Selective cysteine protease inhibitors and uses thereof
The present invention relates to compounds of Formula I, II, IA-VA, IVA1-IVA5, IIIA1-IIIA5 and their pharmaceutical uses. Particular aspects of the invention relate to the use of those compounds for the selective inhibition of one or more cysteine proteases. Also described are methods where the compounds of Formula I, II, IA-VA, IVA1-IVA5, IIIA1-IIIA5 are used in the prevention and/or treatment of various diseases and conditions in subjects, including cysteine protease-mediated diseases and/or caspase-mediated diseases such as sepsis, myocardial infarction, cancer, tissue atrophy, ischemia, ischemic stroke, spinal cord injury (SCI), traumatic brain injury (TBI) and neurodegenerative diseases such as multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), Alzheimer's disease, Parkinson's disease, and Huntington's disease.
1. A compound of Formula I:
wherein
a is 0;
b is 0;
c is 0;
d is 0 or 1;
the line “-” when located between P2 and P3 is a peptide bond or a peptidomimetic bond, wherein when the line “-” is a peptidomimetic bond, the peptidomimetic bond is a bond selected from the group consisting of a CH 2 NH bond, a CO—CH 2 bond, an azapeptide bond, and a retroinverso bond;
P3 is a natural or non-natural amino acid residue;
P2 is alanine, arginine, aspartic acid, asparagine, cysteine, glutamine, isoleucine, histidine, leucine, lysine, methionine, phenylalanine, proline, serine, tryptophan, tyrosine, or a non-natural amino acid residue;
R 1 and R 2 are either in the cis configuration or the trans configuration;
n is 0, 1, or 3;
wherein Z is Tetrazol, Cyano, COR 4 , or COR 5 ;
W is H, alkyl, OH, OR 9 , NH 2 , NHR 9 , NHSOR 9 , halogen, COR 4 , COR 9 , CN, OCOR 9 , OCO 2 R 9 , NO, NO 2 , NR 7 R 8 , NHSO 2 R 9 , NHCOR 9 , SO 2 R 9 , SOR 9 , or SR 9 ;
A is
1) H,
2) R 3 —CH 2 OC(O)—,
3) (4-amino-3-chloro-benzene)-C(O)—, or
4) quinoline-C(O)—;
R 1 is
1) SO 2 R 5 ,
2) SO 3 R 5 ,
3) SOR 5 ,
4) CO 2 R 5 , or
5) COR 5 ;
R 2 is
1) R 1 ,
2) H,
3) halogen,
4) haloalkyl,
5) C 1 -C 6 alkyl,
6) C 2 -C 6 alkene,
7) C 3 -C 7 cycloalkyl,
8) OR 9 ,
9) SR 9 ,
10) N + (R 4 ) 3 ,
11) OCOR 6 ,
12) OCO 2 R 6 ,
13) NR 7 R 8 ,
14) NHSO 2 R 6 ,
15) NHCOR 6 ,
16) aryl,
17) heteroaryl, or
18) heterocyclyl;
R 3 is
1) C 1 -C 6 alkyl,
2) aryl-C 1 -C 6 alkyl,
3) heteroaryl, or
4) heterocyclyl;
R 4 is
1) OH, or
2) OC 1 -C 6 alkyl;
R 5 is
1) H,
2) C 1 -C 6 alkyl,
3) C 2 -C 6 alkene,
4) C 3 -C 7 cycloalkyl,
5) haloalkyl,
6) aryl,
7) heteroaryl,
8) heterocyclyl,
9) NHCH 2 C(O)OH, or
10) (D) or (L) natural or non-natural amino acids optionally protected with an amino acid protecting group;
R 6 is
1) any (D) or (L) amino acid residue,
2) C 1 -C 6 alkyl,
3) C 3 -C 7 cycloalkyl,
4) aryl,
5) heteroaryl, or
6) heterocyclyl,
in which the alkyl or the cycloalkyl are optionally substituted with one or more R 10 substituents; and in which the aryl, heteroaryl or heterocyclyl are optionally substituted with one or more R 20 substituents;
