Process for preparing heteroaryl and unsaturated heterocycloalkylmagnesium reagents and uses thereof Number:7,091,360 from the United States Patent and Trademark Office (PTO) owispatent The present invention is directed to a novel process for preparing heteroaryl and unsaturated heterocycloalkylmagnesium reagents that are useful in the synthesis of a variety of pharmaceuticals, in particular certain cysteine protease inhibitors.<H heterocycloalkylmagnesium, unsaturated, Process, for, pre, 7091360.html, Patent, pto, 7091360

Title: Process for preparing heteroaryl and unsaturated heterocycloalkylmagnesium reagents and uses thereof

Abstract: The present invention is directed to a novel process for preparing heteroaryl and unsaturated heterocycloalkylmagnesium reagents that are useful in the synthesis of a variety of pharmaceuticals, in particular certain cysteine protease inhibitors.

Patent Number: 7,091,360 Issued on 08/15/2006 to Li, et al.

Inventors: Li; Jiayao (Foster City, CA), Link; John O. (San Francisco, CA), Colladant; Colette (Bridgewater, NJ)
Assignee: Aventis Pharma S.A. (Bridgewater, NJ)

Appl. No.: 10/418,183

Filed: April 16, 2003

Current U.S. Class: 548/217 ; 546/268.1; 546/271.4; 548/152; 548/215

Current International Class: C07D 263/54 (20060101); C07D 277/62 (20060101)

Field of Search: 548/217,152,215 546/268.1,271.4

Foreign Patent Documents


824175	Nov., 1959	GB
WO 00/55144	Sep., 2000	WO

Other References

Ohmoto, K. et al., "Development of orally active nonpeptidic inhibitors of human neutrophil elastase" J. Med. Chem. (2001); 44:1268-1285. cited by other.

Primary Examiner: Shameem; Golam M. M.
Attorney, Agent or Firm: Townsend and Townsend and Crew LLP

Parent Case Text

CROSS-REFERENCES TO RELATED APPLICATIONS

The present application claims priority to U.S. Provisional Application Ser. No. 60/373,176, filed on Apr. 16, 2002, the disclosure of which is incorporated herein by reference in its entirety.

Claims

What is claimed is:

1. A process of preparing a reagent of formula (Ia): ##STR00040## comprising reacting a compound of formula (I): ##STR00041## wherein: X is --O-- or --S--; Y is nitrogen or --CR.sup.3a--; Y' is nitrogen or --CR.sup.2a-- provided that Y and Y' are not simultaneously nitrogen; one of R.sup.2 and R.sup.3 is hydrogen, (C.sub.1-6)alkyl, (C.sub.1-6)alkoxy, (C.sub.1-6)alkoxy(C.sub.1-6)alkyl, (C.sub.1-6)alkylthio, (C.sub.5-6)cycloalkyl, (C.sub.5-6)cycloalkylalkyl, halo, nitro, halo(C.sub.1-3)alkyl, (C.sub.6-12)aryl, heteroaryl, heterocycloalkyl, (C.sub.6-12)aryl(C.sub.1-6)alkyl, heteroaryl(C.sub.1-6)alkyl, (C.sub.1-6)alkylsulfonyl, (C.sub.6-12)arylsulfonyl, (C.sub.6-12)aryl(C.sub.1-6)alkylsulfonyl, heteroarylsulfonyl, heteroaryl(C.sub.1-6)-alkylsulfonyl, aminosulfonyl, (C.sub.1-6)alkylaminosulfonyl, (C.sub.1-6)dialkylaminosulfonyl, --CONR.sup.4R.sup.5 (where R.sup.4 and R.sup.5 are independently of each other hydrogen, (C.sub.1-6)alkyl, (C.sub.1-6)alkoxy, aryl, aryl(C.sub.1-6)alkyl, heteroaryl, heteroaryl(C.sub.1-6)alkyl, (C.sub.5-6)cycloalkyl, (C.sub.5-6)cycloalkyl(C.sub.1-6)alkyl, heterocycloalkyl, or heterocycloalkyl(C.sub.1-6)alkyl, or R.sup.4 and R.sup.5 together with the nitrogen atom to which they are attached form heterocycloamino), --NHCOR.sup.6 (where R.sup.6 is (C.sub.1-6)alkyl, (C.sub.6-12)aryl, aryl(C.sub.1-6)alkyl, heteroaryl, heteroaryl(C.sub.1-6)alkyl, (C.sub.5-6)cycloalkyl, (C.sub.5-6)cycloalkyl(C.sub.1-6)alkyl, heterocycloalkyl, or heterocycloalkyl(C.sub.1-6)alkyl), --SO.sub.2NR.sup.7R.sup.8 (where R.sup.7 and R.sup.8 are independently of each other hydrogen, (C.sub.1-6)alkyl, (C.sub.6-12)aryl, (C.sub.6-12)aryl(C.sub.1-6)alkyl, heteroaryl, heteroarylalkyl, (C.sub.5-6)cycloalkyl, (C.sub.5-6)cycloalkyl(C.sub.1-6)alkyl, heterocycloalkyl, or heterocycloalkyl(C.sub.1-6)alkyl, or R.sup.7 and R.sup.8 together with the nitrogen atom to which they are attached form heterocycloamino), -alkylene-CONR.sup.4R.sup.5 (where R.sup.4 and R.sup.5 are as defined above), --alkylene-NHCOR.sup.6 (where R.sup.6 is as defined above), or -alkylene-SO.sub.2NR.sup.7R.sup.8 (where R.sup.7 and R.sup.8 are as defined above); and the other of R.sup.2 and R.sup.3 is hydrogen or (C.sub.1-6)alkyl wherein within R.sup.2 or R.sup.3 said aryl, heteroaryl, or heterocycloalkyl is optionally substituted further with one, two, or three substituents independently selected from the group consisting of (C.sub.1-6)alkoxy, (C.sub.1-6)alkyl, (C.sub.6-12)aryl(C.sub.1-6)alkyl, halo, nitro, and halo(C.sub.1-3)alkyl; or when Y and Y' are carbon, then R.sup.2 and R.sup.3 together with the atoms to which they are attached form an optionally substituted benzene, napthyl, (C.sub.3-6)cycloalkyl, or an aromatic or non-aromatic heterocyclic ring; R.sup.2a and R.sup.3a are independently hydrogen or alkyl; or R.sup.2a and R.sup.3a together form a covalent bond, provided that when Y or Y' is nitrogen, R.sup.2a and R.sup.3 or R.sup.2 and R.sup.3a together form a covalent bond; with a Grignard reagent wherein Z is a halogen provided that (I) is not 1,2,4- or 1,3,4-oxadiazole.

2. The process of claim 1 wherein R.sup.2 and R.sup.3 together with the atoms to which they are attached form an optionally substituted benzene.

3. The process of claim 1 wherein the compound of formula (I) is benzoxazole, benzothiazole, 5-phenylbenzoxazole, 5, or 6-methoxybenzoxazole, 5-trifluorobenzoxazole, 5-nitrobenzoxazole, 5-chloro-benzoxazole, oxazolo-[4,5-b]pyridine or 5-aminosulfonylbenzoxazole.

4. The process of claim 1 wherein the Grignard reagent is selected from the group consisting of n-butylmagnesium chloride, isopropylmagnesium chloride, phenylmagnesium chloride, n-butylmagnesium bromide, isopropylmagnesium bromide, or phenylmagnesium bromide and the reaction is carried out in an ethereal organic solvent or a mixture of ethereal and an aromatic organic solvent from about -10.degree. to about 10.degree. C.

5. The process of claim 1 which further comprises reacting the nucleophilic heteroaryl or unsaturated heterocycloalkylmagnesium reagent with an aldehyde of formula (II): ##STR00042## where: PG is an amino protecting group; R.sup.1 is hydrogen or alkyl, or R.sup.1 together with R.sup.10 and the atoms to which they are attached form heterocycloamino; R9 is hydrogen or (C1-6)alkyl; and R.sup.10 is: (i) (C.sub.1-6)alkyl optionally substituted with halo, nitro, --SR.sup.11, --C(O)NR.sup.11R.sup.11, --P(O)(OR.sup.11)OR.sup.11, --OP(O)(OR.sup.11)OR.sup.11, --S(O)R.sup.12, or --S(O).sub.2R.sup.12 wherein R.sup.11 at each occurrence independently is hydrogen, (C.sub.1-6)alkyl or halo-substituted (C.sub.1-3)alkyl and R.sup.12 is alkyl or halo-substituted alkyl; or (ii) (C.sub.5-6)cycloalkyl(C.sub.2-3)alkyl, hetero(C.sub.3-6)cycloalkyl(C.sub.2-3)alkyl, (C.sub.6-12)aryl(C.sub.2-3)alkyl or hetero(C.sub.5-6)aryl(C.sub.2-3)alkyl, wherein said cycloalkyl, heterocycloalkyl, aryl or heteroaryl optionally is substituted further with 1 to 5 radicals independently selected from the group consisting of alkyl, alkylidene, halo, halo-substituted (C.sub.1-4)alkyl, nitro, --X.sup.1NR.sup.14C(O)OR.sup.14, --X.sup.1NR.sup.14C(O)NR.sup.14R.sup.14, --X.sup.1NR.sup.14C(NR.sup.14)NR.sup.14R.sup.14, --X.sup.1OR.sup.14, --X.sup.1SR.sup.14, --X.sup.1C(O)NR.sup.14R.sup.14, --X.sup.1S(O).sub.2NR.sup.14R.sup.14, --X.sup.1P(O)(OR.sup.14)OR.sup.14, --X.sup.1OP(O)(OR.sup.14)OR.sup.14, --X.sup.1NR.sup.14C(O)R.sup.15, --X.sup.1S(O)R.sup.15, and --X.sup.1S(O).sub.2R.sup.15 wherein X.sup.1 is a bond or (C.sub.1-6)alkyl, R.sup.14 at each occurrence independently is hydrogen, (C.sub.1-6)alkyl or halo-substituted (C.sub.1-3)alkyl, and R.sup.15 is (C.sub.1-6)alkyl, halo-substituted (C.sub.1-3)alkyl, or halo; or (iii) R.sup.9 and R.sup.10 taken together with the carbon atom to which both R.sup.9 and R.sup.10 are attached form (C.sub.3-8)cycloalkylene or heterocycloalkylene, wherein said cycloalkylene or heterocycloalkylene is optionally substituted with 1 to 3 radicals independently selected from the group consisting of (C.sub.1-6)alkyl, (C.sub.1-6)alkylidene, halo, halo-substituted (C.sub.1-4)alkyl, nitro, --X.sup.2NR.sup.14C(O)OR.sup.14, --X.sup.2NR.sup.14C(O)NR.sup.14R.sup.14, --X.sup.2NR.sup.14C(NR.sup.14)NR.sup.14R.sup.14, --X.sup.2OR.sup.14, --X.sup.2SR.sup.14, --X.sup.2C(O)NR.sup.14R.sup.14, --X.sup.2S(O).sub.2NR.sup.14R.sup.14, --X.sup.2P(O)(OR.sup.14)OR.sup.14, --X.sup.2OP(O)(OR.sup.14)OR.sup.14, --X.sup.2NR.sup.14C(O)R.sup.15, --X.sup.2S(O)R.sup.15 and --X.sup.2S(O).sub.2R.sup.15 wherein X.sup.2 is a bond or (C.sub.1-6)alkylene, R.sup.14 at each occurrence independently is hydrogen, (C.sub.1-6)alkyl or halo-substituted C.sub.1-3)alkyl, and R.sup.15 is (C.sub.1-6)alkyl, halo-substituted (C.sub.1-3)alkyl, or halo; to provide a compound of formula (III): ##STR00043## where: X, Y, Y', PG, R.sup.2, R.sup.2a, R.sup.3, R.sup.9, and R.sup.10 are as defined above; (i) optionally removing the amino protecting group; (ii) optionally converting the compound obtained in step (i) above, to an acid addition salt; (iii) optionally converting a salt form of a compound of formula (III) to a free base; (iv) optionally separating individual isomers; (v) optionally modifying any of the X, R.sup.2, R.sup.3, R.sup.9 and R.sup.10 groups.

