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  • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
  • C07D223/02—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings
  • C07D223/06—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D223/12—Nitrogen atoms not forming part of a nitro radical
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  • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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  • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
  • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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  • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
  • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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  • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
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  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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  • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
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  • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
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  • C07K5/06—Dipeptides
  • C07K5/06139—Dipeptides with the first amino acid being heterocyclic
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• • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
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  • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
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Definitions

• the present invention relates to methods for treating parasitic diseases using 4- amino-azepan-3-one protease inhibitors.
• the present methods serve to inhibit cysteine proteases of the papain superfamily.
• the present invention is useful for treating parasitic diseases which are mediated by the activity of such proteases.
• the present invention relates to treating malaria by inhibiting falcipain.
• Plasmodium falciparum Infection with Plasmodium falciparum, the most virulent human malaria pathogen, infects over 280 million people and is estimated to be responsible for over 1 million deaths annually (Gibbons, A. Science 1992, 256, 1135; Walsh, J. A. Arm. N. Y. Acad. Sci. 1989, 569, 1135).
• the Plasmodium falciparum parasite has a 48 hour life cycle within host erythrocytes that is responsible for all of the clinical manifestations of falciparum malaria.
• the erythrocyte is invaded by a merozoite, then the intracellular parasite develops from a ring stage into a more metabolically active trophozoite, divides asexually and becomes a schizont, and finally ruptures the host erythrocyte, releasing daughter merozoites that invade other erythrocytes to reinitiate the cycle.
• the trophozoite stage hemoglobin from the host erythrocyte is degraded for use as the parasites principal source of amino acids.
• Rosenthal and coworkers have identified a 28 kD trophozoite cysteine protease (TCP or falcipain) from malaria parasites that mediates host hemoglobin degradation (Rosenthal, P. J.; McKerrow, J. H.; Aikawa, M.; Nagasawa, H.; Leech, J. H. /. Clin. Invest. 1988, 82, 1560) and is expressed only at the trophozoite stage (Rosenthal, P. J.; Kim, J. H.; McKerrow, J. H.; Leech, J. H. J. Exp. Med. 1987, 166, 816).
• a selective inhibitor of falcipain may be an effective anti-malarial therapy either in conjunction with or as a replacement for the quinoline-derived drugs.
• cysteine proteases in their life cycle. These include Trypanosoma cruzi, Trypanosoma Brucei [trypanosomiasis (African sleeping sickness, Chagas disease)], Leishmania mexicana, Leishmania pifanoi,
• Leishmania major (leishmaniasis), Schistosoma mansoni (schistosomiasis), Onchocerca volvulus [onchocerciasis (river blindness)]
• Brugia pahangi Entamoeba histolytica, Giardia lambia, the helminths, Haemonchus contortus and Fasciola hepatica, as well as helminths of the genera Spirometra, Trichinella, Necator and Ascaris, and protozoa of the genera Cryptosporidium, Eimeria, Toxoplasma and Naegleria (McKerrow, J. H. (1995) in Perspect.
• An object of the present invention is to provide methods of treatment which serve to inhibit cysteine proteases, and particularly cysteine proteases of the papain superfamily.
• the present methods are useful for treating parasitic diseases which may be therapeutically modified by altering the activity of such proteases.
• the present invention relates to treating malaria by inhibiting falcipain.
• this invention provides a method of treating parasitic diseases in which the disease pathology may be therapeutically modified by inhibiting proteases, such as cysteine proteases, using 4-amino-azepan-3-ones of Formula I.
• proteases such as cysteine proteases
• these compounds are used in the present method to treat parasitic diseases by inhibiting cysteine proteases of the papain superfamily.
• the present invention provides a method of treating malaria by the inhibition of falcipain with such compounds.
• the present invention provides a method for treating parasitic diseases which may be therapeutically modified by altering the activity of cysteine proteases by administering to a patient in need thereof, particularly an animal, more particularly a mammal, most particularly a human being, one or more compounds of Formula I:
• Rl is selected from the group consisting of:
• R ⁇ is selected from the group consisting of: H, Cj.galkyl, C3_6cycloalkyl-Co_6 a lkyl, Ar-C 0 -6alkyl, Het-C 0 . 6 alkyl, R 9 C(O)-, R 9 C(S)-, R 9 SO 2 -, R 9 OC(O)-, R9R11NC(O)-, R9R11NC(S)-, R 9 (R 11 )NSO 2
• R 3 is selected from the group consisting of: H, Cl-6alkyl, C3_6cycloalkyl-C ⁇ -6alkyl, C2-6alkenyl, C2-6alkynyl, HetC ⁇ - ⁇ alkyl and ArCo-6 lkyl;
• R3 and R' may be connected to form a pyrrolidine, piperidine or morpholine ring;
• R ⁇ is selected from the group consisting of: H, C ⁇ _6 lkyl, C ⁇ .gcycloalkyl-Co- ⁇ alkyl, Ar-C 0 -6alkyl, Het-C 0 -6alkyl, R 5 C(O)-, R 5 C(S)-, R 5 SO 2 -, R 5 OC(O)-, R 5 R 12 NC(0)-, and R5R12NC(S)-; R ⁇ is selected from the group consisting of: H, C galkyl, C 2 _6alkenyl, C 2 -6alkynyl,
• R° is selected from the group consisting of: H, Cj.galkyl, Ar-C()-6alkyl, and Het- C 0 .6 lkyl;
• R ⁇ is selected from the group consisting of: H, C ⁇ galkyl, C3_gcycloalkyl-C()_galkyl, Ar-C 0 _6alkyl, Het-C 0 _6alkyl, R 10 C(O)-, R 10 C(S)-, R 10 SO 2 -, R 10 OC(O)-, R 10 R 13 NC(O)-, and R 10 R 13 NC(S)-;
• R 0 " is selected from the group consisting of: H, Ci-6alkyl, C 2 -6alkenyl, C 2 _6alkynyl, HetC ⁇ -galkyl and ArCo- ⁇ alkyl;
• R 9 is selected from the group consisting of: C j .galkyl, C3_ cycloalkyl-Co_6 l yl, Ar-Co_6alkyl and Het-Co-6 a lkyl;
• RIO is selected from the group consisting of: C j .galkyl, C3_6cycloalkyl-C Q -6alkyl, Ar-Co- ⁇ alkyl and Het-Co_6 a lkyl;
• RU is selected from the group consisting of: H, Cj. ⁇ alkyl, Ar-C()-6alkyl, and Het- C 0 _6alkyl
• Rl2 is selected from the group consisting of: H, C _ ⁇ alkyl, Ar-Co ⁇ 6alkyl, and Het-
• Rl3 is selected from the group consisting of: H, C ⁇ _galkyl, Ar-C ⁇ -6 a lkyl, and Het- C 0 . 6 alkyl;
• R' is selected from the group consisting of: H, C galkyl, Ar-C ⁇ -6alkyl, and Het-C ⁇ . galkyl;
• R" is selected from the group consisting of: H, C j .galkyl, Ar-C ⁇ -6 a lkyl, or Het-C ⁇ _ galkyl; R'" is selected from the group consisting of: H, C j .galkyl, C3_gcycloalkyl-Co_galkyl,
• R" is selected from the group consisting of: Ci-galkyl, C3_gcycloalkyl-Co_galkyl C 2 .galkenyl, C 2 _galkynyl, HetCQ-galkyl and ArCQ.galkyl;
• X is selected from the group consisting of: CH 2 , S, and O; Z is selected from the group consisting of: C(O) and CH ; n is an integer from 1 to 5; and pharmaceutically acceptable salts, hydrates and solvates thereof.
