WO2006107963A2

WO2006107963A2 - Process for preparing dipeptide amides

Info

Publication number: WO2006107963A2
Application number: PCT/US2006/012497
Authority: WO
Inventors: Prasad Koteswara Kapa; Joseph Mckenna; Wen-Chung Shieh; Song Xue
Original assignee: Novartis Ag; Novartis Pharma Gmbh
Priority date: 2005-04-06
Filing date: 2006-04-04
Publication date: 2006-10-12
Also published as: WO2006107963A3

Abstract

The present invention provides a new method of making compounds of the formula (I) with anticancer activity, particularly N-[1-cyclohexyl-2-oxo-2-(6-phenethyl-octahydro-pyrrolo[2,3-c]pyridin-1-yl)-ethyl]-2-methylamino-propionamide and related compounds.

Description

PROCESS FOR PREPARING ORGANIC COMPOUNDS

Background of the Invention

The present invention provides a new method of making dipeptide amide compounds of the formula (I) with anticancer activity, particularly N-[1 -cyclohexyl-2-oxo-2-(6-phenethyl- octahydro-pyrrolo[2,3-c]pyridin-1 -yl)-ethyl]-2-methylamino-propionamide and related compounds.

These compounds have been disclosed in Provisional Application No. U.S. 60/560,186, filed April 7, 2004, the disclosure of which is incorporated by reference. The compounds of formula (I) inhibit the binding of the Smac protein to Inhibitor of Apoptosis Proteins (IAPs). As such, the compound of formula (I) can be used for the treatment of certain proliferative diseases, including cancer.

Previous synthesis of compounds of formula (I) involves the following steps:

Scheme 1

Step i

Step 2

Step 1 involves coupling of the scaffold with a f-Boc protected natural or unnatural amino acid using standard peptide coupling conditions followed by the removal of the f-Boc group with TFA.

Step 2 involves the coupling of the amine generated in the preceding step with a t-Boc protected or tertiary natural or unnatural amino acid using standard peptide coupling conditions followed by the removal of the t-Boc group with TFA if applicable. The product is then purified by high-performance liquid chromatography (HPLC).

The process described in Scheme 1 is inefficient, costly and produces racemates that need further purification.

Thus, there is a need for an alternate process that is cheaper, consistent, convergent, efficient, and produces compounds of formula (I) in high yields.

It is an object of this invention to provide for an alternative process to make compounds of formula (I) efficiently with high and consistent yields.

It is a further object of this invention to make compounds of formula (I) from a convergent synthetic route.

It is a still further object of this invention to make compounds of formula (I) that are optically pure (>99%).

Summary of the Invention

The present invention overcomes the problems encountered in the previous synthesis described in Scheme 1 and typically results in an increased overall yield by more than two fold.

The current invention does not utilize Steps 1 and 2 of the previous synthetic route as described in Scheme 1. Furthermore, the present invention eliminates the need of HBTU/HOBt reagents that are used twice in Steps 1 and 2 of the previous synthetic route as the coupling reagents. These reagents are expensive and inefficient for the synthesis of the compounds of formula (I). The coupling reagent utilized in the process of the current invention, 4-(4,6-dimethoxy-1 ,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMTMM) is efficient, inexpensive and commercially available. Compared to the previous synthesis routes, the current process employs a convergent route, which increases the overall yield by more than two-fold. Thus, the current process is cheaper, more efficient, and provides higher yields. This process will be more suitable for manufacturing purposes.

Detailed Description of the Invention

The present invention provides a new, convergent and efficient method of making compounds of the formula (I)

comprising the following general Scheme 2:

Scheme 2,

DMTMM

wherein R₁ is H; C₁-C₄ alkyl; C₁-C₄ alkenyl; C₁-C₄ alkynyl or cycloalkyl which are unsubstituted or substituted;

R₂ is H; C_rC₄alkyl; C₁-C₄ alkenyl; C₁-C₄ alkynyl or cycloalkyl which are unsubstituted or substituted;

R₃ is H; -CF₃; -C₂F₅; C_rC₄ alkyl; C₁-C₄ alkenyl; C₁-C₄ alkynyl; -CH₂-Z or R₂ and R₃ together with the nitrogen form a het ring;

Z is H; -OH; F; Cl; -CH₃; -CF₃; -CH₂CI; -CH₂F or -CH₂OH;

R₄ is C-i-C-₁6 straight or branched alkyl; C₁-C₁₆ alkenyl; C₁-C₁₆ alkynyl; or -C₃-Ci₀ cycloalkyl; -(CH₂)_I-B-Z₁; -(CH₂)_o.₆-aryl; and -(CH₂)_0-6-het, wherein alkyl, cycloalkyl and phenyl are unsubstituted or substituted;

Z₁ is -N(R₈)-C(0)-C_rC_1oalkyl; -N(R₈)-C(O)-(CH₂)_1-6-C₃-C₇cycloalkyl; -N(R₈)-C(O)-(CH₂)_0- ₆-phenyl; -N(R₈)-C(O)-(CH₂)_1-6-het; -C(O)-N(R₉)(R₁₀); -C(O)-O-C_rC₁₀alkyl; -C(O)-O- (CH₂)_1-6-C₃-C₇cycloalkyl; -C(O)-O-(CH₂)₀-₆-phenyl; -C(O)-O-(CH₂)_1-6-het; -0-C(O)-C₁- C_1oalkyl; -O-C(O)-(CH₂)₁.₆-C₃-C₇cycloalkyl; -0-C(0)-(CH₂)_o.₆-phenyl; -O-C(O)-(CH₂)_1-6- het, wherein alkyl, cycloalkyl and phenyl are unsubstituted or substituted;

het is a 5-7 membered heterocyclic ring containing 1- 4 heteroatoms selected from N, O and S, or an 8-12 membered fused ring system including at least one 5-7 membered heterocyclic ring containing 1 , 2 or 3 heteroatoms selected from N, O, and S, which heterocyclic ring or fused ring system is unsubstituted or substituted on a carbon or nitrogen atom;

R₈ is H, -CH₃, -CF₃ , -CH₂OH or -CH₂CI;

R₉ and Ri₀ are each independently H; C_rC₄alkyl; C₃-C₇cycloalkyl; -(CH₂)_1-6-C₃- C₇cycloalkyl; -(CH₂)_0-6-phenyl; wherein alkyl, cycloalkyl and phenyl are unsubstituted or substituted, or R₉ and Rio together with the nitrogen form het;

R₅ is H; d-C-io-alkyl; C₃-C₇cycloalkyl; -(CH₂)_1-6-C₃-C₇cycloalkyl; -C_rC_1oalkyl-aryl; -(CH₂)_0- ₆-C₃-C₇cycloalkyl-(CH₂)_o-6-phenyl; -(CH₂)_0-4CH-((CH₂)_1-4-phenyl)₂; -(CH₂)_o-6-CH(phenyl)₂- indanyl; -C(O)-C_rC₁₀alkyl; -C(O)-(CH₂)_1-6-C₃-C₇cycloalkyl; -C(0)-(CH₂)_o-6-phenyl; -(CH₂)_o- ₆-het ; -C(O)-(CH₂)i-₆-het; or R₅ is a residue of an amino acid, wherein alkyl, cycloalkyl, phenyl and aryl are unsubstituted or substituted;

