WO2000055144A1 - Amine derivatives as protease inhibitors - Google Patents

Amine derivatives as protease inhibitors Download PDF

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Publication number
WO2000055144A1
WO2000055144A1 PCT/US2000/006885 US0006885W WO0055144A1 WO 2000055144 A1 WO2000055144 A1 WO 2000055144A1 US 0006885 W US0006885 W US 0006885W WO 0055144 A1 WO0055144 A1 WO 0055144A1
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WO
WIPO (PCT)
Prior art keywords
alkyl
halo
substituted
hetero
hydrogen
Prior art date
Application number
PCT/US2000/006885
Other languages
French (fr)
Inventor
John O. Link
Arnold J. Martelli
Valeri Martichonok
John W. Patterson
Oliver L. Saunders
Sheila Zipfel
Original Assignee
Axys Pharmaceuticals, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to AU37507/00A priority Critical patent/AU774664B2/en
Priority to KR1020017011748A priority patent/KR20010110670A/en
Priority to EP00916397A priority patent/EP1161422A1/en
Priority to BR0009044-1A priority patent/BR0009044A/en
Application filed by Axys Pharmaceuticals, Inc. filed Critical Axys Pharmaceuticals, Inc.
Priority to CA002367352A priority patent/CA2367352A1/en
Priority to EA200100970A priority patent/EA004807B1/en
Priority to JP2000605574A priority patent/JP2002539201A/en
Priority to EEP200100486A priority patent/EE200100486A/en
Priority to SK1287-2001A priority patent/SK12872001A3/en
Priority to IL14542800A priority patent/IL145428A0/en
Publication of WO2000055144A1 publication Critical patent/WO2000055144A1/en
Priority to IL145428A priority patent/IL145428A/en
Priority to NO20014483A priority patent/NO20014483L/en
Priority to BG105969A priority patent/BG105969A/en
Priority to HR20010736A priority patent/HRP20010736A2/en

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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
    • C07D213/30—Oxygen atoms
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07D263/14—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with radicals substituted by oxygen atoms
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    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
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Definitions

  • This application relates to compounds and compositions for treating diseases associated with cysteine protease activity, particularly diseases associated with activity of cathepsins B, K, L or S.
  • Cysteine proteases represent a class of peptidases characterized by the presence of a cysteine residue in the catalytic site of the enzyme. Cysteine proteases are associated with the normal degradation and processing of proteins. The aberrant activity of cysteine proteases, e.g. as a result of increased expression or enhanced activation, however, may have pathological consequences. In this regard, certain cysteine proteases are associated with a number of disease states, including arthritis, muscular dystrophy, inflammation, tumor invasion, glomerulonephritis, malaria, periodontal disease, metachromatic leukodystrophy and others.
  • cathepsin B levels and redistribution of the enzyme are found in tumors; thus, suggesting a role for the enzyme in tumor invasion and metastasis.
  • aberrant cathepsin B activity is implicated in such disease states as rheumatoid arthritis, osteo arthritis, pneumocystis carinii, acute pancreatitis, inflammatory airway disease and bone and joint disorders.
  • the prominent expression of cathepsin K in osteoclasts and osteoclast-related multinucleated cells and its high collagenolytic activity suggest that the enzyme is involved in ososteoclast-mediated bone resorption and, hence, in bone abnormalities such as occurs in osteoporosis.
  • cathepsin K expression in the lung and its elastinolytic activity suggest that the enzyme plays a role in pulmonary disorders as well.
  • Cathepsin L is implicated in normal lysosomal proteolysis as well as several disease states, including, but not limited to, metastasis of melanomas.
  • Cathepsin S is implicated in Alzheimer's disease and certain autoimmune disorders, including, but not limited to juvenile onset diabetes, multiple sclerosis, pemphigus vulgaris, Graves' disease, myasthenia gravis, systemic lupus erythemotasus, rheumatoid arthritis and Hashimoto's thyroiditis; allergic disorders, including, but not limited to asthma; and allogeneic immune responses, including, but not limited to, rejection of organ transplants or tissue grafts.
  • autoimmune disorders including, but not limited to juvenile onset diabetes, multiple sclerosis, pemphigus vulgaris, Graves' disease, myasthenia gravis, systemic lupus erythemotasus, rheumatoid arthritis and Hashimoto's thyroiditis
  • allergic disorders including, but not limited to asthma
  • allogeneic immune responses including, but not limited to, rejection of organ transplants or tissue grafts.
  • cysteine protease activity contributes to the pathology and/or symptomatology of the disease
  • molecules which are shown to inhibit the activity of this class of enzymes in particular molecules which are inhibitors of cathepsins B, K, L and/or S, will be useful as therapeutic agents.
  • the present invention relates to protease inhibitors of Formula I:
  • A comprises a heteromonocyclic ring containing 5 to 6 ring member atoms or a fused heteropolycyclic ring system containing 8 to 14 ring member atoms, wherein each ring contains 5 to 7 ring member atoms, X 1 is a ring member carbon atom and each ring member atom other than X 1 is a carbon atom or a heteroatom, with the proviso that (i) at least one ring member atom is a heteroatom and (ii) when A is a heteromonocyclic radical containing 5 ring member atoms, no more than two of the ring member atoms comprising A are heteroatoms; n is 0, 1, 2 or 3;
  • X 1 C- or -CH-;
  • X 2 is a bond or a divalent group of Formula (a) or (b):
  • X 3 and X 4 independently are -C(O)- or -CH 2 S(0) 2 -
  • R 9 and R 10 independently are hydrogen, (C,. 6 )alkyl or as defined below;
  • R 12 and R 13 independently are (i) (C 1 . 6 )alkyl optionally substituted with cyano, halo, nitro, -NR 14 R 14 , -NR 14 C(O)OR 14 , -NR 14 C(0)NR 14 R 14 , -NR 14 C(NR 14 )NR 14 R 14 ,
  • R 15 is (C,. 6 )alkyl or halo-substituted (C, .3 )alkyl, halo, (C ⁇ alkyl or R 16 is (C 3 . 12 )cycloalkyl(C 0 . 5 )alkyl, hetero(C 3 ., 2 )cycloalkyl(C 0 . 6 )alkyl, (C 6 . 12 )aryl(C 0 . 6 )alkyl, hetero(C 5 . 12 )aryl(C 0 . 6 )alkyl, (C 9 .
  • R 17 is hydrogen or (C ⁇ alkyl, and wherein within R 16 said cycloalkyl, heterocycloalkyl, aryl, heteroaryl, polycycloaryl or hete ⁇ olycycloaryl ring optionally is substituted by a group selected from -R 18 , -X 5 OR 18 , -X 5 SR 18 , -X 5 S(0)R 18 , -X 5 S(0) 2 R 18 , -X 5 C(O)R 18 , -X 5 C(0)OR 18 , -X 5 OC(O)R 18 , -X 5 NR 18 R 19 , -X 5 NR 19 C(0)R 18 , -X 5 NR 19 C(0)OR 18 , -X 5 C(0)NR 18 R 19 , -X 5 S(
  • (C ⁇ alkyl and R 19 is (C 3 _ 12 )cycloalkyl(C 0 . 6 )alkyl, hetero(C 3 . 12 )cycloalkyl(C 0 . 6 )alkyl, (C 6.12 )aryl(C 0 . 6 )alkyl, hetero(C 5 . I2 )aryl(C 0 . 6 )alkyl, (C 9 . 12 )polycycloaryl(C 0 . 6 )alkyl or hetero(C g.12 )polycycloaryl(C 0 . 6 )alkyl, or (ii) a group selected from (C 3 .
  • R 12 together with R 9 and/or R 13 together with R 10 form trimethylene, tetramethylene or phenylene-l,2-dimethylene, optionally substituted with 1 to 3 radicals independently selected from (C,. 6 )alkyl, (C 1 . 6 )alkylidene, cyano, halo, halo-substituted (C M )alkyl, nitro, oxo, -X 5 NR 14 C(0)OR 14 , -X 5 NR 14 C(0)NR 14 R 14 ,
  • R 21 is hydrogen or ( _ 6 )alkyl
  • R 20 is (i) (C,. 6 )alkyl optionally substituted by cyano, halo, nitro, -NR 14 R 14 , -NR 14 C(O)OR 14 , -NR 14 C(O)NR 14 R 14 , -NR 14 C(NR 14 )NR 14 R 14 , -OR 14 , -SR 14 , -C(0)OR' 4 , -C(O)NR 14 R 14 , -S(0) 2 NR 14 R 14 , -P(0)(OR 14 )OR 14 , -OP(O)(OR 14 )OR 14 , -NR 14 C(O)R 15 , -S(O)R 15 , -S(0) 2 R 15 , -C(O)R 15 , -OR 22 , -SR 22 , -S(0)R 22 , -S(0) 2 R 22 , -C(0)R
  • R 1 may also represent hydrogen, carboxy, oxalo or carbamoyl;
  • R 2 is hydrogen or (C,. 6 )alkyl;
  • R 3 is (i) (C j . 6 )alkyl optionally substituted with cyano, halo, nitro, -SR 26 , -C(0)OR 26 ,
  • R 26 at each occurrence independently is hydrogen, (C,. 6 )alkyl or halo-substituted (C,. 3 )alkyl and R 27 is (C ⁇ 6 )alkyl or halo-substituted (C,. 3 )alkyl, or (ii) (C 5 . 6 )cycloalkyl(C 2 . 3 )alkyl, hetero(C 3 .
  • X 2 may not represent (i) a bond when R 1 is -C(O)R 20 , -C(0) 2 R 20 or -S(O) 2 R 20 in which R 20 is (C,. 6 )alkyl, phenyl(C M )alkyl, phenyl, (C 3 . 7 )cycloalkyl, camphan-10-yl, naphth-1-yl, naphth-2-yl, phenyl substituted by one or more of (C ] . 4 )alkyl, perfluoro(C 1 . 4 )alkyl, (C,.
  • R 12 is methyl, isopropyl, n-butyl, sec-butyl, tert-butyl, 1-methylpropyl, benzyl, naphth-1-ylmethyl, naphth-2-ylmethyl, thien-2-ylmethyl, thien-3-ylmethyl, or wherein R 9 and R 12 form ethylene, trimethylene, hydroxy-substituted trimethylene, tetramethylene or phenylene-l,2-dimethylene; or
  • R 3 and R 4 taken together with the carbon atom to which both R 3 and R 4 are attached form (C 3.8 )cycloalkylene or (C 3 . 8 )heterocycloalkylene, wherein said cycloalkylene or heterocycloalkylene is optionally substituted with 1 to 3 radicals independently selected from (C,. 6 )alkyl, (C,. 6 )alkylidene, cyano, halo, halo-substituted (C,.
  • R 4 is hydrogen, (C,. 6 )alkyl or as defined above;
  • R 5 is hydrogen and R 6 is hydroxy or R 5 and R 6 together form oxo;
  • R 7 is a group selected from cyano, halo, nitro, -R 29 , -X 5 NR 29 R 30 , -X 5 NR 30 C(O)OR 29 ,
  • R 31 is (C,. 6 )alkyl, (C 3 . 12 )cycloalkyl(C 0.6 )alkyl, hetero(C 3 . 12 )cycloalkyl(C 0 . 6 )alkyl, (C 6 . 12 )aryl(C 0 . 6 )alkyl or hetero(C 5 . ]2 )aryl(C 0 . 6 )alkyl, wherein within R 7 any alicyclic or aromatic ring system present may be substituted further by 1 to 5 radicals independently selected from (C ] . 6 )alkyl, (C,.
  • R 8 at each occurrence independently is selected from (C,. 6 )alkyl, (C,. 6 )alkylidene, cyano, halo, halo-substituted (C,. 4 )alkyl, nitro, -X 5 NR 14 R 14 , -X 5 NR 14 C(0)OR 14 , -X 5 NR 14 C(O)NR 14 R 14 , -X 5 NR I4 C(NR 14 )NR 14 R 14 , -X 5 OR 14 , -X 5 SR 14 , -X 5 C(O)OR 14 , -X 5 C(O)NR 14 R 14 , -X 5 S(O) 2 NR 14 R 14 , -X 5 P(O)(OR 14 )OR 14 , -X 5 OP(0)(OR 14 )OR 14 , -X 5 NR 14 C(O)R 15 , -X 5 S(O)R 15 , -X 5 S(O) 2
  • A comprises a heteromonocyclic ring containing 5 to 6 ring member atoms or a fused heteropolycyclic ring system containing 8 to 14 ring member atoms, wherein each ring contains 5 to 7 ring member atoms, X 1 is a ring member carbon atom and each ring member atom other than X 1 is a carbon atom or a heteroatom, with the proviso that (i) at least one ring member atom is a heteroatom and (ii) when A is a heteromonocyclic radical containing 5 ring member atoms, no more than two of the ring member atoms comprising A are heteroatoms; n is 0, 1, 2 or 3;
  • X 2 is a bond or a divalent group of Formula (a) or (b):
  • X 3 and X 4 independently are -C(O)- or -CH 2 S(0) 2 -;
  • R 9 and R 10 independently are hydrogen, (C,. 6 )alkyl or as defined below; R 11 at each occurrence independently is hydrogen or (C j ⁇ alkyl;
  • R 12 and R 13 independently are (i) (C,. 6 )alkyl optionally substituted with cyano, halo, nitro, -NR 14 R 14 , -NR 14 C(O)OR 14 , -NR ,4 C(0)NR 14 R 14 , -NR 14 C(NR 14 )NR 14 R 14 , -OR 14 , -SR 14 , -C(O)OR 14 , -C(O)NR 14 R 14 , -S(0) 2 NR 14 R 14 , -P(0)(OR 14 )OR 14 , -OP(O)(OR 14 )OR 14 , -NR 14 C(O)R 15 , -S(0)R 15 , -S(0) 2 R 15 , -C(0)R 15 , -OR 16 , -SR 16 , -S(O)R 16 , -S(0) 2 R 16 , -C(O)R 16 , -C(O)OR 16 , -OC(0)R 16
  • R 14 at each occurrence independently is hydrogen, (C,. 6 )alkyl or halo-substituted (C 1 . 3 )alkyl, R 15 (C,. 6 )alkyl or halo-substituted (C 1 . 3 )alkyl, R 16 is (C 3.12 )cycloalkyl(C 0 . 6 )alkyl, hetero(C 3 . 12 )cycloalkyl(C 0 .
  • R 17 is hydrogen or (C,.
  • X 5 is a bond or (C, .6 )alkylene
  • R 18 is hydrogen or (C,. 6 )alkyl
  • R 19 is (C 3.12 )cycloalkyl(C 0 . 6 )alkyl, hetero(C 3 . 12 )cycloalkyl(C 0 . 6 )alkyl, (C 6 . 12 )aryl(C 0 .
  • any alicyclic or aromatic ring system present may be substituted further by 1 to 5 radicals independently selected from (C,. 6 )alkyl, (C,. 6 )alkylidene, cyano, halo, halo-substituted (C,.
  • R 12 together with R 9 and/or R 13 together with R 10 form trimethylene, tetramethylene or phenylene-l,2-dimethylene, , optionally substituted with 1 to 3 radicals independently selected from (C ⁇ alkyl, (C,.
  • R 1 is -X 6 X 7 R 20 , wherein X 6 is -C(O)-, -C(O)C(O)- or -S(0) 2 -, X 7 is a bond, -O- or -NR 21 -, wherein R 21 is hydrogen or (C,.
  • R 20 is (i) (C,_ 6 )alkyl optionally substituted by cyano, halo, nitro, -NR ,4 R 14 , -NR 14 C(O)OR 14 , -NR 14 C(0)NR 14 R 14 , -NR 14 C(NR 14 )NR 14 R 14 , -OR 14 , -SR 14 , -C(0)OR' 4 , -C(0)NR 14 R 14 , -S(O) 2 NR 14 R 14 , -P(0)(OR 14 )OR 14 ,
  • any alicyclic or aromatic ring system present may be substituted further by 1 to 5 radicals independently selected from (C j . 6 )alkyl, (C,. 6 )alkylidene, cyano, halo, halo-substituted (C ⁇ alkyl, nitro, -X 5 NR 14 R 14 , -X 5 NR 14 C(0)OR 14 , -X 5 NR 14 C(O)NR 14 R 14 , -X 5 NR 14 C(NR 14 )NR 14 R 14 , -X 5 OR 14 , -X 5 SR 14 , -X 5 C(0)OR 14 , -X 5 C(0)NR 14 R 14 , -X 5 S(O) 2 NR 14 R 14 , -X 5 P(0)(OR 14 )OR 14 , -X 5 OP(O)(OR 14 )OR 14 , -X 5 NR 14 C(O)R 15 , -
  • R 2 is hydrogen or (C,_ 6 )alkyl
  • R 3 is (i) ( . 6 )alkyl optionally substituted with cyano, halo, nitro, -SR 24 , -C(0)OR 24 , -C(O)NR 24 R 24 , -P(0)(OR 24 )OR 24 , -OP(O)(OR 24 )OR 24 , -S(0)R 25 , -S(0) 2 R 25 or -C(O)R 25 , wherein R 24 at each occurrence independently is hydrogen, (C,. 6 )alkyl or halo-substituted
  • (C ] . 3 )alkyl and R 25 (C ⁇ alkyl or halo-substituted (C ⁇ 3 )alkyl, or (ii) (C 5 . 6 )cycloalkyl(C 2 . 3 )alkyl, hetero(C 3 . 6 )cycloalkyl(C 2 . 3 )alkyl, (C 6 . 12 )aryl(C 2 . 3 )alkyl or hetero(C 5 . 6 )aryl(C 2 . 3 )alkyl, wherein said cycloalkyl, heterocycloalkyl, aryl or heteroaryl optionally is substituted further with 1 to 5 radicals independently selected from (C,.
  • X 2 may not represent (i) a bond when R 1 is -C(O)R 20 , -C(0) 2 R 20 or -S(O) 2 R 20 in which R 20 is (C,. 6 )alkyl, phenyl(C )alkyl, phenyl, (C 3 . 7 )cycloalkyl, camphan-10-yl, naphth-1-yl, naphth-2-yl, phenyl substituted by one or more of (C,. 4 )alkyl, perfluoro(C ].4 )alkyl, (C, ⁇ )alkoxy, hydroxy, halo, amido, nitro, amino, (C,.
  • R 12 is methyl, isopropyl, n-butyl, sec-butyl, tert-butyl, 1-methylpropyl, benzyl, naphth-1-ylmethyl, naphth-2-ylmethyl, thien-2-ylmethyl, thien-3-ylmethyl, or wherein R 9 and R 12 form ethylene, trimethylene, hydroxy-substituted trimethylene, tetramethylene or phenylene-l,2-dimethylene; or
  • R 3 and R 4 taken together with the carbon atom to which both R 3 and R 4 are attached form (C 3 . 8 )cycloalkylene or (C 3 . 8 )heterocycloalkylene, wherein said cycloalkylene or heterocycloalkylene is optionally substituted with 1 to 3 radicals independently selected from (C,. 6 )alkyl, (C,. 6 )alkylidene, cyano, halo, halo-substituted (C,.
  • R 4 is hydrogen, (C,. 6 )alkyl or as defined above;
  • R 5 is hydrogen and R 6 is hydroxy or R 5 and R 6 together form oxo;
  • R 7 is a group selected from cyano, halo, nitro, -R 29 , -X 5 NR 29 R 30 , -X 5 NR 30 C(O)OR 29 ,
  • R 42 is hydrogen, (C,. 6 )alkyl or together with R 43 forms trimethylene, tetramethylene or phenylene-l,2-dimethylene, optionally substituted with hydroxy or oxo, and R 43 is as defined above or is (i) (C,.
  • R 14 at each occurrence independently is hydrogen, (C,. 6 )alkyl or halo-substituted (C,. 3 )alkyl and R 15 (C,. 6 )alkyl or halo-substituted (C,. 3 )alkyl; and the -V-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers; and the pharmaceutically acceptable salts thereof.
  • the present invention relates to a compound of Formula II:
  • A comprises a heteromonocyclic ring containing 5 to 6 ring member atoms or a fused heteropolycyclic ring system containing 8 to 14 ring member atoms, wherein each ring contains 5 to 7 ring member atoms, X 1 is a ring member carbon atom and each ring member atom other than X 1 is a carbon atom or a heteroatom, with the proviso that at least one ring member atom is a heteroatom; n is 0, 1, 2 or 3;
  • X s is (C 1 . 2 )alkylene
  • R 1 is hydrogen, carboxy, oxalo, carbamoyl or -X 6 X 7 R 20 , wherein X 6 is -C(O)-, -C(0)C(0)- or -S(0) 2 -, X 7 is a bond, -O- or -NR 21 -, wherein R 21 is hydrogen or (CJalkyl, and R 20 is (i) (C,.
  • R 15 is (C,. 6 )alkyl or halo-substituted (C,. 3 )alky.
  • R 15 is (C,. 6 )alkyl or halo-substituted (C,. 3 )alkyl
  • R 22 is (C 3 . 12 )cycloalkyl(C 0 . 6 )alkyl, hetero(C 3 _ 12 )cycloalkyl(C 0 . 6 )alkyl, (C 6 ., 2 )aryl(C 0 . 6 )alkyl, hetero(C 5 . 12 )aryl(C 0 . 6 )alkyl, (C 9 . 12 )bicycloaryl(C 0 .
  • R 24 is (C 3 . 6 )cycloalkyl(C 0 . 6 )alkyl, hetero(C 3 . 6 )cycloalkyl(C 0 . 6 )alkyl, phenyl(C 0 . 6 )alkyl or hetero(C 5 . 6 )aryl(C 0 . 6 )alkyl and R 25 at each occurrence independently is hydrogen or (C,.
  • any alicyclic or aromatic ring system present may be substituted further by 1 to 5 radicals independently selected from (C,. 6 )alkyl, (C,. 6 )alkylidene, cyano, halo, halo-substituted (C,.
  • R 2 is hydrogen or (C,. 6 )alkyl
  • R 3 is (i) (C,. 6 )alkyl optionally substituted with cyano, halo, nitro, -NR 1 R 14 , -NR 14 C(0)OR 14 , -NR 14 C(O)NR 14 R 14 , -NR 14 C(NR 14 )NR 14 R 14 , -OR 14 , -SR 14 , -C(0)OR 14 , -C(O)NR 14 R 14 , -S(0) 2 NR 14 R 14 , -P(0)(OR 14 )OR 14 , -OP(0)(OR 14 )OR 14 , -NR 14 C(0)R 15 , -S(O)R 15 , -S(0) 2 R 15 , -C(O)R 15 , -OR 16 , -SR 16 , -S(O)R 16 , -S(O) 2 R 16 , -C(O)R 16 , -C(0)OR 16 , -OC(O)R 16 , -NR 16
  • R 15 is ( . 6 )alkyl or halo-substituted (C,. 3 )alkyl
  • R 15 is ( . 6 )alkyl or halo-substituted (C,. 3 )alkyl
  • R 16 is (C 3 . 12 )cycloalkyl(C 0 . 6 )alkyl, hetero(C 3 . 12 )cycloalkyl(C 0 . 6 )alkyl, (C 6 . 12 )aryl(C 0 . 6 )alkyl, hetero(C 5 . 12 )aryl(C 0 . 6 )alkyl, (C 9 . 12 )polycycloaryl(C 0 .
  • R 18 is hydrogen or (C,. 6 )alkyl and R 19 is (C 3 . I2 )cycloalkyl(C 0 . 6 )alkyl, hetero(C 3 _ 12 )cycloalkyl(C 0 . 6 )alkyl, (C 6 . 12 )aryl(C 0 . 6 )alkyl, hetero(C 5.12 )aryl(C 0 . 6 )alkyl, (C 9 . 12 )polycycloaryl(C 0 .
  • R 3 and R 4 taken together with the carbon atom to which both R 3 and R 4 are attached form (C 3 . 8 )cycloalkylene or (C 3 . 8 )heterocycloalkylene, wherein said cycloalkylene or heterocycloalkylene is optionally substituted with 1 to 3 radicals independently selected from (C,. 6 )alkyl, (C,. 6 )alkylidene, cyano, halo, halo-substituted (C,.
  • R 4 is hydrogen, (C,. 6 )alkyl or as defined above;
  • R 5 is hydrogen and R 6 is hydroxy or R 5 and R 6 together form oxo;
  • R 7 is a group selected from cyano, halo, nitro, -R 29 , -X 5 NR 29 R 30 , -X 5 NR 30 C(O)OR 29 , -X 5 NR 30 C(O)NR 29 R 30 , -X 5 NR 30 C(NR 3O )NR 29 R 30 , -X 5 OR 29 , -X 5 SR 29 , -X 5 C(O)OR 29 , -X 5 C(O)NR 29 R 30 , -X 5 S(O) 2 NR 29 R 30 , -X 5 P(O)(OR 30 )OR 29 , -X 5 OP(O)(OR 29 )OR 29 , -X 5 NR 30 C(O)R 31 , -X 5 S(O)R 31 , -X 5 S(O) 2 R 31 and -X 5 C(0)R 31 , wherein X 5 is as defined above, R 29 is hydrogen or -R 31 , R 30
  • any alicyclic or aromatic ring system present may be substituted further by 1 to 5 radicals independently selected from (C,. 6 )alkyl, (C,_ 6 )alkylidene, cyano, halo, halo-substituted (C,.
  • R 8 at each occurrence independently is selected from (C ⁇ 6 )alkyl, (C,. 6 )alkylidene, cyano, halo, halo-substituted (C,_ 4 )alkyl, nitro, -X 5 NR 14 R 14 , -X 5 NR 14 C(0)OR 14 , -X 5 NR 14 C(0)NR 14 R 14 , -X 5 NR 1 C(NR 1 )NR 14 R 14 , -X 5 OR 14 , -X 5 SR 14 , -X 5 C(0)OR 14 , -X 5 C(0)NR 14 R 14 , -X 5 S(0) 2 NR 14 R 14 , -X 5 P(0)(OR 14 )OR 14 , -X 5 OP(0)(OR 14 )OR 14 ,
  • R 9 is hydrogen or (C,. 6 )alkyl
  • R 32 is (C,. 8 )alkyl, (C 3 ., 2 )cycloalkyl(C 0 . 6 )alkyl, hetero(C 3 . 12 )cycloalkyl(C 0 . 6 )alkyl, (C 6 . 12 )aryl(C 0.6 )alkyl, hetero(C 5 . 12 )aryl(C 0 . 6 )alkyl, (C 9 . 12 )polycycloaryl(C 0 . 6 )alkyl or hetero(C 8.12 )polycycloaryl(C 0 .
  • any alicyclic or aromatic ring system present may be substituted further by 1 to 5 radicals independently selected from (C,. 6 )alkyl, (C,. 6 )alkylidene, cyano, halo, halo-substituted (C,.
  • the present invention relates to a pharmaceutical composition which contains a compound of Formula I or II, or a N-oxide derivative, prodrug derivative, individual isomer or mixture of isomers, or a pharmaceutically acceptable salt thereof in admixture with one or more suitable excipients.
  • the present invention relates to method of treating a disease in an animal in which inhibition of a cysteine protease can prevent, inhibit or ameliorate the pathology and/or symptomatology of the disease, which method comprises administering to the animal a therapeutically effective amount of compound of Formula I or II or a -V-oxide derivative, prodrug derivative, individual isomer or mixture of isomers or a pharmaceutically acceptable salt thereof.
  • the present invention relates to processes for preparing compounds of Formula I and II and the -V-oxide derivatives, prodrug derivative, protected derivatives, individual isomers and mixtures of isomers, and the pharmaceutically acceptable salts thereof as set forth in "Detailed Description of the Invention".
  • the present invention relates to protease inhibitors of Formula III:
  • A comprises a heteromonocyclic radical containing 5 to 6 annular atoms or a fused heteropolycyclic radical containing 8 to 14 annular atoms, wherein each ring contains 5 to 7 annular atoms, X 1 is an annular carbon atom and each annular atom other than X 1 optionally is a heteroatom, with the proviso that when A is a heteromonocyclic radical containing 5 annular atoms, no more than two of the annular atoms comprising the ring are heteroatoms;
  • X 2 is a bond or a divalent group of Formula (a) or (b):
  • X 3 and X 5 independently are -C(O)- or -S(O) 2 -,
  • X 4 is -CHR 11 -, -CH 2 CHR ⁇ - or -CHR"CH 2 - and X 6 is -CHR 12 -, -CH 2 CHR 12 - or -CHR 12 CH 2 - wherein:
  • R 11 and R 12 are independently (i) (C ⁇ alkyl or halo-substituted(C,. 6 )alkyl optionally substituted with -OR 13 , -SR 13 , -S(0)R 13 , -S(0) 2 R 13 , -C(O)R 13 , -C(0)OR 13 , -NR 13 R 14 , -NR 14 C(0)OR 13 , -C(0)NR 13 R 14 , -S(0) 2 NR 13 R 14 , -NR 14 C(0)NR 13 R 14 or -NR 14 C(NR 14 )NR 13 R 14 , wherein R 13 is hydrogen, (C,. 6 )alkyl, (C 3 . 12 )cycloalkyl(C 0 .
  • R 14 is hydrogen or (C,. 5 )alkyl, or
  • R 15 is (C 3 . 12 )cycloalkyl(C 0 _ 3 )alkyl, hetero(C 3 . 12 )cycloalkyl(C 0 . 3 )alkyl, (C 6 . 12 )aryl(C 0 . 3 )alkyl, hetero(C 5 . I2 )aryl(C 0 . 3 )alkyl, (C 9 . 12 )polycycloaryl(C 0 . 3 )alkyl or hetero(C 8 . 12 )polycycloaryl(C 0 . 3 )alkyl and R 16 is hydrogen or (C,. 6 )alkyl, or (iii) together with R 9 or R 10 , respectively, when X 4 is -CHR 11 - and/or X 6 is
  • -CHR 12 - forms trimethylene, tetramethylene or phenylene-l,2-dimethylene, optionally substituted with hydroxy or oxo; wherein any 1 to 3 annular atoms of any aromatic ring with available valences comprising R u and/or R 12 are optionally independently substituted with halo, nitro, cyano, (C,. 6 )alkyl, halo-substituted C ⁇ alkyl, -OR 17 , -C(0)R 17 , -C(0)OR 17 , -C(0)NR 17 R 17 ,
  • R 9 and R 10 are independently hydrogen, (C,. 6 )alkyl or as defined above;
  • R 1 is hydrogen or -X 8 X 9 R 18 , wherein X 8 is -C(O)- or -S(0) 2 -, X 9 is a bond, -O- or
  • R 19 is hydrogen or (C,. 6 )alkyl
  • R 18 is (i) (C,_ 6 )alkyl or halo-substituted(C,. 6 )alkyl optionally substituted with -OR 13 , -SR 13 , -S(O)R 13 , -S(0) 2 R 13 , -C(O)R 13 , -C(0)OR 13 , -NR 13 R 14 , -NR 14 C(O)OR 13 , -C(0)NR 13 R 14 , -S(O) 2 NR 13 R 14 , -NR 14 C(0)NR 13 R 14 or -NR 14 C(NR 14 )NR 13 R 14 , wherein R 13 and R 14 are as defined above, or (ii) (C 3 .
  • R 2 is hydrogen or (C,_ 6 )alkyl
  • R 3 is phenyl(C 2 . 3 )alkyl, hetero(C 5 . 6 )aryl(C 2 . 3 )alkyl, (C 5 . 6 )cycloalkyl(C 2 . 3 )alkyl or hetero(C 5.6 )cycloalkyl(C 2 . 3 )alkyl, wherein any 1 to 3 annular atoms of any aromatic ring with available valences comprising R 3 optionally independently are substituted with halo, nitro, cyano, (C,. 6 )alkyl, halo-substituted(C 1 .
  • R 5 is hydrogen and R 6 is hydroxy or R 5 and R 6 together form oxo;
  • R 7 is halo, nitro, -R 20 , -OR 20 , -C(0)R 20 , -C(0)OR 20 , -S(O) 2 NR 20 R 21 , -C(O)NR 20 R 21 or -C(0)NR 22 CHR 23 C(0)OR 20 and bonded to any annular carbon atom with a free valence comprising A, wherein:
  • R 20 is hydrogen or R 18 , wherein R 18 is as defined above;
  • R 21 is hydrogen or (C,. 6 )alkyl;
  • R 22 is hydrogen, (C,. 6 )alkyl or together with R 23 forms trimethylene or phenylene-l,2-dimethylene, optionally substituted with hydroxy or oxo;
  • R 23 is as defined above or is (i) (C,. 6 )alkyl or halo-substituted(C,. 6 )alkyl optionally substituted with -OR 13 , -SR 13 , -S(O)R 13 , -S(O) 2 R 13 , -C(O)R 13 , -C(0)OR 13 , -NR 13 R 14 , -NR 14 C(O)OR 13 , -C(0)NR 13 R 14 , -S(O) 2 NR 13 R 14 , -NR ,4 C(O)NR 13 R 14 or -NR 14 C(NR 1 )NR 13 R 14 , wherein R 13 and R 14 are as defined above, or (ii) (C 3 _ 10 )cycloalkyl(C 0 .
  • R 8 is hydrogen, halo, hydroxy, formyl, carboxy, carbamoyl, sulfamoyl or (C,. 6 )alkyl and bonded to any annular carbon atom with a free valence comprising A; and the -V-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers; and the pharmaceutically acceptable salts thereof.
  • Alicyclic means a moiety characterized by arrangement of the carbon atoms in closed non-aromatic ring structures having properties resembling those of aliphatics and may be saturated or partially unsaturated with two or more double or triple bonds.
  • Aliphatic means a moiety characterized by straight or branched chain arrangement of the constituent carbon atoms and may be saturated or partially unsaturated with two or more double or triple bonds.
  • alkenyl means alkyl, as defined in this Application, provided that the radical is comprised of at least one double bond.
  • optionally substituted (C 2 . 6 )alkenyl as used in this Application to define R 32 includes 2-bromovinyl (-CHCHBr), buta-l,3-dienyl (-CHCH-CHCH 2 ), 2-chloro-l-methylpropenyl (-C(CH 3 )CC1-CH 3 ), 2-chlorovinyl (-CHCHC1), 4-isopropenyl (-C(CH 3 )CH 2 ), 1-methylpropenyl (-C(CH 3 )CH-CH 3 ), 2-methylpropenyl (-CHC(CH 3 ) 2 ), 2-nitrovinyl (-CHCHN0 2 ), propenyl (-CHCH-CH 3 ), 2-trifluoromethylvinyl (-CHCH-CF 3 ), trifluorovinyl (-CFCF 2 ), vinyl (-CHCHCH
  • Alkoxy means the radical -OR, wherein R is alkyl as defined in this Application, having the number of carbon atoms indicated (e.g., (C,. 4 )alkoxy includes the radicals methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, isobutoxy, tert-butoxy, vinyloxy, allyloxy, 1-propenyloxy, isopropenyloxy, 1 -butenyloxy, 2-butenyloxy, 3-butenyloxy, 2-methylallyloxy, ethynyloxy, 1-propynyloxy, 2-propynyloxy, and the like).
  • Alkyl represented by itself means a straight or branched, saturated or unsaturated, aliphatic radical having the number of carbon atoms indicated (e.g. (C,. 6 )alkyl includes methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methylallyl, ethynyl, 1-propynyl, 2-propynyl, and the like). Alkyl represented along with another radical (e.g.
  • arylalkyl means a straight or branched, saturated or unsaturated aliphatic divalent radical having the number of atoms indicated or when no atoms are indicated means a bond (e.g. (C 6 . 12 )aryl(C 0 . 6 )alkyl includes phenyl, benzyl, phenethyl, 1-phenylethyl 3-phenylpropyl, and the like).
  • Alkylene unless indicated otherwise, means a straight or branched, saturated or unsaturated, aliphatic, divalent radical having the number of carbon atoms indicated (e.g. (C,.
  • a group of Formula (a), wherein R u is hydrogen and R 12 taken together with R 9 forms optionally substituted trimethylene is depicted by the following illustration:
  • R is an optional hydroxy or oxo group and X 3 and R 1 are as defined in the Summary of the Invention for Formulae I and II.
  • Alkylidene means a straight or branched saturated or unsaturated, aliphatic, divalent radical having the number of carbon atoms indicated (e.g. (C,. 6 )alkylidene includes methylene (CH 2 ), ethylidene (CHCH 3 ), isopropylidene (C(CH 3 ) 2 ), propylidene (CHCH 2 CH 3 ), allylidene (CHCHCH 2 ), and the like).
  • amino means the radical -NH 2 .
  • the compounds of the invention containing amino moieties include protected derivatives thereof. Suitable protecting groups for amino moieties include acetyl, tert-butoxycarbonyl, benzyloxycarbonyl, and the like.
  • “Animal” includes humans, non-human mammals (e.g. dogs, cats, rabbits, cattle, horses, sheep, goats, swine, deer, or the like) and non-mammals (e.g. birds, or the like).
  • Aryl means a monocyclic or bicyclic ring assembly (fused or linked by a single bond) containing the total number of ring carbon atoms indicated, wherein each ring is comprised of 6 ring carbon atoms and is aromatic or when fused with a second ring forms an aromatic ring assembly.
  • (C 6 _ 12 )aryl as used in this Application to define R 1 includes phenyl, naphthyl and biphenylyl.
  • “Aromatic” means a moiety wherein the constituent atoms make up an unsaturated ring system, all atoms in the ring system are sp2 hybridized and the total number of pi electrons is equal to 4n + 2.
  • “Carbamoyl” means the radical -C(O)NH 2 . Unless indicated otherwise, the compounds of the invention containing carbamoyl moieties include protected derivatives thereof. Suitable protecting groups for carbamoyl moieties include acetyl, tert-butoxycarbonyl, benzyloxycarbonyl, and the like and both the unprotected and protected derivatives fall within the scope of the invention.
  • “Carboxy” means the radical -C(O)OH.
  • the compounds of the invention containing carboxy moieties include protected derivatives thereof. Suitable protecting groups for carboxy moieties include benzyl, tert-butyl, and the like.
  • a compound of Formula I wherein R 7 contains a carboxy moiety may exist as either the unprotected or a protected derivative, e.g. wherein R 7 is methoxycarbonyl, and both the unprotected and protected derivatives fall within the scope of the invention.
  • Cycloalkyl means a saturated or partially unsaturated, monocyclic ring, bicyclic ring assembly (directly linked by a single bond or fused) or bridged polycyclic ring assembly containing the number of ring member carbon atoms indicated, and any carbocyclic ketone, thioketone or iminoketone derivative thereof (e.g. (C 3 .
  • cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, 2,5-cyclohexadienyl, bicyclohexylyl, cyclopentylcyclohexyl, bicyclo[2.2.2]octyl, adamantan- 1 -yl, decahydronaphthalenyl, oxocyclohexyl, dioxocyclohexyl, thiocyclohexyl, 2-oxobicyclo[2.2.1]hept-l-yl, and the like).
  • Cycloalkylene means a saturated or partially unsaturated, monocyclic ring or bridged polycyclic ring assembly containing the number of annular carbon atoms indicated, and any carbocyclic ketone, thioketone or iminoketone derivative thereof.
  • R 3 and R 4 together with the carbon atom to which both R 3 and R 4 are attached form (C 3 . 8 )cycloalkylene includes, but is not limited to, the following:
  • R 2 , R 5 and R 6 are as defined in the Summary of the Invention, and any substituted derivative thereof.
  • Disease specifically includes any unhealthy condition of an animal or part thereof and includes an unhealthy condition which may be caused by, or incident to, medical or veterinary therapy applied to that animal, i.e., the "side effects" of such therapy.
  • “Fused heteropolycyclic ring system” means a saturated, partially saturated or aromatic moiety containing two or more rings, wherein at least two ring member atoms of one ring are common to a second ring containing the number of ring member atoms indicated in which at least one of the ring member atoms is a heteroatom and any carbocyclic ketone, thioketone, iminoketone or substituted derivative thereof .
  • a fused heteropolycyclic radical containing 8 to 14 ring member atoms may include acridinyl, benzofuryl, benzooxazolyl, benzothiazolyl, carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, indazolyl, indolinyl, indolyl, indolizinyl, isobenzofuryl, isochromenyl, isochromanyl, isoindolinyl, isoquinolyl, naphthyridinyl, perimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolizinyl, quinazolin
  • Guanidino means the radical -NHC(NH)NH 2 .
  • the compounds of the invention containing guanidino moieties include protected derivatives thereof. Suitable protecting groups for amino moieties include acetyl, tert-butoxycarbonyl, benzyloxycarbonyl, and the like and both the unprotected and protected derivatives fall within the scope of the invention.
  • Halo means fluoro, chloro, bromo or iodo.
  • Halo-substituted alkyl as a group or part of a group, means “alkyl” substituted by one or more "halo" atoms, as such terms are defined in this Application.
  • Halo-substituted alkyl includes haloalkyl, dihaloalkyl, trihaloalkyl, perhaloalkyl and the like (e.g. halo-substituted (C,. 3 )alkyl includes chloromethyl, dicloromefhyl, difluoromethyl, trifluromethyl, 2,2,2-trifluoroethyl, perfluoroethyl, 2,2,2-trifluoro-l,l-dichloroethyl, and the like).
  • Heteroaryl means aryl, as defined herein, provided that one or more of the ring member carbon atoms indicated, is replaced by heteroatom moiety selected from -N, -NR-, -O- or -S-, wherein R is hydrogen, (C,. 6 )alkyl or a protecting group, and each ring contained therein is comprised of 5 to 6 ring member atoms. For example, hetero(C 5 .
  • aryl as used in this Application includes benzofuryl, benzooxazolyl, benzothiazolyl, [2,4']bipyridinylyl, carbazolyl, carbolinyl, chromenyl, cinnolinyl, furazanyl, furyl, imidazolyl, indazolyl, indolyl, indolizinyl, isobenzofuryl, isochromenyl, isooxazolyl, isoquinolyl, isothiazolyl, naphthyridinyl, oxazolyl, perimidinyl, 2-phenylpyridyl, phthalazinyl, pteridinyl, purinyl, pyrazinyl, pyradazinyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolizinyl, pyrrolidinyl, pyrrolyl, pyranyl, quina
  • Heteroatom moiety includes -N, -NR-, -0-, -S- or -S(O) 2 -, wherein R is hydrogen, (C,. 6 )alkyl or a protecting group.
  • Heterocycloalkyl means cycloalkyl, as defined herein, provided that one or more of the ring member carbon atoms indicated is replaced by heteroatom moiety selected from -N, -NR-, -O- or -S-, wherein R is hydrogen, (C 1 . 6 )alkyl or a protecting group, and any carbocyclic ketone, thioketone or iminoketone derivative thereof (e.g.
  • hetero(C 5 . ⁇ 2 )cycloalkyl includes [l,4']bipiperidinylyl, dihydrooxazolyl, mo ⁇ holinyl, l-mo ⁇ holin-4-y -piperidinyl, piperazinyl, piperidyl, pirazolidinyl, pirazolinyl, pyrrolinyl, pyrrolidinyl, quinuclidinyl, and the like).
  • Suitable protecting groups include tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, 4-methoxybenzyl, 2-nitrobenzyl, and the like.
  • a compound of Formula I wherein R 1 is piperidin-4-ylcarbonyl may exist as either the unprotected or a protected derivative, e.g. wherein R 1 is l-tert-butoxycarbonylpiperidin-4-ylcarbonyl, and both the unprotected and protected derivatives fall within the scope of the invention.
  • Heterocycloalkylene means cycloalkylene, as defined in this Application, provided that one or more of the ring member carbon atoms indicated, is replaced by heteroatom moiety selected from -N, -NR-, -0-, -S- or -S(0) 2 -, wherein R is hydrogen or (C,_ 6 )alkyl.
  • R 3 and R 4 together with the carbon atom to which both R 3 and R 4 are attached form hetero(C 3 . 8 )cycloalkylene includes, but is not limited to, the following:
  • R is hydrogen, (C ] _ 6 )alkyl or a protecting group and R 2 is as defined in the Summary of the Invention, and any substituted derivative thereof.
  • Heteromonocyclic means a saturated, partially saturated or aromatic monocyclic radical containing the number of ring member atoms indicated in which at least one of the ring member atoms is a heteroatom and any carbocyclic ketone, thioketone, iminoketone or substituted derivative thereof.
  • a heteromonocyclic containing 5 to 6 ring member atoms may include dihydrooxazolyl, furazanyl, furyl, imidazolyl, imidazolidinyl, imidazolinyl, isooxazolyl, isothiazolyl, thiazolyl, thienyl, mo ⁇ holinyl, oxazolyl, piperazinyl, piperidinyl, pirazolidinyl, pirazolinyl, pyranyl, pyrazinyl, pyradazinyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, tetrazolyl, and the like.
  • Heteropolycycloaryl means polycycloaryl, as defined herein, except one or more of the ring member carbon atoms indicated are replaced by a heteroatom moiety selected from -N, -NR-, -O- or -S-, wherein R is hydrogen, (C,_ 6 )alkyl or a protecting group, and any carbocyclic ketone, thioketone or iminoketone derivative thereof.. For example, hetero(C 8 .
  • polycycloaryl includes r,2 , -dihydro-2H-[l,4']bipyridinylyl, chromanyl, imidazolinyl, indolinyl, isochromanyl, isoindolinyl, and the like.
  • “Hydroxy” means the radical -OH. Unless indicated otherwise, the compounds of the invention containing hydroxy radicals include protected derivatives thereof. Suitable protecting groups for hydroxy moieties include benzyl and the like and both the unprotected and protected derivatives fall within the scope of the invention.
  • “Iminoketone derivative” means a derivative containing the moiety -C(NR)-, wherein R is hydrogen or (C,. 6 )alkyl.
  • “Isomers” mean compounds of Formula I having identical molecular formulae but differ in the nature or sequence of bonding of their atoms or in the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are termed "stereoisomers”.
  • stereoisomers that are not mirror images of one another are termed “diastereomers” and stereoisomers that are nonsuperimposable mirror images are termed “enantiomers” or sometimes "optical isomers".
  • a carbon atom bonded to four nonidentical substituents is termed a “chiral center”.
  • a compound with one chiral center has two enantiomeric forms of opposite chirality is termed a "racemic mixture”.
  • a compound that has more than one chiral center has 2" 1 enantiomeric pairs, where n is the number of chiral centers.
  • Compounds with more than one chiral center may exist as ether an individual diastereomer or as a mixture of diastereomers, termed a "diastereomeric mixture”.
  • a stereoisomer When one chiral center is present a stereoisomer may be characterized by the absolute configuration of that chiral center. Absolute configuration refers to the arrangement in space of the substituents attached to the chiral center. Enantiomers are characterized by the absolute configuration of their chiral centers and described by the R- and S-sequencing rules of Cahn, Ingold and Prelog.
  • Ketone derivative means a derivative containing the moiety -C(O)-.
  • Niro means the radical -NO 2 .
  • Oxalo means the radical -C(O)C(O)OH.
  • -V-oxide derivatives means a derivatives of compound of Formula I in which nitrogens are in an oxidized state (i.e., 0 ⁇ N) and which possess the desired pharmacological activity.
  • Phathology of a disease means the essential nature, causes and development of the disease as well as the structural and functional changes that result from the disease processes.
  • “Pharmaceutically acceptable” means that which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable and includes that which is acceptable for veterinary use as well as human pharmaceutical use.
  • “Pharmaceutically acceptable salts” means salts of compounds of Formula I which are pharmaceutically acceptable, as defined above, and which possess the desired pharmacological activity. Such salts include acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or with organic acids such as acetic acid, propionic acid, hexanoic acid, heptanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartatic acid, citric acid, benzoic acid, o(4-hydroxybenzoyl)benzoic acid, cinnamic acid, madelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulf
  • Pharmaceutically acceptable salts also include base addition salts which may be formed when acidic protons present are capable of reacting with inorganic or organic bases.
  • Acceptable inorganic bases include sodium hydroxide, sodium carbonate, potassium hydroxide, ammonium hydroxide, aluminum hydroxide and calcium hydroxide.
  • Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, tromethamine, -V-methylglucamine and the like.
  • Phenylene-l,2-dimethylene means the divalent radical -CH 2 C 6 H 4 CH 2 -, wherein the methylene moieties are attached at the 1- and 2-positions of the phenylene moiety.
  • a group of Formula (a) in which R 12 together with R 9 forms optionally substituted phenylene- 1,2-dimethylene is illustrated by the following formula:
  • R is an optional hydroxy group and X 3 and R 1 are as defined in the Summary of the Invention for Formulae I and II.
  • Polycycloaryl means a bicyclic ring assembly (directly linked by a single bond or fused) containing the number of ring member carbon atoms indicated, wherein at least one, but not all, of the fused rings comprising the radical is aromatic, and any carbocyclic ketone, thioketone or iminoketone derivative thereof (e.g. (C 9 .
  • polycycloaryl includes indanyl, indenyl, 1,2,3,4-tetrahydronaphthalenyl, 1,2-dihydronaphthalenyl, cyclohexylphenyl, phenylcyclohexyl, 2,4-dioxo-l,2,3,4-tetrahydronaphthalenyl, and the like).
  • "Prodrug” means a compound which is convertible in vivo by metabolic means (e.g. by hydrolysis) to a compound of Formula (I). For example an ester of a compound of formula (I) containing a hydroxy group may be convertible by hydrolysis in vivo to the parent molecule.
  • an ester of a compound of Formula (I) containing a carboxy group may be convertible by hydrolysis in vivo to the parent molecule.
  • Suitable esters of compounds of Formula (I) containing a hydroxy group are for example acetates, citrates, lactates, tartrates, malonates, oxalates, salicylates, propionates, succinates, fumarates, maleates, methylene-bis-b-hydroxynaphthoates, gentisates, isethionates, di-/?
  • esters of compounds of Formula (I) containing a carboxy group are for example those described by FJ.Leinweber, Drug Metab. Res., 1987, 18, page 379.
  • An especially useful class of esters of compounds of Formula (I) containing a hydroxy group may be formed from acid moieties selected from those described by Bundgaard et. al., J. Med.
  • substituted (aminomethyl)-benzoates for example, dialkylamino-methylbenzoates in which the two alkyl groups may be joined together and/or interrupted by an oxygen atom or by an optionally substituted nitrogen atom, e.g. an alkylated nitrogen atom, more especially (mo ⁇ holino-methyl)benzoates, e.g. 3- or 4-(mo ⁇ holinomethyl)-benzoates, and (4-alkylpiperazin-l-yl)benzoates, e.g. 3- or 4-(4-alkylpiperazin-l-yl)benzoates.
  • a prodrug derivative of a compound of Formula I wherein R 5 and R 6 together are oxo is depicted by the following formula:
  • Protected derivatives means derivatives of compounds of Formula I in which a reactive site or sites are blocked with protecting groups. Protected derivatives of compounds of Formula I are useful in the preparation of compounds of Formula I or in themselves may be active cysteine protease inhibitors.
  • the compound of Formula I which is 25- amino--V-(2-benzooxazol-2-yl-2-hydroxy-lS-phenethylethyl)-3-cyclohexylpropionamide (i.e., Compound 55, described in Example 6, infra) may be protected with a suitable amino protecting group, e.g. 9H-fluoren-9-ylmefhoxycarbonyl, or a suitable hydroxy protecting group, e.g.
  • tert-butyldimethylsilanyl to provide, respectively, 9H-fluoren-9-ylmethyl lS-(2-benzooxazol-2-yl- 2-hydroxy-lS-phenethylethylcarbamoyl)-2-cyclohexylethylcarbamate (i.e., Compound 51, described in Example 4, infra) and 2S-amino--V-[2-benzooxazol-2-yl- 2-(tcrt-butyldimethylsilanyloxy)-lS-phenethylethyl]-3-cyclohexylpropionamide (i.e., Compound 56, described in Example 7, infra).
  • a comprehensive list of suitable protecting groups can be found in T.W. Greene, Protecting Groups in Organic Synthesis, John Wiley & Sons, Inc. 1981.
  • Ring member as in fused heteropolycyclic ring system containing 8 to 14 ring member atoms, means that the atoms referred to are ring members of the fused heteropolycyclic radical, but not taking into account ring members of any substituents present.
  • a heteropolycyclic radical containing 8 ring member atoms includes benzooxaxol-2-yl, benzofur-2-yl, lH-indol-5-yl, benzothiazol-2-yl, and the like.
  • “Sulfamoyl” means the radical -S(0) 2 N ⁇ 2 . Unless indicated otherwise, the compounds of the invention containing sulfamoyl radicals include protected derivatives thereof. Suitable protecting groups for sulfamoyl radicals include acetyl, tert-butoxycarbonyl, benzyloxycarbonyl, and the like and both the unprotected and protected derivatives fall within the scope of the invention.
  • “Therapeutically effective amount” means that amount which, when administered to an animal for treating a disease, is sufficient to effect such treatment for the disease.
  • Thioketone derivative means a derivative containing the moiety -C(S)-.
  • Treatment or “treating” means any administration of a compound of the present invention and includes:
  • the heteromonocyclic ring or fused heteropolycyclic ring system A is selected from 4,5-dihydrooxazol-2-yl, benzooxazol-2-yl, benzothiazol-2-yl and oxazol-2-yl, each substituted by a group R 7 and optionally substituted with a group R 8 , particularly wherein R 7 is hydrogen, halo, (C,. 4 )alkoxy, (C M )alkoxycarbonyl, nitro or phenyl and R 8 at each occurrence independently is halo, (C,.
  • the ring system A preferably is benzoxazol-2-yl substituted by a group R 7 and optionally substituted with a group R 8 , particularly wherein R 7 is hydrogen, halo, (C]. 4 )alkoxy, (C,. 4 )alkoxycarbonyl or nitro and R 8 at each occurrence independently is halo, (C, ⁇ )alkoxy, (C, .4 )alkoxycarbonyl, nitro or trifluoromethyl.
  • X 2 particularly represents a bond or a divalent group of Formula (a); particularly, wherein within Formula (a) X 3 is -C(O)-, R 9 represents hydrogen, R 11 represents hydrogen or methyl, typically hydrogen, and R 12 particularly represents (i) (C,. 6 )alkyl substituted with -SR 14 , -S(O)R 14 or -S(0) 2 R 14 , wherein R 14 is (C 6 . 12 )aryl(C 0 . 6 )alkyl or hetero(C 5 . 12 )aryl(C 0 . 6 )alkyl or (ii) (C 3 _ 12 )cycloalkyl(C 0.6 )alkyl or (C 6 .
  • R 12 particularly represents a group having the following formula:
  • R 33 at each occurrence independently is selected from a group consisting of (C M )alkyl, cyano, halo, halo-substituted (C,. 4 )alkyl, nitro, -X 5 NR 14 R 14 , -X 5 OR 14 , -X 5 SR 14 , -X 5 C(0)NR 14 R 14 , -X 5 C(0)OR 14 , -X 5 S(0)R 15 , -X 5 S(0) 2 R 15 and -X 5 C(O)R 15 , wherein X 5 is a bond or (C ] . 6 )alkylene, R 14 at each occurrence independently is hydrogen, (C 1 .
  • R 15 is (C,. 3 )alkyl or halo-substituted (C,. 3 )alkyl and R 15 is (C,. 3 )alkyl or halo-substituted (C,. 3 )alkyl; more particularly in which q is 0, 1 or 2 and R 33 at each occurrence independently is selected from a group consisting of (C ⁇ alkyl, cyano, halo, halo-substituted (C,. 4 )alkyl, nitro, -OR 14 , -SR 14 and -C(O)OR 14 , wherein R 14 independently is hydrogen, (C,. 3 )alkyl or halo-substituted (C,.
  • R 33 at each occurrence independently is selected from a group consisting of (C,_ 4 )alkyl, bromo, carboxy, chloro, cyano, difluoromethoxy, fluoro, iodo, methoxy, nitro, trifluoromethoxy, trifluoromethyl and trifluorosulfanyl.
  • R 12 particularly represents benzylsulfonylmethyl, 2-chlorobenzylsulfonylmethyl, 2-cyanobenzylsulfonylmethyl, 2-difluoromethoxybenzylsulfonylmethyl, 3,5-dimethylisooxazol-4-ylmethylsulfonylmethyl, 2-methoxybenzylsulfonylmethyl, 6-methylpyrid-2-ylmethylsulfonylmethyl, 2-nitrobenzylsulfonylmethyl, pyrid-2-ylmethylsulfonylmethyl, o-tolylmethylsulfonylmethyl or 2-trifluoromethylbenzylsulfonylmethyl.
  • R 1 particularly represents -X 6 X 7 R 20 , wherein X 6 is -C(O)- or -S(O) 2 -, X 7 is a bond, -O- or -NR 21 -, wherein R 21 is hydrogen or (C,. 6 )alkyl, and R 20 is (i) (C,. 6 )alkyl optionally substituted by -C(O)OR 14 or (ii) (C 3 . I2 )cycloalkyl(C 0 . 6 )alkyl, hetero(C 3 . 12 )cycloalkyl(C 0 . 6 )alkyl, (C 6 . 12 )aryl(C 0 .
  • R 25 is hydrogen or (C,_ 6 )alkyl; wherein within R 1 any alicyclic or aromatic ring system present may be substituted further by 1 to 5 substituents independently selected from (C ⁇ alkyl, halo, halo-substituted (C,. 4 )alkyl, -OR 14 and -C(0)OR 14 wherein R 14 is hydrogen or (C,. 6 )alkyl, or when X 2 is a divalent group of formula (a) then R 1 may be, but is not limited to, hydrogen or oxalo.
  • R 1 preferably is a group selected from acetyl, azetidin-3-ylcarbonyl, benzyloxycarbonyl, l-benzyloxycarbonylpiperidin-4-ylcarbonyl, benzylsulfonyl, bicyclo[2.2.2]hept-2-ylcarbonyl, bicyclo[2.2.1]hept-2-ylcarbonyl, tert-butoxycarbonyl, carboxyacetyl, 2-carboxypropionyl, 3-carboxypropionyl, 2-cyclohexylacetyl, 4-cyclohexylbutyryl, 2-cyclohexylethylsulfonyl, cyclohexylmethoxycarbonyl, 3-cyclohexylpropionyl, 2-cyclopentylethylsulfonyl, 3-cyclopentylpropionyl, di(2-methoxyethyl)carbamoyl, dimethylcarb
  • R 1 especially represents mo ⁇ holin-4-ylcarbonyl, methoxycarbonyl, methylsulfonyl, piperidin-4-ylcarbonyl, pyrazin-2-ylcarbonyl pyrid-3-ylcarbonyl, pyrid-4-ylcarbonyl, tetrahydropyran-4-ylcarbonyl or tetrahydropyran-4-yloxycarbonyl.
  • R 2 typically is hydrogen.
  • R 3 particularly represents hydrogen, (C,. 6 )alkyl (optionally substituted with cyano, halo, nitro, -SR 26 , -C(0)OR 26 , -C(O)NR 26 R 26 , -P(O)(OR 26 )OR 26 , -OP(0)(OR 26 )OR 26 , -S(0)R 27 , -S(0) 2 R 27 or -C(O)R 27 , wherein R 26 at each occurrence independently is hydrogen, (C,. 6 )alkyl, or halo-substituted (C,. 3 )alkyl and R 27 is (C,. 6 )alkyl or halo-substituted (C ⁇ _ 3 )alkyl) or
  • R 15 is (C,. 6 )alkyl or halo-substituted (C,_ 3 )alkyl, or R 3 and R 4 taken together with the carbon atom to which both R 3 and R 4 are attached form (C 3 . 6 )cycloalkylene.
  • R 3 may be selected from hydrogen, (C M )alkyl (e.g. methyl, ethyl, n-propyl, n-butyl), phenyl(C 2 . 3 )alkyl (e.g. phenethyl) or (C M )alkylsulfonyl(C 2 . 4 )alkyl (e.g.
  • R 3 and R 4 taken together with the carbon atom to which both R 3 and R 4 are attached form (C 3 . 6 )cycloalkylene (e.g. cyclobutylene or cyclohexylene).
  • R 3 preferably is (C,. 4 )alkyl.
  • R 4 particularly represents hydrogen or R 3 and R 4 taken together with the carbon atom to which both R 3 and R 4 are attached form (C 3 . 6 )cycloalkylene (e.g. cyclobutylene or cyclohexylene).
  • C 3 . 6 cycloalkylene
  • R 5 and R 6 preferably together form oxo.
  • X methylene or ethylene;
  • R 1 , R 3 and R 4 are as defined above;
  • R 5 and R 6 together form oxo;
  • R 9 is hydrogen;
  • R 32 is -X 9 R 34 , wherein X 9 is methylene when X 8 is methylene and X 9 is a bond when X 8 is ethylene, R 34 is -CR 35 CHR 36 or -CR 37 NR 38 , wherein R 35 and R 36 together with the atoms to which R 35 and R 36 are attached form (C 2 . 6 )alkenyl, (C 5 . 12 )cycloalkenyl, hetero(C 5 . 12 )cycloalkenyl, (C 6 . 12 )aryl, hetero(C 6 . ]2 )aryl, (C 9 . 12 )bicycloaryl or hetero(C 8 .
  • R 14 at each occurrence independently is hydrogen, (C,. 6 )alkyl or halo-substituted (C,. 3 )alkyl and R 15 is (C, .6 )alkyl or halo-substituted (C,. 3 )alkyl.
  • R 34 particularly represents (C 6 . 12 )aryl or hetero(C 5 . 12 )aryl, each optionally substituted by 1 to 5 radicals selected from a group consisting of (C,. 4 )alkyl, cyano, halo, halo-substituted (C )alkyl, nitro, -X 5 NR 14 R 14 , -X 5 OR 14 , -X 5 SR 14 , -X 5 C(0)NR 14 R 14 , -X 5 C(0)OR 14 , -X 5 S(O)R 15 , -X 5 S(0) 2 R 15 and -X 5 C(O)R 15 , wherein X 5 is a bond or (C,. 2 )alkylene, R 14 at each occurrence independently is hydrogen, (C 1 . 3 )alkyl or halo-substituted (C,. 3 )alkyl and R 15 is
  • R 34 more preferably represents biphenyl, isooxazolyl, naphthyl, phenyl, pyridyl or thienyl, each optionally substituted by 1 to 5 radicals selected from a group consisting of (C ] _ 4 )alkyl, cyano, halo, halo-substituted (C,.
  • R 34 more preferably represents biphenyl-2-yl, 2,4-bistrifluoromethylphenyl, 2,5-bistrifluoromethylphenyl, 4-tert-butylphenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 2-bromo-5-fluorophenyl, 3-chloro-2-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 5-chlorothien-2-yl, 2-chloro-5-trifluoromethyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 1,5-dichlorophenyl, 2,6-dichlorophenyl, 3,4-dichlorophenyl, 2,3-difluorophenyl, 2,4-difluorophenyl, 3,4-difluorophenyl, 2-difluoromethoxypheny
  • 3-trifluoromethylsulfanylphenyl 4-trifluoromethylsulfanylphenyl, 2,3,4-trifluorophenyl, 2,3,5-trifluorophenyl, 2,4,6-trifluorophenyl, 2,4,5-trifluorophenyl or 2,3,6-trifluorophenyl.
  • a preferred group of compounds of Formula II are those in which -X 8 S(0) 2 R 32 represents a group having the following formula:
  • R 33 at each occurrence independently is selected from a group consisting of (C, .4 )alkyl, cyano, halo, halo-substituted (C,. 4 )alkyl, nitro, -X 5 NR 14 R 14 , -X 5 OR 14 , -X 5 SR 14 , -X 5 C(0)NR 14 R 14 , -X 5 C(O)OR 14 , -X 5 S(0)R 15 , -X 5 S(O) 2 R 15 and -X 5 C(0)R 15 , wherein X 5 is a bond or (C,. 2 )alkylene, R 14 at each occurrence independently is hydrogen, (C,.
  • R 15 is (C,. 3 )alkyl or halo-substituted (C,. 3 )alkyl; more particularly in which q is 0, 1 or 2 and R 33 at each occurrence independently is selected from a group consisting of (C ⁇ alkyl, cyano, halo, halo-substituted (C].
  • R 14 at each occurrence independently is hydrogen, (C, .3 )alkyl or halo-substituted (C, .3 )alkyl; more particularly in which R 33 at each occurrence independently is selected from a group consisting of (C )alkyl, bromo, carboxy, chloro, cyano, difluoromethoxy, fluoro, iodo, methoxy, nitro, trifluoromethoxy, trifluoromethyl and trifluorosulfanyl.
  • -X 8 S(0) 2 R 32 represents benzylsulfonylmethyl, 2-chlorobenzylsulfonylmethyl, 2-cyanobenzylsulfonylmethyl, 2-difluoromethoxybenzylsulfonylmethyl, 3,5-dimethylisooxazol-4-ylmethylsulfonylmethyl, 2-methoxybenzylsulfonylmethyl, 6-methylpyrid-2-ylmethylsulfonylmethyl, 2-nitrobenzylsulfonylmethyl, pyrid-2-ylmethylsulfonylmethyl, ⁇ -tolylmethylsulfonylmethyl or 2-trifluoromethy lbenzy lsulf ony lmethy 1.
  • the heteromonocyclic ring or fused heteropolycyclic ring system A is selected from thien-2-yl, oxazol-2-yl, 4,5-dihydrooxazol-2-yl, fur-2-yl, lH-indol-5-yl, pyrid-2-yl, pyrid-3-yl, thiazol-2-yl, 1 -methyl- lH-imidazol-2-yl, l-benzyl-lH-imidazol-2-yl, benzooxazol-2-yl, benzofur-2-yl, benzothiazol-2-yl, lH-benzoimidazol-2-yl, l,l-dioxo-lH-l ⁇ 6 -benzo[b]thien-2-yl, quinol-3-yl, [l,3]dio
  • R 30 at each occurrence is hydrogen or (C,. 6 )alkyl and R 43 is (C,. 6 )alkyl
  • R 8 at each occurrence independently is hydrogen, (C,. 6 )alkyl or halo-substituted (C,. 4 )alkyl; wherein within R 7 any alicyclic or aromatic ring system present may be substituted further by 1 to 5 radicals independently selected from (C,. 6 )alkyl, (C,.
  • X 6 is a bond or (C,. 6 )alkylene
  • R 14 at each occurrence independently is hydrogen, (C,. 6 )alkyl or halo-substituted (C,. 3 )alkyl and R 15 (C,. 6 )alkyl or halo-substituted (C,. 3 )alkyl.
  • the ring system A preferably is oxazol-2-yl, 4,5-dihydrooxazol-2-yl, benzooxazol-2-yl, naphtho[2,3-J
  • the ring system A more preferably is oxazol-2-yl, 4,5-dihydrooxazol-2-yl, benzooxazol-2-yl or naphtho[l,2-J
  • X 2 particularly represents a bond or a divalent group of Formula (a), wherein within Formula (a) X 3 is -C(O)-, R 9 represents hydrogen, R 11 represents hydrogen or methyl, typically hydrogen, and R 12 particularly represents (C,. 6 )alkyl, preferably isobutyl, sec-butyl or isopropyl.
  • R 1 particularly represents hydrogen or -X 8 X 9 R 20 , wherein X 8 is -C(O)- or -S(0) 2 -, X 9 is a bond or -O- and R 20 is (C ⁇ 6 )alkyl, (C 3 . 12 )cycloalkyl(C 0 . 6 )alkyl, hetero(C 3 .
  • R 1 particularly represents acetyl, benzoyl, benzyloxycarbonyl, benzylsulfonyl, bicyclo[2.2.2]hept-2-ylcarbonyl, tert-butoxycarbonyl, tert-butyryl,
  • R 3 preferably represents (C,_ 6 )alkyl or (C 6 _ 10 )aryl(C,. 3 )alkyl, more preferably phenethyl, or R 3 and R 4 taken together with the carbon atom to which both R 3 and R 4 are attached form (C 3 . 6 )cycloalkylene, more preferably cyclopropylene.
  • R 4 preferably represents hydrogen or (C,. 6 )alkyl, preferably hydrogen or methyl or R 3 and R 4 or R 3 and R 4 taken together with the carbon atom to which both R 3 and R 4 are attached form (C 3 . 6 )cycloalkylene, more preferably cyclopropylene.
  • R 5 and R 6 preferably together form oxo.
  • the compounds of the invention are cysteine protease inhibitors, in particular the compounds of the invention inhibit the activity of cathepsins B, L, K and/or S and, as such, are useful for treating diseases in which cathepsin B, L, K and/or S activity contributes to the pathology and/or symptomatology of the disease.
  • the compounds of the invention are useful in treating tumor invasion and metastasis, in particular as anti-angiogenic agents, rheumatoid arthritis, osteo arthritis, pneumocystis carinii, acute pancreatitis, inflammatory airway disease and bone and joint disorders.
  • the compounds of the invention are useful in treating bone reso ⁇ tion disorders, e.g. osteoporosis.
  • the compounds of the invention are inhibitors of cathepsin S and, as such, are useful for treating diseases in which cathepsin S activity contributes to the pathology and or symptomatology of the disease.
  • the compounds of the invention are useful in treating autoimmune disorders, including, but not limited to, juvenile onset diabetes, multiple sclerosis, pemphigus vulgaris, Graves' disease, myasthenia gravis, systemic lupus erythemotasus, rheumatoid arthritis and Hashimoto's thyroiditis, allergic disorders, including, but not limited to, asthma, and allogeneic immune responses, including, but not limited to, organ transplants or tissue grafts.
  • Cathepsin S also is implicated in disorders involving excessive elastolysis, such as chronic obstructive pulmonary disease (e.g. emphysema), bronchiolitis, excessive airway elastolysis in asthma and bronchitis, pneumonities and cardiovascular disease such as plaque rupture and atheroma.
  • Cathepsin S is implicated in fibril formation and, therefore, inhibitors of cathepsins S are of use in treatment of systemic amyloidosis.
  • the cysteine protease inhibitory activities of the compounds of the invention can be determined by methods known to those of ordinary skill in the art. Suitable in vitro assays for measuring protease activity and the inhibition thereof by test compounds are known. Typically, the assay measures protease induced hydrolysis of a peptide based substrate. Furthermore, the compounds of the invention are useful as intermediates in the preparation of other compounds of Formula I. For example, compounds of Formula I in which R 5 is hydroxy can be used to prepare compounds of Formula I in which R 5 and R 6 taken together form oxo.
  • Nomenclature The compounds of Formula I and the intermediates and starting materials used in their preparation are named in accordance with IUPAC rules of nomenclature in which the characteristic groups have decreasing priority for citation as the principle group as follows: acids, esters, amides, etc.. Alternatively, the compounds are named by AutoNom 4.0 (Beilstein Information Systems, Inc.).
  • R 4 is hydrogen; and R 5 and R 6 together form oxo; that is, a compound having the following structure:
  • R 4 each are hydrogen; R 3 is phenethyl; and R 5 and R 6 together form oxo; that is, a compound having the following structure:
  • compounds of Formula I will be administered in therapeutically effective amounts via any of the usual and acceptable modes known in the art, either singly or in combination with another therapeutic agent.
  • a therapeutically effective amount may vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used and other factors.
  • therapeutically effective amounts of a compound of Formula I may range from 0.1 micrograms per kilogram body weight ( ⁇ g/kg) per day to 10 milligram per kilogram body weight (mg/kg) per day, typically 1 ⁇ g/kg/day to 1 mg kg/day. Therefore, a therapeutically effective amount for a 80 kg human patient may range from 10 ⁇ g/day to 100 mg/day, typically 0.1 mg/day to 10 mg/day.
  • a therapeutically effective amount of a compound of Formula I for treating a given disease.
  • compositions can take the form of tablets, pills, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols, or any other appropriate composition and are comprised of, in general, a compound of Formula I in combination with at least one pharmaceutically acceptable excipient.
  • Acceptable excipients are non-toxic, aid administration, and do not adversely affect the therapeutic benefit of the active ingredient.
  • excipient may be any solid, liquid, semisolid or, in the case of an aerosol composition, gaseous excipient that is generally available to one of skill in the art.
  • Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk, and the like.
  • Liquid and semisolid excipients may be selected from water, ethanol, glycerol, propylene glycol and various oils, including those of petroleum, animal, vegetable or synthetic origin (e.g., peanut oil, soybean oil, mineral oil, sesame oil, or the like).
  • Preferred liquid carriers, particularly for injectable solutions include water, saline, aqueous dextrose and glycols.
  • a composition of a compound of Formula I for treating a given disease will comprise from 0.01 %w to 10%w, preferably 0.3%w to l%w, of active ingredient with the remainder being the excipient or excipients.
  • the pharmaceutical composition is administered in a single unit dosage form for continuous treatment or in a single unit dosage form ad libitum when relief of symptoms is specifically required.
  • the compounds of Formula I can be administered alone or in combination with other compounds of Formula I or in combination with one or more other active ingredient(s).
  • the compounds of Formula I can be administered in combination with a therapeutically active amount of a bisphosphonic acid or acid ester derivative or any pharmaceutically acceptable salt thereof.
  • Suitable bisphosphonic acids and acid ester derivatives include compounds corresponding to the following formula:
  • each R 43 independently is hydrogen or (C,. 30 )alkyl
  • R 44 and R 45 are selected independently from a group consisting of hydrogen, halo, optionally substituted (C,. 30 )alkyl, (C 3 . 30 )cycloalkyl, hetero(C 5 . 30 )cycloalkyl, optionally substituted (C 5 . 10 )aryl, hetero(C 6 . 10 )aryl, -NR 46 R 46 , -OR 46 , -SR 46 , wherein each R 46 independently is hydrogen, (C 0 )alkyl, (C 3 .
  • I0 )cycloalkyl optionally substituted (C 6 . 10 )aryl, provided that both R 44 and R 45 are not selected from hydrogen or hydroxy when X 11 is a bond; or R 44 and R 45 taken together form (C 2 . 9 )alkylene; wherein (C 3 . 10 )cycloalkyl includes adamantyl and the like, hetero(C 5 . I0 )cycloalkyl includes pyrrolidinyl and the like, (C 6 . 10 )aryl includes phenyl and naphthyl, and hetero(C 6 .
  • R 44 and/or R 45 are substituted (C,. 30 )alkyl may include, but are not limited to, (C,. 30 )alkyl substituted by hetero(C 5 . )0 )cycloalkyl, (C 6 . )0 )aryl, hetero(C 6 . 10 )aryl, -NR 47 R 47 , -OR 47 and -SR 47 , wherein each R 47 is independently hydrogen or (C 1 .
  • hetero(C 5.10 )cycloalkyl includes pyrrolidinyl and the like
  • (C 6 . 10 )aryl includes phenyl and naphthyl
  • hetero(C 6 . 10 )aryl includes quinolyl, isoquinolyl, pyridyl, furyl, imidazolyl, imidazopyridyl and the like.
  • Suitable optionally substituted aryl groups include, but are not limited to, halo-substituted phenyl.
  • a non-limiting class of bisphosphonic acids and acid ester derivatives thereof suitable for administration in combination with compounds of Formula I include those in which R 44 is selected from the group consisting of hydrogen, hydroxy or halo, and R 45 is selected from the group consisting of optionally substituted (C,. 30 )alkyl, halo and -SR 46 , wherein R 46 is (C,. 10 )alkyl or phenyl.
  • a non-limiting subclass of bisphosphonic acids and acid ester derivatives thereof suitable for administration in combination with compounds of Formula I include those in which R 44 is selected from the group consisting of hydrogen, hydroxy and chloro and R 45 is selected from the group consisting of optionally substituted (C,. 30 )alkyl, chloro and chlorophenylthio.
  • a non-limiting example of a bisphosphonic acid suitable for administration in combination with compounds of Formula I include that in which X 11 is a bond, each R 43 is hydrogen, R 44 is hydroxy and R 45 is 3-aminopropyl, namely 4-amino- 1 -hydroxy butylidene- 1,1 -bisphosphonic acid (aka alendronic acid), or the monosodium trihydrate salt thereof, namely 4-amino- 1 -hydroxybutylidene- 1 , 1 -bisphosphonate monosodium trihydrate (aka alendronate monosodium trihydrate), described in U.S.
  • Further non-limiting examples of bisphosphonic acids suitable for administration in combination with compounds of Formula I include the following: cycloheptylaminomethylene- 1,1 -bisphosphonic acid (aka cimadronic acid), described in U.S.
  • 6-amino-l-hydroxyhexylidene- 1,1 -bisphosphonic acid (aka neridronic acid); 3-(dimethylamino)- 1 -hydroxypropylidene- 1 , 1 -bisphosphonic acid (aka olpadronic acid);
  • 3-amino-l-hydroxypropylidene- 1,1 -bisphosphonic acid (aka pamidronic acid); 2-pyrid-2-ylethylidene- 1,1 -bisphosphonic acid (aka piridronic acid), described in U.S. Patent No. 4,761,406; l-hydroxy-2-pyrid-3-ylethylidene- 1,1 -bisphosphonic acid (aka risedronic acid); 4-chlorophenylthiomethylenebisphosphonic acid (aka tiludronic acid), described in U.S.
  • a non-limiting subclass of bisphosphonic acids suitable for administration in combination with compounds of Formula I include those selected from the group consisting of alendronic acid, cimadronic acid, clodronic acid, tiludronic acid, etidronic acid, ibandronic acid, risedronic acid, piridronic acid, pamidronic acid, zolendronic acid, pharmaceutically acceptable salts thereof, and mixtures thereof.
  • a further example of a bisphosphonic acid suitable for administration in combination with compounds of Formula I is alendronic acid or a pharmaceutically acceptable salt thereof, and mixtures thereof.
  • a further non-limiting example is alendronate monosodium trihydrate.
  • Compounds of Formula I can be administered in combination with a therapeutically active amount of an estrogen receptor agonist.
  • estrogen receptor agonists suitable for administration in combination with the compounds of Formula I include naturally occurring estrogens such as estradiol, estrone and estroil, or synthetic estrogen receptor agonists such as [6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thien-3-yl][4-(2-piperidin-l-ylethoxy)phenyl]methanone (aka raloxifene) and ⁇ 2-[4-(l,2-diphenylbut-l-enyl)phenoxy]ethyl ⁇ dimethylamine (aka tamoxifen).
  • estrogen receptor partial agonists suitable for administration in combination with the compounds of Formula I include estrogen receptor partial agonists (i.e., estrogen receptor agonists with mixed agonist/antagonist properties), sometimes referred to as estrogen receptor modulators.
  • Estrogen receptor partial agonists can exert tissue-selective estrogen agonist effects. Tamoxifen, for example, selectively exerts an estrogen agonist effect on the bone, in humans. Additional suitable estrogen receptor partial agonists are described in Tissue-Selective Actions Of Estrogen Analogs, Bone Vol. 17, No. 4, October 1995, 181S-190S. Certain 3-[4-(2-phenylindol-l-ylmethyl)phenyl]acrylamides, described in U.S.
  • a pharmaceutical composition of this invention may comprise a therapeutically effect amount of a compound of Formula I in combination with one or more active ingredient(s) selected from the group consisting of (i) a therapeutically effect amount of a bisphosphonic acid or acid ester thereof or a pharmaceutically acceptable salt thereof and (ii) a therapeutically effect amount of an estrogen receptor agonist or a pharmaceutically acceptable salt thereof; and one or more pharmaceutically acceptable excipient(s).
  • Non-limiting examples of such bisphosphonic acids include 1,1-dichloromethylene- 1,1 -diphosphonic acid, 1 -hydroxy - 3-pyrrolidin- 1 -ylpropylidene- 1 , 1 -bisphosphonic acid, 1 -hydroxyethylidene- 1 , 1 -diphosphonic acid, 1 -hydroxy-3-(-V-methyl--V-pentylamino)propylidene- 1 , 1 -bisphosphonic acid, 6-amino- 1-hydroxyhexylidene-l, 1 -bisphosphonic acid, 3-(dimethylamino)-l-hydroxypropylidene- 1,1 -bisphosphonic acid, 3-amino-l-hydroxypropylidene- 1,1 -bisphosphonic acid, 2-pyrid-2-ylethylidene- 1 , 1 -bisphosphonic acid, 1 -hydroxy-2-pyrid-3-ylethylidene- 1,1- bisphosphonic acid,
  • n, A, X 1 , X 2 , R 1 , R 2 , R 3 , R 4 , R 7 and R 8 are as defined in the Summary of the Invention for Formulae I and II.
  • reaction is carried out in a suitable solvent (e.g. tetrahydrofuran (THF), ether, or the like) at
  • the organometallic compound of Formula 2 is generated by treating a corresponding organo compound, or a brominated derivative thereof, with n-butyllithium or tert-butyllithium in a suitable solvent (e.g. THF, ether, or the like) at -80 to -70° C, preferably at about -78° C, for approximately 30 minutes to an hour.
  • a suitable solvent e.g. THF, ether, or the like
  • Compounds of Formula I can be prepared by reacting a compound Formula 4 with a compound of the Formula 5(a). The reaction is carried out in a suitable solvent (e.g. chloroform, ethanol, or the like) at reflux temperatures and requires 3 to 24 hours to complete.
  • a suitable solvent e.g. chloroform, ethanol, or the like
  • compounds of Formula I in which A is a heteropolycyclic radical wherein X 1 is a ring member atom of an oxazole ring, R 5 is hydrogen and R 6 is hydroxy can be prepared by reacting a compound of Formula 4 with a compound of Formula 5(b):
  • n 0, 1, 2 or 3 and B is a heteromonocyclic radical containing 5 to 6 ring member atoms or a fused heteropolycyclic radical containing 8 to 11 ring member atoms, wherein each ring contains 5 to 7 ring member atoms and each ring member atom is a carbon atom or a heteroatom, and R 7 and R 8 is as defined in the Summary of the Invention for Formulae I and II.
