CA2203681A1 - Cyclic amidine analogs as inhibitors of nitric oxide synthase - Google Patents

Abstract

Disclosed herein are the heterocyclic compounds and pharmaceutically acceptable salts thereof which have been found to be useful in the treatment of nitric oxide synthase mediated diseases and disorders.

Description

WO 96/14&14 PCI`/US95/14812 IITLE OF THE INVENTION
CYCLIC AMIDINE ANALOGS AS INHIBITORS OF NITRIC OXIDE
SYNTHASE

This application is directed to inhibitors of Nitric oxide synthase, and in particular cyclic amidines.

Nitric Oxide in Biology.

The emergence of nitric oxide (NO), a reactive, inorganic radical gas as a molecule contributing to important physiological and pathological processes is one of the major biological revelations of recent 15 times. This molecule is produced under a variety of physiological and pathological conditions by cells m~ ting vital biological functions.
Examples include endothelial cells lining the blood vessels; nitric oxide derived from these cells relaxes smooth muscle and regulates blood pressure and has significant effects on the function of circulating blood 20 cells such as platelets and neul.ol,hils as well as on smooth muscle, both of the blood vessels and also of other organs such as the airways. In the brain and elsewhere nitric oxide serves as a neurotr~n.~mitter in non-adrenergic non-cholinergic neurons. In these instances nitric oxide appears to be produced in small amounts on an intermittent basis in 25 response to various endogenous molecular si n~l~. In the immune system nitric oxide can be synth~ 1 in much larger amounts on a protracted basis. Its production is induced by exogenous or endogenous infl~mm~tory stim~ notably endotoxin and cytokin~s elaborated by cells of the host defense system in response to infectious and 30 infl~mm~tory stimllli This in~ ce-l production results in prolonged nitric ,~ oxide release which contributes both to host defense processes such as the killin~ of b~cteri~ and viruses as well as pathology associated with acute and chronic infl~mm~tion in a wide variety of diseases. The discovery that nitric oxide production is mediated by a unique series of 35 three closely related enzymes, named nitric oxide synth~es, which utilize WO 96/14844 PCr/US95/14812 the amino acid arginine and molecular oxygen as co-substrates has provided an underst~nt1ing of the biochc~.mi~try of this molecule and provides rli~tin ,t ph~rm~cological t~-~ets for the inhibition of the synthesis of this m~ tor, which should provide significant beneficial effects in a wide variety of diseases.

Nitric Oxlde Synthases Nitric oxide and L-citrulline are formed from L-a~ hle via the dioxygenase activity of specific nitric oxide synthases (NOSs) in m~mm~ n cells. In this reaction, L-ar~ , 2 and NADPH are cosubstrates while F~N, FAD and tetrahydrobiopterin are cofactors.
NOSs fall into two distinct classes, constitutive NOS (cNOS) and inducible NOS (iNOS) . Two constitutive NOSs have been identified.
15 They are:
(i) a constitutive, Ca++/calmodulin dependent enzyme, located in the endoth.~ m (ecNOS or NOS 3), that releases NO in response to receptor or physical stimlll,ltion, (ii) a constitutive, Ca++/calmodulin dependent enzyme, located in the brain (ncNOS or NOS 1) and elsewhere, that releases NO in response to receptor or physical stimulation, The third isoform iclentifi~ is in~ cible NOS (iNOS or NOS 2):
(iii) a Ca++ indepen~,ent enzyme which is in~lll e-l after activation of vascular smooth muscle, macrophages, endothelial cells, and a large number of other cells by endotoxin and cytokines. Once expressed, this in~l~lc.ible NO
synthase produces NO in relatively large amounts for long periods of time.
"
Spectral studies of both the mouse macrophage iNOS and rat brain ncNOS have shown that these enzymes (which has been cl,~sifi~
as P-450-like enzymes from their CO-diLrel~llce spectra) contain a heme moiety. The stmct lr~ imil~rity between NOS and the P-450/flavoploteill complex suggests that the NOS reaction mec.h~ni~m may be simil~r to P-450 hydroxylation and/or peroxidation. This indic~t~s that NOS belongs to a class of flavohemeproteins which contain both heme and flavin binding regions within a single protein in contrast 5 to the multi~roteill NADPH oxidase or Cytochrome P-450/NADPH Cyt c reductase complexes.

Distinct Functions of NO Produced by DiL~l~l-t Nitric Oxide Synthases.
The NO released by the constitutive enzymes (NOS 1 and NOS 3) acts as an autocoid me~ ting a number of physiological responses. Two distinct cDNAs accounting for the activity of NOS 1 and NOS 3 in man have been cloned, one for NOS 1 (Nakane et. al., FEBS
Letters, 316, 175-182, 1993) which is present in the brain and a number of peripheral tissues, the other for an enzyme present in endothelium (NOS 3) (Marsden et. al., FEBS Letters, 307, 287-293, 1992). This latter enzyme is critical for production of NO to m~int~in vasorelaxation. A
second class of enzyme, iNOS or NOS 2, has been cloned from hllm~n liver (Geller et. al., PNAS, 90, 3491-5, 1993), and identified in more than a dozen other cells and tissues, including smooth muscle cells, chondrocytes, the kidney and airways. As with its counterpart from the mllrine macrophage, this enzyme is in~ cerl upon exposure to cytokines such as ~mm~ intelre~ (IFN-~), interleukin-l,~ (IL-l,O, tumor necrosis factor (TNF-a) and LPS (lipopolysaccharide). Once induced, iNOS
expression continues over a prolonged period of time. The enzyme does not require exogenous calmodulin for activity.
Endothelium derived relaxation factor (EDRF~ has been shown to be produced by NOS 3 (Moncada et. al., Pharmacol. Reviews, 43, 109-142, 1991). Studies with substrate analog inhibitors of NOS
30 have shown a role for NO in reg~ ting blood pressure in ~nim~l~ and blood flow in man, a function attributed to NOS 3. NO has also been shown to be an effector of the cytotoxic effects of activated macrophages (Nathan, FASEB J., 6, 3051-64, 1992) for fighting tumour cells and invading microorg~ni.cm~ (Wright et al., Card. Res., 26 ,48-57, 1992 and =

W O96/14844 PCTrUS95/14812 Moncada etal.,PharmacologicalReview,43, 109-142, 1991). Italso appears that the adverse effects of excess NO production, in particular pathological vasodilation and tissue l~m~ge, may result largely from the effects of NO synthesized by the NOS 2.
S NO generated by NOS 2 has been implicated in the pathogenesis of infl~mm~tory diseases. In experime.nt~l ~nim~
hypotension in~ ced by LPS or TNF-a can be reversed by NOS
inhibitors and reiniti~terl by L-algh~ille (Kilbourn et. al., PNAS, 87, 3629-32, 1990). Conditions which lead to cytokine-induced hypotension incIude septic shock, hemodialysis (Beasley and Brenner, Kidney Int., 42, Suppl., 38, S96--S100, 1992) and IL-2 therapy in cancer patients (Hibbs et. al., J. Clin. Invest., 89, 867-77, 1992). NOS 2 is imrlic~te~l in these responses, and thus the possibility exists that a NOS inhibitor would be effective in ameliorating cytokine-in~ ce-l hypotension. Recent studies in ~nim~l models have suggested a role for NO in the pathogenesis of infl~mm~tion and pain and NOS inhibitors have been shown to have beneficial effects on some aspects of the infl~mm~tion and tissue changes seen in models of infl~mm~tory bowel disease, (Miller et. al., J.
Pharmacol. Exp. Ther., 264, 11-16, 1990) and cerebral ischemi~ and al~llilis (Ialenti et. al., Br. J. Pharmacol ., 110, 701-6, 1993; Stevanovic-Racic et al., Arth. & Rheum., 37, 1062-9, 1994). Moreover transgenic mice deficient in NOS 1 show ~iimini~hed cerebral ischemia (Huang et.
al., Science, 265, 1883-5, 1994).
Further conditions where there is an advantage in inhibiting NO production from L-aLgil~ine include therapy with cytokint~s such as TNF, IL-l and IL-2 or therapy with cytokine-in~ rin~ agents, for example 5, 6-dimethylxanthenone acetic acid, and as an adjuvant to short term immnnosuppression in transplant therapy. In addition, compounds which inhibit NO synthesis may be of use in re~ cing the NO
concell~ ion in patients suffering from infl~mm~tory conditions in which an excess of NO contributes to the pathophysiology of the condition, for ex~mple adult re~ tol y distress syndrome (ARDS) and myocarditis.

There is also evidence that an NO synthase enzyme may be involved in the degeneration of cartilage which takes place in toimmllne and/or infl~mm~tory conditions such as arthritis, rheumatoid . arthritis, chronic bowel disease and systemic lupus erythematosis (SLE).
5 It is also thought that an NO synthase enzyme may be involved in insulin- dependent diabetes mellitus. Therefore, a yet further aspect of the present invention provides cyclic amidine derivatives or salts thereof in the manufacture of a medic~ment for use in cytokine or cytokine-inducing therapy, as an adjuvant to short term immnnosuppression in 10 transplant therapy, for the treatmPnt of patients suffering from inflamm~tory conditions in which an excess of NO contributes to the pathophysiology of the condition.

SUMMARY OF THE INVENTION
The invention disclosed herein encompasses compounds of Formnla I

( )~nx~
Rl,R2,R3N, N' 5 R4 R5a and ph~rmacelltically acceptable salts thereof which have been found useful in the tre~tm~.nt of nitric oxide synthase m~.r1i~te~ tii.ce~es and disorders, including neurodegenerative disorders, disorders of ga~LIoilltestinal motility and infl~mm~tion. These diseases and disorders 25 include hypotension, septic shock, toxic shock syndrome, hemodialysis related conditions, tuberculosis, cancer, IL-2 therapy such as in cancer patito.llt.~, c~c.he.xia, immnnosuppression such as in transplant therapy, autoimmune and/or infl~mm~tory indications including sunburn, eczema or psoriasis and res~iralol y conditions such as bronchitis, ~.cthma, 30 oxirl~nt-infl-lce~l lung injury and acute lCSip~ tol~y distress (ARDS), glomerulonephriti~, restenosis, infl~mm~tory sequelae of viral infections, myocarditis, heart failure, atherosclerosis, osteo~ll~ is, rhellm~toid is, septic ~~ is, chronic or infl~mm~tory bowel disease, ulcerative colitis, Crohn's f~ e~.~e, systemic lupus erythematosis (SLE), 5 ocular conditions such as ocular hypertension, retinitis and uveitis, type 1 diabetes, insulin-dependent diabetes mellitus and cystic fibrosis.
Compounds of Formula I are also usful in the treatment of hypoxia, hyperbaric oxygen convulsions and toxicity, dem~.nti~, Al7.heimer's e~.ce, Sydenham's chorea, Parkinson's t1i~e~.~e, Huntington's disease, 10 amyotrophic lateral sclerosis (ALS), multiple sclerosis, epilepsy, Korsakof~s disease, imbecility related to cerebral vessel disorder, NO
mediated cerebral trauma and related sequelae, ischemic brain edema (stroke), sleeping disorders, eating disorders such as anorexia, schizophrenia, depression, pre-menstrual syndrome (PMS), urinary 15 incontinence, anxiety, drug and alcohol addiction, pain, migraine, emesis, immllne complex disease, as immunosupressive agents, acute allograft rejection, infections c~ll.ee.l by invasive microorE~ni~m.c which produce NO and for preventing or reversing tolerance to opiates and diazepines.

The invention disclosed herein encompasses compounds of Forrn ()n ~

R1,R2,R3 I N
R4 Rsa = = =
and ph~ enti~ lly acceptable salts thereof wherein side a or side b has a double bond, n is O, 1, 2, 3 or 4 30 X is selected from CH2, O, S and NH, WO 96/14844 PCrlUS95/14812 Rl, R2 and R3 are each independently selected from the group con~i~ting of (a) hydrogen, (b) C1 12aLkoxy, (c) C1 12aLkylS(O)k wherein k is 0, 1 or 2, (d) mono C1 12aLkylamino, (e) (di-Cl 12aLkyl)amino, (f) Cl 12aLkylcarbonyl, (g) Cl 12alkyl, (h) C2 12aLkenyl, (i) C2 12aLtcynyl, (j) C5 locycloaLkyl~
(k) hetero Cs locycloaLkyl,wherein the hetero C5 locYcloaLkyl optionally contains 1 or 2 heteroatoms selected from S, O
andN, (1) aryl, selected from phenyl or naphthyl, (m) heteroaryl, wherein heteroaryl is selected from the group consisting of:
(1) bç~ ida_olyl,

(2) benzorul~lyl,

(3) benzooxa_olyl,

(4) furanyl,

(5) imi~7,01yl,

(6) indolyl,

(7) isooxaiolyl,

(8) isothia_olyl,

(9) oxadiazolyl,

(10) oxa_olyl,

(11) pyra_inyl,

(12) pyrazolyl,

(13) pyridyl,

(14) pyrimidyl,

(15) pyrrolyl, (17) isoquinolyl, (18) tetrazolyl, (19) thi~ olyl, (20) thiazolyl, . _ (21) thienyl, and (22) triazolyl, (n) amino, (o) oxo, (p) C(O)OH, (q) C(O)OR6, R6 is selected from hydrogen, phenyl, cyclohexyl orCl 6aLkyl, each of (b) to (m) being optionally mono or di- substituted the substit~le-nt.~ being independently selected from (1) hydroxy, (2) carboxy, (3) -NR6R7, where R7 is selected from hydrogen, phenyl, cyclohexylorCl 6alkyl, (4) -OR6, (5) -C(O)OR6, (6) -S(O)kR6, (7) halo selected from F, Cl, Br and I, (8) -C(=NR6)-NHR7, (9)-S -C(=NR6)-NHR7, or when two members of the group Rl, R2 and R3, including the optional substitue.nt.~ present thereon, reside on the same atom of Form~ I, or two of the group Rl, R2 and R3, including the optional substituents present thereon, reside .
on adjacent atoms of Form~ I, said two members may optionally be joined, such that together with the atoms to which they are ~tt~ch~l there is formed a saturated or lln.~tllrated monocyclic ring of 5, 6 or 7 atoms, said monocyclic ring optionally co~t~ lg up to three hetero atoms selected from N, O or S, or when a member of the group Rl, R2 and R3 including the optional substituents present thereon, resides on an atom W O96/14844 PCTrUS95/14812 adjacent to the N on which R4 resides, said member may optionally be joined with R4, such that together with the N
on which R4 resides and the carbon on which said member resides there is formed a saturated or llne~t-lrated monocyclic heterocycle of 5, 6 or 7 atoms, said monocycle optionally cont~ining up to three hetero atoms selected from N, O or S, R4, Rs and Rsa are each independently selected from the group consisting of (a) hydrogen, (b) linear and branched Cl l2aL~yl, optionally mono or di-substitllte-l the substituents being independently selected from (1) hydroxy, (2) carboxy, (3) -NR6R7, (4) -OR6, (5) -C(O)OR6.
(6) -S(O)kR6, (7) halo selected from F, Cl, Br and I, (8) phenyl, optionally mono or di-substituted with hydroxy, halo, Cl 4aL~yl, or Cl 4aL~oxy, (c) -C(O)NRgRg, where R8 and Rg are each independently hydrogen, phenyl, cyclohexyl or C1 6aL~yl, said C1 6aL~yl optionally substituted by (1) hydroxy, (2) amino, (3) carboxy, (4) -NRloR1 1, wherein R1o and Rl 1 are each independently H, C1 6aLkyl, phenyl or benzyl, (S) -ORlo, (6) -C(O)ORlo, (7) -S(O)mRlo, where m is 0, 1 or 2, (8) halo se-lecte~l from F, Cl, Br and I, WO 96/14844 PCI~/US95/14812 (9) optionally substituted aryl wherein aryl and aryl substituents are as de~med above, (10) optionally substit~te~ heteroaryl wherein heteroaryl and heteroaryl substit-lent~ are as defined above, (11) optionally substit~lte-1 C5-lOcycloalkyl wherein cycloaLkyl and cycloalkyl substi~lent~ are as defined above, (12)~ optionally substituted hetero C5 locycloaLkyl wherein hetero cycloaLkyl and hetero cycloalkyl substituents are as defined above, (d) -C(S)NRgRg, (e) -C(O)Rg, (fl -C(O)ORg, (g) -C(S)Rg, (h) phenyl, (i) cyclohexyl, provided that R4 is present only when side a is a single bond and R5a is present only when side b is a single bond.
Within this embodiment is the genus wherein 20 nisO, 1,2,30r4, X is selected from CH2, O, S and NH, Rl, R2 and R3 are each indepentlelltly selected from the group con~i~tin~
of (a) hydrogen, (b) C1 6aLkoxy, (c) Cl 6aLkyl~mino, (d) Cl 6aLkylcarbonyl, (e) C1 6aL~cyl, (f) C2 6alkenyl, ,~
(g) C5, C60rC7cycloaLkyl, (h) hetero C5 or C6 cycloalkyl,wherein the hetero C5 or C6 cycloaLkyl optionally contains 1 heteroatom selected from S, OandN, (i) aryl, selected from phenyl or n~rhthyl, (j) heteroaryl, wherein heteroaryl is selected from the group consisting of:
(1) furanyl, (2) pyrazinyl, (3) pyrazolyl, (4) pyridyl, (5) pyrimidyl, (6) thiazolyl, (7) thienyl, and (8) triazolyl, each of (b) to (j) being optionally mono or di- substituted the substituents being independently selected from (1) hydroxy, (2) carboxy, (3) -NR6R7, where R6 and R7 are each independently hydrogen, phenyl or Cl 4aL~yl, (4) -OR6, (5) -C(O)OR6, (6) -S(O)kR6, where k is 0, 1 or 2, (7) halo selected from F, Cl, Br and I, or when two members of the group Rl, R2 and R3 including the optional substi11lçnte present thereon, reside on the same atom of Formula I, or two of the group Rl, R2 and R3, including the optional substit~l~.nts present thereon, reside on ~ cent atoms of Forrmll~ I, said two members may optionally be joined, such that together with the atoms to which they are attached there is formed a saturated or nn.e~tllrated monocyclic ring of 5, 6 or 7 atoms, said monocyclic ring optionally co,,~ up to three hetero 30 atoms selected from N, O or S, or when a member of the group Rl, R2 and R3 inchl~linp: the optional substituents present thereon, resides on an atom adjacent to the N on which R4 resides, said member may optionally be joined with R4, such that together with the N

on which R4 resides and the carbon on which said member resides there is formed a saturated or ~ln.~tllrated monocyclic heterocycle of 5, 6 or 7 atoms, said monocycle optionally cont~ining up to three hetero atoms selected from N,OorS, R4, Rs and R5a are each independently selected from the group consisting of (a) hydrogen, (b) linear and branched C 1 6alkyl, optionally mono or di-substituted, the substituents being independently selected from (1) hydroxy, (2) carboxy, (3) -NR6R7 (4)-OR6, (5) -C(O)OR6, (6) -S(O)kR6, where k is 0, 1 or 2, (7) halo selected from F, Cl, Br and I, (c) -C(O)NRgRg, where R8 and Rg are each independently hydrogen, phenyl, cyclohexyl or Cl 4alkyl, said Cl 4alkyl optionally substituted by (1) hydroxy, (2) amino, (3) carboxy, (4) -NRloRl 1, wherein Rlo and Rl 1 are each indepen-lently H, Cl 4alkyl, phenyl or benzyl, (S) -OR10, (6) -C(O)OR10, (7) -S(O)mRlo, where m is 0, 1 or 2, (8) halo selected from F, Cl, Br and I, (9 optionally substituted aryl wherein the aryl and substituents are as defined above, (10) optionally substit!ltç~l heteroaryl wherein the heteroaryl and substihle.nt~ are as defined above, (11) optionally substitllte~l C5 or C6 cycloaLkyl wherein the cycloalkyl and substit-lent~ are as defined above, (12) optionally substit lte-l hetero Cs or C6 cycloalkyl wherein the hetero cycloaLkyl and substituents are as defined above, (d) -C(S)NRgRg, (e) -C(O)R9, (~ -C(O)OR9, (g) -C(S)R9, (h) phenyl, (i) cyclohexyl, such that R4 is present only when side a is a single bond and side b is a double bond.

Within this genus is the class of compounds of the form~ e ~X~ R,,R2,R3~X
3 ~N l~ ,R5 <N ~ R5 R4 or R4 wherem X is selected from CH2, S and NH, Rl, R2 and R3 are each in-lepeIl~ently selected from the group consisting 20 of (a) hydrogen, (b) linear and br~nch~ l Cl 4alkyl, said Cl 4alkyl being optionally mono or di- substitllte~l the substit~ t~
being independently selected from (1) carboxy, (2) -NR6R7, wherein R6 and R7 are each indepen~ently hydrogen or Cl 3aLkyl, (3) -OR6, (4) -C(O)OR6, (5) -S(O)kR6, where k is 0, 1 or 2, "
R4 is selected from the group consisting of (a) hydrogen, (b) -C(O)NHRg, where Rg is hydrogen or C 1-4alkyL said C 1-~alkyl optionally substituted by (1) hydroxy, (2) amino, (3) carboxy, (4) -NR1oR1 1, wherein R1o and R1 1 are each independently Cl 3alkyl, (S) -ORlo, (6) -C(O)OR10, (7) -S(O)mRlo, where m is 1 or 2, (8) halo selected from F, Cl, Br and I, (c) -C(S)NHRg;
(d) Cl 3aL~yl;
Rs is selected from the group con.~i~tin~ of (a) hydrogen, (b) -C(O)NHRg, (c) -C(S)NRgRg.
(d) Cl 3alkyl.
As appreciated by those of skill in the art the additional carbon members of the Formula I ring, "( )n" and definitions "CH2" and "NH" under X, provide available positions for the substituents Rl, R2 or R3.
When any variable (e.g. Rl, R2, R3, R4, R5, R6, R7, R8, Ra, k, n, p etc.) occurs in any position of a compound of Formula I, its definition on each occurrence is independent of its definition at every other occul-ellce.
Accordingly, in one aspect the invention disclosed herein encompasses compounds of Formula I

(rn ~
R1,R2,R3N N' 5 and ph~ ceutically acceptable salts thereof wherein S side a or side b has a double bond, nisO, 1,2,30r4 X is selected from CH2, CR12R13, O, S(O)m, NH, and -N(C1 6alkyl)-, m is O, 1 or 2, R1, R2, R3, Rl2 and R13 are each independently selected from the group 10 consisting of (a) hydrogen, (b) C1 12alkoxy, (c) C1 12alkylS(O)k wherein k is 0, 1 or 2, (d) mono C1 12alkylamino, (e) (di-C1 12alkyl)amino, (f) Cl 12alkylcarbon (g) Cl 12aLkyl, (h) C2 12alkenyl, (i) C2 12alkynyl, (j) C5 lOcycloalkyl, (k) heteroCs locycloalkyl,whereintheheteroCs 10cycloalkyl optionally contains 1 or 2 heleroatollls selçcte~l from S, O
andN, (l) aryl, selected from phenyl or n~phthyl, (m) heteroaryl, wherein heteroaryl is selected from the group consisting of:
(1) b~ 7olyl, (2) ben_ofuranyl, (3) ben_ooxa_olyl, (4) rul~lyl, (s) imi~l~7.olyl, W O96/14844 PCT~US95114812

- 16-(6) indolyl, (7) isooxazolyl, (8) isothiazolyl, (9) oxadiazolyl, (10) oxazolyl, (11) pyrazinyl, (12) pyrazolyl, (13) pyridyl, (14) pyrimidyl, -=~ (15) pyrrolyl,

(17) isoquinolyl,

(18) tetra~olyl,

(19) thi~jA7:olyl, ~ (20) thiazolyl, (21) thienyl, and (22) triazolyl, (n) amino, (o) oxo, (p) C(O)OH, (q) C(O)OR6, R6 is selected from hydrogen, phenyl, cyclohexyl orC1 6aLkyl, each of (b) to (m) being optionally mono or di- substit lte-1 the substit~lent~ being indepen~e.ntly selected from (1) hydroxy, (2) carboxy, (3) -NR6R7, where R7 is selected from hydrogen, phenyl, cyclohexylorC1 6aLkyl, (4) -OR6, (S) -C(O)O1~6, (6)-S(O)kR6, (7) halo selected from F, Cl, Br and I, (8) -C(=NR6)-NHR7, (9)-S -C(=NR6)-NHR7, W O 96/14844 PC~rrUS95/14812 or when two members of the group R 1, R2 and R3 including the optional substihlent~ present thereon, reside on the same carbon atom of Formula I, or two of the group R1, R2 and R3, including the optional substituents present thereon, reside on adjacent atoms of Formula I, said two members may optionally be joined, such that together with the atom to which they are attached there is formed a saturated or lm~tllrated monocyclic ring of 5, 6 or 7 atoms, said monocyclic ring optionally cont~ining up to three hetero atoms selected from N, O or S, or when a member of the group R1, R2 and R3 including the optional substitllent~ present thereon, resides on an atom adjacent to the N on which R4 resides, said member may optionally be joined with R4, such that together with the N
on which R4 resides and the carbon on which said member resides there is formed a saturated or lln~tll.ated monocyclic heterocycle of 5, 6 or 7 atoms, said monocycle optionally cont~inin~ up to three hetero atoms selected from N, O or S, with the proviso that one of R12 and R13 is other than hydrogen, R4, Rs and Rsa are each independently selected from the group consisting of (a) hydrogen, (b) linear and branched C 1-12alkYl, optionally mono or di-substihlterl, the substituents being independently selected from (1) hydroxy, (2) carboxy, (3) -NR6R7, (4)-OR6, (5) -C(O)OR6, . (6)-s(o)kR6~
(7) halo selected from F, Cl, Br and I, (8) phenyl, optionally mono or di-substituted with hydroxy, halo, Cl~aLkyl, or Cl 4aLkoxy, (c) -C(O)NRgRg, where R8 and Rg are each independently hydrogen, phenyl, cyclohexyl or Cl 6alkyl, said C1 6aLkyl optionally substituted by (1) hydroxy, (2) amino, (3) carboxy, (4) -NRloRl l, wherein Rlo and R l l are each . . independently H, C1 6aLkyl, phenyl or benzyl, (S) -OR10, (6) -C(O)OR10, (7) -S(O)mRlo, where m is 0, 1 or 2, (8) halo selected from F, Cl, Br and I, (9) optionally substituted aryl wherein aryl and aryl substitllent~ are as defined above, (10) optionally substituted heteroaryl wherein heteroaryl and heteroaryl substituents are as defined above, (11) optionally substi~ltç~ C5-10cycloaLkyl wherein cycloaLkyl and cycloaLkyl substituents are as defined above, (12) optionally substituted hetero Cs locycloaLkyl wherein hetero cycloaLkyl and hetero cycloaL~cyl substituents are as defined above, (d) -C(S)NRgRg, (e) -CORg, (f~ -C(O)ORg, (g) -C(S)Rg, (h) phenyl, (i) cyclohexyl, provided that R4 is present only when side a is a single bond and RSa is present only when side b is a single bond.
Within this embodiment is the genus wherein mis 0, 1 or2, .

W O96/14844 PCTrUS95114812 nisO, 1,2,30r4, X is selected from CH2, CR12R13, O, S(O)m NH, and -N(C1 6alkyl)-, R1, R2, R3, R12 and R13 are each independently selected from the group consisting of (a) hydrogen, (b) Cl-6alkoxy~
(c) Cl 6aLkylamino, (d) Cl 6aL~ylcarbonyl, (e) C1 6alkyl, (f) C2 6alkenyl, (g) C5j C6 or C7cycloalkyl, (h) hetero C5 or C6 cycloalkyl,wherein the hetero C5 o~ C6 cycloalkyl optionally contains 1 heteroatom selected from S, O and N, (i) aryl, selected from phenyl or naphthyl, (j) heteroaryl, wherein heteroaryl is selected from the group consisting of:
(1) furanyl, (2) pyrazinyl, (3) pyrazolyl, (4) pyridyl, (5) ~yl~idyl, (6) thi~olyl, (7) thienyl, and (8) triazolyl, each of (b) to (j) being optionally mono or di- substituted the substituents being independently selected from (1) hydroxy, (2) carboxy, (3) -NR6R7, where R6 and R7 are each independently hydrogen, phenyl or C1 4alkyl, (4) -OR6, (S) -C(O)OR6, (6) -S(O)kR6, where k is 0, 1 or 2, WO 96/14844 PCI/US95tl4812

- 20 -(7) halo selected from F, Cl, Br and I, or when two members of the group Rl, R2 and R3 including the optional substituents present thereon, reside on the same atom of Formula I, or two of the group Rl, R2 and R3, including the optional substituents present thereon, reside on adjacent atoms of Formula I, said two members may optionally be joined, such that together with the atoms to which they are ~tt~'h~-l there is formed a saturated or llm.c~turated monocyclic ring of 5, 6 or 7 atoms, said monocyclic ring optionally cont~ining up to three hetero atoms selected from N, O or S, or when a member of the group Rl, R2 and R3 including the optional substit~lent~ present thereon, resides on an atom adjacent to the N on which R4 resides, said member may optionally be joined with R4, such that together with the N
on which R4 resides and the carbon on which said member resides there is formed a saLur~ted or lm.~ lrated monocyclic heterocycle of 5, 6 or 7 ~tQm~, said monocycle optionally cont~inin~ up to three hetero atoms selected from N,OorS, with the proviso that one of R12 and R13 is other than hydrogen, R4, R5 and Rsa are each independently selected from the group consisting of (a) hydrogen, (b) linear and branched C1 6alkyl, optionally mono or di-substitllte-l the substi~lent.~ being independently selected from (1) hydroxy, (2) carboxy, (3)-NR6R7, (4) -OR6, (5) -C(O)OR6, (6) -S(O)kR6, where k is 0, 1 or 2, (7) halo selected from F, Cl, Br and I,

- 21 -(c) -C(O)NRgRg, where R8 and Rg are each independently hydrogen, phenyl, cyclohexyl or Cl 4aLkyl, said Cl 4aL~yl optionally substituted by (1) hydroxy, (2) amino, (3) carboxy, (4) -NR1oR1 1, wherein R1o and R1 1 are each independently H, Cl 4aL~yl, phenyl or benzyl, (S) -ORlo~ -(6)-c(o)oRlo~
(7~ -S(O)mR1o, where m is 0, 1 or 2, (8) halo selected from F, Cl, Br and I, (9) optionally substituted aryl wherein the aryl and substitllPntc are as defined above, (10) optionally substituted heteroaryl wherein the heteroaryl and substituents are as defined above, (11) optionally substituted C5 or C6 cycloalkyl wherein the cycloaLkyl and substituents are as defined above, (12) optionally substituted hetero C5 or C6 cycloaL~yl wherein the hetero cycloaL~yl and substituents are as defined above, (d) -C(S)NRgRg, (e) -COR9, (f~ -C(O)ORg, (g) -C(S)Rg, (h) phenyl, (i) cyclohexyl, such that R4 is present only when side a is a single bond and side b is a double bond.
Within this genus is the class of compounds of the forrmll~e ,

- 22-~X~ R1,R2,R3~
R1 R2 R3-- J~ <Nl~ R5 R4 or R4 wherein X is selected from CR12R13, S(O)m and -N(Cl 4alkyl)-, Rl,R2, R3, Rl2 and R13 are each selected from the group consisting of (a) hydrogen, (b) hydroxy, (c) linear and branched Cl 4aLkyl or linear and branched Cl 4alkoxy, wherein said Cl 4aLkyl or Cl 4aLkoxy is optionally mono or di- substituted the substituents being independently selected from (1) carboxy, (2) -NR6R7, wherein R6 and R7 are each indepe~tle.ntly hydrogen or C1 3aLkyl, (3) -OR6, (4)-C(O)OR6, (5) -S(O)kR6, where k is 0, 1 or 2, with the proviso that one of R12 and R13 is other than hydrogen, R4 is selected from the group consisting of (a) hydrogen, (b) -C(O)NHRg, where Rg is hydrogen or Cl 4alkyl~ said C
4alkyl optionally substihlte-l by (1) hydroxy, (2) amino, (3) carboxy, (4) -NRloRl 1, wherein Rlo and Rl 1 are each independendy Cl 3alkyl, (5) -OR10, (6) -C(O~ORlo, (7) -S(O)mRlo, where m is 1 or 2, (8) halo selected from F, Cl, Br and I, CA 022036Xl l997-04-24 W O96/14844 PCTnUS95/14812 (c) -C(S)NHRg;
(d) C1 3alkyl;
Rs is selected from the group consisting of (a) hydrogen, (b) -C(O)NHRg, (c) -C(S)NR8Rg.
(d) Cl 3aLkyl.

In an alternative embodiment the invnetion is directed to 10 compounds of the ~orrn~ e ~N1~N, R5 ~Nl~N'R5 R4 or R4 wherein X is -N(Cl 3aLkyl)-, R1, R2 and R3 are èach independently selected from the group consisting of (a) hydrogen, (b) linear and branched Cl 4aLkyl, said Cl 4aLkyl being optionally mono or di- substituted the substitllent~
being independently selected from (1) carboxy, (2) -NHR7, wherein R6 and R7 are each independently hydrogenorCl 3alkyl, (3)-C(O)OR6, and (4) -S(O)kR6, where k is 1 or 2, (c) hydroxy, R4 is selected from the group consisting of (a) hydrogen, (b) C1 3alkyl;
30 Rs is selected from the group consisting of W O96/14844 PCTrUS95/14812 (a) hydrogen, (b) -C(O)NHRg, where Rg is hydrogen or C 1 4aLkyl, said Cl 4aLkyl optionally substit~lte~l by (1) hydroxy, (2) ~mino, (3) carboxy, (4) -NR1oR1 1, wherein R1o and Rl 1 are each indepen-lP.ntly Cl 3aLkyl, (S)-ORlo, (6) -C(O)OR10, (7) -SRlo, and (8) -S(O)mRlo, where m is 1 or 2, (9) halo selected from F, Cl, Br and I, (c) -C(S)NR8Rg.
(d) Cl 3aLkyl;

Wi~in this embodiment is the genus of compound of the forml~

R2XN, 1~N,R5 R~N1\ R5 R4 r R4 wherein Xis -N(Cl 3aLkyl)-, Rl and R2 are each selected from hydrogen or linear and branched C 1 4aLkyl, said C 1 4aLkyl r being optionally mono or di- substituted the substit lP.nt~
being independently selected from (1) carboxy, (2) -NHR7, wherein R6 and R7 are each indepenclelltly hydrogen or Cl 3aLl~yl, -(3)-C(O)OR6, and (4) -S(O)kR6, where k is 1 or 2, R4 is selected from the group consisting of (a) hydrogen, (b) Cl 3alkyl;
Rs is selected from the group consisting of (a) hydrogen, (b) -C(O)NHRg, where Rg is hydrogen or C 1 4alkyl, said Cl 4aLkyl optionally subs~ituted by (1) hydroxy, (2) amino, (3) carboxy, (4) -NRloRl 1, wherein Rlo and Rl 1 are each indepe.n~le.ntlyCl 3aLkyl, (5)-ORlo, (6) -C(O)OR10, (7) -SRlo, and (8) -S(O)mR10, where m is 1 or 2, (9) halo selected from F, Cl, Br and I, (c) -CSNRgRg.
(d) Cl 3aLlcyl.

Within this genus are ~e compounds of the folm R2XNl~N, Rs R~ j~Nl\N~ R~
R4 or Rq 25 wherein X is -N(Cl 3aLkyl)-, Rl is selecte~l from the group con~ ting of hydrogen, hydroxy or linear and branched Cl 4aLI~yl, said Cl~aLkyl being optionally mono or di- substitllte~1 the substituents being independently selected from (1) carboxy, (2) -NHR7, wherein R6 and R7 are each indepPn~lently hydrogen or Cl 3aLkyl, (3)-C(O)OR6, and (4) -S(O)kR6, where k is 1 or 2, R2 is linear and br~nch~1 Cl 4alkyl, R4 is selected from the group con~i.ctin~ of (a) hydrogen, (b) Cl 3aLkyl;
Rs is selected from the group consisting of . (a) hydrogen, (b) -C(O)NHRg, where Rg is hydrogen or C 1 4aLkyl, said Cl 4aLkyl optionally substituted by (1) hydroxy, (2) a~ino, (3) carboxy, (4) -NRloRl 1, wherein Rlo and Rl 1 are each indepen-le~tly Cl 3aLkyl, (S) -ORlo, (6) -C(O)ORlo, (7) -SRlo, and (8) -S(O)mRlo, where m is 1 or 2, (9) halo selected from F, Cl, Br and I, (c) -CSNR8Rg.
(d) Cl 3aLkyl.

Exemplifying the invention are the compounds of Examples 1 through 161.

As appreciated by those of skill in the art, compounds of S Formula I include those wherein there is a double bond at side a or b such as those shown in Formula Ia or Ib or t~1tomPric forms thereof:

(l)n 1 (lrn 1 R4 R5a Ia Ib As also appreciated by those of skill in the art, compounds 10 of Formula 1 wherein or when two members of the group R 1, R2 and R3 are joined together to form a ring are inte.n~e~l to include such formulae as:

~ N N ~a'N ~N

W O96/14844 PCTrUS95/14812 wherein p is 0, 1, or 2 and wherein the second ring may contain up to three hetero atoms selected from N, O or S.
Simil~rly, compounds of Formula I wherein a member of the group Rl, R2 and R3 resides on an atom adjacent to the N on which R4 5 resides and forms a ring therewith may be illustrated by:

( NJ\\N, R~

wherein p is 0, 1, or 2 and wherein the second ring may contain up to three hetero atoms selected from N, O or S
.

In one preferred aspect the compounds of the invention are of the fonn~ e Rl3 ,R3 R, 3 2~Nl\N, R5 RJ~Nl\N~ R5 ~NlN' R5 R4 or R4 or R2 R4 wherem X is selected from CH2, NH and S, Rl, R2 and R3 are each independently selected from ~e group consisting of (a) hydrogen, (b) linear and br~nchP~l C1 6aLkyl, wherein said Cl 6aLkyl is optionally mono or di- substituted the substituents being indepen~lently selected from ~1) carboxy, (2) -NHR7, wherein R6 and R7 are each independently hydrogenorCl 3aL'cyl, .

(3) -OR6, (4) -C(O)OR6, (5) -S(O)kR6, where k is 0, 1 or 2, (c) hydroxy, S (d) Cl 6alkoxy;
R4 is selected from the group consisting of (a) hydrogen, (b) -C(O)NHR9, where Rg is hydrogen or cl-3aLkyl~ said Cl-3aLkyl optionally substi~ltecl by (1) hydroxy, (2) amino, (3) carboxy, (4) -NRloRl 1, wherein Rlo and R1 1 are each indepen~le.IltlyCl 3aLkyl, (5)-OR10, (6) -C(O)OR10, (7) -S(O)mR1o, where m is 0, 1 or 2, (8) halo selected from F, Cl, Br and I, (c) -C(S)NHRg;
(d) Cl 3alkyl;
Rs are each independendy selected from the group consisting of (a) hydrogen, (b) -C(O)NHRg, (c) -C(S)~R8Rg.
(d) -Cl 3aLkyl.

In a second ~cfclrcd aspect the compounds of the invention have cis stereochernistry at the ring junction and are of the formula (R) H

~,Rs (R)R4 R5a =

W O96/14844 PCT~US95/14812 wherein p is 1 or 2, and R3 and the ring formed by the joining of Rl and R2 are optionally mono or di-substit lte-l with substituents selected from the group consisting of (1) hydroxy, (2) carboxy, (3) -NR6R7, where R6 and R7 are each selected from hydrogen, phenyl, cyclohexyl or C1 6alkyl, (4) -OR6, (S) -C(O)OR6, (6)-s(o)kR6~
(7) halo selected from F, Cl, Br and I, (8) -C(-NR6)-NHR7, (9)-S-C(=NR6)-NHR7.

Within this second preferred aspect are the compounds wherein R3 is selected from hydrogen, hydroxy or linear and branched Cl 4alkyl, said Cl 4alkyl, optionally mono or di- substituted the substituents being indepen-lently selected from (1) carboxy, (2) -NHR7, wherein R6 and R7 are each independently hydrogenorCl 3allyl, (3)-C(O)OR6, and (4) -S(O)kR6, where k is 1 or 2;
R4 is selected from the group con.ei.~tinf~ of (a) hydrogen, (b) Cl 3aLkyl, R5 is selecte~ from the group consisting of (a) hydrogen, (b) -C(O)NHRg, where Rg is hydrogen or C 1 4alkyl, said Cl 4aLkyl optionally substit lte-l by (1) hydroxy, - (2) amino, (3) carboxy, (4) -NR1oRl 1, wherein Rlo and R l l are each independently S Cl 3alkyl, (5) -OR1o, (6) -C(O)OR10, (7) -SRlo, and (8) -S(O)mRlo, where m is 1 or 2, (9) halo selected from F, Cl, Br and I, (c) -C(S)NR8Rg.
(d) C1 3alkyl.
For purposes of this specification alkyl is defined to include linear, branched, and cyclic structures, with Cl 6alkyl including methyl, ethyl, propyl, 2-propyl, s- and t-butyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Simil~rly, C1 6alkoxy is inten-led to include alkoxy groups of from 1 to 6 carbon atoms of a straight, branched, or cyclic configuration. Examples of lower alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy, and the like. Likewise, C1 6 alkylthio is inte.n(le(l to incl~ e alkylthio groups of from 1 to 6 carbon atoms of a straight, branched or cyclic configuration. F.x~mrles of lower alkylthio groups include methylthio, propylthio, isopropylthio, cycloheptylthio, etc. By way of illustration, the propylthio group ~i nifies -SCH2CH2CH3.
Heteroaryl includes, but is not limited to furan, thiophene, pyrrole, isoxazole, isothiazole, pyrazole, oxazole, thiazole, imi-l~7.ole, 1,2,3-oxadiazole, 1,2,3-thi~ 70le, 1,2,3-triazole, 1,3,4-ox~ 701e, 1,3,4-thi~ 7ole, 1,3,4-tria_ole, 1,2,5-ox~ 7.ole, 1,2,5-thi~ 7.ole, pyridine, pyritl~7ine, pyrimi~line, pyrazine, 1,2,4-triazine, 1,3,5-tri~7.in~
and 2,4,5-tetrazine.
As olltlin~ l in the sllmm~ry of the invention, the compounds of the instant invention are useful for in the treatment of a number of NOS implicated fli~e~es. The implication of these diseases is well docllmtonte-l in the literature. For example, with regard to psoriasis, see W O96tl4844 PCT~US95114812 Ruzicka et. al., J. Invest. Derm., 103: 397 (1994) or Kolb-Bachofen et.
al., Lancet, 344: 139 (1994) or Bull, et al., J. Invest. Derm., 103:435(1994); with regard to uveitis, see Mandia et. al., Invest Opthalmol., 35: 3673-89 (1994); with regard to type 1 diabetes, see 5 Eisieik & Leijersfam, Diabetes & Metabolism, 20: 116-22 (1994) or Kroncke et. al., BBRC, 175: 752-8 (1991) or Welsh et. al., Endocrinol., 129: 3167-73 (1991); with regard to septic shock, see Petros et. al., T~ncet~ 338: 1~57-8 (l991),Thiemerm~nn & Vane, Eur. J. Ph~ col, 211: 172-82 (1992), or Evans et. al., Infec. Imm., 60: 4133-9 (1992), or 10 Schillin~ et. al., Intensive Care Med., 19: 227-231 (1993); with regards to pain, see Moore et. al., Brit. J. Ph~ ol., 102: 198-202 (1991), or Moore et. al, Brit. J. Ph~ col., 108: 296-97 (1992) or Meller et. al., Europ. J. Pharmacol., 214: 93-6 (1992) or Lee et. al., NeuroReport, 3:
841-4 (1992); with regard to migraine, see Olesen et. al.~ TIPS, 15: 149-15 153 (1994); with regard to rhellm~toid aL~ is, see Kaurs & Halliwell,FEBS Letters, 350: 9-12 (1994); with regard to osteoar~hritis, see Stadler et. al., J. Imm7~nol., 147: 3915-20 (1991); with regard to infl~mm~tory bowel disease, see Miller et. al., Lancet, 34: 465-66 (1993) or Miller et.
al., J. Ph~rm~col. Exp. Ther., 264: 11-16 (1993); with regard to asthma, 20 see Hamid et. al., Lancet, 342: 1510-13 (1993) or Kh~ritonov, et. al., Lancet, 343: 133-5 (1994); with regard to Immune complex diseases, see M~ n et. al., Br. J. Ph~rm~col., 107: 1159-62 (1992); with regard to multiple sclerosis, see Koprowski et. al., P NA 5, 90: 3024-7 (1993); with regard to ischemic brain edema, see Nagafuji et. al., Neurosci., 147: 159-25 62 (1992) or Buisson et. al., Br. J. Phalmacol., 106: 766-67 (1992) or Trifiletti et. al., Europ. J. Pharmacol., 218: 197-8 (1992); with regard to toxic shock syndrome, see Zembowicz & Vane, PNAS, 89: 2051-55 (1992); with regard to heart failure, see Winlaw et. al., Lancet, 344: 373-4 (1994); with regard to ulcerative colitis, see Boughton-Smith et. al., 30 Lancet 342: 338-40 (1993); and with regard to atherosclerosis, see White et. al., PNAS, 91: 1044-8 (1994); with regard to glomerulonephritis, see M u ~ et. al., Br. J. Pharmcol., 112: 1-8 (1994); with regard to Paget's disease and osteoporosis, see Lowick et. al., J. Clin. Invest., 93: 1465-72 (1994); with regard to infl~mm~tory sequelae of viral infections, see W O96/14844 PCT~US95/14812 Koprowski et. al., PNAS, 90: 3024-7 (1993); with regard to retinitis, see Goureau et. al., BBRC, 186: 854-9 (1992); with regard to oxidant in~lnced lung injury, see Berisha et. al., PNAS, 91: 744-9 (1994); with regard to eczema, see Ruzica, et al., J. Invest. Derm., 103:395(1994); with regard 5 to acute allograft rejection, see Devlin, J. et al., Transplantation, 58:592-595 (1994); and with regard to infection caused by invasive microor~ni~m.~ which produce NO, see Chen, Y and Rosazza, J.P.N., Biochem. Biophys. Res. Comm., 203:1251-1258(1994).
The ph~rm~ceutical compositions of the present invention 10 comprise a compound of Form~ I as an active ingredient or a ph~rm~ceutically acceptable salt, thereof, and may also contain a ph~rm~ceutically acceptable carrier and optionally other therapeutic ingredients. The term "ph~rm~eeutically acceptable salts" refers to salts prepared from ph~rm~ceutically acceptable non-toxic acids or bases 15 including inorganic bases and organic bases. Salts derived from inorganic acids include alnminllm~ ammonium, calcium, copper, ferric, ferrous, lithium, m~gnesium, manganic salts, manganous, potassium, sodium, zinc, and the like. Particularly preferred are the ~mmonillm, calcium, magnesium, pot~sillm, and sodium salts. Salts derived from 20 ph~rm~ceutically acceptable organic non-toxic bases inrln~r. salts of primary, secondary, and tertiary ~minrs, substituted amines incln-lin~
naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as a~ e, betaine, caffeine, choline, N,N_-dibenzylethylene.~i~minto, diethylamine, 2-diethylaminoethanol, 2-25 dimethylaminoethanol, ethanol~min-o, ethylene~ mine, N-ethylmorpholine, N-ethylpiperi~ine, glllc~mine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylgll~c~mine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethyl~mine, trimethylamine, ~ r~yl~mine, trometh~mine, and the 30 like.
It will be understood that in the discussion of methods of treatment which follows, referellces to the compounds of Formula I are meant to also include the ph~rm~celltically acceptable salts.

The ph~rm~ceutical compositions cont~inin~ the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.
Compositions intended for oral use may be prepared according to any method known to the art for the m~n~lf~cture of ph~rm~ceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide ph~rm~r~eutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic ph~rm~ceutically acceptable excipients which are suitable for the manufacture of tablets.
These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; gran~ ting and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or ~c~ci~, and lubricating agents, for example, m~gnt~sillm stearate, stearic acid or talc. I'he tablets may be uncoated or they may be coated by known techniques to;delay disintegration and absorption in the ga~ stinal tract and thereby provide a sll,ct~in~d action over a longer period. For ~-x~mple, a time delay m~tçri~l such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by the technique described in the U.S. Patent 4,256,108; 4,166,452; and 4,265,874 to form osmotic therapeutic tablets for control release.
2~ Formlll~tions for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid ~1iluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil m~.rlillm, for example peanut oil, liquid ~rlll, or olive oil.
Aqueous suspensions contain the active material in x~u~e with excipients suitable for the mannf~ctnre of aqueous suspçn~io~. Such excipients are suspending agents, for example sodium carboxymethyl-cellulose, methylcellulose, hydroxy-propylmethycellulose, sodium ~l~in~te, polyvinyl-pyrrolidone, gum -W O96/14844 PCTrUS95/14812 tr~c~ntll and gum acacia; dispersing or wetting agents may be a naturally-occurring phosph~ti~le, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide S with long chain aliphatic alcohols, for example hept~-lec~ethylene-oxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example 10 polyethylene so~ monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose, saccharin or aspartame.
Oily suspensions may be form~ te-l by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyi alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a p~l~t~ble oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in ~-lmixhlre with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.
The ph~rm~ceutical compositions of the invention may also be in the form of an oil-in-water emlll.cions. The oily phase may be a veget~able oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mix1~1res of these. Suitable emulsifying agents may be naturally-occurring phosphatides, for example soy beans, lecithin, . CA 022036X1 1997-04-24 W O96114844 ~CTrUS95114812 and esters or partial esters derived from fatty acids and hexitol anhydrides, for exarnple so.l,ilall monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavouring agents.
Syrups and elixirs may be form~ ted with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such form~ tions may also co,ltaill a demulcent, a preservative and flavoring and coloring agents. The ph~rm~-eutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butane diol.
Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending me~ m For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the pr~tion of-injectables.
Compounds of formula I may also be ~rlminietered in the form of a suppositories for rectal ~fimini.etration of the drug. These compositions can be ~ e~aled by mixin~ the drug with a suitable non-i- . ;I;-t;ll~ excipient which is solid at ordinary temperatures but liquid at the rectal t~nlpel~ture and will ~erefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.
For topical use, creams, ointmPnte, jellies, solutions or suspensions, etc., cont~ining the compound of Formula I are employed. t (For purposes of this application, topical application shall include mouth washes and gargles.) Dosage levels of the order of from about 0.01 mg to about 140 mg/kg of body weight per day are useful in the treatment of the above-indicated conditions, or alternatively about 0.5 mg to about 7 g per patient per day. For example, infl~mm~tion may be effectively treated by the ~lmini~tration of from about 0.01 to 50 mg of the compound per kilogram of body weight per day, or alternatively about 0.5 mg to about 5 3.5 g per patient per day, preferably 2.5 mg to 1 g per patient per day.
The amount of active ingredient that may be combined with the carrier m~teri~ to produce a single dosage form will vary depen(linp upon the host treated and the particular mode of ~-lmini~tration. For example, a form~ tion intended for the oral ~(1mini.ctration of hllm~n~
10 may contain from 0.5 mg to 5 g of active agent compounded with an ~ro~liate and convenient amount of carrier material which may vary from about S to about 95 percent of the total composition. Dosage unit forms will generally contain between from about 1 mg to about 500 mg of an active ingredient, typically 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 15 400 mg, 500 mg, 600 mg, 800 mg, or 1000 mg.
It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the age, body weight, general he~lth, sex, diet, time of ~-lmini~tration, route of ~rlmini~tration~ rate of excretion, drug combination and the 20 severity of the particular ~ e~e undergoing therapy.

