US 12,195,458 B2 · Polyheterocyclic compounds as METTL3 inhibitors

Abstract

The present invention relates to compounds of formula (I) that function as inhibitors of METTL3 (N6-adenosine-methyltransferase 70 kDa subunit) enzyme activity: X—Y—Z (I) wherein X, Y and Z are each as defined herein. The present invention also relates to processes for the preparation of these compounds, to pharmaceutical compositions comprising them, and to their use in the treatment of proliferative disorders, such as cancer, and autoimmune diseases, as well as other diseases or conditions in which METTL3 activity is implicated.

A compound of formula (I) shown below, or a pharmaceutically acceptable salt thereof:

X—Y—Z (I)
wherein:
X is selected from:
wherein
Q1 is selected from NH, N—C1-4alkyl, O and S;
R1a is a group of the formula:
—(CR1cR1d)p—NR1eR1f;
wherein
p is an integer selected from 1 and 2;
R1c and R1d are independently selected from:
(i) hydrogen (including deuterium),
(ii) C1-3alkyl which is optionally substituted by one more substituents selected from cyano, oxo, hydroxy, C1-3alkoxy, halo, C1-3haloalkoxy, —O—C3-4cycloalkyl, and NH2;
wherein —O—C3-4cycloalkyl is optionally substituted with halo, cyano, or hydroxy, and
(iii) R1c and R1d are linked together such that, together with the carbon atom to which they are attached, they form a 3- to 5-membered cycloalkyl or heterocyclic ring, or a spirocyclic ring system, each of which is optionally substituted by one or more substituents selected from C1-2alkyl, C1-2haloalkyl, cyano, hydroxy, C1-2alkoxy, halo, C1-2haloalkoxy, NR1caR1da and —S(O)0-2R1caR1da, wherein R1ca and R1da are H or C1-2alkyl;
R1e and R1f are each independently selected from:
(i) hydrogen (including deuterium);
(ii) C1-6alkyl which is optionally substituted by one more substituents selected from cyano, hydroxy, C1-2alkoxy, halo, C1-2haloalkoxy and NH2;
(iii) a group with the formula:
—(CR1gR1h)q-T1
wherein:
q is 0, 1, 2 or 3;
R1g and R1h are independently selected from:
a) hydrogen (including deuterium);
b) C1-6alkyl which is optionally substituted by one more substituents selected from cyano, hydroxy, C1-4alkoxy, halo, C1-4haloalkoxy, —O—C3-6cycloalkyl, NR1caR1da and —S(O)0-2R1caR1da, wherein R1ca and R1da are H or C1-2alkylNR1gaR1ha or —S(O)0-2R1gaR1ha, wherein R1ga and R1ha are H or C1-2alkyl;
and wherein —O—C3-6cycloalkyl is optionally substituted with halo, cyano or hydroxy;
and
c) R1g and R1h are optionally linked together such that, together with the carbon atom to which they are attached, they form a 3- to 6-membered cycloalkyl or heterocyclic ring which is optionally substituted by one or more substituents selected from C1-2alkyl, C1-2haloalkyl, cyano, hydroxy, C1-2alkoxy, halo, C1-2haloalkoxy, NR1gaR1ha and —S(O)0-2R1gaR1ha, wherein R1ga and R1ha are H or C1-2alkyl;
and T1 is selected from hydrogen, halo, C1-4alkyl, C1-4haloalkyl, cyano, hydroxy, NR1tR2t or —S(O)0-2R1tR2t (wherein R1t and R2t are H or C1-4alkyl), C3-8cycloalkyl, C2-3alkenyl, C2-3alkynyl, aryl, heterocyclyl, a mono- or bicyclic heteroaryl, a spirocyclic carbocyclic or heterocyclic ring system, a bridged C3-8cycloalkyl, a bridged bicyclic C5-12cycloalkyl, and a bridged heterocyclic ring system, each of which is optionally substituted by one or more substituents selected from C1-2alkyl, C1-2haloalkyl, cyano, hydroxy, C1-2alkoxy, halo, C1-2haloalkoxy, C3-6cycloalkyl, NR3tR4t and —S(O)0-2R3tR4t, wherein R3t and R4t are H or C1-2alkyl;
and
(iv) R1e and R1f are linked such that, together with the nitrogen atom to which they are attached, they form a mono- or bicyclic-heterocyclic ring, which is optionally substituted by one or more substituents selected from C1-4alkyl, C1-4haloalkyl, C3-6cycloalkyl, cyano, hydroxy, C1-4alkoxy, halo, C1-4haloalkoxy, NR1iR1j and —S(O)0-2R1iR1j, wherein R1i and R1j are H or C1-4alkyl, and/or the mono- or bicyclic heterocyclic ring formed by R1e and R1f is optionally spiro-fused to a C3-6cycloalkyl or a heterocyclic ring, which in turn is optionally substituted by one or more substituents selected from C1-4alkyl, C1-4haloalkyl, C3-6cycloalkyl, cyano, hydroxy, C1-4alkoxy, halo, C1-4haloalkoxy, NR1iR1j and —S(O)0-2R1iR1j, wherein R1i and R1j are H or C1-4alkyl;
and
p is an integer selected from 1 and 2;
R1b is selected from hydrogen, cyano, halo and C1-3 alkyl;
R1x is selected from hydrogen, cyano, halo and C1-3 alkyl;
R2a, R2b, R2c and R2d are independently selected from hydrogen, cyano, C1-6 alkoxy, C1-6haloalkoxy, halo, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, aryl, heterocyclyl and heteroaryl, each of which is optionally substituted by one or more substituents selected from halo, trifluoromethyl, trifluoromethoxy, amino, and hydroxy;
Y is selected from:
wherein:
R3a1, R3b1, R3e1, R3i1 and R3j1 are selected from hydrogen and methyl;
R3a2, R3b2, R3e2, R3i2 and R3j2 are hydrogen;
and
n is 1 or 2;
Z is selected from:
wherein:
A1 is selected from CR12 and N;
A2 is selected from CR13 and N;
A8 is selected from CR19R20 and NR21;
A11 is selected from CR28R29 and NR30;
(i) R4, R5, and R6 are independently selected from hydrogen, methyl, cyano and halo;
(ii) R12, R13, R18, R19, and R20 are independently selected from hydrogen, halo, cyano and methyl;
(iii) R21 and R30 are independently selected from hydrogen and methyl;
and
(iv) R28 and R29 are selected from hydrogen, halo, methoxy and methyl.

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Polyheterocyclic compounds as METTL3 inhibitors

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Polyheterocyclic compounds as METTL3 inhibitors

Life of this patent

Abstract

Claims21