  • Compounds of Formula I can be prepared by proceeding as in the following Scheme 3:
  • Y is hydrogen or an activating group (e.g. 2,5-dioxopyrrolidin-l-yl (NBS), or the like) and n, A, X 1 , X 2 , R 1 , R 2 , R 3 , R 4 , R 7 and R 8 are as defined in the Summary of the Invention for Formulae I and II.
  • Compounds of Formula I can be prepared by reacting a compound of Formula 6, or a protected derivative thereof, with a compound of the formula R 1 X 2 OY, or a protected derivative thereof, and then optionally deprotecting. The reaction is carried out in the presence of a suitable base (e.g.
  • a suitable solvent e.g. acetonitrile, N,-V-dimethylformamide (DMF), dichloromethane, or any suitable combination thereof, or the like
  • Y is hydrogen
  • N-V-diisopropylethylamine, triethylamine, or the like is required and the reaction requires 2 to 3 hours to complete.
  • Deprotection can be effected by any means which removes the protecting group and gives the desired product in reasonable yield.
  • a detailed description of the techniques applicable to the creation of protecting groups and their removal can be found in T.W. Greene, Protecting Groups in Organic Synthesis, John Wiley & Sons, Inc. 1981.
  • Detailed descriptions of the preparation of a compound of Formula I in accordance with Scheme 3 are set forth in Examples 8, 9, 10 and 12, infra.
  • R 39 is -X 7 X 8 R 20 and n
  • X 1 , X 2 , X 7 , X 8 , R ⁇ R 2 , R 3 , R 4 , R 7 , R 8 and R 20 are as defined in the Summary of the Invention for Formulae I and II.
  • Compounds of Formula I in which A is optionally substituted oxazol-2-yl can be prepared by oxidizing a corresponding compound of Formula I in which A is 4,5-dihydrooxazol-2-yl. The reduction is carried out in the presence of base (e.g. l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), l,5-diazabicyclo[3.4.0]non-5-ene (DBN), or the like) in a suitable solvent (e.g. dichloromethane, or the like) at 20 to 25 ° C and requires 6 to 12 hours to complete.
  • base e.g. l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), l,5-diazabicyclo[3.4.0]non-5-ene (DBN), or the like
  • DBU l,8-diazabicyclo[5.4.0]undec-7-ene
  • Compounds of Formula I in which R 7 is -C(0)OH can be prepared from a corresponding compound of Formula I in which R 7 is methoxycarbonyl.
  • the conversion can be effected by treating the methyl ester with sodium hydroxide in a suitable solvent (e.g, ethanol, or the like) at 20 to 25° C and requires 6 to 12 hours to complete.
  • a suitable solvent e.g, ethanol, or the like
  • Compounds of Formula I in which R 5 and R 6 together form oxo can be prepared by oxidizing a compound of Formula I in which R 5 is hydrogen and R 6 is hydroxy.
  • the oxidation can be carried out with a suitable oxidizing agent (e.g. Dess-Martin periodinate, or the like) in a suitable solvent (e.g. dichloromethane, or the like) at 15 to 25° C and requires 10 to 20 hours to complete.
  • a suitable oxidizing agent e.g. Dess-Martin periodinate, or the like
  • a suitable solvent e.g. dichloromethane, or the like
  • Compounds of Formula I in which R 12 contains a sulfonyl moiety can be prepared by oxidizing a corresponding compound of Formula I containing a sulfanyl moiety.
  • the oxidation is carried out with a suitable oxidizing agent (e.g. potassium peroxymonosulfate (OXONE ® , or the like) in a suitable solvent (e.g. methanol, water, or the like, or any suitable combination thereof) at ambient temperature and requires 16 to 24 hours to complete.
  • a suitable oxidizing agent e.g. potassium peroxymonosulfate (OXONE ® , or the like
  • a suitable solvent e.g. methanol, water, or the like, or any suitable combination thereof
  • a compound of Formula I in which A is l,l-dioxo-lH-l ⁇ 6 -benzo[b]thien-2-yl can be prepared by oxidizing a corresponding compound of Formula I in which A is benzo[b]thien-2-yl. Proceeding in this fashion benzyl l-, lJl,l-dioxo-lH-l ⁇ 6 -benzo,blthien-2-ylcarbonyl.- 3-phenylpropylcarbamoyH-3-methylbutylcarbamate (Compound 209) was prepared.
  • a compound of Formula I can be prepared as a pharmaceutically acceptable acid addition salt by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid.
  • a pharmaceutically acceptable base addition salt of a compound of Formula I can be prepared by reacting the free acid form of the compound with a pharmaceutically acceptable inorganic or organic base.
  • Inorganic and organic acids and bases suitable for the preparation of the pharmaceutically acceptable salts of compounds of Formula I are set forth in the definitions section of this application.
  • the salt forms of the compounds of Formula I can be prepared using salts of the starting materials or intermediates.
  • the free acid or free base forms of the compounds of Formula I can be prepared from the corresponding base addition salt or acid addition salt form.
  • a compound of Formula I in an acid addition salt form can be converted to the corresponding free base by treating with a suitable base (e.g. ammonium hydroxide solution, sodium hydroxide, or the like).
  • a compound of Formula I in a base addition salt form can be converted to the corresponding free acid by treating with a suitable acid (e.g. hydrochloric acid, etc).
  • a suitable acid e.g. hydrochloric acid, etc.
  • the -V-oxides of compounds of Formula I can be prepared by methods known to those of ordinary skill in the art.
  • -V-oxides can be prepared by treating an unoxidized form of the compound of Formula I with an oxidizing agent (e.g.
  • the -V-oxides of the compounds of Formula I can be prepared from the -V-oxide of an appropriate starting material.
  • Compounds of Formula I in unoxidized form can be prepared from /V-oxides of compounds of Formula I by treating with a reducing agent (e.g. sulfur, sulfur dioxide, triphenyl phosphine, lithium borohydride, sodium borohydride, phosphorus trichloride, tribromide, or the like) in an suitable inert organic solvent (e.g. acetonitrile, ethanol, aqueous dioxane, or the like) at 0 to 80°C.
  • a reducing agent e.g. sulfur, sulfur dioxide, triphenyl phosphine, lithium borohydride, sodium borohydride, phosphorus trichloride, tribromide, or the like
  • an inert organic solvent e.g. acetonitrile, ethanol, aqueous dioxane, or the like
  • Prodrug derivatives of the compounds of Formula I can be prepared by methods known to those of ordinary skill in the art (e.g. for further details see Saulnier et ⁇ /.(1994), Bioorganic and Medicinal Chemistry Letters. 4:1985).
  • appropriate prodrugs can be prepared by reacting a non-derivatized compound of Formula I with a suitable carbamylating agent (e.g. 1,1-acyloxyalkylcarbonochloridate, /. ⁇ r ⁇ -nitrophenyl carbonate, or the like).
  • a suitable carbamylating agent e.g. 1,1-acyloxyalkylcarbonochloridate, /. ⁇ r ⁇ -nitrophenyl carbonate, or the like.
  • Protected derivatives of the compounds of Formula I can be made by means known to those of ordinary skill in the art. A detailed description of the techniques applicable to the creation of protecting groups and their removal can be found in T.W. Greene, Protecting Groups in Organic Synthesis, John Wiley
  • Compounds of Formula I can be prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers and recovering the optically pure enantiomer. While resolution of enantiomers can be carried out using covalent diasteromeric derivatives of compounds of Formula I, dissociable complexes are preferred (e.g. crystalline diastereoisomeric salts). Diastereomers have distinct physical properties (e.g. melting points, boiling points, solubilities, reactivity, and the like) and can be readily separated by taking advantage of these dissimilarities.
  • the diastereomers can be separated by chromatography or, preferably, by separation/resolution techniques based upon differences in solubility.
  • the optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that would not result in racemization.
  • a more detailed description of the techniques applicable to the resolution of stereoisomers of compounds from their racemic mixture can be found in Jean Jacques Andre Collet, Samuel H. Wilen, Enantiomers, Racemates and Resolutions, Honh Wiley & Sons, Inc. (1981).
  • an aspect of the invention is a process for preparing a compound of Formula I, which process comprises: (A) reacting an organometallic compound of Formula 2:
  • R 1 , R 2 , R 3 , R 4 , R 7 and R 8 are as defined in the Summary of the Invention for Formulae I and II, to give a compound of Formula I in which the ring comprised by X 1 is a 4,5-tetrahydrooxazol-2-yl or oxazol-2-yl or moiety, respectively, R 5 is hydrogen and R 6 is hydroxy or
  • A, X 1 , X 2 , R 1 , R 2 , R 3 , R 4 , R 7 and R 8 are as defined in the Summary of the Invention for
  • R 39 is -X 7 X 8 R 20 and n
  • A, X 1 , X 2 , X 7 , X 8 , R 2 , R 3 , R 4 , R 7 , R 8 and R 20 are as defined in the Summary of the Invention for Formulae I and II, and deprotecting if necessary to give a compound of Formula I in which R 1 is -X 7 X 8 R 20 ,
  • Compounds Formula 8 can be prepared by reacting a corresponding amino protected carboxy lie acid with NO-dimethylhydroxylamine hydrochloride and then deprotecting.
  • the reaction with the amine is carried out in the presence of a suitable coupling agent (PyBOP®, EDC, HBTU, DCC, or the like) and base (e.g. N-V-diisopropylethylamine, triethylamine, or the like) in a suitable solvent (e.g. dichloromethane, DMF, or the like) at 20 to 30° C, preferably at about 25° C, and requires 2 to 4 hours to complete (e.g. see Reference 1, infra.).
  • a suitable coupling agent PyBOP®, EDC, HBTU, DCC, or the like
  • base e.g. N-V-diisopropylethylamine, triethylamine, or the like
  • a suitable solvent e.g. dichloromethane,
  • Deprotection can be effected by any means which removes the protecting group and gives the desired product in reasonable yield (e.g. see Example 2, infra.).
  • a detailed description of the preparation of a compound of Formula 8 is set forth in References 1 and 6, infra.
  • Compounds of Formula 4 can be prepared by reacting a nitrile of Formula 9:
  • the reaction is carried out by adding the nitrile to a mixture comprising a catalytic amount of dry hydrogen chloride in a suitable solvent (e.g. chloroform, ethanol, or the like) and then allowing the reaction to proceed at 0 to 25° C for 4 to 6 hours.
  • a suitable solvent e.g. chloroform, ethanol, or the like
  • Dry hydrogen chloride is conveniently generated by combining a slightly excessive amount of ethanol with acetyl chloride prior to adding the imidate to the reaction mixture.
  • the hydrogen chloride is introduced to the reaction medium as a gas.
  • Compounds of Formula 6 can be prepared by methods known to those of ordinary skill in the art.
  • compounds of Formula 6 in which A is optionally substituted benzooxazol-2-yl can be prepared by reacting a compound of Formula 10:
  • R 40 is a protecting group, with 2-aminophenol and deprotecting.
  • the reaction with the phenol is carried out in the presence of a suitable base (e.g. diisopropylethylamine, triethylamine, or the like) and in a suitable solvent (e.g. chloroform, or the like) at reflux temperatures to 25° C and requires 10 to 12 hours to complete.
  • a suitable base e.g. diisopropylethylamine, triethylamine, or the like
  • a suitable solvent e.g. chloroform, or the like
  • Compounds of Formula 7 can be prepared by condensing a compound of Formula 6 with a compound of the formula R 40 X 2 OY, wherein R 40 is a protecting group, and then deprotecting.
  • the condensation is carried out in the presence of a suitable base (e.g. triethylamine, diisopropylethylamine, or the like) and in a suitable solvent (e.g. acetonitrile, DMF, dichloromethane, or any suitable combination thereof, or the like) at 10 to 30°C, preferably at about 25 °C, and requires 24 to 30 hours to complete.
  • a suitable coupling agent e.g.
  • PyBOP® benzotriazole-1-yloxytrispyrrolidinophosphonium hexafluorophosphate
  • THF tetrahydrofuran
  • OXONE ® potassium peroxymonosulfate
  • EDC l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
  • a suspension comprised of lithium aluminum hydride (0.885 g, 23.3 mmol) in anhydrous diethyl ether was cooled to -45 ° C under nitrogen and then treated with a solution of benzyl lS-(-V-methoxy--V-methylcarbamoyl)-3-phenylpropylcarbamate (5.53 g, 15.53 mmol), provided as in Reference 1, in ether (75 mL) and THF (25 mL) added dropwise over a period of 30 minutes such that the temperature of the mixture was maintained at -40 to -45° C. The mixture was allowed to warm to 5 ° C and then recooled to -35 ° C.
  • a solution comprised of .sec-butyl lithium (2.78 mL, 3.62 mmol) in cyclohexane was added dropwise and the mixture was stirred for 30 minutes.
  • the mixture was concentrated by rotary evaporation and the residue was treated with ethyl acetate (450 mL), water (300 mL) and saturated sodium bicarbonate until all solids were dissolved.
  • the ethyl acetate layer was separated and washed sequentially with saturated sodium bicarbonate (100 mL), water (100 mL), IN hydrochloric acid (100 mL), water (100 mL) and brine (50 mL).
  • the tert-butyl (S)- 1 -(iV-methoxy--V-methylcarbamoy l)-3-pheny lpropylcarbamate provided above was divided into three portions (5.0 g 15.5 mmol; 4.88 g , 15.1 mmol; and 4.54 g, 14.1 mmol). Each portion was azeotroped with toluene by rotary evaporation and dried under reduced pressure to remove residual ethyl acetate and water. Each portion of the ester was taken up into anhydrous diethyl ether (75 mL) and the mixtures were cooled in an ice bath under nitrogen.
  • Example 15 Proceeding as in Example 15 provided -V-ITSJ2-benzooxazol-2-yl-2-hvdroxy- lS-phenethylethylcarbamoyl)-2-cyclohexylethyllmo ⁇ holine-4-carboxamide (Compound 75).
  • Example 16 Proceeding as in Example 16 provided the following compounds of Formula I: -V-. lR-(lS-benzooxazol-2-ylcarbonyl)-3-phenylpropylcarbamoyl)-
  • the mixture was extracted with ethyl acetate (2x) and the extract washed sequentially with aqeous sodium bicarbonate and brine, dried (MgS0 4 ) and concentrated.
  • the residue was dissolved in methylene chloride (8 mL) and the solution was treated with Dess-Martin reagent (544 mg) .
  • the mixture was stirred for 1.5 hours and then stirred a sodium thiosulfate/sodium bicarbonate solution for 15 minutes.
  • the mixture was extracted with ethyl acetate (2x) and the extract was washed with brine, dried (MgSO 4 ) and then concentrated.
  • the residue was triturated with ethyl acetate and then hexanes.
  • a suspension comprised of lithium aluminum hydride (0.885 g, 23.3 mmol) in anhydrous diethyl ether was cooled to -45 ° C under nitrogen and then treated with a solution of benzyl lS-(-V-methoxy-N-methylcarbamoyl)-3-phenylpropylcarbamate (5.53 g, 15.53 mmol), provided as in Reference 13, in ether (75 mL) and THF (25 mL) was added dropwise over a period of
  • a solution comprised of sgc -butyl lithium (2.78 ml, 3.62 mmol) in cyclohexane was added dropwise and the mixture was stirred for 30 minutes.
  • a mixture comprised of ethyl 3-(2-benzyloxycarbonylamino-4-methylvalerylamino)- 2-hydroxy-5-phenylpentanimidate (0.327 g, 0.63 mmol), diisopropylethylamine (0.218 mL, 1.26 mmol) and ethanolamine (38.4 mg, 0.63 mmol) in chloroform (20 mL) was heated (reflux temperature) for 3 hours and then stirred at room temperature for approximately 12 hours. The mixture was concentrated and the residue was dissolved in ethyl acetate (50 mL).
  • the product was purified from the residue by flash chromatography on silica gel eluting with 1:2 ethyl acetate/hexanes to provide benzyl l-[l-(lH-indol-2-ylcarbonyl)-3-phenylpropylcarbamoyl]-3-methylbutylcarbamate (112 mg, 0.21 mmol) as a white solid.
  • the product was purified from the residue by flash chromatography eluting with 1:3 hexanes/ethyl acetate to provide methyl 2-,2-(2-benzyloxycarbonylamino-4-methylvale-ylamino)-l-hydroxy-4-phenylbutyl1oxazole- 4-carboxylate (12 mg, 0.022 mmol) as a white solid.
  • a mixture comprised of methyl 2-[2-(2-benzyloxycarbonylamino-4-methylvalerylamino)- l-hydroxy-4-phenylbutyl]oxazole-4-carboxylate (2.16 g, 4.02 mmol), provided as in Example 18, and sodium hydroxide (0.815 mL, 1.63 M in water) in methanol (10 mL) was stirred for approximately 12 hours at room temperature, acidified with 1 M hydrochloric acid and concentrated. The residue was dissolved in ethyl acetate (50 mL) and the solution dried (MgSO 4 ).
  • A128-B12-C4-D33 A11-B5-C4-D83 A75-B5-C4-D83 A128-B5-C4-D83
  • test compounds in varying concentrations were prepared in 10 ⁇ L of dimethyl sulfoxide (DMSO) and then diluted into assay buffer (40 ⁇ L, comprising: -V,-V-bis(2-hydroxyethyl)-2-aminoethanesulfonic acid (BES), 50 mM (pH 6); polyoxyethylenesorbitan monolaurate, 0.05%; and dithiothreitol (DTT), 2.5 mM).
  • BES dimethyl sulfoxide
  • DTT dithiothreitol
  • test compounds in varying concentrations were prepared in 10 ⁇ L of dimethyl sulfoxide (DMSO) and then diluted into assay buffer (40 ⁇ L, comprising: MES, 50 mM (pH 5.5); EDTA, 2.5 mM; and DTT, 2.5 mM).
  • assay buffer 40 ⁇ L, comprising: MES, 50 mM (pH 5.5); EDTA, 2.5 mM; and DTT, 2.5 mM).
  • Human cathepsin K (0.0906 pMoles in 25 ⁇ L of assay buffer) was added to the dilutions.
  • the assay solutions were mixed for 5-10 seconds on a shaker plate, covered and incubated for 30 minutes at room temperature.
  • test compounds in varying concentrations were prepared in 10 ⁇ L of dimethyl sulfoxide (DMSO) and then diluted into assay buffer (40 ⁇ L, comprising: MES, 50 mM (pH 5.5); EDTA, 2.5 mM; and DTT, 2.5 mM).
  • assay buffer 40 ⁇ L, comprising: MES, 50 mM (pH 5.5); EDTA, 2.5 mM; and DTT, 2.5 mM).
  • Human cathepsin L (0.05 pMoles in 25 ⁇ L of assay buffer) was added to the dilutions.
  • the assay solutions were mixed for 5-10 seconds on a shaker plate, covered and incubated for 30 minutes at room temperature.
  • test compounds in varying concentrations were prepared in 10 ⁇ L of dimethyl sulfoxide (DMSO) and then diluted into assay buffer (40 ⁇ L, comprising: MES, 50 mM (pH 6.5); EDTA, 2.5 mM; and NaCl, 100 mM).
  • Assay buffer 40 ⁇ L, comprising: MES, 50 mM (pH 6.5); EDTA, 2.5 mM; and NaCl, 100 mM).
  • Human cathepsin S (0.158 pMoles in 25 ⁇ L of assay buffer) was added to the dilutions.
  • the assay solutions were mixed for 5-10 seconds on a shaker plate, covered and incubated for 30 minutes at room temperature.
  • EXAMPLE 32 Ovalbumin Challenge Mouse C57 mice (female) were sensitised with ovalbumin (lO ⁇ g, i.p.) administered together with aluminium hydroxide adjuvant (20 mg, i.p.) on days 0 and 12. Mice are challenged on either day 22, 23 or 24 by exposure for 60 minutes to an aerosol of ovalbumin (10 g / 1) twice, 4 hours apart. Mice are dosed p.o. with either vehicle 5 ml/kg (0.5%MC/0.2 % Tween 80 in H 2 0) or test compound at 0, 8, 23.5 29, 33, 48 and 56 hours.
  • ovalbumin lO ⁇ g, i.p.
  • aluminium hydroxide adjuvant 20 mg, i.p.
  • mice were euthanized with pentobarbitone i.p. after 86 hours (72 hours after the first challenge).
  • the lungs were insufflated for histological examination as soon as possible after euthanization.
  • Lungs were insufflated with 10% neutral buffered formalin (NBF), at 30 cm water pressure.
  • NBF neutral buffered formalin
  • the lungs were removed and placed in pots of 10% NBF. After fixation in 10% NBF for a minimum of 24 hours the lungs were processed through graded alcohols to wax.
  • the lungs were blocked longitudinally and one 2 ⁇ m section for each animal was cut at the level of the main bronchi. Sections then were stained with haematoxylin and eosin. Pathological assessment of sections is performed and a grading is assigned.
  • Histopathological evaluation of the lung tissue demonstrate a dose dependant anti- inflammatory effect on vascular and mucosal beds after treatment with compounds of the invention between 0.03 and 30 mg/kg.
  • Citric Acid Monohydrate 1.05 mg
  • the resulting tablets are useful for administration in accordance with the methods of this invention for treating or preventing a cathepsin mediated disease state, such as osteoporosis, juvenile onset diabetes, multiple sclerosis, pemphigus vulgaris, Graves' disease, myasthenia gravis, systemic lupus erythemotasus, rheumatoid arthritis, Hashimoto's thyroiditis, asthma, organ transplant or tissue graft rejections, chronic obstructive pulmonary disease, bronchiolitis, excessive airway elastolysis in asthma and bronchitis, pneumonities, plaque rupture, atheroma and systemic amyloidosis.
  • a cathepsin mediated disease state such as osteoporosis, juvenile onset diabetes, multiple sclerosis, pemphigus vulgaris, Graves' disease, myasthenia gravis, systemic lupus erythemotasus, rheumatoid arthritis, Hashimoto'

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Abstract

The present invention relates to novel alkanoyl-substituted heterocyclic derivatives which are cysteine protease inhibitors; the pharmaceutically acceptable salts and N-oxides thereof; their uses as therapeutic agents and the methods of their making; according to Formula (I) in which: A comprises a heteromonocyclic ring containing 5 to 6 ring member atoms or a fused heteropolycyclic ring system containing 8 to 14 ring member atoms, wherein each ring contains 5 to 7 ring member atoms, X1 is a ring member carbon atom and each ring member atom other than X1 is a carbon atom or a heteroatom, with the proviso that (i) at least one ring member atom is a heteroatom and (ii) when A is a heteromonocyclic radical containing 5 ring member atoms, no more than two of the ring member atoms comprising A are heteroatoms; n is 0, 1, 2 or 3; X1 is =C- or -CH-; X2 is a bond or a divalent group of Formula (a) or (b); R1 - R8 = as in the application.

Description

AMINE DERIVATIVES AS PROTEASE INHIBITORS
THE INVENTION
This application relates to compounds and compositions for treating diseases associated with cysteine protease activity, particularly diseases associated with activity of cathepsins B, K, L or S.
DESCRIPTION OF THE FIELD
Cysteine proteases represent a class of peptidases characterized by the presence of a cysteine residue in the catalytic site of the enzyme. Cysteine proteases are associated with the normal degradation and processing of proteins. The aberrant activity of cysteine proteases, e.g. as a result of increased expression or enhanced activation, however, may have pathological consequences. In this regard, certain cysteine proteases are associated with a number of disease states, including arthritis, muscular dystrophy, inflammation, tumor invasion, glomerulonephritis, malaria, periodontal disease, metachromatic leukodystrophy and others. For example, increased cathepsin B levels and redistribution of the enzyme are found in tumors; thus, suggesting a role for the enzyme in tumor invasion and metastasis. In addition, aberrant cathepsin B activity is implicated in such disease states as rheumatoid arthritis, osteo arthritis, pneumocystis carinii, acute pancreatitis, inflammatory airway disease and bone and joint disorders. The prominent expression of cathepsin K in osteoclasts and osteoclast-related multinucleated cells and its high collagenolytic activity suggest that the enzyme is involved in ososteoclast-mediated bone resorption and, hence, in bone abnormalities such as occurs in osteoporosis. In addition, cathepsin K expression in the lung and its elastinolytic activity suggest that the enzyme plays a role in pulmonary disorders as well. Cathepsin L is implicated in normal lysosomal proteolysis as well as several disease states, including, but not limited to, metastasis of melanomas. Cathepsin S is implicated in Alzheimer's disease and certain autoimmune disorders, including, but not limited to juvenile onset diabetes, multiple sclerosis, pemphigus vulgaris, Graves' disease, myasthenia gravis, systemic lupus erythemotasus, rheumatoid arthritis and Hashimoto's thyroiditis; allergic disorders, including, but not limited to asthma; and allogeneic immune responses, including, but not limited to, rejection of organ transplants or tissue grafts.
In view of the number of diseases wherein it is recognized that an increase in cysteine protease activity contributes to the pathology and/or symptomatology of the disease, molecules which are shown to inhibit the activity of this class of enzymes, in particular molecules which are inhibitors of cathepsins B, K, L and/or S, will be useful as therapeutic agents.
SUMMARY OF THE INVENTION
In one particular embodiment, the present invention relates to protease inhibitors of Formula I:
Figure imgf000004_0001
I in which:
A comprises a heteromonocyclic ring containing 5 to 6 ring member atoms or a fused heteropolycyclic ring system containing 8 to 14 ring member atoms, wherein each ring contains 5 to 7 ring member atoms, X1 is a ring member carbon atom and each ring member atom other than X1 is a carbon atom or a heteroatom, with the proviso that (i) at least one ring member atom is a heteroatom and (ii) when A is a heteromonocyclic radical containing 5 ring member atoms, no more than two of the ring member atoms comprising A are heteroatoms; n is 0, 1, 2 or 3;
X1 is =C- or -CH-; X2 is a bond or a divalent group of Formula (a) or (b):
Figure imgf000004_0002
(a) (b)
wherein: X3 and X4 independently are -C(O)- or -CH2S(0)2- R9 and R10 independently are hydrogen, (C,.6)alkyl or as defined below; R11 at each occurrence independently is hydrogen or (C,.6)alkyl; R12 and R13 independently are (i) (C1.6)alkyl optionally substituted with cyano, halo, nitro, -NR14R14, -NR14C(O)OR14, -NR14C(0)NR14R14, -NR14C(NR14)NR14R14,
-OR14, -SR14, -C(O)OR14, -C(O)NRI4R14, -S(0)2NR14R14, -P(0)(ORI4)OR14, -OP(0)(OR14)OR14, -NR14C(O)R15, -S(O)R15, -S(0)2R15, -C(O)R15, -OR16, -SR16, -S(0)R16, -S(0)2R16, -C(O)R16, -C(0)OR16, -OC(0)R16, -NR16R17, -NR17C(O)R16, -NR17C(0)OR16, -C(0)NR16R17, -S(0)2NR16R17, -NR17C(0)NR16R17 or -NR!7C(NR17)NR16R17, wherein R14 at each occurrence independently is hydrogen,
(C,.6)alkyl or halo-substituted (C^alkyl, R15 is (C,.6)alkyl or halo-substituted (C,.3)alkyl, halo, (C^alkyl or R16 is (C3.12)cycloalkyl(C0.5)alkyl, hetero(C3.,2)cycloalkyl(C0.6)alkyl, (C6.12)aryl(C0.6)alkyl, hetero(C5.12)aryl(C0.6)alkyl, (C9.12)polycycloaryl(C0.6)alkyl or hetero(C8.12)polycycloaryl(C0.6)alkyl and R17 is hydrogen or (C^alkyl, and wherein within R16 said cycloalkyl, heterocycloalkyl, aryl, heteroaryl, polycycloaryl or heteφolycycloaryl ring optionally is substituted by a group selected from -R18, -X5OR18, -X5SR18, -X5S(0)R18, -X5S(0)2R18, -X5C(O)R18, -X5C(0)OR18, -X5OC(O)R18, -X5NR18R19, -X5NR19C(0)R18, -X5NR19C(0)OR18, -X5C(0)NR18R19, -X5S(O)2NR18R'9, -X5NR19C(0)NR18R19 or -X5NR19C(NR19)NR18R19, wherein X5 is a bond or (C,.6)alkylene, R18 is hydrogen or
(C^alkyl and R19 is (C3_12)cycloalkyl(C0.6)alkyl, hetero(C3.12)cycloalkyl(C0.6)alkyl, (C6.12)aryl(C0.6)alkyl, hetero(C5.I2)aryl(C0.6)alkyl, (C9.12)polycycloaryl(C0.6)alkyl or hetero(Cg.12)polycycloaryl(C0.6)alkyl, or (ii) a group selected from (C3.12)cycloalkyl(C0.6)alkyl, hetero(C3.12)cycloalkyl(C0_6)alkyl, (C6.12)aryl(C0.6)alkyl, hetero(C5.12)aryl(C0.6)alkyl, (C9.12)polycycloaryl(C0.6)alkyl and hetero(C8.12)polycycloaryl(C0.6)alkyl, wherein said cycloalkyl, heterocycloalkyl, aryl, heteroaryl, polycycloaryl or heteφolycycloaryl ring optionally is substituted by a group selected from -R18, -X5OR'8, -X5SR18, -X5S(0)R18, -X3S(0)2R18, -X5C(O)R18, -X5C(0)OR18, -X5OC(O)R18, -X5NR18R19, -X5NR19C(0)R18, -X5NR19C(O)OR18, -X5C(0)NR18R19, -X5S(0)2NR18R19, -X5NR19C(0)NR18R19 or
-X5NR19C(NR19)NR18R19, wherein X5, R18 and R19 are as defined above; wherein within R12 and/or R13 any alicyclic or aromatic ring system present may be substituted further by 1 to 5 radicals independently selected from (C,.6)alkyl, (C,_6)alkylidene, cyano, halo, halo-substituted (CM)alkyl, nitro, -X5NR14R14, -X5NR14C(0)OR14, -X5NR14C(0)NR14R14, -X5NR14C(NR14)NR14R14, -X5OR14, -X5SR14, -X5C(0)OR14, -X5C(0)NR14R14, -X5S(0)2NR14R14, -X5P(0)(OR14)OR14, -X5OP(0)(OR14)OR14, -X5NR14C(O)R15, -X5S(O)R15, -X5S(0)2R15 and -X5C(0)R15, wherein X5, R14 and R15 are as defined above; or
R12 together with R9 and/or R13 together with R10 form trimethylene, tetramethylene or phenylene-l,2-dimethylene, optionally substituted with 1 to 3 radicals independently selected from (C,.6)alkyl, (C1.6)alkylidene, cyano, halo, halo-substituted (CM)alkyl, nitro, oxo, -X5NR14C(0)OR14, -X5NR14C(0)NR14R14,
-X5NR14C(NR14)NR14R14, -XOR14, -X5SR14, -X5C(0)OR14, -X5C(0)NR14R14, -X5S(0)2NR14R14, -X5P(0)(OR14)OR14, -X5OP(0)(OR14)OR14, -X5NR14C(0)R15, -X5S(0)R15, -X5S(O)2R15 and -X5C(0)R15, wherein X5, R14 and R15 are as defined above; and R1 is -X6X7R20, wherein X6 is -C(O)-, -C(O)C(O)- or -S(0)2-, X7 is a bond, -O- or
-NR21-, wherein R21 is hydrogen or ( _6)alkyl, and R20 is (i) (C,.6)alkyl optionally substituted by cyano, halo, nitro, -NR14R14, -NR14C(O)OR14, -NR14C(O)NR14R14, -NR14C(NR14)NR14R14, -OR14, -SR14, -C(0)OR'4, -C(O)NR14R14, -S(0)2NR14R14, -P(0)(OR14)OR14, -OP(O)(OR14)OR14, -NR14C(O)R15, -S(O)R15, -S(0)2R15, -C(O)R15, -OR22, -SR22, -S(0)R22, -S(0)2R22, -C(0)R22, -C(O)OR22, -C(O)NR22R23, -NR22R23, -NR23C(0)R22, -NR23C(0)OR22, -NR23C(0)NR22R23 or -NR23C(NR23)NR22R23, wherein R14 and R15 are as defined above, R22 is (C3.12)cycloalkyl(C0.6)alkyl, hetero(C3.12)cycloalkyl(C0.6)alkyl, (C6_12)aryl(C0.6)alkyl, hetero(C5.12)aryl(C0.6)alkyl, (C9.12)bicycloaryl(C0.6)alkyl or hetero(Cg.12)bicycloaryl(C0.6)alkyl and R23 at each occurrence independently is hydrogen or (C,.6)alkyl, or (ii) (C3.12)cycloalkyl(C0.6)alkyl, hetero(C3.12)cycloalkyl(C0.6)alkyl, (C6.12)aryl(C0.6)alkyl, hetero(C5.I2)aryl(C0.6)alkyl, (C9.12)bicycloaryl(C0.6)alkyl or hetero(C8.12)bicycloaryl(C0.6)alkyl or (iii) (C3.6)cycloalkyl(C0_6)alkyl, hetero(C3.6)cycloalkyl(C0.6)alkyl, phenyl(C0.6)alkyl or hetero(C5.6)aryl(C0.6)alkyl, wherein said cycloalkyl, heterocycloalkyl, phenyl or heteroaryl is substituted by -R24, -X5OR24, -X5SR24, -X5S(0)R24, -X5S(0)2R24, -X5C(0)R24, -X5C(0)OR24, -X5C(0)NR24R25, -X5NR24R25, -X5NR25C(0)R24, -X5NR25C(O)OR24, -X5NR25C(O)NR24R25 or -X5NR25C(NR25)NR24R25, wherein X5 is as defined above, R24 is (C3.6)cycloalkyl(C0.6)alkyl, hetero(C3.6)cycloalkyl(C0.6)alkyl, phenyl(C0.6)alkyl or hetero(C5.6)aryl(C0.6)alkyl and R25 at each occurrence independently is hydrogen or (C,.6)alkyl; wherein within R1 any alicyclic or aromatic ring system present may be substituted further by 1 to 5 radicals independently selected from (C,_6)alkyl, (C,.6)alkylidene, cyano, halo, halo-substituted (CM)alkyl, nitro, -X5NR14R14, -X5NR14C(O)OR14, -X5NR,4C(0)NR14R14, -X5NR14C(NR,4)NR14R14, -X5OR14, -X5SR14, -X5C(0)OR14, -X5C(O)NR14R14, -X5S(0)2NR14R14, -X5P(0)(OR14)OR14,
-XOP(0)(OR14)OR14, -X5NR,4C(O)R15, -X5S(O)R15, -X5S(0)2R15 and -X5C(0)R15, wherein X5, R14 and R15 are as defined above; or when X2 is a divalent group of formula (a) or (b) then R1 may also represent hydrogen, carboxy, oxalo or carbamoyl; R2 is hydrogen or (C,.6)alkyl; R3 is (i) (Cj.6)alkyl optionally substituted with cyano, halo, nitro, -SR26, -C(0)OR26,
-C(0)NR26R26, -P(0)(OR26)OR26, -OP(0)(OR26)OR26, -S(0)R27, -S(0)2R27 or -C(O)R27, wherein R26 at each occurrence independently is hydrogen, (C,.6)alkyl or halo-substituted (C,.3)alkyl and R27 is (Cμ6)alkyl or halo-substituted (C,.3)alkyl, or (ii) (C5.6)cycloalkyl(C2.3)alkyl, hetero(C3.6)cycloalkyl(C2_3)alkyl, (C6.12)aryl(C2.3)alkyl or hetero(C5.6)aryl(C2.3)alkyl, wherein said cycloalkyl, heterocycloalkyl, aryl or heteroaryl optionally is substituted further with 1 to 5 radicals independently selected from (C,.6)alkyl, (C,.6)alkylidene, cyano, halo, halo-substituted (CM)alkyl, nitro, -X5NR14C(O)OR14, -X5NR14C(O)NR14R14, -X5NR14C(NR14)NR14R14, -X5OR14, -X5SR14, -X5C(0)OR14, -X5C(0)NR14R14, -X5S(0)2NR14R14, -X5P(0)(OR14)OR14, -X5OP(0)(OR14)OR14, -X5NR14C(O)R15, -X5S(O)R15, -X5S(O)2R15 and -X5C(O)R15, wherein X5, R14 and R15 are as defined above, provided that when R3 is unsubstituted (C,.5)alkyl and R4 is hydrogen or unsubstituted (C].5)alkyl, then X2 may not represent (i) a bond when R1 is -C(O)R20, -C(0)2R20 or -S(O)2R20 in which R20 is (C,.6)alkyl, phenyl(CM)alkyl, phenyl, (C3.7)cycloalkyl, camphan-10-yl, naphth-1-yl, naphth-2-yl, phenyl substituted by one or more of (C].4)alkyl, perfluoro(C1.4)alkyl, (C,.4)alkoxy, hydroxy, halo, amido, nitro, amino, (CM)alkylamino, (C1.4)dialkylamino, carboxy or (C,.4)alkoxycarbonyl, or naphth-1-yl or naphth-2-yl substituted by one or more of (CM)alkyl, perfluoro(C].4)alkyl, (C,^)alkoxy, hydroxy, halo, amido, nitro, amino, carboxy or (C,.4)alkoxycarbonyl or (ii) a divalent group of formula (a) or (b) in which the moiety R12 is methyl, isopropyl, n-butyl, sec-butyl, tert-butyl, 1-methylpropyl, benzyl, naphth-1-ylmethyl, naphth-2-ylmethyl, thien-2-ylmethyl, thien-3-ylmethyl, or wherein R9 and R12 form ethylene, trimethylene, hydroxy-substituted trimethylene, tetramethylene or phenylene-l,2-dimethylene; or
R3 and R4 taken together with the carbon atom to which both R3 and R4 are attached form (C3.8)cycloalkylene or (C3.8)heterocycloalkylene, wherein said cycloalkylene or heterocycloalkylene is optionally substituted with 1 to 3 radicals independently selected from (C,.6)alkyl, (C,.6)alkylidene, cyano, halo, halo-substituted (C,.4)alkyl, nitro, -X5NR14C(0)OR14, -X5NR14C(0)NR14R14, -X5NR14C(NR14)NR14R14, -X5OR14, -X5SR14, -X5C(O)OR14, -X5C(0)NR14R14, -X5S(0)2NR14R14, -X5P(0)(OR14)OR14, -X5OP(0)(OR14)OR14,
-X5NR14C(0)R15, -X5S(O)R15, -X5S(O)2R15 and -X5C(O)R15, wherein X5, R14 and R15 are as defined above;
R4 is hydrogen, (C,.6)alkyl or as defined above;
R5 is hydrogen and R6 is hydroxy or R5 and R6 together form oxo; R7 is a group selected from cyano, halo, nitro, -R29, -X5NR29R30, -X5NR30C(O)OR29,
-X5NR30C(O)NR29R30, -X5NR30C(NR3O)NR29R30, -X5OR29, -X5SR29, -X5C(O)OR29, -X5C(0)NR29R30, -X5S(0)2NR29R30, -X5P(O)(OR30)OR29, -X5OP(0)(OR29)OR29, -X5NR30C(O)R31, -X5S(O)R31, -X5S(0)2R31 and -X5C(O)R31, wherein X5 is as defined above, R29 is hydrogen or -R31, R30 at each occurrence is hydrogen or (C,.6)alkyl and R31 is (C,.6)alkyl, (C3.12)cycloalkyl(C0.6)alkyl, hetero(C3.12)cycloalkyl(C0.6)alkyl, (C6.12)aryl(C0.6)alkyl or hetero(C5.]2)aryl(C0.6)alkyl, wherein within R7 any alicyclic or aromatic ring system present may be substituted further by 1 to 5 radicals independently selected from (C].6)alkyl, (C,.6)alkylidene, cyano, halo, halo-substituted (CM)alkyl, nitro, -X5NR14R14, -X5NR14C(O)OR14, -X5NR14C(0)NR14R14, -X5NR14C(NR14)NR14R14, -X5OR14, -X5SR14, -X5C(O)OR14, -X5C(O)NR14R14, -X5S(0)2NR14R14, -X5P(O)(OR14)OR'4, -X5OP(0)(OR14)OR14,
-X5NR14C(0)R15, -X5S(0)R15, -X5S(0)2R15 and -X5C(O)R15, wherein X5, R14 and R15 are as defined above; and
R8 at each occurrence independently is selected from (C,.6)alkyl, (C,.6)alkylidene, cyano, halo, halo-substituted (C,.4)alkyl, nitro, -X5NR14R14, -X5NR14C(0)OR14, -X5NR14C(O)NR14R14, -X5NRI4C(NR14)NR14R14, -X5OR14, -X5SR14, -X5C(O)OR14, -X5C(O)NR14R14, -X5S(O)2NR14R14, -X5P(O)(OR14)OR14, -X5OP(0)(OR14)OR14, -X5NR14C(O)R15, -X5S(O)R15, -X5S(O)2R15 and -X5C(O)R15, wherein X5, R14 and R15 are as defined above; and the -V-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers; and the pharmaceutically acceptable salts thereof.; but excluding compounds selected from the group consisting of
((S)- 1 -{ (S)- 1-[(S)- 1 -( 1 -benzooxazol-2-yl-methanoyl)-3-methyl-butylcarbamoyl]-3-methyl- butylcarbamoyl}-3-methyl-butyl)-carbamic acid benzyl ester, { l-[l-(l-lH-imidazol-2-yl- methanoyl)-3-methyl-butylcarbamoyl]-3-methyl-butyl } -carbamic acid tert-butyl ester, [(S)-3-methyl-l-((S)-3-methyl-l-{ l-[l-(2-trimethylsilanyl-ethoxymethyl)-lH-imidazol-2-yl]- methanoyl}-butylcarbamoyl)-butyl]-carbamic acid benzyl ester;
{ (S)- 1 -[(S)- 1 -( 1 - lH-imidazol-2-y l-methanoyl)-3-methyl-buty lcarbamoyl] -3-methyl-buty 1 } - carbamic acid benzyl ester, ((S)-l-{ (S)-l-[l-(l-benzyl-lH-imidazol-2-yl)-methanoyl]-3-methyl- butylcarbamoyl}-3-methyl-butyl)-carbamic acid benzyl ester, {(S)-l-[(S)-l-(l-lH-imidazol-2-yl- methanoyl)-3-methyl -buty lcarbamoyl] -3-methyl-buty 1} -carbamic acid tert-butyl ester, 3-{ [l-(4-chloro-phenyl)-methanoyl]-amino}-4-oxo-4-pyridin-3-yl-butyric acid ethyl ester, 4-furan-2-yl-4-oxo-3-{ [l-(4-trifluoromethyl-phenyl)-methanoyl]-amino}-butyric acid ethyl ester, 3-(2-methyl-propanoylamino)-4-oxo-4-thiophen-2-yl-butyric acid ethyl ester, 4-oxo- 4-thiophen-2-yl-3-[(l-jp-tolyl-methanoyl)-amino]-butyric acid ethyl ester, 4-(5-bromo- thiophen-2-yl)-3-{ [l-(4-chloro-phenyl)-methanoyl]-amino}-4-oxo-butyric acid ethyl ester, 3-{ [l-(4-chloro-phenyl)-methanoyl]-amino}-4-(5-methyl-thiophen-2-yl)-4-oxo-butyric acid ethyl ester, 4-oxo-4-thiophen-3-yl-3-[(l-p-tolyl-methanoyl)-amino]-butyric acid ethyl ester, 3-{ [l-(4-methoxy-phenyl)-methanoyl]-amino}-4-oxo-4-thiophen-3-yl-butyric acid ethyl ester,
3-{ [l-(3,4-dichloro-phenyl)-methanoyl]-amino}-4-oxo-4-thiophen-3-yl-butyric acid ethyl ester,
4-fluoro-.V-[l-(l-thiophen-3-yl-methanoyl)-propyl]-benzamide, 4-{ [l-(4-fluoro-phenyl)- methanoyl]-amino}-5-oxo-5-thiophen-3-yl-pentanoic acid ethyl ester and 3-{ [l-(4-fluoro- phenyl)-methanoyl]-amino}-2-methyl-4-oxo-4-thiophen-3-yl-butyric acid ethyl ester. In another particular embodiment, the present invention relates to protease inhibitors of
Formula I:
Figure imgf000009_0001
I in which:
A comprises a heteromonocyclic ring containing 5 to 6 ring member atoms or a fused heteropolycyclic ring system containing 8 to 14 ring member atoms, wherein each ring contains 5 to 7 ring member atoms, X1 is a ring member carbon atom and each ring member atom other than X1 is a carbon atom or a heteroatom, with the proviso that (i) at least one ring member atom is a heteroatom and (ii) when A is a heteromonocyclic radical containing 5 ring member atoms, no more than two of the ring member atoms comprising A are heteroatoms; n is 0, 1, 2 or 3;
X1 is =C- or -CH-;
X2 is a bond or a divalent group of Formula (a) or (b):
Figure imgf000010_0001
(a) (b) wherein:
X3 and X4 independently are -C(O)- or -CH2S(0)2-;
R9 and R10 independently are hydrogen, (C,.6)alkyl or as defined below; R11 at each occurrence independently is hydrogen or (Cj^alkyl;
R12 and R13 independently are (i) (C,.6)alkyl optionally substituted with cyano, halo, nitro, -NR14R14, -NR14C(O)OR14, -NR,4C(0)NR14R14, -NR14C(NR14)NR14R14, -OR14, -SR14, -C(O)OR14, -C(O)NR14R14, -S(0)2NR14R14, -P(0)(OR14)OR14, -OP(O)(OR14)OR14, -NR14C(O)R15, -S(0)R15, -S(0)2R15, -C(0)R15, -OR16, -SR16, -S(O)R16, -S(0)2R16, -C(O)R16, -C(O)OR16, -OC(0)R16, -NR16R17, -NRπC(0)R16,
-NR17C(0)OR16, -C(0)NR16R17, -S(O)2NR16R17, -NR17C(0)NR16R17 or -NR17C(NR,7)NR16R17, wherein R14 at each occurrence independently is hydrogen, (C,.6)alkyl or halo-substituted (C1.3)alkyl, R15 (C,.6)alkyl or halo-substituted (C1.3)alkyl, R16 is (C3.12)cycloalkyl(C0.6)alkyl, hetero(C3.12)cycloalkyl(C0.6)alkyl, (C6.12)aryl(C0.6)alkyl, hetero(C5.12)aryl(C0.6)alkyl, (C9_12)polycycloaryl(C0.6)alkyl or hetero(C8.12)polycycloaryl(C0.6)alkyl and R17 is hydrogen or (C,.6)alkyl, and wherein within R16 said cycloalkyl, heterocycloalkyl, aryl, heteroaryl, polycycloaryl or heteφolycycloaryl ring optionally is substituted by a group selected from -R18, -X5OR18, -X5SR18, -X5S(O)R18, -X5S(O)2R18, -X5C(0)R18, -X5C(0)OR18, -X5OC(O)R18, -X5NR18R19, -X5NR19C(O)R18, -X5NR19C(0)OR18, -X5C(0)NR18R19,
-X5S(O)2NR18R19, -X5NR19C(0)NR18R19 or -X5NR19C(NR19)NR18R19, wherein X5 is a bond or (C,.6)alkylene, R18 is hydrogen or (C,.6)alkyl and R19 is (C3.12)cycloalkyl(C0.6)alkyl, hetero(C3.12)cycloalkyl(C0.6)alkyl, (C6.12)aryl(C0.6)alkyl, hetero(C5.12)aryl(C0.6)alkyl, (C9.12)polycycloaryl(C0.6)alkyl or hetero(C8.]2)polycycloaryl(C0.6)alkyl, or (ii) a group selected from (C3.,2)cycloalkyl(C0.6)alkyl, hetero(C3.12)cycloalkyl(C0.6)alkyl, (C6.12)aryl(C0.6)alkyl, hetero(C5.12)aryl(C0.6)alkyl, (C9.12)polycycloaryl(C0_6)alkyl and hetero(C8.12)polycycloaryl(C0.6)alkyl, wherein said cycloalkyl, heterocycloalkyl, aryl, heteroaryl, polycycloaryl or heteφolycycloaryl ring optionally is substituted by a group selected from -R18, -X5OR18, -X5SR18, -X5S(O)R18, -X5S(0)2R18, -X5C(O)R18, -X5C(0)OR18, -X5OC(0)R18, -X5NR18R19, -X5NR19C(0)R18, -X5NR19C(0)OR18, -X5C(0)NR18R19, -X5S(0)2NR18R19, -X5NR19C(0)NR18R19 or
-X5NR19C(NR19)NR18R19, wherein X5, R18 and R19 are as defined above; wherein within R12 and/or R13 any alicyclic or aromatic ring system present may be substituted further by 1 to 5 radicals independently selected from (C,.6)alkyl, (C,.6)alkylidene, cyano, halo, halo-substituted (C,.4)alkyl, nitro, -X5NR14R14, -X5NR14C(0)OR14, -X5NR14C(0)NR14R14, -X5NR14C(NR14)NR,4R14, -XOR14, -X5SR14, -X5C(0)OR14,
-X5C(O)NR14R14, -X5S(0)2NR14R14, -X5P(O)(OR14)OR14, -X5OP(0)(OR14)OR14, -X5NR14C(0)R15, -X5S(O)R15, -X5S(O)2R15 and -X5C(0)R15, wherein X5, R14 and R15 are as defined above; or
R12 together with R9 and/or R13 together with R10 form trimethylene, tetramethylene or phenylene-l,2-dimethylene, , optionally substituted with 1 to 3 radicals independently selected from (C^alkyl, (C,.6)alkylidene, cyano, halo, halo-substituted (C^alkyl, nitro, oxo, -X5NR14C(0)OR14, -X5NR!4C(0)NR14R14, -X5NR14C(NR14)NR14R14, -X5OR14, -X5SR14, -X5C(0)OR14, -X5C(0)NR14R14, -X5S(O)2NR,4R14, -X5P(0)(OR14)OR14, -XOP(0)(OR14)OR14, -X5NR14C(0)R15, -X5S(O)R15, -X5S(O)2R15 and -X5C(0)R15, wherein X5, R14 and R15 are as defined above; and
R1 is -X6X7R20, wherein X6 is -C(O)-, -C(O)C(O)- or -S(0)2-, X7 is a bond, -O- or -NR21-, wherein R21 is hydrogen or (C,.6)alkyl, and R20 is (i) (C,_6)alkyl optionally substituted by cyano, halo, nitro, -NR,4R14, -NR14C(O)OR14, -NR14C(0)NR14R14, -NR14C(NR14)NR14R14, -OR14, -SR14, -C(0)OR'4, -C(0)NR14R14, -S(O)2NR14R14, -P(0)(OR14)OR14,
-OP(0)(OR14)OR14, -NR14C(0)R15, -S(O)R15, -S(O)2R15, -C(0)R15, -OR22, -SR22, -S(0)R22, -S(0)2R22, -C(0)R22, -C(0)OR22, -C(0)NR22R23, -NR22R23, -NR23C(0)R22, -NR23C(0)OR22, -NR23C(O)NR22R23 or -NR23C(NR23)NR22R23, wherein R14 and R15 are as defined above, R22 is (C3.12)cycloalkyl(C0.6)alkyl, hetero(C3.12)cycloalkyl(C0.6)alkyl, (C6.12)aryl(C0.6)alkyl, hetero(C5.12)aryl(C0.6)alkyl, (C9.I2)bicycloaryl(C0.6)alkyl or hetero(C8.12)bicycloaryl(C0.6)alkyl and R23 at each occurrence independently is hydrogen or (C).6)alkyl, or (ii) (C3.12)cycloalkyl(C0.6)alkyl, hetero(C3.12)cycloalkyl(C0.6)alkyl, (C6.12)aryl(C0.6)alkyl, diphenyl(C0_6)alkyl, hetero(C5.12)aryl(C0.6)alkyl, dihetero(C5.6)aryl(C0.6)alkyl, (C9.12)bicycloaryl(C0.6)alkyl or hetero(C8.]2)bicycloaryl(C0.6)alkyl wherein said cycloalkyl, heterocycloalkyl, aryl or heteroaryl may be substituted by -R24, -XOR24, -X5SR24, -X5S(0)R24, -X5S(O)2R24, -X5C(0)R24, -X5C(0)OR24, -X5C(0)NR24R25, -X^R^R25, -X5NR25C(0)R24, -X5NR25C(0)OR24, -X5NR25C(0)NR24R25 or -X5NR25C(NR25)NR 4R25, wherein X5 is as defined above, R24 is (C3.12)cycloalkyl(C0.6)alkyl, hetero(C3.I2)cycloalkyl(C0 _6)alkyl, (C6.12)aryl(C0.6)alkyl, hetero(C5.12)aryl(C0.6)alkyl, (C9.12)bicycloaryl(C0.6)alkyl or hetero(C8.12)bicycloaryl(C0.6)alkyl and R25 at each occurrence independently is hydrogen or (C,.6)alkyl; wherein within R1 any alicyclic or aromatic ring system present may be substituted further by 1 to 5 radicals independently selected from (Cj.6)alkyl, (C,.6)alkylidene, cyano, halo, halo-substituted (C^alkyl, nitro, -X5NR14R14, -X5NR14C(0)OR14, -X5NR14C(O)NR14R14, -X5NR14C(NR14)NR14R14, -X5OR14, -X5SR14, -X5C(0)OR14, -X5C(0)NR14R14, -X5S(O)2NR14R14, -X5P(0)(OR14)OR14, -X5OP(O)(OR14)OR14, -X5NR14C(O)R15, -X5S(0)R15, -X5S(O)2R15 and -X5C(0)R15, wherein X5, R14 and R15 are as defined above; or when X2 is a divalent group of formula (a) or (b) then R1 may also represent hydrogen, carboxy, oxalo or carbamoyl;
R2 is hydrogen or (C,_6)alkyl;
R3 is (i) ( .6)alkyl optionally substituted with cyano, halo, nitro, -SR24, -C(0)OR24, -C(O)NR24R24, -P(0)(OR24)OR24, -OP(O)(OR24)OR24, -S(0)R25, -S(0)2R25 or -C(O)R25, wherein R24 at each occurrence independently is hydrogen, (C,.6)alkyl or halo-substituted
(C].3)alkyl and R25 (C^alkyl or halo-substituted (Cμ3)alkyl, or (ii) (C5.6)cycloalkyl(C2.3)alkyl, hetero(C3.6)cycloalkyl(C2.3)alkyl, (C6.12)aryl(C2.3)alkyl or hetero(C5.6)aryl(C2.3)alkyl, wherein said cycloalkyl, heterocycloalkyl, aryl or heteroaryl optionally is substituted further with 1 to 5 radicals independently selected from (C,.6)alkyl, (C^^alkylidene, cyano, halo, halo-substituted (C,.4)alkyl, nitro, -X5NR14C(0)OR14, -X5NR14C(O)NR14R14, -X5NR14C(NR14)NR14R14,
-X5OR14, -X5SR14, -X5C(0)OR14, -X5C(O)NR14R14, -X5S(0)2NR14R14, -X5P(0)(OR14)OR14, -X5OP(0)(OR14)OR14, -X5NR14C(0)R'5, -X5S(O)R15, -X5S(0)2R15 and -X5C(O)R15, wherein X5, R14 and R15 are as defined above, provided that when R3 is unsubstituted (C,.5)alkyl and R4 is hydrogen or unsubstituted (C,.5)alkyl, then X2 may not represent (i) a bond when R1 is -C(O)R20, -C(0)2R20 or -S(O)2R20 in which R20 is (C,.6)alkyl, phenyl(C )alkyl, phenyl, (C3. 7)cycloalkyl, camphan-10-yl, naphth-1-yl, naphth-2-yl, phenyl substituted by one or more of (C,. 4)alkyl, perfluoro(C].4)alkyl, (C,^)alkoxy, hydroxy, halo, amido, nitro, amino, (C,.4)alkylamino, (C1.4)dialkylamino, carboxy or (C,.4)alkoxycarbonyl, or naphth-1-yl or naphth-2-yl substituted by one or more of (C,_4)alkyl, perfluoro(C,.4)alkyl, (C )alkoxy, hydroxy, halo, amido, nitro, amino, carboxy or (CM)alkoxycarbonyl or (ii) a divalent group of formula (a) or (b) in which the moiety R12 is methyl, isopropyl, n-butyl, sec-butyl, tert-butyl, 1-methylpropyl, benzyl, naphth-1-ylmethyl, naphth-2-ylmethyl, thien-2-ylmethyl, thien-3-ylmethyl, or wherein R9 and R12 form ethylene, trimethylene, hydroxy-substituted trimethylene, tetramethylene or phenylene-l,2-dimethylene; or
R3 and R4 taken together with the carbon atom to which both R3 and R4 are attached form (C3.8)cycloalkylene or (C3.8)heterocycloalkylene, wherein said cycloalkylene or heterocycloalkylene is optionally substituted with 1 to 3 radicals independently selected from (C,.6)alkyl, (C,.6)alkylidene, cyano, halo, halo-substituted (C,.4)alkyl, nitro, -X5NR14C(0)OR14, -X5NR14C(O)NR14R14, -X5NR14C(NR14)NR14R14, -X5OR14, -X5SR14, -X5C(O)OR14, -X5C(O)NR14R14, -X5S(O)2NR14R14, -X5P(0)(OR14)OR14, -X5OP(0)(OR14)OR14, -X5NR14C(O)R15, -X5S(O)R15, -X5S(O)2R15 and -X5C(0)R15, wherein X5, R14 and R15 are as defined above; R3 and R4 taken together with the carbon atom to which both R3 and R4 are attached form (C3.8)cycloalkylene or (C3.8)heterocycloalkylene, wherein said cycloalkylene or heterocycloalkylene is optionally substituted with 1 to 3 radicals independently selected from (C,.6)alkyl, (C,.6)alkylidene, cyano, halo, halo-substituted (C,.4)alkyl, nitro, -X5NR14C(0)OR14, -X5NR14C(O)NR14R14, -X5NR14C(NR14)NR14R14, -X5OR14, -X5SR14, -X5C(O)OR14, -X5C(O)NR14R14, -X5S(O)2NR14R14, -X5P(0)(OR14)OR14, -X5OP(O)(OR,4)OR14,
-X5NR14C(O)R15, -X5S(O)R15, -X5S(0)2R15 and -X5C(0)R15, wherein X5, R14 and R15 are as defined above;
R4 is hydrogen, (C,.6)alkyl or as defined above;
R5 is hydrogen and R6 is hydroxy or R5 and R6 together form oxo; R7 is a group selected from cyano, halo, nitro, -R29, -X5NR29R30, -X5NR30C(O)OR29,
-X5NR30C(O)NR29R30, -X5NR30C(NR30)NR29R30, -X5OR29, -X5SR29, -X5C(O)OR29, -X5C(O)NR29R30, -X5S(0)2NR29R30, -X5P(O)(OR30)OR29, -X5OP(0)(OR29)OR29, -X5NR30C(O)R20, -X5S(O)R20, -X5S(O)2R20, -X5C(0)R20 and -C(0)NR42CHR43C(O)OR29, wherein X5 and R20 are as defined as above, R29 is hydrogen or -R20, wherein R20 is defined as above, R30 at each occurrence is hydrogen or (C,.6)alkyl, R42 is hydrogen, (C,.6)alkyl or together with R43 forms trimethylene, tetramethylene or phenylene-l,2-dimethylene, optionally substituted with hydroxy or oxo, and R43 is as defined above or is (i) (C,.6)alkyl optionally substituted with cyano, halo, nitro, -NR14R14, -NR14C(O)OR14, -NR,4C(0)NR14R14, -NR14C(NR14)NR14R14, -OR14, -SR14, -C(0)OR14, -C(O)NR14R14, -S(0)2NR14R14, -P(0)(OR14)OR14, -OP(O)(OR14)OR14, -NR14C(0)R15, -S(O)R15, -S(0)2R15, -C(O)R15, -OR16, -SR16, -S(0)R16, -S(0)2R16, -C(0)R16, -C(O)OR16, -OC(O)R16, -NR16R17, -NR17C(0)R16, -NR17C(0)OR16, -C(0)NR16R17, -S(0)2NR16R17, -NR17C(O)NR16R17 or -NRI7C(NR17)NR16R17 or (ii) a group selected from (C3.12)cycloalkyl(C0.6)alkyl, hetero(C3.12)cycloalkyl(C0.6)alkyl, (C6.I2)aryl(C0.6)alkyl, hetero(C5.12)aryl(C0.6)alkyl, (C9_12)polycycloaryl(C0.6)alkyl and hetero(C8_12)polycycloaryl(C0.6)alkyl, wherein said cycloalkyl, heterocycloalkyl, aryl, heteroaryl, polycycloaryl or heteφolycycloaryl ring optionally is substituted by a group selected from -R18, -X5OR18, -X5SR18, -X5S(O)R18, -X5S(O)2R18, -X5C(0)R18, -X5C(O)OR18, -X5OC(O)R18, -X5NR18R19, -X5NR19C(O)R18, -X5NR19C(O)OR18, -X5C(0)NR18R19, -X5S(O)2NR18R19, -X5NR19C(0)NR18R19 or -X5NR19C(NR19)NR18R19, wherein X5, R14, R15, R16, R17, R18 and R19 are as defined above; wherein within R7 any alicyclic or aromatic ring system present may be substituted further by 1 to 5 radicals independently selected from (C,.6)alkyl, ( ^alkylidene, cyano, halo, halo-substituted (C,.4)alkyl, nitro, -X5NR14R14, -X5NR14C(O)OR14, -X5NR14C(0)NR14R14, -X5NR14C(NR14)NR14R14, -X5OR14, -X5SR14, -X5C(O)OR14, -X5C(0)NR14R14, -X5S(O)2NR14R14, -X5P(0)(OR1 )OR14, -X5OP(0)(OR14)OR14, -X5NR14C(O)R15, -X5S(O)R15, -X5S(O)2R15 and -X5C(O)R15, wherein X5, R14 and R15 are as defined above; and R8 at each occurrence independently is selected from (C,.6)alkyl, halo-substituted
(C,.4)alkyl, (C,.6)alkylidene, cyano, halo, halo-substituted (CM)alkyl, nitro, -X5NR14R14, -X5NR14C(0)OR14, -X5NR14C(O)NR14R14, -X5NR14C(NR14)NR14R14, -X5OR14, -X5SR14, -X5C(O)OR14, -X5C(O)NR14R14, -X5S(O)2NR14R14, -X5P(0)(OR14)OR14, -XOP(0)(OR14)OR14, -X5NR14C(O)R15, -X5S(O)R15, -X5S(0)2R15 and -X5C(O)R15, wherein X5 is a bond or (C,.6)alkylene, R14 at each occurrence independently is hydrogen, (C,.6)alkyl or halo-substituted (C,.3)alkyl and R15 (C,.6)alkyl or halo-substituted (C,.3)alkyl; and the -V-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers; and the pharmaceutically acceptable salts thereof.
In another particular embodiment, the present invention relates to a compound of Formula II:
Figure imgf000015_0001
in which:
A comprises a heteromonocyclic ring containing 5 to 6 ring member atoms or a fused heteropolycyclic ring system containing 8 to 14 ring member atoms, wherein each ring contains 5 to 7 ring member atoms, X1 is a ring member carbon atom and each ring member atom other than X1 is a carbon atom or a heteroatom, with the proviso that at least one ring member atom is a heteroatom; n is 0, 1, 2 or 3;
X1 is =C- or -CH-;
Xs is (C1.2)alkylene;
R1 is hydrogen, carboxy, oxalo, carbamoyl or -X6X7R20, wherein X6 is -C(O)-, -C(0)C(0)- or -S(0)2-, X7 is a bond, -O- or -NR21-, wherein R21 is hydrogen or (CJalkyl, and R20 is (i) (C,.6)alkyl optionally substituted by cyano, halo, nitro, -NR1 R14, -NR14C(0)OR14, -NR14C(O)NR14R14, -NR14C(NR14)NR14R14, -OR14, -SR14, -C(0)OR14, -C(0)NR14R14, -S(O)2NR14R14, -P(O)(OR14)OR14, -OP(0)(OR1 )OR14, -NR14C(0)R15, -S(0)R15, -S(0)2R15, -C(O)R15, -OR22, -SR22, -S(O)R22, -S(O)2R22, -C(0)R22, -C(O)OR22, -C(O)NR22R23, -NR22R23, -NR23C(O)R22, -NR23C(O)OR22,-NR23C(0)NR22R23 or -NR23C(NR23)NR R23, wherein R14 at each occurrence independently is hydrogen, (C,.6)alkyl or halo-substituted (C,.3)alky. , R15 is (C,.6)alkyl or halo-substituted (C,.3)alkyl, R22 is (C3.12)cycloalkyl(C0.6)alkyl, hetero(C3_12)cycloalkyl(C0.6)alkyl, (C6.,2)aryl(C0.6)alkyl, hetero(C5.12)aryl(C0.6)alkyl, (C9.12)bicycloaryl(C0.6)alkyl or hetero(C8.12)bicycloaryl(C0.6)alkyl and R23 at each occurrence independently is hydrogen or (C,.6)alkyl, or (ii) (C3.12)cycloalkyl(C0_6)alkyl, hetero(C3.,2)cycloalkyl(C0.6)alkyl, (C6.12)aryl(C0.6)alkyl, hetero(C5.12)aryl(C0.6)alkyl, (C9.12)bicycloaryl(C0.6)alkyl or hetero(C8.12)bicycloaryl(C0.6)alkyl or (iii) (C3.6)cycloalkyl(C0.6)alkyl, hetero(C3.6)cycloalkyl(C0.6)alkyl, phenyl (C0.6)alkyl or hetero(C5.6)aryl(C0.6)alkyl substituted by -X5OR24, -X5SR24, -X5S(0)R24, -X5S(0)2R24, -X5C(0)R24, -X5C(0)OR24, -X5C(O)NR24R25, -X^R^R25, -X5NR25C(O)R24,
-X5NR25C(0)OR24, -X5NR25C(0)NR24R25 or -X5NR25C(NR25)NR24R25, wherein X5 is a bond or (C,.6)alkylene, R24 is (C3.6)cycloalkyl(C0.6)alkyl, hetero(C3.6)cycloalkyl(C0.6)alkyl, phenyl(C0.6)alkyl or hetero(C5.6)aryl(C0.6)alkyl and R25 at each occurrence independently is hydrogen or (C,.6)alkyl; wherein within R1 any alicyclic or aromatic ring system present may be substituted further by 1 to 5 radicals independently selected from (C,.6)alkyl, (C,.6)alkylidene, cyano, halo, halo-substituted (C,.4)alkyl, nitro, -X5NR14R14, -X5NR14C(0)OR14, -X5NR14C(0)NR14R14, -X5NR14C(NR14)NR14R14, -X5OR14, -X5SR14, -X5C(0)OR14, -X5C(O)NR14R14, -X5S(O)2NR14R14, -X5P(0)(OR14)OR14, -X5OP(0)(OR14)OR14, -X5NR14C(0)R15, -X5S(O)R15, -X5S(O)2R15 and -X5C(O)R15, wherein X5, R14 and R15 are as defined above;
R2 is hydrogen or (C,.6)alkyl;
R3 is (i) (C,.6)alkyl optionally substituted with cyano, halo, nitro, -NR1 R14, -NR14C(0)OR14, -NR14C(O)NR14R14, -NR14C(NR14)NR14R14, -OR14, -SR14, -C(0)OR14, -C(O)NR14R14, -S(0)2NR14R14, -P(0)(OR14)OR14, -OP(0)(OR14)OR14, -NR14C(0)R15, -S(O)R15, -S(0)2R15, -C(O)R15, -OR16, -SR16, -S(O)R16, -S(O)2R16, -C(O)R16, -C(0)OR16, -OC(O)R16, -NR16R17, -NR17C(O)R16, -NRI7C(O)OR16, -C(O)NR16R17, -S(O)2NR16R17, -NRπC(0)NR16R17 or -NR17C(NRπ)NR16R17, wherein R14 at each occurrence independently is hydrogen, (C,.6)alkyl or halo-substituted (C,.3)alkyl, R15 is ( .6)alkyl or halo-substituted (C,.3)alkyl, R16 is (C3.12)cycloalkyl(C0.6)alkyl, hetero(C3.12)cycloalkyl(C0.6)alkyl, (C6.12)aryl(C0.6)alkyl, hetero(C5.12)aryl(C0.6)alkyl, (C9.12)polycycloaryl(C0.6)alkyl or hetero(C8.12)polycycloaryl(C0.6)alkyl and R17 is hydrogen or (C].6)alkyl, and wherein within R16 said cycloalkyl, heterocycloalkyl, aryl, heteroaryl, polycycloaryl or heteφolycycloaryl ring optionally is substituted by a group selected from -R18, -X5OR18, -X5SR18, -X5S(0)R18, -X5S(O)2R18, -X5C(0)R18, -X5C(O)OR18, -X5OC(O)R18, -X5NR18R19, -X5NR19C(0)R18, -X5NR19C(0)OR18, -X5C(O)NRI8R19, -X5S(O)2NR18R19, -X5NR19C(0)NR18R19 or
-X5NR19C(NR19)NR18R19, wherein X5 is as defined above, R18 is hydrogen or (C,.6)alkyl and R19 is (C3.I2)cycloalkyl(C0.6)alkyl, hetero(C3_12)cycloalkyl(C0.6)alkyl, (C6.12)aryl(C0.6)alkyl, hetero(C5.12)aryl(C0.6)alkyl, (C9.12)polycycloaryl(C0.6)alkyl or hetero(C8.12)polycycloaryl(C0.6)alkyl, or (ii) a group selected from (C3.,2)cycloalkyl(C0.6)alkyl, hetero(C3.12)cycloalkyl(C0.6)alkyl, (C6.12)aryl(C0.6)alkyl, hetero(C5.12)aryl(C0.6)alkyl, (C9.12)polycycloaryl(C0.6)alkyl and hetero(C8.,2)polycycloaryl(C0.6)alkyl, wherein said cycloalkyl, heterocycloalkyl, aryl, heteroaryl, polycycloaryl or heteφolycycloaryl ring optionally is substituted by a group selected from -R18, -X5OR18, -X5SR18, -X5S(O)R18, -X5S(0)2R18, -X5C(O)R18, -X5C(0)OR18, -X5OC(O)R18, -X5NR18R19, -X5NR19C(0)R18, -X5NR19C(0)OR18, -X5C(0)NR18R19, -X5S(0)2NR18R19, -X5NR19C(0)NR18R19 or -X5NR19C(NR19)NR18R19, wherein X5, R18 and R19 are as defined above; wherein within R12 and/or R13 any alicyclic or aromatic ring system present may be substituted further by 1 to 5 radicals independently selected from (C,.6)alkyl, (Cj.6)alkylidene, cyano, halo, halo-substituted (C^alkyl, nitro, -X5NR14R14, -X5NR,4C(0)OR14, -X5NR14C(0)NR14R14, -X5NR14C(NR14)NR14R14, -X5OR14, -X5SR14, -X5C(0)OR14, -X5C(O)NR14R14, -X5S(0)2NR14R14, -X5P(O)(OR14)OR14, -X5OP(0)(OR14)OR14, -X5NR14C(O)R15, -X5S(O)R15, -X5S(O)2R15 and -X5C(O)R15, wherein X5, R14 and R15 are as defined above, or
R3 and R4 taken together with the carbon atom to which both R3 and R4 are attached form (C3.8)cycloalkylene or (C3.8)heterocycloalkylene, wherein said cycloalkylene or heterocycloalkylene is optionally substituted with 1 to 3 radicals independently selected from (C,.6)alkyl, (C,.6)alkylidene, cyano, halo, halo-substituted (C,.4)alkyl, nitro, -X5NR,4C(0)OR14, -X5NR14C(0)NR14R14, -X5NR14C(NRI4)NR14R14, -X5OR14, -X5SR14, -X5C(O)OR14, -X5C(O)NR14R14, -X5S(0)2NR,4R14, -X5P(0)(OR14)OR14, -XOP(O)(OR14)OR14, -X5NR14C(0)R15, -X5S(O)R15, -X5S(O)2R15 and -X5C(0)R15, wherein X5, R14 and R15 are as defined above;
R4 is hydrogen, (C,.6)alkyl or as defined above; R5 is hydrogen and R6 is hydroxy or R5 and R6 together form oxo;
R7 is a group selected from cyano, halo, nitro, -R29, -X5NR29R30, -X5NR30C(O)OR29, -X5NR30C(O)NR29R30, -X5NR30C(NR3O)NR29R30, -X5OR29, -X5SR29, -X5C(O)OR29, -X5C(O)NR29R30, -X5S(O)2NR29R30, -X5P(O)(OR30)OR29, -X5OP(O)(OR29)OR29, -X5NR30C(O)R31, -X5S(O)R31, -X5S(O)2R31 and -X5C(0)R31, wherein X5 is as defined above, R29 is hydrogen or -R31, R30 at each occurrence is hydrogen or ( ^alkyl and R31 is (C].6)alkyl, (C3.12)cycloalkyl(C0.6)alkyl, hetero(C3.12)cycloalkyl(C0.6)alkyl, (CM2)aryl(C0.6)alkyl or hetero(C5.!2)aryl(C0.6)alkyl, wherein within R7 any alicyclic or aromatic ring system present may be substituted further by 1 to 5 radicals independently selected from (C,.6)alkyl, (C,_6)alkylidene, cyano, halo, halo-substituted (C,.4)alkyl, nitro, -X5NR14R14, -X5NR14C(0)OR14, -X5NR14C(0)NR14R14, -X5NR1 C(NR14)NR14R14; -X5OR14, -X5SR14, -X5C(O)OR14, -X5C(0)NR14R14, -X5S(O)2NR14R14, -X5P(0)(OR14)OR14, -X5OP(0)(OR14)OR14, -X5NR14C(O)R15, -X5S(O)R15, -X5S(O)2R15 and -X5C(O)R15, wherein X5, R14 and R15 are as defined above; and
R8 at each occurrence independently is selected from (Cμ6)alkyl, (C,.6)alkylidene, cyano, halo, halo-substituted (C,_4)alkyl, nitro, -X5NR14R14, -X5NR14C(0)OR14, -X5NR14C(0)NR14R14, -X5NR1 C(NR1 )NR14R14, -X5OR14, -X5SR14, -X5C(0)OR14, -X5C(0)NR14R14, -X5S(0)2NR14R14, -X5P(0)(OR14)OR14, -X5OP(0)(OR14)OR14,
-X5NR14C(O)R15, -X5S(O)R15, -X5S(0)2R15 and -X5C(0)R15, wherein X5, R14 and R15 are as defined above;
R9 is hydrogen or (C,.6)alkyl; and
R32 is (C,.8)alkyl, (C3.,2)cycloalkyl(C0.6)alkyl, hetero(C3.12)cycloalkyl(C0.6)alkyl, (C6.12)aryl(C0.6)alkyl, hetero(C5.12)aryl(C0.6)alkyl, (C9.12)polycycloaryl(C0.6)alkyl or hetero(C8.12)polycycloaryl(C0.6)alkyl, wherein within R30any alicyclic or aromatic ring system present may be substituted further by 1 to 5 radicals independently selected from (C,.6)alkyl, (C,.6)alkylidene, cyano, halo, halo-substituted (C,.4)alkyl, nitro, -X5NR14R14, -X5NR14C(0)OR14, -X5NR14C(O)NR14R14, -X5NR14C(NR14)NR14R14, -X5OR14, -X5SR14, -X5C(O)OR14, -X5C(O)NR14R14, -X5S(O)2NR14R14, -X5P(0)(OR14)OR14, -X5OP(O)(OR14)OR14,
-X5NR14C(O)R15, -X5S(O)R15, -X5S(O)2R15 and -X5C(0)R15, wherein X5, R14 and R15 are as defined above; and the -V-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers; and the pharmaceutically acceptable salts thereof.
In another particular embodiment, the present invention relates to a pharmaceutical composition which contains a compound of Formula I or II, or a N-oxide derivative, prodrug derivative, individual isomer or mixture of isomers, or a pharmaceutically acceptable salt thereof in admixture with one or more suitable excipients.
In another particular embodiment, the present invention relates to method of treating a disease in an animal in which inhibition of a cysteine protease can prevent, inhibit or ameliorate the pathology and/or symptomatology of the disease, which method comprises administering to the animal a therapeutically effective amount of compound of Formula I or II or a -V-oxide derivative, prodrug derivative, individual isomer or mixture of isomers or a pharmaceutically acceptable salt thereof.
In another particular embodiment, the present invention relates to processes for preparing compounds of Formula I and II and the -V-oxide derivatives, prodrug derivative, protected derivatives, individual isomers and mixtures of isomers, and the pharmaceutically acceptable salts thereof as set forth in "Detailed Description of the Invention".
In another particular embodiment, the present invention relates to protease inhibitors of Formula III:
Figure imgf000019_0001
in which: A comprises a heteromonocyclic radical containing 5 to 6 annular atoms or a fused heteropolycyclic radical containing 8 to 14 annular atoms, wherein each ring contains 5 to 7 annular atoms, X1 is an annular carbon atom and each annular atom other than X1 optionally is a heteroatom, with the proviso that when A is a heteromonocyclic radical containing 5 annular atoms, no more than two of the annular atoms comprising the ring are heteroatoms;
X1 is selected from =C- and -CH-;
X2 is a bond or a divalent group of Formula (a) or (b):
Figure imgf000019_0002
(a) (b) wherein:
X3 and X5 independently are -C(O)- or -S(O)2-,
X4 is -CHR11-, -CH2CHRπ- or -CHR"CH2- and X6 is -CHR12-, -CH2CHR12- or -CHR12CH2- wherein:
R11 and R12 are independently (i) (C^alkyl or halo-substituted(C,.6)alkyl optionally substituted with -OR13, -SR13, -S(0)R13, -S(0)2R13, -C(O)R13, -C(0)OR13, -NR13R14, -NR14C(0)OR13, -C(0)NR13R14, -S(0)2NR13R14, -NR14C(0)NR13R14 or -NR14C(NR14)NR13R14, wherein R13 is hydrogen, (C,.6)alkyl, (C3.12)cycloalkyl(C0.3)alkyl, hetero(C3.]2)cycloalkyl(C0_3)alkyl, (C6.12)aryl(C0.3)alkyl or hetero(C5.12)aryl(C0_3)alkyl and R14 is hydrogen or (C,.5)alkyl, or
(ii) (C3.12)cycloalkyl(C0.3)alkyl, hetero(C3.12)cycloalkyl(C0.3)alkyl, (C6.12)aryl(C0.3)alkyl, hetero(C5.12)aryl(C0.3)alkyl, (C9.12)polycycloaryl(C0.3)alkyl or hetero(C8.12)polycycloaryl(C0.3)alkyl optionally substituted with -R15, -X7OR15, -X7SR15, -S(O)R15, -S(0)2R15, -C(O)R15, -C(0)OR15, -X7NR15R16, -X7NR16C(O)OR15, -C(0)NR15R16, -S(0)2NR15R16, -NR16C(0)NR15R16 or
-NR16C(NR16)NR15R16, wherein X7 is a bond or methylene, R15 is (C3.12)cycloalkyl(C0_3)alkyl, hetero(C3.12)cycloalkyl(C0.3)alkyl, (C6.12)aryl(C0.3)alkyl, hetero(C5.I2)aryl(C0.3)alkyl, (C9.12)polycycloaryl(C0.3)alkyl or hetero(C8.12)polycycloaryl(C0.3)alkyl and R16 is hydrogen or (C,.6)alkyl, or (iii) together with R9 or R10 , respectively, when X4 is -CHR11- and/or X6 is
-CHR12-, forms trimethylene, tetramethylene or phenylene-l,2-dimethylene, optionally substituted with hydroxy or oxo; wherein any 1 to 3 annular atoms of any aromatic ring with available valences comprising Ru and/or R12 are optionally independently substituted with halo, nitro, cyano, (C,.6)alkyl, halo-substituted C^alkyl, -OR17, -C(0)R17, -C(0)OR17, -C(0)NR17R17,
-S(0)2NR17R17, -X7NR17R17, -X7NR17C(0)OR17, -X7NR17C(0)NR17R17 or -X7NR17C(NR17)NR17R17, wherein X7 is as defined above and each R17 independently is hydrogen or (C].6)alkyl; and
R9 and R10 are independently hydrogen, (C,.6)alkyl or as defined above; R1 is hydrogen or -X8X9R18, wherein X8 is -C(O)- or -S(0)2-, X9 is a bond, -O- or
-NR19-, wherein R19 is hydrogen or (C,.6)alkyl, and R18 is (i) (C,_6)alkyl or halo-substituted(C,.6)alkyl optionally substituted with -OR13, -SR13, -S(O)R13, -S(0)2R13, -C(O)R13, -C(0)OR13, -NR13R14, -NR14C(O)OR13, -C(0)NR13R14, -S(O)2NR13R14, -NR14C(0)NR13R14 or -NR14C(NR14)NR13R14, wherein R13 and R14 are as defined above, or (ii) (C3.12)cycloalkyl(C0.6)alkyl, hetero(C3.12)cycloalkyl(C0.6)alkyl, (C6.12)aryl(C0.6)alkyl, diphenyl(C0.6)alkyl, hetero(C5.12)aryl(C0.6)alkyl, dihetero(C5.6)aryl(C0.6)alkyl, (C9.12)polycycloaryl(C0.6)alkyl or hetero(C8.12)polycycloaryl(C0.6)alkyl optionally substituted with -R15, -X7OR15, -X7SR15, -S(O)R15, -S(O)2R15, -C(O)R15, -C(0)OR15, -X7NR15R16, -X7NR16C(0)OR15, -C(0)NRI5R16, -S(O)2NR15R16, -NR16C(O)NR15R16 or -NR16C(NR16)NR15R16, wherein X7, R15 and R16 are as defined above; wherein any 1 to 3 annular atoms of any aromatic ring with available valences comprising R1 optionally independently are substituted with halo, nitro, cyano, (C,.6)alkyl, halo-substituted(C,.6)alkyl, -OR17, -C(0)R17, -C(O)OR17, -C(O)NR17R17, -S(0)2NR17R17, -X7NR17R17, -X7NR17C(0)OR17, -X7NR17C(O)NR17R17 or -X7NR17C(NR17)NR17R17, wherein X7 and R17 are as defined above;
R2 is hydrogen or (C,_6)alkyl; R3 is phenyl(C2.3)alkyl, hetero(C5.6)aryl(C2.3)alkyl, (C5.6)cycloalkyl(C2.3)alkyl or hetero(C5.6)cycloalkyl(C2.3)alkyl, wherein any 1 to 3 annular atoms of any aromatic ring with available valences comprising R3 optionally independently are substituted with halo, nitro, cyano, (C,.6)alkyl, halo-substituted(C1.6)alkyl, -OR17, -C(0)R17, -C(O)OR17, -C(0)NR17R17, -S(O)2NR17R17, -X7NR17Rπ, -X7NR17C(0)OR17, -X7NR17C(O)NR17R17 or -X7NR17C(NR17)NR17R17, wherein X7 and R17 are as defined above, and R4 is hydrogen or R3 and R4 are both methyl, ethyl or propyl or together with the carbon atom to which both R3 and R4 are attached form cyclopropylene, cyclobutylene or cyclopentylene;
R5 is hydrogen and R6 is hydroxy or R5 and R6 together form oxo; R7 is halo, nitro, -R20, -OR20, -C(0)R20, -C(0)OR20, -S(O)2NR20R21, -C(O)NR20R21 or -C(0)NR22CHR23C(0)OR20 and bonded to any annular carbon atom with a free valence comprising A, wherein:
R20 is hydrogen or R18, wherein R18 is as defined above; R21 is hydrogen or (C,.6)alkyl;
R22 is hydrogen, (C,.6)alkyl or together with R23 forms trimethylene or phenylene-l,2-dimethylene, optionally substituted with hydroxy or oxo; and
R23 is as defined above or is (i) (C,.6)alkyl or halo-substituted(C,.6)alkyl optionally substituted with -OR13, -SR13, -S(O)R13, -S(O)2R13, -C(O)R13, -C(0)OR13, -NR13R14, -NR14C(O)OR13, -C(0)NR13R14, -S(O)2NR13R14, -NR,4C(O)NR13R14 or -NR14C(NR1 )NR13R14, wherein R13 and R14 are as defined above, or (ii) (C3_10)cycloalkyl(C0.3)alkyl, hetero(C3.10)cycloalkyl(C0.3)alkyl, (C6.12)aryl(C0.3)alkyl, hetero(C5.12)aryl(C0.3)alkyl, (C9.12)polycycloaryl(C0.3)alkyl or hetero(C8.12)polycycloaryl(C0.3)alkyl optionally substituted with -R15, -X7OR15, -X7SR15, -S(O)R15, -S(O)2R15, -C(O)R15, -C(0)OR15, -X7NR15R16, -X7NR16C(0)OR15, -C(O)NR15R16, -S(O)2NR15R16, -NR16C(0)NR15R16 or -NR16C(NR16)NR15R16, wherein X7, R15 and R16 are as defined above; wherein any 1 to 3 annular atoms of any aromatic ring with available valences comprising R20 and/or R21 optionally independently are substituted with halo, nitro, cyano, (C,.6)alkyl, halo-substituted(C,_6)alkyl, -OR17,
-C(O)R17, -C(O)OR17, -C(0)NR17R17, -S(0)2NR17R17, -X7NR17R17, -X7NR17C(0)OR17, -X7NR17C(0)NR17R17 or -X7NR17C(NR17)NR17R17, wherein X7 and R17 are as defined above; and
R8 is hydrogen, halo, hydroxy, formyl, carboxy, carbamoyl, sulfamoyl or (C,.6)alkyl and bonded to any annular carbon atom with a free valence comprising A; and the -V-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers; and the pharmaceutically acceptable salts thereof.
