HUDSON ANDREW (US)
| CLAIMS We Claim: 1. A radiopharmaceutical conjugate comprising: (a) a targeting ligand that covalently binds to an intracellular KRAS protein, wherein the intracellular KRAS protein is mutated, and wherein the targeting ligand comprises a structure of Formula (III), or a salt or solvate thereof, Formula (III) wherein ring Q1 is a 4-12 membered saturated or partially saturated monocyclic or bicyclic ring, wherein the monocyclic or bicyclic ring is optionally substituted; L1 is a bond, -C(=O)-, or optionally substituted C1-C3 alkylene; L2 is a bond, -C(=O)-, O, S or NR15; E is X is C(=O), P(=O)OR2, C(=S), or S(=O)n, where n is 1 or 2; R2 is hydrogen or optionally substituted C1-C3 alkyl; R5 is hydrogen, cyano, halogen, C1-C6 alkyl, C1-C6 alkoxyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, or C2-C5 heterocycloalkyl, wherein each of the alkyl, alkoxyl, heteroalkyl, cycloalkyl or heterocycloalkyl is optionally substituted, and R7 is hydrogen, cyano, halogen, C1-C6 alkyl, C1-C6 alkoxyl, C1-C6 heteroalkyl, C3-C7 cycloalkyl, C2-C7 heterocycloalkyl, or heteroaryl, wherein each of the alkyl, alkoxyl, heteroalkyl, cycloalkyl, heterocycloalkyl, or heteroaryl is optionally substituted; or R5 and R7 taken together form a bond; or R5 and R7 taken together with the carbon atoms to which they are attached form a 5-8 membered partially saturated cycloalkyl, wherein the cycloalkyl is optionally substituted; R6 is hydrogen, cyano, halogen, C1-C6 alkyl, C1-C6 alkoxyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, C2-C6 heterocycloalkyl, or heteroaryl, wherein each of the alkyl, alkoxyl, heteroalkyl, cycloalkyl, heterocycloalkyl, or heteroaryl is optionally substituted; R12 is hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, -L3-NR15R15’, heterocycloalkyl, -L3- heterocycloalkyl, cycloalkyl, -L3-cycloalkyl, aryl, heteroaryl, -L3-aryl, or -L3-heteroaryl, wherein each of the heterocycloalkyl, cycloalkyl, aryl, heteroaryl, alkyl or heteroalkyl is optionally substituted; L3 is C1-C4 alkylene or C1-C4 heteroalkylene, each of which is optionally substituted; each R13 is independently OH, halogen, oxo, substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C1-C6 heteroalkyl; R14 is hydrogen, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each of the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted; each R15 is independently hydrogen or C1-C3 alkyl; each R15’ is independently hydrogen, acyl, C1-C3 alkyl, C1-C3 heteroalkyl or C1-C3 hydroxyalkyl; m is 0, 1, or 2, wherein the structure of Formula (III) is attached to the rest of the conjugate at any suitable position; and (b) a radionuclide. 2. The radiopharmaceutical conjugate of claim 1, wherein ring Q1 is a 4-12 membered saturated or partially saturated monocyclic or bicyclic ring optionally substituted with one, two, or three groups selected from R18; L1 is a bond, -C(=O)-, or optionally substituted C1-C3 alkylene, wherein the alkylene is optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, and C2-C5 heterocycloalkyl; L2 is a bond, -C(=O)-, O, S or NR15; E is ; X is C(=O), P(=O)OR2, C(=S), or S(=O)n, where n is 1 or 2; R2 is hydrogen or substituted or unsubstituted C1-C3 alkyl, wherein the alkyl is optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C3-C6 cycloalkyl, and C2-C5 heterocycloalkyl; R5 is hydrogen, cyano, halogen, C1-C6 alkyl, C1-C6 alkoxyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, or C2-C5 heterocycloalkyl, each of the alkyl, alkoxyl, heteroalkyl, cycloalkyl or heterocycloalkyl is optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, and C2- C5 heterocycloalkyl; R7 is hydrogen, cyano, halogen, C1-C6 alkyl, C1-C6 alkoxyl, C1-C6 heteroalkyl, C3-C7 cycloalkyl, C2-C7 heterocycloalkyl, or C1-C9 heteroaryl, wherein each of the alkyl, alkoxyl, heteroalkyl, cycloalkyl or heterocycloalkyl is optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, and C2-C5 heterocycloalkyl; or R5 and R7 taken together form a bond; or R5 and R7 taken together with the carbon atoms to which they are attached form a 5-8 membered partially saturated cycloalkyl, wherein the cycloalkyl is optionally substituted with one, two or three groups selected from R17; R6 is hydrogen, cyano, halogen, C1-C6 alkyl, C1-C6 alkoxyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, C2-C6 heterocycloalkyl, or C1-C9 heteroaryl, wherein, each of the alkyl, alkoxyl, heteroalkyl, cycloalkyl, heterocycloalkyl, or heteroaryl is optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3- C6 cycloalkyl, and C2-C5 heterocycloalkyl; R12 is hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, -L3-NR15R15’, C2-C12heterocycloalkyl, -L3- C2- C12heterocycloalkyl, C3-C15cycloalkyl, -L3- C3-C15cycloalkyl, aryl, C1-C9 heteroaryl, -L3-aryl, or -L3- C1-C9 heteroaryl, wherein each of the heterocycloalkyl, cycloalkyl, aryl, heteroaryl, alkyl or heteroalkyl is optionally substituted with one, two, three or four groups selected from R19; L3 is C1-C4 alkylene or C1-C4 heteroalkylene, each of which is optionally substituted with one, two, or three groups selected from R19; each R13 is independently -OH, halogen, oxo, substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C1-C6 heteroalkyl, wherein each of the alkyl and heteroalkyl is optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, and C2-C5 heterocycloalkyl; R14 is hydrogen, C3-C15cycloalkyl, C2-C12heterocycloalkyl, aryl, or C1-C9 heteroaryl, wherein each of the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, three or four groups selected from R16; each R15 is independently hydrogen or C1-C3 alkyl; each R15’ is independently hydrogen, acyl, C1-C3 alkyl, C1-C3 heteroalkyl or C1-C3 hydroxyalkyl; m is 0, 1, or 2; each R17 is independently halogen, hydroxyl, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, amino, cyano, C1-C6 heteroalkyl, C1-C6 hydroxyalkyl, -O-C1-C6haloalkyl, or -S-C1- C6haloalkyl; each R18 is independently halogen, oxo, C1-C6 alkyl, C1-C6 aminoalkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, -CN, -C(O)OR15, -C(O)N(R15)(R15’), -N(R15)(R15’), or OR15, and wherein each of the alkyl, aminoalkyl, haloalkyl, alkenyl, alkynyl, or heteroalkyl is optionally substituted with one, two, or three groups selected from halogen, -CN, -NO2, amino, hydroxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, and C2-C5 heterocycloalkyl; R16 and R19 are each independently selected from halogen, oxo, -CN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C3-C10 cycloalkyl, -C1-3alkylene-C3-6cycloalkyl, C2-C9 heterocycloalkyl, -C1-3alkylene-C2-9heterocycloalkyl, C6-C10 aryl, -C1-3alkylene-C6-10aryl, C1- C9 heteroaryl, -C1-3alkylene-C1-9 heteroaryl, -OR10, -SR10, -N(R10)(R10’), -C(=O)OR10, - OC(=O)N(R10)(R10’), -N(R10’)C(=O)N(R10)(R10’), -N(R10’)C(=O)OR11, -N(R10’)S(=O)2R11, - C(=O)R11, -S(=O)R11, -OC(=O)R11, -C(=O)N(R10)(R10’), -C(=O)C(=O)N(R10)(R10’), - N(R10’)C(O)R11, -S(O)2R11, -S(O)2N(R10)(R10’), -S(=O)(=NH)N(R10)(R10’), - CH2C(O)N(R10)(R10’), -CH2N(R10’)C(=O)R11, -CH2S(=O)2R11, and -CH2S(=O)2N(R10)(R10’), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, -C1-3alkylene-C3-6cycloalkyl, heterocycloalkyl, -C1-3alkylene-C2-C9heterocycloalkyl, aryl, -C1-3alkylene-C6-10aryl, heteroaryl and -C1- 3alkylene-C1-9 heteroaryl are optionally substituted with one, two, three, or four groups independently selected from halogen, oxo, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkyloxy, C1-C6 haloalkoxy, C3-C10 cycloalkyl, C2-C9 heterocycloalkyl, C6-C10 aryl, C1- C9 heteroaryl, -OR10, -SR10, -N(R10)(R10’), -C(=O)OR10, -OC(=O)N(R10)(R10’), - N(R10’)C(=O)N(R10)(R10’), -N(R10’)C(=O)OR11, -N(R10’)S(=O)2R11, -C(=O)R11, -S(O)R11, - OC(=O)R11, -C(=O)N(R10)(R10’), -C(=O)C(=O)N(R10)(R10’), -N(R10’)C(=O)R11, -S(=O)2R11, - S(=O)2N(R10)(R10’)-, S(=O)(=NH)N(R10)(R10’), -CH2C(=O)N(R10)(R10’), - CH2N(R10’)C(=O)R11, -CH2S(=O)2R11, and -CH2S(=O)2N(R10)(R10’); each R10 is independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C2-9heterocycloalkyl, C6-C10 aryl, and C1-C9 heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C2-C9 heterocycloalkyl, C6-C10 aryl, and C1-C9 heteroaryl; each R10’ is independently selected from hydrogen, C1-C6 alkyl, and C1-C6 haloalkyl; and each R11 is independently selected C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C2-C9 heterocycloalkyl, C6-C10 aryl, and C1-C9 heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C2-C9 heterocycloalkyl, C6-C10 aryl, and C1-C9 heteroaryl. 3. The radiopharmaceutical conjugate of claim 1 or claim 2, wherein R12 is C3-C15cycloalkyl, C2-C12heterocycloalkyl, -L3- C2-C12heterocycloalkyl, or -L3- C3- C15cycloalkyl, wherein each of the L3, heterocycloalkyl, cycloalkyl, alkyl, or heteroalkyl is optionally substituted with one, two, three or four groups selected from R19; and wherein each R19 is independently selected from oxo, -CN, C1-C6 alkyl, C1-C6 heteroalkyl, C3-C10 cycloalkyl, -C1-3alkylene-C3-6cycloalkyl, C2-C9 heterocycloalkyl, -C1-3alkylene-C2- 9heterocycloalkyl, C6-C10 aryl, -C1-3alkylene-C6-10aryl, C1-C9 heteroaryl, -C1-3alkylene-C1-9 heteroaryl, -OR10, -SR10, -N(R10)(R10’), -C(=O)OR10, -OC(=O)N(R10)(R10’), - N(R10’)C(=O)N(R10)(R10’), -N(R10’)C(=O)OR11, -N(R10’)S(=O)2R11, -C(=O)R11, -S(=O)R11, - OC(=O)R11, -C(=O)N(R10)(R10’), -C(=O)C(=O)N(R10)(R10’), -N(R10’)C(O)R11, -S(O)2R11, - S(O)2N(R10)(R10’), -S(=O)(=NH)N(R10)(R10’), -CH2C(O)N(R10)(R10’), -CH2N(R10’)C(=O)R11, - CH2S(=O)2R11, and -CH2S(=O)2N(R10)(R10’), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, - C1-3alkylene-C3-6cycloalkyl, heterocycloalkyl, -C1-3alkylene-C2-C9heterocycloalkyl, aryl, -C1- 3alkylene-C6-10aryl, heteroaryl and -C1-3alkylene-C1-9 heteroaryl are optionally substituted with one, two, three, or four groups independently selected from halogen, oxo, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkyloxy, C1-C6 haloalkoxy, C3-C10 cycloalkyl, C2-C9 heterocycloalkyl, C6-C10 aryl, C1-C9 heteroaryl, -OR10, -SR10, -N(R10)(R10’), -C(=O)OR10, - OC(=O)N(R10)(R10’), -N(R10’)C(=O)N(R10)(R10’), -N(R10’)C(=O)OR11, -N(R10’)S(=O)2R11, - C(=O)R11, -S(O)R11, -OC(=O)R11, -C(=O)N(R10)(R10’), -C(=O)C(=O)N(R10)(R10’), - N(R10’)C(=O)R11, -S(=O)2R11, -S(=O)2N(R10)(R10’)-, S(=O)(=NH)N(R10)(R10’), - CH2C(=O)N(R10)(R10’), -CH2N(R10’)C(=O)R11, -CH2S(=O)2R11, and -CH2S(=O)2N(R10)(R10’). 4. The radiopharmaceutical conjugate of claim 3, wherein R12 is -L3- C2-C12heterocycloalkyl, optionally substituted with one, two, three or four groups selected from R19; and wherein each R19 is independently selected from oxo, C1-C6 alkyl, C1-C6 heteroalkyl, -C1- 3alkylene-C6-10aryl, -C1-3alkylene-C1-9 heteroaryl, and OR10, wherein the alkyl, heteroalkyl, and -C1-3alkylene-C6-10aryl, and -C1-3alkylene-C1-9 heteroaryl are optionally substituted with one, two, three, or four groups independently selected from C1-C6 alkyl, C6-C10 aryl, -OR10, - C(=O)OR10, or -N(R10’)C(=O)R11. 5. The radiopharmaceutical conjugate of claim 4, wherein, the targeting ligand comprises a structure of Formula (IIIa-1) or Formula (IIIa-2), or a salt or solvate thereof, Formula (IIIa-1). Formula (IIIa-2). 6. The radiopharmaceutical conjugate of any one of claims 1-5, wherein the structure of Formula (III) is attached to the rest of the conjugate through R19. 7. The radiopharmaceutical conjugate of any one of claims 1-6, wherein , , , , wherein R* is the radionuclide. 8. The radiopharmaceutical conjugate of any one of claims 1-5, wherein 9. The radiopharmaceutical conjugate of any one of claims 1-4 or 6-8, wherein: R5 is hydrogen, halogen or a C1-C3 alkyl optionally substituted with one to three substituents selected from hydroxyl and halogen; R6 is hydrogen, cyano, halogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted C2-C6 heterocycloalkyl; and R7 is hydrogen, cyano, halogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxyl, or optionally substituted C1-C6 heteroalkyl. 10. The radiopharmaceutical conjugate of any one of claims 1-4 or 6-9, wherein: E is or . 11. The radiopharmaceutical conjugate of any one of claims 1-4 or 6-10, wherein ring Q1 is a 6 membered monocyclic ring optionally substituted with one to three R18, wherein R18 is methyl, -CH2CN, oxo, hydroxyl, carboxyl, C(O)OR15. 12. The radiopharmaceutical conjugate of any one of claims 1-4 or 6-11, wherein the targeting ligand comprises a structure of Formula (IIIa), or a salt or solvate thereof, Formula (IIIa), wherein each R18 is independently halogen, oxo, C1-C6 alkyl, C1-C6 aminoalkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, -CN, -C(O)OR15, -C(O)N(R15)(R15’), -N(R15)(R15’), or OR15, and wherein each of the alkyl, aminoalkyl, haloalkyl, alkenyl, alkynyl, or heteroalkyl is optionally substituted with one, two, or three groups selected from halogen, -CN, -NO2, amino, hydroxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, and C2-C5 heterocycloalkyl; and m1 is 0, 1, 2, or 3. 13. The radiopharmaceutical conjugate of any one of claims 1-4 or 6-12, wherein R14 is phenyl, naphthyl, or monocyclic or bicyclic heteroaryl, each optionally substituted with one or more R16, wherein each R16 is independently halogen, -CN, -N(R10)(R10’), -OR10, oxo, -C(O)OR10, - C(O)N(R10)(R10’), -SR10, -OC(=O)R11, -S(O)R11, S(O)2R11, -S(O)2N(R10)(R10’), C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 fluoroalkyl, C1-C6heteroalkyl, C1-C6alkoxy, C1-C6 fluoroalkoxy, C2- C6 heterocycloalkyl, C6-C10 aryl, or C1-C9 heteroaryl, wherein each of the alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one, two, three, or four groups independently selected from halogen, oxo, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkyloxy, C1-C6 haloalkoxy, C3-C10 cycloalkyl, C2-C9 heterocycloalkyl, C6-C10 aryl, C1-C9 heteroaryl, -OR10, - SR10, -N(R10)(R10’), -C(O)OR10, -OC(O)N(R10)(R10’), -N(R10’)C(O)N(R10)(R10’), - N(R10’)C(O)OR11, -N(R10’)S(O)2R11, -C(O)R11, -S(O)R11, -OC(O)R11, -C(O)N(R10)(R10’), - C(O)C(O)N(R10)(R10’), -N(R10’)C(O)R11, -S(O)2R11, -S(O)2N(R10)(R10’)-, S(=O)(=NH)N(R10)(R10’), -CH2C(O)N(R10)(R10’), -CH2N(R10’)C(O)R11, -CH2S(O)2R11, and - CH2S(O)2N(R10)(R10’). 14. The radiopharmaceutical conjugate of any one of claims 1-13, wherein each R16 is independently oxo, halogen, -CN, -NH2, -NH(CH3), -N(CH3)2, -OH, -CO2H, - C(=O)OC1-C4 alkyl, -OC(=O)C1-C4 alkyl, -C(=O)NH2, -C(=O)NH(C1-C4 alkyl), -C(=O)N(C1- C4 alkyl)2, -S(=O)2NH2, -S(=O)2NH(C1-C4 alkyl), -S(=O)2N(C1-C4 alkyl)2, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 fluoroalkyl, C1-C6 heteroalkyl, C1-C4 alkoxy, C1-C4 fluoroalkoxy, -S-C1-4 alkyl, -S(=O)C1-4 alkyl, or -S(=O)2(C1-C4 alkyl). 15. The radiopharmaceutical conjugate of any one claims 1-4 or 6-14, wherein R14 is naphthyl optionally substituted with one or more R16, wherein each R16 is independently halogen, hydroxyl, C1-C3 alkyl, alkoxy, haloalkyl, amino, or cyano. 16. The radiopharmaceutical conjugate of any one claims 1-15, wherein R16 is halogen and the halogen is the radionuclide selected from fluorine-18 (18F), iodine-131 (131I), iodine-123 (123I), iodine-124 (124I), iodine-125 (125I), and astatine-211 (211At). 17. The radiopharmaceutical conjugate of any one of claims 1-4 or 6-15, wherein R14 comprises the radionuclide and the radionuclide is a covalently bonded, wherein the radionuclide is selected from fluorine-18 (18F), iodine-131 (131I), iodine-123 (123I), iodine-124 (124I), iodine-125 (125I), and astatine-211 (211At). 18. The radiopharmaceutical conjugate of any one of claims 1-4 or 6-17, wherein 19. The radiopharmaceutical conjugate of any one of claims 1-4 or 6-18, wherein L3 is C1-C4 alkylene or C1-C4 heteroalkylene, each of which is optionally substituted with one or more R19. 20. The radiopharmaceutical conjugate of any one of claims 1-4 or 6-19, wherein X is C(=O); L1 is a bond; L2 is a bond, O, S or NR15; and L3 is -CH2-. 21. The radiopharmaceutical conjugate of any one of claims 1-4 or 6-20, wherein m is 0 or 1; and each R13 is independently OH, halogen, or C1-C3 alkyl. 22. The radiopharmaceutical conjugate of any one of claims 1-21, wherein the radiopharmaceutical conjugate has a structure of , , , 23. The radiopharmaceutical conjugate of any one of claims 1-22, wherein the targeting ligand is configured to form a covalent bond with a KRAS protein at the G12C position, wherein residue position numbering of the KRAS protein is based on SEQ ID NO:1 or SEQ ID NO:2. 24. A radiopharmaceutical conjugate comprising: (a) a targeting ligand that is configured to form a covalent bond with a KRAS protein at the G12C position, wherein residue position numbering of the KRAS protein is based on SEQ ID NO:1 or SEQ ID NO: 2; comprising a structure of Formula (IV), or a salt or solvate thereof, Formula (IV) wherein E1 and E2 are each independently N or CR21; E3 is CR28R29, C=CR28R29, C═O, C=S, or C=NR28; J is N, NR30, or CR30; M is N, NR33, or CR33; is a single or double bond as necessary to give every atom its normal valence; R21 is independently hydrogen, hydroxyl, cyano, halogen, C1-C6 alkyl, C1-C6 alkoxyl, or C1-C6 heteroalkyl, wherein each of the alkyl, alkoxy, and heteroalkyl are optionally substituted; R22 is hydrogen, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, OR22’, N(R22’)2, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each of the alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted, and each R22’ is independently hydrogen, C1-C6 alkyl, cycloalkyl, heterocycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, aryl, or heteroaryl, wherein each of the alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, and heteroaryl is optionally substituted, or two R22’ together with the nitrogen atom to which they are attached, form a 3-7-membered ring; R23 is hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, wherein each of the alkyl, alkoxy, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, and heteroaryl is optionally substituted; ring A is an optionally substituted 4-7 membered monocyclic ring or optionally substituted 6-11 membered bicyclic, bridged, fused, or spiro ring; R1 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted C2-C5 heterocycloalkyl; L is a bond, C1-C6 alkylene, C1-C6 heteroalkylene, S, O, or NH; E represents a structure of Formula , wherein, X is C(=O), P(=O)OR2, C(=S), or S(=O)n, where n is 1 or 2; R2 is hydrogen or optionally substituted C1-C3 alkyl; R5 is hydrogen, cyano, halogen, C1-C6 alkyl, C1-C6 alkoxyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, or C2-C5 heterocycloalkyl, each of the alkyl, alkoxyl, heteroalkyl, cycloalkyl or heterocycloalkyl is optionally substituted, and R7 is hydrogen, cyano, halogen, C1-C6 alkyl, C1-C6 alkoxyl, C1-C6 heteroalkyl, C3-C7 cycloalkyl, C2-C7 heterocycloalkyl, heteroaryl, -C1-C6alkylene-heteoraryl, -C1-C6alkylene-NH(C1-C6 alkyl), or -C1-C6alkylene-N(C1-C6 alkyl)2, each of the alkyl, alkylene, alkoxyl, heteroalkyl, cycloalkyl, heterocycloalkyl, or heteroaryl is optionally substituted; or R5 and R7 taken together form a bond; or R5 and R7 taken together with the carbon atoms to which they are attached form a 5-8 membered partially saturated cycloalkyl, wherein the cycloalkyl is optionally substituted; R6 is hydrogen, cyano, halogen, C1-C6 alkyl, C1-C6 alkoxyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, heteroaryl, -C1-C6alkylene-heteoraryl, -C1-C6alkylene-NH(C1-C6 alkyl), or -C1-C6alkylene-N(C1-C6 alkyl)2, each of the alkyl, alkylene, alkoxyl, heteroalkyl, cycloalkyl, heterocycloalkyl, or heteroaryl is optionally substituted; R28 and R29 are each independently hydrogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, cyano, nitro, or C3-C6 cycloalkyl, or R28 and R29 taken together with the carbon atom to which they are attached form a 3-6 membered ring; R30 is selected from halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -C1-C6alkylene-cycloalkyl, -C1-C6alkylene- heterocycloalkyl, -C1-C6alkylene-aryl, -C1-C6alkylene-heteroaryl, -C1-C6heteroalkylene- cycloalkyl, -C1-C6heteroalkylene-heterocycloalkyl, -C1-C6heteroalkylene-aryl, -C1- C6alkylene-heteroaryl wherein each of the alkyl, alkoxy, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted; R33 is hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, or C3-C6 cycloalkyl, wherein each of the alkyl, heteroalkyl, and cycloalkyl is optionally substituted; and (b) a radionuclide. 25. The radiopharmaceutical conjugate of claim 24, wherein E1 and E2 are each independently N or CR21; E3 is CR28R29, C=CR28R29, C═O, C=S, or C=NR28; J is N, NR30, or CR30; M is N, NR33, or CR33; is a single or double bond as necessary to give every atom its normal valence; R21 is independently hydrogen, hydroxyl, cyano, halogen, C1-C6 alkyl, C1-C6 alkoxyl, or C1-C6 heteroalkyl, wherein each of the alkyl, alkoxy, and heteroalkyl is optionally substituted with one, two, or three groups selected from halogen, -CN, -NO2, amino, hydroxy, C1-C6 alkyl, C1- C6 haloalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, C6-C10 aryl, and C1-C9 heteroaryl; R22 is hydrogen, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, OR22’, N(R22’)2, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each of the alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three groups selected from halogen, -CN, -NO2, amino, hydroxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, and C2-C5 heterocycloalkyl, and each R22’ is independently hydrogen, C1-C6 alkyl, cycloalkyl, heterocycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, aryl, or heteroaryl, wherein each of the alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, and heteroaryl is optionally substituted with one, two, or three groups selected from halogen, -CN, -NO2, amino, hydroxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, C6-C10 aryl, and C1-C9 heteroaryl; or two R22’ together with the nitrogen atom to which they are attached, form an optionally substituted 3-7- membered ring with one, two, or three groups selected from halogen, -CN, -NO2, amino, hydroxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, C6-C10 aryl, and C1-C9 heteroaryl; R23 is hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, wherein each of the alkyl, alkoxy, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, and heteroaryl is optionally substituted with one, two, or three groups selected from halogen, -CN, -NO2, amino, hydroxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, C6-C10 aryl, and C1-C9 heteroaryl; R24 is ring A is an optionally substituted 4-7 membered monocyclic ring or optionally substituted 6-11 membered bicyclic, bridged, fused, or spiro ring each of which is optionally substituted with one, two, or three groups selected from halogen, -CN, -NO2, amino, hydroxy, C1-C6 alkyl, C1- C6 haloalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, C6-C10 aryl, and C1-C9 heteroaryl; R1 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted C2-C5 heterocycloalkyl each of which is optionally substituted with one, two, or three groups selected from halogen, -CN, - NO2, amino, hydroxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, C6-C10 aryl, and C1-C9 heteroaryl; L is a bond, C1-C6 alkylene, C1-C6 heteroalkylene, S, O, or NH; E represents a structure of Formula (Ic), wherein, X is C(=O), P(=O)OR2, C(=S), or S(=O)n, where n is 1 or 2; R2 is hydrogen or substituted or unsubstituted C1-C3 alkyl, wherein the alkyl is optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C3-C6 cycloalkyl, and C2-C5 heterocycloalkyl, C6-C10 aryl, and C1-C9 heteroaryl; R5 is hydrogen, cyano, halogen, C1-C6 alkyl, C1-C6 alkoxyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, or C2-C5 heterocycloalkyl, each of the alkyl, alkoxyl, heteroalkyl, cycloalkyl or heterocycloalkyl is optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, C6-C10 aryl, and C1-C9 heteroaryl; R7 is hydrogen, cyano, halogen, C1-C6 alkyl, C1-C6 alkoxyl, C1-C6 heteroalkyl, C3-C7 cycloalkyl, C2-C7 heterocycloalkyl, heteroaryl, -C1-C6alkylene-heteoraryl, -C1-C6alkylene-NH(C1-C6 alkyl), or -C1-C6alkylene-N(C1-C6 alkyl)2, each of the alkyl, alkylene, alkoxyl, heteroalkyl, cycloalkyl or heterocycloalkyl is optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, C6-C10 aryl, and C1-C9 heteroaryl; or R5 and R7 taken together form a bond; or R5 and R7 taken together with the carbon atoms to which they are attached form a 5-8 membered partially saturated cycloalkyl, wherein the cycloalkyl is optionally substituted with one, two or three groups selected from R17; R6 is hydrogen, cyano, halogen, C1-C6 alkyl, C1-C6 alkoxyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, heteroaryl, -C1-C6alkylene-heteoraryl, -C1-C6alkylene-NH(C1-C6 alkyl), or -C1-C6alkylene-N(C1-C6 alkyl)2, each of the alkyl, alkylene, alkoxyl, heteroalkyl, cycloalkyl, heterocycloalkyl, or heteroaryl is optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3- C6 cycloalkyl, C2-C5 heterocycloalkyl, C6-C10 aryl, and C1-C9 heteroaryl; each R17 is independently halogen, hydroxyl, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, amino, cyano, C1-C6 heteroalkyl, C1-C6 hydroxyalkyl, -O-C1-C6haloalkyl, or -S-C1- C6haloalkyl; R28 and R29 are each independently hydrogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, cyano, nitro, or C3-C6 cycloalkyl, or R28 and R29 taken together with the carbon atom to which they are attached form a 3-6 membered ring; R30 is selected from halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -C1-C6alkylene-cycloalkyl, -C1-C6alkylene- heterocycloalkyl, -C1-C6alkylene-aryl, -C1-C6alkylene-heteroaryl, -C1-C6heteroalkylene- cycloalkyl, -C1-C6heteroalkylene-heterocycloalkyl, -C1-C6heteroalkylene-aryl, -C1- C6alkylene-heteroaryl wherein each of the alkyl, alkoxy, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, C6-C10 aryl, and C1-C9 heteroaryl; and R33 is hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, or C3-C6 cycloalkyl, wherein each of the alkyl, heteroalkyl, and cycloalkyl is optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, C6-C10 aryl, and C1-C9 heteroaryl. 26. The radiopharmaceutical conjugate of claim 24 or claim 25, wherein the radionuclide is covalently bound to the structure of Formula (IV). 27. The radiopharmaceutical conjugate of any one of claims 24-26, wherein at least one of R21, R22, R23, R24, and R30 comprises the radionuclide. 28. The radiopharmaceutical conjugate of any one of claims 24-27, wherein the radionuclide is fluorine-18 (18F), iodine-131 (131I), iodine-123 (123I), iodine-124 (124I), iodine-125 (125I), or astatine-211 (211At). 29. The radiopharmaceutical conjugate of any one of claims 24-28, wherein the radioisotope is iodine-131 (131I). 30. The radiopharmaceutical conjugate of any one of claims 24-29, wherein R24 is 31. The radiopharmaceutical conjugate of any one of claims 24-30, wherein E3 is C=O; J is NR30; M is N, NR33, or CR33; and R33 is hydrogen or C1-C6 alkyl. 32. The radiopharmaceutical conjugate of any one of claims 24-31, wherein the targeting ligand comprises a structure of Formula (IVa), or a salt or solvate thereof, Formula (IVa). 33. The radiopharmaceutical conjugate of any one of claims 24-32, wherein the targeting ligand comprises a structure of Formula (IVb) or Formula (IVc), or a salt or solvate thereof, Formula (IVb) Formula (IVc). 34. The radiopharmaceutical conjugate of any one of claims 24-33, wherein each R21 is independently hydrogen, hydroxyl, cyano, halogen, C1-C6alkyl, C1-C4haloalkyl, C1- C4alkoxyl, or C1-C4heteroalkyl; R22 is halogen, C1-C6alkyl, C2-C3alkenyl, C2-C3alkynyl, OR22’, N(R22’)2, C3-C6cycloalkyl, C2- C5heterocycloalkyl, C6-C14aryl, or C2-C14heteroaryl, each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted, and each R22’ is independently hydrogen, C1-C6alkyl, C3-C6cycloalkyl, C2-C5heterocycloalkyl, C2-C3alkenyl, C2-C3alkynyl, C6-C14aryl, C2-C14heteroaryl, wherein each of the alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, and heteroaryl is optionally substituted, or two R22’ together with the nitrogen atom to which they are attached, form an optionally substituted 3- 7-membered ring; and R23 is hydrogen, halogen, C1-C6alkyl, C1-C3alkoxy, C3-C6cycloalkyl, C2-C5heterocycloalkyl, C2- C3alkenyl, C2-C3alkynyl, C6-C14aryl, or C2-C14heteroaryl, wherein each of the alkyl, alkoxy, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, and heteroaryl is optionally substituted; and R30 is halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each of the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted. 35. The radiopharmaceutical conjugate of any one of claims 24-34, wherein R21 is hydrogen; R22 is C6-C14aryl or C2-C14heteroaryl, each of which is optionally substituted; and R23 is halogen, C1-C3alkyl, C1-C3haloalkyl; and R30 is C6-C14aryl or C2-C14heteroaryl, each of which is optionally substituted with one or more substituents selected from halogen, C1-C3alkyl, C1-C3alkoxyl, or cyano. 36. The radiopharmaceutical conjugate of any one of claims 24-35 wherein R22 is phenyl, optionally substituted with one or more substituents selected from C1-C3alkyl, halogen, and hydroxyl; or R22 is bicyclic heteroaryl, optionally substituted with one or more substituents selected from C1- C3alkyl, halogen, and hydroxyl. 37. The radiopharmaceutical conjugate of any one of claims 24-36, wherein ring A is piperazinyl substituted with one to three substituents selected from halogen and C1- C3alkyl; L is a bond, C1-C3alkylene, S, O, or NH; and X is C(=O). 38. The radiopharmaceutical conjugate of any one of claims 24-37, wherein L is a bond. 39. The radiopharmaceutical conjugate of any one of claims 24-38, wherein R5 is hydrogen, halogen, or a C1-C3alkyl optionally substituted by one or more hydroxyl and/or halogen; R6 is hydrogen, cyano, halogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted C2-C6 heterocycloalkyl; and R7 is hydrogen, cyano, halogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxyl, or optionally substituted C1-C6 heteroalkyl. 40. The radiopharmaceutical conjugate of any one of claims 24-39, wherein E is 41. The radiopharmaceutical conjugate of any one of claims 24-40, wherein R30 is phenyl or 6-membered heteroaryl, optionally substituted with one or more of C1-C3alkyl. 42. The radiopharmaceutical conjugate any one of claims 24-41, wherein R22 comprises the radionuclide. 43. The radiopharmaceutical conjugate of claim 42, wherein R22 is ; and R* is fluorine-18 (18F), iodine-131 (131I), iodine-123 (123I), iodine-124 (124I), iodine-125 (125I), or astatine-211 (211At). 44. The radiopharmaceutical conjugate of any one of claims 24-43, wherein the radiopharmaceutical conjugate has a structure of or 45. The radiopharmaceutical conjugate of any one of claims 24-41, wherein R23 comprises the radionuclide; and R23 is halogen and the halogen is the radionuclide selected from fluorine-18 (18F), iodine-131 (131I), iodine-123 (123I), iodine-124 (124I), iodine-125 (125I), and astatine-211 (211At). 46. The radiopharmaceutical conjugate of claim 45, wherein R23 is 131I. 47. The radiopharmaceutical conjugate of any one of claims 24-41, 45,or 46, wherein the radiopharmaceutical conjugate has a structure of , 48. The radiopharmaceutical conjugate of any one of claims 1-6, 9-15, 19-21, or 24-42, wherein the radiopharmaceutical conjugate further comprises: a linker covalently bonded to the radionuclide and to the radiolabeled compound, or a salt or solvate thereof. 49. The radiopharmaceutical conjugate of claim 48, wherein the linker is a brush border enzyme- cleavable linker, a hepatocyte-cleavable linker, a cytochrome P450-substrate, an esterase- cleavable linker, or a peptidase-cleavable linker. 50. A radiolabeled compound comprising a structure of Formula (IIIb), or a salt or solvate thereof, Formula (IIIb), wherein LC is a linker comprising 1 to 20 groups independently selected from -CRbRb-, -C(=O)-, -S(=O)-, -C(=O)NRa-, -NRaC(=O)-, -S(=O)2NRa-, -NRaS(=O)2-, -NRaC(=O)NRa-, - NRaC(=O)O-, - OC(=O)NRa-, arylene, and heteroarylene; each Ra is independently hydrogen, halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C8cycloalkyl, C2- C9heterocycloalkyl, aryl, or heteroaryl; each Rb is independently hydrogen, halogen, -CN, -NO2, -ORa, -SRa, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, C3- C8cycloalkyl, C2-C9heterocycloalkyl, aryl, or heteroaryl; L1 is a bond, -C(=O)-, or optionally substituted C1-C3 alkylene, wherein the alkylene is optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, and C2-C5 heterocycloalkyl; L2 is a bond, -C(=O)-, O, S or NR15; X is C(=O), P(=O)OR2, C(=S), or S(=O)n, where n is 1 or 2; R2 is hydrogen or substituted or unsubstituted C1-C3 alkyl, wherein the alkyl is optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C3-C6 cycloalkyl, and C2-C5 heterocycloalkyl; R5 is hydrogen, cyano, halogen, C1-C6 alkyl, C1-C6 alkoxyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, or C2-C5 heterocycloalkyl, each of the alkyl, alkoxyl, heteroalkyl, cycloalkyl or heterocycloalkyl is optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, and C2- C5 heterocycloalkyl; R7 is hydrogen, cyano, halogen, C1-C6 alkyl, C1-C6 alkoxyl, C1-C6 heteroalkyl, C3-C7 cycloalkyl, C2-C7 heterocycloalkyl, or C1-C9 heteroaryl, wherein each of the alkyl, alkoxyl, heteroalkyl, cycloalkyl or heterocycloalkyl is optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, and C2-C5 heterocycloalkyl; or R5 and R7 taken together form a bond; or R5 and R7 taken together with the carbon atoms to which they are attached form a 5-8 membered partially saturated cycloalkyl, wherein the cycloalkyl is optionally substituted with one, two or three groups selected from R17; R6 is hydrogen, cyano, halogen, C1-C6 alkyl, C1-C6 alkoxyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, C2-C6 heterocycloalkyl, or C1-C9 heteroaryl, wherein, each of the alkyl, alkoxyl, heteroalkyl, cycloalkyl, heterocycloalkyl, or heteroaryl is optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3- C6 cycloalkyl, and C2-C5 heterocycloalkyl; R12 is C1-C6 alkyl, C1-C6 heteroalkyl, -L3-NR15R15’, C2-C12heterocycloalkyl, -L3- C2- C12heterocycloalkyl, C3-C15cycloalkyl, -L3- C3-C15cycloalkyl, aryl, C1-C9 heteroaryl, -L3-aryl, or -L3- C1-C9 heteroaryl, wherein each of the heterocycloalkyl, cycloalkyl, aryl, heteroaryl, alkyl or heteroalkyl is optionally substituted with one, two, three or four groups selected from R19; L3 is C1-C4 alkylene or C1-C4 heteroalkylene, each of which is optionally substituted with one, two, or three groups selected from R19; each R13 is independently OH, halogen, oxo, substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C1-C6 heteroalkyl, wherein each of the alkyl and heteroalkyl is optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, and C2-C5 heterocycloalkyl; R14 is hydrogen, C3-C15cycloalkyl, C2-C12heterocycloalkyl, aryl, or C1-C9 heteroaryl, wherein each of the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, three or four groups selected from R16; each R15 is independently hydrogen or C1-C3 alkyl; each R15’ is independently hydrogen, acyl, C1-C3 alkyl, C1-C3 heteroalkyl or C1-C3 hydroxyalkyl; m is 0, 1, or 2; each R17 is independently halogen, hydroxyl, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, amino, cyano, C1-C6 heteroalkyl, C1-C6 hydroxyalkyl, -O-C1-C6haloalkyl, or -S-C1- C6haloalkyl; each R18 is independently halogen, oxo, C1-C6 alkyl, C1-C6 aminoalkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, -CN, -C(O)OR15, -C(O)N(R15)(R15’), -N(R15)(R15’), or OR15, and wherein each of the alkyl, aminoalkyl, haloalkyl, alkenyl, alkynyl, or heteroalkyl is optionally substituted with one, two, or three groups selected from halogen, -CN, -NO2, amino, hydroxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, and C2-C5 heterocycloalkyl; m1 is 0, 1, 2, or 3; R16 and R19 are each independently selected from halogen, oxo, -CN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C3-C10 cycloalkyl, -C1-3alkylene-C3-6cycloalkyl, C2-C9 heterocycloalkyl, -C1-3alkylene-C2-9heterocycloalkyl, C6-C10 aryl, -C1-3alkylene-C6-10aryl, C1- C9 heteroaryl, -C1-3alkylene-C1-9 heteroaryl, -OR10, -SR10, -N(R10)(R10’), -C(=O)OR10, - OC(=O)N(R10)(R10’), -N(R10’)C(=O)N(R10)(R10’), -N(R10’)C(=O)OR11, -N(R10’)S(=O)2R11, - C(=O)R11, -S(=O)R11, -OC(=O)R11, -C(=O)N(R10)(R10’), -C(=O)C(=O)N(R10)(R10’), - N(R10’)C(O)R11, -S(O)2R11, -S(O)2N(R10)(R10’), -S(=O)(=NH)N(R10)(R10’), - CH2C(O)N(R10)(R10’), -CH2N(R10’)C(=O)R11, -CH2S(=O)2R11, and -CH2S(=O)2N(R10)(R10’), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, -C1-3alkylene-C3-6cycloalkyl, heterocycloalkyl, -C1-3alkylene-C2-C9heterocycloalkyl, aryl, -C1-3alkylene-C6-10aryl, heteroaryl and -C1- 3alkylene-C1-9 heteroaryl are optionally substituted with one, two, three, or four groups independently selected from halogen, oxo, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkyloxy, C1-C6 haloalkoxy, C3-C10 cycloalkyl, C2-C9 heterocycloalkyl, C6-C10 aryl, C1- C9 heteroaryl, -OR10, -SR10, -N(R10)(R10’), -C(=O)OR10, -OC(=O)N(R10)(R10’), - N(R10’)C(=O)N(R10)(R10’), -N(R10’)C(=O)OR11, -N(R10’)S(=O)2R11, -C(=O)R11, -S(O)R11, - OC(=O)R11, -C(=O)N(R10)(R10’), -C(=O)C(=O)N(R10)(R10’), -N(R10’)C(=O)R11, -S(=O)2R11, - S(=O)2N(R10)(R10’)-, S(=O)(=NH)N(R10)(R10’), -CH2C(=O)N(R10)(R10’), - CH2N(R10’)C(=O)R11, -CH2S(=O)2R11, and -CH2S(=O)2N(R10)(R10’); each R10 is independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C2-9heterocycloalkyl, C6-C10 aryl, and C1-C9 heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C2-C9 heterocycloalkyl, C6-C10 aryl, and C1-C9 heteroaryl; each R10’ is independently selected from hydrogen, C1-C6 alkyl, and C1-C6 haloalkyl; and each R11 is independently selected C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C2-C9 heterocycloalkyl, C6-C10 aryl, and C1-C9 heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C2-C9 heterocycloalkyl, C6-C10 aryl, and C1-C9 heteroaryl; and R* is fluorine-18 (18F), iodine-131 (131I), iodine-123 (123I), iodine-124 (124I), iodine-125 (125I), or astatine-211 (211At). 51. The radiolabeled compound of claim 50, or a salt or solvate thereof, wherein the radiolabeled compound comprises a structure of Formula (IIIc): Formula (IIIc). 52. A radiolabeled compound comprising a structure of Formula (IVd), or a salt or solvate thereof, Formula (IVd). wherein LC is a linker comprising 1 to 20 groups independently selected from -CRbRb-, -C(=O)-, -S(=O)-, -C(=O)NRa-, -NRaC(=O)-, -S(=O)2NRa-, -NRaS(=O)2-, -NRaC(=O)NRa-, - NRaC(=O)O-, - OC(=O)NRa-, arylene, and heteroarylene; each Ra is independently hydrogen, halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C8cycloalkyl, C2- C9heterocycloalkyl, aryl, or heteroaryl; each Rb is independently hydrogen, halogen, -CN, -NO2, -ORa, -SRa, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, C3- C8cycloalkyl, C2-C9heterocycloalkyl, aryl, or heteroaryl; R21 is independently hydrogen, hydroxyl, cyano, halogen, C1-C6 alkyl, C1-C6 alkoxyl, or C1-C6 heteroalkyl, wherein each of the alkyl, alkoxy, and heteroalkyl is optionally substituted with one, two, or three groups selected from halogen, -CN, -NO2, amino, hydroxy, C1-C6 alkyl, C1- C6 haloalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, C6-C10 aryl, and C1-C9 heteroaryl; R22 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, OR22’, N(R22’)2, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each of the alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three groups selected from halogen, -CN, -NO2, amino, hydroxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, and C2-C5 heterocycloalkyl, and each R22’ is independently hydrogen, C1-C6 alkyl, cycloalkyl, heterocycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, aryl, or heteroaryl, wherein each of the alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, and heteroaryl is optionally substituted with one, two, or three groups selected from halogen, -CN, -NO2, amino, hydroxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, C6-C10 aryl, and C1-C9 heteroaryl; or two R22’ together with the nitrogen atom to which they are attached, form an optionally substituted 3-7-membered ring with one, two, or three groups selected from halogen, -CN, -NO2, amino, hydroxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, C6-C10 aryl, and C1-C9 heteroaryl; R23 is hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, wherein each of the alkyl, alkoxy, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, and heteroaryl is optionally substituted with one, two, or three groups selected from halogen, -CN, -NO2, amino, hydroxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, C6-C10 aryl, and C1-C9 heteroaryl; ring A is an optionally substituted 4-7 membered monocyclic ring or optionally substituted 6-11 membered bicyclic, bridged, fused, or spiro ring each of which is optionally substituted with one, two, or three groups selected from halogen, -CN, -NO2, amino, hydroxy, C1-C6 alkyl, C1- C6 haloalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, C6-C10 aryl, and C1-C9 heteroaryl; L is a bond, C1-C6 alkylene, C1-C6 heteroalkylene, S, O, or NH; E represents a structure of Formula (Ic), wherein, X is C(=O), P(=O)OR2, C(=S), or S(=O)n, where n is 1 or 2; R2 is hydrogen or substituted or unsubstituted C1-C3 alkyl, wherein the alkyl is optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C3-C6 cycloalkyl, and C2-C5 heterocycloalkyl, C6-C10 aryl, and C1-C9 heteroaryl; R5 is hydrogen, cyano, halogen, C1-C6 alkyl, C1-C6 alkoxyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, or C2-C5 heterocycloalkyl, each of the alkyl, alkoxyl, heteroalkyl, cycloalkyl or heterocycloalkyl is optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, C6-C10 aryl, and C1-C9 heteroaryl; R7 is hydrogen, cyano, halogen, C1-C6 alkyl, C1-C6 alkoxyl, C1-C6 heteroalkyl, C3-C7 cycloalkyl, C2-C7 heterocycloalkyl, heteroaryl, -C1-C6alkylene-heteoraryl, -C1-C6alkylene-NH(C1-C6 alkyl), or -C1-C6alkylene-N(C1-C6 alkyl)2, each of the alkyl, alkylene, alkoxyl, heteroalkyl, cycloalkyl or heterocycloalkyl is optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, C6-C10 aryl, and C1-C9 heteroaryl; or R5 and R7 taken together form a bond; or R5 and R7 taken together with the carbon atoms to which they are attached form a 5-8 membered partially saturated cycloalkyl, wherein the cycloalkyl is optionally substituted with one, two or three groups selected from R17; R6 is hydrogen, cyano, halogen, C1-C6 alkyl, C1-C6 alkoxyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, heteroaryl, -C1-C6alkylene-heteoraryl, -C1-C6alkylene-NH(C1-C6 alkyl), or -C1-C6alkylene-N(C1-C6 alkyl)2, each of the alkyl, alkylene, alkoxyl, heteroalkyl, cycloalkyl, heterocycloalkyl, or heteroaryl is optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3- C6 cycloalkyl, C2-C5 heterocycloalkyl, C6-C10 aryl, and C1-C9 heteroaryl; each R17 is independently halogen, hydroxyl, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, amino, cyano, C1-C6 heteroalkyl, C1-C6 hydroxyalkyl, -O-C1-C6haloalkyl, or -S-C1- C6haloalkyl; and R* is fluorine-18 (18F), iodine-131 (131I), iodine-123 (123I), iodine-124 (124I), iodine-125 (125I), or astatine-211 (211At). 53. The radiolabeled compound of claim 52, wherein the radiolabeled compound comprises a structure of Formula (IVe), Formula (IVe). 54. The radiolabeled compound of any one of claims 50-53, wherein integer selected from 1 to 10. 55. The radiolabeled compound of claim 54, wherein each k1 and k2 is independently 0 or an integer selected from 1 to 5. 56. The radiolabeled compound of any one of claims 50-55, wherein , , , 57. The radiolabeled compound of any one of claims 50, 51, or 54-56, wherein the radiolabeled compound is: . 58. The radiolabeled compound of any one of claims 52, 53, or 54-56, wherein the radiolabeled compound is: , , , 59. The radiolabeled compound of claim 1 or 24, further comprising: (a) a linker; and (b) a metal chelator. 60. A conjugate having a structure of Formula (X): TL- LK1-LK2-LK3-CHL Formula (X) wherein, TL represents a targeting ligand; CHL represents a metal chelator, optionally bound to a radionuclide; and each of LK1, LK2, and LK3 independently selected from substituted or unsubstituted C1-C12 alkylene, substituted or unsubstituted C1-C12 heteroalkylene, substituted or unsubstituted C2- C12 alkenylene, substituted or unsubstituted C2-C12 alkynylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, -(CH2CH2O)q-, - (OCH2CH2)q-, -O-, -S-, -S(=O)-, -S(=O)2-, -S(=O)(=NRLK)-, -C(=O)-, -C(=N-ORLK)-, - C(=O)O-, -OC(=O)-, -C(=O)C(=O)-, -C(=O)NRLK-, -NRLKC(=O)-, -OC(=O)NRLK-, -NRLKC (=O)O-, -NRLKC(=O)NRLK-, -C(=O)NRLKC(=O)-, -S(=O)2NRLK-, -NRLKS(=O)2-, -NRLK-, - N(ORLK)-, and a bond; each RLK is independently hydrogen or substituted or unsubstituted C1-C6 alkyl; and q is an integer selected from 1 to 10. 61. The conjugate of claim 60, wherein LK1 is substituted or unsubstituted C1-C12 alkylene or substituted or unsubstituted C1-C12 heteroalkylene. 62. The conjugate of claim 60 or 61, wherein each of LK2 and LK3 is independently a bond, C1-C6 alkylene, C1-C6 heteroalkylene, - (CH2CH2O)1-3-, -(OCH2CH2)1-3-, -O-, or -S-. 63. The conjugate of any one of claims 60-62, wherein the conjugate of Formula (X) has the structure of Formula (X-III) wherein ring Q1 is a 4-12 membered saturated or partially saturated monocyclic or bicyclic ring, wherein the monocyclic or bicyclic ring is optionally substituted; L1 is a bond, -C(=O)-, or optionally substituted C1-C3 alkylene; L2 is a bond, -C(=O)-, O, S or NR15; X is C(=O), P(=O)OR2, C(=S), or S(=O)n, where n is 1 or 2; R2 is hydrogen or optionally substituted C1-C3 alkyl; R5 is hydrogen, cyano, halogen, C1-C6 alkyl, C1-C6 alkoxyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, or C2-C5 heterocycloalkyl, each of the alkyl, alkoxyl, heteroalkyl, cycloalkyl or heterocycloalkyl is optionally substituted, and R7 is hydrogen, cyano, halogen, C1-C6 alkyl, C1-C6 alkoxyl, C1-C6 heteroalkyl, C3-C7 cycloalkyl, C2-C7 heterocycloalkyl, C1-C9 heteroaryl, -C1-C6alkylene-heteoraryl, -C1-C6alkylene-NH(C1- C6 alkyl), or -C1-C6alkylene-N(C1-C6 alkyl)2, each of the alkyl, alkylene, alkoxyl, heteroalkyl, cycloalkyl or heterocycloalkyl is optionally substituted; or R5 and R7 taken together form a bond; or R5 and R7 taken together with the carbon atoms to which they are attached form a 5-8 membered partially saturated cycloalkyl, wherein the cycloalkyl is optionally substituted; R6 is hydrogen, cyano, halogen, C1-C6 alkyl, C1-C6 alkoxyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, C2-C6 heterocycloalkyl, C1-C9 heteroaryl, -C1-C6alkylene- C1-C9 heteroaryl, -C1-C6alkylene- NH(C1-C6 alkyl), or -C1-C6alkylene-N(C1-C6 alkyl)2, each of the alkyl, alkylene, alkoxyl, heteroalkyl, cycloalkyl, heterocycloalkyl, or heteroaryl is optionally substituted; R12 is hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, -L3-NR15R15’, C2-C12 heterocycloalkyl, -L3-C2- C12 heterocycloalkyl, C3-C10 cycloalkyl, -L3- C3-C10cycloalkyl, aryl, C1-C9 heteroaryl, -L3- aryl, or -L3- C1-C9 heteroaryl, wherein each of the heterocycloalkyl, cycloalkyl, aryl, heteroaryl, alkyl or heteroalkyl is optionally substituted; L3 is C1-C4 alkylene or C1-C4 heteroalkylene, each of which is optionally substituted; each R13 is independently OH, halogen, oxo, substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C1-C6 heteroalkyl; R14 is hydrogen, C3-C10cycloalkyl, C2-C12 heterocycloalkyl, aryl, or C1-C9 heteroaryl, wherein each of the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted; each R15 is independently hydrogen or C1-C3 alkyl; each R15’ is independently hydrogen, acyl, C1-C3 alkyl, C1-C3 heteroalkyl or C1-C3 hydroxyalkyl; and m is 0, 1, or 2. 64. The conjugate of any one of claims 60-62, wherein the conjugate of Formula (X) has the structure of Formula (X-IV) E1 and E2 are each independently N or CR21; E3 is CR28R29, C=CR28R29, C═O, C=S, or C=NR28; J is N, NR30, or CR30; M is N, NR33, or CR33; is a single or double bond as necessary to give every atom its normal valence; R21 is independently hydrogen, hydroxyl, cyano, halogen, C1-C6 alkyl, C1-C6 alkoxyl, or C1-C6 heteroalkyl, wherein each of the alkyl, alkoxy, and heteroalkyl are optionally substituted; R22 is hydrogen, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, OR22’, N(R22’)2, C3- C10cycloalkyl, C2-C12 heterocycloalkyl, aryl, or C1-C9 heteroaryl, wherein each of the alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted, and each R22’ is independently hydrogen, C1-C6alkyl, C3-C10cycloalkyl, C2- C12heterocycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, aryl, or C1-C9 heteroaryl, wherein each of the alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, and heteroaryl is optionally substituted, or two R22’ together with the nitrogen atom to which they are attached, form a 3- 7-membered ring; R23 is hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3- C10cycloalkyl, C2-C12heterocycloalkyl, aryl, C1-C9 heteroaryl, wherein each of the alkyl, alkoxy, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, and heteroaryl is optionally substituted; R24 is ; ring A is an optionally substituted 4-7 membered monocyclic ring or optionally substituted 6-11 membered bicyclic, bridged, fused, or spiro ring; R1 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted C2-C5 heterocycloalkyl; L is a bond, C1-C6 alkylene, C1-C6 heteroalkylene, S, O, or NH; E represents a structure of Formula (Ic), ( ), wherein, X is C(=O), P(=O)OR2, C(=S), or S(=O)n, where n is 1 or 2; R2 is hydrogen or optionally substituted C1-C3 alkyl; R5 is hydrogen, cyano, halogen, C1-C6alkyl, C1-C6alkoxyl, C1-C6heteroalkyl, C3-C6cycloalkyl, or C2-C5heterocycloalkyl, each of the alkyl, alkoxyl, heteroalkyl, cycloalkyl or heterocycloalkyl is optionally substituted, and R7 is hydrogen, cyano, halogen, C1-C6 alkyl, C1-C6 alkoxyl, C1-C6 heteroalkyl, C3-C7 cycloalkyl, C2-C7 heterocycloalkyl, C1-C9 heteroaryl, -C1-C6alkylene-C1-C9 heteoraryl, -C1-C6alkylene- NH(C1-C6 alkyl), or -C1-C6alkylene-N(C1-C6 alkyl)2, each of the alkyl, alkylene, alkoxyl, heteroalkyl, cycloalkyl or heterocycloalkyl is optionally substituted; or R5 and R7 taken together form a bond; or R5 and R7 taken together with the carbon atoms to which they are attached form a 5-8 membered partially saturated cycloalkyl, wherein the cycloalkyl is optionally substituted; R6 is hydrogen, cyano, halogen, C1-C6 alkyl, C1-C6 alkoxyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, C1-C9 heteroaryl, -C1-C6alkylene-C1-C9heteoraryl, -C1-C6alkylene- NH(C1-C6 alkyl), or -C1-C6alkylene-N(C1-C6 alkyl)2, each of the alkyl, alkylene, alkoxyl, heteroalkyl, cycloalkyl, heterocycloalkyl, or heteroaryl is optionally substituted; R28 and R29 are each independently hydrogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, cyano, nitro, or C3-C6 cycloalkyl, or R28 and R29 taken together with the carbon atom to which they are attached form a 3-6 membered ring; R30 is selected from halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 heteroalkyl, C3- C10cycloalkyl, C2-C12heterocycloalkyl, aryl, C1-C9heteroaryl, -C1-C6alkylene-C3- C10cycloalkyl, -C1-C6alkylene-C2-C12heterocycloalkyl, -C1-C6alkylene-aryl, -C1-C6alkylene- C1-C9heteroaryl, -C1-C6heteroalkylene-C3-C10cycloalkyl, -C1-C6heteroalkylene-C2- C12heterocycloalkyl, -C1-C6heteroalkylene-aryl, -C1-C6alkylene-C1-C9 heteroaryl wherein each of the alkyl, alkoxy, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted; and R33 is hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, or C3-C6cycloalkyl, wherein each of the alkyl, heteroalkyl, and cycloalkyl is optionally substituted. 65. The conjugate of any one of claims 60-64, wherein the metal chelator is selected from AAZTA, BAT, BAT-TM, Crown, Cyclen, DO2A, CB-DO2A, DO3A, H3HP-DO3A, Oxo-DO3A, p-NH2- Bn-Oxo-DO3A, DOTA, DOTA-3py, DOTA-PA, DOTA-GA, DOTA-4AMP, DOTA-2py, DOTA-1py, p-SCN-Bn-DOTA, CHX-A″-EDTA, MeO-DOTA-NCS EDTA, DOTAMAP, DOTAGA, DOTAGA-anhydride, DOTMA, DOTASA, DOTAM, DOTP, CB-Cyclam, TE2A, CB-TE2A, CB-TE2P, DM-TE2A, MM-TE2A, NOTA, NOTP, HEHA, HEHA-NCS, p-SCN-Bn- HEHA, DTPA, CHX-A″-DTPA, p-NH2-Bn-CHX-A″-DTPA, p-SCN-DTPA, p-SCN-Bz-Mx- DTPA, 1B4M-DTPA, p-SCN-Bn1B-DTPA, p-SCN-Bn-1B4M-DTPA, p-SCN-Bn-CHX-A″- DTPA, PEPA, p-SCN-Bn-PEPA, TETPA, DOTPA, DOTMP, DOTPM, t-Bu-calix[4]arene- tetracarboxylic acid, macropa, macropa-NCS, macropid, H3L1, H3L4, H2azapa, H5decapa, bispa2, H4pypa, H4octapa, H4CHXoctapa, p-SCN-Bn-H4octapa, p-SCN-Bn-H4octapa, TTHA, p-NO2-Bn- neunpa, H4octox, H2macropa, H2bispa2, H4phospa, H6phospa, p-SCN-Bn-H6phospa, TETA, p- NO2-Bn-TETA, TRAP, TPA, HBED, SHBED, HBED-CC, (HBED-CC)TFP, DMSA, DMPS, DHLA, lipoic acid, TGA, BAL, Bis-thioseminarabazones, p-SCN-NOTA, nNOTA, NODAGA, CB-TE1A1P, 3P-C-NETA-NCS, 3p-C-DEPA, 3P-C-DEPA-NCS, TCMC, PCTA, NODIA-Me, TACN, pycup1A1B, pycup2A, THP, DEDPA, H2DEDPA, p-SCN-Bn-H2DEDPA, p-SCN-Bn- TCMC, motexafin, NTA, NOC, 3p-C-NETA, p-NH2-Bn-TE3A, SarAr, DiAmSar, SarAr-NCS, AmBaSar, BaBaSar, TACN-TM, CP256, C-NE3TA, C-NE3TA-NCS, NODASA, NETA- monoamide, C-NETA, NOPO, BPCA, p-SCN-Bn-DFO, DFO-ChX-Mal, DFO, DFO-IAC, DFO- BAC, DiP-LICAM, EC, SBAD, BAPEN, TACHPYR, NEC-SP, Lpy, L1, L2, L3, and EuK-106. 66. The conjugate of any one of claims 60-65, wherein the metal chelator is 2,2',2'',2'''- ((2S,5S,8S,11S)-2,5,8,11-tetramethyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetraacetic acid. 67. The conjugate of any one of claims 60-65, wherein the metal chelator is 2,2',2'',2'''- ((2S,5S,8S,11S)-2,5,8,11-tetraethyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetraacetic acid. 68. The conjugate of any one of claims 60-65, wherein the metal chelator is a chelator in FIG.1 to FIG.15. 69. The conjugate of any one of claims 60-65, wherein the metal chelator is DOTA. 70. The conjugate of any one of claims 60-69, wherein the radionuclide is 62Cu, 64Cu, 67Cu, 68Ga, 89Zr, 90Y, 99mTc, 105Rh, 111In, 134Ce, 148Gd, 149Tb, 152Tb, 153Pm, 167Tm, 175Yb, 177Lu, 209Bi, 212Pb, 213Po, 213Bi, 223Ra, 223Fr, 227Th, 225Ac, or 229Th. 71. A pharmaceutical composition comprising a radiolabeled compound or conjugate of any one of claims 1-70, and a pharmaceutically acceptable excipient or carrier. 72. A method of making a covalently modified KRAS protein in vivo, comprising administering a radiolabeled compound or conjugate of any one of claims 1-70 or a pharmaceutical composition of claim 71 to a subject, wherein the subject has a KRAS protein comprising a glycine to cysteine amino acid substitution at residue 12. 73. The method of claim 72, wherein the subject has a cancer. 74. A method of treating cancer in a subject in need thereof, comprising administering to the subject a radiolabeled compound or conjugate of any one of claims 1-70 or a pharmaceutical composition of claim 71. 75. The method of claim 73 or 74, wherein the cancer is selected from the group consisting of Cardiac cancer: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; Lung cancer: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; Gastrointestinal cancer: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); Genitourinary tract cancer: kidney (adenocarcinoma, Wilm's tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma); Liver cancer: hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Biliary tract cancer: gall bladder carcinoma, ampullary carcinoma, cholangiocarcinoma; Bone cancer: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors; Nervous system cancer: skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal cord neurofibroma, meningioma, glioma, sarcoma); Gynecological cancer: uterus (endometrial 'carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tubes (carcinoma); Hematologic cancer: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma); Skin cancer: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis; and Adrenal glands cancer: neuroblastoma. 76. The method of any one of claims 73 to 75, wherein the cancer is non-small cell lung cancer. 77. The method of any one of claims 74 to 76, wherein the method comprises administering (i) a first radiopharmaceutical conjugate comprising a radionuclide configured for companion diagnostic and (ii) a second radiopharmaceutical conjugate comprising a radionuclide selected from an alpha or beta-particle emitter, wherein the first and the second radiopharmaceutical conjugates have the same structure except for the radionuclide. 78. The method of claim 77, wherein the radionuclide of the first radiopharmaceutical conjugate is selected from 62Cu, 64Cu, 89Zr, 134Ce, 152Tb, 68Ga, 111In, and 99mTc. 79. The method of claim 77, wherein the radionuclide of the first radiopharmaceutical conjugate is selected from 11C, 13N, 15O, 18F, 74As, 76Br, 123I, 124I, and 125I. 80. The method of claim 77, wherein the radionuclide of the second radiopharmaceutical conjugate is selected from 225Ac, 213Bi, 209Bi, 149Tb, 223Ra, 227Th, 223Fr, 148Gd, 229Th 213Po, 67Cu, 177Lu, 90Y, 212Pb, 105Rh, 175Yb, 167Tm, 153Pm, and 111In. 81. The method of claim 77, wherein the radionuclide of the second radiopharmaceutical conjugate is selected from 131I and 211At. 82. A method of killing a cell harboring a G12C KRAS mutation, the method comprising contacting a cell harboring a G12C KRAS mutation with a radiolabeled compound or conjugate of any one of claims 1-70 or a pharmaceutical composition of claim 71, thereby delivering a dose of radiation to the cell. 83. A method of delivering a radionuclide to a cell comprising administering a radiolabeled compound or conjugate of any one of claims 1-70 or a pharmaceutical composition of claim 71. 84. The method of claim 83, wherein the radiolabeled compound or conjugate irreversibly binds to an intracellular protein of the cell. 85. A method of diagnosing cancer patients harboring a G12C KRAS mutation comprising administering to a patient a radiolabeled compound or conjugate of any one of claims 1-70 or a pharmaceutical composition of claim 71. 86. A method of imaging a cancer harboring a G12C KRAS mutation comprising administering to a patient a radiolabeled compound or conjugate of any one of claims 1-70 or a pharmaceutical composition of claim 71. 87. The method of claim 85 or 86, further comprising measuring the concentration of the radiolabeled compound or conjugate accumulated in the patient. 88. The method of any one of claims 85 to 87, further comprising measuring the amount of radiation emitted from the radionuclide. 89. The method of any one of claims 85 to 88, further comprising analyzing the elimination profile of the radiolabeled compound or conjugate in the patient. 90. The method of any one of claims 85 to 89, further comprising measuring an elimination half-life of the radiolabeled compound or conjugate in the patient. 91. A method of producing a compound having a structure of Formula (VIa), Formula (VIb), Formula (VIc), or Formula (VId) in vivo, comprising administering a radiolabeled compound of any one of claims 48-58 to a subject, Formula (VIa) Formula (VIb) Formula (VIc) Formula (VId) wherein R* is fluorine-18 (18F), iodine-131 (131I), iodine-123 (123I), iodine-124 (124I), iodine-125 (125I), or astatine-211 (211At). 92. A method of excreting a compound having a structure of Formula (VIa), Formula (VIb), Formula (VIc), or Formula (VId) from a subject’s body, comprising administering a radiolabeled compound of any one of any one of claims 48-58 to a subject, Formula (VIa) Formula (VIb) Formula (VIc) Formula (VId) wherein R* is fluorine-18 (18F), iodine-131 (131I), iodine-123 (123I), iodine-124 (124I), iodine-125 (125I), or astatine-211 (211At). 93. The method of claim 91 or 92, wherein: the compound having a structure of Formula (VIa) is ; the compound having a structure of Formula (VIb) is ; the compound having a structure of Formula (VIc) is ; or the compound having a structure of Formula (VId) is 94. A covalently modified KRAS protein comprising, a KRAS protein comprising a glycine to cysteine amino acid substitution at residue 12, and a radiolabeled compound comprising a covalently bonded radioisotope, wherein the radiolabeled compound is bonded to the KRAS protein at the cysteine residue 12 of the KRAS protein through a covalent bond, and wherein residue position numbering of the KRAS protein is based on SEQ ID NO:1 or SEQ ID NO:2 as a reference sequence. 95. The covalently modified KRAS protein of claim 94, wherein the radiolabeled compound comprises the structure of a radiolabeled compound of any one of claims 1-58. 96. A conjugate comprising, (a) a targeting ligand that is configured to form a covalent bond with a KRAS protein at the G12C position, wherein residue position numbering of the KRAS protein is based on SEQ ID NO:1 or SEQ ID NO: 2; and (b) a radionuclide, wherein the radionuclide is iodine-131 or astatine-211. 97. A conjugate comprising, (a) a targeting ligand that is covalently bound to an intracellular mutated KRAS protein at the G12C position, wherein residue position numbering of the KRAS protein is based on SEQ ID NO:1 or SEQ ID NO: 2; and (b) a radionuclide. 98. The conjugate of claim 97, wherein the radionuclide is selected from is astatine-211, astatine- 217, actinium-225, americium-243, radium-223, lead-212, lead-203, copper-64, copper-67, copper-60, copper-61, copper-62, bismuth-212, bismuth-213, gallium-68, gallium-67, dysprosium-154, gadolinium-148, gadolinium-153, samarium-146, samarium-147, samarium- 153, terbium-149, thorium-227, thorium-229, iron-59, yttrium-86, indium-111, holmium-166, technetium-94, technetium-99m, yttrium-90, lutetium-177, terbium-161, rhenium-186, rhenium- 188, cobalt-55, scandium-43, scandium-44, scandium-47, dysprosium-166, fluorine-18, and iodine-131. 99. The conjugate of claim 96 or 97, wherein the radionuclide is iodine-131. 100. The conjugate of any one of claims 96 to 99, wherein the targeting ligand comprises an electrophilic functional group. 101. The conjugate of claim 100, wherein the electrophilic functional group comprises a structure of Formula (Ia) or Formula (Ib): , wherein, ring Q is a 3 to 10 membered heterocycloalkylene, wherein Q is optionally substituted; R1 is hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, or substituted or unsubstituted C2- C5 heterocycloalkyl; and E represents a structure of Formula (Ic), wherein, X is C(=O), P(=O)OR2, C(=S), or S(=O)n, where n is 1 or 2; R2 is hydrogen or substituted or unsubstituted C1-C3 alkyl; R5 and R7 are each independently selected from hydrogen, -CN, halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C7 cycloalkyl, or substituted or unsubstituted C2-C7 heterocycloalkyl; or R5 and R7 taken together form a bond; R6 is hydrogen, halogen, -CN, C1-C6 alkyl, C1-C6 heteroalkyl, heteroaryl, aryl, alkylaminylalkyl, dialkylaminylalkyl, cycloalkyl or heterocycloalkyl, each of which is optionally substituted. 102. The conjugate of claim 100 or 101, wherein the electrophilic functional group comprises a structure of Formula (Id), wherein, X is C(=O), OC(=O), NR2C(=O), P(=O)OR2, C(=S), S(=O)n, OS(O)n, NR2S(=O)n, wherein n is 1 or 2; Y is an alkylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, heteroarylene, or a bond, wherein each of the alkylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene is optionally substituted; each R2 is independently hydrogen or substituted or unsubstituted C1-C3 alkyl; R5 and R7 are each independently selected from hydrogen, cyano, halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C7 cycloalkyl, or substituted or unsubstituted C2-C6 heterocycloalkyl; or R5 and R7 taken together form a bond; and R6 is hydrogen, halogen, -CN, C1-C6 alkyl, C1-C6 heteroalkyl, heteroaryl, aryl, alkylaminylalkyl, dialkylaminylalkyl, cycloalkyl or heterocycloalkyl, each of which is optionally substituted. 103. The conjugate of claim 102, wherein E represents a structure of Formula (Ic) that is or 104. The conjugate of claim 102, wherein the electrophilic functional group is , |