• R is preferably in compounds of Formula I.
• R 3 is selected from the group consisting of: H, Cl -galkyl, C3_gcycloalkyl-C ⁇ - galkyl,C 2 .galkenyl, C 2 .galkynyl, Het-C ⁇ _galkyl and Ar-Co_galkyl;
• R 3 is preferably selected from the group consisting of: H, C3-gcycloalkyl-C ⁇ -6alkyl, C .galkenyl, Ar-Co_galkyl, and Ci-galkyl;
• R 3 is more preferably selected from the group consisting of:
• R 3 is even more preferably selected from the group consisting of: toluyl, isobutyl and cyclohexylmethyl.
• R- 3 is most preferably isobutyl.
• R4 is selected from the group consisting of: H, C ⁇ _galkyl, C3_gcycloalkyl- C 0 .galkyl, Ar-C 0 .galkyl, Het-C 0 .galkyl, R 5 C(O)-, R 5 C(S)-, R 5 SO 2 -, R 5 OC(O)-, R 5 R 13 NC(O)-, and R 5 R 13 NC(S)-.
• R4 is preferably selected from the group consisting of: R ⁇ OC(O)-, R ⁇ C(O)- and R 5 SO 2 -. R 4 is most preferably R 5 C(O) ⁇ .
• R 4 is preferably methanesulfonyl.
• R-> is selected from the group consisting of: H, Cj.galkyl, C 2 .galkenyl, C 2 .galkynyl, C3_gcycloalkyl-Co_galkyl, Ar-CQ-galkyl or Het-Cg-galkyl.
• R ⁇ is selected from the group consisting of: C ⁇ _ alkyl, Ar-CQ-galkyl and Het-C 0 .galkyl.
• R-> is selected from the group consisting of: methyl, especially halogenated methyl, more especially trifluoromethyl , especially Ci.galkoxy substituted methyl, more especially phenoxy-methyl , 4-fluoro-phenoxy-methyl , especially heterocycle substituted methyl, more especially 2-thiophenyl-methyl ; ethyl, especially piperidin-1-yl-ethyl; butyl, especially aryl substituted butyl, more especially 4-(4-methoxy)phenyl-butyl; isopentyl; cyclohexyl; pentanonyl, especially 4-pentanonyl; butenyl, especially aryl substituted butenyl, more especially 4,4-bis(4- methoxyphenyl)-but-3-enyl; acetyl; phenyl, especially phenyl substituted with one or more halogens, more especially 3,4-d
• R ⁇ is preferably pyridin-2-yl or l-oxo-pyridin-2-yl.
• R' is selected from the group consisting of: H, Cj.galkyl, Ar-C ⁇ -6alkyl, and Het-Cg. galkyl.
• R' is selected from the group consisting of: H and naphthalen-2-yl-methyl. Most preferably R' is H.
• R" is selected from the group consisting of: H, Cj .galkyl, Ar-C ⁇ -6alkyl, and Het-C ⁇ _ galkyl.
• R" is H.
• R'" is selected from the group consisting of: H, C j .galkyl, C3_gcycloalkyl- C ⁇ -6alkyl, and Het-Co_galkyl.
• R'" is preferably selected from the group consisting of: H and C j .galkyl.
• R'" is more preferably selected from the group consisting of: H, methyl and 6,6- dimethyl.
• methyl is preferably selected from the group consisting of: 6- methyl and 7-methyl.
• R'" is selected from the group consisting of: H, 6-methyl and 7-methyl, most preferably 7-methyl.
• R 3 is selected from the group consisting of: Ci-galkyl, C3-gcycloalkyl-C ⁇ -6 a lkyl, C 2 _ galkenyl, C 2 .galkynyl, Het-CQ.galkyl and Ar-Co_galkyl.
• R 3 is preferably Ci-galkyl.
• R 3 is more preferably selected from the group consisting of methyl, ethyl, n-propyl, n-butyl, isobutyl, t-butyl, cyclohexylmethyl, and toluyl.
• R" is selected from the group consisting of: C galkyl, C3_gcycloalkyl- C ⁇ -6alkyl, C -6alkenyl, C 2 .galkynyl, HetCg-galkyl and ArC Q _galkyl; R"" is preferably C ⁇ _6alkyl;
• R" is more preferably selected from the group consisting of methyl, ethyl, n-propyl, n-butyl, isobutyl and t-butyl.
• R"" is most preferably methyl.
• R , R “, R “, R 4 , and R ⁇ are as described above wherein
• n is preferably an integer of from 1 to 5;
• R , R , R"', R and R-> are as described above wherein
• n is most preferably 3.
• the ring may be unsubstituted or substituted with one or more of Ci.galkyl, C3. gcycloalkyl-Co-galkyl, C 2 -6alkenyl, C .galkynyl, HetCo-galkyl, ArCo-galkyl, or halogen.
• the ring is preferably unsubstituted.