DETAILED DESCRIPTION OF THE INVENTION
Definitions: Unless otherwise stated, the following terms used in the specification and claims are defined for the puφoses of this Application and have the meanings given this Section:
"Alicyclic" means a moiety characterized by arrangement of the carbon atoms in closed non-aromatic ring structures having properties resembling those of aliphatics and may be saturated or partially unsaturated with two or more double or triple bonds. "Aliphatic" means a moiety characterized by straight or branched chain arrangement of the constituent carbon atoms and may be saturated or partially unsaturated with two or more double or triple bonds.
"Alkenyl" means alkyl, as defined in this Application, provided that the radical is comprised of at least one double bond. Hence, optionally substituted (C2.6)alkenyl as used in this Application to define R32 includes 2-bromovinyl (-CHCHBr), buta-l,3-dienyl (-CHCH-CHCH2), 2-chloro-l-methylpropenyl (-C(CH3)CC1-CH3), 2-chlorovinyl (-CHCHC1), 4-isopropenyl (-C(CH3)CH2), 1-methylpropenyl (-C(CH3)CH-CH3), 2-methylpropenyl (-CHC(CH3)2), 2-nitrovinyl (-CHCHN02), propenyl (-CHCH-CH3), 2-trifluoromethylvinyl (-CHCH-CF3), trifluorovinyl (-CFCF2), vinyl (-CHCH2), and the like).
"Alkoxy" means the radical -OR, wherein R is alkyl as defined in this Application, having the number of carbon atoms indicated (e.g., (C,.4)alkoxy includes the radicals methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, isobutoxy, tert-butoxy, vinyloxy, allyloxy, 1-propenyloxy, isopropenyloxy, 1 -butenyloxy, 2-butenyloxy, 3-butenyloxy, 2-methylallyloxy, ethynyloxy, 1-propynyloxy, 2-propynyloxy, and the like).
"Alkyl" represented by itself means a straight or branched, saturated or unsaturated, aliphatic radical having the number of carbon atoms indicated (e.g. (C,.6)alkyl includes methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methylallyl, ethynyl, 1-propynyl, 2-propynyl, and the like). Alkyl represented along with another radical (e.g. as in arylalkyl) means a straight or branched, saturated or unsaturated aliphatic divalent radical having the number of atoms indicated or when no atoms are indicated means a bond (e.g. (C6.12)aryl(C0.6)alkyl includes phenyl, benzyl, phenethyl, 1-phenylethyl 3-phenylpropyl, and the like). "Alkylene", unless indicated otherwise, means a straight or branched, saturated or unsaturated, aliphatic, divalent radical having the number of carbon atoms indicated (e.g. (C,.6)alkylene includes methylene (-CH2-), ethylene (-CH2CH2-), trimethylene (-CH2CH2CH2-), 2-methyltrimethylene (-CH2CH(CH3)CH2-), tetramethylene (-CH2CH2CH2CH2-), 2-butenylene (-CH2CH=CHCH2-), 2-methyltetramethylene (-CH2CH(CH3)CH2CH2-), pentamethylene (-CH2CH2CH2CH2CH2-) and the like). For example, a group of Formula (a), wherein Ru is hydrogen and R12 taken together with R9 forms optionally substituted trimethylene is depicted by the following illustration:
Figure imgf000023_0001
in which R is an optional hydroxy or oxo group and X3 and R1 are as defined in the Summary of the Invention for Formulae I and II.
"Alkylidene" means a straight or branched saturated or unsaturated, aliphatic, divalent radical having the number of carbon atoms indicated (e.g. (C,.6)alkylidene includes methylene (CH2), ethylidene (CHCH3), isopropylidene (C(CH3)2), propylidene (CHCH2CH3), allylidene (CHCHCH2), and the like).
"Amino" means the radical -NH2. Unless indicated otherwise, the compounds of the invention containing amino moieties include protected derivatives thereof. Suitable protecting groups for amino moieties include acetyl, tert-butoxycarbonyl, benzyloxycarbonyl, and the like. "Animal" includes humans, non-human mammals (e.g. dogs, cats, rabbits, cattle, horses, sheep, goats, swine, deer, or the like) and non-mammals (e.g. birds, or the like).
"Aryl" means a monocyclic or bicyclic ring assembly (fused or linked by a single bond) containing the total number of ring carbon atoms indicated, wherein each ring is comprised of 6 ring carbon atoms and is aromatic or when fused with a second ring forms an aromatic ring assembly. For example,(C6_12)aryl as used in this Application to define R1 includes phenyl, naphthyl and biphenylyl.
"Aromatic" means a moiety wherein the constituent atoms make up an unsaturated ring system, all atoms in the ring system are sp2 hybridized and the total number of pi electrons is equal to 4n + 2. "Carbamoyl" means the radical -C(O)NH2. Unless indicated otherwise, the compounds of the invention containing carbamoyl moieties include protected derivatives thereof. Suitable protecting groups for carbamoyl moieties include acetyl, tert-butoxycarbonyl, benzyloxycarbonyl, and the like and both the unprotected and protected derivatives fall within the scope of the invention. "Carboxy" means the radical -C(O)OH. Unless indicated otherwise, the compounds of the invention containing carboxy moieties include protected derivatives thereof. Suitable protecting groups for carboxy moieties include benzyl, tert-butyl, and the like. For example, a compound of Formula I wherein R7 contains a carboxy moiety may exist as either the unprotected or a protected derivative, e.g. wherein R7 is methoxycarbonyl, and both the unprotected and protected derivatives fall within the scope of the invention.
"Cycloalkyl" means a saturated or partially unsaturated, monocyclic ring, bicyclic ring assembly (directly linked by a single bond or fused) or bridged polycyclic ring assembly containing the number of ring member carbon atoms indicated, and any carbocyclic ketone, thioketone or iminoketone derivative thereof (e.g. (C3.12)cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, 2,5-cyclohexadienyl, bicyclohexylyl, cyclopentylcyclohexyl, bicyclo[2.2.2]octyl, adamantan- 1 -yl, decahydronaphthalenyl, oxocyclohexyl, dioxocyclohexyl, thiocyclohexyl, 2-oxobicyclo[2.2.1]hept-l-yl, and the like). "Cycloalkylene" means a saturated or partially unsaturated, monocyclic ring or bridged polycyclic ring assembly containing the number of annular carbon atoms indicated, and any carbocyclic ketone, thioketone or iminoketone derivative thereof. For example, the instance wherein R3 and R4 together with the carbon atom to which both R3 and R4 are attached form (C3.8)cycloalkylene" includes, but is not limited to, the following:
Figure imgf000025_0001
in which R2, R5 and R6 are as defined in the Summary of the Invention, and any substituted derivative thereof.
"Disease" specifically includes any unhealthy condition of an animal or part thereof and includes an unhealthy condition which may be caused by, or incident to, medical or veterinary therapy applied to that animal, i.e., the "side effects" of such therapy.
"Fused heteropolycyclic ring system" means a saturated, partially saturated or aromatic moiety containing two or more rings, wherein at least two ring member atoms of one ring are common to a second ring containing the number of ring member atoms indicated in which at least one of the ring member atoms is a heteroatom and any carbocyclic ketone, thioketone, iminoketone or substituted derivative thereof . For example, the term "a fused heteropolycyclic radical containing 8 to 14 ring member atoms" as used in this Application to define A may include acridinyl, benzofuryl, benzooxazolyl, benzothiazolyl, carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, indazolyl, indolinyl, indolyl, indolizinyl, isobenzofuryl, isochromenyl, isochromanyl, isoindolinyl, isoquinolyl, naphthyridinyl, perimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolizinyl, quinazolinyl, quinolizinyl, quinolyl, quinoxalinyl, quinuclidinyl, xanthenyl, and the like.
"Guanidino" means the radical -NHC(NH)NH2. Unless indicated otherwise, the compounds of the invention containing guanidino moieties include protected derivatives thereof. Suitable protecting groups for amino moieties include acetyl, tert-butoxycarbonyl, benzyloxycarbonyl, and the like and both the unprotected and protected derivatives fall within the scope of the invention.
"Halo" means fluoro, chloro, bromo or iodo.
"Halo-substituted alkyl", as a group or part of a group, means "alkyl" substituted by one or more "halo" atoms, as such terms are defined in this Application. Halo-substituted alkyl includes haloalkyl, dihaloalkyl, trihaloalkyl, perhaloalkyl and the like (e.g. halo-substituted (C,.3)alkyl includes chloromethyl, dicloromefhyl, difluoromethyl, trifluromethyl, 2,2,2-trifluoroethyl, perfluoroethyl, 2,2,2-trifluoro-l,l-dichloroethyl, and the like).
"Heteroaryl" means aryl, as defined herein, provided that one or more of the ring member carbon atoms indicated, is replaced by heteroatom moiety selected from -N, -NR-, -O- or -S-, wherein R is hydrogen, (C,.6)alkyl or a protecting group, and each ring contained therein is comprised of 5 to 6 ring member atoms. For example, hetero(C5.12)aryl as used in this Application includes benzofuryl, benzooxazolyl, benzothiazolyl, [2,4']bipyridinylyl, carbazolyl, carbolinyl, chromenyl, cinnolinyl, furazanyl, furyl, imidazolyl, indazolyl, indolyl, indolizinyl, isobenzofuryl, isochromenyl, isooxazolyl, isoquinolyl, isothiazolyl, naphthyridinyl, oxazolyl, perimidinyl, 2-phenylpyridyl, phthalazinyl, pteridinyl, purinyl, pyrazinyl, pyradazinyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolizinyl, pyrrolidinyl, pyrrolyl, pyranyl, quinazolinyl, quinolizinyl, quinolyl, quinoxalinyl, tetrazolyl, thiazolyl, 4-thiazol-4-ylphenyl, thienyl, xanthenyl, and the like.
"Heteroatom moiety" includes -N, -NR-, -0-, -S- or -S(O)2-, wherein R is hydrogen, (C,.6)alkyl or a protecting group. "Heterocycloalkyl" means cycloalkyl, as defined herein, provided that one or more of the ring member carbon atoms indicated is replaced by heteroatom moiety selected from -N, -NR-, -O- or -S-, wherein R is hydrogen, (C1.6)alkyl or a protecting group, and any carbocyclic ketone, thioketone or iminoketone derivative thereof (e.g. the term hetero(C5.ι2)cycloalkyl includes [l,4']bipiperidinylyl, dihydrooxazolyl, moφholinyl, l-moφholin-4-y -piperidinyl, piperazinyl, piperidyl, pirazolidinyl, pirazolinyl, pyrrolinyl, pyrrolidinyl, quinuclidinyl, and the like). Suitable protecting groups include tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, 4-methoxybenzyl, 2-nitrobenzyl, and the like. For example, a compound of Formula I wherein R1 is piperidin-4-ylcarbonyl may exist as either the unprotected or a protected derivative, e.g. wherein R1 is l-tert-butoxycarbonylpiperidin-4-ylcarbonyl, and both the unprotected and protected derivatives fall within the scope of the invention.
"Heterocycloalkylene" means cycloalkylene, as defined in this Application, provided that one or more of the ring member carbon atoms indicated, is replaced by heteroatom moiety selected from -N, -NR-, -0-, -S- or -S(0)2-, wherein R is hydrogen or (C,_6)alkyl. For example, the instance wherein R3 and R4 together with the carbon atom to which both R3 and R4 are attached form hetero(C3.8)cycloalkylene" includes, but is not limited to, the following:
Figure imgf000027_0001
in which R is hydrogen, (C]_6)alkyl or a protecting group and R2 is as defined in the Summary of the Invention, and any substituted derivative thereof.
"Heteromonocyclic" means a saturated, partially saturated or aromatic monocyclic radical containing the number of ring member atoms indicated in which at least one of the ring member atoms is a heteroatom and any carbocyclic ketone, thioketone, iminoketone or substituted derivative thereof. For example, the term "a heteromonocyclic containing 5 to 6 ring member atoms" as used in this Application to define A may include dihydrooxazolyl, furazanyl, furyl, imidazolyl, imidazolidinyl, imidazolinyl, isooxazolyl, isothiazolyl, thiazolyl, thienyl, moφholinyl, oxazolyl, piperazinyl, piperidinyl, pirazolidinyl, pirazolinyl, pyranyl, pyrazinyl, pyradazinyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, tetrazolyl, and the like. "Heteropolycycloaryl" means polycycloaryl, as defined herein, except one or more of the ring member carbon atoms indicated are replaced by a heteroatom moiety selected from -N, -NR-, -O- or -S-, wherein R is hydrogen, (C,_6)alkyl or a protecting group, and any carbocyclic ketone, thioketone or iminoketone derivative thereof.. For example, hetero(C8.12)polycycloaryl includes r,2,-dihydro-2H-[l,4']bipyridinylyl, chromanyl, imidazolinyl, indolinyl, isochromanyl, isoindolinyl, and the like.
"Hydroxy" means the radical -OH. Unless indicated otherwise, the compounds of the invention containing hydroxy radicals include protected derivatives thereof. Suitable protecting groups for hydroxy moieties include benzyl and the like and both the unprotected and protected derivatives fall within the scope of the invention. "Iminoketone derivative" means a derivative containing the moiety -C(NR)-, wherein R is hydrogen or (C,.6)alkyl. "Isomers" mean compounds of Formula I having identical molecular formulae but differ in the nature or sequence of bonding of their atoms or in the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are termed "stereoisomers". Stereoisomers that are not mirror images of one another are termed "diastereomers" and stereoisomers that are nonsuperimposable mirror images are termed "enantiomers" or sometimes "optical isomers". A carbon atom bonded to four nonidentical substituents is termed a "chiral center". A compound with one chiral center has two enantiomeric forms of opposite chirality is termed a "racemic mixture". A compound that has more than one chiral center has 2" 1 enantiomeric pairs, where n is the number of chiral centers. Compounds with more than one chiral center may exist as ether an individual diastereomer or as a mixture of diastereomers, termed a "diastereomeric mixture". When one chiral center is present a stereoisomer may be characterized by the absolute configuration of that chiral center. Absolute configuration refers to the arrangement in space of the substituents attached to the chiral center. Enantiomers are characterized by the absolute configuration of their chiral centers and described by the R- and S-sequencing rules of Cahn, Ingold and Prelog.
Conventions for stereochemical nomenclature, methods for the determination of stereochemistry and the separation of stereoisomers are well known in the art (e.g. see "Advanced Organic Chemistry", 3rd edition, March, Jerry, John Wiley & Sons, New York, 1985). It is understood that the names and illustration used in this Application to describe compounds of Formula I are meant to be encompassed all possible stereoisomers and any mixture, racemic or otherwise, thereof.
"Ketone derivative" means a derivative containing the moiety -C(O)-.
"Nitro" means the radical -NO2.
"Optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, the phrase "(C,.6)alkyl optionally substituted with cyano, halo, nitro," means that the alkyl group referred to may or may not be substituted in order to fall within the scope of the invention.
"Oxalo" means the radical -C(O)C(O)OH. "-V-oxide derivatives" means a derivatives of compound of Formula I in which nitrogens are in an oxidized state (i.e., 0~N) and which possess the desired pharmacological activity.
"Oxo" means the radical=0. "Pathology" of a disease means the essential nature, causes and development of the disease as well as the structural and functional changes that result from the disease processes.
"Pharmaceutically acceptable" means that which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable and includes that which is acceptable for veterinary use as well as human pharmaceutical use.
"Pharmaceutically acceptable salts" means salts of compounds of Formula I which are pharmaceutically acceptable, as defined above, and which possess the desired pharmacological activity. Such salts include acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or with organic acids such as acetic acid, propionic acid, hexanoic acid, heptanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartatic acid, citric acid, benzoic acid, o(4-hydroxybenzoyl)benzoic acid, cinnamic acid, madelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, /. -chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, /. -toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]oct-2-ene-l-carboxylic acid, glucoheptonic acid,
4,4'-methylenebis(3-hydroxy-2-ene-l-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid and the like.
Pharmaceutically acceptable salts also include base addition salts which may be formed when acidic protons present are capable of reacting with inorganic or organic bases. Acceptable inorganic bases include sodium hydroxide, sodium carbonate, potassium hydroxide, ammonium hydroxide, aluminum hydroxide and calcium hydroxide. Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, tromethamine, -V-methylglucamine and the like.
"Phenylene-l,2-dimethylene" means the divalent radical -CH2C6H4CH2-, wherein the methylene moieties are attached at the 1- and 2-positions of the phenylene moiety. For example, a group of Formula (a) in which R12 together with R9 forms optionally substituted phenylene- 1,2-dimethylene is illustrated by the following formula:
Figure imgf000030_0001
in which R is an optional hydroxy group and X3 and R1 are as defined in the Summary of the Invention for Formulae I and II.
"Polycycloaryl" means a bicyclic ring assembly (directly linked by a single bond or fused) containing the number of ring member carbon atoms indicated, wherein at least one, but not all, of the fused rings comprising the radical is aromatic, and any carbocyclic ketone, thioketone or iminoketone derivative thereof (e.g. (C9.12)polycycloaryl includes indanyl, indenyl, 1,2,3,4-tetrahydronaphthalenyl, 1,2-dihydronaphthalenyl, cyclohexylphenyl, phenylcyclohexyl, 2,4-dioxo-l,2,3,4-tetrahydronaphthalenyl, and the like). "Prodrug" means a compound which is convertible in vivo by metabolic means (e.g. by hydrolysis) to a compound of Formula (I). For example an ester of a compound of formula (I) containing a hydroxy group may be convertible by hydrolysis in vivo to the parent molecule. Alternatively an ester of a compound of Formula (I) containing a carboxy group may be convertible by hydrolysis in vivo to the parent molecule. Suitable esters of compounds of Formula (I) containing a hydroxy group, are for example acetates, citrates, lactates, tartrates, malonates, oxalates, salicylates, propionates, succinates, fumarates, maleates, methylene-bis-b-hydroxynaphthoates, gentisates, isethionates, di-/? -toluoyltartrates, methanesulphonates, ethanesulphonates, benzenesulphonates, p-toluenesulphonates, cyclohexylsulphamates and quinates. Suitable esters of compounds of Formula (I) containing a carboxy group, are for example those described by FJ.Leinweber, Drug Metab. Res., 1987, 18, page 379. An especially useful class of esters of compounds of Formula (I) containing a hydroxy group, may be formed from acid moieties selected from those described by Bundgaard et. al., J. Med. Chem., 1989, 32 , page 2503-2507, and include substituted (aminomethyl)-benzoates, for example, dialkylamino-methylbenzoates in which the two alkyl groups may be joined together and/or interrupted by an oxygen atom or by an optionally substituted nitrogen atom, e.g. an alkylated nitrogen atom, more especially (moφholino-methyl)benzoates, e.g. 3- or 4-(moφholinomethyl)-benzoates, and (4-alkylpiperazin-l-yl)benzoates, e.g. 3- or 4-(4-alkylpiperazin-l-yl)benzoates. A prodrug derivative of a compound of Formula I wherein R5 and R6 together are oxo is depicted by the following formula:
Figure imgf000031_0001
in which X13 is a bond, straight, saturated ethylene or (-CH2CR41R42CH2-), wherein R41 and R42 independently are hydrogen, halo or (C].3)alkyl or taken together form methylene. "Protected derivatives" means derivatives of compounds of Formula I in which a reactive site or sites are blocked with protecting groups. Protected derivatives of compounds of Formula I are useful in the preparation of compounds of Formula I or in themselves may be active cysteine protease inhibitors. For example, the compound of Formula I which is 25- amino--V-(2-benzooxazol-2-yl-2-hydroxy-lS-phenethylethyl)-3-cyclohexylpropionamide (i.e., Compound 55, described in Example 6, infra) may be protected with a suitable amino protecting group, e.g. 9H-fluoren-9-ylmefhoxycarbonyl, or a suitable hydroxy protecting group, e.g. tert- butyldimethylsilanyl, to provide, respectively, 9H-fluoren-9-ylmethyl lS-(2-benzooxazol-2-yl- 2-hydroxy-lS-phenethylethylcarbamoyl)-2-cyclohexylethylcarbamate (i.e., Compound 51, described in Example 4, infra) and 2S-amino--V-[2-benzooxazol-2-yl- 2-(tcrt-butyldimethylsilanyloxy)-lS-phenethylethyl]-3-cyclohexylpropionamide (i.e., Compound 56, described in Example 7, infra). A comprehensive list of suitable protecting groups can be found in T.W. Greene, Protecting Groups in Organic Synthesis, John Wiley & Sons, Inc. 1981.
"Ring member", as in fused heteropolycyclic ring system containing 8 to 14 ring member atoms, means that the atoms referred to are ring members of the fused heteropolycyclic radical, but not taking into account ring members of any substituents present. Thus, for example, a heteropolycyclic radical containing 8 ring member atoms includes benzooxaxol-2-yl, benzofur-2-yl, lH-indol-5-yl, benzothiazol-2-yl, and the like.
"Sulfamoyl" means the radical -S(0)2NΗ2. Unless indicated otherwise, the compounds of the invention containing sulfamoyl radicals include protected derivatives thereof. Suitable protecting groups for sulfamoyl radicals include acetyl, tert-butoxycarbonyl, benzyloxycarbonyl, and the like and both the unprotected and protected derivatives fall within the scope of the invention.
"Therapeutically effective amount" means that amount which, when administered to an animal for treating a disease, is sufficient to effect such treatment for the disease.
"Thioketone derivative" means a derivative containing the moiety -C(S)-. "Treatment" or "treating" means any administration of a compound of the present invention and includes:
(1) preventing the disease from occurring in an animal which may be predisposed to the disease but does not yet experience or display the pathology or symptomatology of the disease,
(2) inhibiting the disease in an animal that is experiencing or displaying the pathology or symptomatology of the diseased (i.e., arresting further development of the pathology and/or symptomatology), or
(3) ameliorating the disease in an animal that is experiencing or displaying the pathology or symptomatology of the diseased (i.e., reversing the pathology and/or symptomatology).
Specific Embodiments or the Invention: While the broadest definition of the invention is set forth in the Summary of the
Invention, certain aspects of the invention are preferred. A preferred aspect of the invention are compounds of Formula I in which X1 is =C-. In particular, the heteromonocyclic ring or fused heteropolycyclic ring system A is selected from 4,5-dihydrooxazol-2-yl, benzooxazol-2-yl, benzothiazol-2-yl and oxazol-2-yl, each substituted by a group R7 and optionally substituted with a group R8, particularly wherein R7 is hydrogen, halo, (C,.4)alkoxy, (CM)alkoxycarbonyl, nitro or phenyl and R8 at each occurrence independently is halo, (C,.4)alkoxy, (C,.4)alkoxycarbonyl, nitro or trifluoromethyl. The ring system A preferably is benzoxazol-2-yl substituted by a group R7 and optionally substituted with a group R8, particularly wherein R7 is hydrogen, halo, (C].4)alkoxy, (C,.4)alkoxycarbonyl or nitro and R8 at each occurrence independently is halo, (C,^)alkoxy, (C,.4)alkoxycarbonyl, nitro or trifluoromethyl.
X2 particularly represents a bond or a divalent group of Formula (a); particularly, wherein within Formula (a) X3 is -C(O)-, R9 represents hydrogen, R11 represents hydrogen or methyl, typically hydrogen, and R12 particularly represents (i) (C,.6)alkyl substituted with -SR14, -S(O)R14 or -S(0)2R14, wherein R14 is (C6.12)aryl(C0.6)alkyl or hetero(C5.12)aryl(C0.6)alkyl or (ii) (C3_12)cycloalkyl(C0.6)alkyl or (C6.12)aryl(C0.6)alkyl; wherein within R12 any alicyclic or aromatic ring system present may be substituted further by 1 to 5 radicals independently selected from (C,.6)alkyl, (C,_6)alkylidene, cyano, halo, halo-substituted (CM)alkyl, nitro, -X5NR14R14, -X5NR14C(0)OR14, -X5NR14C(0)NR14R14, -X5NR14C(NR14)NR14R14, -X5OR14, -X5SR14, -X5C(0)OR14, -X5C(O)NR14R14, -X5S(0)2NR14R14, -X5P(0)(OR14)OR14, -X5OP(0)(OR14)OR14, -X5NR14C(O)R15, -X5S(O)R15, -X5S(0)2R15 and -X5C(O)R15, wherein X5 is a bond or (C, _6)alkylene, R14 at each occurrence independently is hydrogen, (C,.6)alkyl or halo-substituted (C,.3)alkyl and R15 is (C,.6)alkyl or halo-substituted (C,_3)alkyl.
Further preferred, within Formula (a), R12 particularly represents a group having the following formula:
Figure imgf000033_0001
in which q is 0, 1, 2, 4 or 5 and R33 at each occurrence independently is selected from a group consisting of (CM)alkyl, cyano, halo, halo-substituted (C,.4)alkyl, nitro, -X5NR14R14, -X5OR14, -X5SR14, -X5C(0)NR14R14, -X5C(0)OR14, -X5S(0)R15, -X5S(0)2R15 and -X5C(O)R15, wherein X5 is a bond or (C].6)alkylene, R14 at each occurrence independently is hydrogen, (C1.3)alkyl or halo-substituted (C,.3)alkyl and R15 is (C,.3)alkyl or halo-substituted (C,.3)alkyl; more particularly in which q is 0, 1 or 2 and R33 at each occurrence independently is selected from a group consisting of (C^alkyl, cyano, halo, halo-substituted (C,.4)alkyl, nitro, -OR14, -SR14 and -C(O)OR14, wherein R14 independently is hydrogen, (C,.3)alkyl or halo-substituted (C,.3)alkyl; more particularly in which R33 at each occurrence independently is selected from a group consisting of (C,_4)alkyl, bromo, carboxy, chloro, cyano, difluoromethoxy, fluoro, iodo, methoxy, nitro, trifluoromethoxy, trifluoromethyl and trifluorosulfanyl.
Further preferred, within Formula (a), R12 particularly represents benzylsulfonylmethyl, 2-chlorobenzylsulfonylmethyl, 2-cyanobenzylsulfonylmethyl, 2-difluoromethoxybenzylsulfonylmethyl, 3,5-dimethylisooxazol-4-ylmethylsulfonylmethyl, 2-methoxybenzylsulfonylmethyl, 6-methylpyrid-2-ylmethylsulfonylmethyl, 2-nitrobenzylsulfonylmethyl, pyrid-2-ylmethylsulfonylmethyl, o-tolylmethylsulfonylmethyl or 2-trifluoromethylbenzylsulfonylmethyl. R1 particularly represents -X6X7R20, wherein X6 is -C(O)- or -S(O)2-, X7 is a bond, -O- or -NR21-, wherein R21 is hydrogen or (C,.6)alkyl, and R20 is (i) (C,.6)alkyl optionally substituted by -C(O)OR14 or (ii) (C3.I2)cycloalkyl(C0.6)alkyl, hetero(C3.12)cycloalkyl(C0.6)alkyl, (C6.12)aryl(C0.6)alkyl or hetero(C5.12)aryl(C0.6)alkyl or (iii) (C3.6)cycloalkyl(C0.6)alkyl, hetero(C3.6)cycloalkyl(C0_6)alkyl, phenyl(C0.6)alkyl or hetero(C5.6)aryl(C0.6)alkyl, wherein said cycloalkyl, heterocycloalkyl, phenyl or heteroaryl ring is substituted by -X5OR24,-X5C(0)R24, -X5C(0)OR24, -X5C(O)NR24R25, -X5NR24R25, -X5NR25C(0)R24, -X5NR25C(0)OR24, -X5NR25C(O)NR24R25 or -X5NR25C(NR25)NR24R25, wherein X5 is a bond or (C,.6)alkylene, R24 is (C3.6)cycloalkyl(C0.6)alkyl, hetero(C3.6)cycloalkyl(C0_6)alkyl, phenyl(C0.6)alkyl or hetero(C5.6)aryl(C0.6)alkyl and R25 is hydrogen or (C,_6)alkyl; wherein within R1 any alicyclic or aromatic ring system present may be substituted further by 1 to 5 substituents independently selected from (C^alkyl, halo, halo-substituted (C,.4)alkyl, -OR14 and -C(0)OR14 wherein R14 is hydrogen or (C,.6)alkyl, or when X2 is a divalent group of formula (a) then R1 may be, but is not limited to, hydrogen or oxalo.
R1 preferably is a group selected from acetyl, azetidin-3-ylcarbonyl, benzyloxycarbonyl, l-benzyloxycarbonylpiperidin-4-ylcarbonyl, benzylsulfonyl, bicyclo[2.2.2]hept-2-ylcarbonyl, bicyclo[2.2.1]hept-2-ylcarbonyl, tert-butoxycarbonyl, carboxyacetyl, 2-carboxypropionyl, 3-carboxypropionyl, 2-cyclohexylacetyl, 4-cyclohexylbutyryl, 2-cyclohexylethylsulfonyl, cyclohexylmethoxycarbonyl, 3-cyclohexylpropionyl, 2-cyclopentylethylsulfonyl, 3-cyclopentylpropionyl, di(2-methoxyethyl)carbamoyl, dimethylcarbamoyl, 6-hydroxypyrid-3-ylcarbonyl, lH-imidazol-4-ylcarbonyl, methoxycarbonyl, methylsulfonyl, 4-methylvaleryl, moφholin-4-ylcarbonyl, 2-moφholin-4-ylethylcarbonyl, naphth-1-ylacetyl, naphth-1-ylmethylcarbonyl, oxalo, 3-phenylpropionyl, piperazin-1-ylcarbonyl, piperidin-4-ylcarbonyl, pyrazin-2-ylcarbonyl, pyrid-3-ylcarbonyl, pyrid-4-ylcarbonyl, pyrid-3-ylaminocarbonyl, tetrahydropyran-4-ylcarbonyl and tetrahydropyran-4-yloxycarbonyl. R1 especially represents moφholin-4-ylcarbonyl, methoxycarbonyl, methylsulfonyl, piperidin-4-ylcarbonyl, pyrazin-2-ylcarbonyl pyrid-3-ylcarbonyl, pyrid-4-ylcarbonyl, tetrahydropyran-4-ylcarbonyl or tetrahydropyran-4-yloxycarbonyl. R2 typically is hydrogen.
R3 particularly represents hydrogen, (C,.6)alkyl (optionally substituted with cyano, halo, nitro, -SR26, -C(0)OR26, -C(O)NR26R26, -P(O)(OR26)OR26, -OP(0)(OR26)OR26, -S(0)R27, -S(0)2R27 or -C(O)R27, wherein R26 at each occurrence independently is hydrogen, (C,.6)alkyl, or halo-substituted (C,.3)alkyl and R27 is (C,.6)alkyl or halo-substituted (Cι_3)alkyl) or
(C6.12)aryl(C2.3)alkyl, wherein said aryl optionally is substituted further with 1 to 5 radicals independently selected from (C1.6)alkyl, (C,.6)alkylidene, cyano, halo, halo-substituted (C,.4)alkyl, nitro, -X5NR14C(O)OR14, -X5NR14C(O)NR14R14, -X5NR14C(NR14)NR14R14, -X5OR14, -X5SR14, -X5C(O)OR14, -X5C(0)NR14R14, -X5S(0)2NR14R14, -X5P(0)(OR14)OR14, -X5OP(0)(OR1 )OR14, -X5NR14C(0)R15, -X5S(0)R15, -X5S(0)2R15 and -X5C(0)R15, wherein X5 is a bond or (C,.6)alkylene, R14 at each occurrence independently is hydrogen, (C,.6)alkyl or halo-substituted (C,.3)alkyl and R15 is (C,.6)alkyl or halo-substituted (C,_3)alkyl, or R3 and R4 taken together with the carbon atom to which both R3 and R4 are attached form (C3.6)cycloalkylene. In particular, R3 may be selected from hydrogen, (CM)alkyl (e.g. methyl, ethyl, n-propyl, n-butyl), phenyl(C2.3)alkyl (e.g. phenethyl) or (CM)alkylsulfonyl(C2.4)alkyl (e.g. 2-methylsulfonylethyl) or R3 and R4 taken together with the carbon atom to which both R3 and R4 are attached form (C3.6)cycloalkylene (e.g. cyclobutylene or cyclohexylene). R3 preferably is (C,.4)alkyl.
R4 particularly represents hydrogen or R3 and R4 taken together with the carbon atom to which both R3 and R4 are attached form (C3.6)cycloalkylene (e.g. cyclobutylene or cyclohexylene).
R5 and R6 preferably together form oxo.
Compounds of Formula II are preferred in which: n is 0; X1 is =C- and the ring system A is selected from 4,5-dihydrooxazol-2-yl, benzooxazol-2-yl, benzothiazol-2-yl and oxazol-2-yl, each substituted by a group R7 and optionally substituted with a group R8, particularly wherein R7 is hydrogen, halo, (C,.4)al koxy, (C,.4)alkoxycarbonyl, nitro or phenyl and R8 at each occurrence independently is (CM)alkoxy, (C].4)alkoxycarbonyl, nitro or trifluoromethyl. Xs methylene or ethylene;
R1, R3 and R4 are as defined above;
R5 and R6 together form oxo; R9 is hydrogen; and
R32 is -X9R34, wherein X9 is methylene when X8 is methylene and X9 is a bond when X8 is ethylene, R34 is -CR35CHR36 or -CR37NR38, wherein R35 and R36 together with the atoms to which R35 and R36 are attached form (C2.6)alkenyl, (C5.12)cycloalkenyl, hetero(C5.12)cycloalkenyl, (C6.12)aryl, hetero(C6.]2)aryl, (C9.12)bicycloaryl or hetero(C8.12)bicycloaryl and R37 and R38 together with the atoms to which R37 and R38 are attached form hetero(C5.12)cycloalkenyl, hetero(C6.12)aryl or hetero(C8.12)bicycloaryl, wherein within R34 said cycloalkenyl, heterocycloalkenyl, aryl, heteroaryl, bicycloaryl or heterobicycloaryl may be substituted further by 1 to 5 radicals independently selected from (C,.6)alkyl, (C,.6)alkylidene, cyano, halo, halo-substituted (C,_4)alkyl, nitro, -X5NR14R14, -X5NR14C(0)OR14, -X5NR14C(0)NR14R14, -X5NR14C(NR14)NR14R14, -X5OR14, -X5SR14, -X5C(0)OR14, -X5C(0)NR14R14, -X5S(0)2NR14R14, -X5P(0)(OR14)OR14, -X5OP(0)(OR14)OR14, -X5NR14C(0)R15, -X5S(O)R15, -X5S(O)2R15 and -X5C(0)R15, wherein X5 is a bond or (C,.6)alkylene, R14 at each occurrence independently is hydrogen, (C,.6)alkyl or halo-substituted (C,.3)alkyl and R15 is (C,.6)alkyl or halo-substituted (C,.3)alkyl.
R34 particularly represents (C6.12)aryl or hetero(C5.12)aryl, each optionally substituted by 1 to 5 radicals selected from a group consisting of (C,.4)alkyl, cyano, halo, halo-substituted (C )alkyl, nitro, -X5NR14R14, -X5OR14, -X5SR14, -X5C(0)NR14R14, -X5C(0)OR14, -X5S(O)R15, -X5S(0)2R15 and -X5C(O)R15, wherein X5 is a bond or (C,.2)alkylene, R14 at each occurrence independently is hydrogen, (C1.3)alkyl or halo-substituted (C,.3)alkyl and R15 is
(C].3)alkyl or halo-substituted (C,.3)alkyl. R34 more preferably represents biphenyl, isooxazolyl, naphthyl, phenyl, pyridyl or thienyl, each optionally substituted by 1 to 5 radicals selected from a group consisting of (C]_4)alkyl, cyano, halo, halo-substituted (C,.4)alkyl, nitro, -X5NR14R14, -X5OR14, -X5SR14, -X5C(O)NR14R14, -X5C(O)OR14, -X5S(0)R15, -X5S(O)2R15 and -X5C(O)R15, wherein X4 is a bond or (C,.2)alkylene, R14 at each occurrence independently is hydrogen, (C,.3)alkyl or halo-substituted (C,_3)alkyl and R15 is (C,.3)alkyl or halo-substituted (C,.3)alkyl. R34 more preferably represents biphenyl-2-yl, 2,4-bistrifluoromethylphenyl, 2,5-bistrifluoromethylphenyl, 4-tert-butylphenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 2-bromo-5-fluorophenyl, 3-chloro-2-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 5-chlorothien-2-yl, 2-chloro-5-trifluoromethyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 1,5-dichlorophenyl, 2,6-dichlorophenyl, 3,4-dichlorophenyl, 2,3-difluorophenyl, 2,4-difluorophenyl, 3,4-difluorophenyl, 2-difluoromethoxyphenyl, 3-difluoromethoxyphenyl, 4-difluoromethoxyphenyl, 2,5-difluorophenyl, 2,6-difluorophenyl, 3,5-dimethylisooxaxol-4-yl, 3,5-dimethylphenyl, 2-fluoro-6-nitrophenyl, 2-fluorophenyl, 4-fluorophenyl, 2-fluoro- 3-trifluoromethylphenyl, 2-fluoro-4-trifluoromethylphenyl, 2-fluoro-5-trifluoromethylphenyl, 2-fluoro-6-trifluoromethylphenyl, 4-fluoro-2-trifluoromethylphenyl, 4-fluoro- 3-trifluoromethylphenyl, 2-iodophenyl, 3-iodophenyl, 4-iodophenyl, 2-methoxyphenyl, 4-methoxyphenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 6-methylpyrid-2-yl, 3-methyl-2-fluorophenyl, naphth-2-yl, 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 2,3,4,5, 6-pentafluorophenyl, phenyl, prop-2-en-l-yl, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, thien-3-yl, o-tolyl, 2-trifluoromethoxyphenyl, 3-trifluoromethoxyphenyl, 4-trifluoromethoxyphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-trifluoromethylsulfanylphenyl,
3-trifluoromethylsulfanylphenyl, 4-trifluoromethylsulfanylphenyl, 2,3,4-trifluorophenyl, 2,3,5-trifluorophenyl, 2,4,6-trifluorophenyl, 2,4,5-trifluorophenyl or 2,3,6-trifluorophenyl.
A preferred group of compounds of Formula II are those in which -X8S(0)2R32 represents a group having the following formula:
Figure imgf000037_0001
in which q is 0, 1, 2, 4 or 5 and R33 at each occurrence independently is selected from a group consisting of (C,.4)alkyl, cyano, halo, halo-substituted (C,.4)alkyl, nitro, -X5NR14R14, -X5OR14, -X5SR14, -X5C(0)NR14R14, -X5C(O)OR14, -X5S(0)R15, -X5S(O)2R15 and -X5C(0)R15, wherein X5 is a bond or (C,.2)alkylene, R14 at each occurrence independently is hydrogen, (C,.3)alkyl or halo-substituted (C].3)alkyl and R15 is (C,.3)alkyl or halo-substituted (C,.3)alkyl; more particularly in which q is 0, 1 or 2 and R33 at each occurrence independently is selected from a group consisting of (C^alkyl, cyano, halo, halo-substituted (C].4)alkyl, nitro, -OR14, -SR14 and -C(O)OR14, wherein R14 at each occurrence independently is hydrogen, (C,.3)alkyl or halo-substituted (C,.3)alkyl; more particularly in which R33 at each occurrence independently is selected from a group consisting of (C )alkyl, bromo, carboxy, chloro, cyano, difluoromethoxy, fluoro, iodo, methoxy, nitro, trifluoromethoxy, trifluoromethyl and trifluorosulfanyl. In particular, -X8S(0)2R32 represents benzylsulfonylmethyl, 2-chlorobenzylsulfonylmethyl, 2-cyanobenzylsulfonylmethyl, 2-difluoromethoxybenzylsulfonylmethyl, 3,5-dimethylisooxazol-4-ylmethylsulfonylmethyl, 2-methoxybenzylsulfonylmethyl, 6-methylpyrid-2-ylmethylsulfonylmethyl, 2-nitrobenzylsulfonylmethyl, pyrid-2-ylmethylsulfonylmethyl, ø-tolylmethylsulfonylmethyl or 2-trifluoromethy lbenzy lsulf ony lmethy 1.
Reference to the preferred embodiments set forth above is meant to include all combinations of particular and preferred groups.
Further preferred are compounds of Formula I selected from a group consisting of:
25-acetylamino--V-(lS-benzooxazol-2-ylcarbonyl)-3-phenylpropyl)- 3-cyclohexylpropionamide; and
-V-[lS-(lS-benzooxazol-2-ylcarbonyl-3-phenylpropylcarbamoyl)- 2-cyclohexylethylisonicotinamide; and the -V-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers; and the pharmaceutically acceptable salts thereof. Further preferred are compounds of Formula I selected from a group consisting of:
-V-[lR-(lS-benzooxazol-2-ylcarbonylbutylcarbamoyl)-2-benzylsulfonylethyl]moφholine- 4-carboxamide; methyl lR-(lS-benzooxazol-2-ylcarbonylbutylcarbamoyl)-2-benzylsulfonylethylcarbamate; -V-(lS-benzooxazol-2-ylcarbonylbutyl)-
2R-methylsulfonylamino-3-benzylsulfonylpropionamide;
-V-(lS-benzooxazol-2-ylcarbonylbutylcarbamoyl)-2R-(3,3-dimethylureido)- 3-(2-methoxybenzylsulfonyl)propionamide;
-V-[lR-(lS-benzooxazol-2-ylcarbonylbutylcarbamoyl)- 2-(2-difluoromethoxybenzylsulfonyl)ethyl]moφholine-4-carboxamide;
-V-[lR-(15-benzooxazol-2-ylcarbonylbutylcarbamoyl)- 2-(2-methoxybenzylsulfonyl)ethyl]moφholine-4-carboxamide;
-V-[lR-(lS-benzooxazol-2-ylcarbonylpentylcarbamoyl)- 2-benzylsulfonylethyl]moφholine-4-carboxamide; N-[lR-(lS-benzooxazol-2-ylcarbonylpentylcarbamoyl)-
2-(2-chlorobenzylsulfonyl)ethyl]moφholine-4-carboxamide; lR-( 1 S-benzooxazol-2-ylcarbonylpentylcarbamoyl)- -(2-difluoromethoxybenzylsulfonyl)ethylcarbamate;
-V-[lR-(lS-benzooxazol-2-ylcarbonylpentylcarbamoyl)- -(2-difluoromethoxybenzylsulfonyl)ethyl]moφholine-4-carboxyamide;
N-[ lR-( 1 S-benzooxazol-2-ylcarbonylpentylcarbamoyl)- -(3,5-dimethylisoxazol-4-ylmethylsulfonylethyl]isonicotinamide;
-V-[lR-(lS-benzooxazol-2-ylcarbonylpentylcarbamoyl)- -(2-nitrobenzylsulfonyl)ethyl]moφholine-4-carboxamide;
-V-[lR-(15-benzooxazol-2-ylcarbonylpentylcarbamoyl)- -pyridin-2-ylmethylsulfonylethyl]moφholine-4-carboxamide; -V-[ lR-(lS-benzooxazol-2-ylcarbonylpentylcarbamoyl)- -o-tolylmethylsulfonylethyl]moφholine-4-carboxamide; yV-[lR-(lS-benzooxazol-2-ylcarbonylpentylcarbamoyl)- -(2-trifluoromethylbenzylsulfonyl)ethyl]moφholine-4-carboxamide;
-V-[lR-(lS-benzooxazol-2-ylcarbonyl-3-phenylpropylcarbamoyl)- -benzylsulfonylethyl]nicotinamide;
N- [ lR-( 15-benzooxazol-2-ylcarbonyl-3-phenylpropylcarbamoyl)- -benzylsulfonylethyl]pyrazine-2-carboxamide;
-V-[lR-(15-benzooxazol-2-ylcarbonyl-3-phenylpropylcarbamoyl)- -(2-chlorobenzylsulfonyl)ethyl]moφholine-4-carboxamide; -V-[lR-(lS-benzooxazol-2-ylcarbonyl-3-phenylpropylcarbamoyl)- -(2-cyanobenzylsulfonyl)ethyl]isonicotinamide;
-V-[lR-(15-benzooxazol-2-ylcarbonyl-3-methylsulfonylpropylcarbamoyl)- -(2-difluoromethoxybenzylsulfonyl)ethyl]moφholine-4-carboxamide;
N- [ 1 R-( 15-benzooxazol-2-y lcarbony lpenty lcarbamoy 1)- -(2-difluoromethoxybenzylsulfonyl)ethyl]isonicotinamide;
N-[lR-( 1 S-benzooxazol-2-ylcarbonyl)-3-phenylpropylcarbamoyl)- -benzylsulfonylethyl]moφholine-4-carboxamide;
N- [ lR-( 1 S-benzooxazol-2-ylcarbonyl-3-phenylpropylcarbamoyl)- -(6-methylpyrid-2-ylmethylsulfonyl)ethyl]isonicotinamide; -V-[lR-(lS-benzooxazol-2-ylcarbonyl-3-phenylpropylcarbamoyl)- -(2-nitrobenzylsulfonyl)ethyl]moφholine-4-carboxamide;
-V-[lR-(15-benzooxazol-2-ylcarbonyl-3-phenylpropylcarbamoyl)- 2-pyrid-2-ylmethylsulfonylethyl]moφholine-4-carboxamide;
-V-[lR-(lS-benzooxazol-2-ylcarbonyl-3-phenylpropylcarbamoyl)- 2-o-tolylmethylsulfonylethyl]moφholine-4-carboxamide;
-V-[lR-(lS-benzooxazol-2-ylcarbonyl-3-phenylpropylcarbamoyl)- 2-(2-trifluoromethylbenzylsulfonyl)ethyl]tetrahydropyran-4-carboxamide; tetrahydropyran-4-yl lR-( 1 S-benzooxazol-2-ylcarbonyl-3-phenylpropylcarbamoyl)- 2-benzylsulfonylethylcarbamate; and
-V-[lR-(lS-benzooxazol-2-ylcarbonyl- 3-phenylpropylcarbamoyl)-2-(2-cyanobenzylsulfonyl)ethyl]piperidine-4-carboxamide; and the iV-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers; and the pharmaceutically acceptable salts thereof.
A preferred aspect of the invention are compounds of Formula I in which X1 is =C-. In particular, the heteromonocyclic ring or fused heteropolycyclic ring system A is selected from thien-2-yl, oxazol-2-yl, 4,5-dihydrooxazol-2-yl, fur-2-yl, lH-indol-5-yl, pyrid-2-yl, pyrid-3-yl, thiazol-2-yl, 1 -methyl- lH-imidazol-2-yl, l-benzyl-lH-imidazol-2-yl, benzooxazol-2-yl, benzofur-2-yl, benzothiazol-2-yl, lH-benzoimidazol-2-yl, l,l-dioxo-lH-lλ6-benzo[b]thien-2-yl, quinol-3-yl, [l,3]dioxolan-2-yl, naphtho[2,3-J]oxazol-2-yl, naphtho[l,2-<i]oxazol-2-yl and naphtho[2,l-c?]oxazol-2-yl, each substituted by a group R7 and optionally substituted with a group R8, particularly wherein R7 is halo, nitro, -R29, -OR29, -C(0)R20, -C(0)OR29, -S(O)2NR29R30, -C(O)NR29R30 or -C(O)NΗCΗR43C(0)OR29, wherein R20 is (C,.6)alkyl,
(C3.,2)cycloalkyl(C0.6)alkyl, hetero(C3.12)cycloalkyl(C0.6)alkyl, (C6.I2)aryl(C0.6)alkyl, diphenyl(C0.6)alkyl, hetero(C5.12)aryl(C0.6)alkyl or hetero(C8.12)polycycloaryl(C0.6)alkyl and R29 is hydrogen or -R20, wherein R20 is defined as above, wherein said heterocycloalkyl may be substituted with (C6.12)aryl(C0-3)alkyl, R30 at each occurrence is hydrogen or (C,.6)alkyl and R43 is (C,.6)alkyl, and R8 at each occurrence independently is hydrogen, (C,.6)alkyl or halo-substituted (C,.4)alkyl; wherein within R7 any alicyclic or aromatic ring system present may be substituted further by 1 to 5 radicals independently selected from (C,.6)alkyl, (C,.6)alkylidene, cyano, halo, halo-substituted ( -Jalkyl, nitro, -X6NR14R14, -X6NR14C(0)OR14, -X6NR14C(0)NR14R'4, -X6NR14C(NR14)NR14R14, -X6OR14, -X6SR14, -X6C(0)OR14, -X6C(0)NR14R14, -X6S(O)2NR14R14, -X6P(0)(OR14)OR14, -X6OP(0)(OR14)OR14,
-X6NR14C(0)R15, -X6S(O)R15, -X6S(O)2R15 and -X6C(0)R15, wherein X6 is a bond or (C,.6)alkylene, R14 at each occurrence independently is hydrogen, (C,.6)alkyl or halo-substituted (C,.3)alkyl and R15 (C,.6)alkyl or halo-substituted (C,.3)alkyl.
The ring system A preferably is oxazol-2-yl, 4,5-dihydrooxazol-2-yl, benzooxazol-2-yl, naphtho[2,3-J|oxazol-2-yl, naphtho[l,2-J)oxazol-2-yl or naphtho[2,l-J]oxazol-2-yl, each substituted by a group R7 and optionally substituted with a group R8, particularly wherein R7 is halo, -R29, -C(0)R20, -C(O)OR29, -C(O)NR29R30 or -S(0)2NR29R30, wherein R20 is (C,.6)alkyl, (C3.12)cycloalkyl(C0.6)alkyl, (C6.12)aryl(C0.6)alkyl, hetero(C 2)aryl(C0_6)alkyl or hetero(C8_]2)polycycloaryl(C0.6)alkyl.
The ring system A more preferably is oxazol-2-yl, 4,5-dihydrooxazol-2-yl, benzooxazol-2-yl or naphtho[l,2-J|oxazol-2-yl, each substituted by a group R7 and optionally substituted with a group R8, particularly wherein R7 is adamantan-1-ylmethylcarbamoyl, benzyl, benzy lcarbamoyl, benzyl(methyl)carbamoyl, 1 -benzyloxycarbonyl-3-methylbutylcarbamoyl. 4-benzylpiperidin-l -carbonyl, tert-butyl, chloro, 2,3-dihydroindol-l-ylcarbonyl, 3,4-dihydro- lH-isoquinol-2-ylcarbonyl, 3,4-dihydro-lH-quinol-l-ylcarbonyl, diphenylmethylcarbamoyl, fur-2-ylmethylcarbamoyl, hydrogen, 2-(lH-indol-3-yl)ethylcarbamoyl, methoxy, methoxycarbonyl, methyl, 3-methylbutylcarbamoyl, methylcarbamoyl, 1-methylethylcarbamoyl, naphth-1-ylmethylcarbonyl, nitro, phenyl, phenylcarbamoyl, 2-phenylcyclopropylcarbamoyl, 1-phenylethylcarbamoyl, sulfamoyl, trifluoromethyl, phenethylcarbamoyl, 3-phenylpropylcarbamoyl, piperid- 1 -ylcarbonyl, pyrid-2-ylmethylcarbamoyl, pyrid-3-ylmethylcarbamoyl, pyrid-4-ylmethy lcarbamoyl or pyrrolidin-1 -ylcarbonyl and R8 is methyl.
X2 particularly represents a bond or a divalent group of Formula (a), wherein within Formula (a) X3 is -C(O)-, R9 represents hydrogen, R11 represents hydrogen or methyl, typically hydrogen, and R12 particularly represents (C,.6)alkyl, preferably isobutyl, sec-butyl or isopropyl. R1 particularly represents hydrogen or -X8X9R20, wherein X8 is -C(O)- or -S(0)2-, X9 is a bond or -O- and R20 is (Cμ6)alkyl, (C3.12)cycloalkyl(C0.6)alkyl, hetero(C3.12)cycloalkyl(C0.6)alkyl, (C6.12)aryl(C0.6)alkyl or hetero(C5.12)aryl(C0.6)alkyl; wherein within R1 any alicyclic or aromatic ring system present may be substituted further by 1 to 5 radicals independently selected from (C,.6)alkyl, -C(0)OR14, -X6NR14R14 and -X6NR14C(0)OR14, wherein X6 is a bond or (C,.6)alkylene, R14 at each occurrence independently is hydrogen, (C,.6)alkyl or halo-substituted (C,.3)alkyl and R15 (C,.6)alkyl or halo-substituted (C,.3)alkyl. R1 particularly represents acetyl, benzoyl, benzyloxycarbonyl, benzylsulfonyl, bicyclo[2.2.2]hept-2-ylcarbonyl, tert-butoxycarbonyl, tert-butyryl,
4-tcrt-butoxycarbonylpiperazin-l -ylcarbonyl, l-tert-butoxycarbonylpiperidin-4-ylcarbonyl, 2-cyclohexylacetyl, 4-cyclohexylbutyryl, 2-cyclohexylethylsulfonyl, 3-cyclohexylpropionyl, 2-cyclopentylethylsulfonyl, hydrogen, 4-methylpiperazin-l -ylcarbonyl, methylsulfonyl, 4-mefhylvaleryl, 3-moφholin-4-ylpropionyl, naphth-2-ylmethyl, 3-phenylpropionyl, piperazin-1 -ylcarbonyl, piperidin-4-ylcarbonyl or pyrid-3-ylcarbonyl, wherein within R1 any alicyclic or aromatic ring system present may be substituted further by 1 to 3 radicals independently selected from 3-aminomethyl and 3-tcrt-butoxycarbonylaminomethyl. R2 particularly represents hydrogen.
R3 preferably represents (C,_6)alkyl or (C6_10)aryl(C,.3)alkyl, more preferably phenethyl, or R3 and R4 taken together with the carbon atom to which both R3 and R4 are attached form (C3.6)cycloalkylene, more preferably cyclopropylene.
R4 preferably represents hydrogen or (C,.6)alkyl, preferably hydrogen or methyl or R3 and R4 or R3 and R4 taken together with the carbon atom to which both R3 and R4 are attached form (C3.6)cycloalkylene, more preferably cyclopropylene.
R5 and R6 preferably together form oxo.
Reference to the preferred embodiments set forth above is meant to include all combinations of particular and preferred groups.
Pharmacology and Utility:
The compounds of the invention are cysteine protease inhibitors, in particular the compounds of the invention inhibit the activity of cathepsins B, L, K and/or S and, as such, are useful for treating diseases in which cathepsin B, L, K and/or S activity contributes to the pathology and/or symptomatology of the disease. For example, the compounds of the invention are useful in treating tumor invasion and metastasis, in particular as anti-angiogenic agents, rheumatoid arthritis, osteo arthritis, pneumocystis carinii, acute pancreatitis, inflammatory airway disease and bone and joint disorders. Furthermore, the compounds of the invention are useful in treating bone resoφtion disorders, e.g. osteoporosis.
The compounds of the invention are inhibitors of cathepsin S and, as such, are useful for treating diseases in which cathepsin S activity contributes to the pathology and or symptomatology of the disease. For example, the compounds of the invention are useful in treating autoimmune disorders, including, but not limited to, juvenile onset diabetes, multiple sclerosis, pemphigus vulgaris, Graves' disease, myasthenia gravis, systemic lupus erythemotasus, rheumatoid arthritis and Hashimoto's thyroiditis, allergic disorders, including, but not limited to, asthma, and allogeneic immune responses, including, but not limited to, organ transplants or tissue grafts.
Cathepsin S also is implicated in disorders involving excessive elastolysis, such as chronic obstructive pulmonary disease (e.g. emphysema), bronchiolitis, excessive airway elastolysis in asthma and bronchitis, pneumonities and cardiovascular disease such as plaque rupture and atheroma. Cathepsin S is implicated in fibril formation and, therefore, inhibitors of cathepsins S are of use in treatment of systemic amyloidosis.
The cysteine protease inhibitory activities of the compounds of the invention can be determined by methods known to those of ordinary skill in the art. Suitable in vitro assays for measuring protease activity and the inhibition thereof by test compounds are known. Typically, the assay measures protease induced hydrolysis of a peptide based substrate. Furthermore, the compounds of the invention are useful as intermediates in the preparation of other compounds of Formula I. For example, compounds of Formula I in which R5 is hydroxy can be used to prepare compounds of Formula I in which R5 and R6 taken together form oxo.
Nomenclature: The compounds of Formula I and the intermediates and starting materials used in their preparation are named in accordance with IUPAC rules of nomenclature in which the characteristic groups have decreasing priority for citation as the principle group as follows: acids, esters, amides, etc.. Alternatively, the compounds are named by AutoNom 4.0 (Beilstein Information Systems, Inc.). For example, a compound of Formula I in which A is benzooxazol-2-yl; X2 is a group of Formula (a), wherein R9 is hydrogen and R12 is cyclohexylmethyl; R1 is acetyl; R2 is hydrogen; R3 is phenethyl; R4 is hydrogen; and R5 and R6 together form oxo; that is, a compound having the following structure:
Figure imgf000044_0001
is named 2S-acetylamino--V-(l-benzooxazol-2-ylcarbonyl-3-phenylpropyl)-
3-cyclohexylpropionamide; and a compound of Formula I in which A is benzooxazol-2-yl; X2 is a group of Formula (a), wherein R9 is hydrogen and R12 is benzylsulfonylmethyl; R1 is moφholin-4-ylcarbonyl; R2 is hydrogen; R3 is phenethyl; R4 is hydrogen; R5 is hydrogen; and R6 is hydroxy; that is, a compound having the following structure:
Figure imgf000044_0002
is named N- [ 1 S-(2-benzooxazol-2-yl-2-hydroxy- 1 S-phenethylethylcarbamoyl)- 2-benzylsulfonylethyl]-moφholine-4-carboxamide or moφholine-4-carboxylic acid { (R)- 1 - [(S)- 1 -( 1 -benzooxazol-2-yl- 1 -hydroxy-methy l)-3-pheny 1-propy lcarbamoyl] - 2-phenylmethanesulfonyl-ethyl } -amide; and a compound of Formula I in which A is benzooxazol-2-yl; X2 is a group of Formula (a), wherein R9 is hydrogen and R12 is cyclohexymethyl; R1 is carboxy acetyl; R2 is hydrogen; R3 is phenethyl; R4 is hydrogen; and R5 and R6 together form oxo; that is, a compound having the following structure:
Figure imgf000045_0001
is named -V-[lS-(lS-benzooxazol-2-ylcarbonyl-3-phenylpropylcarbamoyl)- 2-cyclohexylethyl]malonamic acid or -V-{(S)-l-[(S)-l-(l-benzooxazol-2-yl-methanoyl)-3-phenyl- propylcarbamoyl]-2-cyclohexyl-ethyl}-malonamic acid; and a compound of Formula I in which A is benzooxazol-2-yl; X2 is a group of Formula (a), wherein R9 is hydrogen and R12 is 2-nitrobenzylsulfonylmethyl; R1 is moφholin-2-ylcarbonyl; R2 is hydrogen; R3 is phenethyl; R4 is hydrogen; and R5 and R6 together form oxo; that is, a compound having the following structure:
Figure imgf000045_0002
is named -V-[lR-(lS-benzooxazol-2-ylcarbonyl-3-phenylpropylcarbamoyl)-
2-(2-nitrobenzylsulfonyl)ethyl]moφholine-4-carboxamide or moφholine-4-carboxylic acid [(R)-l-[(S)-l-(l-benzooxazol-2-yl-methanoyl)-3-phenyl-propylcarbamoyl]-2-(2-nitro- phenylmethanesulfonyl)-ethyl]-amide; and a compound of Formula I in which A is benzooxazol-2-yl; X2 is a group of Formula (a), wherein R9 is hydrogen and R12 is benzylsulfonylmethyl; R1 is tetrahydropyran-4-yloxycarbonyl; R2 is hydrogen; R3 is phenethyl;
R4 is hydrogen; and R5 and R6 together form oxo; that is, a compound having the following structure:
Figure imgf000046_0001
is named tetrahydropyran-4-yl lR-(lS-benzooxazol-2-ylcarbonyl-3-phenylpropylcarbamoyl)-
2-benzylsulfonylethylcarbamate or { (R)-l-[(S)-l-(l-benzooxazol-2-yl-methanoyl)-3-phenyl- propylcarbamoyl]-2-phenylmethanesulfonyl-ethyl} -carbamic acid tetrahydro-pyran-4-yl ester.
A compound of Formula I in which A is pyrid-2-yl; X2 is a group of Formula (a), wherein R9 is hydrogen and R11 is 2-methylpropyl; R1 is benzyloxycarbonyl; R2, R4 and R5 each are hydrogen; R3 is phenethyl; and R6 is hydroxy; that is, a compound having the following structure:
Figure imgf000046_0002
is named benzyl lS-(15-pyrid-2-ylcarbonyl-3-phenylpropylcarbamoyl)-3-methylbutylcarbamate or { (S)-l-[(5)-l-(l -hydroxy- l-pyridin-2-yl-methyl)-3-phenyl-propylcarbamoyl]-3-methyl-butyl}- carbamic acid benzyl ester; and a compound of Formula I in which A is thiazol-2-yl; X2 is a group of Formula (a), wherein R9 is hydrogen and R11 is 2-methylpropyl; R1 is 4-methylpiperazin-l -ylcarbonyl; R2and R4 each are hydrogen; R3 is phenethyl; and R5 and R6 together form oxo; that is, a compound having the following structure:
Figure imgf000047_0001
is named -V-[3-methyl- lS-(3-phenyl-l-ιhiazol-2-ylcarbonylpropylcarbamoyl)butyl]-
4-methylpiperazine-l -carboxamide or 4-methyl-piperazine-l-carboxylic acid or { (S)-3-methyl- l-[(S)-3-phenyl-l-(l-thiazol-2-yl-methanoyl)-propylcarbamoyl]-butyl} -amide; and a compound of Formula I in which A is 4,5-tetrahydro-4-methoxycarbonyloxazol-2-yl; X2 is a group of
Formula (a), wherein R9 is hydrogen and R11 is 2-methylpropyl; R1 is benzyloxycarbonyl; R2and
R4 each are hydrogen; R3 is phenethyl; and R5 and R6 together form oxo; that is, a compound having the following structure:
Figure imgf000047_0002
is named methyl 2S-(2S-benzyloxycarbonylamino-4-methylvalerylamino)-4-phenylbutyryl- 4,5-dihydrooxazole-4-carboxylate or 2-[(S)-2-((S)-2-benzyloxycarbonylamino-4-methyl- pentanoylamino)-4-phenyl-butanoyl]-4,5-dihydro-oxazole-4-carboxylic acid methyl ester.
Certain compounds of Formula I exist in tautomeric equilibrium. Compounds of Formula I which exist as tautomers are named, illustrated or otherwise described in this application as one possible tautomer. However, it is to be understood that the all possible tautomers are meant to be encompassed by such names, illustrations and descriptions.
Certain compounds of Formulae I and II exist in tautomeric equilibrium. Compounds of Formulae I and II which exist as tautomers are named, illustrated or otherwise described in this application as one possible tautomer. However, it is to be understood that the all possible tautomers are meant to be encompassed by such names, illustrations and descriptions.
Administration and Pharmaceutical Compositions:
In general, compounds of Formula I will be administered in therapeutically effective amounts via any of the usual and acceptable modes known in the art, either singly or in combination with another therapeutic agent. A therapeutically effective amount may vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used and other factors. For example, therapeutically effective amounts of a compound of Formula I may range from 0.1 micrograms per kilogram body weight (μg/kg) per day to 10 milligram per kilogram body weight (mg/kg) per day, typically 1 μg/kg/day to 1 mg kg/day. Therefore, a therapeutically effective amount for a 80 kg human patient may range from 10 μg/day to 100 mg/day, typically 0.1 mg/day to 10 mg/day. In general, one of ordinary skill in the art, acting in reliance upon personal knowledge and the disclosure of this Application, will be able to ascertain a therapeutically effective amount of a compound of Formula I for treating a given disease.
The compounds of Formula I can be administered as pharmaceutical compositions by one of the following routes: oral, systemic (e.g., transdermal, intranasal or by suppository) or parenteral (e.g., intramuscular, intravenous or subcutaneous). Compositions can take the form of tablets, pills, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols, or any other appropriate composition and are comprised of, in general, a compound of Formula I in combination with at least one pharmaceutically acceptable excipient. Acceptable excipients are non-toxic, aid administration, and do not adversely affect the therapeutic benefit of the active ingredient. Such excipient may be any solid, liquid, semisolid or, in the case of an aerosol composition, gaseous excipient that is generally available to one of skill in the art.
Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk, and the like. Liquid and semisolid excipients may be selected from water, ethanol, glycerol, propylene glycol and various oils, including those of petroleum, animal, vegetable or synthetic origin (e.g., peanut oil, soybean oil, mineral oil, sesame oil, or the like). Preferred liquid carriers, particularly for injectable solutions, include water, saline, aqueous dextrose and glycols.
The amount of a compound of Formula I in the composition may vary widely depending upon the type of formulation, size of a unit dosage, kind of excipients and other factors known to those of skill in the art of pharmaceutical sciences. In general, a composition of a compound of Formula I for treating a given disease will comprise from 0.01 %w to 10%w, preferably 0.3%w to l%w, of active ingredient with the remainder being the excipient or excipients. Preferably the pharmaceutical composition is administered in a single unit dosage form for continuous treatment or in a single unit dosage form ad libitum when relief of symptoms is specifically required.
The compounds of Formula I can be administered alone or in combination with other compounds of Formula I or in combination with one or more other active ingredient(s). For example, the compounds of Formula I can be administered in combination with a therapeutically active amount of a bisphosphonic acid or acid ester derivative or any pharmaceutically acceptable salt thereof. Suitable bisphosphonic acids and acid ester derivatives include compounds corresponding to the following formula:
Figure imgf000049_0001
wherein X11 is a bond or (C].7)alkylene, each R43 independently is hydrogen or (C,.30)alkyl, R44 and R45 are selected independently from a group consisting of hydrogen, halo, optionally substituted (C,.30)alkyl, (C3.30)cycloalkyl, hetero(C5.30)cycloalkyl, optionally substituted (C5.10)aryl, hetero(C6.10)aryl, -NR46R46, -OR46, -SR46, wherein each R46 independently is hydrogen, (C 0)alkyl, (C3.I0)cycloalkyl, optionally substituted (C6.10)aryl, provided that both R44 and R45 are not selected from hydrogen or hydroxy when X11 is a bond; or R44 and R45 taken together form (C2.9)alkylene; wherein (C3.10)cycloalkyl includes adamantyl and the like, hetero(C5.I0)cycloalkyl includes pyrrolidinyl and the like, (C6.10)aryl includes phenyl and naphthyl, and hetero(C6.10)aryl includes quinolyl, isoquinolyl, pyridyl, furyl, imidazolyl, imidazopyridyl and the like. Instances wherein R44 and/or R45 are substituted (C,.30)alkyl may include, but are not limited to, (C,.30)alkyl substituted by hetero(C5.)0)cycloalkyl, (C6.)0)aryl, hetero(C6.10)aryl, -NR47R47, -OR47 and -SR47, wherein each R47 is independently hydrogen or (C1.10)alkyl; wherein hetero(C5.10)cycloalkyl includes pyrrolidinyl and the like, (C6.10)aryl includes phenyl and naphthyl, and hetero(C6.10)aryl includes quinolyl, isoquinolyl, pyridyl, furyl, imidazolyl, imidazopyridyl and the like. Suitable optionally substituted aryl groups include, but are not limited to, halo-substituted phenyl.
A non-limiting class of bisphosphonic acids and acid ester derivatives thereof suitable for administration in combination with compounds of Formula I include those in which R44 is selected from the group consisting of hydrogen, hydroxy or halo, and R45 is selected from the group consisting of optionally substituted (C,.30)alkyl, halo and -SR46, wherein R46 is (C,.10)alkyl or phenyl.
A non-limiting subclass of bisphosphonic acids and acid ester derivatives thereof suitable for administration in combination with compounds of Formula I include those in which R44 is selected from the group consisting of hydrogen, hydroxy and chloro and R45 is selected from the group consisting of optionally substituted (C,.30)alkyl, chloro and chlorophenylthio. A non-limiting example of a bisphosphonic acid suitable for administration in combination with compounds of Formula I include that in which X11 is a bond, each R43 is hydrogen, R44 is hydroxy and R45 is 3-aminopropyl, namely 4-amino- 1 -hydroxy butylidene- 1,1 -bisphosphonic acid (aka alendronic acid), or the monosodium trihydrate salt thereof, namely 4-amino- 1 -hydroxybutylidene- 1 , 1 -bisphosphonate monosodium trihydrate (aka alendronate monosodium trihydrate), described in U.S. Patents 4,922,007, to Kieczykowski et al., issued May 1, 1990; 5,019,651, to Kieczykowski et al., issued May 28, 1991; 5,510,517, to Dauer et al., issued April 23, 1996; 5,648,491, to Dauer et al., issued July 15, 1997, all of which patents are incoφorated by reference herein in their entirety. Further non-limiting examples of bisphosphonic acids suitable for administration in combination with compounds of Formula I include the following: cycloheptylaminomethylene- 1,1 -bisphosphonic acid (aka cimadronic acid), described in U.S. Patent 4,970,335, to Isomura et al., issued November 13, 1990; l,l-dichloromethylene-l,l-diphosphonic acid (aka clodronic acid) and the disodium salt thereof, namely clodronate disodium, described in Belgium Patent 672,205 (1966) and J. Org. Chem 32, 4111 (1967); l-hydroxy-3-pyrroli din- 1-ylpropylidene- 1,1 -bisphosphonic acid (aka EB-1053); l-hydroxyethylidene-l,l-diphosphonic acid (aka etidronic acid); 1 -hydroxy-3-(-V-methyl-iV-pentylamino)propylidene- 1 , 1 -bisphosphonic acid (aka ibandronic acid), described in U.S. Patent No. 4,927,814, issued May 22, 1990;
6-amino-l-hydroxyhexylidene- 1,1 -bisphosphonic acid (aka neridronic acid); 3-(dimethylamino)- 1 -hydroxypropylidene- 1 , 1 -bisphosphonic acid (aka olpadronic acid);
3-amino-l-hydroxypropylidene- 1,1 -bisphosphonic acid (aka pamidronic acid); 2-pyrid-2-ylethylidene- 1,1 -bisphosphonic acid (aka piridronic acid), described in U.S. Patent No. 4,761,406; l-hydroxy-2-pyrid-3-ylethylidene- 1,1 -bisphosphonic acid (aka risedronic acid); 4-chlorophenylthiomethylenebisphosphonic acid (aka tiludronic acid), described in U.S.
Patent 4,876,248, to Breliere et al., October 24, 1989; and l-hydroxy-2-(lH-imidazol-l-yl)ethylidene- 1,1 -bisphosphonic acid (aka zoledronic acid); all of which patents and other documents referred to above are incoφorated by reference herein in their entirety. A non-limiting subclass of bisphosphonic acids suitable for administration in combination with compounds of Formula I include those selected from the group consisting of alendronic acid, cimadronic acid, clodronic acid, tiludronic acid, etidronic acid, ibandronic acid, risedronic acid, piridronic acid, pamidronic acid, zolendronic acid, pharmaceutically acceptable salts thereof, and mixtures thereof. A further example of a bisphosphonic acid suitable for administration in combination with compounds of Formula I is alendronic acid or a pharmaceutically acceptable salt thereof, and mixtures thereof. A further non-limiting example is alendronate monosodium trihydrate.
Compounds of Formula I can be administered in combination with a therapeutically active amount of an estrogen receptor agonist. Non-limiting examples of estrogen receptor agonists suitable for administration in combination with the compounds of Formula I include naturally occurring estrogens such as estradiol, estrone and estroil, or synthetic estrogen receptor agonists such as [6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thien-3-yl][4-(2-piperidin-l-ylethoxy)phenyl]methanone (aka raloxifene) and {2-[4-(l,2-diphenylbut-l-enyl)phenoxy]ethyl}dimethylamine (aka tamoxifen). A non-limiting subclass of estrogen receptor agonists suitable for administration in combination with the compounds of Formula I include estrogen receptor partial agonists (i.e., estrogen receptor agonists with mixed agonist/antagonist properties), sometimes referred to as estrogen receptor modulators. Estrogen receptor partial agonists can exert tissue-selective estrogen agonist effects. Tamoxifen, for example, selectively exerts an estrogen agonist effect on the bone, in humans. Additional suitable estrogen receptor partial agonists are described in Tissue-Selective Actions Of Estrogen Analogs, Bone Vol. 17, No. 4, October 1995, 181S-190S. Certain 3-[4-(2-phenylindol-l-ylmethyl)phenyl]acrylamides, described in U.S. Patent 5,985,910 to Miller et al., November 16, 1999; benzothiphene compounds, described in U.S. Patent 5,985,897 to Meuhl et al, November 16, 1999; naphthyl compounds, described in U.S. Patent 5,952,350 to Cullinan et al, September 14, 1999; substituted benzothiophene compounds, described in U.S. Patent 5,962,475 to Schmid et al, October 4, 1999, are suitable estrogen receptor partial agonists for administration with the compounds of Formula I; all of which patents and other documents referred to above are incoφorated by reference herein in their entirety.
More particularly a pharmaceutical composition of this invention may comprise a therapeutically effect amount of a compound of Formula I in combination with one or more active ingredient(s) selected from the group consisting of (i) a therapeutically effect amount of a bisphosphonic acid or acid ester thereof or a pharmaceutically acceptable salt thereof and (ii) a therapeutically effect amount of an estrogen receptor agonist or a pharmaceutically acceptable salt thereof; and one or more pharmaceutically acceptable excipient(s). Non-limiting examples of such bisphosphonic acids include 1,1-dichloromethylene- 1,1 -diphosphonic acid, 1 -hydroxy - 3-pyrrolidin- 1 -ylpropylidene- 1 , 1 -bisphosphonic acid, 1 -hydroxyethylidene- 1 , 1 -diphosphonic acid, 1 -hydroxy-3-(-V-methyl--V-pentylamino)propylidene- 1 , 1 -bisphosphonic acid, 6-amino- 1-hydroxyhexylidene-l, 1 -bisphosphonic acid, 3-(dimethylamino)-l-hydroxypropylidene- 1,1 -bisphosphonic acid, 3-amino-l-hydroxypropylidene- 1,1 -bisphosphonic acid, 2-pyrid-2-ylethylidene- 1 , 1 -bisphosphonic acid, 1 -hydroxy-2-pyrid-3-ylethylidene- 1,1- bisphosphonic acid, 4-chlorophenylthiomethylenebisphosphonic acid and 1-hydroxy- 2-(lH-imidazol-l-yl)ethylidene- 1,1 -bisphosphonic acid or acid ester thereof or a pharmaceutically acceptable salt thereof; particularly 1,1-dichloromethylene- 1,1 -diphosphonic acid or a pharmaceutically acceptable salt thereof and preferably 1,1-dichloromethylene- 1,1-diphosphonate monosodium trihydrate.
Chemistry:
Processes for Making Compounds of Formula I: Compounds of Formula I in which R5 and R6 together form oxo can be prepared by proceeding as in the following Scheme 1 :
Scheme 1
Figure imgf000053_0001
in which n, A, X1, X2, R1, R2, R3, R4, R7 and R8 are as defined in the Summary of the Invention for Formulae I and II.
Compounds of Formula I in which R5 and R6 together form oxo (Formula 1(a)) can be prepared by reacting an organometallic compound of Formula 2 with a compound of Formula 3.
The reaction is carried out in a suitable solvent (e.g. tetrahydrofuran (THF), ether, or the like) at
-80 to -70° C, preferably at about -78° C, and requires 30 minutes to an hour to complete. The organometallic compound of Formula 2 is generated by treating a corresponding organo compound, or a brominated derivative thereof, with n-butyllithium or tert-butyllithium in a suitable solvent (e.g. THF, ether, or the like) at -80 to -70° C, preferably at about -78° C, for approximately 30 minutes to an hour. Compounds of Formula I in which the ring comprised by X1 is a 4,5-tetrahydrooxazol-2-yl or oxazol-2-yl or moiety, R5 is hydrogen and R6 is hydroxy can be prepared by proceeding as in the following Scheme 2:
Scheme 2
Figure imgf000054_0001
in which X2, R1, R2, R3, R4, R7 and R8 are as defined in the Summary of the Invention for Formulae I and II.
