AU2004201071A1 - Amine Derivatives as Protease Inhibitors - Google Patents
Amine Derivatives as Protease Inhibitors Download PDFInfo
- Publication number
- AU2004201071A1 AU2004201071A1 AU2004201071A AU2004201071A AU2004201071A1 AU 2004201071 A1 AU2004201071 A1 AU 2004201071A1 AU 2004201071 A AU2004201071 A AU 2004201071A AU 2004201071 A AU2004201071 A AU 2004201071A AU 2004201071 A1 AU2004201071 A1 AU 2004201071A1
- Authority
- AU
- Australia
- Prior art keywords
- alkyl
- halo
- substituted
- hetero
- hydrogen
- Prior art date
- Legal status (The legal status 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 status listed.)
- Abandoned
Links
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
S&FRef: 570082D1
AUSTRALIA
PATENTS ACT 1990 COMPLETE SPECIFICATION FOR A STANDARD PATENT Name and Address of Applicant: Actual Inventor(s): Address for Service: Invention Title: Axys Pharmaceuticals, Inc.
180 Kimball Way South San Francisco California 94080 United States of America John O. Link Arnold J. Martelli Valeri Martichonok John W. Patterson Oliver L. Saunders Sheila Zipfel Spruson Ferguson St Martins Tower Level 31 Market Street Sydney NSW 2000 (CCN 3710000177) Amine Derivatives as Protease Inhibitors The following statement is a full description of this invention, including the best method of performing it known to me/us:- 5845c 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, Lor 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 arinii, 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:
R
2 R5 6 2- R 7 R3 4 A R
(RS)
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 to 7 ring member atoms, X' is a ring member carbon atom and each ring member atom other than X' is a carbon atom or a heteroatom, with the proviso that 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 is0, 1, 2 or 3; X' is or -CH-;
X
2 is a bond or a divalent group of Formula or
R"
1
R
12 Ro Rl R12 R R R R9 (b) wherein: XI and X" independently are or -CH 2
S(O)
2 RI and R' 0 independently are hydrogen, (C,.6)alkyl or as defined below; R" at each occurrence independently is hydrogen or (Cl, 4 )alkyl;
R'
2 and R' 3 independently are (C, 4 6)alkyl optionally substituted with cyano, halo, nitro, _NR1 4 R1 4
-NR'
4 C(O)OR1 4
NR'
4 C(O)NR'1 4
R
4 -NR'1 4 C(NR'1 4 )NR 1 4 R1 4 -OR'1 4 -SR 1 4 -C(O)OR'1 4 -C(O)NR"4R 1 4 -S(O)2NR1 4
R]
4 -P(O)(OR 1 4 )OR 1 4 -OP(O)(OR 1 4 )QR 1 4 -NR 1 4
C(O)R'
5 -S(O)R 1 5
-S(Q)
2 R'1 5 -OR'1 6 -SR 1 6 -S(O)R 1 6
_S(O)
2 R1', -C(O)R 1 6 -C(O)OR 1 6 -OC(O)R 1 6 -NR'1 6 R1', -NR1 7 C(O)R 1 6 -NR'1 7 C(O)OR'1 6
-C(O)NR
6 R 1 7
_S(O)
2 NR1 6 R17, -NR 7 C(O)NR1 6 R'1 7 or -NR'iIC(NR9'P')NR 6 wherein R 1 4 at each occurrence independently is hydrogen,
(C,
16 )alkyl or halo-substituted (C 1 3 )alkyl, R' 5 is (C, 1 6)alkyl or halo-substituted 3 )alkyl, halo, (C, 1 6)alkyl or R'1 6 is (C 3 -12)cycloalky](C 0 ,)alkyl, hetero(C 3 ,12)cycloalkyl(CO.)alkyl, (C, 2 )aryl(C0.)alkyl, hetero(C.,, 2 )aryl(C.)a~kyl,
(C
9 2 )polycycloaryl(C.)alkyI or hetero(C, 2 ,)polycycloary](C,.)alkyl and R' 7 is hydrogen or (C,.6)alkyl, and wherein within R 1 6 said cycloalkyl, heterocycloalkyl, aryl, heteroaryl, polycycloaryl or heterpolycycloaryl rng optionally is substituted by a group selected from -R" 8 -XsOR"s, _X 5
SR'
8 -X5S(O)R 8
-X
5
S(O)
2
R'
8
-X
5
C(O)R'
8 -XsG(O)QR's, -XsOC(O)R' 8
-X-
5 NR 8 R1 9
-X
5
NR'
9
C(O)R'
8
_X
5
NR'
9 C(O)OR's, -XsC(O)NR'gR' 9
-X
5
S(O)
2
NR'
8
R'
9
-X
5
NR'
9
C(O)NR
9
R'
9 or
-X
5 NR1 9
G(NR'
9
)NR
8 wherein X 5 is a bond or (C 1 -6)alkylene, R' 8 is hydrogen or
(C
1 and R' is (C3, 12 )CYCloalkyl(C")alkyl, hetero(C 3 -1 2 )CYCloalkyl(C,0 6 )alkyl, (C6., 2 )aryl(C0.)alkyl, hetero(Cs., 2 )aryl(C0_)alkyl, (C,,)polycycloaryl(C,,)alkyl or hetero(CB-1 2 )POlycycloaryl(Cm)alkyl, or (ii) a group selected from (C3 2 )cycloa~kyl(C0_)alkyl, betero(C3-1 2 )CYCloalkyl(Cm)alkyl, (C6.,,)aryl(Cu)alkyl, hetero(C_,1 2 )aryl(CO.
6 )alkyl, (C.,)polycycloaryl(C 6)alkyI and hetero(Cs.
1 2 )POIycycloaryl(C")alkyl, wherein said cycloalkyl, heterocycloalkyl, aryl, heteroaryl, polycycloaryl or heterpolycycloaryl ring optionally is substituted by a group selected from -R' 8
-X'OR'
8
-X
5 'SR'8, _X 5
S(Q)R'
8
-X
5
S(O)
2 R'B, -X 5
C(O)R
8
-X
5 C(O)OR's, -X5OC(O)RIE, -X5NR' 8
R'
9
-X
5
NR'
9
C(O)R'
8
_X
5 NR1 9
C(O)OR
8
-X
5
C(O)NR'
8
R'
9
-X
5
S(O)
2
NR'
8
R
9
_X
5
NR'
9
C(O)NR
8
R'
9 or
_X
5
NR
19
C(NR'
9
)NR'
8
R'
9 wherein X1, R' 8 and R" 9 are as defined above; wherein within R'1 2 and/or R' 3 any alicyclic or aromatic ring system present may be substituted further by 1 to 5 radicals independently selected from (C,-6)alky1, (C 1 -6)alkylidene, cyano, halo, halo-substituted 4 )alkyl, nitro, -XsNR1 4 R 1 4
-X
5
NR'
4
C(O)OR
4 ,9
-X
5 NR 1 4 C(O)NR 1 4 R1 4
-X
5 NR14C(NR 1 4
)NR'
4 R]4, -X 5 OR1 4 9 _X 5 SR'1 4
-X
5 C(O)QR 1 4
-XSC(O)NR
4 R 1 4
-X
5
S(O)
2 NR1 4
R]
4
-X
5 P(Q)(OR1 4 )OR'1 4
_X
5 Op(Q)(OR' 4
)QR'
4
-X
5 NR1 4 C(Q)R'1 5
-X
5 S(O)R"5, -X 5
S(O)
2 R 1 5 and -X 5
C(O)R'
5 wherein X5 RI" and R1 are as defined above; or
R"
2 together with RI and/or R' 3 together with R' 0 form trimethylene, tetramethylene or phenylene-1,2-dimethylene, optionally substituted with 1 to 3 radicals independently selected from (C,-6)alkyl, 6 )alkylidene, cyano, halo, halo-substituted (C,,)alkyl, nitro, oxo, -X-NR 4 C(O)OR', -X 5 NR 1 4 C(O)NR 1 4 R1 4
-X
5 NR1 4
C(NR
4
)NR
4 R 1 4
-X
5 OR 1 4 -X'SR 1 4
-X
5 C(O)OR 1 4
-X
5 C(O)NR 1 4 R1 4
_X
5
S(O)
2
NR
4 R 1 4
-X
5 P(O)(OR 4 )0R 1 4
-X
5 Op(O)(OR 1 4 )0R 14
-X
5 NR 1 4
C(O)R'
5
-X
5 S(O)R 1 5
-X
5
S(O)
2 R 1 5 and -X5C(O)R 5 wherein X 5 R 1 4 and R' 5 are as defined above; and RI is -XIX 7 R20, wherein X 6 is or -S(0) 2 XI is a bond, or -NR 2 wherein R 22 is hydrogen or (C,.6)alkyl, and R70 is (C,-6)alkyl optionally substituted by cyano, halo, nitro, -NR' 4 R 1 4 -NR 1 4 C(O)OR 1 4 -NR1 4 C(0)NR 4
R
14 -NR1 4
C(NR]
4 )NR 1 4 R1 4 -OR'1 4 -SR 1 4 -C(O)OR M, -C(O)NR 1 4 R1 4
-S(O)
2 NR 1 4 R1 4 -P(O)(OR1 4
)OR'
-OP(O)(OR 1 4 )OR1 4 -NR1 4 C(O)R 1 5
-S(O)R'
5
-S(O)
2 R 1 5
-OR
2 2 -SR 2
-S(O)R
22
-S(O)
2 R 22 -C(O)R22, -C(O)OR22, -C(O)NR22R2, -NWR23, -NR23G(O)R 22 -NR 23 C(O)OR 22
-NR
23 C(O)NR'R 2 1 or -NR13C(NRI)NR 22 RI, wherein R 1 4 and R1 5 -are as defined above, R 22 is (C 3 4 2 )cycloalkyl(C,,)alkyl, hetero(q.
12 ,)cycloalkyl(C.)alkyl, (C6., 2 )aryl(C.)alkyl, 12 )arYl(C0_)alkyl, (C 912 )bicycloaryl(CO-)alkyl or hetero(Cg 8 12 )bicycloaryl(CO.)alkyI and R23 at each occurrence independently is hydrogen or (C 14 6)alkyl, or (ii) (C3.
2 )cycloalky](CO-)alkyI, hetero(C3.
1 2 )cycloalkyl(C .)alkyl, (C6 12 )aryl(CO-)alkyl, 2 )aryI(CQ_)alkyl, (C9_ 1 2 )bicycloaryl(C0.)alkyl or hetero(C 8 12 )bicycloaryl(C7")alkyI or (iii) (C3.)cycloalkyl(CO.)alkyl, hetero(Cm)cycloalky(C,,6)alkyl, pheny](CO-)alkyl or hetero(C5,)aryl(C._6)alkyl, wherein said cycloalkyl, heterocycloalkyl, phenyl or heteroaryl is substituted by -R2A, _X 5 OR24, -X 5 SRI, -X 5 S(O)R 24
-X
5
S(O)
2 -XsC(O)Ru, -X 5 C(O)0R 4 -X5C(O)NR 24
R
2 5, -X-NR24R25, -X3NR25C(O)R4, _X 5 NR 25C(O)OR 24
-X
5 NR25C(0)NR 2 4R 2 or _X 5 NR2C(NR25)NR7AR25, wherein X5 is as defined above, R' is (C 34 )cycloalkyl(C,6)alkyl, hetero(C3-)cycloalkyl(CO-)alkyl, .pheny](C,-)alkyl or hetero(C., 4 )aryl(C.)alkyl and R25 at each occurrence independently is hydrogen or (CI-6)alkyI; wherein within RI any alicyclic or aromatic ring system present may be substituted further by 1 to 5 radicals independently selected from
(C
14 6)alkyl, 6 )alkylidene, cyano, halo, halo-substituted (C 14 )alkyl, nitro, -X 5
NR'
4
R]
4
-X
5 NR1 4 C(O)OR 1 4
-X
5 NR1 4
C(O)NR
4 R 1 4
-X
5 NR14C(NR]4)NR 4 R1 4
-X
5 OR', -X 5 SR 1 4
-X
5 C(O)OR 1 4
-X
5 C(O)NR 1R 1 4
-X
5
S(O)
2 NR1 4
R]
4
-X'P(O)(OR
4
)OR',
-X
5 OP(O)(OR 1 4 )OR 1 4
-X
5 NR1 4
C(O)R'
5
-X
3
S(Q)R'
5
-XSS(O)
2
R'
5 and -X 5
C(O)R'
3 wherein
X
5 R 1 4 and R1 5 are as defined above; or when XI is a divalent group of formula or then RI may also represent hydrogen, carboxy, oxalo or carbanioyl;
R
2 is hydrogen or (C 1 6 )alkyl; RI is (C, 1 6)alkyl optionally substituted with cyano, halo, nitro, -SR 16, -C(O)0R 26
-C(O)NR
2 6 R 26 -P(Q)(OR26)OR 26 -OP(O)(0R 26 )0R 26
-S(O)
2 R 2 or C )R2, wherein R6 .at each occurrence independently is hydrogen, (C 1 -6)alkyl or halo-substituted
(C
1 3 )alkyl and R' is (C, 14 )alkyl or halo-substituted (C 1 3 )alkyl, or (ii) (C, 5 6)cycloalkyl(C 2 3 )alkyl, hetero(C 34 6)cycloalkyl(C 2 3 )alkyl, (C6- 12 )aryl(C 2 3 )alkyI or hetero(C,,)aryl(C 23 )alkyl, wherein said cycloalkyl, heterocycloalkyl, aryl or heteroaryl optionally is substituted further with 1 to radicals independently selected from (C, 14 )alkyl, (C 14 6)alkylidene, cyano, halo,'halo-substituted
(C
14 )alkyl, nitro, -X 5
NR'
4 C(O)OR 1 4
-X
5 NR 1 4 C(O)NR1 4
R
4
-X
5 NR1 4 C(NR 1 4 )NR1 4
R]
4
-X
5 0R 1 4 _X SR 1 4
-X
5 C(O)OR 1 4
-X
5
C(O)NR
4
R]
4 -X5S(O) 2
NR
14 R1 4
-X
5
P(O)(QR'
4 )OR 1 4
-X
5 OP(O)(OR 1 4 )OR 1 4
_X
5
NR
14
C(O)R'
5
-X
5
S(O)RI
5
-X
5
S(O)
2 R 1 5 and _X 5
C(O)R,
5 wherein
X
5 R'1 4 and R'1 5 are is defined above, provided that when RI is unsubstituted (C 15 ,)alkyl and R 4 is hydrogen or unsubstituted (C 1 5 )alkyl, then XI may not represent a bond when III is
-C(O)R
2 0 -C(O),R20 or -S(O) 2 Rl in which RI is (C,,)alkyl, phenyl(C,,)alkyl, phenyl,
(C
3 7 )CYCloalkyl, camphan-1O-yl, naphth-1-yl, naphth-2-yl, phenyl substituted by one or more of (C,,)alkyl, perfluoro(C,,)alkyl, (C,,)alkoxy, hydroxy, halo, amido, nitro, amino,
(C
14 )alkylamnino, (C,,)dialkylamino, carboxy or 4 )alkoxycarbonyl, or naphth-1-yl or naphth-2-yl substituted by one or more of (C 14 )alkyl, perfluoro(C,,)alkyl, (C 1 .4)alkoxy, hydroxy, halo, amnido, nitro, amino, carboxy or (C, 14 )alkoxycarbonyl or (ii) a divalent group of formula (a) or in which the moiety R.' 2 is methyl, isopropyl, n-butyl, sec-butyl, tert-butyl, I1-methylpropyl, benzyl, naphth-1 -ylmethyl, naphth-2-ylmethyl, thien-2-ylmethyl, thien-3-ylmethyl, or wherein R' and R 12 form ethylene, trimethylene, hydroxy-substituted trimethylene, tetrainethylene or phenylene- 1,2-dimethylene; or
R
3 and R 4 taken together with the carbon atom to which both R 3 and R' are attached form (C 3 H)cycloalkylene or (C3 .)heterocycloalkylene, wherein said cycloalkylene or heterocycloalkylene is optionally substituted with 1 to 3 radicals independently selected from
(C
14 6)alkyl, (C 1 -6)alkylidene, cyano, halo, halo-substituted (Cl.)alky1, nitro, -X 5
NR'
4
C(O)OR~
-X
5 NR"4C(O)NR1 4 R]4, -X 5 NR1 4
C(NR'
4
)NR]
4 R 14, _X5OR1 4
-X
5 SR 1 4 _X 5
C(O)OR'
4
_X
5 C(Q)NR1 4
R]
4
-X
5
S(O)
2 NR1 4 R 1 4
-X
5 P(O)(QR 1 4 )OR 14, -X 5 OP(O)(OR1 4 )OR 14, -XsNR' 4
C(O)R'
5
-X
5
S(O)R
2 5
-X
5
S(O)
2 R'1 5 and _X 5
C(O)R'
5 wherein XI, R'1 4 and RI 5 are as defined above; R 4 is hydrogen, (C 1 .,)alkyl or as defined above; is hydrogen and RI is hydroxy or R 5 and R 6 together form oxo; RI is a group selected from cyano, halo, nitro, -X 5 NR 29
R
30
-X
5
NR
30 C(O)0R' 9 _XSNR30C(O)NR29R3O,
-X
5
NR
3 0 C(NR 30 )NR 29
R
30
_X
5 OR 29
_X
5
SR
29 _X5 C(O)0R 29 2 9
R
3 0, -X5S(O) 2 NR 29 R3 0
-X
5 P(O)(OR30)OR 2, _X5Op(O)(OR 9 )QR 29,
_X
5
NR
30 C(Q)R 31
-X
5 S(O)R 31
-XSS(O)
2 R 3 1 and -X 5 C(O)R 31 wherein X 5 is as defined above,
R
29 is hydrogen or -R 31
R
3 1 at each occurrence is hydrogen or (C 14 6)alkyl and R 3 1 is (C .6)alkyl, (C3_ 12 )cycloaky(C.)alkyl, hetero(C 3 12 )CYCloalkyl(CO.
6 )alkyl, (C6 12 )aryl(CO-)alcyl or hetero(C 5 12 )aryl(CO.)alkyl, wherein within R' any alicyclic or aromatic ring system present may be substituted further by 1 to 5 radicals independently selected from (C, 1 ,)alkyl, (C 1 6 )alkylidene, cyano, halo, halo-substituted
(C
1 4 )alkyl, nitro, -X 5
NR'
4 R, -X 5
NR
1 4 C(O)OR 14,
_X
5 NqR1 4 C(O)NR14R',
-X
5 NR1 4 C(NR"1)NR1 4
RI
4
-X
5 OR 1 4
_X
5
SR'
4
-X
5 C(O)0R 14
-X
5 C(Q)NR1 4
RI
4
-X
5
S(O)
2 NR 1 4 R1 4
_X
5
P(O)(OR'
4 )OR 14, -X 5 Op(Q)(OR' 4 )OR 14,
-X
5
NR'
4
C(O)RI
5
-X
5
S(O)R
5
-X
5
S(O)
2
R'
5 and _X 5
C(Q)R'
5 wherein X 5 R 1 4 and are as defined above; and RIat each occurrence independently is selected from (C 14 6)alkyl, (C 1 -6)alkylidene, cyano, halo, halo-substituted 4 )alkyl, nitro, -X 5
NR'
4
R]
4
-X
5
NR'
4 C(Q)OR1'
_X
5 NR1 4 C(O)NR 14R14, -X 5 NR 1 4
G(NR]
4
),R
4 R 1 4
_X
5 OR 1 4
-X
5 SR 1 4
-X
5 C(O)OR 1 4
-X
5
C(O)NR'
4 RI4, -X 5
S(O)
2 NR J 4 R' -X 5
P(O)(QR]
4 )OR 1 4
_X
5 OP(O)(OR'4)OR 14,
-X
5 NR1 4 C(o)R 15, _X 5
S(O)R'
5
-X
5
S(O)
2 R"5 and _X 5
C(O)R'
5 wherein X5, R' 4 and R's are as defined above; and the N-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 bnoxzl2y-ehaol--ehlbtlcrao1--ehl butylcarbamoyl }-3-methyl-butyl)-carbamic acid benzyl ester, (I I -H-imidazol-2-ylmethanoyl)-3-methyl-butylcarbamoyl).3-methyl-butyl J-carbamic acid terr-butyl ester, [(S)-3-methyl- 1-((S)-3-methyl-l- 1-[1 -(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol2-ylp methanoyl }-butylcarbamoyl)-butyl]-carbamic acid benzyl ester; I(S)-1 1-(1 -lH-imidazol- 2 -yl-methanoyl)-3-methyl-butyicarbamoyl-3-mefiylbutyl 1carbarnic acid benzyl ester, -(l-benzyl-IH-imidazol-2-yl)-methanoyl]-3-metiyl.
butylcarbamoyl }-3-methyl-butyl)-carbamic acid benzyl ester, IH-imidazol-2-ylmeffianoyl)-3-methyl-butylcarbamoyl-3-methyl-butyl 1-carbainic acid tert-butyl ester, 3-f [l-(4-chloro--phenyl)-methanoyl] -amino 1-4-oxo-4-pyridin-3-yl-butyric acid ethyl ester, 4-f uran-2-y1-4-oxo-3- [1 -(4-trifluoromethyl-phenyl)-methanoyl]-amino 1-butyric acid ethyl ester, 3 2 -methyl-propanoylamino)A4-oxo4thiophen-2-yi-butyric acid ethyl ester, 4-oxo- 4-thiophen-2-yl-3-[( 1-p-tolyl-methanoyl)-armino]-butyric acid ethyl ester, thiophen-2-yl)-3- [1 -(4-chloro-phenyl)-methanoyl] -amino 1-4-oxo-butyric acid ethyl ester, 3-f [1-(4-chloro-phenyl)-methanoyl]-amino 4 -(5-methyl-thiophen-2-yl)-4-oxo-butyric acid ethyl ester, 4-oxo-4-thiophen-3-yl-3-[(1-p-tolyl-methanoyl)-amino]-butyric acid ethyl ester, 3-f 4 -methoxy-phenyl)-methanoyl]-amino }-4-oxo-4thiophen-3-yl-butyric acid ethyl ester, 3-f [1 3 ,4-dichloro-phenyl)-methanoyl]-amino }4-oxo-4-thiophen-3-yl-butyric acid ethyl ester, 4-fluoro-N-[ l-(l-thiophen-3-y-methanoyl)-propyl]-benzamide, 4-f [1-(4-fluoro-phenyl)methanoyl) -amino 1-5-oxo-5-thiophen-3-yl-pentanoic acid ethyl ester and 3-f [1-(4-fluorophenyl)-methanoyl]-amino 1-2-methyl-4-oxo-4-thiophen-3-yl-butyric acid ethyl ester.
In another particular embodiment, the present invention relates to protease inhibitors of Formula 1:
R
2
R
5 R6
R
3
A
R4 ~(R8)n 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 to 7 ring member atoms, XV is a ring member carbon atom and each ring member atom other than XV is a carbon atom or a heteroatom, with the proviso that at least one ring member atom is a heteroatom. and (ii) when A is a beteromonocyclic radical containing 5 ring member atoms, no more than two of the ring member atoms comprising A are heteroatoms; n isO0, 1, 2 or 3; X' is or -CH-;
V
2 is a bond or a divalent group of Formula or R 11 R 12 R1 1R1 19
R'
1 3
R
9 R
R
(b) wherein:
X
3 and V 4 independently are or -CH 2 R' and R" 0 independently are hydrogen, (C, 6 )alkyl or as defined below; R" at each occurrence independently is hydrogen or (C,-6)alkyl;
R'
2 and R 1 3 independently are (C,,)alkyl optionally substituted with cyano, halo, nitro, _NR1 4 R1 4 -NR1 4 C(O)OR 1 4 -NR1 4 C(O)NR4R4, -NR'1 4 C(NR 1 4 )NR 1 4 R1 4 -OR'1 4 -SR'1 4 -C(O)OR'1 4
-C(O)NR
4 R'1 4
-S(O)
2
NR'
4 R 1 4 -P(O)(OR1 4 )OR'1 4 -OP(O)(OR'1 4 )OR 1 4
-NR'
4
C(O)R'
5 -S(O)R'1 5
-S(O)
2
R]
5
-C(O)R]
5
-OR'
6 -SR'1 6
-S(O)R'
6
-S(O)
2 R 6, -C(O)R'1 6 -C(Q)OR1 6
-QC(O)R
6 -NR3 6 R1 7 -NR1 7
C(O)R'
6
_NR
1 7 C(O)OR 1 6
-C(O)NRI
6 R 1, -S(O) 2
NR'
6
R'
7 -NR 1C(O)NR1 6 R'1 7 or _NR1 7 C(NR. 1)NR 6 R 1 7 wherein R' at each occurrence independently is hydrogen, (C,,)alkyl or halo-substituted 3 )alkyl, R 1 5
(C,
4 6)alkyl or halo-substituted 3 )alkyl, R 1 6 is (C3.1 2 )CYCloalkyl(Cm)alkyl, hetero(C 3 -,)cycloalky(C.)alkyl, (C&1 2 )aryl(C0- 6 )a~kYl, hetero(C5_j 2 )aryI(C")alkyl,
(C
9 2 )polycycloaryl(C,.)alkyI or hetero(C,, 2 )polycycloary(C 0 -6)alkyI and R' 7 is hydrogen or (C,-6)alkyl, and wherein within R'1 6 said cycloalkyl, heterocycloalkyl, aryl, heteroaryl, polycycloaryl or heterpolycycloaryl ring optionally is substituted by a group selected from -R" 8
-X'OR'
8
-X
5 SR 1 8 -XsS(O)RB,
-X
5
S(O)
2
R'
8 -XsC(O)R' 8
-X
5
C(O)OR'
8
-X
5
OC(O)R'
8
-X'NR
8 R -X 5
NR'
9 C(O)R -X'NR' 9
C(O)OR'
8
_X
5
C(O)NR'
8
R'
9
-X
5
S(O)
2
NR'
8
R'
9
-X
5
NR'
9
C(O)NR'
8
R'
9 or -X 5
NR'
9 C(NR'9)NR'8R'9, wherein X 5 is a bond or 6 )alkylene, R" 8 is hydrogen or 6 )alkyl and R1 9 is (C 12 )cycloalkyl(CO.)alkyl, hetero(C 3 12 )cycloalky(CO-)alkyl, (C6.
12 )ary1(C0-)alky1, hetero(C 5 12 )aryl(C")alcyl, (C 9 2 )polycycloaryl(C~)alkyl or hetero(Cg.
12 )polycycloary(CO.)alkyl, or (ii) a group selected from
(C
3 12 )CYCloalky(C")alkyl, hetero(C3- 12 )cycloalky](C-.6)alkyl, (C6.
12 )ary1(CO-)alky1, hetero(C5_ 12 )aryl(C")alkyl, (C9.
1 2 )polycycloaryl(C4)alkyl and hetero(Cg.
12 )polycycloary(C,0.)alkyl, wherein said cycloalkyl, heterocycloalkyl, aryl, heteroaryl, polycycloaryl or heterpolycycloaryl ring optionally is substituted by a group selected from -RII, -X 5
OR'
8
-X
5
SR'
3
-X
5
S(O)R'
8
_X
5
S(O)
2 R'g, -X 5
C(O)R'
8
-X
5
C(O)OR'
8
-X
5
OC(Q)R'
8
-X
5 NR2 8
R]
9 ,I -X 5
NR'
9
C(O)R'
8
-X
5
NR'
9
C(O)OR'
8
-X
5 C(O)NR1 8
R'
9
-X
5
S(O)
2
NRIIR'
9
-X
5 NR1 9 C(O)NR1 8
R'
9 or
_X
5
NR'
9
C(NR'
9 )NR'BR'9, wherein R' 8 and R' 9 are as defined above; wherein within R 1 2 and/or R' 3 any alicyclic or aromatic ring system present may be substituted further by I to 5 radicals independently selected from (C 14 6)alkyl, (CI-)alkylidene, cyano, halo, halo-substituted
(C
14 )alkyl, nitro, -X5NR1 4
R'
4
-X
5 NR 1 4 C(O)OR 1 4
-X
5 NR1 4 C(O)NR1 4
-X
5 NR1 4 C(NR1 4 )NR14R4, -X 5 OR 1 4
-X
5 SR 1 4
-X
5 C(O)OR 1 4
-X
5 C(Q)NR 4
R
1 4, -X 5
S(O)
2 NRi 4 R'1 4
-X
5 P(O)(OR1 4 )OR 1 4 -XsOP(O)(OR' 4
)OR,
-X
5
NR
1 4
C(O)R'
5
-X
5 S(O)R 1 5
_X
5
S(O)
2
R'
5 and -X 5 C(O)R 1 5 wherein XI, R 1 4 and R' are as defined above; or
R'
2 together with RI and/or R' 3 together with R" 0 form trimethylene, tetramethylene or phenylene-1,2-dimethylene, optionally substituted with 1 to 3 radicals independently selected from (C,,)alkyl, (C,,)alkylidene, cyano, halo, halo-substituted (C,,)alkyl, nitro, oxo, -X 5
NR'
4 C(O)OR 1 4
-X
5 NR'1 4 C(O)NR 14R14,
_X
5
NR
1 4 C(NR'4)NR 14R14, _X50R 1 4
_X
5 SR 1 4
-X
5 C(O)OR. 4
-X
5 C(O)NR1 4
R'
4
-X
5
S(Q)
2
NR'
4 R 1, -X 5 P(O)(OR 1 4 )OR 1 4
-X
5 Op(O)(OR1 4 )OR 14, -X 5 NR"4C(O)R' 5
-X
5
S(O)R'
5 and -X 5
C(O)R'
5 wherein X5, R 1 4 and R 15 are as defined above; and RI is -X 6
X
7 RI, wherein X 6 is or -S(O) 2 X' is a bond, or wherein R 2 1 is hydrogen or (Cl, 4 )alkyl, and R2' is (C, 4 6)alkyl optionally substituted by cyano, halo, nitro, -NR1 4 R 1 4 -NR 1 4 C(O)OR 1 4 -NR 1 4
C(O)NR
4 R 14, -NR' 4
C(NR'
4 )NR1 4 R 1 4 -OR 1 4 -SR 1 4 -C(O)OR 1 4 -C(O)NR1 4
R'
4
-S(O)
2
NR'
4 R1 4 -P(O)(OR1 4 )OR 1 4
-OP(O)(OR'
4 )OR 1 4
-NR'
4 C(O)R[5, -S(O)R 5 -S(0) 2 R1 5 -C(O)R1 5
-OR
22 -SR22, -S(O)R 22
-S(Q)
2
R
22 -C(O)R22, C(O)0R 22 -C(O)NR2R 23 -R22R2, -NR23C(O)R22, -NR23C(O)OR22, -NR'3C(O)NR'2R2 or -NR23C(NR23)NR22R2, wherein R 1 4 and R 'I are as defined above, R 22 is (C3- 12 )CYCloalky1(CO.)alkyl, hetero(C3-,2)cycloalky1(C, -)alkyl, 12 )ary(C0.)alkyl, hetero(C, 5 j)aryl(C")akl, (Cq~ 12 )bicycloaryl(C")akyI or hetero(C 8 12 )bicycloaryl(C.)alky1 and R23 at each occurrence independently is hydrogen or (C,.6)alkyl, or (ii) (C3- 12 )cycoalkyl(C-)alkyl, hetero(C 3 1 2 )CYC'oalkyl(CO.)alkyl, (C6.1 2 )aryl(CO.
6 )alkyl, diphenyl(C,,6)alkyl, hetero(C 5 12 )ary(C")alkyl, dihietero(Cd)aryl(CO-)alkyl, (C9- 12 )bicycloaryl(C.)alkyl or hetero(C 8 12 )bicycloaryl(C,,)alkyl wherein said cycloalkyl, heterocycloalkyl, aryl or heteroaryl may be substituted by -R 24
-X
5 QR24, -X 5 SR7A, -X 5 S(O)R'4, 2 R 24
_X
5 C(O)R24, -X 5 C(O)OR24, -XSC(O)NR24R 25
-X
5 NR24R2, -X 5 R 25C(O)R 7A -'NR 25 C(O)0R 2 4
_X
5 NR7C(O)NRIR25 or -X 5 NR25C(NR2)NR 2 5, wherein X 5 is as defined above, RI is (C 3 12 )CYCoalkyl(C")alkyl, hetero(C3 1 2 1)cycloalkyl(CO.)alkyl, (C6 12 )arYl(C0_)alkyl, hetero(C5.
12 )aryl(CO-)alkyl, (Cq.1 2 )bicycloaryl(C 0 _6)alkyl or hetero(Cg- 12 )bicycloaryl(CO-)alkyl and R 25 at each occurrence independently is hydrogen or
(C
1 -6)alkyl; wherein within RI any alicyclic or aromatic ring system present may be substituted further by I to 5 radicals independently selected from (C 1 -6)alkyl, (C, 1 6)alkylidene, cyano, halo, halo-substituted (C,-)alkyl, nitro, _X 5 NR"4R' 4
_X
5
NR'
4 C(O)OR 1 4 -XsNR1 4 C(O)NR 14
R
4
-X
5 NqR' 4 C(NR1 4 )TqR] 4 R1 4
_X
5 OR 1 4
-X
5 SR 1 4
-X
5 C(O)OR 1, -X 5 C(O)NR1 4 R 1 4 2
NR
4 R1 4
-X
5 p(O)(OR 1 4 )QR 1 4
-X
5 OP(O)(OR 1 4 )QR1 4 _XSNR1 4
C(O)RI
5
-X
5
S(O)R]
5
-X
5 S(O),R 1 5 and -X 5 C(O)R 1 5 wherein X 5 R 1 4 and R"5 are as defined above; or when X 2 is a divalent group of formula or then R' may also represent hydrogen, carboxy, oxalo or carbamoyl; RI is hydrogen or (G 1 ,)alkyl; RI is (C,,)alkyl optionally substituted with cyano, halo, nitro, -C(O)0R 2
-C(O)NR
24 R24, -P(O)(0R 24 )0R 24 -QP(O)(0R 2 )0R 24 -S(O)R25, -S(O) 2 R 25 or wherein R 24 at each occurrence independently is hydrogen, (C 1 -,)alkyl or halo-substituted
(C
1 3 )alkyl and R' 4
(C
1 -6)alkyl or halo-substituted (C 1 3 )alkyl, or (ii) (C,.)cycloalkyl(C 3 )alkyl, hetero(C'1 6 )Cycloalkyl(C 2 3 )alkyl, (C6- 12 )aryl(C 2 3 )alcyl or hetero(C5_)aryl(C2 3 )alkyl, wherein said cycloalkyl, heterocycloalkyl, aryl or heteroaryl optionally is substituted further with 1 to radicals independently selected from (C 1 -6)alkyl, (C 1 -6)alkylidene, cyano, halo, halo-substituted
(C
14 )alkyl, nitro, -X 5 NR 1 4 C(O)OR 1 4
-X
5
NIR
14
C(Q)NR
4
RI
4
_X
5 NR1 4 C(NR1 4 )NR1 4
R
4
-X
5 OR 1 4 -XISR 1 4
-X
5 C(O)OR 1 4
-X
5 C(O)NR1 4
R'
4
_X
5
S(O)
2
NR
4 R 1 4
-X
5 P(O)(OR 4 )OR1 4 14 )OR 1 4
-X
5
NR'
4
C(O)R'
5 -XsS(Q)R' 5
-X
5
S(O)
2 R 1 5 and -X 5
C(O)R'
5 wherein R 1 4 and R 1 5 are as defined above, provided that when R' is unsubstituted (C 15 )alkyl and R 4 is hydrogen or unsubstituted (C 1 5 )alkyl, then X 2 may not represent a bond when R' is
-C(Q)
2 R.2 or -S(O) 2 RI in which R2' is (C 14 6)alkyl, phenyl(C,.
4 )alkyl, phenyl, (C 7 )CYCloalkyl, canphan-1O-yl, naphth-1-yl, naphth-2-yl, phenyl substituted by one or more of 4 )alkyl, perfluoro(C 1 4 )alkyl, 4 )alkoxy, hydroxy, halo, amido, nitro, amino, (C, 4 )alkylamnino,
(C
14 )dialkylamino, carboxy or (C,,)alkoxycarbonyl, or naphih- I-yl or naphth-2-yl substituted by one or more of (C,,)alkyl, perfluoro(C 3 4 )alkyl, 4 )alkoxy, hydroxy, halo, amido, nitro, amino, carboxy or (C, 14 )alkoxycarbonyl or (ii) a divalent group of formula or in which the moiety R'1 2 is methyl, isopropyl, n-butyl, sec-butyl, tert-butyl, 1-methyipropyl, benzyl, naphth-1-ylmethyl, naphth-2-ylmethyl, thien-2-ylmethyl, thien-3-ylmethyl, or wherein R" and R' 2 form ethylene, trimethylene, hydroxy-substituted trimethylene, tetramethylene or phenylene-1,2-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 8 )cycloalkylene or (C3- 8 )heterocycloalkylene, wherein said cycloalkylene or heterocycloalkylene is optionally substituted with 1 to 3 radicals independently selected from
(C
1 -,)alkyl, (C,.6)alkylidene, cyano, halo, halo-substituted (CI 14 )alkyl, nitro, -XsNRIIC(O)OR 4
-X
5 N R] 4 C(Q)NqR' 4
R]
4
-X
5 NR1 4
C(NR'
4 )NR 1 4 R1', -X 5 OR. 4
_X
5 SR 1 4
-X
5
C(O)OR
4
-X
5 C(O)NR'1 4 R1 4
-X
5
S(O))
2 NR1 4
R.
14
-X
5 p(O)(OR1 4 )OR 1 4 -X5OP(O)(OR. 4 )OR 14,
_X
5 NR1 4 C(O)R 1 5
_X
5
S(O)R'
5 -XsS(O) 2 R 1 and -X 5
C(O)RI
5 wherein XI, R.' 4 and R1 5 are as defined above; RI and RI taken together with the carbon atom to which both R 3 and R 4 are attached form (C 38 )cycloalkylene or (C,,)heterocycloalkylene, wherein said cycloalkylene or heterocycloalkylene is optionally substituted with 1 to 3 radicals independently selected from
(C
1 -6)alkyl, (CI-6alkylidene, cyano, halo, halo-substituted (CI-4)alkyl, nitro, -X 5 NR1 4 C(O)QR 1 4
X
5 NR1 4 C(Q)NR1 4 R 1 4
_X
5 NR 1 4 C(NR1 4 )NR1 4 R 1 4
_X
5 OR 1 4
-X
5 SR' 4
-X
5 C(O)OR 1 4
-X
5 C(O)NR. 4
R
1 4
-X
5
S(O)
2
NR'
4 R 1 4
-X
5 P(O)(OR 1 4 )OR 4
-X
5 Op(O)(OR1 4 )OR4,
-X
5 NR 4
C(O)R'
5 _XsS(O)RI5, -X 5
S(Q)
2
R'
5 and -X 5
C(O)R'
5 wherein X5 R 1 4 and R"5 are as defined above; R 4 is hydrogen, (C 16 )alkyl or as defined above; R' 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)0R 29
_X
5 NR30C(O)NR 29 R,3, _X 5 NR0CN 30 )NR29R3, -X 5 0R 29
-X
5
SR.
29
_X
5 C(O)0R 29
-X
5 C(O)NR 29
R
30
-X
5 S(0),NR 29 R30, -X 5 P(O)(0R 3 0 )0R 2 9
-X
5
OP(O)(OR
2 )OR 2 9
-X
5
NR
30 C(Q)R20, -X 5
S(O)R
20
-X
5
S(O),
2 R0~, -X 5 IC(O)R20 and -C(O)NR 4 2
CHR
43 C(O)0R 29 wherein X' and R20 are as defined as above, R 29 is hydrogen or -R20, wherein R20 is defined as above, R 30 at each occurrence is hydrogen or (C, 4 6)alkyl, R 42 is hydrogen, (C, 4 6)alkyl or together with R 43 forms trimethylene, tetraniethylene or phenylene-1,2-dimethylene, optionally substituted with hydroxy or oxo, and R1 3 is as defined above or is (C 1 -6)alkyl optionally substituted with cyano, halo, nitro, -NR"R' 4 -NR1 4 C(Q)OR 1 4
-NR'
4 C(O)NR1 4
R
4 -NqR' 4
C(NR]
4 )NR1 4
R]
4 -OR1 4 -SR'1 4
_C(O)NR
4 R'1 4
-S(O)
2
NR'
4 R 1 4
-P(O)(OR'
4
)OR'
4 -OP(O)(OR1 4 )OR 1 4 -NR1 4
C(O)R'
5 5
-C(O)R
5
-OR'
6
-SR'
6
-S(O)R
6 -S(0) 2 R1 6
-C(O)R'
6 ,I -NR1 6 R1 7 -NR1 7
C(O)RI
6 -NR17C(O)OR 6
-C(O)NR'
6 R"7, -S(O) 2
NR'
6 R"7, -NqR' 7 C(O)NR1 6
R
7 or -NIR1C(NRI 7 )NR1 6 R17 or (ii) a group selected from (C3-1 2 )cycloalkyl(CO.)alkyl, hetero(C3-1 2 )cycloalkyl(C")alkyl, (C6-1 2 )aryl(CO.)alkyl, hetero(C 512 )aryl(C 06 )alkyl, (Cg.1 2 )polycycloary](CO.
6 )alkyl and hetero(Cg- 1 2 )polycycloaryl(cO)alkyl, wherein said cycloalkyl, heterocycloalkyl, aryl, heteroaryl, polycycloaryl or heterpolycycloaryl ring optionally is substituted by a group selected from -R" 8
-X
5
QR'
8
-XISR'
8 -XIS(O)RII, -X 5
S(O)
2
R
8
-X
5
C(O)R'
8 -XsC(O)OR' 8
-X
5
OC(O)RIB,
9
-X
5 NR1 9
C(O)RI'
8
-X
5
NR'
9
C(O)OR'
8
-X
5
C(O)NR
8
R'
9
-X
5
S(O)
2
NR'
8 Rt 9
-X
5
NR'
9
C(O)NR'
8
R'
9 or -X 5
NR'
9
C(NR'
9 )NR1 8
R'
9 wherein X 5 R1 4 R1 5 R1 6 R17, R' 8 and R' 9 are as defined above; wherein within R' 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, -X 5 NR1 4
R'
4
-X
5 NR1 4 C(O)OR1 4
-X
5 NR1 4 C(O)NR4R4, -X 5 NR1 4
C(NR
4
)NR
4
R]
4
-X
5
ORI
4
-X
5 SR' -X 5
C(O)OR
4
-X
5 C(O)NR"W 1, -X 5
S(O)
2 NR 1 4 R1 4
-X
5 P(O)(OR 1 4
)OR'
4 -X'OP(O)(OR1 4 )OR'1 4
-X'NR'
4
C(O)R
5
-X-S(O)R'
5 -X5S(O) 2
R'
5 and -X 5
C(O)R'
5 wherein XI, R1 4 and R1 5 are as defined above; and
R
8 at each occurrence independently is selected from (C,-6)alkyl, halo-substituted 4 )alkyl, (C 1 -6)alkylidene, cyano, halo, halo-substituted 4 )alkyl, nitro, -X 5
NR'
4 R1 4
-X
5 NR1 4 C(O)OR14, -X 5 NR1 4
C(O)NR
4
R
4
_X
5 NR"4C(NR1 4 )NR1 4 R4. -X 5
ORI
4
-X
5
SR'
4
-X
5 C(O)OR1 4
-X
5
C(O)NR'
4
R'
4
_X
5
S(O)
2 NR1 4 R1 4
-X
5 P(O)(OR 4
)OR
4
-X
5 Op(O)(OR' 4 )oR14, -X 5 NR1 4 C(Q)R -X 5
S(O)R'
5
_X
5
S(O)
2
R'
5 and -X 5
C(O)R
5 wherein
X
5 is a bond or (C, 4 )allcylene, R1 4 at each occurrence independently is hydrogen, (C,-6)alkyl or halo-substituted 3 )alkyl and R15 (C,,)alkyl or halo-substituted 3 )alkyl; and the N-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: R 32 S x 8 R2 R5 6 I R RJ, NR7 N R 9 0 R R4(R8n 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 to 7 ring member atoms, XI is a ring member carbon atom and each ring member atom other than XV is a carbon atom or a heteroatom, with the proviso that at least one ring member atom is a heteroatom; n isO0, 1, 2or 3; XV is or -CH-;
X
3 s 2 )alkylene; R I is hydrogen, carboxy, oxalo, carbamoyl or -XIX 7
R
20 wherein X' is or X" is a bond, or -NR 1 wherein is hydrogen or 6 )alkyl, and R' is (C, 6 )alkyl optionally substituted by cyano, halo, nitro, _NR1 4 R1 4 -NR 1 4 C(O)OR 1 4 -NR 1 4
C(O)NR
4 R 1 4 -NR 1 4 C(NR1 4
)NR
4 R 1 4 -OR 1 4 -SR 1 4 -C(O)OR 1 4 -C(O)NR'1 4 R1 4
-S(O)
2 NR 1 4 R1' -P(O)(OR 1 4 )OR 1 4 -OP(Q)(OR'")OR 1 4
-NR'
4 C(O)R 1 5 -S(O)RIS, -S(O) 2
RI
5 -SR22, -S(O)R 22
-S(O)
2
R
2
-C(O)R
22 -C(O)OR -C(O)NRR,
-NR
22 R23, -NR 23 C(O)R 22 -NR 23 C(O)0R',-NRIC(0)NRIRI or -NR23C(NR23)NR22R 3 wherein R 1 4 at each occurrence independently is hydrogen, (C 1 -6)alkyl or halo-substituted
(C
13 )alkyl, R 1 5 is 6 )alkyl or halo-substituted 3 )alkyl, R 22 is (Q,,)cycloalkyl(C")alkyl, hetero(C3-1 2 )cycloalkyl(CO-)alkyl, (C6.1 2 )aryI(CO 6 )alkyl, hetero(C,.
12 )ary](C.)alkyl,
(C
9 12 )bicycoary(C")alkyl or hetero(C 8 2 )bicycloaryl(C.)alkyI and RI3 at each occurrence independently is hydrogen or (C,-6)alkyl, or 00i (C 3 .1 2 )CYCloalkyl(CO-)alkyI, hetero(C3-, 2 )CYCloalkyl(C,,)alkyl, (C1 1 2 )aryI(C )alkyl, hetero(C.,_ 2 )arYl(C0.)a]ky1,
(C
91 2 )bicycloary(C~dalky1 or hetero(Cg-1 2 )bicycloaryl(C,0.)alkyl or (iii) (C3,)cycloalkyl(CO-)alkyl, hetero(C 3 -6)Cycloalkyl(Co.)alkyl, phenyl(CO.)alkyl or hetero(C 5 6 )aryl(CQ 6 )alkyl substituted by -X 5 0R 2
-X
5
SR
24
-X
5 S(O)R 24 _X5S(O) 2 R24,
_X
5 C(O)R 24
-X
5 C(O)0R 24
-X
5 C(O)NR24R2, -X 5 NRU'R2, _XSNR 2 5 C(O)R24,
-X
5 NR2C(O)OR24, -X 5 NR25C(O)NTR'R 2 1 or -XSNR'C(NRS)NR24R, wherein X5 is a bond or (C,-6)alkylene, RI' is (C 3 6 )CYCloalkyl(Cu)alkyl, hetero(Cm)cycloalkyI(CO-)alkyl, phenyl(C 1 6 )alkyl or hetero(C5_)aryl(C0_)alky1 and R 2 at each occurrence independently is hydrogen or (CI-6)alkyl; wherein within R' any alicyclic or aromatic ring system present may be substituted further by I to 5 radicals independently selected from (C, 14 )alkyl, (C,.6)alkylidene, cyano, halo, halo-substituted (C,,)alkyl, nitro, -XsNRIRI 4
-X
5
NR'
4
C(O)OR
4 -XsNR 1 4 C(O)NR"1R14, _X5 NR'1 4 C(NR1 4 )NR4R4, -X 5 OR 1 4
-X
5 SR 1 4
-X
5 C(O)OR'1 4
-X
5 C(O)NR"4R' 4
_X
5
S(O)
2 NR1 4 R1 4
-X
5
P(O)(OR'
4 )OR'1 4
-X
5 OP(O)(OR1 4
)OR',
-XsNR1 4 C(O)R 1 5
-X
5
-X
5
S(O)
2
R'
5 and -X 5 C(O)R 1 5 wherein X 5 R 1 4 and RI5 are as defined above; R 2 is hydrogen or (C, 4 6)alkyl; RI is (C 1 -6)alky1 optionally substituted with cyano, halo, nitro, -NR'1 4
R'
4
-NR'
4 C(O)OR'1 4 -NR'1 4 C(O)NR"IR', -NR1 4
C(NR'
4
)NR
4 R'1 4 -OR 14 -SR'1 4
-C(O)OR'
4
_C(O)NR
4 R 1 4
-S(O)
2
NR'
4
R]
4 -P(O)(OR'1 4 )OR 1 4 -QP(O)(QR 1 4 )OR'1 4
-NR'
4 C(Q)R 1 5 -S(O)R1 5
-S(O)
2
R'
5 -C(O)R'1 5 -OR'1 6 -SR'1 6
-S(O)RI
6
-S(O)
2 RI', -C(O)R' 6
-C(O)OR',
-OC(O)RII, _NR1 6 R1 7
_NR'
7 C(O)R'1 6
-NR'
7
C(O)OR
6
-C(O)NR
6
R]
7
-S(O)
2 NR1 6
R'
7
-NR'
7 C(O)NR1 6 R 1 7 or _NR1 7 C(NR1 7 )NR16RI 7 wherein R 1 4 at each occurrence independently is hydrogen, (C,,)alkyl or halo-substituted (C, 1 3 )alkyl, R' 5 is (C, 1 6)alkyl or halo-substituted 3 )alkyl, R 1 6 is (C 3 12 )CYCloalky1(C 0 _6)a1kyl, hetero(Qi- 2 )cycloalkyI(CM)alkyl, 2 )arYl(C0.
6 )alkyl, hetero(C 512 )aryl(C04)alkyl, (CqI2)polycycloaryl(C0)alkyl or hetero(Cg.,)polycycloaryl(Cm)alkyI and R 1 7 is hydrogen or (C,-6)alkyl, and wherein within R' 6 said cycloalkyl, heterocycloalkyl, aryl, heteroaryl, polycycloaryl or heterpolycycloaryl ring optionally is substituted by a group selected from -X'Q R' 8
_X
5 SR'I, -XIS (O)R 1
-X
5
-X
5 C(Q)R'8, -X 5
C(O)OR
8
-X
5
OC(O)R'
8
-X
5
NR'
8
R'
9
-X
5 NR1 9 C(O)Rlg,
-X
5
NR'
9
C(O)ORI
8
-X
5
C(O)NR'
8 RI', -X 5
S(O)
2 NR'sR' 9
-X
5
NR'
9
C(O)NR'
8
R'
9 or -XsNR' 9
C(NR'
9 )NR8RI9, wherein X1 is as defined above, R' 8 is hydrogen or (C,-6)alkyl and
R'
9 is (C 3 2 )CYCloalkyl(C")alkyl, hetero(C 312 )cycloalkyl(CO-)alkyl,
(C
61
I
2 )aryl(C0_)alkyl, hetero(C.
12 )arYl(CQ 6 )alkyl, 12 )polycycloary1(C,)alkyl or hetero(Ca.
12 )polycycloaryl(Cm)alkyl, or (ii) a group selected from (C3.
12 )CYC~oalkyI(C0.,)alky1, hetero(C 12 )cycloalkyl(Cm)alkyl, (C 6 12 )aryl(CO.
6 )alkyl, hetero(CQ 1 2 )aryl(C0.)alkyl,
(C
9 12 )polycycloaryl(CQ-)alkyl and hetero(CS.
12 )POlYCYClOarYl(C( .)alky1, wherein said cycloalkyl, heterocycloalkyl, aryl, heteroaryl, polycycloaryl or heterpolycycloaryl ring optionally is substituted by a group selected from -R' 8 -XIOR1 8 -X5SR's, -X 5
S(O)R'
8
-X
5
S(O)
2
R'
8 8
-X
5
C(O)QR'
8
-X
5
QC(O)R'
8
_X
5
NR
18
R'
9
-X
5 NR1 9
C(O)R]
8
-X
5
NR
9
C(Q)QR
8
-XSC(O))NRIBR]
9
-X
5
S(Q)
2
NR'
8
R'
9
-X
5
NR'
9
C(O)NR'R'
9 or -X 5 NR1 9
C(NR
19
)NR
8
R
9 wherein X1, R' 8 and R" 9 are as defined above; wherein within R 1 2 and/or R' 3 any alicyclic or aromatic ring system present may be substituted further by 1 to 5 radicals'independently selected from (C,,)alkyl, (C 1 -6)alkylidene, cyano, halo, halo-substituted (C,,)alkyl, nitro, _XSNR1 4 R1 4
-X
5
NR'
4 C(Q)OR 1 4
-X
5 NR 4
C(O)NR
4 R 14
-X
5 NR1 4 C(NR1 4 )NR'1 4 R1 4
-X
5 OR'1 4
-X
5 SR 1 4
-X
5 C(O)OR 1 4
_X
5 C(O)NR1 4
R
4
_XSS(O)
2
NR
4
R
4
-X
5
P(O)(OR'
4 )QR 1 4
-X
5 OP(Q)(QR 1 4 )OR 1 4
-X
5 NR'1 4
C(O)R'
5 -XsS(O)R'1 5
-X
5
S(Q)
2 R 1 5 and _X 5
C(Q)R'
5 wherein
X
5 R 1 4 and R' 5 are as defined above, or R 3 and R 4 taken together with the carbon atom to which both R 3 and R 4 are attached form (C3-g)cycloalkylene or (C3,)heterocycloalkylene, wherein said cycloalkylene or heterocycloalkylene is optionally substituted with 1 to 3 radicals independently selected from (Ci-6)alkyl, (C 14 6)alkylidene, cyano, halo, halo-substituted (C 14 )allcyl, nitro, -X 5 NR 1 4 C(O)OR'1 4
-X
5 NR1 4 C(O)NR1 4 R 1 4
-X
5
NR]
4 C(NR1 4 )NR1 4 R1 4
-X
5 QR 1 4
-X
5 SR 1 4
-X
5 C(O)OR 1 4 4 R 1 4
_X
5
S(Q),NR
4 R 1 4
-X
5 p(O)(OR1 4 )OR1 4
-X
5 OP(O)(OR1 4 )QR 1 4
-X
5 NR 1 4 C(O)R 1 5
-X
5 S(O)R 1 5
-XSS(Q)
2
R'
5 and -X 5 C(O)R 15 wherein X 5
R'
4 and R" 5 are as defined above; RW is hydrogen, (C 1 -,)alkyl or as defined above; R' is hydrogen and R 6 is hydroxy or R 5 and RI together form oxo; R" is a group selected from cyano, halo, nitro, -X'NR 2 9 R30, _X5 NR3C(O)OR 9
-X
5
NR
30 C(O)NR29R 30
_X
5
NR
3 0 C(NR 30
)NR
29 R30, _X 5 OR29, -X 5
SR
29
-X
5 C(O)0R 29
-X
5
C(O)NR
29 R30, -X 5 S(0) 2 NR29R3, -X 5 P(O)(0R 30 )0R 29
-X
5 QP(O)(OR2)OR 29
-X
5
NR
30 C(O)R 31
-X
5
S(O)R
1
-X
5
S(O)
2 R 3 and -X 5 C(O)R 3 1, wherein XI is as defined above, R9 is hydrogen or -R 3 R30 at each occurrence is hydrogen or (C 16 )alkyl and R 3 1 is (C, 14 )alkyl,
(C
3 12 )CYCIo'alkyl(C")alkyl, hetero(C3.
12 )CYCloalkyl(CO.)alkyl, (C~ 1 jaryl(C")alkyl or hetero(C.
12 )ary](Cu)alkyl, wherein within R' any alicyclic or aromatic ring system present may be substituted further by 1 to 5 radicals indepen .dently selected from (C 1 -,)alkyl, 6 )allcylidene, cyano, halo, halo-substituted (C,,)alkyl, nitro, -X 5
NR'
4 R, -X 5 NR 4
C(O)OR'
4
-X
5 NR1 4
C(O)NR
4 R 1 4
-X
5 NR1 4
C(NR]
4
)NR
4 R 1 4
-X
5 OR 1 4
-X
5 SR 1 4
-X
5 C(O)OR1', -XJC(O)NR'1 4 R1 4
-X
5
S(O)
2
NR'
4
R]
4
-X
5 P(O)(OR1 4 )OR 1 4
-X
5
OP(O)(OR'
4 )OR1 4
-X
5 NR 1 4 C(O)R 1 5
-X
5
S(O)R'
5
-X
3
S(O)
2 R 1 5 and _X5 C(O)R 15 wherein XI, R 1 4 and R' 5 are as defined above; and RI at each occurrence independently is selected from 6 )alkyl, (C 14 ,)alkylidene, cyano, halo, halo-substituted (C 14 )alkyl, nitro, -XINR1 4 R 1 4
_X
5 NR1 4 C(Q)QR"4,
_X
5 NR 1 4
C(O)NR'
4
-X
5
NR
24 C(NR")NR1 4
-X
5 OR 1 4
-X
5 SR 1, -X 5
C(O)OR'
4
-X
5 C(O)NR"4RI 4
-X
5
S(O)
2
NR'
4
R]
4
-X
5 P(Q)(OR'1 4 )OR 1, -X 5 Op(O)(OR 1 4 )OR 1 4
-X
5 NR 1 4 C(O)R 1 5
-X
5
S(O)R]
5
-X
5 and -X 5
C(O)R
5 wherein X 5 R1 4 and R' 5 are as defined above; R' is hydrogen or -)alkyl; and
R
32 is (C 1 .&)alkyl, (C3 2 )CYCloalky](CO-)alkyl, hetero(C 312 )cycloalkyl(C ")alkyl, 12 )arYl(CO.
6 )alkyl, hetero(Cs.
12 )ary](C,.6)alkyl, (C9.
1 2 )POlYCYCloaryl(C( 6 )alkyl or hetero(Cs.
12 )POlycycloary](CO- 6 )alkyl, wherein within R 3 any alicyclic or aromatic ring system present may be substituted further by 1 to 5 radicals independently selected from (C,,)alkyl,
(C,
1 6)alkylidene, cyano, halo, halo-substituted (C 14 )alkyl, nitro, -X 5
NR'
4 R1 4 -X5 NR"C(O)QR 4
-X
5
NR'
4 C(O)NR1 4 R 1 4
-X
5
NR'
4
(R
4
)NR
4 R 14
-X
5 OR 1 4
-X
5 SR 1 4
-X
5 C(O)OR 1 4 -XSC(O)NR1 4
RI
4
-XIS(O)
2
NR
4 R 1 4
-X
5 P(O)(OR1 4 )OR'1 4
-X
5 Op(O)(QR 1 4 )OR 1 4
-X
5 NR 1 4 C(O)Rls, -X 5 S(O)R 15
-XSS(O)
2 R 1 and _X 5 C(O)R"5, wherein X5, R 1 4 and R 1 5 are as defined above; and the N-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 pharnaceutical 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 ameli orate 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 N-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 N-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 I:
R
2
R
6 R R X 2/ X CA
R
3
R
4
RA
IIl 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, X' is an annular carbon atom and each annular atom other than X' 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' is selected from and -CH-;
X
2 is a bond or a divalent group of Formula or Ro 0 'N 'Xj Y NX6 N N 'X R R9 (b) wherein:
X
3 and X 5 independently are or -S(O) 2
X
4 is -CHCHR"- or -CHR" CH 2 and X 6 is -CHR 12
-CHCHR'
2 or -CHR CH 2 wherein: R" and R 12 are independently (Ci.
