Pyrimidinyl-pyridyloxy-naphthyl compounds and methods of treating IRE1-related diseases and disorders

Patent metadata

Field	Value
Publication number	US-10968203-B2
Application number	US-201815989008-A
Country	US
Kind code	B2
Filing date	May 24, 2018
Priority date	Mar 17, 2017
Publication date	Apr 6, 2021
Grant date	Apr 6, 2021

Abstract

Described herein are pyrimidinyl-pyridyloxy-naphthyl compounds with inositol requiring enzyme 1 (IRE1) modulation activity or function having the Formula I or I′ structure:

or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, and with the substituents and structural features described herein. Also described are pharmaceutical compositions and medicaments that include the Formula I or I′ compounds, as well as methods of using such IRE1 modulators, alone and in combination with other therapeutic agents, for treating diseases or conditions that are mediated or dependent upon estrogen receptors.

First claim

We claim:

1. A compound of the Formula I′:

or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein:
R 1 is C 3 -C 12 cycloalkyl, C 3 -C 12 heterocyclyl, C 1 -C 12 heteroaryl, C 6 -C 20 aryl, —(C 1 -C 6 alkyldiyl)-(C 3 -C 12 cycloalkyl), or —(C 1 -C 6 alkyldiyl)-(C 3 -C 12 heterocyclyl);
R 2 is H, F, Cl, —CN, —OCH 3 , —OCH 2 CH 3 , or C 1 -C 6 alkyl;
R 3 is H, —CN, C 3 -C 12 cycloalkyl, C 3 -C 12 heterocyclyl, C 1 -C 12 heteroaryl, C 6 -C 20 aryl, —O—(C 1 -C 12 heteroaryl), —O—(C 1 -C 6 alkyldiyl)-(C 6 -C 20 aryl), —N(R 8 )(C 1 -C 6 alkyl), —NR 8 C(O)R 9 , —NR 8 C(O)OR 9 , —NR 8 C(O)NHR 9 , —NR 8 SO 2 -(C 1 -C 6 alkyl), —NR 8 SO 2 -(C 2 -C 6 alkenyl), —NR 8 SO 2 -(C 3 -C 12 cycloalkyl), —NR 8 SO 2 -(C 1 -C 12 heteroaryl), —NR 8 SO 2 -(C 1 -C 6 alkyldiyl)-(C 3 -C 12 cycloalkyl), —NR 8 SO 2 -(C 1 -C 6 alkyldiyl)-(C 3 -C 12 heterocyclyl), —NR 8 SO 2 -(C 1 -C 6 alkyldiyl)-(C 1 -C 12 heteroaryl), —NR 8 SO 2 -(C 1 -C 6 alkyldiyl)-(C 6 -C 20 aryl), —NR 8 SO 2 NR 8 R 9 , or —SO 2 NR 8 R 9 ;
R 4 is H, —CN, C 3 -C 2 cycloalkyl, C 3 -C 12 heterocyclyl, C 1 -C 12 heteroaryl, C 6 -C 20 aryl, —O—(C 1 -C 12 heteroaryl), —O—(C 1 -C 6 alkyldiyl)-(C 6 -C 20 aryl), —NR 8 R 9 , —NR 8 C(O)R 9 , —NR 8 C(O)OR 9 , —NR 8 C(O)NHR 9 , —NR 8 SO 2 -(C 1 -C 6 alkyl), —NR 8 SO 2 -(C 2 -C 6 alkenyl), —NR 8 SO 2 -(C 1 -C 12 heteroaryl), —NR 8 SO 2 -(C 3 -C 12 cycloalkyl), —NR 8 SO 2 -(C 3 -C 12 heterocyclyl), —NR 8 SO 2 -(C 1 -C 6 alkyldiyl)-(C 3 -C 12 cycloalkyl), —NR 8 SO 2 -(C 1 -C 6 alkyldiyl)-(C 3 -C 12 heterocyclyl), —NR 8 SO 2 -(C 1 -C 6 alkyldiyl)-(C 1 -C 12 heteroaryl), —NR 8 SO 2 -(C 1 -C 6 alkyldiyl)-(C 6 -C 20 aryl), —NR 8 SO 2 NR 8 R 9 , or —SO 2 NR 8 R 9 ;
