US 12,758,641 B2Granted

BRM targeting compounds and associated methods of use

AssigneePrelude Therapeutics Incorporated

InventorsCorey Howard Basch, Song Mei, Liang Liu, Artem Shvartsbart, Andrew Paul Combs, John A. Rose, Klare L. Bersch, Sina Rezazadeh, Vijayarajan Devannah, Danielle Beam Roth

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Abstract

The disclosure is directed to compounds of Formula I Pharmaceutical compositions comprising compounds of Formula I, as well as methods of their use and preparation, are also described.

Claims66

Dependent claims

A compound of Formula (I):

or a pharmaceutically acceptable salt thereof;
wherein
R1 is halo, C1-6 alkyl, or C1-6 haloalkyl;
each R2 is independently H, D, or F;
each R3 is independently H, D, C1-6 alkyl, C1-6 haloalkyl, C3-6 heterocycloalkyl or C3-6 cycloalkyl;
n is 1, 2 or 3;
m is 1, 2, 3, or 4;
R4 is H, D, C1-6 alkyl, C1-6 alkoxyalkyl, C3-6 cycloalkyl, or C1-6 haloalkyl;
R5 is H, D, or F;
L1 is a bond, O, S, S(O), SO2, NR3, C(R3)2 or CO;
L2 is a bond, O, S, S(O), SO2, NR3, C(R3)2 or CO;
ring A1 is a 6 membered aryl group or a 5-6 membered heteroaryl group;
ring A2 is a 3-7 membered cycloalkyl group or a 4-7-membered heterocycloalkyl group;
X1 is CH2, CO, CH-CH (when X2=CO), or N═CH (when X2=CO);
X2 is CH2, CO, CH═CH (when X1=CO), or N═CH (when X1=CO);
wherein the alkyl group, haloalkyl group, cycloalkyl group, alkoxyalkyl group, aryl group, heteroaryl group or heterocycloalkyl group is optionally substituted by one or more Rf groups;
each Rf is independently D, oxo, halogen, C1-C8 alkoxy, C1-C8alkyl, C1-6 haloalkyl, C1-6 haloalkoxy, —OH, -CN, —NO2, —C2-C6 alkenyl, —C2-C6 alkynyl, C6-10 aryl, C5-12 heteroaryl, C3-8 cycloalkyl, C3-8 cycloalkenyl, C3-8 heterocycloalkyl, C3-8 heterocycloalkenyl, —ORa, —SRa, —NRcRd, —NRaRc, —C(O)Rb, —OC(O)Rb, —C(O)ORb, —C(O)NRcRd, —S(O)Rb, —S(O)2NRcRd, —S(O) (═NRb)Rb, —SF5, —P(O)RbRb, —P(O)RcRd, —P(O)(ORb)(ORb), —B(OR)(ORd), —S(O)2Rb, —C(O)NRbORb, —S(O)2ORb, —OS(O)2ORb, or -OPO(ORb)(ORb);
wherein said C1-C8 alkyl is optionally substituted by 1-6 groups selected from D, halogen, —OH, -CN, —ORa, —SRa, —NRaRd, or NRcRa,
each Ra is independently H, D, —C(O)Rb, —C(O)ORc, —C(O)NRcRd, —C(═NRb)NRbRc, —C(=NORD)NRbRc, —C(═NCN)NRbRc, —P(ORc)2, —P(O)RcRb, —P(O)RcRd, —P(O)ORcORb, —S(O)Rb, —S(O)NRcRd, —S(O)2Rb, —S(O)2NRcRd, SiRb3, —C1-C10 alkyl, —C2-C10 alkenyl, —C2-C10 alkynyl, C6-10 aryl, C3-8 cycloalkyl, C3-8 cycloalkenyl, C5-12 heteroaryl, C3-8 heterocycloalkyl, or C3-8 heterocycloalkenyl;
each Rb, is independently H, D, —C1-C6 alkyl, —C2-C6 alkenyl, —C2-C6 alkynyl, C6-10 aryl, C3-8 cycloalkyl, C3-8 cycloalkenyl, C5-12 heteroaryl, C3-8 heterocycloalkyl, or C3-8 heterocycloalkenyl;
each Rc or Rd is independently H, D, —C1-C10 alkyl, —C2-C6 alkenyl, —C2-C6 alkynyl, —OC1-C6 alkyl, —O-cycloalkyl, C6-10 aryl, C5-12 heteroaryl, C3-8 cycloalkyl, C3-8 cycloalkenyl, C3-8 heterocycloalkyl, or C3-8 heterocycloalkenyl;
or Rc and Rd, together with the atom to which they are both attached, form a monocyclic or multicyclic heterocycloalkyl, or a monocyclic or multicyclic heterocycloalkenyl group.