R 7 and R 8 are independently selected from:
1) H,
2) C 1 -C 6 alkyl,
3) C 3 -C 7 cycloalkyl,
4) haloalkyl,
5) aryl,
6) heteroaryl, or
7) heterocyclyl,
wherein the alkyl and the cycloalkyl are optionally substituted with one or more R 10 substituents, and the aryl, the heteroaryl and the heterocyclyl are optionally substituted with one or more R 20 substituents;
R 9 is
1) H,
2) C 1 -C 6 alkyl,
3) C 3 -C 7 cycloalkyl,
4) aryl,
5) heteroaryl, or
6) heterocyclyl,
in which the alkyl or the cycloalkyl are optionally substituted with one or more R 10 substituents; and in which the aryl, heteroaryl or heterocyclyl are optionally substituted with one or more R 20 substituents;
R 10 is independently selected from:
1) halogen,
2) C 1 -C 6 alkyl,
3) C 3 -C 7 cycloalkyl,
4) haloalkyl,
5) aryl,
6) heteroaryl,
7) heterocyclyl,
8) OR 9 ,
9) S(O) m R 9 ,
10) NR 7 R 8 ,
11) COR 9 ,
12) C(O)OR 9 ,
13) OC(O)R 9 ,
14) SC(O)R 9 ,
15) CONR 7 R 8 , or
16) S(O) 2 NR 7 R 8 ;
wherein m is an integer of 0, 1, or 2;
R 20 is independently selected from:
1) halogen,
2) NO 2 ,
3) CN,
4) C 1 -C 6 alkyl,
5) haloalkyl,
6) C 3 -C 7 cycloalkyl,
7) OR 7 ,
8) NR 7 R 8 ,
9) SR 7 ,
10) aryl,
11) heteroaryl,
12) heterocyclyl,
13) SO 2 R 5 ,
14) SO 3 R 5 ,
15) SOR 5 ,
16) SONHR 5 ,
17) SO 2 NHR 5 ,
18) PO 3 R 5 ,
19) PO(OR 5 ) 2 ,
20) PO(OR 5 ),
21) COR 5 ,
22) COR 7 ,
23) CO 2 R 7 ,
24) S(O) m R 7 ,
25) CONR 7 R 8 , or
26) S(O) 2 NR 7 R 8 ,
wherein the alkyl and the cycloalkyl are optionally substituted with one or more R 6 substituents; and wherein the aryl, the heteroaryl, or the heterocyclyl are optionally substituted with one or more R 30 ; wherein m is an integer of 0, 1, or 2; and
R 30 is
1) NO 2 ,
2) C 2 -C 6 alkene-R 20 ,
3) SO 2 R 5 ,
4) SOR 5 ,
5) SONHR 5 ,
6) SO 2 NHR 5 ,
7) CN,
8) CO 2 R 5 ,
9) COR 5 ,
10) PO 3 R 5 ,
11) PO(OR 5 ) 2 , or
12) PO(OR 5 );
or a pharmaceutically acceptable salt or ester thereof, or the compound is labeled with a detectable label or an affinity tag thereof;
wherein the compound is a caspase inhibitor.
2. The compound according to claim 1 , in which A is H.
3. The compound according to claim 1 , in which A is selected from the group consisting of quinoline-C(O)—, and (4-amino-3-chlorobenzene)-C(O)—.
4. The compound according to claim 1 , in which Z is COR 4 and R 4 is selected from the group consisting of OH, OCH 3 , and OCH 2 CH 3 .
5. The compound according to claim 1 , in which Z is COR 4 and R 4 is OH.
6. The compound according to claim 1 , in which d is 0.
7. The compound according to claim 1 , in which R 1 is in the trans configuration.
8. The compound according to claim 1 , wherein R 1 is
1) SO 2 R 5 ,
2) SO 3 R 5 ,
3) SOR 5 ,
4) CO 2 R 5 , or
5) COR 5 ; and
wherein R 5 is H, C 1 -C 6 alkyl, aryl, or heterocyclyl.
9. The compound according to claim 1 , in which R 2 is
1) H,
2) halogen,
3) haloalkyl,
4) C 1 -C 6 alkyl, or
5) C 3 -C 7 cycloalkyl.