Ri₃ is CrCio-alkyl; phenyl or phenylalkyl such as benzyl;

U is a as shown in structure II:

wherein

n = 0-5;

Ra and Rb are independently an O, S, or N atom or C_0-8 alkyl wherein one or more of the carbon atoms in the alkyl chain may be replaced by a heteroatom selected from O, S or N, and where the alkyl may be unsubstituted or substituted;

Rd is selected from:

(a) -Re - Q - (Rf)p(Rg)q; or

(b) Ar₁-D- Ar₂;

Rc is H or Rc and Rd together form cycloalkyl or het; where if Rd and Rc form a cycloalkyl or het, R₅ is attached to the formed ring at a C or N atom;

p and q are independently 0 or 1 ;

Re is C_1-8 alkyl, or alkylidene, and Re may be unsubstituted or substituted;

Q is N, O, S, S(O), or S(O)₂;

Ar-i and Ar₂ are substituted or unsubstituted aryl or het; Rf and Rg are each independently H; -CrC₁₀ alkyl; C_rCi_Oalkylaryl; -OH; -O-C_rC₁₀alkyl; -(CH₂)Q-₆-C₃-C₇cycloalkyl; -0-(CH₂)o-6-aryl; phenyl; aryl; phenyl-phenyl; -(CH₂)i_-6-het; -O- (CH₂)i-β-het; -OR₁₁; -C(O)-R₁₁; -C(O)-N(R₁₁)(R₁₂); -N(R₁₁)(R₁₂); -S-R₁₁; -S(O)-R₁₁; - S(O)₂-R₁₁; -S(O)₂-NR₁₁R₁₂; -NR₁₁-S(O)₂- R₁₂; S-C_rC_ralkyl; aryl-C_rC₄alkyl; het-C_r C₄alkyl wherein alkyl, cycloalkyl, het and aryl are unsubstituted or substituted; -SO_2-Ci- C₂alkyl; -SO^C-i.C^lkylphenyl; -O-C_rC₄alkyl; or R_g and R_f form a ring selected from het or aryl;

D is -CO-; -C(O)-C_1-7 alkylene or arylene; -CF₂-; -0-; -S(O)_n where r is 0-2; 1 ,3dioaxolane; or C_1-7 alkyl-OH; where alkyl, alkylene or arylene may be unsubstituted or substituted with one or more halogens, OH, -O-CrCβalkyl, -S-CrCβalkyl or -CF₃; or D is -N(Rh) wherein Rh is H; C_1-7 alkyl (unsub or substituted); aryl; -O(C_1-7cycloalkyl) (unsub or substituted); C(O)-C_rC₁₀alkyl; C(O)-C_o-Ci₀alkyl-aryl; C-O-C_rC₁₀alkyl; C-O-C₀- Ci_θalkyl-aryl or SO₂-C_rC₁₀-alkyl; SO₂-(C_o-C₁₀-alkylaryl);

R_6, R₇, R'₆ and R'₇ are each independently H; -C₁-C₁₀ alkyl; -C₁-C₁₀ alkoxy; aryl-C-ι-C_1o alkoxy; -OH; -0-C_rC_1oalkyl; -(CH₂)_o.₆-C₃-C₇cycloalkyl; -0-(CH₂)_o.₆-aryl; phenyl; -(CH₂)_1-6- het; -O-(CH₂)_1-6-het; -OR₁₁; -C(O)-R₁₁; -C(O)-N(R₁₁)(R₁₂); -N(R₁₁)(R₁₂); -S-R₁₁; -S(O)- R₁₁; -S(O)₂-R₁₁; -S(O)₂-NR₁₁R₁₂; -NR₁₁-S(O)₂- R₁₂; wherein alkyl, cycloalkyl and aryl are unsubstituted or substituted; and R₆, R₇, R'₆ and R'₇can be united to form a ring system;

R₁₁ and R₁₂ are independently H; C₁-C₁₀ alkyl; -(CH₂)₀-₆-C₃-C₇cycloalkyl; -(CH₂)_O-6-(CH)_0- ^aIyI)_1-2; -C(O)-C_rC₁₀alkyl; -C(O)-(CH₂)_1-6-C₃-C₇cycloalkyl; -C(0)-0-(CH₂)_o-6-aryl; -C(O)- (CH₂)_o-6-0-fluorenyl; -C(0)-NH-(CH₂)_o-6-aryl; -C(0)-(CH₂)o-6-aryl; -C(O)-(CH₂)_1-6-het; - C(S)-C_rC_1oalkyl; -C(S)-(CH₂)_1-6-C₃-C₇cycloalkyl; -C(S)-0-(CH₂)_o-6-aryl; -C(S)-(CH₂)_o-6-0- fluorenyl; -C(S)-NH-(CH₂)_o-6-aryl; -C(S)-(CH₂)_o.₆-aryl; ^(SHCH^_Le-het; wherein alkyl, cycloalkyl and aryl are unsubstituted or substituted; or R₁₁ and Ri₂ are a substituent that facilitates transport of the molecule across a cell membrane; or R₁₁ and R₁₂ together with the nitrogen are het; aryl of R₁₁ and R₁₂ can be phenyl, naphthyl, or indanyl which is unsubstituted or substituted;

alkyl of R₁₁ and R₁₂ may be unsubstituted or substituted by one or more substituents selected from a C₁-Ci₀ alkene, halogen, OH, -O-CrCεalkyl, -S-CrCεalkyl and -CF₃; cycloalkyl of Rn and Ri₂ may be unsubstituted or substituted by one or more selected from a CrCi_O alkene, one or more halogens, d-Cβalkyl, halogen, OH, -O-CrCβalkyl, -S- Ci-C₆alkyl or -CF₃; and

phenyl or aryl of Rn and R₁₂ may be unsubstituted or substituted by one or more substituents selected from halogen, hydroxy, CrC₄ alkyl, Ci-C₄ alkoxy, nitro,

-CN, -O-C(O)-C_rC₄alkyl and -C(O)-O-C_rC₄-aryl;

or pharmaceutically acceptable salts thereof.

The compounds of formula (I) can be used for the treatment of proliferative diseases, especially those dependent on the binding of Smac protein to Inhibitor of Apoptosis Proteins (IAPs), including certain cancers.

The general terms used hereinbefore and hereinafter preferably have within the context of this disclosure the following meanings, unless otherwise indicated:

"Aryl" is an aromatic radical having 6 to 14 carbon atoms, which may be fused or unfused, and which is unsubstituted or substituted by one or more, preferably one or two substituents, wherein the substituents are as described below. Preferred "aryl" is phenyl, naphthyl or indanyl.