• R 2 is selected from the group consisting of:
• R 2 is selected from the group consisting of: Ar-C ⁇ -6 a lkyl, R C(O)-,
• R 2 is selected from the group consisting of: Ar-C()-6alkyl
• R 2 is R sO 2 .
• R6 is selected from the group consisting of: H, C j .galkyl, Ar-C ⁇ -6alkyl, or Het-CQ. galkyl, preferably H.
• R' is selected from the group consisting of: H, C j .galkyl, C3_gcycloalkyl-Co-galkyl, Ar-Co.galkyl, Het-C 0 -galkyl, RlOc(O)-, R!°C(S)-, R 10 SO 2 -, R 10 OC(O)-, R10R1 NC(O)-, R 10 Rl 4 NC(S)-, R 7 is preferably Rl°OC(O).
• R° > is selected from the group consisting of: H, C galkyl, C 2 .galkenyl, C 2 _galkynyl, HetCo-galkyl and ArCo-galkyl; preferably Cj.galkyl, more preferably isobutyl.
• R is selected from the group consisting of: C galkyl, C3_gcycloalkyl-Co-galkyl, Ar-CQ-galkyl, and Het-Co-galkyl.
• R9 is preferably selected from the group consisting of: C j .galkyl, Ar-C Q -galkyl, and Het-Co.galkyl.
• R 9 is selected from the group consisting of: methyl; ethyl, especially C j -galkyl-substituted ethyl, more especially 2-cyclohexyl-ethyl; propyl; butyl, especially C j .gbutyl, more especially 3-methylbutyl; tert-butyl, particularly when R 2 is R 9 OC(O); isopentyl; phenyl, especially halogen substituted phenyl, more especially 3,4-dichlorophenyl , 4-bromophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 3- chlorophenyl, 4-chlorophenyl, especially C j .galkoxy phenyl, more especially 3- methoxyphenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl, especially cyanophenyl, more especially 2-cyanophenyl,
• R 9 is most preferably selected from the group consisting of: pyridin-2-yl and l-oxy-pyridin-2-yl.
• R 9 is preferably Ar-C 0 -galkyl, more preferably Ar, most preferably substituted phenyl such as 2-methyl phenyl, 4-methyl phenyl, 2-chloro phenyl, and 4-fluoro phenyl.
• R 9 is preferably selected from the group consisting of C ⁇ _ galkyl, C3_gcycloalkyl-Co-galkyl, and Het-Co_galkyl, more preferably l-oxy-pyridin-2-yl, cyclohexyl ethyl, and 3-methyl butyl.
• Rl 1 is selected from the group consisting of: H, C _galkyl, Ar-C ⁇ -6alkyl, and Het- C 0 -galkyl.
• R 11 is preferably H.
• R 2 is Ar-CQ-galkyl
• R 2 is preferably phenyl, especially substituted phenyl, more especially halogen substituted phenyl, even more especially 2-fluorobenzyl.
• R 2 is Cj.galkyl
• R 2 is preferably selected from 1-propyl, 1-butyl, and 1- pentyl.
• Het-Co_galkyl is preferably Het-methyl
• Het in Het- methyl is preferably selected from the group consisting of: pyridinyl, especially pyridin-2-yl, especially C _galkylpyridinyl, more especially 6- methyl-pyridin-2-yl; thiophenyl, especially thiophene-2-yl, more especially thiophen-2-yl or benzo[b]thiophen-2-yl; thiazolyl, especially thiazol-4-yl such as l-(2-morpholin-4-yl-thiazol-4-y ⁇ ), and 1- (isothiazol-3-yl); lH-imidazolyl, especially lH-imidazol-2-yl, lH-imidazol-4-yl, especially C j .galkyl substituted imidazolyl, more especially l-methyl-lH-imidazol-2y
• R 2 is also preferably: H; toluyl; aryl substituted ethyl, especially 2-phenyl ethyl, 2-[3-(pyridin-2-yl) phenyl] ethyl.
• R" and R'" are both H are preferred. Also preferred are such compounds wherein R'" is selected from the group consisting of: 6-methyl and 7- methyl, preferably 7-methyl.
• R 2 is selected from the group consisting of: Ar-C ⁇ -6alkyl, R 9 C(O)-, R 9 SO 2 ,
• R 3 is selected from the group consisting of: H, Ci-galkyl, C3_gcycloalkyl-C ⁇ -galkyl and Ar-Co_galkyl;
• R 4 is selected from the group consisting of: R 5 OC(O)-, R 5 C(O)- and R 5 SO 2 -;
• R ⁇ is selected from the group consisting of: C ⁇ .galkyl, Ar-CQ-galkyl and Het-CQ. galkyl;
• R 6 is H
• R 7 is R 10 OC(O); R 8 is C ⁇ _galkyl;
• R 9 is selected from the group consisting of: C _galkyl, Ar-CQ.galkyl and Het-CQ. galkyl;
• RIO is selected from the group consisting of: C j .galkyl, Ar-C Q .galkyl and Het-CQ. galkyl; R' is H;
• R" is H
• R'" is H
• Z is selected from the group consisting of: C(O) and CH 2 .
• R'" is selected from the group consisting of: 6-methyl and 7-methyl, preferably 7-methyl.
• R 2 is selected from the group consisting of: Ar-Co-galkyl, R 9 C(O)-, R 9 SO 2 .
