CLAIMS What is claimed is: 1. A conjugated donor-acceptor fluorophore having the formula: [donor]-[linker]-[acceptor], or a pharmaceutically acceptable salt thereof, wherein: [donor] has the formula: , Z2 is N-Rzd and Z1 is O, S, C(Rz)2 N-Rz, N=CRz1, or C(CRz1)=C(CRz1); or Z2 is null and Z1 is Z3-N(Rzd)-, wherein Z3 is N=CRz3*, C(CRz3)=C(CRz3); O, S, or C(Rz)2; wherein Rz and Rzd are each case independently optionally substituted C1-6alkyl; Rz1 is in case independently selected from F, Cl, Br, I, NO2, CN, Rz1*, ORz1*, N(Rz1*)2, SO3Rz1*, SO2Rz1*, SO2N(Rz1*)2, C(O)Rz1*; C(O)ORz1*, OC(O)Rz1*; C(O)N(Rz1*)2, N(Rz1*)C(O)Rz1*, OC(O)N(Rz1*)2, N(Rz1*)C(O)N(Rz1*)2, wherein Rz1* is in each case independently selected from hydrogen, C1-8alkyl, C1-8alkoxy, C2-8alkenyl, C2-8alkynyl, aryl, C1-8heteroaryl, C3-8cycloalkyl, or C1-8heterocyclyl; Rz3 is in each case independently selected from F, Cl, Br, I, NO2, CN, Rz3*, ORz3*, N(Rz3*)2, SO3Rz3*, SO2Rz3*, SO2N(Rz3*)2, C(O)Rz3*; C(O)ORz3*, OC(O)Rz3*; C(O)N(Rz3*)2, N(Rz3*)C(O)Rz3*, OC(O)N(Rz3*)2, N(Rz3*)C(O)N(Rz3*)2, wherein Rz3* is in each case independently selected from hydrogen, C1-8alkyl, C1-8alkoxy, C2-8alkenyl, C2-8alkynyl, aryl, C1-8heteroaryl, C3-8cycloalkyl, or C1-8heterocyclyl; R1 is F, Cl, Br, I, NO2, CN, R1a, OR1a, N(R1a)2, SO3R1a, SO2R1a, SO2N(R1a)2, C(O)R1a; C(O)OR1a, OC(O)R1a; C(O)N(R1a)2, N(R1a)C(O)R1a, OC(O)N(R1a)2, N(R1a)C(O)N(R1a)2, wherein R1a is in each case independently selected from hydrogen, C1-8alkyl, C1-8alkoxy, C2-8alkenyl, C2-8alkynyl, aryl, C1-8heteroaryl, C3-8cycloalkyl, or C1-8heterocyclyl; R2 is F, Cl, Br, I, NO2, CN, R2a, OR2a, N(R2a)2, SO3R2a, SO2R2a, SO2N(R2a)2, C(O)R2a; C(O)OR2a, OC(O)R2a; C(O)N(R2a)2, N(R2a)C(O)R2a, OC(O)N(R2a)2, N(R2a)C(O)N(R2a)2, wherein R2a is in each case independently selected from hydrogen, C1-8alkyl, C1-8alkoxy, C2-8alkenyl, C2-8alkynyl, aryl, C1-8heteroaryl, C3-8cycloalkyl, or C1-8heterocyclyl; R3 is F, Cl, Br, I, NO2, CN, R3a, OR3a, N(R3a)2, SO3R3a, SO2R3a, SO2N(R3a)2, C(O)R3a; C(O)OR3a, OC(O)R3a; C(O)N(R3a)2, N(R3a)C(O)R3a, OC(O)N(R3a)2, N(R3a)C(O)N(R3a)2, wherein R3a is in each case independently selected from hydrogen, C1-8alkyl, C1-8alkoxy, C2-8alkenyl, C2-8alkynyl, aryl, C1-8heteroaryl, C3-8cycloalkyl, or C1-8heterocyclyl; and R4 is F, Cl, Br, I, NO2, CN, R4a, OR4a, N(R4a)2, SO3R4a, SO2R4a, SO2N(R4a)2, C(O)R4a; C(O)OR4a, OC(O)R4a; C(O)N(R4a)2, N(R4a)C(O)R4a, OC(O)N(R4a)2, N(R4a)C(O)N(R4a)2, wherein R4a is in each case independently selected from hydrogen, C1-8alkyl, C1-8alkoxy, C2-8alkenyl, C2-8alkynyl, aryl, C1-8heteroaryl, C3-8cycloalkyl, or C1-8heterocyclyl; [acceptor] has the formula: , wherein X1 is Cl, F, Br, I, Rx1, Q-C(=O)Rx1, Q-C(=O)ORx1, Q-C(=O)SRx1, Q-SO2Rx1, Q-SO3Rx1, Q-C(=O)N(Rx1)2, Q-C(=NRx1’)Rx1, Q-C(=NRx’)ORx1, Q-SO2Rx1, Q-SO3Rx1, Q- C(NRx1’)N(Rx1)2, Q-C1-3haloalkyl; Q-CN, Q-NO2; X2 is Cl, F, Br, I, Q-C(=O)Rx2, Q-C(=O)ORx2, Q-C(=O)SRx2, Q-SO2Rx2, Q-SO3Rx2, Q- C(=O)N(Rx2)2, Q-C(=NRx2’)Rx2, Q-C(=NRx’)ORx2, Q-SO2Rx2, Q-SO3Rx2, Q- C(NRx2’)N(Rx2)2, Q-C1-3haloalkyl; Q-CN, Q-NO2, wherein Q is in each case independently selected from null, CH=CH, or C≡C; Rx1 is in each case independently selected from H, optionally substituted C1-6alkyl, optionally substituted C1-6haloalkyl; optionally substituted C1-10aryl; optionally substituted C3- 10cycloalkyl optionally substituted C1-10heteroaryl; optionally substituted C1- 10heterocyclyl; Rx2 is in each case independently selected from H, optionally substituted C1-6alkyl, optionally substituted C1-6haloalkyl; optionally substituted C1-10aryl; optionally substituted C3- 10cycloalkyl optionally substituted C1-10heteroaryl; optionally substituted C1- 10heterocyclyl; [linker] has the formula: , wherein the wavy line marked ‘1’ represents the point of attachment to the [donor] and the wavy line marker ‘2’ represents the point of attachment to the acceptor; Ra is F, Cl, Br, I, NO2, CN, Ra1, ORa1, N(Ra1)2, SO2Ra1, SO2N(Ra1)2, C(O)Ra1; C(O)ORa1, OC(O)Ra1; C(O)N(Ra1)2, N(Ra1)C(O)Ra1, OC(O)N(Ra1)2, N(Ra1)C(O)N(Ra1)2, wherein Ra1 is in each case independently selected from hydrogen, C1-8alkyl, C1-8alkoxy, C2- 8alkenyl, C2-8alkynyl, aryl, C1-8heteroaryl, C3-8cycloalkyl, or C1-8heterocyclyl; Rb is F, Cl, Br, I, NO2, CN, Rb1, ORb1, N(Rb1)2, SO2Rb1, SO2N(Rb1)2, C(O)Rb1; C(O)ORb1, OC(O)Rb1; C(O)N(Rb1)2, N(Rb1)C(O)Rb1, OC(O)N(Rb1)2, N(Rb1)C(O)N(Rb1)2, wherein Rb1 is in each case independently selected from hydrogen, C1-8alkyl, C1-8alkoxy, C2- 8alkenyl, C2-8alkynyl, aryl, C1-8heteroaryl, C3-8cycloalkyl, or C1-8heterocyclyl; Rc is F, Cl, Br, I, NO2, CN, Rc1, ORc1, N(Rc1)2, SO2Rc1, SO2N(Rc1)2, C(O)Rc1; C(O)ORc1, OC(O)Rc1; C(O)N(Rc1)2, N(Rc1)C(O)Rc1, OC(O)N(Rc1)2, N(Rc1)C(O)N(Rc1)2, wherein Rc1 is in each case independently selected from hydrogen, C1-8alkyl, C1-8alkoxy, C2- 8alkenyl, C2-8alkynyl, aryl, C1-8heteroaryl, C3-8cycloalkyl, or C1-8heterocyclyl; Rd is F, Cl, Br, I, NO2, CN, Rd1, ORd1, N(Rd1)2, SO2Rd1, SO2N(Rd1)2, C(O)Rd1; C(O)ORd1, OC(O)Rd1; C(O)N(Rd1)2, N(Rd1)C(O)Rd1, OC(O)N(Rd1)2, N(Rd1)C(O)N(Rd1)2, wherein Rd1 is in each case independently selected from hydrogen, C1-8alkyl, C1-8alkoxy, C2- 8alkenyl, C2-8alkynyl, aryl, C1-8heteroaryl, C3-8cycloalkyl, or C1-8heterocyclyl; Re is F, Cl, Br, I, NO2, CN, Re1, ORe1, N(Re1)2, SO2Re1, SO2N(Re1)2, C(O)Re1; C(O)ORe1, OC(O)Re1; C(O)N(Re1)2, N(Re1)C(O)Re1, OC(O)N(Re1)2, N(Re1)C(O)N(Re1)2, wherein Re1 is in each case independently selected from hydrogen, C1-8alkyl, C1-8alkoxy, C2- 8alkenyl, C2-8alkynyl, aryl, C1-8heteroaryl, C3-8cycloalkyl, or C1-8heterocyclyl; Rf is F, Cl, Br, I, NO2, CN, Rf1, ORf1, N(Rf1)2, SO2Rf1, SO2N(Rf1)2, C(O)Rf1; C(O)ORf1, OC(O)Rf1; C(O)N(Rf1)2, N(Rf1)C(O)Rf1, OC(O)N(Rf1)2, N(Rf1)C(O)N(Rf1)2, wherein Rf1 is in each case independently selected from hydrogen, C1-8alkyl, C1-8alkoxy, C2-8alkenyl, C2-8alkynyl, aryl, C1-8heteroaryl, C3-8cycloalkyl, or C1-8heterocyclyl; wherein any two or more of R1, R2, R3, R4, Ra, Rb, Rc, Rd, Re, Rf, Rz, Rzd, Rz1, Rz3, Rc, Rb, Rx1, and Rx2 may together form a ring. 2. The fluorophore according to claim 1, wherein each of Ra, Rb, Rd, Re, and Rf are hydrogen. 3. The fluorophore according to any preceding claim, wherein Ra is an electron- withdrawing or electron-donating group. 4. The fluorophore according to any preceding claim, wherein Rb is an electron- withdrawing or electron-donating group. 5. The fluorophore according to any preceding claim, wherein Rc is an electron- withdrawing or electron-donating group. 6. The fluorophore according to any preceding claim, wherein Rd is an electron- withdrawing or electron-donating group. 7. The fluorophore according to any preceding claim, wherein Re is an electron- withdrawing or electron-donating group. 8. The fluorophore according to any preceding claim, wherein Rf is an electron-withdrawing or electron-donating group. 9. The fluorophore according to any preceding claim, wherein Ra is an electron- withdrawing group. 10. The fluorophore according to any preceding claim, wherein Rb is an electron- withdrawing group. 11. The fluorophore according to any preceding claim, wherein Rc is an electron- withdrawing group. 12. The fluorophore according to any preceding claim, wherein Rd is an electron- withdrawing group. 13. The fluorophore according to any preceding claim, wherein Re is an electron- withdrawing group. 14. The fluorophore according to any preceding claim, wherein Rf is an electron-withdrawing group. 15. The fluorophore according to any preceding claim, wherein Ra is an electron-donating group. 16. The fluorophore according to any preceding claim, wherein Rb is an electron-donating group. 17. The fluorophore according to any preceding claim, wherein Rc is an electron-donating group. 18. The fluorophore according to any preceding claim, wherein Rd is an electron-donating group. 19. The fluorophore according to any preceding claim, wherein Re is an electron-donating group. 20. The fluorophore according to any preceding claim, wherein Rf is an electron-donating group. 21. The fluorophore according to any preceding claim, wherein Rf is an electron-withdrawing group and Re is an electron-donating group. 22. The fluorophore according to any preceding claim, wherein Rf is an electron-withdrawing group and Rd is an electron-donating group. 23. The fluorophore according to any preceding claim, wherein Re and Rd are both electron- donating groups. 24. The fluorophore according to any preceding claim, wherein Rd is an electron- withdrawing or electron-donating group and Re and Rf are each hydrogen. 25. The fluorophore according to any preceding claim, wherein Re is an electron-withdrawing or electron-donating group and Rd and Rf are each hydrogen. 26. The fluorophore according to any preceding claim, wherein Rf is an electron-withdrawing or electron-donating group and Rd and Re are each hydrogen. 27. The fluorophore according to any preceding claim, wherein Rd is an electron-donating group and Re and Rf are each hydrogen. 28. The fluorophore according to any preceding claim, wherein Re is an electron-donating group and Rd and Rf are each hydrogen. 29. The fluorophore according to any preceding claim, wherein Rf is an electron-donating group and Rd and Re are each hydrogen. 30. The fluorophore according to any preceding claim, wherein Rd is an electron- withdrawing group and Re and Rf are each hydrogen. 31. The fluorophore according to any preceding claim, wherein Re is an electron-withdrawing group and Rd and Rf are each hydrogen. 32. The fluorophore according to any preceding claim, wherein Rf is an electron-withdrawing group and Rd and Re are each hydrogen. 33. The fluorophore according to any preceding claim, wherein Ra is an electron-donating group selected from OH, NH2, OC1-3alkyl, NHC1-3alkyl, N(C1-3alkyl)2, OC1-3alkyl, NHC1- 3alkyl, and N(C1-3alkyl)2, unsubstituted C1-3alkyl, unsubstituted aryl, C1-3alkyl substituted one or more times with OH, NH2, OC1-3alkyl, NHC1-3alkyl, N(C1-3alkyl)2, OC1-3alkyl, NHC1-3alkyl, and N(C1-3alkyl)2. 34. The fluorophore according to any preceding claim, wherein Rb is an electron-donating group selected from OH, NH2, OC1-3alkyl, NHC1-3alkyl, N(C1-3alkyl)2, OC1-3alkyl, NHC1- 3alkyl, and N(C1-3alkyl)2, unsubstituted C1-3alkyl, unsubstituted aryl, C1-3alkyl substituted one or more times with OH, NH2, OC1-3alkyl, NHC1-3alkyl, N(C1-3alkyl)2, OC1-3alkyl, NHC1-3alkyl, and N(C1-3alkyl)2.. 35. The fluorophore according to any preceding claim, wherein Rc is an electron-donating group selected from OH, NH2, OC1-3alkyl, NHC1-3alkyl, N(C1-3alkyl)2, OC1-3alkyl, NHC1- 3alkyl, and N(C1-3alkyl)2, unsubstituted C1-3alkyl, unsubstituted aryl, C1-3alkyl substituted one or more times with OH, NH2, OC1-3alkyl, NHC1-3alkyl, N(C1-3alkyl)2, OC1-3alkyl, NHC1-3alkyl, and N(C1-3alkyl)2. 36. The fluorophore according to any preceding claim, wherein Rd is an electron-donating group selected from OH, NH2, OC1-3alkyl, NHC1-3alkyl, N(C1-3alkyl)2, OC1-3alkyl, NHC1- 3alkyl, and N(C1-3alkyl)2, unsubstituted C1-3alkyl, unsubstituted aryl, C1-3alkyl substituted one or more times with OH, NH2, OC1-3alkyl, NHC1-3alkyl, N(C1-3alkyl)2, OC1-3alkyl, NHC1-3alkyl, and N(C1-3alkyl)2. 37. The fluorophore according to any preceding claim, wherein Re is an electron-donating group selected from OH, NH2, OC1-3alkyl, NHC1-3alkyl, N(C1-3alkyl)2, OC1-3alkyl, NHC1- 3alkyl, and N(C1-3alkyl)2, unsubstituted C1-3alkyl, unsubstituted aryl, C1-3alkyl substituted one or more times with OH, NH2, OC1-3alkyl, NHC1-3alkyl, N(C1-3alkyl)2, OC1-3alkyl, NHC1-3alkyl, and N(C1-3alkyl)2.. 38. The fluorophore according to any preceding claim, wherein Rf is an electron-donating group selected from OH, NH2, OC1-3alkyl, NHC1-3alkyl, N(C1-3alkyl)2, OC1-3alkyl, NHC1- 3alkyl, and N(C1-3alkyl)2, unsubstituted C1-3alkyl, unsubstituted aryl, C1-3alkyl substituted one or more times with OH, NH2, OC1-3alkyl, NHC1-3alkyl, N(C1-3alkyl)2, OC1-3alkyl, NHC1-3alkyl, and N(C1-3alkyl)2. 39. The fluorophore according to any preceding claim, wherein Ra is an electron-withdrawing group selected from F, Cl, Br, I, C1-3haloalkyl, C(O)C1-3alkyl, C(O)OC1-3alkyl, C(O)NHC1-3alkyl, C(O)OH, SO3H, C(O)C1-3haloalkyl, C(O)OC1-3haloalkyl, and C(O)NHC1-3haloalkyl. 40. The fluorophore according to any preceding claim, wherein Rb is an electron-withdrawing group selected from F, Cl, Br, I, C1-3haloalkyl, C(O)C1-3alkyl, C(O)OC1-3alkyl, C(O)NHC1-3alkyl, C(O)OH, SO3H, C(O)C1-3haloalkyl, C(O)OC1-3haloalkyl, and C(O)NHC1-3haloalkyl. 41. The fluorophore according to any preceding claim, wherein Rc is an electron- withdrawing group selected from F, Cl, Br, I, C1-3haloalkyl, C(O)C1-3alkyl, C(O)OC1- 3alkyl, C(O)NHC1-3alkyl, C(O)OH, SO3H, C(O)C1-3haloalkyl, C(O)OC1-3haloalkyl, and C(O)NHC1-3haloalkyl. 