NZ333696A - Amidinoindoles, amidinoazoles, and analogs thereof as inhibitors of trypsin like protease enzymes like thrombin and Xa factor - Google Patents
Amidinoindoles, amidinoazoles, and analogs thereof as inhibitors of trypsin like protease enzymes like thrombin and Xa factorInfo
- Publication number
- NZ333696A NZ333696A NZ333696A NZ33369697A NZ333696A NZ 333696 A NZ333696 A NZ 333696A NZ 333696 A NZ333696 A NZ 333696A NZ 33369697 A NZ33369697 A NZ 33369697A NZ 333696 A NZ333696 A NZ 333696A
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- phenyl
- methyl
- substituted
- alkyl
- amidinoindole
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- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
- C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
- C07D333/58—Radicals substituted by nitrogen atoms
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
- C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D463/00—Heterocyclic compounds containing 1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbacephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D463/02—Preparation
- C07D463/06—Preparation from compounds already containing the ring or condensed ring systems, e.g. by dehydrogenation of the ring, by introduction, elimination or modification of substituents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Abstract
Amidinoindoles and amidinoazoles of the formula 1: W and W3 are CH or N, W1 and W2 are C, CH and N, provided 0-2 of W-W3 are N; D and Da is H, C1-4 alkoxy, CN, C(=NR7)NR8R9, NHC(=NR7)NR8R9, NR8CH(=NR7), C(O)NR8R9 and (CH2)tNR8R9 provided one of D and Da is H and one W-W3 is N, Ja and Jb is substituted by -(CH2)n-Z-A-B. These compounds are used as inhibitors of factor Xa and thrombin.
Description
New Zealand Paient Spedficaiion for Paient Number 333696
s>
Intellectual Property Office of New Zealand Page: 1 of 1
IP Summary Report Date: 09 June 2000
Time: 10:11:56 (iprip02 2.00.23)
(51) Classification: IPC Edition: IPC Status: 70 333696
A61K31/395,
C07D209/08, CMont Ref.
Accepted Version number: 5
• IP type: Patent PCT Inward
C07D209/14, OP662/9001/M JH/lp
C07D209/16,
C07D231/12,
C07D231/56,
C07D401/06,
C07D401/12,
C07D403/10,
C07D471/04
(86) International Application number: US97/11325 Date actions completed:
(87) WO Publication number: 98/01428 Application Accepted 09 June 2000 Elected: Y Next renewal date: 30 June 2001 (22) NZ Filing date: 30 June 1997
Date entered National phase: 11 January 1999
(30) Priority Data: (31) 96 676766 (32) 08 July 1996 (33) US
(30) Priority Data: (31)97 49519 (32) 13 June 1997 (33) US
(71) Applicant: DU PONT PHARMACEUTICALS COMPANY,
1007 Market Street, Wilmington, Delaware 19898, United States of America
(72) Inventors: Dominguez, Celia
Han, Qi
Duffy, Daniel Emmett Quan, Mimi Lifen Wexler, Ruth Richmond Rossi, Karen Anita Park, Jeongsook Maria Contact: CALLINAN LAWRIE, PO Box 43, Matamata, New Zealand
Primary Examiner: ERIKA ANDERSON Journal: 1452
Office title: Amidinoindoles, amidinoazoles, and analogs thereof as inhibitors of trypsin like protease enzymes like thrombin and Xa factor
(54) Applicant title: Amidinoindoles, amidinoazoles, and analogs thereof as inhibitors of factor Xa and of thrombin Drawing:
2 I '-J
.W2„
D4 W
** End of report"
title
AMIDINOINDOLES. AMIDINOAZOLES. AND ANALOGS THEREOF AS INHIBITORS OF FACTOR Xa AND OF THROMBIN
FIELD OF THE INVENTION
This invention relates generally to amidinoindoles, amidinoazoles, and analogs which are inhibitors of trypsin-like serine protease enzymes, especially thrombin and factor Xa, pharmaceutical compositions containing the same, and 10 methods of using the same as anticoagulant agents for treatment and prevention of thromboembolic disorders.
BACKGROUND OF THE INVENTION EP 0,540,051 and JP 06227971 describe a series of 15 compounds useful as factor Xa inhibitors or to treat influenza based on the formula:
r! f?2 r3
nh. „ . , > , . v
V4" J /~X~<CH2)r_Y
NHj '
R4
wherein A is an alkylene linker optionally substituted by hydroxyalkyl, carboxyl, alkoxycarbonyl, alkoxycarbonylalkyl, 20 or carboxyalkyl, X is a bond, O, S, or carbonyl, n is 0-4, and Y is an optionally substituted carbocycle or heterocycle. The present invention does not involve compounds containing the above noted combination of A, X, n, and Y.
Tidwell et al. Thrombosis Research 1981, 24, 73-83, 25 describe factor Xa inhibitory activity of a series of aromatic mono- and di-amidines. The amidino aromatic moieties are include indole, indoline, benzofuran and benzimidazole.
Tidwell et al, J. Med. Chem. 1983, 26, 294-298,
report a series of amidinoindoles of the formula:
xd-
X
wherein one of R1 and R?' is amidine, X may be methyl or ethyl when Y and Z are H, Y may be C(0)CH2CH3 when X and Z are H, and
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PCT/13S97/1132S
Z may be CHO, COCH-), COCF3, or C(0)Ph when X and Y are H. Thrombin inhibition constants are given for these compounds.
EP 0,655,439 discuss Ilb/IIIa antagonists of the formula:
wherein the core ring is a heterocycle, B is a basic group, A is an acidic group, Ri is an optional substituent, R2 is an optional substituent, and La and Lb are linkers which may optionally be substituted. The present invention does not contain the La-A group.
Fairley et al, J. Med. Chem. 1993, 36, 1746-1753, illustrate a series of bis(amidinobenzimidazoles) and bis(amidinoindoles) of the formulae:
wherein R is an amidine or derivative thereof and X is an alkylene, alkenylene, phenylene or phenylenedimethylene linker. The DNA binding capabilities of these compounds were studied and reported, but inhibition of trypsin-like enzymes was not discussed.
WO 95/08540 depicts bis(amidinobenzimidazolyl)alkanes of the formula:
wherein Z is an amidine derivative and R and R1 are selected from a variety of substituents including hydroxyl, amino, and alkoxy. These compounds are said to be useful in the treatment of viruses, specifically HIV. No mention is made of Xa or thrombin inhibition.
Trypsin-like enzymes are a group of proteases which hydrolyzed peptide bonds at basic residues liberating either a C-terminal arginyl or lysyl residue. Among these are enzymes of the blood coagulation and fibrinolytic system required for
2
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WO 98/01428 PCT/US97/11325
hemostasis. They are Factors II, X, VII, IX, XII, kallikrein, tissue plasminogen activators, urokinase-like plasminogen activator, and plasmin. Elevated levels of proteolysis by these proteases can result in disease states. For example, 5 consumptive coagulopathy, a condition marked by a decrease in the blood levels of enzymes of both the coagulation system, the fibrinolytic system and accompanying protease inhibitors is often fatal. More specifically, proteolysis by thrombin is required for blood clotting. Inhibition of thrombin results 10 in an effective inhibitor of blood clotting. The importance of an effective inhibitor of thrombin is underscored by the observation that conventional anticoagulants such as heparin (and its complex with the protein inhibitor, antithrombin III) are ineffective in blocking arterial thrombosis associated 15 with myocardial infarctions and other clotting disorders.
However, a low molecular weight thrombin inhibitor, containing a different functionality, was effective in blocking arterial thrombosis (Hanson and Harker, Proc. Natl. Acad. Sci. U.S.A. 85, 3184 (1988).
Activated factor Xa, whose major practical role is the generation of thrombin by the limited proteolysis of prothrombin, holds a central position that links the intrinsic and extrinsic activation mechanisms in the final common pathway of blood coagulation. The generation of thrombin, the 25 final serine protease in the pathway to generate a fibrin clot, fron its precursor is amplified by formation of prothrombinase complex (factor Xa, factor V, Ca2+ and phospholipid). Since it is calculated that one molecule of factor Xa can generate 138 molecules of thrombin (Elodi, S., 30 Varadi, K.: Optimization of conditions for the catalytic effect of the factor IXa-factor VIII Complex: Probable role of the complex in the amplification of blood coagulation.
Thromb. Res. 1979, 15, 617-629), inhibition of factor Xa may be more efficient that inactivation of thrombin in 35 interrupting the blood coagulation system.
Therefore, efficacious and specific nhibitors of factor Xa or thrombin are needed as potentially valuable therapeutic agents for the treatment of thromboembolic disorders. It is
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WO 98/01428 PCT/IJS97/11325
thus desirable to discover new thrombin or factor Xa inhibitors.
SUMMARY OF THE INVENTTON
Accordingly, one object of the present invention is to provide novel amidinoindoles and analogs thereof which are useful as factor Xa or thrombin inhibitors or pharmaceutically acceptable salts or prodrugs thereof.
It is another object of the present invention to provide pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.
It is another object of the present invention to provide a method for treating thromboembolic disorders comprising administering to a host in need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.
These and other objects, which will become apparent during the following detailed description, have been achieved by the inventors' discovery that compounds of formula (I):
or pharmaceutically acceptaible salt or prodrug forms thereof, wherein D, D3, J, Ja, Jb, W, W1, W2, and W3, are defined below, are effective factor Xa or thrombin inhibitors.
I
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS [1] Thus, in a first embodiment, the present invention provides a novel compound of formula I:
4
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WO 98/01428 PCT/US97/11325
-Wl'
" 'J
.,W* «L,b
.-.Ja
D* W3 I
or stereoisomer or pharmaceutically acceptable salt form thereof wherein:
W and W3 are selected from CH and N;
W1 and W2 are selected from C, CH, and N;
provided that from 0-2 of W, W1, W2, and W3 are N;
one of D and Da is selected from H, Ci_4 alkoxy, CN,
C(=NR7)NRSR9, NHC(=NR7)NRsR9, NRflCH (=NR7) . C(0)NR8R9, and (CH2)tNR8R9- and the other is absent:
provided that if one of D and D3 is H, then at least one of W, W1, w2, and W3 is N;
one of Ja and Jb is substituted by -(CH2)n-Z-A~B;
J, Ja, and Jb combine to form an aromatic heterocyclic system containing from 1-2 heteroatoms selected from the group consisting of N, 0, and S substituted with 0-2 R1, provided that Jb can only be C or N;
J, Ja, and Jb can, alternatively, combine to form a heterocyclic ring wherein Jb is N and J and Ja are CH2 substituted with 0-1 R1;
J, Ja, and Jb can, alternatively, combine to form a heterocyclic ring wherein Jb is CH, J is NR1 and Ja is CH2 substituted with 0-1 R1;
R1 is selected from H, C1-4 alkyl, (CH2)rOR3, (CH2)rNR3R3 '<
(CH2)rC(=0)R2, (CH2)rlCH=CHKCH2)rC(«0)R2.
(CH2) rNR3C (=0) R2 , (CH2)rS02R4, (CH2) rNR3S02R4 , and (CH2)r-
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WO 98/01428 PCT/US97/11325
-membered heterocyclic system having 1-4 heteroatoms selected from N, O, and S;
R2 is selected from H, OR3, C1-4 alkyl, NR3R3', CF3, and C3-10 5 carbocyclic residue substituted with 0-2 R6;
R3 and R3' are independently selected from H, C1-4 alkyl, *nd C3-10 carbocyclic residue substituted with 0-2 R6;
R4 is selected from C1-4 alkyl, NR3R3', and C3-10 carbocyclic residue substituted with 0-2 R6;
Z is selected from CH=CH, CH( (CH2)roQICH2)mR5) .
CH { (CH2)mQ(CH2),rR5)C(0)NR3, CH { <CH2 > mC (0) (CH2)mR5a) , 15 N((CH2)qQ(CH2)mR5) , N (Q' (CH2)mR5) .
C (0) N ( (CH2 ) raQ' (CH2) mR^a) , C (O) (CH2 ) r, C(0)0(CH2)r, OC(O) (CH2)r' C(O) (CH2)rNR3(CH2)r, NR3C(0) (CH2)r,
OC (O) NR3 (CH2 1 r > NR3C (O) O (CH2) r , NR3C (O)NR3<CH2>r, S(0)p(CH2)r, S02CH2, SCH2C(0)NR3, S02NR3(CH2)r, 20 NR3S02(CH2)i, and NR3S02NR3(CH2)r;
Q is selected from a bond, 0, NR3, C(O), C(0)NR3, NR3C(0), S02, NR3S02, and S02NR3;
Q' is selected from a bond, C(O), C(0)NR3, S02, and S02NR3;
R5 is selected from H, C1-4 alkyl, C3_io carbocyclic residue substituted with 0-2 R6, and 5-10 membered heterocyclic system containing from 1-3 heteroatoms selected from the 30 group consisting of N. 0, and S substituted with 0-2 R6.
provided that when Q is S02 or NR3S02, R5 is other than H and when Q' is S02, R5 is other than H;
R5a is selected from NHR5, OR5, and R5;
A is selected from:
ben2yl substituted with 0-2 R6, phenethyl substituted with 0-2 R6,
Printed from Mimosa
XT. 'Z P 0 3
phenyl-CH= substituted with 0-2 R6,
C3-10 carbocyclic residue substituted with 0-2 R6, and 5-10 membered heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, 0, and S 5 substituted with 0-2 R6;
B is selected from:
X-Y, alkyl, C (=NR3) NR3R3, NR3C (=NR3) NR3R3,
benzyl substituted with 0-2 R6,
C3-10 carbocyclic residue substituted with 0-2 R6, and
-10 membered heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, 0, and S substituted with 0-2 R6;
A and B can, alternatively, combine to form a C9-10 carbocyclic residue substituted with 0-2 R6 or a 9-10 membered heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R6;
X is selected from C1-4 alkylene, -C(0)-, -C (O) CR3R3 ' -, -CR3R3'C(C), -S(0)p-, -S (0) PCR3R3' - , -CR3R3'S (0)p-( -S(0)2NR3-, -NR3S(0)2"» -C(0)NR3-, -NR3C(b)-, -NR3-, -NR3CR3R3'-, -CR3R3'NR3-, 0, -CR3R3'0-, and -OCR3R3' - ;
Y is selected from:
C3-10 carbocyclic residue substituted with 0-2 R6, and 5-10 membered heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, 0, and S 30 substituted with 0-2 R6;
R6 is selected from H, OH, (CH2)nOR3, halo, C1-4 alkyl, CN, NO2, <CH2)rNR3R3' , (CH2)rC(0)R3, NR3C(0)R3', NR3C (0)NR3R3', CH(=NH)NH2, NHC(=NH)NH2, S02NR3R3', CONHSO2R4, 35 NR3S02NR3R3', NR3S02-Ci-4 alkyl, and (C1-4 alkyl)-
tetrazolyl;
INTELLECTUAL PROPERTY OFFICE OF n.z.
~ 9 AUG 1339
RECFIVED
R"7 is selected from H. OH, C\-e alkyl, Ci_(, alkylcarbonyl, C1-5 alkoxy, C1-4 alkoxycarbonyl, C6.10 aryloxy. C6-10 aryloxycarbonyl, C6-10 arylmethylcarbonyl, C1-4 alkylcarbonyloxy C1-4 alkoxycarbonyl, Cg-io arylcarbonyloxy C1-4 alkoxycarbonyl, Ci_b alkylaininocarbonyl, phenylaminocarbonyl, and phenyl C1-4 alkoxycarbonyl
R8 is selected from H, C1-6 alkyl and (CH2) n-phenyl ;
R9 is selected from H, Ci-g alkyl and (CH2) r.-phenyl;
n is selected from 0, 1, 2, 3, and 4;
m is selected from 0, 1, and 2;
p is selected from C, 1, and 2;
q is selected from 1 and 2; and,
r is selected from 0, 1, 2, 3, and 4;
provided that:
(a) Z is other than CH2; and,
(b) if Z is CH( (CH2)mQ(CH2)mR5) or CH ( (CH2)mC (O) (CH2)mR5a> , then B is other than X-Y, a C3-10 carbocyclic residue or a 5-10 membered heterocyclic system.
12] In a preferred embodiment, the present invention provides compounds of formula II:
II
wherein: from 0-1 of W, W1, W2, and W3 are N;
8
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R1 is selected from H, Ci_4 alkyl, (CH2)rOR3, (CH2) rNR3R3' . (CH2)rC(=0)R2, (CH2)rNR3C(=0)R2, <CH2)rS02R4, <CH2)rNR3S02R4, and (CH2) r-5-membered heterocyclic system 5 having 1-4 heteroatoms selected from N, 0, and S;
R2 is selected from H, OR3, C1-4 alkyl, NR3R3', and CF3 ;
R3 and R3' are independently selected from H, Ci_4 alkyl, and 10 phenyl
R4 is selected from C1-4 alkyl, phenyl and NR3R3';
Z is selected from CH=Ch\ CH((CH2) mQ(CH2)mR5) , 15 CH ( (CH2 ) mQ (CH2 ) mRS) C (0) NR3 , CH { (CH2 ) mC (O) (CH2 ) mR5a) ,
N( (CH2)qQ(CH2)IBR5) , N(Q' (CH2)mR5) ,
C(0)N{ (CH2)mQ' (CH2)mR5a) , C(0), C(0)CH2, C(0)0, OC(O), C (0) (CH2) rNR3 (CH2) r, NR3C(0), 0C(0)NR3, NR3C(0)0, NR3C(0)NR3, S(0)p, S02CH2, S02NR3. NR3S02) and NR3S02NR3;
B is selected from:
X-Y, C3-6 alkyl,
benzyl substituted with 0-2 R6,
C3-10 carbocyclic residue substituted with 0-2 R5, and 25 5-10 membered heterocyclic system containing from 1-3
heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R6;
A and B can, alternatively, combine to form a C9_io carbocyclic 30 residue substituted with 0-2 R6 or a 9-10 membered heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R6; and,
R6 is selected from H, OH, (CH2)n0R3, halo, C1-4 alkyl, CN, N02, <CH2)rNR3R3' , (CH2) rC (0) R3, NR3C{0)R3', NR3C (O) NR3R3', S02NR3R3', C0NHS02R4, NR3S02NR3R3', NR3S02-C!-4 alkyl and (Ci_4 alkyl)-tetrazolyl.
9
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[3] In a more preferred embodiment, the present invention provides compounds of formula II, wherein:
J, Ja, and Jb combine to form an aromatic heterocyclic system containing from 1-2 nitrogen atoms, substituted with 0-1 R1;
J, Ja, and Jb can, alternatively, combine to form a heterocyclic ring wherein Jb is N and J and Ja are CH2 substituted with 0-1 R1;
J, Ja, and Jb can, alternatively, combine to form a heterocyclic ring wherein Jb is CH, J is NR1 and Ja is CH2 substituted with 0-1 R1;
R1 is selected from H, C1-4 alkyl, (CH2)rOR3- (CH2)rNR3R3' , (CH2)rC(=0)R2, (CH2)rNR3C(=0)R2( <CH2)rS02R4, and (CH2)rNR3S02R4;
Z is selected from CH( (CH2)mQ(CH2)mR5) ,
CH( (CH2)mQ(CH2)mR5)C(0)NR3, CH( (CH2)mC(0)
N( (CH2)qQ{CH2)mR5) . N (Q- (CH2)„,R5) ,
ClO)N( (CH2)n,QMCH2)mR5a) , C(O), C(0)CH2,
C(0) (CH2)rNR3 (CH2)r, NR3C(0). NR3C(0)NR3,
S02NR3, NR3S02, and NR3S02NR3;
A is selected from:
benzyl substituted with 0-2 R6,
C3-10 carbocyclic residue substituted with 0-2 R6, and 5-10 membered heterocyclic system containing from 1-3
heteroatoms selected from the group consisting of N, 0, and S
substituted with 0-2 R6;
B is selected from:
X-Y, C3-6 alkyl,
benzyl substituted with 0-2 R6,
(CH2)r,R5a)( S(0)2, S02CH2,
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C5-6 carbocyclic residue substituted with 0-2 R6, and 5-6 membered heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, 0, and S substituted with 0-2 Re;
X is selected from -C(0)-, -C(0)CR3R3' - , -StOJo-. -S(O)pCR3R3' -, -S(0)2NR3-, -C(0)NR3-, -NR3-, -NR3CR3R3'-, and 0;
Y is selected from:
C5-6 carbocyclic residue substituted with 0-2 R6, and
-6 membered heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, O, and 3 substituted with 0-2 R6;
R6 is selected from H, OH, (CH2)nOR3, halo, Ci-4 alkyl, CN, NO2, (CH2) rNR3R3 ' , (CH2)rC(0)R3, NR3C(0)R3', NR3C (O) NR3R3 ' , S02NR3R3', C0NHS02R4, NR3S02NR3R3', NR3S02-Ci_4 alkyl and (C1-4 alkyl)-tetrazolyl;
n is selected from 0, 1, and 2; and,
r is selected from 0, 1, and 2.
[4] In an even more preferred embodiment, the present invention provides compounds of formula II:
III
wherein:
J and Jb combine to form an aromatic heterocyclic system containing from 1-2 nitrogen atoms, substituted with 0-1
R1;
11
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J and Jb can. alternatively, form a heterocyclic ring wherein Jb is N and J is CH2 substituted with 0-1 R1;
J and Jb can, alternatively, form a heterocyclic ring wherein 5 Jb is CH and J is NR1 ;
Z is selected from C(0)N(Q'R5a) , C(O). C(0)NR3, NR3C(0). and SO2NR3
Q' is selected from C(O) and C(0)NR3;
R5 is selected from H and C1-4 alkyl;
R5a is selected from NHR5, OR5, and R5;
A is selected from:
benzyl substituted with 0-1 R6,
phenyl substituted with 0-1 R6,
piperidinyl substituted with 0-1 r6,
piperazinyl substituted with 0-1 r6, and pyridyl substituted with 0-1 r6;
B is selected from:
X-Y,
benzyl substituted with 0-1 R6,
phenyl substituted with 0-2 R6,
cyclohexyl substituted with 0-1 R6, and pyridyl substituted with 0-1 R6;
X is selected from: -C(O)-, -S{0)2~, SO2CH2, -S(0)2NR3-, -NR3-and -C(0)NR3-;
Y is selected from:
phenyl substituted with 0-2 R6, and
pyridyl substituted with 0-1 R6;
R6 is selected from H, OH, (CH2)nOR3. halo, Cj.-.4 alkyl, CN, N02, (CH2)rNR3R3'. (CH2)rClO)R3, NR3C(0)R3', NR3C{0)NR3R3',
12
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S02NR3R3', C0NHSO2R4 , KR3S02NR3R3', NR3S02-Ci-4 alkyl and (C1-4 alkyl)-tetrazolyl;
n is selected from 0, 1, and 2.
[5] In a further preferred embodiment, the present invention provides compounds of formula IV:
IV
wherein A. B, D, and 2 are as defined above.
[6] In a still further preferred embodiment, the present invention provides compo\_mds selected from:
3- ( (4-cyclohexyl)phenylair.inomethylcarbonyl)methyl-5-amidino indole
3 - (4-p-toluenesulfonyl-piperazinecarbonyl) methyl-5 -amidinoindole
3 - (4 - (2 -aminosulfonylphenyl) pyridine-2 -aminocarbonyl)methyl-5-
amidinoindole;
3- (4- [2-tetrazole]phenyl) phenylaminocarbonyl)methyl-5-amidinoindole;
3- {4-biphenylaminocarbonyl)methyl-5-amidinoindole;
3- (4- (phenylmethylsulfonyl)piperazinecarbonyl)methyl-5-amidinoindole;
3- (4-cyclohexylphenylaminocarbonyl)inethyl-5-amidinoindole;
13
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WO 98/01428 PCT/US97/11325
3- (4-benzylpiperaz inecarbonyl) methyl-5-amidinoindole;
3- (3-amidinobenzylamino (methylcarbonylmethoxy) carbonyl)methyl
5-amidinoindole;
3- (4- (2-aminosulfonyl)phenyl)phenylaminocarbonylmethyl-5-amidinoindole ;
3- {l-benzylpiperidine-4-aminocarbonyl)methyl-5-amidinoindole;
3 - (4 -phenylpipera2inecarbonyl) methyl - 5 -amidinoindole ;
3- (4-benzylpiperidinecarbonyl)methyl-5-amidinoindole;
3-{2-bromo-4-(2-
aminosulfonyl) phenylphenyl aminocarbonyl) methyl-5-cyanoindole;
3-{2-methyl-4-(2-
aminosulf onyl) phenylphenylaminocarbonyl) methyl-5-methylamino indole;
3-(2-fluoro-4-(2-
aminosul f onyl) phenylphenylaminocarbonyl) methyl-5-
amidnoindole;
3-{2-chloro-4-(2-
aminosulfonyl)phenylphenylaminocarbonyl)methyl-5-
cyanoindole;
3 - {2 - iodo-4 - (2 -aminosul fony 1) phenylphenylaminocarbonyl) methyl 5-cyanoindole;
3-{2-methyl-4-(2-
aminosulf onyl) phenylphenylaminocarbonyl) methyl-5-amidinoindole;
14
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3-{2-methyl-4-(2-(t-
butylaminosulfonyl))phenylphenylaminocarbonyl)methyl-5-amidinoindole;
3-{4-(2-aminosulfonyl)phenyl)phenylaminocarbonylmethyl-a-(methylcarboxy methyl ether)-5-amidinoindole;
3-{4-(2-aminosulfonyl)phenyl)phenylaminocarbonylmethyl-a-(benzyl)-5-amidinoindole;
3-{4-(2-trif1uoromethyl)phenyl)pyrid-2-ylaminocarbonylmethy1-5-amidinoindole;
3-{4-(2-ethylaminosulfonyl)phenyl)phenylaninocarbonylmethyl-5-
amidinoindole;
3 -(4-(2-propylaminosulfonyl)phenyl> phenyl}aminocarbonylmethyl-5 -amidino indo1e,-
2-methyl-3-{2-iodo-4-(2-
aminosulfonyl)phenyl)phenyl}aminocarbonylmethyl-5-aunidinoindole;
2-methyl-3 -{4-(2 -
aminosulfonyl)phenyl)phenyl}aminocarbonylmethyl-5-
amidinoindolp■
3-{4-(2-aminosulfonyl)phenyl)phenyl)-N-methylaminocarbonylmethyl-5-amidinoindole;
2-methyl-3-{4-(2 — t-
butylaminosulfonyl)phenyl)phenylJarainocarbonylmethyl-5-methoxyindole; and,
3 -{4-(2-N-methylaminosulf onyl)phenyl)phenyl>-N-methylaminocarbonylmethyl-5-amidinoindole;
Printed from Mimosa
' WO 98/01428 PCT/US97/11325
or a stereoisomer or pharmaceutically acceptable salt form thereof.
(7] In another further preferred embodiment, the present invention provides compounds of formula IVa:
IVa
wherein A, B, D, and Z are as defined above.
[81 In another still further preferred embodiment, the present invention provides compounds selected from:
3-{4-(2-(n-
butylaminosulfonyl)phenylphenylaminocarbonyl(methyl-5-cyano i ndo1ine;
3 — < 4 —(2-(n-
propylaminosulfonyl)phenylphenylaminocarbonyl)methyl-5 -amidinoindoline;
(-)-3-(4-(2-aminosulfonyl)phenyl)pyrid-2-25 ylaminocarbonylmethyl-5-amidinoindoline;
3-{4-(2-aminosulfonyl)phenyl)pyrid-2-ylaminocarbonylmethy1-5-amidinoindoline;
3-(4-(2-
dimethylaminosulfonyl)phenyl)phenylaminocarbonylmethyl-5-amidinoindoline;
{+)-3-{4-(2-t-butylaminosulfonyl)phenyl)pyrid-2-35 ylajninocarbonylmethyl-5-amidinoindoline;
16
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PCTYUS97/I1325
(-)- 3 -{4 -(2-t-butylaminosulfonyl)phenyl)pyrid-2-ylaminocarbonylmethy1-5-amidinoindoline;
3 -{4 -(2-aminosulfonyl)phenyl)pyrid-2-y1)aminocarbonylmethyl-5-aminocarboxyindoline;
3-{4-(2 — t-
butylaminosulfonyl)phenyl(phenyl}aminocarbonylmethyl-5-10 amidinoindoline; and,
3-{4-(2-t-butylaminosulfonyl)phenyl)pyrid-2-
yl)aminocarbonylmethyl-5-amidinoindoline;
or a stereoisomer or pharmacevcically acceptable salt form thereof.
[9] In another further preferred embodiment, the present 20 invention provides compounds of formula IVb:
IVb wherein A, B, D, and Z are as defined above.
[10] In another still further preferred embodiment, the present invention provides compounds selected from:
3 -{4 -(2-aminosulfonyl)phenyl)pyrid-2-ylaminocarbonylmethyl-6-amidinoindazole;
3-{4-(2-aminosulfonyl)phenyl)phenyl aminocarbonylmethyl-6-amidinoindazole;
17
Printed from Mimosa
3 — {4-(2-t-butyl aminosulfonyl(phenyl)pyrid-2-
ylanunocarbonyimethyl-6-amidinoindazole; and,
3 -{4 -(2-t-butylaminosulfonyl)phenyl)phenyl aminocarbonylmethy1-6-amidinoindazole;
or a stereoisomer or pharmaceutically acceptable salt form thereof.
[11] In another further preferred embodiment, the present invention provides compounds of formula IVc:
wherein D, D3, Z, A, and B are as defined above.
[12] In another still further preferred embodiment, the 20 present invention provides compounds selected from:
[4-(phenyl)phenylcarbony1]methyl-6-amidinobenz imidazole; [4-(phenyl)phenylcarbony1]methyl-5-amidinobenzimidazole;
IVc
[4-(3-aminophenyl)phenylcarbony1)methyl-6-axnidinobenzimidazole;
[4-(3-aminopheny1)phenylcarbony1]methyl-5-amidinobenzimidazole;
[4-<4-fluorophenyl)phenylcarbonyl]methyl-6-amidinobenzimidazole;
18
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[4-(4-formylphenyl)phenylcarbonyl]methyl-6-amidinobenzimidazole;
[4 -(2-aminosulfonyIpheny1)phenylcarbony1]methyl-6-5 amidinobenzimidazole;
[4-(2-tert-butylaminosulfonyIpheny1)phenylcarbonyl]methyl-6-amidinobenzimidazole;
{4 -[(2-tetrazolyl)phenyl]phenylcarbonyl)methyl-6-amidinobenzimidazole;
[4 -(2-aminosulfonylphenyl)phenylaminocarbonyl]methyl-6-amidinobenzimidazole;
[4-(2-aminosulfonylphenyl)ph Lnocarbonyl1methyl-5-
amidinobenzimidazole;
1-(4-benzylpiperidinecarbonyl)methyl-6-amidinobenzimidazole;
1-(4-benzylpiperidinecarbonyl)methyl-5-amidinobenzimidazole;
1-(4-benzylpiperidinecarbonyl)methy1-6-amidinobenzimidazole;
2-[4-(2-aminosulfonylphenyl)phenylcarbonyl]methyl-6-amidinobenzimidazole;
2-[4-(2-tert-butylanunosulfonylphenyl)phenylcarbonyl]methyl-5-azabenzimidazole;
2S-[4-(2-tert-aminosulfonylphenyl)phenylaminocarbonyl]methyl-thio-lH-imidazo(4,5-C) pyridine; and,
- [4- (2-ciminosulf onylphenyl) phenylaminocarbonyl ] methy 1-thio-
lH-imidazo(4,5-C) pyridine;
or a stereoisomer or pharmaceutically acceptable salt form thereof.
19
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[13) In a preferred embodiment, the present invention provides compounds of formula V:
H2N
W3 *\
R
V
wherein one of R and Ra is -(CH2)n-Z-A-B and the other H;
W, W2, and W3 are selected from CH and N, provided that at most one of W, W2, and W3 can be N;
J is selected from N and C-R1;
R1 is selected from H, 0, (CH2)rOR3, (CH2)rC<-0)R2, (CH=CH)C(=0)R2, (CH2)rNR3C(=0)R2, (CH2)rS02R4,
(CH2) rNR3S02R4, and (CH2)r-5-membered heterocyclic system having 1-4 heteroatoms selected from N, 0, and S;
R2 is selected from H, OR3, C1-4 alkyl, NR3R3', CF3, and C3_io carbocyclic residue substituted with 0-2 R6;
R3 and R3' are independently selected from H, C1-4 alkyl, and C3-10 carbocyclic residue substituted with 0-2 R6;
R4 is selected from OR3, C1-4 alkyl, NR3R3', and C3-10 carbocyclic residue substituted with 0-2 R6;
Z is selected from CH=CH, CH{CH2)mQ(CH2 )mR6,
CH( (CH2)lnQ{CH2)n,R5)C(0)NR3, CH (CH2) mC (O) (CH2 >mR5a,
N(CH2)qO(CH2)mR5, NO'(CH2)mR5, C (O) N ( <CH2 ) ' (CH2)mR5a) . C(O), C(0)CH2, C(0)0, 0C(0), C(O)NR3(CH2)r, NR3C(0), OCtO)NR3, NR3C(0)0, NR3C(0)NR3, S(0)p, S02CH2, S02NR3, NR3S02, and NR3S02NR3;
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Q is selected from a bond, 0, NR3, C(O), C(OJNR3, NR3C(0), SO2, t-rR3S02, and SO2NR3;
0' is selected from a bond, C(0), C(0)NR3, SOt , and SO2NR3;
R5 is selected from H, Ci_4 alkyl, C3-8 carbocyclic residue substituted with 0-2 R6, and 5-10 membered heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, 0, and S substituted with 0-2 R6, 10 provided that when Q is SO2 or NR3S02, R5 is other than H
and when Q' is SO2, R5 is other than H;
R5a is selected from NHR5, OR5, and R5;
A is selected from:
benzyl substituted with 0-2 R6,
C3-10 carbocyclic residue substituted with 0-2 R6, and 5-10 membered heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, O, and S 20 substituted with 0-2 R6;
B is selected from:
H, X-Y, NR3R3', C (=NR3 )NR3R3 ' , NR3C<=NR3)NR3R3 ' ,
benzyl substituted with 0-2 R6,
C3-10 carbocyclic residue substituted with 0-2 R6, and
-10 membered heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, 0, and S substituted with 0-2 R6;
X is selected from C1-4 alkylene, -C(O)-, -C (O) CR3R3' -, -CR3R3'C(0), -S(O) p-, -S(0)pCR3R3'-CR3R3'S(O)p-, -S(0)2NR3-, -NR3S(0)2-, -C(0)NR3-, -NR3C(0)-, -NR3-, -NR3CR3R3'-, -CR3R3'NR3-, 0, -CR3R3'0-( and -OCR3R3'-;
Y is selected from:
C3_io carbocyclic residue substituted with 0-2 R6, and
21
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WO 98/01428 PCT/US97/11325
-10 membered heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, 0, and S substituted with 0-2 R6;
R6 is selected from H, OH, (CH2)n0Ri/ halo, C1-4 alkyl, CN, NO2, (CH2) rNR3R3 ' , (CH2)rC(0)R3, NR3C(0)R3', NR3C (0) NR3R3 ' , CH(=NH)NH2, NHC(=NH)NH2, C(=0)R3, SO2NR3R3', NR3S02NR3R3' , and NR3S02-Ci_4 alkyl;
n is selected from 0, 1, 2, 3, and 4;
m is selected from 0, 1, and 2;
p is selected from 0, 1, and 2;
q is selected from 1 and 2; and,
r is selected from 0, 1, 2, 3, and 4.