19 more elements

A compound that is:

3-(6-(4-((5-(((6aS,8R)-6a-(difluoromethyl)-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1′,2′:4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-6-methylpyrazin-2-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;
3-(6-(4-((2-(((6aS,8R)-6a-(Difluoromethyl)-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a, 7,8,9-hexahydropyrrolo[1′,2′:4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-4,6-dimethylpyrimidin-5-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;
3-(6-(4-((2-(((6aS,8R)-6a-(difluoromethyl)-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1′,2′:4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy) pyrimidin-5-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;
(S)-3-(6-(4-((6-(((6aR,8R)-6a-(difluoromethyl)-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a, 7,8,9-hexahydropyrrolo[1′,2′:4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy) pyridin-3-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;
(S)-3-(6-(4-((6-(((6aR,8R)-6a-(difluoromethyl)-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a, 7,8,9-hexahydropyrrolo[1′,2′:4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-5-ethylpyridin-3-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;
(S)-3-(6-(4-((5-(((6aR,8R)-6a-(difluoromethyl)-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a, 7,8,9-hexahydropyrrolo[1′,2′:4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-3-fluoro-4-methylpyridin-2-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;
(S)-3-(6-(4-((5-(((6aS,8R)-6a-(difluoromethyl)-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a, 7,8,9-hexahydropyrrolo[1′,2′:4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-3,4-dimethylpyridin-2-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;
(S)-3-(6-(4-((6-(((6aS,8R)-6a-(difluoromethyl)-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a, 7,8,9-hexahydropyrrolo[1′,2′:4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-5-ethylpyridin-3-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;
(S)-3-(6-(4-((5-(((6aS,8R)-6a-(difluoromethyl)-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a, 7,8,9-hexahydropyrrolo[1′,2′:4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-3,6-dimethylpyrazin-2-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;
(S)-3-(6-(4-((5-(((6aS,8R)-6a-(difluoromethyl)-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a, 7,8,9-hexahydropyrrolo[1′,2′:4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy) pyridin-2-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;
3-(6-(4-((2-(((6aS,8R)-6a-(difluoromethyl)-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1′,2′:4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-4-isopropylpyrimidin-5-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;
3-(6-(4-((5-(((6aS,8R)-6a-(difluoromethyl)-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1′,2′:4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-3-methylpyrazin-2-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;
3-(6-(4-((5-(((6aS,8R)-6a-(difluoromethyl)-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1′,2′:4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy) pyrazin-2-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;
3-(6-(4-((6-(((6aS,8R)-6a-(difluoromethyl)-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1′,2′:4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-5-methoxypyridin-3-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;
3-(6-(4-((6-(((6aS,8R)-6a-(difluoromethyl)-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1′,2′:4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-5-fluoropyridin-3-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;
3-(6-(4-((6-(((6aR,8R)-2-(3-fluoro-2-hydroxyphenyl)-6a-methyl-5,6,6a,7,8,9-hexahydropyrrolo[1′,2′:4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-4-methylpyridin-3-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;