42. The fluorophore according to any preceding claim, wherein Rd is an electron- withdrawing group selected from F, Cl, Br, I, C1-3haloalkyl, C(O)C1-3alkyl, C(O)OC1- 3alkyl, C(O)NHC1-3alkyl, C(O)OH, SO3H, C(O)C1-3haloalkyl, C(O)OC1-3haloalkyl, and C(O)NHC1-3haloalkyl. 43. The fluorophore according to any preceding claim, wherein Re is an electron-withdrawing group selected from F, Cl, Br, I, C1-3haloalkyl, C(O)C1-3alkyl, C(O)OC1-3alkyl, C(O)NHC1-3alkyl, C(O)OH, SO3H, C(O)C1-3haloalkyl, C(O)OC1-3haloalkyl, and C(O)NHC1-3haloalkyl. 44. The fluorophore according to any preceding claim, wherein Rf is an electron-withdrawing group selected from F, Cl, Br, I, C1-3haloalkyl, C(O)C1-3alkyl, C(O)OC1-3alkyl, C(O)NHC1-3alkyl, C(O)OH, SO3H, C(O)C1-3haloalkyl, C(O)OC1-3haloalkyl, and C(O)NHC1-3haloalkyl. 45. The fluorophore according to any preceding claim, wherein Ra and Rb together form a ring. 46. The fluorophore according to any preceding claim, wherein Ra and Rb together form a ring, and Rd, Re, and Rf are hydrogen. 47. The fluorophore according to any preceding claim, wherein Ra and Rb together form a ring, and Rd is an electron-donating group. 48. The fluorophore according to any preceding claim, wherein Ra and Rb together form a ring, and Re is an electron-donating group. 49. The fluorophore according to any preceding claim, wherein Ra and Rb together form a ring, and Rf is an electron-donating group. 50. The fluorophore according to any preceding claim, wherein Ra and Rb together form a ring, and Rd is an electron-withdrawing group. 51. The fluorophore according to any preceding claim, wherein Ra and Rb together form a ring, and Re is an electron-withdrawing group. 52. The fluorophore according to any preceding claim, wherein Ra and Rb together form a ring, and Rf is an electron-withdrawing group. 53. The fluorophore according to any preceding claim, wherein Ra and Rb together form a ring, and Rd is an electron-donating group selected from OH, NH2, OC1-3alkyl, NHC1- 3alkyl, N(C1-3alkyl)2, OC1-3alkyl, NHC1-3alkyl, and N(C1-3alkyl)2, unsubstituted C1-3alkyl, unsubstituted aryl, C1-3alkyl substituted one or more times with OH, NH2, OC1-3alkyl, NHC1-3alkyl, N(C1-3alkyl)2, OC1-3alkyl, NHC1-3alkyl, and N(C1-3alkyl)2. 54. The fluorophore according to any preceding claim, wherein Ra and Rb together form a ring, and Re is an electron-donating group selected from OH, NH2, OC1-3alkyl, NHC1- 3alkyl, N(C1-3alkyl)2, OC1-3alkyl, NHC1-3alkyl, and N(C1-3alkyl)2, unsubstituted C1-3alkyl, unsubstituted aryl, C1-3alkyl substituted one or more times with OH, NH2, OC1-3alkyl, NHC1-3alkyl, N(C1-3alkyl)2, OC1-3alkyl, NHC1-3alkyl, and N(C1-3alkyl)2. 55. The fluorophore according to any preceding claim, wherein Ra and Rb together form a ring, and Rf is an electron-donating group selected from OH, NH2, OC1-3alkyl, NHC1- 3alkyl, N(C1-3alkyl)2, OC1-3alkyl, NHC1-3alkyl, and N(C1-3alkyl)2, unsubstituted C1-3alkyl, unsubstituted aryl, C1-3alkyl substituted one or more times with OH, NH2, OC1-3alkyl, NHC1-3alkyl, N(C1-3alkyl)2, OC1-3alkyl, NHC1-3alkyl, and N(C1-3alkyl)2. 56. The fluorophore according to any preceding claim, wherein Ra and Rb together form a ring, and Rd is an electron-withdrawing group selected from F, Cl, Br, I, C1-3haloalkyl, C(O)C1-3alkyl, C(O)OC1-3alkyl, C(O)NHC1-3alkyl, C(O)OH, SO3H, C(O)C1-3haloalkyl, C(O)OC1-3haloalkyl, and C(O)NHC1-3haloalkyl. 57. The fluorophore according to any preceding claim, wherein Ra and Rb together form a ring, and Re is an electron-withdrawing group selected from F, Cl, Br, I, C1-3haloalkyl, C(O)C1-3alkyl, C(O)OC1-3alkyl, C(O)NHC1-3alkyl, C(O)OH, SO3H, C(O)C1-3haloalkyl, C(O)OC1-3haloalkyl, and C(O)NHC1-3haloalkyl. 58. The fluorophore according to any preceding claim, wherein Ra and Rb together form a ring, and Rf is an electron-withdrawing group selected from F, Cl, Br, I, C1-3haloalkyl, C(O)C1-3alkyl, C(O)OC1-3alkyl, C(O)NHC1-3alkyl, C(O)OH, SO3H, C(O)C1-3haloalkyl, C(O)OC1-3haloalkyl, and C(O)NHC1-3haloalkyl. 59. The fluorophore according to any preceding claim, wherein the [linker] has the formula: , wherein: A1 is selected from C(Ra1)2, N(Ra1*)na1, O, S, -C(Ra1)2— C(Ra1)2-, -C(Ra1)=C(Ra1)-, -C(Ra1)=N-; Ra1 is selected from F, Cl, Br, I, NO2, CN, Ra1$, ORa1$, N(Ra1$)2, SO2Ra1$, SO2N(Ra1$)2, C(O)Ra1$; C(O)ORa1$, OC(O)Ra1$; C(O)N(Ra1$)2, N(Ra1$)C(O)Ra1$, OC(O)N(Ra1$)2, N(Ra1$)C(O)N(Ra1$)2, wherein Ra1$ is in each case independently selected from hydrogen, C1-8alkyl, C1-8alkoxy, C2-8alkenyl, C2-8alkynyl, aryl, C1-8heteroaryl, C3-8cycloalkyl, or C1- 8heterocyclyl; na1 is 0, 1 or 2; when na1 is 1 then Ra1* is selected from Ra1$, SO2Ra1$, SO2N(Ra1$)2, C(O)Ra1$; C(O)ORa1$, C(O)N(Ra1$)2, N(Ra1$)C(O)Ra1$, wherein Ra1$ is in each case independently selected from hydrogen, C1-8alkyl, C1-8alkoxy, C2-8alkenyl, C2-8alkynyl, aryl, C1-8heteroaryl, C3- 8cycloalkyl, or C1-8heterocyclyl; when na1 is 2 then Ra1* is in each case independently selected from hydrogen, C1-8alkyl, C1- 8alkoxy, C2-8alkenyl, C2-8alkynyl, aryl, C1-8heteroaryl, C3-8cycloalkyl, or C1-8heterocyclyl; A2 is selected from null, C(Ra2)2, N(Ra2*)na2, O, S, -C(Ra2)2— C(Ra2)2-, -C(Ra2)=C(Ra2)-, - C(Ra2)=N-; Ra2 is selected from F, Cl, Br, I, NO2, CN, Ra2$, SRa2$, SeRa2$, ORa2$, N(Ra2$)2, SO2Ra2$, SO2N(Ra2$)2, C(O)Ra2$; C(O)ORa2$, OC(O)Ra2$; C(O)N(Ra2$)2, N(Ra2$)C(O)Ra2$, OC(O)N(Ra2$)2, N(Ra2$)C(O)N(Ra2$)2, whereinRa2$ is in each case independently selected from hydrogen, C1-8alkyl, C1-8alkoxy, C2-8alkenyl, C2-8alkynyl, aryl, C1-8heteroaryl, C3- 8cycloalkyl, or C1-8heterocyclyl; na2 is 0, 1 or 2; when na2 is 1 then Ra2* is selected from Ra2$, SO2Ra2$, SO2N(Ra2$)2, C(O)Ra2$; C(O)ORa2$, C(O)N(Ra2$)2, N(Ra2$)C(O)Ra2$, wherein Ra2$ is in each case independently selected from hydrogen, C1-8alkyl, C1-8alkoxy, C2-8alkenyl, C2-8alkynyl, aryl, C1-8heteroaryl, C3- 8cycloalkyl, or C1-8heterocyclyl; when na2 is 2 then Ra2* is in each case independently selected from hydrogen, C1-8alkyl, C1- 8alkoxy, C2-8alkenyl, C2-8alkynyl, aryl, C1-8heteroaryl, C3-8cycloalkyl, or C1-8heterocyclyl; A3 is selected from C(Ra3)2, N(Ra3*)na3, O, S, -C(Ra3)2— C(Ra3)2-, -C(Ra3)=C(Ra3)-, -C(Ra3)=N-, Ra3 is selected from F, Cl, Br, I, NO2, CN, Ra3$, ORa3$, N(Ra3$)2, SO2Ra3$, SO2N(Ra3$)2, C(O)Ra3$; C(O)ORa3$, OC(O)Ra3$; C(O)N(Ra3$)2, N(Ra3$)C(O)Ra3$, OC(O)N(Ra3$)2, N(Ra3$)C(O)N(Ra3$)2, wherein Ra3$ is in each case independently selected from hydrogen, C1-8alkyl, C1-8alkoxy, C2-8alkenyl, C2-8alkynyl, aryl, C1-8heteroaryl, C3-8cycloalkyl, or C1- 8heterocyclyl; na3 is 0, 1 or 2; when na3 is 1 then Ra3* is selected from Ra3$, SO2Ra3$, SO2N(Ra3$)2, C(O)Ra3$; C(O)ORa3$, C(O)N(Ra3$)2, N(Ra3$)C(O)Ra3$, wherein Ra3$ is in each case independently selected from hydrogen, C1-8alkyl, C1-8alkoxy, C2-8alkenyl, C2-8alkynyl, aryl, C1-8heteroaryl, C3- 8cycloalkyl, or C1-8heterocyclyl; when na3 is 2 then Ra3* is in each case independently selected from hydrogen, C1-8alkyl, C1- 8alkoxy, C2-8alkenyl, C2-8alkynyl, aryl, C1-8heteroaryl, C3-8cycloalkyl, or C1-8heterocyclyl. 60. The fluorophore according to any preceding claim, wherein A2 is CHRa2, O, S, NRa2*, or N+(Ra2*)2, A1 is CH2 or CH2CH2, preferably CH2 and A3 is CH2 or CH2CH2, preferably CH2. 61. The fluorophore according to any preceding claim, wherein A2 is CHRa2, A1 is CH2 or CH2CH2, preferably CH2 and A3 is CH2 or CH2CH2, preferably CH2. 62. The fluorophore according to any preceding claim, wherein A2 is O, A1 is CH2 or CH2CH2, preferably CH2 and A3 is CH2 or CH2CH2, preferably CH2. 63. The fluorophore according to any preceding claim, wherein A2 is A1 is CH2 or CH2CH2, preferably CH2 and A3 is CH2 or CH2CH2, preferably CH2. 64. The fluorophore according to any preceding claim, wherein A2 is NRa2*, A1 is CH2 or CH2CH2, preferably CH2 and A3 is CH2 or CH2CH2, preferably CH2. 65. The fluorophore according to any preceding claim, wherein A2 is N+(Ra2*)2, A1 is CH2 or CH2CH2, preferably CH2 and A3 is CH2 or CH2CH2, preferably CH2. 66. The fluorophore according to any preceding claim, wherein the [linker] has the formula: wherein Qa is null, CH2, CH2CH2, or CH2CH2CH2, and Ra2* is in each case independently selected from C1-4alkyl, benzyl phenyl, or H. 67. The fluorophore according to any preceding claim, wherein Qa is null or CH2. 68. The fluorophore according to any preceding claim, wherein A2 is null. 69. The fluorophore according to any preceding claim, wherein A2 is null and the [linker] has the formula: . 70. The fluorophore according to any preceding claim, wherein A2 is null and the [linker] has the formula: . wherein 71. The fluorophore according to any preceding claim, wherein A2 is null and the [linker] has the formula: . A1 is C(Ra1*)2 and A3 is NRa3*. 72. The fluorophore according to any preceding claim, wherein A2 is null and the [linker] has the formula: . A1 is NRa1* and A3 is C(Ra3*)2. 73. The fluorophore according to any preceding claim, wherein A2 is null and the [linker] has the formula: . A1 is C(Ra1*)2 and A3 is O. 74. The fluorophore according to any preceding claim, wherein A2 is null and the [linker] has the formula: . A3 is C(Ra3*)2 and A1 is O. 75. The fluorophore according to any preceding claim, wherein A2 is null and the [linker] has the formula: . A1 is O and A3 is NRa3*. 76. The fluorophore according to any preceding claim, wherein A2 is null and the [linker] has the formula: . A3 is O and A1 is NRa1*. 77. The fluorophore according to any preceding claim, wherein A2 is null and the [linker] has the formula: , wherein A1 is CRa1* and A3 is CRa3*. 78. The fluorophore according to any preceding claim, wherein A2 is null and the [linker] has the formula: , wherein A1 is N and A3 is CRa3*. 79. The fluorophore according to any preceding claim, wherein A2 is null and the [linker] has the formula: , wherein A1 is CRa1* and A3 is N. 80. The fluorophore according to any preceding claim, wherein [linker] has the formula: , wherein Ra2 is H, CH3, CF3, CH2F, CHF2, CH2CH3, CH(CH3)2, C(CH3)3, F, Cl, Br, OH, NH2, SO3H, PO3H2, COOH, OCH3, OCH2CH3, OCH(CH3)2, OCF3, OCH2CF3, NHCH3, N(CH3)2, ϕ, CH2CH3, CH2CF3, CH2CH2F, CH2CHF2, CH(CH3)2, C(CH3)3, CH2OH, CH2NH2, CH2SO3H, CH2PO3H2, CH2COOH, CH2OCH3, CH2OCF3, CH2OCH2CF3, CH2NHCH3, CH2N(CH3)2, CH2ϕ, CH2CH2CH3, CH2CH2CF3, CH2CH2CH2F, CH2CH2CHF2, CH2CH(CH3)2, CH2C(CH3)3, CH2CH2OH, CH2CH2NH2, CH2CH2SO3H, CH2CH2PO3H2, CH2CH2COOH, CH2CH2OCH3, CH2CH2OCF3, CH2CH2OCH2CF3, CH2CH2NHCH3, CH2CH2N(CH3)2, or CH2CH2ϕ, wherein ϕ is an aryl or heteroaryl group. 81. The fluorophore according to any preceding claim, wherein [linker] has the formula: , wherein Ra2 is SOH, Sϕ, SCH2CH3, SCH2CF3, SCH2CH2F, SCH2CHF2, SCH(CH3)2, SC(CH3)3, SCH2ϕ, SCH2CH2CH3, SCH2CH2CF3, SCH2CH2CH2F, SCH2CH2CHF2, SCH2CH(CH3)2, SCH2C(CH3)3, SCH2CH2OH, SCH2CH2NH2, SCH2CH2SO3H, SCH2CH2PO3H2, SCH2CH2COOH, SCH2CH2OCH3, SCH2CH2OCF3, SCH2CH2OCH2CF3, SCH2CH2NHCH3, SCH2CH2N(CH3)2, or SCH2CH2ϕ, wherein ϕ is an aryl or heteroaryl group. 82. The fluorophore according to any preceding claim, wherein [linker] has the formula: , wherein Ra2 is SeOH, Seϕ, SeCH2CH3, SeCH2CF3, SeCH2CH2F, SeCH2CHF2, SeCH(CH3)2, SeC(CH3)3, SeCH2ϕ, SeCH2CH2CH3, SeCH2CH2CF3, SeCH2CH2CH2F, SeCH2CH2CHF2, SeCH2CH(CH3)2, SeCH2C(CH3)3, SeCH2CH2OH, SeCH2CH2NH2, SeCH2CH2SO3H, SeCH2CH2PO3H2, SeCH2CH2COOH, SeCH2CH2OCH3, SeCH2CH2OCF3, SeCH2CH2OCH2CF3, SeCH2CH2NHCH3, SeCH2CH2N(CH3)2, or SeCH2CH2ϕ, wherein ϕ is an aryl or heteroaryl group. 83. The fluorophore according to any preceding claim, wherein [linker] has the formula: f , wherein Ra2 is ϕ, CH2ϕ, CH2CH2ϕ, Oϕ, OCH2ϕ, OCH2CH2ϕ, Sϕ, SCH2ϕ, SCH2CH2ϕ, Seϕ, SeCH2ϕ, or SeCH2CH2ϕ, and ϕ is an aryl or heteroaryl group. 