INHIBITORS OF THE MENIN-MLL INTERACTION
The present disclosure is directed to inhibitors of Formula (0), or a stereoisomer thereof, or pharmaceutically acceptable salt thereof, of the interaction of menin with MLL and MLL fusion proteins, pharmaceutical compositions containing the same, and their use in the treatment of cancer and other diseases mediated by the menin-MLL interaction.
1 . A compound of Formula 0,
a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein
W is N or CH;
X is C═O, S(═O)(═NR 5 ), or S(═O) 2 ;
Y is NH, O, or a bond;
R 1 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 3 -C 12 cycloalkyl, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl; wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally substituted by one or more halo, OH, OBn, oxo, CN, N(R N ) 2 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, or C 1 -C 6 alkoxy;
R 2 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 3 -C 12 cycloalkyl, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl; wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally substituted with one or more halo, OH, OBn, oxo, CN, N(R N ) 2 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, or C 1 -C 6 alkoxy;
R 1 and R 2 optionally form a 3- to 12-membered heterocyclyl, wherein the heterocyclyl is optionally substituted with one or more C 1 -C 6 alkyl, halo, OH, CN, or C 1 -C 6 alkoxy;
R 3 is H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 3 -C 12 cycloalkyl, NH 2 , NH—C 1 -C 6 alkyl, N—(C 1 -C 6 alkyl) 2 , C 6 -C 10 aryl, 5- to 10-membered heteroaryl, 3- to 12-membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally substituted with one or more halo, OH, OBn, oxo, CN, N(R N ) 2 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy or aryl;
R 4 is H, halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, or N(R N ) 2 ;
each R N is independently H, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; and
each R 5 is independently H, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
2 . A compound of Formula 0,
a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein
W is N or CH;
X is C═O, S(═O)(═NR 5 ), or S(═O) 2 ;
Y is NH, O, or a bond;
R 1 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 3 -C 12 cycloalkyl, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl; wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally substituted by one or more halo, OH, OBn, oxo, CN, N(R N ) 2 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, or C 1 -C 6 alkoxy;
R 2 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 3 -C 12 cycloalkyl, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl; wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally substituted with one or more halo, OH, OBn, oxo, CN, N(R N ) 2 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, or C 1 -C 6 alkoxy;
R 1 and R 2 optionally form a 3- to 12-membered heterocyclyl, wherein the heterocyclyl is optionally substituted with one or more C 1 -C 6 alkyl, halo, OH, CN, or C 1 -C 6 alkoxy;
R 3 is H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 3 -C 12 cycloalkyl, NH 2 , NH—C 1 -C 6 alkyl, N—(C 1 -C 6 alkyl) 2 , C 6 -C 10 aryl, 5- to 10-membered heteroaryl, 3- to 12-membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally substituted with one or more halo, OH, OBn, oxo, CN, N(R N ) 2 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, or aryl;
R 4 is H, halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, or N(R N ) 2 ;
each R N is independently H, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; and
each R 5 is independently H, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
3 . The compound of claims 1 or 2 , wherein W is N.
4 . The compound of claims 1 or 2 , wherein W is CH.
5 . The compound of any one of the preceding claims , wherein X is C═O, or S(═O) 2 .
6 . The compound of any one of the preceding claims , wherein X is S(═O) 2 .
7 . The compound of any one of the preceding claims , wherein Y is NH, O, or a bond.
8 . The compound of any one of the preceding claims , wherein Y is NH or a bond.
9 . The compound of any one of the preceding claims , wherein Y is NH.
10 . The compound of any one of the preceding claims , wherein R 1 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, wherein the alkyl, alkenyl, alkynyl, alkoxy is optionally substituted by one or more halo, OH, OBn, oxo, CN, or C 3 -C 6 cycloalkyl.
11 . The compound of any one of the preceding claims , wherein R 1 is C 1 -C 6 alkyl, C 1 -C 6 alkoxy, wherein the alkyl, alkoxy is optionally substituted by one or more halo, OH, oxo, CN, or C 3 -C 6 cycloalkyl.
12 . The compound of any one of the preceding claims , wherein R 1 is C 1 -C 6 alkyl, optionally substituted by one or more halo, OH, oxo, CN, or C 3 -C 6 cycloalkyl.
13 . The compound of any one of the preceding claims , wherein R 1 is C 1 -C 4 alkyl, optionally substituted by one or more halo, OH, oxo, CN, or C 3 -C 6 cycloalkyl.
14 . The compound of any one of the preceding claims , wherein R 1 is C 1 -C 4 alkyl, optionally substituted by one or more halo.
15 . The compound of any one of the preceding claims , wherein R 1 is C 1 -C 4 alkyl.
16 . The compound of any one of the preceding claims , wherein R 1 is ethyl substituted by one or more halo.
17 . The compound of any one of the preceding claims , wherein R 1 is —CH 2 —CHF 2 , or —CH 2 —CF 3 .
