US 2022/0177438 A1Published application

Compounds, compositions and methods

AssigneeDenali Therapeutics Inc.

InventorsRobert A. Craig, II, Javier de Vicente Fidalgo, Jianwen A. Feng, Maksim Osipov, Arun Thottumkara

Life of this patent

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Abstract

The present disclosure relates generally to eukaryotic initiation factor 2B modulators, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or prodrug thereof, and methods of making and using thereof.

Claims31

Dependent claims

A compound of Formula I:

or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein:
ring A is bicyclo[1.1.1]pentane or bicyclo[2.1.1]hexane, wherein each is optionally substituted with one to eight R14;
ring B is a 5- or 6-membered heteroaryl or phenyl;
wherein each is optionally substituted with one to three R13;
Q1 and Q2 are each independently O, S or NR15;
L is a C1-6 alkylene linker, optionally substituted with one to three substituents independently selected from halo, cyano, nitro, —OR6, —SR, —SF5, —NR6R7, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, —C(O)R6, —C(O)OR6, —OC(O)OR6, —OC(O)R6, —C(O)NR6R7, —OC(O)NR6R7, —NR6C(O)NR7R8, —S(O)1-2R6, —S(O)1-2NR6, —NR6S(O)1-2R7, —NR6S(O)1-2NR7R, —NR6C(O)R7, and —NR6C(O)OR7;
z is 0 or 1;
X1 is O, NR9 or a bond;
R1 is hydrogen, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-10 cycloalkyl, or heterocyclyl, each of which, other than hydrogen, is optionally substituted with one to three R11;
R2 is C1-6 haloalkyl;
R3 is hydrogen, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which, other than hydrogen, is optionally substituted with one to five R1, provided that when ring A is bicyclo[1.1.1]pentane, then R3 is other than cyclobutyl substituted with —OCF3;
R4 and R5 are independently hydrogen, C1-12 alkyl, C2-12 alkenyl or C2-12 alkynyl, each of which, other than hydrogen, is independently optionally substituted with one to five R1;
or R3 and R4, together with the atoms to which they are attached, join to form a C3-10 cycloalkyl or heterocyclyl, each of which is optionally substituted with one to five R11;
or R4 and R5, together with the atoms to which they are attached, join to form a C3-10 cycloalkyl or heterocyclyl, each of which is optionally substituted with one to five R11;
each of R6, R7, and R8 is independently hydrogen, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, —C(O)R20, —C(O)OR20, —C(O)NR20R21, —S(O)1-2R20 or —S(O)1-2NR20, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl of R6, R7, and R8 is independently optionally substituted with one to five R12;
or two of R6, R7, and R8 are taken together with the atoms to which they are attached to form heterocyclyl independently optionally substituted by one to three halo, oxo, or C1-12 alkyl independently optionally substituted by one to three oxo, halo, hydroxyl, or amino;
R9 is hydrogen, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-10 cycloalkyl, or heterocyclyl, each of which, other than hydrogen, is optionally substituted with one to three R11;
each R11 is independently halo, cyano, nitro, oxo, —OR6, —SR6, —SF5, —NR6R7, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, —C(O)R6, —C(O)OR6, —OC(O)OR6, —OC(O)R6, —C(O)NR6R7, —OC(O)NR6R7, —NR6C(O)NR7R8, —S(O)1-2R6, —S(O)1-2NR6, —NR6S(O)1-2R7, —NR6S(O)1-2NR7R, —NR6C(O)R7, or —NR6C(O)OR7, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl of R11 is independently optionally substituted with one to five R12;
each R12 is independently halo, cyano, nitro, oxo, —OR30, —SR30, —SF5, —NR3OR31, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, —C(O)R30, —C(O)OR30, —OC(O)OR30, —OC(O)R30, —C(O)NR30R31, —OC(O)NR30R31, —NR30C(O)NR3OR31, —S(O)12R30, —S(O)1-2NR30, —NR30S(O)1-2R31, —NR30S(O)1-2NR30R31, —NR30C(O)R31, or —NR30C(═O)OR31, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl of R2 is independently optionally substituted with one to three halo or C1-12 alkyl independently optionally substituted by one to three oxo, halo, hydroxyl, or amino;
each R13 is independently halo, cyano, nitro, oxo, —OR30, —SR30, —SF5, —NR3OR31, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, —C(O)R30, —C(O)OR30, —OC(O)OR30, —OC(O)R30, —C(O)NR30R31, —OC(O)NR30R31, —NR30C(O)NR30R31, —S(O)1-2R30, —S(O)1-2NR30, —NR30S(O)1-2R31, —NR30S(O)1-2NR30R31, —NR30C(O)R31, or —NR30C(═O)OR31, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl of R13 is independently optionally substituted with one to three halo or C1-12 alkyl independently optionally substituted by one to three oxo, halo, hydroxyl, or amino;
each R14 is independently halo, C1-12 alkyl, or C1-12 haloalkyl;
each R15 is independently hydrogen, C1-6 alkyl, or C1-6 haloalkyl;
each R20 and R21 is independently hydrogen or C1-12 alkyl independently optionally substituted with one to three oxo, halo, hydroxyl, or amino;
or R20 and R21 are taken together with the atoms to which they are attached to form heterocyclyl independently optionally substituted by one to three halo or C1-12 alkyl independently optionally substituted by one to three oxo, halo, hydroxyl, or amino;
and
each R30 and R31 is independently hydrogen or C1-12 alkyl independently optionally substituted with one to three oxo, halo, hydroxyl, or amino;
or R30 and R31 are taken together with the atoms to which they are attached to form heterocyclyl independently optionally substituted by one to three halo or C1-12 alkyl independently optionally substituted by one to three oxo, halo, hydroxyl, or amino.