3-(6-(4-((6-(((6aR,8R)-6a-Ethyl-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1′,2′:4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-4-methylpyridin-3-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;
(S)-3-(6-(4-((5-(((6aR,8R)-6a-ethyl-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1′,2′:4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-3-methylpyrazin-2-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;
(S)-3-(6-(4-((6-(((6aR,8R)-2-(3-Fluoro-2-hydroxyphenyl)-6a-(fluoromethyl)-5,6,6a,7,8,9-hexahydropyrrolo[1′,2′:4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-4-methylpyridin-3-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;
5-((4~ (2-((S)-2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperazin-1-yl)methyl)-2-(((6aR,8R)-6a-ethyl-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1′,2′:4,59pyrazino[2,3-c]pyridazin-8-yl)oxy)-6-methylnicotinonitrile;
3-(6-(4-((6-(((6aR,8R)-6a-ethyl-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1′,2′:4,5]pyrazino[2,3-c]pyridazin-8-yl)thio)-4-methylpyridin-3-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;
3-(6-(4-((6-(((6aR,8R)-6a-ethyl-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a, 7,8,9-hexahydropyrrolo[1′,2′:4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-5-fluoro-4-methylpyridin-3-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;
3-(6-(4-((6-(((6aR,8R)-6a-ethyl-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a, 7,8,9-hexahydropyrrolo[1′,2′:4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-2,4-dimethylpyridin-3-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;
3-(6-(4-((6-(((6aR,8R)-2-(3,5-difluoro-2-hydroxyphenyl)-6a-ethyl-5,6,6a, 7,8,9-hexahydropyrrolo[1′,2′:4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy) pyridin-3-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;
(S)-3-(6-(4-((5-(((6aR,8R)-2-(3-fluoro-2-hydroxyphenyl)-6a-(fluoromethyl)-5,6,6a,7,8,9-hexahydropyrrolo[1′,2′:4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-6-methylpyrazin-2-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;
(S)-3-(6-(1-((5-(((6aR,8R)-2-(3-Fluoro-2-hydroxyphenyl)-6a-(fluoromethyl)-5,6,6a,7,8,9-hexahydropyrrolo[1′,2′:4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-6-methylpyrazin-2-yl)methyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;
(S)-3-(6-(4-((5-(((6aS,8R)-2-(3-fluoro-2-hydroxyphenyl)-6a-(fluoromethyl)-5,6,6a,7,8,9-hexahydropyrrolo[1′,2′:4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-6-methylpyrazin-2-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;
(S)-3-(6-(4-((6-ethyl-5-(((6aR,8R)-2-(3-fluoro-2-hydroxyphenyl)-6a-(fluoromethyl)-5,6,6a, 7,8,9-hexahydropyrrolo[1′,2′:4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy) pyrazin-2-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;
(S)-3-(6-(1-((6-ethyl-5-(((6aR,8R)-2-(3-fluoro-2-hydroxyphenyl)-6a-(fluoromethyl)-5,6,6a, 7,8,9-hexahydropyrrolo[1′,2′:4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy) pyrazin-2-yl)methyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;
(S)-3-(6-(4-((5-fluoro-6-(((6aS,8R)-2-(3-fluoro-2-hydroxyphenyl)-6a-(fluoromethyl)-5,6,6a, 7,8,9-hexahydropyrrolo[1′,2′:4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-2-methylpyridin-3-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;
3-(6-(4-((5-fluoro-6-(((6aR,8R)-2-(3-fluoro-2-hydroxyphenyl)-6a-(fluoromethyl)-5,6,6a, 7,8,9-hexahydropyrrolo[1′,2′:4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy) pyridin-3-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;
(S)-3-(6-(4-((5-fluoro-6-(((6aR,8R)-2-(3-fluoro-2-hydroxyphenyl)-6a-(fluoromethyl)-5,6,6a, 7,8,9-hexahydropyrrolo[1′,2′:4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-4-methylpyridin-3-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;
(S)-3-(6-(4-((5-(((6aR,8R)-6a-Ethyl-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1′,2′:4,5]pyrazino[2,3-c]pyridazin-8-yl) oxy)-3-fluoropyridin-2-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;