"Het" refers to heteroaryl and heterocyclic rings and fused rings containing aromatic and non-aromatic heterocyclic rings. "Het" is a 5-7 membered heterocyclic ring containing 1- 4 heteroatoms selected from N, O and S, or an 8-12 membered fused ring system including at least one 5-7 membered heterocyclic ring containing 1 , 2 or 3 heteroatoms selected from N, O, and S. Suitable het substituents include unsubstituted and substituted pyrrolidyl, tetrahydrofuryl, tetrahydrothiofuranyl, piperidyl, piperazyl, tetrahydropyranyl, morphilino, 1,3-diazapane, 1 ,4-diazapane, 1 ,4-oxazepane, 1 ,4- oxathiapane, furyl, thienyl, pyrrole, pyrazole, triazole, 1 ,2,3-triazole, tetrazolyl, oxadiazole, thiophene, imidazole, pyrrolidine, pyrrolidone, thiazole, oxazole, pyridine, pyrimidine, isoxazolyl, pyrazine, quinoline, isoquinoline, pyridopyrazine, pyrrolopyridine, furopyridine, indole, benzofuran, benzothiofuran, benzindole, benzoxazole, pyrroloquinoline, and the like. The het substituents are unsubstituted or substituted on a carbon atom by halogen, especially fluorine or chlorine, hydroxy, CrC₄ alkyl, such as methyl and ethyl, CrC₄ alkoxy, especially methoxy and ethoxy, nitro, -O-C(O)-C_rC₄alkyl or -C(O)-O-CrC₄alkyl or on a nitrogen by C_rC₄ alkyl, especially methyl or ethyl, -O- C(O)-C_rC₄alkyl or -C(O)-O-C_rC₄alkyl, such as carbomethoxy or carboethoxy.

When two substituents together with a commonly bound nitrogen are het, it is understood that the resulting heterocyclic ring is a nitrogen-containing ring, such as aziridine, azetidine, azole, piperidine, piperazine, morphiline, pyrrole, pyrazole, thiazole, oxazole, pyridine, pyrimidine, isoxazolyl, and the like.

Halogen is fluorine, chlorine, bromine or iodine, especially fluorine and chlorine.

Unless otherwise specified "alkyl" includes straight or branched chain alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl and branched pentyl, n-hexyl and branched hexyl, and the like.

A "cycloalkyl" group means C₃ to Ci₀cycloalkyl having 3 to 8 ring carbon atoms and may be, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl. Preferably, cycloalkyl is cycloheptyl. The cycloalkyl group may be unsubstituted or substituted with any of the substituents defined below, preferably halo, hydroxy or CrC₄ alkyl such as methyl.

Unsubstituted is intended to mean that hydrogen is the only substituent.

Any of the above defined aryl, het, alkyl, cycloalkyl, or heterocyclic groups may be unsubstituted or independently substituted by up to four, preferably one, two or three substituents, selected from the group consisting of: halo (such as Cl or Br); hydroxy; lower alkyl (such as CrC₃ lower alkyl); lower alkyl which may be substituted with any of the substituents defined herein; lower alkenyl; lower alkynyl; lower alkanoyl; alkoxy (such as methoxy); aryl (such as phenyl or benzyl); substituted aryl (such as fluoro phenyl or methoxy phenyl); amino; mono- or disubstituted amino; amino lower alkyl (such as dimethylamino); acetyl amino; amino lower alkoxy (such as ethoxyamine); nitro; cyano; cyano lower alkyl; carboxy; esterified carboxy (such as lower alkoxy carbonyl e.g. methoxy carbonyl); n-propoxy carbonyl or iso-propoxy carbonyl; alkanoyl; benzoyl; carbamoyl; N-mono- or N,N-disubstituted carbamoyl; carbamates; alkyl carbamic acid esters; amidino; guanidine; urea; ureido; mercapto; sulfo; lower alkylthio; sulfoamino; sulfonamide; benzosulfonamide; sulfonate; sulfanyl lower alkyl (such as methyl sulfanyl); sulfoamino; substituted or unsubstituted sulfonamide (such as benzo sulfonamide); substituted or unsubstituted sulfonate (such as chloro-phenyl sulfonate); lower alkylsulfinyl; phenylsulfinyl; phenyl-lower alkylsulfinyl; alkylphenylsulfinyl; lower alkanesulfonyl; phenylsulfonyl; phenyl-lower alkylsulfonyl; alkylphenylsulfonyl; halogen- lower alkylmercapto; halogen-lower alkylsulfonyl; such as especially trifluoromethane sulfonyl; phosphono (-P(=O)(OH)₂); hydroxy-lower alkoxy phosphoryl or di-lower alkoxy- phosphoryl; substituted urea (such as 3-trifluoro-methyl-phenyl urea); alkyl carbamic acid ester or carbamates (such as ethyl-N-phenyl-carbamate) or -NR₄R₅, wherein R₄ and R₅ can be the same or different and are independently H; lower alkyl (e.g. methyl, ethyl or propyl); or R₄ and R₅ together with the N atom form a 3- to 8-membered heterocyclic ring containing 1-4 nitrogen, oxygen or sulfur atoms (e.g. piperazinyl, pyrazinyl, lower alkyl-piperazinyl, pyridyl, indolyl, thiophenyl, thiazolyl, n-methyl piperazinyl, benzothiophenyl, pyrrolidinyl, piperidino or imidazolinyl) where the heterocyclic ring may be substituted with any of the substituents defined herein.

Preferably the above mentioned alkyl, cycloalkyl, aryl or het groups may be substituted by halogen, carbonyl, thiol, S(O), S(O₂), -OH, -SH, -OCH₃, -SCH₃, -CN, -SCN or nitro.

In an alternative embodiment of the present invention, the process for the synthesis of chiral compounds of formula (III) is described as follows:

Scheme 3.

DMTMM

In a preferred embodiment of the present invention, the process of making compound A9 is described as follows:

Scheme 4

The process described in Scheme 4 starts with commercially available amino acids (S)- C-Cyclohexyl-C-methoxycarbonyl-methyl-ammonium chloride (Z7d) and (S)-2-(tert- Butoxycarbonyl-methyl-amino)-propionic acid (Z7c) for the synthesis of dipeptide (S)- [(S)-2-(tert-Butoxycarbonyl-methyl-amino)-propionylamino]-cyclohexyl-acetic acid (Z7a) in two steps. Coupling intermediate 6-phenethyl-octahydro-pyrrolo[2,3-c]pyridine (A7) with dipeptide Z7a utilizing DMTMM as the coupling reagent furnishes penultimate compound {(S)-1 -[(S)-1 -Cyclohexyl-2-oxo-2-((3aR,7aS)-6-phenethyl-octahydro- pyrrolo[2,3-c]pyridin-1-yl)-ethylcarbamoyl]-ethyl}-methyl-carbamic acid tert-butyl ester (A8). Reacting A8 with acid (such as HCI) produces compound N-[1-cyclohexyl-2-oxo-2- (6-phenethyl-octahydro-pyrrolo[2,3-c]pyrindin-1-yl)-ethyl]-2-methylamino-propionamide (A9) in high yield.