24 more elements

A method of preparing a compound of Formula I, or a salt, isotopically enriched analog, stereoisomer, or mixture of stereoisomers thereof:

comprising contacting a compound of Formula 1:
wherein R100 is halo and R101 is the moiety
or a nitrogen protecting group;
with a compound of Formula H-Q1-L-Q2-R2, under conditions suitable to provide a compound of Formula 2:
wherein:
a) when R101 is the moiety
the method provides the compound of Formula I, or a salt, isotopically enriched analog, stereoisomer, or mixture of stereoisomers thereof, and
b) when R101 is a nitrogen protecting group, the method further comprises removing the nitrogen protecting group and contacting the compound of Formula 2 with a compound of Formula 3:
wherein LG is a leaving group, under conditions suitable to provide the compound of Formula I, or a salt, isotopically enriched analog, stereoisomer, or mixture of stereoisomers thereof;
and
ring A is bicyclo[1.1.1]pentane or bicyclo[2.1.1]hexane, wherein each is optionally substituted with one to eight R14;
ring B is a 5- or 6-membered heteroaryl or phenyl;
wherein each is optionally substituted with one to three R13;
Q1 and Q2 are each independently O, S or NR15;
L is a C1-6 alkylene linker, optionally substituted with one to three substituents independently selected from halo, cyano, nitro, —OR6, —SR, —SF5, —NR6R7, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, —C(O)R6, —C(O)OR6, —OC(O)OR6, —OC(O)R6, —C(O)NR6R7, —OC(O)NR6R7, —NR6C(O)NR7R8, —S(O)1-2R6, —S(O)1-2NR6, —NR6S(O)1-2R7, —NR6S(O)1-2NR7R, —NR6C(O)R7, and —NR6C(O)OR7;
z is 0 or 1;
X1 is O, NR9 or a bond;
R1 is hydrogen, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-10 cycloalkyl, or heterocyclyl, each of which, other than hydrogen, is optionally substituted with one to three R11;
R2 is C1-6 haloalkyl;
R3 is hydrogen, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which, other than hydrogen, is optionally substituted with one to five R1, provided that when ring A is bicyclo[1.1.1]pentane, then R3 is other than cyclobutyl substituted with —OCF3;
R4 and R5 are independently hydrogen, C1-12 alkyl, C2-12 alkenyl or C2-12 alkynyl, each of which, other than hydrogen, is independently optionally substituted with one to five R1;
or R3 and R4, together with the atoms to which they are attached, join to form a C3-10 cycloalkyl or heterocyclyl, each of which is optionally substituted with one to five R11;
or R4 and R5, together with the atoms to which they are attached, join to form a C3-10 cycloalkyl or heterocyclyl, each of which is optionally substituted with one to five R11;
each of R6, R7, and R8 is independently hydrogen, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, —C(O)R20, —C(O)OR20, —C(O)NR20R21, —S(O)1-2R20 or —S(O)1-2NR20, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl of R6, R7, and R8 is independently optionally substituted with one to five R12;