• R 2 is selected from the group consisting of: Ar-C ⁇ -galkyl, R C(O)- and R 9 SO 2 ;
• R 3 is selected from the group consisting of: H, methyl, ethyl, n-propyl, prop-2-yl, n- butyl, isobutyl, but-2-yl, cyclopropylmethyl, cyclohexylmethyl, 2-methanesulfinyl-ethyl, 1- hydroxyethyl, toluyl, naphthalen-2-ylmethyl, benzyloxymethyl, and hydroxymethyl;
• R 4 is R 5 C(O)-;
• R-> is selected from the group consisting of: methyl, especially halogenated methyl, more especially trifluoromethyl , especially C ⁇ _galkoxy substituted methyl, more especially phenoxy-methyl , 4-fluoro-phenoxy-methyl , especially heterocycle substituted methyl, more especially 2-thiophenyl-methyl ; ethyl, especially piperidin-1-yl-ethyl; butyl, especially aryl substituted butyl, more especially 4-(4-methoxy)phenyl-butyl; isopentyl; cyclohexyl; pentanonyl, especially 4-pentanonyl; butenyl, especially aryl substituted butenyl, more especially 4,4-bis(4- methoxyphenyl)-but-3-enyl; acetyl; phenyl, especially phenyl substituted with one or more halogens, more especially 3,4-dichlorophenyl and 4-fluorophenyl, especially
• R 9 is selected from the group consisting of: methyl; ethyl, especially C j -galkyl-substituted ethyl, more especially 2-cyclohexyl-ethyl; propyl; butyl, especially C ⁇ _gbutyl, more especially 3-methylbutyl; tert-butyl, particularly when R 2 is R 9 OC(O); isopentyl; phenyl, especially halogen substituted phenyl, more especially 3,4-dichlorophenyl , 4-bromophenyl, 2-fluorophenyl, 3-fluoro ⁇ henyl, 4-fluorophenyl, 2-chlorophenyl, 3- chlorophenyl, 4-chloro ⁇ henyl, especially Cj.galkoxy phenyl, more especially 3- methoxyphenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl, especially cyanophenyl, more especially 2-cyanophenyl; especially C
• R' is H; R" is H; and
• R'" is H.
• R'" is selected from the group consisting of: 6-methyl and 7-methyl, preferably 7-methyl.
• the following compounds are preferred for use in the present methods of treatment:
• Naphthlene-2-carboxylic acid ((S)-3-methyl-l- ⁇ 3-oxo-l-[2-(3-pyridin-2-yl-phenyl)ethyl]- azepan-4-ylcarbamoyl ⁇ -butyl)amide; lH-Indole-2-carboxylic acid [(S)-l-(l-benzenesulfonyl-3-oxo-azepan-4-ylcarbamoyl)-3- methyl-butyl] amide;
• Naphthalene-2-carboxylic acid ⁇ (S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-butyl ⁇ -amide; Quinoline-3-carboxylic acid ⁇ (S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-butyl ⁇ amide;
• Benzofuran-2-carboxylic acid ⁇ (S)-3-methyl-l-[(4R,7R)-7-methyl-3-oxo-l-(pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl ⁇ -amide; Benzofuran-2-carboxylic acid ⁇ (S)-l-[-(3-fluoro-benzensulfonyl)-3-oxo-azepan-4- ylcarbamoyl]-3-methyl-l-butyl ⁇ -amide;
• Naphthalene- 1 -carboxylic acid ⁇ (S)-3-methyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-butyl ⁇ -amide;
• the present invention includes deuterated analogs of the inventive compounds.
• a representative synthetic route for the deuterated compounds of the present invention is set forth in Scheme 7, below.
• the deuterated compounds of the present invention exhibit superior chiral stability compared to the protonated isomer.
• the compounds used in the present invention includes all hydrates, solvates, complexes and prodrugs of the compounds of this invention.
• Prodrugs are any covalently bonded compounds which release the active parent drug according to Formula I in vivo. If a chiral center or another form of an isomeric center is present in a compound of the present invention, all forms of such isomer or isomers, including enantiomers and diastereomers, are intended to be covered herein.
• Compounds containing a chiral center may be used as a racemic mixture, an enantiomerically enriched mixture, or the racemic mixture may be separated using well-known techniques and an individual enantiomer may be used alone.
• any substituent at any one occurrence in Formula I or any subformula thereof is independent of its meaning, or any other substituent's meaning, at any other occurrence, unless specified otherwise.
• Abbreviations and symbols commonly used in the peptide and chemical arts are used herein to describe the compounds of the present invention. In general, the amino acid abbreviations follow the IUPAC-IUB Joint Commission on Biochemical Nomenclature as described in Eur. J. Biochem., 158, 9 (1984).
• proteases are enzymes that catalyze the cleavage of amide bonds of peptides and proteins by nucleophilic substitution at the amide bond, ultimately resulting in hydrolysis.
• proteases include: cysteine proteases, serine proteases, aspartic proteases, and metalloproteases.
• the compounds of the present invention are capable of binding more strongly to the enzyme than the substrate and in general are not subject to cleavage after enzyme catalyzed attack by the nucleophile. They therefore competitively prevent proteases from recognizing and hydrolyzing natural substrates and thereby act as inhibitors.
• amino acid refers to the D- or L- isomers of alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine.
• Ci-galkyl as applied herein is meant to include substituted and unsubstituted methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and t-butyl, pentyl, n- pentyl, isopentyl, neopentyl and hexyl and the simple aliphatic isomers thereof.
• O ⁇ .galkyl may be optionally substituted by a moiety selected from the group consisting of: OR 4 ,
• R is selected from the group consisting of: H, C ⁇ _ galkyl, C 2 .galkenyl, C 2 .galkynyl, C3_gcycloalkyl-CQ_galkyl, Ar-CQ.galkyl and Het-CQ. galkyl; and Rl 4 is selected from the group consisting of: H, C j .galkyl, Ar-Co_galkyl, and Het-C Q _galkyl;
• C3-gcycloalkyl as applied herein is meant to include substituted and unsubstituted cyclopropane, cyclobutane, cyclopentane and cyclohexane.
• C 2 .g alkenyl as applied herein means an alkyl group of 2 to 6 carbons wherein a carbon-carbon single bond is replaced by a carbon-carbon double bond.
• C 2 .galkenyl includes ethylene, 1-propene, 2-propene, 1-butene, 2-butene, isobutene and the several isomeric pentenes and hexenes. Both cis and trans isomers are included.
• C _galkynyl means an alkyl group of 2 to 6 carbons wherein one carbon-carbon single bond is replaced by a carbon-carbon triple bond.
• C 2 _g alkynyl includes acetylene, 1- propyne, 2-propyne, 1-butyne, 2-butyne, 3-butyne and the simple isomers of pentyne and hexyne.
• Halogen means F, Cl, Br, and I.
• Ar or aryl means phenyl or naphthyl, optionally substituted by one or more of Ph-Co-galkyl; Het-C 0 .galkyl; C j .galkoxy; Ph-C 0 .galkoxy; Het-C Q .galkoxy; OH, (CH 2 ) ⁇ .
