Abstract

N/A

Information

Application ID	191/MUMNP/2003
Invention Field	CHEMICAL
Date of Application	2003-02-06
Publication Number	0

Applicants

Name	Address	Country	Nationality
ASTRAZENECA AB	S-151 85 SODERTALJE, SWEDEN	Sweden	Sweden

Inventors

Name	Address	Country	Nationality
JULIE B. BARTLETT	ASTRAZENECA R & D ALDERLEY, MERSIDE, ALDERLEY PARK, MACCLESFIED, CHESHIRE SK10 4TG, GREAT BRITAIN	U.K.	U.K.

Specification

FORM 2
THE PATENTS ACT, 1970
[39 OF 1970]
COMPLETE SPECIFICATION
[See Section 10; rule 13]
"BICYCLIC PYRROLYL AMIDE COMPOUND"
ASTRAZENECA AB, a Swedish company, of S-151 85 Sodertalje, Sweden,

The following specification particularly describes the nature of the invention and the manner in which it is to be performed :-

The present invention relates to a bcyclic pyprolyl amide compound.
The present invention relates to heterocyclic amide derivatives, pharmaceutically acceptable salts and in vivo hydrolysable esters thereof. These heterocyclic amides possess glycogen phosphorylase inhibitory activity and accordingly have value in the treatment of disease states associated with increased glycogen phosphorylase activity and thus are potentially useful in methods for the treatment of a warm-blooded animal such as man. The invention also relates to processes for the manufacture of said heterocyclic amide derivatives, to pharmaceutical compositions containing them and to their use in the manufacture of 10 medicaments to inhibit glycogen phosphorylase activity in a warm-blooded animal such as man.
The liver is the major organ regulating glycaemia in the post-absorptive state.
Additionally, although having a smaller role in the contribution to post-prandial blood glucose
levels, the response of the liver to exogenous sources of plasma glucose is key to an ability to
15 maintain euglycaemia. An increased hepatic glucose output (HGO) is considered to play an
important role in maintaining the elevated fasting plasma glucose (FPG) levels seen in type 2
diabetics; particularly those with a FPG >140mg/dl (7.8mM). (Weyer et al, (1999), J Clin
Invest 104: 787-794; Clore & Blackgard (1994), Diabetes 43: 256-262; De Fronzo, R. A., et
al, (1992) Diabetes Care 15; 318 - 355; Reaven, G.M. (1995) Diabetologia 38; 3-13).
20 Since current oral, anti-diabetic therapies fail to bring FPG levels to within the normal,
non-diabetic range and since raised FPG (and glycHbAlc) levels are risk factors for both macro- (Charles,. M.A. et al (1996) Lancet.348,1657-1658; Coutinho, M. et al (1999) Diabetes Care 22; 233-240; Shaw, J.E. et al (2000) Diabetes Care 23, 34-39) and micro-vascular disease (DCCT Research Group (1993) New. Eng. J. Med. 329; 977-986); the reduction and normalisation of elevated FPG levels remains a treatment goal in type 2 diabetes.
It has been estimated that, after an overnight fast, 74% of HGO is derived from ' glycogenosis with the remainder derived from gluconeogenic precursors (Hellerstein et al (1997) Am J Physiol, 272: E163). Glycogen phosphorylase is a key enzyme in the generation 30 by glycogenosis of glucose-1-phosphate, and hence glucose in liver and also in other tissues such as muscle and neuronal tissue.
Liver glycogen phosphorylase activity is elevated in diabetic animal models including the db/db mouse and the fa/fa rat (Aiston S et al (2000). Diabetalogia 43, 589-597).


Inhibition of hepatic glycogen phosphorylase with chloroindole inhibitors (CP91149 and CP320626) has been shown to reduce both glucagon stimulated glycogenosis and glucose output in hepatocytes (Hoover et al (1998) J Med Chem 41, 2934-8; Martin et al
(1998) PNAS 95, 1776-81, WO 96/39384 and WO 96/39385). Additionally, plasma glucose 5 concentration is reduced, in a dose related manner, in db/db and ob/ob mice following treatment with these compounds.
Studies in conscious dogs with glucagon challenge in the absence and presence of another glycogen phosphorylase inhibitor, Bay K 3401, also show the potential utility of such agents where there is elevated circulating levels of glucagon, as in both Type 1 and Type 2 l0 diabetes. In the presence of Bay R 3401, hepatic glucose output and arterial plasma glucose levels following a glucagon challenge were reduced significantly (Shiota et al, (1997), Am J Physiol, 273: E868).
ES 2,081,747 discloses that certain amide derivatives of 4/f-thieno[3,2-b]pyrroles and 4i?-thieno[2,3-b]pyrroles are CCK antagonists and are useful in the treatment of gastric 15 secretion disorders and in the regulation of appetite. The compounds disclosed in this document are disclaimed from the compound claims of the present invention.
US 3,706,810 discloses that certain N-(aminoalkyl) derivatives of thieno[3,2-
b]pyrrole-5-carboxamide are useful as analgesic and anti-depressant agents. The compounds
disclosed in this document are disclaimed from the compound claims of the present invention.
20 US 4,751,231 discloses that certain thieno[2,3-b]pyrrole-5-sulfonamides are useful in
the treatment of elevated intraocular pressure and glaucoma. Certain amides are disclosed as intermediates. The compounds disclosed in this document are disclaimed from the compound claims of the present invention.
US 4,794,120 discloses 4if-thieno[3,2-b]pyrrole-5-carboxylic acid hydrazide and 6H-25 thieno[2,3-b]pyrrole-5-carboxylic acid hydrazide as intermediates in the preparation of corresponding (5-nitro-2-furanyl)methylenehydrazides which are antibacterials, fungicides and protozoacides. The compounds disclosed in this document are disclaimed from the compound claims of the present invention.
3

Co-pending application EP 1088824 discloses that a compound of Formula A: a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutically

5
acceptable salt of the prodrug, wherein
Q is aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
each z and X are independently (C, CH or CH2), N, O or S;
X]isNRa,-CH2-,OorS;
each — is independently a bond or is absent, provided that both — are not
10 simultaneously bonds;
R1 is hydrogen, halogen, -OCrC8alkyl, -SCi-C8alkyl, -CrC8alkyl, -CF3, -NH2-,
-NHCi-Cgalkyl, -N(C,-C8alkyl)2, -N02, -CN, -C02H, -C02Ci-C8alkyl,
-C2-C8alkenyl, or-C2-C8alkynyl;
each Ra and Rb is independently hydrogen or -Ci-C8alkyl;
15 Yis

or absent;
R2 and R3 are independently hydrogen, halogen, -Ci-C8alkyl, -CN,
20 -C=C-Si(CH3)3, -OCi-Cgalkyl, -SCrC8alkyl, -CF3, -NH2, -NHCrC8all-yl,
-NCd-Cgalkyl),, -N02, -C02H, -COzd-Cgalkyl, -C2-C8alkenyl, or
4


-C2-C8alkynyl, or R2 and R3 together with the atoms on the ring to which they are attached form a five or six membered ring containing from 0 to 3 heteroatoms and
from 0 to 2 double bonds;
R4 is -C(=0)-A;
A is -NRdRd, -NRaCH2CH2ORa

each Rd is independently hydrogen, C1-C8alkyl, Cj-C8alkoxy, aryl, substituted aryl,
heteroaryl, or substituted heteroaryl;
each Rc is independentiy hydrogen, -C(=O)ORa, -ORa, -SRa, or -NRaRa; and each n is
independently 1-3, are useful in treating diabetes, insulin resistance, diabetic neuropathy, diabetic nephropathy,
diabetic retinopathy, cataracts, hyperglycemia, hypercholesterolemia, hypertension,
hyperinsulinemia, hyperlipidemia, atherosclerosis, or tissue ischemia. These compounds are
disclaimed from the present application.
The heterocyclic amides of the present invention possess glycogen phosphorylase inhibitory activity and accordingly are expected to be of use in the treatment of type 2 diabetes, insulin resistance, syndrome X, hyperinsuhnaemia, hyperglucagonaemia, cardiac ischaemia and obesity, particularly type 2 diabetes.
The present invention provides a compound of formula (I):

R1
"]n-R2
(I)
wherein:
-X-Y-Z- is selected from -S-CR4=CR5-, -CR4=CR5-S-, -0-CR4=CR5-, -CR4=CR5-0-, -N=CR4-S-, -S-CR4=N-, -NR6-CR4=CR5- and -CR4=CR5-NR6-;
5


wherein R4 and R5 are independently selected from hydrogen, halo, nitro, cyano, hydroxy, fluoromethyl, difluoromethyl, trifluorometbyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, ureido, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkoxy, Ci_6alkanoyl, C1.6alkanoyloxy, N-(C1-6alkyl)amino, N,N-(C1-6alkyl)2amino, C1-.6alkanoylamino, N-(C1-6alkyl)carbamoyl, N,N-(C1-6alkyl)2carbamoyl, C1-6alkylS(0)a wherein a is 0 to 2, C1-6alkoxycarbonyl, C1-6alkoxycarbonylamino, N-(C1-6alkyl)sulphamoyl, N,N(C1-6alkyrhsulphamoyl, C1-6alkylsulphonylamino and C1-6alkylsulphonyl-N'-(C1-6alkyl)ainino; R6 is hydrogen or C1-6alkyl;
R1 is selected from hydrogen, halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, ureido, C1_6alkyl, C2-6alkenyl, C2-6alkynyl, C1_6alkoxy, C1-6alkanoyl, C1-6alkanoyloxy, N(C1-6alkyl)amino, N,N-(C1-6alkyl);;amino, C1-6alkanoylamino, N(C1-6alkyl)carbamoyl,N,N-(C1-4alkyl)2carbamoyl, C1-6alkylS(O)a wherein a is 0 to 2, C1-6alkoxycarbonyl, C1-6alkoxycarbonylamino, N(C1-6alkytysulphamoyl, N,N-(C1-6alkyl)2Sulphamoyl, C1-6alkylsulphonylamino, C1-6alkylsulphonyl-A''-(C1-6alkyl)aminoi C3-8cycloalkyl, C3-8cycloalkylC1-6alkyl, aryl, arylC1-6alkyl, heterocyclic group and • (heterocyclic group)C1-6alkyl; wherein R1 may be optionally substituted on carbon by one or more groups selected from P and wherein if said heterocyclic group contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R;
R2 is selected from hydrogen, halo, nitro, cyano, hydroxy, fluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, ureido, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkoxy, C1-6alkanoyl, C1-6alkanoyloxy,N-(C1-6alkyl)amino, N,N(C1-6alkyl)2amino, C1-6alkanoylarnino, N-(C1-6alkyl)carbamoyl, N,N-(C1-4alkyl)2carbamoyl,N-(C1-6alkyl)-N-(C1-6alkoxy)carbamoyl, C1-6alkylS(O)a wherein a is 0 to 2, C1-6alkoxycarbonyl, C1-6alkoxycarbonylamino, N-(C1-6alkyl)sulphamoyl, N;N-(C1-6allcyl)2Sulphamoyl, sulphamoylamino, N-(C1-6alkyl)sulphamoylamino, N,N-(C1-6alkyl)2Sulphamoylamino, C1-6alkylsulphonylamino, C1-6alkylsulphonylarninocarbonyl, C1-6alkylsulphonyl-N-(C1-6alkyl)amino and a group -E-F-G-H;
wherein E and G are independently selected from a direct bond, -0-, -S-, -SO-, -SO2-, -OC(O)-, -C(O)0-, -C(O)-, -NRa-, -NRaC(O)-, -C(O)NRa-, -SO2NRa-, -NRaSO2-, -NRaC(O)NRb-, -OC(O)NRa-, -NRaC(O)0-, -NRaSO2NRb-, -SO2NRaC(O)- and
6

-C(O)NRaSO2-; wherein Ra and Rb are independently selected from hydrogen or C1-6alky! which is optionally substituted by a group V;
F is C1-6alkylene optionally substituted by one or more Q or a direct bond; H is selected from aryl, C3-8cycloalkyl and heterocyclic group; wherein H may be optionally substituted on carbon by one or more groups selected from S and wherein if said heterocyclic group contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from T;
R3 is hydrogen or C1-6alkyl;
n is selected from 0-4; wherein the values of RJ may be the same or different; and wherein the values of R3 may be the same or different;
P, S and Q are independently selected from halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, ureido, C1-6alkyl, C2-6allcenyl, C2-6alkynyl, C1-6alkoxy, C1-6a!k:arioyl, C1.6alkanoyloxy, N-(C1-6alkyl)amino, N,N-(C1-6alkyl)2amino, C1-6alkanoylamin6, N-(C1-6alkyl)carbamoyl, N,N-(C1-6alkyl)2carbamoyl, N-(C1.6alkyl)-N-(C1-6alkoxy)carbamoyl, C1-6alkylS(O)a wherein a is 0 to 2, C1-6alkoxycarbonyl, C1-6alkoxycarbonylamino, N-(C1-6alkyl)sulphamoyl, N,N-(C1-6alkyl)2sulphamoyl, C1-6alkylsulphonylamino, C1-6alkylsulphonyl-N-(C1-6alkyl)amino, C3-8cycloalkyl, aryl and heterocyclic group; wherein P, S and Q may be optionally and independently substituted on carbon by one or more groups selected from V and wherein if said heterocyclic group contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from U;
V is selected from halo, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, carboxy, carbamoyl, mercapto, sulphamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoy], methylthio, ethylthio, methylsulphinyl, ethylsulphinyl, mesyl, ethylsulphonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulphamoyl, N-ethylsulphamoyl, N,N-dimethylsulphamoyl, N,N-diemylsulphamoyl, N-methyl-N-ethylsulphamoyl, morpholino, morpbolinocarbonyl, N- benzylcarbamoyl, and 4-hydroxypiperidinocarbonyl;
R, T and U are independently selected from C1-4alkyl, C1-4alkanoyl, C1-4alkylsulphonyl, C1-4alkoxycarbonyl, carbamoyl,N-(C1-4alkyl)carbamoyl,

N,N-(C1-4alkyl)carbamoyl, phenyl, benzyl, benzyloxycarbonyl, benzoyl and phenylsulphonyl
wherein R, T and U may be optionally and independently substituted on carbon by one or
more groups selected from V;
or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof;
with the provisos:
i) when -X-Y-Z- is -S-CH=CH-, R2-(CR'R3)n- cannot be amino, l-phenyl-5-methyl-lH-l,5-benzodiazepine-2,4(3H,5H)dion-3-yl, l-methyl-5-phenyl-2-oxo-2,3-dihydro-lH-benzo(E)(l,4)diazepin-3-yl, 2-(4-phenyl-l)2,5,6-tetrahydropyrid-l-yl)ethyl,3-(4-phenyl-1,2,5,6-tetrahydropyrid-l-yl)propyl, 2-(4-phenylpiperazin-1 -yl)ethyl, 2-(N-memylamino)ethyl, 2-morpholinoethyl or 2-(N-memyl-N-benzylamino)ethyl;
ii) when -X-Y-Z- is -CH=CH-S-, R2-(CR'R3)n- cannot be amino or l-methyl-5-phenyl-2-oxo-
2,3-dihydro-lH-benzo(E)( 1,4)diazepin-3-yl; iii) when -X-Y-Z- is -CH=C(SO2NH2)-S-, R2-(CRJR3)n- cannot be methyl or isobutyl; and iv) when -X-Y-Z- is as initially defined, n is 1, R1 is arylmethyl, substituted arylmethyl, (heterocyclic group)methyl and substituted (heterocyclic group)methyl and R3 is hydrogen then R2 is not a group -C(=O)-A or a group -CH(OH)-C(=0)-A in which A is NRdRd, -NRaCH2CH2ORa, or

(each Ra and Rb is independently hydrogen or -C1-C8alkyl;
each Rd is independently hydrogen, C1-C8alkyl, C1-C8alkoxy, aryl, substituted aryl,
heteroaryl, or substituted heteroaryl;
each Rc is independently hydrogen, -C(=O)OR°, -ORa, -SRa, or -NRaRa; and each n is
independently 1-3, and
X]isNRa,-CH2-,OorS.
8

-8-
In another aspect the present invention provides a compound of formula (I):
R1

(I)
wherein:
-X-Y-Z- is selected from -S-CR4=CR5-, -CR4=CR5-S-, -0-CR4=CR5-, -CR4=CR5-0-,
-N=CR4-S-, -S-CR4=N-, -NR6-CR4=CR5- and -CR4=CR5-NR6-;
wherein R4 and Rs are independently selected from hydrogen, halo, nitro, cyano,
hydroxy, fluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, amino, carboxy,
carbamoyl, mercapto, sulphamoyl, ureido, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkoxy;
C1-6alkanoyl, C1-6alkanoyloxy, N-(C1.6alkyl)amino, N,N-(C1-6alkyl)2amino, .
C1-6alkanoylamino, N(C1-6alkyl)carbamoyl, N, N(C1-6alkyi)2carbamoyl, C1-6alkylS(0)a
wherein a is 0 to 2, C1-6alkoxycarbonyl, C1-6alkoxycarbonylamino, N-(C1-6alkyl)sulphamoyl,
N,N-(C1-6alkyl)2Sulphamoyl, Ci-6alkylsulphonylamino and
C1-6alkylsulphonyl-iV-(C1-6alkyl)amino; R6 is hydrogen or C1-6alkyl;
R1 is selected from hydrogen, halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, ureido, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkoxy, C1-6alkanoyl, C1-6alkanoyloxy, N-(C1-6alky^arnino,N,N(C1-6alkyl)2amino, C1-6alkanoylamino, N-(C1-6allcyl)carbamoyl, N,N-(C1-4alkyl)2carbamoyl, C1-6alkylS(O)a wherein a is 0 to 2, Ci-6alkoxycarbonyl, Ci-6alkoxycarbonylamino, N-(Ci-6alkyl)sulphamoyl, N,N-(Ci-6alkyl)2Suiphamoyl, C1-6alkylsulphonylamino, C1-6alkylsulphonyl-N(Ci.6alkyl)amino, C3-8cycloalkyl, C3-8cycloalkylC1-6alkyl, aryl, arylCi_6alkyl, heterocychc group and (heterocyclic group)Ci-6alkyl; wherein R1 may be optionally substituted on carbon by one or more groups selected from P and wherein if said heterocyclic group contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R;
R is selected from hydrogen, halo, nitro, cyano, hydroxy, fluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamo3'l, mercapto, sulphamoyl, ureido, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkoxy, C1-6alkanoyl,