10. The compound according to claim 9 , in which R 2 is H or Cl.
11. The compound according to claim 10 , in which R 2 is Cl.
12. The compound according to claim 9 , wherein the compound is selected from the group consisting of: 4-amino-3-chlorobenzene carbonyl-t-Leu-Pro-Asp methyl vinyl sulfone (compound 14), 2-Quinoline carbonyl-t-Leu-Pro-Asp methyl vinyl sulfone (compound 6), Quinoline-6-carbonyl-t-Leu-Pro-Asp methyl vinyl sulfone (compound 10), 2-Quinoline carbonyl-t-Leu-(Azetidine-2-carbonyl)-Asp methyl vinyl sulfone (compound 20), (4-amino-3-chlorobenzene carbonyl)-t-Leu-Pro-β-Cyano-Ala methyl vinyl sulfone (compound 90), 4-amino-3-chlorobenzene carbonyl-t-Leu-Pro-β-Cyano-Ala α-chlorovinyl methyl vinyl sulfone (compound 91), (4-amino-3-chlorobenzene carbonyl-t-Leu-Pro-(β-1H tetrazole-Ala) methyl vinyl sulfone (compound 92), 4-amino-3-chlorobenzene carbonyl)-t-Leu-Pro-(β-1H tetrazole-Ala) α-chlorovinyl methyl vinyl sulfone (compound 93), 2-Quinoline carbonyl-t-Leu-Pro-β-Cyano-Ala methyl vinyl sulfone (compound 94), 2-Quinoline carbonyl-t-Leu-Pro-(β-Cyano-Ala) α-chlorovinyl methyl vinyl sulfone (compound 95), 2-Quinoline carbonyl-t-Leu-Pro-(β-1H tetrazole-Ala) methyl vinyl sulfone (compound 96), 2-Quinoline carbonyl-t-Leu-Pro-(β-1H tetrazole-Ala) α-chlorovinyl methyl vinyl sulfone (compound 97), (4-amino-3-chlorobenzene carbonyl)-t-Leu-Pro-(β-1H tetrazole-Ala) α-chlorovinyl Ethyl Vinyl Ester (compound 113), (4-amino-3-chlorobenzene carbonyl)-t-Leu-Pro-(β-1H tetrazole-Ala) Ethyl Vinyl Ester (compound 112), 4-amino-3-chlorobenzene carbonyl-t-Leu-Pro-Asp α-chlorovinyl Ethyl Vinyl Ester (compound 117), 2-Quinoline carbonyl-t-Leu-Pro-(β-1H tetrazole-Ala) Ethyl Vinyl Ester (compound 114), 2-Quinoline carbonyl-t-Leu-Pro-(β-1H tetrazole-Ala) α-chlorovinyl Ethyl Vinyl Ester (compound 115), 4-amino-3-chlorobenzene carbonyl-t-Leu-Pro-Asp Ethyl Vinyl Ester (compound 116), 2-Quinoline carbonyl-t-Leu-Pro-Asp Ethyl Vinyl Ester (compound 118), and 2-Quinoline carbonyl-t-Leu-Pro-Asp α-chlorovinyl Ethyl Vinyl Ester (compound 119).
13. The compound according to claim 1 , in which n is 1.
14. A compound of Formula IA:
wherein
a is 0;
b is 0;
c is 0;
d is 0 or 1;
AA 3 is the side chain of a natural or non-natural amino acid;
AA 2 is the side chain of alanine, arginine, aspartic acid, asparagine, cysteine, glutamine, isoleucine, histidine, leucine, lysine, methionine, phenylalanine, proline, serine, tryptophan, tyrosine, or a non-natural amino acid;
R 1 and R 2 can be either in the cis configuration or the trans configuration;
n is 0, 1, or 3;
Z is Tetrazol, Cyano, COR 4 , or COR 5 ;
W is H, alkyl, OH, OR 9 , NH 2 , NHR 9 , NHSOR 9 , halogen, COR 4 , COR 9 , CN, OCOR 9 , OCO 2 R 9 , NO, NO 2 , NR 7 R 8 , NHSO 2 R 9 , NHCOR 9 , SO 2 R 9 , SOR 9 , or SR 9 ;
A is
1) H,
2) R 3 —CH 2 OC(O)—,
3) (4-amino-3-chloro-benzene)-C(O)—, or
4) quinoline-C(O)—;
R 1 is
1) SO 2 R 5 ,
2) SO 3 R 5 ,
3) SOR 5 ,
4) CO 2 R 5 , or
5) COR 5 ;
R 2 is
1) R 1 ,
2) H,
3) halogen,
