ concentrated onto silica, and purified by MPLC (hexane/ethyl acetate gradient 90:10 to 40:60). Concentration of the fractions containing the desired product gave 0.1015 g of Compound 86 (79% yield).

Spectral analysis of the product was consistent with Compound 86: MS (APCI) 372.2 (M+H^4").

Elemental analysis for (C₂₁H₂₉N₃O₃) calculated: C 68.95, H 6.71, N 9.65; found: C 68.88, H 6.73, N 9.30. EXAMPLE 19D

Synthesis of 9,13-Imino-6H-azocino [2,1-a] isoquinoline-14-carboxamide, N -(1,1- dimethylethyl')- 5.8.9.10,11, 12.13.13a-octahvdro-4-methoxy-8-oxo-(Compound 87) Compound 87

This compound was prepared similar to Example ID, using Compound A (0.0816 g, 0.299 mmol), DMF (1.0 mL), t-butyl isocyanate (0.1056 mL, 0.899 mmol). The reaction was added to 5 mL brine, filtered and the solids were dissolved in CH₂CI₂ concentrated onto silica, and purified by MPLC (hexane/ethyl acetate gradient 90:10 to 40:60). Concentration of the fractions containing the desired product gave 0.0619 g of Compound 87 (56% yield).

Spectral analysis of the product was consistent with Compound 87: MS (APCI) 372.2 (M+H⁴).

Elemental analysis for (C₂₅H₂₉N₃O₄0.15C₄H₈O₂0.30C₆H₁₄) calculated: C 68.46, H 8.45, N 10.24; found: C 68.69, H 8.47, N 9.99.

EXAMPLE 20D Synthesis of 9.13-Imino-6H-azocino [2.1-a] isoquinoline-14-carboxamide,N-(l,l- dimethylethyl)5, 8,9,10,11, 12,13, 13a-octahvdro-3-methoxy-8-oxo-(Compound 88)

This compound was prepared similar to Example ID, using Compound B (0.0867 g, 0.318 mmol), DMF (1.0 mL), t-butyl isocyanate (0.112 mL, 0.955 mmol). The reaction was added to 5 mL brine, filtered. The water layer was extracted with 3x10 mL CH2CI2. The organic layers were combined, and the filtered product was added and dissolved. The mixture was dried over MgSO₄, filtered and concentrated onto silica and the solids were dissolved in CH₂C1₂ concentrated onto silica, and purified by MPLC (hexane/ethyl acetate gradient 90:10 to 40:60). Concentration of the fractions containing the desired product gave 0.0978 g of Compound 88 (83% yield).

Spectral analysis of the product was consistent with Compound 88: MS (APCI) 372.2 (M+H⁺).

Elemental analysis for (C₂iH₂₉N₃O₃ O.lSGΗ i 0.15C₆H₁₄) calculated: C 67.97, H 8.19, N 10.57; found: C 67.94, H 8.31, N 10.62.

EXAMPLE 21D Synthesis of 9,13-Imino-6H-azocino [2,1-a] isoquinoline-14-carboxamide,N-(l,l- dimethylethyl)-5, 8,9, 10,11, 12,13, 13a-octahydro-l,3-dimethoxy-8-oxo-(Compound 89)

This compound was prepared similar to Example ID, using Compound C

(0.897 g, 0.296 mmol), DMF (1.0 mL), t-butyl isocyanate (0.104 mL, 0.890 mmol). The reaction was added to 5 mL brine, filtered. The water layer was extracted with 3x10 mL CH₂CI₂. The organic layers were combined, and the filtered product was added and dissolved. The mixture was dried over MgSO₄, filtered and concentrated onto silica and the solids were dissolved in CH2CI₂ concentrated onto silica, and purified by MPLC (hexane/ethyl acetate gradient 90:10 to 40:60). Concentration of the fractions containing the desired product gave 0.095 g of Compound 89 (80% yield).

Spectral analysis of the product was consistent with Compound 89: MS (APCI) 402.2 (M+H⁴). Elemental analysis for (C₂₂H₃₁N₃O₄0.150^0₂ 0.15C₆H₁₄) calculated: C 66.00, H 8.08, N 9.83; found: C 65.96, H 8.08, N 9.91.

EXAMPLE 22D Synthesis of 9,13-Imino-6H-azocino[2,l-a]isoquinoline-14- carboxamide,5,8,9,10.11.12.13, 13a-octahydro-4-methoxy-N-(3-methylphenyl)-8-oxo- (Compound 90)

This compound was prepared similar to in Example ID, using Compound A (0.0871 g, 0.320 mmol), DMF (1.0 mL), 3-methylphenyl isocyanate (0.121 mL, 0.960 mmol). The mixture was added to 5 mL brine and filtered. The mixture was extracted with 3x5 mL CH₂CI₂. The organic layers were combined, dried over MgSO₄, filtered and concentrated onto silica. The crude material was purified by MPLC (hexane/ethyl acetate gradient 90:10 to 40:60). Concentration of the fractions containing the desired product gave 0.0463 g of Compound 90 (36% yield).

Spectral analysis of the product was consistent with Compound 90: MS (APCI) 406.1 (M+H⁴).

Elemental analysis for (C24H2₇N3O3 O.3OC H8O2) calculated: C 70.47, H 7.17, N 9.45; found: C 70.14, H 7.00, N 9.55.

EXAMPLE 23D Synthesis of 9,13-Imino-6H-azocino[2,l-a]isoquinoline-14- carboxamide,5 ,8,9, 10, 11,12,13, 13a-octahydro- 1 ,3-dimethoxy-N-(4-nitrophenyl)-8-oxo- (Comρound 91)

Compound 91

This compound was prepared similar to Example ID, using Compound C (0.0744 g, 0.246 mmol), DMF (1.0 mL), 4-nitrophenyl isocyanate (0.0806 g, 0.960 mmol). The mixture was added to 1 mL HCI (1.0 M) and the mixture was extracted with 3x5 mL CH2CI2. The organic layers were combined, dried over MgSO₄, filtered and concentrated onto silica. The crude material was purified by MPLC (hexane/ethyl acetate gradient 90: 10 to 40:60). Concentration of the fractions containing the desired product gave 0.0245 g of Compound 91 (22% yield).

Spectral analysis of the product was consistent with Compound 91: MS (APCI) 467.2 (M+H⁴).

Elemental analysis for

calculated: C 61.79, H 5.62, N 12.01; found: C 60.69, H 5.92, N 12.66.

EXAMPLE 24D Synthesis of 9,13-Imino-6H-azocino[2,l-a]isoquinoline-14-carboxamide,N-(2,4- difluorophenyl)-5, 8,9,10,11, 12,13, 13a-octahvdro-l,3-dimethoxy-8-oxo-(Compound 92)

Compound 92

This compound was prepared similar to Example ID, using Compound C

(0.0694 g, 0.229 mmol), DMF (1.0 mL), 2,4-difluorophenyl isocyanate (0.0544 mL, 0.459 mmol). The mixture was added to 1 mL HCI (1.0 M) and the mixture was extracted with 3x5 mL CH₂CI₂. The organic layers were combined, dried over MgSO₄, filtered and concentrated onto silica. The crude material was purified by MPLC (hexane/ethyl acetate gradient 90: 10 to 40:60). Concentration of the fractions containing the desired product gave 0.0599 g of Compound 92 (57% yield). Spectral analysis of the product was consistent with Compound 92: MS (APCI) 458.2 (M+H^4"). Elemental analysis for

calculated: C 63.01, H 5.51, N 9.19; found: C 62.77, H 5.61, N 8.93.

EXAMPLE 25D Synthesis of 9,13-Imino-6H-azocino r2,l-a]isoquinoline-14-carboxamide,N-(piperidin- l-ylV5.8.9,10,ll,12,13,13a-octahvdro-l,3-dimethoxy-8-oxo-(Compound 93)

To an ice-cold mixture of l,r-carboxyldiimidazole (81 mg, 0.5 mmol) in CH₂CI₂ (2.5 mL) was added 1-aminopiperidine (54 mL, 0.5 mmol). After 45 minutes, Compound C (151 mg, 0.5 mmol) was added and stirred for another 2 hours. The solution was concentrated and purified by flash column chromatography (5% MeOH in CH₂CI₂), affording 160 mg (75% yield) of the title compound.

Spectral analysis of the product was consistent with Compound 93: 1H NMR (CDCI₃): δ 6.15 (IH, s), 6.01 (IH, s), 4.85 (IH, s), 4.69 (IH, dd, J = 11.7, 3.0 Hz), 4.48 (IH, s), 4.37 (IH, s), 3.65 (3H, s), 3.56 (3H, s), 2.74 - 2.57 (IH, m), 2.51 - 2.39 (IH, m), 2.37 (2.13 (IH, m). HRMS (MALDI) calculated for C₂₃H₃₃N₄O₄ (M+H⁴) 429.2502; found 429.2483.

EXAMPLE 26D Synthesis of 9,13-Imino-6H-azocino [2,1-a] isoquinoline-14-carboxamide, N-(pyrrol-l- yl -5,8,9,10.11,12,13,13a-octahvdro-1.3-dimethoxy-8-oxo-(Compound 94)

This compound was prepared similar to Example 25D from Compound C. A

95% yield was obtained.

Spectral analysis of the product was consistent with Compound 94:

1H NMR (CDCI₃): δ 7.00 (IH, s), 6.41 - 6.29 (4H, m), 6.07-6.03 (2H, m), 4.96 - 4.87

(2H, m), 4.66 (2H, s), 3.87 (3H, s), 3.81 (3H, s), 3.02 - 2.89 (IH, m), 2.77 - 2.66 (IH, m), 2.56 (IH, d, J = 15.6 Hz), 2.14 - 2.00 (2H, m).

Elemental analysis for (C₂₂H₂₆N₄O₄ H₈O) calculated: C 61.67, H 6.59, N 13.08; found:

C 61.83, H 6.35, N 13.06. EXAMPLE 27D

Synthesis of Compound 131

Compound 131

Compound 131 was prepared according to Scheme D, using Compound L (0.10 g, 0.39 mmol) DMF (1.7 ml), and 2-methylphenyl isocyanate (0.051 g, 0.39 mmol). The reaction was quenched with 5 ml NaCl, and the solution was extracted with 3x5 ml CH2θ₂. The organic layers were combined, dried over MgSO₄, filtered and concentrated onto silica. The crude material was purified by MPLC (hexane/ethyl acetate gradient 90:10 to 40:60). Concentration of the fractions containing the desired product gave 0.103 g of Compound 131 (68% yield). Spectral analysis of the product was consistent with Compound 131:

MS (APCI) m/z 390.2 (MM).

CHN for (C2₄H₂₇N₃O₂O.05CH₂Cl2O.7C₄H₈O₂) calculated: C 74.01, H 6.99, N 10.79; found: C 71.11, H 6.82, N 8.85.

