Inhibitors of EGFR and/or HER2 and methods of use

Patent metadata

Field	Value
Publication number	US-11945816-B2
Application number	US-202117451538-A
Country	US
Kind code	B2
Filing date	Oct 20, 2021
Priority date	Aug 31, 2017
Publication date	Apr 2, 2024
Grant date	Apr 2, 2024

Abstract

The application relates to a compound having Formula X: which modulates the activity of HER2 and/or a mutant thereof, and/or EGFR and/or a mutant thereof, a pharmaceutical composition comprising the compound, and a method of treating or preventing a disease in which HER2 and/or a mutant thereof, and/or EGFR and/or a mutant thereof, plays a role.

First claim

The invention claimed is:

1. A compound of Formula X:

or a pharmaceutically acceptable salt thereof, wherein:
X 1 is CH or N;
X 2 is N;
X 3 is —NR 2 —C(O)— or —N═CR 2 —;
X 4 is NH, O, or S;
R 1 is H, C 1 -C 4 alkyl, C(O)—(C 1 -C 4 alkyl), C 3 -C 8 cycloalkyl, heterocyclyl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, phenyl, or heteroaryl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the cycloalkyl, heterocyclyl, phenyl, or heteroaryl is optionally substituted with one or more R a1 ; and R 2 is Q-R 2 ′, wherein Q is (CH 2 )O 3 and R 2 ′ is C 3 -C 8 cycloalkyl, heterocyclyl comprising one 4- to 7-membered ring and 1-3 heteroatoms selected from N, O, and S, phenyl, or heteroaryl comprising one 5- or 6-membered ring and 1-3 heteroatoms selected from N, O, and S, wherein the cycloalkyl, heterocyclyl, phenyl, or heteroaryl is substituted with one or more R b1 , provided that when Q is (CH 2 ) 0 , R 2 ′ is pyrrolidinyl, and R 3 is phenyl or phenyl substituted with halogen, then R 1 is not substituted phenyl; or
R 1 is phenyl or heteroaryl comprising one 5- or 6-membered ring and 1-3 heteroatoms selected from N, O, and S, wherein the phenyl or heteroaryl is substituted with one or more R a2 ; and R 2 is H, NH 2 , C 1 -C 4 alkyl, or C 3 -C 6 cycloalkyl, wherein the alkyl or cycloalkyl is optionally substituted with one or more R b2 ;
R 3 is C 6 -C 10 aryl or heteroaryl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the aryl or heteroaryl is optionally substituted with one or more R 7 ;
R 4 and R 5 are each independently H or C 1 -C 4 alkyl;
each R 7 is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, OH, halogen, CN, or NR n3 R n4 ;
each R a1 is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, OH, halogen, NH—C(O)—(C 2 -C 4 alkenyl), NR n3 R n4 , O—(CH 2 ) 1-4 —NR n1 R n2 , NR n1 —(CH 2 ) 1-4 —NR n2 , C 3 -C 8 cycloalkyl, heterocyclyl comprising one or two 4- to 6-membered rings and 1-4 heteroatoms selected from N, O, and S, phenyl, or heteroaryl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the alkyl, cycloalkyl, heterocyclyl, phenyl, or heteroaryl is optionally substituted with one or more R 11 ;
each R b1 is independently W, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, OH, halogen, or NR n3 R n4 , wherein at least one R b1 is W, or when the at least one R b1 is bonded to a nitrogen atom in a heterocyclyl ring comprising at least one nitrogen atom, R b1 is C(O)R 9 ;
each R a2 is independently W, NH—C(O)—(C 1 -C 4 alkyl), C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, OH, halogen, NR n3 R n4 , O—(CH 2 ) 0-4 —NR n1 R n2 , NR n1 —(CH 2 ) 1-4 —NR n1 R n2 , C 3 -C 8 cycloalkyl, heterocyclyl comprising one or two 4- to 6-membered rings and 1-4 heteroatoms selected from N, O, and S, phenyl, or heteroaryl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the alkyl, cycloalkyl, heterocyclyl, phenyl, or heteroaryl is optionally substituted with one or more R 11 , wherein at least one R a2 is W;
each R b2 is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, OH, halogen, NR n3 R n4 , or heterocyclyl comprising one 4- to 6-membered rings and 1 or 2 heteroatoms selected from N, O, and S;
each R 8 is independently H or C 1 -C 4 alkyl;
each R 9 is independently C 2 -C 4 alkenyl optionally substituted with one or more R 10 ;
each R 10 is independently NR n3 R n4 ;
each R 11 is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, OH, halogen, CN, NR n3 R n4 , C 3 -C 8 cycloalkyl, or heterocyclyl comprising one or two 4- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the cycloalkyl or heterocyclyl is optionally substituted with one or more C 1 -C 6 alkyl, halogen, or C(O)—(C 2 -C 4 alkenyl);
each R n1 and each R n2 are independently H or C 1 -C 4 alkyl, or R n1 and R n2 , together with the nitrogen atom to which they are bonded, form a 4- to 7-membered heterocyclyl ring comprising 1 to 3 heteroatoms selected from N, O, and S, wherein the heterocyclyl is optionally substituted with one or more C 1 -C 6 alkyl;
each R n3 and each R n4 are independently H or C 1 -C 4 alkyl;
W is NR 8 C(O)R 9 , C(O)R 9 , or is of formula:

