Renin inhibitors

专利摘要:

公开号:AU2006272348A1
申请号:U2006272348
申请日:2006-07-20
公开日:2007-01-25
发明作者:Christopher I. Bayly；Austin C. Chen；Daniel Dube；Laurence Dube；Michel Gallant；Erich L. Grimm；Patrick Lacombe；Dwight Macdonald；Daniel Mckay；David A. Powell
申请人:Merck Frosst Canada Ltd；
IPC主号:C07C237-20

专利说明:
WO 2007/009250 PCT/CA2006/001196 TITLE OF THE INVENTION RENIN INHIBITORS JOINT RESEARCH AGREEMENT 5 The claimed invention was made as a result of activities undertaken within the scope of a joint research agreement between Merck & Co., Inc. and Actelion Pharmaceuticals Ltd. The agreement was executed on December 4, 2003. The field of the invention is described below. FIELD OF THE INVENTION ) The invention relates to novel renin inhibitors of the general formula (I). The invention also concerns related aspects including processes for the preparation of the compounds, pharmaceutical compositions containing one or more compounds of formula (I) and especially their use as renin inhibitors in cardiovascular events and renal insufficiency. 5 BACKGROUND OF THE INVENTION In the renin-angiotensin system (RAS) the biologically active angiotensin II (Ang H) is generated by a two-step mechanism. The highly specific enzyme renin cleaves angiotensinogen to angiotensin I (Ang I), which is then further processed to Ang II by the less specific angiotensin-converting enzyme (ACE). Ang II is known to work on at least two receptor subtypes called D AT1 and AT2. Whereas AT1 seems to transmit most of the known functions of Ang II, the role of AT2 is still unknown. Modulation of the RAS represents a major advance in the treatment of cardiovascular diseases. ACE inhibitors and AT1 blockers have been accepted to treat hypertension (Waeber B. et al., "The renin-angiotensin system: role in experimental and human hypertension", in Birkenhager W. H., 5 Reid J. L. (eds): Hypertension, Amsterdam, Elsevier Science Publishing Co, 1986, 489-519; Weber M. A., Am. J. Hypertens., 1992, 5, 247S). In addition, ACE inhibitors are used for renal protection (Rosenberg M. E. et al., Kidney International, 1994, 45, 403; Breyer J. A. et al., Kidney International, 1994, 45, S156), in the prevention of congestive heart failure (Vaughan D. E. et al., Cardiovasc. Res., 1994, 28, 159; Fouad-Tarazi F. et al., Am. J Med, 1988, 84 (Suppl. 3A), 83) and myocardial infarction S (Pfeffer M. A. et al., N. Engl. J. Med, 1992, 327, 669). The rationale to develop renin inhibitors is the specificity ofrenin (Kleinert H. D., Cardiovasc. Drugs, 1995, 9, 645). The only substrate known for renin is angiotensinogen, which can only be processed (under physiological conditions) by renin. In contrast, ACE can also cleave bradykinin besides Ang I and can be by-passed by chymase, a serine protease (Husain A., J Hypertens., 1993, 11, 5 1155). In patients inhibition of ACE thus leads to bradykinin accumulation causing cough (5-20%) and potentially life-threatening angioneurotic edema (0.1-0.2%) (Israili Z. H. et al., Annals of Internal Medicine, 1992, 117, 234). Chymase is not inhibited by ACE inhibitors. Therefore, the formation of Ang II is still possible in patients treated with ACE inhibitors. Blockade of the AT1 receptor (e.g. by losartan) -1- WO 2007/009250 PCT/CA2006/001196 on the other hand overexposes other AT-receptor subtypes (e.g. AT 2 ) to Ang II, whose concentration is significantly increased by the blockade of AT 1 receptors. In summary, renin inhibitors are expected to demonstrate a different pharmaceutical profile than ACE inhibitors and ATI blockers with regard to efficacy in blocking the RAS and in safety aspects. Only limited clinical experience (Azizi M. et al., J. Hypertens., 1994, 12, 419; Neutel J. M. et al., Am. Heart, 1991, 122, 1094) has been created with renin inhibitors because of their insufficient oral activity due to their peptidomimetic character (Kleinert H. D., Cardiovasc. Drugs, 1995, 9, 645). The clinical development of several compounds has been stopped because of this problem together with the high cost of goods. Only one compound containing four chiral centers has entered clinical trials ) (Rahuel J. et al., Chem. Biol., 2000, 7, 493; Mealy N. E., Drugs of the Future, 2001, 26, 1139). Thus, renin inhibitors with good oral bioavailability and long duration of action are required. Recently, the first non-peptide renin inhibitors were described which show high in vitro activity (Oefner C. et a!., Chem. Biol., 1999, 6, 127; Patent Application WO97/09311; Mdrki H. P. et al., II Farmaco, 2001, 56, 21). However, the development status of these compounds is not known. The present invention relates to the identification of renin inhibitors of a non-peptidic nature and of low molecular weight. Described are orally active renin inhibitors of long duration of action which are active in indications beyond blood pressure regulation where the tissular renin-chymase system may be activated leading to pathophysiologically altered local functions such as renal, cardiac and vascular remodeling, atherosclerosis, and possibly restenosis. So, the present invention describes these ) non-peptidic renin inhibitors. The compounds described in this invention represent a novel structural class of renin inhibitors. SUMMARY OF THE INVENTION 5The present invention is directed to certain compounds and their use in the inhibition of the renin enzyme, including treatment of conditions known to be associated with the renin system. The invention includes compounds of Formula I and pharmaceutically acceptable salts thereof, or an optical isomer thereof: O
R
1
R
2 Ar 2 -X'- (CH 2 )-X / Y N /
(CHR
3
)
n
(CH
2 )1- 2 Ar 2 I NR 4
R
5 ) wherein, m is 1 or 2; n, in each instance in which it occurs, is independently 0, 1 or 2; p, in each instance in which it occurs, is independently 0, 1 or 2; X and Xl are each independently selected from the group consisting of CH 2 , O, and S(O)p, provided that when both X and X1 are each independently O or S(O)p, m is 2; -2- WO 2007/009250 PCT/CA2006/001196 Y is selected from the group consisting of N(Ra), CH(Ra), O, and S(O)p;
R
1,
R
3 , and Ra are each independently selected from the group consisting of H, Cl-C6alkyl and C2 C6alkenyl, wherein the alkyl and alkenyl group is unsubstituted or substituted with one, two, three or four substituents independently selected from: 1) OH, 2) CN, 3) CF3, 4) COOH, 5) C1-C6alkoxy, ) 6) C(O)Rb, 7) C(O)N(Rc) 2 , 8) S(O)pCl-C6alkyl, 9) SO 2 N(Rc) 2 , 10) N(Rc) 2 , S11) NHC(O)Rb, 12) NHC(O)NHRd, 13) NHC(S)NHRd, 14) NH(NRC)NH Rc, 15) tetrazolyl, and e ) 16) -(CH2)1-2 R
R
4 is selected from the group consisting of H, Cl-C6alkyl and C2-C6alkenyl, wherein the alkyl and alkenyl group is unsubstituted or substituted with one, two, three or four substituents independently selected from: 1) OH, 5 2) CN, 3) CF3, 4) COOH, 5) C I-C6alkoxy, 6) C(O)Rb, 0 7) C(O)N(Rc) 2 , 8) S(0)pC1-C6alkyl, 9) SO 2 N(Rc) 2 , 10) N(Rc) 2 , 11) NHC(O)Rb, 5 12) NHC(O)NHRd, 13) NHC(S)NHRd, 14) NH(NRC)NH Rc, and 15) tetrazolyl, -3- WO 2007/009250 PCT/CA2006/001196 or R 4 , together with R 5 , forms a 5- or 6-membered heterocyclic ring which is unsubstituted or mono or di-substituted with a substituent selected from the group consisting of =0 and C 1
-C
6 alkyl;
R
5 is selected from the group consisting of hydrogen and -C(NH(NH 2 ), or R 5, together with R 4 , forms a 5- or 6-membered heterocyclic ring which is unsubstituted or mono- or di-substituted with a 5 substituent selected from the group consisting of =0 and C l-C 6 alkyl;
R
2 and Rb are independently selected from the group consisting of H, C1-C6alkyl, C2-C6alkenyl, C1-C6alkoxy, CF3 and CH2CF3; Rc is selected from the group consisting of H, Cl-C6alkyl and CH2CF3; Rd is selected from the group consisting of H and C1-C6alkyl, wherein the alkyl group is unsubstituted 0 or substituted with one, two, three or four substituents selected from the group consisting of: 1) OH, 2) CN, 3) CF3, 4) COOH, and 5 5) C(0)NHRc, and 6) tetrazolyl; R is a 5- or 6-membered heteroaryl ring having I or 2 nitrogen atoms; Ar 1 is an unsubstituted or substituted aryl ring or an unsubstituted or substituted 5- or 6-membered heteroaryl ring containing 1 to 3 heteroatoms selected from O, S and N, wherein the substituted aryl .0 ring and substituted heteroaryl ring are substituted with one, two three or four substituents independently selected from the group consisting of: 1) OH, 2) CN, 3) halogen, 5 4) N3, 5) NO2, 6) COOH, 7) OCF2H, 8) CF3, '0 9) Cl-C6alkyl, 10) C2-C6alkenyl, 11) C 1 -C6alkoxy, 12) C(O)Cl -C6alkyl, and 13) S(O)pC 1-C6alkyl, 5 wherein substituents (9) - (13) are unsubstituted or substituted with one, two three or four substituents independently selected from the group consisting of: a) OH, b) COOH, -4-.
WO 2007/009250 PCT/CA2006/001196 c) CN, d) CF3, e) C 1 -C6alkoxy, f) S(O)pC1-C6alkyl; 5 Ar 2 is independently selected from the group consisting of Ar 1 and a 9- or 10 membered fused bicyclic aryl or heteroaryl ring, wherein the fused bicyclic heteroaryl contains 1 to 4 heteroatoms selected from O, S and N, wherein the fused bicyclic aryl and heteroaryl are each unsubstituted or substituted with one, two, three or four substituents independently selected from the group consisting of: 1) OH, 0 2) CN, 3) halogen, 4) N3, 5) NO2, 6) COOH, 5 7) OCF2H, 8) CF 3 , 9) C I-C6alkyl, unsubstituted or substituted with Ar 3 , 10) Cl-C6alkyl, 11) C2-C6alkenyl, .0 12) Cl -C6alkoxy, 13) C(O)C1-C6alkyl, 14) S(O)pC1-C6alkyl, 15) -O(CH2)1-2Ar 3 , 16) -O(CH2)1-2D, 5 17) -OC(O)D, 18) -OC(O)NH(C 1 -C6alkylene)C(O)NH2, and 19) -OC(O)NH(C 1-C6alkylene)(OH)Rd; wherein substituents (10) - (14) are unsubstituted or substituted with one, two three or four substituents independently selected from the group consisting of: 0 a) OH, b) COORd, c) CN, d) CF 3 , e) C1-C6alkoxy, 5 f) S(O)pC 1-C6alkyl, g) tetrazolyl h) -C(O)NH 2 , i) -COONa, -5- WO 2007/009250 PCT/CA2006/001196 j) -NRdRd, and k) -NRdC(O)Rd; Ar 3 is an unsubstituted or substituted aryl ring or an unsubstituted or substituted 5- or 6-membered heteroaryl ring containing 1 to 3 heteroatoms selected from O, S and N, wherein the substituted aryl 5 ring and substituted heteroaryl ring are substituted with one, two three or four substituents independently selected from the group consisting of: 1) OH, 2) CN, 3) OCF2H, 10 4) CF3, 5) C1-C3alkyl, 6) C1-C3alkoxy, and 7) -SO 2 Rd; and D is a 5- or 6-membered saturated heterocyclic ring having 1 or 2 nitrogen atoms and 0 or 1 oxygen 15 atoms, wherein the ring may be unsubstituted or substituted with C 1 -C6alkyl. DETAILED DESCRIPTION OF THE DISCLOSURE The compounds of Formula I above, and pharmaceutically acceptable salts thereof, are renin inhibitors. The compounds are useful for inhibiting renin and treating conditions such as 20 hypertension. One embodiment of the invention relates to compounds of Formula I, or a pharmaceutically acceptable salt thereof, wherein Y is CH(Ra), wherein Ra is as originally defined. Within this subset, all other variables are as originally defined. Another embodiment of the invention relates to compounds of Formula I, or a 25 pharmaceutically acceptable salt thereof, wherein R1 is H. Within this subset, all other variables are as originally defined. Within another subset of this embodiment Y is CH(Ra), wherein Ra is as originally defined and all other variables are as originally defined. Another embodiment of the invention relates to compounds of Formula I, or a pharmaceutically acceptable salt thereof, wherein n is 1. Within this subset, all other variables are as 30 originally defined. Within another subset of this embodiment Y is CH(Ra), wherein Ra is as originally defined and all other variables are as originally defined. Within another subset of this embodiment Y is CH(Ra), wherein Ra is as originally defined, R1 is H and all other variables are as originally defined. Within another subset of this embodiment R1 is H, Y is CH2 or -CH(CH2Ar 3 ), R 2 is C1-C6 alkyl or C1-C6 alkenyl, and all other variables are as originally defined 35 Another embodiment of the invention relates to compounds of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 2 is C1-C6alkyl. Within this subset, all other variables are as originally defined. -6- WO 2007/009250 PCT/CA2006/001196 Another embodiment of the invention relates to compounds of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 2 is C3-C6cycloalkyl. Within this subset, all other variables are as originally defined. Specific examples of compounds of formula I, and pharmaceutically acceptable salts 5 thereof, include The compounds represented by the structures shown above have the following names: (i) N- { 3-[(Acetyl-methyl-amino)-methyl]-benzyl }-2-aminomethyl-N-cyclopropyl-3- {4-[2-(2,6 dichloro-4-methyl-phenoxy)-ethoxy]-phenyl}-propionamide, (ii) 2-Aminomethyl-N-cyclopropyl-3- {4-[2-(2,6-dichloro-4-methyl-phenoxy)-ethoxy]-phenyl }-N 10 (1,2,3,4-tetrahydro-quinolin-8-ylmethyl)-propionamide, (iii) 2-Aminomethyl-N-cyclopropyl-3- {4-[2-(2,6-dichloro-4-methyl-phenoxy)-ethoxy]-phenyl}-N quinolin-4-ylmethyl-propionamide, (iv) 3-Amino-N-cyclopropyl-2- { 4-[2-(2,6-dichloro-4-methyl-phenoxy)-ethoxy]-benzyl } -N-(2,3 dimethyl-benzyl)-propionamide, 15 (v) 2-Aminomethyl-N-cyclopropyl-3- {4-[2-(2,6-dichloro-4-methyl-phenoxy)-ethoxy]-phenyl } -N-[3-(2 methanesulfonyl-ethyl)-benzyl]-propionamide, (vi) 5-(2-[Cyclopropyl-(2,3-dichloro-benzyl)-carbamoyl]-3- { 4-[2-(2,6-dichloro-4-methyl-phenoxy) ethoxy]-phenyl}-propylamino)-pentanoic acid methyl ester, (vii) 6-(2-[Cyclopropyl-(2,3-dichloro-benzyl)-carbamoyl]-3- {4-[2-(2,6-dichloro-4-methyl-phenoxy) 20 ethoxy]-phenyl } -propylamino)-hexanoic acid, (viii) 6-(2-[Cyclopropyl-(2,3-dichloro-benzyl)-carbamoyl]-3- {4-[2-(2,6-dichloro-4-methyl-phenoxy) ethoxy]-phenyl}-propylamino)-hexanoic acid methyl ester, (ix) N-Cyclopropyl-N-(2,3-dichloro-benzyl)-3- {4-[2-(2,6-dichloro-4-methyl-phenoxy)-ethoxy] phenyl}-2-[(2,2,2-trifluoro-ethylamino)-methyl]-propionamide, 25 (x) 2-Aminomethyl-N-cyclopropyl-3- {4-[2-(2,6-dichloro-4-methyl-phenoxy)-ethoxy]-phenyl }-N-[3-(3 methoxy-propyl)-benzyl]-propionamide, (xi) 2-Aminomethyl-N-[2-chloro-5-(3-methoxy-propyl)-benzyl]-N-cyclopropyl-3- { 4-[2-(2,6-dichloro-4 methyl-phenoxy)-ethoxy]-phenyl}-propionamide, (xii) 2-[(2-[Cyclopropyl-(2,3-dichloro-benzyl)-carbamoyl]-3- {4-[2-(2,6-dichloro-4-methyl-phenoxy) 30 ethoxy]-phenyl}-propylamino)-methyl]-cyclopropanecarboxylic acid, (xiii) 2-[(2-[Cyclopropyl-(2,3-dichloro-benzyl)-carbamoyl]-3- {4-[2-(2,6-dichloro-4-methyl-phenoxy) ethoxy]-phenyl}-propylamino)-methyl]-cyclopropanecarboxylic acid ethyl ester, (xiv) 2-Aminomethyl-3- { 4-[3-(2-chloro-3,6-difluoro-phenoxy)-propyl]-phenyl }-N-cyclopropyl-N-[3-(3 methoxy-propyl)-benzyl]-propionamide, 35 (xv) 2-Aminomethyl-3-{4-[3-(2-chloro-3,6-difluoro-phenoxy)-propyl]-phenyl }-N-[2-chloro-5-(3 methoxy-propyl)-benzyl]-N-cyclopropyl-propionamide, (xvi) 3-Amino-N-cyclopropyl-N-(2,3-dichloro-benzyl)-2- {4-[2-(2,6-dichloro-4-methyl-phenoxy)-ethyl] benzyl}-propionamide, -7- WO 2007/009250 PCT/CA2006/001196 (xvii) 2-Aminomethyl-3- {4-[3-(2-chloro-3,6-difluoro-phenoxy)-propyl]-phenyl}-N-cyclopropyl-N-(2,3 dichloro-benzyl)-2-methyl-propionamide, (xviii) 3-Amino-N-cyclopropyl-N-(2,3-dichloro-benzyl)-2- {4-[2-(2,6-dichloro-4-methyl-phenoxy) ethoxy]-benzyl}-propionamide, 5 (ixx) 2-Aminomethyl-N-cyclopropyl-N-(2,3-dichloro-benzyl)-3- {4-[3-(2,6-dichloro-4-methyl phenoxy)-propyl]-phenyl } -propionamide, (xx) 3- { 4-[3-(2-Chloro-3,6-difluoro-phenoxy)-propyl]-phenyl }-N-cyclopropyl-N-(2,3-dichloro-benzyl) 2-methylaminomethyl-propionamide, (xxi) 2-(Benzylamino-methyl)-3- {4-[3-(2-chloro-3,6-difluoro-phenoxy)-propyl]-phenyl } -N 0 cyclopropyl-N-(2,3-dichloro-benzyl)-propionamide, (xxii) 2-Aminomethyl-3- { 4-[3-(2-chloro-3,6-difluoro-phenoxy)-propyl]-phenyl}-N-cyclopropyl-N-(2,3 dichloro-benzyl)-propionamide, and (xxiii) 2-Aminomethyl-N-[2-chloro-5-(2-methoxy-ethyl)-benzyl]-N-cyclopropyl-3- { 4-[2-(2,6-dichloro 4-methyl-phenoxy)-ethoxy]-phenyl } -propionamide. 5 The present invention also encompasses a pharmaceutical formulation comprising a pharmaceutically acceptable carrier and the compound of Formula I or a pharmaceutically acceptable crystal form or hydrate thereof. A preferred embodiment is a pharmaceutical composition of the compound of Formula I, comprising, in addition, a second agent. The compounds of the present invention may have chiral centers, e.g. one chiral center 0 (providing for two stereoisomers, (R) and (S)), or two chiral centers (providing for up to four stereoisomers, (R,R), (S,S), (R,S), and (S,R)). This invention includes all of the optical isomers and mixtures thereof. Unless specifically mentioned otherwise, reference to one isomer applies to any of the possible isomers. Whenever the isomeric composition is unspecified, all possible isomers are included. Tautomers of compounds defined in Formula I are also included within the scope of the 5 present invention. For example, compounds including carbonyl -CH2C(O)- groups (keto forms) may undergo tautomerism to form hydroxyl -CH=C(OH)- groups (enol forms). Both keto and enol forms are included within the scope of the present invention. In addition compounds with carbon-carbon double bonds may occur in Z- and E- forms with all isomeric forms of the compounds being included in the present invention. 0 List of abbreviations: ABTS 2,2'-Azino-bis(3-ethylbenzthiazoline-6-sulfonic Acid) 2NH3 Ac acetyl ADDP 1,1 '-(azodicarbonyl)-dipiperidine AIBN 2,2'-azobis(2-methylpropionitrile) 5 Boc t-butyloxycarbonyl BSA bovine serum albumin DIBAL diisobutylaluminum hydride DME dimethoxyethane -8- WO 2007/009250 PCT/CA2006/001196 DMF dimethylformamide DMP Dess-Martin periodinane DMSO dimethylsulfoxide EDTA ethylenediaminetetraacetic acid 5 EIA enzyme immunoassay HATU O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate LAH lithium aluminum hydride PBS phosphate-buffered saline TBAF tetra-n -butylammonium fluoride 0 TBS tert-butyldimethylsilyl THF tetrahydrofuran TBSO tert-butyldimethylsilyloxy Embodiments of the method of the present invention include those in which the compound of Formula I administered to the subject is as defined in the compound embodiments, classes 5 and sub-classes set forth above. As used herein except where noted, "alkyl" is intended to include both branched- and straight-chain saturated aliphatic hydrocarbon groups, and is intended to include the cyclic group cycloalkyl, including all isomers, having the specified number of carbon atoms. The term "cycloalkyl" means carbocycles containing no heteroatoms. Examples of cycloalkyl include cyclopropyl, cyclobutyl, 20 cyclopentyl, cyclohexyl. Commonly used abbreviations for alkyl groups are used throughout the specification, e.g. methyl may be represented by "Me" or CH 3 , ethyl may be represented by "Et" or
CH
2
CH
3 , propyl may be represented by "Pr" or CH 2
CH
2
CH
3 , butyl may be represented by "Bu" or
CH
2
CH
2
CH
2
CH
3 , etc. "Cl-6 alkyl" (or "C 1-C6 alkyl") for example, means linear or branched chain alkyl groups, including all isomers, having the specified number of carbon atoms. C1-6 alkyl includes all .5 of the hexyl alkyl and pentyl alkyl isomers as well as n-, iso-, sec- and t-butyl, n- and isopropyl, ethyl and methyl. "C1-4 alkyl" means n-, iso-, sec- and t-butyl, n- and isopropyl, ethyl and methyl. The term "alkylene" refers to both branched- and straight-chain saturated aliphatic hydrocarbon groups, including all isomers, having the specified number of carbons, and having two terminal end chain attachments. For illustration, the term "unsubstituted A-C4alkylene-B" represents A-CH2-CH2-CH2-CH 2 -B. The term 0 "alkoxy" represents a linear or branched alkyl group of indicated number of carbon atoms attached through an oxygen bridge. The term "alkenyl" includes both branched and straight chain unsaturated hydrocarbon groups containing at least two carbon atoms joined by a double bond. The alkene ethylene is represented, for example, by "CH 2 CH2" or alternatively, by "H 2
C=CH
2 ". "C2-5 alkenyl" (or "C2-C5 5 alkenyl") for example, means linear or branched chain alkenyl groups having from 2 to 5 carbon atoms and includes all of the pentenyl isomers as well as 1-butenyl, 2-butenyl, 3-butenyl, 1-propenyl, 2 propenyl, and ethenyl (or ethylenyl). Similar terms such as "C2-3 alkenyl" have an analogous meaning. -9- WO 2007/009250 PCT/CA2006/001196 Unless otherwise specifically noted as only "unsubstituted" or only "substituted", alkyl, cycloalkyl, alkylene, alkoxy, and alkenyl groups are unsubstituted or substituted with 1 to 3 substituents on each carbon atom, with halo, Cl-C20 alkyl, CF3, NH2, N(C1-C6 alkyl)2, NO2, oxo, CN, N3, -OH, O(C1 -C 6 alkyl), C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, (CO-C 6 alkyl) S(O)0-2-, (CO-C 6 5 alkyl)S(O)0-2(CO-C 6 alkyl)-, (CO-C 6 alkyl)C(O)NH-, H2N-C(NH)-, -O(C1 -C 6 alkyl)CF3, (CO-C 6 alkyl)C(O)-, (CO-C 6 alkyl)OC(O)-, (CO-C 6 alkyl)O(C1-C6 alkyl)-, (CO-C 6 alkyl)C(O)1-2(CO-C6 alkyl)-,
(CO-C
6 alkyl)OC(O)NH-, -NH(CI-C6 alkyl)NHC(O)NH(C1-C6 alkyl), -NHSO2NH2, -NH(C1-C6 alkyl)NHSO2(C1-C6 alkyl), -(CO-C 6 alkyl)NHSO2(C 1-C6 alkyl), tetrazolyl, aryl, aralkyl, heterocycle, heterocyclylalkyl, halo-aryl, halo-aralkyl, halo-heterocycle, halo-heterocyclylalkyl, cyano 0 aryl, cyano-aralkyl, cyano-heterocycle and cyano-heterocyclylalkyl. The tennrm "Co" as employed in expressions such as "CO-6 alkyl" means a direct covalent bond. Similarly, when an integer defining the presence of a certain number of atoms in a group is equal to zero, it means that the atoms adjacent thereto are connected directly by a bond. For example, in the Q structure T , wherein s is an integer equal to zero, 1 or 2, the structure is T when s is 5 zero. The term "C3-8 cycloalkyl" (or "C3-C8 cycloalkyl") means a cyclic ring of an alkane having three to eight total carbon atoms (i.e., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl). The terms "C3-7 cycloalkyl", "C3-6 cycloalkyl", "C5-7 cycloalkyl" and the like have analogous meanings. :0 The term "halogen" (or "halo") refers to fluorine, chlorine, bromine and iodine (alternatively referred to as fluoro (F), chloro (Cl), bromo (Br), and iodo (I)). The term "C1-6 haloalkyl" (which may alternatively be referred to as "CI-C6 haloalkyl" or "halogenated C1-C6 alkyl") means a Cl to C6 linear or branched alkyl group as defined above with one or more halogen substituents. The term "C1-4 haloalkyl" has an analogous meaning. The term "C1 15 6 fluoroalkyl" has an analogous meaning except that the halogen substituents are restricted to fluoro. Suitable fluoroalkyls include the series (CH2)0-4CF3 (i.e., trifluoromethyl, 2,2,2-trifluoroethyl, 3,3,3 trifluoro-n-propyl, etc.). The term "carbocycle" (and variations thereof such as "carbocyclic" or "carbocyclyl") as used herein, unless otherwise indicated, refers to (i) a C3 to C8 monocyclic, saturated or unsaturated ring 0 or (ii) a C7 to Cl2 bicyclic saturated or unsaturated ring system. Each ring in (ii) is either independent of, or fused to, the other ring, and each ring is saturated or unsaturated. The carbocycle may be attached to the rest of the molecule at any carbon atom which results in a stable compound. The fused bicyclic carbocycles are a subset of the carbocycles; i.e., the term "fused bicyclic carbocycle" generally refers to a C7 to C 10 bicyclic ring system in which each ring is saturated or unsaturated and two adjacent carbon 5 atoms are shared by each of the rings in the ring system. A fused bicyclic carbocycle in which one ring is saturated and the other is saturated is a saturated bicyclic ring system. A fused bicyclic carbocycle in which one ring is benzene and the other is saturated is an unsaturated bicyclic ring system. A fused -10- WO 2007/009250 PCT/CA2006/001196 bicyclic carbocycle in which one ring is benzene and the other is unsaturated is an unsaturated ring system. Saturated carbocyclic rings are also referred to as cycloalkyl rings, e.g., cyclopropyl, cyclobutyl, etc. Unless otherwise noted, carbocycle is unsubstituted or substituted with C1-6 alkyl, C1-6 alkenyl, Cl -6 alkynyl, aryl, halogen, NH2 or OH. A subset of the fused bicyclic unsaturated carbocycles are 5 those bicyclic carbocycles in which one ring is a benzene ring and the other ring is saturated or unsaturated, with attachment via any carbon atom that results in a stable compound. Representative examples of this subset include the following: 0 The term "aryl" refers to aromatic mono- and poly-carbocyclic ring systems, wherein the individual carbocyclic rings in the polyring systems are fused or attached to each other via a single bond. Suitable aryl groups include phenyl, naphthyl, and biphenylenyl. The term "heterocycle" (and variations thereof such as "heterocyclic" or "heterocyclyl") broadly refers to (i) a stable 4- to 8-membered, saturated or unsaturated monocyclic ring, or (ii) a stable 5 7- to 12-membered bicyclic ring system, wherein each ring in (ii) is independent of, or fused to, the other ring or rings and each ring is saturated or unsaturated, and the monocyclic ring or bicyclic ring system contains one or more heteroatoms (e.g., from 1 to 6 heteroatoms, or from 1 to 4 heteroatoms) selected from N, O and S and a balance of carbon atoms (the monocyclic ring typically contains at least one carbon atom and the ring systems typically contain at least two carbon atoms); and wherein any one or -0 more of the nitrogen and sulfur heteroatoms is optionally oxidized, and any one or more of the nitrogen heteroatoms is optionally quaternized. Unless otherwise specified, the heterocyclic ring may be attached at any heteroatom or carbon atom, provided that attachment results in the creation of a stable structure. Unless otherwise specified, when the heterocyclic ring has substituents, it is understood that the substituents may be attached to any atom in the ring, whether a heteroatom or a carbon atom, provided 25 that a stable chemical structure results. Unless otherwise specifically noted as only "unsubstituted" or only "substituted", cycloalkyl, aryl and heterocycle groups are unsubstituted or substituted. As used herein, the terms "substituted C3-8 cycloalkyl", "substituted aryl" and "substituted heterocycle" are intended to include the cyclic group containing from 1 to 3 substituents in addition to the point of attachment to the rest of 30 the compound. Preferably, the substituents are selected from the group which includes, but is not limited to, halo, C1-C20 alkyl, CF3, NH2, N(C1-C6 alkyl)2, NO2, oxo, CN, N3, -OH, -O(C 1
-C
6 alkyl), C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, (CO-C 6 alkyl) S(O)0-2-, aryl-S(O)0-2-, (CO-C 6 alkyl)S(O)0 2(CO-C 6 alkyl)-, (CO-C 6 alkyl)C(O)NH-, H2N-C(NH)-, -O(C1 -C 6 alkyl)CF3, (CO-C 6 alkyl)C(O)-, (C 0 -11- WO 2007/009250 PCT/CA2006/001196 C6 alkyl)OC(O)-, (CO-C6alkyl)O(C1-C6 alkyl)-, (CO-C 6 alkyl)C(O)1-2(CO-C6 alkyl)-, (CO-C 6 alkyl)OC(O)NH-, aryl, aralkyl, heteroaryl, heterocyclylalkyl, halo-aryl, halo-aralkyl, halo-heterocycle, halo-heterocyclylalkyl, cyano-aryl, cyano-aralkyl, cyano-heterocycle and cyano-heterocyclylalkyl. Saturated heterocyclics form a subset of the heterocycles; i.e., the term "saturated 5 heterocyclic" generally refers to a heterocycle as defined above in which the entire ring system (whether mono- or poly-cyclic) is saturated. The term "saturated heterocyclic ring" refers to a 4- to 8-membered saturated monocyclic ring or a stable 7- to 12-membered bicyclic ring system which consists of carbon atoms and one or more heteroatoms selected from N, O and S. Representative examples include piperidinyl, piperazinyl, azepanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, 10 isoxazolidinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, isothiazolidinyl, and tetrahydrofuryl (or tetrahydrofuranyl). Heteroaromatics form another subset of the heterocycles; i.e., the term "heteroaromatic" (alternatively "heteroaryl") generally refers to a heterocycle as defined above in which the entire ring system (whether mono- or poly-cyclic) is an aromatic ring system. The term "heteroaromatic ring" refers 15 a 5- or 6-membered monocyclic aromatic ring or a 7- to 12-membered bicyclic which consists of carbon atoms and one or more heteroatoms selected from N, O and S. In the case of substituted heteroaryl rings containing at least one nitrogen atom (e.g., pyridine), such substitutions can be those resulting in N-oxide formation. Representative examples of heteroaromatic rings include pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, thienyl (or thiophenyl), thiazolyl, furanyl, imidazolyl, pyrazolyl, triazolyl, 20 tetrazolyl, oxazolyl, isooxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, and thiadiazolyl. Representative examples of bicyclic heterocycles include benzotriazolyl, indolyl, isoindolyl, indazolyl, indolinyl, isoindolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, chromanyl, isochromanyl, tetrahydroquinolinyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, O 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzo-1,4-dioxinyl (i.e., O ), imidazo(2,1-b)(1,3)thiazole, S C -N 0 0 25 (i.e., ), and benzo-1,3-dioxolyl (i.e., ). In certain contexts herein, 0 is alternatively referred to as phenyl having as a substituent methylenedioxy attached to two adjacent carbon atoms. Unless expressly stated to the contrary, an "unsaturated" ring is a partially or fully unsaturated ring. For example, an "unsaturated monocyclic C6 carbocycle" refers to cyclohexene, 30 cyclohexadiene, and benzene. Unless expressly stated to the contrary, all ranges cited herein are inclusive. For example, a heterocycle described as containing from "I to 4 heteroatoms" means the heterocycle can contain 1, 2, 3 or 4 heteroatoms. When any variable occurs more than one time in any constituent or in any formula 35 depicting and describing compounds of the invention, its definition on each occurrence is independent of -12- WO 2007/009250 PCT/CA2006/001196 its definition at every other occurrence. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds. The term "substituted" (e.g., as in "aryl which is optionally substituted with one or more substituents ... ") includes mono- and poly-substitution by a named substituent to the extent such single 5 and multiple substitution (including multiple substitution at the same site) is chemically allowed. The term "hydrate" as used herein means a compound of the invention or a salt thereof, that further includes a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces. The term "clathrate" as used herein means a compound of the invention or a salt thereof 10 in the form of a crystal lattice that contains spaces (e. g., channels) that have a guest molecule (e. g., a solvent or water) trapped within. In compounds of the invention having pyridyl N-oxide moieties, the pyridyl-N-oxide portion is structurally depicted using conventional representations such as N N-O 15 which have equivalent meanings. For variable definitions containing terms having repeated terms, e.g., (CRiRJ)r, where r is the integer 2, Ri is a defined variable, and RIJ is a defined variable, the value of RI may differ in each instance in which it occurs, and the value of RI may differ in each instance in which it occurs. For example, if Ri and Ri are independently selected from the group consisting of methyl, ethyl, propyl and 20 butyl, then (CRiRJ) 2 can be I
H
3
CH
2
C-C-CH
3
H
3
CH
2
CH
2
CH
2 C- C- CH 2
CH
2
CH
3 Pharmaceutically acceptable salts include both the metallic (inorganic) salts and organic salts; a list of which is given in Remington's Pharmaceutical Sciences, 17th Edition, pg. 1418 (1985). It is well known to one skilled in the art that an appropriate salt form is chosen based on physical and 25 chemical stability, flowability, hydro-scopicity and solubility. As will be understood by those skilled in the art, pharmaceutically acceptable salts include, but are not limited to salts of inorganic acids such as hydrochloride, sulfate, phosphate, diphosphate, hydrobromide, and nitrate or salts of an organic acid such as malate, maleate, fumarate, tartrate, succinate, citrate, acetate, lactate, methanesulfonate, p toluenesulfonate or palmoate, salicylate and stearate. Similarly pharmaceutically acceptable cations 30 include, but are not limited to sodium, potassium, calcium, aluminum, lithium and ammonium (especially ammonium salts with secondary amines). Preferred salts of this invention for the reasons cited above include potassium, sodium, calcium and ammonium salts. Also included within the scope of this invention are crystal forms, hydrates and solvates of the compounds of Formula I. -13- WO 2007/009250 PCT/CA2006/001196 The compounds of Formula I can be administered in the form of pharmaceutically acceptable salts. The term "pharmaceutically acceptable salt" refers to a salt which possesses the effectiveness of the parent compound and which is not biologically or otherwise undesirable (e.g., is neither toxic nor otherwise deleterious to the recipient thereof). Suitable salts include acid addition salts 5 which may, for example, be formed by mixing a solution of the compound of the present invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, or benzoic acid. Certain of the compounds employed in the present invention carry an acidic moiety (e.g., -COOH or a phenolic group), in which case suitable pharmaceutically acceptable salts thereof can include alkali metal salts (e.g., sodium or potassium salts), alkaline earth metal salts 10 (e.g., calcium or magnesium salts), and salts formed with suitable organic ligands such as quaternary ammonium salts. Also, in the case of an acid (-COOH) or alcohol group being present, pharmaceutically acceptable esters can be employed to modify the solubility or hydrolysis characteristics of the compound. The invention relates to a method for the treatment and/or prophylaxis of diseases which are related to hypertension, congestive heart failure, pulmonary hypertension, systolic hypertension, renal 15 insufficiency, renal ischemia, renal failure, renal fibrosis, cardiac insufficiency, cardiac hypertrophy, cardiac fibrosis, myocardial ischemia, cardiomyopathy, glomerulonephritis, renal colic, complications resulting from diabetes such as nephropathy, vasculopathy and neuropathy, glaucoma, elevated intra ocular pressure, atherosclerosis, restenosis post angioplasty, complications following vascular or cardiac surgery, erectile dysfunction, hyperaldosteronism, lung fibrosis, scleroderma, anxiety, cognitive 20 disorders, complications of treatments with immunosuppressive agents, and other diseases known to be related to the renin-angiotensin system, which method comprises administrating a compound as defined above to a human being or animal. In another embodiment, the invention relates to a method for the treatment and/or prophylaxis of diseases which are related to hypertension, congestive heart failure, pulmonary 25 hypertension, renal insufficiency, renal ischemia, renal failure, renal fibrosis, cardiac insufficiency, cardiac hypertrophy, cardiac fibrosis, myocardial ischemia, cardiomyopathy, complications resulting from diabetes such as nephropathy, vasculopathy and neuropathy. In another embodiment, the invention relates to a method for the treatment and/or prophylaxis of diseases, which are associated with a dysregulation of the renin-angiotensin system as 30 well as for the treatment of the above-mentioned diseases. The invention also relates to the use of compounds of formula (I) for the preparation of a medicament for the treatment and/or prophylaxis of the above-mentioned diseases. Compounds of formula (I) or the above-mentioned pharmaceutical compositions are also of use in combination with other pharmacologically active compounds comprising ACE-inhibitors, 35 neutral endopeptidase inhibitors, angiotensin II receptor antagonists, endothelin receptors antagonists, vasodilators, calcium antagonists, potassium activators, diuretics, sympatholitics, beta-adrenergic antagonists, alpha-adrenergic antagonists or with other drugs beneficial for the prevention or the treatment of the above-mentioned diseases. -14- WO 2007/009250 PCT/CA2006/001196 The term "administration" and variants thereof (e.g., "administering" a compound) in reference to a compound of Formula I mean providing the compound or a prodrug of the compound to the individual in need of treatment or prophylaxis. When a compound of the invention or a prodrug thereof is provided in combination with one or more other active agents (e.g., an agent such as 5 anangiotensin 11 receptor antagonist, ACE inhibitor, or other active agent which is known to reduce blood pressure), "administration" and its variants are each understood to include provision of the compound or prodrug and other agents at the same time or at different times. When the agents of a combination are administered at the same time, they can be administered together in a single composition or they can be administered separately. 0 As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combining the specified ingredients in the specified amounts. By "pharmaceutically acceptable" is meant that the ingredients of the pharmaceutical composition must be compatible with each other and not deleterious to the recipient thereof. 5 The term "subject" as used herein refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment. The term "effective amount" as used herein means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician. In one 20 embodiment, the effective amount is a "therapeutically effective amount" for the alleviation of the symptoms of the disease or condition being treated. In another embodiment, the effective amount is a "prophylactically effective amount" for prophylaxis of the symptoms of the disease or condition being prevented. The term also includes herein the amount of active compound sufficient to inhibit renin and thereby elicit the response being sought (i.e., an "inhibition effective amount"). When the active 25 compound (i.e., active ingredient) is administered as the salt, references to the amount of active ingredient are to the free form (i.e., the non-salt form) of the compound. In a preferred embodiment, this amount is comprised between 1 mg and 1000 mg per day. In a particularly preferred embodiment, this amount is comprised between 1 mg and 500 mg per day. In a more particularly preferred embodiment, this amount is comprised between 0 1 mg and 200 mg per day. In the method of the present invention (i.e., inhibiting renin), the compounds of Formula I, optionally in the form of a salt, can be administered by any means that produces contact of the active agent with the agent's site of action. They can be administered by any conventional means available for use in conjunction with pharmaceuticals, either as individual therapeutic agents or in a combination of 5 therapeutic agents. They can be administered alone, but typically are administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice. The compounds of the invention can, for example, be administered orally, parenterally (including subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques), by -15- WO 2007/009250 PCT/CA2006/001196 inhalation spray, or rectally, in the form of a unit dosage of a pharmaceutical composition containing an effective amount of the compound and conventional non-toxic pharmaceutically-acceptable carriers, adjuvants and vehicles. Liquid preparations suitable for oral administration (e.g., suspensions, syrups, elixirs and the like) can be prepared according to techniques known in the art and can employ any of the 5 usual media such as water, glycols, oils, alcohols and the like. Solid preparations suitable for oral administration (e.g., powders, pills, capsules and tablets) can be prepared according to techniques known in the art and can employ such solid excipients as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like. Parenteral compositions can be prepared according to techniques known in the art and typically employ sterile water as a carrier and optionally other ingredients, such as a 10 solubility aid. Injectable solutions can be prepared according to methods known in the art wherein the carrier comprises a saline solution, a glucose solution or a solution containing a mixture of saline and glucose. Further description of methods suitable for use in preparing pharmaceutical compositions for use in the present invention and of ingredients suitable for use in said compositions is provided in Remington's Pharmaceutical Sciences, 18 th edition, edited by A. R. Gennaro, Mack Publishing Co., 1990. 15 Assays Demonstrating Biological Activity Inhibition of human recombinant renin The enzymatic in vitro assay was performed in 384-well polypropylene plates (Nunc). The assay buffer consisted of PBS (Gibco BRL) including 1 mM EDTA and 0.1% BSA. The reaction 20 mixture were composed of 47.5 pL per well of an enzyme mix and 2.5 pL of renin inhibitors in DMSO. The enzyme mix was premixed at 4'C and consists of the following components: * human recombinant renin (40pM) * synthetic human angiotensin(1-14) (0.5 pM) * hydroxyquinoline sulfate (1 mM) 25 The mixtures were then incubated at 37'C for 3 h. The enzyme reaction was stopped by placing the reaction plate on wet ice. To determine the enzymatic activity and its inhibition, the accumulated Ang I was detected by an enzyme immunoassay (EIA) in 384-well plates (Nunc). 5 gL of the reaction mixture or standards were transferred to immuno plates which were previously coated with a covalent complex of 30 Ang I and bovine serum albumin (Ang I - BSA). 75 pL of Ang 1-antibodies in assay buffer above including 0.01% Tween 20 were added and the plates were incubated at 4 'C overnight. An alternative protocol could be used by stopping the enzymatic reaction with 0.02N final concentration of HC1. 5 pL of the reaction mixture or standards were transferred to immuno plates and 75 pL of Ang I-antibodies in assay buffer above including 0.01% Tween 20 were added and the 35 plates were incubate at RT for 4 h. The plates were washed 3 times with PBS including 0.01% Tween 20, and then incubated for 2 h at RT with an anti rabbit-peroxidase coupled antibody (WA 934, Amersham). After washing the plates 3 times, the peroxidase substrate ABTS ((2,2'-Azino-bis(3-ethylbenzthiazoline-6-sulfonic -16- WO 2007/009250 PCT/CA2006/001196 Acid) 2NH 3 ) was added and the plates incubated for 60 min at RT. The plate was evaluated in a microplate reader at 405 nm. The percentage of inhibition was calculated for each concentration point and the concentration of renin inhibition was determined that inhibited the enzyme activity by 50%
(IC
5 0 ). The ICs-values of all compounds tested were below 1 pM. 5 Inhibition of renin in human plasma The enzymatic in vitro assay was performed in 384-well polypropylene plates (Nunc). The assay buffer consisted of PBS (Gibco BRL) including 1 mM EDTA and 0.1% BSA. The reaction mixture was composed of 80 pL per well of human plasma, enzyme, Ang I-antibodies mix and 5 pIL of 0 renin inhibitors in DMSO. The human plasma mix was premixed at 4 0 C and consists of * human plasma from 10 normal donors * human recombinant renin (3pM) * Ang I-antibodies. The mixtures were then incubated at 37'C for 2 h. 5 To determine the enzymatic activity and its inhibition, the accumulated Ang I was detected by an enzyme immunoassay (EIA) in 384-well plates (Nunc). 10 pL of the reaction mixture or standards were transferred to immuno plates which were previously coated with a covalent complex of Ang I and bovine serum albumin (Ang I - BSA). 70 pL assay buffer were added and the plates were incubated at 4 'C overnight. The plates were washed 3 times with PBS including 0.01% Tween 20, and .0 then incubated for 2 h at RT with an anti rabbit-peroxidase coupled antibody (WA 934, Amersham). After washing the plates 3 times, the peroxidase substrate ABTS ((2,2'-Azino-bis(3-ethylbenzthiazoline-6 sulfonic Acid) 2NH 3 ) was added and the plates incubated for 60 min at RT. The plate was evaluated in a microplate reader at 405 nm. The percentage of inhibition was calculated of each concentration point and the concentration of renin inhibition was determined that inhibited the enzyme activity by 50% (IC 50 ). 25 The ICso 0 -values of all compounds tested were below 10pM. In vivo animal model - Female double transgenic rats were purchased from RCC Ltd, Filllingsdorf, Switzerland. All animals were maintained under identical conditions and had free access to normal pelleted rat chow and water. Rats were initially treated with enalapril (1 mg/kg/day) during 2 months. 0 After approximately two weeks following cessation of enalapril treatment the double transgenic rats become hypertensive and reach mean arterial blood pressures in the range of 160-170 mmHg. Transmitter implantation - The rats were anaesthetised with a mixture of 90 mg/kg Ketamin-HCI (Ketavet, Parke-Davis, Berlin FRG) and 10 mg/kg xylazin (Rompun, Bayer, Leverkusen, FRG) i.p. The 5 pressure transmitter was implanted under aseptic conditions into the peritoneal cavity with the sensing catheter placed in the descending aorta below the renal arteries pointing upstream. The transmitter was sutured to the abdominal musculature and the skin closed. -17- WO 2007/009250 PCT/CA2006/001196 Telemetry-System - Telemetry units were obtained from Data Sciences (St. Paul, MN). The implanted sensor consisted of a fluid-filled catheter (0.7 mm diameter, 8 cm long; model TAl 1PA-C40) connected to a highly stable low-conductance strain-gauge pressure transducer, which measured the absolute arterial pressure relative to a vacuum, and a radio-frequency transmitter. The tip of the catheter was filled with a 5 viscous gel that prevents blood reflux and was coated with an antithrombogenic film to inhibit thrombus formation. The implants (length = 2.5 cm, diameter = 1.2 cm) weighted 9 g and have a typical battery life of 6 months. A receiver platform (RPC-1, Data Sciences) connected the radio signal to digitized input that was sent to a dedicated personal computer (Compaq, deskpro). Arterial pressures were calibrated by using an input from an ambient-pressure reference (APR-1, Data Sciences). Systolic, mean and diastolic 10 blood pressure was expressed in millimeter of mercury (mmHg). Hemodynamic measurements - Double transgenic rats with implanted pressure transmitters were dosed by oral gavage with vehicle or 10 mg/kg of the test substance (n=6 per group) and the mean arterial blood pressure was continuously monitored. The effect of the test substance is expressed as maximal decrease 15 of mean arterial pressure (MAP) in the treated group versus the control group. Methods of Synthesis Compounds of the present invention can be made by a variety of methods depicted in the illustrative synthetic reaction schemes shown and described below. The starting materials and reagents 20 used in preparing these compounds generally are either available from commercial suppliers, such as Aldrich Chemical Co., or are prepared by methods known to those skilled in the art following procedures set forth in references such as Fieser and Fieser's Reagents for Organic Synthesis; Wiley & Sons: New York, Volumes 1-21; R. C. LaRock, Comprehensive Organic Transformations, 2.sup.nd edition Wiley VCH, New York 1999; Comprehensive Organic Synthesis, B. Trost and I. Fleming (Eds.) vol. 1-9 25 Pergamon, Oxford, 1991; Comprehensive Heterocyclic Chemistry, A. R. Katritzky and C. W. Rees (Eds) Pergamon, Oxford 1984, vol. 1-9; Comprehensive Heterocyclic Chemistry II, A. R. Katritzky and C. W. Rees (Eds) Pergamon, Oxford 1996, vol. 1-11; and Organic Reactions, Wiley & Sons: New York, 1991, Volumes 1-40. The following synthetic reaction schemes and examples are merely illustrative of some methods by which the compounds of the present invention can be synthesized, and various modifications 30 to these synthetic reaction schemes can be made and will be suggested to one skilled in the art having referred to the disclosure contained in this application. The starting materials and the intermediates of the synthetic reaction schemes can be isolated and purified if desired using conventional techniques, including but not limited to, filtration, distillation, crystallization, chromatography, and the like. Such materials can be characterized using 35 conventional means, including physical constants and spectral data. Unless specifically stated otherwise, the experimental procedures were performed under the following conditions. Evaporation of solvent was carried out using a rotary evaporator under reduced pressure (600-4000 pascals: 4.5-30 mm Hg) with a bath temperature of up to 60 oC. Reactions are typically run under nitrogen atmosphere at ambient temperature if not otherwise mentioned. Anhydrous -18- WO 2007/009250 PCT/CA2006/001196 solvent such as THF, DMF, Et 2 0, DME and Toluene are commercial grade. Reagents are commercial grade and were used without further purification. Flash chromatography is run on silica gel (230-400 mesh). The course of the reaction was followed by either thin layer chromatography (TLC) or nuclear magnetic resonance (NMR) spectrometry and reaction times given are for illustration only. The structure 5 and purity of all final products were ascertained by TLC, mass spectrometry, 1 H NMR and high-pressure liquid chromatography (HPLC). Chemical symbols have their usual meanings. The following abbreviations have also been used: v (volume), w (weight), b.p. (boiling point), m.p. (melting point), L (liter(s)), mL (milliliter(s)), g (gram(s)), mg (milligram(s)), mol (mole(s)), mmol (millimole(s)), eq. (equivalent(s)). Unless otherwise specified, all variables mentioned below have the meanings as 0 provided above. Compounds of the present invention can be prepared according to the following general methods as exemplified in Scheme 1-11. For example a Knoevenagel type condensation between cyanoacetate II and appropriately substituted aldehyde III can povide c,3-unsaturated ester IV. Concomitant reduction of the alkene and the cyano groups in IV can be accomplished stepwise or in one 15 step using hydrogenation or with reducing agents such as CoC1 2 -NaBH 4 . The resulting saturated amine can be better isolated after protection with for example an N-BOC to give derivative V. Saponification of ester V and coupling of the resulting acid with amine VI will provide protected aminoamide VII. Finally, removal of the protecting group can provide the desired aminoamide VIII. (Scheme 1). Scheme 1 Z Z Z zz z
