CA2446795A1 - Sulfamide, sulfamate, sulfonamide, urea, amide, alpha, alpha-difluoro amide oxalyl diamide, and heterobicycles fkbp-binding 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
1 o 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-15 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:
20 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).
25 The 12-kiloDalton FK-506 binding protein, FKBP-12, binds FK-506 with high affinity. Such binding has been directly measured using mierocalorimetry 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-[1-14C]-benzoyl-FK-506 (see Harding et al., Nature, 341, 758-60 (1989)). Binding affinity of other 3o 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 35 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., Bioclzina.

Biophys. Acta, 791, 87 (1984); Fischer et al., Biozzzed. 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. Chezn., 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-to 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 15 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
20 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;
25 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 98137882, WO 99/45006, WO 00127811, WO 00/09102, WO 00/05232, WO 99/6251, WO
30 00/46181, and WO 00/32588. See also U.S. Serial No. 09/726,314, filed December l, 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 FKSP-type immunophilins, there remains a need for additional neurotrophic agents. In particular, 35 there is a need for neurotropic agents that are potent inhibitors of the enzyme activity and especially of the cis-traps propyl isomerase (rotamase) activity of the FI~BP-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 FKEP is not necessary for neuronal activity.
DISCLOSURE OF INVENTION:
The invention relates to certain small-molecule neurotrophic compounds, such as those having affinity for FKEP-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 2o 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 ischernia 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 3o 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):
(I) and to pharmaceutically acceptable salts, solvates, prodrugs, pharmacologically active metabolites of such compounds, and pharmaceutically acceptable salts of said to metabolites. In Formula (I):
O O C
II
O- i ~O , -C-Q~ ~ -C_C-Q~~ E\ H, Z is Q O , or F G
R' R' I I
Q is R1, -OR1, -N Ri, or -N'NRiR";
R' R' _ I I R1 Q' Rl, -ORl, N R~ , -N'NRi R" or R' R' I
Q" is -OR1, -N-R1, or -N'NRiR"
wherein:
Rl is hydrogen; substituted or unsubstituted alkyl, alkenyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, or cycloalkenyl; or C (Rll)(Rl~)(R13), wherein Rll and R12 each independently is substituted or unsubstituted alkyl, or Ril and 2o 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 (CHZ)n O-Ll, where n is 0, 1, 2, or 3, Ll 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 Rl 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 Rl 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 T' groups, where I' 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 (II):
X' D
' X' i E
(B) 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;
to 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 2o pharmaceutically acceptable salt, solvate, prodrug, phahrnacologically 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 FI~BP 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 3o 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 to 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 2o 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 de ict p the bond that is the point of attachment of the moiety or substituent to the core or 3o 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 monovalent 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-l0 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,0, > > > >
and 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 20 nitrogen, oxygen, and sulfur. Illustrative examples of heterocycloalkyl groups include the following moieties:

R O
O N
RN NR
N ~ N N N
O~ R O R R R
> > > > > > >
N O~ O
O
,N ~ ~ S~NR
N
S ~N J O R
> > > > >
O O
N O NJ N N
R R R and > > > > > .
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 1o 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, I-H-tetrazol-5-yl, indolyl, quinolinyl, benzofuranyl, benzothiophenyl (thianaphthenyl), and the like.
Illustrative examples of aryl groups include the following moieties:
/ / \ / \ \
\ , \ / , \ / / , and 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:

I \ N I \ N
n N I ~ ~ ~~ N I \
s R ~ S ~ N ~ O ~ R ~ S ~ S
I N / / N i~ /
N~ I ~ ~ ~ ~ J ~ I ~ N
R O N N N N
> > > > > > >
N/\N NON N/\N / I \ / \
II I II \ N~ I
wN \ N N~ N R \ S
> > > > >
/ N
/ N / ~. / \
v \ I N I ~ N I
\ ~ r~ \
R O \ ~ N
> > > >
N
/ \ ~ I ~N / ~N / I
\ I iN \ NJ \ I iN \ N
a > > > >
\ I \ ~ / S N.~ I \ ~N
N
1o R , S , and N
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 15 defined below.
As used herein, the term "sulfonyl" refers to the -SOZ-R radical, where R is as defined below.
As used herein, the term "nitro" refers to the - C (N02)-R radical, where R is as defined below.
2o 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 -ORa , where Ra 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 to substituted, the substituent may be a: halogen (chloro, iodo, bromo, or fluoro); Cl_~-alkyl; Cl_~-alkenyl; CI_~-alkynyl; hydroxyl; Cl_6 alkoxyl; amino; vitro;
imine; 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, isoquinolinyl, acridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, benzimidazolyl, benzothiophenyl, or benzofuranyl);
amino (primary, secondary, or tertiary); vitro; O-lower alkyl; O-aryl; aryl; aryl-lower alkyl;
C02CH3; CONH~; OCHZCONH2; NH2; SOZNHZ; OCHF2; CF3; Or OCF3. Such moieties may also be optionally substituted by a fused-ring structure or bridge, for example OCHa-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, 3o 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 to 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,G-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, ~y-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, malefic acid, succinic acid, rnandelic 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.
3o 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.
to "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 15 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. Chefn., 40, (1997); Shan et al., J. Phann. Sci., 86 (7), 765-767; Bagshawe, Drug Dev.
Res., 34, 220-230 (1995); Bodor, Advances iu Drug Res., 13, 224-331 (1984); Bundgaard, 20 Design of Prodrugs (Elsevier Press 1985); and Larsen, "Design and_Application of Prodrugs, Drug Design and Development" (I~rogsgaard-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 25 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 3o 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 35 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 (IIa):
X' (IIa) wherein:
R, D', X', A, D, E, and Q are as previously defined for the compound of 2o Formula (II).
Preferably, Q is phenylmethyl, 3-methylphenyl, 1-naphthalenyl, 4-(4-pyridinyloxy)-phenyl, 4-methylphenyl, 4-(1,1-dimethylethyl)phenyl, 4-(1-methylethyl)phenyl, 4-ethylphenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 2,4-dinitrophenyl, 2-(1-naphthalenyl)ethyl, l,l'-biphenyl, 3-[(3,4,5-trimethoxyphenyl)amino]phenyl, 3',4'-dichloro[1,1'-biphenyl]-4-yl, 3',4'-dichloro[1,1'-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, where 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, 6-(4-morpholinyl)-3-pyridinyl, 3-pyridinyl, or 6-fluoro-3-pyridine.
Preferably, X' is 3-methoxy, 1,3-dimethoxy, 4-methoxy, or 1,3-dimethoxy-4-chloro.
Preferably, D' is carbon.
l0 R is preferably hydrogen.
Particularly preferred are compounds of the Formula (IIb):
X' wherein:
R, D', X', A, D, E, and Q' are as previously defined for the compound of Formula (II).
Preferably, Q' is 1-1H-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.
2o Preferably, D' is carbon.
Preferably, R is hydrogen.
Particularly preferred are also compounds of the Formula (IIc):

X' R
X' (IIc) 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-1H-pyrrol-1-yl)-oxo, or oxo-1-piperidinyl.
to 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 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride;
DCC is 1,3-dicyclohexylcarbodiimide; DMAP is 4-dimethylaminopyridine; DMF is N, N-dimethylformamide; HATU is O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; HRMS is high resolution mass spectrum;
2o 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 N X.
/~ H
O' -N' D
D~ I E

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):
to i8 Scheme 1 /Z =__--1. phi Acetic anhydride N NHz HOOC N~COOH °
Z 1 ~~ C O O O 2~ Ac otic anhydride Z
N ---__ 2. TFA
O N OH
N
1. NaBH4 '~",~~yPh 4a + Z
O N O
'~~t,.~yPh diastereomeric H2/Pd-C
mixture HO N O
"" 4b .~yPh ~nthesis of 9,I3-Imino-8H-azocino(2,1-alisoquinolin-8-one,5,6,9,10,11,12,13,13a-octahydro-6-methyl-,(6S,9S,13R,13aR)-(9C1)- (Compound 6) Step 1: Synthesis of Compound 1:
HOO ~N~ COO
Compound 1 2,6-Pyridine dicarboxylic acid (25 g, 0.15 mol) was dissolved in 2.0M NaOH
(154 mL) and H20 (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 2o 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 HCl and extracted with ethyl acetate (EtOAc).
The EtOAc was passed over a short plug of Na2S04 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).
to Spectral analysis of the product was consistent with Compound 1:
Rf = 0.06 (10% MeOH/CHCl3).
+iH NMR: 81.49 -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:
z _N~~~
O O O
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 ira vacuo, to afford Compound 2 (18.5 g, 100°70) 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: 81.57 - 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:
z N
O' 'N ~O Compound 3 """.:~Ph A suspension of piperidine-1, 2, 6-tricarboxylic acid 1-benzyl ester (Compound 3o 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 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): 8 7.40 - 7.I2 (10H, m), 5.18 - 5.08 (3H, m), 4.82 (1H, br s), 4.74 (1H, br s), 3.29 (IH, dd, J = 13.7, 10 Hz), 3.03 (IH, dd, J = 13.69, 6.8 Hz), 1.8I-1.48 (6H, m), 1.43 (3H, d, J = 6.9 Hz).
Step 4: Synthesis of Compound 5:
Z
N
Compound 5 Compound 4b NO N O
''~~~,.:~Ph 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°70 yield.
to Spectral analysis of the product was consistent with Compound 5:
MS (electrospray): 391 (M+).
1H NMR (CDC13, mixture of rotamers): 8 7.54 - 7.51 (1H, m), 7.39 - 7.12 (8H, m), 5.30 -5.03 (3H, m), 4.73 - 4.45 (2H, m), 4.36 (1H, s), 3.10 (1H, dd, J = 15.5, 6. 7 Hz), 2.63 -2.55 (1H, 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[2,1-a]isoquinolin-8-one,5,6,9,1011,12,13,13a-octahydro-6-methyl-,(6S,9S,13R,13aR)-(9C1) (Compound Compound 6 (Core D) 6):
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 H2 atmosphere at room temperature for 18 hours. The mixture was filtered through a 0.45 ~, PFTE
membrane and the filtxate 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): 8 7.29-7.16 (4H, m), 4.89 (1H, q, J = 6.5 Hz), 4.37 (1H, s), 4.01 (1H, s), 3.46 (1H, br s), 3.15 (1H, dd, J = 15.8, 6. 5 Hz), 2.55 (1H, 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 /Z
1. ph~
Acetic anhydride N NHp HOOC ~~COOH a Z 1 70 C O O p 2~ Ac otic anhydride Z
i i N
Z 2. TFA
/ O N OH -'-' N
1. NaBH4 ,~Ph $a O N O + 'Z
i ~Ph N diastereomeric H2/Pd-C
mixture HO ~N ~O $b ~Ph _) Synthesis of 9,13-Imino-8H-azocino f2,1-al isoquinolin-8-one, 5,6,9,10,11,12,13,13a-octahydro-6-methyl-, (6R, 9R, 135, l3aS)-(9Cl) (Compound 10) Step 1: Synthesis of Compound 7:
z N
O N O Compound 7 ~Ph 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 rnmol) 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 (CDCl3): b 7.39-7.12 (10H, m), 5.16 - 5.09 (3H, m), 4.82 (1H, br s), 4.74 (1H, br s), 3.29 (1H, dd, J = 13.7, 10 Hz), 3.03 (1H, 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:
1o MS (ESP): 391 (M+).
1H NMR (CDCl3, mixture of rotamers): 8 7.54 - 7.51 (1H, m), 7.35 - 7.16 (8H, m), 5.30 -5.04 (3H, m), 4.67 - 4.47 (2H, m), 4.36 (1H, s), 3.10 (1H, dd, J = 15.4, 6.6 Hz), 2.63 -2.55 (1H, 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, 135, l3aS)-(9C1) (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 1--Step 5). The title compound was obtained in quantitative yield.
2o Spectral analysis of the product was consistent with Compound 10:
1H NMR (CDCl3): 8 7.27 - 7.16 (4H, m), 4.90 (1H, q, J = 6.5 Hz), 4.37 (1H, s), 4.02 (1H, s), 3.47 (1H, br s), 3.15 (1H, dd, J =15.8, 6.5 Hz), 2.55 (1H, 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 O-Z
1. H2N
Acetic anhydride HOOC H COON o Z 1 ~0 C O O O 2. Ac otic anhydride 1. NaBH4 2. TFA

12 13 (Core C) Synthesis of 9,13-Imino-8H-azocino f2,1-al isoduinolin-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 1--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): 8 7.39 - 7.32 (5H, m), 6.39 (2H, d, J = 2.2 Hz), 6.32 (1H, 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).
2o 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 1--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:
1o MS (ESP): 437 (M+).
1H NMR (CDC13, mixture of rotamers): 8 7.30 - 7.19 (4H, m), 6.90 - 6.89 (1H, m), 6.36 and 6.21 (1H, two s), 6.24 (1H, s), 5.17 (1H, s), 5.09 - 4.70 (4H, m), 4.59 and 4.58 (1H, two s), 3.85, 3.80, 3.78 and 3.64 (6H, four s), 2.96 - 2.87 (1H, m), 2.79 -2.64 (1H, m), 2.50 (1H, d, J = 5.9 Hz), 2.09 - 1.90 (2H, m), 1.80 - 1.60 (4H, m).
15 Step 3: 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- (9C1) (Compound 13):
Compound 13 (Core C) The cyclized product 12 was deprotected in a fashion similar to that of the Compound 6 synthesis (Example 1--Step 5). The title compound was obtained in 2o quantitative yield.
Spectral analysis of the product was consistent with Compound 13:
1H NMR (CDC13): 8 6.35 (1H, d, J = 2.2 Hz), 6.27 (1H, d, J = 1.9 Hz), 4.97 (1H, m), 3.80 (6H, s), 3.74 (1H, s), 3.52 (1H, s), 3.03-2.92 (1H, m), 2.68 (1H, dt, J =
7.4, 2.8 Hz), 2.57 (1H, d, J = 16.2 Hz), 2.00 - 1.59 (6H, m).
25 Scheme 4, which is depicted below, is useful for preparing Compound 17 (Compound G):

Scheme 4 z z l.aqueous Acetic anhydride N NHzOH N
HOOC Z 1 COO ~o°C O O O 2- o O N O
~H 14 z Br~O~ N
/~ l1 // IaBH4 KpCOg l18-crown-6 -FA O
o ~ i o H
N
H2/Pd-C
O N ~ 1 ~ (Core G) / Oi Synthesis of 9,13-Imino-oxa-6-8H-azocino f~,1-al isoquinolin-8-one,5,9,10,11,12,13,13a-heptahydro-3-methox~(9Cl) (Compound 17) to Step 1: Synthesis of Compound 14:
z N
Compound 14 O N O
OH
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 15 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 lOlH ion exchange resin (prewashed, 80 mL) was added to the 2o 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 l0 (Compound 14, 1.26 g) in 64% yield.
Spectral analysis of the product was consistent with Compound 17:
1H NMR (DMSO-d~): S 10.43 (1H, 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 (1H, m).
Step 2: Synthesis of Compound 15:
mpound 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): S 7.40 - 7.22 (6H, m), 7.06-7.01 (2H, m), 6.91 - 6.87 (1H, 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 (1H, 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 1--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~) to ~H NMR (CDCI3, mixture of rotamers): ~ 7.35 - 7.08 (6H, m), 6.87 - 6.85 and 6.65 -6.61 (1H, two sets of m), 6.55 (1H, 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, 5,9,10,11,12,13,13a-heptahydro-3-methoxy-(9Cl) (Compound 17):
impound 17 (Core G) 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:
2o MS (ESP): 275 (M+) 1H NMR (CDCI3): S 7.14 (1H, d, J = 8.7 Hz), 6.85 (1H, dd, J = 8.6, 2.5 Hz), 6.59 (1H, d, J = 2.5 Hz), 5.43 (1H, d, J = 14.5 Hz), 4.83 (1H, d, J = 14.5 Hz), 4.94 (1H, s), 3.86 (1H, s), 3.80 (3H, s), 3.58 (1H, s), 2.06 -1.67 (6H, m).
General Scheme 5, which is depicted below, is useful for preparing Compounds K, and L:
Scheme 5 ~z 2j i TFAEt3) N
AczO N 1) P~~NHZ N~ ii. BF3:OEt~
HOC Nz C02H ~ 2) AczO O N O ~ O N I
O O O Ph /

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 (I.1 eq.) was added and the mixture was stirred for I.5 hours at room l0 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, NaHC03 (saturated aqueous) and 30% H202 were added and the mixture was stirred for 30 minutes at room temperature. The solution was then concentrated, diluted with water, extracted with CHZCl2 , organics combined, dried over MgSO~/NaZS04, filtered and concentrated. The residual oil was taken up in dry CHZC12 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 NaHC03 (saturated aqueous), extracted with CH2Cl2, dried over MgS04/Na2S04, 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.
3o EXAMPLE 5 ~nthesis of Compound K
H
N
O N
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++1).
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 rnmol) THF (15 ml), TFA (2 ml), CHZC12 (15 ml) I5 and BF3:OEt2 (1.0 ml). Concentration of the fractions containing the desired product gave 0.5193 g of 127K (69% yield from 3I~).
Spectral analysis of the product was consistent with Compound 127K:
MS (APCI) m/z 261.0 (M++1).