(14] In another more preferred embodiment, the present invention provides compounds of formula VI;
VI
wherein one of R and Ra is - (CH2)n-Z-A-B and the other H;
W and W2 are selected from CH and N, provided that at most one of W and W2 can be N;
J is selected from N and C-R1;
R1 is selected from H, (CH2>rOR3. (CH2)rC(=0)R2,
(CH2)rNR3C(=0)R2, (CH=CH)C(=0)R2, (CH2)rS02R4, and 35 <CH2)rNR3S02R4;
22
Printed from Mimosa
R2 is selected from H, OR3, Ci_4 alkyl, NR3R3' , and CF3;
R3 and R3' are independently selected from H, Ci_4 alkyl, and 5 phenyl;
R4 is selected from OR3, C1-4 alkyl, NR3R3' , and phenyl;
Z is selected from C(0), C(0)CH2, C(0)NR3, NR3C(0), S(0)2, 10 SO2CH2, S02NR3, NR3S02, and NR3S02NK3;
A is selected from:
C3-10 carbocyclic residue substituted with 0-2 R6, and 5-10 membered heterocyclic system containing from 1-3 15 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R6;
B is selected from:
x-Y,
C3-10 carbocyclic residue substituted with 0-2 R6, and
-10 membered heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, 0, and 5 substituted with 0-2 R6;
X is selected from -C(O)-, -C(0)CR3R3' -, -CR3R3'C(0), -S(0)p-, -S(0) pCR3R3 ' - , -CR3R3'S(O)p-, -S(0)2NR3-, -NR3S(0)2-, -C (O) NR3-, -NR3-, -NR3CR3R3'-, and -CR3R3'NR3-;
Y is selected from:
C3-10 carbocyclic residue substituted with 0-2 R6, and
-10 membered heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, 0, and S substituted with 0-2 R6;
R6 is selected from H, OH, (CH2)nOR-3/ halo, C1-4 alkyl, CN, NO2, (CH2) rNR3R3 ' - (CH2)rC(0)R3, NR3C(0)R3', NR3C (O) NR3R3 ', C (=0) R3, S02NR3R3', NR3S02NR^3', and NR3S02-Ci-4 alkyl;
23
Printed from Mimosa
n is selected from 0, 1, 2, 3, and 4;
p is selected from 0, 1, and 2; and,
r is selected from 0, 1, 2, 3, and 4.
[15] In another even more preferred embodiment, the present invention provides compounds of formula VII:
vii wherein, W and W2 are selected from CH and N, provided that at most one of W and W2 can be N;
R1 is selected from H, (CH2)r0R3, (CH2) rC (=0)R2,
(CH2)rNR3C(=0)R2, (CH=CH) C (=0) R2 , (CH2)rS02R4, and <CH2)rNR3S02R4;
R2 is selected from H, OR3, C1-4 alkyl, NR3R3', and CF3;
R3 and R3' are independently selected from H, C1-4 alkyl, and
R4 is selected from OR3, C1-4 alkyl, NR3R3', and phenyl; Z is lected from C(0), C(0)CH2, CtO)NR3, S(0)2- S02CH2,
A is selected from:
C3-10 carbocyclic residue substituted with 0-2 R6, and 5-10 membered heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R6;
phenyl;
S02NR3, and NR3S02NR3;
24
Printed from Mimosa
B is selected from:
X-Y,
C3_io carbocyclic residue substituted with 0-2 R6, and 5 5-10 membered heterocyclic system containing from 1-3
heteroatoms selected from the group consisting of N, 0, and S substituted with 0-2 R6;
X is selected from -S(0)p-, -S(0)pCR3R3'- , -CR3R3'S(0)p-, 10 -S(0)2NR3-, -NR3S(0)2-, and -C{0)NR3-;
Y is selected from:
C3-10 carbocyclic residue substituted with 0-2 R6, and 5-10 membered heterocyclic system containing from 1-3 15 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R6;
R6 is selected from K, OH, (CH2>nOR3, halo, Ci_4 alkyl, CN, NO2, (CH2)rNR3R3' . (CH2)rC(0)R3, NR3C(0)R3', NR3C (O) NR3R3 ' , 20 C (=0) R3, S02NR3R3', NR3S02NR3R3', and NR3S02-Ci-4 alkyl;
n is selected from 0, 1, 2, 3, and 4;
p is selected from 0, 1, and 2; and,
r is selected from 0, 1, 2, 3, and 4.
[16] In another further preferred embodiment, the present 30 invention provides compounds selected from:
1 - (4 -benzylpiperidinecarbony1) methyl - 5 -amidinoindole ;
1- (4-benzylpiperidinecarbonyl) ethyl-5-amidinoindole;
1- (4- (3-f luoro)benzylpiperidinecarbonyl)methyl-5-
amidinoindole;
Printed from Mimosa
1-(1-(4-amidino)benz* 5-amidinoindol
- (methylacetate)aminocarbonyl)methyl-
methyl 1-(4-benzylpiperidinecarbonyl)methyl-5-amidinoindole-3
propanoate;
1-((4-benzylpiperidinecarbonyl)methyl-(3-ethanehydroxyl)-5-amidinoindole;
1-(4-benzylpiperidine-1-carbony1)methyl-3-methylcarboxylic acid- 5 -amidinoindole
1- (1-benzylpiperidine-4-aminocarbonyl) methyl - 5 - amidinoindole
1- (4-benzoylpiperidinecarbonyl)methyl-5-amidinoindole;
1- (4 -(3 -fluoro)benzylpiperazinecarbony1)methyl- 5-amidinoindole;
1-(4-phenylbenzylaminocarbonyl)methyl-5-amidinoindole;
methyl 1-(4-benzylpiperidinecarbonyl)methyl-5-amidinoindole-3 propenoate; and,
1- (4-(2-fluoro)benzylpiperidinecarbonyl)methyl-5-amidinoindole;
or a stereoisomer or pharmaceutically acceptable salt form thereof.
In a second embodiment, the present invention provides novel pharmaceutical compositions, comprising: a pharmaceutically acceptable carrier and a therapeutically
effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or prodrug form thereof.
26
Printed from Mimosa
"*r> ^ A
t; % , >~\ 1
* • *> ' >
In a third embodiment, the present invention provides novel method for treating or preventing a thromboembolic disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound of 5 formula (I) or a pharmaceutically acceptable salt or prodrug form thereof.
In a fourth embodiment, the present invention provides a novel method for treating or preventing a thromboembolic disorder, comprising: administering to a non-human patient in 10 need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or prodrug form thereof.
DEFINITIONS
'15
The compounds herein described may have asymmetric centers. Compounds of the present invention containing an asymmetrically substituted atom may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis from optically active starting materials. Many geometric isomers of olefins, C=N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms. All chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomeric form is specifically indicated.
When any variable (e.g., R®) occurs more than one time in any constituent or formula for a compound, its definition on each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-2 R6, then said group may optionally be substituted with up to two R6 and R6 at each occurrence is 35 selected independently from the defined list of possible R6. Also, combinations of substituents and/or variables are
permissible only if such combinations result compounds.
27
' 9 a'j3 1s89 received
'1
•>
a.- a\
•JO
As used herein, "C1-4 alkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, examples of which include, but are not limited to, methyl, ethyl,
27a intellectual ^operty office
OF n.z
-9 AU3 1SS9
received
WO 98/01428 PCT /US97/11325
n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, and t-butyl; "Alkenyl" is intended to include hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbon-carbon bonds which may occur in any stable 5 point along the chain, such as ethenyl, propenyl, and the like.
"Halo" or "halogen" as used herein refers to fluoro, chloro, bromo, and iodo; and "counterion" is used to represent a small, negatively charged species such as chloride, bromide, 10 hydroxide, acetate, sulfate, and the like.
As used herein, "carbocycle" or "carbocyclic residue" is intended to mean any stable 3- to 7-membered monocyclic or bicyclic or 1- to 10-membered bicyclic or tricyclic, any of which may be saturated, partially unsaturated, or aromatic. 15 Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adaroantyl, cyclooctyl,; [3.3.0]bicyclooctane. [4.3.0]bicyclononane, [4.4.0]bicyclodecane (decalin), [2.2 .2]bicyclooctane, phenyl, naphthyl, indanyl, adamantyl, or 20 tetrahydronaphthyl (tetralin).
As used herein, the term "heterocycle" or "heterocyclic system" is intended to mean a stable 5- to 7- membered monocyclic or bicyclic or 7- to 10-membered bicyclic heterocyclic ring which is saturated partially unsaturated or 25 unsaturated (aromatic), and which consists of carbon atoms and from 1 to 4 heteroatoms independently selected from the group consisting of N, O and S and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The nitrogen and sulfur heteroatoms may 30 optionally be oxidized. The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. If specifically 35 noted, a nitrogen in the heterocycle may optionally be quaternized. It is preferred that when the total number of S and 0 atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another.
28
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PCT/US97/U325
As used herein, the term "aromatic heterocyclic system" is intended to mean a stable 5- to 7- membered monocyclic or bicyclic or 7- to 10-membered bicyclic heterocyclic ring which consists of carbon atoms and from 1 to 4 heterotams 5 independently selected from the group consisting of N, 0 and S. It is preferred that the total number of S and 0 atoms in the aromatic heterocycle is not more than 1.
Examples of heterocycles include, but are not limited to, lH-indazole, 2-pyrrolidonyl, 2H,6H-1, 5,2-dithiazinyl, 2H-10 pyrrolyl, 3H-indolyl, 4-piperidonyl, 4aH-carbazole, 4H-quinolizinyi, 6H-1,2,5-thiadiazinyl, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiophenyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalonyl, carbazolyl, 4aH-carbazolyl, (3-carbolinyl, 15 chromanyl, chromenyl, cinnolinyl, decahydroguinolinyl, 2H.6H-1,5,2-d:thiazinyl, dihydrofuro[2,3-b)tetrahydrofuran, furanyl, furazanyl, imidazolidinyi, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, isobenzofuranyl, isochromanyl, isoindolinyl, isoindolyl, 20 isoquinolinyl (benzimidazolyl), isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxazolidinyl., oxazolyl, oxazolidinylperimidinyl, phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, 25 piperazinyl, piperidinyl, pteridinyl, 4-piperidonyl,
pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl, 30 quinolinyl, 4H-guinolizinyl, quinoxalinyl, quinuclidinyl, carbolinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6W-1,2,5-thiadiazinyl, thianthrenyl, thiazolyl, thienyl, thienothiazole, thienooxazole, thienoimidazole, thiophenyl, triazinyl, xanthenyl. Preferred 35 heterocycles include, but are not limited to, pyridinyl,
furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, indolyl, benzimidazolyl, lH-indazolyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, or isatinoyl. Also
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included are fused ring and spiro compounds containing, for example, the above heterocycles.
When a bond to a substituent is shown to cross the bond connecting two atoms in a ring, then such substituent may be 5 bonded to any atom on the ring. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent nay be bonded via any atom in such substituent. Combinations of substituents and/or variables 10 are permissible only if such combinations result in stable compounds.
The term "substituted", as used herein, means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the 15 designated atom's normal valency is not exceeded, and that the substitution results in a stable compound. When a substitent is keto (i.e., =0), then 2 hydrogens on the atom are replaced.
As used herein, "pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds wherein the parent 20 compound is modified by making acid or base salts thereof.
Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The 25 pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as 30 hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric,
nitric and the like,- and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic,
lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, 35 sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic,
methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.
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The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting 5 the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two;
generally, nonaqueous media like ether, ethyl acetate,
ethanol, isopropanol, or acetonitrile are preferred. Lists of 10 suitable salts are found in Remington•s Pharmaceutical
Sciences, 17th ed., Mack Publishing Company, Easton, pa, 1985, p. 1418, the disclosure of which is hereby incorporated by reference.
The phrase "pharmaceutically acceptable" is employed 15 herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or 20 complication, commensurate with a reasonable benefit/risk ratio.
"Prodrugs" are intended to include any covalently bonded carrieis which release the active parent drug according to formula (I) in vivo when such prodrug is administered to a 25 mammalian subject. Prodrugs of a compound of formula (I) are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound. Prodrugs include compounds of formula (I) wherein a 30 hydroxy, amino, or sulfhydryl group is bonded to any group that, when the prodrug or compound of formula (I) is administered to a mammalian subject, cleaves to form a free hydroxyl, free amino, or free sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, 35 formate and benzoate derivatives of alcohol and amine functional groups in the compounds of formula (I), and the like. Preferred prodrugs are amidine prodrugs wherein either D or Da is C (=NH) N (H) R10, and R10 is selected from OH, Ci_4
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aikoxy, Cg-io aryloxy. C1-4 alkoxycarbonyl, Cs-io aryloxycarbonyl. C6_:o arylmethylcarbonyl, C1-4
alkylcarbonyloxy C1-4 alkoxycarbonyl, and Cs-io arylcarbonyloxy C1-4 alkoxycarbonyl. More preferred prodrugs are where R7 is 5 OH, methoxy, ethoxy, benzyloxycarbonyl, methoxycarbonyl, and methylcarbonyloxymethoxycarbonyl.
"Stable compound" and "stable structure" =ire meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction 10 mixture, and formulation into an efficacious therapeutic agent.
synthesis
Compounds of the present invention can be prepared in a 15 number of ways well known to one skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those 20 skilled in the art. Preferred methods include, but are not limited to, those methods described below. Each of the references cited below are hereby incorporated herein by reference. All the temperatures are reported herein in degrees Celsius.
The compounds of Formula I can be prepared using the reactions and techniques described below. The reactions are performed in a solvent appropriate to the reagents and materials employed and suitable for the transformations being effected. It will be understood by those skilled in the art 10 of organic synthesis that the functionality present on the molecule should be consistent with the transformations proposed. This will sometimes require a judgment to modify the order of the synthetic steps or to select one particular process scheme over another in order to obtain a desired 35 compound of the invention. It will also be recognized that another ma}or consideration in the planning of any synthetic route in this field is the judicious choice of the protecting group used for protection of the reactive functional groups
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present in the compounds described in this invention. An authoritative account describing the many alternatives to the trained practitioner is Greene and Wuts (Protective Groups In Organic Synthesis, Wiley and Sons, 1991).
The following descriptions detail general methods of making benziraidazoles, indazoles and indoles through a variety of intermediates. These methods are not intended to represent all of the possible means of making the above compounds,
merely a broad representation. One of ordinary skill in the 10 art would readily understand what starting groups would be necessary to make all of the present compounds.
Intermediate 1 which can be formed via acylation of 4-amino-3-nitrobenzonitrile (Aldrich Chemical Co.) with an acyl chloride (F^CHO) or an anhydride ((R1C0)20) in the presence of 15 a base, followed by hydrogenation is shown below in Scheme 1. Reductive amination of an aldehyde (RCHO) in the presence of 1 using borane-pyridine in acetic acid can afford N-alkylated product 2. Alkylation of 1 with a halide (PbX) in the presence of a base, such as CS2CC3, can provide compound 3. Compounds 2 20 and 3 can be subjected to the Pinner reaction to give 6-
amidino-benzimidazole derivative 4 and 5-amidino-benzimidazole derivative 5, respectively (see Khanna et al J. Org. Chem. 199S, 60, 960).
Schame 1: Aaidizto-benziaidazoles via 4-amino-3-
nitrobanzonitrile
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XXr"
n I
P3
y— r1
Scheme 2 shows palladium (0) catalyzed coupling of 3-amino-4-nitrophenyl halides with zinc cyanide in DMF under 5 reflux can provide compound 6 (see Lawton et al J. Org. Chem. 1959, 24, 26). Acylation of 6 with an acyl chloride or anhydride in the presence of base, followed by hydrogenation can form compound 7. Alkylation of 7 with a halide in the presence of a base, such as CS2CO3, can provide compound 8.
Reductive amination of an aldehyde with 7 using borane-pyridine in acetic acid can afford N-alkylated product 9. Compounds 8 and 9 can be converted to either their 6-amidino-benzimidazole or 5-amidino-benzimidazole derivatives, respectively via the Pinner reaction.
Schema 2: Amidino-boTHiiaidazolas via 3-amino-4-nitrophanyl halites
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NC
Zn(CN)2 pd (0) NC
•N02 DMF
reflux
X = Br, I
T3
N
NH2
N
N02
1) R1C0C1 or (R1C0)20, NaH
2) H2, 10% Pd/C, MeOH
"Jllmann reaction of 4-chloro-3-nitrobenzonitrile with an amine (P3NH2) in the presence of a base, such as NaHCOj, can 5 form compound 10 shown in Scheme 3. Hydrogenation of 10,
followed by cyclization with an acid, such as formic acid, can give compound 5, which can be converted to its 5-amidino-benzimidazole derivatives as described above. In addition, compound 5 could be derivatized by addition of Br-(CH2)n-Z-A-B 10 and the resulting mixture subjected to the Pinner reaction and separated by standard techniques.
Schane 3: no-hanginidazplaa via tha Ullaaxm Raaction
N
» k
V'
As described in Scheme 4, bromination of 4-amino-benzonitrile with NBS, followed by treatment with NaNC>2 and CU2O in conc. HCl can provide compound 11 {see Tsuji et al 20 Chem. Pharm. Bull. 1992, 40, 2399). Ullmann reaction of 11 with an amine in the presence of a base, such as NaHC03, can form compound 12. Hydrogenation of 11, followed by cyclization with formic acid can give compound 8, which can be
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converted to its 6-amidino-benzimidazole derivative as described above.
Schane 4: Amidino-benzimidezolas via the Ullmann Reaction
Scheme 5 details the synthesis of 2-substituted-amidino-benzimidazoles from 3,4-diamino-benzomtrile and 3-amino-4-10 hydroxybenzonitrile 13 which are obtained by hydrogenation of 4-an\ino-3-nitro-benzonitrile or 4-hydroxy-3-nitrobenzonitrile. Treatment of 13 with an acyl chloride or an acid in the presence of PPA can form compound 14 (see Walker et al Synthesis 1981, 303). Compound 14 can be converted to its 15 amidino derivative via the Pinner reaction. Alternatively, when Y is NH, alkylation of 14 with a halide in the presence of a base, such as K2CO3, can afford a mixture of two regioisomers 15 and 16, which can, after being separated, be subjected to the Pinner reaction to give 2-substituted-6-20 amidino-benzimidazoles and 2-substituted-5-amidino-benzimidazole derivatives, respectively.
Scheme 5: 2 - ituted-amidino-be X12 imidazole*
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Protection of 6-hydroxy-indazole with pivalic anhydride in the presence of a base, followed by treatment with triflic 5 anhydride can give compound 17 as shown in Scheme 6.
Palladium (0) catalyzed coupling of 17 with zinc cyanide cam provide compound IB. Deprotection of compound IB under acidic conditions, followed by alkylation of with a halide in the presence of a base can yield compound 19, which can be 1C converted to its 6-amidino-indazole derivative via the Pinner reaction.
Schema 6: *■>< a*nn-h«nTvia 6-hydroxy-indazole
1-Substituted-amidino-indoles and -indazoles could be made from 5-cyanoindole as outlined below in Scheme 7. Intermediate 21 can easily be obtained via alkylation of 20 20 with Br{CH2)nz- Peptide coupling with H-A-B using the BOP
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reagent or alkylation should afford intermediate 22 which is can then be converted to amidine 23 under Pinner conditions.
Schwa* 7: 1-Substituted-aaidino-indoles and -ind*zolen from 5-cyanoindole (or K)
1.NaH, DMF
Br(CH2)
peptide __
coupling, acylation, or alkylation H-A-B
A-B
hn
22
23
Scheme 8 shows 3-substituted-amidino-indoles and 10 -indazoles are also derivable from 5-cyanoindole. Compound 26 may be obtained by substitution of R1 on 24 to form 25 and acylation of 25 in the presence of oxalyl chloride at r.t. under nitrogen atmosphere. The compound can be subjected to selective ketone reduction with triechylsilane in 15 trifluoroacetic acid for 3h and then coupled with H-A-B.
Scheme 8: 3 - Substituted-amidino-indoles and indazoles f cyanoindole (J**CH or N)
-
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1 . TFA
EtjSiH
2 . KOH
3. peptide coupling
H-A-B
A-B 1.HC1,
MeOH
2 . (NH4)2C03
A-B
The piperazine phenylsu1fonamide, 31, and various other sulfonamide analogues can be prepared from commercially 5 available BOC-piperazine via sulfonation with phenylsuIfonyl chloride in CH2CI2 and triethylamine as indicated in Scheme 9.
Schema 9: Pheny 1 >ulfonylp ipar&zinaa from Boc-piparazina
R6-PhS02Cl
- r \ _ "v
V~r6
Bocl^^NH
29
CH2Cl2/Et3N
Biphenyl compounds may be prepared by procedures known to those of skill in the art. For example. Scheme 10 shows how to obtain substituted biphenyls via a Suzuki coupling with BOC 15 protected 4-bromoaniline (or l-bromo-4-nitrobenzene) to afford compound 35.
Schi
: Biphanyls fran bromoanilina
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B(OH)2
NaH
ij (boo2o r i
Compound 38 can be obtained via deprotection of the t-butyl group when R6 = SC>2NH-t-Bu, with TFA followed by alkylation or acylation with R^X as outlined in Scheme 11.
Scheae 11: Preparation of 4' -amino-biphanyl-2-aulfonud.das
TFA
S02NH-t-Bu so2nh-r3
Scheme 12 shows how intermediates 43-45 may be obtained via the same intermediate 39. Acylation with oxalyl chloride followed by addition of methanol should yield ketoester 40 and selective reduction with triethyl silane may afford methyl acetate 42. Reduction with sodium borohydride can give the alcohol which then can be converted to 45 with R^X.
Intermediate 43 may be obtained via formylation with poci3 in DMF to yield aldehyde 41 which could then subjected to a Wittig olefination to afford compound 43.
Scheme 12: Addition of R1 substituent to l-substitut«d indoles or inda2oles
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B-
\
(
1.(C0C1)2
CH2C12
2. MeOH
CN
39
OMe
Ph3P=CH2R THF
DMF, POCl3
TFA, Et3SiH
R2
1.NaBH4 EtOH
2.XR3, NaH
OMe
1.NaBH4 EtOH
2.XR3. NaH
A.
CN
43
6^
OR3
CN 45
Sulfonyl chloride 49 may be obtained via aldehyde 47. The aldehyde can be reduced with sodium borohydride, sulfonated with methane sulfonyl chloride, and displaced with sodium sulfite in ethanol. Sulfonyl chloride 49 should then be obtained via chlorination with sulfonyl chloride as detailed in Scheme 13.
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SchaM 13: Addition of R1 to 1-protected indoles or indazoles
P0C13
N vm—
px ^
H NaBH4
N-Ja
1.NaH, MsCl
2.Na2S03 3.SOCl2
so2ci
49
P is a protecting group e.g. MEM-group.
Scheme 14 details how substitution at the 2-position of the indole may be acomplished via lithiation with s-BuLi at -78"C followed by addition of R^X to yield compound 51. Compound 51 can then converted to compound 52 by the previously mentioned methodology.
Sch«
14: Addition of two R1' s to 1-protected indolt
1.s-BuLi
-78°C, THF 2 .XR1
In Scheme 15, it is shown how the 5-cyanoindole compound 54 may be prepared via compound 53 by using sodium methoxide in the presence of nitromethane, followed by Zn reduction and condensation.
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Scheme 15: Formation of indoles
1.NaOMe
CH3N02
2. Zn/EtOH TFA
NC\j^w r.r>
54
Groups A and B are available either through commercial sources, known in the literature or readily synthesized by the adaptation of standard procedures known to practioners skilled in the art of organic synthesis. The required reactive 10 functional groups appended to analogs of A and B are also available either through commercial sources, known in the literature or readily synthesized by the adaptation of standard procedures known to practioners skilled in the art of organic synthesis. In the tables that follow the chemistry 15 required to effect the coupling of A to B is outlined.
Table 1: Preparation of Amide, Estar, Urea, Sulfonamide and Sulf amide linkages between A and B.
Rxn. No.
if A contains :
then the reactive substituent of Y is :
to give the following product A-X-Y :
1
A-NHR3 as a substituent
C1C(0)-Y
A-NR3-C(0)-Y
2
a secondary NH as part of a rinq or chain
CIC(O)-Y
A-C(O)-Y
3
A-OH as a substituent
CIC(O)-Y
A-O-C(O)-Y
4
A-NHR3 as a substituent
C1C(0)-CR3R3 ' -Y
A-NR3-C(0)-CR3R3'-Y
a secondary NH as part of a rinq or chain
CIC(O)-CR3R3'-Y
A-C(0)-CR3R3'-Y
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PCT/US97/I1325
6
A-OH as a substituent
ClC(O)-CR3R3'-Y
A-O-C(O)-CR3R3'-Y
7
A-NHR3 as a substituent
C1C(0)NR3-Y
A-NR3-C(0)NR3-Y
8
a secondary NH as part of a ring or chain
C1C(0)NR3-Y
A-C{0)NR3-Y
o
A-OH as a substituent
C1C(0)NR3-Y
A-O-C(0)NR3-Y
A-NHR3 as a substituent
C1S02-Y
A-NR3-SO2-Y
11
a secondary NH as part of a rinq or chain
CISO2-Y
A-S02-Y
12
A-NHR3 as a substituent
CISO2-CR3R3'-Y
A-NR3-S02-CR3R3'-Y
13
a secondary NH as part of a rinq or chain
CISO2-CR3 R3'-Y
A-SO2-CR3R3'-Y
14
A-NHR3 as a substituent
CISO2-NR3-Y
A-NR3-SO2-NR3-Y
a secondary NH as part of a rinq or chain
C1S02-NR3-Y
A-302-NR3-Y
16
A-C(0)C1
HO-Y as a substituent
A-C(O)-O-Y
17
A-C(0)Cl
NHR3-Y as a substituent
A-C(0)-NR3-Y
18
A-C(0)Cl a secondary NH as part of a ring or chain
A-C(Ol-Y
19
A-CR3R3"C(0)C1
HO-Y as a substituent
A-CR3R3'C(0)-0-Y
A-CR3R3"C(0)C1
NHR3-Y as a substituent
A-CR3R3'C(O)-NR3-Y
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21
A-CR3R3'C(0)C1
a secondary NH as part of a ring or chain
A-C(R3)2C(O)-Y
22
A-S02C1
NHR3-Y as a substituent
A-S02-NR3-Y
23
A-S02C1
a secondary NH as part of a ring or chain
A-S02-Y
24
A-CR3R3'S02C1
NHR3-Y as a substituent
A-CR3R3'S02-NR3-Y
A-CR3R3'S02C1
a secondary NH as part of a ring or chain
A-CR3R3'S02-Y
The chemistry of Table 1 can be carried out in aprotic solvents such as a chlorocarbon, pyridine, benzene or toluene, at temperatures ranging from -20 C to the reflux point of the 5 solvent and with or without a trialkylamine base.
Tabla 2: Preparation of k>ton< linkages betwan X and B.
Rxn.
No.
if A contains':
then the reactive substituent of Y is :
to give the following product A-X-Y :
1
A-C(O)Cl
BrMq-Y
A-C(O)-Y
2
A-CR3R3'C(0)C1
BrMq-Y
A-CR3R3'2C(0)-Y
3
A-C(0)C1
BrMgCR3R3'-Y
A-C(0)CR3R3'-Y
4
A-CR3R3 *C(0)C1
BrMgCR3R3'-Y
A-CR3R3'C(0)CR3R3'-Y
The coupling chemistry of Table 2 can be carried out by a 10 variety of methods. The Grignard reagent required for Y is prepared from a halogen analog of Y in dry ether, dimethoxyethane or tetrahydrofuran at 0 C to the reflux point of the solvent. This Grignard reagent can be reacted directly under very controlled conditions, that is low temeprature (-15 20 C or lower) and with a large excess of acid chloride or with catalytic or stoichiometric copper bromide'dimethyl
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sulfide complex in dimethyl sulfide as a solvent or with a variant thereof. Other methods available include transforming the Grignard reagent to the cadmium reagent and coupling according to the procedure of Carson and Prout (Org. Syn. Col. Vol. 3 (1955) 601) or a coupling mediated by Fe(acac>3 according to Fiandanese et al.(Tetrahedron Lett., (1984) 4805), or a coupling mediated by manganese (II) catalysis (Cahiez and Laboue, Tetrahedron Lett., 33(31), (1992) 4437).
Table 3: Preparation of ether and thioether linkages between
A and B
then the reactive to give the
Rxn.
substituent of following
No.
if A contains :
Y is :
product a-X-Y :
1
A-OH
Br-Y
A-O-Y
2
A-cr3r3'-OH
Br-Y
A-CR3R3'O-Y
3
A-OH
Br-CR3R3'-Y
A-OCR3R3'-Y
4
A-SH
Br-Y
> 1
in i
a-cr3r3'-sh
Br-Y
A-CR3R3's-y
6
A-SH
Br-CR3R3'-Y
A-SCR3R3'-Y
The ether and thioether linkages of Table 3 can be prepared by reacting the two components in a polar aprotic solvent such as acetone, dimethylformamide or dimethylsuifoxide in the presence of a base such as potassium carbonate, sodium hydride or potassium t-butoxide at temperature ranging from ambient temperature to the reflux point of the solvent used.
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Table 4: preparation of -SO- and -S02- linkages from thloathers of Table 3.
and it is oxidized
and it is oxidized with m-chloroper
with Alumina (wet)/
benzoic acid (Satoh
if the
Oxone (Greenhalgh,
et al., Chem. Lett.
Rxn.
starting
Synlett,(1992) 235)
(1992) 381, the
No.
material is :
the product is :
product is :
1
a-s-y a-s(o)-y a-s02-y
2
a-cr3r3's-y a-cr3r3's(o)-y a-cr3r3's02-y
3
a-scr3r3'-y a-s(o)cr3r3'-y a-s02cr3r3'-y
The thioethers of Table 3 serve as a convenient starting 5 material for the preparation of the sulfoxide and sulfone analogs of Table 4. A combination of wet alumina and oxone provides a reliable reagent for the oxidation of the thioether to the sulfoxide while m-chloroperbenzoic acid oxidation will give the sulfone.
Other features of the invention will become apparent in the course of the following descriptions of exemplary embodiments which are given for illustration fo the invention and are not intended to be limiting thereof.
The synthesis of representative compounds according to the invention is described in further detail below with reference to the following specific, but non-limiting 20 examples.
Abbreviations used in the Examples are defined as follows: "°c" for degrees Celsius, "d" for doublet, "dd" for doublet of doublets, "DAST" for diethylaminosulfur trifluoride, "eq" for equivalent or equivalents, "g" for gram 25 or grams, "mg" for milligram or milligrams, "mL" for milliliter or milliliters, "H" for hydrogen or hydrogens, "hr" for hour or hours, "m" for multiplet, "M" for molar, "min" for minute or minutes, "MHz" for megahertz, "MS" for mass spectroscopy, "nmr" or "UMR" for nuclear magnetic resonance
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spectroscopy, "t" for triplet, "TLC" for thin layer chromatography.
Examples 1-15 were prepared by Michael addition of 5-cyano-benzimidazole to the a,^-unsaturated esters by using K2C03 (2 mmol) as a base in DMF (10 mL) at 9C-110°C for 16-24 hours, followed by the Pinner reaction. A mixture of jneta-and para-isomers was obtained by purification on TLC plates with 10-20% MeOH in CH2CI2 • The pure meta- or para-isomer was separated by HPLC.
-Cyanobenzimidazole
H
NC- NO, 1)H2.5%Pd-C NC
^ MeOH ^ -
NH 2) HCOOH * reflux
K> * W
N
I
H
A solution of 4-amino-3-nitrobenzonitrile (20 mmol) in
MeOH (3 00mL) in the presence o£ 5% of Pd/C (1 g) was treated with hydrogen at room temperature for 16 hours. The reaction mixture was filtered and concentrated to give 3,4-diaminobenzonitrile (2.4 g, Jt)% of yield), which was directly 20 treated with formic acid (20 mL) under reflux for 4 hours. After removal of the excess formic acid, the residue was dissolved in EtOAc, washed with 10% sodium bicarbonate and brine, and dried over MgS04. Concentration gave 5-cyanobenzimidazole (2.2 g, 85%). 1H NMR (CD3OD) 88.39 (s, 1H) 25 8.05 (s, 1H), 7.76 (d, J = 8.4 Hz, 1H), 7.59 (dd, J = 8.4 Hz, J = 1.1 HZ, 1H); MS: 144 (M+H)+.
preparation of Ethyl 2-(3-cyanophenyl)etbacrylate and Ethyl
2-(4-cyanophenyl)ethacrylate
To a stirred suspension of zinc powder mmol) in THF (10 mL) was added 1,2-dibromoethylene (0.2 g) at room temperature and the mixture was stirred for 30 minutes. A solution of 3-cyanobenzylbromide or 4-cyanobenzylbromide (20 35 mmol) in THF (25 mL) was slowly added at a rate of one drop
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per five seconds at 5-10°C. The mixture was stirred for 3 hours, and then transferred into a solution of copper (I) cyanide (20 mmol) and lithium chloride (40 mmol) in THF (20 mL) at -78°C. The resulting mixture was warmed up and stirred 5 at -20°C for 20 minutes, and was then cooled to -78°C. After ethyl 2-(bromomethyl)acrylate (20 mmol) was slowly added, the mixture was stirred at -78°C for 2 hours, and then warmed to room temperature overnight. Ether (100 mL) and aqueous saturated ammonium chloride (50 mL) were added to the mixture 10 and the mixture filtered. The filtrate was washed with water and brine, and dried over MgSC>4. Concentration gave a residue, which was purified by column chromatography with gradient solvent system (CH2Cl2-EtOAc) to give ethyl 2- (3 — cyanophenyl)ethacrylate (1.2 g, 26.2%) and ester ethyl 2 — (4-15 cyanophenyl)ethacrylate (3.6 g, 78.6%).
For ethyl 2-(4-cyanophenyl)ethacrylate: NMR (CDCI3) 8
7.58 (dd, J = 8.4 Hz, J = 1.8 Hz, 2H) , 7.28 (d, J = 8.4 Hz, 2H) , 6.17 (d, J = 1.1 Hz, 1H), 5.48 (dd, J = 2.6 Hz, J = 1.1 Hz, 1H), 4.22 (q, J = 7.3 Hz, 2H) , 2.86 (dd, J = 8.6 Hz, J = 20 7.1 Hz, 2H), 2.61 (dd, J = 8.6 Hz, J = 7.0 Hz, 2H),1.32 (t, J = 7.0 Hz, 3H); MS: 247 (m+NH4)*.
For ethyl 2-(3-cyanophenyl)ethacrylate: XH NMR (CDCI3) 5
7.51-7.36 (m, 4H), 6.17 (s, 1H), 5.48 (d, J = 1.1 Hz, 1H), 4.22 (q, J = 7.3 Hz, 2H), 2.84 (dd. J = 8.4 Hz, J = 7.0 Hz, 25 2H) , 2.61 (dd, J = 8.4 Hz, J = 7.0 Hz, 2H),1.32 <t, J = 7.0 Hz, 3H) ; 13C NMR (CDCI3) 5166.80, 142.85, 139.41, 133.14,
132.05, 129.85, 129.17, 118.94, 112.43, 60.79, 34.50, 33.57, 14.22; MS 247 (M+NH4)+.
Preparation of Ethyl [3 -(4-cyanophanyl) -2-broaoa»ethyl]acrylats
To a solution of 4-cyanobenzylbromide (40 mmol) in xylene (40 mL) was added triphenylphosphine (40 mmol) and the resulting solution was heated at 110°C for 2 hours. After 35 removal of xylene, a white solid was obtained, which was dissolved in a mixture of THF (40 mL) and EtOH (40 mL) ,
treated with DBU (40 mmol) at room temperature for one hour, and then to it was added ethyl pyruvate (40 mmol). The
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resulting mixture was stirred at room temperature overnight and filtrated to remove Ph3PO. The filtrate was concentrated, dissolved in EtOAc, washed with IN HC1, water and brine, and dried over MgS04. Concentration gave a mixture of cis and trans olefins in almost quantitative yield. A solution of the olefins (5 mmol), NBS (5 mmol), and AIBN (0.25 mmol) in CCI4 (200 mL) was refluxed under nitrogen for 16 hours, filtered, concentrated and purified by column chromatography with gradient solvent system (CH2Cl2-EtOAc) to give the title compound (1.25 g, 85 %) as a white solid. XH NMR (CDCI3) 67.71
(d, J = 1.4 Hz. 1H), 7.68 (d, J = 8.8 Hz, 2H), 7.58 (J = 8.5 Hz, 2H), 4.29 (q, J = 7.3 Hz, 2H) , 4.23 (s. 2H), 1.32 (t, J = 7.3 Hz, 3H).