EXAMPLE 28D Synthesis of Compound 132

This compound was prepared as described in Scheme D, using Compound L

(0.10 g, 0.38 mmol), DMF (1.7 ml), and 2-methylphenyl isocyanate (0.051 g, 0.39 mmol). The reaction was quenched with 5 ml NaCl, and the solution was extracted with 3x5 ml CH₂C1₂. The Organic layers were combined, dried over MgSO₄, filtered and concentrated onto silica. The crude material was purified by MPLC (hexane/ethyl acetate gradient 90:10 to 40:60). Concentration of the fractions containing the desired product gave 0.058 g of Compound 132 (39% yield).

Spectral analysis of the product was consistent with Compound 132:

MS (APCI) m/z 394.1 (M⁺+l). CHN for (C₂3H2₄FN₃O₂O.15CH2Cl2O.65C₄H₈θ2) calculated: C 70.21, H 6.15, N 10.68; found: C 66.87, H 6.17, N 8.68.

The amides and ,α-difluoro amides of the present invention may be prepared in the manner depicted in Schemes E and F respectively shown below:

Scheme E

wherein:

R is selected from substituted or unsubstituted aryl, alkoxy aryl, and hydroxy aryl.

Scheme F

The following examples are illustrative of the present invention:

EXAMPLE IE Synthesis of 9,13-Imino-8H-azocino [2,1-a] isoquinolin-8-one,14-(diphenylacetyl)- 5,6,9,10,ll,12,13,13a-octahvdro-l,3-dimethoxy-(Compound 106)

Diphenylacetic acid (0.056 g, 0.264 mmol) and HOBt (0.05 g, 0.370 mmol) were dissolved in THF (1.3 mL) prior to addition of EDC (0.080g, 0.417 mmol). After stirring for approximately 5 minutes a solution of Compound C (0.080 g, 0.264 mmol) and triethylamine (TEA, 0.06 mL, 0.430 mmol) in THF (2 mL) was added. The mixture was stirred at room temperature for 5 hours with product formation monitored by MS. Upon completion of the reaction as judged by disappearance of Compound C, the reaction mixture was concentrated onto silica and purified by MPLC (hexanes/ethyl acetate). Concentration afforded 0.075 g of Compound 106 (57% yield).

Spectral analysis of the product was consistent with Compound 106: MS (APCI) m/z 49 .1 (M+H^4").

Elemental analysis for (C₃ιH₃₂N₂O 0.05 H₂O) calculated: C 74.84, H 6.50, N 5.63; found: C 74.46, H 6.65, N 5.36.

EXAMPLE 2E Synthesis of 9,13-Imino-8H-azocino [2,l~a] isoquinolin-8-one,14-[bis(4- chlorophenyDacetyl] -5,6,9,10,11,12,13, 13 a-octahydro- 1 ,3-dimethoxy-(Compound 105)

This compound was prepared similar to Example IE, using Compound C (0.080 g, 0.264 mmol), bis-(4-chlorophenyl)acetic acid (0.093, 0.330 mmol), THF (3.3 mL), EDC (0.080 g, 0.417 mmol), HOBt (0.05g, 0.370 mmol) and TEA (0.06mL, 0.430 mmol). Purification afforded 0.111 g of Compound 105 (74% yield).

Spectral analysis of the product was consistent with Compound 105: MS (APCI) 565.1 (M+H^4").

Elemental analysis for (C₃₁H₃oCl₂N₂O₄) calculated: C 65.84, H 5.35, N 4.95; found: C 66.23, H 5.42, N 4.74. EXAMPLE 3E

Synthesis of 9,13-Imino-8H-azocino [2,1-a] isoquinolin-8-one,14-(3,4- dimethoxybenzoyl)-5,6,9,10,ll,12,13,13a-octahydro-l,3-dimethoxy-(Compound 107)

This compound was prepared similar to Example IE, using Compound C (0.080 g, 0.264 mmol), 2-oxo-3,4-dimethoxyphenyl acetic acid (0.055, 0.264 mmol), THF (3.3 mL), EDC (0.080 g, 0.417 mmol), HOBt (0.05 g, 0.370 mmol) and TEA (0.06 mL, 0.430 mmol). Purification afforded 0.012 g of Compound 107 (10% yield) as a byproduct.

Spectral analysis of the product was consistent with Compound 107: MS (APCI) 467.2 (M+H⁴).

Elemental analysis for (C₂₆H₃₀N₂O₆ 0.40 H₂O 0.15 C₆H₁ ) calculated: C 66.39, H 6.81, N 5.76; found: C 66.66, H 6.71, N 5.36.

EXAMPLE 4E Synthesis of 9,13-Imino-8H-azocino [2,1-al isoquinolin-8-one,14- (3,4- dichlorobenzo yl-5 ,6,9,10,11,12,13,13 a-octahvdro-4-methoxy-(Compound 100)

This compound was prepared similar to Example IE, using Compound A (0.200 g, 0.734 mmol), 2-oxo-3,4-dichlorophenyl acetic acid (0.193, 0.881 mmol), CH₂C1₂ instead of THF (8 mL), EDC (0.170 g, 0.881 mmol), HOBt (0.120 g, 0.881 mmol) and TEA (0.13 mL, 0.881 mmol). Purification afforded 0.072 g of Compound 100 (22% yield) as a byproduct.

Spectral analysis of the product was consistent with Compound 100: MS (APCI) 445.1 (M+H^4").

Elemental analysis for (C₂₃H22CI₂N₂O₃ 0.15 C₆H₁₄) calculated: C 62.64, H 5.30, N 6.11; found: C 62.51, H 5.13, N 5.81.

EXAMPLE 5E Synthesis of 9,13-Imino-8H-azocino [2,1-a] isoquinolin-8-one,14-(3,4- dichlorobenzoyl-5 ,6,9,10, 11,12, 13, 13a-octahydro-3-methoxy-(Compound 101)

This compound was prepared similar to Example IE, using Compound B (0.200 g, 0.734 mmol, synthesized according to a published procedure [Katoh, S. and et al. WO 0004020]), 2-oxo-3,4-dichlorophenyl acetic acid (0.190, 0.881 mmol), CH₂C1₂ instead of THF (8 mL), EDC (0.170 g, 0.881 mmol), HOBt (0.120g, 0.881 mmol) and TEA (0.13mL, 0.881 mmol). Purification afforded 0.049g of Compound 101 (15% yield) as a byproduct.

Spectral analysis of the product was consistent with Compound 101: MS (APCI) 445.1 (M+H^4").

Elemental analysis for (C₂₃H₂₂CI₂N₂O₃ 0.15 H₂O) calculated: C 61.66, H 5.02, N 6.25; found: C 61.26, H 5.19, N 6.02. EXAMPLE 6E

Synthesis of 9,13-Imino-8H-azocino [2,1-a] isoquinolin-8-one, 5,6,9,10,11,12,13,13a- octahydro-3-methoxy-14-(4-methoxybenzoyl)-(Compound 98)

To a solution of the amine (Compound B, 0.786 g, 2.9 mmol) in DMF (10 mL) at room temperature were added 4-methoxybenzoic acid (0.52 g, 2.9 mmol), HATU (1.1 g, 2.9 mmol) and N-methylmorpholine (0.4 mL, 3.9 mmol). After stirring at room temperature for 5 days, the mixture was dropped into cold aqueous sodium bicarbonate and the resulting precipitate was collected by filtration and washed with water. The solids were dissolved in ethyl acetate, dried over sodium sulfate and concentrated to dryness. The crude residue was titrated with t-butylmethyl ether/hexanes and collected by filtration to give 0.87 g of the title Compound (70% yield).

Spectral analysis of the product was consistent with Compound 98: MS (ESP): 407 (M⁴).

Elemental analysis for (C₂₄H_2fiN₂O₄) calculated: C 70.91, H 6.45, N 6.89; found: C 0.95, H 6.46, N 6.86.

EXAMPLE 7E Synthesis of 9.13-Imino-8H-azocino [2,1-a] isoquinolin-8-one, 5,6,9,10,11,12,13,13a- octahvdro-3-hvdroxy-14-(4-hvdroxybenzoyl)-(Compound 99)

To a solution of Compound 98 (0.8 g, 1.8 mmol) in dichloromethane (20 mL) at 0°C was added dropwise a solution of boron tribromide (1M in dichloromethane, 18 mL, 18 mmol). After allowing the mixture to warm with stirring from 0°C to room temperature over 18 hours, the mixture was added cautiously to 0.5 N HCI and extracted with ethyl acetate (3x). The combined extracts were washed with brine, dried over sodium sulfate and concentrated to dryness. The crude residue was titrated with t- butylmethyl ether to give 428 mg of the title compound as a solid which was collected by filtration (58% yield).

Spectral analysis of the product was consistent with Compound 99: MS (ESP): 379 (M⁺). Elemental analysis for (C₂₂H₂₂N₂O₄ 0.3H₂0) calculated: C 68.84, H 5.94, N 7.30; found: C 68.77, H 5.87, N 7.13.

EXAMPLE 8E Synthesis of 9,13-Imino-6-oxa-8H-azocino [2,1-a] isoquinoline-8-one, 14-(1-1H- indozol-3-yl-methanoyl)-5,9, 10, 11,12, 13, 13a-heptahydro-3-methoxy-(Compound 97)

Compound 97

This compound was prepared similar to Example 6E from the amine (Compound G, 90 mg, 0.33 mmol), 3-indazole carboxylic acid (53 mg, 0.33 mmol), HATU (125 mg, 0.33 mmol) and N-methylmorpholine (0.044 mL, 0.4 mmol) to afford 103 mg of the title compound (74% yield).

Spectral analysis of the product was consistent with Compound 97: MS (ESP): 419 (M⁴).

Elemental analysis for (C₂₃H₂₂N₄O₄O.8H₂0) calculated: C 63.82, H 5.50, N 12.94; found: C 63.73, H 5.30, N 13.20.

EXAMPLE 9E Synthesis of 9,13-Imino-8H-azocino [2,1-a] isoquinolin-8-one, 5,6,9,10,11,12,13,13a- octahvdro-4-methoxy-14-(l-naphthalenylcarbonyl)-(Compound 95) Compound 95

To a solution of the amine (Compound A, 45 mg, 0.17 mmol) in dichloromethane (3 mL) were added 1-naphthoyl chloride (0.031 mL, 0.21 mmol) and diisopropylethyl amine (0.043 mL, 0.25 mmol) at 0°C. After 5 hours, the mixture was partitioned between ethyl acetate and 0.5 N HCI at 25°C. The aqueous layer was extracted with ethyl acetate (2x). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated. The crude residue was titrated with t-butylmethyl ether/hexanes and collected by filtration to give 69 mg of the title compound (95% yield).