Compounds of Formula I can be prepared by reacting a compound Formula 4 with a compound of the Formula 5(a). The reaction is carried out in a suitable solvent (e.g. chloroform, ethanol, or the like) at reflux temperatures and requires 3 to 24 hours to complete. In a similar fashion, using analogous reaction conditions to those described in Scheme 1, compounds of Formula I in which A is a heteropolycyclic radical wherein X1 is a ring member atom of an oxazole ring, R5 is hydrogen and R6 is hydroxy can be prepared by reacting a compound of Formula 4 with a compound of Formula 5(b):
Figure imgf000054_0002
in which n is 0, 1, 2 or 3 and B is a heteromonocyclic radical containing 5 to 6 ring member atoms or a fused heteropolycyclic radical containing 8 to 11 ring member atoms, wherein each ring contains 5 to 7 ring member atoms and each ring member atom is a carbon atom or a heteroatom, and R7 and R8 is as defined in the Summary of the Invention for Formulae I and II. Compounds of Formula I can be prepared by proceeding as in the following Scheme 3:
Scheme 3
Figure imgf000055_0001
l. R^OY
2. optionally deprotecting
Figure imgf000055_0002
in which Y is hydrogen or an activating group (e.g. 2,5-dioxopyrrolidin-l-yl (NBS), or the like) and n, A, X1, X2, R1, R2, R3, R4, R7 and R8 are as defined in the Summary of the Invention for Formulae I and II. Compounds of Formula I can be prepared by reacting a compound of Formula 6, or a protected derivative thereof, with a compound of the formula R1X2OY, or a protected derivative thereof, and then optionally deprotecting. The reaction is carried out in the presence of a suitable base (e.g. triethylamine, diisopropylethylamine, or the like) and in a suitable solvent (e.g. acetonitrile, N,-V-dimethylformamide (DMF), dichloromethane, or any suitable combination thereof, or the like) at 10 to 30°C, preferably at about 25°C, and requires 24 to 30 hours to complete. When Y is hydrogen a suitable coupling agent
(e.g. benzotriazole-1-yloxytrispyrrolidinophosphonium hexafluorophosphate (PyBOP®), l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC), Obenzotriazol-1-yl- -V,N-V',-V'-tetramethyluronium hexafluorophosphate (HBTU), 0(7-azabenzotriazol- 1 -yl)- 1 , 1 ,3,3-tetramethyluronium hexafluorophosphate (HATU), 1,3-dicyclohexylcarbodiimide (DCC), or the like) and base (e.g. N-V-diisopropylethylamine, triethylamine, or the like) is required and the reaction requires 2 to 3 hours to complete. Deprotection can be effected by any means which removes the protecting group and gives the desired product in reasonable yield. A detailed description of the techniques applicable to the creation of protecting groups and their removal can be found in T.W. Greene, Protecting Groups in Organic Synthesis, John Wiley & Sons, Inc. 1981. Detailed descriptions of the preparation of a compound of Formula I in accordance with Scheme 3 are set forth in Examples 8, 9, 10 and 12, infra.
Compounds of Formula I can be prepared by proceeding as in the following Scheme 4:
Scheme 4
Figure imgf000056_0001
R39OH
Figure imgf000056_0002
in which R39 is -X7X8R20 and n, X1, X2, X7, X8, R\ R2, R3, R4, R7, R8 and R20 are as defined in the Summary of the Invention for Formulae I and II.
Additional Processes for Preparing Compounds of Formula I: Compounds of Formula I in which A is optionally substituted oxazol-2-yl can be prepared by oxidizing a corresponding compound of Formula I in which A is 4,5-dihydrooxazol-2-yl. The reduction is carried out in the presence of base (e.g. l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), l,5-diazabicyclo[3.4.0]non-5-ene (DBN), or the like) in a suitable solvent (e.g. dichloromethane, or the like) at 20 to 25 ° C and requires 6 to 12 hours to complete.
Compounds of Formula I in which R7 is -C(0)OH can be prepared from a corresponding compound of Formula I in which R7 is methoxycarbonyl. The conversion can be effected by treating the methyl ester with sodium hydroxide in a suitable solvent (e.g, ethanol, or the like) at 20 to 25° C and requires 6 to 12 hours to complete.
Compounds of Formula I in which R7 is -C(0)NR29R30 or -C(0)NR42CHR43C(0)OR29. can be prepared by reacting a corresponding compound of Formula I in which R7 is -C(0)OH with a compound of the formula NHR20R21 or NHR42CHR43C(0)OR29, respectively. The reaction is carried out in the presence of a suitable coupling agent (PyBOP®, EDC, HBTU, DCC, or the like) and base (e.g, N-V-diisopropylethylamine, triethylamine, or the like) in a suitable solvent (e.g., DMF, or the like) at 20 to 25° C and requires 2 to 4 hours to complete.
Compounds of Formula I in R1 is -X6X7R20can be prepared by reacting a compound of Formula I in which R1 is hydrogen with a compound of the formula R20X7X6OH. The reaction is carried out by procedures analogous to those described above for carrying out Reaction Scheme 3.
Compounds of Formula I in which R5 and R6 together form oxo can be prepared by oxidizing a compound of Formula I in which R5 is hydrogen and R6 is hydroxy. The oxidation can be carried out with a suitable oxidizing agent (e.g. Dess-Martin periodinate, or the like) in a suitable solvent (e.g. dichloromethane, or the like) at 15 to 25° C and requires 10 to 20 hours to complete.
Compounds of Formula I in which R12 contains a sulfonyl moiety can be prepared by oxidizing a corresponding compound of Formula I containing a sulfanyl moiety. The oxidation is carried out with a suitable oxidizing agent (e.g. potassium peroxymonosulfate (OXONE®, or the like) in a suitable solvent (e.g. methanol, water, or the like, or any suitable combination thereof) at ambient temperature and requires 16 to 24 hours to complete.
A compound of Formula I in which A is l,l-dioxo-lH-lλ6-benzo[b]thien-2-yl can be prepared by oxidizing a corresponding compound of Formula I in which A is benzo[b]thien-2-yl. Proceeding in this fashion benzyl l-, lJl,l-dioxo-lH-lλ6-benzo,blthien-2-ylcarbonyl.- 3-phenylpropylcarbamoyH-3-methylbutylcarbamate (Compound 209) was prepared. Η NMR (CDClj): δ 0.83 - 0.95 (m, 6Η), δ 1.35 - 1.52 (m, IH), δ 1.61 - 1.69 (m, 2H). δ 2.07 - 2.20 (m, IH), δ 2.36 - 2.71 (m, 3H), δ 4.57 (m, IH), δ 4.76 (m, IH), δ 4.98 - 5.26 (m, 3H), δ 5.35 (bs, IH), δ 7.06 - 7.62 (m, 14H);
A compound of Formula I can be prepared as a pharmaceutically acceptable acid addition salt by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid. Alternatively, a pharmaceutically acceptable base addition salt of a compound of Formula I can be prepared by reacting the free acid form of the compound with a pharmaceutically acceptable inorganic or organic base. Inorganic and organic acids and bases suitable for the preparation of the pharmaceutically acceptable salts of compounds of Formula I are set forth in the definitions section of this application. Alternatively, the salt forms of the compounds of Formula I can be prepared using salts of the starting materials or intermediates. The free acid or free base forms of the compounds of Formula I can be prepared from the corresponding base addition salt or acid addition salt form. For example, a compound of Formula I in an acid addition salt form can be converted to the corresponding free base by treating with a suitable base (e.g. ammonium hydroxide solution, sodium hydroxide, or the like). A compound of Formula I in a base addition salt form can be converted to the corresponding free acid by treating with a suitable acid (e.g. hydrochloric acid, etc). The -V-oxides of compounds of Formula I can be prepared by methods known to those of ordinary skill in the art. For example, -V-oxides can be prepared by treating an unoxidized form of the compound of Formula I with an oxidizing agent (e.g. trifluoroperacetic acid, permaleic acid, perbenzoic acid, peracetic acid, ct -chloroperoxybenzoic acid, or the like) in a suitable inert organic solvent (e.g. a halogenated hydrocarbon such as dichloromethane) at approximately 0°C. Alternatively, the -V-oxides of the compounds of Formula I can be prepared from the -V-oxide of an appropriate starting material.
Compounds of Formula I in unoxidized form can be prepared from /V-oxides of compounds of Formula I by treating with a reducing agent (e.g. sulfur, sulfur dioxide, triphenyl phosphine, lithium borohydride, sodium borohydride, phosphorus trichloride, tribromide, or the like) in an suitable inert organic solvent (e.g. acetonitrile, ethanol, aqueous dioxane, or the like) at 0 to 80°C.
Prodrug derivatives of the compounds of Formula I can be prepared by methods known to those of ordinary skill in the art (e.g. for further details see Saulnier et α/.(1994), Bioorganic and Medicinal Chemistry Letters. 4:1985). For example, appropriate prodrugs can be prepared by reacting a non-derivatized compound of Formula I with a suitable carbamylating agent (e.g. 1,1-acyloxyalkylcarbonochloridate, /. αrα-nitrophenyl carbonate, or the like). Protected derivatives of the compounds of Formula I can be made by means known to those of ordinary skill in the art. A detailed description of the techniques applicable to the creation of protecting groups and their removal can be found in T.W. Greene, Protecting Groups in Organic Synthesis, John Wiley & Sons, Inc. 1981.
Compounds of Formula I can be prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers and recovering the optically pure enantiomer. While resolution of enantiomers can be carried out using covalent diasteromeric derivatives of compounds of Formula I, dissociable complexes are preferred (e.g. crystalline diastereoisomeric salts). Diastereomers have distinct physical properties (e.g. melting points, boiling points, solubilities, reactivity, and the like) and can be readily separated by taking advantage of these dissimilarities. The diastereomers can be separated by chromatography or, preferably, by separation/resolution techniques based upon differences in solubility. The optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that would not result in racemization. A more detailed description of the techniques applicable to the resolution of stereoisomers of compounds from their racemic mixture can be found in Jean Jacques Andre Collet, Samuel H. Wilen, Enantiomers, Racemates and Resolutions, Honh Wiley & Sons, Inc. (1981).
In summary, an aspect of the invention is a process for preparing a compound of Formula I, which process comprises: (A) reacting an organometallic compound of Formula 2:
h χlAR (Rl°)„
with a compound of Formula 3:
Figure imgf000060_0001
wherein n, A, X1, X2, R1, R2, R3, R4, R7 and R8 are as defined in the Summary of the Invention for Formulae I and II, to give a compound of Formula I in which R5 and R6 together form oxo; or (B) reacting a compound of Formula 4:
R
Figure imgf000060_0002
4 with a compound of Formula 5(a) or 5(b):
Figure imgf000060_0003
5(a) 5(b) wherein the dashed line represents an optional bond and B is a monocyclic radical containing 5 to 6 ring member atoms or a fused polycyclic radical containing 8 to 11 ring member atoms, wherein each ring contains 5 to 7 ring member atoms and each ring member atom is a carbon atom or a heteroatom and n, R1, R2, R3, R4, R7 and R8 are as defined in the Summary of the Invention for Formulae I and II, to give a compound of Formula I in which the ring comprised by X1 is a 4,5-tetrahydrooxazol-2-yl or oxazol-2-yl or moiety, respectively, R5 is hydrogen and R6 is hydroxy or
(C) reacting a compound of Formula 6:
Figure imgf000061_0001
with a compound of the formula R!X2OY, wherein Y is hydrogen or an activating group and n,
A, X1, X2, R1, R2, R3, R4, R7 and R8 are as defined in the Summary of the Invention for
Formulae I and II, to give a compound of Formula I in which R5 is hydrogen and R6 is hydroxy; or
(D) reacting a compound of Formula 7:
Figure imgf000061_0002
7 or a protected derivative thereof, with R39OH, wherein R39 is -X7X8R20 and n, A, X1, X2, X7, X8, R2, R3, R4, R7, R8 and R20 are as defined in the Summary of the Invention for Formulae I and II, and deprotecting if necessary to give a compound of Formula I in which R1 is -X7X8R20,
(E) optionally oxidizing a compound of Formula I in which R5 is hydrogen and R6 is hydroxy to give a compound of Formula I in which R5 and R6 together form oxo;
(F) optionally oxidizing a compound of Formula I in which A is optionally substituted 4,5-dihydroxyoxazol-2-yl to give a compound of Formula I in which A is optionally substituted oxazol-2-yl;
(G) optionally converting a compound of Formula I in which R7 is -C(O)OH to a compound of Formula I in which R7 is methoxycarbonyl;
(H) optionally converting a compound of Formula I into a pharmaceutically acceptable salt; (I) optionally converting a salt form of a compound of Formula I to non-salt form; (J) optionally converting an unoxidized form of a compound of Formula I into a pharmaceutically acceptable -V-oxide; (K) optionally converting an JV-oxide form of a compound of Formula I its unoxidized form; (L) optionally converting a non-derivatized compound of Formula I into a pharmaceutically prodrug derivative; and
(M) optionally converting a prodrug derivative of a compound of Formula I to its non-derivatized form.
Processes for Preparing Intermediates:
Compounds of Formula 3 can be prepared by reacting a compound of the Formula 8:
Figure imgf000062_0001
8 with a compound of the formula R'X2OY, in which Y is hydrogen or an activating group (NBS, or the like). The reaction is carried out under conditions analogous to those set for Reaction Scheme 3.
Compounds Formula 8 can be prepared by reacting a corresponding amino protected carboxy lie acid with NO-dimethylhydroxylamine hydrochloride and then deprotecting. The reaction with the amine is carried out in the presence of a suitable coupling agent (PyBOP®, EDC, HBTU, DCC, or the like) and base (e.g. N-V-diisopropylethylamine, triethylamine, or the like) in a suitable solvent (e.g. dichloromethane, DMF, or the like) at 20 to 30° C, preferably at about 25° C, and requires 2 to 4 hours to complete (e.g. see Reference 1, infra.). Deprotection can be effected by any means which removes the protecting group and gives the desired product in reasonable yield (e.g. see Example 2, infra.). A detailed description of the preparation of a compound of Formula 8 is set forth in References 1 and 6, infra. Compounds of Formula 4 can be prepared by reacting a nitrile of Formula 9:
Figure imgf000062_0002
9 with ethanol. The reaction is carried out by adding the nitrile to a mixture comprising a catalytic amount of dry hydrogen chloride in a suitable solvent (e.g. chloroform, ethanol, or the like) and then allowing the reaction to proceed at 0 to 25° C for 4 to 6 hours. Dry hydrogen chloride is conveniently generated by combining a slightly excessive amount of ethanol with acetyl chloride prior to adding the imidate to the reaction mixture. Alternatively, the hydrogen chloride is introduced to the reaction medium as a gas.
Compounds of Formula 6 can be prepared by methods known to those of ordinary skill in the art. For example, compounds of Formula 6 in which A is optionally substituted benzooxazol-2-yl can be prepared by reacting a compound of Formula 10:
Figure imgf000063_0001
10 in which R40 is a protecting group, with 2-aminophenol and deprotecting. The reaction with the phenol is carried out in the presence of a suitable base (e.g. diisopropylethylamine, triethylamine, or the like) and in a suitable solvent (e.g. chloroform, or the like) at reflux temperatures to 25° C and requires 10 to 12 hours to complete. Deprotection can be effected by any means which removes the protecting group and gives the desired product in reasonable yield. A detailed description of the preparation of a compound of Formula 6 is set forth in Reference , infra. Compounds of Formula 7 can be prepared by condensing a compound of Formula 6 with a compound of the formula R40X2OY, wherein R40 is a protecting group, and then deprotecting. The condensation is carried out in the presence of a suitable base (e.g. triethylamine, diisopropylethylamine, or the like) and in a suitable solvent (e.g. acetonitrile, DMF, dichloromethane, or any suitable combination thereof, or the like) at 10 to 30°C, preferably at about 25 °C, and requires 24 to 30 hours to complete. When Y is hydrogen a suitable coupling agent (e.g. PyBOP®, EDC, HBTU, HATU, DCC, or the like) and base (e.g. N-V-diisopropylefhylamine, triethylamine, or the like) is required and the reaction requires 2 to 3 hours to complete. Deprotection can be effected by any means which removes the protecting group and gives the desired product in reasonable yield.
Examples: The following abbreviations used in this Application area defined as follows:
PyBOP® = benzotriazole-1-yloxytrispyrrolidinophosphonium hexafluorophosphate; THF = tetrahydrofuran; OXONE® = potassium peroxymonosulfate; EDC = l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride;
DMF = -V,-V-dimethylformamide;
HATU = 0-(7-azabenzotriazol-l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate; HOBT = 1-hydroxybenzotriazole hydrate.
REFERENCE 1 Benzyl lS-(-V-methoxy--V-methylcarbamoyl)-3-phenylpropylcarbamate
A solution of 2-benzyloxycarbonylamino-4-phenylbutyric acid (5.05 g, 16.1 mmol) in dichloromethane (70 mL) was cooled to 0°C and treated with diisopropylethylamine (2.82 mL, 16.2 mmol) added dropwise and then PyBOP® (8.53 g, 16.4 mmol) added in one portion. The mixture was stirred for 5 minutes and then treated with -V,0-dimethylhydroxylamine hydrochloride (1J3 g, 17.71 mmol) added in one portion. The mixture was neutralized with diisopropylethylamine (4.6 mL, 26.44 mmol) added dropwise, stirred for 2 hours at room temperature and then diluted with dichloromethane (70 mL). The dilution was washed sequentially with IN aqueous hydrochloric acid (3x 40 mL), saturated sodium bicarbonate (3x 40 mL) and brine (40 mL) and then concentrated. The product was purified from the residue by column chromatography eluting with 2:3 ethyl acetate/hexane to provide benzyl lS-(-V-methoxy- V-methylcarbamoyl)-3-phenylproρylcarbamate (5.48 g, 15.4 mmol) as an oil. MS(PCI) m/z = 357 (M +1).
Proceeding as in Reference 1 provided tert-butyl 1 S- ( -V-methoxy-N-methylcarbamoyl)- 3-phenylpropylcarbamate; Η ΝMR (CDC13): δ 1.35 (s, 9H), δ 1.64 - 1.72 (m, 2H), δ 2.40 - 2.54 (m, IH), δ 2.60 - 2.77 (m, IH), δ 3.00 (s, 3H) 3.52 (s, 3H), δ 4.23 (m, IH), δ 7.10 - 7.37 (m, 5H). REFERENCE 2 3-(2-Cvanobenzylsulfanyl)-2R-pyrid-4-ylcarbonylaminopropionic acid
A mixture of isonicotinic acid (3 g), -V-hydroxysuccinimide (2.79 g) and -V,-V-dicyclohexylcarbodiimide (5.52 g) was stirred in THF (200 mL) for 16 hours. The solid was filtered off and the solvent evaporated under reduced pressure. The residue was triturated with ethyl acetate and more solid filtered off. The filtrates were concentrated under reduced pressure gave 2,5-dioxopyrrolidin-l-yl isonicotinate (5.27 g). MS: 221 [MH]+.
A solution of L-cysteine (6 g) in ethanol (57 mL) was treated sequentially with aqueous 2N sodium hydroxide solution (30 mL) and 2-bromomethylbenzonitrile (9.71 g). The reaction mixture was stirred 2 hours at room temperature then neutralized by addition of concentrated hydrochloric acid. A resulting solid was collected by filtration and wash sequentially with water, ethanol and diethylether to provide 2R-amino-3-(2-cyanobenzylsulfanyl)propionic acid as a white solid. MS: 237 [MH]+. MS: 235 [M]".
A solution of 2R-amino-3-(2-cyanobenzylsulfanyl)propionic acid (590 mg) in dichloromethane was treated with 2,5-dioxopyrrolidin-l-yl isonicotinate (1.41 g) and diisopropylethyamine (0.435 mL). The reaction mixture was stirred for 6 hours and then concentrated. The residue was treated with water and a resulting insoluble solid was filtered off. The aqueous filtrate was extracted twice with ethyl acetate and the combined extracts were dried over magnesium sulfate and then concentrated to provide 3-(2-cyanobenzylsulfanyl)- 2R-pyrid-3-carbonylaminopropionic acid (340 mg) as a gum. MS: 342 [MH]+. HPLC:RT = 10.63 minutes.
REFERENCE 3 3-Benzylsulfanyl-2R-tetrahvdropyran-4-yloxycarbonylaminopropionic acid
A solution of tetrahydropyran-4-ol (200 mg) in acetonitrile (5 mL) was treated with bis(2,5-dioxocyclopentyl) carbonate (0.753 g) and triethylamine (0.81 mL). The reaction mixture was stirred for 4 hours at room temperature and then concentrated. The residue was dissolved in ethyl acetate and the solution was washed with a saturated sodium bicarbonate solution, dried over magnesium sulfate and then concentrated to provide 2,5-dioxo-pyrrolidin-l-yl tetrahydropyran-4-yl carbonate. A solution of 2R-amino-3-benzylsulfanylpropionic acid (1 g) and triethylamine (0.8 mL) in dichloromethane (40 mL) was treated with 2,5-dioxo-pyrrolidin-l-yl tetrahydro-pyran-4-yl carbonate (1.15 g). The mixture was stirred for 16 hours at room temperature and then concentrated. The residue was dissolved in ethyl acetate and the solution was washed sequentially with hydrochloric acid and brine, dried over magnesium sulfate and then concentrated. The residue was subjected to flash column chromatography on silica eluting with a mixture of ethyl acetate and pentane (1:1, v/v) to provide 3-benzylsulfanyl-2R- tetrahydropyran-4-yloxycarbonylaminopropionic acid (800 mg) as an oil.
REFERENCE 4 3-Benzylsulfanyl-2R-moφholin-4-ylcarbonylaminopropionic acid
A solution of 3-benzylsulfanyl-2R-aminopropionic acid hydrochloride (25 g, 0.118 mol) in 2N sodium hydroxide (59 mL, 0.118 mol) was cooled in an ice bath and then treated simultaneously with moφholine-4-carbonyl chloride (13.8 mL, 0.118 mol) and IN sodium hydroxide (118 mL, 0.118 mol). The mixture was stirred at 0°C for 30 minutes and then filtered. The filtrate was acidified with 5N hydrochloric acid and extracted with ethyl acetate (5x 100 mL). The combined extracts were dried (MgS04), filtered and concentrated to provide 3-benzylsulfanyl-2R-moφholin-4-ylcarbonylaminopropionic acid (19.65 g, 60.6 mmol) as a white solid.
REFERENCE 5 3-Benzylsulfonyl-2R-moφholin-4-ylcarbonylaminopropionic acid
A solution of 3-benzylsulfanyl-2R-moφholin-4-ylcarbonylaminopropionic acid (17.58 g, 54.2 mmol), provided as in Reference 4, in methanol (550 mL) was treated with a solution of OXONE® (50 g, 81.4 mL) in water (550 mL). The mixture was stirred at room temperature for 2 hours and then concentrated to dryness. The residue was taken up into water (90 mL) and ethyl acetate (600 mL). The mixture was stirred vigorously and the aqueous layer was separated and extracted with ethyl acetate (2x 100 mL). The combined ethyl acetate layers were dried (MgS04) and concentrated. The residue was triturated with diethyl ether and the solid material was collected by filtration to provide 3-benzylsulfonyl-2R-moφholin-4-ylcarbonylaminopropionic acid.
REFERENCE 6
2-Amino--V-methoxy-N-methyl-4-phenylbutyramide trifluoroacetic acid salt
A solution of tert-butyl l-(-V-methoxy--V-methylcarbamoyl)-3-phenylpropylcarbamate
(9.32 g, 29 mmol), provided as in Reference 1, in dichloromethane (100 mL) was cooled to 0° C and then treated with anisole (5 mL, 46.5 mmol) and trifluoroacetic acid (50 mL, 296 mmol). The mixture was stirred for 30 minutes, while allowing it to warm to room temperature, and then concentrated. The residue was dissolved in toluene (100 mL) and the solution was concentrated. The residue was again dissolved in toluene (100 mL) and concentrated to provide 2-amino--V-methoxy--V-methyl-4-phenylbutyramide trifluoroacetic acid salt (9.74 g 29 mmol) as a crude product. MS(PCI) m/z = 223 (M +1).
REFERENCE 7 Ethyl 3S-benzyloxycarbonylamino-2-hydroxy-5-phenylpentanimidate
A suspension comprised of lithium aluminum hydride (0.885 g, 23.3 mmol) in anhydrous diethyl ether was cooled to -45 ° C under nitrogen and then treated with a solution of benzyl lS-(-V-methoxy--V-methylcarbamoyl)-3-phenylpropylcarbamate (5.53 g, 15.53 mmol), provided as in Reference 1, in ether (75 mL) and THF (25 mL) added dropwise over a period of 30 minutes such that the temperature of the mixture was maintained at -40 to -45° C. The mixture was allowed to warm to 5 ° C and then recooled to -35 ° C. A saturated solution of sodium bicarbonate (7 mL, 0.5 M) was added dropwise and the mixture was allowed to warm to 0° C. The mixture was allowed to warm to room temperature and stirred for 1 hour to provide a precipitate. The precipitate was collected by filtration and washed with ether (100 mL). The filtrate and washings were combined and washed sequentially with ice cold IN hydrochloric acid (2x 50 mL), saturated sodium bicarbonate (2 x 50 mL) and brine (50 mL), dried (Na2S04) and concentrated in vacuo to provide benzyl lS-formyl-3-phenylpropylcarbamate (4.01 g, 13.5 mmol) as a colorless oil. MS (PCI) m z = 298 (M + 1).
A solution of benzyl lS-formyl-3-phenylpropylcarbamate (4.557 g, 15.3 mmol) in anhydrous dichloromethane (50 mL) was stirred while sequentially treated with 2-hydroxy- 2-methylpropionitrile (4.25 mL, 46.2 mmol) and triethylamine (1.28 mL, 9.20 mmol). The mixture was stirred for 4 hours at room temperature and concentrated in vacuo. The residue was dissolved in ether (100 mL) and the solution was washed sequentially with water (5 x 20 mL) and brine (20 mL), dried (MgSO4) and concentrated to provide benzyl
2-cyano-2-hydroxy-15-phenethylethylcarbamate (4.957 g, 15.3 mmol) as a yellow oil. 'H NMR (CDC13): δ 1.75 - 2.01 (m, 2H), δ 2.08 - 2.24 (m, IH), δ 2.51 - 2.80 (m, 2H), δ 3.70 - 4.02 (m, IH), δ 5.07, δ 5.33 (m, 3H), δ 7.10 - 7.47 (m, 10H).
A mixture of chloroform (30 mL) and anhydrous ethanol (30 mL, 510 mmol) was cooled to 0° C and then treated with acetyl chloride (32.6 mL, 459 mmol) added dropwise over a period of 30 minutes. The mixture was cooled by adding a solution of crude benzyl 2-cyano- 2-hydroxy-lS-phenethylethylcarbamate (4.957 g, 15.3 mmol) in chloroform (30 mL). The mixture was stirred for 2 hours at 0°C and then 6 hours at room temperature and concentrated in vacuo to provide ethyl 3S-benzyloxycarbonylamino-2-hvdroxy-5-phenylpentanimidate (6.212 g 15.3 mmol) as a crude yellow oil. MS (PCI) m/z = 371 (M + 1).
REFERENCE 8
2S-Amino-4-phenyl-l-(4S-phenyl-4.5-dihydrooxazol-2-yl)butan-l-ol
(a) A mixture comprised of ethyl 3S-benzyloxycarbonylamino-2-hydroxy- 5-phenylpentanimidate (0.78 g, 1.92 mmol), provided as in Reference 7, diisopropylethylamine (0.218 μL, 1.26 mmol) and 2S-amino-2-phenylethanol (0.260 g, 1.9 mmol) in chloroform (25 mL) was heated at reflux for 3 hours and then was stirred for approximately 12 hours, while allowing to cool to room temperature. The mixture was concentrated and the residue was dissolved in ethyl acetate (50 mL). The solution was washed sequentially with 0.5N sodium hydroxide (40 mL) and brine (40 mL), dried (MgSO4) and then concentrated. Product was purified from the residue by flash chromatography eluting with 1:3 hexanes/ethyl acetate to provide benzyl 2-hydroxy-2-(4,5-dihydro-4S-phenyloxazol-2-yl)-lS-phenyethylethylcarbamate (0.475 g, 1.1 mmol) as an oily mixture of diastereomers. MS (PCI) m/z = 445 (M +1). (C27H28N204).
(b) A solution comprised of benzyl 2-hydroxy-2-(4,5-dihydro-4S-phenyloxazol-2-yl)- lS-phenyethylethylcarbamate (100 mg, 0.22 mmol) in methanol (10 mL) was placed under a nitrogen atmosphere and stirred while Pearlman's catalyst (20 mg) was added. The mixture was stirred vigorously under a hydrogen atmosphere until the reaction was complete and then filtered. The filter was washed with methanol (2 x 25 mL). The combined filtrates were concentrated to provided 2S-amino-4-phenyl- 1 -(4S-phenyl-4.5-dihydrooxazol-2-yl)butan- 1 -ol (51 mg, 0.16 mmol) as a clear oil. MS (PCI) m/z = 311(M +1). (C19H22N2O2).
Proceeding as in Reference 8 provided methyl 2-(2S-benzyloxycarbonylamino- l-hydroxy-4-phenylbutyl)-4,5-dihydrooxazole-4-carboxylate.
REFERENCE 9
2S-Amino- 1 -oxazol-2-yl-4-phenylbutan- 1 -ol trifluoroacetic acid salt
A solution comprised of oxazole (0.25 g, 3.62 mmol) in THF (20 mL) was treated with borane tetrahydrofuran complex (3.62 mL, 3.62 mmol) under nitrogen and the mixture was stirred for 30 minutes and then cooled to -78 °C. A solution comprised of .sec-butyl lithium (2.78 mL, 3.62 mmol) in cyclohexane was added dropwise and the mixture was stirred for 30 minutes. A solution comprised of tert-butyl (S)-l-formyl-3-phenylpropylcarbamate (0.476 g, 1.81 mmol) in THF (25 mL) was added and the mixture was stirred and allowed to warm while the reaction proceeded to completion. The mixture then was cooled to -78 °C, quenched by slowly adding 5% acetic acid in ethanol (20 mL), allowed to warm to ambient temperature and stirred for 18 hours. The mixture was concentrated to dryness and the residue was extracted with ether (2x25 mL). The combined extracts were washed with brine, dried (MgSO4) and concentrated to dryness to provide tert-butyl 2-hydroxy-2-oxazol-2-yl-lS-phenethylethylcarbamate (0.125 g, 0.376 mmol) as a yellow oil. MS (PCI) m/z = 333 (M + 1).
A mixture comprised of tert-butyl 2-hydroxy-2-oxazol-2-yl-lS-phenethylethylcarbamate (0.125 g, 0.376 mmol), anisole (0.2 mL) and trifluoroacetic acid (0.6 mL) in dichloromethane (20 mL) was stirred at room temperature for 2 hours and then concentrated to provide 2S-amino-l-oxazol-2-yl-4-phenylbutan-l-ol trifluoroacetic acid salt ( 0.08 g, 0.229 mmol) as a yellow oil. MS (PCI) m z = 233 (M + 1). REFERENCE 10 Methyl 2-(25-amino- 1 -hvdroxy-4-phenylbutyl)oxazole-4-carboxylate
A solution comprised of methyl 2-(2S-benzyloxycarbonylamino-l -hydroxy - 4-phenylbutyl)-4,5-dihydrooxazole-4-carboxylate (0.100 g, 0.235 mmol), provided as in Reference 10, in dichloromethane (3 mL) was cooled to 0° C and then treated with DBU
(39 mL, 0.26 mmol) and bromotrichloromethane (26 mL, 0.26 mmol). The mixture was stirred for 6 hours at 0° C, washed with ammonium chloride (10 mL) and concentrated. The residue was dried (MgS04) to provide methyl 2-(2S-benzyloxycarbonylamino-l -hydroxy - 4-phenylbutyl)oxazole-4-carboxylate. MS(PCI) m/z = 425 (M +1). Deprotecting provided methyl 2-(2S-amino- 1 -hydroxy -
4-phenylbutyl)oxazole-4-carboxylate.
REFERENCE 11 2-Benzooxazol-2-yl-2-(tert-butyl-dimethyl-silanyloxy)-lS-phenethylethylamine
A solution of 2S-amino-l-benzooxazol-2-yl-4-phenylbutan-l-ol (600 mg), provided as in Referenced, in dichloromethane (15 mL) was cooled to 0°C and then treated with 2,6-lutidine (0.57 mL) followed by tert-butyldimethylsilyl trifluoromethanesulfonate (1.08 mL). The solution was stirred for 3 hours and then additional dichloromethane was added (50 mL). The mixture was washed sequentially with a saturated sodium bi-carbonate solution (50 mL) and brine (50 mL x2), dried over magnesium sulphate and concentrated under reduced pressure to provide 2-benzooxazol-2-yl-2-(tgrt-butyl-dimethyl-silanyloxy)-lS-phenethylethylamine as an orange oil.
REFERENCE 12 2S- Amino- 1 -benzooxazol-2-yl-4-phenylbutan- 1 -ol
A solution of (S)-2-tert-butoxycarbonylamino-4-phenylbutyric acid (500 g, 179 mmol), EDC (37.8 g, 197 mmol), HOBT (41.1g, 269 mmol) and NO-dimethylhydroxylamine hydrochloride (19.2 g, 197 mmol) in , dichloromethane (500 mL) was cooled in an ice bath and then treated with a solution of triethylamine (27.5 mL, 197 mmol) in dichloromethane (150 mL). The ice bath was removed and the reaction mixture was stir at room temperature for approximately 12 hours. The mixture was concentrated by rotary evaporation and the residue was treated with ethyl acetate (450 mL), water (300 mL) and saturated sodium bicarbonate until all solids were dissolved. The ethyl acetate layer was separated and washed sequentially with saturated sodium bicarbonate (100 mL), water (100 mL), IN hydrochloric acid (100 mL), water (100 mL) and brine (50 mL). The solution was dried over anhydrous magnesium sulfate and concentrated to provide tert-butyl (S)-l-(-V-methoxy--V-methylcarbamoyl)- 3-phenylpropylcarbamate (53.41 g, 93% yield) as a clear, colorless oil.
The tert-butyl (S)- 1 -(iV-methoxy--V-methylcarbamoy l)-3-pheny lpropylcarbamate provided above was divided into three portions (5.0 g 15.5 mmol; 4.88 g , 15.1 mmol; and 4.54 g, 14.1 mmol). Each portion was azeotroped with toluene by rotary evaporation and dried under reduced pressure to remove residual ethyl acetate and water. Each portion of the ester was taken up into anhydrous diethyl ether (75 mL) and the mixtures were cooled in an ice bath under nitrogen. Each of the mixtures were treated with lithium aluminum hydride (IM in diethyl ether, 23.3 mL, 22.7 mL, and 21.1 mL, respectively) added by syringe and the mixtures were stirred at 0°C for 90 minutes. The mixtures were treated with ethyl acetate (5 mL), stirred for 15 minutes, further treated with saturated KH2PO4 (5 mL), IN hydrochloric acid (1 mL) and then additional IN hydrochloric acid until the solid mass dissolved. The resulting solutions were combined and extracted with ethyl acetate (3x 200 mL). The extracts were dried over anhydrous magnesium sulfate and concentrated. The residue was dried under reduced pressure to provide tert-butyl (S)-l-formyl-3-phenylpropylcarbamate (11.61 g, 99% yield).
A solution of tert-butyl (S)-l-formyl-3-pheny lpropylcarbamate (11.15 g, 42.3 mmol) in dichloromethane (25 mL) was cooled in an ice bath under nitrogen and then treated sequentially with acetone cyanohydrin (10.8 mL, 119 mmol) and triethylamine (3.5 mL, 25.4 mmol). The reaction was stirred for approximately 12 hours at room temperature and then concentrated by rotary evaporation. The residue was dissolved in 1:1 hexanes:ethyl acetate (250 mL) and the solution was washed sequentially with water (3x 100 mL) and brine (50 mL), dried over anhydrous magnesium sulfate and concentrated. Product was purified from the residue by silica gel chromatography using 2: 1 hexanes:ethyl acetate eluent to provide tert-butyl 2-cyano-2-hydroxy-lS-phenethylethylcarbamate (12.05 g, 98% yield). A mixture of chloroform (12.8 mL) and absolute ethanol (9 mL, 153 mmol), under a nitrogen stream with an attached Firestone valve bubbler, was cooled in an ice bath and then treated with acetyl chloride (9.2 mL, 129 mmol) added by syringe. The mixture was allowed to stand for 5 minutes and then a solution of tert-butyl
2-cyano-2-hydroxy-15-phenethylethylcarbamate (2.34 g, 8 mmol) in chloroform (19.2 mL) was added. The nitrogen inlet was removed and the mixture was stirred and slowly warm to room temperature over approximately 12 hours. The mixture then was concentrated by rotary evaporation and the residue was treated with absolute ethanol (40 mL)and ø-aminophenol (873 mg, 8 mmol). The mixture was heated at 95°C under nitrogen for 5 hours and then stirred at room temperature for approximately 12 hours. The mixture was treated with diethyl ether (150 mL) and the resulting solution was washed repeatedly with IN KOH until the aqueous wash layer was colorless. The organic phase was separated, dried over anhydrous magnesium sulfate and concentrated. The residue was recrystallized from hot hexane and a minimum amount of ethyl acetate to give a tan powder (335 mg). The mother liquor was combined with the mixed fractions from a similarly performed reaction run and purified by silica gel chromatography using 5% methanol in dichloromethane to provide 2S-amino- 1 -benzooxazol-2-yl-4-phenylbutan- 1 -ol (1.27 g, 52% average yield) as an orange semi-solid mass.
Proceeding as in Reference 12 provided the following compounds:
2-amino- 1 -benzooxazol-2-yl-ethanol;
2-amino- 1 -benzooxazol-2-yl-2-methyl-propan- 1 -ol;
(S)-2-amino- 1 -benzooxazol-2-yl-hexan- 1 -ol; 1 -( 1 -amino-cvclopropyl)- 1 -benzooxazol-2-yl -methanol;
(S)-2-amino- 1 -benzooxazol-2-yl-propan- 1 -ol:
(S)-2-amino- 1 -benzooxazol-2-yl-4-methanesulfonyl-butan- 1 -ol:
(S)-2-amino- 1 -benzooxazol-2-yl-ρentan- 1 -ol;
(S)-2-amino- 1 -benzooxazol-2-yl-butan- 1 -ol; and 2-Amino- 1 -benzooxazol-2-yl-3-methoxy-propan- 1 -ol : ]H NMR (CDC13): 7J0 (m, IH),
7.53 (m, IH), 7.34 (m, 2H), 4.88-5.0 (m, IH), 3.60 (m, IH), 3.53 (m, 3H), 3.37 (s, IH), 3.30 (s, IH); EXAMPLE 1 -V- iR-(2-Benzooxazol-2-yl-2-hvdroxy-15-phenethylethylcarbamoyl)-2-benzylsulfonylethyll- moφholine-4-carboxamide (Compound 1)
Figure imgf000073_0001
A mixture of 2S-amino-l-benzooxazol-2-yl-4-phenylbutan-l-ol (2.2 g, 7.8 mmol), provided as in Reference 12, 2-moφholin-4-ylcarbonylamino-3-benzylsulfonylpropionic acid (2.78 g, 7.8 mmol), EDC (1.64 g, 8.57 mmol), 1-hydroxybenzotriazole hydrate (1.58 g, 11.7 mmol) and -V-methylmoφholine (2.4 mL, 17.1 mmol) in dichloromethane was stirred for 1 hour. The mixture was treated with additional amounts of EDC (0.1 eq) and
1-hydroxybenzotriazole hydrate (0.1 eq) and stirred for 30 minutes. The mixture was treated with an additional amount of EDC (0.1 eq) and stirred for 15 minutes. The mixture was treated with an additional amount of EDC (0.1 eq) and stirred for 30 minutes. The mixture was concentrated and the residue was taken up into ethyl acetate. The mixture was washed sequentially with IN hydrochloric acid (3x 50 mL), saturated sodium bicarbonate solution (2x 50 mL) and brine (50 mL), dried (MgS04) and concentrated to provide -V-riR-(2-benzooxazol-2-yl-2-hvdroxy-lS-phenethylethylcarbamoyl)-
2-benzylsulfonylethyllmoφholine-4-carboxamide (4 g, 6.44 mmol); Η NMR (CDC13): 7.68 (m, IH), 7.52 (m, IH), 7.10-7.45 (m, 12H), 6.0-6.25 (m, IH), 4.95-5.1 (m, IH), 4.52-4.80 (m, IH), 4.15-4.5 (m, 3H), 3.1-3.75 (m, 10H), 2.69 (m, 2H), 2.06 (m, IH), 1.80 (m, IH); MS: m/e 621.0;
EXAMPLE 2 2S-Acetylamino--V-(2-oxazol-2-yl-2-hydroxy-lS-phenethylethyl)-3-cyclohexylpropionamide
(Compound 2)
Figure imgf000074_0001
A mixture comprised of 2-acetylamino-3-cyclohexylpropionic acid (0.45 g, 0.211 mmol), PyBOP® (0.11 g, 0.21 mmol) and diisopropylethylamine (0.037 g, 0.211 mmol) in DMF (10 mL) was stirred for 15 minutes at room temperature and a solution comprised of 2S-amino- l-oxazol-2-yl-4-phenylbutan-l-ol trifluoroacetic acid salt, provided as in Reference 9, in DMF and neutralized with diisopropylethylamine was added. Additional diisopropylethylamine (0.037 g, 0.211 mmol) was added and the mixture was stirred for 2 hours at room temperature and then poured into 100 mL of ice cold water. The aqueous phase was extracted with ethyl acetate (3 x 25 mL) and the combined organic layers were washed sequentially with 1 N hydrochloric acid (2 x 25 mL), water (2 x 25 mL) and brine (2 x 25 mL), dried (MgS04) and concentrated. Product was purified from the residue by flash chromatography eluting with 1:3 hexanes/ethyl acetate to provide 2S-acetylamino--V-(2-oxazol-2-yl- 2-h ydroxy- 1 S-phenethylethvD-3 -c yclohexyl propionamide (0.036 g, 0.084 mmol) as an oil. MS (ESI) m/z = 428 (M + 1); Η-NMR (300 MHz, CD3OD): δ 0.80 (m, 2H), δ 1.12 (m, 4H), δ 1.40(m, 2H), δ 1.65 (m, 6H), δ 1.80 (m, IH), δ 2.00 (m, 4H), δ 2.70 (m, IH), δ 2.80 (m, IH), δ 4.44 (m, IH), δ 4.51 (m, IH), δ 7.11 - 7.47 (m, 6H), δ 7.99 (s, IH), (C24H33N304).
Proceeding as in Example 2 provided the following compounds of Formula I:
3-cyclohexyl--V- _ 2-hvdroxy-2-(5-phenyloxazol-2-yl)- 1 S-phenethylethyl Ipropionamide
(Compound 3); MS (ESI) m/z = 448 (M + 1); Η-NMR (300 MHz, CDC13): δ 0.89 (m, 2H), δ 1.20 (m, 4H), δ 1.45 (m, IH), δ 1.65 (m, 6H), δ 1.80 (m, IH), δ 2.09 (m, 4H), δ 2.73 (t, J = 4 Hz, 2H), δ 4.51 (m, IH), δ 4.96 (m, 2H), δ 6.00 (m, IH), δ 7.11 - 7.47 (m, 9H), δ 7.60 (m, 2H), (C28H35N203);
25-acetylamino--V-r2-hvdroxy-lS-phenethyl-2-(5-phenyloxazol-2-yl)ethvn- 3-cvclohexylpropionamide (Compound 4): MS (ESI) m/z = 505 (M + 1); 'H-NMR (300 MHz, CDC13): δ 0.80 (m, 2H), δ 1.12 (m, 4H), δ 1.40 (m, 2H), δ 1.65 (m, 6H), δ 1.80 (m, IH), δ 2.00 (m, 5H), δ 2.70 (m, 2H), δ 4.51 (m, IH), δ 4.96 (m, 2H), δ 6.19 (m, IH), δ 6.98 (m, IH), δ 7.11 - 7.47 (m, 9H), δ 7.62 (m, 2H), (C30H38N3O4); and
-V-(lS-benzothiazol-2-ylcarbonyl-3-phenylpropyl)-3-cvclohexylpropionamide (Compound 5); Η NMR: δ 0.83 (m, 2H), δ 1.20 (m, 5H), δ 1.48 (q, 2H, J = 9 Hz), δ 1.67 (m, 4H), δ 2.20 (m, 3H), δ 2.48 (m, IH), δ 2.75 (m, 2H), δ 5.95 (m, IH), δ 6.35 (d, IH, J = 9 Hz), δ 7.25 (m, 5H), δ 7.57 (m, 2H), δ 7.93 (d, IH, J = 9 Hz), δ 8.18 (d, IH, J = 9 Hz); ES-MS m/z 435 (MH+); and
2S-acetylamino-N-(lS-benzothiazol-2-ylcarbonyl-3-phenylpropyl)- 3-cvclohexylpropionamide (Compound 6); 'H NMR: δ 0.87 (m, 8H), δ 1.22 (m, 6H), δ 1.92 (m, IH), δ 2.12 (m, IH), δ 2.48 (m, IH), δ 2.78 (m, 2H), δ 3.87 (d, IH, J = 7 Hz), δ 5.62 (m, IH), δ 7.20 (m, 6H), δ 7.53 (m, 2H), δ 7.98 (d, IH, J = 7 Hz), δ 8.18 (d, IH, J = 7 Hz); ES-MS m/z 492 (MH+).
N-\ 1 S-( 1 S-phenethyl-2-benzooxazol-2-yl- 1 -oxoethylcarbamoyl)- 2-naphth-2-ylethyllpiperidine-4-carboxamide (Compound 7), Η NMR (DMSO-d6): δ 1.32 - 1.76 (m, 4H), δ 1.90 - 2.09 (m, 2H), δ 2.22 - 2.60 (m, 2H), δ 2.65 - 3.26 (m, 6H), δ 4.72 - 4.86 (m, IH), δ 5.26 (m, IH), δ 7.06 - 7.31 (m, 5H), δ 7.45 (m, 4H), δ 7.55 (dt, J = 1.26, 7.84 Hz, IH), δ 7.65 (dt, J = 1.18, 8.00 Hz, IH), δ 7.72 - 7.88 (m, 3H), δ 7.90 (d, J = 8.06 Hz, IH), δ 7.99 (d, J = 7.86 Hz, IH), δ 8.14 (bs, IH), δ 8.24 (d, J = 8.04 Hz, IH), δ 8.46 (bs, IH), δ 8.94 (d, J = 6.43 Hz, IH);
2S-acetylamino--V-(lS-benzooxazol-2-ylcarbonyl-3-phenylpropyl)- 3-cvclohexylpropionamide (Compound 8); MS (ESI) m/z = 476 (M + 1); Η-NMR (300 MHz, CDC13): δ 0.85 (m, 2H), δ 1.26 (m, 4H), δ 1.47 (m, 2H), δ 1.64 (m, 6H), δ 1.99 (s, 3H), δ 2.15 (m, 2H), δ 2.41 (m, IH), δ 2.72 (t, J = 6Hz, 2H), δ 4.59 (q, J = 4Hz, IH), δ 5.65 (q, J = 2Hz, IH), δ 6.26 (d, J = 6 Hz, IH), δ 7.10 - 7.26 (m, 6H), δ 7.41 - 7.65 (m, 3H), δ 7.86 (d, J = 6Hz IH), (C28H33N3O4); tert-butyl 1 S-( 1 S-benzooxazol-2-ylcarbonyl-3-phenylpropylcarbamoyl)- 2-cvclohexylefhylcarbamate (Compound 9);
-V-ri-(benzooxazol-2-ylcarbonyl)-3-phenylpropyll-3-cvclohexylpropionamide (Compound 10);
3-cvclohexyl-N-r3S-phenyl-l-(5-phenyloxazol-2-ylcarbonyl)propyllpropionamide (Compound 11); MS (ESI) m z = 445 (M + 1); Η-NMR (300 MHz, CDC13): δ 0.89 (m, 2H), δ 1.20 (m, 4H), δ 1.55 (m, 2H), δ 1.68 (m, 6H), δ 2.12 (m, IH), δ 2.27 (t, J = 4Hz, 2H), δ 2.48 (m, IH), δ 2.76 (m, 2H), δ 5.70 (m, IH), δ 6.35 (d, J = 4 Hz, IH), δ 7.19 - 7.30 (m, 5H), δ 7.48 (m, 3H), δ 7.57 (s, IH), δ 7.79 (d, J = 4Hz, 2H), (C28H32N203);
2S-acetylamino--V-riS-(5-phenyloxazol-2-ylcarbonyl)-3-phenylpropyll- 3-cvclohexylpropionamide (Compound 12); MS (ESI) m/z = 502 (M + 1); Η-NMR (300 MHz, CDC13): δ 0.80 (m, 2H), δ 1.12 (m, 4H), δ 1.50 (m, IH), δ 1.65 (m, 6H), δ 1.80 (m, IH), δ 2.05 (s, 3H), δ 2.12 (m, IH), δ 2.48 (m, IH), δ 2.70 (t, J = 6Hz, 2H), δ 4.52 (q, J = 2Hz, IH), δ 5.60 (q, J = 2Hz, IH), δ 5.98 (d, J = 6 Hz, IH), δ 6.92 (d, J = 6Hz, IH), δ 7.19 - 7.30 (m, 5H), δ 7.48 (m, 3H), δ 7.57 (s, IH), δ 7.79 (d, J = 4Hz, 2H), (C30H35N3O4); benzyl lS-(benzooxazol-2-ylcarbonylmethylcarbamoyl)-3-methylbutylcarbamate
(Compound 13); benzyl lS-(5-phenylbenzooxazol-2-ylcarbonylmethylcarbamoyl)-3-methylbutylcarbamate (Compound 14);
2S-acetylamino--V-(lS-oxazol-2-ylcarbonyl-3-phenylpropyl)-3-cyclohexylpropionamide (Compound 15); MS (ESI) m/z = 426 (M + 1); Η-NMR (300 MHz, CDC13): δ 0.85 (m, 2H), δ 1.20 (m, 4H), δ 1.50 (m, 2H), δ 1.65 (m, 6H), δ 2.05 (s, 3H), δ 2.48 (m, IH), δ 2.70 (t, J = 6Hz, 2H), δ 4.52 (q, J = 2Hz, IH), δ 5.60 (q, J = 2Hz, IH), δ 5.93 (d, J = 6 Hz, IH), δ 6.89 (d, J = 6Hz, IH), δ 7.19 - 7.38 (m, 5H), δ 7.47 (s, IH), δ 7.79 (s, IH), (C^^A); benzyl 1 S-benzooxazol-2-ylcarbonyl-3-phenylpropylcarbamate (Compound 16); 2-acetylamino--V-(lS-benzooxazol-2-ylcarbonyl-3-phenylpropyl)-3-phenylpropionamide
(Compound 17);
-V-(lS-benzooxazol-2-ylcarbonyl-3-phenylpropyl)benzylsulfonamide (Compound 18); 'H NMR (CDC13): 7.88 (d, J=6.2Hz, IH), 7.67 (d, J=6.2Hz, IH), 7.60 (t, J=6.2Hz, IH), 7.51 (t, J=6.2Hz, IH), 7.35 (d, J=6.2Hz, 2H), 7.08-7.29 (m, 7H), 6.96 (t, J=6.2Hz, IH), 5.52 (d, JK=9.4 Hz, IH), 4.90 (td, J=9.4, 3.1Hz, IH), 4.31 (dd, J=10.9, 10.9Hz, 2H), 2.80 (m, IH), 2.27 (m, IH), 2.04 (m, IH); MS: m/e=435.0;
-V-(lS-benzooxazol-2-ylcarbonyl-3-phenylpropyl)-2-cyclohexylethanesulfonamide (Compound 19); 'H NMR (CDC13): 7.94 (d, J=6.3Hz, IH), 7.70 (d, J=6.3Hz, IH), 7.62 (t, J=6.3Hz, IH), 7.52 (t, J=6.3Hz, IH), 7.17-7.34 (m, 5H), 5.42 (d, J=9.5Hz, IH), 5.17-5.25 (m, IH), 2.79-3.09 (m, 4H), 2.38-2.55 (m, IH), 2.08-2.21 (m, IH), 1.52-1.79 (m, 7H), 1.08-1.34 (m, 4H), .77-1.01 (m, 2H); MS m/e=455.1; -V-(l-benzooxazol-2-ylcarbonyl-3-phenylpropyl)-3-cvclopentylpropionamide
(Compound 20);
-V-(lS-benzooxazol-2-ylcarbonyl-3-phenylpropyl)-2-cvclohexylacetamide (Compound 21);
-V-(lS-benzooxazol-2-ylcarbonyl-3-phenylpropyl)-2-bicyclor2.2.11hept-2-ylacetamide (Compound 22);
-V-(lS-benzooxazol-2-ylcarbonyl-3-phenylpropyl)-4-methylpentanamide (Compound 23);
N-( 1 S -benzooxazol-2-ylcarbony l-3-phenylpropyl)-2-naphthalen- 1 -ylacetamide (Compound 24); Η NMR (CDC13): 7.96 (m, IH), 7.84 (m, 2H), 7.82 (m, IH), 7.42-7.75 (m, 6H), 7.14 (m, 4H), 6.86 (m, 2H), 6.25 (m, IH), 5.64 (m, 2H), 4.08 (m, IH), 2.45 (m, 2H),2.42 (m, IH), 1.90 (m, IH);
-V-(l-benzooxazol-2-ylcarbonyl-3-phenylpropyl)-3-phenylpropionamide (Compound 25); Η NMR (CDC13): 7.90 (d,J=8.0Hz, IH), 7.65 (d,J=8.0Hz, IH), 7.59 (m, IH), 7.56 (m, IH), 7.05-7.35 (m, 11H), 6.20 (d, J=7.0Hz, IH), 5.76 (m, IH), 2.97 (m, 2H), 2.5-2.7 (m, 4H), 2.4 (m, IH), 2.1 (m, IH); methyl 2-.2-(3S-cvclohexylpropionylamino)-4-phenylbutyryl~l-
4.5-dihvdrooxazole-4S-carboxylate (Compound 26); MS (ESI) m/z = 429 (M + 1); Η-NMR (300 MHz, CDC13): δ 0.89 (m, 2H), δ 1.22 (m, 4H), δ 1.51 (m, IH), δ 1.65 (m, 6H), δ 2.05 (m, IH), δ 2.20 (t, J = 4 Hz, 2H), δ 2.46 (m, IH), δ 2.73 (m, 2H), δ 3.80 (s, 3H), δ 4.55 (m, IH), δ 4.60 (m, IH), δ 5.00 (m, IH), δ 5.45 (m, IH), δ 6.15 (m, IH), δ 7.13 - 7.35 (m, 5H), (C24H32N2O5); methyl 2-,2-(3S-cvclohexylpropionylamino)-4-phenylbutyrvHoxazole-4-carboxylate (Compound 27); MS (ESI) m/z = 427 (M + 1); Η-NMR (300 MHz, CDC13): δ 0.89 (m, 2H), δ 1.22 (m, 4H), δ 1.49 (m, IH), δ 1.65 (m, 6H), δ 2.20 (m, 3H), δ 2.46 (m, IH), δ 2.74 (m, 2H), δ 3.99 (s, 3H), δ 5.62 (m, IH), δ 6.20 (d, J = 4Hz, IH), δ 7.15 - 7.35 (m, 5H), δ 8.40 (s, IH), (C24H30N2O5); benzyl lS-(lS-benzooxazol-2-ylcarbonyl)- 3-phenylpropylcarbamoyl)-2-naphthalen-2-ylethylcarbamate (Compound 28); 2-acetylamino--V-(lS-benzooxazol-2-ylcarbonyl-3-phenylpropyll- 3-(2-fluorophenyl)propionamide (Compound 29);
2S-acetylamino--V-(lS-benzooxazol-2-ylcarbonyl-3-phenylρroρyl)-2-methyl- 3-phenylpropionamide (Compound 30); tert-butyl lS-(lS-benzooxazol-2-ylcarbonyl-3-phenylpropylcarbamoyl)-
3-phenylpropylcarbamate (Compound 31);
-V-(l-benzooxazol-2-ylcarbonyl)-3-ρhenylpropyl)-4-cvclohexylbutyramide (Compound 32); Η NMR (CDC13): 7.94 (d, J=7.9Hz, IH), 7.68 (d, 7.9Hz, IH), 7.58 (t,J=7.9Hz, IH), 7.50 (t, J=7.9Hz, IH), 7.10-7.32 (m, 5H), 6.27 (d, J=11.8Hz, IH), 5J6-5.89 (m, IH), 2J4-2.89 (m, 2H), 2.42-2.61 (m, IH), 2.11-2.32 (m, 3H), 1.53-1.79 (m, 9H), 1.05-1.32 (m, 4H), 0.79-1.0 (m, 2H); MS: m/e=433; methyl 2-.2S-(3-cvclohexy-propionylamino)-4-phenylbutyryll- 4.5-dihvdrooxazol-4S-ylcarboxylate (Compound 33); MS (ESI) m z = 429 (M + 1); Η-NMR (300 MHz, CDC13): δ 0.89 (m, 2H), δ 1.22 (m, 4H), δ 1.51 (m, IH), δ 1.65 (m, 6H), δ 2.05 (m, IH), δ 2.20 (t, J = 4 Hz, 2H), δ 2.46 (m, IH), δ 2.73 (m, 2H), δ 3.80 (s, 3H), δ 4.58 (m, 2H), δ 5.00 (m, IH), δ 5.45 (m, IH), δ 6.15 (m, IH), δ 7.13 - 7.35 (m, 5H), (C24H32N2O5);
3-cvclohexyl--V- . 1 -(5-methoxybenzooxazol-2-ylcarbonyl)-3-phenylpropyl1propionamide (Compound 34); MS (ESI) m/z = 449 (M + 1); Η-NMR (300 MHz, CDC13): δ 0.95 (m, 2H), δ 1.22 (m, 4H), δ 1.51 (m, 2H), δ 1.65 (m, 6H), δ 2.15 (m, IH), δ 2.20 "(t, J = 4 Hz, 2H), δ 2.50 (m, IH), δ 2.77 (q, J = 2 Hz, 2H), δ 3.92 (s, 3H), δ 5.78 (m, IH), δ 6.37 (m, IH), δ 7.13 - 7.35 (m, 5H), δ 7.53 (d, J = 6 Hz, IH), (C27H32N204);
2-acetyl--V-(lS-benzooxazol-2-ylcarbonyl- 3-phenylpropyD- 1 ,2,3,4-tetrahydroisoquinoline-3S-carboxamide (Compound 35);
2S-acetylamino--V-(lS-benzooxazol-2-ylcarbonyl-3-phenylpropyl)- 3-(2-chlorophenyl)propionamide (Compound 36);
3-cvclohexyl-JV-[lS-(6-methoxybenzooxazol-2-ylcarbonyl)-3-phenylpropyllpropionamide (Compound 37); MS (ESI) m/z = 449 (M + 1); Η-NMR (300 MHz, CDC13): δ 0.95 (m, 2H), δ 1.22 (m, 4H), δ 1.51 (m, 2H), δ 1.65 (m, 6H), δ 2.15 (m, IH), δ 2.20 (t, J = 4 Hz, 2H), δ 2.50 (m, IH), δ 2.77 (q, J = 2 Hz, 2H), δ 3.95 (s, 3H), δ 5.78 (m, IH), δ 6.37 (d, J = 6 Hz, IH), δ 7.10 - 7.35 (m, 5H), δ 7.77 (d, J = 6 Hz, IH), (C27H32N2O4);
3-cvclohexyl--V-riS-(5-trifluoromethylbenzooxazol-2-ylcarbonyl)- 3-phenylpropyllpropionamide (Compound 38); MS (ESI) m/z = 487 (M + 1); Η-NMR (300 MHz, CDC13): δ 0.95 (m, 2H), δ 1.22 (m, 4H), δ 1.51 (m, IH), δ 1.65 (m, 6H), δ 2.20 (m, 3H), δ 2.51 (m, IH), δ 2.80 (q, J = 2 Hz, 2H), δ 5.76 (m, IH), δ 6.22 (d, J = 6 Hz, IH), δ 7.15 - 7.35 (m, 5H), δ 7.77 (m, 2H), δ 8.25(s, IH), (C27H29F3N203);
2-acetylamino--V-(l-benzooxazol-2-ylcarbonyl-3-phenylpropyl)- 3-(2-trifluoromethylphenyl)propionamide (Compound 39);
N-(l-benzooxazol-2-ylcarbonyl-3-phenylpropyl)-3-moφholin-4-ylpropionamide (Compound 40);; Η NMR (CDC13): 7.90 (m, IH), 7.76 (m, IH), 7.06-7.36 (m, 7H), 4.00 (m, IH), 3.12 (m, 4H), 2.50-3.5 (m, 2H), 2.0-2.5 (m, 2H), 1.83 (m, 4H); MS: m/e=421.9;
3-cvclohexyl--V-riS-(5-nitrobenzooxazol-2ylcarbonyl)-3-phenylpropyllpropionamide (Compound 41); MS (ESI) nVz = 464 (M + 1); Η-NMR (300 MHz, CDC13): δ 0.95 (m, 2H), δ 1.22 (m, 4H), δ 1.51 (m, IH), δ 1.65 (m, 6H), δ 2.20 (m, 3H), δ 2.51 (m, IH), δ 2.80 (m, 2H), δ 5.67 (m, IH), δ 6.17 (d, J = 6 Hz, IH), δ 7.09 - 7.35 (m, 5H), δ 7.77 (d, J = 6Hz, IH), δ 8.50 (d, J = 6 Hz, IH), δ 8.77 (s, IH), (C26H29N3O5); methyl 2-_2S-(3-cvclohexylproρionylamino)-4-phenylbutyrvHbenzooxazole-6-carboxylate (Compound 42); MS (ESI) m/z = 477 (M + 1); Η-NMR (300 MHz, CDC13): δ 0.95 (m, 2H), δ 1.22 (m, 4H), δ 1.51 (m, IH), δ 1.65 (m, 6H), δ 2.23 (m, 3H), δ 2.50 (m, IH), δ 2.77 (m, 2H), δ 4.00 (s, 3H), δ 5.78 (m, IH), δ 6.27 (d, J = 6 Hz, IH), 7.15 - 7.35 (m, 5H), δ 7.98 (d, J = 6 Hz, IH), δ 8.22 (d, J = 6Hz, IH ), δ 8.39 (s, IH), (C28H32N2O5);
W-. lS-(5-chlorobenzooxazol-2-ylcarbonyl)-3-phenylpropyll-3-cvclohexylpropionamide (Compound 43); MS (ESI) m/z = 453 (M + 1); Η-NMR (300 MHz, CDC13): δ 0.95 (m, 2H), δ 1.22 (m, 4H), δ 1.53 (m, 2H), δ 1.65 (m, 5H), δ 2.20 (m, 3H), δ 2.50 (m, IH), δ 2.77 (m, 2H), δ 5.74 (m, IH), δ 6.20 (d, J = 6 Hz, IH), δ 7.09 - 7.35 (m, 5H), δ 7.60 (m, 2H), δ 7.90 (s, IH ), (C26H29ClN2O3); benzyl lS-(lS-benzooxazol-2-ylcarbonyl-3-phenylpropylsulfamoylmefhyl)- 3-methylbutylcarbamate (Compound 44); 'H NMR (CDC13): 7.92 (d, J=7.7Hz, IH), 7.64 (m, IH), 7.57 (m, IH), 7.50 (m, IH), 7.21-7.34 (m, 10H), 6.30 (d,j=9.2Hz, IH), 5.34 (m, IH), 5.11 (m, IH), 4.91 (d,J=9.6Hz, IH), 4.51 (m, IH), 3.11 (m, 2H), 2.89 (m, 2H), 2.50 (m, IH), 2.20 (m, IH), 1.70 (m, IH), 1.5 (m, IH), 1.23-1.46 (m, IH), 0.;92 (t,J=7.4Hz, H); MS: m/e=578.1; -V-{ lS-riS-(benzooxazol-2-ylcarbonyl)-3-phenylpropylsulfamoylmethyll- 3-methylbutyllacetamide (Compound 45); Η NMR (CDC13): 7.89 (d,J=7.7Hz, IH), 7.62 (m, IH), 7.55 (m, IH), 7.49 (m, IH), 7.18-7.30 (m, 5H), 6.7 (d, J=8.9Hz, IH), 5.61 (d, J=9.4Hz, IH), 5.34 (m, IH), 4.86 (m, IH), 3.06 (m, 2H), 2.90 (t, J=7.7Hz,. 2H), 2.24 (m, IH), 2.22 (m, IH), 2.04 (s, 3H), 1.66 (m, IH), 1.48 (m, IH), 1.38 (m, IH), 0.91 (t, J=6.2Hz, 6H); MS: m e=486.1; benzyl lR-(lS-benzooxazol-2-ylcarbonyl-3-phenylpropylsulfamoylmethyl)- 3-methylbutylcarbamate (Compound 46) Η NMR (CDC13): 7.9 (m, IH), 7.60 (m, IH), 7.58 (m, IH), 7.5 (m, IH), 7.75-7.4 (m, 10H), 5.85 (m, IH), 5.0-5.4 (m, 3H), 4.2 (m, IH), 3.15-3.35 (m, 2H), 2.65-2.85 (m, 2H), 2.45 (m, IH), 2.15 (m, IH), 1.9 (m, IH), 1.4-1.7 (m, 3H), 0.9 (m, 6H); MS: m e=578.1; and
-V-ri-(l-benzooxazol-2-ylcarbonyl-3-phenylpropylsulfamoylmethyl)- 3-methylbutyllacetamide (Compound 47) Η NMR (CDC13): 7.9 (m, IH), 7.65 (m, IH), 7.61 (m, IH), 7.60 (m, IH), 7.18-7.30 (m, 5H), 6.0 (m, IH), 5.85 (m, IH), 5.28 (m, IH), 4.50 (m, IH), 3.20 (m, IH), 2.85 (m, IH), 2.70 (m, IH), 1.8-2.2 (m, 2H), 1.95 (S, 3H), 1.35-1.70 (m, 2H), 0.9 (m, 6H); MS: m/e=486.0.
EXAMPLE 3 tert-Butyl lR-(2-benzooxazol-2-yl- 2-hydroxy-lS-phenethylethylcarbamoyl)-2-(2-cyanobenzylsulfanyl)ethylcarbamate (Compound 48)
Figure imgf000080_0001
A solution of 2R-tert-butoxycarbonylamino-3-(2-cyanobenzylsulfanyl)propionic acid (336 mg), 2S-amino-l-benzooxazol-2-yl-4-phenylbutan-l-ol (282mg), l-(3-dimethylaminopropyl)- 3-ethylcarbodiimide hydrochloride (211 mg) and 1-hydroxybenzotriazole (197 mg) in dichloromethane (20 mL) was treated with -V-methylmoφholine (2.2 mL). The reaction mixture was stirred 0.5 hour and then concentrated by evaporation. The residue was dissolved in ethyl acetate (40 mL) and the solution was washed sequentially with water (20 mL), IN hydrochloric acid (30 mL), a saturated sodium bicarbonate solution (30 mL) and then brine (30mL), dried over magnesium sulfate and concentrated by evaporation. The residue was subjected to flash column chromatography on silica eluting with diethyl ether to provide tert-butyl lR-(2-benzooxazol-2-yl-2-hvdroxy-lS-phenethylethylcarbamoyl)- 2-(2-cyanobenzylsulfanyl)ethylcarbamate as an off white solid. MS: 601 [MH]+.
Proceeding as in Example 3 provided tert-butyl lR-(2-benzooxazol-2-yl-2-hvdroxy- lS-phenethylethylcarbamoyl)-2-benzylsulfanylethylcarbamate (Compound 49), MS: 576 [MH]+.
EXAMPLE 4
N- , lR-(2-Benzooxazol-2-yl-2-hvdroxy- 1 S-phenethylethylcarbamoyl)-
2-(2-cvanobenzylsulfanyl)ethyllisonicotinamide
(Compound 50)
Figure imgf000081_0001
A solution of 3-(2-cyanobenzylsulfanyl)-2R-(pyrid-4-ylcarbonyl)aminopropionic acid (425 mg), provided as in Reference 2, 2S-amino-l-benzooxazol-2-yl-4-phenylbutan-l-ol (356 mg) and HATU (356 mg) in dimethylformamide (40 mL) was treated with diisopropylamine (0.239 mL). The reaction mixture was stirred for 16 hours at room temperature then concentrated by evaporation. The residue was dissolved in ethyl acetate and the solution was washed with saturated sodium bicarbonate solution, dried over magnesium sulfate and then concentrated by evaporation. The residue was subjected to flash column chromatography on silica eluting with ethyl acetate to provide N- . 1 R-(2-benzooxazol-2-y 1- 2-hvdroxy-lS-phenethylethylcarbamoyl)-2-(2-cvanobenzylsulfanyl)ethyllisonicotinamide (216 mg) as a gum. MS: 606 [MH]+. HPLC: Rτ= 13.20 minutes.
Proceeding as in Example 4 provided 9H-fluoren-9-ylmethyl 1 S-(2-benzooxazol-2-yl- 2-hvdroxy-lS-phenethylethylcarbamoyl)-2-cvclohexylethylcarbamate (Compound 51);
9H-fluoren-9-ylmethyl lS-,2-benzooxazol-2-vI-2-(tert-buWldimethylsilanyloxy)- lS-phenethylethylcarbamoyll-2-cvclohexylethylcarbamate (Compound 52), MS: 772 [MΗ]+.
EXAMPLE 5 2R-Amino--V-(2-benzooxazol-2-yl-2-hvdroxy-lS-phenethylethyl)-3-(2-cyanobenzylsulfanyl)- propionamide hydrochloride (Compound 53)
Figure imgf000082_0001
A solution tert-butyl lR-(2-benzooxazol-2-yl-2-hydroxy-lS-phenethylethylcarbamoyl)- 2-(2-cyanobenzylsulfanyl)ethylcarbamate (145 mg), provided as in Example 3, in dioxane (20 mL) was treated with hydrogen chloride, bubbling the gas through the solution for 30 minutes. The reaction mixture was concentrated by evaporation and the residue was triturated with diethyl ether to provide 2R-amino--V-(2-benzooxazol-2-yl-2-hvdroxy-lS-phenethylethyl)-3- (2-cyanobenzylsulfanyl)propionamide hydrochloride (117 mg) as a an off-white solid. MS: 537 [MH]+.
Proceeding as in Example 5 provided 2R-amino-N-.2-benzooxazol-2-yl-2-hydroxy- 1 S-phenethylethyl)-3-benzylsulf ony Ipropionamide hydrochloride (Compound 54), MS: 508 [MH]+.
EXAMPLE 6 2S-Amino--V-(2-benzooxazol-2-yl-2-hvdroxy-lS-phenethylethyl)-3-cvclohexylpropionamide
(Compound 55)
Figure imgf000083_0001
A solution of 9H-fluoren-9-ylmethyl lS-(2-benzooxazol-2-yl-2-hydroxy- lS-phenethylethylcarbamoyl)-2-cyclohexylethylcarbamate (165 mg), provided as in Example 4, in dichloromethane (30 mL) was treated with tris(2-aminoethyl)amine bound to polysterene beads (4.48 g). The mixture was stirred at room temperature for 48 hours and then filtered. The resin was washed four times with dichloromethane (20 mL) and the combined filtrates were concentrated under reduced pressure to provide 2S-amino--V-(2-benzooxazol-2-yl- 2-hvdroxy-lS-phenethylethyl)-3-cvclohexylpropionamide (147 mg) as a colourless oil. EXAMPLE 7 2S-Amino--V-r2-benzooxazol-2-yl-2-(tert-butyldimethylsilanyloxy)-lS-phenethylethvn-
3-cvclohexylpropionamide (Compound 56), a protected compound of Formula I
Figure imgf000084_0001
A solution of 9H-fluoren-9-ylmethyl lS-[2-benzooxazol-2-yl- 2-(tcrt-butyldimethylsilanyloxy)-lS-phenethylethylcarbamoyl]-2-cyclohexylethylcarbamate (1.48 g), provided as in Example 4, in dichloromethane (50 mL) was treated with tris-(2- aminoethyl)amine (14.4 mL). The reaction mixture was stirred for 75 minutes and then additional dichloromethane was added (50 mL). The mixture was washed sequentially with brine (50 mL x4) and a pΗ 5.3 buffer (50 mL x3), dried over magnesium sulphate and concentrated to provide 2S-amino-N-.2-benzooxazol-2-yl-2-(tert-butyldimethylsilanyloxy)- lS-phenethylethyll-3-cvclohexylpropionamide as an orange oil.
EXAMPLE 8 tgrt-Butyl 4-[lR-(2-benzooxazol-2-yl-2-hvdroxy-15-phenethylethylcarbamoyll-
2-(2-cvanobenzylsulfanyl)ethylcarbamoylpiperidine-l-carboxylate
(Compound 57)
Figure imgf000085_0001
A solution of 2R-amino--V-(2-benzooxazol-2-yl-2-hydroxy-lS-phenethylethyl)- 3-(2-cyanobenzylsulfanyl)propionamide hydrochloride (170 mg), provided as in Example 5, in dimethylformamide (7 mL) was treated with l-tert-butoxycarbonylpiperidine-4-carboxylic acid tetrafluorophenyl ester tert-butyl ester on resin (excess), prepared according to the procedure described in International Patent Application No. W099/67228, and triethylamine (0.053mL). The suspension was agitated for 16 hours, then filtered, and the filtrate was washed with dimethylaformamide and then concentrated by evaporation. The residue was subjected to flash column chromatography on silica eluting with ethyl acetate to give tert-butyl 4-. lR-(2-benzooxazol-2-yl-2-hvdroxy-lS-phenethylethylcarbamoyH- 2-(2-cvanobenzylsulfanyl)ethylcarbamoylρiρeridine-l-carboxylate (95mg) as a gum. MS: 712 [MH]+.
Proceeding as in Example 8 provided benzyl 4-flS-(2-benzooxazol-2-yl-2-hvdroxy- lS-phenethylethylcarbamoyl)-2-cvclohexylethylcarbamoyllpiperidine-l-carboxylate (Compound 58), MS: 681 [M]+. EXAMPLE 9 Λ-riR-(2-Benzooxazol-2-yl-2-hvdroxy-lS-phenethylethylcarbamoyl)-2-benzylsulfonylethyll- tetrahydropyran-4-carboxamide (Compound 59)
Figure imgf000086_0001
A mixture of 2R-amino--V-(2-benzooxazol-2-yl-2-hydroxy-lS-phenethylethyl)- 3-benzylsulfonylpropionamide hydrochloride (0.3 g), prepared as in Example 5, tetrahydropyran- 4-carboxylic acid (0.072 g), l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.116 g) and 1-hydroxybenzotriazole (0.112 g) in dichloromethane (20 mL) was treated with 4--V-methylmoφholine (0.12 mL). After stirring at room temperature for 4 hours the reaction mixture was left to stand 16 hours and then concentrated by evaporation. The residue was treated with dichloromethane (50 mL) and the mixture was washed sequentially with IN hydrochloric acid solution (5 mL), saturated sodium bicarbonate solution (5 mL) and brine (5 mL), dried over magnesium sulfate and then concentrated by evaporation. The residue was subjected to flash column chromatography on silica eluting with ethylacetate to provide iV-ITR- (2-benzooxazol-2-yl-2-hvdroxy-lS-phenethylethylcarbamoyl)-2-benzylsulfonylethyl1- tetrahvdropyran-4-carboxamide (66 mg) as a cream solid. MS: 618 [MH]+.
Proceeding as in Example 9 provided the following compounds of Formula I:
N-\ lR-(2-benzooxazol-2-yl-2-hydroxy- 1 S-phenethylethylcarbamoyl)- 2-benzylsulfonylethyll-nicotinamide (Compound 60), MS: 613 [MH]+; -V-riR-(2-benzooxazol-2-yl-2-hvdroxy-lS-phenethylethylcarbamoyl)-2-benzylsulfonyl- ethyllpyrazine-2-carboxamide (Compound 61), MS: 614 [MH]+;
4-_ lS-(2-benzooxazol-2-yl-2-hydroxy-lS-phenethylethylcarbamoyl)-2-cvclohexyl- ethylcarbamoyllpiperidine- 1 -carboxylate (Compound 62); and N- , 1 S-(2-benzooxazol-2-yl-2-hydroxy- 1 S-phenethylethylcarbamoyl)-2-cyclohexylethyll - isonicotinamide (Compound 63).
EXAMPLE 10 tert-Butyl 4-. lR-(2-benzooxazol-2-yl-2-hvdroxy- lS-phenethylethylcarbamoyll- 2-(3-methylpyrid-2-ylmethylsulfonyl)ethylcarbamoyllpiperidine-r-carboxylate (Compound 64)
Figure imgf000087_0001
A solution of 2R-amino--V-(2-benzooxazol-2-yl-2-hydroxy-15-phenethylethyl)- 3-(3-methylpyrid-2-ylmethylsulfonyl)propionamide (178 mg), HATU (137 mg) and l-tert-butoxycarbonylpiperidine-4-carboxylic acid (69 mg) in dimethylformamide (10 mL) was treated with N,-V-diisopropylethylamine (0.174 mL). The reaction mixture was stirred for 9 hours and then concentrated by evaporation. The residue was dissolved in ethyl acetate and the solution was washed with saturated sodium bicarbonate solution, dried over magnesium sulfate and then concentrated by evaporation. The residue was subjected to flash column chromatography on silica eluting with ethyl acetate to provide tert-butyl 4-|TRJ2-benzooxazol-2- yl-2-hvdroxy- 1 S-phenethylethylcarbamoyll -
2-(3-methylpyrid-2-ylmethylsulfonyl)ethylcarbamoynpiperidine-l-carboxylate (81 mg). MS: 734 [MH]+. Proceeding as in Example 10 provided the following compounds of Formula I: tetrahvdropyran-4-yl lR-(2-benzooxazol-2-yl-2-hvdroxy- 1 S-phenethylefhylcarbamoyl)- 2-benzylsulfanylethylcarbamate (Compound 65);
N-\ 15-(2-benzooxazol-2-yl-2-hydroxy- 1 S-phenethylethylcarbamoyl)- 2-cvclohexylethylltetrahvdropyran-4-carboxamide (Compound 66), MS: 548 [M]+; and
-V-ri5-(2-benzooxazol-2-yl-2-hvdroxy-lS-ρhenethylethylcarbamoyl)-2-cvclohexylethyll- 6-hydroxynicotinamide (Compound 67).
EXAMPLE 11 -V-r2-Benzooxazol-2-yl-2-(tgrt-butyldimethylsilanyloxy)-lS-phenethylethyn-3-cvclohexyl- 2S-(3-pyrid-3-ylureido)propionamide
(Compound 68), a protected compound of Formula I
Figure imgf000088_0001
A solution of 2S-amino-N-[2-benzooxazol-2-yl-2-(tert-butyldimethylsilanyloxy)- 15-phenethylethyl]-3-cyclohexylpropionamide (200.1 mg), provided as in Example 7, in dichloromethane (10 mL) was treated with 3-pyridyl isocyanate (48 mg). The mixture was stirred at room temperature for 16 hours and the solvent evaporated under reduced presssure. The residue was subjected to flash column chromatography on silica eluting with a mixture of pentane and ethylacetate (2:1, v/v) to provide /V-.2-benzooxazol-2-yl-2-(tert- butyldimethylsilanyloxy)-lS-phenethylethvn-3-cvclohexyl-2S-(3-pyrid-3-ylureido)propionamide (172 mg) as a colorless oil. EXAMPLE 12
Λr-{ lS-[2-Benzooxazol-2-yl-2-(tgrt-butyldimethylsilanyloxy)-lS-phenethylethylcarbamoyll-
2-c vclohexylethyl } moφholine-4-carboxamide
(Compound 69), a protected compound of Formula I
Figure imgf000089_0001
A solution of 25-amino-iV-[2-benzooxazol-2-yl-2-(tgrt-butyldimethylsilanyloxy)- lS-phenethylethyl]-3-cyclohexylpropionamide (200 mg), provided as in Example 7, in dichloromethane (8 mL) was treated with 4-moφholinecarbonyl chloride (0.094 mL) and triethylamine (0.112 mL). The solution was stirred at room temperature for 20 hours. The solvent was evaporated under reduced pressure and the residue was purified by flash chromatography on silica eluting with a mixture of pentane and ethylacetate (2:1, v/v) to provide -V-{ lS-.2-benzooxazoI-2-yl-2-(tgrt-butyldimethylsilanyloxy)- lS-phenethylethylcarbamoyl1-2-cvclohexylethyl ,moφholine-4-carboxamide (143 mg) as a white solid. MH+ 663.
EXAMPLE 13 tert-butyl 4-[lR-(2-benzooxazol-2-yl-2-hvdroxy-lS-phenethylethylcarbamoyll-
2-(2-cvanobenzylsulfonyl)ethylcarbamoylpiperidine-l-carboxylate
(Compound 70)
Figure imgf000090_0001
A solution of tgrt-butyl 4-[lR-(2-benzooxazol-2-yl-2-hydroxy-lS- phenethylethylcarbamoyl]-2-(2-cyanobenzylsulfanyl)ethylcarbamoylpiperidine-l-carboxylate (95 mg), provided as in Example 8, in methanol (8 mL) was treated with a solution of OXONE® (246 mg) in water (8 mL). After stirring at room temperature for 10 hours the methanol was distilled under reduced pressure and the remaining aqueous phase was extracted four times with ethyl acetate (20mL). The combined extracts were dried over magnesium sulfate and then concentrated by evaporation. The residue was subjected to flash column chromatography on silica eluting with ethyl acetate to give the tgrt-butyl 4-ITR-.2-benzooxazol-2-yl-2-hvdroxy-lS- phenethylethylcarbamoyll -2-(2-cyanobenzylsulfonyl)ethylcarbamoylpiperidine- 1 -carboxylate (35 mg) as a gum. MS: 744 [MH]+.