, W O96/14844 PCTrUS95/14812 Assay Protocol for NOS activity NOS activity is measured as the formation of L-[2,3,4,5-3H]Citmlline from L-~2,3,4,5-3H]Arginine. The incubation buffer (100 5 ,uL) cont~in~(1; 100 mM TES, pH 7.5, 5 ,uM FAD, 5 ,uM F~N, 10 ~M
BH4, 0.5 mM NADPH, 0.5 mM DTT, 0.5 mg/mL BSA, 2 mM CaC12, 10 ~lg/mL calmodulin (bovine), 1 ~M L-Arg, 0.2 ~Ci L-[2,3,4,5-3H~Arg, and the inhibitor in aqueous DMSO (max. 5 %). The reaction is initiated by addition of enzyme. Incubations are performed at room tempe ~lule 10 for 30 minlltes and stopped by the addition of an equal volume of quenching buffer consisting of 200 mM sodium citrate, pH 2.2, 0.02~o sodium azide. Reaction products are separated by p~ssin~ through a cation e~çh~n~e resin and q~ ecl as cpm by scintill~tion counting.
Percent inhibition is calc~ te~l relative to enzyme incubated without 15 inhibitor according to: % inhibition = 100 x (cpm L-[2,3,4,5-3H]Cit with inhibitor / cpm L-r2,3,4,5-3H]Cit without inhibitor).

Illustrative of the utility of the compounds of Formula I is the ability of such compounds to inhibit NO synthase as shown in Tables 20 1-5 and as me~sllred by the assay described above:

R1~ NR5 Rl R2 R5 (50uM) H {~H3 H 97 \
/~ N(H)R5 N

R5 % inhibition (50uM) -CH2-phenyl 3 ~yclohexyl 8 W O 96/14844 PCT~US95/14812 % inhibition Compound (SOuM) ~ 90 N NH
H

~ 100 N
H NH

~= N H
H

~N NH
H

~ 100 --N~NH

O o o o o o o o o o E
Vl Z A Vl Vl Vl Vl Vl Vl Vl Vl Vl A Vl Vl _ O o , D
Vl Z A Vl Vl Vl Vl Vl Vl A Vl Vl A A A ~

O O O O O O O O O cn-~
._ Vl Vl A Vl Vl A Vl Vl Vl Vl Vl Vl Vl Vl Vl ~_ O
_ ~' ~ O

~Z "~ ~ ~

o ~o ~,o ~ ~ S ~ ~ ~ C ~ o ~-~

E ~ E--~, U ' 8 c C~ V t ~ = = C ~ 2 ,~o _ O _ ~ ~ ~ -' ~ OD
~ ~ ~ X ~ ~ S ~ ~ ~ ~ ~ ~ ~ ~ _ ~ ~

_ -- ~
U:

D ~ ~

Z o o o o o o o o o o, Vl Vl Vl Vl Vl Vl Vl Vl Vl ~ Vl Vl Vl V Vl ~~ ~

O Z ~ 1n U~ ~
V ~ Vl ~ Vl Vl Vl Vl Vl ~ ~ ~ Vl Vl Vl ~ Vl c.~

. z o o o _ O O O O O o o O 0 3 ~

.a ~ 2 :J: S S S S ~ S S S S S S ~r S ~o _ P ,~ c~
Z ~ ~ .

æ~æ O ,~"0 ~cy x ~ x ;c ,~c:c S S ~ S ~ r o co~
c ~3 ~ ~ ~ U ~ V ~

C~ C X X X S ~

x x~ r o ~ v -cs ~ r s ~ r~ x ~

r _ .1 - - V~ C ~ O O O O O _ O O C
' Vl Vl ~ ~ ~ Vl Vl ~ Vl Vl Vl Vl Vl A Vl Vl Vl Vl ~ o Z ~ O O C _ Vl Vl ~ ~ ~ Vl ~ ~ ~ Vl ~ ~ Vl ~ ~ Vl Vl Vl o -- -- -- O C O C O O O O O
.Z Vl Vl Vl Vl ~ Vl Vl Vl Vl Vl Vl Vl Vl Vl Vl Vl Vl Vl = = = = = _ = _ T -- _ ~ ' ' ' ~
G-x Z~ ~ ~ S

~ U -- IL' t~ -- ~ ~1 ~ = Z -- -- C V' --U ~ S S
S S S ~ V ~ U 5 S ~ ~ ~ ' ~ ~ ~ ~

,, U-. ", _ S S S = = ,~ X = = _ ~_~ = _ = T ,~,, _ =

,. o S ~ _ -- -- -- -- -- -- -- -- _ _ _ _ ~,_ X ~ U Z V Cj V ~ V ~ ~ U Z Z U U ~

U-~
~O

W O96/14844 PCTrUS95/14812 z O O C O O C C O O O C
C Vl A Vl Vl Vl A A A ~ Vl Vl . A ~ Vl ~ Vl Vl O z o O C C -- o ~~ o C, C O O O O C u~ u~
t_) ~ Vl A Vl Vl Vl A A A ~ Vl A A A A A A A
o C ~ C rr C C O O C C C ~^
._ Vl A Vl Vl Vl A Vl A A Vl Vl A Vl Vl A Vl ~

C~ ~ ~ = = = ~ = -- = = = = _ = = = =

r~. _ Z C _ _ = _ _ T = =

U

~-r v ~

U ~ O ~) ~ ~ U 3: U C

6 ~
-- = ~ -- -- ~r T C~ -- T -- _ T 5 = =
O _ _ D X U ~ U U U U U U ~J Z C ~ _ _ T Z

D

W O96/14844 PCTnUS95114812 Z o C O O O C o o o O C
Vl A A Vl Vl Vl A A Vl AVl V V Vl A A
_ o o Z O O C O O O C C C -- O O O O _ Vl A A A Vl A A A A A Vl V V Vl A A
o O O O C O C O O C -- C
z 4 In ~) ~ U, ~ ~r7 ~ _ _ ~
._ Vl Vl A Vl Vl Vl A A Vl A Vl Vl Vl Vl A A
C
~,~ 5 = ~r T--~r Z Z Z = = _ = = _ _ I~
r~ tJ

~-x~z~ ~ ~ ~ U

c C~ U ~ ~I ~ ~ U _= _ U U ~ U
E

~ ..

C ~ ~ S ô ~ ~ ~ ~ . _ = S

.~ U.
o Z C~ ~r ~ :c ~ _ _ _ _ _ _ _ = _ = =
.. o DX S S z z z ~ ~ _ = _ ~ _ U U U U U U U ~ V ~ ~) Z

.
~ .

WO 96/14844 PCI~/US95/14812 --4 fj -Z V~ C C
A ~ ~ A Vl Vl Vl Vl Vl ~ A Vl Vl Vl Vl ' O
o Z _ _ _ 1,, _ V ~ ~ ~ Vl Vl Vl ~ ~ Vl Vl ~ Vl o o o C C -- C C C o o C C C
._ A Vl A A Vl A Vl Vl Vl A A Vl Vl A Vl A A

C--X Z~ T -- ~ T

T ~ a ~ T --cy ~ c v v ~

o = = -- = -- s ~ ~ = = = = = = =

~o - S -V V ~ V Us ~ S~ V5 Z V V Z ~ U V Z

o O ^ ~

~=) Y ~v v v V " Yl;

.Z V V V V K ~C ~

o _ ~ ", ~ .
C~ T' X ~ ~ ~ ~ ,~ ~ o D ~I D

G tl~ t j 3 ~

C~ ~ --E ~ u .e ~ ~ ~ ~ O

o 3 O
Z Z

~ X c~ E

~ ,.

W O96/14844 PCTrUS95/14812 ~ 48 -o O O O O o ~ ~,e ~ - vl vl vl vl vl ~ vl vl vl vl vl o E-, ~

_ ~ o o o o o o o o _ C ~ o Vl A Vl Vl Vl ~ Vl Vl Vl Vl Vl ~ ~ D~

~ _ ~ _ _ _ ._ Vl Vl Vl Vl Vl Vl Vl Vl Vl Vl Vl ~ ,., ~,~

o _ - ~ ~ X~: ~ ~

y ~ ~ F c~ ~5 5 co C~ F D~ C

CC Z ~ X s ~ ~ ~ X ~
~--X~ C ~ D S

T ~ = ~ e ~ C ~ ~ ~ 5 E E-E ~

~ T O y~ =

z ~ ~ 3 ~ ~ ~ ~ ~ ~ ~ ~ ~ o o o g C
5 ~ t,~ V ~ ~ ~) V ~ ~ E

C T ~_ O

V~ o Z _ _ _ _ ~ Z
Vl Vl Vl Vl Vl Vl o E ~

o Z _ _ ~ ~ ~ o Vl Vl Vl ~ Vl Vl -- -- -- -- o _, ._ Vl Vl Vl Vl Vl Vl , C_ o _ ~t D C
O r O

~Z ~ ~ X ~
~z ~ y ~ ~ e B' -E ~2 c E ~ ~ E ,~ -,, e o ',' ~ O~
z 0~ ~ O D -O ~ O

v C '- = ~ E

~ ~ _ ~

. CA 02203681 1997-04-24 W O 96/14844 PCTrUS95114812 .

V~ .
Oo o o - ~s ,_ ~ Vl Vl Vl ~ ~\ ~ Vl Vl Vl ~;
t V ~15 O Z O _ ~ _ V G~ Vl Vl Vl A ~ ~ ~ Vl Vl ~I
O _ _ ~
3 vl vl vl A vl ~ A Vl Vl Vl 4 ~ V V ~ v ~ :~
. ' ~o~ ~ . _ V O o æ' ~ ~ x T~ ~ X 5~ Y D

G C~, ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~

E ~ o E ,o o~
-- o~ ~ ._ _ s c~ V _ ~' ~
o ,_ o .~: _ O ~ ~ c~
~ ~r CO
O g~

s X V V V Z Z Z Z Z Z Z Z ~

W O96/14844 . PCTrUS95/14812 Stereochemical Preferences for NOS Inhibition Fx~mrle iNOS ecNNOS ncNOS
No. IC50 (uM) IC50 (uM) IC50 (uM) 87 0.015 0.05 0.02 88 0.022 0.1 0.009 89 0.24 7.3 1.2 1.63 9.9 5.0 91 0.62 8.3 0.58 92 0.14 1.9 0.25 93 0.42 3.4 0.~2 94 0.1 2.2 0.12 0.038 0.65 0.12 96 0.047 2.3 0.75 97 4.5 > 20 2.2 98 13.3 > 20 8.0 103 0.528 5.5 5.5 102 0.186 12.5 0.246 104 0.133 0.87 0.036 104 0.009 0.36 0.021 105 > 2.5 > 2.5 0.61 105 0.02 0.83 0.0~3 W O 96/14844 PCTrUS95/14812 Several methods for ~re~alillg the compounds of this invention are illustrated in the following schemes and examples. Some of the compounds are known in the litelaLule but none are reported to be inhibitors of NO Synthase. In one method outlined in scheme 1 and 5 illustrated in F.x~mple 2, the compounds are ~r~aled by reacting a cyclic iminoether with an a~ro~liate amine or its salt such as a hydrochloride, hydrobromide, sulfate, aLkyl sulfonate, acetate etc at a temperature between 0-100 C. The required intermediate iminoether substrates can be prepared by O-aLkylation of the corresponding l~ct~m 10 by reagents such as methyl trifluoromethanesulfonate, trimethyloxonium fluoborate, methyl sulfate etc. Other methods for preparation of iminoether known in the art of organic synth~si~ may also be employed.
Many of the lactam starting m~tt~ are commercially available or they can be obtained by lit~ ur~; procedures. One useful method for the 15 ~ tion of substilllte-l lactams is illustrated in example 1.

(~ or ~1 N O MeOTf OMe H

(R)2NH.HCI

(R1,R2,R3) ~N ,N

Another me~od for preparing compounds of this invention is shown in scheme 2. In this method a thiol~ct~m is first reacted with an wo 96/14844 Pcr/usss/l4sl2 alkylating agent such as methyl iodide or methyl sulfate and the resulting iminothioether salt is reacted with an amine to furnish the desired jqmitlin.os. The thiol~ct~m substrates for this process are known in the literature or they can be prepared from the corresponding lactam by 5 treatment with reagents such as P2Ss or Lawesson's reagent (2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide) as illustrated in example 3.

(R1,R2,R3) P2S5 (R" R2.R3) (~ or (~~~
N o Lawesson's N S
R4 Reagent R4 a. Mel b. RNH2 (R1 ~R2.R3) (~
N ~`N' R

~ ltern~tively, the cyclic amidine compounds may also be synthesized from acyclic precursors as described by G~rigir~ti (Tet. Lett.
15 31, 1969-1972 (1990) ). In this method (Scheme 3) an amino nitrile is converted to an ~ll.."i"~,." amide by reaction with an alkylalllmimlm reagent such as trimethyl~lllminllm and in situ cyclization of this intermediate filrni~hes the desired amidines.

W O96/14844 PCT~US95/14812 ., (R1~R2~R3) (R1~R2~R3) CN Me3AI (~
NH N NH

Alternatively, the cyclic ~mi~line compounds may also be synthesized from substihlte~l or unsubsti~lterl 2-aminopyridines by the method of Freifelder (M. Freifelder, R. W. Mattoon, Y. H. Ng, J. Org.
Chem.. 29, 3730-3732 (1964)) employing catalytic hydrogenation under acidic.conditions (Scheme 4). The addition of acid during the 10 hydrogenation is important (T. B. Grave, J. Am. Chem. Soc. 46, 1460-1470 (1924)) (R1 ,R2,R3) (R1 ~R2.R3) ¢N~lNH2 H2, catalyst Cyclic amidines may also be ~l~ared from acyclic precursors as shown in scheme S and demonstrated in example 6. Thus, a ~ich~el addition of a nitro~lk~n~q to an acrylate ester by the method of 20 Bunce and Drllmri~:ht (Org. Prod. Prep. lnt. 19, 471-475 (1987)) leads to an est~r of 4-nitrobutyric acid. Reduction of ~e nitro group and cyclization gives a lactam which is converted to an ~mil1ine by the procedures described in sch~m~ 1 or 2.

.~

_ 55 _ R2 R1 R3 NO2 ~R1 H2, PtO2, 50psi ~1 COOR4 BU R COOR4 R3 ,N o a. Me3OBF4 , _~ (R)2NHCI, 80 C _~`OMe Many cyclic ~mit1ines claimed in this specification can have 5 gtereoisomers and such individual stereoisomers may be ~re~aled from chiral l~ct~m.c. Numerous methods for the synthesis of stereochemically pure lactams have been described in literature. One such method using amino acids as starting materials is described by Reetz and Rohrig (Angew. Chem. Int. Ed. Engl. 28, 1706-1709 (1989)) and is shown in 10 scheme 6. The key feature of this procedure is the stereospecific addition of organometallic reagents to an lm.c~ ated ester and the reversal of the stereoselectivity with an lm.~hlrated malonate, thus allowing synthesis of two diastereomers from the same aldehyde inte.rm~diate.

Scheme 6 R1~CO2H 3steps Rl~,CHO (EtO)2POCH2CO2Et R ~,CO2Et NH2 N(CH2Ph)2 N(CH2Ph)2 CH2(CO2Me)2 Me2CuLi ClTi(OiPr)3 Me R1~CO2Me Rl~,CO2Et (cH2ph)2N CO2Me N(CH2Ph)2 Me2CuLi a H2, Pd Me Me Rl~CO2Me ~
(CH2Ph)2N co2Me Rl--~N~O
H
(4S,5S) a. Acid b. Base Me~

Rl~ O
H
(4R,5S) Synthetic methodology also exists for the preparation of chirally substituted 2-imino-piperi-1ine~. As shown in Scheme 7, addition of organocuprates to the O-tert-butyldimethylsilyl-protected (S)-(-)-5(hydroxymethyl)-2(5H)-furanone B derived from A (available from 10 Aldrich Chemical Co., Milwaukee, WI) will yield stereoisomer C (S.

WO 96114844 PCI/US95tl4812 ; Hanessian and P. J. Murray, Tetrahedron, 43, 5055-5072 (1987)).
Deprotection of ~ yields the free alcohol D which is converted to lactam F
by described methodology (C. Herdeis and D. Waibel, Arch. Pharm.
(Weinheim) 1991, 324, 269-274). Tre~tment with Meerwien's salt followed S by reaction with ammonium chloride in r~ x i . ~ ethanol yields chiral 2-imino-piperidines I and I. Other substituents and substitution p~tern~ are available by analogous chemical manipulations from described intermediates (S. Hanessian, Aldrichimica Acta 22, 3-15 (1989)).

HO~O ~ 2CuLi,E~O, ~ O

DMAP,DMF

~u4NF~HF ~ thenNaN~DMF~ ~ H2,MeOH,10%Pd(C) g~ n R1 E

HO~ (MeO)3BF4. CH2C12 ~ HO~

OMe OMe H
E~NH4Cl,EtOH, r~flux .HCI ~ HCI

b NH H NH

.

Another method for the synth~.si~ of chiral amidines is shown scheme 8. This synth~si.~ utilizes commercially available 15 individual enantiomers of citronellic acid that allow preparation of chiral W O 96/14844 PCTrUS95114812 2-iminopiperidines. Treatment of methyl citronellate with ozone and further oxidation of the intermediate gives an acid which was used in a Curtius reaction to furnish A upon reaction with benzyl alcohol.
Hydrolysis, cyclization and removal of the Cbz group of A leads to a 5 chiral lactam (B) and reaction of B with trimethyloxonium fluoroborate followed by NH4Cl as detailed in scheme 1 fi~ hes a cyclic ~micline.
Citronellic acid is also a useful starting material for chiral 5-methyl-2-iminopiperidines as shown in scheme 9. In this case citronellic acid is first subjected to the Curtius reaction to give a protected amine (C).
10 Cleavage of the double bond of C by ozone and further oxidation directly leads to D and this lactam is converted to an enantiomerically pure ~mitline in 3 steps.
Scheme 8 Me Me a. CH2N2 b. O3, HOAc ~
CO2H c. H22 ~ NHCO2Me Jl~ e PhCH20H Cbz R-Citronellic a. NaOH
b. ClCO2Et, Et3N
c. 110C
d. H2, Pd(OH)2 Me Me a. Me3OBF4 ~, HN NH b. NH4CI NH~O

Scheme 9 Me a. (PhO)2PON
CO2H b. PhCH20H
~ N-Cbz R-Citronellic C
acid a. o3~CH2C12 b. Jones Me Me a. H2, Pd(OH)2 ~
~NH ' b. Me30BF4 ~ Cbz NH c. NH4CI O
D

Citronellic acid can also be used in the synthesis of chiral 4,5-disubstituted 2-iminopiperidines as shown in shown in scheme 10.
This method relies on stereoselective aLkylation using the oxazolidone chiral ~llxili~ry developed by Evans (J. Amer. Chem. Soc. 104, 1737-1739 ( 1982)) and the product is then converted to E. Ozonolysis of the double bond of E and cyclization of the resulting aldehyde gives F.
Treatment of F with ozone followed by further oxidation gives an amino acid which is cyclized to a chiral lactam (G). Usual transformation of G
filrni.~hes cyclic ~mi~1ine.

W O96/14844 PCTrUS95/14812 Scheme 10 Me b- uAlA~Ilation Me Me c MsCI f~R1 a. 03, HOAc ~R
CO2H d. NaN3 ~ N Cbz b. Ac20 ~N
e. LiAlH4 l H
~ f. CbzCI ~ E F Cbz S-Citronellic acid a. O3 b. Jones Me Me Me ~,R1 a. Me3oBF4 ~R1 b ClCO2Et ~R1 HN N b. NH4CI O N c. H2, Pd/C C02H N-CbZ H H CHO
G

The invention will now be illustrated by the following non-limitin,~ examples in which, unless stated otherwise:

All operations were carried out at room or ambient 10 temper~ e, that is, at a temperature in the range 18-25C; evaporation of solvent was carried out using a rotary evaporator under rerlllce~l pressure (600-4000 pascals: 4.5-30 mm. Hg) with a bath tempel~lur~ of up to 60C; the course of reactions was followed by thin layer chromatography (TLC) and reaction times are given for illustration only; melting points 15 are uncorrected and 'd' indicates decomposition; the mPltin~ points given are those obtained for the m~tt~ prepared as described; polymorphism may result in isolation of m~ter~l~ with different melting points in some preparations; the structure and purity of all final products were assured by at least one of the following techniques: TLC, mass spectrometry, WO 96/14844 PCT/US9~/14812 nuclear m~gnt.tic resonance (NMR) spectrometry or microanalytical data;
yields are given for illustration only; when given, NMR data is in the form of delta (o) values for major diagnostic protons, given in parts per million (ppm) relative to tetramethylsilane (TMS) as int~rn~l standard, 5 determin~l at 400 MHz or 500 MHz using the indicated solvent;
conventional abbreviations used for signal shape are: s. singlet; d.
doublet; t. triplet; m. multiplet; br. broad; etc.: in addition "Ar" ~i~nifies an aromatic .ci~n~l; chemical symbols have their usual me~nin~.~; the following abbreviations hàve also been used v (volume), w (weight), b.p.
10 (boiling point), m.p. (melting point), L (liter(s)), mL (milliliters), g (gram(s)), mg (milligrams(s)), mol (moles), mmol (millimoles), eq (equivalent(s)) .

, ~CH3 N O
3 -Methyl-2-piperidone S
Step A: 1-(1.2-diphenyl-2-hydroxy)ethyl-3-methylpiperidine.

A rnixture of 1.96 g (10 mmoles) of commercially available trans-stilbene oxide and 990 mg (10 mmoles) of 3-methyl piperidine was 10 h~te-l one day in refluxing ethanol. The solvent was then removed in vacuo to give the desired amino alcohol in quall~i~ti~e yield.

Step B: 1-(1 2-diphenyl-2-hydroxy)ethyl-3-methyl-2-piperidone &
l-(lt2-diphenyl-2-hvdroxy)ethyl-5-methyl-2-piperidone A mixture of the crude amino alcohol(10 mmoles) from step A, 6.39 g (20 mmoles) of mercuric acetate and 7.5 g (20 mrnoles) of ethylene ~ mine tetraacetic acid disodium salt in 80 mL of 1% acetic acid in water was he~te-l to reIlux 1.5 hrs. After cooling the reaction 20 llli~lufe, methylene chloride was added and the mixhlre was swirled around to dissolve all organic matter. The organic and aqueous layers were ~lec~nt~l from the shiny met~llic mercury by-product. The aqueous layer was sepalated and extracted further wi~ methylene chloride. The combined organic layers were washed with water and salul~led sodium 25 chloride solution. After drying over anhydrous m~nPsium sulfate, solvent was removed to give a brown crude product, which was puridfied on silica gel using 1:3 ethyl acetate and hexane mix~lre to give 639 mg of 1-(1,2--liph~-nyl-2-hydroxy)ethyl-3-methyl-2-piperidone and 1.5 g of 1-(1,2-diphenyl-2-hydroxy)ethyl-5-methyl-2-piperidone.
Step C: l-(lt2-diphenyl-2-oxo)ethvl-3-methyl-2-piperidone.

..
0.7 mL of 8N Jones reagent was added dropwise to an ice-cooled solution of 620 mg (2 mmoles) of 1-(1,2-diphenyl-2-hy~roxy)~othy!-3-m.eth.yl=2=piperldG~in 10 r~ ûf acetone. lne reaction mixt~lre was then stirred one hour. 1 mL of isopropyl alcohol was added 5 and the mixtllre was stirred 10 minlltes. The solvent was then removed in vacuo. The residue was stirred with water and ethyl acetate until all solids dissolved. The aqueous phase was separated and extracted with ethyl ~cet~te The combined ethyl acetate phases were washed with water and saturated sodium chloride solution. After drying over 10 anhydrous m~gn~sium sulfate, the solvent was removed in vacuo to afford the desired lactam ketone as foam in qll~ntit~tive yield.

Step D: 3-Methyl-2-piperidone lS A mixture of 550 mg (1.8 mmoles) of 1-(1,2-diphenyl-2-oxo)ethyl-3-methyl-2-piperidone and 715 mg (11 mmoles) of zinc dust in 8 mL of glacial acetic acid was heated to reflux for 1 day. The mixture was cooled and filtered and the solids washed with ethyl acetate. The filtrate was concentrated to ~5 mL. 25 mL of toluene was added and the 20 solvents were removed in vacuo. The residue was dissolved in ethyl ~cet~t~ and made basic with cautious addition of concentrated ammonium hydroxide. The initially formed precipitate dissolved upon further addition. After stirring 10 ~ e~, anhydrous m~gn~sium sulfate was added in excess. After 20 ll~illules, the solids were filtered and washed 25 with ethyl acetate. The filtrate was concel~ ted to give a residue which was purified on silica gel using 1:1 mixture of ethyl ~cet~te and hexane first and then using 10% meth~nol in ethyl ~cet~te to give 148 mg of 3-methyl-2-piperidone as fluffy solid.

30 1H NMR(CDC13): 3.3 (m, CH2N); 2.48 (m, CH2C=0); 1.45-2.0 (m, CH2's); 1.24 (d, CH3) ; 5.95 (b,NH) Following the above procedures, the following lactams were synthesized:

W O 96/14844 PCTrUS9Stl~812 5-Methyl-2-piperidone:

lH NMR(CDC13): 3.3 & 2.92 (m, CH2N); 2.35 (m, CH2C=O); 1.4-2.0 (m, CH2's); 1.0 (d, CH3); 6.1 (b,NH) 4-Methyl-2-piperidone:

lH NMR(CDC13): 3.35 (m, CH2N); 2.48 & 2.8 (m, CH2C=O); 1.35-2.04 (m, CH2's); 1.04 (d, CH3); 6.05 (b,NH) 4-Propvl-2-piperidone:

lH NMR(CDC13): 3.32 (m, CH2N); 2.5 & 1.98 (m, CH2C=O); 1.25-1.95 (m, CH2's); 0.90 (t, CH3); 6.1 (b,NH) 5 ~5-Dimethyl-2-piperidone:

lH NMR(CDC13j: 3.01 (s, CH2N); 2.38 (t, CH2C=O); 1.60 (t, CH2);
1.04 (s, CH3~S); 6.1(b,NH) 3 .5-Dimethyl-2-piperidone:

lH NMR(CDC13): 3.3 & 2.9 (m, CH2N); 2.52 (m, CHC=O); 1.56-2.1 (m, CH2's); 1.0 & 1.28 (d, CH3~s); 5.95(b,NH) 4-Benzyl-2-piperidone:

lH NMR(CDC13): 3.3 (m, CH2N); 2.62 (m, CH2C=O); 1.35-2.48 (m, CH2's); 7.1-7.3 (m, Aromatic); 6.05 (b,NH) 4-Etho~ycall~onyl-2-piperidone:

.

lH NMR(CDCl3): 4.16 (q; CH20); 3.35 (m, CH2N); 2.60 (d, CH2C=0);2.80 (CHCOOEt); 1.82-2.16 (m, CH2's); 1.24 (t, CH3); 6.58 (b,NH) .

W O 96114844 PCT~US95/14812 1 ~23~4-Tetrahydro- 1 -quinolone:

lH NMR(CDC13): 3.6 (t, CH2N);3.0 (t, CH2); 7.2-8.05 (m, Aromatic);
6.6 (b,NH) s 4-Ethoxvcarbonyl-2-piperizinone:

lH NMR(CDC13): 4.26 (q, CH20);4.12 (s, NCH2C=O); 3.38 & 3.66 (b, CH2's); 1.26 (t, CH3); 6.66 (b, NH~

,~, 15 1-Aza-2-methoxv-1-cyclononene Trimethyloxonium tell~fluoroborate (750 mg; 5 mmol) was added in one portion to 2-azacyclononanone (700 mg; 5 mM) in 10 mL
of anhydrous methylene chloride. The resulting mixtllre was stirred 20 overnight at room tempei~ l.e. The next morninglO% Sodium bicarbonate solution was cautiously added to neutralize fluoroboric acid and the mixture was then ~ lte~l with 20 mL of ethyl ~cet~te. The organic layer was separated and the aqueous layer was extracted with ethyl ~ et~te The combined organic layers were washed with 10%
25 sodium bicarbonate solution and with brine. After dIying over anhydrous m~gnesium sulfate, the organic layer was concentrated to remove the solvents. The residue was taken up in hexane and filtered through a small bed of wet silica gel in hexane. l he filtrate was conce~ ated to give 320 mg of the desired l-aza-2-methoxy-1-cyclononene.

lH NMR: 3.52 (s, OCH3), 3.36 (m, CH2N=), 2.24 (m, N=C-CH2); 1-3-1.7(m).

.
The following iminoethers were synthesized according to the above general procedure. In the case of low molecula~ weight imino ethers such as l-aza-2-methoxy-1-cyclopentene and its methyl analogs, 1-aza-2-5 methoxy-l-cyclohexene and its methyl analogs, it was neces~1y to use low vacuum to remove the solvents in order to reduce the loss of these more volatile products. All lH NMR's are reported as ~ values and were run in CDC13 10 1-Aza-2-methoxy-1-cvclopentene:

lH NMR: 3.72 (s, OCH3), 3.58 (t, CH2N=)~2.36 (t, N=C-CH2), 1-94 (m)-15 1-Aza-2-methoxv-5-methyl-1-cyclopentene:

lH NMR: 3.7 & 3.73 (2s, OCH3), 3.85 (m, CHN=), 2.38 (m, N=C-CH2); 2.14(m) & 1.42(m)(2H), 1.12 (d, C-CH3).

20 1-Aza-2-methoxy-3-methyl-1-cyclopentene:

lH NMR: 3.68 & 3.70 (2s, OCH3), 3.38 & 3.60 (2t, CH2N=), 2.13 &
2.58 (2m, N=C-CH), l.40 (m), 1.16 (d, C-CH3).

25 1 -Aza-2-methoxy- 1 -cyclohexene:

1H NMR: 3.55 (s, OCH3), 3.40 (m, CH2N=), 2.08 (m, N=C-CH2), 1.48 & 1.64(m).

30 1 -Aza-2-methoxy-3-methyl- 1 -cvclohexene:

1H NMR: 3.51 (s, OCH3), 3.35 (m, CH2N=), 2.25 (m, N=C-CH2), 1-34-1.74(m), 1.13 (d, C-CH3).

W O96/14844 PCTrUS95114812 1-Aza-2-methoxy-4-methyl-1-cyclohexene:

H NMR: 3.54 (s, OCH3), 3.29 (m, CH2N=), 2.15 (m, N=C-CH2), 1.56-1.66 (m), 0.86 (d, C-CH3).
s 1-Aza-2-methoxy-4-propyl- 1 -cyclohexene:

H NME~: 3.52 (br, OCH3), 3.30 (m, CH2N=), 2.16 (m, N=C-CH2), 1.20-1.64 (m), 0.80 (t, C-CH3).
1-Aza-2-methoxy-5-methyl- 1 -cyclohexene:

1H NMR: 3.60 (b, OCH3), 3.58 & 2.96 (2m, CH2N=), 2.20 (m, N=C-CH2), 1.32-1.77 (m), 0.92 (d, C-CH3).
1-Aza-2-methoxy-5.5-dimethyl- 1 -cvclohexene:

1H NMR: 3.62 (b, OCH3), 3.17 (s, CH2N=), 2.16 (t, N=C-CH2), 1.47(t, CH2), 0.90 (s, C-CH3).
1-Aza-2-me~oxy-3.5-dimethvl-1-cyclohexene:

1H NMR: 3.52 (s, OCH3), 2.86 (m, CH2N=), 2.32 (m, N=C-CH2), 1.46-1.72 (m, CH2), 0.86(s, C-CH3) 1.09 (s, C-CH3).
1-Aza-2-methoxy-4-benzyl- 1 -cyclohexene:

1H NMR: 3.61 (b, OCH3), 3.36 (m, CH2N=), 1.1-2.6(m).

30 1-Aza-2-methoxv- 1 -cycloheptene:

lH NMR: 3.34(s, OCH3), 3.26 (m, CH2N=j, 2.23 (m, N=C-CH2), 1-37-1.60(m).

-W O96/14844 PCTrUS95114812 l -Aza-2-methoxy- 1 -cvclooctene:

lH NMR: 3.56 (b, OCH3), 3.34 (m, CH2N=), 2.24 (m, N=C-CH2), 1.3-1.6~m).
s 3.4-Dihydro-2-methoxy~luinoline:

lH NMR: 6.9-7.1 (m, aromatic H), 3.78 (s, OCH3), 2.32 (t, CH2N=), = 2.73 (t, N=C-CH2)-3.4.5.6-Tetrahydro-4-ethoxycarbonyl-2-methoxy-pyrazine:

lH NMR: 4.15 (q, 2H), 3.90 (s, 2H), 3.65 (s, OCH3), 3.42 (m, 2H), 2.50 (m, 2H), 1.22 (t,3H).

,~
N NH HCI

2-Imino- l-azacyclononane hydrochloride A mixture of l-aza-2-methoxy-1-cyclononene (62 mg; 0.4 mmol) and ammonium chloride (20.5 mg; 0.4 mmol) in 1 mL of 25 anhydrous ethanol was heated to reflux for 3 hours. The solvent was then removed in vacuo and the residue was lfilul~led with Et20 to give almost a qn~ntit~tive yield of 2-imino-1-azacyclononane hydrochloride as an amorphous solid.

30 lH NMR(CDC13): 8.7, 9.0 & 9.6 (3 br,NH's), 3.4 (m, CH2N), 2.7 (m, CH2C=N), 1.5-2.0(m).
Mass Spectrum m/e = 141 W O96/14844 PCTrUS95/14812 Note: In some cases a slight molar excess (5 - 10%) of the iminoether was used. The workup was effected by ~ u~athlg the residual product with ethyl ~cet~t~. or Et2O. In speci~led cases the products were obtained S as ~ick oils.

The following cyclic amidines (Examples 4-42) were synthesized according to the above general procedure by employing an a~roL,liate iminoether instead of l-aza-2-methyl-1-cyclononene and 10 a~r~liate amine hydrochloride instead of ammonium chloride. All NMR's are reported as o values.

H NH HCI

1-Aza-2-imino-cyclopentane hydrochloride:

20 lH NMR(CDC13): 9.44, 9.13 & 8.77 (3br, N-H's), 2.88 (t, CH2N), 2.88 (t, CH2C=N), 2.10(m).
Mass Spectrum m/e = 85 (M+1).

r( N NH HCI
H

l-Aza-2-imino-3-methylcyclopentane hydrochloride:

WO 96/14844 PCTIUS9S~14812 lH NMR(CDC13): 9.48, 9.1 & 8.82 (3br, N-H's), 3-6-3-2 (mt CH2N), 2.36 (t, CHC=N), 1.80 (m), 1.42 (d, C-CH3).
- Mass Spectrum m/e = 99. (M+l).
s CH3~;;)~NH HCI

10 1-Aza-2-imino-5-methylcyclopentane hydrochloride:

lH NMR(CDC13): 9.S, 9.18 & 8.78 (3br, N-H's), 4.06 (t, CHN); 3.04-2.92 (m, CH2C=N), 2.35 (m, CH2), 1.32 (d,CCH3).
Mass Spectrum m/e = 99 (M+l).

~;~N,CH3 HCI

l-Aza-2-methvlamino-1-cvclopentene hydrochloride: (oil) lH NMR (CDC13): 10.1 & 10.03 (2br, N-H's), 3.66 (b, CH2N), 3.08 (d, N-CH3), 2.91 (t, CH2C=N), 2.12 (m).
25 Mass Spectrum m/e = 99 (M+l).

;

I~
,C2H5 HCI

1-Aza-2-ethylarnino-1-cvclopentene hydrochloride: (oil) lH NMR (D6-DMSO): 10.13 & 9.9 (2br, N-H's), 3.7 (m, CH2N), 3.58 5 (m, N-CH3), 2.96 (m, CH2C=N), 2.12 (m), 1.28 (t, CCH3).
Mass Spectrum m/e = 113 (M+l).

[~ H--¢~ HCI

l-Aza-2-benzylamino-1-cyclopentene hvdrochloride:

15 lH NMR (D6-DMSO): 10.16 (br,N-H's), 7.3-7.4 (m, aromatic H's), 4.54 (s, CH2Ph), 3.56 (t, CH2N), 2.84 (t, CH2C=N), 2.06 (m).
Mass Spectrum m/e = 175 (M+1).

H HCI

l-Aza-2-cyclohexylamino-1-cyclopentene hydrochloride.
1H NMR (D6-DMSO): 9.8 & 9.5 (2br, N-H's), 3.55 (t, CH2N), 2.78 (t, CH2C=N), 2.04 (m), 1.2-1.88(m).
Mass Spectrum m/e = 167 (M+1).

-W O96/14844 PCTfUS95/14812 H ~n~
O HCI

l-Aza-2-methoxycarbonylmethylamino-1-cvclopentene hvdrochloride:
5 (oil) lH NMR (D6-DMSO): 10.0 (br, N-H's), 4.25 (s, -NCH2COOMe), 3.7 (s, COOCH3), 3.6 (t, CH2N), 2.86 (t, CH2C=N), 2.1(m).
Mass Spectrum m/e = 157 (M+l).

[;~H ~OH

HCI
1 -Aza-2-((3~4-dihydro~cvphenyl)ethvl)amino- 1 -cyclopentene hydrochloride:

lH NMR (D6-DMSO): 9.5 (b,N-H's), 6.46-6.76 (m, aromatic H), 3.54 (t, 20 CH2), 3.36 (t, CH2), 2.74 (t, CH2~, 2.02(m).
Mass Spectrum m/e = 221 (M+l).

,CH3 l-Aza-2.2-dimethylamino-1-cyclopentene hydrochloride.

W O96114844 PCT~US95/14812 lH NMR(CDC13): 11.24 (b, N-H's), 3.8 (t, CH2N), 3.4 (s, N-CH3), 3.16 (t, CH2C=N), 2.86 (t, CH2), 2.2(m).
Mass Spectrum m/e = 113 (M+l).

[~NH HCI

2-Iminopiperidine hydrochloride Commercially available sample was used.

~lN,CH3 HCI

20 1-Aza-2-methvlamino-1-cvclohexene hydrochloride: (oil) lH NMR(D6-DMSO): 9.3 & 9.22 (2br, NH's), 3 30 (m, CH3), 2.78 (d, CH3), 2.52 (m, CH2C=N);1.70(m).
Mass Spectrum m/e = 113 (M+l).

[~ N,C2H5 HCI

.. . . . .. ... _ . . . . .

1-Aza-2-ethylamino-1-cyclohexene hydrochloride:

1H NMR (D6-DMSO): 9.3 (br, NH's), 3.28 (m, CH2N) 3.20 (m, CH2N), 5 2.5 (m, CH2C=N), 1.20 (t, CH3).
Mass Spectrum mJe = 127 (M+1).

[~lN,CH3 HCI

1-Aza-2-dimethylamino-1-cvclohexene hydrochloride.

15 lH NMR (CDCl3): 10.7 (br, NH's), 3.60 (m, CH2N), 3.40 & 3.12 (2s, CH3), 2.63-2.52 (m, CH2), 1.85-1.77 (m).
Mass Spectrum m/e = 127 (M+1).

~CH3 ~ H~NH HCI

2-Imino-3-methvlpiperidine hydrochloride:
- lH NMR (D6-DMSO): 9.5 & 8.6 (2br,NH's), 3.25 (m, CH2N), 2.7 (m, CHC=N), 1.4-1.9 (m), 1.25 (d, CH3).
Mass Spectrum m/e = 113.1 (M+1).

PCTnUS95/14812 HN NH HCI

5 2-Imino-4-me~ylpiperidine hydrochloride:

lH NMR (D6-DMSO): 9.5, 8.68 & 8.35 (3br, NH's), 3.24 (m, CH2N), 2.55 & 2.15 (m, CH2C=N), 1.35-1.85 (m), 0.96 (d,CH3).
Mass Spectrum m/e = 113 (M+l).

~NH HCI

2-Imino-4-propylpiperidine hydrochloride:
lH NMR (D6-DMSO): 9.5 & 8.7 (2br, NH's), 3.22 (m, CH2N), 2.6-2.16 (m, CH2C=N), 1.3-1.8(m), 0.85 (t, CH3).
Mass Spectrum m/e = 141 (M+1).

~NH HCI

.

WO 96/14844 PCrlUS95114812 2-Imino-4-benzylpiperidine hydrochloride:

lH NMR (D6-DMSO): 9.54, 8.64 & 8.36 (3br, NH's), 7.15-7.35 (m, 5 aromatic H), 3.35 & 3.2 (m, CH2N), 2.6(m, CH2C=N), 1.4-2.06(m).
Mass Spectrum m/e = 190 (M+l).

CH3~
~ H ~ NH HCI

2-Imino-S-methylpiperidine hydrochloride:
lH NMR (D6-DMSO): 9.5, 8.7 & 8.4 (3br, NH's), 3.3 & 2.8 (m, CH2N), 15 2.55 (m, CH2C=N), 1.3-1.8 (m), 0.92 (d, CH3).
Mass Spectrum m/e = 113 (M+l).

CH3--~
H NH HCI

2-Imino-S.5-dimethylpiperidine hvdrochloride:

25 lH NMR (D6-DMSO): 9.5 & 8.4 (2br, NH's), 2.95 (s, CH2N), 2.52 (t, CH2C--N), 1.48 (t, CH2), 0.92 (d, CH3).
Mass Spectrum rnJe = 127 (M+l).

W O96/14844 PCT~US95tl4812 .

CH3 ~CH3 H NH HCI

2-Imino-3 5-dimethylpiperidine hvdrochloride:
s lH NMR (D6-DMSO): 9.45, 8.7 & 8.5 (3br, NH's), 3-32 (m, CH2N), 2.64 (m, CHC=N), 1.6-2;22(m).
Mass Spectrum m/e = 113 (M~1).

(~NH HCI

15 1^Aza-2-iminocycloheptane hydriochloride:

1H NMR (CDCl3): 9.S, 9.0 & 8.45 (3br,NH's), 3.4 (m, CH2N), 2.75 (m, CH2C=N), 1.4-1.8(m).
Mass Spectrum m/e = 127 (M+1).

..

(~ N-CH3 HCI

1-Aza-2-methylamino-1-cycloheptene hydrochloride:

lH NMR (CDCl3): 10.0 & 9.S (2br, NH's), 3.50 (m, CH2), 3.0 (d, CH3), 2.8 (m, CH2C=N), 1.6-1.84(m).

Mass Spectrum m/e = 127 (M+l).
.~ .

~H-c2H5 HCI

1 -Aza-2-ethylamino- 1 -cycloheptene hydrochloride: (oil) 10 lH NMR (CDC13): 9.8 & 9.54 (2br, NH's), 3.52 (m, CH2), 2.85 (m, CH2C=N), 1.70 (m), 1.3 (t, CH3).
Mass Spectrum m/e = 141 (M+l).

Ç~ N,CH3 HCI

l-Aza-2-dimethylamino-1-cycloheptene hydrochloride.
lH NMR (CDC13): 3.65 (m, CH2N), 3.42 & 3.25 (2s, CH3), 2.72 (m,CH2), 1.6-1.85(m).
Mass Spectrum m/e = 141 (M+l).

W O96/14844 PCTrUS95/14812 HCI
~N N~

l-Aza-2-benzylamino-1-cycloheptene hydrochloride:

S lH NMR (D6-DMSO): 9.9 & 9.6 (2br, NH's), 7.4 (m, aromatic H), 4.48 (b, CH2), 3.45 (m, C~I2N), 2.76 (m, CH2C=N), 1.5-1.75 (m).
Mass Spectrum m/e = 203 (M+l).

(~ N~

l-Aza-2-cvclohexylamino- l-cvcloheptene hvdrochloride.
lH NM~ (D6-DMSO): 9.2 (br, N-H's), 3.38 (m, CH2N), 2.68 (t, CH2C=N), 1.1-1.88 (m).
Mass Spectrum m/e = 195 (M+l).

C)~NH HCI

25 1-Aza-2-iminocyclooctane hydriochloride:
-lH NMR (CDCl3): 9.6, 9.0 & 8.7 (3br, NH's), 3.45 (m, CH2N), 2.7 (m, CH2C=N), 1.5-2.0(m).
Mass Spectrum m/e = 127 (M+l).

N H

10 l-Aza-2-methylamino-l-cyclooctene hydrochloride:

lH NMR (CDC13): 10.0 & 9.34 (2br, NH's), 3.55 (m,CH2),3.05 (d, CH3), 2.75 (m, CH2C--N), 1.48-l.95(m).
Mass Spectrum m/e = 141 (M+l).

l-Aza-2-ethvlamino-1-cyclooctene hydrochloride:

lH NMR (CDCl3): 8.2-lO.O(br, NH's), 3.55 (m, CH2), 2.5-2.76 (m, CH2C=N), 1.26-2.05 (m), 1.3 (t, CH3).
25 Mass Spectrum m/e = 155 (M+l).

W O96tl4844 PCT~US95/14812 Gl N ~

l-Aza-2-benzylamino-1-cyclooctene hydrochloride:

5 lH NMR (D6-DMSO): 9.9 & 9.3 (2br, NH's), 7.36 (m, aromatic H), 4.5 (b, CH2), 3.5 (m, CH2~), 2.7 (m, CH2C=N), 1.3-1.75(m).
Ma$s Spectrum m/e = 217 (M+l).

(~_ ,CH3 HCI

1-Aza-2-me~vlamino-1-cvclononene hydrochloride:
lH NMR (D6-DMSO): 9.64 & 8.95 (2br, NH's), 3.5 (m, CH2), 3.05 (d, CH3), 2.82 (d, CH3), (2.64 (m, CH2C=N), 1.25-1.8(m).
Mass Spectrum m/e = lSS (M+l).

~NH2 HCI
25 3~4-Dihydro-2-aminoquinoline hydrochloride:

lH NMR (D6-DMSO): 9.7 & 8.9 (2br, NH's), 7.1-7.3 (m, aromatic H), 2.9 (m, CH2).

W O96/14844 PCTrUS95/14812 Mass Spectrum m/e = 147 (M+l).

s ~ N,CH3 HCI

3~4-Dihydro-2-methylaminoquinoline hvdrochloride:

10 lH NMR (D6-DMSO): 11.3 & 10.45 (2br, NH's), 7.1-7.5 (m, aromatic H), 3.1 (d, CH3), 2.9 (CH2)-Mass Spectrum m/e = 161 (M+l).

0~N~C2H5 HCI

3.4-Dihydro-2-ethylaminoquinoline hvdrochloride:
lH NMR (D6-DMSO): 10.4 (br, NH's), 7.1-7.5 (m, aromatic H), 3.58 (m, CH2), 2.9 (CH2), 1.25 (t, CH3).
Mass Spectrum m/e = 175 (M+l).

H--~ HCI

W O~6114844 PCTrUS95/14812 3.4-Dihvdro-2-benzylarninoquinoline hydrochloride:

lH NMR (D6-DMSO): 10.75 (br, NH's), 7.1-7.55 (m, aromatic H), 4.86 S (b, CH2), 3.1 (d, CH3), 2.95 (m, CH2).
Mass Spectrum m/e = 237 (M+l).

. - - -~H~ HCI

3 4-Dihydro-2-cyclohexylaminoquinoline hvdrochloride:

15 lH NMR (D6-DMSO): 10.2 (br, NH's), 7.1-7.6 (m, aromatic H), 2.9 (CH2), 1.1-2.0(m).
Mass Spectrum m/e - 229 (M+l).

,Clt3 HCI

3 4-Dihvdro-2-dimethylaminoquinoline hydrochloride:
lH NMR (D6-DMSO): 8.8 (br, NH's), 7.1-7.6 (m, aromatic H), 3.4 &
3.3 (2s, CH3), 2.95(CH2~.
Mass Spectrum m/e = 175 (M+l).

Oq~OC2H5 ~N~
~ H~NH HCI

4-Ethoxycarbonyl-2-imino-piperazine hydrochlonde:

lH NMR (D6-DMSO): 9.1 & 8.8 (2br, NH's), 4.38 (br, CH2), 4-1 (q, CH2), 3.56 (br, CH2), 3.35 (t, CH2), 1.2 (t, CH3~.
Mass Spectrum m/e = 172 (M+l).

.

N~
NH Hl 5-(S)-2-Imino-l-aza-bicyclo(3.3.0)octane hydroiodide Step A: l-t-butoxycarbonyl-2-(S)-pyrrolidinomethanol To a vigourously stirring solution of 2.5 g (24.7 mmol) 2-20 (S)-pyrrolidinomethanol in 20 mL of saturated sodium bicarbonate solution at RT was added 6.25 mL (27.2 mmol) of di-t-butyl dicarbonate.
Reaction was continued overnight at room temperature. Reaction mixture was diluted with water and extracted with EtOAc. EtOAc layer was washed with water, brine, dried, filtered and the filtrate was 25 concentrated. Tfilulation of thç white solid with hexane followed by filtration yielded 4.3 g of the desired compound.

lH NMR (CDCl3): 4.76 (br s, lH), 3.98 (br, lH), 3.29-3.67 (m, 4H), 2.00-2.06(m, lH), 1.78-1.84(m, 2H), 1.48 (s, 9H).

W O96/14844 PCTrUS95114812 Step B: l-t-Butoxycarbonyl-2-(S)-formyl-pyrrolidine.

To a solution of 0.44 mL (6.2 mmol) of DMSO in 3 mL of S CH2C12 at -78 C was added 0.36 mL (4.1 mmol) of Oxalyl chlonde.
After 10 min 0.402 g (2 mmol) of 1-t-butoxycarbonyl-2-(S)-pyrrolidinomethanol was added and stirred for 20 min. Triethylamine (1.7 mI., 12.4 mmol) was added to the reaction mixture and it was allowed to warm to room tempel~tulc;. After stirring for 15 min at room 10 temperaLult;, the reaction was diluted with water and extracted with CH2C12. The CH2C12 layer was washed with brine, dried and the filtrate was concenlrated. The residue was chromatographed using 20% Et2-hexane to isolate 0.436 g (qu ~tative) of the title compound mixed with a small amount Q~ DMSO whic -~ was used in the next step.
Step C: l-t-Butoxvcarbonyl-2-(S)-methoxycarbonylethyl-pyrrolidine.

To a suspension of 0.16 g (4 mmol) of NaH in 10 mL of THF was added 0.73 mL (4 mmol) of methyl diethylphosphonoacetate.
20 After 10 min a solution of 0.436 g (2 mmol) of 1-t-butoxycarbonyl-2-(S)-formyl-pyrrolidine prepared in step B was added. After st~ ng for 1 h the reaction was quenched by ~ lin~ saturated NH4Cl and extracted with CH2C12. The CH2C12 layer was washed with brine, dried, conce~ dled and the residue was purified by chromatography using 20% EtOAc-25 hexane to furnish 0.383 g of oil.

lH NMR (CDCl3): 6.82 ( dd, J= 15.5, 6 Hz, lH), 5.83 (d, J= 15.5, lH),4.4 (m, lH), 3.72 (s, 3H), 3.40 (m, 2H), 2.08 (m, lH), 1.86 (m, lH), 1.77 (m, lH), 1.43 (s, 9H).
30 13C NMR (CDC13 in ppm). 166.87, 148.84, 120.00, 57.81,51.53, 46.18, 31.68, 28.35, 22.86.
A solution of 0.383 g of this oily product in 5 mL of me.th~nol and 50 mg of 10 % Pd/C was stirred under H2 atmosphere ovçrni.~ht The next morning the catalyst was filtered through a plug of WO 96/14844 PCI/US95tl4812 - celite and the filtrate was conce~ ated to obtain 0.368 g (72%) of the title compound sufficiently pure for use in the next step.
, lH NMR (CDC13): 3.78(m, lH), 3.65 (s, 3H), 3.28 (m, 2H), 2.32 (t, 5 J=7.5 Hz, 2H), 1.45 (s, 9H).