Spectral analysis of the product was consistent with Compound 95: MS (ESP): 427 (M+).

Elemental analysis for (C27H26N2O3.0.4H2O) calculated: C 74.77, H 6.23, N 6.46; found: C 74.62, H 6.28, N 6.24.

EXAMPLE 10E Synthesis of 9,13-Imino-8H-azocino [2,1-a] isoquinolin-8-one, 5,6,9,10,11,12,13,13a- octahydro-6-methyl-14-(l-naphthalenylcarbonyl)-, (6R, 9S, 13R, 13aR)-(Compound 96)

Compound 96

This compound was prepared similar to Example 9E from the amine (Compound E, 45 mg, 0.17 mmol), 1-naphthoyl chloride (0.03 mL, 0.2 mmol) and Hunig's base (0.04 mL, 0.23 mmol). The compound was purified by flash chromatography on silica gel using gradient elution of ethyl acetate/hexanes (25-50%) to give 30 mg of the title compound (43% yield).

Spectral analysis of the product was consistent with Compound 96: MS (ESP): 411 (M⁺). Elemental analysis for (C₂₇H₂₆N₂O2 0.7H₂O) calculated: C 76.64, H 6.53, N 6.62; found: C 76.56, H 6.69, N 6.25.

EXAMPLE HE Synthesis of Carbamic acid,[2-[(5, 8,9,10,11, 12,13, 13a-octahvdro-l,3-dimethoxy-8- oxo-9,13-Imino-6H-azocino[2,l-a] isoquinolin-14-yl)carbonyllphenyll-, phenylmethyl ester~(Compound 109)

Compound 109

This compound was prepared similar to Example IE, using Compound C (0.101 g, 0.330 mmol), 2-oxo-N-[(benzyloxy) carbonyl]-2-aminophenyl acetic acid (0.120 g, 0.530 mmol), THF (4 mL), EDC HCI (0.096 g, 0.500 mmol), HOBt (0.067 g, 0.500 mmol) and TEA (0.08 mL, 0.530 mmol). Purification afforded 0.015 g of Compound 109 (8% yield).

Spectral analysis of the product was consistent with Compound 109: MS (APCI) 556.3 (M+H⁴).

Elemental analysis for (C₃₂H₃₃N₃O₆0.30H₂O 0.40C₆H₁₄) calculated: C 69.38, H 6.64, N 7.06; found: C 69.08, H 6.86, N 6.69.

EXAMPLE 12E Synthesis of 9,13-Imino-8H-azocino[2,l-a]isoquinolin-8-one,14-(2,4-dichlorobenzoyl)- 5,6,9,10,ll,12,13,13a-octahvdro-6-l,3-dimethoxy-(Compound 108) Compound 108

This compound was prepared similar to Example IE, using Compound C (0.100 g, 0.330 mmol), 2,4-Dichlorophenyl acetic acid (0.088 g, 0.396 mmol), THF (6 mL), EDCHC1 (0.095 g, 0.500 mmol), HOBt (0.067 g, 0.500 mmol) and TEA (0.05 mL, 0.530 mmol). Purification afforded 0.030 g of Compound 108 (19% yield). Spectral analysis of the product was consistent with Compound 108:

MS (APCI) 475.1 (M+H*^").

Elemental analysis for (C₂₄H₂₄C1₂N₂O 0.05C₆H₁ ) calculated: C 60.58, H 5.19, N 5.84; found: C 61.24, H 5.37, N 5.56.

EXAMPLE 13E Synthesis of 13-Imino-6H-azocino[2,l-a]isoquinoline-14-carbamate,O(l, 1- dimethylethyl)5, 8,9,10,12,13, 13a-octahydro-1.3-dimethoxy-8-oxo-(Compoundl 17)

Compound 117

This compound was prepared similar to Example 9E, using Compound C (0.147 g, 0.487 mmol), Boc₂O (0.159 g, 0.73 mmol), Et₃N (0.136 mL, 0.974 mmol) and 1,4- dioxane (2 mL). Purification afforded 0.181 g of Compound 117 (92% yield). Spectral analysis of the product was consistent with Compound 117: LCMS 403 (M+H⁴), 425 (M+Na⁺), 346 (M-t-Bu+H⁴).

Elemental analysis for (C₂₂H₃₀N₂O₅) calculated: C 65.65, H 7.51, N 6.96; found: C 65.62, H 7.58, N 6.81. EXAMPLE 14E

Synthesis of Compound 133 Compound 133

This compound was prepared as described in Scheme E, using Compound C (0.080 g, 0.264 mmol), 4-chlorophenylacetic acid (0.056 g, 0.330 mmol), THF (3.3 ml), EDCΗC1 (0.080g, 0.417 mmol), HOBt (0.05g, 0.370 mmol) and TEA (0.06ml, 0.430 mmol). Purification afforded 0.070g of Compound 133 (58% yield).

Spectral analysis of the product was consistent with Compound 133: MS (APCI) m/z 455.1 (M⁺+l).

CHN for (C2₅H₂₇Cl₁N₂O₄) calculated: C 66.00, H 5.98, N 6.16; found: C 65.98, H 6.26, N 5.80. EXAMPLE 15E

Synthesis of Compound 134

Compound 134

Compound 134 was prepared as described in Scheme E using, Compound C

(0.080 g, 0.264 mmol), 4-bromophenylacetic acid (0.057, 0.264 mmol), THF (3.3 ml), EDCHCl (0.080g, 0.417 mmol), HOBt (0.05g, 0.370 mmol) and TEA (0.06ml, 0.430 mmol). Purification afforded 0.085g of Compound 134 (64% yield).

Spectral analysis of the product was consistent with Compound 134: MS (APCI) m/z 499..0 (M⁺+l).

CHN for (C₂5H2₇BrιN2θ₄) calculated: C 60.13, H 5.45, N 5.61; found: C 59.85, H 5.60, N 5.34. EXAMPLE 16E

Synthesis of Compound 135

This compound was prepared as described Scheme E, using Compound C (0.080 g, 0.264 mmol), 2-methoxy-2-phenylacetic acid (0.052, 0.330 mmol), THF (3.3 ml), EDC HCI (0.080 g, 0.417 mmol), HOBt (0.05 g, 0.370 mmol) and TEA (0.06 ml, 0.430 mmol). Purification afforded 0.055 g of Compound 135 (46% yield).

Spectral analysis of the product was consistent with Compound 135: MS (APCI) m/z 451.2 (M⁺+l).

CHN for (C₂6H₃oN₂O₅O.05 H₂O) calculated: C 69.18, H 6.72, N 6.21; found: C 68.78, H 5.42, N 5.95.

EXAMPLE 17E Synthesis of Compound 136

This compound was prepared as described in Scheme E, using Compound C

(0.080 g, 0.264 mmol), 3,5-di-tert-butyl-4-hydroxyphenylacetic acid (0.084, 0.330 mmol), THF (3.3 ml), EDCHCl (0.080 g, 0.417 mmol), HOBt (0.05 g, 0.370 mmol) and TEA (0.06 ml, 0.430 mmol). Purification afforded 0.090 g of Compound 136

(62% yield). Spectral analysis of the product was consistent with Compound 136:

MS (APCI) m/z 549.3 (M⁺+l).

CHN for (C₃₃H₄₄N₂O₅O.I5 H₂O) calculated: C 71.88, H 8.10, N 5.08; found: C 71.62,

H 8.12, N 4.87.

EXAMPLE 18E Synthesis of Compound 137

This compound was prepared as described in Scheme E, using Compound C (0.080 g, 0.264 mmol), 3-(3,4,5-trimethoxyphenyl)proprionic acid (0.076, 0.330 mmol), THF (3.3 ml), EDCHCl (0.080 g, 0.417 mmol), HOBt (0.05 g, 0.370 mmol) and TEA (0.06 ml, 0.430 mmol). Purification afforded 0.070 g of Compound 137

(51% yield).

Spectral analysis of the product was consistent with Compound 137: MS (APCI) m/z 525.2 (MM).

CHN for (C₂₉H₃₆N₂O₇) calculated: C 66.40, H 6.92, N 5.34; found: C 66.00, H 6.88, N

5.12.

EXAMPLE 19E

Synthesis of Compound 138 Compound 138

This compound was prepared as described in Scheme E, using Compound C (0.080 g, 0.264 mmol), 3,4,5-trimethoxyphenylacetic acid (0.057, 0.330 mmol), THF (3.3 ml), EDCHCl (0.080 g, 0.417 mmol), HOBt (0.05 g, 0.370 mmol) and TEA (0.06ml, 0.430 mmol). Purification afforded 0.080 g of Compound 138 (59% yield). Spectral analysis of the product was consistent with Compound 138: MS (APCI) m/z 511.2 (M⁺+l).

CHN for (C₂₈H₃₄N₂O₇0.30 H₂O) calculated: C 65.18, H 6.76, N 5.43; found: C 64.92, H 6.84, N 5.21.

EXAMPLE 20E Synthesis of Compound 139

This compound was prepared as described in Scheme E, using Compound C (0.100 g, 0.330 mmol), 3-(3,4-dimethoxyphenyl)proprionic acid (0.083, 0.412 mmol), THF (4.8 ml), EDCHCl (O.lOOg, 0.520 mmol), HOBt (0.063 g, 0.500 mmol) and TEA (0.075 ml, 0.538 mmol). Purification afforded 0.110 g of Compound 139 (67% yield). Spectral analysis of the product was consistent with Compound 139: MS (APCI) m/z 495.1 (M⁺+1).

CHN for (C28H3 N2O6O.2O CH₂C1₂) calculated: C 66.21, H 6.78, N 5.48; found: C 66.17, H 6.81, N 5.15. EXAMPLE 21E

Synthesis of Compound 140

This compound was prepared as described Scheme E, using Compound C (0.200 g, 0.661 mmol), 4-chloromandelic acid (0.148, 0.788 mmol), THF (10 ml), EDCHCl (0.200 g, 1.040 mmol), HOBt (0.125 g, 0.925 mmol) and TEA (0.15 ml, 1.076 mmol). Purification afforded 0.014 g of Compound 140 (5% yield). Spectral analysis of the product was consistent with Compound Compound 140:

MS (APCI) m/z 469.1 (M⁺+l).

CHN for (CzsH^Cl^Os'O.SS C₆H₁₄ 0.15 H₂O) calculated: C 65.23, H 6.77, N 5.38; found: C 64.99, H 6.53, N 4.98.

EXAMPLE 22E Synthesis of Compound 146

This compound was prepared as described in Scheme E, using Compound C (0.101 g, 0.330 mmol), 2-oxo-N-[(benzyloxy)carbonyl]-2-aminophenyl acetic acid (0.120 g, 0.530 mmol), THF (4 ml), EDCHCl (0.096 g, 0.500 mmol), HOBt (0.067g, 0.500 mmol) and TEA (0.08 ml, 0.530 mmol). Purification afforded 0.015 g of Compound 146 (8% yield) as a byproduct.