L 3 is a bond or an optionally substituted C 1 -C 4 hydrocarbon chain, optionally wherein one or more carbon units of the hydrocarbon chain are independently replaced with —C═O—, —O—, —S—, —NR L3a —, —NR L3a C(═O)—, —C(═O)NR L3a —, —SC(═O)—, —O(═O)S—, —OC(═O)—, —C(═O)O—, —NR L3a C(═S)—, —C(═S)NR L3a —, trans-CR L3b ═CR L3b —, cis-CR L3b ═CR L3b , —C≡C—, —S(═O)—, —S(═O)O—, —OS(═O)—, —S(═O)NR L3a —, —NR L3a S(═O)—, —S(═O) 2 —, —S(═O) 2 O—, —OS(═O) 2 —, —S(═O) 2 NR L3a —, or —NR L3a S(═O) 2 —;
R L3a is H, optionally substituted C 1 -C 6 alkyl, or a nitrogen protecting group;
each R L3b is independently H, halogen, optionally substituted C 1 -O 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted heterocyclyl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, optionally substituted C 6 -C 10 aryl, or optionally substituted heteroaryl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, or two R L3b groups are joined to form an optionally substituted C 3 -C 8 carbocycle or optionally substituted 4- to 7-membered heterocyclyl ring comprising 1 to 3 heteroatoms selected from N, O, and S;
L 4 is a bond or an optionally substituted C 1 -C 6 hydrocarbon chain;
each of R E1 , R E2 , and R E3 is independently H, halogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted heterocyclyl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, optionally substituted 06-C 10 aryl, or optionally substituted heteroaryl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, CN, CH 2 OR EE , CH 2 N(R EE ) 2 , CH 2 SR EE , OR EE , N(R EE ) 2 , Si(R EE ) 3 , or SR EE , or R E1 and R E3 , or R E2 and R E3 , or R E1 and R E2 are joined to form an optionally substituted C 3 -C 8 carbocycle or optionally substituted 4- to 7-membered heterocyclyl ring comprising 1 to 3 heteroatoms selected from N, O, and S;
each R EE is independently H, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 alkoxy, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted heterocyclyl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selec

Assignees

• Dana Farber Cancer Inst Inc

Inventors

• Hatcher John M
• Gray Nathanael S
• Jang Jaebong
• De Clercq Dries
• Janne Pasi
• Saxon Jamie A
• Eck Michael
• Scott David A
• Verano Alyssa

Classifications

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• C07D487/04

  Ortho-condensed systems · CPC title

• A61P35/00 Primary

  Antineoplastic agents · CPC title