4) haloalkyl,
5) C 1 -C 6 alkyl,
6) C 2 -C 6 alkene,
7) C 3 -C 7 cycloalkyl,
8) OR 9 ,
9) SR 9 ,
10) N + (R 4 ) 3 ,
11) OCOR 6 ,
12) OCO 2 R 6 ,
13) NR 7 R 8 ,
14) NHSO 2 R 6 ,
15) NHCOR 6 ,
16) aryl,
17) heteroaryl, or
18) heterocyclyl;
R 3 is
1) C 1 -C 6 alkyl,
2) aryl-C 1 -C 6 alkyl,
3) heteroaryl, or
4) heterocyclyl;
R 4 is
1) OH, or
2) OC 1 -C 6 alkyl;
R 5 is
1) H,
2) C 1 -C 6 alkyl,
3) C 2 -C 6 alkene,
4) C 3 -C 7 cycloalkyl,
5) haloalkyl,
6) aryl,
7) heteroaryl,
8) heterocyclyl,
9) NHCH 2 C(O)OH, or
10) (D) or (L) natural or non-natural amino acids optionally protected with an amino acid protecting group;
R 6 is
1) any (D) or (L) amino acid residue,
2) C 1 -C 6 alkyl,
3) C 3 -C 7 cycloalkyl,
4) aryl,
5) heteroaryl, or
6) heterocyclyl,
in which the alkyl or the cycloalkyl are optionally substituted with one or more R 10 substituents; and in which the aryl, heteroaryl or heterocyclyl are optionally substituted with one or more R 20 substituents;
R 7 and R 8 are independently selected from:
1) H,
2) C 1 -C 6 alkyl,
3) C 3 -C 7 cycloalkyl,
4) haloalkyl,
5) aryl,
6) heteroaryl, or
7) heterocyclyl,
wherein the alkyl and the cycloalkyl are optionally substituted with one or more R 10 substituents, and the aryl, the heteroaryl and the heterocyclyl are optionally substituted with one or more R 20 substituents;
R 9 is
1) H,
2) C 1 -C 6 alkyl,
3) C 3 -C 7 cycloalkyl,
4) aryl,
5) heteroaryl, or
6) heterocyclyl,
in which the alkyl or the cycloalkyl are optionally substituted with one or more R 10 substituents; and in which the aryl, heteroaryl or heterocyclyl are optionally substituted with one or more R 20 substituents;
R 10 is independently selected from:
1) halogen,
2) C 1 -C 6 alkyl,
3) C 3 -C 7 cycloalkyl,
4) haloalkyl,
5) aryl,
6) heteroaryl,
7) heterocyclyl,
8) OR 9 ,
9) S(O) m R 9 ,
10) NR 7 R 8 ,
11) COR 9 ,
12) C(O)OR 9 ,
13) OC(O)R 9 ,
14) SC(O)R 9 ,
15) CONR 7 R 8 , or
16) S(O) 2 NR 7 R 8 ,
wherein m is an integer of 0, 1, or 2;
R 20 is independently selected from:
1) halogen,
2) NO 2 ,
3) CN,
4) C 1 -C 6 alkyl,
5) haloalkyl,
6) C 3 -C 7 cycloalkyl,
7) OR 7 ,
8) NR 7 R 8 ,
9) SR 7 ,
10) aryl,
11) heteroaryl,
12) heterocyclyl,
13) SO 2 R 5 ,
14) SO 3 R 5 ,
15) SOR 5 ,
16) SONHR 5 ,
17) SO 2 NHR 5 ,
18) PO 3 R 5 ,
19) PO(OR 5 ) 2 ,
20) PO(OR 5 ),
21) COR 5 ,
22) COR 7 ,
23) CO 2 R 7 ,
24) S(O) m R 7 ,
25) CONR 7 R 8 , or
26) S(O) 2 NR 7 R 8 ,
wherein the alkyl and the cycloalkyl are optionally substituted with one or more R 6 substituents; and wherein the aryl, the heteroaryl, or the heterocyclyl are optionally substituted with one or more R 30 ; wherein m is an integer of 0, 1, or 2; and
R 30 is
1) NO 2 ,
2) C 2 -C 6 alkene-R 20 ,
3) SO 2 R 5 ,
4) SOR 5 ,
5) SONHR 5 ,
6) SO 2 NHR 5 ,
7) CN,
8) CO 2 R 5 ,
9) COR 5 ,
10) PO 3 R 5 ,
11) PO(OR 5 ) 2 , or
12) PO(OR 5 );
or a pharmaceutically acceptable salt or ester thereof, or the compound is labeled with a detectable label or an affinity tag thereof;
wherein the compound is a caspase inhibitor.