Synthesis of Com op and L
H
N
p~N I \
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 ~.
Spectral analysis of the product was consistent with Compound 3L:
MS (APC~ m/z 407.1 (M++1).
Step 2: Synthesis of Compound L (Compound 127L):
3o Compound 127L was prepared according to Scheme5--Step 2, using 3L (I.48 g, 3.64 mmol), Li(HBEt3) (6.19 ml, 6.19 mmol) THF (18 ml), TFA (5 ml), CHZCl2 (20 ml) and BF3:OEt2 (2.0 ml). Concentration of the fractions containing the desired product gave 0.550 g of 127L (60 % yield from 3L).
Spectral analysis of the product was consistent with Compound 127L:
MS (APCI) m/z 257.0 (M++1).
to Scheme 6, which is depicted below, is useful for preparing cc,a-difluoro acids:
Scheme 6 O F F ~ F F
~OH -oASr ~OH
~N
Ar oH~ r~ ~ + Ar O O O
NaOH
F F
Ar~OH
O

Synthesis of a,a-difluoro-3, 4,5-trimethoxy-phenylacetic acid (Compound 18) Compound 18 /_ compound 19 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 2o 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): ~ 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 (CDC13): 8 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+) 2o Synthesis of oc,cc-Difluoro-4-choro-phenylacetic acid (Compound 20) F F F F
OH
o ci ~ o ci Compound 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°10 overall).
Spectral analysis of the product was consistent with Compound 20:
1H NMR (CDCl3): & 9.25 (1H, 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 3o derivative (Compound 21):
' H NMR (CDC13): 8 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, I~, L, and Compounds I 8-Z I were used to prepare sulfonamides, sulfamides, sulfamates, ureas, amides, oxalyl diamides, oc,cc-difluoroarylacyl heterobicycles derivatives of the present invention:
N N N
O
O N ~ \ O N ~ \ O N ~ \
O
Compound A Compound B Compound C (Compound (W00004020) ' (W00004020) ' 13) ' N
. ,o~H H
O N \ O N \ O N \
/ ~N
.~, I I, O
Compound D ' Compound E ~ Compound F
(Compound 6) (Compound 10) (Tetrahedron Lefters 2000, 41, 5307-5311 ) H H
N N
N
O N ~ \ F O N ~ \
p ~ / / /
O/ , , 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
O Si Ra \\
H O

O N Y Base O N Y
X X
wherein:
X and Y are as defined in Compound (~;

Ra is selected from substituted or unsubstituted aryl, alkyl, heteroaryl, and heterocycloalkyl.
The following examples are illustrative of the present invention:

Synthesis of 9,13-Imino-8H-azocino f2,1-al isoquinolin-8-one, 5,6,9,10,11,12,13,13a-octahydro-4-methoxy-14-f(3-methylphenyl)sulfon l~l-(Compound 63) 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).
2o Spectral analysis of the product was consistent with Compound 63:
MS (APC)7 427.1 (M+H+).
Elemental analysis for (C23HZ~N204S O.lOC3H7NO O.OSHZO) calculated: C 64.37, H
6.21, N 6.77; found: C 64.05, H 6.06, N 6.42.

Synthesis of 9,13-Imino-8H-azocino f 2,1-al isoquinolin-8-one, 5,6,9,10,11,12,13,13a-octahydro-4-methoxy-14-f(4-methylphenyl) sulfonyll-(Compound 36) pound 36 /O
This compound was prepared similar to Example 1A, using Compound A
(0.0326 g, 0.1189 mmol), which was synthesized according to a published procedure (I~atoh, S. and et al. W00004020), 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 1o 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 (C23H2GN204S O.15C3H7NO~O.15H~O) calculated: C 63.98, H
6.26, N 6.84; found: C 63.7, H 6.05, N 6.45.
is EXAMPLE 3A
Synthesis of 9,13-Imino-8H-azocino f2,1-al iso~uinolin-8-one, 5,6,9,10,11,12,13,13a-octahydro-3-methoxy-14-f (4-methy~henyl) sulfonyll-(Compound 37) impound 37 This compound was prepared similar to Example 1A, using Compound B
20 (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:
25 MS (APCI) 427.1 (M+H+) Elemental analysis for (C23H26N204S~O.1OC3H7NO~O.4H2O) calculated: C 63.45, H
6.28, N 6.67; found: C 63.11, H 6.00, N 6.30.

Synthesis of 9,13-Imino-8H-azocino X2.1-al isoauinolin-8-one. 14-f~4-(1.1 dimeth 1~! ethyl) phenyllsulfonyll-5,6,9,10,11,12,13,13a-octahydro-3-methox~
(Compound 38) I I

O N ~ \ Compound 38 O~
l0 This compound was prepared similar to Example 1A, 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 annine (0.0339 mL, 0.195 mmol). Filtration of the final precipitate gave 0.0691 g of Compound 38 (75% yield).
15 Spectral analysis of the product was consistent with Compound 38:
MS (APCI) 469.1 (M+H+).
Elemental analysis for (C26H32N2O4S~O.OSC3H7NO~O.65HZO) calculated: C 64.90, H
7.01, N 5.93; found: C 64.5, H 6.78, N 5.63.

20 Synthesis of 9,13-Imino-8H-azocino X2,1-al iso~uinolin-8-one, 5,6,9,10,11,12,13,13a octahydro-3-methoxy-14-([4-(1-methylethyl) phenyllsulfon~l-(Compound 39) I I
\ Compound 39 O N , This compound was prepared similar to Example 1A using Compound B
(0.0521 g, 0.191 mmol), DMF (1 mL), p-i-propyl phenylsulfonyl chloride (0.0626 g, 25 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+Ii+).

Elemental analysis for (C24H3~N2O4S~1.45HZO) calculated: C 62.46, H 6.90, N
5.83;
found: C 62.18, H 6.28, N 5.60.

Synthesis of 9,13-Imino-8H-azocino~2,1-al isoduinolin-8-one, 5,6,9,10,11,12,13,13a-octahydro-1,3-dimethoxy-14-f (4-meth~phenyl)sulfonyll-(Compound 40) Compound 40 This compound was prepared similar to Example 1A 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 CHZC12 (3x10 mL). The organic layers were combined, dried over MgS04, 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:
2o MS (APCI) 457.2 (M+H+).
Elemental analysis for (C24HZgN2O5S~O.15C6H14) calculated: C 63.70, H 6.46, N
5.97;
found: C 64.03, H 6.65, N 5.68.

Synthesis of 9,13-Imino-8H-azocino f2,1-al isoquinolin-8-one, 5,6,9,10,11,12,13,13a-octahydro-1,3-dimethox -~phenylmethyl)sulfon~(Compound 41) Compound 41 This compound was prepared similar to Example 1A, 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
CHZCl2. The organic layers were combined, dried over MgS04, filtered, concentrated l0 onto silica and purified by MPLC (hexane/ethyl acetate gradient 90:10 to 40:60).
Concentration of the fractions containing the desired pxoduct 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+).
15 Elemental analysis for (C24H28N205S~0.15C4H802) calculated: C 62.90, H
6.27, N 5.96;
found: C 62.83, H 6.54, N 5.64.
EXAMPLE ~A
Synthesis of 9,13-Imino-8H-azocino f2,1-al isoquinolin-8-one, 14-ff4-(1,1-dimethylethyl) phenyllsulfonyll-5,6,9,10,11,12,13,13a-octahydro-1,3-dimethoxy-20 (Compound 42) and 42 This compound was prepared similar to Example 1A 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 25 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:
3o MS (APCI) 499.1 (M+H+) Elemental analysis for (C27H34NZOSS) calculated: C 65.04, H 6.87, N 5.62;
found: C
65.19, H 7.02, N 5.24.

Synthesis of 9,13-Imino-8H-azocino f2,1-al isoquinolin-8-one, 5,6,9,10,11,12,13,13a-octahydro-1,3-dimethoxy-I4-ff4-(1-methylethyl)phenyllsulfon~l-(Compound 43) ipound 43 This compound was prepared similar to Example 1A 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 mL, 0.369 mmol). Filtration of the final precipitate gave the product which was dissolved in CH2C1~, 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+H+).
Elemental analysis for (C26H32N2~SS) calculated: C 64.44, H 6.66, N 5.78;
found: C
64.50, H 6.94, N 5.52.

Synthesis of 9,13-Imino-8H-azocino f2,1-al isoquinolin-8-one, 14-f(4-ethylphenyl)sulfonyll-5,6,9,10,11,12,13,13a-octah~dro-1,3-dimethoxy (Compound 44) npound 44 This compound was prepared similar to Example 1A 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 CHaCl2, concentrated onto silica and purified by MPLC (liexanelethyl acetate gradient 90:10 to 40:60).
Concentration to 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 (C~SH3oN205S'0.3C~H14) calculated: C 64.84, H 6.94, N
5.64;
found: C 64.85, H 7.08, N 5.47.

S~esis of 9,13-Imino-8H-azocino X2,1-al isoquinolin-8-one, 14-f(2-bromophenyl) sulfonyll-5,6,9,10,11,12,13,13a-octahydro-1, 3-dimethoxx (Compound 47) Compound 47 This compound was prepared similar to Example 1A 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
CHZCIz. The organic layers were combined, dried (MgS04), filtered and concentrated onto silica and purified by MPLC (hexanelethyl 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+).
3o Elemental analysis for (C~3H25BrN2O5S~O.15C6H14) calculated: C 53.72, H
5.11, N
5.24; found: C 54.09, H 4.98, N 4.91.

Synthesis of 9,13-Imino-8H-azocino f2,1-al isoauinolin-8-one, 14-f(3-bromophen~
sulfonyll-5,6,9,10,11,12,13,13a-octahydro-1, 3-dimethoxy (Compound 48) Compound 48 This compound was prepared similar to Example 1A, using Compound C
to (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 3x20 mL
CH2C12. The organic layers were combined, dried over MgS04, 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 (C23H2~BTNZOSS~O.3C6H14O.15C4I38O2) calculated: C
54.43, H
5.47, N 5.00; found: C 54.57, H 5.34, N 4.61.

Synthesis of 9,13-Imino-8H-azocino f 2,1-al iso~c uinolin-8-one, 14- f (4-bromophenyl) sulfonyll-5,6,9,10,11,12,13,13a-octahydro-1, 3-dimethoxy (Compound 49) Compound 49 This compound was prepared similar to Example 1A 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
CHZCl2. The organic layers were combined, dried over MgS04, 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 fox (C23H25BrN205S~O.5C4I3gO2) calculated: C 56.10, H 5.17, N
4.95; found: C 56.49, H 4.89, N 5.03.

Synthesis of 9,13-Imino-8H-azocino f2,1-al isoquinolin-8-one, 14-x(2,4-dinitrophenyl) sulfonyll-5,6,9,10,11,12,13,13a-octahydro-1, 3-dimethoxy (Compound 50) O~N
mpound 50 This compound was prepared similar to Example 1A, 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
CHaCh. 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+).
Elemental analysis for (C23H2$BTN2OSS~O.25C~H14) calculated: C 53.11, H 5.00, N
10.11; found: C 53.12, H 4.76, N 9.72.

Synthesis of 9,13-Imino-8H-azocino r2 1-al iso uinolin-8-one 5 6 9 10 11 2L13,23a-octahydro-1, 3-dimethoxy-I4-~~2-(1-na~hthalen 1y leth~lsulfo~ll (Compound 5I) Compound 51 This compound was prepared similar to Example 1A, using Compound C
(0.1028 g, 0.340 mmol), DMF (I mL), 2-(I-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
CH2Cl2. The organic layers were combined, dried over MgS04, filtered and concentrated onto silica and purified by MPLC (hexaneiethyl acetate gradient 90:10 to 40:60). Concentration of the fractions containing the desired product gave 0.0203 g of Compound 51 (17°lo yield).
Spectral analysis of the product was consistent With Compound 51:
MS (APCI) 521.1 (M+H~).
Elemental analysis for (Cz9H32N205S~0.I5C6H14~0.3C4HgO2) calculated: C 66.70, H
2o 6.57, N 5.00; found: C 66.91, H 6.48, N 4.71.

Synthesis of 9,I3-Imino-8H-azocino T21-al isoduinolin-8-one 14-(f I I'-biphenyll-4-ylsulfonyl)-5,6 9 1011 12 13 13a-octahydro-1 3-dimethoxy (Compound 52) pound 52 This compound was prepared similar to Example 1A, using Compound C
(0.1076 g, 0.356 mmol), DMF (I 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
CH2C12. The organic layers were combined, dried over MgS04, 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 (C29H3pN2O5S~O.3C4HgO2) calculated: C 66.55, H 5.99, N
5.14;
found: C 66.42, H 5.87, N 5.20.

Synthesis of 9,13-Imino-8H-azocino j2,1-al isoquinolin-8-one, 5,6,9,10,11,12,13,13a-octahydro-1, 3-dimethoxy-14-jj3-j(3,4,5-trimethoxyphenyl)aminolphenyllsulfony1l (Compound 55) H
ni O
O-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. Et20 (1.0 mL) was added to the mixture, and the mixture was filtered through celite, concentrated, dissolved in 10 mL CH2C12, 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 (C32H37N3OgS~O.3C4IigO2~O.15C6H1ø) calculated: C 61.77, H
6.31, N 6.34; found: C 62.14, H 6.28, N 6.03.