84. The fluorophore according to any preceding claim, wherein [linker] has the formula: , wherein Ra2 is ϕ, CH2ϕ, CH2CH2ϕ, Oϕ, OCH2ϕ, OCH2CH2ϕ, Sϕ, SCH2ϕ, SCH2CH2ϕ, Seϕ, SeCH2ϕ, or SeCH2CH2ϕ, and ϕ is an aryl or heteroaryl having the formula: wherein Rca is selected from H, C1-3alkyl, C1-3haloalkyl, C1-3alkoxyl, F, Cl, Br, OH, NH2, NHCH3, N(CH3)2, or COOH, Rcb is selected from H, C1-3alkyl, C1-3haloalkyl, C1-3alkoxyl, F, Cl, Br, OH, NH2, NHCH3, N(CH3)2, or COOH, Rcc is selected from H, C1-3alkyl, C1-3haloalkyl, C1-3alkoxyl, F, Cl, Br, OH, NH2, NHCH3, N(CH3)2, or COOH, Rcd is selected from H, C1-3alkyl, C1-3haloalkyl, C1-3alkoxyl, F, Cl, Br, OH, NH2, NHCH3, N(CH3)2, or COOH, and Rce is selected from H, C1-3alkyl, C1-3haloalkyl, C1-3alkoxyl, F, Cl, Br, OH, NH2, NHCH3, N(CH3)2, or COOH. 85. The fluorophore according to any preceding claim, wherein [linker] has the formula: , wherein Ra2 is ϕ, CH2ϕ, CH2CH2ϕ, Oϕ, OCH2ϕ, OCH2CH2ϕ, Sϕ, SCH2ϕ, SCH2CH2ϕ, Seϕ, SeCH2ϕ, or SeCH2CH2ϕ, and ϕ is an aryl having the formula: , wherein Rca is selected from H, C1-3alkyl, C1-3haloalkyl, C1-3alkoxyl, F, Cl, Br, OH, NH2, NHCH3, N(CH3)2, or COOH, Rcb is selected from H, C1-3alkyl, C1-3haloalkyl, C1-3alkoxyl, F, Cl, Br, OH, NH2, NHCH3, N(CH3)2, or COOH, Rcc is selected from H, C1-3alkyl, C1-3haloalkyl, C1-3alkoxyl, F, Cl, Br, OH, NH2, NHCH3, N(CH3)2, or COOH, Rcd is selected from H, C1-3alkyl, C1-3haloalkyl, C1-3alkoxyl, F, Cl, Br, OH, NH2, NHCH3, N(CH3)2, or COOH, and Rce is selected from H, C1-3alkyl, C1-3haloalkyl, C1-3alkoxyl, F, Cl, Br, OH, NH2, NHCH3, N(CH3)2, or COOH. 86. The fluorophore according to any preceding claim, wherein [linker] has the formula: , wherein Ra2 is ϕ, CH2ϕ, CH2CH2ϕ, Oϕ, OCH2ϕ, OCH2CH2ϕ, Sϕ, SCH2ϕ, SCH2CH2ϕ, Seϕ, SeCH2ϕ, or SeCH2CH2ϕ, and ϕ is heteroaryl having the formula: wherein Rca is selected from H, C1-3alkyl, C1-3haloalkyl, C1-3alkoxyl, F, Cl, Br, OH, NH2, NHCH3, N(CH3)2, or COOH, Rcb is selected from H, C1-3alkyl, C1-3haloalkyl, C1-3alkoxyl, F, Cl, Br, OH, NH2, NHCH3, N(CH3)2, or COOH, Rcc is selected from H, C1-3alkyl, C1-3haloalkyl, C1-3alkoxyl, F, Cl, Br, OH, NH2, NHCH3, N(CH3)2, or COOH, Rcd is selected from H, C1-3alkyl, C1-3haloalkyl, C1-3alkoxyl, F, Cl, Br, OH, NH2, NHCH3, N(CH3)2, or COOH, and Rce is selected from H, C1-3alkyl, C1-3haloalkyl, C1-3alkoxyl, F, Cl, Br, OH, NH2, NHCH3, N(CH3)2, or COOH. 87. The fluorophore according to any preceding claim, wherein [linker] has the formula: f , wherein Ra2 is ϕ, CH2ϕ, CH2CH2ϕ, Oϕ, OCH2ϕ, OCH2CH2ϕ, Sϕ, SCH2ϕ, SCH2CH2ϕ, Seϕ, SeCH2ϕ, or SeCH2CH2ϕ, and ϕ is a heteroaryl having the formula: wherein Rca is selected from H, C1-3alkyl, C1-3haloalkyl, C1-3alkoxyl, F, Cl, Br, OH, NH2, NHCH3, N(CH3)2, or COOH, Rcb is selected from H, C1-3alkyl, C1-3haloalkyl, C1-3alkoxyl, F, Cl, Br, OH, NH2, NHCH3, N(CH3)2, or COOH, Rcc is selected from H, C1-3alkyl, C1-3haloalkyl, C1-3alkoxyl, F, Cl, Br, OH, NH2, NHCH3, N(CH3)2, or COOH, Rcd is selected from H, C1-3alkyl, C1-3haloalkyl, C1-3alkoxyl, F, Cl, Br, OH, NH2, NHCH3, N(CH3)2, or COOH, and Rce is selected from H, C1-3alkyl, C1-3haloalkyl, C1-3alkoxyl, F, Cl, Br, OH, NH2, NHCH3, N(CH3)2, or COOH. 88. The fluorophore according to any preceding claim, wherein [linker] has the formula: , wherein Ra2 is Ra2 is ϕ, CH2ϕ, CH2CH2ϕ, Oϕ, OCH2ϕ, OCH2CH2ϕ, Sϕ, SCH2ϕ, SCH2CH2ϕ, Seϕ, SeCH2ϕ, or SeCH2CH2ϕ, and ϕ is a heteroaryl having the formula: wherein Rca is H or C1-3alkoxyl, Rcb is selected from H or NH2, Rcc is selected from H or NH2, , Rcd is H or C1-3alkoxyl, and Rce is H or C1-3alkoxyl. 89. The fluorophore according to any preceding claim, wherein Rca is H, Rcb is H, Rcc is H, Rcd is H, Rce is H. 90. The fluorophore according to any preceding claim, wherein [linker] has the formula: , wherein Ra2 is H, CH3, CH2CH3, CH(CH3)2, or C(CH3)3. 91. The fluorophore according to any preceding claim, wherein [linker] has the formula: f , wherein Ra2 is CF3, CH2F, CHF2, F, Cl, Br, OH, NH2, SO3H, PO3H2, or COOH. 92. The fluorophore according to any preceding claim, wherein [linker] has the formula: , wherein Ra2 is OCH3, OCH2CH3, OCH(CH3)2, OCF3, OCH2CF3, NHCH3, N(CH3)2. 93. The fluorophore according to any preceding claim, wherein [linker] has the formula: , wherein Ra2 is CH2OH, CH2NH2, CH2SO3H, CH2PO3H2, CH2COOH, CH2OCH3, CH2OCF3, CH2OCH2CF3, CH2NHCH3, CH2N(CH3)2, CH2CH2OH, CH2CH2NH2, CH2CH2SO3H, CH2CH2PO3H2, CH2CH2COOH, CH2CH2OCH3, CH2CH2OCF3, CH2CH2OCH2CF3, CH2CH2NHCH3, or CH2CH2N(CH3)2. 94. The fluorophore according to any preceding claim, wherein [linker] has the formula: , wherein Ra2 is OCH2OCH3, OCH2OCF3, OCH2OCH2CF3, OCH2CH2OH, OCH2CH2NH2, OCH2CH2SO3H, OCH2CH2PO3H2, OCH2CH2COOH, OCH2CH2OCH3, OCH2CH2OCF3, OCH2CH2OCH2CF3, OCH2CH2NHCH3, or OCH2CH2N(CH3)2. 95. The fluorophore according to any preceding claim, wherein [linker] has the formula: , wherein Ra2 is SCH2OCH3, SCH2OCF3, SCH2OCH2CF3, SCH2CH2OH, SCH2CH2NH2, SCH2CH2SO3H, SCH2CH2PO3H2, SCH2CH2COOH, SCH2CH2OCH3, SCH2CH2OCF3, SCH2CH2OCH2CF3, SCH2CH2NHCH3, or SCH2CH2N(CH3)2. 96. The fluorophore according to any preceding claim, wherein [linker] has the formula: , wherein Ra2 is SeCH2OCH3, SeCH2OCF3, SeCH2OCH2CF3, SeCH2CH2OH, SeCH2CH2NH2, SeCH2CH2SO3H, SeCH2CH2PO3H2, SeCH2CH2COOH, SeCH2CH2OCH3,Se, SeCH2CH2OCH2CF3, SeCH2CH2NHCH3, or SeCH2CH2N(CH3)2. 97. The fluorophore according to any preceding claim, wherein Rc is F, Cl, Br, I, C1-8alkyl, C3-8cycloalkyl, C3-8cycloalkyl, aryl, heteroaryl, or NRc1Rc2, wherein Rc1 is selected from H, C1-8alkyl, C3-8cyckoalkyl, C1-8alkyl-OH, C1-8alkyl-COOH, C1-8alkyl-NH2, C1-8alkyl-NHCH3, or C1-8alkyl-N(CH3)2, and Rc2 is selected from H, C1-8alkyl, C3-8cyckoalkyl, C1-8alkyl-OH, C1-8alkyl-COOH, C1-8alkyl-NH2, C1-8alkyl-NHCH3, or C1-8alkyl-N(CH3)2, wherein Rc1 and Rc2 can together form a ring. 98. The fluorophore according to any preceding claim, wherein Rc is F, Cl, Br, or I. 99. The fluorophore according to any preceding claim, wherein Rc is NRc1Rc2, wherein Rc1 and Rc2 are different or the same, and are selected from H, CH3, CH2CH3, CH(CH3)2, CH2CH2OH, CH2COOH, CH2CH2COOH. 100. The fluorophore according to any preceding claim, wherein Rc is NRc1Rc2, wherein Rc1 and Rc2 are the same, and are selected from H, CH3, CH2CH3, CH(CH3)2, CH2CH2OH, CH2COOH, CH2CH2COOH. 101. The fluorophore according to any preceding claim, wherein Rc2 is hydrogen, and Rc1 is a C1-8alkyl group, optionally substituted one or more times by OH, NH2, COOH, or a combination thereof. 102. The fluorophore according to any preceding claim, wherein Rc2 is hydrogen, and Rc1 is CH2CH2OH, CH(COOH)CH2OH, CH2CH(OH)COOH, CH2CH2CH(NH2)COOH, CH2CH2CH2CH2CH(NH2)COOH, or CH2CH2CH2CH2CH2COOH. 103. The fluorophore according to any preceding claim, wherein Rc is NRc1Rc2, wherein Rc1 and Rc2 together form a heterocyclic ring. 104. The fluorophore according to any preceding claim, wherein Rc is NRc1Rc2, wherein Rc1 and Rc2 together form a heterocyclic ring substituted one or more times by F, Cl, Br, I, NO2, CN, Rc3, ORc3, N(Rc3)2, SO2Rc3, SO2N(Rc3)2, C(O)Rc3; C(O)ORc3, OC(O)Rc3; C(O)N(Rc3)2, N(Rc3)C(O)Rc3, OC(O)N(Rc3)2, N(Rc3)C(O)N(Rc3)2, wherein Rc3 is in each case independently selected from hydrogen, C1-8alkyl, C1-8alkoxy, C2-8alkenyl, C2- 8alkynyl, aryl, C1-8heteroaryl, C3-8cycloalkyl, or C1-8heterocyclyl. 105. The fluorophore according to any preceding claim, wherein Rc is NRc1Rc2, wherein Rc1 and Rc2 together form a piperidine, pyrrolidine, morpholine, piperazine ring. 106. The fluorophore according to any preceding claim, wherein Rc is NRc1Rc2, wherein Rc1 and Rc2 together form a piperidine, pyrrolidine, morpholine, piperazine ring, said ring substituted one or more times by F, Cl, Br, I, NO2, CN, Rc3, ORc3, N(Rc3)2, SO2Rc3, SO2N(Rc3)2, C(O)Rc3; C(O)ORc3, OC(O)Rc3; C(O)N(Rc3)2, N(Rc3)C(O)Rc3, OC(O)N(Rc3)2, N(Rc3)C(O)N(Rc3)2, wherein Rc3 is in each case independently selected from hydrogen, C1-8alkyl, C1-8alkoxy, C2-8alkenyl, C2-8alkynyl, aryl, C1-8heteroaryl, C3- 8cycloalkyl, or C1-8heterocyclyl. 107. The fluorophore according to any preceding claim, wherein Rc has the formula: wherein A4 is selected from O, S, C(Rc4)na4, N(Rc5)na4; na4 is 0, 1, or 2; Rc4 is in each case independently selected from F, Cl, Br, I, NO2, CN, Rc4$, Q4-ORc4$, Q4- N(Rc4$)2, Q4-SO2Rc4$, Q4-SO2N(Rc4$)2, Q4-C(O)Rc4$; Q4-C(O)ORc4$, Q4-OC(O)Rc4$; Q4- C(O)N(Rc4$)2, Q4-N(Rc4$)C(O)Rc4$, Q4-OC(O)N(Rc4$)2, Q4-N(Rc4$)C(O)N(Rc4$)2, wherein Q4 is null or a C1-4alkylene group, and Rc4$ is in each case independently selected from hydrogen, C1-8alkyl, C1-8alkoxy, C2-8alkenyl, C2-8alkynyl, aryl, C1- 8heteroaryl, C3-8cycloalkyl, or C1-8heterocyclyl; Cc5 is in each case independently selected from Rc5$, Q5-ORc5$, Q5-N(Rc5$)2, Q5-SO2Rc5$, Q5- SO2N(Rc5$)2, Q5-C(O)Rc5$; Q5-C(O)ORc5$, Q5-C(O)N(Rc5$)2, wherein Q5 is null or a C1- 4alkylene group, and Rc5$ is in each case independently selected from hydrogen, C1- 8alkyl, C1-8alkoxy, C2-8alkenyl, C2-8alkynyl, aryl, C1-8heteroaryl, C3-8cycloalkyl, or C1- 8heterocyclyl;and wherein any two of more of Rc4 and Rc5 can together form a ring. 108. The fluorophore according to any preceding claim, wherein Rc is a group having the formula: , wherein Rc4 is F, Cl, Br, I, NO2, CN, Rc4$, Q4-ORc4$, Q4-N(Rc4$)2, Q4-SO2Rc4$, Q4-SO2N(Rc4$)2, Q4-C(O)Rc4$; Q4-C(O)ORc4$, Q4-OC(O)Rc4$; Q4-C(O)N(Rc4$)2, Q4-N(Rc4$)C(O)Rc4$, Q4- OC(O)N(Rc4$)2, Q4-N(Rc4$)C(O)N(Rc4$)2, wherein Q4 is null or a C1-4alkylene group, and Rc4$ is in each case independently selected from hydrogen, C1-8alkyl, C1-8alkoxy, C2- 8alkenyl, C2-8alkynyl, aryl, C1-8heteroaryl, C3-8cycloalkyl, or C1-8heterocyclyl. 109. The fluorophore according to any preceding claim, wherein Rc4 is Rc4$, Q4-ORc4$, Q4-N(Rc4$)2, or Q4-C(O)ORc4$, Q4 is null, -CH2-, -CH2CH2- or -CH2CH2CH2-, and Rc4$ is independently H, CH3, CH2CH3, CH(CH3)2, or C(CH3)3, preferably H. 110. The fluorophore according to any preceding claim, wherein X1 is Q2-CO2H, Q2-CO2C1- 3alkyl, Q2-CO2C1-3haloalkyl, Q2-SO3H, Q2-SO3C1-3alkyl, Q2-SO3C1-3haloalkyl, Q2-SO2C1- 3alkyl, CSO2C1-3haloalkyl, Q2-C(O)NHC1-3alkyl, Q2-C(O)NHC1-3haloalkyl, Q2- C(O)NH2, Q2-C(O)NHC1-3alkyl, Q2-C(O)NHC1-3haloalkyl, wherein Q2 is null or - CH=CH-, and X2 is selected from Cl, F, CN, C1-3haloalkyl. 111. The fluorophore according to any preceding claim, wherein both of X1 and X2 are CN. 112. The fluorophore according to any preceding claim, wherein X2 is selected from Cl, F, CN, CF3, CHF2, CH2F, CF2CF3, and CH2CF3. 113. The fluorophore according to any preceding claim, wherein X1 is -CO2H, -SO3H, - CH=CH-CO2H, --CH=CH-SO3H, and X2 is selected from F, Cl, CN, or CF3 114. The fluorophore according to any preceding claim, wherein X2 is Q2-CO2H, Q2-CO2C1- 3alkyl, Q2-CO2C1-3haloalkyl, Q2-SO3H, Q2-SO3C1-3alkyl, Q2-SO3C1-3haloalkyl, Q2-SO2C1- 3alkyl, CSO2C1-3haloalkyl, Q2-C(O)NHC1-3alkyl, Q2-C(O)NHC1-3haloalkyl, Q2- C(O)NH2, Q2-C(O)NHC1-3alkyl, Q2-C(O)NHC1-3haloalkyl, wherein Q2 is null or - CH=CH-, and X1 is selected from Cl, F, CN, C1-3haloalkyl. 115. The fluorophore according to any preceding claim, wherein X1 is selected from Cl, F, CN, CF3, CHF2, CH2F, CF2CF3, and CH2CF3. 116. The fluorophore according to any preceding claim, wherein X2 is -CO2H, -SO3H, - CH=CH-CO2H, --CH=CH-SO3H, and X1 is selected from F, Cl, CN, or CF3 117. The fluorophore according to any preceding claim, wherein the [acceptor] has the formula: wherein xs is independently selected from 1 or 2; X#1 and X#2 are independently selected from oxo, thioxo, imino, and CH2, provided that both X#1 and X#2 are not each CH2; X$ is -ethylene-, -propylene-, -ethenyl-, O-methylene, -NR#3-methylene-, O-ethylene, -NR#3- ethylene-,-O-ethylene-O-, -NR#3-ethylene-O-, -NR#3-ethylene-NR#3-, -O-C(=O)-O-, - NR#3-C(=O)-O-, -NR#3-C(=O)-NR#3-, -O-C(=S)-O-, -NR#3-C(=S)-O-, -NR#3-C(=S)- NR#3-,-O-propylene-, -NR#3-propylene-, -O-propylene-O-, -NR#3-propylene-O-, -NR#3- propylene-NR#3-, aryl, cycloalkyl, heteroaryl, or heterocyclyl, wherein R#3 is in each case independently selected from H and C1-4alkyl. wherein said methylene, ethylene, ethenyl, propylene, propenyl, aryl, cycloalkyl, heteroaryl, and heterocyclyl may be substituted one or more times by halo, cyano, NH2, COOH, CONH2, -(CH2CH2O)oCH3 (o = 1-16, 1-12, 1-8, 1-6, 1-4, or 1-2), -(CH2CH2O)oH (o = 1-16, 1-12, 1-8, 1-6, 1-4, or 1-2), C1-3alkyl, C1-3haloalkyl, C1-3alkoxy, C1-3haloalkoxy, C1- 3aminoalkyl, or C1-3aminohaloalkyl. 118. The fluorophore according to any preceding claim, wherein X1 and X2 together form a ring having the formula: , wherein Rx3 is selected from H, F, Cl, Br, I, CN, NH2, COOH, CONH2, -(CH2CH2O)oCH3 (o = 1- 16, 1-12, 1-8, 1-6, 1-4, or 1-2), -(CH2CH2O)oH (o = 1-16, 1-12, 1-8, 1-6, 1-4, or 1-2), C1- 3alkyl, C1-3haloalkyl, C1-3alkoxy, C1-3haloalkoxy, C1-3aminoalkyl, or C1-3aminohaloalkyl. wherein Rx4 is selected from H, F, Cl, Br, I, CN, NH2, COOH, CONH2, -(CH2CH2O)oCH3 (o = 1- 16, 1-12, 1-8, 1-6, 1-4, or 1-2), -(CH2CH2O)oH (o = 1-16, 1-12, 1-8, 1-6, 1-4, or 1-2), C1- 3alkyl, C1-3haloalkyl, C1-3alkoxy, C1-3haloalkoxy, C1-3aminoalkyl, or C1-3aminohaloalkyl. wherein Rx5 is selected from H, F, Cl, Br, I, CN, NH2, COOH, CONH2, -(CH2CH2O)oCH3 (o = 1- 16, 1-12, 1-8, 1-6, 1-4, or 1-2), -(CH2CH2O)oH (o = 1-16, 1-12, 1-8, 1-6, 1-4, or 1-2), C1- 3alkyl, C1-3haloalkyl, C1-3alkoxy, C1-3haloalkoxy, C1-3aminoalkyl, or C1-3aminohaloalkyl. wherein Rx6 is selected from H, F, Cl, Br, I, CN, NH2, COOH, CONH2, -(CH2CH2O)oCH3 (o = 1- 16, 1-12, 1-8, 1-6, 1-4, or 1-2), -(CH2CH2O)oH (o = 1-16, 1-12, 1-8, 1-6, 1-4, or 1-2), C1- 3alkyl, C1-3haloalkyl, C1-3alkoxy, C1-3haloalkoxy, C1-3aminoalkyl, or C1-3aminohaloalkyl, wherein any two or more of Rx3, Rx4, Rx5, and Rx6 can together form a ring, wherein any two or more of Rx3, Rx4, Rx5, and Rx6 can together form a ring. 119. The fluorophore according to any preceding claim, wherein X1 and X2 together form a ring having the formula: wherein R#3 is in each case independently selected from H and C1-4alkyl. In some embodiments, R#3 C1-4alkyl substituted one or more times with OH, aryl, F, Cl, Br, I, SO3H, COOH, NH2, NH(CH3), N(CH3)2, N+(CH3)3, or PO3H2. 