Pyrazine derivatives for optical imaging and therapy
View Patent ↗The invention provides compounds, including compositions, preparations and formulations, and methods of using and making such compounds. Compounds of the present invention include pyrazine derivatives having a pyrazine core and a plurality of substituents. In some embodiments, pyrazine derivatives of the invention are pyrazine core compounds having one or more electron donating groups and one or more electron withdrawing groups optionally functionalized to provide useful optical, biological, pharmacokinetic and/or physical properties.
1. A compound of the formula (FX1):
wherein:
each of Z 1 and Z 2 is independently O, S, CH═CH, —NR 37 , or CH 2 ;
each of W 1 and W 2 is independently CH or N;
each of L 1 and L 2 is independently —(CH 2 ) c —, —(HCCH) c —, —O—, —S—, —SO—, —SO 2 —, —SO 3 —, —OSO 2 —, —NR 22 —, —CO—, —COO—, —OCO—, —OCOO—, —CONR 23 —, —NR 24 CO—, —OCONR 25 —, —NR 26 COO—, —NR 27 CONR 28 —, or —NR 29 CSNR 30 —;
each c is independently an integer from 1 to 10, and each of R 22 -R 30 is independently hydrogen, C 1 -C 10 ) alkyl, C 3 -C 10 cycloalkyl, or C 5 -C 10 aryl;
each of X and Y is independently hydrogen, C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, C 5 -C 10 aryl, C 1 -C 10 acyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 5 -C 10 alkylaryl, halo, halomethyl, dihalomethyl, trihalomethyl, —CN, —CO 2 R 1 , —CONR 2 R 3 , —COR 4 , —NO 2 , —SOR 5 , —OSR 36 , —SO 2 R 6 , —SO 2 OR 7 , —SO 2 NR 8 R 9 , —PO 3 R 10 R 11 , —OR 12 , —SR 13 , —NR 14 R 15 , —NR 16 COR 17 , or
Z 3 is a single bond, —CR 18 R 19 —, —O—, —NR 20 —, —NCOR 21 —, —S—, —SO—, or —SO 2 —;
each of R 1 to R 21 , R 36 and R 37 is independently hydrogen or C 1 -C 10 alkyl;
each of m and n is independently 1, 2, or 3, provided that m+n≧3 if Z 3 is a single bond;
each of R 31 and R 32 is independently H, C 1 -C 6 alkyl, halo, halomethyl, dihalomethyl, or trihalomethyl;
R 33 is H, NR 34 R 35 , C 1 -C 6 alkyl, halo, halomethyl, dihalomethyl, or trihalomethyl;
each of R 34 and R 35 is independently hydrogen or C 1 -C 3 alkyl; and
each of d and e is independently 0 or 1.
2. The compound of claim 1 , having the formula (FX2):
wherein:
each of Z 1 and Z 2 is independently O, S, CH═CH, —NR 37 , or CH 2 ;
each of W 1 and W 2 is independently CH or N;
each of X and Y is independently hydrogen, C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, C 5 -C 10 aryl, C 1 -C 10 acyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 5 -C 10 alkylaryl, halo, halomethyl, dihalomethyl, trihalomethyl, —CN, —CO 2 R 1 , —CONR 2 R 3 , —COR 4 , —NO 2 , —SOR 5 , —OSR 36 , —SO 2 R 6 , —SO 2 OR 7 , —SO 2 NR 8 R 9 , —PO 3 R 10 R 11 , —OR 12 , —SR 13 , —NR 14 R 15 , —NR 16 COR 17 , or
Z 3 is a single bond, —CR 18 R 19 —, —O—, —NR 20 —, —NCOR 21 —, —S—, —SO—, or —SO 2 —;
each of R 1 to R 21 , R 36 and R 37 is independently hydrogen or C 1 -C 10 alkyl;
each of m and n is independently 1, 2, or 3, provided that m+n≧3 if Z 3 is a single bond;
each of R 31 and R 32 is independently H, C 1 -C 6 alkyl, halo, halomethyl, dihalomethyl, or trihalomethyl;
R 33 is H, NR 34 R 35 , C 1 -C 6 alkyl, halo, halomethyl, dihalomethyl, or trihalomethyl; and
each of R 34 and R 35 is independently hydrogen or C 1 -C 3 alkyl.