Preparation of Ethyl 2- (4-banzyloxyph«nyl)msthacrylat«
A mixture of 4-bromophenol {40 mmol), benzylbromide (40 mmol) and Na2CC>3 in DMF (200 mL) was stirred at room temperature for 24 hours and was then poured into water. A solid was collected and was further recrystallized from hexane to give 4-benzyloxybenzene bromide in almost quantitative yield. A solution of the bromide in THF (100 mL) was treated with BuLi (44 mmol) at -7 8°c over 30 minutes and then with a solution of Znl2 (40 mmol) in THF(40 mL) over 20 minutes.
After the resulting mixture was warmed to room temperature over an hour, it was cooled to -78°C and a solution of copper (I) cyanide (40 mmol) and lithium chloride (80 mmol) in THF (50 mL) was slowly added. The resulting mixture was warmed and stirred at -20°C for 20 minutes, cooled to -78°C, and to it was added ethyl 2-(bromomethyl)acrylate (40 mmol). The resulting mixture was stirred at -78°C for 2 hours and was then warmed to room temperature overnight. Ether and aqueous saturated ammonium chloride were added and filtered. The filtrate was washed with water and brine, and dried over MgSOj. Concentration gave a residue, which was purified by column chromatography with gradient solvent system (CH2CI2-EtOAc) to give the title compound (3.6 g, 3 0.4%): 1H NMR (CDCI3)8 7.44-7.26 (m, 5H),7.12 (d, J = 8.4 Hr, 2H) , 6.91 (d, J = 8.4 Hz,
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2H), 6.20 (s, 1H), 5.92 (s, 1H), 5.07 Is, 2H), 4.18 (q, J = 7.4 Hz, 2H), 3.57 (s, 2H) , 1.27 (t, J = 7.4 Hz, 3H) ; MS: 314 (M+NH4)+.
I
Preparation of Ethvl 2-(3-amidinophenvl>efchvl-3-15-»Hl*1nfffr»n?iifflifl»g'?lT)p:ronlonate and Ethvl 2-(3-amldinophenvl) ethvl - T-1nr>heT»»4«J ) DtonioMf
A mixture of 5-cyanobenzimidazole (2 mmol), ethyl 2-(3-
cyanophenyl)ethacrylate (2 mmol) and K2CO3 (2 mmol) in DMF (10 mL) was heated at 90°C under nitrogen for 16 hours. The mixture was diluted with EtOAc (150 mL), washed with IN HC1, water, and brine, and dried over MgS04. After filtration and 15 concentration, a residue was purified by column chromatography with gradient solvent system (CH2Cl2~EtOAc) to give a mixture of ethyl 2-(3-cyanophenyl)ethyl-3-(6-cyanobenzimidazole)propionate and ethyl 2-(3-
cyanophenyl)methyl-3-(5-cyanobenzimidazole)propionate (0.57 g, 20 76.4%) as a colorless oil. 1H NMR (CDCI3) 5 8 .13-7 . 36 (m, 8H) ,
4.55 (dd, J = 14.3 Hz, J = 9.2 Hz, 1H), 4.28 (dd, J = 14.3 Hz, J = 5.5 Hz, 1H), 4.07 (q, J = 7.0 Hz, 2H), 3.00-2.91 (m, 1H) , 2.80-2.64 (m, 2H), 2.18-2.07 (m, 1H), 1.92-1.82 (m, 1H), 1.12 (t, J = 7.0, 3H).
E»«wpleg 2 **¥& 3
Preparation of Ethvl 2-(3-a»irt4nrmhenvl)athvl-3-(5-
and Ethvl 2-0-
"■< ""phenyl) ethvl-3- < <S-amidinob»TiriiB-Jdazole\T,r^r>^QT1t|^T
The mixture of esters obtained in Example 1 was treated with HC1 (gas) in anhydrous ethanol (10 mL) for 15 minutes at 0°C and then stirred for 16 hours. After removal of excess HC1 (gas) and ethanol, the residue ' is treated with (NH4)2C03 (5 35 equivalents) in anhydrous ethanol (10 mL) at room temperature for 24 hours. Concentration gave a residue, which was purified on TLC plates with 10% MeOH in CH2CI2 to give a mixture of the title compounds (400 mg, 65.4%): mp 160-165°C;
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ESMS: 204.2 (M+2H)2+. The mixture was further separated by HPLC on chiral OJ column with COa/MeOH/TEA (80/20/0.1) to give Example 2, ethyl 2 -(3-amidinopheny1)ethyl-3-(5 -amidinobenzimidazole)propionate, and Example 3, ethyl 2-(3-5 amidinophenyl)ethyl-3-(6-amidinobenzimidazole)propionate.
Example 2: 1H NMR (CD3OD) 68.36 (s, 1H) , 8.17 (s, 1H) ,7.75-7.72 (m, 2H) , 7.63 (bs, 2H), 7.50-7.48 (m, 2H), .4.66 (dd, J = 9.5 Hz, J = 14.3 Hz, 1H), 4.55 (dd, J = 5.? Hz, J = 10 14.2 HZ, 1H), 4.02-3.92 (m, 2H), 3.14-3.08 <m, 1H), 2.81 (t, J = 7.0 Hz, 2H), 2.19-1.93 (m, 2H), 1.04 (t, J = 7.0 Hz, 3H); ESMS: 204.2 (M+2H)2+ .
Example 3: >H NMR (CD3OD) 6 8.37 (s, 1H) , 8.10 (s, 1H) 15 ,7.84 (d, J = 8.4 Hz, 1H) , 7.72 (d, J = 8.4 Hz, 1H), 7.65-7.62 (m, 2H) , 7.55-7.46 (m, 2H), 4.68 (dd, J = 9.5 Hz, J = 14.3 Hz, 1H), 4.56 (dd, J = 5.5 Hz, J = 14.2 Hz, 1H), 4.04-3.94 (m, 2H), 3.24-3.18 (m, ?H), 2.83 (t, J = 7.0 Hz, 2H), 2.19-1.95 (m, 2H), 1.05 (t, J = 7.0 Hz, 3H); ESMS: 204.2 (M+2H)2*.
ESfiSBlft-1
Preparation of Ethvl 2-(4-amidinophenvl)ethvl-3-f5-
propionate Ethvl 2-f4-,Wli0in?r>>ianvl>«thv1 -3-' fi-eaiainobei>gjmi*»»»gl«)propionate
Example 4 was made using the same method as described for Example 1, except ethyl 2-(4-cyanophenyl)ethacrylate (2 mmol) was used (100 mg, 13% for two steps): mp 230°C (Dec.); ESMS: 407 (M+H)\- HRMS: 407.2200 (obs.), 407.2195 (calcd. ) for 30 C22H26N602 • Example 4 was further separated to give Examples 5 and 6.
? a"* ?
Preparation of Etborl 2-(4-aaidlnophonvl)aehvl-3-(5-35 and Ethvl 2- (4-
W^^"9Phenvl) ethyl-3- (6 -amidinobenz imidazole) proplaaita
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The mixture of compounds obtained in Example 4 were further separated to give Examples 5 and 6.
Example 5, ethyl 2-(4-amidinophenyl)ethyl-3-(5-5 amidinobenzimidazole)propionate: XH NMR (DMSO-d6):59.43-9.08 (m, 6H), 7.74-7.65 (m, 2H), 7.40-7.38 <m, 2H) , 7.35-7.00 (m, 4H), 4.67-4.55 (m, 2H), 4.06 (bs, 2H) , 3.48 {bs, 2H), 3.20 (bs, 1H), 2.70 (bs, 2H), 1.00 (bs, 3H) ; ESMS: 407 (M+H)+.
Example 6, ethyl 2-(4-amidinophenyl)ethyl-3-(6-
amidinobenzimidazole)propionate: :H NMR (DMSO-d6) : 6 9 . 23-9 .12
(m, 6H), 8.41 (s, 1H), 8.21 (s, 1H), 7.84-7.82 (m, 1H), 7.74 (d, J = 8.1 Hz, 2H), 7.41 (d, J = 7.8 Hz, 2H), 7.24 (bs, 1H), 4.58-4.56 (m, 2H) , 3.95-3.89 (m, 2H) , 3.10-3.00 (m, 1H), 2.73-15 2.71 (m, 2H), 1.90-1.88 (m, 2H), 0.98-0.96 (m, 3H); ESMS: 407 (M+H)*.
Bxamla 7
Preparation of Ethv3 n-(4-MQidinoph«nvl)-2-(B-20 thvllacrvlaf
A mixture of 5-cyanobenzimidazole (2 mmol), ethyl t3-(4-cyanophenyl)-2-bromomethyl]aerylate (2 mmol) and K2CO3 (2 mmol) in DMF (10 mL) was heated at 90°C under nitrogen for 24 hours. 25 The mixture was diluted with EtOAc (150 mL), washed with IN
HC1, water, and brine, and dried over MgS04. After filtration and concentration, the residue was purified by column chromatography (CH2Cl2-EtOAc) to give ethyl [3-(4-cyanophenyl) -2-(5-cyanobenzimidazole)methyl]acrylate (0.401 g, 56.3 %) as a 30 colorless oil. NMR (CDCI3) 8 8 .10-8 . 00 (m, 4H) , 7.83-7.77
(m, , 2H), 7.52-7.44 (m, 2H), 7.01-6.98 (m, 1H), 5.20 (s, 2H), 4.24 (q, J = 7.3 Hz, 2H), 1.25 (t, J = 7.3 Hz, 3H); MS: 357 (M+H)*.
The Pinner reaction converted ethyl [3-(4-cyanophenyl)-2-35 (5-cyanobenzimidazole)methyl]acrylate (0.42 mmol) to the title compound (400 mg, 65.4%): ^-H NMR (CD3OD) 8 8.19-8.12 (m, 2H) ,
7.92-7.88 (m, 3H) , 7.74-7.69 (m, 4H), 4.22-4.19 (m, 2H), 1.24-
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1.20 (m, 3H); ESMS: 196.2 (M4-2H)2*; HRMS: 391.1889 (obs.), 391.1882 (calcd.).
Rfftirnrl t a
p-rrrrfitign nf EtihYil ^-f4-nail 1 nrphmvi)methvi- 3 - < s -
Vddi,r,PKTzAni^»ftl«'^pgoplQn»t:« md Ethvl 2-/4-ml*!* i nrefrTBYl) ^r^bYl - 3 - (V^i4jjy?^TriaiiiVug;iT>pgppian»fc?
Ethyl [3-(4-cyanophenyl)-2-(5-10 cyanobenziraidazole)methyl]acrylate was hydrogenated in MeOH in the presence of 10% palladium on active carbon to give ethyl 2- (4-cyanophenyl)methyl-3-(6-cyanobenzimidazole)propionate and ethyl 2-(4-cyanophenyl)methyl-3-(5-
cyanobenzimidazole)propionate: ^H NMR (CDCI3) 88.24-8.02 (m, 15 2H) , 7.87-7.50 (m,, 4H), 7.34-7.28 (m, 2H), 4.58-4.55 (m, 1H), 4.32-4.27 (m, 1H), 4.12-3.93 (m, 2H). 3.20-2.91 (m. 2H) , 2.79-2.72 (m, 1H), 1.10-0.95 <m, 3H).
The mixture obtained {1.5 mmol) was subjected to the Pinner reaction to obtain the title compound (300 mg, 48%): 20 NMR (CD3OD) : 8 8.63 (bs, 1H) , 8.27-7.96 (m, 7H) , 4.98-4.54 (m, 2H) , 3.98-3.80 (m, 2H), 3.53-3.45 (m, 1H), 3.37-3.09 (m, 2H) , 1.00-0.96 (m, 3H); ESMS: 197 (M+2H)2+.
Examples 51-63 were prepared by Method A, B. or C. All 25 compounds were finally purified by HPLC (CH3CN/H2/O.05% TFA).
Method A: Examples 51-59 were made by Suzuki coupling reactions of [(4-bromophenyl)carbonyl)methyl-6-cyanobenzimidazole or [ (4-bromophenyl) carbonyl]methyl-5-30 cyanobenzimidazole with a variety of boronic acids by using Na2C03 (2-4 equivalents) and Pd(PPlv})4 (5-10% mmol"1) as catalyst in THF (80% in H20, 10 mL/mmol), followed by Pinner reactions.
A mixture of [ (4-bromophenyl)carbonyl]methyl-6-35 cyanobenzimidazole and [ (4-bromophenyl)carbonyl]methy 1-5-
cyanobenzimidazole was made in over 90% yield by alkylation of 5-cyano-benzimidazole (36 nanol) with 2, 4'-dibromoacetophenone (36 mmol) by using NaH (48 mmol) as a base in THF (80 mL) .
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The mixture were isolated by HPLC on chiralcel OJ column with MeOH/CC>2 (2 0/80) to give pure individual compounds.
[ (4-Bromophenyl)carbonyl]methyl-6-cyanobenzimidazole: NMR (CDClj) 58.35 (s, 1H), 8.11 (dd, J = 1.1 Hz, J = 0.7 Hz,
1H) , 8.08 (d, J = 8.8 Hz, 2H), 7.81 (d, J = 8.4 Hz, 2H), 7.56 (dd, J = 8.4 Hz, J = 1.8 Hz, 1H), 6.16 (s, 1H); ESMS:
340/342 (M+H)+.
[ (4-Bromophenyl)carbonyl]methyl-5-cyanobenzimidazole: XH NMR (CDC13) 5 8.31 (s, 1H) , 8.13 (t, J = 0.7 Hz, 1H), 8.07 (d, J
= 8.8 HZ, 2H), 7.81 (d, J = 8.8 Hz, 2H), 7.75 (dd, J = 8.4 Hz, J = 0.7 Hz, 1H). 7.57 (dd, J = 8.4 Hz, j = 1.1 Hz, 1H), 6.15 (s, 1H); ESMS: 340/342 (M+H)+.
il
preparation 9* [4-^toy3.|ph«nvlearbonvl1aathvl-6-
MP: 155-157°C; XH NMR (CD3OD) 58.44 (s, 1H) , 8.23 (d, J = 8.4 Hz, 1H) , 8.07 (d, J = 1.1 Hz, 1H), 7.91 (d, J = 8.8 Hz, 20 1H), 7.88 (dd, J = 8.4, 2H), 7.72 (dd, J = 8.4 Hz, J = 1.1 Hz, 3H) , 7.52-7.41 (m, 3H), 6.10 (s, 2H); MS: 355 (M+H)*, HRMS: 355.1554 (obs.), 355.1559 (calcd.); Anal.: (C22H18N4Oi + 0.9TFA + 1.2HC1 + O.5H2O) C, H, N, F, Cl.
fiml? ESI
Preparation of 14 - (phenyl)phenvlcarbonvl1aethvl-5-
MP: 260-261°C; iH NMR (CD3OD) 5 8.41 (s, 1H) , 8.22 (s, 30 1H), 8.20 (d, J = 8.8 Hz, 2H) , 7.87 (d, J = 8.4 Hz, 2H) , 7.73-7.70 (m, 4H) , 7.51-7.41 (m, 3H) , 6.10 (s, 2H) ,- MS: 355.2 (M+H)*; HRMS: 355.1538 (obs.), 355.1559 (calcd.); Anal.: (C22Hi8N40! + 1.5TFA +■ 0.08HC1 + 1H20) C, H, N, Cl.
ESMPl«. 51
Preparatior f 4 - f ? ~ V* T^henvl) phenylcarbonvl 1 aethvl-6-
wlfllirfrnniniflnsgflt
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lH NMR (DMSO-d6) 69.22 (s, 1.5 H) , 9.04 (s. 1.5 H) , 8.48 (s, 1H) , 8.22 (d, J = 1.4 Hz, 1H) . 8.18 Id, J = 8.3 Hz, 2H) , 7.91 (d, J = 8.5 Hz, 1H), 7.84 (d, J = 8.5 Hz, 2H) , 7.69 (dd, J = 8.6 Hz, 1.7 Hz, 1H), 7.21 (t, J 3 1.8 Hz. 1H), 7.04 (s, 1H), 7.00 (d, J = 8.4 Hz, 1H), 6.73 (d, J = 8.1 Hz, 1H), 6.14 (s, 2H) ; 13C NMR (DMSO-d6> 5 192.4, 165.9, 148.6. 147.6,
146.7, 146.2, 139.3, 134.3, 132.9, 129.7, 128.8, 126.8, 121.8, 121.3, 119.7, 115.6, 115.1, 113.0, 111.8. 51.0; MS: 370 (M+H)+; HRMS: 370.1664 (obs.), 370.1668 (calcd.)
brwplf i1
Praoaratlon of f4-(3-nuinophenvl)phenyl c; a fbonvl 1 methyl-5-
amidinobfp»imldi|^q>i«
XH NMR (CD3OD) 58.48 (s, 1H) , 8.32 (d, J = 8.4 Hz, 2H) ,
7.87 (d, J = 845 Hz. 2H). 7.74 (s. 2H) , 7.62-7.56 (m, 2H) ,
7.53 (d , J = 8.4 Hz, 2H), 7.25 (d, J = 7.4 Hz, 1H) , 6.12 <s,
2H); MS: 370 (M+H)", HRMS: 370.1664 (obs.), 370.1668 (calcd.)
BX&BB1AJ5£
Praoaratlon of f4- (4-fluorophanvllphonylcarbonvllMethyl-6-
ffj^ln^^^tipidagola
MP: 102-105°C; 1H NMR (CD3OD) 5 8.54 (bs, 1H), 8.23 (d, J 25 = 8.8 Hz, 2H), 8.10 (bs, 1H), 7.92 (bs, 1H) , 7.86 (d, J = 8.4 Hz, 2H) ; 19F NMRS-116.3, -77.65 (TFA); 13C NMR (CD3OD) 5
192.9, 168.6. 165.0, 163.5, 147.2, 137.1, 134.3, 130.3, 130.2, 130.1, 126.5, 124.7, 123.4, 120.8, 117.1, 116.9, 112.9, 52.5; MS: 373.2 [(M+H)+; HRMS: 373.1481 (obs.), 373.1465 (calcd.); Anal.: (C22H17N4O1.F1 + 1.9TFA + 0.1HC1 + 2H20) C, H, N, F, Cl.
8xancl£__56
Praparation of [4- (4-formviphanvl) phanvlcarbonvll mathvl-6-
MP: 125-128°C; *H NMR (CD3OD) 510.05 (s, 1H), 8.48 (s, 1H) , 8.27 (d, J = 8.4 Hz, 1H), 8.07 (bs, 1H) , 8.05 (d. J = 8.4 Hz, 2H), 7.97 (d, J = 8.1 Hz, 2H), 7.95 (d, J = 8.1 Hz, 2H),
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7.93 (d, J = 8.4 Hz, 2H) , 7.73 (dd, J = 8.4 Hz, J = 1.8 Hz, 1H), 6.12 (s j 2H) ; 13C NMR (CD3OD) 5 192.99, 168.67, 147.86,
140.90, 140.15, 134.44, 130.10, 128.64, 128.57, 128.09, 124.63, 123.41, 120.75, 112.87, 104.26, 54.45; MS: 192.2 5 (M+2H)2t; HRMS: 383.1531 (obs.), 383.1508 (calcd.).
bftmkpl? ?7 Pruaratlon ef t«-<2-utti 1 noii 1 f onvl nhnvl > ph«nvlcarbonvl ] Mthvl - 6 -10 ^ n">^n2imldazole
MP: 126-128°C; *H NMR (CD3OD) 5 8.55 (bs, 1H), 8.18 (d, J = 8.4 Hz, 2H), 8.13 (dd, J = 7.7 Hz, J = 1.4 Hz, 1H) , 8.09 (s, 1H), 7.94 (d, J = 8.8 Hz, 1H), 7.71 (dd, J = 8.4 Hz, J = 15 1.4 Hz, 1H), 7.67 (d, J = 7.8 Hz, 1H) , 7.65 <d. J = 8.1 Hz,
2H), 7.60 (dd, J = 7.8 Hz, J = 1.4 Hz, 1H), 7.36 (dd, J = 7.3 HZ, J = 1.4 HZ, 1H), 6.13 (S, 2H); MS: 217.7 (M+2H)2*; HRMS: 434.1303 (obs.), 434.1287 (calcd.)
BBMl* 58
Preparation of [4-(2-frt-b^tylmin?»ul{'?pvloh«wliph«nvlg»gboiiv:ni—thvi-6-
MP: 118-120°C; *H NMR (CD3OD) 5 8.60 (bs, 1H), 8.19 (d,
J = 8.4 Hz, 2H) , 8.13 (dd, J = 7.7 Hz, J = 1.4 Hz, 1H) , 8. 0C (s, 1H), 7.95 (d, J = 8.8 Hz, 1H), 7.76 (dd, J = 8.4 Hz, J = 1.4 Hz, 1H), 7.67 (d, J = 8.4 Hz, 2H), 7.63 (dd, J = 7.7 Hz, J = 1.5 Hz, 1H), 7.60 (dd, J = 7.7 Hz, J = 1.4 Hz, 1H), 7.34 30 (dd, J = 7.7 Hz. J = 1.4 Hz, 1H) , 6.14 (s, 2H), 1.09 (s, 9H>; 13C NMR (CD3OD) 5 193.25, 168.78, 149.52, 147.86,
143.50,140.87, 134.76, 133.27, 133.07, 132.83, 131.58, 130.45, 129.77, 129.49, 128.76, 127.34, 124.45, 123.22, 120.99, 112.68, 55.30, 52.38, 30.22; Anal.: (C26H27N5O3S1 + 1. 9TFA + 35 1H20) C, H, N, F, S, Cl.
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Exaanlfi-&2
pr«o*ration of M-K2-t«trazolvl)ph»nvllph«nvlcarbonvl)Mfchvl-
MP: 144-145°C; NMR (CD3OD) 6 8.56 (bs, 1H) , 8.11-8.09
( m, 3H), 7.93 (d, J = 8.5 Hz, 1H), 7.76 (dd, J = 8.5 Hz, J = 1.7 Hz, 1H), 7.73 (d, J = 7.3 Hz, 2H), 7.67-7.62 (m, 2H) , 7.38 (d, J = 8.8 Hz, 2H), 6.09 (s, 2H) ; 13C NMR (CD3OD) 5 192.97, 168.66. 156.91,149.40, 147.07, 146.51,142.32, 135.60, 134.66,
132.64, 131.79, 131.71, 130.90, 129.88, 129.47, 124.56,
123.43, 120.75, 112.87, 52.45; MS: 212.2 (M+2H)2'"; HRMS: 423.1686 (obs.), 423.1682(calcd.); Anal.: (C23Hi8N8Oi+ 1.9TFA + 1 HCl +0.5H20) C, H, N, F, S, Cl.
ttethod B: Examples 60, 61 and 62 were made by alkylation of 5-cyanobenzimidazole with [4-(2-tert-buty1amino su1f onyIpheny1)pheny1ami nocarbonyl]methylene chloride, or (4-benzylpiperidinecarbonyl)methylene chloride, followed by Pinner reactions.
Bmwiip1«g $o $1 FrtPturfrtiga pf f4-(2-
amlnoaulf onvlohnvl) Phenyl nor nrbonvl 1 imathvl - 6 -
<tanarlir fffft ind ti-fa-
fonvlohanvl) phenylnai norwrhonvl 1 methvl-5-
anifl<pr.hOT7i<mtrta»r>'i« fWvimnle fill
[4-(2-tert-Butylaminosulfonylphenyl)phenyl-aminocarbonyl]methylene chloride was prepared by acylation of
4-[ (o-S02NHtBu)phenyl 1 aniline (3 mmol) with a-chloroacetyl chloride (4 mmol) in CH3CN (100 mL) and K.2CO3 (4 mmol) .
Alkylation of 5-cyanobenzimidazole (2 mmol) with [4-(2-tert-butylaminosulf onylphenyl) phenyl-aminocarbonyl] methylene chloride (2 mmol) in DMF (10 mL) and K2CO3 (4 mmol) at r.t.
over 16 hours, followed by purification on thin layer TLC plates, and further isolation by HPLC gave [4-(2-tert-bu ty 1 amino su 1 f ony Ipheny 1) pheny 1 aminocarbonyl ] me thy 1 - 6 -cyanobenzimidazole (240 mg, 56%) and 14-(2-tert-
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butylaminosulfonylphenyl)phenylaminocarbonyl]methyl-5-cyanobenzimidazole (160 mg, 37%).
[4-(2 -1er t -Buty1aminosu1f ony1pheny1)phenyl-aminocarbonyl]methyl-6-cyanobenzimidazole was converted to 5 Example 60 via the Pinner reaction and purified by HPLC: MP: 13 4 - 136°C; *H NMR (CD3OD) 8 8.73 (bs. 1H) , 8.15 (s, 1H) , 8.10
(dd, J = 8.6 Hz, J = 1.2 Hz, 1H) , 7.93 (d, J = 8.3 Hz, 1H), 7.75 (d, J = 7.4 Hz, 1H), 7.64 (d, J = 8.4 Hz, 2H), 7.60 <dd, J = 7.6 Hz, J = 1.2 Hz, 1H), 7.52 (td, J = 7.6, J = 1.4 Hz, 10 1H), 7.40 (d. J = 8.8 Hz. 2H), 7.32 (dd, J = 7.6 Hz, J = 1.2 Hz, 1H), 5.36 (s, 2H); 13C NMR (CD3OD) 5168.79, 166.75,
143.05, 141.48, 138.93, 137.50, 133.63, 132.92, 131.28, 128.75, 128.59, 124.63, 123.35, 120.96, 120.53, 112.80, 47.51; MS: 449.3 (M+HP; HRMS: 449.1401 (obs.), 449.1396 (Calcd.); 15 Anal.: (C22H20N6O3S1+ 1. 8TFA + 0.25 HC1 +1H20) C, H, N, F, S, cl.
[4-(2-cert-Butylaminosulfonylphenyl)phenylaminocarbonyl] methyl-5-cyanobenzimidazole was converted to Example 61 via the Pinner reaction and purified by HPLC: MP: 20 254°C (Dec.); *H NMR (CD3OD) 68.55 (s, 1H) , 8.22 (s, 1H) ,
8.08 (d, J = 6.6 Hz, 1H), 7.83-7.75 (m, 2H), 7.62 (d, J = 8.8, 2H) , 7.59-7.52 (m, 2H), 7.39 (d, J = 8.4 Hz, 2H), 7.31 (d, J = 7.4 Hz, 1H), 5.33 (s, 2H) ; 13C NMR (DMSO-d6) 8165.73,
164.97, 147.72, 142.58, 142.19, 139.43, 138.17, 137.63, 25 135.23, 132.31, 131.35, 129.69, 127.39, 127.23, 122.20,
121.03, 120.96, 120.17, 118.21, 118.12, 111.24, 47.51; MS: 449.3 (M+H)+; HRMS: 449.1414 (obs.), 449.1396 (calcd.);
Anal.: (C22H20N6O3S1+ 2TFA + 0.15 HC1 +1.5H20) C, H, N, F, S, cl.
Preparation of 1 - (4-benrrlpiparidinecarbonvl)methvl-6-
ind w*-hen* vlpip«r *fllnecarbonvl)mefchvl-
(4-Benzylpiperidinecarbonyl)methylene chloride was prepared by acylation of 4-benzylpiperidine (100 mmol) with a-chloroacetyl chloride (100 mmol) in THF (250 mL) and K2CO3 (100
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mL. Alkylation of 5-cyanobenzimidazole (2 mmol) with (4-benzylpiperidinecarbonyl)methylene chloride (2 mmol) in DMF (5 rriL) in the presence of NaH (3 mmol) at from 0°C to room temperature over 16 hours, followed by purification on TLC 5 places gave 1-(4-benzylpiperidinecarbonyl)methyl-6-
cyanobenzimidazole and 1-(4-ben.zylpiperidinecarbonyl)n\ethyl-5-cyanobenzimidazole (0.4 g, 56% of yield). This mixture (1.11 mmol) was then carried through the Pinner reaction, followed by purification on TLC places with 10% MeOH in CH2CI2, and 10 further purification by HPLC to give the title compounds: MP: 54-56°C; MS: 376.4 (M+H)*; HRMS:376.2118 (obs.), 376.2137 (calcd.); Anal.: (C22H25N5O1+ 1.8TFA + 0.1 HC1).
Method C: Example 63 was made by L'lmann coupling 15 reaction of 4-chloro-3-nitrobenzenitrile with (4-
benzylpiperidinecarbonyDmethylamine, followed by reduction of 4- [ (4-benzylpiperidinecarbonyl)methyl J amino-3-nitrobenzonitrile, cyclization with formic acid, and finally the Pinner reaction.
Preparation of 1 - (4 -banzvlpjparidinacarbonvl) —thvl- 6 -tmi fliagfrr**jjaida*ola
(4-Benzylpiperidinecarbonyl)methylaroine was made by treatment of (4-benzylpiperidinecarbonyl)methylene chloride with NaN3 in aqueous acetone, followed by hydrogenation with 5% Pd/C. Reaction of (4-benzylpiperidinecarbonyl)methylamine (8.6 mmol) with 4-chloro-3-nitro-benzonitrile (10 mmol) in DMF 30 (10 mL) in the presence of NaHC03 (10 mmol) at 100°C for 16 hours gave 4-[(4-benzylpiperidinecarbonyl)methyl)amino-3-nitrobenzonitrile (1.6 g, 49.2% of yield), which was then hydrogenated in MeOH in the presence of 5% of Pd/C (10% w/w) to produce 1-(4-benzylpiperidinecarbonyl)methyl-6-35 cyanobenzimidazole (1.3 g, 90% of yield). 1-(4 —
Benzylpiperidinecarbonyl)methyl-6-cyanobenzimidazole (0.57 mmol) was then carried through the Pinner reaction, followed by purification on TLC plates with 10% MeOH in CH2CI2, and
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further purification by HPLC to give the title compound: mp: 68-70°C; iH NMR (CD3OD) 5 8.52 (s, 1H) , 8.20 (s, 1H) , 7.75 <s,
2H) , 7.29-7.24 (m, 2H), 7.18-7.16 (m, 3H), 5 43 (dd, J = 17.2 Hz, J = 24.5 Hz, 2H), 4.40 (d, J = 12.8 Hz, 1H), 4.00 (d, J = 5 12.8 Hz, 1H), 3.18 (t, J = 12.8 Hz, 1H), 2.68 (t, J = 12.8 Hz, 1H), 2.59 (d, J = 7.00 Hz, 2H), 1.87-1.78 (m, 2H), 1.72-1.68 (m, 1H, 1.42-1.35 (m, 1H) . 1.22-1.15 (m, 1H) ; 13C NMR (CD3OD) 8 168.76, 166.06, 148.73, 141.23, 139.50, 130.17, 17- 45, 129.33, 127.35, 127.11, 124.04, 120.40, 113.19, 4 /.36. 46.36, 10 43.93, 43.73, 39.15, 33.35, 32.73; MS: 188.8 (M+2H)2";
HRMS:376.2130 {obs.), 376.2137 (calcd.); Anal.: (C22H25N5O1+ 1.85TFA + 0.18HC1+ 0.5H20).
Exarole 64
Preparation ot 2-f4-(2-
tlili n°n? *"nvlphenvl 1 phenvlcarbonvl 1 methvl-6-
nmi Hi nmfttm4 niflf t
N-ethylnalonyl-4'<-aaiinobiphenyl-2-tert-butylsul£onaaide. To a
solution of 1.01 g of 4'-aminobiphenyl-2-tert-butylsulfonamide in 30 mL anhydrous methylene chloride and 0.93 mL triethylamine was added 0.43 mL of ethylmalonyl chloride by dropwise addition. Let reaction mixture stir overnight at ambient temperature. Concentrated in vacuo to give a residue 25 which was taked up in 50mL ethyl acetate. The organics were washed 3x2 0 mL water. The resulting organics were dried over magnesium sulfate and concentrated under reduced pressure to give the crude product. The crude product was purified via standard chromatographic technique to give 0.70 g of N-30 ethylmalonyl-4'-aminobiphenyl-2-tert-butylsulfonamide.
LRMS(NH3-CI) : 436 (M+NH4) . 1HNMR(CDC13, 300MHz): 8 9.42 (s,
1H), 8.19 (d, 1H), 7.79 (d, 2H), 7.52 (m, 3H), 7.49 (d, 1H), 7.30 (d, 1H), 4.30 (q, 2H), 3.60 (s, 1H), 3.50 (s, 2H), 1.35 (t, 3H), 1.0 (s, 9H).
2-14-(2-uninoaulfonyIpheny1)phenylcarbonyl]mthyl-6-
cyanobenzimidazole. A mixture of 0.32 g of 3,4-diaminobenzonitrile and 0.70 g of N-ethylmalonyl-4'-
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aminobiphenyl-2-tert-butylsulfonamide was heated to 180UC for 20h. Let mixture cool to ambient temperature. Concentration and high vacuum gave 0.09 g of crude 2—[4—(2— aminosulfonylphenyl)phenylcarbonyl]methyl-6-5 cyanobenzimidazole. The crude material was carried through to the next reaction sequence. LRMS(ES+): 43KM+H).
2- [4- (2-oainoaulfonylphenyl)phenylcarbony 1 ]methyl -6-
amidinobenz imidazole. A solution of the crude 2- [4- (2-10 aminosulfonylphenyl) phenylcarbonyl)methyl-6-
cyanobenzimidazole in 10 mL 1:1 anhydrous chloroform to anhydrous ethanol was stirred in an ice bath. Hydrogen choride gas was bubbled into the reaction vessel for 20 minutes. Then the reaction mixture was allowed to warm to 15 ambient temperature over 15h. Concentrated the reaction mixture under reduced pressure and placed the crude product on high vacuum. The resultant ethylimidate was treated directly with 0.30 g of ammonium carbonate in anhydrous ethanol. The reaction mixture was stirred at ambient temperature for 24h. 20 Concentrated reaction mixture under reduced pressure and purified crude product via standard HPLC technique to give purified 2-[4-(2-aminosulfonylphenyl)phenylcarbonyl]methyl-6-amidinobenzimid-azole. LRMS(ES+): 449(m+H). HRMS(FAB): calcd 449.139586 mass 449.139273. *H NMR (DMSO,d6,300MHz) : 6 10.50
(s, 1H) , 9.20 (bs, 2H), 8.67 (bs, 2H), 7.79 (d, 2H), 7.55 (m, 4H), 7.25 (m, 4H), 4.05 (s, 2H).
tltvnrlft »
Preparation of 2-U-(2-tart -30 hutvlaainomilf onvlphenvl) phenvlcarbonvl 1 methvl-5-
N-etbylmalonyl-4' -aaiinobiphanyl-2- tert-butylBulforuunida. To a solution of 1.01 g of 4'-aminobiphenyl-2-tert-butylsulfonamide 35 in 30 mL anhydrous THF and 0.93 mL of triethylamine was added 0.43 mL of ethylmalonyl chloride by dropwise addition. Let reaction mixture stir for 24h. Concentrated in vacuo to give a residue which was taked up in 50mL ethyl acetate. The
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organics were washed 3x20mL water. The resultant organics were dried over magnesium sulfate and concentrated under reduced pressure. The crude product was purified via standard chromatographic technique to give 0.63g of N-ethylmalonyl-4'-5 aminobiphenyl-2-tert-butylsulfonamide. LRMS(NH3-CI):
4 3 6(M+NH4) . NMR(CDCl3, 3 00MHz): 6 9.42 (s.1H), 8.18 (d, 1H) , 7.79 (d,2H), 7.52 (m,3H), 7.49 ld,lH), 7.30 (d,lH).
2- [4- (2-fcert-butylaainosul f onylphenyl) phenylcarbonyl ] methyl-5-
azabenzimidazole. A mixture of 0.026 g of 3, 4-diaminopyridine and 0.10 g of N-ethylmalonyl-4'-aminobiphenyl-2-terc-butylsulfonamide was heated to 165 °C for 20h. Let mixture cool to ambient temperature. Purified crude material by standard chromatographic technique to give the 2-[4-(2-tert-15 butylaminosulfonylphenyl)phenylcarbonyl]methyl-6-azabenzimidazole. LRMS(ES+): 464(M+H). HRMS(NH4-CI): Mass 464.175637 Calcd 464.175630. XH NMR(CDCI3,3C0MHz): 6 9.49 (s,lH), 8.40 (s,1H), 8.15 (d,1H), 7.98 (s,lH), 7.47 (m,3H), 7.31 (d,2H), 7.25 (d,2H), 4.30 (s,2H), 1.0 (S,9H).
