Covalent inhibitors of menin-MLL interaction for diabetes mellitus
Disclosed herein are heterocyclic compounds that inhibit the binding of menin and MLL or MLL fusion proteins for the treatment of diabetes mellitus. Also described are specific covalent inhibitors of menin-MLL interaction. Also disclosed are pharmaceutical compositions that include the described compounds. Methods of using the menin-MLL covalent inhibitors are disclosed, alone or in combination with other therapeutic agents, for the treatment of diabetes mellitus.
1. A method for reducing HbA1c in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound according to Formula (I)
or a pharmaceutically acceptable salt thereof, wherein
A is carbon or nitrogen;
Cy is substituted or unsubstituted
Q is —N(H)—;
Z is —CR 5a ═ or —N═;
X is —NR 3a — or —C(R 3b ) 2 —;
Y is a single bond, —NR 3a —, or —C(R 3b ) 2 —;
W is —C(O)— or —S(O) 2 —;
one of R 1 and R 2 is Cy 2 -N(H)C(O)—C(R 6a )═C(R 6b )(R 6c ) or CH 2 -Cy 2 -N(H)C(O)—C(R 6a )═C(R 6b )(R 6c ); and the other is hydrogen;
Cy 2 is an optionally substituted group selected from phenyl, pyridyl, or a 4- to 7-membered heterocycloalkyl ring having one nitrogen;
each R 3a and R 3b is hydrogen;
each R 4a and R 4b is independently hydrogen, fluoro, or methyl;
R 5a is hydrogen;
each R 6a and R 6b is independently hydrogen or C 1-6 alkyl; or
R 6a and R 6b are joined together to form a bond;
R 6c is hydrogen or substituted or unsubstituted C 1-6 alkyl;
m is one, two, or three; and
n is one, two, three, or four.
2. The method according to claim 1 , wherein —X—W—Y— is —N(H)—C(O)—N(H)—, —N(H)—C(O)—CH 2 —, —CH 2 —C(O)—N(H)—, —N(H)—S(O) 2 —N(H)—, —N(H)—S(O) 2 —CH 2 —, —CH 2 —S(O) 2 —N(H)—, or —N(H)—C(O)—.
3. The method according to claim 1 , wherein the compound is according to Formula (XXIIIa), (XXIIIb), (IVa), or (IVb)
or a pharmaceutically acceptable salt thereof; and wherein p is zero, one, two, or three.
4. The method according to claim 1 , wherein Cy is
wherein R 7 is
5. The method according to claim 1 , wherein the compound is according to Formula (XXIVa) or (XXIVb)
or a pharmaceutically acceptable salt thereof; wherein
p is zero, one, two, or three; and
R 7 is
6. The method according to claim 1 , wherein the compound is according to Formula (VIIa), (VIIb), (VIIc), (VIIIa), (VIIIb), (VIIIc), (XXVIa), (XXVIb), or (XXVIc)
or a pharmaceutically acceptable salt thereof.
7. The method of claim 1 , wherein
i) R 6a is hydrogen;
R 6b is hydrogen; and
R 6c is hydrogen; or
ii) R 6a is hydrogen;
R 6b is hydrogen; and
R 6c is CH 3 or CH 2 CH 3 ; or
iii) R 6a is hydrogen;
R 6b is hydrogen; and
R 6c is CH 2 N(CH 3 ) 2 ; or
iv) R 6a and R 6b , joined together, form a single bond; and R 6c is CH 3 .
8. The method of claim 1 , wherein each of R 6a and R 6b is hydrogen; and R 6c is substituted or unsubstituted alkyl.
9. The method according to claim 1 , wherein the compound is according to Formula (IXa), (IXb), (IXc), (Xa), (Xb), (Xc), (XIa), (XIb), (XIc), (XIIa), (XIIb), (XIIc), (XIIIa), (XIIIb), (XIIIc), or (XIVa)
or a pharmaceutically acceptable salt thereof.
10. The method according to claim 1 , wherein the compound is according to Formula (XVI) or (XVII)
or a pharmaceutically acceptable salt thereof.
11. The method according to claim 1 , wherein the compound is according to Formula (XXVIIa), (XXVIIb), (XXVIIc), (XXVIIIa), (XXVIIIb), (XXVIIIc), (XXIXa), (XXIXb), or (XXIXc)
or a pharmaceutically acceptable salt thereof.
12. The method according to claim 1 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
13. The method according to claim 1 , wherein the compound is Compound 10
or a pharmaceutically acceptable salt thereof.
14. The method of claim 1 , wherein the compound is any one of the compounds selected from
Compound
ID
Structure
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
or
Compound
ID
Structure
101
102
103
104
105
106
107
108
109
110
111
112
15. The method of claim 1 , wherein the HbA1c is lowered by at least 0.5% within one month of dosing.
16. The method of claim 1 , wherein the HbA1c is lowered by 1%-3.5% between day 21 and day 29 of dosing.
17. The method of claim 1 , wherein reducing HbA1c occurs within four weeks of dosing.