RO
2 CvCN + CHO
C
N
CO
2 R
CO
2 R Boc-HN II III IV V z z Ar2" NHR 2 0 , O , O VI N Ar2 N Ar 2 Boc-HN R 2
H
2 N R 2 VII VIII Z = Arl-X 1
-(CH
2 )m-X
-
, TBSO(CH 2 )m-X 20 R= H, C 1
-C
6 alkyl Alternatively, the sequence can be modified with the initial coupling of amine VI with cyanoacetic acid IX to give amide precursor X (Scheme 2). Subsequent Knoevenagel condensation with substituted aldehyde III can deliver the of3-unsaturated amide XI. Reduction of the double bond and nitrile group can be accomplished using for example the CoC1 2 -NaBH 4 reagent. The resulting saturated 25 amine is most conveniently isolated as the N-BOC derivative VII. Finally, removal of the BOC protecting group under acidic conditions furnishes the desired aminoamide VIII -19- WO 2007/009250 PCT/CA2006/001196 Scheme 2 Z 0
HO
2 CvCN r(N Ar2 I Ar 2
,NHR
2 - CN I 0 - VilI Ix R2 N Ar 2 CN R 2 VI X X XI Z = Ar'-X'-(CH 2 )m-X
-
, TBSO(CH 2 )m-X It is also possible to obtain the title compounds by alkylation of cyanoamide X using a base such as potassium hexamethyldisilazide with an appropriately substituted benzyl halide XII 5 (Scheme 3). The resulting cyanoamide can be further alkylated with, for example, an alkyl halide to give the corresponding disubstituted analog XIV. Scheme 3 z Z N -Ar 2 / O VII CN 1 2F R2 N Ar 2 X CN1
R
2 X XII XIII Z Z Z = Ar'-X 1
-(CH
2 )m-X-, TBSO(CH 2 )m-X O O R1IN Ar2 R1 N Ar CN 1 21
R
2 Boc-HN R 2 XIV XV 10 The 3-amino amide XXI can be built from the corresponding 3-pentenoate XVI by alkylation using a strong base and an appropriate benzyl halide XII as described in Scheme 4. After the amide formation, the double bond in XVIII can be cleaved by ozonolysis followed by reduction to the primary alcohol XIX. The latter could be transformed to the azide XX by, for example, displacement of the corresponding mesylate. Reduction of azide group to amine will then provide the desired product 15 XXI. -20- WO 2007/009250 PCT/CA2006/001196 Scheme 4 Z Z z z OR + 0 0 OR N Ar 2 x XI IV R2 v l XVI XII XVII XVIII z Z Z 0 00 I 1 1 2 N ~Ar 2 N' N"'Ar2
R
2 R2 R2 OH
N
3
R
2
NH
2 XIX XX XXI Z = Ar 1
-X
1
-(CH
2 )m-X-, TBSO(CH 2 )m-X R = H, C 1 -Coalkyl The alpha-amino amide homologue XXIV can be built from commercially available amino acid derivatives using standard chemistry for alkylation of phenol and amide formation as 5 exemplified in Scheme 5. Scheme 5 OH Z 0 o OOR OR N r 0~ -- 0 NHP' NHP' NHP' R2 XXII XXIII XXIV Z = Ar 1
-X'-(CH
2 )-O-, TBSO(CH 2
)
2
-O
P'= H, Boc R = H, C 1
-C
6 alkyl N-alkylation of aminoamide VIII, to afford the secondary amine XXV, and the secondary amine precursors VI used in the amide formation could be readily achieved via the reductive 0 amination of the corresponding aldehydes (Scheme 6). -21- WO 2007/009250 PCT/CA2006/001196 Scheme 6 Z NaBH 3 CN I1
R
2 -NH + OHC-Ar 2 MeOH, AcOH HNAr 2 2 MeOH, AcOH HN Ar2 O or - or --- 1 2 or N Ar 2 0 R I 1. 3A MS HN 2 VIII + OHC-R 1 2. NaBH 4 R VINR4 XXV 3A MS refers to 3 Angstrom molecular sieves Conversion of the amine such as VIII into its corresponding guanidine analogue XXVII could be affected through the use of diimidothiotricarbonate XXVI (Scheme 7) followed by acid 5 promoted deprotection. Scheme 7 Z Me O S O Me O Vill + Me-i'- "1..'-N"0-...l Me NL.r..2 VII Me O N N O Me N Ar 2 HXIHN
R
2 XXV HN
NH
2 XXV introduction of a P3-substituent (i.e. XXIX) can be readily accomplished, for example, via reaction of an organocuprate with c,3-unsaturated amide XI (Scheme 8). Subsequent reduction of 10 XXVIII using, for example the CoCl 2 -NaBI4 reagent, would afford the desired product XXIX. Scheme 8 Z Z I 0 XI + Ra 2 CuLi Ra N Ar 2 R N Ar 2 CN R 2
H
2 N R 2 XXVIII XXIX Inhibitors possessing a substituent c to the amino group (i.e. XXXIII) can be accessed 15 by alkylation of P3-ketoester XXX (Scheme 9) with an appropriately substituted benzyl halide XII in the presence of a base such as potassium hexamethyldisilazide. Conversion of the resulting ester XXXI intoo P3-ketoamide XXXII and its subsequent reductive amination with ammonium acetate is one way of synthesizing the desired aminoamide XXXIII. -22- WO 2007/009250 PCT/CA2006/001196 Scheme 9 Z Z Z 0 0 VI 0 Ri.[ J OR + X IO - ,-O O_ RjOOR + OR N Ar 2 N Ar 2 I I
R
1 0 R 1
OR
2 R
R
1
NH
2 XXX XXXI XXXII XXXIII R = H, C 1
-C
6 alkyl Z = Arl-X 1
-(CH
2 )m-X
-
, TBSO(CH 2 )m-X The aldehydes used in the preparation of VI can be obtained from the corresponding bromobenzoate XXXV (Scheme 10). Suzuki type coupling of XXXV with for example borane XXXIV 5 can afford ester XXXVI. The desired aldehydes XXXVII can be obtained by direct reduction of the ester using DIBAL or via a two-step sequence, for example a reduction with LAH followed by oxidation with Dess-Martin periodinane (DMP). Scheme 10 R2RO 2 C OHC B- OMe+ + Br MeO v MeO XXXIV XXXV XXXVI XXXVII R= H, C 1
-C
6 alkyl 0 Aldehyde of type XL with a methoxyethyl chain can also be prepared from the corresponding bromobenzoate XXXV (Scheme 11). For example, a copper mediated Grignard displacement with allylbromide can furnish alkene XXXVIII. Its ozonolysis followed by a reductive workup can provide alcohol XXXIX. Subsequent methylation with iodomethane and reduction of the ester with LAH and then oxidation can deliver the desired aldehyde XL. 15 Scheme 11
RO
2 C 2 RO2C OHC N XXXV - H IHOY MeO XXXVIII XXXIX XL R = H, Cl-C 6 alkyl Alternatively, the aldehydes like XLIII can be prepared from the corresponding iodo or bromo phenyl using palladium-catalyzed carbonylation (Scheme 12). In this example, the nucleophilic displacement of iodobenzyl bromide XLI by methylsulfone salt provides the methylsulfone XLII. 0 Subsequent reductive palladium-catalyzed carbonylation with carbon monoxide affords the desired aldehyde XLIII. -23- WO 2007/009250 PCT/CA2006/001196 Scheme 12 I "Pd" OHC Br
SO
2 Me CO MeO 2 S XLI XLII XLIII Formylation using DMF from lithium halogen exchange of a bromo or iodo phenyl analog is another strategy for the synthesis of, for example, aldehyde XLV or XLVII (Scheme 13). 5 Starting with dibromophenyl analogue such as XLVI would allow for palladium-mediated elaboration of the aryl bromide obtained following formylation to give, for example, XLVIII. Scheme 13 Br NMe OHC NMe 0 Me ,- O..Me XLIV XLV n-BuLi, DMF OMe or a or Br NBr OHCO Br Pd OHC OH OH OH XLVI XLVII XLVIII Radical bromination of a benzyl analog such as XLIX followed by oxidation would 10 constitute another approach to the synthesis of the desired aldehyde LI (Scheme 14). Scheme 14 Me NBr OHC
O-OM
e 0 OMe 0 OMe XLIX L LI The requisite benzyl amine VI can also be prepared in two steps from the corresponding acid or acid chloride (Scheme 15). The intermediate amide LII is readily reduced to the amine using for 15 example, a reagent such as borane. Scheme 15 Ar 2 CO2H or + R 2
NH
2 p Ar 2
CONHR
2 VI Ar 2 COCI LII The aryl aldehydes LV, can be assembled as depicted in Scheme 16. The substituted phenol can be heated neat at 150 oC with ethylene carbonate and imidazole to deliver the alcohol LIII. 20 Subsequent coupling with 4-hydroxybenzaldehyde under typical Mitsunobu type conditions then can afford aldehyde LV. Alternatively, the requisite aldehydes can be obtained via sequential etherification and palladium-catalyzed reductive carbonylation of alcohol LIV. -24- WO 2007/009250 PCT/CA2006/001196 Scheme 16 0OH oL u OH OO_ [ O /OH | CHO imidazole HO Lill ICHO LIII - CHO Br yOH Br HOO HO - LV 0-1 LIV The cyclopropylamine building blocks in Table 1 were synthesized as follows. Table 1 Compound Structure Compound Structure Me Cl Amine 1 "N Me Amine 6H H MeO Cl CI Amine 2 HN Cl Amine 7 MeOv
-.
N Amine 3 N Amine 8 MeO2S N N Amine 4 N Amine 9 H I mn9MeN Me 0 Cl Amine 5 H Amine 10N MeO MeN Me 0 5 -25- WO 2007/009250 PCT/CA2006/001196 Table 1 (Con't) Compound Structure Compound Structure N 1 I N Amine 11 H Amine 20 H HO NC Cl Me Amine 12 H Amine 21 H MeO-O MeO N N CF 3 H N Amine 13 Amine 22 H I CF 3 N./ CN AVN; N N N Amine 14 H Amine 23 H Me2N: Me 2 Nv NC Me ANCl Cl Me Amine 15 N Amine 24 N N MeO N Amine 16 H I Amine 25 N H NC N NN Amine 17 H N Amine 26 N H MeO Cl AN Cl Amine 18 HAmine 27 F N C I Amne7F H CN Me N Me Me Amine 19 H Amine 28 MeN H MeO I_ -26- WO 2007/009250 PCT/CA2006/001196 Table 1 (Con't) Compound Structure Compound Structure CI HN O0 7 N K I~O~ Amine 29 H Amine 38 0 OMe MeO o MeH___Amine_39 OMe M.N Cl HN O Me N Amine 30 H Amine 39 MeO0 CF 3 CI CI N HN N. Amine 31 H Amine 40 N MeOve MeO Me CIl M Me N HN OMe Amine 32 H Amine 41N MeO MeO CI SHN OTBS Amine 33 H Amine 42 N MeO MeO N CHN Amine 34 N Amine 43 OMe MeO MeO CI Me N HN O Amine 35 H I Amine 44 N MeMeo SMe MeOO (0 2 'N OTBS N Amine 36 H Amine 45 HN N.
O MeOG M 0 N MeO Ci HNO Amine 37 Amine 46 H N CO 2 Et OMe -27- WO 2007/009250 PCT/CA2006/001196 Table 1 (Con't) Compound Structure Compound Structure Br HIN 'YoI Amine 47 H N Amine 50 H CO 2 Et Br HN "- N! Amine48 I Amine 51 to OO C Br Amine 49 HN 1 /_ CO 2 Et Amine 1 N-(2,3-Dimethylbenzyl)cyclopropanamine A mixture of 2,3-dimethylbenzaldehyde (1 eq.), cyclopropylamine (1.2 eq.) and 5 sodium bicarbonate (1.5 eq.) were heated at reflux in MeOH (0.5 M) for 1 h. The reaction mixture was then cooled in ice and sodium borohydride (1.2 eq.) was introduced portionwise. Following the completion of addition, the reaction mixture was warmed to RT and stirred at RT for 1 h. The volatiles were then removed in vacuo and the resulting residue was partitioned between H 2 0 and CH 2 Cl 2 . The organic layer was separated, washed with brine, dried over MgSO 4 and filtered. Concentration of the 10 filtrate in vacuo afforded the title compound as a light yellow oil. Amine 2 N-(2,3-Dichlorobenzyl)cyclopropanamine Amine 2 was prepared according to the procedure described in Amine 1, but using instead 2,3-dichlorobenzaldehyde as the starting aldehyde. Purification of the crude product by way of 15 flash chromatography (SiO 2 , 98:2 - 1:1 (v/v) Hex : EtOAc) afforded the title compound as a colorless oil. Amine 3 N-(Quinolin-4-ylmethyl)cyclopropanamine A mixture of 4-quinolinecarboxaldehyde (1 eq.), cyclopropylamine (1 eq.) and sodium 20 cyanoborohydride (1.5 eq.) were combined in MeOH (0.2 M). At 0 oC, acetic acid (3 eq.) was added dropwise and the reaction mixture was slowly warmed to RT over 16 h. The reaction mixture was then diluted with ether and quenched with IN aq. NaOH. The aqueous layer was separated and back extracted with ether. The combined organic extracts were then washed with water and brine, dried over MgSO 4 and filtered. Concentration of the filtrate in vacuo afforded a purple residue. Purification of the 25 crude product thus obtained by way of flash chromatography (SiO 2 , 98:2 (v/v) CH 2 C1 2 : 2 M NH 3 in MeOH) afforded the title compound as a viscous, yellow oil. -28- WO 2007/009250 PCT/CA2006/001196 Amine 4 N-(Quinolin-8-ylmethyl)cyclopropanamine Amine 4 was prepared according to the procedure described in Amine 3, but using instead 8-quinolinecarboxaldehyde as the starting material. The title compound was isolated as a 5 viscous, yellow oil. Amine 5 N-[3-(3-Methoxypropyl)benzyl]cyclopropanamine Step 1: Ethyl 3-(3-methoxvpropyl)benzoate To a THF solution (0.1 M) of allyl methyl ether (1.4 eq.) was added, at 0 oC, 9 10 borabicyclo[3.3.1 ]nonane (2.4 eq.) over a period of 30 min. The solution was stirred at 0 oC for 1 h and then warmed slowly to RT over 16 h. To the resulting clear solution was then added sodium methoxide (2.4 eq.), C12Pd(dppf)-dichloromethane complex (5% loading) and ethyl 3-bromobenzoate (1 eq.). The now brown suspension was heated to reflux for 16 h. The reaction mixture was cooled to RT, quenched with sat. aq. NH 4 Cl and extracted with ether. The combined organic extracts were washed with brine, 15 dried over MgSO 4 and filtered. Concentration of the filtrate in vacuo afforded a brown oil. Purification of the crude product thus obtained by way of flash chromatography (SiO 2 , Hex - 4:1 (v/v) Hex : EtOAc) afforded the title compound as a light yellow oil. Step 2: [3-(3-Methoxvpropyl)phenvl]methanol To a THF solution (0.2 M) of ethyl 3-(3-methoxypropyl)benzoate from the previous step 20 (1 eq.) was added lithium aluminum hydride (1.0 M THF solution, 5 eq.) at 0 oC over a period of 20 min. The resulting suspension was stirred at 0 C for I h and then at RT for 1 h. The reaction was quenched, at 0 oC, with the dropwise addition of H 2 0 and then 1 N aq. NaOH. The biphasic mixture was allowed to stir at RT for 10 min, poured into HO0 and extracted with ether. The combined organic extracts were washed with brine, dried over MgSO 4 and filtered. Concentration of the filtrate in vacuo afforded a 25 cloudy oil. Purification of the crude product thus obtained by way of flash chromatography (SiO 2 , 7:3 (v/v) Hex : EtOAc) afforded the title compound as a colorless oil. Step 3: 3-(3-Methoxypropyl)benzaldehyde To a CH 2 Cl 2 solution (0.3 M) of [3-(3-methoxypropyl)phenyl]methanol from the previous step (1 eq.) was added Dess-Martin periodinane (1.2 eq.). The resulting suspension was stirred 30 at RT for 2 h. The reaction was quenched with sat. aq. NaHCO 3 and 2 N aq. Na 2
S
2 03. The biphasic mixture was allowed to stir at RT for 20 min, poured into sat. aq. NaHCO 3 and extracted with CH 2 Cl 2 . The combined organic extracts were washed with brine, dried over MgSO 4 and filtered. Concentration of the filtrate in vacuo afforded a cloudy oil. Purification of the crude product thus obtained by way of flash chromatography (SiO 2 , Hex - 7:3 (v/v) Hex : EtOAc) afforded the title compound as a colorless 35 oil. Step 4: Amine 5 -29- WO 2007/009250 PCT/CA2006/001196 Amine 5 was prepared according to the procedure described in Amine 3, but using instead 3-(methoxypropyl)benzaldehyde from the previous step as the starting material. The title compound was isolated as a colorless oil. Amine 6 5 N-[2-Chloro-5-(3-methoxypropyl)benzyl]cyclopropanamine Amine 6 was prepared according to the reaction sequence described for Amine 5, but using instead ethyl 5-bromo-2-chlorobenzoate as the starting material. The title compound was isolated as a colorless oil. Amine 7 10 N-[2-Chloro-5-(2-methoxyethyl)benzyl]cyclopropanamine Step 1: tert-Butvl 5-bromo-2-chlorobenzoate 5-bromo-2-chlorobenzoic acid (1 eq.) and anhydrous DMF (1.2 eq.) was taken up in toluene (0.9 M). To this was then added, dropwise over 5 min, oxalyl chloride (1.2 eq.) and the reaction mixture was stirred at RT for 1 h. The volatiles were then removed in vacuo and the resulting residue 15 was taken up in toluene (0.9 M). At 0 oC, potassium tert-butoxide (2.5 eq.) was added and the reaction mixture was stirred at RT for 1 h. The reaction mixture was poured into H 2 0 and extracted with ether. The combined organic extracts were washed with brine, dried over MgSO 4 and filtered. Concentration of the filtrate in vacuo afforded a pale yellow oil. Purification of the crude product thus obtained by way of flash chromatography (SiO 2 , Hex - 85:15 (v/v) Hex : EtOAc) afforded the title compound as a light 20 yellow oil. Step 2: tert-Butyl 5-allvl-2-chlorobenzoate At 0 'C, isobutylmagnesium bromide (2.0 M ether solution, 1.2 eq.) and n-butyl lithium (2.5 M hexane solution, 2.4 eq.) were added to anhydrous THF (0.3 M). After stirring at 0 oC for 30 min, the reaction mixture was cooled to -40 C and tert-butyl 5-bromo-2-chlorobenzoate from the 25 previous step (1 eq.) was added over 15 min. The now red solution was stirred at -40 oC for 1 h before copper (I) cyanide (30% loading) was added. The resulting suspension was stirred at -40 C for 15 min and then added allyl bromide (3 eq.). After stirring at -40 oC for another 2 h, the reaction mixture was quenched with sat. aq. NH4Cl and warmed to RT. The biphasic mixture was poured into more sat. aq.
NH
4 CI and extracted with ether. The combined organic extracts were washed with brine, dried over 30 MgSO 4 and filtered. Concentration of the filtrate in vacuo afforded a brown oil. Purification of the crude product thus obtained by way of flash chromatography (SiO 2 , Hex - 19:1 (v/v) Hex : ether) afforded the title compound as a light yellow oil. Step 3: tert-Butyl 2-chloro-5-(2-hydroxvethyl)benzoate To a solution of tert-butyl 5-allyl-2-chlorobenzoate from the previous step (1 eq.) in 35 CH 2 Cl 2 (0.4 M) was bubbled, at -78 oC, freshly generated ozone until a persistent blue color was obtained. The reaction solution was stirred at -78 C for a further 1 h before sodium borohydride (2 eq.) in (0.4 M) MeOH was added. The resulting mixture was warmed to RT and stirred at RT for 1 h. The reaction mixture was diluted with sat. aq. NaHCO 3 and extracted with ether. The combined organic -30- WO 2007/009250 PCT/CA2006/001196 extracts were washed with brine, dried over MgSO 4 and filtered. Concentration of the filtrate in vacuo afforded a colorless oil. Purification of the crude product thus obtained by way of flash chromatography (SiO 2 , 4:1 - 1:1 (v/v) Hex : EtOAc) afforded the title compound as a colorless oil. Step 4: tert-Butvl 2-chloro-5-(2-methoxvethyl)benzoate 5 To a suspension of sodium hydride (60% w/w dispersion in oil, 2 eq.) in anhydrous THF (0.23 M) was added tert-butyl 2-chloro-5-(2-hydroxyethyl)benzoate from the previous step (1 eq.). The reaction mixture was heated at reflux for 30 min before iodomethane (7.9 eq.) was added. After carefully quenching with sat. aq. NaHCO 3 , the resulting mixture was extracted with ether. The combined organic extracts were washed with brine, dried over MgSO 4 and filtered. Concentration of the filtrate in vacuo 10 afforded a cloudy oil. Purification of the crude product thus obtained by way of flash chromatography (SiO 2 , Hex - 85:15 (v/v) Hex : EtOAc) afforded the title compound as a colorless oil. Step 5: [2-Chloro-5-(2-methoxyethyl)phenvl] methanol To a solution of tert-butyl 2-chloro-5-(2-methoxyethyl)benzoate from the previous step (1 eq.) in anhydrous THF (0.26 M) was added, at 0 oC, lithium aluminum hydride (1.0 M THF solution, 3 15 eq.). The resulting suspension was stirred at 0 C for 1 h and then at RT for 1 h. After carefully quenching with EtOAc and H 2 0, sat. aq. sodium potassium tartrate was added. The resulting biphasic mixture was vigorously stirred at RT for 30 min and then extracted with ether. The combined organic extracts were washed with brine, dried over MgSO 4 and filtered. Concentration of the filtrate in vacuo afforded a cloudy oil. Purification of the crude product thus obtained by way of flash chromatography 20 (SiO2, 90:10 - 70:30 (v/v) Hex: EtOAc) afforded the title compound as a colorless oil. Step 6: 2-Chloro-5-(2-methoxyethyl)benzaldehyde To a solution of [2-chloro-5-(2-methoxyethyl)phenyl]methanol from the previous step (1 eq.) in CH 2
CI
2 (0.4 M) was added Dess-Martin periodinane (1.2 eq.) portionwise. The resulting suspension was stirred at RT for 2 h. The reaction was quenched with sat. aq. NaHCO 3 and sat. aq. 25 NaHSO 3 . The biphasic mixture was allowed to stir at RT for 20 min before it was extracted with
CH
2 C2. The combined organic extracts were washed with brine, dried over MgSO 4 and filtered. Concentration of the filtrate in vacuo afforded a colorless oil. Purification of the crude product thus obtained by way of flash chromatography (SiO 2 , Hex - 9:1 (v/v) Hex : EtOAc) afforded the title compound as a colorless oil. 30 Step 7: Amine 7 Amine 7 was prepared according to the procedure described in Amine 3, but using instead 2-chloro-5-(2-methoxyethyl)benzaldehyde from the previous step as the starting material. The title compound was isolated as a colorless oil. Amine 8 35 N- { 3-[2-(Methylsulfonyl)ethyl]benzyl} cyclopropanamine Step 1: 2-(3-Iodophenyl)ethyl methyl sulfone To a solution of dimethyl sulfone (1 eq.) in 60 mL of anhydrous THF (0.2 M) was added, at -78 oC, n-butyl lithium (1.6 M hexane solution, 1.2 eq.) over a period of 10 min. The resulting mixture -31- WO 2007/009250 PCT/CA2006/001196 was stirred at -78 C for 1 h. To the now yellow solution was added, at -78 oC, 3-iodobenzyl bromide (1 eq.). The reaction mixture was then slowly warmed to RT over 16 h. The reaction was carefully quenched with 10% aq. HCI and extracted with ether. The combined organic extracts were washed with brine, dried over MgSO 4 and filtered. Concentration of the filtrate in vacuo afforded a viscous oil. 5 Purification of the crude product thus obtained by way of flash chromatography (SiO 2 , Hex - 1:1 (v/v) Hex : EtOAc) followed by trituration with hexanes afforded the title compound as a white crystalline solid. Step 2: 3-[2-(Methylsulfonvl)ethyl]benzaldehyde To a solution of 2-(3-iodophenyl)ethyl methyl sulfone from the previous step (1 eq.) in 10 anhydrous, deoxygenated DMF (0.5 M) was added freshly-dried sodium formate (1.5 eq.) and Pd(PPh 3 )C1 2 (2% loading). Through the resulting yellow suspension, was bubbled CO and then reaction was heated to 95 oC for 6 h. The now black reaction suspension was cooled to RT, diluted with water, and extracted with ether. The combined organic extracts were washed with brine, dried over MgSO 4 and filtered. Concentration of the filtrate in vacuo afforded an orange semi-solid. Purification of the crude 15 product thus obtained by way of flash chromatography (SiO 2 , 1:1 (v/v) Hex : EtOAc) afforded the title compound as a colorless oil. Step 3: Amine 8 Amine 8 was prepared according to the procedure described in Amine 3, but using instead 3-[2-(methylsulfonyl)ethyl]benzaldehyde from the previous step as the starting material. The title 20 compound was isolated as a colorless oil. Amine 9 N- { 3-[(Cyclopropylamino)methyl]benzyl }-N-methylacetamide Step 1: N-(3-Bromobenzvl)-N-methylacetamide To a DMF (0.1 M) solution of 3-bromo-N-methylbenzylamine (1 eq.), Hunig's base (3 25 eq) and 4-(dimethylamino)pyridine (5% loading) was added acetyl chloride (1.5 eq). The resulting reaction mixture was stirred at RT for 16 h. After quenching the reaction with sat. aq. NaHCO 3 , the mixture was extracted with EtOAc. The organic extract was washed with 10% aq. HCI, sat. aq. NaHCO 3 , and brine. Drying over Na 2
SO
4 , filtration and concentration of the filtrate in vacuo afforded the crude product as a yellow oil. Purification by way of flash chromatography (SiO 2 , 4:1 (v/v) Hex: 30 EtOAc -4 EtOAc) afforded the title compound as a yellow oil. Step 2: N-(3-Formylbenzyl)-N-methylacetamide To a solution of N-(3-bromobenzyl)-N-methylacetamide from the previous step (1 eq.) in anhydrous, deoxygenated DMF (0.5 M) was added freshly-dried sodium formate (1.5 eq.) and Pd(PPh 3 )C1 2 (5% loading). Through the resulting yellow suspension was bubbled CO and then the 35 reaction was heated to 80 oC for 16 h. The now black reaction suspension was cooled to RT, diluted with water and extracted with ether. The combined organic extracts were washed with brine, dried over Na 2
SO
4 and filtered. Concentration of the filtrate in vacuo afforded an orange semi-solid. Purification of -32- WO 2007/009250 PCT/CA2006/001196 the crude product thus obtained by way of flash chromatography (SiO 2 , 7:3 (v/v) Hex : EtOAc) afforded the title compound as a light yellow oil. Step 3: Amine 9 Amine 9 was prepared according to the procedure described in Amine 3, but using 5 instead N-(3-formylbenzyl)-N-methylacetamide from the previous step as the starting material. The title compound was isolated as a colorless oil. Amine 10 N-{4-Chloro-3-[(cyclopropylamino)methyl]benzyl)-N-methylacetamide 0 Step 1: (5-Bromo-2-chlorophenyl)methanol To a solution of ethyl 5-bromo-2-chlorobenzoate (1 eq.) in THiIF (0.03 M) was added, at 78 0 C, DIBAL (2.5 eq). The reaction was stirred at -78 0 C for I h and then warmed slowly to RT over 1 h. The reaction mixture was then diluted with ether and carefully quenched with aq. 6 M HCL. The organic layer was separated and the aqueous layer was back extracted with ether. The combined organic extracts 15 were washed with sat. aq. NaHCO 3 and brine, dried over MgSO 4 and filtered. Concentration of the filtrate in vacuo afforded a white semi-solid. Purification of the crude product thus obtained by way of flash chromatography (SiO 2 , 3:1 (v/v) Hex : EtOAc) afforded the title compound as a light yellow oil. Step 2: [(5-Bromo-2-chlorobenzvl)oxyl(tert-butyl)dimethylsilane To a solution of (5-bromo-2-chlorophenyl)methanol from the previous step (1 eq.) in 20 DMF (0.25 M) was added imidazole (1.2 eq.) and tert-butyldimethylsilyl chloride (1.1 eq.). The resulting solution was stirred at RT for 3 h. The reaction mixture was quenched with sat. aq. NH 4 CI and extracted with ether. The combined organic extracts were washed further with aq. 10% HC1, sat. aq. NaHCO 3 , and brine. Concentration of the organic extracts in vacuo afforded an orange oil. Purification of the crude product thus obtained by way of flash chromatography (SiO 2 , 9:1 (v/v) Hex : EtOAc) 25 afforded the title compound as a light yellow oil. Step 3: 3-( { [tert-Butyl(dimethyl)silvl]oxv} methyl)-4-chlorobenzaldehyde To a solution of [(5-bromo-2-chlorobenzyl)oxy](tert-butyl)dimethylsilane from the previous step (1 eq.) in THF (0.08 M) was added, at -78 oC, n-butyl lithium (2.5 M hexane solution, 1.1 eq) dropwise over 15 mrin. The reaction mixture was stirred at - 78 oC for a further 30 min before DMF 30 (2 eq.) was slowly added. The resulting solution was allowed to warm to RT over 3 h and then quenched with H 2 0. The organic layer was separated and the aqueous layer was back-extracted with EtOAc. The combined organic extracts were washed with sat. aq. NaHCO 3 and brine, dried over Na 2
SO
4 and filtered. Concentration of the filtrate in vacuo afforded an orange oil. Purification of the crude product thus obtained by way of flash chromatography (SiO 2 , 9:1 (v/v) Hex : EtOAc) afforded the title compound as a 35 yellow oil. Step 4: [3-({ [tert-Butyl(dimethyl)silyl]loxyl}methyl)-4-chlorobenzyl]methylamine To a solution of 3-({ [tert-butyl(dimethyl)silyl]oxy}methyl)-4-chlorobenzaldehyde from the previous step (1 eq.) in THF (0.3 M) was added methylamine (2.0 M THF solution, 5 eq.) and -33- WO 2007/009250 PCT/CA2006/001196 freshly-activated 3A molecular sieves. The resulting mixture was stirred at RT for 16 h. The molecular sieves were then filtered off and the filtrate was evaporated in vacuo. The resulting residue was taken up in ethanol (0.25 M) and added sodium borohydride (3 eq.). After 3 h of stirring at RT, the reaction was quenched by the addition of 1 N aq. HCI and then basified with 1 N aq. NaOH. This was extracted with 5 EtOAc. The combined organic extracts were washed with brine, dried over Na 2
SO
4 and filtered. Concentration of the filtrate in vacuo afforded a cloudy oil. Purification of the crude product thus obtained by way of flash chromatography (SiO2, 19:1 (v/v) CH 2 Cl 2 : 2 M NH 3 in MeOH) afforded the title compound as a pale yellow oil. Step 5: N-[3-({ [tert-Butvl(dimethyl)silvlloxyl} methyl)-4-chlorobenzvl]-N-methylacetamide 0 To a solution of [3-({ [tert-butyl(dimethyl)silyl]oxy}methyl)-4 chlorobenzyl]methylamine from the previous step (1 eq.) in pyridine (0.09 M) was added acetic anhydride (1.1 eq.) The resulting reaction mixture was stirred at RT for 3 h. After quenching the reaction with H20, the mixture was extracted with EtOAc. The combined organic extracts were washed with 10% aq. HCI, sat. aq. NaHCO 3 , and brine. Drying over Na 2
SO
4 , filtration and concentration of the 15 filtrate in vacuo afforded the crude product as a brown oil. Purification by way of flash chromatography (SiO 2 , 7:3 (v/v) Hex: EtOAc -4 EtOAc) afforded the title compound as a pale yellow oil. Step 6: N-[4-Chloro-3-(hydroxvmethyl)benzvl]-N-methylacetamide To a solution of N-[3-( { [tert-butyl(dimethyl)silyl]oxy} methyl)-4-chlorobenzyl]-N methylacetamide from the previous step (1 eq.) in THF (0.8M) was added tetrabutylammonium fluoride 20 (1.0 M THF solution, 1.5 eq.). The resulting reaction mixture was stirred at RT for 1 h. After quenching the reaction with 10% aq. HC1, the mixture was extracted with EtOAc. The combined organic extracts were washed with sat. aq. NaHCO 3 and brine, dried over Na 2
SO
4 and filtered. Concentration of the filtrate in vacuo afforded a pale yellow oil. Purification of the crude product thus obtained by way of flash chromatography (SiO 2 , 9:1 (v/v) CH 2 Cl2 : MeOH) afforded the title compound as a light yellow oil. 25 Step 7: N-(4-Chloro-3-formylbenzvl)-N-methylacetamide To a solution of N-[4-chloro-3-(hydroxymethyl)benzyl]-N-methylacetamide from the previous step (1 eq.) in CH 2 Cl 2 (0.8 M) was added Dess-Martin periodinane (1.2 eq.) portionwise. The resulting suspension was stirred at RT for 3 h. The reaction was quenched with MeOH and H 2 0. The organic layer was separated and the aqueous layer was back-extracted with EtOAc. The combined 30 organic extracts were washed sat. aq. NaHCO 3 and brine, dried over Na2SO 4 and filtered. Concentration of the filtrate in vacuo afforded a pale yellow oil. Purification of the crude product thus obtained by way of flash chromatography (SiO2, EtOAc) afforded the title compound as a pale yellow oil. Step 8: Amine 10 To a solution of N-(4-chloro-3-formylbenzyl)-N-methylacetamide from the previous step 35 (1 eq.) in THF (0.08 M) was added cyclopropylamrnine (2 eq.) and freshly activated 3A molecular sieves. The resulting mixture was stirred at RT for 48 h. The molecular sieves were then filtered off and the filtrate was evaporated in vacuo. The resulting residue was taken up in methanol (0.07 M) and added sodium borohydride (2 eq.). After 2 h of stirring at RT, the reaction was quenched by the addition of 1 N -34- WO 2007/009250 PCT/CA2006/001196 aq. HC1. The volatiles were removed in vacuo and the resulting residue was partitioned between EtOAc and H 2 0. The organic layer was separated and the aqueous layer was back extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na 2 SO4 and filtered. Concentration of the filtrate in vacuo afforded the title compound as a colorless oil. 5 Amine 11 3- {4-Chloro-3-[(cyclopropylamino)methyl]phenyl}propan-l1-ol Amine 6 (1 eq.) in chloroform (0.3 M) was added iodotrimethylsilane (9 eq.). The resulting solution was stirred at RT for 8 h. The reaction was then quenched with MeOH before the volatiles were removed in vacuo. The resulting reddish-orange oil was taken up in dichloromethane and 0 washed sequentially with 1 N aq. NaOH, water and brine. The organic layer was separated, dried over MgSO 4 , filtered and the filtrate concentrated in vacuo to afford a pale yellow oil. Purification of the crude product thus obtained by way of flash chromatography (SiO 2 , 95:5 (v/v) CH 2
CI
2 : 2 M NH 3 in MeOH) afforded the title compound as a viscous, pale yellow oil. Amine 12 5 N-[2-Chloro-5-(2-methoxyethoxy)benzyl]cyclopropanamine Step 1: 1-Chloro-4-(2-methoxyethoxy)-2-methylbenzene To a solution of ethyl 4-chloro-3-methylphenol (1 eq.) in acetone (0.2 M) was added potassium carbonate (5 eq.) and 1-bromo-2-methoxyethane (1.3 eq.). The resulting suspension was refluxed for 25 h. The insolubles were removed via filtration and the filtrate was concentrated in vacuo 20 to furnish the title compound. Step 2: 2-(Bromomethyl)-l1-chloro-4-(2-methoxvethoxy)benzene To a solution of 1 -chloro-4-(2-methoxyethoxy)-2-methylbenzene from the previous step (1 eq.) in carbon tetrachloride (0.02 M) was added N-bromosuccinimide (1 eq.) and a few crystals of AIBN (1.1 eq.). The resulting mixture was irradiated with sunlamp at reflux for 1 h. The insolubles 25 were removed via filtration and the filtrate was concentrated in vacuo to furnish the title compound. Step 3: 2-Chloro-5-(2-methoxvethoxy)benzaldehyde To a solution of 2-(bromomethyl)- I -chloro-4-(2-methoxyethoxy)benzene from the previous step (1 eq.) in dioxane (0.2 M) was added 4-methylmorpholine N-oxide (3 eq.). The reaction mixture was heated at 80oC. The resulting solution was allowed to cool to RT, poured into brine and 0 then extracted with EtOAc. The combined organic extracts were dried over MgSO 4 , filtered and the filtrate concentrated in vacuo. Purification of the crude product thus obtained by way of flash chromatography (SiO,, Hex -) 2:1 (v/v) Hex: EtOAc) afforded the title compound as a pale yellow oil. Step 4: Amine 12 Amine 7 was prepared according to the procedure described in Amine 3, but using 5 instead 2-chloro-5-(2-methoxyethoxy)benzaldehyde from the previous step as the starting material. The title compound was isolated as a colorless oil. Amine 13 N- { [6-(pyridine-4-ylmethyl)quinoline-8-yl]methyl} cyclopropanamine -35- WO 2007/009250 PCT/CA2006/001196 Step 1: 6-(Pyridine-4-vlmethyl)quinoline-8-carbaldehyde To a solution of 8-bromo-6-(pyridine-4-ylmethyl)quinoline (1 eq.) in THF (0.13 M) was added, at -78 oC, n-butyl lithium (2.5 M hexane solution, 1.1 eq) dropwise over 15 min. The reaction mixture was stirred at - 78 oC for a further 30 min before DMF (1.5 eq.) was slowly added. The resulting 5 solution was allowed to warm to RT over 3 h and then quenched with H 2 0. The organic layer was separated and the aqueous layer was back-extracted with EtOAc. The combined organic extracts were washed with sat. aq. NaHCO 3 and brine, dried over Na 2
SO
4 and filtered. Concentration of the filtrate in vacuo afforded a brown oil. Purification of the crude product thus obtained by way of flash chromatography (SiO 2 , 7:3 (v/v) Hex : EtOAc -4 EtOAc) afforded the title compound. 10 Step 2: Amine 13 To a solution of 6-(pyridine-4-ylmethyl)quinoline-8-carbaldehyde from the previous step (1 eq.) in THF (0.07 M) was added cyclopropylamine (2 eq.) and freshly activated 3A molecular sieves. The resulting mixture was stirred at RT for 18 h. The molecular sieves were then filtered off and the filtrate was evaporated in vacuo. The resulting residue was taken up in methanol (0.07 M) and added 15 sodium borohydride (1 eq.). After 2 h of stirring at RT, the reaction was quenched by the addition of water. The volatiles were removed in vacuo and the resulting residue was partitioned between EtOAc and H 2 0. The organic layer was separated and the aqueous layer was back extracted with EtOAc. The combined organic extracts were washed with sat. aq. NaHCO 3 , dried over Na 2
SO
4 and filtered. The filtrate was concentrated in vacuo to afford the title compound as a pale yellow oil. 20 Amine 14 N- {2-Chloro-5-[3-(dimethylamino)propyl]benzyl}cyclopropanamine Step 1: 5-Bromo-2-chloro-N-cyclopropvlbenzamide To a toluene solution (1 M) of 5-bromo-2-chlorobenzoic acid (1 eq.) and DMF (1.2 eq.) was added at 0 oC oxalyl chloride (1.2 eq.) dropwise over 1 h. The resulting solution was stirred at 0 C 25 for 2 h before the volatiles were removed in vacuo. The resulting residue was taken up in dichloromethane (1 M), cooled to 0 oC and added sequentially cyclopropylamine (1.5 eq.) and Hunig's base (2 eq.) dropwise over 1 h. The resulting suspension was stirred at RT for 18 h. The reaction was quenched with 1 N HCI and extracted with dichloromethane. The combined organic extracts were dried over MgSO 4 , filtered and the filtrate concentrated in vacuo to - 1/3 in volume. The resulting white 30 suspension was added an equivalent volume of hexanes and the title compound was isolated via vacuum filtration. Step 2: N-(5-Bromo-2-chlorobenzyl)cyclopropanamine At 0 'C, a suspension of 5-bromo-2-chloro-N-cyclopropylbenzamide from the previous step (1 eq.) in THF (0.4 M) was added borane (1 M THF solution, 3 eq.). The resulting suspension was 35 warmed to RT over 1 h and then heated at reflux for 1 h. The now pale yellow solution was re-cooled to 0 C and carefully quenched with 1 N aq. HC1. The resulting mixture was heated at reflux for 1 h to ensure complete breakdown of the amine-borane complex. Following careful neutralization with 1 N aq. NaOH, the aqueous layer was separated and back extracted with EtOAc. The combined organic extracts -36- WO 2007/009250 PCT/CA2006/001196 were washed with brine, dried over MgSO 4 and filtered. The filtrate was concentrated in vacuo and the crude product thus obtained was purified further by way of column chromatography (SiO 2 , Hex - 80:20 (v/v) Hex: Et20) to reveal the title compound as a colorless oil. Step 3: tert-Butvl (5-bromo-2-chlorobenzyl)cyclopropvlcarbamate 5 A THtF solution (0.3 M) of N-(5-bromo-2-chlorobenzyl)cyclopropanamine from the previous step (1 eq.) was added at -78 oC potassium hexamethyldisilazide (0.5 M in toluene, 1.2 eq.). After I h of stirring at -78 C, di-tert-butyl dicarbonate was added and the resulting mixture was slowly warmed to RT over 2 h. The reaction was quenched with sat. aq. NH 4 Cl and then extracted with ether. The combined organic extracts were washed with brine, dried over MgSO 4 , filtered and the filtrate 10 concentrated in vacuo. Further purification by way of column chromatography (SiO 2 , Hex -- 80:20 (v/v) Hex : Et 2 O) to reveal the title compound as a pale yellow oil. Step 4: tert-Butyl (5-allyl-2-chlorobenzvl)cyclopropylcarbamate A THIF solution (0.13 M) of tert-butyl (5-bromo-2-chlorobenzyl)cyclopropylcarbamate from the previous step (1 eq.), Pd(PCy 3
)
2 (0.05 eq.) and cesium fluoride (2.0 eq.) was added allyl 15 tributylstannane (1.2 eq.). The resulting brown solution was heated at reflux for 8 h and then filtered through a pad of SiO 2 . The insolubles were rinsed further with ether and the filtrate was concentrated in vacuo to afford a brown semisolid. Purification of the crude product thus obtained by way of column chromatography (SiO 2 , Hex -4 90:10 (v/v) Hex : Et 2 0) afforded the title compound as a colorless oil. Step 5: tert-Butvl [2-chloro-5-(3-(hydroxypropropyl)benzyl]cyclopropylcarbamate 20 To a solution of tert-butyl (5-allyl-2-chlorobenzyl)cyclopropylcarbamate from the previous step (1 eq.) in THF (0.3 M) was added dropwise at 0 OC BH 3 SMe 2 complex (1.1 eq.) over 20 min. The resulting solution was stirred at 0 oC for 1 h and then at RT for another 2 h. The reaction was then quenched at 0 oC with NaOH (1 N aqueous solution, 4 eq.) and H 2 0 2 (30% w/w aqueous solution, 4 eq.). The biphasic mixture was slowly warmed to RT and stirred at RT for 2 h. The aqueous layer then 25 was separated and back extracted with ether. The combined organic extracts were washed with brine, dried over MgSO 4 and filtered. Concentration of the filtrate in vacuo afforded the title compound which can be purified further by way of column chromatography (SiO 2 , 90:10 (v:v) Hex : EtOAc -- 40:60 (v/v) Hex: EtOAc). Step 6: tert-Butyl {2-chloro-5-[3-(dimethylamino)propvl]benzyl}cyclopropylcarbamate 30 To a solution of tert-butyl [2-chloro-5-(3 (hydroxypropropyl)benzyl]cyclopropylcarbamate from the previous step (1 eq.) in dichloromethane (0.1 M) was added Dess-Martin periodinane (1.2 eq.). The resulting suspension was stirred at RT for 2 h. The reaction was then quenched with sat. aq. NaHSO 3 and extracted with dichloromethane. The combined organic extracts were washed with brine, dried over MgSO 4 and filtered. Concentration of the '5 filtrate in vacuo afforded the crude aldehyde as a pale yellow oil. This was then taken up in MeOH (0.15 M) and added, sequentially, sodium cyanoborohydride (1.3 eq.), dimethylamine (2 M THF solution, 2.5 eq.) and acetic acid (2.5 eq.). After 18 h of stirring at RT, the reaction was concentrated in vacuo and partitioned between ether and sat. aq. NaHCO 3 . The aqueous layer was separated and back extracted -37- WO 2007/009250 PCT/CA2006/001196 with ether. The combined organic extracts were washed with brine, dried over MgSO 4 and filtered. Concentration of the filtrate in vacuo afforded the crude product as a yellow oil. Further purification by way of column chromatography (SiO 2 , 79:19:2 (v:v:v) Hex: EtOAc : NEt 3 -4 98:2 (v/v) EtOAc : NEt 3 ) afforded the title compound as a pale yellow oil. 5 Step 7: Amine 14 To a solution of tert-butyl {2-chloro-5-[3 (dimethylamino)propyl]benzyl} cyclopropylcarbamate from the previous step (1 eq.) in dichloromethane (0.2 M) was added HCI (4 M dioxane solution, 8 eq.). The resulting mixture was stirred at RT for 18 h. The reaction was quenched with I N aq. NaOH and extracted with dichloromethane. The combined 10 organic extracts were washed with brine, dried over MgSO 4 and filtered. Concentration of the filtrate in vacuo afforded the crude product as a pale yellow oil. Further purification by way of column chromatography (SiO 2 , CH 2
C
2 - 93:7 (v/v) CH 2 Cl2 : 2.0 M NH 3 in MeOH) afforded the title compound as a colorless oil. Amine 15 15 N-[2,3-dihloro-5-(3-methoxypropyl)benzyl]cyclopropanamine Step 1: 5-Bromo-2.3-dichlorobenzaldehvde To a THF solution (0.2 M) of diisopropylamine (1.2 eq.) was added at 0 oC n butyl lithium (2.3 M hexane solution, 1.2 eq.) dropwise over 10 min. The resulting pale yellow solution was stirred at 0 C for 30 min before 1-bromo-3,4-chlorobenzene was added at -78 oC. After 1 h of 20 stirring at -78 'C, DMF (5 eq.) was added and the resulting solution was stirred at -78 oC for another 2 h. The reaction then allowed to warm slowly to RT before it was quenched with sat. aq. NH 4 CI. The aqueous layer was separated and back extracted with ether. The combined organic extracts were washed with brine, dried over MgSO 4 , filtered and the filtrate concentrated in vacuo. The crude product thus obtained was purified by way of column chromatography (SiO 2 , Hex - 95:5 (v/v) Hex: EtOAc) to 25 afford the title compound as a white solid. Step 2: N-(5-Bromo-2,3-dichlorobenzvl)cyclopropanamine A mixture of 5-bromo-2,3-dichlorobenzaldehyde from the previous step (1 eq.), cyclopropylamine (1 eq.) and sodium cyanoborohydride (1.5 eq.) were combined in MeOH (0.2 M). At 0 oC, acetic acid (3 eq.) was added dropwise and the reaction mixture was slowly warmed to RT over 16 h. 30 The reaction mixture was then diluted with ether and quenched with IN aq. NaHCO 3 . The aqueous layer was separated and back-extracted with ether. The combined organic extracts were then washed with brine, dried over MgSO 4 , filtered and the filtrate concentrated in vacuo. Purification of the crude product thus obtained by way of flash chromatography (SiO 2 , Hex - 80:20 (v/v) Hex : EtOAc) afforded the title compound as a colorless oil. 5 Step 3: tert-Butvl (5-bromo-2,3-dichlorobenzyl)cyclopropylcarbamate A THF solution (0.3 M) of N-(5-bromo-2,3-dichlorobenzyl)cyclopropanamine from the previous step (1 eq.) was added at -78 oC potassium hexamethyldisilazide (0.5 M in toluene, 1.2 eq.). After I h of stirring at -78 °C, di-tert-butyl dicarbonate was added and the resulting mixture was slowly -38- WO 2007/009250 PCT/CA2006/001196 warmed to RT over 2 h. The reaction was quenched with sat. aq. NH4Cl and then extracted with ether. The combined organic extracts were washed with brine, dried over MgSO 4 , filtered and the filtrate concentrated in vacuo. Further purification by way of column chromatography (SiO 2 , Hex - 95:5 (v/v) Hex : Et 2 0) to reveal the title compound as a colorless oil. 5 Step 4: tert-Butvl (5-allvl-2,3-dichlorobenzvl)cyclopropylcarbamate A THF solution (0.12 M) of tert-butyl (5-bromo-2,3 dichlorobenzyl)cyclopropylcarbamate from the previous step (1 eq.), Pd(PCy 3
)
2 (0.05 eq.) and cesium fluoride (2.0 eq.) was added allyl tributylstannane (1.2 eq.). The resulting brown solution was heated at reflux for 8 h and then filtered through a pad of SiO 2 . The insolubles were rinsed further with ether and 0 the filtrate was concentrated in vacuo to afford a brown semisolid. Purification of the crude product thus obtained by way of column chromatography (SiO 2 , Hex - 90:10 (v/v) Hex : Et 2 0) afforded the title compound as a pale yellow oil. Step 5: tert-Butyl cyclopropyl[2,3-dichloro-5-(3-(hydroxypropropyl)benzylicarbamate To a solution of tert-butyl (5-allyl-2,3-dichlorobenzyl)cyclopropylcarbamate from the 5 previous step (1 eq.) in THF (0.16 M) was added dropwise at 0 C BH3 SMe 2 complex (1.2 eq.) over 20 min. The resulting solution was stirred at 0 oC for 1 h and then at RT for another 2 h. The reaction was then quenched at 0 oC with NaOH (1 N aqueous solution, 4 eq.) and H 2 0 2 (30% w/w aqueous solution, 4 eq.). The biphasic mixture was slowly warmed to RT and stirred at RT for 2 h. The aqueous layer then was separated and back extracted with ether. The combined organic extracts were washed with brine, .0 dried over MgSO 4 and filtered. Concentration of the filtrate in vacuo afforded the title compound which can be purified further by way of column chromatography (SiO 2 , 80:20 (v:v) Hex: EtOAc -4 60:40 (v/v) Hex: EtOAc). Step 6: tert-Butvl cyclopropyl[2.3-dichloro-5-methoxvpropyl)benzyl]carbamate To a solution of tert-butyl cyclopropyl[2,3-dichloro-5-(3 15 (hydroxypropropyl)benzyl]carbamate from the previous step (1 eq.) in THF (0.2 M) was added sodium hydride (2 eq.). The resulting suspension was stirred at RT for 30 min and then added iodomethane (8 eq.). After 12 h of heating at reflux, the reaction mixture was cooled to RT and quenched with sat. aq.
NH
4 C1. The aqueous layer was separated and extracted with ether. The combined organic extracts were washed with brine, dried over MgSO 4 and filtered. Concentration of the filtrate in vacuo afforded the 0 crude product as a yellow oil. Further purification by way of column chromatography (SiO 2 , Hex 80:20 (v/v) Hex : EtOAc) afforded the title compound as a pale yellow oil. Step 7: Amine 15 To a solution of tert-butyl cyclopropyl[2,3-dichloro-5-methoxypropyl)benzyl]carbamate from the previous step (1 eq.) in dichloromethane (0.2 M) was added HCI (4 M dioxane solution, 8 eq.). 5 The resulting mixture was stirred at RT for 18 h. The reaction was quenched with 1 N aq. NaOH and extracted with dichloromethane. The combined organic extracts were washed with brine, dried over MgSO 4 and filtered. Concentration of the filtrate in vacuo afforded the crude product as a pale yellow -39- WO 2007/009250 PCT/CA2006/001196 oil. Further purification by way of column chromatography (SiO 2 , CH 2 Cl 2 -- 93:7 (v/v) CH 2 Cl2 : 2.0 M
NH