6. The process of claim 5 which further comprises removing the amino protecting group in compound (III) to provide a compound of formula (IV): ##STR00044## where Y, X, R.sup.2, R.sup.3, R.sup.9 and R.sup.10 are as defined above; and optionally forming an acid addition salt and reacting (IV) with a compound of formula (V): ##STR00045## where: R.sup.25 and R.sup.27 are independently of each other hydrogen or (C.sub.1-6)alkyl; R.sup.28 is: (i) (C.sub.1-6)alkyl optionally substituted by cyano, halo, nitro, --NR.sup.14R.sup.14, --NR.sup.14C(O)OR.sup.14, --NR.sup.14C(O)NR.sup.14R.sup.14, --NR.sup.14C(NR.sup.14)NR.sup.14R.sup.14, --OR.sup.14, --SR.sup.14, --C(O)NR.sup.14R.sup.14, --S(O).sub.2NR.sup.14R.sup.14, --P(O)(OR.sup.14)OR.sup.14, --OP(O)(OR.sup.14)OR.sup.14, --NR.sup.14C(O)R.sup.15, --S(O)R.sup.15, --S(O).sub.2R.sup.15, --C(O)R.sup.15, --OR.sup.16, --SR.sup.16, --S(O)R.sup.16, --S(O).sub.2R.sup.16, --C(O)NR.sup.16R.sup.17, --NR.sup.16R.sup.17, --NR.sup.17C(O)R.sup.16, --NR.sup.17C(O)OR.sup.16, --NR.sup.17C(O)NR.sup.16R.sup.17 or --NR.sup.17C(NR.sup.17)NR.sup.16R.sup.17, wherein R.sup.14 and R.sup.15 are as defined above, R.sup.16 is (C.sub.3-12)cycloalkyl(C.sub.0-6)alkyl, heterocycloalkyl(C.sub.0-6)alkyl, (C.sub.6-12)aryl(C.sub.0-6)alkyl, heteroaryl(C.sub.0-6)alkyl, (C.sub.9-12)bicycloaryl(C.sub.0-6)alkyl or heterobicycloaryl(C.sub.0-6)alkyl and R.sup.17 at each occurrence independently is hydrogen or (C.sub.1-6)alkyl; or (ii) (C.sub.3-6)cycloalkyl(C.sub.0-6)alkyl, hetero(C.sub.3-12)cycloalkyl(C.sub.0-6)alkyl, (C.sub.6-12)aryl(C.sub.0-6)alkyl, hetero(C.sub.5-12)aryl(C.sub.0-6)alkyl, (C.sub.9-12)bicycloaryl(C.sub.0-6)alkyl or hetero(C.sub.8-12)bicycloaryl(C.sub.0-6)alkyl; or (iii) (C.sub.3-6)cycloalkyl(C.sub.0-6)alkyl, hetero(C.sub.3-6)cycloalkyl(C.sub.0-6)alkyl, phenyl(C.sub.0-6)alkyl or hetero(C.sub.5-6)aryl(C.sub.0-6)alkyl, wherein said cycloalkyl, heterocycloalkyl, phenyl or heteroaryl is substituted by --R.sup.18, --X.sup.3OR.sup.18, --X.sup.3SR.sup.18, --X.sup.3S(O)R.sup.18, --X.sup.3S(O).sub.2R.sup.18, --X.sup.3C(O)R.sup.18, --X.sup.3C(O)OR.sup.18, --X.sup.3C(O)NR.sup.18R.sup.19, --X.sup.3NR.sup.18R.sup.19, --X.sup.3NR.sup.19C(O)R.sup.18, --X.sup.3NR.sup.19C(O)OR.sup.18, --X.sup.3NR.sup.19C(O)NR.sup.18R.sup.19 or --X.sup.3NR.sup.19C(NR.sup.19)NR.sup.18R.sup.19, wherein X.sup.3 is a bond or (C.sub.1-6)alkylene, R.sup.18 is (C.sub.3-6)cycloalkyl(C.sub.0-6)alkyl, hetero(C.sub.3-6)cycloalkyl(C.sub.0-6)alkyl, phenyl(C.sub.0-6)alkyl or hetero(C.sub.5-6)aryl(C.sub.0-6)alkyl and R.sup.19 at each occurrence independently is hydrogen or (C.sub.1-6)alkyl; wherein within R.sup.28 any alicyclic or aromatic ring system present may be substituted further by 1 to 5 radicals independently selected from the group consisting of (C.sub.1-6)alkyl, (C.sub.1-6)alkylidene, cyano, halo, halo-substituted (C.sub.1-4)alkyl, nitro, --X.sup.4NR.sup.14R.sup.14, --X.sup.4NR.sup.14C(O)OR.sup.14, --X.sup.4NR.sup.14C(O)NR.sup.14R.sup.14, --X.sup.4NR.sup.14C(NR.sup.14)NR.sup.14R.sup.14, --X.sup.4OR.sup.14, --X.sup.4SR.sup.14, --X.sup.4C(O)OR.sup.14, --X.sup.4C(O)NR.sup.14R.sup.14, --X.sup.4S(O).sub.2NR.sup.14R.sup.14, --X.sup.4P(O)(OR.sup.14)OR.sup.14, --X.sup.4OP(O)(OR.sup.14)OR.sup.14, --X.sup.4NR.sup.14C(O)R.sup.15, --X.sup.4S(O)R.sup.15, --X.sup.4S(O).sub.2R.sup.15 and --X.sup.4C(O)R.sup.15, wherein X.sup.4 is a bond or (C.sub.1-6)alkylene, R.sup.14 and R.sup.15 are as defined above; and R.sup.26 is: (i) (C.sub.1-6)alkyl optionally substituted with cyano, aryl, halo, nitro, --NR.sup.14R.sup.14, --NR.sup.14C(O)OR.sup.14, --NR.sup.14C(O)NR.sup.14R.sup.14, --NR.sup.14C(NR.sup.14)NR.sup.14R.sup.14, --OR.sup.14, --SR.sup.14, --C(O)NR.sup.14R.sup.14, --S(O).sub.2NR.sup.14R.sup.14, --P(O)(OR.sup.14)OR.sup.14, --OP(O)(OR.sup.14)OR.sup.14, --NR.sup.14C(O)R.sup.15, --NR.sup.14SO.sub.2R.sup.15, --S(O)R.sup.15, --S(O).sub.2R.sup.15, --C(O)R.sup.15, --OR.sup.16, --SR.sup.16, --S(O)R.sup.16, --S(O).sub.2R.sup.16, --OC(O)R.sup.16, --NR.sup.16R.sup.17, --NR.sup.17C(O)R.sup.16, --NR.sup.17C(O)OR.sup.16,--C(O)NR.sup.16R.sup.17, --S(O).sub.2NR.sup.16R.sup.17, --NR.sup.17C(O)NR.sup.16R.sup.17 or --NR.sup.17C(NR.sup.17)NR.sup.16R.sup.17, wherein R.sup.14, R.sup.15, R.sup.16 and R.sup.17 are as defined above, and wherein within R.sup.16 said cycloalkyl, heterocycloalkyl, aryl, heteroaryl, bicycloaryl or heterbicycloaryl ring optionally is substituted by a group selected from --R.sup.20, --X.sup.5OR.sup.20, --X.sup.5SR.sup.20, --X.sup.5S(O)R.sup.20, --X.sup.5S(O).sub.2R.sup.20, --X.sup.5C(O)R.sup.20, --X.sup.5C(O)OR.sup.20, --X.sup.5OC(O)R.sup.20, --X.sup.5NR.sup.20R.sup.21, --X.sup.5NR.sup.21C(O)R.sup.20, --X.sup.5NR.sup.21C(O)OR.sup.20, --X.sup.5C(O)NR.sup.20R.sup.21, --X.sup.5S(O).sub.2NR.sup.20R.sup.21, --X.sup.5NR.sup.19C(O)NR.sup.20R.sup.21 and --X.sup.5NR.sup.21C(NR.sup.21)NR.sup.20R.sup.21, wherein X.sup.5 is a bond or (C.sub.1-6)alkylene, R.sup.20 is hydrogen or (C.sub.1-6)alkyl and R.sup.21 is (C.sub.3-12)cycloalkyl(C.sub.0-6)alkyl, hetero(C.sub.3-12)cycloalkyl-(C.sub.0-6)alkyl, (C.sub.6-12)aryl(C.sub.0-6)alkyl, hetero(C.sub.5-12)aryl(C.sub.0-6)alkyl, (C.sub.9-12)polycycloaryl(C.sub.0-6)alkyl or hetero(C.sub.8-12)polycycloaryl(C.sub.0-6)alkyl; or (ii) a group selected from (C.sub.3-12)cycloalkyl(C.sub.0-6)alkyl, hetero(C.sub.3-12)cycloalkyl(C.sub.0-6)alkyl, (C.sub.6-12)aryl(C.sub.0-6)alkyl, hetero(C.sub.5-12)aryl(C.sub.0-6)alkyl, (C.sub.9-12)polycycloaryl(C.sub.0-6)alkyl and hetero(C.sub.8-12)polycycloaryl(C.sub.0-6)alkyl, wherein said cycloalkyl, heterocycloalkyl, aryl, heteroaryl, polycycloaryl or heterpolycycloaryl ring optionally is substituted by a group selected from --R.sup.20, --X.sup.6R.sup.20, --X.sup.6SR.sup.20, --X.sup.6S(O)R.sup.20, --X.sup.6S(O).sub.2R.sup.20, --X.sup.6C(O)R.sup.20, --X.sup.6C(O)OR.sup.20, --X.sup.6OC(O)R.sup.20, --X.sup.6NR.sup.20R.sup.21, --X.sup.6NR.sup.21C(O)R.sup.20, --X.sup.6NR.sup.21C(O)OR.sup.20, --X.sup.6C(O)NR.sup.20R.sup.21, --X.sup.6S(O).sub.2NR.sup.20R.sup.21, --X.sup.6NR.sup.19C(O)NR.sup.20R.sup.21 and --X.sup.6NR.sup.21C(NR.sup.21)NR.sup.20R.sup.21, wherein X.sup.6 is a bond or (C.sub.1-6)alkylene, R.sup.20 and R.sup.21 are as defined above; wherein within R.sup.26 any alicyclic or aromatic ring system present may be substituted further by 1 to 5 radicals independently selected from the group consisting of (C.sub.1-6)alkyl, (C.sub.1-6)alkylidene, cyano, halo, halo-substituted (C.sub.1-4)alkyl, nitro, --X.sup.7NR.sup.14R.sup.14, --X.sup.7NR.sup.14C(O)OR.sup.14, --X.sup.7NR.sup.14C(O)NR.sup.14R.sup.14, --X.sup.7NR.sup.14C(NR.sup.14)NR.sup.14R.sup.14, --X.sup.7OR.sup.14, --X.sup.7SR.sup.14, --X.sup.7C(O)OR.sup.14, --X.sup.7C(O)NR.sup.14R.sup.14, X.sup.7S(O).sub.2NR.sup.14R.sup.14, --X.sup.7P(O)(OR.sup.14)OR.sup.14, --X.sup.7OP(O)(OR.sup.14)OR.sup.14, --X.sup.7NR.sup.14C(O)R.sup.15, --X.sup.7S(O)R.sup.15, --X.sup.7S(O).sub.2R.sup.15 and --X.sup.7C(O)R.sup.15, wherein X.sup.7 is a bond or (C.sub.1-6) alkylene, and R.sup.14 and R.sup.15 are as defined above; or R.sup.26 together with R.sup.27 form trimethylene, tetramethylene or phenylene-1,2-dimethylene, optionally substituted with 1 to 3 radicals independently selected from the group consisting of (C.sub.1-6)alkyl, (C.sub.1-6)alkylidene, cyano, halo, halo-substituted (C.sub.1-4)alkyl, nitro, oxo, --X.sup.8NR.sup.14C(O)OR.sup.14, --X.sup.8NR.sup.14C(O)NR.sup.14R.sup.14, --X.sup.8NR.sup.14C(NR.sup.14)NR.sup.14R.sup.14, --X.sup.8OR.sup.14, --X.sup.8SR.sup.14, --X.sup.8C(O)OR.sup.14, --X.sup.8C(O)NR.sup.14R.sup.14, --X.sup.8S(O).sub.2NR.sup.14R.sup.1, --X.sup.8R.sup.14S(O).sub.2R.sup.15, --X.sup.8P(O)(OR.sup.14)OR.sup.14, --X.sup.8OP(O)(OR.sup.14)OR.sup.14, --X.sup.8NR.sup.14C(O)R.sup.15, --X.sup.8S(O)R.sup.15, --X.sup.8S(O).sub.2R.sup.15 and --X.sup.8C(O)R.sup.15, wherein X.sup.8 is a bond or (C.sub.1-6)alkylene, R.sup.14 and R.sup.15 are as defined above; under coupling reaction conditions to provide a compound of formula (VI): ##STR00046## where X, Y, Y' , R.sup.2, R.sup.2a, R.sup.3, R.sup.9, R.sup.10, R.sup.25--R.sup.28 are as defined above; (i) optionally protecting the hydroxy group; (ii) optionally converting a compound of formula (VI) to an acid addition salt; (iii) optionally converting a salt form of a compound of formula (VI) to a free base; (iv) optionally separating individual isomers; (v) optionally modifying any of the X, Y, R.sup.2, R.sup.3, R.sup.9, R.sup.10, R.sup.25--R.sup.28 groups.