The intermediate compound A7 can be prepared using the processes disclosed in a provisional patent application entitled "Process for the Synthesis of 6-phenethyl- octahydro-pyrrolo[2,3-c]pyridine and related compounds" [Case No. 4-34202], which is being filed concurrently herewith. The disclosure of that application is incorporated herein by reference.

In another embodiment, the process of the current invention can also be used to prepare analogues of A9 (such as a 5,7-fused or a 6,6-fused bicyclic system, Scheme 5, E1).

Scheme 5

\

In yet another embodiment, this process can also be utilized to couple compound A7 with various peptides (Scheme 6, E2). Scheme 6

DMTMM peptides

The following example more particularly illustrates the present invention, but do not limit the invention in any way.

Example 1

Preparation of N-[1 -cyclohexyl-2-oxo-2-(6-phenethyl-octahydro-pyrrolo[2,3-c]pyridin-1 - yl)-ethyl]-2-methylamino-propionamide (A9)

1) Step Z7d + Z7c → Z7b

Z7d Z7c ^Z7b

Into a 3-liter, 4-neck flask equipped with a mechanical stirrer, a thermometer, and an addition funnel are charged N-α-t-Boc-(S)-N-methylalanine Z7c (91.8 g, 0.45 mol), (S)- cyclohexylglycine methyl ester hydrochloride Z7d (93.6 g, 0.45 mol), 2-chloro-4,6- dimethoxy-1 ,3,5-triazine (CDMT, 82.8 g, 0.47 mol), and EtOAc (1.8 L) under nitrogen purge. The resulting white suspension is cooled to 0 - 5 ⁰C. N-methylmorpholine (113.4 g, 1.12 mol) is added and the mixture is allowed to warm to 25 ⁰C under vigorous stirring. The mixture is stirred for an additional 1.5 h. Any white precipitation is removed by filtration and rinsed with EtOAc (450 ml_). The combined organic solution is washed with aqueous sat. NaHCO₃, aqueous 10% citric acid, and sat. sodium chloride solution. The organic layer is concentrated under vacuum at 25 ⁰C to give a hazy oil. The oil is dissolved in MeOH (400 imL) and concentrated again under vacuum. The hazy oil is dissolved into MeOH (450 ml_). Water (450 ml_) is added to the solution under stirring. The resulting mixture is cooled to 10 ⁰C, seeded with solid Z7b, and stirred vigorously to obtain a white suspension. More water (450 ml.) is added. The mixture is cooled to 0 - 5 ⁰C and stirred for an additional 30 min. Any solid is collected by filtration, rinsed with water (450 ml_), and dried under vacuum to give Z7b as a white solid (140 g, 87% yield): m.p. = 74 - 77 ⁰C; ¹H NMR (DMSO-d₆) δ 7.95 (bd, 1 H), 4.52 (bd, 1 H), 4.13 (s, 1 H), 3.63 (s, 3H), 2.76 (s, 3H), 1.50 - 1.76 (m, 6H), 1.38 (s, 9H), 0.96 - 1.28 (m, 8H).

2) Step Z7b → Z7a

Z7b ^Z7a

Into a 5-liter, 4-neck flask equipped with a mechanical stirrer, a thermometer, and an addition funnel are charged compound Z7b (128 g, 0.36 mol) and THF (2.4 L) under nitrogen purge. The resulting solution is cooled to 0 - 5 ⁰C. A solution of lithium hydroxide monohydrate (19.6 g, 0.47 mol) in water (1.6 L) is added, keeping the batch temperature below 17 ⁰C. After the addition, the mixture is warmed to 25 ⁰C and stirred for an additional 1 h. A solution of citric acid (128 g) in water (350 mL) is added. The mixture is concentrated under vacuum at 25 ⁰C to remove THF. The remaining aqueous solution is extracted with EtOAc twice. The combined organic layers are washed with water, dried over MgSO₄, and concentrated under vacuum at 25 ⁰C to give an oil, which slowly crystallized in the freezer to furnish Z7a as a white solid (113 g, 92%): ¹H NMR (DMSO-d₆) δ 12.55 (s, 1 H), 7.68 (bd, 1 H), 4.52 (bd, 1 H), 4.13 (s, 1 H), 2.76 (s, 3H), 1.55 - 1.74 (m, 6H), 1.40 (s, 9H), 1.00 - 1.28 (m, 8H).

3) Step A7 + Z7a → A8

Into a 500-mL, 4-neck flask equipped with a mechanical stirrer, a thermometer, and an addition funnel are charged amine hydrochloride salt A7 (16.8 g, 63 mmol) and THF (150 mL) under nitrogen purge. Potassium trimethylsilanolate (8.1 g, 63 mmol) is added and the mixture is stirred for an additional 15 min. A solution of Z7a (21.6 g, 63 mmol) in THF (150 mL) is added and the resulting mixture is cooled to -20 ⁰C. DMTMM (18 g, 65 mmol) is added and the mixture is allowed to warm to 20 ⁰C, and stirred for an additional 45 min. Any precipitation is removed by filtration. The organic solution is concentrated under vacuum at 25 ⁰C to obtain an oil. The oil is dissolved in EtOAc and washed in sequence with aqueous sat. NaHCO₃, sat. NaCI, and water (250 mL) containing 10% citric acid (10 mL). The organic layer is concentrated under vacuum at 25 ⁰C to give a foamy solid (35.8 g), which is purified with chromatography (silica gel, EtOAc first, followed by CH₂CI₂: MeOH = 94 : 6) to obtain compound A8 as a foamy solid (28.0 g, 80% yield): ¹H NMR (500 MHz, CDCI₃) δ 7.15 - 7.31 (m, 5H), 6.60 (bs, 1 H), 4.64 (t, J = 8.6 Hz, 0.5H), 4.50 (t, J = 8.5 Hz, 0.5H), 4.30 (m, 0.5H), 4.06 (m, 0.5H), 3.72 (q, 9.5 Hz, 0.5H), 3.55 - 3.65 (m, 1 H), 3.45 (m, 0.5H), 3.30 (m, 0.5H), 3.13 (m, 0.5H), 2.75 - 2.90 (m, 6H)₁ 2.55 - 2.70 (m, 3H), 2.42 (m, 0.5H), 2.00 - 2.35 (m, 3.5H), 1.60 - 1.90 (m, 9H), 1.50 (s, 9H), 1.32 (m, 3H), 0.95 - 1.25 (m, 6H).