3 in MeOH) afforded the title compound as a colorless oil. Amine 16 { 8-Cyclopropylamino)methyl]quinoline-6-yl} acetonitrile 5 Step 1: (8-Formvlquinolin-6-yl)acetonitrile To a solution of (8-bromoquinolin-6-yl)acetonitrile (1 eq.) in anhydrous, deoxygenated DMF (0.08 M) was added freshly-dried sodium formate (1.5 eq.) and Pd(PPh 3 )C1 2 (2% loading). Through the resulting yellow suspension, was bubbled CO and then reaction was heated to 80 oC for 16 h. The now black reaction suspension was cooled to RT, diluted with water, and extracted with EtOAc. 0 The combined organic extracts were washed with brine, dried over MgSO 4 and filtered. Concentration of the filtrate in vacuo afforded the title compound. Step 2: Amine 16 Amine 16 was prepared according to the procedure described in Amine 3, but using instead (8-formylquinolin-6-yl)acetonitrile from the previous step as the starting material. The title 5 compound was isolated as a yellow oil. Amine 17 N- { [2-(3-Methoxypropyl)quinoline-4-yl]methyl } cyclopropanamine Step 1: Methyl 2-hydroxvquinoline-4-carboxylate To a solution of 2-hydroxyquinoline-4-carboxylic acid (1 eq.) in methanol (0.11 M) was .0 added HCI (4 M dioxane solution, 1 eq.) and the resulting suspension was heated at reflux for 24 h. The reaction was quenched with sat. aq. NaHCO 3 and extracted with EtOAc. The combined organic extracts were washed with brine, dried over MgSO 4 and filtered. Concentration of the filtrate in vacuo afforded the title compound. Step 2: Methyl 2-{ [trifluoromethyl)sulfonylloxy} quinoline-4-carboxvlate 5 To a solution of methyl 2-hydroxyquinoline-4-carboxylate from the previous step (1 eq.) in dichloromethane (0.2 M) was added sequentially at 0 oC pyridine (1.4 eq.) and triflic anhydride (1.1 eq.). The reaction mixture was stirred at 0 oC for I h and then at RT for 2 h. The reaction mixture was quenched with water and extracted with EtOAc. The combined organic extracts were washed with water, sat. aq. NaHCO 3 and brine. Drying over MgSO 4 , filtration and concentration of the filtrate in vacuo 0 afforded the title compound. Step 3: Propyl 2-[( 1E)-3-methoxyprop- 1-en-1-yllquinoline-4-carboxylate Methyl 2- { [trifluoromethyl)sulfonyl]oxy} quinoline-4-carboxylate from the previous step (1 eq.) and 2-[(1E)-3-methoxyprop- 1-en-I -yl]-4,4,5,5-tetramethyl- 1,3,2-dioxaborolane (1 eq.) were combined in n-propanol (0.1 M). To this solution was then added palladium acetate (5% loading), 5 triphenylphosphine (15% loading) and sodium carbonate (2 M aqueous solution, 4 eq.). The resulting suspension was heated at 80 oC for 2 h. The reaction mixture was quenched with water and extracted with EtOAc. The combined organic extracts were washed with water, sat. aq. NaHCO 3 and brine. Drying over MgSO 4 , filtration and concentration of the filtrate in vacuo afforded the crude product as a -40- WO 2007/009250 PCT/CA2006/001196 brown tar. Purification by way of column chromatography (SiO 2 , 10:1 (v/v) Hex: EtOAc -4 1:1 (v/v) Hex : EtOAc) afforded the title compound as a yellow oil. Step 4: Propyl 2-(3-methoxvpropyl]quinoline-4-carboxylate To a solution of propyl 2-[(1E)-3-methoxyprop-l1-en-1-yl]quinoline-4-carboxylate from 5 the previous step (1 eq.) in toluene (0.06 M) was added at 80 oC benzenesulfonyl hydrazide (3 x 1 eq.) over 3 h. The reaction mixture was diluted with EtOAc and washed sequentially with water, sat. aq. NaHCO 3 and brine. Drying over MgSO 4 , filtration and concentration of the filtrate in vacuo afforded the crude product as a yellow oil. Purification by way of column chromatography (SiO 2 , 10:1 (v/v) Hex: EtOAc 4-) 1:1 (v/v) Hex: EtOAc) afforded the title compound as a yellow oil. 0 Step 5: [2-(3-Methoxypropyl)quinoline-4-vl]lmethanol To a solution of propyl 2-(3-methoxypropyl]quinoline-4-carboxylate from the previous step (1 eq.) in toluene (0.1 M) was added at -78 oC DIBAL (1.5 M toluene solution, 2 eq.) dropwise over 10 min. The reaction mixture was stirred at -78 C for 30 min and then at 0 oC for 2 h. The reaction mixture was quenched with sat. aq. Rochelle's salt and extracted with EtOAc. The combined organic 5 extracts were washed sequentially with water, sat. aq. NaHCO 3 and brine. Drying over MgSO 4 , filtration and concentration of the filtrate in vacuo afforded the crude product as a milky oil. Purification by way of column chromatography (SiO 2 , 10:1 (v/v) Hex : EtOAc -> EtOAc) afforded the title compound as a pale yellow oil. Step 6: 2-(3-Methoxypropyl)quinoline-4-carbaldehyde 0 To a solution of [2-(3-methoxypropyl)quinoline-4-yl]methanol from the previous step (1 eq.) in CH 2 Cl 2 (0.05 M) was added Dess-Martin periodinane (1.1 eq.) portionwise. The resulting suspension was stirred at RT for 3 h. The reaction was quenched with MeOH and H 2 0. The organic layer was separated and the aqueous layer was back-extracted with EtOAc. The combined organic extracts were washed sat. aq. NaHCO 3 and brine, dried over Na 2
SO
4 and filtered. Concentration of the 5 filtrate in vacuo afforded the title compound which was purified further by way of flash chromatography (SiO 2 , 2:1 (v/v) Hex : EtOAc). Step 7: Amine 17 To a solution of 2-(3-methoxypropyl)quinoline-4-carbaldehyde from the previous step (1 eq.) in THF (0.05 M) was added cyclopropylamine (2 eq.) and magnesium sulfate (1 eq.). The resulting 0 mixture was stirred at RT for 3 h. The insolubles were then filtered off and the filtrate evaporated in vacuo. The resulting residue was taken up in methanol (0.05 M) and added sodium borohydride (2 eq.). After 2 h of stirring at RT, the reaction was quenched by the addition of 1 N aq. HC1. The volatiles were removed in vacuo and the resulting residue was partitioned between EtOAc and H 2 0. The organic layer was separated and the aqueous layer was back extracted with EtOAc. The combined organic extracts 5 were washed with brine, dried over Na 2
SO
4 and filtered. Concentration of the filtrate in vacuo afforded the title compound as a pale yellow oil. Amine 18 3- 4-Chloro-3-[(cyclopropylamino)methyl]phenyl } propanenitrile -41- WO 2007/009250 PCT/CA2006/001196 Step 1: (2E)-3-[3-( { [tert-Butvl(dimethyl)silyl]oxy methyl)-4-chlorophenvl]acrylonitrile To a solution of diethyl cyanomethylphosphonate (1.1 eq.) in THIF (0.14 M) was added at 0 C potassium tert-butoxide (1 M THF solution, 1.1 eq.). The resulting yellow solution was stirred at 0 oC for 1 h before 3-({ [tert-butyl(dimethyl)silyl]oxy}methyl)-4-chlorobenzaldehyde from step 3 of 5 Amine 10 synthesis (1 eq.) in THF (0.14 M) was added. The resulting mixture was stirred at RT 3 h. The reaction was quenched by the addition of sat. aq. NH4Cl and then extracted with EtOAc. The combined organic extracts were washed with sat. aq. NaHCO 3 , dried over MgSO 4 and filtered. Concentration of the filtrate in vacuo afforded an orange oil. Purification of the crude product thus obtained by way of flash chromatography (SiO 2 , Hex - 2:1 (v/v) Hex : EtOAc) afforded the title 10 compound. Step 2: 3-[4-Chloro-3-(hydroxymethyl)phenyl]propanenitrile To a solution of (2E)-3-[3-({ [tert-butyl(dimethyl)silyl]oxy}methyl)-4 chlorophenyl]acrylonitrile from the previous step (1 eq.) in toluene (0.01 M) was added at 80 oC benzenesulfonyl hydrazide (3 x I eq.) over 3 h. The reaction mixture was diluted with EtOAc and 5 washed sequentially with water, sat. aq. NaHCO 3 and brine. Drying over MgSO 4 , filtration and concentration of the filtrate in vacuo afforded a yellow oil. The residue was taken up in THF (0.1 M) and added tetrabutylammonium fluoride (1.0 M THF solution, 1.1 eq.). The resulting reaction mixture was stirred at RT for 2 h. After quenching the reaction with sat. aq. NH4C1, the mixture was extracted with EtOAc. The combined organic extracts were washed with sat. aq. NaHCO3 and brine, dried over .0 MgSO 4 and filtered. Concentration of the filtrate in vacuo and purification of the crude product thus obtained by way of flash chromatography (SiO 2 , Hex - 1:1 (v/v) Hex: EtOAc) afforded the title compound as a pale yellow oil. Step 3: 3-(4-Chloro-3-formvlphenvyl)propanenitrile To a solution of 3
-[
4 -chloro-3-(hydroxymethyl)phenyl]propanenitrile from the previous .5 step (1 eq.) in CH 2 Cl (0.1 M) was added Dess-Martin periodinane (1.1 eq.) portionwise. The resulting suspension was stirred at RT for 2 h. The reaction was quenched with MeOH and H 2 0. The organic layer was separated and the aqueous layer was back-extracted with EtOAc. The combined organic extracts were washed sat. aq. NaHCO 3 and brine, dried over Na 2
SO
4 and filtered. Concentration of the filtrate in vacuo afforded the title compound as a pale yellow oil. 0 Step 4: Amine 18 To a solution of 3
-(
4 -chloro-3-formylphenyl)propanenitrile from the previous step (1 eq.) in THF (0.1 M) was added cyclopropylamine (2 eq.) and MgSO 4 (1 eq.). The resulting suspension was stirred at RT for 3 h. The insolubles were then filtered off and the filtrate evaporated in vacuo. The resulting residue was taken up in methanol (0.1 M) and added sodium borohydride (2 eq.). After 2 h of 5 stirring at RT, the reaction was quenched by the addition of 1 N aq. HCI. The volatiles were removed in vacuo and the resulting residue was partitioned between EtOAc and H 2 0. The organic layer was separated and the aqueous layer was back extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na 2
SO
4 and filtered. Concentration of the filtrate in vacuo and purification -42- WO 2007/009250 PCT/CA2006/001196 of the crude product thus obtained by way of column chromatography (SiO 2 , Hex -4 EtOAc) afforded the title compound as a pale yellow oil. Amine 19 N-[5-(3-Methoxypropyl)-2-methylbenzyl]cyclopropanamine 5 Amine 19 was prepared according to the procedure described in Amine 14, but using instead 5-chloro2-methylbenzoic acid from the previous step as the starting material in step 1 and [BrPdP'Bu 3
]
2 as the palladium source in step 4. The title compound was isolated as a pale yellow oil. Amine 20 {4-Chloro-3-[(cyclopropylamino)methyl]phenyl } acetonitrile 0 Step 1: [3-( { [tert-Butvl(dimethyl)silvlloxy } methyl)-4-chlorophenyllmethanol To a solution of 3-({ [tert-butyl(dimethyl)silyl]oxy} methyl)-4-chlorobenzaldehyde from step 3 of Amine 10 synthesis (1 eq.) in methanol (0.14 M) was added sodium borohydride (5 eq.). The resulting mixture was stirred at RT 3 h. The reaction was quenched by the addition of sat. aq. NH 4 CI and then extracted with EtOAc. The combined organic extracts were washed with sat. aq. NaHCO 3 , dried 5 over MgSO 4 and filtered. Concentration of the filtrate in vacuo afforded an colorless oil. Purification of the crude product thus obtained by way of flash chromatography (SiO 2 , Hex -- 1:1 (v/v) Hex : EtOAc) afforded the title compound. Step 2: [3-( { [tert-Butvl(dimethyl)silvl]oxv} methyl)-4-chlorophenyl]acetonitrile To a solution of [3-({ [tert-butyl(dimethyl)silyl]oxy} methyl)-4-chlorophenyl]methanol .0 from the previous step (1 eq.) in dichloromethane (0.14 M) was added sequentially at 0 oC Hunig's base (1 eq.) and methanesulfonyl chloride (1.1 eq.). The reaction mixture was warmed to RT and stirred at RT for 3 h. The reaction was then quenched with water and extracted with EtOAc. The combined organic extracts were washed with brine, dried over MgSO 4 , filtered and the filtrate concentrated in vacuo. The crude mesylate thus obtained was taken up in DMF (0.14 M) and added sodium cyanide (1.5 5 eq.). After 16 h of stirring at RT, the reaction mixture was partitioned between water and ether. The organic layer was separated and washed with sat. aq. NaHCO 3 and brine, dried over MgSO 4 and filtered. Concentration of the filtrate in vacuo and purification of the crude product thus obtained by way of flash chromatography (SiO 2 , Hex - 2:1 (v/v) Hex: EtOAc) afforded the title compound as a pale yellow oil. Step 3: [4-Chloro-3-(hydroxvmethyl)phenyllacetonitrile 0 To a solution of 3-( { [tert-butyl(dimethyl)silyl]oxy} methyl)-4-chlorophenyl] acetonitrile from the previous step (1 eq.) in THF (0.15 M) and added tetrabutylammonium fluoride (1.0 M THF solution, 1.2 eq.). The resulting reaction mixture was stirred at RT for 2 h. After quenching the reaction with water, the resulting mixture was extracted with EtOAc. The combined organic extracts were washed with sat. aq. NaHCO 3 and brine, dried over MgSO 4 and filtered. Concentration of the filtrate in 5 vacuo and purification of the crude product thus obtained by way of flash chromatography (SiO 2 , Hex 1:1 (v/v) Hex : EtOAc) afforded the title compound as a pale yellow oil. Step 4: (4-Chloro-3-formvlphenyl)acetonitrile -43- WO 2007/009250 PCT/CA2006/001196 To a solution of [4-chloro-3-(hydroxymethyl)phenyl]acetonitrile from the previous step (1 eq.) in CH 2 Cl 2 (0.14 M) was added Dess-Martin periodinane (1.1 eq.) portionwise. The resulting suspension was stirred at RT for 3 h. The reaction was quenched with MeOH and H 2 0. The organic layer was separated and the aqueous layer was back-extracted with EtOAc. The combined organic 5 extracts were washed sat. aq. NaHCO 3 and brine, dried over Na 2
SO
4 and filtered. Concentration of the filtrate in vacuo afforded the title compound as a pale yellow oil. Step 5: Amine 20 To a solution of (4-chloro-3-formylphenyl)acetonitrile from the previous step (1 eq.) in THIF (0.1 M) was added cyclopropylamine (2 eq.) and MgSO 4 (1 eq.). The resulting suspension was 10 stirred at RT for 18 h. The insolubles were then filtered off and the filtrate evaporated in vacuo. The resulting residue was taken up in methanol (0.1 M) and added sodium borohydride (2 eq.). After 2 h of stirring at RT, the reaction was quenched by the addition of 1 N aq. HC1. The volatiles were removed in vacuo and the resulting residue was partitioned between EtOAc and H 2 0. The organic layer was separated and the aqueous layer was back extracted with EtOAc. The combined organic extracts were 15 washed with brine, dried over Na 2
SO
4 and filtered. Concentration of the filtrate in vacuo and purification of the crude product thus obtained by way of column chromatography (SiO 2 , Hex - EtOAc) afforded the title compound as a pale yellow oil. Amine 21 N-[5-(2-Methoxyethyl)-2-methylbenzyl]cyclopropanamine 20 Step 1: tert-Butvl cyclopropyl[5-(2-hydroxyethyl)-2-methylbenzyllcarbamate To a dichloromethane solution (0.33 M)oftert-butyl (5-allyl-2 methylbenzyl)cyclopropylcarbamate from step 4 of Amine 19 synthesis (1 eq) was bubbled, at -78 oC, ozone until a persistent blue color was observed. At this time, the reaction mixture was diluted with an equivalent volume of ethanol and added sodium borohydride (2.5 eq.). The reaction was then allowed to 25 slowly warm to RT overnight. The reaction was quenched by the addition of sat. aq. NH 4 CI before the volatiles were removed in vacuo. The resulting residue was extracted with ether. The combined organic extracts were washed with brine, dried over MgSO 4 and filtered. Concentration of the filtrate in vacuo and purification of the crude product thus obtained by way of flash chromatography (SiO 2 , Hex -- 3:2 (v/v) Hex : EtOAc) afforded the title compound as a colorless oil. 0 Step 2: tert-Butyl cyclopropyl[5-(methoxvethyl)-2-methylbenzyl]carbamate To a solution of tert-butyl cyclopropyl[5-(2-hydroxyethyl)-2-methylbenzyl]carbamate from the previous step (1 eq.) in THF (0.2 M) was added sodium hydride (2 eq.). The resulting suspension was stirred at RT for 30 min and then added iodomethane (8 eq.). After 12 h of heating at reflux, the reaction mixture was cooled to RT and quenched with sat. aq. NH4CI. The aqueous layer was 5 separated and extracted with ether. The combined organic extracts were washed with brine, dried over MgSO 4 and filtered. Concentration of the filtrate in vacuo afforded the crude product as a colorless oil. Further purification by way of column chromatography (SiO 2 , Hex -- 7:3 (v/v) Hex : EtOAc) afforded the title compound as a colorless oil. -44- WO 2007/009250 PCT/CA2006/001196 Step 3: Amine 21 To a solution of tert-butyl cyclopropyl[5-(methoxyethyl)-2-methylbenzyl]carbamate from the previous step (1 eq.) in dichloromethane (0.2 M) was added HCI (4 M dioxane solution, 5 eq.). The resulting mixture was stirred at RT for 16 h. The reaction was quenched with 1 N aq. NaOH and 5 extracted with dichloromethane. The combined organic extracts were washed with brine, dried over MgSO 4 and filtered. Concentration of the filtrate in vacuo afforded the crude product as a pale yellow oil. Further purification by way of column chromatography (SiO 2 , Hex -4 3:2 (v/v) Hex: EtOAc) afforded the title compound as a pale yellow oil. Amine 22 0 N-[2,5-Bis(trifluoromethyl)benzyl]cyclopropanamine Amine 22 was prepared according to the reaction sequence described for Amine 3, but using instead 2,5-bis(trifluoromethyl)benzaldehyde as the starting material. The title compound was isolated as a colorless oil. Amine 23 5 2- {8-[(Cyclopropylamino)methyl]quinoline-6-yl}-2-methylpropanenitrile Amine 23 was prepared according to the procedure described in Amine 16, but using instead 2-(8-bromoquinolin-6-yl)-2-methylpropanenitrile acetonitrile as the starting material. The title compound was isolated as a yellow oil. Amine 24 0 N-(1 -Phenylethyl)cyclopropanamine To a solution of 1-phenylethanone (1 eq.) in dichloromethane (0.17 M) was added cyclopropylamine (3 eq.) and magnesium sulfate (9 eq.). The resulting mixture was stirred at reflux for 2 days. The insolubles were then filtered off and the filtrate evaporated in vacuo. The resulting residue was taken up in methanol (0.2 M) and added sodium borohyride (1.5 eq.). The reaction mixture was then 5 stirred at RT overnight. After quenching with 1 N aq. HCI, the volatiles were removed in vacuo. The resulting residue was partitioned between 1 N NaOH and extracted with ether. The combined organic extracts were washed with brine, dried over MgSO 4 and filtered. Concentration of the filtrate in vacuo afforded the title compound as a colorless oil. Amine 25 0 N-Benzylcyclopropanamine Amine 26 was prepared according to the procedure described in Amine 24, but using instead benzaldehyde as the starting material. The title compound was isolated as a colorless oil. Amine 26 N-(2-Phenylethyl)cyclopropanamine 5 To a solution of cyclopropanamine (1 eq.) in dichloromethane (0.13 M) was added sequentially at 0 oC pyridine (1.5 eq.) and phenylacetyl chloride (9 eq.). The resulting mixture was slowly warmed to RT and stirred at RT for 3 h. After quenching with 1 N aq. HC1, the reaction mixture was extracted with EtOAc. The combined organic extracts were washed with sat. aq. NaHCO 3 and brine, -45- WO 2007/009250 PCT/CA2006/001196 dried over MgSO 4 , filtered and the filtrate concentrated in vacuo. The crude amide thus obtained was taken up in THF (0.3 M) and added BH 3 SMe 2 complex (3 eq.). The reaction was heated to reflux and the volatiles were slowly distilled off. The resulting distillation residue was carefully quenched with 1 N aq. HCI and allowed to stir at 50 oC overnight. The reaction was cooled to 0 oC and the pH of the 5 solution was brought to -12 with 1 N aq. NaOH before it was extracted with ether. The combined organic extracts were washed with brine, dried over MgSO 4 , filtered and the filtrate concentrated in vacuo. The crude product thus obtained could be further purified by way of column chromatography (SiO 2 , 2:1 (v/v) Hex : EtOAc -4 EtOAc) afforded the title compound as a colorless oil. Amine 27 0 N-(2,3-dichlorobenzyl)-2,2,2-trifluoroethanamine Amine 27 was prepared according to the reaction sequence described for Amine 3, but using instead 2,3-dichlorobenzaldehyde as the starting aldehyde and 2,2,2-trifluoroethylamine as the starting amine. The title compound was isolated as a colorless oil. Amine 28 5 N-methyl-2-phenylpropan-2-amine To a solution of 2-phenylpropan-2-amine (1 eq.) in benzene (0.25 M) was added formaldehyde (37% w/w aqueous solution, 2 eq.). The vessel attached a Dean-Stark apparatus and heated at 80 oC for 36 h. The reaction mixture was cooled to RT, dried with Na 2
SO
4 and filtered. Concentration of the filtrate in vacuo afforded the crude imine. This was then taken up in methanol (1.4 20 M) and added sodium borohydride (10 eq.). The resulting mixture was stirred at RT for 2 h and then quenched with I N aq. HC1. The volatiles were removed in vacuo and the pH of the resulting residue was carefully brought up to - 12 with 1 N aq. NaOH. The mixture was then extracted with EtOAc. The combined organic extracts were washed with brine, dried over MgSO 4 , filtered and the filtrate concentrated in vacuo. Purification of the crude product thus obtained by way of column 5 chromatography (SiO 2 , 2:1 (v/v) Hex : EtOAc -- EtOAc) afforded the title compound as a colorless oil. Amine 29 1-[2-Chloro-5-(2-methoxyethyl)phenyl]-N-(cyclopropylmethyl)methanamine To a solution of 2-chloro-5-(2-methoxyethyl)benzaldehyde from Amine 7, Step 6 (1 eq.) in methanol (0.8 M) was added 1-cyclopropylmethanamine (1.2 eq.) and sodium bicarbonate (1.5 eq). 0 The vessel was sealed and heated at 70 C for 2 h. The insolubles were removed via filtration and to the filtrate was then added sodium borohydride (1.5 eq.) at 0 C. The reaction mixture was allowed to warm slowly to RT overnight. The volatiles were removed in vacuo and the resulting residue was partitioned between 1 N aq. NaOH and ether. The aqueous layer was separated and back extracted with ether. The combined ethereal extracts were washed with brine, dried over Na 2
SO
4 and filtered. Concentration of the 5 filtrate in vacuo afforded the title compound. Amine 30 1-[ 2 -Chloro-5-(2-methoxyethyl)phenyl]-N-methylmethanamine -46- WO 2007/009250 PCT/CA2006/001196 Amine 30 was prepared according to the reaction sequence described for Amine 29, but using instead methylamine (2.0 M solution in methanol) as starting material. The title compound was isolated as a colorless oil. 5 Amine 31 1 -[2-Chloro-5-(2-methoxyethyl)phenyl]-N-(cyclobutylmethyl)methanamine Step 1: 1-Cyclobutylmethanamine To a solution of cyclobutane carbonitrile (1 eq.) in ethanol (0.5 M) was added glacial acetic acid (1.05 eq.) and platinum oxide (5% loading). The resulting suspension was hydrogenated on a 0 Parr apparatus at 52 psi for 18 h. The reaction suspension was then filtered and the filtrate concentrated in vacuo. The resulting residue was partitioned between 1 N aq. NaOH and ether. The aqueous layer was separated and back extracted with ether. The combined ethereal extracts were washed with brine, dried over MgSO 4 and filtered. Concentration of the filtrate in vacuo afforded the title compound. Step 2: Amine 31 5 Amine 31 was prepared according to the procedure described in Amine 30, but using instead 1 -cyclobutylmethanamine from the previous step as the starting material. The title compound was isolated as a colorless oil. Amine 32 N-2-Chloro-5-(2-methoxyethyl)benzyl]propan-2-amine 0 Amine 32 was prepared according to the procedure described in Amine 30, but using instead isopropylamine as the starting material. The title compound was isolated as a colorless oil. Amine 33 N-2-Chloro-5-(2-methoxyethyl)benzyl]prop-2-en- 1-amine Amine 33 was prepared according to the procedure described in Amine 30, but using ,5 instead allylamine as the starting material. The title compound was isolated as a colorless oil. Amine 34 N-2-Chloro-5-(2-methoxyethyl)benzyl]cyclobutanamine Amine 34 was prepared according to the procedure described in Amine 30, but using instead cyclobutylamine as the starting material. The title compound was isolated as a colorless oil. 0 Amine 35 N-[2-Chloro-5-(2-methoxyethyl)phenyl]-N-ethanamine Amine 35 was prepared according to the reaction sequence described for Amine 29, but using instead ethylamine (2.0 M solution in methanol) as starting material. The title compound was isolated as a colorless oil. 5 Amine 36 N-[3- { [tert-Butyl(dimethyl)silyl]oxy } -5-(3-methoxypropyl)benzyl]cyclopropanamine Step 1: 3-Bomo-5-hydroxybenzaldehyde -47- WO 2007/009250 PCT/CA2006/001196 To a toluene solution (1.6 M) of n-butyl lithium (2.5 M hexane solution, 2.1 eq.) was added at -10 C n-butyl magnesium chloride (2.0 M THF solution, 0.6 eq.). The reaction mixture was stirred at -10 oC for 30 min before a toluene solution (0.7 M) of 3,5-dibromophenol (1 eq.) was added dropwise at -10 C over a period of 35 min. After stirring at -10 C for a further 30 min, the reaction 5 mixture was cooled to -40 oC before DMF (20 eq.) was added dropwise over 20 min. The reaction mixture was then slowly wanted to RT and allowed to stir at RT for 1 h. The reaction was carefully quenched at 0 oC with 10% aq. HCI and extracted with ether. The combined organic extracts were washed with water and brine, dried over MgSO 4 and filtered. Concentration of the filtrate in vacuo afforded a yellow solid. Recystallization of the crude product thus obtained from ether - hexane 10 afforded the title compound as a beige powder. Step 2: 3-Hydroxv-5-[(1E)-3-methoxyprop- 1-en-1-yl]benzaldehyde 3-Bomo-5-hydroxybenzaldehyde from the previous step (1 eq.) and 2-[(lE)-3 methoxyprop-1-en-1-yl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1 eq.) were combined in DMF (0.05 M). To this solution was then added palladium acetate (10% loading), triphenylphosphine (20% loading) 5 and sodium carbonate (2 M aqueous solution, 4 eq.). The resulting suspension was heated at 80 C for 16 h. The reaction mixture was quenched with 10% aq. HCI and extracted with ether. The combined organic extracts were washed with water, sat. aq. NaHCO 3 and brine. Drying over MgSO 4 , filtration and concentration of the filtrate in vacuo afforded the crude product as a brown tar. Purification by way of column chromatography (SiO 2 , 4:1 (v/v) Hex : EtOAc -) 2:1 (v/v) Hex: EtOAc) afforded the title 20 compound as a yellow oil. Step 3: 3-([tert-Butvl(dimethyl)silyl]oxyl}-5-[(lE)-3-methoxyprop-l1-en-1-vl]benzaldehyde 3-Hydroxy-5-[(1E)-3-methoxyprop- 1-en- 1-yl]benzaldehyde from the previous step (1 eq.) and tert-butylchlorodimethylsilane (1 eq.) were combined in DMF (0.5 M). To this solution was then added imidazole (1.5 eq.) and the reaction mixture was stirred at RT for 16 h. The resulting 5 solution was quenched with water and extracted with 1:1 (v:v) ether : hexanes. The combined organic extracts were washed with brine, dried over MgSO 4 and filtered through a plug of SiO 2 . Concentration of the filtrate in vacuo afforded the title compound as a pale yellow oil. Step 4: N- {3- { [tert-Butyl(dimethyl)silyl]oxy}-5-[( 1E)-3-methoxvprop- 1-en-1 yl]lbenzyl } cyclopropanamine 0 To a solution of 3- { [tert-butyl(dimethyl)silyl]oxy}-5-[(1E)-3-methoxyprop- 1-en-1 yl]benzaldehyde from the previous step (1 eq.) in dichloromethane (0.5 M) was added cyclopropylamine (2 eq.) and magnesium sulfate (1.5 eq.). The resulting suspension was stirred at RT for 12 h. The insolubles were removed via filtration. Concentration of the filtrate in vacuo afforded the crude imine as a yellow oil. This was then taken up in methanol (0.3 M) and then added at 0 oC sodium borohydride 5 (1.5 eq.) portionwise over 5 min. The reaction mixture was slowly warmed to RT over 1 h and then stirred at RT for 2 h. After carefully quenching with sat. aq. NaHCO 3 , the resulting mixture was extracted with ether. The combined organic extracts were washed with water and brine, dried over -48- WO 2007/009250 PCT/CA2006/001196 MgSO 4 and filtered. Concentration of the filtrate in vacuo afforded the title compound as a golden, yellow oil. Step 5: Amine 36 To a solution of N- {3- { [tert-butyl(dimethyl)silyl]oxy} -5-[( 1E)-3-methoxyprop- 1-en-1 5 yl]benzyl}cyclopropanamine from the previous step (1 eq.) in EtOAc (0.04 M) was added palladium (10% w/w over activated carbon, 10% loading). The vessel was evacuated and back filled with hydrogen. The reaction suspension was then stirred under a balloon atmosphere of hydrogen for 1.5 h. The reaction was quenched with dichloromethane and filtered through a bed of celite. The insolubles were washed further with EtOAc and methanol. Concentration of the filtrate in vacuo afforded the title 0 compound as a colorless oil. Amine 37 Ethyl 2- { [2-chloro-3-[(cyclopropylamino)methyl]-5-(3-methoxypropyl)phenoxy]methyl } cyclopropane carboxylate Step 1: 3- { [tert-Butyl(dimethyl)silyl]oxy } -5-(3-methoxypropyl)benzaldehyde 5 To a solution of 3- { [tert-butyl(dimethyl)silyl]oxy}-5-[( 1 E)-3-methoxyprop- 1-en-1 yl]benzaldehyde from Amine 36, Step 3 (1 eq.) in EtOAc (0.1 M) was added palladium (10% w/w over activated carbon, 10% loading). The vessel was evacuated and back filled with hydrogen. The reaction suspension was then stirred under a balloon atmosphere of hydrogen for 1 h. The reaction was quenched with dichloromethane and filtered through a bed of celite. The insolubles were washed further with 20 EtOAc and methanol. Concentration of the filtrate in vacuo and purification of the crude product thus obtained by way of column chromatography (SiO 2 , Hex -4 3:2 (v/v) Hex : EtOAc) afforded the title compound as a pale yellow oil. Step 2: 3-Hydroxy-5-(3-methoxypropvl)benzaldehyde To a solution of 3-{ [tert-butyl(dimnethyl)silyl]oxy}-5-(3-methoxypropyl)benzaldehyde 5 from the previous step (1 eq.) in THF (0.2 M) was added tetrabutylammonium fluoride (1.0 M THF solution, 1.1 eq.). The resulting reaction mixture was then stirred at RT for 30 min. The reaction was quenched sat. aq. NH4Cl and then extracted with ether. The combined organic extracts were washed with water and brine, dried over MgSO 4 , filtered and the filtrate concentrated in vacuo. Further purification of the crude product thus obtained by way of column chromatography (SiO 2 , Hex - 3:2 (v/v) Hex : EtOAc) 0 afforded the title compound as a pale yellow oil. Step 3: 2-Chloro-3-hydroxy-5-(3-methoxypropyl)benzaldehyde To a solution of 3-hydroxy-5-(3-methoxypropyl)benzaldehyde from the previous step (1 eq.) in dichloromethane (0.2 M) was added sulfuryl chloride (1 eq.). The resulting reaction mixture was then stirred at RT for 18 h. The volatiles were removed in vacuo and purification of the crude product 5 thus obtained by way of column chromatography (SiO 2 , Hex - 3:2 (v/v) Hex : EtOAc) afforded the title compound as a yellow oil. Step 4: Ethyl 2- { [2-chloro-3-fornnvl-5-(3-methoxypropyl)phenoxy]methylcyclopropanecarboxviate -49- WO 2007/009250 PCT/CA2006/001196 To a solution of ethyl 2-(hydroxymethyl)cyclopropanecarboxylate from Experiment 86, Step 1 (1.2 eq.) in dichloromethane (0.15 M) was added at -78 C Hunig's base (3 eq.) and methanesulfonyl chloride (1.5 eq.). The resulting solution was stirred at -78 oC for 15 min and then warmed to RT over 3 h. The reaction was quenched with sat. aq. NaHCO 3 and then extracted with ether. 5 The combined organic extracts were washed with water and brine, dried over MgSO 4 , filtered and the filtrate concentrated in vacuo to afford the crude mesylate as a pale yellow oil. This was then taken up in DMF (0.014 M) and added cesium carbonate (1.2 eq.) and 2-chloro-3-hydroxy-5-(3 methoxypropyl)benzaldehyde from the previous step (1 eq.). The resulting suspension was stirred at 50 oC for 3 h. The reaction was quenched with sat. aq. NI-H4Cl and then extracted with ether. The combined 0 organic extracts were washed with water and brine, dried over MgSO 4 and filtered. Concentration of the filtrate in vacuo and purification of the crude product thus obtained by way of column chromatography (SiO 2 , Hex -- 7:3 (v/v) Hex: EtOAc) afforded the title compound. Step 5: Amine 37 Amine 37 was prepared according to the procedure described in Amine 3, but using 5 instead ethyl 2- { [2-chloro-3-formyl-5-(3-methoxypropyl)phenoxy]methyl } cyclopropanecarboxylate from the previous step as the starting material. The title compound was isolated as a white foam. Amine 38 ,N-[3,5-Bis(2-methoxyethoxy)benzyl]cyclopropanamine Step 1: 3.5-Bis(2-methoxyethoxy)benzaldehyde 20 To a solution of 3,5-dihydroxybenzaldehyde (1 eq.) in DMF (0.5 M) was added 2 bromoethyl methyl ether (3.5 eq.) and cesium carbonate (5 eq.). The resulting suspension was heated at 80 oC for 16 h. The reaction was quenched with sat. aq. NH 4 Cl and then extracted with ether. The combined organic extracts were washed with water and brine, dried over Na 2
SO
4 , filtered and the filtrate concentrated in vacuo. Purification of the crude product thus obtained by way of column 15 chromatography (SiO 2 , Hex - 3:1 (v/v) Hex : EtOAc) afforded the title compound as a yellow oil. Step 2: Amine 38 To a solution of 3,5-bis(2-methoxyethoxy)benzaldehyde from the previous step (1 eq.) in dichloromethane (0.3 M) was added cyclopropylamine (2 eq.) and magnesium sulfate (1.5 eq.). The resulting suspension was stirred at RT for 12 h. The insolubles were removed via filtration. '0 Concentration of the filtrate in vacuo afforded the crude imine as a yellow oil. This was then taken up in methanol (0.8 M) and then added at 0 oC sodium borohydride (1.5 eq.) portionwise over 5 min. The reaction mixture was slowly warmed to RT over 1 h and then stirred at RT for 1.5 h. The reaction was quenched with sat. aq. NaHCO 3 and then extracted with EtOAc. The combined organic extracts were washed with water and brine, dried over MgSO 4 , filtered and the filtrate concentrated in vacuo. 5 Purification of the crude product thus obtained by way of column chromatography (SiO 2 , 95:5 (v/v) CH2C1 2 : EtOH - 90:10 (v/v) CH 2 C1 2 : EtOH) afforded the title compound as a colorless oil. Amine 39 N-[3,5-Bis(4,4,4-trifluorobutoxy)benzyl]cyclopropanamine -50- WO 2007/009250 PCT/CA2006/001196 Amine 39 was prepared according to the reaction sequence described for Amine 38, but using instead 4,4,4-trifluorobutan-1-ol as starting material. The title compound was isolated as a colorless oil. Amine 40 5 [5-Chloro-2-(3-methoxy-propyl)-pyridin-4-ylmethyl]-cyclopropyl-amine Step 1: 2-Bromo-5-chloro-pyridine-4-carbaldehyde To a stirred sol. of diisopropylamine (20.9 mL, 148 mmol) in dry THF (350 mL) at -5 'C was added dropwise BuLi (1.6M in hexane, 89.5 mL, 143 mmol), and the resulting sol. was stirred for 30 min at -5 'C. The sol. was allowed to cool to -70 'C, and a sol. of 2-bromo-5-chloropyridine (25.0 g, 0 130 mmol) in THF ( 100 mL) was added dropwise at -70 'C over 15 min, such that the internal temperature did not exceed -65 'C. The mixture was stirred at -70 'C for 30 min. DMF (10.52 mL, 136 mmol) was added dropwise over 20 min such that the internal temperature did not exceed -70 oC. The orange mixture was stirred at -70 'C for 40 min. The mixture was allowed to warm up to rt, and was poured onto a mixture of water (200 mL) and aq. I M NaOH (50 mL). The mixture was extracted with 5 EtOAc (2x), and the combined org. extracts were washed back with aq. 1IM NaOH (2x). The org. extracts were dried over MgSO 4 , filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (EtOAc/heptane 1:9 -> 1:8 - 1:6 -> 1:4 -- 1:2 -> 1:1) yielded the title compound (21.55 g, 72 %). LC-MS: tR = 0.74 min; ES+: 295.01. Step 2: 2-Bromo-5-chloro-4-dimethoxvmethyl-pyridine :0 To a sol. of 2-bromo-5-chloro-pyridine-4-carbaldehyde (43.9 g, 199 mmol) in MeOH (800 mL) were successively added at rt trimethyl orthoformate (65.3 mL, 597 mmol) and p toluenesulfonic acid monohydrate (1.90 g, 10.0 mmol). This reaction mixture was then heated to reflux for 3 h. The mixture was allowed to cool to rt and was concentrated under reduced pressure. The residue was dissolved in CH2C 2 and this mixture was washed with aq. 10% K2CO 3 . The org. layer was 5 dried over MgSO 4 , filtered, and the solvents were removed under reduced pressure. Drying under high vacuum yielded the title compound (51.7 g, 97 %). LC-MS: tR = 0.92 min; ES+: 309.06. Step 3: 5-Chloro-4-dimethoxymethyl-2-(3-methoxy-propyl)-pyridine To a suspension of Mg (911 mg, 37.5 mmol) and of iodine (one crystal) in dry THF (30 mL) was added dropwise 5% of the total amount of 1-bromo-3-methoxypropane (4.59 g, 30.0 mmol). 0 The mixture was heated to reflux with the help of a heat gun until the Grignard formation had started. The rest of the 1-bromo-3-methoxypropane was added slowly, while an exothermic reaction proceeded. After the end of the addition, the reaction mixture was stirred under reflux for 20 min, and was allowed to cool to rt. This Grignard sol. (IM in THF, 23.5 mL, 23.5 mmol) was added dropwise to a mixture of 2-bromo-5-chloro-4-dimethoxymethyl-pyridine (2.50 g, 9.38 mmol) and Ni(dppp)C1 2 (495 mg, 0.938 5 mmol) in THF (50 mL) at 0 'C. The reaction mixture was stirred at rt for 30 min, and was then heated to reflux for 2 h. The mixture was allowed to cool to rt, and was dissolved with EtOAc. This mixture was washed with aq. sat. NaHCO 3 . The org. layer was dried over MgSO 4 , filtered, and the solvents were -51- WO 2007/009250 PCT/CA2006/001196 removed under reduced pressure. Purification of the residue by FC (heptane --- > EtOAc/heptane 1:1) yielded the title compound (1.51 g, 62%). LC-MS: tR = 0.80 min; ES+: 260.15. Step 4: 5-Chloro-2-(3-methoxv-propyl)-pyridine-4-carbaldehyde 5-Chloro-4-dimethoxymethyl-2-(3-methoxy-propyl)-pyridine (25.5 g, 98.2 mmol) was 5 dissolved in aq. IM HCI (500 mL), and the mixture was heated to 80 oC for 2 h. The mixture was allowed to cool to rt, and EtOAc was added. The mixture was cooled to 0 'C, and was basified with an aq. 2.5M NaOH until a pH = 10 was reached. The layers were separated, and the org. layer was dried over MgSO 4 , filtered, and concentrated under reduced pressure. Drying the residue under high vacuum yielded the crude title compound (98.1 mmol, 99%) that was used further without purification. LC-MS: 0 tR = 0.62 min; ES+: 246.12. Step 5: [5-Chloro-2-(3-methoxy-propyl)-pyridin-4-vlmethyl]-cyclopropyl-amine A mixture of 5-chloro-2-(3-methoxy-propyl)-pyridine-4-carbaldehyde (21.0 g, 98.2 mmol) and cyclopropylamine (13.8 mL, 196 mmol) in MeOH (450 mL) was stirred at rt overnight. NaBH4 (4.83 g, 128 mmol) was added at 0 'C, and the mixture was stirred at rt overnight. Ice was 5 added, and the mixture was concentrated under reduced pressure. The crude product was dissolved in EtOAc, and this mixture was washed with aq. I M NaOH. The aq. layer was extracted back with EtOAc. The combined org. extracts were dried over MgSO 4 , filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC ( EtOAc/heptane 1:5 -> 1:4 -+ 1:3 -> 1:1 -> 3:1 --> EtOAc) yielded the title compound (11.8 g) and [5-chloro-2-(3-methoxy-propyl)-pyridin-4-ylmethylene] ,0 cyclopropyl-amine (10.7 g). This unreacted imine was dissolved in MeOH (20 mL), and this sol. was cooled to 0 oC. NaBH 4 (3.20 g, 84.6 mmol) was added, and the mixture was stirred at rt overnight. NaBH 4 (3.20 g, 84.6 mmol) was added again, and the mixture was stirred for 3 days. Ice was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The crude product was dissolved in EtOAc and the resulting mixture was washed with aq. IM NaOH. The aq. phase was 5 extracted back with EtOAc. The combined org. extracts were dried over MgSO 4 , filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (EtOAc/heptane 1:3 1:2 -> 1:1 - EtOAc) yielded the title compound (9.4 g). The fractions of the title compound were mixed together (21.2 g, 85%). LC-MS: tR = 0.55 min; ES+: 296.16. Amine 41 0 N- { [2-Methoxy-6-(3-methoxypropyl)pyridin-4-yl]methyl} cyclopropanamine Step 1: 2.6-Dichloro-N-cyclopropylisonicotinamide To a solution of 2,6-dichloroisonicotinic acid (1 eq.) in DMF (0.05 M) was added sequentially cyclopropylamine (1.05 eq.), Hunig's base (3 eq.) and O-(7-azabenzotriazol-l-yl) N,N,N',N'-tetramethyluronium hexafluorophosphate (1.2 eq.). The resulting solution was stirred at RT 5 for 4 h. The reaction was quenched with sat. aq. NH 4 Cl and extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na 2
SO
4 , filtered and the filtrate concentrated in vacuo. Purification of the crude product thus obtained by way of flash chromatography (SiO 2 , 10:1 (v/v) CHCl 2 : EtOAc) afforded the title compound as a white solid. -52- WO 2007/009250 PCT/CA2006/001196 Step 2: 2-Chloro-N-cyclopropvl-6-methoxvisonicotinamide To a solution of 2,6-dichloro-N-cyclopropylisonicotinamide from the previous step (1 eq.) in methanol (0.2 M) was added sodium methoxide (6 eq.). The reaction vessel was sealed and the resulting solution was heated in the microwave at 105 oC for 30 min. The volatiles were removed in 5 vacuo and the resulting residue was partitioned between sat. aq. NH4Cl and EtOAc. The organic layer was separated and washed further with brine. Drying over Na 2
SO
4 , filtration and concentration of the filtrate in vacuo afforded the title compound as a white solid. Step 3: N-Cyclopropvl-2-methoxy-6-[( 1E)-3-methoxyprop- 1-en-1-yl] isonicotinamide To a solution of 2-chloro-N-cyclopropyl-6-methoxyisonicotinamide from the previous 0 step (1 eq.) in DMF (0.3 M) was added (2-[(I1E)-3-methoxyprop-1-en-1-yl]-4,4,5,5-tetramethyl-1,3,2 dioxaborolane (1 eq.), palladium bromide (5% loading), triphenylphosphine (10% loading) and sodium carbonate (2 M aqueous solution, 3 eq.). The resulting suspension was heated at 100 C for 7 h. The reaction mixture was quenched with water and extracted with ether. The combined organic extracts were washed with sat. aq. NaHCO 3 and brine. Drying over Na 2
SO
4 , filtration and concentration of the filtrate 5 in vacuo afforded the crude product as a brown tar. Purification by way of column chromatography (SiO 2 , 1:1 (v/v) Hex : EtOAc) followed by recrystallization from Hex : ether afforded the title compound as a white solid. Step 4: N-Cyclopropyl-2-methoxy-6-(3-methoxvpropyl)isonicotinamide To a solution of N-cyclopropyl-2-methoxy-6-[(l E)-3-methoxyprop- 1-en- 1 20 yl]isonicotinamide from the previous step (1 eq.) in EtOAc (0.2 M) was added palladium (10% w/w over activated carbon, 15% loading). The reaction vessel was evacuated and back-filled with hydrogen. The reaction suspension was then stirred under a balloon atmosphere of hydrogen for 4 h. The reaction was quenched with CH2Cl 2 , filtered through celite and the insolubles washed further with EtOAc. Concentration of the filtrate in vacuo afforded the title compound as a white solid. 25 Step 5: Amine 41 To a solution of N-cyclopropyl-2-methoxy-6-(3-methoxypropyl)isonicotinamide from the previous step (1 eq.) in THF (0.2 M) was added lithium aluminum hydride (1.0 M THF solution, 5 eq.). The resulting solution was then heated at 70 oC for 1 h. The reaction was quenched carefully with sat. aq. NaHCO 3 . The resulting gel was then diluted with EtOAc and sat. aq. Rochelle's salt and the biphasic 30 mixture was stirred at RT for 3 h. The organic layer was separated, washed with brine, dried over MgSO 4 and filtered. Concentration of the filtrate in vacuo and purification of the crude product thus obtained by way of column chromatography (SiO 2 , 90:9:1 (v/v/v) CH 2 Cl 2 : EtOH : conc. N-H40H) afforded the title compound as a colorless oil. Amine 42 5 N- { [2- { [tert-butyl(dimethyl)silyl] oxy} -6-(3-methoxypropyl)pyridin-4-yl]methyl } cyclopropanamine Step 1: 4-[(Cyclopropylamin)methyl]-6-(3-methoxvpropyl)pyridin-2-ol To a solution of N- { [2-methoxy-6-(3-methoxypropyl)pyridin-4 yl]methyl}cyclopropanamine (1 eq.) in DMF (0.13 M) was added at 0 oC sodium hydride (60% w/w -53- WO 2007/009250 PCT/CA2006/001196 dispersion in mineral oil, 2.5 eq.) and ethanethiol (2.5 eq.). The resulting mixture was stirred at 150 'C for 1.5 h. The reaction was diluted with water and washed with EtOAc. The aqueous layer was then separated, saturated with NH 4 C1 and extracted with EtOAc. Concentration of the combined organic extracts in vacuo afforded the title compound as a white solid. 5 Step 2: Amine 42 To a solution of 4-[(cyclopropylamin)methyl]-6-(3-methoxypropyl)pyridin-2-ol from the previous step (1 eq.) in DMF (0.1 M) was added and tert-butylchlorodimethylsilane (1.1 eq.) and imidazole (1.1 eq.). The resulting reaction mixture was stirred at RT for 18 h. The reaction was quenched with water and extracted with ether. The combined organic extracts were washed with brine, 10 dried over MgSO 4 and filtered. Concentration of the filtrate in vacuo and purification of the crude product thus obtained by way of column chromatography (SiO 2 , 80:15:5 (v/v/v) Hex : EtOAc: triethylamine) afforded the title compound as a colorless oil. Amine 43 N- { [2,6-bis(3 -methoxypropyl)pyridin-4-yl]methyl } cyclopropanamine 5 Step 1: N-Cyclopropyl-2,6-bis[( I E)-3-methoxvprop- 1-en- 1 -vyl]isonicotinamide To a solution of 2
,
6 -dichloro-N-cyclopropylisonicotinamide from Amine 41, Step 1 (1 eq.) in DMF (0.08 M) was added (2-[( 1E)-3-methoxyprop- 1-en-1-yl]-4,4,5,5-tetramethyl-1,3,2 dioxaborolane (2.7 eq.), palladium bromide (5% loading), triphenylphosphine (10% loading) and sodium carbonate (2 M aqueous solution, 5 eq.). The resulting suspension was heated at 100 C for 8 h. The 0 reaction mixture was quenched with water and extracted with ether. The combined organic extracts were washed with sat. aq. NaHCO 3 and brine. Drying over Na 2
SO
4 , filtration and concentration of the filtrate in vacuo afforded the crude product as a red oil. Purification by way of column chromatography (SiO 2 , 1:1 (v/v) Hex: EtOAc) afforded the title compound as a yellow oil. Step 2: N-Cyclopropyl-2.6-bis(3-methoxypropyl)isonicotinamide 5 To a solution of N-cyclopropyl-2,6-bis[(I E)-3-methoxyprop- I1-en- 1-yl] isonicotinamide from the previous step (1 eq.) in EtOAc (0.2 M) was added palladium (10% w/w over activated carbon, 40% loading). The reaction vessel was evacuated and back-filled with hydrogen. The reaction suspension was then stirred under a balloon atmosphere of hydrogen for 24 h. The reaction was quenched with CH 2 Cl 2 , filtered through celite and the insolubles washed further with EtOAc. 0 Concentration of the filtrate in vacuo and purification of the crude product thus obtained by way of column chromatography (SiO 2 , 1:1 (v/v) Hex : EtOAc -4 1:4 (v/v) Hex : EtOAc) afforded the title compound as a colorless oil. Step 3: Amine 43 To a solution of N-cyclopropyl-2,6-bis(3-methoxypropyl)isonicotinamide from the 5 previous step (1 eq.) in THF (0.1 M) was added lithium aluminum hydride (1.0 M TIHF solution, 6 eq.). The resulting solution was then heated at 70 C for 2 h. The reaction was quenched carefully with sat. aq. NaHCO 3 . The resulting gel was then diluted with EtOAc and sat. aq. Rochelle's salt and the biphasic mixture was stirred at RT for 3 h. The organic layer was separated, washed with brine, dried over -54- WO 2007/009250 PCT/CA2006/001196 MgSO 4 and filtered. Concentration of the filtrate in vacuo and purification of the crude product thus obtained by way of column chromatography (SiO 2 , 95:5:1 (v/v/v) CH 2
C
2 : EtOH: conc. NH40H 90:10:1 (v/v/v) CH 2 Cl2 : EtOH : conc. NH 4 OH) afforded the title compound as a pale yellow oil. Amine 44 5 N-({2-(3-methoxypropyl)-6-[(3-(methylthio)propoxy]pyridin-4-yl}methyl)cyclopropanamine Amine 44 was prepared according to the reaction sequence described for Amine 41, but using instead the sodium salt of 3-(methylthio)propan-1-ol as starting material and N-methyl-2 pyrrolidinone as solvent in Step 2. The title compound was isolated as a yellow oil. Amine 45 10 N- { [2-(3-methoxypropyl)-6-(2-(morpholin-4-ylethoxy)pyridin-4-yl]methyl } cyclopropanamine Amine 45 was prepared according to the reaction sequence described for Amine 41, but using instead the sodium salt of 2-morpholine-4-ylethanol as starting material and N-methyl-2 pyrrolidinone as solvent in Step 2. The title compound was isolated as a colorless oil. Amine 46 5 N-(Pyridin-4-ylmethyl)cyclopropanamine Amine 46 was prepared according to the reaction sequence described for Amine 3, but using instead isonicotinaldehyde as the starting material. The title compound was isolated as a yellow oil. Amine 47 !0 N-(Pyridin-3-ylmethyl)cyclopropanamine Amine 47 was prepared according to the reaction sequence described for Amine 3, but using instead nicotinaldehyde as the starting material. The title compound was isolated as a yellow oil. Amine 48 N-(Pyridin-2-ylmethyl)cyclopropanamine 5 Amine 47 was prepared according to the reaction sequence described for Amine 3, but using instead pyridine-2-carbaldehyde as the starting material. The title compound was isolated as a yellow oil. Amine 49 Ethyl (2-bromo-3 [(cyclopropylamino)methyl]phenoxy)acetate 0 Step 1: Ethyl (2-bromo-3-formylphenoxy)acetate To a solution of 2-bromo-3-hydroxybenzaldehyde (1 eq.) in DMF (0.4 M) was added cesium carbonate (1.2 eq.) and ethyl bromoacetate (1 eq.). The resulting suspension was stirred at RT for 16 h. The reaction mixture was quenched with water and extracted with EtOAc. The combined organic extracts were washed with water and brine. Drying over MgSO 4 , filtration and concentration of the 5 filtrate in vacuo afforded the crude product as a red oil. Purification by way of column chromatography (SiO 2 , 5:1 (v/v) Hex : EtOAc -4 1:1 (v/v) Hex : EtOAc) afforded the title compound. Step 2: Amine 49 -55- WO 2007/009250 PCT/CA2006/001196 Amine 47 was prepared according to the reaction procedure described in Amine 3, but using instead ethyl (2-bromo-3-formylphenoxy)acetate from the previous step as the starting material. The title compound was isolated as a pale yellow oil. Amine 50 5 Ethyl 3- { 2-bromo-3-[(cyclopropylamino)methyl]phenoxy} propanoate Step 1: 3-(2-Bromo-3-formvlphenoxy)propanoic acid To a solution of 2-bromo-3-hydroxybenzaldehyde (1 eq.) in THIF (1.2 M) was added sequentially potassium tert-butoxide (1.0 M THF solution, 0.8 eq.) and oxetan-2one at RT. The resulting yellow suspension was stirred at RT for 16 h. The reaction mixture was quenched with 10% aq. HCI and 0 extracted with EtOAc. The combined organic extracts were washed with water and brine. Drying over MgSO 4 , filtration and concentration of the filtrate in vacuo afforded the title compound as a white solid. Step 2: Ethyl 3-(2-Bromo-3-formvlphenoxy)propanoate To a solution of 3-(2-bromo-3-formylphenoxy)propanoic acid from the previous step (1 eq.) in EtOH (0.13 M) was added conc. sulfuric acid (0.8 eq.). The reaction was heated at reflux for 30 5 min. The reaction mixture was quenched with water and extracted with EtOAc. The combined organic extracts were washed with water and sat. aq. NaHCO 3 . Drying over Na 2