7. The process of claim 6 which further comprises converting a compound of formula (VI) to a compound of formula (VII): ##STR00047## where X, Y, Y', R.sup.2, R.sup.2a, R.sup.3, R.sup.9, R.sup.10, R.sup.25--R.sup.28 are as defined above, with a suitable oxidizing agent; and (i) optionally converting a compound of formula (VII) to an acid addition salt; (ii) optionally converting a salt form of a compound of formula (VII) to a free base; (iii) optionally separating individual isomers; and (iv) optionally modifying any of the X, Y, R.sup.2, R.sup.3, R.sup.9, R.sup.10, R.sup.25--R.sup.28 groups.

Description

STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

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BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention is directed to a novel process for preparing heteroaryl and unsaturated heterocycloalkylmagnesium reagents that are useful in the synthesis of a variety of pharmaceuticals, in particular certain cysteine protease inhibitors.

2. State of the Art

Heteroaryl and unsaturated heterocycloalkylmagnesium reagents are useful in the synthesis of a variety of pharmaceuticals, such as renin inhibitors and cysteine protease inhibitors. For example, heteroarylmagnesium reagents are used in the synthesis of 1-hydroxy-1-(heteroaryl or unsaturated heterocycloalkyl)-2-N-protected-aminoethyl intermediates which are then used in the synthesis of a number of peptidic pharmaceutically active agents (see EP 0376012 which discloses the use of 1-hydroxy-1-(heteroaryl)-2-aminoethyl in the synthesis of renin inhibitors and PCT Application Publication No. WO 00/55144 and Ohmoto, K. et. al., J. Med. Chem. 2001, 44, 1268 which disclose the use of 1-hydroxy-1-(heteroaryl or heterocycloalkyl)-2-aminoethyl in the synthesis of protease inhibitors). At present, 1-hydroxy-1-(heteroaryl)-2-N-protected-aminoethyl intermediates used are prepared by reacting an aldehyde with a heteroarylmagnesium reagent or by assembly of the heterocyclic/heteroaryl ring. The heteroarylmagnesium reagent used in this process is prepared by first treating a heteroaryl with an organolithium reagent and then converting the resulting lithiated species into a Grignard reagent under transmetallation reaction conditions. The drawbacks of these procedures are that they require very low reaction temperatures, typically -78.degree. C., or are not the most economical or expedient route.

In order to avoid low temperature chemistry, the heteroarylmagnesium reagent can be prepared by reacting the corresponding heteroaryl halide with magnesium turnings in the presence of an initiation mixture containing ethyl bromide and iodine crystals. The drawback of this procedure is that the initiation of the reaction is very unpredictable and the reaction is highly exothermic and hence requires appropriate set up to keep the reaction temperature under control. Additionally, this method can be subject to undesirable side reactions, such as Wurtz coupling. These drawbacks make the use of heteroaryl or unsaturated heterocycloalkylmagnesium reagents unattractive for large-scale synthesis of pharmaceuticals.

Accordingly, there is a need for a synthetic process that would be amenable to large-scale synthesis of these compounds without the limitations discussed above. The present invention fulfills this and related needs.

BRIEF SUMMARY OF THE INVENTION

The present invention is directed to a novel process for preparing heteroaryl and unsaturated heterocycloalkylmagnesium reagents and their use in the synthesis of certain cysteine protease inhibitors. As discussed above, the current synthesis of these reagents makes their use in large-scale synthesis unattractive. Applicants have surprisingly discovered that heteroaryl or unsaturated heterocycloalkylmagnesium reagents can be prepared under mild reaction conditions by treating a corresponding heteroaryl or unsaturated heterocycloalkyl compound directly with a Grignard reagent.

Accordingly, in one aspect, this invention is directed to a process of preparing a nucleophilic heteroaryl or unsaturated heterocycloalkylmagnesium reagent comprising reacting a compound of formula (I):

##STR00001## wherein:

X is --O-- or --S--;

Y is nitrogen or --CR.sup.3a--;

Y' is nitrogen or --CR.sup.2a-- provided that Y and Y' are not simultaneously nitrogen;

one of R.sup.2 and R.sup.3 is hydrogen, (C.sub.1-6)alkyl, (C.sub.1-6)alkoxy, (C.sub.1-6)alkoxy(C.sub.1-6)alkyl, (C.sub.1-6)alkylthio, (C.sub.5-6)cycloalkyl, (C.sub.5-6)cycloalkylalkyl, halo, nitro, halo(C.sub.1-3)alkyl, (C.sub.6-12)aryl, heteroaryl, heterocycloalkyl, (C.sub.6-12)aryl(C.sub.1-6)alkyl, heteroaryl(C.sub.1-6)alkyl, (C.sub.1-6)alkylsulfonyl, (C.sub.6-12)arylsulfonyl, (C.sub.6-12)aryl(C.sub.1-6)alkylsulfonyl, heteroarylsulfonyl, heteroaryl (C.sub.1-6)alkylsulfonyl, aminosulfonyl, (C.sub.1-6)alkylaminosulfonyl, (C.sub.1-6)dialkylaminosulfonyl, --CONR.sup.4R.sup.5 (where R.sup.4 and R.sup.5 are independently of each other hydrogen, (C.sub.1-6)alkyl, (C.sub.1-6)alkoxy, aryl, aryl(C.sub.1-6)alkyl, heteroaryl, heteroaryl(C.sub.1-6)alkyl, (C.sub.5-6)cycloalkyl, (C.sub.5-6)cycloalkyl(C.sub.1-6)alkyl, heterocycloalkyl, or heterocycloalkyl(C.sub.1-6)alkyl, or R.sup.4 and R.sup.5 together with the nitrogen atom to which they are attached form heterocycloamino), --NHCOR.sup.6 (where R.sup.6 is (C.sub.1-6)alkyl, (C.sub.6-12)aryl, aryl(C.sub.1-6)alkyl, heteroaryl, heteroaryl (C.sub.1-6)alkyl, (C.sub.5-6)cycloalkyl, (C.sub.5-6)cycloalkyl(C.sub.1-6)alkyl, heterocycloalkyl, or heterocycloalkyl(C.sub.1-6)alkyl), --SO.sub.2NR.sup.7R.sup.8 (where R.sup.7 and R.sup.8 are independently of each other hydrogen, (C.sub.1-6)alkyl, (C.sub.6-12)aryl, (C.sub.6-12)aryl(C.sub.1-6)alkyl, heteroaryl, heteroarylalkyl, (C.sub.5-6)cycloalkyl, (C.sub.5-6)cycloalkyl(C.sub.1-6)alkyl, heterocycloalkyl, or heterocycloalkyl(C.sub.1-6)alkyl, or R.sup.7 and R.sup.8 together with the nitrogen atom to which they are attached form heterocycloamino), -alkylene-CONR.sup.4R.sup.5 (where R.sup.4 and R.sup.5 are as defined above), -alkylene-NHCOR.sup.6 (where R.sup.6 is as defined above), or -alkylene-SO.sub.2NR.sup.7R.sup.8 (where R.sup.7 and R.sup.8 are as defined above); and

the other of R.sup.2 and R.sup.3 is hydrogen or (C.sub.1-6)alkyl wherein within R.sup.2 or R.sup.3 said aryl, heteroaryl, or heterocycloalkyl is optionally substituted further with one, two, or three substituents independently selected from the group consisting of (C.sub.1-6)alkoxy, (C.sub.1-6)alkyl, (C.sub.6-12)aryl(C.sub.1-6)alkyl, halo, nitro, and halo(C.sub.1-3)alkyl; or

when Y and Y' are carbon, then R.sup.2 and R.sup.3 together with the atoms to which they are attached form an optionally substituted benzene, napthyl, (C.sub.3-6)cycloalkyl, or an aromatic or non-aromatic heterocyclic ring;