• R 15 and Rl 6 are H, C galkyl, Ph-C 0 .galkyl, naphthyl-CQ_galkyl or Het-CQ.galkyl; and R 7 is phenyl, naphthyl, or C ⁇ .galkyl.
• Het represents a stable 5- to 7-membered monocyclic, a stable 7- to 10-membered bicyclic, or a stable 11- to 18-membered tricyclic heterocyclic ring which is either saturated or unsaturated, and which consists of carbon atoms and from one to three heteroatoms selected from the group consisting of N, O and S, and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring.
• the heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure, and may optionally be substituted with one or two moieties selected from C Q .gAr, Cl .galkyl, ORI 7 , N(R 17 ) 2 , SR 17 , CF 3 , NO 2 , CN, CO 2 Rl 7 , CON(R 17 ), F, Cl, Br and I, where R 17 is phenyl, naphthyl, or C ⁇ .galkyl.
• heterocycles include piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, pyridinyl, 1-oxo- pyridinyl, pyrazinyl, oxazolidinyl, oxazolinyl, oxazolyl, isoxazolyl, morpholinyl, thiazolidinyl, thiazolinyl, thiazolyl, quinuclidinyl, indolyl, quinolinyl, quinoxalinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, benzoxazolyl, furanyl, benzoimid
• CQ denotes the absence of the substituent group immediately following; for instance, in the moiety ArC Q .galkyl, when C is 0, the substituent is Ar, e.g., phenyl. Conversely, when the moiety ArC Q ,galkyl is identified as a specific aromatic group, e.g., phenyl, it is understood that the value of C is 0. Certain radical groups are abbreviated herein.
• t-Bu refers to the tertiary butyl radical
• Boc refers to the t-butyloxycarbonyl radical
• Fmoc refers to the fluorenylmethoxycarbonyl radical
• Ph refers to the phenyl radical
• Cbz refers to the benzyloxycarbonyl radical.
• m-CPBA 3-chloroperoxybenzoic acid
• EDC N-ethyl-N'(dimethylaminopropyl)-carbodiimide
• DMF dimethyl formamide
• DMSO dimethyl sulfoxide
• TEA triethylamine
• TFA trifluoroacetic acid
• THF tetrahydrofuran
• Epoxidation of 3 with standard oxidizing agents common to the art such as m-CPBA provide the epoxide 4.
• Nucleophilic epoxide ring opening may be effected with a reagent such as sodium azide to provide the azido alcohol (not shown) which may be reduced to the amino alcohol 5 under conditions common to the art such as 1,3-propanedithioln and triethylamine in methanol or with hydrogen gas in the presence of a catalyst such as palladium on carbon.
• Acylation of 5 with an acid such as Cbz- leucine in the presence of a coupling agent such as EDC followed by removal of the BOC protecting group under acidic conditions provides the amine salt 6.
• Coupling of 6 with Cbz- leucine was effected with a coupling agent such as EDC provides the intermediate alcohol (not shown) which was oxidized with an oxidant such as pyridine sulfur trioxide complex in DMSO and triethylamine to provide the ketone 7.
• a coupling agent such as EDC provides the intermediate alcohol (not shown) which was oxidized with an oxidant such as pyridine sulfur trioxide complex in DMSO and triethylamine to provide the ketone 7.
• Nucleophilic epoxide ring opening may be effected with a reagent such as sodium azide to provide the azido alcohol (not shown) which may be reduced to the amino alcohol 12 with a reducing agent such as propanedithiol in the presence of triethylamine.
• a reducing agent such as propanedithiol in the presence of triethylamine.
• Acylation of 12 with N-Boc-leucine and a coupling agent such as EDC followed by removal of the Cbz protecting group under hydrogenolysis conditions provides the amine 13.
• Coupling of 13 with a carboxylic acid was effected with a coupling agent such as EDC followed by removal of the acid labile N-Boc protecting group with an acid such as HCl or TFA provides intermediate 14.
• Reagents and conditions a.) NaH, 5-bromo-l-pentene, DMF; b.) bis(tricyclohexylphosphine)benzylidine ruthenium (IV) dichloride catalyst, CH 2 C1 2 ; c.) m-CPBA, CH 2 C1 2 ; d.) NaN 3 , CH 3 OH, H 2 0, NH 4 C1; e.) propanedithiol, CH 3 OH, TEA; f.) Boc-leucine, EDC, CH 2 C1 2 ; g.) 10% Pd/C, H 2 ; h.) R,C0 2 H, EDC, CH 2 C1 2 or R,COCl, CH 2 C1 2 ; i.) HCl/ EtOAc; j.) R.CO j H, EDC, CH 2 C1 2 ; k.) pyridine sulfur trioxide complex, DMSO, TEA.
• amine 13 treatment of amine 13 with an isocyanate followed by deprotection of the N-Boc group provides the amine salt 18.
• Acylation and oxidation provides the ketone 19.
• Further derivatization of amine 13 may be effected by treatment with a sulphonyl chloride followed by deprotection of the N-Boc group to provide the amine salt 20.
• Acylation and oxidation provides the ketone 21.
• Reagents and conditions a.) R,CHO, NaBH(OAc) 3 ; b.) HCl; c.) I ⁇ CO.H, EDC, CH 2 C1 2 ; d.) pyridine sulfurtrioxide complex, DMSO, TEA; e.) R,NCO, base; f.) R I S0 2 C1, TEA, CH 2 C1 2 .
• Compounds of the general formula I may be prepared in a fashion analogous to that outlined in Schemes 4, 5, 6, and 7
• 2-Methyl-pent-4-enoic acid ethyl ester is converted to a N-2-pyridinesulfonyl-azapine by reduction to the aldehyde, reductive amination with allylamine, sulfonylation with 2- pyridyl sulfonyl chloride, and olefin metathesis with Grubbs' catalyst.
• Epoxidation with mCPBA affords a mixture of epoxides that are separable by column chromatography.
• the syn epoxide is converted into an amino alcohol by opening with sodium azide followed by reduction with triphenylphosphine.
• 5-Hexen-2-one is converted to a N-carbobenzyloxy-azapine by reductive amination with allylamine, protection with carbobenzyloxy chloride, and olefin metathesis with Grubbs' catalyst.