120. A pharmaceutical composition, comprising the fluorophore according to any preceding claim and at least one pharmaceutically acceptable excipient. 121. A method of treating a proliferative disorder in a subject in need thereof, comprising administering to the subject a fluorophore according to any preceding claim. 122. The method according to any preceding claim, wherein the proliferative disorder is cancer. 123. The method according to any preceding claim, wherein the proliferative disorder is acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), cancer in adrenocortical carcinoma, adrenal cortex cancer, AIDS-related cancers, Kaposi sarcoma, AIDS-related lymphoma, primary CNS lymphoma, anal cancer, appendix cancer, carcinoid tumors, astrocytomas, atypical teratoid/rhabdoid tumor, basal cell carcinoma, skin cancer (nonmelanoma), bile duct cancer, extrahepatic bladder cancer, bladder cancer, bone cancer (includes Ewing sarcoma and osteosarcoma and malignant fibrous histiocytoma), brain tumors, breast cancer, bronchial tumors, Burkitt lymphoma (non-Hodgkin), carcinoid tumor, cardiac (heart) tumors, atypical teratoid/rhabdoid tumor, embryonal tumors, germ cell tumors, lymphoma, primary - cervical cancer, cholangiocarcinoma, chordoma, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic myeloproliferative neoplasms, colorectal cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, ductal carcinoma in situ (DCIS), embryonal tumors, central nervous system, endometrial cancer, ependymoma, esophageal, esthesioneuroblastoma, extracranial germ cell tumor, extragonadal germ cell tumor, eye cancer, intraocular melanoma, retinoblastoma, fallopian tube cancer, fibrous histiocytoma of bone, malignant, and osteosarcoma, gallbladder cancer, gastric (stomach) cancer, gastric (stomach) cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumors (GIST), gastrointestinal stromal tumors (GIST), germ cell tumors, central nervous system, extracranial, extragonadal, ovarian testicular, gestational trophoblastic disease, gliomas, hairy cell leukemia, head and neck cancer, heart tumors, hepatocellular (liver) cancer, histiocytosis, Langerhans Cell, Hodgkin’s lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell tumors, pancreatic neuroendocrine tumors, Kaposi sarcoma, kidney - langerhans cell histiocytosis, laryngeal cancer, laryngeal cancer and papillomatosis, leukemia, lip and oral cavity cancer, liver cancer (primary), lung cancer, lung cancer, lymphoma - macroglobulinemia, Waldenström –Non-Hodgkin lymphoma, male breast cancer, malignant fibrous histiocytoma of bone and osteosarcoma, melanoma, intraocular (eye), Merkel cell carcinoma, mesothelioma, malignant, mesothelioma, metastatic squamous neck cancer with occult primary, midline tract carcinoma involving NUT gene, mouth cancer, multiple endocrine neoplasia syndromes, multiple myeloma/plasma cell neoplasms, mycosis fungoides, myelodysplastic syndromes, myelodysplastic/myeloproliferative neoplasms and chronic myeloproliferative neoplasms, myelogenous leukemia, chronic (CML), myeloid leukemia, acute (AML), nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, nasopharyngeal cancer, neuroblastoma, non-hodgkin lymphoma, non-small cell lung cancer, oral cancer, lip and oral cavity cancer and oropharyngeal cancer, osteosarcoma and malignant fibrous histiocytoma of bone, ovarian cancer, pancreatic cancer and pancreatic neuroendocrine tumors (islet cell tumors), papillomatosis, paraganglioma, paraganglioma, paranasal sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pheochromocytoma, pituitary tumor, plasma cell neoplasm/multiple myeloma, pleuropulmonary blastoma, pregnancy and breast cancer, primary central nervous system (CNS) lymphoma, primary peritoneal cancer, prostate cancer, rectal cancer, renal cell (kidney) cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, salivary gland tumors, Ewing sarcoma, Kaposi sarcoma, osteosarcoma, rhabdomyosarcoma, uterine sarcoma, vascular tumors, Sézary syndrome, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, squamous neck cancer with occult primary, metastatic, stomach (gastric) cancer, stomach (gastric) cancer, T-cell lymphoma, cutaneous, testicular cancer, throat cancer, thymoma and thymic carcinoma, thyroid cancer, ureter and renal pelvis, transitional cell cancer, urethral cancer, uterine cancer, endometrial and uterine sarcoma, vaginal cancer, vaginal cancer, vascular tumors, vulvar cancer, Waldenström Macroglobulinemia, Wilms Tumor. 124. A method of imaging a system, comprising contacting the system with a compound according to any preceding claim and irradiating the compound. 125. The method of imaging according to the preceding claim, wherein the system is living tissue. 126. The method of imaging according to any preceding claim, wherein the system is a human. 127. The method of imaging according to any preceding claim, wherein cancerous tissue or cells are imaged. |
. In some embodiments, R 2 and R 3 in the [Donor] can together form a ring wherein R 23 is a substituent defined herein; n23 is 1 when R 23 is bonded to an sp 2 hybridized atom and 2 when R 23 is bonded to an sp 3 hybridized atom; wherein two geminal R 23 groups can together form an oxo or thiooxo; Z 23 is in case independently selected from CR 23 , C(R 23 ) 2 , O, S, N, or NH. The skilled person understands such compounds have the formula: In some embodiments, R 3 and R 4 in the [Donor] can together form a ring:
wherein R 34 is a substituent defined herein; n34 is 1 when R 34 is bonded to an sp 2 hybridized atom and 2 when R 34 is bonded to an sp 3 hybridized atom; wherein two geminal R 34 groups can together form an oxo or a thiooxo; Z 34 is in case independently selected from CR 34 , C(R 34 ) 2 , O, S, N, or NH. The skilled person understands that such compounds have the formula: In some instances, Z 2 can be N-R zd : The skilled person understands such a compound has formula: . In certain embodiments when Z 2 is NR zd , R zd and R 1 may together form a ring:
Such rings may be substituted one or more times as defined herein. In some embodiments where Z 2 is N-R zd , Z 1 can be O, S, C(R z ) 2 N-R z , N=CR z1 , or C(CR z1 )=C(CR z1 ), e.g., the donor can have the formula: The skilled person understands such compounds have the formula: In some embodiments, Z 2 is null and Z 1 is Z 3 -N(R zd )-: , The skilled person understands such compounds have the formula: . Exemplary Z 3 groups include N=CR z1 , or C(CR z1 )=C(CR z1 ), O, S, or C(R z ) 2 . In some instances when Z 2 is null and Z 1 is Z 3 -N(R zd )- the [donor] may have the formula: The skilled person understands that such compounds can have the formula:
. In some embodiments, R zd and R 4 in the [donor] may together form a ring: wherein Z zd4 is independently selected from CH 2 , CH, NR zd , N, O, or S. Examples of such ring systems include:
In certain embodiments, the [donor] may be: . In some embodiments, R zd is C 1-8 alkyl, optionally substituted one or more times with aryl, OH, NH 2 , NHC 1-3 alkyl, N(C 1-3 alkyl) 2 , N + (C 1-3 alkyl) 3 ,X-, SO 3 H, CO 2 H, wherein X- is a pharmaceutically acceptable anion. Exemplary R zd groups include methyl, ethyl, benzyl, propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, 2-hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl, 2-aminoethyl, 3-aminopropyl, 4-aminobutyl, 2-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, 2- (dimethylamino)ethyl, 3-(dimethylamino)propyl, 4-(dimethylamino)butyl, 2- (trimethylammonium iodide)ethyl, 3-(trimethylammonium iodide)propyl, 4- (trimethylammonium iodide)butyl, 2-ethanesulfonic acid, 3-propanesulfonic acid, and 4- butanesulfonic acid. The iodide anion may be replaced with another acceptable anion, including bromide, chloride, sulfate, citrate, acetate, ect. In certain embodiments, one of R 1 , R 2 , R 3 and R 4 is an electron-withdrawing group, and the remaining three of R 1 , R 2 , R 3 and R 4 are each hydrogen. Exemplary electron-withdrawing groups include F, Cl, Br, I, NO 2 , CN, SO 2 R 1a , SO 2 N(R 1a ) 2 , C(O)R 1a ; C(O)OR 1a , and C(O)N(R 1a ) 2 (here R 1a groups, defined above, are used in the exemplary, not limiting, fashion). In some embodiments the electron-withdrawing group is an alkyl group substituted with one or more of F, Cl, Br, I, NO 2 , CN, SO 2 R 1a , SO 2 N(R 1a ) 2 , C(O)R 1a ; C(O)OR 1a , and C(O)N(R 1a ) 2 . Preferable electron-withdrawing groups include F, Cl, Br, I, C 1-3 haloalkyl, C(O)C 1-3 alkyl, C(O)OC 1-3 alkyl, C(O)NHC 1-3 alkyl, C(O)OH, SO 3 H, C(O)C 1-3 haloalkyl, C(O)OC 1-3 haloalkyl, and C(O)NHC 1- 3 haloalkyl. In some embodiments, R 1 is an electron-withdrawing group as defined herein and each of R 2 , R 3 , and R 4 are hydrogen. In some embodiments, R 2 is an electron-withdrawing group as defined herein and each of R 1 , R 3 , and R 4 are hydrogen. In some embodiments, R 3 is an electron-withdrawing group as defined herein and each of R 1 , R 2 , and R 4 are hydrogen. In some embodiments, R 4 is an electron-withdrawing group as defined herein and each of R 1 , R 2 , and R 3 are hydrogen. In some embodiments, R 1 and R 3 are independently electron-withdrawing group as defined herein and each of R 2 , and R 4 are hydrogen. In some embodiments, R 2 and R 4 are independently electron-withdrawing group as defined herein and each of R 1 , and R 3 are hydrogen. In certain embodiments, when Z 2 is N-R zd , R 3 is an electron-withdrawing group as defined herein and each of R 1 , R 2 , and R 4 are hydrogen. In certain embodiments, when Z 2 is N- R zd , R 1 is an electron-withdrawing group as defined herein and each of R 2 , R 3 , and R 4 are hydrogen. In other embodiments, R 1 and R 3 are electron-withdrawing groups as defined herein and R 2 and R 4 are hydrogen. In certain embodiments, when Z 2 is N-R zd , R 1 and R 3 are electron- withdrawing groups as defined herein and R 2 and R 4 are hydrogen. In certain embodiments, when Z 2 is null, R 2 is an electron-withdrawing group as defined herein and each of R 2 , R 3 , and R 4 are hydrogen. In certain embodiments, when Z 2 is null, R 4 is an electron-withdrawing group as defined herein and each of R 1 , R 2 , and R 3 are hydrogen. In other embodiments, R 2 and R 4 are electron-withdrawing groups as defined herein and R 1 and R 3 are hydrogen. In certain embodiments, when Z 2 is null, R 2 and R 4 are electron-withdrawing groups as defined herein and R 1 and R 3 are hydrogen. In other embodiment, one of R 1 , R 2 , R 3 and R 4 is an electron-donating group, and the remaining three of R 1 , R 2 , R 3 and R 4 are each hydrogen. Exemplary electron-donating groups include OR 1a and N(R 1a ) 2 (here R 1a groups, defined above, are used in the exemplary, not limiting, fashion). Preferable electron-donating groups include OH, NH 2 , OC 1-3 alkyl, NHC 1- 3alkyl, N(C 1-3 alkyl) 2 , OC 1-3 alkyl, NHC 1-3 alkyl, and N(C 1-3 alkyl) 2 , as well as unsubstituted alkyl and aryl groups, and alkyl and aryl groups substituted with one or more of OH, NH 2 , OC 1-3 alkyl, NHC 1-3 alkyl, N(C 1-3 alkyl) 2 , OC 1-3 alkyl, NHC 1-3 alkyl, and N(C 1-3 alkyl) 2 . In some embodiments, R 1 is an electron-donating group as defined herein and each of R 2 , R 3 , and R 4 are hydrogen. In some embodiments, R 2 is an electron-donating group as defined herein and each of R 1 , R 3 , and R 4 are hydrogen. In some embodiments, R 3 is an electron-donating group as defined herein and each of R 1 , R 2 , and R 4 are hydrogen. In some embodiments, R 4 is an electron-donating group as defined herein and each of R 1 , R 2 , and R 3 are hydrogen. In some embodiments, R 1 and R 3 are independently electron-donating group as defined herein and each of R 2 , and R 4 are hydrogen. In some embodiments, R 2 and R 4 are independently electron-donating group as defined herein and each of R 1 , and R 3 are hydrogen. In certain embodiments, when Z 2 is N-R zd , R 3 is an electron-donating group as defined herein and each of R 1 , R 2 , and R 4 are hydrogen. In certain embodiments, when Z 2 is N-R zd , R 1 is an electron-donating group as defined herein and each of R 2 , R 3 , and R 4 are hydrogen. In other embodiments, R 1 and R 3 are electron-donating groups as defined herein and R 2 and R 4 are hydrogen. In certain embodiments, when Z 2 is N-R zd , R 1 and R 3 are electron-donating groups as defined herein and R 2 and R 4 are hydrogen. In certain embodiments, when Z 2 is null, R 2 is an electron-donating group as defined herein and each of R 2 , R 3 , and R 4 are hydrogen. In certain embodiments, when Z 2 is null, R 4 is an electron-donating group as defined herein and each of R 1 , R 2 , and R 3 are hydrogen. In other embodiments, R 2 and R 4 are electron-donating groups as defined herein and R 1 and R 3 are hydrogen. In certain