3. The compound of claim 1 , having the formula (FX3) to (FX9):
wherein in formula (FX7) Z 1 is O, S, or CH;
wherein in formula (FX8) Z 2 is O, S, or CH;
wherein in formula (FX9) each of Z 1 and Z 2 is independently O, S, or CH; wherein in each of (FX3); (FX4); (FX5); (FX6); (FX7); (FX8); and (FX9):
each of X and Y is independently hydrogen, C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, C 5 -C 10 aryl, C 1 -C 10 acyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 5 -C 10 alkylaryl, halo, halomethyl, dihalomethyl, trihalomethyl, —CN, —CO 2 R 1 , —CONR 2 R 3 , —COR 4 , —NO 2 , —SOR 5 , —OSR 36 , —SO 2 R 6 , —SO 2 OR 7 , —SO 2 NR 8 R 9 , —PO 3 R 10 R 11 , —OR 12 —, —SR 13 , —NR 14 R 15 , —NR 16 COR 17 , or
Z 3 is a single bond, —CR 18 R 19 —, —O—, —NR 20 —, —NCOR 21 —, —S—, —SO—, or —SO 2 —;
each of R 1 to R 21 and R 36 is independently hydrogen or C 1 -C 10 ) alkyl;
each of m and n is independently 1, 2, or 3, provided that m+n≧3 if Z 3 is a single bond;
each of R 31 and R 32 is independently H, C 1 -C 6 alkyl, halo, halomethyl, dihalomethyl, or trihalomethyl;
R 33 is H, NR 34 R 35 , C 1 -C 6 alkyl, halo, halomethyl, dihalomethyl, or trihalomethyl; and
each of R 34 and R 35 is independently hydrogen or C 1 -C 3 alkyl.
4. The compound of claim 1 , wherein:
one of X or Y is —CN, —CO 2 R 1 , —CONR 2 R 3 , —COR 4 , —NO 2 , —SOR 5 , —SO 2 R 6 , —SO 2 OR 7 , —SO 2 NR 8 R 9 , or —PO 3 R 10 R 11 ;
the other of X or Y is —OR 12 , —SR 13 , —NR 14 R 15 , —NR 16 COR 17 , or
Z 3 is a single bond, —CR 18 R 19 —, —O—, —NR 20 —, —NCOR 21 —, —S—, —SO—, or —SO 2 —;
each of R 1 to R 21 is independently hydrogen or C 1 -C 6 alkyl; and
each of m and n is independently 1, 2, or 3, provided that m+n≧3 if Z 3 is a single bond.
5. The compound of claim 1 , wherein:
one of X or Y is —CN, —CO 2 R 1 , —CONR 2 R 3 , —COR 4 , —NO 2 , —SOR 5 , —SO 2 R 6 , —SO 2 OR 7 , —SO 2 NR 8 R 9 , or —PO 3 R 10 R 11 ;
each of R 1 -R 11 is independently hydrogen or C 1 -C 3 alkyl;
the other of X or Y is —NR 14 R 15 ; and
each of R 14 -R 15 is independently hydrogen or C 1 -C 3 alkyl.
6. The compound of claim 1 , wherein one of X and Y is an electron withdrawing group, and the other of X and Y is an electron donating group.
7. The compound of claim 1 , wherein one of X and Y is an electron withdrawing group, and the other of X and Y is hydrogen.