Formula (III) wherein ring Q 1 is a 4-12 membered saturated or partially saturated monocyclic or bicyclic ring, wherein the monocyclic or bicyclic ring is optionally substituted; L 1 is a bond, -C(=O)-, O, S, NR 15 , optionally substituted C 1 -C 3 alkylene, optionally substituted C 1 -C 3 heteroalkylene; L 2 is a bond, -C(=O)-, O, S or NR 15 ; E is X is C(=O), P(=O)OR 2 , C(=S), or S(=O) n , where n is 1 or 2; R 2 is hydrogen or optionally substituted C 1 -C 3 alkyl; R 5 is hydrogen, cyano, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxyl, C 1 -C 6 heteroalkyl, C 3 -C 6 cycloalkyl, or C 2 -C 5 heterocycloalkyl, each of the alkyl, alkoxyl, heteroalkyl, cycloalkyl or heterocycloalkyl is optionally substituted, and R 7 is hydrogen, cyano, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxyl, C 1 -C 6 heteroalkyl, C 3 -C 6 cycloalkyl, C 2 -C 5 heterocycloalkyl, heteroaryl, -C 1 -C 6 alkylene-heteoraryl, -C 1 -C 6 alkylene-NH(C 1 -C 6 alkyl), or -C 1 - C 6 alkylene-N(C 1 -C 6 alkyl) 2 , each of the alkyl, alkylene, alkoxyl, heteroalkyl, cycloalkyl or heterocycloalkyl is optionally substituted; or R 5 and R 7 taken together form a bond; or R 5 and R 7 taken together with the carbon atoms to which they are attached form a 5-8 membered partially saturated cycloalkyl, wherein the cycloalkyl is optionally substituted; R 6 is hydrogen, cyano, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxyl, C 1 -C 6 heteroalkyl, C 3 -C 6 cycloalkyl, C 2 -C 5 heterocycloalkyl, heteroaryl, -C 1 -C 6 alkylene-heteoraryl, -C 1 -C 6 alkylene-NH(C 1 -C 6 alkyl), or -C1- C6alkylene-N(C 1 -C 6 alkyl)2, each of the alkyl, alkylene, alkoxyl, heteroalkyl, cycloalkyl, heterocycloalkyl, or heteroaryl is optionally substituted; R 12 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, -L 3 -NR 15 R 15’ , heterocycloalkyl, -L 3 -heterocycloalkyl, cycloalkyl, -L 3 -cycloalkyl, aryl, heteroaryl, -L 3 -aryl, or -L 3 -heteroaryl, wherein each of the heterocycloalkyl, cycloalkyl, aryl, heteroaryl, alkyl or heteroalkyl is optionally substituted; L 3 is C 1 -C 4 alkylene or C 1 -C 4 heteroalkylene, each of which is optionally substituted; each R 13 is independently OH, halogen, oxo, substituted or unsubstituted C 1 -C 6 alkyl, or substituted or unsubstituted C 1 -C 6 heteroalkyl; R 14 is hydrogen, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each of the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted; each R 15 is independently hydrogen or optionally substituted C 1 -C 3 alkyl; each R 15’ is independently hydrogen, acyl, optionally substituted C 1 -C 3 alkyl, optionally substituted C 1 -C 3 heteroalkyl or optionally substituted C 1 -C 3 hydroxyalkyl; and m is 0, 1, or 2; provided that at least one of L 1 , L 2 , R 12 , R 13 and R 14 comprises a covalently bonded radioisotope R*. [0152] In some embodiments, R* is fluorine-18 ( 18 F), iodine-131 ( 131 I), iodine-123 ( 123 I), iodine-124 ( 124 I), iodine-125 ( 125 I), or astatine-211 ( 211 At). In some embodiments, R* is 131 I. In some embodiments, R* is selected from a radioisotope in Table 6C or Table 6D. [0153] In one aspect, provided herein is a radiolabeled compound of Formula (III), or a salt or solvate thereof Formula (III) wherein ring Q 1 is a 4-12 membered saturated or partially saturated monocyclic or bicyclic ring, wherein the monocyclic or bicyclic ring is optionally substituted; L 1 is a bond, -C(=O)-, or optionally substituted C 1 -C 3 alkylene; L 2 is a bond, -C(=O)-, O, S or NR 15 ; E is X is C(=O), P(=O)OR 2 , C(=S), or S(=O)n, where n is 1 or 2; R 2 is hydrogen or optionally substituted C 1 -C 3 alkyl; R 5 is hydrogen, cyano, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxyl, C 1 -C 6 heteroalkyl, C 3 -C 6 cycloalkyl, or C 2 -C 5 heterocycloalkyl, wherein each of the alkyl, alkoxyl, heteroalkyl, cycloalkyl or heterocycloalkyl is optionally substituted, and R 7 is hydrogen, cyano, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxyl, C 1 -C 6 heteroalkyl, C 3 -C 7 cycloalkyl, C 2 - C7 heterocycloalkyl, or heteroaryl, wherein each of the alkyl, alkoxyl, heteroalkyl, cycloalkyl or heterocycloalkyl is optionally substituted; or R 5 and R 7 taken together form a bond; or R 5 and R 7 taken together with the carbon atoms to which they are attached form a 5-8 membered partially saturated cycloalkyl, wherein the cycloalkyl is optionally substituted; R 6 is hydrogen, cyano, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxyl, C 1 -C 6 heteroalkyl, C 3 -C 6 cycloalkyl, C 2 - C 6 heterocycloalkyl, or heteroaryl, wherein each of the alkyl, alkoxyl, heteroalkyl, cycloalkyl, heterocycloalkyl, or heteroaryl is optionally substituted; R 12 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, -L 3 -NR 15 R 15’ , heterocycloalkyl, -L 3 -heterocycloalkyl, cycloalkyl, -L 3 -cycloalkyl, aryl, heteroaryl, -L 3 -aryl, or -L 3 -heteroaryl, wherein each of the heterocycloalkyl, cycloalkyl, aryl, heteroaryl, alkyl or heteroalkyl is optionally substituted; L 3 is C 1 -C 4 alkylene or C 1 -C 4 heteroalkylene, each of which is optionally substituted; each R 13 is independently OH, halogen, oxo, substituted or unsubstituted C 1 -C 6 alkyl, or substituted or unsubstituted C 1 -C 6 heteroalkyl; R 14 is hydrogen, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each of the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted; each R 15 is independently hydrogen or C 1 -C 3 alkyl; each R 15’ is independently hydrogen, acyl, C 1 -C 3 alkyl, C 1 -C 3 heteroalkyl or C 1 -C 3 hydroxyalkyl; m is 0, 1, or 2, wherein the structure of Formula (III) is attached to the rest of the conjugate at any suitable position; and (b) a radionuclide. [0154] In some embodiments, ring Q 1 is a 4-12 membered saturated or partially saturated monocyclic or bicyclic ring optionally substituted with one, two, or three groups selected from R 18 ; L 1 is a bond, -C(=O)-, or optionally substituted C 1 -C 3 alkylene, wherein the alkylene is optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, and C 2 -C 5 heterocycloalkyl; L 2 is a bond, -C(=O)-, O, S or NR 15 ; E is ; X is C(=O), P(=O)OR 2 , C(=S), or S(=O)n, where n is 1 or 2; R 2 is hydrogen or substituted or unsubstituted C 1 -C 3 alkyl, wherein the alkyl is optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 alkoxy, C 3 -C 6 cycloalkyl, and C 2 -C 5 heterocycloalkyl; R 5 is hydrogen, cyano, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxyl, C 1 -C 6 heteroalkyl, C 3 -C 6 cycloalkyl, or C 2 -C 5 heterocycloalkyl, each of the alkyl, alkoxyl, heteroalkyl, cycloalkyl or heterocycloalkyl is optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, and C 2 -C 5 heterocycloalkyl; R 7 is hydrogen, cyano, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxyl, C 1 -C 6 heteroalkyl, C3-C7 cycloalkyl, C 2 - C 7 heterocycloalkyl, or C 1 -C 9 heteroaryl, wherein each of the alkyl, alkoxyl, heteroalkyl, cycloalkyl or heterocycloalkyl is optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, and C 2 -C 5 heterocycloalkyl; or R 5 and R 7 taken together form a bond; or R 5 and R 7 taken together with the carbon atoms to which they are attached form a 5-8 membered partially saturated cycloalkyl, wherein the cycloalkyl is optionally substituted with one, two or three groups selected from R 17 ; R 6 is hydrogen, cyano, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxyl, C 1 -C 6 heteroalkyl, C 3 -C 6 cycloalkyl, C 2 - C6 heterocycloalkyl, or C 1 -C 9 heteroaryl, wherein, each of the alkyl, alkoxyl, heteroalkyl, cycloalkyl, heterocycloalkyl, or heteroaryl is optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, and C 2 -C 5 heterocycloalkyl; R 12 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, -L 3 -NR 15 R 15’ , C 2 -C 12 heterocycloalkyl, -L 3 - C 2 - C 12 heterocycloalkyl, C 3 -C 15 cycloalkyl, -L 3 - C 3 -C 15 cycloalkyl, aryl, C 1 -C 9 heteroaryl, -L 3 -aryl, or - L 3 - C 1 -C 9 heteroaryl, wherein each of the heterocycloalkyl, cycloalkyl, aryl, heteroaryl, alkyl or heteroalkyl is optionally substituted with one, two, three or four groups selected from R 19 ; L 3 is C 1 -C 4 alkylene or C 1 -C 4 heteroalkylene, each of which is optionally substituted with one, two, or three groups selected from R 19 ; each R 13 is independently OH, halogen, oxo, substituted or unsubstituted C 1 -C 6 alkyl, or substituted or unsubstituted C 1 -C 6 heteroalkyl, wherein each of the alkyl and heteroalkyl is optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, and C 2 -C 5 heterocycloalkyl; R 14 is hydrogen, C 3 -C 15 cycloalkyl, C 2 -C 12 heterocycloalkyl, aryl, or C 1 -C 9 heteroaryl, wherein each of the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, three or four groups selected from R 16 ; each R 15 is independently hydrogen or C 1 -C 3 alkyl; each R 15’ is independently hydrogen, acyl, C 1 -C 3 alkyl, C 1 -C 3 heteroalkyl or C 1 -C 3 hydroxyalkyl; m is 0, 1, or 2; each R 17 is independently halogen, hydroxyl, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, amino, cyano, C 1 -C 6 heteroalkyl, C 1 -C 6 hydroxyalkyl, -O-C 1 -C 6 haloalkyl, or -S-C 1 - C 6 haloalkyl; each R 18 is independently halogen, oxo, C 1 -C 6 alkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, -CN, -C(O)OR 15 , -C(O)N(R 15 )(R 15’ ), -N(R 15 )(R 15’ ), or OR 15 , and wherein each of the alkyl, aminoalkyl, haloalkyl, alkenyl, alkynyl, or heteroalkyl is optionally substituted with one, two, or three groups selected from halogen, -CN, -NO2, amino, hydroxy, C1- C6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, and C 2 -C 5 heterocycloalkyl; R 16 and R 19 are each independently selected from halogen, oxo, -CN, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C2- C6 alkynyl, C 1 -C 6 heteroalkyl, C3-C10 cycloalkyl, -C1-3alkylene-C3-6cycloalkyl, C2-C9 heterocycloalkyl, -C1-3alkylene-C2-9heterocycloalkyl, C 6 -C 10 aryl, -C1-3alkylene-C6-10aryl, C 1 -C 9 heteroaryl, -C1-3alkylene-C1-9 heteroaryl, -OR 10 , -SR 10 , -N(R 10 )(R 10’ ), -C(=O)OR 10 , - OC(=O)N(R 10 )(R 10’ ), -N(R 10’ )C(=O)N(R 10 )(R 10’ ), -N(R 10’ )C(=O)OR 11 , -N(R 10’ )S(=O)2R 11 , - C(=O)R 11 , -S(=O)R 11 , -OC(=O)R 11 , -C(=O)N(R 10 )(R 10’ ), -C(=O)C(=O)N(R 10 )(R 10’ ), - N(R 10’ )C(O)R 11 , -S(O)2R 11 , -S(O)2N(R 10 )(R 10’ ), -S(=O)(=NH)N(R 10 )(R 10’ ), -CH2C(O)N(R 10 )(R 10’ ), -CH 2 N(R 10’ )C(=O)R 11 , -CH 2 S(=O) 2 R 11 , and -CH 2 S(=O) 2 N(R 10 )(R 10’ ), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, -C 1-3 alkylene-C 3-6 cycloalkyl, heterocycloalkyl, -C 1-3 alkylene-C 2 - C9heterocycloalkyl, aryl, -C1-3alkylene-C6-10aryl, heteroaryl and -C1-3alkylene-C1-9 heteroaryl are optionally substituted with one, two, three, or four groups independently selected from halogen, oxo, -CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkyloxy, C 1 -C 6 haloalkoxy, C 3 -C 10 cycloalkyl, C 2 -C 9 heterocycloalkyl, C 6 -C 10 aryl, C 1 -C 9 heteroaryl, -OR 10 , -SR 10 , -N(R 10 )(R 10’ ), - C(=O)OR 10 , -OC(=O)N(R 10 )(R 10’ ), -N(R 10’ )C(=O)N(R 10 )(R 10’ ), -N(R 10’ )C(=O)OR 11 , - N(R 10’ )S(=O) 2 R 11 , -C(=O)R 11 , -S(O)R 11 , -OC(=O)R 11 , -C(=O)N(R 10 )(R 10’ ), - C(=O)C(=O)N(R 10 )(R 10’ ), -N(R 10’ )C(=O)R 11 , -S(=O) 2 R 11 , -S(=O) 2 N(R 10 )(R 10’ )-, S(=O)(=NH)N(R 10 )(R 10’ ), -CH 2 C(=O)N(R 10 )(R 10’ ), -CH 2 N(R 10’ )C(=O)R 11 , -CH 2 S(=O) 2 R 11 , and - CH 2 S(=O) 2 N(R 10 )(R 10’ ); each R 10 is independently selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -C 10 aryl, and C 1 -C 9 heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, C 2 -C 9 heterocycloalkyl, C 6 -C 10 aryl, and C 1 -C 9 heteroaryl; each R 10’ is independently selected from hydrogen, C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl; and each R 11 is independently selected C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 2 -C 9 heterocycloalkyl, C 6 -C 10 aryl, and C 1 -C 9 heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, C 2 -C 9 heterocycloalkyl, C 6 -C 10 aryl, and C 1 -C 9 heteroaryl. [0155] In some embodiments of Formula (III) or (X-III), Q 1 is optionally substituted with one or more R 18 , wherein R 18 is oxo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, cyano, -C(O)OR 15 , - C(O)N(R 15 )(R 15’ ), -N(R 15 )(R 15’ ), wherein the alkyl, alkenyl, alkynyl, or heteroalkyl is optionally substituted. In some embodiments, Q 1 is optionally substituted with one to three R 18 , wherein R 18 is independently halogen, oxo, C 1 -C 6 alkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, -CN, -C(O)OR 15 , -C(O)N(R 15 )(R 15’ ), -N(R 15 )(R 15’ ), or OR 15 , and wherein each of the alkyl, aminoalkyl, haloalkyl, alkenyl, alkynyl, or heteroalkyl is optionally substituted with one, two, or three groups selected from halogen, -CN, -NO2, amino, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, and C 2 -C 5 heterocycloalkyl. In some embodiments, Q 1 is a 6 membered monocyclic ring, where in the monocyclic ring is optionally substituted with one to three R 18 , wherein R 18 is methyl, CN, -CH2CN, carbonyl, hydroxyl, carboxyl, or C(O)OR 15 . In some embodiments, Q 1 is a 6 membered monocyclic ring substituted with -CH2CN. [0156] In some embodiments of Formula (III), Formula (IIIa), Formula (IIIb), Formula (IIIc), Formula (X-III), Formula (IV), Formula (IVa), Formula (IVb), Formula (IVc), Formula (IVd), and Formula (IVe), or Formula (X-IV), R 5 is hydrogen, cyano, halogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 alkoxyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted C 3 -C 6 cycloalkyl, or optionally substituted C 2 -C 5 heterocycloalkyl. In some embodiments, each of the alkyl, alkoxyl, heteroalkyl, cycloalkyl or heterocycloalkyl is optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, and C 2 -C 5 heterocycloalkyl. [0157] In some embodiments of Formula (III), Formula (IIIa), Formula (IIIb), Formula (IIIc), Formula (X-III), Formula (IV), Formula (IVa), Formula (IVb), Formula (IVc), Formula (IVd), and Formula (IVe), or Formula (X-IV), R 5 is hydrogen or a C 1 -C 3 alkyl optionally substituted by one to three substituents selected from hydroxyl and halogen. In some embodiments, R 5 is a halogen. In some embodiments, R 5 is C 1 -C 6 heteroalkyl. In some embodiments, R 5 is -C(O)NR 15 R 15’ . In some embodiments, R 5 is fluoro. [0158] In some embodiments of Formula (III), Formula (IIIa), Formula (IIIb), Formula (IIIc), Formula (X-III), Formula (IV), Formula (IVa), Formula (IVb), Formula (IVc), Formula (IVd), and Formula (IVe), or Formula (X-IV), R 7 is hydrogen, cyano, halogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 alkoxyl, or optionally substituted C 1 -C 6 heteroalkyl In some embodiments, R 7 is hydrogen. In some embodiments, R 7 is C 1 -C 6 heteroalkyl selected from -NHC(O)-C 1 -C 3 alkyl and - CH 2 NHC(O)-C 1 -C 3 alkyl. [0159] In some embodiments of Formula (III), Formula (IIIa), Formula (IIIb), Formula (IIIc), Formula (X-III), Formula (IV), Formula (IVa), Formula (IVb), Formula (IVc), Formula (IVd), and Formula (IVe), or Formula (X-IV), R 5 and R 7 taken together with the carbon atoms to which they are attached form a 5-8 membered partially saturated cycloalkyl, wherein the cycloalkyl is optionally substituted with one or more R 17 , wherein each R 17 is independently halogen, hydroxyl, C 1 -C 6 alkyl, cycloalkyl, alkoxy, haloalkyl, amino, cyano, heteroalkyl, hydroxyalkyl, -O-haloalkyl, or -S-haloalkyl. [0160] In some embodiments of Formula (III), Formula (IIIa), Formula (IIIb), Formula (IIIc), Formula (X-III), Formula (IV), Formula (IVa), Formula (IVb), Formula (IVc), Formula (IVd), and Formula (IVe), or Formula (X-IV), R 6 is hydrogen, cyano, halogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 alkoxyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted C 3 -C 6 cycloalkyl, or optionally substituted C 2 -C 6 heterocycloalkyl. In some embodiments, R 6 is hydrogen. In some embodiments, R 6 is C 1 -C 6 heteroalkyl selected from -NHC(O)-C 1 -C 3 alkyl and -CH2NHC(O)-C 1 -C 3 alkyl. [0161] In some embodiments of Formula (III), Formula (IIIa), Formula (IIIb), Formula (IIIc), or Formula (X-III), R 14 is hydrogen, cycloalkyl, heterocycloalkyl, aryl, aralkyl, or heteroaryl, wherein each of the cycloalkyl, heterocycloalkyl, aryl, aralkyl, and heteroaryl is optionally substituted with one or more R 16 wherein each R 16 is independently halogen, hydroxyl, C 1 -C 6 alkyl, cycloalkyl, alkoxy, acetyl, carboxyl, - C(O)OR 15 , haloalkyl, amino, cyano, heteroalkyl, hydroxyalkyl, -O-haloalkyl, or -S-haloalkyl. In some embodiments, R 16 is halogen. [0162] In some embodiments of Formula (III), Formula (IIIa), Formula (IIIb), Formula (IIIc), or Formula (X-III), R 14 is aryl or heteroaryl, optionally substituted with one or more R 16 , wherein each R 16 is independently D, halogen, -CN, -NH2, -NH(alkyl), -N(alkyl)2, -OH, oxo, -CO2H, -CO2alkyl, -C(=O)NH2, -C(=O)NH(alkyl), -C(=O)N(alkyl)2, -S(=O)2NH2, -S(=O)2NH(alkyl), -S(=O)2N(alkyl)2, alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, or arylsulfone, wherein each of the alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, or arylsulfone is optionally substituted. [0163] In some embodiments of Formula (III), Formula (IIIa), Formula (IIIb), Formula (IIIc), or Formula (X-III), R 14 is aryl or heteroaryl, optionally substituted with one or more R 16 , wherein each R 16 is independently D, amino, cyano, oxo, hydroxy, nitro, halogen, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkoxy, C 3-7 cycloalkyl, aryl, heteroaryl, C 1-6 heteroalkyl, C 2-7 heterocycloalkyl, C 1-6 alkyl-OH, trihalo-C 1-6 alkyl, mono- C 1-6 alkylamino, di-C 1-6 alkylamino, -C(=O)NH 2 , hydroxy-C 1-6 alkylamino, hydroxy-C 1-6 alkyl, 4-7 membered heterocycle-C 1-6 alkyl, amino-C 1-6 alkyl, mono-C 1-6 alkylamino-C 1-6 alkyl, and di-C 1-6 alkylamino-C 1-6 alkyl. [0164] In some embodiments of Formula (III), Formula (IIIa), Formula (IIIb), Formula (IIIc), or Formula (X-III), R 14 is aryl or heteroaryl, optionally substituted with one or more R 16 , wherein each R 16 is independently halogen, hydroxyl, C 1 -C 3 alkyl, alkoxy, haloalkyl, amino, or cyano. In some embodiments, R 14 is optionally substituted monocyclic heteroaryl. In some embodiments, R 14 is optionally substituted bicyclic heteroaryl. [0165] In some embodiments of Formula (III), Formula (IIIa), Formula (IIIb), Formula (IIIc), or Formula (X-III), R 14 is an aryl. In some embodiments, R 14 is phenyl. In some embodiments, R 14 is napthyl. In some embodiments, R 14 is an aryl substituted with one or more R 16 groups. In some embodiments, R 14 is napthyl substituted with one to three R 16 groups. In some embodiments, R 14 is napthyl substituted with one to three R 16 , wherein each R 16 is independently halogen, hydroxyl, C 1 -C 3 alkyl, alkoxy, haloalkyl, amino, or cyano. [0166] In some embodiments of Formula (III), Formula (IIIa), Formula (IIIa-1), Formula (IIIa-2), Formula (IIIb), Formula (IIIc), or Formula (X-III), each R 16 is independently D, oxo, halogen, -CN, -NH2, -NH(CH3), -N(CH3)2, -OH, -CO2H, -CO2(C1-C4 alkyl), -OCO(C1-C4 alkyl), -C(=O)NH2, -C(=O)NH(C1-C4 alkyl), -C(=O)N(C1-C4 alkyl)2, -S(=O)2NH2, -S(=O)2NH(C1-C4 alkyl), -S(=O)2N(C1-C4 alkyl)2, C1-C4 alkyl, C 3 -C 6 cycloalkyl, C1-C4 fluoroalkyl, C 1 -C 6 heteroalkyl, C1-C4 alkoxy, C1-C4 fluoroalkoxy, -SC1-C4 alkyl, - S(=O)C1-C4 alkyl, or -S(=O)2(C1-C4 alkyl). In some embodiments, each R 16 is independently D, oxo, halogen, -CN, -NH2, -OH, -NH(CH3), -N(CH3)2, - NH(cyclopropyl), -CH3, -CH2CH3, -CF3, -OCH3, or - OCF3. In some embodiments, each R 16 is independently substituted or unsubstituted C 1 -C 3 alkyl, amino, or -CN. [0167] In some embodiments of Formula (III), Formula (IIIa), Formula (IIIb), Formula (IIIc), or Formula (X-III), R 14 is phenyl or naphthyl optionally substituted with one or more R 16 . In some embodiments, R 14 is phenyl optionally substituted with one or more R 16 . In some embodiments, R 14 is naphthyl optionally substituted with one or more R 16 . In some embodiments, each R 16 is independently halogen, hydroxyl, C1- C3 alkyl, alkoxy, haloalkyl, amino, or cyano. [0168] In some embodiments of Formula (III), Formula (IIIa), Formula (IIIb), Formula (IIIc), or Formula (X-III), R 14 comprises the covalently bonded radioisotope R*. In some embodiments, R* is selected from a radioisotope in Table 6C or Table 6D. In some embodiments, R 14 comprises a radionuclide selected from fluorine-18 ( 18 F), iodine-131 ( 131 I), iodine-123 ( 123 I), iodine-124 ( 124 I), iodine-125 ( 125 I), and astatine-211 ( 211 At). [0169] In some embodiments of Formula (III), Formula (IIIa), Formula (IIIa-1), Formula (IIIa-2), Formula (IIIb), Formula (IIIc), or Formula (X-III), R 16 is halogen and the halogen is a radioisotope selected from iodine-131 ( 131 I), iodine-123 ( 123 I), iodine-124 ( 124 I), and iodine-125 ( 125 I). In some embodiments, R 16 is 131 I. In some embodiments, R 12 is phenyl or naphthyl substituted with one or two R 16 and each R 16 is independently hydroxyl or 131 I. [0170] In some embodiments of Formula (III), Formula (IIIa), Formula (IIIb), Formula (IIIc), or Formula (X-III), R 14 is , , In some embodiments, R 14 is [0171] In some embodiments of Formula (III), or Formula (IIIa), R 12 is hydrogen, alkyl, heteroalkyl, - L 3 -alkylaminyl, -L 3 -dialkylaminyl, -L 3 -NR 15 R 15’ , heterocycloalkyl, -L 3 - heterocycloalkyl, cycloalkyl, -L 3 - cycloalkyl, aryl, heteroaryl, -L 3 -aryl, or -L 3 -heteroaryl, wherein each of the L 3 , heterocycloalkyl, cycloalkyl, aryl, heteroaryl, alkyl or heteroalkyl is optionally substituted with one or more R 19 , wherein each R 19 is independently hydrogen, oxo, acyl, hydroxyl, hydroxyalkyl, cyano, halogen, alkyl, aralkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkoxy, dialkylaminyl, dialkylamidoalkyl, or dialkylaminylalkyl, wherein the alkyl, aralkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl is optionally substituted. [0172] In some embodiments of Formula (III), Formula (IIIa), Formula (IIIb), Formula (IIIc), or Formula (X-III), R 12 is alkyl, heteroalkyl, -L 3 -alkylaminyl, -L 3 -dialkylaminyl, -L 3 -NR 15 R 15’ , heterocycloalkyl, -L 3 - heterocycloalkyl, cycloalkyl, or -L 3 -cycloalkyl, wherein each of the L 3 , heterocycloalkyl, cycloalkyl, alkyl, or heteroalkyl is optionally substituted with one or more R 19 . In some embodiments, R 12 is optionally substituted Cl-C6 alkyl. In some embodiments, R 12 is optionally substituted Cl-C6 heteroalkyl. [0173] In some embodiments of Formula (III), Formula (IIIa), Formula (IIIb), Formula (IIIc), or Formula (X-III), R 12 is optionally substituted C 1 -C 6 alkyl. In some embodiments, R 12 is optionally substituted C 1 -C 6 heteroalkyl. In some embodiments, R 12 is optionally substituted monocyclic heterocycloalkyl In some embodiments, R 12 is optionally substituted pyrrolidine. In some embodiments, R 12 is optionally substituted bicyclic heterocycloalkyl. In some embodiments, R 12 is optionally substituted monocyclic cycloalkyl. In some embodiments, R 12 is optionally substituted bicyclic cycloalkyl. [0174] In some embodiments of Formula (III), Formula (IIIa), Formula (IIIb), Formula (IIIc), or Formula (X-III), R 12 is -L 3 -C1-6 alkylaminyl, -L 3 - C1-6 dialkylaminyl, each of which is optionally substituted. [0175] In some embodiments of Formula (III), Formula (IIIa), Formula (IIIb), Formula (IIIc), or Formula (X-III), R 12 is -L 3 -heterocycloalkyl. In some embodiments, R 12 is -L 3 -heterocycloalkyl, wherein the heterocycloalkyl is an optionally substituted 4-6 membered ring with 1-3 nitrogen atoms. In some embodiments, R 12 is -L 3 -heterocycloalkyl, wherein the heterocycloalkyl is an optionally substituted monocyclic heterocycloalkyl. In some embodiments, R 12 is -L 3 -heterocycloalkyl, wherein the heterocycloalkyl is an optionally substituted bicyclic heterocycloalkyl. In some embodiments, R 12 is -L 3 - heterocycloalkyl, wherein the heterocycloalkyl is an optionally substituted 5-membered ring with 1 nitrogen atom. [0176] In some embodiments of Formula (III), Formula (IIIa), Formula (IIIb), Formula (IIIc), or Formula (X-III), R 12 is C 3 -C 15 cycloalkyl, C 2 -C 12 heterocycloalkyl, -L 3 - C 2 -C 12 heterocycloalkyl, or -L 3 - C 3 - C 15 cycloalkyl, wherein each of the L 3 , heterocycloalkyl, cycloalkyl, alkyl, or heteroalkyl is optionally substituted with one, two, three or four groups selected from R 19 ; and wherein each R 19 is independently selected from oxo, -CN, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 3 -C 10 cycloalkyl, -C 1-3 alkylene-C 3-6 cycloalkyl, C 2 -C 9 heterocycloalkyl, -C 1-3 alkylene-C 2-9 heterocycloalkyl, C 6 -C 10 aryl, -C 1-3 alkylene-C 6-10 aryl, C 1 -C 9 heteroaryl, -C 1-3 alkylene-C 1-9 heteroaryl, -OR 10 , -SR 10 , -N(R 10 )(R 10’ ), -C(=O)OR 10 , -OC(=O)N(R 10 )(R 10’ ), - N(R 10’ )C(=O)N(R 10 )(R 10’ ), -N(R 10’ )C(=O)OR 11 , -N(R 10’ )S(=O) 2 R 11 , -C(=O)R 11 , -S(=O)R 11 , -OC(=O)R 11 , - C(=O)N(R 10 )(R 10’ ), -C(=O)C(=O)N(R 10 )(R 10’ ), -N(R 10’ )C(O)R 11 , -S(O) 2 R 11 , -S(O) 2 N(R 10 )(R 10’ ), - S(=O)(=NH)N(R 10 )(R 10’ ), -CH 2 C(O)N(R 10 )(R 10’ ), -CH 2 N(R 10’ )C(=O)R 11 , -CH 2 S(=O) 2 R 11 , and - CH 2 S(=O) 2 N(R 10 )(R 10’ ), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, -C 1-3 alkylene-C 3-6 cycloalkyl, heterocycloalkyl, -C 1-3 alkylene-C 2 -C 9 heterocycloalkyl, aryl, -C 1-3 alkylene-C 6-10 aryl, heteroaryl and -C 1- 3 alkylene-C 1-9 heteroaryl are optionally substituted with one, two, three, or four groups independently selected from halogen, oxo, -CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkyloxy, C 1 -C 6 haloalkoxy, C 3 -C 10 cycloalkyl, C 2 -C 9 heterocycloalkyl, C 6 -C 10 aryl, C 1 -C 9 heteroaryl, -OR 10 , -SR 10 , - N(R 10 )(R 10’ ), -C(=O)OR 10 , -OC(=O)N(R 10 )(R 10’ ), -N(R 10’ )C(=O)N(R 10 )(R 10’ ), -N(R 10’ )C(=O)OR 11 , - N(R 10’ )S(=O)2R 11 , -C(=O)R 11 , -S(O)R 11 , -OC(=O)R 11 , -C(=O)N(R 10 )(R 10’ ), -C(=O)C(=O)N(R 10 )(R 10’ ), - N(R 10’ )C(=O)R 11 , -S(=O)2R 11 , -S(=O)2N(R 10 )(R 10’ )-, S(=O)(=NH)N(R 10 )(R 10’ ), -CH2C(=O)N(R 10 )(R 10’ ), - CH2N(R 10’ )C(=O)R 11 , -CH2S(=O)2R 11 , and -CH2S(=O)2N(R 10 )(R 10’ ). [0177] In some embodiments of Formula (III), Formula (IIIa), Formula (IIIb), Formula (IIIc), or Formula (X-III), R 12 is -L 3 - C2-C12heterocycloalkyl, optionally substituted with one, two, three or four groups selected from R 19 ; and wherein each R 19 is independently selected from oxo, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, -C1-3alkylene-C6-10aryl, -C1-3alkylene-C1-9 heteroaryl, and OR 10 , wherein the alkyl, heteroalkyl, and -C1- 3alkylene-C6-10aryl, and -C1-3alkylene-C1-9 heteroaryl are optionally substituted with one, two, three, or four groups independently selected from C 1 -C 6 alkyl, C 6 -C 10 aryl, -OR 10 , -C(=O)OR 10 , or -N(R 10’ )C(=O)R 11 . In some embodiments, R 12 is -L 3 - C2-C12heterocycloalkyl, optionally substituted with one, two, or three groups selected from R 19 wherein L 3 is methylene, the heterocycloalkyl is an optionally substituted 5- membered ring with 1 nitrogen atom, and each R 19 is independently selected from oxo, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, -C1-3alkylene-C6-10aryl, -C1-3alkylene-C1-9 heteroaryl, and OR 10 , wherein the alkyl, heteroalkyl, and -C1-3alkylene-C6-10aryl, and -C1-3alkylene-C1-9 heteroaryl are optionally substituted with one, two, three, or four groups independently selected from C 1 -C 6 alkyl, C 6 -C 10 aryl, -OR 10 , -C(=O)OR 10 , or - N(R 10’ )C(=O)R 11 . [0178] In some embodiments, the structure of Formula (III), Formula (IIIa), Formula (IIIb), Formula (IIIc), or Formula (X-III) is attached to the rest of the conjugate through R 12 . In some embodiments, the structure of Formula (III), Formula (IIIa), Formula (IIIb), Formula (IIIc), or Formula (X-III) is attached to the linker or to the metal chelator via R 12 group. In some embodiments, the structure of Formula (III), Formula (IIIa), or Formula (IIIb) is attached to the rest of the conjugate through R 14 . [0179] In some embodiments, the targeting ligand comprises a structure of Formula (IIIa-1) or Formula (IIIa-2), or a salt or solvate thereof, Formula (IIIa-1). Formula (IIIa-2). [0180] In some embodiments, the targeting ligand comprises a structure of Formula (IIIa-1) or a salt thereof. In some embodiments, the targeting ligand comprises a structure of Formula (IIIa-2) or a salt thereof. [0181] In some embodiments, the structure of Formula (III), Formula (IIIa), Formula (IIIa-1), Formula (IIIa-2), Formula (IIIb), or Formula (IIIc) comprises the radionuclide through R 19 . In some embodiments of Formula (III), Formula (IIIa), Formula (IIIa-1), or Formula (IIIa-2), R 16 is the radionuclide. In some embodiments of Formula (III), Formula (IIIa), Formula (IIIa-1), Formula (IIIa-2), Formula (IIIb), , , , , wherein R* is the radionuclide. In some embodiments, R* is selected from a radioisotope in Table 6C or Table 6D. In some embodiments, R* is iodine-131 ( 131 I) or astatine-211 ( 211 At). [0182] In some embodiments of Formula (III), Formula (IIIa), Formula (IIIa-1), Formula (IIIa-2), Formula (IIIb), or Formula (IIIc), R 19 is , , , , [0183] In some embodiments of Formula (III), Formula (IIIa), Formula (IIIb), Formula (IIIc), or Formula (X-III), R 12 is -L 3 -cycloalkyl. In some embodiments, R 12 is -L 3 -cycloalkyl, wherein the cycloalkyl is an optionally substituted 4-6 membered ring. In some embodiments, R 12 is -L 3 -cycloalkyl, wherein the cycloalkyl is an optionally substituted monocyclic ring. In some embodiments, R 12 is -L 3 -cycloalkyl, wherein the cycloalkyl is an optionally substituted bicyclic ring. In some embodiments, R 12 is 3 to 6 membered cycloalkyl. [0184] In some embodiments of Formula (III), Formula (IIIa), Formula (IIIb), Formula (IIIc), or Formula (X-III), L 3 is C 1 -C 4 alkylene or C 1 -C 4 heteroalkylene, each of which is optionally substituted with one or more R 19 . In some embodiments, L 3 is an optionally substituted methylene. In some embodiments, L 3 is an optionally substituted ethylene. In some embodiments, L 3 is an optionally substituted C2-C4 alkylene. In some embodiments, L 3 is an optionally substituted C2-C4 heteroalkylene. [0185] In some embodiments of Formula (III), Formula (IIIa), Formula (IIIa-1), Formula (IIIa-2), Formula (IIIb), Formula (IIIc), or Formula (X-III), R 19 is hydrogen, oxo, acyl, hydroxyl, hydroxyalkyl, cyano, halogen, alkyl, aralkyl, aryl heteroalkyl, cycloalkyl, heterocycloalkyl, alkoxy, dialkylaminyl, dialkylamidoalkyl, or dialkylaminylalkyl. In some embodiments, R 19 is an optionally substituted alkyl, aralkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments, R 19 is alkyl, aralkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl substituted with one or more of hydrogen, hydroxyl, cyano, halogen, or C 1 -C 3 alkyl. In some embodiments, R 19 is an optionally substituted C 1 -C 3 alkyl. In some embodiments, R 19 is an optionally substituted C 1 -C 3 heteroalkyl. In some embodiments, R 19 is hydrogen, oxo, acyl, hydroxyl, hydroxyalkyl, cyano, halogen, or C 1 -C 3 alkyl. In some embodiments, R 19 is optionally substituted C 1 -C 3 alkyl. In some embodiments, R 19 is C 1 -C 3 alkyl substituted with one or more of, hydroxyl, cyano, or halogen. In some embodiments, R 19 is optionally substituted –(CH 2 ) 0-2 C 6 -C 10 aryl. In some embodiments, R 19 is –(CH 2 )phenyl. In some embodiments, R 19 is optionally substituted –(CH 2 )phenyl. In some embodiments, R 19 is C 6 -C 10 aryl. In some embodiments, R 19 is phenyl. In some embodiments, R 19 is C 2 -C 9 heteroalkyl. In some embodiments, R 19 is C 3 -C 7 cycloalkyl. In some embodiments, R 19 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, R 19 is C 2 -C 7 heterocycloalkyl. In some embodiments, R 19 is pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrothiophene, tetrahydrofuranyl, pyranyl, or morpholino. [0186] In some embodiments of Formula (III), Formula (IIIa), Formula (IIIb), Formula (IIIc), or Formula (X-III), X is C(=O). [0187] In some embodiments of Formula (III), Formula (IIIa), Formula (IIIb), Formula (IIIc), or Formula (X-III), L 1 is a bond. [0188] In some embodiments of Formula (III), Formula (IIIa), Formula (IIIb), Formula (IIIc), or Formula (X-III), L 2 is a bond, O, S or NR 15 . In some embodiments, L 2 is O. [0189] In some embodiments of Formula (III), Formula (IIIa), Formula (IIIb), Formula (IIIc), or Formula (X-III), each R 13 is independently OH, halogen, or C 1 -C 3 alkyl. [0190] In some embodiments of Formula (III), Formula (IIIa), Formula (IIIb), Formula (IIIc), or Formula (X-III), m is 0 or 1. In some embodiments, m is 0. [0191] In some embodiments of Formula (III), Formula (IIIa), Formula (IIIb), Formula (IIIc), or Formula (X-III), E is In some embodiments, E is [0192] In some embodiments, the radiolabeled compound comprises a structure of Formula (IIIa), or a salt or solvate thereof, Formula (IIIa), wherein m1 is 0, 1, 2, or 3; and each R 18 is independently halogen, oxo, C 1 -C 6 alkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C2- C6 alkynyl, C 1 -C 6 heteroalkyl, -CN, -C(O)OR 15 , -C(O)N(R 15 )(R 15’ ), -N(R 15 )(R 15’ ), or OR 15 , and wherein each of the alkyl, aminoalkyl, haloalkyl, alkenyl, alkynyl, or heteroalkyl is optionally substituted. [0193] In some embodiments, the radiolabeled compound comprises a structure listed in Table 4A. [0194] In one aspect, provided herein is a radiolabeled compound comprising: (a) a structure of Formula (III), or a salt or solvate thereof, Formula (III) wherein ring Q 1 is a 4-12 membered saturated or partially saturated monocyclic or bicyclic ring, wherein the monocyclic or bicyclic ring is optionally substituted; L 1 is a bond, -C(=O)-, O, S, NR 15 , optionally substituted C 1 -C 3 alkylene, optionally substituted C 1 -C 3 heteroalkylene; L 2 is a bond, -C(=O)-, O, S or NR 15 ; E is X is C(=O), P(=O)OR 2 , C(=S), or S(=O)n, where n is 1 or 2; R 2 is H or optionally substituted C 1 -C 3 alkyl; R 5 is hydrogen, cyano, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxyl, C 1 -C 6 heteroalkyl, C 3 -C 6 cycloalkyl, or C 2 -C 5 heterocycloalkyl, each of the alkyl, alkoxyl, heteroalkyl, cycloalkyl or heterocycloalkyl is optionally substituted, and R 7 is hydrogen, cyano, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxyl, C 1 -C 6 heteroalkyl, C 3 -C 6 cycloalkyl, C 2 -C 5 heterocycloalkyl, heteroaryl, -C 1 -C 6 alkylene-heteoraryl, -C 1 -C 6 alkylene-NH(C 1 -C 6 alkyl), or -C1- C6alkylene-N(C 1 -C 6 alkyl)2, each of the alkyl, alkylene, alkoxyl, heteroalkyl, cycloalkyl or heterocycloalkyl is optionally substituted; or R 5 and R 7 taken together form a bond; or R 5 and R 7 taken together with the carbon atoms to which they are attached form a 5-8 membered partially saturated cycloalkyl, wherein the cycloalkyl is optionally substituted; R 6 is hydrogen, cyano, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxyl, C 1 -C 6 heteroalkyl, C 3 -C 6 cycloalkyl, C 2 -C 5 heterocycloalkyl, heteroaryl, -C 1 -C 6 alkylene-heteoraryl, -C 1 -C 6 alkylene-NH(C 1 -C 6 alkyl), or -C 1 - C 6 alkylene-N(C 1 -C 6 alkyl) 2 , each of the alkyl, alkylene, alkoxyl, heteroalkyl, cycloalkyl, heterocycloalkyl, or heteroaryl is optionally substituted; R 12 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, -L 3 -NR 15 R 15’ , heterocycloalkyl, -L 3 -heterocycloalkyl, cycloalkyl, -L 3 -cycloalkyl, aryl, heteroaryl, -L 3 -aryl, or -L 3 -heteroaryl, wherein each of the heterocycloalkyl, cycloalkyl, aryl, heteroaryl, alkyl or heteroalkyl is optionally substituted; L 3 is C 1 -C 4 alkylene or C 1 -C 4 heteroalkylene, each of which is optionally substituted; each R 13 is independently OH, halogen, oxo, substituted or unsubstituted C 1 -C 6 alkyl, or substituted or unsubstituted C 1 -C 6 heteroalkyl; R 14 is hydrogen, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each of the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted; each R 15 is independently hydrogen or optionally substituted C 1 -C 3 alkyl; each R 15’ is independently hydrogen, acyl, optionally substituted C 1 -C 3 alkyl, optionally substituted C 1 -C 3 heteroalkyl or optionally substituted C 1 -C 3 hydroxyalkyl; and m is 0, 1, or 2; (b) a covalently bonded radioisotope R*; and (c) a linker covalently connecting the radioisotope R* and the structure of Formula (III) or a salt or solvate thereof. In some embodiments, R* is selected from a radioisotope in Table 6C or Table 6D. [0195] In some embodiments, the radiolabeled compound comprises a structure of Formula (IIIb),
Formula (IIIb), wherein L C is a linker comprising 1 to 20 groups independently selected from -CR b R b -, -C(=O)-, -S(=O)-, -S(=O)2- , -NR a -, , , -CR b =CR b -, -C C-, -O-, -S-, -C(=O)O-, -OC(=O)-, -C(=O)NR a -, - NR a C(=O)-, -S(=O) 2 NR a -, -NR a S(=O) 2 -, -NR a C(=O)NR a -, - NR a C(=O)O-, -OC(=O)NR a -, arylene, heteroarylene; each R a is independently hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 2 - C 9 heterocycloalkyl, aryl, or heteroaryl; each R b is independently hydrogen, halogen, -CN, -NO 2 , -OR a , -SR a , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 2 -C 9 heterocycloalkyl, aryl, or heteroaryl; each R 18 is independently halogen, oxo, C 1 -C 6 alkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, -CN, -C(O)OR 15 , -C(O)N(R 15 )(R 15’ ), -N(R 15 )(R 15’ ), or OR 15 , and wherein each of the alkyl, aminoalkyl, haloalkyl, alkenyl, alkynyl, or heteroalkyl is optionally substituted with one, two, or three groups selected from halogen, -CN, -NO 2 , amino, hydroxy, C 1 - C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, and C 2 -C 5 heterocycloalkyl; R 12 is C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, -L 3 -NR 15 R 15’ , C 2 -C 12 heterocycloalkyl, -L 3 - C 2 - C12heterocycloalkyl, C3-C15cycloalkyl, -L 3 - C3-C15cycloalkyl, aryl, C 1 -C 9 heteroaryl, -L 3 -aryl, or - L 3 - C 1 -C 9 heteroaryl, wherein each of the heterocycloalkyl, cycloalkyl, aryl, heteroaryl, alkyl or heteroalkyl is optionally substituted with one, two, three or four groups selected from R 19 ; m1 is 0, 1, 2, or 3; and R* is fluorine-18 ( 18 F), iodine-131 ( 131 I), iodine-123 ( 123 I), iodine-124 ( 124 I), iodine-125 ( 125 I), or astatine- 211 ( 211 At); and the other variables are as defined in Formula (III), Formula (IIIa), Formula (IIIa-1) or Formula (IIIa-2). [0196] In some embodiments, the radiolabeled compound comprises a structure of Formula (IIIc), Formula (IIIc). [0197] Compounds of Formula (III), Formula (IIIa), Formula (IIIa-1), Formula (IIIa-2), Formula (IIIb), and Formula (IIIc) including pharmaceutically acceptable salts, prodrugs, active metabolites, and pharmaceutically acceptable solvates thereof, can form a covalent bond with KRAS G12C. [0198] In some embodiments of Formula (III), Formula (IIIa), Formula (IIIa-1), Formula (IIIa-2), Formula (IIIb), or Formula (IIIc), the radiolabeled compound comprises a structure listed in Table 4B. [0199] In some embodiments of Formula (IIIb) or Formula (IIIc), L C is a linker as described herein. [0200] In some embodiments of Formula (IIIb) or Formula (IIIc), L C comprises a structure of Table 3C. In some embodiments, L C comprises one or more structures of Table 3A and 3B. [0201] In some embodiments of Formula (IIIb) or Formula (IIIc), L C comprises , , , , , , In some embodiments of Formula (IIIb) or Formula (IIIc), L C is selected from the group consisting of , [0202] In some embodiments, the radiolabeled compound comprises a structure of Formula (IIIb) or 1 to 10. In some embodiments, each k1 and k2 is independently 0 or an integer selected from 1 to 5. In some embodiments, k1 is 0 to 5 and k2 is 0 to 2. In some embodiments, k1 is 2 to 4 and k2 is 0 to 1. [0203] In some embodiments, the radiolabeled compound comprises a structure of Formula (IIIb) or Formula (IIIc) wherein L C -R* is , , ,
in Table 6C or Table 6D. In some embodiments, R* is iodine-131 ( 131 I) or astatine-211 ( 211 At). [0204] In some embodiments, provided herein are compounds having the structures of the radiolabeled compounds described herein (e.g., a compound of Formula (III), Formula (IIIa), Formula (IIIa-1), Formula (IIIa-2), Formula (IIIb), or Formula (IIIc), except that the radioisotope is replaced with a surrogate (e.g., 131 I replaced with iodine), i.e., a cold compound. In some embodiments, a radionuclide of the radiolabeled compounds described herein can be replaced with a surrogate (e.g., 131 I replaced with iodine) for testing and experimental purposes. [0205] In one aspect, provided herein is a radiolabeled compound has a structure of Formula (IV), or a salt or solvate thereof, Formula (IV) wherein E 1 and E 2 are each independently N or CR 21 ; E 3 is CR 28 R 29 , C=CR 28 R 29 , C═O, C=S, or C=NR 28 ; J is N, NR 30 , or CR 30 ; M is N, NR 33 , or CR 33 ; is a single or double bond as necessary to give every atom its normal valence; R 21 is independently H, hydroxyl, cyano, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxyl, or C 1 -C 6 heteroalkyl, wherein each of the alkyl, alkoxy, and heteroalkyl is optionally substituted; R 22 is hydrogen, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, OR 22’ , N(R 22’ )2, cycloalkyl, -C1- C3alkylene-cycloalkyl, heterocycloalkyl, -C 1 -C 3 alkylene-heterocycloalkyl, aryl, -C 1 -C 3 alkylene-aryl, heteroaryl, or -C 1 -C 3 alkylene-heteroaryl, wherein each of the alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted, and each R 22’ is independently H, C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, aryl, or heteroaryl, wherein each of the alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, and heteroaryl is optionally substituted, or two R 22’ together with the nitrogen atom to which they are attached, form a 3-7-membered ring; R 23 is hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -L 4 -cycloalkyl, -L 4 -heterocycloalkyl, -L 4 -aryl, or -L 4 -heteroaryl, wherein each of the alkyl, alkoxy, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, and heteroaryl is optionally substituted; L 4 is C 1 -C 4 alkylene or C 1 -C 4 heteroalkylene, each of which is optionally substituted; ring A is an optionally substituted 4-7 membered monocyclic ring or optionally substituted 6-11 membered bicyclic, bridged, fused, or spiro ring; R 1 is H, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted C 3 -C 6 cycloalkyl, or optionally substituted C 2 -C 5 heterocycloalkyl; L is a bond, S, O, or NR 10’ , optionally substituted C 1 -C 6 alkylene, or optionally substituted C 1 -C 6 heteroalkylene; E represents a structure of Formula (Ic), wherein, X is C(=O), P(=O)OR 2 , C(=S), or S(=O)n, where n is 1 or 2; R 2 is H or optionally substituted C 1 -C 3 alkyl; R 5 is hydrogen, cyano, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxyl, C 1 -C 6 heteroalkyl, C 3 -C 6 cycloalkyl, or C 2 -C 5 heterocycloalkyl, each of the alkyl, alkoxyl, heteroalkyl, cycloalkyl or heterocycloalkyl is optionally substituted, and R 7 is hydrogen, cyano, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxyl, C 1 -C 6 heteroalkyl, C 3 -C 6 cycloalkyl, C 2 -C 5 heterocycloalkyl, heteroaryl, -C 1 -C 6 alkylene-heteoraryl, -C 1 -C 6 alkylene-NH(C 1 -C 6 alkyl), or -C1- C6alkylene-N(C 1 -C 6 alkyl)2, each of the alkyl, alkylene, alkoxyl, heteroalkyl, cycloalkyl or heterocycloalkyl is optionally substituted; or R 5 and R 7 taken together form a bond; or R 5 and R 7 taken together with the carbon atoms to which they are attached form a 5-8 membered partially saturated cycloalkyl, wherein the cycloalkyl is optionally substituted; R 6 is hydrogen, cyano, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxyl, C 1 -C 6 heteroalkyl, C 3 -C 6 cycloalkyl, C 2 -C 5 heterocycloalkyl, heteroaryl, -C 1 -C 6 alkylene-heteoraryl, -C 1 -C 6 alkylene-NH(C 1 -C 6 alkyl), or -C1- C 6 alkylene-N(C 1 -C 6 alkyl) 2 , each of the alkyl, alkylene, alkoxyl, heteroalkyl, cycloalkyl, heterocycloalkyl, or heteroaryl is optionally substituted; R 28 and R 29 are each independently hydrogen, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, cyano, nitro, C 3 -C 6 cycloalkyl, or C 2 -C 5 heterocycloalkyl, or R 28 and R 29 taken together with the carbon atom to which they are attached form a 3-6 membered ring; R 30 is selected from halogen, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -L 4 -cycloalkyl, -L 4 -heterocycloalkyl, -L 4 -aryl, -L 4 -heteroaryl, - OR 10 , -SR 10 , -N(R 10 )(R 10’ ), -C(O)OR 10 , -OC(O)N(R 10 )(R 10’ ), -N(R 10’ )C(O)N(R 10 )(R 10’ ), - N(R 10’ )C(O)OR 11 , -N(R 10’ )S(O) 2 R 11 , -C(O)R 11 , -S(O)R 11 , -OC(O)R 11 , -C(O)N(R 10 )(R 10’ ), - C(O)C(O)N(R 10 )(R 10’ ), -N(R 10’ )C(O)R 11 , -S(O) 2 R 11 , -S(O) 2 N(R 10 )(R 10’ )-, S(=O)(=NH)N(R 10 )(R 10’ ), - CH 2 C(O)N(R 10 )(R 10’ ), -CH 2 N(R 10’ )C(O)R 11 , -CH 2 S(O) 2 R 11 , or -CH 2 S(O) 2 N(R 10 )(R 10’ ), wherein each of the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted; R 33 is H, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, or C 3 -C 6 cycloalkyl, wherein each of the alkyl, heteroalkyl, and cycloalkyl is optionally substituted; each R 10 is independently selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -C 10 aryl, and C 1 -C 9 heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, C 2 -C 9 heterocycloalkyl, C 6 -C 10 aryl, and C 1 -C 9 heteroaryl; each R 10’ is independently selected from hydrogen, C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl; and each R 11 is independently selected C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 2 -C 9 heterocycloalkyl, C 6 -C 10 aryl, and C 1 -C 9 heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, C2-C9 heterocycloalkyl, C 6 -C 10 aryl, and C 1 -C 9 heteroaryl; provided that at least one of R 21 , R 22 , R 23 , R 24 , and R 30 comprises a covalently bonded radioisotope R*. [0206] In some embodiments, R* is selected from a radioisotope in Table 6C or Table 6D. [0207] In one aspect, described herein is a radiopharmaceutical conjugate comprising a) a targeting ligand that is configured to form a covalent bond with a KRAS protein at the G12C position, wherein the residue position numbering of the KRAS protein is based on SEQ ID NO:1 or SEQ ID NO: 2 and b) a radionuclide. In some embodiments, the targeting ligand comprises a structure of Formula (IV), or a salt or solvate thereof, Formula (IV) wherein E 1 and E 2 are each independently N or CR 21 ; E 3 is CR 28 R 29 , C=CR 28 R 29 , C═O, C=S, or C=NR 28 ; J is N, NR 30 , or CR 30 ; M is N, NR 33 , or CR 33 ; is a single or double bond as necessary to give every atom its normal valence; R 21 is independently hydrogen, hydroxyl, cyano, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxyl, or C 1 -C 6 heteroalkyl, wherein each of the alkyl, alkoxy, and heteroalkyl are optionally substituted; R 22 is hydrogen, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, OR 22’ , N(R 22’ )2, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each of the alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted, and each R 22’ is independently hydrogen, C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, aryl, or heteroaryl, wherein each of the alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, and heteroaryl is optionally substituted, or two R 22’ together with the nitrogen atom to which they are attached, form a 3-7-membered ring; R 23 is hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, wherein each of the alkyl, alkoxy, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, and heteroaryl is optionally substituted; ring A is an optionally substituted 4-7 membered monocyclic ring or optionally substituted 6-11 membered bicyclic, bridged, fused, or spiro ring; R 1 is hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted C 3 -C 6 cycloalkyl, or optionally substituted C 2 -C 5 heterocycloalkyl; L is a bond, C 1 -C 6 alkylene, C 1 -C 6 heteroalkylene, S, O, or NH; E represents a structure of Formula (Ic), wherein, X is C(=O), P(=O)OR 2 , C(=S), or S(=O)n, where n is 1 or 2; R 2 is hydrogen or optionally substituted C 1 -C 3 alkyl; R 5 is hydrogen, cyano, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxyl, C 1 -C 6 heteroalkyl, C 3 -C 6 cycloalkyl, or C 2 -C 5 heterocycloalkyl, each of the alkyl, alkoxyl, heteroalkyl, cycloalkyl or heterocycloalkyl is optionally substituted, and R 7 is hydrogen, cyano, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxyl, C 1 -C 6 heteroalkyl, C3-C7 cycloalkyl, C2- C7 heterocycloalkyl, heteroaryl, -C 1 -C 6 alkylene-heteoraryl, -C 1 -C 6 alkylene-NH(C 1 -C 6 alkyl), or - C 1 -C 6 alkylene-N(C 1 -C 6 alkyl)2, each of the alkyl, alkylene, alkoxyl, heteroalkyl, cycloalkyl or heterocycloalkyl is optionally substituted; or R 5 and R 7 taken together form a bond; or R 5 and R 7 taken together with the carbon atoms to which they are attached form a 5-8 membered partially saturated cycloalkyl, wherein the cycloalkyl is optionally substituted; R 6 is hydrogen, cyano, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxyl, C 1 -C 6 heteroalkyl, C 3 -C 6 cycloalkyl, C2- C5 heterocycloalkyl, heteroaryl, -C 1 -C 6 alkylene-heteoraryl, -C 1 -C 6 alkylene-NH(C 1 -C 6 alkyl), or - C 1 -C 6 alkylene-N(C 1 -C 6 alkyl)2, each of the alkyl, alkylene, alkoxyl, heteroalkyl, cycloalkyl, heterocycloalkyl, or heteroaryl is optionally substituted; R 28 and R 29 are each independently hydrogen, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, cyano, nitro, or C3- C6 cycloalkyl, or R 28 and R 29 taken together with the carbon atom to which they are attached form a 3-6 membered ring; R 30 is selected from halogen, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -C 1 -C 6 alkylene-cycloalkyl, -C 1 -C 6 alkylene-heterocycloalkyl, - C 1 -C 6 alkylene-aryl, -C 1 -C 6 alkylene-heteroaryl, -C 1 -C 6 heteroalkylene-cycloalkyl, -C1- C 6 heteroalkylene-heterocycloalkyl, -C 1 -C 6 heteroalkylene-aryl, -C 1 -C 6 alkylene-heteroaryl wherein each of the alkyl, alkoxy, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted; and R 33 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, or C 3 -C 6 cycloalkyl, wherein each of the alkyl, heteroalkyl, and cycloalkyl is optionally substituted. In some embodiments, the structure of Formula (IV) is attached to the rest of the conjugate at any suitable position. [0208] In some embodiments, the radionuclide is covalently bound to the structure of Formula (IV). In some embodiments, the structure of Formula (IV) is attached to the linker or to the rest of the conjugate via group J or group E 3 . In some embodiments, J is NR 30 , and the structure of Formula (IV) is attached to the linker or to the rest of the conjugate via group R 30 . In some embodiments, the structure of Formula (IV) is attached to the linker or to the rest of the conjugate via group R 22 . [0209] In some embodiments of Formula (IV), E 1 and E 2 are each independently N or CR 21 ; E 3 is CR 28 R 29 , C=CR 28 R 29 , C═O, C=S, or C=NR 28 ; J is N, NR 30 , or CR 30 ; M is N, NR 33 , or CR 33 ; is a single or double bond as necessary to give every atom its normal valence; R 21 is independently hydrogen, hydroxyl, cyano, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxyl, or C 1 -C 6 heteroalkyl, wherein each of the alkyl, alkoxy, and heteroalkyl is optionally substituted with one, two, or three groups selected from halogen, -CN, -NO2, amino, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, C 2 -C 5 heterocycloalkyl, C 6 -C 10 aryl, and C 1 -C 9 heteroaryl; R 22 is hydrogen, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, OR 22’ , N(R 22’ ) 2 , cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each of the alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three groups selected from halogen, -CN, -NO 2 , amino, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, and C 2 -C 5 heterocycloalkyl, and each R 22’ is independently hydrogen, C 1 - C 6 alkyl, cycloalkyl, heterocycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, aryl, or heteroaryl, wherein each of the alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, and heteroaryl is optionally substituted with one, two, or three groups selected from halogen, -CN, -NO 2 , amino, hydroxy, C 1 - C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, C 2 -C 5 heterocycloalkyl, C 6 -C 10 aryl, and C 1 -C 9 heteroaryl; or two R 22’ together with the nitrogen atom to which they are attached, form an optionally substituted 3-7-membered ring with one, two, or three groups selected from halogen, - CN, -NO 2 , amino, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, C 2 -C 5 heterocycloalkyl, C 6 -C 10 aryl, and C 1 -C 9 heteroaryl; R 23 is hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, wherein each of the alkyl, alkoxy, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, and heteroaryl is optionally substituted with one, two, or three groups selected from halogen, -CN, -NO 2 , amino, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 3 - C 6 cycloalkyl, C 2 -C 5 heterocycloalkyl, C 6 -C 10 aryl, and C 1 -C 9 heteroaryl; R 24 is ring A is an optionally substituted 4-7 membered monocyclic ring or optionally substituted 6-11 membered bicyclic, bridged, fused, or spiro ring each of which is optionally substituted with one, two, or three groups selected from halogen, -CN, -NO2, amino, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, C 2 -C 5 heterocycloalkyl, C 6 -C 10 aryl, and C 1 -C 9 heteroaryl; R 1 is hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted C 3 -C 6 cycloalkyl, or optionally substituted C 2 -C 5 heterocycloalkyl each of which is optionally substituted with one, two, or three groups selected from halogen, -CN, -NO2, amino, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, C 2 -C 5 heterocycloalkyl, C6- C10 aryl, and C 1 -C 9 heteroaryl; L is a bond, C 1 -C 6 alkylene, C 1 -C 6 heteroalkylene, S, O, or NH; E represents a structure of Formula (Ic), wherein, X is C(=O), P(=O)OR 2 , C(=S), or S(=O)n, where n is 1 or 2; R 2 is hydrogen or substituted or unsubstituted C 1 -C 3 alkyl, wherein the alkyl is optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 alkoxy, C 3 -C 6 cycloalkyl, and C 2 -C 5 heterocycloalkyl, C 6 -C 10 aryl, and C 1 -C 9 heteroaryl; R 5 is hydrogen, cyano, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxyl, C 1 -C 6 heteroalkyl, C 3 -C 6 cycloalkyl, or C 2 -C 5 heterocycloalkyl, each of the alkyl, alkoxyl, heteroalkyl, cycloalkyl or heterocycloalkyl is optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, C 2 -C 5 heterocycloalkyl, C 6 -C 10 aryl, and C1- C9 heteroaryl; R 7 is hydrogen, cyano, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxyl, C 1 -C 6 heteroalkyl, C3-C7 cycloalkyl, C2- C7 heterocycloalkyl, heteroaryl, -C 1 -C 6 alkylene-heteoraryl, -C 1 -C 6 alkylene-NH(C 1 -C 6 alkyl), or - C 1 -C 6 alkylene-N(C 1 -C 6 alkyl) 2 , each of the alkyl, alkylene, alkoxyl, heteroalkyl, cycloalkyl or heterocycloalkyl is optionally substituted with one, two, or three groups selected from halogen, - CN, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, C 2 -C 5 heterocycloalkyl, C 6 -C 10 aryl, and C 1 -C 9 heteroaryl; or R 5 and R 7 taken together form a bond; or R 5 and R 7 taken together with the carbon atoms to which they are attached form a 5-8 membered partially saturated cycloalkyl, wherein the cycloalkyl is optionally substituted with one, two or three groups selected from R 17 ; R 6 is hydrogen, cyano, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxyl, C 1 -C 6 heteroalkyl, C 3 -C 6 cycloalkyl, C 2 - C 5 heterocycloalkyl, heteroaryl, -C 1 -C 6 alkylene-heteoraryl, -C 1 -C 6 alkylene-NH(C 1 -C 6 alkyl), or - C 1 -C 6 alkylene-N(C 1 -C 6 alkyl) 2 , each of the alkyl, alkylene, alkoxyl, heteroalkyl, cycloalkyl, heterocycloalkyl, or heteroaryl is optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, C 2 -C 5 heterocycloalkyl, C 6 -C 10 aryl, and C 1 -C 9 heteroaryl; each R 17 is independently halogen, hydroxyl, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, amino, cyano, C 1 -C 6 heteroalkyl, C 1 -C 6 hydroxyalkyl, -O-C 1 -C 6 haloalkyl, or -S-C1- C6haloalkyl; R 28 and R 29 are each independently hydrogen, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, cyano, nitro, or C3- C6 cycloalkyl, or R 28 and R 29 taken together with the carbon atom to which they are attached form a 3-6 membered ring; R 30 is selected from halogen, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -C 1 -C 6 alkylene-cycloalkyl, -C 1 -C 6 alkylene-heterocycloalkyl, - C 1 -C 6 alkylene-aryl, -C 1 -C 6 alkylene-heteroaryl, -C 1 -C 6 heteroalkylene-cycloalkyl, -C1- C6heteroalkylene-heterocycloalkyl, -C 1 -C 6 heteroalkylene-aryl, -C 1 -C 6 alkylene-heteroaryl wherein each of the alkyl, alkoxy, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, C 2 -C 5 heterocycloalkyl, C 6 -C 10 aryl, and C 1 - C 9 heteroaryl; and R 33 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, or C 3 -C 6 cycloalkyl, wherein each of the alkyl, heteroalkyl, and cycloalkyl is optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, C 2 -C 5 heterocycloalkyl, C 6 -C 10 aryl, and C 1 -C 9 heteroaryl. [0210] In some embodiments of Formula (IV), Formula (IVa), or Formula (X-IV), E 1 is N. In some embodiments, E 1 is CR 21 . [0211] In some embodiments of Formula (IV), Formula (IVa), or Formula (X-IV), E 2 is N. In some embodiments, E 2 is CR 21 . [0212] In some embodiments of Formula (IV) or Formula (X-IV), E 3 is C=O, C=S, or C=NH. In some embodiments, E 3 is C=O. [0213] In some embodiments of Formula (IV) or Formula (X-IV), J is NR 30 . In some embodiments, J is N. In some embodiments, J is CR 30 . [0214] In some embodiments of Formula (IV) or Formula (X-IV), M is N. In some embodiments, M is NR 33 . In some embodiments, M is CR 33 . [0215] In some embodiments of Formula (IV) or Formula (X-IV), when J is NR 30 , M is N or CR 33 . In some embodiments, when M is NR 33 , J is N or CR 30 . In some embodiments, when J is CR 30 , M is N or NR 33 . In some embodiments, when M is CR 33 , J is N or NR 30 . [0216] In some embodiments of Formula (IV) or Formula (X-IV), E 1 is N; E 2 is CR 21 ; J is NR 30 ; and M is N. In some embodiments, E 1 is CR 21 ; E 2 is CR 21 ; J is NR 30 ; and M is N. [0217] In some embodiments of Formula (IV), Formula (IVa), Formula (IVb), Formula (IVc), Formula (IVd), Formula (IVe), or Formula (X-IV), R 21 is independently hydrogen, hydroxyl, cyano, halogen, C1- C6alkyl, C1-C4haloalkyl, C1-C4alkoxyl, or C1-C4heteroalkyl. In some embodiments, R 21 is independently hydrogen, hydroxyl, cyano, halogen, or methyl. In some embodiments, R 21 is hydrogen. [0218] In some embodiments of Formula (IV), Formula (IVa), Formula (IVb), Formula (IVc), or Formula (IVd), R 22 is halogen, C 1 -C 6 alkyl, C 2 -C 3 alkenyl, C2-C3alkynyl, OR 22’ , N(R 22’ )2, C 3 -C 6 cycloalkyl, C 2 - C 5 heterocycloalkyl, C 6 -C 14 aryl, or C 2 -C 14 heteroaryl, each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted, and each R 22’ is independently hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 5 heterocycloalkyl, C 2 -C 3 alkenyl, C 2 -C 3 alkynyl, C 6 -C 14 aryl, C 2 - C 14 heteroaryl, wherein each of the alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, and heteroaryl is optionally substituted, or two R 22’ together with the nitrogen atom to which they are attached, form an optionally substituted 3-7-membered ring. [0219] In some embodiments of Formula (IV), Formula (IVa), Formula (IVb), Formula (IVc), or Formula (IVd), R 22 is C 0 -C 3 akylene-C 3 -C 14 cycloalkyl, C 0 -C 3 alkylene-C2-C14 heterocycloalkyl, C 0 -C 3 akylene- C 6 -C 14 aryl, or C 0 -C 3 akylene-C 2 -C 14 heteroaryl, each of which is optionally substituted. In some embodiments, R 22 is hydrogen. [0220] In some embodiments of Formula (IV), Formula (IVa), Formula (IVb), Formula (IVc), Formula (IVd), Formula (IVe), or Formula (X-IV), R 22 is optionally substituted monocyclic cycloalkyl. In some embodiments, R 22 is optionally substituted bicyclic cycloalkyl. In some embodiments, R 22 is optionally substituted monocyclic heterocycloalkyl. In some embodiments, R 22 is optionally substituted bicyclic heterocycloalkyl. [0221] In some embodiments of Formula (IV), Formula (IVa), Formula (IVb), Formula (IVc), Formula (IVd), Formula (IVe), or Formula (X-IV), R 22 is C 6 -C 14 aryl or C 2 -C 14 heteroaryl, each of which is optionally substituted. In some embodiments, R 22 is aryl or heteroaryl substituted with one or more C 1 -C 3 alkyl, halogen, and/or hydroxyl. In some embodiments, R 22 is C 6 -C 10 aryl optionally substituted. In some embodiments, R 22 is optionally substituted phenyl. In some embodiments, R 22 is optionally substituted naphthyl. In some embodiments, R 22 is optionally substituted C 2 -C 9 heteroaryl. In some embodiments, R 22 is optionally substituted pyrrolyl, imidazolyl, pyridinyl, pyrazinyl, indolyl, or quinolinyl. In some embodiments, R 22 is phenyl, optionally substituted with one or more C 1 -C 3 alkyl, halogen, and/or hydroxyl. In some embodiments, R 22 is phenyl substituted with fluorine and hydroxyl. [0222] In some embodiments of Formula (IV), Formula (IVa), Formula (IVb), Formula (IVc), Formula (IVd), Formula (IVe), or Formula (X-IV), R 22 is optionally substituted with one or more substituents selected from: C 1 -C 12 alkyl, C 1 -C 12 heteroalkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 5 -C 20 aryl, C 5 -C 20 heteroaryl, C 6 -C 24 alkaryl, C 6 -C 24 aralkyl, halo, hydroxyl, sulfhydryl, C 1 -C 12 alkoxy, C 2 -C 12 alkenyloxy, C 2 -C 12 alkynyloxy, C 5 -C 20 aryloxy, acyl (including C 2 -C 24 alkylcarbonyl (—CO-alkyl)), oxo, amino, -CN, isocyano, nitro, C3-C10cycloalkyl, and C2-C10heterocycloalkyl, each of which is optionally further substituted. [0223] In some embodiments, of Formula (IV), Formula (IVa), Formula (IVb), Formula (IVc), Formula (IVd), Formula (IVe), or Formula (X-IV) is attached to the linker or to the rest of the conjugate via group R 22 . In some embodiments, of Formula (IV), Formula (IVa), Formula (IVb), Formula (IVc), Formula (IVd), Formula (IVe), or Formula (X-IV) is attached to the linker or to the rest of the conjugate via a substituent of group R 22 . [0224] In some embodiments of Formula (IV), Formula (IVa), Formula (IVb), Formula (IVc), Formula (IVd), or Formula (IVe), R 22 comprises the covalently bonded radioisotope R*. In some embodiments of Formula (IV), Formula (IVa), Formula (IVb), or Formula (IVc), R 22 is , and R* is fluorine-18 ( 18 F), iodine-131 ( 131 I), iodine-123 ( 123 I), iodine-124 ( 124 I), iodine-125 ( 125 I), or astatine-211 ( 211 At). In some embodiments, R* is 131 I. [0225] In some embodiments of Formula (IV), Formula (IVa), Formula (IVb), Formula (IVc), Formula (IVd), Formula (IVe), or Formula (X-IV), R 23 is hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 3 alkoxy, C 3 - C 6 cycloalkyl, C 2 -C 5 heterocycloalkyl, C 2 -C 3 alkenyl, C 2 -C 3 alkynyl, C 6 -C 14 aryl, or C 2 -C 14 heteroaryl, wherein each of the alkyl, alkoxy, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, and heteroaryl is optionally substituted. In some embodiments, R 23 is halogen, C 1 -C 3 alkoxy, or C 1 -C 3 alkyl where the C 1 - C 3 alkyl is optionally substituted with a halo group. In some embodiments, R 23 is hydrogen. [0226] In some embodiments of Formula (IV), Formula (IVa), Formula (IVb), Formula (IVc),or Formula (IVd), R 23 comprises the radionuclide. In some embodiments, the radionuclide is covalently bound. [0227] In some embodiments of Formula (IV), Formula (IVa), Formula (IVb), or Formula (IVc), R 23 is halogen and the halogen is the radionuclide selected from fluorine-18 ( 18 F), iodine-131 ( 131 I), iodine-123 ( 123 I), iodine-124 ( 124 I), iodine-125 ( 125 I), and astatine-211 ( 211 At). In some embodiments, R 23 is halogen and the halogen is a radioisotope selected from 124 I, 125 I, and 131 I. In some embodiments, R 23 is 131 I. [0228] In some embodiments of Formula (IV), Formula (IVa), Formula (IVb), Formula (IVc), Formula (IVd), Formula (IVe), or Formula (X-IV), R 23 is C 3 -C 6 cycloalkyl or C 2 -C 5 heterocycloalkyl. In some embodiments, R 23 is cyclopropyl or cyclopentyl optionally substituted. In some embodiments, R 23 is cyclopropyl optionally substituted with hydroxyl, halo, or methyl groups. In some embodiments, R 23 is aziridinyl, pyrrolidinyl, tetrahydrothiopheneyl, tetrahydrofuranyl each of which is optionally substituted. [0229] In some embodiments of Formula (IV), Formula (IVa), Formula (IVb), Formula (IVc), Formula (IVd), Formula (IVe), or Formula (X-IV), R 23 is C 1 -C 3 haloalkyl. In some embodiments, R 23 is halogen. In some embodiments, R 23 is -CF3. In some embodiments, R 23 is F. [0230] In some embodiments of Formula (IV), Formula (IVa), Formula (IVb), Formula (IVc), Formula (IVd), Formula (IVe), or Formula (X-IV), R 23 is C 6 -C 14 aryl or C2-C14heteroaryl, each of which is optionally substituted. In some embodiments, R 23 is optionally substituted C 6 -C 10 aryl. In some embodiments, R 23 is optionally substituted phenyl. In some embodiments, R 23 is optionally substituted naphthyl. In some embodiments, R 23 is optionally substituted C2-C9 heteroaryl. In some embodiments, R 23 is optionally substituted pyrrolyl, imidazolyl, pyridinyl, pyrazinyl, indolyl, or quinolinyl. In some embodiments, R 23 is phenyl, optionally substituted with one or more C 1 -C 3 alkyl, halogen, and/or hydroxyl. In some embodiments, R 23 is phenyl substituted with fluorine and hydroxyl. [0231] In some embodiments of Formula (IV) or Formula (X-IV), R 24 is . In some embodiments, R 24 is [0232] In some embodiments of Formula (IV), Formula (IVa), Formula (IVb), Formula (IVc), Formula (IVd), Formula (IVe), or Formula (X-IV), ring A is a substituted or unsubstituted 4-7 membered monocyclic ring. In some embodiments, ring A is substituted or unsubstituted 6 membered monocyclic heterocyclic ring. In some embodiments, ring A is piperazinyl substituted with halogen or C 1 -C 3 alkyl. In some embodiments, ring A is piperazinyl substituted with methyl. In some embodiments, ring A is unsubstituted piperazinyl. [0233] In some embodiments of Formula (IV), Formula (IVa), Formula (IVb), Formula (IVc), Formula (IVd), Formula (IVe), or Formula (X-IV), L is L is a bond, C 1- C 6 alkylene, -O-C 0- C 5 alkylene, -S-C 0- C 5 alkylene, or -NH-C 0- C 5 alkylene, and for C 2- C 5 alkylene, -O-C 2- C 5 alkylene, -S-C 2- C 5 alkylene, and NH-C 2- C5 alkylene, one carbon atom of the alkylene group can optionally be replaced O, S, or NH. [0234] In some embodiments of Formula (IV), Formula (IVa), Formula (IVb), Formula (IVc), Formula (IVd), Formula (IVe), or Formula (X-IV), L is a bond, C 1 -C 3 alkylene, S, O, or NH. In some embodiments, L is a bond, CH2, O, or NH. In some embodiments, L is a bond. [0235] In some embodiments of Formula (IV), Formula (IVa), Formula (IVb), Formula (IVc), Formula (IVd), Formula (IVe), or Formula (X-IV), X is C(=O). In some embodiments of Formula (IV), Formula (IVa), Formula (IVb), Formula (IVc), Formula (IVd), Formula (IVe), or Formula (X-IV), R 5 is hydrogen, cyano, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxyl, C 1 -C 6 heteroalkyl, C 3 -C 6 cycloalkyl, or C 2 -C 5 heterocycloalkyl, each of which is optionally substituted. In some embodiments, R 5 is hydrogen or a C 1 -C 3 alkyl optionally substituted by one or more hydroxyl and/or halogen. In some embodiments, R 5 is a halogen. In some embodiments, R 5 is fluoro. In some embodiments, R 5 is C 1 -C 6 heteroalkyl. In some embodiments, R 5 is hydrogen. In some embodiments of Formula (IV), Formula (IVa), Formula (IVb), Formula (IVc), Formula (IVd), Formula (IVe), or Formula (X-IV), R 7 is hydrogen, cyano, halogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 alkoxyl, or optionally substituted C 1 -C 6 heteroalkyl. In some embodiments, R 7 is hydrogen. In some embodiments, R 7 is C 1 -C 6 heteroalkyl selected from -NHC(O)-C 1 -C 3 alkyl and -CH2NHC(O)-C 1 -C 3 alkyl. In some embodiments of Formula (IV), Formula (IVa), Formula (IVb), Formula (IVc), Formula (IVd), Formula (IVe), or Formula (X-IV), R 5 and R 7 taken together with the carbon atoms to which they are attached form a 5-8 membered partially saturated cycloalkyl, wherein the cycloalkyl is optionally substituted with one or more R 17 , wherein each R 17 is independently halogen, hydroxyl, C 1 -C 6 alkyl, cycloalkyl, alkoxy, haloalkyl, amino, cyano, heteroalkyl, hydroxyalkyl, -O-haloalkyl, or -S-haloalkyl. [0236] In some embodiments of Formula (IV), Formula (IVa), Formula (IVb), Formula (IVc), Formula (IVd), Formula (IVe), or Formula (X-IV), R 6 is hydrogen, cyano, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxyl, C1- C6 heteroalkyl, C 3 -C 6 cycloalkyl, or C 2 -C 6 heterocycloalkyl, each of which is optionally substituted. In some embodiments, R 6 is hydrogen. In some embodiments, R 6 is C 1 -C 6 heteroalkyl selected from - NHC(O)-C 1 -C 3 alkyl and -CH2NHC(O)-C 1 -C 3 alkyl. In some embodiments of Formula (IV) or Formula (X-IV), R 28 and R 29 are each independently hydrogen, C 1 -C 3 alkyl, hydroxy, C 1 -C 3 alkoxy, cyano, nitro, or C 3 -C 6 cycloalkyl. [0237] In some embodiments of Formula (IV), Formula (IVa), Formula (IVb), Formula (IVc), Formula (IVd), Formula (IVe), or Formula (X-IV), R 30 is halogen, cyano, C1-C8alkyl, C3-C14cycloalkyl, C 6 -C 14 aryl, C1-C8heteroalkyl, C2-C14heterocycloalkyl, C2-C14heteroaryl, C 1 -C 3 alkyl-C 6 -C 14 aryl, C 1 -C 3 alkyl-C3- C14cycloalkyl, C 1 -C 3 alkyl2-C14heterocycloalkyl, C 1 -C 3 alkyl-C2-C14heteroaryl, C1-C8alkoxy, C0- C3heteroalkyl-C6-C1aryl, C 0 -C 3 heteroalkyl-C2-C14heteroaryl, C 0 -C 3 heteroalkyl-C3-C14cycloalkyl, C0- C3heteroalkyl-C2-C14heterocycloaklyl, each of which is optionally substituted. [0238] In some embodiments of Formula (IV), Formula (IVa), Formula (IVb), Formula (IVc), Formula (IVd), Formula (IVe), or Formula (X-IV), R 30 is C1-C8 alkyl, C 0 -C 3 alkylene-C 6 -C 14 aryl, C 0 -C 3 alkylene-C3- C 14 cycloalkyl, C 0- C 3 alkylene-C 2- C 14 heterocycloalkyl, C 0- C 3 alkylene-C 2- C 14 heteroaryl, C 1- C 6 alkoxy, O- C 0- C 3 alkylene-C 6- C 14 aryl, O-C 0- C 3 alkylene-C 3- C 14 heteroaryl, O-C 0- C 3 alkylene-C 3- C 14 cycloalkyl, O-C 0- C3 alkylene-C2-C14 heterocycloaklyl, NH-C1-C8 alkyl, N(C1-C8 alkyl)2, NH-C 0 -C 3 alkylene-C 6 -C 14 aryl, NH- C 0- C 3 alkylene-C 2- C 14 heteroaryl, NH-C 0- C 3 alkylene-C 3- C 14 cycloalkyl, NH- C 0- C 3 alkylene-C 2- C 14 heterocycloalkyl, halo, cyano, or C 1- C 6 alkylene-amine. [0239] In some embodiments, R 30 is C 6 -C 14 aryl, optionally substituted with one or more of halogen, C 1 - C 3 alkyl, C 1 -C 3 alkoxyl, or cyano. In some embodiments, R 30 is a phenyl, optionally substituted with one or more of C 1 -C 3 alkoxyl, or cyano. In some embodiments, R 30 is C 2 -C 14 heteroaryl, optionally substituted with one or more of halogen, C 1 -C 3 alkyl, C 1 -C 3 alkoxyl, or cyano. In some embodiments, R 30 is a 6-membered heteroaryl, optionally substituted with one or more of C 1 -C 3 alkyl. [0240] In some embodiments of Formula (IV) or Formula (X-IV), R 33 is hydrogen, C 1- C 6 alkyl, C 1- C 6 haloalkyl, C 1- C 6 alkylamine, or C 3- C 14 cycloalkyl. In some embodiments, R 33 is C 1- C 6 alkyl, C 1- C 6 haloalkyl, C 1- C 6 alkylamine, or C 3- C 14 cycloalkyl. In some embodiments, R 33 is C 1- C 6 alkyl. In some embodiments, R 33 is methyl, ethyl, propyl, or isopropyl. In some embodiments, R 33 is C 3- C 6 cycloalkyl. In some embodiments, R 33 is cyclopropyl or cyclopentyl. In some embodiments, R 33 is C 1- C 3 haloalkyl or C 1- C 3 alkylamine. In some embodiments, R 33 is hydrogen. [0241] In some embodiments, the radiolabeled compound comprises a structure of Formula (IVa), or a salt or solvate thereof,
