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US 2022/0033409 A1Published application
Brm targeting compounds and associated methods of use
AssigneePrelude Therapeutics Incorporated
InventorsHong Lin, Philip Pitis, Liang Lu, Andrew Paul Combs
Life of this patent
Estimating the term…
Abstract
The present disclosure provides bifunctional compounds comprising a target protein binding moiety and a E3 ubiquitin ligase binding moiety, and associated methods of use.
Claims22
-45. (canceled)
A compound of Formula IA-7 or IA-8:
- or a pharmaceutically acceptable salt or solvate thereof,
- wherein:
- R1 is a chemical moiety represented by the formula:
- —(A)q—,
- wherein:
- q is an integer from 1 to 14;
- each A is independently selected from the group consisting of CR1aR1b, O, S, SO, SO2, NR1c, SO2NR1c, SONR1c, SO(═NR1c), SO(═NR1c)NR1d, CONR1c, NR1cCONR1d, NR1cC(O)O, NR1cSO2NR1d, CO, CR1a═CR1b, C≡C, SiR1aR1b, P(O)R1a, P(O)OR1a, (CR1aR1b)1-4, —(CR1aR1b)1-4O(CR1aRth)1-4, —(CR1aR1b)1-4S(CR1aRth)1-4, —(CR1aR1b)1-4NR(CR1aR1b)1-4, NR1cC(═NCN)NR1dNR1cC(═NCN), NR1cC(═CNO2)NR1d, 3-11 membered cycloalkyl, optionally substituted with 0-6 R1a and/or R1b groups, 3-11 membered heterocyclyl optionally substituted with 0-6 R1a and/or R1b groups, aryl optionally substituted with 0-6 R1a and/or R1b groups, or heteroaryl optionally substituted with 0-6 R1a and/or R1b groups,
- wherein R1a, R1b, R1c, R1d and R1e are each independently, —H, D, -halo, —C1-C8alkyl, —O—C1-C8alkyl, —C1-C6haloalkyl, —N(C1-C8alkyl)2, 3-11 membered cycloalkyl, aryl, heteroaryl, 3-11 membered heterocyclyl, —O-(3-11 membered cycloalkyl), —S-(3-11 membered cycloalkyl), NH-(3-11 membered cycloalkyl), N(3-11 membered cycloalkyl)2, N-(3-11 membered cycloalkyl)(C1-C8alkyl), —OH, —NH2, —SH, —SO2C1-C8alkyl, SO(NH)C1-C8alkyl, P(O)(OC1-C8alkyl)(C1-C8alkyl), —P(O)(OC1-C8alkyl)2, —C≡C—C1-C8alkyl, —C≡CH, —CH═CH(C1-C8alkyl), —C(C1-C8alkyl)═CH(C1-C8alkyl), —C(C1-C8alkyl)═C(C1-C8alkyl)2, —Si(OH)3, —Si(C1-C8alkyl)3, —Si(OH)(C1-C8alkyl)2, —C(O)C1-C8alkyl, —CO2H, —CN, —CF3, —CHF2, —CH2F, —NO2, —SF5, —SO2NHC1-C8alkyl, —SO2N(C1-C8alkyl)2, —SO(NH)NHC1-C8alkyl, —SO(NH)N(C1-C8alkyl)2, —SONHC1-C8alkyl, —SON(C1-C8alkyl)2, —CONHC1-C8alkyl, —CON(C1-C8alkyl)2, —N(C1-C8alkyl)CONH(C1-C8alkyl), —N(C1-C8alkyl)CON(C1-C8alkyl)2, —NHCONH(C1-C8alkyl), —NHCON(C1-C8alkyl)2, —NHCONH2, —N(C1-C8alkyl)SO2NH(C1-C8alkyl), —N(C1-C8alkyl)SO2N(C1-C8alkyl)2, —NHSO2NH(C1-C8alkyl), —NHSO2N(C1-C8alkyl)2, or —NHSO2NH2;
- and where R1a or R1b, each independently may be optionally linked to other groups to form cycloalkyl and/or heterocyclyl moiety, optionally substituted with 0-4 R1e groups;
- m=1 to 3;
- W is optionally substituted —CH2—, —C(O)—, —S(O)—, or —S(O)2—;
- wherein when n=2 or 3, only one W may be —C(O)—, —S(O)—, or —S(O)2—;
- Rc1 and Rd1 are independently H, D, Halo, C1-3 alkyl, C1-3 haloalkyl, or C1-4 alkoxyl;
- Re3 is H, —C(O)Rf, or —P(O)(ORg)2;
- wherein Rf and Rg are independently H, C1-4 alkyl, C1-4 substituted alkyl, C3-8 cyclcoalkyl, C3-8 substituted cyclcoalkyl, C3-8 heterocyclcoalkyl, or C3-8 substituted heterocyclcoalkyl;
- wherein;
- X is optionally substituted —CH2—, or NH;
- or, if R1 is attached to X, then X is —CH— or N;
- and Q is optionally substituted —CH2—, optionally substituted —(CH2)2—, —C(O)—, optionally substituted —CH2C(O)—, —S(O)—, —S(O)2—, optionally substituted —CH2S(O)2—, or optionally substituted —CH2S(O)—
- R9 is —CN or optionally substituted
- V is H or F;
- R4 is H, D, haloalkyl, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, —CORd, or —CONRe1Re2;
- R7 is H, D, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted haloalkyl, Rd is H, or optionally substituted alkyl;
- each Re1 and Re2 is independently H, D, optionally substituted alkyl,
- or Re1 and Re2 together with the nitrogen atom to which they are attached form a 4-7 membered heterocyclyl.