embodiments, when Z 2 is null, R 2 and R 4 are electron-donating groups as defined herein and R 1 and R 3 are hydrogen. In certain embodiments, each of R a , R b , R d , R e , and R f in the [linker] are hydrogen. In other embodiments, R e is an electron-withdrawing or electron-donating group and R d and R f are each hydrogen. In some preferred embodiments R e is an electron-donating group and R d and R f are each hydrogen. In other embodiments, R f is an electron-withdrawing or electron- donating group and R d and R e are each hydrogen. In some preferred embodiments, R f is an electron-withdrawing group and R d and R e are each hydrogen. Preferable electron-donating groups for R d , R e , and R f include OH, NH 2 , OC 1-3 alkyl, NHC 1-3 alkyl, N(C 1-3 alkyl) 2 , OC 1-3 alkyl, NHC 1-3 alkyl, and N(C 1-3 alkyl) 2 , as well as unsubstituted alkyl and aryl groups, and alkyl and aryl groups substituted with one or more of OH, NH 2 , OC 1- 3 alkyl, NHC 1-3 alkyl, N(C 1-3 alkyl) 2 , OC 1-3 alkyl, NHC 1-3 alkyl, and N(C 1-3 alkyl) 2 . Preferable electron-withdrawing groups for R d , R e , and R f include F, Cl, Br, I, C 1- 3haloalkyl, C(O)C 1-3 alkyl, C(O)OC 1-3 alkyl, C(O)NHC 1-3 alkyl, C(O)OH, SO 3 H, C(O)C 1- 3 haloalkyl, C(O)OC 1-3 haloalkyl, and C(O)NHC 1-3 haloalkyl. In some embodiments R e is an electron-donating group and R f is an electron-withdrawing group. In some preferred embodiments R a and R b together form a ring, e.g., the [linker] has the formula: wherein: A 1 is selected from C(R a1 ) 2 , N(R a1* )na1, O, S, -C(R a1 ) 2 — C(R a1 ) 2 -, -C(R a1 )=C(R a1 )-, -C(R a1 )=N-; R a1 is selected from F, Cl, Br, I, NO 2 , CN, R a1$ , OR a1$ , N(R a1$ ) 2 , SO 2 R a1$ , SO 2 N(R a1$ ) 2 , C(O)R a1$ ; C(O)OR a1$ , OC(O)R a1$ ; C(O)N(R a1$ ) 2 , N(R a1$ )C(O)R a1$ , OC(O)N(R a1$ ) 2 , N(R a1$ )C(O)N(R a1$ ) 2 , wherein R a1$ is in each case independently selected from hydrogen, C 1- 8alkyl, C 1-8 alkoxy, C 2-8 alkenyl, C 2-8 alkynyl, aryl, C 1-8 heteroaryl, C 3-8 cycloalkyl, or C 1- 8 heterocyclyl; na1 is 0, 1 or 2; when na1 is 1 then R a1* is selected from R a1$ , SO 2 R a1$ , SO 2 N(R a1$ ) 2 , C(O)R a1$ ; C(O)OR a1$ , C(O)N(R a1$ ) 2 , N(R a1$ )C(O)R a1$ , wherein R a1$ is in each case independently selected from hydrogen, C 1-8 alkyl, C 1-8 alkoxy, C 2-8 alkenyl, C 2-8 alkynyl, aryl, C 1-8 heteroaryl, C 3-8 cycloalkyl, or C 1-8 heterocyclyl; when na1 is 2 then R a1* is in each case independently selected from hydrogen, C 1-8 alkyl, C 1- 8 alkoxy, C 2-8 alkenyl, C 2-8 alkynyl, aryl, C 1-8 heteroaryl, C 3-8 cycloalkyl, or C 1-8 heterocyclyl; A 2 is selected from null, C(R a2 ) 2 , N(R a2* )na2, O, S, -C(R a2 ) 2 — C(R a2 ) 2 -, -C(R a2 )=C(R a2 )-, - C(R a2 )=N-; R a2 is selected from F, Cl, Br, I, NO 2 , CN, R a2$ , SR a2$ , SeR a2$ , OR a2$ , N(R a2$ ) 2 , SO 2 R a2$ , SO 2 N(R a2$ ) 2 , C(O)R a2$ ; C(O)OR a2$ , OC(O)R a2$ ; C(O)N(R a2$ ) 2 , N(R a2$ )C(O)R a2$ , OC(O)N(R a2$ ) 2 , N(R a2$ )C(O)N(R a2$ ) 2 , wherein R a2$ is in each case independently selected from hydrogen, C 1-8 alkyl, C 1-8 alkoxy, C 2-8 alkenyl, C 2-8 alkynyl, aryl, C 1-8 heteroaryl, C 3-8 cycloalkyl, or C 1-8 heterocyclyl; na2 is 0, 1 or 2; when na2 is 1 then R a2* is selected from R a2$ , SO 2 R a2$ , SO 2 N(R a2$ ) 2 , C(O)R a2$ ; C(O)OR a2$ , C(O)N(R a2$ ) 2 , N(R a2$ )C(O)R a2$ , wherein R a2$ is in each case independently selected from hydrogen, C 1-8 alkyl, C 1-8 alkoxy, C 2-8 alkenyl, C 2-8 alkynyl, aryl, C 1-8 heteroaryl, C 3-8 cycloalkyl, or C 1-8 heterocyclyl; when na2 is 2 then R a2* is in each case independently selected from hydrogen, C 1-8 alkyl, C 1- 8alkoxy, C 2-8 alkenyl, C 2-8 alkynyl, aryl, C 1-8 heteroaryl, C 3-8 cycloalkyl, or C 1-8 heterocyclyl; A 3 is selected from C(R a3 ) 2 , N(R a3* )na3, O, S, -C(R a3 ) 2 — C(R a3 ) 2 -, -C(R a3 )=C(R a3 )-, -C(R a3 )=N-, R a3 is selected from F, Cl, Br, I, NO 2 , CN, R a3$ , OR a3$ , N(R a3$ ) 2 , SO 2 R a3$ , SO 2 N(R a3$ ) 2 , C(O)R a3$ ; C(O)OR a3$ , OC(O)R a3$ ; C(O)N(R a3$ ) 2 , N(R a3$ )C(O)R a3$ , OC(O)N(R a3$ ) 2 , N(R a3$ )C(O)N(R a3$ ) 2 , wherein R a3$ is in each case independently selected from hydrogen, C 1- 8 alkyl, C 1-8 alkoxy, C 2-8 alkenyl, C 2-8 alkynyl, aryl, C 1-8 heteroaryl, C 3-8 cycloalkyl, or C 1- 8 heterocyclyl; na3 is 0, 1 or 2; when na3 is 1 then R a3* is selected from R a3$ , SO 2 R a3$ , SO 2 N(R a3$ ) 2 , C(O)R a3$ ; C(O)OR a3$ , C(O)N(R a3$ ) 2 , N(R a3$ )C(O)R a3$ , wherein R a3$ is in each case independently selected from hydrogen, C 1-8 alkyl, C 1-8 alkoxy, C 2-8 alkenyl, C 2-8 alkynyl, aryl, C 1-8 heteroaryl, C 3-8 cycloalkyl, or C 1-8 heterocyclyl; when na3 is 2 then R a3* is in each case independently selected from hydrogen, C 1-8 alkyl, C 1- 8alkoxy, C 2-8 alkenyl, C 2-8 alkynyl, aryl, C 1-8 heteroaryl, C 3-8 cycloalkyl, or C 1-8 heterocyclyl. In some embodiments, the [linker] has the formula wherein R a2* is in each case independently selected from C 1-4 alkyl, benzyl phenyl, or H. In the case of the quaternary ammonium ion, the compound will be electronically neutral by virtue of a separate, pharmaceutically acceptable anion (e.g., iodide, bromide, chloride, acetate, sulfate, etc), or from an anionic group (e.g., sulfonate, carboxylate, phosphonate, etc) somewhere else within the molecule. When A 2 is N + (R a2* ) 2 , R a2* can in each case be independently selected from methyl, ethyl, n-propyl, n-butyl, and benzyl. When A 2 is CHR a2* , R a2* can be H, methyl, ethyl, n- propyl, n-butyl, isopropyl, tert-butyl, phenyl, and benzyl. In certain instances when A 2 is CHR a2 O, S, NR a2* ,or N + (R a2* ) 2 , A 1 can be CH 2 or CH 2 CH 2 , preferably CH 2 and A 3 is CH 2 or CH 2 CH 2, preferably CH 2 . In other instances, A 2 is null, and the [linker] has the formula: , In certain instances when A 2 is null, A 1 can be CR a1* or C(R a1* ) 2 , depending on valence, and A 3 can be CR a3* or C(R a3* ) 2 , depending on valence. The skilled person understands that when A 1 is CR a1* (i.e., a sp 2 hybridized carbon atom) then A 3 is CR a3* . Likewise, when A 1 is C(R a1* ) 2 (i.e., a sp 3 hybridized carbon atom) then A 3 is C(R a3* ) 2 . In other instances, A 1 can be N and A 3 can be CR a3* , or A 1 can be CR a1* and A 3 can be N. In further embodiments, In other instances, A 1 can be NR a1* and A 3 can be C(R a3* ) 2 , or A 1 can be C(R a1* ) 2 and A 3 can be NR a3* . In some instances, the [linker] has the formula: f , wherein Q a is null, CH 2 , CH 2 CH 2 , or CH 2 CH 2 CH 2 , and R a2 is H, CH 3 , CF 3 , CH 2 F, CHF2, CH 2 CH 3 , CH(CH 3 ) 2 , C(CH 3 ) 3 , F, Cl, Br, SH, SeH, OH, NH 2 , SO 3 H, PO 3 H 2 , COOH, SCH 3 , SCH 2 CH 3 , SCH(CH 3 ) 2 , SeCH 3 , SeCH 2 CH 3 , SeCH(CH 3 ) 2 ,OCH 3 , OCH 2 CH 3 , OCH(CH 3 ) 2 , OCF 3 , OCH 2 CF 3 , NHCH 3 , N(CH 3 ) 2 , ϕ, CH 2 CH 3 , CH 2 CF 3 , CH 2 CH 2 F, CH 2 CHF2, CH(CH 3 ) 2 , C(CH 3 ) 3 , CH 2 OH, CH 2 NH 2 , CH 2 SO 3 H, CH 2 PO 3 H 2 , CH 2 COOH, CH 2 OCH 3 , CH 2 OCF 3 , CH 2 OCH 2 CF 3 , CH 2 NHCH 3 , CH 2 N(CH 3 ) 2 , CH 2 ϕ, CH 2 CH 2 CH 3 , CH 2 CH 2 CF 3 , CH 2 CH 2 CH 2 F, CH 2 CH 2 CHF 2 , CH 2 CH(CH 3 ) 2 , CH 2 C(CH 3 ) 3 , CH 2 CH 2 OH, CH 2 CH 2 NH 2 , CH 2 CH 2 SO 3 H, CH 2 CH 2 PO 3 H 2 , CH 2 CH 2 COOH, CH 2 CH 2 OCH 3 , CH 2 CH 2 OCF 3 , CH 2 CH 2 OCH 2 CF 3 , CH 2 CH 2 NHCH 3 , CH 2 CH 2 N(CH 3 ) 2 , CH 2 CH 2 ϕ, SCH 2 ϕ, SCH 2 CH 2 CH 3 , SCH 2 CH 2 CF 3 , SCH 2 CH 2 CH 2 F, SCH 2 CH 2 CHF 2 , SCH 2 CH(CH 3 ) 2 , SCH 2 C(CH 3 ) 3 , SCH 2 CH 2 OH, SCH 2 CH 2 NH 2 , SCH 2 CH 2 SO 3 H, SCH 2 CH 2 PO 3 H 2 , SCH 2 CH 2 COOH, SCH 2 CH 2 OCH 3 , SCH 2 CH 2 OCF 3 , SCH 2 CH 2 OCH 2 CF 3 , SCH 2 CH 2 NHCH 3 , SCH 2 CH 2 N(CH 3 ) 2 , SCH 2 CH 2 ϕ, OCH 2 ϕ, OCH 2 CH 2 CH 3 , OCH 2 CH 2 CF 3 , OCH 2 CH 2 CH 2 F, OCH 2 CH 2 CHF 2 , OCH 2 CH(CH 3 ) 2 , OCH 2 C(CH 3 ) 3 , OCH 2 CH 2 OH, OCH 2 CH 2 NH 2 , OCH 2 CH 2 OO 3 H, OCH 2 CH 2 PO 3 H 2 , OCH 2 CH 2 COOH, OCH 2 CH 2 OCH 3 , OCH 2 CH 2 OCF 3 , OCH 2 CH 2 OCH 2 CF 3 , OCH 2 CH 2 NHCH 3 , OCH 2 CH 2 N(CH 3 ) 2 , OCH 2 CH 2 ϕ, SeCH 2 ϕ, SeCH 2 CH 2 CH 3 , SeCH 2 CH 2 CF 3 , SeCH 2 CH 2 CH 2 F, SeCH 2 CH 2 CHF 2 , SeCH 2 CH(CH 3 ) 2 , SeCH 2 C(CH 3 ) 3 , SeCH 2 CH 2 OH, SeCH 2 CH 2 NH 2 , SeCH 2 CH 2 SEO 3 H, SeCH 2 CH 2 PO 3 H 2 , SeCH 2 CH 2 COOH, SeCH 2 CH 2 OCH 3 , SeCH 2 CH 2 OCF 3 , SeCH 2 CH 2 OCH 2 CF 3 , SeCH 2 CH 2 NHCH 3 , SeCH 2 CH 2 N(CH 3 ) 2 , SeCH 2 CH 2 ϕ, wherein ϕ is an aryl or heteroaryl group. In some instances ϕ is an aryl or heteroaryl having the formula: wherein R ca is selected from H, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxyl, F, Cl, Br, OH, NH 2 , NHCH 3 , N(CH 3 ) 2 , or COOH, R cb is selected from H, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxyl, F, Cl, Br, OH, NH 2 , NHCH 3 , N(CH 3 ) 2 , or COOH, R cc is selected from H, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxyl, F, Cl, Br, OH, NH 2 , NHCH 3 , N(CH 3 ) 2 , or COOH, R cd is selected from H, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxyl, F, Cl, Br, OH, NH 2 , NHCH 3 , N(CH 3 ) 2 , or COOH, and R ce is selected from H, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxyl, F, Cl, Br, OH, NH 2 , NHCH 3 , N(CH 3 ) 2 , or COOH. In preferred embodiments Q a is null or CH 2 . In certain embodiments, R c can be F, Cl, Br, I, C 1-8 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl, aryl, heteroaryl, OR c1 , SR 2a , or NR c1 R c2 , wherein R c1 is selected from H, C 1-8 alkyl, C 3-8 cyckoalkyl, C 1-8 alkyl-OH, C 1-8 alkyl-COOH, C 1-8 alkyl-NH 2 , C 1-8 alkyl-NHCH 3 , or C 1-8 alkyl-N(CH 3 ) 2 , and R c2 is selected from H, C 1-8 alkyl, C 3-8 cyckoalkyl, C 1-8 alkyl-OH, C 1-8 alkyl-COOH, C 1-8 alkyl-NH 2 , C 1-8 alkyl-NHCH 3 , or C 1-8 alkyl-N(CH 3 ) 2 , wherein R c1 and R c2 can together form a ring. In certain preferred embodiments, R c is F, Cl, Br or I. In some embodiments, R c is SR c1 , wherein R c1 is selected from H, CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , CH 2 CH 2 OH, CH 2 COOH, CH 2 CH 2 COOH. In some embodiments, R c is OR c1 , wherein R c1 is selected from H, CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , CH 2 CH 2 OH, CH 2 COOH, CH 2 CH 2 COOH. = In some embodiments, R c is NR c1 R c2 , wherein R c1 and R c2 are different or the same, and are selected from H, CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , CH 2 CH 2 OH, CH 2 COOH, CH 2 CH 2 COOH. In certain preferred embodiments, R c1 and R c2 are the same, and are selected from H, CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , CH 2 CH 2 OH, CH 2 COOH, CH 2 CH 2 COOH. In certain embodiments, R c is NR c1 R c2 , wherein R c2 is hydrogen, and R c1 is a C 1-8 alkyl group substituted one or more times by OH, NH 2 , COOH, or a combination thereof. By way of example, R c1 can be CH 2 CH 2 OH, CH(COOH)CH 2 OH, CH 2 CH(OH)COOH, CH 2 CH 2 CH(NH 2 )COOH, CH 2 CH 2 CH 2 CH 2 CH(NH 2 )COOH, or CH 2 CH 2 CH 2 CH 2 CH 2 COOH. In other embodiments R c is NR c1 R c2 and R c1 and R c2 can together form a heterocyclic ring, for instance a piperidine, pyrrolidine, morpholine, piperazine, which may be further substituted one or more times by F, Cl, Br, I, NO 2 , CN, R c3 , OR c3 , N(R c3 ) 2 , SO 2 R c3 , SO 2 N(R c3 ) 2 , C(O)R c3 ; C(O)OR c3 , OC(O)R c3 ; C(O)N(R c3 ) 2 , N(R c3 )C(O)R c3 , OC(O)N(R c3 ) 2 , N(R c3 )C(O)N(R c3 ) 2 , wherein R c3 is in each case independently selected from hydrogen, C 1-8 alkyl, C 1-8 alkoxy, C 2-8 alkenyl, C 2-8 alkynyl, aryl, C 1-8 heteroaryl, C 3-8 cycloalkyl, or C 1-8 heterocyclyl. In some implementations, R c has the formula: , wherein X f is OH or NH 2 , X f1 is null, phenyl, C 1-4 alkylene, and X f2 is null, O, NH, or S. The skilled person understands various tautomers exist for the pteridine ring (i.e., including one or more carbonyl or imine functional groups). The depiction of one tautomeric form is intended to cover each and every tautomer, either as a mixture or single compound. In some embodiments, R c has the formula: wherein A 4 is selected from O, S, C(R c4 )na4, N(R c5 )na4; na4 is 0, 1, or 2; R c4 is in each case independently selected from F, Cl, Br, I, NO 2 , CN, R c4$ , Q 4 -OR c4$ , Q 4 - N(R c4$ ) 2 , Q 4 -SO 2 R c4$ , Q 4 -SO 2 N(R c4$ ) 2 , Q 4 -C(O)R c4$ ; Q 4 -C(O)OR c4$ , Q 4 -OC(O)R c4$ ; Q 4 - C(O)N(R c4$ ) 2 , Q 4 -N(R c4$ )C(O)R c4$ , Q 4 -OC(O)N(R c4$ ) 2 , Q 4 -N(R c4$ )C(O)N(R c4$ ) 2 , wherein Q 4 is null or a C 1-4 alkylene group, and R c4$ is in each case independently selected from hydrogen, C 1- 8alkyl, C 1-8 alkoxy, C 2-8 alkenyl, C 2-8 alkynyl, aryl, C 1-8 heteroaryl, C 3-8 cycloalkyl, or C 1- 8heterocyclyl; and C c5 is in each case independently selected from R c5$ , Q 5 -OR c5$ , Q 5 -N(R c5$ ) 2 , Q 5 -SO 2 R c5$ , Q 5 - SO 2 N(R c5$ ) 2 , Q 5 -C(O)R c5$ ; Q 5 -C(O)OR c5$ , Q 5 -C(O)N(R c5$ ) 2 , wherein Q 5 is null or a C 1-4 alkylene group, and R c5$ is in each case independently selected from