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US 10,913,727 B2Granted
Modulators of the integrated stress pathway
AssigneeAbbVie Inc.
InventorsMarina Pliushchev, Jennifer M. Frost, Lawrence A. Black, Xiangdong Xu, Ramzi Farah Sweis, Lei Shi, Qingwei I. Zhang, Yunsong Tong, Charles W. Hutchins, Seungwon Chung, Michael J. Dart
Life of this patent
Estimating the term…
Abstract
Provided herein are compounds, compositions, and methods useful for modulating the integrated stress response (ISR) and for treating related diseases; disorders and conditions.
Claims18
A compound of Formula (I):
- or a pharmaceutically acceptable salt thereof, wherein:
- D is selected from the group consisting of
- L1 is CH2O—*, wherein “—*” indicates the attachment point to A;
- R1 and R2 are each independently hydrogen or C1-C6 alkyl;
- Q is C(O) or S(O)2;
- A is phenyl and W is phenyl or 5-6 membered heteroaryl, wherein each phenyl or 5-6-membered heteroaryl is optionally substituted with 1-5 RY;
- each RX is independently selected from the group consisting of C1-C6 alkyl, hydroxy-C1-C6 alkyl, halo-C1-C6 alkyl, amino-C1-C6 alkyl, cyano-C1-C6 alkyl, oxo, halo, cyano, —ORA, —NRBRC, —NRBC(O)RD, —C(O)NRBRC, —C(O)RD, —C(O)OH, —C(O)ORD, —SRE, —S(O)RB, —S(O)2RD, and G2;
- each RY is independently selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 alkenyl, hydroxy-C1-C6 alkyl, hydroxy-C1-C6 alkenyl, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, amino-C1-C6 alkyl, amido-C1-C6 alkyl, cyano-C1-C6 alkyl, siloxy-C1-C6 alkoxy, hydroxyl-C1-C6 alkoxy, C1-C6 alkoxy-C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkenyl, C1-C6 alkoxy-C1-C6 alkoxy, oxo, halo, cyano, —ORA, —NRBRC, —NRBC(O)RD, —C(O)NRBRC, —C(O)RD, —C(O)OH, —C(O)ORD, —S(RF)m, —S(O)RD, —S(O)2RD, —S(O)NRBRC, —NRBS(O)2RD, —OS(O)RD, —OS(O)2RD, RFS—C1-C6 alkyl, RDC(O)NRB—C1-C6 alkyl, (RB)(RC)N—C1-C6 alkoxy, RDOC(O)NRB—C1-C6 alkyl, G1, G1-C1-C6 alkyl, G1-N(RB), G1-C1-C6 alkenyl, G1-O—, G1C(O)NRB—C1-C6 alkyl, and G1-NRBC(O);
- or
- 2 RY groups on adjacent atoms, together with the atoms to which they are attached form a fused phenyl, a 3-7-membered fused cycloalkyl ring, a 3-7-membered fused heterocyclyl ring, or a 5-6-membered fused heteroaryl ring, each optionally substituted with 1-5 RX;
- each G1 or G2 is independently 3-7 membered cycloalkyl, 4-7-membered heterocyclyl, aryl, or 5-6-membered heteroaryl, wherein each 3-7 membered cycloalkyl, 4-7-membered heterocyclyl, aryl, or 5-6-membered heteroaryl is optionally substituted with 1-6 RZ;
- each RZ is independently selected from the group consisting of ORA, C(O)RD, halo, halo C1-C6 alkyl, C1-C6 alkyl, C(O)RD, and C(O)ORD;
- RA is, at each occurrence, independently hydrogen, C1-C6 alkyl, halo-C1-C6 alkyl, —ORA1, —C(O)NRBRC, —C(O)RD, —C(O)OH, or —C(O)ORD;
- each of RB and RC is independently hydrogen, C1-C6 alkyl, hydroxy-C1-C6 alkyl, G1-C1-C6 alkyl, 3-7 membered cycloalkyl, or 4-7-membered heterocyclyl, wherein each alkyl, cycloalkyl, or heterocyclyl is optionally substituted with 1-6 RZ;
- or
- RB and RC together with the atom to which they are attached form a 3-7-membered cycloalkyl or heterocyclyl ring optionally substituted with 1-6 RZ;
- RD is, at each occurrence, independently C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkyl, or halo-C1-C6 alkyl;
- each RE is independently hydrogen C1-C6 alkyl, or halo-C1-C6 alkyl;
- each RF is independently hydrogen, C1-C6 alkyl, or halo;
- each RA1 is hydrogen, C1-C6 alkyl, halo-C1-C6 alkyl, 3-7 membered cycloalkyl, or 4-7-membered heterocyclyl;
- m is 1, 3, or 5;
- and
- t is 0 or 1.