22 more elements
A compound, where said compound is a compound of Formula IA-9a or IA-10a:
- or a pharmaceutically acceptable salt or solvate thereof,
- wherein X is N or CH;
- R1 is a chemical moiety represented by the formula:
- —(A)q—,
- wherein:
- q is an integer from 1 to 14;
- each A is independently selected from the group consisting of CR1aR1b, O, S, SO, SO2, NR1c, SO2NR1c, SONR1c, SO(═NR1c), SO(═NR1c)NR1d, CONR1c, NR1cCONR1d, NR1cC(O)O, NR1cSO2NR1d, CO, CR1a═CR1b, C≡C, SiR1aR1b, P(O)R1a, P(O)OR1a, (CR1aR1b)1-4, —(CR1aR1b)1-4O(CR1aR1b)1-4, —(CR1aR1b)1-4S(CR1aR1b)1-4, —(CR1aR1b)1-4NR(CR1aR1b)1-4 NR1cC(═NCN)NR1dNR1cC(═NCN), NR1cC(═CNO2)NR1d, 3-11 membered cycloalkyl, optionally substituted with 0-6 R1a and/or R1b groups, 3-11 membered heterocyclyl optionally substituted with 0-6 R1a and/or R1b groups, aryl optionally substituted with 0-6 R1a and/or R1b groups, or heteroaryl optionally substituted with 0-6 R1a and/or R1b groups,
- wherein R1a, R1b, R1c, R1d and R1e are each independently, —H, D, -halo, —C1-C8alkyl, —O—C1-C8alkyl, —C1-C6haloalkyl, —S—C1-C8alkyl, —NHC1-C8alkyl, —N(C1-C8alkyl)2, 3-11 membered cycloalkyl, aryl, heteroaryl, 3-11 membered heterocyclyl, —O-(3-11 membered cycloalkyl), —S-(3-11 membered cycloalkyl), NH-(3-11 membered cycloalkyl), N(3-11 membered cycloalkyl)2, N-(3-11 membered cycloalkyl)(C1-C8alkyl), —OH, —NH2, —SH, —SO2C1-C8alkyl, SO(NH)C1-C8alkyl, P(O)(OC1-C8alkyl)(C1-C8alkyl), —P(O)(OC1-C8alkyl)2, —C≡C—C2-C8alkyl, —C≡CH, —CH═CH(C1-C8alkyl), —C(C1-C8alkyl)═CH(C1-C8alkyl), —C(C1-C8alkyl)═C(C1-C8alkyl)2, —Si(OH)3, —Si(C1-C8alkyl)3, —Si(OH)(C1-C8alkyl)2, —C(O)C1-C8alkyl, —CO2H, —CN, —CF3, —CHF2, —NO2, —SF5, —SO2NHC1-C8alkyl, —SO2N(C1-C8alkyl)2, —SO(NH)NHC1-C8alkyl, —SO(NH)N(C1-C8alkyl)2, —SONHC1-C8alkyl, —SON(C1-C8alkyl)2, —CONHC1-C8alkyl, —CON(C1-C8alkyl)2, —N(C1-C8alkyl)CONH(C1-C8alkyl), —N(C1-C8alkyl)CON(C1-C8alkyl)2, —NHCONH(C1-C8alkyl), —NHCON(C1-C8alkyl)2, —NHCONH2, —N(C1-C8alkyl)SO2NH(C1-C8alkyl), —N(C1-C8alkyl)SO2N(C1-C8alkyl)2, —NHSO2NH(C1-C8alkyl), —NHSO2N(C1-C8alkyl)2, or —NHSO2NH2;
- and where R1a or R1b, each independently may be optionally linked to other groups to form cycloalkyl and/or heterocyclyl moiety, optionally substituted with 0-4 R1e groups;
- n=0-3;
- m=1 to 3;
- Rk is C1-3 alkyl, and s=0 or 1
- W is optionally substituted —CH2—, —C(O)—, —S(O)—, or —S(O)2—;
- wherein when n=2 or 3, only one W may be —C(O)—, —S(O)—, or —S(O)2—;
- Rc1 and Rd1 are independently H, D, Halo, C1-3 alkyl, C1-3 haloalkyl, or C1-4 alkoxyl;
- Re3 is H, —C(O)Rf, or —P(O)(ORg)2;
- wherein Rf and Rg are independently H, C1-4 alkyl, C1-4 substituted alkyl, C3-8 cyclcoalkyl, C3-8 substituted cyclcoalkyl, C3-8 heterocyclcoalkyl, or C3-8 substituted heterocyclcoalkyl;
- wherein;
- R9 is —CN or optionally substituted
- V is H or F;
- R4 is H, D, haloalkyl, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, —CORd, or —CONRe1Re2;
- R7 is H, D, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted haloalkyl,
- Rd is H, or optionally substituted alkyl;
- each Re1 and Re2 is independently H, D, optionally substituted alkyl,
- or Re1 and Re2 together with the nitrogen atom to which they are attached form a 4-7 membered heterocycyl.
22 more elements
-87. (canceled)
(canceled)
Dependencies are inferred from the claim text.