18 . The compound of any one of claims 1-15 , wherein R 1 is isopropyl.
19 . The compound of any one of claims 1-9 , wherein R 1 is C 3 -C 12 cycloalkyl, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein the cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally substituted by one or more halo, OH, oxo, CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, or C 1 -C 6 alkoxy.
20 . The compound of any one of claims 1-9 , wherein R 1 is C 3 -C 12 cycloalkyl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein the cycloalkyl, heteroaryl, or heterocyclyl is optionally substituted by one or more halo, OH, oxo, CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, or C 1 -C 6 alkoxy.
21 . The compound of any one of claims 1-9 , wherein R 1 is C 3 -C 12 cycloalkyl, wherein the cycloalkyl is optionally substituted by one or more halo, OH, oxo, CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, or C 1 -C 6 alkoxy.
22 . The compound of any one of claims 1-9 , wherein R 1 is 3- to 6-membered heterocyclyl, optionally substituted by one or more halo, OH, oxo, CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, or C 1 -C 6 alkoxy.
23 . The compound of any one of claims 1-9 , wherein R 1 is 3- to 6-membered heterocyclyl, optionally substituted by one or more halo, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
24 . The compound of any one of claims 1-9 , wherein R 1 is 3- to 6-membered heterocyclyl, optionally substituted by one or more C 1 -C 6 alkyl or OH.
25 . The compound of any one of claims 1-9 , wherein R 1 is 3- to 5-membered heterocyclyl, optionally substituted by one or more C 1 -C 6 alkyl or OH.
26 . The compound of any one of claims 1-9 , wherein R 1 is 3- to 5-membered heterocyclyl, substituted by one or more C 1 -C 6 alkyl or OH.
27 . The compound of any one of the preceding claims , wherein R 2 is C 1 -C 6 alkyl, C 1 -C 6 alkoxy, wherein the alkyl, alkoxy is optionally substituted by one or more halo, OH, oxo, CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, or C 1 -C 6 alkoxy.
28 . The compound of any one of the preceding claims , wherein R 2 is C 1 -C 4 alkyl, optionally substituted by one or more halo.
29 . The compound of any one of the preceding claims , wherein R 2 is C 1 -C 3 -alkyl, optionally substituted by one or more halo.
30 . The compound of any one of the preceding claims , wherein R 2 is ethyl.
31 . The compound of any one of claims 1-29 , wherein R 2 is propyl.
32 . The compound of claim 31 , wherein R 2 is isopropyl.
33 . The compound of any one of claims 1-32 , wherein R 3 is H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, NH 2 , NH—C 1 -C 6 alkyl, N—(C 1 -C 6 alkyl) 2 , wherein the alkyl, alkenyl, alkynyl, alkoxy, is optionally substituted with one or more halo, OH, oxo, CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, or C 1 -C 6 alkoxy.
34 . The compound of any one of claims 1-32 , wherein R 3 is C 1 -C 6 alkyl, NH—C 1 -C 6 alkyl, N—(C 1 -C 6 alkyl) 2 , alkyl, alkenyl, alkynyl, alkoxy, is optionally substituted with one or more halo, OH, oxo, CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, or C 1 -C 6 alkoxy.
35 . The compound of any one of claims 1-32 , wherein R 3 is C 1 -C 6 alkyl, NH—C 1 -C 6 alkyl, N—(C 1 -C 6 alkyl) 2 wherein the alkyl is optionally substituted with one or more halo.
36 . The compound of any one of claims 1-32 , wherein R 3 is C 1 -C 6 alkyl, NH—C 1 -C 6 alkyl, N—(C 1 -C 6 alkyl) 2 , or 5- to 10-membered heteroaryl, wherein the alkyl or heteroaryl is optionally substituted with one or more halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 cycloalkyl, or C 1 -C 6 alkoxy.
37 . The compound of any one of claims 1-32 , wherein R 3 is C 3 -C 12 cycloalkyl, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, 3- to 12-membered heterocyclyl, wherein the cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally substituted with one or more halo, OH, oxo, CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, or C 1 -C 6 alkoxy.
38 . The compound of any one of claims 1-32 , wherein R 3 is 5- to 10-membered heteroaryl, wherein the heteroaryl is optionally substituted with one or more halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, or C 1 -C 6 alkoxy.
39 . The compound of any one of claims 1-32 , wherein R 3 is 5- to 10-membered heteroaryl, wherein the heteroaryl is optionally substituted with one or more halo or C 1 -C 6 alkyl.
40 . The compound of any one of claims 1-32 , wherein R 3 is 5- to 6-membered heteroaryl, wherein the heteroaryl is optionally substituted with one or more C 1 -C 6 alkyl.
41 . The compound of any one of claims 1-32 , wherein R 3 is 5-heteroaryl, wherein the heteroaryl is optionally substituted with one or more C 1 alkyl.