15. The compound according to claim 14 , in which A is H.
16. The compound according to claim 14 , in which A is quinolone-C(O)—, or (4-amino-3-Chlorobenzene)-CO—.
17. The compound according to claim 14 , in which Z is COR 4 and R 4 is OH, OCH 3 , or OCH 2 CH 3 .
18. The compound according to claim 14 , in which Z is COR 4 and R 4 is OH.
19. The compound according to claim 14 , in which d is 0.
20. The compound according to claim 14 , in which R 1 is in the trans configuration.
21. The compound according to claim 14 , wherein R 1 is
1) SO 2 R 5 ,
2) SO 3 R 5 ,
3) SOR 5 ,
4) CO 2 R 5 , or
5) COR 5 ;
wherein R 5 is H, C 1 -C 6 alkyl, aryl, or heterocyclyl.
22. The compound according to claim 14 , in which R 2 is
1) H,
2) halogen,
3) haloalkyl,
4) C 1 -C 6 alkyl, or
5) C 3 -C 7 cycloalkyl.
23. The compound according to claim 22 , in which R 2 is H or Cl.
24. The compound according to claim 23 , in which R 2 is Cl.
25. The compound according to claim 14 , wherein
A is
1) H, or
2) R 3 —CH 2 OC(O); and
AA 2 is the (R) or (S) amino acid side chain of 2-azetidine, Leu, Pro, Met, Ala, His, Ser (O-phosphate), Tyr, Trp, Ile, or Lys.
26. A compound of Formula IIIIA 2a:
wherein AA 3 is the side chain of a natural or non-natural amino acids;
R 1 and R 2 can be either in the cis configuration or the trans configuration;
n is 0, 1, or 3;
Z is Tetrazol, Cyano, COR 4 , or COR 5 ;
W is H, alkyl, OH, OR 9 , NH 2 , NHR 9 , NHSOR 9 , halogen, COR 4 , COR 9 , CN, OCOR 9 , OCO 2 R 9 , NO, NO 2 , NR 7 R 8 , NHSO 2 R 9 , NHCOR 9 , SO 2 R 9 , SOR 9 , or SR 9 ;
A is
1) H,
2) C 1 -C 6 alkyl,
3) aryl,
4) heteroaryl,
5) heterocyclyl,
6) R 3 —C(O)—,
7) R 3 —OC(O)—,
8) R 3 —CH 2 OC(O)—,
9) R 3 —C(O)O—,
10) R 3 —S(O) 2 —,
11) (4-amino-3-chloro-benzene)-C(O)—,
12) PhCH 2 OC(O)—, or
13) quinoline-C(O)—;
R 1 is
1) aryl,
2) heteroaryl,
3) heterocyclyl,
4) C 2 -C 6 alkene-R 20 ,
5) SO 2 R 5 ,
6) SO 3 R 5 ,
7) SOR 5 ,
8) SONHR 5 ,
9) SO 2 NHR 5 ,
10) CN,
11) CO 2 R 5 ,
12) COR 5 ,
13) PO 3 R 5 ,
14) PO(OR 5 ) 2 , or
15) PO(OR 5 ),
wherein the aryl, the heteroaryl, or the heterocyclyl are optionally substituted with one or more R 30 ;
R 2 is
1) R 1 ,
2) H,
3) halogen,
4) haloalkyl,
5) C 1 -C 6 alkyl,
6) C 2 -C 6 alkene,
7) C 3 -C 7 cycloalkyl,
8) OR 9 ,
9) SR 9 ,
10) N + (R 4 ) 3 ,
11) OCOR 6 ,
12) OCO 2 R 6 ,
13) NR 7 R 8 ,
14) NHSO 2 R 6 ,
15) NHCOR 6 ,
16) aryl,
17) heteroaryl, or
18) heterocyclyl;
R 3 is
1) C 1 -C 6 alkyl,
2) aryl-C 1 -C 6 alkyl,
3) heteroaryl, or
4) heterocyclyl;
R 4 is
1) OH,
2) OC 1 -C 6 alkyl,
3) NR 7 R 8 ,
4) NHSO 2 R 9 ,
5) alkyl, or
6) heteroalkyl;
R 5 is
1) H,
2) C 1 -C 6 alkyl,