Woji2#aS3
S is selected from fluoro, chloro, hydroxy, trifluoromethyl, sulphamoyl, ureido, methyl, ethyl, methoxy, N,N-dimethylamino, acetamido and phenyl; wherein S may be optionally substituted on carbon by one or more groups selected from V; Q is hydroxy; V is carbamoyl; and
T is independently selected from methyl or phenyl;
Particularly R2 is selected from N,N-dimethylcarbamoyl, N,N-dimethylsulphamoyl-amino, mesylaminocarbonyl, 2-methoxyphenyl, phenoxy, 2-phenylcyclopropyl, thien-2-yl, 4-fluorophenyl, benzoyl, thiomorpholino, anilinocarbonyl, pyrid-2-ylamino, thiazol-2-yl, 10 benzylsulphonylamino, 2,3-dihydro-l,5-benzothiazepin-4(5H)-one-3-yl, l-phenyl-2,3-
dimethyl-5-oxo-3-pyrazolin-4-yl, 3-phenyl-2-oxazolidinon-5-yl, 5-hydroxy- 1,3,4,5-tetrahydro-benzo[b]azepin-2-onyl, 3-phenyl-5-oxo-2-isoxazolin-4-yl, imidazofl ,2-a]pyridin-2-yl, benzothiazol-2-yl, 2,5-dioxoimidazolidin-3-yl, naphlii-2-ylaminocarbonyl, phenyl, 4-sulphamoylphenethyl, 4-(N,N-dimethylamino)phenyl, 4-sulphamoylphenyl, anilino, 4-hydroxyphenyl, quinolin-3-yl, 4-chlorophenyl, 2-methoxypyrid-5-yl, 3-methylisothiazol-5-yl, 3-trifluoromethylpyrid-2-yl, tetrazol-5-yl, benzyloxycarbonylamino, benzimidazol-2-yl, 2-trifluoromethylpyrid-5-yl, pyridazin-2-yl, pyridazin-3-yloxy, pyrid-2-yl, imidazol-5-yl, 4-acetamidophenoxy, 2-ureidothiazol-4-yl, benzylthio, 2-phenyl-l,3-dioxolan-2-yl, 4-carbamoylmethylphenoxy, (N-benzylcarbamoylrnethyl), phenethyl, 3-phenylpropyl, [2-(2-20 hydroxyphenyl)ethyl], -(a,a-dimethylphenethyl), (l-phenylcyclobutyl)methyl), (β-methylphenethyl), (l,2,3,4-tetrahydronaphth-2-yl), benzyl, (N-benzyl-N-methylcarbamoylmethyl), (N-methyl-N-phenylcarbamoylmethyl), N-(2-cyanoethyl)-N-phenylcarbamoylmethyl], [N-(4-methoxyphenyl)carbamoylmethyl], [N-(4-fluorophenyI)carbamoyImethyl], [N-(4-nitrophenyl)carbamoyrmethyl], [N-(2,6-dimethylphenyl)carbamoylmethyl], [N-methyl-N-(4-methylphenyl)carbamoylmethyl], [N-memyl-N-(3-methylphenyl)carbamoylmethyl], N-(3-chorophenyl) JV-methylcarbamoyl-methyl], [N-(2-hydroxyethyl)-N-phenylcarbamoylmethyl], [N-( 1,1 -dimethyl-2-hydroxyethyl)carbamoylmethyl], [N-(2-hydroxyethyl)-.N-methylcarbamoyl-methyl], [N-(2-hydroxyethyl)carbamoylmethyl], [N-(3-hydroxypropyI)carbamoylmethyl], [N-(4-30 hydroxybutyl)carbamoylmethyl], {N-[bis(h5'droxymethyl)methyl]carbamoylmethyl},
[N-(2,3-dihydroxypropyl)carbamoylmethyl], [N-(4-hydroxymethylphenyl)-carbamoylmethyl], [N-(5-isoquinolyl)carbamoylmethyl], [N-(3-hydroxymethy)lphenyl]-carbamoylmethyl], {N-[4-
17

10
15
20
25
30

(2-hydroxyethyl)phenyl]carbamoyl-methyl}, [N-(2,4-difluorophenyl)-N-methyl-carbamoylmethyl], [(l,2,3,4-tetrahydro-l-quinolyl)carbonyl-methy]], [7V-(2-cyanoethyl)-N-methylcarbamoylmethyl], [N-(4-hydroxypiperidino)-carbamoylinethyl], (N-cyclopentylcarbamoylmethyl), (N-isopropyl-carbamoylmethyl), (N-isopropyl-N-methylcarbamoylmethyl), (thiomoipholin-carbonylmethyl), (morpholino-carbonylmethyl), [(1,1 -dioxothiomorpholino)carbonyl-methyl], [(1 -oxothiomorpholino)-carbonylmethyl], (2-indanyl), (benz[l,2]oxazol-3-ylmethyl), {2-[2-(hydroxymethyl)phenyl]-ethyl}, (4-phenylisoxazol-3-ylmethyl), {2-[2-(2-morpholino-ethoxy)phenyl]ethyl}, {2-[2-(methoxycarbonyl-methoxy)phenyl]ethyl}, {2-[2-(carboxy-methoxy)phenyl]ethyl}, [2-(3-methoxyphenyl)ethyl], (2-oxo-l,2,3,4-tetrahydroquinol-3-yl), {2-[2-(2-methoxyethoxy)phenyl]ethyl}, {2-[2-(carbamoylmettioxy)phenyl]ethyl}, {2-[2-(N-methylcarbamoylmethoxy)phenyl]ethyl}, {2-[2-(N,N-dimethylcarbamoyl-methoxy)phenyl]ethyl}, 2-[2-(morpholinocarbonylmethoxy)-phenyl]ethyl, 2-[2-(N-benzylcarbamoylmethoxy)phenyl]ethyl, 2-[2-(4-hydroxypiperidinocarbonylmethoxy)-phenyl]ethyl,[ 1 -(5-ethoxycarbonyl-1,3,4-oxadiazo-2-yl)-2-phenylethyl], [ 1 -(4-memoxycarbonyl-oxazo-5-yl)-2-phenylethyl], [2-phenylethyl-l-(pyrid-3-yl)], [2-phenylethyl -l-(3-phenyl-l,2,4-oxadiazo-5-yl) ], (l-hydroxyindan-2-yl), [(lS,2S)-2-indan-l-ol], [(1R,2R)-2-indan-l-ol], (3-indanyl), (1-hydroxy-1,2,3,4-tetrahydronaphth-2-yl) , (6-fluoro-l-hydroxyindan-2-yl), (7-methoxy-l-oxo-l,2,3,4-tetrahydronaphth-2-yl), -(3-methylisoxazol-5-yl)methyl], (4-hydroxy-l,l-dioxotetrahydrothiophen-3-yl), -{iV-methyl-7V-[(l-oxo-l,2,3,4-tetrahydronaphth-2-yl)memyl]carbamoylmethyl}, (3-methylisoxazol-5-yl)methyl], (4-hydroxy-lil-dioxotetrahydrothiophen-3-yl), {ALmethyl-7V-[(l-oxo-l,2,3,4-tetrahydronaphth-2-yl)methyl]carbamoylmethyl}, (2-oxo-l,2,3,4-terrahydroquinol-3-yl), (1,2,3,4-tetrahydroquinol-3-yl), (l-methyl-2-oxo-l,2,3,4-tetrahydroquinol-3-yl), (3-oxo-2,3,4,5-tetrahydro-l.#-benz[2]azepin-4-yl), (l-methoxyindan-2-yl), {1-[JV-(1,1-dimemylethoxy)carbonylamino]indan-2-yl}, (l-aminoindan-2-yl)], (l-acetamidoindan-2-yl), [l-(methanesulphonamido)indan-2-ylj, [l-(methylamino)indan-2-yl], or [l-(N-methylacetamido)indan-2-yl] .
More particularly R2 is selected from N,N-dimemylcarbamoyl, N,N-dimemylsulphamoylarnino, mesylaminocarbonyl, 2-metiioxyphenyl, phenoxy, 2-phenylcyclopropyl, thien-2-yl, 4-fluorophenyl, benzoyl, thiomorpholino, anilinocarbonyl, pyrid-2-ylarnino, thiazol-2-yl, berizylsulphonylarnino, 2,3-dihydro-l,5-benzothiazepin-4(5H)-


one-3-yl, l-phenyl-2,3-dimethyl-5-oxo-3-pyrazolin-4-yl, 3-phenyl-2-oxazolidinon-5-yl, 5-hydroxy-l,3,4,5-tetrahydro-benzo[b]azepin-2-onyl, 3-phenyl-5-oxo-2-isoxazohn-4-yl, J irnidazo[l,2-a]pyridin-2-yl, benzothiazol-2-yl, 2,5-dioxoimidazohdin-3-yl, naphth-2-ylaminocarbonyl, phenyl, 4-sulphamoylphenethyl, 4-(N,N-dimemylamino)phenyl, 4-sulphamoylphenyl, anilino, 4-hydroxyphenyl, quinohn-3-yl, 4-chlorophenyl, 2-methoxypyrid-5-yl, 3-methylisothiazol-5-yl, 3-trifluoromefhylpyrid-2-yl, tetrazol-5-yl, benzyloxycarbonylamino, benzimidazol-2-yl, 2-trifluoromethylpyrid-5-yl, pyridazin-2-yl, pyridazin-3-yloxy, pyrid-2-yl, imidazol-5-yl, 4-acetamidophenoxy, 2-ureidothiazol-4-yl, benzylthio, 2-phenyl-l,3-dioxolan-2-yl and 4-carbamoylmethylphenoxy.
10
Most particularly R2 is selected from N,N-dimefhylcarbamoyl, phenoxy, 2-phenylcyclopropyl, thien-2-yl, 4-fluorophenyl, benzoyl, thiomorpholino, anilinocarbonyl, pyrid-2-ylamino or thiazol-2-yl.
Preferably R3 is hydrogen.
15
Preferably n is selected from 0-3; wherein the values of R1 may be the same or different; and wherein the values of R3 may be the same or different.
More preferably n is selected from 0-2; wherein the values of R1 may be the same or different; and wherein the values of R3 may be the same or different.
In one aspect of the invention preferably n is 2; wherein the values of R1 may be the . same or different; and wherein the values of R3 may be the same or different.
20
In one aspect of the invention preferably n is 1..
In one aspect of the invention preferably n is 0.
In another aspect of the invention, preferred compounds of-the invention are any one of the Examples or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof.
25
In another aspect the present invention provides a compound of formula (I) (as depicted above) wherein:
-X-Y-Z- is selected from -S-CR4=CR5-, -CR4=CR5-S-, -0-CR4=CR5- and -N=CR4-S-;
R and R5 are independently selected from hydrogen, halo or C^aUcyl; R1 is selected from hydrogen, hydroxy, C1-6alkyl, Ci_6alkoxycarbonyl, arylC1-6alkyl and (heterocyclic group)Ci_6alkyl; wherein R1 may be optionally substituted on carbon by one 30 or more groups selected from P; and
P is selected from hydroxy and Ci.6alkylsulphonyl-N-(C1-6al]syl)airiino; R is selected fromN,N-(C1-4alkyl)2carbamoyl,N,N-(C1-6alkyl)2Sulphamoylairrino, C1-6alkylsulphonylaminocarbonyl and a group -E-F-G-H;
19

PCT/SE01/01880

wherein E and G are independently selected from a direct bond, -O-, -S-, -C(O)-,
-NRa -C(O)NRa-, -NRaSO2- and -NRaC(O)0-; wherein Ra is hydrogen;
' F is C1-6alkylene optionally substituted by one or more Q or a direct bond;
H is selected from aryl, C3.8cycloalkyl and heterocyclic group; wherein H may be optionally substituted on carbon by one or more groups selected from S and wherein if said heterocyclic group contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from T;
S is selected from halo, hydroxy, trifluoromethyl, sulphamoyl, ureido, C1-6alkyl, C1-6alkoxy, N,N-(C1-6alkyl)2amino, C1-6alkanoylamino and aryl; wherein S may be optionally substituted on carbon by one or more groups selected from V; Q is hydroxy; V is carbamoyl; and
T is independently selected from C1-4alkyl or phenyl;
R3 is hydrogen;
15 n is selected from 0-3; wherein the values of R1 may be the same or different;
or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof; with the provisos:
i> when -X-Y-Z- is -S-CH=CH-, R2-CR'R3)N cannot be l-phenyl-5-methyl-lH-l,5-
benzodiazepine-2,4(3H,5H)dion-3-yl, l-methyl-5-phenyl-2-oxo-2,3-dihydro-lH-
20 benzo(E)(l,4)diazepin-3-yl, 2-(4-phenyl-l,2,5,6-tetrahydropyrid-l-yl)ethyl, 3-(4-
phenyl-l,2,5,6-tetrahydropyrid-l-yl)propyl, 2-(4-phenylpiperazin-l-yl)ethyl or 2-morpholinoethyl; ii) when -X-Y-Z- is -CH=CH-S-, R2CR1R3),,- cannot be l-methyl-5-phenyl-2-oxo-2,3-
dihydro-lH-benzo(E)(l,4)diazepin-3-yl;and iii) when -X-Y-Z- is as initially defined, n is 1, R1 is arylmethyl, substituted arylmethyl, (heterocyclic group)methyl and substituted (heterocyclic group)methyl and R3 is hydrogen then R2 is not a group -C(=0)-A or a group -CH(OH)-C(=O)-A in which A is NRdRd, -NRaCH2CH2ORa, or

30
20


each Ra and R is independently hydrogen or -C1-C8alkyl;
each Rd is independently hydrogen, C1-C8alkyl, Ci-C8alkoxy, aryl, substituted aryl,
heteroaryl, or substituted heteroaryl;
each Rc is independently hydrogen, -C(=O)ORa -ORa, -SRa, or -NRaRa; and each n is
independently 1-3, and
X1isNRa,-CH2-,OorS.
In yet another aspect the present invention provides a compound of formula (I) (as
depicted above) wherein:
-X-Y-Z- is selected from -S-C(C1)=C(C1)-, -S-C(C1)=CH-, -S-CH=C(C1)-,
10 -S-C(Br)=CH-, -S-CH=CH-, -CH=CH-S-, -0-CH=CH- and -N=C(Me)-S-;
R1 is selected from hydrogen, hydroxy, methyl, methoxycarbonyl,
mesyl-N-(methyl)aminomethyl and hydroxymethyl;
R2 is selected from N,N-dimefhylcarbamoyl, N,N-dimethylsulphamoylamino,
mesylaminocarbonyl, 2-methoxyphenyl, phenoxy, 2-phenylcyclopropyl, thien-2-yl, 4-
15 fluorophenyl, benzoyl, thiomorpholino, anilinocarbonyl, pyrid-2-ylamino, thiazol-2-yl,
benzylsulphonylamino, 2,3-dihydro-l,5-benzothiazepin-4(5H)-one-3-yl, l-phenyl-2,3-
dimethyl-5-oxo-3-pyrazolin-4-yl, 3-phenyl-2-oxazolidinon-5-yl, 5-hydroxy-l ,3,4,5-tetrahydro-
benzo[B]azepin-2-onyl, 3-phenyl-5-oxo-2-isoxazolin-4-yl, imidaz of 1,2-a]pyridin-2-yl,
benzothiazol-2-yl, 2,5-dioxoimidazolidin-3-yl, naphth-2-ylaminocarbonyl, phenyl, 4-
20 sulphamoylphenethyl, 4-(N,N-dimethylamino)phenyl, 4-sulphamoylphenyl, anilino, 4-
hydroxyphenyl, quinolin-3-yl, 4-chlorophenyl, 2-methoxypyrid-5-yl, 3-methylisothiazol-5-yl,
3-trifluoromethylpyrid-2-yl, tetrazol-5-yl, benzyloxycaibonylamino, benzimidazol-2-yl, 2-
trifluoromethylpyrid-5-yl, pyridazin-2-yl, pyridazin-3-yloxy, pyrid-2-yl, imidazol-5-yl, 4-
acetamidophenoxy, 2-ureidothiazol-4-yl, benzylthio, 2-phenyl-l,3-dioxolan-2-yl and 4-
25 carbamoylmefhylphenoxy;
R is hydrogen; and
n is selected from 0-3; wherein the values of R1 may be the same or different;
or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof.
21


In a first preferred aspect the present invention provides a compound of formula (I) (as
depicted above) wherein:
-X-Y-Z- is selected from -S-CR4=CR5- or -CR4=CR5-S-;
wherein R4 and R5 are independently selected from hydrogen, halo, nitro, cyano, 5 hydroxy, fluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, ureido,C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkoxy, Ci.6alkanoyl, C1-6alkanoyloxy, N-(C1-6alkyl)amino, N,N-(C1-6alkyl)2amino, C-16alkanoylajmino, N-(C1-6alkyl)carbamoyl, NN-(C1.6alkyl)2carbamoyl, C1-6alkylS(O)a wherein a is 0 to 2, C1-6alkoxycarbonyl, C1-6alkoxycarbonylamino, N-(C1-6alkyl)sulphamoyl, N,N(C1-6alkyl)2sulphamoyl, C1-6alkylsulphonylamino and C1-6alkylsulphonyl-N-(C1-6alkyl)aniino; nis 0;
R2 is a group -E-F-G-H;
wherein E, F and G are each a direct bond;
lj5 H is a C3-12cycloalkyl which is optionally fused to a benz ring wherein H may be
optionally substituted on carbon by one or more groups S which are independently selected from halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, ureido, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkoxy, C1-6alkanoyl, C1-6alkanoyloxy, N-(C1-6alkyl)amino, N,N'-(C1-6alkyl)2amino, 2(1) C1-6alkanoylamino, N-(C1-6alkyl)carbamoyl, N, N(C1-6alkyl)2carbamoyl, N(C1-6alkyl)-N-(C1-6alkoxy)carbamoyl, C1-.6alkylS(O)a wherein a is 0 to 2, C1-6alkoxycarbonyl, C1-6alkoxycarbonylamino, iV-(C1-6alkyl)sulphamoyl, N,N-(C1-6alkyl)2Sulphamoyl, C1-6alkylsulphonylamino, C1-6alkylsulphonyl-N-(C1-6alkyl)amino, C3-8cycloalkyl, aryl and heterocyclic groups; wherein S may be optionally substituted on carbon by one or more groups selected from V;
V is selected from halo, nitro, cyano, hydroxy, trifluoromethoxy, trifluorometh3'l, amino, carboxy, carbamoyl, mercapto, sulphamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, 30 N, N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulphinyl, ethylsulphinyl, mesyl, ethylsulphonyl, methoxycarbonyl, ethoxycarbonyl, JV-methylsulphamoyl, iV-ethylsulphamoyl, N, N-dimethylsulphamoyl, N,Ndiethylsulphamoyl,
22