Proceeding as in Example 13 provided -V-_ lRJ2-benzooxazol-2-yl-2-hvdroxy- lS-phenethylethylcarbamoyl)-2-(2-cvanobenzylsulfonyl)ethyllisonicotinamide (Compound 71), HPLC: Rτ= 12.89 minutes. EXAMPLE 14 tgrt-Butyl lR-(2-benzooxazol-2-yl-2-hvdroxy-15-phenethylethylcarbamoyl)-
2-benzylsulfonylethylcarbamate
(Compound 72)
Figure imgf000091_0001
A solution of tgrt-butyl lR-(2-benzooxazol-2-yl-2-hydroxy-lS- phenethylethylcarbamoyl)-2-benzylsulfanylethylcarbamate (3.62 g), provided as in Example 3, in dichloromethane (174 mL) was treated with meto-chloroperbenzoic acid (6.9 g). After stirring at room temperature for 5 hours the reaction mixture was diluted with dichloromethane (100 mL), washed sequentially with a saturated sodium bicarbonate solution (100 mL) and brine (100 mL), dried over magnesium sulfate and then concentrated by evaporation. The residue was subjected to flash column chromatography on silica eluting with a mixture of pentane and ethylecetate (1: 1, v/v) to provide tert-butyl lR-(2-benzooxazol-2-yl-2-hvdroxy- lS-phenethylethylcarbamoyl)-2-benzylsulfonylethylcarbamate (0.95 g) as a yellow solid. MS: 608 [MH]+.
Proceeding as in Example 14 provided A7-. lRJ2-benzooxazol-2-yl-2-hydroxy- lS-phenethylethylcarbamoyl)-2-pyrid-3-ylmethylsulfonylethyl1pyrazine-2-carboxamide (Compound 73). EXAMPLE 15
-V-(2-Benzooxazol-2-yl-2-hvdroxy-lS-phenethylethyl)-3-cvclohexyl-
2S-(3-pyrid-3-ylureido)propionamide (Compound 74)
Figure imgf000092_0001
A solution of N- [2-benzooxazol-2-yl-2-(tgrt-butyldimethylsilanyloxy)- 1 S-pheneth ylethyl] -
3-cyclohexyl-2S-(3-pyrid-3-ylureido)propionamide (172 mg) in tetrahydrofuran (5 mL), provided as in Example 11, under an inert atmosphere at room temperature was treated with a solution of tetrabutylammoniumfluoride in IM tetrahydrofuran (0.4 mL). After stirring at room temperature for 90 minutes, the solvent was distilled under reduced pressure. The residue was subjected to flash column chromatography on silica eluting with a mixture of ethylacetate and pentane (5:1, v/v) to provide H-(2-benzooxazol-2-yl-2-hvdroxy-lS-phenethylethyl)-3-cvclohexyl- 2S-(3-pyrid-3-ylureido)propionamide (108 mg) as a white solid.
Proceeding as in Example 15 provided -V-ITSJ2-benzooxazol-2-yl-2-hvdroxy- lS-phenethylethylcarbamoyl)-2-cyclohexylethyllmoφholine-4-carboxamide (Compound 75).
EXAMPLE 16 tert-Butyl 4-, lRJlS-benzooxazol-2-ylcarbonyl-3-phenylpropylcarbamoyl)-2-(2-cyano- benzylsulf onvDethylcarbamoyllpiperidine- 1 -carboxylate
(Compound 76)
Figure imgf000093_0001
A solution tgrt-butyl 4-[lR-(2-benzooxazol-2-yl-2-hydroxy-lS- phenethylethylcarbamoyl]-2-(2-cyanobenzylsulfonyl)ethylcarbamoylpiperidine-l -carboxylate (35 mg, prepared as in Example 13, in dichloromethane (10 mL) was treated with Dess-Martin reagent (60 mg). The reaction mixture was stirred at room temperature for 5 hours, then washed with sodium thiosulfate in saturated sodium bi-carbonate solution, dried over magnesium sulfate and then concentrated by evaporation. The residue was subjected to flash column chromatography on silica eluting with a mixture of ethyl acetate and pentane (1:1, v/v) to give tgrt-butyl 4-, lR-(lS-benzooxazol-2-ylcarbonyl-3-phenylpropylcarbamoyl)- 2-(2-cvanobenzylsulfonyl)ethylcarbamovnpiperidine-l-carboxylate (26 mg) as a gum. MS: 742 [MH]+.
Proceeding as in Example 16 provided the following compounds of Formula I: -V-. lR-(lS-benzooxazol-2-ylcarbonyl)-3-phenylpropylcarbamoyl)-
2-benzylsulfonylethylltetrahydropyran-4-carboxamide (Compound 77), m.p. 178-180°C, MS:
618 [MH]+; -V-, lR-(lS-benzooxazol-2-ylcarbonyl-3-phenylpropylcarbamoyl)-
2-benzylsulfonylethvnnicotinamide (Compound 78), m.p. 193-195°C, MS: 611 [MH]+; /V-f lR-(lS-benzooxazol-2-ylcarbonyl-3-phenylpropylcarbamoyl)-
2-benzylsulfonylethyllpyrazine-2-carboxamide (Compound 79), m.p. 194-196°C. MS: 612 [MH]+; tgrt-butyl 4-, lS-(lS-benzooxazol-2-ylcarbonyl-3-phenylpropylcarbamoyl)- 2-cvclohexylethylcarbamoyllpiperidine- 1 -carboxylate (Compound 80); tgrt-butyl 4-FlS-(l-benzooxazol-2-ylcarbonyl-3-phenylpropylcarbamoyl)- 2-(6-methylpyrid-2-ylmethylsulfonyl)ethylcarbamoyllpiperidine-l-carboxylate (Compound 81), MS: 732 [MH]+, HPLC: Rτ = 15.18 minutes;
-V-_ lR-(lS-benzooxazol-2-ylcarbonyl-3-phenylpropylcarbamoyl)- 2-(2-cvanobenzylsulfonyl)ethvnisonicotinamide (Compound 82), m.p. 204-206 °C, MS: 636 [MH]+; tetrahydropyran-4-yl lR-(lS-benzooxazol-2-ylcarbonyl-3-phenylpropylcarbamoyl -
2-benzylsulfonylethylcarbamate (Compound 83), m.p. 93 °C (with decomposition), MS: 634 [MH]+; benzyl 4- _ 1 S-( 1 S-benzooxazol-2-ylcarbonyl-3-ρhenylpropylcarbamoyl)- 2-cvclohexylethylcarbamovnpiperidine- 1 -carboxylate (Compound 84), MS: 677 [M]"; N-(lS-benzooxazol-2-ylcarbonyl-3-phenylpropyl)-3-cvclohexyl-
2S-(3-pyrid-3-ylureido)propionamide (Compound 85), MS: 554 [M]+;
N- . 1 S-( 1 S-benzooxazol-2-ylcarbonyl-3-phenylpropylcarbamoyl)- 2-cyclohexylethynmoφholine-4-carboxamide (Compound 86), MS: 547 [MH]+;
N- . 1 S-( 1 S-benzooxazol-2-ylcarbonyl-3 -phenylpropylcarbamoyl)- 2-cvclohexylethylisonicotinamide (Compound 87), MS: 537 [M] ";
-V-, lS-(lS-benzooxazoI-2-ylcarbonyl-3-phenyrpropylcarbamoyl)- 2-cvclohexylethylltetrahydropyran-4-carboxamide (Compound 88), MS: 546 [M]+; and
N- . 1 S-( 1 S-benzooxazol-2- ylcarbonyl-3 -pheny lpropy lcarbamoyl)-2-c yclohexyleth yll - 6-hvdroxynicotinamide (Compound 89), MS: 555 [M]\
EXAMPLE 17
-V-riR-(lS-Benzooxazol-2-ylcarbonyl)-3-phenylpropylcarbamoyl)-
2-benzylsulfonylethyHmoφholine-4-carboxamide
(Compound 90)
Figure imgf000095_0001
A mixture of -V-[lS-(2-benzooxazol-2-yl-2-hydroxy-lS-phenethylethylcarbamoyl)- 2-benzylsulfonylethyl]moφholine-4-carboxamide (7.2 g, 11.6 mmol), prepared as in Example 1, and Dess-Martin periodinane (9.87 g, 23.3 mmol) in dichloromethane (57 mL) was stirred at room temperature for 1 hour and then diluted with a solution of 0.26 M sodium thiosulfate in saturated sodium bicarbonate. The dilution was extracted with ethyl acetate and the extract was filtered. The filtrate was concentrated to provide -V-[lS-(lS-benzooxazol-2-ylcarbonyl)-3-phenylpropylcarbamoyl)-
2-benzylsulfonylethyl]moφholine-4-carboxamide (2.33 g) as an orange/tan oil. The solids collected from the filtration were taken up into dichloromethane (700 mL) and the mixture was washed sequentially with water and saturated sodium bicarbonate solution, dried and concentrated to provide -V-, lR-(lS-benzooxazol-2-ylcarbonyl)-3-phenylpropylcarbamoyl)- 2-benzylsulfonylethvnmoφholine-4-carboxamide (4.2 g) as a white powder. 'H NMR (DMSO- d6) 8.024 (d, J=6.68Hz, IH), 7.9787 (d, J=7.92Hz, IH), 7.8857 (d, J=8.16Hz, IH), 7.6471 (td, J=8.41, 0.99 Hz, IH), 7.5455 (td, J=8.16, 1.24Hz, IH), 7.3806 (s, 5H), 7.2479 (m, 5H), 7.1210 (d, J=4.53Hz), IH, 5.2578 (m, IH), 4.7395 (m, IH), 4.5059 (s, 2H), 3.5342 (m, 4H), 3.4082 (m, 2H), 3.30 (m, 4H (+water)), 2.6963 (m, 2H), 2.2768 (m, IH), 2.0497 (m, IH). MS (M+l) 619.2. Proceeding as in Example 17 provided the following compounds of Formula I:
-V-riR-(2-benzooxazol-2-yl-l.l-dimethyl-2-oxoethylcarbamoyl)- 2-benzylsulfonylethyllmoφholine-4-carboxamide (Compound 91); Η NMR: (DMSO) 9.26 (s, IH), 7.79 (d, J=8Hz, IH), 7.73 (d, J=8Hz, IH), 7.56 (t, J=8Hz, IH), 7.47 (t, J=8Hz, IH), 7.36- 7.25 (m, 5H), 6.70 (d, J=8Hz, IH), 4.67 (m, IH), 4.39 (d, J=14Hz, IH), 4.32 (d, J=14Hz, IH), 3.49-3.00 (m, 10H), 1.56 (s, 3H), 1.51 (s, 3H); MS: (M++l) 543;
-V-, lR-(lS-benzooxazol-2-ylcarbonylpentylcarbamoyl)- 2-(3.5-dimethylisoxazol-4-ylmethylsulfonyl)ethyllmoφholine-4-carboxamide (Compound 92); :H NMR: (DMSO) 8.66 (d, J=6.6Hz, IH), 7.99 (d, J=8Hz, IH), 7.88 (d, J=8Hz, IH), 7.62 (t, J=8Hz, IH), 7.52 (t, J=8Hz, IH), 7.02 (d, J=7.7Hz, IH), 5.24 (m, IH), 4.76 (m, IH), 4.39 (d,
J=14Hz, IH), 4.27 (d, J=14Hz, IH), 3.63-3.20 (m, 10H), 2.33 (s, 3H), 2.15 (s, 3H), 1.94 (m, IH), 1.69 (m, IH), 1.40-1.22 (m, 4H), 0.84 (t, J=6.7Hz, 3H); MS: (M++l) 590; and
-V-. lRJlS-benzooxazol-2-ylcarbonylpentylcarbamoyl)- 2-(3.5-dimethylisoxazol-4-ylmethylsulfonylethvnisonicotinamide (Compound 93); Η NMR: (DMSO) 9.23 (d, J=8Hz, IH), 8.87 (d, J=7Hz, IH), 8.71 (m, 2H), 7.98 (d, J=8Hz, IH), 7.87 (d, J=8Hz, IH), 7.70 (m, 2H), 7.62 (t, J=8Hz, IH), 7.51 (t, J=8Hz, IH), 5.28 (m, IH), 5.10 (m, IH), 4.44 (d, J=14Hz, IH), 4.37 (d, J=14Hz, IH), 3.80-3.52 (m, 2H), 2.33 (s, 3H), 2.14 (s, 3H), 1.95 (m, IH), 1.69 (m, IH), 1.40-1.22 (m, 4H), 0.82 (t, J=6.7Hz, 3H); MS: (M++l) 582.
EXAMPLE 18
-V-, lR-dS-Benzooxazol-2-ylcarbonyl-
3-phenylpropylcarbamoyl)-2-(2-cyanobenzylsulfonyl)ethyllpiperidine-4-carboxamide
(Compound 94)
Figure imgf000097_0001
A solution of tgrt-butyl 4-[lR-(lS-benzooxazol-2-ylcarbonyl-3-phenylpropylcarbamoyl)- 2-(2-cyanobenzylsulfonyl)ethylcarbamoyl]piperidine-l -carboxylate (26 mg), provided as in Example 16, in ethyl acetate (10 mL) was treated with hydrogen chloride, bubbling the gas through the solution for 3 minutes. A white solid formed which was filtered and dried under reduced pressure to provide JV-. lR-(lS-benzooxazol-2-ylcarbonyl-3-phenylpropylcarbamoyl)- 2-(2-cvanobenzylsulfonyl)ethyllpiperidine-4-carboxamide (19 mg) as a solid, m.p. = 155-157°C. MS: 678 [MH]+.
Proceeding as in Example 18 provided -V-|TS-dS-benzooxazol-2-ylcarbonyl- 3-phenylpropylcarbamoyl)-2-cvclohexylethyllpiperidine-4-carboxamide hydrochloride (Compound 95), MS: 634 [MH]+; and
-V-riR-(lS-benzooxazol-2-ylcarbonyl-3-phenylpropylcarbamoyl)- 2-(6-methylpyrid-2-ylmethylsulfonyl)ethyllpiperidine-4-carboxamide (Compound 96), MS: 632 [MH]+, HPLC: Rτ = 12.05 minutes. EXAMPLE 19 -V-(lS-Benzooxazol-2-ylcarbonylbutyl)-2R-methylsulfonylamino-3-benzylsulfonylpropionamide
(Compound 159)
Figure imgf000098_0001
A solution of (R)-2-(2-methylsulfonylacetylamino)-3-benzylsulfonylpropionic acid (212 mg, 0.66 mmol), (S)-2-amino-l-benzooxazol-2-ylpentan-l-ol (150 mg, 0.66 mmol), EDCI (165 mg, 0.858 mmol) and HOBT (110 mg, 0.726 mmol) in methylene chloride (3 mL) was stirred at room temperature for 2 hours, sequentially washed with hydrochloric acid, sodium bicarbonate solution and brine and then concentrated. The residue was dissolved in dichloromethane and the solution was treated with Dess-Martin reagent (340 mg, 0.8 mmol) for 1 hour. The mixture was stirred with a sodium thiosulfate/sodium bicarbonate solution and the mixture was extracted with ethyl acetate. The extract was washed sequentiall with dilute hydrochloric acid, sodium bicarbonate and brine, dried (MgS04) and then concentrated to provide -V-( 1 S-benzooxazol-2-ylcarbonylbutyl)-
2R-methylsulfonylamino-3-benzylsulfonylproρionamide (49 mg, 0.09 mmol). Η NMR (DMSO): 9.0 (d,J = 7Hz, IH), 8.0 (d,J = 8Hz, IH), 7.90 (d,J = 9Hz, IH), 7.66 (t,J = 8Hz, IH), 7.55 (t,J =9Hz, IH), 7.39 (s, 5H), 5.32 (m, IH), 4.55 (m, 3H), 3.35 (m, 3H), 2.95 (s, 3H), 1.94 (m, IH), 1.71 (m, IH), 1.45(m, 2H), 0.92 (t, J=8Hz, 3H); MS: m/e=522.03. EXAMPLE 20 Methyl lR-(lS-benzooxazol-2-ylcarbonylbutylcarbamoyl)-2-benzylsulfonylethylcarbamate
(Compound 158)
Figure imgf000099_0001
A solution of (R)-2-(2-methoxycarbonylamino)-3-benzylsulfonylpropionic acid (200 mg,
0.66 mmol), (S)-2-amino-l-benzooxazol-2-ylpentan-l-ol (150 mg, 0.66 mmol), EDCI (165 mg, 0.858 mmol) and HOBT (110 mg, 0.726 mmol) in methylene chloride (3 mL) was stirred at room temperature for 2 hours, sequentially washed with hydrochloric acid, sodium bicarbonate solution and brine and then concentrated. The residue was treated with Dess-Martin reagent (340 mg, 0.8 mmol) in dichloromethane (4 mL) for 1 hour. The mixture was stirred with a sodium thiosulfate/sodium bicarbonate solution and the mixture was extracted with ethyl acetate. The extract was washed sequentially with dilute hydrochloric acid, sodium bicarbonate and brine, dried (MgS04) and then concentrated. The residue was heated with ethyl acetate and then treated with tgrt-butyloxymethyl. The mixture was let stand for approximately 12 hours and then cooled in an ice bath. Resulting solids were collected by filtration and washed with cold ethyl acetate to provide methyl
1 R-( 15-benzooxazol-2-ylcarbonylbutylcarbamoyl)-2-benzylsulf onylethy Icarbamate (133 mg, 0.26 mmol). Η NMR (DMSO): 8.77 (d,J =7Hz, IH), 8.01 (d,J = 9Hz, IH), 7.90 (d,J = 9Hz, IH), 7.6 (m, 2H), 7.55 (t,J=9Hz, IH), 7.39 (s, 5H), 5.3 (m, IH), 4.68 (m, IH), 4.48 (s, 2H), 3.55 (s, 3H), 3.52-3.4 (m, IH), 3.3 (m, IH), 1.92 (m, IH), 1.73 (m, IH), 1.42 (m, 2H), 0.91 (t, J=8Hz, 3H); MS: m/e=502.05. EXAMPLE 21 -V-riR-(lS-Benzooxazol-2-ylcarbonylbutylcarbamoyl)-2-benzylsulfonylethyllmoφholine-
4-carboxamide (Compound 158)
Figure imgf000100_0001
A solution of (R)-2-(2-moφholin-4-ylcarbonylamino)-3-benzylsulfonylpropionic acid (356 mg, 1 mmol), EDCI (240 mg, mmol) and HOBT (178 mg, mmol) in methylene chloride (8 mL) was (S)-2-amino-l-benzooxazol-2-ylpentan-l-ol (220 mg, mmol). The mixture was stirred at room temperature for 1.5 hours and then treated with addtional EDCI (80 mg). The mixture was stirred for an additional 0.5 hours and then poured into cold, dilute hydrochloric acid. The mixture was extracted with ethyl acetate (2x) and the extract washed sequentially with aqeous sodium bicarbonate and brine, dried (MgS04) and concentrated. The residue was dissolved in methylene chloride (8 mL) and the solution was treated with Dess-Martin reagent (544 mg) . The mixture was stirred for 1.5 hours and then stirred a sodium thiosulfate/sodium bicarbonate solution for 15 minutes. The mixture was extracted with ethyl acetate (2x) and the extract was washed with brine, dried (MgSO4) and then concentrated. The residue was triturated with ethyl acetate and then hexanes. The mixture cooled in an ice bath and resulting solids were collected and dried to provide N-\ lR-( lS-benzooxazol-2-ylcarbonylbutylcarbamoyl)- 2-benzylsulfonylethyllmoφholine-4-carboxamide (408 mg, 73% yield). Η NMR 300mHz: 8.65 (d,J=7.1H3, IH), 8.01 (d, J=8.8H3, IH), 7.91 (d, J=9.1H3, IH), 7.65 (t, J=8.2H3, IH), 7.55 (t, J=9.1H3, IH), 7.38 (s, 5H), 7.05 (d, J=9.4H3, IH), 5.29 (m, IH), 4.73 (m, IH), 4.48 (s, 2H), 3.53 (m, 4H), 3.4-3.2 (m, 6H), 1.94 (m, IH), 1.73 (m, IH), 1.42 (m, 2H), 0.91 (t, J=8H3, 3H), MS=557.21 M+=556.20. Proceeding by methods analogous to those described in this Application provided the following compounds of Formula I:
2S-acetylamino--V-(2-benzooxazol-2-yl-lS-butyl-2-hydroxyethyl)- 3-cvclohexylpropionamide (Compound 97); Η NMR (CDC13): 7.67 (d, J=8.0Hz, IH), 7.53 (d, J=6.0Hz, IH), 7.34 (m, 2H), 6.64 (d, J=8.1Hz, IH), 5.99 (d, J=8.1Hz, IH), 5.03 (m, IH), 4.39 (m, 2H), 2.02-0J0 (m, 22Hz); MS ESI: MH+ 430;
2S-acetylamino--V-(lS-benzooxazol-2-ylcarbonylpentyl)-3-cyclohexylpropionamide (Compound 98); Η NMR (CDC13): 7.93 (d, J=7.5Hz, IH), 7.67 (d, J=8.1Hz, IH), 7.54 (t, J=7.2Hz, IH), 7.46 (t, J=7.8Hz, IH), 6J8 (d, J=7.2Hz, IH), 5.91 (d, J=8.4Hz, IH), 5.63 (m, IH), 4.59 (m, IH), 2.09-0.85 (m, 24Hz); MS ESI: MH+ 428; tgrt-butyl lS-|T-benzooxazol-2-ylcarbonyl)-3-phenylpropylcarbamoyl)- 2-cyclohexylethyllcarbamate (Compound 99);
2S-acetylamino-N-( 1 -benzooxazol-2-ylcarbonyl)- 3-phenylpropyl)-3-cvclohexylpropionamide (Compound 100); 2S-acetylamino--V-(l-benzooxazol-2-ylcarbonylcvclobutyl)-3-cyclohexylpropionamide
(Compound 101);
2S-acetylamino-A7-(lR-benzooxazol-2-ylcarbonyl-3-phenylpropyl)- 3-cyclohexylpropionamide (Compound 102);
2S-acetylamino--V-(2-benzooxazol-2-yl-2-hvdroxy-lR-phenyethylethyl)- 3-cyclohexylpropionamide (Compound 103);
-V-riS-(lS-benzooxazol-2-ylcarbonyl)-3-phenylpropylcarbamoyl1- 2-cvclohexylethyll succinamic acid (Compound 104); 'H NMR (CDC13): 7.87 (m, IH), 7.62 (m, IH), 7.52 (m, IH), 7.43 (m, IH), 7.15 (m, 6H), 6.89 (m, IH), 5.62 (m, IH), 4.56 (m, IH), 2.75 (m, 2H), 2.70 (m, IH), 2.48 (m, 2H), 2.16 (m, IH), 1.6 (m, 7H), 0.7-1.4 (m, 7H); MS: m e 534; -V-|TS-(2-benzooxazol-2-yl-2-hvdroxy- lS-phenethylethylcarbamoyl)-2-cvclohexylethyllsuccinamic acid (Compound 105); Η NMR (CDC13): 12.04 (s, IH), 7.89 (m, IH), 7.80 (m, IH), 7.65 (m, 2H), 7.36 (m, 2H), 7.13-7.29 (m, 4H), 6.08-6.23 (m, IH), 4.62-4.93 (m, IH), 4.15 (m, IH), 2.64 (m, IH), 2.50 (m, IH), 2.34 (m, 6H), 1.78 (m, IH), 1.45-1.68 (m, 4H), 1.37 (m, IH), 0.95-1.3 (m, 3H), 0.87 (m, 2H); MS: m/e=535.8; -V-< IS-, lS-benzooxazol-2-ylcarbonyl)-3-phenylpropylcarbamoyll- 2-cvclohexylethyl . oxalamic acid (Compound 106); Η NMR (CDC13): 6.6-7.9 (m,10H), 5.6 (m, IH), 4.5 (m, IH), 2.72 (m, IH), 2.45 (m, IH), 0.8-2.1 (m, 15H); MS: m/e 506.2;
-V- T 1 S-( 1 S-benzooxazol-2-ylcarbonyl-3-phenylpropylcarbamoyl)-2-c yclohexylefhyl , - 3H-imidazole-4-carboxamide (Compound 107); !Η NMR (CDC13): 8.1 (m,lH), 7.3-7.6 (m, 3H), 6.95-7.2 (m, 8H), 5.62 (m, IH), 4.74 (m, IH), 2.77 (m, 2H), 2.38 (m, IH), 2.25 (m, IH), 0.8-1.9 (m, 13H); MS: m/e 528.2;
-V-[ lS-(2-benzooxazol-2-yl-2-hydroxy-lS-phenylethylethylcarbamoyl)- 2-cvclohexylethyl]-3H-imidazole-4-carboxamide (Compound 108); 'Η NMR (CDC13): 7.0-7.6 (m, 12Η), 5.05 (m, IH), 4.5 (m, IH), 2.75 (m, 2H), 0.6-2.2 (m, 15H); MS: m/e 529.6; tgrt-butyl lR-(l-benzooxazol-2-ylcarbonylcyclobutylcarbamoyl)- 2-benzylsulfonylethylcarbamate (Compound 109), m.p. = 70-85 °C, MH+ 542; iV-_ lS-(lS-benzooxazol-2-ylcarbonyl-3-phenylpropylcarbamoyl)- 2-cvclohexylethyllmalonamic acid (Compound 110); Η NMR (CDC13): 6.8-7.9 (m, 9H), 5.63 (m, IH), 4.56 (m, IH), 2.6-2.8 (m, 4H), 2.0-2.4 (m, 2H), OJ-2.0 (m, 13H); MS: m/e 520.4;
-V-riR-(15-benzooxazol-2-ylcarbonyl-3-phenylpropylcarbamoyl)- 2-o-tolylmethylsulfonylethyl1moφholine-4-carboxamide (Compound 111); ]H NMR 300mHz (DMSO-d6) PPM, 8.841 (d, J=6.2Hz, IH), 7.942 (d, J=5.2Hz, IH), 7.860 (d, J=8.4Hz, IH), 7.618 (t, J=8.1Hz, IH), 7.516 (t, J=8.1Hz, IH), 7.16 (m, 10H), 5.22 (m, IH), 4J8 (m, IH), 4.516 (s, 2H), 3.567 (m, 2H), 3.500 (m, 6H), 3.3 (s, 3H), 2.75 (m, IH), 2.65 (m, IH), 2.44 (m, IH), 2.26 (m, 2H), 2.01 (m, IH); MS: M+=633.4 M =631.4;
-V-, lR-( 1 S-benzooxazol-2-ylcarbonyl-3-phenylpropylcarbamoyl)- 2-(2-nitrobenzylsulfonyl)ethyllmoφholine-4-carboxamide (Compound 112); ]H NMR 300mHz (DMSO-d6) PPM, 8.840 (d, J=7.0Hz, IH), 8.025 (d, J=8.0Hz, IH), 7.950 (d, J=8.4Hz, IH), 7.858 (d, J=7.7Hz, IH), 7.730 (d, J-8.8Hz, IH), 7.646 (t, J=8.4Hz, IH), 7.515 (t, J=7.7Hz, IH), 5.223 (m, IH), 5.004 (s, 2H), 4.694 (m, IH), 3.561 (m, 2H), 3.510 (m, 6H), 2.756 (m, IH), 2.652 (m, IH), 2.429 (m, 2H), 2.243 (m, IH), 1.983 (m, IH); MS: M+=664.2 M-=662.4;
N-\~ lR-( lS-benzooxazol-2-ylcarbonyl-3-phenylpropylcarbamoyl)- 2-(2-chlorobenzylsulfonyl)ethvnmoφholine-4-carboxamide (Compound 113); 'H NMR 300mHz (DMSO-d6) PPM, 8.851 (d, J=6.2Hz, IH), 7.953 (d, J=8.8Hz, IH), 7.855 (d, J=8.4Hz, IH),
7.627 (t, J=6.6Hz, IH), 7.498 (m, 3H), 7.365 (m, 2H), 7.211 (m, 6H), 5.220 (m, IH), 4.774 (m, IH), 4.659( m, 2H), 3.578 (m, 2H), 3.499 (m, 6H), 2.752 (m, IH), 2.648 (m, IH), 2.472 (m, 2H), 2.243 (m, IH), 1.992 (m, IH); MS: M+=653.2;
-V-riR-(lS-benzooxazol-2-ylcarbonylpentylcarbamoyl)- 2-benzylsulfonylethyllmoφholine-4-carboxamide (Compound 114); NMR 300mHz (DMSO-d6), 8.64 (d, J=7.4H3, IH), 8.01 (d, J=8.8H3, IH), 7.91 (d, J=9.1H3 , IH), 7.68 (t, J=6H3, IH), 7.55 (t, J=8.2H3, IH), 7.38 (s, 5H), 7.05 (d, J=9.6H, IH), 5.26 (m, IH), 4.72 (m, IH), 4.49 (s, 2H), 3.55 (m, 4H), 3.5-3.2(m, 6H), 1.96 (m, IH), 1.76 (m, IH), 1.38 (m, 4H), 0.87 (t, J=7.4H3, 3H); MS: 571.24 M+=570.20;
-V-ITRJ 1 S-benzooxazol-2-ylcarbonylpentylcarbamoyl)- 2-o-tolylmethylsulfonylethyllmoφholine-4-carboxamide (Compound 115); NMR 300mHz (DMSO-d6), 8.70 (d, J=6.9H3, IH), 8.01(d, J=9.1H3, IH), 7.91 (d, J=8.8H3, IH), 7.67 (t, J=8H3, IH), 7.55 (t, J=8.5H, 3H), 7.3-7.1 (m, 4H), 7.05 (d, J=9.6H3 H), 5.26 (m, IH), 4.80 (m, IH), 4.53 (s, 2H), 3.58 (m, 4H), 3.33 (m, 6H), 2.33 (s, 3H), 1.96 (m, IH), 1.72 (m, IH), 1.35 (m, 4H), 0.87 (t, J=7.7H3); MS=585.30, M+=584.23;
JV-. lR-dS-benzooxazol-2-ylcarbonylpentylcarbamoyl)- 2-(2-nitrobenzylsulfonyl)ethyllmoφholine-4-carboxamide (Compound 116); NMR 300mHz (DMSO-d6), 8.70 (d, J=7.2H3, IH), 8.1-7.5 (m, 8H), 7.05 (d, J=9.3H3, IH), 5.26 (m, IH), 5.01 (s, 2H), 4.70 (m, IH), 3.57 (m, 5H), 3.30 (m, 5H), 1.96 (m, IH), 1.72 (m, IH), 1.34 (m, 4H), 0.87 (t, J=7.7H3, 3H); MS: 616.09 M+=615.20;
-V-. lR-(lS-benzooxazol-2-ylcarbonylpentylcarbamoyl)- 2-(2-chlorobenzylsulfonyl)ethyllmoφholine-4-carboxamide (Compound 117); NMR 300mHz (DMSO-d6), 8.71 (d, J=7.1H3, IH), 8.1-73 (m, 8H), 7.06 (d,J=9.6H3, IH), 5.26 (m, IH), 4.79 (m, IH), 4.72 (d, J=15H3, IH), 4.65 (d, J=15H3, IH), 3.56 (m, 4H), 3.30 (m, 6H), 1.96 (m, IH), 1.73 (m, IH), 1.35 (m, 4H), 0.87 (t, J=7.7H3, 3H); MS: 605.24 M+=605.10;
N- lR-(2-benzooxazol-2-yl- 1.1 -dimethyl-2-oxoethylcarbamoyl)- 2-o-tolylmethylsulfonylethyllmoφholine-4-carboxamide (Compound 118); MS: (M++l) 557;
'N-\ lR-(2-benzooxazol-2-yl- 1.1 -dimethyl-2-oxoethylcarbamoyl)- 2-(2-chlorobenzylsulfonyl)ethyllmoφholine-4-carboxamide (Compound 119); MS: (M++l) 578;
N-\ lR-(2-benzooxazol-2-yl- 1.1 -dimethyl-2-oxoethylcarbamoyl)- 2-(2-nitrobenzylsulfonyl)ethyllmoφholine-4-carboxamide (Compound 120); Η NMR: (DMSO) 9.34 (s, IH), 8.02 (d, J=7.7Hz, IH), 7.82-7.45 (m, 7H), 6.74 (d, J=8.8Hz, IH), 4.87 (m, 2H), 4.64 (m, IH), 3.44-3.11 (m, 10H), 1.56 (s, 3H), 1.50 (s, 3H); MS: (M++l) 588;
-V-[lR-(lS-benzooxazol-2-ylcarbonyl-3-phenylpropylcarbamoyl)- 2-pyrid-2-ylmethylsulfonylethvHpiperidine-4-carboxamide (Compound 121); MS:m/e +1=616.2;
-V-_ lR-( lS-benzooxazol-2-ylcarbonylpentylcarbamoyl)- 2-pyrid-2-ylmethylsulfonylethyllmoφholine-4-carboxamide (Compound 122); Η NMR : 8.62 (d, 6.9 Hz, 1 H), 8.55 (d, 3.2 Hz, IH), 8.00 (d, 7.0 Hz, IH), 7.86 (m, 2H), 7.65 (t. 6.2 Hz, IH), 7.48-7.58 (m, 2H), 7.40 (m, IH), 7.06-7.25 (m, 3H), 5.28 (m, IH), 4.74 (m, IH), 4.67 (d, 1.1 Hz, 2H), 3.53 (m, 4H), 3.31 (m, 4H), 1.99 (m, IH), 1.75 (m,lH), 1.32 (m, 4H), 0.87 (t, 6.7 Hz, 3H); MS: M+l = 571.8;
N-\ lR-( lR-benzooxazol-2-ylcarbonyl-3-phenylpropylcarbamoyl)- 2-benzylsulfonylethyllmorpholine-4-carboxamide (Compound 123); -V-riR-(l-benzooxazol-2-ylcarbonylcyclobutylcarbamoyl)-
2-benzylsulfonylethyllmoφholine-4-carboxamide (Compound 124), MH+ 555; benzyl lS-(2-benzooxazol-2-yl-2-hvdroxyethylcarbamoyl)-3-methylbutylcarbamate (Compound 125);
2S-acetylamino- Λf-(2-benzooxazol-2-yl-lS-methyl-2-oxoethyl)-3-cyclohexylpropionamide (Compound 126); 'H NMR (CDC13): 7.92 (d, J=8.4Hz, IH), 7.73-7.67 (m, IH), 7.60-7.48 (m, 2H), 5.94 (d, J=8.7Hz, IH), 6.65 (m, IH), 2.03 (d, J=7.2Hz, 2H), 1.64 (m, 6H), 1.56-0.92 (m, 10Hz); MS ESI: MH+ 386; tgrt-butyl lR-(l-benzooxazol-2-ylcarbonylcvclobutylcarbamoyl)- 2-benzylsulfanylethylcarbamate (Compound 127);
H-. lR-(lS-benzooxazol-2-ylcarbonvI-3-methylsulfonylpropylcarbamoyl)- 2-benzylsulfonylethyllmorpholine-4-carboxamide (Compound 128); Η NMR (CDC13): 7.89 (d, J=7.4Hz, 1H), 7.65 (m, IH), 7.57 (m, IH), 7.48 (m, IH), 7.4 (m, 5H), 6.0 (m, IH), 5.7 (m, IH), 4.93 (m, IH), 4.33 (m, 3H), 3.70 (m, 5H), 3.25-3.4 (m, 7H), 2.93 (m, 3H), 2.8 (m, IH), 2.35 (m, IH); MS: m/e 653.2; iV-. lJlS-benzooxazol-2-ylcarbonylpentylcarbamoyl)- 3-phenylsulfanylpropynmoφholine-4-carboxamide (Compound 129); Η NMR (DMSO): 8.52 (d,J = 8Hz, IH), 8.98 (d,J = 8Hz, IH), 8.88 (d,J = 9Hz, IH), 7.64 (t,J = 8Hz, IH), 7.53 (t,J = 9Hz, IH), 7.30 (m, 4H), 7.19 (m, IH), 5.25 (m, IH), 4.35 (m, IH); 3.51 (m, 4H), 3.26 (m, 4H), 2.94 (t, J=8Hz, 2H), 1.9 (m, 3H), 1.7 (m, IH), 1.31 (m, 4H), 0.86 (t,J=8Hz, 3H), 6.53 (d,J=9Hz, IH); MS: m/e=539.24;
-V-, lR-(lS-benzooxazol-2-ylcarbonylpentylcarbamoyl)- 2-(2-trifluoromethylbenzylsulfonyl)ethyllmoφholine-4-carboxamide (Compound 131); 'H NMR: (DMSO) 8.78 (d, J=8Hz, IH), 8.06-7.50 (m, 8H), 7.04 (d, J=8Hz, IH), 5.27 (m, IH), 4.82-4.64 (m, 3H), 3.65-3.25 (m, 10H), 1.96 (m, IH), 1.71 (m, IH), 1.41-1.22 (m, 4H), ), 0.84 (t, J=7Hz, 3H). MS: (M++l) 639; -V-riR-(lS-benzooxazol-2-ylcarbonyl-3-phenylpropylcarbamoyl)-
2-pyrid-2-ylmethylsulfonylethyllmoφholine-4-carboxamide (Compound 132);Η NMR (DMSO): 8.78 (d,J=7.2Hz, IH), 8.56 (d,J=5.4Hz, IH), 7.98 (d,J=8.4Hz, IH), 7.85 (m, 2H), 7.64 (t,J=12.1Hz, IH), 7.52 (m, 2H), 7.38 (m, IH), 7.10-7.34 (m, 8H), 5.25 (m, IH), 4.70 (m, 3H), 3.55-3.70 (m, 4H), 3.35 (s, 4H), 2.80 (m, 2H), 2.25 (m, IH), 2.0 (m, IH); MS: m/e (+1) = 620.0; -V-riR-(lS-benzooxazol-2-ylcarbonyl-3-methylsulfonylpropylcarbamoyl)-
2-pyrid-2-ylmethylsulfonylethyllmoφholine-4-carboxamide (Compound 133); 'H NMR (DMSO): 8.83 (d,J=7.6Hz, IH), 8.55 (d,J=4.0Hz, IH), 7.97 (d,J=7.6Hz, IH), 7.88 (m, 3H), 7.64 (t,J=7.2Hz, IH), 7.39-7.54 (m, 4H), 7.15 (d, J=7.6Hz, IH), 5.36 (m, IH), 4.70 (m, 3H), 3.56 (m, 6H), 3.24 (m, 4H), 2.40 (m, IH), 2.15 (m, IH), 2.99 (s, 3H); MS: m/e (+1) = 622.2; 2-.2-(l-benzooxazol-2-ylcarbonylpentylcarbamoyl)-
2-morpholin-4-ylcarbonylamino)ethanesulfonylmethyllpyridine 1-oxide (Compound 134); Η NMR (DMSO): 8.75 (d, J=6.5Hz, IH), 8.38 (m, 2H), 7.96 (d, J=7.7Hz, IH), 7.89 (d,J=7JHz, IH), 7.48-7.69 (m, 6H), 7.05 (d, J=6.8Hz, IH), 5.22 (m, IH), 4.95 (d, J=2.7Hz, 2H), 5.85 (m, IH), 5.53 (m, 4H), 3.30 (s, 4H), 1.95 (m, IH), 1.70 (m, IH), 1.30 (m, 4H), 0.88 (t, J=5.4Hz, 3H); MS: MW = 587.65 M+l = 588.2;
-V-. lR-(lS-benzooxazol-2-ylcarbonylbutylcarbamoyl)- 2-(2-difluoromethoxybenzylsulfonyl)ethyl1moφholine-4-carboxamide (Compound 135); NMR 300mHz (DMSO-d6), 8.70 (d, J=7.1H3, IH), 8.01 (d, J=8.8H3, IH), 7.91 (d, J=9.1H3, IH), 7.65 (t, J=8H3, IH), 7.55 (t, J=8.2H), 7.11 (t, J=8.2H), 7.4-6.8 (m, 5H), 5.28 (m, IH), 4.76 (m, IH), 4.5 (s, 2H), 3.55 (m, 4H), 3.3 (m, 6H), 1.93 (m, IH), 1.71 (m, IH), 1.42 (m, 2H), 0.91 (t, J=8H3, 3H); MS: 623.38 M+=622.19;
N-.3-phenylsulfonyl- 1 -( 1 S-benzooxazol-2-ylcarbonylpentylcarbamoyl)propyllmoφholine-4-carboxamide (Compound 136); Η NMR (DMSO): 8.5 (m, 2H), 8.00 (d,J = 9Hz, IH), 7.9-7.5 (m, 8H), 6.54 (t,J = 9Hz, IH), 4.28 (m, IH), 3.49 (m, 4H), 3.24 (m, 6H), 1.90 (m, 3H), 1.65 (m, IH), 1.31 (m, 4H), 0.85 (t,J=7Hz, 3H); MS: m/e=571.39;
-V-, lR-(lS-benzooxazol-2-ylcarbonylpentylcarbamoyl)- 2-(2-difluoromethoxybenzylsulfonyl)ethyl]moφholine-4-carboxyamide (Compound 137); Η NMR: (DMSO) 8.66 (d, J=6.6Hz, IH), 7.99 (d, J=8Hz, IH), 7.87 (d, J=8Hz, IH), 7.67-6.83 (m, 8H), 5.25 (m, IH), 4.73 (m, IH), 4.54 (s, 2H), 3.60-3.23 (m, 10H), 1.93 (m, IH), 1.68 (m, IH), 1.40-1.22 (m, 4H), 0.84 (t, J=6.7Hz, 3H); MS: (M++l) 637; -V-riR-(lS-benzooxazol-2-ylcarbonylpentylcarbamoyl)-
2-(2-difluoromethoxybenzylsulfonyl)ethvHisonicotinamide (Compound 138); Η NMR: (DMSO) 9.22 (d, J=8Hz, IH), 8.87 (d, J=6Hz, IH), 8.70 (m, 2H), 7.97-7.19 (m, 10H), 7.08 (t, JH,^74Hz, IH), 5.30-5.09 (m, 2H), 4.58 (s, 2H), 3.73-3.59 (m, 2H), 1.94 (m, IH), 1.71 (m, IH), 1.41-1.22 (m, 4H), ), 0.82 (t, J=6JHz, 3H); MS: (M++l) 629; -V-riR-(lS-benzooxazol-2-ylcarbonylbutylcarbamoyl)-
2-pyrid-2-ylmethylsulfonyl)ethyllmoφholine-4-carboxamide (Compound 139);^ NMR (DMSO): 8.6 (m, 2H), 8.05 (d,J=5.1Hz, IH), 7.85 (m, 2H), 7.3-7.8 (m, 4H), 7.2 (m, 3H), 5.32 (m, IH), 4.72 (m, IH), 4.65 (d,J=3.1Hz, 2H), 3.21-3.75 (m, 8H), 1.90 (m, IH), 1.75 (m, IH), 1.45 (m, 2H), 0.90 (t,J=4.5Hz, 3H); MS:m/e +1=558.2;MS: m/e (+1) = 558.2; 2-, 2R-(lS-benzooxazol-2-ylcarbonylbutylcarbamoyl)-
2-moφholin-4-ylcarbonylaminoethylsulfonylmethvHpyridine 1-oxide (Compound 140); Η NMR (DMSO): 8.57 (m, 3H), 7.97 (m, IH), 7.63-7.82 (m, 3H), 7.35-7.45 (m, 4H), 6.93 (m, IH), 4.50- 4.95 (m, 2H), 4.18 (m, 2H), 3.10-3.80 (m, 8H), 1.10-1.70 (m, 4H), 0.82 (t,J=5.4Hz, 3H); MS:m/e (+1) =574.2; lR-(lS-benzooxazol-2-ylcarbonylpentylcarbamoyl)-
2-(2-difluoromethoxybenzylsulfonyl)ethylcarbamate (Compound 141); MS: (M++l) 582;
-V-riR-(lS-benzooxazol-2-ylcarbonylpentylcarbamoyl)-2-benzylsulfonylethvnsuccinamic acid (Compound 142); Η NMR: (DMSO) 12.09 (s, IH), 8.63 (d, J=6Hz, IH), 8.51 (d, J=8Hz, IH), 7.98 (d, J=8Hz, IH), 7.87 (d, J=8Hz, IH), 7.62 (t, J=8Hz, IH), 7.52 (t, J=8Hz, IH), 7.38- 7.30 (m, 5H), 5.25 (m, IH), 4.84 (m, IH), 4.46 (s, 2H), 3.53-3.21 (m, 2H), 5.28-5.25 (m, 4H), 1.93 (m, IH), 1.68 (m, IH), 1.40-1.22 (m, 4H), 0.84 (t, J=6.2Hz, 3H); MS: (M++l) 558;
2R-.3,3-bis(2-methoxyethyl)ureidol--V-(lS-benzooxazol-2-ylcarbonylpenwl)- 3-benzylsulfonylpropionamide (Compound 143); Η NMR: (DMSO) 8.50 (d, J=6.6Hz, IH), 7.98 (d, J=8Hz, IH), 7.88 (d, J=8Hz, IH), 7.62 (t, J=8Hz, IH), 7.52 (t, J=8Hz, IH), 7.38-7.30 (m, 5H), 6.82 (d, J=8Hz, IH), 5.26 (m, IH), 4.70 (m, IH), 4.46 (s, 2H), 3.52-3.22 (m, 10H), 3.31 (s, 6H), 1.94 (m, IH), 1.69 (m, IH), 1.40-1.22 (m, 4H), 0.85 (t, J=6.6Hz, 3H); MS: (M++l) 617; N-\ lR-( 1 S-benzooxazol-2-ylcarbonyl-3-phenylpropylcarbamoyl)- 2-(6-methv-pyrid-2-ylmethylsulfonyl)ethvπisonicotinamide (Compound 144); 'H NMR (DMSO): 8069 (t,J =6Hz, IH), 8.55 (d,J =9Hz, IH), 7.91 (m, 2H), 7.51 (m, 3H), 4.51 (m, IH), 4.11 (d,J =6Hz, 2H), 1.5 (m, 15H); MS: m/e=328.05;
N- . lR-( 1 S-benzooxazol-2-ylcarbonyl-3-phenylpropylcarbamoyl)- 2-benzylsulf onylethyll succinamic acid (Compound 145); MS (ESI) MH+ 478.2;
-V-flR-(lS-benzooxazol-2-ylcarbonyl-3-phenylpropylcarbamoyl)- 2-(2-trifluoromethylbenzylsulfonyl)ethvntetrahvdropyran-4-carboxamide (Compound 146);
N-\ lR-( 1 S-benzooxazol-2-ylcarbonyl-3-phenylpropylcarbamoyl)- 2-thien-3-ylmethylsulfonylethyllisonicotinamide (Compound 147); -V-riR-(lS-benzooxazol-2-ylcarbonyl-3-phenylpropylcarbamoyl)-
2-(6-methylpyrid-2-ylmethylsulfonyl)ethylltetrahydropyran-4-carboxamide (Compound 148);
N-\ lR-( 1 -benzooxazol-2-ylcarbonylcvclobutylcarbamoyl)- 2-(2-trifluoromethylbenzylsulfonyl)ethylltetrahvdropyran-4-carboxamide (Compound 149);
-V-riR-(lS-benzooxazol-2-ylcarbonyl-3-phenylpropylcarbamoyl)- 2-pyrid-3-ylmethylsulfonylethyllpyrazine-2-carboxamide (Compound 150);
-V-. 1 -( 1 -benzooxazol-2-yl carbonyl-3-phenylpropylcarbamoy D- 2-thien-3-ylmethylsulfonylethyllpiperidine-4-carboxamide (Compound 151);
-V-. lSJlS-benzooxazol-2-ylcarbonyl-3-phenylpropylcarbamoyl)- 2-thien-3-ylmethylsulfonylethyllazetidine-3-carboxamide (Compound 152); -V-riR-(lS-benzooxazol-2-ylcarbonyl)butylcarbamoyl)-
2-pyrid-3-ylmethylsulfonylethyllmoφholine-4-carboxamide (Compound 153); Η NMR (DMSO): 8.66 (d, J=6.7Hz, IH), 8.56 (m, 3H), 8.01 (d, J=7.9Hz, IH), 7.90 (d,J=8.1Hz, IH), 7.79 (m, IH), 7.65 (t, J=7.1Hz, IH), 7.55 (t, J=7.1Hz, IH), 7.43 (dd, J=4.9,7.9Hz, 2H), 6.93 (d, J=8.40Hz, IH), 5.30 (m, J=lHz, IH), 4.76 (m, IH), 4.57 (d, J=3.7Hz, 2H), 3.24-3.70 (m, 8H), 1.91 (m, IH), 1.73 (m, IH), 1.40 (m, 2H), 0.82 (t, J=5.4Hz, 3H); MS:m/e (+1) = 555.8;
-V-, lR-(lS-benzooxazol-2-ylcarbonyl-3-phenylpropylcarbamoyl)- 2-benzylsulfonylethyllpiperazine- 1 -carboxamide (Compound 154);
-V-. lR-(lS-benzooxazol-2-ylcarbonyl-3-methylsulfonylpropylcarbamoyl)- 2-(2-difluoromethoxybenzylsulfonyl)ethyllmoφholine-4-carboxamide (Compound 155); ]H NMR (CDCL3, 300MHz) 7.8944 (d, J=7.92Hz, IH), 7.67 (m, IH), 7.58 (m, IH), 4.49 (m, 2H), 7.415 (m, IH), 7.24 (m, 3H), 6.5811 (t, J=73.24Hz, IH), 5.7633 (m, IH), 4.9199 (m, IH), 4.4871 (dd, J=13.61, 23.75Hz, 2H), 3.7101 (m, 4H), 3.4189 (m, 4H), 3.27 (m, 2H), 2.9289 (s, 3H), 2.77 (m, IH), 2.37 (m, IH); MS: (M+) 687.3 (M") 685.6;
-V-riR-(lS-benzooxazol-2-ylcarbonyl-3-methylesulfonylpropylcarbamoyl)- 2-(2-methoxybenzylsulfonyl)ethyllmoφholine-4-carboxamide (Compound 156); 'H NMR (CDClj): 7.89 (m, IH), 7.45-7.8 (m, 3H), 7.35 (m, 2H), 6.9-7.05 (m, 2H), 5.83-5.9 (m, IH), 5.62-5.8 (m, IH), 4.82 (m, IH), 4.40 (m, 2H), 3.89 (s, 3H), 3.70 (m, 5H), 3.25-3.42 (m, 7H), 2.95 (s, 3H), 2.75 (m, IH), 2.35 (m, IH); MS: m/e 651.4;
-V-riR-(lS-benzooxazol-2-ylcarbonylpentylcarbamoyl)- 2-benzylsulfonylethyllpiperazine- 1 -carboxamide (Compound 157); !H NMR: (DMSO) 9.20- 9.11 (m, 2H), 8.73 (m, IH), 7.98 (d, J=8Hz, IH), 7.88 (d, J=8Hz, IH), 7.63 (t, J=8Hz, IH), 7.52 (t, J=8Hz, IH), 7.39-7.30 (m, 5H), 5.24 (m, IH), 4.74 (m, IH), 4.50 (s, 2H), 3.62-3.30 (m, 6H), 3.05-2.95 (m, 4H), 1.94 (m, IH), 1.69 (m, IH), 1.40-1.22 (m, 4H), 0.84 (t, J=6.6Hz, 3H); MS: (M++l) 570;
-V-(lS-benzooxazole-2-ylcarbonyl-3-methylsulfonylpropyl)-2R-methylsulfonylamino- 3-benzylsulfonv ropionamide (Compound 160); Η NMR (DMSO-d6) 7.9498 (m, 2H), 7.6577 (m, IH), 7.5556 (m, IH), 7.3870 (m, 5H), 5.4016 (m, IH), 4.5444 (m, 3H), 3.32 (m, 2H), 2.9784 (s, IH), 2.9326 (s, IH), 2.49 (m, IH), 2.20 (m, IH); MS: (M+) 586.0, (M ) 584.0; methyl lR-( 1 S-benzooxazol-2-ylcarbonyl-3-phenyrpropylcarbamoyl)- 2-pyrid-2-ylmethylsulfonylethylcarbamate (Compound 161); MS: m/e (+1) = 564.6; methyl lR-(lS-benzooxazol-2-ylcarbonyl-3-methylsulfonylpropylcarbamoyl)- 2-benzylsulfonylethylcarbamate (Compound 162); 'H NMR (DMSO): 9.03 (d, J=7.2Hz, IH), 7.97 (d, J=7.9Hz, IH), 7.90 (d, J=8.2Hz, IH), 7.65 (td, J=7.2, 1.2Hz, IH), 7.55 (t, J=7.9Hz, IH), 7.37 (m, 5H), 5.32 (m, IH), 4.65 (m, IH), 4.50 (m, 2H), 3.53 (m, IH), 3.49 (s, 3H), 3.33 (s, 2H), 3.24 (m, IH), 2.98 (s, 3H), 2.41 (m, IH), 2.18 (m, IH); MS: m/e 653.2;
N-(lS-benzooxazol-2-ylcarbonylpentyl)-2R-, 3,3-di(2-methoxyethyl)ureidol- 3-pyrid-2-ylmethylsulfonylpropionamide (Compound 163); MS.m/e +1=615.6;
N- . lR-( 1 S-benzooxazol-2-ylcarbonylbutylcarbamoyl)- 2-(2-methoxybenzylsulfonyl)ethyllmorpholine-4-carboxamide (Compound 164); 'H NMR (DMSO): 8.66 (d,J =6Hz, IH), 8.03 (d,J = 9Hz, IH), 7.93 (d,J = 9Hz, IH), 7.68 (t,J = 8Hz, IH), 7.58 (t,J =9Hz, IH), 7.36 (m, 2H), 7.0 (m, 3H), 5.29 (m, IH), 4.77 (m, IH), 4.54 (d,J = 14Hz, IH), 4.43 (d,J =14Hz, IH), 3.84 (s, 3H), 3.5-3.3 (m, 10H), 1.95 (m, IH), 1.74 (m, IH), 1.46 (m, 2H), 0.93 (t, J=8Hz, 3H); MS: m/e=587.31;
/\ -(lS-benzooxazol-2-ylcarbonylbutylcarbamoyl)-2R-(3.3-dimethylureido)- 3-(2-methoxybenzylsulfonyl propionamide (Compound 165); NMR 300mHz (DMSO-d6), 8.63 (d, J=6.9H3, IH), 8.03 (d, J=8.8H3, IH), 7.92 (d, J=9.1, IH), 7.70 (t, J=8.8H3, IH), 7.58 (t, J=8.2H3, IH), 7.37 (m, 2H), 7.08 (d, J=9.1H3, IH), 6.98 (t, J=8.2H3, IH), 6.71 (d, J=9.1H3, IH), 5.27 (m, IH), 4.77 (m, IH), 4.55 (d, J=15.1H3, IH), 4.43 (d, J=15.1H3, IH), 3.79 (s, 3H), 3.47 (d, J=6.9H3, 2H), 2.83 (s, 6H), 1.93 (m, IH), 1.75 (m, IH), 1.43 (m, 2H), 0.93 (t, J=8H3, 3H); N-( 1 S-benzooxazol-2-ylcarbonylbutyl)-2-methylsulf onylamino- 3J2-methoxybenzylsulfonvDpropionamide (Compound 166); Η NMR (DMSO): 9.0 (d,J = 6Hz, IH), 8.01 (d,J = 8Hz, IH), 7.91 (d,J = 8Hz, IH), 7.67 (t,J = 7Hz, IH), 7.57 (t,J = 8Hz, IH), 7.36 (t, J=8Hz, 2H), 7.07 (d, J=8Hz, IH), 6.97 (dt, J=2,7Hz, IH), 7.85 (m, IH); 5.33 (m, 4H), 4.5 (m, 3H), 3.8 (s, 3H), 3.35 (m, 2H), 2.92 (s, 3H), 1.93 (m, IH), 1.72 (m, IH), 1.44 (m, 2H), 0.91 (t, J=7Hz, 3H); MS: m/e=552.19;
3-cvclohexyl-N-r2-hvdroxy-2-(5-nitrobenzooxazol-2-yl)-lS-phenethylethyllpropionamide (Compound 167); MS (ESI) m/z = 466 (M + 1); 'H-NMR (300 MHz, CDC13): δ 0.95 (m, 2H), δ 1.22 (m, 4H), δ 1.51 (m, 2H), δ 1.65 (m, 6H), δ 2.15 (m, 2H), δ 2.65 (m, 2H), δ 4.15 (m, IH), δ 4.50 (m, IH), δ 5.08 (m, IH), δ 5.80 (d, J = 6 Hz, IH), δ 6.09 (m, IH), δ 7.00 - 7.35 (m, 5H), δ 7.60 (m, IH), δ 8.40 (m, IH), δ 8.55 (m, IH), (C26H31N3O5); methyl 2- .2S-(3-cvclohexylpropionylamino)- 1 -hydroxy - 4-phenylbutyllbenzooxazole-6-carboxylate (Compound 168); MS (ESI) m z = 478 (M + 1); Η-NMR (300 MHz, CDC13): δ 0.84 (m, 2H), δ 1.22 (m, 4H), δ 1.51 (m, 7H), δ 1.90 (m, IH), δ 2.11 (m, 2H), δ 2.65 (m, 2H), δ 3.95 (s, 3H), δ 4.19 (m, IH), δ 4.50 (m, IH), δ 5.09 (s, IH), δ 6.09 (m, IH), δ 6.49 (m, IH), δ 7.01 - 7.35 (m, 5H), δ 7.65 (m, IH), δ 8.01 (m, IH), δ 8.17 (m, IH), (C28H34N2O5);
Ar-r2-(5-chlorobenzooxazol-2-yl)- 2-hvdroxy-lS-phenethylethvn-3-cvclohexylρropionamide (Compound 169); MS (ESI) m/z = 455 (M + 1); 'H-NMR (300 MHz, CDC13): δ 0.84 (m, 2H), δ 1.12 (m, 4H), δ 1.20 (m, 2H), δ 1.51 (m, 6H), δ 2.00 (m, 3H), δ 2.65 (m, 2H), δ 4.21 (m, IH), δ 4.50 (m, IH), δ 5.02 (s, IH), δ 6.44 (m, IH), δ 7.01 - 7.47 (m, 7H), δ 7.65 (s, IH), (C26H31ClN2O3); benzyl lS-(2-benzooxazol-2-yl-2-hvdroxy-lS-phenethylethylsulfamoylmethyl)- 3-methylbutylcarbamate (Compound 170); Η NMR (CDC13): 7.71 (m, IH), 7.52 m, IH), 7.20- 7.40 (m, 12H), 5.9 (m, 0.5H), 5.6 (m, 0.5H), 4.80-5.20 (m, 5H), 4.1-4.3 (m, 2H), 2.7-2.9 (m, 4H), 1.7-2.0 (m, 2H), 0.90 (m, 3H), 0.79 (m, 3H), 3.30 (m, IH);
N-\ 1 S-(2-benzooxazol-2-yl-2-hvdroxy- 1 S-phenethylethylsulf amoylmethyl)- 3-methylbutyllacetamide (Compound 171); benzyl 1 S(2-benzooxazol-2-yl-2-hydroxy- lSphenethylethylsulfamoylmethyl)-3-methylbutylcarbamate (Compound 172); !H NMR (DMSO): 7.71 (m, IH), 7.5 (m, IH), 7.0-7.4 (m, 12H), 4.9-6.2 (m, 6H), 4.0-4.35 (m, 2H), 3.75 (m, IH), 3.20-3.60 (m, 2H), 2.5-3.0 (m, 2H), 1.15-2.15 (m, 3H), 0.6-1.05 (m, 6H); MS: m/e 580.1;
-V-riR-(2-benzooxazol-2-yl-2-hvdroxy-lS-phenethylethylsulfamoylmethyl)- 3-methylbutyllacetamide (Compound 173);
2S-acetylamino--V-(2-benzooxazol-2-yl-2-hydroxy-lS-phenethylethyl)- 3-cvclohexylpropionamide (Compound 174); tgrt-butyl 1 S-(2-benzooxazol-2-yl-2-hvdroxy- 1 S-phenethylethyll - 2-cyclohexylethyl)carbamate (Compound 175);
2-acetylamino-N-2-benzooxazol-2-yl- 1.1 -dimefhyl-2-oxoethyl)- 3-cyclohexylpropionamide (Compound 176); benzyl lS-.2-(5-phenylbenzooxazol-2-yl)-2-hvdroxyethylcarbamovH-
3-methylbutylcarbamate (Compound 177);
-V-(2-benzooxazol-2-yl-2-hvdroxy-lS-phenethylethyl)-3-cvclopentylpropionamide (Compound 178); 'H NMR (CDC13): 7.72 (m, IH), 7.53 (m, IH), 7.08-7.19 (m, 8H), 5.98 (m, IH), 5.05 (m, 2H), 4.51 (m, IH), 2.6-2.8 (m, 4H), 2.17-2.29 (m, IH), 1.95-2.15 (m, 2H), 1.8- 1.95 (m, IH), 1.68-1.78 (m, IH), 1.3-1.7 (m, 6H), 1.0-1.12 (m, IH), 0.85-1.0 (m, IH); Λ7-(2-benzooxazol-2-yl-2-hvdroxy- 1 S-phenvethylethyl)-2-bicvclo_ 2.2.1 lhept-2-ylacetamide (Compound 179);
-V-(2-benzooxazol-2-yl-2-hvdroxy- 1 S-phenethylethyl)-2-naphthalen- 1 -ylacetamide (Compound 180); -V-(2-benzooxazol-2-yl-2-hydroxy-lS-phenethylethyl)-3-phenylpropionamide
(Compound 181); Η NMR (CDC13): 7.69 (m, IH), 7.53 (m, IH), 7.37 (m, 2H), 7.03-7.35 (m, 10H), 5.9 (m, IH), 4.98 (m, IH), 4.40-4.55 (m, IH), 3.0 (m, IH), 2.80 (t, J=7.7Hz, 2H), 2.55 (m, 2H), 2.38 (t, J=7.5Hz, 2H); methyl 2-.2S-(3-cvclohexylpropionylamino)-l-hydroxy-4-phenylbutyll- 4,5-dihvdrooxazole-4S-carboxylate (Compound 182); MS (ESI) m/z = 431 (M + 1); Η-NMR (300 MHz, CDC13): δ 0.89 (m, 2H), δ 1.20 (m, 4H), δ 1.48 (m, 2H), δ 1.65 (m, 6H), δ 2.00 (m, 2H), δ 2.15 (m, 2H), δ 2.73 (t, J = 4 Hz, 2H), δ 3.76 (s, 3H), δ 4.30 - 4.65 (m, 5H), δ 6.00 (d, J = 6Hz, IH), δ 7.13 - 7.35 (m, 5H), (C24H34N2O5); methyl 2-.2S-(3-cvclohexylpropionylamino)-l-hydroxy- 4-phenylbutylloxazole-4-carboxylate (Compound 183);
-V-(2-benzooxazol-2-yl-2-hvdroxy-lS-phenethyl)-4-cvclohexylbutyramide (Compound 184); Η NMR (CDC13): 7.62-7.73 (m, IH), 7.46-7.59 (m, IH), 7.05-7.43 (m, 2H), 6.22-6.38 (m, IH), 5.11 (s, IH), 4.50-4.69 (m, IH), 2.58-2.82 (m, 2H), 2.14-2.24 (m, IH), 2.0, 2.14 (m, IH), 1.50-1.76 (m, 6H), 1.31-1.50 (m, IH), 0.94-1.31 (m, 7H), 0.63-0.93 (m, 2H); MS: m/e=435.1; methyl 2-, 2S-(3-cyclohexylpropionylamino)-l-hvdroxy-4-phenylbutyl1- 4.5-dihvdrooxazole-4R-carboxylate (Compound 185); MS (ESI) m z = 431 (M + 1); 'H-NMR (300 MHz, CDC13): δ 0.89 (m, 2H), δ 1.20 (m, 4H), δ 1.48 (m, 2H), δ 1.65 (m, 6H), δ 2.00 (m, 2H). δ 2.15 (m, 2H), δ 2.73 (t, J = 4 Hz, 2H), δ 3.76 (s, 3H), δ 4.35 - 4.72 (m, 5H), δ 5.75 (m, IH), δ 7.13 - 7.35 (m, 5H), (C24H34N2O5);
3-cvclohexyl--V-.2-hvdroxy-2-(5-trifluoromethylbenzooxazol-2-yl)- 1 S-phenethylethyllpropionamide (Compound 186); MS (ESI) m/z = 489 (M + 1); Η-NMR (300 MHz, CDC13): δ 0.77 (m, 2H), δ 1.22 (m, 4H), δ 1.51 (m, 2H), δ 1.60 (m, 6H), δ 2.15 (m, 4H), δ 2.70 (m, 2H), δ 4.51 (m, IH), δ 5.11 (s, IH), δ 6.10 (d, J = 6 Hz, IH), δ 7.00 - 7.35 (m, 5H), δ 7.56 (s, 2H), δ 7.99 (s, IH), (C27H31F3N203);
2S-acetylamino-N-(2-benzooxazol-2-yl-2-hydroxy-lS-phenethylethyl)- 3-(2-trifluoromethylphenyl)propionamide (Compound 187); methyl 1 -( 1 -benzooxazol-2-ylcarbony 1-3-phenylpropylcarbamoyl)- 2-cvclohexylethylcarbamate (Compound 188); Η NMR (CDC13): 7.89 (d,J=7.4Hz, IH), 7.62 (M, 1H0, 7.54 (m, IH), 7.46 (m, IH), 7.13-7.30 (m, IH), 6.87 (d, J=7.9Hz, IH), 5.68 (m, IH), 5.04 (d, J=9.6Hz, IH), 4.24 (m, IH), 3.66 (s, 3H), 2.75 (5,J=8.3Hz, 2H), 2.45 (m, IH), 2.19 (m, IH), 2.00 (M, IH), 1.52-1.80 (m=5H), 1.44 (m, IH), 1.12-1.27 (m, 4H), 0.89 (m, 2H); MS: m/e=492.04;
N-( 1 -benzooxazol-2-ylcarbonyl-3-phenylpropyl)-3-cyclohexyl- 2-methylsulfonylaminopropionamide (Compound 189); Η NMR (CDC13): 7.87 (m, IH), 7.62 (m, IH), 7.55 (m, IH), 7.46 (m, IH), 7.13-7.28 (m, 5H), 6.79 (d, J=7.9Hz, IH), 5.71 (m, IH), 4.92 (m, IH), 4.00 (m, IH), 2.95 (2, 3H), 2.75 (m, 2H), 2.48 (m, IH), 2.21 (m, IH), 1.78 (m, IH), 1.61 (m, 5H), 1.45 (m, IH), 1.16 (m, 4H), 0.89 (m, 2H); cvclohexylmethyl l-benzooxazol-2-ylcarbonyl-3-phenylpropylcarbamate (Compound 190); Η NMR (CDC13): 7.88 (m, IH), 7.62 (m, IH), 7.52 (m, IH), 7.49 (m, IH), 7.13-7.23 (m, 5H), 5.57 (m, IH), 3.89 (d, J=6.5Hz, 2H), 2.79 (m, 2H), 2.42 (m, IH), 2.12 (m, IH), 1.50-1.73 (m, 6H), 1.24 (m, 6H), 0.89 (m, 2H); MS: m/e=421.0; benzyl 1 -( l-benzooxazol-2-ylcarbonyl-3-phenylpropylsulfamoylmethyl)- 2-methylbutylcarbamate (Compound 191); Η NMR (CDC13): 7.88 (d.J=7JHz, IH), 7.62 (m, IH), 7.55 (m, IH), 7.47 (m, IH), 7.33 (m, 5H), 7.19 (m, 5H), 6.35 (d, J=7JHz, IH), 5.45 (m, IH), 5.13 (s, 2H), 5.0 (m, IH), 4.43 (m, IH), 3.06 (m, IH), 2.87 (m, IH), 2.45 (m, IH), 2.15 (m, IH), 1.41 (m, IH), 1.07 (m, IH), 0.88 (m, 6H); MS: m/e=5J8.1;
-V-_ lR-(lS-benzooxazol-2-ylcarbonyl-3-phenylpropylcarbamoyl)- 2-(6-methylpyrid-2-ylmethylsulfonyl)ethyllthiophene-3-carboxamide (Compound 192);
N- , 1 R-( 1 S-benzooxazol-2- ylcarbonyl)- 3-phenylpropylcarbamoyl)-2-(2-methylpyrid-3-ylmethylsulfonyl)ethyllnicotinamide (Compound 193);
-V-riR-(lS-benzooxazol-2-ylcarbonyl-3-phenylpropylcarbamoyl)- 2-(2-cvanobenzylsulfonyl)ethyllazetidine-3-carboxamide (Compound 194); tert-butyl lR-( 1 -benzooxazol-2-ylcarbonylcyclobutylcarbamoyl)- 2-(2-difluoromethoxybenzylsulfonyl)ethylcarbamate (Compound 195); tert-butyl lR-(lS-benzooxazol-2-ylcarbonyl-3-phenylpropylcarbamoyl)- 2-(4-trifluoromethylpyrid-3-ylmethylsulfonyl)ethylcarbamate (Compound 196); -V-f lR-( 1 -benzooxazol-2-ylcarbonylcvclobutylcarbamoyl)-
2-(2-difluoromethoxybenzylsulfonyl)ethylmoφholine-4-carboxamide (Compound 197);
N- _ lR-( 1 S-benzooxazol-2-ylcarbonyl pentylcarbamoyl)- 2-pyrid-3-ylmethylsulfonylethvnisonicotinamide (Compound 198); methyl lR-(lS-benzooxazol-2-ylcarbonylbutylcarbamoyl)- 2-(2-methoxybenzylsulfonyl)ethylcarbamate (Compound 199);
-V-. lRJlS-benzooxazol-2-ylcarbonylpropylcarbamoyl)- 2-benzylsulfonylethyllmoφholine-4-carboxamide (Compound 200); NMR 300mHz (DMSO-d6), 8.65 (d, J=7.1H3, IH), 8.01 (d, J=8.2H3, IH), 7.91 (d, J=8.8H3, IH), 7.66 (t, J=8H3, IH), 7.55 (t., J=7JH3, IH), 7.38 (s, 5H), 7.05 (d, J=9.4H3, IH), 5.21 (m, IH), 4J5 (m, IH), 4.49 (s, 2H), 3.53 (m, 4H), 3.45 (m, 2H), 3.32 (m, 4H), 2.02 (m, IH), 1.77 (m, IH), 0.96 (t, J=8H3, 3H); M=543.24 M+=542.61;
-V-(lR-benzooxazol-2-ylcarbonylpropyl)-2-(3.3-dimethylureidoV 3-(2-methoxybenzylsulfonyl)propionamide (Compound 201); NMR 300mHz (DMSO-d6), 8.61 (d, J=7.4H3, IH), 8.01 (d, J=8.5H3, IH), 7.90 (d, J=7.1H3, IH), 7.65 (t, J=8H3, IH), 7.55 (t, J=8H3, IH), 7.33 (m, 2H), 7.05 (d, J=8.8H3, IH), 6.96 (t, J=8.2H3, IH), 6.70 (d, J=9.1H3, IH), 5.20 (m, IH), 4.53 (d, J=15.4H3, IH), 4.41 (d, J=15.4H3, IH), 3.77 (s, 3H), 3.45 (d, J=7.1H3, 2H), 2.81 (s, 6H), 2.0 (m, IH), 1.7 ( m, IH), 0.96 (t, J=8H3, 3H); MS=651.33 M+=650.59; methyl lR-(lS-benzooxazol-2-ylcarbonylpropylcarbamoyl)- 2-(2-methoxybenzylsulfonylethyl)carbamate (Compound 202);
-V-(l-benzooxazol-2-ylcarbonylpentyl)-2R-r3.3-bis(2-methoxyethyl)ureidol- 3-pyrid-3-ylmethylsulfonylpropionamide (Compound 203); -V-(lS-benzooxazol-2-ylcarbonylpentyl)-2R-r3,3-bis(2-methoxyethyl)ureido1-
3-(3.5-dimethylisoxazol-4-ylmethylsulfonyl)propionamide (Compound 204);
-V-(lS-benzooxazol-2-ylcarbonylpropyl)-3-(3.5-dimethylisoxazol-4-ylmethylsulfonyl)- 2R-methylsulfonylaminopropionamide (Compound 205); Η NMR: (DMSO) 9.04 (d, J=6.6Hz, IH), 8.00-7.87 (m, 3H), 7.63 (t, J=8Hz, IH), 7.53 (t, J=8Hz, IH), 5.25 (m, IH), 4.61-4.36 (m, 3H), 3.56-3.31 (m, 2H), 2.91 (s, 3H), 2.36 (s, 3H), 2.17 (s, 3H), 2.02 (m, IH), 1.74 (m, IH), 0.96 (t, J=7Hz, 3H); MS: (M++l) 527; methyl lR-( 1 S-benzooxazol-2-ylcarbonylpropylcarbamoyl)- 2-(3.5-dimethylisoxazol-4-ylmethylsulfonyl)ethylcarbamate (Compound 206); 'H NMR: (DMSO) 8.78 (d, J=5.8Hz, IH), 7.99 (d, J=8Hz, IH), 7.87 (d, J=8Hz, IH), 7.69 (d, J=8.5Hz, IH), 7.62 (t, J=8Hz, IH), 7.52 (t, J=8Hz, IH), 5.20 (m, IH), 4.68 (m, IH), 4.39 (d, J=14Hz, IH), 4.29 (d, J=14Hz, IH), 3.52 (s, 3H), 3.60-3.28 (m, 2H), 2.37 (s, 3H), 2.15 (s, 3H), 2.02 (m, IH), 1.74 (m, IH), 0.95 (t, J=7Hz, 3H); MS: (M++l) 507;
N-\ lR-( 1 -benzooxazol-2-ylcarbonylpentylcarbamoyl)- 2-pyrid-2-ylmethylsulfonylethyllisonicotinamide (Compound 207); NMR IH: 9.15-9.30 (m, IH), 8.4-8.9 (m, 4 H), 7.32-8.05 (m, 9H), 5.28 (m, IH), 5.10 (m, IH), 4.75 (m, 2H), 3.75 (m, IH), 3.62 (m, IH), 1.95 (m, IH), 1.75 (m, IH), 1.05-1.45 (m, 4H), 0.87 (m, 3H); MS: M+l = 564.0; and
4-|TR-(lS-benzooxazoI-2-ylcarbonylpentylcarbamoyl)- 2-pyrid-2-ylmethylsulfonylethylcarbamoyllpyridine 1 -oxide (Compound 208).
REFERENCE 13
Benzyl lS-(-V-methoxy-N-methylcarbamoyl)-3-phenylpropylcarbamate A solution of 2-benzyloxycarbonylamino-4-phenylbutyric acid (5.05 g, 16.1 mmol) in methylene chloride (70 mL) was cooled to 0°C and treated with diisopropylethylamine (2.82 mL, 16.2 mmol) added dropwise and then PyBOP® (8.53 g, 16.4 mmol) added in one portion. The mixture was stirred for 5 minutes and then treated with -V,0-dimethylhydroxylamine hydrochloride (1.73 g, 17.71 mmol) was added in one portion. The mixture was neutralized with diisopropylethylamine (4.6 mL, 26.44 mmol) added dropwise, stirred for 2 hours at room temperature and then diluted with methylene chloride (70 mL). The dilution was washed with IN aqueous hydrochloric acid (3x 40 mL), saturated sodium bicarbonate (3x 40 mL) and brine (40 mL) and then concentrated. The product was purified from the residue by column chromatography eluting with 2:3 ethyl acetate/hexane to provide benzyl lS-.-V-methoxy--V-methylcarbamoyl)-3-phenylpropylcarbamate (5.48 g, 15.4 mmol) as an oil. MS(PCI) m z = 357 (M +1).
Proceeding as in Reference 13 provided tgrt-butyl lS-.-V-methoxy- N-methylcarbamoyl)-3-phenylpropylcarbamate: Η NMR (CDC13): δ 1.35 (s, 9H), δ 1.64 - 1.72 (m, 2H), δ 2.40 - 2.54 (m, IH), δ 2.60 - 2J7 (m, IH), δ 3.00 (s, 3H) 3.52 (s, 3H), δ 4.23 (m, IH), δ 7.10 - 7.37 (m, 5H).
REFERENCE 14
2S-Amino--V-methoxy-N-methyl-4-phenylbutyramide trifluoroacetic acid salt
A solution of tert-butyl l-(iV-methoxy--V-methylcarbamoyl)-3-phenylpropylcarbamate
(9.32 g, 29 mmol), provided as in Reference 13, in methylene chloride (100 mL) was cooled to 0° C and then treated with anisole (5 mL, 46.5 mmol) and trifluoroacetic acid (50 mL, 296 mmol). The mixture was stirred for 30 minutes, while allowing it to warm to room temperature, and then concentrated. The residue was dissolved in toluene (100 mL) and the solution was concentrated. The residue was again dissolved in toluene (100 ml) and concentrated to provide 2S-amino--V-methoxy-/V-methyl-4-ρhenylbutyramide trifluoroacetic acid salt (9.74 g 29 mmol) as a crude product. MS(PCI) m/z = 223 (M +1). REFERENCE 15 Benzyl 14 l-(-V-methoxy-N-methylcarbamoyl)-3S-phenylpropylcarbamoyll-
3-methylbutylcarbamate
A solution comprised of 2S-amino--V-methoxy--V-methyl-4-phenylbutyramide trifluoroacetic acid salt (9.74 g, 29 mmol), provided as in Reference 2, in DMF (75 mL) was cooled to 0° C and then neutralized with diisopropylethylamine added dropwise. A solution comprised of 2,5-dioxopyrrolidin-l-yl 2-benzyloxycarbonylamino-4-methylvalerate (10.50 g,
29 mmol) in DMF (75 mL) and an additional amount of diisopropylethylamine (10.10 mL, 58 mmol) were added to the cooled butyramide solution. The mixture was stirred for 2 hours, while allowing it to warm to room temperature, and then poured into ice water (300 mL). The mixture was let stand for 1 hour to provide a white precipitate. The precipitate was collected by filtration and dried (P2O5) under vacuum to provide benzyl 1-ITJ-V-methoxy- N-methylcarbamoyl)-3-phenylpropylcarbamoyll-3-methylbutylcarbamate (12.24 g, 26.1 mmol). Η NMR (CDC13): δ 0.91 (d, J = 5.88 Hz, 6H), δ 1.45 - 1.55 (m, IH), δ 1.45 - 1.55 (m, 2H), δ 1.77 - 2.00 (m, IH), δ 2.11 - 2.22 (m, IH), δ 2.70 (m, 2H), δ 3.20 (s, 3H) 3.60 (s , 3H) 4.25 (m, IH), δ 5.00 (m, IH), δ 5.15 (s, 2H), δ 6.6 (d, J = 8.15 Hz, IH), δ 7.15 - 7.45 (m, 10H).
REFERENCE 16 Ethyl 3S-benzyloxycarbonylamino-2-hydroxy-5-phenylpentanimidate
A suspension comprised of lithium aluminum hydride (0.885 g, 23.3 mmol) in anhydrous diethyl ether was cooled to -45 ° C under nitrogen and then treated with a solution of benzyl lS-(-V-methoxy-N-methylcarbamoyl)-3-phenylpropylcarbamate (5.53 g, 15.53 mmol), provided as in Reference 13, in ether (75 mL) and THF (25 mL) was added dropwise over a period of
30 minutes such that the temperature of the mixture was maintained at -40 to -45 ° C. The mixture was allowed to warm to 5° C and then recooled to -35 ° C. A saturated solution of sodium bicarbaonate (7 mL, 0.5 M) was added dropwise and the mixture was allowed to warm to 0° C. The mixture was allowed to warm to room temperature and stirred for 1 hour to provide a precipitate. The precipitate was collected by filtration and washed with ether (100 mL). The filtrate and washings were combined and washed with ice cold IN hydrochloric acid (2x 50 mL), saturated sodium bicarbonate (2 x 50 mL) and brine (50 mL), dried (Na2S04) and concentrated in vacuo to provide benzyl lS-formyl-3-phenylpropylcarbamate (4.01 g,
13.5 mmol) as a colorless oil. MS (PCI) m/z = 298 (M + 1).
A solution of benzyl lS-formyl-3-phenylpropylcarbamate (4.557 g, 15.3 mmol) in anhydrous methylene chloride (50 mL) was stirred while sequentially treating with 2-hydroxy- 2-methylpropionitrile (4.25 mL, 46.2 mmol) and triethylamine (1.28 ml, 9.20 mmol). The mixture was stirred for 4 hours at room temperature and concentrated in vacuo. The residue was dissolved in ether (100 mL) and the solution was washed with water (5 x 20 mL) and brine (20 mL), dried (MgS04) and concentrated to provide benzyl
2-cyano-2-hydroxy-lS-phenethylethy Icarbamate (4.957 g, 15.3 mmol) as a yellow oil. Η NMR (CDC13): δ 1.75 - 2.01 (m, 2H), δ 2.08 - 2.24 (m, IH), δ 2.51 - 2.80 (m, 2H), δ 3J0 - 4.02 (m,
IH), δ 5.07, δ 5.33 (m, 3H), δ 7.10 - 7.47 (m, 10H).
A comprised of chloroform (30 mL) and anhydrous ethanol (30 mL, 510 mmol) was cooled to 0° C and then treated with acetyl chloride (32.6 mL, 459 mmol) added dropwise over a period of 30 minutes. The mixture was cooled with solution of crude benzyl 2-cyano- 2-hydroxy-l-phenethylethylcarbamate (4.957 g, 15.3 mmol) in chloroform (30 mL). The mixture was stirred for 2 hours at 0°C and then 6 hours at room temperature and concentrated in vacuo to provide ethyl 3S-benzyloxycarbonylamino-2-hvdroxy-5-phenylpentanimidate
(6.212 g 15.3 mmol) as a crude yellow oil. MS (PCI) m/z = 371 (M + 1).