Step D: 5-(S)-l-Aza-bicyclo(3.3.0)octan-2-one A solution of 0.201 g (0.78 mmol) of 1-t-butoxycarbonyl-2-10 (S)-methoxycarbonylethyl-pyrrolidine in 3 mL of CH2C12 at 0 C was treated with 1 mL of trifluoroacetic acid. During the next 1 h as the solution warmed to room tempeld~ e the reaction was complete. The reaction was concentrated and saturated K2CO3 solution was added to the residue until it was basic. The mixture was h~te~l in a 75 C for 18 h.
15 The reaction was cooled and extracted with CH2C12 and the organic layer was washed with brine, dried and concentrated. The residue was chromatographed on a flash column using 10:45:45 mixt~lre of MeOH:EtOAc:hexane to isolate 96 mg (98%) of the title compound.

20 lH NMR (CDCl3): 3.88 (m, lH), 3.53 (m, lH), 3.03 (m, lH), 2.72 (m, lH), 2.31 (m, lH), 2.02-2.28 (m, 3H), 1.73 (m, lH), 1.32 (m, lH).
13C NMR (CDC13 in ppm): 174.71, 62.04, 40.94, 35.35, 32.18, 27.15, 26.97.

25 Step E: 5-(S)-l-Aza-bicyclo(3.3.0)octan-2-thione To a solution of 80 mg (0.64 mmol) of 5-(S)-l-aza-bicyclo(3.3.0)octan-2-one in 4 mL of toluene was added 0.388 g (0.96 mmol) of Lawesson's reagent and the mixture was he~te-l in a 90 C bath.
30 After 18 h the reaction was cooled, concentrated and the residue was chromatographed using 20% EtOAc-h~x~ne to furnish 83 mg (92%) of the title compound.

W O 96/14844 P~li~b5S/14812 lH NMR (CDC13): 4.17 (m, lH), 3.72 (m, lH), 3.40-3.23 (m, 3H), 2.38-2.21 (m, 4H), 1.78 (m, lH), 1.47 (m, lH).
13C NMR (CDC13 in ppm): 69.68, 49.36, 44.56, 31.60, 29.36, 27.50.

S Step F: S-(S)-2-Imino-l-aza-bicvclo(3.3.0)octane. hydroiodide Methyl iodide (1.5 mL) was added to 83 mg (0.59 mmol) of S-(S)-l-aza-bicyclo(3,3,0)octan-2-thione and the mixture was stirred overni~ht Next morning excess methy iodide was removed in vacuo 10 leaving a solid resi~lle lH NMR (D20): 4.66 (m, lH), 3.53 (m, lH), 3.68-3.57 (m, 4H), 2.76 (s, 3H), 2.53-2.41 (m, 3H), 2.26 (m, lH), 2.03 (m, lH), 1.66 (m, lH).
13C NMR (D20 in ppm): 187.28, 75.86, 45.84, 43.19, 29.53, 27.52, 15 27.05, 15.40.

The solid obtained from the above reaction was dissolved in S mL of MeOH and the solution was saturated with NH3. After stirring for 18 h the reaction mixh~re was conce~ t~d leaving a white solid 20 residue. The solid was ~ aled with e~er and dried to isolate 0.161 g (qll~nt~tive) of the title compound as a hydroiodide salt.

lH NMR (D2O): 4.31 (m, lH), 3.40 (m, 2H), 3.25 (m, lH), 3.04 (m, lH), 2.36-2.27 (m, 4H), 1.94 (m, lH), 1.53 (m, lH).
25 13C NMR (D2O in ppm): 165.37, 69.08, 49.03, 42.66, 35.96, 30.38, 27.83, 27.18.

H

NH Hl W O~6/14844 PCT~US95114812 2-Imino-l-aza-bicyclo(4.3.0)nonane hvdroiodide Step A: l-t-butoxycarbonvl-2-(R+S)-piperidinodinomethanol Starting from 5 gm (43.4 mmol) of 2-(R+S)-piperidinodinomethanol and following the procedure as in example 43, step A gave 7.06 gm of the title product.

lH NMR (CDC13): 4.26 (m, lH), 3.92 (m, lH), 3.77(m, lH), 3.59 (m, lH), 2.84 (m, lH), 1.49-1.60 (m, 3H), 1.44 (s, 9H).
13C NMR (CDC13 in ppm): 79.72, 61.40, 52.37, 39.95, 33.88, 28.37, 25.19, 25.11, 19.50.

Step B: l-t-Butoxycarbonyl-2-(R+S)-formvl-piperidine Starting from 0.7 gm (3.2 mmol) of 1-t-butoxycarbonyl-2-(R+S)-piperidinodinomethanol and following the procedure as in example 43, step B, gave 0.675 gm of the desired compound.

lH NMR (CDC13): 9.60 (d, J=5.7 Hz, lH), 4.55 (br s,lH), 3.95 (br s, lH), 2.94 (br s, lH), 2.17 (m, lH), 1.67-1.28 (m, SH), 1.48 (s, 9H).

Step C: l-t-Butoxycarbonvl-2-(R+S)-methoxycarbonylethyl-piperidine To a suspension of 0.088 g (3.7 mmol) of NaH in 5 mL of THF was added 0.68 mL (4 mmol) of methyl diethylphosphono~cet~te at -10C. After 10 min a solution of 0.528 g (2.47 mmol) of l-t-butoxycarbonyl-2-(R+S)-formyl-pipe.ritlin~. prepared in step B was added.
After stirring for 1 h the reaction was qllench~.-l by ~ ling saturated NH4Cl and extracted with EtOAc. The EtOAc layer was washed with brine, dried, concentrated and the residue was purified by chromatography using 5% EtOAc-hexane to furnish 0.579 g of oil.

-lH NMR (CDC13): 6.88 ( m, lH), 5.81 (d, J= 15.8, lH), 4.94 (m, lH), 3.98 (m, 2H), 3.74 (s, 3H), 2.81 (m, lH), 1.81-1.60 (m, 5H), 1.45 (s, 9H).
13C NMR (CDC13 in ppm): 166.61, 154.94, 121.56, 79.79, 51.53, 28.89, 28.33, 25.22, l9.gl.
s A solution of 0.570 g of this oily product in 5 mL of methanol and 50 mg of PtO2 was stirred under H2 atmosphere overnight.

The next morning the catalyst was filtered through a plug of celite and the filtrate was concentrated to obtain 0.548 g of the title compound 10 sufficiently pure for use in the next step.

lH NMR (CDC13): 4.24(m, lH), 3.66 (s, 3H), 2.73 (m, lH), 2.31-2.25 (m, 2H), 2.13-2.07 (m, lH), 1.69-1.50 (m, 6H 1.45 (s, 9H).

13C NMR (CDCl3 in ppm): 174.00, 154.96, 79.20, 51.49, 49.88, 30.89, 15 28.85, 28.37, 28.27, 25.50, 24.96, 19.01.

Step D: 5-(R+S)-l-Aza-bicyclo(4.3.0)nonan-2-one A solution of 0.548 g (2.02 mmol) of 1-t-butoxycarbonyl-2-20 (R+S)-methoxycarbonylethyl-piperidine in 3 mL of CH2C12 at 0 C was treated with 1 mL of trifluoro~ce~ic acid. During the next 1 h as the solution warmed to room teL~ the reaction was complete. The reaction was concentrated and sa~ ted K2C03 solution was added to the residue until it was basic. The mixblre was heated in a 75 C for 2 h.

25 The reaction was cooled and e~tr~cte~l with CH2C12 and the organic layer was washed with brine, dried and conc~ ted. The residue was chromatographed on a flash column using 10:45:45 mixture of MeOH:EtOAc:hexane to isolate 0.187 g (67%) of ~e title compound.

30 lH NMR (CDCl3): 4.04 (m, lH), 3.34 (m, lH), 2.54 (m, lH), 2.27 (m, lH), 2.14 (m, lH), 1.80 (m, 2H), 1.63 (m, lH), 1.50 (m, lH), 1.36-1.23 (m, 2H), 1.09 (m, lH).

13C NMR (CDC13 in ppm): 173.47, 57.17, 40.11, 33.48, 30.20, 25.23, 24.35, 23.58.

Step E: 5-(R+S)-l-Aza-bicyclo(4.3.0)nonan-2-thione To a solution of 90 mg (0.64 mmol) of 5-(R+S)-l-aza-5 bicyclo(4.3.0)nonan-2-one in 4 mL of toluene was added 0.392 g (0.97 mmol) of Lawesson's reagent and the mixture was h.o~te~l in a 90 C bath.
After 18 h the reaction was cooled, concentrated and the residue was chromatographed using 70% CH2Cl2-hex~nP to furnish 95 mg (96~o) of the title compound.
lH NMR (CDC13): 4.85 (m, lH), 3.71 (m, lH), 3.05 (m,lH), 2.94 (m, lH), 2.83 (m, lH), 2.26 (m, lH), 2.00 (m, lH), 1.89 (m, lH), 1.83 (m, lH), 1.65 (m, lH), 1.53-1.42 (m, 2H), 1.28 (m, lH).
13C NMR (CDC13 in ppm): 199.15, 65.13, 45.53, 43.40, 33.34, 26.66, 15 24.23, 22.99.

Step F: 5-(R+S)-2-Imino-l-aza-bicyclo(4.3.0)nonane.hvdroiodide Methyl iodide (1 mL) was added to 50 mg (0.32 mmol) of 5-20 (R+S)-l-aza-bicyclo(4.3.0)nonan-2-thione and the mixhlre was stirred for 5 hr. Excess methy iodide was removed in vacuo leaving a solid residue.

lH NMR (D2O): 4.20 (m, lH), 4.07 (m, lH), 3.45-3.26 (m, 3H), 2.74(s, 3H), 2.51 (m, lH), 2.11 (m, lH), 1.90 (m, 2H), 1.58-1.49 (m, 3H).
25 13C NMR (D2O in ppm): 70.41, 48.57, 37.01, 32.30, 25.43, 23.66, 21.73, 14.91.

The solid obtained from the above reaction was dissolved in S mL of MeOH and the solution was salul~ted with NH3. After stirrinp 30 for 18 h the reaction mixhlre was conce~ ted leaving a white solid resi~l~le. The solid was ~ilurated with e~er and dried to isolate 83 mg (qll~nt~tive) of the title compound as a hydroiodide salt.

. CA 022036X1 1997-04-24 W O96114844 PCT~US9~/14812 lH NMR (D20): 3.84-3.78 (m, 2H), 3.07 (m, lH), 2.85 (m, 2H), 2.32(m, lH), 2.01 (m, lH), 1.86-1.72 (m, 4H), 1.48 (m, 2H), 1.34 (m, lH).
13C NMR (D2O in ppm): 166.27, 63.61, 43.14, 31.94, 29.93, 25.30,

23.30, 21.97.
s CH3~NH HOAc cis-4.6-Dimethyl-2-imino-piperidine~ acetic acid salt.

2-Amino-4,6-dimethyl-pyridine (2.00 g, 16.4 mmol) was lS dissolved in 10.0 mL of glacial acetic acid and 0.90 g of 5% rhodium on min~ was added. The mixtl~re was .sh~k~n under a hydrogen atmosphere at 40 psi for 16 h. After filterin~ the ~ e dlrough Celite and washing the catalyst with an ~dditional 25 mL of acetic acid, the f~trate was conc~ ed to a weight of 4.5 g. Toluene (3xlO mL) and then ethyl 20 ~et~t~ (20 mL) were added sequentially, with evaporation of the solvent under v~c~ m following the addition of each portion. The residue was dissolved in methanol and filtered ~rough a 0.45 micron membrane. The filtrate was evaporated and ~e residue was dissolved in 20 mL of ethyl ~cet~te and cooled to 0 C. Filtration and drying under v3~nlm yielded 958 25 mg (31% yield) of cis-4,6-dimethyl-2-imino-piperi(1inP, acetic acid salt.

lH-NMR (400 MHz, CD3OD) ~ 3.58 (m, lH), 2.62 (ddd, lH, J = 17.5, 4.5, 2 Hz), 2.16 (ddd, J = 17.5, 12, 1.5 Hz), 2.00-1.90 (m, 2H), 1.89 (s, 3H), 1.27 (d, 3H, J = 6 Hz), 1.11 (q, lH, J = 12 Hz), 1.06 (d, 3H, J - 6 Hz).
30 Mass spectrum: 127 (M+l).
-Following the above procedures, the following 2-iminopiperi~lin-~s (Examples 46-59) were synthesized from the a~ro~liate 2-aminopyridine:

~NH HOAc 10 2-Imino-4-methvl-piperidine. acetic acid salt lH-NMR (400 MHz, CD30D) ~ 3.24 (ddd, lH, J = 13, 5.5, 2.5 Hz), 3.14 (ddd, lH, J = 13, 10, 5 Hz), 2.45 (ddd, lH, J = 17.5, 5, 1.5 Hz), 2.04 (dd, J
= 17.5, 10 Hz), 1.88-1.68 (m, 2H), 1.64 (s, 3H), 1.30 (dtd, lH, J = 13, 10, 15 5.5 Hz), 0.95 (d, 3H, J = 6 Hz).
Chemical Analysis. Calc. for CgH16N2O2: 55.79% C, 9.36% H, 16.27%
N. Found: 55.95% C, 9.29% H, 16.33% N.

C2H~j~NH HOAC

6-Ethyl-2-imino-4-methvl-piperidine~ acetic acid salt.
lH-NMR (400 MHz, CD30D) o 3.48-3.39 (m, lH), 2.63 (ddd, lH, J =
17.5, 4.5, 2 Hz), 2.17 (ddd, lH, J = 17.5, 12, 1.5 Hz), 2.03-1.90 (m, 2H), 1.90 (s, 3H), 1.69 (dqd, J = 14, 7, 5 Hz), 1.56 (dq, J = 14, 7 Hz), 1.10 (q, J =12 Hz), 1.07 (d, 3H, J = 7 Hz), 0.98 (t, J = 7 Hz).

WO 96J1~844 . PCT/US9S/14812 ~CH3 N NH HCI

4-Imino-S-cis-methyl-3-azabicyclo r43.0l nonane. hydrochloride.

lH NMR (400 MHZ, CDC13) o 3.42 (drn, lH, J=13Hz), 3.23 (d, lH, 10 J=13Hz), 2.84-2.87 (m,lH), 2.62-2.49 (lH, m), 2.02-1.95 (lH, m~, 1.93-1.86 (lH, m), 1.76-1.69 (lH, m), 1.41-1.28 (2H, m), 1.249 (3H, d, J=7Hz), 0.95-0.86 (lH, m).

Mass spectrum m/e = 153 (M+l).

H2N~

cis-S-Aminomethyl4~6--limetllyl-2-imino-piperidine~ dihydrochloride.

lH NMR (400 MHz, CDCl3) ~ 3.95-3-88 (m, lH), 3.05(t, 2H, J=SHz), 2.73 (dd, lH, J=17Hz, J=5.5Hz), 3 Q~ (t, 2H J=4.5 Hz), 2.73 (dd, lH, 25 J=18Hz, J=S.SHz), 2.37 (dd, lH, J=18Hz, J=9.SHz), 2.4-2.3 (m, lH), 2.25-2.20 (m, lH,), 1.37 (d, 3H, J=7.1Hz), 1.15 (d, 3H, J=6.7Hz).

Mass spectrum m/e = 156 (M+l).

.

NH NH HCI
s cis-3-Ethyl-2-imino-4-methyl-piperidine. hydrochloride.

lH NMR (S00 MHz, CD30D) ~ 3.44 (m, 1 H), 3.38 (m, 1 H), 2.48 (dd, J = 4 Hz, 1 H), 2.16 (m, J = 10 & 4 Hz, 1 H), 1.83 (m, 1 H), 1.74 (m, 2 10 H), 1.67 (m, lH), I.06 (t,J=8Hz,3H), 1.05 (d,J=7Hz,3H).

Mass spectrum m/e = 141 lS EXAMPLE Sl H NH HCI

cis-2-Imino-4-methyl-3-n-propvl-piperidine. hydrochloride.
lH NMR (500 MHz, CD30D) ~ 3.44 (m, 1 H), 3.38 (m, 1 H), 2.55 (dd, J=SHz, 1 H),2.15 (m,J= 10&4Hz, 1 H), 1.83 (m, 1 H,H5), 1.76 (m, 1 H), l.S9 (m, 2 H), 1.45 (m, 2 H), l.OS (d, J = 7 Hz, 3 H), 0.99 (t, J = 7 Hz, 3 H).
Mass spectrum m/e = lSS
A~

WO 96/14844 PC~/US95114812 HO2C~

~HN~NH HOAc cis/trans-2-Imino-4-methyl-piperidine-S-carboxylic acid~ acetic acid salt.

lH NMR (400 MHz, CD30D) ~ 1.04 (d, 1.5H), 1.08 (d, 1.5H).

Mass spectrum m/e = 156 (M).

CH302C~
~ HN~NH HOAc 15 cis/trans-2-Imino-4-methyl-piperidine-S-carboxylic acid~ methyl ester~
acetic acid salt.

lH NMR (400 MHz, CD30D) ~ 1.05 (d, l.SH), 1.09 (d, 1.5H), 3.74 (d, 3H).
Mass s~ecLIulLl m/e = 171 (M+1).

CH ~N~
HN NH HOAc cis/trans-5-Acetamidomethvl-2-imino-4-methyl-piperidine. acetic acid salt.
-lH NMR (400 MHz, CD30D) ~ 1.02 (d, 1.5H), 1.10 (d, 1.5H).

Mass spectrum m/e = 184 (M+l).

~ ~
~H~NH HOAc 2-Imino-5-n-propyloxy-piperidine acetic acid salt.
15 lH NMR (400 MHz, CD30D) ~ 0.95 (t, 3H), 1.59 (m, 2H).
Mass spectrum m/e = 157 (M+l).

CH3~N~
~ NH HOAc cis/trans-5-Acetamido-2-imino-4-methyl-piperidine. acetic acid salt.
lH NMR (400 MHz, CD30D) ~ 1.00 ~d, l.5H), 1.05 (d, 1.5H), 1.97 (d, 3H).
~c .
Mass spectrum m/e =170 (M+l).

=

W O96/14844 PCTrUS95/14812 `~l N NH HOAc H
5-Cyclohexyl-2-imino-piperidine. acetic acid salt.
lH NMR (40Q MHz, CD30D) ~ 1.00-1.85 (br m, 1 lH).
10 Mass spectrum m/e = 181 (M~l).

H NH HOAc cis/trans-5-Cyclohexyl-2-imino-4-methyl-piperidine, acetic acid salt.

lH NMR (400 MHz, CD30D) ~ 0.90 (d, l.5H), 1.05 (d, l.5H).
Mass spectrum m/e = 195 (M+l).

CF3 ~
HN NH

, WO 96/14844 PCrlUS95114812 _ 99 _ 2-Imino-5-trifluoro-piperidine..acetic acid salt r lH NMR (400MHz, CD30D) o 1.83-1.97 (br m, lH), 2.14-2.20 (br m, . lH), 2.74-2.80 (br m, 2H), 2.86-3.00 (br m, lH), 3.337-3.44 (m, lH), 3.62-S 3.68 (q, lH).
Mass spectrum m/e = 167 (M+l).

C2Hs~NH HCI

2-Imino-S-ethyl-4-methylpyrrolidine hydrochloride Step A: Methvl 3-methyl-4-nitrohexanoate A solu~ion of 4 g (40 mmol) of methyl crotonate and 4.72 g (53 mmol) of l-ni~lo~r~alle in 20 mL of ~cetQnitrile was treated 20 with 6 mL (40 mmol) of 1,8-diazobicyclo[5.4.0]undec-7-ene (DBU).
After stirrin~ for 22 h at room tempel~lur~ the reaction ~ lur~ was ~lil.lte-l with water and acidified with 2 N HCl. The solution was e~tr~ctefl with Et20 and the Et20 layer was washed with brine, dried and concell~ ed. The residue was chromatographed on a flash column using 25 10 % Et2O-Hexane to isolate 6.41 g (85%) of the title compound.

lH NMR (CDC13, since stereoisomers were present multiple peaks were observed and ppm ranges are given): 4.44 & 4.38 (2m, lH), 3.70 & 3.69 (2s, 3H), 2.65-1.7 (m, SH), 1.06 & 1.01 (2d, 3H, J=7 Hz), 0.97 (t, 3H, J=7 30 Hz).

Step B: 5-Ethyl4-methyl-2-pvrrolidone W O 96/14844 PCT~US95/14812 A solution of 4.0 g (21 mmol) of methyl 3-methyl-4-nitrohexanoate (from step A) in 20 mL of EtOH co~ 0.4 g of PtO2 was hydrogenated on a Parr apparatus for 3 days. The catalyst was S filtered and washed with EtOH and the filtrate was concentrated.
Vacuum distillation of the residue furnished 1.6 g (61%) of the title compound: bp 102-107 C/2 mm.

lH NMR (CDC13, since stereoisomers were present multiple peaks were 10 observed and ppm ranges are given): 6.9 (br s, lH~ 3.50 & 3.11 (2 m, 1 H), 2.65-1.3 (m, 5H), 1.14 & 1.04 (2d, 3H, J=7 Hz), 0.96 (t, 3H, J=7 Hz).

Step C: 1-aza-5-ethvl-2-methoxy-4-methyl-1-cvclopentene To a solution of 0.254 g (2 mmol) of 5-ethyl-4-methyl-2-pyrrolidone (from step B) in 3 mL of CH2C12 was added 0.355 g (2.4 mmol) of trimethyloxonium tetrafluoroborate under a N2 atmosphere. After stirring overni~ht the reaction mixtrue was quenched with saturated K2CO3 solution and diluted with Et2O. The solution was filtered and the filtr~te was conce~ al~d. The residue was purified by flash chromatography using Et2O-hexane to isolate 0.224 g (79%) of the title compound.

lH NMR (CDC13, since stereoisomers were present mllltiple peaks were observed and ppm ranges are given): 3.8 (s, 3 H), 3.6-3.4 (m, 1 H), 2.7-0.8 (m, 10H).

Step D: 2-Imino-S-ethyl-4-methylpyrrolidine hydrochloride A mixture of 0.1 g (0.71 mmol) in 3 mL of EtOH
cont~inin 0.03 g (0.56 m m ol) of NH4Cl was heated to reflux. After 4 h the solution was cooled and conct;~ ated and the residue was suspended in EtOAc. The precil.~(ete-l solid was filtered washed with EtOAc and dried to furnish 0.072 g (79%) of the title compound.

W O96/14844 PCTrUS95/14812 r lH NMR (D2O, since stereoisomers were present multiple peaks were observed and ppm ranges are given): 3.82 & 3.50 (2 q, lH), 3.1-2.45 (m, 2 H), 2.31 & 1.64 (2 m, lH), 1.6-1.45 (m, 2H), 1.11 & 1.0 (2 d, 3H, J=7 S Hz), 0.92 (t, 3H, J=7 Hz).

Mass spectrum m/e = 127 (M+l) The following 2-imino-pyrrolidines (F.x~mples 61-78) were ~r~aled by 10 the method of Fx~mple 60 by sub~ uling ~r~liate nitro~lk~n~. and acrylate esters.

t;~ NH HCI

2-Imino-4-methylpyrrolidine hydrochloride 20 lH NMR (D2O): 3.73 (t, lH), 3.22 (dd, lH), 2.97 (dd, lH), 2.65 (m, lH), 2.47 (dd, lH), 1.08 (d, 3H).

Mass spectrum m/e = 99 (M+l) CzH~

N NH HCI

30 2-Imino-4-ethylpyrrolidine hydrochloride W O96tl4844 PCT~US95/14812 lH NMR (D2O): 3.75 (dd, lH), 3.31 (dd, lH), 2.98 (q, lH), 2.54 (m, 2H), 1.49 (m, 2H), 0.89 (t, 3H).

5 Massspectrumm/e=113(M+1) CH3--~ NH HCI

2-Imino-4.5-dimethylpyrrolidine hydrochloride lH NMR (D20, since stereoisomers were present multiple peaks were 15 observed and ppm ranges are given): 4.05 & 3.69 (2 m, lH), 2.99 & 2.94 (2 dd, 1 H), 2.66 & 2.17 (2m, lH), 2.54 & 2.51 (2t, lH), 1.25, 1.13, 1.1 &
0.99 (4d, 6H).

Mass spectrum m/e = 113 (M+l) 1~ NH HCI

2-Imino-4-methyl-5-propylpyrrolidine hydrochloride lH NMR (D2O, since stereoisomers were present mul~ple peaks were observed and ppm ranges are given): 3.69 & 3.30 (2 q, lH), l.9S- 2.6 (m, 30 3 H), 1.2-1.6 ( m, 4H), 1.08 & 0.96 (2 d, 3H), 0.90 (t, 3H).

Mass spectrum m/e = 142 (M+1) -CH3~)e NH HCI

2-Imino-5-me~yl-4-propvlpyrrolidine hvdrochloride Mass spectrum m/e = 141 (M+1) ' 15 C~NH HCI

2-Imino-5-ethyl-4-~r~vlpyrrolidine hydrochloride 20 Mass spectrum m/e = 155 (M+l) C2H5~e NH HCI

2-Imino-S-e~yl-3-methylpyrroli~line hydrochloride -WO 96/14844 PCr/US95114812 Mass spectrum m/e = 127 (M+l) s CH3~

2-Imino-5~5-dimethylpyrrolidine hydrochloride lH NMR (D2O): 2.91 (t, 2H), 2.04 (t, 2H), 1.33 (s, 6H).
Mass spectrum m/e = 113 (M+l) CH~

2-Imino-3.5~5-~ime~ylpyrrolidine hydrochloride Mass spectrum m/e = 127 (M+l~

CH3~ NH HCI

2-Imino~-ethyl-S-methylpyrrolidine hydrochloride .
lH NMR (D20, since stereoisomers were present multiple peaks were observed and ppm ranges are given): 4.08 & 3.71 (2 m, lH), 3.1-2.4 (m, 3 H), 1.6-1.2 (m, 2H), 1.26 & 1.11 (2 d, 3H), 0.90 (t, 3H).

S Mass spectrum m/e = 127 (M+l) ~N ~ NH HCI

2-Imino-4-propylpyrrolidine hydrochloride lH NMR (D2O): 3.74 (dd, lH), 3.30 (dd, 1 H), 2.97 (dd, lH), 2.6 (m, 15 2H), 1.45 (q,2H), 1.31 (m, 2H), 0.88 (t, 3H).

Mass spectrum m/e - 127 (M+l) N NH HCI

2-Imino4-(2-methyl-ethvl)pyrrolidine hvdrochloride lH NMR (D20): 3.72 (t, lH), 3.37 (dd, 1 H), 2.91 (dd, lH), 2.63 (dd, lH), 2.39 (m, lH), 1.66 (m, lH), 0.88 (2d, 6H).

Mass spectrum m/e = 127 (M+l) . CA 02203681 1997-04-24 W O96/14844 PCTnUS95114812 W, ~;~NH HCI

2-Imino-4-phenylpvrrolidine hydrochlonde lH NMR (D20): 7.4 (m, 2H), 7.32 (m, 3H), 4.02 (dd, lH), 3.82 (m, lH), 10 3.62 (m, lH), 3.25 (dd, lH), 2.97 (dd, lH).

Mass spectrum m/e = 161 (M+l) EXAl\IPLE 74 ~)eNH HCI

2-Imino-3.4-dimethyl~ylrulidine hvdrochloride lH NMR (D20, since stereoisomers were pr~sellt mllltiple peaks were observed): 3.74 & 3.68 (2 dd, lH), 3.25 & 3.19 (2 dd, 1 H), 3.12 & 2.23 (2m,1H),2.68(m,1H),1.27&1.17(2d,3H,),1.12&1.0(2d,3H).

25 Mass specwm m/e = 113 (M+l) -W O96/14844 PCTrUS95/14812 C2H5~_~CH3 <~b NH HCI

2-Imino-4-ethyl-3-methylpvrrolidine hydrochloride S lH NMR (D20, since stereoisomers were present multiple peaks were observed and ppm ranges are given): 3.77 & 3.67 (2 t, lH), 3.32 & 3.26 (2t, 1 H), 1.6-3.1(m, 2H), 1.51 & 1.40 (2m, 2H), 1.29 & 1.17 (2 d, 3H, ), O.gO (m, 3H).

10 Mass spectrum m/e = 127 (M+l) ~NH HCI

2-Imino-5-methyl-4-propylpyrrolidine hydrochloride lH NMR (D20, since stereoisomers were present multiple peaks were 20 observed and ppm ranges are given): 3.82 & 3.50 (2 q, lH), 2.45- 3.1 (m, 2 H), 2.31 & 1.64 (2 m, lH), 1.45-1.6 (m, 2H), 1.11 & 1.0 (2 d, 3H, J=7 Hz), 0.92 (t, 3H, J=7 Hz).

Mass spectrum m/e = 127 (M+l) ;

~NH HCI

2-Imino-3-azabicyclo(4.3.0)nonane hvdrochloride S lH NMR (D2O)- 3.56 (dd, lH), 3.32 (dd, 1 H), 3.02 (q, lH), 2.56 (q, lH), 1.2-2.0 (m, 8H).

Mass spectrum m/e = 139 (M+l) ~NH HCI

15 2-Imino-3-azabicyclo(3.3.0)octane hydrochloride lH NMR (D20): 3.82 (dd, lH), 3.48 (dt, 1 H), 3.32 (dd, lH), 2.98 (m, lH), 1.4-2.1(m, 6H).

20 Mass spe~;l,.lm m/e = 125 (M+l) The compounds of examples 79 and 80 were synthesized from the commercially available pyrrolidone interrne~i~tes by the proce~ re olltline~ in step C and D in example 60.

PCI~/US95/14812 ~NH HCI

2-Imino-3-methylpvrrolidine hvdrochloride 5 lH NMR (D20): 9.48 (s, lH), 9.1 (s, lH), 8.82 (s, lH), 3.6 (m, lH), 3.28 (m, lH), 2.37 (m, lH), 1.78 (m, lH), 1.40 (d, 3H).

CH3~;~NH HCI

2-Imino-5-methyl~ylrulidine hydrochloride 15 lH NMR (D20): 9.49 (s, lH), 9.18 (s, lH), 8.79 (s, lH), 4.05 (m, lH), 3.02 (m, lH), 2.92 (m, lH), 2.33 (m, lH), 1.73 (m, lH), 1.32 (d, 3H).

CH3 ~, O~ .~ NH HCI

2-Imino-5-(S)-acetyloxymethylpyrrolidine hydrochloride t 25 The cûmmercially available (S) 5-(hydroxymethyl)-2-pyrrolidone was acylated with acetic anhydride and the product was subjected to the procedure of Example 60, steps C and D to isolate the title compound.

W O96/14844 PCTnUS95114812 H NMR (D20): 4.28 (m, 2H), 4.07 (m, 1 H), 2.92 (m, 2H), 2.37 (m, lH),2.11 (s,3H),2.0(m, lH).

CH3~0_~NH HCI

2-Imino-5-(R)-ace~tyloxymethvlpvrrolidine hydrochloride The title compound was prepared by the procedure of example 81 t~rtin~from (R) 5-(hydroxymethyl)-2-pyrrolidone.

lH NMR (D2O): 4.3(m, 2H), 4.09 (q, 1 H), 2.92 (m, 2H), 2.39 (m, lH), 15 2.10(s,3H),2.0(m, lH).

Mass spectrum m/e = 157 (M+l) HO~.-"`~;~NH HCI

2-Imino-5-(S)-hydroxymethylpyrrolidine hydrochloride A solution of 15 mg (0.078 mmol) of 2-im~no-5-(S)- ~' acetyloxymethyl~y~ line hydrochloride yl~aled in ex~mple 81 in 3 mL of m~th~nol was sa~ te~l with NH3 and the solution was stirred for 3 h. The reaction mix~lre was concentrated and the residual solid was suspended in Et20-EtOAc, filtered and washed with Et20 and dried to isolate 6 mg of the ti~le compound.

WO 96/14844 PCI~/US95114812 lH NMR (D2O): 4.10 (m, lH), 3.70 (m, 1 H), 3.57 (m, lH), 2.87 (m, 2H), 2.29 (m,lH), 1.97 (m, lH).

S Mass spec~um m/e = 115 (M~1) HO_(~NH HCI
H
2-Imino-S-(R)-hydroxymethylpyrrolidine hydrochloride The title compound was obtained from 2-imino-5-(R)-lS acetyloxymethylpyrrolidine hydrochloride (example ) by the method described in example 83.

lH NMR (D20): 4.12 (m, lH), 3.72 (dd, 1 H), 3.57 (dd, lH), 2.88 (m, 2H), 2.3 (m, lH), 1.96 (m, lH).
Mass spectrum m/e = 115 (M+l) C2H5 ~
r ~ NH'bNH HOAc S-Ethyl-2-imino-4-methyl-piperidine~ acetic acid salt 30 Step A: S-Nitro-4-methyl-2-trimethvlacetylaminopyridine W O 96/14844 ~CT~US95/14812 To a mixture of 5-nitro-4-methyl-2-aminopyridine (1.0 g, 6.53 mmol) in 15 mL of methylene chloride was added triethyl~mine (1.14 mL, 8.16 mmol) and cooled to 0 C. To this was added dro~wise a 5 solution of trimethylacetyl chloride (0.89 mL, 7.18 mmol) and the mixture allowed to warm to room temperature and stirred 72 h. The solution was diluted with 100 mL of methylene chloride, washed with saturated sodium bicarbonate, water, brine, dried (Na2SO4), and evaporated to an amber oil. This was subjected to flash silica gel 10 chromatography using 10% ethyl acetate/hexane as eluant to yield the title compound.

lH NMR (400 MHz, CDC13): ~ 1.34 (s,9H); 2.65 (s,3H); 8.18 (b,lH);
8.29 (s,lH); 8.94 (s,lH) Step B: S-Amino-4-methyl-2-trimethylacetylaminopyridine A solution of 5-r~itro4-methyl-2-trimethylacetylaminopyridine (4.5 g, 18.97 mmol) in 50 mL of acetic 20 acid co~ g 10% ~ m/carbon was hydrogenated at atmospheric pressure for 48 h. The catalyst was removed by filtration and the filtrate was concentrated. The residue was coevaporated with toluene to give the tide compound.

lH NMR (400MHz, CDC13): ~ 1.29 (s,9~I); 2.19 (s,3H); 7.60 (s,1H);
8.04 (s,lH); 8.50 (b,lH) Step C: S-Iodo-4-methyl-2-trimethylacetylaminopyridine A ~ lule of 5-an~ino-4-methyl-2-trimethylacetyl~minopyridine (1.0 g, 4.82 mmol) in 34 mL of diiodomPth~ne co"l~;l,;"g isoamyl nitrite (4.0 mL, 29.77 mmol) was h~o~tçd at 85 C for 0.5 h, cooled to room temper~lult; and evaporated at 60 C under high v~cll~lm to give a red semi-solid. The crude m~tçri~l W O96/14844 PCTrUS95/14812 was subjected to flash chromatography using 10% ether / hexane as eluant to give the title compound.
;

lH NMR (400 MHz, CDC13): o 1.30 (s,9H); 2.40 (s,3H); 7.90 (b,lH);
5 8.22 (s,lH); 8.45 (s,lH) Step D: 5-Ethvnyl-4-methvl-2-trimethylacetylaminopyridine To a mixture of 5-iodo-4-methyl-2-10 trimethylacetylaminopyridine (176 mg, 0.55 mmol) in tetrahydrofuran (0.60 ml), triethyamine (3.32 ml), bis(triphenylphosphine)p~ m(II)chloride (4 mg), copper a) iodide (1.1 mg) and (trimethylsilyl)acetylene (117 ul, 0.83 mmol) were ~ld~l The mi~lure was stirred at room temperature for 3 h. The mixture was 15 diluted with chloroform (50 mL), dried (Na2SO4), and evaporated to give a tan solid. The crude solid was dissolved in methanol (S mL), treated with lN pot~sillm hydroxide (0.61 mL) and stirred at room temper~lu~e 18 h. The mixture was evaporated to dryness, taken up in chloroform (S0 mL), dried (Na2SO4), and evaporated to give a solid. The 20 product was purified by flash chromatography using 10% ethyl ~-~et~te /
hexane to yield the title compound.

lH NMR (400MHz, CD3OD): ~ 1.30 (s,9H); 2.45 (s,3H); 3.85 (s,lH);
8.02 (s,lH); 8.30 (s,lH) Mass spectrum m/e = 217 (M+1).

Step E: 5-Ethyl-4-methyl-2-trimethylacetylaminopvridine A solution of S-ethynyl-4-methyl-2-trimethylacetylaminopyridine (115 mg, 0.53 mmol) in ethyl ~cet~te (2 mL) co--t~;"i"g 10% p~ rlillm / carbon (20 mg) was hydrogenated atatmospheric pressure for 15 minlltes. The catalyst was removed by filtration through a ~llex-HV 0.45 um Filter Unit and the filtrate was WO 96~14844 PCI~/US95/14812 concentrated. P~lrif;c~tion was achieved by flash chromatography using 10% ethyl ~eet~te / hexane to give ~e title compound.

lH NMR (400MHz, C D 3 0 D ): o 1.20 (t,3 H); 1.3 0 (s,9 H); 2.34 (s,3 H);
2.65 (q,2 H); 7.84 (s,lH); 8.02 (s,lH) Mass spectrum: m/e = 221 (M+l).

Step F: 5-Ethyl-4-methyl-2-aminopyridine A solution of 5-ethyl-4-methyl-2-trimethylacetylaminopyridine (192 mg, 0.87 mmol) in 2N hydrochloric acid (3 mL) was refluxed at 100 for 18 h. The mixture was diluted with water (10 mL) and washed with ether. The aqueous layer was made basic 15 with 10% sodium carbonate and extracted with ethyl acetate. The EtOAc layer was dried (Na2SO4) and evaporated to give the title compound.

lH NMR (400 MHz, CD30D): â 1.14 (t,3H); 2.20 (s,3H); 2.50 (q,2H);
6.42 (s,lH); 7.60 (s,3H) Mass spectrum: m/e = 136 (M+).

Step G: S-Ethyl-2-imino-4-methvl-piperidine. acetic acid salt A solution of 5-ethyl-4-methyl-2-aminopyridine (42 mg, 0.31mmol) in acetic acid (1 mL) co-.l~;-.i-~g pl~tinllm oxide (25 mg) was hydrogenated at 40 psi for 6 h. The catalyst was removed by fil~ation through a Millex-HV 0.45um Filter Unit and the filtrate was evaporated to give the title compound.
lH NMR (400MHz, CD30D): ~ 0.97 (m,6H); 1.35-3.50 (m,SH); 2.63-3.50 (m,3H) Mass spectrum m/e = 141 (M+l).

W O96/14844 PCTrUS95tl4812 ~.

~ N~NH HOAc S H

2-Imino-4-methyl-5-(1-pentyl)-piperidine. acetic acid salt Step A: 5-(1-Pentynyl)-4-methyl-2-trimethylacetylaminopyridine The above compound was prepared in a simil~r fashion as Fx~mple 85, Step D, but subslilulh~g l-pentyne in place of (trimethylsilyl)acetylene to yield the title compound.

lH NMR (400 MHz, CD30D): ~ 1.08 (t,3H); 1.30 (s,9H); 1.65 (q,2H);
2.40 (s,3H); 2.45 (t,2H); 7.98 (s,lH); 8.20 (s,lH) Step B: 5-(1-Pentyl)-4-methyl-2-trimethylacetylaminopyridine A solution of 5-(1-pentynyl)-4-methyl-2-trimethylacetylaminopyridine (225 mg, 0.87 mmol) in ethyl ~ret~te (4.5 ml) cont~ining pl~tinnm oxide (45 mg) was hydrogenated at atmospheric pressure for l.S h. The catalyst was removed by filtration through a Millex-HV 0.45um Filter Unit. Evaporation of the filtrate gave the title compound.

lH NMR (400 MHz, CD30D): o 0.95 (t,3H); 1.33(s,9H); 1.40 (m,4H);
1.60 (m,2H); 2.35 (s,3H); 2.63 (m,2H); 7.84 (s,lH); 8.00 (s,lH) Mass spectrum m/e = 263 (M+l).

Step C: S-(l-Pentyl)-4-methyl-2-aminopyridine A suspension of 5-(1-pentyl)-4-methyl-2-trimethylacetylamino-pyridine (233 mg, 0.89 mmol) in 2N
hydrochloric acid (3 mL) was h~t~-~l at 100 C for 18 h. The solution was 5 cooled to room ~~ r~lure, made basic with 20% aqueous sodium carbonate and extracted with chloroform. The organic layer was dried (Na2S04), and evaporated. The product was purified by flash chromatography using 2% methanol / methylene chloride to give the title compound.
lH NMR (400MHz, CD30D): o 0.90 (t,3H); 1.35 (s,4H); 1.50 (m,2H);
2.20 (s,3H); 2.45 (m,2H); 6.40 (s,lH); 7.58 (s,lH) Mass spectrum m/e = 179 (M+l).
Step D: 2-Imino-4-methyl-5-(1-pentyl)-piperidine. acetic acid salt The above compound was prepared in a .~imil~r fashion as Fx~mple85,StepG, butsub~ S-(l-pentyl)-4-methyl-2-20 aminopyridine in place of 5-ethyl-4-methyl-2-aminopyridine to yield the tide com~o~ d.

lH NMR (400MHz, CD30D): o 0.93 (m,6H); 1.50-1.76 (m,4H); 2.10-2.43 (m,4H); 2.65-2.80 (m,2H); 2.95-3.15 (m,2H); 3.35-3.50 (m,2H) 25 Mass spectrum: m/e- 183 (M+1).

EXAMPLE ~7 I

HN NH HCI
4(R)-Me~vl-2-iminopiperidine hydrochloride W O96tl4844 PCTnUS95/14812 Step A: Methyl (R)-citronellate Diazomethane in ether was cautiously added to a solution of 5 (R)-citronellic acid (17.2 g, 0.1 M) in ether at 0 C until yellow color persisted. After the addition was complete, the reaction mixture was stirred 30 mins and the solvent was removed in vacuo to give the qll~.,tit~tive yield of the desired methyl ester as a colorless oil.

10 1H NMR (CDCl3): 0.92(d,3H); 1.2(m,1H); 1.32(m,1H); 1.58(s,3H);
1.65(s,3H); l.95(m,2H); 2.1(q,1H); 2.4(q,1H~; 3.64(s,3H); 5.06(t,1H) Step B: Methvl 3(R)-methyl-5-hydroxycarbonylpentanoate A stream of 4% ozone in oxygen was p~se~l through a solution of methyl (R)-citronellate (7 g, 39 mmol) in 140 mL of glacial acetic acid at room tempe.~ c; for 45 mins. 14 mL of 30% hydrogen peroxide was then added and the reaction mixture was h~tto.-l to reflux 2 hrs. Solvent was removed in vacuo to afford 6.5 g of the desired acid as a 20 colorless oil.

lH NMR (CDCl3): 0.94(d,3H); 1.52(m,1H); 1.69(m,1H); 1.98(m,1H);
2.15(q,1H); 2.3(q,1H); 2.36(m,2H) 25 Step C: Methyl 3(R)-methyl-5-benzyloxvcarbonylamino pentanoate Diphenyl phosphoryl azide (5.3 mL, 24.53 mmol) was added to a mixtllre of methyl 3(R)-methyl-5-hydroxycarbonyl pentanoate (3.88 g, 22.3 mmol) and triethyl~min~ (3.45 mL, 24.53 mmol) in 22 mL of p-30 xylene. The mixture was then stirred 1 hr at 80 C. 4.5 mL (45 mmol) ofbenzyl alcohol was then added and the mixture was he~te-l at reflux for 4 hr. The reaction miture was cooled, diluted with ethyl acetate and washed with water, and sodium chloride and dried over ahydrous m~gnt~sium sulfate. Solvent removal gave a crude product, which was CA 0220368l l997-04-24 W O96tl4844 PCTnUS95/14812 purified on silica gel using 10% ethyl ~cet~tç in hexane as solvent to afford 3.9 g of the desired carbamate as an oil.

lH NMR (CDC13): 0.95(d,3H); 1.4(m,1H); 1.62(m,1H); 2.02(m,1H);
5 2.18(q,1H); 2.3(q,1H); 3.22(m,2H); 3.65(s,3H); 5.07(s,2H); 7.3(m,5H) Step D: 3(R)-Methyl-5-benzyloxycarbonylamino pentanoic acid A 2N sodium hydroxide (7.5 ml, 15 mmol) solution was 10 added to 3.9 g (14 mmol) of methyl 3R-methyl-5-benzyloxycarbonylamino pent~no~te in 70 mL of 2: 1 mixhlre of methanol:water. This n~ ul~e was then h~te-l 1 hr at 60 C and 7.5 mL
of 2N hydrochloric acid was added after cooling. Most of the volatiles were removed in vacuo. The rem~inin~ mixtme was extracted with ethyl 15 acetate. The combined ethyl acetate extracts were dried over anhydrous m~n~sinm sulfate. Solvent removal afforded 2.9 g of the desired acid as an oil.

lH NMR (CDC13): 0.98 (d,3H); 1.42(m,1H); 1.56(m,1H); 2.02(m,1H);
20 2.2(m,1H); 2.35(m,1H); 3.2(m,2H); 5.08(s,2H); 7.3(m,5H) StepE: 4(R)-Methyl-l-benzyloxycarbonyl-2-piperidone Ethyl chloroformate (1.92 mL, 20 mmol) was added 25 dr~ vise to a solution of 3(R)-methyl-5-benzyloxycarbonylarmino pentanoic acid (2.65 g, 10 mmol) and triethyl amine (2.8 mL, 20 mmol) in 50 mL of ethyl ~cet~te at 0 C. After stinin~ 1 hr at room temp~ e, the solids formed were filtered and washed with ethyl ~cet~te. The filtrate was concentr~te-l to give an oil which was taken up in 45 mL of 30 toluene. This solution was h~tetl to reflux for 4 hr. Solvent was then removed in vacuo and the nsidue was purified on silica gel using 20%
e~yl ~cet~t~ in hex~n~ as solvent to give 1.39 g of the desired l~ct~m as an oil.

WO 96/14844 PCI`/US95/14812 lH NMR (CDC13): 1.02(d,3H); 1.44(m,1H); 2.0(m,3H); 3.62(q,1H);
3.55(q,1H); 3.88(q,1H); 5.28(2H); 7.35(m,5H) Step F: 4(R)-Methyl-2-piperidone s 10% Palladium hydroxide on carbon (350 mg) was added to a solution of 4(R)-Methyl-l-benzyloxycarbonyl-2-piperidone (1.3 g) in 20 mL of m~.th~nol and the mix~lre was hydrogenated on Parr shaker at 50 psi and room te~ dlul~. After 4 hrs, the catalyst was filtered and 10 washed with methanol. The filtrate was concentrated to give 700 mg of the crude product which was purified on silica gel using 5% methanol in ethyl acetate as solvent to give 510 mg of the desired lactam as a white solid.

15 lH NMR (DMSO): 0.92 (d,3H); 1.26 (m,lH); 1.75(m,3H); 2.18(q,1H);
3.12 (m,2H) Step G: 4(R)-Methyl-2-imino piperidine hydrochloride The title compound was yL~aled from 4R-methyl-2-piperidone as described in Fx~mples 2 and 3.

lH NMR (DMSO): 0.96(d,3H); 1.25(m,1H); 1.75(m,1H); 1.85(m,1H);
2.15(q,1H); 2.55(q,1H0; 3.24(m,1H); 3.34(m,1H); 8.28(b,1H);
8.62(b,1H); 9.35(b,1H) ~NH HCI
H

4(S)-Methyl-2-imino~i~t;Lidine hydrochloride -W O 96/14844 PCTrUS95/14812 The title compound was synthesized according to the procedure of F.x~mple 87 starting with (S)-citronellic acid.
, ~

CH3 ",~
~ N~NH HCI

10 S(R)-Methyl-2-iminopiperidine hydrochloride Step A: 2(R).6-Dimethyl-l-benzylo~ycalbonylamino-S-heptene Diphenylphosphoryl azide (14 mL, 65 mmol) was added 15 dr~ise to a solution of (R)-citronellic acid ~lOg, S9 mmol) and triethyl~mine (9.1 mL, 65mmol) in 60 mL of toluene. The mixture was h~te~l for 1 hr at 80 C. 12 mL (120 mmol) of benzyl alcohol was added and the .~ t; was he~te-l to reflux for 4 hrs. The reaction mixture was cooled, diluted with ethyl ~cet~te and washed with water, saluldted 20 sodium chloride solution. After drying over anhydrous m~gn~si~lm snlf~te, the solvent was removed in vacuo to give a crude product which was purified on silica gel using 5% ethyl ~cet~te in he~ne as solvent to afford 9.8 g of ~e desired carbamate as a thick oil.

25 lH NMR (CDC13): 0.89(d,3H); 1.13(m,1H); 1.35(m?1H); 1.5(m,1H);
1.6(m,1H); 1.58(s,3H); 1.66(s,3H); 1.98(m,1H); 3.0(m,1H); 3.14(m,1H);
5.06(m,1H); 5.08(s,2H); 7.35(m,5H) Step B: 5(R)-Methyl-l-benzylo~yc~hl,onyl-2-piperidone Ozone in oxygen (4%) was passed through a solution of 2-(R),6-dimethyl-1-benzyloxycarbonyl~mino-5-heptene (9.8 g) in 150 mL
of methylene chloride at -78 C until the blue color persicte~l Nitrogen CA 0220368l l997-04-24 W O96/14844 PCTrUS95/14812 was then bubbled for 15 mins. 16 mL of dimethyl sulfide was added and the mix~lre was stirred 1 hr as it warmed to room temperature and then conce~ aled to give a re~ l oil. This was taken up in 100 mL of acetone and cooled in ice bath. Jones reagent was added dro~wise until S orange color was sust~in~d. After stirrin~ 30 mis, 4 mL of isoprpopyl alcohol was added and the mixture was stirred for an additional 15 mins.
Solvent was then removed in vacuo and the residue was stirred with water and ethyl ~cet~te. The organic phase was separated and the aqueous phase was extracted with ethyl acetate. The combined ethyl 10 ~cet~te extracts were dried over anhydrous m~gnesium sulfate and the solvent was removed in vacuo. The resulting residue was purified on silica gel using first 10% ethyl ~cet~t~ in hexane as solvent to give 2.0 g of 5(R.)-methyl-l-benzyloxycarbonyl-2-piperidone as an oil.

15 lH NMR (CDC13): 1.02(d,3H); 1.45(m,1H); 1.87(m,1H); 1.94(m,1H);
2.54(m,2H); 3.16(q,1H); 3.88(q,1H); 5.26(s,2Hj; 7.36(m,5H) Further elution of the column with 1 % methanol in ethyl ~cet~te gave 5.8 g of 3(R)-methyl-N-(benzyloxycarbonyl)-N-formyl-4-20 aminobutanoic acid as a thick oil, which can be utilized in the synthesis of 4-(R)-2-imino-4-methylpyrrolidne.