Formula (IVa). [0242] In some embodiments, the radiolabeled compound comprises a structure of Formula (IVb), or a salt or solvate thereof, Formula (IVb). [0243] In some embodiments, the radiolabeled compound comprises a structure of Formula (IVc), or a salt or solvate thereof, Formula (IVc). [0244] In some embodiments of Formula (IV), Formula (IVa), Formula (IVb), or Formula (IVc), the radiolabeled compound comprises a structure listed in Table 4C. In some embodiments, the radiolabeled compound has a structure listed in Table 4C. [0245] In one aspect, provided herein is a radiolabeled compound, comprising (a) a structure of Formula (IV), or a salt or solvate thereof, Formula (IV) wherein E 1 and E 2 are each independently N or CR 21 ; E 3 is CR 28 R 29 , C=CR 28 R 29 , C═O, C=S, or C=NR 28 ; J is N, NR 30 , or CR 30 ; M is N, NR 33 , or CR 33 ; is a single or double bond as necessary to give every atom its normal valence; R 21 is independently hydrogen, hydroxyl, cyano, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxyl, or C 1 -C 6 heteroalkyl, wherein each of the alkyl, alkoxyl, and heteroalkyl is optionally substituted; R 22 is hydrogen, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, OR 22’ , N(R 22’ )2, cycloalkyl, -C1- C3alkylene-cycloalkyl, heterocycloalkyl, -C 1 -C 3 alkylene-heterocycloalkyl, aryl, -C 1 -C 3 alkylene-aryl, heteroaryl, or -C 1 -C 3 alkylene-heteroaryl, wherein each of the alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted, and each R 22’ is independently H, C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, aryl, or heteroaryl, wherein each of the alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, and heteroaryl is optionally substituted, or two R 22’ together with the nitrogen atom to which they are attached, form a 3-7-membered ring; R 23 is hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -L 4 -cycloalkyl, -L 4 -heterocycloalkyl, -L 4 -aryl, or -L 4 -heteroaryl, wherein each of the alkyl, alkoxy, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, and heteroaryl is optionally substituted; L 4 is C 1 -C 4 alkylene or C 1 -C 4 heteroalkylene, each of which is optionally substituted; ring A is an optionally substituted 4-7 membered monocyclic ring or optionally substituted 6-11 membered bicyclic, bridged, fused, or spiro ring; R 1 is H, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted C 3 -C 6 cycloalkyl, or optionally substituted C 2 -C 5 heterocycloalkyl; L is a bond, S, O, or NR 10’ , optionally substituted C 1 -C 6 alkylene, or optionally substituted C 1 -C 6 heteroalkylene; E represents a structure of Formula (Ic), wherein, X is C(=O), P(=O)OR 2 , C(=S), or S(=O)n, where n is 1 or 2; R 2 is H or optionally substituted C 1 -C 3 alkyl; R 5 is hydrogen, cyano, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxyl, C 1 -C 6 heteroalkyl, C 3 -C 6 cycloalkyl, or C 2 -C 5 heterocycloalkyl, each of the alkyl, alkoxyl, heteroalkyl, cycloalkyl or heterocycloalkyl is optionally substituted, and R 7 is hydrogen, cyano, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxyl, C 1 -C 6 heteroalkyl, C 3 -C 6 cycloalkyl, C 2 -C 5 heterocycloalkyl, heteroaryl, -C 1 -C 6 alkylene-heteoraryl, -C 1 -C 6 alkylene-NH(C 1 -C 6 alkyl), or -C1- C6alkylene-N(C 1 -C 6 alkyl)2, each of the alkyl, alkylene, alkoxyl, heteroalkyl, cycloalkyl or heterocycloalkyl is optionally substituted; or R 5 and R 7 taken together form a bond; or R 5 and R 7 taken together with the carbon atoms to which they are attached form a 5-8 membered partially saturated cycloalkyl, wherein the cycloalkyl is optionally substituted; R 6 is hydrogen, cyano, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxyl, C 1 -C 6 heteroalkyl, C 3 -C 6 cycloalkyl, C 2 -C 5 heterocycloalkyl, heteroaryl, -C 1 -C 6 alkylene-heteoraryl, -C 1 -C 6 alkylene-NH(C 1 -C 6 alkyl), or -C1- C6alkylene-N(C 1 -C 6 alkyl)2, each of the alkyl, alkylene, alkoxyl, heteroalkyl, cycloalkyl, heterocycloalkyl, or heteroaryl is optionally substituted; R 28 and R 29 are each independently hydrogen, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, cyano, nitro, C 3 -C 6 cycloalkyl, or C 2 -C 5 heterocycloalkyl, or R 28 and R 29 taken together with the carbon atom to which they are attached form a 3-6 membered ring; R 30 is selected from halogen, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -L 4 -cycloalkyl, -L 4 -heterocycloalkyl, -L 4 -aryl, -L 4 -heteroaryl, - OR 10 , -SR 10 , -N(R 10 )(R 10’ ), -C(O)OR 10 , -OC(O)N(R 10 )(R 10’ ), -N(R 10’ )C(O)N(R 10 )(R 10’ ), - N(R 10’ )C(O)OR 11 , -N(R 10’ )S(O) 2 R 11 , -C(O)R 11 , -S(O)R 11 , -OC(O)R 11 , -C(O)N(R 10 )(R 10’ ), - C(O)C(O)N(R 10 )(R 10’ ), -N(R 10’ )C(O)R 11 , -S(O) 2 R 11 , -S(O) 2 N(R 10 )(R 10’ )-, S(=O)(=NH)N(R 10 )(R 10’ ), - CH 2 C(O)N(R 10 )(R 10’ ), -CH 2 N(R 10’ )C(O)R 11 , -CH 2 S(O) 2 R 11 , or -CH 2 S(O) 2 N(R 10 )(R 10’ ), wherein each of the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted; R 33 is H, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, or C 3 -C 6 cycloalkyl, wherein each of the alkyl, heteroalkyl, and cycloalkyl is optionally substituted; each R 10 is independently selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -C 10 aryl, and C 1 -C 9 heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, C2-C9 heterocycloalkyl, C 6 -C 10 aryl, and C 1 -C 9 heteroaryl; each R 10’ is independently selected from hydrogen, C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl; and each R 11 is independently selected C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C2-C9 heterocycloalkyl, C 6 -C 10 aryl, and C 1 -C 9 heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, C2-C9 heterocycloalkyl, C 6 -C 10 aryl, and C 1 -C 9 heteroaryl; (b) a covalently bonded radioisotope R*; and (c) a linker covalently connecting the radioisotope R* and the structure of Formula (IV) or a salt or solvate thereof . In some embodiments, R* is selected from a radioisotope in Table 6C or Table 6D. [0246] In some embodiments, the radiolabeled compound comprises a structure of Formula (IVd) Formula (IVd) wherein L C is a linker comprising 1 to 20 groups independently selected from -CR b R b -, -C(=O)-, -S(=O)-, -S(=O)2- , -NR a -, , , -CR b =CR b -, -C C-, -O-, -S-, -C(=O)O-, -OC(=O)-, -C(=O)NR a -, - NR a C(=O)-, -S(=O)2NR a -, -NR a S(=O)2-, -NR a C(=O)NR a -, - NR a C(=O)O-, -OC(=O)NR a -, arylene, heteroarylene; each R a is independently hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 2 - C 9 heterocycloalkyl, aryl, or heteroaryl; each R b is independently hydrogen, halogen, -CN, -NO 2 , -OR a , -SR a , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 2 -C 9 heterocycloalkyl, aryl, or heteroaryl; R 22 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, -C 1 -C 3 alkylene-cycloalkyl, heterocycloalkyl, -C 1 -C 3 alkylene-heterocycloalkyl, aryl, -C 1 -C 3 alkylene-aryl, heteroaryl, or -C 1 -C 3 alkylene-heteroaryl, wherein each of the alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted; and R* is fluorine-18 ( 18 F), iodine-131 ( 131 I), iodine-123 ( 123 I), iodine-124 ( 124 I), iodine-125 ( 125 I), or astatine- 211 ( 211 At). [0247] In some embodiments, the radiolabeled compound comprises a structure of Formula (IVe), Formula (IVe). [0248] In some embodiments of Formula (IV), Formula (IVd), or Formula (IVe), the radiolabeled compound comprises a structure listed in Table 4D. [0249] In some embodiments of Formula (IVd) or Formula (IVe),, L C is a linker as described herein. [0250] In some embodiments of Formula (IVd) or Formula (IVe),, L C comprises a structure of Table 3C. In some embodiments, L C comprises one or more structures of Table 3A and 3B. [0251] In some embodiments of Formula (IVd) or Formula (IVe), L C comprises , In some embodiments of Formula (IVd) or Formula (IVe), L C is selected from the group consisting of wherein R* is connected to the phenylene. [0252] In some embodiments, the radiolabeled compound comprises a structure of Formula (IVd) or Formula (IVe), wherein L C -R* is
k1 and k2 is independently 0 or an integer selected from 1 to 10. In some embodiments, each k1 and k2 is independently 0 or an integer selected from 1 to 5. In some embodiments, k1 is 0 to 5 and k2 is 0 to 2. In some embodiments, k1 is 2 to 4 and k2 is 0 to 1. [0253] In some embodiments, the radiolabeled compound comprises a structure of Formula (IVd) or ,
.In some embodiments, R* is selected from a radioisotope in Table 6C or Table 6D. In some embodiments, R* is iodine-131 ( 131 I) or astatine-211 ( 211 At). In some embodiments, R* is iodine-131 ( 131 I). [0254] In some embodiments, provided herein are compounds having the structures of the radiolabeled compounds described herein (e.g., a compound of Formula (IV), Formula (IVa), Formula (IVb), Formula (IVc), Formula (IVd), Formula (IVe), or Formula (IVe), except that the radioisotope is replaced with a surrogate (e.g., 131 I replaced with iodine), i.e., a cold compound. In some embodiments, a radionuclide of the radiolabeled compounds described herein can be replaced with a surrogate (e.g., 131 I replaced with iodine) for testing and experimental purposes. Linkers [0255] Provided herein are radiolabeled compounds that comprise a covalently bonded radioisotope. Provided herein are modified KRAS G12C proteins comprising a covalently bonded radiolabeled compound which further comprises a covalently bonded radioisotope. In some embodiments, the covalently bonded radioisotope is attached to the radiolabeled compound through a chemical linker. In some embodiments, the chemical linker is L C as described herein. In some embodiments, the covalently bonded radioisotope can comprise one or more linkers. The one or more linkers can each independently binds a radioisotope. In some embodiments, the radioisotope is selected from a radioisotope in Table 6C or Table 6D. In some embodiments, the radioisotope is selected from fluorine-18 ( 18 F), iodine-131 ( 131 I), iosine-123 ( 123 I), iodine-124 ( 124 I), iodine-125 ( 125 I), or astatine-211 ( 211 At). In some embodiments, the radioisotope is 131 I. In some embodiments, the radioisotope is 124 I. In some embodiments, the radioisotope is 125 I. In some embodiments, the radioisotope is 211 At. [0256] In some embodiments, the radioisotope is covalently bound to the linker as illustrated by a structure selected from Formula (Va), Formula (Vb), Formula (Vc), Formula (Vd), and Formula (Ve): Formula (Ve), wherein, R* is fluorine-18 ( 18 F), iodine-131 ( 131 I), iodine-123 ( 123 I), iodine-124 ( 124 I), iodine-125 ( 125 I), or astatine- 211 ( 211 At); and R a is hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 2 -C 9 heterocycloalkyl, aryl, or heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted. [0257] For the avoidance of doubt, Formula (Va), Formula (Vb), Formula (Vc), Formula (Vd), and Formula (Ve) comprise all or a part of a linker and the radioisotope R*. [0258] In some embodiments, of Formula (Va), Formula (Vb), Formula (Vc), Formula (Vd), or Formula (Ve)the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl are independently optionally substituted by one or more halogen, amino, -OH, -NO2, oxo, -CN, C1-3 alkoxyl, C1-3 alkyl and C1-3 haloalkyl. In some embodiments, R a is hydrogen. In some embodiments, R a is C1-C4alkyl. In some embodiments, R a is C1-C4cycloalkyl. In some embodiments, R * is 131 I. [0259] In some embodiments, the radioisotope is covalently bound to the linker as illustrated by the following structures selected from Formula (Va), Formula (Vb), Formula (Vc), Formula (Vd), and Formula (Ve): , , , , . In some embodiments, the radiolabeled compound comprises a structure of Formula (Va), Formula (Vb), Formula (Vc), Formula (Vd), or Formula (Ve). [0260] A linker described herein (such as group L C of Formula (IIIb), (IIIc), (IVd) and (IVe)) can have a prescribed length thereby linking the radioisotope and the radiolabeled compound while allowing an appropriate distance therebetween. In some embodiments, the linker has 1 to 100 atoms, 1 to 60 atoms, 1 to 30 atoms, 1 to 15 atoms, 1 to 10 atoms, 1 to 5, or 2 to 20 atoms in length. In some embodiments, the linker has 1 to 10 atoms in length. In some embodiments, the linker has 1 to 10 atoms in length. In some embodiments, the linker is between 5 and 20 carbon atoms long. In some embodiments, the linker is between 2 and 18 carbon atoms long. In some embodiments, the linker is between 2 and 20 carbon atoms long. In some embodiments, the linker is between 5 and 10 atoms long. In some embodiments, the linker is between 10 and 15 atoms long. In some embodiments, the linker is between 15 and 20 atoms long. In some embodiments, the linker is between 10 and 20 atoms long. [0261] A linker described herein can comprise flexible and/or rigid regions. Exemplary flexible linker regions include those comprising Gly and Ser residues (“GS” linker), glycine residues, alkylene chain, PEG chain, etc. Exemplary rigid linker regions include those comprising alpha helix-forming sequences (e.g., EAAAK (SEQ ID NO: 3)), proline-rich sequences, spirocycles, hetercycloalkylene moieties, cycloalkylene moieties, and regions rich in double and/or triple bonds. [0262] A linker described herein (such as group L C of Formula (IIIb), (IIIc), (IVd) and (IVe)) can be cleavable, e.g., under physiological conditions, e.g., under intracellular conditions, e.g., under extracellular conditions such that cleavage of the linker separates the radiolabeled compound from the covalently bonded radioisotope. In some embodiments, the linker is a peptidase-cleavable linker. The linker can be, e.g., a peptidyl linker that is cleaved by an intracellular peptidase or protease enzyme, including, but not limited to, a lysosomal or endosomal protease. In some embodiments, the peptidyl linker is at least two amino acids long or at least three amino acids long. Cleaving agents can include cathepsins B and D and plasmin. In other embodiments, the linker is not cleavable. In some embodiments, the linker is pH-sensitive, i.e., sensitive to hydrolysis at certain pH values. For example, the pH-sensitive linker can be hydrolyzable under acidic conditions. For example, a linker can be an acid-labile linker that is hydrolyzable in the lysosome (e.g., a hydrazone, semicarbazone, thiosemicarbazone, cis-aconitic amide, orthoester, acetal, ketal, or the like). Such linkers can be relatively stable under neutral pH conditions, such as those in the blood, but are unstable at below pH 5.5 or 5.0, the approximate pH of the lysosome. In some embodiments, the hydrolyzable linker is a thioether linker. In some embodiments, the linker is an esterase-cleavable linker. The linker can be, e.g., an ester containing linker that is cleaved by an esterase. In some embodiments, the linker can be cleaved in vivo by esterases present in the kidney, liver, plasma, or other tissue. In some embodiments, the linker is cleavable by carboxylesterase-1. In some embodiments, the linker is cleavable by carboxylesterase-2. In some embodiments, the linker is cleavable by butyrylcholinesterase (BChE). In some embodiments, the linker is cleavable by acetylcholinesterase (AChE). In some embodiments, the linker is cleavable by paraoxonase (PON1). In some embodiments, the linker is cleavable by brush-border enzymes. In some embodiments, the linker comprises a brush-border enzyme cleavable sequence, e.g., glycine-tyrosine, glycine-O-methyltyrosine, glycine-lysine, Glycine-phenylalanine-lysine, methionine- valine, methionine-valine-lysine, glycine-aspartate, or glycine-glutamate. In some embodiments, the brush-border cleavable linker comprises glycine-lysine, glycine-tyrosine, glycine-phenylalanine-lysine, or methionine-valine-lysine. In some embodiments, the brush-border cleavable linker comprises glycine- lysine. In some embodiments, the brush-border cleavable linker comprises glycine-tyrosine. In some embodiments, the brush-border cleavable linker comprises glycine-phenylalanine-lysine. In some embodiments, the brush-border cleavable linker comprises methionine-valine-lysine. In some embodiments, the linker is a hepatocyte-cleavable linker. In some embodiments, the linker is metabolized by cytochrome P450. In some embodiments, the linker is cleaved by cytochrome P450. In some embodiments, the linker is metabolized or cleaved by cytochrome P4503A4. In some embodiments, the linker is a cytochrome P450 substrate. In some embodiments, the linker is oxidized by cytochrome P450 3A4 and subsequently cleaved. In some embodiments, the linker is oxidized by flavin monooxygenase, monoamine oxidase, alcohol dehydrogenase, aldehyde dehydrogenase, aldehyde oxidase or xanthine oxidase. [0263] In some embodiments, A linker described herein comprises one or more of substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. In some embodiments, the linker comprises substituted or unsubstituted C 1 -C 30 alkylene. In some embodiments, the linker comprises polyethylene glycol such as (-CH 2 -CH 2 -O-) 1-10 . [0264] In some embodiments, A linker described herein (such as L C )comprises a structure selected from Table 3A. Table 3A
wherein each k1 and k2 is independently 0 or an integer selected from 1 to 20. [0265] In some embodiments of Table 3A and Table 3C, k1 is selected from 0-12. In some embodiments, k1 is 0. In some embodiments, k1 is 1. In some embodiments, k1 is 2. In some embodiments, k1 is 3. In some embodiments, k1 is 4. In some embodiments, k1 is 5. In some embodiments, k1 is 6. In some embodiments, k1 is 7. In some embodiments, k1 is 8. In some embodiments, k1 is 9. In some embodiments, k1 is 10. In some embodiments of Table 3A and Table 3C, k2 is selected from 0-12. In some embodiments, k2 is 0. In some embodiments, k2 is 1. In some embodiments, k2 is 2. In some embodiments, k2 is 3. In some embodiments, k2 is 4. In some embodiments, k2 is 5. In some embodiments, k2 is 6. In some embodiments, k2 is 7. In some embodiments, k2 is 8. In some embodiments, k2 is 9. In some embodiments, k2 is 10. [0266] In some embodiments, a linker described herein comprises a structure selected from Table 3B. Table 3B , wherein Het is a 5-6 membered heteroaryl ring containing 1-3 heteroatoms independently selected from N, S, and O. In some embodiments, Het is pyridinyl or pyrimidinyl. [0267] In some embodiments, a linker described herein comprises a structure selected from Table 3C. Table 3C , , , and k2 is independently 0 or an integer selected from 1 to 10. [0268] In some embodiments, a linker described herein (e.g., L C ) comprises a structure in Table 3A, Table 3B, or Table 3C. In some embodiments, a linker described herein (e.g., L C ) comprises a structure in Table 2A in combination with a structure in Table 3B. In some embodiments, a linker described herein (e.g., L C ) consists of a structure in Table 2A in combination with a structure in Table 3B. In some embodiments, a linker described herein (e.g., L C ) consists of a structure in Table 3C. In some embodiments, the radionuclide is attached to the phenylene or heteroarylene moiety in Table 3B or Table 3C. In some embodiments, a -LK 1 -LK 2 -LK 3 linker described herein (e.g., in Formula (X-III) and Formula (X-IV)) comprises a structure in Table 3A, Table 3B, or Table 3C. In some embodiments, a -LK 1 -LK 2 -LK 3 linker described herein (e.g., in Formula (X-III) and Formula (X-IV)) comprises a structure in Table 2A in combination with a structure in Table 3B. In some embodiments, a -LK 1 -LK 2 -LK 3 linker described herein (e.g., in Formula (X-III) and Formula (X-IV)) consists of a structure in Table 2A in combination with a structure in Table 3B. In some embodiments, a -LK 1 -LK 2 -LK 3 linker described herein (e.g., in Formula (X-III) and Formula (X-IV)) consists of a structure in Table 3C. [0269] In some embodiments, the linker comprises one or more of substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. In some embodiments, the linker comprises substituted or unsubstituted C 1 -C 30 alkylene. In some embodiments, the linker comprises polyethylene glycol such as (-CH 2 -CH 2 -O-) 1-10 . In some embodiments, the linker comprises a structure selected from: from any one thereof. [0270] In some embodiments, the linker comprises a click chemistry residue. In some embodiments, the linker is attached to the peptide, to the metal chelator, or both via click chemistry, thereby forming a click chemistry residue. For example, the peptide can comprise an azide group (at N- or C-terminus or at a non- terminal amino acid) that reacts with an alkyne moiety of the linker. For another example, the peptide can comprise an alkyne group (at N- or C-terminus or at a non-terminal amino acid) that reacts with an azide of the linker. The metal chelator and the linker can be attached similarly. In some embodiments, the linker comprises an azide moiety, an alkyne moiety, or both. In some embodiments, the linker comprises a triazole. In some embodiments, the click chemistry residue is (DBCO-azide residue),
[0271] In some embodiments, the click chemistry residue is a DIBO-azide residue, BARAC-azide residue, DBCO-azide residue, DIFO-azide residue, COMBO-azide residue, BCN-azide residue, or DIMAC-azide residue. In some embodiments, the linker comprises a residue of nitrone dipole cycloaddition. In some embodiments, the linker comprises a residue of tetrazine ligation. In some embodiments, the linker comprises a residue of quadricyclane ligation. Exemplary groups of click chemistry residue are shown in Hein at al., “Click Chemistry, A Powerful Tool for Pharmaceutical Sciences,” Pharmaceutical Research volume 25, pages2216–2230 (2008); Thirumurugan et al, “Click Chemistry for Drug Development and Diverse Chemical–Biology Applications,” Chem. Rev. 2013, 113, 7, 4905–4979; US20160107999A1; US10266502B2; and US20190204330A1, each of which is incorporated by reference in its entirety. [0272] In some embodiments, a linker of the present disclosure (e.g., L C and -LK 1 -LK 2 -LK 3 ) comprises at least one group selected from the group consisting of a bond, alkylene, alkenylene, alkynylene, cycloalkylene, arylene, heteroalkylene, heterocycloalkylene and heteroarylene, wherein each of the alkylene, alkenylene, alkynylene, cycloalkylene, arylene, heteroalkylene, heterocycloalkylene or heteroarylene, is optionally substituted. In some embodiments, the alkylene, alkenylene, alkynylene, cycloalkylene, arylene, heteroalkylene, heterocycloalkylene or heteroarylene are each independently substituted with one or more groups, each substituent group being independently selected from the group consisting of -O-, -S-, silicone, amino, optionally substituted alkyl (e.g., alkoxy, haloalkyl) and optionally substituted heterocycloalkylene (e.g., polyTHF). In some embodiments, the linker comprises substituted or unsubstituted C 1 -C 10 alkylene or substituted or unsubstituted C 1 -C 10 heteroalkylene. In some embodiments, the C1-C10 alkylene or C1-C10 heteroalkylene is substituted with one or more substituents selected from halogen, amino, -OH, -NO2, oxo, -CN, C1-3 alkoxyl, C1-3 alkyl, C1-3 hydroxyalkyl, C1-3 aminoalkyl, and C1-3 haloalkyl. In some embodiments, the linker comprises substituted or unsubstituted C1- C6 alkylene or substituted or unsubstituted C1-C10 heteroalkylene. In some embodiments, the C 1 -C 6 alkylene or C 1 -C 6 heteroalkylene is substituted with one or more substituents selected from halogen, amino, -OH, -NO2, oxo, -CN, C1-3 alkoxyl, C1-3 alkyl, C1-3 hydroxyalkyl, C1-3 aminoalkyl, and C1-3 haloalkyl. In some embodiments, the linker is or comprises propyl ethyl ether. SGR Docket No.59541-719.601 [0273] In some embodiments, the linker is or comprises at least one amino acid. In some embodiments, the linker L is or comprises two amino acids. In some embodiments, the linker L is or comprises three amino acids. [0274] In some embodiments, a linker of the present disclosure comprises one or more groups selected from -O-, -S-, -S-S-, -NH-, -NH-(CH2)p-NH, -NH-(CH2)p-O, -O-(CH2)p-O, -(C=O)-, -(C=O)-O-, -O(C=O)- , -O(C=O)-O-, -OC(=O)-NH-, -C(=O)NH-, -NHC(=O)-, -NHC(=O)-O-, or -NHC(=O)-NH-, -(C=O)- (CH2CH2)q-(C=O)-, -(C=O)-(CH=CH)q-(C=O), -(C=O)-(OCH2CH2O)q-(C=O)-, -(CH2CH2O)q-, - (OCH2CH2)q-, –(C=O)-(CH2CH2O)q-, and -(CH(CH3)C(=O)O)q-, wherein q is 1-20 and p is 1-20. In some embodiments, the linker is or comprises a polyethylene glycol (PEG) or polypropylene glycol (PPG) linker. In some embodiments, the linker is or comprises -(CH2CH2O)q- or -(OCH2CH2)q-. In some embodiments, the linker comprises -O-. In some embodiments, the linker comprises substituted or unsubstituted C1-C6 alkylene. In some embodiments, q is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, p is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, a linker of the present disclosure comprises -C(=O)NH- or - NHC(=O)-. In some embodiments, a linker of the present disclosure comprises -NHC(=O)-O- or -OC(=O)- NH-. [0275] In some embodiments, a linker of the present disclosure comprises 1 to 20 groups independently selected from O-, -S-, -C(=O)O-, -OC(=O)-, -C(=O)NR a -, -NR a C(=O)-, -S(=O) 2 NR a -, -NR a S(=O) 2 -, -NR a C(=O)NR a -, - NR a C(=O)O-, -OC(=O)NR a -, arylene, heteroarylene, wherein each R a is independently hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 2 - C 9 heterocycloalkyl, aryl, or heteroaryl, and wherein each R b is independently hydrogen, halogen, -CN, -NO 2 , -OR a , -SR a , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 2 -C 9 heterocycloalkyl, aryl, or heteroaryl. [0276] In some embodiments, a linker of the present disclosure comprises 1 to 5, 1 to 3, or 1 to 10 groups as described above. [0277] In some embodiments, a linker of the present disclosure (e.g., L C and -LK 1 -LK 2 -LK 3 ) comprises . In some embodiments, a linker of the present disclosure comprises [0278] In some embodiments, the linker has a structure of wherein each LK is independently -O-, – R LK -, –N(R LK ) 2 + -, -OP(=O)(OR LK )O-, -S-, -S(=O)-, - S(=O) 2 -, =CH-, -C(=O)-, -C(=O)O-, -OC(=O)-, -OC(=O)O-, -C(=O)NR LK -, -NR LK C(=O)-, -OC(=O)NR LK - , -NR LK C(=O)O-, -NR LK C(=O)NR LK -, -NR LK C(=S)NR LK -, -CR LK =N-, -N=CR LK , -NR LK S(=O) 2 -, - S(=O) 2 NR LK -, -C(=O)NR LK S(=O) 2 -, -S(=O) 2 NR LK C(=O)-, substituted or unsubstituted C 1 -C 30 alkylene, substituted or unsubstituted C 2 -C 30 alkenylene, substituted or unsubstituted C 2 -C 30 alkynylene, substituted or unsubstituted C 1 -C 30 heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, -(C 1 -C 30 alkylene)-O-, -O-(C 1 -C 30 alkylene)-, -(C 1 -C 30 alkylene)-NR LK - , -NR LK -(C 1 -C 30 alkylene)-, -(C 1 -C 30 alkylene)-N(R LK ) 2 + -, -N(R LK ) 2 + -(C 1 -C 30 alkylene)-, or a click chemistry residue; and each R LK is independently hydrogen, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 1 -C 4 heteroalkyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 2 -C 5 alkynyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted C 2 -C 7 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and p is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15. [0279] In some embodiments, the linker has a structure of wherein each of q and p is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15. In some embodiments, the linker has a structure of , wherein each of q and p is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15, and each of methylene can be substituted or unsubstituted. In some embodiments, p is 0, 1, 2, 3, 4, or 5. In some embodiments, q is 0, 1, 2, 3, 4, or 5. [0280] In some embodiments, the linker has a structure of , wherein each LK is independently -O-, –NR LK -, –N(R LK )2 + -, -OP(=O)(OR LK )O-, -S-, -S(=O)-, -S(=O)2-, -CH=CH-, =CH-, - C≡C-, -C(=O)-, -C(=O)O-, -OC(=O)-, -OC(=O)O-, -C(=O)NR LK -, -NR LK C(=O)-, -OC(=O)NR LK -, - NR LK C(=O)O-, -NR LK C(=O)NR LK -, -NR LK S(=O)2-, -S(=O)2NR LK -, -C(=O)NR LK S(=O)2-, or - S(=O)2NR LK C(=O)-. [0281] In some embodiments, the linker comprises substituted or unsubstituted C 1 -C 3 0 alkylene, C1-C12 alkylene, C1-C8 alkylene, C 1 -C 6 alkylene, or C 2 -C 6 alkylene. In some embodiments, the linker comprises C 2 -C 6 alkylene. In some embodiments, the linker comprises C4-C6 alkylene. [0282] In some embodiments, the linker has a structure of Formula (II-2) wherein each LK 1 , LK 2 , and LK 3 is independently -O-, –NR LK -, –N(R LK )2 + -, -OP(=O)(OR LK )O-, - S-, -S(=O)-, -S(=O)2-, =CH-, -C(=O)-, -C(=O)O-, -OC(=O)-, -OC(=O)O-, -C(=O)NR LK -, -NR LK C(=O)-, - OC(=O)NR LK -, -NR LK C(=O)O-, -NR LK C(=O)NR LK -, -NR LK C(=S)NR LK -, -CR LK =N-, -N=CR LK , - NR LK S(=O)2-, -S(=O)2NR LK -, -C(=O)NR LK S(=O)2-, -S(=O)2NR LK C(=O)-, substituted or unsubstituted C1- C30 alkylene, substituted or unsubstituted C2-C30 alkenylene, substituted or unsubstituted C2-C30 alkynylene, substituted or unsubstituted C 1 -C 3 0 heteroalkylene, substituted or unsubstituted C1-C15 arylene, -(C 1 -C 30 alkylene)-O-, -O-(C 1 -C 30 alkylene)-, -(C 1 -C 30 alkylene)-NR LK -, -NR LK -(C 1 -C 30 alkylene)-, -(C 1 - C 30 alkylene)-N(R LK ) 2 + -, -N(R LK ) 2 + -(C 1 -C 30 alkylene)-, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, or a click chemistry residue; and R LK2 is hydrogen, azide, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1- C 4 heteroalkyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 2 -C 5 alkynyl, substituted or unsubstituted cycloalkynyl, substituted or unsubstituted C 3 -C 30 cycloalkyl, substituted or unsubstituted C 2 -C 30 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R LK is hydrogen, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 1 -C 4 heteroalkyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 2 -C 5 alkynyl, substituted or unsubstituted C 3 -C 30 cycloalkyl, substituted or unsubstituted C 2 -C 30 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; X LK is N or CR LK ; and each of r, p, and q is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15. [0283] In some embodiments, the linker has a structure of or wherein each LK 1 and LK 2 is independently -O-, –NR LK -, –N(R LK ) 2 + -, -OP(=O)(OR LK )O-, -S-, - S(=O)-, -S(=O) 2 -, -CH=CH-, =CH-, -C≡C-, -C(=O)-, -C(=O)O-, -OC(=O)-, -OC(=O)O-, -C(=O)NR LK -, - NR LK C(=O)-, -OC(=O)NR LK -, -NR LK C(=O)O-, -NR LK C(=O)NR LK -, -NR LK S(=O)2-, -S(=O)2NR LK -, - C(=O)NR LK S(=O)2-, -S(=O)2NR LK C(=O)-, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted C1-C20 alkylene, or -(CHR LK -CHR LK -O)1- 10-; R LK is hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 2 -C 5 alkynyl, substituted or unsubstituted C3-C8 cycloalkyl, or substituted or unsubstituted C2-C7 heterocycloalkyl; R LK2 is hydrogen, azide, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1- C4 heteroalkyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 2 -C 5 alkynyl, substituted or unsubstituted cycloalkynyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; q is 0-5; and p is 0-5. [0284] In some embodiments, LK 2 is -O-, –NR LK -, –N(R LK ) 2 + -, -OP(=O)(OR LK )O-, -S-, -S(=O)-, - S(=O)2-, -C(=O)-, -C(=O)O-, -OC(=O)-, -OC(=O)O-, -C(=O)NR LK -, -NR LK C(=O)-, -OC(=O)NR LK -, - NR LK C(=O)O-, -NR LK C(=O)NR LK -, -NR LK S(=O) 2 -, -S(=O) 2 NR LK -, -C(=O)NR LK S(=O) 2 -, - S(=O) 2 NR LK C(=O)-, substituted or unsubstituted C 1 -C 6 alkylene, or -(CH 2 -CH 2 -O) 1-6 -. [0285] In some embodiments, LK 1 is -O-, –NR LK -, –N(R LK ) 2 + -, -OP(=O)(OR LK )O-, -S-, -S(=O)-, - S(=O) 2 -, -CH=CH-, =CH-, -C≡C-, -C(=O)-, -C(=O)O-, -OC(=O)-, -OC(=O)O-, -C(=O)NR LK -, - NR LK C(=O)-, -OC(=O)NR LK -, -NR LK C(=O)O-, -NR LK C(=O)NR LK -, -NR LK S(=O) 2 -, -S(=O) 2 NR LK -, - C(=O)NR LK S(=O) 2 -, -S(=O) 2 NR LK C(=O)-, substituted or unsubstituted C 1 -C 20 alkylene, or -(CH 2 -CH 2 -O) 1- 6 -. [0286] In some embodiments, R LK is hydrogen or substituted or unsubstituted C 1 -C 4 alkyl. [0287] In some embodiments, R LK2 is hydrogen, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 3 -C 30 cycloalkyl, substituted or unsubstituted C 2 -C 30 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. [0288] In some embodiments, p is 1, 2.3, 4, or 5. In some embodiments, q is 1, 2.3, 4, or 5. [0289] In some embodiments, R LK2 is hydrogen, substituted or unsubstituted C 6 -C 10 aryl, substituted or unsubstituted C 5 -C 9 heteroaryl, or a sterol. [0290] In some embodiments, at least one LK 1 is unsubstituted C 3 -C 20 alkylene. [0291] In some embodiments, the linker comprises one or more of a substituted or unsubstituted C 6 -C 10 aryl, substituted or unsubstituted C5-C9 heteroaryl, a sterol, sulfonamide, phosphate ester, polyethylene glycol, or C 3 -C 20 alkylene, or amino acid residues. [0292] In some embodiments, the linker is configured to reversibly bind to a plasma protein such as albumin. In some embodiments, a dissociation constant (Kd) between the linker and human serum albumin is at most 15 µM, as determined at room temperature in human serum condition. In some embodiments, the Kd is from about 0.1 nM to about 10 µM. In some embodiments, the Kd is from about 10 nM to about 10 µM. In some embodiments, the Kd is from about 50 nM to about 1 µM. In some embodiments, the Kd is from about 100 nM to about 10 µM. [0293] Exemplary configurations of the radiolabeled compound described herein are illustrated in Table 4A, Table 4B, Table 4C, and Table 4D. Table 4A
Table 4B
Table 4C
Table 4D
[0294] Provided herein are radiopharmaceutical conjugates and pharmaceutical compositions comprising the conjugates. The conjugates and compositions can be useful for treating cancer. The conjugates and compositions can also be useful in imaging and disease diagnosis. [0295] In one aspect, described herein is a conjugate that comprises a targeting ligand that binds to an intracellular mutated KRAS protein, optionally a linker, and a metal chelator that is configured to bind with a radionuclide. In some embodiments, the targeting ligand can form an irreversible covalent bond to a KRAS protein. In some embodiments, the KRAS protein is mutated. In some embodiments, the KRAS mutation comprises a glycine to cysteine mutation at amino acid residue 12 (G12C mutation). In some embodiments, the conjugate descried herein forms a bond with the KRAS protein at G12C position. In some embodiments, the conjugate comprises a radionuclide such as 225 Ac bound to the metal chelator. [0296] In some embodiments, described herein is a conjugate comprising: (a) a targeting ligand that covalently binds a mutated KRAS protein at G12C position, (b) a linker that covalently attaches the targeting ligand to the metal chelator, and (c) a metal chelator configured to bind with a radionuclide. The targeting ligand can form a covalent bond with the mutated KRAS protein at G12C position. In some embodiments, the conjugate comprises a radionuclide such as 225 Ac bound to the metal chelator. [0297] In some embodiments, provided herein is a conjugate that has a structure of Formula (X), TL- LK 1 -LK 2 -LK 3 -CHL Formula (X) wherein, TL represents the targeting ligand; CHL represents the metal chelator, optionally bound to a radionuclide; and each of LK 1 , LK 2 , and LK 3 is independently selected from substituted or unsubstituted C1-C12 alkylene, substituted or unsubstituted C1-C12 heteroalkylene, substituted or unsubstituted C2- C12 alkenylene, substituted or unsubstituted C2-C12 alkynylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, -(CH2CH2O)q-, -(OCH2CH2)q- , -O-, -S-, -S(=O)-, -S(=O)2-, -S(=O)(=NR LK )-, -C(=O)-, -C(=N-OR LK )-, -C(=O)O-, -OC(=O)-, -C(=O)C(=O)-, -C(=O)NR LK -, -NR LK C(=O)-, -OC(=O)NR LK -, -NR LK C (=O)O-, - NR LK C(=O)NR LK -, -C(=O)NR LK C(=O)-, -S(=O)2NR LK -, -NR LK S(=O)2-, -NR LK -, -N(OR LK )-, and a bond; each R LK is independently hydrogen or substituted or unsubstituted C 1 -C 6 alkyl; and q is an integer selected from 1 to 10. [0298] In some embodiments of Formula (X), the targeting ligand comprises MRTX849, AMG510, JNJ74699157, LY3499446, LY3537982, GDC6036, JDQ443, D1553, or a derivative thereof. [0299] In some embodiments of Formula (X), the targeting ligand comprises a structure of , wherein the structure is attached to the rest of the conjugate at any suitable position, e.g. through the 1-methylpyrrolidin-2-yl group. [0300] In some embodiments of Formula (X), the targeting ligand comprises a structure of , wherein the structure is attached to the rest of the conjugate at any suitable position, e.g. through the 1-methylpyrrolidin-2-yl group. [0301] [0302] In some embodiments of Formula (X), the targeting ligand is wherein the structure is attached to the rest of the conjugate at any suitable position (e.g., through group R 22 ). [0303] In some embodiments of Formula (X), the targeting ligand is , wherein the structure is attached to the rest of the conjugate at any suitable position (e.g., through group R 22 ). [0304] In some embodiments of Formula (X), the targeting ligand is , wherein the structure is attached to the rest of the conjugate at any suitable position (e.g., through group R 22 ). [0305] In some embodiments, the targeting ligand TL has a structure disclosed herein. For example, TL can have a structure of Formula (III), a structure of Formula (IV), or a salt, solvate or derivative thereof. [0306] In some embodiments, a conjugate of Formula (X) has a structure of Formula (X-III): . In some embodiments, a conjugate of Formula (X-III) is complexed with a radionuclide. [0307] In some embodiments, a conjugate of Formula (X) has a structure of Formula (X-IV): . In some embodiments a conjugate of Formula (X-IV) is complexed with a radionuclide. [0308] In some embodiments of Formula (X), Formula (X-III), or Formula (X-IV), LK 1 is substituted or unsubstituted C 1 -C 12 alkylene. In some embodiments, LK 1 is substituted or unsubstituted C 1 -C 3 alkylene. In some embodiments, LK 1 is [0309] In some embodiments Formula (X), Formula (X-III), or Formula (X-IV), LK 1 is substituted or unsubstituted C 1 -C 12 heteroalkylene. In some embodiments, LK 1 is substituted or unsubstituted C 2 -C 6 heteroalkylene. In some embodiments, LK 1 is substituted or unsubstituted C 3 -C 8 heteroalkylene. [0310] In some embodiments Formula (X), Formula (X-III), or Formula (X-IV), LK 1 is C 1 -C 6 alkylene, C 1 -C 6 heteroalkylene, -(CH 2 CH 2 O) 1-6 -, -(OCH 2 CH 2 ) 1-6 -, -O-, or -S-. In some embodiments, LK 1 is - (CH 2 CH 2 O) 1-6 - or -(OCH 2 CH 2 ) 1-6 -. In some embodiments, LK 1 is -(CH 2 CH 2 O) 5 -. In some embodiments, LK 1 is -(CH 2 CH 2 O) 4 -. In some embodiments, LK 1 is -(CH 2 CH 2 O) 3 -. In some embodiments, LK 1 is - (CH 2 CH 2 O) 2 -. In some embodiments, LK 1 is -CH 2 CH 2 O-. In some embodiments, LK 1 is -(OCH 2 CH 2 ) 5 -. In some embodiments, LK 1 is -(OCH 2 CH 2 ) 4 -. In some embodiments, LK 1 is -(OCH 2 CH 2 ) 3 -. In some embodiments, LK 1 is -(OCH2CH2)2-. In some embodiments, LK 1 is -OCH2CH2-. [0311] In some embodiments Formula (X), Formula (X-III), or Formula (X-IV), LK 1 is -NH-. In some embodiments, LK 1 is a bond. [0312] In some embodiments Formula (X), Formula (X-III), or Formula (X-IV), LK 2 is C 1 -C 6 alkylene, C 1 -C 6 heteroalkylene, -(CH2CH2O)1-3-, -(OCH2CH2)1-3-, -O-, or -S-. In some embodiments, LK 2 is - (CH2CH2O)1-3- or -(OCH2CH2)1-3-. In some embodiments, LK 2 is -(CH2CH2O)2-. In some embodiments, LK 2 is -CH2CH2O-. In some embodiments, LK 2 is -(OCH2CH2)2-. In some embodiments, LK 2 is - OCH2CH2-. [0313] In some embodiments Formula (X), Formula (X-III), or Formula (X-IV), LK 2 is substituted or unsubstituted cycloalkylene, or substituted or unsubstituted heterocycloalkylene. In some embodiments, LK 2 is monocyclic. In some embodiments, LK 2 is 3-6 membered substituted or unsubstituted heterocycloalkylene. In some embodiments, LK 2 is . [0314] In some embodiments Formula (X), Formula (X-III), or Formula (X-IV), LK 2 is O-, -S-, -S(=O)- , -S(=O)2-, -S(=O)(=NR LK )-, -C(=O)-, -C(=N-OR LK )-, -C(=O)O-, -OC(=O)-, -C(=O)C(=O)-, -C(=O)NR LK - , -NR LK C(=O)-, -OC(=O)NR LK -, -NR LK C (=O)O-, -NR LK C(=O)NR LK -, -C(=O)NR LK C(=O)-, - S(=O)2NR LK -, -NR LK S(=O)2-, or -NR LK -. [0315] In some embodiments Formula (X), Formula (X-III), or Formula (X-IV), LK 2 is -O-. In some embodiments, LK 2 is -C(=O)NR LK - or - NR LK C(=O)-. In some embodiments, LK 2 is -C(=O)NH-. In some embodiments, LK 2 is -NHC(=O)-. [0316] In some embodiments Formula (X), Formula (X-III), or Formula (X-IV), LK 2 is a bond. [0317] In some embodiments Formula (X), Formula (X-III), or Formula (X-IV), LK 3 is substituted or unsubstituted C1-C12 alkylene. In some embodiments, LK 3 is substituted or unsubstituted C 1 -C 3 alkylene. [0318] In some embodiments Formula (X), Formula (X-III), or Formula (X-IV), LK 3 is substituted or unsubstituted C 1 -C 12 heteroalkylene. In some embodiments, LK 3 is substituted or unsubstituted C 2 -C 6 heteroalkylene. In some embodiments, LK 3 is substituted or unsubstituted C 3 -C 8 heteroalkylene. [0319] In some embodiments Formula (X), Formula (X-III), or Formula (X-IV), LK 3 is C 1 -C 6 alkylene, C 1 -C 6 heteroalkylene, -(CH 2 CH 2 O) 1-3 -, -(OCH 2 CH 2 ) 1-3 -, -O-, or -S-. In some embodiments, LK 3 is substituted or unsubstituted C 1 -C 12 heteroalkylene. In some embodiments, LK 3 is substituted or unsubstituted C 2 -C 6 heteroalkylene. In some embodiments, LK 3 is substituted or unsubstituted C 3 -C 8 heteroalkylene. [0320] In some embodiments Formula (X), Formula (X-III), or Formula (X-IV), LK 3 is a bond. [0321] Exemplary configurations of conjugates of Formula (X), Formula (X-III), and Formula (X-IV) described herein are illustrated in Table 5A, Table 5B, Table 5C and Table 5D. In some embodiments, provided herein are conjugates comprising a structure of Table 5A or Table 5C, and a radionuclide (e.g., 2 25 Ac, 177 Lu). In some embodiments, a conjugate describe herein contains a radioactive isotope, e.g., conjugates 225Ac-CHL-001 to 225Ac-CHL-018 in Table 5B. In some embodiments, a conjugate describe herein does not contain a radioactive isotope, e.g., conjugates CHL-001-CHL-018 in Table 5A. Table 5A. Structures of Exemplary Conjugates
Table 5B. Structures of Exemplary Conjugates Table 5C. Structures of Exemplary Conjugates Table 5D. Structures of Exemplary Conjugates [0322] It is understood that the structures of conjugates in Tables 5A-5D are shown for illustration purposes. A person skilled in the art would appreciate that the bonding between the radionuclide ( 177 Lu or 2 25 Ac) and the metal chelator in conjugates of Tables 5B and 5D is not shown. [0323] A metal chelator such as DOTA can interact with a radionuclide (e.g., 177 Lu or 225 Ac) via one or more functional groups and/or atoms. For example, a metal chelator can interact with a radionuclide via nitrogen and/or oxygen atoms. As another example, a metal chelator can interact with a radionuclide via carbonyl, carboxylic acid, amino, and/or amide groups of the metal chelator. In some embodiments, the interaction of a metal chelator and a radionuclide of the conjugates disclosed herein can be illustrated as . In some embodiments, the interaction of a metal chelator and a radionuclide of the conjugates disclosed herein can be illustrated as . In some embodiments, the interaction of a metal chelator and a radionuclide of the conjugates disclosed herein can be illustrated as . In some embodiments, the interaction of a metal chelator and a radionuclide of the conjugates disclosed herein can be illustrated as . In some embodiments, the radionuclide exists in a positive oxidation state e.g., 225 Ac 3+ , 177 Lu 3+ . In some embodiments, for example in certain aqueous conditions, the radionuclide exists in a salt form, e.g., as 225 Ac 3+ , 177 Lu 3+ . In some embodiments, for example in certain acidic aqueous conditions, the radionuclide exists in a salt form, e.g., as 225 Ac 3+ , 177 Lu 3+ . In some embodiments, the conjugate is in a salt form. In some embodiments, one or more of the carboxylic acid groups of the conjugate may exist as carboxylate anions. In some embodiments, one or more of the carboxylate anions of the conjugate may coordinate to the radionuclide. A person of ordinary skill would appreciate that the dissociation of an acid can depend on the pH value of the environment and its pK value. Accordingly, in some embodiments, a conjugate described herein can exist in a completely ionized, partially ionized or non-ionized form. [0324] In some embodiments, a conjugate disclosed herein comprises a conjugate of Table 5A, or a salt or solvate thereof. In some embodiments, a conjugate disclosed herein is a conjugate of Table 5B, or a salt or solvate thereof. In some embodiments, a conjugate disclosed herein comprises a conjugate of Table 5C, or a salt or solvate thereof. In some embodiments, a conjugate disclosed herein is a conjugate of Table 5D, or a salt or solvate thereof. In some embodiments, a conjugate disclosed herein comprises a conjugate of Tables 5A and 5C, and a radionuclide selected from Tables 6A and 6B. In some embodiments, a conjugate disclosed herein comprises a targeting ligand selected from Table 1, a radionuclide selected from Tables 6A and 6B, a metal chelator selected from FIGs.1-15, and optionally a linker that connects the metal chelator with the targeting ligand. In some embodiments, a conjugate disclosed herein comprises a targeting ligand selected from Table 1 and a metal chelator selected from FIGs.1-15. Metal Chelator [0325] In one aspect, described herein are conjugates (e.g., conjugates of Formula (X), Formula (X-III), and Formula (X-IV)) that comprise a metal chelator that is configured to bind with a radionuclide. The metal chelator can refer to a moiety of the conjugate that is configured to bind with a radionuclide. In some embodiments, a conjugate described herein comprises two or more independent metal chelators, e.g., 2, 3, 4, 5, or more metal chelators. In some embodiments, a conjugate described herein comprises two metal chelators, which can be the same or different. In some embodiments, a conjugate described herein comprises two or more metal chelators. In some embodiments, the conjugate comprises two radionuclides bound to the metal chelators. The metal chelator can be attached to the linker or the peptide through any suitable group/atom of the chelator. [0326] In some embodiments of a conjugate described herein (e.g., conjugates of Formula (X), Formula (X-III), and Formula (X-IV)), the metal chelator is capable of binding a radioactive atom. The binding can be direct, e.g., the metal chelator can make hydrogen bonds or electrostatic interactions with the radioactive atom. The binding can also be indirect, e.g., the metal chelator binds to a molecule that comprises a radioactive atom. In some embodiments, the metal chelator comprises, or is, a macrocycle. In some embodiments, the metal chelator comprises, or is, 2,2′,2′′,2′′′-(1,4,7,10-Tetraazacyclododecane-1, 4,7,10- tetrayl)tetraacetic acid (DOTA) or 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA). In some embodiments, the metal chelator comprises a macrocycle, e.g., a macrocycle comprising an O and/or a N, DOTA, NOTA, one or more amines, one or more ethers, one or more carboxylic acids, EDTA, DTPA, TETA, DO3A, PCTA, or desferrioxamine. [0327] In some embodiments of a conjugate described herein (e.g., conjugates of Formula (X), Formula (X-III), and Formula (X-IV)), the metal chelator comprises a plurality of amines. In some embodiments, the metal chelator includes 4 or more N, 4 or more carboxylic acid groups, or a combination thereof. In some embodiments, the metal chelator does not comprise S. In some embodiments, the metal chelator comprises a ring. In some embodiments, the ring comprises an O and/or an N. In some embodiments, the metal chelator is a ring that includes 3 or more N, 3 or more carboxylic acid groups, or a combination thereof. In some embodiments, the metal chelator is poly polydentate. [0328] In some embodiments of a conjugate described herein (e.g., conjugates of Formula (X), Formula (X-III), and Formula (X-IV)), a metal chelator described herein is selected from: DOTA, DOTA-GA, pBn- DOTA, pBn-SCN-DOTA, NH2-DOTA, NH2-DOTA-GA, p-NCS-Bn-DOTA-GA, p-NH2-Bn-oxo- DO3A, p-SCN-Bn-oxo-DO3A, NOTA, NODA-GA, NH2-NODA-GA, p-NCS-Bn-NODA-GA, p-NH2- Bn-NOTA, p-SCN-Bn-NOTA, NCS-MP-NODA, NH2-MPAA-NODA, PCTA, p-NH2-Bn-PCTA, p- SCN-Bn-PCTA, p-SCN-Bn-HEHA, H2-MACROPA-NCS, H1-MACROPA, H2-MACROPA-NH2, H4- OCTAPA, tetra-(S, S, S, S)-Me-DOTA, tetra-(S, S, S, S)-Et-DOTA, tetra-(S, S, S, S)-iBu-DOTA, or maleimide-nBu-DOTA. [0329] In some embodiments of a conjugate described herein (e.g., conjugates of Formula (X), Formula (X-III), and Formula (X-IV)), a metal chelator described herein has a structure of
( ) , chelator described herein has a structure of ( ) [0330] In some embodiments of a conjugate described herein (e.g., conjugates of Formula (X), Formula (X-III), and Formula (X-IV)), a metal chelator described herein comprises a cyclic chelating agent. Exemplary cyclic chelating agents include, but are not limited to, AAZTA, BAT, BAT-TM, Crown, Cyclen, DO2A, CB-DO2A, DO3A, H3HP-DO3A, Oxo-DO3A, p-NH2-Bn-Oxo-DO3A, DOTA, DOTA- 3py, DOTA-PA, DOTA-GA, DOTA-4AMP, DOTA-2py, DOTA-1py, p-SCN-Bn-DOTA, CHX-A″- EDTA, MeO-DOTA-NCS EDTA, DOTAMAP, DOTAGA, DOTAGA-anhydride, DOTMA, DOTASA, DOTAM, DOTP, CB-Cyclam, TE2A, CB-TE2A, CB-TE2P, DM-TE2A, MM-TE2A, NOTA, NOTP, HEHA, HEHA-NCS, p-SCN-Bn-HEHA, DTPA, CHX-A″-DTPA, p-NH2-Bn-CHX-A″-DTPA, p-SCN- DTPA, p-SCN-Bz-Mx-DTPA, 1B4M-DTPA, p-SCN-Bn1B-DTPA, p-SCN-Bn-1B4M-DTPA, p-SCN-Bn- CHX-A″-DTPA, PEPA, p-SCN-Bn-PEPA, TETPA, DOTPA, DOTMP, DOTPM, t-Bu-calix[4]arene- tetracarboxylic acid, macropa, macropa-NCS, macropid, H3L 1 , H3L 4 , H2azapa, H5decapa, bispa 2 , H4pypa, H4octapa, H4CHXoctapa, p-SCN-Bn-H4octapa, p-SCN-Bn-H4octapa, TTHA, p-NO2-Bn-neunpa, H4octox, H2macropa, H2bispa 2 , H4phospa, H6phospa, p-SCN-Bn-H6phospa, TETA, p-NO2-Bn-TETA, TRAP, TPA, HBED, SHBED, HBED-CC, (HBED-CC)TFP, DMSA, DMPS, DHLA, lipoic acid, TGA, BAL, Bis- thioseminarabazones, p-SCN-NOTA, nNOTA, NODAGA, CB-TE1A1P, 3P-C-NETA-NCS, 3p-C-DEPA, 3P-C-DEPA-NCS, TCMC, PCTA, NODIA-Me, TACN, pycup1A1B, pycup2A, THP, DEDPA, H2DEDPA, p-SCN-Bn-H2DEDPA, p-SCN-Bn-TCMC, motexafin, NTA, NOC, 3p-C-NETA, p-NH2-Bn- TE3A, SarAr, DiAmSar, SarAr-NCS, AmBaSar, BaBaSar, TACN-TM, CP256, C-NE3TA, C-NE3TA- NCS, NODASA, NETA-monoamide, C-NETA, NOPO, BPCA, p-SCN-Bn-DFO, DFO-ChX-Mal, DFO, DFO-IAC, DFO-BAC, DiP-LICAM, EC, SBAD, BAPEN, TACHPYR, NEC-SP, L py , L1, L2, L3, and EuK-106. In some embodiments, the metal chelator is DOTA, TRITA, TETA, DOTA-MA, DO3A-HP, DOTMA, DOTA-pNB, DOTP, DOTMP, DOTEP, DOTMPE, F-DOTPME, DOTPP, DOTBzP, DOTA- monoamide, p-NCS-DOTA, p-NCS-PADOTA, BAT, DO3TMP-Monoamide, p-NCS-TRITA, NOTA, and CHX-A″-DTPA. In some embodiments, a metal chelator described herein comprises an acyclic chelating agent. Exemplary acyclic chelating agents include, but are not limited to, DTA, CyEDTA, EDTMP, DTPMP, DTPA, CyDTPA, Cy2DTPA, DTPA-MA, DTPA-BA, and BOPA. In some embodiments, a metal chelator described herein comprises DOTA, DOTP, DOTMA, DOTAM, DTPA, NTA, EDTA, DO3A, DO2A, NOC, NOTA, TETA, TACN, DiAmSar, CB-Cyclam, CB-TE2A, DOTA-4AMP, or NOTP. In some embodiments, a metal chelator described herein comprises H 4 pypa, H 4 octox, H 4 octapa, p-NO 2 -Bn- neunpa, p-SCN–Bn–H 4 neunpa, TTHA, t Bu 4 pypa-C7-NHS, H 4 neunpa, H 2 macropa, HP-DO3A, BT-DO3A, DO3A-Nprop, DO3AP, DO2A2P, DOA3P, DOTP, DOTPMB, DOTAMAE, DOTAMAP, DO3AM Bu , DOTMA, TCE-DOTA, DEPA, PCTA, p-NO 2 -Bn-PCTA, p-NO 2 -Bn-DOTA, symPC2APA, symPCA2PA, asymPC2APA, asymPCA2PA, TRAP, AAZTA, DATA m , THP, HEHA, or HBED. [0331] In some embodiments of a conjugate described herein (e.g., conjugates of Formula (X), Formula (X-III), and Formula (X-IV)), the metal chelator is DO3A. In some embodiments, the metal chelator is PEPA. In some embodiments, the metal chelator is EDTA. In some embodiments, the metal chelator is CHX-A″-DTPA. In some embodiments, the metal chelator is HEHA. In some embodiments, the metal chelator is DOTMP. In some embodiments, the metal chelator is t-Bu-calix[4]arene-tetracarboxylic acid. In some embodiments, the metal chelator is macropa. In some embodiments, the metal chelator is macropa- NCS. In some embodiments, the metal chelator is H 4 pypa. In some embodiments, the metal chelator is H 4 octapa. In some embodiments, the metal chelator is H 4 CHXoctapa. In some embodiments, the metal chelator is DOTP. In some embodiments, the metal chelator is crown. [0332] In some embodiments of a conjugate described herein (e.g., conjugates of Formula (X), Formula (X-III), and Formula (X-IV)), the metal chelator is DOTA. In some embodiments, the metal chelator is a chiral derivative of DOTA. Exemplary chiral DOTA chelators are described in Dai et al., Nature Communications (2018) 9:857. In some embodiments, the metal chelator is 2,2',2'',2'''-((2S,5S,8S,11S)- 2,5,8,11-tetramethyl-1,4,7,10-tetraazacyclododecane-1,4,7,10 -tetrayl)tetraacetic acid. In some embodiments, the metal chelator has a structure of . In some embodiments, the metal chelator is 2,2',2'',2'''-((2S,5S,8S,11S)-2,5,8,11-tetraethyl-1,4,7,10-t etraazacyclododecane- 1,4,7,10-tetrayl)tetraacetic acid. In some embodiments, the metal chelator has a structure of [0333] In some embodiments of a conjugate described herein (e.g., conjugates of Formula (X), Formula (X-III), and Formula (X-IV)), the metal chelator has a structure of , wherein each R e is independently selected from hydrogen, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylcycloalkyl, alkylheterocycloalkyl, alkylaryl, alkylheteroaryl, or an amino acid side chain. In some embodiments, the metal chelator has a structure of wherein each R e is independently selected from hydrogen, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylcycloalkyl, alkylheterocycloalkyl, alkylaryl, alkylheteroaryl, or an amino acid side chain. [0334] In some embodiments, the conjugate comprises DOTA. In some embodiments, the conjugate comprises a DOTA derivative such as p-SCN-Bn-DOTA and MeO-DOTA-NCS. In some embodiments, the conjugate comprises two independent metal chelators, and at least one or both are DOTA. The structures of some exemplary metal chelators are illustrated in FIGs.1-15 (without showing the attachment points). Exemplary metal chelators are further described in WO2012/174136; US20130183235A1; US20120219495A1; Ramogidaand et al., EJNMMI radiopharm. chem.4, 21 (2019); Thiele et al., Cancer Biotherapy and Radiopharmaceuticals 2018; Li et al., Bioconjugate Chem. 2019, 30, 5, 1539–1553; and Baranyai et al., Eur. J. Inorg. Chem.36–56 (2020), each of which is incorporated by reference in its entirety. Radionuclide [0335] In one aspect, described herein are conjugates (e.g., a conjugate of formula Formula (III), Formula (IIIa), Formula (IIIa-1), Formula (IIIa-2), Formula (IIIb), Formula (IIIc), Formula (IV), Formula (IVa), Formula (IVb), Formula (IVc), Formula (IVd), Formula (IVe), Formula (X), Formula (X-III), or Formula (X-IV)) that comprise a radionuclide. Exemplary radionuclides include, but are not limited to, astatine- 211, astatine-217, actinium-225, americium-243, radium-223, lead-212, lead-203, copper-64, copper-67, copper-60, copper-61, copper-62, bismuth-212, bismuth-213, gallium-68, gallium-67, dysprosium-154, gadolinium-148, gadolinium-153, samarium-146, samarium-147, samarium-153, terbium-149, thorium- 227, thorium-229, iron-59, yttrium-86, indium-111, holmium-166, technetium-94, technetium-99 m , yttrium-90, lutetium-177, terbium-161, rhenium-186, rhenium-188, cobalt-55, scandium-43, scandium-44, scandium-47, dysprosium-166, fluorine-18, or iodine-131. [0336] Generally, the type of radionuclide used in a therapeutic radiopharmaceutical can be tailored to the specific type of cancer, the type of targeting moiety, etc. Radionuclides that undergo α-decay produce particles composed of two neutrons and two protons, and radionuclides that undergo β-decay emit energetic electrons from their nuclei. Radionuclides that undergo β+-decay emit positrons which can be detected with positron emission tomography (PET). Substitution with positron emitting isotopes, such as carbon- 11, nitrogen-13, oxygen-15, and fluorine-18, can be useful in PET imaging studies. Some radionuclides can also emit Auger. In some embodiments, the conjugate comprises an alpha particle-emitting radionuclide. Alpha radiation can cause direct, irreparable double-strand DNA breaks compared with gamma and beta radiation, which can cause single-stranded breaks via indirect DNA damage. The range of these particles in tissue and the half-life of the radionuclide can also be considered in designing the radiopharmaceutical conjugate. Tables 6A, 6B, 6C, and 6D below illustrate some properties of exemplary radionuclides. [0337] In one aspect, described herein are conjugates that comprise a radionuclide. Generally, the type of radionuclide used in a therapeutic radiopharmaceutical can be tailored to the specific type of cancer, the type of targeting moiety (e.g., KRAS G12C covalent binders), etc. Radionuclides that undergo α-decay produce particles composed of two neutrons and two protons, and radionuclides that undergo β-decay emit energetic electrons from their nuclei. Some radionuclides can also emit Auger. In some embodiments, the conjugate comprises an alpha particle-emitting radionuclide. Alpha radiation can cause direct, irreparable double-strand DNA breaks compared with gamma and beta radiation, which can cause single-stranded breaks via indirect DNA damage. The range of these particles in tissue and the half-life of the radionuclide can also be considered in designing the radiopharmaceutical conjugate. Tables 6A, 6B, 6C, and 6D below illustrate some properties of exemplary radionuclides. Table 6A. Exemplary radionuclides suitable for therapeutic use with a metal chelator Table 6B. Exemplary radionuclides suitable for diagnostic use with a metal chelator Table 6C. Exemplary covalent radionuclides suitable for therapeutic use Table 6D. Exemplary covalent radionuclides suitable for diagnostic use [0338] In some embodiments, a conjugate described herein comprises one or more independent radionuclides. In some embodiments, the conjugate comprises two radionuclides. In some embodiments, each of the one or more radionuclides is bound to a metal chelator of the conjugate. In some embodiments, two radionuclides of a conjugate are bound to the same metal chelator. In some embodiments, two radionuclides of a conjugate are bound to two independent metal chelators. In some embodiments, each of the one or more radionuclides is an alpha particle-emitting radionuclide. [0339] In some embodiments, a conjugate described herein comprises an alpha particle-emitting radionuclide. In some embodiments, the alpha particle-emitting radionuclide is actinium-225 ( 225 Ac), radium-223 ( 223 Ra), radium-224 ( 224 Ra), bismuth-209 ( 209 Bi), bismuth-213 ( 213 Bi), Gadolinium-148 ( 148 Gd), Terbium-149 ( 149 Tb), polonium-213 ( 213 Po), francium-223 ( 223 Fr), thorium-227 ( 227 Th), or thorium- 229 ( 229 Th). In some embodiments, the alpha particle-emitting radionuclide is selected from 148 Gd, 149 Tb, 209 Bi, 213 Po, 213 Bi, 223 Ra, 223 Fr, 227 Th, 225 Ac, and 229 Th. In some embodiments, the alpha particle-emitting radionuclide is 225 Ac. In some embodiments, the alpha particle-emitting radionuclide is 213 Bi. In some embodiments, the alpha particle-emitting radionuclide is 212 Bi. In some embodiments, the alpha particle- emitting radionuclide is 212 Pb. In some embodiments, the alpha particle-emitting radionuclide is 224 Ra. In some embodiments, the alpha particle-emitting radionuclide is 223 Ra. In some embodiments, the alpha particle-emitting radionuclide is 227 Th. In some embodiments, the alpha particle-emitting radionuclide is 149 Tb. In some embodiments, the radionuclide is Zirconium-89 ( 89 Zr). [0340] In some embodiments, a conjugate described herein comprises a radionuclide selected from 62 Cu, 64 Cu, 67 Cu, 90 Y, 109 Pd, 111 Ag, 134 Ce, 149 Pm, 153 Sm, 166 Ho, 99m Tc, 67 Ga, 68 Ga, 111 In, 90 Y, 177 Lu, 186 Re, 188 Re, 197 Au, 198 Au, 199 Au, 105 Rh, 165 Ho, 161 Tb, 149 Pm, 153 Pm, 44 Sc, 47 Sc, 213 Po, 212 Pb, 209 Bi, 212 Bi, 213 Bi, 225 Ac, 117m Sn, 67 Ga, 149 Tb, 152 Tb, 167 Tm, 175 Yb, 223 Ra, 223 Fr, 227 Th, 229 Th, 201 Tl, 148 Gd, 160 Gd, 148 Nd, 89 Sr, and 89 Zr. In some embodiments, the radionuclide is selected from 62 Cu, 64 Cu, 67 Cu, 68 Ga, 89 Zr, 90 Y, 99m Tc, 105 Rh, 111 In, 134 Ce, 148 Gd, 149 Tb, 152 Tb, 153 Pm, 167 Tm, 175 Yb, 177 Lu, 209 Bi, 212 Pb, 213 Po, 213 Bi, 223 Ra, 223 Fr, 227 Th, 225 Ac, and 229 Th. In some embodiments, the radionuclide is 225 Ac. In some embodiments, the radionuclide is a decay daughter of 225 Ac such as 221 Fr, 217 At, 213 Bi, 213 Po, 209 Tl, 209 Pb, or 209 Bi. In some embodiments, the conjugate comprises two 225 Ac radionuclides. In some embodiments, the radionuclide is 177 Lu. In some embodiments, the conjugate comprises two 177 Lu radionuclides. [0341] In some embodiments, the conjugate comprises an alpha particle-emitting radionuclide bound to the metal chelator. In some embodiments, the alpha particle-emitting radionuclide is actinium-225, thorium-227, or radium-223. In some embodiments, the alpha particle-emitting radionuclide is actinium- 225, bismuth-213, bismuth-209, terbium-149, radium-223, thorium-227, francium-223, gadolinium-148, thorium-229 or polonium-213. In some embodiments, the alpha particle-emitting radionuclide is actinium- 225. [0342] In some embodiments, the conjugate comprises a beta particle-emitting radionuclide bound to the metal chelator. In some embodiments, the beta particle emitting radionuclide is zircronium-89, yttrium-90, samarium-153, lutetium-177, or lead-212. [0343] In some embodiments, the radionuclide is an alpha particle-emitting radionuclide. In some embodiments, the alpha particle-emitting radionuclide is selected from actinium-225, radium-223, lead- 204, and thorium-227. In some embodiments, the radionuclide is a beta particle-emitting radionuclide. In some embodiments, the beta particle-emitting radionuclide is lutetium-177, copper-64, zircronium-89, yttrium-90, copper-67, indium-111, samarium-153, rhodium-105, ytterbium-175, thulium-167 or lead-212. In some embodiments, the beta particle-emitting radionuclide is lutetium-177. In some embodiments, the radionuclide is a gamma particle-emitting radionuclide. In some embodiments, the gamma particle- emitting radionuclide is indium-111 or tin-117m. In some embodiments, the radionuclide is a positron- emitting radionuclide. In some embodiments, the positron-emitting radionuclide is gallium-68, copper-64, or yttrium-90. In some embodiments, the conjugate comprises a gamma particle emitting radionuclide. In some embodiments, the gamma particle emitting radionuclide is indium-111. [0344] In some embodiments, conjugates described herein do not contain any radionuclide, i.e., a cold conjugate. For example, in some cases, a radionuclide can be replaced with a surrogate (e.g., 225 Ac replaced with lanthanum) for testing and experimental purposes. [0345] In some embodiments, the radionuclide is no-carrier added (i.e., non-carrier-added or n.c.a.) 177 Lu. In some embodiments, the radionuclide is no-carrier added (i.e., non-carrier-added or n.c.a.) 225 Ac. In some embodiments, the radionuclide is 177 Lu free of long-lived radioactive contaminants and byproducts. In some embodiments, the radionuclide is a non-carrier-added radionuclide. [0346] In some embodiments, a compound or protein described herein comprises one or more independent radionuclides. In some embodiments, the compound or protein comprises two radionuclides. In some embodiments, each of the one or more radionuclides is an alpha particle-emitting radionuclide. In some embodiments, each of the one or more radionuclides is a beta particle-emitting radionuclide. In some embodiments, a radiolabeled compound described herein comprises a radionuclide selected from 11 C, 13 N, 15 O, 18 F, 70 As, 71 As, 72 As, 73 As, 74 As, 76 As, 77 As, 76 Br, 123 I, 124 I, 125 I, 131 I, and 211 At. [0347] In some embodiments, a radiolabeled compound described herein comprises an alpha particle- emitting radionuclide. In some embodiments, the alpha particle-emitting radionuclide is astatine-211 ( 211 At). [0348] In some embodiments, the compound or protein comprises a covalently bound beta particle- emitting radionuclide. In some embodiments, the beta particle emitting radionuclide is iodine-131. [0349] In some embodiments, the compound or protein comprises a covalently bound β+ positron- emitting radionuclide. In some embodiments, the β+ positron emitting radionuclide is fluorine-18. [0350] In some embodiments, the compound or protein comprises a gamma particle emitting radionuclide. In