hydrogen, C 1-8 alkyl, C 1-8 alkoxy, C 2 - 8 alkenyl, C 2-8 alkynyl, aryl, C 1-8 heteroaryl, C 3-8 cycloalkyl, or C 1-8 heterocyclyl; wherein any two of more of R c4 and R c5 can together form a ring. In some implementations, R c5 has the formula: , wherein X f is OH or NH 2 , X f1 is null, phenyl, C 1-4 alkylene, and X f2 is null, O, NH, or S. The skilled person understands various tautomers exist for the pteridine ring (i.e., including one or more carbonyl or imine functional groups). The depiction of one tautomeric form is intended to cover each and every tautomer, either as a mixture or single compound. In certain preferred embodiments, R c is a group having the formula: , wherein R c4 is F, Cl, Br, I, NO 2 , CN, R c4$ , Q 4 -OR c4$ , Q 4 -N(R c4$ ) 2 , Q 4 -SO 2 R c4$ , Q 4 -SO 2 N(R c4$ ) 2 , Q 4 -C(O)R c4$ ; Q 4 -C(O)OR c4$ , Q 4 -OC(O)R c4$ ; Q 4 -C(O)N(R c4$ ) 2 , Q 4 -N(R c4$ )C(O)R c4$ , Q 4 - OC(O)N(R c4$ ) 2 , Q 4 -N(R c4$ )C(O)N(R c4$ ) 2 , wherein Q 4 is null or a C 1-4 alkylene group, and R c4$ is in each case independently selected from hydrogen, C 1-8 alkyl, C 1-8 alkoxy, C 2-8 alkenyl, C 2 - 8alkynyl, aryl, C 1-8 heteroaryl, C 3-8 cycloalkyl, or C 1-8 heterocyclyl. In some implementations, R c4 has the formula: , wherein X f is OH or NH 2 , X f1 is null, phenyl, C 1-4 alkylene, and X f2 is null, O, NH, or S. The skilled person understands various tautomers exist for the pteridine ring (i.e., including one or more carbonyl or imine functional groups). The depiction of one tautomeric form is intended to cover each and every tautomer, either as a mixture or single compound. In some embodiments when R c is: , R c4 can be R c4$ , Q 4 -OR c4$ , Q 4 -N(R c4$ ) 2 , or Q 4 -C(O)OR c4$ , Q 4 is null, -CH 2 -, -CH 2 CH 2 - or - CH 2 CH 2 CH 2 -, and R c4$ is independently H, CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , or C(CH 3 ) 3 , preferably H. In some embodiments, one of X 1 or X 2 is Q 2 -CO 2 H, Q 2 -CO 2 C 1-3 alkyl, Q 2 -CO 2 C 1- 3 haloalkyl, Q 2 -SO 2 OH, Q 2 -SO 2 OC 1-3 alkyl, Q 2 -SO 2 OC 1-3 haloalkyl, Q 2 -SO 2 C 1-3 alkyl, CSO 2 C 1- 3haloalkyl, Q 2 -C(O)NHC 1-3 alkyl, Q 2 -C(O)NHC 1-3 haloalkyl, Q 2 -C(O)NH 2 , Q 2 -C(O)NHC 1-3 alkyl, Q 2 -C(O)NHC 1-3 haloalkyl, wherein Q 2 is null or -CH=CH-, and the other of X 1 or X 2 is selected from Cl, F, CN, C 1-3 haloalkyl, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2- trifluoroethyl, and the like. In some implementations, both of X 1 and X 2 are CN. In some embodiments, X 1 and X 2 can together form a ring in the [acceptor]: , , , wherein xs is independently selected from 1 (sulfoxide) or 2 (sulfone); X #1 and X #2 are independently selected from oxo, thioxo, imino, and CH 2 , provided that both X #1 and X #2 are not each CH 2 ; X $ is -ethylene-, -propylene-, -ethenyl-, O-methylene, -NR #3 -methylene-, O-ethylene, - NR #3 -ethylene-,-O-ethylene-O-, -NR #3 -ethylene-O-, -NR #3 -ethylene-NR #3 -, -O-C(=O)-O-, -NR #3 - C(=O)-O-, -NR #3 -C(=O)-NR #3 -, -O-C(=S)-O-, -NR #3 -C(=S)-O-, -NR #3 -C(=S)-NR #3 -,-O- propylene-, -NR #3 -propylene-, -O-propylene-O-, -NR #3 -propylene-O-, -NR #3 -propylene-NR #3 -, aryl, cycloalkyl, heteroaryl, or heterocyclyl, wherein R #3 is in each case independently selected from H and C 1-4 alkyl. wherein said methylene, ethylene, ethenyl, propylene, propenyl, aryl, cycloalkyl, heteroaryl, and heterocyclyl may be substituted one or more times by F, Cl, Br, I, CN, NH 2 , COOH, CONH 2 , -(CH 2 CH 2 O) o CH 3 (o = 1-16, 1-12, 1-8, 1-6, 1-4, or 1-2), -(CH 2 CH 2 O) o H (o = 1- 16, 1-12, 1-8, 1-6, 1-4, or 1-2), C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1- 3aminoalkyl, or C 1-3 aminohaloalkyl. The skilled person understands that such compounds may be depicted: , When X 1 and X 2 together form a ring, exemplary ring systems include:
wherein R x1 is in each case independently selected from H, F, Cl, Br, I, CN, NH 2, COOH, CONH 2 , - (CH 2 CH 2 O) o CH 3 (o = 1-16, 1-12, 1-8, 1-6, 1-4, or 1-2), -(CH 2 CH 2 O) o H (o = 1-16, 1-12, 1-8, 1-6, 1-4, or 1-2), C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 aminoalkyl, or C 1- 3aminohaloalkyl. R x1* is in each case independently selected from H, CONH 2 , -(CH 2 CH 2 O) o CH 3 (o = 1-16, 1-12, 1-8, 1-6, 1-4, or 1-2), -(CH 2 CH 2 O)oH (o = 1-16, 1-12, 1-8, 1-6, 1-4, or 1-2), C 1-3 alkyl, or C 1- 3haloalkyl, wherein two geminal R x1 groups can together form an oxo, wherein two geminal or adjacent R x1 groups can together form a ring, and wherein two adjacent R x1 groups can together form a double bond. In certain embodiments, X 1 and X 2 together form a ring having the formula: , wherein R x3 is selected from H, F, Cl, Br, I, CN, NH 2 , COOH, CONH 2 , -(CH 2 CH 2 O)oCH 3 (o = 1- 16, 1-12, 1-8, 1-6, 1-4, or 1-2), -(CH 2 CH 2 O)oH (o = 1-16, 1-12, 1-8, 1-6, 1-4, or 1-2), C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 aminoalkyl, or C 1-3 aminohaloalkyl. wherein R x4 is selected from H, F, Cl, Br, I, CN, NH 2 , COOH, CONH 2 , -(CH 2 CH 2 O)oCH 3 (o = 1- 16, 1-12, 1-8, 1-6, 1-4, or 1-2), -(CH 2 CH 2 O)oH (o = 1-16, 1-12, 1-8, 1-6, 1-4, or 1-2), C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 aminoalkyl, or C 1-3 aminohaloalkyl. wherein R x5 is selected from H, F, Cl, Br, I, CN, NH 2, COOH, CONH 2 , -(CH 2 CH 2 O) o CH 3 (o = 1- 16, 1-12, 1-8, 1-6, 1-4, or 1-2), -(CH 2 CH 2 O)oH (o = 1-16, 1-12, 1-8, 1-6, 1-4, or 1-2), C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 aminoalkyl, or C 1-3 aminohaloalkyl. wherein R x6 is selected from H, F, Cl, Br, I, CN, NH 2, COOH, CONH 2 , -(CH 2 CH 2 O) o CH 3 (o = 1- 16, 1-12, 1-8, 1-6, 1-4, or 1-2), -(CH 2 CH 2 O)oH (o = 1-16, 1-12, 1-8, 1-6, 1-4, or 1-2), C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 aminoalkyl, or C 1-3 aminohaloalkyl. wherein any two or more of R x3 , R x4 , R x5 , and R x6 can together form a ring. In certain embodiments, X 1 and X 2 together form a ring having the formula: wherein R #3 is in each case independently selected from H and C 1-4 alkyl. In some embodiments, R #3 C 1-4 alkyl substituted one or more times with OH, aryl, F, Cl, Br, I, SO 3 H, COOH, NH 2 , NH(CH 3 ), N(CH 3 ) 2 , N+(CH 3 ) 3 , or PO 3 H 2 . In certain embodiments, the fluorophore is a compound of Formula (1a): In some embodiments the compound is a compound of Formula (1a1): [Formula (1a1)]. wherein A 1 , A 2 , and A 3 have the meanings given above. In further embodiments, the fluorophore is a compound of Formula (1a2): [Formula (1a2)], wherein A 2 is selected from null, O, S, CHR a2 , NR a2** , or N + (R a2* ) 2 , R a2 is selected from F, Cl, Br, I, NO 2 , CN, R a2$ , SR a2$ , SeR a2$ , OR a2$ , N(R a2$ ) 2 , SO 2 R a2$ , SO 2 N(R a2$ ) 2 , C(O)R a2$ ; C(O)OR a2$ , OC(O)R a2$ ; C(O)N(R a2$ ) 2 , N(R a2$ )C(O)R a2$ , OC(O)N(R a2$ ) 2 , N(R a2$ )C(O)N(R a2$ ) 2 , whereinR a2$ is in each case independently selected from hydrogen, C 1-8 alkyl, C 1-8 alkoxy, C 2-8 alkenyl, C 2-8 alkynyl, aryl, C 1-8 heteroaryl, C 3-8 cycloalkyl, or C 1-8 heterocyclyl; wherein both of R a2* is selected from CH 3 , or both of R a2* together a pyrrolidine or piperidine ring. In some embodiments, the fluorophore is a compound of Formula (1a3) or Formula (1a4): [Formula (1a3)], [Formula (1a4)], wherein R 3 is as defined above. In certain embodiments for the compounds of Formula (1a), Formula (1a1), Formula (1a2), Formula (1a3), R 3 is H, F, Cl, Br, I, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, or C 1- 3 aminoalkyl. In certain embodiments for the compounds of Formula (1a), Formula (1a1), Formula (1a2), Formula (1a3), and Formula (1a4) A 2 is NCH 2 CH 2 OH, NCH 3 , NH, NOH, NOCH 3 , NCH 2 CH 3 , NCH(CH 3 ) 2 , CH, CHC(CH 3 ) 3 , CHCH(CH 3 ) 2 , CHCH 2 CH 3 , CHCH 2 OH, CHOH, CHCH 2 CH 2 OH, CHOC(CH 3 ) 3 , CHOCH(CH 3 ) 2 , CHOCH 2 CH 3 , CHCH 2 OH, CHOH, CHOCH 2 CH 2 OH, CHSC(CH 3 ) 3 , CHSCH(CH 3 ) 2 , CHSCH 2 CH 3 , CHSCH 2 CH 2 OH, CHSeC(CH 3 ) 3 , CHSeCH(CH 3 ) 2 , CHSeCH 2 CH 3 , or CHSeCH 2 CH 2 OH. In some embodiments of the compound of Formula (1a), Formula (1a1), Formula (1a2), Formula (1a3), and Formula (1a4), A 2 is null. In some embodiments of the compound of Formula (1a), Formula (1a1), Formula (1a2), Formula (1a3), and Formula (1a4), X 2 is COOR x2 , wherein R x2 is H, C 1-3 alkyl, C 1-3 haloalkyl; and X 1 is F, Cl, CN, or C 1-3 haloalkyl. In some embodiments of the compound of Formula (1a), Formula (1a1), Formula (1a2), Formula (1a3), and Formula (1a4), R zd is benzyl, C 1-8 alkyl, preferably C 1-4 alkyl. In certain embodiments, said C 1-8 alkyl and C 1-4 alkyl are n-alkyl groups, e.g., n-propyl, n-butyl, n-pentyl, n- hexyl, n-heptyl, and n-octyl In some embodiments, said benzyl, C 1-8 alkyl, preferably C 1-4 alkyl groups are not substituted, while in other embodiments said benzyl, C 1-8 alkyl, preferably C 1-4 alkyl groups are substituted one or more times by OH, SO 3 H, PO 3 H 2 , COOH, N(CH 3 ) 2 , NH 2 , NHCH 3 , or a combination thereof. In some embodiments, the fluorophore is a compound of Formula (1a5) or Formula (1a6):
wherein R 3 , R zd , Q a , X 1 , and X 2 are as defined above. In certain embodiments, R a2 is H, F, Cl, Br, I, OH, SO 3 H, PO 3 H 2 , COOH, N(CH 3 ) 2 , NH 2 , NHCH 3 , benzyl, phenyl, or C 1-8 n-alkyl, preferably C 1-4 n- alkyl groups. In certain embodiments, said benzyl, phenyl, or C 1-8 n-alkyl, preferably C 1-4 n-alkyl groups are not substituted, while in other embodiments said benzyl, phenyl, or C 1-8 n-alkyl, preferably C 1-4 n-alkyl groups are substituted one or more times by OH, SO 3 H, PO 3 H 2 , COOH, N(CH 3 ) 2 , NH 2 , NHCH 3 , or a combination thereof. In some others, the fluorophore is a compound of Formula (1a7) or Formula (1a8): wherein R 3 , R zd , X 1 , and X 2 are as defined above. In certain embodiments, R a2** is H, benzyl, phenyl, or C 1-8 alkyl, preferably C 1-4 alkyl groups. In certain embodiments, said benzyl, phenyl, and C 1-8 alkyl, preferably C 1-4 alkyl groups are not substituted, while in other embodiments said benzyl, phenyl, or C 1-8 alkyl, preferably C 1-4 alkyl groups are substituted one or more times by OH, SO 3 H, PO 3 H 2 , COOH, N(CH 3 ) 2 , NH 2 , NHCH 3 , or a combination thereof. In some others, the fluorophore is a compound of Formula (1a9) or Formula (1a10): wherein R 3 , R zd , X 1 , and X 2 are as defined above. In certain embodiments, each R a2* is benzyl, or C 1- 8alkyl, preferably C 1-4 alkyl groups, most preferably methyl. In certain embodiments, said benzyl, phenyl, and C 1-8 alkyl, preferably C 1-4 alkyl groups are not substituted, while in other embodiments said benzyl, phenyl, or C 1-8 alkyl, preferably C 1-4 alkyl, most preferably methyl groups are substituted one or more times by OH, SO 3 H, PO 3 H 2 , COOH, N(CH 3 ) 2 , NH 2 , NHCH 3 , or a combination thereof. In some embodiments of the compound of Formula (1a), Formula (1a1), Formula (1a2), Formula (1a3), Formula (1a4), of Formula (1a5), Formula (1a6), Formula (1a7), Formula (1a8), Formula (1a9), and Formula (1a10), R c may be F, Cl, or Br. In other embodiments, R c is a OR c1 , N(R c1 ) 2 , SR c1 , wherein R c1 is in each case independently selected from hydrogen, C 1-8 alkyl, aryl, C 1-8 heteroaryl, C 3-8 cycloalkyl, or C 1-8 heterocyclyl. In some embodiments of the compound of Formula (1a), Formula (1a1), Formula (1a2), Formula (1a3), Formula (1a4), of Formula (1a5), Formula (1a6), Formula (1a7), Formula (1a8), Formula (1a9), and Formula (1a10), R c is OR c1 , wherein R c1 is selected from H, CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , CH 2 CH 2 OH, CH 2 COOH, CH 2 CH 2 COOH. In some embodiments of the compound of Formula (1a), Formula (1a1), Formula (1a2), Formula (1a3), Formula (1a4), of Formula (1a5), Formula (1a6), Formula (1a7), Formula (1a8), Formula (1a9), and Formula (1a10), R c is NR c1 R c2 , wherein R c1 and R c2 are different or the same, and are selected from H, CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , CH 2 CH 2 OH, CH 2 COOH, CH 2 CH 2 COOH. In certain preferred embodiments, R c1 and R c2 are the same, and are selected from H, CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , CH 2 CH 2 OH, CH 2 COOH, CH 2 CH 2 COOH. In certain embodiments of the compound of Formula (1a), Formula (1a1), Formula (1a2), Formula (1a3), Formula (1a4), of Formula (1a5), Formula (1a6), Formula (1a7), Formula (1a8), Formula (1a9), and Formula (1a10) R c is NR c1 R c2 , wherein R c2 is hydrogen, and R c1 is a C 1-8 alkyl group substituted one or more times by OH, NH 2 , COOH, or a combination thereof. By way of example, R c1 can be CH 2 CH 2 OH, CH(COOH)CH 2 OH, CH 2 CH(OH)COOH, CH 2 CH 2 CH(NH 2 )COOH, CH 2 CH 2 CH 2 CH 2 CH(NH 2 )COOH, or CH 2 CH 2 CH 2 CH 2 CH 2 COOH. In other embodiments of the compound of Formula (1a), Formula (1a1), Formula (1a2), Formula (1a3), Formula (1a4), of Formula (1a5), Formula (1a6), Formula (1a7), Formula (1a8), Formula (1a9), and Formula (1a10), R c is NR c1 R c2 and R c1 and R c2 can together form a heterocyclic ring, for instance a piperidine, pyrrolidine, morpholine, piperazine, which may be further substituted one or more times by F, Cl, Br, I, NO 2 , CN, R c3 , OR c3 , N(R c3 ) 2 , SO 2 R c3 , SO 2 N(R c3 ) 2 , C(O)R c3 ; C(O)OR c3 , OC(O)R c3 ; C(O)N(R c3 ) 2 , N(R c3 )C(O)R c3 , OC(O)N(R c3 ) 2 , N(R c3 )C(O)N(R c3 ) 2 , wherein R c3 is in each case independently selected from hydrogen, C 1-8 alkyl, C 1-8 alkoxy, C 2-8 alkenyl, C 2-8 alkynyl, aryl, C 1-8 heteroaryl, C 3-8 cycloalkyl, or C 1-8 heterocyclyl; In some embodiments of the compound of Formula (1a), Formula (1a1), Formula (1a2), Formula (1a3), Formula (1a4), of Formula (1a5), Formula (1a6), Formula (1a7), Formula (1a8), Formula (1a9), and Formula (1a10), R c has the formula: R c4 is R c4$ , Q 4 -OR c4$ , or Q 4 -N(R c4$ ) 2 , wherein Q 4 is null or a C 1-4 alkylene group, and R c4$ is in each case independently selected from hydrogen, C 1-8 alkyl, aryl, C 1-8 heteroaryl, C 3-8 cycloalkyl, or C 1-8 heterocyclyl; and C c5 is R c5$ , wherein Q 5 is null or a C 1-4 alkylene group, and R c5$ is in each case independently selected from hydrogen, C 1-8 alkyl, aryl, C 1-8 heteroaryl, C 3-8 cycloalkyl, or C 1-8 heterocyclyl. In certain preferred embodiments, Q 4 is null, -CH 2 -, -CH 2 CH 2 - or -CH 2 CH 2 CH 2 -, and R c4$ and R c5$ are H, OH, NH 2 , NHCH 3 , N(CH 3 ) 2 , SH, COOH, CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , C(CH 3 ) 3 , CH 2 CH 2 OH, CH 2 COOH, CH 2 CH 2 COOH. In some embodiments, the fluorophore has the formula: wherein X 1 , X 2 , Z 1 , Q a , R c , R 3 , R a2 , and R zd are as defined above. For example, the fluorophore may have the formula:
In preferred embodiments, R a2 is H, phenyl, pyridinyl, tert-butyl, isopropyl, or benzyl, R 3 is H, F, Cl, Br, I, COOH, X 1 is CN, Cl, F, or CF 3 , X 2 is COOH, Z 1 is S, O, -CH=CH-, or C(CH 3 ) 2 , and R zd is unsubstituted C 1-8 alkyl or C 1-8 alkyl substituted one or more times by OH, NH 2 , COOH, SO 3 H, PO 3 H 2 , or phenyl. The disclosed compounds can have cytotoxic properties and as such may be effectively used for the treatment of proliferative disorders, including cancer and similar diseases. Exemplary cancers include acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), cancer in adrenocortical carcinoma, adrenal cortex cancer, AIDS-related cancers, Kaposi sarcoma, AIDS-related lymphoma, primary CNS lymphoma, anal cancer, appendix cancer, carcinoid tumors, astrocytomas, atypical teratoid/rhabdoid tumor, basal cell carcinoma, skin cancer (nonmelanoma), bile duct cancer, extrahepatic bladder cancer, bladder cancer, bone cancer (includes Ewing sarcoma and osteosarcoma and malignant fibrous histiocytoma), brain tumors, breast cancer, bronchial tumors, Burkitt lymphoma (non-Hodgkin), carcinoid tumor, cardiac (heart) tumors, atypical teratoid/rhabdoid tumor, embryonal tumors, germ cell tumors, lymphoma, primary - cervical cancer, cholangiocarcinoma, chordoma, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic myeloproliferative neoplasms, colorectal cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, ductal carcinoma in situ (DCIS), embryonal tumors, central nervous system, endometrial cancer, ependymoma, esophageal, esthesioneuroblastoma, extracranial germ cell tumor, extragonadal germ cell tumor, eye cancer, intraocular melanoma, retinoblastoma, fallopian tube cancer, fibrous histiocytoma of bone, malignant, and osteosarcoma, gallbladder cancer, gastric (stomach) cancer, gastric (stomach) cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumors (GIST), gastrointestinal stromal tumors (GIST), germ cell tumors, central nervous system, extracranial, extragonadal, ovarian testicular, gestational trophoblastic disease, gliomas, hairy cell leukemia, head and neck cancer, heart tumors, hepatocellular (liver) cancer, histiocytosis, Langerhans Cell, Hodgkin’s lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell tumors, pancreatic neuroendocrine tumors, Kaposi sarcoma, kidney - langerhans cell histiocytosis, laryngeal cancer, laryngeal cancer and papillomatosis, leukemia, lip and oral cavity cancer, liver cancer (primary), lung cancer, lung cancer, lymphoma - macroglobulinemia, Waldenström –Non-Hodgkin lymphoma, male breast cancer, malignant fibrous histiocytoma of bone and osteosarcoma, melanoma, intraocular (eye), Merkel cell carcinoma, mesothelioma, malignant, mesothelioma, metastatic squamous neck cancer with occult primary, midline tract carcinoma involving NUT gene, mouth cancer, multiple endocrine neoplasia syndromes, multiple myeloma/plasma cell neoplasms, mycosis fungoides, myelodysplastic syndromes, myelodysplastic/myeloproliferative neoplasms and chronic myeloproliferative neoplasms, myelogenous leukemia, chronic (CML), myeloid leukemia, acute (AML), nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, nasopharyngeal cancer, neuroblastoma, non- hodgkin lymphoma, non-small cell lung cancer, oral cancer, lip and oral cavity cancer and oropharyngeal cancer, osteosarcoma and malignant fibrous histiocytoma of bone, ovarian cancer, pancreatic cancer and pancreatic neuroendocrine tumors (islet cell tumors), papillomatosis, paraganglioma, paraganglioma, paranasal sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pheochromocytoma, pituitary tumor, plasma cell neoplasm/multiple myeloma, pleuropulmonary blastoma, pregnancy and breast cancer, primary central nervous system (CNS) lymphoma, primary peritoneal cancer, prostate cancer, rectal cancer, renal cell (kidney) cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, salivary gland tumors, Ewing sarcoma, Kaposi sarcoma, osteosarcoma, rhabdomyosarcoma, uterine sarcoma, vascular tumors, Sézary syndrome, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, squamous neck cancer with occult primary, metastatic, stomach (gastric) cancer, stomach (gastric) cancer, T-cell lymphoma, cutaneous, testicular cancer, throat cancer, thymoma and thymic carcinoma, thyroid cancer, ureter and renal pelvis, transitional cell cancer, urethral cancer, uterine cancer, endometrial and uterine sarcoma, vaginal cancer, vaginal cancer, vascular tumors, vulvar cancer, Waldenström Macroglobulinemia, Wilms Tumor. In the field of medical oncology it is normal practice to use a combination of different forms of treatment to treat each patient with cancer. In medical oncology the other component(s) of such conjoint treatment in addition to compositions of the present invention may be, for example, surgery, radiotherapy, chemotherapy, signal transduction inhibitors and/or monoclonoal antibodies. Accordingly, the disclosed compounds may be administered in combination with one or more anticancer agents for example mitotic inhibitors, alkylating agents, anti-metabolites, antisense DNA or RNA, intercalating antibiotics, growth factor inhibitors, signal transduction inhibitors, cell cycle inhibitors, enzyme inhibitors, retinoid receptor modulators, proteasome inhibitors, topoisomerase inhibitors, biological response modifiers, anti-hormones, angiogenesis inhibitors, cytostatic agents anti-androgens, targeted antibodies, HMG-CoA reductase inhibitors, and prenyl-protein transferase inhibitors. Exemplary anti-cancer agents include nucleoside analogues, antifolates, antimetabolites, topoisomerase I inhibitor, anthracyclines, podophyllotoxins, taxanes, vinca alkaloids, alkylating agents, platinum compounds, proteasome inhibitors, nitrogen mustards & oestrogen analogue, monoclonal antibodies, tyrosine kinase inhibitors, mTOR inhibitors, retinoids, immunomodulatory agents, histone deacetylase inhibitors, and combinations thereof. In certain embodiments, the anti-cancer agent is selected from one or more of abiraterone acetate, methotrexate, paclitaxel albumin-stabilized nanoparticle, brentuximab vedotin, ado- trastuzumab emtansine, doxorubicin hydrochloride, afatinib dimaleate, everolimus, netupitant, palonosetron hydrochloride, imiquimod, aldesleukin, alectinib, alemtuzumab, melphalan hydrochloride, melphalan, pemetrexed disodium, chlorambucil, aminolevulinic acid, anastrozole, aprepitant, pamidronate disodium, exemestane, nelarabine, arsenic trioxide, ofatumumab, asparaginase erwinia chrysanthemi, atezolizumab, bevacizumab, axitinib, azacitidine, carmustine, belinostat, bendamustine hydrochloride, bevacizumab, bexarotene, tositumomab, bicalutamide, bleomycin, blinatumomab, blinatumomab, bortezomib, bosutinib, busulfan, cabazitaxel, cabozantinib, alemtuzumab, irinotecan hydrochloride, capecitabine, fluorouracil, carboplatin, carfilzomib, bicalutamide, lomustine, ceritinib, daunorubicin hydrochloride, cetuximab, chlorambucil, cyclophosphamide, clofarabine, cobimetinib, dactinomycin, cobimetinib, crizotinib, ifosfamide, ramucirumab, cytarabine, dabrafenib, dacarbazine, decitabine, daratumumab, dasatinib, daunorubicin hydrochloride, decitabine, efibrotide sodium, defibrotide sodium, degarelix, denileukin diftitox, denosumab, dexamethasone, dexrazoxane hydrochloride, dinutuximab, docetaxel, doxorubicin hydrochloride, dacarbazine, rasburicase, epirubicin hydrochloride, elotuzumab, oxaliplatin, eltrombopag olamine, aprepitant, elotuzumab, enzalutamide, epirubicin hydrochloride, cetuximab, eribulin mesylate, vismodegib, erlotinib hydrochloride, etoposide, raloxifene hydrochloride, melphalan hydrochloride, toremifene, panobinostat, fulvestrant, letrozole, filgrastim, fludarabine phosphate, flutamide, methotrexate, pralatrexate, recombinant hpv quadrivalent vaccine, recombinant hpv nonavalent vaccine, obinutuzumab, gefitinib, gemcitabine hydrochloride, gemtuzumab ozogamicin, afatinib dimaleate, imatinib mesylate, glucarpidase, goserelin acetate, eribulin mesylate, trastuzumab, topotecan hydrochloride, palbociclib, ibritumomab tiuxetan, ibrutinib, ponatinib hydrochloride, idarubicin hydrochloride, idelalisib, imiquimod, axitinib, recombinant interferon alfa-2b, tositumomab, ipilimumab, gefitinib, romidepsin, ixabepilone, ixazomib citrate, ruxolitinib phosphate, cabazitaxel, ado-trastuzumab emtansine, palifermin, pembrolizumab, lanreotide acetate, lapatinib ditosylate, lenalidomide lenvatinib mesylate, leuprolide acetate, olaparib, vincristine sulfate, procarbazine hydrochloride, mechlorethamine hydrochloride, megestrol acetate, trametinib, mercaptopurine, temozolomide, mitoxantrone hydrochloride, plerixafor, busulfan, azacitidine, gemtuzumab ozogamicin, vinorelbine tartrate, necitumumab, nelarabine, sorafenib tosylate, nilotinib, ixazomib citrate, nivolumab, romiplostim, obinutuzumab, ofatumumab, olaparib, omacetaxine mepesuccinate, pegaspargase, ondansetron hydrochloride, osimertinib, panitumumab, panobinostat, peginterferon alfa-2b, pembrolizumab, pertuzumab, plerixafor, pomalidomide, ponatinib hydrochloride, necitumumab, pralatrexate, procarbazine hydrochloride, aldesleukin, denosumab, ramucirumab, rasburicase, regorafenib, lenalidomide, rituximab, rolapitant hydrochloride, romidepsin, ruxolitinib phosphate, siltuximab, dasatinib, sunitinib malate, thalidomide, dabrafenib, osimertinib, talimogene, atezolizumab, temsirolimus, thalidomide, dexrazoxane hydrochloride, trabectedin, trametinib, trastuzumab, lapatinib ditosylate, dinutuximab, vandetanib, rolapitant hydrochloride, bortezomib, venetoclax, crizotinib, enzalutamide, ipilimumab, trabectedin, ziv-aflibercept, idelalisib, ceritinib, and pharmaceutically acceptable salts thereof. The disclosed compounds fluoresce at a wavelength of 800 nm or more, and as such are useful as imaging agents. According, in some aspects the invention relates to methods of diagnosing or imaging a tumor or other condition in a body. Embodiments including one or more basic atoms (e.g., basic nitrogen and the like) can further be used a pH-sensitive probes. As used herein, terms "treat" or "treatment" refer to therapeutic, prophylactic, palliative or preventative measures. Beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable. "Treatment" can also mean prolonging survival as compared to expected survival if not receiving treatment. As used herein, the term "mammal" refers to a warm-blooded animal that has or is at risk of developing a disease described herein and includes, but is not limited to, guinea pigs, dogs, cats, rats, mice, hamsters, and primates, including humans. Compounds of the invention may be administered by any convenient route, e.g. into the gastrointestinal tract (e.g. rectally or orally), the nose, lungs, musculature or vasculature, or transdermally or dermally. Compounds may be administered in any convenient administrative form, e.g. tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches etc. Such