Step C: 5(R)-Methyl-2-piperidone 10% p~ m hydroxide on carbon (700 mg) was added to a solution of 4(R)-methyl- l-benzyloxycarbonyl-2-piperidone (2.0 g) in 40 mL of methanol and the mixtllre was hydrogenated on Parr shaker at 50 psi and room tempe,~Lure. After 4 hrs, the catalyst was filtered and washed with mto.th~nol. The filtrate was concentrated to give 1.4 g of the crude product, which was purified on silica gel using 5% methanol in ethyl ~et~te as solvent to give 1 g of the desired l~ct~m as a white solid.

lH NMR (CDC13): l.O(d,3H); 1.45(m,1H); 2.86(m,2H); 2.38(m,2H);
2.9(q,1H); 3.3(q,1H)6.6(b,1H) WO 96/14&14 PCTJUS95/14812 Step D: 5(R)-Methyl-2-iminopiperidine hvdrochloride The title compound was synthesized from 5(R)-methyl-2-5 piperidone according to the procedure described in Examples 2 and 3.

lH NMR (DMSO): 0.93(d,3H); 1.34(m,1H); 1.76(m,2H); 2.54(q,2H);
2.8(q,1H); 3.32(m,1H); 8.35(b,1H); 8.68(b,1H); 9.42(b,1H).

CH3 ~
H NH HCI

15 5(S)-Methyl-2-iminopiperidine hydrochloride The title compound was prepared by the me~od of example 89 starting with (S)-citronellic acid.

CH3 ".~
~ H~NH HCI

4(S)~S(R)-Dimethyl-2-imino-piperidine hydrochloride: .

Step A:(S)-Citronelloyl chloride Oxalyl chloride (8.1 mL, 92 mmol) of was added to 14.4 g 30 (83.7~ mmol) of (S)-Citronellic acid in 150 mL of methylene chloride at O C. 12.9 mL (92 mmol) of triethyl~mine was then added drol~wise cautiously so that the gases evolved can be vented effectively. After the addition was complete, the mixture was stirred 1 hour at the same tempe,~lur~. After dilution with 300 mL of ether, the solids precipitated S were filtered and washed with ether. The filtrate was concentrated to give a brown liquid. This was dissolved in ether and the small amount of solid was filtered and washed with ether. The filtrate was concentrated in vacuo to give almost q~ ive yield of the desired acid chloride as brown oil.
1H NMR (CDCl3): l.O(d, 3H); 1.58(s,3H); 1.68(s,3H); 2.66 & 2.88(2q;
2H); 5.05(t,1H) Step B: 3(3(S)~7-Dimethvl-6-octenoyl)-4(R)-phenylmethyl-2-15 oxazolidinone A 1.6M solution of n-butylli~iulll (52 mL, 83 rnmol) was added dropwise to a solution of 4R-phenylmethyl-2-oxazolidinone (13.3g, 75 mmol) in 150 rnL of THF at -78 C. The reaction mixhlre was 20 stirred for 15 min after the addition and a solution of the above S-citronelloyl chloride in 50 mL of THF was added dr~wise and the l~;x~ e was stirred for 15 min at that temp~;lalule. The cooling bath was removed and the ~ixl~l~e was allowed to warm to room tempoe~ e and stirred 1 hr at room temperalule. After quenching with salulated 25 ~mmonil~m chloride solution, the reaction mixture was partitioned between lN hydrochloric acid and ethyl ~cet~te. The ethyl ~cet~te extracts were washed with salul~led sodium chloride solution and dried over anhydrous m~gn~sillm sulfate. Solvent removal gave an oil which was chromatographed on silica gel using 10% ethyl ~cet~te in hexane as 30 solvent to give the title compound in 65% yield.

lH NMR (CDCl3): l.O(d,3H); 1.6(s,3H); 1.66(s,3H); 2.74(q,1H);
2.85(m;2H); 3.3(q,1H); 4.15(m,2H); 4.66(m,1H); 5.08(t,1H); 7.28(m,5H) W O96/14844 PCTrUS95/14812 Step C: 3(2(R)3(S).7-Trimethyl-6-octenoyl)-4(R)-phenylmethyl-2-oxazolidinone 55 mL (55 mmol) of lM solution of sodium S bis(trimethylsilyl)~mi-le in THF was added dropwise to a solution of 15 g (45.4 mmol) of 3(3(S),7-dimethyl-6-octenoyl)-4(R)-phenylmethyl-2-oxazolidinone in 120 mL of THF at -78 C. The reaction mixture was stirred 30 mins at that temper~lule and 21 mL (333 mmol) of methyl iodide in 20 mL of THF was added dr~wise. The res-llting mixture was 10 stirred 1 day at -78 C. After w~ "~i"~ to room temperature, the reacton mixture was quenched with ammonium chloride solution and partitioned between lN hydrochloric acid and ethyl ~et~t~. The ethyl ~cet~te extracts were washed with sodium thiosulfate solution, saturated sodium bicarbonate solution, brine and dried over anhydrous magnesium sulfate.
15 Solvent removal afforded essentailly pure desired methylated oxazolidinone derivative in q~l~"lil~t;ve yield.

lH NMR (CDCl3): 0.88(d, 2H); 1.13(d,3H); 1.58(s,3H); 1.66(s,3H);
2.75(q,1H); 3.26(q,1H); 3.68(m,1H); 4.15(m,2H); 4.63(m,1H);
20 5.08(t,1H)7.25(m,5H) StepD: 2(R)3(S)~7-Trimethyl-6-octen-1-ol A solution of 6.8 g (20 mmol) of 3(2(R)~3(s)~7-trimethyl-6 25 octenoyl)-4(R)-phenylmethyl-2-ox~7olirliT~one in 30 mL of THF was added dr~wise to a suspension of 1.634 g (43 mmol) of lilh;~
~l,.",i"l"" hydride in 40 mL of THF at 0 C. The reaction mixture was then stirred 6 h at ambient te~ el~Lule The reaction mixture was then recooled in ice bath and 5 mL of m~th~nol was added dr~wise very 30 cautiously. After the effervescence subsided, the reaction mixture was conc~~ ted to about 30% of the origin~l volume The reaction mixture was then stirred with salul~ted solution of pot~e~eillm sodium la,L ate and extracted with ethyl acetate. The combined ethyl ~et~te extracts were dried over anhydrous m~gne~eillm slllf~te Solvent removal afforded a crude oil, which was purified on silica gel using 10% ethyl acetate in hex~nP. as solvent to give 2.0 g (62%) of the desired alcohol as a colorless oil.

lH NMR (CDC13): 0.78(d, 2H); 0.79(d,2H);1.6(s,3H); 1.66(s,3H);
3.44(q,1H); 3.54(q,1H); 5.1(t,1H) Step E: 2(R).3(S)~7-Trimethvl-6-octen-1-methanesulfonate To a solution of 510 mg (3 mmol) of 2(R),3(S),7-trimethyl-6-octen-1-ol in 3 mL of pyndine at ice bath tempe~ e 0.7 mL (9 mmol) of methanesulfonyl chloride was dropwise added. The mixtllre was then stirred for 8 hrs at room tempelatule. After diluting with ethyl ~cet~te, the reaction mixture was washed with saturated sodium bicarbonate, lN
citric acid and water. After drying over anhydrous m~gnesillm slllf~te, the solvent was removed to give 722 mg of the desired mesylate as a yellow oil.

lH NMR (CDC13): 0.8(d,3H); 0.87(d,3H); 1.6(s,3H); 1.67(s,3H);
2.98(s,3H); 4.02(q,1H); 4.13(q,1H); 5.06(t,1H) Step F: 2(R)3(S).7-Trimethyl-l-azido-6-octene 975 mg (15 mmol~ of sodium azide was added to a solution of 2(R),3(S),7-trimethyl-6-octen-1-met~n~ sulfonate (720 mg, ~3 mmol) in 6 mL of N,N-dimethylform~mide and the mixture was h~.~ted overnight at 80 C. The reaction mixture was ~ te-l with ethyl ~cet~te and washed several times with saturated sodium chloride solution. After drying over anhydrous m~gnesjllm slllf~t~, the solvents were removed in vacuo to give crude azide as an oil. This m~teri~l was purified on silica gel using 30% ether in hexane as solvent to give 545 mg of the desired azide as a colorless oil.

W O96/14844 PCTrUS95/14812 lH NMR (CDC13): 0.78(d,3H); 0.84(d,3H), 1.59(s,3H); 1.66(s,3H);
3.1(q,1H); 3.21(q,3H); 5.07(t,1H) StepG: 2(R).3(S).7-T~imethyl-l-~nino-6-octene s 6.3 mL (6.3 mmol) of lM lithium aluminum hydride in THF
- was added dr~ise to a solution of 2(R),3(S),7-trimethyl-1-azido-6-octene in 10 mL of THF at 0 C. The reaction mixture was he~t~cl to reflux 18 hrs. After cooli~g in ice bath, - 1 mL of methanol was added 10 d~ wise cautiously. After the effervescence stopped, the reaction mixture was conce~ ted to 30% of the volume and lN solution of pot~si~tm sodium ~llate was ~ 1P-1 After stirring 15 mins, the reaction mixtllre was extracted with ethyl ~cet~tç. The combined ethyl acetate layers were dried over anhydrous m~gnesi~lm sulfate and the solvent was 15 removed to give 399 mg of the desired amine as an oil.

lH NMR (CDC13): 0.76(d,3H); 0.78(d,3H); 1.60(s,3H); 1.67(s,3H);
2.49(q.1H); 2.62(q,1H); 5.1(t,1~) 20 Step H: 2(R)3($).7-Trimethyl-l-benzyloxycarbonylamino-6-octene S~te solutions of 2(R),3(S),7-trimethyl-1-amino-6-octene (0.87 g, 5.2 mmol) in 8 mL of dioxane, and benzyl chloroforrn~te (0.86 mL, ~6 mmol) in 8 mL of dioxane were added d~ vise 25 ~iml~lt~neously to a stirred solution of 1.05 g (10.5 mmol) of pot~sium hydrogen carbonate in 20 mL of water at 0 C. After ~e additions, the ..~;x~--.e was stirred 8 hrs at room tempe~ t;. Most of the volatile solvents were removed in vacuo. The rern~ining reaction mixtllre was extracted with ethyl ~cet~te. The combined organic phases were dried 30 over anhydrous In~gnesillm snlf~te. Solvent removal gave the crude product which was pll~ d on silica gel using 10% ethyl acetate in hP~n~ as solvent to give 1.4 g of the desired carbamate as a colorless oil.

, W 096/14844 ~ /148 lH NMR (CDC13): 0.77(d,6H); 1.18(m,1H); 1.3(m,1H); 1.5(m,1H);
1.6(s,3H); 1.66(s,3H); 1.95(m,2H); 3.04(m,1H); 1.12(m,1H); 4.7(b,1H);
5.08(s & m,3H)7.34(m,5H) 5 StepI: 4(S)~5(R)-Dimethyl-6-benzyloxycarbonylamino-hexan-1-al A stream of 4% ozone in oxygen was bubbled through a solution of 1.79 g (~6 mmol) of 2(R),3(S),7-trimethyl-1-benzyloxycarbonylamino-6-octene in 25 mL of methylene chloride at 10 -78 C until blue color persisted. Nitrogen gas was bubbled through the reaction mixture at the same tempelalule for 15 min. 3 mL of dimethyl sulfide was added and the mixture was stirred 15 mins and then warmed to 0 C. The solvents and o~her volatile materi~l~ wers rem.ovsd undet!
house vacuum. Traces of solvent were then removed in vacuo to give 1.3 15 g of the desired aldehyde as a thick oil.

lH NMR (CDC13): 0.8(2d,6H); 1.48 & 1.54(m,4H); 2.42(m,2H);
3.04(m,1H); 3.14(m,1H); 5.08(s,2H); 7.34(m,5H); 9.74(s,1H) 20 Step J: 3(R)~4(S)-Dimethyl-l-benzvloxycarbonyl-2.3.4.5-tetrahydro-azepine A mixture of 1.2 g (-4.2 mmol) of 4(S),5(R)-dimethyl-6-benzyloxycarbonylamino-hexan-l-al, 1.26 mL (13.2 mmol) of acetic 25 anhydride and 120 mg (1.2 mmol) of pot~sillm ~et~te was hto~te~l at 160 C for 2 hours . Excess acetic anhydride was removed in vacuo and the residue was purified on silica gel using 20% ethyl acetate in hexane as solvent to give ~190 mg of the desired azepine derivative as an oil.

30 lH NMR (CDC13): 0.95 & 1.0 (2d,6H); 2.0(m,1H); 2.17(m,1H);
3.64(m,1H); 3.74(m,1H); 4.9(m,1H); S.l(s,2H); 6.6(m,1H); 7.35(m.1H) e Step K: 3(S).4(R)-Dimethyl-6-(benzyloxycarbonyl)foImimido-l-pentanoic acid W O96/14844 PCTrUS95/14812 ..
A stream of 4% ozone in oxygen was bubbled through a solution of 130 mg (0.5 mmol) of 3(R),4(S)-dimethyl-l-benzyloxycarbonyl-2,3,4,5-tetrahydroazepine in 5 mL of glacial acetic 5 acid at room tempel~t~e for 10 mins. 0.3 mL of 30% hydrogen peroxide was added and the mixt~lre was he~te~l to reflux 2 hrs. The solvent was removed and the traces w~ azeotroped with toluene to give 100 mg of the desired acid as a thick oil.

10 lH ~MR (CDC13): 0.76(d?3H); 0.87(d,3H); l.9(m,1H); 2.0(m,1H);
2.18(q,1H); 2.32(q,1H); 3.5(q,1H); 3.6(q,1H); 5.28(s,2H); 7.37(m,5H);
9.26(s,1H) - Step L: 3(S).4(R)-Dimethvl-6-benzyloxycarbonylamino-1-pentanoic 15 acid A solution of 2N sodium hydroxide (0.4 mL, 0.8 mmol) was added to a solution of 90 mg (0.3 mmol) of 3(S),4(R)-dimethyl-6-(benzyloxycarbonyl)form~mido-l-pentanoic acid in a mixtllre of 2 mL of 20 methanol and 1 mL of water. This mixture was heated 2 hrs at 60 C.
The reaction ..li~ .e was cooled and 0.4 mL of 2N hydrochloric acid was added. Solvents were removed and the residue was extracted with ethyl ~cet~te. The organic layer was dried over anhydrous m~nesium sulfate and ~e solvent removal afforded 62 mg of the desired acid as an oil.
lH NMR (CDC13): 0.82(d,3H); 0.88(d,3H); 1.68(m,1H); 2.08(m,1H);
2.2(m.1H); 2.35(m,1H); 3.1(m,2H); 5.1(2H); 7.3(m,SH) StepM: 4(S)~5(R)-Dimethvl-2-piperidone Ethyl chloroformate (0.048 m~, 0.5 mmol) was added to a solution of 3(S),4(R)-dim~.tllyl-6-benzyloxycarbonylarnino-1-pentanoic acid (62 mg, 0.25 mmol) and triethyl~mine (0.07 mL, 0.5 mmol) in 2 mL
of ethyl ~et~te cooled in ice bath. After stirrin~ 1 hr, the solids were filtered and washed with ethyl ~cet~t~. The filtrate was concentrated to give the carbonate as oil. 2 mL of toluene was added to this resiue and heated to reflux 5 hrs. The solvent was dlen removed in vacuo to give the N-protected ~ t~ as oil. 25 mg of p~ lium hydroxide was added to a 5 solution of the above residue in 2 mL of methanol and dle mixhlre was hydrogenated 4 hrs on a Parr shaker. The catalyst was filtered and washed with methanol. The filtrate was concentrated to give 31 mg of the desired lactam as a waxy solid.

10 lH NMR (CDC13): 0.95(d,3H); 0.97(d,3H); 1.54(m,2H); 1.98(m, lH);
2.44(m,1H); 2.9(m,1H); 3.25(m,1H).

StepN: 4(S)~5(R)-Dimethyl-2-iminopiperidinehvdrochloride The title compound was prepared from 4(S),5(R)-Dimethyl-2-piperidone according to the procedure described in examples 2 and 3.

lH NMR (DMSO): 0.89(d,3H); 0.93(d,3H); 1.50(m,2H); 2.20(m,1H);
2.55(m,1H); 2.83(m,1H); 8.3(b,1H); 8.65(b,1H); 9.40(b,1H) Specific rotation = +62.8 (c=0.21, EtOH) CH3 ~
~ N~NH HCI
H
4(R).5(S)-Dimethyl-2-imino-piperidine hvdrochloride:

The tide compound is prepared according to dle procedure f 30 of F.x~rnple 89 starting with (R)-citronellic acid and 4(S)-phenylmethyl-2-oxazolidinone.

W O96/14844 PCTrUS95114812 Specific rotation = -65.2 (c=0.21, EtOH) s CH3 ~
HN NH HCI

4(S)~5(S)-Dimethvl-2-imino-piperidine hydrochloride:

The title compound is prepared according to the procedure of Fx~mrle 91 starting with (S)-citronellic acid and 4(S)-phenylmethyl-2-oxæolidinone.

lH NMR (DMSO): 0.84(d,3H); 0.86(d,3H); 1.98(m,1H); 2.26(m,1H);
2.64(m,1H); 2.98(m,1H); 7.25(b~1H); 8.25(b,1H); 8.64(b,1H) Specific rotation = -23 (c=0.2, EtOH) CH3 ".f ~
~ N~NH HCI

4(R).5(R)-Dimethyl-2-imino-piperidine hydrochloride:
The title compound is ~r~d according to the procedure of Fx~mrle 91 starling with (R)-citronellic acid and 4(R)-phenylmethyl-2-oxæolidinone.

Specific rotation = +25 (c=0.22, EtOH) ..

S

CH30~
~H'bNH HCI

2-Imino-5(S)-methoxy-4(S)-methyl-piperidine hydrochloride.
Step A: 5-O-tert-Butyldimethylsilyl-2 3-dideoxv-D-glycero-pent-2-eno-1~4-lactone To a solution of 2,3-dideoxy-D-glycero-pent-2-eno-1,4-15 lactone (580 mg, 5.08 mmol) in dry N,N-dimethylfonn~mi~lç (DMF) (7 mT~) were added triethyl~min~ (1.06 mL, 7.60 mmol) and 4-dimethylaminopyridine (63 mg, 0.51 mmol). The reaction mi~clulc~ was cooled in an ice-bath, and tert-but~yltlim~t~ylsilyl chloride (1.02 g, 6.77 mmol) was added. The ..,ix~l..e was allowed to attain room tempelature and stirred an additional 3 hours. The mixtllre was then ~ lterl with diethyl ether, washed with water, 2N hydrochloric acid, salul~ted sodium bicarbonate solution, saturated brine solution, dried (Na2SO4), and evaporated. This procedure was repeated with 600 mg (5.26 mmol) of 2,3-dideoxy-D-glycero-pent-2-eno-1,4-lactone. The two runs were combined after workup, and the product was purified by flash chromatography ellltin~ with 15% acetone in hexane. The resulting oil cryst~lli7e-1 upon st~n~lin~; yield 1.65 g (70~o).

lH NMR (400 MHz, CDC13): ~ 0.03 (s, 3H), 0.05 (s, 3H), 0.85 (s, 9H), f 30 3.78 (dd, lH), 3.91 (dd, lH), 5.03 (m, lH), 6.14 (dd, lH), 7.48 (dd, lH).

WO 96/14844 PCT/US9~11481Z

Step B: 2.3-Dideoxv-3-C-methyl-5-O-tert-butyldimethylsilyl-D-ervthro-~ell~ollo- 1.4-lactone To a vigorously stirred suspension of copper(I) bromide-5 dimethyl sulfide complex (7.42 g, 36.1 mmol) in diethyl ether (80 mL) was added methyllithillm (51 mL of a 1.4M solution in hexane, 71.4 mmol) over 5-6 mimltes. The resulting solution was cooled to -23C
(CCl4/dry ice bath), and a solution of 5-O-tert-butyldimethylsilyl-2,3-dideoxy-D-glycero-pent-2-eno-1,4-lactone (1.65 g, 7.22 rnmol) was 10 added in one portion. The suspension was stirred at -23C for 20 minlltes and quenched by the cautious addition of sa~ ted aqueous ammonium chloride (39 mL). The mixhlre was transferred to a separatory funnel and shaken vigorously to break down excess reagent. The organic layer was washed-with saturated brine solution, dried (MgSO4), and evaporated.
15 The pro-duct was purified by flash silica gel chromatography eluting initi~lly with 5% ethyl ~eet~te in hexane and subsequently with 10%
ethyl ~cet~te in hexane; yield 1.42 g (80%).

lH NMR (400 MHz, CDC13): o 0.04 (s,3H), 0.06 (s, 3H), 0.88 (s, 9H), 20 1.16 (d, 3H), 2.11 (dd, lH), 2.52 (m, lH), 2.77 (m, lH), 3.71 (dd, lH), 3.82 (dd, lH), 4.08 (m, lH).

Step C: 2.3-Dideoxv-3-C-methyl-D-e7ythro-pentono-1~4-lactone 2,3-Dideoxy-3-C-methyl-5-O-te?~-butyl~1imethylsilyl-D-e7ythro-pentono-1,4-lactone (1.4 g, 6.13 mmol) was treated with tetra-n-butylammonium fluoride (8.7 mL of a 1.0M solution in tetrahy~ru an, 8.7 mmol) for 90 minlltes at room tempef~lure. The reaction ~ ure was evaporated, and the crude product subjected to flash silica gel chromatography eluting initi~lly with 15% acetone in hexane and subsequently with 25% acetone in hex~ne. Pure title compound was obtained as an oil; yield 710 mg (89%).

, - lH NMR (400 MHz, CDC13): ~ 1.16 (d, 3H), 2.21 (dd, lH), 2.50 (m, lH), 2.72 (dd, lH).
,.
STEP D: 5-Azido-2.3.5-trideoxy-3-C-methyl-D-erythro-pentono-1.4-5 lactone To a solution of 2,3-dideoxy-3-C-methyl-D-erythro-pentono-1,4-lactone (490 mg, 3.76 mmol) in methylene chloride (10 mL) cooled in an ice-bath were added 2,6-hlti~line (501 mL, 4.30 mmol) and 10 trifluoromethanesulfonic anhydride (682 mL, 4.05 mmol). The reaction mixtllre was stirred at 0C for 30 minnte~, diluted with methylene chloride, washed with water, 2N hydrochloric acid, saturated sodium hydrogen carbonate solution, saturated brine solution, dried (Na2SO4), and evaporated. The crude product was taken up in DMF (6 mL) and 15 treated with sodium azide (856 mg, 13.2 mmol) at room temperature for 30 Illillll~es. The mix11lre was (lilllte-l with ethyl acetate, washed with water, dried (Na2SO4), and evaporated. The pure title compound was obtained after flash chromatography el~lting with 25% ethyl acetate in hexane; yield 358 mg (61%).
lH NMR (400 MHz, CDC13): ~ 1.15 (d, 3H), 2.21 (dd, lH), 2.42 (m, lH), 2.74 (dd, lH), 3.44 (dd, lH), 3.60 (dd, lH), 4.15 (m, lH); mass spectrum: 128 (M+l - N2).

25 STEP E: 5(S)-Hydroxy-4(S)-methyl-2-piperidone A solution of 5-azido-2,3,5-trideoxy-3-C-methyl-D-erythro-pentono-1,4-lactone (358 mg, 2.31 mmol) in methanol (4 mL) was hydrogen~te.~l under a balloon atmosphere of hydrogen gas in the 30 presence of 10% p~ lm-on-charcoal (50 mg) overnight at room te~ er~Lul~. The catalyst was then removed by filtration through Celite, and the filter washed with m~.th~nol. The combined filtrate and w~hing~
were evaporated, and the resulting product cryst~lli7e~1 upon st~n~ling;
yield 128 mg (43%).

-. CA 02203681 1997-04-24 1H NMR (400 MHz, CDCl3): o 1.03 (d, 3H), 2.05 (m, lH), 2.17-2.28 (m, 2H), 3.27 (dd, lH), 3 40 (dd, lH), 3.86 (m, lH); mass spectrum: 130 (M+l).
STEP F: 2-Imino-5(S)-methoxy-4(S)-methvl-piperidine hydrochlorîde.

To a solution of S(S)-hydroxy-4(S)-methyl-2-piperidone (119 mg, 0.921 mmol) in methylene chloride (3 mL) was added 10 trimethyloxonium tetrafluoroborate (285 mg, 1.93 mmol). The reaction mixture was st~red for 24 hours at room temp~lalu-e. Thin-layer chromatography (10% MeOH/CH2C12) indicated the formation of two more mobile products: the 5-methoxy-4-methyl imino-methyl ether and the 5-hydroxy-4-methyl imino-methyl ether. The mixture was diluted 15 with ethyl ~cet~te, washed with salul~led sodium hydrogen carbonate solution, saturated brine solution, dried (MgSO4), and carefully evaporated (bath te~ l~e ~15C) to avoid loss of the volatile imino ethers. The crude product mixhlre in ethyl ~e~te was applied to a column of silica gel (p~cl~e~l as a slurry in 4% methanol/CH2C12). Rapid 20 elution with 4% m~.th~nol/CH2Cl2 afforded the 5-methoxy-4-methyl imino-methyl ether (yield ~ 16.7 mg), and subsequent elution with 10%
MeOH/CH2C12 afforded the 5-hydroxy~-methyl imino-methyl ether (yield ~13.6 mg). Evaporations of the column fractions c- ,.t~
product was pelro.llled with extreme caution to avoid loss of the volatile 25 imino ethers.
The 5-methoxy-4-methyl imino-methyl ether (~16.7 mg) was treated with ammonium chloride (4.5 mg) for 4 h in l~n..~ g EtOH
(2 mL). The reac~on mixture was evaporated, and the resulting solid dried in vacuo; yield 14.3 mg. r lH NMR (400 MHz, CDCl3): ~ 1.10 (d, 3H), 2.12 (m, lH), 2.40 (dd, lH), 2.53 (dd, lH), 3.40 (s, 3H), 3.52 (m, lH), 3.67 (dd, lH).

Mass spectrum m/e = 143 (M+l).

, H0~
~ N~NH HCI

2-Imino-5(S)-hydroxv-4(S)-methvl-piperidine hydrochloride.

10The 5-hydroxy-4-methyl-imino methyl ether from Step F of Fx~rnrle 95 (~13.6 mg) was treated with ammonium chloride (4.4 mg) in refluxing EtOH (2 mL) for 4 h . The reaction mixture was evaporated, and resulting solid dried in vacuo; yield 9.5 mg.

15 lH NMR (400 MHz, CDC13): â 1.10 (d, 3H), 2.08 (m, lH) ,2.47 (dd, lH), 2.55 (dd, lH), 3.40 (dd, lH), 3.50 (dd, lH), 3.93 (m, lH).

Mass spectrum m/e = 129 (M+l).

CH30~
~H~NH HCI

25 2-Imino-5(S)-methoxy-4(R)-methyl-piperidine hydrochloride Step A: 2.3-Dideoxy-3-C-methyl-5-O-tert-butyldimethylsilyl-D-threo-pentono-1.4-lactone The title compound was prepared according to the method descnbed by S. ~n~Ssi~n and P.J. Murray for the corTesponding 5-O-tert-butyldiphenylsilyl derivative tTetrahedron: 43, 5055-5072, 1987].

S lH NMR (400 MHz, CDCl3~: ~ 0.04 (s, 3H); 0.05 (s, 3H); 0.87 (s, 9H);
1.17 (d, 3H); 2.37 (dd, lH); 2.48 (dd, lH); 2.71 (m, lH); 3.78 (dd, lH);
3.83 (dd, lH); 4.40 (m, lH).

Step B: 2~3-Dideoxy-3-C-methyl-D-threo-pentono-1~4-lactone 2,3-Dideoxy-3-C-methyl-5-O-tert-butyldimethylsilyl-D-threo-pentono-1,4-lactone (1.8 g, 7.36 mmol) was treated with tetra-n-butylammonium ~uonde (9.8 mL of a 1.0 M solution in tetrahydrofuran, 9.8 mmol) for 90 mimltes at room temperature. The reaction rnixture was 15 evaporated, and the crude product subjected to flash chromatography eluting with 25% acetone~exane; yield 795 mg (83%) of a colorless oil.

Step C: 5-Azido-2.3.5-trideoxy-3-C-methyl-D-threo-pentono-1.4-lactone This compound was prepared in a ~imil~r m~nn~.r as Step D of Fx~mrle 95 starting with 2,3-dideoxy-3-C-methyl-D-threo-pentono-l,~
lactone (795 mg, 6.11 mmol). The title compound was obtained as an oil after flash chromatography eluting with 25% ethyl ~cet~te in hexane;
25 yield 575 mg (61%).

H NMR (400 MHz, CDCl3): o 1.09 (d, 3H); 2.31 (dd, lH); 2.66 (dd, lH); 3.50 (dd, lH); 3.57 (dd, lH); 4.54 (dd, lH).

30 Step D: 5(S)-Hydroxy-4(R)-methyl-2-piperidone A solution of 5-azido-2,3,5-trideoxy-3-C-methyl-D-threo-pentono-1,4-lactone ( 361 mg, 2.33 mmol) in e~yl ~cet~te (23 mL) was hydrogen~t~rl at 40 psi in the presence of 20% p~ m hydroxide on - carbon (42 mg) for 2 hours at room temperature. The catalyst was removed by filtration through a pad of Celite. The filtrate was evaporated, and the residue taken up in toluene (25 mL) and methanol (2 mL) and h.o.~te-l for 24 hours at 100C. The mixture was evaporated, and S the crude product recrystallized from hot ethyl ~cet~te; yield 160 mg (53%).

H NMR (400 MHz, CD30D): ~ 1.04 (d, 3H); 1.95 (m, lH); 1.99 (dd, lH); 2.53 (dd, lH); 3.08 (dd, lH); 3.41 (dd, lH); 3.60 (m, lH).
Step E: 2-Imino-5(S)-methoxv-4(R)-methyl-piperidine hydrochloride To a solution of 5(S)-hydroxy-4(R)-methyl-2-piperidone 15 (157 mg, 1.22 mmol) in methylene chloride (4 mL) was added trimethyloxonium tetrafluoroborate (376 mg, 2;54 mmol). The reaction mixtllre was stirred for 24 hours at room tempe,~lule. Thin-layer chromatography (10% methanol/CH2C12) indicated the formation of two more mobile products: the predomin~nt product being the 5-methoxy-4-20 methyl-imino-methyl ether followed by a sm~ller amount of the 5-hydroxy-4-methyl-imino-methyl ether. The mixhlre was diluted with ethyl acetate, washed with salu,ated sodium hydrogencarbonate solution, salu,~ted brine solution, dried (MgSO4), and carefully evaporated (bath te~ ul~ <15C) to avoid loss of the volatile imino ethers. The crude 25 product "ixl.~.e was subjected to flash silica gel chromatography (p~ k~.d as a slurry in 4% methanol/CH2C12). Rapid elution with 4%
methanol/CH2C12 afforded the 5-methoxy-4-methyl-imino-methyl ether.
Subsequent elution with 10% methanol/CH2C12 afforded the 5-hydroxy-4-methyl-imino-methyl ether. Evaporations of the column fractions 30 co,.t~;~,in~ product were pelroll"ed with e~ t~"e caution to avoid loss of the volatile imino ethers.
The 5-methoxy-4-methyl-imino-methyl ether was treated with ammonium chloride (32 mg, 0.60 mmol) in refluxing ethanol (4 mL) for 4 h.

The cooled reaction mi~lre was evaporated, and the resulting solid dried in vacuo; yield 61 mg.

lH NMR (400 MHz, CD30D): ~ 1.08 (dd, lH); 2.23 (m, IH); 2.32 (dd, lH);
5 2.81 (dd, lH); 3.38 (dd, lH); 3.40 (s, 3H); 3.42 (m, 1H); 3.55 (dd, lH) Mass spectrum m/e = 143 (m +1).

HO~
~H~NH HCI

2-Imino-S(S)-hydroxy-4(R)-methyl-piperidine. hydrochloride The S-hydroxy~-methyl-imino-methyl ether from Step E of Example 97 was treated with ammonium chloride (16 mg, 0.30 mmol) in r~ g ethanol (3 mL) for 4 hours. The cooled reaction mixture was evaporated. The solid was talcen up in m~.th~nol, and the product cryst~lli7.e-120 out upon addition of die~yl ether; yield 22 mg.

lH NMR (400 MHz, CD30D): ~ 1.08 (d, 3H); 2.01 (m, lH); 2.33 (dd, lH);
2.85 (dd, lH); 3.19 (dd, lH); 3.54 (dd, lH); 3.71 (m, lH).

25 Mass spectrum m/e = 128 (M +1).

WO 96/1484kl PCI/US95114812 .

CH3 ~r~ ~
N NH HCI

2-Imino-5(S)-acetyloxy-4(R)-methyl-piperidine hydrochloride 5 Step A: 5(S)-Acetyloxv-4(R)-methyl-2-piperidone 5(S)-Hydroxy4(R)-methyl-2-piperidone (43 mg, 0.33 mmol) was treated with pyridine (0.5 mL) and acetic anhydride (0.3 mL) overni~ht at room tempelaluie. The mixture was evaporated and 10 coevaporated several times with toluene. Flash silica gel chromatography eluting with 2% m~th~nollcH2cl2 gave pure title compound; yield 17.7 mg.

lH NMR (400 MHz, CD30D): o 1.04 (d, 3H); 2.08 (s, 3H); 2.09 (dd, 15 lH); 2.21 (m, lH); 2.58 (dd, lH); 3.22 (dd, lH); 3.56 (dd, lH); 4.83 (m, lH).

Step B: 2-Imino-5(S)-acetvloxy-4(R)-methyl-piperidine hydrochloride -20 To a solution of 5(S)-acetyloxy-4(R)-methyl-2-piperidone (17.7 mg, 0.103 mmol) in methylene chloride (1.5 mL) was added ~im~thyloxonium tell~auoroborate (16.8 mg, 0.113 mmol). The reaction ~u~ e was stirred for 18 hours at room tempe~lur~. The ~..;xl...t; was lte-l with ethyl ~cet~te7 washed with salulated sodium 25 hydrogencarbonate solution, saLul~ted brine solution, dried (MgSO4), and carefully evaporated (bath telll~ lule <15C) to avoid loss of the volatile imino ether. The residue was treated with ammonium chloride (4.4 mg, 0.082 mmol) in lenw~ g ethanol (1.5 mL) for 3 hours. The reaction .,.ix~...e was evaporated and ~ ur~ted with ethyl ~cet~te. The 30 resllltin~ solid was filtered, washed with ethyl acetate, and dried in vacuo.

lH NMR (400 MHz, CD30D): o 1.09 (d, 3H); 2.08 (s, 3H); 2.26 (m, lH); 2.45 (dd, lH); 2.89 (dd, lH); 3.37 (dd, lH); 3.69 (dd, lH).

Mass spect~um m/e = 171 (M +1).

CH3 ~r~ ~
~N~NH HCI
~--2-Imino-3(S)~4(R)-O-isopropylidene-S(R)-acetyloxy-piperidine hydrochloride Step A: 3(R).4(R)-0-Isopropvlidene-5(R)-acetyloxv-2-piperidone A solution of 5(R)-azidomethyl-3(R),4(R)-0-isopropylidene-dihydro-2(3H)-furanone ~lG~ar~d according to Herdeis and Waibel, Arch.
Pharm: 324, 269-274 (1991)] (460 mg, 2.16 mmol) in mto,th~nol (12 mL) was hydrogen~te~ under a balloon atmosphere of hydrogen gas in the presence of 20% p~ dium hydroxide on carbon (75 mg) for 4 hours at room temperature.
20 The catalyst was removed by filtration through an Anotop 25 Dispo Syringe ~;ilter (0.2 ,um). The filtr~te was evaporated, and the resulting solid dried invacuo. The solid was treated with acetic anhydride (2 mL) and pyridine (3 mL) until ~in layer chromatography (10% meth~nol/CH2Cl2) indicated complete conversion into a more mobile product. The reaction mixture was 25 evaporated and coev~ ted several times with toluene. The product was p~rifie~l by flash silica gel chromatography eluting with 2-3%
me~anol/CH2C12. Pure title compound was obtained as a solid; yield 185 mg (37%).
.

30 Step B: 2-Imino-3(S).4(R)-0-Isopropylidene-5(R)-acetvloxy-piperidine hydrochloride WO 96/14844 PCTfUS95/14812 To a solution of 3(R),4(R)-O-isopropylidene-5(R)-acetyloxy-2-piperidone (99 mg, 0.432 mmol) in methylene chloride (3 mL) was added trimethyloxonium tetrafluoroborate (70 mg, 0.473 mmol). The reaction 5 ~ ule was stirred for 18 hours at room temperalule. The mixtllre was flilllte-l with ethyl aceta~te, washed with saturated sodium hydrogencarbonate solution, saturated brine solution, dried (MgSO4), and carefully evaporated (bath temperalule <15C) to avoid loss of the volatile imino ether. The residue was treated with ammonium chloride (18.4 mg, 0.344 mmol) in lellllx~
10 ethanol (4 mL) for 5 hours. The reaction mixture was evaporated, and the residue llilul~ted with a mixture of ethyl acetate and diethyl ether. The solid was filtered, washed with diethyl ether, and dried in vacuo.

lH NMR (400 MHz, CD30D): â 1.44 (s, 3H); 1.48 (s, 3H); 2.08 (s, 3H); 3.48 15 (dd, lH); 3.57 (dd, lH); 4.73 (dd, lH); 5.00 (d, lH); 5.32 (m, lH).

Mass spectrum m/e = 229 (M +1).

~~' '' o~CH3 CH3 ~ro~o~CH3 O ~ ,~ O
H NH HCI

2-Imino-3(S).4(R).5(R)-tliacetyloxy-piperidine hydrochloride Step A: 3(R).4(R).5(R)-Triacetyloxy-2-piperidone 3(R),4(R)-O-Isopropylidene-5(R)-acetyloxy-2-piperidone (80 mg, 0.349 mmol) was treated with 90% aqueous trifllloroacetic acid until thin-layer 30 chromatography (TLC) indicated complete disappearance of starting m~teri~l.

WO 96/14&~4 PCl`JUS95114812 The reaction mi~ e was evaporated and coevaporated several times with toluene. The residue was treated wîth pyridine (1 mL) and acetic anhydride (0~7 mL) until complete conversion into a more mobile product by TLC~ The reactîon mixture was evaporated and coevaporated several tîmes with tollle~e~
S The product was purîfied by flash silica gel chromatography eluting wi~ 2%
methanol/CH2C12; yield 48.2 mg (51%).

lH NMR (400 MHz, CDC13): ~ 2.06 (s, 3H); 2.12 (s, 3H); 2.14 (s, 3H); 3.52 (m, 2H); 5.30 (td, lH), 5.50 (d, lH); 5.69 (m, lH); 5.76 (br s, lH).
Step B: 2-Imino-3(S~.4(R).~(R~-triacetyloxy-pîperîdine hydrochloride To a solution of 3(R),4(R),5(R)-triacetyloxy-2-pîperidone (46~7 mg, 0.171 mmol) în methylene chloride (2 mL) was added trim~thyloxonium 15 tel~ oroborate (28 mg, 0.189 mmol). The reactîon mixture was stirred for 18 hours at room tempe~ e~ The mixture was dîll-te-l wîth ethyl acetate, washed with saturated sodium hydrogencarbonate solution, saturated brîne solutîon, dried (MgS04), and carefully evaporated (bath tempel~lure <15C) to avoîd loss of the volatile îmino ether. The resîdue was treated with 20 ~nmonium chlorîde (6~8 mg, 0.127 mmol) in l~ xîll~ ethanol (2~5 mL) for 4 hours. The reaction mix~lre was evaporated, and the resulting solîd drîed in vacuo.

lH NMR (400 MHz, CD3OD): ~ 2.03 (s, 3H); 2.09 (s, 3H); 2.12 (s, 3H); 3.43 25 (dd, lH); 3.51 (dd, lH); 5.40 (m, lH); 5.61 (d, lH); 5.68 (m, lH).

Mass spectrum m/e _ 274.

~, N~NH HCI
-W O96/14844 rCTnUS95/14812 - cis-Decahydro-2-iminoquinoline hydrochloride StepA: cis-Octahydroquinolin-2(1H)-one A suspension of lg of 3,4,5,6,7,8-hexahydro-2(1H)-quinolinone in 1: 1 mixture of dioxane and ethanol was hydrogenated in presçnce of 250 mg of 10% p~ m on carbon at 60 psi and room te~ eralule for 4 hours. The catalyst was filtered on a bed of filter cel and washed with dioxane-ethanol mixture. The filtrate was concellll~ted to give a residue which was purified on silica gel using ethyl ~cet~te as solvent to give 510 mg of the desired product co"~ about 10%
trans-isomer. Recryst~11i7~tion from htq.x~n~ did not improve the isomer ratio.

lH NMR (CDC13): 3.49(m,1H); 2.33(m,2H)1.2-2.0(m,1 lH) Step B: cis-Decahydro-2-iminoquinoline hydrochloride The title compound was synthesized as described in examples 2 and 3 from cis-octahydroquinolin-2(1H)-one.

lH NMR (DMSO): 3.49(m, lH); 2.53(m,2H); 1.25-2.0(m,1 lH);
8.16(b,1H); 8.7(b,1H); 9.65(b,1H) . o~
H NH HCi trans-Decahydro-2-iminoquinoline hydrochloride Step A: trans-Octahydroquinolin-2(1H)-one A mixtllre of lg (6.62 mmol) of 3,4,5,6,7,8,-hexahydro-2(1H)-quinolinone, 2.8g (41 mmol) o~ sodium formate and 5 mL of formic acid was heated to reflux for 1 day The reaction mixtllre was then cooled and 20% sodium hydroxide solution was added to make it basic.
This mixture was then extracted with ethyl ~et~te. The combined ethyl ~cet~te extracts were dried over anhydrous m~nesium sulfate and the solvent was removed to give a crude product. This was pu~fied on silica gel using ethyl acetate as solvent to provide 752 mg of the desired product with about 10% of the cis- isomer. Reclyst~ 7~tion of ~is 10 material from cyclohexane did not improve the ratio of the isomers.

lH NMR (CDC13): 2.88(m,1H); 2.4(m,2H)l.0-l .9(m,1 lH) Step B: trans-Decahvdro-2-iminoquinoline hydrochloride The title compound was synth~i7e~1 from trans-octahydroquinolin-2(1H)-one as described in examples 2 and 3.

lH NMR (DMSO): ~.95(m, lH); 2.58(m,2H); 1.0-2.0(m,1 lH);
20 8.12(b,1H); 8.76(b,1H); 9.70(b,1H) t CH3 ~ CH3 ~NH HCI G~NH HCI
H H ~ H
4(S)-Methyl-4a(S)~7a(S)-perhydro-2-imino-1-pyrin~line hydrochloride and 4(R)-Methyl-4a(R).7a(R)-perhydro-2-imino-1-pyrindine hydrochloride Step A: 4(R+S)-Methyl-4a(R+S)~7a(R+S)-perhydro-l-pyrindin-2-one:

A mixture of 1 g of 2-hydroxy-4-methyl-6,7-dihydro-SH- 1-pyrintlin.o (prepared according to A. Sakurai and H. Midorikawa, Bull Chem Soc Japan, 41, 165, 1968) and pl~t;~ n oxide (0.5g) in 50 mL of glacial acetic acid was hydrogenated on a Parr shaker at room tempelal~lr~ and 50 psi for 2 days. The catalyst was filtered and washed with acetic acid. The filtrate was conc~ ted to give the desired lactam as a white solid after purification on silica gel using 2% methanol in ethyl ~cet~te as solvent.

Step B: 4(S)-Methyl-4a(S).7a(S)-perhydro-l-pyrindin-2-one and 4(R)-Methyl-4a(R).7a(R)-perhydro- 1 -pyrindin-2-one:

The mixture of enantiomers obtained from the step A was separated into its chiral components using ChiralCel OD column using 90:10 hexane:iso~r~a,lol mixture as solvent on HPLC. The faster moving enantiomer was 4(S)-methyl-4a(S),7a(S)-perhydro-l-pyrindin-2-one and the slower moving enantiomer was 4(R)-methyl-4a(R),7a(R)-perhydl~ylilldin-2-one.

lH NMR (CDC13): 5.45(b,1H); 3.8(m,1H);1.4-2.3(m,10H); 0.96(d,3H) Step C: 4(S)-Methyl-4a(S).7a(S)-perhydro-2-imino-1-pyrin~line hydrochloride and 4(R)-Methyl-4a(R).7a(R)-perhydro-2-imino-1-pyrintlinç hydrochloride The title compounds were ~r~ared according to the method described in Fx~mples 2 and 3. The stereoch~mic~ nm~o.ntc for these two compounds were co"f . .-.~l by x-ray structure detçrmin~tion.

lH NMR (CD30D): 3.9(m,1H); 1.4-2.5(m, lH); 1.06(d,3H) 4(S)-Methyl-4a(S),7a(S)-perhydro-2-imino-1-pyrin~linlo hydrochloride specific rotation = +53.95 (c = 0.215, EtOH) WO 96/14844 . ~ PCT/US95/14812 . . .

4(R)-Methyl4a(R),7a(R)-perhydro-2-imino-1-pyrin-line hydrochloride specific rotation = -54.55 (c - 0.22, EtOH) s CH3 ~ CH3 ~NH HCI C~NH HCI

- 4(S)-Methyl-4a(S).8a(S~-decahydro-2-iminoquinoline hvdrochloride and 4(R)-Methvl-4a(R) 8a(R)-decahydro-2-iminoquinoline hydrochloride Step A: 4(R~S)-Methyl-4afR~S)~8a(R+S)-decahydroquinoline-2-one:

A n~ ul~ of 2-hydroxy-4-methyl quinoline (lg) and pl~ti~l...l oxide (0.5g) in 50 mL of glacial acetic acid was hydrogenated 15 on a Parr shaker at room temp~ ~lu-e and 50 psi for 2 days. The catalyst was filtered and washed with acetic acid. I'he filtrate was concentrated to give the desired l~c~m as a white solid after purification on silica gel using 2% metll~nol in ethyl ~cet~te as solvent.

20 Step B: 4(S)-Methyl-4a(S).8a(S)-decahydroquinolin-2-one and 4(R)-Methyl4a(R).8a(R)-decahydroquinolin-2-one:

Ihe .,;xl...e of enantiomers obtained from the step A was separated into its chiral components using ChiralCel OD column using 25 90:10 hexane:isopropanol --i,~l..~ as solvent on HPLC. The faster moving enantiomer was 4(S)-me~yl-4a(S),8a(S)-decahydroquinolin-2-oni~ and the slower moving enantiomer was 4(~)-methyl-4a(R),8a(R)-decahydroquinolin-2-one.

30 lH NMR (CDC13): 5.42(b,1H); 3.6(m,1H); 2.3(m,1H); 2.0(m,1H); 1.1-1.7(m,8H); 0.96(d,3H) WO 96/14844 . PCT/US95/14812 - Step C: 4(S)-Methyl-4a(S).8a(S)-decahydro-2-iminoquinoline hvdrochloride and 4(R)-Methyl-4a(R).8a(R)-decahydro-2-iminoquinoline hydrochloride The title compounds were prepared according to the method 5 described in Fx~mples 2 and 3 and the ~si~nment of stereochemistry was confimed by x-ray crystal structure determin~tion.

lH NMR (CD30D): 3.68(m,1H); 2.6(m, lH); 2.3(m,1H); 2.1(m,1H);
1.25-1.96(m,9H); 1.04(d,3H) 4(S)-Methyl-4a(S),8a(S)-decahydro-2-iminoquinoline hydrochloride specific rotation = +12.31 (c = 0.195, EtOH) 4(R)-Methyl-4a(R),8a(R)-decahydro-2-iminoquinoline hydrochloride 15 specific rotation = -12.5 (c = 0.2, EtOH) ro H
~0~
~ H NH HCI

2-Imino-octahvdro-quinolin-6(5H)-one-6-ethylene ketal hydrochloride Step A: 3~4~7.8-Tetrahydro-quinolin-2(1H)-6(5H)-dione-6-ethylene ketal A solution of 1,4-cyclohtox~ne~lione monoethylene ketal (10 g, 0.64 mol) and pyrrolidine (11.6 mL, 0.13 mol) in toluene (50 mL) was hP~te~l at reflux for 2 h collecting water in a Dean-Stark trap. Half the volume was distilled off and the reaction cooled to room tempel~lule. To 30 the ."i~ e was added a solution of acryl~mide (10.9 g, 0.15 mol) in N,N--lim~thyl~cet~mi~le (25 mL) and the lll;xL---e h~tecl at 78 C for 18 h and 135 C for 4 h. The reaction was cooled, water (100 mL) was added and ~e mixture stirTed O.5h. The mixture was ex~acted with methylene chloride, dried (Na2S04), and evaporated. The solid was ~lilulated with ether, collected and dried to give the title compound.

5 lH NMR (CDC13): o 1.48-2.65 (m,lOH); 3.88-4.05 (m,4H); 4.80 (m,4H);
7.70 (b,lH) Mass spectrum m/e = 210 (M+l) 10 Step B: 3.4~4a.7~8.8a-Hexahydro-quinolin-2(1Hl-6(5H)-dione-6-ethylene ketal - -A suspension of 3,4,7,8-tetrahydro-quinolin-2(1H)-6(5H)-dione-6-ethylene ketal (0.5 g, 2.39 mmol) in ethanol (25 mL) in the 15 presence of 5% rhodium / alumina (0.5 g) was hydrogenated at 50 psi for 2.5 h. The catalyst was removed by filtration through Celite and evaporated to give the title compound.

lH NMR (400 MHz, CDC13): o 1.45-2.45 (m,llH); 3.55 (m,lH); 3.94 20 (m,4~I); 5.74 (b,lH); 5.95 (b,lH) Mass spectrum m/e = 212 (M+l) Step C: 2-Imino-octahydro-quinolin-6(5H)-one-6-ethylene ketal 25 hydrochloride To a solution of 3,4,4a,7,8,8a-hexahydro-quinolin-2(1H)-6(5H)-dione-6-ethylene ketal (100 mg, 0.47 mmol) in methylene chloride (2 mL) was added trim~thyloxonium tetrafluoro~ ,~rate (77 mg, 0.52 30 mmol) and the mixtllre stirred at r~om temper~ e for 18 h. The reaction mixtllre was diluted with ethyl ~cet~t~ (25 mL), neutralized with salul~ted sodium call,ollate, the aqueous layer washed with ethyl ~cet~te, and the combined organics washed with brine, dried (Na2S04) and evaporated below room temperature to give a crude oil. The oil was taken .
-WO 96tl4844 PCT/US95/14812 .

up in ethanol (2ml), ammonium chloride (18mg, 0.33mmol)was added and the mix~lre reflllxe-l for 3 h. The reaction mixt lre was evaporated to dryness, the residue ~ ul~ted with ethyl ~cet~te and purified by flash chromatography using (80:20:2) aceto,lillile: water: acetic acid as eluant to yield the title compound.

lH NMR (400 MHz, CD30D): ~ 1.60-2.73 (m,l lH); 3.63 (m,lH); 3.93 (m,4H) Mass spectrum m/e = 211 (M+l) O
--N NH HCI
~ H
2-Imino-octahydro-quinolin-6(5H)-one hydrochloride Step A: Hexahydro-quinolin-2(1H)~6(5H)-dione A solution of 3,4,4a,7,8,8a-hexahydro-quinolin-2(1H)-6(5H)-dione-6-ethylene ketal (~l~ed as ~lesçrihed in Fx~mple 106,Step B), (300 mg, 1.42 mmol) in 80% acetic acid / water (8 mL) was h.o~te~ at 65 C for 1 h, evaporated to dryness, and coevaporated with toluene to 25 give a solid. pllrific~tion was accomplished by flash silica gel chromatography using 3% methanol / methylene chloride as eluant to give the title compound.

lH NMR (400 MHz, CDC13): ~ 1.60-2.50 (m, llH); 3.78 (m,lH); 6.60 30 (b,lH) Mass spectrum m/e = 168 (M+l) Step B: 2-Imino-octahydro-quinolin-6(5H)-one hydrochloride The above compound was prepared in a ~imil~r fashion as 5 Fx~mple 106, Step C, but substituting hexahydro-quinolin-2(1H),6(5H)-dione in place of 3,4,4a,7,8,8a-hexahydro-quinolin-2(1H)-6(5H)-dione-6-ethylene ketal to yield the title compound.

lH NMR (400 MHæ, CD30D): ~ 1.70-2.64 (m,lOH); 2.73 (m,lH); 3.97 10 (m,lH) Mass spectrum m/e = 167 (M+l) lS EXAMPLE 108 C~3 ~rO~NH HCi 2-Imino-6-acetyloxy-cis-decahydroquinoline hydrochloride Step A: cis-3.4~4a.7~8.8a-Hexahydro-quinolin-2(1H)-6(5H)-dione-6-ethylene ketal The above compound was ~l~art;d in a .~imil~r fashion as 25 Fx~mple 106, Step B, but was fractionally cryst~ e~l from ethyl acetate to give greater than 96% cis isomer as the title compound.