R.sup.2a and R.sup.3a are independently hydrogen or alkyl; or R.sup.2a and R.sup.3a together form a covalent bond, provided that when Y or Y' is nitrogen, R.sup.2a and R.sup.3 or R.sup.2 and R.sup.3a together form a covalent bond;

with a Grignard reagent provided that (I) is not 1,2,4- or 1,3,4-oxadiazole.

In the context of the present invention, functional groups when present on (I) are those that are compatible with the general use of a Grignard reagent and are well known to those of skill in the art. Certain functional groups, whose presence might lead to reduced yields can be suitably protected prior to contacting the compound of formula (I) with the Grignard reagent. Again, suitable protecting groups are known to those of skill in the art and can be found in, for example, Greene and Wuts, Protective Groups in Organic Synthesis, 2nd ed., John Wiley & Sons, Inc. 1991.

Preferably, a compound of formula (I) where Y' is --CR.sup.2a--.

Preferably, the Grignard reagent has an empirical formula R.sup.1MgZ where R.sup.1 is alkyl or optionally substituted phenyl and Z is halo, preferably Z is chloro or bromo and the reaction is carried out in a suitable organic solvent. Preferably the Grignard reagent is selected from the group consisting of n-butylmagnesium chloride, isopropylmagnesium chloride, phenylmagnesium chloride, n-butylmagnesium bromide, isopropylmagnesium bromide, or phenylmagnesium bromide. More preferably the Grignard reagent is isopropylmagnesium chloride in tetrahydrofuran.

Preferably, the reaction solvent is an ethereal organic solvent such as tetrahydrofuran and the like, or a mixture of ethereal and an aromatic organic solvent. Preferably, it is carried out in a 1:1 mixture of tetrahydrofuran and toluene.

Preferably the reaction is carried out from about -78.degree. to about 40.degree. C., more preferably from about -10.degree. to about 40.degree. C. More preferably from about -10.degree. to about 10.degree. C., most preferably at about -5.degree. C.

Preferably,

##STR00002## ring in (I) is 4,5-dihydrooxazole, thiazole, or oxazole wherein one of R.sup.2 and R.sup.3 is hydrogen or (C.sub.1-4)alkyl and the other of R.sup.2 and R.sup.3 is selected from the group consisting of hydrogen, halo, (C.sub.1-4)alkyl, (C.sub.6-12)aryl, --CONR.sup.4R.sup.5 (where R.sup.4 and R.sup.5 are independently of each other hydrogen, (C.sub.1-6)alkyl, (C.sub.1-4)alkoxy, (C.sub.6-12)aryl, (C.sub.6-12)aryl(C.sub.1-6)alkyl, heteroaryl, heteroaryl(C.sub.1-6)alkyl, (C.sub.5-6)cycloalkyl, (C.sub.5-6)cycloalkyl(C.sub.1-6)alkyl, heterocycloalkyl, or heterocycloalkyl(C.sub.1-6)alkyl, or R.sup.4 and R.sup.5 together with the nitrogen atom to which they are attached form heterocycloamino), --SO.sub.2NR.sup.7R.sup.8 (where R.sup.7 and R.sup.8 are independently of each other hydrogen, (C.sub.1-6)alkyl, (C.sub.6-12)aryl, (C.sub.6-12)aryl(C.sub.1-6)alkyl, heteroaryl, heteroaralkyl, (C.sub.5-6)cycloalkyl, (C.sub.5-6)cycloalkyl(C.sub.1-6)alkyl, heterocycloalkyl, or heterocycloalkyl(C.sub.1-6)alkyl, or R.sup.7 and R.sup.8 together with the nitrogen atom to which they are attached form heterocycloamino), nitro, and trifluoromethyl wherein within R.sup.2 or R.sup.3 said aryl, heteroaryl, or heterocycloalkyl is optionally substituted further with one, two, or three substituents independently selected from the group consisting of (C.sub.1-6)alkoxy, (C.sub.1-6)alkyl, (C.sub.6-12)aryl(C.sub.1-6)alkyl, halo, nitro, and halo(C.sub.1-3)alkyl. Preferably, one of R.sup.2 and R.sup.3 is hydrogen or methyl and the other of R.sup.2 and R.sup.3 is selected from the group consisting of hydrogen, phenyl, phenylaminocarbonyl, benzylaminocarbonyl, aminosulfonyl, 2-phenylethylaminocarbonyl, 3-phenylpropylaminocarbonyl, aminocarbonyl, methylaminocarbonyl, 4-benzylpiperidin-1-ylcarbonyl, furan-2-ylmethylaminocarbonyl, pyridin-2-ylmethylaminocarbonyl, pyridin-3-ylmethyl-aminocarbonyl, pyridin-4-yl-methylaminocarbonyl, 2-,3-, or 4-chlorobenzylamino-carbonyl, isopropylaminocarbonyl, 1-phenylethylaminocarbonyl, N-methyl-N-benzylaminocarbonyl, pyrrolidin-1-yl-carbonyl, piperidin-1-ylcarbonyl, 1,2,3,4-tetrahydroquinolin-1-ylcarbonyl, napthyl-1-yl-methylamino-carbonyl, 1,2,3-tetrahydroindol-1-ylcarbonyl, and admant-1-ylmethylaminocarbonyl.

Preferebly, (I) is a compound where R.sup.2 and R.sup.3 together with the atoms to which they are attached form an optionally substituted benzene ring. Preferably, the benzene ring is optionally subsituted with (C.sub.1-4)alkyl, halo, (C.sub.1-4)alkoxy, (C.sub.6-12)aryl, --CONR.sup.aR.sup.b (where R.sup.a and R.sup.b are independently of each other hydrogen, (C.sub.1-6)alkyl, (C.sub.1-4)alkoxy, (C.sub.6-12)aryl, (C.sub.6-12)aryl(C.sub.1-6)alkyl, heteroaryl, heteroaryl(C.sub.1-6)alkyl, (C.sub.5-6)cycloalkyl, (C.sub.5-6)cycloalkyl-(C.sub.1-6)alkyl, heterocycloalkyl, or heterocycloalkyl(C.sub.1-6)alkyl, or R.sup.a and R.sup.b together with the nitrogen atom to which they are attached form heterocycloamino), --SO.sub.2NR.sup.aR.sup.b (where R.sup.a and R.sup.b are independently of each other hydrogen, (C.sub.1-6)alkyl, (C.sub.6-12)aryl, (C.sub.6-12)aryl(C.sub.1-6)alkyl, heteroaryl, heteroaralkyl, (C.sub.5-6)cycloalkyl, (C.sub.5-6)cycloalkyl(C.sub.1-6)alkyl, heterocycloalkyl, or heterocycloalkyl(C.sub.1-6)alkyl, or R.sup.a and R.sup.b together with the nitrogen atom to which they are attached form heterocycloamino), nitro, or trifluoromethyl.

Preferebly, (I) is benzoxazole, benzothiazole, 5-phenylbenzoxazole, 5, or 6-methoxybenzoxazole, 5-trifluorobenzoxazole, 5-nitrobenzoxazole, 5-chloro-benzoxazole, oxazolo[4,5-b]pyridine, or 5-aminosulfonylbenzoxazole, most preferably benzoxazole.

Preferably, the nucleophilic heteroaryl or unsaturated heterocycloalkylmagnesium reagent generated by the above process has the structure (Ia):

##STR00003## wherein X, Y, Y', R.sup.2, and R.sup.3 are as defined in formula (I) above, including the preferred embodiments and Z is halo, preferably chloro or bromo.

Preferebly,

##STR00004## in (Ia) is benzoxazol-2-yl, benzothiazol-2-yl, 5-phenylbenzoxazol-2-yl, 5- or 6-methoxybenzoxazol-2-yl, 5-trifluorobenzoxazol-2-yl, 5-nitrobenzoxazol-2-yl, 5-chloro-benzoxazol-2-yl, oxazolo[4,5-b]pyridin-2-yl, or 5-aminosulfonylbenzoxazol-2-yl, most preferably benzoxazol-2-yl.