^fyle 66 Preparation of 25-14-(2-tert-fonvlphenvl> nhenvlaminocarbonyl1rathvl-thio-ip-
ini<fr»gpu.g-c) pyridine
To a solution of IH-imidazo(4,5-C) pyridine-2-thiol (37 mg, 0.245 mmol) in DMF (2.5 mL) was added 4-(2-tert-butylaminosulfonylphenyl)phenylaminocarbonyl]methyl chloride (75 mg, 0.197 mmol) and then K2CO3 (58 mg, 0.42 mmol), and the 30 resulting mixture was heated at 120°C for 1 hour. To the mixture at room temperature was added HC1 (IN in Et20, 1 mL) and then MeOH (6 mL), a clear solution was obtained. To it was then slowly added Et20 (200 ml), and a white suspension was observed, which was filtered and a white solid (120 mg) 35 was collected. The solid was soluble in DMSO (8 mL), and the resulting solution was purified by HPLC with H2O-CH3CN-TFA to give the title compound (60 mg). HRMS (M+H)+ calc. m/z: 496.1477, obs: 496.1492.
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bxmpjl? . 67 Preparation of 2S-U-(2-ami noeulfonvlphenvl > phenyl ami norwrhrmvllnethvi-thio- 1H-5 IttidazoU.S-C) pyridine
A solution of Example 66 (26 mg) in TFA (0.5 mL) was heated for 16 hours. Removed all of the solvent and purified by HPLC with H2O-CH3CN-TFA to give the title compound (13 mg). 10 HRMS (M+H)* calc. m/z : 440.0851, obs : 440.0831.
Baaaplt 193
Preparation of 1-(4-benzylpiperidinecarbonyl)—thvl-S-
aaidlnoindole
-Cyanoindole-l-nethylacetate. To a stirred solution of 5-cyanoindole (5.0 g, 35.2 mmol) in 10 mL of dry DMF at O'C under N2 atmosphere was added NaH (l.lg, 42.2mmol). The reaction was stirred for 30 min. and then a-bromomethyl-
acetate (5.4g, 35.2mmol) was added and stirred at room temperature for 2h. It was then quenched with H20. extracted with ethyl acetate (3x), dried with Na2S04, filtered and concentrated in vacuo to afford a light yellow solid (7.5g, 35.2 mmol). '•H NMR (CDCI3) 8ppm3.2 (s, 2H) , 3.8 (s, 3H) ,
7.03 (s, 1H), 7.32 (d, 1H, J= 7.5Hz), 7.41 (d, 1H, J=7.5Hz), 7.61 (S, 1H), 7.81 (s, 1H). LRMS NH3-CI m/z (M+H) + 229, (M+NH4)+ 246.
3-(5-Cyanoindole) acetic acid. Methyl-5-cyanoindole-l-acetate 30 was saponified in MeOH, KOH (3.3eq) at rt for 18h. The mixture was concentrated in vacuo, dissolved in water, extracted with diethylether (2x) and the acidic aqueous layer was acidified with 2N HC1. The resulting white solid was filtered and dried in a vacuum oven to afford 6.2 g of the 35 title compound. LRMS ESI (M+H)+ 201.
l-(4-Benzylpiperidinecarbonyl)aethyl-5-cyanoindole. To a stirred complex of 3-acetic acid-5-cyanoindole (2.0g,
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O.liratiol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (DEC) in dry CH2CI2 was added 4-benzylpiperidine (1.8g, O.Olmmol). The mixture was stirred under N2 atmosphere for I8h, then concentrated in vacuo, dissolved in ethyl 5 acetate, washed with IN HC1 (3x) , NaHCC>3 (3x) , brine (2x) , dried with Na2S04, filtered and concentrated in vacuo to afford a white solid (2.8g). HRMS for C23H24N3O (M+H)+ calc. 358.191938, found 358.193278.
1- (4-Benzylpiperidinecarbonyl) methyl-5-aiaidinoindole. N-l-Acetyl-l-N'-piperidinyl-4-benzyl-5-cyanoindole (500mg), was dissolved in dry MeOH (30 mL) cooled to O'C and saturated with HCl(g). The resulting solution was allowed to warm up to rt over 18h. The mixture was concentrated in vacuo, re-dissolved 15 in dry MeOH and (NH<|)2C03 (672.0 mg) was added, flask sealed and stirred for 18 at rt. The resulting suspension was filtered through Celite®, rinsed with dry MeOH, concentrated in vacuo to afford 997mg of product (89% by HPLC); 100 mg of which was further purified via prep HPLC to afford 29 mg (100% 20 purity by HPLC). M.p. 214-215 *C HRMS (NH3-CI) for C23H26N4O (M+H)* calc. 375.217601, found 375.218487. l-H NMR (CD3OD) 6 ppm 1.05 (qd, 1H, J= 7.5 Hz, J= 2-5 Hz), 1.25 (qd, 1H, J=7.5, J=2.5 Hz), 1.65 (bd, 1H, J=7.5 Hz), 1.76 (bd, 1H, J=7.1- <!-) , 1.83 (m, 1H), 2.58 (d, 2H, J=6.0 HzO, 2.63 (t, lH, J= 75 Hz), 25 3.07 (t, 1H, J=7.5 Hz), 4.03 (bd, 1H, J=7.5 Hz), 4.2 (bd, 1H, J=7.5 Hz), 5.21 (qd, 2H, J= 7.5 Hz), 6.63 (s, 1H), 7.18 (m, 3H), 7.23 (m, 2H), 7.38 (s, 1H), 7.51 (d, 1H, J= 5.0 Hz), 7.58 (d, 1H, J=5.0 Hz), 8.05 (s, 1H) .
BKMPl* 102
Preparation of 1-(4-benzylpiperidinecarbonyl)ethvl-5-
amidinoindole
Methyl-5-cyanoindole-3-propionate. To a stirred solution of 35 5-cyanoindole (l.Og, 7.0ntmol), K2CO3 (0.966 g, 7.0nmol) in acetonitrile was added 3-bromomethylpropionate (1.17 g, 7.0mmol). The mixture was stirred at reflux for 18h under a nitrogen atmosphere., cooled, diluted with H2O, extracted with
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ethyl acetate, dried with Na2S04, filtered and concentrated in vacuo to afford 1.59 g of product. *H NMR (CD3OD) Sppm 2.85
(t, 2H. J= 6.6 Hz), 3.61 (s, 3H), 4.58 (t, 2H, J= 6.6 Hz). 6.61 (s, 1H), 7.42, (m. 3H), 7.62 (d, 1H, j= 8.4 Hz), 7.99 (s, 1H) .
-cyanoindole-3-propionic acid. Methy-5-cyanoindole-3-propionate (200 mg) was saponified in MeOH dOxnL)/KOH (150 mg, 0.88mmol) at rt for }8h. The solution was concentrated in vacuo, dissolved in water and washed with chloroform. The acidic layer was acidified and extracted with ethyl acetate, dried with Na2S04, filtered and concentrated in vacuo to afford 188 mg of product. NMR (CD3OD) Sppm 2.83 (t, 2H,
J=6.6Hz), 4.43 (t, 2H, J=6.6 Hz), 6.6 (nd,lH, J3.2 Hz), 7.42 (d, 2H, J= 7.3 Hzl, 7.43 (s, 1H), 7.61 (d. 1H, J=7.3 Hz), 7.99 (s, 1H); LRMS ESI (M+H)* 215.
1-(4-Benzylpiperidinecarbonyl)ethyl-5- amidinoindole.
Preparation follows the same last two steps of example 101. Afforded 156 mg of the TFA salt *H NMR (DMSO-d6) Sppm 2.42
(m, 4H), 2.89 (m, 4H), 3.21 (d, 2H, J= 5.0 Hz), 3.72 (bd, 1H, J=10.0 Hz), 4.12 (m,1H), 4.38 (bd, 1H, J= 10 H2) , 4.51 (m, 2H), 6.62 (s, 1H), 7.1-7.31 (m, 5H), 7.62 <m,2H), 7.72 (d, 1H, J=6.0 Hz), 8.21 (b.->, 1H) , KfcMS (M+H)* for C24H29N4O calc. 389.234137, found }B9.23125B
ex«ple 103
Preparation of 1- <4-(3-fluoro)henrrlpiceridinecarbonvllaethvl-
?a>aldiaeiaafili
4-(3-Fluorobenzyl)piperidine. To a stirred solution of 1-benzylpiperidin-4-one (0.99mL, 5.34mmol) in THF was added Ph3P=CH-(3-fluoro(phenyl (2.41g, 5.34mmol) at 0'C under a nitrogen atmosphere. After stirring for 4h at rt, the reaction was quenched with H2O, concentrated in vacuo and the residue was chromatographed on silica gel using 1:1 hexanes:ethyl acetate as the eluant to afford 313mg of product. LRMS NH3-CI (M+H)* 282. The product (330 mg) was
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hydrogenated in MeOH, 10% Pd/C (300mg) and conc. HCl (5ml.) in a parr shaker at 50psi for 18h. The reaction was filtered through Celite® and the filtrate was concentrated in vacuo to afford 250 mg of the title compound. LRMS NH3-CI (M+K)* 194.
1- (4- (3-Fluoro)benzylpepiridinocarbonyl)methyl-5-cyano indole.
Prepared as in example 101. LRMS ESI (M+H)* 376.
1-(4-(3-Fluoro)benzylpepiridinocarbonyl)methyl-5-
amidinoindole. Example 103 was prepared via the same method as example 101. HRMS FAB glycerol matrix for C23H26N4FO (M+H)* calc. 393.209065, found 393.208858.
minimi ft 104
Preoez-atior of 1-(1-<4-«u»idino)benzvl-N-
(methvlacetate)aminocnrbonvl)methyl-S- amidinoindole
(4-Cyano)benzyl-N- (methylacetate)amine. a-Bromo-tolunitrile. (2•0g, IO.SitctoI) was dissolved in CHCI3 and glycine methyl 20 ester (2.64g, 21.0mmol) and triethyl amine (2.92mL, 10.5mmol) was added. The mixture was stirred for 18h under nitrogen atmosphere, concentrated in vacuo and purified via silica gel column using 1:1 hexanes:ethyl acetate as the eluant to afford 1.07g of the title compound (5.25mmol). LRMS ESI (M+H)* 205. 25 XH NMR (CDCI3) 5ppm 3.42 (s, 2H), 3.7B (s, 3H), 3.91 (s, 2H),
7.42 (d, 2H, J=8.0 Hz), 7.62 (d, 2H, J=8.0 Hz).
1- (1- (4-Cyano)benzyl-N- (methylacetate) aminocarbonyl) methyl-5-cyanoindole. Compound was prepared using the same coupling 30 procedure as in example 101. HRMS NH3-CI for C23H20N4O3 (M+H)* calc. 401.161366, found 401.159527.
1- (1- (4-Amidino) benzyl-N- (methylacetate) aminocarbonyl) methyl-5-amidinoindole. Prepared by the same Pinner conditions as 35 example 101. LRMS ESI (M+2H)*2 218.
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?lf 1<J5
Preparation of Methyl 1- (4-bensvlpiperidine-l-carbonvl)Me thvl-5-Mtidinoindola-3 -nropanoita
Methyl 1 - (4 -benzy lpiperidine-1 -c arbony1) nethy 1 - 5-cyanoindole-
3-propanoate. 1-(4-Benzylpiperidine-l-carbonyl)-5-cyanoindole (l.Og, 2.8mmol) was dissolved in 2 0mL of dry CH2CI2, cooled to O'C and oxalyl chloride (1.07g, 8.4 mmol) was added. The reaction stirred for 3h at rt. It was then concentrated in 10 vacuo and dissolved in dry MeOH (20mL) and stirred for 18h. The resulting yellow solution was concentrated in vacuo and l.Og (2.3mmol) was taken up in TFA (20mL) at O'C and triethylsilane (535 mg, 4.6mmol) was slowly added. The reaction stirred at O'C for 3h and then it was concentrated in 15 vacuo, dissolved in CH2CI2 and washed with sat. NaHC03, dried with sodium sulfate, filtered and concentrated. The resulting residue was chromatographed via silica gel using 7% MeOH/CHCl3 as the eluant to afford 840 mg of the title compound. LRMS ESI (M+H)+ 430.
1 - (4 -Benzy lpiperidine-1 -carbonyl) methyl - 3 -nethylacetate-5 -amidinoindole. The amidine was prepared as in example 101. HRMS NH3-CI for C26H34N4O3 (M+H)+ calc. 447.239616, found 447.241907.
Preparation of 1- ((♦-toenavlPiPeridinecarbonvDaethvl-13-ef hanehvdroKV\>-S-Mnoindole
1- (4-Benzy lpiperidine -1 -carbonyl) zaethy 1 - 3-ethanehydroxy1 - 5 -
cyanoindole. Methyl 1-acetyl-(4-benzylpiperidin-l-yl)-3-acetate-5-cyanoindole (lOOmg, 0.233 mmol) was dissc j.*- d in ethanol and sodium borohydride (20mg, 0.51mmol) was added and the solution stirred at rt for 18h. The reaction was
concentrated in vacuo diluted with water and extracted with methylene chloride (3x), dried over sodium sulfate, filtered and concentrated in vacuo to afford 93.0 mg of the title compound. LRMS DCI-NH3 (M+NH4)+ 419.
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1 - (4 -Benzylpiperidine-1 -carbonyl) methyl - 3-ethanehydroxy 1 -5-amidinoindole. The amidine was prepared as in example 101. HRMS NH3-CI for C25H31N4O2 (M+H)+ calc. 419.244702, found 5 419.245383.
107
Preparation of 1-(4-b«ngylpiPTidlne-l-carbonvl)methvl-3-methvlcarboxvllc acid-5-ami <H noindole
Methyl 1-acetyl-(4-benzylpiperidin-l-yl)-3-acetate-5-amidinoindole was hydrolyzed in TFA/H2O for 18h. Purified via prep HPLC to afford the title compound. LRMS (M+H)+ 433.
108
Praoaratlon of 1 - (1 -Benxvlpjperidina - 4 - aminocarbonyl) methvl - S -
1 - (1 -Benzylpiparidine-4 - aminocarbonyl) Mthyl - S -cyanoindole.
To a stirred complex of N-l-methylenecarbohydroxy-5-
cyanoindole (3 00mg, l.Smmol) and DEC was added 4-amino-l benzylpiperidine and triethylamine (0.209 mL» l.Smmol). The reaction was stirred at rt for 18h. The volatiles were removed in vacuo and the residue was purified via silica gel 25 using l%MeOH/CH2Cl2 as the eluant to afford 160 mg of product. HRMS NH3-CI for C23H24N4O (M+H)+ calc 373.204.204739, found 373.202837.
1- (l-Benzylpiperidine-4-aminocarbonyl) methyl-5-a&idinoindole.
The amidine was prepared as in exeunple 101 to afford 96mg of the title compound. HRMS NH3-CI calc. 390.229386, found 390.229386.
fftrmimlT 19°
Preparation of 1- U-benzovlpipgridinecarbonyDmefchvl-S-
"wftfttipimaole
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1-(4-Benxoylpiperidinecarbonyl)methyl-5-cyanoindole. Prepared as in example 108 except using 4-benzoylpiperidine. HRMS NH3-CI (M+H)+ for C23H21N3O2 calc.372.171702, found 372.171620.
1-(4-Benxoylpip«ridinacarbonyl)mathyl-5-aHiidinoittdol«. The amidine was prepared using the same method as in example 101. HRMS (M+H)+ for C23H24N4O3 calc. 389.197751. found 389.198109.
bmarow hp
Preparation of 1 - < 4 - (3 -fluoro)banzvlpiPTazinacarbonvl 1methyl, -
{>-»%•> jtonoimtolg
1 - (4 - (3 - Fluoro) banzy lpiparaz inacarbonyl) mm thy 1 - 5-cyanoindole.
To a stirred solution of 1-acetyl-(1-piperazine)-5-cyanoindole 15 (400mg, 1.31mmol), triethylamine (0.0.36 mL, 2.62mmol) in diethyl ether was added 3-fluorobenzyl bromide (0.161 mL, 1.31 mmol) and stirred at room temperature under N2 atmosphere for 18h. The reaction quenced with water, extracted with ethyl acetate, dried with sodium sulfate, filtered and concentrated 20 in vacuo to afford 438mg product. LRMS (M+H)* 377.
1- (4- (3-Fluoro)b«nzy.\piperaziMcarbonyl)iMthyl-5-
m prepared as in example 101. HRMS (M+H)* for C22H24N5OF calc. 394.204314, found 394.204917.
Preparation of 1- (4-ph»nvlhan«vla»i,afw»rr^nvl)«athvl-5-
1- (4-Phanylb«nzylaininocarbonyl)*«thyl-5-cyano±ndola. To a stirred complex of 1-acetic acid 5-cyanoindole (250mg,
1.25mmol) and DEC (239mg,1.25mmol) in methylene chloride was added 4-phenybenzylamine (228mg,1.25mmol). After stirring at rt for 18h under a nitrogen atmosphere, the reaction was 35 concentrated in vacuo, dissolved in ethyl acetate, washed with IN HCl, sodium bicarbonate, and brine, dried with sodium sulfate, filtered and concentrated in vacuo to afford 215mg of product. HRMS (M+H)+ calc. 366.260637, found 366.160323.
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X- (4-Phenylbenrylaminocarbonyl) methyl-5-amidinoindole.
Prepared as in example 101. HRMS calc. 383.187187 found 383.189667.
f^-tple 112
Preoartion of aethvl 1-(4-benzylpiperidinecarbonyl)methvl-S-amidinni nriol.e-3-propenoate
Methyl 1-(4-benzylpiperidinecarbonyl)methyl-5-cyanoindole-3-propenoate. To a stirred solution of DMF (15mL) and POCI3 (256mg, 1.7mmol) at 0°C was added 1-(4-benzylpiperidinecarbonyl )methyl-5-cyanoindole (199mg, 0.56mmol). After stirring 3h, the reaction was quenched with 2N sodium 15 hydroxide and stirred for 30 min. It was then extracted with chloroform, dried with sodium sulfate, filtered and concentrated in vacuo to afford product. LRMS (M+H)'1" 386. The product was then refluxed in the presence of triphenyl phosphonium(methylenecarbomethoxy)ylide in THF under a 20 nitrogen atmosphere for 18h. The reaction was concentrated in vacuo and the residue purified via silica gel chromatography using 7% MeOH/CHCl3 as the eluant to afford 140mg of product.
Methyl 1- (4 -benzy lp iper idinecarbony 1) methyl - 5 - amidinoindo le - 3 -
propenoate. Prepared as in example 101. LRMS (M+H)+ 459.
113
Preparation of 1- (4-<2-f luoro) benzylpiperidinecarbonyl) methyls'ml fllnglnflpl*
4-(2-Fluoro)benzylpiperidine. To a stirred solution of triphenylphosphonium-2-fluorobenzylbromide in dry THF at -78'C was added n-buLi (2.5M, 2.13mL) and stirred for 30 min. To it was then added 1-benzyl-4-piperidinene (0.99mL) and the 35 mixture stirred at rt for 4h. The reaction was quenched with water and concentrated in vacuo. The resulting residue was purified via silica gel chromatography using 1:1 hexanes:ethyl acetate as the eluant to afford 313mg. LRMS
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(M+H)+ 282. The product was hydrogenated in a parr shaker at 50psi in MeOH (10mL), 5.oml conc. HCl and 10%Pd/C (300mg) for 18h. The mixture was filterd through celite® and concentrated in vacuo to afford 250mg of product. LRMS (M+H)+ 194.
1 - (4 - (2-Fluoro) benzylpiperidinecarbonyl) methyl-5-cyanoindole.
Prepared by coupling 3-acetic acid-5-cyanoindole with 4-(2-fluoro)benzylpiperidine using the method described in example 101. LRMS (M+H)+ 376.
1- (4- (2 -Fluoro ) benzylpiperidinecarbonyl) methyl - 5 -amidinooindole. Prepared as in example 101. HRMS (M+H) + calc. 393.209065, found 393.20885B .
Preparmfcion of 3-M4-cvclohejcvl) phenyl nw i noww thvlcarbonvl) methyl,flinoindole
Methyl 5-cyanoindole-3-acetate. To a stirred solution of 5-cyanoindole (10.0g/ in dry methylene chloride was added (3.0eq, 61.43mL) of oxalyl chloride. After stirring for lh under a nitrogen atmosphere at rt, the resulting precipitate was filtered and rinsed with diethyl ether. The solids were then taken up in dry MeOH and stirred for lh. At this time the solids were filtered and rinsed with MeOH and diethyl ether to afford 5.93g of methyl a-ketoacetate 5-cyanoindole. LRMS (M+H)+ 229. Methyl a-ketoacetate (4.90g) was dissolved in 50 mL trifluoro acetic acid at 0°C and triethyl silane (5.0g) was slowly added via a drop funnel (20 min.) . It was then stirred at 0°C for 3h. The resulting yellow solution was concentrated in vacuo, neutralized with sodium bicarbonate, extracted with diethyl acetate, dried with magnesium sulfate filtered and concentrated in vacuo. Purification was accomplished via silica gel chromatography using 1%
MeOH/CH2Cl2 as the eluant to afford 2.48g of product. LRMS (M+H)* 232.
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3-(5-Cyanoindole) acetic acid. The above ester was saponified in KOH/MeOH at rt for 18h. The solution 3 was then concentrated in vacuo, dissolved in water, extracted with ethylacetate and the acidic layer was then acidified with IN 5 HCl at 0°C. The resulting white solids were filtered and further dried under high vacuum to afford the product. M.p. 196.5-198.5; Calc. C66.00 H4.04 N13.99, found C65.71 H4.24 N13.94. -^H NMR (CD3OD) 6ppm3.78 (s, 2H) , 7.28 (s, 1H) , 7.38
(d, 1H, J= 8.6 Hz), 7.45 (d, 1H, J= 8.6 Hz), 7.89 (s, 1H) ; 10 LRMS (M+) + 199.
3 - (4 - Cyc lohexylphenylaminoae thy lcarbony 1) methyl - 5 - cyanoindole.
To a stirred complex of the 5-cyanoindole acetic acid (312mg, 1.5mmol) and BOP reagent (1.03g) in DMF was added 4-15 cyclohexylphenylaminomethyl. After heating at 50'C under a nitrogen atmosphere for 18h, the reaction was cooled to rt diluted with water and extracted with ethyl acetate, washed with IN HCl, sat. sodium bicarbonate, and brine, dried with sodium sulfate, filtered and concentrated in vacuo. The 20 residue was purified via chromatography using 100% ethyl acetate as the eluant to afford 210mg of product. LRMS (M+H)+ 372.
3- ((4-Cyclohaxy 1)phenylnmincmetehylcarbony 1)methyl-5-
amidinoindole. Prepared as in example 101. HRMS (M+H)+ for C24H29N4O calc. 389.234137, found 389.232086.
Preparation off 3- (4-p-toJ.uenesulfonvl-30 piperazinecarbonvl) methyl - ? -nfflifll TIM*4 11
3-(4-Paxatoluonsulfonylpiperazlnecarbonyl)methyl-5-eyanoindole. To a stirred solution of 3-
(piperazinecarbonyl)methyl-5-cyanoindole hydrochloride (200mg, 35 Q.66mmol) and triethylamine (134mg, 185^L) in chloroform was added toluenesulfonylchloride (126mg, 0.66inmol). After stirring for 18h at rt under a nitrogen atmosphere, the reaction was quenched with water, extracted with chloroform,
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washed with IN HCl, sat sodium bicarbonate, and brine, dried with sodium sulfate, filtered and concentrated in vacuo to afford 237mg of product. LRMS (M+H)+ 423.
3- (4-Paratoluen«ulfonylpiperazinecarbonyl)methyl-5-
aoidinoindole. Prepared as in example 101. HRMS (M+H)+ for C22H26N5°3S< calc. 440.174611, found 440.175637.
ftwaplt 303
Preparation of 3-(4-(2-amino«ulfonvlphenvl)pvridln«-2-
> methvl - 5-amidinoindole
3-<4-(2-Aminoaulfonylphenyl)pyridine-2-aminocarbonyl)methyl-5-cyanoindole. To a stirred solution of 5-cyano-3-acetic acid 15 indole (400mg, 2.0mmol), BOP (884mg, 3.0mmol) in DMF (15mL) was added 4-(2-aminosulfonyl)phenyl-2-aminopyridine (912mg, 3.0mmol) and heated at 50"C for 3h. The reaction was diluted with water, extracted with ethyl acetate, washed with 10% HCl, sodium bicarbonate, brine, and water, dried with magnesium 20 sulfate, filtered and concentrated in vacuo to afford 420mg of product. LRMS 488. The t-butyl group was removed in TFA reflux for lh and the product purified via silica gel using 100% ethyl acetate as the eluant to afford 101 mg of product. LRMS 432.
3 - (4 - {2 - JU&inosulf ony lphenyl) pyr idine-2-amiaoc&rbony 1) methyl - 5 -
amidinoindole. Prepared as in example 101. HRMS (M+H)+ for C22H22N5°3S calc. 449.139586, found 449.139058.
Bttnagli? 3P-f
Psromratiw of 3-14-12-tetrazole ] phenyl) phenyl aainocarbonvl 1 methvl - * - yj jpplndole
3-(4-[2-Tetr&zole]phenyl)phenylaminocarbonyl)methyl-5-35 cyanoindole. 5-cyanoindole-3-acetic acid was dissolved in DMF/CH2CI2. DEC (3 82mg), and DMAP (lOmg) and the reaction mixture stirred for 15 min. 4-{(2-Tetrazole)phenyl)aniline was added and the reactin mixture stirred for 2h. The
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reaction was concentrated in vacuo, dissolved in ethylacetate and washed with water and brine, dried with magnesium sulfate, filtered and concentrated in vacuo. Purification was done via silical gel using 1:1 hexanes:ethylacetate to afford 660mg of 5 product. The trityl group was cleaved in THF (30mL) and 4M HCl dioxane (0.988mL) at rt for 18h. It was then basified with NaOH to pH 11, washed with ether, acidified to pH 3 with 10% HCl and the precipitate was collected and dried under high vacuum to afford 250mg of product. LRMS (M+H)+ 420.
0
3-(4-[2-Tetrazole]phenyl)phenylaa±nocarbonyl)iiethyl-5-amidinoindole. Prepared as in example 101. HRMS for C23H20N8° (M+H)^ calc. 437.183833, found 437.186710.
Example 20S
Preparation of 3-(4-biphenvlawlnocarbonvl)methvl-S-
rrtfi'urrlnflffjt
The title compound was prepared as in example 101. HRMS 20 (M+H)+ for C23H20N4O calc. 369.172173, iound 369.171537.
206
Preparation of 3-(4-(phanvlmathvlaulf onvl) piperazlnecarbonvl U»ethvl-5-
The title compound was prepared as in exeunple 101. HRMS (M+H)+ C22H25N5O3S calc. 440.176204, found 440.175637.
frUMPl* 297
Preparation of 3-U-cvclohMEYlPhenvlniiinocwThonvllMfchvl-g-
The title compound was prepared as in example 101. HRMS 35 (M+H)+ C23H26N4O calc. 375.218732. found 375.218487.
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bxmplt 2P*
Preparation of 3 - (* -bensvlpiperazi-mcarbonvl 1 methvl- 5 -
The title compound was prepared as in example 101. HRMS (M+H!+ for C22H25N50 calc. 376.213722, found 376.213736.
gynla 209
frip^ratlgn *f ?-(3-10 ri1 'VntttrP™! no (methvlcarbopvlaethoxv) carbonvl ) methvl-S-
The title compound was prepared as in example 101. HRMS cal. 435.214464, found 435.216822.
BKinnlf 21Q Preparation of l-i»athvl-3- (4-rTll-ii ngtmrvl Mlin? (p>«thvlcarhon vlmef hoxv > carbonvl) methvl-S-
The title compound was prepared as in example 101. HRMS calc.435.214464, found 435.213247.
211
Preparation of l-methvl-3-(4-f2-
ulintnl^ny1 l^t'^ritvlmiiiiomrhottvl >
The title compound was prepared as in example 201. LRMS 476, m.p. 231'C.
BXUlttl* 217
Preparation of l-nethvl-3-(4-pfaenvlbensvlMdnonarbonyl) methvl -
The title compound was prepared as in exeunple 201. HRMS calc. 397.202837, found 397.204520.
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Rxamplf. 213
Preparation of l-mathvl-3-(4-phenylpjperazinecarbonyl>m«fchvl-
The title compound was prepared as in example 201. HRMS calc. 389.234137, found 389.234635.
ttmmpl* 214
Preparation of 3-(4-T2-10 Tiring'"1*™™1 >nh«nv1nhiinv1 OB^nmrhnnvl -"-m|jfl|ng,flr'lgl*
The title compound was prepared as in example 203. HRMS calc.448.144337 found 448.143656.
215
Preparation of 3-1l-ben»vlplperidine-4-aminocarbonyl)methyl-5-
«iiflinp*tvi1?lt
The title compound was prepared as in example 201. HRMS calc. 20 390.229386, found 390.230305.
Bk—Pit 216
Preparation of 3-(4-phenvlciperazinac arbonvl)methvl-5-
The title compound was prepared as in example 201. HRMS calc. 362.198086, found 362.197315.
cmn>l£_2lz
Preparation of 3-(4-benTvTniperldinecarbonvl)methvl-5-
The title compound was prepared as in example 201. HRMS calc. 374.210662 found 374.210386.
bka9blfi_2u
Preparation of l-methvl-3-(5-(?-r»<po«ulfonvl)phanvlpyxidine-2-fllffli""earbonvl)methvl-5-amidinoindole
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The title compound was prepared as in example 201. HRMS calc. 463.155236, found 463.155236.
bnim?1? 21?
Preparation of 3- (2-bro«no-4- (2-aminosul £ onyl) phenylphenylaminocarbonyl) Mthyl - 5 - cyano indole
A solution of 3-{2-bromo-4-(2-10 aminosulfonyl)phenylphenylaminocarbonyl(methyl-5-cyanoindoline (1.2378 mmol, 0.7 g) in anhydrous methyl acetate (15 mL) and anhydrous methanol (0.5 mL, 10.0 eq) was saturated with dry hydrogen chloride gas at -20°C for 20 rain. The reaction mixture was stoppered tightly and left at ambient temperature 15 for 18 h. This reaction mixture was evaporated and pumped on for several hours to remove any residual HCl. To this imidate in anhydrous methanol (15 mL) was added ammonium carbonate (1.189 g, 10.0 eq.). This reaction mixture was allowed to stir at ambient temperature for 24 h. This final reaction 20 mixture was evaporated and purified by HPLC on a C-18 column eluted with solvent mixture A (water:TFA 99.95:0.05) and solvent mixture B (acetonitrile:TFA 99.95:0.05) using a gradient starting with A at 80 % and changing to B at 100 % over 60 min. After lyophylization, 0.122 g of pure product 25 (15%) was obtained; HRMS (M+H)+ calc. 526.054848, found 526.053791 for o-Br compound.
fbmbpl- i7n Preparation of 3-{2-methyl-4-(2-3 0 aainoaulf onyl) phenylphenylaminocarbonyl) methyl-5-nethylamino indole
To the solution of 3-(2-methyl-4-(2-
aminosulfonyl)phenylphenylaminocarbonyl(methyl-5-cyano indole 35 (0.5992 mmol, 0.3 g) in absolute ethanol:TFA 4:6 was added palladium hydroxide on carbon (0.06 g, 20 % weight equivalent of starting material used). This reaction mixture was stirred under house vacuum for 10 minutes at ambient temperature to
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remove oxygen. Then subjected to 1 atm H2 via balloon method for 3 h. The reaction mixture was filtered through celite to remove catalyst and washed with ethanol (20 mL). The filtrate was evaporated to give the desired product with t-butyl 5 sulfonamide. This product was treated with trifluoroacetic acid at 55°C for 2 h for deprotection of sulfonamide. The reaction mixture was evaporated and purified by HPLC on a C-18 column eluted with solvent mixture A (water:TFA 99.95:0.05) and solvent mixture B (acetonitrile:TFA 99.95:0.05) using a 10 gradient starting with a at 80 % and changing to B at 100 %
over 60 min. to give 10.0 mg of pure product (3 %, poor yield due to poor solubility); HRMS (M+H)+ calc. 449.164738, found 449.165207.
371
Preparation of 3-{2-fluoro-4-(2-aminosul fonyl) phenylphenylaminocarbonyl) methyl - 5i nr.* w^r»i»
The titled compound was prepared as in Example 203. HRMS 20 (NH3-CI/DEP) (M+H)+ for C23H21N5SO3F calculated 466.134915; found 466.133832.
ekmpI? Ill
Preparation of 3-{2-chloro-4-(2-2 5 aminosulf onyl) phenylphenylaminocarbonyl) methyl-5-cyanoindole
The titled compound was prepared as in Example 203. HRMS for C25H21N5SO3CI (M+H)+ calc. 482.105364; found 482.103835.
Kumrtt 32"*
Preparation of 3-{2-iodo-4-(2-aminosulf onyl) phenylphenylaminocarbonyl) methyl - 5-cyanoindole
The titled compound was prepared as in Example 203. HRMS for 35 C23H21IN5O3S (M+H)+ calc. 574.040989; found 574.042800.
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Kwirol* 224 Preparation of 3-{2-mathy1-4-(2-aminoffulfonyl) phenylphanyl axiinocarbony 1) methyl - 5 - amidinoindole
The titled compound was prepared as in Example 203. HRMS for C24H24N5O3S (M+H)- calc. 462.159987; found 462.158553.
BWiBPlt 22*
Preparation of 3-{2-methyl-4-(2-(t-10 butylaminoaulfonyl))phenylphenylaminocarbonyl )methyl-5-
amidinoindole
The titled compound was prepared as in Example 203. HRMS for C28H32N5O3S (M+H)+ calc.518.222587; found 518.22; '98.
ffiHUTPlt 22 -Preparatioa of 3-(4-(2-aminoaulf onyl) phenyl) pheny laminocarbonylmethyl-a-
(methyl car boxy methyl r *^7 r
The titled compound (racemic) was prepared as in Example 203. HRMS for C26H25N5O5S (M+H)+ calc 520.166599; found 520.165466.
bxwpl* 227
Preparation of 3-(4-(2-
aminoaulf onyl) phenyl) phenylaminocarbonylaethyl-a- (benzyl) -5-
amidinoindole
The titled compound (racemic) was prepared as in Example 203. 30 HRMS for C30H29N5O3S (M+H)+ calc. 538.191287; found 538.191263.
bkmplo ^29
preparation of 3 - { 4 - (2 - trif luoroeie thy 1) phenyl) pyrid-2-ylarainocarbonylmethyl-5 - amidinoindole
The titled compound was prepared as in Example 203. HRMS for C23H20N5O1F3 (M+H)+ 438.154170; found 438.152166.
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flMunnlft. 233
Preparation of 3-{4-(2-athylamino«ulfonyl) phenyl) phwnylami noc arbonylnathy1 - 5 -
amidinoindole
The titled compound was prepared as in Exfiiple 203. HRMS for C26H27N5O3S1 (M+H)*- calc. 476.175637; found 476.175892.
EmnPle 230
Preparation of 3-{4-(2-
propylaainoaulf onyl) phenyl) phenyl) aminocarbonylmethyl-5-
aaidinoindole
The titled compound was prepared as in Example 203. HRMS for 15 C26H27N5O3S (M+H)+ calc. 490.191287; found 490.190996.
Bywnplo 33\
Preparation of 2-*ethyl-3-{2-iodo-4-(2-aainosul f onyl) phenyl) phenyl) aainocarbonylm thy 1 - 5 -20 a»t<Hinolndole
The titled compound was prepared as in Example 203. HRMS for 4H23IN5O3S1 (M+H)+ calc. 558.056639; found 55e.057057.