Spectral analysis of the product was consistent with Compound 146: MS (APCI) m/z 556.3 (M⁺+l). CHN for (C₃₂H₃₃N₃O₆O.3O H₂O O.4O C₆H₁₄) calculated: C 69.38, H 6.64, N 7.06; found: C 69.08, H 6.86, N 6.69.

EXAMPLE 23E

Synthesis of Compound 147

This compound was prepared as described in Scheme E, using Compound C

(0.100 g, 0.330 mmol), 2,4-dichlorophenyl acetic acid (0.088 g, 0.396 mmol), THF (6 ml), EDCHCl (0.095 g, 0.500 mmol), HOBt (0.067 g, 0.500 mmol) and TEA (0.05 ml,

0.530 mmol). Purification afforded 0.030 g of Compound 147 (19% yield) as a byproduct. Spectral analysis of the product was consistent with Compound 147:

MS (APCI) m/z 475.1 (M⁺+l).

CHN for (C₂₄H₂₄ C1₂N₂O₄O.05 C₆H₁₄) calculated: C 60.58, H 5.19, N 5.84; found: C

61.24, H 5.37, N 5.56.

EXAMPLE 24E Synthesis of Compound 148

Compound 148

A mixture of Compound B (1.00 g, 3.67 mmol), 1-naphthylacetic acid (0.75 g, 4.04 mmol), 1-hydroxybenzotriazole hydrate (0.62 g, 4.04 mmol), l-(3- dimethylaminopropyl)3-ethylcarbodiimide hydrochloride (0.77 g, 4.04 mmol) and 4- methylmorpholine (0.51 mL, 4.59 mmol) in 50 mL of CH₂CI2 was stirred at room temperature for 12 hours. The solution was concentrated, then partitioned between EtOAc and saturated NaHCO₃ solution. The organic extract was washed with sat. KH₂PO₄ and brine solutions, dried (MgSO₄), filtered and concentrated to an off-white solid. The sample was washed with diethyl ether to give 1.52 g (94%) of the titled compound as a white solid, mp 107-137 °C.

Spectral analysis of the product was consistent with Compound 148:

Calculated for C₂₈H₂8N₂O₃ x 0.57 EtOAc (490.768): C, 74.11; H, 6.69; N, 5.71, found:

C, 74.20; H, 6.70; N, 5.71. EXAMPLE 25E

Synthesis of Compound 149

Compound 149

This compound was prepared in a manner analogous to Example 24E, using appropriate starting materials. A white solid with melting point of 198-200 °C was made.

Spectral analysis of the product was consistent with Compound 149: Calculated for C₂₆H₂₆N₂O₃S x 0.19 H₂O (449.996): C, 69.40; H, 5.91; N, 6.22; found: C, 69.39; H, 5.96; N, 6.07.

EXAMPLE 26E Synthesis of Compound 150

Compound 150

This compound was prepared in a manner analogous to Example 24E, using appropriate starting materials. A white solid with melting point of 167-170 °C was prepared. Spectral analysis of the product was consistent with Compound 150:

Calculated for C₂₆H₂₆N₂O₄ x 0.16 H₂O (433.391): C, 72.06; H, 6.12; N, 6.46; found: C, 72.07; H, 6.17; N, 6.39. EXAMPLE 27E

Synthesis of Compound 151

Compound 151

A mixture of 2-Bromo-l-phenyl-ethanone (0.4 g, 1.98 mmol) and Compound C (0.5g, 1.65 mmol) was heated at 300 °C for 15 minutes. The fused mass was crushed into powder and chromatographed (MPLC, Siθ₂, 20% ethyl acetate and 5% methanol in hexanes) and converted to hydrochloride salt to give 0.176 g (23%) of the title compound as a tan solid with melting point of 132.5 °C, M+1 = 421.2.

Spectral analysis of the product was consistent with Compound 151:

Calculated for C₂₅H₂₈N₂O₄xl.2 HClx0.2 H₂O (467.857): C, 64.18; H, 6.38; N, 5.99; H₂O, 0.77; found: C, 63.83; H, 6.30; N, 6.13; H₂O, 1.15.

EXAMPLE 28E Synthesis of Compound 152

A mixture of Compound C (0.5 g, 1.65mmol), 2-bromo-l-(-4-fluoro-phenyl)- ethanone (0.35 g, 1.98 mmol) and potassium carbonate (0.57 g, 4.13 mmol) in 25 mL of acetonitrile was refluxed under N₂ for 15 hours. The sample was concentrated, then partitioned between EtOAc and sat. NaHCO₃ solution. The organic extract was washed with brine solution, dried (MgSO₄), filtered and concentrated. The crude sample was chromatographed (MPLC, silica gel, 35% ethyl acetate in hexanes) and converted to hydrochloride salt to give 0.075 g (10%) of the title compound as a brown solid with melting point of 132-135 °C, M+1 = 439.2. Spectral analysis of the product was consistent with Compound 152:

Calculated for C₂₅H2₇F₁N₂O₄x0.6 HClxl.4 H₂O (485.589): C, 61.84; H, 6.31; N, 5.77;

H₂O, 5.19; found: C, 62.13; H, 5.74; N, 5.20; H₂O, 5.53.

EXAMPLE 29E

Synthesis of Compound 153

This compound was prepared in a manner analogous to Example 28E, using appropriate starting materials. A tan solid compound with mp 173-175 °C, M+1 = 500.1 was made.

Spectral analysis of the product was consistent with Compound 153: Calculated for C₂₅H₂₇Br₁N₂O₄ l .25 HClx0.45 H₂O (553.080): C, 54.29; H, 5.31 ; N, 5.06; H₂O, 1.47; found: C, 54.03; H, 5.38; N, 4.97; H₂0, 1.82.

EXAMPLE 30E Synthesis of Compound 157

A mixture of Compound C (0.2 g, 0.66 mmol), (3,4-dichloro-phenyl)-acetic acid (0.205 g, 1 mmol) HBTU (0.38 g, 1 mmol) and N-ethyldiisopropylamine (0.6 mL, 3.3 mmol) in 50 mL of DMF was stirred under N₂ for 15 hours. The sample was concentrated, then partitioned between EtOAc and sat. NaHCO₃ solution. The organic extract was washed with brine solution, dried (MgSO ), filtered and concentrated. The crude sample was chromatographed (MPLC, silica gel, 50% EtOAc in hexanes) and recrystallized from EtOAc to give 0.27g (84%) of the titled compound as a white solid with mp 120-122 °C, M+1 = 491.1.

Spectral analysis of the product was consistent with Compound 157: Calculated for C25H2₆CI₂N2O XO.2I H₂O (493.174): C, 60.88; H, 5.40; N, 5.68; H₂O, 0.77; found: C, 60.33; H, 5.46; N, 5.44; H₂O, 0.39.

EXAMPLE IF Synthesis of 9,13-Imino-8H-azocino [2,1-a] isoquinolin-8-one,14-[difluoro(3,4,5- trimethoxyphenyDacetyl] -5 ,6,9, 10.11 , 12.13 , 13 a-octahydro- 1 ,3-dimethoxy-(Compound 102)

The amine (Compound C, 0.080 g, 0.264 mmol) and α,α-difluoro-3,4,5- trimethoxy-phenylacetic acid (18, 0.083 g, 0.316 mmol) were dissolved in acetonitrile (3 mL). EDC (0.076 g, 0.396 mmol) and DMAP (0.032 g, 0.264 mmol) were added to the solution. The mixture was stirred at room temperature for 5 hours with product formation monitored by mass spec. Upon completion, the reaction mixture was concentrated onto silica and purified by MPLC (hexanes/ethyl acetate 80:20 to 20:80).

Concentration afforded 0.040 g of Compound 102 (28% yield). Spectral analysis of the product was consistent with Compound 102:

MS (APCI) 547.2 (M+H⁴).

Elemental analysis for (C₂₈H₃₂F₂N₂O₇) calculated: C 61.53, H 5.90, N 5.13; found: C

61.60, H 5.93, N 4.89.

EXAMPLE 2F Synthesis of 9,13-Imino-8H-azocino [2,1-a] isoquinolin-8-one,14-[difluoro(3,4,5- trimethoxyphenyl)acetyl]-5,6,9,10,ll, 12,13, 13a-octahvdro-4-methoxy-(Compound

103)

This compound was prepared similar to Example IF, using Compound A (0.080 g, 0.294 mmol, synthesized according to a published procedure [Katoh, S. and et al. WO 0004020]), α,α-difluoro-3,4,5-trimethoxy-phenylacetic acid (18, 0.092 g, 0.352 mmol), CH₃CN (9 mL), EDC (0.070 g, 0.367 mmol) and DMAP (0.036 g, 0.294 mmol). Purification afforded 0.017 g of Compound 103 (12% yield).

Spectral analysis of the product was consistent with Compound 103: MS (APCI) 517.1 (M+H^4").

Elemental analysis for (C₂₇H₃₀F₂N₂O₆) calculated: C 62.78, H 5.85, N 5.42; found: C 62.86, H 5.97, N 5.11.

EXAMPLE 3F Synthesis of 9,13-Imino-8H-azocino [2,1-a] isoquinolin-8-one,14-[(4- chlorophenyl)difluoroacetyl1-5,6,9, 10,11, 12,13, 13a-octahydro-l,3-dimethoxy- (Compound 104)

This compound was prepared similar to Example IF, using Compound C (0.080 g, 0.264 mmol), α, -difluoro-4-chloro-phenylacetic acid (20, 0.066 g, 0.317 mmol), CH₃CN (9 mL), EDC (0.063 g, 0.330 mmol) and DMAP (0.032 g, 0.264 mmol). Purification afforded 0.027 g of Compound 104 (21% yield).

Ill O 02/089806

Spectral analysis of the product was consistent with Compound 104:

MS (APCI) 491.0 (M+H*).

Elemental analysis for (C₂₅H₂₅Cl₁F₂N₂O₄0.15 C₆H₁₄) calculated: C 61.74, H 5.42, N

5.56; found: C 61.69, H 5.47, N 5.18.

EXAMPLE 4F Synthesis of Compound 142

Step 1: Synthesis of Compound 141:

To a stirred 1M solution of lithium aluminum hydride in THF (3.3 ml, 3.30 mmol) under nitrogen atmosphere, cooled in an ice bath, was added Compound C (0.500 g, 1.65 mmol) in THF (6 ml) dropwise. Upon addition, the ice bath removed and a heating mantle and condenser added. The reaction heated to reflux for 30 minutes, cooled with an ice bath, and carefully quenched with water. To the reaction was added 3 N sodium hydroxide (20 ml) prior to filtering through a pad of Celite. The Celite washed with acetone and ether. The reaction mixture was concentrated to approximately a third of the original volume, and made acidic with 2 N hydrochloric acid. Reaction mixture was washed with ether prior to being made basic with potassium hydroxide pellets. Extracted basic aqueous layer with ether, dried over magnesium sulfate, filtered, and concentrated to yield 0.406 g (85%) of Compound 141.