some embodiments, the gamma particle emitting radionuclide is iodine-123. [0351] In some embodiments, provided herein are compounds having the structures of the radiolabeled compounds described herein, except that the radioisotope is replaced with a surrogate (e.g., 131 I replaced with iodine), i.e., a cold compound. In some embodiments, a radionuclide of the radiolabeled compounds described herein can be replaced with a surrogate (e.g., 131 I replaced with iodine) for testing and experimental purposes. [0352] In some embodiments, a radiolabeled compound (i.e., a radiopharmaceutical conjugate) described herein is designed to have a prescribed elimination profile. The elimination profile can be designed by adjusting the chemical properties of the radiolabeled compound, the chemical properties of the linker, etc. In some embodiments, the radiolabeled compound has an elimination half-life in mammals of about 0.1 to about 120 hours. In some embodiments, the radiolabeled compound has an elimination half-life in mammals of about 10 minutes to 30 minutes. In some embodiments, the radiolabeled compound has an elimination half-life in mammals of about 30 minutes to 60 minutes. In some embodiments, the radiolabeled compound has an elimination half-life in mammals of about 1 hour to 2 hours. In some embodiments, the radiolabeled compound has an elimination half-life in mammals of about 2 hours to 3 hours. In some embodiments, the radiolabeled compound has an elimination half-life in mammals of about 3 hours to 4 hours. In some embodiments, the radiolabeled compound has an elimination half-life in mammals of about 4 hours to 5 hours. In some embodiments, the radiolabeled compound has an elimination half-life in mammals of about 5 hours to 6 hours. In some embodiments, the radiolabeled compound has an elimination half-life of at least 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 7 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, or 24 hours. In some embodiments, the radiolabeled compound has an elimination half-life of at most 120 hour, 80 hours, 70 hours, 60 hours, 50 hours, 40 hours, 30 hours, 24 hours, 12 hours, 10 hours, 5 hours, 3 hours, 2 hours, 1 hour, 30 minutes, or 15 minutes. In some embodiments, the radiolabeled compound has an elimination half-life of about 0.1 to 24 hours. In some embodiments, the radiolabeled compound has an elimination half-life of about 10 minutes to 1 hour. In some embodiments, the radiolabeled compound has an elimination half-life of about 30 minutes to 12 hours. In some embodiments, the radiolabeled compound has an elimination half-life of about 2 to 24 hours. In some embodiments, the radiolabeled compound has an elimination half-life of about 6 to 24 hours. In some embodiments, the elimination half-life is determined in mice. In some embodiments, the elimination half-life is determined in rats. In some embodiments, the elimination half-life is determined in humans. [0353] In some embodiments, a radiolabeled compound described herein can have an elimination half- life in a tumor and non-tumor tissue of the subject. The elimination half-life in a tumor can be the same as or different from (either longer or shorter than) the elimination half-life in a non-tumor issue. In some embodiments, the elimination half-life of the radiolabeled compound in a tumor is at least about 0.1, 0.5, 1, 3, 6, 12, 24, 48, 72, 96 or more than 96 hours. In some embodiments, the elimination half-life of the radiolabeled compound in a tumor tissue is at least 1.1, 1.2, 1.3, 1.4, 1.5, 2.0, 2.5, 3.0, 4.0, 5.0, 10, 25, 50, or 100 fold greater than the elimination half-life of the a radiolabeled compound in a non-tumor tissue of the subject. [0354] As used herein, the “elimination half-life” can refer to the time it takes from the maximum concentration after administration to half maximum concentration. In some embodiments, the elimination half-life is determined after intravenous administration. In some embodiments, the elimination half-life is measured as biological half-life, which is the half-life of the cold pharmaceutical in the living system. In some embodiments, the elimination half-life is measured as effective half-life, which is the half-life of a radiopharmaceutical in a living system taking into account the half-life of the radioisotope. [0355] A radiolabeled compound described herein can have a described time-integrated activity coefficient (i.e., ã) in a tumor or non-tumor tissues of a subject. As used herein, ã represents the cumulative number of nuclear transformations occurring in a source tissue over a dose-integration period per unit administered activity. The ã value of a radiolabeled compound can be tuned by modifications of the radiolabeled compound. The ã value can be determined using a method known in the art. In some embodiments, the ã value of the radiolabeled compound in a tumor is from about 6 hours to 14 days. In some embodiments, the ã value in a tumor is about 2 to 10 days. In some embodiments, the ã value in a tumor is about 4 to 7 days. In some embodiments, the ã value in a tumor is about 7 to 10 days. In some embodiments, the ã value in a tumor is from about 1 day, 2 days, 3 days, or 4 days to about 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, or 12 days. In some embodiments, the ã value in a tumor is about 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, or 12 days. In some embodiments, the ã value of the radiolabeled compound in a non-tumor tissue is from about 6 hours to 14 days. In some embodiments, the ã value in a non-tumor tissue is about 2 to 10 days. In some embodiments, the ã value in a non-tumor tissue is about 4 to 7 days. In some embodiments, the ã value in a non-tumor tissue is about 7 to 10 days. In some embodiments, the ã value in a non-tumor tissue is from about 1 day, 2 days, 3 days, or 4 days to about 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, or 12 days. In some embodiments, the ã value in a non-tumor tissue is about 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, or 12 days. The ã value of the radiolabeled compound in a tumor can be the same as the ã value of the radiolabeled compound in a non-tumor tissue of the subject. The ã value of the radiolabeled compound in a tumor can be longer or shorter than the ã value of the radiolabeled compound in a non- tumor tissue of the subject. In some embodiments, the ã value of the radiolabeled compound in a tumor is at least 1.1, 1.2, 1.3, 1.4, 1.5, 2.0, 2.5, 3.0, 4.0, or 5.0 fold of the ã value of the radiolabeled compound in a non-tumor tissue of the subject. [0356] A radiolabeled compound described herein can have an ã value in an organ of a subject. In some embodiments, the radiolabeled compound has an ã value in a kidney of the subject of at most 24 hours. In some embodiments, the ã value of the radiolabeled compound in a kidney of the subject is at most 18 hours, 15 hours, 12 hours, 10 hours, 8 hours, 6 hours, or 5 hours. In some embodiments, the ã value of the radiolabeled compound in a kidney of the subject is about 30 minutes to about 24 hours. In some embodiments, the ã value of the radiolabeled compound in a kidney of the subject is about 2 to 24 hours. In some embodiments, the ã value of the radiolabeled compound in a kidney of the subject is more than 24 hours. In some embodiments, the ã value of the radiolabeled compound in a liver of the subject is at most 24 hours. In some embodiments, the ã value of the radiolabeled compound in a liver of the subject is at most 18 hours, 15 hours, 12 hours, 10 hours, 8 hours, 6 hours, or 5 hours. In some embodiments, the ã value of the radiolabeled compound in a liver of the subject is about 30 minutes to about 24 hours. In some embodiments, the ã value of the radiolabeled compound in a liver of the subject is about 2 to 24 hours. In some embodiments, the ã value of the radiolabeled compound in a liver of the subject is more than 24 hours. [0357] In some cases, the elimination profile of the radiolabeled compound can be adjusted by a reversible binding between the radiolabeled compound and a plasma protein such as albumin. A suitable affinity between the radiolabeled compound and the plasma protein can utilize the plasma protein as a reservoir for the radiolabeled compounds, attaching and preserving the radiolabeled compound at high concentration and releasing the radiolabeled compound at a lower concentration, thereby improving elimination profile. In some embodiments, a dissociation constant (Kd) between the radiolabeled compound and human serum albumin is at most 500 µM, as determined at room temperature in human serum condition. In some embodiments, the Kd is from about 0.1 nM to about 1000 µM. In some embodiments, the Kd is at most 100 µM. In some embodiments, the Kd is at most 15 µM. In some embodiments, the Kd is from about 1 nM to about 10 µM. In some embodiments, the Kd is from about 10 nM to about 10 µM. In some embodiments, the Kd is from about 50 nM to about 1 µM. In some embodiments, the Kd is from about 100 nM to about 10 µM. [0358] In some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein possess one or more double bonds. The compounds presented herein include cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as the corresponding mixtures thereof. In some situations, the compounds described herein possess one or more chiral centers and each center exists in the R configuration or S configuration. The compounds described herein include diastereomeric, enantiomeric, and epimeric forms as well as the corresponding mixtures thereof. In additional embodiments of the compounds and methods provided herein, mixtures of enantiomers and/or diastereoisomers, resulting from a single preparative step, combination, or interconversion are useful for the applications described herein. In some embodiments, the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers, and recovering the optically pure enantiomers. In some embodiments, dissociable complexes are preferred. In some embodiments, the diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and are separated by taking advantage of these dissimilarities. In some embodiments, the diastereomers are separated by chiral chromatography, or preferably, by separation/resolution techniques based upon differences in solubility. In some embodiments, the optically pure enantiomer is then recovered, along with the resolving agent. Tautomers [0359] A "tautomer" refers to a molecule wherein a proton shift from one atom of a molecule to another atom of the same molecule is possible. The compounds presented herein, in certain embodiments, exist as tautomers. In circumstances where tautomerization is possible, a chemical equilibrium of the tautomers will exist. The exact ratio of the tautomers depends on several factors, including physical state, temperature, solvent, and pH. Some examples of tautomeric equilibrium include: [0360] In some instances, the compounds disclosed herein exist in tautomeric forms. The structures of said compounds are illustrated in the one tautomeric form for clarity. The alternative tautomeric forms are expressly included in this disclosure. Labeled compounds [0361] In some embodiments, the compounds described herein exist in their isotopically-labeled forms. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds as pharmaceutical compositions. Thus, in some embodiments, the compounds disclosed herein include isotopically-labeled compounds, which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds described herein, or a solvate, or stereoisomer thereof, include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, and chloride, such as 2 H, 3 H, 13 C, 14 C, l5 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, and 36 Cl, respectively. Compounds described herein, and the pharmaceutically acceptable salts, solvates, or stereoisomers thereof which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this disclosure. Certain isotopically-labeled compounds, for example those into which radioactive isotopes such as 3 H and 14 C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3 H and carbon-14, i.e., 14 C, isotopes are notable for their ease of preparation and detectability. Further, substitution with heavy isotopes such as deuterium, i.e., 2H, produces certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements. In some embodiments, the isotopically labeled compound or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is prepared by any suitable method. [0362] In some embodiments, the compounds described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels. Pharmaceutically acceptable salts [0363] In some embodiments, the compounds described herein exist as their pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions. As used herein, a “pharmaceutically acceptable salt” refers to any salt of a compound that is useful for therapeutic purposes of a subject. [0364] In some embodiments, the compounds described herein possess acidic or basic groups and therefore react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt. In some embodiments, these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein, or by separately reacting a purified compound in its free form with a suitable acid or base, and isolating the salt thus formed. [0365] Examples of pharmaceutically acceptable salts include those salts prepared by reaction of the compounds described herein with a mineral acid, organic acid, or inorganic base, such salts including acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyn-1,4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne-1,6-dioate, hydroxybenzoate, γ-hydroxybutyrate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate, metaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate, monohydrogenphosphate, 1-napthalenesulfonate, 2-napthalenesulfonate, nicotinate, nitrate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate, thiocyanate, tosylate, undeconate, and xylenesulfonate. [0366] Further, the compounds described herein can be prepared as pharmaceutically acceptable salts formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, including, but not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid, and the like; and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2- hydroxyethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo- [2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid, 4,4’-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and muconic acid. [0367] In some embodiments, those compounds described herein which comprise a free acid group react with a suitable base, such as the hydroxide, carbonate, bicarbonate, or sulfate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine. Representative salts include the alkali or alkaline earth salts, like lithium, sodium, potassium, calcium, and magnesium, and aluminum salts, and the like. Illustrative examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N+(C1-4 alkyl)4, and the like. [0368] Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like. It should be understood that the compounds described herein also include the quaternization of any basic nitrogen- containing groups they contain. In some embodiments, water or oil-soluble or dispersible products are obtained by such quaternization. Solvates [0369] In some embodiments, the compounds described herein exist as solvates. This disclosure provides for methods of treating diseases by administering such solvates. This disclosure further provides for methods of treating diseases by administering such solvates as pharmaceutical compositions. [0370] Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and, in some embodiments, are formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein can be conveniently prepared or formed during the processes described herein. In addition, the compounds provided herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein. Accordingly, one aspect of the present disclosure pertains to hydrates and solvates of compounds of the present disclosure and/or their pharmaceutical acceptable salts, as described herein, that can be isolated and characterized by methods known in the art, such as, thermogravimetric analysis (TGA), TGA-mass spectroscopy, TGA- Infrared spectroscopy, powder X-ray diffraction (PXRD), Karl Fisher titration, high resolution X-ray diffraction, and the like. Preparation of the Compounds [0371] The compounds used in the reactions described herein are made according to organic synthesis techniques known to those skilled in this art, starting from commercially available chemicals and/or from compounds described in the chemical literature. “Commercially available chemicals” are obtained from standard commercial sources including Acros Organics (Pittsburgh, PA), Aldrich Chemical (Milwaukee, WI, including Sigma Chemical and Fluka), Apin Chemicals Ltd. (Milton Park, UK), Avocado Research (Lancashire, U.K.), BDH, Inc. (Toronto, Canada), Bionet (Cornwall, U.K.), Chem Service Inc. (West Chester, PA), Crescent Chemical Co. (Hauppauge, NY), Eastman Organic Chemicals, Eastman Kodak Company (Rochester, NY), Fisher Scientific Co. (Pittsburgh, PA), Fisons Chemicals (Leicestershire, UK), Frontier Scientific (Logan, UT), ICN Biomedicals, Inc. (Costa Mesa, CA), Key Organics (Cornwall, U.K.), Lancaster Synthesis (Windham, NH), Maybridge Chemical Co. Ltd. (Cornwall, U.K.), Parish Chemical Co. (Orem, UT), Pfaltz & Bauer, Inc. (Waterbury, CN), Polyorganix (Houston, TX), Pierce Chemical Co. (Rockford, IL), Riedel de Haen AG (Hanover, Germany), Spectrum Quality Product, Inc. (New Brunswick, NJ), TCI America (Portland, OR), Trans World Chemicals, Inc. (Rockville, MD), and Wako Chemicals USA, Inc. (Richmond, VA). [0372] Suitable reference books and treatises that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation, include for example, “Synthetic Organic Chemistry”, John Wiley & Sons, Inc., New York; S. R. Sandler et al., “Organic Functional Group Preparations,” 2nd Ed., Academic Press, New York, 1983; H. O. House, “Modern Synthetic Reactions”, 2nd Ed., W. A. Benjamin, Inc. Menlo Park, Calif. 1972; T. L. Gilchrist, “Heterocyclic Chemistry”, 2nd Ed., John Wiley & Sons, New York, 1992; J. March, “Advanced Organic Chemistry: Reactions, Mechanisms and Structure”, 4th Ed., Wiley-Interscience, New York, 1992. Additional suitable reference books and treatises that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation, include for example, Fuhrhop, J. and Penzlin G. “Organic Synthesis: Concepts, Methods, Starting Materials”, Second, Revised and Enlarged Edition (1994) John Wiley & Sons ISBN: 3-527-29074-5; Hoffman, R.V. “Organic Chemistry, An Intermediate Text” (1996) Oxford University Press, ISBN 0-19- 509618-5; Larock, R. C. “Comprehensive Organic Transformations: A Guide to Functional Group Preparations” 2nd Edition (1999) Wiley-VCH, ISBN: 0-471-19031-4; March, J. “Advanced Organic Chemistry: Reactions, Mechanisms, and Structure” 4th Edition (1992) John Wiley & Sons, ISBN: 0-471- 60180-2; Otera, J. (editor) “Modern Carbonyl Chemistry” (2000) Wiley-VCH, ISBN: 3-527-29871-1; Patai, S. “Patai's 1992 Guide to the Chemistry of Functional Groups” (1992) Interscience ISBN: 0-471- 93022-9; Solomons, T. W. G. “Organic Chemistry” 7th Edition (2000) John Wiley & Sons, ISBN: 0-471- 19095-0; Stowell, J.C., “Intermediate Organic Chemistry” 2nd Edition (1993) Wiley-Interscience, ISBN: 0-471-57456-2; “Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopedia” (1999) John Wiley & Sons, ISBN: 3-527-29645-X, in 8 volumes; “Organic Reactions” (1942-2000) John Wiley & Sons, in over 55 volumes; and “Chemistry of Functional Groups” John Wiley & Sons, in 73 volumes. [0373] Specific and analogous reactants are optionally identified through the indices of known chemicals prepared by the Chemical Abstract Service of the American Chemical Society, which are available in most public and university libraries, as well as on-line. Chemicals that are known but not commercially available in catalogs are optionally prepared by custom chemical synthesis houses, where many of the standard chemical supply houses (e.g., those listed above) provide custom synthesis services. A reference for the preparation and selection of pharmaceutical salts of the compounds described herein is P. H. Stahl & C. G. Wermuth “Handbook of Pharmaceutical Salts”, Verlag Helvetica Chimica Acta, Zurich, 2002. IV. Pharmaceutical Compositions [0374] The radiopharmaceutical conjugate described herein, including e.g., pharmaceutically acceptable salt or solvate thereof, can be administered per se as a pure chemical or as a component of a pharmaceutically acceptable formulation. In some embodiments, a conjugate described herein is combined with a pharmaceutically suitable or acceptable carrier selected on the basis of a chosen route of administration and standard pharmaceutical practice as described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 21st Ed. Mack Pub. Co., Easton, PA (2005)). Provided herein is a pharmaceutical composition comprising at least one conjugate described herein, or a stereoisomer, pharmaceutically acceptable salt, amide, ester, solvate, or N-oxide thereof, together with one or more pharmaceutically acceptable carriers. The carrier(s) (or excipient(s)) is acceptable or suitable if the carrier is compatible with the other ingredients of the composition and not deleterious to the recipient (i.e., the subject or patient) of the composition. [0375] In one aspect, the disclosure provides a pharmaceutical composition comprising a herein described conjugate, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient or carrier. In certain embodiments, the conjugate as described is substantially pure, in that it contains less than about 10%, less than about 5%, or less than about 1%, or less than about 0.1%, of other organic small molecules, such as unreacted intermediates or synthesis by-products that are created, for example, in one or more of the steps of a synthesis method. [0376] Pharmaceutical compositions can include pharmaceutically acceptable carriers, diluents or excipients. Exemplary pharmaceutically acceptable carriers include solvents (aqueous or non-aqueous), solutions, emulsions, dispersion media, coatings, isotonic and absorption promoting or delaying agents, compatible with pharmaceutical administration. Such formulations can be contained in a liquid; emulsion, suspension, syrup or elixir, or solid form; tablet (coated or uncoated), capsule (hard or soft), powder, granule, crystal, or microbead. Supplementary components (e.g., preservatives, antibacterial, antiviral and antifungal agents) can also be incorporated into the compositions. Pharmaceutical compositions can be formulated to be compatible with a particular local or systemic route of administration. Thus, pharmaceutical compositions include carriers, diluents, or excipients suitable for administration by particular routes. [0377] The compounds and pharmaceutical compositions of the current disclosure can be administered by any suitable means, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal and epidural and intranasal, and, if desired for local treatment, intralesional administration. The term parenteral as used herein includes e.g., subcutaneous, intravenous, intramuscular, intrasternal, intraperitoneal, and infusion techniques. The term parenteral also includes injections, into the eye or ocular, intravitreal, intrabuccal, transdermal, intranasal, into the brain, including intracranial and intradural, into the joints, including ankles, knees, hips, shoulders, elbows, wrists, and the like, and in suppository form. In certain embodiments, the compounds and/or formulations are administered orally. In certain embodiments, the compounds and/or formulations are administered by systemic administration. In certain embodiments, the compounds and/or formulations are administered parenterally. In certain embodiments, the compounds and/or formulations are administered locally at a targeted site. [0378] In some embodiments, conjugates, or pharmaceutically acceptable salts or solvates thereof, and pharmaceutical compositions described herein are administered via parenteral injection as liquid solution, which can include other chemical components, such as carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, preservatives, or excipients. Parenteral injections can be formulated for bolus injection or continuous infusion. The pharmaceutical compositions can be in a form suitable for parenteral injection as a sterile suspension, solution or emulsion in oily or aqueous vehicles, and can contain formulatory agents such as suspending, stabilizing or dispersing agents. Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water soluble form. Solutions or suspensions used for parenteral, intradermal, or subcutaneous application can include: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid, gentisic acid, or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates; surfactants such as polysorbate 80; and agents for the adjustment of tonicity such as sodium chloride or dextrose. pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide. In some embodiments, the pharmaceutical composition comprises a reductant. The presence of a reductant can help minimize potential radiolysis. In some embodiments, the reductant is ascorbic acid, gentisic acid, sodium thiosulfate, citric acid, tartaric acid, or a combination thereof. [0379] In some embodiments, conjugates, or pharmaceutically acceptable salts or solvates thereof, and pharmaceutical compositions described herein are administered via intravenous administration. In some embodiments, the pharmaceutical composition is formulated for intravenous administration. [0380] Pharmaceutical compositions comprising the conjugates or pharmaceutically acceptable salts or solvates thereof described herein can be prepared according to standard techniques and further comprise a pharmaceutically acceptable carrier. In some embodiments, normal saline can be employed as the pharmaceutically acceptable carrier. Other suitable carriers include, e.g., water, buffered water, 0.9% isotonic saline, 0.4% saline, 0.3% glycine, and the like, including glycoproteins for enhanced stability, such as albumin, lipoprotein, globulin, etc. These compositions can be sterilized by conventional sterilization techniques. The resulting aqueous solutions may be packaged for use or filtered under aseptic conditions and lyophilized. In some embodiments, the lyophilized preparation is combined with a sterile aqueous solution prior to administration. The compositions can contain pharmaceutically acceptable auxiliary substances as appropriate to approximate physiological conditions, such as pH adjusting and buffering agents, tonicity adjusting agents and the like, for example, sodium acetate, sodium lactate, sodium chloride, potassium chloride, calcium chloride, sodium lactate, sorbitan monolaurate, triethanolamine oleate, etc. Pharmaceutical compositions can be selected according to their physical characteristic, including, but not limited to fluid volumes, viscosities and other parameters in accordance with the particular mode of administration selected. The amount of conjugates administered can depend upon the particular targeting moiety used, the disease state being treated, the therapeutic agent being delivered, and the judgment of the clinician. [0381] The concentration of the conjugates or pharmaceutically acceptable salts or solvates thereof described herein in the pharmaceutical formulations can vary. In some embodiments, the conjugate is present in the pharmaceutical composition from about 0.05% to about 1% by weight, about 1% to about 2% by weight, about 2% to about 5% by weight, about 5% to about 10% by weight, about 10% to about 30% by weight, about 30% to about 50% by weight, about 50% to about 75% by weight, or about 75% to about 99% by weight. [0382] Pharmaceutical compositions are administered in a manner appropriate to the disease to be treated. An appropriate dose and a suitable duration and frequency of administration will be determined by such factors as the condition of the subject, the type and severity of the subject's disease, the particular form of the active ingredient, and the method of administration. In some embodiments, an appropriate dose and treatment regimen provides the composition(s) in an amount sufficient to provide therapeutic and/or prophylactic benefit (e.g., an improved clinical outcome), or a lessening of symptom severity. Optimal doses are generally determined using experimental models and/or clinical trials. The optimal dose depends upon the body mass, weight, or blood volume of the subject. [0383] The amount of conjugates or pharmaceutically acceptable salts or solvates thereof and/or pharmaceutical compositions administered can be sufficient to deliver a therapeutically effective dose of the particular subject. In some embodiments, conjugate dosages can be between about 0.1 pg and about 50 mg per kilogram of body weight, 1 µg and about 50 mg per kilogram of body weight, or between about 0.1 and about 10 mg/kg of body weight. Therapeutically effective dosages can also be determined at the discretion of a physician. By way of example only, the dose of the conjugate or a pharmaceutically acceptable salt or solvate thereof described herein for methods of treating a disease as described herein is about 0.001 mg/kg to about 1 mg/kg body weight of the subject per dose. In some embodiments, the dose of conjugate or a pharmaceutically acceptable salt or solvate thereof described herein for the described methods is about 0.001 mg to about 1000 mg per dose for the subject being treated. In some embodiments, a conjugate or a pharmaceutically acceptable salt or solvate thereof described herein is administered to a subject at a dosage of from about 0.01 mg to about 500 mg, from about 0.01 mg to about 100 mg, or from about 0.01mg to about 50 mg. In some embodiments, a conjugate or a pharmaceutically acceptable salt or solvate thereof described herein is administered to a subject at a dosage of about 0.01 picomole to about 1 mole, about 0.1 picomole to about 0.1 mole, about 1 nanomole to about 0.1 mole, or about 0.01 micromole to about 0.1 millimole. In some embodiments, a conjugate or a pharmaceutically acceptable salt or solvate thereof described herein is administered to a subject at a dosage of about 0.0001 Gbq to about 1000 Gbq, 0.01 Gbq to about 1000 Gbq, about 0.5 Gbq to about 100 Gbq, or about 1 Gbq to about 50 Gbq. In some embodiments, a conjugate or a pharmaceutically acceptable salt or solvate thereof described herein is administered to a subject at a dosage of about 5kBq/kg to about 50,000kBq/kg body weight per dose. In some embodiments, a conjugate or a pharmaceutically acceptable salt or solvate thereof described herein is administered to a subject at a dosage of about 1kBq/kg to about 0.2GBq/kg body weight per dose. In some embodiments, a conjugate or a pharmaceutically acceptable salt or solvate thereof described herein is administered to a subject at a dosage of about 20k Bq/kg to about 5,000kBq/kg body weight per dose. In some embodiments, a conjugate or a pharmaceutically acceptable salt or solvate thereof described herein is administered to a subject at a dosage of about 50k Bq/kg to about 500 kBq/kg body weight per dose. In some embodiments, the dose is administered once a day, 1 to 3 times a week, 1 to 4 times a month, or 1 to 12 times a year. [0384] The pharmaceutical formulations can be packaged in unit dosage form for ease of administration and uniformity of dosage. A unit dosage form can refer to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the pharmaceutical carrier or excipient. V. Method of Use, Diagnosis, and Treatment [0385] In one aspect, the disclosure provides methods of treating a disease or condition in a subject in need thereof. In some embodiments, the methods comprise administering a conjugate or a pharmaceutically acceptable salt or solvate thereof described herein, or a pharmaceutical composition comprising the same to the subject in need thereof. In some embodiments, provided herein is a method of providing a therapeutic and/or prophylactic benefit to a subject in need thereof comprising administering a compound or pharmaceutical composition described herein. [0386] In some embodiments, the methods comprise administering to a subject a therapeutically effective amount of a conjugate or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the conjugate or pharmaceutically acceptable salt or solvate thereof is administered in a pharmaceutical composition. In some embodiments, the subject has cancer. In some embodiments, the cancer is a solid tumor or hematological cancer. [0387] In one aspect, provided herein are methods for killing a cell comprising contacting the cell with a conjugate (or a pharmaceutically acceptable salt or solvate thereof) or a pharmaceutical composition comprising the same, wherein the cell expresses a mutated KRAS protein having G12C mutation. In one aspect, provided herein are methods for delivering a radionuclide to a cell comprising administering a conjugate (or a pharmaceutically acceptable salt or solvate thereof) or a pharmaceutical composition comprising the same, wherein the cell expresses a mutated KRAS protein having G12C mutation. After contacting a cell, the described conjugate can permeate into the cell. In some embodiments, the conjugate or pharmaceutically acceptable salt or solvate thereof binds to mutated intracellular protein KRAS in a cell. [0388] In some embodiments, provided herein are methods of making a covalently modified KRAS protein in vivo comprising administering a radiolabeled compound (or a pharmaceutically acceptable salt or solvate thereof) or a pharmaceutical composition comprising the same as described herein, to a subject having a KRAS G12C mutation. [0389] In some embodiments, provided herein are methods for killing a cell comprising contacting the cell with a conjugate or a pharmaceutically acceptable salt or solvate thereof, wherein the cell expresses a mutated KRAS protein having G12C mutation. In one aspect, provided herein are methods for killing a cell harboring a mutated KRAS protein with a G12C mutation, the method comprising contacting the cell with a conjugate (or a pharmaceutically acceptable salt or solvate thereof) or a pharmaceutical composition comprising the same, thereby delivering a dose of radiation to the cell. In some embodiments, the conjugate or pharmaceutically acceptable salt or solvate thereof binds to a structure inside the cell. In some embodiments, the conjugate or pharmaceutically acceptable salt or solvate thereof releases a number of alpha particles by natural radioactive decay. In some embodiments, the conjugate or pharmaceutically acceptable salt or solvate thereof releases a number of beta particles, gamma rays, and/or Auger electrons by natural radioactive decay. The conjugate described herein can kill a cell by radiation. In some embodiments, the conjugate kills the cell directly by radiation. In some embodiments, the radiation creates, in the cell, oxidized bases, abasic sites, single-stranded breaks, double-stranded breaks, DNA crosslink, chromosomal rearrangement, or a combination thereof. In some embodiments, the conjugate kills the cell by inducing double-stranded DNA breaks. In some embodiments, the released alpha particles are sufficient to kill the cell. In some embodiments, the released alpha particles are sufficient to stop cell growth. In some embodiments, the conjugate kills the cell indirectly via the production of reactive oxygen species (ROS) such as free hydroxyl radicals. In some embodiments, the conjugate kills the cell indirectly by releasing tumor antigens from one or more different cells, which can have vaccine effect. In some embodiments, the conjugate kills the cell by abscopal effect. In some embodiments, the cell is a cancer cell. In some embodiments, the method comprises killing a cell with an alpha-particle emitting radionuclide. [0390] In one aspect, provided herein are methods for diagnosing cancer patients harboring a KRAS G12C mutation comprising administering to a patient a conjugate described herein (or a pharmaceutically acceptable salt or solvate thereof) or a pharmaceutical composition comprising the same. In one aspect, provided herein are methods for imaging a cancer harboring a G12C KRAS mutation comprising administering to a patient a conjugate described herein (or a pharmaceutically acceptable salt or solvate thereof) or a pharmaceutical composition comprising the same. In some embodiments, the method further comprises selecting or confirming that a tumor in the patient has a G12C mutation. In some embodiments, the method further comprises measuring the concentration of the conjugate accumulated in the patient. In some embodiments, the method further comprises measuring the amount of radiation emitted from the radionuclide. In some embodiments, the method further comprises analyzing the elimination or clearance profile of the conjugate in the patient. In some embodiments, the method further comprises measuring an elimination half-life of the conjugate in the patient. In some embodiments, the method further comprises analyzing the clearance profile of the conjugate in the patient. In some embodiments, the method of imaging or diagnosing cancer comprises administering a conjugate that comprises a radionuclide of Table 4B, such as 68 Ga. For example, conjugates of the present disclosure can be administered for patient selection purposes, such as to confirm the tumor has the appropriate expression of the G12C target. As another example, conjugates of the present disclosure can be administered to a patient so that the patient’s care team can make sure the conjugate is cleared from the body in a suitable timeframe so that undesired irradiation of other tissues is minimized. [0391] In some embodiments, a method described herein comprises administering to a patient two conjugates of the present disclosure. In some embodiments, the two conjugates can have the same targeting ligand and/or linker. In some embodiments, a method described herein comprises administering (i) a conjugate of the present disclosure that comprises a radionuclide of Table 6B, and followed by (ii) a conjugate of the present disclosure that comprises a radionuclide of Table 6A. In some embodiments, a method described herein comprises administering (i) a conjugate of the present disclosure that comprises a radionuclide of Table 6D, and followed by (ii) a conjugate of the present disclosure that comprises a radionuclide of Table 6C. [0392] In one aspect, the disclosed conjugate or a pharmaceutically acceptable salt or solvate thereof is configured to treat cancer by ablating tumor cells. In some embodiments, the conjugate or a pharmaceutically acceptable salt or solvate thereof does not modulate the biology of the tumor cell and/or the surrounding stroma. In some embodiments, the conjugate or a pharmaceutically acceptable salt or solvate thereof does not modulate immune cells. In some embodiments, the ablating of tumor cells can lead to a downstream immunological cascade. [0393] Further provided herein are methods of treating a cancer associated with a KRAS G12C mutation. Non-limiting examples of cancers to be treated by the methods of the present disclosure can include melanoma (e.g., metastatic malignant melanoma), renal cancer (e.g., clear cell carcinoma), prostate cancer (e.g., hormone refractory prostate adenocarcinoma), pancreatic adenocarcinoma, breast cancer, colon cancer, lung cancer (e.g., non-small cell lung cancer), esophageal cancer, squamous cell carcinoma of the head and neck, liver cancer, ovarian cancer, cervical cancer, thyroid cancer, glioblastoma, glioma, leukemia, lymphoma, and other neoplastic malignancies. In some embodiments, a subject or population of subjects to be treated with a pharmaceutical composition of the present disclosure have a solid tumor. In some embodiments, a solid tumor is a melanoma, renal cell carcinoma, lung cancer, bladder cancer, breast cancer, cervical cancer, colon cancer, gall bladder cancer, laryngeal cancer, liver cancer, thyroid cancer, stomach cancer, salivary gland cancer, prostate cancer, pancreatic cancer, or Merkel cell carcinoma. In some embodiments, a subject or population of subjects to be treated with a pharmaceutical composition of the present disclosure have a hematological cancer. In some embodiments, the subject has a hematological cancer such as Diffuse large B cell lymphoma (“DLBCL”), Hodgkin’s lymphoma (“HL”), Non-Hodgkin’s lymphoma (“NHL”), Follicular lymphoma (“FL”), acute myeloid leukemia (“AML”), or Multiple myeloma (“MM”). In some embodiments, a subject or population of subjects to be treated having the cancer selected from the group consisting of ovarian cancer, lung cancer and melanoma. [0394] In some embodiments, provided herein are methods and compositions for treating a disease or condition associated with KRAS G12C mutation. Exemplary disease or condition includes refractory or recurrent malignancies whose growth may be inhibited using the methods of treatment of the present disclosure. In some embodiments, the disease or condition is a cancer. In some embodiments, the cancer is breast cancer, head and neck squamous cell carcinoma, non-small cell lung cancer, hepatocellular cancer, colorectal cancer, gastric adenocarcinoma, melanoma, or advanced cancer. In some embodiments, a cancer to be treated by the methods of treatment of the present disclosure is selected from the group consisting of carcinoma, squamous carcinoma, adenocarcinoma, sarcomata, endometrial cancer, breast cancer, ovarian cancer, cervical cancer, fallopian tube cancer, primary peritoneal cancer, colon cancer, colorectal cancer, squamous cell carcinoma of the anogenital region, melanoma, renal cell carcinoma, lung cancer, non-small cell lung cancer, squamous cell carcinoma of the lung, stomach cancer, bladder cancer, gall bladder cancer, liver cancer, thyroid cancer, laryngeal cancer, salivary gland cancer, esophageal cancer, head and neck cancer, glioblastoma, glioma, squamous cell carcinoma of the head and neck, prostate cancer, pancreatic cancer, mesothelioma, sarcoma, hematological cancer, leukemia, lymphoma, neuroma, and combinations thereof. In some embodiments, a cancer to be treated by the methods of the present disclosure include, for example, carcinoma, squamous carcinoma (for example, cervical canal, eyelid, tunica conjunctiva, vagina, lung, oral cavity, skin, urinary bladder, tongue, larynx, and gullet), and adenocarcinoma (for example, prostate, small intestine, endometrium, cervical canal, large intestine, lung, pancreas, gullet, rectum, uterus, stomach, mammary gland, and ovary). In some embodiments, a cancer to be treated by the methods of the present disclosure further include sarcomata (for example, myogenic sarcoma), leukosis, neuroma, melanoma, and lymphoma. In some embodiments, a cancer to be treated by the methods of the present disclosure is breast cancer. In some embodiments, a cancer to be treated by the methods of treatment of the present disclosure is triple negative breast cancer (TNBC). In some embodiments, a cancer to be treated by the methods of treatment of the present disclosure is pancreatic cancer. [0395] In some embodiments, a cancer to be treated by the methods of the present disclosure include, for example, Cardiac cancer: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; Lung cancer: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; Gastrointestinal cancer: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); Genitourinary tract cancer: kidney (adenocarcinoma, Wilm's tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma); Liver cancer: hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Biliary tract cancer: gall bladder carcinoma, ampullary carcinoma, cholangiocarcinoma; Bone cancer: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors; Nervous system cancer: skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal cord neurofibroma, meningioma, glioma, sarcoma); Gynecological cancer: uterus (endometrial 'carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tubes (carcinoma); Hematologic cancer: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma); Skin cancer: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis; and Adrenal glands cancer: neuroblastoma. In some embodiments, the cancer is non-small cell lung cancer. [0396] In some embodiments, a conjugate described herein can be administered alone or in combination with one or more additional therapeutic agents. For example, the combination therapy can include a composition comprising a conjugate described herein co-formulated with, and/or co-administered with, one or more additional therapeutic agents, e.g., one or more anti-cancer agents, e.g., cytotoxic or cytostatic agents, immune checkpoint inhibitors, hormone treatment, vaccines, and/or immunotherapies. In some embodiments, the conjugate is administered in combination with other therapeutic treatment modalities, including surgery, cryosurgery, and/or chemotherapy. Such combination therapies may advantageously utilize lower dosages of the administered therapeutic agents, thus avoiding possible toxicities or complications associated with the various monotherapies. [0397] When administered in combination, two (or more) different treatments can be delivered to the subject during the course of the subject's affliction with the disorder, e.g., the two or more treatments are delivered after the subject has been diagnosed with the disorder and before the disorder has been cured or eliminated. In some embodiments, the delivery of one treatment is still occurring when the delivery of the second begins, so that there is overlap. This is sometimes referred to herein as “simultaneous” or “concurrent delivery.” In some embodiments, the delivery of one treatment ends before the delivery of the other treatment begins. In some embodiments of either case, the treatment is more effective because of combined administration. For example, the second treatment is more effective, e.g., an equivalent effect is seen with less of the second treatment, or the second treatment reduces symptoms to a greater extent, than would be seen if the second treatment were administered in the absence of the first treatment, or the analogous situation is seen with the first treatment. In some embodiments, delivery is such that the reduction in a symptom, or other parameter related to the disorder is greater than what would be observed with one treatment delivered in the absence of the other. The effect of the two treatments can be partially additive, wholly additive, or greater than additive. The delivery can be such that an effect of the first treatment delivered is still detectable when the second is delivered. [0398] In some embodiments, the herein-described conjugate is used in combination with a chemotherapeutic agent, e.g., a DNA damaging chemotherapeutic agent. Non-limiting examples of DNA damaging chemotherapeutic agents include topoisomerase I inhibitors, topoisomerase II inhibitors; alkylating agents; DNA intercalators; DNA intercalators and free radical generators such as bleomycin; and nucleoside mimetics. In some embodiments, the herein-described conjugate is used in combination with a radiation sensitizer, which makes tumor cells more sensitive to radiation therapy. In some embodiments, the herein-described conjugate is used in combination with a DNA damage repair inhibitor (or DNA damage response (DDR) inhibitor). [0399] In some embodiments, provided herein are methods of producing a compound having a structure of Formula (VIa), Formula (VIb), Formula (VIc), or Formula (VId) in vivo, comprising administering a radiolabeled compound, or pharmaceutically salt or solvate thereof, as described herein, to a subject, o u a (V a) o u a (V b) o u a (V c) o u a (V d) wherein R* is fluorine-18 ( 18 F), iodine-131 ( 131 I), iodine-123 ( 123 I), iodine-124 ( 124 I), iodine-125 ( 125 I), or astatine- 211 ( 211 At). In some embodiments, R* is selected from a radioisotope in Table 6C or Table 6D. In some embodiments, the method comprises administering a radiolabeled compound of Formula (III), Formula (IIIa), Formula (IIIa-1), Formula (IIIa-2), Formula (IIIb), Formula (IIIc), Formula (IV), Formula (IVa), Formula (IVb), Formula (IVc), Formula (IVd), or Formula (IVe). [0400] In some embodiments, provided herein are methods of excreting a compound having a structure of Formula (VIa), Formula (VIb), Formula (VIc), or Formula (VId) from a subject’s body, comprising administering a radiolabeled compound, or pharmaceutically salt or solvate thereof, as described herein, to the subject, wherein R* is fluorine-18 ( 18 F), iodine-131 ( 131 I), iodine-123 ( 123 I), iodine-124 ( 124 I), iodine-125 ( 125 I), or astatine- 211 ( 211 At). In some embodiments, R* is selected from a radioisotope in Table 6C or Table 6D. In some embodiments, the method comprises administering to the subject a radiolabeled compound of Formula (III), Formula (IIIa), Formula (IIIa-1), Formula (IIIa-2), Formula (IIIb), Formula (IIIc), Formula (IV), Formula (IVa), Formula (IVb), Formula (IVc), Formula (IVd), or Formula (IVe). [0401] In some embodiments, the compound of formula (VIa) is . In some embodiments, the compound of formula (VIb) is In some embodiments, the compound of formula (VIc) is . In some embodiments, the compound of formula (VId) is [0402] In some embodiments, the subject is 4 to 100 years old. In some embodiments, the subject is 5 to 10, 5 to 15, 5 to 18, 5 to 25, 5 to 35, 5 to 45, 5 to 55, 5 to 65, 5 to 75, 10 to 15, 10 to 18, 10 to 25, 10 to 35, 10 to 45, 10 to 55, 10 to 65, 10 to 75, 15 to 18, 15 to 25, 15 to 35, 15 to 45, 15 to 55, 15 to 65, 15 to 75, 18 to 25, 18 to 35, 18 to 45, 18 to 55, 18 to 65, 18 to 75, 25 to 35, 25 to 45, 25 to 55, 25 to 65, 25 to 75, 35 to 45, 35 to 55, 35 to 65, 35 to 75, 45 to 55, 45 to 65, 45 to 75, 55 to 65, 55 to 75, or 65 to 75 years old. In some embodiments, the subject is at least 5, 10, 15, 18, 25, 35, 45, 55, or 65 years old. In some embodiments, the subject is at most 10, 15, 18, 25, 35, 45, 55, 65, or 75 years old. [0403] In addition to the methods of treatment described above, the compounds and compositions described herein can be used to image, and/or as part of a treatment for diseases. Conjugates for imaging applications, e.g., single-photon emission computed tomography (SPECT) and positron emission tomography (PET), can comprise a radionuclide suitable for use as imaging isotopes such as the isotopes in Table 6B or 6D. Accordingly, the conjugate can be administered as a companion diagnostic. [0404] In some embodiments, provided herein are methods of producing a compound having a structure of Formula (VIa), Formula (VIb), Formula (VIc), or Formula (VId) in vivo, comprising administering a radiolabeled compound, or pharmaceutically salt or solvate thereof, as described herein, to a subject, Formula (VIa) Formula (VIb) Formula (VIc) Formula (VId) wherein R* is fluorine-18 ( 18 F), iodine-131 ( 131 I), iodine-123 ( 123 I), iodine-124 ( 124 I), iodine-125 ( 125 I), or astatine- 211 ( 211 At). In some embodiments, R* is selected from a radioisotope in Table 6C or Table 6D. In some embodiments, the method comprises administering to the subject a radiolabeled compound of Formula (III), Formula (IIIa), Formula (IIIa-1), Formula (IIIa-2), Formula (IIIb), Formula (IIIc), Formula (IV), Formula (IVa), Formula (IVb), Formula (IVc), Formula (IVd), or Formula (IVe).. [0405] In some embodiments, provided herein are methods of excreting a compound having a structure of Formula (VIa), Formula (VIb), Formula (VIc), or Formula (VId) from a subject’s body, comprising administering a radiolabeled compound, or pharmaceutically salt or solvate thereof, as described herein, to the subject, Formula (VIa) Formula (VIb) Formula (VIc) Formula (VId) wherein R* is fluorine-18 ( 18 F), iodine-131 ( 131 I), iodine-123 ( 123 I), iodine-124 ( 124 I), iodine-125 ( 125 I), or astatine- 211 ( 211 At). In some embodiments, R* is selected from a radioisotope in Table 6C or Table 6D. In some embodiments, the method comprises administering to the subject a radiolabeled compound of Formula (III), Formula (IIIa), Formula (IIIa-1), Formula (IIIa-2), Formula (IIIb), Formula (IIIc), Formula (IV), Formula (IVa), Formula (IVb), Formula (IVc), Formula (IVd), or Formula (IVe). [0406] In some embodiments, the compound of formula (VIa) is In some embodiments, the compound of formula (VIb) is o . In some embodiments, the compound of formula (VIc) is o . In some embodiments, the compound of formula (VId) is VI. Method of Manufacturing Labelled Compounds [0407] In some embodiments, radiolabeled compounds described herein can be synthesized from a boronic acid, boronate, or stannane precursor. Boronic acid, boronate, and stannane precursors can be formed according to the following general reaction Scheme 1: Scheme 1 , where R is a variable chemical moiety, for example alkyl or hydrogen. A halogen on ring Y, for example chloro, bromo, or iodo, can undergo a palladium mediated coupling reaction with a boronic acid, boronate, or stannane compound to form an intermediate compound wherein group M has replaced halogen X. [0408] A radioisotope, for example R* such as fluorine-18 ( 18 F), iodine-131 ( 131 I), iodine-123 ( 123 I), iodine-124 ( 124 I), iodine-125 ( 125 I), or astatine-211 ( 211 At), or any other radioisotope of Table 6C and Table 6D can be formed, for example, from the intermediate compound according to the following general reactions: Scheme 2 , Scheme 3 , or Scheme 4 , where R is a variable chemical moiety, for example alkyl or hydrogen. [0409] In some embodiments, radiolabeled compounds described herein can be synthesized from a chloro, bromo, or iodo precursor according to the following general reaction: Scheme 5: where R* is a radioisotope, for example, fluorine-18 ( 18 F), iodine-131 ( 131 I), iodine-123 ( 123 I), iodine-124 ( 124 I), iodine-125 ( 125 I), astatine-211 ( 211 At), or a radioisotope of Table 6C and Table 6D. [0410] The radiolabeling reactions depicted above are used as example procedures in the synthesis of radiolabeled compounds described herein. Additional reactions, including nucleophilic substitution, electrophilic substitution, isotopic exchanges, bromine-radioiodine exchange, radioiododestannylation, radioiododeboronation, and transition metal mediated halogen exchange are contemplated and procedures can be found in Berdal et al., “Investigation on the reactivity of nucleophilic radiohalogens with arylboronic acids in water: access to an efficient single-step method for the radioiodination and astatination of antibodies” Chemical Science 2021, 12, 1458, and Dubost et al., “Recent Advances in Synthetic Methods for Radioiodination” J. Org. Chem, 2020, 85, 13, 8300-8310, both of which are incorporated by reference herein in their entirety. [0411] Accordingly, in one aspect, described herein is a method of synthesizing a radiolabeled compound of Formula (III), Formula (IIIa), Formula (IIIa-1), Formula (IIIa-2), Formula (IIIb), Formula (IIIc), Formula (IV), Formula (IVa), Formula (IVb), Formula (IVc), Formula (IVd), or Formula (IVe) or salt or solvate or pharmaceutical composition thereof. In some embodiments, the method comprises replacing a halogen on a precursor compound with a radioisotope, e.g., a fluorine-18 ( 18 F), iodine-131 ( 131 I), iodine- 123 ( 123 I), iodine-124 ( 124 I), iodine-125 ( 125 I), astatine-211 ( 211 At), or a radioisotope of Table 6C and Table 6D. In some embodiments, the method comprises a transition metal (e.g., palladium) mediated coupling reaction with a boronic acid, boronate, or stannane compound to form an intermediate compound. In some embodiments, the method further comprises exchanging the boronic acid, boronate, or stannane group with the radioisotope, e.g., as illustrated above. In some embodiments, the method comprises nucleophilic substitution, electrophilic substitution, isotopic exchanges, bromine-radioiodine exchange, radioiododestannylation, radioiododeboronation, and/or transition metal mediated halogen exchange reactions. Exemplary procedures of the radioisotope labelling steps are illustrated in Schemes 1-7. [0412] In some embodiments, provided herein are precursor compounds of compounds of Formula (III), Formula (IIIa), Formula (IIIa-1), Formula (IIIa-2),Formula (IIIb), Formula (IIIc), Formula (IV), Formula (IVa), Formula (IVb), Formula (IVc), Formula (IVd), or Formula (IVe), wherein the radioisotope is replaced with a halogen or hydrogen. In some embodiments, provided herein are precursor compounds having a structure of Formula (III’), Formula (IIIa’), Formula (IIIa-1’), Formula (IIIa-2’),Formula (IIIb’), Formula (IIIc’), Formula (IV’), Formula (IVa’), Formula (IVb’), Formula (IVc’), Formula (IVd’), or Formula (IVe’), each of which have the corresponding structure of Formula (III), Formula (IIIa), Formula (IIIb), Formula (IIIc), Formula (IV), Formula (IVa), Formula (IVb), Formula (IVc), Formula (IVd), or Formula (IVe), respectively, except that the precursor compounds contain a halogen, amine (e.g., NH 2 ), B(OH) 2 , Si(Me) 3 , Sn(Bu) 3 , hydrogen or the like in lieu of the radioisotope R*. [0413] In some embodiments, provided herein are methods of synthesizing a compound of Formula (III), comprising: (i) reacting a precursor compound having a structure of Formula (III’) Formula (III’) wherein the Q 1 , E, R 13 , m, R 14 , L 1 , L 2 ,and R 12 are defined in Formula (III), except that the radioisotope R* is replaced with a halogen (e.g., F, Cl, or I), amine (e.g., NH 2 ), B(OH) 2 , Si(Me) 3 , Sn(Bu) 3 , hydrogen or the like in formula (III’), and (ii) replacing the halogen with the R*. [0414] In some embodiments, provided herein are methods of synthesizing a compound of Formula (IV), comprising: (i) reacting a precursor compound having a structure of Formula (IV’) Formula (IV’) wherein the E 1 , E 2 , E 3 , M, R 22 , R 23 , R 24 , and J are defined in Formula (IV), except that the radioisotope R* is replaced with a halogen (e.g., F, Cl, or I), amine (e.g., NH 2 ), B(OH) 2 , Si(Me) 3 , Sn(Bu) 3 , hydrogen or the like in formula (IV’), and (ii) replacing the halogen with the R*. [0415] In some embodiments, provided herein is a precursor compound of Formula (III’) Formula (III’), wherein the radioisotope R* is replaced with R* Pre , and the remaining groups are defined in Formula (III), wherein R* Pre is a precursor of a radioisotope. In some embodiments, R* Pre can be a halogen (e.g., F, Cl, or I), amine (e.g., NH 2 ), B(OH) 2 , Si(Me) 3 , Sn(Bu) 3 , hydrogen or the like. [0416] In some embodiments, provided herein is a precursor compound of Formula (IIIa’) Formula (IIIa’), wherein the radioisotope R* is replaced with R* Pre , and the remaining groups are defined in Formula (IIIa), wherein R* Pre is a precursor of a radioisotope. [0417] In some embodiments, provided herein is a precursor compound of Formula (IIIa-1’) Formula (IIIa-1’), wherein the radioisotope R* is replaced with R* Pre , and the remaining groups are defined in Formula (IIIa-1), wherein R* Pre is a precursor of a radioisotope. [0418] In some embodiments, provided herein is a precursor compound of Formula (IIIa-2’) Formula (IIIa-2’), wherein the radioisotope R* is replaced with R* Pre , and the remaining groups are defined in Formula (IIIa-2), wherein R* Pre is a precursor of a radioisotope. [0419] In some embodiments, provided herein is a precursor compound of Formula (IIIb’) Formula (IIIb’), wherein R* Pre is a precursor of a radioisotope and the remaining groups are defined in Formula (IIIb). In some embodiments, R* Pre can be a halogen (e.g., F, Cl, or I), amine (e.g., NH 2 ), B(OH) 2 , Si(Me) 3 , Sn(Bu) 3 , hydrogen or the like. [0420] In some embodiments, provided herein is a precursor compound of Formula (IIIc’), Formula (IIIc’). wherein R* Pre is a precursor of a radioisotope and the remaining groups are defined in Formula (IIIc). In some embodiments, R* Pre can be a halogen (e.g., F, Cl, or I), amine (e.g., NH2), B(OH)2, Si(Me)3, Sn(Bu)3, hydrogen or the like. [0421] In some embodiments, provided herein is a precursor compound of Formula (IV’) Formula (IV’), wherein the radioisotope R* is replaced with R* Pre , and the remaining groups are defined in Formula (IV), wherein R* Pre is a precursor of a radioisotope. In some embodiments, R* Pre can be a halogen (e.g., F, Cl, or I), amine (e.g., NH2), B(OH)2, Si(Me)3, Sn(Bu)3, hydrogen or the like. [0422] In some embodiments, provided herein is a precursor compound of Formula (IVa’) Formula (IVa’), wherein the radioisotope R* is replaced with R* Pre , and the remaining groups are defined in Formula (IV), wherein R* Pre is a precursor of a radioisotope. [0423] In some embodiments, provided herein is a precursor compound of Formula (IVd’), Formula (IVd’). wherein R* Pre is a precursor of a radioisotope and the remaining groups are defined in Formula (IVd). In some embodiments, R* Pre can be a halogen (e.g., F, Cl, or I), amine (e.g., NH 2 ), B(OH) 2 , Si(Me) 3 , Sn(Bu) 3 , hydrogen or the like. [0424] In some embodiments, provided herein is a precursor compound of Formula (IVe’),
Formula (IVe’) wherein R* Pre is a precursor of a radioisotope and the remaining groups are defined in Formula (IVe). In some embodiments, R* Pre can be a halogen (e.g., F, Cl, or I), amine (e.g., NH2), B(OH)2, Si(Me)3, Sn(Bu)3, hydrogen or the like. [0425] It is to be understood that any groups or substituents (except R*) provided in this disclosure for any of the Formula (III), Formula (IIIa), Formula (IIIa-1), Formula (IIIa-2), Formula (IIIb), Formula (IIIc), Formula (IV), Formula (IVa), Formula (IVb), Formula (IVc), Formula (IVd), or Formula (IVe) are also applicable to Formula (III’), Formula (IIIa’), Formula (IIIa-1’), Formula (IIIa-2’), Formula (IIIb’), Formula (IIIc’), Formula (IV’), Formula (IVa’), Formula (IVb’), Formula (IVc’), Formula (IVd’), or Formula (IVe’), respectively, unless explicitly stated otherwise. [0426] In some embodiments, R* Pre is halogen (e.g., F, Cl, or I). In some embodiments, R* Pre is I. In some embodiments, R* Pre is Br. In some embodiments, R* Pre is H. In some embodiments, R* Pre is NH 2 . In some embodiments, R* Pre is B(OH) 2 . In some embodiments, R* Pre is Si(Me) 3 . In some embodiments, R* Pre is Si(C 1-4 alkyl) 3 . In some embodiments, R* Pre is Sn(Bu) 3. . In some embodiments, R* Pre is Sn (C 1-4 alkyl) 3 . In some embodiments, R* Pre is SnH 3 . In some embodiments, R* Pre is B(O-alkyl) 2, wherein the two alkyl groups can form a ring. In some embodiments, R* Pre is boronate. In some embodiments, R* Pre is B(pinacol). [0427] Accordingly, in one aspect, described herein is a method of synthesizing a radiolabeled compound of Formula (III), Formula (IIIa), Formula (IIIa-1), Formula (IIIa-2), Formula (IIIb), Formula (IIIc), Formula (IV), Formula (IVa), Formula (IVb), Formula (IVc), Formula (IVd), or Formula (IVe) or salt or solvate thereof, comprising replacing a precursor group in a structure of Formula (III’), Formula (IIIa’), Formula (IIIa-1’), Formula (IIIa-2’),Formula (IIIb’), Formula (IIIc’), Formula (IV’), Formula (IVa’), Formula (IVb’), Formula (IVc’), Formula (IVd’), or Formula (IVe’), respectively, with a radioisotope R*. [0428] In some embodiments, the reacting and replacing occur in a one step reaction, e.g., an isotopic exchange. In some embodiments, the isotopic exchange comprises bromine-radioiodine exchange. In some embodiments, the reacting and replacing comprise two or more steps. For example, compounds containing iodonium salts can be used as intermediates. In some embodiments, the reacting and replacing comprise direct electrophilic aromatic substitution. In some embodiments, the reacting and replacing comprise Silver(I) triflimide mediated electrophilic radioiodination. In some embodiments, the reacting and replacing comprise nickel mediated Halogen exchange. In some embodiments, the reacting and replacing comprise radioiododestannylation. Radioiododestannylation can be performed with any suitable organostannane compounds, e.g., with fluorine-rich organostannanes or ionic liquid supported organostannane. In some embodiments, the reacting and replacing comprise radioiododesilylation. In some embodiments, the reacting and replacing comprise electrophilic iododeboronation from boronic acids. In some embodiments, the reacting and replacing comprise KOAc-catalysed iododeboronation. [0429] Although the present disclosure and its advantages have been described in detail, it should be understood that various changes, substitutions and alterations can be made herein without departing from the spirit and scope of the disclosure as defined in the appended claims. The present disclosure is further illustrated in the following Examples which are given for illustration purposes only and are not intended to limit the disclosure in any way. EXAMPLES A: Synthesis of the Compounds [0430] General Information [0431] 1 H NMR spectra were recorded on either a Bruker Avance III 400 (400 MHz), or Bruker Avance 300 (400 MHz) spectrometer. Chemical shifts are reported in ppm with solvent resonance as the internal standard (CDCl 3 :7.27 ppm, DMSO-d 6 : 2.50 ppm, CD 3 OD: 3.31 ppm). Data are reported as follows: chemical shift, integration, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, p = pentet, m = multiplet), and coupling constants (Hz). [0432] Liquid chromatography was performed using forced flow (flash chromatography) on silica gel (SiO 2 , 1000 mesh) or by column chromatography (silica gel, 1000 mesh). Thin layer chromatography (TLC) was performed on a 20-25 μm silica gel glass backed plates. Preparative TLC was performed on a 40-45μm silica gel glass backed plates. Visualization was performed using ultraviolet light (254 nm), iodide, or KMnO4 in water. [0433] Reaction solvents Tetrahydrofuran (THF), dichloromethane (DCM), toluene, N, N- dimethylformamide (DMF), methanol (MeOH) and 1, 4-dioxane were supplied by WuXi EHS department which were purified with Pure-Solv MD-6 solvent purification system (Innovation technology Limited), by passing the solvents through 4A molecular sieve column. All reaction reagents were purchased from Alfa Aesar, Aldrich or domestic vendors which were used without further purification. [0434] A1. Synthesis of Int 1 Scheme 6.