SO
4 , filtration and concentration of the filtrate in vacuo afforded the title compound as a yellow oil. Step 3: Amine 50 Amine 50 was prepared according to the reaction procedure described in Amine 3, but ,0 using instead ethyl 3
-(
2 -bromo-3-fonrnylphenoxy)propanoate from the previous step as the starting material. The title compound was isolated as a pale yellow oil. Amine 51 Ethyl 5- { 2-bromo-3-[(cyclopropylamino)methyl]phenoxy)pentanoate Amine 51 was prepared according to the reaction sequence described for Amine 49, but 5 using instead ethyl 5- {2-bromo-3-[(cyclopropylamino)methyl]phenoxy}pentanoate as the starting material. The title compound was isolated as a pale yellow oil. The aldehyde building blocks in Table 2 were synthesized as follows. Table 2 Compound Structure Cl [ ,CHO Aldehyde 1 OCHOO Me Cl CI l CHO Aldehyde 2 FOC -, CHO Aldehyde 3 TBSOC -56- WO 2007/009250 PCT/CA2006/001196 Me CI CHO Aldehyde 4 ' - O Cl C HO Aldehyde 5 TBSO, O., Aldehyde 1 4-[2-(2,6-Dichloro-4-methylphenoxy)ethoxy]benzaldehyde Step 1: 2-(2.6-Dichloro-4-methylphenoxy)ethanol 2,6-Dichloro-4-methylphenol (1 eq.), ethylene carbonate (1 eq.) and imidazole (0.5% 5 loading) were combined and heated at 150 oC for 4 h to afford the title compound as a brown oil. Step 2: Aldehyde 1 2-(2,6-Dichloro-4-methylphenoxy)ethanol from the previous step (1 eq.) and 4 hydroxybenzaldehyde (I eq.) were taken up in freshly deoxygenated 3:1 (v/v) toluene : THF (0.3 M). To this solution was then added 1,1'-(azodicarbonyl)-dipiperidine (1.2 eq.) and finally tributylphosphine 10 (1.2 eq.). The resulting orange solution was heated at 80 C for 4 h. The reaction mixture was cooled to RT, diluted with ether, and washed with 1 N aq. NaOH. The aqueous wash was back extracted with ether and the combined organic extracts were dried over MgSO 4 . Filtration and concentration of the filtrate in vacuo afforded a yellow semi-solid. Purification of the crude product thus obtained by way of flash chromatography (SiO 2 , Hex - 4:1 (v/v) Hex : EtOAc) afforded the title compound as white 5 needles. Aldehyde 2 4-[3-(2-Chloro-3,6-difluorophenoxy)propyl]benzaldehyde Step 1: 3-(4-Bromophenyl)propan-1-ol To a THF solution (0.5 M) of methyl (2E)-3-(4-bromophenyl)acrylate (1 eq.) was added, 20 at 0 oC, lithium aluminum hydride (1.0 M THF solution, 1 eq.) dropwise over a period of for 3 h. The reaction mixture was then warmed slowly to RT over I h. At 0 C, the reaction was carefully quenched with freshly-deoxygenated H20. The organic layer was separated and washed with cold 10% aq. HCI. The aqueous washes were combined and back-extracted with ether. The organic extracts were then washed further with sat. aq. NaHCO 3 and brine, dried over MgSO 4 , filtered and the filtrate concentrated !5 in vacuo to reveal a yellow oil. Purification by way of full vacuum distillation afforded the title compound as a colorless oil. Step 2: 2-[3-(4-Bromophenvl)propoxyl-3-chloro-1,4-difluorobenzene 3-(4-Bromophenyl)propan-1-ol from the previous step (1 eq.) and 2-chloro-3,6 difluorophenol (1 eq.) were taken up in freshly deoxygenated toluene (0.3 M). To this solution was then 0 added 1,1 '-(azodicarbonyl)-dipiperidine (1.2 eq.) and finally tributylphosphine (1.2 eq.). The resulting yellow solution was heated at 80 oC for 2 h. The reaction mixture was cooled to RT, diluted with ether, and washed with 1 N aq. NaOH. The aqueous wash was back extracted with ether and the combined organic extracts were dried over MgSO 4 . Filtration and concentration of the filtrate in vacuo afforded a -57- WO 2007/009250 PCT/CA2006/001196 yellow semi-solid. Purification of the crude product thus obtained by way of flash chromatography (SiO 2 , Hex -- 15:1 (v/v) Hex : EtOAc) afforded the title compound as a colorless oil. Step 3: Aldehyde 2 To a solution of 2-[3-(4-bromophenyl)propoxy]-3-chloro-1,4-difluorobenzene from the 5 previous step (1 eq.) in anhydrous, deoxygenated DMF (0.5 M) was added freshly dried sodium formate (1.5 eq.) and Pd(PPh 3 )Cl2 (2% loading). The resulting yellow suspension was bubbled CO and then heated to 95 C for 6 h. The now black reaction suspension was cooled to RT, diluted with water, and extracted with ether. The combined organic extracts were washed with brine, dried over MgSO 4 and filtered. Concentration of the filtrate in vacuo afforded a yellow oil. Purification of the crude product 0 thus obtained by way of flash chromatography (SiO 2 , Hex - 4:1 (v/v) Hex : EtOAc) afforded the title compound as a colorless oil. Aldehyde 3 4-(3- { [tert-Butyl(dimethyl)silyl]oxy} propyl)benzaldehyde Step 1: [3-(4-Bromophenyl)propoxy] (tert-butyl)dimethylsilane 5 To a solution of 3-(4-bromophenyl)propan-1-ol (1 eq.) in DMF (0.25 M) was added imidazole (1.2 eq.) and tert-butyldimethylsilyl chloride (1.1 eq.). The resulting solution was stirred at RT for 13 h. The reaction mixture was quenched with sat. aq. NH 4 Cl and extracted with hexanes. The combined organic extracts were washed further with water and brine. Concentration of the organic extracts in vacuo afforded the title compound as a colorless oil. 0 Step 2: Aldehyde 3 To a solution of [ 3
-(
4 -bromophenyl)propoxy](tert-butyl)dimethylsilane from the previous step (1 eq.) in anhydrous, deoxygenated DMF (1.2 M) was added freshly dried sodium formate (1.5 eq.) and Pd(PPh 3
)CI
2 (2% loading). The resulting yellow suspension was bubbled CO and then heated to 90 0 C for 8 h. The now black reaction suspension was cooled to RT, diluted with water, and 5 extracted with hexanes. The combined organic extracts were washed with brine, dried over MgSO 4 and filtered. Concentration of the filtrate in vacuo afforded a yellow oil. Purification of the crude product thus obtained by way of flash chromatography (SiO 2 , Hex - 4:1 (v/v) Hex : EtOAc) afforded the title compound as a colorless oil. Aldehyde 4 0 4
-[
2 -(2,6-dichloro-4-methylphenoxy)ethyl]benzaldehyde Step 1: 2-[2-(4-Bromophenyl)ethoxy]-1,3-dichloro-5-methylbenzene 2-(4-Bromophenyl)ethanol (1 eq.) and 2,6-dichloro-4-methylphenol (1.5 eq.) were taken up in freshly deoxygenated toluene (0.1 M). To this solution was then added 1,1 '-(azodicarbonyl) dipiperidine (1.2 eq.) and finally tributylphosphine (1.2 eq.). The resulting yellow solution was heated at 5 80 C for 2 h. The reaction mixture was cooled to RT, diluted with ether, and washed with I N aq. NaOH. The aqueous wash was back extracted with ether and the combined organic extracts were dried over MgSO 4 . Filtration and concentration of the filtrate in vacuo afforded a yellow semi-solid. -58- WO 2007/009250 PCT/CA2006/001196 Purification of the crude product thus obtained by way of flash chromatography (SiO 2 , Hex -- 10:1 (v/v) Hex : EtOAc) afforded the title compound as a colorless oil. Step 2: Aldehyde 4 To a solution of 2-[2-(4-bromophenyl)ethoxy]-1,3-dichloro-5-methylbenzene from the 5 previous step (1 eq.) in THF (0.08 M) was added, at -78 oC, n-butyl lithium (2.5 M hexane solution, 1.1 eq) dropwise over 15 min. The reaction mixture was stirred at - 78 oC for a further 30 min before DMF (2 eq.) was slowly added. The resulting solution was allowed to warm to RT over 3 h and then quenched with H 2 0. The organic layer was separated and the aqueous layer was back extracted with ether. The combined organic extracts were washed with sat. aq. NaHCO 3 and brine, dried over MgSO 4 and filtered. 10 Concentration of the filtrate in vacuo afforded the title compound as a yellow oil. Aldehyde 5 4-(2-{ [tert-Butyl(dimethyl)silyl]oxy}ethoxy)benzaldehyde Step 1: 2-(4-Bromophenoxy)ethanol 4-Bromophenol (1 eq.), ethylene carbonate (1 eq.) and imidazole (0.5% loading) were 15 combined and heated at 150 'C for 2 h to afford the title compound as a brown oil. Step 2: 2-[(4-Bromophenoxy)ethoxy](tert-butyl)dimethylsilane To a solution of 2-[(4-bromophenoxy)ethanol (1 eq.) in DMF (0.5 M) was added imidazole (1.2 eq.) and tert-butyldimethylsilyl chloride (1.1 eq.). The resulting solution was stirred at RT for 13 h. The reaction mixture was quenched with sat. aq. NH4CI and extracted with hexanes. The 20 combined organic extracts were washed further with water and brine. Concentration of the organic extracts in vacuo afforded the title compound as a yellow oil. Step 3: Aldehyde 5 To a solution of 2-(4-bromophenoxy)ethoxy](tert-butyl)dimethylsilane from the previous step (1 eq.) in THF (0.2 M) was added, at -78 oC, n-butyl lithium (2.5 M hexane solution, 1.1 eq) 25 dropwise over 15 min. The reaction mixture was stirred at - 78 oC for a further 30 min before DMF (2 eq.) was slowly added. The resulting solution was allowed to warm to RT over 3 h and then quenched with H 2 0. The organic layer was separated and the aqueous layer was back-extracted with ether. The combined organic extracts were washed with sat. aq. NaHCO 3 and brine, dried over MgSO 4 and filtered. Concentration of the filtrate in vacuo afforded the title compound as a yellow oil. 30 Compounds of the present invention were prepared according to the following methods. Example 1 3-Amino-N-cyclopropyl-2-{ 4
-[
2 -(2,6-dichloro-4-methylphenoxy)ethoxy]benzy l}-N-(2,3 dimethylbenzyl)propanamide Me Cl Me Me CIS ClO Meb O N N
NH
2 -59- WO 2007/009250 PCT/CA2006/001196 Step 1: 2-Cvano-N-cyclopropyl-N-(2.3-dimethylbenzvl)acetamide To a DMF solution (0.6 M) of cyanoacetic acid (1 eq.), Hunig's base (3 eq.) and Amine 1 (1 eq.) was added portionwise O-(7-azabenzotriazol- I -yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.2 eq.). The resulting reaction solution was stirred at RT for 16 h. The now 5 reddish solution was diluted with ether and washed with H 2 0 and 10% aq. HC1. The aqueous washes were back extracted with ether. The combined organic extracts were washed with brine, dried over MgSO 4 , filtered and the filtrate concentrated in vacuo to afford a yellow semi-solid. Purification of the crude product thus obtained by way of flash chromatography (SiO 2 , 10:1 -- 1:1 (v/v) Hex : EtOAc) afforded the title compound as off-white crystalline plates. 10 Step 2: (2E)-2-Cvano-N-cyclopropyl-3- {4-[2-(2.6-dichloro-4-methylphenoxy)ethoxvy] phenyll-N-(2,3 dimethylbenzvl)acrylamide 2-Cyano-N-cyclopropyl-N-(2,3-dimethylbenzyl)acetamide from the previous step (1 eq.) and Aldehyde 1 (1 eq.) were combined in benzene (0.04 M). To this solution was then added a few drops of piperidine and a Dean-Stark apparatus was attached to the reaction vessel. The resulting pale 5 yellow solution was heated at reflux for 48 h. The volatiles were removed in vacuo and the crude product thus obtained was purified by way of column chromatography (SiO2, 10:1 -- ) 1:1 (v/v) Hex: EtOAc). The title compound was isolated as a white foam. Step 3: tert-Butvl (3-[cyclopropvl(2,3-dimethylbenzyl)amino]-2-14-[2-(2,6-dichloro-4 methylphenoxy)ethoxy]benzyl} 1-3-oxopropyl)carbamate 20 (2E)-2-Cyano-N-cyclopropyl-3-
{
4
-[
2
-(
2 ,6-dichloro-4-methylphenoxy)ethoxy] phenyl } N-(2,3-dimethylbenzyl)acrylamide from the previous step (1 eq.) and cobalt(II) chloride hexahydrate (2 eq.) were combined in a 8:1 (v/v) MeOH : THF solution (0.02 M). To this mixture was then added sodium borohydride (10 eq.) slowly and portionwise. The resulting black suspension was stirred at RT for 8 h. The reaction mixture was then diluted with 95:5 (v/v) CH 2
CI
2 : MeOH and quenched with 1 N 5 aq. NaOH. The resulting emulsion was then filtered through a bed of celite and the insolubles were rinsed with 95:5 (v/v) CH 2 C1 2 : MeOH. The organic layer was separated and washed further with 1 N aq. NaOH, H 2 0 and brine. Drying over MgSO 4 , filtration and concentration of the filtrate in vacuo afforded the crude amine as a golden oil. This residue was then taken up in CH 2 C1 2 (0.06 M) and added di-tert butyl dicarbonate (1 eq.). Finally, sodium hydroxide (1.0 N aqueous solution, 3 eq.) was added and the 0 resulting biphasic mixture was vigorously stirred for 4 h. Following careful acidification with 10% aq. HCI to a pH of -2, the aqueous layer was separated and back extracted with ether. The combined organic extracts were then washed H, 2 0 and brine, dried over MgSO 4 and filtered. Concentration of the filtrate in vacuo afforded a yellow oil. Purification of the crude product thus obtained by way of column chromatography (SiO2, Hex - 1:1 (v/v) Hex : EtOAc) afforded the title compound as a white froth. 5 Step 4: 3-Amino-N-cyclopropvl-2-{4-[ 2
-(
2 ,6-dichloro-4-methylphenoxy)ethoxy] benzyl}-N-(2,3 dimethylbenzyl)propanamide To a CH 2
CI
2 solution (0.05 M) of tert-butyl(3-[cyclopropyl(2,3-dimethylbenzyl)amino] 2- { 4
-[
2
-(
2
,
6 -dichloro-4-methylphenoxy)ethoxy]benzyl}-3-oxopropyl)carbamate from the previous step (1 -60- WO 2007/009250 PCT/CA2006/001196 eq.) was added HCI (4.0 M dioxane solution, 30 eq.). The resulting solution was stirred at RT for 3 h. Following the removal of the volatiles in vacuo, the resulting residue was directly loaded onto a Si02 column packed with 97:3 (v/v) CH 2 CI: 2.0 M NH 3 in MeOH. Elution with the same solvent system furnished the title compound as a white froth. MS (ESI+): 555.0. 5 Example 2 3-Amino-N-cyclopropyl- } -N-(2,3-dichlorobenzyl)-2- { 4-[2-(2,6-dichloro-4 methylphenoxy)ethoxy]benzyl } propanamide Me Cl a0 CI CICI O ON
I
NH
2 Prepared according to the procedure described in Example 1 but using instead Amine 2 10 as starting material. The title compound was obtained as a white froth. MS (ESI+): 595.0. Example 3 3-Amino-N-cyclopropyl-2- { 4
-[
2 -(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl}-N-( 1,2,3,4 tetrahydroquinolin-8-ylmethyl)propanamide Me Cl Cl HN
NH
2 5 Prepared according to the procedure described in Example 1 but using instead Amine 4 as starting material. The title compound was obtained as a white froth. MS (ESI+): 582.2. Example 4 3-Amino-N-cyclopropyl-2-{4-[ 2
-(
2
,
6 -dichloro-4-methylphenoxy)ethoxy]benzy }-N-[3-(3 methoxypropyl)benzyl]propanamide Me Cl C1 0 N ' OMe 0 NH 2 Prepared according to the procedure described in Example 1 but using instead Amine 5 as starting material. The title compound was obtained as a colorless oil. MS (ESI+): 599.5. Example 5 3-Amino-2- { 4-[3-(2-chloro-3,6-difluorophenoxy)propyl]benzyl }-N-cyclopropyl-N-[3-(3 5 methoxypropyl)benzyl]propanamide -61- WO 2007/009250 PCT/CA2006/001196 F F O Cl O N 1 OMe
NH
2 Prepared according to the procedure described in Example 1 but using instead Amine 5 and Aldehyde 2 as starting materials. The title compound was obtained as a colorless oil. MS (ESI+): 584.9. 5 Example 6 3-Amino-N-[2-chloro-5-(3-methoxypropyl)benzyl]-N-cyclopropyl-2- {4-[2-(2,6-dichloro-4 methylphenoxy)ethoxy]benzyl} propanamide Me Cl LY(0~ CI ClC I cIS N. ON"V OMe
NH
2 Prepared according to the procedure described in Example 1 but using instead Amine 6 10 as starting material. The title compound was obtained as a colorless oil. MS (ESI+): 633.0. Example 7 3-Amino-2- {4-[3-(2-chloro-3,6-difluorophenoxy)propyl]benzyl }-N-[2-chloro-5-(3 methoxypropyl)benzyl]-N-cyclopropylpropanamide -- F F O CI. CI ON c OMe
NH
2 5 Prepared according to the procedure described in Example 1 but using instead Amine 6 and Aldehyde 2 as starting materials. The title compound was obtained as a colorless oil. MS (ESI+): 618.9. Example 8 3-Amino-N-cyclopropyl-2- { 4
-[
2
-(
2 ,6-dichloro-4-methylphenoxy)ethoxy]benzyl} -N- {3-[2 0 (methylsulfonyl)ethyl]benzyl} propanamide -62- WO 2007/009250 PCT/CA2006/001196 Me ~ CI
CI
4 ~. " O O N SO 2 Me
NH
2 Prepared according to the procedure described in Example 1 but using instead Amine 8 as starting material. The title compound was obtained as a colorless oil. MS (ESI+): 633.1. Example 9 5 3-Amino-N-cyclopropyl-2- {4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl } -N-(quinolin-4 ylmethyl)propanamide Me Cl Cl O N
NH
2 Step 1: Methyl (2E)-2-cyano-3- {4-[2-(2,6-dichloro-4-methylphenoxy)ethoxylphenyl}acrvlate Methyl cyanoacetate (1 eq.) and Aldehyde 1 (1 eq.) were combined in toluene (0.16 M). 0 To this solution was then added a few drops of piperidine and a Dean-Stark apparatus was attached to the reaction vessel. The resulting pale yellow solution was heated at reflux for 3 h. The volatiles were removed in vacuo to afford the title compound was isolated as an off-white powder. Step 2: Methyl 3-[(tert-butoxycarbonyl)amino]-2- {4-[2-(2,6-dichloro-4 methylphenoxy)ethoxy]benzyl}propanoate 5 Methyl (2E)-2-cyano-3- { 4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl } acrylate from the previous step (1 eq.) and cobalt(II) chloride hexahydrate (2 eq.) were combined in a 5:3 (v/v) THF : MeOH solution (0.016 M). To this mixture was then added sodium borohydride (10 eq.) slowly and portionwise. The resulting black suspension was stirred at RT for 2 h. The reaction mixture was then carefully quenched with 10% aq. HCI and extracted with ether. The combined organic extracts were 0 washed further with H 2 0 and brine. Drying over MgSO 4 , filtration and concentration of the filtrate in vacuo afforded the crude amine as a golden oil. This residue was combined with di-tert-butyl dicarbonate (1 eq.), Hunig's base (1.5 eq.) and a few crystals of 4-(dimethylamino)pyridine in CH 2 Cl 2 (0.06 M). The resulting yellow solution was stirred at RT for 8 h. The volatiles were then removed in vacuo to afford an orange residue which was partitioned between ether and 10% aq. HC1. The organic 5 layer was separated and the aqueous layer was back extracted with ether. The combined organic extracts were then washed H 2 0 and brine, dried over MgSO 4 and filtered. Concentration of the filtrate in vacuo afforded a yellow oil. Purification of the crude product thus obtained by way of column chromatography (SiO 2 , Hex -- ) 1:1 (v/v) Hex: EtOAc) afforded the title compound as a pale yellow oil. -63- WO 2007/009250 PCT/CA2006/001196 Step 3: 3-[tert-Butoxycarbonvyl)amino]-2- {4-[2-(2.6-dichloro-4-methylphenoxy) ethoxv]benzyl } propanoic acid Methyl 3-[(tert-butoxycarbonyl)amino]-2- {4-[2-(2,6-dichloro-4 methylphenoxy)ethoxy]benzyl}propanoate from the previous step (1 eq.) was dissolved in a 2:1 (v/v) 5 THF: MeOH solution (0.056 M). To this was then added sodium hydroxide (1.0 M aqueous solution, 3 eq.) and the resulting solution was stirred at RT for 18 h. The volatiles were then removed in vacuo. Following careful acidification of the resulting mixture to pH - 1 with 10% aq. HCI, the solution was extracted with ether and EtOAc. The combined organic extracts were washed further with HO 2 0 and brine, dried over MgSO 4 and filtered. Concentration of the filtrate in vacuo afforded a yellow oil. 10 Purification of the crude product thus obtained by way of column chromatography (SiO 2 , 66:33:1 (v/v/v) Hex: EtOAc: AcOH) afforded the title compound as a white froth. Step 4: tert-Butyl (3-[cyclopropvl(quinolin-4-ylmethyl)amino]-2- {4-[2-(2,6-dichloro-4 methylphenoxv)ethoxy]benzvl}-3-oxopropyl)carbamate 3-[tert-Butoxycarbonyl)amino]-2- {4-[2-(2,6-dichloro-4-methylphenoxy) 15 ethoxy]benzyl}propanoic acid from the previous step (1 eq.) was combined with Hunig's base (3 eq.) and Amine 3 (1 eq.) in anhydrous DMF (0.6 M). To this was then added portionwise O-(7-azabenzotriazol 1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.2 eq.). The resulting yellow solution was stirred at RT for 18 h. The now reddish solution was diluted with ether and washed with HO 2 0. The aqueous washes were back extracted with ether. The combined organic extracts were washed with brine, 20 dried over MgSO 4 , filtered and the filtrate concentrated in vacuo to afford a yellow semi-solid. Purification of the crude product thus obtained by way of flash chromatography (SiO 2 , 10:1 (v/v) Hex: EtOAc -4 EtOAc) afforded the title compound as a white froth. Step 5: 3-Amino-N-cyclopropyl-2-14-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]benzyvli -N-(quinolin-4 vlmethyl)propanamide 5 To a CH2Cl 2 solution (0.05 M) of tert-butyl ( 3 -[cyclopropyl(quinolin-4-ylmethyl)amino] 2- { 4 -[2-(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl}-3-oxopropyl)carbamate from the previous step (1 eq.) was added HCI (4.0 M dioxane solution, 30 eq.). The resulting solution was stirred at RT for 3 h. Following the removal of the volatiles in vacuo, the resulting residue was directly loaded onto a SiO 2 column packed with 95:5 (v/v) CH 2 Cl 2 : 2.0 M NH 3 in MeOH. Elution with the same solvent system 0 furnished the title compound as a white froth. MS (ESI+): 578.0. Example 10 3-Amino-N-cyclopropyl-2- { 4
-[
2
-(
2
,
6 -dichloro-4-methylphenoxy)ethoxy]benzyl}-N-(quinolin-8 ylmethyl)propanamide Me Cl ON CI O ~N
NH
2 -64- WO 2007/009250 PCT/CA2006/001196 Prepared according to the procedure described in Example 9 but using instead Amine 4 as starting material. The title compound was obtained as a white froth. MS (ESI+): 578.1. Example 11 3-Amino-N-[2-chloro-5-(2-methoxyethyl)benzyl]-N-cyclopropyl-2- {4-[2-(2,6-dichloro-4 5 methylphenoxy)ethoxy]benzyl} propanamide Me C1 Cl O C OO
N
V OMe
NH
2 Prepared according to the procedure described in Example 9 but using instead Amine 6 as starting material. The title compound was obtained as a colorless oil. MS (ESI+): 619.3. Example 12 0 N-(3- { [Acetyl(methyl)amino]methyl} benzyl)-3-amino-N-cyclopropyl-2- {4-[2-(2,6-dichloro-4 methylphenoxy)ethoxy]benzyl } propanamide Me Cl O-N Me 0 ,[ 0 O NV Me
NH
2 Prepared according to the procedure described in Example 9 but using instead Amine 9 as starting material. The title compound was obtained as a white froth. MS (ESI+): 612.2. 5 Example 13 N-(5- { [Acetyl(methyl)amino]methyl } -2-chlorobenzyl)-3-amino-N-cyclopropyl-2- { 4-[2-(2,6-dichloro-4 methylphenoxy)ethoxy]benzyl}propanamide Me Cl C( Me CI OC OO N Me
NH
2 Prepared according to the procedure described in Example 9 but using instead Amine 10 0 as starting material. The title compound was obtained as a white froth. MS (ESI+): 646.1. Example 14 3-Amino-N-cyclopropyl-N-(2,3-dichlorobenzyl)-2- {4-[3-(2,6-dichloro-4 methylphenoxy)propyl]benzyl } propanamide -65- WO 2007/009250 PCT/CA2006/001196 Me. C CC cCl O N
N
0 NV
NH
2 Step 1: [4-(3- { [tert-Butyl(dimethyl)silvlloxy} propvl)phenvllmethanol At 0 0 C, sodium borohydride (1.5 eq.) was added portionwise to a MeOH solution (0.2 M) of Aldehyde 3 (1 eq.). The resulting mixture was stirred at 0 oC for 15 min and then at RT for 30 5 min. Following the removal of the volatiles in vacuo, the resulting residue was partitioned between ether and 1 N aq. NaOH. The aqueous layer was separated and back extracted with ether. The combined organic extracts were washed with HO 2 0 and brine, dried over MgSO 4 and filtered. Concentration of the filtrate in vacuo afforded the title compound as a colorless oil. Step 2: tert-Butvil{3-[4-(iodomethyl)phenvl]propoxy}dimethylsilane 10 At 0 'C, iodine (1.2 eq.) and imidazole (1.2 eq.) were added to a CH 2 Cl2 solution (0.12 M) of triphenylphosphine (1.2 eq.). The resulting yellow-orange suspension was stirred at 0 0 C for 10 min and then at RT for 30 min. Finally, 4
-(
3 -{[tert-butyl(dimethyl)silyl]oxy}propyl)phenyl]methanol from the previous step (1 eq.) was added. After another 5 h of stirring at RT, the volatiles were removed in vacuo. The resulting brown residue was partitioned between ether and H20. The aqueous layer was 5 separated and back-extracted with ether. The combined organic extracts were washed with I M aq. Na 2
S
2 03 and brine, dried over MgSO 4 and filtered. The filtrate was added hexanes and passed through a plug of SiO 2 . Removal of the volatiles in vacuo afforded the title compound as a pale pink oil. Step 3: 3-[4-(3- { [tert-Butvl(dimethyl)silvl]oxy}propyl )phenvl]-2-cvano-N-cvclopropyl-N-(2,3 dichlorobenzvl)propanamide 20 2 -Cyano-N-cyclopropyl-N-(2,3-dichlorobenzyl)acetamide (1 eq.), prepared from Amine 2 and cyanoacetic acid as detailed in Step 1 of Example 1, was dissolved in THF (0.1 M). At -78 0 C, potassium bis(trimethylsilyl)amide (15% w/w toluene solution, 1 eq.) was then added and the resulting yellow suspension was stirred at -78 'C for 15 min and at -40 oC for 15 min. tert-Butyl {3-[4 (iodomethyl)phenyl]propoxy}dimethylsilane from the previous step (1 eq.) was then added, at -78 'C, as 5 a 0.33 M THF solution over a period of 10 min. The resulting pale yellow mixture was allowed to warm slowly to RT over 5 h. The reaction was quenched with sat. aq. NH 4 CI and extracted with ether. The combined organic extracts were washed with HO0 and brine, dried over MgSO 4 and filtered. Concentration of the filtrate in vacuo afforded a viscous yellow oil. Purification of the crude product thus obtained by way of column chromatography (SiO 2 , 10:1 (v/v) Hex: EtOAc -- ) EtOAc) afforded the 0 title compound as a colorless oil. Step 4: 2-Cyano-N-cyclopropyl-N-(2,3-dichlorobenzyl)-3-[4-(3-hydroxypropyl) phenylipropanamide To a solution of 3-[4-(3- { [tert-butyl(dimethyl)silyl]oxy} propyl)phenyl]-2-cyano-N cyclopropyl-N-(2,3-dichlorobenzyl)propanamide from the previous step (1 eq.) in THF (0.1 M) was added tetrabutylammonium fluoride (1.0 M THF solution, 1.5 eq.). The resulting reaction mixture was -66- WO 2007/009250 PCT/CA2006/001196 stirred at RT for 3 h. After quenching the reaction with 10% aq. HCI, the mixture was extracted with ether. The combined organic extracts were washed with sat. aq. NaHCO 3 and brine, dried over MgSO 4 and filtered. Concentration of the filtrate in vacuo afforded a pale yellow oil. Purification of the crude product thus obtained by way of flash chromatography (SiO 2 , 10:1 (v/v) Hex: EtOAc -- EtOAc) 5 afforded the title compound as a colorless oil. Step 5: 2-Cvano-N-cyclopropvl-N-(2.3-dichlorobenzyl)-3- {4- [(3-(2.6-dichloro-4 methylphenoxy)propyl]phenyl}propanamide 2-Cyano-N-cyclopropyl-N-(2,3-dichlorobenzyl)-3-[4-(3 hydroxypropyl)phenyl]propanamide from the previous step (1 eq.) and 2,6-dichloro-4-methylphenol (2 10 eq.) were taken up in freshly-deoxygenated toluene (0.1 M). To this solution was then added 1,1' (azodicarbonyl)-dipiperidine (2 eq.) and finally tributylphosphine (2 eq.). The resulting yellow solution was heated at 80 C for 2 h. The reaction mixture was cooled to RT, diluted with ether, and washed with 1 N aq. NaOH. The aqueous wash was back extracted with ether and the combined organic extracts were dried over MgSO 4 . Filtration and concentration of the filtrate in vacuo afforded a yellow semi-solid. 5 Purification of the crude product thus obtained by way of flash chromatography (SiO 2 , 10:1 (v/v) Hex: EtOAc 4-) EtOAc) afforded the title compound as a colorless oil. Step 6: 3-Amino-N-cyclopropvl-N-(2.3-dichlorobenzyl)-2-(4-[3-(2,6-dichloro-4 methylphenoxy)propyllbenzyl } propanamide 2-Cyano-N-cyclopropyl-N-(2,3-dichlorobenzyl)-3-
{
4 -[(3-(2,6-dichloro-4-methylphenoxy) .0 propyl]phenyl}propanamide from the previous step (1 eq.) and palladium (10% w/w over carbon, 50% loading) were suspended in freshly deoxygenated MeOH (0.03 M). Then, HCI (4.0 M dioxane solution, 20 eq) was added and the resulting suspension was stirred under a static atmosphere of H 2 for 16 h. The reaction mixture was basified with ammonia (2.0 M MeOH solution), diluted with CH 2 Cl 2 and filtered through a bed of celite. The insolubles were washed further with EtOAc. The combined filtrates were 5 concentrated in vacuo and the crude product thus obtained was purified by way of flash chromatography (SiO 2 , 97:3 -- 95:5 (v/v) CH 2
C
2 : 2.0 M NH 3 in MeOH) to furnish the title compound as a colorless oil. MS (ESI+): 593.0. Example 15 3-Amino-2- {4-[3-(2-chloro-3,6-difluorophenoxy)propyl]benzyl}-N-cyclopropyl-N-(2,3 0 dichlorobenzyl)propanamide F Cl Cl CO C O N N 0
NH
2 -67- WO 2007/009250 PCT/CA2006/001196 Prepared according to the procedure described in Example 14 but using 2-chloro-3,6 difluorphenol instead of 2,6-dichloro-4-methylphenol in Step 5. The title compound was obtained as a colorless oil. MS (ESI+): 580.9. Example 16 5 3-Amino-2- {4-[3-(2-chloro-3,6-difluorophenoxy)propyl]benzyl }-N-cyclopropyl-N-(2,3-dichlorobenzyl) 2-methylpropanamide F CI CI N M
NH
2 Step 1: 3-[4-(3- { [tert-Butyl(dimethyl)silvl]oxy}propyl)phenvl]-2-cvano-N-cyclopropyl-N-(2,3 dichlorobenzvl)-2-methylpropanamide 10 To a solution of 3-[4-(3-{ [tert-butyl(dimethyl)silyl]oxy}propyl)phenyl]-2-cyano-N cyclopropyl-N-(2,3-dichlorobenzyl)propanamide (prepared as detailed in Example 14, 1 eq.) in THF (0.1 M) was added, at -78 oC, potassium bis(trimethylsilyl)amide (15% w/w toluene solution, 1 eq.). The resulting yellow suspension was stirred at -78 oC for 15 min and at -40 oC for 15 min. Iodomethane (1 eq.) was then added and the reaction mixture was slowly warmed to RT over 14 h. The reaction was 5 quenched with sat. aq. NH4Cl and extracted with ether. The combined organic extracts were washed with H 2 0 and brine, dried over MgSO 4 and filtered. Concentration of the filtrate in vacuo afforded a pale yellow oil. Purification of the crude product thus obtained by way of column chromatography (SiO 2 , 10:1 4 1:1 (v/v) Hex : EtOAc) afforded the title compound as a colorless oil. Step 2: 2-Cyano-N-cyclopropyl-N-(2,3-dichlorobenzyl)-3-[4-(3-hydroxypropyl)phenyl]-2 !0 methylpropanamide To a solution of 3-[4-(3- { [tert-butyl(dimethyl)silyl]oxy} propyl)phenyl]-2-cyano-N cyclopropyl-N-(2,3-dichlorobenzyl)-2-methylpropanamide from the previous step (1 eq.) in THF (0.2 M) was added tetrabutylammonium fluoride (1.0 M THF solution, 8 eq.). The resulting reaction mixture was stirred at RT for 4 h. After quenching the reaction with 10% aq. HCI, the mixture was extracted with 5 ether. The combined organic extracts were washed with sat. aq. NaHCO 3 and brine, dried over MgSO 4 and filtered. Concentration of the filtrate in vacuo afforded a pale yellow oil. Purification of the crude product thus obtained by way of flash chromatography (SiO 2 , 10:1 (v/v) Hex : EtOAc - EtOAc) afforded the title compound as a colorless oil. Step 3: 3- {4-[3-(2-Chloro-3,6-difluorophenoxy)propyllphenyl }-2-cyano-N-cyclopropyl-N-(2,3 0 dichlorobenzvl)-2-methylpropanamide 2-Cyano-N-cyclopropyl-N-(2,3-dichlorobenzyl)-3-[4-(3-hydroxypropyl) phenyl]-2 methylpropanamide from the previous step (1 eq.) and 2-chloro-3,6-difluorphenol (4 eq.) were taken up in freshly deoxygenated toluene (0.05 M). To this solution was then added 1,1 '-(azodicarbonyl) -68- WO 2007/009250 PCT/CA2006/001196 dipiperidine (4 eq.) and finally tributylphosphine (4 eq.). The resulting yellow solution was heated at 80 C for 3 h. The reaction mixture was cooled to RT, diluted with ether, and washed with 1 N aq. NaOH. The aqueous wash was back extracted with ether and the combined organic extracts were dried over MgSO 4 . Filtration and concentration of the filtrate in vacuo afforded a yellow semi-solid. Purification of 5 the crude product thus obtained by way of flash chromatography (SiO 2 , Hex - 3:2 (v/v) Hex : EtOAc) afforded the title compound as a colorless oil. Step 4: 3-Amino-2- {4-[3-(2-chloro-3,6-difluorophenoxy)propyl]benzyl}-N-cyclopropyl-N-(2,3 dichlorobenzvl)-2-methylpropanamide 3- {4-[3-(2-Chloro-3,6-difluorophenoxy)propyl]phenyl}-2-cyano-N-cyclopropyl-N-(2,3 0 dichlorobenzyl)-2-methylpropanamide from the previous step (1 eq.) and cobalt(II) chloride hexahydrate (2 eq.) were combined in MeOH (0.1 M). To this mixture was then added sodium borohydride (10 eq.) slowly and portionwise. The resulting black suspension was stirred at RT for 1 h. The volatiles were then removed in vacuo. The resulting black tar was partitioned between EtOAc and 1 N aq. NaOH. The aqueous layer was separated and back-extracted with EtOAc. The combined organic extracts were 5 washed further with H 2 0 and brine, dried over MgSO 4 and filtered. Concentration of the filtrate in vacuo revealed a brown oil. Purification of the crude product thus obtained by way of column chromatography (SiO 2 , CH 2 Cl 2 -4 95:5 (v/v) CH2Cl2 : 2.0 M NH 3 in MeOH) afforded the title compound as a colorless oil. MS (ESI+): 595.0. Example 17 !0 Ethyl 2- { [(3-[cyclopropyl(2,3-dichlorobenzyl)amino]-2- {4-[2-[2-(2,6-dichloro-4 methylphenoxy)ethoxy]benzyl }-3-oxopropyl)amino]methyl } cyclopropanecarboxylate Me I Cl NX CI CCl O NN HNv,,<CO 2 Et A mixture of 3-amino-N-cyclopropyl- N-(2,3-dichlorobenzyl)-2- {4-[2-(2,6-dichloro-4 methylphenoxy)ethoxy]benzyl } propanamide (Example 2, 1 eq.), trans-ethyl 2-formyl- 1 5 cyclopropanecarboxylate (1 eq.) and sodium cyanoborohydride (1.5 eq.) were combined in MeOH (0.02 M). At 0 oC, acetic acid (3 eq.) was added dropwise and the reaction mixture was slowly warmed to RT over 2 h. The reaction mixture was then diluted with ether and quenched with 1 N aq. NaOH. The aqueous layer was separated and back extracted with ether. The combined organic extracts were then washed with water and brine, dried over MgSO 4 and filtered. Concentration of the filtrate in vacuo 0 afforded a purple residue. Purification of the crude product thus obtained by way of flash chromatography (SiO 2 , 96:4 (v/v) CH 2 CI2 : MeOH) afforded the title compound as a colorless oil. MS (ESI+): 721.1. -69- WO 2007/009250 PCT/CA2006/001196 Example 18 3-(Benzylamino)-2- {4-[3-(2-chloro-3,6-difluorophenoxy)propyl]benzyl}-N-cyclopropyl-N-(2,3 dichlorobenzyl)propanamide F ON - CI CI HN 5 Prepared according to the procedure described in Example 17 but using instead 3-amino 2- {4-[3-(2-chloro-3,6-difluorophenoxy)propyl]benzyl }-N-cyclopropyl-N-(2,3 dichlorobenzyl)propanamide (Example 15) and benzaldehyde. The title compound was obtained as a colorless oil. MS (ESI+): 670.8. Example 19 0 Methyl 5-[(3-[cyclopropyl(2,3-dichlorobenzyl)amino]-2- {4-[2-(2,6-dichloro-4 methylphenoxy)ethoxy]benzyl }-3-oxopropyl)amino]pentanoate Me Cl CCl 0 N HN _ CO2M In a vessel equipped with a Dean-Stark apparatus, a benzene solution (0.01 M) of 3 amino-N-cyclopropyl- N-(2,3-dichlorobenzyl)-2- {4-[2-(2,6-dichloro-4 5 methylphenoxy)ethoxy]benzyl}propanamide (Example 2, 1 eq.) and methyl 5-oxopentanoate was heated at reflux for 8 h. The now yellow solution was cooled to RT and then concentrated in vacuo. The resulting residue was taken up in a 7:2 (v/v) MeOH : THF solution (0.01 M) and then added sodium borohydride (10 eq.) portionwise. After stirring at RT for 24 h, the mixture was diluted with ether and quenched with 1 N aq. NaOH. The aqueous phase was separated and back extracted with ether. The 0 combined organic extracts were then washed with water and brine, dried over MgSO 4 and filtered. Concentration of the filtrate in vacuo afforded a yellow oil. Purification of the crude product thus obtained by way of flash chromatography (SiO 2 , 97:3 (v/v) CH 2 C2 : 2.0 M NH 3 in MeOH) afforded the title compound as a colorless oil. MS (ESI+): 709.0. Example 20 5 Methyl 6
-[(
3 -[cyclopropyl(2,3-dichlorobenzyl)amino]-2- {4-[2-(2,6-dichloro-4 methylphenoxy)ethoxy]benzyl}-3-oxopropyl)amino]hexanoate -70- WO 2007/009250 PCT/CA2006/001196 Me Cl C1 CCI 0 ~0 N O' HN , CO 2 Me Prepared according to the procedure described in Example 19 but using instead methyl 6-oxohexanoate. The title compound was obtained as a colorless oil. MS (ESI+): 723.2. Example 21 5 N-Cyclopropyl-N-(2,3-dichlorobenzyl)-2- {4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl } -3-[(2,2,2 trifluoroethyl)amino]propanamide Me Cl CCl CI O. CI OcN
HNCF
3 Prepared according to the procedure described in Example 19 but using instead 2,2,2 trifluoro-1-methoxyethanol. The title compound was obtained as a colorless oil. MS (ESI+): 677.0. 0 Example 22 2- {4-[3-(2-Chloro-3 ,6-difluorophenoxy)propyl]benzyl} -N-cyclopropyl-N-(2.3-dichlorobenzyi)-3 (methylamino)propanamide F Cl Cl 0 CI 0 N NHMe Prepared according to the procedure described in Example 19 but using instead 3-amino 5 2- {4-[3-(2-chloro-3,6-difluorophenoxy)propyl]benzyl} -N-cyclopropyl-N-(2,3 dichlorobenzyl)propanamide (Example 15) and paraformaldehyde. The title compound was obtained as a colorless oil. MS (ESI+): 595.3. Example 23 6-[(3-[Cyclopropyl(2,3-dichlorobenzyl)amino]-2- {4-[ 2
-(
2
,
6 -dichloro-4-methylphenoxy)ethoxy]benzyl
}
0 3-oxopropyl)amino]hexanoic acid -71- WO 2007/009250 PCT/CA2006/001196 Me CI CCl 0 0 HN ~CO 2 H Methyl 6 -[(3-[cyclopropyl(2,3-dichlorobenzyl)amino]-2- {4-[2-(2,6-dichloro-4 methylphenoxy)ethoxy]benzyl}-3-oxopropyl)amino]hexanoate (Example 20, 1 eq.) was dissolved in a 2:1 (v/v) THF : MeOH solution (0.01 M). To this was then added sodium hydroxide (1.0 M aqueous 5 solution, 3 eq.) and the resulting solution was stirred at RT for 18 h. The volatiles were then removed in vacuo. Following careful acidification of the resulting residue to a pH of- 4 with 10% aq. HC1, the mixture was saturated with sodium chloride and extracted with EtOAc. The combined organic extracts were concentrated in vacuo. The resulting solid residue was then azeotroped with toluene to give the title compound as a white solid. MS (ESI+): 709.1. 10 Example 24 2- { [(3-[cyclopropyl(2,3-dichlorobenzyl)amino]-2- {4-[2-[2-(2,6-dichloro-4 methylphenoxy)ethoxy]benzyl } -3-oxopropyl)amino]methyl } cyclopropanecarboxylic acid Me CI Cl 0 ~N HN - CO 2 H To an ethanol solution (0.04 M) of ethyl 2
-{[(
3 -[cyclopropyl(2,3-dichlorobenzyl)amino] 5 2- { 4
-[
2
-[
2 -(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl }-3 oxopropyl)amino]methyl}cyclopropanecarboxylate (Example 17, 1 eq.) was added sodium hydroxide (1.0 M aqueous solution, 4 eq.). The resulting solution was then heated at 80 C for 18 h. The volatiles were then removed in vacuo. Following careful acidification of the resulting residue to a pH of- 4 with 10% aq. HCI, the mixture was saturated with sodium chloride and extracted with EtOAc. The combined 0 organic extracts were dried over activated Na 2
SO
4 and filtered. Concentration of the filtrate in vacuo afforded the title compound as a white solid. MS (ESI+): 693.1. Example 25 3-Amino-N-cyclopropyl-N-(2,3-dichlorobenzyl)-2- {4-[2-(2,6-dichloro-4 methylphenoxy)ethyl]benzyl } propanamide -72- WO 2007/009250 PCT/CA2006/001196 Me O c 0
.
0 N'
NH
2 Step 1: {4-[2-(2,6-Dichloro-4-methylphenoxv)ethyl]phenvl} I methanol At 0 C, sodium borohydride (1.5 eq.) was added portionwise to a MeOH solution (0.2 M) of Aldehyde 4 (1 eq.). The resulting mixture was stirred at 0 oC for 15 min and then at RT for 30 5 min. Following the removal of the volatiles in vacuo, the resulting residue was partitioned between ether and 1 N aq. NaOH. The aqueous layer was separated and back extracted with ether. The combined organic extracts were washed with H 2 0 and brine, dried over MgSO 4 and filtered. Concentration of the filtrate in vacuo afforded the title compound as a colorless oil. Step 2: 2- {2-[4-(Bromomethyl)phenyl]ethoxyl-1,3-dichloro-5-methvlbenzene 0 To a solution of triphenylphosphine dibromide (1.2 eq.) and Hunig's base (2 eq.) in dichloromethane (0.09 M) was added, dropwise over 5 min, {4-[2-(2,6-dichloro-4 methylphenoxy)ethyl]phenyl} methanol prepared in the previous step (1 eq.). The resulting mixture was stirred at RT for 2 h and then concentrated in vacuo. The residue was suspended in a 10:1 (v/v) Hex : ether solution and filtered through a pad of SiO 2 . The filtrate was concentrated in vacuo to afford the 5 title compound as a white solid. Step 3: 2-Cvano-N-cyclopropyl-N-(2,3-dichlorobenzyl)-3- {4-[2,6-dichloro-4 methylphenoxv)ethyl]phenvl} propanamide 2-Cyano-N-cyclopropyl-N-(2,3-dichlorobenzyl)acetamide (1 eq.), prepared from Amine 2 and cyanoacetic acid as detailed in Step 1 of Example 1, was dissolved in THF (0.1 M). At -78 0 C, 0 potassium bis(trimethylsilyl)amide (15% w/w toluene solution, 1.2 eq.) was then added and the resulting yellow suspension was stirred at -78 'C for 15 min and at -40 oC for 15 min. 2-{2-[4 (bromomethyl)phenyl]ethoxy}-1,3-dichloro-5-methylbenzene from the previous step (1 eq.) was then added, at -78 'C, as a 0.6 M THF solution over a period of 10 min. Finally, tetrabutylammonium iodide (10% loading) was added. The resulting pale yellow mixture was allowed to warm slowly to RT over 15 5 h. The reaction was quenched with sat. aq. NH 4 Cl and extracted with ether. The combined organic extracts were washed with H 2 0 and brine, dried over MgSO 4 and filtered. Concentration of the filtrate in vacuo afforded a viscous yellow oil. Purification of the crude product thus obtained by way of column chromatography (SiO 2 , Hex - 1:1 (v/v) Hex : EtOAc) afforded the title compound as a colorless oil. Step 4: tert-Butyl (3-[cyclopropyl(2,3-dichlorobenzyl)amino]-2- {4-[2-(2.6-dichloro-4 0 methylphenoxv)ethyl] benzvl l-3-oxopropvl)carbamate 2-Cyano-N-cyclopropyl-N-(2,3-dichlorobenzyl)-3- {4-[2,6-dichloro-4 methylphenoxy)ethyl]phenyl}propanamide from the previous step (1 eq.) and cobalt(II) chloride hexahydrate (2 eq.) were combined in MeOH (0.07 M). To this mixture was then added sodium -73- WO 2007/009250 PCT/CA2006/001196 borohydride (10 eq.) slowly and portionwise. The resulting black suspension was stirred at RT for 2 h. The reaction mixture was then diluted with EtOAc and quenched with 1 N aq. NaOH. The resulting emulsion was then filtered through a bed of celite and the insolubles were rinsed with EtOAc and
CH
2 Cl 2 . The organic layer was separated and washed further with 1 N aq. NaOH, H 2 0 and brine. 5 Drying over MgSO 4 , filtration and concentration of the filtrate in vacuo afforded the crude amine as a golden oil. This residue was then taken up in CH 2 C1 2 (0.06 M). To this solution was added Hunig's base (4.7 eq.) and di-tert-butyl dicarbonate (2 eq.). The resulting reaction mixture was stirred at RT for 16 h. Following careful acidification with 10% aq. HCI to a pH of-2, the aqueous layer was separated and back extracted with EtOAc. The combined organic extracts were then washed HO 2 0 and brine, dried over 10 MgSO 4 and filtered. Concentration of the filtrate in vacuo afforded a yellow oil. Purification of the crude product thus obtained by way of column chromatography (SiO 2 , Hex - 1:1 (v/v) Hex: EtOAc) afforded the title compound as a white froth. Step 5: 3-Amino-N-cyclopropvl-N-(2,3-dichlorobenzyl)-2- {4-[2-(2,6-dichloro-4 methylphenoxy)ethyl]benzvl } propanamide 15 To a CH2Cl 2 solution (0.06 M) of tert-butyl (3-[cyclopropyl(2,3-dichlorobenzyl)amino] 2- {4-[2-(2,6-dichloro-4-methylphenoxy)ethyl]benzyl}-3-oxopropyl)carbamate (1 eq.) from the previous step was added HCI (4.0 M dioxane solution, 14 eq.). The resulting solution was stirred at RT for 3 h. Following the removal of the volatiles in vacuo, the resulting residue was directly loaded onto a SiO2 column packed with 97:3 (v/v) CH 2
CI
2 : 2.0 M NH 3 in MeOH. Elution with the same solvent system 20 furnished the title compound as a white froth. MS (ESI+): 578.9. Example 26 4-Amino-N-cyclopropyl-N-(2,3-dichlorobenzyl)-2- {4-[2-(2,6-dichloro-4 methylphenoxy)ethoxy]benzyl } butanamide Me Cl Cl 0 C N, O NV
H
2 N 5 Step 1: [4-(2- [tert-Butyl(dimethyl)silvll oxy I ethoxy)phenyl]methanol At 0 0 C, sodium borohydride (1.5 eq.) was added portionwise to a MeOH solution (0.5 M) of Aldehyde 5 (1 eq.). The resulting mixture was stirred at 0 oC for 30 min and then at RT for 30 min. Following the removal of the volatiles in vacuo, the resulting residue was partitioned between ether and 1 N aq. NaOH. The aqueous layer was separated and back extracted with ether. The combined 0 organic extracts were washed with H 2 0 and brine, dried over MgSO 4 and filtered. Concentration of the filtrate in vacuo afforded the title compound as a colorless oil. Step 2: tert-Butyl { 2 -[4-(iodomethyl)phenoxy]ethoxy}dimethylsilane At 0 'C, iodine (1.2 eq.) and imidazole (1.2 eq.) were added to a CH 2 Cl 2 solution (0.05 M) of triphenylphosphine (1.2 eq.). The resulting yellow-orange suspension was stirred at 0 oC for 10 -74- WO 2007/009250 PCT/CA2006/001196 min and then at RT for 15 min. Finally, [4-(2-{ [tert-butyl(dimethyl)silyl]oxy}ethoxy)phenyl]methanol from the previous step (1 eq.) was added over 30 min as a 0.2 M CH 2
CI
2 solution. After another 10 h of stirring at RT, the volatiles were removed in vacuo. The resulting brown residue was suspended in ether and rapidly passed through a plug of SiO 2 . Removal of the volatiles in vacuo afforded the title 5 compound as a pink oil. Step 3: Ethyl 2-[4-(2- { [tert-butyl(dimethyl)silylloxvy} ethoxy)benzyl]pent-4-enoate To a solution of diisopropylamine (1.1 eq.) in THF (0.12 M) was added, at -78 'C, n butyllithium (1.6 M hexane solution, 1.1 eq.) over a period of 5 min. The resulting mixture was stirred at -78 'C for 15 min and then warmed at RT for 10 min. With the reaction mixture re-cooled to -78 OC, 0 ethyl pent-4-enoate (1.1 eq.) was added dropwise as a 1.6 M THF solution. The resulting solution was stirred for 30 min at -78 0 C. Finally, tert-butyl {2-[4-(iodomethyl)phenoxy]ethoxy}dimethylsilane (1 eq.) was added dropwise as a 1.5 M THF solution. The reaction mixture was allowed to warm slowly to RT over 12 h. After the reaction was carefully quenched with the addition of a sat. aq. NH 4 CI solution, the reaction mixture was extracted with ether. The combined organic extracts were washed with brine, dried 5 over MgSO 4 , filtered and the filtrate concentrated in vacuo. Purification of the crude product thus obtained by way of column chromatography (SiO 2 , 10:1 (v/v) Hex : ether) afforded the title compound as a colorless oil. Step 4: Ethyl 2-[4-(2-hydroxyethoxy)benzvl]pent-4-enoate To a solution of ethyl 2-[4-(2- { [tert-butyl(dimethyl)silyl]oxy}ethoxy)benzyl]pent-4 ,0 enoate from the previous step (1 eq.) in THF (0.2 M) was added tetrabutylammonium fluoride (1.0 M THF solution, 2 eq.). The resulting reaction mixture was stirred at RT for 2 h. After quenching the reaction with sat. aq. NH 4 C1, the mixture was extracted with ether. The combined organic extracts were washed with water and brine, dried over MgSO 4 , filtered and the filtrate concentrated in vacuo. Purification of the crude product thus obtained by way of flash chromatography (SiO 2 , 10:1 (v/v) Hex: 5 EtOAc -- EtOAc) afforded the title compound as a colorless oil. Step 5: Ethyl 2-(4- {2-[(2.6-dichloro-4-methylphenoxy)ethoxy]benzyl)pent-4-enoate Ethyl 2
-[
4 -(2-hydroxyethoxy)benzyl]pent-4-enoate from the previous step (1 eq.) and 2,6-dichloro-4-methylphenol (2 eq.) were taken up in freshly deoxygenated toluene (0.1 M). To this solution was then added 1,1'-(azodicarbonyl)-dipiperidine (3 eq.) and finally tributylphosphine (3 eq.). 0 The resulting yellow solution was heated at 80 oC for 2 h. The reaction mixture was cooled to RT, quenched with 1 N aq. NaOH and extracted with ether. The combined organic extracts were dried over MgSO 4 , filtered and the filtrate concentrated in vacuo. Purification of the crude product thus obtained by way of flash chromatography (SiO 2 , Hex -) 7:3 (v/v) Hex: EtOAc) afforded the title compound as a colorless oil. 5 Step 6: 2- {4-[2-(2,6-Dichloro-4-methylphenoxy)ethoxylbenzyl}pent-4-enoic acid Ethyl 2-(4- {2-[(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl}pent-4-enoate from the previous step (1 eq.) was dissolved in a 2:1 (v/v) THF : MeOH solution (0.06 M). To this was then added lithium hydroxide (1.0 M aqueous solution, 3.4 eq.) and the resulting solution was stirred at 50 oC -75- WO 2007/009250 PCT/CA2006/001196 for 12 h. The volatiles were then removed in vacuo. Following careful acidification of the resulting residue with 10% aq. HCI, the mixture was extracted with EtOAc. The combined organic extracts were washed with H 2 0 and brine, dried over MgSO 4 and filtered. Concentration of the filtrate in vacuo afforded the title compound as a viscous oil. 5 Step 7: N-Cyclopropyl-N-(2,3-dichlorobenzyl)-2- {4-[2-(2.6-dichloro-4 methylphenoxy)ethoxy]benzvl } pent-4-enamide 2- {4-[2-(2,6-Dichloro-4-methylphenoxy)ethoxy]benzyl} pent-4-enoic acid from the previous step (1 eq.) was combined with Hunig's base (3 eq.) and Amine 2 (1.1 eq.) in anhydrous DMF (0.2 M). To this was then added portionwise O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium 0 hexafluorophosphate (1.2 eq.). The resulting yellow solution was stirred at RT for 12 h. The reaction was quenched with I N aq. HCI and extracted with ether and EtOAc. The combined organic extracts were washed with H 2 0 and brine, dried over MgSO 4 , filtered and the filtrate concentrated in vacuo. Purification of the crude product thus obtained by way of flash chromatography (SiO 2 , Hex - 1:1 (v/v) Hex : EtOAc) afforded the title compound as a viscous oil. 5 Step 8: N-Cvclopropyl-N-(2,3-dichlorobenzyl )-2- {4-[2-(2.6-dichloro-4-methylphenoxy)ethoxy]benzyl } 4-hydroxybutanamide At -78 'C, a 1:1 (v/v) THF : MeOH solution (0.02 M) of N-cyclopropyl-N-(2,3 dichlorobenzyl)-2- {4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl}pent-4-enamide from the previous step (1 eq.) was bubbled ozone for 20 min. The resulting solution was purged of excess ozone 0 by bubbling with nitrogen. Sodium borohydride (4 eq.) was then added and the reaction mixture was warm to RT over 16 h. The resulting mixture was concentrated in vacuo, diluted with 1 N aq. NaOH and extracted with EtOAc. The combined organic extracts were washed with brine, dried over MgSO 4 , filtered and the filtrate concentrated in vacuo. Purification of the crude product thus obtained by way of column chromatography (SiO 2 , 10:1 (v/v) Hex: EtOAc -4 EtOAc) afforded the title compound as a 5 viscous oil. Step 9: 4-Azido-N-cyclopropvl-N-(2,3-dichlorobenzyl)-2- {4-r2-(2.6-dichloro-4 methylphenoxy)ethoxvylbenzvl}butanamide N-Cyclopropyl-N-(2,3-dichlorobenzyl)-2- {4-[2-(2,6-dichloro-4 methylphenoxy)ethoxy]benzyl}-4-hydroxybutanamide from the previous step (1 eq.) and Hunig's base 0 (3.5 eq.) were combined in CH 2 C12 (0.024 M). At -78 'C, methanesulfonyl chloride (1.5 eq) was added and the reaction mixture was stirred at -78 'C for 10 min and at 0 'C for 10min. The resulting mixture was quenched with sat. aq. NaHCO 3 and extracted with CH 2