Synthesis of Benzoic acid, 2-f ~3-f(5,8,9,10,11,12,13,13a-octahydro-l, 3-dimethox oxo-9,13-imino-6H-azocinof 2,1-alisoquinolin-14-~)sulfonyllphenyll aminol-,ether ester (Compound 56) H
ni OEt 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), Cs2C03 (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. EtzO (1.0 mL) was added to the mixture, and the mixture was filtered through celite, concentrated, dissolved in 10 rnL CH2C12, 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:
2o MS (APCn 606.2 (M+H+) Elemental analysis fox (C32H3sN307S'0.15CHzC12~0.9CH30H) calculated: C 61.33, H
6.06, N 6.49; found: C 61.51, H 6.04, N 6.12.

Synthesis of 9,13-Imino-8H-azocino f2,1-al isoquinolin-8-one, 14-[(3',4'-dichlorofl,l'-biphenyll-4-yl)sulfonyll-5~6,9,10,11,12,13,13a-octahydro-1,3-dimethoxy (Compound 57) ind 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 NaZC03 (0.0203 g, 0.1916 mmol in 0.9 mL water) to the mixture. The mixture to 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 CHZC12, 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+).
Elemental analysis for (C29H2gC12N205S~O.45C~H14) calculated: C 60.79, H 5.52, N
4.47; found: C 60.91, H 5.60, N 4.08.

2o Synthesis of 9,13-Imino-8H-azocino f2,1-al isoquinolin-8-one, 14-~(3', 4'-dichloro 1,~ 1'-biphenyll-3-yl)sulfonyll-5,6,9,10,11,12,13,13a-octahydro-1,3-dimethoxy (Compound 58 ) ound 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 Na2C03 (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 CHZC12, re-concentrated onto silica and purified by MPLC (hexane/ethyl acetate gradient 90:10 to 40:60). Concentration of the fractions to containing the desired product gave 0.0479 g of Compound 58 (85°7o yield).
Spectral analysis of the product was consistent with Compound 58:
MS (APCI) 587.1 (M+H+).
Elemental analysis for (CZ~HZ8C12NZOSS'0.45C~H14 0.3C4H802) calculated: C
59.59, H
5.23, N 4.47; found: C 59.23, H 5.33, N 4.11.

Synthesis of 9,13-Imino-8H-azocino f2,1-al isoquinolin-8-one, 14-f(4-cyanophen~
sulfon~l-5,6,9,10,11,12,13,13a-octahydro-1,3-dimethoxx (Compound 59) Compound 59 This compound was prepared similar to Example 1A 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 CHZCh.
The organic layers were combined, dried over MgS04, 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°Io yield).
Spectral analysis of the product was consistent with Compound 59:
MS (APCI) 468.1 (M+H+).
3o Elemental analysis for (C24H25N305S~O.3C6H14) calculated: C 62.81, H 5.97, N 8.52;
found: C 62.98, H 5.94, N 8.12.

Synthesis of 9,13-Imino-8H-azocinof2,1-aliso~uinolin-8-one,5,6,9,10,11,12,13,13a-octahydro-1,3-dimethoxy-14-f (3-meth~phenyl)sulfon ~~11 (Compound 64) Compound 64 This compound was prepared similar to Example 1A, 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
CH2Ch. The organic layers were combined, dried over MgS04, 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+H~) Elemental analysis for (C24H28NZOSS O.3C6H14) calculated: C 63.70, H 6.46, N
5.97;
found: C 64.20, H 6.75, N 5.62.

Synthesis of 7,11-Tmino-2H-~yrazino f 1,2-al azocine-3, 6(4H,7H)-dione,2-(3,5-dimethoxyphenyl)-8,9,10,11-tetrahydro-I2-~(phenylmethyl)sulfonyll (Compound 23) 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 CHZCl2 (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 CHZC12 (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 (CDC13): 8 7.37 (5H, m), 6.43 (3H, m), 5.49 (1H, s), 4.48 (2H, AB), 4.39 (1H, s), 4.25 (3H, s), 3.80 (6H, s).
HRMS (FAB): calculated for CZSH28N30~S (M+H+) 498.1699; found 498.1712.

Synthesis of 9,13-Imino-8H-azocino f2,1-al isoquinolin-8-one, 14-f(6-chloro-3-pyridinyl) sulfon 1~9,10,11,12,13,13a-octahydro-3-methoxy (Compound 60) ipound 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 (CDC13): 8 8.12 (1H, d, J = 2.4 Hz), 7.28 (1H, dd, J = 8.2, 2.3 Hz), 6.95 (1H, d,J=8.5Hz),6.90(lH,d,J=8.lHz),6.70(lH,dd,J=8.5,2.3Hz),6.38(lH,d,J=
3.0 Hz), 4.81 (1H, br s), 4.74 - 4.66 (1H, m), 4.49 (1H, br s), 4.40 (1H, s), 3.78 (3H, s), 2.73-2.61 (1H, m), 2.44-1.66 (7H, m).
MS (ESP) 448 (M+H+).
Elemental analysis for (CZIHa2C1N3O4S): C 56.31 H 4.95 N 9.38; found C 56.28 H
4.92 N 9.35.

Synthesis of 9,13-Imino-8H-azocino f2,1-al isoquinolin-8-one, 5,6,9,10,11,12,13 13a-octahydro-6-methyl-14-f(3-meth~phenyl) sulfonyll-,(6S,9S=13R,13aR) (Compound 26) NMM, ~ ~S-CI
Core D 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:l) 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 (CDCl3): ~ 7.29 - 7.03 (7H, m), 6.93 (1H, d, J = 6.9 Hz), 5.11 (1H, s), 5.01 4.96(IH,s),4.39(2H,s),2.38(lH,dd,J=16.1,6.2Hz),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 fox (C23H2gN2O3S O.IHZO) 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.

Synthesis of 9,13-Imino-8H-azocino f2,1-al isoq-uinolin-8-one, 5,6 9 10 11 12 13 13a-octahydro-6-methyl-14-f(3-meth~phenyl)sulfon~l-,(6R,9R,13S,I3aS) (Compound25) 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).
to Spectral analysis of the product was consistent with Compound 25:
11-INMR (CDC13): ~ 7.28 - 7.03 (7H, m), 6.93 (1H, d, J = 6.9 Hz), 5.11 (1H, s), 5.01 -4.95(lH,m),4.39(2H,s),2.38(lH,dd,J=16.1,6.1Hz),2.25(lH,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 (C23H26N2~3S O.3HZO) 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.

Synthesis of 9 13-Imino-8H-azocino f2 1-al isoquinolin-8-one, 5,6,9,10,11,12,13,13a-octahydro-6-methyl-14-(1-naphthalenylsulfonyl)-,(6S,9S,13R,13aR) (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 (CDCl3, mixture of rotamers, major rotamer reported): 8 8.07 (2H, d, J =
7.3 Hz), 7.82 (1H, d, J = 8.3 Hz), 7.71 (1H, d, J = 7.6 Hz), 7.43 (1H, t, J = 7.2 Hz), 7.35 -6.89 (5H, m), 6.72 (1H, d, J = 7.3 Hz), 5.11 - 5.03 (1H, m), 4.89 (1H, s), 4.54 (1H, s), 4.40 (1H, s), 2.46 -1.60 (8H, m), 1.08 (3H, d, J = 7.0 Hz).
Elemental analysis for (C26Ha6Nz03S 0.6H2O): calculated: C 68.28 H 5.99, N
6.13, S
l0 7.O1; found: C 68.27, H 6.02, N 6.14, S 6.93.

Synthesis of 9,13-Imino-8H-azocino X2,1-al isoduinolin-8-one, 5,6,9,10,11,12,13,13a-octahydro-1,3-dimethoxy-14-f (3-meth~phenyl)sulfonyll-,(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), HATLT (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.
2o 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 1N NaOH to ~pH 11 and extracted with ethyl acetate (2x). The extracts were combined with the earlier organics and were washed with 0.5N
HCl (3x), brine (lx), dried over sodium sulfate, concentrated to dryness and set aside.
The acidic aqueous washings were basified with lON 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%
1o yield).
Spectral analysis of the product was consistent with Compound 24:
1HNM1ZR (CDCl3): ~ 7.21 - 7.09 (4H, m), 6.32 (1H, d, J = 2.3 Hz), 6.00 (1H, d, J = 2.3 Hz), 4.94 (1H, s), 4.73 - 4.68 (1H, m), 4.50 - 4.47 (2H, m), 3.84 (3H, s), 3.80 (3H, s), 2.50 (1H, dt, J = 12.9, 3.0 Hz), 2.23 (3H, s), 2.23 - 1.63 (8H, m).
15 Elemental analysis for (C24H2$N2O5S) 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.

Synthesis of 9,13-Imino-8H-azocino f2,1-al isoquinolin-8-one, 5,6,9,10,11,12,13,13a-octahydro-6-methyl-14-f f4-(4-pyridinyloxy)phenyll sulfonyll-,(6S,9S,13R,13aR) 20 (Compound 35) d 35 This compound was prepared similar to Example 25A, using Compound A (145 mg, 0.37 mmol), Palladium on Carbon (10%, 50 mg) in 5 mL ethyl acetate/ethanol, 25 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 mg of the title compound (36% yield).
Spectral analysis of the product was consistent with Compound 35:
3o 1H NMR (CDCl3): 8 8.54 (2H, d, J = 4.5 Hz), 7.32 - 7.19 (5H, m), 6.98 (1H, d, J = 7.5 Hz), 6.83 (2H, d, J = 6.2 Hz), 6.79 (2H, d, J = 8.9 Hz), 5.14 (1H, s), 5.07 -5.02 (1H, m), 4.44 (1H, m), 4.38 (1H, m), 2.48 (1H, dd, J =15.7, 6.3 Hz), 2.34 (1H, dd, J = 16.1, 3.2 Hz), 2.27 -1.60 (6H, m), 1.17 (3H, d, J = 7.4 Hz).
Elemental analysis for (C27Hz7N304S) 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.

to 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 (MgS04), 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).
2o Spectral analysis of the product was consistent with Compound 130:
MS (APCn m/z 411.2 (M++1).
CHN for (C23Ha6N30sS~0.2C4H80:0.25C~H1$) calculated: C 67.29, H 6.38, N 6.82;
found: C 67.97, H 6.62, N 5.88.

Synthesis of Compound 145 impound 145 This compound prepared as described in Scheme A, using Compound A (0.100 g, 0.330 rnmol) 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++1).
CHN for (C23H2~N205S~0.15 HBO) calculated: C 62.05, H 5.95, N 6.29; found: C
62.02, H 6.06, N 6.19.

S n~hesis of Compound 154 ~~ Compound 154 A mixture of Compound A (0.2 g, 0.73mmo1), 1-methyl-1H-imidazole-4-sulfonyl chloride (0.325 g, l.8mmol) and potassium carbonate (0.255 g, 1.83mmo1) in mL of acetonitrile was stirred under NZ for 15 hours. The sample was concentrated, then partitioned between EtOAc and sat. NaHC03 solution. The organic extract was 2o washed with brine solution, dried (MgSO~.), 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+1 =
417.1; mp >230 °C.
Spectral analysis of the product was consistent with Compound 154:
25 Calculated for CZOH~~.N404S1 (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.

Synthesis of Compound 155 N S
O N
~O 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:
to Calculated for C2oH22N2O4Sz (418.532): C, 57.22; H, 5.32; N, 6.67; S, 15.28; HZO, 0.30, found: C, 56.83; H, 5.18; N, 6.43; S, 15.07; H20, 0.18.

Synthesis of Compound 156 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 CZpH2~N2O4S2 (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
R\N/ R"
~S02CI
1) CIS03H/Et3N N HNR'R"
N ~ 2) PCIS ~~5-Iutidii m J..s Sulfamoyl Chlorides wherein:
Me 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 to substituted or unsubstituted heterocycle.
Scheme C
ORb %S02 ~bOH (5-6eq) /NaH (2-3eq), 70°C N
:thylene Glycol Dimethyl Ether O N
Me \OMe Sulfamoyl Chlorides wherein:
Rb is selected from hydrogen, substituted or unsubstituted alkyl and aryl.
The following examples are illustrative of the present invention:

S~thesis of Sulfomoyl Chloride A
To a CH~,C12 solution (10 mL) of Compound B
(1.l 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 C1S03H (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 ifz vacuo after which benzene (2x20 mL) was added and evaporated to remove trace amount of Et3N and water. Benzene (30 mL) and PCl5 (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 CH2C12 (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 to the title compound as an off white solid.
Spectral analysis of the product was consistent with sulfamoyl chloride A:
1H NMR (CDC13): 8 7.29 (1H, d, J = 8.7 Hz), 6.82 (1H, dd, J = 8.7, 2.8 Hz), 6.64 (1H, d, J = 8.6 Hz), 5.12 (1H, m), 4.84 (1H, m), 4.64 (1H, s), 4.58 (1H, m), 3.79 (3H, s), 3.16 - 2.95 (2H, m), 2.72 (1H, m), 2.35 (1H, m).

Synthesis of sulfamoyl chloride B
~S02CI
N jS02Cl N O/
O~
O N ~ \
O N ~ \
/ ~ O~
O~
CI
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%
2o 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 (CDC13): b 6.38 (1H, d, J = 2.1 Hz), 6.23 (1H, d, J = 2.3 Hz), 5.18 (1H, m), 4.99 (1H, m), 4.66 (1H, br s), 4.59 (1H, m), 3.85 (3H, s), 3.78 (3H, s), 3.63 (1H, m), 25 2.77 (1H, m), 2.56 (1H, d, J = 16.2 Hz).

Synthesis of sulfamoyl chloride D

~S02CI
N
,,,.H
O N ~ \ 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:
l0 1H NMR (CDC13): S 7.38 (1H, br d), 7.35 - 7.22 (2H, m), 7.14 (1H, br d), 5.23 (1H, br s), 5.03 (1H, s, J = 6.3 Hz), 4.58 (1H, br s), 4.54 (1H, s), 3.19 (1H, dd, J =
16.2, 6 Hz), 2.56 (1H, dd, J =16.8, 5.4 Hz), 2.45 (1H, m), 2.25 (1H, m), 1.32 (3H, d, J =
6.6 Hz).

Synthesis of 9,13-Imino-6H-azocino f2,1-al isoquinoline-14-15 sulfonamide,5,8,9,10,11,12,13,13a-octahydro-3-methoxy-8-oxo-N-(3,4,5-trimethox hens (Compound 28) Fund 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 CHZCl2 (2 mL) at 20 25°C. After 20 hours, the mixture was diluted with CHZC12 (SO mL) and washed with 5% HCl solution (ice-cold, 2x40 mL) and brine (1x50 mL). The solution was dried over MgS04 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.
25 Spectral analysis of the product was consistent Compound 28:
1H NMR (CDC13): ~ 7.09 (1H, d, J = 8.5 Hz), 6.73 (1H, dd, J = 8.6, 2.6 Hz), 6.49 (1H, d, J = 2.8 Hz), 6.12 (1H, br s), 5.94 (2H, s), 4.8 - 4.69 (2H, m), 4.50 (1H, br s), 4.44 (1H, 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 (1H, m), 2.51 (1H, dt, J = 16.0, 3.6 Hz), 2.17 (1H, m).
MS (ESP) positive 5I8 (M+Na+) negative 516 (M-H+).
EXAMPLE SS
Synthesis of 9,13-Imino-6H-azocino f2,1-al isoguinoline-14-sulfonamide,N-(6-chloro-l0 3-pyridinYl~- 5,8,9,10,11,12,13,13a-octahydro-3-methoxy-8-oxo-(Compound 29) n_ a 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 2S°C. After 20 hours, the mixture was diluted with EtOAc (50 mL) and washed with concentrated CuS04 solution (2x40 mL). The solution was dried over Na2S04 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 (CDCl3): ~ 8.48 (1H, br s), 7.94 (1, d, J = 2.8 Hz), 7.20 (1H, dd, J =
8.7, 2.8 2o Hz), 7.10 (1H, d, J = 8.7 Hz), 6.92 (1H, d, J = 8.7 Hz), 6.75 (IH, dd, J =
8.7, 2.6 Hz), 6.57 (1H, d, J = 2.8 Hz), 4.73 - 4.85 (2H, m), 4.55 (1H, s), 4.36 (1H, m), 3.82 (3H, s), 2.96 - 2.76 (2H, m), 2.59 (1H, m).
HRMS (MALDI) calculated for C~1H~,.C1Nø04S (M+H+) 463.1201; found 463.1184.