X
WO 02/20530 PCT/SE01/01880
N-methyl-N-ethylsulphamoyl, morpholino , morpholinocarbonyl, N- benzylcarbamoyl, and 4-
hydroxypiperidinocarbonyl;
or a pharmaceutically acceptable salt thereof.
Preferred values of R2, R4, and R5 are as follows. Such values may be used where appropriate with any of the definitions, claims or embodiments defined hereinbefore or hereinafter.
In this first preferred aspect preferably R4 and R5 are independently selected from hydrogen, halo or Ci-ealkyl.
In this first preferred aspect preferably H is indanyl, 1,2,3,4-tetrahydronaphthyl or l0 cyclopropyl. More preferably H is indanyl or 1,2,3,4-tetrahydronaphthyl. Most preferably H is indanyl.
In this first preferred aspect preferably S is independently selected from from halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, C1-6alkcyl, C1-6alkoxy, Ci.6alkanoyl, C1-6alkanoyloxy, N-(C1-6alkyl)arninoN,N-(C1-6alkyl)2amino, C1-6alkanoylamino, 15 N-(C1-6alkyl)carbarnoyl, N,N(C1-6alkyl)2carbamoyl,N-(C1.6alkyl)-N-(C1-6aIkoxy)carbamoyl) C1-6alkylS(0)a wherein a is 0 to 2, C1-6alkoxycarbonyl, C1-6alkoxycarbonylamino, C3-8cycloalkyl and aryl. More preferably S is selected from hydroxy, amino, C1-6alkoxy and C1-6alkoxycarbonylamino.
In a second preferred aspect the present invention provides a compound of formula (I) (as depicted above) wherein:
-X-Y-Z- is selected from -S-CR4=CR5- or -CR4=CR5-S-;
wherein R and R are independently selected from hydrogen, halo, nitro, cyano,
hydroxy, fluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, amino, carboxy,
carbamoyl, mercapto, sulphamoyl, ureido, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkoxy,
C1-6alkanoyl, C1-6allcanoyloxy,N-(C1-6alkyl)amino, N,N-(C1-6alkyl)2arnino,
C1-6alkanoylamino, N-(C1-6alkyl)carbamoyl, N,N(C1-6alkyr)2carbamoyl, C1-6alkylS(O)a
wherein a is 0 to 2, C1_6alkoxycarbonyl, Ci-6alkoxycarbonylairiino, N-(C1-6alkyl)sulphamoyl,
N,N-(C1-6alkyl)2Sulphamoyl, C1.6alkylsulphonylamino and C1-6alkylsulphonyl-N-
(C1-6alkyl)amino;
30 n is 0;
R2 is a group -E-F-G-H;
wherein E, F and G are each a direct bond; and
H is a cyclic amide of formula
23


in which k is 0, 1, 2 or 3 and 1 is 0,1, 2 or 3 such that the sum of k and 1 is 2 or 3 and wherein one of the carbon atoms governed by k or 1 may be replaced by sulphur and wherein H is optionally substituted on carbon by one or more groups selected from S and may be independently optionally substituted on nitrogen by a group selected from T;
S is selected from halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, ureido, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkoxy, C1-6alkanoyl, C1-6alkanoyloxy,N-(C1-6alkyl)amino, N, N-(C1-6alkyl)2amino, C1-6alkanoylamino, N-(C1-6alkyl)carbamoyl,N,N(C1-6alkyl)2carbamoyl, N-(Ci.6alkyl)-N-(Ci-6alkoxy)carbamoyl, Ci-6alkylS(O)a wherein a is 0 to 2, Ci-6alkoxycarbonyl, Ci_6alkoxycarbonylamino, N,(C1-6alkyl)sulphamoyl, N,N(C1-6alkyl)2Sulphamoyl, C1-6alkylsulphonylamino, C1-6alkylsulphonyl-N-(C1-6alkyl)amino, C3-8cycloalkyl, aryl and heterocyclic group; wherein S may be optionally and independently substituted on carbon by one or more groups selected from V and wherein if said heterocyclic group contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from U;
T and U are independently selected from C1-4allcyl, C1-4alkanoyl, C1-4alkylsulphonyl, C1-4alkoxycarbonyl, carbamoyl, N-(C1-4alkyl)carbamoyl, N,N-(C1-4alkyl)carbamoyl, phenyl, benzyl, benzyloxycarbonyl, benzoyl and phenylsulphonyl wherein T and U may be optionally and independently substituted on carbon by one or more groups selected from V;
V is selected from halo, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, carboxy, carbamoyl, mercapto, sulphamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, Ar-methyl-ALethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N -ethylcarbamoyl, methylthio, ethylthio, methylsulphinyl, ethylsulphinyl, mesyl, ethylsulphonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulphamoyl, N-ethylsuIphamoyl,N,N-dimethylsulphamoyl,N,N-diethylsulphamoyl,
24



N-methyl-N-ethylsulphamoyl, morpholino, morpholinocarbonyl, N- benzylcarbamoyl and 4~ hydroxypiperidinocarbonyl; i or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof.
Preferred values of R4, R5 and H are as follows. Such values maybe used where appropriate with any of the definitions, claims or embodiments defined hereinbefore or hereinafter.
In this second preferred aspect preferably R4 and R5 are independently selected from hydrogen, halo or C1-6alkyl.
In this second preferred aspect preferably H is 1,2,3,4-tetrahydroquinolyl, 2-oxo-10 1,2,3,4-tetrahydroquinolyl, 4-oxo-2,3,4,5-tetrahydrobenz[l,5]thiazepin-3-yl, 2-oxo-2,3,4,5-tetrahydro-lH-benz[6]azepinyl, 2,3,4,5-tetrahydro-lH-benz[6]azepinyl or 3-oxo-2,3,4,5-tetrahydro-lH-benz[c]azepinyl each optionally substituted on carbon by one or more groups selected from S wherein S is selected from hydroxy, C1-6alkyl or C1-6alkoxy, and each independently optionally substituted on nitrogen by a group selected from T wherein T is 15 selected from C1-4alkyl or C1-4alkanoyl.
More preferably H is 2-oxo-l,2,3,4-tetrahydroquinol-3-yl, l-methyl-2-oxo-l,2,3,4-
tetrahydroquinol-3-yl, 4-oxo-2,3,4,5-tetrahydrobenz[l,5]thiazepin-3-yl, 5-hydroxy-2-oxo-
2,3,4,5-tetrahydro-lH-benz[Z?]azepin-4-yl, 2-oxo-2,3,4,5-tetrahydro-lH-benz[b]azepin-3-yl or
3-oxo-2,3,4,5-tetrahydro-lH-benz[cjazepin-4-yl.
20 In a third preferred aspect the present invention provides a compound of formula (I)
(as depicted above) wherein:
-X-Y-Z- is selected from -S-CR4=CR5- or -CR4=CR5-S-; wherein R4 and R5 are independently selected from hydrogen, halo or C1-6alkyl. n is 1;
R1 is hydrogen or arylC1-6alkyl; R is selected from a group -E-F-G-H; wherein E, F and G are each a direct bond;
H is an unsaturated five membered heterocyclic group containing at least one nitrogen atom and one or two ring atoms selected from oxygen and sulphur and wherein H may be 30 optionally substituted on carbon by one or more groups S which are independently selected from halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, ureido, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, Ci-6alkoxy, C1_6alkanoyl, C1-6alkanoyloxy, N-(C1-6allcyl)amino, N,N-(C1-6alkyl)2amino,


C1-6alkcanoylamino, N-(C1-6alkyl)carbamoyl, N, N(C1-6alkyrl)2carbamoyl, N-(C1-6alkyl)-N-(C1-6alkoxy)carbamoyl, C1-6aIkylS(O)a wherein a is 0 to 2, C1-6alkoxycarbonyl, C1-6alkoxycarbonylamino, N(C1-6alkyl)sulphamoyl, N,N-(C1-6alkyl)2Sulphamoyl, C1-6alkylsulphonylamino, C1-6alkylsulphonyl-.A/'-(C1-6alkyl)arrrino, C3.8cycloalkyl and aryl groups;
R3 is hydrogen or C1-6alkyl; or a pharmaceutically acceptable salt thereof.
Preferred values of R1, R3 and H are as follows. Such values may be used where appropriate with any of the definitions, claims or embodiments defined hereinbefore or 10 hereinafter.
In this third preferred aspect preferably R1 is selected from hydrogen or benzyl and more preferably benzyl.
In this third preferred aspect preferably R is hydrogen.
In this third preferred aspect preferably H is 1,3,4-oxadiazolyl, isoxazolyl, oxazolyl or 15 1,2,4-oxadiazolyl. More preferably H is 5-ethoxycarbonyl-l,3,4-oxadiazol-2-yl, 4-
phenylisoxazol-3-yl, 3-phenyl-l,2,4-oxadiazol-5-yl, 4-methoxycarbonyloxazol-5-yl or 3-methylisoxazol-5-yl.
In this third preferred aspect preferably H may be optionally substituted on carbon by one or more groups S which are independently selected from halo, carboxy, C1-6alkyl, 20 C1-6alkoxy, C1-6alkanoyloxy, N-(C1-6alkyl)amino, N,N(C1-6alkylhamino, C1-6alkanoylamino, C1-6alkoxycarbonyl, C3.8cycloalkyl and aryl groups. Preferably S is C1-6alkoxy, C1-6atkoxycarbonyl or phenyl.
In a fourth preferred aspect the present invention provides a compound of formula (I)
(as depicted above) wherein:
25 -X-Y-Z- is selected from -S-CR4=CR5- or -CR4=CR5-S-;
wherein R4 and R5 are independently selected from hydrogen, halo or C1-6alkcyl. n is O;
R2 is a group -E-F-G-H;
wherein E is a direct bond;
30 F is methylene;
wherein G is -C(O)NRa-, wherein Ra is selected from hydrogen or C1-6alkyl which is optionally substituted by a group V ;


H is aryl which may be optionally substituted on carbon by one or more groups selected from S;
S is selected from halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, ureido, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, 5 C1-6alkoxy, C1.6alkanoyl, Ci.6alkanoyloxy, N-(C1-6alkyl)amino, N, N-(C1-6alkyl)2amino, C1-6alkanoylamino, N-(Ci.6alkyl)carbamoyl, N,N-(C1-6alkyl)2carbamoyl, N-(C1-6alkyl)-N-(C1-6alkoxy)carbamoyl, C1-6alkylS(O)a wherein a is 0 to 2, Ci.6alkoxycarbonyl, C].6alkoxycarbonylamino,N-(C1-6alkyl)sulphamoyl, N,N-(C1-6alkyl)2Sulphamoyl, C1-6aIkylsulphonylamino, C1-6alkylsulphonyl-N-(C1-6alkyl)amino, C3-8cycloalkyi, aryl and heterocyclic group; wherein S may be optionally and independently substituted on carbon by one or more groups selected from V ;
V is selected from halo, nitro, cyano, hydroxy, trifluorornethoxy, trifluoromethyl, amino, carboxy, carbamoyl, mercapto, sulphamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylaimno, 15 acetylamino, N'-methylcarbamoyl,N-ethylcarbamoyl, N, N-dimethylcarbamoyl,
N;N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulphinyl, ethylsulphinyl, mesyl, ethylsulphonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulphamoyl, N-ethylsulphamoyl, N,N-dimethylsulphamoyl,N,N-diethylsulphamoyl, N-methyl-N-ethylsulphamoyl, morpholino, morpholinocarbonyl, N- benzylcarbamoyl, and 4-20 hydroxypiperidinocarbonyl;
or a pharmaceutically acceptable salt thereof.
Preferred values of R1, R2, R3, -X-Y-Z-and n are as follows. Such values may be used
where appropriate with any of the definitions, claims or embodiments defined hereinbefore or
hereinafter.
25 In this fourth preferred aspect preferably H is aryl.
In this fourth preferred aspect preferably V is cyano or hydroxy. Specific compounds of the present invention are: 2,3-dicliloro-5-[N-(2-phenoxyethyl)carbamo}d]-4H-thieno[3,2-6]pyrrole; 2,3-dichloro-5-{N42-(2-thienyl)ethyl]carbamoyl}-4H-thieno[3,2-b]pyrrole; 2,3-dichloro-5- {N-[2-(2-methoxyphenyl)ethyl]carbamoyl} -4H-thieno[3,2-b]pyrrole; 2,3-dichloro-5-[N(2-phenyl-l-cyclopropyl)carbamoyl]4H-thieno[3,2-6]pyrrole; 2,3-dichoro-5-{N-[2-(4-fluorophenyl)ethyl]carbamoyl}4H-thieno[3,2-b]pyrrole; 2,3-dichoro-5-[N-(N-phenylcarbamoylmemyl)carbamoyl]-4H-thieno[3,2-b]pyrrole;

23-dicmoro-5-(N-{2-[(2-pyridyl)amino]ethyl}carbamoyl)-4H-tbieno[3,2-b]pyrrole;
2,3-dichloro-5- {N-[2-(N-methylmethanesulphonamido)- l-(thiazol-2-yl)ethyl]carbamoyl} -4H-
thieno[3,2-6]pyrrole;
2,3-dichloro-5-{N-[2-(thiomorpholino)ethyl]carbamoyl}-4H-4hieno[3,2-6]pyrrole;
5-[N-(benzoylmethyl)carbamoyl]-2,3-dichloro-4H-thieno[3,2-6]pyirrole;
3-choro-5-[N-(N-phenylcarbamoylmethyl)carbamoyl]-4H-thieno[3,2-6]pyrrole;
3-choro-5-{N-[2-(thomorpholino)ethyl]carbaiiioyl}4H-thieno[3,2-b]pyrrole;
3-chloro-5- {N-[2-(N-methylmethanesulphonaniido)-1 -(ttiiazol-2-yl)ethyl] carbamoyl} -4H-
thieno [3,2-6]pyrrole;
S-chloro-5-N-(benzoylmethyl)carbamoyl]4H-thieno[3-2-b]pyrrole;
3-chloro-5-{N-[2-(2-methoxyphenyl)ethyl]carbamoyl}-4H-thieno[3,2-b]]pyiTole;
3-chloro-5-{N-[2-(2-thienyl)ethyl]carbamoyl}-4H-thieno[3,2-b]pyrrole;
3-chloro-5-[N-(2-phenyl-1 -cyclopropyl)carbamoyl] -4H-thieno[3,2-b]pyrrole;
3-chloro-5-{N-[2-(4-fluorophenyl)ethyl]carbanioyl}-4H-thieno[3,2-b]pyrrole;
3-chloro-5-[N-(2-phenoxyethyl)carbamoyl]-4H-thieno[3,2-b]pyrrole;
3-cbloro-5-{N-[2-(l-phenylmethanesulphonamido)athyl]carbamoy}-4Hi-thieno[3,2-b]pyrrole;
3-chloro-5-[N-(4-oxo-2,3,4,5-tetrahydrobenz[l,5]thiazepin-3-yl)carbamoyl]-4H-thieno[3,2-
b]pyrrole;
2-chloro-5-[N-(benzoylmethyl)carbamoyl]-4H-thieno[3,2-b)]pyrrole;
2-chloro-5-[N'-(2-phenyl-l-cyclopropyl)carbamoyl]-4H-thieno[3,2-b]pyrrole;
2-chloro-5-[N-(iV-phenylcarbamoylmethyl)carbamoyl]-4H-thieno[3,2-b]pyrrole;
2-chloro-5-(N-{2-[(2-pyridyl)arnino]ethyl}carbamoyl)-4H-thieno[3,2-b]pyimole;
2-chloro-5- {N-[2-(2-methoxyphenyl)ethyl]carbamoyl} -4H-thieno[3,2-6]pyrrole;
2-chloro-5-[N-(2-phenoxyet±iyl)carbamoyl]-4H-thieno[3,2-b)]pyimole;
2-chloro-5- (N-[2-(2-thienyl)ethyl]carbamoyl} -4H-thieno[3,2-b]pyrrole;
2-chloro-5-{N-[2-(4-fluorophenyl)ethyl]carbamoyl}-4H-thieno[3,2-b)]pyrrole;
2-chlono-5-{N[2-(N-methylmetiianesulphonamido)-1-(thiazol-2-yl)ethyl]carbamoy}-4H-
thieno [3,2-b]pyrrole;
2-chloro-5-{N-[2-(thomoipholino)etiiyl]carbamoyl}-4H-thieno[3 2-b]pyrrole;
2,3-dichloro-5-[N-(2,3-dimethyl-5-oxo-1 -phenyl-2,5-dihydro- lH-pyrazol-4-yl)carbamoyl]-
4H-thieno [3,2-b]pyrrole;
2,3-dichloro-5-[N(4-sulphamoylphenylmethyl)carbamoyl]-4H-thleno[3,2-b]pyrrole;
23-dicbloro-5-[N'-(2-hydroxy-l-phenethyl)carbamoyl]-4H-ttiieno[3,2-b]pyiTole;