(S)-3-(5-(4-((5-(((6aS,8R)-6a-ethyl-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1′,2′:4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-3-(trifluoromethyl) pyridin-2-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;
(S)-3-(5-(4-((5-(((6aS,8R)-6a-ethyl-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1′,2′:4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-3-methylpyridin-2-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;
(S)-3-(6-(4-((2-(((6aR,8R)-2-(3-fluoro-2-hydroxyphenyl)-6a-methyl-5,6,6a,7,8,9-hexahydropyrrolo[1′,2′:4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-4,6-dimethylpyrimidin-5-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;
5-((4-(2-((S)-2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperazin-1-yl)methyl)-2-(((6aS,8R)-2-(3-fluoro-2-hydroxyphenyl)-6a-methyl-5,6,6a, 7,8,9-hexahydropyrrolo[1′,2′:4,59pyrazino[2,3-c]pyridazin-8-yl)oxy) isonicotinonitrile;
(S)-3-(6-(1-((2-(((6aR,8R)-2-(3-fluoro-2-hydroxyphenyl)-6a-methyl-5,6,6a,7,8,9-hexahydropyrrolo[1′,2′:4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-4-methylpyrimidin-5-yl)methyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;
(S)-3-(6-(1-((2-(((6aR,8R)-2-(3-fluoro-2-hydroxyphenyl)-6a-methyl-5,6,6a,7,8,9-hexahydropyrrolo[1′,2′:4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-4,6-dimethylpyrimidin-5-yl)methyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;
(S)-3-(6-(4-((5-(((6aS,8R)-2-(3-fluoro-2-hydroxyphenyl)-6a-methyl-5,6,6a,7,8,9-hexahydropyrrolo[1′,2′:4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy) pyrazin-2-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;
(S)-3-(6-(4-((5-(((6aS,8R)-2-(3-fluoro-2-hydroxyphenyl)-6a-methyl-5,6,6a,7,8,9-hexahydropyrrolo[1′,2′:4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-3,6-dimethylpyridin-2-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;
(S)-3-(6-(4-((5-(((6aR,8R)-2-(3-fluoro-2-hydroxyphenyl)-6a-methyl-5,6,6a,7,8,9-hexahydropyrrolo[1′,2′:4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-3-methylpyridin-2-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;
(S)-3-(6-(4-((5-(((6aS,8R)-2-(3-fluoro-2-hydroxyphenyl)-6a-methyl-5,6,6a, 7,8,9-hexahydropyrrolo[1′,2′:4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-3-methylpyridin-2-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;
(S)-3-(6-(4-((6-(((6aS,8R)-2-(3-fluoro-2-hydroxyphenyl)-6a-methyl-5,6,6a,7,8,9-hexahydropyrrolo[1′,2′:4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-5-methylpyridin-3-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;
3-(6-(4-((6-(((6aR,8R)-6a-(difluoromethyl)-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1′,2′:4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-5-fluoropyridin-3-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;
3-(6-(4-((5-chloro-6-(((6aR,8R)-6a-(difluoromethyl)-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a, 7,8,9-hexahydropyrrolo[1′,2′:4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy) pyridin-3-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;
(S)-3-(6-(4-((6-(((6aR,8R)-6a-(difluoromethyl)-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a, 7,8,9-hexahydropyrrolo[1′,2′:4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-4,5-dimethylpyridin-3-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;
(S)-3-(6-(4-((6-(((6aR,8R)-6a-(difluoromethyl)-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a, 7,8,9-hexahydropyrrolo[1′,2′:4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-2,5-dimethylpyridin-3-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;
3-(6-(1-((6-(((6aR,8R)-6a-(difluoromethyl)-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a, 7,8,9-hexahydropyrrolo[1′,2′:4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-5-fluoropyridin-3-yl)methyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;
(S)-3-(6-(1-((6-(((6aS,8R)-6a-(difluoromethyl)-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a, 7,8,9-hexahydropyrrolo[1′,2′:4,5]pyrazino[2,3-c]pyridazine-8-yl)oxy)-5-fluoro-4-methylpyridin-3-yl)methyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;