Spectral analysis of the product was consistent with Compound 141: MS (APCI) m/z 289.1 (MM).

CHN for (C₁₇H₂₄N₂O₂0.15 C₆H₁₄ 0.40 H₂O) calc: C 69.69, H 8.79, N 9.08; found: C 69.58, H 8.51, N 8.70. Step 2: Synthesis of Compound 142:

This compound was prepared as described in Scheme F, using Compound 141 (0.173 g, 0.600 mmol), α, -difluoro-3,4,5-trimethoxy-phenylacetic acid (0.188, 0.720 mmol), CH₃CN (7 ml), EDCHCl (0.173 g, 0.900 mmol) and DMAP (0.073 g, 0.600 mmol). Purification afforded 0.061 g of Compound 142 (19% yield).

Spectral analysis of the product was consistent with Compound 142: MS (APCI) m/z 533.3 (M⁺+l).

CHN for (C₂₈H₃₄F₂N₂O₆) calculated: C 63.15, H 6.43, N 5.26; found: C 63.37, H 6.66, N 4.93.

The oxalyl diamides compounds of the present invention may be prepared in the manner depicted in Scheme G below:

Scheme G

wherein:

R_e and R_f are selected from alkoxy, heterocycloalkyl, heteroaryl, hydrogen, aryl, alkyl, or R_e and R_f together taken with an adjacent nitrogen atom form a heterocycle.

The following examples are illustrative of the present invention:

EXAMPLE IG Synthesis of 9,13-Imino-8H-azocino[2,l-a]isoquinoline-14-oxoacetate, O-methyl- 5,6,9, 10,11, 12,13, 13a-octahydro-3-methoxy-8-oxo-(Compound 110)

To a solution of the amine (Compound B, 1.65 g, 6 mmol, synthesized according to a published procedure [Katoh, S. and et al. WO00/04020]), in dichloromethane (30 mL) at 0°C were added methyl chlorooxoacetate (0.6 mL, 6.5 mmol) and N-methylmorpholine (0.77 mL, 7 mmol). After allowing the mixture to warm from 0°C to room temperature for over 5 hours, the mixture was partitioned between ethyl acetate and 0.5 N HCI. The aqueous layer was extracted with ethyl acetate (2x). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated. The crude residue was titrated with t-butylmethyl ether/hexanes and collected by filtration to give 1.83 g of the title compound (85% yield) yield.

Spectral analysis of the product was consistent with Compound 110: MS (ESP): 359 (M⁴).

Elemental analysis for (C₁₈H₂₂N₂O₅) calculated: C 63.68, H 6.19, N 7.82; found: C 63.43, H 6.21, N 7.74.

EXAMPLE 2G Synthesis of 9,13-Imino-8H-azocino [2,1-a] isoquinolin-8-one, 5,6,9,10,11,12,13,13a- octahvdro-3-methoxy-14-(oxo-l-pyrrolidinylacetyl)-(Compound 111)

A suspension of Compound 110 (0.15 g, 0.42 mmol) in pyrrolidine (1 mL) was stirred at room temperature for 30 minutes. The suspension was diluted with ethanol (1 mL) and stirred at room temperature for 18 hours. The mixture, which remained heterogeneous, was filtered and the solids washed with t-butylmethyl ether to give 136 mg of the title compound (78% yield).

Spectral analysis of the product was consistent with Compound 111: MS (ESP): 398 (M⁴).

Elemental analysis for (C₂2H₂₇N₃O₄ 0.2H₂O) calculated: C 65.88, H 6.89, N 10.48; found: C 65.87, H 6.74, N 10.49.

EXAMPLE 3G Synthesis of 9,13-Imino-8H-azocino [2,1-a] isoquinolin-8-one, 5,6,9,10,11,12,13,13a- octahydro-3-methoxy- 14-(oxo- 1 -pyperidinylacetyl)- (Compound 112)

To a suspension of Compound 110 (0.15 g, 0.42 mmol) in ethanol (1 mL) was added piperidine (10 mmol). The mixture, which quickly became homogenous, was stirred at room temperature for 18 hours, then at 50°C for 5 hours. The mixture was removed from heat and partitioned between ethyl acetate and 0.5 N HCI. The aqueous layer was extracted with ethyl acetate (2x). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated to dryness. The crude residue was titrated with ethyl acetate/hexanes and decanted leaving a small amount of insoluble residue behind. Upon standing at room temperature, a solid crystallized from the supernatant and was collected by filtration to give 80 mg of the title compound (46% yield). Spectral analysis of the product was consistent with Compound 112:

MS (ESP): 412 (M⁴).

Elemental Analysis for (C₂₃H₂₉N₃O₄) calculated: C 67.13, H 7.10, N 10.21; found: C 66.87, H 6.22, N 10.04. EXAMPLE 4G

Synthesis of 9,13-Imino-8H-azocino [2,1-a] isoquinolin-8-one, 14- [(2,5-dihydro-lH- pyrrol-l-yl)oxoacetyn- 5,6,9, 10,11, 12,13, 13a-octahydro-3-methoxy-(Compound 113)

To a suspension of Compound 110 (0.6 g, 1.68 mmol) in dioxane (2 mL) was added 3-pyrroline (1 mL, 12.8 mmol). The mixture, which quickly became homogenous, was stirred at 50°C for 4 hours, then allowed to cool to room temperature. As the mixture cooled, a solid began to precipitate from the solution. The solid was collected by filtration and washed with t-butylmethyl ether to give 0.525 g of the title compound (79% yield).

Spectral analysis of the product was consistent with Compound 113: MS (ESP): 396 (M⁴).

Elemental analysis for (C₂₂H₂₅N₃O₄) calculated: C 66.82; H 6.37, N 10.63; found: C 66.73, H 6.34, N 10.60. EXAMPLE 5G

Synthesis of 9,13-lmino-8H-azocino [2,1-a] isoquinolin-8-one, 14- [(cis-3,4-dihydroxy- l-pyrrolidinyl)oxoacetyl1- 5,6,9, 10, 11, 12, 13, 13a-octahvdro-3-methoxy-(Compound 115)

To a solution of the pyrroline amide (0.515 g, 1.3 mmol) in acetone (15 mL) at room temperature was added osmium tetroxide (2.5% in 2-methyl-2-propanol, 1.6 mL, 0.13 mmol) followed by N-methylmorpholine N-oxide^'(0.6 g, 5.1 mmol) as a solution in 2-methyl-2-propanol/water (1:1, 4mL). After stirring at room temperature for 4.75 hours, the mixture was quenched with 10% aqueous sodium bisulfite (2 mL) and stirred at room temperature for 30 minutes. The mixture was filtered and the filtrate partitioned between ethyl acetate and brine. The aqueous layer was extracted with ethyl acetate (5x). The combined organic layers dried over sodium sulfate and concentrated to dryness. The crude residue was purified by radial chromatography using gradient elution of 0-10% methyl alcohol in chloroform to give 0.36 g of the title compound (64% yield).

Spectral analysis of the product was consistent with Compound 115: MS (ESP): 430 (M⁴).

Elemental analysis for (C₂₂H₂₇N₃O₆0.4H₂O) calculated: C 60.51, H 6.42, N 9.62; found: C 60.33, H 6.31, N 9.44.

EXAMPLE 6G Synthesis of 9,13-Imino-8H-azocino [2,1-al isoquinolin-8-one, 5,6,9,10,11,12,13,13a- octahvdro-3-methoxy- 14- [oxo-(cis-3 ,6-tetrahydro-2,2-dimethyl-5H- 1 ,3-dioxolo[4,5- c1pyrrol-5-yl)acetyl]-(Compound 114)

To a solution of crude diol (-90% pure, 100 mg, 0.23 mmol) in dichloromethane (5 mL) at room temperature were added 2-methoxy propene (0.055 mL, 0.58 mmol) and p-toluenesulfonic acid (10 mg, 0.05 mmol). After stirring at room temperature for 2 hours, the mixture was partitioned between ethyl acetate and phosphate buffer (IM, pH=7). The aqueous layer was extracted with ethyl acetate (2x). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated to dryness. The crude residue was titrated with t-butylmethyl ether/hexanes and collected by filtration. The solid was recrystallized from t- butylmethyl ether to give 75 mg of the title compound (-90% pure, 69% yield). Spectral analysis of the product was consistent with Compound 114:

MS (ESP): 470 (M^4").

Elemental analysis for (C25H31N3O6O.6H₂O) calculated: C 62.51, H 6.76, N 8.75; found: C 62.41, H 6.73, N 8.73.

EXAMPLE 7G Synthesis of 9,13-Irnino-8H-azocino [2,1-al isoquinolin-8-one, 5,6,9,10,11,12.13.13a- octahvdro-3-methoxy-14-[oxo-(cis-3,6-tetrahvdro-2-oxo-5H-l,3-dioxolo[4,5-c]pyrrol- 5-yl)acetyl]-(Compound 116)

To a suspension of the diol (50 mg, 0.116 mmol) in dry THF (5 mL) was added carbonyl diimidazole (113 mg, 0.7 mmol). The mixture, which became homogenous, was stirred at 40°C for 1 hour. The mixture was removed from heat resulting in a suspension as the mixture cooled. The suspension was partitioned between ethyl acetate and 0.5 N HCI. The aqueous layer was extracted with ethyl acetate/methyl alcohol (9:1; 2x). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated to dryness. The crude solid residue was titrated with t- butylmethyl ether, collected by filtration, washed with water and dried under vacuum to give 21 mg of the title compound (39% yield). Spectral analysis of the product was consistent with Compound 116:

MS (ESP): 456 (M^4").

Elemental analysis for (C₂₃H₂₅N₃O₇O.3H₂0) calculated: C 59.94, H 5.60, N 9.12; found: C 59.93, H 5.66, N 9.04.

EXAMPLE 8G Synthesis of (Compound 121)

Compound 121 To a suspension of the methyl oxalate (Compound 110, 0.05 g, 0.14 mmol) in dioxane (0.5 mL) was added 6,7 -Dimethoxy- 1, 2,3 ,4-tetrahydroisoquinoline (0.13 g, 0.77 mmol). The mixture, which quickly became homogenous, was stirred at 50°C for 19 hours, then allowed to cool to room temperature. The mixture was then partitioned between ethyl acetate and citrate buffer (pH 4.5). The aqueous layer was extracted with ethyl acetate (2X). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated to dryness. The residue was purified by radial chromatography using a 2mm silica rotor with gradient elution of 0 to 3% methanol in chloroform to give the title compound (0.029 g) in 47% yield.

