Prodrugs of CGRP antagonists

1. A compound having General Formula 1, comprising a CGRP Parent Molecule having at least one functionalizable moiety Z:

wherein:

the CGRP Parent Molecule having at least one functionalizable moiety Z is

Z is a functionalizable moiety present on the CGRP Parent Molecule;

m is at least 1;

R 1 is

or —CH 2 OP(═O)(OH) 2 ;

R 2 is —[C(R 3 ) 2 ] n R 4 , —NR 3 R 4 , or —OR 4 , wherein each R 3 is independently hydrogen or C1-C10 alkyl wherein R 3 are optionally connected to form a ring, and R 4 is a substituted or unsubstituted C1-C20 alkyl group, a substituted or unsubstituted C2-C20 alkenyl group, a substituted or unsubstituted C2-C20 alkynyl group, a substituted or unsubstituted C1-C20 heteroalkyl group, a substituted or unsubstituted C2-C20 heteroalkenyl group, a substituted or unsubstituted C2-C20 heteroalkynyl group, a substituted or unsubstituted C3-C20 cycloalkyl group, a substituted or unsubstituted C3-C20 heterocycloalkyl group, a substituted or unsubstituted C6-C20 aryl group, or a substituted or unsubstituted C1-C20 heteroaryl group, and n is 0 or 1,

wherein, when m is at least 2, R 2 are optionally connected to form a ring.

2. The compound according to claim 1 , having one of Formulae (I) to (IV):

wherein, in Formulae (I) to (IV),

each R 1 is independently H,

or —CH 2 OP(═O)(OH) 2 , provided that at least one R 1 is

or —CH 2 OP(═O)(OH) 2 ;

R 2 is —[C(R 3 ) 2 ] n R 4 , —NR 3 R 4 , or —OR 4 , wherein each R 3 is independently hydrogen or C1-C10 alkyl group, wherein R 3 are optionally connected to form a ring, and R 4 is a substituted or unsubstituted C1-C20 alkyl group, a substituted or unsubstituted C2-C20 alkenyl group, a substituted or unsubstituted C2-C20 alkynyl group, a substituted or unsubstituted C1-C20 heteroalkyl group, a substituted or unsubstituted C2-C20 heteroalkenyl group, a substituted or unsubstituted C2-C20 heteroalkynyl group, a substituted or unsubstituted C3-C20 cycloalkyl group, a substituted or unsubstituted C3-C20 heterocycloalkyl group, or a substituted or unsubstituted C6-C20 aryl group, or a substituted or unsubstituted C1-C20 heteroaryl group, and n is 0 or 1,

wherein, when each R 1 is

R 2 are optionally connected to form a ring.

3. The compound according to claim 2 , wherein, in Formulae (I) and (II), each R 1 is

4. The compound according to claim 2 , wherein at least one R 3 is not hydrogen.

5. The compound according to claim 2 , wherein at least one R 3 is a methyl group.

6. The compound according to claim 2 , wherein each R 3 is not hydrogen.

7. The compound according to claim 2 , wherein each R 3 is a methyl group.

8. The compound according to claim 2 , wherein R 4 is each independently a substituted or unsubstituted C1-C10 alkyl group, a substituted or unsubstituted C2-C10 alkenyl group, a substituted or unsubstituted C2-C10 alkynyl group, a substituted or unsubstituted C1-C10 heteroalkyl group, a substituted or unsubstituted C2-C10 heteroalkenyl group, a substituted or unsubstituted C2-C10 heteroalkynyl group, a substituted or unsubstituted C3-C10 cycloalkyl group, a substituted or unsubstituted C3-C10 heterocycloalkyl group, a substituted or unsubstituted C6-C10 aryl group, or a substituted or unsubstituted C1-C10 heteroaryl group.

9. The compound according to claim 2 , wherein Formula (I) is represented by one of Formulae (Ia), (Ib), and (Ic), and wherein Formula (II) is represented by one of Formulae (IIa), (IIb), and (IIc):

wherein, in Formulae (Ia), (Ib), (Ic), (IIa), and (IIb), R 2 is the same as that in claim 1 .