[0435] 6.1 Preparation of compound 2 To a solution of benzyl (2S)-2-(cyanomethyl)piperazine-1-carboxylate (14.5 g, 55.9 mmol, 1 eq) and tert- butyl 2,4-dichloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carbox ylate (17.0 g, 55.9 mmol, 1.0 eq) in DMSO (150 mL) was added DIEA (18.1 g, 140 mmol, 24.4 mL, 2.5 eq) and the mixture stirred at 50 °C for 12 h. The residue was diluted with water (300 mL), pH adjusted with the addition of a saturated NaHCO3 solution to pH = 8-9 and extracted with EtOAc (150 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether:EtOAc = 20:1 to 3:1) to give tert-butyl 4-[(3S)- 4-benzyloxycarbonyl-3-(cyanomethyl)piperazin-1-yl]-2-chloro- 6,8-dihydro-5H-pyrido[3,4-d]pyrimidine- 7-carboxylate (25.5 g, 48.4 mmol, 87% yield) as a brown oil; 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.49 (9 H, s), 2.60 - 2.88 (4 H, m), 3.11 (1 H, td, J=12.20, 3.12 Hz), 3.23 - 3.48 (3 H, m), 3.74 - 3.92 (2 H, m), 4.02 - 4.13 (2 H, m), 4.39 - 4.49 (1 H m), 4.60 - 4.74 (2 H, m), 5.20 (2 H, s), 7.39 (5 H, s). [0436] 6.2 Preparation of compound 3 A mixture of tert-butyl 4-[(3S)-4-benzyloxycarbonyl-3-(cyanomethyl)piperazin-1-yl]-2 -chloro-6,8- dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate (40.0 g, 75.9 mmol, 1 eq) and HCl (4 M, 113 mL, 6.0 eq) was degassed and purged with N2 3 times. The reaction was stirred at 0 °C for 1 h under a N2 atmosphere. The solvent was concentrated under reduced pressure. The residue was diluted with water (200 mL), pH adjusted with saturated NaHCO3 solution to pH = 8-9 and extracted with EtOAc (80 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give crude benzyl (2S)-4-(2-chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4- yl)-2-(cyanomethyl)piperazine-1-carboxylate (30.0 g) as a white solid; 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.60 - 2.74 (3 H, m), 2.77 - 2.89 (1 H, m), 2.97 - 3.21 (3 H, m), 3.23 - 3.40 (2H, m), 3.91 (1 H, br d, J=12.8 Hz), 3.98 - 4.16 (5 H, m), 4.57 - 4.70 (1 H, m), 5.16 - 5.22 (2 H, m), 7.32 - 7.45 (5 H, m). [0437] 6.3 Preparation of compound 4 A mixture of benzyl (2S)-4-(2-chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4- yl)-2- (cyanomethyl)piperazine-1-carboxylate (15.0 g, 35.1 mmol, 1 eq), 1-bromo-8-chloro-naphthalene (21.2 g, 87.8 mmol, 2.5 eq), RuPhos Pd G3 (2.94 g, 3.51 mmol, 0.1 eq) and Cs 2 CO 3 (34.4 g, 105 mmol, 3 eq) in dioxane (150 mL) was degassed and purged with N 2 3 times, and the mixture stirred at 100 °C for 16 h under a N 2 atmosphere. The reaction mixture was filtered, concentrated under reduced pressure and purified by column chromatography (SiO 2 , petroleum ether:EtOAc = 10:1 to 5:1) to give benzyl (2S)-4-[2- chloro-7-(8-chloro-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]p yrimidin-4-yl]-2- (cyanomethyl)piperazine-1-carboxylate (15.0 g, 25.5 mmol, 73% yield) as a white solid; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.53 - 3.00 (3 H, m), 3.02 - 3.37 (4 H, m), 3.42 - 3.64 (2 H, m), 3.83 - 4.06 (2 H, m), 4.12 - 4.24 (2H, m), 4.47 (1 H, dd, J=18.2, 11.4 Hz), 4.68 (1 H, br s) 5.17 - 5.26 (2 H, m), 7.17 - 7.25 (1 H, m), 7.32 - 7.49 (7 H, m), 7.51 - 7.56 (1 H, m), 7.63 (1 H, dd, J=7.4, 5.3 Hz), 7.76 (1 H, d, J=8.1 Hz). [0438] 6.4 Preparation of compound 5 A mixture of benzyl (2S)-4-[2-chloro-7-(8-chloro-1-naphthyl)-6,8-dihydro-5H-pyri do[3,4-d]pyrimidin-4- yl]-2-(cyanomethyl)piperazine-1-carboxylate (3.0 g, 5.10 mmol, 1 eq) , tert-butyl (2S)-2- (hydroxymethyl)pyrrolidine-1-carboxylate (1.23 g, 613 µmol, 1.2 eq), Cs2CO3 (3.3 g, 1.02 mmol, 2 eq) and Xantphos Pd G4 (491 mg, 51.1 µmol, 0.1 eq) in dioxane (10 mL) was degassed and purged with N23 times. The reaction was stirred at 95 °C for 4 h under a N2 atmosphere. The reaction mixture was filtered, concentrated under reduced pressure and purified by column chromatography (SiO2, petroleum ether:EtOAc = 20:1 to 5:1) to give benzyl (2S)-4-[2-[[(2S)-1-tert-butoxycarbonylpyrrolidin-2- yl]methoxy]-7-(8-chloro-1-naphthyl)-6,8-dihydro-5H-pyrido[3, 4-d]pyrimidin-4-yl]-2- (cyanomethyl)piperazine-1-carboxylate (2.23 g, 3.1 mmol, 80% yield) as a white solid; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.40 - 1.46 (9 H, m), 1.75 - 2.04 (5 H, m), 2.44 - 2.60 (1 H, m), 2.72 - 2.86 (1 H, m), 2.93 - 3.23 (4 H, m), 3.29 - 3.46 (3 H, m), 3.57 (1 H, br s), 3.75 - 4.12 (6 H, m), 4.14- 4.17 (2 H, m), 4.59 - 4.78 (1 H, m), 5.21 (2 H, s), 7.19 (1 H, br d, J=7.2 Hz), 7.30 - 7.48 (7 H, m), 7.50 - 7.55 (1 H, m), 7.58 - 7.66 (1 H, m), 7.75 (1 H, br d, J=8.2 Hz). [0439] 6.5 Preparation of compound 6 A mixture of benzyl (2S)-4-[2-[[(2S)-1-tert-butoxycarbonylpyrrolidin-2-yl]methox y]-7-(8-chloro-1- naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cya nomethyl)piperazine-1-carboxylate (14.0 g, 18.6 mmol, 1.0 eq), Pd/C (19.7 g, 18.6 mmol, 10% purity, 1 eq) , ZnBr2 (419 mg, 1.86 mmol, 93 µL, 0.1 eq) and NH3.H2O (261 mg, 1.86 mmol, 287 µL, 25% purity, 0.1 eq) in MeOH (20 mL) was degassed and purged with N23 times. The reaction was stirred at 20 °C for 12 h under a N2 atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to give tert-butyl (2S)-2-[[7-(8-chloro-1- naphthyl)-4-[(3S)-3-(cyanomethyl)piperazin-1-yl]-6,8-dihydro -5H-pyrido[3,4-d]pyrimidin-2- yl]oxymethyl]pyrrolidine-1-carboxylate (9.0 g, 14.6 mmol, 78 % yield) as a white solid; MS (ESI) m/z: 618.5 (M + H) + , R t =0.80 min. [0440] 6.6 Preparation of compound 7 To a solution of tert-butyl (2S)-2-[[7-(8-chloro-1-naphthyl)-4-[(3S)-3-(cyanomethyl)pipe razin-1-yl]-6,8- dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxymethyl]pyrrolidine -1-carboxylate (2.0 g, 3.24 mmol, 1 eq) in DCM (20 mL) was added prop-2-enoyl chloride (351 mg, 3.88 mmol, 317 µL, 1.2 eq) and TEA (982 mg, 9.71 mmol, 1.35 mL, 3 eq). The mixture was stirred at 0 °C for 1 h under a N 2 atmosphere. The reaction mixture was filtered, concentrated under reduced pressure and purified by column chromatography (SiO 2 , petroleum ether:EtOAc = 10:1 to 0:1) to give tert-butyl (2S)-2-[[7-(8-chloro-1-naphthyl)-4-[(3S)-3- (cyanomethyl)-4-prop-2-enoyl-piperazin-1-yl]-6,8-dihydro-5H- pyrido[3,4-d]pyrimidin-2- yl]oxymethyl]pyrrolidine-1-carboxylate (1.8 g, 2.68 mmol, 83% yield) as a white solid; 1 H NMR (400 MHz, CDCl 3 ) δ (ppm) 1.43 - 1.48 (9H, m), 1.53 - 1.72 (2H, m), 1.81 - 2.03 (4H, m), 2.59 (1H, d, J = 1.6 Hz), 2.80 - 3.00 (2H, m), 3.11 - 3.27 (3H, m), 3.27 - 3.43 (3H, m), 3.50 - 3.66 (2H, m), 3.94 (2H, s), 4.16 (3H, d, J = 8.0 Hz), 4.47 (2H, s), 5.82 (1H, d, J = 10.4 Hz), 6.36 - 6.44 (1H, m), 6.54 - 6.61 (1H, m), 7.18 - 7.26 (1H, m), 7.33 (1H, t, J = 7.6 Hz), 7.43 (1H, s), 7.52 (1H, d, J = 7.6 Hz), 7.61 (1H, d, J = 7.6 Hz), 7.75 (1H, d, J = 8.0 Hz). MS (ESI) m/z: 672.4 (M + H) + , R t = 0.69 min. [0441] 6.7 Preparation of compound Intermediate 1 To a mixture of tert-butyl (2S)-2-[[7-(8-chloro-1-naphthyl)-4-[(3S)-3-(cyanomethyl)-4-p rop-2-enoyl- piperazin-1-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]o xymethyl]pyrrolidine-1-carboxylate 3 (2.4 g, 3.57 mmol, 1.0 eq) in DCM (18 mL) was added TFA (9.24 g, 81.0 mmol, 6 mL, 23 eq) and the mixture stirred at 0 °C for 2 h. The mixture was diluted with DCM (30 mL), washed with a solution of Na2CO3 (50 mL), brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC to give 2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-pyrrolidin-2-yl] methoxy]-6,8- dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piper azin-2-yl]acetonitrile TFA salt (1.25 g, 1.82 mmol, 51% yield) as a brown solid; 1 H NMR (400 MHz, CDCl3) δ (ppm) 1.89 - 2.28 (5H, m), 2.68 (2H, d, J = 14.4 Hz), 2.95 (1H, dd, J = 15.6, 8.4 Hz), 3.11 - 3.43 (4H, m), 3.45 - 3.62 (4H, m), 3.88 - 4.12 (3H, m), 4.49 (3H, dd, J = 18.4, 11.2 Hz), 4.75 - 4.91 (2H, m), 4.96 - 5.10 (1H, m), 5.86 (1H, d, J = 10.0 Hz), 6.37 - 6.46 (1H, m), 6.51 - 6.63 (1H, m), 7.25 (1H, s), 7.36 (1H, t, J = 7.6 Hz), 7.47 (1H, t, J = 7.6 Hz), 7.55 (1H, d, J = 7.6 Hz), 7.69 (1H, d, J = 8.0 Hz), 7.78 (1H, d, J = 8.0 Hz). MS (ESI) m/z: 572.4 (M + H) + , Rt = 0.71 min. [0442] A2. Synthesis of Int 2 Scheme 7. [0443] 7.1 Preparation of compound 9 2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-pyrrolidin-2-yl] methoxy]-6,8-dihydro-5H-pyrido[3,4- d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile TFA salt (250 mg, 364 umol, 1 eq) in DCM (5 mL) was cooled to 0 °C, NaBH(OAc)3 (116 mg, 547 umol, 1.5 eq), TEA (111 mg, 1.09 mmol, 152 uL, 3 eq) and tert-butyl N-(2-oxoethyl)carbamate (70 mg, 437 umol, 1.2 eq) added and the reaction stirred at 25 °C for 1 h. The reaction was diluted with DCM (20 mL), washed with brine (30 × 2 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (DCM:MeOH = 100:1 to 20:1) to give tert-butyl N-[2-[(2S)-2-[[7-(8-chloro-1-naphthyl)-4-[(3S)-3- (cyanomethyl)-4-prop-2-enoyl-piperazin-1-yl]-6,8-dihydro-5H- pyrido[3,4-d]pyrimidin-2- yl]oxymethyl]pyrrolidin-1-yl]ethyl]carbamate (150 mg, 210 umol, 58% yield) as a yellow solid; 1 H NMR (400 MHz, METHANOL-d 4 ) δ ppm 1.45 (9H, s), 1.73 - 1.94 (3H, m), 2.07 - 2.21 (1H, m), 2.51 - 2.81 (3H, m), 2.86 - 2.97 (1H, m), 3.06 - 3.31 (8H, m), 3.44 - 3.66 (2H, m), 3.66 - 3.83 (1H, m), 4.09 (1H, s), 4.15 (2H, s), 4.29 - 4.46 (3H, m), 4.49 - 4.78 (2H, m), 4.50 - 4.87 (3H, m), 5.02 - 5.23 (1H, m), 5.75 - 6.03 (1H, m), 6.23 - 6.51 (1H, m), 6.71 - 6.99 (1H, m), 7.30 - 7.43 (2H, m), 7.46 - 7.58 (2H, m), 7.67 - 7.72 (1H, m), 7.80 - 7.90 (1H, m). MS (ESI) m/z: 715.6 (M + H) + , Rt = 0.89 min. [0444] 7.2 Preparation of compound Int.2 TFA (924 mg, 8.10 mmol, 600 uL, 39 eq) was added to a solution of tert-butyl N-[2-[(2S)-2-[[7-(8-chloro- 1-naphthyl)-4-[(3S)-3-(cyanomethyl)-4-prop-2-enoyl-piperazin -1-yl]-6,8-dihydro-5H-pyrido[3,4- d]pyrimidin-2-yl]oxymethyl]pyrrolidin-1-yl]ethyl]carbamate (0.15 g, 210 umol, 1 eq) in DCM (3 mL) at 0 o C. The reaction was stirred at 25 °C for 1 h and concentrated under reduced pressure to give crude 2- [(2S)-4-[2-[[(2S)-1-(2-aminoethyl)pyrrolidin-2-yl]methoxy]-7 -(8-chloro-1-naphthyl)-6,8-dihydro-5H- pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]a cetonitrile as a yellow solid; MS (ESI) m/z: 615.6 (M + H) + , R t = 0.82 min.
[0445] A3. Synthesis of Int.3 Scheme 8: [0446] 8.1 Preparation of compound 10 A mixture of 2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-pyrrolidin-2-yl] methoxy]-6,8-dihydro-5H- pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]a cetonitrile (1.0 g, 1.75 mmol, 1.0 eq) , tert- butyl N-(4-bromobutyl)carbamate (441 mg, 1.75 mmol, 358 µL, 1 eq), K 2 CO 3 (725 mg, 5.24 mmol, 3.0 eq) and KI (290 mg, 1.75 mmol, 1 eq) in ACN (10 mL) was degassed and purged with N 2 3 times. The reaction was stirred at 60 °C for 16 h under a N 2 atmosphere. The reaction mixture was filtered, concentrated under reduced pressure and purified by column chromatography (SiO 2 , Petroleum ether:EtOAc = 10/1 to 0/1) to give tert-butyl N-[4-[(2S)-2-[[7-(8-chloro-1-naphthyl)-4-[(3S)-3- (cyanomethyl)-4-prop-2-enoyl-piperazin-1-yl]-6,8-dihydro-5H- pyrido[3,4-d]pyrimidin-2- yl]oxymethyl]pyrrolidin-1-yl]butyl]carbamate (1.2 g, 1.61 mmol, 92 % yield) as a white solid; MS (ESI) m/z: 743.6 (M + H) + , R t = 0.76 min. [0447] 8.2 Preparation of compound Int.3 To a solution of tert-butyl N-[4-[(2S)-2-[[7-(8-chloro-1-naphthyl)-4-[(3S)-3-(cyanomethy l)-4-prop-2- enoyl-piperazin-1-yl]-6,8-dihydro-5H-pyrido[3,4d]pyrimidin-2 -yl]oxymethyl]pyrrolidin-1- yl]butyl]carbamate (1.0 g, 1.35 mmol, 1 eq) in DCM (10 mL) was added TFA (3 mL). The reaction was degassed and purged with N23 times, and stirred at 20 °C for 1 h under a N2 atmosphere. The reaction mixture was filtered, concentrated under reduced pressure and purified by prep-HPLC to give 2-[(2S)-4- [2-[[(2S)-1-(4-aminobutyl)pyrrolidin-2-yl]methoxy]-7-(8-chlo ro-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4- d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile (0.3 g, 466 µmol, 35% yield) as a white solid; MS (ESI) m/z: 643.5 (M + H) + , Rt = 0.66 min. [0448] A4. Synthesis of Int.4 Scheme 9. [0449] 9 Preparation of compound Int.4 Intermediate 4 was synthesized following similar procedures as Scheme 7.
[0450] A5. Synthesis of Int.5 Scheme 10: [0451] 10.1 Preparation of compound 13 A mixture of benzyl (2S)-4-(2-chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4- yl)-2- (cyanomethyl)piperazine-1-carboxylate (29 g, 67.9 mmol, 1 eq), 1,8-dibromonaphthalene (38.9 g, 136 mmol, 2 eq), Xantphos (7.86 g, 13.6 mmol, 0.2 eq), Cs2CO3 (44.3 g, 136 mmol, 2 eq) and Pd2(dba)3 (6.22 g, 6.79 mmol, 0.1 eq) in PhMe (300 mL) was degassed and purged with N23 times, and the mixture stirred at 100°C for 16 h under a N2 atmosphere. The reaction mixture was filtered, diluted with a saturated NH4Cl solution (300 mL) and extracted with EtOAc (200 mL × 3). The combined organic layers were concentrated under reduced pressure and purified by column chromatography (SiO2, petroleum ether:EtOAc=10:1 to 1:10) to give benzyl (2S)-4-[7-(8-bromo-1-naphthyl)-2-[[(2S)-1-tert-butoxycarbony lpyrrolidin-2- yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(c yanomethyl)piperazine-1-carboxylate (40 g, 50.2 mmol, 74 % yield) as a white solid; MS (ESI) m/z: 631.1 (M + H) + , Rt =0.99 min. [0452] 10.2 Preparation of compound 14 A mixture of benzyl (2S)-4-[7-(8-bromo-1-naphthyl)-2-chloro-6,8-dihydro-5H-pyrid o[3,4-d]pyrimidin-4- yl]-2-(cyanomethyl)piperazine-1-carboxylate (37.0 g, 58.5 mmol, 1 eq) and TMSI (87.9 g, 439 mmol, 59.8 mL, 7.5 eq) in CH3CN (370 mL) was degassed and purged with N2 for 3 times, and the mixture stirred at 20 °C for 5 h under a N2 atmosphere. The reaction mixture was concentrated under reduced pressure and the residue purified by column chromatography (SiO2, Petroleum ether:EtOAc=10:1 to 5:1) to give 2- [(2S)-4-[7-(8-bromo-1-naphthyl)-2-chloro-6,8-dihydro-5H-pyri do[3,4-d]pyrimidin-4-yl]piperazin-2- yl]acetonitrile (26 g, 52.2 mmol, 89% yield) as a yellow solid. MS (ESI) m/z: 497.2 (M + H) + , R t =0.74 min. [0453] 10.3 Preparation of compound 15 To a solution of 2-[(2S)-4-[7-(8-bromo-1-naphthyl)-2-chloro-6,8-dihydro-5H-py rido[3,4-d]pyrimidin-4- yl]piperazin-2-yl]acetonitrile (22 g, 44.2 mmol, 1 eq)in DCM (20 mL) was added TEA (13.4 g, 133 mmol, 18.5 mL, 3 eq) and prop-2-enoyl chloride (4.8 g, 53.0 mmol, 4.32 mL, 1.2 eq). The mixture was stirred at 0 °C for 0.5 h. The reaction mixture was concentrated under reduced pressure and the residue purified by column chromatography (SiO 2 , petroleum ether:EtOAc=10/1 to 5/1) to give 2-[(2S)-4-[7-(8-bromo-1- naphthyl)-2-chloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-y l]-1-prop-2-enoyl-piperazin-2- yl]acetonitrile (9.0 g, 16.3 mmol, 37% yield) as a yellow solid. MS (ESI) m/z: 551.2 (M + H) + , R t =0.89 min. [0454] 10.4 Preparation of compound 16 A mixture of 2-[(2S)-4-[7-(8-bromo-1-naphthyl)-2-chloro-6,8-dihydro-5H-py rido[3,4-d]pyrimidin-4-yl]- 1-prop-2-enoyl-piperazin-2-yl]acetonitrile (15.0 g, 27.2 mmol, 1 eq), tert-butyl (2S)-2- (hydroxymethyl)pyrrolidine-1-carboxylate (6.56 g, 32.6 mmol, 1.2 eq), XantPhosPd G4 (5.23 g, 5.43 mmol, 0.2 eq) and Cs 2 CO 3 (17.7 g, 54.4 mmol, 2 eq) in t-AmylOH (150 mL) was degassed and purged with N 2 for 3 times. The reaction mixture was stirred at 100 °C for 2 h under a N 2 atmosphere. The mixture was filtered, diluted with water (50 mL), extracted with 3:1 DCM:isopropanol (120 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC to give tert-butyl(2S)-2-[[7-(8- bromo-1-naphthyl)-4-[(3S)-3-(cyanomethyl)-4-prop-2-enoyl-pip erazin-1-yl]-6,8-dihydro-5H-pyrido[3,4- d]pyrimidin-2-yl]oxymethyl]pyrrolidine-1-carboxylate (2.1 g, 293 µmol, 32% yield) as a white solid; 1 H NMR (CHLOROFORM-d): δ 7.75-7.86 (2H, m), 7.58-7.70 (1H, m), 7.46 (1H, q, J=7.9,12.3 Hz), 7.21- 7.27 (2H, m), 6.51-6.71 (1H, m), 6.40 (1H, br d, J=16.8 Hz), 5.82 (1H, br d, J=11.0 Hz), 4.89-5.25 (1H, m), 4.53-4.73 (1H, m), 4.29-4.49 (2H, m), 4.17-4.23 (1H, m), 3.97-4.11 (2H, m), 3.50-3.96 (4H, m), 2.98- 3.45 (7H, m), 2.48-2.94 (3H, m), 1.76-2.01 (3H, m), 1.45 (9H, s). [0455] 10.5 Preparation of compound 17 A mixture of tert-butyl (2S)-2-[[7-(8-bromo-1-naphthyl)-4-[(3S)-3-(cyanomethyl)-4-pr op-2-enoyl- piperazin-1-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]o xymethyl]pyrrolidine-1-carboxylate (0.30 g, 419 µmol, 1 eq), NaI (314 mg, 2.09 mmol, 5 eq), CuI (159 mg, 837 µmol, 2 eq) in dioxane (2 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 85 °C for 72 h under a N2 atmosphere. The reaction mixture was filtered and concentrated under reduced pressure and the residue purified by column chromatography (SiO2, petroleum ether:EtOAc=10:1 to 5:1) to give tert-butyl (2S)-2- [[4-[(3S)-3-(cyanomethyl)-4-prop-2-enoyl-piperazin-1-yl]-7-( 8-iodo-1-naphthyl)-6,8-dihydro-5H- pyrido[3,4-d]pyrimidin-2-yl]oxymethyl]pyrrolidine-1-carboxyl ate (0.20 g, 262 µmol, 63% yield) as a yellow solid; 1 H NMR (CHLOROFORM-d): δ 8.23 (1H, dd, J=1.6, 7.2 Hz), 7.84 (1H, br d, J=8.1 Hz), 7.64 (1H, br dd, J=4.9, 7.7 Hz), 7.37-7.58 (2H, m), 7.34 (1H, br d, J=7.4 Hz), 7.08 (1H, t, J=7.7 Hz), 6.51-6.71 (1H, m), 6.39 (1H, br d, J=16.8 Hz), 5.82 (1H, br d, J=10.0 Hz), 4.92-5.15 (1H, m), 4.50-4.72 (1H, m), 4.27-4.43 (2H, m), 3.83-3.94 (1H, m), 3.05-3.71 (11H, m), 2.46-2.84 (3H, m), 1.80-1.99 (4H, m), 1.43 (9H, br s). [0456] 10.6 Preparation of Int.5 A mixture of tert-butyl (2S)-2-[[4-[(3S)-3-(cyanomethyl)-4-prop-2-enoyl-piperazin-1- yl]-7-(8-iodo-1- naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxymeth yl]pyrrolidine-1-carboxylate (0.50 g, 650 µmol, 1 eq) in DCM (1 mL) was added TFA (1ml), the reaction degassed and purged with N23 times, then stirred at 0°C for 1 h under a N2 atmosphere. The residue was purified by prep-HPLC to give 2-[(2S)-4-[7- (8-iodo-1-naphthyl)-2-[[(2S)-pyrrolidin-2-yl]methoxy]-6,8-di hydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1- prop-2-enoyl-piperazin-2-yl]acetonitrile (126 mg, 189 µmol, 48% yield) as a white solid. 1 H NMR (DMSO-d6) δ 9.12-9.26 (1H, m), 8.61-8.79 (1H, m), 8.22 (1H, d, J=7.3 Hz), 7.99 (1H, d, J=8.1 Hz), 7.77 (1H, dd, J=3.6, 7.7 Hz), 7.53-7.66 (1H, m), 7.36-7.48 (1H, m), 7.17 (1H, t, J=7.7 Hz), 6.65-6.99 (1H, m), 6.19 (1H, br d, J=16.6 Hz), 5.66-5.87 (1H, m), 4.21-4.68 (8H, m), 3.93-4.06 (5H, m), 3.12-3.44 (8H, m), 2.80-2.92 (1H, m), 2.06-2.16 (1H, m), 1.91 (2H, ddd, J=2.5 and 7.4, 15.4 Hz), 1.64-1.78 (1H, m). MS (ESI) m/z: 664.4 (M + H) + , Rt = 0.72 min. [0457] A6. Synthesis of Compound Ex-1 Scheme 11. [0458] 11.1 Preparation of compound 19 To a solution of ethylene glycol (418 mg, 6.74 mmol, 377 µL, 2 eq) and TBAI (124 mg, 337 µmol, 0.1 eq) in THF (20 mL) was added 1-(bromomethyl)-3-iodo-benzene (1.0 g, 3.37 mmol, 1 eq) and the mixture was stirred for 20 minutes at 0 °C. NaH (135 mg, 3.37 mmol, 60% purity, 1 eq) was added to the mixture at 0 °C and the reaction stirred at 25°C for 3 h. The reaction mixture was quenched by a saturated solution of NH4Cl (30 mL) and extracted with EtOAc (20 mL × 3). The combined organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by prep-TLC (SiO2, petroleum ether: EtOAc = 1:1) to give 2-[(3-iodophenyl)methoxy]ethanol (0.38 g, 1.37 mmol, 41% yield) as a colorless oil; 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.59 - 3.64 (2 H, m), 3.76 - 3.82 (2 H, m), 4.52 (2 H, s), 7.10 (1 H, t, J=7.75 Hz), 7.31 (1 H, d, J=7.63 Hz), 7.64 (1 H, d, J=7.87 Hz), 7.72 (1 H, s). MS (ESI) m/z: 278.0 (M + H) + , Rt = 0.72 min. [0459] 11.2 Preparation of compound 20 To a mixture of 2-[(3-iodophenyl)methoxy]ethanol 19 (150 mg, 539 µmol, 1 eq) and DIEA (209 mg, 1.62 mmol, 282 µL, 3 eq) in THF (4 mL) was added MsCl (154 mg, 1.35 mmol, 104 µL, 2.5 eq) at 0 °C. The mixture was stirred at 25°C for 1 h. The reaction mixture was quenched with a saturated NaHCO3 solution (5 mL), extracted with dichloromethane (5 mL × 3), the combined organic phase dried over Na2SO4, filtered and concentrated under reduced pressure to give crude 2-[(3-iodophenyl)methoxy]ethyl methanesulfonate (0.17 g) as a colorless oil; 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.06 (3 H, s), 3.73 - 3.80 (2 H, m), 4.36 - 4.46 (2 H, m), 4.53 (2 H, s), 7.10 (1 H, t, J=7.8 Hz), 7.30 (1 H, br d, J=7.7 Hz), 7.65 (1 H, d, J=7.8 Hz), 7.71 (1 H, s). MS (ESI) m/z: 356.0 (M + H) + , R t = 0.81 min. [0460] 11.3 Preparation of compound Ex-1 To a mixture of 2-[(3-iodophenyl)methoxy]ethyl methanesulfonate 20 (0.17 g, 477 µmol, 1 eq) and 2- [(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-pyrrolidin-2-yl]me thoxy]-6,8-dihydro-5H-pyrido[3,4- d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile (273 mg, 477 µmol, 1 eq) in CH3CN (4 mL) was added K2CO3 (66 mg, 477 µmol, 1 eq) and the mixture stirred at 50 °C for 20 h. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by prep-TLC (SiO2, petroleum ether:EtOAc = 1:1) to give 2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-[2-[(3- iodophenyl)methoxy]ethyl]pyrrolidin-2-yl]methoxy]-6,8-dihydr o-5H-pyrido[3,4-d]pyrimidin-4-yl]-1- prop-2-enoyl-piperazin-2-yl]acetonitrile (5.5 mg, 6.58 µmol, 1.4% yield) a white solid; 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.66 - 1.91 (4 H , m), 1.95 - 2.12 (1 H , m), 2.28 - 2.43 (1 H , m), 2.56 - 2.73 (2 H , m), 2.77 - 2.86 (1 H , m), 2.89 - 3.05 (2 H , m), 3.08 - 3.33 (5 H , m) 3.35 - 3.50 (1 H , m), 3.54 - 3.72 (3 H , m), 3.77 - 3.97 (2 H , m), 4.01 - 4.19 (3 H , m), 4.33 - 4.52 (4 H , m) 4.94 - 5.30 (1 H , m), 5.83 (1 H , br d, J=10.5 Hz), 6.34 - 6.47 (1 H , m), 6.50 - 6.67 (1 H , m), 7.00 - 7.08 (1 H , m), 7.18 - 7.26 (2 H , m), 7.34 (1 H , br t, J=7.8 Hz), 7.40 - 7.49 (1 H , m), 7.52 (1 H , br d, J=6.2 Hz) 7.56 - 7.65 (2 H , m) 7.68 (1 H , s) 7.76 (1 H , br d, J=8.2 Hz). MS (ESI) m/z: 831.2 (M + H) + , Rt = 2.54 min. [0461] : A7. Synthesis of compound Ex-2 Scheme 12 [0462] 12.1 Preparation of compound 22 To a solution of (3-iodophenyl)methanol 21 (300 mg, 1.28 mmol, 1 eq) and 1,3-dibromopropane (3.11 g, 15.4 mmol, 1.57 mL, 12 eq) were added 50% NaOH aqueous solution (31 mg, 0.3 eq) and hydrogen sulfate; tetrabutylammonium (4.4 mg, 12.8 µmol, 0.01 eq). The mixture was stirred at 80°C for 4 h. The reaction mixture was extracted with EtOAc (10 mL × 3). The combined organic layers were washed with brine (10 mL × 2), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether:EtOAc = 10:1) to give crude 1-(3- bromopropoxymethyl)-3-iodo-benzene 22 (400 mg) as a white oil; 1H NMR (400 MHz, CHLOROFORM- d) δ ppm 2.15 (1 H, quin, J=6.16 Hz), 3.52 - 3.63 (2 H, m), 4.04 (1 H, dt, J=5.6, 1.31 Hz), 4.47 (2 H, s), 5.17 - 5.40 (1 H, m), 5.83 - 6.11 (1 H, m), 7.09 (1 H, td, J=7.8, 2.1 Hz), 7.31 (1 H, br t, J=6.3 Hz), 7.63 (1 H, br d, J=7.8 Hz), 7.71 (1 H, d, J=7.8 Hz). [0463] 12.2 Preparation of compound Ex-2 A mixture of 1-(3-bromopropoxymethyl)-3-iodo-benzene 22 (149 mg, 210 µmol, 50% purity, 1.2 eq), 2- [(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-pyrrolidin-2-yl]me thoxy]-6,8-dihydro-5H-pyrido[3,4- d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile (100 mg, 175 µmol, 1 eq), K2CO3 (72 mg, 524 µmol, 3 eq), KI (29 mg, 175 µmol, 1 eq) in CH 3 CN (2 mL) was degassed and purged with N 2 3 times. The mixture was stirred at 50 °C for 5 h under a N 2 atmosphere. The reaction mixture was filtered, concentrated under reduced pressure and purified by prep-TLC (SiO2, EtOAc: MeOH = 10:1) to give 2- [(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-[3-[(3-iodopheny l)methoxy]propyl]pyrrolidin-2- yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-pr op-2-enoyl-piperazin-2-yl]acetonitrile (28 mg, 33 µmol, 19% yield) as a white solid; 1 H NMR 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.53 (2 H, br s), 1.65 - 1.83 (5 H, m), 1.90 - 2.03 (1 H, m), 2.13 - 2.24 (1 H, m), 2.33 - 2.43 (1 H, m), 2.46 - 2.57 (1 H, m), 2.62 - 2.75 (1 H, m), 2.80 (1 H, br s), 2.87 - 2.97 (2 H, m), 3.00 - 3.13 (3 H, m), 3.13 - 3.23 (1 H, m), 3.26 - 3.39 (1 H, m), 3.41 - 3.47 (2 H, m), 3.48 - 3.55 (1 H, m), 3.72 (1 H, br d, J=17.6 Hz), 3.78 - 3.86 (1 H, m), 3.94 - 4.03 (2 H, m), 4.24 - 4.41 (4 H, m), 4.82 - 5.15 (1 H, m), 5.74 (1 H, br d, J=10.3 Hz), 6.28 - 6.37 (1 H, m), 6.43 - 6.59 (1 H, m), 6.92 - 6.99 (1 H, m), 7.17 (2 H, br d, J=3.2 Hz), 7.26 (1 H, t, J=7.76 Hz), 7.36 (1 H, dt, J=12.7, 7.8 Hz), 7.44 (1 H, d, J=7.3 Hz), 7.49 (1 H, d, J=8.0 Hz), 7.54 (1 H, t, J=7.1 Hz), 7.58 (1 H, s), 7.68 (1 H, d, J=8.07 Hz). MS (ESI) m/z: 846.3, 423.8 (1/2 m/z), R t = 2.52 min.
[0464] A8. Synthesis of compound Ex-3 Scheme 13. [0465] 13.1 Preparation of compound 23 To a solution of (3-iodophenyl)methanol 21 (1.0 g, 4.27 mmol, 1 eq) in DMF (5 mL) was slowly added NaH (427 mg, 10.7 mmol , 2.5 eq), the mixture stirred at 0 °C for 15 minute, 1,4-dibromobutane (9.23 g, 42.7 mmol, 10 eq) added at 0 °C and the mixture stirred at 15 °C for 3 h. The reaction mixture was quenched with a saturated NH4Cl solution (20 mL) and extracted with EtOAc (20 mL × 3). The combined organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue purified by column chromatography (petroleum ether: EtOAc = 10:1 to 5:1) to give 1-(4-bromobutoxymethyl)-3-iodo- benzene (1.03 g, 2.79 mmol, 65 % yield) as a colorless oil; 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.73 - 1.85 (2 H, m), 1.94 - 2.02 (2 H, m), 3.42 - 3.52 (4 H, m), 4.45 (2 H, s), 7.09 (1 H, t, J=7.75 Hz), 7.30 (1 H, d, J=7.63 Hz), 7.63 (1 H, d, J=7.88 Hz), 7.70 (1 H, s). MS (ESI) m/z: 367.9 (M + H) + , Rt = 0.89 min. [0466] 13.2 Preparation of compound Ex-3 To a solution of 1-(4-bromobutoxymethyl)-3-iodo-benzene 23 (65 mg, 175 µmol, 1 eq), 2-[(2S)-4-[7-(8- chloro-1-naphthyl)-2-[[(2S)-pyrrolidin-2-yl]methoxy]-6,8-dih ydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1- prop-2-enoyl-piperazin-2-yl]acetonitrile (0.10 g, 175 µmol, 1 eq) in CH3CN (3 mL) was added K2CO3 (72 mg, 524 µmol, 3 eq) and KI (29 mg, 175 µmol, 1 eq). The mixture was stirred at 50 °C for 16 h. The reaction mixture was filtered, concentrated under reduced pressure and purified by prep-HPLC to give 2- [(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-[4-[(3-iodopheny l)methoxy]butyl]pyrrolidin-2-yl]methoxy]- 6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-p iperazin-2-yl]acetonitrile (77 mg, 90 µmol, 51% yield) as a white solid; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.62 (3 H, br d, J=6.0 Hz), 1.78 (4 H, br s), 1.94 - 2.07 (1 H, m), 2.18 - 2.31 (1 H, m), 2.33 - 2.46 (1 H, m), 2.53 - 2.65 (1 H, m), 2.68 - 2.94 (4 H, m), 3.02 (1 H, br dd, J=16.7, 8.34 Hz), 3.10 - 3.31 (4 H, m), 3.38 - 3.52 (3 H, m), 3.56 - 3.65 (1 H, m), 3.76 - 3.95 (2 H, m), 3.99 - 4.18 (3 H, m), 4.31 - 4.44 (4 H, m), 4.75 - 5.34 (1 H, m), 5.82 (1 H, br d, J=10.4 Hz), 6.34 - 6.44 (1 H, m), 6.50 - 6.65 (1 H, m), 7.05 (1 H, t, J=7.8 Hz), 7.17 - 7.26 (2 H, m), 7.33 (1 H, t, J=7.8 Hz), 7.44 (1 H, dt, J=13.59, 7.8 Hz), 7.52 (1 H, br d, J=7.3 Hz), 7.57 - 7.64 (2 H, m), 7.67 (1 H, s), 7.75 (1 H, br d, J=8.1 Hz). MS (ESI) m/z: 859.2 (M/2 + H), Rt = 2.57 min. [0467] : A9. Synthesis of compound Ex-4 Scheme 14. [0468] 14.1 Preparation of compound 25 To a solution of 3-iodobenzoic acid 24 (0.50 g, 2.02 mmol, 1 eq) and 3-bromopropan-1-ol (560 mg, 4.03 mmol, 364 µL, 2 eq) in DCM (5 mL) was added CDI (360 mg, 2.22 mmol, 1.1 eq), DMAP (123 mg, 1.01 mmol, 0.5 eq) and Et 3 N (306 mg, 3.02 mmol, 421 µL, 1.5 eq). The mixture was stirred at 15°C for 16 h. The reaction mixture was quenched with a saturated NH 4 Cl solution (10 mL) and extracted with EtOAc (10 mL × 3). The combined organic phase was dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether: EtOAc = 10: 1 to 5:1) to give 3-bromopropyl 3-iodobenzoate 25 (0.12 g, 330 µmol, 16 % yield) as a white solid; 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.33 (2 H, q, J=6.3 Hz), 3.55 (2 H, t, J=6.5 Hz), 4.48 (2 H, t, J=6.1 Hz), 7.20 (1 H, t, J=7.9 Hz), 7.90 (1 H, d, J=8.0 Hz), 8.01 (1 H, d, J=7.8 Hz), 8.37 (1 H, t, J=1.53 Hz). MS (ESI) m/z: 367.9 (M + H) + , R t = 0.94 min. [0469] 14.2 Preparation of compound Ex-4 To a solution of 3-bromopropyl 3-iodobenzoate 25 (64.5 mg, 175 µmol, 1 eq), 2-[(2S)-4-[7-(8-chloro-1- naphthyl)-2-[[(2S)-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-p yrido[3,4-d]pyrimidin-4-yl]-1-prop-2- enoyl-piperazin-2-yl]acetonitrile (0.10 g, 175 µmol, 1 eq) in CH3CN (2 mL) was added KI (29 mg, 175 µmol, 1 eq) and K2CO3 (72 mg, 524 µmol, 3 eq). The mixture was stirred at 50 °C for 16 h. The reaction mixture was filtered, concentrated under reduced pressure and purified by prep-HPLC to give 3-[(2S)-2- [[7-(8-chloro-1-naphthyl)-4-[(3S)-3-(cyanomethyl)-4-prop-2-e noyl-piperazin-1-yl]-6,8-dihydro-5H- pyrido[3,4-d]pyrimidin-2-yl]oxymethyl]pyrrolidin-1-yl]propyl 3-iodobenzoate (36 mg, 42.2 µmol, 24% yield) as a white solid; 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.78 (3 H, br s) 1.96 - 2.06 (3 H, m), 2.22 - 2.31 (1 H, m), 2.51 - 2.62 (2 H, m), 2.69 - 2.88 (2 H, m), 2.91 (1 H, br s), 3.00 - 3.19 (5 H, m), 3.20 - 3.29 (1 H, m), 3.32 - 3.50 (1 H, m), 3.58 (1 H, br d, J=10.5 Hz), 3.75 - 3.86 (1 H, m), 3.88 - 4.19 (4 H, m), 4.29 - 4.43 (4 H, m), 4.91 - 5.22 (1 H, m), 5.83 (1 H, br d, J=9.9 Hz), 6.34 - 6.47 (1 H, m), 6.52 - 6.71 (1 H, m), 7.11 (1 H, br t, J=7.8 Hz), 7.17 - 7.25 (1 H, m), 7.34 (1 H, br t, J=7.8 Hz), 7.44 (1 H, dt, J=12.99, 7.8 Hz), 7.52 (1 H, br d, J=7.5 Hz), 7.61 (1 H, br t, J=7.5 Hz), 7.76 (1 H, br d, J=8.0 Hz), 7.81 (1 H, br d, J=7.7 Hz), 7.95 (1 H, br d, J=7.2 Hz), 8.33 (1 H, s). MS (ESI) m/z: 859.2 (M + H) + , Rt = 0.85 min. [0470] A10. Synthesis of compound Ex-5 Scheme 15. [0471] 15.1 Preparation of compound 26 To a solution of 3-iodobenzoic acid 24 (1.0 g, 4.03 mmol, 1.0 eq) in DMF (20 mL) was added HATU (1.69 g, 4.44 mmol, 1.1 eq) and DIEA (1.04 g, 8.06 mmol, 1.40 mL, 2 eq) at 0°C. The mixture was stirred at 0°C for 1h, 3-bromopropan-1-amine hydrobromide (1.03 g, 4.03 mmol, 1 eq, HCl) added at 0°C, the reaction mixture diluted with H2O (40 mL) and extracted with EtOAc (20 mL × 2). The combined organic layers were washed with H2O (40 mL × 2), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether:EtOAc=10:1 to 3:1) to give N-(3-bromopropyl)-3-iodo-benzamide (0.70 g, 1.90 mmol, 47% yield) as a white solid; 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.21 (2 H, quin, J=6.48 Hz), 3.50 (2 H, t, J=6.4 Hz), 3.62 (2 H, q, J=6.5 Hz), 6.39 (1 H, br s), 7.18 (1 H, t, J=7.83 Hz), 7.72 (1 H, dt, J=7.8, 1.3 Hz), 7.84 (1 H, dt, J=7.8, 1.3 Hz), 8.11 (1 H, t, J=1.7 Hz). MS (ESI) m/z: 368.0 (M + H) + , Rt = 0.80 min. [0472] 15.2 Preparation of compound Ex-5 A mixture of 2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-pyrrolidin-2-yl] methoxy]-6,8-dihydro-5H- pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]a cetonitrile (100 mg, 175 µmol, 1 eq), N-(3- bromopropyl)-3-iodo-benzamide (64 mg, 175 µmol, 1 eq), K 2 CO 3 (72 mg, 524 µmol, 3 eq), KI (29 mg, 175 µmol, 1 eq) in CH 3 CN (2 mL) was degassed and purged with N 2 for 3 times, and the mixture stirred at 80°C for 2 h under a N2 atmosphere. The reaction mixture was filtered, concentrated under reduced pressure and the residue purified by prep-HPLC to give N-[3-[(2S)-2-[[7-(8-chloro-1-naphthyl)-4-[(3S)-3- (cyanomethyl)-4-prop-2-enoyl-piperazin-1-yl]-6,8-dihydro-5H- pyrido[3,4-d]pyrimidin-2- yl]oxymethyl]pyrrolidin-1-yl]propyl]-3-iodo-benzamide (35 mg, 40 µmol, 23% yield) as a white solid; 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.71 - 1.95 (5 H, m), 1.99 - 2.12 (1 H, m), 2.20 - 2.41 (1 H, m), 2.44 - 2.57 (1 H, m), 2.59 - 2.75 (2 H, m), 2.76 - 3.09 (5 H, m), 3.11 - 3.35 (5 H, m), 3.53 - 3.65 (2 H, m), 3.67 - 4.07 (4 H, m), 4.17 - 4.39 (3 H, m), 4.78 - 5.15 (1 H, m), 5.83 (1 H, br d, J=10.5 Hz), 6.32 - 6.43 (1 H, m), 6.47 - 6.67 (1 H, m), 7.07 (1 H, q, J=7.5 Hz), 7.15 - 7.23 (1 H, m), 7.34 (1 H, t, J=7.8 Hz), 7.43 - 7.56 (2 H, m), 7.60 - 7.72 (2 H, m), 7.73 - 7.89 (2 H, m), 8.11 (1 H, br s), 9.04 (1 H, br s). MS (ESI) m/z: 859.1 (M + H) + , R t = 2.44 min. [0473] A11. Synthesis of Ex-6 [0474] 16.1 Preparation of compound 27 A mixture of (3-iodophenyl)methanol (0.20 g, 855 µmol, 1 eq), 4-bromobutanoyl chloride (190 mg, 1.03 mmol, 119 µL, 1.2 eq) and TEA (173 mg, 1.71 mmol, 238 µL, 2 eq) in DCM (5 mL) was degassed and purged with N23 times, and the mixture stirred at 0 °C for 4 h under a N2 atmosphere. The reaction mixture was quenched with a saturated NH4Cl solution (5 mL) and then extracted with EtOAc (5 mL × 4). The combined organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC (SiO2, PE: EA = 3:1) to give (3-iodophenyl)methyl 4-bromobutanoate (0.27 g, 705 µmol, 82% yield) as a white oil; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.21 (2 H, quin, J=6.8 Hz), 2.58 (2 H, t, J=7.2 Hz) 3.48 (2 H, t, J=6.4 Hz), 5.07 (2 H, s), 7.11 (1 H, t, J=7.8 Hz), 7.32 (1 H, d, J=7.6 Hz), 7.67 (1 H, d, J=8.0 Hz), 7.72 (1 H, s). MS (ESI) m/z: 381.9 (M + H) + , Rt = 0.94 min. [0475] 16.2 Preparation of compound Ex-6 A mixture of (3-iodophenyl)methyl 4-bromobutanoate (100 mg, 261 µmol, 5 eq) , 2-[(2S)-4-[7-(8-chloro- 1-naphthyl)-2-[[(2S)-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H -pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2- enoyl-piperazin-2-yl]acetonitrile (30 mg, 52 µmol, 1 eq) and TEA (26 mg, 261 µmol, 36 µL, 5 eq) in CH 3 CN (2 mL) was degassed and purged with N 2 3 times. The mixture was stirred at 50 °C for 16 h. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by prep- HPLC to give (3-iodophenyl)methyl4-[(2S)-2-[[7-(8-chloro-1-naphthyl)-4-[( 3S)-3-(cyanomethyl)-4-prop- 2-enoyl-piperazin-1-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidi n-2-yl]oxymethyl]pyrrolidin-1- yl]butanoate (13.0 mg, 14.9 µmol, 29% yield) as a white solid. 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.60 - 1.91 (7 H, m), 2.01 (1 H, br s), 2.23 (1 H, br s) 2.34 - 2.50 (3 H, m), 2.60 (1 H, br d, J=13.6 Hz), 2.76 - 2.93 (3 H, m), 2.97 - 3.31 (5 H, m), 3.35 - 3.66 (2 H, m), 3.74 - 3.93 (2 H, m), 3.96 - 4.18 (3 H, m), 4.20 - 4.52 (2 H, m), 5.01 (2 H, br d, J=4.1 Hz), 5.82 (1 H, br d, J=10.5 Hz), 6.39 (1 H, br d, J=16.8 Hz), 6.59 (1 H, br s), 7.06 (1 H, br t, J=7.7 Hz), 7.18 - 7.25 (1 H, m), 7.29 (1 H, br s), 7.33 (1 H, br t, J=7.8 Hz), 7.44 (1 H, dt, J=13.4, 7.7 Hz), 7.52 (1 H, br d, J=7.5 Hz), 7.59 - 7.65 (2 H, m), 7.68 (1 H, s), 7.75 (1 H, br d, J=8.0 Hz). MS (ESI) m/z: 873.2 (M + H) + , R t = 3.87 min.
[0476] A12. Synthesis of compound Ex-7 Scheme 17. [0477] 17.1 Preparation of compound 29 A mixture of tert-butyl 2,2-dimethyl-4-oxo-butanoate (85.5 mg, 459 µmol, 1.5 eq), 2-[(2S)-4-[7-(8-chloro- 1-naphthyl)-2-[[(2S)-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H -pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2- enoyl-piperazin-2-yl]acetonitrile (175 mg, 306 µmol, 1 eq), NaBH(OAc) 3 (97 mg, 459 µmol, 1.5 eq) in DCM (1 mL) was degassed and purged with N 2 for 3 times, and stirred at 25 °C for 2 h under a N 2 atmosphere. The reaction mixture was quenched by addition DCM (2 mL) at 25°C and concentrated under reduced pressure. The residue was purified by prep-TLC (SiO 2 , EtOAc:MeOH = 5:1) to give tert-butyl 4- [(2S)-2-[[7-(8-chloro-1-naphthyl)-4-[(3S)-3-(cyanomethyl)-4- prop-2-enoyl-piperazin-1-yl]-6,8-dihydro- 5H-pyrido[3,4-d]pyrimidin-2-yl]oxymethyl]pyrrolidin-1-yl]-2, 2-dimethyl-butanoate (60 mg, 81 µmol, 26 % yield) as a white solid.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.10 - 1.15 (6 H, m), 1.18 (2 H, s), 1.42 (9 H, d, J=2.1 Hz), 1.45 (4 H, s) 1.80 (4 H, br d, J=6.9 Hz), 2.02 - 2.05 (1 H, m), 2.13 - 2.42 (2 H, m), 2.55 - 2.65 (1 H, m), 2.77 - 2.93 (3 H, m), 3.00 - 3.24 (4 H, m), 3.56 - 3.64 (1 H, m), 3.71 (1 H, t, J=6.7 Hz), 3.78 - 3.86 (1 H, m), 3.99 - 4.10 (2 H, m), 4.33 - 4.48 (2 H, m), 5.83 (1 H, br d, J=11.1 Hz), 6.40 (1 H, br d, J=17.0 Hz), 6.55 - 6.72 (1 H, m), 7.18 - 7.26 (1 H, m), 7.34 (1 H, t, J=7.8 Hz), 7.45 (1 H, dt, J=12.7, 7.8 Hz), 7.51 - 7.54 (1 H, m), 7.62 (1 H, t, J=7.3 Hz) 7.74 - 7.78 (1 H, m). MS (ESI) m/z: 742.4 (M + H) + , Rt = 0.85 min. [0478] 17.2 Preparation of compound 30 A mixture of tert-butyl 4-[(2S)-2-[[7-(8-chloro-1-naphthyl)-4-[(3S)-3-(cyanomethyl)- 4-prop-2-enoyl- piperazin-1-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]o xymethyl]pyrrolidin-1-yl]-2,2-dimethyl- butanoate (20 mg, 26.9 µmol, 1 eq), TFA (770 mg, 6.75 mmol, 0.5 mL, 251 eq), in DCM (0.5 mL) was degassed and purged with N2 for 3 times at 0°C, and the mixture was stirred at 20°C for 1 h under N2 atmosphere. The reaction was concentrated under reduced pressure to give crude 4-[(2S)-2-[[7-(8-chloro- 1-naphthyl)-4-[(3S)-3-(cyanomethyl)-4-prop-2-enoyl-piperazin -1-yl]-6,8-dihydro-5H-pyrido[3,4- d]pyrimidin-2-yl]oxymethyl]pyrrolidin-1-yl]-2,2-dimethyl-but anoic acid (20 mg) as a yellow oil. MS (ESI) m/z: 686.6 (M + H) + , Rt = 0.74 min. [0479] 17.3 Preparation of compound Ex-7 A mixture of 4-[(2S)-2-[[7-(8-chloro-1-naphthyl)-4-[(3S)-3-(cyanomethyl)- 4-prop-2-enoyl-piperazin-1- yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxymethyl]pyr rolidin-1-yl]-2,2-dimethyl-butanoic acid (100 mg, 146 µmol, 1 eq), 1-(bromomethyl)-3-iodo-benzene (130 mg, 437 µmol, 3 eq), K2CO3 (60 mg, 437 µmol, 3 eq), KI (24 mg, 146 µmol, 1 eq) in DMF (2 mL) was degassed and purged with N23 times. The reaction was stirred at 40 °C for 16 h under a N 2 atmosphere and concentrated under reduced pressure. The residue was diluted with H 2 O (3 mL), extracted with EtOAc (50 mL) and purified by prep-HPLC to give (3-iodophenyl)methyl4-[(2S)-2-[[7-(8-chloro-1-naphthyl)-4-[( 3S)-3-(cyanomethyl)-4-prop-2-enoyl- piperazin-1-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]o xymethyl]pyrrolidin-1-yl]-2,2-dimethyl- butanoate (8 mg, 8.87 µmol, 6.1% yield) as a yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.23 - 1.27 (6 H, m), 1.99 - 2.16 (4 H, m), 2.18 - 2.33 (2 H, m), 2.58 - 2.77 (2 H, m), 2.85 - 3.00 (3 H, m), 3.04 - 3.11 (1 H, m), 3.13 - 3.20 (2 H, m), 3.51 - 3.60 (3 H, m), 3.67 - 3.78 (2 H, m), 3.88 (1 H, dt, J=11.5, 5.9 Hz), 3.94 - 4.11 (2 H, m), 4.18 - 4.29 (1 H, m), 4.41 - 4.56 (2 H, m), 4.69 - 4.78 (1 H, m), 4.89 - 5.12 (4 H, m), 5.85 (1 H, br d, J=9.8 Hz), 6.35 - 6.46 (1 H, m), 6.51 - 6.67 (1 H, m), 7.07 - 7.14 (1 H, m), 7.21 - 7.25 (1 H, m), 7.30 - 7.32 (1 H, m), 7.35 (1 H, t, J=7.8 Hz), 7.46 (1 H, td, J=7.8, 5.3 Hz), 7.52 - 7.56 (1 H, m), 7.63 - 7.70 (3 H, m), 7.77 (1 H, d, J=8.3 Hz). MS (ESI) m/z: 902.5 (M + H) + , R t =0.88 min.