400MHz ' H NMR (CDC13): ~ 1.45-2.45 (m, 1 lH); 3.55 (m, lH); 5.80 (b, lH) Step B: cis-Hexahydro-quinolin-2(1H)~6(5H)-dione WO~6/14844 PCr/US95114812 .

- The above compound was ~r~ared in a ~imil~r fashion as Fx~mple 107, Step A, to give the title compound.

lH NMR (CDCl3): o 1.70-2.50 (m, llH); 3.78 (m, lH), 6.57 (b, lH) s Step C: 6-Hydroxy-cis-(4a.8a)-octahvdro-quinolin-2(1H)-one To a solution of cis-hexahydro-quinolin-2(1H),6(5H)-dione (50 mg, 0.30 mmol) in methanol (1 ml) cooled to O C was added sodium 10 borohydride (11 mg, 0.30 mmol) and the solution stirred for 0.5 h. Water (0.25 ml) was added and the reaction mixture was evaporated to give the crude title compound.

lH NMR (400 MHz, CD30D): o 1.32-2.00 (m,lOH); 2.28 (m,2H); 3.54 15 (m,lH); 3.64 (m,lH) Step D: 6-Acetvloxy-cis-(4a8a)-octahydro-quinolin-2(1H)-one To a ~ Lur~; of crude 6-hydroxy-cis-(4a,8a)-octahydro-20 quinolin-2(1H)-one (203 mg, 0.86 mmol) in methylene chloride (5 mL), was added pyridine (2.8 mL), acetic anhydride (1.4 mT .), and 4-dimethylaminopyridine (23 mg). After 6 h the reaction mix~lre was ltetl with methylene chloride (50 mL), washed with water, salul~led sodium bicarbonate, brine, dried (Na2S04), and evaporated to give a pale 25 yellow solid. It was subjected to flash chromatography using 2%

mPth~nol / methylene chloride as eluant to give the title compound.

lH NMR (400 MHz, CDCl3): o 1.56-2.02 (m, 12H); 2.35 (m, 2H); 3.55 (m, lH); 4.75 (m,lH); 5.74 (b?lH) Mass spectrum m/e = 212 (M+l) .
Step E: 2-Imino-6-acetyloxy-cis-decahydroquinoline hydrochloride .

W O96/14844 PCTrUS95tl4812 The above compound was prepared in a ~imil~r fashion as Fx~mple 106, Step C, but sub~ ;n~ 6-acetyloxy-cis-(4a,8a)-octahydro-quinolin-2(1H)-one in place of 3,4,4a,7,8,8a-hexahydro-quinolin-2(1H)-6(5H)-dione-6-e~ylene ketal to yield the title compound.
S
lH NMR (400 MHz, CD30D): ~ 1.50-2.20 (m,12H); 2.65 (m,2H); 3.64 (m,lH); 4.80 (m,lH) Mass spectrum m/e = 21 l (M+l) HO~
~ N~NH HCI
2-Imino-6-hvdroxy-cis-decahydroguinoline hydrochloride Ammonia gas was bubbled to a solution of 2-imino-6-acetyloxy-cis-decahydroqninoline hydrochloride, prepared previously as 20 described in Fx~mrle 108, Step E, (38 mg, 0.15 mmol) in met~l~nol (2 ml) at O C for ~ min. The reaction flask was ~lo~eled and stirred at O C
for 3 h and at room temp~ ur~ for 72 h. ~he reaction was evaporated to dryness and pllrifi~ by ~ash cl~ natography using (80:16:2) ace~ ile: water: acetic acid as eluant to give the title compound.
lH NMR (400 MHz, CD30D): o 1.28-2.13 (m,lOH); 2.63 (m,2H); 3.60 (m,lH); 3.68 (m, lH) Mass spectrum m/e = 169 (M+l) EXAMPLES 110.111 ~NH HCI ~NH HCI

2-Imino-5-methoxy-cis-perhydro-pyrindene hydrochloride (Example 110) and 2-imino-5-hydroxy-cis-perhydro-pyrindene hydrochloride 5 (Example 111) Step A: 3.4.6.7-Tetrahydro-pyrindene-2(1H)-5-dione A mixture of 1,3-cyclopent~n~o-lione (20 g, 0.20 mol), 10 acrylamide (29 g, 0.41 mol), and p-toluenesulfonic acid monohydrate (2.3 g, 0.01 mol) in N,N-dimethylacetamide (20 mL) was hP~te~l at 85 C
for 18 h and 150 C for 3 h. The reaction ~ e was cooled, water (100 mL) was added and stirred for 0.5 h. Methylene chloride (100 mL) was e~l, the layers were se~ te~l, the aqueous layer washed with 15 methylene chloride, the combined organics dried (Na2SO4) and evaporated to give a gum. Pllrific~tion by flash chromatography using 2%
m~th~nol / methylene chloride as eluant gave the title compound.

lH NMR (400 MHz, CDC13): ~ 2.52 (m, 4H); 2.62 (m, 4H); 8.32 (b, lH) Mass spectrum m/e = 152 (M+l) Step B: 5-Hydroxy-cis-perhvdro-pvrinden-2(1H)-one A suspension of 3,4,6,7-tetrahydro-pyrindene-2(1H)-5-dione (2.8 g, 0.19 mol) in ethanol (150 mL) in the presence of 5% rhodium /
~lnmin~ was hydrogenated at 50 psi for 18 h. The catalyst was removed by filtration through Celite and evaL~olated to give the title compound.

1 H NMR (400 MHz, CDC13). ~ 1.69-1.95 (m, 7H); 2.14-2.33 (m, 2H);
2.47 (m, lH); 3.74 (m, lH); 4.33 (m,lH); 4.33 (m,lH); 6.04 (b, lH) Compound A: 2-Imino-5-methoxv-cis-perhydro-pyrindene hydrochloride Compound B: 2-Imino-5-hydroxy-cis-perhydro-pyrindene hvdrochloride The above compounds were prepared in a ~imil~r fashion as S F.x~mple 106, StepC, butsub~ u~ g5-hydroxy-cis-perhydro-pyrinden-2(1H)-one in place of 3,4,4a,7,8,8a-hexahydro-quinolin-2(1H)-6(5H)-dione-6-ethylene ketal. Purification by flash chromatography using (80:
8: 2) acetonitrile: water: acetic acid as a eluant s~ted the above two title compounds A and B;
Compound A: lH NMR (400 MHz, CD30D): ~ 1.70-2.10 (m,8H); 2.47 (m,3H); 2.70 (m,lH); 3.85 (m, 2H) Mass spectrum m/e = 169 (M+l) Compound B: lHNMR (400 MHz, CD30D): ~ 1.70-2.10 (m,7H~; 2.34-2.52 (m,2H); 2.75 (m,lH); 3.85 (m,lH); 4.29 (m,lH) Mass spectrum m/e - 155 (M+l) . ~

HN NH HCI

L-776,009-OOlV
2-Imino-5-hydroxy~a-methyl-trans-(4a 8a)-deca~ydroquinoline hydrochloride StepA: 4a-Methyl-3.4.6.7-tetrahydro-quinolin-2(1H).5(4aH)-dione W O96/14844 PCTrUS95/14812 The title compound was obtained from 2-methylcyclohexane-1,3-dione and acryl~mi~le by the method described in ex~mrle 110, step A.

lH NMR (CDC13): 7.77 (br, lH), 5.14 (dd, 1 H), 2.78 (m, lH), 2.58 (m, 5 2H), 2.53 (m, lH), 2.43 (m, 2H), 2.04 (m, lH), 1.80 (m, lH), 1.38 (s, 3H).

Mass spectrum m/e = 180 (M+l) Step B: 5-Hydroxy-4a-methyl-trans-(4a.8a)-octahydro-quinolin-2(1H)-one The title compound was obtained from 500 mg of 4a-methyl-15 3,4,6,7-tetrahydro-quinolin-2(1H),5(4aH)-dione by the method described in example 110, step B with the following additions: The crude solid was p~ e-l by silica gel chromatography on a 21 x 130 mm column eluting a gradient from 0 to 5% methanol in methylene chloride to afford 185 mg of the title compound.
lH NMR (CDCl3): 5.64 (br, lH), 3.37 (dt, lH), 3.08 (dd, lH), 2.47 (m, 2H), 2.11 (m, lH), 1.80 (m, 2H), 1.57 (m, 2H), 1.46 (m, 4H), 0.95 (s, 3H).

25 Mass spectrum m/e = 184 (~1+1) Step C: 2-Imino-5-hydroxy-4a-methvl-trans-(4a.8a)-decahydroquinoline hydrochloride The title compound was obtained from 180 mg of 5-hydroxy-4a-methyl-trans-(4a,8a)-octahydro-quinolin-2(1H)-one by the method described in ex~mples 2 and 3.

W O96~14844 PCTrUS95/14812 lH NMR (CD30D): 3.36 (dt, lH), 3.12 (dd, lH), 2.70 (dd, 2H), 2.08 (m, lH), 1.83 (m, lH), 1.70 (m, 2H), 1.57 (m, 2H), 1.44 (m, 2H), 0.87 (s, 3H).

5 Mass spectrum m/e = 183 (M+l) . F~ ..

N NH HCI

2-Imino-5-fluoro-5-methyl-cis-(4a.8a)-decahvdroquinoline hydrochloride Step A: 5-Fluoro-~-methyl-cis-(4a.8a)-octahydro-quinolin-2(1H~-one To a solution of 150 mg (0.82 mmol) of 5-hydroxy-4a-methyl-trans-(4a,8a)-oc~ahydro-quinolin-2(1H)-one in 2 mL methylene chloride at 0 C was added 0.108 mL (0.82 mmol) diethyl~minosulfur trifluoride dloywise. After stirrin~? for one hour, apply reaction .~ix~ e directly to a 20 21 x 300 mm silica column and purify by eluting with 20%
acetone/methylene chloride to afford 55 mg of the tide compound as a 4: 1 mixtnre of cis:trans diastereomers.

lH NM~ (CDC13): 6.19 (l~r, lH), 3.31 (dt, i H~, 2.51 (m, lH), 2.28 (m, 25 lH), 2.21-1.90 (m, 5H), 1.85-1.50 (m, 4H), 1.40 (d, J = 22 Hz, 3H).

Mass spectrum m/e = 186 ~M+1) 30 StepB: 2-Imino-5-fluoro-5-methyl-cis-(4a,8a)-decahydroquinoline hydrochloride WO 96/14844 PC~/US95114812 .

The title compound was obtained from 55 mg of 5-fluoro-5-methyl-cis-(4a,8a)-octahydro-quinolin-2(1H)-one by the method described in F.x~mples 2 and 3.

S lH NMR (CD30D): 3.57 (dt, lH), 2.67 (m, 2H), 2.20 (m, 2H), 2.08 (m, lH), l.9S (m, lH), 1.88-1.68 (m, 5H), 1.44 (d, J = 23 Hz, 3H).

Mass spectrum m/e = 185 (M+l) ~Nd~NH HCI

15 5-Acetoxy-2-irr~ino-~is-(4a.8a)-decahydroquinoline hydrochloride Step A: S-Acetoxy-cis-(4a.8a)-octahydroquinolin-2(1H)-one To a solution of 100 mg (0.59 mmol) of 5-hydroxy-cis-(4a,8a)-20 oct~hydroquinolin-2(1H)-one (prepared as shown in Fx~mple 110, Step A and B) in 1 mL pyridine at 25 C was added 0.046 mL (0.65 mmol) acetic anhydride and 8 mg dimethylaminopyridine. After stirring for 16 hours, apply reaction mix directly to a 21 x 130 mm silica column and purify by elll~in~ a gradient from 0 to 5% methanol/methylene chloride to 25 afford 80 mg of the title compound as a cis r~celn~te lH NMR (CDC13): 6.19 (br, lH), 4.88 (m, lH), 3.41 (m, 1 H), 2.47 (m, lH), 2.35 (m, 2H), 2.05 (s, 3H), 1.77 (m, 5H), 1.45 (m, 2H), 1.30 (m, lH).
Mass spectrum m/e = 212 (M+l) W O96114844 PCTrUS95/14812 .

Step B: S-Acetoxv-2-imino-cis-(4a.8a)-decahydroquinoline hydrochloride S The title compound was obtained from 80 mg of S-acetoxy-cis-(4a,8a)-octahydroquinolin-2(1H)-one by the method described in examples 2 and 3.

lH NMR (CD30D): 4.94 (dt, lH), 3.59 (dt, lH), 2.73 (dt, lH), 2.62 (m, lH), 2.40 (m, lH), 2.04 (s, 3H), 1.89 (m, 2H), 1.86-1.71 (m, 4H), 1.53 (m, 2H).

Mass spectrum m/e = 211 (M+l) HO

~NH HCI

5-Hydroxy-2-imino-cis-(4a.8a)-decahydroquinoline hydrochloride To a solution of 30 mg (0.14 mmol) of 5-acetoxy-2-imino-cis-(4a,8a)-decahydroquinoline hydrochloride in 1 mL meth~nol at 0 C was added ammonia gas by bubbling in through a n~e~lle. After stilTing for 64 hours, apply reac*on mix directly to a 8 x 50 mm silica column and purify by ~hl*n~ 80:16:4 acelo ~ ile/water/acetic acid to afford 15 mg of ~e title compound as a cis racemate.

lH NMR (CD30D): 3.80 (dt, lH), 3.52 (dt, lH), 2.74 (dt, lH), 2.58 (m, lH), 2.21 (m, lH), 193 (m, 2H), 1.77 (m, 2H), 1.66 (m, 2H), 1.35 (m, 2H).

Mass spectrum m/e = 169 (M+l) W O96/14844 PCTrUS95/14812 .

. . ~= ~ . -. . .

<,~hlH HCI

2-Imino-octahydroquinolin-7(8H)-one-7-ethvlene ketal hydrochloride Step A: ~-Acetyl-ry-ethoxypimelonitrile 10 ' ' To a 50 mL round bottom flask fitted with a Teflon stirrer were added 13 gm (100 mmol) of ethyl ~ceto~cetate~ 15 mL of tert-butanol and 7.5 mL of benzyltrim~tllylammonium hydroxide (Triton BTM, 40 % by weight) in methanol. The solution was cooled to 4 C with ice 15 and added dr~vise over 10 min 10.6 g (100 mmol) of acrylonitrile keeping the solution temper~lu.e <20 C. The reaction was stirred for 4 h at 25 C. The product falls out of solution and the ,,,i~lll,~ became a solid mass. Cold water (100 mL) was added to suspend the precipikite and filtered. The cryst~lline product was washed with 2X 20 mL of ice 20 water and dried under re-iuce~l pressure at 60 C overnight to recover 18.5 g (78%) of product.

lH NMR (400 MHz, CDC13) o 1.30(t, 3~, J=7 Hz); 2.1-2.4(m, 8H);
2.19 (s, 3H); 4.27 (q, 2H, J=7 Hz).
Step B: 3.4~4a.5-Tetrahydroquinolin-2(1H)-7(6H)-dione This procedure is taken from C. F. Koelsch et al. J. Am.
Chem. Soc., 1959, 72,346. ~-Acetyl-~y-ethoxypimelonitrile (18.5 g) was 30 treated with a hot solution (120 C) of 41 mL of concentrated sulphuric acid and 18 mL of water. After h~.~tin~: at 140 C for 15 min, the solution was poured into 200 mL of ice water with me~h~nical stirrin W O96/14844 PCT~US95/14812 and added CaC03 until the pH> 6Ø The precipitated CaS04 was filtered and washed with 3X 100 mL of water. The water was removed under reduced pressure and the residue was recryst~ l from boiling water to recovered 4.5 g (36%) of product; (Lit. yield= 42%). mp=233-5 235 C (Lit = 234-235 C).

1H NMR 400 MHz(CDC13) ~ 1.55-1.85(m, 2H); 2.0-2.1(m, lH); 2.15-2.25 (m, lH); 2.35-2.7 (m, 5H); 5.40 (s, lH); 7.90 (bs, lH).
- - -Step C: 3.4.4a.5-Tetrahydro-quinolin-2(1H).7(6H)-dione 7-ethyleneketal A ,,~i,$l.,~ of the vinylogous imide 3,4,4a,5-tetrahydroquinolin-2(1H)-7(6H)-dione (1.30 gm, 7.9 mmol), ethylene 15 glycol (4.7 mL), p- toluenesulphonic acid (100 mg), and be~7e-~ (200 mL) was he~ttorl under reflux with stirnnE using a Dean Stark water separator for 40 h. After the solvent was removed under re~ ce~1 pressure, the resulting residue was extracted with chloroform. The extract was washed with salurated NaHCO3 and brine, evaporated to give 20 a solid which was chromatographed on silica gel (95/5 - CH2C12/
MeOH). Chromatography gave 980 mg of product. Yield=60%.

lH NMR (400 MHz, CDC13) o 1.7-1.8(m, 3H); 2.0-2.1(m, lH); 2.1-2.2 (m, 5H); 2.4-2.5(m, 2H); 3.97 (s, 4H); 7.28 (bs, lH).
Step D: Hexahydro-quinolin-2(1H).7(8H)-dione.7-ethylen~.k~t~l The product of step C (980 mg, 4.7 mmol) was hydrogenated over 5% Rhodium/~ minA (1.0 g) in 10 mL of ethanol at 30 50 psi for 18 h. The catalyst was filtered from the solution and the filtrate .
evaporated under re~hlcerl pressure. The solid was chromatographed on silica gel (97/3 - CH2C12/ MeOH) and 570 mg of the desired product was recovered along with 150 mg of starting m~tçri~l, mp=171-173.

W O 96/14844 PCTrUS95/14812 lH NMR 400 MHz(CDC13) ~ 1.4-2.3 (m, 9H); 2.4-2.55(m, 2H); 3.75(m, lH); 3.9 (bs, 4H); 6.2 (bs, lH).

Step E: 2-Methoxy-hexahydro-quinolin-7(8H)-one-7-ethyleneketal In a 10 mL round bottomed flask fitted with a stirrer bar were added 100 mg of 3~ molecular sieves (Linde), 4 mL of methylene chloride and 162 mg of trimethyloxonium tetrafluoroborate (1.1 mmol) and cis-octahydro-quinoline-2-one,7-ethyleneketal (211 mg, 1.0 mmol).
10 The ~ ule was stirred under N2 for 4 h at 22 C. The solution was nte-1 with 10 mT . of CH2C12 and washed with 2 x 5 mL of 5%
NaHCO3. The organic layer was dried over MgSO4, filtered, and conce~ d. Recovered 190 mg of a cream colored solid which by NMR was the desired product.
lH NMR 400 MHz(CDC13) ~ 1.3-1.65(m, 5H); 1.8-l.9(m, 3H);
2.03(ddd, lH, J=14Hz, J=7Hz, J=3Hz); 2.2 (m, 2H); 3.61 (s, 3H);
3.77(bd, lH); 3.9-4.0 (m, 4H).

20 Step F: 2-Imino-octahydroquinolin-7(8H)-one-7-ethylene ketal hydrochloride = ~ ~ In--a~25 mL glass pressure bottle fitted with a Teflon stirrin~
bar were added iminoether (180 mg, 0.8 mmol), ammonium chloride (39 25 mg, 0.72 mmol) and 2 mL of ethanol. The tube was sealed and he.~terl at 100 C overnight The solvent was removed in vacuo and added ethyl ~cet~te when the product ~leci~ilaled. The solid was f;ltered and dried to recover 120 mg of the hydrochloride salt.

30 lH NMR 400 MHz(CD30D) ~ 1.55-1.62(m, lH); 1.63-1.88(m, SH);
1.925 (d, lH, J=2Hz); 1.936 (d, lH, J=2Hz);2.1(m, lH,); 2.65(dt, 2H, J=10 Hz, J=2.5 Hz); 3.77 (m, lH).

Mass Spectrum m/e = 207 (M+l).

O~NH HCI

2-Imino-octahydro-quinolin-7(8H)-one hydrochloride Step A: cis-Octahydroquinolin-2(1H)~7(8H)-dione Hexahydro-quinolin-2(1H),7(8H)-dione,7-ethyleneketal (160 mg, 76 mmoL) was suspended in S mL of 2N HCl and stirred overni~ht at room temperature. Then solid K2C03 was added to neutralize the solution. The solvent was removed under reduced pressure 15 and the residue extracted with chlor~fo~ . The CHC13 solution was concentrated under reduced pressure and the residue recry~t~ 7~l from EtOAc and he~ne. Recovered 110 mg of product.

lH NMR (400 MHz, CDC13) ~ 1.8-2.1(m, 5H~; 2.3-2.45(m, SH); 1.65 20 (dd, IH, J=17Hz, J=6H); 3.95(m, lH); 6.15 (bs, lH).

Step B: 2-Methoxy-hexahvdro-quinolin-7(8H)-one This product was made by the procedure described for step 25 E of ex~mple 116.

lH NMR (400 MHz, CDCl3) o 1.75-l.9(m, 4H); 2.1-2.17(m, lH); 2.19 (t, lH,J=6Hz);2.30(t, lH,J=6Hz); 2.41 (dd,lH,J=16Hz,J=7Hz);2.67 (dd,lH, J=14 Hz, J=5 Hz); 3.58 (s, lH); 3.89 (m, lH).
Step C: 2-Imino-octahvdro-quinolin-7(8H)-one hvdrochloride This product was made by the procedure described for step F
of example 116.

lH NMR (400 MHz, CD30D) ~ 1.9-2.0(m, 3H); 2.04(m, lH, J=7Hz);
5 2.4-2.5 (m, 3H); 2.58(dd, lH, J=12 Hz, J=7 Hz); 2.65-2.8 (m, 3H); 4.0-4.07 (m, lH).

CHaJ~O~NH HCI

7-Acetyloxy-2-imino-trans-(4a.8a)-decahydroquinoline hydrochloride 15 Step A: 7-Hydroxy-octahydro-trans-(4a.8a)-quinolin-2(1H)-one 3,4,4a,5-Tetrahydroquinolin-2(1H)-7(6H)-dione (2.92g, 17 mmol) was added to a small Parr pressure bottle with 220 mg of pl~tinllm oxide and 75 mL of acetic acid. The solution was pressurized to 50 psi 20 with H2 and ~h~k~.n for 18 h. The catalyst was removed by filtration and the acetic acid stripped off under re-l-lce~l pressure. Two major products were observed by TLC (97/3 CH2Cl2/MeOH). The lower Rf m~teri~l, a . ., e of 4a,8a- cis and trans ring junction 7-ol's (400 mg) was isolated by column chromatography (97/3 CH2C12/MeOH). This m~teri~l was 25 further pmifi~rl by recryst~lli7~tion from ethyl ~cet~te whereupon the trans-4a,8a-ring junction -7-ol crys~lli7e~1 out of solution (7-OH
configuration unknown).

lH NMR 400 MH_(CDCl3) ~ 1.05-1.15(m, lH); 1.2-1.7(m, SH); 1.7-1.8 30 (m, 2H,); 1.95-2.15 (m, 2H); 2.3-2.5 (m, 2H); 2.65 (bs, lH, -OH); 2.95 (m, lH); 3.7 (m, lH); 6.45 (bs, lH).

Step B: 7-Acetyloxy-octahydro-trans-(4a 8a)-quinolin-2(1H)-one WO 96/14844 ~ PCI/US95/14812 7-Hydroxy-octahydro-trans-(4a,8a)-qwnolin-2(1H)-one (89 mg, 0.82 mmol) was dissolved in 5 mL of pyridine. After cooling to 4 C acetyl chloride (116 ,uL) was added dr~wise with stin in~. The 5 reaction was stirred 20 minutes, the solvent was removed in vacuo, then added 10 mL of CH2C12 and washed with 2x2 mL of 2 N HCl. The organic layer was dried over MgS04. The filtrate was redllce-l in volume and chromatographed (97/3 CH2C12/MeOH) to give 51 mg of the title compound.
lH ~MR (400 MHz, CDC13) o 1.2(dq, lH, J-12 Hz, J=3Hz); 1.3-1.5(m, SH); 1.75-1.85 (m, 2H,); 2.01 (s, 3H); 2.0-2.05 (m,lH); 2.1-2.15 (m, lH);
2.3-2.5 (m, 2H); 3.0 (m, lH); 4.7 (m, lH); 6.25 (bs, lH).

15 Step C: 7-Acetyloxy-2-methoxy-octahydro-trans-(4a~8a)-quinoline 7-Acetyloxy-octahydro-trans-(4a,8a)-quinolin-2(1H)-one was converted to the above c~ ~ou~d as previously described in step E
of example 116.
lH NMR (400 MHz, CDC13) o 1.0-1.2(m, 2H); 1.22-1.35(m, lH); 1.35-1.45 (m, 2H,); 1.72-1.8(m, 2H); 2.02 (s, 3H); 2.2-2.3 (m, 2H); 2.4-2.5 (m,lH); 2.85-2.9 (m, lH), 2.95 (m, lH); 3.61 (s, 3H); 4.82 (m, lH).

25 StepD: 7-Acetyloxy-2-imino-trans-(4a.8a)-decahydroquinoline hvdrochloride 7-Acetyloxy-2-me~oxy-octahydro-~ans-(4a,8a)-quinoline was converted to the tide compound as prevously described in step F of 30 example 116.

lH NMR (400 MHz, CD30D) ~1.25-1.35(m, lH); 1.4-1.55 (m, 4H,);
1.85-l.95(m, 2H); 2.02 (s, 3H); 2.0-2.15 (m,lH); 2.33-2.4 (m, lH); 2.7-2.8 (m, 2H); 3.1-3.2 (m, lH); 4.84.9 (m, lH).

, , WO 96tl4844 PCI/US95/14812 ~, HO~ N~NH HCi H

7-Hvdroxy-2-imino-trans-(4a~8a)-decahydroquinoline~ acetic acid salt 7-Acetyloxy-2-imino-trans-(4a,8a)-decahydroquinoline 10 hydrochloride (28 mg, 0.12 mmol) was added to 1 mL of methanol in a 2 dram vial. The solution was cooled to 4 C and ammonia gas was slowiy bubbled in with vigorous stirnng. The vial was sealed and the solution let stand at 4 C overnight The next morning, the solvent was removed under re~ ce~l pressure and the residue chromatographed over silica gel 15 (17/2/1 - aceto~ ile/watel/acetic acid). The title compound was recovered (Rf=0.25, 7mg).

lH NMR (200 MHz, CDCl3) ~ 1.20-1.60(m, 5H);; 1.8-l.9(m, 2H);
1.95-2.1 (m,2H); 2.3-2.4 (m, lH); 2.7-2.8 (m, 2H); 3.1-3.2 (m, lH) (9~-20 proton); 3.6-3.8 (m, lH).

Mass Spectrum m/e = 169 (M+1) CH3J~O~NH HOAc 7-Acetyloxy-2-imino-decahydroquinoline~ acetic acid salt Step A: 7-Acetyloxy-octahydro-quinolin-2(1H)-one WO 96/14844 PCr/US95/14812 7-Hydroxy-octahydro-quinolin-2(1H)-one, ((3/7 ratio), 250 mg, 1.48 mmol) was recovered from the mother liquors from the PtO2 catalyzed hydrogenation of 3,4,4a,5-tetrahydroquinolin-2(1H)-7(6H)-5 dione (example 118 step A). This m~t~ri~l was acetylated with aceticanhydride (2.4 mL) and 4-(dimethylamino)pyridine (40 mg) in pyridine (4.8 mL) at 0 C. After 6 h, no starting m~teri~l was seen by TLC. The solvent was removed under reduced pressure. Methylene chloride (100 mL) was added to the resiclll~, which was sequentially washed with 3x 25 10 mL of water, 2x 25 mL of 5% sodium bicarbonate, and 2x 25 rnL of brine. After drying over MgS04, the solution was filtered and reduced in volume. Chromatography (96/4 CH2Cl2/MeOH) gave 160 mg of a 60/40 mixtllre of cis/trans isomers (by NMR).

15 lH NMR (400 MHz, CDC13) ~ 2.007 (s,3H) (cis acetyl); 2.013 (s,3H) (trans acetyl); 3.0 (m, lH), 3.75 (m, lH).

Step ~: 7-Acetyloxy-2-methoxy-octahydro-~uinoline 7-Acetyloxy-octahydro-quinolin-2(1H)-one (120 mg) was 20 converted to the above compound as previously described in Step E of example 116. This product was c~rrie~l on through to the ~ ine ~cet~te wi~out characteri7~tion.

Step C: 7-Acetyloxv-2-imino-decahydroquinoline. acetic acid salt 7-Acetyloxy-2-methoxy-octahydro-quinoline was converted to the title compound as prevously clescribed in step F of example 116.

Mass Spectrum m/e - 21 l(M+l).

W O96/14844 PCTrUS95/14812 o CH3 ~NH HCI

2-Imino-3-Methyl-octahydro-cis-pyrano~4.3-b~-pyridine hydrochloride 5 Step A: Benzyl-(tetrahydro-pyran-4-vlidene)-amine A solution of tetrahydro-(4H)-pyran-4-one (10 g, 100 mmol), benzyl~mine (10.7 g, 100 mmol), and 50 mL of toluene was h~o~terl to reflux with a Dean-Stark trap under N2 for 20 h. The ~ ll,e 10 was cooled and the solvent removed under re~ ce~l pressure. The residue was distilled under re~l-lce~l pressure (105-107, O.O9mm Hg) and 5.6 g of product was isolated, yield=30%. The buL~ of the reaction mixhlre polymeri7erl during ~ till~tion.

lH NMR (200 MHz, CDC13) ~ 2.5 (q,4H, J=8 Hz); 3.73-3.83 (t, 2H, J=8Hz), 3.85-3.95 (t, 2H, J=8Hz); 4.58 (s,2H); 7.2-7.4 (m, SH).

Step B: 1-Benzyl-3-methyl-1.3.4.5.7.8-hexahydro-pyrano~4.3-b~pyridin-2-one -~ ~ ~- To a solution of benzyl-(tetrahydro-pyran-4-ylidene)-~mine, (950 mg, 5 mmol) in a glass wall pyrolysis tube was added methyl meth~crylate (750 mg, 7.5mmol, 1.5 equiv). This mixhlre was he~te-l for 5 days. Then another 1.5 g of methyl methacylate was added (15 mmol, 25 2 equiv) and h~ting continlle~l for 4 more days. The mixhlre was transferred to a round bottomed flask and the volatile component removed under re~ ce~l pressure. The residue was chromatographed (80/20 hexane/ethyl~cet~te) and a lower Rf spot (530 mg, W active on fluorescent treated silica gel plate) was isolated.
1H NMR (400 MHz, CDCl3) ~ 1.25(d,3H, J=7 Hz); 1.9-2.0 (m, lH); 2.1-2.17(m, 2H); 2.1-2.17(m, lH); 2.6-2.7 (m, lH); 3.68-3.75 (m, lH); 3.75--W O96/14844 PCT~US95rl4812 3.83 (m, lH); 4.06 (q, 2H, J=14 Hz); 4.72 (d,lH, J=16 hZ); 4.92 (d,lH, J=16 Hz); 7.12 (d, lH, J=7 Hz); 7.20 (t, lH, J=7 Hz); 7.25-7.29 (m, 3H).

Step C: l-Benzyl-3-methyl-octahydro-cis-pyrano~4.3-b7pyridin-2-one s l-Benzyl-3-methyl-1,3,4,5,7,8-hexahydro-pyranor4,3-b]pyridin-2-one (570 mg, 22.2 mmol) was dissoved in ethanol (10 mL) and placed in a small Parr pressure flask con~inin~ 270 mg of 5%
rhodium/A1203. This mixture was pressl1ri7~fl to 60 psi and shaken for 10 20 h. The catalyst was filtered and the filtrate reduced in volume. Three separate spots were observed by TLC (65/35 hexane/ EtOAc). The W
active derivative was isolated by flash chromatography (90 mg) and shown to be the desired product by NMR.

15 lH NMR (400 MHz, CDC13) ~ 1.30 (d,3H, J=7 Hz); 1.7-1.8 (m, lH);
1.82-1.95 (m, 2H); 2.08(q, lH, J=13 Hz); 2.45.2.55 (m, lH); 3.24 (dt, lH, J=16 Hz, J=2 Hz); 3.3-3.4 (m, lH); 3.48(dd, lH, J=16 Hz, J=2 Hz); 3.77 (d,lH, J=12 Hz); 3.926 (d,lH, J=15 Hz); 3.90 (m, lH); 5.27 (d, lH, J=15 Hz); 7.2-7.35 (m, 5~).
Step D: 3-Methyl-octahydro-cis-pyranor4.3-b7pyridin-2-one 1 -Benzyl-3-methyl-oc~hydro-cis-pyrano[4,3-b]pyridin-2-one (90 mg, 0.35 mmoL) was placed in a 25 mL 3-neck flask fitted with a 25 Teflon stirrer bar, gas inlet valve and a d~y ice con~len~er. The flask was flll~h~-l with N2 and ~mmoni~ was con~l~n~e~ into the flask (15 mL).
Then sodium metal was added portionwise into the solution until a blue color just persisted (-25 mg). After 1 h, 30 mg of ammonium chloride was added. The ~mmo~ gas was allowed to evaporate, 3 mL of water 30 was added and the reslllt~nt solution extracted with CH2C12. The organic layer was dried over MgSO4, filtered and the residue chomatographed on silica gel (98/2 CH2C12/MeOH) to recover 22 mg of product.

, lH NMR (400 MHz, CDC13) ~ 1.18 (d,3H, J=10 Hz); 1.7-1.85 (m, 4H);
2.0-2.1(m, lH); 2.35.2.45 (m, lH); 3.35-3.4 (m, lH); 3.5-3.6(m, lH);
3.62 (dd,lH, J=12 Hz, J=3 Hz); 3.77(d,1H, J=12 Hz); 3.75-3.80 (m, lH).

5 Step E: 2-Methoxy-3-methyl-hexahydro-cis (4H)pyrano~4.3-b]pvridine 3-Methyl-octahydro-cis-pyrano[4,3-b]pyridin-2-one (22 mg, 0.14 mmol) was converted to the imino ether by the method as previously described in step E of example 116 to recover 20 mg of product.
.
lH NM~ 200 MHz(CDC13) o 1.14(d,3H, J=7 Hz); 1.3-l.S (m, lH); 1.6-1.9 (m, SH); 2.2-2.4(m, lH); 3.37 (dt, lH, J=12 Hz, J=2 Hz); 3.5-3.62 (m, lH); 3.61 (s, 3H); 3.6-3.7(m, lH); 3.8-3.9 (m, lH).

lS Step P: 2-Imino-3-Methyl-octahydro-cis-pyranor4.3-b~-pyridine hydrochloride 2-Methoxy-3-methyl-hexahydro-cis (4H)pyrano[4,3-b]pyridine (20 mg, 0.1 mmol) was converted to the above compound as 20 prevously described in step F of example 116.

lH NMR (400 MHz, CD30D) o 1.18-1.25 (m, lH); 1.36 (d,3H, J=7 Hz), 1.7-l.9(m, 4H); 2.0-2.1 (m, lH); 2.8-2.9(m, lH); 3.425 (dt, lH, J=12 Hz, J=3 Hz); 3.65-3.7 (m, lH); 3.6-3.7(m, lH); 3.7-3.8 (m, 2H); 3.9 (m, lH).
Mass Spectrum (M+l)=l91.
.

NH HCI

2-Imino-4-methyl-octahydro-pyrano~4~3-b1pyridine hydrochloride Step A: l-Benzyl-4-methyl- 1 3~4~5~7~8-hexahydro-pyranor4.3-b 7pyridin-2-one To a solution o~ benzyl-(tetrahydro-pyran-4-ylidene)-amine, (S.Og, 26 mmol) in a glass wall pyrolysis tube was added me~yl crotonate (40g, 260 ~nol, lOequiv) and he~t~l for 7 days. The mixture was transfered to a round bottomed flask and ~e volatile component 10 removed under reduced pressure. The ~ixl-~re was chromatographed (75/25 hexane/ethylacetate) to give ~ree spots. The hi,eht~st Rf m~t.ori~1 was the Michael addition adduct of benzyl amine to methyl crotonate.
The next lower Rf spot is 4-methyl-1,3,4,4a,5,7-hexahydro-pyrano~4,3-b]pyndin-2-ylidene-~n in~, the 8,8a lmc~l...ated analog of the bicyclic 15 pyran while the lowest Rf product is the desired int~ t~ (900 mg, 3.5 mmol) lH NMR (400 MHz, CDC13) ~ 1.02 (d,3H, J=6 Hz); 2.1-2.2 (m, lH);
2.25-2.35(m, 3H); 2.70 (dd,lH, J=12 Hz, J=6 Hz); 3.65-3.70 (m, lH);
20 3.75-3.85 (m, lH); 4.10 (q, 2H, J=14 Hz); 4.65 (d,lH, J=16 Hz); 5.01 (d,lH, J=16 Hz); 7.1-7.3 (m, 5H).

Step B: 4-Methyl-1.3.4.5.7.8-hexahvdro-pyranor4 3-b~pyridin-2-one 2~ 1-Benzyl-4-medlyl-1,3,4,5,7,8-hexahydro-pyrano[4,3-b]pyIidin-2-one (800 mg, 3.2 mmol) was debenzylated according to ~e ~e method of example 121, step D to recover 190 mg of product.

lH NMR ~400 MHz, CDC13) ~ 1.02 (d,3H, J=6 Hz); 2.14 (m, 2H); 2.27-30 2.35(m, 2H); 2.61 (dd,lH, J=12 Hz, J=6 Hz); 3.81(t, 2H, J=9 Hz); 4.10 (q, 2H, J=14 hZ).

StepC: 4-Methyl-octahydro-cis-pyrano~4.3-b1pgridin-2-one W O96/14844 PCTrUS95/14812 4-Methyl-1,3,4,5,7,8-hexahydro-pyrano[4,3-b]pyridin-2-one (210 mg, 1.25 mmol) was hydrogenated using 5% rhodium on alumina as prevously described in example 121 step C for l-benzyl-3-methyl-octahydro-cis-pyrano[4,3-b]pyridin-2-one. Recovered 61 mg of product.
5 The NMR indicated approxim~tely a 9/1 ratio of the ,B/a4-methyl product.

lH NMR (400 MHz, CDC13) o 0.99 (d,3H, J=6 Hz); 1.53 (d, lH, J=18 Hz); 1.95-2.1 (m, 4H); 2.34 (dd,lH, J=18 Hz, J-6 Hz); 3.44 (t, lH, J=12 10 Hz); 3.53 (t, lH, J=12 Hz); 3.7-3.78 (m, 2H); 3.80 (dd, lH, J=12 Hz, J=5 Hz); 6.35 (bs, lH).

Step D: 2-Methoxy-4-methyl-hexahydro-cis~ trans(4H)pyranor4.3-blpyridine 4-Methyl-octahydro-cis-pyrano[4,3-b]pyridin-2-one (60 mg, 0.35 mmoL) was converted to the above compound as previously described in step E of example 116 for 2-methoxy-hexahydro-quinolin-7(8H)-one-7-ethylenloket~l A mixture of cis and trans ring junction 20 delivaLives was isolated. (20 mg).

lH NMR (400 MHz, CDC13) o 0.95 (d, 3H, J=7 Hz); 1.01 (d, 3H, J=7 Hz); 136 (d,3H, J=7 Hz), 3.69 (s, 3H); 3.74 (s, 3H).

25 Step E: 2-Imino-4-methyl-octahydro-pyrahor4.3-b7pyridine hydrochloride 2-Methoxy-a"~-4-methyl-hexahydro-cis,trans(4H)pyrano- [4,3-b]pyridine (20mg) was converted to the above compound as prevously 30 tlescrihed in example 116,step F.

- lH NMR (400 MHz, CD30D) o l.O9(d, 3H, J=7 Hz); 1.03 (d,3H, J=7 Hz).

CA 0220368l l997-04-24 W O96/14844 PCTrUS95/14812 ^ 172-Mass Spectrum m/e = 168.(M~l) EXAMPLl~ 123 ~NH HOAC

2-Imino-4-Methyl- 1 3.4~5.7.8-hexahvdro-pyranor4 3-b 7pyridine. acetic acid salt Step A: 2-Methoxy-4-methvl-3.5.7.8-tetrahydro-4H-pyranor4.3-blpyridine 4-Me~yl-1,3,4,5,7,8-hexahydro-pyrano[4,3-b]pyridin-2-one 15 (42 mg, 0.25 mmoL), obtained in step A examplel22, was converted to the above compound as previously described in example 116 step E.

lH NMR 400 MHz(CDCl3) ~ 0.92 (d,3H, J=7 Hz); 2.1-2.15 (m, 2H);
2.2-2.6(m, 3H); 3.30 (d,lH, J=12 Hz); 3.80(s, 3H); 4.05-4.2(q, 2H, J=16 20 hZ).

Step B: 2-Imino4-Methyl- 1.3.45.7.8-hexahydro-pyranor4.3-b 7pyridine.
acetic acid salt 2-Me~oxy-4-methyl-3,5,7,8-tetrahydro-4H-pyrano[4,3-b~pyIidine (16 mg, 0.1 mmoL) was converted to the above compound as prevously described in example 116 step F.

lH NMR (400 MHz, CD30D) ~ 1.044(d, 3H, J=7Hz); 1.93 (s, 3H, ~cet~te protons); 2.2-2.3 (m, 2H); 2.4-2.47 (m, lH); 2.56 (dd, lH, J=12 Hz, J=6 Hz); 3.94 (dd,lH, L=16 Hz, J=5 Hz); 3.33(dd, lH, J=9 Hz, J=2Hz); 3.84 (t lH, J=5 Hz); 4.1-4.23(m, lH).

Mass Spectrum m/e =167.(M+1) ~NH HCI

2-Imino-l-methvl-piperidine hydrochloride This compound was prepared according to the procedure ~esçribed by Rama Rao et al.in Syn. Comm.: 1$, 877-880 (1988).

1H NMR (400 MHz, CD30D): o 1.89 (m, 4H), 2.62 (t, 2H); 3.14 (s, 3H);
15 3.53 (t, 2H).

Mass spectrum m/e - 114 (M+l) Nb~N~¢~

N-(1 -Benzyl-2-piperidinylidene)-N'-(phenyl)-urea Step A: 2-Imino-1-benzyl-piperidine tetrafluoroborate To a solution N-benzyl-valerol~-,t~ (1.3 g, 6.87 mmol) in methylene chloride (25 mL) was added trimethyloxonium WO g6/14844 PCT/US9S/14812 tetrafluoroborate (1.12 g, 7.57 mmol). The reaction mL~ture was stirred overnight at room temp~ ul~ under a nitrogen atmosphere. Dry ammonia gas was then bubbled through the reaction mixt-lre for one hour, and the mixture was allowed to stand for an additional hour at room S te~ lur~. The mixture was evaporated under ~limini~h~od pressure and dried in vacuo. The crude product was used without further pll~ific~tion in Step B.

Step B: N-(l-Benzyl-2-piperidinylidene)-N'-(phenyl)-urea The fluoboric acid salt from Step A was treated with several mL's of 50% sodium hydroxide, and the free 2-imino-1-benzyl-piperi(line was extracted with ben7~ne. The benzene layer was dec~nt~
dried (K2C03), and evaporated to give an oil. 300 mg of the resulting oil 15 was dissolved in methylene chloride (2.5 mL) and treated with 1,8-diazabicyclo[5.4.0~undec-7-ene (204 ,uL, 1.36 mmol) and phenyl isocyanate (148 ,uL, 1.36 mmol). The reaction mixture was stirred overni~ht at room te~ dture, tlihltetl wi~ methylene chloride, washed with 2 N hydrochloric acid, sa~ ted sodium hydrogencarbonate 20 solution, saturated brine solution, dried (Na2S04), and evaporated. ~he product was cryst~lli7~(1 from ethyl acetate; yield lS0 mg.

lH NMR (400 MHz, CDC13): ~ 1.76 (m, 4H); 3.04 (t, 2H); 3.25 (t, 2H);
4.78 (s, 2H); 6.93-7.34 (m, lOH).
Mass spect~um m/e = 308 (M +1).

N-(2-Piperidinylidene)-N'-(phenvl)-urea N-(l-Benzyl-2-piperidinylidene)-N'-(phenyl)-urea (70 5 mg, 0.228 mmol, from Example 125) in glacial acetic acid (2 rnL) was hydrogenolyzed in the presence of 10% Pd/C (30 mg) for 8 h. The catalyst was removed by filtration through an Anotop 25 Dispo Syringe Filter (0.2 ,um). The filtrate was evaporated and coevaporated several times with toluene. The product was purified by flash silica gel 10 chromatography eluting with 1-5% methanol/CH2C12; yield 15 mg.

lH NMR (400 MHz, CD30D): ~ 1.85 (m, 4H); 2.59 (br m, 2H); 3.50 (br m, 2H); 7.05 (t, lH); 7.28 (t, 2H); 7.50 (d, 2H).

15 Mass spectrum m/e = 218 (M +1).

~3J ~

N-rl-(4-Methoxybenzyl)-2-piperidinylidenel-N'-(phenyl)-urea Step A: 2-Imino-1-(4-methoxybenzyl)-piperidine tetrafluoroborate This compound was pr~paled in a simil~r m~nner as in Step A of Fx~mple 126. The crude product was used without ~urther purification in Step B.

30 StepB: N-rl-(4-Methoxybenzyl)-2-piperidinylidenel-N'-(phenvl)-urea -W O96/14844 ~CT~US95/14812 The fluoboric acid salt from Step A was treated with several mL's of 50% sodium hydroxide, and the free 2-imino- 1-(4-methoxybenzyl)-piperi~line was extracted with be~7~nP.. The benzene layer was dec~nted, dried (K2CO3), and evaporated to give an oil. 300 5 mg of the res~lltin~ oil was dissolved in methylene chloride (2 mL) and treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (204 IlL, 1.36 mmol) and phenyl isocyanate (148 ,~LL, 1.36 mmol). The reaction n~ixture was stirred for 2 hours at room tempelalur~ te(1 with methylene chloride, washed with 2 N hydrochloric acid, saturated sodium hydrogencarbonate 10 solution, saturated brine solution, dried (Na2S04), and evaporated. The product was pllrif1e~1 by flash silica gel chromatography eluting with 30%
ethyl ~( et~te in hexane; yield 127 mg.

lH NMR (400 MHz, CDC13): â 1.73 (m, 4H); 3.03 (t, 2H); 3.22 (t, 2H);
15 3.79 (s, 3H) 4.70 (s, 2H); 6.83-7.27 (m, 9H).

Mass spectrum m/e = 338 (M +1).

, ~N~NH
HN~O

2-Imino~ benzylaminocarbonvl)-piperidine To a mixt-lre of 2-imino-pipçritline hydrochloride (250 mg, 1.86 mmol) in acetc~illile (8 mL) cooled in an ice-badl were added 1,8-diazabicyclo~5.4.0]undec-7-ene (277 ,uL, 1.85 mmol) and benzyl isocyanate (229 ,uL, 1.85 mmol). The reaction mixture was stirred 30 ove.rni~ht at room temp~ ule and then e~aporated. The product was W O96/14844 P~ S/14812 purified by flash silica gel chromatography eluting with 2-3%
methanol/CH2Cl2-lH NMR (400 MHz, CD30D): o 1.78 (m, 4H) 2.37 (m, 2H); 3.39 (m, 5 2H); 4.34 (s, 2H); 7.18-7.31 (m, 5H).

Mass spectrum m/e = 232 (M + 1).

~~ .
~ H NH HCI

Cis-Octahydro-3-imino-2H-1.4-benzoxazine hydrochloride:
Step A: Cis-hexahydro-1.4-benzoxazin-3(4H)-one:

A mixhlre of 2H-1,4-benzox~7in-3(4H)-one (lg) and pl~ti,,ll,,, oxide (O.Sg) in 50 mT . of glacial acetic acid was hydrogenated 20 on Parr shaker at room tempel~lule and 50 psi for 2 days. The catatlyst was filtered and washed with acetic acid. The filtrate was concentrated to give the desired lact~m as white solid after purification on silica gel using 2% methanol in ethyl ~et~te as solvent.

25 Step B: Cis-Octahydro-3-imino-2H-1.4-benzoxazine hydrochloride The title compouhd was ~r~al~d according to the method described in Fx~rnples 2 and 3.

30 lH NMR (D6-DMSO): 4.52(m,2H); 3.88(m,1H); 1.16-1.8(m,8H) ~ H~NH HCI

2-Iminopiperazine hydrochloride s Step A: 2-Ketopiperazine A solution of 10.2 g (81 mmol) of ethyl chloroacetate in 50 mL of ethanol was added ~wise over 1 hr to a solution of 30 g (0.5 M) 10 of ethylene di~minP in 125 rnL of ethanol at room tempel~lure. The lule was stirred 3 hrs and 4.4 g (81 mmol) of sodium methoxide was added and the ~ lurt; was stirred additional 4 hours. The resulting voluminous white precipi~te was filtered and ~e filtrate was con~e.rltrated to give oily residue which was h~ l at 200 C (bath 15 temp~lalul~;) for 5 mins with a wide distillation head. A solid deposited in the distillation head during the distillation. After 1.5 hrs of ~li.etill~tion, distillation head was washed with meth~nol to remove the desired product. Methanol washes were cor~ce~ ted to give a crude product which was pllrifie-l on silica gel using 5:2 mixhlre of 20 chloroforrn mto.th~nol as solvent to provide 2.3 g of the desired product as yellow solid.

lH NMR (DMSO): 2.74(m,2H); 3.1(m,2H); 3.13(s,2H); 7.58(b,1H) 25 Step B: 4-t-Butoxycarbonyl-2-keto~i~erazine A mixt~lre of 500 mg (5 mmol) of 2-kelo~i~erazine, 1.2 g ,' (5.5 mmol~ of t-butyldicarbonate and 2 g of sodium chloride in 7.5 mL of water and 10 mL of chloroform was he~te~l to reflux 4 hrs. The reaction 30 mixtllre was cooled to room temp~lalur~; and extracted with ethyl ac~ e.
The combined ethyl acetate extr~te were dried over anhydrous m~gTlPeium sulfate . Solvent removal gave a crude product which w~s f purified on silica gel using 5% mt~th~nol in ethyl acetate as solvent to give 925 mg of the desired call.alllate lactam as white solid.

lH NMR (CDC13): 1.46(s,9H); 3.37(m,2H); 3.62(m,2H); 4.08(s,2H) Step C: 4-t-Butoxycarbonvl-2-imino piperazine hydrochloride The title compouind was prepared according to the procedure described in Examples 2 and 3.
lH NMR (DMSO): 1.42(s,9H); 3.35(m,2H); 3.52(m,2H); 4.32(s,2H);
8.75(b,1H); 9.04(b,1H); 10.05(b,1H).