CI
2 . The combined organic extracts were dried over MgSO 4 , filtered and the filtrate concentrated in vacuo. The resulting residue was taken up in DMF (0.06 M) and added sodium azide (5 eq). This mixture was then allowed to stir at RT for 24 h. 5 The resulting mixture was poured into water and extracted with ether. The combined organic extracts were washed with water and brine, dried over MgSO4, filtered and the filtrate concentrated in vacuo. Purification of the crude product thus obtained by way of column chromatography (SiO 2 , Hex 4) 1:1 (v/v) Hex : EtOAc) afforded the title compound as a viscous oil. -76- WO 2007/009250 PCT/CA2006/001196 Step 10: 4-Amino-N-cyclopropvl-N-(2.3-dichlorobenzyl)-2- {4-[2-(2,6-dichloro-4 methylphenoxy)ethoxy]benzylbutanamide To a THF solution (0.036 M) of 4-azido-N-cyclopropyl-N-(2,3-dichlorobenzyl)-2- {4-[2 (2,6-dichloro-4-methylphenoxy)ethoxy]benzyl}butanamide from the previous step (1 eq.) was added 5 triphenylphosphine (1.1 eq) and H20 (1.6 eq.). The resulting solution was stirred at RT for 24 h. The volatiles were then removed in vacuo. Purification of the crude product thus obtained by way of column chromatography (SiO 2 , 97 : 3 (v/v) CH2Cl2 : 2.0 M NH 3 in MeOH) afforded the title compound as a colorless oil. MS (ESI+): 608.7. Example 27 0 4-Amino-N-cyclopropyl-N-(2,3-dichlorobenzyl)-2- {4-[3-(2,6-dichloro-4 methylphenoxy)propyl]benzyl } butanamide Me CI C CI CIC ON
H
2 N Prepared according to the procedure described in Example 26 but using instead Aldehyde 3. The title compound was obtained as a colorless oil. MS (ESI+): 607.0. 5 Example 28 N-Cyclopropyl-N-(2,3-dichlorobenzyl)-O-[2-(2,6-dichloro-4-methylphenoxy)ethyl]tyrosinamide Me Cl C cCl CCI
ONH
2 Step 1: Methyl N-(tert-butoxycarbonvl)-O-[2-(2.6-dichloro-4-methylphenoxy)ethyl] tyrosinate Methyl N-(tert-butoxycarbonyl)tyrosinate (1 eq.) and 2-(2,4-dichloro-4 .0 methylphenoxy)ethanol (1 eq.) were taken up in freshly-deoxygenated toluene (0.18 M). To this solution was then added 1,1 '-(azodicarbonyl)-dipiperidine (1.1 eq.) and finally tributylphosphine (3 eq.). The resulting yellow solution was heated at 80 oC for 3 h. The reaction mixture was cooled to RT, diluted with H 2 0 and extracted with EtOAc. The combined organic extracts were washed with sat. aq. NaHCO 3 and brine, dried over MgSO 4 and filtered. Concentration of the filtrate in vacuo afforded the 5 title compound. Step 2: N-(tert-Butoxycarbonvyl)-O-[2-(2,6-dichloro-4-methylphenoxy)ethyl]tyrosine Methyl N-(tert-butoxycarbonyl)-O-[2-(2,6-dichloro-4-methylphenoxy)ethyl] tyrosinate from the previous step (1 eq.) was dissolved in a 2:1 (v/v) THF : MeOH solution (0.07 M). To this was then added lithium hydroxide (1.0 M aqueous solution, 5 eq.) and the resulting solution was stirred at RT 0 for 16 h. The volatiles were then removed in vacuo. Following careful acidification of the resulting -77- WO 2007/009250 PCT/CA2006/001196 residue with 10% aq. HC1, the mixture was extracted with EtOAc. The combined organic extracts were washed with H 2 0 and brine, dried over MgSO 4 and filtered. Concentration of the filtrate in vacuo afforded the title compound. Step 3: N-(tert-Butoxycarbonvl)-N-cyclopropvl-N-(2.3-dichlorobenzyl)-O-[2-(2,6-dichloro-4 5 methylphenoxy)ethyl]tyrosinamide N-(tert-Butoxycarbonyl)-O-[2-(2,6-dichloro-4-methylphenoxy)ethyl]tyrosine from the previous step (1 eq.) was combined with Hunig's base (3 eq.) and Amine 2 (1.2 eq.) in anhydrous DMF (0.04 M). To this was then added portionwise O-(7-azabenzotriazol-1-yl)-NAN',N'-tetramethyluronium hexafluorophosphate (1.5 eq.). The resulting solution was stirred at RT for 16 h. The reaction was 10 quenched with 1 N aq. HCI and extracted with EtOAc. The combined organic extracts were washed with sat. aq. NaHCO 3 and brine, dried over MgSO 4 , filtered and the filtrate concentrated in vacuo. Purification of the crude product thus obtained by way of flash chromatography (SiO2, 10:1 (v/v) Hex: EtOAc -- ) EtOAc) afforded the title compound as a viscous oil. Step 4: N-Cyclopropyvl-N-(2.3-dichlorobenzvl)-O-[2-(2.6-dichloro-4-methylphenoxy)ethyl]tyrosinamide 5 To a CH2C12 solution (0.03 M) of N-(tert-butoxycarbonyl)-N-cyclopropyl-N-(2,3 dichlorobenzyl)-O-[2-(2,6-dichloro-4-methylphenoxy)ethyl]tyrosinamide from the previous step (1 eq.) was added HCI (4.0 M dioxane solution, 10 eq.). The resulting solution was stirred at RT for 5 h. Following the removal of the volatiles in vacuo, the resulting residue was directly loaded onto a SiO 2 column packed with 95:5 (v/v) CH 2
C!
2 : 2.0 M NH 3 in MeOH. Elution with the same solvent system .0 furnished the title compound as a white froth. MS (ESI+): 581.3. Example 29 Methyl (2R)-2- {2-[(3-[cyclopropyl(2,3-dichlorobenzyl)amino]-2- {4-[2-[2-(2,6-dichloro-4 methylphenoxy)ethoxy]benzyl } -3-oxopropyl)amino]ethyl } -3 -methylbutanoate Me Cl Cl CI
O
N O HN OMe Me Me 5 A mixture of 3-amino-N-cyclopropyl- N-(2,3-dichlorobenzyl)-2- {4-[2-(2,6-dichloro-4 methylphenoxy)ethoxy]benzyl}propanamide (Example 2, 1 eq.) and methyl (2R)-3-methyl-2-(2 oxoethyl)butanoate (1.2 eq.) were combined in toluene (0.1 M). To this was then added a few crystals of p-toluenesulfonic acid monohydrate and the resulting solution was azeotroped for 3 h. The reaction mixture was then cooled to RT and added sodium cyanoborohydride (1.2 eq.) was added portionwise. 0 After 1 h of stirring, the reaction mixture was quenched with 10% aq. Na 2
CO
3 and extracted with EtOAc. The combined organic extracts were then washed with brine, dried over MgSO 4 and filtered. Concentration of the filtrate in vacuo afforded a brown residue. Purification of the crude product thus -78- WO 2007/009250 PCT/CA2006/001196 obtained by way of flash chromatography (SiO 2 , 97:3:1 (v/v/v) CH 2
CI
2 : Acetone :2.0 M NH 3 in MeOH) afforded the title compound as a colorless oil. MS (ESI+): 739.1. Example 30 N-Cyclopropyl-N-(2,3-dichlorobenzyl)-2-
{
4
-[
2
-(
2
,
6 -dichloro-4-methylphenoxy)ethoxy]benzyl } -3-[(3R) 5 3-isopropyl-2-oxopyrrolidin- 1-yl]propanamide Me I Cl Cl ci N Me To a solution of methyl (2R)-2- { 2
-[(
3 -[cyclopropyl(2,3-dichlorobenzyl)amino]-2- {4-[2 [2-(2,6-dichloro-4-methylphenoxy)ethoxy]benzyI}-3-oxopropyl)amino]ethyl}-3-methylbutanoate (Example 29, 1 eq.) in MeOH (0.1 M) was added KOH (8.0 M aq. solution, 2 eq.). The resulting 0 solution was then stirred at RT for 2 h. Removal of the volatiles in vacuo and purification of the crude product thus obtained by way of flash chromatography (SiO 2 , 3:2 (v/v) Hex: EtOAc) afforded the title compound as a colorless oil. MS (ESI+): 707.2. 5 Example 31 Methyl (2S)-2- {2-[(3-[cyclopropyl(2,3-dichlorobenzyl)amino]-2- {4-[2-[2-(2,6-dichloro-4 methylphenoxy)ethoxy]benzyl}-3-oxopropyl)amino]ethyl } -3-methylbutanoate Me I CI N.( CIX CCl N ' V o O N 0 HN.= OM e Me Me A mixture of 3-amino-N-cyclopropyl- N-(2,3-dichlorobenzyl)-2- {4-[2-(2,6-dichloro-4 0 methylphenoxy)ethoxy]benzyl}propanamide (Example 2, 1 eq.) and methyl (2S)-3-methyl-2-(2 oxoethyl)butanoate (1.3 eq.) were combined in toluene (0.2 M). To this was then added a few crystals of p-toluenesulfonic acid monohydrate and the resulting solution was azeotroped for 3 h. The reaction mixture was then cooled to RT, concentrated in vacuo and the resulting residue taken up in THF (0.2 M). At 0 oC, sodium borohydride (1.3 eq.) was added. After O/N of stirring, the reaction mixture was 5 quenched with 10% aq. NH 4 Cl and extracted with EtOAc. The combined organic extracts were then washed with brine, dried over MgSO 4 and filtered. Concentration of the filtrate in vacuo and purification -79- WO 2007/009250 PCT/CA2006/001196 of the crude product thus obtained by way of flash chromatography (SiO 2 , 95:4:1 (v/v/v) CH 2 Cl2: Acetone : 2.0 M NH 3 in MeOH) afforded the title compound as a colorless oil. MS (ESI+): 739.2. Example 32 5 N-Cyclopropyl-N-(2,3-dichlorobenzyl)-2- {4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl} -3- { [2-(2 napthyl)ethyl]amino}propanamide Me Cl CI CCl 0 ~N HN A mixture of 3-amino-N-cyclopropyl- N-(2,3-dichlorobenzyl)-2- {4-[2-(2,6-dichloro-4 methylphenoxy)ethoxy]benzyl}propanamide (Example 2, 1 eq.), 2-(2-bromoethyl)naphthalene (1 eq.) 10 and sodium hydride (60% w/w dispersion in oil, 1 eq.) were combined at 0 'C in DMF (0.2 M). The cooling bath was removed and the reaction mixture was allowed to stir at RT O/N. The resulting cloudy suspension was diluted with EtOAc and quenched with 10% aq. NH 4 C1. The organic layer was separated, washed further with water and brine, dried over MgSO 4 and filtered. Concentration of the filtrate in vacuo and purification of the crude product thus obtained by way of flash chromatography 5 (SiO2, 97:3 (v/v) CH 2
CI
2 : 2.0 M NH 3 in MeOH) afforded the title compound as a pale yellow oil. MS (ESI+): 750.1. Example 33 2-(Aminomethyl)-N-cyclopropyl-3- { 4 -[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl} -N-(2,3 dimethylbenzyl)-4-pyridin-2-ylbutanamide Me I Cl Me Meb O ON S NH 2 0 N Step 1: 2-Cvano-N-cyclopropyl-3- { 4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy] phenyl -N-(2.3 dimethylbenzyl)-4-pyridin-2-ylbutanamide To a THF solution (0.5 M) of 2-bromopyridine (2.8 eq.) was added, at -78 'C, n-butyl lithium (1.6 M hexane solution, 2.8 eq.) dropwise over 15 min. The resulting yellow suspension was 5 stirred at -78 oC for a further 15 min before an ether solution (0.5 M) of cuprous iodide (1.4 eq.) and dibutyl sulfide (2.8 eq.) was added over 15 min. The resulting reaction mixture was allowed to stir at -78 oC for 15 min and then at 0 oC for 15 min. Finally, to this was added dropwise at 0 'C, a THF solution -80- WO 2007/009250 PCT/CA2006/001196 (0.1 M) of (2E)-2-cyano-N-cyclopropyl-3- {4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy] phenyl }-N-(2,3 dimethylbenzyl)acrylamide (Example 1, Step 2, 1 eq.). The resulting emerald green suspension was stirred at 0 C for 15 min and then at RT for 2 h. The reaction was quenched with 3:1 (v:v) sat. aq.
NH
4 CI : conc. aq. NH 4 OH solution and extracted with ether. The combined organic extracts were 5 washed with brine, dried over MgSO 4 , filtered and the filtrate concentrated in vacuo. The crude product thus obtained was purified by way of column chromatography (SiO 2 , 10:1 -) 1:1 (v/v) Hex : EtOAc). The title compound was isolated as a mixture of diastereomers. Step 2: tert-Butvl (2- { [cyclopropyl(2,3-dimethylbenzyl)amino]carbonyl l-3- {4-[2-(2,6-dichloro-4 methylphenoxy)ethoxy]phenyl}-4-pvridin-2-vlbutvl)carbamate 0 2-Cyano-N-cyclopropyl-3- {4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy] phenyl}-N-(2,3 dimethylbenzyl)-4-pyridin-2-ylbutanamide from the previous step (1 eq.) and cobalt(II) chloride hexahydrate (1 eq.) were combined in MeOH (0.06 M). To this mixture was then added sodium borohydride (3 eq.) slowly and portionwise. The resulting black suspension was stirred at RT for 1 h. The reaction mixture was then diluted with 95:5 (v/v) CH 2 Cl 2 : MeOH and quenched with 1 N aq. NaOH. 5 The resulting emulsion was then filtered through a bed ofcelite and the insolubles were rinsed with 95:5 (v/v) CH2Cl 2 : MeOH. The organic layer was separated and washed further with 1 N aq. NaOH, H 2 0 and brine. Drying over MgSO 4 , filtration and concentration of the filtrate in vacuo afforded the crude amine as a white froth. This residue was then taken up in CH 2 C1 2 (0.03 M) and added di-tert-butyl dicarbonate (1 eq.). Finally, sodium hydroxide (1.0 N aqueous solution, 3 eq.) was added and the resulting biphasic .0 mixture was vigorously stirred for 4 h. The aqueous layer was separated and back extracted with ether. The combined organic extracts were then washed H 2 0 and brine, dried over MgSO 4 and filtered. Concentration of the filtrate in vacuo afforded a yellow oil. Purification of the crude product thus obtained by way of column chromatography (SiO 2 , 10:1 (v/v) Hex : EtOAc -4 EtOAc) afforded the title compound as a mixture of diastereomers. 5 Step 3: 2-(Aminomethyl)-N-cyclopropvl-3- {4-[2-(2.6-dichloro-4-methylphenoxv)ethoxy]phenyl-N-(2.3 dimethylbenzvl)-4-pyridin-2-ylbutanamide To a CH 2
C
2 solution (0.03 M) of tert-butyl (2-{[cyclopropyl(2,3 dimethylbenzyl)amino]carbonyl } -3- { 4
-[
2 -(2,6-dichloro-4-methylphenoxy)ethoxy]phenyI}-4-pyridin-2 ylbutyl)carbamate from the previous step (1 eq.) was added HCI (4.0 M dioxane solution, 30 eq.). The 0 resulting solution was stirred at RT for 4 h. Following the removal of the volatiles in vacuo, the resulting residue was directly loaded onto a SiO 2 column packed with 95:5 (v/v) CH 2 C1 2 : 2.0 M NH 3 in MeOH. Elution with the same solvent system furnished the title compound as a white froth. Diastereomer A: MS (ESI+): 646.0. Diastereomer B: MS (ESI+): 646.0. Example 34 5 3-Amino-N-[ 2 -chloro-5-(2-methoxyethyl)benzyl]-N-cyclopropyl-2- {4-[2-(2,6-dichloro-4 methylphenoxy)ethoxy]benzyl } butanamide -81- WO 2007/009250 PCT/CA2006/001196 Me CI ClC 0OMe Me
NH
2 Step 1: {4-[2-(2.6-Dichloro-4-methylphenoxy)ethyoxy]phenyl} methanol At 0 C, sodium borohydride (1.5 eq.) was added portionwise to a MeOH solution (0.2 M) of Aldehyde 1 (1 eq.). The resulting mixture was stirred at 0 GC for 15 min and then at RT for 30 5 min. Following the removal of the volatiles in vacuo, the resulting residue was partitioned between ether and 1 N aq. NaOH. The aqueous layer was separated and back extracted with ether. The combined organic extracts were washed with H 2 0 and brine, dried over MgSO 4 and filtered. Concentration of the filtrate in vacuo afforded the title compound as a colorless oil. Step 2: 1,3-Dichloro-2- {2-[4-(iodomethyl)phenoxy]ethoxy} -5-methylbenzene 0 To a solution of triphenylphosphine (1.2 eq.) in dichloromethane (0.09 M) was added iodine (1.2 eq.) and the resulting reddish-orange mixture was stirred at RT for 15 min. At 0 oC, a dichloromethane solution (0.1 M) of {4-[2-(2,6-dichloro-4-methylphenoxy)ethyoxy]phenyl} methanol prepared in the previous step (1 eq.) and imidazole (3 eq.) was then added dropwise over 15 min. The resulting orange-yellow suspension was stirred at 0 oC for I h and then at RT for 15 min. The reaction 5 was quenched with 10% (w/w) aq. NaHSO 3 and extracted with ether. The organic extracts were combined, washed with brine, dried over MgSO 4 , filtered and the filtrate concentrated in vacuo. The resulting residue was triturated in a 10:1 (v/v) Hex : ether solution and filtered through a pad of SiO 2 . The filtrate was concentrated in vacuo to afford the title compound as a white solid. 10 Step 3: Methyl 2-{4-[2.6-dichloro-4-methylphenoxy)ethoxy]benzyl}-3-oxobutanoate Methyl 3-oxobutanoate (1.2 eq.) in THF (0.1 M) was added, at -78 oC, potassium bis(trimethylsilyl)amide (15% w/w toluene solution, 1.2 eq.). The resulting yellow suspension was stirred at -78 oC for 15 min and at -40 oC for 15 min. 1,3-Dichloro-2-{2-[4 (iodomethyl)phenoxy]ethoxy}-5-methylbenzene from the previous step (1 eq.) was then added, at -78 oC, 5 as a 0.6 M THF solution over a period of 15 min. The resulting pale yellow mixture was allowed to warm slowly to RT over 15 h. The reaction was quenched with sat. aq. NH4Cl and extracted with ether. The combined organic extracts were washed with H 2 0 and brine, dried over MgSO 4 and filtered. Concentration of the filtrate in vacuo afforded a viscous yellow oil. Purification of the crude product thus obtained by way of column chromatography (SiO 2 , Hex - 1:1 (v/v) Hex : EtOAc) afforded the title 0 compound as a colorless oil. Step 4: Methyl 2- { 4
-[
2 -(2,6-dichloro-4-methylphenoxy)ethoxylbenzyll}-3-hydroxybutanoate Methyl 2-{4-[2,6-dichloro-4-methylphenoxy)ethoxy]benzyl}-3-oxobutanoate from the previous step (1 eq.) in 2:1 (v:v) THF : MeOH (0.1 M) was added sodium borohydride (1.2 eq.) in one rapid portion. After 30 min of stirring at RT, the volatiles were removed in vacuo and the resulting -82- WO 2007/009250 PCT/CA2006/001196 residue partitioned ether and 1 N aq. NaOH. The aqueous layer was separated and back extracted with ether. The combined ethereal extracts were then washed further with water and brine, dried over MgSO 4 and filtered. Concentration of the filtrate in vacuo afforded a pale yellow oil. Purification of the crude product thus obtained by way of column chromatography (SiO 2 , Hex -4 1:1 (v/v) Hex: EtOAc) afforded 5 the title compound as a colorless oil. Step 5: 2- {4-[2-(2.6-Dichloro-4-methylphenoxy)ethoxy]benzyll-3-hydroxybutanoic acid Methyl 2- {4-[2,6-dichloro-4-methylphenoxy)ethoxy]benzyl}-3-hydroxybutanoate from the previous step (1 eq.) in 1:1 (v:v) THF : MeOH (0.1 M) was added lithium hydroxide (1.0 M aqueous solution, 2 eq.). The resulting solution was stirred at RT for 12 h. Following the removal of the volatiles 10 in vacuo, the resulting residue was carefully acidified to pH - 2 with I N aq. HCI and extracted with EtOAc. The combined organic extracts were washed further with water and brine, dried over MgSO 4 , filtered and the filtrate concentrated in vacuo to afford the title compound as a a white froth. Step 6: N-[2-Chloro-5-(2-methoxyethyl)benzyl]-N-cyclopropyl-2- {4-[2-(2,6-dichloro-4 methylphenoxy)ethoxy]benzyl}-3-hydroxybutanamide 5 2- {4-[2-(2,6-Dichloro-4-methylphenoxy)ethoxy]benzyl}-3-hydroxybutanoic acid from the previous step (1 eq.) was combined with Hunig's base (3 eq.) and Amine 7 (1.2 eq.) in anhydrous DMF (0.06 M). To this was then added portionwise O-(7-azabenzotriazol-1-yl)-N,N,N',N' tetramethyluronium hexafluorophosphate (1.2 eq.). The resulting solution was stirred at RT for 18 h. The reaction was quenched with 1 N aq. HC1 and extracted with EtOAc. The combined organic extracts .0 were washed with brine, dried over MgSO 4 , filtered and the filtrate concentrated in vacuo. Purification of the crude product thus obtained by way of flash chromatography (SiO 2 , 10:1 (v/v) Hex : EtOAc 4-) EtOAc) afforded the title compound as a viscous oil. Step 7: N-[2-Chloro-5-(2-methoxyethyl)benzvl]-N-cyclopropyl-2-{4-[2-(2,6-dichloro-4 methylphenoxy)ethoxylbenzvl }-3-oxobutanamide 5 N-[ 2 -Chloro-5-(2-methoxyethyl)benzyl]-N-cyclopropyl-2- {4-[2-(2,6-dichloro-4 methylphenoxy)ethoxy]benzyl}-3-hydroxybutanamide from the previous step (1 eq.) in dichloromethane (0.05 M) was added at 0 oC Dess-Martin periodinane (1.2 eq.). The resulting solution was allowed to warm to RT over 2 h before the reaction was quenched with methanol and diluted with ether. This was then washed sequentially with sat. aq. NaHCO 3 , water and brine. Drying of the organic layer over 0 MgSO 4 , filtration and concentration of the filtrate in vacuo afforded the crude product as a colorless oil. Further purification by way of flash chromatography (SiO 2 , Hex 4-) 10:1 (v/v) Hex : EtOAc) afforded the title compound as a viscous oil. Step 8: 3 -Amino-N-[2-chloro-5-(2-methoxyethyl)benzyll-N-cyc prpy-2-4-[2-(2,6-dichloro-4 methylphenoxy)ethoxy] benzyl } butanamide 5 N-[ 2 -Chloro-5-(2-methoxyethyl)benzyl]-N-cyclopropyl-2-{4-[2-(2,6-dichloro-4 methylphenoxy)ethoxy]benzyl}-3-oxobutanamide from the previous step (1 eq.) and ammonium acetate (10 eq.) were combined in MeOH (0.06 M). After the addition of sodium cyanoborohydride (1.2 eq.), the resulting reaction mixture was heated at reflux for 2 h. The volatiles were then removed in vacuo and -83- WO 2007/009250 PCT/CA2006/001196 the resulting residue partitioned between EtOAc and I N aq. NaOH. The aqueous wash was separated and back extracted with EtOAc. The combined organic extracts were then washed further with water and brine, dried over MgSO 4 , filtered and the filtrate concentrated in vacuo. The crude product thus obtained was purified further by way of flash chromatography (SiO 2 , 96:4 (v/v) CH 2 Cl 2 : 2.0 M NH 3 in MeOH) to 5 reveal the title compound as a white froth. MS (ESI+): 635.3. Example 35 3-Amino-N-[2-chloro-5-(3-hydroxypropyl)benzyl]-N-cyclopropyl-2-{4-[2-(2,6-dichloro-4 methylphenoxy)ethoxy]benzyl} propanamide Me Cl O Cl ClS N O1NV OH
NH
2 0 Prepared according to the procedure described in Example 9 but using instead Amine 11 as starting material. The title compound was obtained as a colorless oil. MS (ESI+): 620.8. Example 36 3-Amino-N-[2-chloro-5-(2-methoxyethoxy)benzyl]-N-cyclopropyl-2- {4-[2-(2,6-dichloro-4 methylphenoxy)ethoxy]benzyl } propanamide 5 NH 2 Prepared according to the procedure described in Example 9 but using instead Amine 12 as starting material. The title compound was obtained as a colorless oil. MS (ESI+): 635. Example 37 3 -Amino-N-cyclopropyl-2- { 4
-[
2
-(
2 ,6-dichloro-4-methylphenoxy)ethoxy]benzyl } -N- { [6-(pyridin-4 10 ylmethyl)quinoline-8-yl]methyl}propanamide Me Cl cI~ I N N O N 0
NH
2 Prepared according to the procedure described in Example 9 but using instead Amine 13 as starting material. The title compound was obtained as a pale yellow oil. MS (ESI+): 669.2. Example 38 -84- WO 2007/009250 PCT/CA2006/001196 3-Amino-N-[2-chloro-5-(3-methoxypropyl)benzyl]-N-cyclopropyl-2- 4-[2-(2,6-dichloro-4 methylphenoxy)ethyl]benzyl } propanamide Me Cl Cl C °. O N OMe
NH
2 Prepared according to the procedure described in Example 9 but using instead Aldehyde 5 4 as starting material in step 1 and Amine 6 as starting material in step 4. The title compound was obtained as a pale yellow oil. MS (ESI+): 617.1. Example 39 3-Amino-N-[2-chloro-5-(2-methoxyethyl)benzyl]-N-cyclopropyl-2- { 4-[2-(2,6-dichloro-4 methylphenoxy)ethyl]benzyl } propanamide Me CI I CI C C CCO M e ON 0 NH 2 Prepared according to the procedure described in Example 9 but using instead Aldehyde 4 as starting material in step 1 and Amine 7 as starting material in step 4. The title compound was obtained as a pale yellow oil. MS (ESI+): 603.2. Example 40 5 3-Amino-N- {2-chloro-5-[3-(dimethylamino)propyl)benzyl }-N-cyclopropyl-2- {4-[2-(2,6-dichloro-4 methylphenoxy)ethoxy]benzyl } propanamide Me Cl
CI
O, N NMe 2
NH
2 Prepared according to the procedure described in Example 9 but using instead Amine 14 as starting material. The title compound was obtained as a colorless oil. MS (ESI+): 646.1. 0 Example 41 3-Amino-N-cyclopropyl-N-[2,3-dichloro-5-[3-methoxypropyl)benzyl }-2- { 4-[2-(2,6-dichloro-4 methylphenoxy)ethoxy]benzyl}propanamide -85- WO 2007/009250 PCT/CA2006/001196 Me CI CIl O O N V OMe
NH
2 Prepared according to the procedure described in Example 9 but using instead Amine 15 as starting material. The title compound was obtained as a colorless oil. MS (ESI+): 667.0. Example 42 5 3-Amino-N-cyclopropyl-N-[2,3-dichloro-5-[3-methoxypropyl)benzyl } -2- { 4-[2-(2,6-dichloro-4 methylphenoxy)ethyl]benzyl} propanamide Me cl Cl C . N OMe
NH
2 Prepared according to the procedure described in Example 9 but using instead Aldehyde 4 as starting material in step 1 and Amine 15 as starting material in step 4. The title compound was 0 obtained as a colorless oil. MS (ESI+): 652.2. Example 43 3-Amino-N- { [6-(cyanomethyl)quinoline-8-yl]methyl } -N-cyclopropyl]-2- {4-[2-(2,6-dichloro-4 methylphenoxy)ethoxy]benzyl} propanamide Me CI PO N, Cl CN N
NH
2 5 Prepared according to the procedure described in Example 9 but using instead Amine 16 as starting material. The title compound was obtained as a colorless oil. MS (ESI+): 617.1. Example 44 3-Amino-N-cyclopropyl-2- {4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl } -N- { [2-(3 methoxypropyl)quinoline-4-yl]methyl}propanamide -86- WO 2007/009250 PCT/CA2006/001196 Me , CI Cl OMe
NH
2 Prepared according to the procedure described in Example 9 but using instead Amine 17 as starting material. The title compound was obtained as a colorless oil. MS (ESI+): 650.2. Example 45 5 3-Amino-N-[2-chloro-5-(2-cyanoethyl)benzyl]-N-cyclopropyl-2- {4-[2-(2,6-dichloro-4 methylphenoxy)ethoxy]benzyl } propanamide Me Cl PON
C
1 O N
NH
2 Prepared according to the procedure described in Example 9 but using instead Amine 18 as starting material. The title compound was obtained as a colorless oil. MS (ESI+): 616.1. 0 Example 46 3-Amino-N-cyclopropyl-2- { 4 -[2-(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl } -N-[5-(3 methoxypropyl)-2-methylbenzyl]propanamide Me Cl 0 Me. CI O MOMe 0 0 N
NH
2 Prepared according to the procedure described in Example 9 but using instead Amine 19 5 as starting material. The title compound was obtained as a colorless oil. MS (ESI+): 613.0. Example 47 3 -Amino-N-[2-chloro-5-(2-cyanomethyl)benzyl]-N-cyclopropyl-2- {4-[2-(2,6-dichloro-4 methylphenoxy)ethoxy]benzyl } propanamide Me Cl C O Cl C O LN
NH
2 -87- WO 2007/009250 PCT/CA2006/001196 Prepared according to the procedure described in Example 9 but using instead Amine 20 as starting material. The title compound was obtained as a colorless oil. MS (ESI+): 601.4. Example 48 3-Amino-N-cyclopropyl-2- { 4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl} -N-[5-(3-methoxyethyl) 5 2-methylbenzyl]propanamide Me Cl Cl OI M e O e
CI
1 N OMe O N
NH
2 Prepared according to the procedure described in Example 9 but using instead Amine 21 as starting material. The title compound was obtained as a colorless oil. MS (ESI+): 599.1 Example 49 0 3-Amino-N-[2,5-bis(trifluoromethyl)benzyl]-N-cyclopropyl-2- {4-[2-(2,6-dichloro-4 methylphenoxy)ethoxy]benzyl } propanamide Me Cl
F
3 CC O N
NH
2 Prepared according to the procedure described in Example 9 but using instead Amine 22 as starting material. The title compound was obtained as a colorless oil. MS (ESI+): 702.3. 5 Example 50 3-Amino-N- { [6-(1 -cyano- 1 -methylethyl)quinoline-8-yl]methyl } -N-cyclopropyl-2- {4-[2-(2,6-dichloro-4 methylphenoxy)ethoxy]benzyl } propanamide Me. CI lN N N,. 1 " 1 "" M NIMe ClK Me o NDON CN
NH
2 Prepared according to the procedure described in Example 9 but using instead Amine 23 0 as starting material. The title compound was obtained as a colorless oil. MS (ESI+): 645.2. Example 51 3-Amino-N-cyclopropyl-2- {4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl}-N-(1 phenylethyl)propanamide -88- WO 2007/009250 PCT/CA2006/001196 Me Cl Cl O Me O NN
NH
2 Prepared according to the procedure described in Example 9 but using instead Amine 24 as starting material. The title compound was obtained as a colorless oil. MS (ESI+): 541.3. Example 52 5 3-Amino-N-benzyl-2- {4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl } -N-methylpropanamide Me Cl CI N O N N Me
NH
2 Prepared according to the procedure described in Example 9 but using instead N-methyl 1-phenylmethanamine as starting material. The title compound was obtained as a colorless oil. MS (ESI+): 501.4. 0 Example 53 3-Amino-N-benzyl-N-cyclopropyl-2- {4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl} propanamide Me CI ON C I L NO
NH
2 Prepared according to the procedure described in Example 9 but using instead Amine 25 as starting material. The title compound was obtained as a colorless oil. MS (ESI+): 527.1. 5 Example 54 3-Amino-N-benzyl-N-cyclopropyl-2-{ 4
-[
2
-(
2 ,6-dichloro-4-methylphenoxy)ethoxy]benzyI}-N-(2 phenylethyl)propanamide Me Cl I I Xo Cl ON
NH
2 Prepared according to the procedure described in Example 9 but using instead Amine 26 0 as starting material. The title compound was obtained as a colorless oil. MS (ESI+): 541.4. -89- WO 2007/009250 PCT/CA2006/001196 Example 55 3-Amino-2-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl} -N-methyl-N-(2 phenylethyl)propanamide Me Cl ON O N Me
NH
2 5 Prepared according to the procedure described in Example 9 but using instead N-methyl 2-phenylethanamine as starting material. The title compound was obtained as a colorless oil. MS (ESI+): 515.1. Example 56 3-Amino-2-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl}-N-methyl-N-(1 10 phenylethyl)propanamide Me Cl CI Me O N 1O Me
NH
2 Prepared according to the procedure described in Example 9 but using instead N-methyl 1-phenylethanamine as starting material. The title compound was obtained as a colorless oil. MS (ESI+): 515.2. 5 Example 57 3-Amino-N-(2,3-dichlorobenzyl)-2-
{
4
-[
2 -(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl}-N-(2,2,2 trifluoroethyl)propanamide Me. Cl 1 C CC O 'O NCF 3
NH
2 Step 1: (2E)-2-Cyano-3- { 4
-[
2
-(
2 ,6-dichloro-4-methylphenoxy)ethoxyphenyl acrylic acid 0 To a 2:1 (v/v) THF : MeOH solution (0.1 M) of methyl (2E)-2-cyano-3-{4-[2-(2,6 dichloro-4-methylphenoxy)ethoxy]phenyl}acrylate from Example 9, Step 1 (1 eq.) was added sodium hydroxide (1.0 M aq. solution, 3 eq.). The resulting solution was stirred at RT for 18 h before the volatiles were removed in vacuo. Following careful acidification of the resulting mixture to pH - I with 10% aq. HC1, the solution was extracted with EtOAc. The combined organic extracts were washed -90- WO 2007/009250 PCT/CA2006/001196 further with water and brine, dried over MgSO 4 and filtered. Concentration of the filtrate in vacuo afforded the title compound as a yellow semi-solid. Step 2: (2E)-2-Cvano-N-(2.,3-dichlorobenzyl)-3-
{
4 -[2-(2.6-dichloro-4-methylphenoxV)ethoNxy]phenvl1 N-(2,2,2-trifluoroethyl)acrylamide 5 To a solution of (2E)-2-cyano-3-{4-[2-(2,6-dichloro-4 methylphenoxy)ethoxy]phenyl}acrylic acid from the previous step (1 eq.) in dichloromethane (0.02 M) was added oxalyl chloride (1.2 eq.). Then, several drops of neat DMF were added dropwise. After no further gaseous evolution could be discerned, the crude reaction mixture was diluted with toluene and the volatiles were removed in vacuo. The resulting residue was taken up in dichloromethane (0.02 M) and 0 added sequentially Amine 27 (2 eq.), triethylamine (2 eq.) and a few crystals of DMAP. After 16 h of stirring at RT, the reaction was quenched with sat. aq. NH 4 CI and then extracted with EtOAc. The combined organic extracts were washed with water and brine, dried over MgSO 4 , filtered and the filtrate concentrated in vacuo. Purification of the crude product thus obtained by way of column chromatography (SiO 2 , Hex -) 7:3 (v/v) Hex : EtOAc) afforded the title compound as a white foam. S5 Step 3: tert-Butyl (3-[(2,3-dichlorobenzyl)(2.2,2-trifluoroethyl)amino]-2- {4-[2-(2,6-dichloro-4 methylphenoxy)ethoxybenzvl}-3-oxopropyl)carbamate (2E)-2-Cyano-N-(2,3-dichlorobenzyl)-3- { 4-[2-(2,6-dichloro-4 methylphenoxy)ethoxy]phenyl}-N-(2,2,2-trifluoroethyl)acrylamide from the previous step (1 eq.) and cobalt(II) chloride hexahydrate (2 eq.) were combined in a 7:3 (v/v) THF : MeOH solution (0.003 M). .0 To this mixture was then added sodium borohydride (10 eq.) slowly and portionwise. The resulting black suspension was stirred at RT for 2 h. The reaction mixture was then carefully quenched with 10% aq. HCI and extracted with ether. The combined organic extracts were washed further with HO 2 0 and brine. Drying over MgSO 4 , filtration and concentration of the filtrate in vacuo afforded the crude amine. This residue was combined with di-tert-butyl dicarbonate (1 eq.), Hunig's base (1.5 eq.) and a few 5 crystals of 4-(dimethylamino)pyridine in CH 2 C1 2 (0.06 M). The resulting solution was stirred at RT for 3 h. The volatiles were then removed in vacuo and purification of the crude product thus obtained by way of column chromatography (SiO 2 , Hex -- 7:3 (v/v) Hex : EtOAc) afforded the title compound as a pale yellow oil. Step 4: 3-Amino-N-(2.3-dichlorobenzvl)-2- { 4
-[
2 -(2.6-dichloro-4-methylphenoxy)ethoxylbenl-N 0 ( 2 ,2,2-trifluoroethyl)propanamide To a CH 2
C
2 solution (0.05 M) of tert-butyl (3-[(2,3-dichlorobenzyl)(2,2,2 trifluoroethyl)amino]-2- { 4
-[
2
-(
2
,
6 -dichloro-4-methylphenoxy)ethoxy]benzyl } -3-oxopropyl)carbamate from the previous step (1 eq.) was added HCI (4 M dioxane solution, 20 eq.). The resulting solution was stirred at RT for 13 h. Following the removal of the volatiles in vacuo, the resulting residue was directly 5 loaded onto a SiO 2 column packed with 95:5 (v/v) CH 2
C
2 : 2.0 M NH 3 in MeOH. Elution with the same solvent system furnished the title compound as a colorless oil. MS (ESI+): 638.2. -91- WO 2007/009250 PCT/CA2006/001196 Example 58 3-Amino-2- {4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl } -N-methyl-N-( 1-methyl-1 phenylethyl)propanamide Me Cl Cl O MeM OI N Me
NH
2 5 Prepared according to the procedure described in Example 9 but using instead Amine 28 as starting material. The title compound was obtained as a colorless oil. MS (ESI+): 529.1. Example 59 3-Amino-N-[2-chloro-5-(2-methoxyethyl)benzyl]-N-(cyclopropyl)methyl)-2- {4-[2-(2,6-dichloro-4 10 methylphenoxy)ethoxy]benzyl} propanamide Me CI CI. 0 O 0 N OMe
NH
2 Prepared according to the procedure described in Example 9 but using instead Amine 29 as starting material. The title compound was obtained as a colorless oil. MS (ESI+): 633.2. Example 60 5 3-Amino-N-[2-chloro-5-(2-methoxyethyl)benzyl]-2- {4-[2-(2,6-dichloro-4 methylphenoxy)ethoxy]benzyl}-N-methylpropanamide Me CI Cl O-: ONP O- O NMe OMe
NH
2 Prepared according to the procedure described in Example 9 but using instead Amine 30 as starting material. The title compound was obtained as a colorless oil. MS (ESI+): 593.2. 0 Example 61 3-Amino-N-[2-chloro-5-(2-methoxyethyl)benzyp]-N-(cyclobutylmethyl)-2-{4-[2-(2,6-dichloro-4 methylphenoxy)ethoxy]benzyl}propanamide -92- WO 2007/009250 PCT/CA2006/001196 Me Cl ClI C1 O0N OMe
NH
2 Prepared according to the procedure described in Example 9 but using instead Amine 31 as starting material. The title compound was obtained as a colorless oil. MS (ESI+): 647.3. Example 62 5 3-Amino-N-[2-chloro-5-(2-methoxyethyl)benzyl]-2-{4-[2-(2,6-dichloro-4 methylphenoxy)ethoxy]benzyl}-N-isopropylpropanamide Me CI I. CI 1 Cl OOC Oa :O Nr NM Me OMe Me
NH
2 Prepared according to the procedure described in Example 9 but using instead Amine 32 as starting material. The title compound was obtained as a colorless oil. MS (ESI+): 621.1. 0 Example 63 N-Allyl-3-amino-N-[2-chloro-5-(2-methoxyethyl)benzyl]-2-{4-[2-(2,6-dichloro-4 methylphenoxy)ethoxy]benzyl} propanamide Me Cl I C, ClOC O 0 N OMe
NH
2 Prepared according to the procedure described in Example 9 but using instead Amine 33 5 as starting material. The title compound was obtained as a colorless oil. MS (ESI+): 619.2. Example 64 3-Amino-N-[2-chloro-5-(2-methoxyethyl)benzyl]-N-cyclobutyl-2- {4-[2-(2,6-dichloro-4 methylphenoxy)ethoxy]benzyl}propanamide Me CI 0 O
.
0 N OMe
NH
2 -93- WO 2007/009250 PCT/CA2006/001196 Prepared according to the procedure described in Example 9 but using instead Amine 34 as starting material. The title compound was obtained as a colorless oil. MS (ESI+): 633.2 Example 65 3-Amino-N-[2-chloro-5-(2-methoxyethyl)benzyl]-2- {4-[2-(2,6-dichloro-4 5 methylphenoxy)ethoxy]benzyl } -N-ethylpropanamide Me Cl Cly O C C I 0 O N Me OMe
NH
2 Prepared according to the procedure described in Example 9 but using instead Amine 35 as starting material. The title compound was obtained as a colorless oil. MS (ESI+): 607.2 Example 66 10 3- { [Amino(imin o)methyl]amino} -N-[2-chloro-5-(3-methoxypropyl)benzyl]-N-cyclopropyl-2- {4-[2-(2,6 dichloro-4-methylphenoxy)ethoxy]benzyl } propanamide Me Cl CI O C OMe 0 ON IX V HN NH
NH
2 Step 1: Di-tert-bu(tvl(Z)-[(3-[[2-chloro-5-(3-methoxvpropvl)benzvlyl(cyclopropyl)amino]-N-2-{4-[2 (2.,6-dichloro-4-methylphenoxy)ethoxylbenzyl -3-oxopropyl)amino]methylvlidene)biscarbamate 5 To a solution of 3-amino-N-[2-chloro-5-(3-methoxypropyl)benzyl]-N-cyclopropyl-2-{4
[
2 -(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl}propanamide (Example 6, 1 eq.) in DMF (0.04 M) was added sequentially O,O-di-tert-butyl diimidothiocarbonate (1.2 eq.), triethylamine (2.2. eq.) and EDCI (1.2 eq.). sodium hydroxide (1.0 M aq. solution, 3 eq.). The resulting solution was stirred at RT for 18 h. The reaction mixture was diluted with water and then extracted with ether. The combined -0 organic extracts were washed further with water and brine, dried over MgSO 4 , filtered and the filtrate concentrated in vacuo. Purification of the crude product thus obtained by way of column chromatography (SiO 2 , Hex -4 EtOAc) afforded the title compound. Step 2: 3- { [Amino(imino)methyllaminol}-N-[2-chloro-5-(3-methoxvpropvl)benzyl]-N-cyclopropyl-2- {4 [2-(2.6-dichloro-4-methylphenoxy)ethoxy]benzvl }propanamide 5 To a CH 2 0CI 2 solution (0.04 M) of di-tert-butyl {(Z)-[(3-[[2-chloro-5-(3 methoxypropyl)benzyl](cyclopropyl)amino]-N-2- { 4
-[
2
-(
2 ,6-dichloro-4-methylphenoxy)ethoxy]benzyl} 3 -oxopropyl)amino]methylylidene)biscarbamate from the previous step (1 eq.) was added trifluoroacetic acid (190 eq.). The resulting solution was stirred at RT for 3 h. Following the removal of the volatiles in -94- WO 2007/009250 PCT/CA2006/001196 vacuo, the resulting residue was directly loaded onto a SiO 2 column packed with 90:10 (v/v) CH 2
CI
2 : 2.0 M NH 3 in MeOH. Elution with the same solvent system furnished the title compound as a white solid. MS (ESI+): 675.3. Example 67 5 2- { [Amino(imino)methyl]amino } -N-cyclopropyl-N-(2,3 -dichlorobenzyl)-3- { 4-[2-(2,6-dichloro-4 methylphenoxy)ethoxy]benzyl} propanamide Me I Cl NX CI CIC 0 O N NH
H
2 N INH Prepared according to the procedure described in Example 66 but using instead N-cyclopropyl-N-( 2 ,3-dichlorobenzyl)-O-[2-(2,6-dichloro-4-methylphenoxy)ethyl]tyrosinamide 0 (Example 28) as starting material. The title compound was obtained as a colorless oil. MS (ESI+): 625.0. Example 68 2-Amino-N-[2-chloro-5-(3-methoxypropyl)benzyl]-N-cyclopropyl-3- {4-[2-(2,6-dichloro-4 methylphenoxy)ethoxy]benzyl}propanamide Me Cl o Cl OMe 5O
NNH
2 Prepared according to the procedure described in Example 28 but using instead Amine 6 as starting material. The title compound was obtained as a colorless oil. MS (ESI+): 619.5. Example 69 2- { [Amino(imino)methyl]amino } -N- [2-chloro-5-(3-methoxypropyl)benzyl]-N-cyclopropyl-3- {4- [2-(2,6 0 dichloro-4-methylphenoxy)ethoxy]benzyl } propanamide Me Cl N, ( CI C1 O COMe O NOjN Hp NH
H
2 N"- NH Prepared according to the procedure described in Example 66 but using instead 2-amino-N-[2-chloro-5-(3-methoxypropyl)benzyl]-N-cyclopropyl-3- { 4-[2-(2,6-dichloro-4 methylphenoxy)ethoxy]benzyl}propanamide (Example 68) as starting material. The title compound was 5 obtained as a colorless oil. MS (ESI+): 661.1. -95- WO 2007/009250 PCT/CA2006/001196 Example 70 3-Amino-N-cyclopropyl-2- {4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl}-N-[3-hydroxy-5-(3 methoxypropyl)benzyl]propanamide Me I Cl OH Cl OMe O ~ N
NH
2 5 Step 1: tert-Butyl (3-[[3-{[tert-buyl(dimethyl)silvyl]oxy}-5-(3 methoxypropvl)benzyl](cyclopropvl)amino]-2- 4-[2-(2.6-dichloro-4-methylphenoxy)ethoxvLy]benzyl}-3 oxopropyl)carbamate 3-[tert-Butoxycarbonyl)amino]-2- {4-[2-(2,6-dichloro-4-methylphenoxy) ethoxy]benzyl}propanoic acid from Example 9, Step 3 (1 eq.) was combined with Hunig's base (3 eq.) 10 and Amine 36 (1 eq.) in anhydrous DMF (0.5 M). To this was then added portionwise O-(7 azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.2 eq.). The resulting yellow solution was stirred at RT for 18 h. The now reddish solution was diluted with ether and washed with H 2 0. The aqueous washes were back extracted with ether. The combined organic extracts were washed with brine, dried over MgSO 4 , filtered and the filtrate concentrated in vacuo. Purification of the 5 crude product thus obtained by way of flash chromatography (SiO 2 , 3:1 (v/v) Hex : EtOAc) afforded the title compound as a colorless oil. Step 2: tert-Butyl (3-{cyclopropy f3-hydroxy-5-(3-methoxypropyl)benzv]y](cvclopropyl)amino -2-{4-[2 (2,.6-dichloro-4-methylphenoxy)ethoxy benzvl }-3-oxopropyli)carbamate To a solution of tert-butyl (3-[[3-{[tert-butyl(dimethyl)silyl]oxy}-5-(3 0 methoxypropyl)benzyl](cyclopropyl)amino]-2- {4-[ 2
-(
2 ,6-dichloro-4-methylphenoxy)ethoxy]benzyl}-3 oxopropyl)carbamate from the previous step (1 eq.) in THF (0.05 M) was added tetrabutylammonium fluoride (1.0 M THF solution, 1.5 eq.). The resulting golden yellow solution was stirred at RT for 8 h. The reaction mixture was quenched with sat. aq. NH 4 Cl and then extracted with ether. The combined organic extracts were washed with brine, dried over MgSO 4 , filtered and the filtrate concentrated in 5 vacuo. Purification of the crude product thus obtained by way of flash chromatography (SiO 2 , 2:1 (v/v) Hex : EtOAc -4 1:1 (v/v) Hex : EtOAc) afforded the title compound as a white semisolid. Step 3: 3-Amino-N-cyclopropyvl-2-f 4
-[
2
-(
2 ,6-dichloro-4-methylphenoxy)ethoLxy]benzyll-N-[3-hydroxy 5-(3-methoxvpropvl)benzyllpropanamide To a CH 2
CI
2 solution (0.08 M) of tert-butyl (3-{cyclopropyl[3-hydroxy-5-(3 0 methoxypropyl)benzyl](cyclopropyl)amino }-2- { 4 -[2-( 2
,
6 -dichloro-4-methylphenoxy)ethoxy]benzyl }-3 oxopropyl)carbamate from the previous step (1 eq.) was added HCI (4.0 M dioxane solution, 20 eq.). The resulting solution was stirred at RT for 3 h. Following the removal of the volatiles in vacuo, the resulting residue was directly loaded onto a SiO2 column packed with 92:8 (v/v) CH 2 C1 2 : 2.0 M NH 3 in -96- WO 2007/009250 PCT/CA2006/001196 MeOH. Elution with the same solvent system furnished the title compound as a white froth. MS (ESI+): 615.0. Example 71 3-Amino-N-cyclopropyl-2- { 4 -[2-(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl} -N-[3-(3 5 methoxypropyl)-5-(2-pyrrolidin-1-ylethoxy)benzyl]propanamide Me Cl O N O N OICD 1 V~ 0 I-ON I V
NH
2 Step 1: tert-Buivl (3- {cyclopropyl[3-(3-methoxypropvl)-5-(2-pyrrolidin- I -vlethoxy)benzyl]amino} -2- 4 [2-(2.6-dich loro-4-methylphenoxy)ethoxy]benzvl }1-3-oxopropyl)carbamate To a solution of tert-butyl (3- {cyclopropyl[3-hydroxy-5-(3 0 methoxypropyl)benzyl](cyclopropyl)amino }-2- {4-[ 2 -(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl }-3 oxopropyl)carbamate from Example 70, Step 2 (1 eq.) in DMF (0.05 M) was added 1-(2 chloroethyl)pyrrolidine (1.2 eq.) and cesium carbonate (1.3 eq.). The resulting suspension was heated at 60 oC for 5 h. The reaction mixture was quenched sat. aq. NaHCO 3 and then extracted with ether. The combined organic extracts were washed with water and brine, dried over MgSO 4 , filtered and the filtrate 5 concentrated in vacuo. Purification of the crude product thus obtained by way of flash chromatography (SiO 2 , CH 2
CI
2 -- ) 95:5 (v/v) CH 2 C1 2 : 2.0 M NH 3 in MeOH) afforded the title compound as a colorless oil. Step 2: 3-Amino-N-cyclopropyl-2-f4-[2-(2.6-dichloro-4-methylphenoxy)ethoxy]benzyal-N-[3-(3 methoxypropyl)-5-(2-pyrrolidin-1-vlethoxy)benzvl]propanamide To a CH 2 Cl2 solution (0.03 M) of tert-butyl (3-{cyclopropyl[3-(3-methoxypropyl)-5-(2 0 pyrrolidin- 1-ylethoxy)benzyl]amino }-2- { 4
-[
2
-(
2
,
6 -dichloro-4-methylphenoxy)ethoxy]benzyl } -3 oxopropyl)carbamate from the previous step (1 eq.) was added HCI (4.0 M dioxane solution, 20 eq.). The resulting solution was stirred at RT for 3 h. Following the removal of the volatiles in vacuo, the resulting residue was directly subjected to column chromatography (SiO 2 , CH 2 C12 - 90:10 (v/v) CH2Cl2: 2.0 M NH 3 in MeOH) to afford the title compound. MS (ESI+): 712.2. 5 Example 72 3-Amino-N-cyclopropyl-2-f 4
-[
2
-(
2 ,6-dichloro-4-methylphenoxy)ethoxy]benzyl}-N-[3-(3 methoxypropyl)-5-(pyridin-2-ylmethoxy)benzyl]propanamide Me~ CI N CM OMe O ON
NH
2 -97- WO 2007/009250 PCT/CA2006/001196 Prepared according to the procedure described in Example 71 but using instead 2-(chloromnethyl)pyridine as starting material. The title compound was obtained as a colorless oil. MS (ESI+): 706.4. Example 73 5 3-Amino-N-cyclopropyl-2-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl }-N-[3-(2 methoxyethoxy)-5-(3-methoxypropyl)benzyl]propanamide Me, Cl o OMe CI O OMe O N
NH
2 Prepared according to the procedure described in Example 71 but using instead 2-bromoethyl methyl ether as starting material. The title compound was obtained as a colorless oil. MS 0 (ESI+): 673.2. Example 74 3-Amino-N-[3-(3-cyanopropoxy)-5-(3-methoxypropyl)benzyl]-N-cyclopropyl-2- {4-[2-(2,6-dichloro-4 methylphenoxy)ethoxy]benzyl } propanamide Me I Cl O ,- CN N CI N OMe O N
NH
2 5 Prepared according to the procedure described in Example 71 but using instead 4-bromobutanenitrile as starting material. The title compound was obtained as a colorless oil. MS (ESI+): 682.2. Example 75 3-Amino-N-cyclopropyl-2- {4-[ 2
-(
2 ,6-dichloro-4-methylphenoxy)ethoxy]benzyl}-N- {3-(3 0 methoxypropyl)-5-[(3-methylthio)propoxy]benzyl} propanamide Me C Cl O' SMe Cl rb O OMe O ON
NH
2 Step 1: 3-(Methylthio)propyl methanesulfonate To a solution of 3-(methylthio)propan-1-ol in dichloromethane (0.2 M) was added sequentially at -78 C Hunig's base (1.3 eq.) and methanesulfonyl chloride (1.3 eq.). The resulting 5 reaction mixture was stirred at -78 C for I h and then wannrmed slowly to RT. The reaction was quenched -98- WO 2007/009250 PCT/CA2006/001196 with sat. aq. NH 4 Cl and then extracted with ether. The combined organic extracts were washed with water and brine, dried over MgSO 4 , and filtered. Concentrated of the filtrate in vacuo afforded the title compound as a yellow oil. Step 2: tert-Butyl (3-{ cyclopropvl y{3-(3-methoxvpropvl)-5-[3-(methylthio)propoxy]benzvllamino)-2- 4 5 [2-(2.6-dichloro-4-methvlphenoxy)ethoxy]benzyl }-3-oxopropyl)carbamate To a solution of tert-butyl (3-{cyclopropyl[3-hydroxy-5-(3 methoxypropyl)benzyl](cyclopropyl)amino } -2- { 4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl } -3 oxopropyl)carbamate from Example 70, Step 2 (1 eq.) in DMF (0.05 M) was added 3 (methylthio)propyl methanesulfonate from the previous step (1.4 eq.) and cesium carbonate (1.4 eq.). 0 The resulting suspension was heated at 60 oC for 12 h. The reaction mixture was quenched sat. aq. NaHCO 3 and then extracted with ether. The combined organic extracts were washed with water and brine, dried over MgSO 4 , filtered and the filtrate concentrated in vacuo. Purification of the crude product thus obtained by way of flash chromatography (SiO2, 3:2 (v/v) Hex: EtOAc -) 2:3 (v/v) Hex: EtOAc) afforded the title compound as a colorless oil. 5 Step 3: 3-Amino-N-cyclopropvl-2- {4-[2-(2,6-dichloro-4-methylphenoLxy)ethoxylbenzyl!-N-{3-(3 methoxypropyl)-5-[(3-methylthio)propoxy]benzvl}propanamide To a CH 2 Cl 2 solution (0.08 M) of tert-butyl (3-{cyclopropyl{3-(3-methoxypropyl)-5-[3 (methylthio)propoxy]benzyl}amino)-2- {4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl}-3 oxopropyl)carbamate from the previous step (1 eq.) was added HCI (4.0 M dioxane solution, 20 eq.). 0 The resulting solution was stirred at RT for 3 h. Following the removal of the volatiles in vacuo, the resulting residue was directly subjected to column chromatography (SiO 2 , CH 2
CI
2 -4 95:5 (v/v) CH 2 Cl 2 : 2.0 M NH 3 in MeOH) to afford the title compound. MS (ESI+): 703.0. Example 76 3-Amino-N-cyclopropyl-2- {4-[ 2 -(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl } -N- 3-(3 5 methoxypropyl)-5-[(3-methylsulfonyl)propoxy]benzyl } propanamide Me , CI O' SO 2 Me CIl O OMe O N
NH
2 Step 1: tert-Butyl (3- cyclopropyl3 1-(3-methoxvpropyl)-5-[3-(methylsulfonyl)propoxy]benzylI amino) 2-{4-[2-(2.6-dichloro-4-methylphenoxy)ethoxybenzvll-3-oxopropyl)carbamate To tert-butyl (3-{cyclopropyl {3-(3-methoxypropyl)-5-[3 0 (methylthio)propoxy]benzyl} amino)-2- {4-[ 2
-(