Spectral analysis of the product was consistent with Compound 121: Elemental Analysis for (C₂₉H₃₃N₃O₆O.l MTBE Η₂O) calculated: C 64.84; H 6.68; N 7.69; found: C 65.02; H 6.53; N 7.38. MS (electrospray): 520 (M⁴).

EXAMPLE 9G Synthesis of (Compound 122)

To a suspension of the methyl oxalate (Compound 110, 0.05 g, 0.14 mmol) in dioxane (0.5 mL) was added N-methylhomoveratryl amine (0.281 g, 1.4 mmol). The mixture, which quickly became homogenous, was stirred at 50°C for 19 hours, then allowed to cool to room temperature. The mixture was then partitioned between ethyl acetate and citrate buffer (pH 4.5). The aqueous layer was extracted with ethyl acetate (2X). The combined organics were washed with brine, dried over sodium sulfate and concentrated to dryness. The residue was purified by radial chromatography using a 2mm silica rotor with gradient elution of 0 to 5% methanol in chloroform to give the title compound (0.029 g) in 40% yield.

Spectral analysis of the product was consistent with Compound 122: Elemental Analysis for (C₂₉H₃₅N₃O₆ ' 0.4 MTBE ' 0.5H₂O) calculated: C 65.80; H 7.27; N 7.43; found: C 65.93; H 7.32; N 7.07. MS (electrospray): 522 (M^4").

EXAMPLE 10G Synthesis of (Compound 123

A suspension of the methyl oxalate (Compound 110, 0.05 g, 0.14 mmol) and l,2,3,4-tetrahydropyrido[4,3-B][l,6]naphthyridine (0.268 g, 1.4 mmol) in 2 mL dioxane was irradiated with microwaves at 2.45 GHz using a variable power (300 watt max) programmable microwave apparatus by Personal Chemistry. The solution was irradiated for 25 minutes at 140°C. Some solid remained which was removed by filtration. The filtrate was then partitioned between ethyl acetate and citrate buffer (pH 4.5). The aqueous layer was extracted with ethyl acetate (2X). The combined organics were washed with brine, dried over sodium sulfate and concentrated to dryness. The residue was purified by radial chromatography using a 2mm silica rotor with gradient elution of 0 to 5% methanol in chloroform to give (0.023 g) of the title compound in 32% yield.

Spectral analysis of the product was consistent with Compound 123: Elemental Analysis for (C₂₉H₂₉N₅O₄'1.4H₂O) calculated: C 64.89; H 5.97; N 13.05; found: C 64.89; H 5.98; N 12.65.

MS (electrospray): 512 (M⁴).

EXAMPLE 11G Synthesis of (Compound 124)

Compound 124

A solution of the methyl oxalate (Compound 110, 0.05 g, 0.14 mmol) and 4- piperidine ethanol (0.193 g, 1.4 mmol) in 2 mL dioxane was irradiated with microwaves at 2.45 GHz using a variable power (300 watt max) programmable microwave apparatus by Personal Chemistry. The solution was irradiated for 25 minutes at 140°C. The mixture was then partitioned between ethyl acetate and citrate buffer (pH 4.5). The aqueous layer was extracted with ethyl acetate (2X). The combined organics were washed with brine, dried over sodium sulfate and concentrated to dryness. The residue was purified by radial chromatography using a 2mm silica rotor with gradient elution of 0 to 6% methanol in chloroform to give (0.036 g) of the title compound in 56% yield.

Spectral analysis of the product was consistent with Compound 124: Elemental Analysis for (C₂₅H₃₃N₃O₅ ' 0.3 MTBE Η₂O) calculated: C 63.65; H 7.78; N 8.40; found: C 63.82; H 7.62; N 8.01. MS (electrospray): 456 (M⁴).

EXAMPLE 12G

Synthesis of (Compound 125)

A solution of the methyl ester (Compound 110, 0.05 g, 0.14 mmol) and l-(2- morpholinoethyl)-piperazine (0.293 g, 1.4 mmol) in 2 mL dioxane was irradiated with microwaves at 2.45 GHz using a variable power (300 watt max) programmable microwave apparatus by Personal Chemistry. The solution was irradiated twice for 25 minutes at 140°C. The mixture was then partitioned between ethyl acetate and brine. The aqueous layer was extracted with ethyl acetate (3X). The combined organics were washed with brine, dried over sodium sulfate and concentrated to dryness. The residue was purified by radial chromatography using a 2mm silica rotor with gradient elution of 0 to 8% methanol in chloroform to give the title compound (0.037 g) in 50% yield.

Spectral analysis of the product was consistent with Compound 125: Elemental Analysis for (C₂₈H₃₉N₅O₅ ' 0.3 CHC1₃ ' 0.75H₂O ' 0.75hexanes) calculated: C 61.59; H 8.09; N 10.95; found: C 61.54; H 7.97; N 10.68. MS (electrospray): 526 (M⁺).

EXAMPLE 13G Synthesis of (Compound 126)

A solution of the methyl ester (Compound 110, 0.05 g, 0.14 mmol) and l-(3- methoxyphenyl)-piperazine (0.273 g, 1.4 mmol) in 2 mL dioxane was irradiated with microwaves at 2.45 GHz using a variable power (300 watt max) programmable microwave apparatus by Personal Chemistry. The solution was irradiated for 2 minutes at 100°C, 5 minutes at 200°C, 15 minutes at 150°C, then twice for 25 minutes 140°C. The mixture was then partitioned between ethyl acetate and citrate buffer (pH 4.5). The aqueous layer was extracted with ethyl acetate (2X). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated to dryness. The residue was purified by radial chromatography using a 2mm silica rotor with gradient elution of 0 to 5% methanol in chloroform to give the title compound (0.027 g) in 37% yield. Spectral analysis of the product was consistent with Compound 126: Elemental Analysis for (C₂₉H₃ N₄O₅ ^' 0.2 MTBE ' H₂O) calculated: C 65.01; H 6.98; N

10.11; found: C 64.93; H 6.62; N 9.83.

MS (electrospray): 519 (M⁴).

EXAMPLE 14G

Synthesis of Compound 143

This compound was prepared as described Scheme G, using Compound 141

(0.208 g, 0.721 mmol), 2-oxo-3,4,5-trimethoxy -phenylacetic acid (0.208 g, 0.865 mmol), , THF (6 ml), EDCHCl (0.207 g, 1.080 mmol), HOBt (0.146 g, 1.080 mmol) and TEA (0.160 ml, 1.150 mmol). Purification afforded 0.086 g of Compound 143 (29% yield). Spectral analysis of the product was consistent with Compound 143:

MS (APCI) m/z 511.2 (M⁺+l).

CHN for (C₂₈H₃₄N₂O₇O.25 C₆H₁₄) calculated: C 66.59, H 7.10, N 5.26; found: C 66.98, H 7.25, N 5.07.

EXAMPLE 15G Synthesis of Compound 144

This compound was prepared as described in Scheme G, using Compound 141 (0.173 g, 0.600 mmol), 2-oxo-3,4-dichlorophenylacetic acid (0.158, 0.720 mmol), ), THF (6 ml), EDCHCl (0.172 g, 0.900 mmol), HOBt (0.121 g, 0.859 mmol) and TEA (0.135 ml, 0.959 mmol). Purification afforded 0.045 g of Compound 144 (15% yield).

Spectral analysis of the product was consistent with Compound 144: MS (APCI) m/z 489.1 (M⁺+l).

CHN for (C₂₅H₂6CI₂N₂O O.3O C₆H₁₄) calculated: C 62.47, H 5.91, N 5.44; found: C 62.43, H 5.78, N 5.09.

The heterobicycles compounds of the present invention may be prepared in the manner depicted in Scheme H below:

Scheme H

or

Heterobicycles

Heterobicycles

Wherein:

A', B' are nitrogen, sulfur, or oxygen. Example IH

Synthesis of Compound 158

Compound 158

An intimate mixture of 2-chlorobenzothiazole (1.05 mL, 8.06 mmol) and Compound B (2.00 g, 7.34 mmol) was heated at 150 °C under N₂ for 12 hours. The sample was cooled to room temperature, then partitioned between EtOAc and 10 % aqueous NH_tOH solution. The organic extract was washed with brine solution, dried (MgSO₄), filtered and concentrated. The crude sample was chromatographed (MPLC, silica gel, 25% EtOAc in hexanes) to give 0.41 g (14%) of the titled compound as a white solid, mp 168-170 °C.

Spectral analysis of the product was consistent with Compound 158: Calculated for C₂₃H₂₃N₃O₂S x 0.21 H₂O (409.306): C, 67.49; H, 5.77; N, 10.27; found: C, 67.49; H, 5.73; N, 10.06.

Example 2H Synthesis of Compound 159

Compound 159 This compound was prepared in a process analogous to Example IH, using

Compound C (Compound 13). An off-white solid, mp 207-209 °C.

Spectral analysis of the product was consistent with Compound 159:

Calculated for C₂₄H₂₅N₃O₃S x 0.20 H₂O (439.152): C, 65.64; H, 5.83; N, 9.57; found:

C, 65.66; H, 5.77; N, 9.38. Example 3H

Synthesis of Compound 160

Compound 160

A mixture of Compound B (2.00 g, 7.34 mmol), 2-chlorobenzoxazole (0.92 mL,

8.06 mmol) and N-ethyldiisopropylamine (1.41 mL, 8.10 mmol) in 100 mL of toluene was refluxed under N₂ for 12 hours. The sample was concentrated, then partitioned between EtOAc and saturated NaHCO₃ solution. The organic extract was washed with brine solution, dried (MgSO₄), filtered and concentrated. The crude sample was chromatographed (MPLC, silica gel, 25% EtOAc in hexanes) and recrystalhzed from CH₂Cl₂-Et₂O to give 1.29 g (45%) of the titled compound as a white solid, mp 175-178 °C.

Spectral analysis of the product was consistent with Compound 160: Calculated for C₂₃H₂₃N₃O₄ (389.458): C, 70.93; H, 5.95; N, 10.79; found: C, 70.81; H, 6.02; N, 10.70.

Example 4H Synthesis of Compound 161

Compound 161

This compound was prepared in a process analogous to Example 3H, using Compound C (Compound 13). A white solid, mp 202-210 °C.

Spectral analysis of the product was consistent with Compound 161: Calculated for C₂₄H₂₅N₃O₄ x 0.33 H₂O (425.430): C, 67.76; H, 6.08; N, 9.88; found: C, 67.75; H, 5.92; N, 9.55.

BIOCHEMICAL AND BIOLOGICAL ASSAYS :

A variety of assays and techniques may be employed to determine the activities of the compounds of the present invention. The activity of a compound of the invention for stimulation of neurite outgrowth can be directly related to its binding affinity for FKBP-12 and its ability to inhibit FKBP-12 rotamase activity. In order to quantify these latter properties, assays known in the art for measuring ligand binding and enzyme activity may be employed.