2,3-dichloro-5- {N-(2-[(3-trifluoromethylpyrid-2-yl)amino]ethyl)carbamoyl} -4H-thieno[3,2-b]pyrrole;
2,3-dichloro-5-{N-[3-(5-tetrazolyl)propyl]carbamoyl}-4H-thieno[3,2-b]pyirole; 2,3-dichloro-5-[N-(5-oxo-3-phenyl-4,5-dihydroisoxa2ol-4-yl)carbamoyl]-4H-thieno[3,2-5 b]pyrrole;
2,3-dichloro-5-[N-(5-hydroxy-2-oxo-2,3,4,5-tetrahydro-lH-benz[b]azepin-4-yl)carbamoyl]-
4if-thieno[3,2-6]pyrrole;
2-chloro-5-{iV'-[3-(benzyloxycarbonylainino)propyl]carbamoyl}4H-thzieno[3,2-6]pyrrole; 23-dichoro-5-{N-[(4-dimethylariimophenyl)methyl]carbamoy}-4H-thieno[3,2-b]pyrrole;
5-[N-(l-benzyl-2-hydroxyethyl)carbamoyl]-2,3-dichloro-4H-thieno[3,2-b]pyrrole; 2,3 -dichloro-5- {N- [2- (phenyl amino)ethyl] carbamoyl} -4H-thieno [3,2-b]pyrrole; 23-dichloro-5-[N-(β-(R)-hydxoxy-a-methylphenethyl)carbamoy]-4H-thieno[3,2-b]pyrrole;
2,3-dichoro-5-[N-(P-hydroxyphenethyl)carbamoyl)-4ii/-thieno[3,2-6]pyrrole; 23-dichloro-5-{N-[2-(4-hydroxyphenyl)ethyl]carbamoyl}4i/'-tbieno[3,2-6]pyrrole; 15 23-dichoro-5-{N-[(benzimdazol-2-yl)mEthyl]carbamoy}-4H-thieno[3,2-b]pyrrole;
23-dichoro-5-{N-[2-(4-chlorophenyl)-2-hydroxy-l-(methoxycarbonyl)ethyl]carbamoyl}-4H-thieno[3,2-6]pyrrole;
2,3-dichoro-5-{N(imidazo[l,2-a]pyrid-2-yl)carbarnoyl}-4H-thieno[3,2-6]pyrrole;
5-N-[(benzthazol-2-yl)methyl]carbamoyl}-2,3-dichoro-4H-theno[3,2-b]pyrrole;
20 23-dichloro-5-{N-[(6-trifluoromethylpyrid-3-yl)methyl]carbamoyl}-4H-thieno[3,2-6]pyrrole
23-dichoro-5-{N-(2-[(2-pyridazinyl)memyl]carbamoyl}-4H-thieno[3,2-b]pyimole;
2,3-dichloro-5-{N-[ N-(2-hydroxy-3-phenoxypropyl)carbamoylmethyl] carbamoyl}-4H-
tbieno[3,2-b]pyirole.;
2,3-dichloro-5- {N-[N(3-methylisothiazol-5-yl)carbamoylmethyl]carbamoyl} -4H-tbieno[3,2-25 | b]pyrrole;
23-dichloro-5-{N-[2-(pyridazm-3-yloxy)emyl]carbairioyl}-4H-thieno[3,2-b]pyrrole; 2-chloro-5-(A''-{2-[(3-trifluoromemylpyrid-2-yl)arnino]emyl}carbamoyl)-4H-thieno[3,2-b]pyrrole;
2,3-dichloro-5- [N- [2-(4-sulphamoylphenyl)ethyl] carbamoyl} -4H-thieno [3,2-b]pyrrole; 30 2,3-dichloro-5-{N-[2-(2-pyridyl)ethyl]carbamoyl}-4H-tliieno[3,2-b]pyrrole;
23-dichloro-5-{N-(2-[l-hyalroxymethyl-2-(4-imidazolyl)ethyl]carbamoyl}-4H-tmeno[3,2-b]pyrrole;

23-dichloro-5-{N-(2-[(3-quinolyl)methyl]carbamoyl}-4H-thieno[3)2-b]pyrrole;
5-{N'-[3-(4-acetamidophenoxy)-2-hydxoxypropyl]carbamoyl}-23-dichloro-4H-thieno[3,2-
b]pyrrole;
23-dichloro-5-{N-[3-(N-methylsulphonylcarbamoyl)propyl]carbamoyl}-4H-thieno[3,2-
b]pyrrole;
2,3-dichloro-5-[N-(2-{[2-(guarudino)thiazoM-yL)methylthio}-4H-thieno[3,2-b]pyrrole
b]]pyrrole;
23-dichloro-5-{N-[2-(2,4-dioxoimida2olidin-l-yl)ethyl]carbamoyl}-4H-thieno[3,2-b]pyrrole;
5-{iV-[2-benzylthio-l-(hydroxymethyl)ethyl]carbamoyl}-23-dichloro-4H-thieno[3,2-10 b]pyrrole;
2,3-dichloro-5- {N-[2-(dimetiiyaniinosulphonylamino)ethyl]carbamoyl} -4H-thieno[3,2-
b]pyrrole;
23-dichloro-5-{N-[(6-methoxypyrid-3-yl)methyl]carbamoyl}4H-thieno[3,2-b]pyrrole;
(S)-23-dichloro-5-{N-[(2-oxo-3-phenyl-2,3,4,5-tetrahydrooxazol-5-yl)methyI]carbamoyl}-
4H-thieno[3,2-b]pyrrole;
23-dichloro-5-(N-{2-[3-(carbamoylmethyl)phenoxy]ethyl}carbamoyl)-4H-thieno[3,2-
b]pyrrole;
5-(N- {[6-(benzo[l ,3]dioxol-5-yl)-4-methylmorpholin-2-yl]methyl} carbamoyl)-2,3-dichloro-4i/-thieno[3,2-6]pyrrole; 20 5-(N-benzylcarbamoyl)- 2,3-dichloro-4H-tbieno[3,2-b)]pyrrole; 2,3-dichloro-5-(N-phenethylcarbamoyl)-4H-thieno[3,2-b]pyrrole; 213-dichloro-5-[N(3-phenylpropyl)carbamoyl]-4H-thJ.eno[3,2-b]pyrrole; 23-dichloro-5-{N'-[2-(2-hydroxyphenyl)ethyl]carbampyl}-4H-thieno[3,2-b]pymole; 23-dichloro-5-[N'-(a,a-dimethylphenethyl)carbamoyl]-4H-thieno[3,2-b]pyrrole; 2,3-dichloro-5- [N-( 1 -phenylcycIobutyl)m'ethyl)carbamoyI]-4i7-thieno [3,2-b]pyrrole; 2,3-dichloro-5-[N-(P-methylphenethyl)carbamoyl]-4H-thieno[3,2-b]pymole; 23-dichloro-5-[N-(l,2,3,4-tetrahydronaphth-2-yl)carbamoyl]-4H-thieno[3,2-b]pyrrole; 5-[N-(N-benzylcarbamoylmeliyl)carbamoyl]-23-dichloro-4H-thieno[3,2-b)]pymole; 5-[N(N'-benzyl-N-methylcarbamoylmethyl)carbamoyl]-23-dichloro-4H-theno[3,2-b]pymole; 3|0 23-dichoro-5-[N(N-methyl-N-phenylcarbamoylcarbamoylmethyl]-4H-thieno[3,2-b]pyrrole
23-dichloro-5-{N-[N-(2-cyanoethyl)-N-phenylcarbamoylmethyl]carbamoyl}4H-thieno[3,2-b]pyrrole;
30


-30-
23-dichloro-5-{N-[N-(4-methoxyphenyl)carbamoylmethyl]carbamoyl}-4H-thieno[3,2-b]pyrrole;
23-dichoro-5-{N-[N-(4-fluorophenyl)carbamoylmethyl]carbvamoyl}-4H-thieno[3,2-b]pyrrole;
2,3-dichloro-5- {N[N-(4-nitropb.enyl)carbamoylmethyI3carbamoyl} -4H-thieno[3,2-b]pyrrole; 5 23-dichoro-5-{N-[N-(2,6-dimethylphenyl)carbamoylmethyl]carbamoyl}-4H-thieno[3,2 b]pyrrole;
23-dichloro-5-{N-[N-methyl-N-(4-methylphenyl)carbamoylmethyl]carbamoyl}-4H-thieno[3,2-b]pyrrole;
23-dichloro-5-{N-[N-methyl-N-(3-methylphenyl)carbamoylmethyl]carbamoyl}-4H-10 thieno[3,2-b]pyirole;
2,3-dichoro-5-{N-[N-(3-chonophenyl)N-methylcaAamoy]methyl]carbamoyl}4H-thieno[3,2~b]pyrrole;
2,3-dichloro-5- {N- [N-(2-hydroxyethyl)-N-phenylcarbanioylmethyl]carbamoyl} -4H-thieno[3,2-6]pyrrole; 15 2,3-dicbloro-5- {N-[N-( 1, l-dimethyI-2-hydroxyethyl)carbamoylmethyI]carbamoyl }-4H-thieno[3,2-b]pyrrole;
23-dichloro-5-{N-[N-(2-hydroxyethyl)-N-methylcarbamoyimethyl]carbamoyl}-4H-thieno[3,2-b]pyrrole;
23-chloro-5-{N-[N-(2-hydroxyethyl)carbamoylmethyl]carbamoyl}-4H-thieno[3,2-20 b]pyrrole;
2,3-dichloro-5- {N-[N-(3-hydroxypropyl)carbamoybiiethyl]Garbamoyl} -4H-thieno[3,2-b]pyrrole;
23-dichloro-5-{N-[N(4-hydroxybutyl)carbamoylmethyl]carbamoyl}-4H-thieno[3,2-
b]pyrrole;
25 23-dichloro-5-(JV-{N-[bis(hydroxymethyl)methyl]carbamoylmethyl}carbamoyl)-4H-thieno[3,2-b]pyrrole;
23-dichoro-5-{N-[N-(23-dihydroxypropyl)carbamoylmethyl]carbamoyl}-4H-thieno[3,2-b]pyrrole;
23-dichoro-5-{N[N-(4-hydroxymethylphenyl)carbamoylmethyl]-4H-thieno[3,2-30 b]pyrrole;
23-dichloro-5-{N-[N-(5-isoquinolyl)carbamoylmethyl]carbamoyl}-4H-thieno[3,2-b
2,3-dichloro-5-{N-[N-(3-
hydroxymethyl)phenyl]carbamoylmethyl)carbamoyl}-4H-thieno[3,2-b] pyrrole
-31-


2,3-dichloro-5-(N- {N-[4-(2-hydroxyethyl)phenyl]carbamoylmethyl} carbamoyl)-4H-thieno[3,2-b]pyrrdle;
2,3-dichloro-5-{N-[N-(2,4-difluorophenyl)-N-methyl-carbamoylmethyl]carbamoyl}-4H-thieno[3,2-b]pyrrole;
2,3-dichloro-5- {N- [(1,2,3,4-tetrahydro-1 -quinolyl)carbonylmethyl] carbamoyl} -4H-thieno [3,2-b]pyrrole;
2,3-dichloro-5- {N-[N:(2-cyanoethyl)-N-methylcarbamoylmethyl]carbamoyl} -4H-thieno[3,2-b]pyrrole;
2,3-dichloro-5-{N-[N-(4-hydroxypiperidmo)carbainoylmethyl]carbamoyl}-4H-tbieno[3,2-10 b]pyrrole;
2,3-dichloro-5-[N-(N-cyclopentylcarbamoylmethyl)carbamoyl]-4H-thieno[3,2-b]pyrrole; 2)3-dichloro-5-[N-(N--isopropylcarbamoylmethyl)carbiimoyl]-4H-thieno[3,2-b]pyrrole; 2,3-dichloro-5-[N-(N-isopropyl-N-metiiylcarbamoylmethyl)carbamoyl]-4H-thieno[3,2-b]pyrrole; 15 2,3-dichloro-5-[N-(thiomorpholinocarbonylmethyl)carbamoyl]-4H-thieno[3,2-b]pyrrole; 2,3-dichloro-5-[N-(morpholinocarbonylmethyl)carbamoyl]-4H-thieno[3,2-b]pyrrole; 2,3 -dichloro-5- {N- [(1,1 -dioxothiomorpholino)carbonylmethyl] carbamoyl} -4H-thieno [ 3,2b] -pyrrole;
2,3-dichloro-5- {N-[( 1 -oxothiomorpholino)carbonyrmetxiyl]carbamoyl} -4H-tfiieno[3,2-b]pyrrole;
2-chloro-5-[N-(2-indanyl)carbamoyl]-6H-thieno[2,3-b]pyrrole; 5-[b-(benz[l,2]oxazol-3-ylmethyl)caxbainoyl]-23-dicliloro-4H-thieno[3,2-b]pyn:ole; 2,3-dichloro-5-(N- {2-[2-(hydroxymethyl)phenyl]ethyl} carbamoyl)-4H-thieno[3,2-b]pyrrole; 2,3-dichloro-5-[N-(4-phenybsoxazol-3-ylmethyl)carbamoyl]-4H-thieno[3,2-b]pyrrole; 2,3-dichloro-5-(N-{2-[2-(2-morpholinoethoxy)phenyl]ethyl}carbamoyl)-4H-thieno[3,2-b]pyrrole;
2,3 -dichloro-5-(N- {2- [2-(methoxycarbonylmethoxy)ph enyl] ethyl}carbamoyl)-4.H-thieno [3,2-b]pyrrole;
5-(N-{2-[2-(carboxymethoxy)phenyl]ethyl)carbamoyl)-2,3-dichoro-4H-thieno[3,2-b]pyrrole; 30 2,3-dichloro-5-{N-[2-(3-memoxyphenyl)ethyl]carbamoyl}-4H-tbieno[3,2-b]pyrrole;
2,3-dichloro-5-[N-(2-oxo-l,2,3,4-tetrahydroquinol-3-yl)carbamoyl]-4H-thieno[3,2-6]pyrrole; 2,3-dichloro-5-(N- {2-[2-(2-methoxyethoxy)phenyl]ethyl} carbamoyl)-4H-thierio[3,2-b]pyrrole;

(III)
and thereafter if necessary:
i) converting a compound of the formula (I) into another compound of the formula (I); ii) removing any protecting groups;
iii) forming a pharrhaceutically acceptable salt or in vivo hydrolysable ester. Specific reaction conditions for the above reaction are as follows. Process a) Acids of formula (II) and amines of formula (III) may be coupled together in the presence of a suitable coupling reagent. Standard peptide coupling reagents 10 known in the art can be employed as suitable coupling reagents, or for example
carbonyldiimidazole, l-ethyl-3-(3-dimethylaminopropyl)carbodi-irnide hydrochloride and dicyclohexyl-carbodiimide, optionally in the presence of a catalyst such as 1-hydroxybenzotriazole, dimethylaminopyridine or 4-pyrrolidinopyridine, optionally in the presence of a base for example triethylamine, di-isopropylethylamine, pyridine, or 15 2,6-di-a/&y/-pyridines such as 2,6-lutidine or 2,6-di-ter/'-butyrpyridine. Suitable solvents include dimethylacetamide, dichloromethane, benzene, tetrahydrofuran and dimethylformamide. The coupling reaction may conveniently be performed at a temperature in the range of -40 to 40°C.

-35
Suitable activated acid derivatives include acid halides, for example acid chlorides,
and active esters, for example pentafluorophenyl esters. The reaction of these types of
compounds with amines is well known in the art, for example they may be reacted in the
presence of a base, such as those described above, and in a suitable solvent, such as those
described above. The reaction may conveniently be performed at a temperature in the range of
-40 to 40°C.
25 The acids of formula (II) may be prepared according to Scheme J:

WOQ2/20530 PCT/SEfll#1880
Scheme 1 Compounds of formula (Ila) and amines of formula (1TI) are commercially available or they are known compounds or they are prepared by processes known in the art.
It will be appreciated that certain of the various ring substituents in the compounds of the present invention may be introduced by standard aromatic substitution reactions or generated by conventional functional group modifications either prior to or immediately following the processes mentioned above, and as such are included in the process aspect of the invention. Such reactions and modifications include, for example, introduction of a substituent by means of an aromatic substitution reaction, reduction of substituents, alkylation of substituents and oxidation of substituents. The reagents and reaction conditions for such procedures are well known in the chemical art. Particular examples of aromatic substitution reactions include the introduction of a nitro group using concentrated nitric acid, the introduction of an acyl group using, for example, an acyl halide and Lewis acid (such as aluminium trichloride) under Friedel Crafts conditions; the introduction of an alkyl group using an alkyl halide and Lewis acid (such as aluminium trichloride) under Friedel Crafts conditions; and the introduction of a halogeno group. Particular examples of modifications include the reduction of a nitro group to an amino group by for example, catalytic hydrogenation with a nickel catalyst or treatment with iron in the presence of hydrochloric acid with heating; oxidation of alkylthio to alkylsulphinyl or alkylsulphonyl.
It will also be appreciated that in some of the reactions mentioned herein it may be necessary/desirable to protect any sensitive groups in the compounds. The instances where protection is necessary or desirable and suitable methods for protection are known to those skilled in the art. Conventional protecting groups may be used in accordance with standard practice (for illustration see T.W. Green, Protective Groups in Organic Synthesis, John Wiley and Sons, 1991). Thus, if reactants include groups such as amino, carboxy or hydroxy it may be desirable to protect the group in some of the reactions mentioned herein.
A suitable protecting group for an amino or alkylamino group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl or ^-butoxycarbonyl group, an arylmethoxycarbonyl group, for example benzyloxycarbonyl, or an aroyl group, for example benzoyl. The deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or alkoxycarbonyl group or an aroyl group may be removed for example, by hydrolysis with a suitable base such as an alkali

WOW/25530 PCTjiSEWW880
metal hydroxide, for example lithium or sodium hydroxide. Alternatively an acyl group such as a /-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid as hydrochloric, sulphuric or phosphoric acid or triffuoroacetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon, or by treatment with a Lewis acid for example boron tris(trifluoroacetate). A suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group which may be removed by treatment with an alkylamine, for example dimethylammopropylarnine, or with hydrazine.
A suitable protecting group for a hydroxy group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an aroyl group, for example benzoyl, or an arylmethyl group, for example benzyl. The deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.
A suitable protecting group for a carboxy group is, for example, an esterifying group, for example a methyl or an ethyl group which may be removed, for example, by hydrolysis with a base such as sodium hydroxide, or for example a /-butyl group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.
The protecting groups may be removed at any convenient stage in the synthesis using conventional techniques well known in the chemical art.
As stated hereinbefore the compounds defined in the present invention possesses glycogen phosphorylase inhibitory activity. This property may be assessed, for example, using the procedure set out below. Assay
The activity of the compounds is determined by measuring the inhibitory effect of the compounds in the direction of glycogen synthesis, the conversion of glucose-1-phosphate into glycogen with the release of inorganic phosphate, as described in EP 0 846 464 A2. The reactions were in 96well microplate format in a volume of lOOul The change in optical
37