REFERENCE 17 2S-Amino-4-phenyl-l-(4S-phenyl-4.5-dihvdrooxazol-2-yl)butan-l-ol
A mixture comprised of ethyl 3S-benzyloxycarbonylamino-2-hydroxy- 5-phenylpentanimidate (0.78 g, 1.92 mmol), provided as in Reference 16, diisopropylethylamine (0.218 μL, 1.26 mmol) and 2S-amino-2-phenylethanol (0.260 g, 1.9 mmol) in chloroform (25 mL) was heated at reflux for 3 hours and then was stirred for approximately 12 hours, while allowing to cool to room temperature. The mixture was concentrated and the residue was dissolved in ethyl acetate (50 ml). The solution was washed with 0.5N sodium hydroxide (40 mL) and brine (40 mL), dried (MgS04) and then concentrated. Product was purified from the residue by flash chromatography eluting with 1:3 hexanes/ethyl acetate to provide benzyl 2-hydroxy- 2-(4,5-dihydro-4S-phenyloxazol-2-yl)-lS-phenyethylethylcarbamate (0.475 g, 1.1 mmol) as an oily mixture of diastereomers. MS (PCI) m/z = 445 (M +1). (C27H28N2O4). A solution comprised of benzyl 2-hydroxy-2-(4,5-dihydro-4S-phenyloxazol-2-yl)- 15-phenyethylethylcarbamate (100 mg, 0.22 mmol) in methanol (10 mL) was placed under a nitrogen atmosphere and stirred while Pearlman's catalyst (20 mg) was added. The mixture was stirred vigorously under a hydrogen atmosphere until the reaction was complete and then filtered. The filter was washed with methanol (2 x 25 mL). The combined filtrates were concentrated to provided 2S-amino-4-phenyl-l-(4.5-dihvdro-4S-phenyloxazol-2-yl)butan-l-ol (51 mg, 0.16 mmol) as a clear oil. MS (PCI) m/z = 311(M +1). (C19H22N202).
REFERENCE 18 2S- Amino- 1 -oxazol-2-yl-4-phenylbutan- 1 -ol
A solution comprised of oxazole (0.25 g, 3.62 mmol) in THF (20 mL) was treated with borane tetrahydrofuran complex (3.62 mL, 3.62 mmol) under nitrogen and the mixture was stirred for 30 minutes and then cooled to -78 °C. A solution comprised of sgc -butyl lithium (2.78 ml, 3.62 mmol) in cyclohexane was added dropwise and the mixture was stirred for 30 minutes. A solution comprised of tgrt-butyl (S)-l-formyl-3-pheny lpropylcarbamate (0.476 g, 1.81 mmol) in THF (25 mL) was added and the mixture was stirred and allowed to warm while the reaction proceeded to completion. The mixture then was cooled to -78 °C, quenched by slowly adding 5% acetic acid in ethanol (20 mL), allowed to warm to ambient temperature and stirred for 18 hours. The mixture was concentrated to dryness and the residue was extracted with ether (2x25 mL). The combined extracts were washed with brine, dried (MgSO4) and concentrated to dryness to provide tert-butyl 2-hydroxy-2-oxazol-2-yl-lS-phenethylethy Icarbamate (0.125 g, 0.376 mmol) as a yellow oil. MS (PCI) m/z = 333 (M + 1).
A mixture comprised of tgrt-butyl 2-hydroxy-2-oxazol-2-yl-lS-phenethylethylcarbamate (0.125 g, 0.376 mmol), anisole (0.2 mL) and trifluoroacetic acid (0.6 mL) in methylene chloride (20 mL) was stirred at room temperature for 2 hours and then concentrated to provide
2S-amino-l-oxazol-2-yl-4-phenylbutan-l-ol trifluoroacetic acid salt ( 0.08 g, 0.229 mmol) as a yellow oil. MS (PCI) m z = 233 (M + 1). REFERENCE 19 Methyl 2-(2S-amino- 1 -hvdroxy-4-phenylbutyl)oxazole-4-carboxylate
A solution comprised of methyl 2-(2S-benzyloxycarbonylamino-l -hydroxy - 4-phenylbutyl)-4,5-dihydrooxazole-4-carboxylate (0.100 g, 0.235 mmol) in methylene chloride (3 mL) was cooled to 0° C and then treated with DBU (39 mL, 0.26 mmol) and bromotrichloromethane (26 ml, 0.26 mmol). The mixture was stirred for 6 hours at 0° C, washed with ammonium chloride (10 mL) and concentrated. The residue was dried (MgS04) to provide methyl 2- (2S-benzy loxy carbony lamino- 1 -hy droxy-4-pheny lbuty l)oxazole-4-carboxy late . MS(PCI) m/z = 425 (M +1).
Deprotecting provided methyl 2-(2S-amino- 1 -hy droxy- 4-ρhenylbutyl)oxazole-4-carboxylate.
EXAMPLE 19
Benzyl lS-.2-(4,5-d.hvdrooxazol-2-yl)-2-hvdroxy-lS-phenethylethylcarbamoyll-
3-methylbutylcarbamate (Compound 210)
Figure imgf000118_0001
A mixture comprised of ethyl 3-(2-benzyloxycarbonylamino-4-methylvalerylamino)- 2-hydroxy-5-phenylpentanimidate (0.327 g, 0.63 mmol), diisopropylethylamine (0.218 mL, 1.26 mmol) and ethanolamine (38.4 mg, 0.63 mmol) in chloroform (20 mL) was heated (reflux temperature) for 3 hours and then stirred at room temperature for approximately 12 hours. The mixture was concentrated and the residue was dissolved in ethyl acetate (50 mL). The solution was washed with 0.5 M sodium hydroxide (40 mL) and brine (40 mL), dried (MgS04) and concentrated in vacuo. Product was purified from the residue by flash chromatography eluting with 3:1 ethyl acetate/hexanes to provide benzyl lS-.2-.4,5-dihydrooxazol-2-yl)-2-hvdroxy- lS-phenethylethylcarbamoyll-3-methylbutylcarbamate (38 mg, 0.079 mmol) as a white solid. MS (PCI) m/z = 482 (M +1). (C27H35N3O5).
Proceeding as in Example 19 provided benzyl lS-,2-(lH-benzoimidazol-2-yl)-
2-hvdroxy-lS-phenvethylethylcarbamoyll -3-methylbutylcarbamate (Compound 211);
EXAMPLE 20 Benzyl lS-r2-(4.5-dihvdro-4S-phenyloxazol-2-yl)-2-hvdroxy-lS-phenethylethylcarbamoyll-
3-methylbutylcarbamate (Compound 212)
Figure imgf000119_0001
A solution comprised of 2S-amino-4-phenyl-l-(4S-phenyl- 4,5-dihydrooxazol-2-yl)butan-l-ol (51 mg, 0.165 mmol), provided as in Example 18, in DMF (2 mL) was cooled to 0° C and a second solution comprised of 2,5-dioxopyrrolidin-l-yl 2S-benzyloxycarbonylamino-4-methylvalerate (0.063 g, 0.174 mmol) and diisopropylethylamine (30.3 μL, 0.174 mmol) in DMF (3 mL) was added. The mixture was stirred for 2 hours, while allowing to warm to room temperature, and then concentrated. Product was purified from the residue by column chromatography eluting with ethyl 1:1 acetate/hexane to provide benzyl 1 S- .2-(4,5-dihvdro-4S-phenyloxazol-2-yl)-2-hydroxy- 1 S-phenethylethylcarbamoyll - 3-methylbutylcarbamate (34 mg, 0.061 mmol) as a clear oil. MS (PCI) m/z = 558(M +1). (C33Η39N305). Proceeding as in Example 20 provided the following compounds of Formula I:
benzyl 1 S-(2-benzooxazol-2-yl-2-hydroxy- 1 S-phenethylethy lcarbamoyl)- 3-methylbutylcarbamate (Compound 213); MS (ESI) m/z = 530 (M + 1); Η-NMR (300 MHz, CDC13,): δ 0.65 - 0J (dd, 6H), δ 0.98 (d, J = 6 Hz 2H), δ 1.10 - 1.55 (m, 3H), δ 1.65 - 1.85 (m, IH), 2.08 (m, IH), δ 2J0 (m, 2H), δ 3.99 - 4.13 (m, IH), δ 4.50(m, IH), δ 4.90 - 5.21 (m, 3H), δ 6.40 - 6J0 (dd, IH), δ 7.05 - 7.35 (m, 10H), δ 7.47 (d, J = 4 Hz, 2H), δ 7.51 (d, J = 2 Hz, 2H), (C3IH35N305); benzyl l-,2J4.5-dihvdro-5-phenyloxazol-2-yl)-2-hvdroxy-l-phenethylethylcarbamoyl1- 3-methylbutylcarbamate (Compound 214); benzyl l-,2J4,5-dihvdro-4S-methyl-5S-phenyloxazol-2-yl)-2-hvdroxy- l-phenvethylcarbamoyll-3-methylbutylcarbamate (Compound 215); benzyl 3-methyl-l-(2-hvdroxy-2-naphtho,2.3-cfloxazol-2-yl- 1 -phenethylethv lcarbamoyl 1 butylcarbamate (Compound 216); MS (ESI) m z - 580 (M + 1); 'H-NMR (300 MHz, CDC13): δ 0.65 - 0.95 (m, 6H), δ 1.25 (m, 3H), δ 1.54 (m, 3H), δ 2.20 (m, IH), δ 2.82 (t, J = 4 Hz, 2H), δ 4.00 - 4.20 (m, IH), δ 4.35 - 4.55 (m, IH), δ 4.90 - 5.09 (m, 3H), δ 6.60 (m, IH), δ 7.23 (m, 10H), δ 7.56 (m, 2H), δ 7.96 (m, 3H), δ 8.18 (s, IH), (C35H37N3O5); benzyl 1 S-(2-benzooxazol-2-yl-2-hvdroxy- 1 S-phenethylethylcarbamoyl)- 2-methylpropylcarbamate (Compound 217); benzyl 1 S-(2-benzooxazol-2-yl-2-hvdroxy- 1 S-phenethylethylcarbamoyl)- 3-mefhylbutylcarbamate (Compound 218); benzyl lS-.2-.4.5-dihvdro-4.4-dimethyloxazol-2-yl)-2-hvdroxy- lS-phenethylethylcarbamoyll-3-methylbutylcarbamate (Compound 219), MS (PCI) m/z = 510 (M +1); Η NMR (CDC13): δ 0.8 - 0.99 (d, J = 6 Hz, 6H) , 1.11 - 1.35 (m, 6H), δ 1.4 - 1.78 (m, 3H), δ 1.82 - 2.01 (m, 2H), δ 2.55 - 2.72 (m, 2H), δ 3.95 (m, IH), δ 4.0 - 4.25 (m, 3H), δ 4.30 (s, IH), δ 5.10 (s, 2H), δ 5.35 (s, IH), δ 6.58 (m, IH) 7.1 - 7.37 (m, 10H); (C29H39N305); methyl 2- .2-(2-benzyloxycarbonylamino-4-methylvalerylamino)- 1 -hvdroxy- 4-phenylbutyll-4.5-dihvdrooxazole-4-carboxylate (Compound 220), MS(PCI) m/z = 540 (M +1); Η NMR (CDC13): δ 0.8 - 0.99 (d, J = 6 Hz, 6H) ,1.25 (m, IH), δ 1.47 (m, IH) 1.65 (m, 2H), δ 1.99 (m, 2H), δ 2.15 (s, IH), δ 2.65 (t, J = 4Hz, 2H), δ 3J0 (s, 3H) 4.18 (m, IH), δ 4.25 - 4.50 (m, 3H), δ 4.51 - 4.64 (m, 2H), δ 5.17 (m, 2H), δ 5.35 (d, J = 5Hz, IH) 6.65 (d, J = 6Hz, IH), δ 7.17 - 7.45( m, 10H); (C29H37N307); methyl 2-[2-(2.2-dimethylpropionylamino)-4-phenylbutyrylloxazole-4-carboxylate (Compound 221); MS (ESI) m/z = 373 (M + 1); Η-NMR (300 MHz, CDC13): δ 1.25 (s, 9H), δ 2.20 (m, IH), δ 2.46 (m, IH), δ 2.77 (t, J = 4 Hz, 2H), δ 3.99 (s, 3H), δ 5.55 (m, IH), δ 6.41 (d, J = 4 Hz, IH), δ 7.20 - 7.38 (m, 5H), δ 8.41 (s, IH), (C20H24N2O5); tgrt-butyl 4-{ lS-, 2-(5-tgrt-butylbenzooxazoI-2-yl)-2-hvdroxy- lS-phenethylethylcarbamoyll-3-methylbutylcarbamoyl}piperidine-l-carboxylate (Compound 222); tgrt-butyl 4-{ lS-r2-hvdroxy-lS-phenethyl- 2-(5-sulfamoylbenzooxazol-2-yl)ethylcarbamoyll-3-methylbutylcarbamoyl)piperidine- 1 -carboxylate (Compound 223); tgrt-butyl 4-[lS-(2-hydroxy-2-naphthof l.2-<iloxazol-2-yl-lS-phenethylethylcarbamoyl)- 3-methylbutylcarbamovπpiperidine- 1 -carboxylate (Compound 224); tert-butyl 4-riS-(2-hvdroxy-2-naphthor2.1-<Jloxazol-2-yl-lS-phenethylethylcarbamoyl)- 3-methylbutylcarbamoyllpiperidine- 1 -carboxylate (Compound 225); tert-butyl 4-{ lS-.2-hvdroxy-lS-phenethyl-
2-(5-phenylbenzooxazol-2-yl)ethylcarbamovn-3-methylbutylcarbamoyl Ipiperidine- 1 -carboxylate (Compound 226); tgrt-butyl 4-riS-(2-benzooxazol-2-yl)-2-hvdroxy-lS-phenethylethylcarbamoyl)- 2-methylbutylcarbamovnpiperidine- 1 -carboxylate (Compound 227); MS (ESI) m/z = 607 (M + 1); Η-NMR (300 MHz, CDC13): δ 0.50 - 0.61 (m, IH), δ 0.75 - 0.98 (m, 6H), δ 1.22 (m, IH), δ 1.41 (s, 9H), δ 1.81 - 1.85 (m, IH), δ 1.99 - 2.06 (m, IH), δ 2.70 (m, 2H), 4.24 (d, J = 2 Hz 2H), δ 4.50 - 4.70 (m, IH), δ 4.99 - 5.14 (m, 2H), δ 6.96 - 7.81 (m, 15H), (C34H46N406); tgrt-butyl 3-T lS-.2-benzooxazol-2-yl)-2-hvdroxy-lS-phenethylethylcarbamoyl)- 2-methylbutylcarbamoyllbenzylcarbamate (Compound 228); tert-butyl 4-riS-(2-benzooxazol-2-yl)-2-hvdroxy-lS-phenethylethylcarbamoyl)-
2-cvclohexylethylcarbamoyllpiperidine- 1 -carboxylate (Compound 229); benzyl 3-methyl-lS-.2-hydroxy-lS-phenethyl- 2-(5-phenyloxazol-2-yl)ethylcarbamoyl1butylcarbamate (Compound 230); MS (ESI) m/z = 556 (M + 1); Η-NMR (300 MHz, CDC13): δ 0.75 - 0.95 (m, 6H), δ 1.25 - 1.80 (m, 5H), δ 2.00 (m, 2H), δ 2.67 (m, 2H), δ 4.15 (m, IH), δ 4.55(m, IH), δ 4.85 - 5.20 (m, 2H), δ 5.50 (m, IH), δ 6.80 (d, J = 6Hz, IH), δ 7.12 - 7.48 (m, 14H), δ 7. 62 (d, J = 2 Hz, 2H), (C33H37N305); pyrid-3-yl 3-methyl- 1 S-[2-hydroxy- lS-phenethyl- 2-(5-phenyloxazol-2-yl)ethylcarbamoyl]butylcarbamate (Compound 231); MS (ESI) m/z = 527 (M + 1); Η-NMR (300 MHz, CDC13): δ 0.75 - 0.95 (m, 6H), δ 1.45 - 1.75 (m, 5H), δ 2.00 (m, 2H), δ 2.67 (m, 2H), δ 4.40 - 5.10 (m, 3H), δ 5.60(s, IH), δ 7.00 - 7.47 (m, 10H), δ 7.62 (m, 2H), δ 8.15 (m, IH), δ 8.65 ( m, IH), δ 9.15 (m, IH), (C31H34N404); and benzyl 1 S- [2-hy droxy- 1 S-phenethyl- 2-(5-phenyloxazol-2-yl)ethylsulfamoylmethyl]-2R-methylbutylcarbamate (Compound 232); MS (ESI) m/z = 606 (M + 1); 'H-NMR (300 MHz, CDC13): δ 0.75 - 0.95 (m, 6H), δ 1.30 - 1.50 (m, 5H), δ 1.98 (m, 2H), δ 2.77 (m, 3H), δ 3.55 (m, 2H), δ 4.09 (m, IH), δ 4.90 - 5.10 (m, 3H), δ 5.60 (m, IH), δ 7.02 - 7.47 (m, 14H), δ 7.62 (m, 2H), (C33H39N306S).
EXAMPLE 21 Benzyl 3-methyl-lS-(lS-pyrid-2-ylcarbonyl-3-phenylpropylcarbamoyl')butylcarbamate
(Compound 233)
Figure imgf000122_0001
A solution comprised of 2-bromopyridine (0.291 mL, 3.06 mmol) in dry THF (2 mL) was cooled to -78° C and then a solution of n-butyllithium (1.6 mL, 2.72 mmol) in pentane was added dropwise over 2 minutes. The mixture was stirred at -78° C for 10 minutes and then a solution of benzyl l-[l-(/V-methoxy-/V-methylcarbamoyl)-3-phenylpropylcarbamoyl]- 3-methylbutylcarbamate (0.3 g, 0.64 mmol) in THF (2 mL) was added slowly. The mixture was stirred, while allowing to slowly warm to room temperature, and then poured into a solution comprising acetic acid (0.163 mL) in diethyl ether (50 mL). The organic phase was washed with brine (40 mL), dried (MgS04) and concentrated in vacuo. Product was purified from the residue by flash chromatography on silica gel eluting with 1 :2 ethyl acetate/hexanes to provide benzyl 3-methyl-l-(l-pyrid-2-ylcarbonyl-3-phenylpropylcarbamoyl)butylcarbamate (82 mg, 0.17 mmol) as a white solid. MS (ESI) m/z = 488 (M + 1); Η NMR (CDC13): δ 0.8 - 1.05 (d, J = 4 Hz, 6H) , 1.5 (m, IH), δ 1.6 - 1.78 (t, 2H), δ 1.99 - 2.20 (m, IH), δ 2.6 - 2.9 (m, IH), δ 2.55 - 2.85 (m, 2H), δ 4.25 (m, IH), δ 5.17 (s, 2H), δ 5.25 (m, IH), δ 6.00 (m, IH), δ 6.85 - 6.95 (d, J = lOHz, IH), δ 7.1 - 7.4 (m, 10H) 7.50( t, J = 4Hz, IH), δ 7.85 (t, J = 6Hz, IH) 8.01 (d, J = 8 hz, IH), δ 8.69 (m, IH). Anal (C29H33N304).
Proceeding as in Example 21 provided the following compounds of Formula I:
benzyl l-[l-(pyrid-3-ylcarbonyl)-3-phenylpropylcarbamovn-3-methylbutylcarbamate (Compound 234), MS(PCI) m/z = 488 (M +1); Η NMR (CDC13): δ 0.8 - 1.05 (d, J = 4 Hz, 6H) , 1.5 (m, IH), δ 1.6 - 1.78 (t, 2H), δ 1.80 - 2.01 (m, 2H), δ 2.25 (m, IH) 2.6 - 2.9 (t, J =3 Hz, IH), δ 2.55 - 2.85 (m, 2H), δ 4.30 (m, IH), δ 5.17 (s, 2H), δ 5.35 (d, J = 6Hz, IH), δ 5.55 (m, IH), δ 7.02 (d, J = 8Hz, IH), δ 7.1 - 7.4 (m, 10H) 8.05( d, J =5 Hz, IH), δ 8.78 (d, J = 4Hz, IH), δ 9.10 (s, IH); (C29H33N3O4); and benzyl l-ri-(quinol-3-ylcarbonyl)-3-phenylpropylcarbamoyll-3-methylbutylcarbamate (Compound 235), MS(PCI) m/z = 538 (M +1); Η NMR (CDC13): δ 0.8 - 1.05 (d, J = 4 Hz, 6H) , 1.5 (m, IH), δ 1.6 - 1.78 (m, 2H), δ 1.99 - 2.20 (m, IH), δ 2.6 - 2.9 (m, IH), δ 2.55 - 2.85 (m, 2H), δ 4.35 (m, IH), δ 5.17 - 5.25 (m, 3H), δ 5.70 (m, IH), δ 6.75 - 6.85 (d, J = lOHz, IH), δ 7.20 - 7.45 (m, 10H), δ 7.65 (t, J = 6Hz, IH), δ 7.77 - 7.90 (m, 2H), δ 8.22 (d, J = 7, IH), δ 8.46 (s, IH), δ 9.4 (s, IH); (C33H35N304).
EXAMPLE 22 Benzyl l-ri-(lH-indol-5-ylcarbonyl)-3-phenylpropylcarbamovn-3-methylbutylcarbamate
(Compound 236)
Figure imgf000124_0001
A mixture comprised of potassium hydride (0.29 g, 2.56 mmol, 67% in mineral oil) in anhydrous ether (5 mL) was cooled to 0° C and then a solution comprised of 5-bromo-lH-indole (0.5 g, 2.56 mmol) in anhydrous ether (5 mL) was added. The mixture was stirred for 15 minutes and then cooled to -78° C under nitrogen. A solution comprised of tgrt-butyllithium (3 mL in pentane, 5.08 mmol) in anhydrous ether (5 mL) was cooled to -78° C and added to the indole mixture over 2 minutes. The mixture was stirred for 10 minutes and then a solution comprised of benzyl l-[l-(-V-methoxy--V-methylcarbamoyl)-3-phenylpropylcarbamoyl]- 3-mefhylbutylcarbamate (0.3 g, 0.64 mM) in ether (10 mL) was added. The mixture was allowed to warm to room temperature and then poured into a cold solution at 0° C of phosphoric acid (25 mL, 1 M in water). The aqueous layer was separated and extracted with ethyl acetate (25 mL). The organic layers were combined and washed with saturated sodium bicarbonate (25 mL), dried (MgSO4) and concentrated. The product was purified from the residue by flash chromatography on silica gel eluting with 1:2 ethyl acetate/hexanes to provide benzyl l-[l-(lH-indol-2-ylcarbonyl)-3-phenylpropylcarbamoyl]-3-methylbutylcarbamate (112 mg, 0.21 mmol) as a white solid. MS (ESI) m/z = 526(M + 1); Η NMR (CDC13): δ 0.8 - 1.05 (d, J = 4 Ηz, 6Η) , 1.5 (s, IH), δ 1.5 - 1.78 (m, 3H), δ 2.00 (m, IH), δ 2.4 (m, IH), δ 2.65 (m, 2H), δ 4.35 (m, IH), δ 5.17 (s, 2H), δ 5.25 (d,J = 6 Hz IH), δ 5.75 (m, IH), δ 6.55 (s, IH) 7.05 (d, J = 4Hz, IH), δ 7.1 - 7.45 (m, 10H) 7.7( d, J = 4Hz, IH), δ 8.15 (d, J = 4Hz, IH) 8.78 (m, IH). (C32H35N304). EXAMPLE 23 benzyl l-ri-(benzofur-2-ylcarbonyl)-3-phenylpropylcarbamovn-3-methylbutylcarbamate
(Compound 237)
Figure imgf000125_0001
A solution comprised of benzofuran (0.302 g, 2.56 mmol) in anhydrous ether (5 mL) was cooled to -15° C under a nitrogen atmosphere and then a solution of n-butyllithium (1.6 mL in hexanes) was added dropwise over 2 minutes. The mixture was stirred for 1 hour and then a solution comprised of benzyl l-[l-(N-methoxy--V-methylcarbamoyl)-3-phenylpropylcarbamoyl]- 3-methylbutylcarbamate (0.3 g, 0.64 mmol) in diethyl ether was added. The mixture was stirred at -15 ° C until the reaction was complete. The mixture was quenched with a solution of acetic acid (0.153 mL) in diethyl ether (50 mL). The organic phase was washed with brine (40 mL), dried (MgSO4) and concentrated in vacuo. The product was purified from the residue by flash chromatography eluting with 2:3 ethyl acetate/hexanes to provide benzyl 1 - r 1 -(benzofur-2-ylcarbonyl)-3-phenylρropylcarbamoyll -3-methylbutylcarbamate (70 mg, 0.13 mmol) as a white solid. Η NMR (CDC13): δ 0.8 - 0.99 (d, J = 4 Hz, 6H) , 1.5 (m, IH), δ 1.6 - 1.72 (m, 2H), δ 1.99 - 2.18 (m, IH), δ 2.22 - 2.41 (m, IH), δ 2.6 - 2.75 (m, 2H), δ 4.21 (m, IH), δ 5.01 (m, IH), δ 5.17 (s, 2H), δ 5.50 (m, IH), δ 6.75 - 6.81 (d, J = 7 Hz, IH), δ 7.10 - 7.37 (m, 11H) 7.4 - 7.59( m, , 3H), δ 7.64 (d, J = 7 Hz, IH). (C32H34N2O5).
Proceeding as in Example 23 provided the following compounds of Formula I:
benzyl l-ri-(benzothiazol-2-ylcarbonyl)-3-phenylpropylcarbamoyll-
3-methylbutylcarbamate (Compound 238), Η NMR (CDC13): δ 0.91 (d, J = 5.88 Hz, 6H), δ 1.39 - 1.54 (m, IH), δ 1.60 - 1.72 (m, 2H), δ 2.11 - 2.25 (m, IH), δ 2.40 - 2.54 (m, IH), δ 2.72 (m, 2H), δ 4.21 (m, IH), δ 5.10 (s, 3H), δ 5.84 (m, IH), δ 6.87 (d, J = 8.15 Hz, IH), δ 7.10 - 7.40 (m, 10H), δ 7.54 (dt, J = 1.62, 8.10 Hz, IH), δ 7.58 (dt, J = 1.46, 7.80 Hz, IH), δ 7.97 (dd, J = 1.80, 8.15 Hz, IH), δ 8.17 (dd, J = 1.66, 7.67 Hz, IH); benzyl 3-methyl-lS-(3-phenyl-lS-thiazol-2-ylcarbonylpropylcarbamoyl)butylcarbamate (Compound 239);
-V-r3-methyl-lS-(3-phenyl-lS-thiazol-2-ylcarbonylpropylcarbamoyl)butyll- 4-methylpiperazine- 1 -carboxamide (Compound 240); tgrt-butyl 4- _ 3-methyl- 1 S-(3-phenyl- lS-thiazol-2-ylcarbonylpropylcarbamoyl)butylcarbamoyllpiperazine-l -carboxylate (Compound 241); benzyl 3-methyl-lS-(3-phenyl-lS-thien-2-ylcarbonylpropylcarbamoyl)butylcarbamate (Compound 242); benzyl lS-. lSJl-methyl-lH-imidazol-2-ylcarbonyl-3-phenylpropylcarbamoyll- 3-methylbutylcarbamate (Compound 243); benzyl lS-(lS-thiazol-2-ylcarbonyl-3-phenylpropylcarbamoyl)-2-methy lpropylcarbamate
(Compound 244);
-V-r3-methyl-lS-(3-phenyl-lS-thiazol-2-ylcarbonylpropylcarbamoyl)butyllpiperazine- 1 -carboxamide (Compound 245); benzyl 1S-. lS-(4-methylthiazol-2-ylcarbonyl)-3-phenylpropylcarbamoyH- 3-methylbutylcarbamate (Compound 246); benzyl lS-(lS-furyl-2-ylcarbonyl-3-phenylpropylcarbamoyl)-3-methylbutylcarbamate (Compound 247), Η NMR (CDC13): δ 0.91 (d, J = 6.18 Ηz, 6Η), δ 1.42 - 1.70 (m, 3H), δ 1.98 - 2.13 (m, IH), δ 2.19 - 2.37 (m, IH), δ 2.69 (t, J = 7.60 Hz, 2H), δ 4.22 (m, IH), δ 5.10 (d, J = 7.76 Hz, IH), δ 5.12 (s, 2H), δ 5.54 (m, IH), δ 6.76 (d, J = 8.15 Hz, IH), δ 7.16 - 7.36 (m, 10H), δ 7.39 (dt, J = 1.82, 7.86 Hz, IH), δ 7.47 (dt, J = 1.63, 7.79 Hz, IH), δ 7.69 (s, IH), δ 7.80 (d, J = 7.15 Hz, IH), δ 7.85 (d, J = 8.18 Hz, IH); benzyl IS-, lSJl-benzyl-lH-imidazol-2-ylcarbonyl-3-phenylpropylcarbamoyl1- 3-methylbutylcarbamate (Compound 248); benzyl 3-phenyl-l-(4,5-dihvdro-4S-phenyloxazol-2-ylcarbonyl)propyHcarbamate (Compound 249); benzyl 3-phenyl-l-(4.5-dihvdro-5-phenyloxazol-2-ylcarbonylpropyllcarbamate (Compound 250); benzyl . 1 -(4.5-dihvdro-4S-methyl-5S-phenyloxazol-2-ylcarbonyl)- 3 -pheny lpropyll carbamate (Compound 251); and ethyl 2- , 2-(2-benzyloxycarbony lamino-4-methylvalerylamino)- 4-phenylbutyryllthiazole-4-carboxylate (Compound 252).
EXAMPLE 24
Methyl 2-.2-(2-benzyloxycarbonylamino-4-methylvalerylamino)-l-hvdroxy-
4-phenylbutvnoxazole-4-carboxylate
(Compound 253)
Figure imgf000127_0001
A solution comprised of methyl 2-[2-(2-benzyloxycarbonylamino-4-methylvalerylamino)- l-hydroxy-4-phenylbutyl]-4,5-dihydrooxazole-4-carboxylate (0.036 g, 0.067 mmol) in methylene chloride (3 mL) was cooled to 0° C and then DBU (11.2 mg, 72.7 μmol) and bromotrichloromethane (14.6 mg, 73.7 μmol) were added. The mixture was stirred for 6 hours at room temperature and concentrated. The residue was dissolved in ethyl acetate (20 mL) and the solution was dried (MgS04) and concentrated. The product was purified from the residue by flash chromatography eluting with 1:3 hexanes/ethyl acetate to provide methyl 2-,2-(2-benzyloxycarbonylamino-4-methylvale-ylamino)-l-hydroxy-4-phenylbutyl1oxazole- 4-carboxylate (12 mg, 0.022 mmol) as a white solid. MS(PCI) m z = 538 (M +1) Η NMR (CDCI3): δ 0.8 - 1.05 (d, J = 4 Hz, 6H), δ 1.55 - 1.70 (m, 3H), δ 2.00 (m, IH), δ 2.40 (m, IH), δ 2.69 (m, 2H), δ 3.99 (m, 3H) 4.45 (m, IH), δ 5.17 (s, 2H), δ 5.78 (m, IH), δ 7.01 (d, J = 4Hz IH), δ 7.14 - 7.47 (m, 10H) 7.72( d, J = 4Hz, IH), δ 8.40 (s, IH). (C29H35N3O7). EXAMPLE 25 2-r2-(2-Benzyloxycarbonylamino-4-methylvalerylamino)-l-hydroxy-4-phenylbutylloxazole-
4-carboxvlic acid
(Compound 254)
Figure imgf000128_0001
A mixture comprised of methyl 2-[2-(2-benzyloxycarbonylamino-4-methylvalerylamino)- l-hydroxy-4-phenylbutyl]oxazole-4-carboxylate (2.16 g, 4.02 mmol), provided as in Example 18, and sodium hydroxide (0.815 mL, 1.63 M in water) in methanol (10 mL) was stirred for approximately 12 hours at room temperature, acidified with 1 M hydrochloric acid and concentrated. The residue was dissolved in ethyl acetate (50 mL) and the solution dried (MgSO4). The product was recrystallized from methanol and ether to provide 2-[2-(2-benzyloxycarbonylamino-4-methylvalerylamino)-l-hydroxy-4-phenylbutyl]oxazole- 4-carboxylic acid (1J7 g, 3.38 mmol) as an off white solid.
EXAMPLE 26
Benzyl 3-methyl-l-.2-hvdroxy-l-phenethyl-
2-(4-phenylcarbamoyloxazol-2-yl)ethylcarbamoyllbutylcarbamate
(Compound 255)
Figure imgf000129_0001
A solution comprised of 2-[2-(2-benzyloxycarbonylamino-4-methylvalerylamino)- l-hydroxy-4-phenylbutyl]oxazole-4-carboxylic acid (0.05 g, 0.096 mmol), provided as in Example 7, in DMF (5 mL) was stirred while PyBOP® (0.05 g, 0.096 mmol) and aniline (9 mg, 0.096 mmol) were added. The mixture was stirred for an additional 2 minutes and diisopropylethylamine (12.4 mg, 0.096 mmol) was added. The mixture was stirred for 2 hours at room temperature, poured into cold water 0° C at and extracted with ethyl acetate (4 x 30mL). The extracts were combined, dried (MgS04) and then concentrated. The product was purified from the residue by flash chromatography eluting with 1:2 hexanes/ethyl acetate to provide benzyl 3 -methyl- 1 - [2-hy droxy- 1 -phenethy 1- 2-(4-phenylcarbamoyloxazol-2-yl)ethylcarbamoyl]butylcarbamate (30 mg, 0.05 mmol) as a white solid. MS (ESI) ) m/z = 599 (M + 1); Η NMR (CDC13): δ 0.8 - 1.05 (d, J = 4 Hz, 6H) , 1.35 (m, IH), δ 1.55 (m, IH), δ 2.00 - 2.15 (m, 2H), δ 2.62 (m, 2H), δ 2.80 (m, 2H), δ 3.65 (m, 2H), δ 4.11 (m, IH), δ 4.30 (m, IH), δ 4.45 (m, IH), δ 4.95 (s, IH) 5.17 (s, 2H), δ 5.2 (d, J =4Hz, IH), δ 6.70 (d, J = 5Hz IH), δ 7.1 - 7.45 (m, 15H) 7.7( d, J = 4Hz, IH), δ 8.19 (s, IH), δ 8.99 (s, IH). (C34H38N406).
Proceeding as in Example 26 provided the following compounds of Formula I: benzyl l-r2-(4-benzylcarbamoyloxazol-2-yl)-2-hvdroxy-l-phenethylethylcarbamoyll- 3-methylbutylcarbamate (Compound 256), MS (ESI) ) m/z = 613 (M + 1); Η NMR (CDC13): δ 0.8 - 1.05 (d, J = 4 Hz, 6H), δ 1.25 - 1.75 (m, 3H), δ 2.00 - 2.20 (m, 2H), δ 2.69 (m, 2H), δ 3.85 (m, IH), δ 3.95 (m, IH), δ 4.25 (m, IH), δ 4.60 (m, 2H), δ 4.80 (s, IH), δ 5.17 (s, 2H), δ 5.59 (m, IH), δ 6.59 (d, J = 4Hz IH), δ 7.05 - 7.47 (m, 15H), δ 8.20 (s, IH); (C35H40N4O6); and benzyl 3-methy 1- 1 - r2-hydroxy- 1 -phenethyl- 2-(4-phenvethylcarbamoyloxazol-2-yl)ethylcarbamoyllbutylcarbamate (Compound 257), MS (ESI) ) m z = 627 (M + 1); Η NMR (CDC13): δ 0.8 - 1.05 (d, J = 4 Hz, 6H), δ 1.25 - 1.75 (m, 4H), δ 2.00 (m, 2H), δ 2.59 (m, 2H) 2.88 (m, 2H), δ 3.65 (m, 2H), δ 4.02 (m, IH), δ 4.25 (m,lH), δ 4.80 (s, IH), δ 5.17 (s, 2H), δ 6.59 (d, J = 4 Hz, IH), δ 7.00 - 7.42 (m, 15H), δ 8.20 (s, IH); (C36H42N406).
EXAMPLE 27 benzyl l-ri-(4.5-dihydro-4S-phenyloxazol-2-ylcarbonyl)-3-phenylpropylcarbamoyl1-
3-mefhylbutylcarbamate (Compound 258)
Figure imgf000130_0001
A solution comprised of benzyl lS-[2-(4,5-dihydro-4S-phenyloxazol-2-yl)-2-hydroxy- lS-phenethylethylcarbamoyl] -3-methy Ibuty Icarbamate (0.038 g, 0.078 mmol), provided as in Example 14, and Dess-Martin Periodinane (0.031 g, 0.072 mmol) in methylene chloride (5 mL) was stirred while a mixture of 0.001:1 methylene chloride/water (2 mL) was slowly added. The mixture was stirred until the reaction was complete and then concentrated. The residue was dissolved in ethyl acetate (50 mL) and the solution was washed with saturated sodium bicarbonate (40 mL), sodium thiosulfate (40 mL, 10% wt/wt), water (40 mL) and brine (40 mL), dried (MgS04) and then concentrated. Product was purified from the residue by flash chromatography eluting with 3: 1 ethyl acetate/hexanes to provide benzyl l-[l-(4,5-dihydro- 4S-phenyloxazol-2-ylcarbonyl)-3-phenylpropylcarbamoyl]-3-methylbutylcarbamate (0.014g, 37.5%) as a white solid. MS (PCI) m/z = 556 (M +1) 'H NMR (CDC13): δ 0.8 - 1.05 (d, J = 6 Hz, 6H), δ 1.4 - 1.78 (m, 3H), δ 1.87 - 2.12 (m, IH), δ 2.40 (m, IH), δ 2.65(t, J = 4Hz, 2H), δ 4.25 (t, J = 3Hz, 2H), δ 4.75 (t, J = 4 Hz, IH), δ 5.10 (s, 2H), δ 5.40(d J = 3Hz , IH), δ 5.50 (t, J = 4 Hz, IH), δ 6.97 (d, J = 3Hz, IH) 7.1 - 7.49( m, 15H). (C33H37N3O5).
Proceeding as in Example 27 provided the following compounds of Formula I:
benzyl lS-(lS-benzooxazol-2-ylcarbonyl-3-phenylpropylcarbamoyl)-
3-methylbutylcarbamate (Compound 259); benzyl lS-. lS-(4,5-dihvdrooxazol-2-ylcarbonyl)-3-phenylpropylcarbamovH- 3-methylbutylcarbamate (Compound 260), MS (PCI) m/z = 480 (M +1) Η NMR (CDC13): δ 0.8 - 1.05 (d, J = 6 Hz, 6H), δ 1.4 - 1.78 (m, 3H), δ 1.82 - 2.01 (m, 2H), δ 2.65 (t, J = 5 Hz 2H), δ 2.99 (t, J = 4Hz, IH), δ 3.75 (d, J = 3Hz,lH), δ 4.10 - 4.35 (m, 3H), δ 4.50 (m, IH), δ 5.17 (s, 3H), δ 6.85 (s, IH), δ 7.1 - 7.49( m, 10H), (C27H33N3O5);
N-.3-methyl-lSJ3-phenyl- lS-benzooxazol-2-ylcarbonylpropylcarbamoyl)butyllpiperidine-4-carboxamide (Compound 261), 'H NMR (DMSO-d6): δ 0.83 (d, J = 6.91 Hz, 6H), δ 1.34 - 1.87 (m, 7H), δ 1.92 - 2.07 (m, IH), δ 2.20 - 2.33 (m, IH), δ 2.41 - 2.54 (m, IH), δ 2.62 - 2.92 (m, 4H), δ 3.26 (bd, J = 12.12 2H), δ 4.39 (m, IH), δ 5.18 (m, IH), δ 7.16 - 7.33 (m, 5H), δ 7.54 (t, J = 7.64 Hz, IH), δ 7.64 (t, 7.82 Hz, IH), δ 7.87 (d, J = 8.40 Hz, IH), δ 7.96 (d, J = 7.67 Hz, IH), δ 8.07 (d, J = 8.15 Hz, IH), δ 8.29 (bs, IH), δ 8.60 (bs, IH), δ 8.76 (d, J = 6.45 Hz, IH); benzyl l-|T-.4,5-dihvdro-5-phenyloxazol-2-ylcarbonyl)- 3-phenylpropylcarbamovn3-methylbutylcarbamate (Compound 262); benzyl l-[l-(4.5-dihydro-5S-phenyl-4S-methyloxazol-2-ylcarbonyl)- 3-phenylpropylcarbamoyl)-3-methylbutylcarbamate (Compound 263); benzyl 1 S-( 1 S-phene thyl-2-benzimidazol-2-yl- 1 -oxoethylcarbamoyl)- 3-methylbutylcarbamate (Compound 264), Η NMR (CDC13): δ 0.82 - 0.96 (m, 6H), δ 1.44 - 1.75 (m, 3H), δ 2.17 - 2.32 (m, IH), δ 2.43 - 2.56 (m, IH), δ 2.61 - 2.80 (m, 2H), δ 4.55 (m, IH), δ 5.13 (m, 2H), δ 5.35 (d, J = 8.67 Hz, IH), δ 5.70 - 5.88 (m, IH), δ 7.00 - 7.42 (m, 14H), δ 7.50 - 7.83 (m, 2H); benzyl 1-. lJnaphtho.2,3-- loxazol-2-ylcarbonyl)-3-phenylpropylcarbamoyll- 3-methylbutylcarbamate (Compound 265); methyl 2-,2-(2-benzyloxycarbonylamino-4-methylvalerylamino)-4-phenylbutyryll-
4.5-dihvdrooxazole-4-carboxylate (Compound 266), MS(PCI) m z = 538 (M +1); Η NMR (CDC13): δ 0.8 - 0.99 (d, J = 6 Hz, 6H) ,1.25 (m, IH), δ 1.47 (m, IH) 1.65 (m, 3H), δ 1.99 (m, IH), δ 2.35 (m, IH), δ 2.65 (m, 2H), δ 3.70 (m, 3H) 4.18 (m, 2H), δ 4.55 (m, IH), δ 5.17 (s, 2H), δ 5.35 (m, IH) 6.75 (m, IH), δ 7.17 - 7.45( m, 10H), (C29H35N307); benzyl lS-riS-(4,5-dihvdro-4,4-dimethyloxazol-2-ylcarbonyl)-3-phenylpropylcarbamoyll-
3-methylbutylcarbamate (Compound 267), MS(PCI) m/z = 508 (M +1); Η NMR (CDC13): δ 0.8 - 0.99 (d, J = 6 Hz, 6H), δ 1.36 (s, 6H), δ 1.5 (m, IH), δ 1.65 (m, 2H) 1.82 - 2.01 (m, IH), δ 2.35 (m, IH), δ 2.6 (t, J = 6 Hz, 2H), δ 4.05 (s, 2H), δ 4.25 (m, 2H), δ 5.10 (s, 2H), δ 5.4 (m, IH), δ 6.75 (d J = 8Hz, IH) 7.1 - 7.38( m, 10H); (C29H37N3O5); benzyl lS-(lS-benzooxazol-2-ylcarbonyl-3-phenylpropylcarbamoyl)-
2-methylpropylcarbamate (Compound 268), Η NMR (CDC13): δ 0.90 (d, J = 6.91 Hz, 3H), δ 0.97 (d, J = 6.94 Hz, 3H), δ 2.06 - 2.25 (m, 2H), δ 2.38 - 2.55 (m, IH), δ 2.74 (m, 2H), δ 4.03 (dd, J = 1.73, 6.45 Hz, IH), δ 5.10 (s, 2H), δ 5.29 (d, J = 8.67 Hz, IH), δ 5.73 (m, IH), δ 6.66 (d, J = 7.42 Hz, IH), δ 7.09 - 7.40 (m, 10H), δ 7.46 (dt, J = 1.62, 8.10 Hz, IH), δ 7.55 (dt, J = 1.83, 7.76 Hz, IH), δ 7.64 (d, J = 8.06 Hz, IH), δ 7.89 (d, J = 7.46 Hz, IH); benzyl lS-(lS-benzooxazol-2-ylcarbonyl-3-phenylpropylcarbamoyl)- 2-methylbutylcarbamate (Compound 269), Η NMR (CDC13): δ 0.88 (t, J = 7.43 Hz, 3H), δ 0.91 (d, J = 6.67 Hz, 3H), δ 1.04 - 1.21 (m, IH), δ 1.40 - 1.55 (m, IH), δ 1.78 - 1.93 (m, IH), δ 2.10 - 2.24 (m, IH), δ 2.40 - 2.54 (m, IH), δ 2.74 (t, J = 7.60 Hz, 2H), δ 4.06 (t, J = 6.21 Hz, IH), δ 5.09 (s, 2H), δ 5.29 (d, J = 8.67 Hz, IH), δ 5.72 (m, IH), δ 6.66 (d, J = 8.00 Hz, IH), δ 7.09 - 7.39 (m, 10H), δ 7.46 (dt, J = 1.68, 7.80 Hz, IH), δ 7.55 (dt, J = 1.44, 7.56 Hz, IH), δ 7.63 (d, J = 8.04 Hz, IH), δ 7.89 (d, J = 7.82 Hz, IH); benzyl lS-, lS-(5-chlorobenzooxazol-2-ylcarbonyl)-3-phenylpropylcarbamoyl]- 3-methylbutylcarbamate (Compound 270), Η NMR (CDC13): δ 0.90 (m, 6H), δ 1.39 - 1.53 (m, IH), δ 1.59 - 1.70 (m, 2H), δ 2.07 - 2.21 (m, IH), δ 2.37 - 2.52 (m, IH), δ 2.73 (t, J = 7.91 Hz, 2H), δ 4.20 (m, IH), δ 5.06 (d, J = 7.91 Hz, IH), δ 5.10 (s, 2H), δ 5.64 (m, IH), δ 6.77 (d, J = 7.67 Hz, IH), δ 7.09 - 7.37 (m, 10H), δ 7.53 (dq, J = 1.86, 8.91 Hz, 2H), δ 7.89 (d, J = 1.73 Hz, IH);
-V- 13-methyl-lS-r 3-phenyl- lS-(5-chlorobenzooxazol-2-ylcarbonyl)propylcarbamoyllbutyl}piperidine-4-carboxamide (Compound 271); -V-.2-cvclohexyl-lSJ3-phenyl- lS-benzooxazol-2-ylcarbonylpropylcarbamoyl)ethyllpiperidine-4-carboxamide (Compound 272); MS (ESI) m/z = 545 (M + 1); Η-NMR (300 MHz, CDC13, CD3OD): δ 0.85 (m, 2H), δ 1.02 - 1.58 (m, 4H), δ 1.40 - 1.71 (m, 7H), δ 1.75 - 2.21 (m, 5H), δ 2.38 (m, IH), δ 2.51 (m, IH), δ 2.69 (t, J = 4 Hz, 2H), δ 3.32 (m, 2H), δ 4.39 (q, J = 6 Hz IH), δ 5.53 (q, J = 3 Hz IH), δ 7.11 - 7.21 (m, 5H), δ 7.24 (s, IH), δ 7.38 - 7.61 (m, 3H), δ 7.73 (d, J = 6 Hz, IH), δ 7.82(d, J = 6 Hz, IH), (C32H40N4O4); methyl 2-(2-benzyloxycarbonylamino-4-methylvalerylamino)-4-phenylbutyryloxazole- 4-carboxylate (Compound 273); benzyl 1-. lJ4-phenylcarbamoyloxazol-2-ylcarbonyl)-3-ρhenylpropylcarbamovH- 3-methylbutylcarbamate (Compound 274), MS (ESI) ) m/z = 597 (M + 1); 'H NMR (CDC13): δ 0.8 - 1.05 (d, J = 4 Hz, 6H), δ 1.55 (m, IH), δ 1.70 (s, 2H), δ 2.00 - 2.20 (m, IH), δ 2.40 (m, IH), δ 2.69 (m, 2H), δ 2.97 (t, J = 4 Hz, 2H), δ 3.70(q, J = 3 Hz, 2H) 4.25 (m, IH), δ 5.17 (s, 2H), δ 5.59 (m, IH), δ 6.99 (d, J = 4Hz IH), δ 7.14 - 7.47 (m, 15H) 7.72( d, J = 4Hz, IH), δ 8.47 (s, IH), δ 8.65 (s, IH), (C34H36N4O6); benzyl 1-, l-(4-benzylcarbamoyloxazol-2-ylcarbonyl)-3-phenylpropylcarbamovH-
3-methylbutylcarbamate (Compound 275), MS (ESI) ) m/z = 611 (M + 1); Η NMR (CDC13): δ 0.8 - 1.05 (d, J = 4 Hz, 6H), δ 1.45 - 1.70 (m, 4H), δ 2.00 - 2.20 (m, IH), δ 2.40 (m, IH), δ 2.69 (m, 2H), δ 4.25 (m, IH), δ 4.67 (t, J = 3 Hz, 2H), δ 5.17 (m, 3H), δ 5.59 (m, IH), δ 6.85 (d, J = 4Hz IH), δ 7.10 - 7.47 (m, 15H), δ 8.47 (s, IH), (C35H38N4O6); tgrt-butyl 4-( lS-riS-(5-tert-butylbenzooxazol-2-ylcarbonyl)-3-phenylpropylcarbamoyll-
3-methylbuty lcarbamoyl Ipiperidine- 1 -carboxylate (Compound 276), Η NMR (CDC13): δ 0.86 - 0.97 (m, 6H), δ 1.34 - 1.85 (m, 7H), δ 1.38 (s, 9H), δ 1.43 (s, 9H), δ 2.09 - 2.30 (m, 2H), δ 2.37 - 2.52 (m, IH), δ 2.72 (m, 4H), δ 4.11 (bd, J = 12.85, 2H), δ 4.49 (m, IH), δ 5.66 (m, IH), δ 5.97 (d, J = 7.91 Hz, IH), δ 6.89 (d, J = 7.67 Hz, IH), δ 7.11 - 7.27 (m, 5H), δ 7.50 - 7.64 (m, 2H), δ 7.86 (d, J = 1.56 Hz, IH); tgrt-butyl 4- { lS-\ lS-(5-sulfamoylbenzooxazol-2-ylcarbonyl)-3-phenylpropylcarbamoyll- 3-methylbutylcarbamoyl Ipiperidine- 1 -carboxylate (Compound 277), Η NMR (CDC13): δ 0.85 - 0.96 (m, 6H), δ 1.37 - 1.82 (m, 7H), δ 1.42 (s, 9H), δ 2.08 - 2.46 (m, 3H), δ 2.71 (m, 4H), δ 4.02 (bs, 2H), δ 4.56 (m, IH), δ 5.38 (bs, IH), δ 5.78 (bs, 2H), δ 6.38 (d, J = 8.42 Hz, IH), δ 7.07 - 7.25 (m, 5H), δ 7.70 (dd, J = 3.48, 8.64 Hz, IH), δ 8.08 (dd, J = 1.73, 8.67 Hz, IH), δ 8.41 (dd, J = 1.49, 3.96 Hz, IH); N- { 3-methyl- IS-.3-phenyl- lS-(5-tgrt-butylbenzooxazol-2-ylcarbonyl)ρropylcarbamoyllbutyl)piperidine-4-carboxamide (Compound 278), 'H NMR (DMSO-d6): δ 0.82 (t, J = 6.18 Hz, 6H), δ 1.36 (s, 9H), δ 1.33 - 1.88 (m, 7H), δ 1.91 - 2.06 (m, IH), δ 2.19 - 2.34 (m, IH), δ 2.42 - 2.54 (m, IH), δ 2.61 - 2.92 (m, 4H), δ 3.27 (bd, J = 12.02 2H), δ 4.39 (m, IH), δ 5.19 (m, IH), δ 7.15 - 7.33 (m, 5H), δ 7.74 (dq, J = 1.97, 7.91 Hz, 2H), δ 7.90 (d, J = 1.83 Hz, IH), δ 8.07 (d, J = 8.15 Hz, IH), δ 8.27 (bs, IH), δ 8.56 (bs, IH), δ 8.72 (d, J = 6.43 Hz, IH);
N-{ 3-methyl- IS- .3-phenyl- lS-(5-sulfamoylbenzooxazol-2-ylcarbonyl)propylcarbamoyllbutyl }piperidine-4-carboxamide (Compound 279), Η NMR (DMSO-d6): δ 0.80 - 0.88 (m, 6H), δ 1.31 - 1.86 (m, 7H), δ 1.92 - 2.05 (m, IH), δ 2.22 - 2.33 (m, IH), δ 2.41 - 2.52 (m, IH), δ 2.63 - 2.89 (m, 4H), δ 3.26 (bd, J = 11.88 2H), δ 4.40 (m, IH), δ 5.13 (m, IH), δ 7.16 - 7.31 (m, 5H), δ 7.57 (s, 2H), δ 8.05 (m, 3H), δ 8.25 (bs, IH), δ 8.32 (s, IH), δ 8.55 (bs, IH), δ 8.82 (d, J = 6.18 Hz, IH), δ 8.88 (d, J = 6.84 Hz, IH); tgrt-butyl 4-riS-(lS-naphthori.2-(/]oxazol-2-ylcarbonyl-3-ρhenylpropylcarbamoyl)- 3-methylbutylcarbamoyllpiperidine- 1 -carboxylate (Compound 280), Η NMR (CDC13): δ 0.87 - 0.95 (m, 6H), δ 1.39 - 1.85 (m, 7H), δ 1.44 (s, 9H), δ 2.13 - 2.32 (m, 2H), δ 2.45 - 2.60 (m, IH), δ 2.65 - 2.81 (m, 4H), δ 4.12 (m, 2H), δ 4.53 (m, IH), δ 5.79 (m, IH), δ 6.00 (d, J = 7.94 Hz, IH), δ 6.90 (d, J = 7.67 Hz, IH), δ 7.12 - 7.26 (m, 5H), δ 7.56 - 7.80 (m, 3H), δ 7.93 - 8.00 (m, 2H), δ 8.52 (dd, J = 1.97, 8.00 Hz, IH); tgrt-butyl 4-riS-(lS-naphthor2.1-- loxazol-2-ylcarbonyl-3-phenylpropylcarbamoyl)-
3-methylbutylcarbamoyllpiperidine- 1 -carboxylate (Compound 281), :H NMR (CDC13): δ 0.88 - 0.97 (m, 6H), δ 1.38 - 1.86 (m, 7H), δ 1.43 (s, 9H), δ 2.15 - 2.31 (m, 2H), δ 2.43 - 2.57 (m, IH), δ 2.67 - 2.79 (m, 4H), δ 4.11 (m, 2H), δ 4.52 (m, IH), δ 5.73 (m, IH), δ 5.96 (d, J = 7.94 Hz, IH), δ 6.90 (d, J = 7.91 Hz, IH), δ 7.12 - 7.26 (m, 5H), δ 7.66 (m, 2H), δ 7.85 (s, IH), δ 7.99 (dd, J = 1.85, 7.80 Hz, IH), δ 8.33 (dd, J = 1.97, 7.94 Hz, IH); tgrt-butyl 4-1 lS-\ IS- .5-phenylbenzooxazol-2-ylcarbonyl)-3-phenylpropylcarbamoyl 1- 3-methylbutylcarbamoyl Ipiperidine- 1 -carboxylate (Compound 282); MS (ESI) m/z = 681 (M + 1); Η-NMR (300 MHz, CDC13): δ 0.85 - 0.98 (m, 6H), δ 1.43 (s, 9H), δ 1.60 - 1.85 (m, 5H), δ 2.14 - 2.30 (m, 2H), δ 2.56 (m, IH), δ 2.75 (m, 4H), δ 4.12 (m, 2H), δ 4.52 (m, IH), δ 5.69 (m, IH), δ 5.92 (d, J = 6 Hz, IH), δ 6.85 (d, J = 6 Hz, IH), δ 7.13 - 7.26 (m, 7H), δ 7.36 - 7.80 (m, 7H), δ 8.05 (s, IH), (C40H48N4O6); AM 3-methyl-lS-r3-phenyl- lS-(naphthori.2-Jloxazol-2-ylcarbonyl)propylcarbamoyllbutyl}piperidine-4-carboxamide (Compound 283), Η NMR (DMSO-d6): δ 0.81 (m, 6H), δ 1.35 - 1.86 (m, 7H), δ 1.96 - 2.11 (m, IH), δ 2.26 - 2.53 (m, 2H), δ 2.64 - 2.91 (m, 4H), δ 3.26 (bd, J = 11.63 2H), δ 4.42 (m, IH), δ 5.27 (m, IH), δ 7.19 - 7.36 (m, 5H), δ 7.70 (t, J = 7.91 Hz, IH), δ 7.83 (t, J = 7.43 Hz, IH), δ 8.01 (d, J = 8.91 Hz, IH), δ 8.08 (m, IH), δ 8.18 (d, J = 8.91 Hz, 2H), δ 8.27 (bs, IH), δ 8.39 (d, J = 7.91 Hz, IH), δ 8.56 (bs, IH), δ 8.75 (d, J = 6.45 Hz, IH);
-V- .3-methyl-lS-.3-phenyl- lSJnaphtho, 2, 1 --/lbenzooxazol-2-ylcarbonyl)propylcarbamoyllbutyl }piperidine-4-carboxamide (Compound 284),. Η NMR (DMSO-d6): δ 0.81 (t, J = 6.43 Hz, 6H), δ 1.34 - 1.87 (m, 7H), δ 1.97 - 2.12 (m, IH), δ 2.24 - 2.38 (m, IH), δ 2.42 - 2.53 (m, IH), δ 2.66 - 2.93 (m, 4H), δ 3.26 (bd, J = 10.12 2H), δ 4.41 (m, IH), δ 5.26 (m, IH), δ 7.16 - 7.34 (m, 5H), δ 7.77 (m, 2H), δ 7.97 (d, J = 8.91 Hz, IH), δ 8.05 (d, J = 8.86 Hz, IH), δ 8.07 (d, J = 8.64 Hz, IH), δ 8.19 (d, J = 7.91 Hz, IH), δ 8.26 (bs, IH), δ 8.28 (d, J = 7.67 Hz, IH), δ 8.56 (bs, IH), δ 8.78 (d, J = 6.43 Hz, IH); -V- .3-methyl- 1 - .3-phenyl- l-(5-phenylbenzooxazol-2-ylcarbonyl)propylcarbamoyllbutyl)piperidine-4-carboxamide (Compound 285); benzyl 1-T1 - (4-phenyethylcarbamoyloxazol-2-ylcarbonyl)-3-phenylpropylcarbamoyl 1- 3-methylbutylcarbamate (Compound 286), MS (ESI) ) m/z = 625 (M + 1); Η NMR (CDC13): δ 0.8 - 1.05 (d, J = 4 Hz, 6H), δ 1.50 (m, IH), δ 1.65 (m, 3H), δ 2.00 - 2.20 (m, IH), δ 2.35 (m, IH), δ 2.60 (m, 2H), δ 2.99 (t, J = 4Hz, 2H), δ 3.67(q, J = 3 Hz, 2H),4.19 (m, IH), δ 5.17 (s, 2H), δ 5.59 (m, IH), δ 6.85 - 6.98 (m, 2H), δ 7.10 - 7.47 (m, 15H), δ 8.43 (s, IH); (C36H 0N4O6); benzyl l-{ l-.4-(3-phenylpropylcarbamoyl)oxazoI-2-ylcarbonyll- 3-phenylpropylcarbamoyl } -3-methylbutylcarbamate (Compound 287); MS (ESI) m/z = 639 (M + 1); Η-NMR (300 MHz, CDC13): δ 0.95 (d, J = 6 Hz, 6H), δ 1.50 (m, IH), δ 1.65 (m, 3H), δ 2.00 (m, 4H), δ 2.35 (m, IH), δ 2.67 (m, 4H), δ 3.49 (m, 2H), δ 4.20 (m, IH), δ 5.09 (s, 2H), δ 5.50 (m, IH), δ 6.85 (m, IH), δ 7.23(m, 15H), δ 8.35 (s, IH), δ (C37H42N406); tert-butyl 4-. lSJlS-benzooxazol-2-ylcarbonyl-3-phenylpropylcarbamoyl)- 2-methylbutylcarbamoyllpiperidine- 1 -carboxylate (Compound 288); tgrt-butyl 3-. lS-( lS-benzooxazol-2-ylcarbonyl-3-phenylpropylcarbamoyl)- 2-methylbutylcarbamoyllbenzylcarbamate (Compound 289);
-V-.2-methyl-lSJ3-phenyl- lS-benzooxazol-2-ylcarbonylpropylcarbamoyl)butyllpiperidine-4-carboxamide (Compound 290);
-V-r2-methyl-lS-(3-phenyl-lS-benzooxazol-2-ylcarbonylpropylcarbamoyl)butyll- 3-aminomethylbenzamide (Compound 291); benzyl l-π-.4-(2-indol-3-ylethylcarbamoyl)oxazol-2-ylcarbonyll-
3-phenylpropylcarbamoyl } -3-methylbutylcarbamate (Compound 292); MS (ESI) m/z = 664 (M + 1); Η-NMR (300 MHz, CDC13): δ 0.94 (d, J = 6 Hz, 6H), δ 1.40 - 1.70 (m, 6H), δ 2.00 (m, IH), δ 2.25(m, IH), δ 2.67 (m, 2H), δ 3.09 (m, 2H), δ 3.52 - 3.85 (m, 2H), δ 4.20 (m, IH), δ 5.09 (s, 2H), δ 5.50 (m, IH), δ 6.80 (d, J = 6 Hz, IH), δ 6.99 - 7.41(m, 14H), δ 7.65 (d, J = 6 Hz, IH), δ 8.35 (s, IH), δ 8.39 (s, IH), (C38H41N5O6); benzyl l-, l-(4-methylcarbamoyloxazol-2-ylcarbonyl)-3-phenylpropylcarbamoyll- 3-methylbutylcarbamate (Compound 293); MS (ESI) m/z = 535 (M + 1); Η-NMR (300 MHz, CDC13): δ 0.95 (d, J = 6 Hz, 6H), δ 1.33 - 1.70 (m, 5H), δ 2.00 (m, IH), δ 2.28 (m, IH), δ 2.67 (m, 2H), δ 2.99 (d, J = 2 Hz, 3H), δ 4.15 (m, IH), δ 5.09 (m, 2H), δ 5.50 (m, IH), δ 6.88 (m, IH), δ 7.09 - 7.38 (m, 10H), δ 8.35 (s, IH), (C29H34N406); benzyl 2- .2-, 2-(2-benzyloxycarbonylamino-4-methylvalerylamino)- 4-phenylbutyrylloxazol-2-ylcarbonylamino . valerate (Compound 294); benzyl lS-πS-_4-.4-benzylpiperidin-l-ylcarbonyl)oxazol-2-ylcarbonyll- 3-phenylpropylcarbamoyl _ -3-methylbutylcarbamate (Compound 295); MS (ESI) m/z = 679 (M + 1); Η-NMR (300 MHz, CDC13): δ 0.92 (m, 6H), δ 1.25 (m, IH), δ 1.48 (q, J = 4 Hz, IH), δ 1.52 - 1.85 (m, 6H), δ 2.09(m, IH), δ 2.36 (m, IH), δ 2.53 - 2.77 (m, 3H), δ 3.03 (t, J = 8 Hz, 4H), δ 4.19 (m, IH), δ 4.65 (m, IH), δ 5.02 - 5.13 (m, 3H), δ 5.53 (m, IH), δ 6.68 (d, J = 6 Hz, IH), δ 7.08 - 7.39 (m, 15H), δ 8.28 (s, IH), (C^H^N.O^; benzyl lS-, lS-(4-fur-2-ylmethylcarbamoyloxazol-2-ylcarbonyl)- 3-phenylpropylcarbamoyl1-3-methylbutylcarbamate (Compound 296); MS (ESI) m/z = 601 (M + 1); 'H-NMR (300 MHz, CDC13): δ 0.98 (d, J = 6 Hz 6H), δ 1.58 (q, J = 6 Hz IH), 1.62 (m, 4H), δ 2.00 (m, IH), δ 2.27 (m, IH), δ 2.76 (m, 2H), δ 4.20 (m, IH), δ 4.70 (d, J = 4 Hz, 2H), δ 4.98 - 5.18 (m, 2H), δ 5.56 (m, IH), δ 6.82 (m, IH), δ 7.05 - 7.42 (m, 13H), δ 8.32 (d, J = 4 Hz, IH), (C33H36N4O7); benzyl 3-methyl-lS-, lSJ4-pyrid-2-ylmethylcarbamoyloxazol-2-ylcarbonyl)- 3-phenylpropylcarbamoyllbutylcarbamate (Compound 297); MS (ESI) m z = 612 (M + 1); 'H-NMR (300 MHz, CDC13): δ 0.98 (d, J = 6 Hz 6H), δ 1.4 - 2.15 (m, 5H), δ 2.32 (m, IH), δ 2.71 (m, 2H), δ 4.21 (m, IH), δ 4.75 (d, J = 2 Hz, 2H), δ 5.09 (m, 2H), δ 5.15 - 5.5 (m, IH), δ 7.10 - 7.38 (m, 13H), δ 7.7 (t, J = 4 Hz, IH), δ 7.95 (m, IH), δ 8.32 (d, J = 4 Hz, IH), δ 8.59 (s, IH), (C34H37N5O6); benzyl 3-methyl-lS-riS-(4-pyrid-3-ylmethylcarbamoyloxazol-2-ylcarbonyl)- 3-phenylpropylcarbamoyllbutylcarbamate (Compound 298); MS (ESI) m/z = 612 (M + 1); 'H-NMR (300 MHz, CDC13); δ 0.98 (d, J = 6 Hz 6H), δ 1.5 (q, J= 4 Hz, IH), δ 1.65 (m, 2H), δ 1.95 (m, 3H), 2.25 δ (m, IH), δ 2.68 (m, 2H), δ 4.19 (m, IH), δ 4.72 (d, J = 2 Hz, 2H), δ 5.09 (s, 2H), δ 5.41 (m, IH), δ 6.90 (t, J= 2 Hz, IH), δ 7.05 - 7.35 (m, 10H), δ 7.46 (m, IH), δ 7.72 (d, J= 6 Hz, IH), δ 8.31 (d, J = 4 Hz, IH), δ 8.62 (d, J = 4 Hz IH), δ 8.73 (s, IH), (C34H37N506); benzyl 3 -methyl- 1 S- . 1 S-(4-pyrid-4- ylmethylcarbamoy loxazol-2- ylcarbon yl)- 3-phenylpropylcarbamoyllbutylcarbamate (Compound 299); MS (ESI) m/z = 612 (M + 1); Η-NMR (300 MHz, CDC13): δ 0.98 (d, J = 6 Hz, 6H), δ 1.5 (q, J = 4 Hz, IH), 1.65 (m, 2H), 1.95 (m, 3H), 2.25 (m, IH), 2.68 (m, 2H), 4.19 (m, IH), 4.72 (t, J = 2 Hz, 2H), 5.11 (d, J= 4 Hz, 2H), 5.43 (m, IH), 6.92 (d, J= 6 Hz, IH), 7.05 - 7.35 (m, 1 IH), 7.46 (m, IH), 8.33 (d, J = 4 Hz, IH), 8.58 (m, 2H), (C34H37N5O6); benzyl 1 S- { 1 S-, 4-(2-chlorobenzylcarbamoyl)oxazol-2-ylcarbonyll - 3-phenylpropylcarbamoyl 1 -3-methylbutylcarbamate (Compound 300); MS (ESI) m/z = 646 (M + 1); Η-NMR (300 MHz, CDC13): δ 0.98 (d, J = 6 Hz, 6H), δ 1.5 (q, J = 4 Hz, IH), δ 1.62 (m, 4H), 1.95 δ (m, IH), δ 2.30 (m, IH), δ 2.65 (m, 2H), δ 4.19 (m, IH), δ 4.70 (d, J = 2 Hz, 2H), δ 5.09 (m, 2H), δ 5.47 (m, IH), δ 6.82 (m, IH) δ 7.05 - 7.45 (m, 14H), δ 8.33 (d, J = 4 Hz, IH), (C35H37ClN4O6); benzyl lS-{ lS-.4-(3-chlorobenzylcarbamoyl)oxazol-2-ylcarbonyl1- 3-phenylpropylcarbamoyl 1 -3-methylbutylcarbamate (Compound 301); MS (ESI) m/z = 646 (M + 1); Η-NMR (300 MHz, CDC13): δ 0.98 (d, J = 6 Hz, 6H), δ 1.5 (q, J = 4 Hz, IH), δ 1.62 (m, 4H), δ 2.00 (m, IH), δ 2.25 (m, IH), δ 2.65 (m, 2H), δ 4.20 (m, IH), δ 4.68 (d, J = 2 Hz, 2H), δ 5.09 (m, 2H), δ 5.43 (m, IH), δ 6.85 (d, J = 6 Hz, IH), δ 7.05 - 7.45 (m, 14H), δ 8.33 (d, J = 4 Hz, IH), (C35H37C1N406); benzyl lS-{ lS-.4-(4-chlorobenzylcarbamoyl)oxazol-2-ylcarbonyll- 3-pheny lpropylcarbamoyl } -3-methylbutylcarbamate (Compound 302); MS (ESI) m z = 646 (M + 1); 'H-NMR (300 MHz, CDC13): δ 0.98 (d, J = 6 Hz, 6H), δ 1.5 (q, J = 4 Hz, IH), δ 1.62 (m, 4H), δ 2.00 (m, IH), δ 2.25 (m, IH), δ 2.65 (m, 2H), δ 4.20 (m, IH), δ 4.68 (d, J = 2 Hz, 2H), δ 5.09 (m, 2H), δ 5.43 (m, IH), δ 6.85 (m, IH), δ 7.05 - 7.45 (m, 14H), δ 8.33 (d, J = 4 Hz, IH), (C35H37ClN4O6); benzyl 3-methyl-lS-| lS-r4-(2S-phenylcvcloprop-lS-ylcarbamoyl)oxazol-2-ylcarbonyll- 3-phenylpropylcarbamoyl . -3-mefhylbutylcarbamate (Compound 303); MS (ESI) m/z = 637 (M + 1); "H-NMR (300 MHz, CDC13): δ 0.92 (d, J = 6 Hz, 6H), δ 1.46 - 1.78 (m, 6H), δ 2.00 (m, 3H), δ 2.31 (m, IH), δ 2.67 (m, 2H), δ 2.99 - 3.22 (m, IH), δ 4.20 (m, IH), δ 5.04 (d, J = 6 Hz, IH), δ 5.11 (s, 2H), δ 5.54 (m, IH), δ 6.87 (m, IH), δ 7.08 - 7.47 (m, 15H), δ 8.30 (d, J = 2 Hz, IH), (C37H40N4O6); benzyl 3-methyl-lS-riS-(4-diphenylmethylmethylcarbamoyloxazol-2-ylcarbonyl)- 3-phenylpropylcarbamoyll-3-methylbutylcarbamate (Compound 304); MS (ESI) m/z = 687 (M + 1); Η-NMR (300 MHz, CDC13): δ 0.98 (d, J = 6 Hz, 6H), δ 1.48 (q, J = 4 Hz, IH), δ 1.62 (m, 2H), δ 2.00 (m, IH), δ 2.30 (m, IH), δ 2.67 (m, 2H), δ 4.18 (m, IH), δ 5.09 (m, 3H), δ 5.43 (m, IH), δ 6.42 (d , J = 6 Hz, IH), δ 6.80 (d, J = 6Hz, IH), δ 7.02 - 7.72 (m, 20H), δ 7.79 (d, J = 6 Hz, IH), δ 8.33 (d, J = 4 Hz, IH), (C41H42N4O6); benzyl IS-. lS-(4-adamantan-l-ylmethylcarbamoyloxazol-2-ylcarbonyl)-
3-phenylpropylcarbamoyll-3-methylbutylcarbamate (Compound 305); MS (ESI) m/z = 670 (M + 1); 'H-NMR (300 MHz, CDC13): δ 0.92 (m, 8H), δ 1.18 - 1.78 (m, 16H), δ 2.00 (m, IH), δ 2.31 (m, IH), δ 2.67 (m, 2H), δ 2.99 - 3.09 (m, 2H), δ 4.21 (m, IH), δ 5.11 (m, 3H), δ 5.51 (m, IH), δ 6.87 (m, IH), δ 7.02 (m, IH), δ 7.08 - 7.47 (m, 10H), δ 8.31 (d, J = 2 Hz, IH), (C39H4gN406); benzyl 1- { l-.4-(l-methylethylcarbamoyl)oxazoI-2-ylcarbonyl1-
3-phenylpropylcarbamoyl } -3-methylbutylcarbamate (Compound 306); benzyl l-{ l-.4-(lS-phenylethylcarbamoyl)oxazol-2-ylcarbonyl"l- 3-phenylpropylcarbamoyl 1 -3-methylbutylcarbamate (Compound 307); MS (ESI) m/z = 625 (M + 1); Η-NMR (300 MHz, CDC13): δ 0.92 (d, J = 6 Hz, 6H), δ 1.54 - 1.65 (m, 7H), δ 2.00 (m, IH), δ 2.25 (m, IH), δ 2.65 (m, 2H), δ 4.15 (m, IH), δ 4.99 (d, J = 2 Hz, IH), δ 5.09 (s, 2H), δ 5.32 (m, IH), δ 5.43 (m, IH), δ 6.79 (d, J = 6 Hz, IH), δ 7.05 - 7.45 (m, 15H), δ 8.31 (s, IH), (C36H40N4O6); benzyl 1- . l-r4-(lR-phenylethylcarbamoyl)oxazol-2-yIcarbonyl1- 3-pheny lpropylcarbamoyl I -3-methylbutylcarbamate (Compound 308); MS (ESI) m/z = 625 (M + 1); Η-NMR (300 MHz, CDC13): δ 0.92 (d, J = 6 Hz, 6H), δ 1.45 - 1.68 (m, 7H), δ 2.00 (m, IH), δ 2.25 (m, IH), δ 2.65 (m, 2H), δ 4.15 (m, IH), δ 4.99 (d, J = 2 Hz, IH), δ 5.09 (s, 2H), δ 5.32 (m, IH), δ 5.43 (m, IH), δ 6.79 (d, J = 6 Hz, δ IH), δ 7.05 - 7.45 (m, 15H), δ 8.31 (s, IH), (C36H40N4O6); benzyl l-{ l-r4-(N-benzyl--V-methylcarbamoyl)oxazol-2-ylcarbonyll- 3-phenylpropy lcarbamoyl 1 -3-methylbutylcarbamate (Compound 309); MS (ESI) m/z = 625 (M + 1); 'H-NMR (300 MHz, CDC13): δ 0.90 (d, J = 6 Hz, 6H), δ 1.27 - 1.68 (m, 4H), δ 2.00 (m, IH), δ 2.25 (m, IH), δ 2.65 (m, 2H), δ 3.10 (s, IH), δ 4.19 (m, IH), δ 4.71 (s , 2H), δ 5.09 (s, 2H), δ 5.22 (m, IH), δ 5.43 (m, IH), δ 6.99 (d, J = 6 Hz, IH), δ 7.05 - 7.45 (m, 15H), δ 7.60 (m, IH), δ 8.31 (s, IH), (C36H40N4O6); benzyl 1 - . 1 -(4-pyrrolidin- 1 -ylcarbonyloxazol-2-ylcarbonyl)-3-phenylρropylcarbamovn- 3-methylbutylcarbamate (Compound 310); MS (ESI) m/z = 575 (M + 1); 'H-NMR (300 MHz, CDC13): δ 0.93 (d, J = 6 Hz, 6H), δ 1.45 - 1.73 (m, 3H), δ 1.85 - 2.12 (m, 5H), δ 2.34 (m, IH), δ 2.64 (m, 2H), δ 3.62 (t, J = 4 Hz, 2H), δ 3.82 (m, 2H), δ 4.21 (m, IH), 4.99 - 5.11 (m, 2H), δ 5.55 (m, IH), δ 5.43 (m, IH), δ 6.79 (m, IH), δ 7.05 - 7.45 (m, 10H), δ 8.31 (d, J = 2Hz, IH), (C32H38N406); benzyl 1 -f 1 -(4-piperidin- 1 -ylcarbonyloxazol-2-ylcarbonyl)-3-phenylpropylcarbamoyll - 3-methylbutylcarbamate (Compound 311); MS (ESI) m/z = 589 (M + 1); Η-NMR (300 MHz,
CDC13): δ 0.90 (d, J = 6 Hz, 6H), δ 1.25 (m, 2H), δ 1.49 - 1.66 (m, 6H), δ 2.12 (m, IH), δ 2.34
(m, IH), δ 2.64 (m, 2H), δ 3.65 (m, 2H), δ 3.85 (m, 2H), δ 4.17 (m, IH), δ 4.99 - 5.11 (m, 3H), δ 5.55 (m, IH), δ 6.67 (m, IH), δ 7.08 - 7.39 (m, 11H), δ 8.27 (s, IH), (C33H40N4O6); benzyl 1 - 1 1 -.4-(2.3-dihydroindol- 1 -ylcarbonyl)oxazol-2-ylcarbonyll - 3-phenv lpropylcarbamoyl } -3-methylbutylcarbamate (Compound 312); benzyl l-π-.4-(3,4-dihvdro-lH-isoquinol-2-ylcarbonyl)oxazol-2-ylcarbonyll- 3-pheny lpropylcarbamoyl 1 -3-methylbutylcarbamate (Compound 313); MS (ESI) m/z = 637 (M + 1); 'Η-NMR (300 MHz, CDC13): δ 0.90 (d, J = 6 Hz, 6H), δ 1.25 (m, 2H), δ 1.45 - 1.79 (m, 4H), δ 2.11 (m, IH), δ 2.40 (m, IH), δ 2.68 (m, 2H), δ 2.95 (t, J = 4 Hz, 2H), δ 3.96 (t, J = 4 Hz, IH), δ 4.15 (m, 2H), δ 4.86 (d, J = 6 Hz, IH), δ 4.99 - 5.11 (m, 3H), δ 5.59 (m, IH), δ 6.70 (m, IH), δ 7.05 - 7.45 (m, 12H), δ 8.35 (s, IH), (C37H40N4O6); benzyl l-π-_4J3.4-dihvdro-2H-quinol-l-vIcarbonyl')oxazol-2-ylcarbonylJ.- 3-phenylpropylcarbamoyl ,-3-methylbutv Icarbamate (Compound 314); MS (ESI) m/z = 637 (M + 1); 'H-NMR (300 MHz, CDC13): δ 0.90 (d, J = 6 Hz, 6H), δ 1.25 (m, 2H), δ 1.40 - 1.69 (m, 3H), δ 2.05 (m, 2H), δ 2.52 (t, J = 6 Hz, 2H), δ 2.82 (t, J = 4 Hz, 2H), δ 3.80 - 4.21 (m, 4H), δ 4.86 (d, J = 6 Hz, IH), δ 5.09 (s, 2H), δ 5.21 (m, IH), δ 6.62 (m, IH), δ 6.85 - 7.31 (m, 11H), δ 7.51 (m, IH), δ 7.67 (m, IH), δ 8.31 (s, IH), (C37H40N4O6); benzyl 1 -. 1 -(4-naphth- 1 -ylmethylcarbamoyloxazol-2-ylcarbonyl)- 3-phenylpropylcarbamoyll-3-methylbutylcarbamate (Compound 315); MS (ESI) m/z = 661 (M + 1); 'H-NMR (300 MHz, CDC13): δ 0.90 (d, J = 6 Hz, 6H), δ 1.25 (m, 2H), δ 1.54 (m, 3H), δ 2.05 (m, IH), δ 2.59 (t, J = 6 Hz, IH), δ 2.82 (t, J = 4 Hz, 2H), δ 4.12 (m, IH), δ 4.90 - 5.09 (m, 4H), δ 5.34 (m, IH), δ 6.71 (m, IH), δ 6.95 - 7.12 (m, 3H), δ 7.27 (m, 10H), δ 7.5 l(m, 2H), δ 7.88 (t, J = 6 Hz, IH), δ 8.06 (d, J = 6 Hz, IH), δ 8.35 (s, IH), (C39H40N4O6); tgrt-butyl 4-. lS-(lS-benzooxazol-2-ylcarbonyl)-3-phenylpropylcarbamoyl)- 2-cvclohexylethylcarbamoyllpiperidine- 1 -carboxylate (Compound 316);
1 S- { 1 S- , 4- ( 3 ,4-dihvdro-2H-quinol- 1 - v lcarbonyl)oxazol-2- ylcarbonyll -ethy lcarbamoyl } - 3 -methylbutylcarbamate (Compound 317); benzyl 3-methyl-lS-_ lS-(5-phenyloxazol-2-ylcarbonyl)- 3-phenylpropylcarbamovnbutylcarbamate (Compound 318); MS (ESI) m/z = 554 (M + 1); 'Η-NMR (300 MHz, CDC13): δ 0.97 (d, J = 4 Hz, 6H), δ 1.50 (t, J = 4 Hz, IH), δ 1.65 - 1.82 (m, 3H), δ 2.20 (m, IH), δ 2.48 (m, IH), δ 2.75 (t, J = 4 Hz, 2H), δ 4.27 (m, IH), δ 5.09 (s, 2H), δ 5.65 (m, IH), δ 6.85 (d, J = 6Hz, IH), δ 7.12 - 7.62 (m, 14H), δ 7. 77 (d, J = 2 Hz, 2H), (C33H35N305); pyrid-3-yl 3-methyl-lS-_ lS-(5-phenyloxazol-2-ylcarbonyl)- 3-phenylpropylcarbamoyllbutylcarbamate (Compound 319); MS (ESI) m/z = 525 (M + 1); 'H-NMR (300 MHz, CDC13): δ 0.80 - 1.05 (m, 6H), δ 1.27 (m, 3H), δ 1.72 (m, 3H), δ 2.15 (m, IH), δ 2.46 (m, IH), δ 2.77 (t, J = 4 Hz, 2H), δ 4.75 (m, IH), δ 5.65 (m, IH), δ 6.95 (d, J = 4Hz, IH), δ 7.02 (d, J = 4Hz, IH), δ 7.09 - 7.35 (m, 5H), δ 7.37 - 7.62 (m, 3H), δ 7.80 (d, J = 4 Hz, IH), δ 8.15 (d, J = 6Hz, IH), δ 8.75 ( m, IH), δ 9.09 (s, IH), (C31H32N4O4); benzyl IS-. lS-.5-phenyloxazol-2-ylcarbonyl)- 3-phenylpropylsulfamoylmethvn-2R-methylbutylcarbamate (Compound 320); MS (ESI) m z = 604 (M + 1); 'H-NMR (300 MHz, CDC13): δ 0.95 (m, 6H), δ 1.25 (m, IH), δ 1.49 (m, IH), δ 1.65 (m, IH), δ 2.15 (m, IH), δ 2.48 (m, IH), δ 2.85 (m, 2H), δ 3.12 (m, 2H), δ 4.46 (m, IH), δ 4.99 (d, J = 8Hz, IH), δ 5.12 (m, 3H), δ 6.32 (d, J = 6Hz, IH), δ 7.19 - 7.55 (m, 14H), δ 7.76 (m, 2H), (C33H37N3O6S); benzyl 3-methyl- 1 - , 2-hydroxy- 1 -phenethyl- 2-f4-(3-phenylpropylcarbamoyl)oxazol-2-yllethylcarbamoyl }butylcarbamate (Compound 321); benzyl l- .2-hvdroxy-2-.4-(2-indol-3-ylethylcarbamoyl)oxazol-2-yll- 1 -phenethylethylcarbamoyl } -3-methylbutylcarbamate (Compound 322); MS (ESI) m/z = 666 (M + 1); Η-NMR (300 MHz, CDC13): δ 0.90 (d, J = 6 Hz, 6H), δ 1.40 - 1.80 (m, 6H), δ 2.00 (m, IH), δ 2.67 (m, 2H), δ 3.09 (m, 2H), δ 3.52 - 3.85 (m, 2H), δ 3.99 - 4.20 (m, 2H), δ 4.26 - 4.44 (m, IH), δ 4.81 (s, IH), δ 5.09 (s, 2H), δ 5.50 (m, IH), δ 6.72 (d, J = 6 Hz, IH), δ 6.99 - 7.41 (m, 14H), δ 8.18 (s, IH), δ 8.39 (s, IH), (C38H43N5O6); benzyl 3-methyl- l-, 2-hvdroxy-2-(4-methylcarbamoyloxazol-2-viy
1-phenethylethylcarbamoyllbutylcarbamate (Compound 323); MS (ESI) m/z = 537 (M + 1); 'H-NMR (300 MHz, CDC13): δ 0.90 (d, J = 6 Hz, 6H), δ 1.33 - 1.80 (m, 6H), δ 2.00 (m, IH), δ 2.67 (m, 2H), 2.89 (m, 3H), δ 4.10 (m, IH), δ 4.25 (m, IH), δ 4.81 (s, IH), δ 5.09 (m, 3H), δ 6.68 (d, J = 4 Hz, IH), δ 7.09 - 7.38 (m, 10H), δ 8.18 (s, IH), (C29H36N4O6); benzyl 2- .2-.2-(2-benzyloxycarbonylamino-4-methylvalerylamino)-l-hydroxy-
4-ρhenylbutyll oxazol-2-ylcarbonylamino ) valerate (Compound 324); MS (ESI) m z = 727 (M + 1); Η-NMR (300 MHz, CDC13): δ 0.95 (m, 12H), δ 1.45 - 1.80 (m, 9H), δ 2.00 (m, IH), δ 2.67 (m, 2H), δ 3.99 - 4.15 (m, 2H), δ 4.85 (m, 2H), δ 5.09 (m, 4H), δ 5.50 (m, IH), δ 6.88 (m, IH), δ 7.12 - 7.45 (m, 15H), δ 8.18 (s, IH), (C41H50N4O8); benzyl lS- _ 2-.4-(4-benzylpiperidin-l-ylcarbonyl)oxazol-2-yll-2-hvdroxy-
1 S-phenethylethylcarbamoyl I -3-methylbutylcarbamate (Compound 325); benzyl lS-.2-(4-fur-2-ylmethylcarbamoyloxazol-2-yl)-2-hvdroxy- lS-phenethylethylcarbamovfl-3-methylbutylcarbamate (Compound 326); benzyl 3-methyl- 1 S- .2-hvdroxy- 1 S-phenethyl- 2-(4-pyrid-2-ylmethylcarbamoyloxazol-2-yl)ethylcarbamoyllbutylcarbamate (Compound 327); benzyl 3-methyl-lS-,2-hvdroxy-lS-phenethyl- 2-(4-pyrid-3-ylmethylcarbamoyloxazol-2-yl)ethylcarbamoyllbutylcarbamate (Compound 328); benzyl 3-methyl- 1 S- .2-hvdroxy- 1 S-phenethy 1- 2-(4-pyrid-4-ylmethylcarbamoyloxazol-2-yl)ethylcarbamoyllbutylcarbamate (Compound 329); benzyl 3-methyl-lS-, 2-_4J2-chlorobenzylcarbamoyl)oxazol-2-yll-2-hvdroxy- lS-phenethylethylcarbamoyllbutylcarbamate (Compound 330); benzyl 3-methyl-lS- _ 2-,4-(3-chlorobenzylcarbamoyl)θxazol-2-yl1-2-hvdroxy- lS-phenethylethylcarbamovUbutylcarbamate (Compound 331); benzyl 3-methyl-lS- _ 2-,4-(4-chlorobenzylcarbamoyl)oxazol-2-yl]-2-hvdroxy- lS-phenethylethylcarbamoyl Ibutylcarbamate (Compound 332); benzyl 3-methyl- 1 S- f 2-hvdroxy-lS-phenethyl- 2-r4-(2R-phenylcvcloprop-lS-ylcarbamoyl)oxazol-2-yllethylcarbamoyl)butylcarbamate (Compound 333); benzyl lS-.2-(4-adamantan-l-ylmethylcarbamoyloxazol-2-yl)- 2-hvdroxy-methyl)-lS-phenethylethylcarbamovn-3-methylbutylcarbamate (Compound 334); benzyl 3-methyl-lS-r2-hydroxy-lS-phenethyl-2-(4-diphenylmethylcarbamoyloxazol- 2-yl)ethylcarbamovnbutylcarbamate (Compound 335); benzyl 3-methyl- 1 - { 2-hydroxy-2-.4-( 1 -methylethy lcarbamoyl)oxazol-2-yll - 1 -phenethylethylcarbamoyl Ibutylcarbamate (Compound 336); benzyl 3-methyl- 1 - { 2-hydroxy- 1 -phenethyl- 2-.4-(lS-phenylethylcarbamoyl)oxazol-2-yllethylcarbamoyl Ibutylcarbamate (Compound 337); benzyl 3 -methyl- 1 - { 2-hvdroxy- 1 -phenethyl-
2-,4-(lR-phenylethylcarbamoyl)oxazol-2-vHethylcarbamoyl Ibutylcarbamate (Compound 338); benzyl 3-methyl-l-<2-r4-(-V-benzyl-H-methylcarbamoyl)oxazol-2-yll-2-hvdroxy- 1 -phenethylethylcarbamoyl } buty Icarbamate (Compound 339); benzyl 3-methyl- 1 -[2-hvdroxy- 1 -phenethyl- 2-(4-pyrrolidin-l-ylcarbonyloxazol-2-yl)ethylcarbamoyllbutylcarbamate (Compound 340); benzyl 3-methyl- 1 -_ 2-hvdroxy- 1 -phenethyl- 2-(4-piperidin-l-ylcarbonyloxazol-2-yl)ethylcarbamoyllbutylcarbamate (Compound 341); benzyl 3-methyl- 1 - ( 2-.4-(2,3-dihydroindol- 1 -ylcarbonyl)oxazol-2-yll -2-hvdroxy- l-phenethylethylcarbamovnbutylcarbamate (Compound 342); benzyl 3-methyl-l-{2-r4-(3.4-dihvdro-lH-isoquinol-2-ylcarbonyl)oxazol-2-vn-2-hydroxy-
1 -phenethylethylcarbamoyl } butylcarbamate (Compound 343); benzyl 3-methyl-l-{2-r4-(3.4-dihvdro-lH-quinol-l-ylcarbonyl)oxazol-2-yll-2-hydroxy- 1 -phenethylethylcarbamoyl Ibutylcarbamate (Compound 344); benzyl 3-methyl- 1 - .2-hvdroxy-2-(4-naphth- 1 -ylmethylcarbonyloxazol-2-yl)- 1-phenethylethylcarbamovHbutylcarbamate (Compound 345); and benzyl 1 S- { 2- I4- 3.4-dihydro-2H-quinol- 1 -ylcarbon yl)oxazol-2-vn -2-hy drox v- lS-methylethylcarbamoyll-3-methylbutylcarbamate (Compound 346). Proceeding by methods analogous to those described above provided the following compounds of Formula I:
-V- r 3 -methyl- 1 S-( 1 S-thiazol-2-y lcarbonylethy lcarbamovDbutyll - 4-morpholin-4-ylbenzamide (Compound 347); and N-\ lS-(2-benzooxazol-2-yl- 1 , l-dimethyl-2-oxoethylcarbamoyl)-3-methylbutyl 1-
4-(4-methylpiperazin- 1 -yPbenzamide (Compound 348).