6 )alkyl or halo-substituted(C 4 )alkyl optionally substituted with -OR 1 3
-S(O)R'
3 -17-
-S(Q)
2
R'
3 -C(O)R'1 3 -C(O)OR 1 3 -NR1 3 R 1 4 -NR14C(O)OR 1 3
_C(O)NR
3 R. 4
-S(O)
2 NR1 3 R1 4
-NR.'
4
C(Q)NR
3 R 1 4 or -NR' 4 C(NR 1 4 )NR1 3 R 1 4 wherein R 1 3 is hydrogen, (CI-6)alkyl, (C 3 12 )cycloalky1(CO.
3 )alkyl, hetero(C 3 1 2 )cycloalky1(C 3 )alkyl, (C6-1 2 )arYl(CO- 3 )alkyl or hetero(C5-1 2 )aryl(CO- 3 )alkyI and R 1 4 is hydrogen or (C 14 6)alkyl, or (ii) (C 3 -,2)cycloalkyl(CO- 3 )alkyl, hetero(C3_1 2 )cycloalky(CO 3 )alkyl, (C6.1 2 )arYl(CO.
3 )alkyl, hetero(C5, 2 )ayl(CO- 3 )alkyl, (C9-, 2 )P0lycycloary(CO- 3 )alkyl or hetero(Cg-1 2 )polycycloary(CO 3 )a'lcyl optionally substituted with 5
_X
7
OR'
5
_X
7 SR1 5
-S(O)R'
5
-S(O)
2 RI", -C(O)R 1 5 -C(O)OR 1 5
_X
7 NR1 5 R 1 6
_X
7 NR1 6
C(O)OR'
5 -C(O)NR5R 1 6
-S(O)
2 NR 1 5 R1 6 -NR 6 C(O)NR1 5 R 1 6 or -NR. 6 C(NR1 6
)NR]
5 R. 6 wherein X 7 is a bond or methylene, R1 5 is
(C
3 1 )cycloalkyl(CO- 3 )alky1, hetero(C3i, 2 )cycloalky(C.
3 )alkyl, (C6-1 2 )aryl(CO.
3 )alkyl, hetero(C., 2 )ary](CO 0 3 )alkyl, (C 9 1 2 )PolYCYC10aryl(CO.
3 )alkyl or hetero(C&1 2 )polycycloary(CO, 3 )alkyl and R11 is hydrogen or (C, 4 6)alkyl, or (iii) together with RI or R' 0 respectively, when V 4 is -CHR1"- and/or X11 is -CHRII-, forms nimethylene, tetramethylene or phenylene-1,2-dimethylene, optionally substituted with hydroxy or oxo; wherein any I to 3 annular atoms of any aromatic ring with available valences comprising RII and/or R1 2 are optionally independently substituted with halo, nitro, cyano, (C,-6)alkyl, halo-substituted(C,-6)alkyl,
-OR"
7 -C(O)R 1 7 -C(O)qR 7 R'1 7
_S(O)
2
NR'
7
R]
7
_X
7 NR1 7 R. 7
-X
7
NR'
7 C(O)OR 1 7 _X7 NR1 7 C(O)NR1 7 R 1 7 or
-X
7 NR 1 7
C(NRI
7 )NR1 7 R 1 7 wherein X 7 is as defined above and each R 1 7 independently is hydrogen or (C,-6)alkyl; and
R
9 and RIO are independently hydrogen, (C 1 6 )alkyl or as defined above; R' is hydrogen or -XWXR' 8 wherein X1 is or 3(9 is a bond, or
-NR'
9 wherein R" 9 is hydrogen or (C,.6)alkyl, and R11 is (C, 4 6)alkyl or halo-substituted(C,.6)alkyl optionally substituted with -OR'1 3 -SR 1 3 3
-S(O)
2 R 1 3
-C(O)R'
3
-C(O)OR'
3 -qR' 3 R 1 4 _pM1 4 C(O)QR 1 3 9 -C(O)NR' 3 R1 4
S(O)
2 NR1 3 R 1,
-NR'
4 C(Q)NR1 3 R 1 4 or -NR' 4
C(NR
4
)NR
3 R, wherein R' and R.
4 are as defined above, or (ii) (C .I 2 )cycloalkyl(CO_)alkyl, hetero(C-3, 2 )CYCloalkyl(CO.)alkyl, (C6-1 2 )arYl(CO-)alkyl, diphenyl(CO4)alkyl, hetero(C 512 )ary](CO.)alkyl, dihetero(Cs-6)ary](CO-)alkyl, (Cg-1 2 )polycycloary](C(, 6 )alkyI or hetero(Cs-1 2 )polycycloaryl(CO-)alkyI optionally substituted with -R1 5 _X7 OR' 5
-X
7
SR'
5
-S(O)
2
R'
5
-C(O)R'
5 -C(O)OR"5, -'NR 5 R'1 6
-X
7
NR'
6 C(O)OR15, -C(O)NR"5R 6 -S(0) 2 NR15R1 6
-NR'
6
C(O)NR
5
RI
6 or _NR1 6 C(NR1 6 )NR'sR] 6 wherein X 7
R'
5 and R' 6 are as defined above; wherein any I to 3 annular atoms of any aromatic ring with available valences comprising R' optionally independently are substituted with halo, nitro, cyano, (C,.6)alkyl, halo-substituted(C,.,)alkyl,
-OR'
7
-C(O)R'
7 -C(O)OR1 7 -C(O)NR1 7 R' 7
-S(O)
2
NR'
7
R'
7 -X'7NR1 7
R
7
-X
1
NR'
7
C(O)OR'
7 -X'NR"C(O)NR 7
R'
7 Or -X 7 NR"7C(nR' 7
)NR
7
R]
7 wherein X 7 and R17 are as defined above; R' is hydrogen or (C,-6)alkyl;
R
3 is phenyl(C 2 3 )alkyl, hetero(C.,)aryl(C 2 3 )alkyl, (C 5 -6)cycloalkyl(C2.
3 )alkyl or hetero(C 5 _)cycloalky1(C 2 3 )alkyl, wherein any I to 3 annular atoms of any aromatic ring with available valences comprising R 3 optionally independently are substituted with halo, nitro, cyano,
(C,
4 6)alkyl, halo-substituted(C,,)alkyl, -C(O)OR"7, -C(O)NRIR"7, -S 2 RR7, -X'NR"R" _X 7 NR"7C(O)OR" -X 7 NR"7C(O)NR"7R" or -X7NR17C(NR")NR"R", wherein X7 and R17 are as defined above, and R" is hydrogen or R and R' are both methyl, ethyl or propyl or together with the carbon atom to which both R 3 and R"are attached form cyclopropylene, cyclobutylene or cyclopentylene; RI is hydrogen and R 6 is hydroxy or RI and R 6 together form oxo; R7 is halo, nitro, -R 20 -OR20, -C(O)QR20, -S(O) 2 NR 2R 21
-C(O)NR'R
21 or -C(O)NRz 2 CHR23C(O)ORI and bonded to any annular carbon atom with a free valence comprising A, wherein: is hydrogen or R" 8 wherein R 8 is as defined above; R1 1 is hydrogen or 6 )alkyl; R11 is hydrogen, 6 )alkyl or together with RI forms triniethylene or phenylene-l,2-dimethylene, optionally substituted with hydroxy or oxo; and R13 is as defined above or is 6 )alkyl or halo-substituted(C,,)alkyl optionally substituted with -OR' 3
-S(O)R'
3 -S(0) 2 R1 3
-C(Q)R'
3 -NR1 3
R'
4
-NR'
4 C(O)OR", -C(Q)NR"3R 4
-S(O)
2 NR1 3
R'
4 -NR1 4 C(O)NR"3R 4 or -NR1 4
C(NR]
4 3
RI
4 wherein R13 and R1 4 are as defined above, or (ii) (C3,, 0 )cycloalkyl(CO.3)alkyl, hetero(C3,1 0 )cycloalkyl(CO- 3 )alkyl, (C6 12 )aryl(CO,)alkyl, hetero(C5_1 2 )aryl(C 3 )alkyl, (C 9 2 polycycloaryl(C0.
3 )alkyl or hetero(Ca., 2 )polycycloaryl(CO-3)alkyI optionally substituted with -RI 5
-X
7 OR", -X7SR 5 -19-
-S(O)R'
5
-S(O),R
1
-C(O)R'
5
-C(O)OR'
5
-X
7
NR
5
R'
6 -X'NR6C(O)OR 5
-C(O)NR
S
R
6
-S(O)
2
NR
5
R'
6
-NR'
6
C(O)NR'SR
6 or -NR' 6
C(NR'
6
)NR'
S
R'
6 wherein X 7
R
1 5 and R' 6 are as defined above; wherein any 1 to 3 annular atoms of any aromatic ring with available valences comprising R 20 and/or R 2 optionally independently are substituted with halo, nitro, cyano, (C,-)alkyl, halo-substituted(C )alkyl, -OR' 7
-C(O)R
17
-C(O)OR
1 7
-C(O)NR
7
R"
7
-S(O)
2
NR'
7
-X
7 NR1 7
R'
7
-X
7
NR'
7
C(O)OR'
7
-X
7
NR'
7
C(O)NRI'
7
R
7 or -X 7
NR'
7
C(NR'
7
)NR'
7
R
1 7 wherein X 7 and R' 7 are as defined above; and
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 N-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 purposes 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 (C,)alkenyl as used in this Application to define R 3 2 includes 2-bromovinyl (-CHCHBr), buta-1,3-dienyl (-CHCH-CHCH,), 2-chloro-l-methylpropenyl
(-C(CH
3
)CCI-CH
3 2-chlorovinyl (-CHCHCI), 4-isopropenyl (-C(CH3)CH), 1-methylpropenyl
(-C(CH
3
)CH-CH
3 2 -methylpropenyl (-CHC(CH 3 2 2-nitrovinyl (-CHCHNO), propenyl (-CHCH-CH 3 2-trifluoromethylvinyl
(-CH.CH-CF
3 trifluorovinyl (-CFCF 2 vinyl (-CHCH 2 and the like).
"Alkoxy" means the radical -OR, wherein R is alkyl as defined in this Application, having the number of carbon atoms indicated (C,,)alkoxy includes the radicals methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, isobutoxy, tert-butoxy, vinyloxy, allyloxy, 1-propenyloxy, isopropenyloxy, I1-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 (C.
4 )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 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 (C- 12 )aryl(Co)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,,)alkylene includes methylene (-CH 2 ethylene (-CHCH 2 trimethylene (-CH 2
CHCH
2 2-methyltrimethylene
(-CH
2
CH(CH
3
)CH
2 tetramethylene (-CH 2
CH
2 CHCH,-), 2-butenylene
(-CH
2
CH=CHCH
2 2-methyltetramethylene
(-CH
2
CH(CH
3
)CHCH
2 pentamnethylene
(-CH
2
CHCH,CH,CH
2 and the like). For example, a group of Formula wherein R" is hydrogen and R' 2 taken together with R 9 forms optionally substituted trimethylene is depicted by the following illustration: N X3
I
R
in which R is an optional hydroxy or oxo group and X' and R' 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
(C.
6 ,)alkylidene includes methylene
(CH
2 ethylidene (CHCH 3 isopropylidene (C(CH 3 propylidene (CHCHCH 3 -21allylidene (CHCHCH 2 and the like).
"Amino" means the radical -NH 2 Unless indicated otherwise, the compounds of the invention containing amino moieties include protected derivatives thereof. Suitable protecting groups for amino moieties include acetyl, rert-butoxycarbonyl, benzyloxycarbonyl, and the like.
"Animal" includes humans, non-human mammals dogs, cats, rabbits, cattle, horses, sheep, goats, swine, deer, or the like) and non-mammals 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,(C,-1 2 )aryl as used in this Application to define R' 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 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 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 (C 3 1 2 )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 R 3 and R 4 together with the carbon atom to which both R 3 and R 4 are attached form (C3.8)cycloalkylene" includes, but is not limited to, the following:
R
2
R
5 R6
R
2
R
5 6 in which 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, 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)NH 2 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 halo-substituted
(C
1 3 )alkyl includes chloromethyl, dicloromethyl, difluoromethyl, trifluromethyl, 2 ,2,2-trifluoroethyl, perfluoroethyl, 2,2,2-trifluoro-1,1-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 -NR-, or 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,, 2 )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 or wherein R is hydrogen,
(C
1 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, or wherein R is hydrogen, (CI)alkyl or a protecting group, and any carbocyclic ketone, thioketone or iminoketone derivative thereof the term hetero(Cs 1 2 )cycloalkyl includes [1,4']bipiperidinylyl, dihydrooxazolyl, morpholinyl, 1-morpholin-4-ylpiperidinyl, 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 R' is piperidin-4-ylcarbonyl may exist as either the unprotected or a protected derivative, e.g.
wherein RI is 1-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 or -S(O) 2 wherein R is hydrogen or (C,6)alkyl. For example, the instance wherein R 3 and R 4 together with the carbon atom to which both R 3 and
R
4 are attached form hetero(Cz.)cycloalkylene" includes, but is not limited to, the following:
R
2 R R6 R 2
R
5
R
2 R 2 0 0 in which R is hydrogen, (C,4)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. 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, morpholinyl, 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 or wherein R is hydrogen, (C 4 ,)alkyl or a protecting group, and any carbocyclic ketone, thioketone or iminoketone derivative thereof.. For example, hetero(C.z 2 ,)polycycloaryl includes 1',2'-dihydro-2H-[1,4']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 wherein R is hydrogen or (C.,)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 n 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 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 "Nitro" means the radical -NO 2 "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,,)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.
"N-oxide derivatives" means a derivatives of compound of Formula I in which nitrogens are in an oxidized state O-N) and which possess the desired pharmacological activity.
"Oxo" means the radical=O.
"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, p-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, p-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, N-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. For example, a group of Formula in which R 1 2 together with R 9 forms optionally substituted phenylene-1,2-dimethylene is illustrated by the following formula: I in which R is an optional hydroxy group and X 3 and R' 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 1 )polycycloaryl includes indanyl, indenyl, 1, 2 3 ,4-tetrahydronaphthalenyl, 1,2-dihydronaphthalenyl, cyclohexylphenyl, phenylcyclohexyl, 2,4-dioxo-1,2,3,4-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 For example an ester of a compound of formula containing a hydroxy group may be convertible by hydrolysis in vivo to the parent molecule. Alternatively an ester of a compound of Formula 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-p-toluoyltartrates, methanesulphonates, ethanesulphonates, benzenesulphonates, p-toluenesulphonates, cyclohexylsulphamates and quinates. Suitable esters of compounds of Formula containing a carboxy group, are for example those described by F.J.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 (morpholino-methyl)benzoates, e.g. 3- or 4-(morpholinomethyl)-benzoates, and 4 -alkylpiperazin-l-yl)benzoates, e.g. 3- or4-(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: 1 3
R
2
/X\
1 0 0 R X 2R4 in which X' 3 is a bond, straight, saturated ethylene or (-CH 2
CR
4 1
R
4 2
CH
2 wherein R 41 and R 42 independently are hydrogen, halo or 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 2Samino-N-(2-benzooxazol-2-yl-2-hydroxy-1S-phenethylethyl)-3-cyclohexylpropionamide Compound 55, described in Example 6, infra) may be protected with a suitable amino protecting group, e.g. 9H-fluoren-9-ylmethoxycarbonyl, or a suitable hydroxy protecting group, e.g. tertbutyldimethylsilanyl, to provide, respectively, 9H-fluoren-9-ylmethyl 1S-(2-benzooxazol-2-yl- 2-hydroxy-lS-phenethylethylcarbamoyl)-2-cyclohexylethylcarbamate Compound 51, described in Example 4, infra) and 2S-amino-N-[2-benzooxazol-2-yl- 2-(tert-butyldimethylsilanyloxy)-1S-phenethylethyl]-3-cyclohexylpropionamide 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, 1H-indol-5-yl, benzothiazol-2-yl, and the like.
"Sulfamoyl" means the radical -S(O) 2
NH
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 "Treatment" or "treating" means any administration of a compound of the present invention and includes: 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, inhibiting the disease in an animal that is experiencing or displaying the pathology or symptomatology of the diseased arresting further development of the pathology and/or symptomatology), or ameliorating the disease in an animal that is experiencing or displaying the pathology or symptomatology of the diseased 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 X' is 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 R 7 and optionally substituted with a group R 8 particularly wherein R 7 is hydrogen, halo, (C.4)alkoxy, (C,4)alkoxycarbonyl, nitro or phenyl and R 8 at each occurrence independently is halo, (C 1 ,)alkoxy, (C, 4 )alkoxycarbonyl, nitro or trifluoromethyl. 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, (Ci 4 )alkoxy, (C, 4 )alkoxycarbonyl or nitro and R 8 at each occurrence independently is halo, (C,4)alkoxy, (C,,)alkoxycarbonyl, nitro or trifluoromethyl.
X
2 particularly represents a bond or a divalent group of Formula particularly, wherein within Formula X 3 is R 9 represents hydrogen, R" represents hydrogen or methyl, typically hydrogen, and R 2 particularly represents (C1,6)alkyl substituted with -SR 1 4 -SO) 4or -S(O) 2
R'
4 wherein R" 4 is (C6.1 2 )aryl(C0_)alkyl or hetero(Cs- 12 )aryl(CO.)alkyl or 0i0 (C 312 )CYCloalkyl(C")alkyl or (C6., 2 )aryl(C")alkyl; wherein within R 1 2 any alicyclic or aromatic ring system present may be substituted further by I to 5 radicals independently selected from (C 1 -6)alkyl, (Cl, 4 )alkylidene, cyano, halo, halo-substituted (C 14 )alkyl, nitro,
-X
5
NR
4 R 1 4
-X
5 NR1 4
C(O)QR'
4
_X
5 NR1 4 C(O)NR1 4
R
4
_X
5 NR 4 C(NR1 4
)NR'
4 R 1 4
_X
5 OR 1 4 _X SR 1 4
-X
5 C(O)QR. 4
_X
5 C(O)NR1 4
RI
4
_X
5
S(O)
2 NR1 4 R1 4
-X
5 P(O)(OR1 4 )OR 14
-X
5 Op(O)(OR1 4 )OR 1 4
-X
5 NR1 4 C(O)R'1 5
-X
5 S(O)R 1, -X 5
S(O)
2 R,5 and -X 5
C(O)RI
5 wherein XI is a bond or (C,.6)alkylene, R1 4 at each occurrence independently is hydrogen, (C, 14 )alkyl or halo-substituted 3 )alkyl and R 1 5 is 6 )alkyl or halo-substituted 3 )alkyl.
Further preferred, within Formula R 1 2 particularly represents a group having the following formula: in which q is 0, 1, 2, 4 or 5 and R 3 1 at each occurrence independently is selected from a group consisting of (C,,)alkyl, cyano, halo, halo-substituted (C,,)alkyl, nitro, _X 5
NR'
4
-X'QR
_X
5 SR 1 4
-X
5
C(O)NR'
4
R'
4
-X
5 C(O)0R 1 4
-X
5 S(O)R 1 5
-X'S(O)
2 R 1 5 and -X 5
C(O)R'
5 wherein
X
5 is a bond or (C, 14 )alkylene, R" 4 at each occurrence independently is hydrogen, (C 1 3 )alkyl or halo-substituted 3 )alkyl and is (C 13 )alkyl or halo-substituted (C 1 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 14 )alkyl, nitro, -OR'1 4 -SR"4 and -C(O)OR 1 4 9 wherein R 1 4 independently is hydrogen, (Cl.
3 )alkyl or halo-substituted (C,-,)alkyl; more particularly in which R 33 at each occurrence independently is selected from a group consisting of (C 14 )alkyl, bromo, carboxy, chloro, cyano, difluoromethoxy, fluoro, iodo, methoxy, nitro, trifluoromethoxy, trifluoromethyl and trifluorosulfanyl.
Further preferred, within Formula R' 2 particularly represents benzylsulfonylmethyl, 2-chlorobenzylsulfonylmethyl, 2-cyanobenzylsulfonylmethyl, -31- 2-difluoromethoxybenzylsulfonylmethyl, 3,5-dimethylisooxazol-4-ylmethylsulfonylmethyl, 2-methoxybenzylsulfonylmethyl, 6-methylpyrid-2-yhnethylsulfonylmethyl, 2-nitrobenzylsulfonyhnethyl, pyrid-2-ylmethylsulfonylmethyl, o-tolylmethylsulfonylmethyl or 2-trifluoromethylbenzylsulfonylmethyl.
particularly represents AXXRI, wherein XI is or XI is a bond, -0or -NR 21 wherein R 2 1 is hydrogen or (C, 14 )alkyl, and RI is (C 1 -6)alkyl optionally substituted by -C(O)OR 1 4 or (ii) (C3- 1 2 )cycloalkyl(CO-)alkyl, hetero(C 312 cycloakyl(C,,)alkyl, (C6.
12 )aryl(CO-)alkyl or hetero(C,.,)ary(C")alkyl or (iii) (C 3 6 )cycloakyl(C4)alkyl, hetero(Q3-)cycloalkyI(C.)alkyl, phenyl(C.)alkyI or hetero(C...)aryl(C.)alkyl, wherein said cycloalkyl, heterocycloalkyl, phenyl or heteroaryl ring is substituted by -X 5
ORI,-X
5
C(O)R
4
-X
5 C(O)QR24, -X 5 C(O)NR 24 R25, -XSNR24R2, -X 5 NR25C(O)R 24
-X
5 NR25C(O)OR 24,
-X
5 NRIC(O)NRIRI or -X'NRIC(NRI)NR24RI, wherein XVis a bond or (C 1 -6)alkylene, R 1 4 is (Q,_)cycloalkyI(C0.)alkyl, hetero(C3.
6 )cycloalkyl(CO.)alkyl;I phenyl(CO-)alkyI or hetero(C-1 6 )aryl(CO-)alkyl and RI is hydrogen or (C 1 -6)alkyl; wherein within RI any alicyclic or aromatic ring, system present may be substituted further by I to 5 substituents independently selected from (CI-6)alkyl, halo, halo-substituted (C, 14 )alkyl, -OR 14 and -C(O)OR 1 4 wherein R 1 4 is hydrogen or (C 1 -6)alkyl, or when X 2 is a divalent group of formula then RI may be, but is not limited to, hydrogen or oxalo.
R1 preferably is a group selected from acetyl, azetidin-3-ylcarbonyl, benzyloxycarbonyl, 1 -benzyloxycarbonylpiperidin-4-ylcarbonyl, benzylsulfonyl, bicyclo[2.2.2]hept-2-ylcarbonyl, bicyclol2.2.1I 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, morpholin-4-ylcarbonyl, 2-morpholin-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.
RI especially represents morpholin-4-ylcarbonyl, methoxycarbonyl, methylsulfonyl, piperidin-4-ylcarbonyl, pyrazin-2-ylcarbonyl pyrid-3-ylcarbonyl, pyrid-4-ylcarbonyl, tetrahydropyran-4-ylcarbonyl or tetrahydropyran-4-yloxycarbonyl.
RI typically is hydrogen.
R 3 particularly represents hydrogen, (C 1 .6)alkyl (optionally substituted with cyano, halo, nitro, -SRI, -C(O)QR26, -C(O)NR26R 26 -P(O)(OR26)QR2, -OP(Q)(0R X)0R 26
-S(Q)R
2 '7,
-S(Q)
2
R
27 or -C(O)R 27 wherein RI at each occurrence independently is hydrogen, (C 1 .6)alky1, or halo-substituted 3 )alkyl and RI is (C 3 .6)alkyI or halo-substituted 3 )alkyl) Or (C6.
12 )arYl(C 2 3 )alkyl, wherein said aryl optionally is substituted further with 1 to 5 radicals independently selected from (C,,)alkyl, (C, 14 )alkylidene, cyano, halo, halo-substituted
(C
14 )alkyl, nitro, -X 5 NR1 4 C(O)OR'1 4
-X
5
NR'
4 C(O)NR1 4 R 1, -X 5
NR'
4 C(NR 1 4 )NR4R"4,
_X
5 OR 1 4
_X
5 SR 1 4
-X
5 C(O)OR 4
-XSC(O)NR
4
R
4
-X
5
S(O)
2
NR
4
R)
4 -X5P(O)(OR1 4 )OR 1 4
-X
5 OP(O)(OR 1 4 )OR1 4
_X
3
NR'
4 C(O)R 1 5
-X
5
S(Q)R
5
-X
5
S(O)
2 R" and -X 5 C(Q)R1', wherein is a bond or (C,.6)alkylene, R 1 4 at each occurrence independently is hydrogen, (C 14 6)alkyl or halo-substituted (C 1 3 )alkyl and R' 5 is 6 )alkyl or halo-substituted (C 1 3 )alkyl, or R 3 and R 4 taken together with the carbon atom to which both R 3 and R" are attached form (C3-)cycloalkylene. In particular, R 3 may be selected from hydrogen, (C 14 )alkyl methyl, ethyl, n-propyl, n-butyl), phenyl(C 2 3 )alkyl phenethyl) or (C 1 .,)alkysulfonyl(C2,)alkyl (e.g.
2-methylsulfonylethyl) or R 3 and R 4 taken together with the carbon atom to which both R 3 and R4are attached form (C_,)cycloalkylene cyclobutylene or cyclohexylene). R 3 preferably is (C 1 4 )alkyl.
particularly represents hydrogen or R 3 and R' taken together with the carbon atom to which both RI and RI are attached form (C,.)cycloalkylene cyclobutylene or cyclohexylene).
and R 6 preferably together form oxo.
Compounds of Formula HI are preferred in which: n isO0; X1 is 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 RI and optionally substituted with a group R1, particularly wherein R' is hydrogen, halo, (C,,)alkoxy,
(C
14 )alkoxycarbonyl, nitro or phenyl and R 8 at each occurrence independently is (C 1 4)alkoxy,
(C
1 .,)alkoxycarbonyl, nitro or trifluoromethyl.
X' methylene or ethylene; R 3 and R" are as defined above; R 5 and R1 together form oxo; R' is hydrogen; and
R
32 is -X 9
R
3 4 wherein X' is methylene when XI is methylene and X' is a bond when X' is ethylene, RI is -CR 3 1CHR 36 or -CR 3 7
:NR
3 1, wherein R 3 1 and R 3 1 together with the atoms to which R 3 1 and R 36 are attached form (C 2 .)alkenyl, 12 )cycloalkenyl, hetero(C 5 2 )cycloallcenyl, (C6.
12 )aryl, hetero(C6 12 )ary1, (C 12 )bicyclowryl or hetero(Cg.,bicycloary1 and R 3 1 and R 3 1 together with the atoms to which R 37 and R" are attached form hetero(CS.
12 )CYCloalkenyl, hetero(Q 1 2 )aryl or hetero(C- 1 2 )bicycloaryI, wherein within RI said cycloalkenyl, heterocycloalkenyl, aryl, heteroaryl. bicycloaryl or heterobicycloaryl may be substituted further by 1 to 5 radicals independently selected from (C,,)alkyl,
(C
1 6 )alkylidene, cyano, halo, halo-substituted (C,,)alky1, nitro, -XINR 1 4 R'1 4 -XsNR14C(O)OR 1 4
-X
5 NR 4
C(O)NR
4 R 14
-X
5 NR 1 4 C(NR1 4
)NR
4 R 1 4
_X
5 OR 1 4
-X
5 SR 1, -X 5 C(O)0R 14
-X
5
C(Q)NR
4
IR'
4
-XSS(O)
2
NR'
4
R'
4 -XSP(O)(OR 1 4 )OR 1 4
-X
5
OP(O)(ORI
4 )QR 1 4
-X
5 NR1 4
C(O)R'
5
-X
5
S(O)R
15
-X'S(O)
2 R 1 5 and -X'C(Q)R 1 5 wherein XI is a bond or
(C
1 -6)alkylene, R 1 4 at each occurrence independently is hydrogen, (C, 14 )alkyl or halo-substituted
(C
23 )alkyl and R'1 5 is (C,.6)alkyl or halo-substituted (CI.
3 )alkyl.
R34 particularly represents (C6- 12 )aryl or hetero(C,- 12 )aryl, each optionally substituted by 1 to 5 radicals selected from a group consisting of (C 14 )alkyl, cyano, halo, halo-substituted (C,,)alkyl, nitro, -X 5 NR1 4 R 1 4 _X5 OR1 4
_X
5 SR1 4
-X
5
C(Q)NR'
4
RI
4
-X
5 C(O)OR 1 4
-X
5 S(O)RI', -X 5
S(O)
2
RI
5 and -XIC(O)R 1 5 wherein XI is a bond or (C,-,)alkylene, R1 4 at each occurrence independently is hydrogen, (C 1 3 )alkyl or halo-substituted (C,-.)alkyl and R 1 5 is
(C,
3 ,)alkyl or halo-substituted (C 1 3 )alkyl. RI more preferably represents biphenyl, isooxazolyl, naphthyl, phenyl, pyridyl or thienyl, each optionally substituted by 1 to 5 radicals selected from a group consisting of 4 )alkyl, cyano, halo, halo-substituted (C,,)alkyl, nitro, -X 5
NR'
4
R'
_X
5 OR 14 _X5 SR 1 4
-XSC(Q)NR
4 R 1 4
_X
5 C(O)0R 1 4
-X
5
S(O)RI
5
-X
5
S(O)
2 R5 and -X-C(O)R 1 5 wherein X 4 is a bond or (C 1 2 )alkylene, R1 4 at each occurrence independently is hydrogen, (C 13 )alkyl or halo-substituted (CI.
3 )alkyl and R' 5 is 3 )alkyl or halo-substituted
(C
1 3 )alkyl. R34 more preferably represents biphenyl-2-yl, 2,4-bistrifluoromethyphenyl, 4-tert-butylphenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 3-chloro-2-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 5-chlorothien-2-yl, 2-chloro-5-trifluoromethyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, I ,5-dichlorophemyl, 2,6-dichlorophenyl, 3,4-dichiorophenyl, 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, 2-fluoro-6-nitrophenyl, 2-fluorophenyl, 4-fluorophenyl, 2-fluoro- 3-trifluoromethylphenyl, 2-fluoro-4-trifluoromethylphenyl, 2-fluoro-6-trifluoromethylphenyl, 4-fluoro-2-trifluoromethylphenyl, 4-fluoro- 3-trifluoromethylphenyl, 2-iodophenyl, 3-lodophenyl, 4-iodophenyl, 2-methoxyphenyl, 4-methoxyphenyl, 2-methyiphenyl, 3-methyiphenyl, 4-methyiphenyl, 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-1-yl, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, thien-3-yl, o-tolyl, 2-trifluoromethoxyphenyl, 3-trifluoromethoxyphenyl, 4-trifluoromethoxyphenyl, 3-trifluoromethylphenyl, 4-trifluoromethyiphenyl, .2-trifluoromethylsulfanylphenyl, 3-trifluoromethylsulfanyiphenyl, 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(Q)
2
R
3 2 represents a group having the following formula: 3 S(O)2 in which q is 0, 1, 2, 4 or 5 and R 33 at each occurrence independently is selected from a group consisting of (C,,)alkyl, cyano, halo, halo-substituted (C,,)alkyl, nitro, -X 5
NRI
4 R'1 4
_X
5 0R'1 4
-X
5 SR'1 4 -XSC(0)NR 4
R'
4
-X
5 C(O)OR. 4
-X
5 S(0)R' 5
-X
5
S(O)
2
R'
5 and -X 5
C(O)R'
5 wherein XI is a bond or 2 )alkylene, R' 4 at each occurrence independently is hydrogen, 3 )alkyl or halo-substituted (C 1 3 )alkyl and R1 5 is 3 )aIkyl or halo-substituted 3 )alkyl; more particularly in which q is 0, 1 or 2 and R 3 1 at each occurrence independently is selected from a group consisting of (C,,)alkyl, cyano, halo, halo-substituted (C 14 )alkyl, nitro, -SR'1 4 and wherein R" 4 at each occurrence independently is hydrogen, 3 )alkyl or halo-substituted (CI.
3 )alkyl; more particularly in which 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.
In particular, -X 8
S(O)
2 R 3 1 represents benzylsulfonylmethyl, 2-chlorobenzylsulfonylmethyl, 2-cyanobenzylsulfonylmethyl, 2-difluoromethoxybenzylsulfonylmethyl, 3,5-dimethylisooxazol-4-ylmethylsulfonylmethyl, 2-methoxybenzylsulfonylmethyl, 6-niethylpyrid-2-ylmethylsulfonylnethyl, 2-nitrobenzylsulfonylmethyl, pyrid-2-ylmethylsulfonylmethyl, o-tolylmethylsulfonylmethyl or 2-trifluoromethylbenzylsulfonymethyl.
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: 2S-acetylamino-N-(1S-benzooxazol-2-ylcarbonyl)-3-phenylpropyl).
3-cyclohexylpropionamide; and lS-(lS-benzooxazol-2-ylcarbonyl-3-phenylpropylcarbamoyl).
2-cyclohexylethylisonicotinamide; and the N-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: N-f lR.(lS-benzooxazol-2-ylcarbonylbutylcarbamoyl)2-benzylsulfonyethyllmorpholine.
4-carboxamide; methyl IR(Sbnoxzl2ycroybtiabaol--ezlufnltycraae 1S-benzooxazol-2-ylcarbonylbutyl)- 2 R-methylsulfonylamino-3-benzylsulfonylpropionamide, lS-benzooxazol-2-ylcarbonylbutylcarbamoyl)2R-(3,3-dimethylureido)- 3 2 -methoxybenzylsulfonyl)propionamide; 1R-(lS-benzooxazol-2-ylcarbonylbutylcarbamoyl)- 2-2d looehxbnysloy~ty~opoie4croaie N-f 1R-(lS-benzooxazol-2-ylcarbonylbutylcarbamoyl)- 2 2 -methoxybenzylsulfonyl)ethyl]morpholine-4-carboxamide; 1R-(lS-benzooxazol-2-ylcarbonylpentylcarbamoyl)- 2 -benzylsulfonylethylJmorpholine-4-carboxamide; lR-(IS-benzooxazol-2-ylcarbonylpentylcarbanoyl)- 2 2 -chlorobenzylsulfonyl)ethyl]morpholine4carboxamide; lR-( IS-benzooxazol-2-ylcarbonylpentylcarbamoyl)- 2 -(2-difluoromethoxybenzylsulfonyl)ethylcarbamate; N4[ lR-(1S-benzooxazol-2-ylcarbonylpentylcarbamoyl).
2 2 -difluoromethoxybenzyIsulfonyl)ethyl]morpholine-4-caboxyamide; 1R-( 1S-benzooxazol-2-ylcarbonylpentylcarbamoyl)- 2 3 5 -dimetbylisoxazol4ylmethylsufonylethyllisonicotinamide; 1R-(1 S-benzooxazol-2-ylcarbonylpentylcarbamoyl)- 2 2 -nitrobenzylsulfonyI)ethyJlmorpholine-4carboxamide; 1R-(1S-benzooxazol-2-ylcarbonylpentylcarbaioyl).
2-yii--lehlufnltylopoie4croaie lR-(1S-benzooxazol-2-ylcarbonylpentylcarbamoyl)- 2 -o-tolylmethylsulfonylethyllmorpholine-4-carboxamide; lR-(lS-benzooxazo-2-ylcarbonylpentylcarbamoyl).
2-2tilooehlezlufnlehlmrhln4croaie lR-(lS-benzooxazol-2-ylcabonyl-3-phenylpropylcarbamoyl..
2-benzylsulfonylethyl]nicotinaniide; lR-(1S-benzooxazol-2-ylcarbonyl-3-phenylpropylcarbamoyl)- 2 -benzylsulfonylethyllpyrazine-2-carboxamide; IR-(1S-benzooxazol-2-ylcarbonyl-3-phenylpropylcarbamoyl)- 2 2 -chlorobenzylsulfony)ethy]morphoine4carboxamide; 1R-(1 S-benzooxazol-2-ylcarbonyl-3-phenylpropylcarbamoyl).
2 -(2-cyanobenzylsulfonyl)ethyl]isonicotinamide; 1R-( 1S-benzooxazol-2-ylcarbonyl-3-methylsulfonylpropylcarbamoyl).
2 2 -difluoromethoxybenzylsulfonyl)ethylJmorpholine-cabxamid; 1R-( lS-benzooxazol-2-ylcarbonylpentylearbamoyl)- 2 -(2-difluoromethoxybenzylsulfonyI)ethy]isonicotinaide; 1R-(1 S-benzooxazol-2-ylcarbonyi)-3-phenylpropylcarbamoyl)- 2 -benzylsulfonylethyl]morpholine4-carboxamide; lR-(1S-benzooxazol-2-ylcarbonyl-3-phenylpropylcarbamoyl)- 2-6mtyprd2ymtyslfnlehlioioiaie lR-(1S-benzooxazol-2-ylcarbonyl-3-phenylpropylcarbamoyl)- 2 2 -nitrobenzylsulfonyl)ethyllmorpholine-4-carboxamide; IR-( 1S-benzooxazol-2-ylcarbonyl-3-phenylpropylcarbamoyl)- 2 -pyrid-2-ylmethylsulfonylethyl]morpholine--carboxapajde; IR-(1S-benzooxazol-2-ylcarbonyl-3-phenylpropylcarbamoyl)- 2 -o-tolylmethylsulfonyethyl]rorpholne4carboxarnide; N-[lR-(1S-benzooxazol-2-ylcarbonyl-3-phenylpropylcarbamoyl).
2 2 -trfluoromethybenzysufonyl)ethy]tetrahydropyran.4carboxamide; tetrahydropyran-4-yl 1R-(1S-benzooxazol-2-ylcarbonyl-3-phenylpropylcarbamoyl).
2-benzylsulfonylethylcarbamate; and 1R-(1S-benzooxazol-2-ylcarbonyl- 3-hnlrplabmy)2(-ynbnysloy~ty~ieiie4croaie and the N-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 XI is In particular, the heteromonocyclic ring or fused beteropolycyclic ring system A is selected from thien-2-yl, oxazol-2-yl, 4,5-dihydrooxazol-2-yl, fur-2-yl, 1.H-indol-5-yl, pyrid-2-yl, pyrid-3-yl, thiazol-2-yl, I -methyl-JH-imidazol-2-yl, 1 -benzyl-IH-imidazol-2-yl, benzooxazol-2-yl, benzofur-2-yl, benzothiazol-2-yl, 1H-benzoimidazol-2-yl, 1,1 -dioxo- IH- I X-benzo[b]thien-2-yl, quinol-3-yl, [1 ,3]dioxolan-2-yl, naphtho[2,3-doxazol.2-yl, naphtho[ 1,2-d~oxazol-2-yl and naphtho[2,I -d~oxazol-2-yl, each substituted by a group RI and optionally substituted with a group
R
8 particularly wherein RI is halo, nitro, -R 2 9
-OR'
9
-S(O)
2
NRIIR
0
-C(O)NR
9
R
3 or -C(O)NHCHR 43 C(O)0R 9 wherein R' is (C 1 -6)alkyl,
(Q
1 2 )CYCloalkyl(C0_)aIkyl, hetero(C 3 12 )cycloalkyl(Cm)alkyl, (C6.1)aryl(CO-)alkyl, diphenyl(CO.)alkyl, hetero(C_ 12 )aryl(Cm)alkyl or hetero(C 8 12 )polycycloary](C!0.)alkyI and R 2 1 is hydrogen or -R 20 wherein R 20 is defined as above, wherein said heterocycloalkyl may be substituted with (C6.
1 2 )ary](CO- 3 )alkyl, R31 at each occurrence is hydrogen or (C, 1 6)alkyl and R' 3 is (C, 1 6)alkyl, and RI at each occurrence independently is hydrogen, (C 1 -,)alkyl or halo-substituted (C,,)allcyl; wherein within R' any alicyclic or aromatic ring system present may be substituted further by 1 to 5 radicals independently selected from (C 1 -6)alkyl, (C 14 6)alkylidene, cyano, halo, halo-substituted (C 14 )alkyl, nitro, -X 6
NR'
4
R'
4
_X
6 NR"C(O)OR 1 4
-X
6 NR1 4 C(O)NR 1 4 R14, -X 6 NR 4 C(NR1 4 )NR1 4
R]
4
_X
6 OR 1 4
_X
6
SR
14
-X
6
C(O)QR'
4
_X
6 C(O)NR1 4 R 1 4
-X
6
S(O)
2 NR1 4
R]
4
-X
6 p(O)(QR 1 4 )OR 1 4
_X
6 Qp(O)(ORj 4 )ORI4,
_X
6 NR1 4
C(O)R]
5
-X
6
S(O)R]
5
_X
6
S(O)
2 R'5 and -X 6
C(O)R'
5 wherein X 6 is a bond or
(C
1 -6)alkylene, R' 4 at each occurrence independently is hydrogen, (C 1 -6)alkyl or halo-substituted (Cl.
3 )alkyl and R"I (C 1 -6)alkyl or halo-substituted (C 13 )alkyl.
.The ring system A preferably is oxazol-2-yl, 4,5-dihydrooxazol-2-yl, benzooxazol-2-yl, naphtho[2,3-d]oxazol-2-yl, naphtho[1,2-dloxazol-2-yl or naphtho[2, 1 -d]oxazol-2-yl, each substituted by a group R' and optionally substituted with a group RI, particularly wherein R' is halo, -R 29 -C(O)R20, -C(O)0R 29
-C(O)NRIR
0 or -S(Q) 2
NR
29 wherein R' is (C 14 6)alkyl, (C3- 12 )CYCloalkyl(C 6)alkyl, (C6.j 2 )aryl(CO,)alkyl, hetero(C 5 2 )ary(Cm)alkyl or hetero(Cs- 12 )POlycycloaryl(Cm)alkyl.
The ring system A more preferably is oxazol-2-yl, 4,5-dihydrooxazol-2-yi, benzooxazol-2-yl or naphtho[1,2-djoxazol-2-yl, each substituted by a group R' and optionally substituted with a group RI, particularly wherein R 7 is adamantan-1-ylmethylcarbanoyl, benzyl, benzylcarbamoyl, benzyl(methyl)carbamoyl, 1-benzyloxycarbonyl-3-methylbutylcarbamoyl, 4-benzylpiperidin-lI-carbonyl, trn-butyl, chloro, 2,3-dihydroindol- 1-ylcarbonyl, 3,4-dihydro- 1H-isoquinol-2-ylcarbonyl, 3,4-dihydro- 1H-quinol-1 -ylcarbonyl, diphenylmethylcarbamoyl, fur-2-yhnethylcarbamoyl, hydrogen, 2-(1H-indol-3-yl)ethylcarbainoyl, methoxy, methoxycarbonyl, methyl, 3-methylbutylcarbamoyl, methylcarbamoyl, I -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-ylmethylcarbamoyl or pyrrolidin-1-ylcarbonyl and RI is methyl.
X
2 particularly represents a bond or a divalent group of Formula wherein within Formula XI is RI represents hydrogen, RI" represents hydrogen or methyl, typically hydrogen, and RI 2 particularly represents (CI-6)allcyl, preferably isobutyl, sec-butyl or isopropyl.
RI particularly represents hydrogen or -XIX 9 R20, wherein V 8 is or -S(0) 2 X, is a bond or and R20 is (C 14 )alkyl, (C 3 1 7,)cycloalkyl(CO.)alkyl, hetero(C3-1)cycloalkyl(CO-)alkyl, (C6- 1 ,)aryl(C4)alkyl or hetero(C5_j 2 )aryl(CO4)alkyl; wherein within RI any alicyclic or aromatic ring system present may be substituted further by I to radicals independently selected from (C 1 .6)alkyl, -C(O)OR 4
-X
6
NR'
4 R 1 4 and
-X
6 NR 4 C(O)OR', wherein V 6 is a bond or (C 1 -6)alkylene, R 1 4 at each occurrence independently is hydrogen, (C 1 -6)alkyl or halo-substituted 3 )alkyl and R' 5 (C,,)alkyl or halo-substituted (C 1 3 )alkyl.
-39- R' particularly represents acetyl, benzoyl, benzyloxycarbonyl, benzylsulfonyl, bicyclo[2.2.2]hept-2-ylcarbonyl, tert-butoxycarbonyl, tert-butyryl, 4-tert-butoxycarbonylpiperazin-1-ylcarbonyl, 1-rert-butoxycarbonylpiperidin-4-ylcarbonyl, 2-cyclohexylacetyl, 4-cyclohexylbutyryl, 2-cyclohexylethylsulfonyl, 3-cyclohexylpropionyl, 2-cyclopentylethylsulfonyl, hydrogen, 4-methylpiperazin-l-ylcarbonyl, methylsulfonyl, 4-methylvaleryl, 3-morpholin-4-ylpropionyl, naphth-2-ylmethyl, 3-phenylpropionyl, piperazin-l-ylcarbonyl, piperidin-4-ylcarbonyl or pyrid-3-ylcarbonyl, wherein within RI 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.
R
2 particularly represents hydrogen.
R
3 preferably represents (C.6)alkyl or (C6.
1 i)aryl(C 1 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,)cycloalkylene, more preferably cyclopropylene.
R
4 preferably represents hydrogen or (C.
4 )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 (C3.)cycloalkylene, more preferably cyclopropylene.
R
5 and R 6 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 resorption 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 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.). For example, a compound of Formula I in which A is benzooxazol-2-yl; X 2 is a group of Formula wherein R 9 is hydrogen and R 12 is cyclohexylmethyl; R' is acetyl; R 2 is hydrogen; R 3 is phenethyl; R 4 is hydrogen; and R 5 and R 6 together form oxo; that is, a compound having the following structure: -41is named 2S-acetylamino-N-(1 -benzooxazol-2-ylcarbonyl-3-phenylpropyl)- 3-cyclohexyipropionamide; and a compound of Formula I in which A is benzooxazol-2-yl; X 2 is a group of Formula wherein RI is hydrogen and R' 2 is benzylsulfonylmethyl; RI is 5morpholin-4-ylcarbonyl; R 2 is hydrogen; R' is phenethyl; RI is hydrogen; RI is hydrogen; and RI is hydroxy; that is, a compound having the following structure: 0~~
S
0 OH H H4 0~ 00 is named N-f 1S-(2-benzooxazol-2-yl-2-hydroxy-1 S-phenethylethylcarbamoyl)- 2 -benzylsulfonylethylj-morpholine-4-carboxamide or morpholine-4-carboxylic acid 1(R)-i 1-(1 -benzooxazol-2-yl1-hydroxy-methyl)-3-phenyl-propylcarbamoyl]- 2-phenylmethanesulfonyl-ethyl }-am-ide; and a compound of Formula I in which A is benzooxazol-2-yt; X 2 is a group of Formula wherein RI is hydrogen and R 12 is cyclohexymethyl; R' is carboxyacetyl; RI is hydrogen; R 3 is phenethyl; R" is hydrogen; and RI and R' together form oxo; that is, a compound having the following structure: is named IS-(lS-benzooxazol-2-ylcarbonyl-3-phenylpropylcarbamoyl)- 2-cyclohexylethyl]malonainic acid or 1-(1 -benzooxazol-2-yl-methanoyl)-3-phenylpropylcarbamoyl]-2-cyclohexyl-ethyl )-malonamic acid; and a compound of Formula I in which A is benzooxazol-2-yl; XI is a group of Formula wherein R 9 is hydrogen and R' 2 is 2-nitrobenzylsulfonylmethyl; RI is morpholin-2-ylcarbonyl; RI is hydrogen; RI is phenethyl; R' is hydrogen; and R 5 and RI together form oxo; that is, a compound having the following structure: is named 1R-( IS-benzooxazol-2-ylcarbonyl-3-phenylpropylcarbamoyl)- 2-(2-nitrobenzylsulfonyl)ethyllmorpholine-4-carboxamide or morpholine-4-carboxylic acid -benzooxazol-2-yl-methanoyl)-3-phenyl-propylcarbamoyl]-2-(2-nitro- -43phenylmethanesulfonyl)-ethyl]-amide; and a compound of Formula I in which A is benzooxazol-2-yl; X' is a group of Formula wherein RI is hydrogen and R' 2 is benzylsulfonylmethyl; RI is tetrahydropyran-4-yloxycarbonyl; R 2 is hydrogen; RI is phenethyl; R" is hydrogen; and R' and RI together form oxo; that is, a compound having the following structure: is named tetrahydropyran-4-yl lR-(1S-benzooxazol-2-ylcarbonyl-3-phenylpropylcarbamoyl)- 2-benzylsulfonylethylcarbamate or (R)-1I 1 -benzooxazol-2-yl-methanoyl)-3-phenylpropylcarbamoyl]-2-phenylmethanesulfonyl-ethyl 1-carbamic acid tetrahydro-pyran-4-yl ester.
A compound of Formula I in which A is pyrid-2-yI; X 2 is a group of Formula wherein R' is hydrogen and R Iis 2-methyipropyl; R' is benzyloxycarbonyl; R" and R' each are hydrogen; RI is phenethyl; and RI is hydroxy; that is, a compound having the following structure: is named benzyl 1S-( 1S-pyrid-2-ylcarbonyl-3-phenylpropylcarbamoyl)-3-methylbutylcarbamate or -hydroxy- 1 -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; XI is a group of Formula wherein RI is hydrogen and RI is 2-methyipropyl; RI is 4-methylpiperazin- I -ylcarbonyl; R 2 and R 4 each are hydrogen; R 3 is phenethyl; and R' and R' together form oxo; that is, a compound having the following structure: is named N-[3-methyl- 1S-(3-phenyl- 1-thiazol-2.ylcarbonylpropylcarbamoyl)butyll- 4-methylpiperazine-1-carboxamide or 4-methyl-piperazine-l-carboxylic acid or I (S)-3-methyl- I -jI(S)-3-phenyl-lI -thiazol-2-yl-methanoyl)-propylcarbanioyl]-butyI I -amiide; and a compound of Formula I in which A is 4,5-tetrahydro-4-methoxycarbonyloxazol-2-yl; X 2 is a group of Formula wherein R" is hydrogen and R" is 2-methyipropyl; RI is benzyloxycarbonyl; RI and W' each are hydrogen; R 3 is phenethyl; and RI and R 6 together form oxo; that is, a compound having the following structure: is named methyl 2S-(2S-benzyloxycarbonylainino-4-methylvalerylamino)-4-phenylbutryl- 4,5-dihydrooxazole-4-carboxylate or 2-[(S)-2-((S)-2-benzyloxycarbonylamnino-4-miethylpentanoylamino)-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 (g/kg) per day to 10 milligram per kilogram body weight (mg/kg) per day, typically 1 ig/kg/day to 1 mg/kg/day. Therefore, a therapeutically effective amount for a 80 kg human patient may range from 10 tg/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 transdermal, intranasal or by suppository) or parenteral 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 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 1%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:
P(O)(OR
43
)OR
43 R44-X -R 4
P(O)(OR
4 3
)OR
4 3 wherein X" is a bond or (C, 7 )alkylene, each R 4 3 independently is hydrogen or (CI.30)alkyl, R 4 and R 4 5 are selected independently from a group consisting of hydrogen, halo, optionally substituted (Ci.
3 0 )alkyl, (C3.
3 0 )cycloalkyl, hetero(Cs.3 0 )cycloalkyl, optionally substituted (C,.o)aryl, hetero(C6.
0 )aryl, -NR' 6 R, -OR 6 -SR, wherein each R 4 independently is hydrogen, (Ci.-I)alkyl, (C3.-)cycloalkyl, optionally substituted (C6.
1 )aryl, provided that both R 4 4 and R 4 5 are not selected from hydrogen or hydroxy when X" is a bond; or R" and R 4 5 taken -47together form (C 2 9 )alkylene; wherein (C 3 -o)cycloalkyl includes adamantyl and the like, hetero(Cs, 1 0 )cycloalkyl includes pyrrolidinyl and the like, (C.O 0 )aryl includes phenyl and naphthyl, and hetero(C6.o)aryl includes quinolyl, isoquinolyl, pyridyl, furyl, imidazolyl, imidazopyridyl and the like.
Instances wherein R" and/or R 4 5 are substituted (C.
3 o)alkyl may include, but are not limited to, (C-30)alkyl substituted by hetero(Cs5 1 0 )cycloalkyl, (C.
0 )aryl, hetero(C.
1 0 )aryl, -NR47R4 7
-OR
4 7 and -SR 47 wherein each R 4 7 is independently hydrogen or (C, 0 io)alkyl; wherein hetero(C, 1 0 )cycloalkyl includes pyrrolidinyl and the like, (C6.o)aryl includes phenyl and naphthyl, and hetero(C 6 .)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" is selected from the group consisting of hydrogen, hydroxy or halo, and R 4 5 is selected from the group consisting of optionally substituted (Ci.30)alkyl, halo and wherein R 4 6 is (C 1 1 0 )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" is selected from the group consisting of hydrogen, hydroxy and chloro and R 4 5 is selected from the group consisting of optionally substituted 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" is a bond, each R 4 3 is hydrogen, R" is hydroxy and R 4 5 is 3-aminopropyl, namely 4-amino-l-hydroxybutylidene- 1,1-bisphosphonic acid (aka alendronic acid), or the monosodium trihydrate salt thereof, namely 4-amino-l-hydroxybutylidene-l,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 incorporated 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; 1,1-dichloromethylene-1,1-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); 1-hydroxy-3-pyrrolidin- 1-ylpropylidene- 1,1-bisphosphonic acid (aka EB-1053); 1-hydroxyethylidene-1,1 -diphosphonic acid (aka etidronic acid); 1-hydroxy-3-(N-methyl-N-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)-l-hydroxypropylidene-l,l-bisphosphonic acid (aka olpadronic acid); 3-amino-l-hydroxypropylidene-1,l-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; 1-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 1-hydroxy-2-(1H-imidazol-l-yl)ethylidene-l,l-bisphosphonic acid (aka zoledronic acid); all of which patents and other documents referred to above are incorporated 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-(1,2-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 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- -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 incorporated 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 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-(N-methyl-N-pentylamino)propylidene-1,1-bisphosphonic acid, 6-amino- 1-hydroxyhexylidene-1,1-bisphosphonic acid, 3-(dimethylamino)-1-hydroxypropylidene- 1,1-bisphosphonic acid, 3-amino-1-hydroxypropylidene-1,1-bisphosphonic acid, 2-pyrid-2-ylethylidene- 1,1-bisphosphonic acid, 1-hydroxy-2-pyrid-3-ylethylidene-1,1bisphosphonic acid, 4-chlorophenylthiomethylenebisphosphonic acid and 1-hydroxy- 2-(1H-imidazol-1-yl)ethylidene-1,1-bisphosphonic acid or acid ester thereof or a pharmaceutically acceptable salt thereof; particularly 1,1-dichloromethylene-1,1-diphosphonic
I
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 R 5 and R 6 together form oxo can be prepared by proceeding as in the following Scheme 1: Scheme 1 X/7 Li' R7
(R
8 )n 2
R
2 0 R-X 2- N, O
R
3 4
R
S3
R
2
O
RR7 R (R8 )n I(a) in which n, A, X 2
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 in which R 5 and R 6 together form oxo (Formula 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 tetrahydrofuran (THF), ether, or the like) at 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 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 X' is a 4,5-tetrahydrooxazol-2-yl or oxazol-2-yl or moiety, R 5 is hydrogen and R 6 is hydroxy can be prepared by proceeding as in the following Scheme 2: Scheme 2
R
2
OH
R X 21N
O
R NH 4 HO R 7 H2N R8
R
2
OH
RI 'X2- 0
R
7 RO R 7 R R 4 N- R8 I(b) in which X 2
R
2
R
3
R
4
R
7 and R' 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 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 X' 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
HO
R7
H
2 N B (R )n 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 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: Scheme 3
R
2
OH
Hnx R 7X
R
3 4 I A R c (R )n 6 2. optionally deprotecting
R
2
OH
I I X R p 4 A R (R )n I(c) in which Y is hydrogen or an activating group 2,5-dioxopyrrolidin-l-yl (NBS), or the like) and n, A, X 2
R
2
R
3
R
4
R
7 and R I are as defined in the Summary of the Invention for Formulae I and I.
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'XOY, or a protected derivative thereof, and then optionally deprotecting. The reaction is carried out in the presence of a suitable base triethylamine, diisopropylethylamine, or the like) and in a suitable solvent acetonitrile, NN-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.
benzotriazole-l-yloxytrispyrrolidinophosphonium hexafluorophosphate (PyBOP@), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC), O-benzotriazol-l-yl- N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU), O-(7-azabenzotriazol-1 -yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU), 1,3-dicyclohexylcarbodiimide (DCC), or the like) and base NN-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
R
39 0H
R
2
X
I(c) in which R 39 is -X 7
XR
2 0 and n, X1, X 2
X
7
X
8
R
2
R
3
R
4
R
7
R
8 and R 2 0 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.
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-diazabicyclo[3.4.0]non-5-ene (DBN), or the like) in a suitable solvent dichloromethane, or the like) at 20 to 25* C and requires 6 to 12 hours to complete.
Compounds of Formula I in which R 7 is -C(O)OH can be prepared from a corresponding compound of Formula I in which R' is methoxycarbonyl. The conversion can be effected by treating the methyl ester with sodium hydroxide in a suitable solvent ethanol, or the like) at 20 to 25 C and requires 6 to 12 hours to complete.
Compounds of Formula I in which R' is -C(O)NRR" 3 or -C(O)NR 42
CHR
4 3
C()OR
2 9 can be prepared by reacting a corresponding compound of Formula I in which R 7 is -C(O)OH with a compound of the formula NHR2R 21 or NHR 4 2 CHR4 3
C()OR
29 respectively. The reaction is carried out in the presence of a suitable coupling agent (PyBOP@, EDC, HBTU, DCC, or the like) and base N,N-diisopropylethylamine, triethylamine, or the like) in a suitable solvent DMF, or the like) at 20 to 250 C and requires 2 to 4 hours to complete.
Compounds of Formula I in R' is -X 6 X'R can be prepared by reacting a compound of Formula I in which R' is hydrogen with a compound of the formula R2X'X 6 OH. The reaction is carried out by procedures analogous to those described above for carrying out Reaction Scheme 3.
Compounds of Formula I in which R' 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 Dess-Martin periodinate, or the like) in a suitable solvent dichloromethane, or the like) at 15 to 25° C and requires 10 to 20 hours to complete.
Compounds of Formula I in which R' 2 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 potassium peroxymonosulfate (OXONE®, or the like) in a suitable solvent 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 1,1-dioxo-1H-lX 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 -141-(1,l-dioxo-1H-1X 6 -benzofblthien-2-vlcarbonyl- 3-phenvlpropylcarbamovl1-3-methylbutvlcarbamate (Compound 209) was prepared. 'H NMR (CDC1 3 8 0.83 0.95 6H), 8 1.35 1.52 1H), 8 1.61 1.69 2H), 5 2.07 2.20 (m, 1H), 6 2.36 2.71 3H), 5 4.57 IH), 5 4.76 1H), 8 4.98 5.26 3H), 5 5.35 (bs, 1H), 8 7.06 7.62 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 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 hydrochloric acid, etc).
The N-oxides of compounds of Formula I can be prepared by methods known to those of ordinary skill in the art. For example, N-oxides can be prepared by treating an unoxidized form of the compound of Formula I with an oxidizing agent trifluoroperacetic acid, permaleic acid, perbenzoic acid, peracetic acid, meta-chloroperoxybenzoic acid, or the like) in a suitable inert organic solvent a halogenated hydrocarbon such as dichloromethane) at approximately 0°C. Alternatively, the N-oxides of the compounds of Formula I can be prepared from the N-oxide of an appropriate starting material.