Synthesis of 9,13-Irnino-6H-azocino X2,1-al iso~e,uinoline-14-sulfonamide, N-(3,4-difluorophenyl)- 5,8,9,10,11,12,13,13a-octahydro-3-methoxy-8-oxo(Compound 22) F
F
ound 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 (CDCl3): b 7.13 (1H, d, J = 8.9 Hz), 6.86 (1H, t, J = 8.5 Hz), 6.81 -6.74 (1H, m), 6.48 - 6.64 (4H, m), 4.86 - 4.74 (2H, m), 4.54 (1H, s), 4.36 (1H, s), 3.82 (3H, s), l0 2.98 - 2.75 (2H, m), 2.66 - 2.56 (1H, m), 2.11 - 2.26 (1H, m), 2.05 -1.75 (5H, m).
HRMS (MALDI) calculated for CZZH23F2N3~4SNa (M+Na+) 486.1270; found 486.1255.

Synthesis of 9,13-Imino-8H-azoeino X2,1-al isoquinolin-8-one, 5,6,9,10,11,12,13,13a-octahydro-3-methoxy 14-(1-piperidinylsulfon~-(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.
2o Spectral analysis of the product was consistent with Compound 30:
1H NMR (CDCl3): 8 7.20 (1H, d, J = 8.9 Hz), 6.80 (1H, dd, J = 8.9, 2.6 Hz), 6.65 (1H, d, J = 2.8 Hz), 4.88 - 4.79 (1H, m), 4.71 (1H, m), 4.57 (1H, br s), 4.18 (1H, m), 3.78 (3H, s), 3.15 - 2.90 (2H, m), 2.81 - 2.64 (5H, m) HRMS (MALDI) calculated for CZ1H30N3~4S (M+H+) 420.1952; found 420.1970.

Synthesis of 9,13-Imino-8H-azocino f2,1-al isoci,uinolin-8-one, 5,6,9,10,11,12,13,13a-octahydro-3-methoxy-14-(4-morpholinylsulfonyl)-(Compound 31) n 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): 8 7.20 (1H, d, J = 8.7 Hz), 6.81 (1H, dd, J = 8.7, 2.7 Hz), 6.66 (1H, d, J = 2.7 Hz), 4.90 - 4.80 (1H, m), 4.72 (1H, m), 4.59 (1H, br s), 4.22 (1H, m), 3.78 1o (3H, s), 3.38 (4H, m), 3.13 - 2.9 (2H, m), 2.8 - 2.65 (5H, m), 2.20 (1H, m).
HRMS (MALDI) calculated for CZOH28N3O5S (M+H+) 422.1744; found 422.1761.

S~thesis of 9,13-Imino-6H-azocino f2,1-al isoquinoline-14-sulfanomide, 5,8,9,10,11,12,13,13a-octahydro-3-methoxy-N-(6-methox~3-p ridinyl)-8-oxo-(Compound 32) N
~~O-N
Compound 32 This compound was prepared from sulfamoyl chloride A by a synthetic method analogous to Example 4B. A 31°70 yield was obtained.
Spectral analysis of the product was consistent with Compound 32:
1H NMR (CDC13): ~ 7.28 (1H, s), 7.06-7.14 (2H, m), 6.72 (1H, dd, J = 8.7, 2.6 Hz), 6.58(lH,d,J=2.8Hz),6.38(lH,d,J=8.5Hz),6.32(lH,s),4.85-4.80(lH,m),4.79 - 4.72 (1H, m), 4.51 (1H, s), 4.36 (1H, s), 3.88 (3H, s), 3.82 (3H, s), 3.03-2.87 (2H, m), 2.69 -2.57 (1H, rn), 2.23 - 2.09 (1H, m), 2.08 - 1.99 (2H, m), 1.97 - 1.77 (3H, m).
HRMS (MALDI) calculated for C22H27N405S (M+H+) 459.1697; found 459.1701.

Synthesis of 9,13-Imino-8H-azocino f2,1-al iso~uinolin-8-one, 14-~(cis-2,6-dimeth~-4-morpholinyl)sulfonyll-5,6,9,10,11,12,13,13a-octahydro-3-methox~(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 (CDC13): 8 7.45 (1H, d, J=8.9 Hz), 7.05 (1H, dd, J = 8.6, 2.6 Hz), 6.91 (1H, d, J = 2.6 Hz), 5.17 - 5.08 (1H, m), 4.97 (1H, br s), 4.84 (1H, s), 4.43 (1H, br s), 4.02 (3H, to s), 3.54 - 3.66 (1H, m), 3.46 - 3.06 (5H, m), 2.99-2.90 (1H, m), 2.53 -2.02 (8H, m), 1.22 (3H, d, J = 6.4 Hz), 1.13 (3H, d, J = 6.4 Hz).
MS (ESP) 450 (M+H+).
Elemental analysis for (CZZH31N3~SS) calculated: C 58.78, H 6.95, N 9.35;
found C
58.92, H 7.00, N 9.22.

Synthesis of 9 13-Irnino-6H-azocino f2,1-al isoduinoline-14-sulfonamide, N-(3,4-difluorophenyl)-5,8,9,10,11,12,13,13a-octahydro-1,3-dimethoxy-8-oxo-(Compound 34) F
F
npound 34 This compound was prepared from sulfamoyl chloride B (containing 25%
2o 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 (CDCl3): S 7.91 (1H, br s), 6.94 (1H, q, d = 8.7 Hz), 6.81 (1H, m), 6.70 (1H, m), 6.34 (1H, d, J = 2.3 Hz), 6.17 (1H, d< J=2.4 Hz), 4.9-4.75 (2H, m), 4.59 (1H, br s), 4.34 (1H, m), 3.84 (3H, s), 3.78 (3H, s), 2.84 - 2.59 (2H, m), 2.42 (1H, d, J
= 15.6 Hz).
HRMS (MALDI) calculated for C23H2~F2N305S (M+H+) 494.1556; found 494.1575.

thesis of 9,13-Imino-6H-azocino f 2,1-al isoc~uinoline-14-sulfonamide, 5, 8, 9,10,11,12,13,13a-octa~dro-3-methoxy-8-oxo-N- (2,3,4-trifluorophenyl)-(Compound 45) F
~~02 N w I F
N
l F
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): 8 6.97 (1H, d, J = 9.4 Hz), 6.65 - 6.47 (3H, m), 6.43 (1H, d, J = 2.6 1o Hz), 6.18 (1H, s), 4.77 - 4.64 (2H, m), 4.44 (1H, s), 4.37 (1H, s), 3.72 (3H, s), 2.86 -2.63 (2H, m), 2.54 - 2.44 (1H, m), 2.22 - 2.08 (1H, m), 2.02 - 1.93 (2H, m), 1.89 - 1.7 (3H, m).
MS (ESP) 482 (M+H+).
Elemental analysis for (CZZH22FsN304S 0.35H20) calculated: C 54.17, H 4.69, N
8.61;
15 found: C 54.40, H 4.89, N 8.22.

Synthesis of 9,13-Imino-6H-azocino f2,1-al isoquinoline-14-sulfonamide, , 8,9,10,11,12,13 ,13 a-octahydro-3-methoxy-8-oxo-N-(3 ,4, 5-trifluorophenyl)-(Compound 46) F
F
O
-S? NH
N
F
O N ~ ~ 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 (CDCl3): b 7.23 (1H, s), 6.93 (1H, d, J = 8.7 Hz), 6.59 (1H, dd, J =
8.9, 2.6 Hz), 6.42 (1H, d, J = 2.8 Hz), 6.31 (2H, dd, J = 8.9, 5.8 Hz), 4.67 - 4.58 (2H, m), 4.38 (1H, s), 4.17 (1H, s), 3.63 (3H, s), 2.81 - 2.64 (2H, m), 2.52 - 2.39 (1H, m), 2.05 - 1.89 (1H, m), 1.88 - 1.55 (5H, m).

MS (ESP) 482 (M+H+) Elemental analysis for (C2zH22F3N3~4S) calculated: C 54.88, H 4.61, N 8.73;
found C
54.93, H 4.64, N 8.56.

Synthesis of 9,13-Imino-6H-azocino f2,1-al isoduinoline-14-sulfonamide, l0 5,8,9,10,11,12,13,13a-octahydro-3-methoxy-8-oxo-N-(2,4,5-trifluorophen~)-(Compound S3) F
F
O
N'g? NH
F
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 (CDCl3): 8 7.06 (1H, d, J = 8.3 Hz), 6.84 - 6.65 (3H, m), 6.52 (1H, d, J = 2.6 Hz), 6.25 (1H, s), 4.85 - 4.74 (2H, m), 4.53 (1H, s), 4.40 (1H, s), 3.78 (3H, s), 2.96 -2.80 (2H, m), 2.66 - 2.55 (1H, m), 2.30 - 2.15 (1H, m), 2.09 - 2.0 (2H, m), 1.97 - 1.80 (3H, m).
2o MS (ESP) 482 (M+H+) Elemental analysis for (C22H22F3N304S) calculated: C 54.88, H 4.61, N 8.73;
found C
54.71, H 4.73, N 8.54.

Synthesis of 9,13-Imino-6H-azocino f2,1-al isoquinoline-14-sulfonamide, 5,8,9,10,11,12,13,13a-octahydro-3-methox -~-(4-morpholin l~p~yll-8-oxo-(Compound 54) N
\ N
g~NH
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 (CDCl3): 8 7.67 (1H, d, J = 2.4 Hz), 7.14 (1H, d, J = 9.2 Hz), 7.09 (1H, dd, J =
1o 8.9,3.2Hz),6.75(lH,dd,J=8.7,2.3Hz),6.60(lH,d,J=2.6Hz),6.29(lH,d,J=
8.9 Hz), 4.87 - 4.82 (1H, m), 4.80 - 4.73 (1H, m), 4.53 (1H, s), 4.36 (1H, 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 (1H, m), 2.25 - 2.10 (1H, m), 2.09 -1.79 (6H, m).
MS (ESP) 514 (M+H'-).
Elemental analysis for (CasHsiNsCsS) calculated: C 58.21, H 6.28, N 12.76;
found C
58.22, H 6.26, N 12.67.

mor~holinyl) sulfonyll 5 6 9,10 11 1213 13a-octahydro-1 3-dimethoxy- (Compound 61) and 9' 13 Imino 8H azocino~21 alisoauinolin-8-one,l4-f (cis-2 6-dimeth~l-4-momholinyl sulfonyll 5 6 9 10 11 12 13 13a-octahydro-13-dimethoxy-4-chloro-(Compound 62) impound 61 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 CHzCl2): 30 mg of Compound 62, 70 mg of Compound 61 and 180 mg mixture of Compound 62 and Compound 61 (1:4).
Spectral analysis of the product was consistent with Compound 61:
Rf= 0.25 (3% THF in CH2Cl2).
1H NMR (CDC13): 8 6.36 (1H, d, J = 2.4 Hz), 6.27 (1H, d, J = 2.3 Hz), 4.95 (1H, m), 4.67 (1H, m), 4.62 1H, br s), 4.23 (1H, m), 3.84 (3H, s), 3.77 (3H, s), 3.22 -3.07 (2H, m), 3.05 - 2.9 (2H, m), 2.72 (1H, td, J = 12.4, 2.6 Hz), 2.58 (1H, d, J =16 Hz), 1.06 (3H, d, J = 6.2 Hz), 0.94 (3H, d, J = 6.2 Hz).
HRMS (MALDI) calculated for C23H34N3O~S (M+H+) 480.2163; found 480.2174.
Spectral analysis of the product was consistent with Compound 62:
Rf= 0.27 (3% THF in CH2C12).
1H NMR (CDC13): d 6.47 (1H, s), 5.00 (1H, m), 4.63 (2H, s), 4.20 (1H, m), 3.91 (3H, s), 3.90 (3H, s), 3.38 (1H, m), 3.22 - 3.09 (2H, m), 3.01 (1H, dt, J = 11.9, 2.3 Hz), 2.94 - 2.60 (3H, m).
2o LCMS: 515 (M+H+). The structure shown was confirmed by single crystal X-ray analysis.

Synthesis of 9 13 Imino 6H-azocinof2 1-alisoduinoline-14-sulfonamide,N-(pyrrol-~)-5 8 9 10 11 12 13 13a-octahydro-3-methoxy-8-oxo-(Compound 66) ~,./SwN,~ N
"'~I H
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 (CDCl3): 8 7.10 (1H, d, J = 9 Hz), 6.75 (1H, dd, J = 9, 3 Hz), 6.64 (1H, d, J =
3.1 Hz), 6.38 (2H, t, J = 2.1 Hz), 5.87 (2H, t, J = 2.1 Hz), 4.81 - 4.71 (2H, m), 4.54 (1H, s), 4.26 (1H, m), 3.79 (3H, s), 3.15 - 2.92 (2H, m), 2.67 (1H, m).
LCMS 417 (M+H+).

EXAMPLE 1~B
Synthesis of 9 13-Imino-6H-azocinof2,1-alisoduinoline-14-sulfonamide 5 8 9 10 11 12 13 13a-octahydro-3-methox -~-(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 (CDCl3): 8 7.28 (1H, d, J = 9 Hz), 6.84 (1H, dd, J = 9, 2.8 Hz), 6.66 (1H, d, J
= 2.9 Hz), 4.91 - 4.79 (2H, m), 4.59 (1H, s), 4.31 (1H, m), 4.18 (2H, br s), 3.79 (3H, s), 3.10(lH,m),2.96(lH,td,J=12,3Hz),2.71 (lH,dt,J=15,3Hz),2.18(lH,m).
LCMS 352 (M+H+).

Synthesis of 9 13-Imino-6H-azocinof2 1-alisoquinoline-14-sulfonamide,N-(6-fluoro-3-pyridinyl)-5 8 9 10 11 12 13 13a-octahydro-3-methoxy-8-oxo-(Compound 118) sound 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 (CDCl3): 8 7.63 (1H, br s), 7.38 - 7.30 (2H, m), 7.08 (1H, d, J = 8.7 Hz), 6.74 (1H, m), 6.61 - 6.52 (2H, m), 4.84 - 4.72 (2H, m), 4.53 (1H, s), 4.36 (1H, br s), 3.81 (3H, s), 2.98 - 2.80 (2H, m), 2.67 - 2.53 (1H, m), 2.12 (1H, m).
LCMS 447 (M+H+).
Elemental analysis for (C21H23FN404S) calculated: C 56.49, H 5.19, N 12.55;
found C
56.72, H 5.38, N 12.30.