Proceeding by methods analogous to those set forth in this Application compounds of Formula I are provided which are comprised by the elements A, B, C and D listed in the following Table 1.
TABLE 1
Figure imgf000143_0001
Figure imgf000144_0001
Figure imgf000145_0001
Figure imgf000146_0001
Figure imgf000147_0001
Figure imgf000148_0001
Figure imgf000149_0001
Figure imgf000150_0001
Figure imgf000151_0001
Figure imgf000152_0001
Figure imgf000153_0001
Figure imgf000154_0001
Figure imgf000155_0001
Figure imgf000156_0001
Figure imgf000157_0001
Figure imgf000158_0001
Figure imgf000159_0001
Figure imgf000160_0001
Figure imgf000161_0001
Figure imgf000162_0001
Figure imgf000163_0001
Figure imgf000164_0001
Figure imgf000165_0001
Figure imgf000166_0001
While any combination of the elements A, B and C may comprise the compounds of the Invention, certain combinations are preferred. For example, the following combinations
A11-B5-C4-D1 A17-B5-C4-D1 A66-B5-C4-D1 A75-B5-C4-D1 A128-B5-C4-D1 A11-B6-C4-D1 A17-B6-C4-D1 A66-B6-C4-D1 A75-B6-C4-D1 A128-B6-C4-D1 A11-B8-C4-D1 A17-B8-C4-D1 A66-B8-C4-D1 A75-B8-C4-D1 A128-B8-C4-D1 A11-B12-C4-D1 A17-B12-C4-D1 A66-B12-C4-D1 A75-B12-C4-D1 A128-B12-C4-D1 A11-B11-C4-D1 A17-B11-C4-D1 A66-B11-C4-D1 A75-B11-C4-D1 A128-B11-C4-D1 A11-B14-C4-D1 A17-B14-C4-D1 A66-B14-C4-D1 A75-B14-C4-D1 A128-B14-C4-D1 A11-B5-C4-D2 A17-B5-C4-D2 A66-B5-C4-D2 A75-B5-C4-D2 A128-B5-C4-D2 A11-B6-C4-D2 A17-B6-C4-D2 A66-B6-C4-D2 A75-B6-C4-D2 A128-B6-C4-D2 A11-B8-C4-D2 A17-B8-C4-D2 A66-B8-C4-D2 A75-B8-C4-D2 A128-B8-C4-D2 A11-B12-C4-D2 A17-B12-C4-D2 A66-B12-C4-D2 A75-B12-C4-D2 A128-B12-C4-D2 A11-B11-C4-D2 A17-B11-C4-D2 A66-B11-C4-D2 A75-B11-C4-D2 A128-B11-C4-D2 A11-B14-C4-D2 A17-B14-C4-D2 A66-B14-C4-D2 A75-B14-C4-D2 A128-B14-C4-D2
A61-B5-C4-D1 A64-B5-C4-D1 A37-B5-C4-D1 A38-B5-C4-D1 A90-B5-C4-D1 A92-B5-C4-D1 A133-B5-C4-D1 A61-B6-C4-D1 A64-B6-C4-D1 A37-B6-C4-D1 A38-B6-C4-D1 A90-B6-C4-D1 A92-B6-C4-D1 A133-B6-C4-D1 A61-B12-C4-D1 A64-B12-C4-D1 A37-B12-C4-D1 A38-B12-C4-D1 A90-B12-C4-D1 A92-B12-C4-D1 A133-B12-C4-D1
A11-B31-C4-D1 A75-B31-C4-D1 A128-B31-C4-D1 A11-B13-C4-D1
A75-B13-C4-D1 A128-B13-C4-D1 A11-B21-C4-D1 A75-B21-C4-D1
A128-B21-C4-D1 A11-B46-C4-D1 A75-B46-C4-D1 A128-B46-C4-D1
A11-B49-C4-D1 A75-B49-C4-D1 A128-B49-C4-D1 A11-B50-C4-D1
A75-B50-C4-D1 A128-B50-C4-D1 A11-B51-C4-D1 A75-B51-C4-D1
A128-B51-C4-D1 A11-B52-C4-D1 A75-B52-C4-D1 A128-B52-C4-D1
A11-B53-C4-D1 A75-B53-C4-D1 A128-B53-C4-D1
A11-B5-C36-D1 A75-B5-C36-D1 A128-B5-C36-D1 A11-B6-C36-D1 A75-B6-C36-D1 A128-B6-C36-D1 A11-B12-C36-D1 A75-B12-C36-D1 A128-B12-C36-D1 A11-B5-C11-D1 A75-B5-C11-D1 A128-B5-C11-D1 A11-B6-C11-D1 A75-B6-C11-D1 A128-B6-C11-D1 A11-B12-C11-D1 A75-B12-C11-D1 A128-B12-C11-D1 A11-B5-C10-D1 A75-B5-C10-D1 A128-B5-C10-D1 A11-B6-C10-D1 A75-B6-C10-D1 A128-B6-C10-D1 A11-B12-C10-D1 A75-B12-C10-D1 A128-B12-C10-D1 A11-B5-C35-D1 A75-B5-C35-D1 A128-B5-C35-D1 A11-B6-C35-D1 A75-B6-C35-D1 A128-B6-C35-D1 A11-B12-C35-D1 A75-B12-C35-D1 A128-B12-C35-D1
A11-B5-C4-D33 A75-B5-C4-D33 A128-B5-C4-D33 A11-B6-C4-D33
A75-B6-C4-D33 A128-B6-C4-D33 A11-B12-C4-D33 A75-B12-C4-D33
A128-B12-C4-D33 A11-B5-C4-D83 A75-B5-C4-D83 A128-B5-C4-D83
A11-B6-C4-D83 A75-B6-C4-D83 A128-B6-C4-D83 A11-B12-C4-D83
A75-B12-C4-D83 A128-B12-C4-D83 A11-B5-C4-D86 A75-B5-C4-D86
A128-B5-C4-D86 A11-B6-C4-D86 A75-B6-C4-D86 A128-B6-C4-D86 A11-B12-C4-D86 A75-B12-C4-D86 A128-B12-C4-D86 A11-B5-C4-D123
A75-B5-C4-D123 A128-B5-C4-D123 A11-B6-C4-D123 A75-B6-C4-D123
A128-B6-C4-D123 A11-B12-C4-D123 A75-B12-C4-D123 A128-B12-C4-D123
EXAMPLE 28 Cathepsin B Assay
Solutions of test compounds in varying concentrations were prepared in 10 μL of dimethyl sulfoxide (DMSO) and then diluted into assay buffer (40 μL, comprising: -V,-V-bis(2-hydroxyethyl)-2-aminoethanesulfonic acid (BES), 50 mM (pH 6); polyoxyethylenesorbitan monolaurate, 0.05%; and dithiothreitol (DTT), 2.5 mM). Human cathepsin B (0.025 pMoles in 25 μL of assay buffer) was added to the dilutions. The assay solutions were mixed for 5-10 seconds on a shaker plate, covered and incubated for 30 minutes at room temperature. Z-FR-AMC (20 nMoles in 25 μL of assay buffer) was added to the assay solutions and hydrolysis was followed spectrophotometrically at ( λ 460 nm) for 5 minutes. Apparent inhibition constants (J were calculated from the enzyme progress curves using standard mathematical models.
Compounds of the invention were tested by the above-described assay and observed to exhibit cathepsin B inhibitory activity with a Kj of less than or equal to 10 μM.
EXAMPLE 29 Cathepsin K Assay
Solutions of test compounds in varying concentrations were prepared in 10 μL of dimethyl sulfoxide (DMSO) and then diluted into assay buffer (40 μL, comprising: MES, 50 mM (pH 5.5); EDTA, 2.5 mM; and DTT, 2.5 mM). Human cathepsin K (0.0906 pMoles in 25 μL of assay buffer) was added to the dilutions. The assay solutions were mixed for 5-10 seconds on a shaker plate, covered and incubated for 30 minutes at room temperature. Z-Phe-Arg-AMC (4 nMoles in 25 μL of assay buffer) was added to the assay solutions and hydrolysis was followed spectrophotometrically at ( λ 460 nm) for 5 minutes. Apparent inhibition constants (Kj) were calculated from the enzyme progress curves using standard mathematical models.
Compounds of the invention were tested by the above-described assay and observed to exhibit cathepsin K inhibitory activity with a IC, of less than or equal to 10 μM.
EXAMPLE 30 Cathepsin L Assay
Solutions of test compounds in varying concentrations were prepared in 10 μL of dimethyl sulfoxide (DMSO) and then diluted into assay buffer (40 μL, comprising: MES, 50 mM (pH 5.5); EDTA, 2.5 mM; and DTT, 2.5 mM). Human cathepsin L (0.05 pMoles in 25 μL of assay buffer) was added to the dilutions. The assay solutions were mixed for 5-10 seconds on a shaker plate, covered and incubated for 30 minutes at room temperature. Z-Phe-Arg-AMC (1 nMoles in 25 μL of assay buffer) was added to the assay solutions and hydrolysis was followed spectrophotometrically at ( λ 460 nm) for 5 minutes. Apparent inhibition constants (Kj) were calculated from the enzyme progress curves using standard mathematical models.
Compounds of the invention were tested by the above-described assay and observed to exhibit cathepsin L inhibitory activity with a Kj of less than or equal to 10 μM.
EXAMPLE 31 Cathepsin S Assay
Solutions of test compounds in varying concentrations were prepared in 10 μL of dimethyl sulfoxide (DMSO) and then diluted into assay buffer (40 μL, comprising: MES, 50 mM (pH 6.5); EDTA, 2.5 mM; and NaCl, 100 mM). Human cathepsin S (0.158 pMoles in 25 μL of assay buffer) was added to the dilutions. The assay solutions were mixed for 5-10 seconds on a shaker plate, covered and incubated for 30 minutes at room temperature. Z-Val-Val-Arg-AMC (9 nMoles in 25 μL of assay buffer) was added to the assay solutions and hydrolysis was followed spectrophotometrically at ( λ 460 nm) for 5 minutes. Apparent inhibition constants (KJ were calculated from the enzyme progress curves using standard mathematical models.
Compounds of the invention were tested by the above-described assay and observed to exhibit cathepsin S inhibitory activity with a Kj of less than or equal to 10 μM.
EXAMPLE 32 Ovalbumin Challenge Mouse C57 mice (female) were sensitised with ovalbumin (lOμg, i.p.) administered together with aluminium hydroxide adjuvant (20 mg, i.p.) on days 0 and 12. Mice are challenged on either day 22, 23 or 24 by exposure for 60 minutes to an aerosol of ovalbumin (10 g / 1) twice, 4 hours apart. Mice are dosed p.o. with either vehicle 5 ml/kg (0.5%MC/0.2 % Tween 80 in H20) or test compound at 0, 8, 23.5 29, 33, 48 and 56 hours.
Mice were euthanized with pentobarbitone i.p. after 86 hours (72 hours after the first challenge). The lungs were insufflated for histological examination as soon as possible after euthanization. Lungs were insufflated with 10% neutral buffered formalin (NBF), at 30 cm water pressure. The lungs were removed and placed in pots of 10% NBF. After fixation in 10% NBF for a minimum of 24 hours the lungs were processed through graded alcohols to wax. The lungs were blocked longitudinally and one 2 μm section for each animal was cut at the level of the main bronchi. Sections then were stained with haematoxylin and eosin. Pathological assessment of sections is performed and a grading is assigned.
Histopathological evaluation of the lung tissue demonstrate a dose dependant anti- inflammatory effect on vascular and mucosal beds after treatment with compounds of the invention between 0.03 and 30 mg/kg.
EXAMPLE 32 Representative Pharmaceutical Formulations Containing a Compound of Formula I
ORAL FORMULATION
Compound of Formula I 10-100 mg
Citric Acid Monohydrate 105 mg
Sodium Hydroxide 18 mg
Flavoring
Water q.s. to 100 mL
INTRAVENOUS FORMULATION
Compound of Formula I 0.1-10 mg
Dextrose Monohydrate q.s. to make isotonic
Citric Acid Monohydrate 1.05 mg
Sodium Hydroxide 0.18 mg
Water for Injection q.s. to 1.0 mL
TABLET FORMULATION
Compound of Formula I 1 %
Microcrystalline Cellulose 73%
Stearic Acid 25% Colloidal Silica 1%.
The resulting tablets are useful for administration in accordance with the methods of this invention for treating or preventing a cathepsin mediated disease state, such as osteoporosis, juvenile onset diabetes, multiple sclerosis, pemphigus vulgaris, Graves' disease, myasthenia gravis, systemic lupus erythemotasus, rheumatoid arthritis, Hashimoto's thyroiditis, asthma, organ transplant or tissue graft rejections, chronic obstructive pulmonary disease, bronchiolitis, excessive airway elastolysis in asthma and bronchitis, pneumonities, plaque rupture, atheroma and systemic amyloidosis.

Claims

WE CLAIM:
1. A compound of Formula I:
Figure imgf000172_0001
I in which: A comprises a heteromonocyclic ring containing 5 to 6 ring member atoms or a fused heteropolycyclic ring system containing 8 to 14 ring member atoms, wherein each ring contains 5 to 7 ring member atoms, X1 is a ring member carbon atom and each ring member atom other than X1 is a carbon atom or a heteroatom, with the proviso that (i) at least one ring member atom is a heteroatom and (ii) when A is a heteromonocyclic radical containing 5 ring member atoms, no more than two of the ring member atoms comprising A are heteroatoms; n is 0, 1, 2 or 3;
X1 is =C- or -CH-;
X2 is a bond or a divalent group of Formula (a) or (b):
Figure imgf000172_0002
(a) (b)
wherein:
X3 and X4 independently are -C(O)- or -CH2S(0)2- R9 and R10 independently are hydrogen, (C,.6)alkyl or as defined below; R11 at each occurrence independently is hydrogen or (C^alkyl; R12 and R13 independently are (i) (C,.6)alkyl optionally substituted with cyano, halo, nitro, -NR14R14, -NR14C(O)OR14, -NR14C(0)NR14R14, -NR14C(NR14)NR14R14,
-OR14, -SR14, -C(O)OR14, -C(O)NR14R14, -S(0)2NR,4R14, -P(O)(OR14)OR14, -OP(0)(OR14)OR14, -NR14C(O)R15, -S(0)R15, -S(0)2R15, -C(O)R15, -OR16, -SR16, -S(O)R16, -S(O)2R16, -C(O)R16, -C(0)OR16, -OC(0)R16, -NR16R17, -NR17C(0)R16, -NR17C(0)OR16, -C(O)NR16R17, -S(0)2NR16R17, -NR17C(O)NR16R17 or -NR17C(NR17)NR16R17, wherein R14 at each occurrence independently is hydrogen, (C,.6)alkyl or halo-substituted (C,.3)alkyl, R15 is (C^alkyl or halo-substituted (C,.3)alkyl, halo, (C,.6)alkyl or R16 is (C3.12)cycloalkyl(C0.6)alkyl, hetero(C3.ι2)cycloalkyl(C0.6)alkyl, (C6.12)aryl(C0.6)alkyl, hetero(C5.I2)aryl(C0.6)alkyl, (C9_12)polycycloaryl(C0.6)alkyl or hetero(C8.I2)polycycloaryl(C0.6)alkyl and R17 is hydrogen or (C,.6)alkyl, and wherein within R16 said cycloalkyl, heterocycloalkyl, aryl, heteroaryl, polycycloaryl or heterpolycycloaryl ring optionally is substituted by a group selected from -R18, -X5OR18, -X5SR18, -X5S(0)R18, -X5S(0)2R18, -X5C(0)R18,
-X5C(0)OR18, -XOC(O)R18, -X5NR18R19, -X5NR19C(0)R18, -X5NR19C(0)OR18, -X5C(0)NR18R19, -X5S(0)2NR18R19, -X5NR19C(0)NR18R19 or -X5NR19C(NR19)NR18R19, wherein X5 is a bond or (C,.6)alkylene, R18 is hydrogen or (C,.6)alkyl and R19 is (C3.12)cycloalkyl(C0.6)alkyl, hetero(C3.12)cycloalkyl(C0.6)alkyl, (C6.12)aryl(C0.6)alkyl, hetero(C5.I2)aryl(C0.6)alkyl, (C9.12)polycycloaryl(C0.6)alkyl or hetero(C8.12)polycycloaryl(C0.6)alkyl, or (ii) a group selected from (C3.12)cycloalkyl(C0.6)alkyl, hetero(C3.12)cycloalkyl(C0.6)alkyl, (C6.12)aryl(C0.6)alkyl, hetero(C5_12)aryl(C0.6)alkyl, (C9.12)polycycloaryl(C0.6)alkyl and hetero(C8.,2)polycycloaryl(C0.6)alkyl, wherein said cycloalkyl, heterocycloalkyl, aryl, heteroaryl, polycycloaryl or heteφolycycloaryl ring optionally is substituted by a group selected from -R18, -X5OR18, -X5SR18, -X5S(0)R18, -X5S(0)2R18, -X5C(O)R18, -X5C(0)OR18, -X5OC(O)R18, -X5NR18R19, -X5NR19C(0)R18, -X5NR19C(0)OR18, -X5C(0)NR18R19, -X5S(O)2NR18R19, -X5NR19C(O)NR18R19 or -X5NR19C(NR19)NR18R19, wherein X5, R18 and R19 are as defined above; wherein within R12 and/or R13 any alicyclic or aromatic ring system present may be substituted further by 1 to 5 radicals independently selected from (C, .6)alkyl, ( .6)alkylidene, cyano, halo, halo-substituted (C,.4)alkyl, nitro, -X5NR14R14, -X5NR14C(0)OR14, -X5NR14C(O)NR1 R14, -X5NR14C(NR14)NR14R14, -X5OR14, -X5SR14, -X5C(O)OR14, -X5C(0)NR14R14, -X5S(O)2NR14R14, -X5P(0)(OR14)OR14, -X5OP(O)(OR14)OR14, -X5NR14C(O)R15, -X5S(O)R15, -X5S(O)2R15 and -X5C(0)R15, wherein X5, R14 and R15 are as defined above; or
R12 together with R9 and/or R13 together with R10 form trimethylene, tetramethylene or phenylene- 1 ,2-dimethylene, optionally substituted with 1 to 3 radicals independently selected from (C,.6)alkyl, (C,.6)alkylidene, cyano, halo, halo-substituted (Chalky-, nitro, oxo, -X5NR14C(0)OR14, -X5NR14C(O)NR14R14, -X5NR14C(NR14)NR14R14, -X5OR14, -X5SR14, -X5C(O)OR14, -X5C(O)NR14R'4, -X5S(0)2NR14R14, -X5P(O)(OR14)OR14, -X5OP(0)(OR14)OR14, -X5NR14C(0)R15,
-X5S(O)R15, -X5S(O)2R15 and -X5C(0)R15, wherein X5, R14 and R15 are as defined above; and
R1 is -X6X7R20, wherein X6 is -C(O)-, -C(0)C(O)- or -S(O)2-, X7 is a bond, -O- or -NR21-, wherein R21 is hydrogen or (C^alkyl, and R20 is (i) (C,.6)alkyl optionally substituted by cyano, halo, nitro, -NR14R14, -NR14C(0)OR14, -NR14C(0)NR14R14, -NR14C(NR14)NR14R14, -OR14, -SR14, -C(0)OR14, -C(0)NR14R14, -S(0)2NR14R14, -P(0)(OR14)OR14, -OP(0)(OR14)OR14, -NR14C(O)R15, -S(0)R15, -S(0)2R15, -C(0)R15, -OR22, -SR22, -S(0)R22, -S(O)2R22, -C(O)R22, -C(O)OR22, -C(0)NR22R23, -NR22R23, -NR23C(O)R22, -NR23C(O)OR22,-NR23C(O)NR22R23 or -NR23C(NR23)NR22R23, wherein R14 and R15 are as defined above, R22 is (C3.I2)cycloalkyl(C0.6)alkyl, hetero(C3.12)cycloalkyl(C0_6)alkyl, (C6.12)aryl(C0.6)alkyl, hetero(C5.12)aryl(C0.6)alkyl, (C9.12)bicycloaryl(C0.6)alkyl or hetero(C8_12)bicycloaryl(C0.6)alkyl and R23 at each occurrence independently is hydrogen or (Cμ6)alkyl, or (ii) (C3.12)cycloalkyl(C0.6)alkyl, hetero(C3.I2)cycloalkyl(C0.6)alkyl, (C6.12)aryl(C0.6)alkyl, hetero(C5.12)aryl(C0.6)alkyl, (C9.12)bicycloaryl(C0_6)alkyl or hetero(C8.12)bicycloaryl(C0_6)alkyl or (iii) (C3.6)cycloalkyl(C0.6)alkyl, hetero(C3.6)cycloalkyl(C0.6)alkyl, phenyl(C0.6)alkyl or hetero(C5.6)aryl(C0.6)alkyl, wherein said cycloalkyl, heterocycloalkyl, phenyl or heteroaryl is substituted by -R24, -X5OR24, -X5SR24, -X5S(O)R24, -X5S(O)2R24, -X5C(O)R24, -X5C(O)OR24, -X5C(O)NR24R25, -X^R^R25, -X5NR25C(O)R24, -X5NR25C(O)OR24, -X5NR25C(O)NR24R25 or -X5NR25C(NR25)NR24R25, wherein X5 is as defined above, R24 is (C3.6)cycloalkyl(C0.6)alkyl, hetero(C3.6)cycloalkyl(C0.6)alkyl, phenyl(C0.6)alkyl or hetero(C5.6)aryl(C0.6)alkyl and R25 at each occurrence independently is hydrogen or (C^alkyl; wherein within R1 any alicyclic or aromatic ring system present may be substituted further by 1 to 5 radicals independently selected from (C,.6)alkyl, (C,.6)alkylidene, cyano, halo, halo-substituted (C,.4)alkyl, nitro, -X5NR14R14, -X5NR14C(O)OR14, -X5NR14C(0)NR,4R14, -X5NR14C(NR14)NR14R14, -X5OR14, -X5SR14, -X5C(O)OR14, -X5C(O)NR14R14, -X5S(0)2NR14R14, -X5P(0)(OR14)OR14, -X5OP(0)(OR14)OR14, -X5NR14C(0)R15, -X5S(O)R15, -X5S(O)2R15 and -X5C(O)R15, wherein X5, R14 and R15 are as defined above; or when X2 is a divalent group of formula (a) or (b) then R1 may also represent hydrogen, carboxy, oxalo or carbamoyl; R2 is hydrogen or (C,.6)alkyl;
R3 is (i) (C,.6)alkyl optionally substituted with cyano, halo, nitro, -SR26, -C(0)OR26, -C(O)NR26R26, -P(O)(OR26)OR26, -OP(0)(OR26)OR26, -S(O)R27, -S(O)2R27 or -C(O)R27, wherein R26 at each occurrence independently is hydrogen, (C,.6)alkyl or halo-substituted (C,.3)alkyl and R27 is (C^alkyl or halo-substituted (C,.3)alkyl, or (ii) (C5.6)cycloalkyl(C2_3)alkyl, hetero(C3.6)cycloalkyl(C2_3)alkyl, (C6.12)aryl(C2.3)alkyl or hetero(C5.6)aryl(C2.3)alkyl, wherein said cycloalkyl, heterocycloalkyl, aryl or heteroaryl optionally is substituted further with 1 to 5 radicals independently selected from (C,.6)alkyl, (C,.6)alkylidene, cyano, halo, halo-substituted (C,.4)alkyl, nitro, -X5NR14C(0)OR14, -X5NR14C(O)NR14R14, -X5NR14C(NR14)NR14R14, -X5OR14, -X5SR14, -X5C(O)OR14, -X5C(0)NR1 R14, -X5S(0)2NR14R14, -X5P(O)(OR14)OR14, -X5OP(O)(OR14)OR14, -X5NR14C(0)R15, -X5S(O)R15, -X5S(O)2R15 and -X5C(O)R15, wherein X5, R14 and R15 are as defined above, provided that when R3 is unsubstituted (C^alkyl and R4 is hydrogen or unsubstituted (C,_5)alkyl, then X2 may not represent (i) a bond when R1 is -C(O)R20, -C(O)2R20 or -S(O)2R20 in which R20 is (C,.6)alkyl, phenyl(C,.4)alkyl, phenyl, (C3.7)cycloalkyl, camphan-10-yl, naphth-1-yl, naphth-2-yl, phenyl substituted by one or more of (CM)alkyl, perfluoro(C,.4)alkyl, (CM)alkoxy, hydroxy, halo, amido, nitro, amino, (CM)alkylamino, (Cj. dialkylamino, carboxy or (C,.4)alkoxycarbonyl, or naphth-1-yl or naphth-2-yl substituted by one or more of (C,.4)alkyl, perfluoro(C,.4)alkyl, (CM)alkoxy, hydroxy, halo, amido, nitro, amino, carboxy or (C,.4)alkoxycarbonyl or (ii) a divalent group of formula (a) or (b) in which the moiety R12 is methyl, isopropyl, n-butyl, sec-butyl, tert-butyl, 1-methylpropyl, benzyl, naphth-1-ylmethyl, naphth-2-ylmethyl, thien-2-ylmethyl, thien-3-ylmethyl, or wherein R9 and R12 form ethylene, trimethylene, hydroxy-substituted trimethylene, tetramethylene or phenylene- 1,2-dimethylene; or
R3 and R4 taken together with the carbon atom to which both R3 and R4 are attached form (C3.8)cycloalkylene or (C3.8)heterocycloalkylene, wherein said cycloalkylene or heterocycloalkylene is optionally substituted with 1 to 3 radicals independently selected from (Cj alkyl, (C,.6)alkylidene, cyano, halo, halo-substituted (CM)alkyl, nitro, -X5NR14C(O)OR14, -X5NR14C(O)NR14R14, -X5NR14C(NR14)NR14R14, -X5OR14, -X5SR14, -X5C(O)OR14, -X5C(O)NR14R14, -X5S(O)2NR14R14, -X5P(0)(OR14)OR14, -X5OP(0)(OR14)OR14, -X5NR14C(O)R15, -X5S(O)R15, -X5S(0)2R15 and -X5C(O)R15, wherein X5, R14 and R15 are as defined above;
R4 is hydrogen, (Cj.6)alkyl or as defined above; R5 is hydrogen and R6 is hydroxy or R5 and R6 together form oxo; R7 is a group selected from cyano, halo, nitro, -R29, -X5NR29R30, -X5NR30C(O)OR29, -X5NR30C(O)NR29R30, -X5NR30C(NR30)NR29R30, -X5OR29, -X5SR29, -X5C(O)OR29, -X5C(O)NR29R30, -X5S(O)2NR29R30, -X5P(O)(OR30)OR29, -X5OP(O)(OR29)OR29, -X5NR30C(O)R31, -X5S(O)R31, -X5S(O)2R31 and -X5C(O)R31, wherein X5 is as defined above, R29 is hydrogen or -R31, R30 at each occurrence is hydrogen or (C,.6)alkyl and R31 is (C^alkyl, (C3.12)cycloalkyl(C0.6)alkyl, hetero(C3.12)cycloalkyl(C0.6)alkyl, (C6.12)aryl(C0.6)alkyl or hetero(C5.12)aryl(C0.6)alkyl, wherein within R7 any alicyclic or aromatic ring system present may be substituted further by 1 to 5 radicals independently selected from (C^alkyl, (C^alkylidene, cyano, halo, halo-substituted (CM)alkyl, nitro, -X5NR14R14, -X5NR14C(0)OR14, -X5NR14C(O)NRI4R14, -X5NR14C(NR14)NR14R14, -X5OR14, -X5SR14, -X5C(O)OR14, -X5C(O)NR14R14, -X5S(O)2NR14R14, -X5P(O)(OR14)OR14, -X5OP(O)(OR14)OR14, -X5NR14C(O)R15, -X5S(O)R15, -X5S(O)2R15 and -X5C(O)R15, wherein X5, R14 and R15 are as defined above; and
R8 at each occurrence independently is selected from (C,_6)alkyl,
Figure imgf000176_0001
cyano, halo, halo-substituted (CM)alkyl, nitro, -X5NRI4R14, -X5NR14C(O)OR14, -X5NR14C(0)NR14R14, -X5NR14C(NR14)NR14R14, -X5OR14, -X5SR14, -X5C(0)OR14, -X5C(O)NR14R14, -X5S(O)2NR14R14, -X5P(0)(OR14)OR14, -X5OP(0)(OR1 )OR14,
-X5NR14C(0)R15, -X5S(0)R15, -X5S(0)2R15 and -X5C(0)R15, wherein X5, R14 and R15 are as defined above; and the -V-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers; and the pharmaceutically acceptable salts thereof.; but excluding compounds selected from the group consisting of ((S)- 1 - { (S)- 1 - [(S)- 1 -( 1 -bnzooxazol-2-yl-methanoyl)-3-methy l-butylcarbamoyl]-3-methyl- butylcarbamoyl}-3-methyl-butyl)-carbamic acid benzyl ester, { l-[l-(l-lH-imidazol-2-yl- methanoyl)-3-methyl-butylcarbamoyl]-3-methyl-butyl} -carbamic acid tert-butyl ester, [(S)-3-methyl- 1 -((S)-3-methy 1- 1 - { 1 - [ 1 -(2-trimethylsilanyl-ethoxymethy 1)- lH-imidazol-2-y 1] - methanoyl}-butylcarbamoyl)-butyl] -carbamic acid benzyl ester; { (S)-l-[(S)-l-(l-lH-imidazol-2-yl-methanoyl)-3-methyl-butylcarbamoyl]-3-methyl-butyl }- carbamic acid benzyl ester, ((S)-l-{ (S)-l-[l-(l-benzyl-lH-imidazol-2-yl)-methanoyl]-3-methyl- buty lcarbamoyl }-3-methyl-butyl)-carbamic acid benzyl ester, { (S)-l-[(S)-l-(l-lH-imidazol-2-yl- methanoyl)-3-methyl-butylcarbamoyl]-3-methyl-butyl}-carbamic acid tert-butyl ester, 3-{ [l-(4-chloro-phenyl)-methanoyl]-amino}-4-oxo-4-pyridin-3-yl-butyric acid ethyl ester, 4-furan-2-yl-4-oxo-3-{ [l-(4-trifluoromethyl-phenyl)-methanoyl]-amino}-butyric acid ethyl ester, 3-(2-methyl-propanoylamino)-4-oxo-4-thiophen-2-yl-butyric acid ethyl ester, 4-oxo- 4-thiophen-2-yl-3-[(l-p-tolyl-methanoyl)-amino]-butyric acid ethyl ester, 4-(5-bromo- thiophen-2-yl)-3-{ [l-(4-chloro-phenyl)-methanoyl]-amino}-4-oxo-butyric acid ethyl ester, 3-{ [l-(4-chloro-phenyl)-methanoyl]-amino}-4-(5-methyl-thiophen-2-yl)-4-oxo-butyric acid ethyl ester, 4-oxo-4-thiophen-3-yl-3-[(l-/ tolyl-methanoyl)-amino]-butyric acid ethyl ester, 3-{ [l-(4-methoxy-phenyl)-methanoyl] -amino }-4-oxo-4-thiophen-3-yl-butyric acid ethyl ester, 3-{ [l-(3,4-dichloro-phenyl)-methanoyl]-amino}-4-oxo-4-thiophen-3-yl-butyric acid ethyl ester, 4-fluoro--V~- [ 1 -( 1 -thiophen-3-y l-methanoyl)-propyl] -benzamide, 4- { [ 1 -(4-fluoro-phenyl)- methanoyl]-amino}-5-oxo-5-thiophen-3-yl-pentanoic acid ethyl ester and 3-{ [l-(4-fluoro- phenyl)-methanoyl] -amino }-2-methyl-4-oxo-4-thiophen-3-yl-butyric acid ethyl ester.
2. The compound of Claim 1 in which X2 is a bond or a divalent group of Formula (a).
3. The compound of Claim 2 in which:
A is selected from 4,5-dihydrooxazol-2-yl, benzooxazol-2-yl, benzothiazol-2-yl and oxazol-2-yl, each substituted by a group R7 and optionally substituted with a group R8, wherein R7 is hydrogen, halo, (C,.4)alkoxy, (CM)alkoxycarbonyl, nitro or phenyl, R8 at each occurrence independently is halo, (C,.4)alkoxy, (C,.4)alkoxycarbonyl, nitro or trifluoromethyl; X1 is =C-;
X2 is a bond or a divalent group of Formula (a), wherein within Formula (a) R9 is hydrogen, R11 is hydrogen or methyl and R12 is (i) (C^alkyl substituted with -SR14, -S(0)R14 or -S(O)2R14, wherein R14 is (C6.12)aryl(C0.6)alkyl or hetero(C5.12)aryl(C0.6)alkyl or (ii) (C3.12)cycloalkyl(C0.6)alkyl or (C6.12)aryl(C0.6)alkyl; wherein within R12 any alicyclic or aromatic ring system present may be substituted further by 1 to 5 radicals independently selected from (C,.6)alkyl, (C,.6)alkylidene, cyano, halo, halo-substituted (C,.4)alkyl, nitro, -X5NR14R14, -X5NR14C(O)OR14, -X5NR14C(O)NR14R14, -X5NR14C(NR14)NR14R14, -X5OR14, -X5SR14, -X5C(0)OR14, -X5C(0)NR14R14, -X5S(O)2NR14R14, -X5P(0)(OR14)OR14, -X5OP(0)(OR14)OR14, -X5NR14C(O)R15, -X5S(O)R15, -X5S(0)2R15 and -X5C(0)R15, wherein X5 is a bond or (C,.6)alkylene, R14 at each occurrence independently is hydrogen, (C,.6)alkyl or halo-substituted (C,.3)alkyl and R15 is ( .^alkyl or halo-substituted (C,.3)alkyl;
R1 is -X6X7R20, wherein X6 is -C(O)- or -S(0)2-, X7 is a bond, -O- or -NR21-, wherein R21 is hydrogen or (C,.6)alkyl, and R20 is (i) (C^alkyl optionally substituted by -C(0)OR14 or (ii) (C3.12)cycloalkyl(C0.6)alkyl, hetero(C3.12)cycloalkyl(C0.6)alkyl, (C6.12)aryl(C0.6)alkyl or hetero(C5.12)aryl(C0.6)alkyl or (iii) (C3.6)cycloalkyl(C0.6)alkyl, hetero(C3.6)cycloalkyl(C0.6)alkyl, phenyl(C0.6)alkyl or hetero(C5_6)aryl(C0.6)alkyl, wherein said cycloalkyl, heterocycloalkyl, phenyl or heteroaryl is substituted by -X5OR24,-X5C(O)R24, -X5C(O)OR24, -X5C(O)NR24R25, -X5NRMR25, -X5NR25C(O)R24, -X5NR25C(0)OR24, -X5NR25C(0)NR24R25 or -X5NR25C(NR25)NR24R25, wherein X5 is a bond or (C^alkylene, R24 is
(C3.6)cycloalkyl(C0.6)alkyl, hetero(C3.6)cycloalkyl(C0.6)alkyl, phenyl(C0.6)alkyl or hetero(C5.6)aryl(C0.6)alkyl and R25 is hydrogen or (C,.6)alkyl; wherein within R1 any alicyclic or aromatic ring system present may be substituted further by 1 to 5 substituents independently selected from (C,_6)alkyl, halo, halo-substituted (CM)alkyl, -OR14 and -C(O)OR14 wherein R14 is as defined above, or when X2 is a divalent group of formula (a) then R1 may be, but is not limited to, hydrogen or oxalo; R2 is hydrogen;
R3 is hydrogen, (C,.6)alkyl (optionally substituted with cyano, halo, nitro, -SR24, -C(O)OR24, -C(O)NRMR24, -P(O)(OR24)OR24, -OP(O)(OR24)OR24, -S(O)R25, -S(O)2R25 or -C(O)R25, wherein R24 at each occurrence independently is hydrogen, (C^alkyl or halo-substituted (Cι_3)alkyl and R25 is halo, (C,.6)alkyl or halo-substituted (C,.3)alkyl) or (C6.12)aryl(C2.3)alkyl, wherein said aryl optionally is substituted further with 1 to 5 radicals independently selected from (C,.6)alkyl, (C^alkylidene, cyano, halo, halo-substituted (CM)alkyl, nitro ,-X5NR14C(O)OR14, -X5NR14C(O)NR14R14, -X5NR14C(NR14)NR14R14, -X5OR14, -X5SR14, -X5C(O)OR14, -X5C(0)NR14R14, -X5S(0)2NR14R14, -X5P(O)(OR14)OR14, -XOP(O)(OR14)OR14, -X5NR14C(O)R15, -X5S(O)R15, -X5S(O)2R15 and -X5C(O)R15, wherein X5 is a bond or (C,.6)alkylene and R14 and R15 are as defined above, or R3 and R4 or R3 and R4 taken together with the carbon atom to which both R3 and R4 are attached form cyclopropylene, cyclobutylene, cyclopentylene or cyclohexylene; R4 is hydrogen or as defined above; and
R5 and R6 together form oxo; and he iV-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers; and the pharmaceutically acceptable salts thereof.
4. The compound of Claim 3 in which:
A is benzoxazol-2-yl substituted by R7, wherein R7 is hydrogen, halo, (Cj.4)alkoxy, (C].4)alkoxycarbonyl or nitro and R8 at each occurrence independently is halo, (C,.4)alkoxy, (C,.4)alkoxycarbonyl, nitro or trifluoromethyl;
X2 is a bond or a divalent group of Formula (a), wherein within Formula (a) X3 is -C(O)- , R11 is hydrogen and R12 is a group having the following formula:
Figure imgf000179_0001
in which q is 0, 1, 2, 4 or 5 and R33 at each occurrence independently is selected from a group consisting of (C )alkyl, cyano, halo, halo-substituted (C^alkyl, nitro, -X5NR14R14, -X5OR14, -X5SR14, -X5C(O)NR14R14, -X5C(0)OR14, -X5S(O)R15, -X5S(O)2R15 and -X5C(O)R15, wherein X5 is a bond or (C].6)alkylene, R14 at each occurrence independently is hydrogen, (C,.3)alkyl or halo-substituted ( .^alkyl and R15 is (C,.3)alkyl or halo-substituted (C,.3)alkyl; R1 is selected from a group consisting of acetyl, azetidin-3-ylcarbonyl, benzyloxycarbonyl, l-benzyloxycarbonylpiperidin-4-ylcarbonyl, benzylsulfonyl, bicyclo[2.2.2]hept-2-ylcarbonyl, bicyclo[2.2. l]hept-2-ylcarbonyl, tert-butoxycarbonyl, carboxyacetyl, 2-carboxypropionyl, 3-carboxypropionyl, 2-cyclohexylacetyl, 4-cyclohexylbutyryl, 2-cyclohexylethylsulfonyl, cyclohexylmethoxycarbonyl, 3-cyclohexylpropionyl, 2-cyclopentylethylsulfonyl, 3-cyclopentylpropionyl, di(2-methoxyethyl)carbamoyl, dimethylcarbamoyl, 6-hydroxypyrid-3-ylcarbonyl, lH-imidazol-4-ylcarbonyl, methoxycarbonyl, methylsulfonyl, 4-methylvaleryl, moφholin-4-ylcarbonyl, 2-moφholin-4-ylethylcarbonyl, naphth-1-ylacetyl, naphth-1-ylmethylcarbonyl, oxalo, 3-phenylpropionyl, piperazin-1 -ylcarbonyl, piperidin-4-ylcarbonyl, pyrazin-2-ylcarbonyl, pyrid-3-ylcarbonyl, pyrid-4-ylcarbonyl, pyrid-3-ylaminocarbonyl, tetrahydropyran-4-ylcarbonyl and tetrahydropyran-4-yloxycarbonyl; R3 is selected from hydrogen, (C,.4)alkyl, phenyl(C2.3)alkyl or
(CM)alkylsulfonyl(C2.4)alkyl or R3 and R4 taken together with the carbon atom to which both R3 and R4 are attached form (C3.6)cycloalkylene;
R4 is hydrogen or as defined above; and the iV-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers; and the pharmaceutically acceptable salts thereof.
5. The compound of Claim 4 in which q is 0, 1 or 2, R1 is moφholin-4-ylcarbonyl, methoxycarbonyl, methylsulfonyl, piperidin-4-ylcarbonyl, pyrazin-2-ylcarbonyl pyrid-3-ylcarbonyl, pyrid-4-ylcarbonyl, tetrahydropyran-4-ylcarbonyl or tetrahydropyran-4-yloxycarbonyl, R3 is methyl, ethyl, n-propyl, n-butyl, 2-methylsulfonylethyl or phenyethyl or R3 and R4 taken together with the carbon atom to which both R3 and R4 are attached form cyclobutylene and R33 at each occurrence independently is (C^alkyl, cyano, halo, halo-subsituted (C,.4)alkyl, nitro, -OR14, -SR14 or -C(0)OR14, wherein R14 at each occurrence independently is hydrogen, (C,.3)alkyl or halo-substituted (C].3)alkyl; and the -V-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers; and the pharmaceutically acceptable salts thereof.
6. The compound of Claim 5 in which R33 at each occurrence independently is selected from a group consisting of (C,.4)alkyl, bromo, carboxy, chloro, cyano, difluoromethoxy, fluoro, iodo, methoxy, nitro, trifluoromethoxy, trifluoromethyl and trifluorosulfanyl; and the iV-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers; and the pharmaceutically acceptable salts thereof.
7. The compound of Claim 6 in which within Formula (a) R12 is benzylsulfonylmethyl, 2-chlorobenzylsulfonylmethyl, 2-cyanobenzylsulfonylmethyl, 2-difluoromethoxybenzylsulfonylmethyl, 3,5-dimethylisooxazol-4-ylmethylsulfonylmethyl, 2-methoxybenzylsulfonylmethyl, 6-methylpyrid-2-ylmethylsulfonylmethyl, 2-nitrobenzylsulfonylmethyl, pyrid-2-ylmethylsulfonylmethyl, o-tolylmethylsulfonylmethyl or 2-trifluoromethylbenzylsulfonylmethyl; and the /V-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers; and the pharmaceutically acceptable salts thereof.
8. A compound of Formula II:
Figure imgf000181_0001
in which:
A comprises a heteromonocyclic ring containing 5 to 6 ring member atoms or a fused heteropolycyclic ring system containing 8 to 14 ring member atoms, wherein each ring contains 5 to 7 ring member atoms, X1 is a ring member carbon atom and each ring member atom other than X1 is a carbon atom or a heteroatom, with the proviso that at least one ring member atom is a heteroatom; n is 0, 1, 2 or 3;
X1 is =C- or -CH-;
X8 is (C^alkylene;
R1 is hydrogen, carboxy, oxalo, carbamoyl or -X6X7R20, wherein X6 is -C(O)-, -C(0)C(0)- or -S(0)2-, X7 is a bond, -O- or -NR21-, wherein R21 is hydrogen or (C^alkyl, and R20 is (i) (C^alkyl optionally substituted by cyano, halo, nitro, -NR14R14, -NR14C(O)OR14, -NR14C(0)NR14R14, -NR14C(NR14)NR14R14, -OR14, -SR14, -C(0)OR14, -C(O)NR14R14, -S(0)2NR14R14, -P(O)(OR14)OR14, -OP(O)(OR14)OR14, -NR14C(0)R15, -S(O)R15, -S(O)2R15, -C(O)R15, -OR22, -SR22, -S(O)R22, -S(O)2R22, -C(O)R22, -C(0)OR22, -C(O)NR22R23,
-NR 2R23, -NR23C(O)R22, -NR23C(O)OR22,-NR23C(0)NR22R23 or -NR23C(NR23)NR2 R23, wherein R14 at each occurrence independently is hydrogen, (C1.6)alkyl or halo-substituted (C,.3)alkyl, R15 is (C^alkyl or halo-substituted (Cj-3)alkyl, R22 is (C3.12)cycloalkyl(C0.6)alkyl, hetero(C3.12)cycloalkyl(C0.6)alkyl, (C6.12)aryl(C0.6)alkyl, hetero(C5.12)aryl(C0.6)alkyl,
(C9.12)bicycloaryl(C0.6)alkyl or hetero(C8.12)bicycloaryl(C0.6)alkyl and R23 at each occurrence independently is hydrogen or (C,.6)alkyl, or (ii) (C3.]2)cycloalkyl(C0.6)alkyl, hetero(C3.12)cycloalkyl(C0.6)alkyl, (C6.12)aryl(C0.6)alkyl, hetero(C5.12)aryl(C0.6)alkyl, (C9.12)bicycloaryl(C0.6)alkyl or hetero(C8.I2)bicycloaryl(C0_6)alkyl or (iii) (C3.6)cycloalkyl(C0.6)alkyl, hetero(C3.6)cycloalkyl(C0.6)alkyl, phenyl(C0.6)alkyl or hetero(C5.6)aryl(C0.6)alkyl substituted by -X5OR24, -X5SR24, -X5S(0)R24, -X5S(0)2R24, -X5C(0)R24, -X5C(0)OR24, -X5C(0)NR24R25, -X5NR 4R25, -X5NR25C(O)R24, -X5NR25C(O)OR24, -X5NR25C(0)NR24R25 or -X5NR25C(NR25)NR24R25, wherein X5 is a bond or (C,.6)alkylene, R24 is (C3.6)cycloalkyl(C0.6)alkyl, hetero(C3.6)cycloalkyl(C0.6)alkyl, phenyl (C0.6)alkyl or hetero(C5.6)aryl(C0.6)alkyl and R25 at each occurrence independently is hydrogen or (C^alkyl; wherein within R1 any alicyclic or aromatic ring system present may be substituted further by 1 to 5 radicals independently selected from (C,_6)alkyl, (C,.6)alkylidene, cyano, halo, halo-substituted (C,.4)alkyl, nitro, -X5NR14R14, -X5NR14C(O)OR14, -X5NR14C(O)NR14R14, -X5NR14C(NR14)NR14R14, -X5OR14, -X5SR14, -X5C(O)OR14, -X5C(0)NR14R14, -X5S(0)2NR14R14, -X5P(0)(OR14)OR14, -X5OP(0)(OR14)OR14,
-X5NR14C(0)R15, -X5S(0)R15, -X5S(0)2R15 and -X5C(0)R15, wherein X5, R14 and R15 are as defined above;
R2 is hydrogen or (C,.6)alkyl;
R3 is (i) (C,.6)alkyl optionally substituted with cyano, halo, nitro, -NR14R14, -NR14C(0)OR14, -NR14C(O)NR14R14, -NR14C(NR14)NR14R14, -OR14, -SR14, -C(0)OR14, -C(O)NR1 R14, -S(O)2NR14R14, -P(O)(OR14)OR14, -OP(0)(OR14)OR14, -NR14C(0)R15, -S(O)R15, -S(O)2R15, -C(O)R15, -OR16, -SR16, -S(O)R16, -S(0)2R16, -C(O)R16, -C(0)OR16, -OC(O)R16, -NR16R17, -NR17C(O)R16, -NR17C(O)OR16, -C(O)NR16R17, -S(O)2NR16R17, -NR17C(0)NR16R17 or -NR17C(NR17)NR16R17, wherein R14 at each occurrence independently is hydrogen, (C,_6)alkyl or halo-substituted (C,.3)alkyl, R15 is (C,.6)alkyl or halo-substituted ( .^alkyl, R16 is (C3.12)cycloalkyl(C0.6)alkyl, hetero(C3.12)cycloalkyl(C0.6)alkyl, (C6.ι2)aryl(C0.6)alkyl, hetero(C5.12)aryl(C0.6)alkyl, (C9.12)polycycloaryl(C0.6)alkyl or hetero(C8.12)polycycloaryl(C0.6)alkyl and R17 is hydrogen or (C, .6)alkyl, and wherein within R16 said cycloalkyl, heterocycloalkyl, aryl, heteroaryl, polycycloaryl or heteφolycycloaryl ring optionally is substituted by a group selected from -R18, -X5OR18, -X5SR18, -X5S(0)R18, -X5S(O)2R18, -X5C(O)R18, -X5C(O)OR18, -X5OC(O)R18, -X5NR18R19, -X5NR19C(0)R18, -X5NR19C(O)OR18, -X5C(O)NR18R19, -X5S(O)2NR18R19, -X5NR19C(O)NR18R19 or -X5NR19C(NR19)NR18R19, wherein X5 is as defined above, R18 is hydrogen or (Cμ6)alkyl and R19 is (C3.12)cycloalkyl(C0.6)alkyl, hetero(C3.12)cycloalkyl(C0.6)alkyl, (C6.12)aryl(C0.6)alkyl, hetero(C5.!2)aryl(C0.6)alkyl, (C9.12)polycycloaryl(C0.6)alkyl or hetero(C8.12)polycycloaryl(C0.6)alkyl, or (ii) a group selected from (C3.12)cycloalkyl(C0.6)alkyl, hetero(C3.12)cycloalkyl(C0.6)alkyl, (C6.12)aryl(C0.6)alkyl, hetero(C5.12)aryl(C0.6)alkyl, (C9.12)polycycloaryl(C0.6)alkyl and hetero(C8.12)polycycloaryl(C0.6)alkyl, wherein said cycloalkyl, heterocycloalkyl, aryl, heteroaryl, polycycloaryl or heteφolycycloaryl ring optionally is substituted by a group selected from -R18, -X5OR18, -X5SR18, -X5S(0)R18, -X5S(0)2R18, -X5C(O)R18, -X5C(O)OR18, -XOC(0)R18, -X5NR18R19, -X5NR19C(0)R18, -X5NR19C(0)OR18, -X5C(O)NR18R19, -X5S(O)2NR18R19, -X5NR19C(O)NR18R19 or -X5NR19C(NR19)NR18R19, wherein X5, R18 and R19 are as defined above; wherein within R12 and/or R13 any alicyclic or aromatic ring system present may be substituted further by 1 to 5 radicals independently selected from (C,.6)alkyl, (C,.6)alkylidene, cyano, halo, halo-substituted (C,.4)alkyl, nitro, -X5NR14R14, -X5NR14C(0)OR14, -X5NR14C(0)NR14R14, -X5NR14C(NR14)NR14R14, -X5OR14, -X5SR14, -X5C(0)OR14, -X5C(0)NR14R14, -X5S(0)2NR14R14, -X5P(0)(OR14)OR14,
-X5OP(0)(OR14)OR14, -X5NR14C(0)R15, -X5S(0)R15, -X5S(0)2R15 and -X5C(0)R15, wherein X5, R14 and R15 are as defined above, or
R3 and R4 taken together with the carbon atom to which both R3 and R4 are attached form (C3.8)cycloalkylene or (C3.8)heterocycloalkylene, wherein said cycloalkylene or heterocycloalkylene is optionally substituted with 1 to 3 radicals independently selected from (C^alkyl, (C,.6)alkylidene, cyano, halo, halo-substituted (C,.4)alkyl, nitro, -X5NR14C(0)OR14, -X5NR14C(O)NR14R14, -X5NR14C(NR14)NR14R14, -X5OR14, -X5SR14, -X5C(O)OR14, -X5C(O)NR14R14, -X5S(O)2NR14R14, -X5P(O)(OR14)OR14, -X5OP(0)(OR14)OR14, -X5NR14C(O)R15, -X5S(O)R'5, -X5S(O)2R15 and -X5C(O)R15, wherein X5, R14 and R15 are as defined above;
R4 is hydrogen, (C,.6)alkyl or as defined above; R5 is hydrogen and R6 is hydroxy or R5 and R6 together form oxo; R7 is a group selected from cyano, halo, nitro, -R29, -X5NR29R30, -X5NR30C(O)OR29, -X5NR30C(O)NR29R30, -X5NR30C(NR30)NR29R30, -X5OR29, -X5SR29, -X5C(O)OR29, -X5C(O)NR29R30, -X5S(O)2NR29R30, -X5P(O)(OR30)OR29, -X5OP(O)(OR29)OR29,
-X5NR30C(O)R31, -X5S(O)R31, -X5S(0)2R31 and -X5C(O)R31, wherein X5 is as defined above, R29 is hydrogen or -R31, R30 at each occurrence is hydrogen or (C,.6)alkyl and R31 is (C,.6)alkyl, (C3_12)cycloalkyl(C0.6)alkyl, hetero(C3.12)cycloalkyl(C0.6)alkyl, (C6.12)aryl(C0.6)alkyl or hetero(C5.12)aryl(C0.6)alkyl, wherein within R7 any alicyclic or aromatic ring system present may be substituted further by 1 to 5 radicals independently selected from (C,.6)alkyl, (C,.6)alkylidene, cyano, halo, halo-substituted (CM)alkyl, nitro, -X5NR14R14, -X5NR14C(O)OR14, -X5NR,4C(O)NR14R14, -X5NR14C(NR14)NR14R14, -XOR14, -X5SR14, -X5C(O)OR14, -X5C(O)NR14R14, -X5S(O)2NR14R14, -X5P(0)(OR1 )OR14, -X5OP(0)(OR14)OR14, -X5NR14C(O)R15, -X5S(O)R15, -X5S(O)2R15 and -X5C(0)R15, wherein X5, R14 and R15 are as defined above; and
R8 at each occurrence independently is selected from (C,.6)alkyl, (C,.6)alkylidene, cyano, halo, halo-substituted (C,.4)alkyl, nitro, -X5NR14R14, -X5NR14C(O)OR14, -X5NR14C(O)NR14R14, -X5NR14C(NR14)NR14R14, -X5OR14, -X5SR14, -X5C(0)OR14, -X5C(O)NR14R14, -X5S(O)2NR14R14, -X5P(0)(OR14)OR14, -X5OP(0)(OR14)OR14, -X5NR14C(O)R15, -X5S(O)R15, -X5S(O)2R15 and -X5C(0)R15, wherein X5, R14 and R15 are as defined above; R9 is hydrogen or (Cι_6)alkyl; and
R32 is (C,.8)alkyl, (C3.12)cycloalkyl(C0.6)alkyl, hetero(C3.12)cycloalkyl(C0.6)alkyl, (C6.12)aryl(C0.6)alkyl, hetero(C5.12)aryl(C0.6)alkyl, (C9.12)polycycloaryl(C0.6)alkyl or hetero(C8.12)polycycloaryl(C0.6)alkyl, wherein within R30 any alicyclic or aromatic ring system present may be substituted further by 1 to 5 radicals independently selected from (C,.6)alkyl, (C,.6)alkylidene, cyano, halo, halo-substituted (CM)alkyl, nitro, -X5NR14R14, -X5NR14C(0)OR14, -X5NR14C(O)NR14R14, -X5NR14C(NR14)NR14R14, -X5OR14, -X5SR14, -X5C(O)OR14, -X5C(O)NR14R14, -X5S(O)2NRI4R14, -X5P(O)(OR14)OR14, -X5OP(O)(OR14)OR14, -X5NR14C(O)R15, -X5S(O)R15, -X5S(O)2R15 and -X5C(0)R15, wherein X5, R14 and R15 are as defined above; and the iV-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers; and the pharmaceutically acceptable salts thereof.
9. The compound of Claim 8 in which:
A is selected from 4,5-dihydrooxazol-2-yl, benzooxazol-2-yl, benzothiazol-2-yl and oxazol-2-yl, each substituted by a group R7 and optionally substituted with a group R8, wherein R7 is hydrogen, halo, (CM)alkoxy, (CM)alkoxycarbonyl, nitro or phenyl, R8 at each occurrence independently is halo, (C,.4)alkoxy, (C,.4)alkoxycarbonyl, nitro or trifluoromethyl;
X1 is =C-
X8 is methylene or ethylene;
R1 is -X6X7R20, wherein X6 is -C(O)- or -S(0)2-, X7 is a bond, -O- or -NR21-, wherein R21 is hydrogen or (C,.6)alkyl, and R20 is (i) (Cj .6)alkyl optionally substituted by -C(O)OR14 or (ii) (C3.12)cycloalkyl(C0.6)alkyl, hetero(C3.12)cycloalkyl(C0.6)alkyl, (C6.12)aryl(C0.6)alkyl or hetero(C 2)aryl(C0.6)alkyl or (iii) (C3.6)cycloalkyl(C0.6)alkyl, hetero(C3.6)cycloalkyl(C0.6)alkyl, phenyl (C0.6)alkyl or hetero(C5.6)aryl(C0.6)alkyl, wherein said cycloalkyl, heterocycloalkyl, phenyl or heteroaryl is substituted by -X5OR24,-X5C(O)R24, -X5C(0)OR24, -X5C(O)NR24R25, -X5NR24R25, -X5NR25C(O)R24, -X5NR25C(0)OR24, -X5NR25C(0)NR24R25 or -X5NR25C(NR25)NR24R25, wherein X4 is a bond or (C,.6)alkylene, R24 is (C3.6)cycloalkyl(C0.6)alkyl, hetero(C3.6)cycloalkyl(C0.6)alkyl, phenyl(C0.6)alkyl or hetero(C5.6)aryl(C0_6)alkyl and R25 is hydrogen or (C, _6)alkyl; wherein within R1 any alicyclic or aromatic ring system present may be substituted further by 1 to 5 substituents independently selected from (C,.6)alkyl, halo, halo-substituted (C,.4)alkyl, -OR14 and -C(0)OR14 wherein R14 is as defined above, or when X2 is a divalent group of formula (a) then R1 may be, but is not limited to, hydrogen or oxalo;
R2 and R9 each are hydrogen;
R3 is hydrogen, (C^alkyl (optionally substituted with cyano, halo, nitro, -SR24, -C(0)OR24, -C(O)NR24R24, -P(O)(OR24)OR24, -OP(0)(OR24)OR24, -S(O)R25, -S(O)2R25 or -C(O)R25, wherein R24 at each occurrence independently is hydrogen, (C,.6)alkyl or halo-substituted (C,.3)alkyl and R25 is (C^alkyl or halo-substituted (C,.3)alkyl) or
(C6.12)aryl(C2.3)alkyl, wherein said aryl optionally is substituted further with 1 to 5 radicals independently selected from (C,.6)alkyl, (C,.6)alkylidene, cyano, halo, halo-substituted (C,.4)alkyl, nitro,-X5NR14C(O)OR14, -X5NR14C(O)NR14R14, -X5NR14C(NR14)NR14R14, -X5OR14, -X5SR14, -X5C(O)OR14, -X5C(O)NR14R14, -X5S(0)2NR14R14, -X5P(O)(OR14)OR14, -X5OP(0)(OR14)OR14, -X5NR,4C(O)R15, -X5S(O)R15, -X5S(0)2R15 and -X5C(O)R15, wherein X5, R14 and R15 are as defined above, or R3 and R4 taken together with the carbon atom to which both R3 and R4 are attached form cyclopropylene, cyclobutylene, cyclopentylene or cyclohexylene;
R4 is hydrogen or as defined above; R5 and R6 together form oxo; and
R32 is -X9R34, wherein X9 is methylene when X8 is methylene or is a bond when X8 is ethylene, R34 is -CR35CHR36 or -CR37NR38, wherein R35 and R36 together with the atoms to which R35 and R36 are attached form (C2.6)alkenyl, (C5.12)cycloalkenyl, hetero(C5.12)cycloalkenyl, (C6.12)aryl, hetero(C6.12)aryl, (C9.12)bicycloaryl or hetero(C8.12)bicycloaryl and R37 and R38 together with the atoms to which R37 and R38 are attached form hetero(C5.12)cycloalkenyl, hetero(C6.12)aryl or hetero(C8.12)bicycloaryl, wherein within R34 said cycloalkenyl, heterocycloalkenyl, aryl, heteroaryl, bicycloaryl or heterobicycloaryl may be substituted further by 1 to 5 radicals independently selected from (C,.6)alkyl, (C,.6)alkylidene, cyano, halo, halo-substituted (CM)alkyl, nitro, -X5NR14R14, -X5NR14C(0)OR14, -X5NR14C(0)NR14R14, -X5NR14C(NR14)NR14R14, -X5OR14, -X5SR14, -X5C(O)OR14, -X5C(O)NR14R14, -X5S(O)2NR14R14, -X5P(0)(OR14)OR14, -X5OP(0)(OR14)OR14, -X5NR!4C(O)R15, -X5S(O)R15, -X5S(O)2R15 and -X5C(O)R15, wherein X5 is a bond or
(C, _6)alkylene, R14 at each occurrence independently is hydrogen, (C,.6)alkyl or halo-substituted (C,.3)alkyl and R15 is (C,.6)alkyl or halo-substituted (C,.3)alkyl; and the -V-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers; and the pharmaceutically acceptable salts thereof.
10. The compound of Claim 9 in which:
A is benzooxazol-2-yl, wherein R7 is hydrogen, halo, (C,_4)alkoxy, (C,.4)alkoxycarbonyl or nitro and R8 at each occurrence independently is halo, (CM)alkoxy, (C,.4)alkoxycarbonyl, nitro or trifluoromethyl;
-X8S(0)2R32 is a group having the following formula:
Figure imgf000186_0001
in which q is 0, 1, 2, 4 or 5 and R33 at each occurrence independently is selected from a group consisting of (C,.4)alkyl, cyano, halo, halo-substituted (C,.4)alkyl, nitro, -X5NR1 R14, -X5OR14, -X5SR14, -X5C(0)NR14R14, -X5C(O)OR14, -X5S(O)R15, -X5S(O)2R15 and -X5C(O)R15, wherein X5 is a bond or ( .^alkylene, R14 at each occurrence independently is hydrogen, (C,.3)alkyl or halo-substituted (C,.3)alkyl and R15 is ( .^alkyl or halo-substituted (C,.3)alkyl; R1 is selected from a group consisting of acetyl, azetidin-3-ylcarbonyl, benzyloxycarbonyl, 1 -benzyloxycarbonylpiperidin-4-ylcarbonyl, benzylsulfonyl, bicyclo[2.2.2]hept-2-ylcarbonyl, bicyclo[2.2.1]hept-2-ylcarbonyl, tert-butoxycarbonyl, carboxyacetyl, 2-carboxypropionyl, 3-carboxypropionyl, 2-cyclohexylacetyl, 4-cyclohexylbutyryl, 2-cyclohexylethylsulfonyl, cyclohexylmethoxycarbonyl, 3-cyclohexylpropionyl, 2-cyclopentylethylsulfonyl, 3-cyclopentylpropionyl, di(2-methoxyethyl)carbamoyl, dimethylcarbamoyl, 6-hydroxypyrid-3-ylcarbonyl, lH-imidazol-4-ylcarbonyl, methoxycarbonyl, methylsulfonyl, 4-methylvaleryl, moφholin-4-ylcarbonyl, 2-moφholin-4-ylethylcarbonyl, naphth-1-ylacetyl, naphth-1-ylmethylcarbonyl, oxalo, 3-phenylpropionyl, piperazin-1 -ylcarbonyl, piperidin-4-ylcarbonyl, pyrazin-2-ylcarbonyl, pyrid-3-ylcarbonyl, pyrid-4-ylcarbonyl, pyrid-3-ylaminocarbonyl, tetrahydropyran-4-ylcarbonyl and tetrahydropyran-4-yloxycarbonyl; R3 is selected from hydrogen, (C,.4)alkyl, phenyl(C2.3)alkyl or (C,.4)alkylsulfonyl(C2.4)alkyl or R3 and R4 taken together with the carbon atom to which both R3 and R4 are attached form (C3.6)cycloalkylene;
R4 is hydrogen or as defined above; and R34 is (C6.12)aryl or hetero(C5.12)aryl, each optionally substituted by 1 to 5 radicals selected from a group consisting of (C,.4)alkyl, cyano, halo, halo-substituted (C,^)alkyl, nitro, -X5NR14R14, -X5OR14, -X5SR14, -X5C(0)NR14R14, -X5C(0)OR14, -X5S(O)R15, -X5S(0)2R15 and -X5C(O)R15, wherein X5, R14 and R15 are as defined above; and the -V-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers; and the pharmaceutically acceptable salts thereof.
11. The compound of Claim 10 in which q is 0, 1 or 2, R1 is moφholin-4-ylcarbonyl, methoxycarbonyl, methylsulfonyl, piperidin-4-ylcarbonyl, pyrazin-2-ylcarbonyl pyrid-3-ylcarbonyl, pyrid-4-ylcarbonyl, tetrahydropyran-4-ylcarbonyl or tetrahydropyran-4-yloxycarbonyl, R3 is ethyl, butyl, 2-methylsulfonylethyl, phenethyl or propyl and -XnS(0)2R32 is benzylsulfonylmethyl, 2-chlorobenzylsulfonylmethyl,
2-cyanobenzylsulfonylmethyl, cyclohexylmethyl, 2-difluoromethoxybenzylsulfonylmethyl, 3,5-dimethylisooxazol-4-ylmethylsulfonylmethyl, 2-methoxybenzylsulfonylmethyl, 6-methylpyrid-2-ylmethylsulfonylmethyl, 2-nitrobenzylsulfonylmethyl, pyrid-2-ylmethylsulfonylmethyl, o-tolylmethylsulfonylmethyl or 2-trifluoromethylbenzylsulfonylmethyl; and the TV-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers; and the pharmaceutically acceptable salts thereof.
12. The compound of Claim 11 selected from a group consisting of:
N-[ lR-( 1 S-benzooxazol-2-ylcarbonylbutylcarbamoyl)-2-benzylsulfonylethyl]moφholine- 4-carboxamide; methyl lR-(lS-benzooxazol-2-ylcarbonylbutylcarbamoyl)-2-benzylsulfonylethylcarbamate;
N-( 1 S-benzooxazol-2-ylcarbonylbutyl)- 2R-methylsulfonylamino-3-benzylsulfonylpropionamide; -V-(lS-benzooxazol-2-ylcarbonylbutylcarbamoyl)-2R-(3,3-dimethylureido)-
3-(2-methoxybenzylsulfonyl)propionamide;
-V-[lR-(lS-benzooxazol-2-ylcarbonylbutylcarbamoyl)- -(2-difluoromethoxybenzylsulfonyl)ethyl]moφholine-4-carboxamide;
-V-[lR-(lS-benzooxazol-2-ylcarbonylbutylcarbamoyl)- -(2-methoxybenzylsulfonyl)ethyl]moφholine-4-carboxamide;
N- [ lR-( 1 S-benzooxazol-2-ylcarbonylpentylcarbamoyl)- -benzylsulfonylethyl]moφholine-4-carboxamide;
7V-[lR-(lS-benzooxazol-2-ylcarbonylpentylcarbamoyl)- -(2-chlorobenzylsulfonyl)ethyl]moφholine-4-carboxamide; lR-(lS-benzooxazol-2-ylcarbonylpentylcarbamoyl)- -(2-difluoromethoxybenzylsulfonyl)ethylcarbamate; iV-[lR-(lS-benzooxazol-2-ylcarbonylpentylcarbamoyl)- -(2-difluoromethoxybenzylsulfonyl)ethyl]moφholine-4-carboxyamide; iV-[lR-(lS-benzooxazol-2-ylcarbonylpentylcarbamoyl)- -(3,5-dimethylisoxazol-4-ylmethylsulfonylethyl]isonicotinamide; iV-[lR-(lS-benzooxazol-2-ylcarbonylpentylcarbamoyl)- -(2-nitrobenzylsulfonyl)ethyl]moφholine-4-carboxamide;
-V- [ 1 R-( 1 S-benzooxazol-2-y lcarbony lpentylcarbamoyl)- -pyridin-2-ylmethylsulfonylethyl]moφholine-4-carboxamide; -V-[lR-(lS-benzooxazol-2-ylcarbonylpentylcarbamoyl)- -o-tolylmethylsulfonylethyl]moφholine-4-carboxamide; iV-[lR-(lS-benzooxazol-2-ylcarbonylpentylcarbamoyl)- -(2-trifluoromethylbenzylsulfonyl)ethyl]moφholine-4-carboxamide;
-V-[lR-(lS-benzooxazol-2-ylcarbonyl-3-phenylpropylcarbamoyl)- -benzylsulfonylethyl]nicotinamide;
-V-[lR-(lS-benzooxazol-2-ylcarbonyl-3-phenylpropylcarbamoyl)- -benzylsulfonylethyl]pyrazine-2-carboxamide; -V-[lR-(lS-benzooxazol-2-ylcarbonyl-3-phenylpropylcarbamoyl)- 2-(2-chlorobenzylsulfonyl)ethyl]moφholine-4-carboxamide;
-V-[lR-(lS-benzooxazol-2-ylcarbonyl-3-phenylpropylcarbamoyl)- 2-(2-cyanobenzylsulfonyl)ethyl]isonicotinamide; -V-[lR-(lS-benzooxazol-2-ylcarbonyl-3-methylsulfonylpropylcarbamoyl)-
2-(2-difluoromethoxybenzylsulfonyl)ethyl]moφholine-4-carboxamide;
-V-[lR-(lS-benzooxazol-2-ylcarbonylpentylcarbamoyl)- 2-(2-difluoromethoxybenzylsulfonyl)ethyl]isonicotinamide;
N-[lR-(lS-benzooxazol-2-ylcarbonyl)-3-phenylpropylcarbamoyl)- 2-benzylsulfonylethyl]moφholine-4-carboxamide;
-V-[lR-(lS-benzooxazol-2-ylcarbonyl-3-phenylpropylcarbamoyl)- 2-(6-methylpyrid-2-ylmethylsulfonyl)ethyl]isonicotinamide;
-V-[lR-(lS-benzooxazol-2-ylcarbonyl-3-phenylpropylcarbamoyl)- 2-(2-nitrobenzylsulfonyl)ethyl]moφholine-4-carboxamide; TV-[lR-(lS-benzooxazol-2-ylcarbonyl-3-phenylpropylcarbamoyl)-
2-pyrid-2-ylmethylsulfonylethyl]moφholine-4-carboxamide;
-V-[lR-(lS-benzooxazol-2-ylcarbonyl-3-phenylpropylcarbamoyl)- 2-o-tolylmethylsulfonylethyl]moφholine-4-carboxamide;
TV- [ lR-( 1 S-benzooxazol-2-ylcarbonyl-3-phenylpropylcarbamoyl)- 2-(2-trifluoromethylbenzylsulfonyl)ethyl]tetrahydropyran-4-carboxamide; tetrahydropyran-4-yl lR-(lS-benzooxazol-2-ylcarbonyl-3-phenylpropylcarbamoyl)- 2-benzylsulfonylethylcarbamate; and
TV-[lR-(lS-benzooxazol-2-ylcarbonyl- 3-phenylpropylcarbamoyl)-2-(2-cyanobenzylsulfonyl)ethyl]piperidine-4-carboxamide; and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers; and the pharmaceutically acceptable salts thereof.
13. A pharmaceutical composition comprising a compound of Claim 1, or a TV-oxide derivative, prodrug derivative, individual isomer, mixture of isomers, or a pharmaceutically acceptable salt thereof in admixture with one or more suitable excipients.