each R 5 and R 7 are independently H, F, Cl, —CN, —CH 2 H, —C(O)NH 2 , —OH, —OCH 3 , —OCH 2 CH 3 , or C 1 -C 6 alkyl;
n is 0, 1, 2, or 3;
each R 6 is independently H, F, Cl, Br, I, —CN, —NO 2 , —O—(C 1 -C 6 alkyl) or C 1 -C 6 alkyl;
each R 8 is independently H, or C 1 -C 6 alkyl;
each R 9 is independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 3 -C 2 cycloalkyl, C 3 -C 12 heterocyclyl, C 1 -C 12 heteroaryl, C 6 -C 20 aryl; —(C 1 -C 6 alkyldiyl)-(C 3 -C 12 cycloalkyl), —(C 1 -C 6 alkyldiyl)-(C 3 -C 2 heterocyclyl), —(C 1 -C 6 alkyldiyl)-(C 1 -C 6 heteroaryl), —(C 1 -C 6 alkyldiyl)-(C 6 -C 20 aryl), or —(C 1 -C 6 alkyldiyl)-O—(C 6 -C 20 aryl); and
wherein cycloalkyl, heterocyclyl, heteroaryl, aryl, alkyl, alkyldiyl, and alkenyl are optionally and independently substituted with one or more substituents selected from the group consisting of F, Cl, Br, I, —CN, —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , —CH(CH 3 ) 2 , —CH 2 CH(CH 3 ) 2 , —CH(CH 3 )CH 2 CH 3 , —CH 2 C(CH 3 ) 3 , —CH 2 OH, —CH 2 OCH 3 , —CH 2 CH 2 OH, —C(CH 3 ) 2 OH, —CH(OH)CH(CH 3 ) 2 , —C(CH 3 ) 2 CH 2 OH, —CH 2 CH 2 CH 2 OH, —CH 2 CH 2 C(CH 3 ) 2 OH, —CH 2 CH 2 OCH 3 , —CH 2 CH(CH 3 )OCH 3 , —CH 2 CH 2 CH 2 OCH 3 , —CH 2 CH 2 C(CH 3 ) 2 OCH 3 , —CH 2 CH 2 SO 2 CH 3 , —CH 2 OP(O)(OH) 2 , —CH 2 F, —CHF 2 , —CH 2 NH 2 , —CH 2 NHSO 2 CH 3 , —CH 2 NHCH 3 , —CH 2 N(CH 3 ) 2 , —CF 3 , —CH 2 CF 3 , —CH 2 CHF 2 , —CH 2 CH 2 CHF 2 , —CH 2 CH 2 CF 3 , —CH(CH 3 )CN, —C(CH 3 ) 2 CN, —CH 2 CN, —CO 2 H, —COCH 3 , —C 2 CH 3 , —CO 2 C(CH 3 ) 3 , —COCH(OH)CH 3 , —CONH 2 , —CONHCH 3 , —CONHCH 2 CH 3 , —CONHCH(CH 3 ) 2 , —CON(CH 3 ) 2 , —C(CH 3 ) 2 CONH 2 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —N(CH 3 )CH 2 CH 3 , —NHCOCH 3 , —N(CH 3 )COCH 3 , —NHS(O) 2 CH 3 , —N(CH 3 )C(CH 3 ) 2 CONH 2 , —N(CH 3 )CH 2 CH 2 S(O) 2 CH 3 , —NO 2 , ═O, —OH, —OCH 3 , —OCH 2 CH 3 , —OCH 2 CH 2 OCH 3 , —OCH 2 CH 2 OH, —OCH 2 CH 2 N(CH 3 ) 2 , —OP(O)(OH) 2 , —S(O) 2 N(CH 3 ) 2 , —SCH 3 , —S(O) 2 CH 3 , —S(O) 3 H, cyclopropyl, cyclopropylamide, cyclobutyl, oxetanyl, azetidinyl, 1-methylazetidin-3-yloxy, N-methyl-N-oxetan-3-ylamino, azetidin-1-ylmethyl, benzyloxyphenyl, pyrrolidin-1-yl, pyrrolidin-1-yl-methanone, phenyl, piperazin-1-yl, piperidin-1-yl, morpholinomethyl, morpholino-methanone, and morpholino.