This invention also provides a process as described above, which further comprises reacting the nucleophilic heteroaryl or unsaturated heterocycloalkylmagnesium reagent prepared as described above (including the preferred embodiments) with an aldehyde of formula (II):

##STR00005## where:

PG is an amino protecting group;

R.sup.1 is hydrogen or (C.sub.1-6)alkyl, or R.sup.1 together with R.sup.10 and the atoms to which they are attached form heterocycloamino;

R.sup.9 is hydrogen or (C.sub.1-6)alkyl; and

R.sup.10 is:

(i) (C.sub.1-6)alkyl optionally substituted with halo, nitro, --SR.sup.11, --C(O)NR.sup.11R.sup.11, --P(O)(OR.sup.11)OR.sup.11, --OP(O)(OR.sup.11)OR.sup.11, --S(O)R.sup.12, or --S(O).sub.2R.sup.12 wherein R.sup.11 at each occurrence independently is hydrogen, (C.sub.1-6)alkyl or halo-substituted (C.sub.1-3)alkyl and R.sup.12 is alkyl or halo-substituted (C.sub.1-3)alkyl; or

(ii) (C.sub.5-6)cycloalkyl(C.sub.2-3)alkyl, hetero(C.sub.3-6)cycloalkyl(C.sub.2-3)alkyl, (C.sub.6-12)aryl(C.sub.2-3)alkyl or hetero(C.sub.5-6)aryl(C.sub.2-3)alkyl, wherein said cycloalkyl, heterocycloalkyl, aryl or heteroaryl optionally is substituted further with 1 to 5 radicals independently selected from the group consisting of alkyl, alkylidene, halo, halo-substituted (C.sub.1-4)alkyl, nitro, --X.sup.1NR.sup.14C(O)OR.sup.14, --X.sup.1NR.sup.14C(O)NR.sup.14R.sup.14, --X.sup.1NR.sup.14C(NR.sup.14)NR.sup.14R.sup.14, --X.sup.1OR.sup.14, --X.sup.1SR.sup.14, --X.sup.1C(O)NR.sup.14R.sup.14,--X.sup.1S(O).sub.2NR.sup.14R.sup.14, --X.sup.1P(O)(OR.sup.14)OR.sup.14, --X.sup.1OP(O)(OR.sup.14)OR.sup.14, --X.sup.1NR.sup.14C(O)R.sup.15, --X.sup.1S(O)R.sup.15, and --X.sup.1S(O).sub.2R.sup.15 wherein X.sup.1 is a bond or (C.sub.1-6)alkyl, R.sup.14 at each occurrence independently is hydrogen, (C.sub.1-6)alkyl or halo-substituted (C.sub.1-3)alkyl, and R.sup.15 is (C.sub.1-6)alkyl, halo-substituted (C.sub.1-3)alkyl, or halo; or

(iii) R.sup.9 and R.sup.10 taken together with the carbon atom to which both R.sup.9 and R.sup.10 are attached form (C.sub.3-8)cycloalkylene or heterocycloalkylene, wherein said cycloalkylene or heterocycloalkylene is optionally substituted with 1 to 3 radicals independently selected from the group consisting of (C.sub.1-6)alkyl, (C.sub.1-6)alkylidene, halo, halo-substituted (C.sub.1-4)alkyl, nitro, --X.sup.2NR.sup.14C(O)OR.sup.14, --X.sup.2NR.sup.14C(O)NR.sup.14, --X.sup.2NR.sup.14C(NR.sup.14)NR.sup.14R.sup.14,--X.sup.2OR.sup.14, --X.sup.2SR.sup.14, --X.sup.2C(O)NR.sup.14R.sup.14, --X.sup.2S(O).sub.2NR.sup.14R.sup.14, --X.sup.2P(O)(OR.sup.14)OR.sup.14, --X.sup.2OP(O)(OR.sup.14)OR.sup.14, --X.sup.2NR.sup.14C(O)R.sup.15, --X.sup.2S(O)R.sup.15, and --X.sup.2S(O).sub.2R.sup.15 wherein X.sup.2 is a bond or (C.sub.1-6)alkylene, R.sup.14 at each occurrence independently is hydrogen, (C.sub.1-6)alkyl or halo-substituted (C.sub.1-3)alkyl, and R.sup.15 is (C.sub.1-6)alkyl, halo-substituted (C.sub.1-3)alkyl, or halo; to provide a compound of formula

##STR00006## where:

X, Y, Y', PG, R.sup.2, R.sup.3, R.sup.9, and R.sup.10 are as defined above;

(i) optionally removing the amino protecting group;

(ii) optionally converting the compound obtained in step (i) above, to an acid addition salt;

(iii) optionally converting a salt form of a compound of formula (III) to a free base;

(iv) optionally separating individual isomers;

(v) optionally modifying any of the PG, R.sup.2, R.sup.3, R.sup.9 and R.sup.10 groups.

Preferably the moiety,

##STR00007## in compound (III) is as defined in the preferred embodiments for formula (I) above; R.sup.9 is hydrogen or (C.sub.1-6)alkyl and R.sup.10 is (C.sub.1-6)alkyl or (C.sub.6-12)aryl(C.sub.2-3)alkyl, or R.sup.9 and R.sup.10 taken together with the carbon atom to which both R.sup.9 and R.sup.10 are attached form (C.sub.3-8)cycloalkylene. More preferably, R.sup.9 is hydrogen or methyl, more preferably hydrogen and R.sup.10 is methyl, ethyl, propyl, butyl, phenylmethyl, or 2-phenylethyl, or R.sup.9 and R.sup.10 taken together with the carbon atom to which both R.sup.9 and R.sup.10 are attached form cyclopropylene, cyclopentylene or cyclohexylene. Even more preferably, R.sup.10 is ethyl and the stereochemistry at the carbon atom to which R.sup.10 is attached is (S).

Preferably, the reaction is carried out in an aromatic organic solvent such as toluene, benzene, and the like.

This invention also provides a process as described in the immediately above, additionally comprising:

removing the amino protecting group in compound (III) to provide a compound of formula (IV):

##STR00008## where Y, X, R.sup.2, R.sup.3, R.sup.9 and R.sup.10 are as defined above (including the preferred embodiments) and optionally forming an acid addition salt; and

reacting (IV) with a compound of formula (V):

##STR00009## where:

R.sup.25 and R.sup.27 are independently of each other hydrogen or (C.sub.1-6)alkyl;

R.sup.28 is:

(i) (C.sub.1-6)alkyl optionally substituted by cyano, halo, nitro, --NR.sup.14R.sup.14, --NR.sup.14C(O)OR.sup.14, --NR.sup.14C(O)NR.sup.14R.sup.14, --NR.sup.14C(NR.sup.14)NR.sup.14R.sup.14, --OR.sup.14, --SR.sup.14, --C(O)NR.sup.14R.sup.14, --S(O).sub.2NR.sup.14R.sup.14, --P(O)(OR.sup.14)OR.sup.14, --OP(O)(OR.sup.14)OR.sup.14, --NR.sup.14C(O)R.sup.15, --S(O)R.sup.15, --S(O).sub.2R.sup.15, --C(O)R.sup.15, --OR.sup.16, --SR.sup.16, --S(O)R.sup.16, --S(O).sub.2R.sup.16, --C(O)NR.sup.16R.sup.17, --NR.sup.16R.sup.17, --NR.sup.17C(O)R.sup.16, --NR.sup.17C(O)OR.sup.16, --NR.sup.17C(O)NR.sup.16R.sup.17 or NR.sup.17C(NR.sup.17)NR.sup.16R.sup.17, wherein R.sup.14 and R.sup.15 are as defined above, R.sup.16 is (C.sub.3-12)cycloalkyl(C.sub.0-6)alkyl, heterocycloalkyl(C.sub.0-6)alkyl, (C.sub.6-12)aryl(C.sub.0-6)alkyl, heteroaryl(C.sub.0-6)alkyl, (C.sub.9-12)bicycloaryl(C.sub.0-6)alkyl or heterobicycloaryl(C.sub.0-6)alkyl and R.sup.17 at each occurrence independently is hydrogen or (C.sub.1-6)alkyl; or

(ii) (C.sub.3-12)cycloalkyl(C.sub.0-6)alkyl, hetero(C.sub.3-12)cycloalkyl(C.sub.0-6)alkyl, (C.sub.6-12)aryl(C.sub.0-6)alkyl, hetero(C.sub.5-12)aryl(C.sub.0-6)alkyl, (C.sub.9-12)bicycloaryl(C.sub.0-6)alkyl or hetero(C.sub.8-12)bicycloaryl(C.sub.0-6)alkyl; or

(iii) (C.sub.3-6)cycloalkyl(C.sub.0-6)alkyl, hetero(C.sub.3-6)cycloalkyl(C.sub.0-6)alkyl, phenyl(C.sub.0-6)alkyl or hetero(C.sub.5-6)aryl(C.sub.0-6)alkyl, wherein said cycloalkyl, heterocycloalkyl, phenyl or heteroaryl is substituted by --R.sup.18, --X.sup.3OR.sup.18, --X.sup.3SR.sup.18, --X.sup.3S(O)R.sup.18, --X.sup.3S(O).sub.2R.sup.18, --X.sup.3C(O)R.sup.18, --X.sup.3C(O)OR.sup.18, --X.sup.3C(O)NR.sup.18R.sup.19, --X.sup.3NR.sup.18R.sup.19, --X.sup.3NR.sup.19C(O)R.sup.18, --X.sup.3NR.sup.19C(O)OR.sup.18, --X.sup.3NR.sup.19C(O)NR.sup.18R.sup.19 or --X.sup.3NR.sup.19C(NR.sup.19)NR.sup.18R.sup.19, wherein X.sup.3 is a bond or (C.sub.1-6)alkylene, R.sup.18 is (C.sub.3-6)cycloalkyl(C.sub.0-6)alkyl, hetero(C.sub.3-6)cycloalkyl(C.sub.0-6)alkyl, phenyl(C.sub.0-6)alkyl or hetero(C.sub.5-6)aryl(C.sub.0-6)alkyl and R.sup.19 at each occurrence independently is hydrogen or (C.sub.1-6)alkyl;

wherein within R.sup.28 any alicyclic or aromatic ring system present may be substituted further by 1 to 5 radicals independently selected from the group consisting of (C.sub.1-6)alkyl, (C.sub.1-6)alkylidene, cyano, halo, halo-substituted (C.sub.1-4)alkyl, nitro, --X.sup.4NR.sup.14R.sup.14, --X.sup.4NR.sup.14C(O)OR.sup.14, --X.sup.4NR.sup.14C(O)NR.sup.14R.sup.14, --X.sup.4NR.sup.14C(NR.sup.14)NR.sup.14R.sup.14, --X.sup.4OR.sup.14, --X.sup.4SR.sup.14, --X.sup.4C(O)OR.sup.14, --X.sup.4C(O)NR.sup.14R.sup.14, --X.sup.4S(O).sub.2NR.sup.14R.sup.14, --X.sup.4P(O)(OR.sup.14)OR.sup.14, --X.sup.4OP(O)(OR.sup.14)OR.sup.14, --X.sup.4NR.sup.14C(O)R.sup.15, --X.sup.4S(O)R.sup.15, --X.sup.4S(O).sub.2R.sup.15 and --X.sup.4C(O)R.sup.15, wherein X.sup.4 is a bond or (C.sub.1-6)alkylene, and R.sup.14 and R.sup.15 are as defined above; and

R.sup.26 is:

(i) (C.sub.1-6)alkyl optionally substituted with cyano, aryl, halo, nitro, --NR.sup.14R.sup.14, --NR.sup.14C(O)OR.sup.14, --NR.sup.14C(O)NR.sup.14R.sup.14, --NR.sup.14C(NR.sup.14)NR.sup.14R.sup.14, --OR.sup.14, --SR.sup.14, --C(O)NR.sup.14R.sup.14, --S(O).sub.2NR.sup.14R.sup.14, --P(O)(OR.sup.14)OR.sup.14, --OP(O)(OR.sup.14)OR.sup.14, --NR.sup.14C(O)R.sup.15, --NR.sup.14SO.sub.2R.sup.15, --S(O)R.sup.15, --S(O).sub.2R.sup.15, --C(O)R.sup.15, --OR.sup.16, --SR.sup.16, --S(O)R.sup.16, --S(O).sub.2R.sup.16, --OC(O)R.sup.16, --NR.sup.16R.sup.17, --NR.sup.17C(O)R.sup.16, NR.sup.17C(O)OR.sup.16, --C(O)NR.sup.16R.sup.17, --S(O).sub.2NR.sup.16R.sup.17, --NR.sup.17C(O)NR.sup.16R.sup.17 or --NR.sup.17C(NR.sup.17)NR.sup.16R.sup.17, wherein R.sup.14, R.sup.15, R.sup.16 and R.sup.17 are as defined above, and wherein within R.sup.16 said cycloalkyl, heterocycloalkyl, aryl, heteroaryl, bicycloaryl or heterobicycloaryl ring optionally is substituted by a group selected from --R.sup.20, --X.sup.5OR.sup.20, --X.sup.5SR.sup.20, --X.sup.5S(O)R.sup.20, --X.sup.5S(O).sub.2R.sup.20, --X.sup.5C(O)R.sup.20, --X.sup.5C(O)OR.sup.20, --X.sup.5OC(O)R.sup.20, --X.sup.5NR.sup.20R.sup.21, --X.sup.5NR.sup.21 C(O)R.sup.20, --X.sup.5NR.sup.21C(O)OR.sup.20, --X.sup.5C(O)NR.sup.20R.sup.21, --X.sup.5S(O).sub.2NR.sup.20R.sup.21, --X.sup.5NR.sup.19C(O)NR.sup.20R.sup.21 and --X.sup.5NR.sup.21C(NR.sup.21)NR.sup.20R.sup.21, wherein X.sup.5 is a bond or (C.sub.1-6)alkylene, R.sup.20 is hydrogen or (C.sub.1-6)alkyl and R.sup.21 is (C.sub.3-12)cycloalkyl(C.sub.0-6)alkyl, hetero(C.sub.3-12)cycloalkyl-(C.sub.0-6)alkyl, (C.sub.6-12)aryl(C.sub.0-6)alkyl, hetero(C.sub.5-12)aryl(C.sub.0-6)alkyl, (C.sub.9-12)polycycloaryl(C.sub.0-6)alkyl or hetero(C.sub.8-12)polycycloaryl(C.sub.0-6)alkyl; or

(ii) a group selected from (C.sub.3-12)cycloalkyl(C.sub.0-6)alkyl, hetero(C.sub.3-12)cycloalkyl(C.sub.0-6)alkyl, (C.sub.6-12)aryl(C.sub.0-6)alkyl, hetero(C.sub.5-12)aryl(C.sub.0-6)alkyl, (C.sub.9-12)polycycloaryl(C.sub.0-6)alkyl and hetero(C.sub.8-12)polycycloaryl(C.sub.0-6)alkyl, wherein said cycloalkyl, heterocycloalkyl, aryl, heteroaryl, polycycloaryl or heterpolycycloaryl ring optionally is substituted by a group selected from --R.sup.20, --X.sup.6OR.sup.20, --X.sup.6SR.sup.20, --X.sup.6S(O)R.sup.20, --X.sup.6S(O).sub.2R.sup.20, --X.sup.6C(O)R.sup.20, --X.sup.6C(O)OR.sup.20, --X.sup.6OC(O)R.sup.20, --X.sup.6NR.sup.20R.sup.21, --X.sup.6NR.sup.21C(O)R.sup.20, --X.sup.6NR.sup.21C(O)OR.sup.20, --X.sup.6C(O)NR.sup.20R.sup.21, --X.sup.6S(O).sub.2NR.sup.20R.sup.21, --X.sup.6NR.sup.19C(O)NR.sup.20R.sup.21 and

--X.sup.6NR.sup.21C(NR.sup.21)NR.sup.20R.sup.21, wherein X.sup.6 is a bond or (C.sub.1-6)alkylene, R.sup.20 and R.sup.21 are as defined above;

wherein within R.sup.26 any alicyclic or aromatic ring system present may be substituted further by 1 to 5 radicals independently selected from the group consisting of (C.sub.1-6)alkyl, (C.sub.1-6)alkylidene, cyano, halo, halo-substituted (C.sub.1-4)alkyl, nitro, --X.sup.7NR.sup.14R.sup.14, --X.sup.7NR.sup.14C(O)OR.sup.14, --X.sup.7NR.sup.14C(O)NR.sup.14R.sup.14, --X.sup.7NR.sup.14C(NR.sup.14)NR.sup.14R.sup.14, --X.sup.7OR.sup.14, --X.sup.7SR.sup.14, --X.sup.7C(O)OR .sup.14, --X.sup.7C(O)NR.sup.14 R.sup.14, --X.sup.7S(O).sub.2NR.sup.14R.sup.14, --X.sup.7P(O)(OR.sup.14)OR.sup.14, --X.sup.7OP(O)(OR.sup.14)OR.sup.14, --X.sup.7NR.sup.14C(O)R.sup.15, --X.sup.7S(O)R.sup.15, --X.sup.7S(O).sub.2R.sup.15 and --X.sup.7C(O)R.sup.15, wherein X.sup.7 is a bond or (C.sub.1-6)alkylene, and R.sup.14 and R.sup.15 are as defined above; or

R.sup.26 together with R.sup.27 form trimethylene, tetramethylene or phenylene-1,2-dimethylene, optionally substituted with 1 to 3 radicals independently selected from the group consisting of (C.sub.1-6)alkyl, (C.sub.1-6)alkylidene, cyano, halo, halo-substituted (C.sub.1-4)alkyl, nitro, oxo, --X.sup.8NR.sup.14C(O)OR.sup.14, --X.sup.8NR.sup.14C(O)NR.sup.14R.sup.14, --X.sup.8NR.sup.14C(NR.sup.14)NR.sup.14R.sup.14, --X.sup.8OR.sup.14, --X.sup.8SR.sup.14, --X.sup.8C(O)OR.sup.14, --X.sup.8C(O)NR.sup.4R.sup.14, --X.sup.8S(O).sub.2NR.sup.14R.sup.14, --X.sup.8R.sup.14S(O).sub.2R.sup.15, --X.sup.8P(O)(OR.sup.14)OR.sup.14, --X.sup.8OP(O)(OR.sup.14)OR.sup.14, --X.sup.8NR.sup.14C(O)R.sup.15, --X.sup.8S(O)R.sup.15, --X.sup.8S(O).sub.2R.sup.15 and --X.sup.8C(O)R.sup.15, wherein X.sup.8 is a bond or (C.sub.1-6)alkylene, R.sup.14 and R.sup.15 are as defined above;

under coupling reaction conditions to provide a compound of formula (VI):

##STR00010## where X, Y, Y', R.sup.2, R.sup.3, R.sup.9, R.sup.10, R.sup.25-R.sup.28 are as defined above;

(i) optionally protecting the hydroxy group;

(ii) optionally converting a compound of formula (VI) to. an acid addition salt;

(iii) optionally converting a salt form of a compound of formula (VI) to a free base;

(iv) optionally separating individual isomers;

(v) optionally modifying any of the X, R.sup.2, R.sup.3, R.sup.9, R.sup.10, and R.sup.25--R.sup.28 groups.

Preferably, the moiety,

##STR00011## R.sup.9 and R.sup.10 are as defined in preferred embodiments above;

R.sup.27 represents hydrogen;

R.sup.25 represents hydrogen or methyl, preferably hydrogen; and

R.sup.26 represents (i) (C.sub.1-6)alkyl optionally substituted with --SR.sup.14, --S(O)R.sup.14--S(O).sub.2R.sup.14 or --S(O).sub.2R.sup.16 wherein R.sup.14 is (C.sub.1-6)alkyl and R.sup.16 is (C.sub.3-6)cycloalkyl(C.sub.1-6)alkyl, (C.sub.6-12)aryl(C.sub.0-6)alkyl or hetero(C.sub.5-12)aryl(C.sub.0-6)alkyl; or (ii) (C.sub.3-12)cycloalkyl(C.sub.0-6)alkyl or (C.sub.6-12)aryl(C.sub.0-6)alkyl; wherein within R.sup.26 any alicyclic or aromatic ring system present may be substituted further by 1 to 5 radicals independently selected from the group consisting of (C.sub.1-6)alkyl, (C.sub.1-6)alkylidene, cyano, halo, halo-substituted (C.sub.1-4)alkyl, nitro, --X.sup.5NR.sup.14R.sup.14, --X.sup.5NR.sup.14C(O)OR.sup.14, --X.sup.5NR.sup.14C(O)NR.sup.14R.sup.14, --X.sup.5NR.sup.14C(NR.sup.14)NR.sup.14R.sup.14, --X.sup.5OR.sup.14, --X.sup.5SR.sup.14, --X.sup.5C(O)OR.sup.14, --X.sup.5C(O)NR.sup.14R.sup.14, --X.sup.5S(O).sub.2NR.sup.14R.sup.14, --X.sup.5P(O)(OR.sup.14)OR.sup.14, --X.sup.5OP(O)(OR.sup.4)OR.sup.14, --X.sup.5NR.sup.14C(O)R.sup.15, --X.sup.5S(O)R.sup.15, --X.sup.5S(O).sub.2R.sup.15 and --X.sup.5C(O)R.sup.15, wherein X.sup.5 is a bond or (C.sub.1-6)alkylene, R.sup.14 at each occurrence independently is hydrogen, (C.sub.1-6)alkyl or halo-substituted (C.sub.1-3)alkyl and R.sup.15 is (C.sub.1-6)alkyl or halo-substituted (C.sub.1-3)alkyl. Preferably R.sup.26 is cyclohexylmethyl, isobutyl, sec-butyl, 2-fluorobenyl, benzyl, phenylethyl, 2-chlorobenzyl, 2-trifluoromethylbenzyl, 2-cyanobenzylsulfanylmethyl, benzylsulfanylmethyl, 2-cyanobenzylsulfanylmethyl, benzylsulfanylmethyl, 2-phenylsulfanylethyl, trifluoromethylbenzylsulfonylmethyl, 2-phenylsulfonylethyl, thien-3-ylmethylsulfonylmethyl, benzylsulfonylmethyl, 2-chlorobenzylsulfonylmethyl, 2-cyanobenzylsulfonylmethyl, 2-difluoromethoxybenzylsulfonylmethyl, 3,5-dimethylisoxazol-4-ylmethylsulfonylmethyl, 2-methoxybenzylsulfonylmethyl, 6-methylpyrid-2-ylmethylsulfonylmethyl, 2-methylpyrid-3-ylmethylsulfonylmethyl, pyrid-3-ylmethylsulfonylmethyl, pyrid-2-ylmethylsulfonylmethyl, 2-nitrobenzylsulfonylmethyl, pyrid-2-ylmethylsulfonylmethyl, o-tolylmethylsulfonyl-methyl, isopropylmethylsulfonylmethyl, cyclopropylmethylsulfonylmethyl, 2-trifluoromethylbenzylsulfonylmethyl. More preferably R.sup.26 is cyclopropylmethylsulfonylmethyl or isopropylmethylsulfonylmethyl; and