2 ,6-dichloro-4-methylphenoxy)ethoxy]benzyl }-3 oxopropyl)carbamate from Example 75, Step 2 (1 eq.) in a 1:1 (v/v) methanol : water solution (0.05 M) was added oxone (2.5 eq.) and sodium bicarbonate (10 eq.). The reaction mixture was stirred at RT for 1 h. The volatiles were then removed in vacuo and the result residue was extracted with ether. The combined organic extracts were washed with water and brine, dried over MgSO 4 , filtered and the filtrate -99- WO 2007/009250 PCT/CA2006/001196 concentrated in vacuo. Purification of the crude product thus obtained by way of flash chromatography (SiO 2 , 3:2 (v/v) Hex: EtOAc -4 1:3 (v/v) Hex: EtOAc) afforded the title compound as a colorless oil. Step 2: 3-Amino-N-cyclopropvl-2-14-[2-(2,6-dichloro-4-methylphenoxy)ethoxylbenyl}-A-13-(3 methoxvpropyl)-5-[(3-methylsulfonvl)propoxy]benzyl}propanamide 5 To a CH 2 Cl 2 solution (0.08 M) of tert-butyl ( 3 -{cyclopropyl {3-(3-methoxypropyl)-5-[3 (methylsulfonyl)propoxy]benzyl} amino)-2- { 4
-[
2 -(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl}-3 oxopropyl)carbamate from the previous step (1 eq.) was added HCI (4.0 M dioxane solution, 20 eq.). The resulting solution was stirred at RT for 4 h. Following the removal of the volatiles in vacuo, the resulting residue was directly subjected to column chromatography (SiO 2 , CH 2 Cl 2 -- 92:8 (v/v) CH 2
CI
2 : 0 2.0 M NH 3 in MeOH) to afford the title compound. MS (ESI+): 734.8. Example 77 3-Amino-N-cyclopropyl-2- {4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl } -N-[3-(3 methoxypropyl)-5-(pyridin-3-ylmethoxy)benzyl]propanamide Me CI O - OMe N O NO
NH
2 5 Prepared according to the procedure described in Example 71 but using instead 3-(chloromethyl)pyridine as starting material. The title compound was obtained as a pale yellow oil. MS (ESI+): 706.4. Example 78 3-Amino-N-cyclopropyl-2- { 4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl } -N-[3-(3 0 methoxypropyl)-5-(pyridin-4-ylmethoxy)benzyl]propanamide C 1 OMe O ON
NH
2 Prepared according to the procedure described in Example 71 but using instead 4-(chloromethyl)pyridine as starting material. The title compound was obtained as a pale yellow oil. MS (ESI+): 706.4. 5 Example 79 3-Amino-N-cyclopropyl-2- { 4
-[
2
-(
2 ,6-dichloro-4-methylphenoxy)ethoxy]benzyl } -N- {3-(3 methoxypropyl)-5-[(1-oxidopyridin-2-yl)methoxy]benzyl}propanamide -100- WO 2007/009250 PCT/CA2006/001196 0 0 Me CO N PO N CIK. OMe 0~t ONV
NH
2 Step 1: tert-Butyl (3-(cyclopropvl {3-(3-methoxypropvl)-5-[( -oxidopyridin-2 yl)methoxy]benzyl I amino)-2-{4-[2-(2.6-dichloro-4-methylphenoxy)ethoxy]benzyl} 1-3 oxopropyl)carbamate 5 To a solution of tert-butyl (3- {cyclopropyl[3-(3-methoxypropyl)-5-(pyridin-2 ylmethoxy)benzyl]amino} -2- {4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl } -3 oxopropyl)carbamate from Example 72, Step 1 (1 eq.) in dichloromethane (0.02 M) was added 3-chloroperoxybenzoic acid (2 eq.). The reaction mixture was stirred at RT for 1 h. The reaction was quenched with sat. aq. NaHCO 3 and then extracted with ether. The combined organic 0 extracts were washed with water and brine, dried over MgSO 4 , filtered and the filtrate concentrated in vacuo. Purification of the crude product thus obtained by way of flash chromatography (SiO 2 , CH 2 Cl2 97:3 (v/v) CH 2 Cl 2 : 2.0 M NH 3 in MeOH) afforded the title compound. Step 2: 3-Amino-N-cyclopropvl-2- {4-[2-(2.6-dichloro-4-methylphenoxy)ethoxy]benzyl -N- 13-(3 methoxypropyl)-5-[( 1 -oxidopyridin-2-yl)methoxvy]ben l} propanamide 5 To a CH2Cl 2 solution (0.03 M) of tert-butyl (3-(cyclopropyl {3-(3-methoxypropyl)-5-[(1 oxidopyridin-2-yl)methoxy]benzyl} amino)-2- { 4-[ 2 -(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl}-3 oxopropyl)carbamate from the previous step (1 eq.) was added HCI (4.0 M dioxane solution, 20 eq.). The resulting solution was stirred at RT for 24 h. Following the removal of the volatiles in vacuo, the resulting residue was directly subjected to column chromatography (SiO 2 , 98:2 (v/v) CH 2
CI
2 : 2.0 M NH 3 0 in MeOH -) 90:10 (v/v) CH2Cl 2 : 2.0 M NH 3 in MeOH) to afford the title compound. MS (ESI+): 721.8. Example 80 3-Amino-N-cyclopropyl-2- {4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl}-N- {3-(3 methoxypropyl)-5-[(1-oxidopyridin-3-yl)methoxy]benzyl } propanamide Me Cl 0, O8 O OMe 0 N N
NH
2 5 Prepared according to the procedure described in Example 79 but using instead tert-butyl (3- {cyclopropyl[ 3
-(
3 -methoxypropyl)-5-(pyridin-3-ylmnethoxy)benzyl]amino}-2- {4-[2-(2,6 dichloro- 4 -methylphenoxy)ethoxy]benzyl}-3-oxopropyl)carbamate from Example 77, Step 1 as starting material. The title compound was obtained as a colorless oil. MS (ESI+): 721.8. -101- WO 2007/009250 PCT/CA2006/001196 Example 81 3-Amino-N-cyclopropyl-2- { 4
-[
2 -(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl}-N- {3-(3 methoxypropyl)-5-[(1 -oxidopyridin-4-yl)methoxy]benzyl } propanamide Me C1 0e O ON I,
NH
2 5 Prepared according to the procedure described in Example 79 but using instead tert-butyl (3- {cyclopropyl[3-( 3 -methoxypropyl)-5-(pyridin-4-ylmethoxy)benzyl]amino} -2- {4- [2-(2,6 dichloro-4-methylphenoxy)ethoxy]benzyl}-3-oxopropyl)carbamate from Example 78, Step 1 as starting material. The title compound was obtained as a colorless oil. MS (ESI+): 721.8. Example 82 0 3-Amino-N-cyclopropyl-2- { 4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl }-N-[3-(3 methoxypropyl)-5-(2-pyridin-2-ylethoxy)benzyl]propanamide Me Cl O N N CiK1 OMe ON
NH
2 Step 1: tert-Butyl (3- {cyclopropy [3-( 3 -methoxypropyl)-5-(2-pyridin-2-ylethoxy)benzyl]aminol}-2- {4-[2 (2,6-dichloro-4-methylphenoxv)ethoxy]benzvll-3-oxopropyl)carbamate 5 To a solution of tert-butyl (3-{cyclopropyl[3-hydroxy-5-(3 mnethoxypropyl)benzyl](cyclopropyl)amino }-2- {4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl }-3 oxopropyl)carbamate from Example 70, Step 2 (1 eq.) in toluene (0.1 M) was added 2-pyridin-2 ylethanol (1.2 eq.) and 1,1'-(azodicarbonyl)-dipiperidine (1.2 eq.). The resulting orange solution was deoxygenated before tributylphosphine (1.2 eq.) was added. The now yellow-orange solution was heated 0 at 100 C for 14 h. The reaction mixture was cooled to RT, diluted with ether, and washed with 1 N aq. NaOH. The aqueous wash was back extracted with ether and the combined organic extracts were dried over MgSO 4 . Filtration and concentration of the filtrate in vacuo afforded a red oil. Purification of the crude product thus obtained by way of flash chromatography (SiO 2 , 4:1 (v/v) Hex : EtOAc -- EtOAc) afforded the title compound as a pale yellow oil. 5 Step 2: 3-Amino-N-cyclopropyl-2-{ 4
-[
2
-(
2 ,6-dichloro-4-metbylphenoxy)ethoxy]benzvyl-N-[3-(3 methoxypropyl)-5-(2-pyridin-2-ylethoxy)benzyll] propanamide To a CH 2 C1 2 solution (0.03 M) of tert-butyl ( 3 - {cyclopropyl[3-(3-methoxypropyl)-5-(2 pyridin-2-ylethoxy)benzyl]amino}-2-
{
4
-[
2
-(
2
,
6 -dichloro-4-methylphenoxy)ethoxy]benzyl}-3 oxopropyl)carbamate from the previous step (1 eq.) was added HCI (4.0 M dioxane solution, 30 eq.). -102- WO 2007/009250 PCT/CA2006/001196 The resulting solution was stirred at RT for 12 h. Following the removal of the volatiles in vacuo, the resulting residue was directly subjected to column chromatography (SiO 2 , 90:10 (v/v) CH 2 Cl 2 : 2.0 M
NH
3 in MeOH) to afford the title compound as a white froth. MS (ESI+): 720.0. Example 83 5 3-Amino-N-cyclopropyl-2- {4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl} -N- {3-(3 methoxypropyl)-5-[2-(1 -oxidopyridin-2-yl)ethoxy]benzyl}propanamide ooN Me CI O Ol OMe oO N
NH
2 Prepared according to the procedure described in Example 79 but using instead lert-butyl (3- {cyclopropyl[3-(3-methoxypropyl)-5-(2-pyridin-2-ylethoxy)benzyl] amino }-2- { 4-[2-(2,6 0 dichloro-4-methylphenoxy)ethoxy]benzyl}-3-oxopropyl)carbamate from Example 82, Step 1 as starting material. The title compound was obtained as a white froth. MS (ESI+): 735.9. Example 84 3-Amino-N-cyclopropyl-2- {4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl } -N-[3-(3 methoxypropyl)-5-(2-morpholin-4-ylmethoxy)benzyl]propanamide $o (^ O Me , Cl O N CIO OMe o ON 5 NH 2 Prepared according to the procedure described in Example 71 but using instead 4-(2-chloroethyl)morpholine as starting material. The title compound was obtained as a colorless oil. MS (ESI+): 728.0. Example 85 0 3-Amino-N-cyclopropyl-2- { 4
-[
2
-(
2
,
6 -dichloro-4-methylphenoxy)ethoxy]benzyl } -N- [3 -(3 methoxypropyl)-5- { [4-(methylsulfonyl)benzyl]oxy} benzyl)propanamide Me C 0 O 2 Me Cl; :,)a S02Me CI O6, 0 N, OMe
NH
2 -103- WO 2007/009250 PCT/CA2006/001196 Prepared according to the procedure described in Example 71 but using instead 4-(chloromethyl)phenyl methyl sulfone as starting material. The title compound was obtained as a colorless oil. MS (ESI+): 782.8. Example 86 5 Ethyl 2- { [3- { [(3-amino-2- { 4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl } propanoyl) (cyclopropyl)amino]methyl}-5-(3-methoxypropyl)phenoxy]methyl}cyclopropanecarboxylate Me Cl
ON'KPCO
2 Et Cl O OMe 0O N
NH
2 Step 1: Ethyl 2-(hydroxvmethyl)cyclopropanecarboxylate To a solution of ethyl 2-formylcyclopropanecarboxylate in methanol (0.7 M) was added 0 at -0 oC sodium borohydride portionwise. The resulting reaction mixture was stirred at 0 oC for 30 min and then at RT for 1.5 h. The reaction was quenched with sat. aq. NH 4 Cl and then extracted with ether. The combined organic extracts were washed with water and brine, dried over MgSO 4 , and filtered. Concentrated of the filtrate in vacuo afforded the title compound as a colorless oil. Step 2: Ethyl 2- r[3- { [(3-[tert-butoxycarbonyl)amino]-2- {4-[2-(2,6-dichloro-4 5 methylphenoxy)ethoxy]benzyl } propanoyl) (cyclopropyl)aminolmethyl}-5-(3 methoxypropvl)phenoxvymethyl } cyclopropanecarboxylate To a solution of tert-butyl (3- { cyclopropyl[3-hydroxy-5-(3 methoxypropyl)benzyl](cyclopropyl)amino }-2- {4-[ 2 -(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl }-3 oxopropyl)carbamate from Example 70, Step 2 (1 eq.) in toluene (0.06 M) was added ethyl 2 0 (hydroxymethyl)cyclopropanecarboxylate from the previous step (2 eq.) and 1,1 '-(azodicarbonyl) dipiperidine (2.4 eq.). The resulting orange solution was deoxygenated before tributylphosphine (2.4 eq.) was added. The now yellow-orange solution was heated at 80 C for 24 h. The reaction mixture was cooled to RT, quenched with water and diluted with EtOAc. The biphasic mixture was vigorously stirred at RT for 16 h. The organic layer was then separated and washed sequentially with water, 5% aq. HCI, 5 sat. aq. NaHCO 3 and brine. The organic layer was dried over MgSO 4 , filtered and the filtrate concentrated in vacuo. Purification of the crude product thus obtained by way of flash chromatography (SiO 2 , 10:1 (v/v) toluene : acetone) afforded the title compound as a colorless oil. Step 3: Ethyl 2- { [3- { [(3-amino-2- f 4 -f 2
-(
2 .6-dichloro-4-methylphenoxy)ethoxy]benzyl propanoyl) (cyclopropyl)aminolmethyl }-5-(3 -methoxypropyl)phenoxy]methyl 1 cyclopropanecarboxylate 0 To a CH 2 C1 2 solution (0.03 M) of ethyl 2 -{[3-{[(3-[tert-butoxycarbonyl)amino]-2-{4-[2
(
2
.
6 -dichloro-4-methylphenoxy)ethoxy]benzyl}propanoyl)(cyclopropyl)amino]methyl}-5-(3 methoxypropyl)phenoxy]methyl}cyclopropanecarboxylate from the previous step (1 eq.) was added HCI (4.0 M dioxane solution, 25 eq.). The resulting solution was stirred at RT for 3 h. Following the removal of the volatiles in vacuo, the resulting residue was directly subjected to column chromatography -104- WO 2007/009250 PCT/CA2006/001196 (SiO 2 , 95:5 (v/v) CH 2 C1 2 : 2.0 M NH 3 in MeOH) to afford the title compound as a colorless oil. MS (ESI+): 741. 'H NMR (acetone-d 6 ): 0.31 (mi, 1H), 0.65-0.69 (min, 2H), 0.88 (min, 1H), 1.05 (mi, 1H), 1.18 (mi, 1H), 1.24 (t, J= 6.9 Hz, 3H), 1.74 (im, 1H), 1.75-1.9 (min, 3H), 2.33 (s, 3H), 2.41 (min, 1H), 2.61 (t, J= 7.5 Hz, 2H), 2.74-2.83 (min, 4H), 2.90 (t, J = 10.7 Hz, IH), 3.28 (s, 3H), 3.30-3.34 (min, 2H), 3.59 (t, J= 5 10.6 Hz, 1H), 3.83 (t,J = 7.4 Hz, 1H), 3.95-4.07 (mi, 2 H), 4.09-4.12 (min, 2H), 4.26 (d,J= 14.9 Hz, 1H), 4.37-4.40 (mi, 4H), 4.67 (d,J = 14.9 Hz, 1H), 6.65 (brs, 3H), 6.86 (d,J = 7.1 Hz, 2H), 7.16 (d,J= 7.1 Hz, 2H), 7.27 (s, 2H). Example 87 Sodium 2- { [3- { [(3-amino-2- {4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl} propanoyl) 0 (cyclopropyl)amino]methyl}-5-(3-methoxypropyl)phenoxy]methyl} cyclopropanecarboxylate Me I Cl
ONKT<CO
2 Na Cl 1 OMe 0O N
NH
2 To a ethanol solution (0.03 M) of ethyl 2-{[3-{[(3-amino-2-{4-[2-(2,6-dichloro-4 methylphenoxy)ethoxy]benzyl } propanoyl) (cyclopropyl)amino]methyl } -5-(3 methoxypropyl)phenoxy]methyl}cyclopropanecarboxylate from Example 86 was added sodium 5 hydroxide (1 N aqueous solution, 2.2 eq.). The resulting solution was stirred at 80 oC for 18 h. The volatiles were removed in vacuo and the resulting solid residue was suspended in dichloromethane. The insolubles were then filtered off and the filtrate was concentrated in vacuo to afford the title compound as a white solid. MS for the corresponding free acid (ESI+): 713.2. 1 H NMR (methanol-d 4 ): 0.41 (inm, 1H), 0 0.70-0.83 (m, 4H), 1.11 (mi, 1H), 1.52 (min, 1H), 1.72 (min, 1H), 1.80-1.87 (min, 2H), 2.24 (min, 1H), 2.31 (s, 3H), 2.59-2.62 (mi, 2H), 2.75-2.80 (inm, 2H), 2.84 (dd, J= 13.2, 9.5 Hz, 1H), 2.95 (dd, J= 12.7, 7.5 Hz, 1H), 3.31 (s, 3H), 3.37 (t, J= 6.4 Hz, 2H), 3.73 (min, 1H), 3.85 (d, J= 6.7 Hz, 2H), 4.22-4.45 (min, 4H), 4.48 (d,J= 14.6 Hz, 1H), 4.58 (d,J= 14.8 Hz, 1H), 6.58 (s, 1H), 6.62 (s, 1H), 6.65 (s, 1H), 6.78 (d,J = 8.6 Hz, 2H), 7.08 (d, J= 8.5 Hz, 2H), 7.22 (s, 2H). 5 Example 88 Ethyl 2- { [3-{ [(3-amino-2- {4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl } propanoyl) (cyclopropyl)amino]methyl } -2-chloro-5-(3-methoxypropyl)phenoxy]methyl } cyc lopropanecarboxylate Me C C
O-,<'CO
2 Et 0::( CI CI O C . OMe 0 ON
NH
2 -105- WO 2007/009250 PCT/CA2006/001196 Prepared according to the procedure described in Example 9 but using instead Amine 37 as starting material. The title compound was obtained as a colorless oil. MS (ESI+): 777.2. Example 89 Sodium 2- { [3- { [(3-amino-2- {4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl}propanoyl) 5 (cyclopropyl)amino]methyl } -2-chloro-5-(3-methoxypropyl)phenoxy]methyl } cyclopropanecarboxylate Me C O:" CO2 Na Cl O. OMe O
NH
2 Prepared according to the procedure described in Example 87 but using instead ethyl 2 { [3- { [(3-amino-2- {4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl } propanoyl)(cyclopropyl) amino]methyl I} -2-chI oro-5-(3-methoxypropyl)phenoxy]methyl I} cyclopropanecarboxylate from Example 0 88 as starting material. The title compound was obtained as a white solid. MS for the corresponding free acid (ESI+): 747.3. Example 90 Ethyl 2-[3- { [(3-amino-2- {4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl } propanoyl) (cyclopropyl)amino]methyl}-5-(3-methoxypropyl)phenoxy]-2-methylpropanoate Me Me Me 1 Cl 0 CO 2 Et Cl Ob OMe O N 15
NH
2 Prepared according to the procedure described in Example 71 but using instead_ethyl 2 bromo-2-methylpropanoate as starting material. The title compound was obtained as a colorless oil. MS (ESI+): 729. Example 91 20 Sodium 2-[3- { [(3-amino-2- {4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl} propanoyl) (cyclopropyl)amino]methyl } -5-(3-methoxypropyl)phenoxy]-2-methylpropanoate Me Me Me Cl 0 CO 2 Na CI OMe o ~0N
NH
2 Prepared according to the procedure described in Example 87 but using instead ethyl 2 [3- { [(3-amino-2- {4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl } propanoyl)(cyclopropyl)amino] -106- WO 2007/009250 PCT/CA2006/001196 methyl}-5-(3-methoxypropyl)phenoxy]-2-methylpropanoate from Example 90 as starting material. The title compound was obtained as a white foam. MS for the corresponding free acid (ESI+): 700. Example 92 3-Amino-N-[3,5-bis(2-methoxyethoxy)benzyl]-N-cyclopropyl-2- {4-[2-(2,6-dichloro-4 5 methylphenoxy)ethoxy]benzyl } propanamide Me Cl o OMe Cl O Oj 0-_OMe O N
NH
2 Prepared according to the procedure described in Example 9 but using instead Amine 38 as starting material. The title compound was obtained as a colorless oil. MS (ESI+): 672.0. Example 93 10 3-Amino-N-[3,5-bis(4,4,4-trifluorobutoxy)benzyl]-N-cyclopropyl-2- {4-[2-(2,6-dichloro-4 methylphenoxy)ethoxy]benzyl}propanamide Me C I O CF 3 0 Cl O 0-
CF
3 O N KI- D >7'
NH
2 Prepared according to the procedure described in Example 9 but using instead Amine 39 as starting material. The title compound was obtained as a pale yellow oil. MS (ESI+): 779.1. 5 Example 94 3-Amino- N-cyclopropyl-2- { 4
-[
2
-(
2 ,6-dichloro-4-methylphenoxy)ethoxy]benzyl } -N- { 3-(3 methoxypropyl)-5-[3-( H-tetrazol-5-yl)propoxy]benzyl } propanamide H Me Cl O N Cl O OMe N
NH
2 To a solution of tert-butyl (3-[[3-(3-cyanopropoxy)-5-(3 0 methoxypropyl)benzyl](cyclopropyl)amino]-2- {4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl}-3 oxopropyl)carbamate from Example 74 in dichlorobenzene (0.08 M) was added azidotributyltin (2 eq.). The resulting mixture was heated to 150 oC for 22 h. The reaction was quenched with glacial acetic acid (6 eq.) and directly loaded onto a silica gel column packed with 85:15 (v/v) CH 2 Cl 2 : 2.0 M NH 3 in -107- WO 2007/009250 PCT/CA2006/001196 MeOH. Elution with the same solvent system afforded the title compound as a yellow oil. MS (ESI+): 725.4. Example 95 3-Amino-N- { [5-chloro-2-(3-methoxypropyl)pyridin-4-yl]methyl } -N-cyclopropyl-2-14-[2-(2,6-dichloro-4 5 methylphenoxy)ethoxy]benzyl } propanamide Me Cl IV- CI CI O C OMe O
NH
2 Prepared according to the procedure described in Example 9 but using instead Amine 40 as starting material. The title compound was obtained as a pale yellow oil. MS (ESI+): 779.1. Example 96 10 3-Amino-N- { [5-chloro-2-(3-methoxypropyl)-l-oxidopyridin-4-yl]methyl } -N-cyclopropyl-2- {4-[2-(2,6 dichloro-4-methylphenoxy)ethoxy]benzyl } propanamide Me N CI CI O- OMe O
NH
2 Step 1: tert-Butyl (3-[{ [5-chloro-2-(methoxypropyl)- 1-oxidopyridin-4-vllmethyl } (cyclopropyl)amino]-2 {4-[2-(2,6-dichloro-4-methylphenoxy)ethoxvylbenzyl}-3-oxopropyl)carbamate 5 To a solution of tert-butyl (3-[{ [5-chloro-2-(methoxypropyl)pyridin-4 yl]methyl}(cyclopropyl)amino]-2- {4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl}-3 oxopropyl)carbamate from Experiment 94, Step 4 in dichloromethane (0.03 M) was added 3 chloroperoxybenzoic acid. The reaction mixture was stirred at RT for 16 h. The reaction was quenched with water and then extracted with EtOAc. The combined organic extracts were washed with 10% aq. .0 HCI and brine, dried over MgSO 4 , filtered and the filtrate concentrated in vacuo. Purification of the crude product thus obtained by way of flash chromatography (SiO 2 , 1:1 (v/v) Hex : EtOAc -4 EtOAc) afforded the title compound. Step 2: 3-Amino-N- {1[5-chloro-2-(methoxypropyl)- 1 -oxidopyridin-4-yl]methyl } -N-cyclopropyl-2- 4-[2 (2,6-dichloro-4-methylphenoxy)ethoxy]benzyl } propanamide 15 To a CH 2 Cl 2 solution (0.07 M) of tert-butyl (3-[{[5-chloro-2-(methoxypropyl)-1 oxidopyridin-4-yl]methyl}(cyclopropyl)amino]-2- {4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl} 3-oxopropyl)carbamate from the previous step (1 eq.) was added HCI (4.0 M dioxane solution, 30 eq.). The resulting solution was stirred at RT for 16 h. Following the removal of the volatiles in vacuo, the -108- WO 2007/009250 PCT/CA2006/001196 resulting residue was directly subjected to column chromatography (SiO 2 , 95:5 (v/v) CH 2 Cl 2 : 2.0 M NH 3 in MeOH) to afford the title compound as an oil. MS (ESI+): 651. Example 97 3-Amino- N-cyclopropyl-2- {4-[ 2
-(
2
,
6 -dichloro-4-methylphenoxy)ethoxy]benzyl }-N- { [2-methoxy-6-(3 5 methoxypropyl)pyridin-4-yl]methyl} propanamide Me I Cl OMe C IO OMe O ON
NH
2 Prepared according to the procedure described in Example 9 but using instead Amine 41 as starting material. The title compound was obtained as a pale yellow oil. MS (ESI+): 630.0. 10 Example 98 3-Amino- N-cyclopropyl-2- { 4
-[
2
-(
2
,
6 -dichloro-4-methylphenoxy)ethoxy]benzyl } -N- { [2-hydroxy-6-(3 methoxypropyl)pyridin-4-yl]methyl} propanamide Me ICl O OH Cl O OMe O ON I- V
NH
2 Step 1: tert-Butyl (3-[ { [2- { [tert-butvl(dimethyl)silylloxyl-6-(3-methoxypropyl)pyridin-4 5 vllmethyl } (cyclopropyl)amino]-2- { 4 -[2-(2.6-dichloro-4-methylphenoxv)ethoxy]benzvl } -3 oxopropvl)carbamate 3-[tert-Butoxycarbonyl)amino]-2-
{
4
-[
2 -(2,6-dichloro-4-methylphenoxy) ethoxy]benzyl}propanoic acid from Example 9, Step 3 (1 eq.) was combined with Hunig's base (3 eq.) and Amine 42 (1.2 eq.) in anhydrous DMF (0.5 M). To this was then added portionwise O-(7 0 azabenzotriazol-1-yl)-NN,N,NN'-tetramethyluronium hexafluorophosphate (1.2 eq.). The resulting yellow solution was stirred at RT for 48 h. The now reddish solution was diluted with ether and washed with H 2 0. The aqueous washes were back extracted with ether. The combined organic extracts were washed with brine, dried over MgSO 4 , filtered and the filtrate concentrated in vacuo. Purification of the crude product thus obtained by way of flash chromatography (SiO2, 3:1 (v/v) Hex : EtOAc -- ) EtOAc) 5 afforded the title compound as a colorless oil. Step2: 3-Amino- N-cyclopropyl-2- { 4
-[
2
-(
2
,
6 -dichloro-4-methylphenoxy)ethoxy]benzvl } -N- { [2 hydroxy-6-(3-methoxypropyl)pyvridin-4-yllmethylIpropanamide To a CH 2 Cl 2 solution (0.03 M) of tert-butyl ( 3 -[{ [ 2 -{ [tert-butyl(dimethyl)silyl]oxy}-6
(
3 -methoxypropyl)pyridin-4-yl]methyl} (cyclopropyl)amino]-2- {4-[2-(2,6-dichloro-4 -109- WO 2007/009250 PCT/CA2006/001196 methylphenoxy)ethoxy]benzyl}-3-oxopropyl)carbamate from the previous step (1 eq.) was added HCI (4.0 M dioxane solution, 60 eq.). The resulting solution was stirred at RT for 3 h and the volatiles were removed in vacuo. The resulting residue was recrystallized from ether-dichloromethane to afford the title compound as a white solid. MS (ESI+): 616.1. 5 Example 99 3-Amino- N- { [2,6-bis(3-methoxypropyl)pyridin-4-yl]methyl }- N-cyclopropyl-2- {4-[2-(2,6-dichloro-4 methylphenoxy)ethoxy]benzyl } propanamide Me Cl OMe OIN Cl I OMe O N
NH
2 Prepared according to the procedure described in Example 9 but using instead Amine 43 0 as starting material. The title compound was obtained as a pale yellow oil. MS (ESI+): 672. Example 100 3-Amino- N-cyclopropyl-2- { 4
-[
2
-(
2 ,6-dichloro-4-methylphenoxy)ethoxy]benzyl}-N-({2-(3 methoxypropyl)-6-[3-(methylthio)propoxy]pyridin-4-yl } methyl } propanamide Me C Cl O- SMe Cl O OMe 0 ON NV
NH
2 5 Step 1: tert-Butyl (3-[cyclopropyl({2-(3-methoxvpropyl)-6-[3-(methylthio)propoxy]pyridin-4 vllmethyl)amino]-2- { 4
-[
2
-(
2 ,6-dichloro-4-methylphenoxy)ethoxy]benzyl}-3-oxopropvl)carbamate 3-[tert-Butoxycarbonyl)amino]-2-
{
4
-[
2 -(2,6-dichloro-4-methylphenoxy) ethoxy]benzyl}propanoic acid from Example 9, Step 3 (1 eq.) was combined with Hunig's base (3 eq.) and Amine 44 (1.1 eq.) in anhydrous DMF (0.15 M). To this was then added portionwise O-(7 0 azabenzotriazol-1-yl)-N,N,N'N'-tetramethyluronium hexafluorophosphate (1.2 eq.). The resulting yellow solution was stirred at RT for 18 h. The now reddish solution was diluted with EtOAc and washed with H 2 0. The aqueous washes were back extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO 4 , filtered and the filtrate concentrated in vacuo. Purification of the crude product thus obtained by way of flash chromatography (SiO 2 , 7:3 (v/v) Hex: 5 EtOAc 4-) 1:1 (v/v) Hex : EtOAc) afforded the title compound as a colorless oil. Step 2: 3-Amino- N-cyclopropyl-2- {4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]benzvl}-N-({2-(3 methoxypropyl)-6-[3-(methylthio)propoxvlpyridin-4-yl methyl propananide To a CH 2 C1 2 solution (0.04 M) of tert-butyl ( 3 -[cyclopropyl({2-(3-methoxypropyl)-6-[3 (methylthio)propoxy]pyridin-4-yl]methyl)amino]-2- {4-[2-(2,6-dichloro-4 -110- WO 2007/009250 PCT/CA2006/001196 methylphenoxy)ethoxy]benzyl}-3-oxopropyl)carbamate from the previous step (1 eq.) was added HCI (4.0 M dioxane solution, 30 eq.). The resulting solution was stirred at RT for 1 h and the volatiles were removed in vacuo. Purification of the crude product thus obtained by way of column chromatography (SiO 2 , 94:6 (v/v) CH2Cl2: 2.0 M NH 3 in MeOH) afforded the title compound as an oil. MS (ESI+): 704. 5 Example 101 3-Amino- N-cyclopropyl-2- {4-[ 2
-(
2
,
6 -dichloro-4-methylphenoxy)ethoxy]benzyl}-N-({2-(3 methoxypropyl)-6-[3-(methylsulfonyl)propoxy]pyridin-4-yl } methyl} propanamide Me . Cl
O'-SO
2 Me Cl OMe 0 O N
NH
2 Step 1: tert-Butyl (3-[cyclopropyl(f2-(3-methoxypropyl)-6-[3-(methylsulfonvyl)propoxy]pyridin-4 0 vllmethyl)amino]-2- {4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl }-3-oxopropvl)carbamate To a 2:1:1 (v/v/v) THIF : MeOH : water solution (0.1 M) of tert-butyl (3-[cyclopropyl({2 (3-methoxypropyl)-6-[3-(methylthio)propoxy]pyridin-4-yl]methyl)amino]-2- {4-[2-(2,6-dichloro-4 methylphenoxy)ethoxy]benzyl}-3-oxopropyl)carbamate from Example 100, Step 1 (1 eq.) was added oxone T M (2.2 eq.) The resulting solution was stirred at RT for 2 h. The reaction was quenched with sat. 5 aq. NaHCO 3 and then extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO 4 , filtered and the filtrate concentrated in vacuo. Purification of the crude product thus obtained by way of flash chromatography (SiO 2 , 95:5 (v/v) CH 2 Cl 2 : EtOH) afforded the title compound as a colorless oil. Step 2: 3-Amino- N-cyclopropyl-2- {4-[ 2 -(2.6-dichloro-4-methylphenoxy)ethoxy]benzyl}-N-({2-(3 0 methoxypropyl)-6-[3-(methylsulfonvl)propoxvy]pyvridin-4-yl l methyl propanamide To a CH 2 Cl2 solution (0.04 M) of tert-butyl ( 3 -[cyclopropyl({2-(3-methoxypropyl)-6-[3 (methylsulfonyl)propoxy]pyridin-4-yl]methyl)amino]-2- {4-[2-(2,6-dichloro-4 methylphenoxy)ethoxy]benzyl}-3-oxopropyl)carbamate from the previous step (1 eq.) was added HCI (4.0 M dioxane solution, 30 eq.). The resulting solution was stirred at RT for 1.5 h and the volatiles were 5 removed in vacuo. Purification of the crude product thus obtained by way of column chromatography (SiO 2 , 94:6 (v/v) CH 2
CI
2 : 2.0 M NH 3 in MeOH -- 90:10 (v/v) CH 2 CI: 2.0 M NH 3 in MeOH) afforded the title compound as an oil. MS (ESI+): 736. Example 102 3-Amino- N-cyclopropyl-2- { 4
-[
2
-(
2 ,6-dichloro-4-methylphenoxy)ethoxy]benzyl } -N-( {2-(3 0 methoxypropyl)-6-[3-(methylsulfonyl)propoxy]-1-oxidopyridin-4-yl} methyl } propanamide -111- WO 2007/009250 PCT/CA2006/001196 Me Cl
O"-SO
2 Me o, %O O I OMe O- O
NH
2 Step 1: tert-Butvl (3-[cyclopropyl ({2-(3-methoxypropyl)-6-[3-(methylsulfonyl)propoxyl -I -oxidopyridin 4-yl]methyl)amino]-2- {4-[2-(2.6-dichloro-4-methylphenoxy)ethoxy]benzyl }-3-oxopropvl)carbamate To a dichloromethane solution (0.06 M) of tert-butyl (3-[cyclopropyl({2-(3 5 methoxypropyl)-6-[3-(methylsulfonyl)propoxy]pyridin-4-yl]methyl)amino]-2- {4-[2-(2,6-dichloro-4 methylphenoxy)ethoxy]benzyl}-3-oxopropyl)carbamate from Example 101, Step 1 (1 eq.) was added 3 chloroperoxybenzoic acid (3.6 eq.). The resulting solution was stirred at RT for 18 h. The reaction was quenched with sat. aq. NaHCO 3 and then extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na 2
SO
4 , filtered and the filtrate concentrated in vacuo. Purification of the 0 crude product thus obtained by way of flash chromatography (SiO2, 90:10 (v/v) CH 2 Cl 2 : EtOH -- 85:15 (v/v) CH 2 Cl 2 : EtOH) afforded the title compound. Step 2: 3-Amino- N-cyclopropvl-2- { 4-[2-(2,6-dichloro-4-methylphenoxv)ethoxy]benzvl -N-( { 2-(3 methoxypropyl)-6-[3-(methylsulfonvyl)propoxvy]- 1 -oxidopvridin-4-vl } methyl } propanamide To a CH 2 C1 2 solution (0.04 M) of tert-butyl (3-[cyclopropyl({2-(3-methoxypropyl)-6-[3 5 (methylsulfonyl)propoxy]- 1-oxidopyridin-4-yl]methyl)amino]-2- {4-[2-(2,6-dichloro-4 methylphenoxy)ethoxy]benzyl}-3-oxopropyl)carbamate from the previous step (1 eq.) was added HCI (4.0 M dioxane solution, 20 eq.). The resulting solution was stirred at RT for I h and the volatiles were removed in vacuo. Purification of the crude product thus obtained by way of column chromatography (SiO2, 95:5 (v/v) CH 2
CI
2 : 2.0 M NH 3 in MeOH -- 90:10 (v/v) CH 2 Cl 2 : 2.0 M NH 3 in MeOH) afforded 10 the title compound as an oil. MS (ESI+): 752. Example 103 3-Amino- N-cyclopropyl-2- {4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl }-N- { [2-(3 methoxypropyl)-6-(2-morpholin-4-ylethoxy)pyridin-4-yl]methyl } propanamide (^o Me Cl O N Cl OOMe N
NH
2 5 Prepared according to the procedure described in Example 9 but using instead Amine 45 as starting material. The title compound was obtained as a pale yellow oil. MS (ESI+): 729.2. -112- WO 2007/009250 PCT/CA2006/001196 Example 104 3-Amino-N-[3-(2-amino-2-oxoethoxy)-5-(3-methoxypropyl)benzyl]-N-cyclopropyl-2- { 4-[2-(2,6-dichloro 4-methylphenoxy)ethoxy]benzyl}propanamide Me 0 CN O H2 ,;o Cl OMe
NH
2 5 Prepared according to the procedure described in Example 71 but using instead 2 bromoacetamide as starting material. The title compound was obtained as an off-white solid. MS (ESI+): 672. Example 105 3- { [(3-Amino-2- {4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl } propanoyl)(cyclopropyl)amino] 0 methyl }-5-(3-methoxypropyl)phenyl ethylcarbamate NHEt Me Cl 0 0 CI O OMe 0 ~ N
NH
2 Step 1: 3- { [(3-[(tert-Butoxycarbonyl)amino]-2- {4-[2-(2.6-dichloro-4 methylphenoxy)ethoxy]benzyl } propanoyl)(cyclopropyl)amino]methyl } -5-(3-methoxypropyl)phenvl ethylcarbamate 5 To a solution of tert-butyl (3- {cyclopropyl[3-hydroxy-5-(3 methoxypropyl)benzyl](cyclopropyl)amino }-2- { 4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl }-3 oxopropyl)carbamate from Example 70, Step 2 (1 eq.) in dichloromethane (0.08 M) was added ethyl isocyanate (3 eq.), triethylamine (3 eq.) and a few crystals of DMAP. The resulting solution was stirred at RT for 1.5 h. The reaction mixture was concentrated in vacuo and directly subjected to purification by 0 way of column chromatography (SiO2, 3:2 (v/v) Hex: EtOAc -4 2:3 (v/v) Hex: EtOAc). The title compound was isolated as a colorless oil. Step 2: 3- { [(3-Amino-2- {4-[2-(2.6-dichloro-4-methylphenoxy)ethoxy]benzyl }propanovl)(cyvclopropyl) amino]methyl I -5-(3-methoxypropyl)phenyl ethylcarbamate To a CH2Cl 2 solution (0.07 M) of 3-{ [(3-[(tert-butoxycarbonyl)amino]-2-{4-[2-(2,6 5 dichloro-4-methylphenoxy)ethoxy]benzyl } propanoyl)(cyclopropyl)amino]methyl } -5-(3 methoxypropyl)phenyl ethylcarbamate from the previous step (1 eq.) was added HCI (4.0 M dioxane solution, 35 eq.). The resulting solution was stirred at RT for 3 h. Following the removal of the volatiles in vacuo, the resulting residue was directly subjected to column chromatography (SiO 2 , 94:6 (v/v) CH2C1 2 : 2.0 M NH 3 in MeOH) to afford the title compound. MS (ESI+): 686. -113- WO 2007/009250 PCT/CA2006/001196 Example 106 3- { [(3-Amino-2- {4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl } propanoyl)(cyclopropyl)amino] methyl }-5-(3-methoxypropyl)phenyl morpholine-4-carboxylate N Me I 0Cl O0 Cl O r OMe 0, N
NH
2 5 Prepared according to the procedure described in Example 105 but using instead morpholine-4-carbonyl chloride as starting material. The title compound was obtained as colorless oil. MS (APCI+): 728. Example 107 0 3- { [(3-Amino-2- {4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl} propanoyl)(cyclopropyl)amino] methyl}-5-(3-methoxypropyl)pheny 4-methylpiperazine- 1-carboxylate Me (N) N Me , Cl O OJ CI Ob OMe 0 N
NH
2 Prepared according to the procedure described in Example 105 but using instead 4 methylpiperazine-l-carbonyl chloride as starting material. The title compound was obtained as colorless 5 oil. MS (APCI+): 741. Example 108 3- { [(3-Amino-2- {4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl } propanoyl)(cyclopropyl)amino] methyl }-5-(3-methoxypropyl)phenyl (3-amino-2,2-dimethyl-3-oxopropyl)carbamate -114- WO 2007/009250 PCT/CA2006/001196 Me NH 2 Me O HN Me Cl 00 " OO ON CiK N6 OMe 0, 11: , O N
NH
2 Step 1: 3- { [(3-[(tert-Butoxycarbonyl)amino]-2- {4-[2-(2,6-dichloro-4 methylphenoxv)ethoxylbenzvl } propanovl)(cyclopropyl)amino]methyl -5-(3-methoxvpropyl)phenyl (3 amino-2,2-dimethyl-3-oxopropyl)carbamate 5 To a solution oftert-butyl (3-{cyclopropyl[3-hydroxy-5-(3 methoxypropyl)benzyl](cyclopropyl)amino }-2- {4-[ 2
-(
2
,
6 -dichloro-4-methylphenoxy)ethoxy]benzyl }-3 oxopropyl)carbamate from Example 70, Step 2 (1 eq.) in dichloromethane (0.13 M) was added triphosgene (0.3 eq.) and then sodium hydroxide (1 M aq. solution, 3 eq.). The resulting mixture was stirred at RT for 2 h. The reaction was quenched with brine. The organic phase was separated and then 0 added 3 -amino-2,2-dimethylpropanamide (4 eq.). The resulting suspension was allowed to stir at RT for 16 h. The reaction was quenched with water and then extracted with EtOAc. The combined organic extracts were washed with brine, dried over MgSO 4 , filtered, and the filtrate concentrated in vacuo. The crude product thus obtained was purified further by way of column chromatography (SiO 2 , 1:1 (v/v) Hex : EtOAc -) EtOAc) to afford the title compound as a colorless oil. 5 Step 2: 3- { [(3-Amino-2- {4-F[ 2 -(2.6-dichloro-4-methylphenonxy)ethoxylbenzyal propano l)(cvclopropy) aminolmethyl }-5-(3-methoxvpropvl)phenyl (3-amino-2,2-dimethyl-3-oxopropyl)carbamate To a CH 2 C12 solution (0.07 M) of 3 -{[(3-[(tert-butoxycarbonyl)amino]-2-{4-[2-(2,6 dichloro-4-methylphenoxy)ethoxy] benzyl } propanoyl)(cyclopropyl)amino]methyl } -5-(3 methoxypropyl)phenyl ethylcarbamate from the previous step (1 eq.) was added HCI (4.0 M dioxane 0 solution, 35 eq.). The resulting solution was stirred at RT for 3 h. Following the removal of the volatiles in vacuo, the resulting residue was directly subjected to column chromatography (SiO2, 95:5 (v/v)
CH
2
CI
2 : 2.0 M NH 3 in MeOH -) 90:10 (v/v) CH 2 Cl 2 : 2.0 M NH 3 in MeOH) to afford the title compound as a white solid. MS (ESI+): 757. Example 109 5 3- { [(3-Amino-2- { 4
-[
2
-(
2
,
6 -dichloro-4-methylphenoxy)ethoxy]benzyl } propanoyl)(cyclopropyl)amino] methyl } -5-(3-methoxypropyl)phenyl (2-hydroxypropyl)carbamate -115- WO 2007/009250 PCT/CA2006/001196 Me OH HN Me C l 0 10 Cl O OMe 0ON N
NH
2 Prepared according to the procedure described in Example 108 but using instead 1 aminopropan-2-ol as starting material. The title compound was obtained as colorless oil. MS (ESI+): 716. 5 Example 110 3-Amino-N-cyclopropyl-2-{ 4
-[
2
-(
2
,
6 -dichloro-4-methylphenoxy)ethoxy]benzyl}-N-(pyridin-4 ylimethyl)propanamide Me Cl ON/ CI N 0 NON
NH
2 Step 1: tert-Butyl ( 3 -[cyclopropvl(pyridin-4-vlmethyl)amino-2-{4-[2-(2,6dichloro-4 0 methylphenoxv)ethoxy]benzyl} 1-3-oxopropyl)carbamate 3-[tert-Butoxycarbonyl)amino]-2-{ 4
-[
2 -(2,6-dichloro-4-methylphenoxy) ethoxy]benzyl}propanoic acid from Example 9, Step 3 (1 eq.) was combined with 1 hydroxybenzotriazole hydrate (1.5 eq.) and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide HCI salt (1.5 eq.) in chloroform (0.08 M). To this yellow solution was then added Amine 46 (4 eq.) and 5 triethylamine (1.5 eq.). The resulting brown solution was stirred at RT for 48 h. The reaction solution was diluted with EtOAc and washed with H 2 0. The aqueous washes were back extracted with EtOAc. The combined organic extracts were washed with brine, dried over MgSO 4 , filtered and the filtrate concentrated in vacuo. Purification of the crude product thus obtained by way of flash chromatography (SiO2, 2:3 (v/v) Hex: EtOAc -4 EtOAc) afforded the title compound. 0 Step 1: 3-Amino-N-cyclopropyl.-2- 4
-[
2
-(
2 6-dichloro-4-methylphenoxy)ethoxy]beny}-N-(pyridin-4 yhvmethyl)propanamide To a CH 2
CI
2 solution (0.09 M) of tert-butyl ( 3 -[cyclopropyl(pyridin-4-ylmethyl)amino] 2- {4-[ 2
-(
2
,
6 -dichloro-4-methylphenoxy)ethoxy]benzyl}-3-oxopropyl)carbamate from the previous step (1 eq.) was added HCI (4.0 M dioxane solution, 46 eq.). The resulting solution was stirred at RT for 5 h. 5 The reaction was quenched with 2.0 M NH 3 in MeOH and concentrated in vacuo. The resulting residue was directly loaded onto a SiO 2 column packed with 90:9:1 (v/v) CH 2
CI
2 : MeOH: conc. NH 4 OH. Elution with the same solvent system furnished the title compound. MS (ESI+): 527.9. -116- WO 2007/009250 PCT/CA2006/001196 Example 111 3-Amino-N-cyclopropyl-2- {4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl}-N-(pyridin-3 ylmethyl)propanamide Me Cl I NN 0O V
NH
2 5 Prepared according to the procedure described in Example 110 but using instead Amine 47 as starting material. The title compound was obtained as colorless oil. MS (ESI+): 527.9. Example 112 3-Amino-N-cyclopropyl-2-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl} -N-(pyridin-2 ylmethyl)propanamide Me Cl ON 0
NH
2 Prepared according to the procedure described in Example 110 but using instead Amine 48 as starting material. The title compound was obtained as colorless oil. MS (ESI+): 527.9. Example 113 3-Amino-N-cyclopropyl-2- {4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl }-N-[( 1 -oxidopyridin-4 5 yl)methyl]propanamide Me Ci N 0 N 0 N
NH
2 Step 1: tert-Butvl (3- { cyclopropyl[(1-oxidopyridin-4-yl)methyll amino }-2- 4-[2-(2.6-dichloro-4 methylphenoxy)ethoxy]benzyl}-3-oxopropyl)carbamate To a solution of tert-butyl (3-[cyclopropyl(pyridin-4-ylmethyl)amino]-2- {4-[2-(2,6 0 dichloro-4-methylphenoxy)ethoxy]benzyl}-3-oxopropyl)carbamate from Example 110, Step 1 (1 eq.) in dichloromethane (0.12 M) was added 3-chloroperoxybenzoic acid (1.3 eq.). The reaction mixture was stirred at RT for 1.5 h. The reaction was then quenched with 10% aq. Na 2
S
2 0 3 and sat. aq. NaHCO 3 . The organic layer was separated and the aqueous layer were were back extracted with ether. The combined organic extracts were washed with water, dried over Na 2
SO
4 , filtered and the filtrate -117- WO 2007/009250 PCT/CA2006/001196 concentrated in vacuo. Purification of the crude product thus obtained by way of flash chromatography (SiO 2 , EtOAc -4 4:1 (v/v) EtOAc : MeOH) afforded the title compound. Step 1: 3-Amino-N-cvclopropyl-2-{4-[2-(2.6-dichloro-4-methylphenoxy)ethoNxy]benzy1}-N-[(1 oxidopyridin-4-yl)methyl]propanamide 5 To a CH 2 Cl 2 solution (0.1 M) tert-butyl (3-{cyclopropyl[(1-oxidopyridin-4 yl)methyl]amino }-2- {4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl }-3-oxopropyl)carbamate from the previous step (1 eq.) was added HCI (4.0 M dioxane solution, 40 eq.). The resulting solution was stirred at RT for 5 h. The reaction was quenched with 2.0 M NH 3 in MeOH and concentrated in vacuo. The resulting residue was directly loaded onto a SiO2 column packed with 86:13:1 (v/v) CH 2 Cl 2 : MeOH: 0 conc. NH40H. Elution with the same solvent system furnished the title compound. MS (ESI+): 543.9. Example 114 3-Amino-N-cyclopropyl-2- { 4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl }-N-[(1-oxidopyridin-3 yl)methyl]propanamide Me Cl Cl I O N
NH
2 5 Prepared according to the procedure described in Example 113 but using instead tert butyl (3-[cyclopropyl(pyridin-3-ylmethyl)amino]-2- {4-[2-(2,6-dichloro-4 methylphenoxy)ethoxy]benzyl}-3-oxopropyl)carbamate from Example 111, Step 1 as starting material. The title compound was obtained as colorless oil. MS (ESI+): 543.9. 20 Example 115 3-Amino-N-cyclopropyl-2- {4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl}-N-[(1-oxidopyridin-2 yl)methyl]propanamide Me Cl CIO O ~ N
NH
2 Prepared according to the procedure described in Example 113 but using instead tert 25 butyl (3-[cyclopropyl(pyridin-2-ylmethyl)amino]-2- {4-[2-(2,6-dichloro-4 methylphenoxy)ethoxy]benzyl}-3-oxopropyl)carbamate from Example 112, Step 1 as starting material. The title compound was obtained as colorless oil. MS (ESI+): 543.9. -118- WO 2007/009250 PCT/CA2006/001196 Example 116 Ethyl 3- { [(3-amino-2- {4-[2-(2,6-dichloro-4 methylphenoxy)ethoxy]benzyl} propanoyl)(cyclopropyl)amino]methyl}-2-bromophenoxy)acetate 0 OEt Me~ Cl O Br . ON N
NH
2 5 Prepared according to the procedure described in Example 9 but using instead Amine 49 as starting material. The title compound was obtained as colorless oil. MS (ESI+): 708.9. Example 117 Ethyl 3-(3-{ [(3-amino-2-{4-[2-(2,6-dichloro-4 methylphenoxy)ethoxy] benzyl} propanoyl)(cyclopropyl)amino]methyl } -2-bromophenoxy)propanoate OEt 0 Me C0 ClBr 0 1 0 NH 2 Prepared according to the procedure described in Example 9 but using instead Amine 50 as starting material. The title compound was obtained as colorless oil. MS (ESI+): 722.9. Example 118 Ethyl 5-(3- { [(3-amino-2- {4-[2-(2,6-dichloro-4 5 methylphenoxy)ethoxy]benzyl} propanoyl)(cyclopropyl)amino]methyl}-2-bromophenoxy)pentanoate O Me Cl O - OEt CN: O Br C N O NN NI-1
NH
2 Prepared according to the procedure described in Example 9 but using instead Amine 51 as starting material. The title compound was obtained as colorless oil. MS (ESI+): 750.9. Example 119 .0 Sodium 3- { [(3-amino-2- {4-[2-(2,6-dichloro-4 methylphenoxy)ethoxy]benzyl}propanoyl)(cyclopropyl)amino]methyl} -2-bromophenoxy)acetate -119- WO 2007/009250 PCT/CA2006/001196 OONa Me Cl O Br CI 0 N V
NH
2 Prepared according to the procedure described in Example 87 but using instead ethyl (3 { [(3-amino-2- {4-[2-(2,6-dichloro-4 methylphenoxy)ethoxy]benzyl } propanoyl)(cyclopropyl)amino]methyl }-2-bromophenoxy)acetate from 5 Example 116 as starting material. The title compound was obtained as colorless oil. MS for the corresponding free acid (ESI+): 681.3. Example 120 Sodium 5-(3- { [(3-amino-2- {4-[2-(2,6-dichloro-4 methylphenoxy)ethoxy]benzyl} propanoyl)(cyclopropyl)amino]methyl}-2-bromophenoxy)pentanoate O Me C O ' ONa Cl Br N O O 10 NH 2 Prepared according to the procedure described in Example 87 but using instead ethyl 3 (3- { [(3-amino-2- {4-[2-(2,6-dichloro-4 methylphenoxy)ethoxy]benzyl} propanoyl)(cyclopropyl)amino]methyl}-2-bromophenoxy)pentanoate from Example 118 as starting material. The title compound was obtained as colorless oil. MS (ESI+): 5 723.2. Example 121 3-Amino-N-cyclopropyl-2- {4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl}-N-[3-(3 methoxypropyl)-5-(2-morpholin-4-yl-2-oxoethoxy)benzyl]propanamide (^o Me ~ Cl OI( N N .X 1 0 Cl N OMe O N
NH
2 0 Prepared according to the procedure described in Example 71 but using instead 4 (chloroacetyl)morpholine as starting material. The title compound was obtained as an off-white solid. MS (ESI+): 742.3. -120- WO 2007/009250 PCT/CA2006/001196 Example 122 2- { 4-[2-(4-Allyl-2,6-dichlorophenoxy)ethoxy]benzyl }-3-amino-N- [2-chloro-5-(3-methoxypropyl)benzyl] N-cyclopropanamide CCI ciK OMe ON
NH
2 5 Step 1: Ethyl 2-cyano-3-[4-(hydroxyethoxy)phenyllacrylate Ethyl cyanoacetate (1.1 eq.) and 4-(2-hydroxyethoxy)benzaldehyde (1 eq.) were combined in ethanol (1.2 M). The reaction mixture was stirred at RT for 48. To this was then added an equal volume of hexane and the title compound was isolated by filtration as a pale yellow solid. Step 2: Ethyl 3-[(tert-butoxycarbonvyl)amino]-2-[4-(2-hydroxyethoxy)benzyl]propanoate 0 Ethyl 2-cyano-3-[4-(hydroxyethoxy)phenyl]acrylate was combined with di-tert-butyl dicarbonate (1.2 eq.) and platinum(IV) oxide (20% loading) were combined in EtOH (0.18 M). The resulting suspension was shaken on a Parr apparatus under 50 psi of hydrogen gas for one week. The mixture was diluted with dichloromethane and filtered through a bed of celite. The filtrate was concentrated in vacuo to afford a viscous pale yellow oil. 5 Step 3: 3-[(tert-Butoxycarbonyl)amino]-2-[4-(2-hydroxvethoxy)benzyl]propanoic acid To a 5:3 (v/v) solution of EtOH and THF (0.2 M) of ethyl 3-[(tert butoxycarbonyl)amino]-2-[4-(2-hydroxyethoxy)benzyl]propanoate from the previous step (1 eq.) was added LiOH (1 M aqueous solution, 2 eq.). The resulting mixture was stirred at RT for 48 h. Following the removal of the volatiles in vacuo, the resulting residue was partitioned between ether and I N aq. 0 NaOH. The aqueous layer was separated and washed further with ether. The aqueous layer was then acidified to pH -2 with conc. HC1 and the resulting suspension extracted with dichloromethane. The combined dichloromethane extracts was concentrated in vacuo. The crude product thus obtained was recrystallized from EtOAc - hexane to afford the title compound as a white solid. Step 4: tert-Butyl {(3-[[2-chloro-5-(3-methoxvpropyl)benzvl](cyclopropvl)aminol-2-[4-(2 5 hydroxyethoxy)benzyl]-3-oxopropyl)carbamate 3-[(tert-Butoxycarbonyl)amino]-2-[4-(2-hydroxyethoxy)benzyl]propanoic acid from the previous step (1 eq.) was combined with Hunig's base (3 eq.) and Amine 6 (1 eq.) in anhydrous DMF (0.7 M). To this was then added portionwise O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.2 eq.). The resulting yellow solution was stirred at RT for 18 h. The reaction 0 solution was diluted with ether and washed with water. The aqueous washes were back extracted with ether. The combined organic extracts were washed with brine, dried over MgSO 4 , filtered and the filtrate concentrated in vacuo. Purification of the crude product thus obtained by way of flash chromatography (SiO 2 , 5:1 (v/v) Hex: EtOAc -- EtOAc) afforded the title compound pale yellow oil. -121- WO 2007/009250 PCT/CA2006/001196 Step 5: tert-Butyl {2-( 4 -f 2
-(
4 -allvl-2.6-dichlorophenoxy)ethoxy]benzyl}-3-[[2-chloro-5-(3 methoxypropyl)benzvl](cyclopropyl)aminol-3-oxopropyl)carbamate To a solution of 2,6-dichlorophenol (1.2 eq.) in acetone (1.4 M) was added allyl bromide (1.2 eq.) and potassium carbonate (1.4 eq). The resulting suspension was heated to reflux for 4 h. The 5 insolubles were removed via filtration and the filtrate was concentrated in vacuo. The resulting residue was heated at 160 oC for 17 h. This was then taken up in toluene (0.13 M) and added tert-butyl {(3-[[2 chloro-5-(3-methoxypropyl)benzyl](cyclopropyl)amino]-2-[4-(2-hydroxyethoxy)benzyl]-3 oxopropyl)carbamate from the previous step (1 eq.) and 1,1 '-(azodicarbonyl)dipiperidine (1.2 eq.). The resulting reaction mixture was deoxygenated and then added tributylphosphine (3 eq.). After 3 h of 10 heating at 80 'C, the reaction was quenched with I N NaOH and diluted with EtOAc. The aqueous layer was separated and back extracted with EtOAc. The combined organic extracts were washed further with 1 N aq. HCI, water and brine, dried over Na 2
SO
4 and filtered. Concentration of the filtrate in vacuo afforded a brown oil that, following flash chromatography (SiO 2 , 5:1 (v/v) Hex: EtOAc -- 1:1 (v/v) Hex : EtOAc), revealed the title compound as a pale yellow oil. 5 Step 6: 2- { 4
-[
2
-(
4 -Allvl-2,6-dichlorophenoxy)ethoxy]benzvl -3-amino-N-[2-chloro-5-(3 methoxvpropvl)benzyll-N-cyclopropanamide To a CH 2 Cl 2 solution (0.1 M) of tert-butyl { 2
-{
4 -[2-(4-allyl-2,6 dichlorophenoxy)ethoxy]benzyl }-3-[[2-chloro-5-(3-methoxypropyl)benzyl](cyclopropyl)amino]-3 oxopropyl)carbamate from the previous step (1 eq.) was added HCI (4.0 M dioxane solution, 35 eq.). 0 The resulting solution was stirred at RT for 4 h. Removal of the volatiles in vacuo afforded the title compound. MS (ESI+): 661.8. Example 123 3-Amino-N-[ 2 -chloro-5-(3-methoxypropyl)benzyl]-N-cyclopropyl-2-(4- {2-[2,6-dichloro-4-(3 hydroxypropyl)phenoxy]ethoxy } benzyl } propanamide OH Cl C N o CI CI O OMe 0 ON 5
NH
2 Step : tert-Butyl [3-[[2-chloro-5-(3-methoxypropyl)benzyl(cyclopropyl)amino-2-(4-{2-[2,6-dichloro 4-(3-hydroxypropyl)phenoxy]ethoxy} benzyl -3-oxopropyl] carbamate To a THF solution (0.04 M) of tert-butyl { 2
-{
4 -[2-(4-allyl-2,6 dichlorophenoxy)ethoxy]benzyl } -3-[[2-chloro-5-(3-methoxypropyl)benzyl](cyclopropyl)amino]-3 S oxopropyl)carbamate from Example 122, Step 5 (1 eq.) was added 9 -borabicyclo[3.3.1]nonane (0.5 M THF solution, 2.6 eq.) dropwise at 0 oC. The resulting solution was warmed slowly to RT over 16 h. The reaction was quenched at 0 oC with the dropwise addition of ethanol. Then, NaOH (1 N aqueous solution, 4 eq.) and H 2 0 2 (30% w/w aqueous solution, 12 eq.) were added. After I h of stirring at 0 C -122- WO 2007/009250 PCT/CA2006/001196 and another 4 h of stirring at RT, the reaction mixture was diluted with EtOAc. The organic layer was separated, washed with water, dried over Na 2
SO
4 and filtered. Concentration of the filtrate in vacuo and purification of the crude product thus obtained by way of flash chromatography (SiO 2 , 3:1 (v/v) Hex: EtOAc -4 EtOAc), revealed the title compound. 5 Step 2: 3-Amino-N-[2-chloro-5-(3-methoxvpropyl)benzyl]-N-cyclopropvl-2-(4- {2-[2,6-dichloro-4-(3 hydroxypropvl)phenoxy]ethoxy} benzyl } propanamide To a CH 2 C1 2 solution (0.1 M) of tert-butyl [3-[[2-chloro-5-(3 mnethoxypropyl)benzyl](cyclopropyl)amino]-2-(4- {2-[2,6-dichloro-4-(3 hydroxypropyl)phenoxy]ethoxy}benzyl}-3-oxopropyl]carbamatefrom the previous step (1 eq.) was 0 added HCI (4.0 M dioxane solution, 35 eq.). The resulting solution was stirred at RT for 4 h. The reaction was quenched with 2.0 M NH 3 in MeOH and concentrated in vacuo. The resulting residue was directly loaded onto a SiO 2 column packed with 90:9:1 (v/v) CH 2 Cl 2 : MeOH : conc. NH 4 OH. Elution with the same solvent system furnished the title compound. MS (ESI+): 677.2. 5 0 -123-