EXAMPLE ZOB
Synthesis of 9,13-Imino-6H-azocino~2,1-alisoauinoline-14-sulfonamide,N-(3-p~yl)-5,8,9,10,11,12,13,13 a-octahydro-3-methoxy-8-oxo-(Compoundl 19) !g? NH
N
O~N ~ \ Compound 119 O
This compound was prepared from sulfamoyl chloride A by a synthetic method to analogous to Example 5B. A 7% yield was obtained.
Spectral analysis of the product was consistent with Compound 119:
1H NMR (CDC13): 8 8.19 (1H, br s), 8.08 (1H, br s), 7.29 (1H, d), 7.15 (1H, d, J = 9.3 Hz), 7.03 (1H, m), 6.75 (1H, dd, J = 9, 3 Hz), 6.53 (1H, d, J = 3 Hz), 4.87 -4.74 (2H, m), 4.57 (1H, s), 4.40 (1H, m), 3.79 (3H, s), 2.96 - 2.74 (2H, m), 2.59 (1H, m), 2.17 (1H, m).
LCMS 429 (M+H+) EXAMPLE ~1B
Synthesis of (Compound 120) N
g? NH
N
. ,,,~H
O N~\y%~ Compound 120 o,,,.. I ICI/
2o 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 (CDC13): ~ 8.09 (1H, s), 7.73 (1H, s), 7.30 (1H, m), 7.24 - 7.08 (3H, m), 7.04 (1H, d, J = 8.1 Hz), 6.46 (1H, dd, J = 9.3, 3.9 Hz), 4.99 - 4.85 (2H, m), 4.46 - 4.38 (2H, m), 2.92 (1H, dd, J = 16.5, 6 Hz), 2.41 (1H, dd, J =16.5, 4.5 Hz), 1.23 (3H, d, J = 6.6 Hz).
HRMS calculated for C21H2~FN403S (M+H~) 431.1553; 431.1554 s EXAMPLE 1C
Synthesis of 9,13-Imino-6H-azocinof2,1-alisoc~uinoline-14-sulfate O-phenyl-8,9,10,11,12,13,13a-octahydro-3-methox~8-oxo-(Compound 67) N.~ I
Compound 67 To an ethylene glycol dimethyl ether solution (2.5 mL) of phenol (160 mg, 1.68 to 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 CH2Cl2 (25 mL) and washed with ice-cold saturated Na2C03 solution (3x30 mL). The solution was then dried over MgS04 and concentrated. The residue was purified by flash column is 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 (CDCl3): 8 7.21-7.1 (4H, m), 6.81 (1H, dd, J = 9.3 Hz), 6.73 - 6.69 (2H, m), 4.62 (1H, s), 4.43 (1H, m), 3.78 (3H, s), 3.03 - 2.82 (2H, m), 2.61 (1H, m), 2.23 (1H, 20 m).
LCMS 429 (M+H~) Synthesis of 9,13-Imino-6H-azocinof2,1-aliso~uinoline-14-sulfate,0-(2-propyl)-5,8,9,10,11,12,13,13a-octahydro-3-methoxy-8-oxo-(Compound 68) Compound 68 2s This compound was prepared from sulfamoyl chloride A by a synthetic method analogous to Example 1C. A 61% yield was obtained.
Spectral analysis of the product was consistent with Compound 68:

1H NMR (CDCl3): 8 7.22 (1H, d, J = 9 Hz), 6.80 (1H, dd, J ~ 9, 3 Hz), 6.65 (1H, d, J =
3 Hz), 4.88 - 4.74 (2H, m), 4.57 (1H, s), 4.37 - 4.21 (2H, m), 3.79 (3H, s), 3.13 - 2.93 (2H, m), 2.70 (1H, m), 2.19 (1H, m), 1.09 (3H, d, J = 6.3 Hz), 0.92 (3H, d, J
= 6.3 Hz).
LCMS 395 (M+H~).
The ureas compounds of the present invention may be prepared in the manner depicted in Scheme D below:
Scheme D
H
N R~NCO
O N ~ '~~ DMF

wherein:
1~ R~ is selected from hydrogen, substituted or unsubstituted aryl, alkyl, heteroaryl or heterocycloalkyl.
The following examples are illustrative of the present invention:

Synthesis of 9,13-Imino-6H-azocino X2,1-a1 isoduinoline-14-carboxamide, N-ethyl-5 8,9,10,11,12,13,13a-octahydro-4-methoxy-8-oxo-(Compound 69) Compound 69 O\
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 mrnol) 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+H+).
Elemental analysis for (C1~HZSN303.1.35H20) calculated: C 62.06, H 7.59, N
11.43;
found: C 61.69, H 7.17, N 11.62.

Synthesis of 9,13-Imino-6H-azocino f2,1-al isoquinoline-14-carboxamide,N-ethyl-5,8,9,10,11,12,13,13a-octahydro-3-methoxy-8-oxo-(Compound 70) mpound 70 This compound was prepared similar to Example 1D, 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 (O.OIO mL, 0.114 mmol).
Filtration of the final precipitate gave 0.0174 g of Compound 70 (44°7o yield).
Spectral analysis of the product was consistent with Compound 70:
MS (APCI) 344.1 (M+H+).
Elemental analysis for (C19H~SN3O3 0.4H20 0.15C3H7N0) calculated: C 64.61, H
7.48, N 12.20; found: C 64.36, H 7.11, N 11.83.

Synthesis of 9,13-Imino-6H-azocino X2,1-al isoquinoline-14-carboxamide, 5,8,9,10,11,12,13,13a-octahydro-3-methoxy-N-(2-methylphen,~rl)- 8-oxo-(Compound 71) N
Compound 71 This compound was prepared similar to Example 1D, 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 CHZC12. The organic layers were combined, dried over MgS04, to 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+) 15 Elemental analysis for (C24H27N3O3 0.15CH30H 0.45C4H80z) calculated: C
69.27, H
6.99, N 9.34; found: C 69.02, H 6.76, N 9.63.

Synthesis of 9,13-Imino-6H-azocino f2,1-al isoquinoline-14-carboxamide, 5,8,9,10,11,12,13,13a-octahydro-4-methoxy-N-(4-methylphenyl)- 8-oxo-(Compound 20 72) Compound 72 O~
This compound was prepared similar to Example 1D, 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
25 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 nnL
CHZCl2.
The organic layers were combined, dried over MgS04, 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 (APCl) 406.1 (M+H+).
Elemental analysis for (C24H27N3O3 0.15C6H14 0.30C4H802) calculated: C 70.47, H
7.17, N 9.45; found: C 70.54, H 7.02, N 9.30.
EXAMPLE SD
Synthesis of 9,13-Imino-6H-azocino f2,1-al iso~uinoline-14-carboxamide, 5,8,9,10,11,12,13,13a-octahydro-3-methoxy-N-(4-metl~lphenyl)-8-oxo-(Compound 73) N
Compound 73 2o This compound was prepared similar to Example 1D, 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
CH~C12.
The organic layers were combined, dried over MgS04, 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:
3o MS (APC>7 406.1 (M+H~'~).

Elemental analysis for (C2qH27N3O3 0.30C4H802) calculated: C 70.08, H 6.86, N
9.73;
found: C 70.04, H 7.00, N 10.01.

Synthesis of 9,13-Imino-6H-azocino f2,1-al isoquinoline-14-carboxamide, N-(2,4-difluorophenyl)-, 5,8,9,10,11,12,13,13a-octah dro- 4-methoxy- 8-oxo-(Compound 74) F
~F
Compound 74 This compound was prepared similar to Example 1D, using Compound A
(0.0912 g, 0.335 mmol), DMF (I.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
CH2Cl2.
The organic layers were combined, dried over MgS04, 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).
2o Spectral analysis of the product was consistent with Compound 74:
MS (APCI) 428.1 (M+H~).
Elemental analysis for (C23H23F2N3O3 0.45C4Ii802) calculated: C 63.77, H 5.74, N
9.00; found: C 63.60, H 5.4, N 9.1.

Synthesis of 9,13-Imino-6H-azocino 12,1-a1 isoquinoline-14-carboxamide, 5,8,9,10,11,12,13,13a-octahydro-4-methoxy-8-oxo-N-phenyl-(Compound 75) Compound 75 O\
This compound was prepared similar to Example 1D, 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 HCl, and the solution was extracted with 3x5 mL CH2C12. The organic layers were combined, dried over MgS04, 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 (APC>] 392.3 (M+H+).
Elemental analysis for (C23Hz5N3O3 0.15C4H80z O.4C~H14) calculated: C 71.11, H
7.30, N 9.57; found: C 71.28, H 7.20, N 9.24.

Synthesis of 9,13-Imino-6H-azocino f2,1-al isoquinoline-14-carboxamide, 5,8,9,10,11,12,13,13a-octahydro-3-methoxy-8-oxo-N-phenyl-(Compound 76) Compound 76 This compound was prepared similar to Example 1D, using Compound B
(0.0576 g, 0.211 mmol), DMF (1.0 mL), phenyl isocyanate (0.lmL, 0.920 mmol).
The reaction was quenched with 3 mL 1.0 M HCI, and the solution was extracted with 3x5 mL CHZCh. The organic layers were combined, dried over MgS04, 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°7o yield).
Spectral analysis of the product was consistent with Compound 76:
MS (APCI) 392.3 (M+H+).
1o Elemental analysis for (C23H25N3O3 0.35C4H802) calculated: C 69.40, H 6.64, N 9.95;
found: C 69.15, H 6.75, N 10.22.

Synthesis of 9 13-Imino-6H-azocino f2,1-al isoquinoline-14-carboxamide, N-(2,6-dimeth~phenyl)-5,8,9,10,11,12,13,13a-octahydro-3-methoxy-8-oxo-(Compound 77) N
Compound 77 ,/
This compound was prepared similar to Example 1D, 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 CH2Cl2. The organic layers were combined, dried over MgS04, 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,H7.21,N9.66.

Synthesis of 9,13-Imino-6H-azocino f2,1-al isoduinoline-14-carboxamide, 5 , 8,9,10,11,12 13 13 a-octahYdro-3-methoxy-N-(3-methoxyphenyl)-8-oxo-(Compound 78) Compound 78 This compound was prepared similar to Example 1D, 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 CH2Cl2. The organic layers were combined, dried over MgS04, 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 (C~,~H27N304 0.15CH2C12) calculated: C 66.80, H 6.34, N
9.68;
found: C 67.15, H 6.60, N 9.42.

Synthesis of 9,13-Imino-6H-azocino f2,1-al isoquinoline-14-carboxamide,5~
8,9,10,11,12,13,13a-octahydro-1,3-dimethoxy-N ~3-methoxyphenyl)-8-oxo-(Compound 79) N ~ l o-Compound 79 This compound was prepared similar to Example 1D, 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 MgS04, filtered and concentrated onto silica. The crude material was purified by MPLC

O

(hexanelethyl 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 (CZSHZ~N3O5 0.15C4H802) calculated: C 66.16, H 6.55, N
9.04;
to found: C 66.34, H 6.58, N 8.76.

~nthesis of 9,13-Imino-6H-azocino f 2,1-al isoquinoline-14-carboxamide, 5,8,9,10,11,12,13,13a-octahydro-4-methoxy-8-oxo-N-(phenylmeth.~(Compound 80) Compound 80 15 This compound was prepared similar to Example 1D, 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 CH2Cl2. The organic layers were combined, dried over MgS04, filtered and concentrated onto silica. The crude material was purified by MPLC
(hexane/ethyl 20 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+H+) Elemental analysis for (Ca4H27N3O3 0.15C4H802) calculated: C 70.57, H 6.79, N

10.04;
25 found: C 70.33, H 6.87, N 9.94.

Synthesis of 9,13-Imino-6H-azocino f2,1-al isoquinoline-14-carboxamide, 5,8,9,10,11,12,13,13a-octahydro-3-methoxy-8-oxo-N-(phen 1y methyl)-(Compound 81) O
Compound 81 This~compound was prepared similar to Example 1D, 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 CHZCl2. The organic layers were combined, dried over MgS04, 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 (APC~ 406.1 (M+H+).
Elemental analysis for (C24H27N3O3 0.3C4H802) calculated: C 70.08, H 6.86, N
9.73;
found: C 70.06, H 6.85, N 9.87.

Synthesis of 9 13-Imino-6H-azocino f2 1-al isoauinoline 14 carboxamide 5,8,9,IO,I1 12 I3,13a-octahvdro-1 3-dimethoxy-8-oxo-N ( henylmethyl) (Compound 82) i O~
Compound 82 w This compound was prepared similar to Example 1D, using Compound C
(0.0822 g, 0.272 rnmol), DMF (1.0 mL), benzyl isocyanate (0.0667 mL, 0.544 mrnol).
The reaction was quenched with 3 mL 1.0 M HCl, and the solution was extracted with 3x5 mL CH2Cl2. The organic layers were combined, dried over MgSO4, filtered and concentrated onto silica. The crude material was purified by MPLC
(hexane/ethyl 8i 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 0.3C4Ii802) calculated: C 68.12, H 6.85, N
9.10;
l0 found: C 68.01, H 6.69, N 9.25.

Synthesis of 9,13-Imino-6H-azocino X2,1-al isoquinoline-14-carboxamide, 5,8,9,10,11,12,13,13a-octahydro-4-methoxy-N-(4-nitrophenyl)-8-oxo-(Compound 83) J \
O
O-\ Compound 83 15 This compound was prepared similar to Example 1D, 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 HCl, and the solution was extracted with 3x5 mL CH2C12. The organic layers were combined, dried over MgS04, filtered and concentrated onto silica. The crude material was purified by MPLC
20 (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+).
Elemental analysis for (C23H24IV4O5 0.15C4H802) calculated: C 61.90, H 5.45, N
12.47;
25 found: C 61.56, H 5.38, N 12.42.

Synthesis of 9,13-Imino-6H-azocino f2,1-al isoquinoline-14-carboxamide, 5,8,9,10,11,12,13,13a-octahydro-3-methoxy-N-(4-nitro~henyl)-8-oxo-(Compound 84) / +~O
N
O-\~ Compound 84 This compound was prepared as described in Example 1D, 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 CH2C12. The organic layers were combined, dried over MgS04, 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+H+).
Elemental analysis for (C23H~N4O5 0.15C4Ii802) calculated: C 61.90, H 5.45, N
12.47;
found: C 62.24, H 5.51, N 12.08.

Synthesis of 9 13-Imino-6H-azocino f2,1-al isoquinoline-14-carboxamide, 5, 8,9,10,11,12,13,13 a-octahydro-3-methoxy N-(3-methylphenyl)-8-oxo-(Compound 85) N
Compound 85 / _/
This compound was prepared similar to Example 1D, 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 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 0.0785 g of Compound 85 (60% yield).

Spectral analysis of the product was consistent with Compound 85:
MS (APCI) 406.1 (M+H+) Elemental analysis for (C24Hz7N3O3 0.15C4H802) calculated: C 70.57, H 6.79, N
10.04;
found: C 70.65, H 6.87, N 9.78.

Synthesis of 9,13-Imino-6H-azocino f2,1-al isoquinoline-14-carboxamide, 5,8,9,10,11,12,13,13a-octahydro-1, 3-dimethoxy-8-oxo-N- (3-methylphenyl)-(Compound 86) Compound 86 w/ /
This compound was prepared similar to Example 1D, 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 CH2Clz 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 2o 0.1015 g of Compound 86 (79°~o yield).
Spectral analysis of the product was consistent with Compound 86:
MS (APCI) 372.2 (M+H~) Elemental analysis for (C21H29N3~3) calculated: C 68.95, H 6.71, N 9.65;
found: C
68.88, H 6.73, N 9.30.