4) Step A8 → A9

Into a 1 L, 4-neck flask equipped with a mechanical stirrer, a thermometer, and an addition funnel are charged compound A8 (33.2 g, 60 mmol), MeOH (330 ml_), and cone. HCI (35.4 g, 360 mmol). The mixture is stirred at 40 ⁰C for 16 h. The mixture is concentrated under vacuum to remove MeOH. An aqueous solution of KHCO₃ (69 g, 690 mmol) in water (500 ml_) is added to the residue. The product is extracted into EtOAc, washed with sat. NaCI, dried over MgSO₄, and concentrated under vacuum to yield an oil. The oil is seeded with crystalline A9, and stirred in heptane to obtain A9 as a white solid (24.6 g, 90%): m.p. = 103 - 105 ⁰C; ¹H NMR (500 MHz, CDCI₃) δ 7.63 (d, J = 9.2 Hz, 0.5H), 7.54 (d, J = 9.5 Hz, 0.5H), 7.16 - 7.32 (m, 5H), 4.62 (t, J = 8.8 Hz, 0.5H), 4.52 (t, J = 9.1 Hz, 0.5H), 4.3 (m, 0.5H), 4.15 (m, 0.5H), 3.78 (q, 8.9 Hz, 0.5H), 3.41 - 3.71 (m, 2 H), 3.05 - 3.17 (m, 1.5H), 2.60 - 2.95 (m, 5H), 2.45 (m, 0.5H), 2.42 (d, 5.8 Hz, 3H), 2.40 (m, 1 H), 1.95 - 2.20 (m, 3H), 1.60 - 1.95 (m, 8.5H), 1.32 (t, J = 5.2 Hz, 3H), 1.00 - 1.30 (m, 6H); ¹³C NMR (125 MHz, CDCI₃) δ 175.0, 174.6, 170.9, 170.6, 140.7, 140.6, 129.2, 129.1, 128.7, 126.3, 60.72, 60.68, 60.65, 56.4, 55.8, 55.0, 54.8, 54.2, 53.1 , 49.8, 48.6, 46.4, 44.9, 42.2, 41.3, 36.2, 35.3, 34.2, 34.0, 33.9, 30.1 , 29.9, 29.2, 28.9, 27.4, 26.61 , 26.57, 26.52, 26.45, 26.42, 26.37, 26.1, 25.9, 24.4.

Example 2A Preparation of 6-phenethyl-octahydro-pyrrolo[2,3-c]pyridine (A7)

Step i: A1 + A2 → A3

A1 A2 A3

Into a 12-liter, 4-neck flask equipped with a mechanical stirrer, a thermometer and an addition funnel are charged phenethylamine A2 (2 kg, 16.7 mol), potassium carbonate (766 g, 5.6 mol, 325 mesh), and acetonitrile (8 L) under nitrogen atmosphere. 4-Bromo- 1-butene A1 (576 g, 5 mol) is added slowly at 20-25 ⁰C over a period of 30 min. After the addition, the mixture is heated to 50 ⁰C and stirred for an additional 3 h. The mixture is cooled to rt and stirred for an additional 12 h. The stirrer is stopped and any solid is allowed to settle. The supernatant (organic solution) is separated from the solid by siphoning. The remaining solid is filtered through a pad of celite, which is rinsed with acetonitrile (1 L). The organic solutions containing A3 are combined and evaporated under vacuum. The remaining concentrate is distilled under high vacuum to remove excess phenethylamine until its content in the pot residue is 1% or less. The remaining oil, compound A3, can be used as is. ¹H NMR (500 MHz, CDCI₃) δ 7.20-7.35 (m, 5H), 5.79 (m,1H) 5.00 - 5.10 (m, 2H), 2.92 (m, 2H), 2.84 (t, J = 6.8 Hz, 2H), 2.73 (t, J = 6.8 Hz, 2H), 2.27 (m, 2H).

Step 2: M3c + M3b → M3a

Into a 22-liter, 4-neck flask equipped with a mechanical stirrer, a thermometer, and an addition funnel are charged (R)-(+)-1-(1-naphthyl)ethylamine M3b (823 g, 4.8 mol) and acetonitrile (12.5 L) under nitrogen atmosphere. To this solution, potassium carbonate (1.33 kg, 9.6 mol) and 2,3-dibromopropionate M3c (1.42 kg, 5.8 mol) are added. The mixture is heated to 60 ⁰C and stirred for an additional 2h. The mixture is cooled to rt and stirred for another 16h. Any solid is removed by filtration. The filtrate is concentrated under vacuum to obtain an oily residue. The oil is dissolved into terf-butyl methyl ether (2L) and hexane (1 L), filtered through a pad of celite, and concentrated under vacuum to yield a brown oil (1.52 kg). The oil is purified by chromatography (silica gel; ethyl acetate/heptane 35:65) to obtain product M3a as an oil (1.18 kg, 96% yield): ¹H NMR (500 MHz, CDCI₃) δ 7.75 - 8.05 (m, 4H), 7.50 (m, 3H), 3.84 (s, 1.2 H), 3.72 (s, 1.8 H), 3.35 (m, 1 H), 2.50 (s, 0.6 H), 2.37 (m, 0.4 H), 2.25 (s, 0.4 H), 2.10 (m, 0.6 H), 1.95 (d, J = 6.4 Hz, 0.6 H), 1.60 - 1.70 (m, 3.4 H).

Step 3: A3 → A4

Into a 22-liter, 4-neck flask equipped with a mechanical stirrer, a thermometer, and an addition funnel are charged M3a (1.11 kg, 4.35 mol) under nitrogen atmosphere. To the solution, potassium trimethylsilanolate (558 g, 4.35 mol) is added over a period of 20 min. After the addition, the mixture is stirred at rt for an additional 16 h. The mixture is concentrated under vacuum at 30 ⁰C to give an oily residue. The oil is dissolved in dichloromethane (11 L) and cooled to 0 ⁰C. Pivaloyl chloride (551 g, 4.6 mol) is added slowly and the mixture is warmed to rt, and stirred for an additional 1h. The mixture is cooled to 0 - 5 °C and compound A3 (800 g, 4.57 mol) is added. The mixture is warmed to rt and stirred for an additional 16 h. An aqueous solution of 1 N NaOH (5 L) is added. The organic layer is separated, dried over MgSO₄, and concentrated under vacuum at 30 ⁰C to obtain compound A4 an oil (1.97 kg), which will be used for the next step without further purification.

Step 4: A4 → A5

Into a 2-liter, 4-neck flask equipped with a mechanical stirrer, a thermometer, and an addition funnel is charged DW-therm (900 g, purchased from Huber) under nitrogen atmosphere. The solvent is heated to 240 ⁰C. A solution of amide A4 (443 g, 1.1 mol) in DW-therm (400 g) is added over a period of 45 min, maintaining the batch temperature at 240 ⁰C. After the addition, the mixture is stirred for an additional 20 min. The mixture is cooled to rt and allowed to settle into a two-phase solution. The thick bottom layer is separated and purified by chromatography (silica gel; EtOAc/heptane/ diethylamine 40:60:1 ) to isolate the first crop of product A5 as an solid. The upper layer is concentrated under vacuum at 60 - 70 °C/0.5 mmHg until small amount of DW-therm is present. The residual oil is purified by chromatography (silica gel; EtOAc/heptane/diethylamine 40:60:1 ) to isolate the second crop of product A5. Both crops of A5 are combined and recrystallized from a mixture of te/Y-butyl methyl ether and heptane to afford A5 as a solid: m.p. 103 - 106 ⁰C. ¹H NMR (500 MHz, CDCI₃) δ 8.36 (m, 1 H), 7.80 (m, 1 H), 7.72 (d, J = 8.2 Hz, 1 H), 7.47 (d, J = 7.3 Hz, 1 H), 7.40 (m, 3H), 7.28 (m, 4H), 7.20 (m, 1 H), 5.36 (q, J = 6.7 Hz, 1 H), 3.76 (m, 1 H), 3.65 (m, 1 H), 3.51 (d, J = 8.2 Hz, 1 H), 3.35 (m, 1 H), 2.92 - 3.05 (m, 3H), 2.45 - 2.55 (m, 2H), 2.22 (m, 1 H), 1.65 - 1.80 (m, 2H), 1.57 (d, J = 6.7 Hz₁ 3H), 1.53 (m, 1 H), 1.27 (m, 1 H). ¹³C NMR (125 MHz, CDCI₃) δ 170.0, 140.3, 139.7, 134.4, 132.9, 129.3, 129.0, 128.6, 128.7, 126.8, 125.7, 125.65, 125.61 , 125.27, 124.0, 61.9, 52.1 , 50.3, 45.6, 4.6, 36.7, 34.6, 29.6, 28.9, 9.5.