Compounds of Formula I in unoxidized form can be prepared from N-oxides of compounds of Formula I by treating with a reducing agent sulfur, sulfur dioxide, triphenyl phosphine, lithium borohydride, sodium borohydride, phosphorus trichloride, tribromide, or the like) in an suitable inert organic solvent acetonitrile, ethanol, aqueous dioxane, or the like) at 0 to Prodrug derivatives of the compounds of Formula I can be prepared by methods known to those of ordinary skill in the art for further details see Saulnier et al.(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 1,1-acyloxyalkylcarbonochloridate, para-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 crystalline diastereoisomeric salts). Diastereomers have distinct physical properties 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).
summarYaspeois a process for preparing a compound of Formula I, which process comprises: reacting an organometallic compound of Formula 2: Li\ R7 I (R )n 2 with a compound of Formula 3: wherein n, A, X 2
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 R 5 and R 6 together form oxo; or reacting a compound of Formula 4: with a compound of Formula 5(a) or HO R 7 H2N-,.(R)n HO 7
H
2 NB(R 8)n
(R)
wherein the dashed line represents an optional bond and B is a monocyclic radical containing 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, 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' is a 4,5-tetrahydrooxazol-2-yl or oxazol-2-yl or moiety, respectively, R 5 is hydrogen and R 6 is hydroxy or reacting a compound of Formula 6: with a compound of the formula R'X 2 OY, wherein Y is hydrogen or an activating group and n, A, X 2
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 R 5 is hydrogen and R 6 is hydroxy; or reacting a compound of Formula 7:
R
2
OH
X x
R
3 4 R "4 -(R8)n 7 or a protected derivative thereof, with R 39 OH, wherein R 39 is -X'XR 2 and n, A, X 2
X
7
X
8
R
2
R
3
R
4
R
7
R
8 and R 2 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' is -XXR 2 0 optionally oxidizing a compound of Formula I in which R 5 is hydrogen and R 6 is hydroxy to give a compound of Formula I in which R 5 and R 6 together form oxo; 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; optionally converting a compound of Formula I in which R 7 is -C(O)OH to a compound of Formula I in which R 7 is methoxycarbonyl; optionally converting a compound of Formula I into a pharmaceutically acceptable salt; optionally converting a salt form of a compound of Formula I to non-salt form; optionally converting an unoxidized form of a compound of Formula I into a pharmaceutically acceptable N-oxide; optionally converting an N-oxide form of a compound of Formula I its unoxidized form; -59optionally converting a non-derivatized compound of Formula I into a pharmaceutically prodrug derivative; and 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:
R
2
O
R
3 R
I
R
8 with a compound of the formula R'X 2 IY, 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 carboxylic acid with N,O-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 N,N-diisopropylethylamine, triethylamine, or the like) in a suitable solvent dichloromethane, DMF, or the like) at 20 to 300 C, preferably at about 25 C, and requires 2 to 4 hours to complete see Reference 1, infra.). Deprotection can be effected by any means which removes the protecting group and gives the desired product in reasonable yield 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:
R
2
OH
1
I
R X2/N
CN
R 4
R
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 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
R
2
OH
OEt
R
3 R4 in which R 4 is a protecting group, with 2-aminophenol and deprotecting. The reaction with the phenol is carried out in the presence of a suitable base diisopropylethylamine, triethylamine, or the like) and in a suitable solvent 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 RX3OY, wherein R 4 is a protecting group, and then deprotecting. The condensation is carried out in the presence of a suitable base triethylamine, diisopropylethylamine, or the like) and in a suitable solvent acetonitrile, DMF, dichloromethane, or any suitable combination thereof, or the like) at 10 to 30 0
C,
preferably at about 25 C, and requires 24 to 30 hours to complete. When Y is hydrogen a suitable coupling agent PyBOP@, EDC, HBTU, HATU, DCC, or the like) and base N,N-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.
Examples: The following abbreviations used in this Application area defined as follows: PyB OP® benzotriazole-1 -yloxytrispyrrolidinophosphonium hexafluorophosphate; THF tetrahydrofuran; OXONE® potassium peroxymonosulfate; EDC 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; DMF =NfN-dimethylformamide; HATU O-(7-azabenzotriazol-1-yl)- 1,1 ,3,3-tetramethyluronium hexafluorophosphate; HOBT 1 -hydroxybenzotriazole hydrate.
REFERENCE 1 Benzyl I S-(N-methoxv-N-methvlcarbamoyl)-3-]2henvlproplvcarbamate A solution of 2-benzyloxycarbonylamino-4-phenylbutyric acid (5.05 g, 16.1 mmol) in dichioromethane (70 mL) was cooled to 0 0 C and treated with diisopropylethylamine (2.82 ML, 16.2 inmol) 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 NO-dimethylhydroxylamine hydrochloride (1.73 g, 17.71 mmnol) added in one portion. The mixture was neutralized with diisopropylethylamnine (4.6 mL, 26.44 mmol) added dropwise*, stirred for 2 hours at room temperature and then diluted with dichloromethane (70 miL). The dilution was washed sequentially with IN aqueous hydrochloric acid (3x 40 mL), saturated sodium bicarbonate (3x 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 benz L I S-(N-methoxv-N-methylcarbamofl-3-,phenvhlrovlcarbamate (5.48 g, 15.4 mmol) as an oil.
MS(PCI) mlz 357 (M Proceeding as in Reference 1 provided tert-butvl IS-(N-methox-N-methlcarbamovl)- 3 -phenvlpropvcraae 'HNR(DI) 813 s 8 1.64 1.72 (in, 2H), 8 2.40 -2.54 (in, IH), 8 2.60 2.77 (in, 111), 8 3.00 311) 3.52 3H), 8 4.23 (in, JH), 8 7.10 7.37 (im, REFERENCE 2 3-(2-Cvanobenzvlsulfanvl)-2R-pyrid-4-vlcarbonylaminopropionic acid A mixture of isonicotinic acid (3 N-hydroxysuccinimide (2.79 g) and N,N-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-1-yl isonicotinate (5.27 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 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 MS: 235 A solution of 2R-amino-3-(2-cyanobenzylsulfanyl)propionic acid (590 mg) in dichloromethane was treated with 2,5-dioxopyrrolidin-1-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-cvanobenzvlsulfanvl)- 2R-pyrid-3-carbonvlaminopropionic acid (340 mg) as a gum. MS: 342 HPLC:RT= 10.63 minutes.
REFERENCE 3 3-Benzvlsulfanvl-2R-tetrahvdropvran-4-yloxvcarbonvlaminopropionic 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 tetrahydropyran-4-yl carbonate.
-63- A solution of 2 R-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 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 v/v) to provide 3-benzvlsulfanyl-2Rtetrahvdropvran-4-vloxvcarbonvlaminopropionic acid (800 mg) as an oil.
REFERENCE 4 3 -Benzvlsulfanvl-2R-morpholin-4-vlcarbonvlaminopropionic 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 morpholine4-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 100 mL). The combined extracts were dried (MgSO 4 filtered and concentrated to provide 3 -benzvlsulfanvl-2R-morpholin-4-lcarbonvlaminopropionic acid (19.65 g, 60.6 mmol) as a white solid.
REFERENCE 3 -Benzvlsulfonvl-2R-morpholin-4-vlcarbonvlaminopropionic acid A solution of 3 -benzylsulfanyl-2R-morpholin-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 (MgSO 4 and concentrated. The residue was triturated with diethyl ether and the solid material was collected by filtration to provide 3 -benzvlsulfonvl-2R-morpholin-4-vlcarbonylaminopropionic acid.
REFERENCE 6 2 -Amino-N-methoxv-N-methvl-4-phenvlbutvramide trifluoroacetic acid salt A solution of tert-butyl 1-(N-methoxy-N-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-N-methoxv-N-methvl-4-phenvlbutvranide trifluoroacetic acid salt (9.74 g 29 mmol) as a crude product. MS(PCI) m/z 223 (M REFERENCE 7 Ethyl 3S-benzvloxvcarbonvlamino-2-hvdroxy-5-phenvlpentanimidate 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-(N-methoxy-N-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 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 (Na 2
SO,)
and concentrated in vacuo to provide benzyl 1S-formyl-3-phenylpropylcarbamate (4.01 g, 13.5 mmol) as a colorless oil. MS (PCI) m/z 298 (M 1).
A solution of benzyl 1S-formyl-3-phenylpropylcarbamate (4.557 g, 15.3 mmol) in anhydrous dichloroinethane (50 xnL) was stirred while sequentially treated with 2-hydroxy- 2-methylpropionitrile (4.25 mL, 46.2 mmol) and triethylamine (1.28 ml, 9.20 inmol). The mixture was stirred for 4 hours at room temperature and concentrated in vacua. The residue was dissolved in ether (100 mL) and the solution was washed sequentially with water (5 x niL) and brine (20 inL), dried (MgSO 4 and concentrated to provide benzyl 2 -cyano- 2 -hydroxy-IS-phenethylethylcarbmate (4.957 g, 15.3 mmol) as a yellow oil. IH NMR
(CDC
3 8 1.75 2.01 (mn, 2H), 8 2.08 2.24 (mn, I 5 2.51 2.80 (in, 2H), 8 3.70 4.02 (mn, 1H1), 8 5.07, 8 5.33 (mn, 3H), 5 7.10 7.47 (mn, I OH).
A mixture of chloroform (30 mL) and anhydrous ethanol (30 niL, 5 10 mrnol) was cooled to 0 C and then treated with acetyl chloride, (32.6 rnL, 459 nimol) added dropwise over a period of 30 minutes. The mixture was cooled by adding a solution of crude benzyl 2-cyano- 2 -hydroxy-IS-phenethylethylcarbamate (4.957 g, 15.3 nimol) in chloroform (30 niL). The mixture was stir-red for 2 hours at 0 *C and then 6 hours at room temperature and concentrated in vacuo to provide ethyl 3 (6.212 g 15.3 nimol) as a crude yellow oil. MS (PCI) m/z =371 (M 1).
REFERENCE 8 2S-Amino-4-Rhenvl- 1 -(4S-nhenv]4.5-dihvdrooxazol-2-yl)butan. I -ol A mixture comprised of ethyl 3 S-benzyloxycarbonylamino-2-hydroxy.
(0.78 g, 1.92 mmol), provided as in Reference 7, diisopropylethylamine (0.218 /gL, 1.26 inmol) and 2 S-amino-2-phenylethanol (0.260 g, 1.9 mmol) in chloroform (25 niL) 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 niL). The solution was washed sequentially with 0.5N sodium hydroxide mL) and brine (40 niL), dried (MgSO 4 and then concentrated. Product was purified from the residue by flash chromatography eluting with 1:3 hexanes/ethyl acetate to provide benzyl 2-yrx--45dhdo4-hnlxzo--l-Speytyehlabmt (0.475 g, 1.1 mmol) as an oily mixture of diastereomers. MIS (PCI) m/z 445 (M (C 27 H2uN 2
O
4 A solution comprised of benzyl 2 -hydroxy- 2 -(4,5-dihydro4S-phenyloxazol.2-yl)- IS-phenyethylethylcarbamate (100 mig, 0.22 nimol) in methanol (10 niL) was placed under a nitrogen atmosphere and stirred while Pearlman's catalyst (20 mng) 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-nhenl- 1 -(4S-phenvl-4.5-dihvdrooxazol-2-vl)butan- 1 -ol (51 mg, 0.16 mmol) as a clear oil. MS (PCI) m/z 311(M (CIHN 2 00.
Proceeding as in Reference 8 provided methyl 2-(2S-benzyloxycarbonylamino- 1-hydroxy4-phenylbutyl)-4,5-dihydrooxazole-4-carboxylate.
REFERENCE 9 2S-Amino-1-oxazol-2-vl-4-phenvlbutan- 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)-1-formyl-3-phenylpropylcarbamate (0.476 g, 1.81 mmol) in THiF (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 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 (MgSO 4 and concentrated to dryness to provide tert-butyl 2-hydroxy-2-oxazol-2-yl-1S-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-1S-phenethylethylcarbamate (0.125 g, 0.376 mmol), anisole (0.2 mL) and trifluoroacetic acid (0.6 mL) in dichloromethane mL) was stirred at room temperature for 2 hours and then concentrated to provide 2S-amino-1-oxazol-2-v-4-phenlbutan-1-ol trifluoroacetic acid salt 0.08 g, 0.229 mmol) as a yellow oil. MS (PCI) m/z 233 (M 1).
-67- REFERENCE Methyl 2-(2S-amino- 1-hvdroxy-4-Rhenvlbutvl ~oxazole-4-carboxyl ate A solution comprised of methyl 2-(2S-benzyloxycarbonylamino-1-hydroxy- 4-phenylbutyl)-4,5-dihydrooxazole4-carboxylate 100 g, 0.235 mmol), provided as in Reference 10, in dichioromethane (3 mL.) was cooled to 00 C and then treated with DBU (39 m.L, 0.26 mmol) and bromotrichlorornethane (26 mL, 0.26 mniol). The mixture was stirred for 6 hours at 0' C, washed with ammonium chloride (10 mL) and concentrated. The residue was dried (MgSO 4 to provide methyl 2-(2S-benzyloxycarbonylamino-1I-hydroxy- 4-phenylbutyl)oxazole-4-carboxylate. MS(PCI) m/z 425 (M Deprotecting provided methyl 2-(2S-amino- I -hydroxy- 4-phenylbutvl)oxazole-4-carboxylate.
REFERENCE I1I 2-Benzooxazol-2-vl-2-(tert-butvl-dimethl-silanloxy). 1S-Rhenethvlethyiamine A solution of 2S-ainino-l-benzooxazol-2-y1-4-phenylbutan-l1-ol (600 mg), provided as in Referencel2, in dichloromethane (15 mL) was cooled to M 0 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 The mixture was washed sequentially with a saturated sodium bi-carbonate solution (50 mL) and brine mL. x2), dried over magnesium sulphate and concentrated under reduced pressure to provide 2-benzooxazol-2-vl-2-(tert-butvl-dimethyl-silanyloxy 1S-pVhenethvlethylamine as an orange oil.
REFERENCE 12 2S-Amino- I -benzooxazol-2-vl-4-phenvlbutan- I -ol A solution of (S)-2-tert-butoxycarbonylamino-4-phenylbutyric acid (500 g, 179 mmol), EDC (37.8 g, 197 mmol), HQBT 4 1.1 g, 269 mmol) and NO-dimethylhydroxylamine hydrochloride (19.2 g, 197 nixol) in, dichloromethane (500 mL.) was cooled in an ice bath and then treated with a solution of triethylamine (27.5 mL., 197 mniol) in dichloromethane (150 m.L).
The ice bath was removed and the reaction mixture was stir at room temperature for -68approximately 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-(N-methoxy-N-methylcarbamoyl)- 3-phenylpropylcarbamate (53.41 g, 93% yield) as a clear, colorless oil.
The ter-butyl (S)-1-(N-methoxy-N-methylcarbamoyl)-3-phenylpropylcarbamate 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 (1M 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 minutes, further treated with saturated KH 2 PO, (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)-1-formyl-3-phenylpropylcarbamate (11.61 g, 99% yield).
A solution of tert-butyl (S)-l-formyl-3-phenylpropylcarbamate (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-1S-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 -69stand for 5 minutes and then a solution of tert-butyl 2-cyano-2-hydroxy-1IS-phenethylethylcarbamate (2.34 g, 8 rumol) 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 o-aniinophenol (873 mg, 8 mmol). The mixture was heated at 95 0 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 1N KOH until the aqueous wash layer was colorless. The organic phase was separated, dried over anhydro us 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-l-benzooxazol-2-yl-4-phenylbutan-1-oI (1.27 g, 52% average yield) as an orange semi-solid mass.
Proceeding as in Reference 12 Provided the following compounds: 2-amnino-I -benzooxazol-2-vl-ethanol; 2-amino-I -benzooxazol-2-vl-2-methyl-propan- I-ol;I (S)-2-amino-l1-benzooxazol-2-yl-hexan-lI-ol; 1 -amino-cvclop2royfl-l1-benzooxazol-2-vl -methanol; (S')-2-amino-l1-benzooxazol-2-vl-propan-I -ol; (S)-2-amino-lI-benzooxazol-2-yl-4-methanesulfonvl-butan- I-ol; (S'l-2-amino-lI-benzooxazol-2-vl-pentan-l -ol; (S)-2-amino-I -benzooxazol-2-vl-butan-I -01; and 2-Amino-l-benzooxazol-2-vl-3-methoxv-propan-l-ol; 'H NMR (CDC 3 7.70 (in, 111), 7.53 (in, 1H), 7.34 (in, 2H), 4.88-5.0 (in, 111), 3.60 (in, IH), 3.53 (in, 311), 3.37 lH), 3.30 (s,
IH);
EXAMPLE I N-r IR-(2-Benzooxazol-2-yl-2-hydroxy- 1S-phenethylethylcarbamovI)-2-benzvlsulfonvlethyl1.
morpholine-4-carboxamide (Compound 1) 0 OH
H
N JN fN Y0 r
H
0 06 N A mixture of 2S-amino-1-benzooxazol-2-yl-4-phenylbutan-1.o (2.2 g, 7.8 mxnol), provided as in Reference 12, 2 -morpholin-4-ylcarbonylamino-3-benzylsulfonylpropionic acid (2.78 g, 7.8 mmol), EDC (1.64 g, 8.57 mniol), 1-hydroxybenzotriazole hydrate (1.58 g, 11.7 mmol) and N-methylmorpholine (2.4 mL, 17.1 mmol) in dichioromethane was stirred for I hour. The mixture was treated with additional amounts of EDC 1 eq) and 1 -hydroxybenzotriazole hydrate 1 eq) and stirred for 30 minutes. The mixture was treated with an additional amount of EDC 1 eq) and stirred for 15 minutes. The mixture was treated with an additional amount of EDC 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 mL) and brine (50 mL), dried (MgSO,) and concentrated to provide N-r 1R-(2-benzooxazol-2-yl-2-hvdroxv-I1S-phenethvlethvlcarbamovl- 2 -benZylsulfonvlethvllmoriholine-4-carboxamide (4 g, 6.44 mniol); 1H NMR (CDCI 3 7.68 (in, IH), 7.52 (in, IH), 7.10-7.45 (mn, 12H), 6.0-6.25 (mn, 11H), 4.95-5.1 (in, IH), 4.52-4.80 (in, 1H), 4.15-4.5 (mn, 3H1), 3.1-3.75 (in, 1011), 2.69 (mn. 2H), 2.06 (mn, 11H), 1.80 (mn, 1H); MS: m/e 621.0; EXAMPLE 2 2S-Acetvlamino-N-(2-oxazol-2-vl-2-hvdroxyv 1 S-phenethylethyfl-3-cvclohexvlnropionamide (Compound 2) 0 OH H C N H
A
A mixture comprised of 2 -acetylamino-3-cyclohexylpropionic acid (0.45 g, 0.211 mmol), PyBOP® 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-aminol-oxazol-2-yl-4-phenylbutan-l-ol trifluoroacetic acid salt, provided as in Reference 9, in DMEF and neutralized with diisopropylethylamine was added. Additional diisopropylethylamine (0.037 g, 0.211 minol) 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 I N hydrochloric acid (2 x 25 mL), water (2 x 25 mL) and brine (2 x 25 m1L), dried (MgSO 4 and concentrated. Product was purified from the residue by flash chromatography eluting with 1:3 hexanes/ethyl acetate to provide 2S-acetvlamino-N-(2-oxazol-2-vv.
2 -hvdroxy-IS-p2henethylethyl)-3-cvclohexyln)Roionamide (0.036 g, 0.084 mmol) as an oil. MS (ESI) m/z 428 (M 'H-NMR (300 MHz, CD 3 OD): 850.80 (in, 2H), 5 1. 12 (in, 4H), 1.40(m, 2H4), 8 1.65 (in, 6H), 8 1.80 (mn, 1H), 852.00 (mn, 4H), &52.70 (in, IH), 852.80 (in, IH), 4.44 (in, 1H), 854.51 (in, 1H), 5 7.11 7.47 (in, 6H), 857.99 1H), (C 41 33
N
3
O
4 Proceeding as in Example 2 provided the following compounds of Formula I: 3-cyclohexyl-N-1I2-hvdroxv-2-(5-Rhenvloxazol-2-l).I S-Dhenethylethvl ipropionamide (Compound MS (ESI) in/z 448 (M 'H-NMR (300 MiHz, CDCI 3 8 0.89 (mn, 2H), 6 1.20 4H), 5 1.45 1H), 6 1.65 6H), 6 1.80 1H), 52.09 4H), 52.73 J 4 Hz, 2H), 54.51 1H), 54.96 2H), 6 6.00 (mn, 1H), 8 7.11 7.47 9H), 8 7.60 2H), (CnH 35
N
2 0 3 2S-acetvlaiino-N-[2-hvdroxv- 1S- henethvl-2-(5-Dhenloxazol-2-vI)ethvll- 3-cyclohexylronionamide (Comnound MS (ESI) m/z 505 (M 'H-NMR (300 MHz,
CDCI
3 60.80 2H), 6 1.12 4H), 6 1.40 2H), 6 1.65 6H), 1.80 1H), 6 2.00 5H), 8 2.70 2H), 5 4.51 1H), 54.96 2H), 5 6.19 1H), 8 6.98 1H), 67.11 -7.47 9H), 67.62 2H), (CH 3
,N
3
O
4 and N-(I S-benzothiazol-2-vycarbonvy-3-phenypropy)-3-cvclohexvyroionamide (Compound 'H NMR: 6 0.83 2H), 5 1.20 5H), 6 1.48 2H, J 9 Hz), 5 1.67 (m, 4H), 6 2.20 3H), 5 2.48 1H), 6 2.75 2H), 6 5.95 1H), 5 6.35 1H, J =9 Hz), 6 7.25 5H), 6 7.57 2H), 6 7.93 1H, J 9 Hz), 5 8.18 1H, J 9 Hz); ES-MS l/z 435 and 2S-acetlamino-N-(1 S-benzothiazol-2-vlcarbonvi-3-phenvynrolvI)- 3-cyclohexylpropionamide (Compound 'H NMR: 6 0.87 8H), 6 1.22 6H), 6 1.92 (m, IH), 6 2.12 1H), 6 2.48 1H), 6 2.78 2H), 6 3.87 1H, J 7 Hz), 8 5.62 1H), 67.20 6H), 5 7.53 2H), 67.98 1H, J 7 Hz), 8.18 1H, J 7 Hz); ES-MS m/z 492 N-r lS-(1S-phenethvl-2-benzooxazol-2-vl- 1-oxoethylcarbamovl)- 2-naphth-2-vlethvllineridine-4-carboxamide (Compound 'H NMR (DMSO-d 6 6 1.32 1.76 4H), 5 1.90 2.09 2H), 6 2.22 2.60 2H), 5 2.65 3.26 6H), 54.72 -4.86 (m, 1H), 5 5.26 1H), 6 7.06 7.31 5H), 8 7.45 4H), 6 7.55 (dt, J 1.26, 7.84 Hz, 1H), 6 7.65 (dt, J 1.18, 8.00 Hz, 1H), 6 7.72 7.88 3H), 5 7.90 J 8.06 Hz, 1H), 6 7.99 (d, J 7.86 Hz, 1H), 6 8.14 (bs, 1H), 6 8.24 J 8.04 Hz, 1H), 5 8.46 (bs, 1H), 6 8.94 (d, J 6.43 Hz, 1H); 2S-acetvlain I S-benzooxazol-2-vlcarbonvl-3-ohenvlnropvl)- 3-cyclohexyinropionamide (Compound MS (ESI) n/z 476 (M 'H-NMR (300 MHz, CDC1 3 50.85 2H), 6 1.26 4H), 6 1.47 2H), 6 1.64 6H), 6 1.99 3H), 5 2.15 2H), 5 2.41 1H), 6 2.72 J 6Hz, 2H), 64.59 J 4Hz, 1H), 8 5.65 J 2Hz, 1H), 8 6.26 J 6 Hz, 1H), 8 7.10 7.26 6H), 6 7.41 7.65 3H), 5 7.86 J 6H 1H), (C28H 33
N
3
O
4 tert-butvl 1 1S-benzooxazol-2-ylcarbonvl-3-phenylpropylcarbamol)- -73- 2-cyclohexylethyicarbainate (Compound 9); N-fl -(benzooxazo-2-vicarbonI-3-henylpronvI1-3-cvclobexvipromionamid (Compound 3-cyclohexyl-N-r3S-phenvl-l1-(5-phenyloxazol-2-vlcarbonvl)p2ronllpropionainide (Compound 11); MS (ESI) ni/z 445 (M IH-NMR (300 MHz, CDCI 3 &80.89 (mn, 2H), 8 1.20 (mn, 4H), 8 1.55 (in, 2H), 8 1.68 (mn, 6H), 8 2.12 (in, 1H), 852.27 J 4Hz, 2H), 5 2.48 (mn, 1H), 8 2.76 (mn, 2H), 5 5.70 (in, IH), 8 6.35 J 4 Hz, 1H), 8 7.19 7.30 (mn, 5H), 8 7.48 (mn, 3H), 8 7.57 1H), 5 7.79 J =4Hz, 2H), (C 2 sH 32
N
2 0 3 2S-acetviamino-N-f 1S-(5-phenvloxazol-2-ylcarbonfl)-3-Rhenvln2RoYvl- 3-cyciohexylproionamide (Compound 12); MS (ESI) mlz 502 (M l);'H-NMR (300 MlHz, CDC1 3 &50.80 (mn, 2H1), 8 1. 12 (mn, 4HD, 8 1.50 (mn, 111), 8 1.65 (in, 6H), 8 1.80 (mn, 1H), 8 2.05 3H1), 8 2.12 (mn, 1H), 8 2.48 (mn, IH), 8 2.70 J3 6Hz, 211), 8 4.52 J 2Hz, 1H), 6 5.60 J 2Hz, IH), 8 5.98 (di, J 6 Hz, 1H), 8 6.92 (di, J 6Hz, 1H), 8 7.19 7.30 (mn, 511), 8 7.48 (mn, 3H), 8 7.57 1H1), 8 7.79 J 4Hz, 2H), (C 30
H
35
N
3 0 4 benzyvI 1S-(benzooxazol-2-vlcarbonylmethylcarbanovi)-3-methylbutvlcarbainate (Compound 13); benzy] 1 S-(5-phenylbenzooxazol-2-ylcarbonylinethlcarbamovl)-3-inethvlbutvlcarbamate (Compound 14); 2S-acetvlamino-N-(lS-oxazol-2-vlcarbonvi-3-:phenylpopyl)-3-cyclohexvlTnropionamide (Compound 15); MS (ESI) m/z 426 (M IH-NMR (300 MIHz, CDCI 3 8 0.85 (in, 2H), 8 1.20 (mn, 4H), 8 1.50 (in, 2H1), 8 1.65 (in, 6H), 852.05 3H), 8 2.48 (in, 111), 8 2.70 (t, J =6Hz, 2H), 84.52 J =2Hz, IH), 85.60 J =2Hz, 1H), 85.93 (d,I1= 6HRz, IH), 86.89 J 6Hz, 1H), 8 7.19 7.38 (mn, 5H), 8 7.47 IH), 8 7.79 IH), (CH_ 3
N
3
O
4 benzyl 1 S-benzooxazol-2-ycarbonl-3-Dhenlpopvlcarbamate (Compound 16); 2-acetvlaniino-N-0 S-benzooxazol-2-vlcarbonyl-3-Rhenvlvropvl')-3-phenvlpropionamide (Compound 17); N-(1S-benzooxazol-2-lcarbonvi-3-Rhenvloroov!)benzvisulfonamide (Compound 18); 'H NMR (CDC1 3 7.88 (di, 3=6.2Hz, IH), 7.67 (di, J=6.2Hz, LH), 7.60 J=6.2Hz, 111), 7.51 (t, J=6.211z, 1H), 7.35 3=6.2Hz, 2H), 7.08-7.29 (mn, 7H), 6.96 J=6.2Hz, IH), 5.52 (di, JK=9.4 Hz, JH), 4.90 (td, 3=9.4, 3.1Hz, IH), 4.31 (dd, J=10.9, 10.9Hz, 2H), 2.80 11), 2.27(in, 1H), 2.04 (mn, 1H); MS: in/e=435.0; N-(1S-benzooxazol-2-vlcarbonvi-3-nhenvlpropvl)-2-cvclohexylethanesulfonarnide (Compound 19); 'H NMR (CDC1 3 7.94 J=6.3Hz, 1H), 7.70 J=6.311z, 1H), 7.62 (t, J=6.3Hz, 11), 7.52 J-6.3Hz, 1H), 7.17-7.34 5H), 5.42 J=9.5H, 11), 5.17-5.25 (m, 1H), 2.79-3.09 4H), 2.38-2.55 1H), 2.08-2.21 1H), 1.52-1.79 711), 1.08-1.34 (m, 4H), .77-1.01 2H); MS m/e=455.1; 1 -benzooxazol-2-vlcarbonvl-3-phenvlro XD-3-cyclpentvlproonamide (Compound N-(I S-benzooxazol-2-vlcarbonvl-3-phenvlpronvl)-2-cvclohexvlacetamide (Compound 21); N-(1S-benzooxazol-2-vlcarbonvl-3-phenvlropyl)-2-bicvclor2.2. lhept-2-vlacetamide (Compound 22); N-(1 S-benzooxazol-2-ylcarbonl-3-Rhenvlprovl)-4-methvlpentanamide (Compound 23); N-(1S-benzooxazol-2-vlcarbonvl-3-henvlrovl)-2-nphthalen-1 -viacetamide (Compound 24); 'H NMR (CDC 3 7.96 1H), 7.84 2H), 7.82 11), 7.42-7.75 (m, 6H), 7.14 4H), 6.86 2H), 6.25 1H), 5.64 21), 4.08 1H), 2.45 2H),2.42 1H), 1.90 11); N-(1 -benzooxazol-2-ylcarbonvl-3-phenvlropl)-3-thenlpropionanide (Compound 'H NMR (CDCI 3 7.90 (d,J=8.OHz, 1H), 7.65 (d,J=8.OHz, 11), 7.59 11), 7.56 1H), 7.05-7.35 111), 6.20 J=7.0Hz, 1H), 5.76 1H), 2.97 21), 2.5-2.7 4H), 2.4 (m, IH), 2.1 (in, 1H); methyl 2-F2-(3S-cclohexvlpronionlamino)-4-henlbutvrvll- 4.5-dihdrooxazole-4S-carboxvlate (Compound 26); MS (ESI) m/z 429 (M 'H-NMR (300 MHz, CDC 3 60.89 2H), 6 1.22 4H), 6 1.51 1H), 6 1.65 6H), 62.05 (m, 1H), 8 2.20 J 4 Hz, 2H), 5 2.46 1H), 6 2.73 2H), 6 3.80 3H), 8 4.55 1H), 64.60 11), 6 5.00 IH), 6 5.45 1H), 6 6.15 1H), 67.13 7.35
(CH,
2
N
2
Q
5 methyl 2-f2-(3S-cyclohexvlrotionvlamino)4-Rhenlbutvrvlloxazole-4-carboxvlate (Compound 27); MS (ESI) m/z 427 (M 'H-NMR (300 MHz, CDCI 3 6 0.89 2H), 6 1.22 4H), 6 1.49 1H), 5 1.65 61), 62.20 3H), 62.46 11), 62.74 2H), 3.99 311), 6 5.62 11), 6 6.20 J 4Hz, 11), 6 7.15 7.35 511), 6 8.40 11), (C2,H3IN 2
Q);
benzvl 1 S-(I S-benzooxazol-2-vlcarbonvl)- 3-phenvlrovlcarbaovyl)-2-naphthalen-2-vlethvlcarbamate (Compound 28); 2-acetylainino-N-(1 S-benzooxazol-2-ylcarbonyl-3-nhenylpronvyll- 3-(2-flugoRohenyl&Motionainide (Compound 29); 2S-acetvlainino-N-(IS-benzooxazol-2-ylcarbonvl-3-phenvlR opyl).2-methl- 3-phenylpropionamide (Compound tert-bulyl IS-(IS-benzooxazol-2-ylcarbonyl-3-phenvlnrovvlcarbamovfl.
3-phenvl]rEpvicarbamate (Compound 31); N-0 -benzooxazol-2-vlcarbonyl)-3-nhenylprpvl)-4-cvclohexvlbutvrmide (Compound 32); 'H NMR (CDC 13): 7.94 J=7.9Hz, 1H), 7.68 7.9Hz, 111), 7.58 (t,J=7.9Hz, 111), 7.50 J=7.911z, IH), 7.10-7.32 (in, 5H1), 6.27 (di, J=11.8Hz, 1H1), 5.76-5.89 (in, 1H), 2.74-2.89 (in, 2H), 2.42-2.61 (in, 1H), 2.11-2.32 (in, 3H), 1.53-1.79 (in, 9H), 1.05-1.32 (in, 4H); 0.79-1.0 (in, 2H); MS: in/e=433; methyl 2-[2S-(3-cvcloh-exylpropionvlainino)-4-phenvlbutvrvll- 4.5-dihydrooxazol-4S-ylcarboxylate (Compound 33); MS (ESI) m/z 429 (M 'H-NMR (300 MlHz, CDCI 3 0.89 (in, 211), 8 1.22 (mn, 411), 8 1.51 (in, 111), 8 1.65 (mn, 6H), 8 2.05 (in, 1H), 8 2.20 J 4 Hz, 2H), 8 2.46 (mn, 111), 8 2.73 (mn, 2H), 8 3.80 3H), 584.58 (in, 211), 8 5.00 (mn, 111), 8 5.45 (mn, 111), 8 6.15 (in, 111), 8 7.13 7.35 (in, 511), (C24H 32
N
2
Q
5 3-cvclohexyl-N-[1 -(5-methoxvbenzooxazol-2-vlcarbonfl)-3-phenvlpronvllpronionanide (Compound 34); MS (ESI) rn/z 449 (M 'H-NMR (300 M~H, CDC1 3 860.95 (mn, 2H), 8 1.22 (in,411), 8 1.51 (mn, 211), 8 1.65 (in, 611), 8 2.15 (in, I 8 2.20"(t, J 4 Hz, 2H1), 8 2.50 (mn, 1H), 8 2.77 J 2 Hz, 211), 8 3.92 3H), 8 5.78 (in, 1H), 8 6.37 (in, 111), 8 7.13 7.35 (mn, 5H), 8 7.53 J 6 Hz, 1H), (C 7H 3
,N
2
O
4 2-acetvl-N-(1S-benzooxazol-2-ylcarbonyl- 3-phenylpropyl)- 1 .2,34-tetrahydroisoquinoline-3S-carboxainide (Compound 2S-acetvlamino-N-(1S-benzooxazol-2-ylcarbonvl-3-phenylpropyl)- 3-(2-chlorophenvl~propionam-ide (Compound 36); 3-cvclohexyl-N-[ 1 S-(6-methoxybenzooxazol-2-ylcarbonvl)-3-phenylpropvyllpropionanide (Compound 37); MS (ESI) in/z 449 (M IH-NMR (300 Mliz, CDCI 3 8 0.95 (mn, 2H), 8 1.22 (mn, 4H), 8 1.51 (mn, 211), 8 1.65 (in, 6H), 8 2.15 (in, 111), 8 2.20 J 4 Hz, 211), 8 2.50 (in, 1H), 8 2.77 J 2 Hz, 211), 8 3.95 311), 8 5.78 (mn, 1H), 8 6.37 (di, J 6 Hz, 1H1), 8 7.10 7.35 (in, 5H1), 8 7.77 (di, J 6 Hz, 111), (C 27
H
32
N
2 Oj); 3-cyclohexyl-N-rl1S-(5-trifluoromethylbenzooxazol-2-ylcarbonl).
3-RhenvynrpvI~ylropionainide (Compound 38); MS (ESI) xn/z 487 (M 'H-NMR (300 M[Hz, CDC 3 50.95 2H), 8 1.22 4H), 8 1.51 1H), 8 1.65 6H), 52.20 3H), 8 2.51 1H), 62.80 J 2 Hz, 2H), 8 5.76 1H), 6 6.22 J 6 Hz, 1H), 5 7.15 7.35 511), 6 7.77 2H), 5 8.25(s, 1H), (C 27 H2F 3
N
2
O
3 2-acetvlaiino-N-(1 -benzooxazol-2-vlcarbonvl-3thenvlprovi)- 3-(2-trifluoromethvlpbenvl)rotionamide (Compound 39); N-(1-benzooxazol-2-v oy3hnvl)3ghi4lroad (Compound 'H NMR (CDC1 3 7.90 1H), 7.76 11), 7.06-7.36 71), 4.00 (m, 11), 3.12 4H), 2.50-3.5 2H), 2.0-2.5 21), 1.83 4H); MS: n/e=421.9; 3-cvclohexvi-N-[ 1S-(5-nitrobenzooxazo 2vlcarbonl)-3henlyroyvllDroDionamide (Compound 41); MS (ESI) i/z 464 (M 'H-NMR (300 MHz, CDCI 3 5 0.95 211), 8 1.22 4H), 5 1.51 11), 5 1.65 6H), 8 2.20 3H), 5 2.51 1H), 8 2.80 2H), 8 5.67 1H), 5 6.17 J 6 Hz, 1H), 8 7.09 7.35 5H), 5 7.77 J 6Hz, 1H), 5 8.50 J 6 Hz, Il), 8 8.77 11), (C26H 29
N
3
O
5 methyl 2- 2S-(3-cclohexylpr~ionylamino)-4Mheny buLMvlbenzooxazole-6carboxylate (Compound 42); MS (ESI) i/z 477 (M 'H-NMR (300 MHz, CDC1 3 8 0.95 21), 8 1.22 411), 5 1.51 1H), 5 1.65 61), 8 2.23 3H), 8 2.50 1H), 8 2.77 2H), 854.00 3H), 5 5.78 11), 8 6.27 J 6 Hz, 1H), 7.15 7.35 5H), 5 7.98 J 6 Hz, 1H), 5 8.22 J 6Hz, 1H 8 8.39 IH), (C 2
,H
3
,N
2 0 5 orobenzooxazol -lcarbonyl)-3-henynropyll-3-cclohexylropionamide (Compound 43); MS (ESI) n/z 453 (M 'H-NMR (300 MHz, CDCl 3 5 0.95 211), 8 1.22 4H), 8 1.53 21), 8 1.65 5H), 5 2.20 3H), 8 2.50 11), a 2.77 211), 8 5.74 11), 8 6.20 J 6 Hz, 11), 5 7.09 7.35 511), 8 7.60 21), 5 7.90 111),
(C
26
H
2 9CIN 2
O
3 benzvl 1 S-(lS-benzooxazo -2-yvcarbonl-3-henlropvylsulfamovlmethvl)- 3-iethylbutvlcarbamate (Compound 44); 'H NMR (CDC1 3 7.92 1=7.7Hz, 11), 7.64 (m, 11), 7.57 LH), 7.50 11), 7.21-7.34 101), 6.30 (dj=9.2Hz, 11), 5.34 1H), 5.11 1H), 4.91 (dJ=9.6Hz, 11), 4.51 11), 3.11 2H), 2.89 2.50 11), 2.20 (m, 11), 1.70 1H), 1.5 1H), 1.23-1.46 1H), 0.;92 (tJ=7.4Hz, MS: le=578.1; NI IS-[1S-(benzooxazo-2-lcarbonvy)-3ihenl3roylsulfamnoylethyll- 3-methyibuyl lacetamide (Compound 45); '11 NMR (CDC1 3 7.89 (d,J=7.7Hz, 11), 7.62 (m, 11), 7.55 1H), 7.49 1H), 7.18-7.30 5H), 6.7 1=8.9Hz, 11), 5.61 J=9.4Hz, 1H), 5.34 11), 4.86 11), 3.06 211), 2.90 J=7.7Hz,. 21), 2.24 1H), 2.22 11), -77- 2.04 3H), 1.66 (in, 1H), 1.48 (in, 111), 1.38 (mn, IH), 0.91 J=6.211z, 6H); MS: n/e=486.1; benzyl IR-(1S-benzooxazol-2-ylcarbonv-3-Rhenvpropvlsulfamolnethvl)- 3-inethylbutylcarbamate (Compound 46) 11H NMR (CDCL 3 7.9 (in, 1H), 7.60 (mn, IH), 7.58 (mn, 1H), 7.5 (in, 1H), 7.75-7.4 (mn, IOH), 5.85 (mn, 1H), 5.0-5.4 (in, 3H), 4.2 (mn, IH), 3.15-3.35 (mn, 2H), 2.65-2.85 (mn, 2H), 2.45 (mn, IH), 2.15 (mn, 111), 1.9 (in, 111), 1.4-1.7 (mn, 3H1), 0.9 (in, 611); MS: inle=578. 1; and N-fl -(1-benzooxazol-2-vlcarbonv-3-phenvronvlsulfamolmethvl)- 3-rnethylbutvllacetamide (Compound 47)'H NMR (CDC 1 3 7.9 (mn, IH), 7.65 (mn, 1H), 7.61 (mn, 1H), 7.60 (in, 111), 7.18-7.30 (mn, 5H), 6.0 (mn, 1H), 5.85 (mn, 111), 5.28 (mn, 1H), 4.50 (in, IH), 3.20(in, 1H), 2.85 1H), 2.70(in, 1H), 1.8-2.2(in, 2H), 1.95 3H), 1.35-1.70(in, 2H), 0.9 (mn, 6H); MS: inle=486.0.
EXAMPLE 3 tert-Butvl IR-(2-benzooxazol-2-yi- 2-hydroxy-1 S-phenethylethylcarbamgl)-2-(2-canobenzysulfanl~ethvlcarbanate (Compound 48)
NC-
S
0 OH
H
NN 0 Hf t 0 N A solution of 2R-tert-butoxycarbonylamino-3-(2-cyanobenzylsulfanyl)propionic acid (336 2S-ainino-lI-benzooxazol-2-yI-4-phenylbutan-lI-ol (282mg), 1-(3-dimethylaminopropyl)- 3-ethylcarbodiinide hydrochloride (211 mng) and 1-hydroxybeazotriazole (197 mg) in dichloroinethane (20 mL) was treated with N-methylinorpholine (2.2 inL). 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 rnL), IN hydrochloric acid (30 niL), a saturated sodium bicarbonate solution (30 niL) and then brine (3OmL), 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-bulyl IR-(2-benzooxazol-2-yl-2-hvdroxy- IS-phenethylethylcarbamovl)- 2-(2-cvanobenzylsulfanyl)ethvlcarbamnate as an off white solid. MS: 601 [H+ Proceeding as in Example 3 provided tert-butvl IR-(2-benzooxazol-2-vl-2-hydroxv- IS-1nhenethylethvlcarbamofl)-2-benzlsulfaiylethylcarbamate (Compound 49), MS: 576 [iY EXAMPLE 4 N-F lR-(2-Benzooxazol-2-vl-2-hvdroxy-1 S-nhenethvlethvlcarbamoyl)- 2-(2-cyanobenzvlsulfanl)ethllisonicotinamide (Compound
NC
S
0 OH
H
NN
H
0N A solution of 3-2caoezlufnl-R(yi--labnlaiorpoi acid (425 mg), provided as in Reference 2, 2S-amino- 1 -benzooxazol-2-yl-4-phenylbutan- I1-ol (356 mg) and HATU (356 mg) in dimethylformamide (40 niLL) was treated with diisopropylamine (0.239 rnL). 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-f lR-(2-benzooxazol-2-vl- 2-hydroxy- 1S-phenethylethvlcarbainoyJ)-2-(2-cvanobenzylsulfanvl)ethyllisonicotinamide (216 mg) as a gum. MS: 606 [1v1IH]. HPLC: RT= 13.20 minutes.
Proceeding as in Example 4 provided 9H-fluoren-9-vlmethyl IS-(2-benzooxazol-2-vl- 2-hydroxy- IlS-phenethvlethvlcarbamov)-2-cvclobexvlethvcarbamate (Compound 51); 9H-fluoren-9-ylmethvl lS-r2-benzooxazol-2-vl-2-(tert-butvldimethylsilanvloxv)- 1S-ohenethylethvlcarbarnovll-2-cyclohexvlethvlcarbamate (Compound 52), MS: 772 EXAMPLE 2R-Amino-N-(2-benzooxazol-2-vl-2-hvdroxy-IS-phenethlethl)-3-(2-cvanobenzvlsulfanvl)nRopionaxnide hydrochloride (Compound 53) A solution tert-butyl IR-(2-benzooxazol-2-yl-2-hydroxy-LS-phenethylethylcarbamoyl)- 2-(2-cyanobenzylsulfanyl)ethylcarbamate (145 mg), provided as in Example 3, in dioxane niL) was treated with hydrogen chloride, bubbling the gas through the solution for minutes. The reaction mixture was concentrated by evaporation and the residue was triturated with diethyl ether to provide 2R-amino-N-(2-benzooxazol-2-yl-2-hydroxv- I S-p~henethylethyl)-3- (2-cyanobenzvlsulfanvl)propionamide hydrochloride (117 mg) as a an off-white solid. MS: 537 Proceeding as in Example 5 provided 2R-amino-N-[2-benzooxazol-2-vl-2-hvdroxv- 1 S-lphenethylethyl)-3-benzylsulfonylnroTpionamide hydrochloride (Compound 54), MS: 508 EXAMPLE 6 2S-Amino-N-(2-benzooxazol-2-vl-2-hvdroxy-I1S-phenethylethyl)-3-cvclohexvlprovpionamide (Compound A solution of 9H-fluoren-9-ylmethyl IS-(2-benzooxazol-2-yl-2-hydroxy- 1S-phenethylethylcarbamoyl)-2-cyclohexylethylcarbanlate (165 mg), provided as in Example 4, in dichloromethane (30 mL) was treated with tris(2-aminoethyl)amine bound to polysterene beads (4.48 The mixture was stirred at room temperature for 48 hours and then filtered.
The resin was washed four times with dichlorometbane (20 mL) and the combined filtrates were concentrated under reduced pressure to provide 2S-amino-N-(2-benzooxazol-2-vI_- 2-hydroxy-lS-phenethylethyl)-3-cvciohexylpropionamide (147 mg) as a colourless oil..
EXAMPLE 7 2S-Amino-N-r2-benzooxazol-2-vl-2-(tert-butvldimethvlsilanyloxv)- IS-p2henethviethvfl- 3-cyclohexyinronionamnide (Compound 56), a protected compound of Formula I A solution of 9H-fluoren-9-ylmethyl IS-[2-benzooxazol-2-yi- 2-(tert-butyldimethylsilanyloxy)- lS-phenethylethylcarbamoyl]-2-cyclohexylethycarbanate (1.48 provided as in Example 4, in dichloromethane (50 mL) was treated with tris-(2amninoethyl)amine (14.4 mL). The reaction mixture was stirred for 75 minutes and then additional dichioromethane was added (50 mL). The mixture was washed sequentially with brine (50 mL x4) and a pH 5.3 buffer (50 mL x3), dried over magnesium sulphate and concentrated to provide 2S-amino-N-f2-benzooxazol-2-yl-2-(tert-butvldimethvlsilanvloxy)- IS-phenethylethvll-3-cvclohexylpropionamide as an orange oil.
EXAMPLE 8 rert-Butvl 1R-(2-benzooxazol-2-yl-2-hydroxy-IS-vhenethylethlcabamovll- 2-(2-cvanobenzylsulfanyl )ethvlcarbamovlvineri dine-I -carboxylate (Compound 57)
NC
H
No
N
H
O No 0 A solution of 2R-amino-N-(2-benzooxazol-2-yl-2-hydroxy- IS-phenethylethyl)- 3-(2-cyanobenzylsulfanyl)propionamide hydrochloride (170 mg), provided as in Example 5, in dimethylformamide (7 niL) was treated with 1-tert-butoxycarbonylpiperidine-4-carboxylic acid tetrafluorophenyl ester ten-butyl ester on resin (excess), prepared according to the procedure described in International Patent Application No. W099167228, 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-butl IR-(2-benzooxazol-2-yl-2-hvdroxv- 1S-nhenethvlethvlcarbamovll- 2-(2-cvanobenzvlsulfanvlethvlcarbampvlpiR'eridine-l1-carboxylate (95mg) as a gum.
MS: 712 [M.HI+.
Proceeding as in Example 8 provided benzvl 4-rlS-(2-benzooxazol-2-yl-2-hydroxv- 1S-phenethylethylcarbamoyl)-2-cvclohexvlethvlcarbamoyllperidine-lI-carboxvlate (Compound 58), MS: 681 EXAMPLE 9 N-r IR-(2-Benzooxazol-2-vl-2-hydroxv- 1S-Dhenethlethylcarbamovl)-2-benzvlsulfonvlethvlltetrahydropvran-4-carboxamide (Compound 59)
S
0 OH
H
NfN J 0
H
0 06 A mixture of 2R-arnino-N-(2-benzooxazol-2-yl-2-hydroxy-1S-phenethylethyl)- 3-benzylsulfonylpropionamide hydrochloride (0.3 prepared as in Example 5, tetrahydropyran- 4-carboxylic acid (0.072 1 -(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride 116 g) and 1 -hydroxybenzotriazole 112 g) in dichloromethane (20 mL) was treated with 4-N-methylmorpholine 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 mE) and brine mE), dried over magnesium sulfate and then concentrated by evaporation. The residue was subjected to flash column chromatography on silica eluting with ethylacetate to provide N-[1R- (2-benzooxazol-2-vl-2-hydroxv-I1S-phenethylethylcarbamovl)-2-benzylsulfonvlethvlltetrahydropyran-4-carboxamide (66 mg) as a cream solid. MS: 618 MH.
Proceeding as in Example 9 provided the following compounds of Formula 1: N-r I R-(2-benzooxazol -2-yl-2-hydroxy- I S-phenethylethylcarbamovl)- 2-benzylsulfonylethyll-nicotinamide (Compound 60), MS: 613 -84- N-f IR-(2-benzooxazol-2-vl-2-hydroxv- lS-Rhenethylethvlcarbamoyl)-2-benzylsulfonylethyllvvrazine-2-carboxamide (Compound 61), MS: 614 [H~ 4-r 1S-(2-benzooxazol-2-yl-2-hvdroxv-IS-phenethvlethyjcarbamovfl-2-cclohexl ethylcarbamovllpiperidine-l1-carboxylate (Compound 62); and N-ri S-(2-benzooxazol-2-vl-2-hydroxv- IS-Rhenethvlethvlcarbamovl)-2-cyclohexylethv!1isonicotinamide (Compound 63).
EXAMPLE tert-Butvl 4-f 1R-(2-benzooxazol-2-vl-2-hvdroxy-I1S-Rhenethylethvlcarbamovll- 2 -(3-methvlpvrid-2-vlmethvlsulfonvl)ethvlcarbamovllp~iperidine-lcarboxylate (Compound 64)
N
0 OH
H
NfN
H
0 YNC 0 N A solution of 2R-amino-N-(2-b>enzooxazol-2-yl-2-hydroxy- iS-phenethylethyl)- 3 -(3-methylpyrid-2-ylmethylsulfonyl)propionamide (178 mg), HATU (137 mg) and 1 -terr-butoxycarbonylpiperidine-4-carboxylic acid (69 mg) in dimethylformamide (10 mL) was treated with NN-diisopropylethylainine 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-butvl 4-f 1R-(2-benzooxazol-2yl-2-hydroxy-I1S-Rhenethvlethlcarbamovll- 2 3 -methvlnvrid-2-vlmethylsulfonvr~ethvlcarbamoyllpiperidine-l-carboxylate (81 mg). MS: 734 [Ill1]- Proceeding as in Example 10 provided the following compounds of Formula 1: tetrahydpvR3an-4-vl 1R4(2-benzooxazol-2-vl-2-hydroxy- 1S-phenethvlethvlcarbamovl)- 2-benzvlsulfanylethvlcarbamate (Compound N-f IS-(2-benzooxazol-2-yl-2-hvdroxv-l S-phenethvlethylcarbamovl)- 2-cvclohexvlethvlltetrahvdronvran-4-carboxamide (Compound 66), MS: 548 and N-f IS-(2benzooxazol-2-l-2-hydroxv-IS-Rhenethylethylcarbamol)-2-cclohexyleth vii- 6-hydroxynicotinamide (Compound 67).
EXAMPLE 11I A-r2-Benzooxazol-2-vl-2-(tert-butvldimethvlsilanvloxv)-1 S-phenethylethvll-3-cyclohexvl- 2S-(3-pvrid-3-vlureido)npropionamide (Compound 68), a protected compound of Formula I
H
0 NN
N
A solution of 2S-amino-N-Ii2-benzooxazol-2-yl-2-(tert-butyldimethylilalyloxy)- 1S-phenethylethyl]-3-cyclohexylpropionamnide (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 1, v/v) to provide N-r2-benzooxazol-2-vl-2-(tertbutvldimethylsilanvloxv)- 1 2henethylethyI1-3-cvclohexyi-2S-(3-pvyrid-3-lureido~phrOionamide (172 mg) as a colorless oil.
EXAMPLE 12 N-1 IS-[2-Benzooxazol-2-vl-2-(tert-butvldimethvlsilanyioxvy) S-Rhenethylethylcarbamoyll- 2-cyclohexylethyl lmorpholine-4-carboxamide (Compound 69), a protected compound of Formula 1 0
H
A solution of 2S-amino-N-[2-benzooxazol-2-yl-2-(tert-butyldimethylsilanyloxy)- IS-phenethylethyl]-3-cyclohexylpropionamide (200 mg), provided as in Example 7, in dichloromethane (8 mL) was treated with 4-morpholinecarbonyl chloride (0.094 mL) and triethylamine 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 1, v/v) to provide N-I 1S-[2-benzooxazol-2-vl-2-(tert-butvldimethvlsilanvloxv)- IS-vhenethvlethvlcarbamoyll-2-cyclohexvlethvl lmorholine-4-carboxamide (143 mg) as a white solid. NIH+ 663.
EXAMPLE 13 tert-butvl 4-i IR-(2-benzooxazol-2-vI-2-hydroxv-1 S-phenethylethylcarbamovll- 2-(2-cvanobenzvlsulfonvl)ethlcarbamoylpipeidine-1 -carboxylate (Compound
NC
0 OH Nf
H
0QYN,, 0 N A solution of tert-butyl 44 IR-(2-benzooxazol-2-yl-2-hydroxy-1Sphenethylethylcarbamoyll-2-(2-cyanobenzylsulfanyl)ethylcarbamoylpiperidine- 1 -carboxylate mg), provided as in Example 8, in methanol (8 xnL) was treated with a solution of OXONE' (246 mg) in water (8 niL). 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 (20OmL). 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 tert-butvl 4-F lR-(2-benzooxazol-2-vl-2-hvdroxy-IS- Rhenethvlethvlcarbamovll-2-(2-cvanobenzvlsulfonvl)ethvlcarbamovIlpiperidine I -carboxylate (35 mg) as a gum. MS: 744 MI.
Proceeding as in Example 13 provided N-r lR-(2-benzooxazol-2-yl-2-hvdroxv- IS-Dphenethylethvlcarbamoyl)-2-(2-cvanobenzvlsulfonyl)ethyllisonicotinamide (Compound 71), HPLC: RT= 12.89 minutes.
EXAMPLE 14 tert-Butvl IR4(2-benzooxazol-2-yl-2-hydroxv-I1S-n~henethylethylcarbamoyl)- 2-benzylsulfonviethylcarbamate (Compound 72) 0 OH H0
H
0 N/ A solution of tert-butyl 1R-(2-benzooxazol-2-yl-2-hydroxy-1Sphenethylethylcarbamoyl).2-benzylsulfanylethylcarbamate (3.62 provided as in Example 3, in dichioromethane (174 mL) was treated with meta-chloroperbenzoic acid (6.9 After stir-ring at room temperature for 5 hours the reaction mixture was diluted with dichioromethane (100 mL), washed sequentially with a saturated sodium bicarbonate solution (100 mL) and brine (100 niL), 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, v/v) to provide ter-butvl I R-(2-benzooxazol-2-yl-2-hydroxy- IS-phenethylethylcarbarnovl)-2-benzvlisulfonylethylcarbamate (0.95 g) as a yellow solid. MS: 608 [MAH]-.
Proceeding as in Example 14 provided N-F 1R-(2-benzooxazol-2-vl-2-hydroxv- 1 S-nhenethvlethvlcarbamoyl)-2-pdd-3-ylmethvlsulfonylethvillpvrazine-2carboxamide (Compound 73).
-89- EXAMPLE N-(2-Benzooxazol-2-vl-2-hvdroxy- IS-phenethylethvl')-3-cvclohexvl- 2S-(3-Dvrid-3-ylureido)popionamide (Compound 74) 0 OH N N H H 0N A solution of N-[2-benzooxazol-2-yl-2-(tert-butyldimethylsilanyloxy)- IS-phenethylethyl]- 3-cyclohexyl-2S-(3-pyrid-3-ylureido)propionamide (172 mg) in tetrahydrofuran (5 niL), provided as in Example 11, under an inert atmosphere at room temperature was treated with a solution of te~trabutylaminoniumfluoride in 1M 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 1, v/v) to provide N-(2-benzooxazol-2-vl-2-hydroxv- IS-Rhenethylethyl)-3-cvclohexvl- 2S-(3-:vrid-3-vlureido)propionamide (108 mig) as a white solid.
Proceeding as in Example 15 provided N- 1 S-(2-benzooxazol -2-vl-2-hydroxy- IS-phenethylethylcarbamovl)-2-cvclohexylethyllmorholine-4-carboxamide (Compound EXAMPLE 16 tert-Butvl 4-f 1R-(1 S-benzooxazol-2-vlcarbonvI-3-phenvvrovvlcarbamVI)-2-(2-cyanObenzvlsulfonvl)ethvlcarbamovllpiperidine-1 -carboxylate (Compound 76)
NC
'I
0 0
H
A solution tert-butyl 4-[I R-(2-benzooxazol-2-yl-2-hydroxy-1 Sphenethylethylcarbamoyl]-2-(2-cyanobenzylsulfolyl)ethylcarbamoylpiperidile- I -carboxylate mg, prepared as in Example 13, in dichioromethane (10 xnL) 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, v/v) to give tert-butvl 441 1S-benzooxazol-2-vlcarbonvl-3-nhenvlproovylcarbamol)- 2-(2-cyanobenzvlsulfonvl)ethvlcarbamovllniperidile-l1-carboxylate (26 mg) as a gum. MS. 742
M].