Step D: 2-Imino piperazine hydrochloride Hydrogen chloride gas was bubbled through 6 mL of ethyl ~cet~te at 0 C for 3 mins. Solid 4-t-butoxycarbonyl-2-imino piperazine hydrochloride (36 mg) was added and the lni~Lule was stirred overnight at room tempelalul~;. Solvent and hydrochloric acid gas were evaporated 20 in vacuo to give 24 mg of the desired imino piperazine hydrochloride as white solid.

lH NMR (DMSO): 3.35(3H); 3.54(m,2H); 4.12(s,2H); 8.98(b,1H);
9.3(b,1H); 10.16(b,1H) ~N~
~= H NH HCI

4-Methyl-2-imino~ erazine hydrochloride WO 96/14844 PCI~/US9~/14812 Step A: 4-Methyl-2-oxo-piperazine hydrochloride:

4.4 g (100 mmol) of ethyleneimine was added to 7.8 g (66 mmol) of sarcosine ethyl ester with stirTing at 60 C. The mixture was S then heated 1 day at the same te~ )er~ e. Volatile materials were removed in vacuo and the residue was purified on silica gel using methanollethyl acetate gradient mixtures to give the title compound.

lH NMR (CDC13): 3.35~2H); 3.06(2H); 2.58(2H); 2.32(3H) Tk~e hydrochloride salt was ~le~ ed by ~lAin,~ ethereal hydrochloride solution to a solution of the above tertiary amine and stirrin~ the ..,i~ e for 1 hour. The resulting solid was fîltered and washed with ether and dried.
Step B: 4-Methyl-2-methoxy-3.4~5~6-tetrahydro pyrazine A mix1nre of l.SOS g (lOmM) of 4-methyl-2-oxo-piperazine hydrochloride from step A and 3.0 g (20 mM) of trim~tllyloxonium 20 tetra~uoroborate in lSO mL of chloroform was stirred for 4 days at room te~ eralul~ under nitrogen. Excess s~ te~l sodium bicarbonate was added and stirred 30 mins. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over anhydrous m~ sillm sulfate. After filtration the 25 solvent was removed to give a mixture of dle title compound and 4-methyl-piperazin-2-one as an oil.

lH NMR (CDC13): 3.64(s,3H); 3.36 and 3.56(4:11)(m,2H); 3.08 and 2.9 (4: l l)(s,2H); 2.6 and 2.4 (4: l l)(m,2H); 2.33 and 2.3(6: 16.5)(s,3H) t Step C: 4-Methyl-2-iminopiperazine hvdrochloride and 4-Methyl-2-oxo-piperazine hydrochloride:

This compound was ~r~ar~d from 4-methyl-2-methoxy-3,4,5,6-tetrahydro pyrazine according to the procedure of example 3.
This product was cont~in~l some 4-methyl-piperazin-2-one which was present in the starting m~te.ri~l.
s 1H NMR (CD30D): 2.92 and 2.43 (s,3H); 3.8 and 3.42(s,2H); 2.75 and 3.56(t, 2H); 3.45 and 3.8(t,2H) = ~ ~

H
~,N~
~ H NH HCI

2-Imino-decahydro-cis-quinoxaline dihydrochloride Step A: Decahydro-2(1H)-quinxalinone To a solution of 2.28 g (20 mmol) of cis-1,2-minocyclohf-.x~ne in 100 mL of water, 1.74 g (30 mmol) of glyoxal 20 was added. After stirring for 4 h the reaction ,~ixl...e was filtered and the filtrate was concenllated in vacuo. The resi~ l oil was absorbed on a flash column and the column was eluted with 50% EtOAc/h~x~n~, 10%
MeOH/EtOAc and 50% MeOH/EtOAc to isolate 1.19 g of the title compound as an oil.

Step B: 4-t-Butyloxycarbonyl-decahydro-2(1H)-quinoxalinone A solution of 1.19 g (7.72 mmol) of decahydro-2(1H)-quinxalinone in 10 mL of salulated NaHC03 was treated with 2.2 g (10 30 mmol) of di-tert-butyl dicarbonate. After stirring for 2 h the reaction mixture was extracted with EtOAc and the EtOAc layer was washed with WO 96/14844 PCr/US95/14812 brine and dried. The filtrate was concentlat~d and the residue was purified on a flash column to isolate 0.667 g of the title compound.

Step C: 4-t-Butyloxycarbonyl-2-methoxy-3.4.5.6.7.8.5a.8.a-octahydro-5 quinoxalinone.

To a solution of 0.254 g (1 mmol) of 4-t-butyloxycarbonyl-decahydro-2(1H)-quinoxalinone in 3 mL of CH2C12 was added 0.191 g (1.3 mmol) of trimethyloxonium tetrafluoroborate and the mixt~lre was 10 stirred overni~ht The reaction mixture was partitioned between saturated NaHC03 and CH2Cl2. The organic layer was washed with water, brine dried and concentrated. The residue was chromatographed using 20%
Et20-hexane as an eluent to isolate 0.124 g of the title compound.

15 StepD: 4-t-Butoxy-2-imino-decahydro-cis-quinoxaline A solution of 0.123 g (0.45 mmol) of 4-t-Butyloxycarbonyl-2-me~oxy-3,4,5,6,7,8,5a,8,a-octahydro-quinoxalinone in 3 mL of EtOH
co--t~ i..g 22 mg (0.41 mmol) of NH4Cl was he~te~l to reflux. After 3 h 20 at reflux the reaction n~ e was conce~ ated, the residue was ~ ~dted with Et20 and the solid was filtered and dried to isolate 0.055 mg of the title compound.

Step E: 2-Imino-decahydro-cis-quinoxaline To 46 mg of 4-t-butoxy-2-imino-decahydro-cis-quinoxaline 3 mL of EtOAc salulated with HCl was added. The reaction turned clear mom~ont~rily and another solid was formed. After 30 min the solid was filtered washed with Et20 and dried to furnish 32 mg of the title 30 compound.

lH NMR (D20): 1.50 (br s, 3H), 1.66 (br s, lH), 1.89 (br s, 4H), 3.92 (m, lH), 4.0 (m, lH), 4.37 ~s, 2H) W O96114844 PCTnUS95/14812 , .L
~N~

H NH HCI

2-In~ino-decahydro-trans-quinoxaline dihydrochloride The title compound was l~r~yared by the procedure of example 132 starting with trans-1,2-~ minocyclohex~ne..
lH NMR (D20): 1.3-1.6 (m,4H), 1.8-1.9 (m, 2H), 2.16 (t, 2H), 3.3 (td, - lH, J = 11 and 4 Hz), 3.55 (td, lH, J = 11 and 4 Hz), 4.41 (ABq, 2H) CH 3J~N~NH HCI

4-6-Dimethyl-2-irnino-piperazine hvdrochloride Step A: 4.6-Dimethyl-2-keto-piperazine A solution of 0.8 mL (10.2 mmol) 2-methylaziridine (90%), 0.998 g (11.21 mmol) of sarcosine and 30 mg of NH4Cl in 4 mL of water 25 was he~te-l to 100 C in a sealed tube for 2 h. The mixture was allowed to stand overni~ht, then conce~ ated in vacuo. The residue was purified by chromatography using 30% MeOH-EtOAc to yield 0.637 g (49%) of the desired product.

lH NMR (CDC13): 1.13 (d, 3H), 2.03 (m, lH~, 2.28 (s, 3H), 2.77 (m, 2H), 3.23 (d, lH), 3.62 (br s, lH), 6.8 (br s, lH).

StepB: 4.6-Dimethyl-piperazin-2-thione To a solution of 1.011 g (5.09 mmol) of 4,6--lim~-t~yl-2-keto-piperazine in 25 mL of dioxane, 4.704 g (56 mmol) of NaHC03 and 1.56 g (3.56 mmol) of phosphorus pentasulfide were added and the ~ixllll~; was h.o~te~l in a 70 C bath. After 6 h the reaction was cooled, 10 quenched by ~rl~ling water (gas evolution) and stirred overni~ht The solution was extracted with EtOAc. The EtOAc layer was washed with brine, dried and concel~L~a~ed. The residue was chromatographed using a gradient of 0-10% MeOH/EtOAc to isolate 91 mg of the desired product.

15 StepC: 4-6-Dimethyl-2-imino-piperazinehydrochloride Ammonia gas p~se.l through a THF (5 mL) solution of 72 mg (0.499 mmol) of 4,6-dimethyl-~i~e~ -2-thione kept in a 50 C bath for 5 min. To this solution 149 mg (0.55 mmol) of HgC12 was added and 20 the reaction was heated to 50 C for 15 min after it turned black. The solution was filtered ~rough a pad of celite and the pad was rinsed with MeOH. The combined filtrate was concent. ~te~l and ~e residue was purified on a flash column using MeCN followed by 70:2: 1 ~ L~ of MeCN:H20:HOAC to isolate 30 mg of the title compound.
lH NMR (CD30D): 1.25 (d, 3H), 1.9 (s, 3H), 2.27 (dd, lH), 2.9 (dd, lH), 3.22 (d, lH), 3.45 (d, lH), 3.72 (m, lH).

Mass spectrum m/e = 127 , -WO 96/14844 PCTtUS95114812 H

~ N~NH HCI

2-Imino-4-methyl-6-(2-methylpropyl)-5-oxo-piperazine hydrochloride 5 Step A: N-t-Butyloxycarbonyl~lycinvlsarcosine ethyl ester To a solution of 0.629 g (3.59 mmol) of t-butoxycarbonyoxyglycine in 8 mT . of CH2Cl2 0.58 g (4.31 mmol) of hydroxyben7tri~iole,0.87 mL (7.9 mmol) of N-methylmorpholine and 10 0.826 g (4.31 mmol) of EDAC were added. After 10 min 0.607 g (3.95 mmol) of sarcosine ethyl ester hydrochloride was added and the mixtllre was stirred ove.rni~ht The reaction was poured into water and extracted with CH2C12. The organic layer was washed with brine, dried and the filtrate was conce~ ted. The residue was purified on a flash column 15 eluting with 50% EtOAc-hexane to obtain 0.985 (96%) of N-t-butyloxycarbonylglycinylsarcosine ethyl ester.

Step B: l-Methyl-2.5-diketopiperazine A solution of 0.942 g (3.43 mmol) of N-t-butyloxycarbonylglycinylsarcosine ethyl ester in 10 ml of EtOAc was salur~ted with HCl gas. After stirring for 1 h the solution was concel~ ed in vacuo to leave a white solid. The solid was dissolved in 10 mL of EtOH, 0.474 g (3.43 mmol) of powdered K2CO3 was added and the lllir.lure was he~tet1 in a 60 C bath overni~ht The solid was filtered and rinsed with EtOH and the combined filtrate was concentrated to leave a solid. The solid was washed with ether and dried to furnish 0.499 g of the title compound.

lH NMR (CDCl3): 2.98 (s, 3H), 3.97 (s, 2H), 4.02 (s, 2H), 6.23 (br s, lH).

W O96/14844 PCT~US95/14812 Step C: 2-Methoxv-4-methyl-3~4-dihydro-5(6H)-pyrazinone.

Tre~tment of 1-methyl-2,5-diketopiperazine with trimethyloxonium tetrafluoroborate as described in example 132 step C
5 gave the title compound.

Step D: 2-Methoxy-4-methyl-6-(2-methylpropYl)-3.4-dihvdro-5(6H)-pvrazinone.

To a solution of 0.171 g (1.2 mmol) of 2-methoxy-4-methyl-3,4-dihydro-5(6H)-pyrazinone in 6 mL of THF cooled in a -78 C bath, 0.72 mL (2M in THF, 1.44 mmol) of LDA was added. After 10 min 0.17 mT . (1.56 mmol) of 1-bromo-2-methylpropane was added and the solution was allowed to warm to room tempel~LIlle over the next 2 h.
15 A~ter stirring for 0.5 h the reaction was quenched by ~ ling water and the e was extracted with EtOAc. The EtOAc layer was washed with brine, dried and the ~lltrate was conc~ ted. I`he residue was purified on a flash column using a gradient of 30-50% EtOAc-hexane to isolate 0.1 g (42~7O) of the title compound.
lH NMR (CDC13): 0.91 (d, 3H), 0.94 (d, 3H), 1.4-1.9 (m, 3H), 2.93 (s, 3H), 3.69 (s, 3H), 3.81 and 3.94 (ABq, 2H), 4.09 (m, lH).

Step E: 2-Imino-4-me~yl-6-(2-methylpropyl)-5-oxo-piperazine A solution of 0.1 g of 2-methoxy-4-methyl-6-(2-methyl~lo~yl)-3,4-dihydro-5(6H)-pyrazinone in 1 mL of EtOH was reacted with NH4Cl as described in example 132 step D to furnish the tide co~l~oulld.
lH NMR (CD30D): 0.96 (d, 6H), 1.6-1.9 (m, 3H), 3.0 (s, 3H), 4.11 (t, lH), 4.47 and 4.61 (AB q, 2H).

Mass spectrum m/e = 184 (M+l) . .

Oq~O~
N
~ N~NH HCI
S H

4-Benzyloxvcarbonyl-2-imino-(1~2~3.4)tetrahydro-quinoxaline hvdrochloride 10 Step A: 3~4-Dihydo-2(1H)-quinaxolone To a solution of 1.2 g (8.2 mmol) of 2-hydroxyquinoxaline in 10 mL of EtOH, 220 mg of PtO2 was added and the solution was hydrogenated on a Parr a~araLus overnight The catalyst was filtered 15 and washed with EtOH and the filtrate was conce~ ated to yield 1.17 g (96%) of the title compound sufficiently pure for use without purification.

lH NMR (CDC13): 3.97 (s, 2H), 6.6-6.9 (m, 4H), 8.1 (br s, lH).
StepB: 4-Benzyloxycarbonyl-3~4-dihydro-2(1H)-quinaxolone A solution of o.41 g (2.77 mmol) of 3,4-dihydo-2(1H)-quinaxolone in 5 mL of CH2C12 and 5 mL of salurated NaHCO3 was 25 treated with 0.44 rnL (3.05 mrnol) of benzylchloroformate. After stirring for 4 h, the reaction was diluted with CH2C12, washed with water, brine and dried. The filtrate was concellt,ated and the residue was chromatographed using 30% EtOAc-hexane to isolate 0.31 g of the desired product.

-CA 0220368l l997-04-24 W Og6/14844 PCTnUS95/14812 lH NMR (CDC13): 4.44 and 4.58 (2s, 2H), 5.24 and 5.28 (2s, 2H), 6.8-7.4 (m, 9H).

Step C: 4-Benzvlo~yca,l,onyl-2-imino-(1.2.3.4)tetrahydro-quinoxaline S hydrochloride The 4-benzyloxycarbonyl-3,4-dihydro-2(1H)-quinaxolone obtained in step B was subjected to the reactions described in example 134 steps B and C fi~ h.otl the title compound.

1H NMl~ (CD30D): 4.31 (s, 2H), 5.23 (s, 2H), 6.9-7.5 (m, 9H).

Mass spectrum m/e = 282 (M+l) . = . .

Example 137 Oq~CH3 ~N

H NH HCI

20 4-Acetyl-2-imino-(1.2.3.4)tetrahydro-quinoxaline hvdrochloride = =~ . . . ~ .
StepA: 4-Acetyll-3.4-dihydro-2(1H)-quinaxolone A solution of 0.212 g (1.43 mmol) of 3,4-dihydo-2(1H)-25 quinaxolone (example 136, step A) in 7 mL of CH2Ck was treated with 0.12 mL (1.72 mmol) of acetyl chloride and 0.26 mL (1.86 mmol) of Et3N. After 2 h ano~er 0.04 mL of acetyl chloride was added to complett the reaçtion and the solution was partitioned between water and CH2Cl2. The CH2C12 layer was washed widl brine, dried and 30 conce~ ed. The residue was pllrifie-l by chromatography.

, WO 96tl4844 PCTIUS95/14812 A StepB: 4-Acetyl-2-imino-(1.2.3.4)tetrahydro-quinoxaline Tleatelllent of 4-acetyll- 1,2,3,4-tetrahydro-2-quinaxolone by the method of example 134 steps B and C f~lrnich~-l the title compound.

lH NMR (CD30D): 2.24 (s, 3H), 4.5 (s, 2H), 7.0-7.5 (m, 4H).

Mass spectrum m/e = 189 (M+l) C~N~NH HCI

15 2-Imino-4-methyl-decahydro-trans-quinoxaline. acetic acid salt StepA: 4-methyl-octahydro-trans-2(1H)-quinoxalone To 0.537 g of 4-t-butyloxycarbonyl-octahydro-trans-2(1H)-0 quinoxalone (F.x~mple 133), 10 mL of EtOAc saLu,ated with HCl gas was After stirring for 2 h the solvent was removed in vacuo to give 0.483 g of a brown solid.

To a solution of 0.147 g (0.77 mmol) of this solid in 5 mL of 25 MeOH and 1 mL of form~l-lehyde (37% aq. solution) was added 50 mg of 10 % Pd/C and the mixture was hydrogenated under 41 psi for 3 h.
The catalyst was filtered through a pad of celite and the pad washed with MeOH and the filtrate was concelll,ated to yield 0.325 g of the title compound.
Step B: 2-Imino-4-methyl-decahydro-trans-quinoxaline. acetic acid salt WO 96114844 PCI~/US95114812 The product of step A was reacted as described in example 134 steps B and C to isolate the title compound lH NMR (CD30D): 1.2-2.2 (m, 9H), 1.92 (s, 3H), 2.31 (s, 3H), 3.18 (m, lH), 3.31 (d, lH), 3.70 (d, lH).

Mass spec~um m/e = 168 (M+l) ~s~
~N~NH HCI

3-Imino~iomo~pholine hydrochloride.
Step A: Thiomolpholin-3-one To 6.5 g (0.15 mol) of ethyleneimine was added to 12 g (0.1 mol) of ethyl thiol acetate with ~tirrin~ at 60 C. After the addition, the 20 -~ixl~..e was h~t~ for 2.5 h at the same tempel~luie. It was then allowed to cool to room temp~lulc; and then allowed to stand 1 day at room temp~,~alult;. Robust white crystals formed. The liquid was tl~.c~nte~l and the solid was washed with ice cold ethyl alcohol to afford 6.2 g of the desired thiomorpholinone.
lH NMR (CDCl3): 2.8(m,2H); 3.28(s,2H); 3.62(m,2H); 6.62(b,1H) Step B: Thiomorpholin-3-thione A mixtllre of 1.17 g (10 mmol) of thiomorphoLin-3-one and 11 mmoles of Lawesson's reagent in 2~5 mL of toluene was heated to reflux 2 hrs. The reaction l~lixl.l,e was cooled and ~e solvent was removed to give a residue. This was taken up in methylene chloride and applied on silica gel column and eluted with ethyl acetate cont~ining methylene chloride (10%). The desired thiomorpholin-3-thione in 65%
yield as solid.

5 lH NMR (CDCl3): 2.90(m,2H); 3.62(m,2H); 3.76(s,2H); 8.65(b,1H) StepC: 3-Iminothiomorpholinehydrochloride The title ~micline was prepared from thiomorpholin-3-thione 10 according to the procedure of example 43 step F.

lH NMR ~DMSO): 2.92(m,2H); 3.52(m,2H); 3.62(s,2H); 8.85(b,1H);
9.28(b, IH); 9.9(b, lH) ~H~NH l-ICI

20 3-Imino-5-propyl-thiomorpholine Step A: 2-Butoxycarbonylamino-l-pentanol To a solution of 1.1 mL (9.8 mmol) of 2-amino-1-~ell~lol 25 in 10 mL of MeCN was added 2.18 g (10 mmol) of di-t-butyl dicarbonate followed by a solution of 1.06 g (10 mmol) of Na2CO3 in 10 mL of water. After stirring for 4 h the reaction mixture was partitioned between Et2O:EtOAc (1: 1) and water. The organic layer was washed with water, brine and dried. The filtrate was concentrated to furnish 2.8 g of a liquid 30 which was used in the next step without purification.

lH NMR (CDC13): 0.91 (t, 3H), 1.3-1.9 (m, llH), 2.31 (t, 2H), 2.4 (br s, lH), 3.0 (s, 3H), 3.8 (br, lH), 4.15 (dd, lH, J=10 and 4 Hz), 4.22 (m, lH), 4.57 (br, lH).
. .
5 StepB: Ethyl((2-butoxycarbonylaminopentyl)thio)acetate A solution of 0.7 g of 2-butoxycarbonylamino-1-pe~ lol c~ d in step A in S mL of CH2C12 was treated with 0.23 mL (3 mmol) of methanesulfonyl chloride. The mixture was cooled in ice bath 10 and 0.42 mL (3 mmol) of Et3N was added and the solution was allowed to warm to room tt;l~ ;rature. After 1 h another 0.05 mL (0.65 mmol) of m~th~nesulfonyl chloride and 0.1 mL (0.71 mmol) of Et3N were added and stirred for 15 min. the reaction mixture was diluted with CH2C12 and washed with saturated NaHCO3 solution, water, 1.2 N HCl and brine.
15 The organic layer was dried and concelll~aled to yield 0.94 g of the mesylate as a white solid.

lH NMR (CDC13): 0.91 (t, 3H), 1.2-1.9 (m, 1 lH), 2.32 (t, 2H), 3.51 (m, lH), 3.63 (m, 2H), 4.57 (br s, lH).
To a solution of dle mesylate in 5 mT . of EtOH 0.3 mL (2.7 mmol) of ethyl 2-melc~lo~eet~te and 0.42 g (3 mmol) of powdered K2C03 were added. The ~.~ixl...e was h~t.o~l in a 50 C ba~ for 2 h, then t,~l with water and extraced wi~ EtOAc. The EtOAc layer was 25 washed with water, brine, dried and con~e~ ted. The residue was chromatographed on a flash column using a gradient of 20-50% EtOAc-Hex~n~ to isolate 0.48 g (63%) of the tide compound.

lH NMR (CDC13): 0.90 (t, 3H), 1.2-2.3 (m, 16H), 2.72 (m, 2H), 3.23 30 (ABq, 2H), 3.75 (br, lH), 4.19 (q,2H),4.57 (br s, lH).

Step C: 5-Propyl-thiomorpholin-3-one -Ice cold EtOAc (5 mL) was saturated with HCl gas and this solution was added to 0.48 g (1.57 rnmol) of ethyl ((2-butoxycarbonylamino~ yl)thio)~et~te. After stirring for 1 h the solution was concentrated to give 0.42 g of ~mine hydrochloride as an oil.
5 The oil was dissolved in 3 mL of EtOH and 0.207 g (1.5 mmol) of powdered K2CO3 was added. After heating the mixt~lre in a 80 C bath for 2.5 h the reaction was cooled and partitioned between water and - EtOAc. The organic layer was washed with water, brine, dried and conce~ ted. The residue was purified by flash chromatography using 10 30-I00% EtOAc-hexane to yield 0.15 g (60%) of the title compound as a white solid.

lH NMR (CDCl3): 0.94 (t, 3H), 1.36 (m, 2H), 1.57 (m, 2H), 2.53 (dd, lH, J=13 and 9 Hz), 2.78 (dd, lH, J=13 and 4 Hz), 3.26 (ABq, 2H), 3.63 15 (m, lH), 5.8 (br s, lH).

Step D: 5-Propyl-thiomorpholin-3-thione A solution of 0.15 g (0.94 mmol) of 5-propyl-thiomorpholin-20 3-one in 3 mL of toluene was treated with 0.44 g (1.1 mmol) of Lawesson's reagent and the reaction was heated to reflux. After 1 h the solution was cooled to room te~ al--le, ~lilute-l with 2 mL of hexane and allowed to stand overnight The solid formed was removed by filterin~ through a 0.5 u filter and the filtrate was concellllated. The 25 residue was chromatographed using 10-30% EtOAc/hex~ne to obtain 0.131 g (80%) of the title compound.

H NMR (CDCl3): 0.95 (t, 3H), 1.41 (m, 2H), 1.64 (m, 2H), 2.60 (dd, lH, J=13 and 9 Hz), 2.89 (dd, lH, J=13 and 4 Hz), 3.57 (m, lH), 3.74 30 (ABq, 2H, J=17Hz), 8.3 (br s, lH).

StepF: 3-Imino-5-propvl-thiomorpholine , W O96tl4844 PCTrUS95/14812 A solution of 0.131 g (0.75 mmol) of 5-propyl-thiomorpholin-3-thione in 3 mL of CH2Cl2 was stirred with 4 A
molecular sieves. After 10 min 0.125 g (0.85 mmol) of trimethyloxonium te~ oroborate was added and the mixture was S stirred for 2.5 h. The reaction was qllenrhe~l by adding saturated NaHCO3 solution then extraced with CH2C12. The organic layer was washed with brine, dried and conce~ ted to give 0.115 g of a brown oil.

lH NMR (CDCl3): 0.94 (t, 3H), 1.4 - 1.8 (m, 4H), 2.29 (s, 3H), 2.3 (m, 10 lH), 2.73 (dd, lH, J=13 and 4 Hz), 3.12 (ABq, 2H), 3.43 (m, lH).

The brown oil in 1 mL of EtOH was trated with 30 mg (0.56 mmol? of NH4Cl and the mixtllre was he~te~l to reflux. After 1 h the solution was concellllated and ~e residue was chromatographed on a 15 flash column using a gradient of MeCN, MeCN/HOAc - 95:5, MeCN/H20/HOAc - 90:5:5 and ~mally MeCN/H20/HOAc - 85: 10:5 to isolate 37 mg (23%) of the title compound as an acetic acid salt.

lH NMR (CDC13): 0.94 (t, 3H), 1.3 - 1.8 (m, 4H), 2.05 (s, 3H), 2.63 20 (dd, lH, J=13 and 9 Hz), 2.92 (dd, lH, J=13 and 4 Hz), 3.65 (m, 3H), 8.2 (br s, lH).

Mass spectrum m/e = 159 (M+l) 25 The compounds of F~x~nlrles 141-145 were prepared by the method of example 101 starting from the a~lu~iate ~mino~lcohol.

CH3~HlNH HCI

3 -Imino-5 -methvl-thiomorpholine W O96/14844 PCT~US95/14812 lH NMR (CD30D): 1.38 (d, 3H), 2.71 (dd, lH, J=13 and 9 Hz), 3.07 (dd, lH, J=13 and 4 Hz), 3.60 (ABq, 2H, J=16 Hz), 3.82 (m, lH).

s C2H5~`HN~NH HCI

10 3-Imino-5-ethvl-thiomolpholine lH NMR (CD30D): 1.03 (t, 3H), 1.75 (m, 2H), 2.75 (dd, lH, J=13 and 9 Hz), 3.1 (dd, lH, J=13 and 4 Hz), 3.6 (m, 3H).

.

~H~NH HCI

.~ , . . ~
20 3-Imino-S-butyl-thiomorpholine lH NMR (CDCl3): 0.95 (t, 3H), 1.3 - 1.~ (m, 6H), 2.75 (dd, lH, J=13 and 9 Hz), 3.1 (dd, lH, J=13 and 4 Hz), 3.60 (m, 3H).

25 Mass spectrum m/e = 173 (M+l) S

~NH HCI

3-Imino-5(S)-(2-methyl propvl)-thiomorpholine 5 lH NMR (CDC13): 0.97 (d, 6H), 1.6 (m, 2H), 1.77 (m, lH), 2.72 (dd, lH, J=13 and 9 Hz), 3.1 (dd, lH, J=13 and 4 Hz), 3.52 (d, lH, J=16 Hz), 3.68 (d, lH, J=16 Hz), 3.75 (m, lH).

Mass spectrum m/e = 173 (M+l) ~ N~NH HCI

3-Imino-5(R)-(2-medlyl propyl)-thiomorpholine lH NMR (CDC13): 0.97 (d, 6H), 1.6 (m, 2H), 1.77 (m, lH), 2.72 (dd, lH, J=13 and 9 Hz), 3.1 (dd, lH, ~=13 and 4 Hz), 3.52 (d, lH, J=16 Hz), 20 3.68 (d, lH, J=16 Hz), 3.75 (m, lH).

Mass spectrum m/e = 173 (M+1) ~o~

H NH HCI

= ~

WO 96/14844 PCI~/US95/14812 1 -ftert-Butoxycarbonyl)-hexahydro-3-irnino-( lH)- 1 ~4-diazepine hydrochloride.

S StepA: 4-(tert-Butoxycarbonvl)-hexahydro-(2~ 4-diazepin-2-one.

Hexahydro-(2H)-1,4-diazepin-2-one (300 mg, 2.63 mmol), obtained by the procedure of B. KoteLko, R. (~Tlink~, R. Guryn, and J.
S~umillo (Acta Pol. Pharm., 1984, 41, 651-7; CA 104:50859y), was 10 dissolved in chloroforrn (5.3 mL). Di-tert-butyl dicarbonate (0.63 g, 2.9 rnrnol) was adde~ along with additional chloroform (3 x 0.15 mL) to aid in the transfer. The solution was stirred for 0.5 h at room tempe.dLllle followed by 3 h at reflux. The solution was then diluted w. ith ~t~llyl Zl~et~te (20 mL) and wæhed with saturated aqueous sodium bicarbonate 15 (5 mL). The aqueous layer was extracted with ethyl ~cet~te (10 mL) The combined organic layers were dried (sodium sulfate), lec~nt~l, and evaporated to give 549 mg (97%) of 4-(tert-butoxycarbonyl)-hexahydro-(2h7)-1,4-diazepin-2-one as white crystals.

20 lH NMR (400 MHz, CD30D): ~ 4.08-4.02 (m, 2H), 3.58 (bt, 2H, J = S
Hz), 3.29-3.26 (m, 2H), 1.81 (broad (~ .tet, 2H, J = 5 Hz), 1.45 (s, 9H).

Mass spectrum (FAB) m/e = 215 (M+l).

25 Step B: l-(tert-Buto~ycall,onyl)-2.5.6~7-tetrahydro-3-methoxy-(lH)-1.4-diazepine.

By analogy to the procedure of Example 2, 4-(tert-butoAycall,onyl)-hexahydro-(2H)- 1 ,4-diazepin-2-one gave 1 -(tert-30 butoxycarbonyl)-2,5,6,7-tetrahydro-3-methoxy-(1H)-1,4-diazepine as a colorless oil in 94% yield.
. .
lH NMR (400 MHz, CD30D): ~ 4.16-4.10 (m, 2H), 3.59 (bs, 3H), 3.56 (bt, 2H, J = 6 Hz), 3.53-3.48 (m, 2H), 1.87-1.77 (m, 2H), 1.44 (s, 9H).

-W O96/14844 PCT~USg5/14812 Mass spectrum (FAB) m/e = 229 (M+l).

Step C: l-(tert-Butoxycarbonyl)-hexahydro-3-imino-(1H)-1~4-5 diazepine hvdrochloride.

By analogy to ~e procedure of Example 3, l-(tert-butoxycarbonyl)-2,5,6,?-tetrahydro-3-methoxy-(lH~-1,4-diazepine gave l-(tert-butoxycarbonyl)-hexahydro-3-imino-(lH)- 1,4-diazepine 10 hydrochloride in q~ l;ve yield as white crystals.

lH NMR (400 MHz, CD30D): o 4.36 (bs, 2H), 3.69-3.62 (m, 2H), 3.60-3.55 ~m, 2H), 1.84-1.76 (m, 2H), 1.47 (s, 9H).

== H

~N~NH 2HCI

20 Hexahydro-2-imino-(1H)-1.4-diazepine dihydrochloride.

By analogy to the procedure of Px~mrle 130 (Step D), 1-(tert-buto~yc~l,onyl)-hexahydro-3-imino-(1H)-1,4-diazepine hydrochloride salt gave hexahydro-2-imino-(1H)-1,4-diazepine 25 dihydrochloride as a fime white solid in ~ t;~e yield.

lH NMR (400 MHz, CD30D): o 4.38 (s, 2H), 3.72-3.68 (m, 2H), 3.52 (t, 2H, J = 5.5 Hz), 2.08 (4uilllet, 2H, J = 5.5 Hz).

30 Mass spectrum (FAB) m/e = 114 (M-2HCl+l).

.

CH

S Hexahydro-2-imino-5-methyl-(1 H)- 1.4-diazepine dihvdrochloride.

Step A: N-(2-Cyano-l-methylethyl)glvcine ethyl ester.

Aqueous sodium hydroxide (2.5 N, 13 mL, 32.5 mmol) was 10 added to a mixhlre of 4.54 g (32.5 mmol) of glycine ethyl ester hydrochloride in 6 mT of eth~nol The solution was cooled in an ice bath and 2.4 g (35.6 mmol) of crotonitrile was added in portions over 5 min.
After 20 min, the ice bath was removed and the reaction was stirred 1.5 h at 25 C followed by 3.5 h at 70 C. The reaction was cooled to room 15 tempe,~ e, 5 g of sodium chloride was added, and the mixtllre was extracted with 2 x 35 mL of ethyl ~cet~te. The organic extracts were dried over sodium slll~te, ~lec~nte~l~ and evaporated. The residue was dissolved in m~t!l~nol, filtered through a 0.45 micron membrane, and evaporated to give 1.30 g (24% yield) of N-(2-cyano-1-20 methyle~yl)glycine ethyl ester as a yellow oil.

H NMR (400 MHz, CDC13): ~ 4.20 (q, 2 H, H=7 Hz), 3.47 (d, lH, J =16 Hz), 3.41 (d, lH, J = 16 Hz), 3.05 (sex.tet, lH, J = 7 Hz), 2.49-2.38 (m, 2H), 1.29 (t, 3H, J = 7 Hz), 1.27 (d, 3H, J = 7 Hz).
Step B: Hexahydro-5-methvl-(2H)-1.4-diazepin-2-one.

N-(2-cyano-1-methylethyl)glycine ethyl ester (1.30 g, 7.64 mmol) was dissolved in 4.5 mL of m~th~nol. Raney nickel (70 mg) was 30 added and the reaction vessel was pressurized with 1000 psi of hydrogen and h~t~ to 50 C for 6 h and to 100 C for 4 h. The supern~t~nt was lec~nte~l and filtered through a 0.45 micron membrane and the catalyst was washed with 3 x 3 mL of methanol. The combined filtrate was evaporated and the residue was chromatographed on 60 g of silica gel ellltin~ with 5-7% methanol in dichlorom~th~nP- to give 0.33 g of colorless oil. Chromatography on 15 g of silica gel ellltin~ with 20%
S methanol in ethyl ~ret~te gave 217 mg (22% yield) of pure hexahydro-5-methyl-(2H)- 1,4-diazepin-2-one.

lH NMR (400 MHz, CD30D): ~ 3.52 (d, lH, J = 15 Hz), 3.37 (d, lH, J
= lS Hz), 3.35 (lH, partially obscured by solvent), 3.23 (ddd, lH, J = 15, 10 6, 2 Hz), 2.89 (dqd, lH, J = 10, 6, 3 Hz), 1.82 (dddd, J = 14, 6, 3, 1 Hz), 1.39(m, lH), 1.12(d,3H,J=6Hz).

Mass spectrum (FAB) m/e = 129 (M+l).

15 Step C: 4-(tert-Butoxycarbonyl)-hexahydro-S-methyl-(2H)-1.4-diazepin-2-one.

Hexahydro-5-me~yl-(2H)-1,4-diazepin-2-one (200 mg, 1.56 mmol) was dissolved in 3.0 mL of chlorofo~ and di-tert-butyl 20 dicarbonate (0.37 g, 1.69 mmol) was added with 0.4 rnL of chlolrollll.
The solution was sti~red at room tempel~ture for 0.5 h and then at reflux for 4.5 hr. The solution was diluted with 20 mL of ethyl ~ce~te and washed with S mL of satulaled aqueous sodium bicarbonate and S mL of salulated aqueous sodium chloride. The aqueous layers were extracted in 25 sllccession with lO mL of ethyl ~ce~te. The combined organic layers were dried (sodium sulfate), d~c~ntç~1, and evaporated to give 360 mg (100% yield) of 4-(tert-butoxycarbonyl)-hexahydro-5-methyl-(2H)-l,~
diazepin-2-one as almost colorless crystals.

30 lH NMR (400 MHz, ~D30D): ~ 4.39-4.02 (m, 2H), 3.80 (bd, lH, J = 17 Hz), 3.19 (dd, lH, J - 14, 7 Hz), 3.13-3.02 (m, lH), 2.13 (dt, lH, J = 15, 6 Hz), 1.80 (dtd, lH, J = 15, 10, 2 Hz), 1.46 (s, 9H), 1.16 (d, 3H, J = 6.5 Hz).

Mass spectrum (ESI) m/e = 229 (M+l).

Step D: l-(tert-Butoxycarbonyl)-2.5.6.7-tetrahydro-3-methoxv-7-methyl-(lH)-1.4-diazepine.

By analogy to the procedure of Fx~mrle 2, 4-(tert-butoxycarbonyl)-hexahydro-5-methyl-(2H)-1,4-diazepin-2-one gave 1-(tert-butoxycarbonyl)-2,5,6,7-tetrahydro-3-methoxy-7-methyl-( lH)- 1,4-diazepine as an almost colorless oil in 86% yield.
lH NMR (400 MHz, CD30D): o 4.55-4.10 (m, 2H), 3.75-3.55 (m, 2H), 3.60 (s, 3H), 3.40 (dd, lH, J= 16, 11 Hz), 2.02-1.90 (m, lH), 1.65 (dt, lH, J = 15, 11 Hz), 1.45 (s, 9H), 1.12 (d, 3H, J = 6.5 Hz).

15 Step E: 4-(tert-Butoxycarbonyl)-hexahydro-2-irnino-5-methvl-(lH)-1~4-diazepine hvdrochloride.

By analogy to the procedure of F.x~mrle 3, l-(tert-butoxycarbonyl)-2,5,6,7-tetrahydro-3-methoxy-7-methyl-(lH)- 1,4-20 diazepine gave 4-(tert-butoxycarbonyl)-hexahydro-2-imino-5-methyl-(1H)-1,4-diazepine hydrochloride in q~ ive yield.

lH NMR (400 MHz, CD30D): o 4.60-4.20 (m, 3H), 4.53 (dd, lH, J =
14, 7 Hz), 3.34-3.23 (partially obscured by solvent, lH), 2.19-2.07 (m, lH), 1.93 (dt, lH, J = 15, 10 Hz), 1.19 (d, 3H, J = 7 Hz).

Mass spectrum (ESI) m/e = 228 (M-HCl+l).

Step F: Hexahydro-2-imino-5-methvl-(1H)-1~4-diazepine 30 dihydrochloride.

By analogy to the procedure of Fx~mple 130 (Step D), 4-(tert-l,.l~oxycarbonyl)-hexahydro-2-imino-5-methyl-(lH)-1,4-diazepine , WO 96114~44 PCT/US95~14812 hydrochloride gave hexahydro-2-imino-5-methyl-(1H)-1,4-diazepine dihydrochloride as a hygroscopic brittle foam in q~ tive yield.

lH NMR (400 MHz, CD30D): o 4.52 (d, lH, J = lS Hz), 4.18 (d, lH, J
5 = 15 Hz), 3.76-3.62 (m, 3H), 2.17 (dm, lH, J = 15 Hz), 1.89-1.77 (m, lH), 1.43 (d, 3H, J = 6 Hz).

Mass spectrum (FAB) m/e = 128 (M-2HCl+l).

CH3 ..

~,~

15 Hexahydro-2-imino-4-methyl-(1 H)- 1 ~4-diazepine hydrochloride.

By analogy to the procedl1re of F.x~mrl~ 140 step F, 2,5,6,7-tetrahydro-3-methylthio- l-methyl-(lH)- 1,4-diazepine (~ar~d by the route of R. Guryn, Polish J. Chem., 1989, 63, 265-271; CA
20 112:178916x) gave hexahydro-2-imino-4-methyl-(lH)-1,4-diazepine hydrochloride. The crude product obtained from 124 mg (0.784 mmol) of the starting iminothioether was dissolved in 0.55 mL of chlor~fo~ at 45 C and 0.25 mL of ethyl ~cet~tç was added. After cooling to room telllL,eLalul~, the resulting pale tan crystals were s~al~ted and dried 25 under vacuum to give 108 mg (84% yield) of product.

lH NMR (400 MHz, CD30D): ~ 3.68 (s, 3H), 3.54-3.50 (m, 2H), 2.97 (t, 2H, J = 5.5 Hz), 1.80 (4uilllet, 2H, J = S Hz).

30 Mass spectrum (FAB) m/e = 128 (M-HCl+l).

H ~NH 2HCI

5 3-Amino-hexahydro-2-imino-(lH)-azepine dihydrochloride.

- Step A: 3-(tert-Butoxycarbonylamino)-epsilon-caprol~ct~m 3-Amino-epsilon-caprolactam (2.00 g, 15.6 mmol) was 10 dissolved in 25 mL of chloroform and di-tert-butyl dicarbonate (3.70 g, 16.9 mmol) was added with 5 mL of chloroform. The solution was stirred at room tempelalu.c for 2 hr. The reaction was diluted with 10 mL of chloroform and washed with 2 x 10 mL of 2 N aqueous hydrochloric acid, 10 mL of saturated aqueous sodium bicarbonate, and 15 10 mL of saturated aqueous sodium chloride. The combined organic layers were dried (sodium sulfate), clec~nte~l, and evaporated to give an almost colorless crystalline solid. This m~teri~l was dissolved in 15 mL
of hexane and 20 mL of ethyl ~cet~te at 75 C, cooled to room tempel~ture, and filtered to give 2.02 g (57% yield) of 3-(tert-20 butoxycarbonylamino)-epsilon-caprolactam as white crystals.

1H NMR (400 MHz, CD30D): o 4.26 (d, lH, J = 10 Hz), 3.29-3.16 (m, 2H), 2.03-1.70 (m, 4H), 1.60-1.27 (m, 2H), 1.44 (s, 9H).

25 Mass spectrum (FAB) m/e = 229 (M+l).

Step B: 3-(tert-Butoxycarbonylamino)-4.5.6 7-tetrahydro-2-methoxy-(3H)-azepine.

By analogy to the procedure of Example 2, 3-(tert-butoxycarbonylamino)-epsilon-caprol~ct~m gave 3-(tert--butoxycarbonylamino)-4,5,6,7-tetrahydro-2-methoxy-(3hr)-azepine as a colorless oil in 95% yield.

lH NMR (400 MHz, CDC13): o 5.38 (bd, lH, J = 6 Hz), 4,58 (bdd, lH, J
5 = 10, 8 Hz), 3.68-3.62 (m, lH), 3.29 (t, lH, J = 12 Hz), 1.99-1.70 (m, 4H), 1.46 (s, 9H), 1.46-1.22 (m, 2H).

Step C: 3-(tert-Butoxvcarbonylamino)-hexahydro-2-imino-(lH)-azepine hydrochloride.
3-(tert-Butoxycarbonylamino)-4,5,6,7-tetrahydro-2-methoxy-(3H~-azepine (503 mg, 2.08 mmol) was dissolved in 6.0 mL of ethanol and 111 mg (2.08 mmol) of ammonium chloride was ~ ed The mixtllre was heated to reflux for 3 h, cooled to room tempelaLule, and lS evaporated. The residue was dissolved in 4 mL of chloroform, filtered through a 0.45 micron membrane, and evaporated under a stream of nitrogen to a weight of 1.18 g. Dioxane (4.0 mL) was added and the ..re was stirred briefly until it bec~mç homogeneous. After crystals had formed, the mixtllre was cooled to 0 C and filtered to give 3-(te7~-20 butoxycarbonylamino)-hexahydro-2-imino-(lH)-azepine hydrochloride as whil~ ~rystals (623 mg, 85% yield) which retained 1 equivalent of dioxane.

lH NMR (400 MHz, CD30D): o 4.57 (d, lH, J = 10 Hz), 3.57-3.46 (m, 25 2H), 2.06-1.94 (m, 2H), 1.89-1.66 (m, 3H), 1.51-1.42 (m, lH), 1.46 (s, 9H).

Mass spec~um (FAB) m/e = 228 (M+l).

30 Step D: 3-Amino-hexahydro-2-imino-(lH)-azepine dihvdrochloride.

By analogy to the procedure of F~mrle 130 (Step D), 3-(tert-butoxycarbonylamino)-hexahydro-2-imino-(lH)-azepine, W O96J14844 PCTrUS95/14812 hydrochloride salt gave 3-amino-hexahydro-2-imino-(lH)-azepine dihydrochloride as fine white crystals in qll~ntit~tive yield.

lH NMR (400 MHz, CD30D): o 4.71 (dd, lH, J = 10, 1.5 Hz), 3.61-5 3.50 (m, 2H), 2.15-1.82 (m, 5H), 1.60-1.47 (m, lH).

Mass spectrum (FAB) m/e = 128 (M-2HCl+l).

EXAMP~E lSl ~NH2 (S)-3-Amino-2-imin~i~elidine dihydrochloride.
Step A: (S)-3-(tert-Butoxvcarbonylamino)-2-piperidone.

l-Hydroxybenzotriazole (960 mg, 7.10 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbo(1iimide hydrochloride (1.36 g, 7.09 20 mmol) were added to a stirred suspension of 1.50 g (6.46 mmol) of N-alpha-(te7~-butoxycarbonyl)-L-o. ,.;ll.i...o in 15 mL of N,N-~imethylform~mi~le. After stirrin~ ov~.rnipht at room tempel~lulc, most of the solvent was removed on a rotary evaporator and the residue was flilute-l with 50 mL of ethyl ~et~te. The mixture was washed with 15 25 mL each of 2 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, and sat~ted aqueous sodium chloride. The organic layer was dried (sodium sulfate), lec~nte-l, and evaporated to give 706 mg (55~o yield) of (S)-3-(tert-butoxycarbonylamino)-2-piperidone as a colorless viscous syrup.
lH NMR (400 MHz, CD30D): o 4.02-3.92 (m, lH), 3.30-3.22 (m, 2H), 2.15-2.05 (m, lH), 1.97-1.70 (m, 3H), 1.45 (s, 9H).

W O96/14844 . PCTrUS95/14812 Step B: (S)-3-(te7t-Butoxycarbonylamino)-3.4.5.6-tetrahydro-2-methoxypyridine.

By analogy to ~e procedure of Fx~mrle 2, (S)-3-(te~-5 butoxycarbonylamino)-2-piperidone gave (5)-3-(tert-butoxycarbonylamino)-3,4,5,6-tetrahydro-2-methoxypyridine as white crystals in (83% yield).

lH NMR (400 MHz, CDC13): ~ 4.85-4.75 (bs, lH), 4.19-4.09 (bs, lH), 10 3.63 (s, 3H), 3.49 (t, 2H, J = 6 Hz), 2.12-2.02 (m, lH), 1.86-1.61 (m, 3H), 1.46 (s, 9H). -Mass spectrum (FAB) m/e - 229 (M+l).

Step C: ~5)-3-(te7~-Butoxvcarbonylamino)-2-iminopiperidine hydrochloride.

By analogy to ~e procedure of Fx~mple 3, (S)-3-(tert-20 butoxycarbonylamino)-3,4,5,6-tetrahydro-2-methoxypyridine gave (5)-3-(tert-butoxycarbonyl~mino)-2-iminopiperidine hydrochloride as white crystals in qu~ntit~tive yield.

lH NMR (400 MHz, CD30D): ~ 4.40-4.33 (m, lH), 3.4~-3.30 (m, 2H), 25 2.10-1.84 (m, 4H), 1.47 (s, 9H).

Mass spectrum (FAB) m/e = 214 (M-HCl+l).

Step D: (S)-3-Amino-2-iminopiperidine dihydrochloride.
By analogy to the procedure of F.~mple 130 (Step D), (S)-3-(tert-butoxycarbonylamino)-2-iminopiperi~line hydrochloride gave (S)-3-amino-2-imino~ipelidine dihydrochloride as a white crystalline solid in q~ ve yield.

W O96/14844 PCTrUS95/14812 lH NMR (400 MHz, CD30D): o 4.48 (t, lH, J = 6 Hz), 3.47 (t, 2H, J =
6 Hz), 2.37-2.24 (m, lH), 2.08-1.90 (m, 3H).

5 Mass spectrum (FAB) m/e = 114 (M-2HCl+l).

.' , ~o~

0 ~ N~NH HCI
Hexahydro-3-imino-1.4-oxazepine hydrochloride.

Step A: 2.5.6~7-Tetrahydro-3-methoxy-1.4-oxazepine.
Using the method described Example 2, 4,5,6,7-tetrahydro-(2H)-1,4-oxazepin-3-one (prepared by the method of S. Suzuki, U.S.
patent 4126614, 1978: CA ~Q:138397) was converted into 2,5,6,7-tetrahydro-3-methoxy- 1,4-oxazepine.
lH NMR (400 MHz, CDC13): ~ 4.18 (s, 2H), 3.87 (t, 2H, J = 6 Hz), 3.64-3.60 (m, 2H), 3.58 (s, 3H), 1.93-1.86 (m, 2H).

Step B: Hexahydro-3-imino-1.4-oxazepine hydrochloride.
Using the method described in F.x~mple 3, 2,5,6,7-tetrahydro-3-methoxy-1,4-oxazepine was converted into hexahydro-3-imino-1,4-oxazepinehydrochloride.

30 lH NMR (400 MHz, CD30D): ~ 4.47 (s, 2H), 3.96 (t, 2H, J = S Hz), 3.64-3.60 (m, 2H), 1.90 (4uilltet, 2H, J = 5 Hz).

. CA 02203681 1997-04-24 W O 96J14844 PCT~US95114812 .

Mass spectrum (FAB): m/e = 115 (M-HCl+l).

N~NH HCI

Hexahydro-3-imino-1.4-thiazepine hydrochloride.

10 Step A: 4.5.6.7-Tetrahvdro-(2H)-1.4-thiazepin-3-thione.

Phosphorus pentasulfide (1.18 g, 2.66 mmol as P4Slo) and sodium bicarbonate (3.56 g, 42.5 mmol) were added to a stilTed solution of 500 mg (3.81 mmol) 4,5,6,7-tetrahydro-(2H)-1,4-thiazepin-3-one 15 (~r~ar~d by the method of M.F. Shostakovskii, et al. Zh. Obshch. Khim., 1961, 31, 1453; CA 55:22177g) in 15 mL of dry dioxane and the mixture was stirred at 75 C for 4 h. The solvent was removed in vacuo, water (15 mL) was cautiously ~ e~l~ and the mixture was h.o~te~ to 50 C for 1 h. The reaction was cooled to room temyer~lule and sodium chloride 20 (6.1 g) was added followed by 40 mL of dichloromethane. To f~-ilit~te s~ar~tion of the layers, 30 mL of saLur~ted aqueous sodium chloride and 100 mL of ethyl acetate were also added. The aqueous layer was extracted with 3 x 40 mL of ethyl ~et~te. The combined organic layers were dried (sodium sulfate), tlec~nt~ nd evaporated. The crude 25 product was chromatographed on 30 g silica gel, eluting with 1.25 L of 20% ethyl acetate/hexane and 200 mL of 5% of ethyl ~ret~t~ dichloromethane to give 380 mg (68% yield) of 4,5,6,7-tetrahydro-(2H)-1,4-thiazepin-3-thione as a white solid.

30 lH NMR (400 MHz, CDC13): ~ 8.55 (bs, lH), 3.74 (s, 2H), 3.51-2.44 (m, 2H), 2.92-2.87 (m, 2H), 1.97 (quintet, 2H, J = 5 Hz).

Mass spectrum (FAB): m/e = 148 (M+l).

Step B: 2~5~6.7-Tetrahvdro-3-ethoxy-1 4-thiazepine.