Itmwnl* 333
Preparation of 2-wethyl-3-{4-(2-anino sulfonyl) phenyl} phenyl) aminocarbonylmethyl-5-
aiidlnolndole
The titled compound was prepared as in Example 203. LRMS for c24h23n5o3s1 (M+H)* 462-
Preparation of 3-{4-(2-aminoaulfonyl)phenyl)phenyl}-N-35 aethylaminocarbonyljaetbyl-5-amidinoindole
The titled compound was prepared as in Example 203 . LRMS for C24H24N5O3S1 (M+H)+ 462.
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magpie 234 preparation of 2-Mthyl-3-(4-(2-t-butylaminosulf oayl )phenyl)phenyl) aminocarbonylmethyl-5-5 methoxyindole
The titled compound was prepared as in Example 2011. LRMS for C28H31N3O4S1 (M+H) + 506.
yr1' 235
Preparation of 3 - { 4 - (2 -N-aethylaninosulfony 1) phenyl) phenyl > -N-aethy laminocarbonylaethyl - 5 -amidinoindole
The titled compound was prepared as in Example 203. HRMS for 15 C24H23N5O3S (M+H)+ cacl. 462.159987; found 462.159054.
bxttwl* h6 Preparation of 3-(4-(2-(n-butylaminosulf onyl) phenylphenylaminocarbonyl )methyl-5-2 0 cyanoisdoline
To a solution of 3-acetic acid indoline (0.001 mol, 0.2 g) [or indoline acid (0.001 mol, 0.202 g)) in anhydrous acetonitrile (10 mL) was added thionyl chloride (0.3 mL, 4.0 eq.) [for 25 indoline, 1.0 M HCl in ethyl ether (0.05 mL, 1.0 eq.) was added before thionyl chloride]. This reaction mixture was warmed up at 50°C for 10 min. then allowed to cool to ambient temperature and stirred for 2 h. The solvent and extra thionyl chloride were removed in vacuo and the residue was 30 pumped on for several hours for further dry. To this dried residue was added a mixture of A-B (0.338 g, 1.0 eq.) and triethyl amine (0.14 mL, 1.0 eq.; 2.0 eq. for HCl salt) in anhydrous methylene chloride (10 mL). This reaction mixture was allowed to stir at ambient temperature for 2 h. The 35 reaction mixture was evaporated and purified by flash chromatography on a silica gel column (50 g) eluted with 3:1 hex&ne:ethyl acetate to give 0.4 g of pure product with n-butyl sulfonamide (51 %).
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.222
Preparation of 3-{4-(2-(n-propylaminoaulfonyl) p hanylph any 1 aminocarbonyl) »•thy1-5-5 amitlinoindolins
The titled compound was prepared as in Example 203. HRMS for C26H30N5SO3 (M+H)+ calc. 492.206937; found 492.207667.
Example 236
Praparation of (-)-3-{4-(2-a*ino«ulfonyl)phenyl)pyrid-2-ylaainocarbonylmethyl-5-aaidinoindolina
The titled compound was prepared as in Example 203 . HRMS for 15 C22H24N6O3S1 (M+H)* calc.451.155236; found 451.154317.
Exaaple 239
preparation of 3-{4 - (2-aminouulf onyl) phenyl) pyrid-2-ylaminocarbonylnathyl-5-aaidinoindoline
The titled compound (racemic) was prepared as in Example 203. HRMS for C22H24N6O3S1 (M+H)+ calc. 451.15523 6; found 451.154317.
Bn«pl* 2AO
Praparation of 3-{4-(2-dijnatby laainosulf ony 1) phenyl) phenylaainocarbony Ine thy 1 -5-
aaddino indoline
The titled compound (racemic) was prepared as in Example 203. HRMS for C25H26N5O3S1 (M+H)+ calc. 450.159987; found 450.159435.
.241
Praparation of ( + ) —3—<4- (2-t-butylaminoaulfonyl) phenyl )pyr id -2-ylaminocarbonylmethyl-5-amirtinoindoline
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The tided compound was prepared as in Example 203. HRMS for C2&H10N6O3S1 (M+H)+ calc. 507.217836; found 507.217901. 98%ee: rotation (+) 19.23.
34?
preparation of (-) -3-{4- (2-t-butylaminosulf onyl) phenyl )pyrid-2 -y 1 aminocarbonylmethyl - 5 - amidinoindoline
The titled compound was prepared as in Exeunple 203 . HRMS for 10 C26H30N6O3S1 (M+H)+ calc.507.217836; found 507.217678. 98%ee; rotaion -16.28.
Preparation of 3-{4-(2-aminosulfonyl)phenyl)pyrid-2-15 y 1) aminocarbonylmethyl - 5 - aminocarboxyindoline
The titled compound (racemic) was prepared as in Example 203. HRMS for C22H23N603Si (M+H) * calc. 451.1552036; found 451 .154691.
I« 244
Preparation of 3-(4-(2-t-butylaminosulf onyl )phenyl)phenyl> aminocarbonylmethyl-5-
amidinoindoline
The titled compound was prepared as in Example 203. LRMS for C2?H3iN503Si (M+H)- calc. 506.3; found 506.4.
Preparation of 3-{4-(2-t-butylaminosulfonyl)phenyl)pyrid-2-y 1} aminocarbonylmethyl-5-amidinoindolin*
The titled compound (racemic) was prepared as in Example 203. LRMS for C26H30N6O3S1 (M+H)+ calc. 507.3; found 507.4.
246
Preparation of 3 - { 4 - (2-aminosulfonyl)phenyl)pyrid-2-ylaminocarbonylnethyl-6-anidinoindazole
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The titled compound was prepared as in Example 203. HRMS for C21H21N703S! (M+H)+ calc. 450.134835; found 450.134725.
tmirolt \\n
Preparation of 3-{4-(2-aainoaulfonyl) phenyl) phenyl aminocarbonylmethyl - 6 - amidinoindazole
The titled compound was prepared as in Example 203. HRMS for 10 C22H22N6O3S1 (M+H)+ calc. 449.139586; found 449.138515.
Preparation of 3-(4- (2-t-butyl aminosulfonyl)phenyl)pyrid-2-yleninocarbonylmethyl- 6 -anidinoindazole
The titled compound was prepared as in Example 203. HRMS for c25h29n7o3s1 (M+H)+ calc.450.134835; 450.134725
brcrng'li* 249
Preparation of 3-/4-(2-t-butylutinosulfonyl)phenyl)phenyl aaisoc .. t bonylme thy 1 - 6 - nai rtinoindazole
The titled compound was prepared as in Example 203. HRMS for C26H30N6O3S1 (M+H)* calc.505.202186; found 505.202631.
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Table 5
<3
v-oet h^Oc) *
Ex
Aa.
Poa.
A
B
MS (100H) or HRMS
1
a+b phenethvl
3-amidino
204 (M+2H)2+
2
b phenerhyl
3-amidino
204.2 (M+2H>2+
3
a
Dhenethvl
3-amidino
204.2 <M+2H>2+
4
a+b phenethvl
4-amidino
407.2200
b phenethyl
4-amidino
204 (M+2H)2 +
6
a
Dhenethvl
4-amidino
204 (M+2H)2+
7
a+b phenyl-CH=
4-amidino
196.2 (M+2H)2+
8
a-b phenyl
4-amidino
197 (M+2H)2+
86
Printed from Mimosa
Table 6a
H2N
Ex
Am. Poa.
Z
A
B
MS (100\) or HRMS
51
a
C (0)
phenyl
4-phenyl
355.1554
52
b
C (0)
phenyl
4-phenyl
355.1559
53
a
C(0)
phenyl
4-(3-NH2)phenyl
370 (M+H)+
54
b
C (0)
phenyl
4-(3-NH2)phenyl
370 (M+H)+
55
a
C<0>
phenyl
4-(4-F)phenyl
373.1481
56
a
C(0)
phenyl
4-(4-CHO)phenyl
383.1531
57
a
CIO)
phenyl
4 -(2-NH2SO2)phenyl
434.1303
58
a
CIO)
phenyl
4-(2-tBuNHS02) phenyl
59
a
C(0>
phenyl
4-(2-tetrazolyl) phenyl
423.1686
60
a
C (0) NH
phenyl
4-(2-NH2SO2)phenyl
449.1414
61
b
C (0) NH
phenyl
4-(2-NH2SO2)phenyl
449.1401
62
a+b
C(0)
1-piperidine
4-benzyl
376.2118
63
b
C(0)
1-piperidine
4-benzyl
376.2130
64
a
C(O)
phenyl
4 -(2-NH2 SO2)phenyl
449.1393
65*
6-aza
C(0)
phenyl
4-(2-tBuNHS02) phenyl
436
*Ex. 65 contains the CHj-Z-A-B group at the 2-position.
87
Printed from Mimosa
W0 9S/01428
PCT/US97/1U25
Table 6b ay-*-
Xx
Z'
A
B
HRMS
65*
CH?C(0)
phenyl
4-(2-tBuNHS02)phenyl
464.1756
66
SCH3C(0)NH
Dhenvl
4-{2-tBuNHS02)phenyl
496.1477
67
SCH2C(0)NH
phenyl
4-(2-NH2 SO?)pheny1
440.0831
88
Printed from Mimosa
Tmbl* 7
EX
R1
2'
A
B
MS or HRMS
101
h c(0)
1-piperidine
4-benzvl
375.218
102
h ch2c(0)
1-piperidine
4-benzvl
389.231
103
h cl 0)
1-piperidine
4-13-F)benzvl
393.209
104
h c(0)n(ch2
co2ch3)
benzyl
4-amidino
218
105
ch2-C02Me cio)
1-piperidine
4-benzyl
447 .242
106
ch2-ch20h cio)
1-piperidine
4-benzyl
419.245
107
ch2-co2h cio)
1-piperidine
4-benzyl
433
108
h c(o)nh
4-piperidine
1-benzvl
390.229
109
h cio)
1-piperidine
4-benzoyl
389.198
110
h cio)
1-piperazinyl
4-(3-F)benzvl
394.205
111
h c(0)nh benzvl
4-phenyl
383.190
112
ch=ch-c02me cio)
piperidine
4-benzyl
459
113
h cio)
piperidine
4-I2-F)benzvl
393.209
89
Printed from Mimosa
Table 8a*
Bx
D
R1
Z
A
B
MS or HRMS
201
Am h
c(0>-
ch2nh phenyl
4-cyclohexyl
389.232
202
Am h
c(0)
1-
piperazinvl
4-p-toluenesulfonyl
440.176
203
Am h
c <0)nh
2-pyridyl
4- (2-aminosulfonyl) phenyl
449.139
204
Am h
c(0)nh
1-phenyl
4- (2-tetrazol-5-vl)phenyl
437.187
205
Am h
c(0)nh
1-phenyl
4-phenyl
369.171
206
Am h
c(0)
1-
piDerazinvl
4-phenyl-methvlsulfonvl
440.176
207
Am h
c(0)nh
1-phenyl
4-cvclohexvl
375.218
208
Am h
c(o)
1-
piperazinyl
4-benzyl
376.214
209
Am
Me c(0)n-(ch2c02
ch3)
benzyl
3-amidino
435.217
210
Am
Me c(o)n-(ch2c02
ch3)
benzyl
4-amidino
435,213
211
Am
Me c(0)nh benzyl
4 — (2 — aminosulfonyl) phenyl
476
212
Am
Me c(0)nh benzyl
4-phenyl
397.205
213
Am
Me c(0)ch2
1-
piperazinvl
4-benzyl
389.235
90
Printed from Mimosa
W0 9&Q1428
214
Am
H
C(0)NH
phenyl
4-(2-aminosulfonyl) phenyl
448.144
215
Am
H
C(0)
4-
piperidinyl
1-benzyl
390.230
216
Am
H
C(O)
1-
piperazinvl
4-phenyl
362.197
217
Am
H
C(O)
1-
piperidinyl
4-benzyl
374.210
218
Am
Me
C(0)NH
2-pyridyl
- (2-aminosulfonyl) phenyl
463.155
219
CN
H
C(0)NH
2-Br-phenyl
4- (2-aininosul fonyl) phenyl
526.054
220
CH3-NH
H
C(0)NH
2-Me-phenyl
4- (2-aininosul fonyl) phenyl
449.164
221
Am
H
C|0)NH
2-F-phenyl
4-<2-aminosul fonyl) phenyl
466.134
222
CN
H
C (0) NH
2-Cl-phenyl
4- (2-aminosulfonyl) phenyl
482.104
223
CN
H
C(0)NH
2-I-phenyl
4- (2-aminosulfonyl) phenyl
574.043
224
Am
H
C(0)NH
2-Me-phenyl
4- (2-aminosulfonyl) phenyl
462.156
225
Am
H
C (0) NH
2-Me-phenyl
4-(2-t-Bu-aminosulfonyl) phenyl
518.222
226
Am
H
(CH30-C(0)-CH2)CH
phenyl
4-(2-aminosulfonyl) phenyl
520.165
91
Printed from Mimosa
227
Am
H
(phenyl
-ch2)ch phenyl
4 - (2 -aminosulfonyl) phenyl
538.191
228
Am h
c(o)nh
2-pyridyl
4- !2-CF3-phenyl)
438.152
229
Am h
c (o)nh phenyl
4- {2-ethylaninosulfon yl)phenyl
476.176
230
Am h
c (o) NH
phenyl
4- (2-p ropy1amino-sulfonyl>phenyl
490.191
231
Am h
c(0)nh (R1=2-methyl)
2-I-phenyl
4-12-aminosulfonyl) phenyl
558.057
232
Am h
c (0) NH (R1=2-methvl)
phenyl
4- (2-axninosulf onyl) phenyl
462
233
Am h
C<0)-NCH3
phenyl
4- (2-aminosulfonyl) phenyl
462
234
CH3O
h c(0)nh (R1=2-methvl)
pheny1
4-(2-t-Bu-aminosulfonyl) phenyl
506
235
Am h
c(0) -nch3
phenyl
4- (2-me thy1aminosul fonyl )phenyl
462.160
♦For all Examples, but 226 and 277, n=l. For Examples 226 and 227, n=0.
92
Printed from Mimosa
Table 8b
PCT7US97/11325
Ex
D
R1
Z
A
B
MS or HRMS
236
CN
H
C (0) NH
phenyl
4-(2-n-Bu-aminosulfonyl) phenyl
237
Am
H
C (0) NH
phenyl
4-(2-propylamino-sulfonyl)phenyl
492.208
238 (-)
Am
H
C (0) NH
2-pyridyl
4-(2-aminosulfonyl) phenyl
451.154
239
Am
H
C (0 (NH
2-pyridyl
4-(2-aminosulfonyl) phenyl
451.155
240
Am
H
C(C)NH
phenyl
4-(2-N.N-dimethylamino-sulf crnyl ) phenyl
450.160
241
M
Am
H
C (0) NH
2-pyridyl
4-(2-t-Bu-amino-sulfonyl)phenyl
507.218
242
(-)
Am
H
C (0) NH
2-pyridyl
4-(2-t-Bu-amino-sulf onyl)phenyl
507.218
243
NH2-C(O)
H
C(0)NH
2-pyridyl
4-(2-aminosulfonyl) phenyl
451.154
244
Am
H
C(0)NH
phenyl
4-(2-t-Bu-amino-sulf onyl )phenyl
506.4
245
Am
H
C (0)NH
2-pyridyl
4-(2-t-Bu-amino-suIfonyl)phenyl
507.4
93
Printed from Mimosa
PCTAJS97/11325
Table 8c
Sx
D
R1
Z
A
B
MS or HRMS
246
Am
H
C (O) NH
2-pyridyl
4- (2-aminosulfonyl) phenyl
450.135
247
Am
H
C(0)NH
phenyl
4- (2-aminosulfonyl) phenyl
449.139
248
Am
H
CtOINH
2-pyridyl
4-(2-t-Bu-amino-sulfonvl)phenyl
450.135
249
Am
H
C(0)NH
phenyl
4-(2-t-3u-amino-suIfonyl)phenyl
505.203
94
Printed from Mimosa
Table 9
Ex n
z
A-B
301
1
CIO)
4-(2-
aminosulfonvlphenvl)phenvl
302
1
CIO)
4-(2-aminosulfonylphenyl)-2-pvridvl
3 03
1
CIO)
4-(2-methylaminosulfonyl-phenvl)phenvl
304
1
CIO)
4- 12-ethylaminosulfonyl-phenvl)-2-pvridvl
305
1
CIO)
2-aminosulfonyl-4-cvc1ohexvlphenvl
306
1
CIO)
3-aminosulfony1-4-t-buty1-2-pvridyl
307
1
CIO)
2-(5-indazol-5-yl)furanvl
308
1
CIO)
2-(5-indazol-6-vl)thienvl
309
1
CIO)
4-12 -tetrazolvlphenvl)phenvl
310
-4»
C(0)NH
4-(2-
aminosulfonvlphenvl)phenyl
311
1
C(0)NH
4-(2-aminosulfonylphenyl)-2-pvridvl
312
1
C(0)NH
4- (2-methyleuninosulfonylphenyl )phenvl
313
1
C{0)NH
4-12-ethylaminosulfonyl-phenvl )-2-pvridvl
314
1
C(O)NH
2-aminosulfonyl- 4 -eye1ohexy1phenv1
315
1
C{0)NH
3-aminosulfony1-4-t-buty1-2-pyridvl
316
1
C(O)NH
2-(5-indazol-5-vl)furanvl
317
1
C (O)NH
2-(5-indazol-6-vl)thienvl
95
Printed from Mimosa
318
1
c(0)nh
4- (2-tetrazolvlphenvl)phenvl
319
1
nhc(o)
4- (2-
aminosulfonvlphenvl)phenvl
320
nhc(o)
4-(2-aminosulfonylphenyl)-2-pvridvl
321
1
nhc(o)
4 -(2-mechylaminosulfonyl-phenvl)phenvl
322
1
nhc(o)
4-(2-ethylaminosulfonyl-phenvl)-2-pvridvl
323
1
nhc(o)
2-aminosulfony1-4-cvc1ohexv1phenv1
324
1
nhc(o)
3-aminosulfonyl-4-t-butyl-2-pvridvl
325
1
nhc(o)
2-(5-indazol-5-vl)furanvl
326
1
nhc(o)
2 -(5-indazol-6-vl)thienvl
327
1
nhc(o)
4-(2-tetrazolylphenyl)phenvl
328
1
so2nh
4- (2-
aminosulfonvlphenvl> phenvl
329
1
so2nh
4-(2-aminosulfonylphenyl)-2-Pvridvl
330
1
so2nh
4- (2-methylaminosulfonyl-phenvl)phenvl
331
1
so2nh
4-(2-ethylaminosulfonyl-phenvl\-2-pvridvl
332
1
so2nh
2-aminosulfonyl-4-cvclohexvlPhenvl
333
1
so2nh
3-aminosulfonyl-4 -1-butyl-2 -pvridvl
334
1
so2nh
2-(5-ind^zol-5-vl)furanvl
335
1
so2nh
2-(5-indazol-6-vl)thienvl
336
1
so2nh
4-(2-tetrazoIvlphenvl)phenvl
337
0
ch(ch2ch20h)c(0)nh
4- (2-
aminosulfonvlphenvl)phenvl
338
0
ch(ch2ch20h)c(0)nh
4-(2-aminosulfonylphenyl)-2-pvridyl
96
Printed from Mimosa
339
0
CH(CH2CH2OH)C(O)NH
4-(2-methylaminosulfonylphenyl) Dhenvl
340
0
CH(CH2CH20H)C(0)NH
4-(2-ethylaminosulfonylphenyl) -2-pvridvl
341
0
CH(CH2CH2OH)C(O)NH
2-aminosulfonyl-4-cvclohexvlDhenvl
342
0
CH{CH2CH20H)C(O)NH
3-aminosulfonyl-4-t-butyl-2-pvridvl
343
0
CH(CH2CH20H)C(0)NH
2-(5-indazol-5-vl)furanyl
344
0
CH(CH2CH20H)C(0)NH
2-(5-indazol-6-vl)thienyl
345
0
CH(CH2CH20H)C(0)NH
4 -(2 -tetrazolvlphenvl)phenvl
346
0
CH(CH2-tetrazolvl)C (O)NH
4- (2-
aminosulfonylphenyl)phenvl
347
0
CH(CH2-tetrazolvl)C(O)NH
4-(2-aminosulfonylphenyl)-2-pvridvl
348
0
CH(CH2-tetrazolvDC (O)NH
4-(2-methylaminosulfonyl-phenvl)phenvl
349
0
CH(CH2-tetrazolvDC (O)NH
4-(2-ethylaminosulfonyl-phenvl)-2-pyridyl
350
0
CH(CH2-
tetrazolvl)C(O)NH
2-aminosulfonyl-4-cryc 1 ohexvlphenvl
351
0
CH(CH2-terrazolvl)C(0)NH
3-aminosulfonyl-4-t-butyl-2-pvridvl
352
0
CH(CH2-tetrazolvl)C(0)NH
2-(5-indazol-5-yl)furanyl
353
0
CH(CH2-
tetrazolyl)C (O)NH
2-(5-indazol-6-yl)thienyl
354
0
CH(CH2-tetrazolvl)C(0)NH
4-(2-tetrazolylphenyl)phenyl
97
Printed from Mimosa
Table 10
Kx n Z
A-B
401
1
C(O)
4- (2-
aminosulfonvlphenvl)phenvl
402
1
C(O)
4-(2-aminosulfonylphenyl)-2-pvridvl
403
1
C(O)
4-(2-methylaminosulfonyl-phenvl)phenvl
404
1
C(0)
4-<2-ethylaminosulfonyl-phenvl)-2-pvridvl
405
1
C(O)
2-aminosulfonyl-4-cvc1ohexylphenvl
406
1
C(O)
3-aminosulfonyl-4-t-butyl-2-pvridvl
407
1
C(O)
2- (5-indazol-5-vl) fiiranvl
408
1
C{0>
2-(5-indazol-6-vl)thienvl
409
1
C(0>
4-(2-tetrazolvlphenvl)phenvl
410
1
C (0) NH
4-(2-
aminosulfonvlphenvl)phenvl
411
1
C (0) NH
4-(2-aminosulfonylphenyl)-2 -pvridvl
412
1
C(0)NH
4-(2-methylaminosulfonyl-phenvl)phenvl
413
1
C (0) NH
4-(2-ethylaminosulfonyl-phenvl)-2-pvridvl
414
1
C (O) NH
2-aminosulfony1-4-cyc 1 ohexv lphenvl
415
1
C(0)NH
3-aminosulfonyl-4-t-butyl-2-pvridvl
416
1
C (O) NH
2-(5-indazol-5-vl)furanvl
417
1
C(0)NH
2-(5-indazol-6-vl)thienvl
98
Printed from Mimosa
PCT/US97/U325
418
1
c (0)nh
4 -(2 -tetrazolvlphenvl)phenvl
419
1
nhc(o)
4- (2-
aminosulfonvlphenvl)Phenyl
420
1
nhc(o)
4-(2-aminosulfonyIphenyl)-2-pyridvl
421
1
nhc(o)
4-(2-methylaminosulfonyl-phenvl) phenvl
422
1
nhc(0)
4- (2-ethylaminosuifonylphenyl) -2-pvridvl
423
1
nhc(o)
2-aminosulfonyl-4-cvclohexvlDhenvl
424
1
nhc (0)
3-aminosulfonyl-4 -t-butyl-2-pvridvl
425
1
nhc (0)
2-(5-indazol-5-vl)furanyl
426
1
nhc(0)
2-(5-indazol-6-vl)thienvl
427
1
nhc(0)
4-(2-tetrazolvlphenvl)phenvl
428
1
so2nh
4 - (2-
aminosulfonvlohenvl)phenvl
429
1
so2nh
4-(2-aminosulfonyIphenyl)-2-pvridvl
430
1
so2nh
4-(2-methylaminosulfonyl-phenvl )Dhenvl
431
1
s02nh
4-(2-ethylaminosulfonyl-Dhenvl)-2-ovridvl
432
1
so2nh
2-aminosulfonyl-4-eye 1ohexvlphenvl
433
1
so2nh
3 -aminosulfonyl-4-t-butyl-2-pyridvl
434
1
SO2NH
2-(5-indazol-5-yl)furanvl
435
1
s02nh
2- (5-indazol-6-vl)thienyl
436
1
s02nh
4 - (2 -tetrazolvlphenvl)phenvl
437
0
ch (CH2CH2OH) c (0) nh
4- (2-
aminosulf onvlphenvl) phenvl
438
0
ch (CH2CH2OH) c (o) nh
4- (2-aminosulfonyIphenyl)-2-pvridvl
99
Printed from Mimosa
PCTYUS97/11325
439
0
CH(CH2CH20H)C(0)NH
_ — i
4-(2-methylaminosulfonyl-phenyl)phenvl
440
0
CH(CH2CH20H)C(0)NH
4-(2-ethylaminosulfonyl-phenyl)-2-pvridyl
441
0
CH(CH2CH20H)C(0)NH
2-aninosulfonyl-4-cyclohexvlphenvl
442
0
CH(CH2CH20H)C(0)NH
3 -ciminosulfonyl-4-t-butyl-2-pvridvl
443
0
CH(CH2CH2OH)C(0)NH
2 -(5-indazol-5-yl)furanvl
444
0
CH(CH2CH20H)C(0)NH
2-(5-indazol-6-vl)thienyl
445
0
CH(CH2CH2OH)C(0)NH
4-(2-tetrazolylphenvl)Dhenvl
446
0
CH(CH2-tetrazolvl;C(0)NH
4- (2-
aminosulfonvlphenvl)phenvl
447
0
CH(CH2-tetrazolvl)C(O)NH
4 - (2-ciminosulfonylphenyl) -2-pvridvl
448
0
CH(CH2-tetrazolvl)C(O)NH
4- (2-methylaminosulfonylphenyl )phenvl
449
0
CH(CH2-tetrazolvl)C(0)NH
4- (2-ethylaininosulfonylphenyl )-2-pvridvl
450
0
CH(CH2-tetrazolvl)C(O)NH
2-aminosulfonyl-4-cyclohexvlphenvl
451
0
CH(CH2-tetrazolvl)C(0)NH
3-aminosulfonyl-4-t-butyl-2-pvridvl
452
0
CH(CH2-tetrazolvl)C(0)NH
i (5-indazol-5-yl)furanyl
453
0
CH(CH2-tetrazolvl)C(0)NH
2-(5-indazol-6-yl)thienyl
454
0
CH(CH2-tetrazolvl)C(0)NH
4-(2-tetrazolylphenyl)phenyl
100
Printed from Mimosa
Table 11
Ex n
Z
A-B
501
1
C(O)
4-(2-aminosulfonyIphenyl)-2-
pvridvl
502
1
C(O)
4-(2- methylaminosulfonylphenyl )phenyl
503
1
CtO)
4-(2-ethylaminosulfonylphenyl )-2-pvridvl
504
1
C{0>
2-aminosulfony1-4-cvclohexvlphenvl
505
1
C(0)
3-aminosulfonyl-4-t-butyl-2-pyridvl
506
1
C(O)
2-(5-indazol-5-vl)furanvl
507
1
C (0)
2 -(5-indazol-6-vl)thienvl
508
C(0)
4 -(2 -tetrazolvlphenvl)Dhenvl
509
1
C(O)NH
4-(2-aminosulfonylphenyl)-2-pyridvl
510
1
C{0)NH
4-(2-methyl aminosulfonylphenyl )phenvl
511
1
C(0)NH
4-(2-ethylaminosulfonyl-Dhenvl)-2-Dvridvl
512
1
C(0)NH
2-aminosulfonyl-4-cvclohexylphenvl
513
C{0)NH
3-aminosulfony1-4-1-butyl-2-pvridvl
514
1
C(0)NH
2-(5-indazol-5-vl)furanvl
515
1
C(0)NH
2-(5-indazol-6-vl)thienvl
516
1
C(0)NH
4-(2-tetrazolvlphenvl)phenvl
517
1
NHC(0)
4- (2-
aminosulfonvlphenvl)phenvl
101
Printed from Mimosa
518
1
nhc(o)
4- (2-aminosulfonylphenyl)-2-pvridvl
519
1
nhc(0)
4- (2-methylaminosulfonyl-phenvl)phenvl
520
1
nhc(0)
4 - (2-ethylaminosulfonylphenyl) -2-pvridvl
521
1
nhc(0)
2-aminosulfonyl-4-cyc1ohexvlDhenvl
522
1
nhc(0)
3-aminosulfonyl-4-t-butyl-2-pyridvl
523
1
nhc 10)
2-(5-indazol-5-vl)furanvl
524
1
nhc(0)
2-(5-indazol-6-vl)thienyl
525
1
nhc(0)
4-(2-tetrazolvlphenvl)phenyl
52t>
1
so2nh
4- (2-
aminosulfonvlphenvl)phenvl
527
1
so2nh
4-(2-aminosulfonylphenyl)-2-pvridvl
528
1
so2nh
4-(2-methylaminosulfonyl-phenvl)phenvl
529
1
so2nh
4- (2-ethylaminosulfonyl-phenvl)-2-pvridvl
530
1
SO2NH
2-aminosulfonyl-4-cvc1ohexvlDhenvl
531
1
SO2NH
3-aminosulfonyl-4-t-butyl-2-pvridvl
532
1
SO2NH
2-(5-indazol-5-vl)furanyl
533
1
SO2NH
2-(5-indazol-6-vl> thienvl
534
1
SO2NH
4-(2-tetrazolvlphenvl)phenvl
535
0
ch(ch2ch20h)c(0)nh
4- (2-
aminosulfonvlphenvl)phenvl
536
0
ch(ch2ch2oh)c(0)nh
4-(2-aminosulfonyIphenyl)-2-pvridvl
537
0
ch (ch2ch2oh) c (0) nh
4-(2-methylaminosulfonylphenyl )phenvl
538
0
ch (ch2ch2oh) c (0) nh
4-(2-ethylaminosulfonylphenyl )-2-pvridvl
102
Printed from Mimosa
PCMJS97/11325
539
0
CH(CH2CH20H)C(0)NH
2-aminosulfonyl-4-cvc1ohexvlDhenvl
540
0
CH(CH2CH20H)C(0)NH
3-aminosulfonyl-4-t-butyl-2-ovridvl
541
0
CH(CH2CH20H)C(0)NH
2-(5-indazol-5-vl)furanvl
542
0
CH(CH2CH20H)C(0)NH
2-(5-indazol-6-vl)thienvl
543
0
CH(CH2CH20H)C(0)NH
4- (2-tetrazolvlphenvl)phenvl
544
0
CK(CH2-tetrazolvl)C(0)NH
4- (2-
aminosulfonvlphenvl)phenvl
545
0
CH(CH2-tetrazolvl)C(0)NH
4- (2-aminosulfonyIphenyl)-2-pvridvl
546
0
CH(CH2-tetrazoiyDC (O)NH
4- (2-methylaminosulfonyl-phenvl)phenvl
547
0
CH(CH2-tetrazoiyl)C (0) NH
4- (2-ethylaminosulfonyl-phenvl)-2-pyridyl
548
0
CH(CH2-tetrazolvl)C(O)NH
2-aminosulfonyl-4-cvc1ohexyIpheny1
549
0
CH(CH2-tetrazolvl)C(O)NH
3-aminosulfonyl-4-t-butyl-2-pyridvl
550
0
CH(CH2-tetrazolvl)C(O)NH
2-(5-indazol-5-yl)furanyl
551
0
CH(CH2-tetrazolvl)C(0)NH
2-(5-indazol-6-yl)thienyl
552
0
CH(CH2-tetrazolvl)C(O)NH
4 - (2-tetrazolylpheny1)phenyl
103
Printed from Mimosa
Tabl* 12
£X
n
Z
A-B
601
1
C(O)
4- (2-
euninosulf onvlphenvl) Dhenvl
602
1
C(0>
4 - (2-aminosulfonyIphenyl)-2-pvridvl
603
1
C(O)
4-(2-methylaminosulfonylphenyl) phenvl
604
1
C(0)
4-(2-ethylaminosulfonyl-phenvl)-2-pyridvl
605
1
C(O)
2-aminosulfonyl-4-cvclohexvlDhenvl
606
1
C(O)
3-aminosulfonyl-4-t-butyl-2-pyridvl
607
C(O)
2-(5-indazol-5-vl)furanvl
608
1
C (O)
2-(5-indazol-6-vl)thienvl
609
1
C(O)
4-(2-tetrazolylphenvDDhenvl
610
1
C(0)NH
4 — (2 -
aminosulfonvlphenvl)Dhenvl
611
1
C(0)NH
4-(2-aminosulfonyIphenyl)-2-pvridvl
612
1
C(0)NH
4-(2-methylaminosulfonylphenyl) Dhenyl
613
1
C(0)NH
4-(2-echylaminosulfonyl -phenvl)-2-Dvridyl
614
1
C(0)NH
2-aminosulfonyl-4-cvc1ohexylphenvl
615
1
C(0)NH
3-aminosulfonyl-4-t-butyl-2-pyridyl
616
1
C (0) NH
2-{5-indazol-5-vl)furanvl
617
1
C(0)NH
2- (5-ir.dazol-6-yl) thienvl
104
Printed from Mimosa
618
1
c (0) nh
4- (2-tetrazolvlDhenvl)Dhenvl
619
1
nhc(0)
4- (2-
aminosulfonylphenvl)Dhenvl
620
1
nhc(0)
4- (2-aminosulfonylphenyl)-2-pvridvl
621
1
nhc(0)
4- (2-methylaminosulfonyl-Dhenvl)Dhenvl
622
1
nhc(0)
4- (2-ethylaminosulfonyl-Dhenvl)-2-pvridvl
623
1
nhc(0)
2-aminosulfony1-4-cvclohexvlohenvl
624
nhc (0)
3-aminosulfonyl-4-t-butyl-2-Dvridvl
625
1
nhc(0!