Proceeding as in Example 16 provided the following compounds of Formula 1: 1R-( 1S-benzooxazol-2-vlcarbonvl)-3-nhenvypRo~lcarbamovl)- 2-benzvlsulfonylethylltetrahvdrowvan-4-carboxamide (Compound 77), m.p. 178-1 80*C, MS: 618 [MWY; N-f lR-( 1S-benzooxazol-2-vlcarbonvl-3phellroi~ylcarbamoyl)- 2-benzylsulfonvlethyllnicotinamide (Compound 78), m.p. 193-195 MS: 611 [MiH] 4 N-f IR-( lS-benzooxazo-2-lcarbonl-3-i~heylroi~rOvcarbamoyV)- 2-benzvlsulfonylethyllnvrazine-2-carboxamide (Compound 79), m.p. 194-196'C. MS: 612 tert-butvl 4-r 1S-( 1S-benzooxazol-2-vlcarbonyl-3-Rhenvlprovvlcarbamovl)- 2-cyclohexylethylcarbamovlpiperidine-lI-carboxylate (Compound tert-butyl 4-4 IS-0 -benzooxazol-2-vicarbonyl-3-phenyhpropvlcarbamovl)- 2-(6-methylpRid-2-vlmethylsulfonylhethylcarbamov11vi~eridine-l1-carboxylate (Compound 81), MS: 732 [MH]Y, HPLC: RT 15.18 minutes.; N-ri R-(1 S-benzooxazol-2-ylcarbonyl-3-phenvlpropvlcarbamoyl)- 2-(2-cvanobenzvlsulfonvl)ethyllisonicotinamide (Compound 82), m.p. 204-2060* C, MS: 636
[MH];
tetrahydropvran-4-ylI 1R-( 1S-benzooxazol-2-ylcarbonvl-3-phenlnRopvlcarbamovl)- 2-benzylsulfonylethylcarbamate (Compound 83), m.p. 93 0 C (with decomposition), MS: 634
[MM";
benzyl 4-rl 1S-benzooxazol-2-ylcarbonvl-3-phenlpropvlcarbamol)- 2-cvclohexylethylcarbamoyllpiperidine-l1-carboxylate (Compound 84), MS: 677 1S-benzooxazol-2-ylcarbonyl-3-RhenvIpronvI)-3-cyclohexvJ- 2S-(3-p~vrid-3-ylureido~throionamide (Compound 85), MS: 554 N-rI S-(1 S-benzooxazol-2-ylcarbonyl-3-phenvynrpvlcarbamoyl)- 2-cyclohexylethyllmorpholine-4-carboxamide (Compound 86), MS: 547 N-FI 1S-benzooxazol-2-vlcarbonvl-3-D~henylpropvlcarbamoyl)- 2-cyclohexylethylisonicotinamide (Compound 87), MS: 537 N-r 1S-( IS-benzooxazol-2-ylcarbonyl-3-iphenylpropvlcarbamoyl)- 2-cvclohexylethwlltetrahvdropvran-4-carboxamide (Compound 88), MS: 546 and N-f I S-(1 S-benzooxazol-2-ylcarbonvl-3-Rhenvlpropvlcarbamoyl)-2-cvclohexylethv]L- 6-hydroxynicotinamide (Compound 89), MS: 555 EXAMPLE 17 1R-( 1S-Benzooxazol-2-vlcarbonfl)-3-phenvlpro ylcarbamovl)- 2-benzvlsulfonylethyllmorholine-4-carboxamide (Compound 0 0 N .)KN N 0 0 0 N N/\ A mixture of 1S-(2-benzooxazol-2-yl-2-hydroxy- IS-phenethylethylcarbainoyl)- 2-benzylsulfonylethyljmorpholine-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 nmL) was stirred at room temperature for 1 hour and then diluted. with a solution of 0.26 M sodium thiosuif ate in saturated sodium bicarbonate. The dilution was extracted with ethyl acetate and the extract was filtered. The filtrate was concentrated to provide 1S-( 1S-benzooxazol-2-ylcarbonyl)-3-phenylpropylcarbamoyl)- 2-benzylsulfonylethyl]morpholine-4-carboxami de (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 N-fl 1S-benzooxazol-2-vlcarbonvl)-3-nhenvloronvlcarbamovl)- 2-benzylsulfonylethyllmoroholine-4-carboxamide (4.2 g) as a white powder. 'H NMR (DMSOd6) 8.024 (di, J=6.68Hz, 7.9787 (di, J=7.92Hz, 1H), 7.8857 J=8.l6Hz, 11H), 7.6471 (td, J=8.41, 0.99 Hz, IH), 7.5455 (td, J=8.16, 1.24Hz, 7.3806 5H1), 7.2479 (in, 5H), 7.1210 J=4.53Hz), IH, 5.2578 (in, 1H), 4.7395 (in, 1H), 4.5059 214), 3.5342 (in, 4H), 3.4082 (in, 211), 3.30 (in, 4H (+water)), 2.6963 (in, 2H), 2.2768 (in, 111), 2.0497 (in, 1H1). MS 619.2.
Proceeding as in Example 17 provided the following compounds of Formula 1: N-F 1R-(2-benzooxazol-2-yl- 1.1-dimethvl-2-oxoethylcarbamoyl)- 2-benzylsulfonlethvllmorcholine-4-carboxamide (Compound 91); 'H NMR: (DMS0) 9.26 (s, 1H), 7.79 J=8Hz, IH), 7.73 3=8Hz, IH), 7.56 3=8Hz, 1H1), 7.47 J=8Hz, 1H), 7.36- 7.25 (in, 5H), 6.70 J=8Hz, 111), 4.67 (in, 1H1), 4.39 3=14H, 1H), 4.32 J=l4Hz, 1H), 3.49-3.00 (mn, 1OH), 1.56 3H), 1.51 3H); MS: 543; N-F JR-( 1S-benzooxazol-2-vlcarbonvlpentvlcarbamoyl)- 2-(3 .5-dimethylisoxazol-4-lmethlsulfonl)ethvllmorholine-4-carboxamide (Compound 92); 'H NMR: (DM50) 8.66 3=6.6Hz, 1H), 7.99 3=8Hz, 11H), 7.88 J=8Hz, 1H), 7.62 (t, J=8Hz, 1H), 7.52 3=8Hz, 1H1), 7.02 3=7.7Hz, 1H1), 5.24 (in, 1H), 4.76 (in, 1H), 4.39 (d, J=l4Hz, 111), 4.27 J=14Hz, 1H), 3.63-3.20 (in, 101-1), 2.33 3H), 2.15 3H), 1.94 (in, 1H), 1.69 (mn, 1H1), 1.40-1.22 (in, 4H), 0.84 J=6.7Hz, 3H1); MS: 590; and N-ri 1S-benzooxazol-2-vlcarbonylpentylcarbamoyl)- 2-(3,5-dimethvlisoxazol-4-vmethvlsulfonylethyllisonicotinamide (Compound 93); 'H NMR: (DMSQ) 9.23 3=8Hz, 1H), 8.87 J=7Hz, 1H), 8.71 (in, 211), 7.98 3=8Hz, 111), 7.87 (d, 3=8Hz, 111), 7.70 (mn, 2H), 7.62 J=8Hz, 111), 7.51 3=8Hz, 1H1), 5.28 (in, IH), 5.10 (in, IH), 4.44 J=14Hz, 1H), 4.37 J=l4Hz, IH), 3.80-3.52 (mn, 2H1), 2.33 3H), 2.14 311), 1.95 (mn, 1H), 1.69 (in, 111), 1.40-1.22 (mn, 4H1), 0.82 3=6.7Hz, 3H); MS: 582.
-94- EXAMPLE 18 N-rlR-(1 S-Benzooxazol-2-ylcarbonvl- 3-phenylproj~vlcarbamoyl)-2-(2-canobnzlsufony)ethyllpiRndine-4-carboxamide (Compound 94) A solution of tert-butyl 4-[1R-(1S-benzooxazol-2-ylcarbonyl-3-phenylpropylcarbamoyl)- 2-(2-cyanobenzylsulfonyl)ethylcarbamoyllpiperidine- 1-carboxylate (26 mg), provided as in Example 16, in ethyl acetate (10 niL) 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 1R-(1 S-benzooxazol-2-ylcarbonvl-3-phenylproplcarbamol)- 2-(2-cyanobenzylsulfonyl)ethvllnin~erdine-4-carboxamide (19 mig) as a solid, m.p. 155-157 0
C.
MS: 678 Proceeding as in Example 18 provided N-rlS-(1S-benzooxazol-2-lcarbonyl- 3-phenylnropvylcarbamoyl)-2-cvclohexylethylllviTeridine-4-carboxamide hydrochloride (Compound 95), MS: 634 and 1R-( IS-benzooxazol-2-ylcarbonyl-3-n2henyvLropvlcarbamovl)- 2-(6-methylpvrid-2-vlmethylsulfonl)ethyllpiperidine-4-carboxamide (Compound 96), MS: 632 WYH], HPLC: RT 12.05 minutes.
EXAMPLE 19 LS-Benzooxazol-2-ylcarbonylbutvl)-2R-methylsulfonylamino-3-benzvlsulfonvlpropionamide' (Compound 159) 0 0N 0 H H A solution of (R)-2-(2-methylsulfonylacetylamino)-3-benzylsulfonylpropionic acid (212 mg, 0.66 mmol). (S)-2-amino-lI-benzooxazol.-2-ylpentan-lI-ol (150 mg, 0.66 mmol), EDGI (165 mg, 0.858 mmol) and HQBT (110 mg, 0.726 mmol) in methylene chloride (3 m.L) 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 dichioromethane 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 (MgSO 4 and then concentrated to provide 1S-benzooxazol-2-ylcarbonvlbutvl)- 2R-rnethvlsulfonvlamino-3-benzylsulfonyvlproiionamide (49 mg, 0.09 mmol). IH NMR (DMSO): (dJ 7Hz, 1H), 8.0 (d,J 8Hz, 1H), 7.90 (dJ 9Hz, 1H), 7.66 (tj 8Hz, 1H), 7.55 (tJ =9Hz, 1H), 7.39 5H), 5.32 (in, IH), 4.55 (in, 3H), 3.35 (in, 3H), 2.95 3H), 1.94 (in, 1H), 1.71 (in, 1H), 1.45(m, 2H), 0.92 1=8Hz, 3H); MS: m/e=522.03.
-96- EXAMPLE Methyl lR-(lS-benzooxazol-2-ylcarbonvlbu~ycabamoyl}.2-benzylsulfonylethvlcarbamate (Compound 158) 0 0
H
N 0
H
0 N i A solution of (R)-2-(2-methoxycarbonylamaino)-3-benzylsulfonylpropionic acid (200 mg, 0.66 Imnol), (S)-2-aniino-1-benzooxazol-2-ylpentan-1-oI (150 mg, 0.66 inmol), EDCI (165 mg, 0.858 mmol) and HOBT (110 mg, 0.726 minol) 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 mnmol) in dichloromethane (4 xnL) 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 (MgSO 4 and then concentrated. The residue was heated with ethyl acetate and then treated with tert-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 IR-(lS-benzooxazol-2-lcarbonylbutylcarbamoy)-2-benzvlsulfonvlethvlcarbamate (133 mg, 0.26 mmol). 'H NMR (DMSO): 8.77 (d,J =711z, 1H), 8.01 (dJ 9Hz, 111), 7.90 (d,J 9Hz, 111, 7.6 (in, 2H), 7.55 (t,J=9Hz, 1H1), 7.39 5H), 5.3 (in, IH), 4.68 (in, 1H), 4.48 211), 3.55 3H), 3.52-3.4 (in, 1H), 3.3 (in, 111), 1.92 (in, 1H1), 1.73 (mn, 111), 1.42 (in, 2H), 0.91 J=8Hz, 3H); MS: mi/e=502.05.
EXAMPLE 21 N-i IR-(1S-Benzooxazol-2-lcarbonlbuvlcarbamol)2-benzlsulfonylethyllmor.,holne.
4-carboxamide (Compound 158) 0 0
H
N Nfa
H
00 N/\b A solution of 2 2 -morpholin- 4 -ylcarbonylamino)-3-benzylsulfonylpropionic acid (356 mg, 1 mmol), EDCI (240 mg, mniol) and HOBT (178 mg, mmol) in methylene chloride (8 mL) was (S)-2-amino- 1-benzooxazol-2-ylpentan-l1-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 (MgSO 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. The mixture cooled in an ice bath and resulting solids were collected and dried to provide 1R-( 1S-benzooxazol-2-vlcarbonvlbutvlcarbamovl).
2-benzylsulfonvlethyllmorp~holine-4-carboxamide (408 mg, 73% yield). 1 H NMR 300mHz: 8.65 (d,3=7.1IH 3 1H), 8.01 J=8.8H 3 1H), 7.91 J=9.lH 3 1H), 7.65 J=8.2H 3 1H), 7.55 (t, J=9.1H 3 IH), 7.38 5H), 7.05 J=9.4H 3 1H), 5.29 (in, 1H), 4.73 (in, IH), 4.48 2H), 3.53 (in, 4H), 3.4-3.2 (mn, 6H), 1.94 (mn, IH), 1.73 (mn, 1H), 1.42 (in, 211), 0.91 J=8H 3 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-acetvlaniino-N-(2-benzooxazol-2-lI-S-buiy-2-hydroxvethl) 3-cvlohxvlRoionamide (Compound 97); 'HI NMvR (CDCI 3 7.67 J=8.0 z, 1H), 7.53 (d, J=6.OHz, 7.34 (mn, 2H), 6.64 J=8.l11z, 111), 5.99 J=8. lHz, 5.03 (mn, 11H), 4.39 (mn, 2H), 2.02-0.70 (in, 22Hz); MS ESI: MH* 430; 2S-acetvlainino-N-( 1S-benzooxazol-2-vcabonlpdntv1)-3-cyclohexylpropionamide (Compound 98); 'H N1M'R (CDCl 3 7.93 J=7.5Hz, I 7.67 J=8.lIRZ, 1H), 7.54 (t, J=7.2Hz, 111), 7.46 J=7.8Hz, 111), 6.78 J=7.2Hz, 1H), 5.91 J=8.4Hz, 111), 5.63 (mn, 111), 4.59 (mn, lH), 2.09-0.85 (mn, 24Hz); MS ESI: MH* 428; tert-butvl 1S-[l-benzooxazol-2-lcarbonfl-3-nhenlpropylcarbamovl).
2-cyclohexylethyllcarbainate (Compound 99); 2S-acetvlainino-N-( 1-benzooxazol-2-lcarbonyl)- 3-nhenyvLoRopl)-3-cyclohexylpronionamide (Compound 100); 2S-acetylamino-N-(1 -benzooxazol-2-ylcarbonvicvclobutyl)-3-cyclohexvlroionamide (Compound 101); 2S-acetylamino-N-( lR-benzooxazol-2-vlcarbonvl-3- henylpro l)- 3-cyclohexylpronionainide (Compound 102); 2S-acetylainino-N-(2-benzooxazol-2-yl-2-hydroxy- 1R-phenyethylethyvW 3-cvclohexylo~ronionamide (Compound 103); N-Fl S-(1 S-benzooxazol-2-vlcarbonyl)-3-phenvlprovvylcarbainoyll- 2-cvclohexylethyllsuccinamic acid (Compound 104); 'H NMR (CDC 3 7.87 (mn, 11H), 7.62 (in, 1H1), 7.52 (mn, 111), 7.43 (in, 111), 7.15 (in, 6H1), 6.89 (mn, 1H), 5.62 (mn, 111), 4.56 (mn, 111), 2.75 (in, 2H1), 2.70 (mn, 111), 2.48 (mn, 211), 2.16 (mn, 111), 1.6 (in, 7H), 0.7-1.4 (in, 7H); MS: in/e 534; N-F lS-(2-benzooxazol-2-yl-2-hvdroxv- IS-vphenethylethylcarbaxnofl-2-cyclohexvlethyllsuccinamic acid (Compound 105); 'H NMR (CDC1 3 12.04 1H1), 7.89 (in, 111), 7.80 (mn, 111), 7.65 (in, 211), 7.36 (mn, 211), 7.13-7.29 (in, 411), 6.08-6.23 (mn, 111), 4.62-4.93 (in, 1H), 4.15 (mn, 111), 2.64 (mn, 111), 2.50 (mn, 111), 2.34 (in, 6H1), 1.78 (mn, 111), 1.45-1.68 (mn, 4H), 1.37 (in, 1H), 0.95-1.3 (in, 3H1), 0.87 (mn, 2H); MS: mle=535.8;
IY
N-1IiS-fI S-benzooxazol-2-vlcarbonvl)-3-henhlrovycarbamov1 2-cyclohexylethyl Ioxalamic acid (Compound 106); 'H NMR (CDCI 3 6.6-7.9 (m,1OH), 5.6 (m, 11), 4.5 LH), 2.72 LH), 2.45 1H), 0.8-2.1 15H); MS: n/e 506.2; N-F 1S-(1S-benzooxazol-2-vlcarbonvl-3-phenylprpnvlcarbamvl)-2-cvclohexvlethyll- 3H-iiidazole-4-carboxaiide (Compound 107); 'H NMR (CDCI 3 8.1 7.3-7.6 3H), 6.95-7.2 8H), 5.62 1H), 4.74 1H), 2.77 2H), 2.38 IH), 2.25 1H), 0.8-1.9 13H); MS: m/e 528.2; N- 1S-(2-benzooxazol-2-vl-2-hvdroxv- 1 S-phenvlethvlethvlcarbamovl)- 2-cvclohexlethvll-3H-iiidazole-4-carboxamide (Compound 108); 'H NMR (CDC1 3 7.0-7.6 12H), 5.05 1H), 4.5 11), 2.75 2H), 0.6-2.2 15H); MS;i m/e 529.6; tert-butvl 1R-(I -benzooxazol-2-vlcarbonvlcvclobutylcarbamovl)- 2-benzvlsulfonvlethvlcarbaiate (Compound 109), i.p. 70-85'C, MH1 542; N-r 1S-(1S-benzooxazol-2-vlcarbonvl-3-nhenvylropvlcarbamovl)- 2-cvclohexvlethvllialonami c acid (Compound 110); 'H NMR (CDCI 3 6.8-7.9 9H), 5.63 1H), 4.56 11), 2.6-2.8 4H), 2.0-2.4 2H), 0.7-2.0 13H); MS: /e 520.4; N-F IR-(S-benzooxazol-2-lcarbonl-3-,henylpropvlcarbamoyl)- 2-o-tolvlmethvlsulfonvlethyllmgholine-4-carboxamide (Compound 111); 'H NMR 300mHz (DMSO-d 6 PPM, 8.841 J=6.2Hz, 1H), 7.942 3=5.2Hz, 1H), 7.860 J=8.4Hz, 1H), 7.618 J=8.lHz, 1H), 7.516 J=8.lHz, 1H), 7.16 IOH), 5.22 IH), 4.78 1H), 4.516 2H), 3.567 2H), 3.500 6H), 3.3 3H), 2.75 1H), 2.65 1H), 2.44 IH), 2.26 2H), 2.01 1H); MS: M--633.4 M-=631.4; N-fIR-(S-benzooxazol-2-vlcarbonvl-3-nhenvlnroovlcarbamovl)- 2-(2-nitrobenzvlsulfonyl)ethvllmorpholine-4-carboxamide (Compound 112); 'H NMR 300mHz (DMSO-d 6 PPM, 8.840 J=7.OHz, 1H), 8.025 J=8.OHz, 1H), 7.950 3=8.4Hz, 1H), 7.858 3=7.7Hz, 1H), 7.730 J-8.8Hz, 11), 7.646 J=8.4Hz, 1H), 7.515 J=7.7Hz, 1H), 5.223 11), 5.004 21), 4.694 1H), 3.561 2H), 3.510 6H), 2.756 1H), 2.652 1H), 2.429 2H), 2.243 1H), 1.983 1H); MS: M+=664.2 M-=662.4; N-F 1R-(S-benzooxazol-2-vlcarboni-3-phenvlngropvlcarbamovl)- 2-(2-chlorobenzylsulfonvl)ethyllmorholine-4-carboxamide (Compound 113); 'H NMR 300mHz (DMSO-d) PPM, 8.851 J=6.2z, 1H), 7.953 J=8.81z, 1H), 7.855 J=8.4Hz, 1H), 7.627 J=6.6Hz, 1H), 7.498 3H), 7.365 2H), 7.211 6H), 5.220 1H), 4.774 (m, 1H), 4.659( m, 2H), 3.578 2H), 3.499 6H), 2.752 1H), 2.648 1H), 2.472 2H), -100- N-F lR-(lS-benzooxazol-2-vlcarbonylpentylcarbamovl)- 2 -benzvlsulfonvlethyllmnorrjholine-4carboxamide (Compound 114); NMR 300mHz (DMSO-d 6 8.64 J=7.411 3 1H), 8.01 J=8.8H 3 1H), 7.91 J=9.1IH 3 1H), 7.68 J-6H 3 1H1), 7.55 (t, J=8.2H 3 111), 7.38 5H1), 7.05 J=9.6J1, 111), 5.26 (mn, IH), 4.72 (mn, 111), 4.49 211), 3.55 (in, 4H1), 3.5-3.2(m, 611), 1.96 (mn, IH), 1.76 (in, 111), 1.38 (in, 4H), 0.87 J=7.4H3, 3H); MS: 571.24 M'=570.20; N-F lR-(lS-benzooxazl-2-lcarbonvlpentvlcarbamol).
2 -o-tolvlmethvlsulfonvlethyllmortjholine-4-carboxaiie (Compound 115); NMR 300mHz (DMSO-d 6 8.70 J=6.9H3. IH), 8.01(d, J=9.1H 3 1H), 7.91 J=8.8H 3 1H), 7.67 J=8H 3 1H), 7.55 J=8.511, 3H), 7.3-7.1 (in, 411), 7.05 J=9.61 3 5.26 (mn, IH), 4.80 (in, 1H), 4.53 2H1), 3.58 (in, 4H), 3.33 (mn, 6H), 2.33 311), 1.96 (in, IH), 1.72 (in, LH), 1.35 (in, 4H1), 0.87 J=7.711 3 MS=585.30, M'=584.23; N-f IR-(1S-benzooxazol-2-vlcarbonylpentvlcarbamol).
2 2 -nitrobenzylsulfonyl)ethvljinorholine.4-carboxamide (Compound 116); NMR 300mHz (DMSO-d 6 8.70 J=7.2H 3 111), 8.1-7.5 (in, 8H), 7.05 J=9.3H 3 IH), 5.26 (in, 111), 5.01 2H), 4.70 (in, 1H), 3.57 (mn, 5H), 3.30 (in, 5H1), 1.96 (in, 1H), 1.72 (in, 1H1), 1.34 (in, 4H1), 0.87 J=7.7HO,31); MS: 616.09 W--615-20; N-Fl R-(1 S-benzooxazol-2-vlcarbonvlpentvcarbamol).
2 2 -chlorobenzvlsulfonflethyllmrpholine.4carboxamicie (Compound 117); NMR 300mHz (DMSO-d 6 8.71 J=7.1IH 3 111), 8.1-73 (in, 8H1), 7.06 (dJ=9.6H 3 1H), 5.26 (in, 111), 4.79 (mn, 1H), 4.72 (di, J=15H 3 111), 4.65 (di, J=15H 3 1H), 3.56 (mn, 4H), 3.30 (mn, 6H), 1.96 (in, 111), 1.73 (in, 111), 1.35 (in, 411), 0.87 J=7.7H 3 3H); MS: 605.24 M+=605. N-f 1R-(2-benzooxazol-2-vI- 1.1-dimethyl-2-oxoethylcarbainoyl)- 2 -o-tolylmethvlsulfonylethvllmor~holine4-carboxamidie (Compound 118); MS: 557; N-F 1R-(2-benzooxazol-2-yvI .1-dimethyl-2-oxoethylcarbamovl)- 2 2 -chlorobenzvlsulfonvl)ethyIlmowholine-4carboxamiie (Compound 119); MS: (M 4 578; N-F 1R-(2-benzooxazol-2-v-1 -dimethyl-2-oxoethylcarbamovl).
2 2 -nitrobenzylsulfonyl)ethyllinomholine-4.carboxainide (Compound 120); IH NNM: (DMSO) 9.34 111), 8.02 J=7.7Hz, 111), 7.82-7.45 (mn, 711), 6.74 (di, J=8.811lz, 111), 4.87 (in, 211), 4.64 (mn, JH), 3.44-3.11 (in, 1011), 1.56 3H), 1.50 3H1); MS: 588; N-f IR-(1 S-benzooxazo1-2-vlcarbonyI-3-phenylpropylcarbamoyl)- 1- 2 -ovrid- 2 -vmmethlsulfonlethvyliperidine-4carboxaiie (Compound 121); MS:in/e 1=616.2; N-f 1R-( lS-benzooxazoI-2-vlcarbonylontvycabamovI.
2 -Pvrd- 2 -ylinethylsulfonylethyllmor~holine.4-carboxaiie (Compvound 122); 'H NMR 8.62 6.9 Hz, I 8.55 (di, 3.2 Hz, 111), 8.00 7.0 Hz, 111), 7.86 (mn, 2H1), 7.65 6.2 Hz, 1H), 7.48-7.58 (in, 2H1), 7.40 (in, 1H1), 7.06-7.25 (in, 3H1), 5.28 (mn, 111), 4.74 (nm, IH), 4.67 1.1 Hz, 2H), 3.53 (mn, 411), 3.31 (in, 4H), 1.99 (mn, 111), 1.75 (in,1H), 1.32 (mi, 411), 0.87 6.7 Hz, 3H); MS: M+1 571.8; N-F lR-(lR-benzooxazol-2-vlcarbonv..3..henylpropv carbanoyl)- 2 -benzylsulfonvlethyllinoiholine-4carboxamiie (Compound 123); N-F lR-(l-benzooxazo-2-ylcarbonvicyclobuNylcarbamnov)- 2 -benzvlsulfonvlethyllmorpholine-4carboxaie (Compound 124), NMW555; benzyl IS(-ezoao--l2hdoytylabmy)3mtybiiabmt (Compound 125); 2S-acetvlamino- N-(2-benzooxazol-2-vi-IS-methyl 2 -oxoethfl)-3-cyclohexylpopionanicie (Compound 126); 'H NM (CDC1 3 7.92 (di, 1=8.4Hz, I1H), 7.73-7.67 (mn, IH), 7.60-7.48 (in, 2H), 5.94 (di, J=8.7Hz, JH), 6.65 (in, 111), 2.03 J=7.2Hz, 2H), 1.64 (in, 6H), 1.56-0.92 (mi, 10Hz); MS ESI: NM' 386; tert-butvl R-(1 -benzooxazol-2-ylcarbonvylcyclobutvlcarbainoyl)- 2 -benzvlsulfanylethylcarbainate (Compound 127); N-F 1R-( lS-benzooxazo- 2 -ylcarbonyi-3-methvsulfonVypRopyIcarbarnoyI)- 2 -benzylsulfonvlethyllmorpholine4carboxaiie (Compound 128); 'H NMR (CDCI,): 7.89 (di, 1=7.4Hz, 1H), 7.65 (mn, 111), 7.57 (mn, 1H), 7.48 (mi, 111), 7.4 (in, 5H), 6.0 (mn, 111), 5.7 (in, IH), 4.93 (mn, 111), 4.33 (mn, 3H), 3.70 (mn, 5H), 3.25-3.4 (in, 7H1), 2.93 (mn, 311), 2.8 (mn, 1H), 2.35 (mn, 1H); MS: ni/e 653.2; N-rl -(1S-benzooxazol-2-vlcarbonyipentylcarbamovl).
3 -nphenvlsulfapyllpropyllmgMholine-4carboxanide (Compound 129); 'H NMR (DMS0): 8.52 (d41 8Hz, IH), 8.98 (d,J 8Hz, 111), 8.88 (dJ 9Hz, 111), 7.64 (tJ 8Hz, IH), 7.53 (tj 9Hz, 1H), 7.30 (mn, 4H), 7.19 (mn, 111), 5.25 (mn, 1H), 4.35 (in, 1H); 3.51 (mn, 4H), 3.26 (mi, 4H), 2.94 1=8Hz, 2H), 1.9 (mn, 3H), 1.7 (mn, 1H), 1.31 (in, 411), 0.86 (t,J=8Hzi, 3H), 6.53 (d,J=9HZ, 1H); MS: ni/e=539.24; N-f IR-( 1S-benzooxazoI-2-yicarbonvItntvlcarbainovI) -102- 2-(2-trifluoromethvlbenzvlsulfonvl)ethyllmornholine-4carboxamide (Compound 131); 'H NMR: (DMSO) 8.78 J=8Hz, 1H), 8.06-7.50 8H), 7.04 J=8Hz, 11), 5.27 1H), 4.82-4.64 3H), 3.65-3.25 10H), 1.96 1H), 1.71 1.41-1.22 4H), 0.84 J=7Hz, 3H). MS: 639; N-f 1R-(S-benzooxazol-2-vlcarbonvl-3-phenvIropvlcarbamofl)- 2-vrid-2-vmethvlsulfonylethyllmorholine4-carboxamide (Compound 132);'H NMR (DMSO): 8.78 (d,J=7.2Hz, 11), 8.56 (d,J=5.4Hz, 1H), 7.98 (d,J=8.4Hz, 11), 7.85 2H), 7.64 (tJ=12.lHz, 1H), 7.52 2H), 7.38 11), 7.10-7.34 8H), 5.25 11), 4.70 3H), 3.55-3.70 41), 3.35 4H), 2.80 2H), 2.25 11), 2.0 11); MS: W/e 620.0; N-FIR-( 1S-benzooxazol-2-lcarbonvl-3-nethylsulfonvhproovlcarbainovW 2-nviid-2-lmethvlsulfonvlethvllmorpboline-4-carboxaide (Compound 133); 'H NMR (DMSO): 8.83 (d,J=7.6Hz, 1H), 8.55 (dJ=4.0Hz, 1H), 7.97 (dJ=7.6Hz, 1H), 7.88 3H), 7.64 (tJ=7.2Hz, 11), 7.39-7.54 4H), 7.15 J=7.6Hz, 1H), 5.36 (in, 11), 4.70 31), 3.56 (m, 6H), 3.24 4H), 2.40 1H), 2.15 1H), 2.99 3H); MS: i/e 622.2; 2-r2-(1-benzooxazol-2-vlcarbonvlentvlcarbamoyJ)- 2-morpholin4-vlcrbonvlaoamino)ethanesulfonlmethllpvridine 1-oxide (Compound 134); 'H NMR (DMSQ): 8.75 J=6.5Hz, 1H), 8.38 21), 7.96 3=7.7Hz, 11), 7.89 (d,J=7.7Hz, 11), 7.48-7.69 6H), 7.05 3=6.8Hz, 1H), 5.22 IF), 4.95 J=2.7Hz, 2H), 5.85 (m, 1H), 5.53 4H), 3.30 411), 1.95 11), 1.70 IH), 1.30 4H), 0.88 J=5.4Hz, 3H); MS: MW 587.65 Mi1 588.2; N-riR-(1S-benzooxazol-2-lcarbonlbutvlcarbamovl- 2 -(2-difluorometboxvbenzvlsulfonvl)ethvllmIorholine4-carboxamide (Compound 135); NMR 300mHz (DMSO-d 6 8.70 J=7.1H 3 1H), 8.01 J=8.8H 3 1H), 7.91 J=9.1113, 1H), 7.65 J=8H 3 11), 7.55 J=8.2H), 7.11 3=8.21), 7.4-6.8 5H), 5.28 IH), 4.76 IH), 4.5 211), 3.55 41), 3.3 6H), 1.93 11), 1.71 11), 1.42 2H), 0.91 J=8H 3 311); MS: 623.38 M+=622.19; N-[3-phenlsulfonvl- 1-(1 S-benzooxazol-2-vlcarbonvlentlcarbamoyllropvllmorphohne-4-carboxaiide (Compound 136); 'H NMR (DMSO): 8.5 2H), 8.00 (dJ 9Hz, 11), 7.9-7.5 81), 6.54 9Hz, 11), 4.28 1H), 3.49 41), 3.24 611), 1.90 3H), 1.65 11), 1.31 (m, 411), 0.85 (tJ=7Hz, 31); MS: m/e=571.39; N-f IR-( 1S-benzooxazol-2-vlcarbonvylentvlcarbamovl)- -103- 2 2 -difluoromethoxvbenzvlsulfonyl)ethvlmozholine-4-carboxvamide (Compound 137); 'H NMR: (DMSO) 8.66 J=6.6Hz, 1H), 7.99 3=8Hz, 1H), 7.87 3=8Hz, 1H), 7.67-6.83 (m, 8H), 5.25 1H), 4.73 1H), 4.54 2H), 3.60-3.23 IOH), 1.93 1H), 1.68 JH), 1.40-1.22 4H), 0.84 3=6.7Hz, 3H); MS: 637; IR-] S-benzooxazol-2-vycarbonvypentvcarbamoyI)- 2-( 2 -difluoroethoxybenZylsulfonvl)ethylisonicotinamide (Compound 138); 'H NMR: (DMSO) 9.22 J=8Hz, 1H), 8.87 3=6Hz, 1H), 8.70 2H), 7.97-7.19 101), 7.08 JH.F= 74
Z,
1H), 5.30-5.09 2H), 4.58 2H), 3.73-3.59 211), 1.94 1H), 1.71 11), 1.41-1.22 4H), 0.82 J=6.7Hz, 3H); MS: 629; N-F 1R-(1S-benzooxazol-2-lcarbonvlbulcarbamovl).
2 -pid-2-lmethylsulfonl)ethvllmgrholine-4.carboxamide (Compound 139);'H NMR (DMSO): 8.6 2H), 8.05 (dJ=5.lHz, IH), 7.85 2H), 7.3-7.8 4H), 7.2 3H), 5.32 1H), 4.72 1H), 4.65 (d,J=3.lHz, 2H), 3.21-3.75 8H), 1.90 IH), 1.75 1H), 1.45 2H), 0.90 (tJ=4.5Hz, 3H); MS:m/e +1=558.2;MS: m/e 558.2; 2-[2R-(1 S-benzooxazoJ-2-vlcarbonvlbutvlcarbamovl).
2 -morpholin-4-vlcarbonylaminoethlsulfonlethyllpw jcine I-oxide (Compound 140); 'H NMR (DMSO): 8.57 31), 7.97 11), 7.63-7.82 3H), 7.35-7.45 4H), 6.93 11), 4.50- 4.95 2H), 4.18 2H), 3.10-3.80 8H), 1.10-1.70 411), 0.82 (tJ=5.4Hz, 3H); MS:m/e =574.2; 1R-(lS-benzooxazol-2-vlcarbonvlpentvlcarbamoyl).
2 2 -difluoromethoxvbenzvlsulfonyl)ethlcarbamate (Compound 141); MS: 582; N-[IR-(I S-benzooxazol-2-vlcarbonvlpentvlcarbamovl)-2-benzvlsulfonvlethvllsuccinamic acid (Compound 142); 'H NMR: (DMSO) 12.09 1H), 8.63 J=6Hz, 11), 8.51 J=8Hz, 11), 7.98 3=8Hz, LH), 7.87 3=8Hz, 1H), 7.62 3=8Hz, 11), 7.52 3=8Hz, 1H), 7.38- 7.30 51), 5.25 11), 4.84 1H), 4.46 2H), 3.53-3.21 2H), 5.28-5.25 41), 1.93 1H), 1.68 1H), 1.40-1.22 4H), 0.84 J=6.2Hz, 3H); MS: 558; 2R-r3.3-bis(2-methoxvethvl ureidol-N-( S-benzooxazo]-2-vlcarbonvlentyl)- 3-benzylsulfonvlpropionaiide (Compound 143); 'H NMR: (DMSO) 8.50 J=6.6H, 1H), 7.98 3=8Hz, 1H), 7.88 3=8Hz, 11), 7.62 =8Hz, 11), 7.52 =8Hz, 11), 7.38-7.30 (m, 5H), 6.82 3=8Hz, 11), 5.26 IH), 4.70 1H), 4.46 2H), 3.52-3.22 101), 3.31 (s, 611), 1.94 11), 1.69 1H), 1.40-1.22 4H), 0.85 3=6.6Hz, 3H); MS: 617; N-F1R-(1S-benzooxazol-2-vlcarbonl-3-vhenvlpropplcarbamoyly -104- 2-(6-methvlpviid-2-ylmethvlsulfonvl)ethyllisonicotinamide (Compound 144); 'H NMR (DMSO): 8069 (tj =6Hz, IH), 8.55 (dJ =9Hz, IN), 7.91 (in, 2H), 7.51 (in, 3H), 4.51 (mn, 1H), 4.11 (dJ =6Hz, 2H), 1.5 (in, 15H); MS: mle=328.05; 1S-benzooxazol-2-vlcarbonyl-3-iphenvlprovcarbamoyfl- 2-benzylsulfonvlethvilsuccinamic acid (Compound 145); MS (ESI) ME+ 478.2; N-f IR-( 1S-benzooxazoI-2-yicarbonyl-3-phenyltpro~ylcarbamoyD)- 2-(2-trifluoromethvlbenzvlsulfonyl)ethvlltrtrahydrovran-4-carboxamide (Compound 146); N-fl 1S-benzooxazol-2-ylcarbonyl-3-v~henylprovvlcarbamovl- 2-thien-3-ylmethylsulfonylethyllisonicotinanide (Compound 147); N-f 1R-( IS-benzooxazoI-2-vlcarbonyl-3-DhenyvLnovvlcarbamoy'I)- 2-(6-methvlpvrid-2-ylmethvlsulfonyl)ethylltetrahydropvran-4-carboxaide (Compound 148); N-f 1R-(1 -benzooxazol-2-ylcarbonvlcvclobutvlcarbamol)- 2-(2-trifluoromethylbenzvlsulfonyl)ethvlltetrahvdrotmvran4-Carboxamide (Compound 149); N-f IR-( 1S-benzooxazol-2-ylcarbonvl-3-iphenyliprotvylcarbamoyl)- .2-nvrid-3-vlmethylsulfonylethyllpyrazine-2-carboxainide (Compound 150); N-ri -benzooxazol-2-vlcarbonyl-3-yhenylipropvlcarbamoyl)- 2-thien-3-vlmethylsulfonylethvllpiveridine-4-carboxamide (Compound 151); N-ri 1S-benzooxazol-2-ylcarbonyl-3-phenvlyrool~ycarbamoyl)- 2-thien-3-ylmethylsulfonylethyllazetidine-3-carboxainide (Compound 152); N-f 1R-( 1S-benzooxazol-2-vlcarbonvl)butvlcarbamoyl)- 2-pvrrd-3-vlmethvlsuilfonylethyllmorpholine-4-carboxainide (Compound 153); 'H NMR (DMS0): 8.66 J=6.7Hz, 1H), 8.56 (in, 3H), 8.01 J=7.9Hz, 1H), 7.90 (d,J=8.lHz, 1H), 7.79 (mn, IH), 7.65 J=7.lHz, 111), 7.55 3=7.1Hz, 1H), 7.43 (dd, 3=4.9,7.9Hz, 2H), 6.93 (d, J=8.4OHz, IN), 5.30 (mn, J=lHz, iN), 4.76 (mn, IN), 4.57 J=3.7Hz, 2H), 3.24-3.70 (mi, 8H), 1.91 (mn, 1H), 1.73 (Mn, 1H), 1.40 (mn, 2H), 0.82 J=5.4Hz, 3H); MS:m/e 555.8; N-f IR-( 1S-benzooxazol-2-ylcarbonyl-3-phenvlvronvlcarbamofl)- .2-benzvlsulfonylethyllniperazine-1 -carboxamide (Compound 154); N-f 1R-(1S-benzooxazoI-2-vlcarbonvI-3-methylsulfonvlnro vlcarbamol)- 2-(2-difluoromethoxvbenzylsulfonyl)ethvllmorpholine-4-carboxamide (Compound 155); 'H NMR
(CDCL,
3 300MIHz) 7.8944 3=7.92Hz, 1H), 7.67 (in, iN), 7.58 (in, IN), 4.49 (mn, 2H), 7.415 (mn, 1H), 7.24 (mn, 3H), 6.5811 3=73.24Hz, 1H), 5.7633 (mn, IH), 4.9199 (in, 1H), 4.48 '71 (dd, J= 13.61, 23.75Hz, 2H), 3.7 101 (in, 4H), 3.4189 (in, 4H), 3.27 (mn, 2H), 2.9289 311), 2.77 (in, -105- IH), 2.37 IH); MS: 687.3 685.6; N-FIR-(1 S-benzooxazol-2-vlCarbonyl-3-methylesulfonylproplcarbamol)- 2 2 -methoxvbenzvlsulfonyvethvllmorholine-4-carboxamide (Compound 156); 'H NMR
(CDCI
3 7.89 11), 7.45-7.8 31), 7.35 21), 6.9-7.05 2H), 5.83-5.9 11), 5.62-5.8 1H), 4.82 11), 4.40 2H), 3.89 3H), 3.70 5H), 3.25-3.42 71), 2.95 311), 2.75 1H), 2.35 1H); MS: i/e 651.4; N-F1R-(l S-benzooxazol-2-ylcarbonylpentylcarbaiovl).
2-benzvlsulfonylethyllpiDerazine-l -carboxamide (Compound 157); 'H NMR: (DMSO) 9.20- 9.11 2H), 8.73 1H), 7.98 1=8Hz, 1H), 7.88 J=8Hz, 1H), 7.63 1=8Hz, 11), 7.52 J=8Hz, 1H), 7.39-7.30 5H), 5.24 1H), 4.74 11), 4.50 2H), 3.62-3.30 6H), 3.05-2.95 41), 1.94 IH), 1.69 11), 1.40-1.22 411), 0.84 1=6.6Hz, 3H); MS: 570; N-(lS-benzooxazole-2-vlcarbonyl-3-methlsufonylroDl)-2R-methysulfonvlamino 3-benzvlsulfonyjropionamide (Compound 160); 'H NMR (DMSO-d6) 7.9498 2H), 7.6577 11), 7.5556 1H), 7.3870 511), 5.4016 11), 4.5444 3H), 3.32 211), 2.9784 11), 2.9326 11), 2.49 11), 2.20 11); MS: 586.0, 584.0; methyl 1R-( S-benzooxazol-2-vlcarbonvl-3-phenvlorpovlcarbamol)- 2-nvrid-2-ylmethylsulfonylethylcarbamate (Compound 161); MS: m/e 564.6; methyl lR-(1S-benzooxazol-2-vlcarbonvl-3-methylsulfonylprovlcarbamoyl)- 2-benzvlsulfonylethvlcarbamate (Compound 162); 'H NIR (DMSO): 9.03 J=7.2Hz, 11), 7.97 1=7.9Hz, 11), 7.90 J=8.2Hz, IH), 7.65 (td, J=7.2, 1.2Hz, 1H), 7.55 J=7.9Hz, 11), 7.37 5H), 5.32 11), 4.65 11), 4.50 2H), 3.53 11), 3.49 3H), 3.33 2H), 3.24 (in, 11), 2.98 311), 2.41 (in, 1H), 2.18 (in, 11); MS: m/e 653.2; N-(1 S-benzooxazol-2-vlcarbonylpentv)-2R-r3.3-di(2-metoxethyl)ureido 3 -ivrid-2-ylmethylsulfonylproionamide (Compound 163); MS:m/e +1=615.6; N-[1R-(I S-benzooxazol-2-vlcarbonlbutvlcarbamoyl).
2 2 -iethoxbenzvlsulfonyl)ethllm or~holine4-carboxaiide (Compound 164); 'H NMR (DMSO): 8.66 (dJ =6Hz, 11), 8.03 (d,J 9Hz, 11), 7.93 (d,J 9Hz, 1H), 7.68 (tJ 8Hz, 11), 7.58 (tJ =9Hz, 11), 7.36 2H), 7.0 311), 5.29 11), 4.77 11), 4.54 (d,J 14Hz, 11), 4.43 (d,J =14Hz, 11), 3.84 311), 3.5-3.3 1OH), 1.95 11), 1.74 IH), 1.46 (m, 2H), 0.93 1=8Hz, 31); MS: m/e=587.31; S-benzooxazol-2-vicarbonvlbutvlcarbamoyl)-2R-(3.3-dimethy ureido) -106- 3-(2-iethoxvbenzvlsulfonvl)proionamide (Compound 165); NMR 300mHz (DMSO-d 6 8.63 J=6.9H 3 1H), 8.03 J=8.8H3, 11), 7.92 J=9.1, 1H), 7.70 J=8.8H, 1H), 7.58 (t, J=8.2H 3 1H), 7.37 211), 7.08 J=9.1H 3 1H), 6.98 1=8.2H3, 1H), 6.71 J=9.1H 3
IH),
5.27 4.77 1H), 4.55 J=15.1H 3 11), 4.43 J=15.1IH, 11), 3.79 3H), 3.47 J=6.9H 3 211), 2.83 611), 1.93 1H), 1.75 1H), 1.43 2H), 0.93 1=83, 3H); N-(1S-benzooxazol-2-vlcarbonvlbutvl)-2-methvlsulfonlamino- 3-(2-methoxvbenzvlsulfonvl)pronpionarmide (Compound 166); 'H NMR (DMSO): 9.0 (d,J 6Hz, IH), 8.01 (d,J 8Hz, 1H), 7.91 (d,J 8Hz, 7.67 (tJ 7Hz, 1H), 7.57 (tJ 8Hz, 1f), 7.36 J=8Hz, 2H), 7.07 1=8Hz, 1H), 6.97 (dt, J=2,7Hz, 1H), 7.85 1H); 5.33 4H), 3H), 3.8 3H), 3.35 (in, 2H), 2.92 311), 1.93 11), 1.72 IH), 1.44 211), 0.9] J=7Hz, 311); MS: mle=552.19; 3-cvclohexvl-N-f2-hdrox-2-(5-nitrobenzooxazol-2-vl)- S-phenethlethvllpoi onamide (Compound 167); MS (ESI) r/z 466 (M 'H-NMR (300 MHz, CDCI 3 80.95 2H), 8 1.22 41), 8 1.51 2H), 8 1.65 6H), 8 2.15 2H), 82.65 2H), 84.15 1H), 8 4.50 11), 6 5.08 1H), 8 5.80 J 6 Hz, 1H), 8 6.09 1H), 8 7.00 7.35 8 7.60 1H), 8 8.40 IH), 8 8.55 11), (C 26
H
31
N
3 0 5 methyl 2-f2S-(3-cvclohexvlpropionyaiino)-l -hydroxY- 4-phenvlbutvllbenzooxazole-6-carboxylate (Compound 168); MS (ESI) m/z 478 (M 1); 'H-NMR (300 MHz, CDC1 3 8 0.84 2H), 8 1.22 41), 8 1.51 711), 8 1.90 11), 82.11 211), 82.65 2H), 83.95 3H), 84.19 11), 84.50 1H), 85.09 11), 8 6.09 1H), 8 6.49 1H), 8 7.01 7.35 511), 8 7.65 11), 8 8.01 11), 8 8.17 (m, N-f2-(5-chlorobenzooxazol-2-vl)- 2-hvdroxv-1S-Rhenethylethyll-3-cclohexylpropionamide (Compound 169); MS (ESI) i/z 455 (M 'H-NMR (300 MHz, CDC13): 8 0.84 2H), 8 1.12 4H), 8 1.20 211), 8 1.51 6H), 8 2.00 311), 82.65 2H), 84.21 11), 84.50 1H), 8 5.02 11), 8 6.44 11), 8 7.01 7.47 7H), 8 7.65 11), (C 26
H
31
CIN
2 0 3 benzvl 1S-(2-benzooxazol-2-vI-2-hydroxv-l S-phenethlethlsulfamovlmethvl)- 3-nethvlbutvlcarbamate (Compound 170); 'H NMR (CDC1 3 7.71 11), 7.52 m, 11), 7.20- 7.40 1211), 5.9 0.5H), 5.6 0.5H), 4.80-5.20 51), 4.1-4.3 211), 2.7-2.9 (m, 4H), 1.7-2.0 21), 0.90 311), 0.79 311), 3.30 11); N- [IS-(2-benzooxazol-2-vl-2-hydroxy- 1S-phenethyethylsulfamovliethyl)- -107- 3-methylbutyllacetamid (Compound 171); benzyl 1S(2-benzooxazol-2-yI-2-hydroxylSp~henethylethvlsulfamolmethyl)-3-methlbutvlcarbamate (Compound 172); 'H NMR (DMSO): 7.71 (in, 1H), 7.5 (in, 111), 7.0-7.4 (in, 12H), 4.9-6.2 (in, 6H), 4.0-4.35 (mn, 2H), 3.75 (mn, 1H), 3.20-3.60 (in, 2H), 2.5-3.0 (in, 2H), 1.15-2.15 (in, 3H), 0.6-1.05 (in, 6H1); MS: rn/e 80. 1; N-r IR-(2-benzooxazol-2-yi-2-hvdroxv- 1S-phenethylethvlsulfainoylietl) 3-inethylbulyllacetamide (Compound 173); 2S-acetvlainino-N-(2-benzooxazol-2-yl-2-hvdroxv- 1S-phenethvlethyl)- 3-cvclohexylp oionainide (Compound 174); tert-buMy 1 S-(2-benzooxazol-2-yl-2-hvdroxy-I1S-phenethylethyll- 2-cvclohexylethyl)carbamate (Compound 175); 2-acetvlamino-N-2-benzooxazol-2-vl- 1. 1 -dimethyl-2-oxoethyl)- 3-cyclohexvyiproionamide (Compound 176); benzvl 1 S-f2-(5-phenvlbenzooxazol-2-vl)-2-hydroxyethlcarbamoll.
3-methvlbutvlcarbamate (Compound 177); N-(2-benzooxazol-2-yI-2-hydroxy-I1S-phenethylethvl)-3-cvcloventVlp2rOpionanide (Compound 178); 'H NMR (CDC 3 7.72 (in, 1H), 7.53 (in, 1H), 7.08-7.19 (in, 8H), 5.98 (in, 111), 5.05 (mn, 2H1), 4.51 (in, 1H), 2.6-2.8 (mn, 4H), 2.17-2.29 (in, 1H), 1.95-2.15 (mn, 2H1), 1.8- 1.95 (mn, 1H), 1.68-1.78 (mn, 1H), 1.3-1.7 (in, 6H), 1.0-1.12 (mn, 1H), 0.85-1.0 (mn, 1H); N-(2-benzooxazol-2-yl-2-hvdroxy- IS- henyethylethyl)-2-bicvcdo 2.2.1 hept-2- lacetainide (Compound 179); N-(2-benzooxazol-2-vl-2-hydroxy-I1S-phenethylethfl)-2-naphthalen-l1-vlacetamide (Compound 180); N-(2-benzooxazol-2-l-2-hvdroxy- lS-nhenethylethvl)-3-phenvlnronionainide (Compound 181); 'H NMR (CDCI 3 7.69 (mn, 1H1), 7.53 (mn, 111), 7.37 (mn, 2H), 7.03-7.35 (in, 1011), 5.9 (nm, 1H), 4.98 (mn, 111), 4.40-4.55 (in, 111), 3.0 (in, IN), 2.80 J=7.7Hz, 2H1), 2.55 (in, 2H), 2.38 J=7.5Hz, 2H); methyl 2-f 2S-(3-cyclohexylpropionylamino)- 1-hydroxy-4-phenylburvll- 4,5-dihvdrooxazole-4S-carboxlate (Compound 182); MS (ESI) m/z 431 (M IH-NMR (300 MHz, CDC1 3 5 0.89 (mn, 2H), 5 1.20 (in, 4H), 8 1.48 (in, 2H), 8 1.65 (mn, 6H), 5 2.00 (in, 2H), 5 2.15 (in, 2H1), 5 2.73 J 4 Hz, 2H), 8 3.76 3H), 854.30 -4.65 (in, 5H1), 5 6.00 (d, -108- J 6Hz, 1H), 5 7.13 7.35 5H), (C 24
HN
2
O);
methyl 2 2 S-(3-cvclohexvlropionlamino)-l-hydroxy- 4 -Rhenlbutvlloxazole4-carboxylate (Compound 183); N-(2-benzooxazol-2-Yl-2-hydroxy-I S-nhenethyl)-4-cvclohexvlbutyramide (Compound 184); 'H NMR (CDC1 3 7.62-7.73 IH), 7.46-7.59 11), 7.05-7.43 2H), 6.22-6.38 1H), 5.11 111), 4.50-4.69 11), 2.58-2.82 2H), 2.14-2.24 1H), 2.14 1H), 1.50-1.76 6H), 1.31-1.50 0.94-1.31 7H), 0.63-0.93 2H); MS: n/e=435.1; methyl 2-r2S-(3-cyclohexylropionlaiino). I -hvdroxy-4-Rhenyjbutvll- 4.5-dihdrooxazole-4R-carboxylate (Compound 185); MS (ESI) m/z 431 (M 'H-NMR (300 MHz, CDCI 3 850.89 2H), 5 1.20 4H), 8 1.48 211), 6 1.65 6H), 5 2.00 (m, 2H), 5 2.15 2H), 5 2.73 J 4 Hz, 2H), 6 3.76 3H), 5 4.35 4.72 5H), 5 5.75 (m, 11), 6 7.13 7.35 5H), (C 24 H3N 2
O
5 3 -cclohexvl-N-f2-hyroxv-2-(5-trifluoromethyibenzooxazoIM2-yl 1S-nhenethlethllpropionamide (Compound 186); MS (ESI) i/z 489 (M 'H-NMR (300 MHz, CDCI 3 0.77 21), 5 1.22 4H), 8 1.51 2H), 8 1.60 6H), 8 2.15 411), 2.70 2H), 6 4.51 11), 5 5.11 IH), 8 6.10 J 6 Hz, 11), 5 7.00 7.35 8 7.56 2H), 5 7.99 1H), (C 2
,H
31
F
3
N
2 0 3 2 S-acetvlamino-N-(2-benzooxazol-2-vl-2-hvroxy. 1S-Rhenethylethyl)-, 3 -(2-trifluoromethylnhenvl)propionamide (Compound 187); methyl 1-(1-benzooxazol-2-vlcarbonvl-3-henvropvlicarbamovl) 2-cyclohexylethylcarbamate (Compound 188); 'H NMR (CDC 13): 7.89 (d,J=7.4Hz, 11), 7.62 IHO, 7.54 111), 7.46 11), 7.13-7.30 IH), 6.87 J=7.9Hz, 111), 5.68 1H), 5.04 J=9.6Hz, 11), 4.24 111), 3.66 31), 2.75 (5,J=8.3Hz, 211), 2.45 IH), 2.19 (m, 11), 2.00 111), 1.52-1.80 1.44 iH), 1.12-1.27 4H), 0.89 211); MS: i/e=492.04; N-(1 -benzooxazol-2-ylcarbonyl-3-Rhenvpropyl)-3cvclohexyl.
2 -methylsulfonylaminopropionamide (Compound 189); 'H NMR (CDC1 3 7.87 111), 7.62 111), 7.55 11), 7.46 11), 7.13-7.28 51), 6.79 J=7.9Hz, 1H), 5.71 111), 4.92 1H), 4.00 11), 2.95 3H), 2.75 2H), 2.48 1H), 2.21 111), 1.78 (m, I1H), 1.61 5H), 1.45 111), 1.16 4H), 0.89 211); cyclohexylmethy I-benzooxazol-2-ylcarbonvl-3-phenylnrop)Ylcarbamate -109- (Compound 190); 'H NMR (CDCI,): 7.88 (in, 1H), 7.62 (in, 111), 7.52 (in, 1H), 7.49 (in, 1H), 7.13-7.23 (in, 5H), 5.57 (mn, 1H1), 3.89 1=6.5Hz, 211), 2.79 (mn, 2H), 2.42 (mn, IH), 2.12 (in, 111), 1.50-1.73 (mn, 6H), 1.24 (mn, 6H), 0.89 (in, 2H1); MS: m/e=421.0; benzy] I l-benzooxazoJ-2-ylcarbonvI-3-phenvlproovjsulfainovyinelvI).
2-inethvlbutylcarbainate (Compound 191); 'H NMR (CDCI 3 7.88 (d.J=7.7Hz, 1H), 7.62 (in, 111), 7.55 (mn, 111), 7.47 (mn, 1H1), 7.33 (mn, 5H1), 7.19 (mn, 5H1), 6.35 J=7.7Hz, 1H), 5.45 (mn, 1H), 5.13 2H), 5.0 (in, 1H), 4.43 (in, 111), 3.06 (in, 1H), 2.87 (in, 111), 2.45 (mn, 1H), 2.15 (in, 111), 1.41 (mn, JH), 1.07 (in, 111), 0.88 (mn, 6H); MS: m/e=5.78.1; N-f IR-(1S-benzooxazol-2-vlcarbonyl-3-phenvlprovlcarbamovl)- 2 6 -methy]Rvrid-2-ylmnethvsufonl)ethllthihene3-carboxmide (Compiound 192); N-F 1R-(1 S-benzooxazol-2-vlcarbonyl)- 3 -phenvypREpvlcarbanoyI)-2-(2-inethyi~Ryii3vylmethvisufonyI)efiVIlnicotinamiie (Compound 193); N-f lR-(1S-benzooxazol-2-ylcarbony1-3-phenvlpronv~carbanoyl) 2 2 -cyanobenzylsulfonvI)ethyllazetidine-3-cairboxamide (Compound 194); tert-butvl IR-(1 -benzooxazol-2-ylcarbonvlcyclobutvlcarbamovfl).
2 -(2-difluoromethoxvbenzvlsulfonvI~ethylcarbainate (Compound 195); tert-butyl IR-(S-benzooxazo-2-vlcarbonyI-3-henyprpylcarbamv1l..
2 4 -trifluoroinethylpdrd-3-yimethylsulfony)ethylcarbaa (Compound 196); N-f IR-(1 -benzooxazo1-2-ylcarbonIcclobuiycarbamorl)- 2 2 -difluoromethoxbenzvisufonv)ethynmboine.4..,arboxaiie (Compound 197); N-F IR-( IS-benzooxazol-2-vlcarbonvIpentvlcarbamovl)- 2 -tpvrid-3-ylmethvlsulfonylethyllisonicotinamiie (Compound 198); methyl IR-(S-benzooxazo-2-ylcarbonylbuIycarbano1).
2 2 -nlethoxvbenzylsulfonyl)ethvlcarbamate (Compound 199); IR-( 1S-benzooxazol-2-ylcarbonyljpRoylcarbamoyl..
2 -benzylsuffonvlethvllmprholine-4.caboxaiie (Compound 200); NMR 300mHz (DMSO-d 6 8.65 J=7.1H 3 1H1), 8.01 (di, J=8.2H 3 111), 7.91 (di, J=8.8H 3 IM1, 7.66 J=8H 3 1H1), 7.55 J=7.7H3, 111), 7.38 5H), 7.05 J=9.4H 3 IH), 5.21 (in, 111I), 4.75 (in, 1H), 4.49 21H), 3.53 4H), 3.45(n, 211), 3.32 4H), 2.02 (in, 1.77 (in,11), 0.96 (tJ=8H 3 3H); M=543.24 M*-S42.61; 1R-benzooxazol-2-vlcarbonvlnool)-2-(3.3-dimetiylureio).
-110- 3-(2-methoxybenzvlsulfonvl)propionaniide (Compound 201); NMIR 300rnM~ (DMSO-d 6 8.61 J=7.4H 3 1H1), 8.01 J=8.5H 3 1H1), 7.90 J=7.1H 3 1H), 7.65 3=8113, 111), 7.55 (t, J=8113, 1H), 7.33 (in, 2H), 7.05 (di, 1=8.8113, 111), 6.96 J=8.2H 3 1H), 6.70 J=9.1H 3 1H), 5.20 (in, 1H1), 4.53 (di, J=15.4H 3 IH), 4.41 J=15.4H 3 1H1), 3.77 3H1), 3.45 J=7.1113, 2H), 2.81 6H), 2.0 (in, IH), 1.7 (in, 1H), 0.96 J=8H 3 311); MS=651.33 M+=650.59; methyl IR-(1S-benzooxazol-2-ylcarbonylproplcarbamoyl)- 2-(2-methoxybenzylsulfonylethyI)carbamate (Compound 202); N-(l-benzooxazol-2-ylcarbonylpentvl)-2R-33-bis(2-methoxyethvl)ureidol- 3-Tvrfid-3-vlmethlsulfonylpropionamid (Compound 203); N-(1S-benzooxazol-2-ylcarbonylp~entvl)-2R-[3.3-bis(2-methoxyethvl)ureidol- 3-(3,5-diinethylisoxazol-4-ylmethylsulfonyl)ipropionamide (Compound 204); N-(1S-benzooxazol-2-ylcarbonylpropyl)-3-(3.5-dimethylisoxazol-4-lmethylsulfonyl)- 2R-inethylsulfonylaminopropionamide (Compound 205); 'H NMR: (DMSO) 9.04 (di, 3=6.6Hz, 1H1), 8.00-7.87 (in, 3H), 7.63 3=8Hz, 1H1), 7.53 J=8Hz, 111), 5.25 (in, IH), 4.61-4.36 (mn, 3H), 3.56-3.31 (in, 2H), 2.91 3H), 2.36 3H), 2.17 3H), 2.02 (in, IH), 1.74 (mn, IH), 0.96 1=7Hz, 311); MS: (M 4 527; methyl IR-(1S-.benzooxazol-2-ylcarbonylnRopylcarbamoyl)- 2-(3,5-dimethylisoxazol-4-ylmethylsulfonvl)ethylcarbamate (Compound 206); 'H NMR: (DMSO) 8.78 3=5.8Hz, 1H1), 7.99 (di, 3=8Hz, 111), 7.87 J=8Hz, 1H), 7.69 1=8.5Hz, 111), 7.62 J=8Hz, 111), 7.52 J=811z, IH), 5.20 (in, 111), 4.68 (in, 1H), 4.39 (di, J=14Hz, 111), 4.29 (di, J=l4Hz, 111), 3.52 311), 3.60-3.28 (in, 211), 2.37 3H1), 2.15 311), 2.02 (in, 1H), 1.74 (in, 111), 0.95 J=7Hz, 3H); MS: 507; N-[1R-(1-benzooxazol-2-vlcarbonylpentvlcarbamoyl)- 2-nRvrid-2-ylinethylsulfonylethyllisonicotinamide (Compound 207); NMR 1H: 9.15-9.30 (in, 111), 8.4-8.9 (in, 4 7.32-8.05 (in, 911), 5.28 (in, 111), 5.10 (in, 111), 4.75 (in, 211), 3.75 (mn, 111), 3.62 (in, 111), 1.95 (in, 111), 1.75 (in, 111), 1.05-1.45 (in, 411), 0.87 (in, 311); MS: M+l 564.0; and 4-f R-(1S-benzooxazol-2-:ylcarbonylpentvlcarbamovl)- 2-pRicd-2-vlmethylsulfonylethylcarbainoyllpyridine 1 -oxide (Compound 208).