The affinity for FKBP-12 (Kø for the compounds set forth in Table 1 were measured using the assay set forth below:

In a quartz cuvette, a final 1 mL buffer concentration was reached (50mM Hepes, 100 mM NaCl, pH 8.0). Within this final reaction volume, 3.5 μL 20 mM FKBP-12 (in 50 mM Hepes, 100 mM NaCl, pH 8.0) and 10 μL test compound in DMSO were added. The reaction was initiated by adding 10 μL chymotrypsin (100 mg/mL in 1 mM HCI) followed by 5 μL (1-20 mM succinyl-Ala-Leu-Pro-Phe-pNA in 240 mM LiCl/TFE). The absorbance at 390 nM versus time was monitored for up to 400 seconds.

Rate constants were determined from the absorbance versus time plots generated.

NI = no inhibition at the concentration tested; ND = not detected; NSI = no significant inhibition at the concentration tested

PHARMACEUTICALS COMPOSITIONS AND TREATMENTS:

The compounds of the invention may be used to prepare pharmaceutical compositions, such as those described below. The pharmaceutical compositions of this invention comprise an effective neurite-outgrowth-stimulating compound of Formula (I) or (II) and an inert, pharmaceutically acceptable carrier or diluent. The pharmaceutical compositions may additionally comprise a neurotrophic factor.

In one embodiment, efficacious levels of non-peptide rotamase-inhibiting compounds are provided so as to provide therapeutic benefits involving regulation of FKBP. By "efficacious levels" of compounds is meant levels in which the FKBP binding of FKBP-12 is, at a minimum, regulated. The compounds may be administered in the form of a prodrug which, in general, is designed to enhance absorption and is cleaved in vivo to form the active component. Efficacious levels may also be achieved by administration of pharmaceutically active metabolites (products of metabolic conversions) of the compound.

The inventive agents may be administered by any of a variety of suitable routes, such as orally, rectally, transdermally, subcutaneously, intravenously, intramuscularly, or intranasally. The agents are preferably formulated into compositions suitable for the desired routes before being administered.

An inventive agent is preferably administered in conventional dosage form prepared by combining a therapeutically effective amount of an agent (e.g., a compound of Formula I or LI) as an active ingredient with appropriate pharmaceutical carriers or diluents according to conventional procedures. These procedures may involve mixing, granulating and compressing or dissolving the ingredients as appropriate to the desired preparation. A pharmaceutical composition or preparation according to the invention comprises an effective amount of the neurotrophic agent and a pharmaceutically acceptable carrier, such as a diluent or excipient for the agent. When the carrier serves as a diluent, it may be a solid, semi-solid, or liquid material acting as a vehicle, excipient, or medium for the active ingredient(s). Compositions according to the invention may be made by admixing the active ingredient(s) with a carrier, or diluting it with a carrier, or enclosing or encapsulating it within a carrier, which may be in the form of a capsule, sachet, paper container, or the like. Exemplary ingredients, in addition to one or more cell-cycle control agents and any other active ingredients, include Avicel (microcrystalline cellulose), starch, lactose, calcium sulfate dihydrate, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid, peanut oil, olive oil, glyceryl monostearate, Tween 80 (polysorbate 80), 1,3-butanediol, cocoa butter, beeswax, polyethylene glycol, propylene glycol, sorbitan monostearate, polysorbate 60, 2-octyldodecanol, benzyl alcohol, glycine, sorbic acid, potassium sorbate, disodium hydrogen phosphate, sodium chloride, and water. The compositions may be prepared in any of a variety of forms suitable for the desired mode of administration. For example, pharmaceutical compositions may be prepared in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as solids or in liquid media), ointments (e.g., containing up to 10% by weight of a cell-cycle control agent), soft-gel and hard-gel capsules, suppositories, sterile injectable solutions, sterile packaged powders, and the like.

Similarly, the carrier or diluent may include time-delay or time-release material known in the art, such as glyceryl monostearate or glyceryl distearate alone or with a wax, ethylcellulose, hydroxypropylmethylcellulose, methylmethacrylate and the like. A variety of pharmaceutical forms can be employed. Thus, if a solid carrier is used, the preparation can be tableted, placed in a hard gelatin capsule in powder or pellet form or in the form of a troche or lozenge. The amount of solid carrier may vary, but generally will be from about 25 mg to about 1 g. If a liquid carrier is used, the preparation can be in the form of syrup, emulsion, soft gelatin capsule, sterile injectable solution or suspension in an ampoule or vial or non-aqueous liquid suspension. To obtain a stable water-soluble dose form, a pharmaceutically acceptable salt of an agent is dissolved in an aqueous solution of an organic or inorganic acid, such as 0.3M solution of succinic acid or citric acid. If a soluble salt form is not available, the agent may be dissolved in a suitable cosolvent or combinations of cosolvents. Examples of suitable cosolvents include, but are not limited to, alcohol, propylene glycol, polyethylene glycol 300, polysorbate 80, gylcerin and the like in concentrations ranging from 0-60% of the total volume. In an exemplary embodiment, a compound of Formula (I) or (II) is dissolved in DMSO and diluted with water. The composition may also be in the form of a solution of a salt form of the active ingredient in an appropriate aqueous vehicle such as water or isotonic saline or dextrose solution. It will be appreciated that the actual dosages of the agents used in the compositions of this invention will vary according to the particular complex being used, the particular composition formulated, the mode of administration and the particular site, host and disease being treated. Optimal dosages for a given set of conditions can be ascertained by those skilled in the art using conventional dosage- determination tests in view of the experimental data for an agent. For oral administration, an exemplary daily dose generally employed is from about 0.001 to about 1000 mg/kg of body weight, with courses of treatment repeated at appropriate intervals. Administration of prodrug is typically dosed at weight levels which are chemically equivalent to the weight levels of the fully active form. The compositions of the invention may be manufactured in manners generally known for preparing pharmaceutical compositions, e.g., using conventional techniques such as mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing. Pharmaceutical compositions may be formulated in a conventional manner using one or more physiologically acceptable carriers, which may be selected from excipients and auxiliaries that facilitate processing of the active compounds into preparations which can be used pharmaceutically.

Proper formulation is dependent upon the route of administration chosen. For injection, the agents of the invention may be formulated into aqueous solutions, preferably in physiologically compatible buffers such as Hanks's solution, Ringer's solution, or physiological saline buffer. For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.

For oral administration, the compounds can be formulated readily by combining the active compounds with pharmaceutically acceptable carriers known in the art. Such carriers enable the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient to be treated. Pharmaceutical preparations for oral use can be obtained using a solid excipient in admixture with the active ingredient (agent), optionally grinding the resulting mixture, and processing the mixture of granules after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients include: fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; and cellulose preparations, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, or polyvinylpyrrolidone (PVP). If desired, disintegrating agents may be added, such as crosslinked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.

Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, polyvinyl pyrrolidone, Carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active agents.

Pharmaceutical preparations which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules can contain the active ingredients in admixture with fillers such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate, and, optionally, stabilizers. In soft capsules, the active agents may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added. All formulations for oral administration should be in dosages suitable for such administration. For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner. For administration intranasally or by inhalation, the compounds for use according to the present invention are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebuliser, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of gelatin for use in an inhaler or insufflator and the like may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.

The compounds may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion. Formulations for injection may be presented in unit-dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active agents may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.

For administration to the eye, a compound of the Formula (I) or (II) is delivered in a pharmaceutically acceptable ophthalmic vehicle such that the compound is maintained in contact with the ocular surface for a sufficient time period to allow the compound to penetrate the corneal and internal regions of the eye, including, for example, the anterior chamber, posterior chamber, vitreous body, aqueous humor, vitreous humor, cornea, iris/cilary, lens, choroid/retina and selera. The pharmaceutically acceptable ophthalmic vehicle may be an ointment, vegetable oil, or an encapsulating material. A compound of the invention may also be injected directly into the vitreous and aqueous humor.

Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use. The compounds may also be formulated in rectal compositions such as suppositories or retention enemas, e.g, containing conventional suppository bases such as cocoa butter or other glycerides. In addition to the formulations described above, the compounds may also be formulated as a depot preparation. Such long-acting formulations may be administered by implantation (for example, subcutaneously, intramuscularly, or intraocularly) or by intramuscular injection. Thus, for example, the compounds may be formulated with suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion-exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.

A pharmaceutical carrier for hydrophobic compounds is a cosolvent system comprising benzyl alcohol, a nonpolar surfactant, a water-miscible organic polymer, and an aqueous phase. The cosolvent system may be a VPD co-solvent system. VPD is a solution of 3% w/v benzyl alcohol, 8% w/v of the nonpolar surfactant polysorbate 80, and 65% w/v polyethylene glycol 300, made up to volume in absolute ethanol. The VPD co-solvent system (VPD: 5W) contains VPD diluted 1:1 with a 5% dextrose in water solution. This co-solvent system dissolves hydrophobic compounds well, and itself produces low toxicity upon systemic administration. Naturally, the proportions of a co-solvent system may be varied considerably without destroying its solubility and toxicity characteristics. Furthermore, the identity of the co-solvent components may be varied: for example, other low-toxicity nonpolar surfactants may be used instead of polysorbate 80; the fraction size of polyethylene glycol may be varied; other biocompatible polymers may replace polyethylene glycol, e.g. polyvinyl pyrrolidone; and other sugars or polysaccharides may be substituted for dextrose.

Alternatively, other delivery systems for hydrophobic pharmaceutical compounds may be employed. Liposomes and emulsions are known examples of delivery vehicles or carriers for hydrophobic drugs. Certain organic solvents such as dimethylsulfoxide also may be employed, although usually at the cost of greater toxicity. Additionally, the compounds may be delivered using a sustained-release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent. Various sustained-release materials have been established and are known by those skilled in the art. Sustained-release capsules may, depending on their chemical nature, release the compounds for a few weeks up to over 100 days. Depending on the chemical nature and the biological stability of the therapeutic reagent, additional strategies for protein stabilization may be employed.

The pharmaceutical compositions also may comprise suitable solid- or gel- phase carriers or excipients. Examples of such carriers or excipients include calcium carbonate, calcium phosphate, sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols. Some of the compounds of the invention may be provided as salts with pharmaceutically compatible counter ions. Pharmaceutically compatible salts may be formed with many acids, including hydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic, etc. Salts tend to be more soluble in aqueous or other protonic solvents than are the corresponding free-base forms. The inventive agents may be prepared using the reaction routes and synthesis schemes as described below, employing the techniques available in the art using starting materials that are readily available.