2-(5-indazol-5-vl)furanvl
626
1
nhc (0)
2 -(5-indazol-6-vl)thienvl
627
1
nhc (0)
4-(2-tetrazolvlDhenvl)Dhenvl
628
1
so2nh
4-(2-
aminosulfonvlDhenvl)Dhenvl
629
1
so2nh
4- (2-aminosulfonyIphenyl)-2-Dvridvl
630
1
so2nh
4-(2-methylaminosulfony1-Dhenvl)Dhenvl
631
1
so2nh
4-(2-ethylaminosulfonyl-Dhenvl)-2-Dvridvl
632
1
so2nh
2-aminosulfonyl-4-cvc1ohexvlohenv1
633
1
so2nh
3-aminosulfonyl-4-t-butyl-2-
DVridyl
634
1
so2nh
2-(5-indazol-5-vl)Curanvl
635
1
so2nh
2-(5-indazol-6-vl)thienvl
636
1
so2nh
4-(2-tetrazolvlDhenvl)Dhenvl
637
0
ch(ch2ch20h)c(0)nh
4-(2-
aminosulf onvloheny1)Dhenvl
638
0
ch{ch2c.-j2oh)c(0)nh
4-(2-aminosulfonylphenyl)-2-Dvridvl
105
Printed from Mimosa
PCTYUS97/11325
639
0
CH(CH2CH20H)C(0)NH I
4-(2-methylaminosulfonylphenyl )phenyl
640
0
CH(CH2CH20H)C{O)NH
4-(2-ethylaminosulfonyl-phenyl)-2-pyridyl
641
0
CH(CH2CH20H)C(0)MH
2-aminosulfony1-4-cvc1ohexylpheny1
642
0
CH(CH:CH20H)C(O)NH
3-aminosulfonyl-4-t-butyl-2-pyridvl
643
0
CK(CH2CH20H)C(0)NH
2- (5-indazol-5-yl)furanvl
644
0
CH(CH2CH20H)C{0)NH
2-(5-indazol-6-vl)thienvl
645
0
CH(CH2CH2OH)C(0)NH
4 -(2 -tetrazolvlphenvl)Dhenvl
646
0
CH(CH2-tetrazolyl)C(0) NH
4-<2-
aminosulfonvlphenyl)phenvl
647
0
CH(CH2-tetrazolvl)C(0)NH
4-(2-aminosulfonyIpheny1)-2-pvridvl
648
0
CH(CH2-tetrazolvl)C(0)NH
4-(2-methylaminosulfonyl-Dhenvl)Dhenvl
649
0
CH(CH2-tetrazolvl)C(0)NH
4-(2-ethylaminosulfonyl-Dhenvl)-2-Dvridvl
650
0
CH{CH2-tetrazolyl)C(0)NH
2-aminosulfonyl-4-cvclohexvlphenvl
651
0
CH(CH2-tetrazolvl)C(0)NH
3-aminosulfonyl-4-t-butyl-2-Dvridvl
652
0
CH(CH2-tetrazolvl)C(0)NH
2-(5-indazol-5-yl)furanyl
653
0
CH{CH2-tetrazolvl)C(0)NH
2-(5-indazol-6-yl)thienyl
654
0
CH(CH2-tetrazolvl)C(0)NH
4- (2-tetrazolylphenyl)phenyl
106
Printed from Mimosa
Tabla 13
Ex n
Z
A-H
701
1
C(0)
4- (2-
aminosulfonvlphenvl)phenvl
702
1
C(O)
4-(2-aminosulfonylphenyl)-2-pvridvl
703
1
C(O)
4 - (2-methylaminosulfonyl-phenyl)phenvl
704
1
C(O)
4-{2-ethylaminosulfonylphenyl )-2-pvridvl
705
1
C(O)
2-aminosulfonyl-4-cyclohexvlphenvl
706
1
C(O)
3-aminosulfonyl-4-t-butyl-2-pyridvl
707
1
C(O)
2-(5-indazol-5-vl)furanvl
708
1
CIO)
2-(5-indazol-6-vl)thienvl
709
1
C(O)
4-(2-tetrazolvlphenvl}Dhenvl
710
1
C(0)NH
4-(2-methylaminosulfonyl-phenvl)phenvl
711
1
C (0) NH
4-(2-ethylaminosulfony1-ohenvl)-2-pvridvl
712
1
C (0) NH
2-aminosulf onyl-4-cvclohexvlDhenvl
713
1
C (0) NH
3-ciminosulf onyl-4-t-butyl-2-pvridvl
714
1
C (0) NH
2-(5-indazol-5-vl)furanvl
715
1
C(0)NH
2-(5-indazol-6-vl)thienvl
716
1 •L
C(0)NH
4-(2-tetrazolvlDhenvl)Dhenvl
717
1
NHC(0)
4- (2-
aminosulfonvlDhenvl)Dhenvl
107
Printed from Mimosa
718
1
nhc(0)
4-(2-aminosulfonyIphenyl)-2-pyridvl
719
1
nhc(0)
4-f2-methylaminosulfonyl-phenvl)phenvl
720
1
nhc(0)
4- (2-ethylaminosulfonyl-phenvl)-2-pvridvl
721
1
nhc(0)
2-aminosulfonyl-4-cvc1ohexvlphenvl
722
1
nhc (0)
3-aminosulfonyl-4-t-butyl-2-pvridvl
723
1
nhc(0)
2-(5-indazol-5-vl)furanvl
724
nhc(0)
2 -(5-indazol-6-yl)thienyl
725
1
nhc(0)
4- (2-tetrazolylphenyl)phenvl
726
1
so2nh
4-12-
aminosulfonylphenvl)phenyl
727
1
so2nh
4-(2-aminosulfonylphenyl)-2-pyridvl
728
1
so2nh
4- (2-methylaminosulfonyl-phenvl)phenvl
729
1
so2nh
4- (2-ethylaminosulfony1-phenvl)-2-pyridvl
730
1
SO2NH
2-aminosulfonyl-4-cvclohexvlphenvl
731
1
so2nh
3-aminosulfonyl-4-t-butyl-2 -pvridvl
732
1
so2nh
2-(5-indazol-5-yl)furanvl
733
1
so2nh
2-(5-indazol-6-vl)thienvl
734
1
so2nh
4-(2-tetrazolylphenyl)phenvl
735
0
ch (CH2CH2OH) c (o) nh
4 - (2 -
aminosulfonylphenvl)phenvl
736
0
ch(ch2ch2oh)c(o)nh
4-(2-aminosulfonyIphenyl)-2-pvridvl
737
0
ch(ch2ch20h)c(o)nh
4-(2-methylaminosulfonyl-phenvl)phenvl
738
0
ch (ch2ch2oh) c (o) nh
4-(2-ethylaminosulfonyl-phenvl)-2-pvridvl
108
Printed from Mimosa
PCT7US97/11325
739
0
CH(CH2CH2OH)C (O)NH
2-aminosulfonyl-4-cyclohexvlphenyl
740
0
CH(CH2CH20H)C<0)NH
3-aminosulfony1-4-t-buty1-2-pvridvl
741
0
CH(CH2CH2OH)C(O)NH
2-(5-indazol-5-vl)furanyl
742
0
CH'CH2CH2OH)C(O)NH
2-(5-indazol-6-vl)thienvl
743
0
CH(CH2CH20H)C(O)NH
4-(2-tetrazolylphenvl)phenvl
744
0
CH(CH2-tetrazolvl)C (0) NH
4- (2-
aminosulfonylphenyl)phenvl
745
0
CH(CH2-tetrazolvl)C(0) NH
4-(2-aminosulfonyIphenyl)-2-pvridvl
746
0
CK(CH2-tetrazolyl)C(0)NH
4-(2-methylaminosulfonylphenyl )phenyl
747
0
CHICH2-tetrazolvl) C (O) NH
4-(2-ethylaminosulfonylphenyl) -2-pvridvl
748
0
CH(CH2-tetrazolvl)C(O) NH
2-aminosulfonyl-4-cvclohexvlpheny1
749
0
CH(CH2-tetrazolvl)C(O)NH
3-aminosulfony1-4-t-butyl-2-pvridvl
750
0
CH<CH2-tecrazolvl)C(O)NH
2 -(5-inda2ol-5-yl)furanyl
751
0
CH(CH2-tetrazolvl)C(O)NH
2-(5-indazol-6-yl)thienyl
752
0
CH(CH2-tetrazolyl)C(0)NH
4 -(2-tetrazolyIphenyl)phenyl
109
Printed from Mimosa
PCI7US97M1325
Table 14
K*
n
Z
A-B
801
1
C(O)
4 — (2 —
aminosulfonvlDhenvl)phenvl
802
1
C(O)
4-(2-aminosulfonylphenyl)-2-pvridvl
803
-
C(O)
4-(2-methylaminosulfonylphenyl )phenvl
804
1
C(O)
4-(2-ethylaminosulfonyl-phenvl)-2-pvridvl
805
1
C(O)
2-aminosulfonyl-4-cvc1ohexvlDhenv1
806
1
C(O)
3-aminosulfonyl-4-t-butyl-2-pvridvl
807
1
C(O)
2-(5-indazol-5-yl)furanvl
808
1
C(O)
2-(5-indazol-6-vl)thienvl
809
1
C(0)
4-(2-tetrazolvlphenvl)phenvl
810
1
C (0) NH
4-(2-
aminosulfonvlphenvl)phenvl
811
1
C(0)NH
4-(2-aminosulfonyIphenyl)-2-pvridvl
812
1
C (0) NH
4-(2-methylaminosulfonylphenvl )phenvl
813
1
C(0)NH
4-(2-ethylaminosulfonylphenyl) -2-pvridvl
814
1
C(0)NH
2-aminosu1fonyl- 4 -cyclohexvlphenvl
815
1
C(O)NH
3-aminosulfonyl-4-t-butyl-2-pvridvl
816
1
C(0)NH
2-(5-indazol-5-vl)furanvl
817
1
C(0)NH
2-(5-indazol-6-vl)thienvl
110
Printed from Mimosa
PC1YUS97/U325
818
1
C(0)NH
4 -(2 -tetrazolvlDhenvl)Dhenvl
819
1
NHC(0)
4- (2-
aminosulfonylphenvl)Dhenvl
820
1
NHC(0)
4-(2-aminosulfonylphenyl)-2-pvridvl
821
1
NHC (0)
4-i2-methylaminosulfonyl-Dhenvl)Dhenvl
822
NHC(0)
4-(2-ethylaminosulfonyl-Dhenvl)-2-Dvridvl
823
1
NHC(0)
2-aminosulfonyl-4-cvclohexvlDhenvl
824
1
NHC(0)
3-aminosulfonyl-4-t-butyl-2-pvridvl
825
1
NHC 10)
2 -(5 -indazol-5-yl)furanvl
826
1
NHC (0)
2 -(5-indazol-6-vl)thienvl
827
1
NHC(0)
4 -(2 -tetrazolvlDhenvl)phenvl
828
1
so2nh
4- (2-
aminosulfonylphenvl)phenvl
829
1
so2nh
4-(2-aminosulfonylphenyl)-2-DVridvl
830
1
S02NK
4-(2-methylaminosulfonyl-Dhenvl)Dhenvl
831
1
so2nh
4-(2-ethylaminosulfonylphenyl) -2-pvridvl
832
1
S02NH
2-aminosulf ony1-4-cvclohexvlDhenvl
833
1
so2nh
3-aminosulfonyl-4-t-buty1-2-Dvridvl
834
1
SO?NH
2-(5-indazol-5-vl)furanvl
835
1
so2nh
2-(5-indazol-6-vl)thienvl
836
1
S02NH
4-(2-tetrazolvlphenvl)phenvl
837
0
CH(CH2CH20H)C(0)NH
4- (2-
aminosulfonylphenvl)Dhenvl
838
0
CH(CH2CH20H)C(0)NH
4-(2-aminosulfonylphenyl)-2-Dvridvl
111
Printed from Mimosa
WO 9^01428
839
0
CH (ch2ch2oh) C (0) NH
4 -(2-methylaminosulfonyl-phenyl(phenyl
840
0
CH(CH2CH2OH)C (O)NH
4-(2-ethylaminosulfonyl-phenyl)-2-pyridyl
841
0
CH<CH2CH2OH)C(0)NH
2-aminosulfonyl-4-cyc1ohexvlphenyl
842
0
CH(CH2CH20H)C(0)NH
3-aminosulfonyl-4-t-butyl-2-pvridvl
843
0
CH(CH2CH20H)C<0)NH
2-(5-indazol-5-vl)furanvl
844
0
CH(CH2CH20H)C(O)NH
2-(5-indazol-6-yl)thienvl
845
0
CH(CH2CH20H)C(0)NH
4-(2-tetrazolylphenyl)phenvl
846
0
CH(CH2-tetrazolvl)C(0)NH
4- (2-
aminosulfonylphenyl)phenvl
847
0
CH(CH2-tetrazolyl> C(0)NK
4-{2-aminosulfonylphenyl)-2-pyridvl
848
0
CH(CH2-tetrazolvl)C(0)NH
4-(2-methylaminosulfonylphenyl )phenvl
849
0
CH(CH2-tetrazolyl)C(0)NH
4-(2-ethylaminosulfonylphenyl) -2-pyridyl
850
0
CH(CH2-tetrazolvl)C(O)NH
2 -aminosulfony1-4-cyclohexvlphenvl
851
0
CH(CH2-tetrazolyl)C(0)NH
3-aminosulfonyl-4-t-butyl-2-pvridyl
852
0
CH(CH2-tetrazolyl)C(0)NH
2 -(5 -indazol- 5-yl)furanyl
853
0
CH(CH2-tetrazolvl)C(0)NH
2-(5-indazol-6-yl)thienyl
854
0
CH(CH2-tetrazolyl)C(0)NH
4-(2-tetrazolylphenyl)phenyl
112
Printed from Mimosa
Tabl« 15
Ex n
Z
A-B
901
1
C(O)
4- (2-
aminosulfonvlphenvl)phenvl
902
1
C(0)
4-(2-aminosulfonylphenyl)-2-pvridyl
903
1
C(O)
4-(2-methylaminosulfonyl-phenvl)phenyl
904
1
C[0)
4- (2-ethylaminosulfonylphenyl) -2-pvridvl
905
1
C(O)
2-aminosulfonyl- 4 -cvc1ohexvlphenvl
906
1
C(O)
3-aminosulfonyl-4-t-butyl-2-cvridvl
907
1
C(O)
2-(5-indazol-5-vl)furanvl
908
1
C(O)
2-(5-indazol-6-yl)thienvl
909
1
C(O)
4-(2-tetrazolvlchenyl) phenvl
910
1
C (0) NH
4- (2-
aminosulfonvlphenvl) phenvl
911
1
C(0)NH
4-(2-aminosulfonylphenyl)-2-pvridvl
912
1
C (0) NH
4-(2-methyl aminosulfonylphenvl) phenvl
913
1
C(O)NH
4- (2-ethylauiinosulfonyl-phenvl)-2-pvridvl
914
1
C(0)NH
2-aminosulf ony1-4-c vc 1ohexvlphenv1
915
1
C(0)NH
3-aminosulfonyl-4-t-butyl-2-pvridvl
916
1
C(0)NH
2-(5-indazol-5-yl)furanvl
917
1
C (0) NH
2-(5-indazol-6-yl)thienvl
113
Printed from Mimosa
PCT/US97.I1325
918
1
c (0) nh
4-(2-tetrazolvlphenvl'phenyl
919
1
nhc(0)
4- (2-
aminosulfonvlphenvl)phenyl
920
1
nhc(01
4-(2-aminosulfonylphenyl)-2-pvridvl
921
1
nhc(0)
4-(2-methylaminosulfonylphenyl )phenvl
922
1
nhc (0)
4-(2-ethylaminosulfonyl-_phenyl)-2-pyridvl
923
1
nhc (o)
2-aminosulfonyl-4-cvc1ohexvlphenvl
924
1
nhc(0)
3-aminosulfonyl-4-t-butyl-2-pvridvl
925
1
nhc (0)
2- (5-indazol-5--vl) furanvl
926
1
nhc (o)
2-(5-indazol-6-vl)thienvl
927
nhc(0)
4-(2 -tetrazolvlphenvl)phenvl
928
1
so2nh
4- (2-
aminosulfonylphenvl)phenvl
929
1
s02nh
4-(2-aminosulfonylphenyl)-2-pvridvl
930
1
so2nh
4-(2-methylaminosulfonylphenvl )phenvl
931
1
so2nh
4-(2-ethylaminosulfonyl-phenvl)-2-pvridvl
932
1
so2nh
2-aminosulfonyl-4-cvclohexvlphenvl
933
1
so2nh
3-aminosulfony1-4-t-butyl-2-pvridvl
934
1
so2nh
2-(5-indazol-5-vl)furanvl
935
1
so2nh
2-(5-indazol-6-vl)thienvl
936
1
s02nh
4-(2-tetrazolvlphenvl)phenvl
937
0
ch(ch2ch20h)c(o)nh
4- (2-
aminosulfonvlphenvl)phenvl
938
0
ch (ch2ch2oh) c (0) nh
4-(2-aminosulfonylphenyl)-2-pvridvl
114
Printed from Mimosa
0
0
0
0
0.
0.
£
0
0
0
0
0
0
0
PC7WS97/11325
CH(CH2CH20H)C(0)NH
4-(2-methylaminosulfonyl - phenyl)phenyl
CH(CH2CH20H)C(0)NH
(2-ethylaminosulfonyl-phenyl)-2-pyridyl
CH(CH2CH20H)C(0)NH
2-aminosulfonyl-4 -cyclohexvlphenvl
CH(CH2CH2OH)C(O)NH
3-aminosulfonyl-4-t-butyl-2- pyridyl
CH(CH2CH2OH)C(Q)NH
2-(5-indazol-5-yl)furanyl
CH (CH2CH2OH) C (O) NH
2 -(5-indazol-6-yl)thienvl
CH(CH2CH2OH)C(Q)NH
4 -(2 -tetrazolvlphenvl)phenvl
CH(CH2-cetrazolyl)C(Q)NH
4-(2-
aminosulfonylphenvl)phenvl
CH(CH2-tetrazolyl)C(O)NH
4-(2-aminosulfonylphenyl)-2- PVridvl
CH(CH2-tetrazolyl)C(0)NH
4-(2-methylaminosulfonyl- phenvl)phenvl
CH(CH2-tetrazolvl)C(0)NH
4-(2-ethylaminosulfonyl-phenvl)-2-pyridyl
CH(CH2-tetrazolvl)C(0)NH
2-aminosulfonyl-4-cyclohexyIphenyl
CH(CH2-tetrazolvl)C(0)NH
3-aminosulfony1-4-t-butyl-2- pyridyl
CH(CH2-tetrazolvl)C(0)NH
2-(5-indazol-5-yl)furanyl
CH(CH2-tetrazolvl)C(O)NH
2-(5-indazol-6-yl)thienyl
CH(CH2-tetrazolyl)C(0)NH
4-(2 -tetrazolylpheny1)phenyl
115
Printed from Mimosa
Table 16
Ex n
z
A-B
1001
1
C(O)
4- (2-
aminosulfonylDhenvl)Dhenvl
1002
1
C(O)
4-(2-aminosulfonylphenyl)-2-pyridvl
1003
1
C(0>
4-(2-methylaminosulfonylphenyl) phenvl
1004
1
C(O)
4 -(2-ethylaminosulfonyl-phenvl)-2-pyridyl
1005
1
Cl O)
2-aminosulfonyl-4 -eye1ohexvlphenvl
1006
1
C(O)
3-ammosulfonyl-4-t-butyl-2-pyridvl
1007
1
Cl 0)
2-(5-indazol-5-vl)furanvl
1008
1
C(O)
2-(5-indazol-6-vl)thienvl
1009
1
C(O)
4-(2-tetrazolvlphenvl)phenvl
1010
1
C (0) NK
4-(2-
aminosulfonylphenvl)Dhenvl
1011
1
C(0)NH
4-(2-aminosulfonylphenyl)-2-pyridvl
1012
1
C(0)NH
4-(2-methylaminosulfonylphenyl) phenvl
1013
1
C(0)NH
4-(2-ethylaminosulfonylphenyl )-2-pyridyl
1014
1
C (0)NK
2-aminosulfonyl-4-cyclohexvlphenvl
1015
1
C(0)NH
3-aminosulfonyl-4-t-butyl-2-pvridvl
1016
1
C (0)NH
2-(5-indazol-5-vl)furanvl
1017
1
C(0)NH
2-(5-indazol-6-vl)thienvl
116
Prixited from Mimosa
PCTAJS97/11325
1018
1
c (0) nh
4- 12-tetrazolvlDhenvl)phenvl
1019
1
nhc(0)
4- (2-
aminosulf onvlphenvl) phenvl
1020
1
nhc (0)
4-(2-aminosulfonylphenyl)-2-pvridvl
1021
1
nhc(o)
4-(2-methylaminosulfonyl-phenvl)phenvl
1022
1
nhc (o)
4-(2-ethylaminosulfonyl-phenvl)-2-pyridvl
1023
1
nhc (o)
2-aminosulfonyl-4-cvclohexvlphenvl
1024
1
nhc(o)
3-aminosulfonyl-4-t-buty1-2-Dvridvl
1025
1
nhc(o)
2-(5-indazol-5-vl)furanvl
1026
1
nhc(o)
2-(5-indazol-6-vl)thienvl
1027
1
nhc (o)
4-(2-tetrazolvlphenvl)phenvl
1028
1
so2nh
4- (2-
aminosul f onvlphenvl) phenvl
1029
1
so2nh
4-(2-aminosulfonylphenyl)-2-pvridvl
1030
1
so2nh
4- (2-methylaminosulfonylphenvl )phenvl
1031
1
so2nh
4-(2-ethylaminosulfonyl-phenvl)-2-pvridvl
1032
1
so2nh
2-aminosulfonyl-4-cvc1ohexvlphenvl
1033
so2nh
3-aminosulfonyl-4-t-butyl-2-pvridvl
1034
1
sojnh
2-(5-indazol-5-vl)furanyl
1035
1
so2nh
2-(5-indazol-6-yl)thienvl
1036
1
so2nh
4-(2-tetrazolvlphenvl)phenvl
1037
0
ch (ch2ch2oh) c <o) nh
4- (2-
aminosulfonvlphenvl)phenvl
1038
0
ch(ch2ch20h)c(o)nh
4- (2-aminosulfonylphenyl)-2-pvridyl
117
Printed from Mimosa
1039
0
CH(CH2CH20H)C(0)NH
4-12-methylaminosulfonylphenyl) phenyl
1040
0
CH (CK2CH2OH) C (0) NH
4- (2-et.hylaminosulfonyl-phenyl)-2-pyridvl
1041
0
CH(CH2CH2OH)C (O)NH
2-aminosulfonyl-4-cvclohexvlDhenvl
1042
0
CH(CH2CH20H)C(0)NH
3-aminosulfonyl-4-t-butyl-2-pyridvl
1043
0
CH(CH2CH20H)C<0)NH
2-(5-indazol-5-vl)furanvl
1044
0
CH(CH2CH20H)C{0)NH
2- (5-indazol-6-vl)thienvl
1045
0
CH<CH2CH20H)C(0)NH
4-(2-tetrazolvlphenvl)phenvl
1046
0
CH(CH2-tetrazolyl)C(O)NH
4- (2-
aminosulfonvlphenvl)phenvl
1047
0
CH(CH2-tetrazolvl) C (O) NH
4-(2-aminosulfonylphenyl)-2-pvridvl
1048
0
CH(CH2-tetrazolvl)C(O)NH
4-(2-methylaminosulfonyl-phenv1)ohenv1
1049
0
CH(CH2-tetrazolyl) C (O) NH
4-(2-ethylaminosulfonyl-phenvl)-2-pyridvl
1050
0
CH(CH2-tetrazolvl)C(O)NH
2-aminosulf ony1-4-cvc1ohexylphenvl
1051
0
CH(CH2-tetrazolvl)C(0) NH
3-aminosulfonyl-4-t-butyl-2-pvridvl
1052
0
CH(CH2-tetrazolvl)C(O)NH
2-(5-indazol-5-yl)furanyl
1053
0
CH(CH2-tecrazolyl)C(O)NH
2-(5-indazol-6-yl)thienyl
1054
0
CH(CH2-tetrazolvl)C(O)NH
4-(2-tetrazolylphenyl)phenyl
118
Printed from Mimosa
PC1YUS97/11325
Table 17
EX
n z
R1
A-B
1101
1
c(o)
h
3-acetyl-4-benzvlpiperidine
1102
i cio)
h
4-(4-fluorobenzvl)Diperidine
1103
1
cio)
h
4-(2,3-di fluorobenzyl) piperidine
1104
1
cio)
h
4-(2-chloro-4-fluorobenzyl) Diperidine
1105
cio)
ch2ch2oh
3-acetyl-4-benzylpiperidine
1106
l cio)
ch2ch2oh
4-(3-fluorobenzvl)piperidine
1107
1
cio)
ch2ch2oh
4-(4-fluorobenzvl)piperidine
1108
1
cio)
ch2ch2oh
4-(2,3-difluorobenzyl) piperidine
1109
1
cio)
ch2ch20h
4-(2-chloro-4-fluorobenzyl) piperidine
1110
1
cio)
ch2och3
4-benzvlpiperidine
1111
1
cio)
ch2OCHi
3-acetvl-4-benzvlpiperidine
1112
1
cio)
ch2och3
4 -(3 -fluorobenzvl)piperidine
1113
1
cio)
ch2och3
4-(4-fluorobenzvl)piperidine
1114
11
l cio)
ch2och3
4-(2,3-di fluorobenzyl) piperidine
1
cio)
ch2och3
4-(2-chloro-4-fluorobenzyl) piperidine
1116
1
cio)
ch2ch2-tetrazolvl
4-benzylpiperidine
1117
l cio)
ch2ch2-tetrazolyl
3-acetyl-4-benzylpiperidine
1118
1
cio)
ch2ch2-tetrazolvl
4-(3-fluorobenzyl)piperidine
119
Printed from Mimosa
1119
1
C(O)
CH2CH2-tetrazolvl
4 -(4 -fluorobenzyl)piperidine
1120
1
C(0)
CH2CH2-tetrazolyl
4 -(2, 3-di fluorobenzyl) piperidine
1121
1
C(0)
CH2CH2-tetrazolyl
4-(2-chloro-4-fluorobenzyl) piperidine
1122
1
C(0)NH
H
3-acetyl-4-benzylpiperidine
1123
1
C(O)NH
H
4-(3-fluorobenzyl)piperidine
1124
1
C(0)NH
H
4 -(4 -fluorobenzvl)piperidine
1125
1
C(0)NH
H
4 -(2,3-di fluorobenzyl) piperidine
1126
1
C(O)nh
H
4-(2-chloro-4-fluorobenzyl) piperidine
1127
1
C(0)NH
ch2ch2oh
4-benzvlpiperidine
1128
1
C (0) NH
ch2ch2oh
1-acetyl-4-benzvlpiperidine
1129
1
C(0)NH
ch2ch2oh
4-(3 -fluorobenzvl)piperidine
1130
1
C(O)NH
ch2ch2oh
4 -(4 -fluorobenzvl)piperidine
1131
1
c (o) NH
ch2ch2oh
4 -(2,3-di fluorobenzyl) piperidine
1132
1
C(0)NH
ch2ch2oh
4-(2-chloro-4-fluorobenzyl) piperidine
1133
1
c (o) nh ch2och3
4-benzvlpiperidine
1134
1
c(O)nh ch2och3
3-acetyl-4-benzvlpiperidine
1135
C(O)NH
CH2OCH3
4 -(3 -fluorobenzvl)piperidine
1136
1
c(o)nh ch2och3
4 - (4-fluorobenzvl)piperidine
1137
1
c (o) nh ch2och3
4 - (2,3-difluorobenzyl) piperidine
1138
1
c(0)nh ch2och3
4-(2-chloro-4-fluorobenzyl) piperidine
1139
1
C(O)NH
ch2ch2-
tetrazolyl
4-benzylpiperidine
1140
1
C(O)nh
CH2CH2-tetrazolyl
3-acetyl-4-benzylpiperidine
1141
1
C (0)nh
CH2CH2-cetrazolyl
4-(3-fluorobenzyl)piperidine
120
Printed from Mimosa
PCT/US97/U325
1142
1
C (0) NH
ch2ch2-tetrazolvl
4-(4-fluorobenzyl)piperidine
1143
1
C(0)NH
ch2ch2-tetrazolvl
4 - (2,3-di fluorobenzyl) piperidine
1144
1
C (0) NH
CH2CH2-tetrazolvl
4-(2-chloro-4-fluorobenzyl) Diperidine
1145
1
so2nh
H
4-benzvlpiperidine
1146
1
S02NH
H
3-acetyl-4-benzvlpiperidine
1147
1
SOTNH
h
4-(3 -fluorobenzvl)Diperidine
1148
1
so2nh
H
4- (4-fluorobenzvl)piperidine
1149
1
so2nh h
4- (2,3-difluorobenzyl) piperidine
1150
-
so2nh h
4- (2-chloro-4-fluorobenzyl) piperidine
1151
1
SCbNH
CH2CH2OH
4-benzvlDiperidine
1152
1
S02NH
CH2CH2OH
3-acetyl-4-benzvlpiperidine
1153
1
S02NH
CH2CH2OH
4- (3-fluorobenzvl)Diperidine
1154
1
S02NH
CH2CH2OH
4-(4-fluorobenzvl)piperidine
1155
1
so2nh ch2ch2oh
4 - (2,3-difluorobenzyl) piperidine
1156
1
so2nh ch2ch2oh
4-(2-chloro-4-fluorobenzyl) piperidine
1157
1
so2nh ch20ch3
4-benzvlpiperidine
1158
1
so2nh ch20ch3
3-acetyl-4-benzvlpiperidine
1159
1
S02NH
ch20ch3
4-(3-fluorobenzyl)Diperidine
1160
1
SO?NH
ch20ch3
4-(4-fluorobenzvl)piperidine
1161
1
so2nh ch2och3
4- (2,3-difluorobenzyl) piperidine
1162
1
S02NH
ch2och3
4-(2-chloro-4-fluorobenzyl) piperidine
1163
1
so2nh ch2ch2-tetrazolvl
4-benzylpiperidine
1164
1
so2nh ch2ch2-tetrazolvl
3-acetyl-4-benzylpiperidine
1165
1
so2nh ch2ch2-
tetrazolvl
4-(3-fluorobenzyl)piperidine
121
Printed from Mimosa
1166
1
so2nh ch2ch2-tetrazolvl
4-(4-fluorobenzyl)piperidine
1167
1
so2nh ch2ch2-
tetrazolyl
4-(2,3-difluorobenzyl) ■Diperidine
1168
1
so2nh ch2ch2-
tetrazolvl
4-(2-chloro-4-fluorobenzyl) piperidine
122
Printed from Mimosa
Table 18
Ex n
Z
Rl
A-B
1201
1
C( 0)
h
4-benzvlpiperidine
1202
1
C(O)
h
3-ac-etvl -4-benzvlpiperidine
1203
1
C(O)
h
4-(3-fluorobenzvl)piperidine
1204
1
C(0)
h
4-(4-fluorobenzvl)piperidine
1205
1
C(0)
h
4-(2,3-difluorobenzyl) piperidine
1206
1
C{0)
h
4-(2-chloro-4-fluorobenzyl) piperidine
1207
1
C(O)
CH2CH2OH
4-benzylpiperidine
1208
1
C(O)
CH2CH2OH
3-acetyl-4-benzvlpiperidine
1209
1
c (0)
CH2CH2OH
4-(3-fluorobenzvl)piperidine
1210
1
C(O)
CH2CH2OH
4-(4-fluorobenzvl)piperidine
1211
1
C(0)
ch2ch2oh
4-(2,3-difluorobenzyl) piperidine
1212
1
C(0)
ch2ch2oh
4-(2-chloro-4-fluorobenzyl) piperidine
1213
1
C(O)
ch20ch3
4-benzvlpiperidine
1214
1
C(O)
ch20ch3
3-acetvl-4-benzvlpiperidine
1215
1
C(0)
ch20ch3
4-(3-fluorobenzvl)piperidine
1216
1
C(0)
CH2OCH3
4-(4-fluorobenzvl)piperidine
1217
1
C(O)
ch20ch3
4-(2,3-di fluorobenzy1) piperidine
1218
1
C(O)
ch20ch3
4-(2-chloro-4-fluorobenzyl) Diperidine
1219
1
C(O)
ch2ch2-tetrazolvl
4-benzylpiperidine
1220
1
c(o)
CH2CH2-tetrazolvl
3-acetyl-4-benzylpiperidine
123
Drinted from Mimosa
1221
1
c(o)
ch2ch2-tetrazolyl
4 - (3 -fluorobenzyl)piperidine
1222
1
c(o)
ch2ch2-tetrazolyl
4-(4-fluorobenzyl)piperidine
1223
1
c<0)
ch2ch2 -tetrazolyl
4-(2,3-difluorobenzyl) piperidine
1224
1
c CO)
ch2ch2-
tetrazolvl
4-(2-chloro-4-fluorobenzyl) Diperidine
122s
1
c(0)nh h
4-benzylpiperidine
1226
1
c(0)nh h
3-acetyl-4-benzvlpiperidine
1227
1
c(0)nh h
4 -(3 -fluorobenzvl)piperidine
1228
1
c(0)nh h
4-(4-fluorobenzyl)piperidine
1229
1
c(0)nh h
4-(2,3-difluorobenzyl) piperidine
1230
1
c(0)nh h
4-(2-chloro-4-fluorobenzyl) piperidine
1231
1
c(0)nh ch2ch2oh
4-benzvlpiperidine
1232
1
c(0)nh ch2ch2oh
3-acetyl-4-benzvlpiperidine
1233
1
c(0)nh ch2ch2oh
4-(3 -fluorobenzvl)piperidine
1234
1
c (0)nh ch2ch2oh
4-(4-fluorobenzvl)piperidine
1235
1
c(0)nh ch2ch2oh
4-(2,3-di fluorobenzyl) piperidine
1236
1
c(o)nh ch2ch2oh
4-(2-chloro-4-fluorobenzyl) Diperidine
1237
1
c(o)nh ch2och3
4-benzylpiperidine
1238
1
c(0)nh ch2och3
3-acetvl-4-benzvlpiperidine
1239
1
c(0)nh ch2och3
4- (3-fluorobenzvl)piperidine
1240
1
c(0)nh ch2och3
4 -(4 -fluorooenzyl)piperidine
1241
1
c (0)nh ch2och3
4 - (2,3-difluorobenzyl) Diperidine
1242
1
c(0)nh ch2och3
4-(2-chloro-4-fluorobenzyl) piperidine
1243
1
c(0)nh ch2ch2-
tetrazolyl
4-benzylpiperidine
1244
1
c(0)nh ch2ch2-
tetrazolyl
3-acetyl-4-benzylpiperidine
124
Printed from Mimosa
1245
1
c (0) nh ch2ch2-tetrazolvl
4-(3-fluorobenzyl)piperidine
1246
1
c(0)nh ch2ch2-tetrazolvl
4-(4-fluorobenzyl lpiperidine
1247
1
c(0)nh ch2ch2-
tetrazolvl
4- (2,3-di fluorobenzyl) Dioeridine
1248
1
C (0) nh ch2ch2-tetrazolyl
4-(2-chloro-4-fluorobenzyl) piperidine
1249
S02nh h
4-benzylpiperidine
1250
1
so2nh h
3-acetyl-4-benzvlpiperidine
1251
S02nh h
4-(3-fluorobenzvl)piperidine
1252
1
so2nh h
4-(4-fluorobenzvl)piperidine
1253
1
so2nh h
4-(2,3-difluorobenzyl) piperidine
1254
1
s02nh h
4-{2-chloro-4-fluorobenzyl) piperidine
1255
1
so2nh ch2ch2oh
4-benzylpiperidine
1256
1
so2nh ch2ch2oh
3-acetyl-4-benzvlDiperidine
1257
1
so2nh ch2ch20h
4-(3-fluorobenzvl)piperidine
1258
1
so2nh ch2ch20h
4-(4-fluorobenzvl)Diperidine
1259
1
so2nh ch2ch2oh
4-(2,3-difluorobenzyl) Diperidine
1260
1
so2nh ch2ch2oh
4-(2-chloro-4-fluorobenzyl) piperidine
1261
1
so2nh ch2och3
4-benzylpiperidine
1262
1
so2nh ch20ch3
3-acetyl-4-benzvlpiper idine
1263
1
so2nh ch20ch3
4-(3-fluorobenzvl)piperidine
1264
1
so2nh ch2och3
4-(4-fluorobenzvl)piperidine
1265
1
so2nh ch2och3
4-(2,3-difluorobenzyl) piperidine
1266
1
so2nh ch2och3
4-(2-chloro-4-fluorobenzyl) piperidine
1267
1
so2nh ch2ch2-
tetrazolyl
4-benzylpiperidine
1268
1
so2nh ch2ch2--tetrazolvl
3-acetyl-4-benzylpiperidine
125
Printed from Mimosa
PCIYUS97/U325
1269
1
so2nh ch2ch2-
tetrazolvl
4-(3-fluorobenzyl)piperidine
1270
so2nh ch2ch2-tetrazolyl
4- (4-fluorobenzyl)piperidine
1271
1
so2nh ch2ch2-tetrazolvl
4-(2,3-difluorobenzyl) oiDeridine
1272
1
s02nh ch2ch2-tetrazolvl
4-(2-chloro-4-fluorobenzyl) DiDeridine
126
Printed from Mimosa
PCMJS97/II325
Table 19
EX
n
Z
R1
A-B
1301
1
c (o)
h
4-benzvlpiperidine
1302
1
C(O)
h
3-acetyl-4-benzylpiperidine
1303
1
c(o)
h
4-13-fluorobenzvl)piperidine
1304
1
C(O)
h
4 - 14-fluorobenzvl)piperidine
1305
1
c(0)
h
4-12,3-difluorobenzyl) piperidine
1306
1
c(0)
h
4-(2-chloro-4-fluorobenzyl) piperidine
1307
1
c(o)
ch2ch2oh
4-benzvlpiperidine
1308
1
c(o)
ch2ch2oh
3-acetyl-4-benzvlpiperidine
1309
1
c(o)
ch2ch2oh
4-13 -fluorobenzvl)piperidine
1310
1
c(o)
ch2ch2OH
4-(4-fluorobenzvl)piperidine
1311
1
cio)
ch2ch2oh
4-(2,3-difluorobenzyl) piperidine
1312
1
cio)
ch2ch2oh
4-(2-chloro-4-fluorobenzy1) piperidine
1313
1
cio)
ch2och3
4-benzylpiperidine
1314
1
cio)
ch20ch3
3-acetvl-4-benzvlpiperidine
1315
1
cio)
ch20ch3
4-(3-fluorobenzvl)piperidine
1316
1
cio)
ch20ch3
4-(4-fluorobenzvllpiperidine
1317
1
cio)
ch20ch3
4-(2,3-difluorobenzyl) piperidine
1318
1
cio)
ch2och3
4-(2-chloro-4-fluorobenzyl) piperidine
1319
1
cio)
ch2ch2-
tetrazolyl
4-benzylpiperidine
1320
1
cio)
ch2ch2-tetrazolyl
3-acetyl-4-benzylpiperidine
127
Printed from Mimosa
1321
1
c(0)
ch2ch2-
tetrazolyl
4-(3-fluorobenzyllpiperidine
1322
1
c( 0)
ch2ch2-tetrazolyl
4 -(4 -f1uorobenzy1)piperidine
1323
1
c(0)
ch2ch2-tetrazolyl
4-(2,3-difluorobenzyl) Diperidine
1324
1
c(o)
ch2ch2-
tetrazolyl
4-(2-chloro-4-fluorobenzyl) Diperidine
1325
1
c(0)nh h
4-benzvlpiperidine
1326
1
c(0)nh h
3-acetyl-4-benzvlpiperidine
1327
1
c(0)nh h
4-(3-fluorobenzyl)Diperidine
1328
1
c (0) nh h
4-(4-fluorobenzyl)piperidine
1329
1
c(o)nh h
4-(2,3-difluorobenzyl) piperidine
1330
1
c(0)nh h
4-(2-chloro-4-fluorobenzyl) Diperidine
1331
1
c (0) nh ch2ch2oh
4-benzvlpiperidine
1332
1
c(o)nh ch2ch2oh
3-acetyl-4-benzvlpiperidine
1333
1
c(o)nh ch2ch2oh
4-(3-fluorobenzyl)piperidine
1334
1
c (o) nh ch2ch2oh
4-(4-fluorobenzvl)piperidine
1335
1
c(o)nh ch2ch2oh
4-(2,3-difluorobenzyl) piperidine
1336
1
c(o)nh ch2ch2oh
4-(2-chloro-4-fluorobenzyl) piperidine
1337
1
c (0) nh ch2och3
4-benzvlpiperidine
1338
1
c(0)nh ch2och3
3-acetyl-4-benzvlpiperidine
1339
1
c(0)nh ch2och3
4-(3-fluorobenzyl)piperidine
1340
1
c(o)nh ch20ch3
4-(4-fluorobenzvl)piperidine
1341
1
c (0) nh ch20ch3
4 -(2,3-di fluorobenzyl) piperidine
1342
1
c(0)nh ch2och3
4-(2-chloro-4-fluorobenzyl) piperidine
1343
1
c (0) nh ch2ch2-
tetrazolyl
4-benzylpiperidine
1344
1
c(0)nh ch2ch2-
tetrazolvl
3-acetyl-4-benzylpiperidine
128
Printed from Mimosa
1345
c (0) nh ch2ch2-tetrazolyl
4- (3-fluorobenzyl)piperidine
1346
1
clo)nh ch2ch2-tetrazoiyl
4- (4-fluorobenzyl)piperidine
1347
1
c(0)nh ch2ch2-tetrazolyl
4 - (2,3-difluorobenzyl) oioeridine
1348
1
c(0)nh ch2ch2-tetrazolvl
4-(2-chloro-4-fluorobenzyl) oioeridine
1349
1
s02nh
H
4-benzvlpiperidine
1350
1
so2NH
h
3-acetvl-4-benzvloiperidine
1351
1
so2NH
h
4- (3-fluorobenzvl)Diperidine
1352
1
so2nh h
4- (4-fluorobenzvl)Diperidine
1353
1
so2nh h
4-(2,3-difluorobenzyl) DiDeridine
1354
1
s02nh h
4-(2-chloro-4-fluorobenzyl) DiDeridine
1355
1
s02nh ch2ch2oh
4-benzvlpiDeridine
1356
1
s02nh ch2ch2oh
3-acetvl-4-benzvlpiperidine
1357
1
s02nh ch2ch2oh
4 -(3 -fluorobenzvl)Diperidine
1358
1
so2nh ch2ch2oh
4- (4-fluorobenzvl)Diperidine
1359
1
s02nh ch2ch2oh
4-(2,3-difluorobenzyl) Diperidine
1360
1
s02nh ch2ch2oh
4-(2-chloro-4-fluorobenzyl) Diperidine
1361
1
s02nh ch2och3
4- benzvlp iper idine
1362
1
s02nh ch2och3
3-acetvl-4-benzvlpiperidine
1363
1
s02nh ch2och3
4- (3-fluorobenzvl)Diperidine
1364
1
s02nh ch2och3
4-(4-fluorobenzyl)piperidine
1365
1
so^nh ch2och3
4-(2,3-difluorobenzyl) piperidine
1366
1
s02nh ch2och3
4-(2-chloro-4-fluorobenzyl) DiDeridine
1367
1
S02NH
ch2ch2-tetrazolvl
4-benzylpiperidine
1368
1
so2nh ch2ch2-tetrazolvl
3-acetyl-4-benzylpiperidine
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1369
1
so2nh ch2ch2-tetrazolvl
4-13-fluorobenzyl)piperidine
1370
1
so2nh ch2ch2-tetrazolvl
4-(4-fluorobenzyl)piperidine
1371
1
so2nh ch2ch2-
tetrazolvl
4-(2,3-difluorobenzyl) piperidine
1372
1
so2nh ch2ch2-tetrazolyl
4-(2-chloro-4-flucrobenzyl) Diperidine
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Table 20
EX
n
Z
A-B
1401
1
CIO)
4- (2-
aminosulfonvlphenvl)phenvl
1402
1
C(O)
4-(2-aminosulfonylphenyl)-2-ovridvl
1403
1
C(O)
4-(2-methylaminosulfonylphenvl )phenvl
1404
1
C(O)
4-(2-ethylaminosulfonyl-phenvl)-2-pvridvl
1405
1
C(0)
2-aminosulfonyl-4-cvc1ohexvlphenv1
1406
1
C(O)
3-aminosulfonyl-4-t-butyl-2-pvridvl
1407
1
C(O)
2-(5-indazol-5-vl)furanvl
1408
1
C(O)
2-(5-indazol-6-vl)thienvl
1409
1
C(O)
4-(2-tetrazolvlphenvl)phenvl
1410
1
C(0)NH
4-(2-
aminosulfonvlphenvl)phenvl
1411
1
C (0) NH
4-(2-aminosulfonylphenyl)-2-pvridvl
1412
1
C(0)NH
4-(2-methylaminosulfonyl-phenvl)phenvl
1413
1
C(0)NH
4-(2-ethylaminosulfonyl-phenvl)-2-pvridvl
1414
1
C(0)NH
2-aminosulfonyl-4-cvclohexvlphenvl
1415
1
C(0)NH
3-aminosulfonyl-4-t-butyl-2-pvridyl
1416
1
C(0)NH
2-(5-indazol-5-vl)furanvl
1417
1
C(0)NH
2-(5-indazol-6-vl)thienvl
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1418
1
C(0)NH
4 -(2 -tetrazolvlDhenvl)Dhenvl
1419
NHC(0)
4 — (2 -
aminosulfonylDhenvl)phenvl
1420
1
NHC (0)
4-(2-aminosulfonylphenyl)-2-pvridvl
1421
1
NHC (0)
4-(2-methylaminosulfonyl-phenvl)phenvl
1422
1
NHC (O)
4-(2-ethylaminosulfonyl-Dhenvl)-2-pvridvl
1423
1
NHC(0)
2-aminosulfonyl-4-cyc1ohexvlDhenvl
1424
1
NHC (0)
3-aminosulfonyl-4-t-butyl-2-pvridvl
1425
1
NHC (0)
2-(5-indazol-5-vl)furanvl
1426
1
NHC(0)
2-(5-indazol-6-vl)thienvl
1427
1
NHC(O)
4 -(2 -tetrazol/lphenvl)phenvl
1428
1
SO2NH
4- (2-
aminosulfonvlphenvl)phenvl
1429
1
s02nh
4-(2-aminosulfonylphenyl)-2-pvridvl
1430
1
so2nh
4-(2-methylaminosulfonylphenyl )phenvl
1431
1
so2nh
4-(2-ethylaminosulfonylphenyl )-2-pvridvl
1432
1
so2nh
2-aminosulfonyl-4-cvclohexvlDhenvl
1433
1
so2nh
3-aminosulfonyl-4-t-butyl-2-pvridyl
1434
1
s02nh
2-(5-indazol-5-vl)furanyl
1435
1
so2nh
2 -(5-indazol-6-vl)thienvl
1436
1
so2nh
4-(2-tetrazolvlphenvl)phenvl
1437
0
ch(CH2CH20H)c(0)nh
4-(2-
aminosulfonylphenvl)ohenyl
1438
0
CH(ch2ch20h)C(0)NH
4-(2-aminosulfonylphenyl)-2-pyridvl
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1439
0
CH(CH2CH20H)C(0)NH
4-(2-methylaminosulfonylphenyl )phenyl
1440
0
CH(CH2CH20H)C(0)NH
4-(2-ethylaminosulfonylphenyl) -2-pyridyl
1441
0
CH(CH2CH20H)C(0)NH
2-aminosulfonyl-4-cyclohexvlphenyl
1442
0
CH(ch2ch20H)C(0)NH
3-aminosulfonyl-4-t-buty1-2-pyridvl
1443
0
CH(CH2CH20H)C(0)NH
2-(5-indazol-5-vl)furanvl
1444
0
CH(CH?CH20H)C(0)NH
2-(5-indazol-6-vl)thienvl
1445
0
CH(CH2CH20H)C(0)NH
4-(2-tetrazolvlDhenvl)Dhenvl
1446
0
CH(CH2-tetrazolyl)C(O)NH
4- (2-
aminosulf onylDheiiVl) phenvl
1447
0
CH(CH2-tetrazolvl)C(O)NH
4-(2-aminosulfonylphenyl)-2-pyridyl
1448
0
CH(CH2-tetrazolvl)C(0)NH
4-(2-methylaminosulfonyl-phenvl)phenvl
1449
0
CH(CH2-tetrazolyl)C(O)NH
4- (2-ethylaminosulfonyl-phenvl)-2-pvridyl
1450
0
CH<CH2-tetrazolvl)C (O J
2-aminosulfonyl-4-cvc1ohexv lDhenv1