R.sup.28 is methyl, azetidin-3-yl, 1-benzyloxycarbonylpiperidin-4-yl, bicyclo[2.2.2]hept-2-yl, bicyclo[2.2.1]hept-2-yl, tert-butoxy, carboxymethyl, 2-carboxyethyl, cyclohexylmethyl, 3-cyclohexylpropyl, 2-cyclohexylethyl, 2-cyclopentylethyl 6-hydroxypyrid-3-yl, 1H-imidazol-4-yl, morpholin-4-yl, 2-morpholin-4-ylethyl, naphth-1-ylmethyl, naphth-1-ylmethyl, 2-phenylethyl, piperazin-1-yl, piperidin-4-yl, pyrazin-2-yl, pyrid-3-yl, pyrid-4-yl, or tetrahydropyran-4-yl. More preferably, R.sup.28 represents morpholin-4-yl, piperidin-4-yl, pyrazin-2-yl, pyrid-3-yl, pyrid-4-yl, or tetrahydropyran-4-yl and most preferably, morpholin-4-yl.

The deprotection conditions employed in the removal of the amino protecting group depend on the nature of the protecting group. If the group is tert-butoxycarbonyl, it is removed under acidic reaction conditions. Preferably acids are trifluoroacetic acid, hydrochloric acid, and the like. Preferably, the removal of the tert-butoxycarbonyl group is carried out by treating (III) with dioxane/HCl or trimethylsilyl chloride in an ethanolic solvent such as ethanol, isopropanol, and the like.

Preferably, the coupling reaction is carried out with a coupling agent such as benzotriazole-1-yloxytrispyrrolidino-phosphonium hexafluorophosphate (PyBOP.RTM.), O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU), O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU), or 1-hydroxybenzotriazole (HOBT) in the presence of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC), or 1,3-dicyclohexylcarbodiimide (DCC), a base such as N,N-diisopropylethylamine, triethylamine, or N-methylmorpholine. Suitable solvents are dichloromethane, dichloroethane, dimethylformamide, dioxane, tetrahydrofuran, or acetonitrile.

This invention also provides a process as described above additionally comprising converting a compound of formula (VI) to a compound of formula (VII):

##STR00012## where X, Y, Y', R.sup.2, R.sup.3, R.sup.9, R.sup.10, R.sup.25 R.sup.28 are as defined above, with a suitable oxidizing agent; and

(i) optionally converting a compound of formula (VII) to an acid addition salt;

(ii) optionally converting a salt form of a compound of formula (VII) to a free base;

(iii) optionally separating individual isomers; and

(iv) optionally modifying any of the X, R.sup.2, R.sup.3, R.sup.9, R.sup.10, R.sup.25 R.sup.28 groups.

Preferably the moiety,

##STR00013## R.sup.10, R.sup.25 R.sup.28 are as discussed in the preferred embodiments above.

Preferably, the oxidizing agent is selected from the group NaOCl/TEMPO.RTM., Dess-Martin Periodinane, and the like.

The compounds of formula (VII) are cysteine protease inhibitors.

Reference to the preferred embodiments set forth above is meant to include all combinations of particular and preferred groups.

Preferably, this invention is directed to a process of preparing a compound of formula (VIIa):

##STR00014## wherein:

R.sup.30 is isopropylmethyl or cyclopropylmethyl which process comprises:

(i) reacting benzoxazole with a Grignard reagent in a suitable solvent to provide a benzoxazolyl Grignard reagent;

(ii) reacting benzoxazolyl Grignard reagent obtained in Step (i) above with an aldehyde of formula (IIa):

##STR00015## where PG is an amino-protecting group to provide a compound of formula (IIIa):

##STR00016##

(iii) deprotecting the amino group in (IIIa) with a suitable acid to provide a compound of formula (IVa) and optionally converting the free base to an acid addition salt;

##STR00017##

(iv) reacting (IVa) or an acid addition salt thereof with a compound of formula (Va):

##STR00018## where R.sup.30 is cyclopropylmethyl or isopropylmethyl, under coupling reaction conditions to provide a compound of formula (VIa):

##STR00019## and;

(v) oxidizing (VIa) with a suitable oxidizing agent to provide a compound of formula (VIIa);

(vi) optionally converting a compound of formula (VIIa) to an acid addition salt;

(vii) optionally converting a salt form of a compound of formula (VIIa) to a free base; and

(viii) optionally separating individual isomers.

Preferably, Step (i) is carried out at about -10.degree. to 20.degree. C., more preferably from about -10 to about 0.degree. C., even more preferably at about --5.degree. C.

Preferably, in Step (i), the Grignard reagent is n-butylmagnesium chloride/bromide, isopropylmagnesium chloride/bromide or phenylmagnesium chloride/bromide. Preferably, the Grignard reagent is isopropylmagnesium chloride in tetrahydrofuran. Preferably, the reaction solvent is ethereal organic solvent or a mixture of ethereal and aromatic organic solvent. Preferably, the reaction is carried out in aa 1:1 mixture of tetrahydrofuran and toluene.

Preferably, in Step (ii) the reaction is carried out in aromatic organic solvent such as toluene, benzene, and the like or a mixture of ethereal and aromatic organic solvent. Preferably, the amino protecting group is tert-butoxycarbonyl, benzyl, benzyloxycarbonyl, more preferably tert-butoxycarbonyl.

Preferably, the amino protecting group in Step (iii) is removed with hydrochloric acid or trifluoroacetic acid. Preferably, the removal of the tert-butoxycarbonyl group is by treating (IIIa) with trimethylsilyl chloride in an ethanolic solvent such as ethanol, isopropanol, and the like.

Preferably, the coupling reaction in Step (iv) is carried out with a coupling agent such as benzotriazole-1-yloxytrispyrrolidino-phosphonium hexafluorophosphate (PyBOP.RTM.), O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU), O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU), 1-hydroxybenzotriazole (HOBT), and the like. The reaction is carried out in the presence of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC.HCl), 1,3-dicyclohexylcarbodiimide (DCC), and the like, and a base such as N,N-diisopropylethylamine, triethylamine, N-methylmorpholine, and the like. Suitable solvents are dichloromethane, dichloroethane, dimethylformamide, dioxane, tetrahydrofuran, acetonitrile, and the like. Preferably, catalytic amount of HOBT is used.

Preferably, the oxidizing agent in Step (v) is selected from the group NaOCl/TEMPO.RTM., Dess-Martin Periodinane, and the like.

In a second aspect, this invention is directed to 1-hydroxy-1-(heteroaryl or unsaturated heterocycloalkyl)-2-N-protected-aminoethyl intermediates of formula (III):

##STR00020## where:

X is --O-- or --S--;

Y is nitrogen or --CR.sup.3a--;

Y' is nitrogen or --CR.sup.2a-- provide that Y and Y' are not simultaneously nitrogen;

one of R.sup.2 and R.sup.3 is hydrogen, (C.sub.1-6)alkyl, (C.sub.1-6)alkoxy, (C.sub.1-6)alkoxy(C.sub.1-6)alkyl, amino(C.sub.1-6)alkyl, carboxy(C.sub.1-6)alkyl, hydroxy, (C.sub.1-6)alkylthio, (C.sub.5-6)cycloalkyl, (C.sub.5-6)cycloalkylalkyl, halo, nitro, halo(C.sub.1-3)alkyl, (C.sub.6-12)aryl, heteroaryl, heterocycloalkyl, (C.sub.6 -12)aryl(C.sub.1-6)alkyl, heteroaryl(C.sub.1-6)alkyl, (C.sub.1-6)alkylsulfonyl, (C.sub.6-12)arylsulfonyl, (C.sub.6-12)aryl(C.sub.1-6)alkylsulfonyl, heteroarylsulfonyl, heteroaryl(C.sub.1-6)alkylsulfonyl, aminosulfonyl, (C.sub.1-6)alkylaminosulfonyl, (C.sub.1-6)dialkylaminosulfonyl, --CONR.sup.4R.sup.5 (where R.sup.4 and R.sup.5 are independently of each other hydrogen, (C.sub.1-6)alkyl, (C.sub.1-6)alkoxy, aryl, aryl(C.sub.1-6)alkyl, heteroaryl, heteroaryl(C.sub.1-6)alkyl, (C.sub.5-6)cycloalkyl, (C.sub.5-6)cycloalkyl(C.sub.1-6)alkyl, heterocycloalkyl, or heterocycloalkyl(C.sub.1-6)alkyl, or R.sup.4 and R.sup.5 together with the nitrogen atom to which they are attached form heterocycloamino), --NHCOR.sup.6 (where R.sup.6 is (C.sub.1-6)alkyl, (C.sub.6-12)aryl, aryl(C.sub.1-6)alkyl, heteroaryl, heteroaryl(C.sub.1-6)alkyl, (C.sub.5-6)cycloalkyl, (C.sub.5-6)cycloalkyl(C.sub.1-6)alkyl, heterocycloalkyl, or heterocycloalkyl(C.sub.1-6)alkyl), --SO.sub.2NR.sup.7R.sup.8 (where R.sup.7 and R.sup.8 are independently of each other hydrogen, (C.sub.1-6)alkyl, (C.sub.6-12)aryl, (C.sub.6-12)aryl(C.sub.1-6)alkyl, heteroaryl, heteroarylalkyl, (C.sub.5-6)cycloalkyl, (C.sub.5-6)cycloalkyl(C.sub.1-6)alkyl, heterocycloalkyl, or heterocycloalkyl(C.sub.1-6)alkyl, or R.sup.7 and R.sup.8 together with the nitrogen atom to which they are attached form heterocycloamino), -alkylene-CONR.sup.4R.sup.5 (where R.sup.4 and R.sup.5 are as defined above), -alkylene-NHCOR.sup.6 (where R.sup.6 is as defined above), or -alkylene-SO.sub.2NR.sup.7R.sup.8 (where R.sup.7 and R.sup.8 are as defined above); and

the other of R.sup.2 and R.sup.3 is hydrogen or (C.sub.1-6)alkyl wherein within R.sup.2 or R.sup.3 said aryl, heteroaryl, or heterocycloalkyl is optionally substituted further with one, two, or three substituents independently selected from the group consisting of hydroxy, (C.sub.1-6)alkoxy, (C.sub.1-6)alkyl, (C.sub.6-12)aryl(C.sub.1-6)alkyl, halo, nitro, and halo(C.sub.1-3)alkyl; or R.sup.2 and R.sup.3 together with the atoms to which they are attached form an optionally substituted benzene or napthyl, (C.sub.3-6)cycloalkyl, or an aromatic or non-aromatic heterocyclic ring;