权利要求:
Claims (10)
[1] 1. A compound of formula I, or a pharmaceutically acceptable salt thereof, or an optical isomer thereof, having the formula I 0 R1 N R2 Ar! X1 , - (CH 2 )rX / Y N (CHR 3 )n (CH 2 )1-
[2] 2 Ar 2 5 NR 4 R wherein, m is 1 or 2; n, in each instance in which it occurs, is independently 0, 1 or 2; p, in each instance in which it occurs, is independently 0, 1 or 2; 0 X and Xl are each independently selected from the group consisting of CH 2 , O, and S(O)p, provided that when both X and Xl are each independently O or S(O)p, m is 2; Y is selected from the group consisting of N(Ra), CH(Ra), O, and S(O)p; R1, R 3 , and Ra are each independently selected from the group consisting of H, C1-C6alkyl and C2 C6alkenyl, wherein the alkyl and alkenyl group is unsubstituted or substituted with one, two, three or 5 four substituents independently selected from: 1) OH, 2) CN,
[3] 3) CF3,
[4] 4) COOH, :0 5) C1-C6alkoxy, 6) C(O)Rb, 7) C(O)N(Rc) 2 , 8) S(O)pC1-C6alkyl, 9) SO 2 N(Rc) 2 , .5 10) N(Rc) 2 , 11) NHC(O)Rb, 12) NHC(O)NHRd, 13) NHC(S)NHRd, 14) NH(NRC)NH Rc, 0 15) tetrazolyl, and e 16) -(CH2)1-2 R R 4 is selected from the group consisting of H, C1-C6alkyl and C2-C6alkenyl, wherein the alkyl and alkenyl group is unsubstituted or substituted with one, two, three or four substituents independently selected from: 5 1) OH, -124- WO 2007/009250 PCT/CA2006/001196 2) CN, 3) CF 3 , 4) COOH, 5) C1-C6alkoxy, 5 6) C(O)Rb, 7) C(O)N(RC) 2 , 8) S(O)pC1-C6alkyl, 9) SO 2 N(RC) 2 , 10) N(Rc) 2 , 0 11) NHC(O)Rb, 12) NHC(0)NHRd, 13) NHC(S)NHRd, 14) NH(NRC)NH RC, and 15) tetrazolyl, 5 or R 4 , together with R 5 , forms a 5- or 6-membered heterocyclic ring which is unsubstituted or mono or di-substituted with a substituent selected from the group consisting of =0 and C -C 6 alkyl; 5R 5" R 5 is selected from the group consisting of hydrogen and -C(NH(NH 2 ), or R 5 together with R 4 , forms a
[5] 5- or 6-membered heterocyclic ring which is unsubstituted or mono- or di-substituted with a substituent selected from the group consisting of =0 and C 1 -C 6 alkyl; 20 R 2 and Rb are independently selected from the group consisting of H, C1-C6alkyl, C2-C6alkenyl, C1-C6alkoxy, CF3 and CH2CF3; Rc is selected from the group consisting of H, C1-C6alkyl and CH2CF3; Rd is selected from the group consisting of H and C1-C6alkyl, wherein the alkyl group is unsubstituted or substituted with one, two, three or four substituents selected from the group consisting of: Z5 1) OH, 2) CN, 3) CF 3 , 4) COOH, and 5) C(O)NHRc, and 0 6) tetrazolyl; R is a 5- or 6-membered heteroaryl ring having 1 or 2 nitrogen atoms; Ar 1 is an unsubstituted or substituted aryl ring or an unsubstituted or substituted 5- or 6-membered heteroaryl ring containing 1 to 3 heteroatoms selected from O, S and N, wherein the substituted aryl ring and substituted heteroaryl ring are substituted with one, two three or four substituents 5 independently selected from the group consisting of: 1) OH, 2) CN, 3) halogen, -125- WO 2007/009250 PCT/CA2006/001196 4) N3, 5) NO2, 6) COOH, 7) OCF2H, 5 8) CF3, 9) C -C6alky1, 10) C2-C6alkenyl, 11) C 1 -C6alkoxy, 12) C(O)C1-C6alkyl, and 0 13) S(O)pCl -C6alkyl, wherein substituents (9) - (13) are unsubstituted or substituted with one, two three or four substituents independently selected from the group consisting of: a) OH, b) COOH, 5 c) CN, d) CF3, e) C 1-C6alkoxy, f) S(O)pC 1-C6alkyl; Ar 2 is independently selected from the group consisting of Ar 1 and a 9- or 10-membered fused bicyclic 20 aryl or heteroaryl ring, wherein the fused bicyclic heteroaryl contains 1 to 4 heteroatoms selected from O, S and N, wherein the fused bicyclic aryl and heteroaryl are each unsubstituted or substituted with one, two, three or four substituents independently selected from the group consisting of: 1) OH, 2) CN, 25 3) halogen, 4) N3, 5) NO2, 6) COOH, 7) OCF2H, 30 8) CF3, 9) C l-C6alkyl, unsubstituted or substituted with Ar 3 , 10) C1-C6alkyl, 11) C2-C6alkenyl, 12) C l-C6alkoxy, 35 13) C(O)C I -C6alkyl, 14) S(O)pC1-C6alkyl, 15) -O(CH2)1-2Ar 3 , 16) -O(CH2)1-2D, -126- WO 2007/009250 PCT/CA2006/001196 17) -OC(O)D, 18) -OC(O)NH(C 1-C6alkylene)C(O)NH2, and 19) -OC(O)NH(C 1-C 6 alkylene)(OH)Rd; wherein substituents (10) - (14) are unsubstituted or substituted with one, two three or four 5 substituents independently selected from the group consisting of: a) OH, b) COORd, c) CN, d) CF3, 0 e) C 1 -C6alkoxy, f) S(O)pC1-C6alkyl, g) tetrazolyl h) -C(O)NH2, i) -COONa, I5 j) -NRdRd, and k) -NRdC(O)Rd; Ar 3 is an unsubstituted or substituted aryl ring or an unsubstituted or substituted 5- or 6-mnembered heteroaryl ring containing 1 to 3 heteroatoms selected from O, S and N, wherein the substituted aryl ring and substituted heteroaryl ring are substituted with one, two three or four substituents 20 independently selected from the group consisting of: 1) OH, 2) CN, 3) OCF2H, 4) CF3, 25 5) Cl-C3alkyl, 6) C1-C3alkoxy, and 7) -SO 2 Rd; and D is a 5- or 6-membered saturated heterocyclic ring having 1 or 2 nitrogen atoms and 0 or 1 oxygen atoms, wherein the ring may be unsubstituted or substituted with C1 -C6alkyl. 30 2. A compound of Claim 1, or a pharmaceutically acceptable salt thereof, wherein Y is CH(Ra) and R1 is H. 3. A compound of Claim 2, or a pharmaceutically acceptable salt thereof, wherein Y is CH(Ra), R1 is H, and n is 1. 4. A compound of Claim 3, or a pharmaceutically acceptable salt thereof, wherein 35 Y is CH 2 or CH(CH2Ar 3 ) and R 2 is Cl-C6 alkyl or C1-C6 alkenyl. 5. A compound of Claim 1, or a pharmaceutically acceptable salt thereof, wherein R2 is Cl-C6 alkyl or CI-C6 alkenyl. -127- WO 2007/009250 PCT/CA2006/001196
[6] 6. A compound of Claim 5, or a pharmaceutically acceptable salt thereof, wherein R 2 is C3-C6cycloalkyl.
[7] 7. A compound of Claim 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of: 5 N- {3-[(Acetyl-methyl-amino)-methyl]-benzyl }-2-aminomethyl-N-cyclopropyl-3- {4-[2-(2,6-dichloro-4 methyl-phenoxy)-ethoxy]-phenyl}-propionamide, 2-Aminomethyl-N-cyclopropyl-3-{ 4-[2-(2,6-dichloro-4-methyl-phenoxy)-ethoxy]-phenyl}-N-(1,2,3,4 tetrahydro-quinolin-8-ylmethyl)-propionamide, 2-Aminomethyl-N-cyclopropyl-3- {4-[2-(2,6-dichloro-4-methyl-phenoxy)-ethoxy]-phenyl} -N-quinolin-4 10 ylnethyl-propionamide, 3-Amino-N-cyclopropyl-2- {4-[2-(2,6-dichloro-4-methyl-phenoxy)-ethoxy]-benzyl } -N-(2,3-dimethyl benzyl)-propionamide, 2-Aminomethyl-N-cyclopropyl-3- {4-[2-(2,6-dichloro-4-methyl-phenoxy)-ethoxy]-phenyl}-N-[3-(2 methanesulfonyl-ethyl)-benzyl]-propionamide, 5 5-(2-[Cyclopropyl-(2,3-dichloro-benzyl)-carbamoyl]-3- {4-[2-(2,6-dichloro-4-methyl-phenoxy)-ethoxy] phenyl}-propylamino)-pentanoic acid methyl ester, 6-(2-[Cyclopropyl-(2,3-dichloro-benzyl)-carbamoyl]-3- {4-[2-(2,6-dichloro-4-methyl-phenoxy)-ethoxy] phenyl }-propylamino)-hexanoic acid, 6-(2-[Cyclopropyl-(2,3-dichloro-benzyl)-carbamoyl]-3- {4-[2-(2,6-dichloro-4-methyl-phenoxy)-ethoxy] 20 phenyl}-propylamino)-hexanoic acid methyl ester, N-Cyclopropyl-N-(2,3-dichloro-benzyl)-3-{4-[2-(2,6-dichloro-4-methyl-phenoxy)-ethoxy]-phenyl } -2 [(2,2,2-trifluoro-ethylamino)-methyl]-propionamide, 2-Aminomethyl-N-cyclopropyl-3- {4-[2-(2,6-dichloro-4-methyl-phenoxy)-ethoxy]-phenyl}-N-[3-(3 methoxy-propyl)-benzyl]-propionamide, 15 2-Aminomethyl-N-[2-chloro-5-(3-methoxy-propyl)-benzyl]-N-cyclopropyl-3- {4-[2-(2,6-dichloro-4 methyl-phenoxy)-ethoxy]-phenyl } -propionamide, 2-[(2-[Cyclopropyl-(2,3-dichloro-benzyl)-carbamoyl]-3- {4-[2-(2,6-dichloro-4-methyl-phenoxy)-ethoxy] phenyl } -propylamino)-methyl]-cyclopropanecarboxylic acid, 2-[(2-[Cyclopropyl-(2,3-dichloro-benzyl)-carbamoyl]-3- {4-[2-(2,6-dichloro-4-methyl-phenoxy)-ethoxy] 30 phenyl} -propylamino)-methyl]-cyclopropanecarboxylic acid ethyl ester, 2-Aminomethyl-3 - {4-[3-(2-chloro-3,6-difluoro-phenoxy)-propyl]-phenyl } -N-cyclopropyl-N-[3-(3 methoxy-propyl)-benzyl]-propionamide, 2-Aminomethyl-3- {4-[3-(2-chloro-3,6-difluoro-phenoxy)-propyl]-phenyl }-N-[2-chloro-5-(3-methoxy propyl)-benzyl]-N-cyclopropyl-propionamide, 5 3-Amino-N-cyclopropyl-N-(2,3-dichloro-benzyl)-2- {4-[2-(2,6-dichloro-4-methyl-phenoxy)-ethyl] benzyl } -propionamide, 2-Aminomethyl-3- {4-[3-(2-chloro-3,6-difluoro-phenoxy)-propyl]-phenyl } -N-cyclopropyl-N-(2,3 dichloro-benzyl)-2-methyl-propionamide, -128- WO 2007/009250 PCT/CA2006/001196 3-Amino-N-cyclopropyl-N-(2,3-dichloro-benzyl)-2- {4-[2-(2,6-dichloro-4-methyl-phenoxy)-ethoxy] benzyl } -propionamide, 2-Aminomethyl-N-cyclopropyl-N-(2,3-dichloro-benzyl)-3- { 4-[3-(2,6-dichloro-4-methyl-phenoxy) propyl]-phenyl } -propionamide, 5 3- {4-[3-(2-Chloro-3,6-difluoro-phenoxy)-propyl]-phenyl }-N-cyclopropyl-N-(2,3-dichloro-benzyl)-2 methylaminomethyl-propionamide, 2-(Benzylamino-methyl)-3- {4-[3-(2-chloro-3,6-difluoro-phenoxy)-propyl]-phenyl} -N-cyclopropyl-N (2,3-dichloro-benzyl)-propionamide, 2-Aminomethyl-3- {4- [3-(2-chloro-3,6-difluoro-phenoxy)-propyl]-phenyl }-N-cyclopropyl-N-(2,3 0 dichloro-benzyl)-propionamide, 2-Aminomethyl-N-[2-chloro-5-(2-methoxy-ethyl)-benzyl]-N-cyclopropyl-3- {4-[2-(2,6-dichloro-4-methyl phenoxy)-ethoxy]-phenyl} -propionamide, Methyl (2R)-2- {2-[(3-[cyclopropyl(2,3-dichlorobenzyl)amino]-2- {4-[2-[2-(2,6-dichloro-4 methylphenoxy)ethoxy]benzyl } -3-oxopropyl)amino]ethyl } -3-methylbutanoate, 5 N-Cyclopropyl-N-(2,3-dichlorobenzyl)-2- {4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl}-3-[(3R) 3-isopropyl-2-oxopyrrolidin- I -yl]propanamide, Methyl (2S)-2- {2- [(3- [cyclopropyl(2,3-dichlorobenzyl)amino]-2- {4-[2- [2-(2,6-dichloro-4 methylphenoxy)ethoxy]benzyl} -3-oxopropyl)amino] ethyl} -3-methylbutanoate, N-Cyclopropyl-N-(2,3-dichlorobenzyl)-2- {4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl }-3- { [2-(2 ,0 napthyl)ethyl]amino} propanamide, 2-(Aminomethyl)-N-cyclopropyl-3- {4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}-N-(2,3 dimethylbenzyl)-4-pyridin-2-ylbutanamide, 3-Amino-N-[2-chloro-5-(2-methoxyethyl)benzyl]-N-cyclopropyl-2- { 4-[2-(2,6-dichloro-4 methylphenoxy)ethoxy]benzyl} butanamide, .5 3-Amino-N- [2-chloro-5-(3-hydroxypropyl)benzyl]-N-cyclopropyl-2- { 4-[2-(2,6-dichloro-4 methylphenoxy)ethoxy]benzyl} propanamide, 3-Amino-N- [2-chloro-5-(2-methoxyethoxy)benzyl]-N-cyclopropyl-2- {4-[2-(2,6-dichloro-4 methylphenoxy)ethoxy]benzyl } propanamide, 3-Am ino-N-cyclopropyl-2- { 4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl} -N- { [6-(pyridin-4 0 ylmethyl)quinoline-8-yl]methyl} propanamide, 3-Amino-N-[2-chloro-5-(3-methoxypropyl)benzyl]-N-cyclopropyl-2- {4-[2-(2,6-dichloro-4 methylphenoxy)ethyl]benzyl} propanamide, 3-Amino-N-[2-chloro-5-(2-methoxyethyl)benzyl]-N-cyclopropyl-2- {4-[2-(2,6-dichloro-4 methylphenoxy)ethyl]benzyl } propanamide, 5 3-Amino-N- {2-chloro-5-[3-(dimethylamino)propyl)benzyl } -N-cyclopropyl-2- { 4-[2-(2,6-dichloro-4 methylphenoxy)ethoxy]benzyl } propanamide, 3-Amino-N-cyclopropyl-N-[2,3-dichloro-5-[3-methoxypropyl)benzyl }-2- {4-[2-(2,6-dichloro-4 methylphenoxy)ethoxy]benzyl} propanamide, -129- WO 2007/009250 PCT/CA2006/001 196 3 -Amino-N-cyc Iopropyl-N-[2,3 -dichloro-5-[3 -methoxypropyl)benzyl I -2-f 4-[2-(2,6-dichloro-4 methylphenoxy)ethyl]benzyl} propanamide, 3-Amino-N-f { 6-(cyanomethyl)quinoline-8-yl]methyI I -N-cyclopropyl]-2-f 4-[2-(2,6-dIchloro-4 inethylphenoxy)ethoxy]benzyl I propanamide, 5 3 -Amino-N-cyclopropyl-2- {4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]benzyI I -N- { [2-(3 methoxypropyl)quinoline-4-yl]methyl I propanam ide, 3 -Amino-N-[2-chloro-5-(2-cyanoethyl)benzyl]-N-cyclopropyl-2- { 4-f 2-(2.6-dichloro-4 methylphenoxy)ethoxy]benzyl) propanamide, 3-Am ino-N-cyclopropyl-2 - f{4-[2-(2.6-dichloro-4-methylphenoxy)ethoxy]benzyl I -N-[ 5-(3 o rnethoxypropyl)-2-methylbenzyllpropanamide, 3 -Amino-N-[2-chiloro-5-(2-cyanomethyl)benzyl]-N-cyclopropyl-2- f{4-[2-(2,6-dichloro-4 methylphenoxy)ethoxylbenzyl I propanamide, 3 -Amino-N-cyclopropyl-2- t 4-[2-(2, 6-di1chi oro-4-methylphenoxy)ethoxyjbenzyl I -N-f 5-(3-methoxyethyl) 2-m ethyl ben zylI]propanam ide, 5 3-Amino-N-[2,5-bis(trifluoromethyl)benzyll-N-cyclopropyl-2- { 4-[2-(2.6-dichloro-4 methylphenoxy)ethoxy]benzyl}I propanamide, 3)-Amino-N- { [6-(1I -cyano- 1 -methylethyl)quinoline-8-yllmethyl I -N-cyclopropyl-2- {4-[2-(2,6-dichloro-4 rnethylphenoxy)ethoxy]benzyl} propanamide, 3-Am ino-N-cyc Iopropyl-2- { 4- [2-(2, 6-dich loro-4-methylphenoxy)ethoxy] ben zyl } -N-( I o phenylethyl)propanamide, 3-Am ino-N-benzyl-2- f{4- f2-(2,6-dichloro-4-methylphenoxy)ethoxyjbenzyI I -N-methylpropanamide, 3 -Amino-N-benzyl-N-cyclopropyl-2- {4-[2-(2,6-dichloro-4-methylphenoxy)ethoxylbenzyl I propanamide, 3 -Amino-N-benzyl-N-cyclopropyl-2- {4-f2-(2,6-dichloro-4-methylphenoxy)ethoxy] benzyl I -N-(2 phenylethyl)propanamide, 5 3 -Amino-2- {4- 12-(2,6-dichloro-4-methylphenoxy)ethoxy]benzyI } -N-methyl-N-(2 phenylethyl)propanamide, 3-Am ino-2- f{4- [2-(2, 6-dichloro-4-methylphenoxy)ethoxylbenzyl } -N-methyl-N-( 1 phenylethyl)propanamide, 3 -Amino-N-(2,3 -dichlorobenzyl)-2- {4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy] benzyI I -N-(2,2,2 o trifluoroethyl)propanamide, 3-Amnino-2- { 4-[2-(2.6-dichloro-4-methylpheinoxy)etlhoxy] benzyl I -N-methyl-N-( I-methyl- I phenylethyl)propanamide, 3-Amino-N-[2-chloro-5 -(2-methoxyethyl)benzylj -N-(cyclopropyl)methyl)-2-1{4- [2-(2,6-d ichloro-4 methylphenoxy)ethoxy]benzyl I propanamide, 5 3 -Amino-N-[2-chloro-5-(2-methoxyethyl)benzyl]-2- {4- [2-(2,6-dichloro-4 methylphenoxy)ethoxy]benzyl } -N-methylpropanamide, 3 -Aminio-N-f2-ch loro-5-(2-methoxyethyl )benzyl]-N-(cyclobutylm-ethyl)-2- f{4- [2-(2,6-dichloro-4 methylphenoxy)ethoxy] ben zy1 I propanamide, -130- WO 2007/009250 PCT/CA2006/001196 3 -Amino-N-[2-chloro-5-(2-methoxyethyl)benzyl]-2- {4-[2-(2,6-dichloro-4 methylphenoxy)ethoxy]benzyl } -N-isopropylpropanamide, N-Allyl-3-amino-N-[2-chloro-5-(2-methoxyethyl)benzyl]-2- {4-[2-(2,6-dichloro-4 methvlphenoxy)ethoxy]benzyl} propanamide, 5 3-Amino-N-[2-chloro-5-(2-methoxyethyl)benzyl]-N-cyclobutyl-2- {4-[2-(2,6-dichloro-4 methylphenoxy)ethoxy]benzyl } propanamide, 3-Amino-N-[2-chloro-5-(2-methoxyethyl)benzyl]-2- {4-[2-(2,6-dichloro-4 methylphenoxy)ethoxylbenzyl} -N-ethylpropanamide, 3- { [Amino(imino)methyl]amino} -N-[2-chloro-5-(3-methoxypropyl)benzyl]-N-cyclopropyl-2- {4-[2-(2,6 0 dichloro-4-methylphenoxy)ethoxy]benzyl} propanamide, 2- { [Amino(imino)methyl]amino} -N-cyclopropyl-N-(2,3-dichlorobenzyl)-3- {4-[2-(2,6-dichloro-4 methylphenoxy)ethoxy]benzyl } propanamide, 2-Amino-N-[2-chloro-5-(3-methoxypropyl)benzyl]-N-cyclopropyl-3- {4-[2-(2,6-dichloro-4 methylphenoxy)ethoxy]benzyl }propanamide, 5 2- { [Amino(imino)methyl]amino}-N-[2-chloro-5-(3-methoxypropyl)benzyl]-N-cyclopropyl-3-{4-[2-(2,6 dichloro-4-methylphenoxy)ethoxy] benzyl } propanamide, 3-Amino-N-cyclopropyl-2-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl} -N-[3-hydroxy-5-(3 mnethoxypropyl)benzyl]propanamide, 3-Amino-N-cyclopropyl-2-{4-[2-(2.6-dichloro-4-methylphenoxy)ethoxy]benzyl } -N-[3-(3 0 methoxypropyl)-5-(2-pyrrolidin-I -ylethoxy)benzyl]propanamide, 3-Amino-N-cyclopropyl-2- {4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl }-N-[3-(3 methoxypropyl)-5-(pyridin-2-ylmethoxy)benzyl]propanamide, 3 -Amino-N-cyclopropyl-2- {4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl} -N-[3-(2 methoxyethoxy)-5-(3-methoxypropyl)benzyllpropanamide, 5 3-Amino-N-[3-(3-cyanopropoxy)-5-(3-methoxypropyl)benzyl]-N-cyclopropyl-2- {4-[2-(2,6-dichloro-4 methylphenoxy)ethoxy]benzyl}propanamide, 3-Amino-N-cyclopropyl-2- {4-[2-(2.6-dichloro-4-methylphenoxy)ethoxylbenzyl } -N- {3-(3 methoxypropyl)-5-[(3-methylthio)propoxy]benzyl } propanamide, 3-Amino-N-cyclopropyl-2- {4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl} -N- {3-(3 0 methoxvpropyl)-5-[(3-methylsulfonyl)propoxy]benzyl4propanamide, 3 -Am ino-N-cyclopropyl-2- {4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl } -N-[3-(3 methoxypropyl)-5-(pyridin-3-ylmethoxy)benzyl]propanamide, 3-Amino-N-cyclopropyl-2- {4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl} -N-[3-(3 methoxypropyl)-5-(pyridin-4-ylmethoxy)benzyl]propanamide, 5 3 -Amino-N-cyclopropyl-2- {4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl} -N- {3-(3 methoxypropyl)-5-[(1-oxidopyridin-2-yl)methoxy]benzyl4propanamide, 3-Amino-N-cyclopropyl-2- {4-[2-(2.6-dichloro-4-methylphenoxy)ethoxy]benzyl)-N- {3-(3 methoxypropyl)-5-[(1 -oxidopyridin-3-yl)methoxy]benzyl propanamide, -131- WO 2007/009250 PCT/CA2006/001196 3-Amino-N-cyclopropyl-2- { 4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl } -N- {3 -(3 methoxypropyl)-5-[(1-oxidopyridin-4-yl)methoxy]benzyl } propanamide, 3-Amino-N-cyclopropyl-2- {4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl}-N-[3-(3 methoxypropyl)-5-(2-pyridin-2-ylethoxy)benzyl]propanamide, 5 3-Amino-N-cycl opropyl-2- {4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl } -N- { 3-(3 methoxypropyl)-5-[2-(1-oxidopyridin-2-yl)ethoxy]benzyl } propanamide, 3-Amino-N-cyclopropyl-2- {4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl } -N-[3-(3 methoxypropyl)-5-(2-morpholin-4-ylmethoxy)benzyl]propanamide, 3-Amino-N-cyclopropyl-2- {4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl} -N-[3-(3 0 methoxypropyl)-5- { [4-(methylsulfonyl)benzyl]oxy } benzyl)propanamide, Ethyl 2- { [3- { [(3-amino-2- {4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl } propanoyl) (cyclopropyl)amino]methyl}-5-(3-methoxypropyl)phenoxy]methyl } cyclopropanecarboxylate, Sodium 2- { [3- { [(3-amino-2- {4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl} propanoyl) (cyclopropyl)amino]methyl} -5-(3-methoxypropyl)phenoxy]methyl} cyclopropanecarboxylate, 5 Ethyl 2- { [3- { [(3-amino-2- {4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl} propanoyl) (cyclopropyl)amino]methyl } -2-chloro-5-(3-methoxypropyl)phenoxy]methyl)}cyclopropanecarboxylate, Sodium 2- { [3- { [(3-amino-2- {4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl } propanoyl) (cyclopropyl)amino]methyl}-2-chloro-5-(3-methoxypropyl)phenoxy]methyl} cyclopropanecarboxylate, Ethyl 2-[3- { [(3-amino-2- {4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl} propanoyl) 0 (cyclopropyl)amino]methyl } -5-(3-methoxypropyl)phenoxy]-2-methylpropanoate, Sodium 2-[3- { [(3-amino-2- {4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl } propanoyl) (cyclopropyl)amino]methyl}-5-(3-methoxypropyl)phenoxy]-2-methylpropanoate, 3-Amino-N-[3,5-bis(2-methoxyethoxy)benzyl]-N-cyclopropyl-2- { 4-[2-(2,6-dichloro-4 methylphenoxy)ethoxy]benzyl } propanamide, 5 3-Amino-N-[3,5-bis(4,4,4-trifluorobutoxy)benzyl]-N-cyclopropyl-2- {4-[2-(2,6-dichloro-4 methylphenoxy)ethoxy]benzyl } propanamide, 3-Amino- N-cyclopropyl-2- {4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl} -N- {3-(3 methoxypropyl)-5-[3-(1 H-tetrazol-5-yl)propoxy] benzyl } propanamide, 3-Amino-N- { [5-chloro-2-(3-methoxypropyl)pyridin-4-yl]methyl }-N-cyclopropyl-2- {4-[2-(2,6-dichl oro-4 0 methylphenoxy)ethoxy]benzyl } propanamide, 3-Amino-N- { [5-chloro-2-(3-methoxypropyl)- I -oxidopyridin-4-yl]methyl } -N-cyclopropyl-2- {4-[2-(2,6 dichloro-4-methylphenoxy)ethoxy]benzyl} propanamide, 3-Amino- N-cyclopropyl-2- {4-[2-(2,6-dich loro-4-methylphenoxy)ethoxy]benzyl }-N- { [2-methoxy-6-(3 methoxypropyl)pyridin-4-yl]methyl} propanamide, 5 3-Amino- N-cyc lopropyl-2- {4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl } -N- { [2-hydroxy-6-(3 methoxypropyl)pyridin-4-yl]methyl } propanamide, 3-Amino- N- { [2,6-bis(3-methoxypropyl)pyridin-4-yl]methyl} - N-cyclopropyl-2- {4-[2-(2,6-dichloro-4 methylphenoxy)ethoxy]benzyl } propanamide, -132- WO 2007/009250 PCT/CA2006/001196 3-Amino- N-cyclopropyl-2- { 4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl}-N-( {2-(3 methoxypropyl)-6-[3-(methylthio)propoxy]pyridin-4-yl } methyl propanamide, 3-Amino- N-cyclopropyl-2- {4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy] benzyl } -N-( {2-(3 methoxypropyl)-6-[3-(methylsulfonyl)propoxy]pyridin-4-yl} methyl } propanamide, 5 3-Amino- N-cyclopropyl-2- {4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl } -N-( {2-(3 methoxypropyl)-6-[3-(methylsulfonyl)propoxy]- 1 -oxidopyridin-4-yl } methyl } propanamide, 3-Amino- N-cyclopropyl-2- {4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl }-N- { [2-(3 methoxypropyl)-6-(2-morpholin-4-ylethoxy)pyridin-4-yl]methyl} propanamide, 3-Amino-N-[3-(2-amino-2-oxoethoxy)-5-(3-methoxypropyl)benzyl]-N-cyclopropyl-2- {4-[2-(2,6-dichloro 0 4-methylphenoxy)ethoxy]benzyl }propanamide, 3- { [(3-Amino-2- {4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl } propanoyl)(cyclopropyl)amino] methyl}-5-(3-methoxypropyl)phenyl ethylcarbamate, 3- { [(3 -Amino-2- { 4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl } propanoyl)(cyclopropyl)amino] methyl } -5-(3-methoxypropyl)phenyl morpholine-4-carboxylate, 5 3- { [(3-Amino-2- {4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl} propanoyl)(cyclopropyl)amino] methyl } -5-(3-methoxypropyl)pheny 4-methylpiperazine- 1 -carboxylate, 3- { [(3 -Amino-2- {4- [2-(2,6-dichloro-4-methylphenoxy)ethoxy] benzyl } propanoyl)(cyclopropyl)amino] methyl} -5-(3 -methoxypropyl)phenyl (3-amino-2,2-dimethyl-3-oxopropyl)carbamate, 3- { [(3-Amino-2- {4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl} propanoyl)(cyclopropyl)amino] 0 methyl }-5-(3-methoxypropyl)phenyl (2-hydroxypropyl)carbamate, 3-Amino-N-cyclopropyl-2- {4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl}-N-(pyridin-4 ylmethyl)propanamide, 3-Amino-N-cyclopropyl-2- {4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl}-N-(pyridin-3 ylmnethyl)propanamide, 5 3-Amino-N-cyclopropyl-2- { 4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl } -N-(pyridin-2 ylmethyl)propanamide, 3-Amino-N-cyclopropyl-2- {4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl} -N-[(1 -oxidopyridin-4 yl)methyl]propanamide, 3-Amino-N-cyclopropyl-2- { 4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl }-N-[(1 -oxidopyridin-3 0 yl)methyl]propanamide, 3-Amino-N-cyclopropyl-2-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl } -N-[( -oxidopyridin-2 yl)methyl]propanamide, Ethyl 3- { [(3-amino-2- {4-[2-(2,6-dichloro-4 methylphenoxy)ethoxy]benzyl} propanoyl)(cyclopropyl)aminojmethyl}-2-bromophenoxy)acetate, 5 Ethyl 3-(3- { [(3-amino-2- {4-[2-(2,6-dichloro-4 mnethylphenoxy)ethoxy]benzyl } propanoyl)(cyclopropyl)amino]methyl}-2-bromophenoxy)propanoate, Ethyl 5-(3- { [(3-amino-2- {4-[2-(2,6-dichloro-4 methylphenoxy)ethoxy]benzyl} propanoyl)(cyclopropyl)amino]methyl}-2-bromophenoxy)pentanoate, -133- WO 2007/009250 PCT/CA2006/001196 Sodium 3- { [(3-amino-2- {4-[2-(2,6-dichloro-4 methylphenoxy)ethoxy]benzyi } propanoyl)(cyclopropyl)amino]methyl } -2-bromophenoxy)acetate, Sodium 5-(3- {[(3-amino-2- {4-[2-(2,6-dichloro-4 methylphenoxy)ethoxy]benzyl} propanoyl)(cyclopropyl)amino]methyl}-2-bromophenoxy)pentanoate, 5 3-Amino-N-cyclopropyl-2- { 4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl }-N- [3-(3 methoxypropyl)-5-(2-morpholin-4-yl-2-oxoethoxy)benzyl]propanamide, 2- {4-[2-(4-Allyl-2,6-dichlorophenoxy)ethoxy]benzyl}-3-amino-N-[2-chloro-5-(3-methoxypropyI)benzyl] N-cyclopropanamide, and 3-Amino-N-[2-chloro-5-(3-methoxypropyl)benzyl]-N-cyclopropyl-2-(4- {2-[2,6-dichloro-4-(3 0 hydroxypropyl)phenoxy]ethoxy}benzyl }propanamide.
[8] 8. A pharmaceutical composition comprising an effective amount of a compound according to Claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
[9] 9. Use of a compound according to Claim 1, or a composition according to Claim 5 8, for the manufacture of a medicament for the treatment or prophylaxis of diseases which are related to hypertension, congestive heart failure, pulmonary hypertension, renal insufficiency, renal ischemia, renal failure, renal fibrosis, cardiac insufficiency, cardiac hypertrophy, cardiac fibrosis, myocardial ischemia, cardiomyopathy, glomerulonephritis, renal colic, complications resulting from diabetes such as nephropathy, vasculopathy and neuropathy, glaucoma, elevated intra-ocular pressure, atherosclerosis, 0 restenosis post angioplasty, complications following vascular or cardiac surgery, erectile dysfunction, hyperaldosteronism, lung fibrosis, scleroderma, anxiety, cognitive disorders, complications of treatments with immunosuppressive agents, and other diseases known to be related to the renin-angiotensin system.
[10] 10. A method for the treatment or prophylaxis of diseases which are related to hypertension, congestive heart failure, pulmonary hypertension, renal insufficiency, renal ischemia, renal 5 failure, renal fibrosis, cardiac insufficiency, cardiac hypertrophy, cardiac fibrosis, myocardial ischemia, cardiomyopathy, glomerulonephritis, renal colic, complications resulting from diabetes such as nephropathy, vasculopathy and neuropathy, glaucoma, elevated intra-ocular pressure, atherosclerosis, restenosis post angioplasty, complications following vascular or cardiac surgery, erectile dysfunction, hyperaldosteronism, lung fibrosis, scleroderma, anxiety, cognitive disorders, complications of treatments 0 with immunosuppressive agents, and other diseases known to be related to the renin-angiotensin system, comprising the administration to a patient of a phanrmaceutically active amount of a compound according to Claim 1. -134-