[0480] A13. Synthesis of compound Ex-8 Scheme 18. [0481] 18.1 Preparation of compound 31 To a solution of 2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-pyrrolidin-2-yl] methoxy]-6,8-dihydro-5H- pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]a cetonitrile (0.05 g, 87.4 µmol, 1.0 eq) in MeCN (5 mL) was added KI (14.5 mg, 87.4 µmol, 1 eq), K2CO3 (36 mg, 262 µmol, 3 eq) and 4-bromo-2- methyl-butan-2-ol (21.9 mg, 131 µmol, 1.5 eq). The mixture was stirred at 60 °C for 16 h. The reaction mixture was concentrated under reduced pressure and the residue purified by prep-TLC (SiO2, EtOAc:methanol = 10:1) to give 2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-(3-hydroxy-3-m ethyl- butyl)pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]p yrimidin-4-yl]-1-prop-2-enoyl-piperazin- 2-yl]acetonitrile (50 mg, 76 µmol, 87% yield) as a white solid; MS (ESI) m/z: 657.3 (M + H) + , Rt = 0.73 min. [0482] 18.2 Preparation of compound Ex-8 To a solution of 2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-(3-hydroxy-3-m ethyl-butyl)pyrrolidin-2- yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-pr op-2-enoyl-piperazin-2-yl]acetonitrile (45 mg, 68.4 µmol, 1 eq) in DCM (5mL) was added TEA (13.8 mg, 137 µmol, 19.0 µL, 2 eq) and 3- iodobenzoyl chloride (36 mg, 137 µmol, 2 eq). The mixture was stirred at 15 °C for 16 h. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by prep-TLC (SiO 2 , EtOAc : Methanol = 10:1) to give [3-[(2S)-2-[[7-(8-chloro-1-naphthyl)-4-[(3S)-3-(cyanomethyl) -4- prop-2-enoyl-piperazin-1-yl]-6,8-dihydro-5Hpyrido[3,4-d]pyri midin-2-yl]oxymethyl]pyrrolidin-1-yl]- 1,1-dimethyl-propyl] 3-iodobenzoate (20 mg, 23 µmol, 33% yield) as a white solid; 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.58 (6 H, br s), 1.77 (3 H, br s), 1.95 - 2.06 (1 H, m), 2.08 - 2.21 (2 H, m), 2.24 - 2.31 (1 H, m), 2.47 - 2.55 (1 H, m), 2.57 - 2.64 (1 H, m), 2.78 - 2.85 (1 H, m), 2.87 - 2.93 (1 H, m), 2.97 - 3.32 (7 H, m), 3.34 - 3.48 (1 H, m), 3.59 (1 H, br dd, J=11.0, 4.1 Hz), 3.76 - 3.92 (2 H, m), 4.04 - 4.12 (2 H, m), 4.30 - 4.42 (2 H, m), 4.49 - 4.73 (1 H, m), 4.91 - 5.20 (1 H, m), 5.83 (1 H, br d, J=10.3 Hz), 6.34 - 6.46 (1 H, m), 6.53 - 6.69 (1 H, m), 7.10 (1 H, t, J=7.9 Hz), 7.16 - 7.25 (1 H, m), 7.32 - 7.37 (1 H, m), 7.42 - 7.48 (1 H, m), 7.52 (1 H, d, J=6.7 Hz), 7.59 - 7.65 (1 H, m), 7.74 - 7.82 (2 H, m), 7.90 (1 H, d, J=7.9 Hz), 8.28 (1 H, s). MS (ESI) m/z: 887.2 (M + H) + , Rt = 2.65 min. [0483] : A14. Synthesis of compound Ex-9 Scheme 19 [0484] 19.1 Preparation of compound 34 Benzyl (2S)-2-(cyanomethyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]met hoxy]-5,6,7,8- tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxyla te (0.80 g, 1.58 mmol), 1,8- dibromonaphthalene (905 mg, 3.16 mmol), Cs2CO3 (1.60 g, 4.91 mmol), Xantphos (200 mg, 346 umol) and Pd2(dba)3 (160 mg, 175 umol) in toluene (10 mL) was degassed and purged with N23 times. The mixture was stirred at 100 °C for 6 h under a N2 atmosphere. The reaction mixture was filtered and the filtrate concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether:EtOAc=1:1 to DCM:methanol=10:1) to give benzyl (2S)-4-[7-(8-bromo-1-naphthyl)-2- [[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrid o[3,4-d]pyrimidin-4-yl]-2- (cyanomethyl)piperazine-1-carboxylate (0.50 g, 44% yield) as a brown solid. MS (ESI) m/z: 712.3 (M +2H) + , Rt = 0.64 min. [0485] 19.2 Preparation of compound 35 To a solution of benzyl (2S)-4-[7-(8-bromo-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2 -yl]methoxy]-6,8- dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piper azine-1-carboxylate (100 mg, 141 umol) in CH 3 CN (4 mL) was added TMSI (282 mg, 1.41 mmol) at 0 °C. The mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated under reduced pressure and the residue purified by prep-TLC (SiO 2 , DCM:MeOH = 10:1) to give 2-[(2S)-4-[7-(8-bromo-1-naphthyl)-2-[[(2S)-1-methylpyrrolidi n-2- yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piper azin-2-yl]acetonitrile (60 mg, 74% yield) as a brown solid; MS (ESI) m/z: 578.2 (M +2H) + , R t = 0.42 min. [0486] 19.3 Preparation of compound 36 To a solution of 2-[(2S)-4-[7-(8-bromo-1-naphthyl)-2-[[(2S)-1-methylpyrrolidi n-2-yl]methoxy]-6,8- dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]aceton itrile (60 mg, 104 umol) in CH 2 Cl 2 (2 mL) was added TEA (32 mg, 312 umol) and prop-2-enoyl chloride (19 mg, 208 umol). The mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure and the residue purified by prep-HPLC to give 2-[(2S)-4-[7-(8-bromo-1-naphthyl)-2-[[(2S)-1-methylpyrrolidi n-2-yl]methoxy]- 6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-p iperazin-2-yl]acetonitrile (20 mg, 30% yield) as a white solid; 1 H NMR (400 MHz, CD 3 OD): δ (ppm) 1.72 - 2.27 (5H, m), 2.63 - 2.80 (5H, m), 2.86 - 2.97 (1H, m), 3.11 - 3.26 (4H, m), 3.47 - 3.87 (4H, m), 4.05 - 4.37 (4H, m), 4.39 - 4.69 (4H, m), 5.85 (1H, d, J=10.4 Hz), 6.31 (1H, d, J=17.2 Hz), 6.73 - 7.01 (1H, m), 7.30 (1H, t, J = 7.6 Hz), 7.38 (1H, d, J=12.4), 7.48 - 7.58 (1H, m), 7.72 (1H, d, J = 8.4 Hz), 7.82 (1H, d, J = 7.2 Hz), 7.89 (1H, d, J=8.0 Hz). MS (ESI) m/z: 632.2 (M + H) + , R t = 0.56 min. [0487] 19.4 Preparation of compound Ex-9 A mixture of 2-[(2S)-4-[7-(8-bromo-1-naphthyl)-2-[[(2S)-1-methylpyrrolidi n-2-yl]methoxy]-6,8-dihydro- 5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-y l]acetonitrile (10 mg, 15.9 umol), NaI (6.0 mg, 40.0 umol), CuI (2.00 mg, 10.5 umol) in dioxane (2 mL) was degassed and purged with N23 times. The reaction mixture was stirred at 100 °C for 4 h under N2 atmosphere, filtered and the filtrate concentrated under reduced pressure. The residue was purified by prep-HPLC to give 2-[(2S)-4-[7-(8-iodo-1-naphthyl)- 2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyr ido[3,4-d]pyrimidin-4-yl]-1-prop-2- enoyl-piperazin-2-yl]acetonitrile (3.5 mg, 33% yield) as a white solid; 1 H NMR (400 MHz, CD3OD): δ (ppm) 2.03 - 2.28 (3H, m), 2.35 - 2.55 (1H, m), 2.67 - 3.04 (3H, m), 3.05 - 3.11 (3H, m), 3.13 - 3.29 (2H, m), 3.40 - 3.85 (7H, m), 3.87 - 4.04 (1H, m), 4.74 (5H, s), 4.92 - 5.15 (2H, m), 5.87 (1H, d, J = 9.6 Hz), 6.32 (1H, d, J = 16.0 Hz), 6.75 - 6.98 (1H, m), 7.09 - 7.18 (1H, m), 7.42 - 7.51 (1H, m), 7.52 - 7.61 (1H, m), 7.75 (1H, d, J = 8.0 Hz), 7.94 (1H, d, J = 7.6 Hz), 8.27 (1 H, d, J = 7.2Hz). MS (ESI) m/z: 678.3(M/2 + H) + , Rt = 0.57 min. [0488] A15. Synthesis of Compound Ex-10 Scheme 20. [0489] 20.1 Preparation of compound Ex-10 A mixture of 2-[(2S)-4-[7-(8-iodo-1-naphthyl)-2-[[(2S)-pyrrolidin-2-yl]me thoxy]-6,8-dihydro-5H- pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]a cetonitrile (70 mg, 105 µmol, 1 eq), 3- bromopropanoic acid (48 mg, 316 µmol, 33 µL, 3 eq), K 2 CO 3 (44 mg, 316 µmol, 3 eq) and KI (18 mg, 105 µmol, 1 eq) in CH 3 CN (1 mL) was degassed and purged with N 2 3 times. The mixture was stirred at 60 °C for 16 h. The reaction mixture was concentrated under reduced pressure and the residue purified by prep- HPLC to give 3-[(2S)-2-[[4-[(3S)-3-(cyanomethyl)-4-prop-2-enoyl-piperazin -1-yl]-7-(8-iodo-1-naphthyl)- 6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxymethyl]pyrroli din-1-yl]propanoic acid (18.0 mg, 27.2 µmol, 26% yield) as a white solid; 1 H NMR (400 MHz, DMSO-d6) δ ppm 1.77 - 2.10 (3 H, m) 2.14 - 2.27 (1 H, m) 2.64 - 2.85 (3 H, m) 2.86 - 3.21 (6 H, m) 3.60 - 3.72 (4 H, m) 3.85 - 4.17 (6 H, m) 4.34 - 4.59 (3 H, m) 4.63 - 5.07 (2 H, m) 5.78 (1 H, br d, J=11.2 Hz) 6.19 (1 H, br d, J=16.7 Hz) 6.74 - 6.96 (1 H, m) 7.17 (1 H, t, J=7.69 Hz) 7.37 - 7.47 (1 H, m) 7.57 (1 H, q, J=8.3 Hz) 7.76 (1 H, dd, J=8.1, 3.5 Hz) 7.99 (1 H, d, J=8.1 Hz) 8.22 (1 H, d, J=7.2 Hz) 9.35 - 9.67 (1 H, m). MS (ESI) m/z: 735.2 (M + H) + , Rt = 2.26 min. [0490] A16. Synthesis of Ex-11 Scheme 21. [0491] 21.1 Preparation of compound 38 A mixture of 2-[(2S)-4-[7-(8-iodo-1-naphthyl)-2-[[(2S)-pyrrolidin-2-yl]me thoxy]-6,8-dihydro-5H- pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]a cetonitrile (50 mg, 75.4 µmol, 1 eq) and tert- butyl 4-bromobutanoate (134 mg, 603 µmol, 8 eq) in CH3CN (2 mL) was added KI (13 mg, 75 µmol, 1 eq) and K2CO3 (31 mg, 226 µmol, 3 eq). The mixture was stirred at 20 °C for 16 h under a N2 atmosphere. The reaction was concentrated under reduced pressure. to give crude tert-butyl 4-[(2S)-2-[[4-[(3S)-3- (cyanomethyl)-4-prop-2-enoyl-piperazin-1-yl]-7-(8-iodo-1-nap hthyl)-6,8-dihydro-5H-pyrido[3,4- d]pyrimidin-2-yl]oxymethyl]pyrrolidin-1-yl]butanoate (60 mg, 50 µmol, 66 % yield) as a white solid. [0492] 21.2 Preparation of compound Ex-11 A mixture of crude tert-butyl 4-[(2S)-2-[[4-[(3S)-3-(cyanomethyl)-4-prop-2-enoyl-piperazin -1-yl]-7-(8- iodo-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl] oxymethyl]pyrrolidin-1-yl]butanoate (50 mg, 6.21 µmol, 1 eq) in TFA (1 mL) and DCM (3 mL) was stirred at 20 °C for 3 h under a N2 atmosphere. The reaction mixture was concentrated under reduced pressure and the residue purified by prep-TLC (SiO2, EtOAc:MeOH = 5:1) to give 4-[(2S)-2-[[4-[(3S)-3-(cyanomethyl)-4-prop-2-enoyl-piperazin -1-yl]-7-(8- iodo-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl] oxymethyl]pyrrolidin-1-yl]butanoic acid (18.4 mg，19.6 µmol, 36% yield) as a white solid; 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.76 (2 H, br dd, J=12.8, 6.3 Hz), 1.84 - 1.99 (3 H, m), 2.12 - 2.21 (1 H, m), 2.52 - 2.67 (4 H, m), 2.87 (4 H, br d, J=12.8 Hz), 3.02 - 3.26 (4 H, m), 3.33 - 3.55 (4 H, m), 3.60 - 3.85 (2 H, m), 3.92 - 4.13 (2 H, m), 4.19 - 4.38 (2 H, m), 4.40 - 4.72 (2 H, m), 4.93 - 5.18 (1 H, m), 5.82 (1 H, br d, J=10.4 Hz), 6.39 (1 H, br d, J=16.5 Hz), 6.49 - 6.69 (1 H, m), 7.07 (1 H, t, J=7.69 Hz), 7.28 - 7.37 (1 H, m), 7.43 - 7.55 (1 H, m), 7.61 - 7.69 (1 H, m), 7.84 (1 H, br d, J=8.0 Hz), 8.23 (1 H, dd, J=6.9, 3.75 Hz). MS (ESI) m/z: 749.2 (M + H) + , Rt = 2.29 min. [0493] A17. Synthesis of Ex-12 Scheme 22. [0494] 22.1 Preparation of compound 39 To a solution of 2-[(2S)-4-[7-(8-iodo-1-naphthyl)-2-[[(2S)-pyrrolidin-2-yl]me thoxy]-6,8-dihydro-5H- pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]a cetonitrile (80 mg, 121 µmol, 1 eq) and tert- butyl 2,2-dimethyl-4-oxo-butanoate (22.5 mg, 121 µmol, 1 eq) in DCM (1 mL) was added NaBH(OAc) 3 (77 mg, 362 µmol, 3 eq) and TEA (37 mg, 362 µmol, 50 µL, 3 eq) at 0 °C. The mixture was stirred at 20 °C for 1 h, diluted with DCM (10 mL), washed with water (50 mL), brine (30 mL), dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue was purified by prep-TLC (SiO 2 , EtoAc: MeOH = 10:1) to give tert-butyl 4-[(2S)-2-[[4-[(3S)-3-(cyanomethyl)-4-prop-2-enoyl-piperazin -1-yl]-7- (8-iodo-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2- yl]oxymethyl]pyrrolidin-1-yl]-2,2- dimethyl-butanoate (60 mg, 72 µmol, 60% yield) as a white solid; MS (ESI) m/z: 833.3, R t = 0.83 min. [0495] 22.2 Preparation of compound Ex-12 To a solution of tert-butyl 4-[(2S)-2-[[4-[(3S)-3-(cyanomethyl)-4-prop-2-enoyl-piperazin -1-yl]-7-(8-iodo- 1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxyme thyl]pyrrolidin-1-yl]-2,2-dimethyl- butanoate (30 mg, 36 µmol, 1 eq) in DCM (2 mL) was added TFA (1 mL). The mixture was stirred at 20 °C for 2 h. The residue was purified directly by prep-HPLC to give 4-[(2S)-2-[[4-[(3S)-3-(cyanomethyl)- 4-prop-2-enoyl-piperazin-1-yl]-7-(8-iodo-1-naphthyl)-6,8-dih ydro-5H-pyrido[3,4-d]pyrimidin-2- yl]oxymethyl]pyrrolidin-1-yl]-2,2-dimethyl-butanoic acid (23 mg, 29.6 µmol, 41% yield) as a white solid; 1 H NMR (400 MHz, DMSO-d6) δ = 9.59 (1 H, br s), 8.22 (1 H, d, J = 7.3 Hz), 7.99 (1 H, d, J = 8.1 Hz), 7.77 (1 H, dd, J = 3.7, 8.0 Hz), 7.63 - 7.53 (1 H, m), 7.47 - 7.38 (1 H, m), 7.17 (1 H, t, J = 7.7 Hz), 6.95 - 6.75 (1 H, m), 6.19 (1 H, br d, J = 16.5 Hz), 5.84 - 5.75 (1 H, m), 5.01 - 4.70 (1 H, m), 4.59 - 4.50 (1 H, m), 4.40 (1 H, br dd, J = 7.2, 12.1 Hz), 4.14 - 3.90 (6 H, m), 3.44 - 3.26 (4H, m), 3.20 - 3.05 (5 H, m), 2.95 - 2.82 (1 H, m), 3.03 - 2.81 (1 H, m), 2.78 - 2.62 (1 H, m), 2.60 - 2.51 (1 H, m), 2.27 - 2.14 (1 H, m), 2.07 - 1.98 (1 H, m), 1.95 - 1.75 (4 H, m), 1.13 - 1.06 (6 H, m). MS (ESI) m/z: 777.2, Rt = 2.42 min. [0496] A18. Synthesis of compound Ex-13 Scheme 23. [0497] 23.1 Preparation of compound Ex-13 A mixture of 2-[(2S)-4-[7-(8-iodo-1-naphthyl)-2-[[(2S)-pyrrolidin-2-yl]me thoxy]-6,8-dihydro-5H- pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]a cetonitrile (30 mg, 45.2 µmol, 1 eq), 3- bromopropane-1,2-diol (70 mg, 452 µmol, 40 µL, 10 eq), KI (7.5 mg, 45.2 µmol, 1 eq) and K 2 CO 3 (19 mg, 136 µmol, 3 eq) in DMF (2 mL) was degassed and purged with N 2 for 3 times. The reaction mixture was stirred at 80 °C for 16 h under a N 2 atmosphere, concentrated under reduced pressure and the residue purified by prep-HPLC to give 2-[(2S)-4-[2-[[(2S)-1-(2,3-dihydroxypropyl)pyrrolidin-2-yl]m ethoxy]-7- (8-iodo-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4- yl]-1-prop-2-enoyl-piperazin-2- yl]acetonitrile (0.02 g, 27.1 µmol, 60% yield) as a white solid; 1 H NMR (400 MHz, DMSO-d6) δ ppm 1.74 - 1.96 (2 H, m), 1.99 - 2.10 (1 H, m), 2.15 - 2.28 (1H, m), 2.62 - 2.76 (1 H, m), 2.81 - 2.92 (1 H, m), 2.93 - 3.17 (4 H, m), 3.18 - 3.32 (5 H, m), 3.33 - 3.51 (5 H, m), 3.97 - 4.18 (5 H, m), 4.33 - 4.61 (3 H, m), 4.64 - 5.10 (2 H, m), 5.79 (1 H, br d, J=10.9 Hz), 6.19 (1 H, br d, J=16.7 Hz), 6.77 - 6.95 (1 H, m) 7.17 (1 H, t, J=7.7 Hz), 7.36 - 7.47 (1 H, m), 7.57 (1 H, q, J=8.3 Hz), 7.77 (1 H, dd, J=8.1, 3.8 Hz), 7.99 (1 H, d, J=8.1 Hz), 8.22 (1 H, d, J=7.2 Hz), 9.28 - 9.60 (1 H, m). MS (ESI) m/z: 737.2 (M + H) + , R t = 2.21 min. [0498] A19. Synthesis of Ex-14 Scheme 24. [0499] 24.1 Preparation of compound 42 A mixture of (2,2-dimethyl-1,3-dioxan-5-yl)methanol (0.30 g, 2.05 mmol, 1 eq), PPh 3 (645 mg, 2.46 mmol, 1.2 eq), CBr 4 (816 mg, 2.46 mmol, 1.20 eq) and imidazole (210 mg, 3.08 mmol, 1.50 eq) in DCM (3 mL), was stirred at 20 °C for 4 h under a N 2 atmosphere. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-TLC (SiO 2 , petroleum ether:EtOAc = 5:1) to give 5- (bromomethyl)-2,2-dimethyl-1,3-dioxane (0.30 g, 1.43 mmol, 70% yield) as a yellow oil; 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.43 (6H, d, J=12.2 Hz), 1.88 - 2.10 (1 H, m), 3.51 (2 H, d, J=7.0 Hz), 3.72 - 3.85 (2 H, m), 4.05 (2 H, dd, J=12.2, 4.1 Hz). [0500] 24.2 Preparation of compound 43 A mixture of 5-(bromomethyl)-2,2-dimethyl-1,3-dioxane (25 mg, 120 µmol, 5 eq), 2-[(2S)-4-[7-(8-iodo- 1-naphthyl)-2-[[(2S)-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H -pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2- enoyl-piperazin-2-yl]acetonitrile (16 mg, 24 µmol, 1 eq), K2CO3 (9.9 mg, 72 µmol, 3 eq) and KI (4 mg, 24 µmol, 1 eq) in CH3CN (2 mL) was stirred at 80 °C for 16 h under a N2 atmosphere. The reaction mixture was filtered and concentrated. The residue was purified by prep-TLC (SiO2, EtOAc:MeOH = 5:1) to give 2-[(2S)-4-[2-[[(2S)-1-[(2,2-dimethyl-1,3-dioxan-5-yl)methyl] pyrrolidin-2-yl]methoxy]-7-(8-iodo-1- naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop -2-enoyl-piperazin-2-yl]acetonitrile as a white solid. 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.38 (6 h, dd, J=9.23, 5.4 Hz), 1.69 - 1.83 (3 H, m), 1.91 - 2.01 (2 H, m), 2.18 - 2.26 (1 H, m), 2.28 - 2.35 (1 H, m), 2.51 - 2.66 (1 H, m,) 2.76 - 2.94 (4 H, m), 2.97 - 3.17 (3 H, m), 3.18 - 3.30 (2 H, m), 3.59 (1 H, ddd, J=11.52, 7.6, 4.0 Hz), 3.64 - 3.71 (2 H, m), 3.78 - 3.84 (1 H, m), 3.85 - 4.09 (7 H, m), 4.26 - 4.44 (2 H, m), 4.96 - 5.22 (1 H, m), 5.82 (1 H, br d, J=10.3 Hz), 6.34 - 6.47 (1 H, m), 6.54 - 6.69 (1 H, m), 7.08 (1 H, t, J=7.7 Hz), 7.34 (1 H, d, J=6.9 Hz), 7.44 - 7.55 (1 H, m), 7.64 (1 H, t, J=7.5 Hz), 7.79 - 7.89 (1 H, m), 8.23 (1 H, d, J=6.6 Hz). MS (ESI) m/z: 791.2 (M + H) + , Rt = 0.79 min. [0501] 24.3 Preparation of compoundEx-14 A mixture of 2-[(2S)-4-[2-[[(2S)-1-[(2,2-dimethyl-1,3-dioxan-5-yl)methyl] pyrrolidin-2-yl]methoxy]-7-(8- iodo-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl] -1-prop-2-enoyl-piperazin-2- yl]acetonitrile (50 mg, 63 µmol, 1 eq) and TsOH . H2O (1.20 mg, 6.32 µmol, 0.1 eq) in MeOH (1 mL) was stirred at 20 °C for 1 h under a N2 atmosphere. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by prep-TLC (SiO2, EtOAc: MeOH = 5:1) to give 2-[(2S)-4- [2-[[(2S)-1-[3-hydroxy-2-(hydroxymethyl)propyl]pyrrolidin-2- yl]methoxy]-7-(8-iodo-1-naphthyl)-6,8- dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piper azin-2-yl]acetonitrile (19 mg, 25.3 µmol, 67% yield) as a white solid: 1 H NMR (400 MHz, DMSO-d6) δ ppm 1.53 - 1.77 (4 H, m), 1.85 - 1.94 (1 H, m), 2.13 - 2.22 (1 H, m), 2.36 (1 H, dd, J=12.19, 4.44 Hz), 2.62 - 2.76 (2 H, m), 2.83 - 2.93 (1 H, m), 2.96 - 3.14 (3 H, m), 3.15 - 3.28 (3 H, m), 3.34 - 3.72 (7 H, m), 3.79 - 4.15 (5 H, m), 4.22 - 4.29 (1 H, m), 4.35 - 4.51 (1 H, m), 4.72 - 5.06 (1 H, m), 5.78 (1 H, dd, J=10.6, 1.8 Hz), 6.19 (1 H, br d, J=16.6 Hz), 6.75 - 6.96 (1 H, m), 7.17 (1 H, t, J=7.8 Hz), 7.38 - 7.49 (1 H, m), 7.57 (1 H, dt, J=10.1, 7.8 Hz), 7.76 (1 H, dd, J=7.6, 4.8 Hz), 7.99 (1 H, d, J=8.1 Hz), 8.22 (1 H, d, J=6.9 Hz). MS (ESI) m/z: 751.2 (M + H) + , R t = 2.31 min. [0502] It is understood that iodinated compounds used in the above examples can be used for testing and experimental purposes. One skilled in the art understands that the iodo moiety can be replaced with a radioisotope described herein, for example fluorine-18 ( 18 F), iodine-131 ( 131 I), iodine-123 ( 123 I), iodine- 124 ( 124 I), iodine-125 ( 125 I), or astatine-211 ( 211 At). [0503] Example A20. Synthesis of radiolabeled compounds based on Compounds Ex-1 to Ex-14 [0504] Radiolabeled Compound B-8 is synthesized from Compound Ex-1 by procedures depicted in Schemes 1-5. Compound B-8. [0505] Radiolabeled Compound B-3 is synthesized from Compound Ex-2 by procedures depicted in Schemes 1-5. Compound B-3. [0506] Radiolabeled Compound B-29 is synthesized from Compound Ex-3 by procedures depicted in Schemes 1-5. Compound B-29. [0507] Radiolabeled Compound B-23 is synthesized from Compound Ex-4 by procedures depicted in Schemes 1-5. Compound B-23. [0508] Radiolabeled Compound B-11 is synthesized from Compound Ex-5 by procedures depicted in Schemes 1-5. Compound B-11. [0509] Radiolabeled Compound B-26 is synthesized from Compound Ex-6 by procedures depicted in Schemes 1-5. Compound B-26. [0510] Radiolabeled Compound B-24 is synthesized from Compound Ex-7 by procedures depicted in Schemes 1-5. Compound B-24. [0511] Radiolabeled Compound B-25 is synthesized from Compound Ex-8 by procedures depicted in Schemes 1-5. Compound B-25. [0512] Radiolabeled Compound A-1 is synthesized from Compound Ex-9 by procedures depicted in Schemes 1-5. Compound A-1. [0513] Radiolabeled Compound A-4 is synthesized from Compound Ex-10 by procedures depicted in Schemes 1-5. [0514] Radiolabeled Compound A-6 is synthesized from Compound Ex-11 by procedures depicted in Schemes 1-5. [0515] Radiolabeled Compound A-12 is synthesized from Compound Ex-12 by procedures depicted in Schemes 1-5. Compound A-12. [0516] Radiolabeled Compound A-17 is synthesized from Compound Ex-13 by procedures depicted in Schemes 1-5. Compound A-17. [0517] Radiolabeled Compound A-14 is synthesized from Compound Ex-14 by procedures depicted in Schemes 1-5. [0518] Example A21. Synthesis of radiolabeled compounds of Table 4A, Table 4B, Table 4C, and Table 4D [0519] Radiolabeled compounds of Table 4A, Table 4B, Table 4C, and Table 4D are synthesized by installing the radioisotope on their respective precursor compounds. The precursor compounds are synthesized by methods known in the art, e.g., see Example A1 and Section XVI. Methods of Manufacturing labelled Compounds. The radioisotope is installed according to a method described in Scheme 1, Scheme 2, Scheme 3, Scheme 4, and/or Scheme 5. In some cases, the radioisotope is installed by methods known in the art, see e.g., Berdal et al., “Investigation on the reactivity of nucleophilic radiohalogens with arylboronic acids in water: access to an efficient single-step method for the radioiodination and astatination of antibodies” Chemical Science 2021, 12, 1458, and Dubost et al., “Recent Advances in Synthetic Methods for Radioiodination” J. Org. Chem, 2020, 85, 13, 8300-8310. [0520] Alternatively, radiolabeled compounds of Table 4A, Table 4B, Table 4C, and Table 4D are synthesized by installing the radioisotope on their respective precursor compounds, for example, according to schemes 25-32 below. [0521] A22. Radioiodination via aryl bromide. Scheme 25. where R 19 is as defined in formula (III). [0522] A23. Radioiodination via boronic acid or stannane intermediate. Scheme 26. where R 19 is as defined in formula (III).
[0523] A24. Radioiodination via linker boronic acid or stannane intermediate. Scheme 27. [0524] A25. Radioiodination via linker boronic acid Scheme 28. [0525] A26. Radioiodination via linker stannane intermediate Scheme 29.
[0526] A27. Radioiodination via linker bromine Scheme 30. [0527] A28. Radioiodination via linker diazotization procedure Scheme 31. For diazotization procedure for radioiodination see: Sloan, N. L.; Luthra, S. K.; McRobbie, G.; Pimlott, S. L.; Sutherland, A. A One-Pot Radioiodination of Aryl Amines via Stable Diazonium Salts: Preparation of 125I-Imaging Agents. Chem. Commun. 2017, 53 (80), 11008–11011 which is incorporated herein by reference. [0528] A29. Radioiodination via naphthyl bromine Scheme 32
[0529] A30. Preparation of compound CHL-001 and Lu-CHL-001 Scheme 33. [0530] 33.1 Preparation of compound CHL-001 To a mixture of 2-[(2S)-4-[2-[[(2S)-1-(6-aminohexyl)pyrrolidin-2-yl]methoxy] -7-(8-chloro-1-naphthyl)- 6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-p iperazin-2-yl]acetonitrile Int 4 (170 mg, 217 µmol, 1 eq, TFA) and 2-[4,7,10-tris(carboxymethyl)-1,4,7,10-tetrazacyclododec-1-y l]acetic acid (175 mg, 433 µmol, 2.0 eq) in DMF (8 mL) was added DIEA (168 mg, 1.30 mmol, 226 µL, 6.0 eq), HOBt (35.1 mg, 260 umol, 1.2 eq) and EDCI (91 mg, 476 umol, 2.2 eq) at 0 °C. The reaction mixture was stirred at 25°C for 12 h under a N2 atmosphere. The mixture was concentrated under reduced pressure and the residue purified by prep-HPLC to give 2-[4,7-bis(carboxymethyl)-10-[2-[6-[(2S)-2-[[7-(8-chloro-1- naphthyl)-4-[(3S)-3-(cyanomethyl)-4-prop-2-enoyl-piperazin-1 -yl]-6,8-dihydro-5H-pyrido[3,4- d]pyrimidin-2-yl]oxymethyl]pyrrolidin-1-yl]hexylamino]-2-oxo -ethyl]-1,4,7,10-tetrazacyclododec-1- yl]acetic acid CHL-001 (80 mg, 70 umol, 33% yield, 93% purity) as a white solid; 1 H NMR (400 MHz, MeOD-d 4 ): δ (ppm) 1.20 - 1.78 (8H, m), 1.84 - 2.37 (6H, m), 2.61 - 3.21 (18H, m), 3.36 - 3.98 (20H, m), 4.05 - 4.46 (4H, m), 4.67 (4H, d, J = 5.6 Hz), 5.84 (1H, d, J = 10.4 Hz), 6.29 (1H, d, J = 16.4 Hz), 6.70 - 7.00 (1H, m), 7.29 - 7.42 (2H, m), 7.47 - 7.58 (2H, m), 7.69 (1H, d, J = 8.4 Hz), 7.79 - 7.88 (1H, m).MS (ESI) m/z: 529.4 (M/2 + H) + , Rt = 2.76 min. [0531] 33.2 Preparation of compound Lu-CHL-001 To a mixture of 2-[4,7-bis(carboxymethyl)-10-[2-[6-[(2S)-2-[[7-(8-chloro-1-n aphthyl)-4-[(3S)-3- (cyanomethyl)-4-prop-2-enoylpiperazin-1-yl]-6,8-dihydro-5H-p yrido[3,4-d]pyrimidin-2- yl]oxymethyl]pyrrolidin-1-yl]hexylamino]-2-oxo-ethyl]-1,4,7, 10-tetrazacyclododec-1-yl]acetic acid CHL-001 (20 mg, 18.9 umol, 1.0 eq) in MeCN (1 mL) was added aqueous Na2CO3 solution (2 M, 9.5 uL, 1.0 eq). Trichlorolutetium (5.3 mg, 18.9 umol, 1.0 eq) was added to the mixture and stirred at 80°C for 1 h. The mixture was concentrated under reduced pressure and the residue purified by prep-HPLC to give N-[6-[(2S)-2-[[7-(8-chloro-1-naphthyl)-4-[(3S)-3-(cyanomethy l)-4-prop-2-enoyl-piperazin-1-yl]-6,8- dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxymethyl]pyrrolidin- 1-yl]hexyl]-2-(3,16,19-trioxo-2,17,18- trioxa-5,8,11,14-tetraza-1λ3-lutetatricyclo[9.6.3.25,14]doc osan-8-yl)acetamide Lu-CHL-001 (10.4 mg, 8.49 umol, 44.9% yield, 100% purity) as a yellow solid; 1 H NMR (400 MHz, MeOD-d 4 ) :δ (ppm) 1.33 - 1.75 (9H, m), 1.87 - 2.07 (3H, m), 2.22 - 2.58 (6H, m), 2.64 - 2.93 (10H, m), 3.01 - 3.25 (10H, m), 3.40 - 3.81 (12H, m), 4.07 - 4.36 (4H, m), 4.43 - 4.66 (4H, m), 4.97 - 5.16 (1H, m), 5.84 (1H, d, J = 9.6 Hz), 6.29 (1H, d, J = 16.4 Hz), 6.75 - 6.94 (1H, m), 7.30 - 7.42 (2H, m), 7.47 - 7.56 (2H, m), 7.69 (1H, dd, J = 8.0, 2.4 Hz), 7.84 (1H, d, J = 8.0 Hz), 8.53 (1H, s). MS (ESI) m/z: 615.3 (M/2 + H) + , R t = 2.73 min.
[0532] A31. Preparation of compound CHL-002 and Lu-CHL-002 Scheme 34. [0533] 34.1 Preparation of compound CHL-002 A solution of 2-[(2S)-4-[2-[[(2S)-1-(2-aminoethyl)pyrrolidin-2-yl]methoxy] -7-(8-chloro-1-naphthyl)-6,8- dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piper azin-2-yl]acetonitrile (0.15 g, 206 umol, 1 eq, TFA) in DMF (2 mL) was cooled to 0 o C. DIEA (80 mg, 617 umol, 107 uL, 3 eq), 2-[4,7,10- tris(carboxymethyl)-1,4,7,10-tetrazacyclododec-1-yl]acetic acid (100 mg, 247 umol, 1.2 eq), HOBt (42 mg, 309 umol, 1.5 eq) and EDCI (79 mg, 411 umol, 2 eq) were added and the reaction stirred at 25 °C for 1 h. The reaction was filtered and the filtrate purified by prep- HPLC to give 2-[4,7-bis(carboxymethyl)- 10-[2-[2-[(2S)-2-[[7-(8-chloro-1-naphthyl)-4-[(3S)-3-(cyanom ethyl)-4-prop-2-enoyl-piperazin-1-yl]-6,8- dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxymethyl]pyrrolidin- 1-yl]ethylamino]-2-oxo-ethyl]-1,4,7,10- tetrazacyclododec-1-yl]acetic acid (50 mg, 49 umol, 24% yield) as a yellow solid; 1 H NMR (400 MHz, METHANOL-d4) δ ppm 2.01 - 2.42 (4H, m), 2.45 - 3.32 (18H, m), 3.36 - 3.87 (19H, m), 3.88 - 4.00 (1H, m), 4.03 - 4.18 (3H, m), 4.19 - 4.45 (3H, m), 4.49 - 4.77 (2H, m), 4.97 - 5.22 (2H, m), 5.64 - 6.02 (1H, m), 6.22 - 6.49 (1H, m), 6.69 - 7.14 (1H, m), 7.31 - 7.46 (2H, m), 7.48 - 7.61 (2H, m), 7.68 - 7.75 (1H, m), 7.80 - 7.90 (1H, m), 8.42 (1H, s). MS (ESI) m/z: 515.7 (M/2 + H) + , Rt = 0.51 min. [0534] 34.2 Preparation of compound Lu-CHL-002 A solution of 2-[4,7-bis(carboxymethyl)-10-[2-[2-[(2S)-2-[[7-(8-chloro-1-n aphthyl)-4-[(3S)-3- (cyanomethyl)-4-prop-2-enoyl-piperazin-1-yl]-6,8-dihydro-5H- pyrido[3,4-d]pyrimidin-2- yl]oxymethyl]pyrrolidin-1-yl]ethylamino]-2-oxo-ethyl]-1,4,7, 10-tetrazacyclododec-1-yl]acetic acid (40 mg, 40 umol, 0.6 eq) in H2O (1 mL) and CH3CN (2 mL) was adjusted to pH=6 with Na2CO3 (10.6 mg, 99.8 umol, 1.5 eq). LuCl3 (18.7 mg, 66.6 umol, 1 eq) was added and the reaction stirred at 80 °C for 2 h. The filtrate was purified by prep-HPLC to give N-[2-[(2S)-2-[[7-(8-chloro-1-naphthyl)-4-[(3S)-3- (cyanomethyl)-4-prop-2-enoyl-piperazin-1-yl]-6,8-dihydro-5H- pyrido[3,4-d]pyrimidin-2- yl]oxymethyl]pyrrolidin-1-yl]ethyl]-2-(3,16,19-trioxo-2,17,1 8-trioxa-5,8,11,14-tetraza-1λ3- lutetatricyclo[9.6.3.25,14]docosan-8-yl)acetamide (9.0 mg, 7.5 umol, 11% yield) as a yellow solid; 1 H NMR (400 MHz, CD 3 OD) δ ppm 1.69 – 2.90 (21H, m), 3.12 - 3.35 (8H, m), 3.42 – 3.81 (16H, m), 4.05- 4.56 (6H, m), 5.01-5.20 (1H, m),5.79 - 6.06 (1H, m), 6.24 - 6.43 (1H, m), 6.67 - 7.08 (1H, m), 7.31 - 7.45 (2H, m), 7.47 - 7.61 (2H, m), 7.68 - 7.76 (1H, m), 7.80 - 7.90 (1H, m), 8.41 (2H, s). MS (ESI) m/z: 587.4 (M/2 + H) + , R t = 2.12 min.
[0535] A32. Synthesis of CHL-003 and Lu-CHL-003 Scheme 35. [0536] 35.1 Preparation of Compound CHL-003 To a solution of 2-[(2S)-4-[2-[[(2S)-1-(4-aminobutyl)pyrrolidin-2-yl]methoxy] -7-(8-chloro-1-naphthyl)- 6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-p iperazin-2-yl]acetonitrile (0.20 g, 264 umol) in DMF (4 mL) was added DIEA (171 mg, 1.32 mmol), 2-[4,7,10-tris(carboxymethyl)-1,4,7,10- tetrazacyclododec-1-yl]acetic acid (214 mg, 528 umol), HOBt (71 mg, 528 umol) and EDCI (101 mg, 528 umol). The mixture was stirred at 25 o C for 1 h. The reaction mixture was purified by prep-HPLC to give 2-[4,7-bis(carboxymethyl)-10-[2-[4-[(2S)-2-[[7-(8-chloro-1-n aphthyl)-4-[(3S)-3-(cyanomethyl)-4-prop-2- enoylpiperazin-1-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2 -yl]oxymethyl]pyrrolidin-1- yl]butylamino]-2-oxo-ethyl]-1,4,7,10-tetrazacyclododec-1-yl] acetic acid (60 mg, 22% yield) as a yellow gum; 1 H NMR (400 MHz, CD 3 OD): δ (ppm) 1.49 - 1.90 (4H, m), 1.94 - 2.34 (6H, m), 2.72 - 3.22 (18H, m), 3.41 - 3.87 (18H, m), 4.07 - 4.75 (9H, m), 5.02 - 5.23 (1H, m), 5.84 (1H, d, J = 10.8 Hz), 6.18 - 6.44 (1H, m), 6.72 - 7.01 (1H, m), 7.30 - 7.42 (2H, m), 7.45 - 7.58 (2H, m), 7.69 (1H, d, J = 8.0 Hz), 7.83 (1H, d, J = 8.0 Hz). MS (ESI) m/z: 515.7 (M/2 + H) + , Rt = 0.51 min. [0537] 35.2 Preparation of Lu-CHL-003 To a solution of 2-[4,7-bis(carboxymethyl)-10-[2-[4-[(2S)-2-[[7-(8-chloro-1-n aphthyl)-4-[(3S)-3- (cyanomethyl)-4-prop-2-enoylpiperazin-1-yl]-6,8-dihydro-5H-p yrido[3,4-d]pyrimidin-2- yl]oxymethyl]pyrrolidin-1-yl]butylamino]-2-oxo-ethyl]-1,4,7, 10-tetrazacyclododec-1-yl]acetic acid (35 mg, 34 umol) in CH3CN (1 mL) and H2O (1 mL) was added LuCl3 (10 mg, 35 umol). The mixture was stirred at 80 o C for 2 h. The residue was purified by prep-HPLC to give N-[4-[(2S)-2-[[7-(8-chloro-1- naphthyl)-4-[(3S)-3-(cyanomethyl)-4-prop-2-enoyl-piperazin-1 -yl]-6,8-dihydro-5Hpyrido[3,4- d]pyrimidin-2-yl]oxymethyl]pyrrolidin-1-yl]butyl]-2-(3,16,19 -trioxo-2,17,18-trioxa-5,8,11,14-tetrazaλ3- lutetatricyclo[9.6.3.25,14]docosan-8-yl)acetamide (2 mg, 5% yield) as a white solid. 1 H NMR (400 MHz, CD 3 OD): δ (ppm) 1.62 - 2.30 (10H, m), 2.48 - 3.15 (20H, m), 3.43 - 3.70 (10H, m), 3.77 - 4.22 (8H, m), 4.29 - 4.67 (6H, m), 5.81 - 5.94 (1H, m), 6.25 - 6.40 (1H, m), 6.75 - 6.95 (1H, m), 7.36 - 7.44 (2H, m), 7.48 - 7.60 (2H, m), 7.73 (1H, d, J=8.4 Hz), 7.87 (1H, d, J=8.4 Hz). MS (ESI) m/z: 1202.3 (M + H) + , Rt = 0.82 min.
[0538] A33. Synthesis of CHL-004 Scheme 36. [0539] 36.1 Preparation of compound 45 A mixture of (2S)-2-(benzylamino)propan-1-ol 44 (20 g, 121 mmol, 1.0 eq) and PPh3 (47.6 g, 182 mmol, 1.5 eq) in THF (200 mL) was added DEAD (31.6 g, 182 mmol, 33 mL, 1.5 eq) at 0 °C, the mixture purged with N23 times and stirred at 15°C for 16 h under a N2 atmosphere. The pH of the aqueous phase was adjusted to pH~5 by adding citric acid solution, extracted with EtOAc 300 mL (50 mL × 6), the pH of the aqueous phase adjusted to pH~8 and the solution extracted with EtOAc (50 mL × 6). The combined organics were dried over Na2SO4, filtered and concentrated under reduced pressure to give (2S)-1-benzyl- 2-methyl-aziridine (11.4 g, 77.4 mmol, 64% yield) as a yellow oil; 1 H NMR (400 MHz, CHLOROFORM- d) δ ppm 1.22 (3H, d, J=5.50 Hz), 1.40 (1 H, d, J=6.25 Hz), 1.49 - 1.56 (1 H, m), 1.59 (1 H, d, J=3.6 Hz), 3.28 - 3.56 (2 H, m), 7.25 - 7.29 (1 H, m), 7.30 - 7.40 (4 H, m). MS (ESI) m/z: 148.1 (M + H) + , R t = 1.41 min. [0540] 36.2 Preparation of compound 46 A mixture of (2S)-1-benzyl-2-methyl-aziridine 45 (11.0 g, 74.7 mmol, 1 eq) and BF3.Et2O (215 mg, 1.52 mmol, 187 µL, 0.02 eq) in toluene (48 mL) was degassed and purged with N23 times. The mixture was stirred at 110 °C for 5 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with DCM (50 mL) and washed with water (100 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC to give (2S,5S,8S,11S)-1,4,7,10-tetrabenzyl-2,5,8,11-tetramethyl-1,4 ,7,10-tetrazacyclododecane (3.92 g, 6.66 mmol, 8.9% yield) as a white solid; 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.99 (12 H, d, J=6.6 Hz), 2.27 (4 H, dd, J=14.3, 2.5 Hz), 3.08 (4 H, dd, J=14.1, 11.3Hz), 3.30 (4 H, td, J=6.9, 3.2 Hz), 3.45 - 3.71 (8 H, m), 7.10 (8 H, dd, J=6.2, 2.7 Hz), 7.26 - 7.34 (12 H, m). MS (ESI) m/z: 589.5 (M + H) + , Rt = 0.69 min. [0541] 36.3 Preparation of compound 47 A mixture of (2S,5S,8S,11S)-1,4,7,10-tetrabenzyl-2,5,8,11-tetramethyl-1,4 ,7,10-tetrazacyclododecane 46 (1.0 g, 1.70 mmol, 1 eq), ammonium formate (1.07 g, 17.0 mmol, 10 eq) and Pd(OH)2/C (1.67 g, 2.38 mmol, 20% purity, 1.40 eq) in trifluoroethanol (3 mL) was stirred at 70 °C for 20 h. The reaction mixture was filtered and concentrated under reduced pressure to give crude (2S,5S,8S,11S)-2,5,8,11-tetramethyl- 1,4,7,10-tetrazacyclododecane (1.0 g) as a white solid; 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.23 (12 H, br d, J=3.22 Hz), 2.91 (12 H, br s), 8.43 - 8.81 (4 H, m). MS (ESI) m/z: 229.2 (M + H) + , R t = 0.24 min. [0542] 36.4 Preparation of compound 48 A mixture of (2S,5S,8S,11S)-2,5,8,11-tetramethyl-1,4,7,10-tetrazacyclodod ecane (1.0 g, 4.38 mmol, 1 eq) , tert-butyl 2-bromoacetate 47 (4.27 g, 21.9 mmol, 3.24 mL, 5 eq) and K 2 CO 3 (6.05 g, 43.8 mmol, 10 eq) in CH 3 CN (2 mL) was degassed and purged with N 2 3 times. The reaction was stirred at 50 °C for 16 h under a N 2 atmosphere. The reaction was cooled to room temperature, filtered and concentrated under reduced pressure. The residue was dissolved into 2% HCl (60 mL) and extracted with EtOAc (30 × 2 mL). The pH of the aqueous phase was adjusted to pH~8, then extracted with DCM (30 × 2 mL). The combined organic phases were dried over Na 2 SO 4 , filtered, the filtrate concentrated under reduced pressure and the residue purified by prep-HPLC to give tert-butyl 2-[(2S,5S,8S,11S)-4,7,10-tris(2-tert-butoxy-2-oxo-ethyl)- 2,5,8,11-tetramethyl-1,4,7,10-tetrazacyclododec-1-yl]acetate (0.40 g, 584 µmol, 13% yield) as a white solid; 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.83 - 1.26 (12 H, m), 1.36 - 1.59 (36 H, m), 2.02 - 4.21 (20 H, m). MS (ESI) m/z: 684.5 (M + H) + , R t = 0.90 min. [0543] 36.5 Preparation of compound 49 A mixture of tert-butyl 2-[(2S,5S,8S,11S)-4,7,10-tris(2-tert-butoxy-2-oxo-ethyl)-2,5 ,8,11-tetramethyl- 1,4,7,10-tetrazacyclododec-1-yl]acetate 48 (0.30 g, 438 µmol, 1 eq) in HCl (6 M, 2.00 mL) was degassed and purged with N23 times, and stirred at 90 °C for 2 h under a N2 atmosphere. The reaction mixture was concentrated under reduced pressure and the residue purified by prep-HPLC to give 2-[(2S,5S,8S,11S)- 4,7,10-tris(carboxymethyl)-2,5,8,11-tetramethyl-1,4,7,10-tet razacyclododec-1-yl]acetic acid (0.10 g, 217 µmol, 50% yield) as a white solid; 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.92 - 1.41 (11 H, m), 2.75 - 4.17 (21 H, m). MS (ESI) m/z: 460.2 (M + H) + , Rt = 0.25 min. [0544] 36.6 Preparation of compound CHL-004 To a solution of 2-[(2S,5S,8S,11S)-4,7,10-tris(carboxymethyl)-2,5,8,11-tetram ethyl-1,4,7,10- tetrazacyclododec-1-yl]acetic acid 49 (70 mg, 152 µmol, 2 eq) in DMF (2 mL) and 2-[(2S)-4-[2-[[(2S)-1- (4-aminobutyl)pyrrolidin-2-yl]methoxy]-7-(8-chloro-1-naphthy l)-6,8-dihydro-5H-pyrido[3,4- d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile (49 mg, 76.0 µmol, 1 eq) was added DIEA (196 mg, 1.52 mmol, 265 µL, 20 eq) , HOBt (25 mg, 182 µmol, 2.4 eq) and EDCI (64 mg, 334 µmol, 4.4 eq) at 0 °C. The mixture was stirred at 40 °C for 16 h. The reaction mixture was concentrated under reduced pressure and the residue purified by prep-HPLC to yield 2-[(2S,5S,8S,11S)-7,10-bis(carboxymethyl)-4-[2- [4-[(2S)-2-[[7-(8-chloro-1-naphthyl)-4-[(3S)-3-(cyanomethyl) -4-prop-2-enoyl-piperazin-1-yl]-6,8- dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxymethyl]pyrrolidin- 1-yl]butylamino]-2-oxo-ethyl]-2,5,8,11- tetramethyl-1,4,7,10-tetrazacyclododec-1-yl]acetic acid (40 mg, 36.8 µmol, 48% yield) as a white solid; 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.99 - 1.39 (14 H, m), 1.55 - 1.71 (2 H, m), 1.80 - 2.22 (6 H, m), 2.31 - 2.34 (1 H, m), 2.33 - 2.42 (1 H, m), 2.64 - 3.28 (17 H, m), 3.46 - 3.52 (2 H, m) 3.57 - 3.68 (4 H, m) 3.72 - 3.83 (5 H, m) 3.86 - 4.05 (5 H, m) 4.15 - 4.45 (4 H, m) 4.55 - 4.80 (4 H, m), 5.86 (1 H, br d, J=10.8 Hz), 6.31 (1 H, br d, J=17.1 Hz), 6.73 - 6.91 (1 H, m), 7.33 – 7.43 (2 H, m), 7.49 - 7.58 (2 H, m), 7.73 (1 H, dd, J=8.3, 2.1 Hz), 7.86 (1 H, d, J=8.3 Hz). MS (ESI) m/z: 1084.5 (M + H) + , R t = 2.06 min.
[0545] A34. Synthesis of CHL-005 and Lu-CHL-005 Scheme 37. [0546] 37.1 Preparation of compound 51 To a solution of benzaldehyde (20 g, 188 mmol, 19.1 mL, 1 eq) and (2S)-2-aminobutan-1-ol (16.8 g, 188 mmol, 17.9 mL, 1 eq) in EtOH (200 mL) was added NaBH4 (21.4 g, 565 mmol, 3 eq) at 0°C, and the mixture stirred at 20 °C for 3 h under a N 2 atmosphere. The reaction mixture was quenched with H 2 O (800 mL) and extracted with DCM (200 mL × 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, concentrated under reduced pressure and purified by column chromatography (SiO2, petroleum ether:EtOAc=20:1 to 5:1) to give (2S)-2-(benzylamino)butan-1-ol (29.6 g, 165 mmol, 88% yield) as a white solid; 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.87 (3 H, t, J=7.46 Hz), 1.33 - 1.59 (2 H, m), 2.54 - 2.64 (1 H, m), 3.28 (1 H, dd, J=10.64, 6.36 Hz), 3.60 (1 H, dd, J=10.64, 3.91 Hz), 3.68 - 3.82 (2 H, m), 7.17 - 7.32 (5 H, m). MS (ESI) m/z: 180.1 (M + H) + , Rt = 0.99 min. [0547] 37.2 Preparation of compound 52 To a solution of (2S)-2-(benzylamino)butan-1-ol 51 (15 g, 83.7 mmol, 1.0 eq) and PPh3 (32.9 g, 126 mmol, 1.5 eq) in THF (150 mL) was added DEAD (21.9 g, 126 mmol, 22.8 mL, 1.5 eq) at 0 °C. The reaction was purged with N23 times, and the mixture stirred at 20 °C for 16 h under a N2 atmosphere. The pH of the aqueous phase was adjusted to pH~5 by adding citric acid solution, extracted with EtOAc (50 mL × 6), the pH of the aqueous phase was adjusted to pH~8 and extracted with EtOAc (50 mL × 6). The combined organic phases were dried over Na2SO4, filtered and concentrated under reduced pressure to give (2S)-1- benzyl-2-ethyl-aziridine (11.6 g, 71.6 mmol, 86% yield) as a yellow oil; 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.85 - 0.95 (3 H, m), 1.36 - 1.50 (4 H, m), 1.63 (1 H, d, J=2.9 Hz), 3.33 (1 H, d, J=13.4 Hz), 3.52 (1 H, d, J=13.3 Hz), 7.16 - 7.58 (5 H, m). MS (ESI) m/z: 162.1 (M + H) + , R t = 1.65 min. [0548] 37.3 Preparation of compound 53 A mixture of (2S)-1-benzyl-2-ethyl-aziridine 52 (11.0 g, 68.2 mmol, 1 eq) and BF 3 .Et 2 O (215 mg, 1.52 mmol, 187 µL) in PhMe (24 mL) was degassed and purged with N 2 3 times. The mixture was stirred at 110 °C for 5 h. The reaction mixture was concentrated under reduced pressure, diluted with DCM (50 mL) and washed with water (100 mL). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC to give (2S,5S,8S,11S)- 1,4,7,10-tetrabenzyl-2,5,8,11-tetraethyl-1,4,7,10-tetrazacyc lododecane (6.73 g, 10.4 mmol, 15% yield) as a white solid; 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.98 (12 H, t, J=7.3 Hz), 1.17 - 1.34 (4 H, m), 1.62 - 1.82 (4 H, m), 1.96 - 2.14 (4 H, m), 2.91 - 3.17 (12 H, m), 3.68 (4 H, d, J=13.9 Hz), 7.13 - 7.26 (10 H, m), 7.27 - 7.35 (10 H, m). MS (ESI) m/z: 645.4 (M + H) + , R t = 0.97 min. [0549] 37.4 Preparation of compound 54 A mixture of (2S,5S,8S,11S)-1,4,7,10-tetrabenzyl-2,5,8,11-tetraethyl-1,4, 7,10-tetrazacyclododecane 53 (1.0 g, 1.55 mmol, 1 eq), Pd(OH) 2 /C (571 mg, 0.41 mmol, 3.88 mL, 20% purity) and ammonium formate (500 mg, 7.93 mmol, 5.11 eq) in trifluoroethanol (8 mL) was degassed and purged with N2 for 3 times. The mixture was stirred at 70 °C for 20 h. The reaction mixture was filtered and concentrated under reduced pressure to give crude (2S,5S,8S,11S)-2,5,8,11-tetraethyl-1,4,7,10-tetrazacyclodode cane (0.98 g) as a white solid; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.93 (12 H, t, J=7.5 Hz), 1.40 (4 H, dquin, J=14.2, 7.2 Hz), 1.53 - 1.65 (4 H, m), 2.53 - 2.71 (8 H, m), 2.76 - 2.85 (4 H, m), 4.32 - 4.91 (4 H, m) . MS (ESI) m/z: 284.2 (M + H) + , R t = 0.58 min. [0550] 37.5 Preparation of compound 55 A mixture of (2S,5S,8S,11S)-2,5,8,11-tetraethyl-1,4,7,10-tetrazacyclodode cane 54 (0.45 g, 1.58 mmol, 1 eq), tert-butyl 2-bromoacetate (1.54 g, 7.91 mmol, 1.17 mL, 5 eq) and K 2 CO 3 (2.19 g, 15.8 mmol, 10 eq) in CH 3 CN (45 mL) was degassed and purged with N 2 3 times. The mixture was stirred at 50 °C for 16 h. The reaction was cooled to room temperature, filtered and concentrated under reduced pressure. The residue was dissolved in 2% HCl (60 ml) and extracted with EtOAc (30 × 2 mL). The pH of the aqueous phase was adjusted to pH~8 and extracted with DCM (30 mL × 2). The combined organic phases were dried over Na 2 SO 4 , filtered and the filtrate concentrated under reduced pressure. The residue was purified by prep-HPLC to give tert-butyl 2-[(2S,5S,8S,11S)-4,7,10-tris(2-tert-butoxy-2-oxo-ethyl)-2,5 ,8,11- tetraethyl-1,4,7,10-tetrazacyclododec-1-yl]acetate (0.35 g, 472 µmol, 30% yield) as a white solid; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.48 (48 H, br s), 1.75 - 2.29 (8 H, m), 2.68 - 3.06 (5 H, m), 3.09 - 3.47 (5 H, m), 3.65 - 4.06 (6 H, m), 4.38 - 4.65 (3 H, m) 4.76 - 5.04 (1 H, m). MS (ESI) m/z: 741.5 (M + H) + , R t = 3.17 min. [0551] 37.6 Preparation of compound 56 To a solution of HCl (6 M, 1.0 ml) was added tert-butyl 2-[(2S,5S,8S,11S)-4,7,10-tris(2-tert-butoxy-2-oxo- ethyl)-2,5,8,11-tetraethyl-1,4,7,10-tetrazacyclododec-1-yl]a cetate 55 (0.30 g, 405 µmol, 1 eq) and the mixture stirred at 90 °C for 1 h under a N 2 atmosphere. The reaction mixture was concentrated under reduced pressure and the residue purified by prep-HPLC to give 2-[(2S,5S,8S,11S)-4,7,10- tris(carboxymethyl)-2,5,8,11-tetraethyl-1,4,7,10-tetrazacycl ododec-1-yl]acetic acid (173 mg, 335 µmol, 83% yield) as a white solid; 1 H NMR (400 MHz, D2O) δ ppm 0.75 - 1.12 (12 H, m), 1.19 - 1.52 (4 H, m), 1.94 (4 H, br dd, J=12.7, 7.0 Hz), 2.72 - 2.96 (3 H, m), 3.17 (5 H, br d, J=17.4 Hz), 3.34 - 3.69 (5 H, m), 3.73 - 3.91 (4 H, m), 4.08 (3 H, br d, J=16.6 Hz). MS (ESI) m/z: 859.2 (M + H) + Rt = 0.85 min. [0552] 37.7 Preparation of compound CHL-005 To a solution of 2-[(2S,5S,8S,11S)-4,7,10-tris(carboxymethyl)-2,5,8,11-tetrae thyl-1,4,7,10- tetrazacyclododec-1-yl]acetic acid 56 (50 mg, 97 µmol, 2 eq) and 2-[(2S)-4-[2-[[(2S)-1-(4- aminobutyl)pyrrolidin-2-yl]methoxy]-7-(8-chloro-1-naphthyl)- 6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4- yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile (31 mg, 48.4 µmol, 1 eq) in DMF (1 mL) was added DIEA (125 mg, 968 µmol, 169 µL, 20 eq), EDCI (41 mg, 213 µmol, 4.4 eq) and HOBt (16 mg, 116 µmol, 2.4 eq) at 0 °C. The reaction mixture was stirred at 40 °C for 16 h and concentrated under reduced pressure. The residue was purified by prep-HPLC to give 2-[(2S,5S,8S,11S)-7,10-bis(carboxymethyl)-4-[2-[4-[(2S)- 2-[[7-(8-chloro-1-naphthyl)-4-[(3S)-3-(cyanomethyl)-4-prop-2 -enoyl-piperazin-1-yl]-6,8-dihydro-5H- pyrido[3,4-d]pyrimidin-2-yl]oxymethyl]pyrrolidin-1-yl]butyla mino]-2-oxo-ethyl]-2,5,8,11-tetraethyl- 1,4,7,10-tetrazacyclododec-1-yl]acetic acid (19 mg, 16.7 µmol, 34% yield) as a yellow solid; 1 H NMR (400 MHz, methanol-d4) δ ppm 0.94 - 1.16 (12 H, m), 1.20 - 1.51 (5 H, m), 1.53 - 1.67 (2 H, m), 1.73 - 2.28 (10 H, m), 2.32 - 2.43 (1 H, m), 2.69 - 3.00 (6 H, m), 3.03 - 3.25 (10 H, m), 3.36 - 3.85 (13 H, m), 3.85 - 3.85 (1 H, m), 3.89 - 4.17 (6 H, m), 4.20 - 4.42 (3 H, m), 4.47 - 4.83 (4 H, m), 5.85 (1 H, br d, J=10.1 Hz), 6.31 (1 H, br d, J=16.5 Hz), 6.68 - 7.01 (1 H, m), 7.33 - 7.45 (2 H, m), 7.48 - 7.60 (2 H, m), 7.72 (1 H, br d, J=8.1 Hz), 7.86 (1 H, d, J=8.1 Hz). MS (ESI) m/z: 1140.6 (M + H) + , Rt = 2.16 min. [0553] 37.8 Preparation of compound Lu-CHL-005 To a solution of 2-[(2S,5S,8S,11S)-7,10-bis(carboxymethyl)-4-[2-[4-[(2S)-2-[[ 7-(8-chloro-1-naphthyl)-4- [(3S)-3-(cyanomethyl)-4-prop-2-enoyl-piperazin-1-yl]-6,8-dih ydro-5H-pyrido[3,4-d]pyrimidin-2- yl]oxymethyl]pyrrolidin-1-yl]butylamino]-2-oxo-ethyl]-2,5,8, 11-tetraethyl-1,4,7,10-tetrazacyclododec-1- yl]acetic acid (50 mg, 43.8 µmol, 1 eq) in NaOAc (1 mL) was added Lu(NO3)3 (90.2 mg, 438 µmol, 10 eq). The mixture was stirred at 80 °C for 1 h. The mixture was concentrated under reduced pressure and the residue purified by prep-HPLC to give N-[4-[(2S)-2-[[7-(8-chloro-1-naphthyl)-4-[(3S)-3- (cyanomethyl)-4-prop-2-enoyl-piperazin-1-yl]-6,8-dihydro-5H- pyrido[3,4-d]pyrimidin- 2yl]oxymethyl]pyrrolidin-1-yl]butyl]-2-[(6S,9S,12S,21S)-6,9, 12,21-tetraethyl-3,16,19-trioxo-2,17,18- trioxa-5,8,11,14-tetraza-1λ3-lutetatricyclo[9.6.3.25,14]doc osan-8-yl]acetamide (15 mg, 11.5 µmol, 26% yield) as a white solid; 1 H NMR (400 MHz, METHANOL-d4) δ 0.87-1.07 (13 H, m), 1.16-1.48 (5 H, m), 1.66-2.24 (12 H, m), 2.54 (6 H, br d, J=13.9 Hz), 2.80 (5 H, br d, J=9.3 Hz), 2.93-3.18 (8 H, m), 3.42-3.66 (10 H, m), 3.68-3.97 (6 H, m), 3.99-4.21 (2 H, m), 4.29-4.55 (3 H, m), 4.59-4.76 (2 H, m), 4.94-5.17 (1 H, m), 5.85 (1 H, br d, J=10.0 Hz), 6.30 (1 H, br d, J=16.9 Hz), 6.76-6.94 (1 H, m), 7.33-7.43 (2 H, m), 7.48- 7.60 (2 H, m), 7.72 (1 H, d, J=8.2 Hz), 7.85 (1 H, d, J=8.2 Hz). MS (ESI) m/z: 1312.5, R t = 2.19 min.