WOj}2/2tf530 P£I/SEG#01880
density due to inorganic phosphate formation was measured at 620nM in a Labsystems iEMS Reader MF by the general method of (Nordlie R.C and Arion WJ, Methods of Enzymology, 1966, 619-625). The reaction is in 50mM HEPES, 2.5mM MgCl2, 2.25mM ethylene glycol-bis(b-aminoethyl ether) N,N,N',N'-^tiaacetic acid, lOOmM KC1, 2mM D-(+)-glucose pH7.2, containing 0.5mM dithiothreitol, the assay buffer solution, with O.lmg type HI glycogen, 0.15ug glycogen phosphorylase a (GPa) from rabbit muscle and 0.5mM glucose-1-phosphate. GPfl is pre-incubated in the assay buffer solution with the type EI glycogen at 2.5 mg ml"1 for 30 minutes. 40ul of the enzyme solution is added to 25|il assay buffer solution and the reaction started with the addition of 25fil 2mM glucose-1-phosphate. Compounds to be tested are prepared in IOJUJ 10% DMSO in assay buffer solution, with final concentration of 1% DMSO in the assay. The non-inhibited activity of GPa is measured in the presence of 10pl 10% DMSO in assay buffer solution and maximum inhibition measured in the presence of 30uM CP320626 (Hoover et al (1998) J Med Chem 41, 2934-8; Martin et al (1998) PNAS 95, 1776-81). The reaction is stopped after 30min with the addition of 50pl acidic ammonium molybdate solution, 12ug ml"1 in 3.48% H2SO4 with 1% sodium lauryl sulphate and lOug ml"1 ascorbic acid. After 30 minutes at room temperature the absorbency at 620nm is measured.
The assay is performed at a test concentration of inhibitor of lOpM or 1OOPM. Compounds demonstrating significant inhibition at one or both of these concentrations may be further evaluated using a range of test concentrations of inhibitor to determine an IC50, a 20 concentration predicted to inhibit the enzyme reaction by 50%. Activity is calculated as follows:-% inhibition = (1 - (compound OD620 - fully inhibited OD620)/ (non-inhibited rate OD620 -fully inhibited OD620)) * 100. OD620 = optical density at 620nM.
Typical IC50 values for compounds of the invention when tested in the above assay are in the range lOOuM to InM.
The activity of the compounds is alternatively determined by measuring the inhibitory effect of the compounds on glycogen degradation, the production of glucose-1-phosphate from glycogen is monitored by the multienzyme coupled assay, as described in EP 0 846 464 A2, 30 general method of Pesce et al ( Pesce, M A, Bodourian, S H, Harris, R C, and Nicholson, J F (1977) Clinical Chemistry 23, 1171 - 1717). The reactions were in 384well microplate format in a volume of 50ul The change in fluorescence due to the conversion of the co-factor NAD
38

WO 02^530 P£IZSEfll701880
to NADH is measured at 340nM excitation, 465nm emission in a Tecan Ultra Multifunctional Microplate Reader. The reaction is in 50mM HEPES, 3.5mM KH2P04> 2.5mM MgCl2, 2.5mM ethylene glycol-bis(b-aminoethyl ether) N,N,N',N'-tetxaacQtic acid, lOOmM KC1, 8mM D-(+)-glucose pH7.2, containing 0.5mM dithiothreitol, the assay buffer solution. Human recombinant liver glycogen phosphorylase a (hrl GPa) 20nM is pre-incubated in assay buffer solution with 6.25mM NAD, 1.25mg type HI glycogen at 1.25 mg ml"1 the reagent buffer, for 30 minutes. The coupling enzymes, phosphoglucomutase and glucose-6-phosphate dehydrogenase ( Sigma) are prepared in reagent buffer, final concentration 0.25Units per well. 20ui of the hrl GPa solution is added to lOpl compound solution and the reaction started with the addition of 20ul coupling enzyme solution. Compounds to be tested are prepared in lOpl 5% DMSO in assay buffer solution, with final concentration of 1% DMSO in the assay. The non-inhibited activity of GPa is measured in the presence of 10pl 5% DMSO in assay buffer solution and maximum inhibition measured in the presence of 5mgs ml"1 N-ethylmaleimide. After 6 hours at 30°C Relative Fluoresence Units (RFUs) are measured at 340nM excitation, 465nm emission .
The assay is performed at a test concentration of inhibitor of lOpM or lOOpM. Compounds demonstrating significant inhibition at one or both of these concentrations may be further evaluated using a range of test concentrations of inhibitor to determine an IC50, a concentration predicted to inhibit the enzyme reaction by 50%.
Activity is calculated as follows :-% inhibition = (1 - (compound RFUs - fully inhibited RFUs)/ (non-inhibited rate RFUs - fully inhibited RFUs)) * 100.
Typical IC50 values for compounds of the invention when tested in the above assay are in the range lOOpMlto InM.
The inhibitory activity of compounds was further tested in rat primary hepatocytes. Rat hepatocytes were isolated by the collagenase perfusion technique, general method of Seglen (P.O. Seglen, Methods Cell Biology (1976) 13 29-83). Cells were cultured on Nunclon six well culture plates in DMEM with high level of glucose containing 10% foetal calf serum, NEAA, Glutamine, penicillin /streptomycin ((100units/100ug)/ml) for 4 to 6 hours. The hepatocytes were then cultured in the DMEM solution without foetal calf serum and with lOnM insulin and lOnM dexamethasone. Experiments were initiated after 18-20 hours culture by washing the cells and adding Krebs-Henseleit bicarbonate buffer containing 2.5mM CaCl2
39

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PCT/SEOl/01880

temperature for approximately 18 hours. The reaction mixture was washed with water, the organic phase was dried, filtered and concentrated to afford the title compound as an off-white solid (84 mg, 100%). NMR (CDC13): 9.7 (1H, br), 6.9-7.2 (5H, m), 6.5 (1H, s), 6.3 (1H, br), 3.9 (3H, s), 3.7 (2H, m), 3.0 (2H, t); m/z 333.4.
Examples #27 - #31

The following compounds were made by the process of Example #26 using 5-carboxy-2-chloro-4if-thieno[3,2-6]pyrrole (Method #8) and the appropriate amine. S,
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Example #70
5-(N-Benzvlcarbamovl')- 2,3-dichloro-4H-thienor3,2-b]pvrrole
5-Carboxy-2,3-dichloro-4H-thieno[3,2-b]pyn:ole (Method #9, 118mg, 0.5mmol) was dissolved in dichloromethane (10ml) containing benzylamine (55 mg, 0.5 mmol), 1-HOBT (68mg, 0.5mmol) and DIPEA (258pl, 2mmol). The mixture was stirred for one minute before the addition of ED AC (125mg, 0.65mmol). The mixture was stirred at ambient temperature for approximately 16hours before being washed with water. The organic fraction was 1O concentrated and was purified using Bond-Elut silica column chromatography (eluent:
dichloromethane-dichloromethane/methanol 5% gradient) to afford the title compound as a
white solid (121mg, 75%).
NMR: 12.4 (1H, br), 8.8 (1H, t), 7.3 (5H, m), 7.1 (1H, s), 4.5 (2H, d); m/z 323.27
15 The following compounds were made by the process of Example #70 using 5-carboxy-
2,3-dichloro-4#-thieno[3,2-&]pyrrole (Method #9) and the appropriate amine:
20 25
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A solution of 5-(N-carboxymethylcarbamoyl>- 2,3-dichoro-4H-thieno[3,2-b]pyrrole (Method #12, 150mg, 0.51mmol) and 4-methoxyaniline (69mg, 0.56mmol) in tetrahydrofuran (THF) (6ml) was stirred at ambient temperature for 30 minutes. 4-(4,6-


WO Oimsio PCT/SEOl/01880
dimethoxy-l,3,5-triazin-2-yl)-4-metbylmorpholinium chloride (DMTMM) (142mg, 0.51mmol) was added and the reaction mixture stirred at ambient temperature overnight, poured into water (15ml) and extracted with ethyl acetate (3x15ml). The organic extracts were combined and washed with IN citric acid solution (15ml), sodium bicarbonate solution 5 (I5ml), dried over magnesium sulphate, filtered and concentrated to give the title product as a white solid NMR: 12.4 (1H, s), 9.9 (1H, s), 8.6 (1H, t), 7.5 (2H, d), 7.2 (1H, s), 6.85 (2H, d), 4.0 (2H, d), 3.7 (3H, s); m/z 396.38
The following compounds were made by the process of Example #82 using 2,3-10 dichloro-5-[N-carboxymethylcarbamoyl]-4H-thieno[3,2-b]pyrrole (Method #12) and the appropriate commercially available amine:
63
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A solution of 5-(N-arboxymethylcarbamoyl)-2,3-dichloro-4H-thieno[3,2-b]pyrrole (Method #12) (150mg, 0.51mmol), and 4-aminobenzyl alcohol (70.5mg, 0.56mmol) in THF (6ml) was stirred at ambient temperature for 30 minutes. 4-(4,6-dimethoxy-l,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMTMM) (142mg, 0.51mmol) was added and the reaction mixture stirred at ambient temperature overnight, then poured into water (15ml). The resultant precipitate was isolated by filtration, washed with water, ether and dried in vacuo to give the title product as a white solid (149mg, 73%)
NMR: 12.42 (1H, br), 9.9 (1H, s), 8.6 (1H, t), 7.5 (2H, d), 7.2 (2H, d), 7.1 (1H, s), 5.0 (1H, 10 br), 4.4 (2H, s), 4.0 (2H, d); m/z 396.21
The following compounds were made by the process of Example #97 using 5-(N-carboxymethylcarbamoyl)-2,3-dichloro-4H-thieno[3,2-b]pyrrole (Method #12) and the appropriate commercially available amine:



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A solution of m-chloroperbenzoic acid (mCPBA) (14mg, 0.85mmol) in dichloromethane (5ml) was added dropwise to a suspension of 2,3-dichloro-5-[N-(tmiomorpholmocarbonylmethyl)carbamoyl]-4H-thieno[3,2-b]pyrrole (example # 108) in

5 dichloromethane and the reaction mixture stirred at ambient temperature for one hour. 5% sodium metabisulfite solution (5ml) was added and the mixture stirred for several minutes. The aqueous layer was extracted with ethyl acetate (2x15ml) and the combined organic extracts washed with sodium bicarbonate solution (2x15ml) and concentrated. The two component mixture was separated using bond-elute silica column chromatography (eluent:
10 dichloromethane-dichloromethane/methanol 5% gradient) to afford the less polar product (sulfone) as a white powder (57mg 33%) and the more polar product (sulfoxide) as a white solid (62mg, 37%).
NMR: (sulfone) 12.43 (IH, br), 8.4 (IH, t), 7.1 (IH, s), 4.2 (2H, d), 3.9 (4H, br), 3.3 (2H, br), 3.1(2H,br); m/z 408.33 .5 NMR: (sulfoxide) 12.42 (IH, br), 8.4 (IH, t), 7.1 (IH, s), 4.2 (3H, m), 3.9 (2H, d), 3.6 (IH, m), 2.9 (4H, m).
Example #112 2-Chloro-5-N-(2-indanvl)carbamoyl1-6H-thienor23-b]PVrrole
CI-

20
5-Carboxy-2-chloro-6H-thieno[2,3-b]pyrrole (Method #10; lOlmg, 0.5mmol) was dissolved in dichloromethane (6ml) containing 2-aminoindane (68mg, 0.5mmol), 1-Hydroxybenotriazole (HOBT) (68mg, 0.5mmol) and DIPEA (355|il, 2.0mmol). The mixture was stirred for one minute before the addition of EDAC (125mg, 0.65mrnol). The mixture was stirred at ambient temperature for approximately 16 hours before being washed with water. The organic fraction was concentrated and was purified using bon-elute silica column
70

WOj&2/2U530 PCT/SEOJJWSSU
chromatography (eluent: dichloromethane-dichloromethane/methanol 2.5% gradient) to afford the title compound as a beige solid (96mg, 61%).
NMR: 11.80 (1H, br), 8.3 (1H, t), 7.2 (5H, m), 7.0 (1H, s), 4.6 (1H, m), 4.7 (1H, d), 3.2 (2H, m), 2.9 (2H, m); m/z 315.46
Example #113
5[N-(bierizr[121oxazol-3-vlmethvl)carbamovll-23-dichoro-4H-tbienor3,2-b]pmole
H b
.0
5-Carboxy-2,3-dichloro-4H-thieno[3,2-i]pyrrole (Method #9; 118 mg, 0.5 mmol) was dissolved in DMF (5 ml) containing HOBT (83 mg, 0.55 mmol), DIPEA (52 ul, 0.30 mmol) and l,2-Benzisoxazole-3-methylamine (Eur.J.Med.Chem-ChimicaTherapeutica, Jan.-Feb.-10, No.l p32) (89 mg, 0.6 mmol). The mixture was stirred for one minute and EDAC (106 mg, 0.55 mmol) was added. The mixture was stirred at room temperature for approximately 18 hours. Water was added to the solution and a solid precipitated out. This solid was filtered off. and was washed with water before being dried under reduced pressure to afford the title compound as a white solid (174mg) 1H NMR : 4.9(2H,s), 7.1(lH,s), 7.4(lH,t), 7.6(lH,t), (7.8(lH,d), 8.0(lH,d), 9.2(lH,s), 12.5(lH,s); m/z 366 (M+H);
HPLC Hichrome C18 column Acetonitrile/water/0.1 %TFA 5-95% over 7.5 min Rt 4.9min m/z 366 (M+H)
The following compounds were made by the process of Example #113 using 5-carboxy-2,3-dichloro-4ir-thieno[3,2-Z)]pyrrole (Method #9) and the appropriate amine:
i
71

WQj02«e533, water, saturated brine and dried. The organics were filtered, concentrated and chromatographed on Fiuorochem silica 40-63|i 60A (efuent 40:60 EtOAc/isohexane) to afford the title compound as an amorphous solid (44 mg). NMR (DMSOd6): 11.94 (1H, s), 8.04 (1H, d), 7.16 (1H, s), 7.06 (1H, s), 6.90 (2H, m), 6.48 (2H, m), 5.8 (1H, br), 4.18 (1H, m), 3.05 (1H, t), 2.85 (2H, m); MH+332.17.
Example #146

S" N N
H H
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5-Carboxy-2-chloro-6H-thieno[2,3-b]pyrrole (Method #10; 80 mg, 0.4 mmol) was dissolved in DMF (2 nil) containing 3-amino-3,4-dihydro-l-carbostyril [JCS 1965 1080-1087] (71 mg, 0.4 mmol) and HOBT (54 mg, 0.4 mmol). The mixture was stirred for 1 minute before the addition of ED AC (77 mg, 0.4 mmol). The mixture was stirred at ambient temperature for approximately 18 hours before being partitioned between water and EtOAc. The organics were washed with water, saturated aqueous NaHCO3, water, saturated brine and dried. The organics were filtered, concentrated and recrystalised from EtOAc to afford the title compound as an amorphous solid (66 mg). NMR 11.96 (IH, s), 8.54 (IH, d), 7.30 (2H, m), 7.17 (2H, m), 7.08 (2H, m), 4.68 (IH, m), 3.32 (3H, s), 3.14 (IH, m), 3.04 (IH, m); m/z 10 (MET40 360.14
Example #147

15
O 5-Carboxy-2-chloro-6iir-thieno[2,3-b]pyrrole (Method #10; 101 mg, 0.5 mmol) was dissolved in DMF (2.5 ml) containing 4-amino-l,2,4,5-tetrahydro-3H-2-benzazepin-3-one hydrochloride [CAS Reg No 148842-85-7] (107 mg, 0.5 mmol), HOBT (68 mg, 0.5 mmol) and E13N (101 mg, 1.0 mmol). The mixture was stirred for 1 minute before the addition of 20 ED AC (96 mg, 0.5 mmol), then at ambient temperature for approximately 18 hours before
being partitioned between water and EtOAc. The organics were washed with water, saturated aqueous NaHC03, water, saturated brine and dried; filtered and evaporated to afford the title compound as an amorphous solid (26 mg). NMR: 11.92 (IH, s), 8.33 (IH, t), 8.29 (IH, d), 7.2 (6H, m), 5.30 (IH, m), 4.83 (IH, dd), 3.98 (IH, dd), 3.20 (2H, m); m/z (MH+ 360.19. Example #148

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WO 0?#tfS30 PCT/SE01/01880

5-Carboxy-2,3-dichloro4H-mieno[3,2;b]pyrrole (Method #9, 145mg, 0.613rnmol), trans-2-amino-l-methoxyindan (Method #40, lOOmg, 0.163mmol), D1PEA (0.105ml, 0.613mmol), and HOBT (83mg, 0.613mmol) was stirred in dichloromethane (5ml) for one minute. EDAC (147mg, 0.766mmol) was added and the mixture stirred at room temperature for 20 hours. The reaction mixture was evaporated, ethyl acetate (25rnl) added and then washed with water. The organic solution was dried over magnesium sulphate and evaporated to give the title compound as a white powder (180mg, 77%). 10 NMR2.8(1H, dd), 3.3(1H, dd), 3.35(3H, s), 4.1-4.2(1H, m), 5.35-5.45(lH, m), 7.1-7.3(4H, m), 7.15(1H, s), 8.7(1H, d); m/z 380.9/382.9 (M+H).
Example #149
2.3-Dichloro-5-(N- {l-\N-( 1, l-dimethvlethoxv)carbonylamino1indan-2-yl) carbamoyl)-4H-15 thienor3,2-b1pyrrole

5-Carboxy-2,3-dichloro-4H-thieno[3,2-b]pyrrole (Method #9, 1.18g, 5.0mmol), (1R, 2i?)-2-amino-l-[(l,l-dimethylethoxy)carbonylamino]indan (Method #43, 1.25g, 5.0mol), DPEA (0.855ml, 5.0mmol), and HOBT (675mg, 5.0mmol) was stirred in dichloromethane 20 (50ml) for one minute. EDAC (1.2g, 6.25mmol) was added and the mixture stirred at room temperature for 20 hours. The reaction mixture was diluted with dichloromethane (50ml), filtered and dried to give the title compound as a pale green powder (1.95g, 85% ). NMR1.4(9H, s), 2.8(1H, dd), 3.2(1H, dd), 4.5-4.7(lH, m), 5.1-5.2(1H, m), 7.05-7.3(5H, m), 7.4(1H, d), 8.6(1H, d), 12.4(1H, s).
/

