Sulfhydantoins as phosphate isosteres
AssigneeVertex Pharmaceuticals Incorporated
InventorsJeffrey O. Saunders, Gregory F. Miknis, James F. Blake
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Abstract
The present invention relates to novel phosphate isosteres. The invention relates to compounds having a sulfhydantoin or a reverse sulfhydantoin moiety, uses thereof, and related methods. The present invention relates to compounds of formula I or II: 1 or pharmaceutically acceptable salts thereof; wherein Q, T, m, and X are as described herein. These compounds are inhibitors of phosphatases, particularly inhibitors of SHP-2. The invention also provides pharmaceutically acceptable compositions comprising the compounds of the invention and methods of utilizing these compounds and compositions in the treatment of various phosphatase-mediated diseases.
Claims74
A compound of formula (I):
- 32
- or a pharmaceutically acceptable salt thereof, wherein:
- Q is an optionally substituted group selected from C1-8 aliphatic, C6-10 aryl, heteroaryl having 5-10 ring atoms, and heterocyclyl having 3-10 ring atoms;
- T is selected from a C1-6 alkylidene chain wherein one or two non-adjacent methylene units of T are optionally and independently replaced by —O—, —NR—, —S—, —C(O)—, —C(O)NR—, —NRC(O)—, —NRC(O)NR—, —SO—, —SO2—, —NRSO2—, —SO2NR—, or —NRSO2NR—;
- m is selected from zero or one;
- X is selected from —CH2—, —C(O)—, or —CF2—;
- and
- each R is independently selected from hydrogen or an optionally substituted C1-8 aliphatic group, or two R groups bound to the same nitrogen are taken together with the nitrogen to form a 3-7 membered heterocyclic ring having 0-2 heteroatoms in addition to the nitrogen, wherein said heteroatoms are independently selected from nitrogen, oxygen, or sulfur.
A compound of formula (II):
- 34
- or a pharmaceutically acceptable salt thereof, wherein:
- Q is an optionally substituted group selected from C1-8 aliphatic, C6-10 aryl, heteroaryl having 5-10 ring atoms, and heterocyclyl having 3-10 ring atoms;
- T is selected from a C1-6 alkylidene chain wherein one or two non-adjacent methylene units of T are optionally and independently replaced by —O—, —NR—, —S—, —C(O)—, —C(O)NR—, —NRC(O)—, —NRC(O)NR—, —SO—, —SO2—, —NRSO2—, —SO2NR—, or —NRSO2NR—;
- m is selected from zero or one;
- X is selected from —CH2—, —C(O)—, or —CF2—;
- and
- each R is independently selected from hydrogen or an optionally substituted C18 aliphatic group, or two R groups bound to the same nitrogen are taken together with the nitrogen to form a 3-7 membered heterocyclic ring having 0-2 heteroatoms in addition to the nitrogen, wherein said heteroatoms are independently selected from nitrogen, oxygen, or sulfur.
A phosphate isostere having the formula:
- 36
A method for using a compound comprising a sulfhydantoin moiety or a reverse sulfhydantoin moiety as a phosphate isostere comprising the step of contacting said compound with a protein, wherein a natural ligand of said protein comprises at least one mechanistically significant phosphate group.
A method for identifying a compound capable of associating with a protein, wherein said protein has a natural ligand comprising at least one mechanistically significant phosphate group, said method comprising the steps of:
- a.) selecting a first compound comprising a sulfhydantoin moiety or a reverse sulfhydantoin moiety;
- and
- b.) optionally modifying said first compound to optimize at least one additional structural feature for association with said protein.
A method for producing a compound capable of associating with a protein, wherein said protein has a natural ligand comprising at least one mechanistically significant phosphate group, said method comprising the step of replacing said phosphate group in said natural ligand with a sulfhydantoin moiety or a reverse sulfhydantoin moiety to produce said compound.
Dependencies are inferred from the claim text.