Employing the method of E. Mohacsi and E.M. Gordon (Synth. Commun., 1984, 14, 1159), ethyl chloroformate (0.112 mL, 1.17 mmol) was added to a "~lure of 4,5,6,7-tetrahydro-(2H)-1,4-thi~epin-3-thione (150 mg, 1.02 mmol) and 0.30 mL of dry dioxane. The mixtllre was stirred and occasionally swirled for 1.5 h at room temperalule. The 10 ~ixl~e was diluted with 15 mL of ethyl acetate and washed with 15 mL
of saturated aqueous sodium carbonate, 10 mL of saturated aqueous sodium carbonate, and 10 mL of saturated aqueous sodium chloride. The aqueous layers were extracted in succession with 15 mL ethyl ~cet~te.
The combined organic layers were dried (sodium sulfate), dec~nte~l, and 15 carefully evaporated to give 158 mg of crude 2,5,6,7-tetrahydro-3-ethoxy-1,4-thiazepine as a slightly volatile yellow oil.

lH NMR (400 MHz, CDC13): o 4.02 (q, 2H, J = 7 Hz), 3.54-3.50 (m, 2H), 3.28 (s, 2H), 2.88 (t, 2H, J = 5 Hz), 1.94-1.87 (m, 2H), 1.26 (t, 3H J
20 = 7 Hz).

Step C: Hexahvdro-3-imino-1~4-thiazepine hydrochloride.

Using the method described in Fx~mple 3, 2,5,6,7-25 hexahydro-3-ethoxy-1,4-thiazepine (150 mg, 0.94 mmol) was converted into the ~mi~lin~ hydrochloride. In this case, the crude product (138 mg) was recryst~lli7e~1 from m~th~nol/ethyl acetate at 60 C with cooling to 0 C to give 56 mg (29% yield) of hexahydro-3-imino-1,4-thiazepine hydrochloride col-t~i"illp 25% ammonium chloride.
1H NMR (400 MHz, CD30D): ~ 3.62 (s, 2H), 3.60-3.58 (m, 2H), 3.01-2.97 (m, 2H), 1.95 ((luilltet, 2H, J = S Hz).

Mass spectrum (FAB): m/e = 131 (M-HCl+1).

WO 96/14844 PCT/US9SJ1~812 ~H~NH 2 HCI

.
Hexahvdro-3-imino-5-propvl-( lH)- 1.4-diazepine dihydrochloride.

Step A: N-(t-Butoxycarbonyl)-N-(3-oxohexyl)glycine ethyl ester.0 l-Hexen-3-one (5.04 g, 51.3 mmol) was added to a solution of glycine ethyl ester (5.3 g, 51.3 mmol) in 50 mL of chloroform. After 3 h at room temp~ , chloroform (15 mL) was added followed by portionwise addition of di-tert-butyl dicarbonate (12.2 g, 56 mmol). The 15 solution was stirled overni~ht at room tempelalul~ and then washed with 50 mL of saturated aqueous sodium bicarbonate and 50 mL of saturated aqueous sodium chloride. The combined aqueous layers were extracted with 2 x 50 mL of ethyl ~et~t~. The combined organic layers were dried (sodium slllf~te), ~Pc~nte~l and evaporated. Flash column 20 chromatography on 450 g of silica gel eluting with 10% e~yl ~cet~t~ n~ gave 13.7 g (89% yield) of N-(tert-butoxycarbonyl)-N-(3-oxohexyl)glycine e~yl ester as a yellow oil.

lH NMR (400 MHz, CDC13) showed two ~ tin~t rotamers in a 3:2 I~liO.
25 Rotamer A (major): ~ 4.13 (q, 2H, J = 7 Hz), 3.92 (s, 2H), 3.49 (t, 2H, J
= 6 Hz), 2.75 (t, 2H, J = 6 Hz), 2.37 (t, 2H, J = 7 Hz), 1.62-1.50 (m, 2H), 1.38 (s, 9H), 1.25 (t, 3H, J = 7 Hz), 0.87 (t, 3H, J = 6 Hz). Rotamer B
(minor): ~ 4.19 (q, 2H, J = 7 Hz), 3.97 (s, 2H), 3.46 (t, 2H, J = 6 Hz), 2.70 (t, 2H, J = 6 Hz), 2.37 (t, 2H, J = 7 Hz), 1.62-1.50 (m, 2H), 1.45 (s, 30 9H), 1.23 (t, 3H, J--7 Hz), 0.89 (t, 3H, J = 6 Hz).

Mass spectrum (FAB): m/e = 202 (M-99).

Step B: N-(tert-Butoxycarbonyl)-N-(3-(benzylamino)hexyl)glycine ethyl ester.

Benzyl~mine (5.7 g, 53.2 mmol) was added to stirred solution of N-(tert-butoxycarbonyl)-N-(3-oxohexyl)glycine ethyl ester (8.07 g, 26.6 mmol) in 30 mL of pyridine and 30 mL of glacial acetic acid at 0 C. A THF solution of sodium cyanoborohydride (1.0 M, 17.3 mL, 17.3 mmol) was added via syringe at 2.0 mL/h. After completion of 10 the addition, the reaction was continlle~l at 0 C to room tempelalul~
overni~ht The reaction was poured into a mixture prepared from 20 mL
of concentrated hydrochloric acid and 230 g of ice, and extracted with 4 x 200 mL of ethyl ~cet~te. The ethyl acetate layers were washed in succession with 500 mL of s~lul~ted aqueous sodium carbonate and 500 15 mL of salur~ted aqueous sodium chloride, dried (sodium sulfate), ~ec~nt~-l, and concentrated to give a yellow oil. Flash column chromatography on silica gel ellltin~ with 5-50% ethyl ~cet~te/dichlorometh~ne filrnichtq~l 5.44 g (59% yield) of N-(tert-butoxycarbonyl)-N-(3-(benzylamino)hexyl)glycine ethyl ester as a yellow 20 oil.

H NMR (400 MHz, CDC13) was complic~te~l by the presence of a 5:4 ~,~ixl...e of rotamers: o 7.36-7.18 (m, 4H), 4.16 (q, 2H, J = 7 Hz), 3.94-3.67 (m, 5H), 3.45-3.21 (m, 2H), 2.72-2.50 (m, lH), 1.75-1.21 25 (m, 9H), 1.43 and 1.39 (two s, 9H), 0.89 (t, 3H, J = 7Hz).

Mass spectrum (ESI): m/e = 393 (M+l).

Step C: N-(tert-Butoxycarbonyl)-N-(3-aminohexyl)~lycine ethyl 30 ester.

A solution of 5.2 g (13.3 mmol) of N-(te7t-butoxycarbonyl)-N-(3-(benzylamino)hexyl)glycine ethyl ester in 15 mL of ethanol and 7.5 mL of glacial acetic acid was shaken with 2.08 g of 20% p~ m -W O96/14844 PCT~US95/14812 hydroxide on carbon under 45-47 psi of hydrogen for 24 h. The mixture was filtered and catalyst was washed with ethanol. The filtrate was conce~ ated and the residue was partitioned between 100 mL of ethyl ~cet~te and 50 mL of saturated aqueous sodium bicarbonate. The 5 aqueous phase was extracted with 3 x 50 mL of ethyl ~et~te? and the combined organic layers were dried (sodium sulfate), ~lec~nte-l, and concentrated to give N-(te7~-butoxycarbonyl)-N-(3-aminohexyl)glycine e~yl ester as a colorless oil in q~ ive yield.

10 1H NMR (400 MHz, CD30D) was compli~ te~l by the presence of a 2: 1 mixt~lre of rotamers: o 4.21-4.14 (m, 2H), 3.97-3.86 (m, 2H), 3.59-3.50 (m, lH), 3.43-3.17 (m, lH), 2.80-2.68 (m, lH), 1.75-1.65 (m, lH), 1.50-1.23 (m, 8 H), 1.47 and 1.40 (two s, 9H), 0.96-0.90 (m, 3H). MS(FAB):
m/e = 303 (M+1).
Step D: 4-(terf-Butoxycarbonyl)-hexahydro-7-propyl-(2H)-1.4-diazepin-2-one.

A solution of N-(tert-butoxycarbonyl)-N-(3-20 aminohexyl)glycine ethyl ester(3.3 g, 10.4 mmol) in 40 mL of ethanol was re~uxed for 2 d. The solvent was evaporated and the residue was purified by flash chromatography on 200 g of silica gel, eluting with 20-50% e~yl ~cet~te/dichloromethane followed by 10%
m~th~nol/dichlorometh~ne. 4-(tert-Butoxycarbonyl)-hexahydro-7-25 propyl-(2H)-1,4-diazepin-2-one was isolated as 804 mg (30% yield) of white solid arld 1.64 g (62%) of s~ing m~teri~l was recovered.

H NMR (400 MHz, CD30D) was complicated by the presence of a ul~ of rotamers: ~ 4.18-4.01 (m, 2H), 3.84-3.64 (m, lH), 3.51-3.30 30 (m, 2H), 1.98-1.85 (m, lH), 1.71-1.33 (m, SH), 1.45 (s, 9H), 0.94 (t, 3H, J=7Hz).

Mass spectrum (FAB): m/e = 157 (M-99).

r Step E: l-(tert-Butoxycarbonyl)-2.5.6.7-tetrahydro-3-methoxy-5-propyl-(1H)-1.4-diazepine.
"
Using the method described in Example 2, 4-(tert-S butoxycarbonyl)-hexahydro-7-propyl-(2H)-1,4-diazepin-2-one was converted into l-(tert-butoxycarbonyl)-2,5,6,7-tetrahydro-3-methoxy-S-propyl-(lH)- 1,4-diazepine.

lH NMR (400 MHz, CD30D) was complicated by the presence of two ro~amers: o 4.30 and 4.17 (two d, lH, J = 16 Hz), 4.07-3.95 (m, lH), 3.59 (s, 3H), 3.54-3.36 (m, 3H), 1.95-1.78 (m, lH), 1.61-1.32 (m, 5Hj, 1.45(s,9H),0.92(t,3H,J=7Hz).

Mass spectrum (FAB): m/e = 256 (M+l).
Step F: l-(tert-Butoxycarbonyl)-3-(tert-butoxycarbonylimino)-hexahydro-S-propyl-(lH)- 1.4-diazepine.

Using the method described in Example 3, 100 mg (0.373 mmol) of 1-(tert-butoxycarbonyl)-2,5,6,7-tetrahydro-3-methoxy-S-propyl-(lH)-1,4-diazepine yielded 104 mg of crude l-(tert-butoxycarbonyl)-hexahydro-3-imino-S-propyl-(lH)-1,4-diazepine hydrochloride salt as an amber foam. Without purification, this int~rmç~ te was dissolved in 1.0 mT . of chloroform and treated with 0.045 mL (41 mg, 0.36 mmol) of 1,1,3,3-tetramethylgl~nicline and 85 mg (0.392 mmol) of di-tert-butyl dicarbonate. After stirring 24 h at room te.,~elalu.e, the mixhlre was partitioned between 25 mL of chlorofol.l-and 10 mL of salurated aqueous sodium chloride. The aqueous layer was extracted with an additional 25 mL of chloroform and the organic layers were dried (sodium sulfate), ~ec~nte~l, and evaporated. The residue was purified by flash column chromatography on 10 g of silica gel eluting with 20% ethyl ~cet~te/hex~ne to furnish 46 mg (41% yield) of l-(tert-buloxycarbonyl)-3-(tert-butoxycarbonylimino)-hexahydro-5-propyl-(1H)-1,4-diazepine as a colorless film.

WO 96/14844 PCrlUS95/14812 lH NMR (400 MHz, CD30D): o 4.22 (bd, lH, J = 16 Hz), 4.02-3.84 (m, 1 H), 3.96 (d, lH, J = 16 Hz), 3.55-3.44 (m, lH), 3.22-3.08 (m, lH), 1.86-1.72 (m, lH), 1.70-1.67 (m, lH), 1.67-1.36 (m, 4H), l.S0 (s, 9H), 1.44 (s, 9H), 0.96 (t, 3H, J = 7 Hz).

Step G: Hexahydro-3-imino-S-propyl-~1H)-1.4-diazepine~
dihvdrochloride.
, Using the method described in Example 130 (Step D), 1-(tert-butoxycarbonyl)-3-(te~-butoxycarbonylimino)-hexahydro-S-propyl-(1H)-1,4-diazepine was converted into hexahydro-3-imino-S-propyl-(1H)-1,4-diazepine dihydrochloride.

lH NMR (400 MHz, CD30D): ~ 4.44 (d, lH, J = 15 Hz), 4.06 (d, lH, J
= 15 Hz), 3.88 (q, lH, J = 7 Hz), 3.61 (dt, lH, J = 14, 4 Hz), 3.40 (ddd, lH,J= 14, 11,3Hz),2.15(dt, lH,J= 16,4Hz), 1.96-1.80(m,2H),.
1.71-1.60 (m, lH), 1.56-1.40 (m, 2H), 1.00 (t, 3H, J = 7 Hz).

Mass spectrum (FAB): m/e = 156 (M-2HCl+l).

EXAMPLE lSS

N

CH3--~N~NH 2 HCI

Hexahydro-3-imino-S-methyl-~1H)-1.4-diazepine dihydrochloride.

Step A: N-(tert-Butoxycarbonyl)-N-(3-oxobutyl)~lycine ethyl ester.
~
Using the method described in Fx~mple 154 (Step A), methyl vinyl ketone and glycine edlyl ester were combined and reacted WO 96tl4844 PCT/US9S/14812 ~^ wi~ di-tert-butyl dicarbonate to give N-(tert-butoxycarbonyl)-N-(3-oxobutyl)glycine ethyl ester.
, lH NMR (400 MHz, C D C13) showed two distinct rotamers in a 3:2 ratio.
5 Rotamer A (major): ~ 4.14 (q, 2H, J = 7 Hz), 3.92 (s, 2H), 3.49 (t, 2H, J
= 6 Hz), 2.79 (t, 2H, J = 6 Hz), 2.12 (s, 3H), 1.38 (s, 9H), 1.25 (t, 3H, J =
7 Hz). Rotamer B (minor): ~ 4.14 (q, 2H, J = 7 Hz), 3.97 (s, 2H), 3.46 (t, 2H, J = 6 Hz), 2.74 (t, 2H, J = 6 Hz), 2.13 (s, 3H), 1.45 (s, 9H), 1.23 (t, 3H,J=7Hz).
Mass spectrum (ESI): m/e = 296 (M+Na).
..
Step B: N-(tert-Butoxycarbonyl)-N-(3-(benzvlamino)butyl)glycine ethyl ester.
Using the method described in Fxamrle 154 (Step B), N-(tert-butoxycarbonyl)-N-(3-oxobutyl)glycine ethyl ester was converted into N-(tert-butoxycarbonyl)-N-(3-(benzylamino)butyl)glycine ethyl ester.
lH NMR (400 MHz, CDC13? was complirate~l by the presence of two rotamers: ~ 7.36-7.20 (m, 5H), 4.16 (bq, 2H, J = 7 Hz), 3.96-3.68 (m, 4H), 3.50-3.21 (m, 2H), 2.89-2.66 (m, lH), 1.74-1.54 (m, 2H), 1.43 and 1.40 (two s, 9H), 1.26 and 1.24 (two q, 3H, J = 7 Hz), 1.13 and 1.10 (two 25 d,3H,J=6Hz).

Mass spectrum (ESI): m/e = 365 (M+l).

Step C: N-(tert-Butoxycarbonyl)-N-(3-aminobutyl)glvcine ethvl 30 ester.

Using the method described in Example 154 (Step C), N-(te7~-butoxycarbonyl)-N-(3-(benzylamino)butyl)glycine ethyl ester was W O96/14844 PCTnUS95114812 converted into N-(tert-butoxycarbonyl)-N-(3-aminobutyl)glycine ethyl ester.

lH NMR (400 MHz, CDCl3) was complicated by the presence of two 5 rotamers: o 4.18 (q, 2H, J = 6 Hz), 3.99-3.86 (m, 2H), 3.58-3.49 (m, lH), 3.42-3.17 (m, lH), 3.07-2.89 (m, lH), 1.72-1.44 (m, 2 H), 1.47 and 1.41 (two s, 9H), 1.30-1.24 (m, 3H), 1.15-1.10 (m, 3H).

Mass spectrum (ESI): m/e = 275 (M+l).
"
Step D: 4-(tert-Butoxvcarbonyl)-hexahydro-7-methvl-(2H)-1~4-diazepin-2-one.

Using the method described in Example 154 (Step D), N-15 (tert-butoxycarbonyl)-N-(3-aminobutyl)glycine ethyl ester was converted into 4-(tert-butoxycarbonyl)-hexahydro-7-me~yl-(2h~-1,4-diazepin-2-one.

lH NMR (400 MHz, CDC13) was complicated by the presence of 20 rotamers: ~ 4.35-3.35 (m, 5H), 1.90-1.60 (m, 2H), 1.44 (s, 9H), 1.22 (d, J
=6Hz).

Mass spectrum (ESI): m/e = 229 (M+l).

25 StepE: 1-(tert-l~utoxycarbonyl)-2.5~6~7-tetrahydro-3-methoxy-5-methyl-(lH)- 1 ~4-diazepine.

Using the method described in E~ample 2, 4-(tert-butoxycarbonyl)-hexahydro-?-methyl-(2H)- 1,4 diazepin-3-one was 30 converted into l-(te7~-butoxycarbonyl)-2,5,6,7-tetrahydro-3-methoxy-5-methyl-(1H)-1,4-diazepine.

lH NMR (400 MHz, CDCl3) was complicated by the presence of two rotamers: ~ 4.35 and 4.14 (two d, lH, J = 16 Hz), 3.95 (d, lH, J = 16 Hz), 3.64-3.30 (m, 3H), 3.58 (s, 3H), 1.92-1.82 (m, lH), 1.63-1.52 (m, lH), 1.43 (s, 9H), 1.22 (d, 3H, J = 6 Hz).

Mass spectrum (ESI): m/e = 243 (M+l).
s Step F: l-(tert-Butoxycarbonyl)-hexahydro-3-imino-5-methyl-(lH)-1.4-diazepine hydrochloride.

Using the method described in Example 3, l-(tert-10 butoxycarbonyl)-2,5,6,7-tetrahydro-3-methoxy-5 -methyl-( l H)- 1,4-diazepine was treated with ammonium chloride in ethanol.
Recryst~11i7~tion of the crude product from chloroform/dioxane yielded l-(tert-butoxycarbonyl)-hexahydro-3-imino-5-methyl-(lH)- 1,4-diazepine hydrochloride as white crystals.
lH NMR (400 MHz, CD30D) was complicated by the presence of two rotamers: o 4.53 and 4.45 (two d, lH, J = 16 Hz), 4.32 and 4.21 (two d, lH, J = 16 Hz), 4.13 (dt, lH, J = 14, 3 Hz), 3.96-3.86 (m, lH), 3.34-3.20 (m, lH), 1.89-1.81 (m, lH), 1.78-1.62 (m, lH), 1.47 (s, 9H), 1.35 (d, 3H, 20 J = 6 Hz).

Mass spectrum (ESI): m/e = 228 (M-HCl+l).

Step G: Hexahvdro-3-imino-5-methyl-~1H)-1 4-diazepine 25 dihydrochloride.

Using the method described in Example 130 (Step D), 1-(tert-butoxycarbonyl)-hexahydro-3-imino-5-methyl-(lH)- 1,4-diazepine hydrochloride was converted into hexahydro-3-imino-5-methyl-(1H)-1,4-30 diazepine dihydrochloride.

lH NMR (400 MHz, CD30D): o 4.54 (d, lH, J = 15 Hz), 4.21 (d, lH,15 Hz), 4.10-4.01 (m, lH), 3.64 (dt, lH, J = 14, 3 Hz), 3.40 (td, lH, J =

W O96/14844 PCTnUS95/14812 14, 3 Hz), 2.08 (dtd, lH, J = 14, 3, 1 Hz), 2.01-1.88~m, lH), 1.43 (d, 3H, J=7Hz).

Mass spectrum (FAB): m/e = 128 (M-2HCl+l).

- N

C~N~NH 2 HCI

2-Imino-decahvdro-cis-1~4-benzo(e)diazepine dihydrochloride Step A: N-2-Nitrophenylmethyl-~lycine methyl ester To a solution of glycine methyl ester hydrochloride (8.31 g, 66.2 mmol) in 150 ml MeOH were added 2-nitrobeIl7~ Phyde (10 g, 66.2 mmol) and 27 g of powdered molec~ r sieves (3A) . After stirring at room temperature overnight sodium cyanoborohydride (12.5 g,199 mol) in 150 ml of THF was ~de-l, then the reaction mixture was fur~er 20 stirred for 8 h. The solvent was removed under re~luce~l pressure. The residue was suspended in EtOAc and filtered throught a pad of celite. The filtrate was washed with sat. NaHCO3. Ihe aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over anhydrous Na2S04, filtered, concentrated and chromatographed on 25 silica gel eluting wi~ hexane-EtOAc to give 2.94 g of the desired product.

lH-NMR (SOOMHz, CDC13): ~ 7.97(1H, d, J-8Hz), 7.65(1H, d, J=8Hz), 7.6(1H, t, J=8Hz), 7.44(1H, t, J=8Hz), 4.11(2H, s), 3.73(3H, s), 3.47(2H, 30 s).

Mass Spectrum m/e = 225 (M++1) i Step B: N-(2-Aminophenyl)methyl-N-t-butyloxvcarbonyl-glycine methvl ester To a solution of N-2-nitrophenylmethyl-glycine methyl ester (2.94 g, 13.1 mmol) in 80 ml CH3CN was added di-t-butyl dicarbonate (3.43 g, 15.7 mmol) and diisopropylethylamine (6.8 ml, 39 mmol). After stirring at room tempeldLul~ overnight, the solvent was removed under re-lnce~l pressure, diluted with EtOAc, washed with NH4Cl solution. The aqueous layer was extracted with EtOAc twice. The combined organic layers were dried over anhydrous Na2SO4, concentrated and chromatographed on silica gel eluting with hexane-EtOAc to give 4.11 g of N-2-~ henylmethyl-N-t-butyloxycarbonyl-glycine methyl ester.
This material was dissolved in 150 ml of MeOH and hydrogenated in a Parr shaker (50 psi) with 164 mg of 10% Pd/C ovçrnight The reaction mixture was then filtered through a pad of celite and was concentrated.
The residue was chromatographed on silica gel eluting with hexane-EtOAc to give 3.6 g of the desired product.

lH-NMR (500MHz, CDC13): ~ 7.1(1H, t, J=7.6Hz), 6.97(1H, d, J=7Hz), 6.66(2H, multiplet), 4.47(2H, s), 4.41(2H, br. s), 3.71(3H, s), 1.46(9H, s).

Mass spectrum mle = 295 (M++l).

StepC: 4-t-Butvloxycarbonyl-4.5-dihydro-lH-benzo-(e)-1.4-diazepin-2(3H)-one To a 150 ml DMF solution of N-(2-aminophenyl)methyl-N-t-butyloxycarbonyl-glycine methyl ester (3.6 g, 12.2 mmol) was added NaH (308 mg, 12.8 mmol). After stirrin~ overnight, DMF was removed under re luce-l pressure. The residue was diluted with CH2C12 and was washed with aqueous NH4Cl. The aqueous layer was extracted with CH2C12 twice. The combined organic layers were dried over anhydrous Na2S04, filtered and concentrated to give pale yellow fluffy solid. This ~=

W O96/14844 PCTnUS95/14812 m~teri~l was suspended in hexanes: EtOAc = 5:1. The solid m~teri~l was collected by suction filtration to give 2.53 g of desired product as white solid.

5 lH-NMR (SOOMHz, CDC13): ~ 8.1-6.95(4H, br m), 4.6-4.2(4H, br m), 1.4(9H, br m).

Mass spectrum m/e = 263 (M++l), 163(M+-Boc).

10 Step D: 4-t-Butyloxvcarbonvl-octahydro-1H-benzo-(e)-1.4-diazepin-2(3H)-one To HOAc (50 ml) solu~ion of the 4-t-butyloxycarbonyl-4,5-dihydro-lH-benzo-(e)-1,4-diazepin-2(3H)-one (1.0 g ,3.8 mmol) was 1~ added 500 mg of PtO2. Ihis ~ ule was hydrogeI ~tçd in a Parr shaker (50 psi) ovçmight, then filtered through a pad of celite, and concentrated.
The residue was ~ ted with EtOAc, washed with sat NaHC03 twice, dried over anhydrous Na2S04, filtered and concenlr~ted. The residue was chromatographed on silica gel eluting with hex~nP-EtOAc to give 20 965 mg of the desired product.

Mass spectrum m/e = 269(M++1), 169(M+-Boc).

StepE: 4-t-Butyloxycarbonyl-2-imino-decahvdro-cis-1~4-25 benzo(e)diazepine hydrochloride This compound was ~r~cd following the procedure described in examples 2 and 3.

30 Mass spectrum m/e = 268(M+~l) Step F: 2-Imino-decahydro-cis-1.4-benzo(e)diazepine dihydrochloride W O96/14844 ~CTnUS95/14812 To EtOAc (1 mL) solution of 30 mg (0.1 mmol) of 4-t-butylo~yc~ul~onyl-2-imino-decahydro-cis-1,4-benzo(e)diazepine hydrochloride was added 2ml of EtOAc solution of anhydrous HCl.
After stirrin~ for lh, the solvent was removed under reduced pressure to 5 give 21.6 mg of the desired compound.

Mass spectrum m/e = 168 (M++1) = ~ = = EXAMPLE 157 2-Imino-decahydro-cis-3H-benz(e)azepin hydrochloride .

~ .
.HCI
~N~
H NH

StepA: 4~5-Dihydro-3H-benz(e)azepin-2(1H)-one Sodium azide (1.11 g, 17 mmol) was suspended in 7 mL CHC13 /
1.3 mL H2O and cooled to 0 C in an ice bath. Sulfuric acid ( 0.5 mL) was added dropwise, and the suspension was warmed to room te~ e~ e. After 15 minl~tes, the CHC13 layer was removed and dried with Na2SO4. After filtering, the CHC13 solution was added to a solution of 1.0g a-tetralone (6.84 mmol) in 2mL CHC13. The combined solutions were cooled to 0 C in an ice bath, and 2.2 mL sulfuric acid was added dr~wise. After addition, the solution was warmed to 45 C
for 45 minlltes, then cooled to room tempeldlure. The H2SO4 phase was diluted with H2O and cooled to 0 C. A 50% aqueous solution of NaOH
v was added dr~wise until pH=13. The resulting suspension was diluted with H2O / EtOAc and stirred until the solids were dissolved. The aqueous phase was extracted with ethyl acetate, and the combined organic layers were dried with Na2SO4, filtered, concentrated, and chromatographed with htox~nes / ethyl ~cet~te to isolate 0.64g (58%) of the product.

~=

W O96/14844 PCT~US95/14812 lH NMR 500 MHz (CDC13): 2.18-2.27 (m, 4H), 2.76 (t, 2H), 7 ( app. d, lH), 7.12 (app. t, lH), 7.23 (app.t, 2H).

5 Mass spectrum m/e = 162 (M+l) Step B: Octahvdro-cis-3H-benz(e)-azepin-2(1H)-one 4,5-Dihydro-3H-benz(e)azepin-2(1H)-one (0.5 g, 3.1 mmol) was 10 dissolved in 4 mT acetic acid and 0.25 g pl~timlm (IV) oxide was ~ e~l The mixture-was shaken under a hydrogen atmosphere at 50 psi overnight. The mixture was filtered through Celite, which was then washed with 10mL ethyl acetate. The collected solution was conce~ ated to a crystalline solid. Chromatography with hexanes / ethyl 15 ~cet~te isolated 0.4~g (87%) of product.

lH NMR (400MHz, CDC13) 1.1-1.9 (m, 12H), 2.45 (m, 3H), 3.76 (app. s lH), 5.2 (br s lH).

20 Mass spectrum m/e = 168 (M+l) Step C: 2-Imino-decahydro-3H-benz(e)azepin hydrochloride The title compound was prepared following the procedure 25 described in Fx~mples 2 ~nd 3.

lH NMR (500 MHz, CD30D) 1.0-2.4 (m, 13H)~ 2.58-2.76 (m, 3H), 3.34 (m, lH), 3.98 (s, lH).

30 Mass spectrum m/e = 167 (M+l) -WO 96/14844 . PCI/US95/14812 HOAc N NH

S Trans-Octahydro-3-imino-2H-1 4-benzthi~7ine. acetic acid salt The title compound was prepared from trans-2-aminocyclohexanol hydrochloride according to the procedure described in Example 140.

10 Mass spectrum rn/e = 171 (M+l) [~ ~ .HOAc N NH

Cis-Octahydro-3-imino-2H-1.4-ben7thi~ine. acetic acid salt Step A: 2-Ethoxycarbonylme~lylLllio-cyclohexanone A solution of 1.14 rnL (10 mmol) of 2-chlorocyclohe~none in 15 mL of EtOH was ll~ated with 1.1 rnL (10 mmol) of ethyl 2-merc~to~cet~tç and 1.38 g (10 mmol) of K2C03. After stirnn~ for 1 h the reaction ~ e was partitioned between water and Et2O:EtOAC.
The organic layer was washed with water, brine, dried and concentrated.
Purification of the residue by chromatography using a gradient of 10-20%
EtOAc-hexane ~ hed 2.0 g of the title compound.

Step B: Cis-Hexahydro-1.4-ben~thi~xazin-3(4H)-one W O96/14844 . PCTAUS95/14812 To a solution of 0.43 g (2 mmol) of 2-ethoxycarbonylmethylthio-cyclohexanone in 5 mL of MeOH, 0.12 g (2.24 mmol) of NH4Cl was added and strieed for 10 min to allow some of NH4Cl to dissolve. A THF solution of NaCNBH3 (lM, 2.3 mL) was S dropwise added to this mixture with a syringe pump over 40 min. White precipitate was formed as the rerlllcin~ agent was ~d(1e~1 After stirring for 4 h, the reaction was quenched by ~lrlin~ NaHCO3 solution and extracted with EtOAc. The organic layer was washed with water, brine, dried and concentrated. The residue was dissolved in 3 mL of EtOH, 10 h~-~te~ to 50 C for 2 h then allowed to stand for 2 d. The solution was concentrated and the residue was chromatographed using a gradient of 20-100% EtOAc-hexane to isolate 30 mg of the desired product along with 53 mg of the trans-hexahydro-l~4-ben7t~i~xazin-3(4H)-one.

15 lH NMR (CDC13): 1.2-2.0 (m, 8H), 3.08 (m, lH), 3.22 and 3.34 (AB q, 2H, J=16 Hz), 3.75 (m, lH), 6.3 (br s, lH).

Step C: Cis-Octahydro-3-imino-2H-1.4-ben7thi~ine~ acetic acid salt The title compound was prepared from cis-hexahydro- 1,4-ben~thi~7in-3(4H)-one by the method of Fx~mple 140 step D and E.

lH NMR (CD30D): 1.35-2.1 (m, 8H), 1.95 (s, 3H), 3.4 (m, lH), 3.46 (d, lH), 3.74 (m, lH), 3.79 (d, lH).
Mass spectrum m/e = 171 (M+l) 'o ~ N NH HCI
H
2-Imino-5(6H)-oxa-cis-hexahydro-(lH)-quinoline hydrochloride Step A: l-Benzyl-3.4.6.7-tetrahydro-pyrindin-2.5-dione To a solution of 3-benzylamino-cyclopent-2-en-1-one (5.0 g, 0.027 mol) in dry tetrahydl~orul~n (THF) (120 mL) at reflux tempel~t~c; was S added over 90 min. a solution of acryloyl chloride (3.15 g, 0.035 mol) in THF (60 mL). Stirring at reflux temperature was m~int~ine~1 for an additional 10 hours. The reaction mixtme was cooled and washed with sat~ated sodium bicarbonate solution (100 mL). The aqueous layer was extracted with diethyl ether (2 x 100 mL), and the combined organic 10 layers dried (Na2SO4), and evaporated. The residue was chromatographed on silica gel (20-30% acetone/hexane) to afford the title compound as an oil that solidified upon st~n~in~; yield 2.17 g (34%).

lH NMR (400 MHz, CDCl3): d 2.45 (m, 2H); 2.52 (m, 2H); 2.63 (m, 15 2H); 2.73 (t, 2H); 4.91 (s, 2H); 7.18-7.36 (m, 5H).

Mass spectrum: m/e 242 (M + 1).

Step B: l-Benzyl-cis-hexahydro-pyrindin-2~5-dione A mixture of l-benzyl-3,4,6,7-tetrahydro-pyrindin-2,5-dione (780 mg, 3.23 mmol) and sodium carbonate (1-56 mg) in ethanol (40 mL) was hydrogenated in the presence of 10% p~ lm-on charcoal (390 mg) at 50 psi for 48 h. The catalyst was removed by filtration through Celite, 25 washed with methanol, and the combined filtrate and w~chin~c evaporated. TLC indicated a mixture of the saturated ketone and slower-moving alcohol. The crude product was thelc;fore subjected to oxidation with teL~al,r~yl~mmonium per~lthen~te(VII) (TPAP) (52 mg, 0.147 mmol) in methylene chloride (8 mL) in the presence of 4-30 methylmoIpholine N-oxide (514 mg, 4.39 mmol), and powdered 4A
molecular sieves ((1.47 g). After stirring for 1 h at room temper~lule, the reaction mixtllre was placed on top of a column of silica gel (30 g) (p~e~ as a slurry in 20% acetone/hexane). Elution with the same solvent system afforded the title compound; yield 540 mg (69%).

lH NMR (400 MHz, CDC13): d 1.89 (m, lH); 1.96-2.09 (m, 2H); 2.16-2.37 (m, 3H); 2.42 (m, 2H); 2.50 (m, lH); 3.98 (m, lH); 4.25 (d, lH);
5.18 (d, lH); 7.21-7.32 (m, 5H).
s Mass spectrum: m/e 244. (M ~ 1).

Step C: l-Benzyl-5-oxa-cis-hexahydro-quinoline-2~6-dione and 1-benzyl-6-oxa-cis-hexahydro-quinoline-2~5-dione 10 . = ~
To a solution of l-benzyl-cis-hexahydro-pyrindin-2,5-dione (195 mg, 0.801 m~nol) in chloroform (5 mL) was added p-toluenesulfonic acid (10 ~g) and a solution of m-chloroperbenzoic acid (138 mg, 0.801 rnmol) in chlor~fo~lll (5 mL). The reaction . . ,i ~ . . e was stirred for 2 days 15 at room tempelalllle and then evaporated. The residue was chromatographed on silica gel (30% acetone/hexane) to afford a mixture (~55:45) of the tide compounds; yield 73 mg (35~o).

lH NMR (400 MHz, CDC13) for 1-benzyl-5-oxa-cis-hexahydro-20 quinoline-2,6-dione only: d 2.72 (septet, lH); 3.63 (q, lH); 4.01 (d, lH);
4.67 (m, lH); 5.37 (d, lH).

Step D: l-Benzyl-5(6H)-oxa-cis-hexahydro-quinoline-2-one To a solution of the ~ixl~.e of lactones from Step C (65 mg, 0.251 mmol) in THF (1 mL) cooled to -78C was added diisobutylalllminllm hydride (l.OM solution in he~nes) (0.50 rnL, 0.502 mmol). After stirrin~ for 1 hour at -78 C, the reaction was qllen~h~r1 by pouring into sa~ ted ammoI~ium chloride solution at O C. The mixt~lre was extracted with chloroform (2 x 25 mL) and the combined organic extracts dried (Na2S04). The crude lactol was treated wi~ ~iethyl~ n~
(41 rnL, 0.258 mmol) and boron trifluoride-etherate (23 mL, 0.189 mmol) in methylene chloride (1 mL) at -20 C for 1 hour. Additional triethylcil~n~- (27 mL) and boron trifluoride-etherate (21 mL) were ~d~le~1, _ _ _ W O96/14844 PCT~US95/14812 and the mixt~lre was stirred overnight at room tempe.alule. The mixture was diluted with methylene chloride, washed with saturated sodium bicarbonate solution, dried (Na2S04) and e~raporated. Chromatography on silica gel (20% acetone~exane) afforded the title compound as the S faster-moving on TLC of the two products; yield 5.2 mg.

lH NMR (400 MHz, CDC13): d 1.77 (m, lH); 2.09 (m, 2H); 2.45 (dq, lH); 2.77 (septet, lH); 3.29 (m, lH); 3.51 (m, lH); 3.75 (m, lH); 3.88 (m, lH); 4.11 (d, lH); 5.31 (d, lH); 7.21-7.32 (m, 5H).
Mass spectrum: m/e 246 (M + 1).

Step E: 5(6H)-Oxa-cis-hexahvdro-quinoline-(lH)-2-one The above compound is ~l~ared in a .~imil~r fashion as Example 121, Step D, but substi~ting l-benzyl-5(6H)-oxa-cis-hexahydro-quinoline-2-one in place of 1-benzyl-3-methyl-octahydro-cis-pyrano[4,3-b]pyridin-2-one.

20 Step F: 2-Imino-5(6H)-oxa-cis-hexahydro-(lH)-quinoline hydrochloride The above compound is ~le~ared from 5(6H)-oxa-cis-hexahydro-quinoline-(lH)-2-one following the procedures described in Steps E and F of ~x~mple 116.

~NH HCI

30 2-Imino-4-methvl-5(6H)-oxa-cis-hexahydro-(lH)-quinoline hydrochloride WO 96/14844 PCI~/US95/14812 Step A: l-Benzyl-4-methyl-3.4.6.7-tetrahvdro-pyrindin-2.5-dione A solution of 3-benzylamino-cyclopent-2-en-1-one (2.0 g, 10.7 mmol) and diethyl ethylidenemalonate (2.5 mL, 13.7 mmol) was 5 stirred for 5 days at 140 C. The cooled mixtllre was evaporated, and the residue partitioned between ethyl ~cet~ttq and brine solution. The organic layer was evaporated, and the crude product chromatographed on silica gel (25% acetone~exane) to afford the title compound as an oil that solidified upon st~n~in~; yield 950 mg (35%).
lH NMR (400 MHz, CDC13): d 1.11 (d, 3H); 2.42 (m, 2H); 2.53-2.65 (m, 2H); 2.78 (dd, lH); 2.92 (m, lH); 4.79 (d, lH); 5.07 (d, lH); 7.18-7.37 (m, 5H).
Mass spectrum: m~e 256 (M + 1).
Step B: l-Benzyl-4-methyl-cis-hexahvdro-pyrindin-2 5-dione The above compound is ~rc;~a~ed in a .simil~r fashion as Fx~mrle 160, Step B, but sub~ benzyl-4-methyl-3,4,6,7-20 tetrahydro-pyrindin-2,5-dione in place of 1-benzyl-3,4,6,7-tetrahydro-pyrindin-2,5-dione.

Step C: l-Benzvl-4-methyl-5-oxa-cis-hexahydro-quinoline-2.6-dione and l-benzyl-4-methyl-6-oxa-cis-hexahydro-quinoline-25-dione The above compound is ~ ared in a ~imil~r fashion as Fx~rnrle 160, Step C, but Sub~ l-benzyl-4-methyl-cis-hexahydro-pyrindin-2,5-dione in place of 1-benzyl-cis-hexahydro-pyrindin-2,5-dione.
Step D: l-Benzyl-4-methyl-5(6H)-oxa-cis-hexahydro-quinoline-2-one The above compound is prepared in a .cimil~r fashion as Fx~mrle.160, Step D, but sub~ benzyl-4-methyl-5-oxa-cis-W O96/14844 PCTrUS95tl4812 hexahydro-quinoline-2,6-dione and 1-benzyl-6-oxa-cis-hexahydro-quinoline-2,5-dione in place of 1-benzyl-5-oxa-cis-hexahydro-quinoline-2,6-dione and 1-benzyl-6-oxa-cis-hexahydro-quinoline-2,5-dione.

5 StepE: 4-Methyl-5(6H)-oxa-cis-hexahydro-~uinoline-(lH)-2-one The above compound is L).~ed in a ~imil~r fashion as F.x~mple 121, Step D, but sub~liL~ l-benzyl-4-methyl-5(6H)-oxa-cis-hexahydro-quinoline-2-one in place of 1-benzyl-3-methyl-octahydro-cis-10 pyrano[4,3-b]pyridin-2-one.

Step F: 2-Imino-4-methyl-5(6H)-oxa-cis-hexahydro-(lH)-quinoline hydrochloride The above compound is prepared from 4-methyl-5(6H)-oxa-cis-hexahydro-quinoline-(lH)-2-one following the procedures described in Steps E and F of Fx~mple 116.

~NH
.2HCI

H NH

2-Imino-decahydro-trans-1 4-benzo(e)diaiepine dihvdrochloride 25 Step A: (+) and (-) -cis-2-t-Butyloxycarbonylamino-cyclohexanemeth~nol To a 60 mL eth~nol solution of (+)-cis-2-benzylamino-cyclohex~n~qmetll~nol (2 g, 9.1 mmol) was added 0.7 g of lO~o Pd/C.
30 This mi~lule was subjected to hydrogenolysis condition in a Parr shaker (H2, 50 psi) overni~ht Then the catalyst was removed by suction filtration through a pad of Celite. The solvent was removed under . = ~

re~lllce-l pressure and the residue was dissolved in 60 mL of acetonitrile.
To it was added 11 mL of lN NaOH and 2.39 g (11 mmol) of di-t-butyl dicarbonate. After stirring overnight, the solvent was removed under reAu~e-l pressure. Pcesllltin~ oil was chromatogh~rh~l on silica gel S eluting with hexanes/EtOAc to obtain 1.98 g of (+) -cis-2-t-butyloxycarbonylamino-cycloh.ox~nlometh~nol. (-)-cis-2-t-Butyloxycarbonylamino-cyclohexanemethanol was obtained in a ~imil~r fashion starting from (-)-cis-2-benzyl~mino-cyclohexanemetll~nol.

10 lH-NMR (500 MHz, CDC13) d 4.8(br s, lH), 4.2(br s, lH), 4.05(br s, lH), 3.4-3.2(m, 2H)? 1.8-0.8(m, 17H).
.

Step B: cis-2-tButyloxycarbonyl-aminocyclohexanecarboxaldehyde To a 60 mL dry dichloromethane solution of dimethylsulfoxide (1.86 mL, 26.2 mmol) was added oxalyl chloride (1.14 mL, 13.0 mmol) with cooling in a dryice-acetone bath. After stirring for 15 min, a solution of 1 g (4.36 mmol) of (+) -2-t-butylo~ycar~bonyl~mino-cyclohex~ntomethanol and (-) -2-t-butylo~ycall,onylamino-20 cycloh~ n~m~thanol (1 g, 4.36 mmol) in 30 mL of CH2C12 was added with a c~nmll~ The intern~l temper~lulc was m~i"~ l between -50 and -60 C for 35min and the reaction was quenched by addition of 4.86 mL (34.8mmol) of Et3N . The cooling bath was removed and the reaction ~ ulc was warmed up to room t~ll~el~lurc. The solvent was 25 removed under re~llce-l pressure and the residue was rlilllte-l with EtOAc and water. The phases were s~ted and the aqueous phase was extracted twice with small portions of EtOAc. The combined organic phases were dried over anhydrous Na2SO4, filtered, concellllated and chromatographed on silca gel ehlting with hexanes/EtOAc to obtain 2.0 g 30 of the title compound.

lH-NMR (500 MHz, CDC13): d 9.71 (s, lH), 5.23 (br.s, lH), 3.98 (br s, lH), 2.7 (br s, lH), 2.0-1.2 (m., 17H).

Step C: cis/trans-2-t-Butyloxycarbonylamino-cyclohexanecarboxaldehyde (+/-) -cis-2-t-Butyloxycarobonylamino-S cyclohex~nec~rboxaldehyde (2 g, 8.8 mmol) was dissolved in 100 mL of methanol. To it was added NaOMe/MeOH prepared from 10 mg sodium and 5 mL of dry methanol. This mixhlre was he~te-l to reflux for 2 h then 47mg of NH4Cl was added and the solvent was removed under reduced pressure. The residue was chromatoghaphed on silica gel elllting with hexanes/EtOAc to obtain 1.7 g of the title compound. The ratio of cis and trans isomers was detç, I.li.led to be 1: 3.2 (cis/trans) by lH-NMR.

lH-NMR for (+/-) -trans-2-t-Butyloxycarbonylamino-cyclohex~nP.c~rboxaldehyde (500 MHz, CDC13): d 9.6 (s, lH), 4.5 (br s, lH), 3.8 (br.s, lH), 2.05-1.2 (m, 17H).

Step D: N-(cis/trans-(2-t-Butyloxycarbonylamino-cyclohexyl)methyl)-glycine methyl ester = .
To a 75 mL dry methanol solution of (+/-) -cis/trans-2-t-butyloxycarbonylamino-cyclohex~necarbox~ldehyde (1.7 g, 7.5 mmol) were added glycine methylester hydrochloride (1.13 g, 9 mmol) and 3 g of powedered molecular sieves (3A). After ~I ;", ;-,g overnight, a THF
(50 mL) solution of 1.4 g (22.3 mmol) of sodiumcyanoborohydride was added. This mixture was stirred for 8 h and the solvent was removed under re-lnce-l pressure. The residue was suspended in EtOAc and was filtered through a pad of Celite. The filtrate was washed with sat.
NaHCO3, dried with anhydrous Na2SO4, filtered, concetrated and chromatographed on silica gel eluting with hexanes/EtOAc followed by CH2C12/MeOH to obtain 600 mg of the desired compound.

lH-NMR (500MHz, CDC13): d 3.73 (s, 3H), 1.45 (s, 9H) other peaks could not be analyzed due to the bro~tlning .

Mass Spectrum: m/e = 301 (M+l).

Step E: N-(cis/trans-(2-amino-cyclohexyl)methyl)-~lycine methyl ester To a 10 mL EtOAc solution of (+/-)-N-(cis/trans-(2-t-butyloxycarbonylamino-cyclohexyl)methyl)-glycine methyl ester (300 mg, 1.0mmol) was added 10 mL of EtOAc saturated with anhydrous HCl gas. After stirrin~ for 2 h, the solvent was removed under rer1~1ce-1 pressure to give a white solid. This material was chromatographed on silica gel eluing with CHC13:MeOH:NH40H (40:10:1) to obtain 180 mg of the desired product.

lH NMR (500 MHz, CDC13): d 3.75 (s, 3H), 3.05-2.95 (m, 3H), 2.4-2.3 (m, 2H).
MassSpectlum: m/e=201(M+l).

Step F: 4-t-Butyloxycarbonyl-octahydro- lH-benzo(e)-cis/trans 1.4-diazepine-2(3H)-one To a 10 mL absolute ethanol solution of (+/-)-N-(cis/trans-(2-amino-cyclohexyl)methyl)-glycine methyl ester (180 mg, 0.90 mmol) was added 186 mg (1.35 mmol) of pot~inm carbonate. This slurry was h~.~t~d to reflux overnight TLC analysis of the reaction in-lic~tPd that the starting m~t~ri~l disappeared and a product was formed. Then the solvent was removed under re~1lce~1 pressure. ~s~ltin~: m~tt .ri~l was dissolved in 10 mL of acelo~ ile and 2 mL of water, to which was added 254 mg (1.16 mmol) of di-t-butyldicarbonate. After strring overnight, acetonitrile was removed under re~lllce~l pressure and the residue was diluted with EtOAc and sa~ur~ted ammonium chloride solution. The organic phase was separated and the aqueous phase was extracted with EtOAc. The combined organic phases were dried over anhydrous Na2SO4, filtered, concellllated and chromatographed on silica gel eluting with CH2Cl2/MeOH to obtain 146 mg of the desired compound.

lH NMR (500 MHz, CDC13): dS.3 (br.s, 2H), 4.2-3.6 (br m, 4H), 3.05 (br s, lH), 2.8 (br s, lH), 1.47 (s, 9H).

5 MassSpectrum: m/e=269(M+l).

Step G: 4-t-Butyloxycarbonyl-2-imino-decahydro-lH-benzo(e)-trans-1~4-diazepine This compounds were ~r~ared following the procedure of EXAMPLE 43 Step E and F. The cis and trans isomers were s~al~ted by silica gel chromatography eluting with CHCl3:MeOH:NH40H
(40:5-1). =

15 lH-NMR (500 MHz, CDC13): d4.7 (m, lH), 4.2-3.6 (m, 5H), 3.05 (br s, lH), The rest of the spectum could not be analyzed due to line bro~-lnin~.

Mass Spectrum: m/e = 268 (M+l).

20 Step H: 2-Imino-decahydro-trans-1.4-benzo(e)diazepine dihydrochloride Title compound was ~ ared as described in Example 156 Step F.

25 MassSpectrum: m/e=168(M+l).

Claims (24)

WHAT IS CLAIMED IS:

1. A compound of Formula I

R1, R2, I

or a pharmaceutically acceptable salt thereof wherein:
side a or side b has a double bond, n is 0, 1, 2, 3 or 4 X is selected from CH2, CR12R13, O, S(O)m, NH, and -N(C1-6alkyl)-, m is 0, 1 or 2, R1, R2, R3, R12 and R13 are each independently selected from the group consisting of (a) hydrogen, (b) C1-12 alkoxy, (c) C1-12 alkylS(O)k wherein k is 0, 1 or 2, (d) mono C1-12alkylamino, (e) (di-C1-12alkyl)amino, (f) C1-12alkylcarbonyl, (g) C1-12alkyl, (h) C2-12alkenyl, (i) C2-12alklynyl, (j) C5-10cycloalkyl, (k) hetero C5-10cycloalkyl, wherein the hetero C5-10cycloallyl optionally contains 1 or 2 heteroatoms selected from S, O
and N, (l) aryl, selected from phenyl or naphthyl, (m) heteroaryl, wherein heteroaryl is selected from the group consisting of:
(1) benzimidazolyl, (2) benzofuranyl, (3) benzooxazolyl, (4) furanyl, (5) imidazolyl, (6) indolyl, (7) isooxazolyl, (8) isothiazolyl, (9) oxadiazolyl, (10) oxazolyl, (11) pyrazinyl, (12) pyrazolyl, (13) pyridyl, (14) pyrimidyl, (15) pyrrolyl, (17) isoquinolyl, (18) tetrazolyl, (19) thiadiazolyl, (20) thiazolyl, (21) thienyl, and (22) triazolyl, (n) amino, (o) oxo, (p) C(O)OH, (q) C(O)OR6, R6 is selected from hydrogen, phenyl, cyclohexyl or C1-6alkyl, each of (b) to (m) being optionally mono or di- substituted the substituents being independently selected from (1) hydroxy, (2) carboxy, (3) -NR6R7, where R7 is selected from hydrogen, phenyl, cyclohexyl or C1-6alkyl, (4) -OR6, (5) -C(O)OR6, (6) -S(O)kR6, (7) halo selected from F, Cl, Br and I, (8) -C(=NR6)-NHR7, (9)-S-C(=NR6)-NHR7, (r) hydroxy, or when two members of the group R1, R2 and R3 including the optional substituents present thereon, reside on the same atom of Formula I, or two of the group R1, R2 and R3, including the optional substituents present thereon, reside on adjacent atoms of Formula I, said two members may optionally be joined, such that together with the atoms to which they are attached there is formed a saturated or unsaturated monocyclic ring of 5, 6 or 7 atoms, said monocyclic ring optionally containing up to three hetero atoms selected from N, O or S, or when a member of the group R1, R2 and R3 including the optional substituents present thereon, resides on an atom adjacent to the N on which R4 resides, said member may optionally be joined with R4, such that together with the N
on which R4 resides and the carbon on which said member resides there is formed a saturated or unsaturated monocyclic heterocycle of 5, 6 or 7 atoms, said monocycle optionally containing up to three hetero atoms selected from N, O or S, with the proviso that one of R12 and R13 are other than H, R4, R5 and R5a are each independently selected from the group consisting of (a) hydrogen, (b) linear and branched C1-12alkyl, optionally mono or di-substituted, the substituents being independently selected from 1) hydroxy, (2) carboxy, (3) -NR6R7, (4) -OR6, (5) -C(O)OR6, (6) -S(O)kR6, (7) halo selected from F, Cl, Br and I, (8) phenyl, optionally mono or di-substituted with hydroxy, halo, C1-4alkyl, or C1-4alkoxy, (c) -C(O)NR8R9, where R8 and R9 are each independently hydrogen, phenyl, cyclohexyl or C1-6alkyl, said C1-6alkyl optionally substituted by (1) hydroxy, (2) amino, (3) carboxy, (4) -NR10R11, wherein R10 and R11 are each independently H, C1-6alkyl, phenyl or benzyl, (5) -OR10, (6) -C(O)OR10, (7) -S(O)mR10, where m is 0, 1 or 2, (8) halo selected from F, Cl, Br and I, (9) optionally substituted aryl wherein aryl and aryl substituents are as defined above, (10) optionally substituents heteroaryl wherein heteroaryl and heteroaryl substituents are as defined above, (11) optionally substituted C5-10cycloalkyl wherein cycloalkyl and cycloalkyl substituents are as defined above, (12) optionally substituted hetero C5-10cycloalkyl wherein hetero cycloalkyl and hetero cycloalkyl substituents are as defined above, (d) -C(S)NR8R9, (e) -C(O)R9, (f) -C(O)OR9, (g) -C(S)R9, (h) phenyl, (i) cyclohexyl, provided that R4 is present only when side a is a single bond and R5a is present only when side b is a single bond.

