US 11,976,067 B2 · APOL1 inhibitors and methods of use

Abstract

Provided herein are compounds of formula (II): or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein m, n, p, R1, R2, R3, L1, L2, L3, R4, X1, X2, X3, and X4 are as defined herein. Also provided are methods of preparing compounds of formula (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. Also provided are methods of inhibiting APOL1 and methods of treating an APOL1-mediated disease, disorder, or condition in an individual.

A compound of formula (II):

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein:
m is an integer from 0 to 4;
n is an integer from 0 to 2;
p is an integer from 0 to 10;
R1, if present, is independently at each occurrence selected from the group consisting of halo, —CN, C1-6alkoxy, and C1-6alkyl, wherein the C1-6alkoxy of R1 is optionally substituted with one or more halo, and the C1-6alkyl of R1 is optionally substituted with one or more halo;
R2 is H, C1-6alkyl, C3-10cycloalkyl, or 3-15 membered heterocyclyl, wherein the C1-6alkyl of R2 is optionally substituted with one or more deuterium, halo, —OH, —NH2, or C1-6alkoxy, and
the C3-10cycloalkyl of R2 is optionally substituted with one or more —OH;
R3, if present, is C1-6alkyl;
L1 is C1-6alkylene, wherein
the C1-6alkylene of L1 is optionally substituted with one or more deuterium or C1-6alkyl, and wherein
the C1-6alkyl is further optionally substituted with one or more —OH or C1-6alkoxy;
L2 is O or N(Rx), wherein Rx is H or C1-6alkyl;
and
either
(1) L3 is absent or is O, C3-10cycloalkyl, 3-10 membered heterocyclyl, or C1-6alkylene, wherein
the C3-10cycloalkyl of L3 is optionally substituted with one or more —OH or C1-6alkyl,
the C1-6alkylene of L3 is optionally substituted with one or more —OH or C1-6alkyl, wherein
the C1-6alkyl is optionally substituted with one or more —OH, and
the 3-10 membered heterocyclyl of L3 is optionally substituted with one or more —OH or C1-6alkyl;
X1 and X2 are each independently N or C(R5);
and
R4 is:
(i) —S(O)2—Ra;
(ii) 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of R4 is optionally substituted with one or more C1-6alkyl;
(iii) —N(Rd)2, wherein Rd is independently at each occurrence H, C1-6 alkyl, or —S(O)2—Ra, wherein the C1-6alkyl of Rd is optionally substituted with one or more —OH,
(iv) —NS(O)—(C1-6alkyl)2, wherein the C1-6alkyl is optionally substituted with one or more —OH,
(v) —C(O)—N(Re)2 wherein Re is independently at each occurrence H, C1-6 alkyl, or 3-10 membered heterocycle, wherein
the 3-10 membered heterocycle of Re is optionally substituted with one or more oxo, or both Re together with the N to which they are attached are taken together to form a 3-10 membered heterocyclyl, wherein
the 3-10 membered heterocyclyl is optionally substituted with one or more halo, oxo, —OH, NH2, —NH—S(O)2—Ra, or —S(O)2—Ra,
(vi) 3-10 membered heterocyclyl optionally substituted with one or more C1-6alkyl, —OH, oxo or —S(O)2—Ra,
(vii) —S(O)—N(C1-6alkyl)-(C1-6alkyl),
(viii) —CN,
(ix) —(CH2)qOH, wherein q is an integer from 0-6,
(x) —C(O)—C1-6alkyl, or
(xi) —P(O)(C1-6alkyl)2;
or
(2) L3 is absent;
and
one of X1 and X2 is N or C(R5);
and
the other of X1 and X2 is N or C that is taken together with R4, and the atoms to which they are attached, to form a 5-10 membered heterocyclyl or a 5-20 membered heteroaryl, wherein
the 5-10 membered heterocyclyl is optionally substituted with one or more Rb, wherein
Rb is, independently at each occurrence, selected from the group consisting of —OH, halo, oxo, C1-6alkyl, —C(O)—C1-6alkyl, —C(O)—NH2, —C(O)—NH(C1-6alkyl), —C(O)—N(C1-6alkyl)2, —S(O)2—Ra, C3-10cycloalkyl, and 3-10 membered heterocyclyl, wherein
the C1-6alkyl of Rb is optionally substituted with one or more halo, OH, —S(O)2-C1-6alkyl, or C3-10cycloalkyl, and wherein
the C3-10cycloalkyl of the C1-6alkyl of Rb is further optionally substituted with one or more C1-6alkyl or —OH and
the C3-10cycloalkyl of Rb is optionally substituted with one or more —OH, C3-10cycloalkyl, or C1-6alkyl, and wherein the C1-6alkyl of the C3-10cycloalkyl of Rb is further optionally substituted with one or more —OH, deuterium, or halo, and
the 5-20 membered heteroaryl is optionally substituted with one or more Rc, wherein
Rc is, independently at each occurrence, selected from the group consisting of halo, C1-6alkyl, —C(O)—C1-6alkyl, —C(O)—NH2, —C(O)—NH(C1-6alkyl), —C(O)—N(C1-6alkyl)2, —S(O)2—Ra, C3-10cycloalkyl, and 3-10 membered heterocyclyl, wherein
the C1-6alkyl of Rc is optionally substituted with one or more —S(O)2—C1-6alkyl,
the C3-10cycloalkyl of Rc is optionally substituted with one or more —OH or C1-6alkyl, and
the 3-10 membered heterocyclyl of Rc is optionally substituted with one or more —OH or C1-6alkyl, and wherein
the C1-6alkyl of the 3-10 membered heterocyclyl of Rc is further optionally substituted with one or more —OH;
Ra is, independently at each occurrence:
(i) C1-6alkyl optionally substituted with one or more halo, —OH, —S(O)2—C1-6alkyl, or —N(C1-6alkyl)-C(O)—C1-6alkyl,
(ii) C3-10cycloalkyl optionally substituted with one or more —OH, —C(O)2—C1-6alkyl, —C(O)—NH(C1-6alkyl), —C(O)—N(C1-6alkyl)2, or —C(O)—C3-10heterocyclyl, or C1-6alkyl, wherein the C1-6alkyl is optionally substituted with one or more —OH,
(iii) 3-10 membered heterocyclyl optionally substituted with one or more C1-6alkyl, or
(iv) NH(C1-6alkyl);
R5 is, independently at each occurrence, H, halo, —CN, 3-10 membered heterocyclyl, C1-6alkyl, or C1-6alkoxy, wherein
the C1-6alkyl of R5 is optionally substituted with one or more halo or —OH, and
the C1-6alkoxy of R5 is optionally substituted with one or more halo;
X3 is N or C(R6);
X4 is N or C(R7);
and
R6 and R7 are each independently H or halo.

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APOL1 inhibitors and methods of use

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APOL1 inhibitors and methods of use

Life of this patent

Abstract

Claims159