or two of R6, R7, and R8 are taken together with the atoms to which they are attached to form heterocyclyl independently optionally substituted by one to three halo, oxo, or C1-12 alkyl independently optionally substituted by one to three oxo, halo, hydroxyl, or amino;
R9 is hydrogen, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-10 cycloalkyl, or heterocyclyl, each of which, other than hydrogen, is optionally substituted with one to three R11;
each R11 is independently halo, cyano, nitro, oxo, —OR6, —SR6, —SF5, —NR6R7, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, —C(O)R6, —C(O)OR6, —OC(O)OR6, —OC(O)R6, —C(O)NR6R7, —OC(O)NR6R7, —NR6C(O)NR7R8, —S(O)1-2R6, —S(O)1-2NR6, —NR6S(O)1-2R7, —NR6S(O)1-2NR7R, —NR6C(O)R7, or —NR6C(O)OR7, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl of R11 is independently optionally substituted with one to five R12;
each R12 is independently halo, cyano, nitro, oxo, —OR30, —SR30, —SF5, —NR30R31, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, —C(O)R30, —C(O)OR30, —OC(O)OR30, —OC(O)R30, —C(O)NR30R31, —OC(O)NR30R31, —NR30C(O)NR30R31, —S(O)1-2R30, —S(O)1-2NR30, —NR30S(O)1-2R31, —NR30S(O)1-2NR30R31, —NR30C(O)R31, or —NR30C(═O)OR31, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl of R2 is independently optionally substituted with one to three halo or C1-12 alkyl independently optionally substituted by one to three oxo, halo, hydroxyl, or amino;
each R13 is independently halo, cyano, nitro, oxo, —OR30, —SR30, —SF5, —NR30R31, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, —C(O)R30, —C(O)OR30, —OC(O)OR30, —OC(O)R30, —C(O)NR30R31, —OC(O)NR30R31, —NR30C(O)NR30R31, —S(O)1-2R30, —S(O)1-2NR30, —NR30S(O)1-2R31, —NR30S(O)1-2NR30R31, —NR30C(O)R31, or —NR30C(═O)OR31, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl of R13 is independently optionally substituted with one to three halo or C1-12 alkyl independently optionally substituted by one to three oxo, halo, hydroxyl, or amino;
each R14 is independently halo, C1-12 alkyl, or C1-12 haloalkyl;
each R15 is independently hydrogen, C1-6 alkyl, or C1-6 haloalkyl;
each R20 and R21 is independently hydrogen or C1-12 alkyl independently optionally substituted with one to three oxo, halo, hydroxyl, or amino;
or R20 and R21 are taken together with the atoms to which they are attached to form heterocyclyl independently optionally substituted by one to three halo or C1-12 alkyl independently optionally substituted by one to three oxo, halo, hydroxyl, or amino;
and
each R30 and R31 is independently hydrogen or C1-12 alkyl independently optionally substituted with one to three oxo, halo, hydroxyl, or amino;
or R30 and R31 are taken together with the atoms to which they are attached to form heterocyclyl independently optionally substituted by one to three halo or C1-12 alkyl independently optionally substituted by one to three oxo, halo, hydroxyl, or amino.

33 more elements

Dependencies are inferred from the claim text.

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