• Epoxidation with mCPBA affords a mixture of epoxides that are separable by column chromatography. Each epoxide is converted into an amino alcohol by opening with sodium azide followed by reduction with triphenylphosphine.
• Carbobenyzloxy-D-alaninol (Cbz-D-alaninol) is first converted to an iodide, then is reacted with allyl Grignard with a copper (I) catalyst or a similar allyl organometallic reagent. The amine is then alkylated with allyl iodide. Grubbs' catalyst is then used to form the azapine ring by ring closing metathesis. Epoxidation of the alkene followed by separation of the diastereomers followed by opening of the epoxide of the minor component with sodium azide provides the intermediate azido alcohol.
• Deuterated inhibitors can be prepared from the parent inhibitors such as benzofuran-2- carboxylic acid ⁇ (S)-3-methyl-l-[(4S,7R)-7-methyl-3-oxo-l-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-butyl ⁇ -amide by treating with a base such as triethyl amine and stirring for several days in a deteurated protic solvent such as CD 3 OD: D 2 O.
• a base such as triethyl amine
• a deteurated protic solvent such as CD 3 OD: D 2 O.
• the present invention provides a method of inhibiting cysteine proteases of the papain superfamily by administering to a patient in need thereof, particularly an animal, more particularly a mammal, most particularly a human being, one or more of the compounds of Formula I.
• the present invention also provides a method of treating a parasitic disease mediated by a cysteine protease by administering to a patient in need thereof, particularly an animal, more particularly a mammal, most particularly a human being, one or more of the compounds of Formula I.
• cysteine proteases Parasites known to utilize cysteine proteases in their life cycle include Plasmodium falciparum (malaria), Trypanosoma cruzi, Trypanosoma Brucei [trypanosomiasis (African sleeping sickness, Chagas disease)], Leishmania mexicana, Leishmania pifanoi, Leishmania major (leishmaniasis), Schistosoma mansoni (schistosomiasis), Onchocerca volvulus
• the present method provides treatment of diseases caused by infection by these parasites by inhibiting cysteine proteases of the papain superfamily by administering to a patient in need thereof, particularly an animal, more particularly a mammal, most particularly a human being, one or more of the compounds of Formula I.
• the compounds of Formula I used in the inventive method are especially effective in inhibition of one or more of the following parasitic proteases: falcipain (P. falciparum), cruzain (T. cruzi), rhodazain (T. brucei rhodesiensi), leishmania L (Leishmania spp.), leishmania B (Leishmania spp.), and schistosoma B (S. manson ⁇ ).
• the present invention provides a method of treating diseases selected from a group consisting of: malaria, trypanosomiasis (African sleeping sickness, Chagas disease), leishmaniasis, schistosomiasis, onchocerciasis (river blindness) and giardiasis by administering to a patient in need thereof, particularly an animal, more particularly a mammal, most particularly a human being, one or more of the compounds of Formula I.
• diseases selected from a group consisting of: malaria, trypanosomiasis (African sleeping sickness, Chagas disease), leishmaniasis, schistosomiasis, onchocerciasis (river blindness) and giardiasis by administering to a patient in need thereof, particularly an animal, more particularly a mammal, most particularly a human being, one or more of the compounds of Formula I.
• the present invention provides a method of treating malaria, caused by infection with Plasmodium falciparum, by the inhibition of falcipain by administering to a patient in need thereof, particularly an animal, more particularly a mammal, most particularly a human being, one or more of the above-listed compounds.
• the present method may be practiced by administering the above-listed compounds alone or in combination with other therapeutically effective compounds, including but not limited to quinoline-derived drugs.
• t-Bu refers to the tertiary butyl radical
• Boc refers to the t-butyloxycarbonyl radical
• Fmoc refers to the fluorenylmethoxycarbonyl radical
• Ph refers to the phenyl radical
• Cbz refers to the benzyloxycarbonyl radical.
• the present invention includes all esters, hydrates, solvates, complexes and prodrugs of the above-listed compounds useful in the inventive method.
• Prodrugs are any covalently bonded compounds which release the active parent drug in vivo. If a chiral center or another form of an isomeric center is present in a compound of the present invention, all forms of such isomer or isomers, including enantiomers and diastereomers, are intended to be covered herein.
• Inventive compounds containing a chiral center may be used as a racemic mixture, an enantiomerically enriched mixture, or the racemic mixture may be separated using well- known techniques and an individual enantiomer may be used alone.
• compositions which comprise one or more of compounds of Formula I and a pharmaceutically acceptable carrier, diluent or excipient.
• the compounds of Formula I may be used in the manufacture of a medicament useful in the practice oof the present methods of treatment.
• Pharmaceutical compositions of compounds of Formula I prepared as hereinbefore described may be formulated as solutions or lyophilized powders for parenteral administration. Powders may be reconstituted by addition of a suitable diluent or other pharmaceutically acceptable carrier prior to use.
• the liquid formulation may be a buffered, isotonic, aqueous solution.
• Suitable diluents are normal isotonic saline solution, standard 5% dextrose in water, or buffered sodium or ammonium acetate solution.
• Such formulation is especially suitable for parenteral administration, but may also be used for oral administration or contained in a metered dose inhaler or nebulizer for insufflation. It may be desirable to add excipients such as polyvinylpyrrolidone, gelatin, hydroxy cellulose, acacia, polyethylene glycol, mannitol, sodium chloride, or sodium citrate.
• these compounds may be encapsulated, tableted, or prepared in an emulsion or syrup for oral administration.
• Pharmaceutically acceptable solid or liquid carriers may be added to enhance or stabilize the composition, or to facilitate preparation of the composition.
• Solid carriers include starch, lactose, calcium sulfate dihydrate, terra alba, magnesium stearate or stearic acid, talc, pectin, acacia, agar or gelatin.
• Liquid carriers include syrup, peanut oil, olive oil, saline and water.
• the carrier may also include a sustained release material such as glyceryl monostearate or glyceryl distearate, alone or with a wax.
• the amount of solid carrier varies but, preferably, will be between about 20 mg to about 1 g per dosage unit.
• the pharmaceutical preparations are made following the conventional techniques of pharmacy involving milling, mixing, granulating, and compressing, when necessary, for tablet forms; or milling, mixing and filling for hard gelatin capsule forms.