REFERENCE 13 Benzvl 1 S-(N-methoxy-N-inethylcarbamovfl-3-phenylpropylcarbamate -111- A solution of 2-benzyloxycarbonylamino-4-phenylbutyic acid (5.05 g, 16.1 nunol) in methylene chloride (70 mL) was cooled to 0 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 NO-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 inL) 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 benzvl I S-(N-methox-N-methvlcarbamovl)-3-phenlprovlcarbamate (5.48 g, 15.4 mmol) as an oil. MS(PCI) m/z 357 (M Proceeding as in Reference 13 provided tert-butvl I S-(N-methoxy- N-xnethvlcarbamovl)-3-phenylvropvlcarbamate; 1H NMR (CDC1 3 5 1.35 9H), 8 1.64 1.72 (in, 211), 5 2.40 2.54 (mn, 1H), 8 2.60 2.77 (in, IH), 8 3.00 3H) 3.52 3H), 5 4.23 (in, IM1, 8 7.10 7.37 (in, REFERENCE 14 2S-Amino-N-methoxy-N-methvl-4-phenylbutyramide trifluoroacetic acid salt A solution of tert-butyl 1-(N-methoxy-N-methylcarbamoyl)-3-phenylpropylcarbainate (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 mniol) and trifluoroacetic acid (50 nIL, 296 nimol). 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 niL) and the solution was concentrated. The residue was again dissolved in toluene (100 ml) and concentrated to provide 2S-amino-N-methoxy-N-methyl-4-nhenylbutvainide trifluoroacetic acid salt (9.74 g 29 inmol) as a crude product. MS(PCI) m/z 223 (M -112- REFERENCE Benzyl 1-ri -(N-methoxv-N-methvlcarbamov)-3S-Dhenvlpropvlcarbamovll 3-methvlbulvlcarbamate A solution comprised of 2 S-amnino-N-methoxy-N-methyl-4-phenylbutyramide trifluoroacetic acid salt (9.74 g, 29 mmol), provided as in Reference 2, in DMF (75 niL) was cooled to 0* C and then neutralized with diisopropylethylamine added dropwise. A solution comprised of 2,5-dioxopyrrolidin-1-yl 2 -benzyloxycarbonylamino-4-methylvalerate (10.50 g, 29 mmnol) in DMF (75 ruL) and an additional amount of diisopropylethylamine (10.10 mL, 58 mniol) 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 (P 2 0 5 under vacuum to provide benzyl I-[1-(N-methoxy- N-methvlcarbamovly..3..phenlpropvcarbamovl1-3methvlbu~ylcarbamate (12.24 g, 26.1 mmol).
'H NMR (CDCI 3 850.91 J 5.88 Hz, 611), 5 1.45 1.55 (in, 1H1), 8 1.45 1.55 (in, 2H1), 5 1.77-2.00(in, IH), 52.11 -2.22 11), 52.70 (in, 53.20 31)3.60 (s ,3H) 4.25 (in, 111), 5 5.00 (mn, 1H), 5 5.15 211), 5 6.6 J 8.15 Hz, 111), 8 7.15 7.45 (in, 1011).
REFERENCE 16 Ethyl 3 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-(N-inethoxy-N-inethylcarbainoyl)-3phenylpropylcarbamate (5.53 g, 15.53 mmol), provided as in Reference 13, in ether (75 mL) and TBF (25 niL) was added dropwise over a period of minutes such that the temperature of the mixture was maintained at -40 to -450* C. The mixture was allowed to warm to 50* 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 I 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 niL), dried (NaSO,) -113and concentrated in vacuo to provide benzyl 1S-formyl-3-phenylpropylcarbamate (4.01 g, 13.5 mmol) as a colorless oil. MS (PCI) m/z 298 (M 1).
A solution of benzyl 1S-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 mL), dried (MgSO,) and concentrated to provide benzyl 2 -cyano-2-hydroxy-1S-phenethylethylcarbamate (4.957 g, 15.3 mmol) as a yellow oil. 'H NMR (CDCl 3 8 1.75 2.01 2H), 5 2.08 2.24 1H), 8 2.51 2.80 2H), 8 3.70 4.02 (m, 1H), 8 5.07, 8 5.33 3H), 8 7.10 7.47 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 3 (6.212 g 15.3 mmol) as a crude yellow oil. MS (PCI) m/z 371 (M 1).
REFERENCE 17 2 S-Amino-4-phenvl-l-(4S-phenvl-4.5-dihvdrooxazol-2-vl)butan-l-ol A mixture comprised of ethyl 3S-benzyloxycarbonylamino-2-hydroxy- (0.78 g, 1.92 mmol), provided as in Reference 16, diisopropylethylamine (0.218 L, 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 mL), dried (MgSO,) 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)- S-phenyethylethylcarbamate (0.475 g, 1.1 mmol) as an oily mixture of diastereomers. MS (PCI) m/z 445 (M (C 27 H2N 2 04).
-114- A solution comprised of benzyl 2 -hydroxy-2-(4,5-dihydro-4S-phenyloxazol-2-yl)- IS-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-( 4 .5-dihvdro-4S-phenvloxazol-2-vl)butan-1-ol (51 mg, 0.16 mmol) as a clear oil. MS (PCI) m/z 311(M (Cl 9
HIN
2 0 2 REFERENCE 18 2S-Amino-l-oxazol-2-vl-4-phenylbutan-l-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 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 quenched by slowly adding 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 (MgSO 4 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-1S-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 2 S-amino-l-oxazol-2-vl-4-phenvlbutan-l-ol trifluoroacetic acid salt (0.08 g, 0.229 mmol) as a yellow oil. MS (PCI) m/z 233 (M 1).
-115- REFERENCE 19 Methyl 2-(2S-aminio- 1-hydroxy-4-:phenylbutvl)oxazole-4-carboxvlate A solution comprised of methyl 2-(2S-benzyloxycarbonylamino-I-hydroxy- 4-phenylbutyl)-4,5-diliydrooxazole-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 mniol) and bromotrichioromethane (26 ml, 0.26 mniol). The mixture was stirred for 6 hours at 00 C, washed with ammonium chloride (10 mL) and concentrated. The residue was dried (MgSO,) to provide methyl 2-(2S-benzyloxycarbonylamino-1-hydroxy-4-phenylbutyl)oxazole-4-carboxylate.
MS(PCI) rn/z 425 (M Deprotecting provided methyl 2-(2S-amino- 1-hydroxy- 4:-henylbutvl)oxazole-4-carboxylat.
EXAMPLE 19 BenZyl 1S-[2-(4.5-dihydrooxazol-2-yl)-2-hvdroxy- 1S-phenethvlethylcarbamovll- 3-methvlbutvlcarbamate (Compound 210) 0 OH
HH
H 0
O
A mixture comprised of ethyl 3-(2-benzyloxycarbonylamino-4-methylvalerylaxnino)- (0.327 g, 0.63 mmol), diisopropylethylamine (0.218 mL, 1.26 mmol) and ethanolamine (38.4 mg, 0.63 minol) 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 (MgSQ 4 and -116concentrated in vacuo. Product was purified from the residue by flash chromatography eluting with 3:1 ethyl acetate/hexanes to provide benzyl IS-[2-(4,5-dihvdrooxazol-2-vl)-2-hydroxy- IS-phenethylethylcarbamovll-3-methylbutvlcarbama (38 mg, 0.079 mmol) as a white solid.
MS (PCI) m./z =482 (M (C, 7
H
35
N
3 0 5 Proceeding as in Example 19 provided benzvl IS-r2-(1H-benzoimidazol-2-vl).
2-hvdroxy-1S-nhenyethylethylcarbamovll-3-methlbutvcarbamate (Compound 211); EXAMPLE Benzyl IS-r2-(4.5-dihydro-4S-phenloxazol-2-yl)-2hydroxv 1S-phenethvlethylcarbamovll- 3-methylbutylcarbamate (Compound 212) 0 OH f NN N
H
00 A solution comprised of 2S-amino-4-phenyl-1-(4S-phenyl- 4,5-dihydrooxazol-2-yl)butan-l-oI (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-1-yl 2 S-benzyloxycarbonylamino-4-methylvalerate (0.063 g, 0.174 mmol) and diisopropylethylamine (30.3 pL, 0. 174 mmol) in DMP (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 IS-f2-(4.5-dihydroAS-nhenloxazol2-yi-2-hdroxv IS-henethylethvlcarbamoyll- 3-methylbuiylcarbamate. (34 mg, 0.06 1 nimol) as a clear oil. MIS (PCI) m/z 558(M
(C
33
H
39
N
3 0 5 -117- Proceeding as in Example 20 provided the following compounds of Formula I: benzyl IS-(2-benzooxazol-2-yl-2-hydroxv- 1S-nhenethylethvlcarbamoyl)- 3-methylbutvlcarbamate (Compound 213); MS (ESI) xn/z 530 (M 'H-NMR (300 MHz, CDC1 3 8 0.65 0.7 (dd, 6H), 8 0.98 (di, J 6 Hz 2H), 8 1. 10 1.55 (in, 3H), 8 1.65 1.85 (in, 1H1), 2.08 (in, 1H1), 8 2.70 (in, 2H), 8 3.99 4.13 (in, 1H), 8 4.50(m, 1H), 8 4.90 5.21 (in, 311), 8 6.40 6.70 (dd, 11H), 8 7.05 7.35 (in, I1OH), 8 7.47 (di, J 4 Hz, 2H1), 5 7.51 J 2 Hz, 2H),
(C
3
IH
35
N
3 0 5 benzvl 1-[2-(4.5-dihydro-5:,henyloxazol-2-vI)-2-hyciroxv-l1-nhenethylethylcarbamoyll- 3-mnethylbutylcarbamate (Compound 214); benzvl I -r2-(4.5-dihvdro-4S-inethvI-5S-phenyloxazo-2- vl)-2-hvdroxy- I -nhenvethvlcarbamoyll-3-methylbutvlcarbamate (Compound 215); benzvl 3-methyl-i -(2-hydroxv-2-naphthor2,3-dloxazol-2-vl- 1-tnhenethylethvlcarbamoy! lbutvlcarbamate (Compound 216); MS (ESI) in/z 580 (M 1); 'H-NMR (300 MHz, CDCI 3 8 0.65 0.95 (in, 6H), 5 1.25 (mn, 3H), 8 1.54 (in, 3H), 852.20 (in, 111), 5 2.82 J 4 Hz, 2H1), 8 4.00 -4.20 (in, 1H), 5 4.35 4.55 (in, IH), 8 4.90 5.09 (in, 3H), 6.60 (in, 1H), 5 7.23 (in, 10H), 5 7.56 (in, 2H1), 8 7.96 (mn, 311), 5 8.18 1H), (C 35
H
3
,N
3 0 5 benzyl IS-(2-benzooxazol-2-vl-2-hydroxy-I1S-Rhenethylethylcarbamovl)- 2-methylpropylcarbainae (Compound 217); benzyl IS-(2-benzooxazol-2-yl-2-hydroxy-I1S-phenethylethylcarbamoyl)- 3-inethylbutvlcarbamate (Compound 218); benzyl I S-[2-(4,5-dihvdro-4,4-dimethyloxazol-2-vD)-2-hvdroxy- IS-nhenethylethvlcarbamoyll-3-inethvlbutvlcarbanate (Compound 219), MS(PCI) m/z 510 (M IH NMR (CDC 3 8 0.8 0.99 J= 6 Hz, 6H) 11 -1.35 (in, 6H), 5 1.4 -1.78 (in, 3H1), 8 1.82 2.01 (in, 2H), 8 2.55 2.72 (in, 2H), 8 3.95 (mn, 111), 8 4.0 4.25 (in, 3H), 5 4.30 111), 8 5.10 211), 8 5.35 111), 8 6.58 (in, 111) 7.1 7.37 (in, 1011); (CH 39
N
3
Q
5 methyl 2 -2-(2-benzyloxycarbonvlanino-4-methylvalervlanino)-1 -hydroxy- 4 -ohenvylbutll-4,5-dihydrooxazole.4carboxylate (Compound 220), MS(PCI) iniz 540 (M 'H NMvR (CDCI 3 8 0.8 0.99 (di, J 6 Hz, 611),1.25 (in, 111), 8 1.47 (mn, 1H) 1.65 (in, 211), 1.99 (mn, 2H1), 5 2.15 IH), 8 2.65 J 4Hz, 211), 8 3.70 311)4.18 (in, 1H), 8 4.25 4.50 (in, 3H), 5 4.51 4.64 (rn, 21H), 8 5.17 (in, 211), 8 5.35 (di, J 5Hz, 111) 6.65 (di, J 6Hz, 111), 57.17 7.45(mi, IOH); (C~jH 3 7
N
3
O
7 -118methyl 2-f 2-(2,2-dimethy~propionylamino)-4phenlbutrlloxazole-4-carboxylate (Compound 22 MS (ESI) m/z 373 (M 'H-NMR (300 MHz, CDC1 3 5 1.25 9H), 8 2.20 (in, IH), 8 2.46 (in, IH), 8 2.77 J =4 Hz, 2H), 8 3.99 3H), 8 5.55 (in, 1H), 8 6.41 (di, J 4 Hz, 1H), 8 7.20 7.38 (mn, 5H), 5 8.41 1H), (C,2OH2N 2
O
5 tert-butvl 4-1 S-[2-(5-tert-butvlbenzooxazol-2-yl)-2-hydroxy- IS-phenethylethylcarbamovll-3-inethvlbutvlcarbamol Iniperidine- 1-carboxylate (Compound 222); tert-butyl 4-1I S-f2-hydroxv-1S-Rhenethyl- 2-(5-sulfamoylbenzooxazol-2-yl)ethvlcarbamoyll-3-methyibutvlcarbamoyl piperidine- 1-carboxylate (Compound 223); tert-butyl 1S-(2-hydroxy-2-naihthorl1.2-dloxazol-2-vl-1S-nhenethlethlcarbamoyD- 3-methylbutylcarbamovfliperidine-1I-carboxylate (Compound 224); tert-butl 4-f 1S-(2-hydroxy-2-nahthof 2.1-dloxazol-2-yl-1S-phenethylethylcarbamoyl)- 3-methylbutvlcarbamoyllpiperidine- 1-carboxylate (Compound 225); tert-butvl 4-f IS-r2-hvdroxy-IS-phenethyl- 2-(5-phenvlbenzooxazol-2-yl)ethylcarbamovll-3-inethylbutvlcarbamol Ipiperidine- 1 -carboxylae (Compound 226); tert-butvl 4-ri S-(2-benzooxazol-2-yl)-2-hydroxy- 1S-phenethylethylca-bamol)- 2-methylbutvlcarbainoyllpipRidine-1-carboxylate (Compound 227); MS (ESI) m/z 607 (M 'H-NMR (300 MHz, CDC 3 5 0.50 -0.61 (in, 1H), 850.75 0.98 (mn, 6H), 8 1.22 (mn, I1H), 8 1.41 9H), 8 1.81 1.85 (mn, IH), 8 1.99 2.06 (mn, 111), 5 2.70 (mn, 2H), 4.24 (di, J 2 Hz 2H), 5 4.50 4.70 (mn, 1H), 854.99 5.14 (mn, 2H), 8 6.96 7.81 (mn, 151H), (C 34 H46N 4
O
6 tert-butvl 1S-(2-benzooxazol-2-yfl-2-hydroxy-lS-pRhenethylethylcarbamoyl)- 2-methvlbutvlcarbamoyllbenzylcarbamae (Compound 228); tert-butvl 4-f IS-(2-benzooxazol-2-vl)-2-hydroxy-lS-phenethylethylcarbanoyl)- 2-cvclohexylethylcarbamoyllpip2eridine-l-carboxylate (Compound 229); benzy] 3-methyl-IS-[2-hydroxv-IS-n~henethyl- 2-(5-n)henvloxazol-2-yI)ethylcarbainovllbutvlcarbamate (Compound 230); MS (ESI) nI/z =556 (M 'H-NMR (300 iHz, CDC1 3 50.75 -0.95 6H), 51.25 -1.80 5H), 52.00(in, 2H), 5 2.67 (mn, 2H), 5 4.15 (mn, IH), 8 4.55(mn, 1H), 5 4.85 5.20 (mn, 2H1), 5 5.50 (in, 1H), 6.80 (di, J 6Hz, 1H), 5 7.12 7.48 (in, 1411), 8 7. 62 (di, J =2 Hz, 2H1), (C 33
H
3
,N
3 0 5 pyrid-3-yl 3-methyl-I S-[2-hydroxy-IS-phenethyl- -119- 2-(5-phenyloxazol-2-yl)ethylcarbamoyllbutylcarbamate (Compound 231); MS (ESI) m/z 527 (M IH-NMR (300 MHz, CDCl 3 860.75 0.95 (in, 6H), 5 1.45 1.75 (in, 5H1), 6 2.00 (in, 211), 6 2.67 (in, 211), 6 4.40 5. 10 (mn, 3H), 8 5.60(s, I1H), 6 7.00 7.47 (in, I0H), 6 7.62 (in, 2H1), 6 8.15 (in, 111), 6 8.65 (in, 1H), 6 9.15 (mn, 1H), (C31H-N 4
O
4 and benzyl IS-[2-hydroxy-IS-phenethyl- 2 -(5-phenyloxazol-2-yl)ethylsulfamoylnethyll-2R-methylbutylcarbamate (Compound 232); MS (ESI) ni/z 606 (M IH-NMR (300 MHz, CDC 3 6 0.75 0.95 (in, 6H), 6 1.30 1.50 (in, 5H1), 8 1.98 (mn, 2H), 6 2.77 (in, 3H), 5 3.55 (in, 2H1), 6 4.09 (in, 1H1), 6 4.90 5.10 (in, 311), 6 5.60 (in, 111), 6 7.02 7.47 (mn, 14H), 6 7.62 (in, 2H1), (C 33
H
3 9
N
3 0 6
S).
EXAMPLE 21 Benzvl 3 -methvl-IS-(S±vrid-2-vlcarbonl-3-henvipopvlcarbamol)buwlcarbamate (Compound 233) 0 OH
IIH
O~ N
HI
A solution comprised of 2-bromopyridine (0.291 mL, 3.06 minol) in dry THF (2 mL) was cooled to -78o C and then a solution of n-butyllithium (1.6 mL, 2.72 minol) 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-(N-methoxy-N-nethylcarbamoyl)-3-phenylpropylcarbamoyl..
3-inethylbutylcarbainate (0.3 g, 0.64 ninol) in THF (2 inL) 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 inL), dried (MgSO,) and concentrated in vacua. Product was purified from the residue by flash chromatography on silica gel eluting with 1:2 ethyl acetate/hexanes to provide -120benzyl 3-methyl- I -pyrid-2-ylcarbonyl-3-phenylpropylcarbamoyl)butylcarbamate (82 mg, 0.17 mmol) as a white solid. MS (ESI) m/z 488 (M 'H NMvR (CDCl 3 80.8 1.05 (d, J 4 Hz, 6H1), 1.5 (in, 8 1.6 1.78 2H), 8 1.99 -2.20 (in, 11H), 8 2.6 -2.9 (in, 1H).
8 2.55 2.85 (in, 2H), 8 4.25 (mn, IH), 8 5.17 2H), 8 5.25 (in, 1H), 8 6.00 (in, IH), 8 6.85 6.95 J I 10Hz, 1H), 8 7.1 7.4 (in, 1011) 7.50( t, J 4Hz, 1H), 8 7.85 J 6Hz, 1H1) 8.01 J 8 bz, 1H), 8 8.69 (in, 1H). Anal (C2IH 33
N
3
O
4 Proceeding as in Example 21 provided the following compounds of Formula I: benzyl 14 l-(pvrid-3-vcarbonyl)-3-yhenlropvlcarbamovll-3-methvlbutylcarbamate (Compound 234), MS(PCI) m/z 488 (M 'H NMR (CDCI 3 80.8 1.05 J 4 Hz, 6H) 1.5 (in, 111), 8 1.6 1.78 2H), 8 1.80 -2.01 (mn, 2H), 8 2.25 (in, 1H) 2.6 -2.9 J =3 Hz, 111), 8 2.55 2.85 (mn, 21H), 8 4.30 (mn, 111), 8 5.17 2H1), 8 5.35 J 6Hz, 1H), 8 5.55 (mn, IH), 8 7.02 J 8H1z, 1H), 8 7.1 7.4 (mn, 101H) 8.05( d, J =5 Hz, 1H), 8 8.78 J 4Hz, 111), 8 9.10 111); 33
N
3
O
4 and benzy] I -[l-(guinol-3-ylcarbonl)-3-phenlpRo2vlcarbanoll-3-inethlbutlcarbana (Compound 235), MS(PCI) in/z 538 (M 'H NMR (CDCI 3 80.8 1.05 J 4 Hz, 6H) (mn, 1H1), 8 1.6 1.78 (in, 211), 8 1.99 2.20 (in, 111), 8 2.6 2.9 (in, 1H), 8 2.55 2.85 (in, 2H1), 8 4.35 (in, 111), 8 5.17 5.25 (in, 311), 8 5.70 (mn, 111), 8 6.75 6.85 J 10Hz, 1H), &87.20 7.45 (mn, 1OH), 6 7.65 J 6Hz, 1H), 8 7.77 7.90 (in, 211), 8 8.22 J 7, 111), 8 8.46 1H), 8 9.4 IH); (C 33
H
35
N
3 0 4 -121- EXAMPLE 22 Benzvl 1-F 1H-indol-5-ylcarbony])-3-phenvlpronvlcarbamoyll-3-methvlbutvlcarbamate (Compound 236) 0 OH
H
HN N1 A mixture comprised of potassium hydride (0.29 g, 2.56 minol, 67% in mineral oil) in anhydrous ether (5 mL) was cooled to 0* C and then a solution comprised of 5-bromo4.H-indole g, 2.56 mmol) in anhydrous ether (5 mL) was added. The mixture was stirred for minutes and then cooled to -78' C under nitrogen. A solution comprised of tert-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 1-[1-(N-methoxy-N-methylcarbamoyl)-3-phenylpropylcarbamoyl]- 3-methylbutylcarbamate (0.3 g, 0.64 mnM) 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 mnL, 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 niL), dried (MgSO 4 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 1-11I -(lH-indol-2-ylcarbonyl)-3-phenylpropylcarbamoyl].3-methylbutylcarbamate (112 mg, 0.21 nimol) as a white solid. MS (ESI) m/z 526(M 'H NMR (CDCl 3 8 0.8 1.05 (d, J 4 Hz, 6H), 1.5 IH), 8 1.5 1.78 (mn, 3H1), 8 2.00 (in, lH), 8 2.4 (in, 111), 8 2.65 (in, 2H1), 8 4.35 (in, 1H), 8 5. 17 2H1), 8 5.25 (dj 6 Hz 111), 8 5.75 (in, I 8 6.55 111) 7.05 (d, J 4Hz, 111). 8 7.1 7.45 (in, 10H) 7.7( d, J 4Hz, I1H), 8 8.15 J 4Hz, 1 H) 8.78 (in, 1H1).
(C
32
H
35
N
3 0 4 -122- EXAMPLE 23 benzvl i-ri -(benzofur-2-ylcarbonyJ)-3-phenvlnronvcarbamovil-3-methvlbutvIcarbamt (Compound 237) 0 OH II H ON N 0
H:
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-butyliithium (1.6 niL in hexanes) was added dropwise over 2 minutes. The mixture was stirred for 1 hour and then a solution comprised of benzyl i-[1 -(N-methoxy-N-methylcarbamoyl)-3-phenylpropylcabamoyll.
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 153 niL) in diethyl ether (50 mL). The organic phase was washed with brine dried (MgSO,) and concentrated in vacuo. The product was purified from the residue by flash chromatography eluting with 2:3 ethyl acetate/hexanes to provide benzvl 1-ri -(benzofur-2-vylcarbonyl)-3-Rhen ylropvlcarbamov)Y113.methvlbutvicarbamate (70 mg, 0. 13 minol) as a white solid. IIH NMR (CDCI 3 8 0.8 0.99 J 4 Hz, 6H1), 1.5 (in, 1H), 8 1.6 1.72 (in, 211), 8 1.99 2.18 (in, 1H1), 8 2.22 -2.41 (in, 111), 8 2.6 2.75 (mn, 2H1), 8 4.21 (mn, 111), 8 5.01 (mn, 11H), 8 5.17 2H), 8 5.50 (mn, 111), 8 6.75 6.81 J 7 Hz, 111), 8 7.10 7.37 (mn, 11H) 7.4 7.59(mi,, 3H1), 8 7.64 J 7 Hz, 111). (C 32
HMN
2
OS,).
Proceeding as in Example 23 provided the following compounds of Formula 1: benzvl i-ri -(benzothiazol-2-ylcarbonfl-3-nhenvlpronvlcarbamovll- 3-methvlbutvicarbamate (Compound 238), 'H NMR (CDCI,): 8 0.91 J 5.88 Hz, 6H), 8 1.39 1.54 (in, 1H1), 8 1.60 1.72 (in, 2H1), 8 2.11 2.25 (in, 111), 8 2.40 2.54 (in, 111), 8 2.7.2 -123- (in, 2H), 8 4.21 (in, 1H), 8 5.10 3H), 8 5-84 (in, 1H), 8 6.87 J 8.15 Hz, 1H), 8 7.10 7.40 (in, 1OH), 8 7.54 (cit, J 1.62, 8.10 Hz, 1H), 8 7.58 (cit, J 1.46, 7.80 Hz, 111), 8 7.97 (dcl, J 1.80, 8.15 Hz, 111), 8 8.17 (dci, J 1.66, 7.67 Hz, 1H); benzyl 3-methyl-IS-(3-phenvl- lS-thiazo- 2 -ylcarbonylpropvlcarbainovIbuUIcarbamate (Compound 239); N-3mty-S(-hnlI-hao-2v~ab~yirvlabm!btI 4-methylpinperazine- I -carboxamide (Compound 240); tert-butvl 4-3-methyl-IS-(3-Rhenyl- IS-thiazol- 2 -vlcarbonvinronylcarbamovI)but carbamoyllpineraine 1 -carboxylate (Compound 241); benzy] 3-methyl-1S-(3-Dhenvl- lS-thien- 2 -vIcarbonvlpopylcarbamovl)butlcarbamate (Compound 242); benzvl IS-ri S-(1 -methyl-lH-imidazo-2-vlcarbonvi-3-hen I ropcabiol 3 -methylbutvlcarbamate (Compound 243);benzyl IS(Stizl2ycroy-:hnlio eraol-- hlr~labmt (Compound 244);
N
4 3 -methyl-ls-(3henvMSthiazo-2.vcarbonlpro~vlcarbamo1)buyll eain 1-carboxamide (Compound 245); benzy] 154 lS-( 4 -methvlthiazol-2..vlcarbonvI).3-nhenvipropvlcarbamoI1- 3 -methylbutvlcarbamate (Compound 246); benZyl IS(Sfri2vcroy--~eypoplabmv)3mtybilabmt (Compound 247), 'H NMR (CDCI 3 8 0.91 (di, J 6.18 Hz, 611), 8 1.42 1.70 (nm, 3H), 8 1.98 2.13 (in, IH), 6 2.19 2.37 (mn, 111), 8 2.69 J 7.60 Hz, 2H), 6 4.22 (mn, IH), 8 5.10 J 7.76 Hz, 111), 8 5.12 2H1), 8 5.54 (in, 1H), 8 6.76 (di, J 8.15 Hz, 111), 8 7.16 7.36 (in, IOH), 8 7.39 (cit. J 1.82, 7.86 Hz, 1W1, 8 7.47 (dt, J 1.63, 7.79 Hz, 1H1), 8 7.69 11H), 8 7.80 (di, J 7.15 Hz, 11H), 8 7.85 (di, J 8.18 Hz, 11H); benzvl 15-F 1S-(1 -benzylIlH-iinidazoI-2.vcarbonyl..3phnvnrylRQ~carbanoIl- 3 -methylbutvlcarbamate (Compound 248); benzy 3-penyl- l-( 4 .5-dihydro- 4 S-nhbenyloxazol-2vcarbonl)Dronvllcarbamate (Compound 249); benzvl 2:~nll(,-iyr--~hnixzl2IabnIr (Compound 250); -124benzyi fi 4 .5-dihydro-4S-methvJ-5S:phe nvloxazoI-2-vcarbonvI)- 3 -nhenylpropvllcarbamate (Compound 251); and ethyl 2 2 2 -benzvloxvcarbonlamino..4methlvae.v,,amino)- 4 vhenylbutyrvllthiazole-4-carboxylate (Compound 252).
EXAMPLE 24 Methyl 2 2 2 -benzv~oxycarbonylainn methylvalerylaminoy 1 -hydroxy- 4 -pbenylbutylLoxazole-4-carboxylate (Compound 253) 0 OH0
HH
H 0 A solution comprised of methyl 2 2 2 -benzyloxycarbonylamino-4-methylvalerylamino)- (0.036 g, 0.067 mmol) in methylene chloride (3 mL) was cooled to 0* C and then DBU (11.2 mg, 72.7 jimol) and bromotrichioromethane (14.6 mg, 73.7 jimol) 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 (MgSO,) and concentrated. The product was purified from the residue by flash chromatography eluting with 1:3 hexanes/ethyl acetate to provide methyl 2 -f 2 2 -benzy ox carbon lamin..rnthvvalnImn -hydroxy-4-ryhenylbutvlloxazole.
4-carboxylat (12 mg, 0.022 minol) as a white solid. MS(PCI) m/z 538 (M 11H NMR (CDC1 3 8 0.8 1.05 J 4 Hz, 6H), 6 1.55 1.70 (in, 3H), 8 2.00 (in, 111), 8 2.40 (in, I H), 6 2.69 2H), 8 3.99 (in, 3H) 4.45 (in, IM, 65.17 2H), 8 5.78 (mn, 111), 8 7.01 J 4Hz IH), 8 7.14 -7.47 (mn, 1014) 7.72(d, J 4Hz, IH), 8 8.40 1H). (C 29
H
35
N
3 0 7 -125- EXAMPLE 2 -r 2 -(2-Benzyloxycarbonlamino-4-methlval~iamino)- I -hvdroxv-4phenylbuty1oxazole- 4-carboxylic acid (Compound 254) 0 OH 0 N~ N H
OH
A mixture comprised of methyl 2 2 2 -benzyloxycarbonylaminoA-methylvalerylamino)l-hydroxy-4-phenylbutylloxazole.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 I M hydrochloric acid and concentrated. The residue was dissolved in ethyl acetate (50 mL) and the solution dried (MgSO 4 The product was recrystallized from methanol and ether to provide 2 2 2 -benzyloxycarbonylamino-4-methylvalerylamino). I -hydroxy-4-phenylbutyl~oxazole- 4-carboxylic: acid (1.77 g, 3.38 mmol) as an off white solid.
-126- EXAMPLE 26 Benzy] 3-methyl-l1-f -hydroxy- I-p~henethyl- 2 4 -Dhenylcarbamovloxazol-2vJ)ethvlcarbamovllbu lcarbamate (Compound 255) 0 OH 0
NN
A solution comprised of 2 2 2 -benzyloxycarbonylamino.4-methylvalerylamino)l-hydroxy-4-phenylbutyl]oxazole-4carboxylic 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 mxnol) 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 3OmL)- The extracts were combined, dried (MgSO 4 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-i -[2-hydroxy-lI-phenethyl- 2-4peycraolxzl2y~tycraolbtlabmt (30 mg, 0.05 mmol) as a white solid. MS (ESI) miz 599 (M 'H NMR (CDCI 3 5 0.8 1.05 J 4 Hz, 611), 1.35 (in, IH), 5 1.55 (in, 1H), 5 2.00 2.15 (mn, 2M1, 8 2.62 (in, 2H1), 5 2.80 (in, 2H), 5 3.65 (in, 211), 4.11 (in, 111), 5 4.30 (mn, 1H), 854.45 (in, 1H), 5 4.95 111) 5.17 2H), 5 5.2 J=4Hz, 111), 5 6.70 J 5Hz I 8 7.1 7.45 (in, 15H1) 7.7( d, J 4H1z, 111), 5 8.19 111), 5 8.99 111). (C3,H 38
N
4
O
6 Proceeding as in Example 26 provided the following compounds of Formula 1: -127benzyl 1 -r2-(4-benzylcarbamoyloxazol -2-yl)-2-hydroxy- I -henethylethylcarbamovll- 3-methvibutylcarbamate (Compound 256), MS (ESI) m/z 613 (M IH NMR (CDC 3 8 0.8 1.05 J 4 Hz, 6H), 8 1.25 1.75 (in, 3H), 6 2.00 -2.20 (in, 2H), 8 2.69 (in, 2H), 8 3.85 (in, 1H), 8 3.95 (in, 1H), &64.25 (in, 1H), 8 4.60 (in, 2H), 5 4.80 111), 6 5.17 211), 8 5.59 1H), 6 6.59 J =4Hz 1H), 6 7.05 7.47 (mn, 15H1), 8 8.20 I1H); (CHN 4
O
6 and benzyl 3-methvl-l-f2-hvdroxy- 1-vhenethyl- 2 4 -nhenyethvlcarbamoyloxazol-2-vl)ethylcarbamoy11bu~ylcarbainate (Compound 257), MS (ESI) im/z 627 (M IH NMR (CDC1 3 6 0.8 1.05 J 4 Hz, 6H), 8 1.25 1.75 (in, 4H), 6 2.00 (in, 2H1), 6 2.59 (in, 2H1) 2.88 (in, 2H1), 8 3.65 (in, 211), 6 4.02 (in, 11H), 6 4.25 (m,111), 6 4.80 1H), 6 5.17 2H), 5 6.59 J 4 Hz, 111), 6 7.00 7:*42 (mn, 15H), 8 8.20 1H1); (C 3 6
H
4 2
N
4 0 6 EXAMPLE 27 benzvl i-ri 4 ,5-dihydro-4S-phenvloxazol-2-vlcarbonvrl.3:phenylpropylcarbamov1- 3-methylbutvlcarbamate (Compound 258) 0 OH 0 NN
H
0 0 A solution comprised of benzyl IS-[ 2 -(4,5-dihydro-4S-phernyloxazol-2-yl)-2-hydroxy.
ISpeehltycrao113mtybtlabmt (0.038 g, 0.078 minol), provided as in Example 14, and Dess-Martin Periodinane (0.031 g, 0.072 inmol) in methylene chloride (5 rnL) was stirred while a mixture of 0.00 1: 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 inL) and the solution was washed with saturated sodium -128bicarbonate (40 inL), sodium thiosulfate, (40 inL, 10% wt./wt), water (40 mnL) and brine (40 mL), dried (MkSO 4 and then concentrated. Product was purified from the residue by flash chromatography eluting with 3:1 ethyl acetate/hexanes to provide benzyl 1-[1-(4,5-dihydro.
4Speyoao--~abnl--hnlrplabmy]3mtybtlabmt (0.014g, 37.5%) as a white solid. MIS (PCI) in/z 556 (M 'H NMR (CDC1 3 5 0.8 1.05 (di, J 6 Hz, 6H), 8 1.4 1.78 (mn, 3H), 8 1.87 2.12 (in, 1H), 8 2.40 (in, 111), 8 2.65(t, J 4H-z, 211), 8 4.25 J 3Hz, 2H), 8 4.75 J 4 H, 1Hi), 585. 10 211), 5 5.40(d J 3Hz 111), 8 5.50 (t, J 4 Hz, 1H), 8 6.97 J 3Hz, 111) 7.1 7.49( m, 15H). (C 33
H
3 7
N
3 0 5 Proceeding as in Example 27 provided the following compounds of' Formula I: benzvl S-(S-benzooxazol-2-vlcarbonvJ-3-phenyprovlcarbamoi) 3 -methvlbutvlcarbamate (Compound 259); benzyl IS-f lS-( 4 ,5-dihydrooxazol-2-vlcarbonyI)..3..henyI ropylearbamoyll- 3-met hylbutvlcarbamate (Compound 260), MS (PCI) in/z 480 (M 'H NMR (CDC 3 8 0.8 1.05 J=6 Hz, 611)851.4- 1.78 (in, 3H), 8 1.82 -2.01 (in, 2H), 52.65 J 2H), 8 2.99 J 4Hz, 111), 8 3.75 J3 3Hz, 111), 8 4.10 4.35 (in, 311?), 8 4.50 (mn, III), 8 5.17 311), 8 6.85 1H1), 8 7.1 7.49(mi, 1011, (C 2
,H
3 3
N
3 0_ 5 N-f3-iethvl-IS-(3-Rhenyl- IS-benzaooazol.2..vlcarbonvl~ropylcarbamoyI)butyllpiperidine-4..arboxainide (Compound 261), 'H NMR (DMS0-l 6 8 0.83 J 6.91 Hz, 6H), 8 1.34 1.87 (mn, 711), 5 1.9 2.07 (mn, 111), 8 2.20 2.33 (in, 111), 8 2.41 2.54 (in, 111), 8 2.62 2.92 (mn, 411), 8 3.26 (bd, J 12.12 2H), 8 4.39 (in, 111), 5 5.18 (in, IH), 8 7.16 7.33 (in, 511), 8 7.54 J 7.64 Hz, 111), 5 7.64 7.82 Hz, 111), 8 7.87 (di, J 8.40 Hz, 111), 8 7.96 J 7.67 Hz, 111), 8 8.07 J 8.15 Hz, 1H), 8 8.29 (bs, 111), 8 8.60 (bs, IH), 8 8.76 J 6.45 Hz, 1H); benzyl 1-f l-( 4 .5-dihydro-5-phenyloxazo12vlcarbonyl)- 3 -nheny-iprovlcarbamoy]13-methylbutwlcarbainate (Compound 262); benzy] -i 4 ,5-dihvdro-5S-phenyl.4Siethvloxazol2vlcarbonyl)- 3 -Dhenvlpronvlcrbamoyl).3methylbutvlcarbainate (Compound 263); benzy] S-(S-henethvl-2-benziiazol.2.vl-oxoethylcarbainoyl)- 3 -inethvlbutvlcarbamate (Compound 264), '11 NMR (CDC 3 8 0.82 0.96 (mn, 611), 8 1.44 -1.75 (i,311), 82.17 -2.32(in, JH), 82.43 -2.56 11), 82.61 -2.80(in,211), 84.55 -129- (in, 1H), 6 5.13 (in, 2H), 8 5.35 J =8.67 Hz, 1H), 585.70 5.88 (in, 1H), 8 7.00 7.42 (m, 14H), 6 7.50 7.83 (mn, 2H1); benzvl 1-fl npto23doao--vcrbnl--hn]rtvcraal 3-methylbutvicarbamate (Compound 265); mnethyl 2 -f 2 2 -benzvloxcarbonyamino..4-ethylvale~yIamino4Dhenlbui,.all 4 .5-dihydrooxazole..4-carboxylate (Compound 266), MS(PCI) in/z 538 (M 'H NMR CCDC1 3 8 0.8 0.99 J 6 Hz, 6H) ,1.25 (mn, 1H1), 8 1.47 (in, 1) 1.65 (mn, 311), 8 1.99 (m, IH), 8 2.35 (in, I 8 2.65 2H1), 8 3.70 3H)4.18 2H), 8 4.55 (in, IM1, 8 5.17 (s, 2H), 865.35 (mn, 111) 6.75 (mn, IM1, 8 7.17 7.45( in, 10H), (C 29
H
35
N
3 benzy) S-lS-( 4 5-dihydro44diiethloxzoI.2..carbonvi)3h nlpopvIboll 3-inethylbulylcarbamate (Compound 267), MS(P 'Cl) m/z 508 (M IlH NMR (CDC1 3 8 0.8 0.99 J 6 Hz, 6H1), 8 1.36 6H), 8 1.5 (in, 1H), 8 1.65 (in, 2H) 1.82 -2.01 1H), 8 2.35 (mn, IH), 8 2.6 J 6 Hz, 2H), 8 4.05 Cs, 2H1), 8 4.25 (mn, 2H), 8 5. 10 2H), 8 5.4 (in, 111), 8 6.75 (diJ 8Hz, IM1 7.1 7.38( mn, 10M1; (C29H 37
N
3
O
5 benzyl S-(IS-benzooxazol2vcarbonyl 3:henyJnropylcarbamoyD- 2 -inethylpropylcarbamate Compound 268), 'H NMR (CDC 3 8 0.90 J 6.91 Hz, 311), 6 0.97 J 6.94 Hz, 311), 8 2.06 2.25 (mn, 2H), 6 2.38 2.55 (in, 111), 6 2.74 211), 8 4.03 (dd, J 1.73, 6.45 Hz, 111), 8 5.10 211), 8 5.29 J 8.67 Hz, 111), 8 5.73 (mn, IM1, 8 6.66.(d, J 7.42 Hz, 111), 8 7.09 7.40 (mn, 1011), 8 7.46 (dt, J =1.62, 8. 10 Hz, 111), 6 7.55 (dt4 J 1.83, 7.76 Hz, 1H), 8 7.64 J3= 8.06 Hz, 111), 6 7.89 J =7.46 Hz, 111); tbenzvl I lS-benzooxazol-2-ylcarbonv-3-hn I ropvlcarbamoyl)- 2 -methvlbulylcarbamate (Compound 269), 'H NMR (CDC1 3 8 0.88 J 7.43 Hz, 3H1), 8 0.91 J 6.67 Hz, 311), 6 1.04 1.21 111), 6 1.40 1.55 (mn, 111), 8 1.78 1.93 (mn, 111), 8 2.10 2.24 1ff), 8 2.40 2.54 (mn, 111), 6 2.74 Ct, J =7.60 Hz, 2H), 8 4.06 J 6.21 Hz, 111, 6 5.09 2H), 6 5.29 J 8.67 Hz, 111), 8 5.72 111), 6 6.66 J =8.00 Hz, 1H), 8 7.09 7.39 1011), 8 7.46 Cdt, J 1.68, 7.80 Hz, 1H), 8 7.55 Cdt, J 1.44, 7.56Hzf, 111), 6 7.63 J 8.04 Hz, 111), 6 7.89 J 7.82 Hz, 111); benzyl L-r IS-(5-chlorobenzooxazol.2..ycarbonvi).3-henlpropvlcarbamol- 3 -inethvlbutvlcarbgfmate (Compound 270), 'H NMR (CDC1 3 6 0.90 611), 6 1.39 1.53 (m, 111), 8 1.59 1.70 (in, 211, 8 2.07 2.21 111), 6 2.37 2.52 (in, 1H), 8 2.73 J 7.91 Hz, 2H), 6 4.20 (mn, 111), 8 5.06 J 7.91 Hz, 111), 8 5.10 Cs, 211), 8 5.64 111), 6 6.77 (d, J 7.67 Hz, 111), 6 7.09 7.37 1011), 8 7.53 (dq, J3 1.86, 8.9.1 Hz, 211, 6 7.89 J 1.73 -130- Hz, IN); N-13-methl-1S-3-phenyl- 1S-(5-chlorobenzooxazol-2-ylcarbonyl)Dropylcarbamollbutvl I pineridine-4-carboxamide (Compound 271); N-[2-cyclohexyl-1S-(3-phenyl- IS-benzooxazol-2-ylcarbonvlnropvlcarbamoyl)ethyllpidine4carboxamide (Compound 272); MS (ESI) m/z 545 (M 'H-NMR (300 MHz, CDCI, CDOD): 8 0.85 2H), 8 1.02- 1.58 4H), 8 1.40- 1.71 7H), 8 1.75-2.21 5H), 52.38 IH), 82.51 (m, 1H), 8 2.69 J 4 Hz, 2H), 8 3.32 2H), 8 4.39 J 6 Hz 1H), 8 5.53 J 3 Hz 1H), 5 7.11 7.21 5H), 5 7.24 1H), 5 7.38 7.61 3H), 5 7.73 J 6'Hz, 11), 8 7.82(d, J 6 Hz, IN), (C 32 H0NO 4 methyl 2 2 -benzvloxvcarbonlamino-4-methvlvalervyamino)-4-henlbuNtioxazole- 4-carboxylate (Compound 273); benzvl 1-ri-( 4 -phenlcarbamvloxazo-2-lcarbonyI)-3-nhenylpronylcaramoyll.
3-methylbutvlcarbamate (Compound 274), MS (EST)) m/z 597 (M 'H NMR (CDCI,): 0.8 1.05 J 4 Hz, 6H), 8 1.55 1H), 8 1.70 2H), 5 2.00 2.20 11), 5 2.40 (m, IN), 8 2.69 2H), 5 2.97 J 4 Hz, 2H), 5 3.70(q, J 3 Hz, 2H) 4.25 11), 5 5.17 (s, 2H), 5 5.59 1H), 5 6.99 J 4Hz 1H), 857.14 7.47 15H) 7.72( d, J 4Hz, 11), 8 8.47 IN), 5 8.65 JH), (C 34
H
36
N
4 01); benzvl I-rl-( 4 -benzvlcarbamgyloxazol-2-ylcarbonyl).3nhenvnropvlcarbamoll 3-methylbutvlcarbamate (Compound 275), MS (ESI) i/z 611 (M 'H NMR (CDC1 3 0.8 1.05 J 4 Hz, 61), 5 1.45 1.70 4H), 5 2.00 2.20 11), 5 2.40 1H), 6 2.69 211), 5 4.25 IH), 5 4.67 J 3 Hz, 211), 8 5.17 31), 8 5.59 11), 8 6.85 J 4Hz 11), 8 7.10 7.47 (in, 1511), 5 8.47 11), (C 3
,HNO,);
tert-butvl 4-f IS-FlS-(5-rert-butylbenzooxazol-2-carbonv)-3-heny nropylcarbamoyll 3-methylbutylcarbamoyl Ipiteridine-l-carboxylate (Compound 276), 'N NMR (CDCI 3 850.86 0.97 6H), 8 1.34 1.85 8 1.38 91), 8 1.43 Cs, 9H), 5 2.09 2.30 (m, 52.37 -2.52 IN), 8 2.72 4F), 54.11 (bd, J 12.85, 2H), 54.49 IN), 55.66 (m, iN), 8 5.97 J 7.91 Hz, 1H), 5 6.89 J 7.67 Hz, 1H), 5 7.11 7.27 Cm, 5H), 5 7.50 7.64 Cm, 21), 5 7.86 J 1.56 Hz, 1H); tert-butvl 4-f IS-F lS-(5-sulfamovibenzooxazo-2-ylcarbonl)-3phenylprylcarbamoy1l 3-methylbutylcarbamovl Inineridine-l -carboxylate (Compound 277), IH NMR (CDCI 3 -131- 8 0.85 0.96 6H), 8 1.37 1.82 711), 5 1.42 9H), 52.08 2.46 (in, 3H), 82.71 (m, 4H), 5 4.02 (bs, 2H), 8 4.56 11), 8 5.38 (bs, IH), 5 5.78 (bs, 2H), 8 6.38 J 8.42 Hz, 1H), 8 7.07 7.25 5H), 6 7.70 (dd, J 3.48, 8.64 Hz, JH), 8 8.08 (dd, J 1.73, 8.67 Hz, IH), 8 8.41 (dd, J 1.49, 3.96 Hz, 1H); N-13-methyl-1S-43-phenvl- IS-(5-tert-butvbenzooxazJ2-ycarbonyI)vrorvcarbamov11buyineridine-4-carboxamide (Compound 278), 'H NMR (DMSO-l): 8 0.82 (t J 6.18 Hz, 61), 8 1.36 9H), 8 1.33 1.88 7H), 5 1.91 2.06 11), 8 2.19 2.34 IH), 8 2.42 2.54 IH), 82.61 -2.92 (m, 4H), 8 3.27 (bd, J 12.02 2H), 84.39 1H), 8 5.19 1H), 8 7.15 7.33 511), 8 7.74 (dq, J 1.97,7.91 Hz, 21), 8 7.90 J 1.83 Hz, 11), 8 8.07 J 8.15 Hz, 1H), 8 8.27 (bs, 11), 8 8.56 (bs, 1H), 8 8.72 J 6.43 Hz, 1H); N-I 3-methyl-1S-f3-DhenvI.
IS-(5-sulfamovibenzooxazol-2-vcarbonyl)propvlcArbamovilbutvI lvineridine4-carboxamide (Compound 279), 'H NMR (DMSO-d 6 80.80 0.88 61), 8 1.31 1.86 71), 8 1.92 2.05 11), 8 2.22 2.33 111), 8 2.41 2.52 11), 8 2.63 2.89 41), 8 3.26 (bd, J 11.88 21), 8 4.40 11), 8 5.13 11), 8 7.16- 7.31 51), 8 7.57 211), 8 8.05 3H), 8 8.25 (bs, 11), 8 8.32 11), 8 8.55 (bs, 11), 5 8.82 J 6.18 Hz, 11), 8 8.88 (d, J 6.84 Hz, 1H); terz-butyl 4-r1g-(1S-naphtho[ l 2 -dloxazo l-2-iccarbonvi3phenyipropvcarbamoyi) 3 -methvybutvlcarbainovIlpiDeridine I-carboxylate (Compound 280), 'H NMR (CDCI 3 6 0.87 0.95 6H), 6 1.39 1.85 711), 8 1.44 91), 8 2.13 2.32 21), 8 2.45 2.60 11), 82.65 2.81 41), 84.12 21), 84.53 11), 85.79 IH), 8 6.00 (d, J 7.94 Hz, 11), 8 6.90 J 7.67 Hz, 11), 8 7.12 7.26 51), 8 7.56 7.80 3H), 8 7.93 8.00 (ni, 21), 8 8.52 (dd, J 1.97, 8.00 Hz, 11); rert-butvl 4-1S-(S-naphtho[2 l-dloxazol-2-vicarbonI3phenvipR carbamol)- 3-methlbutlcarbamo IlpiRendine- -carboxylate (Compound 281), '1 NMR (CDCI 3 80.88 -0.97 6H), 8 1.38 1.86 7H), 8 1.43 91), 82.15 -2.31 21), 82.43 -2.57 (in, 11), 82.67- 2.79 4H), 84.11 2H), 84.52 11), 85.73 11), 8 5.96 (d, J 7.94 Hz, 11), 86.90 J 7.91 Hz, 111), 8 7.12 7.26 5H), 8 7.66 21), 8 7.85 (s, 11), 8 7.99 (dd, J 1.85, 7.80 Hz, 11), 8 8.33 1.97,7.94Hz, 11); tert-butv 4-1 S--henvlbenzooxazol2vicarbon)3henpronvlcarbaoll 3 -iethvlbutylcarbamovl Iniperidine-1-carboxylate (Compound 282); MS (ESI) i/z 681 (M -132- 'H-NMR (300 MHz, CDCI 3 6 0.85 0.98 6H), 6 1.43 9H), 6 1.60 1.85 (in, 6 2.14 2.30 2H), 6 2.56 11), 6 2.75 4H), 64.12 2H), 64.52 11), 6 5.69 1H), 6 5.92 J 6 Hz, 1H), 6 6.85 J 6 Hz, 11), 6 7.13 7.26 7H), 6 7.36 7.80 7H), 6 8.05 IH), (CH 4
,N
4 N-f3-methvl-i S-r3-phenyl- 1S-(nayhthof 1.
2 -dloxazol-2-ylcarbonyl)proylcarbamoyllbutI )pineridine-4-carboxamide (Compound 283), 'H NMR (DMSQ-d 6 6 0.81 6H), 6 1.35 1.86 7H), 6 1.96 2.11 (m, 1H), 6 2.26 2.53 2H), 6 2.64 2.91 4H), 6 3.26 (bd, J 11.63 2H), 64.42 11), 65.27 1H), 6 7.19 7.36 5H), 6 7.70 J 7.91 Hz, 1H), 6 7.83 J 7.43 Hz, 1H), 6 8.01 J 8.91 Hz, 11), 68.08 1H), 6 8.18 J 8.91 Hz, 2H), 6 8.27 (bs, 11), 6 8.39 J 7.91 Hz, 1H), 6 8.56 (bs, 1H), 6 8.75 J 6.45 Hz,. 11); N-1 3-methyl-1S-[3-henyl- 1S-(naphthor2. 1-dlbenzooxazol-2-vcarbonyl)piovyicarbamovllbuWI l~ieridine-4-carboxamide (Compound 284),.'H NMR (DMSO-d 6 60.81 J 6.43 Hz, 61), 6 1.34 1.87 71), 6 1.97 2.12 11), 6 2.24 2.38 1H), 62.42- 2.53 1H), 6 2.66 2.93 41), 6 3.26 (bd, J 10.12 2H), 6 4.41 1H), 6 5.26 1H), 6 7.16 7.34 5H), 6 7.77 2H), 6 7.97 J 8.91 Hz, 1H), 6 8.05 J 8.86 Hz, 11), 6 8.07 J 8.64 Hz, 1H), 6 8.19 J 7.91 Hz, 11), 6 8.26 (bs, IH), 6 8.28 J 7.67 Hz, 1H), 6 8.56 (bs, IN), 6 8.78 J 6.43 Hz, 11); N-f3-iethyl-1-[3-Rhenvl- 1-(5-vhenvlbenzooxazo-2-vlcarbony)ro1vlcarbamovllbutI I piteridine-4-carboxamid (Compound 285); benzvl 4 -thenvethvlcarbamoyoxazol2y-vlcarbonyl)-3-phenlropvlcarbamoll- 3 -methylbutvlcarbamate (Compound 286), MS (ESI) miz 625 (M 'H NMR (CDC1 3 6 0.8 1.05 J 4 Hz, 61), 6 1.50 11), 6 1.65 3H), 6 2.00 2.20 1H), 6 2.35 (m, 11), 62.60 21), 62.99 J 4Hz, 21), 6 3.67(q, J 3 Hz, 2H),4.19 11), 6 5.17 (s, 2H), 6 5.59 11), 6 6.85 6.98 2H), 67.10- 7.47 1511), 6 8.43 11);
(C
36
H
40
N
4 0 6 benzvl 1-fl1-f 4 3 henvlroplcarbamoyl)oxazoly 3 -lhenvlronylcarbamoyl 1-3-methvlbutvlcarbamate (Compound 287); MS (ESI) m/z 639 (M 'H-NMR (300 MHz, CDCI 3 60.95 J 6Hz, 61), 6 1.50 11), 6 1.65 31), 62.00 41), 62.35 11), 62.67 4H), 6 3.49 2H), 64.20 11), 6 5.09 2H), -133- 8 5.50 (in, 111), 8 6.85 (in, 111), 8 7.23(m, 15H), 6 8.35 111), 6 (C 37 11 42 N,0 6 tert-butvl 4-[1 S-(lS-benzooxazol-2-vlcarbony..3-IhenvlrpropylcarbamoVI)- 2 -methvlbutlcarbamollnipedine-l-carboxylate (Compound 288); terr-butvl 3-rIS-( lS-benzooxazol-2-lcarbonl3henpoplcarbamol) 2 -methvlbutvlcarbamoylibenzylcarbamate (Compound 289); N-r2-methy!-IS-(3pRhenl.
IS-benzooxazol- 2 :vicarbonylprovicarbamovI)butIiiieiine4carboxainide (Compound 290); N-r2-inethyl-IS-(3-phenvl-I S-benzooxazo-2-vicarbony~popvlcarbanov~buiy!1 3 -aininomethylbenzamide (Compound 291); benzvl 111 I-[ 4 2 -indol-3-ylethylcarbamoyloxazol-2.vlcarbonyll- 8 3 -hevprolcarbaniovj I--methylbulylcarbamate (Compound 292); MS (ESI) m/z 664 (M IH-NMR (300 MlHz, CDC1 3 B 0.94 (di, J 6 Hz, 6H), B 1.40 1.70 (mn, 6H1), B 2.00 (in, IH), B 2.25(m, 1ff), B 2.67 (mn, 2H), 8 3.09 (mn, 211), B 3.52 3.85 (mn, 211), B 4.20 (mn, 111), 8 5.09 2H), B 5.50 (mn, IH), B 6.80 J 6 Hz, JH), B 6.99 7.41(m, 1411), B 7.65 J 6 Hz, 1H), B 8.35 111), B 8.39 1H1), (C 3 sH 4 1
N
5 0 6 benzyl -f l-( 4 -methvlcarbamooxazol-2=vlcarbonvl).3Prhenvipr)ovcarbanoyll 3 -methylbutvlcarbainate (Compound 293); MS (ESI) ni/z 535 (M 'H-NMR (300 Mffz,
CDCY
3 B 0.95 J 6 Hz, 6H), B 1.33 1.70 (mn, 5H1), B 2.00 (mn, 1H), B 2.28 (in, IM), B 2.67 (in, 211), B 2.99 (di, J =2 Hz,,3H), B 4.15 (in, 1H), 6 5.09 (in, 211), B 5.50 (in, 111), B 6.88 (mn, 1H), 8 7.09 7.38 (in, 1011), B 8.35 1H), (CgHuN 4
O
6 benzyl 2-f 2 2 2 -benZyloxycarbonylamino-4methylvalerviainino)- 4 -iphenylbutvrlloxazol..2vlcarbonylainino I valerate (Compound 294); benzvl IS-IlS-J4-(4-benzylpiveridin. I-vlcarbonyl~oxazol-2-vlcarbon11..
3 -vhenvlvrOpvlcarbamov I -3-inethvlbutrvlcaraina-t (Compound 295); MS (ESI) m/z 679 (M 'H-NIMR (300 MiHz, CDCI 3 B 0.92 (mn, 61H), B 1.25 (in, IH), B 1.48 J =4Hz, 111), 6 1.52 1.85 (in, 611), B 2.09(m, 1H), B 2.36 (mn, 111), B 2.53 2.77 (in, 3H1), B 3.03 J =8 HIz, 411), B 4.19 (mn, 111), B 4.65 (mn, 1H1), B 5.02 5.13 (in, 311), B 5.53 (in, 1H), B 6.68 J 6 6Hz, 111), B 7.08 7.39 (mn, 15H1), B 8.28 1H1), (CQ 4 6N 4
O
6 benzyl is-rls-( 4 -fur2viethvcarbanovoxazol2lcarbonl)- 3-hn~roycraoil3mtybtlabmt (Compound 296); MS (ESI) mlz 601 (M 'H-NMR (300 MIHz, CDCI 3 B 0.98 (di, J 6HzU 611), B 1.58 J 6 Hz 111), 1.62 (mn, 41-1), 8 2.00 (mn, 111), B 2.27 (mn, 111), B 2.76 (in, 211), B 4.20 (nm, 111), B 4.70 J 4 Hz, 2H1), -134- 6 4.98 5.18 2H), 8 5.56 1H), 8 6.82 1H), 8 7.05 7.42 13H), 8 8.32 J 4 Hz, 1H), (C 33
H,
6
N.