2. A compound according to claim 1 wherein nis 0, 1,2,3 or 4, X is selected from CH2, CR12R13, O, S(O)m, NH, and -N(C1-6alkyl)-, mis 0, 1 or 2, R1, R2, R3, R12 and R13 are each independently selected from the group consisting Of (a) hydrogen, (b) C1-6alkoxy, (c) C1-6alkylamino, (d) C1-6alkylcarbonyl, (e) C1-6alkyl, (f) C2-6alkenyl, (g) C2-6alkynyl, (h) C5, C6 or C7cycloalkyl, (i) hetero C5, C6 or C7cycloalkyl,wherein the hetero C5, C6 or C7cycloalkyl optionally contains 1 or 2 heteroatoms selected from S, O and N, (j) aryl, selected from phenyl or naphthyl, (k) heteroaryl, wherein heteroaryl is selected from the group consisting of:
(1) benzimidazolyl, (2) benzofuranyl, (3) benzooxazolyl, (4) furanlyl, (5) imidazolyl, (6) indolyl, (7) isooxazolyl, (8) isothiazolyl, (9) oxadiazolyl, (10) oxazolyl, (11) pyrazinyl, (12) pyrazolyl, (13) pyridyl, (14) pyrimidyl, (15) pyrrolyl, (16) quinolyl, (17) tetrazolyl, (18) thiadiazolyl, (19) thiazolyl, (20) thienyl, and (21) triazolyl, (1) hydroxy, each of (b) to (k) being optionally mono or di- substituted the substituents being independently selected from (1) hydroxy, (2) carboxy, (3) -NR6R7, where R6 and R7 are selected from hydrogen, phenyl, cyclohexyl or C1-6alkyl, (4) -OR6, (5) -C(O)OR6, (6) -S(O)kR6, (7) halo selected from F, Cl, Br and I, (8) -C(=NR6)-NHR7, (9)-S-C(=NR6)-NHR7, or when two members of the group R1, R2 and R3 including the optional substituents present thereon, reside on the same atom of Formula I, or two of the group R1, R2 and R3, including the optional substituents present thereon, reside on adjacent atoms of Formula I, said two members may optionally be joined, such that together with the atoms to which they are attached there is formed a saturated or unsaturated monocyclic ring of 5, 6 or 7 atoms, said monocyclic ring optionally containing up to three hetero atoms selected from N, O or S, or when a member of the group R1, R2 and R3 including the optional substituents present thereon, resides on an atom adjacent to the N on which R4 resides, said member may optionally be joined with R4, such that together with the N

on which R4 resides and the carbon on which said member resides there is formed a saturated or unsaturated monocyclic heterocycle of 5, 6 or 7 atoms, said monocycle optionally containing up to three hetero atoms selected from N, O or S, with the proviso that one of R12 and R13 is other than hydrogen, R4, R5 and R5a are each independently selected from the group consisting of (a) hydrogen, (b) linear and branched C1-6alkyl, optionally mono or di-substituted, the substituents being independently selected from (1) hydroxy, (2) carboxy, (3) -NR6R7, (4) -OR6, (5) -C(O)OR6, (6) -S(O)kR6, where k is 0, 1 or 2, (7) halo selected from F, Cl, Br and I, (c) -C(O)NR8R9, where R8 and R9 are each independently hydrogen, phenyl, cyclohexyl or C1-4alkyl, said C1-4alkyl optionally substituted by (1) hydroxy, (2) amino, (3) carboxy, (4) -NR10R11, wherein R10 and R11 are each independently H, C1-4alkyl, phenyl or benzyl, (5) -OR10, (6) -C(O)OR10, (7) -S(O)mR10, where m is 0, 1 or 2, (8) halo selected from F, Cl, Br and I, (9) optionally substituted aryl wherein aryl andaryl substituents are as defined above, (10) optionally substituted heteroaryl wherein heteroaryl and heteroaryl substituents are as defined above, (11) optionally substituted C5, C6 or C7cycloalkyl wherein cycloalkyl and cycloalkyl substituents are as defined above, (12) optionally substituted hetero C5, C6 or C7cycloalkyl wherein hetero cycloalkyl and hetero cycloalkyl substituents are as defined above, (d) -C(S)NR8R9, (e) -C(O)R9, (f) -C(O)OR9, (g) -C(S)R9, (h) phenyl, (i) cyclohexyl, such that R4 is present only when side a is a single bond and side b is a double bond.

3. A compound according to claim 2 wherein n is 0, 1,2,3 or 4 X is selected from CH2, CR12R13, O, NH and -N(C1-4alkyl)-, R1, R2, R3, R12 and R13 are each independently selected from the group consisting of (a) hydrogen, (b) C1-6alkoxy, (c) C1-6alkylamino, (d) C1-6alkylcarbonyl, (e) C1-6alkyl, (f) C2-6alkenyl, (g) C5, C6 or C7cycloalkyl, (h) hetero C5 or C6 cycloalkyl,wherein the hetero C5 or C6 cycloalkyl optionally contains 1 heteroatom selected from S, O and N, (i) aryl, selected from phenyl or naphthyl, (j) heteroaryl, wherein heteroaryl is selected from the group consisting of:
(1) furanyl, (2) pyrazinyl, (3) pyrazolyl, (4) pyridyl, (5) pyrimidyl, (6) thiazolyl, (7) thienyl, and (8) triazolyl, (k) hydroxy, each of (b) to (j) being optionally mono or di- substituted the substituents being independently selected from (1) hydroxy, (2) carboxy, (3) -NR6R7, wherein R6 and R7 are each independently hydrogen or C1-4alkyl, (4) -OR6, (5) -C(O)OR6, (6) -S(O)kR6, where k is 0, 1 or 2, (7) halo selected from F, Cl, Br and I, (8) -C(=NR6)-NHR7, (9) -S-C(=NR6)-NHR7, or when two members of the group R1, R2 and R3 including the optional substituents present thereon, reside on the same atom of Formula I, or two of the group R1, R2 and R3, including the optional substituents present thereon, reside on adjacent atoms of Formula I, said two members may optionally be joined, such that together with the atoms to which they are attached there is formed a saturated or unsaturated monocyclic ring of 5, 6 or 7 atoms, said monocyclic ring optionally containing up to three hetero atoms selected from N, O or S, or when a member of the group R1, R2 and R3 including the optional substituents present thereon, resides on an atom adjacent to the N on which R4 resides, said member may optionally be joined with R4, such that together with the N
on which R4 resides and the carbon on which said member resides there is formed a saturated or unsaturated monocyclic heterocycle of 5, 6 or 7 atoms, said monocycle optionally containing up to three hetero atoms selected from N, O or S, with the proviso that one of R12 and R13 is other than hydrogen, R4, R5 and R5a are each independently selected from the group consisting of (a) hydrogen, (b) linear and branched C1-6alkyl, optionally mono or di- substituted, the substituents being independently selected from (1) hydroxy, (2) carboxy, (3) -NR6R7, (4) -OR6, (5) -C(O)OR6, (6) -S(O)kR6, (7) halo selected from F, Cl, Br and I, (c) -C(O)NR8R9, where R8 and R9 are each independently hydrogen, phenyl, cyclohexyl or C1-4alkyl, said C1-4alkyl optionally substituted by (1) hydroxy, (2) amino, (3) carboxy, (4) -NR10R11, wherein R10 and R11 are each independently H, C1-4alkyl, phenyl or benzyl, (5) -OR10, (6) -C(O)OR10, (7) -S(O)mR10, where m is 1 or 2, (8) halo selected from F, Cl, Br and I, (9) optionally substituted aryl wherein aryl and aryl substituents are as defined above, (10) optionally substituted heteroaryl wherein heteroaryl and heteroaryl substituents are as defined above, (11) optionally substituted C5 or C6 cycloalkyl wherein cycloalkcyl and cycloalkyl substituents are as defined above, (12) optionally substituted hetero C5 or C6 cycloalkyl wherein hetero cycloalkyl and hetero cycloalkyl substituents are as defined above, (d) -C(S)NR8R9, (e) -C(O)R9, (f) -C(O)OR9, (g) -C(S)R9, (h) phenyl, (i) cyclohexyl, such that R4 is present only when side a is a single bond and side b is a double bond.

4. A compound according to Claim 3 wherein n is 0, 1, 2 or 3, X is selected from CR12R13, NH and -N(C1-4alkyl)-, R1, R2, R3, R12 and R13 are each independently selected from the group consisting of (a) hydrogen, (b) C1-4alkoxy, (c) C1-4alkylamino, (d) C1-4alkylcarbonyl, (e) linear and branched C1-4alkyl, (f) hydroxy, each of (b) to (e) being optionally mono or di- substituted the substituents being independently selected from (1) hydroxy, (2) carboxy, (3) -NR6R7, wherein R6 and R7 are each independently hydrogen or C1-3alkyl, (4) -OR6, (5) -C(O)OR6, (6) -S(O)kR6, where k is 0, 1 or 2, (7) halo selected from F, Cl, Br and I, or when two members of the group R1, R2 and R3 including the optional substituents present thereon, reside on the same atom of Formula I, or two of the group R1, R2 and R3, including the optional substituents present thereon, reside on adjacent atoms of Formula I, said two members may optionally be joined, such that together with the atoms to which they are attached there is formed a saturated or unsaturated monocyclic ring of 5, 6 or 7 atoms, said monocyclic ring optionally containing up to three hetero atoms selected from N, O or S, or when a member of the group R1, R2 and R3 including the optional substituents present thereon, resides on an atom adjacent to the N on which R4 resides, said member may optionally be joined with R4, such that together with the N
on which R4 resides and the carbon on which said member resides there is formed a saturated or unsaturated monocyclic heterocycle of 5, 6 or 7 atoms, said monocycle optionally containing up to three hetero atoms selected from N, O or S, with the proviso that one of R12 and R13 is other than hydrogen, R4, R5 and R5a are each independently selected from the group consisting of (a) hydrogen, (b) -C(O)NR8R9, where R8 and R9 are each independently hydrogen or C1-3alkyl, said C1-3alkyl optionally substituted by (1) hydroxy, (2) amino, (3) carboxy, (4) -NR10R11, wherein R10 and R11 are each independently H or C1-3alkyl, (5) -OR10, (6) -C(O)OR10, (7) -S(O)mR10, where m is 0, 1 or 2, (8) halo selected from F, Cl, Br and I, (c) -C(S)NR8R9, (d) -C(O)R9, (e) -C(O)OR9, (f) -C(S)R9, (g) -C(S)HR9.
(h) -C1-4alkyl; and R13 is hydrogen.

5. A compound according to Claim 4 wherein n is 0, 1, 2 or 3, X is selected from CR12R13, NH and -N(C1-4alkyl)-, R1, R2, R3,R12 and R13 are each independently selected from the group consisting of (a) hydrogen, (b) C1-4alkoxy, (c) C1-4alkylamino, (d) C1-4alkylcarbonyl, (e) linear and branched C1-4alkyl, (f) hydroxy, each of (b) to (e) being optionally mono or di- substituted the substituents being independently selected from (1) hydroxy, (2) carboxy, (3) -NR6R7, wherein R6 and R7 are each independently hydrogen or C1-3alkyl, (4) -OR6, (5) -C(O)OR6, (6) -S(O)kR6, where k is 0, 1 or 2, (7) halo selected from F, Cl, Br and I, R4 is selected from the group consisting of (a) hydrogen, (b) -C(O)NHR9, where R9 is hydrogen or C1-3alkyl, said C1-3alkyl optionally substituted by (1) hydroxy, (2) amino, (3) carboxy, (4) -NR10R11, wherein R10 and R11 are each independently C1-3alkyl, (5) -OR10, (6) -C(O)OR10, (7) -S(O)mR10, where m is 1 or 2, (8) halo selected from F, Cl, Br and I, (c) -C(S)NHR9;
(d) -C1-4alkyl.
R5 is selected from the group consisting of (a) hydrogen, (b) -C(O)NHR9, (c) -C(S)NR8R9.
(d) -C1-4alkyl, and R5a and R13 are each hydrogen.

6. A compound of Formula I according to Claim 1 I

or pharmaceutically acceptable salts thereof wherein side a or side b has a double bond, n is 0, 1,2,3 or 4 X is selected from CH2, O, S(O)m and NH, R1, R2 and R3 are each independently selected from the group consisting of (a) hydrogen, (b) C1-12alkoxy, (c) C1-12alkylS(O)k wherein k is 0, 1 or 2, (d) mono C1-12alkylamino, (e) (di-C1-12alkyl)amino, (f) C1-12alkylcarbonyl, (g) C1-12alkyl, (h) C2-12alkenyl, (i) C2-12alkynyl, (j) C5-10cycloalkyl, (k) hetero C5-10cycloalkyl,wherein the hetero C5-10cycloalkyl optionally contains 1 or 2 heteroatoms selected from S, O
and N, (l) aryl, selected from phenyl or naphthyl, (m) heteroaryl, wherein heteroaryl is selected from the group consisting of:
(1) benzimidazolyl, (2) benzofuranyl, (3) benzooxazolyl, (4) furanlyl, (5) imidazolyl, (6) indolyl, (7) isooxadolyl, (8) isothiazolyl, (9) oxadiazolyl, (10) oxazolyl, (11) pyrazinyl, (12) pyrazolyl, (13) pyridyl, (14) pyrimidyl, (15) pyrrolyl, (17) isoquinolyl, (18) tetrazolyl, (19) thiadiazolyl, (20) thiazolyl, (21) thienyl, and (22) triazolyl, (n) amino, (o) oxo, (p) C(O)OH, (q) C(O)OR6, R6 is selected from hydrogen, phenyl, cyclohexyl or C1-6alkyl, each of (b) to (m) being optionally mono or di- substituted.
the substituents being independently selected from (1) hydroxy, (2) carboxy, (3) -NR6R7, where R7 is selected from hydrogen, phenyl, cyclohexyl or C1-6alkyl, (4) -OR6, (5) -C(O)OR6, (6) -S(O)kR6, (7) halo selected from F, Cl, Br and I, (8) -C(=NR6)-NHR7, (9) -S-C(=NR6)-NHR7, or when two members of the group R1, R2 and R3 including the optional substituents present thereon, reside on the same atom of Formula I, or two of the group R1, R2 and R3, including the optional substituents present thereon, reside on adjacent atoms of Formula I, said two members may optionally be joined, such that together with the atoms to which they are attached there is formed a saturated or unsaturated monocyclic ring of 5, 6 or 7 atoms, said monocyclic ring optionally containing up to three hetero atoms selected from N, O or S, or when a member of the group R1, R2 and R3 including the optional substituents present thereon, resides on an atom adjacent to the N on which R4 resides, said member may optionally be joined with R4, such that together with the N
on which R4 resides and the carbon on which said member resides there is formed a saturated or unsaturated monocyclic heterocycle of 5, 6 or 7 atoms, said monocycle optionally containing up to three hetero atoms selected from N, O or S, R4, R5 and R5a are each independently selected from the group consisting of (a) hydrogen, (b) linear and branched C1-12alkyl, optionally mono or di-substituted, the substituents being independently selected from (1) hydroxy, (2) carboxy, (3) -NR6R7, (4) -OR6, (5) -C(O)OR6, (6) -S(O)kR6, (7) halo selected from F, Cl, Br and I, (8) phenyl, optionally mono or di-substituted with hydroxy, halo, C1-4alkyl, or C1-4alkoxy, (c) -C(O)NR8R9, where R8 and R9 are each independently hydrogen, phenyl, cyclohexyl or C1-6alkyl, said C1-6alkyl optionally substituted by (1) hydroxy, (2) amino, (3) carboxy, (4) -NR10R11, wherein R10 and R11 are each independently H, C1-6alkyl, phenyl or benzyl, (5) -OR10, (6) -C(O)OR10, (7) -S(O)mR10, where m is 0, 1 or 2, (8) halo selected from F, Cl, Br and I, (9) optionally substituted aryl wherein aryl and aryl substituents are as defined above, (10) optionally substituted heteroaryl wherein heteroaryl and heteroaryl substituents are as defined above, (11) optionally substituted C5-10cycloalkyl wherein cycloalkyl and cycloalkyl substituents are as defined above, (12) optionally substituted hetero C5-10cycloalkyl wherein hetero cycloalkyl and hetero cycloalkyl substituents are as defined above, (d) -C(S)NR8R9, (e) -C(O)R9, (f) -C(O)OR9, (g) -C(S)R9, (h) phenyl, (i) cyclohexyl, provided that R4 is present only when side a is a single bond and R5a is present only when side b is a single bond.

7. A compound according to Claim 6 wherein n is 0, 1, 2, 3 or 4, X is selected from CH2, O, S and NH, R1, R2 and R3 are each independently selected from the group consisting of (a) hydrogen, (b) C1-6alkoxy, (c) C1-6alkylamino, (d) C1-6alkylcarbonyl, (e) C1-6alkyl, (f) C2-6alkenyl, (g) C5, C6 or C7cycloalkyl, (h) hetero C5 or C6 cycloalkyl,wherein the hetero C5 or C6 cycloalkyl optionally contains 1 heteroatom selected from S, O and N, (i) aryl, selected from phenyl or naphthyl, (j) heteroaryl, wherein heteroaryl is selected from the group consisting of:
(1) furanyl, (2) pyrazinyl, (3) pyrazolyl, (4) pyridyl, (5) pyrimidyl, (6) thiazolyl, (7) thienyl, and (8) triazolyl, each of (b) to (j) being optionally mono or di- substituted the substituents being independently selected from (1) hydroxy, (2) carboxy, (3) -NR6R7, where R6 and R7 are each independently hydrogen, phenyl or C1-4alkyl, (4) -OR6, (5) -C(O)OR6, (6) -S(O)kR6, where k is 0, 1 or 2, (7) halo selected from F, Cl, Br and I, or when two members of the group R1, R2 and R3 including the optional substituents present thereon, reside on the same atom of Formula I, or two of the group R1, R2 and R3, including the optional substituents present thereon, reside on adjacent atoms of Formula I, said two members may optionally be joined, such that together with the atoms to which they are attached there is formed a saturated or unsaturated monocyclic ring of 5, 6 or 7 atoms, said monocyclic ring optionally containing up to three hetero atoms selected from N, O or S, or when a member of the group R1, R2 and R3 including the optional substituents present thereon, resides on an atom adjacent to the N on which R4 resides, said member may optionally be joined with R4, such that together with the N
on which R4 resides and the carbon on which said member resides there is formed a saturated or unsaturated monocyclic heterocycle of 5, 6 or 7 atoms, said monocycle optionally containing up to three hetero atoms selected from N; O or S, R4, R5 and R5a are each independently selected from the group consisting of (a) hydrogen, (b) linear and branched C1-6alkyl, optionally mono or di- substituted, the substituents being independently selected from (1) hydroxy, (2) carboxy, (3) -NR6R7, (4) -OR6, (5) -C(O)OR6, (6) -S(O)kR6, where k is 0, 1 or 2, (7) halo selected from F, Cl, Br and I, (c) -C(O)NR8R9, where R8 and R9 are each independently hydrogen, phenyl, cyclohexyl or C1-4alkyl, said C1-4alkyl optionally substituted by (1) hydroxy, (2) amino, (3) carboxy, (4) -NR10R11, wherein R10 and R11 are each independently H, C1-4alkyl, phenyl or benzyl, (5) -OR10, (6) -C(O)OR10, (7) -S(O)mR10, where m is 0, 1 or 2, (8) halo selected from F, Cl, Br and I, (9 optionally substituted aryl wherein the aryl and substituents are as defined above, (10) optionally substituted heteroalyl wherein the heteroaryl and substituents are as defined above, (11) optionally substituted C5 or C6 cycloalkyl wherein the cycloalkyl and substituents are as defined above, (12) optionally substituted hetero C5 or C6 cycloalkyl wherein the hetero cycloalkyl and substituents are as defined above, (d) -C(S)NR8R9, (e) -C(O)R9, (f) -C(O)OR9, (g) -C(S)R9, (h) phenyl, (i) cyclohexyl, such that R4 is present only when side a is a single bond and side b is a double bond.

8. A compound according to Claim 6 of the formula or wherein n is 0, 1 or 2.

9. A compound according to Claim 8 wherein n is 0, 1 or 2, X is selected from CH2 and NH, R1, R2 and R3 are each independently selected from the group consistingof (a) hydrogen, (b) linear and branched C1-6alkyl, wherein said C1-6alkyl is optionally mono or di- substituted the substituents being independently selected from (1) carboxy, (2) -NHR7, wherein R6 and R7 are each independently hydrogen or C1-3alkyl, (3) -OR6, (4) -C(O)OR6, (5) -S(O)kR6, where k is 0, 1 or 2, (c) hydroxy, (d) C1-6alkoxy;
R4 is selected from the group consisting of (a) hydrogen, (b) -C(O)NHR9, where R9 is hydrogen or C1-3alkyl, said C1-3alkyl optionally substituted by (1) hydroxy, (2) amino, (3) carboxy, (4) -NR10R11, wherein R10 and R11 are each independently C1-3alkyl, (5) -OR10, (6) -C(O)OR10, (7) -S(O)mR10, where m is 0, 1 or 2, (8) halo selected from F, Cl, Br and I, (c) -C(S)NHR9;
(d) C1-3alkyl;
R5 are each independently selected from the group consisting of (a) hydrogen, (b) -C(O)NHR9, (c) -C(S)NR8R9.
(d) -C1-3alkyl.

10. A compound according to Claim 9 of the formulae or or wherein X is selected from CH2, NH and S, R1, R2 and R3 are each independently selected from the group consisting of (a) hydrogen, (b) linear and branched C1-6alkyl, wherein said C1-6alkyl is optionally mono or di- substituted the substituents being independently selected from (1) carboxy, (2) -NHR7, wherein R6 and R7 are each independently hydrogen or C1-3alkyl, (3) -OR6, (4) -C(O)OR6, (5) -S(O)kR6, where k is 0, 1 or 2, (c) hydroxy, (d) C1-6aLkoxy;
R4 is selected from the group consisting of (a) hydrogen, (b) -C(O)NHR9, where R9 is hydrogen or C1-3alkyl, said C1-3alkyl optionally substituted by (1) hydroxy, (2) amino, (3) carboxy, (4) -NR10R11, wherein R10 and R11 are each independently C1-3alkyl, (5) -OR10, (6) -C(O)OR10, (7) -S(O)mR10, where m is 0, 1 or 2, (8) halo selected from F, Cl, Br and I, (c) -C(S)NHR9;
(d) C1-3alkyl;
R5 are each independently selected from the group consisting of (a) hydrogen, (b) -C(O)NHR9, (c) -C(S)NR8R9.
(d) -C1-3alkyl.

11. A compound according to Claim 10 wherein X is CH2, R1, R2 and R3 are each independently is selected from the group consisting of (a) hydrogen, (b) linear and branched C1-6alkyl, said C1-6alkyl being optionally mono or di- substituted the substituents being independently selected from (1) carboxy, (2) -NHR7, wherein R6 and R7 are each independently hydrogen or C1-3alkyl, (3)-C(O)R6, and (4) -S(O)kR6, where k is 1 or 2, (c) hydroxy, (d) C1-6alkoxy;
R4 is selected from the group consisting of (a) hydrogen, (b) C1-3alkyl;
R5 is selected from the group consisting of (a) hydrogen, (b) -C(O)NHR9, where R9 is hydrogen or C1-4alkyl, said C1-4alkyl optionally substituted by (1) hydroxy, (2) amino, (3) carboxy, (4) -NR10R11, wherein R10 and R11 are each independently C1-3alkyl, (5) -OR10, (6) -C(O)OR10, (7) -SR10, and (8) -S(O)mR10, where m is 1 or 2, (9) halo selected from F, Cl, Br and I, (c) -C(S)NR8R9.
(d) C1-3alkyl.

12. A compound according to Claim 11 wherein X is CH2, R1 and R2 are each selected from the group consisting of hydrogen, hydroxy or linear and branched C1-6alkyl, said C1-6alkyl being optionally mono or di- substituted the substituents being independently selected from (1)carboxy, (2)-NHR7, wherein R6 and R7 are each independendtly hydrogen or C1-3alkyl, (3)-C(O)OR6, and (4)-S(O)kR6, where k is 1 or 2, R3 is linear and branched C1-4alkyl, R4 is selected from the group consisting of (a) hydrogen, (b) C1-3alkyl;
R5 is selected from the group consisting of (a) hydrogen, (b) -C(O)NHR9, where R9 is hydrogen or C1-4alkyl, said C1-4alkyl optionally substituted by (1) hydroxy, (2) amino, (3) carboxy, (4) -NR10R11, wherein R10 and R11 are each independently C1-3alkyl, (5) -OR10, (6) -C(O)OR10, (7) -SR10, and (8) -S(O)mR10, where m is 1 or 2, (9) halo selected from F, Cl, Br and I, (c) -C(S)NR8R9.
(d) C1-3alkyl.

13. A compound according to Claim 10 wherein X is -N-, R1, R2 and R3 are each independently is selected from the group consisting of (a) hydrogen, (b) linear and branched C1-6alkyl, said C1-6alkyl being optionally mono or di- substituted the substituents being independently selected from (1) carboxy, (2) -NHR7, wherein R6 and R7 are each independently hydrogen or C1-3alkyl, (3) -C(O)OR6, and (4) -S(O)kR6, where k is 1 or 2, (c) hydroxy, (d) C1-6alkoxy;
R4 is selected from the group consisting of (a) hydrogen, (b) C1-3alkyl;
R5 is selected from the group consisting of (a) hydrogen, (b) -C(O)NHR9, where R9 is hydrogen or C1-4alkyl, said C1-4alkyl optionally substituted by (1) hydroxy, (2) amino, (3) carboxy, (4) -NR10R11, wherein R10 and R11 are each independently C1-3alkyl, (5) -OR10, (6) -C(O)OR10, (7) -SR10, and (8) -S(O)mR10, where m is 1 or 2, (9) halo selected from F, Cl, Br and I, (c) -C(S)NHR9.
(d) C1-3alkyl.

14. A compound according to Claim 13 wherein X is -N-, R1 and R2 are each selected from hydrogen, hydroxy or linear and branched C1-4alkyl, said C1-4alkyl being optionally mono or di- substituted the substituents being independently selected from (1) carboxy, (2) -NHR7, wherein R6 and R7 are each independently hydrogen C1-3alkyl, (3) -C(O)OR6, and (4) -S(O)kR6, where k is 1 or 2, R3 is methyl, R4 is selected from the group consisting of (a) hydrogen, (b) C1-3alkyl;
R5 is selected from the group consisting of (a) hydrogen, (b) -C(O)NHR9, where R9 is hydrogen or C1-4alkyl, said C1-4alkyl optionally substituted by (1) hydroxy, (2) amino, (3) carboxy, (4) -NR10R11, wherein R10 and R11 are each independently C1-3alkyl, (5) -OR10, (6) -C(O)OR10, (7) -SR10, and (8) -S(O)mR10, where m is 1 or 2, (9) halo selected from F, Cl, Br and I, (c) -CSNHR9.
(d) C1-3alkyl.

15. A compound according to Claim 10 wherein x is s, R1 and R2 are each independently is selected from the group consisting of (a) hydrogen, (b) linear and branched C1-6alkyl, said C1-6alkyl being optionally mono or di- substituted the substituents being independently selected from (1) carboxy, (2) -NHR7, wherein R6 and R7 are each independently hydrogen or C1-3alkyl, (3) -C(O)OR6, and (4) -S(O)kR6, where k is 1 or 2, (c) hydroxy, (d) C1-6alkoxy;

R4 is selected from the group consisting of (a) hydrogen, (b) C1-3alkyl;
R5 is selected from the group consisting of (a) hydrogen, (b) -C(O)NHR9, where R9 is hydrogen or C1-4alkyl, said C1-4alkyl optionally substituted by (1) hydroxy, (2) amino, (3) carboxy, (4) -NR10R11, wherein R10 and R11 are each independently C1-3alkyl, (5) -OR10, (6) -C(O)OR10, (7) -SR10, and (8) -S(O)mR10, where m is 1 or 2, (9) halo selected from F, Cl, Br and I, (c) -C(S)NHR9.
(d) C1-3alkyl.

16. A compound according to Claim 15 wherein X is S, R1 and R2 are each independently selected from hydrogen, hydroxy or linear and branched C1-6alkyl, said C1-6alkyl being optionally mono or di- substituted the substituents being independently selected from (1) carboxy, (2) -NHR7, wherein R6 and R7 are each independently hydrogen or C1-3alkyl, (3) -C(O)OR6, and (4) -S(O)kR6, where k is 1 or 2, R4 is selected from the group consisting of (a) hydrogen, (b) C1-3alkyl;
R5 is selected from the group consisting of (a) hydrogen, (b) -C(O)NHR9, where R9 is hydrogen or C1-4alkyl, said C1-4alkyl optionally substituted by (1) hydroxy, (2) amino, (3) carboxy, (4) -NR10R11, wherein R10 and R11 are each independently C1-3alkyl, (5) -OR10, (6) -C(O)OR10, (7) -SR10, and (8) -S(O)mR10, where m is 1 or 2, (9) halo selected from F, Cl, Br and I, (c) -CSNHR9.
(d) C1-3alkyl.

17. A compound according to Claim 6 of the formulae or wherein p is 0, 1 or 2; and R3 and the ring formed by the joining of R1 and R2 are optionally mono or di-substituted with substituents selected from the group consisting of (1) hydroxy, (2) carboxy, (3) -NR6R7, where R6 and R7 are each selected from hydrogen, phenyl, cyclohexyl or C1-6alkyl, (4) -OR6, (5) -C(O)OR6, (6) -S(O)kR6, (7) halo selected from F, Cl, Br and I, (8) -C(=NR6)-NHR7, (9) -S-C(=NR6)-NHR7.

18. A compound according to Claim 17 having cis stereochemistry at the ring junction, said compound having the formula wherein p is 1 or 2, and R3 and the ring formed by the joining of R1 and R2 are optionally mono or di-substituted with substituents selected from the group consisting of (1) hydroxy, (2) carboxy, (3) -NR6R7, where R6 and R7 are each selected from hydrogen, phenyl, cyclohexyl or C1-6alkyl, (4) -OR6, (5) -C(O)OR6, (6) -S(O)kR6, (7) halo selected from F, Cl, Br and I, (8) -C(=NR6)-NHR7, (9) -S-C(=NR6)-NHR7.

19. A compound according to Claim 18 wherein R3 is selected from hydrogen, hydroxy or linear and branched C1-4alkyl, said C1-4alkyl, optionally mono or di- substituted the substituents being independently selected from (1) carboxy, (2) -NHR7, wherein R6 and R7 are each independently hydrogen or C1-3alkyl, (3) -C(O)OR6, and (4) -S(O)kR6, where k is 1 or 2;
R4 is selected from the group consisting of (a) hydrogen, (b) C1-3alkyl;
R5 is selected from the group consisting of (a) hydrogen, (b) -C(O)NHR9, where R9 is hydrogen or C1-4alkyl, said C1-4alkyl optionally substituted by (1) hydroxy, (2) amino, (3) carboxy, (4) -NR10R11, wherein R10 and R11 are each independently C1-3alkyl, (5) -OR10, (6) -C(O)OR10, (7) -SR10, and (8) -S(O)mR10, where m is 1 or 2, (9) halo selected from F, Cl, Br and I, (c) -C(S)NR8R9.
(d) C1-3alkyl.

20. A compound of Claim 1 selected from (aa) 1-Aza-2-imino-cyclopentane hydrochloride, (ab) 1-Aza-2-imino-3-methylcyclopentane hydrochloride, (ac) 1-Aza-2-imino-5-methylcyclopentane hydrochloride, (ad) 1-Aza-2-methylamino-1-cyclopentene hydrochloride, (ae) 1-Aza-2-ethylamino-1-cyclopentene hydrochloride, (af) 1-Aza-2-benzylamino-1-cyclopentene hydrochloride, (ag) 1-Aza-2-cyclohexylamino-1-cyclopentene hydrochloride, (ah) 1-Aza-2-methoxycarbonylmethylamino-1-cyclopentene hydrochloride, (ai) 1-Aza-2-((3,4-dihydroxyphenyl)ethyl) amino-1-cyclopentene hydrochloride, (aj) 1-Aza-2,2-dimethylamino-1-cyclopentene hydrochloride, (ak) 2-Iminopiperidine hydrochloride, (al) 1-Aza-2-methylamino-1-cyclohexene hydrochloride, (am) 1-Aza-2-ethylamino-1-cyclohexene hydrochloride, (an) 1-Aza-2-dimethylamino-1-cyclohexene hydrochloride, (ao) 2-Imino-3-methylpiperidine hydrochloride, (ap) 2-Imino-4-methylpiperidine hydrochloride, (aq) 2-Imino-4-propylpiperidine hydrochloride, (ar) 2-Imino-4-benzylpiperidine hydrochloride, (as) 2-Imino-5-methylpiperidine hydrochloride, (at) 2-Imino-5,5-dimethylpiperidine hydrochloride, (au) 2-Imino-3,5-dimethylpiperidine hydrochloride, (av) 1-Aza-2-iminocycloheptane hydrochloride, (aw) 1-Aza-2-methylamino-1-cycloheptene hydrochloride, (ax) 1-Aza-2-ethylamino-1-cycloheptene hydrochloride, (ay) 1-Aza-2-dimethylamino-1-cycloheptene hydrochloride, (az) 1-Aza-2-benzylamino-1-cycloheptene hydrochloride, (bb) 1-Aza-2-cyclohexylamino-1-cycloheptene hydrochloride, (bc) 1-Aza-2-iminocyclooctane hydrochloride, (bd) 1-Aza-2-methylamino-1-cyclooctene hydrochloride, (be) 1-Aza-2-ethylamino-1-cyclooctene hydrochloride, (bf) 1-Aza-2-benzylamino-1-cyclooctene hydrochloride, (bg) 1-Aza-2-methylamino-1-cyclononene hydrochloride, (bh) 3,4-Dihydro-2-aminoquinoline hydrochloride, (bi) 3,4-Dihydro-2-methylaminoquinoline hydrochloride, (bj) 3,4-Dihydro-2-ethylaminoquinoline hydrochloride, (bk) 3,4-Dihydro-2-benzylaminoquinoline hydrochloride, (bl) 3,4-Dihydro-2-cyclohexylaminoquinoline hydrochloride, (bm) 3,4-Dihydro-2-dimethylaminoquinoline hydrochloride, (bn) 4-Ethoxycarbonyl-2-imino-piperazine hydrochloride, (bo) 5-(S)-2-Imino-1-aza-bicyclo(3.3.0)octane, (bp) 2-Imino-1-aza-bicyclo(4.3.0)nonane, (bq) cis-4,6-Dimethyl-2-imino-piperidine, acetic acid salt, (br) 2-Imino-4-methyl-piperidine, acetic acid salt, (bs) 6-Ethyl-2-imino-4-methyl-piperidine, acetic acid salt, (bt) 4-Imino-5-cis-methyl-3-azabicyclo [4.3.0] nonane, hydrochloride, (bu) cis-5-Aminomethyl-4,6-dimethyl-2-imino-piperidine, dihydrochloride, (bv) cis-3-Ethyl-2-imino-4-methyl-piperidine, hydrochloride, (bw) cis-2-Imino-4-methyl-3-n-propyl-piperidine, hydrochloride, (bx) cis and trans-2-Imino-4-methyl-piperidine-5-carboxylic acid, acetic acid salt, (by) cis and trans2-Imino-4-methyl-piperidine-5-carboxylic acid, methyl ester, acetic acid salt, (bz) cis and trans5-Acetamidomethyl-2-imino-4-methyl-piperidine, acetic acid salt, (cc) 2-Imino-5-n-propyloxy-piperidine, acetic acid salt, (cd) cis and trans5-Acetamido-2-imino-4-methyl-piperidine, acetic acid salt, (ce) 5-Cyclohexyl-2-imino-piperidine, acetic acid salt, (cf) cis and trans5-Cyclohexyl-2-imino-4-methyl-piperidine, acetic acid salt, (cg) 2-Imino-5-trifluoro-piperidine, (ch) 2-Imino-5-ethyl-4-methylpyrrolidine hydrochloride, (ci) 2-Imino-4-methylpyrrolidine hydrochloride, (cj) 2-Imino-4-ethylpyrrolidine hydrochloride, (ck) 2-Imino-4,5-dimethylpyrrolidine hydrochloride, (cl) 2-Imino-4-methyl-5-propylpyrrolidine hydrochloride, (cm) 2-Imino-5-methyl-4-propylpyrrolidine hydrochloride, (cn) 2-Imino-5-ethyl-4-propylpyrrolidine hydrochloride (co) 2-Imino-5-ethyl-3-methylpyrrolidine hydrochloride, (cp) 2-Imino-5,5-dimethylpyrrolidine hydrochloride, (cq) 2-Imino-3,5,5-trimethylpyrrolidine hydrochloride (cr) 2-Imino-4-ethyl-5-methylpyrrolidine hydrochloride, (cs) 2-Imino-4-propylpyrrolidine hydrochloride, (ct) 2-Imino-4-(2-methyl-ethyl)pyrrolidine hydrochloride, (cu) 2-Imino-4-phenylpyrrolidine hydrochloride, (cv) 2-Imino-3,4-dimethylpyrrolidine hydrochloride, (cw) 2-Imino-4-ethyl-3-methylpyrrolidine hydrochloride, (cx) 2-Imino-5-methyl-4-propylpyrrolidine hydrochloride, (cy) 2-Imino-3-azabicyclo(4.3.0)nonane hydrochloride, (cz) 2-Imino-3-azabicyclo(3.3.0)octane hydrochloride, (dd) 2-Imino-3-methylpyrrolidine hydrochloride, (de) 2-Imino-5-methylpyrrolidine hydrochloride, (df) 2-Imino-5-(S)-acetyloxymethylpyrrolidine hydrochloride, (dg) 2-Imino-5-(R)-acetyloxymethylpyrrolidine hydrochloride, (dh) 2-Imino-5-(S)-hydroxymethylpyrrolidine hydrochloride, (di) 2-Imino-5-(R)-hydroxymethylpyrrolidine hydrochloride, (dj) 2-Imino-4(S)-methoxy-5(S)-methyl-piperidine, hydrochloride, (dk) 2-Imino-5(S)-hydroxy-4(S)-methyl-piperidine, hydrochloride, (dl) 4(S),5(R)-Dimethyl-2-imino-piperidine hydrochloride, (dm) 4(R),5(S)-Dimethyl-2-imino-piperidine hydrochloride, (dn) 4(S),5(S)-Dimethyl-2-imino-piperidine hydrochloride, (do) 4(R),5(R)-Dimethyl-2-imino-piperidine hydrochloride, (dp) cis-Decahydro-2-iminoquinoline hydrochloride, (dr) cis-2-Imino-4-methyl-decahydroquinoline hydrochloride, (ds) trans-Decahydro-2-iminoquinoline hydrochloride, (dt) 4(R)-Methyl-2-iminopiperidine hydrochloride, (du) 4(S)-Methyl-2-iminopiperidine hydrochloride, (dv) 5(R)-Methyl-2-iminopiperidine hydrochloride, (dw) 5(S)-Methyl-2-iminopiperidine hydrochloride, (dx) 3-Iminothiomorpholine hydrochloride, (dy) 2-Iminopiperazine hydrochloride, (dz) 2-Imino-decahydro-cis-quinoxaline, and (ee) 2-Imino-decahydro-trans-quinoxaline.

21. A compound of Claim 1 selected from (aa) 2-Imino-4-methylpyrrolidine hydrochloride, (ab) 2-Imino-4-ethylpyrrolidine hydrochloride, (ac) 2-Imino-4,5-dimethylpyrrolidine hydrochloride, (ad) 2-Imino-4-methyl-5-propylpyrrolidine hydrochloride, (ae) 2-Imino-5-methyl-4-propylpyrrolidine hydrochloride, (af) 2-Imino-5-ethyl-4-propylpyrrolidine hydrochloride, (ag) 2-Imino-5-ethyl-3-methylpyrrolidine hydrochloride, (ah) 2-Imino-5,5-dimethylpyrrolidine hydrochloride, (ai) 2-Imino-3,5,5-trimethylpyrrolidine hydrochloride, (aj) 2-Imino-4-ethyl-5-methylpyrrolidine hydrochloride, (ak) 2-Imino-4-propylpyrrolidine hydrochloride, (al) 2-Imino-4-(2-methyl-ethyl)pyrrolidine hydrochloride, (am) 2-Imino-4-phenylpyrrolidine hydrochloride, (an) 2-Imino-3,4-dimethylpyrrolidine hydrochloride, (ao) 2-Imino-4-ethyl-3-methylpyrrolidine hydrochloride, (ap) 2-Imino-5-methyl-4-propylpyrrolidine hydrochloride, (aq) 2-Imino-3-azabicyclo(4.3.0)nonane hydrochloride, (ar) 2-Imino-3-azabicyclo(3.3.0)octane hydrochloride, (as) 2-Imino-3-methylpyrrolidine hydrochloride, (at) 2-Imino-5-methylpyrrolidine hydrochloride, (au) 2-Imino-5-(S)-acetyloxymethylpyrrolidine hydrochloride, (av) 2-Imino-5-(R)-acetyloxymethylpyrrolidine hydrochloride, (aw) 2-Imino-5-(S)-hydroxymethylpyrrolidine hydrochloride, (ax) 2-Imino-5-(R)-hydroxymethylpyrrolidine hydrochloride, (ay) 5-Ethyl-2-imino-4-methyl-piperidine, acetic acid salt, (az) 2-Imino-4-methyl-5-(1-pentyl)-piperidine, acetic acid salt, (bb) 4(R)-Methyl-2-iminopiperidine hydrochloride, (bc) 4(S)-Methyl-2-iminopiperidine hydrochloride, (bd) 5(R)-Methyl-2-iminopiperidine hydrochloride, (be) 5(S)-Methyl-2-iminopiperidine hydrochloride, (bf) 4(S),5(R)-Dimethyl-2-imino-piperidine hydrochloride, (bg) 4(R),5(S)-Dimethyl-2-imino-piperidine hydrochloride, (bh) 4(S),5(S)-Dimethyl-2-imino-piperidine hydrochloride, (bi) 4(R),5(R)-Dimethyl-2-imino-piperidine hydrochloride, (bj) 2-Imino-5(S)-methoxy-4(S)-methyl-piperidinne hydrochloride, (bk) 2-Imino-5(S)-hydroxy-4(S)-methyl-piperidine hydrochloride, (bl) 2-Imino-5(S)-methoxy-4(R)-methyl-piperidine hydrochloride, (bm) 2-Imino-5(S)-hydroxy-4(R)-methyl-piperidine hydrochloride, (bn) 2-Imino-5(S)-acetyloxy-4(R)-methyl-piperidine hydrochloride, (bo) 2-Imino-3(S),4(R)-O-isopropylidene-5(R)-acetyloxy-piperidine hydrochloride, (bp) 2-Imino-3(S),4(R),5(R)-triacetyloxy-piperidine hydrochloride, (bq) cis-Decahydro-2-iminoquinoline hydrochloride, (br) trans-Decahydro-2-iminoquinoline hydrochloride, (bs) 4(S)-Methyl-4a(S), 7a(S)-perhydro-2-imino-1-pyrindine hydrochloride, (bt) 4(R)-Methyl-4a(R),7a(R)-perhydro-2-imino-1-pyrindine hydrochloride, (bu) 4(S)-Methyl-4a(S),8a(S)-decahydro-2-iminoquinoline hydrochloride, (bv) 4(R)-Methyl-4a(R),8a(R)-decahydro-2-iminoquinoline hydrochloride, (bw) 2-Imino-octahydro-quinolin-6(5H)-one-6-ethylene ketal hydrochloride, (bx) 2-Imino-octahydro-quinolin-6(5H)-one hydrochloride, (by) 2-Imino-6-acetyloxy-cis-decahydroquinoline hydrochloride, (bz) 2-Imino-6-hydroxy-cis-decahydroquinoline hydrochloride, (cc) 2-Imino-5-methoxy-cis-perhydro-pyrindene hydrochloride, (cd) 2-imino-5-hydroxy-cis-perhydro-pyrindene hydrochloride, (ce) 2-Imino-5-hydroxy-4a-methyl-trans-(4a, 8a)-decahydroquinoline hydrochloride, (cf) 2-Imino-5-fluoro-5-methyl-cis-(4a, 8a)-decahydroquinoline hydrochloride, (cg) 5-Acetoxy-2-imino-cis-(4a,8a)-decahydroquinoline hydrochloride, (ch) 5-Hydroxy-2-imino-cis-(4a,8a)-decahydroquinoline hydrochloride, (ci) 2-Imino-octahydroquinolin-7(8H)-one-7-ethylene ketal hydrochloride, (cj) 2-Imino-octahydro-quinolin-7(8H)-one hydrochloride, (ck) 7-Acetyloxy-2-imino-trans-(4a,8a)-decahydroquinoline hydrochloride, (cl) 7-Hydroxy-2-imino-trans-(4a,8a)-decahydroquinoline, acetic acid salt, (cm) 7-Acetyloxy-2-imino-decahydroquinoline, acetic acid salt, (cn) 2-Imino-3-Methyl-octahydro-cis-pyrano[4,3-b]-pyridine hydrochloride, (co) 2-Imino-4-methyl-octahydro-pyrano[4,3-b]pyridine hydrochloride, (cp) 2-Imino-4-Methyl-1,3,4,5,7,8-hexahydro-pyrano[4,3-b]pyridine, acetic acid salt, (cq) 2-Imino-1-methyl-piperidine hydrochloride, (cr) N-(1-Benzyl-2-piperidinylidene)-N'-(phenyl)-urea, (cs) N-(2-Piperidinylidene)-N'-(phenyl)-urea (ct) N-[1-(4-Methoxybenzyl)-2-piperidinylidene]-N'-(phenyl)-urea, (cu) 2-Imino-1-(benzylaminocarbonyl)-piperidine, (cv) Cis-Octahydro-3-imino-2H-1,4-benzoxazine hydrochloride, (cw) 2-Iminopiperazine hydrochloride, (cx) 4-Methyl-2-iminopiperazine hydrochloride, (cy) 2-Imino-decahydro-cis-quinoxaline dihydrochloride, (cz) 2-Imino-decahydro-trans-quinoxaline dihydrochloride, (da) 4-6-Dimethyl-2-imino-piperazine hydrochloride, (db) 2-Imino-4-methyl-6-(2-methylpropyl)-5-oxo-piperazine hydrochloride.
(dc) 4-Benzyloxycarbonyl-2-imino-(1,2,3,4)tetrahydro-quinoxaline hydrochloride, (dd) 4-Acetyl-2-imino-(1,2,3,4)tetrahydro-quinoxaline hydrochloride, (de) 2-Imino-4-methyl-decahydro-trans-quinoxaline, acetic acid salt, (df) 3-Iminothiomorpholine hydrochloride, (dg) 3-Imino-5-propyl-thiomorpholine, (dh) 3-Imino-5-methyl-thiomorpholine, (di) 3-Imino-5-ethyl-thiomorpholine, (dj) 3-Imino-5-butyl-thiomorpholine, (dk) 3-Imino-5(S)-(2-methyl propyl)-thiomorpholine, (dl) 3-Imino-5(R)-(2-methyl propyl)-thiomorpholine, (dm) 1-(tert-Butoxycarbonyl)-hexahydro-3-imino-(1H)-1,4-diazepine hydrochloride, (dn) Hexahydro-2-imino-(1H)-1,4-diazepine dihydrochloride, (do) Hexahydro-2-imino-5-methyl-(1H)-1,4-diazepine dihydrochloride.
(dp) Hexahydro-2-imino-4-methyl-(1H)-1,4-diazepine hydrochloride, (dq) 3-Amino-hexahydro-2-imino-(1H)-azepine dihydrochloride, (dr) (S)-3-Amino-2-iminopiperidine dihydrochloride, (ds) Hexahydro-3-imino-1,4-oxazepine hydrochloride, (dt) Hexahydro-3-imino-1,4-thiazepine hydrochloride, (du) Hexahydro-3-imino-5-propyl-(1H)-1,4-diazepine dihydrochloride, (dv) Hexahydro-3-imino-5-methyl-(1H)-1,4-diazepine dihydrochloride, (dw) 2-Imino-decahydro-cis-1,4-benzo(e)diazepine dihydrochloride, (dx) 2-Imino-decahydro-3H-benz(e)azepine hydrochloride, (dy) Trans-Octahydro-3-imino-2H-1,4-benzthiazine, acetic acid salt, (dz) 2-Imino-5(6H)-oxa-cis-hexahydro-(1H)-quinoline hydrochloride, and (ea) 2-Imino4-methyl-5(6H)-oxa-cis-hexahydro-(1H)-quinoline hydrochloride.

(eb) (2-Imino-decahydro-cis-3H-benz(e)azepin hydrochloride, (ec) Trans-Octahydro-3-imino-2H-1,4-benzthiazine, acetic acid salt, (ed) Cis-Octahydro-3-imino-2H-1,4-benzthiazine, acetic acid salt, (ee) 2-Imino-5(6H)-oxa-cis-hexahydro-(1H)-quinoline hydrochloride, (ef) 2-Imino-4-methyl-5(6H)-oxa-cis-hexahydro-(1H)-quinoline hydrochloride, and (eg) 2-Imino-decahydro-trans-1,4-benzo(e)diazepine dihydrochloride.

22. A pharmaceutical composition for treating a nitric oxide synthase mediated disease comprising a pharmaceutical carrier and a non-toxic effective amount of the compound accrding to claim 1.

23. A pharmaceutical composition for treating a nitric oxide synthase mediated disease comprising a pharmaceutical carrier and a non-toxic effective amount of the compound accrding to claim 17.

24. A method for inhibiting the activity of nitric oxide synthases comprising administering to a subject suffering from a nitric oxide synthase mediated disease, a non-toxic therapeutically effective amount of the compound of Claim 1.