Compounds, compositions, and methods for treatment of diseases involving acidic or hypoxic diseased tissues

1. A compound of formula (I)

R8-Q-R7   (I)

or a pharmaceutically acceptable salt thereof, wherein:

R 7 is a peptide;

R 8 is selected from the group consisting of:

Q is selected from the group consisting of

R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 9 , R 10 , R 11 , and R 12 are each independently selected from H, C 1-4 alkyl, C 1-4 alkenyl, C 6-10 aryl, 5-10 membered heteroaryl, halo, CN, NO 2 , OR a1 , SR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , OC(O)R b1 , OC(O)NR c1 R d1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)OR a1 , and NR c1 C(O)NR c1 R d1 , wherein said C 1-4 alkyl, C 1-4 alkenyl, C 6-10 aryl, and 5-10 membered heteroaryl are each optionally substituted with 1, 2, or 3 substituents independently selected from halo, CN, NO 2 , OR a1 , SR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , OC(O)R b1 , OC(O)NR c1 R d1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)OR a1 , and NR c1 C(O) NR c1 R d1 ;

or R 1 and R 2 together with the carbon atom to which they are attached form a C3-7 cycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from halo, CN, NO 2 , OR a1 , SR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , OC(O)R b1 , OC(O)NR c1 R d1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)OR a1 , and NR c1 C(O)NR c1 R d1 ;

or R 1 and R 3 together with the carbon atom to which they are attached form a C 3-7 cycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from halo, CN, NO 2 , OR a1 , SR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , OC(O)R b1 , OC(O)NR c1 R d1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)OR a1 , and NR c1 C(O)NR c1 R d1 ;

or R 3 and R 4 together with the carbon atom to which they are attached form an C 3-7 cycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from halo, CN, NO 2 , OR a1 , SR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , OC(O)R b1 , OC(O)NR c1 R d1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)OR a1 , and NR c1 C(O)NR c1 R d1 ;

or R 5 and R 6 together with the carbon atom to which they are attached form an C 3-7 cycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from halo, CN, NO 2 , OR a1 , SR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , OC(O)R b1 , OC(O)NR c1 R d1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)OR a1 , and NR c1 C(O)NR c1 R d1 ;

R 13 is H or C 1-6 alkyl;

A is H or C 1-4 alkyl;

is C 6-10 aryl or 5-10 membered heteroaryl; wherein the 5-10 membered heteroaryl has at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O, and S;

[N, O, S] is NH, O, or S;

[N, O] is NH or O;

[C, N, O] is CR X R Y , NH, or O;

each R X and R Y is independently selected from H and C 1-4 alkyl;

[AA] X is a peptide that may be cleaved by enzymatic action;

S1 is

each R a , R b , R c , and R d is independently selected from H, C 1-4 alkyl, OR a2 , CO 2 R a2 , and OC(═O)R a2 , wherein said C 1-4 alkyl is optionally substituted with OR a2 , CO 2 R a2 , and OC(═O)R a2 ;

R a1 , R b1 , R c1 , and R c1 are each independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, OH, CN, NO 2 , and CO 2 CH 3 ; wherein said C 1-6 alkyl and C 2-6 alkenyl are each optionally substituted with OH, CN, NO 2 , or CO 2 CH 3 ;

R a2 is H or C1-4 alkyl; and

n is 0 or 1.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 7 is a peptide capable of selectively delivering 10-across a cell membrane having an acidic or hypoxic mantle having a pH less than about 6.0.

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 7 is a peptide comprising at least one of the following sequences:

(SEQ ID NO: 1; Pv1)

ADDQNPWRAYLDLLFPTDTLLLDLLWCG;

(SEQ ID NO: 2; Pv2)

AEQNPIYWARYADWLFTTPLLLLDLALLVDADECG;

(SEQ ID NO: 3; Pv3)

ADDQNPWRAYLDLLFPTDTLLLDLLWDADECG;

(SEQ ID NO: 4; Pv4)

Ac-AAEQNPIYWARYADWLFTTPLLLLDLALLVDADEGTKCG;

and

(SEQ ID No. 5; Pv5)

AAEQNPIYWARYADWLFTTPLLLLDLALLVDADEGTC;

and wherein R 7 is attached to Q through a cysteine residue of R 7 .

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 7 is a peptide comprising at least one of the following sequences:

(SEQ ID NO: 1; Pv1)

ADDQNPWRAYLDLLFPTDTLLLDLLWCG,

(SEQ ID NO: 2; Pv2)

AEQNPIYWARYADWLFTTPLLLLDLALLVDADECG,

and

(SEQ ID NO: 3; Pv3)

ADDQNPWRAYLDLLFPTDTLLLDLLWDADECG,

and wherein R 7 is attached to Q through a cysteine residue of R 7 .

5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 7 is a peptide comprising the sequence:

(SEQ ID NO: 1; Pv1)

ADDQNPWRAYLDLLFPTDTLLLDLLWCG.

6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 7 is a peptide comprising the sequence:

(SEQ ID NO: 2; Pv2)

AEQNPIYWARYADWLFTTPLLLLDLALLVDADECG.

7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 7 is a peptide comprising the sequence:

(SEQ ID NO: 3; Pv3)

ADDQNPWRAYLDLLFPTDTLLLDLLWDADECG.

8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 7 is a peptide comprising the sequence:

(SEQ ID NO: 4; Pv4)

Ac-AAEQNPIYWARYADWLFTTPLLLLDLALLVDADEGTKCG.

9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 7 is a peptide comprising the sequence:

(SEQ ID No. 5; Pv5)

AAEQNPIYWARYADWLFTTPLLLLDLALLVDADEGTC.

10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 are each independently selected from H and methyl, and R 3 , R 4 , R 5 , and R 6 are each H.

11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 are each independently selected from H and methyl.

12. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 are each H.

13. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 and R 4 are each H.

14. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5 and R 6 are each H.

15. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 9 , R 10 , R 11 , and R 12 are each independently selected from H and methyl.

16. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the enzyme capable of cleaving [AA] X is Cathepsin B, MMPXX, DPPIV, glycoprotein, peptidase, or caspase.

17. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein [AA] X is a peptide having two to ten amino acid residues.

18. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein S1 is a group having the following structure:

19. A pharmaceutical composition that comprises a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

20. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R8 is:

21. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Q is:

22. The compound of claim 21 , or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 are each independently selected from H and methyl.

23. The compound of claim 21 , or a pharmaceutically acceptable salt thereof, wherein R 3 and R 4 are each H.

24. A compound, which is:

or a pharmaceutically acceptable salt thereof; wherein Pv1 is a peptide comprising the following sequence:

ADDQNPWRAYLDLLFPTDTLLLDLLWCG (SEQ ID NO: 1).

25. A compound, which is:

or a pharmaceutically acceptable salt thereof; wherein Pv1 is a peptide comprising the following sequence:

(SEQ ID NO: 1)

ADDQNPWRAYLDLLFPTDTLLLDLLWCG.

26. A compound, which is:

or a pharmaceutically acceptable salt thereof; wherein Pv2 is a peptide comprising the following sequence:

(SEQ ID NO: 2)

AEQNPIYWARYADWLFTTPLLLLDLALLVDADECG.

27. A pharmaceutical composition comprising a compound of claim 24 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

28. A pharmaceutical composition comprising a compound of claim 25 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

29. A pharmaceutical composition comprising a compound of claim 26 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.