compositions may contain components conventional in pharmaceutical preparations, e.g. diluents, carriers, pH modifiers, sweeteners, bulking agents, and further active agents. If parenteral administration is desired, the compositions will be sterile and in a solution or suspension form suitable for injection or infusion. Such compositions form a further aspect of the invention. The compounds disclosed herein may be formulated in a wide variety of pharmaceutical compositions for administration to a patient. Such compositions include, but are not limited to, unit dosage forms including tablets, capsules (filled with powders, pellets, beads, mini-tablets, pills, micro-pellets, small tablet units, multiple unit pellet systems (MUPS), disintegrating tablets, dispersible tablets, granules, and microspheres, multiparticulates), sachets (filled with powders, pellets, beads, mini-tablets, pills, micro-pellets, small tablet units, MUPS, disintegrating tablets, dispersible tablets, granules, and microspheres, multiparticulates), powders for reconstitution, transdermal patches and sprinkles, however, other dosage forms such as controlled release formulations, lyophilized formulations, modified release formulations, delayed release formulations, extended release formulations, pulsatile release formulations, dual release formulations and the like. Liquid or semisolid dosage form (liquids, suspensions, solutions, dispersions, ointments, creams, emulsions, microemulsions, sprays, patches, spot-on), injection preparations, parenteral, topical, inhalations, buccal, nasal etc. may also be envisaged under the ambit of the invention. Suitable excipients may be used for formulating the dosage forms according to the present invention such as, but not limited to, surface stabilizers or surfactants, viscosity modifying agents, polymers including extended release polymers, stabilizers, disintegrants or super disintegrants, diluents, plasticizers, binders, glidants, lubricants, sweeteners, flavoring agents, anti-caking agents, opacifiers, anti-microbial agents, antifoaming agents, emulsifiers, buffering agents, coloring agents, carriers, fillers, anti-adherents, solvents, taste-masking agents, preservatives, antioxidants, texture enhancers, channeling agents, coating agents or combinations thereof. The compounds disclosed herein may be administered by a number of different routes. For instance, the compounds may be administered orally, topically, transdermally, intravenously, subcutaneously, by inhalation, or by intracerebroventricular delivery. In some embodiments, the compounds disclosed herein may be formulated as nanoparticles. The nanoparticles may have an average particle size from 1-1,000 nm, preferably 10-500 nm, and even more preferably from 10-200 nm. The compounds may be administered to a patient systemically, e.g., by oral or intravenous administration, topically, i.e., by application of a cream, lotion or the like, or locally, e.g., by direct perfusion of a composition containing the compound to a target tissue. The present invention further provides a pharmaceutical composition, which comprises a compound of Formula I or a pharmaceutically acceptable salt thereof, as defined hereinabove. In one embodiment, the pharmaceutical composition includes the disclosed compounds together with a pharmaceutically acceptable diluent or carrier. The present invention further provides a disclosed compound or a pharmaceutically acceptable salt thereof, for use in therapy. In one embodiment, the invention provides the disclosed compounds or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer in a mammal. In one embodiment, the cancer is neuroblastoma. In one embodiment, the cancer is ovarian cancer. In one embodiment, the cancer is pancreatic cancer. In one embodiment, the cancer is colorectal cancer. In one embodiment, the cancer is prostate cancer. Another embodiment of the present invention provides the use of the disclosed compounds, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cancer in a mammal. The compounds disclosed herein may be prepared by condensation, for instance under Vilsmeier Haack conditions, of an appropriate acetone derivative with aldehydes (or masked aldehyde equivalents), followed by condensation with X 1 -CH 2 -X 1 : wherein R a , R b , R d , R f , X 1 , and X 2 are as defined above. The resulting product may be condensed with an appropriate heterocycle, and if desired, the meso chlorine atom exchanged with a different R c group: The condensation with the heterocycle may be carried out in mixtures of an amine base and ethanolic solvent, optionally at elevated temperature (reflux). In some implementations, compounds were prepared according under the following conditions: EXAMPLES The following examples are for the purpose of illustration of the invention only and are not intended to limit the scope of the present invention in any manner whatsoever. Example 1: Synthesis of linker-acceptor compounds 9 mL of DCM and 18 ml of DMF were combined in a 50 mL round bottomed flask in an ice bath. The solution was let to stir in ice bath for 15 minutes. Then 15 mL (58 mmol) of POCl 3 was add slowly into the solution: 1 mL of POCl 3 was added every few minutes to make up to 15 ml of POCl 3 while stirring in reflux, and then stirred for further 30 minutes. After 30 minutes, 4.5 mL (48 mmol) of cyclohexanone 10 was added slowly into Vilsmeier reagent. The flask was taken off the ice bath and stirred under reflux at 80 °C for 4 hours. Upon heating, the reaction mixture turned bright red in color. The reaction was monitored with thin layered chromatography (TLC). With cyclohexanone as the starting material, the reaction mixture was compared on TLC after every hour to see the consumption of cyclohexanone. When the starting material was consumed and yellow product was formed as seen on TLC, the reaction was stopped, and the reaction mixture was poured over iced water in a large Erlenmeyer flask. It was let stir overnight. The overnight stirred bright red mixture in iced water had turned bright yellow. The yellow precipitate 11 was collected by vacuum filtration and was washed with ice cold water. The linker 11 was then reacted with 1,3-diethyl-2-thiobarbituric acid 12 to form the linker acceptor complex 13.3g (17.4 mmol) of linker 11 was taken into a 100 mL round bottomed flask with 3 mL of acetic anhydride.3.48 g (17.4 mmol) of 12 was added into this mixture and let stir until dissolved. Then 2 equivalents of NaOAc weighing 2.85 g (34.8 mmol) was added into the mixture, and refluxed at 70 °C. The reaction progress was monitored with TLC after every hour. Once the TLC showed majority of starting material, compound 11 was consumed and product 13 was formed, the reaction was stopped after 6 hours. 2 This resulting reaction mixture was poured onto iced water and let stir overnight. Product 13 was dark green in color as solid precipitate. The crude product was purified by crystallization in methanol and confirmed by 1 H NMR. Using similar protocols, linker-acceptor compounds having a malononitrile, cyanoacetic acid, and indane-1,3-dione functionality were prepared. Example 2: Synthesis of red-shifted fluorophores (E)-3-(( E)-2-chloro-3-(hydroxymethylene)cyclohex-1-en-1-yl)-2-cyanoa crylic acid (1 eq) and indolium heterocyclic salt (1.2 eq) were dissolved in ethanol (5 mL) and refluxed at 70°C with the addition of 3 drops of triethylamine. The progress of the reaction was monitored by using UV-Vis spectrophotometer. The reaction was continued until the peak around 780 nm was observed and the peak around 440 nm due to heterocyclic salt was disappeared. The reaction was completed after 6 h. After the completion of the reaction, the excess ethanol was evaporated by using rotary evaporator. The crude compound was then dissolved in minimal amount of methanol and diethyl ether was added to it to obtain pure green crystals of donor-π-acceptor fluorophores. (E)-2-((2-chloro-3-(hydroxymethylene) cyclohex-1-en-1-yl)methylene)malononitrile (1 eq) and indolium heterocyclic salt (1.2 eq) were dissolved in ethanol (5 mL) and refluxed at 70 °C with the addition of 3 drops of triethylamine. The progress of the reaction was monitored by using UV-Vis spectrophotometer. The reaction was continued until the peak around 780 nm was observed and the peak around 440 nm due to heterocyclic salt was disappeared. The reaction was completed after 6 h. After the completion of the reaction, the excess ethanol was evaporated by using rotary evaporator. The compound was then dissolved in minimal amount of methanol and diethyl ether was added to it to obtain crude powder of donor-π-acceptor fluorophores. The fluorophores were purified by using column chromatography with solvent system of DCM and acetone. Example 3: Meso functionalization with piperidin-4-yl-methanol Meso-chloro substituted fluorophores (1 eq) and piperidin-4-yl-methanol (5 eq) were dissolved in DMF (2 mL) and heated at 85°C under nitrogen atmosphere. The progress of the reaction was monitored by using UV-Vis spectrophotometer and TLC. The reaction was continued until the peak around 660 nm was observed and the starting fluorophore peak around 780 nm was disappeared and in addition, the starting fluorophore spot was disappeared in TLC. The reaction was completed after 3 h. After the completion of the reaction, diethyl ether was added to the reaction mixture and stirred for an hour to get solid form of crude product. The crude product was purified by using column chromatography with solvent system of DCM and acetone to obtain purple powder of pure meso-modified fluorophores. Example 3: Meso functionalization with pyridine-4-thiol Pyridine-4-thiol (1 eq) and sodium methoxide (2 eq) were dissolved in DMF (1 mL) and stirred at 0°C under nitrogen atmosphere for 30 min. The two donor-π-acceptor fluorophores were dissolved in DMF (2 mL), added dropwise to the reaction mixture, and stirred at room temperature as shown in Equation 20. The progress of the reaction was monitored by using UV- Vis spectrophotometer and TLC. The reaction was continued until the peak around 800 nm was observed and the starting fluorophore peak around 780 nm was disappeared and in addition, the starting fluorophore spot was disappeared in TLC. The reaction was completed after 2 h. After the completion of the reaction, diethyl ether was added to the reaction mixture and stirred for an hour to get solid form of crude product. The crude product was purified by using column chromatography with solvent system of DCM and acetone to obtain green powder of pure meso- modified fluorophores. Following these protocols, the following compounds were prepared:
Other exemplary compounds include:
Example 4: Evaluation of red-shifted flourophores: Optical properties of the fluorophores was measured in ethanol, and compared to ICG (indocyanine green).
The compounds disclosed herein exhibit solvatochromism
The compositions and methods of the appended claims are not limited in scope by the specific compositions and methods described herein, which are intended as illustrations of a few aspects of the claims and any compositions and methods that are functionally equivalent are intended to fall within the scope of the claims. Various modifications of the compositions and methods in addition to those shown and described herein are intended to fall within the scope of the appended claims. Further, while only certain representative compositions and method steps disclosed herein are specifically described, other combinations of the compositions and method steps also are intended to fall within the scope of the appended claims, even if not specifically recited. Thus, a combination of steps, elements, components, or constituents may be explicitly mentioned herein or less, however, other combinations of steps, elements, components, and constituents are included, even though not explicitly stated. The term “comprising” and variations thereof as used herein is used synonymously with the term “including” and variations thereof and are open, non-limiting terms. Although the terms “comprising” and “including” have been used herein to describe various embodiments, the terms “consisting essentially of” and “consisting of” can be used in place of “comprising” and “including” to provide for more specific embodiments of the invention and are also disclosed. Other than in the examples, or where otherwise noted, all numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification and claims are to be understood at the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, to be construed in light of the number of significant digits and ordinary rounding approaches.
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