US 11,945,816 B2
Inhibitors of EGFR and/or HER2 and methods of use
John M. Hatcher, Boston, MA (US); Nathanael S. Gray, Boton, MA (US); Jaebong Jang, Brookline, MA (US); Dries De Clercq, Boston, MA (US); Pasi Janne, Needham, MA (US); Jamie A. Saxon, Boston, MA (US); Michael Eck, Boston, MA (US); David A. Scott, Boston, MA (US); and Alyssa Verano, Boston, MA (US)
Assigned to Dana-Farber Cancer Institute, Inc., Boston, MA (US)
Filed by Dana-Farber Cancer Institute, Inc., Boston, MA (US)
Filed on Oct. 20, 2021, as Appl. No. 17/451,538.
Application 17/451,538 is a division of application No. 16/643,092, granted, now 11,186,574, previously published as PCT/US2018/049186, filed on Aug. 31, 2018.
Claims priority of provisional application 62/552,531, filed on Aug. 31, 2017.
Prior Publication US 2022/0106310 A1, Apr. 7, 2022
Int. Cl. C07D 471/04 (2006.01); A61K 31/4985 (2006.01); A61K 31/519 (2006.01); A61P 35/00 (2006.01); C07D 487/04 (2006.01)
CPC C07D 471/04 (2013.01) [C07D 487/04 (2013.01)] 16 Claims
 
1. A compound of Formula X:

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or a pharmaceutically acceptable salt thereof, wherein:
X1 is CH or N;
X2 is N;
X3 is —NR2—C(O)— or —N═CR2—;
X4 is NH, O, or S;
R1 is H, C1-C4 alkyl, C(O)—(C1-C4 alkyl), C3-C8 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 Ra1; and R2 is Q-R2′, wherein Q is (CH2)O3 and R2′ is C3-C8 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 Rb1, provided that when Q is (CH2)0, R2′ is pyrrolidinyl, and R3 is phenyl or phenyl substituted with halogen, then R1 is not substituted phenyl; or
R1 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 Ra2; and R2 is H, NH2, C1-C4 alkyl, or C3-C6 cycloalkyl, wherein the alkyl or cycloalkyl is optionally substituted with one or more Rb2;
R3 is C6-C10 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 R7;
R4 and R5 are each independently H or C1-C4 alkyl;
each R7 is independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH, halogen, CN, or NRn3Rn4;
each Ra1 is independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH, halogen, NH—C(O)—(C2-C4 alkenyl), NRn3Rn4, O—(CH2)1-4—NRn1Rn2, NRn1—(CH2)1-4—NRn2, C3-C8 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 R11;
each Rb1 is independently W, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH, halogen, or NRn3Rn4, wherein at least one Rb1 is W, or when the at least one Rb1 is bonded to a nitrogen atom in a heterocyclyl ring comprising at least one nitrogen atom, Rb1 is C(O)R9;
each Ra2 is independently W, NH—C(O)—(C1-C4 alkyl), C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH, halogen, NRn3Rn4, O—(CH2)0-4—NRn1Rn2, NRn1—(CH2)1-4—NRn1Rn2, C3-C8 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 R11, wherein at least one Ra2 is W;
each Rb2 is independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH, halogen, NRn3Rn4, or heterocyclyl comprising one 4- to 6-membered rings and 1 or 2 heteroatoms selected from N, O, and S;
each R8 is independently H or C1-C4 alkyl;
each R9 is independently C2-C4 alkenyl optionally substituted with one or more R10;
each R10 is independently NRn3Rn4;
each R11 is independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH, halogen, CN, NRn3Rn4, C3-C8 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 C1-C6 alkyl, halogen, or C(O)—(C2-C4 alkenyl);
each Rn1 and each Rn2 are independently H or C1-C4 alkyl, or Rn1 and Rn2, 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 C1-C6 alkyl;
each Rn3 and each Rn4 are independently H or C1-C4 alkyl;
W is NR8C(O)R9, C(O)R9, or is of formula:

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L3 is a bond or an optionally substituted C1-C4 hydrocarbon chain, optionally wherein one or more carbon units of the hydrocarbon chain are independently replaced with —C═O—, —O—, —S—, —NRL3a—, —NRL3aC(═O)—, —C(═O)NRL3a—, —SC(═O)—, —O(═O)S—, —OC(═O)—, —C(═O)O—, —NRL3aC(═S)—, —C(═S)NRL3a—, trans-CRL3b═CRL3b—, cis-CRL3b═CRL3b, —C≡C—, —S(═O)—, —S(═O)O—, —OS(═O)—, —S(═O)NRL3a—, —NRL3aS(═O)—, —S(═O)2—, —S(═O)2O—, —OS(═O)2—, —S(═O)2NRL3a—, or —NRL3aS(═O)2—;
RL3a is H, optionally substituted C1-C6 alkyl, or a nitrogen protecting group;
each RL3b is independently H, halogen, optionally substituted C1-O6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 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 C6-C10 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 RL3b groups are joined to form an optionally substituted C3-C8 carbocycle or optionally substituted 4- to 7-membered heterocyclyl ring comprising 1 to 3 heteroatoms selected from N, O, and S;
L4 is a bond or an optionally substituted C1-C6 hydrocarbon chain;
each of RE1, RE2, and RE3 is independently H, halogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 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-C10 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, CH2OREE, CH2N(REE)2, CH2SREE, OREE, N(REE)2, Si(REE)3, or SREE, or RE1 and RE3, or RE2 and RE3, or RE1 and RE2 are joined to form an optionally substituted C3-C8 carbocycle or optionally substituted 4- to 7-membered heterocyclyl ring comprising 1 to 3 heteroatoms selected from N, O, and S;
each REE is independently H, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 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 C6-C10 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 REE groups are joined to form an optionally substituted 4- to 7-membered heterocyclyl ring comprising 1 to 3 heteroatoms selected from N, O, and S;
RE5 is halogen;
RE6 is H, optionally substituted C1-C6 alkyl, or a nitrogen protecting group;
each Y is independently O, S, or NRE7;
RE7 is H, optionally substituted C1-C6 alkyl, or a nitrogen protecting group;
a is 1 or 2; and
each z is independently 0, 1, 2, 3, 4, 5, or 6.