Synthesis of 9,13-Imino-6H-azocino [2,1-al isoquinoline-14-carboxamide, N -(1,1-dimeth,~lethyl)- 5,8,9,10,11,12,13,13a-octahydro-4-methoxy-8-oxo-(Compound 87) Compound 87 This compound was prepared similar to Example 1D, 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 CH2Cl2 concentrated onto silica, and purified by MPLC (hexane/ethyl acetate gradient 90:10 to 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+H+).
Elemental analysis for (CZSH29N3O4 0.15C4H802 0.30C~H1~.) calculated: C 68.46, H
8.45, N 10.24; found: C 68.69, H 8.47, N 9.99.

Synthesis of 9,13-Imino-6H-azocino f2,1-al isoquinoline-14-carboxamide,N-(1,1-dimethylethyl)5,8,9,10,11,12,13,13a-octahydro-3-methoxy-8-oxo-(Compound 88) i ound 88 2o This compound was prepared similar to Example 1D, 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 CHZC12. The organic layers were combined, and the filtered product was added and dissolved. The mixture was dried over MgS04, filtered and concentrated onto silica and the solids were 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 0.0978 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 (CZ1H2~N3O3 0.15C4H802 0.15C~H14) calculated: C 67.97, H
l0 8.19, N 10.57; found: C 67.94, H 8.31, N 10.62.

~nthesis of 9,13-Imino-6H-azocino X2,1-al isoquinoline-14-carboxamide,N-(1,1-dimeth l~yl)-5,8,9,10,11,12,13,13a-octahydro-1,3-dimethoxy-8-oxo-(Compound 89) ound 89 15 This compound was prepared similar to Example 1D, 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 CHZC12. The organic layers were combined, and the filtered product was added and dissolved. The mixture was dried over MgS04, filtered and concentrated 20 onto silica and the solids were dissolved in CH2C12 concentrated onto silica, and purified by MPLC (hexanelethyl 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+H+).
25 Elemental analysis for (C2aH31N3O4 O.I5C4I380z 0.15C6H14) calculated: C
66.00, H
8.08, N 9.83; found: C 65.96, H 8.08, N 9.91.

Synthesis of 9,13-Imino-6H-azocinof2,l-aliso~uinoline-14-carboxamide,5,8,9,10,11,12,13,13a-octahydro-4-methoxy-N-(3-methylphenyl)-8-oxo-30 (Compound 90) mpound 90 /O
This compound was prepared similar to in Example 1D, using Compound A
(0.0871 g, 0.320 mmol), DMF (1.0 mL), 3-methylphenyl isocyanate (0.I21 mL, 0.960 mmol). The mixture was added to 5 mL brine and filtered. The mixture was extracted with 3x5 mL CH2Cl2. 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°7o yield) Spectral analysis of the product was consistent with Compound 90:
MS (APCI) 406.1 (M+H+).
Elemental analysis for (C24H27N3O3 0.30C4Ii802) calculated: C 70.47, H 7.17, N
9.45;
found: C 70.14, H 7.00, N 9.55.

Synthesis of 9,13-Imino-6H-azocino~2,l-alisoquinoline-14-carboxamide,5,8,9,10,11,12,13,13a-octahydro-1,3-dimethoxy-N-(4-nitrophenyl)-8-oxo-(Compound 91) ~N ~
N

Compound 91 This compound was prepared similar to Example 1D, 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 HCl (1.0 M) and the mixture was extracted with 3x5 mL CH2C12. The organic layers were combined, dried over MgS04, 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°7o yield).
Spectral analysis of the product was consistent with Compound 91:
MS (APCI) 467.2 (M+H+).
Elemental analysis for (C2qH26N40G 0.015C1H40) calculated: C 61.79, H 5.62, N
12.01;
1o found: C 60.69, H 5.92, N 12.66.

Synthesis of 9,13-Imino-6H-azocinof2,1-alisoquinoline-14-carboxamide,N-(2,4-difluorophenyl)-5,8,9,10,11,12,13,13a-octahydro-1,3-dimethoxy-8-oxo-(Compound 92) Compound 92 15 This compound was prepared similar to Example 1D, 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 HCl (1.0 M) and the mixture was extracted with 3x5 mL CH2C12. The organic layers were combined, dried over MgS04, filtered and concentrated onto silica. The crude material was purified by MPLC
20 (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°Io yield).
Spectral analysis of the product was consistent with Compound 92:
MS (APCI) 458.2 (M+H+).
Elemental analysis for (C24HZSFZN3O4O.15C4H8O2) calculated: C 63.01, H 5.51, N
25 9.19; found: C 62.77, H 5.61, N 8.93.

Synthesis of 9,13-Imino-6H-azocino f 2,1-alisoduinoline-14-carboxamide,N-(piperidin-1-~)-5,8,9,10,11,12,13,13a-octah~dro-1,3-dimethoxy-8-oxo-(Compound 93) 8s Compound 93 To an ice-cold mixture of 1,1'-carboxyldiimidazole (81 mg, 0.5 mmol) in CH2Clz (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 to CHZC12), affording 160 mg (75% yield) of the title compound.
Spectral analysis of the product was consistent with Compound 93:
1H NMR (CDCl3): ~ 6.15 (1H, s), 6.01 (1H, s), 4.85 (1H, s), 4.69 (1H, dd, J =

11.7, 3.0 Hz), 4.48 (1H, s), 4.37 (1H, s), 3.65 (3H, s), 3.56 (3H, s), 2.74 - 2.57 (1H, m), 2.51 -2.39 (1H, m), 2.37 (2.13 (1H, m).
HRMS (MALDI) calculated for C23H33N4O4 (M+I~) 429.2502; found 429.2483.

S~mthesis of 9,13-Imino-6H-azocino (2,1-a1 isoc~uinoline-14-carboxamide, N-(~
rr xl)-5,8,9,10,11,12,13,13a-octahydro-1,3-dimethoxy-8-oxo-(Compound 94) Compound 94 2o 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 (CDCl3): 8 7.00 (1H, 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 (1H, m), 2.77 -2.66 (1H, m), 2.56 (1H, d, J = 15.6 Hz), 2.14 - 2.00 (2H, m).
Elemental analysis for (C2~H26N~.O4 H80) calculated: C 61.67, H 6.59, N 13.08;
found:
C 61.83, H 6.35, N 13.06.

s EXAMPLE 27D
Synthesis of Compound 131 N \
N~ Compound 131 O N
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).
l0 The reaction was quenched with 5 ml NaCI, and the solution was extracted with 3x5 ml CHZCl2. The organic layers were combined, dried over MgS04, 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°7o yield).
15 Spectral analysis of the product was consistent with Compound 131:
MS (APCI) m/z 390.2 (M++1).
CHN for (C2øH27N3OZ~O.O5CH2C12~O.7C4Hg02) calculated: C 74.01, H 6.99, N
10.79;
found: C 71.11, H 6.82, N 8.85.

2o Synthesis of Compound 132 Compound 132 2s 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 NaCI, and the solution was extracted with 3x5 ml CH~,C12. 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) fnlz 394.1 (M++1).
1o CHN for (C23H~iFN3O2~O.15CH2C12~O.65C4HgO2) calculated: C 70.21, H 6.15, N
10.68;
found: C 66.87, H 6.17, N 8.68.
The amides and a,ec-difluoro amides of the present invention may be prepared in the manner depicted in Schemes E and F respectively shown below:

Scheme E
H
N RdCOOH
EDC/HOBt/Et3N
O N~\~/~ OCH (or HATU/N-methylmorpholine) -QCH

or N RdC(O)CI or R COCRd Diisopropylethylamine or Et3N
O NI \V 1j 1 pCH3 wherein:
Rd is selected from substituted or unsubstituted aryl, alkoxy aryl, and hydroxy aryl.
i0 Scheme F
H
N a,a-Difluoro Acid O N ~ EDC/DMAP
~ OCH3 CH3CN
The following examples are illustrative of the present invention:

Synthesis of 9,13-Imino-8H-azocino f 2,1-al isoquinolin-8-one,14-(d~henylace~l)-5,6,9,10,11,12,13,13a-octahydro-1,3-dimethox,~(Compound 106) mpound106 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.
1o 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 (APCZ7 ~~/z 497.1 (M+H+).
Elemental analysis for (C31H32N2~4 0.05 H20) calculated: C 74.84, H 6.50, N
5.63;
found: C 74.46, H 6.65, N 5.36.

Synthesis of 9 13-Imino-8H-azocino f2=1-al isoquinolin-8-one,l4-fbis(4-chloro~henyl)acetyll-5 6 9 10 11 12 13,13a-octahydro-1,3-dimethoxy-(Compound 105) mpound 105 This compound was prepared similar to Example 1E, 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+IT'~).
Elemental analysis for (C31H3oC12N20~) calculated: C 65.84, H 5.35, N 4.95;
found; C
66.23, H 5.42, N 4.74.

Synthesis of 9,13-Imino-8H-azocino f2,1-al isoquinolin-8-one,l4-(3,4-dimethox b~yl)-5,6,9,10,11,12,13,13a-octahydro-1,3-dimethoxy-(Compound 107) mpound 107 This compound was prepared similar to Example 1E, using Compound C (0.080 to 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:
15 MS (APCI) 467.2 (M+H+) Elemental analysis for (C2~H3pNZO6 0.40 H20 0.15 C~HI~.) calculated: C 66.39, H 6.81, N 5.76; found: C 66.66, H 6.71, N 5.36.

Synthesis of 9,13-Imino-8H-azocino X2,1-al isoquinolin-8-one,l4- (3,4-2o dichlorobenzoyl-5,6,9,10,11,12,13,13a-octahydro-4-methoxy-(Compound 100) impound 100 This compound was prepared similar to Example 1E, using Compound A (0.200 g, 0.734 mmol), 2-oxo-3,4-dichlorophenyl acetic acid (0.193, 0.881 mmol), CHZCl2 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+).
Elemental analysis for (C23HZZC12NZO3 0.15 C6H14) calculated: C 62.64, H 5.30, N
6.11; found: C 62.51, H 5.13, N 5.81.
EXAMPLE SE
Synthesis of 9,13-Imino-8H-azocino f2,1-al isoduinolin-8-one,l4-(3,4-dichlorobenzoyl-5,6,9,10,11,12,13,13a-octahydro-3-methox~(Compound 101) pound 101 This compound was prepared similar to Example 1E, 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), CHzCl2 instead of THF (8 mL), EDC (0.170 g, 0.881 mmol), HOBt (0.1208, 0.881 mmol) and TEA (0.13mL, 0.881 mmol). Purification afforded 0.0498 of Compound 101 (15%
2o yield) as a byproduct.
Spectral analysis of the product was consistent with Compound 101:
MS (APCI) 445.1 (M+H+).
Elemental analysis fox (C23H22C12N2O3 0.15 H20) calculated: C 61.66, H 5.02, N
6.25;
found: C 61.26, H 5.19, N 6.02.

Synthesis of 9,13-Imino-8H-azocino f2,1-al isoauinolin-8-one, 5,6,9,10,11,12,13,13a-octahydro-3-methoxy-14-(4-methoxybenzoyl)-(Compound 98) ipound 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.l g, 2.9 mmol) and N-methylmorpholine (0.4 mL, 3.9 mmol). After stirnng at room temperature for 5 days, the mixture was dropped into cold aqueous sodium bicarbonate 1o 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 (M+).
Elemental analysis for (CZ4H26N2~4) calculated: C 70.91, H 6.45, N 6.89;
found: C
0.95, H 6.46, N 6.86.

Synthesis of 9,13-Imino-8H-azocino f2,1-al isoquinolin-8-one, 5,6,9,10,11,12,13,13a-octahydro-3-hydroxy-14-(4-hydroxybenzoyl)-(Compound 99) npound 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 HCl 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+).
l0 Elemental analysis for (CzzHzzNz~a ~0.3Hz0) calculated: C 68.84, H 5.94, N
7.30;
found: C 68.77, H 5.87, N 7.13.

Synthesis of 9,13-Imino-6-oxa-8H-azocino f2,1-al 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 (M+).
Elemental analysis for (Cz3H22N4~4 ~0~8H2O) calculated: C 63.82, H 5.50, N

12.94;
found: C 63.73, H 5.30, N 13.20.

Synthesis of 9,13-Imino-8H-azocino X2,1-al isoquinolin-8-one, 5,6,9,10,11,12,13,13a-octahydro-4-methoxy-14-(1-naphthalenylcarbonyl)-(Compound 95) Compound 95 O~
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 HCl 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 (C27H26N203Ø4H20) calculated: C 74.77, H 6.23, N
6.46;
found: C 74.62, H 6.28, N 6.24.

~nthesis of 9,13-Itnino-8H-azocino f2,1-al isoquinolin-8-one, 5,6,9,10,11,12,13,13a-octahydro-6-methyl-14-(1-naphthalenylcarbonyl)-, (6R, 9S, 13R, l3aR)-(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 acetatelhexanes (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~) l0 Elemental analysis for (CZ~H2~N2O2 ~0.7H20) calculated: C 76.64, H 6.53, N
6.62;
found: C 76.56, H 6.69, N 6.25.

Synthesis of Carbamic acid,f2-f(5,8,9,10,11,12,13,13a-octahydro-1,3-dimethoxy-oxo-9,13-Imino-6H-azocino f 2,1-al isoquinolin-14-~)carbonyllphen l~~henylmethyl 15 ester-(Compound 109) O
~O
i Compound 109 J~
This compound was prepared similar to Example 1E, 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'HCl (0.096 g, 0.500 mmol), HOBt (0.067 g, 0.500 2o 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+H+) Elemental analysis for (C32H33N3O6 0.30H20 0.40C6H14) calculated: C 69.38, H
6.64, N
25 7.06; found: C 69.08, H 6.86, N 6.69.

Synthesis of 9,13-Imino-8H-azocinof2,1-alisoquinolin-8-one,l4-(2,4-dichlorobenzoyl)-5,6,9,10,11,12,13,13a-octahydro-6-1,3-dimethox~-(Compound 108) Compound 108 This compound was prepared similar to Example 1E, using Compound C (0.100 g, 0.330 mmol), 2,4-Dichlorophenyl acetic acid (0.088 g, 0.396 mmol), THF (6 mL), EDC'HCl (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).
to Spectral analysis of the product was consistent with Compound 108:
MS (APCI) 475.1 (M+H+) Elemental analysis for (C24H~C12N2O4O.OSC~H1~.) calculated: C 60.58, H 5.19, N
5.84;
found: C 61.24, H 5.37, N 5.56.

15 Synthesis of 13-Imino-6H-azocinof2,1-alisoquinoline-14-carbamate,0(1,1-dimethylethyl)5,8,9,10,12.13,13a-octah~dro-1,3-dimethoxy-8-oxo-(Compound117) O
N~O
O
Compound 117 O N
O
This compound was prepared similar to Example 9E, using Compound C (0.147 g, 0.487 mmol), Boc20 (0.159 g, 0.73 mmol), Et3N (0.136 mL, 0.974 mmol) and 1,4-20 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+H+), 425 (M+Na+), 346 (M-t-Bu+H+).
Elemental analysis for (C22H3oN20s) calculated: C 65.65, H 7.51, N 6.96;
found: C
65.62, H 7.58, N 6.81.