R.sup.2a and R.sup.3a are independently hydrogen or alkyl; or R.sup.2a and R.sup.3a together form a covalent bond, provided that when Y or Y' is nitrogen, R.sup.2a and R.sup.3 or R.sup.2 and R.sup.3a together form a covalent bond;

R.sup.9 is hydrogen or (C.sub.1-6)alkyl; and

R.sup.10 is:

(i) (C.sub.1-6)alkyl optionally substituted with cyano, halo, nitro, --SR.sup.11, --C(O)OR.sup.11, --C(O)NR.sup.11R.sup.11, --NR.sup.13C(NR.sup.13)NR.sup.13R.sup.13, --P(O)(OR.sup.11)OR.sup.11, --OP(O)(OR.sup.11)OR.sup.11, --S(O)R.sup.12, --S(O).sub.2R.sup.12 or --C(O)R.sup.12, wherein R.sup.11 at each occurrence independently is hydrogen, (C.sub.1-6)alkyl or halo-substituted (C.sub.1-3)alkyl, R.sup.12 is alkyl or halo-substituted alkyl, and R.sup.13 at each occurrence independently is hydrogen or (C.sub.1-6)alkyl; or

(ii) (C.sub.5-6)cycloalkyl(C.sub.2-3)alkyl, hetero(C.sub.3-6)cycloalkyl(C.sub.2-3)alkyl, (C.sub.6-12)aryl(C.sub.2-3)alkyl or hetero(C.sub.5-6)aryl(C.sub.2-3)alkyl, wherein said cycloalkyl, heterocycloalkyl, aryl or heteroaryl optionally is substituted further with 1 to 5 radicals independently selected from the group consisting of (C.sub.1-6)alkyl, alkylidene, cyano, halo, halo-substituted (C.sub.1-4)alkyl, nitro, --X.sup.1NR.sup.14C(O)OR.sup.14, --X.sup.1NR.sup.14C(O)NR.sup.14R.sup.14, --X.sup.1NR.sup.14C(NR.sup.14)NR.sup.14R.sup.14, --X.sup.1OR.sup.14, --X.sup.1SR.sup.14, --X.sup.1C(O)OR.sup.14, --X.sup.1C(O)NR.sup.14R.sup.14, --X.sup.1S(O).sub.2NR.sup.14R.sup.14, --X.sup.1P(O)(OR.sup.14)OR.sup.14, --X.sup.1OP(O)(OR.sup.14)OR.sup.14, --X.sup.1NR.sup.14C(O)R.sup.15, --X.sup.1S(O)R.sup.15, --X.sup.1S(O).sub.2R.sup.15 and --X.sup.1C(O)R.sup.15, wherein X.sup.1 is a bond or (C.sub.1-6)alkylene, R.sup.14 at each occurrence independently is hydrogen, (C.sub.1-6)alkyl or halo-substituted (C.sub.1-3)alkyl, and R.sup.15 is (C.sub.1-6)alkyl, halo-substituted (C.sub.1-3)alkyl, or halo; or

(iii) R.sup.9 and R.sup.10 taken together with the carbon atom to which both R.sup.9 and R.sup.10 are attached form (C.sub.3-8)cycloalkylene or heterocycloalkylene, wherein said cycloalkylene or heterocycloalkylene is optionally substituted with 1 to 3 radicals independently selected from the group consisting of (C.sub.1-6)alkyl, (C.sub.1-6)alkylidene, cyano, halo, halo-substituted (C.sub.1-4)alkyl, nitro, --X.sup.2NR.sup.14C(O)OR.sup.14, --X.sup.2NR.sup.14C(O)NR.sup.14R.sup.14, --X.sup.2NR.sup.14C(NR.sup.14)NR.sup.14R.sup.14, --X.sup.2OR.sup.14, --X.sup.2SR.sup.14, --X.sup.2C(O)OR.sup.14, --X.sup.2C(O)NR.sup.14R.sup.14, --X.sup.2S(O).sub.2NR.sup.14R.sup.14, --X.sup.2P(O)(OR.sup.14)OR.sup.14, --X.sup.2OP(O)(OR.sup.14)OR.sup.14, --X.sup.2NR.sup.14C(O)R.sup.15, --X.sup.2S(O)R.sup.15, --X.sup.2S(O).sub.2R.sup.15 and --X.sup.2C(O)R.sup.15, wherein X.sup.2 is a bond or (C.sub.1-6)alkylene, R.sup.14 and R.sup.15 are as defined above; and individual isomers, mixture of isomers, or a salt thereof; provided that:

when X is O or S, R.sup.2a and R.sup.3a together form a covalent bond, R.sup.9 is hydrogen, R.sup.10 is (C.sub.1-6)alkyl optionally substituted with --SR.sup.11 where R.sup.11 is (C.sub.1-6)alkyl, and one of R.sup.2 and R.sup.3 is hydrogen, then the other of R.sup.2 and R.sup.3is not hydrogen, alkyl, or --COR where R is amino, alkylamino or dialkylamino, or pyridin-2-ylmethylamino;

when

##STR00021## is a benzothiazol-2-yl ring, and one of R.sup.9 and R.sup.10 is hydrogen, then the other of R.sup.9 and R.sup.10 is not methyl;

when PG is benzyloxycarbonyl,

##STR00022## is a benzoxazol-2-yl, 4-azabenzoxazol-2-yl, or 4-, 5-, 6-, or 7-methylbenzoxazol-2-yl, and one of R.sup.9 and R.sup.10 is hydrogen, then the other of R.sup.9 and R.sup.10 is not methyl; and

when PG is benzyloxycarbonyl,

##STR00023## is benzoxazol-2-yl, and one of R.sup.9 and R.sup.10 is hydrogen, then the other of R.sup.9 and R.sup.10 is not isopropyl.

In the above compounds of formula (III), a preferred group of compounds is that wherein the moiety:

##STR00024##

is thiazol-2-yl, 4,5-dihydrooxazol-2-yl, or oxazol-2-yl wherein one of R.sup.2 and R.sup.3 is hydrogen or (C.sub.1-4)alkyl and the other of R.sup.2 and R.sup.3is selected from the group consisting of halo, (C.sub.1-4)alkyl, nitro, trifluoromethyl, --CONR.sup.4R.sup.5 (where R.sup.4 and R.sup.5 are independently of each other hydrogen, (C.sub.1-6)alkyl, (C.sub.1-4)alkoxy, (C.sub.6-12)aryl, (C.sub.6-12)aryl(C.sub.1-6)alkyl, heteroaryl, heteroaryl(C.sub.1-6)alkyl, (C.sub.5-6)cycloalkyl, (C.sub.5-6)-cycloalkyl(C.sub.1-6)alkyl, heterocycloalkyl, or heterocycloalkyl(C.sub.1-6)alkyl, or R.sup.4 and R.sup.5 together with the nitrogen atom to which they are attached form heterocycloamino), and --SO.sub.2NR.sup.7R.sup.8 (where R.sup.7 and R.sup.8 are independently of each other hydrogen, (C.sub.1-6)alkyl, (C.sub.6-12)aryl, (C.sub.6-12)aryl(C.sub.1-6)alkyl, heteroaryl, heteroaralkyl, (C.sub.5-6)cycloalkyl, (C.sub.5-6)cycloalkyl(C.sub.1-6)alkyl, heterocycloalkyl, or heterocycloalkyl(C.sub.1-6)alkyl, or R.sup.7 and R.sup.8 together with the nitrogen atom to which they are attached form heterocycloamino) wherein within R.sup.2 or R.sup.3 said aryl, heteroaryl, or heterocycloalkyl is optionally substituted further with one, two, or three substituents independently selected from the group consisting of hydroxy, (C.sub.1-6)alkoxy, (C.sub.1-6)alkyl, (C.sub.6-12)aryl(C.sub.1-6)alkyl, halo, nitro, and halo(C.sub.1-3)alkyl.

Preferably, one of R.sup.2 and R.sup.3 is hydrogen or methyl and the other of R.sup.2 and R.sup.3 is selected from the group consisting of phenyl, phenylaminocarbonyl, benzylaminocarbonyl, aminosulfonyl, 2-phenylethylaminocarbonyl, 3-phenylpropylaminocarbonyl, aminocarbonyl, methylaminocarbonyl, 4-benzylpiperidin-1-ylcarbonyl, furan-2-ylmethylaminocarbonyl, pyridin-2-ylmethylaminocarbonyl, pyridin-3-ylmethylaminocarbonyl, pyridin-4-yl-methylaminocarbonyl, 2-, 3-, or 4-chlorobenzylaminocarbonyl, isopropylaminocarbonyl, 1-phenylethylaminocarbonyl, N-methyl-N-benzylaminocarbonyl, pyrrolidin-1-yl-carbonyl, piperidin-1-ylcarbonyl, 1,2,3 ,4-tetrahydroquinolin-1-ylcarbonyl, napthyl-1-ylmethyl-aminocarbonyl, 2,3-dihydroindol-1-ylcarbonyl, and admant-1-ylmethylaminocarbonyl.

Another preferred group of compounds of formula (III) is that wherein R.sup.2 and R.sup.3 together with the carbon atoms to which they are attached form an optionally substituted benzene ring. Preferably, the benzene ring is optionally subsituted with (C.sub.1-4)alkyl, halo, (C.sub.1-4)alkoxy, (C.sub.6-12)aryl, --CONR.sup.aR.sup.b (where R.sup.a and R.sup.b are independently of each other hydrogen, (C.sub.1-6)alkyl, (C.sub.1-4)alkoxy, (C.sub.6-12)aryl, (C.sub.6-12)aryl(C.sub.1-6)alkyl, heteroaryl,