8. The compound of claim 1 , wherein one of X and Y is an electron donating group, and the other of X and Y is hydrogen.
9. The compound of claim 1 , wherein each of d and e is 0.
10. The compound of claim 1 , wherein:
one of X and Y is —CN, —CO 2 R 1 , —CONR 2 R 3 , —COR 4 , —NO 2 , —SOR 5 , —SO 2 R 6 , —SO 2 OR 7 , —SO 2 NR 8 R 9 , or —PO 3 R 10 R 11 ;
each of R 1 to R 11 is independently hydrogen or C 1 -C 6 alkyl; and
the other of X and Y is hydrogen.
11. The compound of claim 1 , wherein:
one of X and Y is OR 12 , —SR 13 , —NR 14 R 15 , —NR 16 COR 17 , or
Z 3 is a single bond, —CR 18 R 19 —, —O—, —NR 20 —, —NCOR 21 —, —S—, —SO—, or —SO 2 —;
each of R 12 to R 21 is independently hydrogen or C 1 -C 6 alkyl;
each of m and n is independently 1,2, or 3, provided that m+n≧3 if Z 3 is a single bond; and
the other of X and Y is hydrogen.
12. The compound of claim 1 , wherein:
X is —CN, —CO 2 R 1 , —CONR 2 R 3 , —COR 4 , —NO 2 , —SOR 5 , —SO 2 R 6 , —SO 2 OR 7 , —SO 2 NR 8 R 9 , or —PO 3 R 10 R 11 ;
Y is OR 12 , —SR 13 , —NR 14 R 15 , —NR 16 COR 17 , or
Z 3 is a single bond, —CR 18 R 19 —, —O—, —NR 20 —, —NCOR 21 —, —S—, —SO—, or —SO 2 —;
each of R 1 to R 21 is independently hydrogen or C 1 -C 6 alkyl;
each of m and n is independently 1, 2, or 3, provided that m+n≧3 if Z 3 is a single bond.
13. A pharmaceutical composition comprising:
a compound of formula (FX1)
wherein:
each of Z 1 and Z 2 is independently O, S, CH═CH, —NR 37 , or CH 2 ;
each of W 1 and W 2 is independently CH or N;
each of L 1 and L 2 is independently —(CH 2 ) c —, —(HCCH) c —, —O—, —S—, —SO—, —SO 2 —, —SO 3 —, —OSO 2 —, —NR 22 —, —CO—, —COO—, —OCO—, —OCOO—, —CONR 23 —, —NR 24 CO—, —OCONR 25 —, —NR 26 COO—, —NR 27 CONR 28 —, or —NR 29 CSNR 30 —;
each c is independently an integer from 1 to 10, and each of R 22 -R 30 is independently hydrogen alkyl, C 1 -C 10 cycloalkyl, or C 5 -C 10 aryl;
each of X and Y is independently hydrogen, C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, C 5 -C 10 aryl, C 1 -C 10 acyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 5 -C 10 alkylaryl, halo, halomethyl, dihalomethyl, trihalomethyl, —CN, —CO 2 R 1 , —CONR 2 R 3 , —COR 4 , —NO 2 , —SOR 5 , —OSR 36 , —SO 2 R 6 , —SO 2 OR 7 , —SO 2 NR 8 R 9 , —PO 3 R 10 R 11 , —OR 12 , —SR 13 , NR 14 R 15 , —NR 16 COR 17 , or
Z 3 is a single bond, —CR 18 R 19 —, —O—, —NR 20 —, —NCOR 21 —, —S—, —SO—, or —SO 2 ;
each of R 1 to R 21 , R 36 and R 37 is independently hydrogen or C 1 -C 10 alkyl;
each of m and n is independently 1, 2, or 3, provided that m+n≧3 if Z 3 is a single bond;
each of R 31 and R 32 is independently H, C 1 -C 6 alkyl, halo, halomethyl, dihalomethyl or trihalomethyl;
R 33 is H, NR 34 R 35 , C 1 -C 6 alkyl, halo, halomethyl, dihalomethyl, or trihalomethyl;
each of R 34 and R 35 is independently hydrogen or C 1 -C 3 alkyl; and
each of d and e is independently 0 or 1 and a pharmaceutically acceptable excipient.