7 benzvl 3 -methl-S-lS-(4-vriid-2-ymethylcarbamoyloxazol-2-vcarbon) 3 -phenvlproylcarbamoyllbutvlcarbamate (Compound 297); MS (ESI) n/z 612 (M 1); 'H-NMR (300 MHz, CDCI 3 8 0.98 J 6 Hz 6H), 8 1.4 2.15 5H), 8 2.32 11), 8 2.71 2H), 8 4.21 1H), 584.75 J 2 Hz, 2H), 8 5.09 2H), 8 5.15 5.5 IH), 8 7.10 7.38 13H), 5 7.7 J 4 Hz, 1H), 8 7.95 1H), 8 8.32 J 4 Hz, 1H), 8 8.59 IH), (C,H 37
N,O
6 benzvl 3-methyl-iS4 rlS-( 4 -nvrid- 3 -vlmetbvIcarbamoyoxazol -2-lvcarbonvl) 3 -Dhenvlpro~ylcarbamovllbuylcarbamate (Compound 298); MS (ESI) mlz'= 612 (M 1); 'H-NMR (300 MHz, CDCI 3 6 0.98 J 6 Hz 6H), 8 1.5 J= 4 Hz, 11), 8 1.65 211), 8 1.95 3H), 2.25 8 1H), 8 2.68 2H), 8 4.19 1H), 8 4.72 J 2 Hz, 2H), 8 5.09 2H), 6 5.41 1H), 8 6.90 J= 2 Hz, IH), 8 7.05 7.35 IOH), 8 7.46 1H), 8 7.72 J= 6 Hz, 1H), 8 8.31 J 4 Hz, IH), 8 8.62 J 4 Hz IH), 8 8.73 1H), (C3H 37
N
5
O
6 benzvl 3-methyl-IS4 lS-(4-pvrid -4-vmethvlcarbamoyloxazoI2vcarbnvI) 3 -ohenvnropylcarbamollbutvlcarbamate (Compound 299); MS (ESI) m/z 612 (M 1); 'H-NMR (300 MHz, CDC1 3 8 0.98 J 6 Hz, 6f), 8 1.5 J 4 Hz, 1H), 1.65 2H), 1.95 311), 2.25 1H), 2.68 2H), 4.19 11), 4.72 J 2 Hz, 2H), 5.11 J= 4 Hz, 21), 5.43 1H), 6.92 J= 6 Hz, 1H), 7.05 7.35 11H), 7.46 11), 8.33 J 4 Hz, 1H), 8.58 2H), (CH 3
,N
5 benzyl S-f 1-r 4 2 -chlorobenzvIcarbamol)oxazol-2.ylcarbonylk 3 -ohenylpropylcarbaiovl )-3-methylbutylcarbamate (Compound 300); MS (ESI) m/z 646 (M 'H-NMR (300 MHz, CDCl 3 8 0.98 J 6 Hz, 611), 8 1.5 J 4 Hz, 11), 8 1.62 (m, 4H), 1.95 8 11), 8 2.30 11), 8 2.65 2H), 8 4.19 8 4.70 J 2 Hz, 2H), 8 5.09 2H), 8 5.47 1H), 8 6.82 11) 8 7.05 7.45 14H), 8 8.33 J 4 Hz, 1),
(C
35
H
37 C1N 4 0 6 benzyl S-1 LS-f 4 3 -chlorobenzvlcarbamoyl)oxazol-2-lcarbonll.
3-nhenvhlronylcarbaiovl 3 -methvlbutvlcarbamate (Compound 301); MS (ESI) m/z 646 (M 'H-NMR (300 Mlz, CDCI):8 0.98 J 6 Hz, 6H), 6 1.5 J =4 Hz, 1H), 6 1.62 41), 8 2.00 IH), 8 2.25 IH), 8 2.65 2H), 8 4.20 1H), 8 4.68 J 2 Hz, 2H), 6 5.09 21), 8 5.43 111), 8 6.85 J 6 Hz, 1H), 8 7.05 7.45 14H), 8 8.33 -135- J 4 Hz, 1H), (C 35
H
37
CIN
4 0 6 benzvl IS-f 1S-4-(4-chlorobenzvlcarbamol)oxazol-2-ylcarbonylj 3-Dhenlprpylcarbamovl -3-ethylbutylcarbamate (Compound 302); MS (ESI) m/z 646 (M 'H-NMR (300 MHz, CDCI 3 6 0.98 J 6 Hz, 6H), 5 1.5 J 4 Hz, 6 1.62 (m, 4H), 6 2.00 11), 6 2.25 11), 8 2.65 21), 8 4.20 11), 8 4.68 J 2 Hz, 211), 8 5.09 211), 6 5.43 1H), 8 6.85 11), 8 7.05 7.45 14H), 6 8.33 J 4 Hz, 1H), 37
CIN
4
Q
6 benzvl 3-methyl-IS-i IS-r4-(2S-phenvlcvclopro-IS-vlcarbamovl)oxazol-2-ylcarbonyll.
3-phenylpronylcarbamoyl 1-3-iethylbutylcarbaiate (Compound 303); MS (ESI) i/z 637 (M 'H-NMR (300 MHz, CDCI): 6 0.92 J 6 Hz, 6H), 6 1.46 1.78 6H), 6 2.00 (m, 3H), 6 2.31 IH), 62.67 2H), 6 2.99 3.22 11), 8 4.20 1H), 65.04 J 6 Hz, 11), 8 5.11 2H), 65.54 1H), 6 6.87 11), 8 7.08 7.47 151), 8 8.30 J 2 Hz, IH), (C 37 H4ON 4
Q
6 benzyl 3-methyl-IS-f 1S-( 4 -diphenvlmethvliethvlcarbamoyloxazol-2-ylcarbonyl) 3 -phenvlpropylcarbamoyll-3-methlbutvlcarbamate (Compound 304); MS (ESI) m/z 687 (M 'H-NMR (300 MHz, CDCI,): 8 0.98 J= 6 Hz, 6H), 6 1.48 J 4Hz, 6 1.62 (m, 211), 8 2.00 11), 8 2.30 11), 8 2.67 21), 84.18 11), 65.09 31), 6 5.43 (m, 1H), 8 6.42 J 6 Hz, 1H), 6 6.80 J 6Hz, 11), 67.02 7.72 20H), 6 7.79 J 6 Hz, 1H), 6 8.33 J 4 Hz, 1H), (C 41
H
42
N
4 0 6 benzvl 1S-[1S-(4-adamantan-1 -vlmethvlcarbamoloxazoI-2-ycarbonyi)- 3 -vhenylropvycarbamoyll-3.methylbutvlcarbamate (Compound 305); MS (ESI) i/z 670 (M 'H-NMR (300 MHz, CDC1 3 6 0.92 8H), 6 1.18 1.78 161), 8 2.00 1H), 6 2.31 1H), 62.67 21), 62.99- 3.09 21), 64.21 11), 65.11 31), 6 5.51. 1H), 8 6.87 11), 6 7.02 11), 6 7.08 7.47 1OH), 8 8.31 J 2 Hz, 11), (C39H 4 gN 4
O
6 benzvl 1-I I-r4-(1-methvlethlcarbamovl)oxazol-2ylcarbonyll.
3 -nhenylropylcarbamoyl 1-3-methylbutvlcarbamate (Compound 306); benzvI i-f I 4 -(1S-phenvyethvlcarbamoyl)oxazol-2-vcarbonyIl 3 -phenvlnrolcarbaroyl 1-3-methylbutylcarbamate (Compound 307); MS (ESI) m/z 625 CM 'H-NMR (300 MHz, CDC1 3 8 0.92 J 6 Hz, 61), 8 1.54 1.65 71), 6 2.00 (m, 11), 8 2.25 1H), 6 2.65 Cm, 211), 8 4.15 11), 64.99 J 2 Hz, 11), 6 5.09 Cs, 21), 8 5.32 (in, 111), 6 5.43 11), 6 6.79 J 6 Hz, 11), 6 7.05 7.45 Cm, 15H), 6 8.31 Cs, 11),
(C
36 H4ON 4
O
6 -136benzvl 1-I 1R-henvlethvlcarbamovi)oxazo-2-ylcarbony1- 3-phenylpropylcarbamoyl 1-3-methylbutvlcarbamate (Compound 308); MS (ESI) m/z 625 (M 'H-NMR (300 MHz, CDC1 3 6 0.92 J 6 Hz, 6H), 8 1.45 1.68 7H), 8 2.00 (m, 1H), 8 2.25 11), 5 2.65 2H), 8 4.15 11), 5 4.99 J 2 Hz, 1H), 8 5.09 2H), 855.32 11), 5 5.43 1H), 5 6.79 J 6 Hz, 5 1H), 5 7.05 7.45 15H), 5 8.31 (s, 1H), (C 36 H4ON 4
O
6 benzvl 1- 1-r-(N-benzvl-N-methylcarbamovl)oxazol 2yvlcarbonyll- 3-ohenvlproylcarbarnovl 1-3-methylbutylcarbamate (Compound 309); MS (ESI) m/z 625 (M 'H-NMR (300 MHz, CDCI,): S50.90 J 6 Hz, 6H), 8 1.27 1.68 4H), 8 2.00 (m, 1H), 82.25 11), 5 2.65 2H), 5 3.10 1H), 54.19 1H), 54.71'(s, 2H), 5 5.09 (s, 2H), 5 5.22 1H), 8 5.43 1H), 8 6.99 J 6 Hz, 1H), 5 7.05 7.45 15H), 5 7.60 (m, 1H), 8 8.31 1H), (C 36 H4N 4
O
6 benzvl I-l-(4-pvrrolidin-1-yicarbonvioxazoI-2-ylcarbonyI)-3-Thenylpronyicarbanoyll 3-methylbutvlcarbamate (Compound 310); MS (ESI) m/z 575 (M 'H-NMR (300 MHz,
CDCI
3 50.93 J 6 Hz, 6H), 5 1.45 1.73 3H), 8 1.85 2.12 511), 5 2.34 1H), 2.64 2H), 8 3.62 J 4 Hz, 2H), 5 3.82 211), 5 4.21 IH), 4.99 5.11 2H), 8 5.55 1H), 5 5.43 11), 8 6.79 1H), 5 7.05 7.45 10H), 5 8.31 J 2Hz, 1H),
(C
32
H
3 8
N
4
Q
6 benzvl 1-rl-(4-piperidin--ylcarbonyioxazol-2-vlcarbonyl)-3-nhenylnrpvlcarbamoyll 3-methvlbutvlcarbamate (Compound 311); MS (ESI) nz 589 CM 'H-NMR (300 MHz, CDC1 3 5 0.90 J 6 Hz, 6H), 8 1.25 211), 8 1.49 1.66 6H), 8 2.12 11), 5 2.34 Cm, 1H), 52.64 2H), 53.65 Cm, 2H), 53.85 211), 54.17 11), 84.99-5.11(m, 3H), 8 5.55 Cm, 11), 8 6.67 1H), 5 7.08 7.39 111), 5 8.27 1H), (C 33
H,N
4
O
6 benzvl 1-f 1-F4-(2,3-dihydroindol-1-vlcarbonvl)oxazol-2-ylcarbonvll- 3 -nhenvlprovlcarbaioqyl 1-3-nethylbutvlcarbamate (Compound 312); benzvl 1-Il -f 4 3 4 -dihdro-1H-isoauinol-2-ylcarbonyl)oxazol-2-ylcarbonyllw 3-phenvlpropylcarbamoyj -3-methylbutvlcarbamate (Compound 313); MS (ESI) m/z 637 (M 'H-NMR (300 MHz, CDC1 3 850.90 J 6 Hz, 6H), 8 1.25 2H), 5 1.45 1.79 (m, 41, 5 2.11 11), 5 2.40 11), 8 2.68 2H), 5 2.95 J 4 Hz, 211), 5 3.96 J 4 Hz, 1H), 54.15 Cm, 2H), S 4.86 3 6 Hz, 1H), 54.99 -5.11 3H), 5 5.59 11), 56.70 11), 5 7.05 7.45 1211), 5 8.35 1H), (C 3
,HJN
4
O
6 benzvl -f 1-F4-(3.4-dihydro-2H-guinol-l-vlcarbonyl)oxazol-2-ylcarbonyll- -137- 3-phenvinroivicarbamoyl 1-3-methvlbutvlcarbamate (Compound 314); MS (ESI) m/z 637 (M 'H-NMR (300 MHz, CDCI 3 8 0.90 J 6 Hz, 6H), 8 1.25 2H), 8 1.40 1.69 (m, 3H), 8 2.05 2H), 8 2.52 J 6 Hz, 2H), 8 2.82 J 4 Hz, 2H), 8 3.80 4.21 4H), 4.86 J 6 Hz, 1H), 855.09 2H), 8 5.21 IH), 8 6.62 11), 8 6.85 7.31 11H), 87.51 111), 8 7.67 1H), 8 8.31 1H), (C 37 H4N 4
O
6 benzal I-ri-(4-naphth-1-vmethlcarbamovloxazol-2-vlcarbonyfl 3 -pbenyliropvlcarbamoll-3-methlbuylcarbamate (Compound 315); MS (ESI) i/z 661 (M 'H-NMR (300 MHz, CDCI 3 6 0.90 J 6 Hz, 6H), 8 1.25 2H), 8 1.54 3H), 2.05 11), 5 2.59 J 6 Hz, 1H), 852.82 J 4 Hz, 2H), 5 4.12 11), 5 4.90 5.09 4H), 5 5.34 11), 8 6.71 IH), 56.95 7.12 3H), 8 7.27 1OH), 5 7.51(m, 2H), 8 7.88 J 6Hz, 1H), 5 8.06 J 6 Hz, JH), 8 8.35 1H), (C3 HiNO 6 tert-butMl 44 lS-(S-benzooxazo-2-vlcarbonvl)a.3-henvpropycarbam6y]) 2-cvclohexvlethvcarbamovllpipidine-l-carboxylate (Compound 316); IS-f 1S-r4-(3.4-dihvdro-2H-puinol. -lcarbonvloxazol-2-vlcarbonyll-ethylcarbamovl1- 3-metbvlbutvlcarbamate (Compound 317); benzvl 3 -methyI-1S-1S-(5henyoxazol-2-ycarjny)- 3 -phenvlpropvlcarbamovllbutvlcarbamate (Compound 318); MS (ESI) m/z 554 (M 1); 'H-NMR (300 MHz, CDC1 3 5 0.97 J 4 Hz, 6H), 5 1.50 J 4 Hz, 11), 5 1.65 1.82 3H), 5 2.20 11), 5 2.48 11), 5 2.75 J 4 Hz, 2H), 5 4.27 11), 8 5.09 2H), 5 5.65 1H), 5 6.85 J 6Hz, 11), 5 7.12 7.62 14H), 8 7. 77 J 2 Hz, 2H), (C3H 3 5
IN
3
O
5 pyrid-3-yI 3 -methy-1S-fS-(5-phenloxazol-2-vicarbonvi) 3 -phenvlroovlcabamollbulcarbamate (Compound 319); MS (ESI) i/z 525 (M 1); 'H-NMR (300 MHz, CDCI,): 5 0.80 1.05 6H), 8 1.27 3H), 8 1.72 3H), 5 2.15 (m, 1H), 5 2.46 11), 5 2.77 i 4 Hz, 2H), 854.75 1H), 8 5.65 IH), 5 6.95 J 4Hz, 1H), 8 7.02 J 4Hz, 1H), 5 7.09 7.35 5H), 5 7.37 7.62 3H), 8 7.80 J 4 Hz, 1H), 8 8.15 J 6Hz, 11), 8.75 (im, IH), 8 9.09 1H), (C 3 1
H
3 2
N
4 0 4 benzvl 1S-rl S-(5phenloxazol-2-yvcarbonvl)- 3 -nhenvipropvisufamovlmethv.2RmethlbuWiycarbanate (Compound 320); MS (ESI) miz 604 (M 'H-NMR (300 MHz, CDCI 3 50.95 61), 5 1.25 11), 5 1.49 111), 1.65 5 2.15 1H), 5 2.48 11), 5 2.85 21), 5 3.12 21), 5 4.46 11), 54.99 J 8Hz, 1H), 6 5.12 31), 5 6.32 J 6Hz, 11), 5 7.19 7.55 14H), 5 7.76 -138- 211), (C 33
H
3 7N 3 0 6
S);
benzyl 3-methyl-i-f 2-hydroxy- 1 -phenethyl- 2-[4-(3-phenvlvropv~carbamovl)oxazol-2-yllethvlcarbamovl }butvlcarbamate (Compound 321); benzy] 1-I 2-hydroxy-2-[4-(2-indol-3-yethylcarbamol)oxazol-2-yll- 1-nhenethylethylcarbamoyl 1-3-methylbulylcarbamate (Compound 322); MS (ESI) ni/z 666 (M IH-NMR (300 Mfh, CDCI 3 6 0.90 J 6 Hz, 6H1), 8 1.40 1.80 (in, 6H), 8 2.00 (in, 111), 8 2.67 (in, 2H), 8 3.09 (in, 2H1), 8 3.52 3.85 (in, 211), 8 3.99 4.20 (in, 211), S54.26 4.44 (mn, 1H), 8 4.81 111), 8 5.09 2H1), 5 5.50 (in, 111), 8 6.72 (di, J 6 Hz, 1H1), 8 6.99 -7.41 (in, 14H), 8 8.18 111), 8 8.39 1H1), (C,H 4
NO
6 benzvl 3-methyl- I -r2-hydroxy-2-(4-methvlcarbamovloxazol-2-yl)- I-lphenethylethylcarbamovllbutvlcarbainate (Compound 323); MS (ESI) in/z 537 (M 1); '11-NMR (300 MHz, CDC1 3 80.90 (di, J 6 Hz, 6H), 8 1.33 1.80 (in, 611), 8 2.00 (in, 111), 8 2.67 (in, 211), 2.89 (in, 311), 8 4. 10 (mn, 111), 8 4.25 (in, 111), 8 4.81 111), 8 5.09 (mn, 31-1), 8 6.68 J 4 Hz, 1H1), 5 7.09 7.38 (in, 1011), 8 8.18 111), (C29H 3 6
N
4
O
6 benzyl 2-f 2-[2-(2-benzyloxycarbonylamino-4-nethylvalervlamino)-I -hydroxy- 4-phenvlbutvlloxazol-2-vlcarbonylamino Ivalerate (Compound 324); MS (ESI) in/z 727 (M 'H-NMR (300 MIz, CDCI,): 8 0.95 12H), 8 1.45 1.80 (in, 911), 8 2.00 (in, 111), 8 2.67 (in, 2H1), 8 3.99 4.15 (in, 211), 8 4.85 (mn, 211), 8 5.09 (in, 411), 8 5.50 (in, 111), 8 6.88 (mn, 111), 8 7.12 7.45 (mn, 1511), 8 8.18 111), (C 4
,HON
4
O
8 benzy] is-f 2-[4-(4-benzvlpiperidin-1 -ylcarbonyl)oxazoJ-2-yll-2-hydroxy- 1S-phenethylethylcarbainoyl 1-3-methvlbutvlcarbamate (Compound 325); benzyl IS-r2-(4-fur-2ylnethylcarbanoloxazol-2-I)-2-hydroxy- IS-phenethylethylcarbamoyll-3-methylbutylcarbamate (Compound 326); benzyl 3-methyl-1S-[2-hydroxy- 1S-Rhenethyl- 2 4 -pyrid-2-ylmethylcarbamoyloxazol-2-yI)ethylcarbamoylbutylcarbamate (Compound 327); benzyl 3-methl-IS-[2-hydroxy- 1S-phenethyl- 2 4 -pyrid-3-ylmethylcarbainoyloxazol-2-yl)ethylcarbampyllbutvlcarbamate (Compound 328); benzvl 3-nethyl-IS-r2-hydroxy- 1S-phenethyl- 2 4 -D~yid- 4 -yinethylcarbanoyloxazol-2-y])ethylcarbamoyllbutylcarbamate (Compound 329); benzyl 3-methyl .1S-f 2-r4-(2-chlorobenzylcarbamoylnoxazol-2-yll-2-hyiroxy- 1S-phenethylethylcarbainoyl lbutylcarbamate (Compound 330); benzyl 3-methyl-IS-i 2-r4-(3-chlorobenzvlcarbamoyl)oxazol-2-yll-2-hydroxy- -139- IS-Rhenethylethylcarbamoyl Ibutvlcarbamate (Compound 331); benzvl 3-methyl-IS-f 2 4 -chlorobenzvlcarbamoyl)oxazo-2yl12-hydroxy- IS-phenethylethylcarbamoyl lbutvlcarbamate (Compound 332); benzyl 3-methyl- IS- f 2-hydroxy- I -Rhenethyl- 2 4 2 R-phenylcyclopmRo-IS-ylcarbamoyl)oxazol-2yllethlcarbamovl Ibutylcarbamate (Compound 333); bengvl IS-r 2 4 -adamantan-1-ylmethylcarbamoyloxazol-2yl) 2-hydroxy-methyl)- 1S-n~henethylethvlcarbamyl-3-metlbutvicarbamat-e (Compound 334); benzyl 3 -methl-IS- 2 -hydroxy-IS-r2henethyl-2-4-diphenylmethylcarbamovloxazol- 2 -vl)ethvlcarbamoyllbutylcarbamate (Compound 335); benzyl 3-methyl-I-f 2 -hvdroxv-2-f4-(1-methylethylcarbamol)oxazol-2yll.
l-vhenethylethylcarbamoyl lbutvlcarbamate (Compound 336); benzvl 3-methyl-I-f 2-hydroxy-1 -nhenethyl- 2 -r 4 -(lS-phenvlethylcarbamoyl)oxazol-2yllethylcarbamoyl Ibutylcarbamate (Compound 337); benzyl 3-methyl-I -12-hydroxy-l-yhenethyl- 2 -f 4 -(IR-nhenlethylcarbamgy)oxazol.2.ylethylcarbamoy Ibutylcarbamate (Compound 338); benzvl 3-methyl-i -I 2 -f 4 -(N-benzvl-N-methylcarbamoyl)oxazol-2yllj2hydroxy.
1-phenethylethylcarbamoyl lbutvlcarbamate (Compound 339); benzyl 3-methyl-I -[2-hydroxy-1 -phenethyl- 2-(4-pyrrolidin- 1 -lcarbonyloxazol-2-yl)ethylcarbamoyllbutylcarbamate (Compound 340); benzyl 3-methyl--2-hydroxy-l1-phenethyl- 2 4 -nip~eri din-1I-ylcarbonyloxazol-2-yl)ethylcarbamoyllbutlcarbamate (Compound 341); benzvl 3-methyl-I-f 2-I'4-(2.3-dihydroindol-1I-ylcarbony1)oxazol-2-yrl-2-hydroxy- I -phenethylethylcarbamoyl lbutylcarbamate (Compound 342); .benzvl 3-methyl-I-f 2 4 3 A4dihydro-IH-isgguinol-2-ycarbon)oxazol2yl-2-hydroxy- I -nhenethylethylcarbarnoyl lbutvlcarbamate (Compound 343); benzyl 3-methyl-i-f 2 4 3 4 -dihydro-IH-auinol-1-ylcarbonyl)oxazol-2yl1.2-hydroxy.
I -phenethylethylcarbamgy] I butvlcarbamate (Compound 344); benzy] 3-methyl-I 2 -hydroxy-2-(4-naphth-1-ylmethylcarbonyoxazol-2-y) I:hnty hlabaolbilabmt (Compound 345); and benzyl IS-f 2-f4-(3.4-dihydro-2H-ouino 1 -ylcarbonyl)oxazol-2-vll-2-hydroxy- MS-methylethylcarbarnoyl 1-3-niethylbutylcarbamate (Compound 346).
-140- Proceeding by methods analogous to those described above provided the following compounds of Formula 1: N-f 3-methyl- lS-(IS-thiazol-2-lcarbonyethycarbamoyl)butyll.
4-moroholin4-ylbenzamide (Compound 347); and N-F IS-(2-benzooxazol-2-vl.. 1-dimethyl-2-oxoethylcarbamoyl)-3met hvlbutv] 4-(4-methylpiperaz in-I- -l)benzamide (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 I -141- -142- -143- -144- -145- -146- -147- -148- -149- -150- HO0 0 N 0 0 N I H 0 A46 B46 e 0 =S H 0 A47 0 'd
F*
I I 0 1- -152- -153-
-155- -156- -157- -158- -159- -160- A107 0 0 D107* (fSN A108 D108 A109 0 0 D109 0 CBr 0 0 DI 1 XcI A13 00
DII
A14 )0~~JsO D114 \0uI -161- Al115 n 0 'Nit s s DI 15 -r i A116 00 qlr D1 16 0 9L~ 0
H
A117 00 Br DI 17 Al 18 Al 9 A120 0 0
H
0 DII18
H
D1 19
H
D120
N
A121 D121
H
A122 700 T I I D122
H
-162- -163- 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 Al l-B5-C4-Dl A128-B5-.C4-Dl A75-B6-C4-Dl A66-B8-C4-DI A17-B 12-C4-DI All-B ll-C4-DI A128-Bl l-C4-DI A75-B14-C4-Dl A66-B5-C4-D2 A17-B6-C4-D2 Al l-B8-C4-D2 A17-BS-C4-D1 Al l-B6-C4-D1 A128-B6-C4-Dl A75-B8-C4-D1 A66-B12-C4-Dl A17-BI l-C4-Dl Al 1-B14-C4-Dl Al 28-B 14-C4-D I A75-B5-C4-D2 A66-B6-C4-D2 A17-B8-C4-D2 A66-B5-C4-Dl A17-B6-C4-DI Al l-B8-C4-D1 A128-B8-C4-Dl A75-B 12-C4-D1 A66-B 1 -C4-DI A17-B14-C4-D1 Al I-B5-C4-D2 A128-B5-C4-D2 A75-B6-C4-D2 A66-B8-C4-D2 A75-B5-C4-D1 A66-B6-C4-Dl A17-B8-C4-Dl A11-Bl2-C4-DI A128-B12-C4-DI A75-B 1 1C4-Dl A66-B14-C4-D1 A17-B5-C4-D2 Al I-B&-4D A128-B6-C4-D2 A75-B8-C4-D2 -164- A128-B8-C4-D2 12-C4-D2 A66-BI 1-C4-D2 A17-B 14-C4-D2 A61-BS-C4-DI A90-B5-C4-DI A64-B6-C4-Dl A92-B6-C4-DI A37-B12-C4-DI Al33-B12-C4-Dl Al l-B31-C4-Dl A75-B13-C4-DI A128-B21-C4--DI Al 1-B49-C4-Dl A75-B50-C4-DI A128-B51-C4-DI Al l-B53-C4-DI Al 1-B5-C36-DI A75-B6-C36-DI A128-B 12-C36-DI All-B6-CII-DI 12-Cl 1-DI A128-B5-CIO-DI Al l-B12-CIO-DI A75-B5-C35-DI A128-B6-C35-DI Al l-B5-C4-D33 A75-B6-C4-D33 A128-B12-C4-D33 Al1I-B6-C4-D83 A75-B12-C4-D83 A128-B5-C4-D86 All1-B12-C4-D2 A128-Bl2-C4-D2 A75-BI l-C4-D2 A66-B14-C4-D2 A64-B5-C4-DI A92-B5-C4-D1 A37-B6-C4-DI A133-B6-C4-DI A38-B12-C4-DI A75-B31-C4-Dl- A128-B13-C4-DI Al l-B46-C4-Dl A75-B49-C4-DI A128-B50-C4-DI Al l-B52-C4-Dl A75-B53-C4-DI A75-B5-C36-Dl A128-B6-C36-DI Al l-B5-CI 1-DI A75-B6-Cl 1-DI A128-B12-CI 1-DI Al l-B6-CIO-Dl A75-B12-CIO-Dl Al28-B5-C35-DI Al1-B 12-C35-DI A75-B5-C4-D33 A128-B6-C4-D33 Al l-B5-C4-D83 A75-B6-C4-D83 A128-B12-C4-D83 Al l-B6-C4-D86 A17-B 12-C4-D2 Al 1-B 1 -C4-D2 A128-BlI-C4-D2 A75-B14-C4-D2 A37-B5-C4-DI A133-B5-C4-DI A38-B6-C4-DI A61-B12-C4-DI A90-B 12-C4-DI A128-B31-C4-DI Al l-B11-C4-DI A75-B46-C4-DI A128-B49-C4-Dl Al l-B51-C4-DI A75-B52-C4-Dl A128-B53-C4-DI A128-B5-C36-DI Al I-B12-C36-Dl A75-B5-Cl 1-DI A128-B6-Cl l-Dl Al l-B5-ClO-Dl A75-B6-CIO-DI A128-B12-CIO-DI Al l-B6-C35-DI A75-B 12-C35-DI A128-B5-C4-D33 Al1-B 12-C4-D33 A75-B5-C4-D83 A128-B6-C4-D83 Al l-B5-C4-D86 A75-B6-C4-D86 A66-B12-C4-D2 A 17-B 1 -C4-D2 Al 1-B 14-C4-D2 A128-B 14-C4-D2 A38-B5-C4-DI A61-B6-C4-DI A90-B6-C4-D] A64-B12-C4-DI A92-B 12-C4-DI All-B 13-C4-DI A75-B21-C4-Dl A128-B46-C4-Dl Al l-B50-C4-Dl A75-B51-C4-Dl A128-B52-C4-DI Al l-B6-C36-DI A75-Bl2-C36-Dl A128-B5-Cl l-DI All-B12-CII-DI A75-B5-CIO-DI A128-B6-CIO-DI Al l-B5-C35-Dl A75-B6-C35-DI A128-B12-C35-DI Al l-B6-C4-D33 A75-B12-C4-D33 A128-B5-C4-D83 Al1-B 12-C4-D83 A75-B5-C4-D86 A128-B6-C4-D86 All-B12-C4-D86 A75-B12-C4-D86 A128-B12-C4-D86 All-B5-C4-D123 A75-B5-C4-D123 A128-B5-C4-D123 AII-B6-C4-D123 A75-B6-C4-D123 A128-B6-C4-D123 All-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 pL of dimethyl sulfoxide (DMSO) and then diluted into assay buffer (40 pL, comprising: N,N-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 pL 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 AL of assay buffer) was added to the assay solutions and hydrolysis was followed spectrophotometrically at ,460 nm) for 5 minutes.
Apparent inhibition constants 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 KI of less than or equal to 10 AM.
EXAMPLE 29 Cathepsin K Assay Solutions of test compounds in varying concentrations were prepared in 10 L of dimethyl sulfoxide (DMSO) and then diluted into assay buffer (40 pL, comprising: MES, 50 mM (pH EDTA, 2.5 mM; and DTT, 2.5 mM). Human cathepsin K (0.0906 pMoles in 25 pL 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 pL of assay buffer) was added to the assay solutions and hydrolysis was followed spectrophotometrically at (X 460 nm) for 5 minutes. Apparent inhibition constants 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 -166exhibit cathepsin K inhibitory activity with a KI of less than or equal to 10 uM.
EXAMPLE Cathepsin L Assay Solutions of test compounds in varying concentrations were prepared in 10 JL of dimethyl sulfoxide (DMSO) and then diluted into assay buffer (40 pL, comprising: MES, 50 mM (pH EDTA, 2.5 mM; and DTT, 2.5 mM). Human cathepsin L (0.05 pMoles in 25 pL 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 pL of assay buffer) was added to the assay solutions and hydrolysis was followed spectrophotometrically at 460 nm) for 5 minutes. Apparent inhibition constants (K 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 K, of less than or equal to 10 jM.
EXAMPLE 31 Cathepsin S Assay Solutions of test compounds in varying concentrations were prepared in 10 IL of dimethyl sulfoxide (DMSO) and then diluted into assay buffer (40 tL, comprising: MES, 50 mM (pH EDTA, 2.5 mM; and NaCI, 100 mM). Human cathepsin S (0.158 pMoles in 25 IL 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 fL of assay buffer) was added to the assay solutions and hydrolysis was followed spectrophotometrically at X 460 nm) for 5 minutes. Apparent inhibition constants 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 KI of less than or equal to 10 pM.
EXAMPLE 32 Ovalbumin Challenge Mouse.
-167- C57 mice (female) were sensitised with ovalbumin (10lg, administered together with aluminium hydroxide adjuvant (20 mg, 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.
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 pm 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 antiinflammatory effect on vascular and mucosal beds after treatment with compounds of the invention between 0.03 and 30 mg/kg.
-168- EXAMPLE 32 Representative Pharmaceutical Formulations Containing a Compound of Formula I ORAL FORMULATION Compound of Formula I Citric Acid Monohydrate Sodium Hydroxide Flavoring Water INTRAVENOUS FORMULATION Compound of Formula I Dextrose Monohydrate Citric Acid Monohydrate Sodium Hydroxide Water for Injection TABLET FORMULATION Compound of Formula I Microcrystalline Cellulose Stearic Acid Colloidal Silica 10-100 mg 105 mg 18 mg q.s. to 100 mL 0.1-10 mg q.s. to make isotonic 1.05 mg 0.18 mg q.s. to 1.0 mL 1% 73% 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.
-169-
Claims (12)
1. A compound of Formula I: R 2 R 5 R 6 RK 2 N^^K R 7 SR 3 4 R(R) 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 to 7 ring member atoms, X' is a ring member carbon atom and each ring member atom other than X' is a carbon atom or a heteroatom, with the proviso that 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' is or -CH-; X 2 is a bond or a divalent group of Formula or Rl R12 R 10 R RR 12 1 4 R RR R 3 R 9 (b) wherein: X 3 and X 4 independently are or -CHS(O) R 9 and R' i independently are hydrogen, (C,.)alkyl or as defined below; R" at each occurrence independently is hydrogen or (C. 6 )alkyl; R 1 2 and R" independently are (C, 4 )alkyl optionally substituted with cyano, halo, nitro, -NR' 4 R' 4 -NR 1 4 C(O)OR 1 4 -NR 1 4 C(O)NR 1 4 R" 1 -NR'C(NR 4 )NRI 4 R 4 -OR 1 4 -SR' 4 -C(O)OR' 4 -C(O)NR 1 4 R 1 4 -S(0)2NR' 4 R 1 4 -P(0)(OR' 4 )OR' 4 -OP(O)(OR'4)OR", -NR' 1 C(O)R' 5 -S(O)R Is -S(O),R I5 -C(O)R 1 5 -OR 16 -SR 1 6 -170- -S(O)R 1 6 -S(O) 2 R 1 6 -C(Q)R 16 -C(Q)OR 1 6 -QC(O)R 1 6 -NR1 6 R1 7 -NR 17 C(O)R 1 6 -NR17C(O)QR 1 6 -C(O)NR 1R' 7 _S(O) 2 NR16R 7 -NR' 7 G(O)NR 6 R 7 or -NR1 7 C(NR 7 )NR1 6 R 1 7 wherein R' 4 at each occurrence independently is hydrogen, (C 1 4 6)alkyl or halo-substituted 3 )alkyl, R1 5 is (CI-6)alkyl or halo-substituted (C, 13 )alkyl, halo, (C, 14 )alkyl or R 1 is (C J 2 cycloalkyl(C.)alkyl, hetero(C,,)cycloalkyl(C 6 )alkyl, (C,,)aryl(C,)alkyl, hetero(C,,,)aryl(C,,)alky1, (C9, 1 )polycycloaryl(C,6)alkyl or hetero(C, 2 2 )polycycloaryl(C.)alkyl and R1 7 is hydrogen or (C 1 -6)alkyl, and wherein within R 1 6 said cycloalkyl, heterocycloalkyl, aryl, heteroaryl, polycycloaryl or heterpolycycloaryl ring optionally is substituted by a group selected from -R" 8 -XIOR' 8 -X 5 SR' 8 -X 5 S(O)R' 8 -XIS(Q) 2 R 8 :X5C(O)R]8, -X 5 C(O)OR' 8 -X 5 OC(O)R' 8 -XsNR18Rl 9 -X 5 NR' 9 C(O)RW 8 -X 5 NR' 9 C(O)OR 8 -X 5 C(O)NR1 8 R' 9 -X 5 S(O) 2 NR'R 9 -X 5 NR1 9 C(O)NR' 8 R' 9 or -X 5 NR1 9 C(NR 9 )NRI 8 RII, wherein X 5 is a bond or (C,,)alkylene, R'8 is hydrogen or (C 14 ,)alkyl and R"9 is (C~ 1 2 cycloalkyl(C 0 ,)alkyl, hetero(q. 1 2 ,)cycloalkyI(C .)alkyl, (CQ 12 )aryl(CO-)alkyl,. hetero(C_ 1 ,)aryl(C,,)alkyl, (C7,_ 2 )polycycloaryl(C.)alkyl or hetero(Cg- 12 )polycycloaryl(CO4)alkyl, or (ii) a group selected from (CQ, 1 2 )cycloalkyl(C.)alkyl, hetero(C3-,)cycloalkyl(C: )alkyl, (C6. 12 )ay(C4)alkyl, (C 9 12 )polycycloaryl(C 0 4 6)alkyl and hetero(Cs-, 2 )polycycloaryl(C ,)alkyl, wherein said cycloalkyl, heterocycloalkyl, aryl, heteroaryl, polycycloaryl or heterpolycycloaryl ring optionally is substituted by a group selected from -X 5 ORI 8 -XsSRls, -X 5 S(O)R' 8 -X 5 S(O),RI 8 -X 5 C(O)R' 8 -X 5 C(O)QR' 8 -X 5 OC(O)RI 8 -X 5 NR 18 R 19 -X 5 NR' 9 C(Q)R' 8 -X 5 NR1 9 C(O)OR' 8 -X 5 C(Q)NR' 8 R 9 -X 5 S(O) 2 NR 8 R 19 -XsNR1 9 C(O)NR' 8 R' 9 or -X 5 NR' 9 C(NRI 9 )NR 3 RI 9 wherein X 5 R1 8 and R1 9 are as defined above; wherein within R 1 2 and/or R 1 3 any alicyclic or aromatic ring system present may be substituted further by 1 to 5 radicals independently selected from (C,.)alkyl, (C 1 6 alkylidene, cyano, halo, halo-substituted (C, 4 )alkyl, nitro, -X 5 NR' 4 -X-NR 4 C(O)OR' 4 -X 5 NR' 4 C(O)NR1 4 _X 5 NR14C(NR 4 )NR 4 R 4 -X 5 OR 1 4 -X 5 SR 1 4 -X 5 C(O)OR' 4 -X 5 C(O)NR1 4 R] 4 _XSS(O) 2 NR1 4 R 4 -X'P(O)(OR 1 4 )OR 1 4 -X 5 OP(O)(OR1 4 )OR 1 4 _X 5 NR1 4 C(O)RII, -X 5 S(O)R' 5 -X 5 S(O) 2 R 1 5 and -X 5 C(O)RI 5 wherein X 5 R 1 4 and R1 are as defined above; or R' 2 together with R 9 and/or R 1 3 together with RIO form triniethylene, -17 1- tetraniethylene or phenylene-l ,2-dimethylene, optionally substituted with 1 to 3 radicals independently selected from (C,,)alky1, (C,,)alkylidene, cyano, halo, halo-substituted 4 )alkyl, nitro, oxo, -X 5 NR"IC(O)OR', -X 5 NR1 4 C(O)NR 4 RI', -XsNR 4 C(NR- 4 )NR 1 4 R1 4 -X 5 0R 1 4 -X 5 SR 1 4 -X 5 C(O)QR 1 4 _X 5 C(O)NR1 4 R1 4 _XIS(O) 2 NR1 4 RI 4 -X'P(O)(OR 1 4 )OR1', -X 5 OP(O)(QR' 4 )OR'1 4 _XsNRl 4 C(Q)RzS, _XsS(O)RlS, -X 5 S(O) 2 R 1 and -X 5 C(O)RII, wherein XI, R 1 4 and R" 5 are as defined above; and RI is -X 6 X 7 R2', wherein V 6 is or -S(0) 2 XI is a bond, or -NR 2 1 where in R 2 1 is hydrogen or (C,,)alkyl, and R21 is (C, 4 ,)alkyl optionally substituted by cyano, halo, nitro, -NR1 4 R 1 4 -NR1 4 C(0)OR 1 4 -NR' 4 G(O)NR1 4 R] 4 -NR14C(NR 4 )N'R 4 R 1 4 -OR 1 4 -SR 1 4 -C(Q)OR 1 4 -C(O)NR1 4 R' 4 -S(O) 2 NR1 4 R 1 4 -P(O)(OR' 4 )OR, 4 -S(OX2R2, -C(Q)R22, -C(O)OR -C(O)NR22R2, -NR 22 R 23 _NR23C(O)R22, -NR23C(O)QR22,-NR23C(O)NR22R2 or R3 wherein R 1 4 and R" 5 are as defined above, RI is (C3,, 2 )cycloalkyl(C0,)alkyl, hetero(C3, 2 ,)cycloalkyl(C,,)alkyl, 2 )aryI(C,,)alkyl, hetero(C,)aryl(C,,)aky1, (C,,)bicycloaryl(C,,)alkyI or hetero(C,, 2 )bicycloary](C,,)alkyl and R23 at each occurrence independently is hydrogen or (C,.6)alkyl, or (ii) (C3, 12 )cycloalkyl(C,,6)alkyl, hetero(C,, 12 )CYCloalkyl(C,.6)alkyl, (C6.j 2 )aryl(Cm)alkyl, hetero(C5. 12 )aryl(C0.)alky1, (C9_ 12 )bicycloaryl(C0.)alkyl or hetero(CO.1 2 )bicycloaryl(Cm)alkyl or (iii) (C3_)cycloalkyI(C.)akyl, hetero(C3.)cycloalkyl(C,,6)alkyl, pheny](C",)alkyl. or hetero(C,)aryl(C,)alkyl, wherein said cycloalkyl, heteroicycloalkyl, phenyl or heteroaryl is substituted by -R 24 -XIQR 24 -X 5 SR24, -XSS(O)R24, -X5S(0) 2 R24, -X'C(O)R 2 4, -X 5 C(O)0R 24 -X 5 C(0)NR24R25, -X 5 NR24R2, -X 5 NR2C(O)R24, _X 5 NR2C(O)OR 2 A, -X 5 NR25C(O)NR24R2 or -X 5 NR"C(NR 2)NR 24R 2 wherein X 5 is as defined above, R 2 4 is (C,,)cycloalky(C,6)alkyl, hetero(C_,)cycloalkyl(C,_6)alkyl, phenyl(C,,4)alkyl or hetero(C.,)aryl(C0_)alkyI and R' at each occurrence independently is hydrogen or (C1. 6 )alkyl; wherein within RI any alicyclic or aromatic ring system present may be substituted further by 1 to 5 radicals independently selected from (Cl. 6 )alkyl, (C, 4 6)alkylidene, cyano, halo, halo-substituted (C, 4 ,)alkyl, nitro, -XINR"R 1 4 -XsNR1 4 C(O)OR 1 4 -X5NR 1 4 C(O)NR1 4 RI4, -X 5 NR1 4 C(NR] 4 )NR1 4 R] 4 -X50R1 4 -X 5 SR 1 4 -X 5 C(O)OR'1 4 -X5C(O)NR"4R 4 _X 5 S(O) 2 NR1 4 R1 4 -X 5 P(O)(OR' 4 )OR 1 4 _X 5 Op(O)(OR1 4 )OR 14 -XsNR 1 4 C(O)R 15, -X 5 S(O)RI 5 _X5S(O),R 1 and -X 5 C(O)R' 5 wherein -172- X 3 R" 4 and R1 5 are as defined above; or when X' is a divalent group of formula or then RI may also represent hydrogen, carboxy, oxalo or carbamoyl; RI is hydrogen or (C, 1 6)alky1; R 3 is (C,,)alkyl optionally substituted with cyano, halo, nitro, -SR26, -C(O)0R 26 _C(O)NR26R2, _p(O)(OR 26 )OR26, -OP(O)(OR2)OR 26 -S(Q)R 2 7 -S(O) 2 Rl or wherein R 26 at each occurrence independently is hydrogen, (C,,)alkyl or halo-substituted (C, 1 3 )alkyl and R 1 7 is (C 1 6 )alkyl or halo-substituted 3 )alkyl, or (ii) (G5-)cycloalkyl(C 23 )alkyl, heteo(C)cycloalky(C 2 3 )alkyl, (C6. 2 )aryl(C2. 3 )alkyI or hetero(C5)rlC.)lkl hri said cycloalcyl, heterocycloalkyl, aryl or heteroaryl optionally is substituted further with 1 to radicals independently selected from (CI-6)alkyl, (C, 1 4 )alkylidene, cyano, halo, halo-substituted (C, 4 )alkyl, nitro, -X 5 NR 1 4 C(O)OR 1 4 -X 5 NR 1 4 C(O)NR 14 R 1 4 _X 5 NR 1 4 C(NR 1 4 )NR1 4 R1 4 -X 5 OR 1 4 -X 5 SR 1 4 -X 5 C(O)OR', _X 5 C(O)NR1 4 RI 4 -XSS(Q) 2 NR 1 4 R1 4 -X 5 PF(O)(0W 4 )OR 1 4 -X 5 OP(O)(OR 1 4 )QR 4 -X 5 NR' 4 C(O)R 1 5 -X 5 S(O)RI 5 -X 5 S(O) 2 and -XsC(O)R' 5 wherein X 5 R 1 4 and R 15 are as defined above, provided that when RI is unsubstituted (C 1 5 )alkyl and R 4 is hydrogen or unsubstituted (C,-,)alkyl, then X 2 May not represent a bond when R' is -C(O)R0, -C(O)R 20 or -S(O)RI in which R 2 is (C 1 ,)alkyl, phenyl(C,)alkyl, phenyl,' (C, 7 )cycloalkyl, camphan- 10-yl, naphth- I-yl, naphth-2-yl, phenyl substituted by one or more of (C 1 4 )alkyl, perfluoro(C,,)alkyl, (C 1 ,)alkoxy, hydroxy, halo, amido, nitro, amino, (C 1 4 )alkylainino, (C 14 )dialkylamino, carboxy or (C, 1 4 )alkoxycarbonyl, or naphth-1-yl or naphth-2-yl substituted by one or more of (C,,)alkyl, perfluoro(C, 4 )alkyl, (C, 4 )alkoxy, hydroxy, halo, antido, nitro, amino, carboxy or (C, 4 )alkoxycarbonyl or (ii) a divalent group of formula (a) or in which the moiety R1 2 is methyl, isopropyl, n-butyl, sec-butyl, tert-butyl, 1-methyipropyl, benzyl, naphth-1-ylmethyl, naphth-2-ylmethyl, thien-2-yhnethyl, thien-3-ylmethyl, or wherein R" and R1 2 form ethylene, trimethylene, hydroxy-substituted trimethylene, tetramethylene or phenylene-1,2-dimethylene; or R 3 and R" taken together with the carbon atom to which both R 3 and W 4 are attached form (C 3 4 g)cycloalkylene or (C3-8)heterocycloalkylene, wherein said cycloalkylene or heterocycloalkylene is optionally substituted with I to 3 radicals independently selected from (C 1 -6)alkyl, (C,,)alkylidene, cyano, halo, halo-substituted (C,,)alkyl, nitro, -X 5 NR' 4 C(O)OR 1 4 _X 5 NR1 4 C(Q)NR 14 R 4 -X 5 NR1 4 C(NR1 4 )NR 4 Rl 4 -X 5 OR.14, _X 5 SR 1 4 -X 5 C(O)OR 1 4 -X 5 C(O)NR1 4 R] 4 -X 5 S(O) 2 NR1 4 R] 4 -X'P(Q)(OR1 4 )OR' -X 5 Op(O)(OR' 4 )OR', -X 5 NR1 4 C(O)R' 5 -X 5 S(O)R 1 5 -X 5 S(O) 2 R' 5 and -X 5 C(O)R' 5 wherein X 5 R 1 4 and Ri5 are as -173- -defined above; R' is hydrogen, (C 1 -6)alky1 or as defined above; R 5 is hydrogen and RI is hydroxy or R 5 and k' together form oxo; IV is a group selected from cyano, halo, nitro, -R29, -X 5 NR19R', -X 5 NR3C(O)OR21, -X 5 R3C(O)NR29R 3 -X 5 NR0CQ R30)NR29R 30 -X 5 QR29, -X 5 SR29, -X 5 c(O)0R 29 -X 5 C(O)NR 2 9 R30, -X 5 S(O) 2 NR 29 R30, -X 5 P(O)(0Rn 0 )R 29 -X5OP(O)(0R 29 )0R 29 -X 5 NR"C(O)R 31 -X 5 -X 5 S(Q) 2 R 3 and -X 5 C(O)R 31 wherein X 5 is as defined above, R" is hydrogen or _R31, R 3 at each occurrence is hydrogen or (C 2 -6)alkyl and R 3 is (C,.6)alky1, (C3-,)cycloalkyl(C,)alkyl, hetero(G3- 1 2 )cycloalkyI(C,)alky1, (C6-j)aryl(C0)alky1 or hetero(Q 1 2 )aryl(C0)alcyl, wherein within R" any alicyclic or aromatic ring system present may be substituted further by i to 5 radicals independently selected from (C 1 .,)alkyl, (C,.6)alkylidene, cyano, halo, halo-substituted (C, 4 )alkyl, nitro, -XINR14RI 4 -X 5 NR 24 C(O)OR1 4 -XSNR1 4 C(Q)NR1 4 R' 4 _X 5 NR 14 C(NR1 4 )NR 4 R 1 4 -X 5 OR 1 4 -X 5 SR 1 4 -X 5 C(O)0R 14 -X 5 C(O)NR' 4 RI 4 -X 5 S(O) 2 NR' 4 R 4 -XsP(O)(OR 4 )OR 14, -X 5 OP(O)(OR' 4 )QR 1 4 _X 5 NR14C(O)R 1 5 -X 5 S(O)RI 5 -X 5 S(O) 2 R' 5 and -X 5 C(O)R' 5 wherein V 5 R"1 and R 1 5 are as defined above; and RI at each occurrence independently is selected from (C, 14 )alkyl, (C, 14 )alkylidene, cyano, halo, halo-substituted (C,,)alkyl, nitro, -X 5 NR' 4 R 4 _X 5 NR 1 4 C(O)0R' 4 -X 5 NR 14 C(O)NR1 4 R' 4 -X 5 NR1 4 C(NR 4 )NR 1 4 R] 4 -X 5 OR 1, -X 5 SR 1 4 _X 5 C(O)QR 1 4 _X 5 C(O)NR1 4 R' 4 -X 5 S(Q) 2 NR 1 4 R] 4 -X5P(Q)(QR 1 4 )OR 1 4 _X 5 OP(Q)(OR1 4 )OR 14 -X5NR'4C(O)R'5, -X 5 S(O)R'5, -X 5 S(O)2R 5 and -X 5 C(O)R' 5 wherein X 5 R 1 4 and R' 5 are as defined above; and the N-oxide derivatives, prodrug derivati ves, protected derivatives, individual isomers and mixtures of isomers; and the pharmaceutically acceptable salts thereof.; but excluding compounds selected from the group consisting of 1-(l -bnzooxazol-2-yl-methanoyl)-3-methyl-butylcarbamoyl]-3-nethyl. butylcarbamoyl }-3-methyl-butyl)-carbamic acid benzyl ester, I I 1-H-imidazol-2-yl- methanoyl)-3-methyl-butylcarbamoyl]-3-methyl-buty j -carbamic acid tent-butyl ester, [(S)-3-methyl-l-((S)-3-methyl- 1-I 1-[1 2 -trimethylsilanyl-ethoxymethyl)-1H-im-idazol-2-yl]- methanoyl )-butylcarbainoyl)-butyl]-carbamic acid benzyl ester; carbainic acid benzyl ester, (S)-l-[l-(-benzyl-1H-imidazol-2-y)-methanoyl]-3-methyl- butylcarbamoyl }-3-methyl-butyl)-carbamic acid benzyl ester, I 1-(l-1H-imidazol-2-yl- -174- methanoyl)-3-methyl-butylcarbamoyl]-3-methyl-butyl)I-carbaniic acid teri-butyl ester,
3-4 [1 -(4-chloro-phenyl)-methanoyl]-amino}-4-oxo4-pyridin.3-y-butyric acidethyl ester,
4-furan-2-yl-4-oxo-3- -(4-trifluoromethyl-phenyl)-methanoylJ-amino 1-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-[( 1-p-tolyl-methanoyl)-amino]-butyric acid ethyl ester, thiophen-2-yl)-3-f [1-(4-chloro-phenyl)-methanoyl]-amino I 4-oxo-butyric acid ethyl ester, 3-4 [l-(4-chloro-phenyl)-methanoyl]-amino}A4-(5-methyl-thiophen-2y).4oxo..buyic acid ethyl ester, 4 -oxo- 4 -thiophen-3-y-3-[(1-p-tolyl-methanoyl)-amino]-buty-ic acid ethyl ester, 3-f [1-(4-methoxy-phenyl)-methanoyl]-ainino I-4-oxo-4-thiophen-3-yJ-butyric acid ethyl ester, 3-f [l-(3,4-dichloro-phenyl)-methanoyll-amino)-4-oxoA4-thiophen-3ylbutyic acid ethyl ester, 4-fluoro-N-[ I1-(I -thiophen-3-yl-methanoyl)-propyl]-benzamide, 4-f( [l-(4-fluoro-phenyl)- methanoyl]-amino)-5-oxo-5-thiophen-3-yl-pentanoic acid ethyl ester and 3-f [1-(4-fluoro- phenyl)-methanoyll-amino)}-2-methyl-4-oxo-4-thiophen-3-y-butyric acid ethyl ester. 2. The compound of Claim 1 in which XI is a bond or a divalent group of Formula 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 R' and optionally substituted with a group RI, wherein R' is hydrogen, halo, )alkoxy, (C,,)alkoxycarbonyl, nitro or phenyl, Ra at each occurrence independently is halo, (C,,)alkoxy, (C,,)alkoxycarbonyl, nitro or trifluoromethyl; X, is X 2 is a bond or a divalent group of Formula wherein within Formula R 9 is hydrogen, R" is hydrogen or methyl and R1 2 is (C, 4 )alkyl substituted with -S(O)R"I or 1 4 wherein R' 4 is (C, 12 )aryl(C0.)alkyI or hetero(C 5 .,7.)aryl(C.)alkyl or (ii) (C 3 1 )cycloaky(C0_)alkyI or (C6. 12 )aryl(C0.)alkyl; wherein within R' 2 any alicyclic or aromatic ring system present may be substituted further by 1 to 5 radicals independently selected from (C, 1 6)alkyl, (C 14 6)alkylidene, cyano, halo, halo-substituted (C 14 )alkyl, nitro, _X 5 NR1 4 R1' -XsNRIAC(O)OR 14, -X 5 NR 1 4 C(O)NR1 4 R4, -XSNR1 4 C(NR1 4 )NTR 4 R 4 5 OR 1 4 -X 5 SR 1 4 _X 5 C(Q)OR' 4 _XSC(O)NR 4 RI 4 _X 5 S(O) 2 NR"4R1 4 -X 5 P(Q)(OR' 4 )OR 1 4 -X 5 QP(O)(OR1 4 )OR 14, -XsNR' 4 C(O)R' 5 -X 5 S(O)R' 5 -X 5 S(O) 2 R"5 and -X 5 'C(O)R 15, wherein -175- XI is a bond or (C 1 .,)alkylene, R' 4 at each occurrence independently is hydrogen, (C,-6)alkyl or halo-substituted 3 )alkyl and R1 5 is (CI-6)alkyl or halo-substituted 3 )alkyl; RI is -XIXIR", wherein X 6 is or X 7 is a bond, or -NR 21 wherein R 2 1 is hydrogen or (C,-6)alkyl, and R' is 6 )alkyl optionally substituted by -C(O)OR' or (ii) (Cj, 2 )cycloallyl(C0.)alkyl, hetero(C-3.)cycloalkyl( 06 )alkyl, (C6-1 2 )aryI(Cm)alkyl or hetero(C_,,0ary1(C.)alkyl or (iii) (Cm)cycloalkyl(Gm)alkyl, hetero(C3-)cycloalcyl(C. 6 )alkyl, phenyl(C0.)alkyl or hetero(C,,)aryI(C,)alkyl, wherein said cycloalkyl, heterocycloalkyl, phenyl or heteroaryl is substituted by -X 5 OR 24 ,-X 5 C(O)R -XIC(Q)0R 24 -X 5 NR24Rz, -X 5 NR25C(O)R 24 -XsNR2'C(O)OR24, -X 5 NR2'C(O)NR 2 4R25 or -XINRIC(NRI)NR24RI, wherein X 5 is a bond or 6 )alkylene, R24 is* hetero(C,,)cycloalkyl(C,4)alkyl, phenyl(Co )alkyl or hetero(C.,)aryl(C .)alcyl and R25 is hydrogen or (C 1 -6)alkyl; wherein within RI any alicyclic: or aromatic ring system present may be substituted further by I to 5 substituents independently selected from (C,-,)alkyl, halo, halo-substituted (C,,)alkyl, -OR'1 4 and -C(O)OR"4 wherein R" is as defined above, or when X 2 is a divalent group of formula then RI may be, but is not limited to, hydrogen or oxalo; R 2 is hydrogen; R 3 is hydrogen, (C,,)alkyl (optionally substituted with cyano, halo, nitro, -SR24, -C(O)OR24, 4R 2 R7A, -P(Q)(OR 2 4)OR24, -OP(O)(0R7A)0R 2 4, -S(O)R25, 2 5 or wherein RI' at each occurrence independently is hydrogen, (C, 4 ,)alkyl or halo-substituted 3 )alkyl and R25 is halo, 6 )alkyl or halo-substituted (C, 3 ,)alkyl) or (C6-1 2 )arYl(q- 3 )alkyl, wherein said aryl optionally is substituted further with 1 to 5 radicals independently selected from (C, 4 ,)alkyl, (C, 4 )alkylidene, cyano, halo, halo-substituted (C,,)alkyl, nitro,-XsNR' 4 C(O)OR 1 4 -X 5 NR1 4 C(O)NR1 4 R 4 -X 5 NR 1 4 C(NR1 4 )NR1 4 R 4 _X5OR1 4 -X5SR 1 4 -X-C(O)OR 1 4 _X 5 Q(O)NR1 4 R1 4 -X 5 S(0) 2 NR1 4 R1 4 -XsP(O)(OR] 4 )OR 1 4 -X 5 'OP(O)(OR1 4 )OR 1 4 -X 5 NR1 4 C(O)R' 5 -X 5 S(O)R' 5 -X 5 S(O),R' 5 and -X 5 C(O)R' 5 wherein X 5 is a bond or (C, 4 6)alkylene and R 1 4 and R 1 5 are as defined above, or R 3 and W( or R 3 and R" taken together with the carbon atom to which both R 3 and R" are attached form cyclopropylene, cyclobutylene, cyclopentylene or cyclohexylene; R 4 is hydrogen or as defined above; and R 5 and R(6 together form oxo; and he N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers; and the pharmaceutically acceptable -176- salts thereof. 4. The compound of Claim 3 in which: A is benzoxazol-2-yl substituted by RI, wherein W 7 is hydrogen, halo, (C, 4 )alkoxy, (C, 4 )alkoxycarbonyl or nitro and RI at each occurrence independently is halo, (C, 4 )alkoxy, (C, 4 )alkoxycarbonyl, nitro or trifluoromethyl; XI is a bond or a divalent group of Formnula wherein within Formula XI is R' 1 is hydrogen and R 1 2 is a group having the following formula: 33 (R)q in which q is 0, 1, 2,4 or 5 and R 1 3 at each occurrence independently is selected from a group consisting of (C,,)alkyl, cyano, halo, halo-substituted (C, 4 )alkyl, nitro, -X 5 NR 14 -X 5 OR", -X 5 SR 14 -X 5 C(O)NR 4 R 14 -X 5 C(O)0R 14 -X 5 S(O)RI 5 -X 5 S(O 2 R and -X 5 C(O)R' 15 wherein XI is a bond or (C, 14 )alkylene, R 1 4 at each occurrence independently is hydrogen, (C 1 3 )alkyl or halo-substituted (C 1 3 )alkyl and R' 5 is 3 )alkyl or halo-substituted 3 )alkyl; RI 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)carbarnoyl, dimethylcarbamoyl, 6-hydroxypyrid-3-ylcarbonyl, IH-imidazol-4-ylcarbonyl, methoxycarbonyl, methylsulfonyl, 4-methylvaleryl, morpholin-4-ylcarbonyl, 2-morpholin4-yiethylcarbonyl, naphth-1-ylacetyl, naphth-l-yhnethylcarbonyl, oxalo, 3-phenylpropionyl, piperazin-1-ylcarbonyl, piperidin4-ylcarbonyl, pyrazin-2-ylcarbonyl, pyrid-3-ylcarbonyl, pyrid-4-ylcarbonyl, pyrid-3-ylaminocarbonyl, tetrahydropyran4-ylcarbonyl and tetrahydropyran-4-yloxycarbonyl; R 3 is selected from hydrogen, (C, 4 )alkyl, phenyl(CQ 3 )alkyl or (C 1 4 )alkylsulfonyl(C 2 4 )alkyl or R 3 and RI taken together with the carbon atom to which both R 3 -177- and R 4 are attached form (G3.)cycloalkylene; R' is hydrogen or as defined above; and the N-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, R' is morpholin-4-ylcarbonyl, methoxycarbonyl, methylsulfonyl, piperidin-4-ylcarbonyl, pyrazin-2-ylcarbonyl pyrid-3-ylcarbonyl, pyrid-4-ylcarbonyl, tetrahydropyran-4-ylcarbonyl or tetrahydropyran-4-yloxycarbonyl, RI is methyl, ethyl, n-propyl, n-butyl, 2-methylsulfonylethyl or phenyethyl or R 3 and R 4 taken together with the carbon atom to which both R 3 and R4 are attached form cyclobutylene and R 33 at each occurrence independently is (C,,)alkyl, cyano, halo, halo-subsituted (C,,)alkyl, nitro, -SR' 4 or -C(O)QR 4 wherein R1 4 at each occurrence independently is hydrogen, 3 )alkyl or halo-substituted 3 )alkyl; and the N-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 R 33 at each occurrence independently is selected from a group consisting of (C,,)alkyl, bromo, carboxy, chioro, cyano, difluoromethoxy, fluoro, iodo, methoxy, nitro, trifluoromethoxy, trifluoromethyl and trifluorosulfanyl; and the N-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 R" is benzylsulfonylmethyl, 2-chlorobenzylsulfonylmethyl, 2-cyanobenzylsulfonylmethyl, 2-difluoromethoxybenzylsulfonylniethyl, 3,5-dimethylisooxazol-4-ylmethylsulfonylmethyl, 2-methoxybenzylsulfonyhnediyl, 6-methylpyrid-2-ylmethylsulfonylmethyl, 2-nitirobenzylsulfonylmethyl, pyrid-2-ylniethylsulfonylmethyl, o-tolylmethylsulfonylniethyl or 2-trifluoromethylbenzylsulfonylmethyl; and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers; and the pharmaceutically acceptable salts thereof.