20 more elements
A compound represented by Formula (I-b):
- or a pharmaceutically acceptable salt thereof, wherein:
- D is bicyclo[1.1.1]pentane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, or bicyclo[2.1.1]hexane, each of which is optionally substituted with 1-4 RX;
- L1 CH2O—*, wherein “—*” indicates the attachment point to A;
- R1 and R2 are each independently hydrogen or C1-C6 alkyl;
- A is phenyl optionally substituted with 1-2 RY;
- W is phenyl or 5-6 membered heteroaryl, wherein each phenyl or 5-6-membered heteroaryl is optionally substituted with 1-5 RY;
- each RX is independently C1-C6 alkyl, fluoro, chloro, oxo, OCH3, C(O)OCH3, or G2;
- each RY is independently chloro, fluoro, oxo, CN, OH, CF3, CHF2, CH3, CH2CH3, CH2CH2CH2CH3, CH═CHCH2OH, CH2CH2OH, CH2NH2, NHCH3, CH2NHC(O)CH3, N(CH2CH3)2, CH2N(CH3)2, C(CH3)2OH, CH(CH3)2, CH2CH2CH3, C(CH3)3, CH2CH(CH3)2, CH2CH2OH, CH(OH)CH3, CH2CH2CH2OCH3, CH2CF3, CH2C(CH3)2OH, CH2SCH3, CH2CN, CH2CH2CN, CH2CH2C(CH3)2OH, CH2NHC(O)CH3, OCH3, OCH2CH3, OCH2CH2CH3, OCH2CH2OCH3, OCH(CH3)2, OCF3, OCH2CF3, OCH2CH2N(CH3)2, CH2OH, CH2OCH3, OCH2CH2OH, OCHF2, OCF3, OCH3, CH2OH, C(O)OH, C(O)CH3, C(O)OCH3, C(O)NH2, C(O)NHCH2CH2CH2OH, CH2CN, C(O)OCH2CH3, C(O)NHCH2CH3, OCH2CH2OSi(CH3)2C(CH3)3, CH2N(CH3)2, CH2NHC(O)CH3, CH2NHC(O)OC(CH3)3, CH═CHCH2OCH3, CH═CHC(CH3)2OH, N(CH3)2, N(CH2CH3)2, NHCH2CH3, NHC(O)CH3, NHC(O)CH2OCH3, NHS(O)2CH3, SCH3, SCH2CH3, SO2NH2, S(O)CH3, S(O)2CH3, G1, C(O)NHG1, N(CH3)CH2G1, NHG1, OG1, CH2G1, CH2CH2G1, CH2NHC(O)G1, or CH═CHG1;
- or
- 2 RY groups on adjacent atoms, together with the atoms to which they are attached form a 5-7-membered fused heterocyclyl ring, 5-6-membered fused heteroaryl, a 5-6-membered fused cycloalkyl, or a fused phenyl, each optionally substituted with 1-5 RX;
- G1 and G2 are each independently pyrrolidinyl, azetidinyl, cyclopropyl, cyclohexyl, cyclohexenyl, tetrahydropyranyl, dihydropyranyl, tetrahydropyridinyl, piperidinyl, phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazolyl, morphilino, furanyl, triazolyl, oxetanyl, or pyrazinyl, each of which is optionally substituted with 1-5 RZ;
- each RZ is independently fluoro, chloro, OH, OCH3, oxo, CH3, CHF2, CF3, C(O)CH3 or C(O)OC(CH3)3;
- and
- t is 0 or 1.
11 more elements
A compound selected from the group consisting of:
- or a pharmaceutically acceptable salt thereof.
Dependencies are inferred from the claim text.