Peptidomimetic inhibitors of PSMA

1. A compound of the formula

or a pharmaceutically acceptable salt thereof, wherein

X and Y are independently —O— or —N(R)—, wherein each R is independently hydrogen, —C 1 -C 7 alkyl, —C 1 -C 7 alkylaryl, —C 1 -C 7 alkylheteroaryl, or a protecting group selected from the group consisting of substituted benzyl, t-butyl ester, alkyl esters, and fluorenylmethoxycarbonyl groups;

m is 1, 2, 3, 4, 5, or 6;

n is 1, 2, 3, 4, 5, or 6;

R 1 and R 2 are each independently —C(O)OR 3 , —C(O)N(R 3 ) 2 , —P(O)(OR 3 ) 2 , —OP(O)(OR 3 ) 2 , —S(O) 2 R 3 , —S(O) 2 OR 3 , —S(O) 2 N(R 3 ) 2 , or tetrazolyl; each

R 3 is independently hydrogen, —C 1 -C 7 alkyl, —C 1 -C 7 alkylaryl, —C 1 -C 7 alkylheteroaryl, or a protecting group selected from the group consisting of substituted benzyl, t-butyl ester, alkyl esters, and fluorenylmethoxycarbonyl groups;

R 4 ═CO 2 H

R 5 is hydrogen, —C 1 -C 7 alkyl, —C 1 -C 7 alkylaryl, —C 1 -C 7 alkylheteroaryl, or a protecting group selected from the group consisting of substituted benzyl, t-butyl ester, alkyl esters, and fluorenylmethoxycarbonyl groups;

each R 6 is independently hydrogen, or C 1 -C 4 alkyl;

M is —N(R 31 )—, or —CH 2 —, wherein R 31 is hydrogen, —C 1 -C 7 alkyl, —C 1 -C 7 alkylaryl, —C 1 -C 7 alkylheteroaryl, or a protecting group selected from the group consisting of substituted benzyl, t-butyl ester, alkyl esters, and fluorenylmethoxycarbonyl groups;

R 7 is -L-R 10 , wherein

L is —C(O)—, -(Pep)-C(O)—, —C(O)N(H)—, —C(O)O—, —C(S)N(H)—, or —C(S)O—, wherein Pep is a polypeptide of 1-20 amino acids; and

R 10 is -aryl-R 9 , -heteroaryl-R 9 , —C 1 -C 7 alkyl-aryl-R 9 , —C 1 -C 7 alkyl-hetero aryl-R 9 , —C 1 -C 7 alkyl-R 8 , -aryl-C 1 -C 7 alkyl-R 8 , or -heteroaryl-C 1 -C 7 alkyl-R 8 , wherein

the aryl, heteroaryl, -alkyl-aryl, -aryl-alkyl, -alkyl-heteroaryl, and -heteroaryl-alkyl groups are optionally and independently substituted with one, two, or three groups which are each independently halomethyl, dihalomethyl, trihalomethyl, —C(O)R 11 , —CO(O)R 12 , —C(O)N(R 12 ) 2 , wherein

each R 11 is independently hydrogen, —C 1 -C 7 alkyl, —C 1 -C 7 alkylaryl, or —C 1 -C 7 alkylheteroaryl; and each R 12 is independently R 11 or a protecting group selected from the group consisting of substituted benzyl, t-butyl ester, alkyl esters, and fluorenylmethoxycarbonyl groups;

and

R 8 is —C(H)(COOR 3 )N(R 15 )-L 1 -(C 1 -C 7 )alkyl-R 9 , —C(H)(COOR 3 )N(R 15 )-L 1 -aryl-R 9 , —C(H)(COOR 3 )N(R 15 )-L 1 -heteroaryl-R 9 , —C(H)(COOR 3 )N(R 15 )-L 1 -aryl(C 1 -C 7 )alkyl-R 9 , —C(H)(COOR 3 )N(R 15 )-L 1 -heteroaryl(C 1 -C 7 )alkyl-R 9 , —C(H)(COOR 3 )N(R 15 )-L 1 -G-CH 2 CH 2 —R 9 , —C(H)(COOR 3 )N(R 15 )-L 1 -(C 1 -C 7 )alkyl-O—(C C 1 -C 7 )alkyl-R 9 , or —R 9 ,

wherein R 15 is hydrogen, —C 1 -C 7 alkyl, —C 1 -C 7 alkylaryl, —C 1 -C 7 alkylheteroaryl, or a protecting group selected from the group consisting of substituted benzyl, t-butyl ester, alkyl esters, and fluorenylmethoxycarbonyl groups;