10. The compound according to claim 9 , wherein, in Formulae (Ic) and (IIb), R 2 are connected with a single bond to form a linking group L, as in Formulae (Id) and (IIc), respectively

wherein, L is a substituted or unsubstituted C1-C10 alkylene group, a substituted or unsubstituted C2-C10 alkenylene group, a substituted or unsubstituted C2-C10 alkynylene group, a substituted or unsubstituted C1-C10 heteroalkylene group, a substituted or unsubstituted C2-C10 heteroalkenylene group, a substituted or unsubstituted C2-C10 heteroalkynylene group, a substituted or unsubstituted C3-C10 cycloalkylene group, a substituted or unsubstituted C3-C10 heterocycloalkylene group, a substituted or unsubstituted C6-C10 arylene group, or a substituted or unsubstituted C1-C10 heteroarylene group, or any combination thereof.

11. The compound according to claim 10 , wherein the linking group L is:

wherein

L 1 is a substituted or unsubstituted C1-C10 alkylene group, a substituted or unsubstituted C2-C10 alkenylene group, a substituted or unsubstituted C2-C10 alkynylene group, a substituted or unsubstituted C1-C10 heteroalkylene group, a substituted or unsubstituted C2-C10 heteroalkenylene group, a substituted or unsubstituted C2-C10 heteroalkynylene group, a substituted or unsubstituted C3-C10 cycloalkylene group, a substituted or unsubstituted C3-C10 heterocycloalkylene group, a substituted or unsubstituted C6-C10 arylene group, or a substituted or unsubstituted C1-C10 heteroarylene group, and

R 5 and R 6 are each independently hydrogen or C1-C10 alkyl, wherein two R 5 and two R 6 are optionally connected to form a ring.

12. The compound according to claim 11 , wherein at least one R 5 is not hydrogen and at least one R 6 is not hydrogen.

13. The compound according to claim 11 , wherein at least one R 5 is a methyl group and at least one R 6 is a methyl group.

14. The compound according to claim 11 , wherein each R 5 is not hydrogen and each R 6 is not hydrogen.

15. The compound according to claim 11 , wherein each R 5 is a methyl group and each R 6 is a methyl group.

16. The compound according to claim 2 , wherein Formula (III) is represented by one of Formulae (IIIa), (IIIb), (IIIc), and (IIId), and wherein Formula (IV) is represented by one of Formulae (IVa) and (IVb):

wherein, in Formulae (IIIa), (IIIb), (IIIc), (IIId), (IVa), and (IVb), R 2 is the same as that in claim 1 .

17. The compound according to claim 16 , wherein, in Formulae (IIId) and (IVb), R 2 are connected with a single bond to form a linking group L, as in Formulae (IIIe) and (IVc), respectively:

wherein, in Formulae (IIIe) and (IVc), R 2 is the same as that in claim 1 .

18. The compound according to claim 10 , wherein the linking group is:

wherein

L 1 is a substituted or unsubstituted C1-C10 alkylene group, a substituted or unsubstituted C2-C10 alkenylene group, a substituted or unsubstituted C2-C10 alkynylene group, a substituted or unsubstituted C1-C10 heteroalkylene group, a substituted or unsubstituted C2-C10 heteroalkenylene group, a substituted or unsubstituted C2-C10 heteroalkynylene group, a substituted or unsubstituted C3-C10 cycloalkylene group, a substituted or unsubstituted C3-C10 heterocycloalkylene group, a substituted or unsubstituted C6-C10 arylene group, or a substituted or unsubstituted C1-C10 heteroarylene group, and

R 5 and R 6 are each independently hydrogen or C1-C10 alkyl wherein R 3 are optionally connected to form a ring.

19. A pharmaceutical composition comprising a therapeutically effective amount of a compound in accordance with claim 1 .

20. A kit for treating a condition associated with aberrant levels of CGRP in a patient, the kit comprising:

(a) a pharmaceutical composition comprising a therapeutically effective amount of a compound in accordance with claim 1 ; and

(b) instructions for administering the pharmaceutical composition.