(S)-3-(6-(1-((6-(((6aR,8R)-6a-(difluoromethyl)-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a, 7,8,9-hexahydropyrrolo[1′,2′:4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy) pyridin-3-yl)methyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;
(S)-3-(6-(1-((5-(((6aS,8R)-6a-(difluoromethyl)-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a, 7,8,9-hexahydropyrrolo[1′,2′:4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-6-methylpyrazin-2-yl)methyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;
(S)-3-(6-(1-((5-(((6aS,8R)-6a-(difluoromethyl)-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a, 7,8,9-hexahydropyrrolo[1′,2′:4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-4-methylpyridin-2-yl)methyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;
(S)-3-(6-(1-((6-(((6aR,8R)-2-(3-fluoro-2-hydroxyphenyl)-6a-(fluoromethyl)-5,6,6a,7,8,9-hexahydropyrrolo[1′,2′:4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-4-methylpyridin-3-yl)methyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;
(S)-3-(6-(1-((5-(((6aS,8R)-6a-(difluoromethyl)-2-(2-hydroxy-3-methylphenyl)-5,6,6a, 7,8,9-hexahydropyrrolo[1′,2′:4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-4-methylpyridin-2-yl)methyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;
(S)-3-(6-(1-((5-(((6aR,8R)-6a-ethyl-2-(2-hydroxy-3-methylphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1′,2′:4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-3,4-dimethylpyridin-2-yl)methyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;
(S)-3-(6-(1-((2-(((6aS,8R)-6a-ethyl-2-(2-hydroxy-3-methylphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1′,2′:4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-4,6-dimethylpyrimidin-5-yl)methyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;
(S)-3-(6-(1-((5-(((6aS,8R)-6a-ethyl-2-(2-hydroxy-3-methylphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1′,2′:4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-3-methylpyridin-2-yl)methyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;
(S)-3-(6-(1-((3-chloro-5-(((6aS,8R)-2-(3-chloro-2-hydroxyphenyl)-6a-ethyl-5,6,6a,7,8,9-hexahydropyrrolo[1′,2′:4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy) pyridin-2-yl)methyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;
(S)-3-(6-(1-((6-(((6aR,8R)-2-(3-chloro-2-hydroxyphenyl)-6a-ethyl-5,6,6a,7,8,9-hexahydropyrrolo[11,2′:4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-4-methylpyridin-3-yl)methyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;
(S)-3-(6-(1-((5-(((6aR,8R)-6a-ethyl-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1′,2′:4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-3-fluoropyridin-2-yl)methyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;
(S)-3-(6-(1-((2-(((6aR,8R)-6a-ethyl-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a, 7,8,9-hexahydropyrrolo[1′,2′:4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-4,6-dimethylpyrimidin-5-yl)methyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;
(S)-3-(6-(1-((5-(((6aS,8R)-6a-ethyl-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1′,2′:4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy) pyrazin-2-yl)methyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;
(S)-3-(6-(1-((5-(((6aS,8R)-6a-ethyl-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1′,2′:4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-3-methylpyridin-2-yl)methyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;
(S)-3-(6-(1-((2-(((6aR,8R)-6a-ethyl-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1′,2′:4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-4-methylpyrimidin-5-yl)methyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;
3-(6-(1-((6-(((6aR,8R)-6a-ethyl-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1′,2′:4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-4-methylpyridin-3-yl)methyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;
or a pharmaceutically acceptable salt thereof.