8. A compound of Formula II: -178- 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, XV 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 heteroatomn; n isO0, 1, 2 or 3; XV is or-C XI is (C,-,)alkylene; R' is hydrogen, carboxy, oxalo, carbamoyl or -X 6 XIR 2 0 wherein X 6 is or -S(O) 2 X7 is a bond, or wherein R"2 is hydrogen or (C,,)alkyl, and is (C,.6)aikyl optionally substituted by cyano, halo, nitro, _NR 4 R 1 4 _INR1 4 C(O)OR 1 4 -NR1 4 C(O)NR 4 R 1 4 -NR1 4 C(qR' 4 )NR1 4 R 1 4 -OR 1 4 -SR 1 4 -C(O)NR 1 4 R. 4 -S(O) 2 NR1 4 R 1 4 -P(O)(OR' 4 )OR] 4 -Op(O)(OR 1 4 )OR 1 4 -NR1 4 C(O)R' 5 -S(O)R 15 -S(O) 2 R' 5 -NR22R2, -NR23C(O)R22, -NR23C(O)OR,-NR 2 3 C(O)NR22R2 or -NRIC(NR23)NRuRu, wherein R 14 at each occurrence independently is hydrogen, (C, 4 )alkyl or halo-substituted 3 )alkyl, R' 5 is 6 )alkyl or halo-substituted 3 )alkyl, RI is (C3.1 2 )CYCloalkyl(C,,)alkyl, hetero(C 3 ,1 2 )cyc'oalkyl(C,.6)alky1, 2 )aryI(C 0 6 )alkyl, hetero(C.,1 2 )ary1(CO-)alkyl, (C9.1 2 )bicycloaryl(C,,6)alkyl or hetero(Ca-1 2 )bicycloaryl(CO.)alkyl and R23 at each occurrence independently is hydrogen or (C, 4 6)allcyl, or (ii) (C,,0cycloalkyl(C.)alkyl, hetero(C 3 1 )cycloalkyl(C 0 6 )alkyl, (C6.1 2 )aryl(C 0)alky1, betero(C5.1 2 )aryl(CO.)alkyl, '(G91 2 )bicycloaryl(C )alkyl or hetero(C, 2 )bicycloary1(Cu)alkyI or (iii) (C,,)cycloalkyl(C,,)all, hetero(C 3 -6)CYCloalky](CQ,)alkyI, phenyl(C,,)alkyl or -179- I substituted by -X 5 0R 2 -X 5 SR 24 -X 5 S(O)R 24 -X 5 S(O)2R 2 -X5C(O)R2A, -X 5 C(O)0R 24 -X 5 C(O)NR 2 -XSNR2AR, -XsNR2'C(O)R24, -XsNR7-C(Q)OR24, -XN2CON I2 or -XsNR25C(NR25)NRIR25, wherein X 5 is a bond or (C, 4 )alkylene, R 2 4 is (C3,)cycloalkyl(Ct_)alky1, hetero(C 3 ,)cycloalkyI(C...)alkyl, phenyl(C0.)alkyl or hetero(C 5 _6)ary1(C")alkyl and R2' at each occurrence independently is hydrogen or (C,,)alkyl; wherein within R' any alicyclic or aro matic ring system present may be substituted further by 1 to 5 radicals independently selected from (C,,)alkyJ, (C,,)alkylidene, cyano, halo, halo-substituted 4 )alkyl, nitro, _X 5 NR1 4 R1 4 -X 5 NR1 4 C(O)OR'1 4 1 4 C(O)NR 14R 1 4 -X 5 NR 1 4 C(NR1 4 )NR'1 4 R1 4 _X 5 OR'1 4 -X 5 SR 1 4 -XsC(O)OR 1 4 -X 3 C(O)NR 4 R 1 4 _XSS(O) 2 NR1 4 R' 4 -X 5 P(O)(OR' 4 )OR 1 4 _X 5 OP(O)(OR' 4 )ORI', 4 C(Q)R' 5 -X 5 S(O)R 1 5 -X 5 S(O) 2 R'1 5 and _X 5 C(O)R' 5 wherein VS, R 1 4 and R' 5 are as defined above; RI is hydrogen or (C, 4 6)alkyl; R 3 is (C,-6)alkyl optionally substituted with cyano, halo, nitro, -NR' 4 R' 4 -NR' 4 C(O)QR'1 4 -NR' 4 C(O)NR1 4 R'1 4 -NR'1 4 C(NR 4 )NR 4 R 14 -OR'1 4 -SR'1 4 -C(O)OR 1 4 -C(O)NR1 4 RI 4 _S(O) 2 NR' 4 R[4, -P(O)(OR' 4 )OR 1, -QP(O)(OR' 4 )OR' 4 _NR'1 4 C(O)R1 5 -S(Q)R' 5 -S(O) 2 R 15 -C(O)R' 5 -OR' 6 -SR 1 6 -S(O) 2 R' 6 -C(O)R' 6 -C(O)OR' 6 -OC(Q)R 6 _NR1 6 R1 7 _NR' 7 C(O)R'1 6 -NR1 7 C(O)OR 1 6 -C(O)NR'1 6 R 1 7 _S(O) 2 ,M1 6 R 1 7 -NR 1 7 C(O)NRIIRI" or -NR 1 7 C(NR' 7 )NR1 6 RII, wherein R 1 4 at each occurrence independently is hydrogen, (C,-6)alkyl or halo-substituted 3 )alkyl, is (C 14 6)alkyl or halo-substituted 3 )alkyl, R' 6 is (C3- 12 )cycloalky(C0_)alkyl, hetero(Q, 2 cycloalkyl(C.)alkyl, (C 12 )aryl(CO.)alkyl, hetero( C 5 12 )arYI(C,4)alkyl, (C 9 j 2 polycycoaryl(C,)alkyl or heteio(C 8 12 )polycycloaryl(C,)alkyI and R'1 7 is hydrogen or (C,,)alkyl, and wherein within R 1 6 said cycloalkyl. heterocycloalkyl, aryl, heteroaryl, polycycloaryl or heterpolycycloaryl ring optionally is substituted by a group selected from -X 5 OR' 8 _X 5 SR" 8 -X 5 S(Q)R' 8 -X 5 S(O) 2 R'B, -X 5 C(O)R'8, -X-C(O)OR' 3 -X 5 OC(O)R' 8 -X 5 NR' 8 R]9, -X 5 NR' 9 C(Q)R' 8 -X 5 NR' 9 C(O)QR's, -X 5 C(O)NR' 8 R] 9 -XsS(O),NR'&R' 9 -X 5 NR' 9 C(O)NR 18 R' 9 or -X'NR' 9 C(NR' 9 )NR 8 R' 9 wherein X 5 is as defined above, R's is hydrogen or (C,,)alkyl and R' 9 is 12 )cycloaky(C")alkyl, hetero(C 3 1 )cycloalkyl(C,)alkyl, (C 6 2 )aryl(C,)alkyl, hetero(C5.)aryl(C0)alcyl, (Cq., 2 )polycycloaryl(C 6)alkyl or hetero(C, 1 2 )polycycloaryl(C")alkyl, or (ii) a group selected from (C3_, 2 )cycloaIkyl(C")alkyl, hetero(C 3 2 )cycloalkyl((Q )alkyl, (C6.j 2 )aryl(C 6)alkyl, hetero(C5.10aryl(C0.)alkyl, -180- (Cq., 2 )polycycloaryl(Cod6alkyl and hetero(Cs. 2 )'polycycloary1(CO 4 )alkyl, wherein said cycloalkyl, heterocycloalkyl, aryl, heteroaryl, polycycloaryl or heterpolycycloaryl ring optionally is substituted by a group selected from -R" 8 -X 5 OR' 8 -X'SR's, -X 5 S(O)RIB, -X 5 5(O) 2 R'B, -X 5 C(O)RI 8 -X 5 C(O)OR' 8 -X 5 OC(Q)R 8 -XsNR 18 R' 9 -X 5 NR1 9 C(Q)R' 8 -X 5 NR' 9 C(O)OR 8 -X 5 C(O)NR', -X 5 S(O) 2 NR'9R, -X 5 NR' 9 C(O)NR' 8 IR' 9 or -X 5 NR' 9 C(NR' 9 )NR'BR' 9 wherein X 5 R' 8 and R1 9 are as defined above; wherein within R' 2 and/or R 13 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, -X 5 NR 1 4 R1 4 -X 5 NR 1 4 C(O)OR1 4 -X 5 NR 1 4 C(O)NR1 4 R 1 4 -X 5 NR 14 C(NR 1 4 )NRI 4 R1 4 -X 5 0R1 4 -X 5 SR 14 _X 5 C(O)0R 14 -X 5 C(O)NR 4 R 1 4 -X 5 S(O) 2 NR 14 R1 4 -X 5 P(O)(0R 1 4 )OR, 4 -XSQP(O)(ORI' 4 )OR'1 4 -X 5 NR 1 4 C(Q)R' 5 -X5S(O)R 1 5 -X 5 S(Q),R 15 and -X 5 C(O)R 1 5 wherein XI, R"1 and R 15 are as defined above, or RI and R' taken together with the carbon atom to which both RI and R 4 are attached form (C 3 8 )cycloalkylene or (Cm)heterocycloalkylene, wherein said cycloalkylene or heterocycloalkylene is optionally substituted with 1 to 3 radicals independently selected from (C, 1 6)alkyl, (C,6)alkylidene, cyano, halo, halo-substituted (C, 14 )alkyl, nitro, -X 5 NR 1C(O)OR 1 4 -X 5 NR 1 4 C(O)NR 4 R 1 4 _X5NR14C(nR' 4 )NR1 4 -X 5 OR 1 4 -X 5 SR 1 4 _X 5 C(O)OR' 4 -X 5 C(O)NR1 4 R' 4 -X. 5 S(O) 2 NR 4 R 4 -XsP(O)(OR1 4 )OR 1 4 -X 5 OP(O)(0R 14 )OR 1 4 _X 5 NR1 4 C(O)R 15 -X 5 S(Q)R' 5 -X 5 S(O) 2 R' 5 and _X 5 C(O)R 1, wherein X 5 R 1 4 and R" are as defined above; R" is hydrogen, (C,,)alkyl or as defined above; is hydrogen and R 6 is hydroxy or Rs5 and RI together form oxo; R" is a group selected from cyano, halo, nitro, -X'NR19R', -X 5 NR 30 C(O)OR~, -X'NR 30 C(O)NR 29 R30, -XSNR30C(NR 3 O)NR 29 R0, -X 5 OR 2 9, -X 5 SR 29 -X 5 C(O)0R 29 -X 5 C(O)NR29R3, -X 5 S(Q) 2 NR9R' -XIP(O)(OR30)OR 2 9 -XIOP(O)(OR 29 )OR 29 -X 5 NR 30 C(O)R 3 1 -XsS(Q)R 3 I, -X 5 S(O) 2 R 3 and -X 5 C(O)R 31 wherein X 5 is as defined above, R29 is hydrogen or -R 31 R30 at each occurrence is hydrogen or (CI-6)alkyi and R 3 is (C, 4 6)alkyl, (C 3 2 )cycloalkyl(C 06 )alkyl, hetero(C. 12 cycloalkyl(C 0 ")alkyl, (C(,j 2 )aryl(C04)alkyl or hetero(Q 1 2 )aryl(C")alkyI, wherein within RI any alicyclic or aromatic ring system present may be substituted further by 1 to 5 radicals independently selected from (CI-6)alkyl, (C, 14 )alkylidene, cyano, halo, halo-substituted (C, 14 )alkyl, nitro, _X 5 NR1 4 R 14 -X 5 NR1 4 C(O)OR, 4 -XsNRI 4 C(O)NR 1 4 R1 4 -X 5 NR1 4 C(NR1 4 )NR 4 R 1 4 -X 5 OR J 4 -X 5 SR' 4 -X 5 C(O)OR' 4 -181- -XSC(O)NR' 4 RI 4 -X'S(O) 2 NR1 4 R 1 4 -X 5 P(O)(OR' 4 )QR 1 4 -X 5 QP(O)(QR' 4 )QR'14, _XSNR1 4 C(O)R'5, -X 5 S(O)RI 5 -X 5 S(O) 2 R 5 and _X 5 wherein V 5 R 1 4 and R 1 5 are as defined above; and R8 at each occurrence independently is selected from (C 1 4 6)alkyl, (CI 4 )alkylidene, cyano, halo, halo-substituted (C,,)alkyl, nitro, -X 5 NR1 4 R 1, _X 5 NR 1 4 C(O)OR' 4 _X 5 NR1 4 C(Q)NR 14 R' 4 -X 5 NR1 4 C(NR1 4 )NR1 4 R 4 -X 5 OR 1 4 -XsSR 1 4 -XsC(O)QR 4 _X 5 C(O)NR1 4 R] 4 _XSS(O) 2 NR1 4 R1 4 -X 5 P(O)(QR'1 4 )OR 1 4 -XSOP(O)(QR"4)OR 1 4 _X 5 NR1 4 C(O)R' 5 -X 5 S(O)R 1, -X 5 S(O) 2 R' 5 and _X5Q)R 15, wherein X5 3 R 1 4 and R 1 5 are as defined above; R 9 is hydrogen or (C 1 -6)alkyI; and R 3 1 is alkyl, (C 3 12 )cycloalkyl(CQ.)alkyl, hetero(C3- 12 )CYCloallcl(C:.6)alkyl, (C. 2 )aryl(C7.)alkyl, hetero(C5- 12 )aryl(Cm)alkyl, (C9.)polycycloaryl(C0)alkyl or betero(Cs. 12 )POlYCYCloaryl(C,,6)alkyl, wherein within R' any alicyclic or aromatic ring system present may be substituted further by I to 5 radicals independently selected from (C,,)alkyl, (C,-6)alkylidene, cyano, halo, halo-substituted (C 14 )alkyl, nitro, -XINR 4 -X 5 NR1 4 C(Q)OR 1 4 -X 5 NR1 4 C(O)NR1 4 R 4 -X 5 NR1 4 C(NR 1 4 )NR1 4 RI 4 ,1 -X 5 OR1 4 -X 5 SR 14 ,1 -X 5 SC(O)OR 1 4 _X5C(O)NR14Rl,. -X 5 S(Q),NR 1 4 R14, _Xsp(Q)(OR 4 )OR 1 4 -X 5 OP(O)(OR' 4 )QR' 4 -X 5 NR' 4 C(O)R 1 5 -X 5 S(Q)R 1 5 -X 5 S(O),R' 5 and -X 5 C(Q)R 1 5 2 wherein X 5 R 1 4 and R" 5 are as defined above; and the N-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 substi tuted. by a group RI and optionally substituted with a group RB, wherein R' is hydrogen, halo, (C 1 4 )alkoxy, (C 1 4 )alkoxycarbonyl, nitro or phenyl, RB at each occurrence independently is halo, (C 1 4 )alkoxy, (C 1 4 )alkoxycarbonyl, nitro or trifluoromethyl; X, is =C- X8 is methylene or ethylene; RI is -X 6 IX 7 wherein X 6 is or VZ is a bond, or -NR 21 wherein R 2 1 is hydrogen or (C 1 4 6)alkyl, and RI" is (C 1 6 )alkyl optionally substituted by -C(0)OR" 1 or (ii) (C,3 12 )cycloalkyl(CO.)alkyl, hetero(C .1 2 )cycloalkyl(C,)alkyl, (C 6 12 )aryl(CO-)alkyl or 12 )aryl(C04)alkyl. or (iii) (C3-)cycloalkyl(CO.)alkyl, hetero(C 3 -6)cycloalkyl(Cm)alkyl, -182- phenyl(CO-)alkyl or hetero(C,_)aryl(Cm)alkyl, wherein said cycloalkyl, heterocycloalkyl, phenyl or heteroaryl is substituted by -X 5 0R 2 4 ,-X 5 C(O)R 4 -XIC(O)0R 4 -X 5 NR 24 R25, -XSNR 2 5C(O)R 24 -X5NR25C(O)OR 2 4 -X5NRIC(O)NRuR 25 or -X 5 NR"C(NRI)NRuRI, wherein X 4 is a bond or 6 )alkylene, RI is (C3.)cycloalkyl(C.)all, hetero(C3.)cycloalkyl(C:7 6 )alkyl, phenyl(C.)alkyl or hetero(C,.)aryl(C.)alkyl and RI is hydrogen or (C,'-)alkyl; wherein within RI 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,,)alkyl, -OR'1 4 and -C(O)QR 1 4 wherein R 1 4 is as defined above, or when X 2 is a divalent group of formula then RI may be, but is not limited to, hydrogen or oxalo; RI and R" each are hydrogen; R 3 is hydrogen, 6 )alkyl (optionally substituted with cyano, halo, nitro, -SRI, C(O)OR7A, -C(O)NW4Ru, -P(O)(OR24)0R 24 -OP(O)(OR2)OR 2 4 -S(O)R25, S(O) 2 R25 or wherein R24 at each occurrence independently is hydrogen, (C,,)alkyl or halo-substituted 3 )alkyl and RI is (G, 4 6)alkyl or halo-substituted (Cl. 3 )alkyl) or (C6, 2 )aryl(Q2 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,-X 5 NR 1 4 C(O)OR 1 4 -X 5 NR 14 C(O)NR 4 R 4 _X 5 NR1 4 C(NR 4 )NqR 4 RI 4 -X 5 'OR 1 4 -X5SR'1 4 -X 5 C(Q)OR 1 4 _X 5 C(O)NR1 4 R 4 -X5S(0) 2 NR1 4 R1 4 -X'P(O)(OR' 4 )OR1', -X 5 OP(O)(OR1 4 )OR1 4 -X 5 NR 4 C(O)R' 5 -X 5 S(O)RI- 5 -X-IS(O),R' 5 and -XsC(O)RIs, wherein X 5 R1 4 and R' 5 are as defined above, or R 3 and R 4 taken together with the carbon atom to which both R 3 and R 4 are attached form cyclopropylene, cyclobutylene, cyclopentylene or cyclohexylene; R 4 is hydrogen or as defined above; R' and W 6 together form oxo; and R 32 is -X9R' wherein XI is methylene when XI is methylene or is a bond when XI is ethylene, R34 is -CR 35 CHR 3 6 or -CR 3 7 .NR 3 8 wherein R 3 5 and R 36 together with the atoms to which R 35 and R36 are attached form (Q2-)alkenyl, (C.1,)Cycloalkenyl, hetero(CQ, 2 )cycloalkenyl, (C,1 2 )aryl, hetero(C, 2 )aryl, (Cg-,)bicycloaryl or hetero(C8.,,)bicycloaryl and R37 and R 38 together with the atoms to which R 37 and R 3 1 are attached form hetero(CQ 12 )cycloalkenyl, hetero(C, 2 )aryl or hetero(C,,)bicycloaryl, wherein within RI said cycloalicenyl, heterocycloalkenyl, aryl, heteroaryl, bicycloaryl or heterobicycloaryl -183- may be substituted further by 1 to 5 radicals independently selected from (C 14 6)alkyl, (C 1 -6)alkylidene, cyano, halo, halo-substituted (C, 14 )alkyl, nitro, -X 3 NR 1 4 -X 5 NR1 4 C(O)OR 1 4 -X 5 NR1 4 C(O)NR1 4 R] 4 _XSNR1 4 C(NR] 4 )NR1 4 R1 4 _X 5 OR 1 4 _X 5 SR 1 4 -X 5 C(O)OR' 4 -X 5 C(O)NR 1 4 R1 4 -X 5 S(O) 2 NR' 4 R' 4 -X 5 P(O)(0R 4 )OR 1 4 _X 5 OP(Q)(OR' 4 )OR. 4 -X 5 NR' 4 C(O)R' 5 _X 5 S(O)R 1 5 -X 5 S(Q),R 1 and -X 5 C(Q)R' 5 wherein X 5 is a bond or (C,,)alkylene, R 1 4 at each occurrence independently is hydrogen, (C, 1 6)alkyI or halo-substituted (C 1 3 )alkyl and R 1 5 is (C 14 6)alkyl or halo-substituted 3 )alkyl; and the N-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-yi, wherein R 7 is hydrogen, halo, (C, 1 4)alkoxy, (C 14 )alkoxycarbonyl or nitro and RI at each occurrence independently is halo, (C, 1 ,)alkoxy, (C 1 ,)alkoxycarbonyl, nitro or trifluoromethyl; -X'S(O) 2 R 32 is a group having the following formula: R 3) in which q is 0, 1, 2, 4 or 5 and R 33 at each occurrence independently is selected from a group consisting of (C,,)alkyl, cyano, halo, halo-substituted (C, 4 )alkyl, nitro, -XS 5 NRl 4 RI 4 -X 5 OR 4 -X 5 SR 1 4 _X5C(O)NRi 4 RI 4 -X 5 C(Q)OR 1 4 -X 5 S(O)R 1 5 -X 5 S(Q) 2 R 1 and -X 5 'C(O)R' 5 wherein V 5 is a bond or (C 1 2 )alkylene, R 1 4 at each occurrence independently is hydrogen, (CI- 3 )alkyl or halo-substituted (C 1 3 )alkyl and R1 5 is (C, 1 3 )alkyl or halo-substituted (C, 1 3 )alkyl; RI 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. 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, -184- dimethylcarbamoyl, 6-hydroxypyrid-3-ylcarbonyl, IH-imidazol-4-ylcarbonyl, methoxycarbonyl, methylsulfonyl, 4-methylvaleryl, morpholin-4-ylcarbonyl, 2-morpholin-4-ylethylcarbonyl, naphth- 1-ylacetyl, naphth-1-ylmethylcarbonyl, oxalo, 3-phenyipropionyl, piperazin-1 .ylcarbonyl, piperidin-4-ylcarbonyl, pyrazin-2-ylcarbonyl, pyrid-3-ylcarbonyl, pyrid-4-ylcarbonyl, pyrid-3-ylaminocarbonyl, tetrahydropyran-4ylcarbonyl and tetrahydropyran-4-yloxycarbonyl; RI is selected from hydrogen, (C,,)alkyl, phenyl(C, 2 3 )alkyl or (C,,)alkylSUlfonYl(C 2 ,)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 ,)cycloalkylene; R 4 is hydrogen or as defined above; and RI is (CI, 2 )aryl or hetero(C.,)aryl, each optionally substituted by 1 to 5 radicals selected from a group consisting of 4 )alkyl, cyano, halo, halo-substituted (C,,)alkyl, nitro, -X 5 NR1 4 RI 4 -X 5 QR 1 4 -X 5 SR 1 4 _X 5 C(O)NR1 4 R 4 -X 5 C(O)OR 1, -X 5 S(Q)RIS, -X 5 S(O),R' and -X 5 wherein X 5 R' and R15 are as defined above; and the N-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, RI is morpholin-4-ylcarbonyl, methoxycarbonyl, methylsulfonyl, piperidin-4-ylcarbonyl, pyrazin-2-ylcarbonyl pyrid-3-ylcarbonyl, pyrid-4-ylcarbonyl, tetrahydropyran-4-ylcarbonyl or tetrahydropyran4yloxycarbonyl, R 3 is ethyl, butyl, 2-methylsulfonylethyl, phenethyl or propyl and _XI IS(O)R 32 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 N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers; and the pharmaceutically acceptable salts thereof.
12. The compound of Claim I11 selected from a group consisting of: N-I-I-ezoao--labnluycraol--ezlufnltylopoie 4-carboxamide; -185- methyl IR(Sbnoxzl2ycroybtlabaol--ezlufnltycraae N-(IS-benzooxazol-2-ylcarbanylbutyl)- 2R-methylsulfonylaxnino-3-benzylsulfonylpropionamide; N-(lS-benzooxazol-2-ycarbonylbutycarbamoy)2R(33-dimethylureido 0 3-(2-methoxybenzylsulfonyl)propionamide; N-[1R-(1S-benzooxazol-2-ylcarbonylbutylcarbamoyl). 2 2 -difluoromethoxybenzysufonyl)ethy]morphoine4carboxaind; N-[IR-(1S-benzooxazol-2-ylcarbonylbutylcarbamoyl). 2 2 -methoxybenzylsufony)ethyl]morphoine4carboxmide; N-[lR-(lS-benzooxazol-2-ylcarbonylpentylcarbamoyly. 2-ezlufnlty~orhln--abxnie N-[lR-(lS-benzooxazol-2-ylcarbonylpentylcarbamoyl). 2 2 -chlorobenzylsufony)ethy~morphoine4caioxaide; IR-(lS-benzooxazol-2-ylcarbonylpentylcarbamoyl)- 2 2 -difluoromethoxybenzylsulfonyl)ethylcarbamate; N-[lR-(LS-benzooxazol-2-ylcarbonylpentylcarbamoyl). 2 2 -difluoromethoxybenzysufony)ety]morphoineA-carboxyan-ide; N-[lR-(IS-benzooxazol-2-ylcarbonylpentylcarbamoyl). 2 3 ,S-dimethylisoxazol-4-ylmethylsulfonyethyisoniconamide; N-[lR-(lS-benzooxazol-2-ylcarbonylpentylcarbamoyl). 2 2 -nitrobenzylsufonyl)ethymophoine4carboxamide; N-[lR-(lS-benzooxazol-2-ylcarbonylpentylcarbamoyl). 2 -pyridin- 2 -ylmethylsulfonylethylImorpholine-4-carboxan-tide; N-[lR-(lS-benzooxazol-2-ylcarbonylpentylcarbamoy). 2 -o-toIylmethysufonyethy]mohoine-aboxmide; N4IR-(1S-benzooxazol-2-ylcarbonylpentylcarbamoy). 2 2 -tifluoromethybenzysufonyl)ethy]morphoinecrox~ade; N-[lR-(lS-benzooxazol-2-ycarbonyI3phenypropycrboyI)- 2-benzylsufonyethyl~nicotnmide; N-[lR-(1S-benzooxazol-2ycarbonyl3phenypropycrboyl)- 2-ezlufnlty~yaie2croaie
186- N-[1R-(1S-benzooxazo1-2-ylcarbonyl-3-phenylpropylcarbamoyl)- 2-(2-chlorobenzylsulfonyl)ethyljmorpholine-4-carboxamide; lR-(IS-benzooxazol-2-ylcarbonyl-3-phenylpropylcarbamoyl)- 2-(2-cyanobenzylsulfonyl)ethyl]isonicotinamide; N-[1R-(1S-benzooxazol-2-ylcarbonyl-3-methylsulfonylpropylcarbamoyl)- 2-(2-difluoromethoxybenzylsulfonyl)ethyllrnorpholine-4-carboxamide; lR-(IS-benzooxazol-2-ylcarbonylpentylcarbamoyl)- 2-(2-difluoromethoxybenzylsulfonyl)ethyllisonicotinamide; N-[IR-(JS-benzooxazol-2-ylcarbonyl)-3-phenylpropylcarbamoyl)- 2-benzylsulfonylethyl]morpholine4-carboxamide; N-[1R-(1S-benzooxazol-2-ylcarbonyl-3-phenylpropylcarbamoyl)- 2-(6-methylpyrid-2-ylmethylsulfonyl)ethyl]isonicotinamide; 1R-(1S-benzooxazol-2-ylcarbonyl-3-phenylpropylcarbamoyl)- 2-(2-nitrobenzylsulfonyl)ethyl~morpholine..4-carboxamide; 1R-(1S-benzooxazol-2-ylcarbonyl-3-phenylpropylcarbamoyl)- 2-pyrid-2-ylmethylsulfonylethyllmorpholine-4-carboxam-ide; N-[1R-(IS-benzooxazol-2-ylcarbonyl-3-phenylpropylcarbamoyl)- 2-o-tolylmethylsulfonylethyl~morpholine-4-carboxaniide; N-[1R-(1S-benzooxazol-2-ylcarbonyl-3-phenylpropylcarbamoyl)- 2-(2-trifluoromethylbenzylsulfonyl)ethylltetrahydropyran-4-carboxamide; tetrahydropyran-4-yl 1R-( 1S-benzooxazol-2-ylcarbonyl-3-phenylpropylcarbamoyl)- 2-benzylsulfonylethylcarbamate; and N-[lR-(1S-benzooxazol-2-ylcarbonyl- 3 -phenylpropylcarbamnoyl)-2-(2-cyanobenzylsulfonyl)ethyllpiperidineA..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 N-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 -1 87- contributes to the pathology and/or symptomato logy of the disease, which method comprises administering to the animal a therapeutically effective amount of compound of Formula 1: R 2 R 5 R R (R )n, 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 to 7 ring member atoms, XI is a ring member carbon atom and each ring member atom other than XV is a carbon atom or a heteroatom, with the proviso that 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 isO0, 1, 2 or 3; XI is or -CH-; XI is a bond or a divalent group of Formula or 19 11 131 R R 11 R 1 R 9 (b) wherein: XI and X" independently are or -CH 2 S(O) 2 RI9 and R' 0 independently are hydrogen, (C, 4 6)alkyl or as defined below; R" at each occurrence independently is hydrogen or (C, 4 6)alkyl; R1 2 and R1 3 independently are (C,-6)alkyl optionally substituted with cyano, halo, nitro, _NR 1 4 R1 4 -NR1 4 C(O)OR'1 4 -NR1 4 C(O)NR 4 R 1 4 -NR"4C(NR 4 )NR 4 R 4 -OR'1 4 -SR 34 -C(O)OR 1, -C(O)NR1 4 R 4 2 NRR1 4 -P(O)(QR] 4 )OR'1 4 -QP(O)(OR1 4 )OR 1 4 _NR1 4 C(Q)RI, -S(O)R' 5 -S(O) 2 R's, -C(O)R' 5 -OR'1 6 -SR'1 6 -S(O)R' 6 -S(O) 2 R 1 6 C(O)R'1 6 -C(O)OR1 6 -OC(O)R 1 6 _NR1 6 R1 7 -NR' 7 C(O)R'1 6 -188- -NR 17C(O)OR 1 6 -C(O)NR1 6 R 7 -S(O) 2 NR'1 6 R1 7 ,-N'CO R 6 R 7 o -NR 1 7 C(NR] 7 )NR 16 R' 7 wherein R" 4 at each occurrence independently is hydrogen, (C,,)alkyl or halo-substituted (C 1 3 )alkyl, R' 5 is (C,,)alkyl or halo-substituted (C 13 )alkyl, R 1 6 is (C 3 12 )cycloakyl(C4)alkyl, hetero(C3. 12 )cycloalkyl(C,,)alkyl, (Q 12 )arYl(CO.)alkyl, hetero(G5_ 12 )arYI(C")alkYl, (C9. 12 )POlYCYCloaryl(C,)alky or hetero(C 8 1 2 )polycycloaryl(C.)alkyI and R' 7 is hydrogen or (C,,)alkyl, and wherein within R 1 6 said cycloalkyl, heterocycloalkyl, aryl, heteroaryl, polycycloaryl or heterpolycycloaryl ring optionally is substituted by a group selected from -R' 8 -X 5 0R1 8 -X 5 SR' 8 -X 5 S(O)R' 8 -X 5 S(O) 2 R'g, -X 5 C(O)R' 8 -X 5 C(Q)OR' 8 -X 5 OC(O)R 8 -XsNR' 8 R' 9 -X 5 NR1 9 C(O)R' 8 -X 5 NR1 9 C(O)OR 8 -X 5 CQ)NRVIR 9 2 NR1 8 R1 9 -X 5 NR1 9 C(O)NR 1 8 R1 9 or -X 5 NR' 9 C(NR' 9 )NR' 3 R' 9 wherein XI is a bond or (C 14 6)alkylene, R' 8 is hydrogen or (C, 14 )alkyl and R" 9 is (C3-,)cycloalkyl(C.)alkyl, hetero(G 3 12 )cycloalkyl(CM)alkyl, (C6- 1 2 )aryl(C,)alkyl, hetero(C_ 12 )aryl(CO-)alky1, (C 9 12 )polycycloaryl(CO4)alkyl or hetero(Cs. 12 )polycycloaryl(CO-)alkyl, or (ii) a group selected from (Q 1 ,)cycloal kyl(CoJdalkyl, hetero(C,, 2 )cycloalkyl(C -)alkyl, (C6. 2 )aryl(C,,)alkyl, hetero(C., 1 5 )aryl(CO_)alkyl, (C 9 12 )polycycloary1(C.)alkyl and hetero(C, 1 2)polycycloaryl(C 6 )alkyl, wherein said cycloalkyl, heterocycloalkyl, aryl, heteroaryl, polycycloaryl. or heterpolycycloaryl ring optionally is substituted by a group selected from -R' 8 -X 5 0R1 8 -X 5 SR's, -X 5 S(O)Rls, -X 5 S(O) 2 R' 8 -X 5 C(O)RI 8 -X 5 OC(O)R 1 8 -X 5 NRIBR' 9 -X 5 NR1 9 C(O)R 1 8 _X 5 NR1 9 C(O)OR'g, _X 5 C(O)NR1 8 R' 9 -X 5 S(O) 2 NR1 8 R' 9 -X 5 NR' 9 C(O)NR 8 R' 9 or -X'NR 9 C(NR' 9 )NR 8 R' 9 wherein X5, R 18 and R 9 are as defined above; wherein within R" 2 and/or R 13 any alicyclic or aromatic ring system present may be substituted further by 1 to 5 radicals independently selected from (C, 1 4 )alkyl, (C,.6)alkylidene, cyano, halo, halo-substituted (C,,)alkyl, nitro, _X 6 NR1 4 R1 4 _X 6 NR' 4 C(Q)0R 1 4 -X 6 NR' 4 C(O)NR14R 4 _X 6 NR1 4 CM)R 4 )NR1 4 R1 4 -X 6 0R 14 -X 6 SR'1 4 -X 6 C(O)OR 1 4 _X 6 C(O)NR1 4 R1', _X 6 S(O) 2 NR14R1 4 -X 6 P(O)(OR' 4 )QR 1 4 -X 6 OP(O)(OR' 4 )OR' 4 -X 6 NR"4C(O)R 1, -X 6 S(O)R'1 5 -X 6 S(O) 2 R' 5 and -X 6 C(O)RI 5 wherein X 6 is a bond or (C, 1 4 )alkylene and R 1 4 and R 5 are as defined above; or R 12 together with RI and/or R 1 3 together with RIO form trimethylene, tetramethylene or phenylene- 1,2-dimethylene, optionally substituted with hydroxy or- -189- oxo; and RI is -X'X 8 R 20 wherein X 7 is or -S(0) 2 X 8 is a bond, or -NR 2 1_ wherein R 2 1 is hydrogen or (C,.6)alkyl, and R20 is (C,-6)alkyl optionally substituted by cyano, halo, nitro, -NR' 4 R, -NR1 4 C(O)OR 1 4 -NR1 4 C(O)NR 1 4 R1', -NR1 4 C(NR' 4 )NR 4 R', -OR'1 4 -SR 1 4 -C(O)OR 1 4 -C(O)NR J 4 _S(O) 2 NR1 4 R1 4 -P(O)(OR1 4 )OR 1 4 _S(O) 2 Ru2, -C(O)R 22 -C(O)0R 22 _C(O)NR 22R 2, -NR 2R 2, -NR 7C(O)R 2, -NR23C(O)0R2,-NR 23 C(O)NR22R23 or -NRuC(NRu)NR22R', wherein R 1 4 and R' 5 are as defined above, R" is (C,,Ocycloalkyl(C,,)alkyl, hetero(C3-,,)cycloalky1(CI-)alkyl, (C, 1 2 )aryl(C,,)alkyl, hetero(Qj2)aryl(C")alkyl, (C,,)bicycloaryl(C.)aikyI or hetero(C, 1 2 )bicycloaryl(C")alkyl and R23 at each occurrence independently is hydrogen or (C, 4 6)alkyl, or (ii) (Q, 2 )cycloalkyl(C,)alkyl, hetero(C3.,)cycloalkyl(C")alkyl, (C6_j 2 )ary1(C0.)alkyl, hetero(C5.j 2 )aryI(C04)alkyl, (C 9 2 )bicycloaryl(C0.)alkyl or hetero(G.,, 2 )bicycloaryl(C..)alkyl or (iii) (C3.)cycloalkyl(CO-)all, hetero(C3.)cycloalkyl(C")alkyl, phenyl(CO4)alkyl or hetero(C,)axyl(CO.)aIkyl, wherein said cycloalkyl, heterocycloalkyl, phenyl or heteroaryl is substituted by -X 9 OR24, -X 9 SR24, -X 9 S(O)R24, -X 9 S(O) 2 R 24 -X 9 C(Q)R24, -X 9 C(O)OR24, -X 9 C(O)NR24R2, -X 9 NR24R25, -X 9 NR 25 C(O)R24, -X 9 NR25C(O)OR24, -X9NRIC(O)NRIR25 or -X 9 NRuC(NR25)NRAR25, wherein X 9 is a bond or (C, 14 )alkylene, R' is (C3)cycloa11cyl(CO.)alkyl, hetero(C,,,)cycloalkyl(C,)alkyl, phenyl(C:.)alkyl or hetero(C_,)aryl(C")alkyl and R25 at each occurrence independently is hydrogen or (C, 4 6)alkyl; wherein within RI any alicyclic or aromatic ring system present may be substituted further by i to 5 radicals independently selected from 6 )alkyl, (C 1 4 6)alkylidene, cyano, halo, halo-substituted (C,,)alkyl, nitro, -X 6 NR' 4 R', -X 6 NR'C(O)OR 1 4 -X 6 NR11C(O)NRJ 4 R1', -X 6 NR1 4 C(NR1 4 )NR1 4 R] 4 _X 6 OR 1 4 _X 6 SR1 4 -X 6 C(O)OR 1 4 _X 6 C(O)NR1 4 R 1 4 -X 6 S(O) 2 NR1 4 R 1 4 -X 6 P(O)(OR' 4 )OR 1 4 -X 6 OP(O)(OR1 4 )OR 1 4 -X 6 NR' 4 C(O)R 1 5 -X 6 S(O)R 1 5 -X 6 S(O) 2 R"5 and -X 6 wherein X 6 R' 4 and R 1 5 are as defined above; or when X1 is a divalent group of formula or then R'may also represent hydrogen, carboxy, oxalo or carbainoyl; R 2 is hydrogen or (C, 2 4 )alkyl; R 3 is (C1, 4 )alkyl optionally substituted with cyano, halo, nitro, -SRI, -C(O)0R 6 -C(O)NR26R 26 -P(0)(OR 26 )OR26, -0P(O)(OR26)ORII -S(O) 2 Ru or -C(O)R 2 7 wherein RI' at each occurrence independently is hydrogen, (C 1 4 )alkyl or halo-substituted -190- (C 1 3 )alkyl and RI is (C 1 .6)alkyl or halo-substituted (C 1 3 )alkyl, or (ii) (C 5 -6)CYCloalkyl(C 2 3 )alkyl, hetero(C3-)cycloalky](C 2 3 )alkyl, (C 6 12 )aryl(C 2 3 )alkyl or hetero(C 5 6 )aryl(C 2 .,)alkyl, wherein said cycloalkyl, heterocycloalkyl, aryl or heteroaryl optionally is substituted further with 1 to radicals independently selected from (C 1 .6)alky1, (Cl. 6 )alkylidene, cyano, halo, halo-substituted (C 1 .,)alkyl, nitro, -X 6 NR1 4 C(O)OR 1 4 -X 6 NR1 4 C(Q)NR1 4 R 1 4 -X 6 NR 1 4 C(NR 4 )NR 1 4 R'4, -X 6 OR 1 4 -X 6 SR' 4 -X 6 C(Q)0R 1 4 -X 6 C(O)nR 4 _X 6 S(O) 2 NR1 4 R] 4 -X 6 P(O)(OR 1 4 )OR 1 4 -X 6 OP(Q)(QR' 4 )OR 1 4 -X 6 NR1 4 C(O)R 5 -X 6 S(O)R 1 5 -X 6 S(O),R"5 and -X 6 C(O)R' 5 wherein X 6 R' 4 and R1 5 are as defined above, provided that when RI is unsubstituted (C 15 ,)alkyl and R" is hydrogen or unsubstituted 5 )alkyl, then X 2 may not represent a bond when R' is -C(O)R20, 2 or -S(O) 2 R2' in which RI is (C,-6)alkyl, phenyl(C,,)ilkyl, phenyl, (C3- 7 )cycloalkyl, camphan-1O-yl, naphth-1-yl, naphth-2-yl, phenyl substituted by one or more of (C, 1 4)alkyl, perfluoro(C 14 )alkyl, (C, 14 )alkoxy, hydroxy, halo, amido, nitro, amino, (C, 14 )allcylamidno, (C,,)dialkylamino, carboxy or (C 14 )alkoxycarbonyl, or naphth-1-yl or naphth-2-yl substituted by one or more of (C, 14 )alkyl, perfluoro(C, 14 )alkyl, (C,.4)alkoxy, hydroxy, halo, amido, nitro, amino, carboxy or (C, 14 )alkoxycarbonyl or (ii) a divalent group of formula (a) or in which the moiety R' 2 is methyl, isopropyl, n-butyl, sec-butyl, tert-butyl, 1-methyipropyl, benzyl, naphth-1-ylmethyl, naphth-2-ylmethyl, thien-2-ylmethyl, thien-3-ylmethyl, or wherein RI and R' 2 form ethylene, n-imethylene, hydroxy-substituted trimethylene, tetramethylene or phenylene-1,2-dimethylene; or R 3 and R 4 taken together with the carbon atom to which both R 3 and RI are attached form (C34)cycloalkylene or (C 34 )heterocycloalkylene, wherein said cycloalkylene or heterocycloalkylene is optionally substituted with 1 to 3 radicals independently selected from (C 1 -4)alkyl, (C 1 -6)alkylidene, cyano, halo, halo-substituted (C,,)alkyl, nitro, -X 5 NRI 4 C(O)OR 4 -X 5 NR1 4 C(O)NR4RI 4 I X 5 NR1 4 C(NR'1 4 )NR14RI 4 -X 5 0RI 4 -X 5 SR1 4 1 -X5C(Q)OR 4 -X5G(O)NR1 4 R 4 _X 5 S(O) 2 NR14R1 4 -XsP(O)(QR' 4 )OR 1 4 _X SOP(O)(OR' 4 )QR 1 4 -XSNR1 4 C(O)RII, -X 5 S(O)R 1 5 -X 5 S(Q) 2 R' 5 and -X'C(Q)RII, wherein X 5 R' 4 and R" 5 are as defined above; R'4 is hydrogen, (C 24 6)alkyl or as defined above; R 5 is hydrogen and R" is hydroxy or R 5 and R" together form oxo; R' is a group selected from cyano, halo, nitro, -R29, -X' 0 NR 29 R 30 -XI 0 NR 30 C(Q)OR29, -X' 0 NR30C(O)NR 29 R 3 0 -X' 0 NR30C(NR 3 0 )NR 29 R 3 0 -X' 0 0R 29 -X 10 SR 2 9 -X I 0 C(O)0R 29 -X' 0 C(O)NR 29 RW, -X' 0 S(O) 2 NR 29 R 3 0 -X' 0 P(O)(QR3)OR 2 9 -X' 0 OP(Q)(OR 2 9 )QR9, -191- -X' 0 NR30C(O)R 3 1 -X' 0 S(O)R 31 -XIOS(O) 2 R 3 and -X' 0 C(O)R 3 1 wherein X' 0 is a bond or (C, 1 ,)alkylene, R29 is hydrogen or -R3% RIO at each occurrence is hydrogen or (C, 1 4 )alkyl and R 3 1 is (C 1 6 )alkyl, (C3- 12 )cycloalkyl(CO-)alky1, hetero(C3-, 2 )cycloalky1(Co,)alky1, (C6- 12 )aryl(CO.)alkyl or hetero(C5. 12 )aryl(CO-)alky1, wherein within R' any alicyclic or aromatic ring system present may be substituted further by 1 to 5 radicals independently selected from (Cl.6)alkyl, (C 1 -,)alkylidene, cyano, halo, halo-substituted (C, 1 4 )alkyl, nitro, -X 6 NR MR1 4 -X 6 NR1 4 C(O)OR 1 4 -X 6 NR 1 4 C(O)NR1 4 R] 4 -X 6 NR1 4 C(NR"4)NR1 4 R 4 -X 6 QR 1 4 -X 6 SR 1 4 -X 6 C(O)QR 1 4 -X 6 C(O)NR 14 R1 4 -X 6 S(O) 2 NR1 4 R 1 4 -X 6 P(O)(OR' 4 )OR 1 4 -X 6 OP(O)(OR' 4 )QR. 4 -X 6 NR1 4 C(O)R) 5 -X 6 S(O)R 1 5 -X 6 S(O),R' 5 and -X 6 C(O)RIS, wherein V 6 R 1 4 and R 5 are as defined above; and R' at each occurrence independently is selected from (C,.6)alkyl, (C, 1 6)alkylidene, cyano, halo, halo-substituted (C, 14 )alkyl, nitro, -X 6 NR 2 4 R' 4 -X 6 NR' 4 C(O)OR. 4 -X 6 NR' 4 C(O)NR' 4 R 4 _X 6 NR14C(NR] 4 )NR1 4 R 4 -X 6 QR 1 4 -X 6 SR 1 4 -X 6 C(Q)OR"4, -X 6 C(O)NR1 4 R1 4 -X 6 S(Q) 2 NR'1 4 R1 4 -X 6 P(Q)(OR1 4 )OR 1 4 -X 6 Op(O)(QR 4 )OR 1 4 -X 6 1NR1 4 C(O)R11, -X 6 S(O)R' 5 _X 6 S(Q) 2 R' 5 and -X 6 C(Q)R' 5 wherein X 6 R1 4 and R1 5 are as defined above; or a N-oxide derivative, prodrug derivative, protected derivative, individual isomer or mixture of isomers; or a pharmaceutically acceptable salt thereof. 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 -192- 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 N-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. 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. A compound according to Claim 23 or 24 in which ring A is substituted by R wherein R 7 is hydrogen, halo, (Cl 4 )alkyl, (C 1 4)alkoxycarbonyl, nitro or phenyl. -193- 26. A compound according to any one of Claims 1-8 or 22-25 in which R 3 is (C 1 .4)alkyl optionally substituted by phenyl or (C1. 4 )alkylsulfonyl and R 4 is hydrogen or methyl or R and R taken together with the carbon atom to which they are attached form straight, saturated (C 2 5 )alkylene, wherein within said alkylene any one or two carbon atoms optionally is replaced by a heteroatom selected from or -NR 28 where R 28 is hydrogen or (Ci. 6 )alkyl. 27. A compound according to Claim 26 in which R 3 is (C4)alkyl and R 4 is hydrogen or methyl. 28. A compound according to any one of Claims 9-11 or 26 in which R 3 is (CI. 4 )alkyl and R 4 is hydrogen. 29. A compound according to Claim 28 in which R 3 is n-propyl. 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 -194- contributes to the pathology and/or symptomatology of the disease. 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: R 2 R 4 R X2N( R6 R O R7 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, X' is a ring member carbon atom and each ring member atom other than X' is a carbon atom or a heteroatom, with the proviso that at least one ring member atom is a heteroatom and (ii) when A is a heteromonocyclic radical containing 5 ring member -195- atoms, no more than two of the ring member atoms comprising A are heteroatoms; nisO, 1,2 or 3; X' is or -CH-; X 2 is a bond or a divalent group of Formula or R 1 1 R 12 I X X3- (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 to 7 ring member atoms, X' is a ring member carbon atom and each ring member atom other than X' is a carbon atom or a heteroatom, with the proviso that 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' is or -CH-; X 2 is a bond or a divalent group of Formula or (b) wherein: X 3 and X 4 independently are or -CHzS(O),-; R 9 and RI° independently are hydrogen, (C, 1 )alkyl or as defined below; R" at each occurrence independently is hydrogen or (C,,)alkyl; -196- R" 2 and R' 3 independently are (CI-6)alkyl optionally substituted with cyano, halo, nitro, -NR1 4 R 1 4 -NR 1 4 C(O)OR'1 4 -NR'1 4 C(O)NR 1 4 R1 4 -NR' 4 C(NR' 4 )NR 4 R' 4 -OR'1 4 -C(O)QR 1 4 -C(O)NR 4 R 4 t-S(O) 2 NR' 4 R] 4 -P(O)(OR' 4 )OR'1 4 -QP(O)(OR")OR'1 4 -NR' 4 C(O)R' 5 -S(O)R' 5 5 -C(O)R' 5 -OR'1 6 -SR'1 6 -S(O)R' 6 -S(O),R'1 6 -C(O)RII, -C(O)OR 1 6 -OC(O)R'1 6 -NR.' 6 R"1, -NR' 7 C(O)R 1 6 -NR17C(O)OR1 6 C(O)NR1 6 _S(O) 2 NR 6 R 17 _NR17C(O)NR"6R 7 or -NR1 7 C(NR1 7 )NR 6 R' 7 wherein R 1 4 at each occurrence independently is hydrogen, (C, 4 )alkyl or halo-substituted 3 )alkyl, R' 5 (C,.,)alkyl or halo-substituted (Cl. 3 )alkyl, R 1 6 is (C 3 .,)cycloalky(C,)alkyl, betero(C 3 -,,)cycloalkyl(C,6)alkyl, (C6, 2 )arYl(Cm)alkyl, hetero(C 5 .1 2 )aryl(CO. 6 )alkyl, (C 9 .1)polycycloaryl(C,)alkyl or hetero(C, 1 )polycycloaryl(CO-)alkyI and R'1 7 is hydrogen or (C,,)alkyl, and wherein within R'1 6 said cycloalkyl, heterocycloalkyl, aryl, heteroaryl, polycycloaryl or heterpolycycloaryl ring optionally is substituted by a group selected from -R' 8 -X 5 SR's, -X 5 S(O)R' 8 -X 5 S(O),R' 8 -X 5 C(O)R] 8 -X'C(O)OR 8 -X 5 OC(O)R' 8 -X 5 NR' 8 R' 9 -X 5 NR' 9 C(O)R' 8 -X 5 NR' 9 C(O)OR 8 -X 5 C(O)NR 8 R' 9 -XsS(O) 2 NR' 8 R] 9 -X 5 NR' 9 C(O)NR'&R' 9 or -X 5 NR' 9 C(NR' 9 )NR' 8 R 9 wherein X 5 is a bond or (C,,)alkylene, R' 8 is hydrogen or (C,-6)alkyl and R1 9 is 2 )cycloalkyl(C~m)alkyl, hetero(Q 1 2 ,)cycloalkyl(CO,)alkyl, (C, 2 )ary](C,)alkyl, hetero(C5.1 2 )aryl(C0.)alkyl, (C 9 2 )polycycloaryl(C,,)alkyl or hetero(C, 2 ,)polycycloaryl(C,,)alkyl, or (ii) a group selected from (C,,)cycloalkyl(C")alkyl, hetero(C,, 2 )cycloalkyl(C.)alkyl, (C,,,)aryl(C.,)alkyl, hetero(C, 2 )aryl(C,)alkyl, (C 9 2 )polycycloaryl(C,,)alkyl and hetero(Cs, 2 )polycycloary(C,6)alkyl, wherein said cycloalkyl, heterocycloalkyl, aryl, heteroaryl, polycycloaryl or heterpolycycloaryl ring optionally is substituted by a group selected from -R" 8 -X 5 OR' 8 -X. 5 SR' 8 -X 5 S(O)R' 8 -X5S(O) 2 Rls, -X 5 C(O)R' 8 -XsC(O)OR'8, -X 5 OC(O)R] 8 -X 5 NR1 8 R' 9 -X 5 NR1 9 C(O)R' 8 -X 5 NR1 9 C(O)OR's, -X 5 C(O)NR'gR' 9 -X 5 S(O),NR' 8 R' 9 -X 5 NR' 9 C(O)NR' 8 R' 9 or -X 5 NR1 9 C(NR' 9 )NR' 8 BR' 9 wherein X 5 R' 8 and R' 9 are as defined above; wherein within R 1 2 and/or R'1 3 any alicyclic or aromatic ring system present may be substituted further by I to 5 radicals independently selected from (C,,)alkyl, (CI-6)allcylidene, cyano, halo, halo-substituted (C 14 )alkyl, nitro, -X 5 NR. 4 R 4 _X 5 NR1 4 C(O)OR 1 4 -X 5 NR' 4 C(O)NR 14R 4 -X 5 NR 1 4 C(NR' 4 )NR 1 4 R 4 -X 5 OR' 4 -X 5 SR'1 4 -X 5 C(O)OR'1 4 -197- -XsC(O)NR1 4 RI4, -X 5 S(O) 2 NR 4 R 4 14PO(R~)R~ XO(O(R)R~ -X 5 NR 1 4 C(O)RI-S, -X 5 S(O)R' 5 -XsS(O) 2 and -X5C(O)R 1 5 wherein X5, R 1 4 and R'1 are as defined above; or R" 2 together with R" and/or R" 3 together with RW' form trimethylene, tetramethylene or phenylene-l,2-dimethylene, optionally substituted with I to 3 radicals independently selected from (C, 4 6)ai1kyl, (C 14 ,)alklidene, cyano, halo, halo-substituted (C,,.)alkyl, nitro, oxo, -X 5 NR 1 4 C(O)OR 14, -XsNR 1 4 C(O)pqRI4R4, -X 5 NR1 4 C(NR 1 4 )NR'4R]4, -X 5 OR 1 4 -X 5 SR'14, -X 5 C(O)QR'1 4 -XSC(O)NR 1 4 R14, -XSS(O) 2 N.R 1 4 -X 5 P(O)(OR 1 4 )OR4, -X 5 OP(O)(OR4)OR", -X 5 NR' 4 C(O)R] 5 -XsS(O)R' 5 -X 5 S(O) 2 R 1 5 and -X 5 C(O)RI 5 wherein X 5 R 1 4 and R 1 5 are as defined above; and RI is -XXR 2 1, wherein X 6 is or X 7 is a bond, or 4fl 2 wherein is hydrogen or (C,.,)alkyl, and RIO is (C 1 -6)alkyl optionally substituted by cyano, halo, nitro, -NR' 4 R' 4 -NR 4 C(O)OR 1 4 -NR 1 4 C(O)NR1 4 R4, _NR1 4 C(NR] 4 )NR1 4 R14, -OR' 4 -SR'1 4 -C(O)QR 1, -C(O)NR1 4 R 4 _S(0) 2 NR1 4 R1 4 -P(O)(OR' 4 )OR'1 4 -S(O) 2 R'2, -C(O)OR22, -C(O)NR2nRf, -NR22Rn, -NR 21C(O)R 22, -NR 23C(O)OR 22 -NR nC(O)NR22R' or -NRnC(NRn)NRnR', wherein R"1 and R' 5 are as defined above, R' is (C3., 2 )CYClOalkYl(CO)alcyI, hetero(C3., 2 )cycloalkyl(C,,)alkyl, (C,,)aryl(C,)a~kyI, hetero(C-.1 2 )ary](C")alkyl, (C 9 2 )bicycloaryl(Co)alkyl or hetero(C 8 2 )bicycloaryl(C,.6)alkyl and RI at each occurrence independently is hydrogen or (C 14 6)alkyl, or diphenyl(C,)alkyl, hetero(C5_j2)aryl(CO.)alkyl, (C9,1 2 )bicycloaryl(CO.)alkyl or hetero(Cs-1)bicycloaryl(C.)alkyI wherein said cycloalkyl, heterocycloalkyl, aryl or heteroaryl may be substituted by -RI, -X 5 0R 2 -X 5 SR 2 4, -X 5 S(O)Rl, -XsS(O) 2 Ru, -XsC(O)R 4 -X5C(Q)ORU", _X5C(O)NR 2 4R25, -X 5 NR24R2, _X 5 NR 2C(O)R 7A -XsNR25C(O)OR24, -XsNR25C(O)NRR25 or -XsNR25C(NR2)NR4R2S, wherein X 5 is as defined above, R24 is (C3_j 2 )cycloalkyl(CO.)aIkyl, hetero(C3.1 2 )CYCloalkyl(CO.)alkl, (C 6 .j 2 )aryl(C4)alkyl, hetero(Q, 1 2 )aryl(CO4)akyl, (C9.j 2 )bicycloaryl(C,,)alkyl or hetero(C 1 2 )bicycloaryl(CodalkyI and R25 at each occurrence independently is hydrogen or (C, 4 6)alcyl; wherein within R' any alicyclic: or aromatic ring system present may be substituted further by I to 5 radicals independently selected from (C, 4 )alkyl, (C,,)alkylidene, cyano, halo, -198- halo-substituted (C 1 4 )alkyl, nitro, -X 5 NR' 4 R 1 4 _XSNR1 4 C(O)OR 1 4 -X 5 NR1 4 C(O)NR4R 14, -X 5 NR1.C(NR1 4 )NR1 4 R1 4 -X5OR 1 4 -X5SR 1 4 -X 5 C(Q)0R 4 _X5C(O)NR 4 R] 4 _XSS(O) 2 NR 14 R] 4 ,I -X 5 P(O)(OR 1 4 )OR 1 4 -X 5 OP(Q)(OR 1 4 )QR 1 4 -X 5 NR 4 C(O)R' 5 -XsS(O)R]S, -X 5 S(O) 2 R' 5 and -X 5 C(O)R 1 5 wherein X 5 R 1 4 and R" are as defined above; or when X1 is a divalent group of formula or then R' may also represent hydrogen, carboxy, oxalo or carbamoyl; R 2 is hydrogen or (C 1 6 )alkyl; RI is (C 1 -6)alkyl optionally substituted with cyano, halo, nitro, -SRI, -C(O)0R 4 -C(O)NR24R24, -P(Q)(OR)OR 4 -OP(O)(OR-)OR 2 4 -S(O)R 25 -S(O) 2 R' or -C(O)RI, wherein RI' at each occurrence independently is hydrogen, (C,,)alkyl or halo-substituted (C, 1 3 )alkyl and RI (C 1 -6)alkyl or halo-substituted 3 )alkyl, or (ii) (C3.)cycloalky(C 23 ,)alkyl, hetero(C,.)cycloalkyl(C 2 3 )alkyl, (C& 1 2 )ari(C 2 3 )alkyl or hetero(C.,)aryl(C 2 3 )alkyl, wherein said cycloalkyl, heterocycloalkyl, aryl or heteroaryl optionally is substituted further with 1 to radicals independently selected from (C 1 -6)alkyl, (C 1 6 )alkylidene, cyano, halo, halo-substituted (C,,)alky1, nitro, -X 5 NR' 4 C(O)OR' 4 -X 5 NR 1 4 C(O)NR1 4 R 1 4 -X 5 NR1 4 C(NR1 4 )NR1 4 R 4 -X 5 OR 1 4 -X 5 SR 1 4 -X 5 C(O)OR 1 4 -X 5 C(O)NR1 4 R' 4 _X 5 S(O) 2 NR1 4 R14, -X 5 p(O)(OR' 4 )OR 1 4 -X 5 OP(O)(OR' 4 )OR 1 4 -X'NR"4C(O)R' 5 -X 3 S(O)R 1 5 9 -X 5 S(O) 2 R' 5 and -XSC(O)RI 5 wherein X1, R 1 4 and R1 5 are as defined above, provided that when R 3 is unsubstituted (C 1 5 )alkyl and R 4 is hydrogen or unsubstituted (C, 1 5 )alkyl, then X 2 may not represent a bond when R' is -C(O)R 20 -C(O) 2 R' or -S(O),Rl in which R" is (C,,)alkyl, phenyl(C,,)alkyl, phenyl, (q- 7)cycloalkyl, camphan-10-yl, naphth-1-yl, naphth-2-yl, phenyl substituted by one or more of 4 )alkyl, perfluoro(C,,)alkyl, (C,,)alkoxy, hydroxy, halo, amido, nitro, amino, (C, 4 )alkylamino, (C,4)dialkylamino, carboxy or (C,,)alkoxycarbonyl, or naphth-1-yi or naphth-2-yl substituted by one or more of (C,,)alkyl, perfluoro(C 14 )alcyl, (C, 4 )alkoxy, hydroxy, halo, amido, nitro, amino, carboxy or (C1.4)alkoxycarbonyl or (ii) a divalent group of formula or in which the moiety R 1 2 is methyl, isopropyl, n-butyl, sec-butyl, tert-butyl, 1-methylpropyl, benzyl, naphth-l-ylmethyl, naphth-2-ylmethyl, thien-2-ylmethyl, thien-3-ylinethyl, or wherein RI and R 12 form ethylene, trimethylene, hydroxy-substituted trimethylene, tetramethylene or phenylene-1 ,2-dimethylene; or R' and R' taken together with the carbon atom to which both R 3 and R" are attached form (C 3 8 g)cycloalkylene or (C3-)heterocycloalkylene, wherein said cycloalkylene or heterocycloalkylene is optionally substituted with I to 3 radicals independently selected from (CI-6)alkyl, (C 1 -6)alkylidene, cyano, halo, halo-substituted (CI- 4 )alkyl, nitro, _X 5 NRIIC(O)QR 1 4 -199- -X 5 NR 1 4 C(O)NR1 4 RI4, _X 5 NR1 4 C(NR 14)NR 1R', _X 5 OR'1 4 -X'SR 1 4 -X 5 C(O)OR 1 4 -XC(O)NR1 4 RI 4 -X 5 S(O) 2 NR 1R1 4 _X 5 p(O)(OR' 4 )OR 1 4 _X5Op(O)(OR.'4)OR. -X 5 NR 1 4 C(O)R 1 5 -X 5 S(O)R' 5 -X 5 S(O)2R and -X 5 C(O)R 1 5 wherein X 5 R 1 4 and R 1 5 are as defined above; R 4 is hydrogen, (C1,6)alkyl or as defined above; R 5 is hydrogen and R 6 is hydroxy or R 5 and R 6 together form oxo; R" is a group selected from cyano, halo, nitro, -R 29 -X 5 NR 2 9 R 30 -X 5 NR 3 1C(O)OR~, -X-SNR30C(O)NR29R3O, -XN-(R-N2R0 -X 5 0R 29 -X 5 SR 29 -X 5 C(O)OR29, -X 5 C(O)NR2 R30 -X5S(O)NR 29 R 3 -XsP(O)(QR3n)OR 29 -X 5 OP(O)(OR. 29 )OR29, -X 5 NR3C(O)R20, -X 5 S(O)R20, -X 5 S(O) 2 R20, -X 5 C(O)R' and -C(O)NR 42 CiHR43C(O)QR9, wherein XI and RI are as defined as above, R 29 is hydrogen or -RI, wherein R 20 is defined as above, R 30 at each occurrence is hydrogen or (C, 4 6)alkyl, R 4 1 is hydrogen, (C,-6)alkyl or together with R 4 3 forms triniethylene, tetramethylene or phenylene-1,2-dimethylene, optionally substituted with hydroxy or oxo, and R 43 is as defined above or is (C,-,)alkyl optionally substituted with cyano, halo, nitro, -NR' 4 R' 4 -NR 1 4 C(O)ORI 4 _NR14C(O)NR1 4 R 4 -NR1 4 C(NR 4 )NR1 4 R] 4 -OR 4 1S 4 -C(O)OR. 4 -C(O)NRl 4 R 1 4 -S(O) 2 NR 1 4 R' -P(O)(OR' 4 )OR' 4 -OP(O)(OR' 4 )OR 1 4 -NR1 4 C(O)R 1 5 -S(O)R1 5 -S(O) 2 R 1 5 -C(O)R 5 -OR' 6 -SR' 6 -S(Q)R 1 6 -S(O) 2 R 1 6 -C(O)R 1 6 -C(O)OR 1 6 -OC(O)RI 6 -NR1 6 R]7, -NR' 7 C(O)R 6 -NR' 7 C(O)OR 6 -C(O)NR1 6 RI 7 -S(O) 2 NR1 6 R' 1 -NR 7 C(O)NR1 6 R 7 or -NR1 7 C(NR1 7 )NR1 6 RI 7 or (ii) a group selected from (C 2 )cycloalkyl(Cojalkyl, hetero(C 31 2 )cycloalky](C,)all, (C6.1 2 )arYl(C")alkyl, hetero(Q,1 2 )aryl(C Jalkcyl, (C 9 2 )polycycloaryl(C,)alkyl and hetero(Cs, 2 )polycycoylC,)alkyl, wherein said cycloalkyl, heterocycloalkyl, aryl, heteroaryl, polycycloaryl or heterpolycycloaryl ring optionally is substituted by a group selected from -R' 8 _X 5 OR. 8 -X 5 SR' 8 -X 5 S(O)R' 8 -X 5 S(OX2R'g, -X 3 C(O)RI 8 -X 5 C(O)OR' 8 -X 5 OC(O)R 8 -Xs$NRSRI 9 -X 5 NR1 9 -X 5 NR1 9 C(O)OR 8 -X 5 C(O)NR' 8 R]9 -X 5 S(O) 2 NR'BR' 9 -XsNRl 9 C(Q)NR'8RI9 or -X 5 NR' 9 C(NR' 9 )NqR'gR'9, wherein X 5 R1 5 R'1 6 R1 7 R's and R' 9 are as defined above; wherein within R 7 any alicyclic or aromatic ring system present may be substituted further by I to 5 radicals independently selected from (CI-6)allcyl, 6 )alkylidene, cyano, halo, halo-substituted (C,)alkyl, nitro, -X 5 NR 4 R 4, X 5 NR1C(O)OR' 4 -X 5 NR"4C(O)NR4R'I, 1-X 5 NR14C(NR1 4 )NR1 4 R14, -X5OR 1 4 -X-SR1 4 t _X'C(O)OR 1 4 9 -X 5 C(O)NR14RI _XSS(O) 2 NR1 4 R1 4 -X5P(O)(OR' 4 )OR]4 -X 5 OP(O)(OR 1 4 )OR 4 _XSNR1 4 C(O)R5, -X 5 S(O)R' 5 -X_'S(O)0R 5 and -XIC(O)RS5, wherein X 5 R 1 4 and R 1 5 are as -200- defined above; and R 8 at each occurrence independently is selected from (C 1 -6)alkyl, halo-substituted (C, 1 4 )alkyl, (C,-6)alkylidene, cyano, halo, halo-substituted 4 )alkyl, nitro, -X 5 NR1 4 R 4 -X 5 NR1 4 C(O)OR 1 4 -X 5 NR1 4 C(O)NR1 4 R 1 4 -XsNR1 4 C(NR' 4 )NR1 4 R 1 4 -X 5 OR 1 4 _X 5 SR1 4 -X 5 C(O)0R 14 _X5C(O)NR1 4 R] 4 -X 5 S(O) 2 NR' 4 R 4 -X'P(O)(OR 1 4 )OR"1, -X5OP(O)(OR1 4 )OR 1 4 -X 5 NR1 4 C(O)R 1 5 _X 5 S(O)R'1 5 -X 5 S(O) 2 R' 5 and -X 5 C(O)RII, wherein V 5 is a bond or (C,.6)alkylene, R 14 at each occurrence independently is hydrogen, (C, 1 6)alkyl or halo-substituted (C 1 3 )alkyl and R" 5 6 )alkyl or halo-substituted 3 )alkyl; and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers; and the pharmaceutically acceptable salts thereof. 