3) C 2 -C 6 alkene,
4) C 3 -C 7 cycloalkyl,
5) haloalkyl,
6) aryl,
7) heteroaryl,
8) heterocyclyl,
9) NHCH 2 C(O)OH, or
10) (D) or (L) natural or non-natural amino acids optionally protected with an amino acid protecting group;
R 6 is
1) any (D) or (L) amino acid residue,
2) C 1 -C 6 alkyl,
3) C 3 -C 7 cycloalkyl,
4) aryl,
5) heteroaryl, or
6) heterocyclyl,
in which the alkyl or the cycloalkyl are optionally substituted with one or more R 10 substituents; and in which the aryl, heteroaryl or heterocyclyl are optionally substituted with one or more R 20 substituents;
R 7 and R 8 are independently selected from:
1) H,
2) C 1 -C 6 alkyl,
3) C 3 -C 7 cycloalkyl,
4) haloalkyl,
5) aryl,
6) heteroaryl, or
7) heterocyclyl;
wherein the alkyl and the cycloalkyl are optionally substituted with one or more R 10 substituents, and the aryl, the heteroaryl and the heterocyclyl are optionally substituted with one or more R 20 substituents;
R 9 is
1) H,
2) C 1 -C 6 alkyl,
3) C 3 -C 7 cycloalkyl,
4) aryl,
5) heteroaryl, or
6) heterocyclyl,
in which the alkyl or the cycloalkyl are optionally substituted with one or more R 10 substituents; and in which the aryl, heteroaryl or heterocyclyl are optionally substituted with one or more R 20 substituents;
R 10 is independently selected from:
1) halogen,
2) C 1 -C 6 alkyl,
3) C 3 -C 7 cycloalkyl,
4) haloalkyl,
5) aryl,
6) heteroaryl,
7) heterocyclyl,
8) OR 9 ,
9) S(O) m R 9 ,
10) NR 7 R 8 ,
11) COR 9 ,
12) C(O)OR 9 ,
13) OC(O)R 9 ,
14) SC(O)R 9 ,
15) CONR 7 R 8 , or
16) S(O) 2 NR 7 R 8 ,
wherein m is an integer of 0, 1, or 2;
R 20 is independently selected from:
1) halogen,
2) NO 2 ,
3) CN,
4) C 1 -C 6 alkyl,
5) haloalkyl,
6) C 3 -C 7 cycloalkyl,
7) OR 7 ,
8) NR 7 R 8 ,
9) SR 7 ,
10) aryl,
11) heteroaryl,
12) heterocyclyl,
13) SO 2 R 5 ,
14) SO 3 R 5 ,
15) SOR 5 ,
16) SONHR 5 ,
17) SO 2 NHR 5 ,
18) PO 3 R 5 ,
19) PO(OR 5 ) 2 ,
20) PO(OR 5 ),
21) COR 5 ,
22) COR 7 ,
23) CO 2 R 7 ,
24) S(O) m R 7 ,
25) CONR 7 R 8 , or
26) S(O) 2 NR 7 R 8 ,
wherein the alkyl and the cycloalkyl are optionally substituted with one or more R 6 substituents; and wherein the aryl, the heteroaryl, or the heterocyclyl are optionally substituted with one or more R 30 ; wherein m is an integer of 0, 1, or 2; and
R 30 is
1) NO 2 ,
2) C 2 -C 6 alkene-R 20 ,
3) SO 2 R 5 ,
4) SOR 5 ,
5) SONHR 5 ,
6) SO 2 NHR 5 ,
7) CN,
8) CO 2 R 5 ,
9) COR 5 ,
10) PO 3 R 5 ,
11) PO(OR 5 ) 2 , or
12) PO(OR 5 );
or a pharmaceutically acceptable salt or ester thereof, or the compound is labeled with a detectable label or an affinity tag thereof;
wherein the compound is a caspase inhibitor.