• a liquid carrier When a liquid carrier is used, the preparation will be in the form of a syrup, elixir, emulsion or an aqueous or non-aqueous suspension.
• Such a liquid formulation may be administered directly or filled into a soft gelatin capsule.
• the compounds of Formula I may also be combined with excipients such as cocoa butter, glycerin, gelatin or polyethylene glycols and molded into a suppository.
• an effective amount of one or more compounds of Formula I is administered to inhibit the protease implicated with a particular condition or disease.
• this dosage amount will further be modified according to the type of administration of the compound.
• parenteral administration of an effective amount of a compound of Formula I is preferred.
• An intravenous infusion of the compound in 5% dextrose in water or normal saline, or a similar formulation with suitable excipients, is most effective, although an intramuscular bolus injection is also useful.
• the parenteral dose will be about 0.01 to about 100 mg/kg; preferably between 0.1 and 20 mg/kg, in a manner to maintain the concentration of drug in the plasma at a concentration effective to inhibit the parasitic protease, e.g. falcipain in the case of treatment of malaria.
• the compounds are administered one to four times daily at a level to achieve a total daily dose of about 0.4 to about 400 mg/kg/day.
• the precise amount of an inventive compound which is therapeutically effective, and the route by which such compound is best administered, is readily determined by one of ordinary skill in the art by comparing the blood level of the agent to the concentration required to have a therapeutic effect.
• the compound may be administered in the form of a prodrug which, in general, is designed to enhance absorption and is cleaved in vivo to form the active component. Efficacious levels may also be achieved by administration of pharmaceutically active metabolites or bioisosteres of the compound.
• Prodrugs of compounds of the present invention may be prepared by any suitable method.
• the compounds used in this method may also be administered orally to the patient, in a manner such that the concentration of drug is sufficient to inhibit cysteine proteases, e.g. falcipain in the case of treatment of malaria, or to achieve any other therapeutic indication as disclosed herein.
• a pharmaceutical composition containing the compound is administered at an oral dose of between about 0.1 to about 50 mg/kg in a manner consistent with the condition of the patient.
• the oral dose would be about 0.1 to about 50 mg/kg given 1-2 times/day. No unacceptable toxicological effects are expected when compounds of the present invention are administered in accordance with the present method of treatment.
• the compounds used in the present method may be tested in one of several biological assays to determine the concentration of a compound which is required to have a given pharmacological effect.
• an assay for determining parasitic cysteine protease catalytic activity and an assay to determine the amount of cysteine protease inhibition by a compound of the inventive method are provided.
• cysteine protease catalytic activity Standard assay conditions for the determination of kinetic constants used 10 uM fluorogenic peptide substrate, Cbz-Phe-Arg-AMC for the cysteine proteases from Leishmania spp and Schistosoma Mansoni, Cbz-Leu-Arg-AMC for the cysteine proteases from Plasmodium falciparum and Trypanosoma brucei rhodesiensi, and Ac-Lys-Glu-Lys- Leu-Arg-AMC (4 uM final substrate concentration) for the cysteine protease from Trypoanosoma cruzi, and were determined in 100 mM Na acetate at pH 5.5 containing 5 mM cysteine.
• Stock substrate solutions were prepared at concentrations of 10 mM in DMSO with 10 uM (4 uM for Ac-Lys-Glu-Lys-Leu-Arg-AMC) final substrate concentration in the assays.
• the final DMSO concentration was 2 % and the final volume was 100 uL. All assays were conducted at ambient temperature. Product progress curves were generated over 20 to 30 minutes following formation of AMC product.
• v V m A /[K a (l + VKi app) +A] (1)
• v is the velocity of the reaction with maximal velocity V m
• A is the concentration of substrate with Michaelis constant of K a
• / is the concentration of inhibitor.
• [AMC] v ss t + (VQ - v ss ) [1 - exp (-k 0 b s t)l / k 0 bs (2)
• Table I provides exemplary data resulting from the testing of compounds of the present method for inhibition of one or more of the following parasitic disease cysteine proteases: falcipain, cruzain, rhodazin, leishmania L, leishmania B, schistosoma Bl, and schistosoma B2.
• Plasmodium vinckei Rosenthal, P. J.; Le, G. K.; Smith, R. E. J. Clin. Invest. 1993, 91, 1052-
• Example 18 Following the procedure of Example 6(a)-6(b), except substituting pyridine-2- sulfonyl chloride for benzenesulfonyl chloride in step (a) and naphthalne-2-carboxylic acid for 5-(2-mo ⁇ holin-4-yl-ethoxy)-benzofuran-2-carboxylic acid in step (b), the title compound was prepared. MS (ESI): 537 (M+H+). Example 18
• Example 25 Following the procedure of Example 6(a)-6(b), except substituting pyridine-2- sulfonyl chloride for benzenesulfonyl chloride in step (a) and quinoline-2-carboxylic acid for 5-(2-mo ⁇ holin-4-yl-ethoxy)-benzofuran-2-carboxylic acid in step (b), the title compound was prepared. MS (ESI): 538 (M+H+). Example 25
• Example 28 Following the procedure of Example 6(a)-6(b), except substituting pyridine-2- sulfonyl chloride for benzenesulfonyl chloride in step (a) and quinoline-3-carboxylic acid tert-butyl ester for 5-(2-mo ⁇ holin-4-yl-ethoxy)-benzofuran-2-carboxylic acid in step (b), the title compound was prepared. MS (ESI): 538 (M+H+).
• Example 28 Following the procedure of Example 6(a)-6(b), except substituting pyridine-2- sulfonyl chloride for benzenesulfonyl chloride in step (a) and quinoline-3-carboxylic acid tert-butyl ester for 5-(2-mo ⁇ holin-4-yl-ethoxy)-benzofuran-2-carboxylic acid in step (b), the title compound was prepared. MS (ESI): 538 (M+H+).
• Example 60 Following the procedure of Example 6(a)-6(b), except substituting pyridine-2- sulfonyl chloride for benzenesulfonyl chloride in step (a) and indole-5-carboxylic acid for benzo[l,3]dioxole-5-carboxylic acid in step (b), the title compound was prepared. MS (ESI): 531 (M+H+). Example 60
• Example 63 Following the procedure of Example 6(a)-6(b), except substituting l-oxypyridine-2- sulfonyl chloride for benzenesulfonyl chloride in step (a) and thieno[3,2-b]thiophene-2- carboxylic acid for 5-(2-mo ⁇ holin-4-yl-ethoxy)-benzofuran-2-carboxylic acid in step (b), the title compound was prepared. MS (ESI): 565 (M+H+).