2,3-Dichloro-5-(N- {1 -[(1,1 -dimemylethoxy)carbonylarniao]indan-2-yl) carbamoyl)-4H-thieno[3,2-b]pyrrole (Example #149, l.Og, 2.15mmol) was dissolved in dichloromethane (20ml). Trifluoroacetic acid (2ml) was added and the mixture stirred at room temperature for 24 hours. The reaction was filtered and the isolated solid washed with dichloromethane to give the trifluoroacetic acid salt of the title compound as a pale green powder (800mg, 78%). NMR3.05(1H, dd), 3.4(1H, dd), 4.6-4.85(2H, m), 7.2(1H, d), 7.3-7.45(3H, m), 7.55(1H, d), 10 8.6(3H, broad s), 8.8(1H, d), 12.5(1H, s)
Example #151
5-[N-(l-Acetarmidoindan-2-yl)carbamovll-2,3-dichloro-4H-thienor3.2-b]pvrrole
O

HN H
15 Triethylamine (lOlmg, l.Ommol) was added to a suspension 5-[iV-(l-aminoindan-2-

yl)carbamoyl]-2,3-dichloro-4H-thieno[3,2-b]pyrrole trifluoroacetic acid salt (Example #150, 240mg, 0.5mmol) in dichloromethane (4ml), followed by acetyl chloride (47mg, 0.6mmol) dissolved in dichloromethane (1ml) and the reaction stirred at room temperature for 6 hours during which a white solid precipitated. The reaction was filtered and the crude material purified by silica chromatography with hexane : ethyl acetate to give the title compound as a white solid (50mg, 25%). NMR 1.87(3H, s), 2.82(1H, dd), 3.22(1H, dd), 4.45-4.62(lH, m), 5.38-5.5(lH, m), 7.02-7.27(4H, m), 7.1(1H, s), 8.35(1H, d), 8.59(1H, d), 12.36(1H, broad s); m/z 406.13/408.8 (M-H).
25 Example #152
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WO O2/2O£30-^ PCT/SE01/01880
23-Dichloro-5-(N'-ri-(memanesulphonamido)mdan-2--vl1carbamovl)-4H-tmenor3,2-b]pvn:o

5-Carboxy-2,3-dichloro-4H-thieno[3,2-b]pyrrole (Method #9, 236mg, l.Ommol), (1R,2R)-2-ammo-l-methanesulphonamidoindan (Method #42, 226mg, l.Omol), DIPEA (0.174ml, l.Ommol), and HOBT (135mg, l.Ommol) was stirred in dichloromethane (10ml) for one minute. ED AC (240mg, 1.25mmol) was added and the mixture stirred at room temperature for 20 hours. The mixture was diluted with ethyl acetate, washed with water (2 x 25ml), dried over magnesium sulphate and evaporated to give the title compound as a foam (400mg, 90%). NMR2.84(1H, dd), 2.99(3H, s), 3.22(1H, dd), 4.44-4.64(lH, m), 4.89-5.0(1H, m), 7.14(1H, s), 7.16-7.36(4H, m), 7.84(1H, d), 8.64(1H, d), 12.43(1H, broad s); m/z 442.2/444.0 (M-H).


Example #153
2,3-Dichloro-5-[N-( 1 - [N-[( 1,1 -dimethylethoxy)carbonyl] -N-memylamino} indan-2-yI)carbamoyI]-4H-thieno[3,2-b]pyrroIe (Method #44, 900mg, 1.87mmoI) in dichloromethane (20ml) treated with trifluoroacetic acid (2ml) at room temperature for 1 hour. Evaporation followed by co-evaporation with chloroform and drying gave the trifluoroacetic acid salt of the title compound as a pale brown foam (850mg, 92%). NMR 2.75(3H, s), 3.02(1H, dd), 3.5(1H, dd), 4.7-4.95(2H, m), 7.15(1H, s), 7.28-7.48(3H, m), 7.6(1H, d), 8.68(1H, d), 9.1(2H, broad s); m/z 380.4/382.4 (M+H).
Example #154

2,3-Dichloro-5- [N-[1-(memylamino)indan-2-yl]carbamoyl} -4H-thieno[3,2-b]pyrrole trifluoroacetic acid salt (Example #153, 390mg, 0.79mmol) in dichloromethane (5ml) at 5°C was treated with trethylamirie (0.33ml, 2.37mmol) and acetyl chloride (68mg, 0.86mmol). After stirring at 5°C for 15 minutes the reaction was allowed to warm to room temperature and stirred for a further 2 hours. The mixture was diluted with ethyl acetate (25ml) and washed with saturated sodium bicarbonate and water. Drying over magnesium sulphate followed by . evaporation gave the title compound as a pale brown foam (270mg, 80%). NMR: Indicates an approximate 1:1 ratio of rotamers of the title compound; 2.05(1.5H, s), 2.1(1.5H, s), 2.6(1.5H, s), 2.8(1.5H, s), 2.9-3.08(lH, m), 3.12-3.3(1H, m), 4.7-4.9(lH, m), 5.24(0.5H, d), 6.14(0.5H, d), 6.94-7.35(5H, m), 8.6(0.5H, d), 8.68(0.5H, d), 12.38(0.5H, broad s), 12.46(0.5H, broad s); m/z 421.9/423.9 (M+H)
Preparation of Starting Materials
The starting materials for the Examples above are either commercially available or are readily prepared by standard methods from known materials. For example the following reactions are illustrations but not limitations of the preparation of some of the starting materials used in the above reactions.
20
Method #1
3-Chloro-5-methoxvcarbonyl-4H-thienor3,2-b]pyiTole

H O
Methanolic sodium methoxide solution (28%) (5 ml, 25.9 mmol) was diluted with MeOH (5 ml) and was cooled to -25°C under nitrogen. A solution of 4-chloro-2-
^

thiophenecarboxaldehyde (J Heterocyclic Chem, 1976, 13, 393; 1.1 g, 7.5 mmol) and methyl azidoacetate (3.0 g, 26.1 mmol) in MeOH (20 ml) was added dropwise, maintaining the temperature at -25°C. On completion of addition the solution was allowed to warm to 5°C over a period of approximately 16 hours. The solution was added to saturated aqueous ammonium chloride (250 ml) and the mixture was extracted using DCM. The combined organic layers were concentrated at 0°C. The residue was taken up in xylene (30 ml) and this solution was added dropwise to xylene (120 ml) under reflux. The solution was heated under reflux for 30 minutes before being cooled and concentrated. The title compound was purified by a mixture of crystallisation (EtOAc/isohexane) and chromatography on a Bond Elut column eluting with a graduated solvent of 5-50% EtOAc in isohexane (640 mg, 40%). NMR (CDC13) 9.1 (1H, br), 7.1 (2H, s), 3.9 (3H, s); m/z 214.3.
Methods #2 - #4
The following compounds were made by the process of Method #1 using the appropriate starting materials

8

N-(tert-butoxycarbonyl)glycine (875mg, 5mmol) was dissolved in DMF (7ml) containing DIPEA (3.5ml, 20mmol) and benzylamine (536mg, 5mmol). The mixture was allowed to stand for one minute before addition of O-(7-Azabenzotriazol-l-yl)-N,NN,'N,-tetramethyluronium hexafluorophosphate (HATU) (2.09g, 5.5mmol). The solution was allowed to stand for approximately 18 hours before being partitioned between ethyl acetate (50ml) and water (50ml). The layers were separated and the organic phase dried using magnesium sulphate, filtered, concentrated and purified using bond-elute silica column chromatography (eluent: dichloromethane-dichloromethane/methanol 5% gradient) to afford the title compound as an oil (1.32g, quantitative).
NMR: (CDC13): 7.2 (5H, m), 6.3(1H, br), 5.0(1H, br), 4.4(2H, d), 3.8(2H, d), 1.4(9H, s); m/z 265.4
Method #6
2-Ammo-N-benzvlacetamide

To a solution of N-benzyl-2-(tert-butoxycarbonylamino)acetamide (Method #5 , 1.18g, 4.47mmol) in dichloromethane (6ml) at 0°C was added dropwise, trifluoroacetic acid (2.4ml) and the resulting solution allowed to stir warming to room temperature overnight. The reaction mixture was neutralised by addition of saturated sodium bicarbonate solution and extracted with dichloromethane. The combined organic phases were dried over magnesium . sulphate, filtered, concentrated and purified by bond-elute SCX column chromatography (eluent: methanol/dichloromethane (1:1) then methanol/dichloromethane (l:l)/ammonia5%) to afford the title compound as an oil (215mg, 29%). NMR: (CDCI3): 7.2(6H, m), 4.4(1.4H,d), 4.3(0.6H,d), 3.4(2H, br); m/z 165.17
Method #7
5-Carboxv-3-chloro-4H-thienor3,2-b]pvrrole
93

5
10


3-Chloro-5-methoxycarbonyl-4H-thieno[3,2-b]pyrrole_(Method #1; 0.61 g, 2.83 mmol) was taken up in MeOH (10 ml) and was heated under reflux. Aqueous lithium hydroxide (2.0 M, 3.0 ml, 6.0 mmol) was added portionwise over 45 minutes. The mixture was heated under reflux for 30 minutes before being cooled and concentrated. Water (20 ml) was added and the solution was neutrahsed using aqueous hydrochloric acid (2.0 M, 3.0 ml). The solution was extracted using EtOAc, and the combined organic layers were concentrated to afford the title compound as a yellow solid (0.57 g, 100%). NMR: 12.4 (1H, br), 7.4 (1H, s), 7.0 (1H, s); m/z 200.3.
Methods #8 - #10
The following compounds were made by the process of Method #7 using the appropriate starting materials.


94

PCT/SE01/01880

5-Carboxy-2,3-dichloro-4H-thieno[3,2-b]pyrrole (Method #9,4.0g 16.95mmol) was added to a solution of glycine ethyl ester hydrochloride (2.60g, 18.64mmol) and DIPEA in dichloromethane (200ml) followed by HOBT (2.29g, 16.95mmol). The solution was stirred under nitrogen for 15 minutes before the addition of ED AC (3.89g, 22.03mmol). The mixture was stirred at ambient temperature for approximately 16 hours. The resultant white precipitate was isolated by filtration, washed with water and ether and dried. (4.79g, 88%). NMR: 12.45 (lH,br), 8.75 (lH, t), 7.1 (1H, s), 4.1 (2H, q), 4.0 (2H, d), 1.2 (3H, t); m/z 321.2
10 Method #12
5-(N-Carboxvmethvlcarbamovl)-2,3-dichloro-4H-thienor3,2-b]pyrrole

2N Sodium hydroxide solution (14.3ml, 28.7mmol) was added to a suspension of 2,3-dichl-5-[N-(ethoxycarbonylmemyl)carbamoyl]-4H-thieno[3,2-b]pyrrole (Method #11, 10 4.60g, 14.33mmol) in tetrahydrofuran (THF) (100ml). The resultant solution was stirred at
room temperature for one hour. The reaction mixture was concentrated 'in vacuo', the residue diluted with water (250ml), the solution adjusted to pH=2 by addition of 2N Hydrochloric acid, and then extracted with ethyl acetate (3x150ml). The organic extracts were combined, dried over sodium sulphate then filtered and concentrated to give a white powder (3.34g, 80%); NMR: 12.6 (lH.br), 12.4 (1H, br), 8.6 (1H, t), 7.1 (1H, s), 3.9 (2H, d); m/z 291.17
Method #13
N-(2-Cvanoethvl)-N-phenyl-2-(tert-butoxycarbonylairdno)acetamide
95


N By a similar procedure to Method #5 the title compound was prepared using anilinopropionitrile to give a clear oil (598mg, 39%); NMR: (CDC13): 7.4(3H, m), 7.2(2H, m), 5.2(1H, br), 3.9(2H, t), 3.6(2H, d), 2.6(2H, t), l.'3(9H, s); m/z 304.51
Method .#14 2-Amino-N-(2-cvanoethyl)-N-phenylacetamide

O
By a similar procedure to Method #6 the title compound was prepared using N-(2-10 cyanoethyl)- N-phenyl-2-(tert-butoxycarbonylammo)acetainide (Method #13) to give a clear oil (222mg, 60%); NMR: (CDCI3): 7.4(3H,m),.7.2(lH, d), 7.1(1H, d), 3.9(2H, t), 3.1( 1.33H, s), 3.0(0.67H, s), 2.65(1.33H, t), (0.67H, t); m/z 204.31

li

Method #15
N[(2-Arrnno-2-(2-miazolyl)lethvl-N-methvlmethanesulphonarnide


2-Bromothiazole (6.9 g, 42.0 mmol) was dissolved in dry diethyl ether (15 ml) and was added dropwise to butyl lithium (1.6 M, 29.7 ml, 47.5 mmol) in diethyl ether (40 ml) at -70°C. The mixture was stirred at -70°C for 30 minutes before the addition of a cold solution 20 of. ethyl 2-(N-methylmethauesulphonamido)acetate (Ger Offen, 1976, 27pp; 7.6 g, 39.0

WO 02/2053^"" PCT/SEet/ftlSSO-
mmol) in dry THF (70 ml). The solution was stirred for a further 30 minutes at -70°C before being allowed to warm to ambient temperature. Aqueous ammonium chloride (10%, 200 ml) was added and the solution was extracted using diethyl ether. The aqueous layer was acidified and re-extracted using diethyl ether. The combined organic layers were dried, filtered and concentrated under reduced pressure. The residue (5.30 g, 22.6 mmol) was dissolved in ethanol (100 ml) containing pyridine (18 ml) and hydroxylamine hydrochloride (1.88 g, 27.1 mmol). The mixture was heated under reflux in an inert atmosphere for 2.5 hours before being cooled and concentrated under reduced pressure. The residue was suspended in water and cooled to 0°C. The mixture was acidified to pH 4 using aqueous hydrochloric acid (2.0 M). A
10 solid precipitated out of solution and was filtered off and washed with water. The product was dried under reduced pressure in the presence of phosphorous pentoxide. The dry solid (4.34 g, 17.4 mmol) was dissolved in acetic acid and 5% rhodium on carbon (40% w/w, 1.7 g) was added. The solution was agitated under an atmosphere of hydrogen at 5 bar for 48 hours. The reaction vessel was flushed free of hydrogen using inert gas and the solution was filtered
15 through celite. The filtrate was concentrated under reduced pressure. The residue was
suspended in ethanol and cooled to 0 °C. Aqueous hydrochloric acid (5.0 M) and ethanol (50 ml, 1:1) was added and the mixture was stirred for 30 minutes. A white precipitate was filtered off to afford the title compound (3.16 g) as the hydrochloride salt.
20 Method #16
Ethyl (S)-5-( O -aminophenethylV 1,3,4-oxadiazole-2-carboxylate trifluoroacetate

Ethyl (iS)-5-[D-[(tert-butoxycarbonylamino)phenethyl]-l,3,4-oxadiazole-2-carboxylate, (Borg et al. J. Org. Chem. 1995, 60, 3112; 350mg) was dissolved in trifluoroacetic acid (5ml.) and allowed to stand at ambient temperature for 1 hour. The reaction mixture was concentrated and dried under vacuum to give a glassy solid (322mg) NMR 1.75(3H,t); 3.2-3.4(2H,m); 4.4(2H,q); 5.2(lH,t); 7.1-7.4(5H,m); 8.8-9.2(3H,bs)
96


H O
2-Phenyl-l,3-dioxolan-2-ylmethylamine hydrochloride (65 mg, 0.3 mmol) and 5-carboxy-2,3-dichloro-4H-thieno[3,2-b]pyrrole (Method #9; 71 mg, 0.3 mmol) were dissolved in DCM (10 ml) containing DIPEA (175 ml, 1.0 mmol) and HOBT (40 mg, 0.3 mmol). The mixture was stirred for one minute before the addition of ED AC (75 mg, 0.39 mmol). The solution was stirred at room temperature for approximately 18 hours. The mixture was concentrated and chromatographed on a Bond Elut column eluting with 20% - 40% EtOAc in l0 isohexane. The title compound was isolated as a white solid (100 mg). NMR: 12.4 (IH, s), 8.2 (IH, s), 7.2 (IH, s), 4.0 (2H, m), 3.7 (2H, m), 3.6 (2H, d); m/z 395.2.
Method #18
(S)-5-(D-Aminophenethvl)-3-phenyl-l,2,4-oxadiazole trifluordacetate

15
BOC-Phenylalanine (614mg, 2.32mmol) was dissolved in DCM (20ml) cooled with
ice/water and dicyclohexyl carbodiimide (239mg, 1.16mmol) added. After stirring at 0-5°C
for 1 hour the reaction mixture was filtered and concentrated in vacuo. Phenylamidoxirne
(104mg,0.77mmol) and pyridine (10ml) were added and the mixture heated to reflux for 2
20 hours. The reaction mixture was then evaporated to small volume, dissolved in ethyl acetate,
washed with dilute citric acid, saturated sodium bicarbonate, water and brine, dried with
magnesium sulphate and evaporated to give a crude product which was purified by
chromatography on silica gel (eluted with Hexane/ ethyl acetate 4:1) to (S)-5-[D-(tert-
butoxycarbonylamino)phenethyl]-3-phenyl-l,2,4-oxadiazole(274mg).
97

WO 02/20330 PCT/SE8i



chloroform. The chloroform was concentrated and the residue was recrystallised from ethanol to afford the title compound.
Method #38
2-Amino-6-fluoro-1 -indanol OH


To a solution of sodium carbonate (0.8 g, 7.2 mmol) in water (13 ml) was added 4-fluorophenylalanine (1.3 g, 7.2 mmol) followed by a solution of N-ethoxycarbonylphthalamide (1.6 g, 7.2 mmol) in ethyl acetate (10 ml). The two-phase
10 reaction mixture was stirred for 24 hours at room temperature. The organic phase was
separated and discarded and the aqueous phase was acidified with concentrated HC1 to pH 2. The aqueous phase was then extracted with ethyl acetate (3 x 20 ml) and the combined extracts dried over magnesium sulphate then concentrated under reduced pressure to give 3-(4-fluorophenyl)-2-phthalirnidopropanoic acid as a white solid (2g, 89%); NMR 3.3(lH,dd),
15 3.5(lH,dd), 5.1(lH,dd), 6.3(lH,brs), 7.0(2H,t), 7.1(2H,dd), 7.8(4H,s).
To a solution of 3-(4-fluorophenyl)-2-phmalimidopropanoic acid (2.0 g, 6.4 mmol) in DCM (20 ml) was added thionylchloride (0.6 ml, 6.4 mmol) and 1 drop of DMF. The reaction mixture was stirred at room temperature for 1 hour. Aluminium chloride (2.6 g, 19.2 20 mmol) was added and the reaction mixture stirred for 3 hours at room temperature. The resulting mixture was poured into ice and concentrated HC1 (20 ml) and stirred for 10 ruinutes. This mixture was extracted with DCM (3 x 20 ml) and the combined organic extracts were washed with water (2 x 20 ml), saturated sodium hydrogen carbonate (1 x 20 ml) and water (1 x 20 ml). The organic phase was then dried over magnesium sulphate and concentrated under reduced pressure to give 6-fluoro-2-phthalamido-indan-l-one as a white solid (lg, 53%). NMR 3.3(lH,dd), 3.5(lH,dd), 5.1(lH,dd), 6.8(lH,t), 7.0(lH,dd), 7.7-8.0(5H,m); m/z 296 (M+H)