Step 5: A5 → A6

Into a 3-liter, 4-neck flask equipped with a mechanical stirrer, a thermometer, and an addition funnel are charged compound A5 (40 g, 0.1 mol) and toluene (600 ml_) under nitrogen atmosphere. The solution is cooled to -70 ⁰C. A solution of 1.5M DIBAL in toluene (200 ml_, 0.3 mol) is added slowly, maintaining the batch temperature at - 70 ⁰C. The mixture is warmed to rt over a period of 45 min and stirred for an additional 2 h. Ethyl acetate (200 ml_) is added, maintaining the batch temperature at 20 - 25 ⁰C. A saturated aqueous solution of NaHCO₃ (100 ml_) is added, keeping the batch temperature at 20 - 35 ⁰C. After the addition, the batch is stirred at rt for an additional 1h. Any white solid is removed by filtration and rinsed with EtOAc. The combined filtrate is ished with 15% aqueous NaCI solution and concentrated under vacuum at 35 ⁰C to yield an oil (44.3 g). The oil is purified by chromatography (silica gel; EtOAc/heptane/ diethylamine 80:20:1 ) to obtain product A6 as an oil (36.5 g, 95% yield): ¹H NMR (500 MHz, CDCI₃) δ 8.62.(S₁ 1 H)₁ 7.85 (d, J = 8.8 Hz, 1 H), 7.75 (d, J = 7.9 Hz, 1 H), 7.62 (s, 1 H), 7.32 - 7.52 (m, 3H), 7.10 - 7.32 (m, 5H), 4.56 (m, 1 H), 3.15 (s, 1 H), 2.48 - 2.85 (m, 8H), 2.25 (m, 3H), 1.65 - 1.90 (m, 4H), 1.55 (d, J = 6.1 Hz, 3H). Step 6: A6 → A7

A7

Into a 2.5-liter Parr bottle are charged 20% Pd(OH)₂ on carbon (11.2 g, 50% wet) under nitrogen atmosphere. A solution of compound A6 (56 g, 0.15 mol) in methanol (1 L) is added. The mixture is hydrogenated at 50 psi for 16 h until all A6 is consumed. The mixture is filtered through a pad of celite under nitrogen atmosphere. The filtrate is concentrated under vacuum at 35 ⁰C to give an oil. The oil containing A7 and the byproduct is dissolved into ethyl acetate. A solution of 6N HCI in IPA (27 ml_) is diluted with EtOAc (60 ml_) and added to the solution containing A7 over a period of 40 min at 18 - 27 ⁰C. After the addition, the mixture is cooled to 0 ⁰C and stirred for an additional 1 h. Any solid is collected by filtration to obtain A7 hydrochloride salt as a white solid (33 g, 82%): m.p. = 172 - 178 ⁰C. ¹H NMR (500 MHz, CDCI₃) δ 7.12 - 7.32 (m, 5H), 3.50 (s, 1 H), 3.15 - 3.35 (m, 2H), 2.45 - 2.95 (m, 8H), 2.20 (s, 2H), 1.95 (m, 1 H), 1.70 (m, 2H), 1.45 (s, 1H). By treating the hydrochloride salt with aqueous 1 N NaOH solution, the free base of A7 is obtained as an oil: ¹H NMR (500 MHz, CDCI₃) δ 7.15 - 7.35 (m, 5H), 3.05 (m, 1 H), 2.96 (q_AB, J = 8.2, 4.0 Hz, 1 H), 2.87 (m, 2H), 2.70 (m, 2H), 2.60 (m, 1 H), 2.49 (m, 2H), 2.40 (bs, 1 H)₁ 2.30 (dd, J = 11.6, 3.7 Hz, 1 H), 2.02 (td, J = 11.0, 3.0 Hz, 1 H), 1.88 (m, 1H), 1.77 (m, 1H), 1.52 (m, 2H), 1.36 (m, 1H). ¹³C NMR (125 Hz, CDCI₃) δ 141.0, 129.1, 128.7, 126.3, 60.9, 58.6, 55.0, 53.0, 44.9, 36.6, 34.1 , 31.9, 27.8. Rotation: α²⁵ _Na = -11.519° [c 9.569 mg/1 ml_ CH₃CN].

Example 2 Preparation of 6-phenethyl-octahydro-pyrrolo[2,3-c]pyridine (A7)

A3

9 (racemic)

8 (racemic)

Pd/C

(+)-dibenzoyl-D- . (+)-dibenzoyl-D- tartaric acid

tartaric acid

10 (racemic) 11 (optically pure salt)

A7 (ee > 98%)

Step 1 : Compound (A3)

A 1-L flask is charged with 2-phenylethylamine A2 (47.62 g, 393 mmol), K₂CO₃ (163.7 g, 1.184 mol), 4-bromo-1-butene A1 (35.5 g, 263 mmol), NaI ( 177 g, 1.184 mol) and DMF (500 ml_). The reaction mixture is heated to 100 ⁰C and hold at this temperature for 22 h. Cool the reaction mixture to 20 ⁰C , add water (700 ml_) and TBME (700 ml_). The organic layer is washed with water, dried over MgSO₄ and concentrated to give yellow oil which is further purified by distillation under reduced pressure to give 35.1 g of A3 in 76% yield.

Step 2: Compound (6)

A solution of M3c (25.27 g, 103 mmol) in methanol (75 mL) is slowly added to a pre- cooled solution of benzyl amine 4 ( 38.37 g, 360 mmol) in methanol (250 mL) at 5-6 ⁰C. The reaction mixture is warmed to 20-25 ⁰C and maintained at this temperature for 18 h. The reaction mixture is concentrated and TBME (500 mL) and water (500 mL) are added. The organic layer is washed with water, dried over MgSO₄ and concentrated to give yellow oil. The crude is further purified with column chromatography on silica gel (EtOAc/Hexanes= 1/1) to give 15.43 g of 6 in 78% yield.