1451
0
CH(CH2-tetrazolvDC (O)NH
3-aminosulfonyl-4-t-butyl-2-pvridvl
1452
0
CH(CH2-tetrazolvl)C(0)NH
2-(5-indazol-5-yl)furanyl
1453
0
CH(CH2-tetrazolvl)C(0)NH
2-(5-indazol-6-yl)thienyl
1454
0
CH(CH2-tetrazolvl)C(O)NH
4- (2-tetrazolylphenyl)phenyl
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Tabltt 21
alk-*-
Ex z'
A-B
1501
ch2c(0)nh
4-<2-
aminosulfonvlphenvl)phenvl
1502
ch2c(0)nh
4-(2-aminosulfonylphenyl)-2-ovridvl
1503
ch2c(0)nh
4-(2-methylaminosulfonylphenvl )Dhenvl
1504
ch2c(o)nh
4-(2-ethylaminosulfonyl-phenvl)-2-pvridvl
1505
ch2c(0)nh
2-aminosulfonyl-4-cvclohexvlDhenv1
1506
ch2c(0)nh
3 -aminosulfonyl-4-t-butyl-2-pvridvl
1507
ch2c(o)nh
2-(5-indazol-5-vl)furanvl
1508
ch2c(0)nh
2-(5-indazol-6-vl)thienvl
1509
ch2c(0)nh
4-(2-tetrazolvlDhenvl)Dhenvl
1510
ch2ch2c(0)nh
4- (2-
aminosu1fonvlphenvl)Dhenvl
1511
ch2ch2c(0)nh
4-(2-aminosulfonylphenyl)-2-Dvridvl
1512
ch2ch2c(0)nh
4-(2-tert-butylaminosulfonyl-Dhenvl)phenvl
1513
ch2ch2c(0)nh
4-(2-ethylaminosulfonyl-phenvl)-2-Dvridvl
1514
ch2ch2c(0)nh
2-aminosulfonyl-4-cvc1ohexvlDhenvl
1515
ch2ch2c(0)nh
3-aminosulfonyl-4-t-butyl-2-Dvridvl
1516
ch2ch2c(0)nh
2-(5-indazol-5-vl)furanvl
1517
ch2ch7c(0)nh
2-(5-indazol-6-vl)thienvl
1518
ch2ch;>c(0)nh
4-(2-tetrazolvlDhenvl)ohenvl
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1519
sch2c(0)nh
4- (2-
aminosulfonvlphenvl)ohenvl
1520
sch2c(0)nh
4-(2-aminosulfonyIphenyl)-2-ovridyl
1521
sch2c(0)nh
4-(2-methylaminosulfonyl-phenvl)phenvl
1522
sch2c(o)nh
4-(2-ethylaminosulfonyl-phenvl)-2-pvridvl
1523
sch2c(0)nh
2-aminosulfonyl-4-cvc1ohexvlDhenvl
1524
sch2c(0)nh
3-aminosulfonyl-4-t-buty1-2-pvridvl
1525
sch2c(o)nh
2-(5-indazol-5-vl)furanvl
1526
sch7c(0)nh
2-(5-indazol-6-vl)thienvl
1527
sch2c(0)nh
4-(2-tetrazolvlphenyl)Dhenvl
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Utility
The compounds of this invention are useful as anticoagulants for the treatment or prevention of thromboembolic disorders in mammals. The term "thromboembolic disorders" as used herein includes arterial or venous cardiovascular or cerebrovascular thromboembolic disorders, including, for example, unstable angina, first or recurrent myocardial infarction, ischemic sudden death, transient ischemic attack, stroke, atherosclerosis, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary and cerebral arterial thrombosis, cerebral embolism, kidney embolisms, and pulmonary embolisms. The anticoagulant effect of compounds of the present invention is believed to be due to inhibition of factor Xa or thrombin.
The effectiveness of compounds of the present invention as inhibitor? of factor Xa was determined using purified human factor Xa and synthetic substrate. The rate of factor Xa hydrolysis of chromogenic substrate s2222 (Kabi Pharmacia, Franklin, OH) was measured both in the absence and presence of compounds of the present invention. Hydrolysis of the substrate resulted in the release of pNA, which was monitored spectrophotometrically by measuring the increase in absorbance at 405 nM. A decrease in the rate of absorbance change at 405 nm in the presence of inhibitor is indicative of enzyme inhibition. The results of this assay are expressed as inhibitory constant, Kj..
Factor Xa determinations were made in 0.10 M sodium phosphate buffer, pH 7.5, containing 0.20 M NaCl, and 0.5 % PEG 8000. The Michaelis constant, Km, for substrate hydrolysis was determined at 25°C using the method of Lineweaver and Burk. Values of Ki were determined by allowing 0.2-0.5 nM human factor Xa (Enzyme Research Laboratories,
South Bend, IN) to react with the substrate (0.20 mM-1 mM) in the presence of inhibitor. Reactions were allowed to go for 3 0 minutes and the velocities (rate of absorbance change vs time) were measured in the time frame of 25-30 minutes. The following relationship was used to calculate Kj_ values: tv0-vs)/vs = 1/(Ki (1 + S/Km))
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where:
vD is the velocity of the control in the absence of inhibitor;
vs is the velocity in the presence of inhibitor;
I is the concentration of inhibitor;
Ki is the dissociation constant of the enzyme:inhibitor complex;
S is the concentration of substrate;
Km is the Michaelis constant.
Using the methodology described above, a number of compounds of the present invention were found to exhibit a Kj of <5 Jim, thereby confirming the utility of the compounds of the present invention as effective Xa inhibitors.
The antithrombotic effect of compounds of the present invention can be demonstrated in a rabbit arterio-venous (A1 shunt thrombosis model. In this model, rabbits weighing 2-3 kg anesthetized with a mixture of xylazine (10 mg/kg i.m.) and ketamine (50 mg/kg i.m.) are used. A saline-filled AV shunt device is connected between the femoral arterial and the femoral venous cannulae. The AV shunt device consists of a piece of 6-cm tygon tubing which contains a piece of silk thread. Blood will flow from the femoral artery via the AV-shunt into the femoral vein. The exposure of flowing blood to a silk thread will induce the formation of a significant thrombus. After forty minutes, the shunt is disconnected and the silk thread covered with thrombus is weighed. Test agents or vehicle will be given (i.v., i.p., s.c., or orally) prior to the opening of the AV shunt. The percentage inhibition of thrombus formation is determined for each treatment group. The ID50 values (dose which produces 50% inhibition of thrombus formation) are estimated by linear regression.
The compounds of formula (I) are also considered to be useful as inhibitors of serine proteases, notably human thrombin, plasma kallikrein and plasmin. Because of their inhibitory action, these compounds are indicated for use in the prevention or treatment of physiological reactions, blood coagulation and inflammation, catalyzed by the aforesaid class of enzymes. Specifically, the compounds have utility as drugs
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for the treatment of diseases arising from elevated thrombin activity such as myocardial infarction, and as reagents used as anticoagulants in the processing of blood to plasma for diagnostic and other commercial purposes.
Some compounds of the present invention were shown to be direct acting inhibitors of the serine protease thrombin by their ability to inhibit the cleavage of small molecule substrates by thrombin in a purified system. In vitro inhibition constants were determined by the method described 10 by Kettner et al. in J. Biol. Chem. 265, 18289-18297 (1990), herein incorporated by reference. In these assays, thrombin-mcdiated hydrolysis of the chromogenic substrate S2238 (Helena Laboratories, Beaumont, TX) was monitored spectrophotometrically. Addition of an inhibitor to the assay 15 mixture results in decreased absorbance and is indicative of thrombin inhibition. Human thrombin (Enzyme Research Laboratories, Inc., South Bend, IN) at a concentration of 0.2 nM in 0.10 M sodium phosphate buffer, pH 7.5, 0.20 M NaCl, and 0.5% PEG 6000, was incubated with various substrate 20 concentrations ranging from 0.20 to 0.02 mM. After 25 to 30 minutes of incubation, thrombin activity was assayed by monitoring the rate of increase in absorbance at 405 nm which arises owing to substrate hydrolysis. Inhibition constants were derived from reciprocal plots of the reaction velocity as 25 a function of substrate concentration using the standard method of Lineweaver and Burk. Using the methodology described above, some compounds of this invention were evaluated and found to exhibit a Rj of less than 5 pm, thereby confirming the utility of the compounds of the invention as 30 effective thrombin inhibitors.
The compounds of the present invention can be administered alone or in combination with one or more additional therapeutic agents. These include other anticoagulant or coagulation inhibitory agents, anti-platelet or 35 platelet inhibitory agents, thrombin inhibitors, or thrombolytic or fibrinolytic agents.
The compounds sire administered to a mammal in a therapeutically effective amount. By "therapeutically
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effective amount" it is meant an amount of a compound of Formula I that, when administered alone or in combination with an additional therapeutic agent to a mammal, is effective to prevent or ameliorate the thromboembolic disease condition or 5 the progression of the disease.
By "administered in combination" or "combination therapy" it is meant that the compound of Formula I and one or more additional therapeutic agents are administered concurrently to the mammal being treated. When administered in combination 10 each component may be administered at the same time or sequentially in any order at different points in time. Thus, each component may be administered separately but sufficiently closely in time so as to provide the desired therapeutic effect. Other anticoagulant agents (or coagulation inhibitory 15 agents) that may be used in combination with the compounds of this invention include warfarin and heparin, as well as other factor Xa inhibitors such as those described in the publications identified above under Background of the Invention.
The term anti-platelet agents (or platelet inhibitory agents), as used herein, denotes agents that inhibit platelet function such as by inhibiting the aggregation, adhesion or granular secretion of platelets. Such agents include, but are not limited to, the various known non-steroidal anti-25 inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen, sulindac, indomethacin, mefenamate, droxicam, diclofenac, sulfinpyrazone, and piroxicam, including pharmaceutically acceptable salts or prodrugs thereof. Of the NSAIDS, aspirin (acetylsalicyclic acid or ASA), and piroxicam 30 are preferred. Other suitable anti-platelet agents include ticlopidine, including pharmaceutically acceptable salts or prodrugs thereof. Ticlopidine is also a preferred compound since it is known to be gentle on the gastro-intestinal tract in use. Still other suitable platelet inhibitory agents 35 include Ilb/IIIa antagonists, thromboxane-A2-receptor antagonists and thromboxane-A2-synthetase inhibitors, as well as pharmaceutically acceptable salts or prodrugs thereof.
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The term thrombin inhibitors (or anti-thrombin agents), as used herein, denotes inhibitors of the serine protease thrombin. By inhibiting thrombin, various thrombin-mediated processes, such as thrombin-mediated platelet activation (that 5 is, for example, the aggregation of platelets, and/or the granular secretion of plasminogen activator inhibitor-1 and/or serotonin) and/or fibrin formation are disrupted. A number of thrombin inhibitors are known to one of skill in the art and these inhibitors are contemplated to be used in combination 10 with the present compounds. Such inhibitors include, but are not limited to, boroarginine derivatives, boropeptides, heparins, hirudin and argatroban, including pharmaceutically acceptable salts and prodrugs thereof. Boroarginine derivatives and boropeptides include N-acetyl and peptide 15 derivatives of boronic acid, such as C-terminal a-aminoboronic acid derivatives of lysine, ornithine, arginine, homoarginine and corresponding isothiouronium analogs thereof. The term hirudin, as used herein, includes suitable derivatives or analogs of hirudin, referred to herein as hirulogs, such as 20 disulfatohirudin. Boropeptide thrombin inhibitors include compounds described in Kettner et al.. U.S. Patent No. 5,187,157 and European Patent Application Publication Number 293 881 A2. the disclosures of which are hereby incorporated herein by reference. Other suitable boroarginine derivatives 25 and boropeptide thrombin inhibitors include those disclosed in PCT Application Publication Number 92/07869 and European Patent Application Publication Number 471,651 A2, the disclosures of which are hereby incorporated herein by reference.
The term thrombolytics (or fibrinolytic) agents (or thrombolytics or fibrinolytics), as used herein, denotes agents that lyse blood clots (thrombi). Such agents include tissue plasminogen activator, anistreplase, urokinase or streptokinase, including pharmaceutically acceptable salts or 35 prodrugs thereof. The term anistreplase, as used herein, refers to anisoylated plasminogen streptokinase activator complex, as described, for example, in European Patent Application No. 028,489, the disclosure of which is hereby
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incorporated herein by reference herein. The term urokinase, as used herein, is intended to denote both dual and single chain urokinase, the latter also being referred to herein as prourokinase.
Administration of the compounds of Formula I of the invention in combination with such additional therapeutic agent, may afford an efficacy advantage over the compounds and agents alone, and may do so while permitting the use of lower doses of each. A lower dosage minimizes the potential of side 10 effects, thereby providing an increased margin of safety.
The compounds of the present invention are also useful as scandard or reference compounds, for example as a quality standard or control, in tests or assays involving the inhibition of factor Xa. Such compounds may be provided in a 15 commercial kit, for example, for use in pharmaceutical research involving factor Xa. For example, a compound of the present invention could be used as a reference in an assay to compare its known activity to a compound with an unknown activity. This would ensure the experimenter that the assay 20 was being performed properly and provide a basis for comparison, especially if the test compound was a derivative of the reference compound. When developing new assays or protocols, compounds according to the present invention could be used to test their effectiveness.
The compounds of the present invention may also be used in diagnostic assays involving factor Xa. For example, the presence of factor Xa in an unknown sample could be determined by addition of chromogenic substrate S2222 to a series of solutions containing test sample and optionally one of the 30 compounds of the present invention. If production of pNA is observed in the solutions containing test sample, but no compound of the present invention, then one would conclude factor Xa was present.
Dosage and Formulation
The compounds of this invention can be administered in such oral dosage forms as tablets, capsules (each of which includes sustained release or timed release formulations),
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pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. They may also be administered in intravenous (bolus or infusion), intraperitoneal,
subcutaneous, or intramuscular form, all using dosage forms 5 well known to those of ordinary skill in the pharmaceutical arts. They can be administered alone, but generally will be administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.
The dosage regimen for the compounds of the present invention will, of course, vary depending upon known factors, such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration; the species, age, sex, health, medical condition, and weight of the 15 recipient; the nature and extent of the symptoms; the kind of concurrent treatment; the frequency of treatment; the route of administration, the renal and hepatic function of the patient,and the effect desired. A physician or veterinarian can determine and prescribe the effective amount of the drug 20 required to prevent, counter, or arrest the progress of the thromboembolic disorder.
By way of general guidance, the daily oral dosage of each active ingredient, when used for the indicated effects, will range between about 0.001 to 1000 mg/kg of body weight, 25 preferably between about 0.01 to 100 mg/kg of body weight per day, and most preferably between about 1.0 to 20 mg/kg/day. Intravenously, the most preferred doses will range from about 1 to about 10 mg/kg/minute during a constant rate infusion. Compounds of this invention may be administered in a single 30 daily dose, or the total daily dosage nv be administered in divided doses of two, three, or four times daily.
Compounds of this invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using transdermal skin 35 patches. When administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.
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The compounds are typically administered in admixture with suitable pharmaceutical diluents, excipients, or carriers (collectively referred to herein as pharmaceutical carriers) suitably selected with respect to the intended form of 5 administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices.
For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined 10 with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, methyl callulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like; for oral administration in liquid form, the oral drug components can be 15 combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like. Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents, and coloring agents can also be incorporated into the mixture. Suitable binders 20 include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate,
carboxymethylcellulose, polyethylene glycol, waxes, and the like. Lubricants used in these dosage forms include sodium 25 oleate, sodium stearate. magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.
The compounds of the present invention can also be 30 administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine, or phosphatidylcholines.
Compounds of the present invention may also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol,
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polyhydroxyethylaspartamidephenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues. Furthermore, the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled 5 release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, and crosslinked or amphipathic block 10 copolymers of hydrogels.
Dosage forms (pharmaceutical compositions) suitable for administration may contain from about 1 milligram to about 100 milligrams of active ingredient per dosage unit. In these pharmaceutical compositions the active ingredient will 15 ordinarily be present in an amount of about 0.5-55% by weight based on the total weight of the composition.
Gelatin capsules may contain the active ingredient and powdered carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. 20 Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the 25 tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract.
Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance.
In general, water, a suitable oil, saline, aqueous 30 dextrose (glucose), and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions. Solutions for parenteral administration preferably contain a water soluble salt of the active ingredient, suitable stabilizing agents, and if 35 necessary, buffer substances. Antioxidizing agents such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or combined, are suitable stabilizing agents. Also used are citric acid and its salts and sodium EDTA. In addition,
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parenteral solutions can contain preservatives, such as benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol.
Suitable pharmaceutical carriers are described in 5 Remington's Pharmaceutical Sciences. Mack Publishing Company, a standard reference text in this field.
Representative useful pharmaceutical dosage-forms for administration of the compounds of this invention can be illustrated as follows:
Capsules
A large number of unit capsules are prepared by filling standard two-piece hard gelatin capsules each with 100 milligrams of powdered active ingredient, 150 milligrams of lactose, 50 milligrams of cellulose, and 6 milligrams 15 magnesium stearate.
Soft Gelatin Capsules
A mixture of active ingredient in a digestable oil such as soybean oil, cottonseed oil or olive oil is prepared and injected by means of a positive displacement pump into gelatin 20 to form soft gelatin capsules containing 100 milligrams of the active ingredient. The capsules are washed and dried.
Tablets
A large number of tablets are prepared by conventional procedures so that the dosage unit is 100 milligrams of active 25 ingredient, 0.2 milligrams of colloidal silicon dioxide, 5 milligrams of magnesium stearate, 275 milligrams of microcrystalline cellulose, 11 milligrams of starch and 98.8 milligrams of lactose. Appropriate coatings may be applied to increase palatability or delay absorption.
Injectable
A parenteral composition suitable for administration by injection is prepared by stirring 1.5% by weight of active ingredient in 10% by volume propylene glycol and water. The solution is made isotonic with sodium chloride and sterilized. 35 Suspension
An aqueous suspension is prepared for oral administration so that each 5 mL contain 100 mg of finely divided active ingredient, 200 mg of sodium carboxymethyl
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Printed from Mimosa
Claims (20)
1. A compound of formula I: i or stereoisomer or pharmaceutically acceptable salt form thereof wherein: W and W3 are selected from CH and N; W1 and W2 are selected from C, CH, and N; provided that from 0-2 of W, W1, W2, and W3 are N; one of D and D3 is selected from H, C1-4 alkoxy, CN, C(=NR7)NReR9 , NHC(=NR7)NR®R9, NR8CH(=NR7), C(0)NR8R5, and (CH2)tNR9R9, and the other is absent; provided that if one of D and D3 is H, then at least one of W, W1, W2, and W3 is N; one of Ja and Jb is substituted by -(ch2)n-Z-A-B; J, Ja, and Jb combine to form an aromatic heterocyclic system containing from 1-2 heteroatoms selected from the group consisting of N, 0, and S substituted with 0-2 R1, provided that Jb can only be C or N; J, Ja, and Jb can, alternatively, combine to form a heterocyclic ring wherein Jb is N and J and Ja are CH2 substituted with 0-1 R1; 148 Printed from Mimosa WO 98/01428 PCT/US97/11325 J, Ja, and jb can, alternatively, combine to form a heterocyclic ring wherein jb is CH, j is NR1 and Ja is CH2 substituted with 0-1 R1 5 R1 is selected from H, C1-4 alkyi, (ch2>rOR3, (CH2)rNR3R3', (CH2)rC(=0)R2, (CH2)r(CH=CH) (CH2) rC (=0)R2, (CH2)rNR3C(=0)R2. (CH2)rS02R4, (CH2) rNTR3S02R4. and (CH2)r-5-membered heterocyclic system having 1-4 heteroatoms selected from N, 0, and S; 10 R2 is selected from K, OR3, C1-4 alkyl, NR3R3', cf3, and c3-10 carbocyclic residue substituted with 0-2 R6; R3 and R3' are independently selected from H, Cj.-4 alkyl, and 15 c3-10 carbocyclic residue substituted with 0-2 R6; R4 is selected from C1-4 alkyl, NR3R3 , and C3-10 carbocyclic residue substituted with 0-2 R6; 20 Z is selected from CH=CH, CH( (CH2)mQ(CH2)IT1R5) , CH((CH2)mQ(CH2)mR5)C(0)NR3, CH( (CH2)mC(0) (CH2)mR5a) , N( (CH2)qQ(CH2)mR5) , N (Q' {CH2 ) mR5 ) , C(0)N( (CH2)Bfl' (CH2)mR5a) - ClO)(CH2)r, C(0)0(CH2)r, OC (O) (CH2)r < C(O) (CH2)rNR3(CH2)r. NR3C(0) (CH2)r, 25 0C(0)NR3(CH2)r. NR3C(O)0(CH2)r- NR3C(0)NR3(CH2)r/ S(0)p(CH2)r , so2ch2, SCH2C(0)NR3, S02NR3(CH2)r, NR3S02 (CH2) r, and NR3S02NR3 <CH2) r; Q is selected from a bond, 0, NR3, C(0), C(0)NR3, NR3C(0), S02, 30 NR3S02, and S02NR3; Q' is selected from a bond, C(O), C(0)NR3, S02, and S02NR3; R5 is selected from H, C1-4 alkyl, c3-10 carbocyclic residue 35 substituted with 0-2 R6, eind 5-10 membered heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R6, 149 Printed from Mimosa 333 10 30 provided that when Q is SO2 or NR3SC>2, R5 is other than H and when Q' is SO2, R5 is other than H; R5a is selected from NHR5, OR5, and R5; A is selected from: benzyl substituted with 0-2 R6, phenethyl substituted with 0-2 R6, phenyl-CH= substituted with 0-2 R6, C3-.10 carbocyclic residue substituted with 0-2 R6, and 5-10 membered heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R6; B is selected from: X-Y, C3^ alkyl, C (=NR3) NR3R3', NR3C (=NR3) NR3R3, benzyl substituted with 0-2 R6, C3-10 carbocyclic residue substituted with 0-2 R6, and 5-10 membered heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, 0, and S substituted with 0-2 R6; A and B can, alternatively, combine to form a C9-10 carbocyclic residue substituted with 0-2 R® or a 9-10 membered heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R6; X is selected from C1-4 alkylene, -C(0)-, -C(0)CR3R3' -CR3R3'C(0), -S(0)p-, -S(0)pCR3R3'-, -CR3R3'S (O)p-, -S (0) 2NR3-, -NR3S(0)2-, -C(0)NR3-, -NR3C(0)-, -NR3-, -NR3CR3R3'-, -CR3R3'NR3-, O, -CR3R3'0-, and -OCR3R3'-; Y is selected from: C3-10 carbocyclic residue substituted with 0-2 R6, and 5-10 membered heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R6; 150 intellectual property office of n.z - 9 aug 1239 received WO 98/01428 PCT/US97/11325 R6 is selected from H, OH, (CH2)nOR3, halo, C1-4 alkyl, CN. NO2, (CH2) rNR3R3' - <CH2)rC(0)r3, nr3C(0)r3', nr3C (0)nr3r3 ', ch(=nh>nh2, nhc(=nh)nh2, so2nr3r3', conhso2r*, 5 NR3S02NR3R3', NR3S02-Ci-4 alkyl, and (C1-4 alkyl)- tetrazolyl; R7 is selected from H, OH, C1-6 alkyl, C1-6 alkylcarbonyl, Ci_g alkoxy, Ci_4 alkoxycarbonyl, C6_i0 aryloxy, C6-10 10 aryloxycarbonyl, C6-10 arylmethylcarbonyl, Ci_4 alkylcarbonyloxy ^..4 alkoxycarbonyl, Cg-io arylcarbonyloxy C1-4 alkoxycarbonyl, Ci_6 alkylaininocarbonyl, phenylaminocarbonyl, and phenyl Ci_4 alkoxycarbonyl; 15 R8 is selected from H, C1-6 alkyl and (CH2)n-phenyl; R9 is selected from H, C1-6 alkyl and {CH2)n-Phenyl; 20 n is selected from 0, 1, 2, 3, and 4; m is selected from 0, 1, and 2; p is selected from 0, 1, and 2; 25 q is selected from 1 and 2; and, r is selected from 0, 1, 2, 3, and 4; 30 provided that: (a) Z is other than CH2; and, (b) if Z is CH( (CH2)mQ(CH2)mR5) or CH( {CH2)mC (O) (CH2),„R5a) , then B is other than X-Y, a c3-10 carbocyclic residue or a 5-10 membered heterocyclic system. 35
2. A compound according to Claim 1, wherein the compound is of formula II: 151 Printed from Mimosa WO 98/01428 PCT/US97/11325 15 if w ■Z" ii or a stereoisomer or pharmaceutically acceptable salt, 5 wherein: from 0-1 of W, W1, W2, and W3 are N; R1 is selected from H, C1-4 alkyl, (CH2)rOR3, (CH2) rNR3P.3' , 10 (CH2)rC(=0)R2, (CH2)rNR3C(=0)R2, (CH2)rS02R4, (CH2) rNR3S02R4 . and (CH2)r-5-membered heterocyclic system having 1-4 heteroatoms selected from N, 0, and S; R2 is selected from H, OR3, Ci_4 alkyl, NR3R3', and CF3; R3 and R3' are independently selected from H, C1.4 alkyl, and phenyl; R4 is selected from C1-4 alkyl, phenyl and NR3R3'; 20 Z is selected from CH=CH, CH( (CH^QfCH^mRS) # CH ( {CH2)mQ(CH2)mR5)C(0)NR3, CH < (CH2) mC (O) (CH2),„R*a) , N( (CH2)qQ(CH2)roR5) , N (Q* (CH2)n,R5) , C(0)N((CH2)mQ' (CH2)mR5a) - C{0), C(0)CH2, C(0)0, OC(O), 25 C(O) (CH2)rNR3 (CH2)r, NR*C(0), 0C(0)NR3, NR3C{0)0, NR3C(0)NR3, S(0)p, S02CH2, S02NR3, NR3S02, and NR3S02NR3; B is selected from: X-Y, C}-6 alkyl, 30 benzyl substituted with 0-2 R6, C3-10 carbocyclic residue substituted with 0-2 R6, and 5-10 membered heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R6; 35 152 Printed from Mimosa WO 98/01428 PCT/US97/11325 A and B can, alternatively, combine to form a C9-10 carbocyclic residue substituted with 0-2 R6 or a 9-10 membered heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, O, and S 5 substituted with 0-2 R6; and, R6 is selected from H, OH, (CH2)nOR3. halo, Ci_4 alkyl, CN, NO2. (CH2)rNR3R3' . (CH2) rC(0)R3, NR3C(0)R3', NR3C (O) NR3R3 ' , S02NR3R3 , C0NHS02R4, NR3S02NR3R3' , NR3S02-Ci-4 alkyl and 10 (C1-4 alkyl)-tetrazolyl.