14. A method of treating a disease in an animal in which cysteine protease activity contributes to the pathology and/or symptomatology of the disease, which method comprises administering to the animal a therapeutically effective amount of compound of Formula I:
Figure imgf000190_0001
I in which: A comprises a heteromonocyclic ring containing 5 to 6 ring member atoms or a fused heteropolycyclic ring system containing 8 to 14 ring member atoms, wherein each ring contains 5 to 7 ring member atoms, X1 is a ring member carbon atom and each ring member atom other than X1 is a carbon atom or a heteroatom, with the proviso that (i) at least one ring member atom is a heteroatom and (ii) when A is a heteromonocyclic radical containing 5 ring member atoms, no more than two of the ring member atoms comprising A are heteroatoms; n is 0, 1, 2 or 3;
X1 is =C- or -CH-;
X2 is a bond or a divalent group of Formula (a) or (b):
Figure imgf000190_0002
(a) (b)
wherein:
X3 and X4 independently are -C(O)- or -CH2S(O)2- R9 and R10 independently are hydrogen, (C,.6)alkyl or as defined below; R11 at each occurrence independently is hydrogen or (C^alkyl; R12 and R13 independently are (i) (C,.6)alkyl optionally substituted with cyano, halo, nitro, -NR14R14, -NR14C(O)OR14, -NR14C(0)NR14R14, -NR14C(NR14)NR14R14,
-OR14, -SR14, -C(O)OR14, -C(O)NR14R14, -S(0)2NR14R14, -P(O)(OR14)OR14, -OP(O)(OR14)OR14, -NR14C(O)R15, -S(0)R15, -S(0)2R15, -C(O)R15, -OR16, -SR16, -S(0)R16, -S(O)2R16, -C(O)R16, -C(O)OR16, -OC(O)R16, -NR16R17, -NR17C(0)R16, -NR,7C(0)OR16, -C(O)NR16R17, -S(0)2NR16R17, -NR17C(0)NR16R17 or -NR17C(NR17)NR16R17, wherein R14 at each occurrence independently is hydrogen, (C,.6)alkyl or halo-substituted (C,.3)alkyl, R15 is (C,.6)alkyl or halo-substituted (C,.3)alkyl, R16 is (C3.12)cycloalkyl(C0.6)alkyl, hetero(C3.12)cycloalkyl(C0.6)alkyl, (C6.12)aryl(C0.6)alkyl, hetero(C5.I2)aryl(C0.6)alkyl, (C9.12)polycycloaryl(C0.6)alkyl or hetero(C8.12)polycycloaryl(C0.6)alkyl and R17 is hydrogen or (C^alkyl, and wherein within R16 said cycloalkyl, heterocycloalkyl, aryl, heteroaryl, polycycloaryl or heteφolycycloaryl ring optionally is substituted by a group selected from -R18, -X5OR18, -X5SR18, -X5S(O)R18, -X5S(0)2R18, -X5C(O)R18, -X5C(O)OR18, -X5OC(0)R18, -X5NR18R19, -X5NR19C(0)R18, -X5NR19C(0)OR18, -X5C(0)NR18R19,
-X5S(0)2NR18R19, -X5NR19C(0)NR18R19 or -X5NR19C(NR19)NR18R19, wherein X5 is a bond or (C].6)alkylene, R18 is hydrogen or (C,.6)alkyl and R19 is (C3.12)cycloalkyl(C0.6)alkyl, hetero(C3.12)cycloalkyl(C0.6)alkyl, (C6.12)aryl(C0.6)alkyl, hetero(C5.12)aryl(C0.6)alkyl, (C9.12)polycycloaryl(C0.6)alkyl or hetero(C8.u)polycycloaryl(C0.6)alkyl, or (ii) a group selected from
(C3.12)cycloalkyl(C0.6)alkyl, hetero(C3.12)cycloalkyl(C0.6)alkyl, (C6.12)aryl(C0.6)alkyl, hetero(C5.12)aryl(C0.6)alkyl, (C9.12)polycycloaryl(C0.6)alkyl and hetero(C8.12)polycycloaryl(C0.6)alkyl, wherein said cycloalkyl, heterocycloalkyl, aryl, heteroaryl, polycycloaryl or heteφolycycloaryl ring optionally is substituted by a group selected from -R18, -X5OR18, -X5SR18, -X5S(0)R18, -X5S(O)2R18, -X5C(0)R18,
-X5C(O)OR18, -X5OC(O)R18, -X5NR18R19, -X5NR19C(O)R18, -X5NR19C(0)OR18, -X5C(0)NR18R19, -X5S(0)2NR18R19, -X5NR19C(O)NR18R19 or -X5NR19C(NR19)NR18R19, wherein X5, R18 and R19 are as defined above; wherein within R12 and/or R13 any alicyclic or aromatic ring system present may be substituted further by 1 to 5 radicals independently selected from (C,.6)alkyl, (C,.6)alkylidene, cyano, halo, halo-substituted (C,.4)alkyl, nitro, -X6NR14R14, -X6NR14C(0)OR14, -X6NR14C(O)NR14R14, -X6NR14C(NR14)NR14R14, -X6OR14, -X6SR14, -X6C(0)OR14, -X6C(O)NR14R14, -X6S(0)2NR14R14, -X6P(O)(OR14)OR14, -X6OP(O)(OR14)OR14, -X6NR14C(O)R15, -X6S(0)R15, -X6S(0)2R15 and -X6C(O)R15, wherein X6 is a bond or (C,.6)alkylene and R14 and R15 are as defined above; or
R12 together with R9 and/or R13 together with R10 form trimethylene, tetramethylene or phenylene- 1,2-dimethylene, optionally substituted with hydroxy or oxo; and
R1 is -X7X8R20, wherein X7 is -C(O)-, -C(0)C(O)- or -S(0)2-, X8 is a bond, -O- or -NR21-, wherein R21 is hydrogen or (C,.6)alkyl, and R20 is (i) ( _6)alkyl optionally substituted by cyano, halo, nitro, -NR,4R14, -NR14C(0)OR14, -NR14C(0)NR14R14, -NR14C(NR14)NR14R14, -OR14, -SR14, -C(O)OR14, -C(O)NR14R14, -S(0)2NR14R14, -P(0)(OR14)OR14,
-OP(O)(OR14)OR14, -NR!4C(O)R15, -S(0)R15, -S(0)2R15, -C(0)R15, -OR22, -SR22, -S(O)R22, -S(O)2R22, -C(O)R22, -C(O)OR22, -C(0)NR22R23, -NR22R23, -NR23C(O)R22, -NR23C(0)OR22,-NR23C(O)NR22R23 or -NR23C(NR23)NR22R23, wherein R14 and R15 are as defined above, R22 is (C3.,2)cycloalkyl(C0.6)alkyl, hetero(C3.12)cycloalkyl(C0.6)alkyl, (C6.12)aryl(C0.6)alkyl, hetero(C5.12)aryl(C0.6)alkyl, (C9.12)bicycloaryl(C0.6)alkyl or hetero(C8.12)bicycloaryl(C0.6)alkyl and R23 at each occurrence independently is hydrogen or (C^alkyl, or (ii) (C3_12)cycloalkyl(C0.6)alkyl, hetero(C3.12)cycloalkyl(C0.6)alkyl, (C6.ι2)aryl(C0.6)alkyl, hetero(C5.12)aryl(C0.6)alkyl, (C9.12)bicycloaryl(C0.6)alkyl or hetero(C8.12)bicycloaryl(C0.6)alkyl or (iii) (C3.6)cycloalkyl(C0.6)alkyl, hetero(C3.6)cycloalkyl(C0.6)alkyl, phenyl(C0.6)alkyl or hetero(C5.6)aryl(C0.6)alkyl, wherein said cycloalkyl, heterocycloalkyl, phenyl or heteroaryl is substituted by -X9OR24, -X9SR24, -X9S(O)R24, -X9S(O)2R24, -X9C(O)R24, -X9C(O)OR24, -X9C(O)NR24R25, -X9NR24R25, -X9NR25C(O)R24, -X9NR25C(O)OR24, -X9NR25C(O)NR24R25 or -X9NR25C(NR25)NR24R25, wherein X9 is a bond or (C,.6)alkylene, R24 is (C3.6)cycloalkyl(C0.6)alkyl, hetero(C3.6)cycloalkyl(C0.6)alkyl, phenyl(C0.6)alkyl or hetero(C5.6)aryl(C0.6)alkyl and R25 at each occurrence independently is hydrogen or (Cμ6)alkyl; wherein within R1 any alicyclic or aromatic ring system present may be substituted further by 1 to 5 radicals independently selected from (C,.6)alkyl, (C,.6)alkylidene, cyano, halo, halo-substituted (CM)alkyl, nitro, -X6NR14R14, -X6NR14C(O)OR14, -X6NR14C(O)NR14R14, -X6NR14C(NR14)NR14R14, -X6OR14, -X6SR14, -X6C(O)OR14, -X6C(O)NR14R14, -X6S(0)2NRl4R14, -X6P(O)(OR14)OR14,
-X6OP(O)(OR14)OR14, -X6NR14C(O)R'5, -X6S(O)R15, -X6S(O)2R15 and -X6C(O)R15, wherein X6, R14 and R15 are as defined above; or when X2 is a divalent group of formula (a) or (b) then R1 may also represent hydrogen, carboxy, oxalo or carbamoyl; R2 is hydrogen or (C1.6)alkyl; R3 is (i) (C,.6)alkyl optionally substituted with cyano, halo, nitro, -SR26, -C(0)OR26,
-C(O)NR26R26, -P(O)(OR26)OR26, -OP(0)(OR26)OR26, -S(O)R27, -S(O)2R27 or -C(0)R27, wherein R26 at each occurrence independently is hydrogen, (C,.6)alkyl or halo-substituted (C,.3)alkyl and R27 is (C,.6)alkyl or halo-substituted (C,.3)alkyl, or (ii) (C5.6)cycloalkyl(C2.3)alkyl, hetero(C3.6)cycloalkyl(C2.3)alkyl, (C6.12)aryl(C,.3)alkyl or hetero(C5.6)aryl(C2.3)alkyl, wherein said cycloalkyl, heterocycloalkyl, aryl or heteroaryl optionally is substituted further with 1 to 5 radicals independently selected from (C,.6)alkyl, (Cj.6)alkylidene, cyano, halo, halo-substituted (C,.4)alkyl, nitro, -X6NR14C(O)OR14, -X6NR14C(O)NR14R14, -X6NR14C(NR14)NR14R14, -X6OR14, -X6SR14, -X6C(O)OR14, -X6C(O)NR14R14, -X6S(O)2NR14R14, -X6P(O)(OR14)OR14, -X6OP(0)(OR14)OR14, -X6NR14C(O)R15, -X6S(O)R15, -X6S(O)2R15 and -X6C(0)R15, wherein X6, R14 and R15 are as defined above, provided that when R3 is unsubstituted (C,.5)alkyl and R4 is hydrogen or unsubstituted (C^alkyl, then X2 may not represent (i) a bond when R1 is -C(O)R20, -C(0)2R20 or -S(O)2R20 in which R20 is (C,.6)alkyl, phenyl(C,.4)alkyl, phenyl,
(C3_7)cycloalkyl, camphan-10-yl, naphth-1-yl, naphth-2-yl, phenyl substituted by one or more of (C,.4)alkyl, perfluoro(C,.4)alkyl, (C,.4)alkoxy, hydroxy, halo, amido, nitro, amino, (C,.4)alkylamino, (CM)dialkylamino, carboxy or (CM)alkoxycarbonyl, or naphth-1-yl or naphth-2-yl substituted by one or more of (C,^)alkyl, perfluoro(C1.4)alkyl, (CM)alkoxy, hydroxy, halo, amido, nitro, amino, carboxy or (C1.4)alkoxycarbonyl or (ii) a divalent group of formula (a) or (b) in which the moiety R12 is methyl, isopropyl, n-butyl, sec-butyl, tert-butyl, 1-methylpropyl, benzyl, naphth-1-ylmethyl, naphth-2-ylmethyl, thien-2-ylmethyl, thien-3-ylmethyl, or wherein R9 and R12 form ethylene, trimethylene, hydroxy-substituted trimethylene, tetramethylene or phenylene- 1,2-dimethylene; or R3 and R4 taken together with the carbon atom to which both R3 and R4 are attached form (C3.g)cycloalkylene or (C3.8)heterocycloalkylene, wherein said cycloalkylene or heterocycloalkylene is optionally substituted with 1 to 3 radicals independently selected from (C,.6)alkyl, (C,.6)alkylidene, cyano, halo, halo-substituted (CM)alkyl, nitro, -X5NR14C(0)OR14, -X5NR14C(O)NR14R14, -X5NR14C(NR14)NR14R14, -X5OR14, -X5SR14, -X5C(O)OR14, -X5C(0)NR14R14, -X5S(O)2NR14R14, -X5P(O)(OR14)OR14, -X5OP(O)(OR14)OR14,
-X5NR14C(O)R15, -X5S(O)R15, -X5S(O)2R15 and -X5C(0)R15, wherein X5, R14 and R15 are as defined above;
R4 is hydrogen, (C,.6)alkyl or as defined above;
R5 is hydrogen and R6 is hydroxy or R5 and R6 together form oxo; R7 is a group selected from cyano, halo, nitro, -R29, -X10NR29R30, -X10NR30C(O)OR29,
-X10NR30C(O)NR29R30, -X10NR30C(NR30)NR29R30, -X10OR29, -X10SR29, -X10C(O)OR29, -X10C(O)NR29R30, -X10S(O)2NR29R30, -X10P(O)(OR30)OR29, -X10OP(O)(OR29)OR29, -X10NR30C(O)R3\ -X10S(O)R31, -X10S(O)2R31 and -X10C(O)R31, wherein X10 is a bond or (C,.6)alkylene, R29 is hydrogen or -R31, R30 at each occurrence is hydrogen or (C,.6)alkyl and R31 is (C^alkyl, (C3.12)cycloalkyl(C0.6)alkyl, hetero(C3.12)cycloalkyl(C0.6)alkyl, (C6.12)aryl(C0.6)alkyl or hetero(C5.]2)aryl(C0_6)alkyl, wherein within R7 any alicyclic or aromatic ring system present may be substituted further by 1 to 5 radicals independently selected from (C,.6)alkyl, (C,.6)alkylidene, cyano, halo, halo-substituted (C,.4)alkyl, nitro, -X6NR14R14, -X6NR14C(0)OR14, -X6NR14C(O)NR14R14, -X6NR14C(NR14)NR14R14, -X6OR14, -X6SR14, -X6C(0)OR14, -X6C(O)NR14R14, -X6S(O)2NR14R14, -X6P(0)(OR14)OR14, -X6OP(0)(OR14)OR14, -X6NR14C(0)R15, -X6S(0)R15, -X6S(0)2R15 and -X6C(0)R15, wherein X6, R14 and R15 are as defined above; and
R8 at each occurrence independently is selected from (Cμ6)alkyl, (C, _6)alkylidene, cyano, halo, halo-substituted (C,.4)alkyl, nitro, -X6NR14R14, -X6NR14C(O)OR14, -X6NR,4C(0)NR14R14, -X6NR14C(NR14)NR14R14, -X6OR14, -X6SR14, -X6C(O)OR14, -X6C(0)NR14R14, -X6S(O)2NR14R14, -X6P(0)(OR14)OR14, -X6OP(0)(OR14)OR14, -X6NR14C(O)R15, -X6S(O)R'5, -X6S(O)2R15 and -X6C(O)R15, wherein X6, R14 and R15 are as defined above; or a TV-oxide derivative, prodrug derivative, protected derivative, individual isomer or mixture of isomers; or a pharmaceutically acceptable salt thereof.
15. The method of Claim 14 in which the cysteine protease is cathepsin S.
16. The method of Claim 15 in which the disease is an autoimmune disorder, allergic disorder, allogeneic immune response, a disorder involving excessive elastolysis, cardiovascular disorders or a disorder involving fibril formation.
17. The method of Claim 16 in which the disorder is selected from juvenile onset diabetes, multiple sclerosis, pemphigus vulgaris, Graves' disease, myasthenia gravis, systemic lupus erythemotasus, rheumatoid arthritis, Hashimoto's thyroiditis, asthma, organ transplant or tissue graft rejections, chronic obstructive pulmonary disease, bronchiolitis, excessive airway elastolysis in asthma and bronchitis, pneumonities, plaque rupture, atheroma and systemic amyloidosis.
18. A method for treating a disease in an animal in which cysteine protease activity contributes to the pathology and/or symptomatology of the disease, which method comprises administering to the animal a therapeutically effective amount of compound of Claim 8; or a TV-oxide derivative, prodrug derivative, protected derivative, individual isomer or mixture of isomers; or a pharmaceutically acceptable salt thereof.
19. The method of Claim 18 in which the cysteine protease is cathepsin S.
20. The method of Claim 19 in which the disease is an autoimmune disorder, allergic disorder, allogeneic immune response, a disorder involving excessive elastolysis, cardiovascular disorders or a disorder involving fibril formation.
21. The method of Claim 19 in which the disorder is selected from juvenile onset diabetes, multiple sclerosis, pemphigus vulgaris, Graves' disease, myasthenia gravis, systemic lupus erythemotasus, rheumatoid arthritis, Hashimoto's thyroiditis, asthma, organ transplant or tissue graft rejections, chronic obstructive pulmonary disease, bronchiolitis, excessive airway elastolysis in asthma and bronchitis, pneumonities, plaque rupture, atheroma and systemic amyloidosis.
22. A compound according to any one of Claims 1-8 in which R and R together form oxo.
23. A compound according to Claim 1 or Claim 22 in which ring A is selected from 4,5-dihydrooxazol-2-yl, benzoxazol-2-yl, benzothiazol-2-yl and oxazol-2-yl.
24. A compound according to Claim 23 in which ring A is benzoxazol-2-yl or oxazol-2-yl.
7 25. A compound according to Claim 23 or 24 in which ring A is substituted by R
7 wherein R is hydrogen, halo, (Cμ^alkyl, (C1.4)alkoxycarbonyl, nitro or phenyl. 3
26. A compound according to any one of Claims 1-8 or 22-25 in which R is
(Chalky! optionally substituted by phenyl or (C1. )alkylsulfonyl and R is hydrogen or methyl or R and R taken together with the carbon atom to which they are attached form straight, saturated (C2_5)alkylene, wherein within said alkylene any one or two carbon atoms Q Q ooppttiioonnaallllyy iiss rreeppllaacceedd bbyy a heteroatom selected from -O-, -S- or -NR - where R is hydrogen or (C1.6)alkyl.
27. A compound according to Claim 26 in which R is (Chalky! and R is hydrogen or methyl.
28. A compound according to any one of Claims 9-11 or 26 in which R is (Cl_ 4)alkyl and R is hydrogen.
3 29. A compound according to Claim 28 in which R is n-propyl.
30. A compound according to any preceding claim for use in therapy.
31. A compound or pharmaceutical composition according to any preceding claim for use in treating a disease in an animal in which cysteine protease activity contributes to the pathology and/or symptomatology of the disease.
32. A compound or pharmaceutical composition for use according to claim 31 in which the cysteine protease is cathepsin S.
33. A compound or pharmaceutical composition for use according to claim 32 to treat asthma.
34. Use of a compound according to any preceding claim for the manufacture of a medicament for the treatment of a disease in an animal in which cysteine protease activity contributes to the pathology and/or symptomatology of the disease.
35. Use according to Claim 34 for the treatment of a disease in an animal in which cathepsin S activity contributes to the pathology and/or symptomatology of the disease.
36. Use according to Claim 35 for the treatment of asthma.
37. A compound or pharmaceutical composition according to any preceding claim and an anti-inflammatory agent as a combined preparation for simultaneous, separate or sequential use in the treatment of asthma.
38. A compound, pharmaceutical composition or use thereof substantially as herein described with reference to the Examples.
39. A compound of Formula I:
Figure imgf000197_0001
in which:
A comprises a heteromonocyclic ring containing 5 to 6 ring member atoms or a fused heteropolycyclic ring system containing 8 to 14 ring member atoms, wherein each ring contains 5 to 7 ring member atoms, X1 is a ring member carbon atom and each ring member atom other than X1 is a carbon atom or a heteroatom, with the proviso that (i) at least one ring member atom is a heteroatom and (ii) when A is a heteromonocyclic radical containing 5 ring member atoms, no more than two of the ring member atoms comprising A are heteroatoms; n is 0, 1, 2 or 3; X1 is =C- or -CH-; X2 is a bond or a divalent group of Formula (a) or (b):
Figure imgf000198_0001
(a) (b)
wherein:
A comprises a heteromonocyclic ring containing 5 to 6 ring member atoms or a fused heteropolycyclic ring system containing 8 to 14 ring member atoms, wherein each ring contains 5 to 7 ring member atoms, X1 is a ring member carbon atom and each ring member atom other than X1 is a carbon atom or a heteroatom, with the proviso that (i) at least one ring member atom is a heteroatom and (ii) when A is a heteromonocyclic radical containing 5 ring member atoms, no more than two of the ring member atoms comprising A are heteroatoms; n is 0, 1, 2 or 3;
X1 is =C- or -CH-; X2 is a bond or a divalent group of Formula (a) or (b):
Figure imgf000198_0002
(a) (b)
wherein:
X3 and X4 independently are -C(O)- or -CH2S(0)2-; R9 and R10 independently are hydrogen, (C,.6)alkyl or as defined below; Ru at each occurrence independently is hydrogen or (C,.6)alkyl; R12 and R13 independently are (i) (C^alkyl optionally substituted with cyano, halo, nitro, -NR14R14, -NR14C(0)OR14, -NR,4C(0)NR14R14, -NR14C(NR14)NR14R14, -OR14, -SR14, -C(0)OR14, -C(O)NR14R14, -S(0)2NR14R14, -P(O)(OR14)OR14, -OP(0)(OR1 )OR14, -NR14C(O)R15, -S(O)R15, -S(0)2R15, -C(0)R15, -OR16, -SR16, -S(O)R16, -S(0)2R16, -C(O)R16, -C(O)OR16, -OC(O)R16, -NR16R17, -NR17C(0)R16,
-NR17C(0)OR16, -C(0)NR16R17, -S(0)2NR16R17, -NR17C(0)NR16R17 or -NR17C(NRI7)NR16R17, wherein R14 at each occurrence independently is hydrogen, (C,.6)alkyl or halo-substituted (C,.3)alkyl, R15 (C,.6)alkyl or halo-substituted (C,.3)alkyl, R16 is (C3.12)cycloalkyl(C0.6)alkyl, hetero(C3.12)cycloalkyl(C0.6)alkyl, (C6.12)aryl(C0.6)alkyl, hetero(C5.12)aryl(C0.6)alkyl, (C9.12)polycycloaryl(C0.6)alkyl or hetero(C8.12)polycycloaryl(C0.6)alkyl and R17 is hydrogen or (C^alkyl, and wherein within R16 said cycloalkyl, heterocycloalkyl, aryl, heteroaryl, polycycloaryl or heteφolycycloaryl ring optionally is substituted by a group selected from -R18, -X5OR18, -X5SR18, -X5S(O)R18, -X5S(O)2R18, -X5C(O)R18, -X5C(0)OR18, -X5OC(O)R18, -X5NR18R19, -X5NR19C(0)R18, -X5NR19C(O)OR18, -X5C(0)NR18R19,
-X5S(O)2NR18R19, -X5NR19C(O)NR18R19 or -X5NR19C(NR19)NR18R19, wherein X5 is a bond or (C,.6)alkylene, R18 is hydrogen or (C,_6)alkyl and R19 is (C3.12)cycloalkyl(C0.6)alkyl, hetero(C3.12)cycloalkyl(C0.6)alkyl, (C6.12)aryl(C0.6)alkyl, hetero(C5.12)aryl(C0.6)alkyl, (C9.12)polycycloaryl(C0.6)alkyl or hetero(C8.12)polycycloaryl(C0.6)alkyl, or (ii) a group selected from
(C3.12)cycloalkyl(C0.6)alkyl, hetero(C3.12)cycloalkyl(C0.6)alkyl, (C6.12)aryl(C0.6)alkyl, hetero(C5.12)aryl(C0.6)alkyl, (C9.ι2)polycycloaryl(C0.6)alkyl and hetero(C8.12)polycycloaryl(C0.6)alkyl, wherein said cycloalkyl, heterocycloalkyl, aryl, heteroaryl, polycycloaryl or heteφolycycloaryl ring optionally is substituted by a group selected from -R18, -XOR18, -X5SR18, -X5S(O)R18, -X5S(0)2R18, -X5C(O)R18,
-X5C(O)OR18, -X5OC(0)R18, -X5NR18R19, -X5NR19C(0)R18, -X5NR19C(O)OR18, -X5C(O)NR18R19, -X5S(0)2NR18R19, -X5NR19C(O)NR18R19 or -X5NR19C(NR19)NR18R19, wherein X5, R18 and R19 are as defined above; wherein within R12 and/or R13 any alicyclic or aromatic ring system present may be substituted further by 1 to 5 radicals independently selected from (C,.6)alkyl, (C,_6)alkylidene, cyano, halo, halo-substituted (CM)alkyl, nitro, -X5NR,4R14, -X5NR14C(O)OR14, -X5NR14C(O)NR14R14, -X5NR14C(NR14)NR1 R14, -X5OR14, -X5SR14, -X5C(0)OR14, -X5C(O)NR14R14, -X5S(0)2NR14R14, -X5P(0)(OR14)OR14, -X5OP(0)(OR14)OR14, -X5NR14C(O)R15, -X5S(0)R15, -X5S(O)2R15 and -X5C(0)R15, wherein X5, R14 and R15 are as defined above; or
R12 together with R9 and/or R13 together with R10 form trimethylene, tetramethylene or phenylene- 1 ,2-dirnethylene, , optionally substituted with 1 to 3 radicals independently selected from (C,.6)alkyl, (C].6)alkylidene, cyano, halo, halo-substituted (C,.4)alkyl, nitro, oxo, -X5NR14C(0)OR14, -X5NR14C(0)NR14R14, -X5NR14C(NR14)NR14R14, -X5OR14, -X5SR14, -X5C(0)OR14, -X5C(O)NR14R14, -X5S(0)2NR14R14, -X5P(0)(OR14)OR14, -X5OP(0)(OR14)OR14, -X5NR14C(0)R15, -X5S(O)R15, -X5S(0)2R15 and -X5C(0)R15, wherein X5, R14 and R15 are as defined above; and
R1 is -X6X7R20, wherein X6 is -C(O)-, -C(O)C(0)- or -S(0)2-, X7 is a bond, -O- or -NR21-, wherein R21 is hydrogen or (C[.6)alkyl, and R20 is (i) (C,.6)alkyl optionally substituted by cyano, halo, nitro, -NR14R14, -NR14C(O)OR14, -NR14C(O)NR14R14, -NR14C(NR14)NR14R14, -OR14, -SR14, -C(0)OR'4, -C(0)NR14R14, -S(O)2NR14R14, -P(0)(OR14)OR14,
-OP(O)(OR14)OR14, -NR14C(0)R15, -S(O)R15, -S(O)2R15, -C(O)R15, -OR22, -SR22, -S(0)R22, -S(O)2R22, -C(O)R22, -C(O)OR22, -C(O)NR22R23, -NR22R23, -NR23C(O)R22, -NR23C(0)OR22, -NR23C(O)NR22R23 or -NR23C(NR23)NR22R23, wherein R14 and R15 are as defined above, R22 is (C3.,2)cycloalkyl(C0.6)alkyl, hetero(C3.12)cycloalkyl(C0.6)alkyl, (C6.12)aryl(C0.6)alkyl, hetero(C5.12)aryl(C0.6)alkyl, (C9.I2)bicycloaryl(C0.6)alkyl or hetero(C8.12)bicycloaryl(C0.6)alkyl and R23 at each occurrence independently is hydrogen or (C,.6)alkyl, or (ii) (C3.12)cycloalkyl(C0.6)alkyl, hetero(C3.I2)cycloalkyl(C0.6)alkyl, (C6.12)aryl(C0.6)alkyl, diphenyl(C0.6)alkyl, hetero(C5.12)aryl(C0.6)alkyl, dihetero(C5..6)aryl(C0_6)alkyl, (C9.12)bicycloaryl(C0.6)alkyl or hetero(C8.12)bicycloaryl(C0.6)alkyl wherein said cycloalkyl, heterocycloalkyl, aryl or heteroaryl may be substituted by -R24, -X5OR24, -X5SR24, -X5S(0)R24, -X5S(O)2R24, -X5C(O)R24, -X5C(0)OR24, -X5C(O)NR24R25, -X^R^R25, -X5NR25C(0)R24, -X5NR25C(O)OR24, -X5NR25C(0)NR24R25 or -X5NR25C(NR25)NR2 R25, wherein X5 is as defined above, R24 is (C3.12)cycloalkyl(C0.6)alkyl, hetero(C3.12)cycloalkyl(C0.6)alkyl, (C6.12)aryl(C0.6)alkyl, hetero(C5.12)aryl(C0.6)alkyl, (C9.12)bicycloaryl(C0.6)alkyl or hetero(C8.12)bicycloaryl(C0.6)alkyl and R25 at each occurrence independently is hydrogen or (C,.6)alkyl; wherein within R1 any alicyclic or aromatic ring system present may be substituted further by 1 to 5 radicals independently selected from ( _6)alkyl, (C,.6)alkylidene, cyano, halo, halo-substituted (CM)alkyl, nitro, -X5NR14R14, -X5NR14C(0)OR14, -X5NR14C(O)NR14R14, -X5NR14C(NRI4)NR14R14, -X5OR14, -X5SR14, -X5C(0)OR14, -X5C(0)NR14R14, -X5S(O)2NR14R14, -X5P(0)(OR14)OR14, -X5OP(O)(OR14)OR14, -X5NR14C(O)R15, -X5S(0)R15, -X5S(O)2R15 and -X5C(0)R15, wherein X5, R14 and R15 are as defined above; or when X2 is a divalent group of formula (a) or (b) then R1 may also represent hydrogen, carboxy, oxalo or carbamoyl;
R2 is hydrogen or (C1.6)alkyl;
R3 is (i) (C^alkyl optionally substituted with cyano, halo, nitro, -SR24, -C(0)OR24, -C(O)NR24R24, -P(0)(OR24)OR24, -OP(O)(OR24)OR24, -S(0)R25, -S(0)2R25 or -C(O)R25, wherein R24 at each occurrence independently is hydrogen, (C^alkyl or halo-substituted
(C,.3)alkyl and R25 (C,.6)alkyl or halo-substituted (C,.3)alkyl, or (ii) (C5.6)cycloalkyl(C2.3)alkyl, hetero(C3.6)cycloalkyl(C2.3)alkyl, (C6.,2)aryl(C2.3)alkyl or hetero(C5_6)aryl(C2.3)alkyl, wherein said cycloalkyl, heterocycloalkyl, aryl or heteroaryl optionally is substituted further with 1 to 5 radicals independently selected from (C^alkyl, (C,.6)alkylidene, cyano, halo, halo-substituted (CM)alkyl, nitro, -X5NR14C(0)OR14, -X5NR1 C(O)NR14R14, -X5NR14C(NR14)NR14R14,
-XOR14, -X5SR14, -X5C(O)OR14, -X5C(O)NR14R14, -X5S(0)2NR14R14, -X5P(O)(OR14)OR14, -X5OP(O)(OR14)OR14, -X5NR14C(O)R15, -X5S(O)R15, -X5S(0)2R15 and -X5C(O)R15, wherein X5, R14 and R15 are as defined above, provided that when R3 is unsubstituted (Cj.^alkyl and R4 is hydrogen or unsubstituted (C].5)alkyl, then X2 may not represent (i) a bond when R1 is -C(O)R20, -C(O)2R20 or -S(0)2R20 in which R20 is (C,.6)al kyl, phenyK alkyl, phenyl, (C3.
7)cycloalkyl, camphan-10-yl, naphth-1-yl, naphth-2-yl, phenyl substituted by one or more of (C,. 4)alkyl, perfluoro(C,.4)alkyl, (C,.4)alkoxy, hydroxy, halo, amido, nitro, amino, (C,.4)alkylamino, (Cj.4)dialkylamino, carboxy or (C,.4)alkoxycarbonyl, or naphth-1-yl or naphth-2-yl substituted by one or more of (C,.4)alkyl, perfluoro(C1.4)alkyl, (CM)alkoxy, hydroxy, halo, amido, nitro, amino, carboxy or (C,.4)alkoxycarbonyl or (ii) a divalent group of formula (a) or (b) in which the moiety R12 is methyl, isopropyl, n-butyl, sec-butyl, tert-butyl, 1-methylpropyl, benzyl, naphth-1-ylmethyl, naphth-2-ylmethyl, thien-2-ylmethyl, thien-3-ylmethyl, or wherein R9 and R12 form ethylene, trimethylene, hydroxy-substituted trimethylene, tetramethylene or phenylene- 1,2-dimethylene; or R3 and R4 taken together with the carbon atom to which both R3 and R4 are attached form (C3.8)cycloalkylene or (C3.8)heterocycloalkylene, wherein said cycloalkylene or heterocycloalkylene is optionally substituted with 1 to 3 radicals independently selected from (C,.6)alkyl, (C,.6)alkylidene, cyano, halo, halo-substituted (C,.4)alkyl, nitro, -X5NR14C(0)OR14, -X5NR14C(O)NR14R14, -X5NR14C(NR14)NR14R14, -X5OR14, -X5SR14, -X5C(O)OR14, -X5C(O)NR14R14, -X5S(O)2NR14R14, -X5P(0)(OR14)OR14, -X5OP(0)(OR14)OR14, -X5NR14C(O)R15, -X5S(O)R15, -X5S(O)2R15 and -X5C(0)R15, wherein X5, R14 and R15 are as defined above; R4 is hydrogen, (C,.6)alkyl or as defined above;
R5 is hydrogen and R6 is hydroxy or R5 and R6 together form oxo; R7 is a group selected from cyano, halo, nitro, -R29, -X5NR29R30, -X5NR30C(O)OR29, -X5NR30C(O)NR29R30, -X5NR30C(NR30)NR29R30, -X5OR29, -X5SR29, -X5C(O)OR29, -X5C(0)NR29R30, -X5S(O)2NR29R30, -X5P(O)(OR30)OR29, -X5OP(0)(OR29)OR29, -X5NR30C(O)R20, -X5S(O)R20, -X5S(0)2R20, -X5C(0)R20 and -C(0)NR42CHR43C(O)OR29, wherein X5 and R20 are as defined as above, R29 is hydrogen or -R20, wherein R20 is defined as above, R30 at each occurrence is hydrogen or (C]_6)alkyl, R42 is hydrogen, (C,.6)alkyl or together with R43 forms trimethylene, tetramethylene or phenylene- 1,2-dimethylene, optionally substituted with hydroxy or oxo, and R43 is as defined above or is (i) (C].6)alkyl optionally substituted with cyano, halo, nitro, -NR14R14, -NR14C(O)OR14, -NR14C(0)NR14R14, -NR14C(NR14)NR14R14, -OR14, -SR14, -C(O)OR14, -C(O)NR14R14, -S(O)2NR14R14, -P(0)(OR14)OR14, -OP(O)(OR14)OR14, -NR14C(O)R15, -S(O)R15, -S(0)2R15, -C(O)R15, -OR16, -SR16, -S(0)R16, -S(O)2R16, -C(O)R16, -C(O)OR16, -OC(O)R16, -NR16R17, -NR17C(0)R16, -NR,7C(O)OR16, -C(O)NR16R17, -S(O)2NR16R17, -NR17C(0)NR16R17 or -NR17C(NR17)NR16R17 or (ii) a group selected from (C3.12)cycloalkyl(C0.6)alkyl, hetero(C3.12)cycloalkyl(C0.6)alkyl,
(C6.12)aryl(C0.6)alkyl, hetero(C5.12)aryl(C0.6)alkyl, (C9.12)polycycloaryl(C0_6)alkyl and hetero(C8.12)polycycloaryl(C0.6)alkyl, wherein said cycloalkyl, heterocycloalkyl, aryl, heteroaryl, polycycloaryl or heteφolycycloaryl ring optionally is substituted by a group selected from -R18, -X5OR18, -X5SR18, -X5S(O)R!8, -X5S(O)2R18, -X5C(0)R18, -X5C(O)OR18, -X5OC(O)R18, -X5NR18R19, -X5NR19C(O)R18, -X5NR19C(O)OR18, -X5C(0)NR18R19, -X5S(O)2NR18R19,
-X5NR19C(O)NR18R19 or -X5NR19C(NR19)NR18R19, wherein X5, R14, R15, R16, R17, R18 and R19 are as defined above; wherein within R7 any alicyclic or aromatic ring system present may be substituted further by 1 to 5 radicals independently selected from (C^alkyl, (C^alkylidene, cyano, halo, halo-substituted (C,.4)alkyl, nitro, -X5NRI4R14, -X5NR14C(O)OR14, -X5NR14C(0)NR14R14, -X5NR,4C(NR14)NR14R14, -X5OR14, -X5SR14, -X5C(O)OR14, -X5C(O)NRl4R14, -X5S(O)2NR14R14, -X5P(0)(OR14)OR14, -X5OP(O)(OR14)OR14, -X5NR14C(O)R15, -X5S(O)R15, -X5S(0)2R15 and -X5C(0)R15, wherein X5, R14 and R15 are as defined above; and
R8 at each occurrence independently is selected from (C,.6)alkyl, halo-substituted (C,.4)alkyl, (C,.6)alkylidene, cyano, halo, halo-substituted (C,.4)alkyl, nitro, -X5NR14R14, -X5NR14C(0)OR14, -X5NR14C(O)NR14R14, -X5NR14C(NR14)NR14R14, -X5OR14, -X5SR14, -X5C(0)OR14, -X5C(O)NR14R14, -X5S(O)2NR14R14, -X5P(0)(OR14)OR14,
-X5OP(0)(OR14)OR14, -X5NR14C(O)R15, -X5S(O)R15, -X5S(O)2R15 and -X5C(0)R15, wherein X5 is a bond or ( . alkylene, R14 at each occurrence independently is hydrogen, (C,.6)alkyl or halo-substituted ( .^alkyl and R15 (C,.6)alkyl or halo-substituted (C,.3)alkyl; and the TV-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers; and the pharmaceutically acceptable salts thereof.
40. The compound of Claim 39 in which:
A is selected from thien-2-yl, oxazol-2-yl, 4,5-dihydrooxazol-2-yl, fur-2-yl, lH-indol-5-yl, pyrid-2-yl, pyrid-3-yl, thiazol-2-yl, l-methyl-lH-imidazol-2-yl, 1 -benzyl- lH-imidazol-2-yl, benzooxazol-2-yl, benzofur-2-yl, benzothiazol-2-yl, lH-benzoimidazol-2-yl, l,l-dioxo-lH-lλ6-benzo[b]thien-2-yl, quinol-3-yl, [l,3]dioxolan-2-yl, naphtho[2,3--b|oxazol-2-yl, naphtho[l,2--/]oxazol-2-yl and naphtho[2,l-(floxazol-2-yl, each substituted by a group R7 and optionally substituted with a group R8, wherein R7 is halo, nitro, -R29, -OR29, -C(0)R20, -C(O)OR29, -S(0)2NR29R30, -C(O)NR29R30 or -C(O)NΗCΗR43C(0)OR29, wherein R20 is (C,.6)alkyl, (C3.12)cycloalkyl(C0.6)alkyl, hetero(C3.12)cycloalkyl(C0.6)alkyl, (C6.12)aryl(C0.6)alkyl, diphenyl(C0.6)alkyl, hetero(C5.12)aryl(C0.6)alkyl or hetero(C8.12)polycycloaryl(C0.6)alkyl and R29 is hydrogen or -R20, wherein R20 is defined as above, wherein said heterocycloalkyl may be substituted with (C6.12)aryl(C0.3)alkyl, R30 at each occurrence is hydrogen or (C^alkyl and R43 is (Cμ6)alkyl, and R8 at each occurrence independently is hydrogen, (C,.6)alkyl or halo-substituted (C,.4)alkyl; wherein within R7 any alicyclic or aromatic ring system present may be substituted further by 1 to 5 radicals independently selected from (C,.6)alkyl, (C,.6)alkylidene, cyano, halo, halo-substituted (C,.4)alkyl, nitro, -X5NR14R14, -X5NR14C(O)OR14, -X5NR14C(O)NR,4R14, -X5NR14C(NR14)NR14R14, -X5OR14, -X5SR14, -X5C(O)OR14, -X5C(O)NR14R'4, -X5S(O)2NR14R14, -X5P(O)(OR14)OR14, -X5OP(0)(OR14)OR'4, -X5NR14C(O)R15, -X5S(O)R15, -X5S(O)2R15 and -X5C(0)R15, wherein X5 is a bond or (C,.6)alkylene, R14 at each occurrence independently is hydrogen, (C,.6)alkyl or halo-substituted (C,.3)alkyl and R15 (C,.6)alkyl or halo-substituted (C^alkyl; X2 is a bond or a divalent group of Formula (a) or (b), wherein within Formula (a) X3 is -C(O)-, R9 is hydrogen, R11 is hydrogen or methyl, and R12 is (C,.6)alkyl;
R1 is hydrogen or -X6X7R20, wherein X6 is -C(O)- or -S(O)2-, X7 is a bond or -O- and R20 is (C,.6)alkyl, (C3.12)cycloalkyl(C0.6)alkyl, hetero(C3.12)cycloalkyl(C0.6)alkyl, (C6.12)aryl(C0.6)alkyl or hetero(C5.12)aryl(C0.6)alkyl; wherein within R1 any alicyclic or aromatic ring system present may be substituted further by 1 to 5 radicals independently selected from (C^alkyl, -C(0)OR14, -X5NR14R14 and -X5NR14C(O)OR14, wherein X5 is a bond or (C].6)alkylene, R14 at each occurrence independently is hydrogen, (C,.6)alkyl or halo-substituted (C,.3)alkyl and R15 (C,.6)alkyl or halo-substituted (C,.3)alkyl; R2 is hydrogen;
R3 is (C,.6)alkyl or (C6.10)aryl(C,.3)alkyl or R3 and R4 taken together form straight, saturated (C2.5)alkylene;
R4 is hydrogen or (C,.6)alkyl or as defined above; and
R5 and R6 preferably together form oxo; and the TV-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers; and the pharmaceutically acceptable salts thereof.
41. The compound of Claim 40 in which:
A oxazol-2-yl, 4,5-dihydrooxazol-2-yl, benzooxazol-2-yl, naphtho[2,3-cT|oxazol-2-yl, naphtho[l,2-cT|oxazol-2-yl or naphtho[2,l- ]oxazol-2-yl, each substituted by a group R7 and optionally substituted with a group R8, wherein R7 is halo, -R29, -C(O)R20, -C(O)OR29, -C(O)NR29R30 or -S(0)2NR29R30, wherein R20 is (C,.6)alkyl, (C3.12)cycloalkyl(C0.6)alkyl, (C6.12)aryl(C0.6)alkyl, hetero(C5.12)aryl(C0.6)alkyl or hetero(C8.12)polycycloaryl(C0.6)alkyl;
X2 is a divalent group of Formula (a), wherein within Formula (a) X3 is -C(O)-, R9 and Ru each are hydrogen and R12 is isobutyl, sec-butyl or isopropyl; R1 is select freom acetyl, benzoyl, benzyloxycarbonyl, benzylsulfonyl, bicyclo[2.2.2]hept-2-ylcarbonyl, tert-butoxycarbonyl, tert-butyryl,
4-tert-butoxycarbonylpiperazin- 1 -ylcarbonyl, 1 -tert-butoxycarbonylpiperidin-4-ylcarbonyl, 2-cyclohexylacetyl, 4-cyclohexylbutyryl, 2-cyclohexylethylsulfonyl, 3-cyclohexylpropionyl, 2-cyclopentylethylsulfonyl, hydrogen, 4-methylpiperazin-l -ylcarbonyl, methylsulfonyl, 4-methylvaleryl, 3-moφholin-4-ylpropionyl, naphth-2-ylmethyl, 3-phenylpropionyl, piperazin-1 -ylcarbonyl, piperidin-4-ylcarbonyl and pyrid-3-ylcarbonyl, wherein within R1 any alicyclic or aromatic ring system present may be substituted further by 1 to 3 radicals independently selected from 3-aminomethyl and 3-tert-butoxycarbonylaminomethyl; R3 is phenethyl or R3 and R4 taken together form ethylene; and R4 is hydrogen or methyl or as defined above; and the TV-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers; and the pharmaceutically acceptable salts thereof.
42. The compound of Claim 41 in which
A is selected from oxazol-2-yl, 4,5-dihydrooxazol-2-yl, benzooxazol-2-yl or naphtho[l,2-J]oxazol-2-yl, each substituted by a group R7 and optionally substituted with a group R8, particularly wherein R7 is adamantan-1-ylmethylcarbamoyl, benzyl, benzylcarbamoyl, benzyl(methyl)carbamoyl, l-benzyloxycarbonyl-3-methylbutylcarbamoyl, 4-benzylpiperidin-l -carbonyl, tert-butyl, chloro, 2,3-dihydroindol-l -ylcarbonyl, 3,4-dihydro- lH-isoquinol-2-ylcarbonyl, 3,4-dihydro- lH-quinol- 1 -ylcarbonyl, diphenylme thy lcarbamoyl, fur-2-ylmethylcarbamoyl, hydrogen, 2-(lH-indol-3-yl)ethylcarbamoyl, methoxy, methoxycarbonyl, methyl, 3-methylbuty lcarbamoyl, methylcarbamoyl, 1-methylethylcarbamoyl, naphth-1-ylmethylcarbonyl, nitro, phenyl, phenylcarbamoyl, 2-phenylcyclopropy lcarbamoyl, 1-phenylethy lcarbamoyl, sulfamoyl, trifluoromethyl, phenethy lcarbamoyl, 3-phenylpropylcarbamoyl, piperid- 1 -ylcarbonyl, pyrid-2-ylmethylcarbamoyl, pyrid-3-ylmethylcarbamoyl, pyrid-4-ylmethylcarbamoyl and pyrrolidin-1 -ylcarbonyl and R8 is methyl
X2 is a divalent group of Formula (a), wherein within Formula R12 is isopropyl;
R3 is phenethyl; and
R4 is hydrogen; and the TV-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers; and the pharmaceutically acceptable salts thereof.
43. A pharmaceutical composition comprising a therapeutically effective amount of a compound of Claim 39 in combination with one or more pharmaceutically acceptable excipient(s).
44. The composition of Claim 43 which further comprises one or more active ingredient(s) selected from the group consisting of (i) a therapeutically effective amount of a bisphosphonic acid or acid ester thereof or a pharmaceutically acceptable salt thereof and (ii) a therapeutically effective amount of an estrogen receptor agonist or a pharmaceutically acceptable salt thereof.
45. The composition of Claim 44 wherein the bisphosphonic acid is selected from the group consisting of 1 , 1 -dichloromethylene- 1 , 1 -diphosphonic acid, 1 -hydroxy-
3-pyrrolidin-l -ylpropylidene- 1,1 -bisphosphonic acid, 1 -hydroxyethylidene- 1,1 -diphosphonic acid, 1 -hydroxy-3-(TV-methyl-TV-pentylamino)propylidene- 1 , 1 -bisphosphonic acid, 6-amino- 1 -hydroxyhexylidene- 1 , 1 -bisphosphonic acid, 3-(dimethylamino)- 1 -hydroxypropylidene- 1,1 -bisphosphonic acid, 3-amino-l-hydroxypropyli dene- 1,1 -bisphosphonic acid, 2-pyrid-2-ylethylidene- 1 , 1 -bisphosphonic acid, 1 -hydroxy-2-pyrid-3-ylethylidene- 1,1- bisphosphonic acid, 4-chlorophenylthiomethylenebisphosphonic acid and 1-hydroxy- 2-(lH-imidazol-l-yl)ethylidene-l,l-bisphosphonic acid or acid ester thereof or a pharmaceutically acceptable salt thereof.
46. The composition of Claim 45 wherein the bisphosphonic acid is 1,1 -dichloromethylene- 1 , 1 -diphosphonic acid or a pharmaceutically acceptable salt thereof.
47. The composition of Claim 46 which comprises 1,1-dichloromethylene- 1,1-diphosphonate monosodium trihydrate.
48. A method of treating a disease in an animal in which cysteine protease activity contributes to the pathology and/or symptomatology of the disease, which method comprises administering to the animal a therapeutically effective amount of compound of Formula I:
Figure imgf000206_0001
I in which:
A comprises a heteromonocyclic ring containing 5 to 6 ring member atoms or a fused heteropolycyclic ring system containing 8 to 14 ring member atoms, wherein each ring contains 5 to 7 ring member atoms, X1 is a ring member carbon atom and each ring member atom other than X1 is a carbon atom or a heteroatom, with the proviso that (i) at least one ring member atom is a heteroatom and (ii) when A is a heteromonocyclic radical containing 5 ring member atoms, no more than two of the ring member atoms comprising A are heteroatoms; n is 0, 1, 2 or 3;
X1 is =C- or -CH-;
X2 is a bond or a divalent group of Formula (a) or (b):
Figure imgf000207_0001
(a) (b)
wherein:
X3 and X4 independently are -C(O)- or -CH2S(O)2- R9 and R10 independently are hydrogen, (C,.6)alkyl or as defined below; R11 at each occurrence independently is hydrogen or (C,.6)alkyl; R12 and R13 independently are (i) (C,.6)alkyl optionally substituted with cyano, halo, nitro, -NR14R14, -NR14C(0)OR14, -NR14C(O)NR14R'4, -NR14C(NR1 )NR14R14,
-OR14, -SR14, -C(O)OR14, -C(O)NR14R14, -S(O)2NR14R14, -P(0)(OR14)OR14, -OP(0)(OR14)OR14, -NR14C(O)R15, -S(O)R15, -S(0)2R15, -C(0)R15, -OR16, -SR16, -S(0)R16, -S(O)2R16, -C(O)R16, -C(0)OR16, -OC(O)R16, -NR16R17, -NR17C(0)R16, -NR17C(O)OR16, -C(O)NR16R17, -S(O)2NR16R17, -NR17C(O)NR16R17 or -NR17C(NR17)NR16R17, wherein R14 at each occurrence independently is hydrogen,
(C,.6)alkyl or halo-substituted ( .^alkyl, R15 (C^alkyl or halo-substituted (C,.3)alkyl, R16 is (C3.12)cycloalkyl(C0.6)alkyl, hetero(C3.I2)cycloalkyl(C0.6)alkyl, (C6.12)aryl(C0.6)alkyl, hetero(C5.12)aryl(C0.6)alkyl, (C9.12)polycycloaryl(C0.6)alkyl or hetero(C8.12)polycycloaryl(C0.6)alkyl and R17 is hydrogen or (C,.6)alkyl, and wherein within R16 said cycloalkyl, heterocycloalkyl, aryl, heteroaryl, polycycloaryl or heteφolycycloaryl ring optionally is substituted by a group selected from -R18, -X5OR18, -X5SR18, -X5S(O)R18, -X5S(0)2R18, -X5C(0)R18, -X5C(0)OR18, -X5OC(0)R18, -X5NR18R19, -X5NR19C(O)R18, -X5NR19C(0)OR18, -X5C(0)NR18R19, -X5S(O)2NR18R19, -X5NR19C(0)NR18R19 or -X5NR19C(NR19)NR18R19, wherein X5 is a bond or (C ^alkylene, R18 is hydrogen or (C,.6)alkyl and R19 is (C3.12)cycloalkyl(C0.6)alkyl, hetero(C3.)2)cycloalkyl(C0.6)alkyl, (C6.12)aryl(C0.6)alkyl, hetero(C5.12)aryl(C0.6)alkyl, (C9.12)polycycloaryl(C0.6)alkyl or hetero(C8.12)polycycloaryl(C0.6)alkyl, or (ii) a group selected from (C3.12)cycloalkyl(C0.6)alkyl, hetero(C3.12)cycloalkyl(C0.6)alkyl, (C6.12)aryl(C0.6)alkyl, hetero(C5.I2)aryl(C0.6)alkyl, (C9.12)polycycloaryl(C0.6)alkyl and hetero(C8.12)polycycloaryl(C0.6)alkyl, wherein said cycloalkyl, heterocycloalkyl, aryl, heteroaryl, polycycloaryl or heteφolycycloaryl ring optionally is substituted by a group selected from -R18, -X5OR18, -X5SR18, -X5S(0)R18, -X5S(0)2R18, -X5C(0)R18, -X5C(0)OR18, -X5OC(0)R18, -X5NR18R19, -X5NR19C(0)R18, -X5NR19C(0)OR18, -X5C(0)NR18R19, -X5S(0)2NR18R19, -X5NR19C(O)NR18R19 or -X5NR19C(NR19)NR18R19, wherein X5, R18 and R19 are as defined above; wherein within R12 and/or R13 any alicyclic or aromatic ring system present may be substituted further by 1 to 5 radicals independently selected from ( .6)alkyl, (C,.6)alkylidene, cyano, halo, halo-substituted ( -Jalkyl, nitro, -X6NR14R14, -X6NR14C(0)OR14, -X6NR14C(O)NR14R14, -X6NR14C(NR14)NR14R14, -X6OR14, -X6SR14, -X6C(0)OR14, -X6C(O)NR14R14, -X6S(O)2NR14R14, -X6P(0)(OR14)OR14, -X6OP(0)(OR14)OR14, -X6NR14C(O)R15, -X6S(0)R15, -X6S(0)2R15 and -X6C(O)R15, wherein X6 is a bond or
(C,.6)alkylene and R14 and R15 are as defined above; or
R12 together with R9 and/or R13 together with R10 form trimethylene, tetramethylene or phenylene- 1,2-dimethylene, optionally substituted with hydroxy or oxo; and R1 is -X7X8R20, wherein X7 is -C(O)-, -C(O)C(0)- or -S(0)2-, X8 is a bond, -O- or
-NR21-, wherein R21 is hydrogen or (C, .6)alkyl, and R20 is (i) (C,.6)alkyl optionally substituted by cyano, halo, nitro, -NR14R14, -NR14C(O)OR14, -NR14C(0)NR14R14, -NR14C(NR1 )NR14R14, -OR14, -SR14, -C(O)OR14, -C(O)NR14R14, -S(0)2NR14R14, -P(O)(OR14)OR14, -OP(O)(OR14)OR14, -NR14C(O)R15, -S(0)R15, -S(O)2R15, -C(O)R15, -OR22, -SR22, -S(0)R22, -S(O)2R22, -C(O)R22, -C(O)OR22, -C(0)NR22R23, -NR22R23, -NR23C(0)R22,
-NR23C(0)OR22,-NR23C(O)NR22R23 or -NR23C(NR23)NR22R23, wherein R14 and R15 are as defined above, R22 is (C3.I2)cycloalkyl(C0.6)alkyl, hetero(C3.12)cycloalkyl(C0.6)alkyl, (C6.12)aryl(C0.6)alkyl, hetero(C5.12)aryl(C0.6)alkyl, (C9.12)bicycloaryl(C0.6)alkyl or hetero(C8.12)bicycloaryl(C0.6)alkyl and R23 at each occurrence independently is hydrogen or ( .^alkyl, or (ii) (C3.12)cycloalkyl(C0.6)alkyl, hetero(C3.ι2)cycloalkyl(C0.6)alkyl, (C6.I2)aryl(C0.6)alkyl, diphenyl(C0.6)alkyl, hetero(C5.12)aryl(C0.6)alkyl, dihetero(C5.6)aryl(C0.6)alkyl, (C9.,2)bicycloaryl(C0.6)alkyl or hetero(Cs.12)bicycloaryl(C0.6)alkyl wherein said cycloalkyl, heterocycloalkyl, aryl or heteroaryl may be substituted by -X9OR24, -X9SR24, -X9S(O)R24, -X9S(O)2R24, -X9C(O)R24, -X9C(O)OR24, -X9C(O)NR24R25, -X9NR24R25, -X9NR25C(O)R24, -X9NR25C(O)OR24, -X9NR25C(O)NR24R25 or -X9NR25C(NR25)NR24R25, wherein X9 is a bond or (C,.6)alkylene, R24 is (C3.12)cycloalkyl(C0.6)alkyl, hetero(C3.12)cycloalkyl(C0.6)alkyl, (C6.12)aryl(C0.6)alkyl, hetero(C5.12)aryl(C0.6)alkyl, (C9.12)bicycloaryl(C0.6)alkyl or hetero(C8_12)bicycloaryl(C0„6)alkyl and R25 at each occurrence independently is hydrogen or (C^alkyl; wherein within R1 any alicyclic or aromatic ring system present may be substituted further by 1 to 5 radicals independently selected from (C,.6)alkyl, (Cι.6)alkylidene, cyano, halo, halo-substituted (C,.4)alkyl, nitro, -X6NR14R14, -X6NR14C(O)OR14, -X6NR14C(O)NR14R14,
-X6NR14C(NR14)NR14R14, -X6OR14, -X6SR14, -X6C(O)OR14, -X6C(0)NR14R14, -X6S(O)2NR14R14, -X6P(O)(OR14)OR14, -X6OP(O)(OR14)OR14, -X6NR14C(0)R15, -X6S(O)R15, -X6S(O)2R15 and -X6C(O)R15, wherein X6 is a bond or (C,.6)alkylene and R14 and R15 are as defined above; or when X2 is a divalent group of formula (a) or (b) then R1 may also represent hydrogen, carboxy, oxalo or carbamoyl; R2 is hydrogen or (C].6)alkyl;
R3 is (i) ( Jalkyl optionally substituted with cyano, halo, nitro, -SR24, -C(0)OR24, -C(O)NR24R24, -P(O)(OR24)OR24, -OP(O)(OR24)OR24, -S(O)R25, -S(O)2R25 or -C(0)R25, wherein R24 at each occurrence independently is hydrogen, (C^alkyl or halo-substituted (C,.3)alkyl and R25 (C,.6)alkyl or halo-substituted (C].3)alkyl, or (ii) (C5.6)cycloalkyl(C2.3)alkyl, hetero(C3.6)cycloalkyl(C2.3)alkyl, (C6.12)aryl(C2.3)alkyl or hetero(C5.6)aryl(C2.3)alkyl, wherein said cycloalkyl, heterocycloalkyl, aryl or heteroaryl optionally is substituted further with 1 to 5 radicals independently selected from (C,.6)alkyl, (Cι.6)alkylidene, cyano, halo, halo-substituted (C^alkyl, nitro, -X6NR14C(O)OR14, -X6NR14C(O)NR14R14, -X6NR14C(NRI4)NR14R14, -X6OR14, -X6SR14, -X6C(O)OR14, -X6C(O)NR1 R14, -X6S(O)2NR14R14, -X6P(0)(OR14)OR14, -X6OP(0)(OR14)OR14, -X6NR14C(0)R15, -X6S(O)R15, -X6S(O)2R15 and -X6C(O)R15, wherein X6, R14 and R15 are as defined above, or R3 and R4 taken together form straight, saturated (C2.5)alkylene, wherein within said alkylene any one to two carbon atoms optionally is replaced by a heteroatom selected from -0-, -S- or -NR28- wherein R28 is hydrogen or (C,.6)alkyl;
R4 is hydrogen, (C].6)alkyl or as defined above; R5 is hydrogen and R6 is hydroxy or R5 and R6 together form oxo;
R7 is a group selected from cyano, halo, nitro, -R29, -X10NR29R30, -X10NR30C(O)OR29, -X10NR30C(O)NR29R30, -X10NR30C(NR30)NR29R30, -X10OR29, -X10SR29, -X10C(O)OR29, -X10C(O)NR29R30, -X10S(O)2NR29R30, -X10P(O)(OR30)OR29, -X10OP(O)(OR29)OR29, -X10NR30C(O)R20, -X10S(O)R20, -X10S(O)2R20, -X10C(O)R20 and -C(0)NR42CHR43C(0)OR29, wherein X10 is a bond or (Cμ6)alkylene, wherein R20 is defined as above, R29 is hydrogen or -R20, wherein R20 is defined as above, R30 at each occurrence is hydrogen or (C,.6)alkyl, R42 is hydrogen, ( ^alkyl or together with R43 forms trimethylene, tetramethylene or phenylene- 1,2-dimethylene, optionally substituted with hydroxy or oxo, and R43 is as defined above or is (i) (C,.6)alkyl optionally substituted with cyano, halo, nitro, -NR14R14, -NR14C(O)OR14, -NR14C(O)NR14R14, -NR14C(NR14)NR14R14, -OR14, -SR14, -C(O)OR14, -C(0)NR14R14,
-S(O)2NR14R14, -P(O)(OR14)OR14, -OP(0)(OR14)OR14, -NR14C(O)R15, -S(0)R15, -S(O)2R15, -C(O)R15, -OR16, -SR16, -S(O)R16, -S(O)2R16, -C(O)R16, -C(O)OR16, -OC(O)R16, -NR16R17, -NR17C(O)R16, -NRI7C(O)OR16, -C(0)NR16R17, -S(0)2NR16R17, -NR17C(O)NR16R17 or -NR17C(NR17)NR16R17 or (ii) a group selected from (C3.12)cycloalkyl(C0.6)alkyl, hetero(C3.12)cycloalkyl(C0.6)alkyl, (C6.12)aryl(C0.6)alkyl, hetero(C5.12)aryl(C0_6)alkyl,
(C9.,2)polycycloaryl(C0.6)alkyl and hetero(C8.I2)polycycloaryl(C0.6)alkyl, wherein said cycloalkyl, heterocycloalkyl, aryl, heteroaryl, polycycloaryl or heteφolycycloaryl ring optionally is substituted by a group selected from -R18, -XOR18, -X5SR18, -X5S(O)R18, -X5S(O)2R18, -X5C(O)R18, -X5C(O)OR18, -X5OC(O)R18, -X5NR18R19, -X5NRI9C(O)R18, -X5NR19C(0)OR18, -X5C(O)NR18R19, -X5S(O)2NR18R19, -X5NR19C(O)NR18R19 or -X5NR19C(NR19)NR18R19, wherein X5, R14, R15, R16, R17, R18 and R19 are as defined above; wherein within R7 any alicyclic or aromatic ring system present may be substituted further by 1 to 5 radicals independently selected from (C,.6)alkyl, (C1.6)alkylidene, cyano, halo, halo-substituted (CM)alkyl, nitro, -X6NR14R14, -X6NR14C(O)OR14, -X6NR14C(O)NR14R14, -X6NR14C(NR14)NR14R14, -X6OR14, -X6SR14, -X6C(0)OR14, -X6C(O)NR14R14,
-X6S(0)2NR14R14, -X6P(O)(OR14)OR14, -X6OP(0)(OR14)OR14, -X6NR14C(O)R15, -X6S(O)R15, -X6S(O)2R15 and -X6C(O)R15, wherein X6, R14 and R15 are as defined above; and R8 at each occurrence independently is selected from (C,.5)alkyl, halo-substituted (C,_4)alkyl, (C,.6)alkylidene, cyano, halo, halo-substituted (C,.4)alkyl, nitro, -X6NR14R14, -X6NR14C(0)OR14, -X6NR14C(O)NR14R14, -X6NR14C(NR14)NR14R14, -X6OR14, -X6SR14, -X6C(0)OR14, -X6C(O)NR14R14, -X6S(0)2NR14R14, -X6P(0)(OR14)OR14, -X6OP(0)(OR14)OR14, -X6NR14C(O)R15, -X6S(O)R15, -X6S(0)2R15 and -X6C(O)R15, wherein X6 is a bond or (C,.6)alkylene, R14 at each occurrence independently is hydrogen, (C^alkyl or halo-substituted (C,.3)alkyl and R15 ( _6)alkyl or halo-substituted (C,_3)alkyl; or an TV-oxide derivative, prodrug derivative, protected derivative, individual isomer or mixture of isomer; or a pharmaceutically acceptable salts thereof.
49. The method of Claim 48 wherein the disease is osteoporosis.
50. The method of Claim 49 wherein the animal is a human.
51. The method of Claim 50 wherein the human is a post-menopausal woman.
52. The method of Claim 51 wherein the cysteine protease is cathepsin K.
53. A process for making a compound of Formula I:
Figure imgf000211_0001
I in which:
A comprises a heteromonocyclic ring containing 5 to 6 ring member atoms or a fused heteropolycyclic ring system containing 8 to 14 ring member atoms, wherein each ring contains 5 to 7 ring member atoms, X1 is a ring member carbon atom and each ring member atom other than X1 is a carbon atom or a heteroatom, with the proviso that (i) at least one ring member atom is a heteroatom and (ii) when A is a heteromonocyclic radical containing 5 ring member atoms, no more than two of the ring member atoms comprising A are heteroatoms; n is 0, 1, 2 or 3;
X1 is =C- or -CH-;
X2 is a bond or a divalent group of Formula (a) or (b):
Figure imgf000212_0001
(a) (b)
wherein:
X3 and X4 independently are -C(O)- or -CH2S(0)2- R9 and R10 independently are hydrogen, (C,.6)alkyl or as defined below; R11 at each occurrence independently is hydrogen or (C,.6)alkyl; R12 and R13 independently are (i)
Figure imgf000212_0002
optionally substituted with cyano, halo, nitro, -NR14R14, -NR14C(O)OR14, -NR14C(O)NR14R14, -NR14C(NR14)NR14R14,
-OR14, -SR14, -C(O)OR14, -C(O)NR14R14, -S(O)2NR,4R14, -P(O)(OR14)OR14, -OP(0)(OR14)OR14, -NR14C(O)R15, -S(O)R15, -S(O)2R15, -C(O)R15, -OR16, -SR16, -S(O)R16, -S(0)2R16, -C(O)R16, -C(O)OR16, -OC(O)R16, -NR16R17, -NR17C(O)R16, -NR17C(0)OR16, -C(0)NR,6R17, -S(O)2NR16R17, -NR17C(0)NR16R17 or -NR17C(NR17)NR16R17, wherein R14 at each occurrence independently is hydrogen,
(C,_6)alkyl or halo-substituted (C,.3)alkyl, R15 is (C,.6)alkyl or halo-substituted (C,.3)alkyl, halo, (C,.6)alkyl or R16 is (C3.12)cycloalkyl(C0.6)alkyl, hetero(C3.12)cycloalkyl(C0.6)alkyl, (C6.12)aryl(C0.6)alkyl, hetero(C5.12)aryl(C0.6)alkyl, (C9.12)polycycloaryl(C0.6)alkyl or hetero(C8.12)polycycloaryl(C0.6)alkyl and R17 is hydrogen or (C1.6)alkyl, and wherein within R16 said cycloalkyl, heterocycloalkyl, aryl, heteroaryl, polycycloaryl or heteφolycycloaryl ring optionally is substituted by a group selected from -R18, -X5OR18, -X5SR18, -X5S(O)R18, -X5S(0)2R18, -X5C(O)R18, -X5C(0)OR18, -X5OC(O)R18, -X5NR18R19, -X5NR19C(O)R18, -X5NR19C(O)OR18, -X5C(O)NR18R19, -X5S(O)2NR18R19, -X5NR19C(O)NR18R19 or -X5NR19C(NR19)NR18R19, wherein X5 is a bond or (C,.6)alkylene, R18 is hydrogen or
(C,.6)alkyl and R19 is (C3.12)cycloalkyl(C0.6)alkyl, hetero(C3_12)cycloalkyl(C0.6)alkyl, (C6.I2)aryl(C0.6)alkyl, hetero(C5.12)aryl(C0.6)alkyl, (C9.12)polycycloaryl(C0.6)alkyl or hetero(C8.12)polycycloaryl(C0.6)alkyl, or (ii) a group selected from (C3.]2)cycloalkyl(C0.6)alkyl, hetero(C3.12)cycloalkyl(C0.6)alkyl, (C6.I2)aryl(C0.6)alkyl, hetero(C5.I2)aryl(C0.6)alkyl, (C9.ι2)polycycloaryl(C0.6)alkyl and hetero(C8.12)polycycloaryl(C0.6)alkyl, wherein said cycloalkyl, heterocycloalkyl, aryl, heteroaryl, polycycloaryl or heteφolycycloaryl ring optionally is substituted by a group selected from -R18, -X5OR18, -X5SR18, -X5S(O)R18, -X5S(0)2R18, -X5C(O)R18, -X5C(0)OR18, -X5OC(0)R18, -X5NR18R19, -X5NR19C(0)R18, -X5NR19C(O)OR18, -X5C(0)NR18R19, -X5S(0)2NR18R19, -X5NR19C(0)NR18R19 or -X5NR19C(NR19)NR18R19, wherein X5, R18 and R19 are as defined above; wherein within R12 and/or R13 any alicyclic or aromatic ring system present may be substituted further by 1 to 5 radicals independently selected from (C^alkyl, (C,.6)alkylidene, cyano, halo, halo-substituted (C,.4)alkyl, nitro, -X5NR14R14, -X5NR14C(O)OR14, -X5NR14C(0)NR,4R14, -X5NR14C(NR14)NR14R14, -X5OR14, -X5SR14, -X5C(O)OR14, -X5C(0)NR14R14, -X5S(0)2NR14R14, -X5P(O)(OR14)OR14, -X5OP(O)(OR14)OR14, -X5NR14C(O)R15, -X5S(O)R15, -X5S(O)2R15 and -X5C(O)R15, wherein X5, R14 and R15 are as defined above; or
R12 together with R9 and/or R13 together with R10 form trimethylene, tetramethylene or phenylene- 1,2-dimethylene, optionally substituted with 1 to 3 radicals independently selected from (C,.6)alkyl, (C,.6)alkylidene, cyano, halo, halo-substituted (C,.4)alkyl, nitre oxo, -X5NR14C(0)OR14, -X5NR14C(0)NR14R14,
-X5NR14C(NR14)NR14R14, -X5OR14, -X5SR14, -X5C(0)OR14, -X5C(O)NR14R14, -X5S(0)2NR14R14, -X5P(0)(OR14)OR14, -X5OP(0)(OR14)OR14, -X5NR14C(O)R15, -X5S(0)R15, -X5S(O)2R15 and -X5C(O)R15, wherein X5, R14 and R15 are as defined above; and R1 is -X6X7R20, wherein X6 is -C(O)-, -C(O)C(0)- or -S(O)2-, X7 is a bond, -O- or
-NR21-, wherein R21 is hydrogen or (Cμ6)alkyl, and R20 is (i) (Cμ6)alkyl optionally substituted by cyano, halo, nitro, -NR14R14, -NR14C(O)OR14, -NR14C(0)NR14R14, -NR14C(NR14)NR14R14, -OR14, -SR14, -C(O)OR14, -C(0)NR14R14, -S(O)2NR14R14, -P(O)(OR14)OR14, -OP(O)(OR14)OR14, -NR14C(0)R15, -S(0)R15, -S(O)2R15, -C(O)R15, -OR22, -SR22, -S(0)R22, -S(O)2R22, -C(O)R22, -C(O)OR22, -C(O)NR22R23, -NR22R23, -NR23C(0)R22,
-NR23C(0)OR22,-NR23C(0)NR22R23 or -NR23C(NR23)NR22R23, wherein R14 and R15 are as defined above, R22 is (C3.12)cycloalkyl(C0.6)alkyl, hetero(C3.12)cycloalkyl(C0.6)alkyl, (C6.12)aryl(C0.6)alkyl, hetero(C5.I2)aryl(C0.6)alkyl, (C9.12)bicycloaryl(C0.6)alkyl or hetero(C8.]2)bicycloaryl(C0.6)alkyl and R23 at each occurrence independently is hydrogen or (C,.6)alkyl, or (ii) (C3.12)cycloalkyl(C0.6)alkyl, hetero(C3.]2)cycloalkyl(C0.6)alkyl, (C6.12)aryl(C0.6)alkyl, hetero(C5.12)aryl(C0.6)alkyl, (C9.12)bicycloaryl(C0.6)alkyl or hetero(C8.12)bicycloaryl(C0.6)alkyl or (iii) (C3.6)cycloalkyl(C0.6)alkyl, hetero(C3.6)cycloalkyl(C0.6)alkyl, phenyl(C0.6)alkyl or hetero(C5.6)aryl(C0.6)alkyl, wherein said cycloalkyl, heterocycloalkyl, phenyl or heteroaryl is substituted by -R24, -X5OR24, -X5SRM, -X5S(O)R24, -X5S(O)2R24, -X5C(O)R24, -X5C(0)OR24, -X5C(0)NR24R25, -X5NRMR25, -X5NR25C(O)R24, -X5NR25C(0)OR24, -X5NR25C(0)NR24R25 or -X5NR25C(NR25)NR24R25, wherein X5 is as defined above, R24 is (C3.6)cycloalkyl(C0.6)alkyl, hetero(C3.6)cycloalkyl(C0.6)alkyl, phenyl(C0.6)alkyl or hetero(C5.6)aryl(C0.6)alkyl and R25 at each occurrence independently is hydrogen or (C,.6)alkyl; wherein within R1 any alicyclic or aromatic ring system present may be substituted further by 1 to 5 radicals independently selected from (C^alkyl, (C^alkylidene, cyano, halo, halo-substituted (CM)alkyl, nitro, -X5NR14R14, -X5NR14C(O)OR14, -X5NR14C(O)NR14R14, -X5NR14C(NR14)NR14R14, -X5OR14, -X5SR14, -X5C(O)OR14, -X5C(O)NR14R14, -X5S(O)2NR14R14, -X5P(O)(OR14)OR14, -X5OP(0)(OR14)OR14, -X5NR14C(O)R15, -X5S(O)R15, -X5S(O)2R15 and -X5C(O)R15, wherein X5, R14 and R15 are as defined above; or when X2 is a divalent group of formula (a) or (b) then R1 may also represent hydrogen, carboxy, oxalo or carbamoyl; R2 is hydrogen or (C,.6)alkyl;
R3 is (i) (C,.6)alkyl optionally substituted with cyano, halo, nitro, -SR26, -C(0)OR26, -C(O)NR26R26, -P(O)(OR26)OR26, -OP(O)(OR26)OR26, -S(O)R27, -S(0)2R27 or -C(O)R27, wherein R26 at each occurrence independently is hydrogen, (C,.6)alkyl or halo-substituted (C,.3)alkyl and R27 is (C,.6)alkyl or halo-substituted (C,.3)alkyl, or (ii) (C5.6)cycloalkyl(C2.3)alkyl, hetero(C3.6)cycloalkyl(C2.3)alkyl, (C6.12)aryl(C2.3)alkyl or hetero(C5.6)aryl(C2.3)alkyl, wherein said cycloalkyl, heterocycloalkyl, aryl or heteroaryl optionally is substituted further with 1 to 5 radicals independently selected from ( _6)alkyl, (C,.6)alkylidene, cyano, halo, halo-substituted (C )alkyl, nitro, -X5NR14C(O)OR14, -X5NR14C(O)NR14R14, -X5NR14C(NR14)NR14R14, -X5OR14, -X5SR14, -X5C(O)OR14, -X5C(O)NR14R14, -X5S(0)2NR14R14, -X5P(O)(OR14)OR14, -X5OP(0)(OR,4)OR14, -X5NR14C(O)R15, -X5S(O)R15, -X5S(O)2R15 and -X5C(O)R15, wherein X5, R14 and R15 are as defined above, provided that when R3 is unsubstituted (C,.5)alkyl and R4 is hydrogen or unsubstituted (C].5)alkyl, then X2 may not represent (i) a bond when R1 is -C(O)R20, -C(O)2R20 or -S(O)2R20 in which R20 is (C,.6)alkyl, phenyK alkyl, phenyl, (C3_7)cycloalkyl, camphan-10-yl, naphth-1-yl, naphth-2-yl, phenyl substituted by one or more of (C,.4)alkyl, perfluoro(C,_4)alkyl, (C,_4)alkoxy, hydroxy, halo, amido, nitro, amino, (C,_4)alkylamino, (C,.4)dialkylamino, carboxy or (CM)alkoxycarbonyl, or naphth-1-yl or naphth-2-yl substituted by one or more of (CM)alkyl, perfluoro(C,.4)alkyl, (C,.4)alkoxy, hydroxy, halo, amido, nitro, amino, carboxy or (C,.4)alkoxycarbonyl or (ii) a divalent group of formula (a) or (b) in which the moiety R12 is methyl, isopropyl, n-butyl, sec-butyl, tert-butyl, 1-methylpropyl, benzyl, naphth-1-ylmethyl, naphth-2-ylmethyl, thien-2-ylmethyl, thien-3-ylmethyl, or wherein R9 and R12 form ethylene, trimethylene, hydroxy-substituted trimethylene, tetramethylene or phenylene- 1,2-dimethylene; or
R3 and R4 taken together with the carbon atom to which both R3 and R4 are attached form (C3_s)cycloalkylene or (C3.8)heterocycloalkylene, wherein said cycloalkylene or heterocycloalkylene is optionally substituted with 1 to 3 radicals independently selected from (C,.6)alkyl, (C,.6)alkylidene, cyano, halo, halo-substituted (C^alkyl, nitro, -X5NR14C(0)OR14, -X5NR14C(O)NR14R14, -X5NR14C(NR14)NR14R14, -X5OR14, -X5SR14, -X5C(O)OR14, -X5C(O)NR14R14, -X5S(O)2NR14R14, -X5P(O)(OR14)OR14, -X5OP(0)(OR14)OR14, -X5NR14C(O)R15, -X5S(O)R15, -X5S(O)2R15 and -X5C(0)R15, wherein X5, R14 and R15 are as defined above;
R4 is hydrogen, (C,.6)alkyl or as defined above; R5 is hydrogen and R6 is hydroxy or R5 and R6 together form oxo;
R7 is a group selected from cyano, halo, nitro, -R29, -X5NR29R30, -X5NR30C(O)OR29, -X5NR30C(O)NR29R30, -X5NR30C(NR30)NR29R30, -XOR29, -X5SR29, -X5C(O)OR29, -X5C(O)NR29R30, -X5S(0)2NR29R30, -X5P(O)(OR30)OR29, -X5OP(O)(OR29)OR29, -X5NR30C(O)R31, -X5S(0)R31, -X5S(0)2R31 and -X5C(0)R31, wherein X5 is as defined above, R29 is hydrogen or -R31, R30 at each occurrence is hydrogen or (C,.6)alkyl and R31 is (C,.6)alkyl, (C3.12)cycloalkyl(C0.6)alkyl, hetero(C3.12)cycloalkyl(C0.6)alkyl, (C6.I2)aryl(C0.6)alkyl or hetero(C5.12)aryl(C0.6)alkyl, wherein within R7 any alicyclic or aromatic ring system present may be substituted further by 1 to 5 radicals independently selected from (C^alkyl, (C^^alkylidene, cyano, halo, halo-substituted (C,.4)alkyl, nitro, -X5NR14R14, -X5NR14C(O)OR14, -X5NR14C(O)NR14R14, -X5NR14C(NR14)NR14R14, -X5OR14, -X5SR14, -X5C(O)OR14, -X5C(O)NR14R14, -X5S(0)2NR14R14, -X5P(0)(OR14)OR14, -X5OP(0)(OR14)OR14, -X5NR14C(O)R15, -X5S(O)R15, -X5S(0)2R15 and -X5C(0)R15, wherein X5, R14 and R15 are as defined above; and
R8 at each occurrence independently is selected from (C,.6)alkyl, (C,.6)alkylidene, cyano, halo, halo-substituted (C,.4)alkyl, nitro, -X5NR14R14, -X5NR14C(O)OR14, -X5NR14C(O)NRl4R14, -X5NR14C(NR14)NR14R14, -X5OR14, -X5SR14, -X5C(O)OR14, -X5C(O)NR14R14, -X5S(0)2NR14R14, -X5P(O)(OR14)OR14, -XOP(0)(OR14)OR ,
-X5NR14C(O)R15, -X5S(O)R15, -X5S(O)2R15 and -X5C(0)R15, wherein X5, R14 and R15 are as defined above; and the TV-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers; and the pharmaceutically acceptable salts thereof.; which process comprises: (A) reacting an organometallic compound of Formula 2:
Figure imgf000216_0001
with a compound of Formula 3:
Figure imgf000216_0002
wherein n, A, X1, X2, R1, R2, R3, R4, R7 and R8 are as above, to give a compound of Formula I in which R5 and R6 together form oxo; or (B) reacting a compound of Formula 4:
Figure imgf000216_0003
with a compound of Formula 5(a) or 5(b):
Figure imgf000217_0001
wherein the dashed line represents an optional bond and B is a monocyclic radical containing 5 to 6 ring member atoms or a fused polycyclic radical containing 8 to 11 ring member atoms, wherein each ring contains 5 to 7 ring member atoms and each ring member atom is a carbon atom or a heteroatom and n, R1, R2, R3, R4, R7 and R8 are as defined above, to give a compound of Formula I in which the ring comprised by X1 is a 4,5-tetrahydrooxazol-.2-yl or oxazol-2-yl or moiety, respectively, R5 is hydrogen and R6 is hydroxy or (C) reacting a compound of Formula 6:
Figure imgf000217_0002
with a compound of the formula R'X2OY, wherein Y is hydrogen or or an activating group and n, A, X1, X2, R1, R2, R3, R4, R7 and R8 are as defined above to give a compound of Formula I in which R5 is hydrogen and R6 is hydroxy; or (D) reacting a compound of Formula 7:
Figure imgf000217_0003
or a protected derivative thereof, with R39OH, wherein R39 is -X6X7R20 and n, A, X1, X2, X7, X8, R2, R3, R4, R6, R7 and R20 are as defined above, and deprotecting if necessary to give a compound of Formula I in which R1 is -X6X7R20,
(E) optionally oxidizing a compound of Formula I in which R5 is hydrogen and R6 is hydroxy to give a compound of Formula I in which R5 and R6 together form oxo; (F) optionally oxidizing a compound of Formula I in which A is optionally substituted 4,5-dihydroxyoxazol-2-yl to give a compound of Formula I in which A is optionally substituted oxazol-2-yl;
(G) optionally converting a compound of Formula I in which R7 is -C(O)OH to a compound of Formula I in which R7 is methoxycarbonyl;
(H) optionally converting a compound of Formula I into a pharmaceutically acceptable salt; (I) optionally converting a salt form of a compound of Formula I to non-salt form;
(J) optionally converting an unoxidized form of a compound of Formula I into a pharmaceutically acceptable TV-oxide; (K) optionally converting an TV-oxide form of a compound of Formula I its unoxidized form; (L) optionally converting a non-derivatized compound of Formula I into a pharmaceutically prodrug derivative; and
(M) optionally converting a prodrug derivative of a compound of Formula I to its non-derivatized form.
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