30

Sodium borohydride (512 mg, 14 mmol) was added to a solution 6-fluoro-2-phthalamido-indan-1-one (800 mg, 2.7 mmol) in isopropanol/water (6:1, 10.5 ml) and the


solution stirred at room temperature for 24 hours. Excess acetic acid was then added to the reaction mixture and the resulting solution heated at 60°C for 6 hours. The reaction mixture was then cooled to room temperature and concentrated under reduced pressure to give a white solid which was purified by ion-exchange chromatography using Dowex 50wx2 (watenmethanol 1:1 containing 3% ammonia) to give the title compound as a white solid (141 . mg, 31 %); NMR 3.3(lH,dd), 3.5(lH,dd), 4.8(lH,m), 4.9(lH,d), 6.8-7.4(3H,m); m/Z 168 (M+H)
10 Method #39
2-Amino-l,2,3,4-tetrahvdronaphth-l-ol

■ To a solution of sodium carbonate (0.8 g, 7.2 mmol) in water (13 ml) was added homophenylalanine (1.3 g, 7.2 mmol) followed by a solution of N-ethoxycarbonylphthalamide (1.6 g, 7.2 mmol) in ethyl acetate (10 ml). The two-phase reaction mixture was stirred for 24' hours at room temperature. The organic phase was separated and discarded and the aqueous phase was acidified with concentrated HC1 to pH 2. The aqueous phase was then extracted . with ethyl acetate (3 x 20 ml) and the combined extracts dried over magnesium sulphate then concentrated under reduced pressure to give 4-phenyl-2-phthalimidobutanoic acid as a white 20 solid (1.5 g, 67%); m/z 308 (M-H).
To a solution of 4-phenyl-2-phmalimidobutanoic acid (1.5 g, 4.9 mmol) in DCM (20 ml) was added thionylchloride (0.4 ml, 4.9 mmol) and 1 drop of DMF. The reaction mixture was stirred at room temperature for 1 hour. Aluminium chloride (2.0 g, 14.7 mmol) was
. 15 added and the reaction mixture stirred for 3 hours at room temperature. The resulting mixture was poured into ice and concentrated HC1 (20 ml) and stirred for 10 minutes. This mixture was extracted with DCM (3 x 20 ml) and the combined organic extracts were washed with water (2 x 20 ml), saturated sodium hydrogen carbonate (1 x 20 ml) and water (1 x 20 ml). The organic phase was then dried over magnesium sulphate and concentrated under reduced
30 pressure to give 2-phthalamido-3,4-dihydro-(2H)-naphthalen-l-one as a white solid (880 mg,
112


62%). NMR 2.3(lH,m), 2.7(lH,m), 3.1(lH,dt), 3.3(lH,m), 5.2(lH,dd), 7.3-8.0(8H,m); m/z 292 (M+H)
To a solution of 2-phthalarnido-3,4-dihydro-(2if)-naphthalen-l-one (880 mg, 3 mmol) in isopropanol/water (6:1, 11.5 ml) was added sodium borohydride (567 mg, 15 mmol) and the solution stirred at room temperature for 24 hours. Excess acetic acid was then added to the reaction mixture and the resulting solution heated at 60°C for 6 hours. The reaction mixture was then cooled to room temperature and concentrated under reduced pressure to give a white solid which was purified by ion-exchange chromatography using Dowex 50wx2 10 (water:methanol 1:1 containing 3% ammonia) to give the title compound as a white solid (150 mg, 30 %). NMR 2.8(lH,dd), 3.0(lH,dd), 3.3(lH,m), 3.5(lH,m), 4.5(lH,m), 4.8(lH,d), 7.1-7.4(4H,m); m/z 164 (M+H)

15

Method #40
(+/-) trans-2-Amino-l-methoxyindan


A solution of (+/-) trans-2-bromo-l-hydroxyindan (21.0g, O.lmol) and potassium phmalimide (42.0g, 0.22 mol) in dry DMF (120ml) was heated at 100°C for 5 hours. The reaction mixture was cooled and evaporated to an oil which was triturated with ethyl acetate and filtered. The filtrates were evaporated and purified by chromatography on silica with 2:1 iso- hexane:ethyl acetate as eluent to give (+/-)-trans -l-hydroxy-2-phthalimido indan as a pale yellow amorphous powder (17.7g, 63%). NMR 2.8(1H, dd), 3.15(lHdd), 4.8-5.0(lH, m), 5.4(1H, d), 5.45(1H, d), 7.0-7.3(4H, m), 7.75-8.95(4H, m).
lb To a solution of (+/-) trans-l-hydroxy-2-phtha]irnidoindan (1.4g, 5.0mmol) in dry
tetrahydrofuran (20ml) was added 60% sodium hydride (300mg, 7.5mmol). The mixture was stirred at room temperature for 2 hours and then methyl iodide (0.62ml, lO.Ommol) added. The mixture was stirred for a further 2 hours and then :5% water in tetrahydrofuran (10ml) and ethyl acetate (75ml) added. The solution was washed with water, dried over magnesium
113


sulphate and evaporated to give C+/-)-trans-l-methoxy-2-phthalirnidoindan as a white solid (1.2g, 82%). NMR 2.85(1H, dd), 3.25(3H, s), 3.5(1H, dd), 4.5-4.65(lH, m), 5.55(1H, d), 7.05-7.3(4H, m), 7.85(4H, s).
A mixture of (+/-)-rtransl-methoxy-2-phthalimidoindan (850mg, 2.9mmol) and hydrazine hydrate (5ml) in ethanol was stirred at room temperature for 24 hours. The mixture was evaporated and purified by ion exchange chromatography (Dowex 50W X2 H+ form) and the title compound eluted with 50% aqueous methanol containing 3% ammonium hydroxide to give the title compound a pale yellow solid (400mg, 85%). NMR 2.8(1H, dd), 3.35(3H, s), 3.38(1H, dd),4.05-4.15(lH, m), 4.5-4.6(lH, in), 7.2-7.35(3H, m), 7.45-7.55(lH, m); m/z 164 (M+H).
Method #41
(1R.2S)- l-[(1-dimethvlethoxv)carbonylamino1-2 hydroxyindan

(lR,2S)-l-Arnmo-2-hydroxyindan (lO.Og, 67.1mmol) was dissolved in dichloromethane (550ml) and triethylamine (18.7ml, 134.2mmol). Di-tert-butyl dicarbonate (18.3g, 83,9mmol) in dichloromethane (50ml) was added and the mixture stirred at room temperature for 20 hours then evaporated. Ethyl acetate (200ml) was added, the solution washed with water, dried over magnesium sulphate and evaporated. The crude product was purified by chromatography on silica with 4:1 iso-hexane:ethyl acetate as eluent to give the tide compound as a white solid (16.1g, 96%); NMR 1.42(9H, s), 2.78(1H, dd), 3.0(1H, dd), 4.3-4.42(lH, m), 4.78-4.9(lH, m), 4.9-5.0(lH, m), 6.3(1H, d), 7.0-7.25(4H, m).
Method #42
(1R, 2R)-2- Amino-1 -methanesulphonamidoindan
114


(1R;2S)-l-Amino-2-hydroxyindan (3.0g, 20mmol) was dissolved in dry tetrahydrofuran (40ml) and txiemylamine (8.4ml, 60.0mmol) at 10°C. Methane sulphonyl chloride (5.0g, 44.0mmol) dissolved in tetrahydrofuran (10ml) was added at such a rate that the internal temperature remained below 15°C. Following the addition the mixture was stirred at room temperature for 20hours and then evaporated. To the residue was added ethyl acetate (lOOml) and the mixture washed with saturated aqueous sodium bicarbonate and then water. The organic solution was dried over magnesium sulphate and evaporated to give (1R,2S)-1-methanesulphonamido-2-methylsulphonyloxyindan as a pale yellow solid (5.7g, 93%). NMR: 3.0-3.35(2H, m), 3.1(3H, s), 3.25(3H, s), 5.05-5.2(1H, m), 5.3-5.4(lH, m), 7.2-7.4(4H, m), 7.85-8.0QH, m). mix 304.2 (M-H).
(lR,2S)-l-Methanesulphonamido-2-methylsulphonyloxyindan (2.0g, 6.56mmol) was dissolved in dry dimethyl acetamide (20ml). Sodium azide (1.7g, 26.2mmol) was added and the mixture heated to 90°C for 1 hour. The reaction was cooled, diluted with ethyl acetate (100ml), washed with water (6 x 50ml), dried over magnesium sulphate and filtered. 10% Palladium on activated carbon was added and the mixture stirred under a hydrogen atmosphere for 3 hours. Filtration through celite followed by evaporation gave the title compound as a pale green solid (1.25g, 83%). NMR (CDC13): 1.68(2H, broad s), 2.67(1H, dd), 3.2(3H, s), 3.23(1H, dd), 4.5-4.6(lH, m), 4.6-4.8(lH, m), 7.15-7.35(4H, m); m/z 227.4 (M+H).
Method #43
25 (1R.2S)-2-Ammo-l-[(1,1-dimethvlethoxv)carbonvlamino1indan
115


NH2

5
(lR,2S)-l-[(l,l-Dimemylethoxy)carbonylamino]-2-hydroxyindan (Method #41, 7.5g, 30.1mmol) was dissolved in dry tetrahydrofuran (90ml) and triethylamine (6.3ml, 45.0mmol). Methanesulfonyl chloride (3.78g, 33.0mmol) dissolved in dry tetrahydrofuran (10ml) was added and the mixture stirred at room temperature for 20 hours. The mixture was evaporated and ethyl acetate (250ml) added. After washing with water and drying over magnesium sulphate the organic solution was evaporated to (li?,2S)-l-[(l,l-
dimemylethoxy)carbonylaniino]-2-methanesulphonyloxyindan as white solid (9.7g, 98%). NMR1.45(9H, s), 3.05-3.35(2H, m), 3.18(3H, s), 5.15-5.25(1H, m), 5.28-5.38(lH, m), 7.15-10 7.22(4H, m), 7.45(1H, d).
(lR,2S)-l-[(l,l-Dimemylemoxy)carbonylarniiio]-2-methanesulphonyloxyindan (3.5g, 10.7mmol) was dissolved in dry dimethyl acetamide (50ml). Sodium azide (3.5g,' 53.9mmol) • was added and the mixture heated to 90°C for 3 hours. The reaction was cooled, diluted with ethyl acetate (150ml), washed with water (6 x 50ml) and dried overmagnesium sulphate. 10% Palladium on activated carbon was added and the mixture stirred under a hydrogen atmosphere for 4 hours. Filtration through celite followed by evaporation gave the title compound as a white solid (2.6g, 98%). NMR: 1.45(9H, s), 2.5(1H, dd), 3.0QH, dd), 3.2-3.45(3H, m), 4.5-4.6(lH, m), 7.0-7.25(5H, m).
20

116

To a solution of (lR,2S)-l-[(l ,l-dimethylemoxy)carbonylamino]-2-hydroxyindan (Method #41, 7.0g, 28.1mmol) in dichloromethane (50ml) was added 3,4-dihydro-2H-pyran (4.7g, 56.2mmol) and pyridinium toluene-4-sulphonate (lOOmg). The mixture was stirred for 4 hours, diluted with ethyl acetate (200ml), washed with water (2 x 50ml), dried over magnesium sulphate and evaporated to give (lR,2S)-l-[(l,l-dimethylethoxy)carbonylamino]-2-[(tetrahydropyran-2-yl)oxy]indan as a white solid (8.9g, 96%). NMR1.25-1.85(6H, m), 1.45(9H, d), 2.85-3.1(2H, m), 3.35-3.5(lH, m), 3.68-3.9(lH, m), 4.35-5.1(3H, m), 6.8(1H, dd),7.1-7.3(4H,m).
10 (IR, 2S)-1 -[(1,1 -Dimethylemoxy)carbonylamino]-2-[(tetrahydropyran-2-yl)oxy]indan
(4.0g, 12.0mmol) was dissolved in dry DMA (25ml) at 10°C and 60% sodium hydride (575mg, 14.4mmol) added. The mixture'was stirred at room temperature for 30 minutes and then methyl iodide (2.0g, 14.4rnmol) added after which the reaction was stirred for a further 3 hours at room temperature. The mixture was diluted v/ith ethyl acetate (50ml), washed with
l5 water (6 x 50ml), dried over magnesium sulphate and evaporated to give (li?,25)-l-{iV-[(l,l-dimethylemoxy)]carbonyl-A^-memyl-amino}-2-(tetrahydropyran-2-yl)oxyindan as an oil (4.1g, 98%). NMR 1.4-1.9(6H, m), 1.5(9H, d), 2.7(3H, dd), 2.85-3.3(2H, m), 3.47-3.6(lH, m), 3.72-4.0(lH, m), 4.7-5.0(2H, m), 5.5-5.84(lH, m), 7.15-7.35(4H, m); m/z 348.6 (M+H).
20 To a solution of (lR,2S)-l-{N-[(l,l-dimethylethoxy)carbonyl]-N-methylamino}-2-
(tetrahydropyran-2-yl)oxyindan (4.0g, 11.5mmol) in methanol (50ml) was added toluene-4-sulphonic acid (lOOmg) and the mixture stirred at room temperature for 2 hours. Saturated aqueous sodium bicarbonate (50ml) and water (10ml) was added and the mixture extracted with ethyl acetate. The organic extract was washed with water, dried over magnesium sulphate and evaporated to give (lR,2S)-l-{N-[(l,l-dimethylethoxy)carbonyl]-N-memylamino}-2-hydroxyindan as an oil (3.0g, 100%). NMR 1.45(9H, s), 2.6(3H, s), 2.75(lH,dd), 3.05QH, dd), 4.4-4.57(lH,m), 5.0:5.12(lH, m), 5.34(1H, dd), 7.03-7.33(4H, m).
To a solution give (lR,2S)-l-{N-[(l,l-dimemylethoxy)carbonyl]-N-methylamino}-2-30 hydroxykvdan (3.Og, 11.4 mmol) in dry tetr&hydxofuraa (40mmol) was added teiethylamme (2.4ml, 17.1mmol) and methane sulphonyl chloride (1.44g, 12.55mmol). The mixture was stirred at room temperature for 1 hour, evaporated and diluted with ethyl acetate (100ml). The organic solution was washed with saturated aqueous sodium bicarbonate and then water, dried

over magnesium sulphate and evaporated to give a pale yellow syrup. The crude material was purified by silica chromatography with 4:1 wo-hexanerethyl acetate as eluent to (lR,2S)-l-{N-[(l,l-dimemylethoxy)carbonyl]-N-methyl-amino}-2-rriethanesulphonyloxyindan as a clear colourless syrup (3.1g, 80%). NMR (CDC13): 1.54(9H, s), 2.7(3H, d), 3.0(3H, s), 3.16-3.42(2H, m), 5.35-5.51(lH, m), 5.78(1H, dd), 7.2-7.35(4H, m); m/z 342.5 (M+H),
(1R, 2S)-1 - {N-[( 1,1 -Dimethylethoxy)carbonyl] -N-methyl-amino} -2-
methanesulphonyloxyindan (3.0g, 8.8mmol) was dissolved in dry DMA (30ml) and sodium
azide (2.3g, 35.2mmol) added. The mixture was heated to 90°C for 6 hours, cooled and
diluted with ethyl acetate (100ml). The solution was .washed with water (6 x 50ml), dried over
magnesium sulphate and filtered. 10% Palladium on activated carbon was added and the
mixture stirred under a hydrogen atmosphere for 4 hours. The mixture was filtered,
evaporated and purified by silica chromatography with 10% methanol in dichloromethane to
give (lR,2S)-2-amino-l-{Af-[(l,l-dimethylylethoxy)]carbonyl-N-menthyl-amino}indian as an oil
(1.2g, 55%). NMR 1.36-1.56(9H, m), 2.6(3H, s), 2.7-2.87(lH, m), 3.2-3.35(lH, m), 4.37-4.54(1H, m), 5.4-5.7(lH, m), 6.93-7.1(lH, m), 7.12-7.5(4H, m); m/z 263.48 (M+H).

25

5-Carboxy-2,3-Dichloro-4H-thieno[3,2-b]pyrrole (Method #9, 472mg, 2.0 rnmol), (1R, 2S)-2-amino-1 - {N-[( 1,1 -dimethylethoxy)] carbony l-N'-methyl-amino} indan (524mg, 2.0mmol), DffEA (0.348ml, 2.0mmol) and HOBT (270mg, 2.0mmol) was stirred in dichloromethane (10ml) at room temperature for 2 minutes. EDAC (480mg, 2.5mmol) was added and the mixture stirred at room temperature for 20 hours. The reaction was evaporated, ethyl acetate (50ml) added and washed with water. The organic phase was dried over magnesium sulphate and evaporated to give the title compound as a pale brown foam (900mg, 94%). NMR 1.2-1.45(9H, m), 2.77(3H, s), 2.9-3.26(2H, m), 4.7-4.94(lH, m), 5.5-5.8(lH, m), 6.9-7.34(5H, m), 8.55-8.73(lH, m), 12.25(1H, broad s); m/z 480.3/482.1 (M+H).