A pharmaceutical composition of the invention may be used in a method of inhibiting the rotamase enzyme activity of an FK-506 binding protein, comprising administering the composition to a patient. The inventive compositions may also be used to stimulate the growth of neurites in nerve cells, to stimulate nerve regeneration, or to promote neuronal regeneration. Preferably, the composition further comprises a neurotrophic factor.

While the invention has been illustrated by reference to specific and preferred embodiments, those skilled in the art will recognize, e.g., through routine experimentation and practice of the invention, that variations and modifications may be made. Thus, the invention is intended not to be limited by the foregoing description, but to be defined by the appended claims and their equivalents.

Claims

WHAT IS CLAIMED IS:

A compound of Formula (I):

wherein:

R' R' I

Q iβ R_L -ORi, -N-Rι, or -^N-^NRι^R" ;

R' R' I I Rι-_\-^f

Q' Ri, -ORi, -N-R -N-NR R" or

R' R' I

Q- is -ORi. -N-^ or -N-NRiR" wherein:

R} is hydrogen; substituted or unsubstituted alkyl, alkenyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, or cycloalkenyl; or C (R^π)(R¹²)(R¹³), wherein R¹¹ and R¹² each independently is substituted or unsubstituted alkyl, or R¹¹ and R¹² together with the atom to which they are bound form a substituted or unsubstituted cycloalkyl, and R¹³ is H, OH, substituted or unsubstituted alkyl, aryl, heteroaryl, or heterocycloalkyl, or

where n is 0, 1, 2, or 3, L¹ is R² or C(O)R², and R² is substituted or unsubstituted alkyl; R' is hydrogen; or substituted or unsubstituted alkyl, hydroxyl or amino; or R_\ and R' taken together with the adjacent nitrogen atom form a substituted or unsubstituted heterocycle (e.g., heterocycloalkyl, heteroaryl, etc.); R" is hydrogen or substituted or unsubstituted alkyl; or R_\ and R" taken together with the adjacent nitrogen atom form a substituted or unsubstituted heterocycle (e.g., heterocycloalkyl, heteroaryl, etc.);

A', B', C, and D" are independently carbon, oxygen, sulfur, or nitrogen;

E', F', G', and H' are independently carbon or nitrogen; F is hydrogen, a halide, alkyl, alkoxy, acyl, or amine; wherein there can be 1, 2, or 3 F groups, where I' can be attached to one or more of E', H\ F', or G'; J is hydrogen or substituted or unsubstitued alkyl, alkenyl, cycloalkyl, aryl, or heteroaryl; and

X is hydrogen, cyano, alkoxy, dimethoxymethyl, or oxygen, where when X is oxygen, the C-X bond is a double bond; or

X and J, taken together with the nitrogen heteroatom of the ring structure, form a substituted or unsubstituted heteroaryl or heterocycloalkyl; or a pharmaceutically acceptable salt, solvate, prodrug, pharmacologically active metabolites of said compound, or pharmaceutically acceptable salt of said metabolites.

2. A compound, pharmaceutically acceptable salt, or solvate, as defined in claim 1.

3. A compound, pharmaceutically acceptable salt, solvate, prodrug, or pharmaceutically active metabolite, as defined in claim 1, where: O=S=O

I z is Q

4. A compound, pharmaceutically acceptable salt, solvate, prodrug, or pharmaceutically active metabolite, as defined in claim 1, where:

5. A compound, pharmaceutically acceptable salt, solvate, prodrug, or pharmaceutically active metabolite, as defined in claim 1, where: O C — C Q"

II

Z is O

6. A compound, pharmaceutically acceptable salt, solvate, prodrug, or pharmaceutically active metabolite, as defined in claim 1, where:

7. A compound, pharmaceutically acceptable salt, solvate, prodrug, or pharmaceutically active metabolite, as defined in claim 3, wherein Q is phenylmethyl, 3-methylphenyl, 1-naphthalenyl, 4-(4-pyridinyIoxy)-phenyl, 4- methylphenyl, 4-(l,l-dimethylethyl)phenyl, 4-(l-methylethyl)phenyl, 4- ethylphenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 2,4- dinitrophenyl, 2-(l-naphthalenyl)ethyl, l,l'-biphenyl, 3-[(3,4,5- trimethoxyphenyl)amino]phenyl, 3 ' ,4' -dichloro[ 1 , 1 ' -biphenyl]-4-yl, 3 ' ,4' - dichloro[l,l'-biphenyl]-3-yl, 4-cyanophenyl, 6-chloro-3-pyridinyl, cis-2,6- dimethyl-4-morpholinyl, 1-piperidinyl, 4-morpholinyl, 3-(2-ethoxycarbonyl- phenylamino)-phenyl, or -NHR₂, wherein R₂ is 3,4-difluorophenyl, 3,4,5- trimethoxyphenyl, 6-chloro-3 -pyridinyl, 6-methoxy-3 -pyridinyl, 3,4- difluorophenyl, 2,3,4-trifluorophenyl, 3,4,5-trifluorophenyl, 2,4,5- trifluorophenyl, and 6-(4-morpholinyl)-3-pyridinyl; 3-pyridinyl, or 6-fluoro-3- pyridine.

8. A compound, pharmaceutically acceptable salt, solvate, prodrug, or pharmaceutically active metabolite, as defined in claim 4, wherein Q' is 1-1H- indozol-3-yl-methanoyl, difluoro(3 ,4,5-trimethoxyphenyl), difluoro(4- chlorophenyl), 3,4-dimethoxybenzoyl, or -NHR₄, wherein R₄is phenyl, 3- methoxyphenyl, phenylmethyl, 3-methylphenyl, or 4-nitrophenyl.

9. A compound, pharmaceutically acceptable salt, solvate, prodrug, pharmaceutically active metabolite, or pharmaceutically acceptable salt of said metabolite thereof, as claimed in claim 5, wherein Q"is (2,5-dihydro-lH-pyrrol- l-yl)-oxo or oxo- 1-piperidinyl.

10. A compound of formula:

wherein:

R is hydrogen, or substituted or unsubstituted alkyl; D' is C, O, or N; each X' is independently halogen, methoxy, amine wherein there can be 1, 2, or

3 X' groups, where X' can be attached to one or more of A, D, E, or the carbon atom of the ring;

A, D, and E are each independently carbon, oxygen, or nitrogen; and

R | ' R I '

Q is R i, -ORi -N-R., or ^" -N-NR^

Q' Ri, -ORi, -

R I ' R 1 '

1

Q" is - OR_b ^" -^N-^Rι , or -N- -NR-,R" wherein: R_ϊ is hydrogen; substituted or unsubstituted alkyl, alkenyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, or cycloalkenyl; or C (R^π)(R¹²)(R¹³), wherein R^π and R¹² each independently is substituted or unsubstituted alkyl, or R^π and R¹² together with the atom to which they are bound form a substituted or unsubstituted cycloalkyl, and R¹³ is H, OH, substituted or unsubstituted alkyl, aryl, heteroaryl, or heterocycloalkyl, or (CH₂)_n-O-L¹, where n is 0, 1, 2, or 3, L¹ is R² or C(O)R², and R² is substituted or unsubstituted alkyl; R' is hydrogen; or substituted or unsubstituted alkyl, hydroxyl or amino; or Ri and R' taken together with the adjacent nitrogen atom form a substituted or unsubstituted heterocycle (e.g., heterocycloalkyl, heteroaryl, etc.);

R" is hydrogen or substituted or unsubstituted alkyl; or Ri and R" taken together with the adjacent nitrogen atom form a substituted or unsubstituted heterocycle (e.g., heterocycloalkyl, heteroaryl, etc.);

A', B', C, and D" are independently carbon, oxygen, sulfur, or nitrogen; E\ F', G', and H' are independently carbon or nitrogen;

F is hydrogen, a halide, alkyl, alkoxy, acyl, or amine; wherein there can be 1, 2, or 3 F groups, where F can be attached to one or more of E' , H' , F' , or G' ; or a pharmaceutically acceptable salt, solvate, prodrug, pharmacologically active metabolites of said compound, or pharmaceutically acceptable salt of said metabolites.

11. A compound, pharmaceutically acceptable salt or solvate, as defined in claim 10.

12. A compound, pharmaceutically acceptable salt, solvate, prodrug, or pharmaceutically active metabolite as defined as in claim 10, wherein X' is 3- methoxy, 1,3-dimethoxy, 4-methoxy, or l,3-dimethoxy-4-chloro.

13. A compound, pharmaceutically acceptable salt, solvate, prodrug, or pharmaceutically active metabolite, as defined in claim 10, wherein D' is carbon.

14. A compound, pharmaceutically acceptable salt, solvate, prodrug, or pharmaceutically active metabolite, as defined in claim 10, wherein R is hydrogen

15. A compound of Formula:

wherein:

J is hydrogen or substituted or unsubstituted alkyl, alkenyl, or cycloalkyl;

X is selected from hydrogen, cyano, alkoxy, dimethoxymethyl, and oxygen, where when X is oxygen, the C-X bond is a double bond; or X and J taken together with the nitrogen heteroatom of the ring structure, form a substituted or unsubstituted heteroaryl or heterocyclalkyl ring, or a pharmaceutically acceptable salt, solvate, prodrug, pharmacologically active metabolites of said compound, or pharmaceutically acceptable sait of said metabolites.

16. A compound selected from the group consisting of:

a pharmaceutically acceptable salt or solvate thereof.

17. A compound, pharmaceutically acceptable salt or solvate, as claimed in claim 10, wherein said compound is selected from the group consisting of:

18. A compound according to claim 10, wherein said compound is selected from the group consisting of:

a pharmaceutically acceptable salt or solvate thereof.

19. A compound selected from the group consisting of:

wherein:

Z is benzyloxycarbonyl, t-butoxycarbonyl or FMOC ; or a pharmaceutically acceptable salt or solvate thereof.

20. A pharmaceutical composition for treating a neurological disorder in a patient comprising a therapeutically effective amount of a compound, pharmaceutically acceptable salt, prodrug, solvate, or pharmacologically active metabolite as defined in 1, and a pharmaceutically acceptable carrier.

21. A pharmaceutical composition according to claim 20, further comprising a neurotrophic factor.

22. A method of treating a neurological disorder in a patient, comprising administrating to the patient a therapeutically effective amount of a compound, pharmaceutically acceptable salt, solvate, prodrug, or pharmacologically active metabolite, as defined in claim 1.

23. A method according to claim 22, wherein the neurological disorder is selected from the group consisting of peripheral neuropathies caused by physical injury or disease state, physical damage to the brain, physical damage to the spinal cord, stroke associated with brain damage, and neurological disorders relating to neurodegenaration.

24. A method according to claim 22, wherein the neurological disorder is Parkinson's disease, Alzheimer's disease, or amyotrophiclateral sclerosis.

25. A method according to claim 22, wherein the neurological disorder is memory impairment, hair loss, vision impairment, or hearing loss.