L 1 is —C(O)—, —C(O)N(H)—, —C(O)O—, —C(S)N(H)—, or —C(S)O—; and

the aryl, heteroaryl, arylalkyl, and heteroarylalkyl groups are optionally substituted with one, two, or three groups which are each independently halomethyl dihalomethyl, trihalomethyl, —C(O)R 81 , —CO(O)R 82 , —C(O)N(R 82 ) 2 —, wherein

 each R 81 is independently hydrogen, —C 1 -C 7 alkyl, —C 1 -C 7 alkylaryl, or —C 1 -C 7 alkylheteroaryl; and

 each R 82 is independently R 81 or a protecting group selected from the group consisting of substituted benzyl, t-butyl ester, alkyl esters, and fluorenylmethoxycarbonyl groups;

G is —(CH 2 CH 2 O) q —, wherein q is an integer from 1 to 200;

R 9 is (i) —N 3 , —C≡CH—, —ONH 2 , —C(O)N(H)NH 2 , or —N(H)NH 2 ;

 (ii) a detectable label, a cytotoxic group, or biotin;

 (iii) a pendant group comprising either a detectable label, a cytotoxic group, or biotin; or

 (iv) a pendant group bonded to a solid support,

wherein the cytotoxic group is selected from the group consisting of chelated or bonded radioisotopes, photosensitizers, paclitaxel, camptothecin, doxorubicin, and lysosomal disrupting agents, and

wherein the pendant group is a group of the formula —(C 0 -C 10 alkyl-D) 0-1 -C 0 -C 10 alkyl-, wherein D is a bond, aryl, heteroaryl, C 3 -C 8 cycloalkyl, or heterocyclyl; and no more than one methylene in each alkyl group is optionally and independently replaced by —O—, —S—, —N(R 00 )—, —C(H)═C(H)—, —C(O)—, —S(O)—, —S(O) 2 —, —P(O)(OH)—, —OP(O)(OH)—, —P(O)(OH)O—, —N(R 00 )P(O)(OH)—, —P(O)(OH)N(R 00 )—, —OP(O)(OH)O—, —OP(O)(OH)N(R 00 )—, —N(R 00 )P(O)(OH)O—, —N(R 00 )P(O)(OH)N(R 00 )—, —C(O)O—, —C(O)N(R 00 )—, —OC(O)—, —N(R 00 )C(O)—, —S(O)O—, —OS(O)—, —S(O)N(R 00 )—, —N(R 00 )S(O)—, S(O) 2 O—, —OS(O) 2 —, —S(O) 2 N(R 00 )—, —N(R 00 )S(O) 2 —, —OC(O)O—, —OC(O)N(R 00 )—, —N(R 00 )C(O)O—, —N(R 00 )C(O)N(R 00 )—, —OS(O)O—, —OS(O)N(R 00 )—, —N(R 00 )S(O)O—, —N(R 00 )S(O)N(R 00 )—, —OS(O) 2 O—, —(OS)(O) 2 N(R 00 )—, —N(R 00 )S(O) 2 O—, or —N(R 00 )S(O) 2 N(R 00 )—, wherein each R 00 is independently hydrogen or C 1 -C 7 alkyl.

2. The compound of claim 1 , wherein R 8 is —C(H)(COOR 3 )N(H)C(O)(C 1 -C 7 )alkyl-R 9 , —C(H)(COOR 3 )N(H)C(O)hetero aryl-R 9 , —C(H)(COOR 3 )N(H)C(O)-G-CH 2 CH 2 —R 9 , —C(H)(COOR 3 )N(H)C(O)(C 1 -C 7 )alkyl-O—(C 1 -C 7 ) alkyl-R 9 , or —R 9 .

3. The compound of claim 1 , according to the formula,

and pharmaceutically acceptable salts thereof, wherein p is 0 or 1; R 20 is —C 1 -C 7 alkyl-R 9 , -aryl-R 9 , aryl(C 1 -C 7 ) alkyl-R 9 , or -heteroaryl-R 9 .

4. The compound of claim 1 , wherein R 1 and R 2 are each —C(O)OH.

5. The compound of claim 1 , wherein R 4 is —C(O)OH.

6. The compound of claim 1 , wherein each R 3 is hydrogen.

7. The compound of claim 1 , wherein R 9 is a detectable label.

8. A composition comprising a compound of any one of claims 1 - 5 , 6 and 7 together with a pharmaceutically acceptable carrier, excipient, and/or diluent.

9. The compound of claim 3 , wherein: L 1 is —C(O)— or —C(S)N(H)—; R 20 is -aryl-R 9 or aryl-C 1 alkyl-R 9 and R 9 is a detectable label.

10. The compound of claim 9 , wherein

R 1 and R 2 are —C(O)OR 3 and R 3 is H;

R 5 ═H;

Y═NR and R═H;

n=2;

X═O;

m=3;

R 6 ═H;

R 4 ═CO 2 H;

R 31 ═H;

p=1;

R 3 and R 15 ═H;

L 1 is —C(S)N(H)—;

R 20 is aryl-C 1 alkyl-R 9 ; and

R 9 is detectable label 177 Lu coordinated to chelating group 1,4,7,10-tetraazacyclododecanetetraacetic acid (DOTA).