[0554] A35. Synthesis of CHL-006 and Lu-CHL-006 Scheme 38. [0555] 38 Preparation of compound CHL-006 and Lu-CHL-006 CHL-006 and Lu-CHL-006 are synthesized by following a similar procedure as depicted above in Scheme 37 for CHL-005 and Lu-CHL-005. [0556] Example A36: Synthesis of 177-Lutetium chelated radiopharmaceutical conjugates [0557] Conjugates of Table 5A and 5C are synthesized according to the same methods described in Example A30-A35. [0558] General procedure for 177 Lu-labeling [ 177 Lu]LuCl3 in HCl (50 MBq) is added to a mixture of a conjugate of Table 5A or 5C (1 nmol) in NaOAc buffer (5% EtOH, 0.25 M, pH 5.0-5.5, total volume 100- 120 µL) in a 1.8 mL Eppendorf tube. The resulting mixture is heated at 80-85 °C in a thermal mixer at a shaking speed of 600 rpm for 15-30 min. If necessary, the mixture is purified using a C8 column. Radiochemical purity is determined by radio-RP-HPLC and iTLC. [0559] Accordingly, conjugates of 5B and 5D are synthesized according to Example A36. [0560] Example A37: Synthesis of 225-Actinium chelated conjugates [0561] Conjugates of Table 5A and 5C are synthesized according to the same methods described in Example A30-A35 [0562] General procedure for 225 Ac-labeling [ 225 Ac]Ac(NO3)3 in 1 mM HCl (50 kBq) is added to a mixture of a conjugate of Table 5A or 5C (1 nmol) in NaOAc buffer (100 µL, 0.4 M, pH 5.5-6.5) in a 1.8 mL Eppendorf tube. The resulting mixture is heated at 80-100 °C in a thermal mixer at a shaking speed of 500 rpm for 15-30 min. Radiochemical purity is determined by iTLC. [0563] Accordingly, conjugates of 5B and 5D are synthesized according to Example A37. [0564] Example A38. Exemplary Procedure for Synthesizing Covalently Modified KRAS protein [0565] A compound selected from Table 4A, Table 4B, Table 4C, Table 4D, Table 5A, Table 5B, Table 5C, and Table 5D is administered to a subject having mutated KRAS protein, including G12C according to SEQ ID NO 1 or SEQ ID NO: 2. The compound covalently binds with a KRAS protein in vivo at residue G12C, thereby generating a modified KRAS protein. [0566] A modified KRAS protein is illustrated in FIG.16A and FIG.16B, as an example. The compound in FIG.16A or FIG.16B can be any radiolabeled compound described herein that contains an electrophilic functional group (e.g., FIG. 16A or FIG. 16B also illustrates that the electrophilic functional group reacts with a cysteine residue of the KRAS protein. B: Biological Assays [0567] Example B1: KRAS G12C Nucleotide Exchange Assay [0568] A KRAS (G12C) Nucleotide Exchange Assay kit was used to evaluate compound antagonistic binding. The assay kit (BPS Bioscience. Catalog# 79859) utilizes KRAS (G12C) labeled with BODIPY- GDP to determine if compounds can affect the nucleotide exchange (GDP to GTP) in KRAS signaling. Compounds were typically characterized using both protocols: fixed GTP concentrations and fixed inhibitor concentrations. [0569] Fixed GTP Concentration Characterization [0570] All reagents were prepared following manufacturer’s protocol.5 µL BODIPY-GDP and 10 µL of KRAS buffer were added to each well. A 3-fold serial dilution of compound in 5% DMSO was prepared. Typically, compounds were tested in the range of 0 µM to 50 µM, but the range could be modified depending on the characterization needs. 5 µL of diluted compound was added to the wells and the plate was centrifuged briefly to ensure all components were mixed before incubation at ambient temperature. After incubation for 2 hours, 10 µM GTP and 25 mM EDTA were mixed at a 1:1 ratio and 5 µL was added to the wells. The plate was then incubated for 1 hour at ambient temperature. After incubation, fluorescence was measured at Ex470nm/Em525nm. [0571] Data was analyzed by plotting fluorescence vs GTP concentration for control wells and compound wells. IC50 values for compounds of the present disclosure are provided in Table 7 below. [0572] Table 7 A is <1uM ; B is ≥ 1uM and <10uM; C is ≥ 10uM. [0573] Fixed Inhibitor Concentration Characterization [0574] All reagents are prepared following manufacturer’s protocol.5 µL of compound is added to each test well. Typically, 10 µM of compound is used, but the concentration could be modified depending on characterization needs. For both test wells and control wells, 10 µL of KRAS buffer and 5 µL BODIFY- GDP are added. 5 µL of compound buffer (e.g.5% DMSO) is added to control wells. The plate is briefly centrifuged to ensure all reagents are mixed before incubation at ambient temperature. GTP reagent is serially diluted 0 mM to 1 mM in water. After 2 hours, 2.5 µL of the prepared GTP is add to all wells along with 2.5 µL EDTA at 25 mM. The plate is briefly centrifuged to mix all reagents and incubated at ambient temperature for 1 hour. After incubation, fluorescence is measured at Ex470nm/Em525nm. [0575] Data is analyzed by plotting fluorescence vs compound concentration. EC50 is calculated as the compound concentration that elicited 50% fluorescence. Example B2: Phosphorylated ERK1/ERK2 ELISA [0576] An ERK phosphorylation ELISA kit was used to characterize compounds for KRAS-based cell activity. The sandwich ELISA (RnD Systems. Catalog # DYC1018B) measures human ERK1 that is dually phosphorylated at T202/Y204 and ERK2. Cell lysates from cells before and after treatment with compounds were prepared using kit manufacturer protocols. [0577] All reagents were prepared following the kit’s protocol. The wells of a 96-well microtiter plate were coated with 100 µL of 8.0 µg/mL of capture antibody in PBS. The plate was sealed and left to incubate overnight at ambient temperature. After incubation, the wells were washed with 400 µL of Wash Buffer for a total of 3 washes. Wells were then blocked by adding 300 µL of Block Buffer to each well and incubated at ambient temperature for 1-2 hours. After removal of the Block Buffer by aspirating and washing, 100 µL of standards and samples were added to the plate in duplicates and incubated for 2 hours at ambient temperature. The aspiration and wash steps were repeated to remove unbound standard and samples and 100 µL of 400 ng/mL detection antibody was applied to each well. After 2 hours at ambient temperature, detection antibody was removed by washing and 100 µL of Streptavidin-HRP was added to each well. Incubation of Streptavidin-HRP was at ambient temperature for 20 minutes, after which Streptavidin-HRP was removed by washing. 100 µL of Substrate Solution was added to each well and incubated for 20 minutes before 50 µL of Stop Solution was added to each well. [0578] The optical density of each well was immediately analyzed at 450 nm with a wavelength correction at 540 nm. The standards were plotted by averaging the optical density for each replicate and fitted with a four-parameter logistic curve fit. Concentrations of phosphorylated ERK in cell lysate samples were determined by extrapolation from the standard curve and then adjusted for any dilution factors. IC 50 values for compounds of the present disclosure are provided in Table 8 below. [0579] Table 8 A is <100nM; B is ≥100nM and <1,000nM; C is ≥1,000nM and <10,000nM; and D is ≥10,000nM. Example B3: Inhibition of KRas G12C-dependent Cell Growth [0580] The cellular inhibition of KRas G12C by specific compounds are measured by the inhibition of growth of cells dependent on the KRas G12C mutation. [0581] MiaPaca-2 (ATCC, CRL-1420), NCI-H358 (ATCC CRL-5807), A549 (ATCC CCL-185), and NCI-H1975 (CRL-5908) cell lines are cultured according to ATCC cell culture recommendations. Cells are plated in sterile 96-well plates at a concentration of 60,000 cells/well and allowed to attach for 12-18 hours. Diluted compounds are added to the cells with a final concentration of 0.5% DMSO, in 200uL volume of media. The compounds and remaining media are left to culture for 72 hours. At the end of the 72 hour incubation time, the plates are removed from the incubator and left to equilibrate to room temperature for use in the Cell Titer Glo 2.0 Cell Viability Assay (Promega Catalog #G9241). All reagents are thawed and allowed to equilibrate to room temperature before use in the assay. Reagent preparation followed the manufacturer’s protocol. After reagent dilution, 25uL of the CTG reagent is added to each well of the 96 well plate and set to shake for 20 minutes at room temperature. The plate is read on a SpectraMax iD5 using the Softmax Pro 7 Software from Molecular Devices. The Cell Titer Glo Luminescence protocol is used, reading the plate at a wavelength of 595nM. [0582] Resulting OD values are normalized by subtracting the background values of wells that did not contain cells, and then normalized to 100% by using the DMSO-only treated well. Subsequent cell growth inhibition is calculated for the compound dilution curve and graphed in Graphpad Prism. [0583] Disclosure of the present application is further illustrated in the following list of embodiments, which are given for illustration purposes only and are not intended to limit the disclosure in any way: [0584] Embodiment 1: A conjugate comprising: a) a targeting ligand that covalently binds to an intracellular KRAS protein, wherein the intracellular KRAS protein is mutated; b) a linker; and c) a metal chelator. [0585] Embodiment 2: The conjugate of embodiment 1, further comprising a radionuclide, wherein the radionuclide is bound to the metal chelator. [0586] Embodiment 3: The conjugate of embodiment 1 or 2, wherein the targeting ligand covalently binds to the mutated KRAS protein at residue G12C, and wherein residue position numbering of the KRAS protein is based on SEQ ID NO:1 as a reference sequence. [0587] Embodiment 4: The conjugate of embodiment 3, wherein the targeting ligand irreversibly binds to the mutated KRAS protein at residue G12C. [0588] Embodiment 5: The conjugate of any one of embodiments 1 to 4, wherein the targeting ligand comprises an electrophilic functional group. [0589] Embodiment 6: The conjugate of embodiment 5, wherein the electrophilic functional group forms a covalent bond with a cysteine residue of the mutated protein. [0590] Embodiment 7: The conjugate of embodiment 5 or 6, wherein the electrophilic functional group comprises a functional group selected from an ester, acrylamide, halo-acrylamide, enamide, chloroacetamide, acyl azide, acyl nitrile, aldehyde, ketone, alkyl halide, alkyl sulfonate, anhydride, aryl halides, boronic acid, boronate, carboxylic acid, hydrazide, carbodiimide, diazoalkane, epoxide, haloacetamide, halotriazine, imido ester, isocyanate, isothiocyanate, maleimide, phosphoramidite, silyl halide, sulfonate ester, sulfonyl halide, α,β-unsaturated ester, vinyl sulfone, and propargyl amide, each of which is optionally substituted. [0591] Embodiment 8: The conjugate of any one of embodiments 5 to 7, wherein the electrophilic functional group comprises optionally substituted acrylamide, optionally substituted chloroacetamide, or a derivative thereof. [0592] Embodiment 9: The conjugate of embodiment 8, wherein the electrophilic functional group comprises an acrylamide group, a 2-fluoroacrylamide group, or a 2-methyl acrylamide group. [0593] Embodiment 10: The conjugate of embodiment 7, wherein the electrophilic functional group comprises a substituted enamide group selected from acrylamide, 2-fluoroacrylamide, methacrylamide, 2-methoxyacrylamide, (E)-4-fluorobut-2-enamide, (E)-4-methoxybut-2- enamide, (E)-4-(pyrrolidin-1-yl)but-2-enamide, and (E)-4-(piperidin-1-yl)but-2-enamide. [0594] Embodiment 11: The conjugate of any one of embodiments 5 to 8, wherein the electrophilic functional group comprises a structure of Formula (Ia) or Formula (Ib): , wherein, ring Q is a 3 to 10 membered heterocycloalkylene, wherein Q is optionally substituted; R 1 is H, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 heteroalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, or substituted or unsubstituted C 2 -C 5 heterocycloalkyl; and E represents a structure of Formula (Ic), wherein, X is C(=O), P(=O)OR 2 , C(=S), or S(=O)n, where n is 1 or 2; R 2 is H or substituted or unsubstituted C 1 -C 3 alkyl; R 5 and R 7 are each independently selected from H, -CN, halogen, substituted or unsubstituted C1- C6 alkyl, substituted or unsubstituted C 1 -C 6 heteroalkyl, substituted or unsubstituted C3-C7 cycloalkyl, or substituted or unsubstituted C2-C7 heterocycloalkyl; or R 5 and R 7 taken together form a bond; R 6 is H, halogen, -CN, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, heteroaryl, aryl, alkylaminylalkyl, dialkylaminylalkyl, cycloalkyl or heterocycloalkyl, each of which is optionally substituted. [0595] Embodiment 12: The conjugate of any one of embodiments 5 to 8, wherein the electrophilic functional group comprises a structure of Formula (Id), wherein, X is C(=O), OC(=O), NR 2 C(=O), P(=O)OR 2 , C(=S), S(=O)n, OS(O)n, NR 2 S(=O)n, wherein n is 1 or 2; Y is an alkylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, heteroarylene, or a bond, wherein each of the alkylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene is optionally substituted; each R 2 is independently H or substituted or unsubstituted C 1 -C 3 alkyl; R 5 and R 7 are each independently selected from H, cyano, halogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 heteroalkyl, substituted or unsubstituted C3-C7 cycloalkyl, or substituted or unsubstituted C 2 -C 6 heterocycloalkyl; or R 5 and R 7 taken together form a bond; and R 6 is H, halogen, -CN, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, heteroaryl, aryl, alkylaminylalkyl, dialkylaminylalkyl, cycloalkyl or heterocycloalkyl, each of which is optionally substituted. [0596] Embodiment 13: The conjugate of embodiment 11 or 12, wherein X is C(=O). [0597] Embodiment 14: The conjugate of embodiment 12 wherein X is NR 2 C(=O). [0598] Embodiment 15: The conjugate of any one of embodiments 11 to 14, wherein R 5 is H, halogen, methyl, or -OMe. [0599] Embodiment 16: The conjugate of any one of embodiments 11 to 15, wherein R 5 is H. [0600] Embodiment 17: The conjugate of any one of embodiments 11 to 16, wherein R 6 is H. [0601] Embodiment 18: The conjugate of any one of embodiments 11 to 17, wherein R 7 is H or substituted or unsubstituted C 1 -C 4 alkyl. [0602] Embodiment 19: The conjugate of any one of embodiments 11 to 18, wherein R 7 is H. [0603] Embodiment 20: The conjugate of any one of embodiments 11 to 18, wherein R 7 is -CH 2 F, - CH 2 OMe, or -CH 2- C 2 -C 5 heterocycloalkyl. [0604] Embodiment 21: The conjugate of embodiment 11, wherein E represents a structure of Formula (Ic) that is . [0605] Embodiment 22: The conjugate of embodiment 11, wherein the structure of Formula (Ib) is . [0606] Embodiment 23: The conjugate of any one of embodiments 1 to 4, wherein the targeting ligand comprises a structure of Formula (III), or a salt, solvate, or derivative thereof, Formula (III) wherein Q 1 is a 4-12 membered saturated or partially saturated monocyclic or bicyclic ring, wherein the monocyclic or bicyclic ring is optionally substituted; L 1 is a bond, -C(O)-, or optionally substituted C 1 -C 3 alkylene; L 2 is a bond, O, S or NR 15 ; X is C(=O), P(=O)OR 2 , C(=S), or S(=O) n , where n is 1 or 2; R 2 is H or substituted or unsubstituted C 1 -C 3 alkyl; R 5 is hydrogen, cyano, halogen, alkyl, alkoxyl, heteroalkyl, C 3 -C 6 cycloalkyl, or C 2 -C 5 heterocycloalkyl, each of which is optionally substituted; and R 7 is hydrogen, cyano, halogen, alkyl, alkoxyl, heteroalkyl, C 3 -C 7 cycloalkyl, C 2 -C 7 heterocycloalkyl, heteroaryl, heteorarylalkyl, alkylaminylalkyl, or dialkylaminylalkyl, each of which is optionally substituted; or R 5 and R 7 taken together form a bond; or R 5 and R 7 taken together with the carbon atoms to which they are attached form a 5-8 membered partially saturated cycloalkyl, wherein the cycloalkyl is optionally substituted; R 6 is hydrogen, cyano, halogen, alkyl, alkoxyl, heteroalkyl, cycloalkyl, heterocycloalkyl, heteroaryl, heteorarylalkyl, alkylaminylalkyl, or dialkylaminylalkyl, each of which is optionally substituted; R 12 is hydrogen, alkyl, heteroalkyl, -L 3 -alkylaminyl, -L 3 -dialkylaminyl, -L 3 -NR 15 R 15’ , heterocycloalkyl, -L 3 -heterocycloalkyl, cycloalkyl, -L 3 -cycloalkyl, aryl, heteroaryl, -L 3 -aryl, or -L 3 -heteroaryl, wherein each of the L 3 , heterocycloalkyl, cycloalkyl, aryl, heteroaryl, alkyl or heteroalkyl is optionally substituted; L 3 is C 1 -C 4 alkylene or C 1 -C 4 heteroalkylene, each of which is optionally substituted; each R 13 is independently OH, halogen, substituted or unsubstituted C 1 -C 6 alkyl, oxo, or substituted or unsubstituted C 1 -C 6 heteroalkyl; R 14 is hydrogen, cycloalkyl, heterocycloalkyl, aryl, aralkyl, or heteroaryl, wherein each of the cycloalkyl, heterocycloalkyl, aryl, aralkyl, and heteroaryl is optionally substituted; each R 15 is independently hydrogen or C 1 -C 3 alkyl; each R 15’ is independently hydrogen, acyl, C 1 -C 3 alkyl, heteroalkyl or hydroxyalkyl; and m is 0, 1, or 2; and wherein the structure of Formula (III) is attached to the rest of the conjugate at any suitable position. [0607] Embodiment 24: The conjugate of embodiment 23, wherein the targeting ligand is attached to the linker via the R 12 group. [0608] Embodiment 25: The conjugate of embodiment 23 or 24, wherein R 5 is hydrogen, cyano, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxyl, C 1 -C 6 heteroalkyl, C 3 -C 6 cycloalkyl, or C 2 -C 5 heterocycloalkyl, each of which is optionally substituted. [0609] Embodiment 26: The conjugate of any one of embodiments 23 to 25, wherein R 5 is hydrogen or a C 1 -C 3 alkyl optionally substituted by one or more hydroxyl and/or halogen. [0610] Embodiment 27: The conjugate of any one of embodiments 23 to 25, wherein R 5 is a halogen. [0611] Embodiment 28: The conjugate of any one of embodiments 23 to 25, wherein R 5 is a hydrogen. [0612] Embodiment 29: The conjugate of any one of embodiments 23 to 25, wherein R 5 is C 1 -C 6 heteroalkyl. [0613] Embodiment 30: The conjugate of embodiment 29, wherein R 5 is -C(O)NR 15 R 15’ . [0614] Embodiment 31: The conjugate of any one of embodiments 23 to 30, wherein R 7 is hydrogen, cyano, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxyl, C 1 -C 6 heteroalkyl, each of which is optionally substituted. [0615] Embodiment 32: The conjugate of any one of embodiments 23 to 31, wherein R 7 is H. [0616] Embodiment 33: The conjugate of any one of embodiments 23 to 31, wherein R 7 is C 1 -C 6 heteroalkyl selected from -NHC(O)-C 1 -C 3 alkyl and -CH2NHC(O)-C 1 -C 3 alkyl. [0617] Embodiment 34: The conjugate of embodiment 23, wherein R 5 and R 7 taken together with the carbon atoms to which they are attached form a 5-8 membered partially saturated cycloalkyl, wherein the cycloalkyl is optionally substituted with one or more R 17 , wherein each R 17 is independently halogen, hydroxyl, C 1 -C 6 alkyl, cycloalkyl, alkoxy, haloalkyl, amino, cyano, heteroalkyl, hydroxyalkyl, -O-haloalkyl, or -S-haloalkyl. [0618] Embodiment 35: The conjugate of any one of embodiments 23 to 34, wherein R 6 is hydrogen, cyano, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxyl, C 1 -C 6 heteroalkyl, C 3 -C 6 cycloalkyl, or C 2 -C 6 heterocycloalkyl, each of which is optionally substituted. [0619] Embodiment 36: The conjugate of any one of embodiments 23 to 35, wherein R 6 is hydrogen. [0620] Embodiment 37: The conjugate of any one of embodiments 23 to 35, wherein R 6 is C 1 -C 6 heteroalkyl selected from -NHC(O)-C 1 -C 3 alkyl and -CH2NHC(O)-C 1 -C 3 alkyl. [0621] Embodiment 38: The conjugate of any one of embodiments 23 to 37, wherein Q 1 is optionally substituted with one or more R 18 , wherein R 18 is oxo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, cyano, - C(O)OR 15 , -C(O)N(R 15 )(R 15’ ), -N(R 15 )(R 15’ ), wherein the alkyl, alkenyl, alkynyl, or heteroalkyl is optionally substituted. [0622] Embodiment 39: The conjugate of any one of embodiments 23 to 38, wherein Q 1 is a 6 membered monocyclic ring, where in the monocyclic ring is optionally substituted with one or more R 18 , wherein R 18 is methyl, -CH 2 CN, carbonyl, hydroxyl, carboxyl, C(O)OR 15 . [0623] Embodiment 40: The conjugate of any one of embodiments 23 to 39, wherein R 14 is hydrogen, cycloalkyl, heterocycloalkyl, aryl, aralkyl, or heteroaryl, wherein each of the cycloalkyl, heterocycloalkyl, aryl, aralkyl, and heteroaryl is optionally substituted with one or more R 16 wherein each R 16 is independently halogen, hydroxyl, C 1 -C 6 alkyl, cycloalkyl, alkoxy, acetyl, carboxyl, - C(O)OR 15 , haloalkyl, amino, cyano, heteroalkyl, hydroxyalkyl, -O-haloalkyl, or -S-haloalkyl. [0624] Embodiment 41: The conjugate of any one of embodiments 23 to 40, wherein R 14 is aryl or heteroaryl, optionally substituted with one or more R 16 , wherein each R 16 is independently halogen, hydroxyl, C 1 -C 3 alkyl, alkoxy, haloalkyl, amino, or cyano. [0625] Embodiment 42: The conjugate of any one of embodiments 23 to 40, wherein R 14 is napthyl optionally substituted with one or more R 16 , wherein each R 16 is independently D, halogen, -CN, -NH 2 , -NH(alkyl), -N(alkyl) 2 , -OH, oxo, -CO 2 H, -CO 2 alkyl, -C(=O)NH 2 , -C(=O)NH(alkyl), - C(=O)N(alkyl) 2 , -S(=O) 2 NH 2 , -S(=O) 2 NH(alkyl), -S(=O) 2 N(alkyl) 2 , alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, or arylsulfone, wherein each of the alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, or arylsulfone is optionally substituted. [0626] Embodiment 43: The conjugate of embodiment 42, wherein each R 16 is independently oxo, halogen, -CN, -NH 2 , -NH(CH 3 ), -N(CH 3 ) 2 , -OH, -CO 2 H, -CO 2 (C 1 -C 4 alkyl), -OCO(C 1 -C 4 alkyl), - C(=O)NH2, -C(=O)NH(C1-C4 alkyl), -C(=O)N(C1-C4 alkyl)2, -S(=O)2NH2, -S(=O)2NH(C1-C4 alkyl), -S(=O)2N(C1-C4 alkyl)2, C1-C4 alkyl, C 3 -C 6 cycloalkyl, C1-C4 fluoroalkyl, C 1 -C 6 heteroalkyl, C1-C4 alkoxy, C1-C4 fluoroalkoxy, -SC1-C4 alkyl, -S(=O)C1-C4 alkyl, or -S(=O)2(C1- C4 alkyl). [0627] Embodiment 44: The conjugate of any one of embodiments 23 to 43, wherein R 12 is hydrogen, alkyl, heteroalkyl, -L 3 -alkylaminyl, -L 3 -dialkylaminyl, -L 3 -NR 15 R 15’ , heterocycloalkyl, -L 3 - heterocycloalkyl, cycloalkyl, -L 3 -cycloalkyl, aryl, heteroaryl, -L 3 -aryl, or -L 3 -heteroaryl, wherein each of the L 3 , heterocycloalkyl, cycloalkyl, aryl, heteroaryl, alkyl or heteroalkyl is optionally substituted with one or more R 19 , wherein each R 19 is independently hydrogen, oxo, acyl, hydroxyl, hydroxyalkyl, cyano, halogen, alkyl, aralkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkoxy, dialkylaminyl, dialkylamidoalkyl, or dialkylaminylalkyl, wherein the alkyl, aralkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl is optionally substituted. [0628] Embodiment 45: The conjugate of any one of embodiments 23 to 44, wherein R 12 is alkyl, heteroalkyl, -L 3 -alkylaminyl, -L 3 -dialkylaminyl, -L 3 -NR 15 R 15’ , heterocycloalkyl, -L 3 - heterocycloalkyl, cycloalkyl, or -L 3 -cycloalkyl, wherein each of the L 3 , heterocycloalkyl, cycloalkyl, alkyl, or heteroalkyl is optionally substituted with one or more R 19 . [0629] Embodiment 46: The conjugate of any one of embodiments 23 to 45, wherein L 3 is C 1 -C 4 alkylene or C 1 -C 4 heteroalkylene, each of which is optionally substituted with one or more R 19 . [0630] Embodiment 47: The conjugate of any one of embodiments 44 to 46, wherein R 19 is independently hydrogen, oxo, acyl, hydroxyl, hydroxyalkyl, cyano, halogen, or C 1 -C 3 alkyl. [0631] Embodiment 48: The conjugate of any one of embodiments 23 to 47, wherein X is C(=O). [0632] Embodiment 49: The conjugate of any one of embodiments 23 to 48, wherein L 1 is a bond. [0633] Embodiment 50: The conjugate of any one of embodiments 23 to 49, wherein L 2 is a bond, O, S or NR 15 . [0634] Embodiment 51: The conjugate of any one of embodiments 23 to 50, wherein each R 13 is independently OH, halogen, or C 1 -C 3 alkyl. [0635] Embodiment 52: The conjugate of any one of embodiments 23 to 51, wherein m is 0 or 1. [0636] Embodiment 53: The conjugate of any one of embodiments 1 to 4 or 23, wherein the targeting ligand comprises a structure of , wherein the structure is attached to the rest of the conjugate at any suitable position. [0637] Embodiment 54: The conjugate of any one of embodiments 1 to 4, wherein the targeting ligand comprises a structure of Formula (IV), or a salt, solvate, or derivative thereof, Formula (IV) wherein E 1 and E 2 are each independently N or CR 21 ; J is N, NR 30 , or CR 30 ; M is N, NR 33 , or CR 33 ; is a single or double bond as necessary to give every atom its normal valence; R 21 is independently H, hydroxyl, cyano, halogen, alkyl, alkoxyl, or heteroalkyl, each of which is optionally substituted; R 22 is hydrogen, halogen, alkyl, alkenyl, alkynyl, OR′, N(R′)2, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, each of which is optionally substituted, and each R′ is independently H, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, or heteroaryl, each of which is optionally substituted, or two R′ substituents, together with the nitrogen atom to which they are attached, form a 3-7-membered ring; R 23 is hydrogen, halogen, alkyl, alkoxy, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, or heteroaryl, each of which is optionally substituted; ring A is a substituted or unsubstituted 4-7 membered monocyclic ring or a substituted or unsubstituted 6-11 membered bicyclic, bridged, fused, or spiro ring; R 1 is H, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 heteroalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, or substituted or unsubstituted C 2 -C 5 heterocycloalkyl; L is a bond, alkylene, heteroalkylene, S, O, or NH; E represents a structure of Formula (Ic), wherein, X is C(=O), P(=O)OR 2 , C(=S), or S(=O)n, where n is 1 or 2; R 2 is H or substituted or unsubstituted C 1 -C 3 alkyl; R 5 is hydrogen, cyano, halogen, alkyl, alkoxyl, heteroalkyl, C 3 -C 6 cycloalkyl, or C 2 -C 5 heterocycloalkyl, each of which is optionally substituted, and R 7 is hydrogen, cyano, halogen, alkyl, alkoxyl, heteroalkyl, C3-C7 cycloalkyl, C2-C7 heterocycloalkyl, heteroaryl, heteorarylalkyl, alkylaminylalkyl, or dialkylaminylalkyl, each of which is optionally substituted; or R 5 and R 7 taken together form a bond; or R 5 and R 7 taken together with the carbon atoms to which they are attached form a 5-8 membered partially saturated cycloalkyl, wherein the cycloalkyl is optionally substituted; R 6 is hydrogen, cyano, halogen, alkyl, alkoxyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, heteorarylalkyl, alkylaminylalkyl, or dialkylaminylalkyl, each of which is optionally substituted; E 3 is CR 28 R 29 , C=CR 28 R 29 , C═O, C=S, or C=NR 28 ; R 28 and R 29 are each independently H, alkyl, hydroxy, alkoxy, cyano, nitro, or cycloalkyl, or R 28 and R 29 taken together with the carbon atom to which they are attached, can form a 3-6 membered ring; R 30 is selected from halogen, cyano, alkyl, cycloalkyl, aryl, heteroalkyl, heterocycloalkyl, heteroaryl, alkylaryl, alkylcycloalkyl, alkylheterocycloalkyl, alkylheteroaryl, alkoxy, heteroalkylaryl, heteroalkylheteroaryl, heteroalkylcycloalkyl, heteroalkylheterocycloaklyl, each of which is optionally substituted; and R 33 is alkyl, heteroalkyl, or cycloalkyl, each of which is optionally substituted; wherein the structure of Formula (IV) is attached to the rest of the conjugate at any suitable position. [0638] Embodiment 55: The conjugate of embodiment 54, wherein the targeting ligand is attached to the linker via group R 22 . [0639] Embodiment 56: The conjugate of embodiment 54 or 55, wherein E 1 is N or CR 21 ; E 2 is CR 21 ; J is NR 30 ; and M is N. [0640] Embodiment 57: The conjugate of any one of embodiments 54 to 56, wherein R 21 is independently H, hydroxyl, cyano, halogen, C 1 -C 6 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxyl, or C 1 - C4heteroalkyl. [0641] Embodiment 58: The conjugate of any one of embodiments 54 to 57, wherein R 21 is independently H, hydroxyl, cyano, halogen, or methyl. [0642] Embodiment 59: The conjugate of any one of embodiments 54 to 58, wherein R 21 is H. [0643] Embodiment 60: The conjugate of any one of embodiments 54 to 59, wherein R 22 is halogen, C 1 -C 6 alkyl, C 2 -C 3 alkenyl, C 2 -C 3 alkynyl, OR′, N(R′)2, C 3 -C 6 cycloalkyl, C 2 -C 5 heterocycloalkyl, C 6 -C 14 aryl, C2-C14heteroaryl, each of which is optionally substituted, and each R′ is independently H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 5 heterocycloalkyl, C 2 -C 3 alkenyl, C2- C3alkynyl, C 6 -C 14 aryl, C2-C14heteroaryl, each of which is optionally substituted, or two R′ substituents, together with the nitrogen atom to which they are attached, form a 3-7-membered ring. [0644] Embodiment 61: The conjugate of any one of embodiments 54 to 60, wherein R 22 is C 6 -C 14 aryl or C2-C14heteroaryl, each of which is optionally substituted. [0645] Embodiment 62: The conjugate of any one of embodiments 54 to 61, wherein R 22 is phenyl, optionally substituted with one or more C 1 -C 3 alkyl, halogen, and/or hydroxyl. [0646] Embodiment 63: The conjugate of any one of embodiments 54 to 62, wherein R 23 is H, halogen, C 1 -C 6 alkyl, C 1 -C 3 alkoxy, C 3 -C 6 cycloalkyl, C 2 -C 5 heterocycloalkyl, C 2 -C 3 alkenyl, C 2 -C 3 alkynyl, C 6 -C 14 aryl, or C2-C14heteroaryl, each of which is optionally substituted. [0647] Embodiment 64: The conjugate of any one of embodiments 54 to 63, wherein R 23 is halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl. [0648] Embodiment 65: The conjugate of any one of embodiments 54 to 64, wherein R 23 is halogen. [0649] Embodiment 66: The conjugate of any one of embodiments 54 to 65, wherein R 24 is . [0650] Embodiment 67: The conjugate of any one of embodiments 54 to 66, wherein ring A is a substituted or unsubstituted 4-7 membered monocyclic ring. [0651] Embodiment 68: The conjugate of any one of embodiments 54 to 67, wherein ring A is substituted or unsubstituted 6 membered heterocyclic ring. [0652] Embodiment 69: The conjugate of any one of embodiments 54 to 68, wherein ring A is piperazinyl substituted with halogen or C 1 -C 3 alkyl. [0653] Embodiment 70: The conjugate of any one of embodiments 54 to 69, wherein L is a bond, C 1 - C 3 alkylene, S, O, or NH. [0654] Embodiment 71: The conjugate of any one of embodiments 54 to 70, wherein L is a bond, CH2, O, or NH. [0655] Embodiment 72: The conjugate of any one of embodiments 54 to 71, wherein L is a bond. [0656] Embodiment 73: The conjugate of any one of embodiments 54 to 72, wherein X is C(=O). [0657] Embodiment 74: The conjugate of any one of embodiments 54 to 73, wherein R 5 is hydrogen, cyano, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxyl, C 1 -C 6 heteroalkyl, C 3 -C 6 cycloalkyl, or C 2 -C 5 heterocycloalkyl, each of which is optionally substituted. [0658] Embodiment 75: The conjugate of embodiment of any one of embodiments 54 to 74, wherein R 5 is hydrogen or a C 1 -C 3 alkyl optionally substituted by one or more hydroxyl and/or halogen. [0659] Embodiment 76: The conjugate of any one of embodiments 54 to 74, wherein R 5 is a halogen. [0660] Embodiment 77: The conjugate of any one of embodiments 54 to 74, wherein R 5 is C 1 -C 6 heteroalkyl. [0661] Embodiment 78: The conjugate of any one of embodiments 54 to 75, wherein R 5 is hydrogen. [0662] Embodiment 79: The conjugate of any one of embodiments 54 to 78, wherein R 7 is hydrogen, cyano, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxyl, C 1 -C 6 heteroalkyl, each of which is optionally substituted. [0663] Embodiment 80: The conjugate of any one of embodiments 54 to 79, wherein R 7 is hydrogen. [0664] Embodiment 81: The conjugate of any one of embodiments 54 to 79, wherein R 7 is C 1 -C 6 heteroalkyl selected from -NHC(O)-C 1 -C 3 alkyl and -CH2NHC(O)-C 1 -C 3 alkyl. [0665] Embodiment 82: The conjugate of embodiment 54, wherein R 5 and R 7 taken together with the carbon atoms to which they are attached form a 5-8 membered partially saturated cycloalkyl, wherein the cycloalkyl is optionally substituted with one or more R 17 , wherein each R 17 is independently halogen, hydroxyl, C 1 -C 6 alkyl, cycloalkyl, alkoxy, haloalkyl, amino, cyano, heteroalkyl, hydroxyalkyl, -O-haloalkyl, or -S-haloalkyl. [0666] Embodiment 83: The conjugate of any one of embodiments 54 to 82, wherein R 6 is hydrogen, cyano, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxyl, C 1 -C 6 heteroalkyl, C 3 -C 6 cycloalkyl, or C 2 -C 6 heterocycloalkyl, each of which is optionally substitute. [0667] Embodiment 84: The conjugate of any one of embodiments 54 to 83, wherein R 6 is hydrogen. [0668] Embodiment 85: The conjugate of any one of embodiments 54 to 83, wherein R 6 is C 1 -C 6 heteroalkyl selected from -NHC(O)-C 1 -C 3 alkyl and -CH 2 NHC(O)-C 1 -C 3 alkyl. [0669] Embodiment 86: The conjugate of any one of embodiments 54 to 85, wherein E 3 is C=O, C=S, or C=NH. [0670] Embodiment 87: The conjugate of any one of embodiments 54 to 86, wherein E 3 is C=O. [0671] Embodiment 88: The conjugate of any one of embodiments 54 to 87, wherein R 30 is halogen, cyano, C 1 -C 8 alkyl, C 3 -C 14 cycloalkyl, C 6 -C 14 aryl, C 1 -C 8 heteroalkyl, C 2 -C 14 heterocycloalkyl, C 2 - C 14 heteroaryl, C 1 -C 3 alkyl-C 6 -C 14 aryl, C 1 -C 3 alkyl-C 3 -C 14 cycloalkyl, C 1 -C 3 alkyl 2 - C 14 heterocycloalkyl, C 1 -C 3 alkyl-C 2 -C 14 heteroaryl, C 1 -C 8 alkoxy, C 0 -C 3 heteroalkyl-C 6 -C 1 aryl, C 0 - C 3 heteroalkyl-C 2 -C 14 heteroaryl, C 0 -C 3 heteroalkyl-C 3 -C 14 cycloalkyl, C 0 -C 3 heteroalkyl-C 2 - C 14 heterocycloaklyl, each of which is optionally substituted. [0672] Embodiment 89: The conjugate of any one of embodiments 54 to 88, wherein R 30 is C 6 -C 14 aryl, optionally substituted with one or more of halogen, C 1 -C 3 alkyl, C 1 -C 3 alkoxyl, or cyano. [0673] Embodiment 90: The conjugate of any one of embodiments 54 to 88, wherein R 30 is C 2 - C 14 heteroaryl, optionally substituted with one or more of halogen, C 1 -C 3 alkyl, C 1 -C 3 alkoxyl, or cyano. [0674] Embodiment 91: The conjugate of any one of embodiments 54 to 88, wherein R 30 is a 6- membered heteroaryl, optionally substituted with one or more of C 1 -C 3 alkyl. [0675] Embodiment 92: The conjugate of any one of embodiments 54 to 91, wherein R 33 is C 1- C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkylamine, or C3-C14 cycloalkyl. [0676] Embodiment 93: The conjugate of any one of embodiments 54 to 92, wherein R 33 is C 1 -C 6 alkyl. [0677] Embodiment 94: The conjugate of any one of embodiments 1 to 4 or 54, wherein the targeting ligand wherein the structure is attached to the rest of the conjugate at any suitable position. [0678] Embodiment 95: The conjugate of any one of embodiments 1 to 94, wherein the metal chelator is selected from AAZTA, BAT, BAT-TM, Crown, Cyclen, DO2A, CB-DO2A, DO3A, H3HP- DO3A, Oxo-DO3A, p-NH2-Bn-Oxo-DO3A, DOTA, DOTA-3py, DOTA-PA, DOTA-GA, DOTA-4AMP, DOTA-2py, DOTA-1py, p-SCN-Bn-DOTA, CHX-A″-EDTA, MeO-DOTA-NCS EDTA, DOTAMAP, DOTAGA, DOTAGA-anhydride, DOTMA, DOTASA, DOTAM, DOTP, CB-Cyclam, TE2A, CB-TE2A, CB-TE2P, DM-TE2A, MM-TE2A, NOTA, NOTP, HEHA, HEHA-NCS, p-SCN-Bn-HEHA, DTPA, CHX-A″-DTPA, p-NH2-Bn-CHX-A″-DTPA, p-SCN- DTPA, p-SCN-Bz-Mx-DTPA, 1B4M-DTPA-DTPA, p-SCN-Bn1B-DTPA, p-SCN-Bn-1B4M- DTPA, p-SCN-Bn-CHX-A″-DTPA, PEPA, p-SCN-Bn-PEPA, TETPA, DOTPA, DOTMP, DOTPM, t-Bu-calix[4]arene-tetracarboxylic acid, macropa, macropa-NCS, macropid, H 3 L 1 , H3L 4 , H2azapa, H5decapa, bispa 2 , H4pypa, H4octapa, H4CHXoctapa, p-SCN-Bn-H4octapa, p- SCN-Bn-H 4 octapa, TTHA, p-NO 2 -Bn-neunpa, H 4 octox, H 2 macropa, H 2 bispa 2 , H 4 phospa, H 6 phospa, p-SCN-Bn-H 6 phospa, TETA, p-NO 2 -Bn-TETA, TRAP, TRAP-Pr, TPA, HBED, SHBED, HBED-CC, (HBED-CC)TFP, DMSA, DMPS, DHLA, lipoic acid, TGA, BAL, Bis- thioseminarabazones, p-SCN-NOTA, nNOTA, NODAGA, CB-TE1A1P, 3P-C-NETA-NCS, 3p- C-DEPA, 3P-C-DEPA-NCS, TCMC, PCTA, NODIA-Me, TACN, pycup1A1B, pycup2A, THP, DEDPA, H 2 DEDPA, p-SCN-Bn-H 2 DEDPA, p-SCN-Bn-TCMC, motexafin, NTA, NOC, 3p-C- NETA, p-NH 2 -Bn-TE3A, SarAr, DiAmSar, SarAr-NCS, AmBaSar, BaBaSar, TACN-TM, CP256, C-NE3TA, C-NE3TA-NCS, NODASA, NETA-monoamide, C-NETA, TACN-HSB, NOPO, BPCA, p-SCN-Bn-DRO, DRO-ChX-Mal, DFO, DFO-IAC, DFO-BAC, DiP-LICAM, EC, SBAD, BAPEN, TACHPYR, NEC-SP, L py , L1, L2, L3, and EuK-106. [0679] Embodiment 96: The conjugate of any one of embodiments 1 to 95, wherein the metal chelator is 2,2',2'',2'''-((2S,5S,8S,11S)-2,5,8,11-tetramethyl-1,4,7,10- tetraazacyclododecane-1,4,7,10- tetrayl)tetraacetic acid. [0680] Embodiment 97: The conjugate of any one of embodiments 1 to 95, wherein the metal chelator is 2,2',2'',2'''-((2S,5S,8S,11S)-2,5,8,11-tetraethyl-1,4,7,10-t etraazacyclododecane-1,4,7,10- tetrayl)tetraacetic acid. [0681] Embodiment 98: The conjugate of any one of embodiments 1 to 94, wherein the metal chelator is a chelator in FIG.1 to FIG.15. [0682] Embodiment 99: The conjugate of any one of embodiments 1 to 94, wherein the metal chelator is DOTA. [0683] Embodiment 100: The conjugate of any one of embodiments 2 to 99, wherein the radionuclide is astatine-211, astatine-217, actinium-225, americium-243, radium-223, lead-212, lead-203, copper-64, copper-67, copper-60, copper-61, copper-62, bismuth-212, bismuth-213, gallium-68, gallium-67, dysprosium-154, gadolinium-148, gadolinium-153, samarium-146, samarium-147, samarium-153, terbium-149, thorium-227, thorium-229, iron-59, yttrium-86, indium-111, holmium-166, technetium-94, technetium-99 m , yttrium-90, lutetium-177, terbium-161, rhenium- 186, rhenium-188, cobalt-55, scandium-43, scandium-44, scandium-47, dysprosium-166, fluorine-18, or iodine-131. [0684] Embodiment 101: The conjugate of embodiment 100, wherein the radionuclide is lutetium-177, actinium-225, yttrium-90, bismuth-213, gallium-68, copper-64 or indium-111. [0685] Embodiment 102: The conjugate of any one of embodiments 2 to 99, wherein the radionuclide is an alpha particle-emitting radionuclide. [0686] Embodiment 103: The conjugate of embodiment 102, wherein the alpha particle-emitting radionuclide is actinium-225, astatine-211, thorium-227, or radium-223. [0687] Embodiment 104: The conjugate of embodiment 102 or 103, wherein the alpha particle-emitting radionuclide is actinium-225. [0688] Embodiment 105: The conjugate of any one of embodiments 2 to 99, wherein the radionuclide is a beta particle-emitting radionuclide. [0689] Embodiment 106: The conjugate of embodiment 105, wherein the beta particle-emitting radionuclide is zircronium-89, yttrium-90, iodine-131, samarium-153, lutetium-177, or lead-212. [0690] Embodiment 107: The conjugate of any one of embodiments 2 to 99, wherein the radionuclide is a gamma particle-emitting radionuclide. [0691] Embodiment 108: The conjugate of embodiment 107, wherein the gamma particle-emitting radionuclide is indium-111. [0692] Embodiment 109: The conjugate of any one of embodiments 1 to 108, wherein the linker covalently attaches the targeting ligand to the metal chelator. [0693] Embodiment 110: The conjugate of embodiment 109, wherein the linker comprises substituted or unsubstituted C 1 -C 6 alkylene or substituted or unsubstituted C 1 -C 6 heteroalkylene. [0694] Embodiment 111: The conjugate of embodiment 110, wherein the linker comprises propyl ethyl ether. [0695] Embodiment 112: The conjugate of embodiment 109, wherein the linker comprises one or more amino acids. [0696] Embodiment 113: The conjugate of any one of embodiments 1 to 108, wherein the conjugate has a structure of Formula (X), TL- LK 1 -LK 2 -LK 3 -CHL Formula (X) wherein, TL represents the targeting ligand; CHL represents the metal chelator, optionally bound to a radionuclide; and each of LK 1 , LK 2 , and LK 3 is independently selected from substituted or unsubstituted C1-C12 alkylene, substituted or unsubstituted C1-C12 heteroalkylene, substituted or unsubstituted C2- C12 alkenylene, substituted or unsubstituted C2-C12 alkynylene, -(CH2CH2O)m-, - (OCH2CH2)m-, -O-, -S-, -S(=O)-, -S(=O)2-, -S(=O)(=NR LK )-, -C(=O)-, -C(=N-OR LK )-, - C(=O)O-, -OC(=O)-, -C(=O)C(=O)-, -C(=O)NR LK -, -NR LK C(=O)-, -OC(=O)NR LK -, -NR LK C (=O)O-, -NR LK C(=O)NR LK -, -C(=O)NR LK C(=O)-, -S(=O)2NR LK -, -NR LK S(=O)2-, -NR LK -, - N(OR LK )-, and a bond; each R LK is independently H or substituted or unsubstituted C 1 -C 6 alkyl; m is an integer selected from 1 to 10; and n is an integer selected from 1 to 20. [0697] Embodiment 114: The conjugate of embodiment 113, wherein LK 1 is substituted or unsubstituted C1-C12 alkylene or substituted or unsubstituted C1-C12 heteroalkylene. [0698] Embodiment 115: The conjugate of embodiment 113 or 114, wherein each of LK 2 and LK 3 is independently a bond, C 1 -C 6 alkylene, C 1 -C 6 heteroalkylene, -(CH 2 CH 2 O) 1-3 -, -(OCH 2 CH 2 ) 1-3 -, - O-, or -S-. [0699] Embodiment 116: The conjugate of any one of embodiments 1 to 115, wherein the conjugate has an elimination half-life in a subject of about 0.1 to about 120 hours. [0700] Embodiment 117: The conjugate of any one of embodiments 1 to 115, wherein the conjugate has an elimination half-life in a subject of about 10 minutes to about 20 hours. [0701] Embodiment 118: The conjugate of any one of embodiments 1 to 115, wherein the conjugate has an elimination half-life in a subject of about 30 minutes to about 12 hours. [0702] Embodiment 119: The conjugate of any one of embodiments 1 to 115, wherein the conjugate has an elimination half-life in a subject of about 5 minutes to about 6 hours. [0703] Embodiment 120: The conjugate of any one of embodiments 1 to 115, wherein the conjugate has an elimination half-life in a subject of about 15 minutes to about 3 hours. [0704] Embodiment 121: The conjugate of any one of embodiments 1 to 120, wherein the conjugate has a residence time of about 0.5 to 7 days in a tumor when administered to a subject having the tumor. [0705] Embodiment 122: The conjugate of any one of embodiments 1 to 120, wherein the conjugate has a residence time of about 0.5 to 14 days in a tumor when administered to a subject having the tumor. [0706] Embodiment 123: The conjugate of any one of embodiments 1 to 120, wherein the conjugate has a residence time of about 2 to 7 days in a tumor when administered to a subject having the tumor. [0707] Embodiment 124: The conjugate of any one of embodiments 1 to 120, wherein the conjugate has a residence time of about 3 to 6 days in a tumor when administered to a subject having the tumor. [0708] Embodiment 125: The conjugate of embodiment 1, wherein the conjugate has a structure listed in Tables 1B and 1D. [0709] Embodiment 126: The conjugate of embodiment 1, wherein the conjugate has a structure listed in Tables 1A and 1C. [0710] Embodiment 127: The conjugate of embodiment 126, further comprising a radionuclide selected from lutetium-177, actinium-225, yttrium-90, bismuth-213, gallium-68, copper-64 and indium- 111 bound to the metal chelator. [0711] Embodiment 128: A pharmaceutical composition comprising a conjugate of any one of embodiments 1 to 127, and a pharmaceutically acceptable excipient or carrier. [0712] Embodiment 129: The pharmaceutical composition of embodiment 128, wherein the pharmaceutical composition is formulated for intravenous administration. [0713] Embodiment 130: A method of treating cancer in a subject in need thereof, comprising administering to the subject a conjugate of any one of embodiments 1 to 127, or a pharmaceutical composition of embodiment 128 or 129. [0714] Embodiment 131: The method of embodiment 130, wherein the cancer is KRAS G12C- associated cancer. [0715] Embodiment 132: The method of embodiment 130 or 131, wherein the cancer is selected from the group consisting of Cardiac cancer: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; Lung cancer: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; Gastrointestinal cancer: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); Genitourinary tract cancer: kidney (adenocarcinoma, Wilm's tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma); Liver cancer: hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Biliary tract cancer: gall bladder carcinoma, ampullary carcinoma, cholangiocarcinoma; Bone cancer: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors; Nervous system cancer: skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal cord neurofibroma, meningioma, glioma, sarcoma); Gynecological cancer: uterus (endometrial 'carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tubes (carcinoma); Hematologic cancer: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma); Skin cancer: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis; and Adrenal glands cancer: neuroblastoma. [0716] Embodiment 133: The method of embodiment 130 or 131, wherein the cancer is non-small cell lung cancer. [0717] Embodiment 134: A method of killing a cell harboring a G12C KRAS mutation, the method comprising contacting a cell harboring a G12C KRAS mutation with the conjugate of any one of embodiments 1 to 127, or a pharmaceutical composition of embodiment 128 or 129, thereby delivering a dose of radiation to the cell. [0718] Embodiment 135: A method of delivering a radionuclide to a cell comprising administering the conjugate of any one of embodiments 1 to 127, or a pharmaceutical composition of embodiment 128 or 129. [0719] Embodiment 136: The method of embodiment 135, wherein the conjugate irreversibly binds to an intracellular protein of the cell. [0720] Embodiment 137: A method of diagnosing cancer patients harboring a G12C KRAS mutation comprising administering to a patient the conjugate of any one of embodiments 1 to 127, or a pharmaceutical composition of embodiment 128 or 129. [0721] Embodiment 138: A method of imaging a cancer harboring a G12C KRAS mutation comprising administering to a patient the conjugate of any one of embodiments 1 to 127, or a pharmaceutical composition of embodiment 128 or 129. [0722] Embodiment 139: The method of embodiment 137 or 138, further comprising measuring the concentration of the conjugate accumulated in the patient. [0723] Embodiment 140: The method of any one of embodiments 137 to 139, further comprising measuring the amount of radiation emitted from the radionuclide. [0724] Embodiment 141: The method of any one of embodiments 137 to 140, further comprising analyzing the elimination profile of the conjugate in the patient. [0725] Embodiment 142: The method of any one of embodiments 137 to 141, further comprising measuring an elimination half-life of the conjugate in the patient. [0726] Embodiment 143: A covalently modified KRAS protein comprising, a KRAS protein comprising a glycine to cysteine amino acid substitution at residue 12, and a radiolabeled compound comprising a covalently bonded radioisotope, wherein the radiolabeled compound is bonded to the KRAS protein at the cysteine residue 12 of the KRAS protein through a covalent bond, and wherein residue position numbering of the KRAS protein is based on SEQ ID NO:1 or SEQ ID NO:2 as a reference sequence. [0727] Embodiment 144: The KRAS protein of embodiment 143, wherein the covalently bonded radioisotope is fluorine-18 ( 18 F), iodine-131 ( 131 I), iodine-123 ( 123 I), iodine-124 ( 124 I), iodine-125 ( 125 I), or astatine-211 ( 211 At). [0728] Embodiment 145: The KRAS protein of embodiment 143 or 144, wherein the covalently bonded radioisotope is 131 I. [0729] Embodiment 146: The KRAS protein of any one of embodiments 143 to 145, wherein the covalent bond is formed in vivo. [0730] Embodiment 147: The KRAS protein of any one of embodiments 143 to 146, wherein the radiolabeled compound comprises an electrophilic functional group. [0731] Embodiment 148: The KRAS protein of embodiment 147, wherein the covalent bond is formed between the electrophilic functional group and the cysteine residue 12 of the KRAS protein. [0732] Embodiment 149: The KRAS protein of embodiment 147 or 148, wherein the electrophilic functional group comprises optionally substituted acrylamide or optionally substituted chloroacetamide. [0733] Embodiment 150: The KRAS protein of embodiment 149, wherein the electrophilic functional group comprises an acrylamide group, a 2-fluoroacrylamide group, or a 2-methyl acrylamide group. [0734] Embodiment 151: The KRAS protein of embodiment 147 or 148, wherein the electrophilic functional group comprises a structure of Formula (Ia): wherein, ring Q is an optionally substituted 3 to 10 membered heterocycloalkyl; and E has a structure of Formula (Ic), wherein, X is C(=O), OC(=O), P(=O)OR 2 , C(=S), S(=O)n, or OS(O)n; n is 1 or 2; R 2 is H or substituted or unsubstituted C 1 -C 3 alkyl; R 5 and R 7 are each independently selected from H, -CN, halogen, substituted or unsubstituted C1- C6 alkyl, substituted or unsubstituted C 1 -C 6 heteroalkyl, substituted or unsubstituted C3-C7 cycloalkyl, or substituted or unsubstituted C2-C7 heterocycloalkyl; or R 5 and R 7 taken together form a bond; and R 6 is H, halogen, -CN, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, heteroaryl, aryl, -C 1 -C 6 alkylene-NH(C 1 -C 6 alkyl), -C 1 -C 6 alkylene-N(C 1 -C 6 alkyl)2, C 3 -C 6 cycloalkyl or C 2 -C 5 heterocycloalkyl, wherein each of the alkyl, heteroalkyl, heteroaryl, aryl, alkylene, cycloalkyl, or heterocycloalkyl groups are optionally substituted. [0735] Embodiment 152: The KRAS protein of embodiment 151, wherein ring Q is a C 2 -C 6 optionally substituted monocyclic heterocycloalkyl. [0736] Embodiment 153: The KRAS protein of embodiment 151, wherein ring Q is a C 5 -C 9 optionally substituted bicyclic heterocycloalkyl. [0737] Embodiment 154: The KRAS protein of embodiment 153, wherein ring Q is a spiro bicyclic heterocycloalkyl. [0738] Embodiment 155: The KRAS protein of any one of embodiments 151 to 154, wherein ring Q is optionally substituted with one or more R Q groups, wherein each R Q is independently D, halogen, -CN, -NH 2 , -NH(alkyl), -N(alkyl) 2 , -OH, oxo, -CO 2 H, -CO 2 alkyl, -C(=O)NH 2 , -C(=O)NH(alkyl), -C(=O)N(alkyl) 2 , -S(=O) 2 NH 2 , -S(=O) 2 NH(alkyl), -S(=O) 2 N(alkyl) 2 , alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, or arylsulfone, wherein each of the alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, or arylsulfone is optionally substituted. [0739] Embodiment 156: The KRAS protein of embodiment 155, wherein each R Q is independently D, oxo, halogen, -CN, -NH 2 , -OH, -NH(C 1 -C 3 alkyl), -N(C 1 -C 3 alkyl) 2 , - NH(cyclopropyl), C 1 -C 6 alkyl, or C 1 -C 6 alkoxyl, wherein the alkyl or alkoxyl is optionally substituted with -CN and/or one or more halogens. [0740] Embodiment 157: The KRAS protein of embodiment 147 or 148, wherein the electrophilic functional group comprises a structure of Formula (Ib): wherein, R 1 is H, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 heteroalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, or substituted or unsubstituted C 2 -C 5 heterocycloalkyl; and E has a structure of Formula (Ic), wherein, X is C(=O), OC(=O), P(=O)OR 2 , C(=S), S(=O)n, or OS(O)n; n is 1 or 2; R 2 is H or substituted or unsubstituted C 1 -C 3 alkyl; R 5 and R 7 are each independently selected from H, -CN, halogen, substituted or unsubstituted C1- C6 alkyl, substituted or unsubstituted C 1 -C 6 heteroalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, or substituted or unsubstituted C 2 -C 5 heterocycloalkyl; or R 5 and R 7 taken together form a bond; R 6 is H, halogen, -CN, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, heteroaryl, aryl, -C 1 -C 6 alkylene-NH(C 1 -C 6 alkyl), -C 1 -C 6 alkylene-N(C 1 -C 6 alkyl)2, C 3 -C 6 cycloalkyl or C 2 -C 5 heterocycloalkyl, wherein each of the alkyl, heteroalkyl, heteroaryl, aryl, alkylene, cycloalkyl, and heterocycloalkyl groups are optionally substituted. [0741] Embodiment 158: The KRAS protein of any one of embodiments 151 to 157, wherein X is C(=O), P(=O)OR 2 , S(=O), or S(O)2. [0742] Embodiment 159: The KRAS protein of embodiment 158, wherein X is C(=O). [0743] Embodiment 160: The KRAS protein of any one of embodiments 157 to 159, wherein R 1 is H or substituted or unsubstituted C 1 -C 3 alkyl. [0744] Embodiment 161: The KRAS protein of embodiment 147 or 148, wherein the electrophilic functional group comprises a structure of Formula (Id), wherein, X is C(=O), -OC(=O)-, -NR 2 C(=O)-, -NR 2 C(=NR 2 )-, -C(=NR 2 )-, -NR 2 P(=O)OR 2 -, -P(=O)OR 2 -, C(=S), S(=O)n, -OS(O)n-, -NR 2 S(=O)n-, wherein n is 1 or 2; Y is a bond, C 1 -C 6 alkylene, C 1 -C 6 heteroalkylene, cycloalkyl, heterocycloalkyl, arylene or heteroarylene, each of which is optionally substituted; each R 2 is independently H or substituted or unsubstituted C 1 -C 3 alkyl; R 5 and R 7 are each independently selected from H, -CN, halogen, substituted or unsubstituted C1- C6 alkyl, substituted or unsubstituted C 1 -C 6 heteroalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, or substituted or unsubstituted C 2 -C 5 heterocycloalkyl; or R 5 and R 7 taken together form a bond; R 6 is H, halogen, -CN, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, heteroaryl, aryl, -C 1 -C 6 alkylene-NH(C 1 -C 6 alkyl), -C 1 -C 6 alkylene-N(C 1 -C 6 alkyl)2, C 3 -C 6 cycloalkyl or C 2 -C 5 heterocycloalkyl, wherein each of the alkyl, heteroalkyl, heteroaryl, aryl, cycloalkyl, and heterocycloalkyl are optionally substituted. [0745] Embodiment 162: The KRAS protein of embodiment 161, wherein Y is substituted or unsubstituted C1-C4 alkylene, or substituted or unsubstituted C1-C4 heteroalkylene. [0746] Embodiment 163: The KRAS protein of embodiment 161, wherein Y is substituted or unsubstituted monocyclic arylene, or substituted or unsubstituted monocyclic heteroarylene. [0747] Embodiment 164: The KRAS protein of embodiment 161, wherein Y is substituted or unsubstituted 3 to 10 membered cycloalkyl, or substituted or unsubstituted 3 to 10 membered heterocycloalkyl. [0748] Embodiment 165: The KRAS protein of embodiment 161, wherein Y is substituted or unsubstituted monocyclic or bicyclic heterocycloalkyl. [0749] Embodiment 166: The KRAS protein of any one of embodiments 163 to 165, wherein Y is optionally substituted with one or more R Q groups, wherein each R Q is independently D, halogen, -CN, -NH 2 , -NH(alkyl), -N(alkyl) 2 , -OH, oxo, -CO 2 H, -CO 2 alkyl, -C(=O)NH 2 , -C(=O)NH(alkyl), -C(=O)N(alkyl) 2 , -S(=O) 2 NH 2 , -S(=O) 2 NH(alkyl), -S(=O) 2 N(alkyl) 2 , alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, or arylsulfone, wherein each of the alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, or arylsulfone is optionally substituted. [0750] Embodiment 167: The KRAS protein of embodiment 166, wherein each R Q is independently D, oxo, halogen, -CN, -NH 2 , -OH, -NH(C 1 -C 3 alkyl), -N(C 1 -C 3 alkyl) 2 , - NH(cyclopropyl), C 1 -C 6 alkyl, or C 1 -C 6 alkoxyl, wherein the alkyl or alkoxyl is optionally substituted with one or more halogens. [0751] Embodiment 168: The KRAS protein of any one of embodiments 151 to 167, wherein R 5 is H, halogen, methyl, or -OMe. [0752] Embodiment 169: The KRAS protein of embodiment 168, wherein R 5 is H. [0753] Embodiment 170: The KRAS protein of any one of embodiments 151 to 169, wherein R 6 is H. [0754] Embodiment 171: The KRAS protein of any one of embodiments 151 to 170, wherein R 7 is H or substituted or unsubstituted C1-C4 alkyl. [0755] Embodiment 172: The KRAS protein of embodiment 171, wherein R 7 is H. [0756] Embodiment 173: The KRAS protein of any one of embodiments 151 to 167 or 170, wherein R 5 and R 7 taken together form a bond. [0757] Embodiment 174: The KRAS protein of any one of embodiments 151 to 160, wherein E is . [0758] Embodiment 175: The KRAS protein of any one of embodiments 161 to 167, wherein . [0759] Embodiment 176: The KRAS protein of embodiment 147 or 148, wherein the electrophilic functional group comprises a each R Q is independently D, oxo, halogen, -CN, -NH 2 , -OH, -NH(C 1 -C 3 alkyl), -N(C 1 -C 3 alkyl) 2 , - NH(cyclopropyl), C 1 -C 6 alkyl, or C 1 -C 6 alkoxyl, wherein the alkyl or alkoxyl is optionally substituted with one or more halogens, and m is 0, 1, 2, 3, 4, or 5. [0760] Embodiment 177: The KRAS protein of any one of embodiments 155, 166, or 176, wherein each R Q is independently substituted or unsubstituted C 1 -C 3 alkyl, amino, or -CN. [0761] Embodiment 178: The KRAS protein of embodiment 177, wherein each R Q is methyl, -CH 2 CN, or CN. [0762] Embodiment 179: The KRAS protein of embodiment 147 or 148, wherein the electrophilic functional group comprises a
are optionally substituted. [0763] Embodiment 180: The KRAS protein of any one of embodiments 143 to 179, wherein the radiolabeled compound comprises a linker connecting the radioisotope. [0764] Embodiment 181: The KRAS protein of embodiment 180, wherein the linker comprises C 1 -C 10 alkylene or C 1 -C 10 heteroalkylene, wherein the alkylene or heteroalkylene is optionally substituted with one or more substituents selected from halogen, amino, -OH, -NO 2 , oxo, -CN, C1-3 alkoxyl, C1-3 alkyl, C1-3 hydroxyalkyl, C1-3 aminoalkyl, and C1-3 haloalkyl. [0765] Embodiment 182: The KRAS protein of embodiment 181, wherein the linker comprises C 1 -C 6 alkylene. [0766] Embodiment 183: The KRAS protein of any one of embodiments 180 to 182, wherein the linker comprises one or more functional groups selected from: -O-, -S-, -S-S-, -C(=O)O-, -OC(=O)-, - C(=O)NR a -, -NR a C(=O)-, -S(=O)2NR a -, -NR a S(=O)2-, -NR a C(=O)NR a -, - NR a C(=O)O-, and - OC(=O)NR a -, wherein each R a is independently hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C3- C8cycloalkyl, C2-C9heterocycloalkyl, aryl, or heteroaryl. [0767] Embodiment 184: The KRAS protein of any one of embodiments 180 to 182, wherein the linker comprises 1 to 20 groups independently selected from , NR a C(=O)-, -S(=O) 2 NR a -, -NR a S(=O) 2 -, -NR a C(=O)NR a -, - NR a C(=O)O-, -OC(=O)NR a -, arylene, heteroarylene, wherein each R a is independently hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C3- C8cycloalkyl, C2-C9heterocycloalkyl, aryl, or heteroaryl, and wherein each R b is independently hydrogen, halogen, -CN, -NO2, -OR a , -SR a , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C2- C6alkynyl, C3-C8cycloalkyl, C2-C9heterocycloalkyl, aryl, or heteroaryl. [0768] Embodiment 185: The KRAS protein of embodiment 183 or 184, wherein the linker comprises . [0769] Embodiment 186: The KRAS protein of embodiment 183 or 184, wherein the linker comprises , , wherein each k1 and k2 is independently 0 or an integer selected from 1 to 10. [0770] Embodiment 187: The KRAS protein of embodiment 183 or 184, wherein the linker comprises . [0771] Embodiment 188: The KRAS protein of any one of embodiments 180 to 186, wherein the linker is a brush border enzyme-cleavable linker. [0772] Embodiment 189: The KRAS protein of any one of embodiments 180 to 186, wherein the linker is a hepatocyte-cleavable linker. [0773] Embodiment 190: The KRAS protein of any one of embodiments 180 to 186, wherein the linker is a cytochrome P450-substrate. [0774] Embodiment 191: The KRAS protein of any one of embodiments 180 to 186, wherein the linker is an esterase-cleavable linker. [0775] Embodiment 192: The KRAS protein of any one of embodiments 180 to 186, wherein the linker is a peptidase-cleavable linker. [0776] Embodiment 193: The KRAS protein of any one of embodiments 143 to 192, wherein the radiolabeled compound comprises a structure of Formula (Va), Formula (Vb), Formula (Vc), Formula (Vd), or Formula (Ve): Formula (Ve), wherein R* is fluorine-18 ( 18 F), iodine-131 ( 131 I), iodine-123 ( 123 I), iodine-124 ( 124 I), iodine-125 ( 125 I), or astatine-211 ( 211 At); and R a is hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C3-C8cycloalkyl, C2-C9heterocycloalkyl, aryl, or heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted. [0777] Embodiment 194: The KRAS protein of embodiment 193, wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl are independently optionally substituted by one or more halogen, amino, -OH, -NO2, oxo, -CN, C1-3 alkoxyl, C1-3 alkyl and C1-3 haloalkyl. [0778] Embodiment 195: The KRAS protein of embodiment 193, wherein the radiolabeled compound comprises a structure of . [0779] Embodiment 196: The KRAS protein of any one of embodiments 143 to 148, wherein the radiolabeled compound comprises a structure of Formula (III), or a salt or solvate thereof, Formula (III) wherein ring Q 1 is a 4-12 membered saturated or partially saturated monocyclic or bicyclic ring, wherein the monocyclic or bicyclic ring is optionally substituted; L 1 is a bond, -C(=O)-, O, S, NR 15 , optionally substituted C 1 -C 3 alkylene, optionally substituted C 1 -C 3 heteroalkylene; L 2 is a bond, -C(=O)-, O, S or NR 15 ; X is C(=O), P(=O)OR 2 , C(=S), or S(=O) n , where n is 1 or 2; R 2 is H or optionally substituted C 1 -C 3 alkyl; R 5 is hydrogen, cyano, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxyl, C 1 -C 6 heteroalkyl, C 3 -C 6 cycloalkyl, or C 2 -C 5 heterocycloalkyl, each of the alkyl, alkoxyl, heteroalkyl, cycloalkyl or heterocycloalkyl is optionally substituted, and R 7 is hydrogen, cyano, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxyl, C 1 -C 6 heteroalkyl, C 3 -C 6 cycloalkyl, C 2 -C 5 heterocycloalkyl, heteroaryl, -C 1 -C 6 alkylene-heteoraryl, -C 1 -C 6 alkylene-NH(C 1 -C 6 alkyl), or -C 1 -C 6 alkylene-N(C 1 -C 6 alkyl)2, each of the alkyl, alkylene, alkoxyl, heteroalkyl, cycloalkyl or heterocycloalkyl is optionally substituted; or R 5 and R 7 taken together form a bond; or R 5 and R 7 taken together with the carbon atoms to which they are attached form a 5-8 membered partially saturated cycloalkyl, wherein the cycloalkyl is optionally substituted; R 6 is hydrogen, cyano, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxyl, C 1 -C 6 heteroalkyl, C 3 -C 6 cycloalkyl, C 2 -C 5 heterocycloalkyl, heteroaryl, -C 1 -C 6 alkylene-heteoraryl, -C 1 -C 6 alkylene-NH(C 1 -C 6 alkyl), or -C 1 -C 6 alkylene-N(C 1 -C 6 alkyl) 2 , each of the alkyl, alkylene, alkoxyl, heteroalkyl, cycloalkyl, heterocycloalkyl, or heteroaryl is optionally substituted; R 12 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, -L 3 -NR 15 R 15’ , heterocycloalkyl, -L 3 - heterocycloalkyl, cycloalkyl, -L 3 -cycloalkyl, aryl, heteroaryl, -L 3 -aryl, or -L 3 -heteroaryl, wherein each of the heterocycloalkyl, cycloalkyl, aryl, heteroaryl, alkyl or heteroalkyl is optionally substituted; L 3 is C 1 -C 4 alkylene or C 1 -C 4 heteroalkylene, each of which is optionally substituted; each R 13 is independently OH, halogen, oxo, substituted or unsubstituted C 1 -C 6 alkyl, or substituted or unsubstituted C 1 -C 6 heteroalkyl; R 14 is hydrogen, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each of the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted; each R 15 is independently hydrogen or optionally substituted C 1 -C 3 alkyl; each R 15’ is independently hydrogen, acyl, optionally substituted C 1 -C 3 alkyl, optionally substituted C 1 -C 3 heteroalkyl or optionally substituted C 1 -C 3 hydroxyalkyl; and m is 0, 1, or 2. [0780] Embodiment 197: The KRAS protein of embodiment 196, wherein ring Q 1 is a 4-12 membered saturated or partially saturated monocyclic or bicyclic ring optionally substituted with one, two, or three groups selected from R 18 ; L 1 is a bond, -C(=O)-, O, S, NR 15 , optionally substituted C 1 -C 3 alkylene, or optionally substituted C 1 -C 3 heteroalkylene, wherein the alkylene and heteroalkylene is optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, and C 2 -C 5 heterocycloalkyl; L 2 is a bond, -C(=O)-, O, S or NR 15 ; X is C(=O), P(=O)OR 2 , C(=S), or S(=O)n, where n is 1 or 2; R 2 is H or substituted or unsubstituted C 1 -C 3 alkyl, wherein the alkyl is optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 alkoxy, C 3 -C 6 cycloalkyl, and C 2 -C 5 heterocycloalkyl; R 5 is hydrogen, cyano, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxyl, C 1 -C 6 heteroalkyl, C 3 -C 6 cycloalkyl, or C 2 -C 5 heterocycloalkyl, each of the alkyl, alkoxyl, heteroalkyl, cycloalkyl or heterocycloalkyl is optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, and C2- C5 heterocycloalkyl; R 7 is hydrogen, cyano, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxyl, C 1 -C 6 heteroalkyl, C 3 -C 6 cycloalkyl, C 2 -C 5 heterocycloalkyl, heteroaryl, -C 1 -C 6 alkylene-heteoraryl, -C 1 -C 6 alkylene-NH(C 1 -C 6 alkyl), or -C 1 -C 6 alkylene-N(C 1 -C 6 alkyl)2, each of the alkyl, alkylene, alkoxyl, heteroalkyl, cycloalkyl or heterocycloalkyl is optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, and C 2 -C 5 heterocycloalkyl; or R 5 and R 7 taken together form a bond; or R 5 and R 7 taken together with the carbon atoms to which they are attached form a 5-8 membered partially saturated cycloalkyl, wherein the cycloalkyl is optionally substituted with one, two or three groups selected from R 17 ; R 6 is hydrogen, cyano, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxyl, C 1 -C 6 heteroalkyl, C 3 -C 6 cycloalkyl, C 2 -C 5 heterocycloalkyl, heteroaryl, -C 1 -C 6 alkylene-heteoraryl, -C 1 -C 6 alkylene-NH(C 1 -C 6 alkyl), or -C 1 -C 6 alkylene-N(C 1 -C 6 alkyl) 2 , each of the alkyl, alkylene, alkoxyl, heteroalkyl, cycloalkyl, heterocycloalkyl, or heteroaryl is optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 3 - C 6 cycloalkyl, and C 2 -C 5 heterocycloalkyl; R 12 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, -L 3 -NR 15 R 15’ , heterocycloalkyl, -L 3 - heterocycloalkyl, cycloalkyl, -L 3 -cycloalkyl, aryl, heteroaryl, -L 3 -aryl, or -L 3 -heteroaryl, wherein each of the heterocycloalkyl, cycloalkyl, aryl, heteroaryl, alkyl or heteroalkyl is optionally substituted with one, two, three or four groups selected from R 19 ; L 3 is C 1 -C 4 alkylene or C 1 -C 4 heteroalkylene, each of which is optionally substituted with one, two, or three groups selected from R 19 ; each R 13 is independently OH, halogen, oxo, substituted or unsubstituted C 1 -C 6 alkyl, or substituted or unsubstituted C 1 -C 6 heteroalkyl, wherein each of the alkyl and heteroalkyl is optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, and C 2 -C 5 heterocycloalkyl; R 14 is hydrogen, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each of the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, three or four groups selected from R 16 ; each R 15 is independently hydrogen or optionally substituted C 1 -C 3 alkyl, wherein the alkyl is optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 alkoxy, C 3 -C 6 cycloalkyl, and C 2 -C 5 heterocycloalkyl; each R 15’ is independently hydrogen, acyl, optionally substituted C 1 -C 3 alkyl, optionally substituted C 1 -C 3 heteroalkyl or optionally substituted C 1 -C 3 hydroxyalkyl; m is 0, 1, or 2; each R 17 is independently halogen, hydroxyl, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, amino, cyano, C 1 -C 6 heteroalkyl, C 1 -C 6 hydroxyalkyl, -O-C 1 -C 6 haloalkyl, or -S-C1- C6haloalkyl; each R 18 is independently halogen, oxo, C 1 -C 6 alkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, -CN, -C(O)OR 15 , -C(O)N(R 15 )(R 15’ ), -N(R 15 )(R 15’ ), or OR 15 , and wherein each of the alkyl, aminoalkyl, haloalkyl, alkenyl, alkynyl, or heteroalkyl is optionally substituted with one, two, or three groups selected from halogen, -CN, -NO 2 , amino, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, and C 2 -C 5 heterocycloalkyl; R 16 and R 19 are each independently selected from halogen, oxo, -CN, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, C 3 -C 10 cycloalkyl, -C 1-3 alkylene-C 3-6 cycloalkyl, C 2 -C 9 heterocycloalkyl, -C 1-3 alkylene-C 2-9 heterocycloalkyl, C 6 -C 10 aryl, -C 1-3 alkylene-C 6-10 aryl, C 1 - C 9 heteroaryl, -C 1-3 alkylene-C 1-9 heteroaryl, -OR 10 , -SR 10 , -N(R 10 )(R 10’ ), -C(O)OR 10 , - OC(O)N(R 10 )(R 10’ ), -N(R 10’ )C(O)N(R 10 )(R 10’ ), -N(R 10’ )C(O)OR 11 , -N(R 10’ )S(O) 2 R 11 , - C(O)R 11 , -S(O)R 11 , -OC(O)R 11 , -C(O)N(R 10 )(R 10’ ), -C(O)C(O)N(R 10 )(R 10’ ), -N(R 10’ )C(O)R 11 , -S(O) 2 R 11 , -S(O) 2 N(R 10 )(R 10’ )-, S(=O)(=NH)N(R 10 )(R 10’ ), -CH 2 C(O)N(R 10 )(R 10’ ), - CH 2 N(R 10’ )C(O)R 11 , -CH 2 S(O) 2 R 11 , and -CH 2 S(O) 2 N(R 10 )(R 10’ ), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, -C 1-3 alkylene-C 3-6 cycloalkyl, heterocycloalkyl, -C 1-3 alkylene-C 2 - C 9 heterocycloalkyl, aryl, -C 1-3 alkylene-C 6-10 aryl, heteroaryl and -C 1-3 alkylene-C 1-9 heteroaryl are optionally substituted with one, two, three, or four groups independently selected from halogen, oxo, -CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkyloxy, C 1 -C 6 haloalkoxy, C 3 -C 10 cycloalkyl, C 2 -C 9 heterocycloalkyl, C 6 -C 10 aryl, C 1 -C 9 heteroaryl, -OR 10 , - SR 10 , -N(R 10 )(R 10’ ), -C(O)OR 10 , -OC(O)N(R 10 )(R 10’ ), -N(R 10’ )C(O)N(R 10 )(R 10’ ), - N(R 10’ )C(O)OR 11 , -N(R 10’ )S(O) 2 R 11 , -C(O)R 11 , -S(O)R 11 , -OC(O)R 11 , -C(O)N(R 10 )(R 10’ ), - C(O)C(O)N(R 10 )(R 10’ ), -N(R 10’ )C(O)R 11 , -S(O) 2 R 11 , -S(O) 2 N(R 10 )(R 10’ )-, S(=O)(=NH)N(R 10 )(R 10’ ), -CH2C(O)N(R 10 )(R 10’ ), -CH2N(R 10’ )C(O)R 11 , -CH2S(O)2R 11 , and - CH 2 S(O) 2 N(R 10 )(R 10’ ); each R 10 is independently selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C2-9heterocycloalkyl, C 6 -C 10 aryl, and C 1 -C 9 heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, C2-C9 heterocycloalkyl, C 6 -C 10 aryl, and C 1 -C 9 heteroaryl; each R 10’ is independently selected from hydrogen, C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl; and each R 11 is independently selected C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C2-C9 heterocycloalkyl, C 6 -C 10 aryl, and C 1 -C 9 heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, C2-C9 heterocycloalkyl, C 6 -C 10 aryl, and C 1 -C 9 heteroaryl. [0781] Embodiment 198: The KRAS protein of embodiment 196 or 197, wherein at least one of L 1 , L 2 , R 12 , R 13 and R 14 comprises the covalently bonded radioisotope. [0782] Embodiment 199: The KRAS protein of any one of embodiments 196 to 198, wherein the covalently bonded radioisotope is R* and R* is fluorine-18 ( 18 F), iodine-131 ( 131 I), iodine-123 ( 123 I), iodine-124 ( 124 I), iodine-125 ( 125 I), or astatine-211 ( 211 At). [0783] Embodiment 200: The KRAS protein of any one of embodiments 196 to 198, wherein the covalently bonded radioisotope is R* and R* is iodine-131. [0784] Embodiment 201: The KRAS protein of any one of embodiments 196 to 200, wherein R 5 is hydrogen, cyano, halogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 alkoxyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted C 3 -C 6 cycloalkyl, or optionally substituted C 2 -C 5 heterocycloalkyl. [0785] Embodiment 202: The KRAS protein of embodiment 201, wherein R 5 is hydrogen, halogen or a C 1 -C 3 alkyl optionally substituted with one to three substituents selected from hydroxyl and halogen. [0786] Embodiment 203: The KRAS protein of embodiment 202, wherein R 5 is a hydrogen. [0787] Embodiment 204: The KRAS protein of embodiment 202, wherein R 5 is a halogen. [0788] Embodiment 205: The KRAS protein of embodiment 202, wherein R 5 is a fluorine. [0789] Embodiment 206: The KRAS protein of any one of embodiments 196 to 205, wherein R 7 is hydrogen, cyano, halogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 alkoxyl, or optionally substituted C 1 -C 6 heteroalkyl. [0790] Embodiment 207: The KRAS protein of any one of embodiments 196 to 205, wherein R 7 is H. [0791] Embodiment 208: The KRAS protein of any one of embodiments 196 to 200, wherein R 5 and R 7 taken together with the carbon atoms to which they are attached form a 5-8 membered partially saturated cycloalkyl, wherein the cycloalkyl is optionally substituted. [0792] Embodiment 209: The KRAS protein of any one of embodiments 196 to 208, wherein R 6 is hydrogen, cyano, halogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 alkoxyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted C 3 -C 6 cycloalkyl, or optionally substituted C 2 -C 6 heterocycloalkyl. [0793] Embodiment 210: The KRAS protein of any one of embodiments 196 to 208, wherein R 6 is hydrogen. [0794] Embodiment 211: The KRAS protein of any one of embodiments 196 to 210, wherein ring Q 1 is optionally substituted with one to three R 18 , wherein R 18 is oxo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, cyano, - C(O)OR 15 , -C(O)N(R 15 )(R 15’ ), or -N(R 15 )(R 15’ ), wherein the alkyl, alkenyl, alkynyl, or heteroalkyl is optionally substituted. [0795] Embodiment 212: The KRAS protein of embodiment 211, wherein ring Q 1 is a 6 membered monocyclic ring optionally substituted with one to three R 18 , wherein R 18 is methyl, -CH2CN, oxo, hydroxyl, carboxyl, C(O)OR 15 . [0796] Embodiment 213: The KRAS protein of any one of embodiments 196 to 212, wherein the radiolabeled compound comprises a structure of Formula (IIIa), or a salt or solvate thereof, Formula (IIIa), wherein m1 is 0, 1, 2, or 3. [0797] Embodiment 214: The KRAS protein of any one of embodiments 196 to 213, wherein R 14 is hydrogen, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each of the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one or more R 16 wherein each R 16 is independently halogen, hydroxyl, C 1 -C 6 alkyl, cycloalkyl, C 1 -C 6 alkoxy, acetyl, oxo, -C(O)OR 15 , C 1 -C 6 haloalkyl, amino, cyano, C 1 -C 6 heteroalkyl, C 1 -C 6 hydroxyalkyl, - O- C 1 -C 6 haloalkyl, or -S- C 1 -C 6 haloalkyl. [0798] Embodiment 215: The KRAS protein of any one of embodiments 196 to 214, wherein R 14 is phenyl, napthyl, or monocyclic or bicyclic heteroaryl, each optionally substituted with one or more R 16 , wherein each R 16 is independently halogen, -CN, -NH2, -NH(C 1 -C 6 alkyl), -N(C1- C6alkyl)2, -OH, oxo, -CO2H, -C(=O)O-C1-6alkyl, -C(=O)NH2, -C(=O)NH(C 1 -C 6 alkyl), - C(=O)N(C 1 -C 6 alkyl) 2 , -S(=O) 2 NH 2 , -S(=O) 2 NH(C 1 -C 6 alkyl), -S(=O) 2 N(C 1 -C 6 alkyl) 2 , C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 fluoroalkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 alkoxy, C 1 -C 6 fluoroalkoxy, C 1 -C 6 heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, or arylsulfone, wherein each of the alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, or arylsulfone is optionally substituted. [0799] Embodiment 216: The KRAS protein of any one of embodiments 196 to 215, wherein each R 16 is independently oxo, halogen, -CN, -NH2, -NH(CH3), -N(CH3)2, -OH, -CO2H, -CO2(C1-C4 alkyl), -OCO(C1-C4 alkyl), -C(=O)NH2, -C(=O)NH(C1-C4 alkyl), -C(=O)N(C1-C4 alkyl)2, - S(=O)2NH2, -S(=O)2NH(C1-C4 alkyl), -S(=O)2N(C1-C4 alkyl)2, C1-C4 alkyl, C 3 -C 6 cycloalkyl, C1- C4 fluoroalkyl, C 1 -C 6 heteroalkyl, C1-C4 alkoxy, C1-C4 fluoroalkoxy, -S-C1-4 alkyl, -S(=O)C1-4 alkyl, or -S(=O)2(C1-C4 alkyl). [0800] Embodiment 217: The KRAS protein of any one of embodiments 196 to 216, wherein R 14 is napthyl optionally substituted with one or more R 16 , wherein each R 16 is independently halogen, hydroxyl, C 1 -C 3 alkyl, alkoxy, haloalkyl, amino, or cyano. [0801] Embodiment 218: The KRAS protein of any one of embodiments 196 to 217, wherein R 16 is halogen and the halogen is a radioisotope selected from fluorine-18 ( 18 F), iodine-131 ( 131 I), iodine-123 ( 123 I), iodine-124 ( 124 I), iodine-125 ( 125 I), and astatine-211 ( 211 At). [0802] Embodiment 219: The KRAS protein of any one of embodiments 196 to 217, wherein R 14 comprises the covalently bonded radioisotope R*. [0803] Embodiment 220: The KRAS protein of any one of embodiments 54 to 57, wherein R 14 is [0804] Embodiment 221: The KRAS protein of any one of embodiments 196 to 220, wherein R 12 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, -L 3 -NR 15 R 15’ , heterocycloalkyl, -L 3 - heterocycloalkyl, cycloalkyl, -L 3 -cycloalkyl, aryl, heteroaryl, -L 3 -aryl, or -L 3 -heteroaryl, wherein each of the heterocycloalkyl, cycloalkyl, aryl, heteroaryl, alkyl or heteroalkyl is optionally substituted with one or more selected from R 19 ; wherein each R 19 is independently oxo, acyl, hydroxyl, cyano, amino, halogen, C 1 -C 6 alkyl, C1- C6 hydroxyalkyl, C 1 -C 6 heteroalkyl, C3-C10 cycloalkyl, C2-C9 heterocycloalkyl, or C 1 -C 6 alkoxy, wherein the alkyl, hydroxyalkyl, alkoxy, heteroalkyl, cycloalkyl, or heterocycloalkyl is optionally substituted. [0805] Embodiment 222: The KRAS protein of embodiment 221, wherein R 12 is cycloalkyl, heterocycloalkyl, -L 3 -heterocycloalkyl, or -L 3 -cycloalkyl, wherein each of the L 3 , heterocycloalkyl, cycloalkyl, alkyl, or heteroalkyl is optionally substituted with one or more R 19 . [0806] Embodiment 223: The KRAS protein of embodiment 221 or 222, wherein L 3 is C 1 -C 4 alkylene or C 1 -C 4 heteroalkylene, each of which is optionally substituted with one or more R 19 . [0807] Embodiment 224: The KRAS protein of any one of embodiments 221 to 223, wherein each R 19 is independently oxo, acyl, hydroxyl, cyano, halogen, C 1 -C 6 alkyl, or C 1 -C 6 hydroxyalkyl containing 1 to 3 hydroxyl groups. [0808] Embodiment 225: The KRAS protein of any one of embodiments 196 to 224, wherein X is C(=O). [0809] Embodiment 226: The KRAS protein of any one of embodiments 196 to 225, wherein L 1 is a bond. [0810] Embodiment 227: The KRAS protein of any one of embodiments 196 to 226, wherein L 2 is a bond, O, S or NR 15 . [0811] Embodiment 228: The KRAS protein of any one of embodiments 196 to 227, wherein each R 13 is independently OH, halogen, or C 1 -C 3 alkyl. [0812] Embodiment 229: The KRAS protein of any one of embodiments 196 to 228, wherein m is 0 or 1. [0813] Embodiment 230: The KRAS protein of any one of embodiments 196 to 229, wherein the radiolabeled compound has a structure of , , ,