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, pyrid-2-yl, pyrid-3-yl, thiazol-2-yl, 1-methyl-IH-imidazol-2-yl, I -benzyl-1H-imidazol-2-yl, benzooxazol-2-yl, benzofur-2-yl, benzothiazol-2-yl, IH-benzoimidazol-2-yl, 1, 1-dioxo-1H-1X 6 -benzo[blthien-2-yl, quinol-3-yl, [1 ,3]dioxolan-2-yl, naphtho[2,3-d~oxazol-2-yl, naphtho[1,2-dAoxazol-2-yl and naphtho[2,1-d]oxazol-2-yl, each substituted by a group RI and optionally substituted with a gro up wherein R' is halo, nitro, -OR" 9 -S(O) 2 NR 29 -C(O)NR29R 3 or -C(O)NHCHR 4 3 C(O)0R 9 wherein R' is (C 14 6)alkyl, 12 )cycloalkyl(C4)alkyl, hetero(CQ3 1 2 )cycloalkcyl(CO.)alkyl, (C6, 2 )arYI(CO-)alkyl, diphenyl(C,)alkyl, hetero(CQ 1 2 )aryl(C,6)alkyl or hetero(C 8 2 )polycycloaryl(C,6)alkyI and R1 9 is hydrogen or -RIO, wherein R20 is defined as above, wherein said heterocycloalkyl may be substituted with 2 )aryl(C0.,)alkyl, R30 at each occurrence is hydrogen or (C,,)alkyl and R 4 3 is (C 14 6)alkyl, and R 8 at each occurrence independently is hydrogen, (C 1 .6)alkyl or halo-substituted (C 1 4 )alkyl; wherein within R' any alicyclic or aromatic ring system present may be substituted further by 1 to 5 radicals independently selected from (C 1 -6alkyl, (C,-6)alkylidene, cyano, halo, halo-substituted 4 )alkyl, nitro, -X 5 NR1 4 R 1 4 -X 5 NR1 4 C(O)ORI 4 _X 5 NR 1 4 C(O)NR 1 4 R] 4 1-X 5 NR1 4 C(NR1 4 )NR14R4, -X 5 OR'1 4 -X 5 SR 1 4 -X 5 C(O)OR 1 4 -X 5 C(O)NR1 4 R 4 -X5S(Q) 2 NR1 4 R' 4 -X 5 P(O)(OR' 4 )OR 1 4 -X'OP(O)(OR 1 4 )OR 1 4 -NRC(O)RI 5 -X 5 S(O)R' 5 -X 5 S(O),R 1 and -X 5 C(O)R 5 wherein X 5 is a bond or (C 14 6)alkylene, R 1 4 at each occurrence independently is hydrogen, (C, 1 6)alkyl or halo-substituted (CI. 3 )alkyl and R' (C 1 .6)alkyl or halo-substituted (C 1 3 )alkyl; 1- V 2 is a bond or a divalent group of Formula or wherein within Formula X 3 is R" is hydrogen, R" is hydrogen or methyl, and R" 2 is (C,.6)alkyl; RI is hydrogen or -X 6 X'R 20 wherein X 6 is or -S(0) 2 7, V' is a bond or and R 20 is (C 14 ,)alkyl, (C3.,)cycloalkyl(Cm)alkyl, hetero(C3. 12 )cycloalkyl(C .)alkyl, (C6-, 2 )ayI(C6)alkyl or hetero(C 5 12 )arY1(CO,)alkyl; wherein within R' any alicyclic or aromatic ring system present may be substituted further by 1 to 5 radicals independently selected from (C 1 JalkyI, -IC(O)OR' 4 -X 5 NR 1 4 R1 4 and -X 5 NR'C(O)OR 1 4 wherein X 5 is a bond or (C 1 6 )alkylene, R 1 4 at each occurrence independently is hydrogen, (C,,)alkyl or halo-substituted (C 1 3 )alkyl and R1 5 (C, 4 6)alkyl or halo-substituted (CI- 3 )alkYl; R 2 is hydrogen; R 3 is (C 14 6)allcyl or (C 6 .,,)aryl(C 1 3 )alkyl or R 3 and R 4 taken together form straight, saturated (Q 5 )alkylene; R 4 is hydrogen or (C 1 6 )alkyl or as defned above; and RI and R 6 preferably together form oxo; and the N-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-dloxazol-2-yl, naphtho[l,2-d]oxazol-2-yl or naphtho[2,1-d4oxazol-2-yl, each substituted by a group R' and optionally substituted with a group R 8 wherein R 7 is halo, -C(O)0R 2 -C(O)NR 9 R 0 or -S(O) 2 NR9R' wherein R20 is (C 14 6)alkyl, (C 3 2 )cycloalkyl(C.Wakyl, (C~j 2 )aryI(Cm)alkyl, hetero(C5- 12 )aryl(C70.)alkyl or hetero(C -1)polycycloaryl(CO.)alkyl; X' is a divalent group of Formula wherein within Formula X 3 is R' and RI! each are hydrogen and R 1 2 is isobutyl, sec-butyl or isopropyl; RI 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-ycarbonyl, 2-cyclohexylacetyl, 4-cyclohexylbutyryl, 2-cyclohexylethylsulfonyl, 3-cyclohexylpropionyl, 2-cyclopentylethylsulfonyl, hydrogen, 4-methylpiperazin-1-ylcarbonyl, methylsulfonyl, 4-methylvaleryl, 3-niorpholin-4-ylpropionyl, naphth-2-ylmethyl, 3-phenylpropionyl, piperazin-1-ylcarbonyl, piperidin-4-ylcarbonyl and pyrid-3-ylcarbonyl, wherein within-R' any -202- alicyclic or aromatic ring system present may be substituted further by I to 3 radicals independently selected from 3-aminomethyl and 3-tert-butoxycarbonylaminomethyl; R 3 is phenethyl or R 3 and R" taken together form ethylene; and R" is hydrogen or methyl or as defined above; and the N-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[1,2-d]oxazol-2-yl, each substituted by a group RI and optionally'substituted with a group R8, particularly wherein RI is adamantan-l-ylmethylcarbamoyl, benzyl, benzylcarbanioyl, benzyl(methyl)carbamoyl, I -benzyloxycarbonyl-3-methylbutylcarbamoyl, 4-benzylpiperidin-l-carbonyl, tert-butyl, chloro, 2,3-dihydroindol-l-ylcarbonyl, 3,4-dihydro- 1H-isoquinol-2-ylcarbonyl, 3,4-dihydro-lH-quinol-l-ylcarbonyl, diphenylmethylcarbamoyl, fur-2-ylmethylcarbamoyl, hydrogen, 2-(1H-indol-3-yl)ethylcarbamoyl, mnethoxy, methoxycarbonyl, methyl, 3-methylbutylcarbamoyl, methylcarbamoyl, 1-methylethylcarbamoyl, naphth-l-ylmethylcarbonyl, nitro, phenyl, phenylcarbainoyl, 2-phenylcyclopropylcarbanoyl, 1-phenylethylcarbamoyl, sulfamoyl, trifluoromethyl, phenethylcarbamoyl, 3-phenylpropylcarbamoyl, piperid-l-ylcarbonyl, pyrid-2-ylmethylcarbamoyl, pyrid-3-ylmethylcarbamoyl, pyrid-4-ylmethylcarbamoyl and pyi-rolidin-1-ylcarbonyl and RI is methyl XI is a divalent group of Formula wherein within Formula R" 2 is isopropyl; R 3 is phenethyl; and R" is hydrogen; and the N-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 a therapeutically effective amount of a -203- 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. 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-1-ylpropylidene-1,1 -bisphosphonic acid, 1-hydroxyethylidene-1 ,1-diphosphonic acid, 1-hydroxy-3-(N-methyl-N-pentylamino)propylidene-1,1-bisphosphonic acid, 6-amino- 1-hydroxyhexylidene-1,1-bisphosphonic acid, 3-(dimethylamino)-1-hydroxypropylidene- 1,1-bisphosphonic acid, 3-amino-1-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-(1H-imidazol-1-yl)ethylidene-1,1-bisphosphonic acid or acid ester thereof or a pharmaceutically acceptable salt thereof. 46. The composition of Claim 45 wherein the bisphosphonic acid is 1,l-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: R 2 R 4 1 6 S3 i' R I in which: A comprises a heteromonocyclic ring containing 5 to 6 ring member atoms or a fused -204- heteropolycyclic ring system containing 8 to 14'ring member atoms, wherein each ring contains to 7 ring member atoms, X' is a ring member carbon atom and each ring member atom other than X' is a carbon atom or a heteroatom, with the proviso that 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; XI is or -CH-; X' is a bond or a divalent group of Formula or 11I 12Ri R1R2 R R 1I ~Nxx 3 1 XXX 3 191' I 13 1 R R"R' R 9 (b) wherein: X 3 and X 4 independently are or -CH 2 S(O) 2 R' and R' 0 independently are hydrogen, (C,-6)alkyl or as defined below; R" at each occurrence independently is hydrogen or (C,.6)alkyl; R 1 2 and R'1 3 independently are (G, 4 6)alkyl optionally substituted with cyano, halo, nitro, -NR' 4 R' -NR' 4 C(O)OR 1 4 -NR 1 4 C(O)NR1 4 R 1 4 -NR1 4 C(NR 1 4 )NR1 4 R 4 -OR'1 4 -SR'1 4 -C(O)OR1 4 -C(O)NR' 4 R] 4 -S(O) 2 NR"4R", -P(O)(OR' 4 )QR 1 4 -OP(O)(OR'1 4 -NR 4 C(O)R 5 -S(Q)R 5 -S(O) 2 R"s, -C(O)R' 5 -SR' 6 -S(O)R 1, _S(O) 2 R16, -C(O)R 1 6 -C(O)OR 1, -NR16R17, -NR1 7 C(O)R 1, -NR1 7 C(O)OR 1, -C(O)NR6R'1 7 -S(O) 2 NR"1R1 7 -NR 1 7 C(O)NR16R 1 7 or -NR 1 7 C(NRI 7 )NR16R1 7 wherein R'1 4 at each occurrence independently is hydrogen, (C,,6)alkyl or halo-substituted (CI- 3 )alkyl, R 5 (C,.6)alkyl or halo-substituted 3 )alkyl, R 1 is 2 )cycloalkyl(C04)alkyI, hetero(C 3 2 )cycloallcyl(C,.)alkyl, (C6, 2 )arYl(C")alkyl, hetero(Q,1 2 )arYl(C,.6)alkyl, (Cq., 2 )polycycloaryI(Cu)a~kyl or hetero(Cs., 2 )POlYcycloaryl(CO.)alk and R 1 7 is hydrogen or (C,,)alkyl, and wherein within R"1 said cycloalkyl, heterocycloalkyl, aryl, heteroaryl, polycycloaryl or heterpolycycloaryl. ring optionally is substituted by a group selected from -RII. -X 5 OR"., -X 5 SR' 8 -X 5 S(O)R"8, -X 3 S(O) 2 R"8, -X 5 C(O)R'8, -X'G(O)OR' 8 -X 5 OC(O)RII, -205- -XsNR'BR"9, -XsNR1 9 C(O)R' 8 -X5NR' 9 C7(Q)ORi 8 -X 5 C(Q)NR 1 8 R! 9 -X 5 S(O) 2 NR' 8 R' 9 -X 5 NR' 9 C(O)NR 8 R or -XsNRl 9 C(NR 9 )NR'BR9, wherein X 5 is a bond or (Cl.6)alcylene, R' 8 is hydrogen or (C 14 6)alkyl and R1 9 is (C 312 )CYCloalkyl(C4)alkyl, hetero(Q 22 )cycloalkyl(CM)akyl, (C6 12 )aryl(CO,)aky1, hetero(C5.I)aryl(C")alkyl, (C 912 )polycycloaryl(C,)alkyl or hetero(C8. 12 )Polycycloary(C")alkyl, or (ii) a group selected from (C3. 12 )cycloalkyl(CO.)alkyl, hetero(C3- 2 )CYCloalkyl(C")alkyl, (C6 12 )aryl(C.)alkyl, hetero(C. 1 2 )ary1(QO4)alkyI, (C 9 1 2 )polycycloaryl(C 04 6)alkyl and hetero(C8- 1 2 )polycycloaryl(C ")alkyl, wherein said cycloalkyl, heterocycloalkyl, aryl, heteroaryl, polycycloaryl or heterpolycycloaryl ring optionally is *substituted by a group selected from -RI8, -X'OR' 8 -XISR' 8 -X 5 -X 5 S(O)2, 8 -X5C(O)R 8 -X 5 -X'OC(O)Rlg, -X 5 NR, -X 5 NR' 9 C(O)RI 8 -X 5 NR' 9 C(O)OR 8 -X 5 C(Q)NR'&R' 9 -X 5 5(O),NR' 8 R' 9 _X 5 NR' 9 C(O)NR' 8 R 9 or -X1NR" 9 CM'R 9 )NR'8R9, wherein X 5 R' 8 and R 1 9 are as defined above; wherein within R' 2 and/or R 1 3 any alicyclic or aromatic ring system present may be substituted further by 1 to 5 radicals independently selected from (Cl.6)alkyl, (C, 4 )alkylidene, cyano, halo, halo-substituted (C, 4 )alkyl, nitro, _X 6 NR1 4 R 4 -X 6 NR' 4 C(O)OR'1 4 -X 6 NR1 4 C(O)NR1 4 R 4 -X 6 NR1 4 C(NR14)NR1 4 R 4 _X 6 OR 1 4 _X 6 SR 1 4 -X 6 C(O)OR 1 4 -X 6 C(Q)NR1 4 RI 4 -X 6 S(Q) 2 NR 1 4 R1 4 -X 6 p(O)(OR' 4 )OR 1 4 -X 6 Qp(Q)(QR' 4 )0R 14 -X 6 NR1 4 C(O)R 1 5 -X 6 S(Q)R 1 5 -X 6 S(O) 2 R 15 and -X 6 C(Q)RI 5 wherein X 6 is a bond or (C 14 6)alkylene and R"1 and RI5 are as defined above; or R 1 2 together with R 9 and/or R'1 3 together with RIO form trimethylene, tetramethylene or phenylene-1 ,2-dimethylene, optionally substituted with hydroxy or oxo; and RI is -X 7 X 8 R2, wherein X 7 is or -S(O) 2 X' is a bond, or -NR 21 wherein R 2 1 is hydrogen or (CI-6)alkyl, and R2' is 6 )alkyl optionally substituted by cyano, halo, nitro, _NR1 4 R14, -NR' 4 C(0)0R 1 4 ,9 -NR 1 4 C(O)NR1 4 R] 4 -NR1 4 C(NR' 4 )NR 4 R 1 4 -OR 1 4 -SR1 4 t -C(O)OR 1 4 -C(O)NR1 4 R' 4 _S(O) 2 NR1 4 R1 4 -P(O)(OR' 4 )OR 1 4 -OP(O)(OR 4 )OR 1, -NR14C(O)R 5 -S(O)R' 5 -S(O) 2 R 1 -C(O)R 11, -OR 22, -SR 22, -S(O)R 22 -S(O) 2 R -C(O)R 2, -C(O)OR 2, -C(O)NR 22R 2, -NR 22R 1, -NR2nC(O)R 2, -NRn'C(O)OR2,-NR23C(O)NR22R3 Or -NR23C(NR 23 )NR 22 R73, wherein R1 4 and R' 5 are as defined above, R22 is 2 )cycloalkyl(C,)alkyl. hetero(C, 2 )CYCloalkyI((c,,)alkyl, -206- (C& 1 2 )arYl(C m)alkyl, hetero(C.1 12 )aryl(CO-)alky1, (C 12 )bicycloaryl(C0.)alkyl or hetero(CS- 12 )bicycloaryl(C )alkyI and R23 at each occurrence independently is hydrogen or (C 14 6)alkyl, or (ii) (C._t 2 )cycloalkyl(Cm)alkyl, hetero(C 3 1 2 )cycloalkyl(CO4)alkyl, (Q6 12 )aryl(C")alkyl, diphenyl(C")alkyI, hetero(C 5 12 )aryl(Cm)alkyl, dihetero(q,6)aryl(Cm)alkyI, (C J 2 bicycoaryl(CO_)alkyl or hetero(C 8 1 2 )bicycloary1(C.)alcyl wherein said cycloalkyl, heterocycloalkyl, aryl or heteroaryl may be substituted by -X 9 0R 2 4 -X9SR 24 -X 9 S(Q)R 2 4 -X 9 S(O), 2 u, -X 9 C(O)R24, -X 9 C(Q)0R 24 -X 9 C(Q)NR24R2, -X9NR24R2, -X NR5C(Q)R24, -X9NRC(O)OR24, -X9N2C(O)NR24R25 or -XN'(R)R4' wherein X 9 is a bond or (C 1 -6)alkylene, R24 is 1 )cycloalkyl(C0.)alkyl, hetero(C 12 ccall()lk, 6 1 )ryl()akl hetero(C 5 -J 2 )arYl(C0.)alkYl, (C94 2 )bicycoary(C0 )alkyl. or hetero(C&, 2 )bicycloaryI(C,-)alkyl and RI at each occurrence independently is hydrogen or (C 1 .6)alkyl; wherein within RI any alicyclic: or aromatic ring system present may be substituted further by I to 5 radicals independently selected from (C, 14 )alkyl, (Cl.6)alkylidene, cyano, halo, halo-substituted (Cl 14 )alkyl, nitro, _X 6 NR1 4 R1 4 I-X 6 NR1 4 C(O)OR 1 4 -X 6 NR' 4 C(O)NR1 4 R"4, _X 6 NR1 4 C(NR1 4 )NR1 4 R1 4 -X 6 0R1 4 -X 6 SR 1 4 -X 6 C(O)OR"4, -X 6 C(O)NR14' 4 -X 6 S(O) 2 NR 4 R 4 -X 6 P(Q)(QR 1 4 )OR 1 4 -X 6 OP(O)(OR' 4 )OR] 4 _X 6 NR1 4 C(O)R 5 -X 6 -X6S(O) 2 R 15 and -X 6 C(O)R'5, wherein X" is a bond or (C 14 )alkylene and R 1 4 and RI 5 are as defined above; or when XI is a divalent group of formula or then R' may also represent hydrogen, carboxy, oxalo or carbainoyl; R 2 is hydrogen or (C 1 -6)alkyl; R 3 is (C,,)alkyl optionally substituted with cyano, halo, nitro, -SR 2 4, -C(O)0R 2 -C(O)NR24R2, -P(O)(QR2)OR 2 4, -OP(O)(0R 24 )0R 24 -S(Q)R2, I-S(O) 2 R25 or wherein R' at each occurrence independently is hydrogen, (C, 4 )alkyl or halo-substituted 3 )alkyl and R25 (C, 4 6)alkyl or halo-substituted (C 1 3 )alkyl, or (ii) (C5)cycloalkyl(C 23 )alkyl, hetero(C 3 -6)cycloalkyl(C 23 )alkyl, (C6.j 2 )aryl(C 23 )alkyI or hetero(C5.)aryl(C 23 )alkyl, wherein said cycloalkyl, heterocycloalkyl, aryl or heteroaryl optionally is substituted further with 1 to radicals independently selected from (C 14 6)alkyl, (C, 14 )alkylidene, cyano, halo, halo-substituted (C 14 )alkyl, nitro, -X 6 NR 4 C(O)0R 14 -XNR 4 C(O)NR 4 R' -X 6 NR' 4 C(NR'")N R 1 4 -X 6 OR1 4 -X 6 SR 1 4 -X 6 C(O)OR 1 4 _X 6 C(O)NR1 4 RI 4 X 6 S(O) 2 NR1 4 R1 4 -X 6 P(O)(OR"4)OR1 4 -X 6 OP(O)(OR1 4 )OR 1, -X 6 NR"4C(Q)R' 5 -X 6 S(O)R' 5 -XIS(O),R" and -X 6 C(O)R, 5 wherein R1 4 and R 1 5 are as defined above, or -207- R' and W 4 taken together form straight, saturated (C 2 .5)alkylene, wherein within said ailkylene any one to two carbon atoms optionally is replaced by a heteroatom selected from or -NRn8- wherein RI is hydrogen or 6 )alkyl; R4~ is hydrogen, (C, 4 6)alkyl or as defined above; R 5 is hydrogen and R(6 is hydroxy or R(5 and R 6 together form oxo; RI7 is a group selected from cyano, halo, nitro, -R 2 9 -X' 0 NR 29 R 30 -X' 0 NR 3 0 C(O)0R 29 -X' 0 NR 30 C(Q)NR 29 -X' 0 NR 30 C(NR 30 )NR29R3, -X' 0 0R 29 -XI 0 SR 29 -X' 0 C(O)0R 29 -X' 0 C(O)NR29R30 -X' 0 S(O) 2 NR29R 30 -X t0 P(O)(0R 30 )0R 29 ,I -XI 0 Op(O)(0R2)OR 2 9 -X' 0 NR 30 C(0)R2", -X' 0 S(0)R 20 -X' 0 S(O)2R 2 0 -X' 0 C(Q)R 20 and -C(O)NR 2 CHR 43 C(O)0R 29 wherein X 10 is a bond or (C,,)akylene, wherein R' 0 .is defined as above, 1 is hydrogen or -RI, wherein R20 is defined as above, R(30 at each occurrence is hydrogen or (C, 4 6)alkyl, 1(42 is hydrogen, (CI-6)alkyl or together with R(43 forms trimethylene, tetraniethylene or phenylene- 1,2-dimethylene, optionally substituted with hydroxy or oxo, and R(43 is as defined above or is (i) (C,.,)alkyl optionally substituted with cyano, halo, nitro, -NR' 4 R' 4 -NR1 4 C(O)OR 4 -NR' 4 C(O)NR1 4 RI 4 -NR1 4 C(NR1 4 )NR1 4 R 4 -OR 14, -C(O)OR 1 4 -C(O)NR1 4 R 4 _S(O) 2 NR1 4 R1 4 -P(O)(OR' 4 )OR 1, -OP(0)(OR' 4 )OR] 4 -NR1 4 C(0)R' 5 -S(0)RIS, -S(O) 2 RI 5 -C(O)R' 5 -ORQ116, -SR 1 6 -S(O)R 1 6 -S(O) 2 R 1 6 -C(O)R 1 6 -OC(O)R' 6 -NR1 6 RI 7 -NqR' 7 C(O)R' 6 -NqR"C(0)OR 1 6 -C(O)NR 6 R 7 -S(O) 2 NR1 6 R 1 7 -NRI 7 C(O)NR1 6 R"1 or -NR1 7 C(NR17)NR1 6 R 7 or (ii) a group selected from (Cj 12 )cycloalkyl(C 0 _6)alkyl, hetero(C3- 12 )cyclaalkyl(CO.)alkyl, (C, 2 )aryl(Co,)alkyl, hetero(C3., 2 )aryl(Cm)alkyl, (Cq. 1 ,)polycycloaryl(C")a~kyI and hetero(Cg-,)polycycloaryl(Cm)alkyl, wherein said cycloalkcyl, heterocycloalkyl, aryl, heteroaryl, polycycloaryl or heterpolycycloaryl ring optionally is substituted by a group selected from -X 5 OR' 8 -X'SR' 8 -X 5 S(O)RII, -X'S(O) 2 R' 8 -X 5 C(O)R' 8 -X 5 C(0)OR' 8 -X 5 OC(O)R 8 -X 3 NR' 8 R' 9 -X 5 NR1 9 C(O)R' 8 -X 5 NR1 9 C(O)OR 8 -X 5 C(O)NR'R' 9 -XsS(O) 2 NR'gR 1 9 -X 5 NR1 9 C(O)NR' 8 R' 9 or -X 5 NR19C(NR' 9 )NRIBRI 9 wherein X 5 R(14, 1(15, R(16, R(17, R" 8 and R(19 are as defined above; wherein within R 7 any alicyclic or aromatic ring system present may be substituted further by 1 to 5 radicals independently selected from 6 )alkyl, 6 )alkylidene, cyano, halo, halo-substituted (C,,)allcyl, nitro, _X 6 NR' 4 R1 4 -X 6 NR' 4 C(O)OR 1 4 -X 6 NR1 4 C(O)NR 1 4 R1 4 3 -X 6 NR1 4 C(NR' 4 -X 6 0R 4 _X 6 SR' 4 -X 6 C(O)OR' 4 -X 6 C(0)NR1 4 R"4, -X 6 S(0) 2 NR1 4 R1 4 -X 6 'P(O)(OR' 4 )QR1 4 -X 6 OP(0)(OR 1 4 )OR 1 4 -X 6 NRJ 4 C(Q)R' 5 -X 6 S(O)R' 5 -X 6 S(Q) 2 and -X 6 C(O)R' 5 wherein X 6 R4I and R(1 are as defined above; and -208- R 8 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, -XNR 4 R' 4 -X 6 NR' 4 C(O)ORI 4 -X 6 NR 1 4 C(O)NR' 4 R' 4 -X 6 NR' 4 C(NR4)NR 4 R 1 4 -X 6 OR 1 4 -X 6 SR 1 4 -X 6 C(O)OR 1 4 -X 6 C(O)NR 4 R 14 -X 6 S(O)NR' 4 R 4 -X 6 P(O)(OR' 4 )OR 4 -X 6 OP(O)(OR 4 )OR 4 -X 6 NR' 4 C(O)R' 5 -X 6 S(O)R' 5 -X 6 S(O) 2 R 1 5 and -X 6 C(O)R 15 wherein X 6 is a bond or (C 4 ,)alkylene, R 14 at each occurrence independently is hydrogen, (C 1 6)alkyl or halo-substituted (Cl. 3 )alkyl and R" (C.)alkyl or halo-substituted (C. 3 )alkyl; or an N-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. 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: R 2 RR 6 R 7 R k4 RA (R )n 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 to 7 ring member atoms, X' is a ring member carbon atom and each ring member atom other than X' is a carbon atom or a heteroatom, with the proviso that 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; -209- n is 0, 1, 2 or 3; X' is or -CH-; X 2 is a bond or a divalent group of Formula or RUR12R 10 R 11 R 12 19 13 19 R R R( R 9 (b) wherein: X 3 and V 4 independently are or -CHS(O)- R 9 and RIO independently are hydrogen, (C,-6)alkyl or as defined below; R" at each occurrence independently is hydrogen or (C,-,)alkyl; R' 2 and R" 3 independently are (C 1 -6)alkyl optionally'substituted with. cyano, halo, nitro, -NR'R 4 -NR' 4 C(O)OR', -NR"C(O)NR 4 R 4 -NR"C(NR 4 )NR'R], -OR' 4 -SR1' -C(O)OR 4 C(O)NRI 4 -S(O) 2 NR' 4 R] 4 -P(O)(OR' 4 )ORI', -0P(O)(0R' 4 )OR1', -NR' 4 C(O)R' 5 -S(O)R 5 -S(O) 2 R' 5 -C(O)RI 5 -OR 6 -SR1' -S(O) 2 R' 6 -C(O)R 6 -C(O)OR 6 -0C(O)R1', -NRI 6 RI', -NR"7C(O)R] 6 -NR' 7 C(O)OR 6 -C(O)NR' 6 R' 7 _S(O) 2 NR1 6 R1 7 ,7.NR"7C(O)NR' 6 R' 7 or R~ 7 CN~l 7 N~I 6 I?,wherein R' at each occurrence independently is hydrogen, (C,,)alkyl or halo-substituted 3 )alkyl, R' 5 is 6 )alkyl or halo-substituted 3 )alkyl, halo, (C,,)alkyl or R1 6 is 2 )cycloatkyl(C,,)alkyl, hetero(C3-, 2 )Cycloalkyl(C,,)alkyl, (C1 12 )aryl(CO-)alkyl, hetP-ro(C 5 2 )aryl(C,)alkyl, (C 9 .12)PolYCYCloaryl(C,)alky1 or hetero(Cg- 1 )polycycloaryl(C,-)alyI and R' 7 is hydrogen or (C, 4 ,)alkyl, and wherein within R' 6 said cycloalkyl, heterocycloalkyl, aryl, heteroaryl, polycycloaryl or heterpolycycloaryl ring optionally is substituted by a group selected from -R' 8 -X 5 ORI, -XSR' 8 -X 5 S(O)R' 8 -X 5 S(O) 2 R' 8 -X 5 C(O)RI, -X 5 C(O)OR 8 -X 5 OC(O)R 8 -X 5 NR'sR"9, -X 5 NR' 9 C(O)R 8 -X 5 NR' 9 C(O)OR' 8 -XsC(O)NR'&R'9, -X 5 S(O) 2 NR'BR' 9 -X 5 NR' 9 C(O)NR"R'9 or -X 5 NR"C(NR' 9 )NRSR'9, wherein X 5 is a bond or (C, 4 6)alkylene, R' 8 is hydrogen or (C, 4 alkl ad R 9 i (C, 2 )cycloalkyl(CO.)alkyl, hetero(G,,, 2 )cyc oalkyl(c )alkyl, (C6. 1 2aryl(CO.)alkyl, hetero(C 5 .1 2 )ayl(C4)alkyl, (C 9 -1 2 )PlYCYCloaryl(C!O)alky1 or -2 hetero(C 8 12 )POlycycloary1(C( 6 )alkyl, or (ii) a group selected from (C 3 12 )cycloalkyl(CO-)alkyl, hetero(C,. 12 )CYCloalkyl(C,)alky1, (C, 1 )aryI(C0.)alkyl, hetero(C., 12 )aryl(C0.)alkyl, (Cg.)polycycloaryl(C")alkyl and hetero(C& 12 )POlycycloaryl(CO.)alkyl, wherein said cycloalkyl, heterocycloalkyl, aryl, heteroaryl, polycycloaryl or heterpolycycloaryl ring optionally is substituted by a group selected from -RI 8 -XIQR' 8 -X 5 SR' 8 -X 5 S(Q)R 8 -X 5 S(O) 2 R' 8 _X5C(O)R1s, -X 5 C(O)ORI 8 -X 5 OC(Q)R' 8 -X 5 NR'gR' 9 -X 5 NR1 9 C(O)R' 8 -X 5 NR' 9 C(O)OR' 8 -X 5 C(O)NR'BR' 9 -X 5 S(Q),NR 8 R 9 -X5NR"C(O)NR 8 R' 9 or -XsNR' 9 C(NR 9 )NR"aR, wherein X 5 R" 8 and R" 9 are as defined above; wherein within R" 2 and/or R1 3 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,,)alkyl, nitro, -XINR' 4 RI 4 -X 5 NR1 4 C(O)OR 4 -X 5 NR14C(O)NR1 4 RI 4 _XSNR1 4 C(NR 14 )NR1 4 R 1 4 -X 5 QR 1 4 _X 5 SR 1 4 -X 5 C(O)OR' 4 -X 5 C(O)NR 4 R 1 4 _X 5 S(O) 2 NR1 4 R1 4 -X 5 P(O)(OR' 4 )0W 4 -X 5 OP(O)(OR' 4 )OR] 4 _X 5 NR' 4 C(O)R 1 5 -X5S(O)R' 5 -X5S(O) 2 R] 5 and -X 5 C(O)R 1 5 wherein XI, R 1 4 and R 1 are as defined above; or R 1 2 together with R 9 and/or R" 3 together with R' 0 form trimethylene, tetramethylene or phenylene- 1,2-dimethylene, optionally substituted with 1 to 3 radicals independently selected from (C,,)alkyl, (C,,)alkylidene, cyano, halo, halo-substituted (C 14 )alkyl, nitro, oxo, -X 5 NR 1 4 C(O)OR 1 4 -X 5 NR' 4 C(O)NR1 4 R 4 -XsNR1 4 C(NR]4)NR14R)4, -X50R1 4 -X 5 SR 1 4 -X 5 C(O)0R 14 -X 5 C(O)NR1 4 R"4, -X 5 S(O)2NR1 4 R] 4 -X 5 P(O)(OR] 4 )0R 14 _X 5 Op(O)(OR' 4 )OR 1 4 _X5 NR 1 4 C(O)Rts, -X 5 S(O)R 1 5 -XsS(O) 2 R' 5 and -X5C(O)R' 5 wherein X 5 R 1 4 and R1 5 are as defined above; and R' is XR", wherein X" is or V 7 is a bond, or -NRl 21 wherein is hydrogen or (C 14 6)alkyl, and RI is (C 1 -6)alkyl optionally substituted by cyano, halo, nitro, -NR1 4 R 1 4 -NR14C(O)OR 1 4 -NR1 4 C(O)NR1 4 R 4 -NR3 4 C(NRI 4 )NR 1 4 R14, -OR 14 -SR 1 4 -C(O)OR 1 4 -C(O)NR' 4 R] 4 TSQ 2 R1 4 R1', 1PO(R 4 )OR4, -S(O) 2 R22, -C(O)Rn, -C(0)OR22, C(O)NR22R2, -NR22R23, NR23C(O)R22, -NR23C(O)OR2,-NR2C(O)NR2R2' or -NR2nC(NR23)NR22R23, wherein R"1 and R' 5 are as defined above, RI is (C 3 ,)cycloalkyl(C~)alkyl, hetero(C 312 )cycloalkyl(CO4)alkyl, -211- (C6- 1 2 )aryl(CO-)alkyl, hetero(C.5 1 2 )aryl(CO-)alky1, (Cq~i 2 )bicycloaryl(CO4)alkyl or hetero(C& 12 )bicycloaryl(CO)alkcyl and R13 at each occurrence independently is hydrogen. or (C,-6)alkyI, or (ii) (C3-1 2 )cycloalky(C")alkyl, hetero(C3,1)cycloalky1(CO4)alkyl, (C6_J 2 )ary(CO_)allcyl, hetero(Qi 12 )arY1(C")alkyl, (C9.j2)bicycloary(C4)a~ky1 or hetero(C 1 2 )bicycloaryl(C.)alkyl or (iii) (C 3 _6)cycloalkyl(C 6)alkyl, hetero(C,,)cycloalky1(C")alkyl, phenyI(C")alkyI or hetero(C_,)ary1(C")alkyl, wherein said cycloalkyl, heterocycloalkyl, phenyl or heteroaiyl is substituted by -R 2 1, -X 5 IOR24, -XISR 14 -X 5 S(O)R24, -X 5 S(Q) 2 R 2 4, -X 5 C(O)R 2 4 -X 5 C(O)OR 2 4, -X 5 C(O)NR 2 4R25, -X 5 N4R 2 -X 5 NR25C(O)R 2 4 -X 5 NRzC(O)0R 24 -XsNR2C(O)NR4R25 or -XSNR25C(NR2)NR24R2$, wherein X5 is as defined above, R 24 is (C_,)cycloalky1(CO4)alkyl, hetero(C~dcycloalkyl(CO.)alkyl, phenyl(C")alkyI or hetero(C.,)aryl(C.)alky1 and R21 at each occurrence independently is hydrogen or (CI-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 1 6 )alkyl, (C 14 6)alkylidene, cyano, halo, halo-substituted (C, 4 )alkyl, nitro, -XINR 4 R' 4 -X 5 NR' 4 C(O)oR14, -X 5 NR1 4 C(O)NR' 4 R' 4 I X 5 NR1 4 C(NR4)NR14R'4, -X 5 0R1 4 -X 5 SR 1 4 -X 5 C(Q)QR 4 -X 5 C(Q)NR 4 R 4 -X 5 S(O) 2 NR 4 -X 5 p(O)(OR' 4 )QR14 -X 5 OP(O)(OR] 4 )QR1', _XSNR' 4 C(Q)R' 5 -X 5 S(O)R 1 5 -X 5 S(Q) 2 R 1 5 and -X 5 C(O)R'1 5 wherein R 14 and R1S are as defined above; or when X1 is a divalent group of formula or then R'may also represent hydrogen, carboxy, oxalo or carbanioyl; R 2 is hydrogen or (C,,)alkl; R' is (C, 1 6)a~kyl optionally substituted with cyano, halo, nitro, -SRI,. -C(Q)0R 6 -C(Q)NR26R2, -P(O)(OR26)OR26, -OP(O)(QR2)OR 26 -S(O)Rv7, 2 7 or wherein R26 at each occurrence independently is hydrogen, (C, 1 6)alkyl or halo-substituted (C1. 3 )alkyl and R 27 is (C, 4 6)alkyl or halo-substituted (C 1 3 )alkyl, or (ii) (C..,)cycloalkyl(C 23 )alkyl, hetero(C3,)cycloalkyl(Cq 3 )alkyl, 2 3 )alkyl or hetero(C.,)ary(C-2 3 )alkyl, wherein said cycloalkyl; heterocycloalkyl, aryl or heteroaryl optionally is substituted further with 1 to radicals independently selected from (C, 4 6)alkyl, (C, 4 )alkylidene, cyano, halo, halo-substituted (C,,)alkyl, nitro, -X 5 NR1 4 C(O)OR 1 4 -X 5 NR1 4 C(O)NR14R', -X 5 NqR1 4 C(NR 1 4 )NR14RR", -X 5 QR 1, -X 5 SR1 4 -X 5 -X 5 C(O)NR1 4 -X 5 S(O) 2 NR1 4 R] 4 -X3P(O)(OR")OR' 4 -X 5 Op(O)(QR14 )OR1', -X 5 NR1 4 C(O)R' 5 -XsS(O)R' 5 _X 5 S(O) 2 R' 5 and -X 5 C(Q)R 1 5 wherein X 5 R14 and R' 5 are as defined above, provided that when RI is unsubstituted 5 )alkyl and R 4 is hydrogen or unsubstituted (C 1 5 )alkyl, then X 2 may not represent a bond when RI is -212- -C(O)R 2 0 -C(O) 2 R 20 or -S(O)2R' in which RI is (C] 1 6)alkyl, pheny(C 1 4 )alkyl, phenyl, 7 )cycloalkyJ, camphan- 1O-yl, naphth-1I-yl, naphth-2-yl, phenyl substituted by one or more of (C14)alkyl, perfluoro(C, 4 )alkyl, (C, 4 )alkoxy, hydroxy, halo, amido, nitro, amino, (C 1 4)alkylamino, (C 1 4 ,)dialkylaniino, carboxy or (C, 4 )alkoxycarbonyl, or naphth- I-yl or naphth-2-yl substituted by one or more of (C,,)alkyl, perfluoro(C,,)alkyl, (C 1 4 )alkoxy, hydroxy, halo, amido, nitro, amino, carboxy or (C 1 4 )alkoxycarbonyl or (ii) a divalent group of formula (a) or in which the moiety R1 2 is methyl, isopropyl, n-butyl, sec-butyl, tert-butyl, I-methyipropyl, benzyl, naphth-1-ylmethyl, naphth-2-ylmethyl, thien-2-ylmethyl, thien-3-ylmethyl, or wherein R9 and R11 form ethylene, trimethylene, hydroxy-substituted trimethylene, tetramethylene or phenylene- 1,2-dimethylene; or RI and R' taken together with the carbon atom to which both R 3 and R" are attached form (Q 8 )cycloalkylene or (C34)heterocycloalkylene, wherein said cycloalkylene or beterocycloalkylene is optionally substituted with 1 to 3 radicals independently selected from (Cl. 6 )alkyl, (C 2 .6)alkylidene, cyano, halo, halo-substituted 4 )alkyl, nitro, -XsNRI 4 C(O)OR24, -X 5 NR' 4 C(O)NR14R4 I -X 5 NR' 4 C(NR14)NR1 4 R] 4 -X 5 OR"4, -X 5 SR' 4 -X 5 C(O)QR 4 -XSC(O)NR 4 R]4, _X 5 S(O) 2 NR 14 R14, -X 5 P(O)(OR 1 4 )OR1 4 -X 5 OP(O)(OR'4)OR 14 _X 5 NR1 4 C(O)R' 5 -X 5 S(O)R"5, -X 5 S(O) 2 R' 5 and -X 3 C(O)R 5 wherein V 5 R 1 4 and RIS are as defined above; R' is hydrogen, (CI -)alkyl or as defined above; RI is hydrogen and R" is hydroxy or R5 and R together form oxo; RI is a group selected from cyano, halo, nitro, -R 29 -X 5 NR2"R 30 -X 5 NR 30 C(O)OR 29 -X5NR30C(O)NR2R30, -X 5 NR30C(NR3)NR 29 R 30 _X 5 0R 29 -X 5 SR 29 -X 5 C(O)0R 29 -X5C(O)NR29R 30 -X 5 S(Q) 2 NR 29 R30, -X 5 P(O)(0R 30 )0R 29 _X 5 Op(O)(OR2)OR29, -X 5 NR30C(Q)R 3 -X 5 S(Q)R 31 -X 5 S(O) 2 R 3 and -X 5 C(O)R 3 wherein X 5 is as defined above, R29 is hydrogen or -R 31 R 30 at each occurrence is hydrogen or (C3 1 4 )alkyl and R is (C, 1 6)alkyl, (C3 1)cycloalkyl(C0)alkyl, hetero(C3.)cycloalkyl(C,)alkyl, (C6-,)aryl(C.)alkyl or hetero(C_,j)aryl(C,)alkyl, wherein within R" any alicyclic or aromatic ring system present may be substituted further by 1 to 5 radicals independently selected from (C, 1 4 )akl, 6 )alkylidene, cyano, halo, halo-substituted (C 1 ,)alkyl, nitro, -X 5 NR' 4 R, -XINR' 4 C(Q)0R 14 S0 -XSNR1 4 C(Q)NR'4R"4, -X 5 NR1 4 C(NR] 4 )NR14I4I -X 5 OR 1 4 _X 5 SR1 4 I -X 5 C(O)OR 4 -X 5 C(O)NR"4R'4, -X 5 S(O) 2 NR 1 4 R1 4 -X 5 P(O)(OR 1 4 )OR 14, -X 5 Op(O)(OR14)OR 1 4 9 -X 5 NR 14 C(O)R' 3 -X 5 S(O)Rls,.-XsS(O) 2 .R and -X'C(O)RI 5 wherein X 5 R14 and R"S are as -213- defined above; and R' at each occurrence independently is selected from (C,,)alkyl, (C, 14 )alkylidene, cyano, halo, halo-substituted (C 14 )alkyl, nitro, -X5NR1 4 R14, -X 5 NR1 4 C(Q)OR 14, -X 5 NR' 4 C(O)NR] 4 R 14 -X 5 NR 1 4 C(NR1 4 )NR14R14, -X5OR 1 4 _X 5 SR 1, _X 5 C(O)QR'4, -X 5 C(O)NR1 4 RI 4 _X 5 S(O) 2 NR1 4 R 1 4 -X 5 P(O)(OR 1 4 )OR 14, -XSOP(Q)(QRI4)OR 14, -X 5 NR1 4 C(O)R 1 5 -X-S(O)RI 5 -X 5 S(O) 2 R 15 and -X 5 C(O)R 15, wherein XS, RI 4 and RIS are as defined above; and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers; and the pharmaceutically acceptable salts thereof.; which process comprises: reacting an organometallic compound of Formula 2: 2 with a compound of Formula 3: R 3 4 3 wherein n, A, V, X 2 R 2 R 3 R 4 RI and R' are as above, to give a compound of Formula 1 in which R 5 and R" together form oxo; or reacting a compound of Formula 4: R 2 OH RK 2 1N 3>r R R 4 NH 4 with a compound of Formula 5(a) or -214- HO R 7 HO R 7 H2H:) 8 H(R)n (R )n wherein the dashed line represents an optional bond and B is a monocyclic radical containing 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, R 2 R 3 R 4 R 7 and R 8 are as defined above, to give a compound of Formula I in which the ring comprised by X' is a 4,5-tetrahydrooxazol-2-yl or oxazol-2-yl or moiety, respectively, RS is hydrogen and R 6 is hydroxy or reacting a compound of Formula 6: R2 OH XHNR R 3 R 4 K9K 8 R (R) n 6 with a compound of the formula R'X 2 OY, wherein Y is hydrogen or or an activating group and n, A, X 2 R 2 R 3 R 4 R 7 and R 8 are as defined above to give a compound of Formula I in which R 5 is hydrogen and R 6 is hydroxy; or reacting a compound of Formula 7: R 2 OH X R R7 R 3 R(R8)n 7 or a protected derivative thereof, with R 39 0H, wherein R 39 is -X 6 XR 20 and n, A, X 2 X 7 X 8 R 2 R 3 R 4 R 6 R 7 and R" are as defined above, and deprotecting if necessary to give a compound of Formula I in which R' is -X 6 XR 2 0 optionally oxidizing a compound of Formula I in which R 5 is hydrogen and R 6 is hydroxy to give a compound of Formula I in which R 5 and R 6 together form oxo; -215- 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; optionally converting a compound of Formula I in which R 7 is -C(O)OH to a compound of Formula I in which R 7 is methoxycarbonyl; optionally converting a compound of Formula I into a pharmaceutically acceptable salt; optionally converting a salt form of a compound of Formula I to non-salt form; optionally converting an unoxidized form of a compound of Formula I into a pharmaceutically acceptable N-oxide; optionally converting an N-oxide form of a compound of Formula I its unoxidized form; optionally converting a non-derivatized compound of Formula I into a pharmaceutically prodrug derivative; and optionally converting a prodrug derivative of a compound of Formula I to its non-derivatized form. Dated 15 March, 2004 Axys Pharmaceuticals, Inc. Patent Attorneys for the Applicant/Nominated Person SPRUSON FERGUSON -216- I
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU2004201071A AU2004201071A1 (en) | 1999-03-15 | 2004-03-15 | Amine Derivatives as Protease Inhibitors |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US60/124421 | 1999-03-15 | ||
| AU37507/00A AU774664B2 (en) | 1999-03-15 | 2000-03-15 | Amine derivatives as protease inhibitors |
| AU2004201071A AU2004201071A1 (en) | 1999-03-15 | 2004-03-15 | Amine Derivatives as Protease Inhibitors |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU37507/00A Division AU774664B2 (en) | 1999-03-15 | 2000-03-15 | Amine derivatives as protease inhibitors |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| AU2004201071A1 true AU2004201071A1 (en) | 2004-04-08 |
Family
ID=34140265
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU2004201071A Abandoned AU2004201071A1 (en) | 1999-03-15 | 2004-03-15 | Amine Derivatives as Protease Inhibitors |
Country Status (1)
| Country | Link |
|---|---|
| AU (1) | AU2004201071A1 (en) |
-
2004
- 2004-03-15 AU AU2004201071A patent/AU2004201071A1/en not_active Abandoned
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| AU774664B2 (en) | Amine derivatives as protease inhibitors | |
| AU779177B2 (en) | Novel compounds and compositions as protease inhibitors | |
| PT96234A (en) | HIV PROTEASE INHIBITOR AGENTS IN AIDS TREATMENT | |
| AU2002352663A1 (en) | Cyanoalkylamino derivatives as protease inhibitors | |
| EP1446115A2 (en) | Cyanoalkylamino derivatives as protease inhibitors | |
| WO2001068645A2 (en) | N-cyanomethylcarboxamides and their use as protease inhibitors | |
| JP2004535422A (en) | New compounds and compositions as cathepsin inhibitors | |
| US7662849B2 (en) | Amidino compounds as cysteine protease inhibitors | |
| US7101880B2 (en) | Peptidic compounds as cysteine protease inhibitors | |
| CA2364900A1 (en) | Polycyclic 2-amino-thiazole systems, method for the production thereof and medicament containing said compounds | |
| JP2007505919A (en) | Haloalkyl-containing compounds as cysteine protease inhibitors | |
| AU2004201071A1 (en) | Amine Derivatives as Protease Inhibitors | |
| EP1446392A1 (en) | Oligopeptides and compositions containing them as cathepsin s inhibitors | |
| WO2002070519A1 (en) | Monobactams as cathepsin k inhibitors | |
| US6900237B2 (en) | Sulfonamide compounds as protease inhibitors | |
| US20020156063A1 (en) | Arylacetamido-ketobenzoxazole as cysteine protease inhibitors | |
| EP1516877A1 (en) | Amine derivatives as protease inhibitors | |
| MXPA01009240A (en) | Amine derivatives as protease inhibitors | |
| CA2475069A1 (en) | Amine derivatives as protease inhibitors | |
| WO2002023784A2 (en) | Cysteine protease inhibitors | |
| MXPA01007452A (en) | Utilization of polycyclic 2-amino-thiazole systems in the production of medicaments for prophylaxis or treatment of obesity | |
| MXPA01007281A (en) | Polycyclic 2-amino-thiazole systems, method for the production thereof and medicament containing said compounds | |
| AU2002357716A1 (en) | Oligopeptides and compositions containing them as cathepsin S inhibitors |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MK4 | Application lapsed section 142(2)(d) - no continuation fee paid for the application |