Step 3: Compound (7)

KOTMS (6.38 g, 49.75 mmol) is added to a solution of 6 (9.51 g, 49.75 mmol) in THF (20OmL). The mixture is stirred overnight at room temperature. The mixture is concentrated and the residue dissolved in dichloromethane (20OmL) and cooled to 0 ⁰C. Trimethylacetyl chloride (5.94 g, 49.25 mmol) is added slowly and the mixture is warmed to room temperature over 2 hours. The mixture is cooled to -78 ⁰C, 3 (8.63 g, 49.24) is added and stirred at -78 ⁰C for 1.5 hours. Saturated sodium bicarbonate (10OmL) is added. The mixture is extracted with EtOAc (4x10OmL). The organic extracts are combined, dried and concentrated under vacuum. The residue is purified by flash chromatography (silica gel; Hexane/EtOAc 1 :8) to provide 12.5 g (76%) of the title compound 7.

Step 4: Compound (8)

A solution of 7 (10.7 g, 32 mmol) in DW-ThermHeat Transfer (8 mL) is added within 15 min to a flask containing DW-ThermHeat Transfer fluid ( 10 mL) at 240 ⁰C and this temperature maintained for 30 min. The DW-fluid is distilled under vacuum and the residue is purified by flash chromatography on silica gel (EtOAc/Hexanes) to give 7.50 g of the racemic compound 8 in 70% yield. Step 5: Compound (9)

At 20 ⁰C, 30 mmol of LAH (1 M in THF) is slowly added to a solution of 9.94 g (30 mmol) of 8 in THF (220 ml_), then 60 ⁰C for 3 h. While stirring, 1.1 g of water is added, then 1.1 mL of 15% NaOH (aq), stir, and then 3.4 mL of water is added. The suspension is stirred for 20 min, then filtered through a celite bed. The filtrate is washed with water two times, then brine, then the aqueous layers are combined and extracted with TBME. The organic layer is dried with MgSO₄, and the solvents removed. The product, 8.79 g 9,is obtained as clear amber color oil. Yield: 8.79 g (92 %). HPLC purity 96.7 %.

Step 6: Compound (10)

8.65 g (27 mmol) of 9, 1.1 g of 10% Pd /C (50% wet), and 250 mL of MeOH are stirred under 60 psi hydrogen at RT overnight. The mixture is filtered and then concentrated to obtain 6.28 g of 10 as a yellow oil. Yield: 6.28 g (84%).

Step 7: Compound (11)

16.10 g (70 mOI) of 10 is dissolved in a solution of 85 mL of 2-propanol and 127 mL of 200 proof ethanol. To the clear solution is slowly added a solution of 25.08 g of (+)- dibenzoyl-D-tartaric acid in 84 mL of 200 proof ethanol. 425 mL of toluene is added and stirred for 15 hours at room temperature. The solids are filtered, and the cake rinsed with 30 mL of a mixed solvents (2-propanol : ethanol : toluene = 1 : 2.5 : 5.0 [v/v]). Dry at 50 ⁰C in a vacuum oven. Obtain 21.6 g of 11 as white crystals. Yield: 18.95 g (92%); HPLC Chemical purity: > 99%; Optical purity: > 99%; Rotation: α²⁵ _Na = +69.421 ° [c 10.297 mg/ in 1 mL CH₃CN/H₂O (1 / 1 )].

Step 8: Compound A7

18.07 g of 11 is mixed and stirred with 90 mL of 1 N sodium hydroxide solution, then extracted with methyl t-butyl ether. The organic layer is washed with water, dry with MgSO₄, filtered, and then concentrated to a minimum volume. 6.89 g of A7 identical in all respects with the one described earlier is obtained. Yield: 6.89 g (99%); HPLC: Chemical purity: > 99%; Optical purity: > 99%; Rotation: α²⁵ _Na = -11.519° [c 9.569 mg/1 mL CH₃CN] ¹H NMR (500 MHz, CDCI₃) δ 7.15 - 7.35 (m, 5H), 3.05 (m, 1 H), 2.96 (q_AB, J = 8.2, 4.0 Hz, 1H), 2.87 (m, 2H), 2.70 (m, 2H), 2.60 (m, 1H), 2.49 (m, 2H), 2.40 (bs, 1 H), 2.30 (dd, J = 11.6, 3.7 Hz, 1 H), 2.02 (td, J= 11.0, 3.0 Hz, 1 H), 1.88 (m, 1 H), 1.77 (m, 1H), 1.52 (m, 2H), 1.36 (m, 1H).¹³C NMR (125 Hz, CDCI₃) δ 141.0, 129.1, 128.7, 126.3, 60.9, 58.6, 55.0, 53.0, 44.9, 36.6, 34.1, 31.9, 27.8.

Claims

What is claimed is:

1. A process for the preparation of the compounds of formula (I)

comprising the following reaction:

Scheme 2.

wherein

R₁ is H; C₁-C₄ alkyl; C₁-C₄ alkenyl; C₁-C₄ alkynyl or cycloalkyl which are unsubstituted or substituted;

R₂ is H; CrC₄alkyl; C₁-C₄ alkenyl; C₁-C₄ alkynyl or cycloalkyl which are unsubstituted or substituted;

R₃ is H; -CF₃; -C₂F₅; C₁-C₄ alkyl; C₁-C₄ alkenyl; C₁-C₄ alkynyl; -CH₂-Z or R₂ and R₃ together with the nitrogen form a het ring;

Z is H; -OH; F; Cl; -CH₃; -CF₃; -CH₂CI; -CH₂F or -CH₂OH; R₄ is C₁-C₁₆ straight or branched alkyl; C₁-C₁₆ alkenyl; C₁-C₁₆ alkynyl; or -C₃-C₁₀ cycloalkyl; -(CH₂)i-₆-Z-ι; -(CH₂)₀-6-aryl; and -(CH₂)o-6-het, wherein alkyl, cycloalkyl and phenyl are unsubstituted or substituted;

Z₁ is -N(R₈)-C(0)-C_rC_1oalkyl; -N(R₈)-C(O)-(CH₂)_1-6-C₃-C₇cycloalkyl; -N(R₈)-C(0)-(CH₂)_o- ₆-phenyl; -N(R₈)-C(O)-(CH₂)i_-6-het; -C(O)-N(R₉)(R₁₀); -C(O)-O-C_rC₁₀alkyl; -C(O)-O- (CH₂)_1-6-C₃-C₇cycloalkyl; -C(O)-O-(CH₂)_0-6-phenyl; -C(O)-O-(CH₂)_1-6-het; -0-C(O)-C₁- C_1oalkyl; -O-C(O)-(CH₂)i_-6-C₃-C₇cycloalkyl; -0-C(0)-(CH₂)_o.₆-phenyl; -O-C(O)-(CH₂)_1-6- het, wherein alkyl, cycloalkyl and phenyl are unsubstituted or substituted;

R₈ is H, -CH₃, -CF₃ , -CH₂OH or -CH₂CI;

