Methods and reagents for radiolabeling

Patent metadata

Field	Value
Publication number	US-9994573-B2
Application number	US-201415107229-A
Country	US
Kind code	B2
Filing date	Dec 23, 2014
Priority date	Dec 23, 2013
Publication date	Jun 12, 2018
Grant date	Jun 12, 2018

Abstract

The present invention provides methods for radiolabeling compounds useful as Hsp90 inhibitors. The present invention also provides intermediates useful in such methods, and compositions of radiolabeled compounds. The present invention provides, among other things, novel methods for the synthesis of radiolabeled compounds. In certain embodiments, the present invention provides compounds of formula I.

First claim

What is claimed is:

1. A compound of formula I:

wherein:
X is —CH 2 —, —O—, or —S—;
Y 1 and Y 2 are independently —CR 3a — or —N—;
Z 1 , Z 2 , and Z 3 are independently —CH— or —N—;
R 1 is hydrogen or halogen;
L is a straight or branched, C 2-14 aliphatic group wherein one or more carbons are optionally and independently replaced by -Cy-, —N(R)C(O)—, —C(O)N(R)—, —C(O)N(O)—, —N(R)SO 2 —, —SO 2 N(R)—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —SO—, or —SO 2 —, or wherein one or more carbons are independently replaced by —NR—, wherein R is other than a -Boc protecting group;
each -Cy- is independently an optionally substituted 3-8 membered bivalent, saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an optionally substituted 8-10 membered bivalent saturated, partially unsaturated, or aryl bicyclic ring having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
R 2 is hydrogen or an optionally substituted group selected from the group consisting of C 1-6 aliphatic, phenyl, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 7- to 10-membered saturated or partially unsaturated bicyclic carbocyclyl, 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 7- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, or 8- to 10-membered bicyclic aryl;
each R 3 is independently halogen, —NO 2 , —CN, —OR, —SR, —N(R) 2 , —C(O)R, —CO 2 R, —C(O)C(O)R, —C(O)CH 2 C(O)R, —S(O)R, —S(O) 2 R, —C(O)N(R) 2 , —SO 2 N(R) 2 , —OC(O)R, —N(R)C(O)R, —N(R)N(R) 2 , or optionally substituted C 1-6 aliphatic or pyrrolyl; or
two R 3 groups are taken together with their intervening atoms to form Ring A, wherein Ring A is a 3- to 7-membered partially unsaturated carbocyclyl, phenyl, a 5- to 6-membered partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, or 6-membered aryl;

R 3a is R 3 or hydrogen;
R 4 is C 1-4 alkyl;
each R is independently hydrogen or an optionally substituted group selected from C 1-6 aliphatic, phenyl, 3- to 7-membered saturated or partially unsaturated carbocyclyl, 3- to 7- membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur, or 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, or:
two R groups on the same nitrogen are taken together with their intervening atoms to form an optionally substituted ring selected from 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur, or 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur.

2. The compound of claim 1 , wherein the compound is of formula I-a-1 or I-a:

3. The compound of claim 1 , wherein the compound is of formula I-b, I-c, I-d, I-e, I-f, I-g, I-h, or I-j:

4. The compound of claim 1 , wherein X is —S—.

5. The compound of claim 1 , wherein -L-R 2 comprises a methylene that is replaced with —NH— to form a secondary amine.

6. The compound of claim 1 , wherein L is a straight or branched, C 2-14 aliphatic group wherein a methylene of the aliphatic group is replaced with —NH— to form a secondary amine.

7. The compound of claim 1 , wherein L is a straight or branched, C 2-10 aliphatic group wherein a methylene of the aliphatic group is replaced with —NH— to form a secondary amine.

8. The compound of claim 7 , wherein L is a straight or branched, C 2-8 aliphatic group wherein a methylene of the aliphatic group is replaced with —NH— to form a secondary amine.

9. The compound of claim 1 , wherein R 4 is methyl.

10. The compound of claim 1 , wherein R 4 is butyl.

11. The compound of claim 1 , wherein -L-R 2 is selected from the following:

12. The compound of claim 11 , wherein -L-R 2 is selected from the following:

13. The compound of claim 1 , wherein the compound is selected from:

14. The compound of claim 13 , wherein the compound is:

15. The compound of claim 1 , wherein X is —CH 2 —.

16. The compound of claim 1 , wherein Y 1 is —CR 3a —.

17. The compound of claim 1 , wherein Y 2 is —CR 3a —.

18. The compound of claim 1 , wherein R 1 is hydrogen.

19. The compound of claim 1 , wherein R 1 is fluoro.

20. The compound of claim 1 , wherein R 2 is optionally substituted C 1-6 aliphatic.

21. The compound of claim 4 , wherein Y 1 is —CR 3a —.

22. The compound of claim 21 , wherein Y 2 is —CR 3a —.

23. The compound of claim 22 , wherein each R 3a is hydrogen.

24. The compound of claim 23 , wherein Z 1 , Z 2 , and Z 3 are N.

25. The compound of claim 24 , wherein R l is hydrogen.

26. The compound of claim 25 , wherein —L-R 2 is selected from the following:

27. The compound of claim 26 , wherein R 4 is methyl.

Assignees

• Memorial Sloan Kettering Cancer Center

Inventors

• Ochiana Stefan O
• Pillarsetty Nagavarakishore
• Taldone Tony
• Chiosis Gabriela

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• C07B59/002

  Heterocyclic compounds · CPC title

• C07D473/34 Primary

  attached in position 6, e.g. adenine · CPC title

• C07F7/2208

  Compounds having tin linked only to carbon, hydrogen and/or halogen · CPC title

• C07B2200/05

  Isotopically modified compounds, e.g. labelled · CPC title