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引用文献:

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公开号 | 申请日 | 公开日 | 申请人 | 专利标题

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IL91780A|1988-10-04|1995-08-31|Abbott Lab|Renin inhibiting hexanoic acid amide derivatives, process for their preparation and pharmaceutical compositions containing them|

---

EP0432974A1|1989-12-08|1991-06-19|Merck & Co. Inc.|Cyclic renin inhibitors|

---

MY119161A|1994-04-18|2005-04-30|Novartis Ag|Delta-amino-gamma-hydroxy-omega-aryl-alkanoic acid amides with enzyme especially renin inhibiting activities|

---

DE19614534A1|1996-04-12|1997-10-16|Basf Ag|New carboxylic acid derivatives, their production and use|

---

TW200513461A|2003-10-01|2005-04-16|Speedel Experimenta Ag|Organische verbindungen|

---

CA2540543A1|2003-10-09|2005-05-06|Actelion Pharmaceuticals Ltd|Tetrahydropyridine derivatives|

---

CA2547551A1|2003-12-05|2005-06-16|Actelion Pharmaceuticals Ltd|Diazabicyclononene and tetrahydropyridine derivatives with a new side-chain|

---

EP1910272A4|2005-07-22|2010-08-04|Merck Frosst Canada Ltd|Renin inhibitors|EP1910272A4|2005-07-22|2010-08-04|Merck Frosst Canada Ltd|Renin inhibitors|

---

US8343968B2|2007-05-24|2013-01-01|Merck Canada Inc.|Case of renin inhibitors|

---

JP2010535716A|2007-08-07|2010-11-25|メルクフロストカナダリミテツド|Renin inhibitor|

---

JP2010536800A|2007-08-20|2010-12-02|メルクフロストカナダリミテツド|Renin inhibitor|

---

WO2009087649A1|2007-10-15|2009-07-16|Cadila Healthcare Limited|Renin inhibitors|

---

PT2225200E|2007-12-24|2014-01-21|Dsm Ip Assets Bv|Convergent synthesis of renin inhibitors and intermediates useful therein|

---

SG192543A1|2008-05-05|2013-08-30|Merck Canada Inc|3, 4 - substituted piperidine derivatives as renin inhibitors|

---

US10822357B2|2015-08-28|2020-11-03|Sekisui Medical Co., Ltd.|Benzyl compound|

法律状态:
2011-10-13| FGA| Letters patent sealed or granted (standard patent)|

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2013-02-14| MK14| Patent ceased section 143(a) (annual fees not paid) or expired|

优先权:

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申请号 | 申请日 | 专利标题

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US70202605P| true| 2005-07-22|2005-07-22||

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US60/702,026||2005-07-22||

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PCT/CA2006/001196|WO2007009250A1|2005-07-22|2006-07-20|Renin inhibitors|

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