42 . The compound of any one of claims 1-32 , wherein R 3 is C 1 -C 3 alkyl, NH—C 1 -C 3 alkyl, N—(C 1 -C 3 alkyl) 2 , or 5- to 6-membered heteroaryl, wherein the alkyl or heteroaryl is optionally substituted with one or more halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 cycloalkyl, or C 1 -C 6 alkoxy.
43 . The compound of any one of claims 1-32 , wherein R 3 is C 1 -C 3 alkyl, NH—C 1 -C 3 alkyl, N—(C 1 -C 3 alkyl) 2 , or 5- to 6-membered heteroaryl, wherein the alkyl or heteroaryl is substituted with one or more halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, or C 1 -C 6 alkoxy.
44 . The compound of any one of the previous claims , Ra is H or halo.
45 . The compound of any one of the previous claims , wherein R 4 is H.
46 . The compound of any one of the previous claims , wherein each R 5 is independently H, or C 1 -C 6 alkyl.
47 . The compound of any one of the previous claims , wherein each R 5 is H.
48 . A compound as shown in Table 1 or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
49 . A compound as shown in Table 1 or a pharmaceutically acceptable salt thereof.
50 . A compound as shown in Table 1.
51 . The compound according to any one of the preceding claims , wherein the compound is useful for the treatment of a cancer wherein the compound minimizes hERG binding.
52 . A pharmaceutical composition comprising a compound of any one of claims 1-51 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
53 . A pharmaceutical composition comprising a salt or crystalline form of any one of claims 1-51 , and at least one pharmaceutically acceptable carrier.
54 . A method of inhibiting the interaction between menin and MLL comprising contacting the menin and MLL with a compound of any one of claims 1-51 or a pharmaceutical composition of either claim 52 or 53 .
55 . A method of treating cancer in a patient comprising administering to the patient a compound of any one of claims 1 to 51 or a pharmaceutical composition of either claim 52 or 53 .
56 . The method of claim 55 , wherein the cancer is a hematological cancer.
57 . The method of either claim 55 or 56 , wherein the cancer is a leukemia.
58 . The method of either claim 55 or 56 , wherein the cancer is a lymphoma.
59 . The method of either claim 55 or 56 , wherein the cancer is mixed lineage leukemia (MLL), MLL-related leukemia, MLL-associated leukemia, MLL-positive leukemia, MLL-induced leukemia, rearranged mixed lineage leukemia (MLL-r), leukemia associated with a MLL rearrangement or a rearrangement of the MLL gene, acute leukemia, chronic leukemia, indolent leukemia, lymphoblastic leukemia, lymphocytic leukemia, myeloid leukemia, myelogenous leukemia, childhood leukemia, acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), acute granulocytic leukemia, acute nonlymphocytic leukemia, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), therapy related leukemia, myelodysplastic syndrome (MDS), myeloproliferative disease (MPD), myeloproliferative neoplasia (MPN), plasma cell neoplasm, multiple myeloma, myelodysplasia, cutaneous T-cell lymphoma, lymphoid neoplasm, AIDS-related lymphoma, thymoma, thymic carcinoma, mycosis fungoides, Alibert-Bazin syndrome, granuloma fungoides, Sezary Syndrome, hairy cell leukemia, T-cell prolymphocytic leukemia (T-PLL), large granular lymphocytic leukemia, meningeal leukemia, leukemic leptomeningitis, leukemic meningitis, multiple myeloma, Hodgkin's lymphoma, non Hodgkin's lymphoma (malignant lymphoma), or Waldenstrom's macroglobulinemia.
60 . The method of either claim 55 or 56 , wherein the cancer is an abstract nucleophosmin (NPM1)-mutated acute myeloid leukemia (i.e., NPM1 mut acute myloid leukemia).
61 . The method of either claim 55 or 56 , wherein the cancer is a rearranged mixed lineage leukemia (MLL-r).
62 . A compound of any of claims 1-51 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of either claim 52 or 53 , for use in treating or preventing a disease caused by, or associated with, menin expression, activity, and/or function.
63 . A compound of any of claims 1-51 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of either claim 52 or 53 , for use in treating or preventing cancer.
64 . Use of a compound of any of claims 1-51 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of either claim 52 or 53 , for treating or preventing a disease caused by, or associated with, menin expression, activity, and/or function.
65 . Use of a compound of any of claims 1-51 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of either claim 52 or 53 , in the manufacture of a medicament for treating or preventing a disease caused by, or associated with, menin expression, activity, and/or function.
66 . Use of a compound of any of claims 1-51 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of either claim 52 or 53 , for treating or preventing cancer.
67 . Use of a compound of any of claims 1-51 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of either claim 52 or 53 , in the manufacture of a medicament for treating or preventing cancer.
68 . A kit comprising a compound of any of claims 1-51 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of either claim 52 or 53 .