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), EDC'HCl (0.0808, 0.417 mmol), HOBt (0.058, 0.370 mmol) and TEA (0.06m1, 0.430 to mmol). Purification afforded 0.0708 of Compound 133 (58% yield).
Spectral analysis of the product was consistent with Compound 133:
MS (APCI) m/z 455.1 (M++1).
CHN for (CZSHa7C1iNa0a.) calculated: C 66.00, H 5.98, N 6.16; found: C 65.98, H 6.26, N 5.80.

Synthesis of Compound 134 O
~Br N O~ Compound 134 O Nl\%
~ O~
2o 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), EDC'HCl (0.0808, 0.417 mmol), HOBt (0.058, 0.370 mmol) and TEA (0.06m1, 0.430 mmol). Purification afforded 0.0858 of Compound 134 (64% yield).
Spectral analysis of the product was consistent with Compound 134:
MS (APCI) trrlz 499.0 (M++1).
CHN for (C25H27Br1N2O4) calculated: C 60.13, H 5.45, N 5.61; found: C 59.85, H
5.60, N 5.34.

Synthesis of Compound 135 ;ompound 135 This compound was prepared as described Scheme E, using Compound C
to (0.080 g, 0.264 mmol), 2-methoxy-2-phenylacetic acid (0.052, 0.330 mmol), THF (3.3 ml), EDC'HCl (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 (APCn ~r~lz 451.2 (Mk+1).
CHN for (C26HsoN20s'0.05 H20) calculated: C 69.18, H 6.72, N 6.21; found: C
68.78, H 5.42, N 5.95.

impound 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), 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 0.090 g of Compound 136 (62% yield).

Synthesis of Compound 136 Spectral analysis of the product was consistent with Compound 136:
MS (APCI) m/z 549.3 (M++1).
CHN for (C33H~N20s'0.15 HBO) calculated: C 71.88, H 8.10, N 5.08; found: C
71.62, H 8.12, N 4.87.

Synthesis of Compound 137 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), EDC'HCl (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:
2o MS (APCI) m/z 525.2 (M++1).
CHN for (C2~H3~N207) calculated: C 66.40, H 6.92, N 5.34; found: C 66.00, H
6.88, N
5.12.

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), EDC'HCl (0.080 g, 0.417 mmol), HOBt (0.05 g, 0.370 mmol) and TEA
(0.06m1, 0.430 mmol). Purification afforded 0.080 g of Compound 138 (59°70 yield).
l0 Spectral analysis of the product was consistent with Compound 138:
MS (APCI) m/.z 511.2 (M++1).
CHN for (C28H341V2O7'O.3O H2O) calculated: C 65.18, H 6.76, N 5.43; found: C
64.92, H 6.84, N 5.21.

Synthesis of Compound 139 pound 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), EDC'HCl (0.100g, 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 (C~sH34N206'0.20 CH2Cla) calculated: C 66.21, H 6.78, N 5.48; found: C
66.17,H6.81,N5.15.

Synthesis of Compound 140 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), EDC'HCl (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).
1o Spectral analysis of the product was consistent with Compound Compound 140:
MS (APCI) rnlz 469.1 (M++1).
CHN for (C25H27C11N205'0.55 C~H14'0.15 H20) calculated: C 65.23, H 6.77, N
5.38;
found: C 64.99, H 6.53, N 4.98.

Synthesis of Compound 146 /
0 0 ~
N /
O
C
N ~O
O' ~N~
O~
ompound 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), EDC'HCl (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++1).

CHN for (C32H33N3O6'O.3O H2O'O.4O C~H14) calculated: C 69.38, H 6.64, N 7.06;
found: C 69.08, H 6.86, N 6.69.

Synthesis of Compound 147 ci / ci N ~o Compound 147 a O N~\~/%
'I I~/ O/
to 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), EDC'HCl (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++1).
CHN for (C24.H2,q. C12N204 0.05 C6H14) calculated: C 60.58, H 5.19, N 5.84;
found: C
61.24,H5.37,N5.56.

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), 1-(3-dimethylaminopropyl)3-ethylcarbodiimide hydrochloride (0.77 g, 4.04 mmol) and methylmorpholine (0.51 mL, 4.59 mmol) in 50 mL of CH2C12 was stirred at room temperature for 12 hours. The solution was concentrated, then partitioned between EtOAc and saturated NaHC03 solution. The organic extract was washed with sat.
KH2P04 and brine solutions, dried (MgS04), 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 C2gH2gNZO3 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.
to 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 Ca~H2GN~O3S x 0.19 H20 (449.996): C, 69.40; H, 5.91; N, 6.22;
found:
C, 69.39; H, 5.96; N, 6.07.

2o 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 Ca6H26N20~. 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.

Synthesis of Compound 151 / \

O N~\v%
~ O
~ Compound 151 A mixture of 2-Bromo-1-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 to into powder and chromatographed (MPLC, Si02, 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:
15 Calculated for C25Hz$Nz04x1.2 HC1x0.2 HZO (467.857): C, 64.18; H, 6.38; N, 5.99;
H20, 0.77; found: C, 63.83; H, 6.30; N, 6.13; H20, 1.15.

Synthesis of Compound 152 Compound 152 2o A mixture of Compound C (0.5 g, 1.65mmo1), 2-bromo-1-(-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. NaHC03 solution. The organic extract was washed with brine solution, dried (MgS04), filtered and concentrated. The crude sample was 25 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 CZSHa7FiN20ax0.6 HClxl.4 HZO (485.589): C, 61.84; H, 6.31; N, 5.77;
HZO, 5.19; found: C, 62.13; H, 5.74; N, 5.20; H20, 5.53.

Synthesis of Compound 153 l0 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 CZSHz7BriNa04x1.25 HC1x0.45 H20 (553.080): C, 54.29; H, 5.31;
N, 5.06; H20, 1.47; found: C, 54.03; H; 5.38; N, 4.97; H20, 1.82.

Synthesis of Compound 157 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. NaHC03 solution. The organic extract was washed with brine solution, dried (MgSO4), 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 CZSH2~C12N20~0.21 HZO (493.174): C, 60.88; H, 5.40; N, 5.68;
H20, 0.77; found: C, 60.33; H, 5.46; N, 5.44; H20, 0.39.

~nthesis of 9,13-Imino-8H-azocino f 2,1-al isoquinolin-8-one,14- f difluoro(3,4,5-trimethoxyphenyl)acetyll-5,6,9,10,11,12,13,13a-octahydro-1,3-dimethox~(Compound l0 102) pound 102 The amine (Compound C, 0.080 g, 0.264 mmol) and oc,oc-difluoro-3,4,5-trimethoxy-phenylacetic acid (18, 0.083 g, 0.316 mmol) were dissolved in acetonitrile 15 (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).
2o Spectral analysis of the product was consistent with Compound 102:
MS (APCn 547.2 (M+H+).
Elemental analysis for (C28H32F~N207) calculated: C 61.53, H 5.90, N 5.13;
found: C
61.60, H 5.93, N 4.89.

25 Synthesis of 9,13-Imino-8H-azocino f 2,1-al isoquinolin-8-one,14- f difluoro(3,4,5-trimethoxxphenyl)acetyll-5,6,9,10,11,12,13,13 a-octahydro-4-methoxy-(Compound 103) 11o Compound 103 This compound was prepared similar to Example 1F, using Compound A (0.080 g, 0.294 mmol, synthesized according to a published procedure [I~atoh, 5. and et al.
WO 0004020]), a,a-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 1o 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+).
Elemental analysis for (C27H3oF2N2O6) calculated: C 62.78, H 5.85, N 5.42;
found: C
62.86, H 5.97, N 5.11.

Synthesis of 9,13-Imino-8H-azocino f2,1-al isoquinolin-8-one 14-~(4-chlorophenyl)difluoroacetyll-5,6,9,10,11,12,13,13a-octahydro-1,3-dimethoxy-and 104 2o This compound was prepared similar to Example 1F, using Compound C (0.080 g, 0.264 mmol), a,oc-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).

(Compound 104) Spectral analysis of the product was consistent with Compound 104:
MS (APCI) 491.0 (M+H+).
Elemental analysis for (C25H25C11F~N204 0.15 C6H14) calculated: C 61.74, H
5.42, N
5.56; found: C 61.69, H 5.47, N 5.18.

to Synthesis of Compound 142 Step 2: Synthesis of Compound 141:
;ompound 141 To a stirred 1M solution of lithium aluminum hydride in THF (3.3 ml, 3.30 15 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 20 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 25 141.
Spectral analysis of the product was consistent with Compound 141:
MS (APCI) fYrlz 289.1 (M+-1).
CHN for (C17Hz41V2020.I5 C6H14'0.40 H20) talc: C 69.69, H 8.79, N 9.08; found:
C
69.58,H8.51,N8.70.
3o Step 2: Synthesis of Compound 142:

~O I
i O F
F Compound 142 N
N
O
This compound was prepared as described in Scheme F, using Compound 141 (0.173 g, 0.600 mmol), a,a-difluoro-3,4,5-trimethoxy-phenylacetic acid (0.188, 0.720 mmol), CH3CN (7 ml), EDC~HCI (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) tnlz 533.3 (M++1).
CHN for (CZ$H3dFZN2O6) 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

_ MeOCCCI _ N-methyt-O N ~ morpholine /~OCH3 wherein:
2o Re and Rf are selected from alkoxy, heterocycloalkyl, heteroaryl, hydrogen, aryl, alkyl, or Re and Rf together taken with an adjacent nitrogen atom form a heterocycle.
The following examples are illustrative of the present invention:

Synthesis of 9 13-Imino-8H-azocinof2 1-alisoduinoline-14-oxoacetate, O-methyl-5 6 9 10 11 1213 13a-octah~dro-3-methoxy-8-oxo-(Compound 110) npound 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. W000/04020]), in dichloromethane (30 mL) at 0°C were added methyl chlorooxoacetate (0.6 mL, 6.5 mmol) and N-rnethylmorpholine (0.77 mL, 7 mmol). After allowing the mixture to 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 (M+) Elemental analysis for (C18H22N205) calculated: C 63.68, H 6.19, N 7.82;
found: C
63.43, H 6.21, N 7.74.
2o EXAMPLE 2G
Synthesis of 9,13-Irnino-8H-azocino f2,1-al isoquinolin-8-one, 5,6,9,10,11,12,13,13a-octahydro-3-methoxy-14-(oxo-1-pyrrolidin l~yl)-(Compound 111) npound111 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 (M+).
Elemental analysis for (C22Hz7NsO4 ~0.2H20) calculated: C 65.88, H 6.89, N
10.48;
to found: C 65.87, H 6.74, N 10.49.

Synthesis of 9,13-Imino-8H-azocino f2,1-a1 isoquinolin-8-one, 5,6,9,10,11,12,13,13a-octahydro-3-methoxy-14-(oxo-1-pyperidinylacetyl)- (Compound 112) pound 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 quicldy 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 acetatelhexanes 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 (M+).
Elemental Analysis for (C23H29N3~4) c~culated: C 67.13, H 7.10, N 10.21;
found: C
66.87, H 6.22, N 10.04.

Synthesis of 9,13-Imino-8H-azocino f2,1-al isoquinolin-8-one, 14- f(2,5-dihydro-1H-p rr~yl)oxoacetyll- 5,6,9,10,11,12,13,13a-octahydro-3-methoxy-(Compound 113) pound 113 1o 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 (M+) Elemental analysis for (CZZHzsN3C4) calculated: C 66.82; H 6.37, N 10.63;
found: C
66.73, H 6.34, N 10.60.
2o EXAMPLE 5G
Synthesis of 9,13-Imino-8H-azocino f2,1-al isoquinolin-8-one, 14- ~(cis-3,4-dih d~~
1-pyrrolidinyl)oxoacet~l- 5,6,9,10,11,12,13,13a-octahydro-3-methox~(Compound 115) npound115 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 to 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 (M+).
Elemental analysis for (C22H27N3O6~O.4H2O) calculated: C 60.51, H 6.42, N
9.62;
2o found: C 60.33, H 6.31, N 9.44.

Synthesis of 9 13-Imino-8H-azocino X2,1-al isoquinolin-8-one, 5,6,9,10,11,12,13,13a-octahydro-3-methoxy-14- f oxo-(cis-3,6-tetrahydro-2,2-dimethyl-5H-1,3-dioxoloT4,5-clpyrrol-5- 1)~,~(Compound 114) pound 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 rnmol) and p-toluenesulfonic acid (10 mg, 0.05 mmol). After stirring at room temperature fox 2 hours, the mixture was partitioned between ethyl acetate and phosphate buffer (1M, 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'-) Elemental analysis for (CZSH31N3~6~0~6HaO) calculated: C 62.51, H 6.76, N 8.75 found: C 62.41, H 6.73, N 8.73.

Synthesis of 9,13-Tmino-8H-azocino f2,1-al isoquinolin-8-one, 5,6,9,10,11,12,13,13a-octahydro-3-methoxy-14-foxo-(cis-3,6-tetrahydro-2-oxo-5H-1,3-dioxolo f 4,5-clpyrrol-5-yl)acet.~(Compound 116) >und 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 1o 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+).
Elemental analysis for (C23H25N3~7~O.3HZO) calculated: C 59.94, H 5.60, N
9.12;
found: C 59.93, H 5.66, N 9.04.

2o Synthesis of (Compound 121) o 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 (C29H33N3O~' 0.1 MTBE ' H20) calculated: C 64.84; H
6.68; N
7.69; found: C 65.02; H 6.53; N 7.38.
MS (electrospray): 520 (M+).

Synthesis of (Compound 122) 'O
Compound 122 To a suspension of the methyl oxalate (Compound 110, 0.05 g, 0.14 mmol) in dioxane (0.5 rnL) 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 3o 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 ' 0.5H20) calculated: C 65.80; H
7.27;
N 7.43; found: C 65.93; H 7.32; N 7.07.
MS (electrospray): 522 (M+).

~..~~~~ound 123 A suspension of the methyl oxalate (Compound 110, 0.05 g, 0.14 mmol) and 1,2,3,4-tetrahydropyrido[4,3-B][1,6]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 2o 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 (C29H29NSO41.4H20) calculated: C 64.89; H 5.97; N

13.05;
found: C 64.89; H 5.98; N 12.65.
MS (electrospray): 512 (M'~) Synthesis of (Compound 124) Synthesis of (Compound 123) OH
~N
J
' ~If/
N O
O~N
O~
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 l0 microwave apparatus by Personal Chemistry. The solution was irradiated for 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 15 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 (CZSH33N3~5 ' 0.3 MTBE ' H20) calculated: C 63.65; H
7.78; N
8.40; found: C 63.82; H 7.62; N 8.01.
2o MS (electrospray): 456 (M+).

Synthesis of (Compound 125) ~o ~.,~NJ
Compound 125 25 A solution of the methyl ester (Compound 110, 0.05 g, 0.14 mmol) and 1-(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 to 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 (CZgH39N5O5 ' 0.3 CHCl3 ' 0.75H20 ' 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+).

Synthesis of (Compound 126) i Compound 126 A solution of the methyl ester (Compound 110, 0.05 g, 0.14 mmol) and 1-(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 (C29H34N4O5 ' 0.2 MTBE ' H20) calculated: C 65.01; H
6.98; N
10.11; found: C 64.93; H 6.62; N 9.83.
MS (electrospray): 519 (M+).