R₉ and R₁₀ are each independently H; C_rC₄alkyl; C₃-C₇cycloalkyl; -(CH₂)_1-6-C₃- C₇cycloalkyl; -(CH₂)_o.₆-phenyl; wherein alkyl, cycloalkyl and phenyl are unsubstituted or substituted, or R₉ and R₁₀ together with the nitrogen form het;

R₅ is H; C_rC_1o-alkyl; C₃-C₇cycloalkyl; -(CH₂)_1-6-C₃-C₇cycloalkyl; -C_rC_1oalkyl-aryl; -(CH₂)_o- ₆-C₃-C₇cycloalkyl-(CH₂)_o-6-phenyl; -(CH₂)_o-4CH-((CH₂)i_-4-phenyl)₂; -(CH₂)_o-6-CH(phenyl)₂- indanyl; -C(O)-C_rC₁₀alkyl; -C(O)-(CH₂)₁.₆-C₃-C₇cycloalkyl; -C(0)-(CH₂)_o.₆-phenyl; -(CH₂)_o- ₆-het ; -C(O)-(CH₂)i_-6-het; or R₅ is a residue of an amino acid, wherein alkyl, cycloalkyl, phenyl and aryl are unsubstituted or substituted;

R₁₃ is CrC₁₀-alkyl; phenyl or phenylalkyl such as benzyl;

U is a as shown in structure II:

wherein

n = 0-5;

Ra and Rb are independently an O, S, or N atom or C_o-8 alkyl wherein one or more of the carbon atoms in the alkyl chain may be replaced by a heteroatom selected from O, S or N, and where the alkyl may be unsubstituted or substituted;

Rd is selected from:

(a) -Re - Q - (Rf)_p(Rg)_q; or

(b) Ar₁-D- Ar₂;

p and q are independently 0 or 1 ;

Re is Ci_-8 alkyl, or alkylidene, and Re may be unsubstituted or substituted;

Q is N. O, S, S(O), Or S(O)₂;

An and Ar₂ are substituted or unsubstituted aryl or het;

Rf and Rg are each independently H; -C_rCio alkyl; Ci-Ci_Oalkylaryl; -OH; -O-CrC-ioalkyl; -(CH₂)₀-6-C₃-C₇cycloalkyl; -0-(CH₂)o-₆-aryl; phenyl; aryl; phenyl-phenyl; -(CH₂)_1-6-het; -O- (CH₂)i-β-het; -OR₁₁; -C(O)-R₁₁; -C(O)-N(R₁₁)(R₁₂); -N(R₁₁)(R₁₂); -S-R₁₁; -S(O)-R₁₁; - S(O)₂-Ri₁; -S(O)₂-NR₁₁R₁₂; -NR₁₁-S(O)₂- R₁₂; S-C_rC_ralkyl; aryl-C_rC₄alkyl; het-C_r C₄alkyl wherein alkyl, cycloalkyl, het and aryl are unsubstituted or substituted; -SO_2-C_1- C₂alkyl; -SO^C-^alkylphenyl; -O-C_rC₄alkyl; or R₉ and R_f form a ring selected from het or aryl; D is -CO-; -C(O)-Ci_-7 alkylene or arylene; -CF₂-; -O-; -S(O)₁- where r is 0-2; 1 ,3dioaxolane; or Ci_-7 alkyl-OH; where alkyl, alkylene or arylene may be unsubstituted or substituted with one or more halogens, OH, -O-d-Cβalkyl, -S-Ci-Cεalkyl or -CF₃; or D is -N(Rh) wherein Rh is H; Ci_-7 alkyl (unsub or substituted); aryl; -O(Ci_-7cycloalkyl) (unsub or substituted); C(O)-C_rC₁₀alkyl; C(O)-C_o-C₁₀alkyl-aryl; C-O-CrCi₀alkyl; C-O-C₀- C₁₀alkyl-aryl or S0₂-C_rCio-alkyl; SO₂-(C_o-Ci₀-alkylaryl);

R₆, R₇, R'e and R'₇ are each independently H; -C₁-Ci₀ alkyl; -C₁-Ci₀ alkoxy; aryl-C_rC₁₀ alkoxy; -OH; -O-C_rCi₀alkyl; -(CH₂)o-₆-C₃-C₇cycloalkyl; -O-(CH₂)_0-6-aryl; phenyl; -(CH₂)i_-6- het; -O-(CH₂)i_-6-het; -ORi₁; -C(O)-R₁₁; -C(O)-N(R₁₁)(R₁₂); -N(R₁₁)(R₁₂); -S-R₁₁; -S(O)- R₁₁; -S(O)₂-R₁-_I; -S(O)₂-NR₁₁Ri₂; -NRn-S(O)₂- Ri₂; wherein alkyl, cycloalkyl and aryl are unsubstituted or substituted; and R_6, R₇, R'₆ and R'₇can be united to form a ring system;

Rn and Ri₂ are independently H; C₁-C₁0 alkyl; -(CH₂)_0-6-C3-C₇cycloalkyl; -(CH₂)₀-₆-(CH)_0- i(aryl)_i-2; -C(O)-C_rCi₀alkyl; -C(O)-(CH₂)i-₆-C₃-C₇cycloalkyl; -C(O)-O-(CH₂)₀.₆-aryl; -C(O)- (CH₂)_0-6-O-fluorenyl; -C(O)-NH-(CH₂)_0-6-aryl; -C(O)-(CH₂)_0-6-aryl; -C(O)-(CH₂)i_-6-het; - C(S)-C_rC₁₀alkyl; -C(S)-(CH₂)i_-6-C₃-C₇cycloalkyl; -C(S)-O-(CH₂)_0-6-aryl; -C(S)-(CH₂)_0-6-O- fluorenyl; -C(S)-N H-(C H₂)_0-6-aryl; -C(S)-(CH₂)₀-₆-aryl; -C(S)-(CH₂)i_-6-het; wherein alkyl, cycloalkyl and aryl are unsubstituted or substituted; or Rn and Ri₂ are a substituent that facilitates transport of the molecule across a cell membrane; or Rn and R₁₂ together with the nitrogen are het; aryl of R₁₁ and Ri₂ can be phenyl, naphthyl, or indanyl which is unsubstituted or substituted;

alkyl of R₁₁ and R₁₂ may be unsubstituted or substituted by one or more substituents selected from a C₁-C₁₀ alkene, halogen, OH, -O-CrCealkyl, -S-Ci-C₆alkyl and -CF₃;

cycloalkyl of Rn and Ri₂ may be unsubstituted or substituted by one or more selected from a C₁-C₁0 alkene, one or more halogens, CrC₆alkyl, halogen, OH, -O-CrC₆alkyl, -S- C_rC₆alkyl or -CF₃; and

phenyl or aryl of Rn and Ri₂ may be unsubstituted or substituted by one or more substituents selected from halogen, hydroxy, C_rC₄ alkyl, C_rC₄ alkoxy, nitro,

-CN, -0-C(0)-CrC₄alkyl and -C(O)-O-C_rC₄-aryl; or pharmaceutically acceptable salts thereof.

2. A process for the preparation of the compounds of formula (I)