64 more elements

Dependencies are inferred from the claim text.

Facts

Application: 18/467,790Filed 15 Sep 2023 · us provisional application
Priority: 15 Sep 2022
Published: US 2024/0165244 A123 May 2024
Granted: 13 Oct 2026
Term ends: Not estimatedThe source records don’t support an estimate.

Classification3 codes

A61K 47/55
The modifying agent being an organic compound: the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire…
A61K 47/545
The modifying agent being an organic compound: heterocyclic compounds
A61K
Medicines and medical preparations

Family

Application63/375,739Us provisional application · filed 15 Sep 2022
US 2024/0165244 A1Pre-grant publication · published 23 May 2024
US 12,758,641 B2This patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

The disclosure is directed to compounds of Formula I Pharmaceutical compositions comprising compounds of Formula I, as well as methods of their use and preparation, are also described.

A compound of Formula (I):

or a pharmaceutically acceptable salt thereof;
wherein
R1 is halo, C1-6 alkyl, or C1-6 haloalkyl;
each R2 is independently H, D, or F;
each R3 is independently H, D, C1-6 alkyl, C1-6 haloalkyl, C3-6 heterocycloalkyl or C3-6 cycloalkyl;
n is 1, 2 or 3;
m is 1, 2, 3, or 4;
R4 is H, D, C1-6 alkyl, C1-6 alkoxyalkyl, C3-6 cycloalkyl, or C1-6 haloalkyl;
R5 is H, D, or F;
L1 is a bond, O, S, S(O), SO2, NR3, C(R3)2 or CO;
L2 is a bond, O, S, S(O), SO2, NR3, C(R3)2 or CO;
ring A1 is a 6 membered aryl group or a 5-6 membered heteroaryl group;
ring A2 is a 3-7 membered cycloalkyl group or a 4-7-membered heterocycloalkyl group;
X1 is CH2, CO, CH-CH (when X2=CO), or N═CH (when X2=CO);
X2 is CH2, CO, CH═CH (when X1=CO), or N═CH (when X1=CO);
wherein the alkyl group, haloalkyl group, cycloalkyl group, alkoxyalkyl group, aryl group, heteroaryl group or heterocycloalkyl group is optionally substituted by one or more Rf groups;
each Rf is independently D, oxo, halogen, C1-C8 alkoxy, C1-C8alkyl, C1-6 haloalkyl, C1-6 haloalkoxy, —OH, -CN, —NO2, —C2-C6 alkenyl, —C2-C6 alkynyl, C6-10 aryl, C5-12 heteroaryl, C3-8 cycloalkyl, C3-8 cycloalkenyl, C3-8 heterocycloalkyl, C3-8 heterocycloalkenyl, —ORa, —SRa, —NRcRd, —NRaRc, —C(O)Rb, —OC(O)Rb, —C(O)ORb, —C(O)NRcRd, —S(O)Rb, —S(O)2NRcRd, —S(O) (═NRb)Rb, —SF5, —P(O)RbRb, —P(O)RcRd, —P(O)(ORb)(ORb), —B(OR)(ORd), —S(O)2Rb, —C(O)NRbORb, —S(O)2ORb, —OS(O)2ORb, or -OPO(ORb)(ORb);
wherein said C1-C8 alkyl is optionally substituted by 1-6 groups selected from D, halogen, —OH, -CN, —ORa, —SRa, —NRaRd, or NRcRa,
each Ra is independently H, D, —C(O)Rb, —C(O)ORc, —C(O)NRcRd, —C(═NRb)NRbRc, —C(=NORD)NRbRc, —C(═NCN)NRbRc, —P(ORc)2, —P(O)RcRb, —P(O)RcRd, —P(O)ORcORb, —S(O)Rb, —S(O)NRcRd, —S(O)2Rb, —S(O)2NRcRd, SiRb3, —C1-C10 alkyl, —C2-C10 alkenyl, —C2-C10 alkynyl, C6-10 aryl, C3-8 cycloalkyl, C3-8 cycloalkenyl, C5-12 heteroaryl, C3-8 heterocycloalkyl, or C3-8 heterocycloalkenyl;
each Rb, is independently H, D, —C1-C6 alkyl, —C2-C6 alkenyl, —C2-C6 alkynyl, C6-10 aryl, C3-8 cycloalkyl, C3-8 cycloalkenyl, C5-12 heteroaryl, C3-8 heterocycloalkyl, or C3-8 heterocycloalkenyl;
each Rc or Rd is independently H, D, —C1-C10 alkyl, —C2-C6 alkenyl, —C2-C6 alkynyl, —OC1-C6 alkyl, —O-cycloalkyl, C6-10 aryl, C5-12 heteroaryl, C3-8 cycloalkyl, C3-8 cycloalkenyl, C3-8 heterocycloalkyl, or C3-8 heterocycloalkenyl;
or Rc and Rd, together with the atom to which they are both attached, form a monocyclic or multicyclic heterocycloalkyl, or a monocyclic or multicyclic heterocycloalkenyl group.

19 more elements

Facts

Application

18/467,790Filed 15 Sep 2023 · us provisional application

Priority

15 Sep 2022

Published

US 2024/0165244 A123 May 2024

Granted

13 Oct 2026

Term ends

Not estimatedThe source records don’t support an estimate.

Classification3 codes

A61K 47/55
The modifying agent being an organic compound: the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire…
A61K 47/545
The modifying agent being an organic compound: heterocyclic compounds
A61K
Medicines and medical preparations