2. The compound of claim 1 , or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein the compound is of the Formula Ij:

wherein R 11 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 12 heteroaryl, C 3 -C 12 cycloalkyl, C 3 -C 12 heterocyclyl, —(C 1 -C 6 alkyldiyl)-(C 3 -C 12 cycloalkyl), —(C 1 -C 6 alkyldiyl)-(C 3 -C 12 heterocyclyl), —(C 1 -C 6 alkyldiyl)-(C 1 -C 12 heteroaryl), —(C 1 -C 6 alkyldiyl)-(C 6 -C 20 aryl), —NR 8 —(C 1 -C 12 heteroaryl), —NR 8 —(C 1 -C 6 alkyl), or —NR 8 —(C 1 -C 6 alkyldiyl)-(C 6 -C 20 aryl); wherein cycloalkyl, heterocyclyl, heteroaryl, aryl, alkyl, alkyldiyl, and alkenyl are optionally and independently substituted as defined in claim 1 .

3. The compound of claim 1 , or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R 1 is optionally substituted C 3 -C 12 cycloalkyl or optionally substituted C 3 -C 12 heterocyclyl.

4. The compound of claim 3 , or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R 1 is cyclohexyl or piperidinyl, optionally substituted with one or more substituents selected from the group consisting of F, —CH 3 , and —NH 2 .

5. The compound of claim 3 , or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R 1 is selected from the group consisting of piperidin-3-yl, 5-fluoropiperidin-3-yl, 5-methylpiperidin-3-yl and 5-fluoro-5-methylpiperidin-3-yl.

6. The compound of claim 1 , or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein the compound is of the Formula Ih:

wherein R 10a and R 10b are independently H, F, —CH 3 or —NH 2 .

7. The compound of claim 2 , or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein the compound is of the Formula Ik:

wherein R 10a and R 10b are independently H, F or —CH 3 .

8. The compound of claim 1 , or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein each R 6 is independently H, F, Cl, Br, —OCH 3 , or C 1 -C 6 alkyl.

9. The compound of claim 6 , or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein the compound is of the Formula Ii:

10. The compound of claim 1 , or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R 2 is H, F, Cl or C 1 -C 6 alkyl.

11. The compound of claim 10 , or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R 2 is methyl.

12. The compound of claim 1 , or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R 7 is hydrogen or fluoro.

13. The compound of claim 1 , or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R 5 is H, F, Cl or CH 3 .

14. The compound of claim 1 , or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R 3 is H.

15. The compound of claim 9 , or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein the compound is of the Form

Assignees

• Genentech Inc
• Univ California

Inventors

• Braun Marie-Gabrielle
• Gibbons Paul
• Lee Wendy
• Ly Cuong
• Rudolph Joachim
• Schwarz Jacob
• Ashkenazi Avi
• Fu Leo
• Lai Tommy
• Wang Fei
• Beveridge Ramsay
• Zhao Liang

Classifications

• C07D413/14 Primary

  containing three or more hetero rings · CPC title

• A61P35/00 Primary

  Antineoplastic agents · CPC title

• A61K31/506

  not condensed and containing further heterocyclic rings · CPC title

• C07D401/14 Primary

  containing three or more hetero rings · CPC title

• C07D401/04

  directly linked by a ring-member-to-ring-member bond · CPC title