3. A compound according to Claim 2, wherein: 15 J, Ja, and Jb combine to form an aromatic heterocyclic system containing from 1-2 nitrogen atoms, substituted with 0-1 R1 ; J, Ja, and Jb can, alternatively, combine to form a 20 heterocyclic ring wherein Jb is N and J and Ja are CH2 substituted with 0-1 r1; J, Ja, and Jb can, alternatively, combine to form a heterocyclic ring wherein Jb is CH, J is NK1 and Ja is CH2 25 substituted with 0-1 R1 ; Rl is selected from H, C1-4 alkyl, (CH2)rOR3, (CH2)rNR3R3', (CH2)rC(=0)R2, (CH2)rNR3C(=0)R2, (CH2)rS02R4, and (CH2)rNR3S02R4; 30 Z is selected from CH ( (CH2)roQ (CH2)mR5) . CH( (CH2)ItlQ(CH2)mR5)C(0)NR3, CH ( (CH2)inC(0) (GH2)mR5a) . N( (CH2)qO(CH2)n.R5) . N(Q' (CH2)mR5) , C(0)N( <CH2)mQ' (CH2)mR5a) , C(O). C(0)CH2, 35 C(O) (CH2)rNR3(CH2)r, NR3C(0), NR3C(0)NR3, S(0)2, S02CH2, S02NR3, NR3S02, and NR3S02NR3,- A is selected from: 153 Printed from Mimosa WO 98/01428 PCI7US97/11325 benzyl substituted with 0-2 R6, C3-10 carbocyclic residue substituted with 0-2 R6, and 5-10 membered heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, 0, and S 5 substituted with 0-2 R6; B is selected from: X-Y, C3-6 alkyl, benzyl substituted with 0-2 R6, 10 C5-6 carbocyclic residue substituted with 0-2 R6, and 5-6 membered heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R6; 15 X is selected from -C(0>-, -C (O) CR3R3'-, -S(0)2-, -S (0) pCR3R3' -, -S(0)2NR3-, -C(0)NR3-, -NR3-, -NR3CR3R3'-, and O; Y is selected from: C5-6 carbocyclic residue substituted with 0-2 R6, and 20 5-6 membered heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R6; R6 is selected from H, OH, <CH2)nOR3. halo, Ci_4 alkyl, CN, NO2, 25 (CH2)rNK3R3' , (CH2) rC (O) R3 , NR3C(0)R3", NR3C (O) NR3R3 ' , S02NR3R3', CONHSO2R4, NR3S02NR3R3', NR3S02-C!-4 alkyl and (C1-4 alkyl)-tetrazolyl; n is selected from 0, 1, and 2; and, 30 r is selected from 0, 1, and 2.
4. A compound according to Claim 3, wherein the compound 35 is of formula II: 154 Printed from Mimosa WO 98/0142B PCT/US97/11325 % Da'" Jb .A, (h: Z B III or a stereoisomer or pharmaceutically acceptable salt form thereof, wherein: 5 J and Jb combine to form an aromatic heterocyclic system containing from 1-2 nitrogen atoms, substituted with 0-1 R1 ; 10 J and Jb can, alternatively, form a heterocyclic ring wherein Jb is N and J is CH2 substituted with 0-1 R1,- J and Jb can, alternatively, form a heterocyclic ring wherein Jb is CH and J is NR1; 15 20 Z is selected from C(0)N(Q'R5a) , C(O), C(0)NR3, NR3C{0), and S02NR3; Q' is selected from C(0) and C(0)NR3; R5 is selected from H and C1-4 alkyl; RSa is selected from NHR5, OR5, and R5; 25 A is selected from: benzyl substituted with 0-1 R6, phenyl substituted with 0-1 R6, piperidinyl substituted with 0-1 R6, piperazinyl substituted with 0-1 R6, and 30 pyridyl substituted with 0-1 r6; B is selected from: X-Y, benzyl substituted with 0-1 R6, 35 phenyl substituted with 0-2 R6, 155 Printed from Mimosa ' WO 98/01428 PCT/US97/11325 cyclohexyl substituted with 0-1 R6, and pyridyl substituted with 0-1 R6; X is selected from: -C(O)-, -S(0)2-, so2ch2, -S(0>2nr3-. -NR3-5 and -C(0)NR3-; Y is selected from: phenyl substituted with 0-2 R6, and pyridyl substituted with 0-1 R6; 10 15 r6 is selected from H, oh, (ch2)nor3, halo, C1-4 alkyl, CN, NO2. (CH2)rNR3R3' , (CH2)rC(0)R3, NR3C(0)R3', NR3C (O) NR3R3' , S02NR3R3', C0NHS02R4, NR3S02NR3R3', NR3S02-C1-4 alkyl and (c1-4 alkyl)-tetrazolyl,- n is selected from 0, 1, and 2.
5. A compound according to Claim 4, wherein the compound 20 is of of formula IV: IV or stereoisomer or pharmaceutically acceptable salt form 25 thereof, wherein A, B, D, and Z are as defined above.
6. A compound according to Claim 1, wherein the compound is selected from: 30 3-((4-cyclohexyl)phenylaminomethylcarbonyl)methyl-5-amidinoindole 3-(4-p~ toluenesulfonyl-piperaz inecarbonyl)methyl-5-35 amidinoindole 156 Printed from Mimosa WO 98/01428 PCT7US97/11325 3 -(4 -(2-aminosulfonylphenyl)pyridine-2-aminocarbonyl)methyl-5 amidinoindole; 5 3-(4-[2-tetrazole]phenyl)phenylaminocarbonyl)methyl-5-amidinoindole; 3 -(4-biphenylaminocarbonyl)methyl-5-amidinoindole; 10 3-(4-(phenylmethylsulfonyl)piperazinecarbonyl)methyl-5-amidinoindole; 3 -(4-cyclohexylphenylaminocarbonyl)methyl-5-amidinoindole; 15 3 -(4-benzylpiperazinecarbonyl)methyl-5-amidinoindole; 3-(3-amidinobenzylamino(mechylcarbonylmethoxy)carbonyl)methyl 5-amidinoindole; 20 3-<4-[2-aminosulfonyl)phenylphenylaminocarbonyl)methyl-5-amidinoindole ; 3-(1-benzylpiperidine-4-aminocarbonyl)methyl-5-amidinoindole; 25 3-(4-phenylpiperazinecarbonyl)methyl-5-amidinoindole; 3 -(4-benzylpiperidinecarbonyl)methyl-5-amidinoindole; 3-(2-bromo-4-(2- 30 auninosulfonyl)phenylphenylaminocarbonyl)methyl-5- cyanoindole; 3-{2-methyl-4-(2- cuninosulfonyl)phenylphenylaminocarbonyl)methyl-5- 35 methylamino indole; 157 Printed from Mimosa " WO 98/01428 PCT/US97/11325 3 -{2-fluoro-4 -(2- aminosulfony1)phenylphenylaminocarbonyl)methyl- 5 -amidnoindole; 5 3-{2-chloro-4-{2- aminosulfonyl)phenylphenylaminocarbonyl)methyl-5-cyanoindole; 3-{2-iodo-4-(2-aminosulfonyl)phenylphenylaminocarbonyl)methyl 10 5-cyanoindole; 3 -{2-methyl-4-(2- aminosulfonyl)phenylphenylaminocarbonyl)methyl-5-amidinoindole; 15 3 -{2-methyl-4-(2 -(t- bucylaminosulfonyl))phenylphenylaminocarbonyl)methyl-5-amidinoindole; 20 3-{4-(2-aminosulfonyl)phenyl)phenylaminocarbonylmethyl-a-(methylcarboxy methylether)-5-amidinoindole; 3 - {4 - (2-aminosu.lf onyl) phenyl) phenylaminocarbonylmethy 1-a-(benzyl)-5-amidinoindole; 25 3-{4-<2-trifluoromethy1)phenyl)pyrid-2-ylaminocarbonylmethyl -5-amidinoindole; 3 -{4-(2-ethylsminosulf onyl)phenyl)phenylaminocarbonylmethyl-5 30 amidinoindole; 3-{4-{2-propylaminosulfonyl)phenyl)phenyl)aminocarbonylmethyl 5-amidinoindole; 35 2-methyl-3-{2-iodo-4-(2- aminosulfonyl)phenyl)phenyl)aminocarbonylmethyl-5-amidinoindole; 158 Printed from Mimosa WO 98/01428 PCT/US97/11325 2-methyl-3-{4- (2- aminosulfonyl)phenyl)phenyl}aminocarbonylmethyl- 5-amidinoindole ; 5 3 -{4-(2-aminosulfonyl)phenyl)phenyl}-N- methylaminocarbony lmethyl- 5 -amidinoindole 2-methyl-3-{4-(2-t- butylaminosul fonyl) phenyl) phenyl) aminocarbonylmethyl-5-10 methoxyindole; and, 3 -{4 -(2-N-methylaminosulfonyl)phenyl)phenyl}-N-methylaminocarbonylmethyl -5-amidinoindole ; 15 or a stereoisomer or pharmaceutically acceptable salt form thereof. 20
7. A compound according to Claim 4, wherein the compound is of formula IVa: IVa or a stereoisomer or pharmaceutically acceptable salt thereof, 25 wherein A, B, D, and Z are as defined above.
8. A compound according to Claim 1, wherein the compound is selected from: 30 3-(4-(2-(n- buty laminosul fonyl) phenylphenylaminocarbonyl) methyl - 5 -cyanoindoline; 159 Printed from Mimosa WO 98/01428 PCT/US97/11325 3-{4 -(2-(n- propylaminosulfonyl)phenylphenylaminocarbonyl)methyl- 5-amidinoindoline; 5 (-)- 3 -{4 -(2-aminosulfonyl)phenyl)pyrid-2- ylaminocarbonylmethyl-5-amidinoindoline; 3 -{4- (2-aminosulfonyl)phenyl)pyrid-2-ylaminocarbonylmethyl-5-amidinoindoline; 10 3- {4- (2- dimethylaminosulfonyl)phenyl)phenylaminocarbonylmethyl-5-amidinoindoline; 15 ( + ) -3-{4- (2-t-butylaminosulfonyl)phenyi)pyrid-2-ylaminocarbonylmethyl-5-amidinoindoline; (-)- 3 -{4-< 2-t-butylaminosulfonyl)phenyl)pyrid-2-ylaminocarbonylmethyl-5-amidinoindoline; 20 3 -{4 - (2-aminosulfonyl)phenyl)pyrid-2-y1)arainocarbonylmethyl-5-aminocarboxyindoline; 3 — {4 —(2-t- 25 butylaminosulfonyl)phenyl)phenyl>aminocarbonylmethyl -5- amidinoindoline; and, 3 -{4 -(2-t-butylaminosulfonyl)phenyl)pyrid-2- yl}aminocarbonylmethyl-5-amidinoindoline; 30 or a stereoisomer or pharmaceutically acceptable salt form thereof. 35
9. A compound according to Claim 4, wherein the compound is of formula IVb: 160 Printed from Mimosa WO 98/01428 PCT/US97/I1325 D H B IVb or a stereoisomer or pharmaceutically acceptable salt thereof, wherein A, B, D, and Z are as defined above. 5
10. A compound according to Claim 1, wherein the compound is selected from: 10 3 -(4-(2-aminosulfonyl(phenyl)pyrid-2-ylaminocarbonylmethyl-6-amidinoindazole; 3-{4-(2-aminosulfonyl>phenyl)phenyl aminocarbonylmethyl-6-amidinoindazole; 15 3-{4-(2-t-butyl aminosulfonyl)phenyl)pyrid-2- ylaminocarbonylmethyl-6-amidinoindazole; and, 20 3-{4-(2-t-butylaminosulfonyl)phenyl)phenyl aminocarbonylmethyl-6-amidinoindazole; and. or a stereoisomer or pharmaceutically acceptable salt form thereof. 25
11. A compound according to Claim 4, wherein the compound is of of formula IVc: 30 IVc 161 Printed from Mimosa WO 98/01428 PCT/US97/1132S or a stereoisomer or pharmaceutically acceptable salt thereof, wherein d, Da, Z, A, and B are as defined above. 5
12. A compound according to Claim 1, wherein the compound is selected from: (4- (phenyl)phenylcarbonyl]methyl-6-amidinobenzimidazole; 10 [4- (phenyl)phenylcarbonyl)methyl-5-amidinobenzimidazole; [4-(3 -aminophenyl)phenylcarbonyl)methyl-6 -amidinobenzimidazole; 15 [4-(3-aminophenyl)phenylcarbonylJ methyl-5-amidinobenzimidazole; [4-(4 -fluoropheny1)phenylcarbonyl)me thy 1 -6-amidinobenz imidazole; 20 [4 -(4- forrny Ipheny 1)phenylcarbonyl]methyl-6-amidinobenzimidazole; [4-(2-aminosulfonyIpheny1)phenylcarbonyl]methyl- 6- 25 amidinobenzimidazole; [4-(2-tert-butylaminosulfonyIphenyl)phenylcarbonyl]methyl-6-amidinobenzimidazole; 30 {4- [ (2-tetrazolyl)phenyl]phenylcarbonyl)methyl-6-ami di noben zimidazole,- [ 4 - (2 -aminosul f onylphenyl) phenylaminocarbonyl ] methyl - 6 -amidinobenzimidazole; 35 [ 4 - (2 -aminosul f onylphenyl) phenylaminocarbonyl ] methyl - 5-amidinobenzimidazole; 162 Printed from Mimosa WO 98/01428 PCT/us97/11325 1-(4-benzylpiperidinecarbonyl)methyl-6-amidinobenzimidazole; 1-(4-benzylpiperidinecarbonyl)methyl- 5-amidinobenzimidazole; 5 1-(4-benzylpiperidinecarbonyl)methyl-6-amidinobenzimidazole; and, 2-[4-(2-ter t-butylaminosulfonylphenyl)phenylcarbonyl]methyl-5-azabenzimidazole; 10 2S-[4-(2-tert-aminosulfonyIphenyl)phenylaminocarbonyl]methyl-thio-lH-imidazo(4,5-C) pyridine; and, 2S-[4-(2-aminosulfonylphenyl)phenylaminocarbonyllmethyl-thiols IH-imidazo(4,5-C) pyridine; or a stereoisomer or pharmaceutically acceptable salt form thereof.
13. A compound according to Claim 1, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein the compound is of formula V: V or a stereoisomer or pharmaceutically acceptable salt thereof, wherein one of R and Ra is - (ch2)n~Z-A-B and the other H; 30 W, W2, and W3 are selected from CH and N, provided that at most one of W, W2, and W3 can be N; J is selected from N and C-R1; 163 Printed from Mimosa WO 98/01428 PCT/US97/11325 Ri is selected from H, 0, (CH2)rOR3, (CH2)rC(=0)R2 , (CH=CH) C {=0) R2 , (CH2 ) rNR3C (=0) R2 , (CH2)rS02R4, (CH2) rNR3S02R4. and (CH2)r-5-membered heterocyclic system having 1-4 heteroatoms selected from N, 0, and S; 5 R2 is selected from H, OR3, C1-4 alkyl, NR3R3' , CF3, and C3-10 carbocyclic residue substituted with 0-2 R6; R3 and R3' are independently selected from H, Ci_4 alkyl, and 10 C3-10 carbocyclic residue substituted with 0-2 R6; R4 is selected from OR3, Ci_4 alkyl, NR3R3', and C3-10 carbocyclic residue substituted with 0-2 R6; 15 2 is selected from CH=CH, CH (CH2) mQ ICH2) mR5 , CH ( (CH2)mQ(CH2)n>R5)C(0)NR3, CHICH^C (0) (CH2),nR5a, N(CH2)qQ(CH2)mR5- NQMC^lmR5, C (0) N ( (CH2 ) m0' (CH2) mRSa) , C(0), CtO)CH2, C(0>0, OC(O), C(0)NR3(CH2)r< NR3C(0), 0C(0)NR3, NR3C(0)0, NR3C(0)NR3, S(0)p, S02CH2, S02NR3, 20 NR3S02, and NR3S02NR3; Q is selected from a bond, 0, NR3, C(0), CCOINR3, NR3C(0), S02l NR3S02, and so2nr3; 25 Q' is selected from a bond, C(0). C(0)NR3, S02, and S02NR3 ; R5 is selected from H, C1-.4 alkyl, C3-g carbocyclic residue substituted with 0-2 R6, and 5-10 membered heterocyclic system containing from 1-3 heteroatoms selected from the 30 group consisting of N, O, and 3 substituted with 0-2 R6, provided that when Q is S02 or NR3S02, R5 is other than H and when Q' is S02, R5 is other than H; 35 R5a is selected from NHR5, OR5, and R5; A is selected from: benzyl substituted with 0-2 R6, C3-10 carbocyclic residue substituted with 0-2 R6, and 164 Printed from Mimosa WO 98/01428 PCT/US97/11325 5-10 membered heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R6; 5 B is selected from: H, X-Y. NR3R3', C(=NR3)NR3R3', NR3C(=NR3)NR3R3' , benzyl substituted with 0-2 R6, C3-10 carbocyclic residue substituted with 0-2 R6, and 5-10 membered heterocyclic system containing from 1-3 10 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R6; X is selected from Ci_4 alkylene, -CIO)-, -C(O)CR3R3'-, -CR3R3'C(0), -S(0)p-, -S(0)pCR3R3'- , -CR3R3'S(O)p-, 15 -S(0)2NR3-, -NR3S(0)2-, -C{0)NR3-. -NR3CtO)-, -NR3-, -NR3CR3R3'-, -CR3R3'NR3-, O, -CR3R3 'O-, and -OCR3R3'-; Y is selected from: C3-10 carbocyclic residue substituted with 0-2 R6, and 20 5-10 membered heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, O. and S substituted with 0-2 R6; R6 is selected from H, OH, (CH2)nOR3, halo, Ci_4 alkyl, CN, NO2, 25 (CH2 ) rNR3R3 ', (CH2)rC(0)R3, NR3C(OJR3', NR3C (O) NR3R3', CH(=NH)NK2, NHC(=NH)NH2, C (=0) R3, S02NR3R3', NR3S02NR3R3', and NR3S02~Ci-4 alkyl; 30 n is selected from 0, 1, 2, 3, and 4; m is selected from 0, 1, and 2; p is selected from 0, 1, and 2; 35 q is selected from 1 and 2; and, r is selected from 0, 1, 2, 3, and 4. 165 Printed from Mimosa WO 98/01428 PCT/US97/11325
14. A compound according to Claim 13, wherein the compound is of formula VI: 5 VI or a stereoisomer or pharmaceutically acceptable salt thereof, wherein one of R and Ra is -(CH2>n-Z-A-B and the other H; 10 W and W2 are selected from CH and N, provided that at most one of W and W2 can be N; J is selected from N and C-R1; 15 R1 is selected from H. <CH2)rOR3, (CH2>rC(=0)R2, (CH2)rNR3C(sO)R2, (CH=CH) C (=0) R2 , (CH2)rS02R4, and (CH2)rNR3S02R4; 20 25 R2 is selected from H, OR3, C1-4 alkyl, NR3R3', and cf3; r3 and R3' are independently selected from H, C1-4 alkyl, and phenyl ; R4 is selected from OR3, C1-4 alkyl, NR3R3', and phenyl; Z is selected from C(O), C(0)CH2, C(0)NR3, NR3C(0), S(0)2, so2ch2, S02NR3, NR3S02, and NR3S02NR3; A is selected from: 30 C3-10 carbocyclic residue substituted with 0-2 R6, and 5-10 membered heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R6; 35 B is selected from: 166 Printed from Mimosa WO 98/01428 PCT/US97/11325 10 15 20 25 30 x-y, c3-10 carbocyclic residue substituted with 0-2 R6, and 5-10 membered heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, 0, and S substituted with 0-2 R6; X is selected from -C(0)-, -C(O)CR3R3'-, -CR3R3'C(0), -S(0)p-, -S(0)pCR3R3'-, -CR3R3'S(0)p-, -S(0)2NR3-, -NR3S{0)2-, -C(0)NR3-, -NR3-, -NR3CR3R3'-, and -CR3R3'NR3-; Y is selected from: C3-10 carbocyclic residue substituted with 0-2 R6, and 5-10 membered heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, 0, and S substituted with 0-2 R6; R6 is selected from H, OH, (CH2)nOR3- halo, Cj_4 alkyl, CN, NO2. (CH2)rNR3R3', <CH2)rC(0)R3, NR3C<0)R3', NR3C (0) NR3R3'. C (=0)R3 , S02NR3R3', NR3S02NR3R3', and NR3S02-C1_4 alkyl; n is selected from 0, 1, 2, 3, and 4; p is selected from 0, 1, and 2; and, r is selected from 0, 1, 2, 3, and 4.
15. A compound according to Claim 14, wherein the compound is of formula VII: VII 167 Printed from Mimosa WO 98/01428 PCT/US97/11325 or a stereoisomer or pharmaceutically acceptable salt thereof, wherein, W and W2 are selected from CH and N, provided that at most one of W and W2 can be N; 5 R1 is selected from H, (CH2>rOR3' (CH2)rC(=0) R2 , (CH2)rNR3C(=0)R2, (CH=Ch) C (=0) R2 , (CH2)rS02Rl, and (CH2)rNR3S02R4; 10 15 R2 is selected from H, OR3, C1-4 alkyl, NR3R3', and CF3; R3 and r3' are independently selected from H, Ci-4 alkyl, and phenyl; R4 is selected from OR3, C1-4 alkyl, NR3R3' , and phenyl; Z is selected from C(0), C(0)CH2, C(0)NR3, S<0)2, SO2CH2, S02NR3, and NR3S02NR3; A is selected from: 20 C3-10 carbocyclic residue substituted with 0-2 R6, and 5-10 membered heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R6; 25 B is selected from: X-Y, C3-10 carbocyclic residue substituted with 0-2 R6, and 5-10 membered heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, O, and S 30 substituted with 0-2 R6; X is selected from -S(0)p-, -S(0)pCR3R3'-, -CR3R3'S (0)p-, -S(0)2NR3-, -NR3S(O)2~< and -C(0)NR3-; 35 Y is selected from: C3-10 carbocyclic residue substituted with 0-2 R6, and 168 Printed from Mimosa WO 98/01428 PCT/US97/11325 5-10 membered heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, 0, and S substituted with 0-2 R6; 5 R6 is selected from H, OH, (CH2)nOR3. halo, Ci_4 alkyl, CN, NO2, (CH2)rNR3R3' , (CH2)rC(0)R3, NR3C{0)R3', NR3C(0)NR3R3', C(=0)R3, S02NR3R3', NR3S02NR3R3', and NR3S02-C1_4 alkyl; n is selected from 0, 1, 2, 3, and 4; 10 p is selected from 0, 1, and 2; and, r is selected from 0, 1, 2, 3, and 4. 15
16. A compound according to Claim 13, wherein the compound is selected from: 1-(4-benzylpiperidinecarbonyl)methyl-5-amidinoindole; 20 1-(4-benzylpiperidinecarbonyl)ethyl-5-amidinoindole ; 1-(4-(3-fluoro)benzylpiperidinecarbonyl)methyl-5-amidinoindole; 25 1- (1-(4-amidino)benzyl-N-(methylacetate)aminocarbonyl)methyl-5-amidinoindole; methyl 1-{4-benzylpiperidinecarbonyl)methyl-5-amidinoindole-3-30 propanoate; 1-((4-benzylpiperidinecarbonyl)methyl-(3-ethanehydroxyl)-5-amidinoindole ; 35 1 - (4 -benzy lpiperidine-1 - carbonyl) methyl - 3 -methylcarboxylic ac id- 5-amidinoindole; 1 - (1 -benzy lpiperidine-4 -aminocarbonyl) methyl - 5 -amidinoindol e ; 169 Printed from Mimosa e 3.x ' 0 5 1-(4-benzoylpiperidinecarbonyl)methyl-5-amidinoindole; 5 1- (4-(3 -fluoro)benzylpiperazinecarbony1)methyl-5-amidinoindole; 1 - (4-phenylbenzylaminocarbonyl) methyl - 5-amidinoindole ; methyl 1-(4-benzylpiperidinecarbonyl)methyl-5-amidinoindole-3- 1 - (4-(2-fluoro)benzylpiperidinecarbonyl)methyl- 5 -amidinoindole; 15 or a stereoisomer or pharmaceutically acceptable salt form
17. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically 20 effective amount of a compound according to Claim 1 or a pharmaceutically acceptable salt thereof.
18. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically 25 effective amount of a compound according to Claim 2 or a pharmaceutically acceptable salt thereof.
19. A method for treating or preventing a thromboembolic disorder, comprising: administering to a non- 2q human patient in need thereof a therapeutically effective amount of a compound according to Claim 1 or a pharmaceutically acceptable salt thereof.
20. A method for treating or preventing a 35 thromboembolic disorder, comprising: administering to a non-human patient in need ther-^.^f a therapeutically affective amount of a compound according to Claim 2 or a pharmaceutically acceptable salt thereof. 10 propenoate; and, thereof. 170 intellectual property office OF N.z RECEIVED
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US67676696A | 1996-07-08 | 1996-07-08 | |
| US4951997P | 1997-06-13 | 1997-06-13 | |
| PCT/US1997/011325 WO1998001428A1 (en) | 1996-07-08 | 1997-06-30 | AMIDINOINDOLES, AMIDINOAZOLES, AND ANALOGS THEREOF AS INHIBITORS OF FACTOR Xa AND OF THROMBIN |
Publications (1)
| Publication Number | Publication Date |
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| NZ333696A true NZ333696A (en) | 2000-06-23 |
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| Application Number | Title | Priority Date | Filing Date |
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| NZ333696A NZ333696A (en) | 1996-07-08 | 1997-06-30 | Amidinoindoles, amidinoazoles, and analogs thereof as inhibitors of trypsin like protease enzymes like thrombin and Xa factor |
Country Status (7)
| Country | Link |
|---|---|
| EP (1) | EP0960102A1 (en) |
| JP (1) | JP2002514162A (en) |
| AU (1) | AU3645697A (en) |
| CA (1) | CA2259573A1 (en) |
| IL (1) | IL127873A0 (en) |
| NZ (1) | NZ333696A (en) |
| WO (1) | WO1998001428A1 (en) |
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| WO1999024407A1 (en) * | 1997-11-10 | 1999-05-20 | Array Biopharma, Inc. | Compounds which inhibit tryptase activity |
| WO1999026933A1 (en) * | 1997-11-26 | 1999-06-03 | Axys Pharmaceuticals, Inc. | Substituted amidinoaryl derivatives and their use as anticoagulants |
| WO1999026932A1 (en) * | 1997-11-26 | 1999-06-03 | Axys Pharmaceuticals, Inc. | By amidino group substituted heterocyclic derivatives and their use as anticoagulants |
| DE19753522A1 (en) * | 1997-12-03 | 1999-06-10 | Boehringer Ingelheim Pharma | Substituted indoles, their preparation and their use as pharmaceuticals |
| JP2002509923A (en) | 1998-03-31 | 2002-04-02 | ワーナー−ランバート・カンパニー | Quinoxalinones as serine protease inhibitors such as factor Xa and thrombin |
| TWI248435B (en) * | 1998-07-04 | 2006-02-01 | Boehringer Ingelheim Pharma | Benzimidazoles, the preparation thereof and their use as pharmaceutical compositions |
| US6248770B1 (en) | 1998-07-09 | 2001-06-19 | Boehringer Ingelheim Pharma Kg | Benzimidazoles having antithrombotic activity |
| DE19845153A1 (en) * | 1998-10-01 | 2000-04-06 | Merck Patent Gmbh | Imidazo [4,5] pyridin-4-one derivatives |
| US6362216B1 (en) | 1998-10-27 | 2002-03-26 | Array Biopharma Inc. | Compounds which inhibit tryptase activity |
| AU3127900A (en) | 1998-12-23 | 2000-07-31 | Du Pont Pharmaceuticals Company | Thrombin or factor xa inhibitors |
| CA2358047A1 (en) * | 1998-12-24 | 2000-07-06 | Francis A. Volz | Substituted (aminoiminomethyl or aminomethyl)benzoheteroaryl compounds |
| TW200404789A (en) | 1999-03-15 | 2004-04-01 | Axys Pharm Inc | Novel compounds and compositions as protease inhibitors |
| EP1183234A1 (en) * | 1999-05-24 | 2002-03-06 | Cor Therapeutics, Inc. | INHIBITORS OF FACTOR Xa |
| US6534535B1 (en) * | 1999-08-12 | 2003-03-18 | Millennium Pharmaceuticals, Inc. | Inhibitors of factor Xa |
| GB9924155D0 (en) * | 1999-10-12 | 1999-12-15 | Rhone Poulenc Rorer Pharma | Chemical compounds |
| EP1222182B1 (en) * | 1999-08-26 | 2005-11-16 | Aventis Pharmaceuticals Inc. | Substituted (aminoiminomethyl or aminomethyl) dihydrobenzofurans and benozopyrans |
| ATE374180T1 (en) * | 1999-11-10 | 2007-10-15 | Sanofi Aventis Deutschland | N-ACYLPYRROLIDINE-2-YLALKYLBENZAMIDINE DERIVATIVES AS INHIBITORS OF FACTOR XA |
| US7361663B2 (en) | 1999-11-10 | 2008-04-22 | Aventis Pharmaceuticals Inc. | N-acylpyrrolidin-2-ylalkylbenzamidine derivatives as inhibitors of factor Xa |
| US6451832B2 (en) | 1999-12-23 | 2002-09-17 | Boehringer Ingelheim Pharma Kg | Benzimidazoles with antithrombotic activity |
| EP1324985A4 (en) * | 2000-10-02 | 2004-10-06 | Merck & Co Inc | Inhibitors of prenyl-protein transferase |
| CA2433520A1 (en) | 2000-12-22 | 2002-07-04 | Axys Pharmaceuticals, Inc. | Novel compounds and compositions as cathepsin inhibitors |
| US7030116B2 (en) | 2000-12-22 | 2006-04-18 | Aventis Pharmaceuticals Inc. | Compounds and compositions as cathepsin inhibitors |
| MXPA04002282A (en) | 2001-09-14 | 2005-03-07 | Axis Pharmaceutical Inc | Novel compounds and compositions as cathepsin inhibitors. |
| CN1324018C (en) | 2001-11-14 | 2007-07-04 | 安万特药物公司 | Oligopeptides and compositions containing them as cathepsin S inhibitors |
| EP1569912B1 (en) | 2002-12-03 | 2015-04-29 | Pharmacyclics, Inc. | 2-(2-hydroxybiphenyl-3-yl)-1h-benzoimidazole-5-carboxamidine derivatives as factor viia inhibitors |
| PL372886A1 (en) | 2002-03-07 | 2005-08-08 | F.Hoffmann-La Roche Ag | Bicyclic pyridine and pyrimidine p38 kinase inhibitors |
| AU2003299227A1 (en) * | 2002-12-20 | 2004-07-14 | Ciba Specialty Chemicals Holding Inc. | Synthesis of amines and intermediates for the synthesis thereof |
| TW200508197A (en) | 2003-03-31 | 2005-03-01 | Ucb Sa | Indolone-acetamide derivatives, processes for preparing them and their uses |
| RU2328497C2 (en) | 2003-05-05 | 2008-07-10 | Ф.Хоффманн-Ля Рош Аг | Condensed pirimidine derivative and pharmaceutics with crf related activity |
| EP1828182B1 (en) | 2004-11-29 | 2010-03-10 | Warner-Lambert Company LLC | Therapeutic pyrazolo[3,4-b]pyridines and indazoles |
| GB0507577D0 (en) | 2005-04-14 | 2005-05-18 | Novartis Ag | Organic compounds |
| AR057455A1 (en) | 2005-07-22 | 2007-12-05 | Merck & Co Inc | INHIBITORS OF HIV REVERSE TRANSCRIPTASE AND PHARMACEUTICAL COMPOSITION |
| NL2000291C2 (en) | 2005-11-10 | 2009-02-17 | Pfizer Prod Inc | 1- (1- (2-ethoxyethyl) -3-ethyl-7- (4-methylpyridin-2-ylamino) -1 H -pyrazole (4,3-d) pyrimidin-5-yl) piperidine-4-carboxylic acid and salts thereof. |
| KR20080067697A (en) * | 2005-11-11 | 2008-07-21 | 에프. 호프만-라 로슈 아게 | Carbocyclic fused cyclic amines as inhibitors of the coagulation factor xa |
| TWI530495B (en) | 2010-12-16 | 2016-04-21 | 健生科學愛爾蘭無限公司 | Benzimidazole respiratory syncytial virus inhibitors |
| TWI527814B (en) | 2010-12-16 | 2016-04-01 | 健生科學愛爾蘭無限公司 | Azabenzimidazoles as respiratory syncytial virus antiviral agents |
| TWI541241B (en) | 2010-12-16 | 2016-07-11 | 健生科學愛爾蘭無限公司 | Imidazopyridines as respiratory syncytial virus antiviral agents |
| TWI515187B (en) | 2010-12-16 | 2016-01-01 | 健生科學愛爾蘭無限公司 | Indoles as respiratory syncytial virus antiviral agents |
| TWI501967B (en) | 2010-12-16 | 2015-10-01 | Janssen R&D Ireland | Azaindoles as respiratory syncytial virus antiviral agents |
| WO2012087833A1 (en) | 2010-12-22 | 2012-06-28 | Abbott Laboratories | Hepatitis c inhibitors and uses thereof |
| CN103376329A (en) * | 2012-04-19 | 2013-10-30 | 蓬莱诺康药业有限公司 | Characterization method of stypticity of hemocoagulase atrox for injection and effective components thereof |
| CA2873920C (en) | 2012-06-15 | 2021-07-20 | Janssen R&D Ireland | 1,3-dihydro-2h-benzimidazol-2-one derivatives substituted with heterocycles as respiratory syncytial virus antiviral agents |
| WO2019036562A1 (en) * | 2017-08-18 | 2019-02-21 | Saint Louis University | Err inverse agonists |
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| ZA928276B (en) * | 1991-10-31 | 1993-05-06 | Daiichi Seiyaku Co | Aromatic amidine derivates and salts thereof. |
-
1997
- 1997-06-30 AU AU36456/97A patent/AU3645697A/en not_active Abandoned
- 1997-06-30 NZ NZ333696A patent/NZ333696A/en unknown
- 1997-06-30 IL IL12787397A patent/IL127873A0/en unknown
- 1997-06-30 JP JP50524998A patent/JP2002514162A/en active Pending
- 1997-06-30 CA CA002259573A patent/CA2259573A1/en not_active Abandoned
- 1997-06-30 WO PCT/US1997/011325 patent/WO1998001428A1/en not_active Application Discontinuation
- 1997-06-30 EP EP97933214A patent/EP0960102A1/en not_active Withdrawn
Also Published As
| Publication number | Publication date |
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| WO1998001428A1 (en) | 1998-01-15 |
| AU3645697A (en) | 1998-02-02 |
| EP0960102A1 (en) | 1999-12-01 |
| IL127873A0 (en) | 1999-10-28 |
| JP2002514162A (en) | 2002-05-14 |
| CA2259573A1 (en) | 1998-01-15 |
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