Synthesis of Compound 143 ;ompound 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), EDC'HCl (0.207 g, 1.080 mmol), HOBt (0.146 g, 1.080 mmol) and T'EA (0.160 ml, 1.150 mmol). Purification afforded 0.086 g of Compound 143 (29% yield).
2o Spectral analysis of the product was consistent with Compound 143:
MS (APCI) m/z 511.2 (M++1).
CHN for (C2gH34N2O7~O.25 CGH14) calculated: C 66.59, H 7.10, N 5.26; found: C
66.98, H 7.25, N 5.07.

Synthesis of Compound 144 ompound 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), EDC'HCl (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°1o yield).
Spectral analysis of the product was consistent with Compound 144:
MS (APC~ rr~lz 489.1 (M++1).
CHN for (C25H26C12NZO4 0.30 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
A' CI--N B' O N ~ neat, 150 °-C
/~OCH3 or Heterobicycles A' Cl~~
N B' O N
/~OCH3 N-ethyldiisoprpylamine toluene, retlux Heterobicycles Wherein:
2o A', B' are nitrogen, sulfur, or oxygen.

S
Example 1H
Synthesis of Compound 158 Compound 158 to 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 NH40H solution. The organic extract was washed with brine solution, dried 15 (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 C23H23N3~2s x 0.21 H20 (409.306): C, 67.49; H, 5.77; N, 10.27;
found:
2o C, 67.49; H, 5.73; N, 10.06.
Example 2H
Synthesis of Compound 159 Compound I59 This compound was prepared in a process analogous to Example 1H, 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 C2~.H2~N3O3S x 0.20 H20 (439.152): C, 65.64; H, 5.83; N, 9.57;
found:
C, 65.66; H, 5.77; N, 9.38.
to Example 3H
~nthesis of Compound 160 OMe N NJ
O
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 NaHC03 solution. The organic extract was washed with brine solution, dried (MgS04), filtered and concentrated. The crude sample was 2o chromatographed (MPLC, silica gel, 25% EtOAc in hexanes) and recrystallized from CH2Cl2-Et20 to give 1.29 g (45%) of the titled compound as a white solid, mp °C.
Spectral analysis of the product was consistent with Compound 160:
Calculated for C23Ha3N3O4 (389.458): C, 70.93; H, 5.95; N, 10.79; found: C, 70.81; H, 6.02; N,10.70.
Example 4H
~nthesis 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:
l0 Calculated for C24H2sN3Ca x 0.33 H20 (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 (K;) 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 NaCI, pH 8.0). Within this final reaction volume, 3.5 ~L 20 mM
FKBP-12 (in 50 mM Hepes, 100 mM NaCI, pH 8.0) and 10 ~uL test compound in DMSO were added. The reaction was initiated by adding 10 ~L chymotrypsin (100 mg/mL in 1 mM HCl) followed by 5 p,L (1-20 mM succinyl-Ala-Leu-Pro-Phe-pNA in 240 mM LiCI/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.

Table 1 Compound No. Molecular Structure Ki (FKBP-12) F
22 ~?N ~I F 0.15uM
N
O N~\'i ~/
O~
O
I I
~S~
23 N , ~ ' ~ 1.5 uM
O N, \l IN ~ O
O I /
O~
24 ~ \ ~ I 0.09 uM
N =_ /
'~ O
N oaH
/ O/
25 0 169 uM
o~\s N
H
O N ~ \
26 ~~s ~ / 0.32 uM
_-_ N =_ ,,.wH
O N ~ \
ywoY~. /

27 o S ( ~ 1.3 uM
N r .,,,,,f-I
O N \
O~
O~
2~ 02 H ~ ~ 0.64 uM
S~N w O\
O N ~ \
O~
CI
29 °=N w ~N 0.36 uM
N
O N ~ \
O~
O=N
%S
30 N 0.36 uM
O N~\V%
O' _S~N O
31 N V 0.722 uM
O N ~ \
O' N
S=N~-O
32 NI \ / ~ 0.21 uM
O N ~ \
O~

33 N S-N 0.123 uM
O N ~ \
O~
F
34 ~°=N ~ I F 0.083 uM
N Oi O N~\'/ ~~
O~
35 ~2S ~ / ~ 2.5 uM
N =_ iN
oOVH
O N
~ s' " 0.50 uM
36 N, ~0 6 O N
/O
3 °' 0.416 uM
NHS o O N ~ \
/ /
O
O
!l ~S
38 N o ~ ~ 1.4 uM
O N ~ \
O~
O _ s i 39 N o ~ ~ 1.3 uM
O N ~ \
/

40 O 5~ 0.084 uM
N~ O
O/
O N ~ \
/ /
O
/I

N/ 0 8.2 uM
o~
/ /
O N~~., O
42 °~ / I ~ 0.52 uM
N~so \
o~
/ /
O N~~.,~ ~~
O
43 °.s ~ I 0.459 uM
N/ so o~
O N
O
44 ~S o ~ 0.266 uM
N /
O
O N~~., O
F
45 NHS=N ~ I F 1.2 uM
F
O N~\V%
~/
O~

F
46 N-°? NH / \ F 0.236 uM
F
O N~\'% ~~
O~
Br 47 S~ ~ ~ 0.94 uM
N~ O
O~
/ /
O N~~..i O
48 ~ ~ / 0.054 uM
N/ O / Br O
O N~\\/
/ /
O
y ~Br 49 N~ -o~' ~ / 0.092 uM
o/
O N~\y/
/ /
O
OZN
50 ~S o \ ~ N~Z 3.0 uM
N
O
O N~\
O
/ .
51 /S o 0.364 uM
o~.\~/
O N~\\
/ /
O
/S O
52 N 0.10 uM
o-O N~\'/
/ /
O

F
53 '°? NH ~ ~ F 0.59 uM
N I
F
O N~\y/ ~~
0~

54 -°? NH / \ NJ 0.59 uM
N
O N~\V%
'I~/
O~
H
N
55 AS o \ / \ / ~ 0.288 uM
N o~ o_ o-O N~\
II~/ /
O
O
H
N
56 ~S o \ / \ / oet 1.5 uM
N
O~
O N,\yY, ~/ /
O
CI
N %s o \ l ~ / c1 0.369 uM
o-O N
/ /
O
58 ~S o \ / clCl 0.156 uM
N \ /
O
O N, \'Y\, /I ~ / /
O
CN
59 N/S o 0.082 uM
o~
O N
O

~z / v ci 60 N 0.167 uM
O N ~ \
O~
61 N~SO'N~ 0.09 uM

O N~\y/ ~~
O
62 N o2 N~--~ 0.066 uM
o-O N, \y%Y \1 O~
CI
63 0 ~ ~ 0.214 uM
NHS
O
O N
/O
\ I
64 N/S o 0.104 uM
O N~\~/%
O/

N~S~NH2 65 30 uM
O N~\y O~

~S~ ~N~
66 N H 5.4 uM
O N
O~

~S~
67 0.479 uM
O N~\'i l ~J~~/~/
O~
02 ~
N/S~O
68 3.7 uM
O N~\'/
O~
O
69 N N~ 12 uM
o N
/

70 N~N~ 18 uM
O N
/ Oi O
71 ~N ~ / 382 uM
N
O N~\\rJ ~~
/ Oi O
72 N ~ / 7 uM
N
O N
O~

O ~-73 N ~ ~ 8.9 uM
N
o N I W
o' F
O ~ F
74 N ~ ~ 55 uM
N
O N' \\ Y \, l ~~//II\\~'~~/
O~
O _ N
75 N \ ~ 2.4 uM
O N
O _ N
76 N ~ ~ 2.0 uM
O N~\'/%
~/
O
O _ 77 N \ ~ 736 uM
N
O N~\'/
I'I~/
O
O-O ~' 78 ~ ~ / 1.7 uM
N
N
O N~\\/%
Il O

~N , o- 0.357 uM

O N~\'/
O~
O r 80 N ~ / 4.3 uM
N
O N ~ \
O\
O i 81 N ~ ~ a 5.6 uM
N
Oi ~N~~~,.~
/ O'' i 82 ~N \
N °~ 2.7 uM
O N~\\/
/ Or O N
83 ~ I / N+~~° 5.8 uM
I
o-O N ~ \
/O
N N \
84 / N+~'o 8.2 uM
I
o-O N~\~/%
Il / O/
\\'N
85 N ~ / 1.7 uM
O N~\\/
Il / O/

O~ N
86 N 0.33 uM
o' O N
o~N~
87 N~ /\ 18.5 uM
o~N I w ,o 88 N~ 26.8 uM
O N ~ ~ , N
89 N ~0 10.5 uM
O N
O/
90 N I \ 1.88 uM
O N~\
/O
N
91 N ~ ~ 0.772 uM
~o No2 O N~\\/%
O/
F
N
92 N ~ ~ 7.0 uM
~O F
O N~\y/ ~~
O~

N
N

93 H O~ NSI at 20 uM
O N

~\yi %I I~/
O~

O
N~N~N

94 H o- 30% at 20 uM
O N

~\~%
%I I~/
O~

O

95 N NI at 10 uM
\ /
O N

O~

O

96 ~ ~ ~ NI at 10 uM

N
H \

p~N

O N
~NH

97 N ' 1.95 uM

o s \ ~

98 N 32 uM

O N~\\/%/
O/

O~ ~
/ y--( OH
~~~

99 N 81 uM

O N~\\/%
OH

o ~ ' c1 100 N ~~ 6.5 uM
O N
O~
O CI
101 N _ C, 10.7 uM
o~~N \

/ o 102 0 ~ ~ ~ 0.091 uM
F F/
O N ~ O'\
~~0~
O O
103 0 / \ ~ 1.1 uM
'~F
F
O N
~\~/[~\~~OJ~
F F
O _ 104 ~ / ~i 0.25 uM
N
O
O N~\\J/
O~
CI
105 ~ ~ 65 uM

N ~ c1 O N
O/

106 o NI at 30 uM
N
~O
O N~\\
Il / O~
/ O
107 0 ~ ~ ~ 1.2 uM

N
O
O N
CI
O
10~ N ~o ~ c1 5.3 uM
O N'\ Y \l ~~ O~
O1l O N~O

N
~O - b O Nl\
~ O~
110 0 54 uM
N
O N
/ O/
O N
111 7.4 uM
N O
O N
112 1.45 uM
N O
O N

113 2.24 uM
N O
O~N
O~
O
114 o Ip 44 uM
~N
N~\~~(~O
O N \
OH
115 ° N 365 uM
N
O NI
~~'!~~~0/
p\ /O
116 o N~~° NSI at 10 uM
N
O N ~ \
O/
O
117 ~~~ 10 uM
N ~O
O Nl\J
/ O/
\ F
118 NHS-NH 0.183 uM
O N ~ \
O~

o ~
119 Ness? NH 0.128 uM
O N ~ \
O~
\ F

120 - NHS-NH 0.246 uM
~ . ,,.~H
O' _N \
,.
o / I ~~
121 N o N ~ ~ 0.371 uM
o N
/ o~

122 N~ \ 0 5.2 uM
o I
O N
O/
123 N ~ ~ N 0.63 uM
N O
O N~\y%
l 1I~~ O/
~oH
O ~~ ''N
124 N 12.7 uM
O NI I
~O~
r Q
125 ° ~N I J 23 uM
N b O N_ 1! \1 O~

i 126 0 ~N~o' 2.8 uM
NJ
o N
/
0.241 uM
130 0~
/S o N
O Nl\J
o i I
131 N ~ 0.464 uM
N
O N
O
132 N ~ ~ 1.2 uM
N
O N
CI
133 ~ o~ ND
O N' ~ / Oi O
Br 134 ~ o' 3.4 uM
O Nl Y \
I // O' 135 434 uM
'o' o' N
O N
I / O' 136 Ho o ~
\ ~o ' o O N, Y \
I '' O' 137 ~ ~ O~ 8.4 uM

O
~O' N
O N
%Y \
I~

l\
J
~ O~

O
O

138 ~O~ ND
O~ O-N
O N
%

'\
~ O' O~
I

139 O ~ 4.1 uM
O~
.
O~

N
O N
Y\
~

l\
~ O~

CI

140 ~ ~ 0.208 uM
O
~OH

N
O Nl\
O' 141 N O IVI @ 20 uM

O

~O
142 ~O ~ ~ O~ NI @ 20 uM
O F
F
N
N
/ O~
~O
143 ~O ~ ~ O~ ND
O
'O
N
N
~ O~
CI

'O
N O~
N \
/ O~
145 O,SI / 0.244 uM
N 'O O
O N'\%Y \
O~
/I
146 0~0~
N /

N ~O
O~ ~N~ \
/ Oi CI / CI

~O
pi ~NI~ ~ \

OMe 148 ~ ~ NI @ 20 uM
N NJ
'-'~ \
O O
OMe 149 ~ ~ NI @ 20 uM
s N N
O O
OMe 150 NI @ 20 uM
N N~
O
O O ~ ~
151 1 , ND

O Nl\y%
O
F
152 ~ \ 1.59 uM
o' N O
O Nl Y \
~~~ O~
Br 153 ~ ~ 13.9 uM
o' N O
O N'\J%
~1I~~ O~
154 N \ N~ 0.564 uM
O Nl\
~O

155 N S 1.13 uM
O N~\
.~jl~/
~O
156 ' N ~ 0.415 uM
N
O N ( ~
,O
c~
157 ~ ~ c~ 0.96 uM

o' N
O N~\J
O~
OMe 15 ~ ~ ~ ND
N NJ
S
OMe 159 Me0 19.1 uM
N N-' S
OMe 160 ~ ~ 3.4 uM
N NJ
O

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.
1o 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 15 compounds are provided so as to provide therapeutic benefits involving regulation of FKBP. By "efficacious levels" of compounds is meant levels in which the FI~BP
binding of FI~BP-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 20 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 25 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 II) as an active ingredient with appropriate pharmaceutical carriers or diluents according to conventional procedures. These procedures may 3o 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 Garner, such as a diluent or excipient for the agent. When the Garner 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 l0 invention may be made by admixing the active ingredients) 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 dehydrate, 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.
2o 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.
3o 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 to 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 3o 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 2o 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 fox 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.
2o Pharmaceutical formulations fox 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 3o 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, to 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 fox hydrophobic compounds is a cosolvent system comprising benzyl alcohol, a nonpolar surfactant, a water-miscible organic polymer, 2o and an aqueous phase. The cosolvent system may be a VPD co-solvent system.
VPD
is a solution of 3% wlv 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 corners 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.
2o 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 3o 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 (25)

WHAT IS CLAIMED IS:

1. A compound of Formula (I):
wherein:
Z is wherein:
R1 is hydrogen; substituted or unsubstituted alkyl, alkenyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, or cycloalkenyl; or C(R11)(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 (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 R1 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 R1 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 2, 2, or 3 I' 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:

Z is

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

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

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

Z is

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-pyridinyloxy)-phenyl, 4-methylphenyl, 4-(1,1-dimethylethyl)phenyl, 4-(1-methylethyl)phenyl, 4-ethylphenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 2,4-dinitrophenyl, 2-(1-naphthalenyl)ethyl, 1,1'-biphenyl, 3-[(3,4,5-trimethoxyphenyl)amino]phenyl, 3',4'-dichloro[1,1'-biphenyl]-4-yl, 3',4'-dichloro[1,1'-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 R4 is 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-1H-pyrrol-1-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 Z is wherein:
R1 is hydrogen; substituted or unsubstituted alkyl, alkenyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, or cycloalkenyl; or C (R11)(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 (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 R1 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 R1 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 I' groups, where I' 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 1,3-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 salt 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:

or 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.