• Example 63 Example 63
• Example 73 Following the procedure of Example 6(a)-6(b), except substituting pyridine-2- sulfonyl chloride for benzenesulfonyl chloride in step (a) and 2-Phenyl-5-trifluoromethyl- oxazole-4-carboxylic acid for benzo[l,3]dioxole-5-carboxylic acid in step (b), the title compound was prepared. MS (ESI): 622 (M+H + ). Example 73
• Example 76 Following the procedure of Example 6(a)-6(b), except substituting l-oxypyridine-2- sulfonyl chloride for benzenesulfonyl chloride in step (a) and furan-2-carboxylic acid for 5- (2-mo ⁇ holin-4-yl-ethoxy)-benzofuran-2-carboxylic acid in step (b), the title compound was prepared. MS (ESI): 493 (M+H+). Example 76
• Example 84 Following the procedure of Example 6(a)-6(b), except substituting 4- fluorobenzenesulfonyl chloride for benzenesulfonyl chloride in step (a) and quinoline-2- carboxylic acid for 5-(2-mo ⁇ holin-4-yl-ethoxy)-benzofuran-2-carboxylic acid in step (b), the title compound was prepared. MS (ESI): 555 (M+H + ).
• Example 84 Following the procedure of Example 6(a)-6(b), except substituting 4- fluorobenzenesulfonyl chloride for benzenesulfonyl chloride in step (a) and quinoline-2- carboxylic acid for 5-(2-mo ⁇ holin-4-yl-ethoxy)-benzofuran-2-carboxylic acid in step (b), the title compound was prepared. MS (ESI): 555 (M+H + ).
• Example 84 Following the procedure of Example 6(a)-6(
• Example 100 The title compound was isolated as the first eluting compound from the HPLC purification in Example 57. MS (ESI): 557 (M+H+). Example 100
• Example 122 Following the procedure of Example 6(a)-6(b), except substituting 4- fluorobenzenesulfonyl chloride for benzenesulfonyl chloride in step (a) and 4- methanesulfonylbenzoic acid for benzo[l,3]dioxole-5-carboxylic acid in step (b), the title compound was prepared. MS (ESI): 582 (M+H+). Example 122
• Example 168 Following the procedure of Example 6(a)-6(b), except substituting pyridine-2- sulfonyl chloride for benzenesulfonyl chloride and [(S)-l-(3-hydroxy-6-methyl-azepan-4- ylcarbamoyl)-3-methyl-butyl]-carbamic acid tert butyl ester for [(S)-l-(3-hydroxy-azepan-4- ylcarbamoyl)-3-methyl-butyl]-carbamic acid tert butyl ester in step (a), and benzofuran-2- carboxylic acid for benzo[l,3]dioxole-5-carboxylic acid in step (b), the title compound was prepared. MS (ESI): 541 (M+H+).
• Example 168 Example 168
• Example 6(a)-6(b) Following the procedure of Example 6(a)-6(b), except substituting l-oxypyridine-2- sulfonyl chloride for benzenesulfonyl chloride and [(S)-l-(3-hydroxy-azepan-4-ylcarbamoyl)- 2-cyclohexyl-ethyl]-carbamic acid tert butyl ester for [(S)-l-(3-hydroxy-azepan-4- ylcarbamoyl)-3-methyl-butyl]-carbamic acid tert butyl ester in step (a), and 5,6- dimethoxybenzofuran-2-carboxylic acid for benzo[l,3]dioxole-5-carboxylic acid in step (b), the title compound was prepared. MS (ESI): 643 (M+H+).
• Example 6(a)-6(b) Following the procedure of Example 6(a)-6(b), except substituting pyridine-2- sulfonyl chloride for benzenesulfonyl chloride and [(S)-l-(3-hydroxy-azepan-4-ylcarbamoyl)- 2-(2-naphthyl)-ethyl]-carbamic acid tert butyl ester for [(S)-l-(3-hydroxy-azepan-4- ylcarbamoyl)-3-methyl-butyl]-carbamic acid tert butyl ester in step (a), and naphthalene- 1- carboxylic acid for benzo[l,3]dioxole-5-carboxylic acid in step (b), the title compound was prepared. MS (ESI): 621 (M+H+).
• Example 6(a)-6(b) Following the procedure of Example 6(a)-6(b), except substituting pyridine-2- sulfonyl chloride for benzenesulfonyl chloride and [(S)-l-(3-hydroxy-azepan-4-ylcarbamoyl)- 2-phenyl-ethyl]-carbamic acid tert butyl ester for [(S)-l-(3-hydroxy-azepan-4-ylcarbamoy ⁇ )- 3-methyl-butyl]-carbamic acid tert butyl ester in step (a), and naphthalene- 1 -carboxylic acid for benzo[l,3]dioxole-5-carboxylic acid in step (b), the title compound was prepared. MS (ESI): 571 (M+H+).
• Example 6(a)-6(b) Following the procedure of Example 6(a)-6(b), except substituting pyridine-2- sulfonyl chloride for benzenesulfonyl chloride and [(S)-l-(3-hydroxy-azepan-4-ylcarbamoyl)- 2-phenyl-ethyl]-carbamic acid tert butyl ester for [(S)-l-(3-hydroxy-azepan-4-ylcarbamoyl)- 3-methyl-butyl]-carbamic acid tert butyl ester in step (a), and quinoline-2-carboxylic acid for benzo[l,3]dioxole-5-carboxylic acid in step (b), the title compound was prepared. MS (ESI): 572 (M+H+).
• Hex-5-en-2-one (9.8 g, 11.6 ml, 100 mmol) was added to a stirred solution of allylamine (8.55 mmol, 11.25 ml, 150 mmol), 4 Angstrom molecular sieves (52 g), and p- toluene sulfonic acid (10 mg) in CH 2 C1 2 (200 ml) and was stirred overnight.
• the reaction mixture was concentrated in vacuo by rotary evaporation and was used in the next reaction without further purification (13 g, 95%).

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