[0814] Embodiment 231: The KRAS protein of any one of embodiments 196-217 or 221-229, wherein the radiolabeled compound comprises: a) the structure of Formula (III) or a salt or solvate thereof; b) the covalently bonded radioisotope; and c) a linker covalently bonded to the radioisotope and to the structure of Formula (III) or a salt or solvate thereof. [0815] Embodiment 232: The KRAS protein of embodiment 231, where in the linker comprises C1-C10 alkylene or C1-C10 heteroalkylene, wherein the alkylene or heteroalkylene is optionally substituted with one or more substituents selected from halogen, amino, -OH, -NO2, oxo, -CN, C1-3 alkoxyl, C1-3 alkyl, C1-3 hydroxyalkyl, C1-3 aminoalkyl, and C1-3 haloalkyl. [0816] Embodiment 233: The KRAS protein of embodiment 232, wherein the linker comprises C 1 -C 6 alkylene. [0817] Embodiment 234: The KRAS protein of any one of embodiments 231 to 233, wherein the linker comprises one or more functional groups selected from: -O-, -S-, -S-S-, -C(=O)O-, -OC(=O)-, - C(=O)NR a -, -NR a C(=O)-, -S(=O)2NR a -, -NR a S(=O)2-, -NR a C(=O)NR a -, - NR a C(=O)O-, and - OC(=O)NR a -, wherein each R a is independently hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C3- C8cycloalkyl, C2-C9heterocycloalkyl, aryl, or heteroaryl. [0818] Embodiment 235: The KRAS protein of any one of embodiments 231 to 234, wherein the linker comprises , wherein each k1 and k2 is independently 0 or an integer selected from 1 to 10. [0819] Embodiment 236: The KRAS protein of any one of embodiments 231 to 235, wherein the linker comprises , , ,
. [0820] Embodiment 237: The KRAS protein of any one of embodiments 231 to 236, wherein the linker is a brush border enzyme-cleavable linker. [0821] Embodiment 238: The KRAS protein of any one of embodiments 231 to 236, wherein the linker is a hepatocyte-cleavable linker. [0822] Embodiment 239: The KRAS protein of any one of embodiments 231 to 236, wherein the linker is a cytochrome P450-substrate. [0823] Embodiment 240: The KRAS protein of any one of embodiments 231 to 236, wherein the linker is an esterase-cleavable linker. [0824] Embodiment 241: The KRAS protein of any one of embodiments 231 to 236, wherein the linker is a peptidase-cleavable linker. [0825] Embodiment 242: The KRAS protein of any one of embodiments 231 to 241, wherein the radiolabeled compound comprises a structure of Formula (Va), Formula (Vb), Formula (Vc), Formula (Vd), or Formula (Ve): Formula (Ve), wherein R* is fluorine-18 ( 18 F), iodine-131 ( 131 I), iodine-123 ( 123 I), iodine-124 ( 124 I), iodine-125 ( 125 I), or astatine-211 ( 211 At); and R a is hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C3-C8cycloalkyl, C2-C9heterocycloalkyl, aryl, or heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted. [0826] Embodiment 243: The KRAS protein of embodiment 242, wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with one or more substituents selected from halogen, amino, - OH, -NO2, oxo, -CN, C1-3 alkoxyl, C1-3 alkyl and C1-3 haloalkyl. [0827] Embodiment 244: The KRAS protein of embodiment 242, wherein the radiolabeled compound comprises a structure of . [0828] Embodiment 245: The KRAS protein of any one of embodiments 231 to 244, wherein the radiolabeled compound comprises a structure of Formula (IIIb): Formula (IIIb), wherein L C is a linker comprising 1 to 20 groups independently selected from -CR b R b -, -C(=O)-, -S(=O)-, -C(=O)NR a -, -NR a C(=O)-, -S(=O)2NR a -, -NR a S(=O)2-, -NR a C(=O)NR a -, - NR a C(=O)O-, - OC(=O)NR a -, arylene, heteroarylene; each R a is independently hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C3-C8cycloalkyl, C2- C9heterocycloalkyl, aryl, or heteroaryl; each R b is independently hydrogen, halogen, -CN, -NO2, -OR a , -SR a , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C3- C8cycloalkyl, C2-C9heterocycloalkyl, aryl, or heteroaryl; R 12 is C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, -L 3 -NR 15 -, heterocycloalkyl, -L 3 -heterocycloalkyl, cycloalkyl, -L 3 -cycloalkyl, aryl, heteroaryl, -L 3 -aryl, or -L 3 -heteroaryl, wherein each of the heterocycloalkyl, cycloalkyl, aryl, heteroaryl, alkyl or heteroalkyl is optionally substituted; R* is fluorine-18 ( 18 F), iodine-131 ( 131 I), iodine-123 ( 123 I), iodine-124 ( 124 I), iodine-125 ( 125 I), or astatine-211 ( 211 At); and E, L 1 , L 2 , L 3 R 13 , R 14 , R 18 , m and m1 have the meaning defined above in Formula (III). [0829] Embodiment 246: The KRAS protein of embodiment 245, or a salt or solvate thereof, wherein the radiolabeled compound comprises a structure of Formula (IIIc): Formula (IIIc). [0830] Embodiment 247: The KRAS protein of embodiment 245 or 246, wherein L C comprises . [0831] Embodiment 248: The KRAS protein of embodiment 245 or 246, wherein L C comprises
containing 1-2 heteroatoms independently selected from N, S, and O. [0832] Embodiment 249: The KRAS protein of embodiment 245 or 246, wherein the radiolabeled compound has a structure of: , , ,
. [0833] Embodiment 250: The KRAS protein of embodiment 245 or 246 wherein the radiolabeled compound has a structure of:
. [0834] Embodiment 251: The KRAS protein of any one of embodiments 143 to 148, wherein the radiolabeled compound comprises a structure of Formula (IV), or a salt or solvate thereof, wherein E 1 and E 2 are each independently N or CR 21 ; E 3 is CR 28 R 29 , C=CR 28 R 29 , C═O, C=S, or C=NR 28 ; J is N, NR 30 , or CR 30 ; M is N, NR 33 , or CR 33 ; is a single or double bond as necessary to give every atom its normal valence; R 21 is independently H, hydroxyl, cyano, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxyl, or C 1 -C 6 heteroalkyl, wherein each of the alkyl, alkoxy, and heteroalkyl are optionally substituted; R 22 is hydrogen, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, OR 22’ , N(R 22’ )2, cycloalkyl, - C 1 -C 3 alkylene-cycloalkyl, heterocycloalkyl, -C 1 -C 3 alkylene-heterocycloalkyl, aryl, -C1- C3alkylene-aryl, heteroaryl, or -C 1 -C 3 alkylene-heteroaryl, wherein each of the alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted, and each R 22’ is independently H, C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, aryl, or heteroaryl, wherein each of the alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, and heteroaryl is optionally substituted, or two R 22’ together with the nitrogen atom to which they are attached, form an optionally substituted 3-7-membered ring; R 23 is hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -L 4 -cycloalkyl, -L 4 -heterocycloalkyl, -L 4 -aryl, or -L 4 - heteroaryl, wherein each of the alkyl, alkoxy, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, and heteroaryl is optionally substituted; L 4 is C 1 -C 4 alkylene or C 1 -C 4 heteroalkylene, each of which is optionally substituted; ring A is an optionally substituted 4-7 membered monocyclic ring or optionally substituted 6-11 membered bicyclic, bridged, fused, or spiro ring; R 1 is H, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted C 3 -C 6 cycloalkyl, or optionally substituted C 2 -C 5 heterocycloalkyl; L is a bond, S, O, or NR 10’ , optionally substituted C 1 -C 6 alkylene, or optionally substituted C 1 -C 6 heteroalkylene; E represents a structure of Formula (Ic), wherein, X is C(=O), P(=O)OR 2 , C(=S), or S(=O)n, where n is 1 or 2; R 2 is H or optionally substituted C 1 -C 3 alkyl; R 5 is hydrogen, cyano, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxyl, C 1 -C 6 heteroalkyl, C 3 -C 6 cycloalkyl, or C 2 -C 5 heterocycloalkyl, each of the alkyl, alkoxyl, heteroalkyl, cycloalkyl or heterocycloalkyl is optionally substituted, and R 7 is hydrogen, cyano, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxyl, C 1 -C 6 heteroalkyl, C 3 -C 6 cycloalkyl, C 2 -C 5 heterocycloalkyl, heteroaryl, -C 1 -C 6 alkylene-heteoraryl, -C 1 -C 6 alkylene-NH(C 1 -C 6 alkyl), or -C 1 -C 6 alkylene-N(C 1 -C 6 alkyl)2, each of the alkyl, alkylene, alkoxyl, heteroalkyl, cycloalkyl or heterocycloalkyl is optionally substituted; or R 5 and R 7 taken together form a bond; or R 5 and R 7 taken together with the carbon atoms to which they are attached form a 5-8 membered partially saturated cycloalkyl, wherein the cycloalkyl is optionally substituted; R 6 is hydrogen, cyano, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxyl, C 1 -C 6 heteroalkyl, C 3 -C 6 cycloalkyl, C 2 -C 5 heterocycloalkyl, heteroaryl, -C 1 -C 6 alkylene-heteoraryl, -C 1 -C 6 alkylene-NH(C 1 -C 6 alkyl), or -C 1 -C 6 alkylene-N(C 1 -C 6 alkyl) 2 , each of the alkyl, alkylene, alkoxyl, heteroalkyl, cycloalkyl, heterocycloalkyl, or heteroaryl is optionally substituted; R 28 and R 29 are each independently H, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, cyano, nitro, C 3 -C 6 cycloalkyl, or C 2 -C 5 heterocycloalkyl, or R 28 and R 29 taken together with the carbon atom to which they are attached form a 3-6 membered ring; R 30 is selected from halogen, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -L 4 -cycloalkyl, -L 4 -heterocycloalkyl, -L 4 -aryl, -L 4 - heteroaryl, -OR 10 , -SR 10 , -N(R 10 )(R 10’ ), -C(O)OR 10 , -OC(O)N(R 10 )(R 10’ ), - N(R 10’ )C(O)N(R 10 )(R 10’ ), -N(R 10’ )C(O)OR 11 , -N(R 10’ )S(O) 2 R 11 , -C(O)R 11 , -S(O)R 11 , - OC(O)R 11 , -C(O)N(R 10 )(R 10’ ), -C(O)C(O)N(R 10 )(R 10’ ), -N(R 10’ )C(O)R 11 , -S(O) 2 R 11 , - S(O) 2 N(R 10 )(R 10’ )-, S(=O)(=NH)N(R 10 )(R 10’ ), -CH 2 C(O)N(R 10 )(R 10’ ), -CH 2 N(R 10’ )C(O)R 11 , - CH 2 S(O) 2 R 11 , or -CH 2 S(O) 2 N(R 10 )(R 10’ ), wherein each of the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted; R 33 is H, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, or C 3 -C 6 cycloalkyl, wherein each of the alkyl, heteroalkyl, and cycloalkyl is optionally substituted; each R 10 is independently selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -C 10 aryl, and C 1 -C 9 heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, C2-C9 heterocycloalkyl, C 6 -C 10 aryl, and C 1 -C 9 heteroaryl; each R 10’ is independently selected from hydrogen, C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl; and each R 11 is independently selected C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C2-C9 heterocycloalkyl, C 6 -C 10 aryl, and C 1 -C 9 heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, C2-C9 heterocycloalkyl, C 6 -C 10 aryl, and C 1 -C 9 heteroaryl. [0835] Embodiment 252: The KRAS protein of embodiment 251, wherein E 1 and E 2 are each independently N or CR 21 ; E 3 is CR 28 R 29 , C=CR 28 R 29 , C═O, C=S, or C=NR 28 ; J is N, NR 30 , or CR 30 ; M is N, NR 33 , or CR 33 ; is a single or double bond as necessary to give every atom its normal valence; R 21 is independently H, hydroxyl, cyano, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxyl, or C 1 -C 6 heteroalkyl, wherein each of the alkyl, alkoxy, and heteroalkyl is optionally substituted with one, two, or three groups selected from halogen, -CN, -NO2, amino, hydroxy, C 1 -C 6 alkyl, C1- C6 haloalkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, C 2 -C 5 heterocycloalkyl, C 6 -C 10 aryl, and C 1 -C 9 heteroaryl; R 22 is hydrogen, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, OR 22’ , N(R 22’ ) 2 , cycloalkyl, - C 1 -C 3 alkylene-cycloalkyl, heterocycloalkyl, -C 1 -C 3 alkylene-heterocycloalkyl, aryl, -C1- C 3 alkylene-aryl, heteroaryl, or -C 1 -C 3 alkylene-heteroaryl, wherein each of the alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three groups selected from halogen, -CN, -NO 2 , amino, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, and C 2 -C 5 heterocycloalkyl, and each R 22’ is independently H, C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, aryl, or heteroaryl, wherein each of the alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, and heteroaryl is optionally substituted with one, two, or three groups selected from halogen, -CN, -NO 2 , amino, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, C 2 -C 5 heterocycloalkyl, C 6 -C 10 aryl, and C 1 -C 9 heteroaryl; or two R 22’ together with the nitrogen atom to which they are attached, form an optionally substituted 3-7- membered ring with one, two, or three groups selected from halogen, -CN, -NO 2 , amino, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, C 2 -C 5 heterocycloalkyl, C 6 -C 10 aryl, and C 1 -C 9 heteroaryl; R 23 is hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -L 4 -cycloalkyl, -L 4 -heterocycloalkyl, -L 4 -aryl, or -L 4 - heteroaryl, wherein each of the alkyl, alkoxy, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, and heteroaryl is optionally substituted with one, two, or three groups selected from halogen, -CN, -NO 2 , amino, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, C 2 -C 5 heterocycloalkyl, C 6 -C 10 aryl, and C 1 -C 9 heteroaryl; L 4 is C 1 -C 4 alkylene or C 1 -C 4 heteroalkylene, each of which is optionally substituted with one, two, or three groups selected from halogen, -CN, -NO2, amino, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, C 2 -C 5 heterocycloalkyl, C 6 -C 10 aryl, and C 1 -C 9 heteroaryl; ring A is an optionally substituted 4-7 membered monocyclic ring or optionally substituted 6-11 membered bicyclic, bridged, fused, or spiro ring each of which is optionally substituted with one, two, or three groups selected from halogen, -CN, -NO 2 , amino, hydroxy, C 1 -C 6 alkyl, C 1 - C6 haloalkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, C 2 -C 5 heterocycloalkyl, C 6 -C 10 aryl, and C 1 -C 9 heteroaryl; R 1 is H, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted C 3 -C 6 cycloalkyl, or optionally substituted C 2 -C 5 heterocycloalkyl each of which is optionally substituted with one, two, or three groups selected from halogen, -CN, -NO 2 , amino, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, C 2 -C 5 heterocycloalkyl, C 6 -C 10 aryl, and C 1 -C 9 heteroaryl; L is a bond, S, O, or NR 10’ , optionally substituted C 1 -C 6 alkylene, or optionally substituted C 1 -C 6 heteroalkylene with one, two, or three groups selected from halogen, -CN, -NO 2 , amino, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, C 2 -C 5 heterocycloalkyl, C 6 -C 10 aryl, and C 1 -C 9 heteroaryl; E represents a structure of Formula , wherein, X is C(=O), P(=O)OR 2 , C(=S), or S(=O) n , where n is 1 or 2; R 2 is H or substituted or unsubstituted C 1 -C 3 alkyl, wherein the alkyl is optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 alkoxy, C 3 -C 6 cycloalkyl, and C 2 -C 5 heterocycloalkyl, C 6 -C 10 aryl, and C 1 -C 9 heteroaryl; R 5 is hydrogen, cyano, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxyl, C 1 -C 6 heteroalkyl, C 3 -C 6 cycloalkyl, or C 2 -C 5 heterocycloalkyl, each of the alkyl, alkoxyl, heteroalkyl, cycloalkyl or heterocycloalkyl is optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, C 2 -C 5 heterocycloalkyl, C 6 -C 10 aryl, and C 1 -C 9 heteroaryl; R 7 is hydrogen, cyano, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxyl, C 1 -C 6 heteroalkyl, C 3 -C 6 cycloalkyl, C 2 -C 5 heterocycloalkyl, heteroaryl, -C 1 -C 6 alkylene-heteoraryl, -C 1 -C 6 alkylene-NH(C 1 -C 6 alkyl), or -C 1 -C 6 alkylene-N(C 1 -C 6 alkyl)2, each of the alkyl, alkylene, alkoxyl, heteroalkyl, cycloalkyl or heterocycloalkyl is optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, C 2 -C 5 heterocycloalkyl, C 6 -C 10 aryl, and C 1 -C 9 heteroaryl; or R 5 and R 7 taken together form a bond; or R 5 and R 7 taken together with the carbon atoms to which they are attached form a 5-8 membered partially saturated cycloalkyl, wherein the cycloalkyl is optionally substituted with one, two or three groups selected from R 17 ; R 6 is hydrogen, cyano, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxyl, C 1 -C 6 heteroalkyl, C 3 -C 6 cycloalkyl, C 2 -C 5 heterocycloalkyl, heteroaryl, -C 1 -C 6 alkylene-heteoraryl, -C 1 -C 6 alkylene-NH(C 1 -C 6 alkyl), or -C 1 -C 6 alkylene-N(C 1 -C 6 alkyl)2, each of the alkyl, alkylene, alkoxyl, heteroalkyl, cycloalkyl, heterocycloalkyl, or heteroaryl is optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C3- C6 cycloalkyl, C 2 -C 5 heterocycloalkyl, C 6 -C 10 aryl, and C 1 -C 9 heteroaryl; each R 17 is independently halogen, hydroxyl, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, amino, cyano, C 1 -C 6 heteroalkyl, C 1 -C 6 hydroxyalkyl, -O-C 1 -C 6 haloalkyl, or -S-C1- C 6 haloalkyl; R 28 and R 29 are each independently H, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, cyano, nitro, C 3 -C 6 cycloalkyl, or C 2 -C 5 heterocycloalkyl, or R 28 and R 29 taken together with the carbon atom to which they are attached form a 3-6 membered ring; R 30 is selected from halogen, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -L 4 -cycloalkyl, -L 4 -heterocycloalkyl, -L 4 -aryl, -L 4 - heteroaryl, -OR 10 , -SR 10 , -N(R 10 )(R 10’ ), -C(O)OR 10 , -OC(O)N(R 10 )(R 10’ ), - N(R 10’ )C(O)N(R 10 )(R 10’ ), -N(R 10’ )C(O)OR 11 , -N(R 10’ )S(O) 2 R 11 , -C(O)R 11 , -S(O)R 11 , - OC(O)R 11 , -C(O)N(R 10 )(R 10’ ), -C(O)C(O)N(R 10 )(R 10’ ), -N(R 10’ )C(O)R 11 , -S(O) 2 R 11 , - S(O) 2 N(R 10 )(R 10’ )-, S(=O)(=NH)N(R 10 )(R 10’ ), -CH 2 C(O)N(R 10 )(R 10’ ), -CH 2 N(R 10’ )C(O)R 11 , - CH 2 S(O) 2 R 11 , or -CH 2 S(O) 2 N(R 10 )(R 10’ ), wherein each of the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, C 2 -C 5 heterocycloalkyl, C 6 -C 10 aryl, and C 1 -C 9 heteroaryl; R 33 is H, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, or C 3 -C 6 cycloalkyl, wherein each of the alkyl, heteroalkyl, and cycloalkyl is optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, C 2 -C 5 heterocycloalkyl, C 6 -C 10 aryl, and C 1 -C 9 heteroaryl; each R 10 is independently selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C2-9heterocycloalkyl, C 6 -C 10 aryl, and C 1 -C 9 heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, C2-C9 heterocycloalkyl, C 6 -C 10 aryl, and C 1 -C 9 heteroaryl; each R 10’ is independently selected from hydrogen, C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl; and each R 11 is independently selected C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C2-C9 heterocycloalkyl, C 6 -C 10 aryl, and C 1 -C 9 heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, C2-C9 heterocycloalkyl, C 6 -C 10 aryl, and C 1 -C 9 heteroaryl. [0836] Embodiment 253: The KRAS protein of embodiment 251 or 252, wherein at least one of R 21 , R 22 , R 23 , R 24 , and R 30 comprises the covalently bonded radioisotope. [0837] Embodiment 254: The KRAS protein of any one of embodiments 251 to 253, wherein the covalently bonded radioisotope is R* and R* is fluorine-18 ( 18 F), iodine-131 ( 131 I), iodine-123 ( 123 I), iodine-124 ( 124 I), iodine-125 ( 125 I), or astatine-211 ( 211 At). [0838] Embodiment 255: The KRAS protein of any one of embodiments 251 to 253, wherein the covalently bonded radioisotope is R* and R* is iodine-131 ( 131 I). [0839] Embodiment 256: The KRAS protein of embodiment 251 to 255, wherein the radiolabeled compound comprises a structure of Formula (IVa), or a salt or solvate thereof, Formula (IVa). [0840] Embodiment 257: The KRAS protein of any one of embodiments 251 to 256, wherein the radiolabeled compound comprises a structure of Formula (IVb), or a salt or solvate thereof, Formula (IVb). [0841] Embodiment 258: The KRAS protein of any one of embodiments 251 to 256, wherein the radiolabeled compound comprises a structure of Formula (IVc), or a salt or solvate thereof, Formula (IVc). [0842] Embodiment 259: The KRAS protein of any one of embodiments 251 to 258, wherein each R 21 is independently H, hydroxyl, cyano, halogen, C 1 -C 6 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxyl, or C 1 - C 4 heteroalkyl. [0843] Embodiment 260: The KRAS protein of any one of embodiments 251 to 259, wherein R 21 is H. [0844] Embodiment 261: The KRAS protein of any one of embodiments 251 to 260, wherein R 22 is halogen, C 1 -C 6 alkyl, C 2 -C 3 alkenyl, C 2 -C 3 alkynyl, OR 22’ , N(R 22’ )2, C 3 -C 6 cycloalkyl, C2- C5heterocycloalkyl, C 6 -C 14 aryl, or C2-C14heteroaryl, each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted, and each R 22’ is independently H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 5 heterocycloalkyl, C 2 -C 3 alkenyl, C2- C3alkynyl, C 6 -C 14 aryl, C2-C14heteroaryl, wherein each of the alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, and heteroaryl is optionally substituted, or two R 22’ together with the nitrogen atom to which they are attached, form an optionally substituted 3-7-membered ring. [0845] Embodiment 262: The KRAS protein of any one of embodiments 251 to 261, wherein R 22 is C6- C14aryl or C2-C14heteroaryl, each of which is optionally substituted. [0846] Embodiment 263: The KRAS protein of any one of embodiments 251 to 262, wherein R 22 is phenyl, optionally substituted with one or more substituents selected from C 1 -C 3 alkyl, halogen, and hydroxyl. [0847] Embodiment 264: The KRAS protein of any one of embodiments 251 to 262, wherein R 22 is bicyclic heteroaryl, optionally substituted with one or more substituents selected from C1- C3alkyl, halogen, and hydroxyl. [0848] Embodiment 265: The KRAS protein of any one of embodiments 251 to 262, wherein R 22 comprises a covalently bonded radioisotope R*. [0849] Embodiment 266: The KRAS protein of embodiment 265, wherein R 22 is , and R* is 1 31 I. [0850] Embodiment 267: The KRAS protein of any one of embodiments 251 to 266, wherein R 23 is H, halogen, C 1 -C 6 alkyl, C 1 -C 3 alkoxy, C 3 -C 6 cycloalkyl, C 2 -C 5 heterocycloalkyl, C 2 -C 3 alkenyl, C 2 - C 3 alkynyl, C 6 -C 14 aryl, or C 2 -C 14 heteroaryl, wherein each of the alkyl, alkoxy, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, and heteroaryl is optionally substituted. [0851] Embodiment 268: The KRAS protein of any one of embodiments 251 to 267, wherein R 23 is halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl. [0852] Embodiment 269: The KRAS protein of any one of embodiments 251 to 268, wherein R 23 is halogen and the halogen is a radioisotope selected from fluorine-18 ( 18 F), iodine-131 ( 131 I), iodine-123 ( 123 I), iodine-124 ( 124 I), iodine-125 ( 125 I), and astatine-211 ( 211 At). [0853] Embodiment 270: The KRAS protein of any one of embodiments 251 to 269, wherein R 23 is 131 I. [0854] Embodiment 271: The KRAS protein of any one of embodiments 251 to 255 or 259 to 270, wherein R 24 is . [0855] Embodiment 272: The KRAS protein of any one of embodiments 251 to 271, wherein ring A is an optionally substituted 4-7 membered monocyclic ring. [0856] Embodiment 273: The KRAS protein of any one of embodiments 251 to 272, wherein ring A is an optionally substituted 6 membered heterocyclic ring. [0857] Embodiment 274: The KRAS protein of any one of embodiments 251 to 273, wherein ring A is piperazinyl substituted with one to three substituents selected from halogen and C 1 -C 3 alkyl. [0858] Embodiment 275: The KRAS protein of any one of embodiments 251 to 274, wherein L is a bond, C 1 -C 3 alkylene, S, O, or NH. [0859] Embodiment 276: The KRAS protein of any one of embodiments 251 to 275, wherein L is a bond, CH2, O, or NH. [0860] Embodiment 277: The KRAS protein of any one of embodiments 251 to 276, wherein L is a bond. [0861] Embodiment 278: The KRAS protein of any one of embodiments 251 to 277, wherein X is C(=O). [0862] Embodiment 279: The KRAS protein of any one of embodiments 251 to 278, wherein R 5 is hydrogen, cyano, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxyl, C 1 -C 6 heteroalkyl, C 3 -C 6 cycloalkyl, or C 2 -C 5 heterocycloalkyl, wherein each of the alkyl, alkoxy, heteroalkyl, cycloalkyl and heterocycloalkyl is optionally substituted. [0863] Embodiment 280: The KRAS protein of any one of embodiments 251 to 279, wherein R 5 is hydrogen, halogen, or a C 1 -C 3 alkyl optionally substituted by one or more hydroxyl and/or halogen. [0864] Embodiment 281: The KRAS protein of embodiment 280, wherein R 5 is a halogen. [0865] Embodiment 282: The KRAS protein of embodiment 280, wherein R 5 is a fluorine. [0866] Embodiment 283: The KRAS protein of embodiment 280, wherein R 5 is a hydrogen. [0867] Embodiment 284: The KRAS protein of any one of embodiments 251 to 283, wherein R 7 is hydrogen, cyano, halogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 alkoxyl, or optionally substituted C 1 -C 6 heteroalkyl. [0868] Embodiment 285: The KRAS protein of any one of embodiments 251 to 284, wherein R 7 is hydrogen. [0869] Embodiment 286: The KRAS protein of any one of embodiments 251 to 278, wherein R 5 and R 7 taken together with the carbon atoms to which they are attached form a 5-8 membered partially saturated cycloalkyl, wherein the cycloalkyl is optionally substituted with one or more R 17 , wherein each R 17 is independently halogen, hydroxyl, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, amino, cyano, C 1 -C 6 heteroalkyl, C 1 -C 6 hydroxyalkyl, -O-C 1 - C 6 haloalkyl, or -S-C 1 -C 6 haloalkyl. [0870] Embodiment 287: The KRAS protein of any one of embodiments 251 to 286, wherein R 6 is hydrogen, cyano, halogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 alkoxyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted C 3 -C 6 cycloalkyl, or optionally substituted C 2 -C 6 heterocycloalkyl. [0871] Embodiment 288: The KRAS protein of any one of embodiments 251 to 287, wherein R 6 is hydrogen. [0872] Embodiment 289: The KRAS protein of any one of embodiments 251 to 255 or 259 to 288, wherein E 3 is C=O. [0873] Embodiment 290: The KRAS protein of any one of embodiments 251 to 289, wherein R 30 is halogen, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -L 4 -cycloalkyl, -L 4 -heterocycloalkyl, -L 4 -aryl, -L 4 -heteroaryl, -OR 10 , -SR 10 , wherein each of the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted. [0874] Embodiment 291: The KRAS protein of any one of embodiments 251 to 290, wherein R 30 is C 6 - C14aryl, optionally substituted with one or more substituents selected from halogen, C 1 -C 3 alkyl, C 1 -C 3 alkoxyl, and cyano. [0875] Embodiment 292: The KRAS protein of any one of embodiments 251 to 290, wherein R 30 is C 2 - C14heteroaryl, optionally substituted with one or more substituents selected from halogen, C1- C3alkyl, C 1 -C 3 alkoxyl, or cyano. [0876] Embodiment 293: The KRAS protein of any one of embodiments 251 to 290, wherein R 30 is phenyl or 6-membered heteroaryl, optionally substituted with one or more of C 1 -C 3 alkyl. [0877] Embodiment 294: The KRAS protein of any one of embodiments 251 to 255 or 259 to 293, wherein R 33 is H or C 1 -C 6 alkyl. [0878] Embodiment 295: The KRAS protein of any one of embodiments 251 to 258, wherein the radiolabeled compound has a structure of , [0879] Embodiment 296: The KRAS protein of any one of embodiments 251-264, 267, or 271-294, wherein the radiolabeled compound comprises: a) the structure of Formula (IV) or a salt or solvate thereof; b) the covalently bonded radioisotope; and c) a linker covalently bonded to the structure of Formula (IV) or a salt or solvate thereof and to the radioisotope. [0880] Embodiment 297: The KRAS protein of embodiment 296, wherein the linker comprises C1-C10 alkylene or C1-C10 heteroalkylene, wherein the alkylene or heteroalkylene is optionally substituted with one or more substituents selected from halogen, amino, -OH, -NO2, oxo, -CN, C1-3 alkoxyl, C1-3 alkyl, C1-3 hydroxyalkyl, C1-3 aminoalkyl, and C1-3 haloalkyl. [0881] Embodiment 298: The KRAS protein of embodiment 297, wherein the linker comprises C 1 -C 6 alkylene. [0882] Embodiment 299: The KRAS protein of any one of embodiments 296 to 298, wherein the linker comprises one or more functional groups selected from: -O-, -S-, -S-S-, -C(=O)O-, -OC(=O)-, - C(=O)NR a -, -NR a C(=O)-, -S(=O)2NR a -, -NR a S(=O)2-, -NR a C(=O)NR a -, - NR a C(=O)O-, and - OC(=O)NR a -, wherein each R a is independently hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C3- C8cycloalkyl, C2-C9heterocycloalkyl, aryl, or heteroaryl. [0883] Embodiment 300: The KRAS protein of any one of embodiments 296 to 299, wherein the linker comprises , wherein each k1 and k2 is independently 0 or an integer selected from 1 to 10. [0884] Embodiment 301: The KRAS protein of any one of embodiments 296 to 300, wherein the linker comprises ,
. [0885] Embodiment 302: The KRAS protein of any one of embodiments 296 to 301, wherein the linker is a brush border enzyme-cleavable linker. [0886] Embodiment 303: The KRAS protein of any one of embodiments 296 to 301, wherein the linker is a hepatocyte-cleavable linker. [0887] Embodiment 304: The KRAS protein of any one of embodiments 296 to 301, wherein the linker is a cytochrome P450-substrate. [0888] Embodiment 305: The KRAS protein of any one of embodiments 296 to 301, wherein the linker is an esterase-cleavable linker. [0889] Embodiment 306: The KRAS protein of any one of embodiments 296 to 301, wherein the linker is a peptidase-cleavable linker. [0890] Embodiment 307: The KRAS protein of any one of embodiments 296 to 306, wherein the radiolabeled compound comprises a structure of Formula (Va), Formula (Vb), Formula (Vc), Formula (Vd), or Formula (Ve): Formula (Ve), wherein R* is fluorine-18 ( 18 F), iodine-131 ( 131 I), iodine-123 ( 123 I), iodine-124 ( 124 I), iodine-125 ( 125 I), or astatine-211 ( 211 At); and R a is hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C3-C8cycloalkyl, C2-C9heterocycloalkyl, aryl, or heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted. [0891] Embodiment 308: The KRAS protein of embodiment 307, wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with one or more substituents selected from halogen, amino, - OH, -NO2, oxo, -CN, C1-3 alkoxyl, C1-3 alkyl and C1-3 haloalkyl. [0892] Embodiment 309: The KRAS protein of embodiment 307, wherein the radiolabeled compound comprises a structure of . [0893] Embodiment 310: The KRAS protein of any one of embodiments 296 to 306, wherein the radiolabeled compound comprises a structure of Formula (IVd) wherein L C is a linker comprising 1 to 20 groups independently selected from -CR b R b -, -C(=O)-, -S(=O)-, -C(=O)NR a -, -NR a C(=O)-, -S(=O)2NR a -, -NR a S(=O)2-, -NR a C(=O)NR a -, - NR a C(=O)O-, - OC(=O)NR a -, arylene, heteroarylene; each R a is independently hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C3-C8cycloalkyl, C2- C9heterocycloalkyl, aryl, or heteroaryl; each R b is independently hydrogen, halogen, -CN, -NO2, -OR a , -SR a , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C3- C8cycloalkyl, C2-C9heterocycloalkyl, aryl, or heteroaryl; R* is fluorine-18 ( 18 F), iodine-131 ( 131 I), iodine-123 ( 123 I), iodine-124 ( 124 I), iodine-125 ( 125 I), or astatine-211 ( 211 At); R 22 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, -C 1 -C 3 alkylene-cycloalkyl, heterocycloalkyl, -C 1 -C 3 alkylene-heterocycloalkyl, aryl, -C 1 -C 3 alkylene-aryl, heteroaryl, or - C 1 -C 3 alkylene-heteroaryl, wherein each of the alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted; and E, ring A, L, R 21 , R 22 , R 23 , and R 30 have the meaning defined above in Formula (IV). [0894] Embodiment 311: The KRAS protein of 310, wherein the radiolabeled compound comprises a structure of Formula (IVe), Formula (IVe). [0895] Embodiment 312: The KRAS protein of embodiment 310 or 311, wherein L C comprises [0896] Embodiment 313: The KRAS protein of embodiment 310 or 311, wherein L C comprises , or , wherein Het is a 5-6 membered heteroaryl ring containing 1-2 heteroatoms independently selected from N, S, and O. [0897] Embodiment 314: The KRAS protein of any one of embodiments 143 to 313, wherein the radiolabeled compound is in contact with one or more amino acid residues of a KRAS protein Switch 2 binding pocket. [0898] Embodiment 315: A radiolabeled compound having a structure of Formula (III), or a salt or solvate thereof, Formula (III) wherein ring Q 1 is a 4-12 membered saturated or partially saturated monocyclic or bicyclic ring, wherein the monocyclic or bicyclic ring is optionally substituted; L 1 is a bond, -C(=O)-, O, S, NR 15 , optionally substituted C 1 -C 3 alkylene, optionally substituted C 1 -C 3 heteroalkylene; L 2 is a bond, -C(=O)-, O, S or NR 15 ; X is C(=O), P(=O)OR 2 , C(=S), or S(=O)n, where n is 1 or 2; R 2 is H or optionally substituted C 1 -C 3 alkyl; R 5 is hydrogen, cyano, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxyl, C 1 -C 6 heteroalkyl, C 3 -C 6 cycloalkyl, or C 2 -C 5 heterocycloalkyl, each of the alkyl, alkoxyl, heteroalkyl, cycloalkyl or heterocycloalkyl is optionally substituted, and R 7 is hydrogen, cyano, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxyl, C 1 -C 6 heteroalkyl, C 3 -C 6 cycloalkyl, C 2 -C 5 heterocycloalkyl, heteroaryl, -C 1 -C 6 alkylene-heteoraryl, -C 1 -C 6 alkylene-NH(C 1 -C 6 alkyl), or -C 1 -C 6 alkylene-N(C 1 -C 6 alkyl)2, each of the alkyl, alkylene, alkoxyl, heteroalkyl, cycloalkyl or heterocycloalkyl is optionally substituted; or R 5 and R 7 taken together form a bond; or R 5 and R 7 taken together with the carbon atoms to which they are attached form a 5-8 membered partially saturated cycloalkyl, wherein the cycloalkyl is optionally substituted; R 6 is hydrogen, cyano, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxyl, C 1 -C 6 heteroalkyl, C 3 -C 6 cycloalkyl, C 2 -C 5 heterocycloalkyl, heteroaryl, -C 1 -C 6 alkylene-heteoraryl, -C 1 -C 6 alkylene-NH(C 1 -C 6 alkyl), or -C 1 -C 6 alkylene-N(C 1 -C 6 alkyl)2, each of the alkyl, alkylene, alkoxyl, heteroalkyl, cycloalkyl, heterocycloalkyl, or heteroaryl is optionally substituted; R 12 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, -L 3 -NR 15 R 15’ , heterocycloalkyl, -L 3 - heterocycloalkyl, cycloalkyl, -L 3 -cycloalkyl, aryl, heteroaryl, -L 3 -aryl, or -L 3 -heteroaryl, wherein each of the heterocycloalkyl, cycloalkyl, aryl, heteroaryl, alkyl or heteroalkyl is optionally substituted; L 3 is C 1 -C 4 alkylene or C 1 -C 4 heteroalkylene, each of which is optionally substituted; each R 13 is independently OH, halogen, oxo, substituted or unsubstituted C 1 -C 6 alkyl, or substituted or unsubstituted C 1 -C 6 heteroalkyl; R 14 is hydrogen, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each of the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted; each R 15 is independently hydrogen or optionally substituted C 1 -C 3 alkyl; each R 15’ is independently hydrogen, acyl, optionally substituted C 1 -C 3 alkyl, optionally substituted C 1 -C 3 heteroalkyl or optionally substituted C 1 -C 3 hydroxyalkyl; and m is 0, 1, or 2; provided that at least one of L 1 , L 2 , R 12 , R 13 and R 14 comprises a covalently bonded radioisotope R*. [0899] Embodiment 316: A radiolabeled compound comprising (a) a structure of Formula (III), or a salt or solvate thereof, Formula (III) wherein ring Q 1 is a 4-12 membered saturated or partially saturated monocyclic or bicyclic ring, wherein the monocyclic or bicyclic ring is optionally substituted; L 1 is a bond, -C(=O)-, O, S, NR 15 , optionally substituted C 1 -C 3 alkylene, optionally substituted C 1 -C 3 heteroalkylene; L 2 is a bond, -C(=O)-, O, S or NR 15 ; X is C(=O), P(=O)OR 2 , C(=S), or S(=O)n, where n is 1 or 2; R 2 is H or optionally substituted C 1 -C 3 alkyl; R 5 is hydrogen, cyano, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxyl, C 1 -C 6 heteroalkyl, C 3 -C 6 cycloalkyl, or C 2 -C 5 heterocycloalkyl, each of the alkyl, alkoxyl, heteroalkyl, cycloalkyl or heterocycloalkyl is optionally substituted, and R 7 is hydrogen, cyano, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxyl, C 1 -C 6 heteroalkyl, C 3 -C 6 cycloalkyl, C 2 -C 5 heterocycloalkyl, heteroaryl, -C 1 -C 6 alkylene-heteoraryl, -C 1 -C 6 alkylene-NH(C 1 -C 6 alkyl), or -C 1 -C 6 alkylene-N(C 1 -C 6 alkyl) 2 , each of the alkyl, alkylene, alkoxyl, heteroalkyl, cycloalkyl or heterocycloalkyl is optionally substituted; or R 5 and R 7 taken together form a bond; or R 5 and R 7 taken together with the carbon atoms to which they are attached form a 5-8 membered partially saturated cycloalkyl, wherein the cycloalkyl is optionally substituted; R 6 is hydrogen, cyano, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxyl, C 1 -C 6 heteroalkyl, C 3 -C 6 cycloalkyl, C 2 -C 5 heterocycloalkyl, heteroaryl, -C 1 -C 6 alkylene-heteoraryl, -C 1 -C 6 alkylene-NH(C 1 -C 6 alkyl), or -C 1 -C 6 alkylene-N(C 1 -C 6 alkyl) 2 , each of the alkyl, alkylene, alkoxyl, heteroalkyl, cycloalkyl, heterocycloalkyl, or heteroaryl is optionally substituted; R 12 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, -L 3 -NR 15 R 15’ , heterocycloalkyl, -L 3 - heterocycloalkyl, cycloalkyl, -L 3 -cycloalkyl, aryl, heteroaryl, -L 3 -aryl, or -L 3 -heteroaryl, wherein each of the heterocycloalkyl, cycloalkyl, aryl, heteroaryl, alkyl or heteroalkyl is optionally substituted; L 3 is C 1 -C 4 alkylene or C 1 -C 4 heteroalkylene, each of which is optionally substituted; each R 13 is independently OH, halogen, oxo, substituted or unsubstituted C 1 -C 6 alkyl, or substituted or unsubstituted C 1 -C 6 heteroalkyl; R 14 is hydrogen, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each of the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted; each R 15 is independently hydrogen or optionally substituted C 1 -C 3 alkyl; each R 15’ is independently hydrogen, acyl, optionally substituted C 1 -C 3 alkyl, optionally substituted C 1 -C 3 heteroalkyl or optionally substituted C 1 -C 3 hydroxyalkyl; and m is 0, 1, or 2; (b) a covalently bonded radioisotope R*; and (c) a linker covalently connecting the radioisotope R* and the structure of Formula (III) or a salt or solvate thereof. [0900] Embodiment 317: The radiolabeled compound of 316, or a salt or solvate thereof, wherein the radiolabeled compound comprises a structure of Formula (IIIb) Formula (IIIb), wherein L C is a linker comprising 1 to 20 groups independently selected from -CR b R b -, -C(=O)-, -S(=O)-, -C(=O)NR a -, -NR a C(=O)-, -S(=O) 2 NR a -, -NR a S(=O) 2 -, -NR a C(=O)NR a -, - NR a C(=O)O-, - OC(=O)NR a -, arylene, heteroarylene; each R a is independently hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 2 - C 9 heterocycloalkyl, aryl, or heteroaryl; each R b is independently hydrogen, halogen, -CN, -NO 2 , -OR a , -SR a , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 - C 8 cycloalkyl, C 2 -C 9 heterocycloalkyl, aryl, or heteroaryl; each R 18 is independently halogen, oxo, C 1 -C 6 alkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, -CN, -C(O)OR 15 , -C(O)N(R 15 )(R 15’ ), -N(R 15 )(R 15’ ), or OR 15 , and wherein each of the alkyl, aminoalkyl, haloalkyl, alkenyl, alkynyl, or heteroalkyl is optionally substituted with one, two, or three groups selected from halogen, -CN, -NO 2 , amino, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, and C2- C5heterocycloalkyl; R 12 is C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, -L 3 -NR 15 -, heterocycloalkyl, -L 3 -heterocycloalkyl, cycloalkyl, -L 3 -cycloalkyl, aryl, heteroaryl, -L 3 -aryl, or -L 3 -heteroaryl, wherein each of the heterocycloalkyl, cycloalkyl, aryl, heteroaryl, alkyl or heteroalkyl is optionally substituted; m1 is 0, 1, 2, or 3; R* is fluorine-18 ( 18 F), iodine-131 ( 131 I), iodine-123 ( 123 I), iodine-124 ( 124 I), iodine-125 ( 125 I), or astatine-211 ( 211 At); and E, L 1 , L 2 , R 13 , R 14 , and m have the meaning defined above in Formula (III). [0901] Embodiment 318: The radiolabeled compound of embodiment 317, or a salt or solvate thereof, wherein the radiolabeled compound comprises a structure of Formula (IIIc), Formula (IIIc). [0902] Embodiment 319: The radiolabeled compound of embodiment 317 or 318, wherein L C comprises , [0903] Embodiment 320: The KRAS protein of embodiment 317 or 318, wherein L C comprises , wherein Het is a 5-6 membered heteroaryl ring containing 1-2 heteroatoms independently selected from N, S, and O. [0904] Embodiment 321: A radiolabeled compound comprising a structure of Formula (IV), or a salt or solvate thereof, Formula (IV) wherein E 1 and E 2 are each independently N or CR 21 ; E 3 is CR 28 R 29 , C=CR 28 R 29 , C═O, C=S, or C=NR 28 ; J is N, NR 30 , or CR 30 ; M is N, NR 33 , or CR 33 ; is a single or double bond as necessary to give every atom its normal valence; R 21 is independently H, hydroxyl, cyano, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxyl, or C 1 -C 6 heteroalkyl, wherein each of the alkyl, alkoxy, and heteroalkyl is optionally substituted; R 22 is hydrogen, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, OR 22’ , N(R 22’ ) 2 , cycloalkyl, - C 1 -C 3 alkylene-cycloalkyl, heterocycloalkyl, -C 1 -C 3 alkylene-heterocycloalkyl, aryl, -C 1 - C 3 alkylene-aryl, heteroaryl, or -C 1 -C 3 alkylene-heteroaryl, wherein each of the alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted, and each R 22’ is independently H, C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, aryl, or heteroaryl, wherein each of the alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, and heteroaryl is optionally substituted, or two R 22’ together with the nitrogen atom to which they are attached, form a 3-7-membered ring; R 23 is hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -L 4 -cycloalkyl, -L 4 -heterocycloalkyl, -L 4 -aryl, or -L 4 - heteroaryl, wherein each of the alkyl, alkoxy, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, and heteroaryl is optionally substituted; L 4 is C 1 -C 4 alkylene or C 1 -C 4 heteroalkylene, each of which is optionally substituted; ; ring A is an optionally substituted 4-7 membered monocyclic ring or optionally substituted 6-11 membered bicyclic, bridged, fused, or spiro ring; R 1 is H, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted C 3 -C 6 cycloalkyl, or optionally substituted C 2 -C 5 heterocycloalkyl; L is a bond, S, O, or NR 10’ , optionally substituted C 1 -C 6 alkylene, or optionally substituted C 1 -C 6 heteroalkylene; E represents a structure of Formula (Ic), wherein, X is C(=O), P(=O)OR 2 , C(=S), or S(=O) n , where n is 1 or 2; R 2 is H or optionally substituted C 1 -C 3 alkyl; R 5 is hydrogen, cyano, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxyl, C 1 -C 6 heteroalkyl, C 3 -C 6 cycloalkyl, or C 2 -C 5 heterocycloalkyl, each of the alkyl, alkoxyl, heteroalkyl, cycloalkyl or heterocycloalkyl is optionally substituted, and R 7 is hydrogen, cyano, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxyl, C 1 -C 6 heteroalkyl, C 3 -C 6 cycloalkyl, C 2 -C 5 heterocycloalkyl, heteroaryl, -C 1 -C 6 alkylene-heteoraryl, -C 1 -C 6 alkylene-NH(C 1 -C 6 alkyl), or -C 1 -C 6 alkylene-N(C 1 -C 6 alkyl) 2 , each of the alkyl, alkylene, alkoxyl, heteroalkyl, cycloalkyl or heterocycloalkyl is optionally substituted; or R 5 and R 7 taken together form a bond; or R 5 and R 7 taken together with the carbon atoms to which they are attached form a 5-8 membered partially saturated cycloalkyl, wherein the cycloalkyl is optionally substituted; R 6 is hydrogen, cyano, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxyl, C 1 -C 6 heteroalkyl, C 3 -C 6 cycloalkyl, C 2 -C 5 heterocycloalkyl, heteroaryl, -C 1 -C 6 alkylene-heteoraryl, -C 1 -C 6 alkylene-NH(C 1 -C 6 alkyl), or -C 1 -C 6 alkylene-N(C 1 -C 6 alkyl) 2 , each of the alkyl, alkylene, alkoxyl, heteroalkyl, cycloalkyl, heterocycloalkyl, or heteroaryl is optionally substituted; R 28 and R 29 are each independently H, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, cyano, nitro, C 3 -C 6 cycloalkyl, or C 2 -C 5 heterocycloalkyl, or R 28 and R 29 taken together with the carbon atom to which they are attached form a 3-6 membered ring; R 30 is selected from halogen, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -L 4 -cycloalkyl, -L 4 -heterocycloalkyl, -L 4 -aryl, -L 4 - heteroaryl, -OR 10 , -SR 10 , -N(R 10 )(R 10’ ), -C(O)OR 10 , -OC(O)N(R 10 )(R 10’ ), - N(R 10’ )C(O)N(R 10 )(R 10’ ), -N(R 10’ )C(O)OR 11 , -N(R 10’ )S(O)2R 11 , -C(O)R 11 , -S(O)R 11 , - OC(O)R 11 , -C(O)N(R 10 )(R 10’ ), -C(O)C(O)N(R 10 )(R 10’ ), -N(R 10’ )C(O)R 11 , -S(O)2R 11 , - S(O)2N(R 10 )(R 10’ )-, S(=O)(=NH)N(R 10 )(R 10’ ), -CH2C(O)N(R 10 )(R 10’ ), -CH2N(R 10’ )C(O)R 11 , - CH2S(O)2R 11 , or -CH2S(O)2N(R 10 )(R 10’ ), wherein each of the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted; R 33 is H, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, or C 3 -C 6 cycloalkyl, wherein each of the alkyl, heteroalkyl, and cycloalkyl is optionally substituted; each R 10 is independently selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C2-9heterocycloalkyl, C 6 -C 10 aryl, and C 1 -C 9 heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, C2-C9 heterocycloalkyl, C 6 -C 10 aryl, and C 1 -C 9 heteroaryl; each R 10’ is independently selected from hydrogen, C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl; and each R 11 is independently selected C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C2-C9 heterocycloalkyl, C 6 -C 10 aryl, and C 1 -C 9 heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, C 2 -C 9 heterocycloalkyl, C 6 -C 10 aryl, and C 1 -C 9 heteroaryl; provided that at least one of R 21 , R 22 , R 23 , R 24 , and R 30 comprises a covalently bonded radioisotope R*. [0905] Embodiment 322: A radiolabeled compound, comprising (a) a structure of Formula (IV), or a salt or solvate thereof, Formula (IV) wherein E 1 and E 2 are each independently N or CR 21 ; E 3 is CR 28 R 29 , C=CR 28 R 29 , C═O, C=S, or C=NR 28 ; J is N, NR 30 , or CR 30 ; M is N, NR 33 , or CR 33 ; is a single or double bond as necessary to give every atom its normal valence; R 21 is independently H, hydroxyl, cyano, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxyl, or C 1 -C 6 heteroalkyl, wherein each of the alkyl, alkoxyl, and heteroalkyl is optionally substituted; R 22 is hydrogen, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, OR 22’ , N(R 22’ )2, cycloalkyl, - C 1 -C 3 alkylene-cycloalkyl, heterocycloalkyl, -C 1 -C 3 alkylene-heterocycloalkyl, aryl, -C1- C3alkylene-aryl, heteroaryl, or -C 1 -C 3 alkylene-heteroaryl, wherein each of the alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted, and each R 22’ is independently H, C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, aryl, or heteroaryl, wherein each of the alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, and heteroaryl is optionally substituted, or two R 22’ together with the nitrogen atom to which they are attached, form a 3-7-membered ring; R 23 is hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -L 4 -cycloalkyl, -L 4 -heterocycloalkyl, -L 4 -aryl, or -L 4 - heteroaryl, wherein each of the alkyl, alkoxy, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, and heteroaryl is optionally substituted; L 4 is C 1 -C 4 alkylene or C 1 -C 4 heteroalkylene, each of which is optionally substituted; ring A is an optionally substituted 4-7 membered monocyclic ring or optionally substituted 6-11 membered bicyclic, bridged, fused, or spiro ring; R 1 is H, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted C 3 -C 6 cycloalkyl, or optionally substituted C 2 -C 5 heterocycloalkyl; L is a bond, S, O, or NR 10’ , optionally substituted C 1 -C 6 alkylene, or optionally substituted C 1 -C 6 heteroalkylene; E represents a structure of Formula (Ic), wherein, X is C(=O), P(=O)OR 2 , C(=S), or S(=O) n , where n is 1 or 2; R 2 is H or optionally substituted C 1 -C 3 alkyl; R 5 is hydrogen, cyano, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxyl, C 1 -C 6 heteroalkyl, C 3 -C 6 cycloalkyl, or C 2 -C 5 heterocycloalkyl, each of the alkyl, alkoxyl, heteroalkyl, cycloalkyl or heterocycloalkyl is optionally substituted, and R 7 is hydrogen, cyano, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxyl, C 1 -C 6 heteroalkyl, C 3 -C 6 cycloalkyl, C 2 -C 5 heterocycloalkyl, heteroaryl, -C 1 -C 6 alkylene-heteoraryl, -C 1 -C 6 alkylene-NH(C 1 -C 6 alkyl), or -C 1 -C 6 alkylene-N(C 1 -C 6 alkyl)2, each of the alkyl, alkylene, alkoxyl, heteroalkyl, cycloalkyl or heterocycloalkyl is optionally substituted; or R 5 and R 7 taken together form a bond; or R 5 and R 7 taken together with the carbon atoms to which they are attached form a 5-8 membered partially saturated cycloalkyl, wherein the cycloalkyl is optionally substituted; R 6 is hydrogen, cyano, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxyl, C 1 -C 6 heteroalkyl, C 3 -C 6 cycloalkyl, C 2 -C 5 heterocycloalkyl, heteroaryl, -C 1 -C 6 alkylene-heteoraryl, -C 1 -C 6 alkylene-NH(C 1 -C 6 alkyl), or -C 1 -C 6 alkylene-N(C 1 -C 6 alkyl)2, each of the alkyl, alkylene, alkoxyl, heteroalkyl, cycloalkyl, heterocycloalkyl, or heteroaryl is optionally substituted; R 28 and R 29 are each independently H, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, cyano, nitro, C 3 -C 6 cycloalkyl, or C 2 -C 5 heterocycloalkyl, or R 28 and R 29 taken together with the carbon atom to which they are attached form a 3-6 membered ring; R 30 is selected from halogen, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -L 4 -cycloalkyl, -L 4 -heterocycloalkyl, -L 4 -aryl, -L 4 - heteroaryl, -OR 10 , -SR 10 , -N(R 10 )(R 10’ ), -C(O)OR 10 , -OC(O)N(R 10 )(R 10’ ), - N(R 10’ )C(O)N(R 10 )(R 10’ ), -N(R 10’ )C(O)OR 11 , -N(R 10’ )S(O) 2 R 11 , -C(O)R 11 , -S(O)R 11 , - OC(O)R 11 , -C(O)N(R 10 )(R 10’ ), -C(O)C(O)N(R 10 )(R 10’ ), -N(R 10’ )C(O)R 11 , -S(O) 2 R 11 , - S(O)2N(R 10 )(R 10’ )-, S(=O)(=NH)N(R 10 )(R 10’ ), -CH2C(O)N(R 10 )(R 10’ ), -CH2N(R 10’ )C(O)R 11 , - CH 2 S(O) 2 R 11 , or -CH 2 S(O) 2 N(R 10 )(R 10’ ), wherein each of the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted; R 33 is H, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, or C 3 -C 6 cycloalkyl, wherein each of the alkyl, heteroalkyl, and cycloalkyl is optionally substituted; each R 10 is independently selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -C 10 aryl, and C 1 -C 9 heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, C 2 -C 9 heterocycloalkyl, C 6 -C 10 aryl, and C 1 -C 9 heteroaryl; each R 10’ is independently selected from hydrogen, C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl; and each R 11 is independently selected C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 2 -C 9 heterocycloalkyl, C 6 -C 10 aryl, and C 1 -C 9 heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, C 2 -C 9 heterocycloalkyl, C 6 -C 10 aryl, and C 1 -C 9 heteroaryl; (b) a covalently bonded radioisotope R*; and (c) a linker covalently connecting the radioisotope R* and the structure of Formula (IV) or a salt or solvate thereof . [0906] Embodiment 323: The radiolabeled compound of embodiment 322, or a salt or solvate thereof, wherein the radiolabeled compound comprises a structure of Formula (IVd)
wherein L C is a linker comprising 1 to 20 groups independently selected from -CR b R b -, -C(=O)-, -S(=O)-, -S(=O)2-, -NR a -, -CR b =CR b -, -C C-, -O-, -S-, -C(=O)O-, -OC(=O)-, -C(=O)NR a -, -NR a C(=O)-, -S(=O)2NR a -, -NR a S(=O)2-, -NR a C(=O)NR a -, - NR a C(=O)O-, - OC(=O)NR a -, arylene, heteroarylene; each R a is independently hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C3-C8cycloalkyl, C2- C9heterocycloalkyl, aryl, or heteroaryl; each R b is independently hydrogen, halogen, -CN, -NO2, -OR a , -SR a , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C3- C8cycloalkyl, C2-C9heterocycloalkyl, aryl, or heteroaryl; R 22 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, -C 1 -C 3 alkylene-cycloalkyl, heterocycloalkyl, -C 1 -C 3 alkylene-heterocycloalkyl, aryl, -C 1 -C 3 alkylene-aryl, heteroaryl, or - C 1 -C 3 alkylene-heteroaryl, wherein each of the alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted; R* is fluorine-18 ( 18 F), iodine-131 ( 131 I), iodine-123 ( 123 I), iodine-124 ( 124 I), iodine-125 ( 125 I), or astatine-211 ( 211 At); and E, ring A, L, R 21 , R 23 , and R 30 have the meaning defined above in Formula (IV). [0907] Embodiment 324: The radiolabeled compound of embodiment 323, or a salt or solvate thereof, wherein the radiolabeled compound comprises a structure of Formula (IVe),
Formula (IVe). [0908] Embodiment 325: The radiolabeled compound of embodiment 323 or 324 , wherein L C comprises , [0909] Embodiment 326: The KRAS protein of embodiment 323 or 324, wherein L C comprises , , , , , wherein Het is a 5-6 membered heteroaryl ring containing 1-2 heteroatoms independently selected from N, S, and O [0910] Embodiment 327: The radiolabeled compound of any one of embodiments 315 to 326, wherein R* is iodine-131 ( 131 I) or astatine-211 ( 211 At). [0911] Embodiment 328: The radiolabeled compound of any one of embodiments 315 to 327, wherein the radiolabeled compound is selected from Table 3A, Table 3B, Table 3C, or Table 3D. [0912] Embodiment 329: A pharmaceutical composition comprising a radiolabeled compound of any one of embodiments 315 to 328, and a pharmaceutically acceptable excipient or carrier. [0913] Embodiment 330: The pharmaceutical composition of embodiment 329, wherein the pharmaceutical composition is formulated for intravenous administration. [0914] Embodiment 331: A method of making a covalently modified KRAS protein in vivo, comprising administering a radiolabeled compound of any one of embodiments 315 to 328 or a pharmaceutical composition of embodiment 329 or 330 to a subject, wherein the subject has a KRAS protein comprising a glycine to cysteine amino acid substitution at residue 12. [0915] Embodiment 332: The method of embodiment 331, wherein the subject has cancer. [0916] Embodiment 333: A method of treating cancer in a subject in need thereof, comprising administering to the subject a radiolabeled compound of any one of embodiments 315 to 328 or a pharmaceutical composition of embodiment 329 or 330. [0917] Embodiment 334: The method of embodiment 332 or 333, wherein the cancer is KRAS G12C- associated cancer. [0918] Embodiment 335: The method of any one of embodiments 332 to 334, wherein the cancer is selected from the group consisting of Cardiac cancer: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; Lung cancer: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; Gastrointestinal cancer: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); Genitourinary tract cancer: kidney (adenocarcinoma, Wilm's tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma); Liver cancer: hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Biliary tract cancer: gall bladder carcinoma, ampullary carcinoma, cholangiocarcinoma; Bone cancer: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors; Nervous system cancer: skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal cord neurofibroma, meningioma, glioma, sarcoma); Gynecological cancer: uterus (endometrial 'carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tubes (carcinoma); Hematologic cancer: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma); Skin cancer: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis; and Adrenal glands cancer: neuroblastoma. [0919] Embodiment 336: The method of any one of embodiments 332 to 334, wherein the cancer is non-small cell lung cancer. [0920] Embodiment 337: A method of killing a cell harboring a G12C KRAS mutation in a subject, the method comprising making a covalently modified KRAS protein of any one of embodiments 142 to 314 in the subject. [0921] Embodiment 338: A method of killing a cell harboring a G12C KRAS mutation, the method comprising contacting a cell harboring a G12C KRAS mutation with a radiolabeled compound of any one of embodiments 315 to 328 or a pharmaceutical composition of embodiment 329 or 330, thereby delivering a dose of radiation to the cell. [0922] Embodiment 339: A method of delivering a radionuclide to a cell comprising administering a radiolabeled compound of any one of embodiments 315 to 328 or a pharmaceutical composition of embodiment 329 or 330. [0923] Embodiment 340: The method of embodiment 339, wherein the radiolabeled compound irreversibly binds to an intracellular protein of the cell. [0924] Embodiment 341: A method of diagnosing cancer patients harboring a G12C KRAS mutation comprising administering to a patient a radiolabeled compound of any one of embodiments 315 to 328 or a pharmaceutical composition of embodiment 329 or 330. [0925] Embodiment 342: A method of imaging a cancer harboring a G12C KRAS mutation comprising administering to a patient a radiolabeled compound of any one of embodiments 315 to 328 or a pharmaceutical composition of embodiment 329 or 330. [0926] Embodiment 343: The method of embodiment 341 or 342, further comprising measuring the concentration of the radiolabeled compound accumulated in the patient. [0927] Embodiment 344: The method of any one of embodiments 341 to 343, further comprising measuring the amount of radiation emitted from the radionuclide. [0928] Embodiment 345: The method of any one of embodiments 341 to 344, further comprising analyzing the elimination profile of the radiolabeled compound in the patient. [0929] Embodiment 346: The method of any one of embodiments 341 to 345, further comprising measuring an elimination half-life of the radiolabeled compound in the patient. [0930] Embodiment 347: A method of producing a compound having a structure of Formula (VIa), Formula (VIb), Formula (VIc), or Formula (VId) in vivo, comprising administering a radiolabeled compound of any one of embodiments 316 to 319 or 322 to 325 to a subject, Formula (VIa) Formula (VIb) Formula (VIc) Formula (VId) wherein R* is fluorine-18 ( 18 F), iodine-131 ( 131 I), iodine-123 ( 123 I), iodine-124 ( 124 I), iodine-125 ( 125 I), or astatine-211 ( 211 At). [0931] Embodiment 348: A method of excreting a compound having a structure of Formula (VIa), Formula (VIb), Formula (VIc), or Formula (VId) from a subject’s body, comprising administering a radiolabeled compound of any one of any one of embodiments 316 to 319 or 322 to 325 to a subject, Formula (VIa) Formula (VIb) Formula (VIc) Formula (VId) wherein R* is fluorine-18 ( 18 F), iodine-131 ( 131 I), iodine-123 ( 123 I), iodine-124 ( 124 I), iodine-125 ( 125 I), or astatine-211 ( 211 At). [0932] Embodiment 349: The method of embodiment 347 or 348, wherein the compound having a structure of Formula (VIa) is . [0933] Embodiment 350: The method of embodiment 347 or 348, wherein the compound having a structure of Formula (VIb) is . [0934] Embodiment 351: The method of embodiment 347 or 348, wherein the compound having a structure of Formula (VIc) is . [0935] Embodiment 352: The method of embodiment 347 or 348, wherein the compound having a structure of Formula (VId) is .
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