PCT/SP1/M880
Example 155
The following illustrate representative pharmaceutical dosage forms containing the compound of formula (I), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof (hereafter compound X), for therapeutic or prophylactic use in humans:-

(a): Tablet I mg/tablet
Compound X 100
Lactose Ph.Eur 182.75
Croscarmellose sodium 12.0
Maize starch paste (5% w/v paste) 2.25
Magnesium stearate 3.0

(b): Tablet H mg/tablet
Compound X 50
Lactose Ph.Eur 223.75
Croscarmellose sodium 6.0
Maize starch 15.0
Polyvinylpyrrolidone (5% w/v paste) 2.25
Magnesium stearate 3.0

(c): Tablet HI mg/tablet j
Compound X 1.0
Lactose Ph.Eur 93.25
Croscarmellose sodium 4.0
Maize starch paste (5% w/v paste) 0.75
Magnesium stearate 1.0
118

WO 02/2052)

PCT/SE&W)1880

- 1

(d): Capsule mg/capsule
Compound X 10
Lactose Ph.Eur 488.5
Magnesium stearate 1.5

(e): Injection I (50 mg/ml)
Compound X 5.0% w/v
1M Sodium hydroxide solution 15.0% v/v
0.1M Hydrochloric acid (to adjust pH to 7.6)
Polyethylene glycol 400 4.5% w/v
Water for injection to 100%

(f): Injection II 10 mg/ml
Compound X 1.0% w/v
Sodium phosphate BP 3.6% w/v
0.1M Sodium hydroxide solution 15.0% v/v
Water for injection to 100%

(g): Injection HI (lmg/ml,buffered to pH6)
Compound X 0.1% w/v
Sodium phosphate BP 2.26% w/v
Citric acid 0.38% w/v
Polyethylene glycol 400 3.5% w/v
Water for injection to 100%
Note
The above formulations may be obtained by conventional procedures well known in the pharmaceutical art. The tablets (a)-(c) may be enteric coated by conventional means, for example to provide a coating of cellulose acetate phthalate.

i on

wherein:

wherein R and R5 are independently selected from hydrogen, halo, nitro, cyano, hydroxy, fluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, amino, carboxy,

(heterocyclic group)C1-6allcyl; wherein R1 may be optionally substituted on carbon by one or more groups selected from P and wherein if said heterocyclic group contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R;
R2 is selected from hydrogen, halo, nitro, cyano, hydroxy, fluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto,


which is optionally substituted by a group V ;
F is Ci-6alkylene optionally substituted by one or more Q or a direct bond;
H is selected from aryl, C3-8cycloalkcyl and heterocyclic group; wherein H may be • optionally substituted on carbon by one or more groups selected from S and wherein if said heterocyclic group contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from T;
R3 is hydrogen or C1-6alkyl;
n is selected from 0-4; wherein the values of R1 may be the same or different; and wherein the values of R3 may be the same or different;
P, S and Q are independently selected from halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, ureido,

3 independently substituted on carbon by one or more groups selected from V and wherein if said heterocyclic group contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from U;
122

V is selected from halo, nitro, cyano, hydroxy, trifiuorornethoxy, trifluoromethyl, amino, carboxy, carbamoyl, mercapto, sulphamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, dieemylamino,N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N-dimethylcarbamoyl, " N,N-diethylcarbamoyl, N-memyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulphinyl, ethylsulphinyl, mesyl, ethylsulphonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulphamoyl, N-ethylsulphamoyl, N,N-dimefliylsulphamoyl, N,N-diethylsulphamoyl, N-methyl-N-euiylsulphamoyl, morpholino, morpholinocarbonyl, N- benzylcarbamoyl, and 4-hydroxypiperidinocarbonyl;
R, T and U are independently selected from C1-4allcyl, C1-4alkanoyl, C1-4alkylsulphonyl, C1-4alkoxycarbonyl, carbamoyl, N-(C1-4alkyl)carbamoyl, N,N-(C1-4alkyl)carbamoyl, phenyl, benzyl, benzyloxycarbonyl, benzoyl and phenylsulphonyl wherein R, T and U may be optionally and independently substituted on carbon by one or more groups selected from V;
or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof; with the provisos:
i) when -X-Y-Z- is -S-CH=CH-, R2-(CR1R3),,- cannot be amino, l-phenyl-5-methyl-lH-l,5-benzodiazepine-2,4(3H,5H)dion-3-yl, l-methyl-5-phenyl-2-oxo-2,3-dihydro-lH-benzo(E)(l,4)diazepin-3-yl, 2-(4-phenyl-l,2,5,6-tetrahydropyrid-l-yl)ethyl, 3-(4-0 phenyl-1,2,5,6-tetrahydropyrid-1 -yl)propyl, 2-(4-phenylpiperazin-1 -yl)ethyl, 2-(N-memylarnino)ethyl, 2-morpholinoethyl or 2-(N-memyl-Ar-benzylarriino)ethyl; ii) when -X-Y-Z- is -CH=CH-S-, R2-(CR1R3)n- cannot be amino or l-methyl-5-phenyl-2-oxo-2,3-dihydro-lH-benzo(E)(l,4)diazepin-3-yl;
iii) when -X-Y-Z- is -CH=C(SO2NH2)-S-, R2(CR1R3),,- cannot be methyl or isobutyl; and : iv) when -X-Y-Z- is as initially defined, n is 1, R1 is arylmethyl, substituted arylmethyl, (heterocyclic group)methyl and substituted (heterocyclic group)methyl and R3 is hydrogen then R2 is not a group -C(=G)-A or a group -CH(OH)-C(=0)-A in which A is NRdRd, -NRaCH2CH2ORa, or
123

PCT,5E6£'{HS»£fi=^
123


each Ra and Rb is independently hydrogen or -C1-C8alkyl;
each Rd is independently hydrogen, C1-C8alkyl, C1-C8alkoxy, aryl, substituted aryl,
heteroaryl, or substituted heteroaryl;
each Rc is independently hydrogen, -C(=O)ORa, -ORa, -SRa, or -NRaRa; and each n is
independently 1-3, and
X1isNRa,-CH2-,OorS.
2. A compound of formula (I) as claimed in claim 1, wherein:
-X-Y-Z- is selected from -S-CR4=CR5- or -CR4=CR5-S-;
10 wherein R4 and R5 are independently selected from hydrogen, halo, nitro, cyano, hydroxy,
. fluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl,
mercapto, sulphamoyl, ureido, C1-6alkyl, C2.6alkenyl, C2-6alkynyl, C1-6alkoxy, C1-6alkanoyl,
C1-6alkanoyloxy, N-(C1-6alJkyl)amino,N,NC1-6alkyl^amino, C1-6alkanoylarnino,
N-(Ci-6alkyi)carbamoyl, N;N-(C1-6alkyl)2carbamoyl, C1-6allcylS(O)a wherein a is 0 to 2,
15 C1-6alkoxycarbonyl, C1-6alkoxycarbbnylamino, N(C1-6alkyi)suiphamoyi,
N,N-(C1-6alkyl)2Sulphamoyl, C1-6alklsulphonylamino and
C1-6alkylsulphonyl-N-(C1-6alkyl)arnino;
n is 0; .
20
R~ is a group -E-F-G-H; wherein E, F and G are each a direct bond;
H is a C3-12cycloaIkyl which is optionally fused to a benz ring wherein H may be optionally substituted on carbon by one or more groups S which are independently selected from halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, ureido, C1-6alkyl, C2_6alk:enyl, C2_6alkynyl, C1-6alkoxy, C1-6alkanoyl, C1-6allcanoyloxy, N-(C1-6salky^amino, N,N-(C1-6aIkyl)2aiiiinol C1-6aIkanoylarnino, N(C1-6aIkyl)carbarnoyl, N,N-(C1-6alkyl)2carbamoyl, N-(C1-6alkyl)-N-(C1.6arkoxy)carbamoyl, C1-6alkylS(O)a wherein a is 0 to 2, C1-6alkoxycarbonyl, C1-6aIkoxycarbonylamino, N-(C1-6aIkyl)sulphamoyl,

N,N-(-C1-6alkyl)2sulpham.oyl, C1-6alkylsulphonylamino, C1-6allcylsulphonyl-N-(C1-6alkyl)aminoJ C3.8cycloalkyl, aryl and heterocyclic groups; wherein S may be optionally substituted on carbon by one or more groups selected from V;
V is selected from halo, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl,. amino, carboxy, carbamoyl, mercapto, sulphamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, memylamino, ethylamino, dimemylamino, diethylarnino, N"-memyl-N-emylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl,N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulphinyl, ethylsulphinyl, mesyl, ethylsulphonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulphamoyl, N-ethylsulphamoyl, N;N-drmethylsiilphamoyl,N,N-diethylsulphamoyl, N-methyl-N-emylsulphamoyl, morpholino , morpholinocarbonyl, N- benzylcarbamoyl, and 4-hydroxypiperidinocarbonyl; or a pharmaceutically acceptable salt thereof.
3. A compound of formula (I) as claimed in claim 1 wherein:
-X-Y-Z- is selected from -S-CR4=CR5- or -CR4=CR5-S-;
wherein R4 and R5 are independently selected from hydrogen, halo, nitro, cyano, hydroxy, fluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, ureido, C1-6alky!, C2-6alkenyl, C2-6alkynyI, C1-6alkoxy, C1-6alkanoyl, C1-6alkanoyloxy, N-(C1-6alkyl)amino, N,N(C1-6alkyl)amino, C1-6alkanoylamino, N-(C1-6alkyl)carbamoyl,N,N-(C1-6alkyl)2carbamoyl, C1-6alkylS(0)a wherein a is 0 to 2, C1-6alkoxycarbonyl, C1-6alkoxycarbonylamino, N-(C1-6aIkyI)sulphamoyl, N,N-(C1-6alkyl)2Sulphamoyl, C1-6alkylsulphonylanrino and C1-6alkylsulphonyl-iV-(C1-6alky I) amino;
n is 0;
R2 is a group -E-F-G-H;
wherein E, F and G. are each a direct bond; and
H is a cyclic amide of formula

125

in which k is 0, 1,2 or 3 and 1 is 0,1, 2 or 3 such that the sum of k and 1 is 2 or 3 and wherein one of the carbon atoms governed by k or 1 may be replaced by. sulphur and wherein H is optionally substituted on carbon by one or more-groups selected from S and may be independently optionally substituted on nitrogen by a group selected from T;
S is selected from halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy,

C3.gcycloalkyl, aryl and heterocyclic group; wherein S may be optionally and independently substituted on carbon by one or more groups selected from V and wherein if said heterocyclic group contains an -NH- moiety that nitrogen may be optionally substituted by a group selected fromU;

benzyl, benzyloxycarbonyl, benzoyl and phenylsulphonyl wherein R, T and U may be optionally and independendy substituted on carbon by one or more groups selected from V;
V is selected from halo, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, carboxy, carbamoyl, mercapto, sulphamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimemylamino, daemylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-diimethylcarbamoyl, N, N-diefhylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, memylsmphinyl, ethylsulphinyl, mesyl, ethylsulphonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulphamoyl, N-ethylsulphamoyl, N,N-dimethylsulphamoyl, N,N-diethylsulphamoyl, N-methyl-N-ethylsulphamoyl, morpholino, morpholinocarbonyl, N- benzylcarbamoyl and 4-hydroxypiperidinocarbonyj ; or a pharmaceuticaliy acceptable salt or an in vivo hydrolysable ester thereof.
4. A compound of formula (I) as claimed in claim 1 wherein:
-X-Y-Z- is selected from -S-CR4=CR5- or -CR4=CR5-S-;

• wherein R4 and R5 are independently selected from hydrogen, halo or C1-6alkyl.
nis 1;
R1 is hydrogen or arylC1-6alkyl;
R" is selected from a group -E-F-G-H;
wherein E, F and G are each a direct bond;
H is an unsaturated five membered heterocyclic group containing at least one nitrogen atom and one or two ring atoms selected from oxygen and sulphur and wherein H may be optionally substituted on carbon by one or more groups S which are independently selected from halo, nitro, cyano, hydroxy, trifluoromethyl, uifluoromethoxy, amino, carboxy,

R3 is hydrogen or C1-6allcyl; or a pharmaceutically acceptable salt thereof.
5. A compound of formula (I) as claimed in claim 1 wherein:
-X-Y-Z- is selected from -S-CR4=CR5- or -CR4=CR5-S-; wherein R4 and R5 are independently selected from hydrogen, halo or C1-6alkyl.
n is 0;
R2 is a group -E-F-G-H;
•wherein E is a direct bond;.
F is methylene;
wherein G is -C(0)NRa-, wherein Ra is selected from hydrogen or C1-6allcyl which is optionally substituted by a group V ;
H is aryl which may be optionally substituted on carbon by one or more groups selected from S;
S is selected from halo, nitro, cyano, hydroxy, trifluoromethyl, trrfluoromethoxy, amino,carboxy, carbamoyl, mercapto, sulphamoyl, ureido,
127


C3-8'cycloaIkyl, aryl and heterocyclic group; wherein S may be optionally and independently substituted on carbon by one or more groups selected from V ;
V is selected from halo, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, carboxy, carbamoyl, mercapto, sulphamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-memyl-N-ethylarnino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-memyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulphinyl, ethylsulphinyl, mesyl, ethylsulphonyl, inethoxycarbonyl, ethoxycarbonyl, N-methylsulphamoyl, N-ethylsulphamoyl, N,N-dimethylsulphamoyl, N,N-dietiylsulphamoyl, 7V-methyl-iV-ethylsulphamoyl, morpholino, morpholinocarbonyl, N- benzylcarbamoyl, and 4-hydroxypiperidinocarbonyl; or a pharmaceutically acceptable salt thereof.
6. A compound selected from
2,3-dichloro-5-[N-(2-phenoxyemyl)carbamoyl]-4H-tideno[3,2-b]pyrrole;
2,3-dichloro-5-{N[2(2-thienyl)emyl]carbamoyl}-4H-thieno[3,2-b]pyrrole;
2,3-dichloro-5- {N[2-(2-methoxyphenyl)ethyl]carbamoyl }-4H-thieno[3,2-b]pyrrole;
2,3-dichloro-5-[N-(2-phenyl-l-cyclopropyl)carbamoyl]-4H-thieno[3,2-b]pyimole;
2,3-dichloro-5-{N-[2-(4-fluorophenyl)emyl]carbamoyl}-4H-thieno[3,2-b]pyrrole;
2,3-dichloro-5-[N-(N-phenylcarbamoylmemyl)carbamoyl]-4H-thieno[3,2-b]pyrrole;
2,3-dichloro-5-(N-{2-[(2-pyridyl)aromino]ehtyl}carbamoy)-4H-thieno[3,2-b]pyrrole;
2,3-dichloro-5-{N[2-(N-memyLmemanesulphonaimido)-1-(thiazol-2-yl)ethyl]carbamoy}-4H-
tnieno[3,2-b]pyrrole;
2,3-dichloro-5- {N-[2-(thiomorpholino)ethyl]carbamoyl} -4H-thieno [3,2-b]pyrrole;
5-[N-(benzoylmemyl)carbamoyI]-2,3-dachloro-4H-thieno[3,2-b]pyrrole;
3-chloro-5-[N-(N-phenylcarbamoylmemyl)carbamoyl]-4H-thieno[3,2-b]pyrrole;
3-chloro-5- {N-[2-(thiomorphoIino)ethyl]carbamoyl} -4H-thieno [3,2-b]pyrroIe;
3-chioro-5- {N- [2-(N-methyknethanesulphonamido)-1 -(thiazol-2-yl)ethyl]carbamoyl} -4H-
tbieno[3,2-b]pyrrole;

or a pharmaceuticaUy acceptable salt thereof.
7. A pharmaceutical composition which comprises a compound of the formula (I) as claimed in any one of claims 1-6, or a pharmaceuticaUy acceptable salt or in vivo hydrolysable ester thereof, as defined hereinbefore in association with a pharmaceutically-acceptable diluent or carrier.

Dated this 5th day of February m 2003. [JAYANTA PAL]
Of REMFRY & SAGAR
ATTORNEY FOR THE APPLICANTS
135

Documents

Name	Date
191-MUMNP-2003-CLAIMS(6-2-2003).pdf	2018-08-08
191-MUMNP-2003-CLAIMS(GRANTED)-(19-4-2007).pdf	2018-08-08
191-MUMNP-2003-CORRESPONDENCE(IPO)-(18-7-2007).pdf	2018-08-08
191-MUMNP-2003-DESCRIPTION(COMPLETE)-(6-2-2003).pdf	2018-08-08
191-MUMNP-2003-DESCRIPTION(GRANTED)-(19-4-2007).pdf	2018-08-08
191-MUMNP-2003-FORM 1(6-2-2003).pdf	2018-08-08
191-MUMNP-2003-FORM 2(COMPLETE)-(6-2-2003).pdf	2018-08-08
191-MUMNP-2003-FORM 2(GRANTED)-(19-4-2007).pdf	2018-08-08
191-MUMNP-2003-FORM 2(TITLE PAGE)-(6-2-2003).pdf	2018-08-08
191-MUMNP-2003-FORM 2(TITLE PAGE)-(GRANTED)-(19-4-2007).pdf	2018-08-08
191-MUMNP-2003-FORM 3(6-2-2003).pdf	2018-08-08
191-MUMNP-2003-FORM 5(6-2-2003).pdf	2018-08-08
191-MUMNP-2003-WO INTERNATIONAL PUBLICATION REPORT(6-2-2003).pdf	2018-08-08
191-mumnp-2003-correspondence(ipo)-(19-04-2007).pdf	2007-04-19
191-mumnp-2003-correspondence(30-12-2005).pdf	2005-12-30
191-mumnp-2003-form 3(30-12-2005).pdf	2005-12-30
191-mumnp-2003-petition under rule 137(30-12-2005).pdf	2005-12-30
191-mumnp-2003-petition under rule 138(30-12-2005).pdf	2005-12-30
191-MUMNP-2003-CANCELLED PAGES(21-11-2005).pdf	2005-11-21
191-mumnp-2003-claims(granted)-(21-11-2005).doc	2005-11-21
191-mumnp-2003-claims(granted)-(21-11-2005).pdf	2005-11-21
191-mumnp-2003-form 1a(21-11-2005).pdf	2005-11-21
191-mumnp-2003-form 2(granted)-(21-11-2005).doc	2005-11-21
191-mumnp-2003-form 2(granted)-(21-11-2005).pdf	2005-11-21
191-MUMNP-2003-SPECIFICATION(AMENDED)-(21-11-2005).pdf	2005-11-21
191-mumnp-2003-form 18(22-02-2005).pdf	2005-02-22
191-mumnp-2003-power of authority(23-06-2003).pdf	2003-06-23
191-mumnp-2003-form 1a(06-02-2003).pdf	2003-02-06
191-mumnp-2003-form-pct-ipea-409(06-02-2003).pdf	2003-02-06
191-mumnp-2003-form 3(05-02-2003).pdf	2003-02-05

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