US 12,378,202 B2
Tetrahydrobenzoazepinones and related analogs for inhibiting YAP/TAZ-TEAD
Bart Vanderhoydonck, Diest (BE); Arnaud Marchand, Bierbeek (BE); Aurélie Candi, Werchter (BE); and Matthias Versele, Kessel-Lo (BE)
Assigned to SPRINGWORKS THERAPEUTICS, INC., Stamford, CT (US); KATHOLIEKE UNIVERSITEIT LEUVEN, Vlaams-Brabant Leuven (BE); and VIB VZW, Ghent (BE)
Filed by THE KATHOLIEKE UNIVERSITEIT LEUVEN, Vlaams-Brabant Leuven (BE); SpringWorks Therapeutics, Inc., Stamford, CT (US); and VIB vzw, Ghent (BE)
Filed on Dec. 23, 2022, as Appl. No. 18/145,902.
Claims priority of provisional application 63/293,536, filed on Dec. 23, 2021.
Prior Publication US 2023/0278962 A1, Sep. 7, 2023
Int. Cl. C07D 223/16 (2006.01); A61K 31/4375 (2006.01); A61K 31/4704 (2006.01); A61K 31/55 (2006.01); A61K 45/06 (2006.01); A61P 35/00 (2006.01); C07D 215/227 (2006.01); C07D 471/04 (2006.01)
CPC C07D 223/16 (2013.01) [A61K 31/4375 (2013.01); A61K 31/4704 (2013.01); A61K 31/55 (2013.01); A61K 45/06 (2013.01); A61P 35/00 (2018.01); C07D 215/227 (2013.01); C07D 471/04 (2013.01)] 19 Claims
 
1. A compound of Formula I:

OG Complex Work Unit Chemistry
or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein:
p is 0, 1, or 2;
R1 is selected from the group consisting of:
(i) unsubstituted or substituted C1-C6 alkyl, wherein one or more substituents are independently selected from the group consisting of:
(a) substituted C6-C10 aryl, wherein one or more substituents are independently selected from the group consisting of:
(1) halogen,
(2) cyano,
(3) C1-C6 alkyl,
(4) C3-C6 cycloalkyl,
(5)
—OZ1,
(6) C2-C6 alkenyl, and
(7) C2-C6 alkynyl,
(b) unsubstituted or substituted C3-C6 cycloalkyl, wherein one or more substituents are independently selected from the group consisting of:
(1) halogen,
(2) cyano,
(3) C1-C6 alkyl,
(4) C3-C6 cycloalkyl,
(5) C1-C6 haloalkyl, and
(6) —OZ1,
(c) C2-C6 alkynyl,
(ii) unsubstituted or substituted C6-C10 aryl, wherein one or more substituents are independently selected from the group consisting of:
(a) halogen,
(b) cyano,
(c) C1-C6 alkyl,
(d) C3-C6 cycloalkyl,
(e) C1-C6 haloalkyl,
(f) —OZ1, and
(g) unsubstituted or substituted C6-C10 aryl, wherein one or more substituents are independently selected from the group consisting of halogen, C1-C6 alkyl, and C1-C6 haloalkyl, and —OZ1,
(iii) unsubstituted or substituted 5- to 9-membered heteroaryl, wherein one or more substituents are independently selected from the group consisting of:
(a) halogen,
(b) cyano,
(c) C1-C6 alkyl,
(d) C3-C6 cycloalkyl,
(e) C1-C6 haloalkyl,
(f) —OZ1, and
(g) unsubstituted or substituted C6-C10 aryl, wherein one or more substituents are independently selected from the group consisting of halogen, C1-C6 alkyl, and C1-C6 haloalkyl, and —OZ1,
(iv)unsubstituted or substituted C3-C6 cycloalkyl, wherein one or more substituents are independently selected from the group consisting of:
(a) halogen,
(b) cyano,
(c) C1-C6 alkyl,
(d) C3-C6 cycloalkyl,
(e) C1-C6 haloalkyl, and
(f) —OZ1,
(v) unsubstituted or substituted C3-C6 heterocycle, wherein one or more substituents are independently selected from the group consisting of:
(a) halogen,
(b) cyano,
(c) C1-C6 alkyl,
(d) C3-C6 cycloalkyl,
(e) C1-C6 haloalkyl, and
(f) —OZ1,
(vi) —S(═O)2Z2, and
(vii) —C(═O)Z2;
R2 and R3 are independently selected from the group consisting of hydrogen and C1-C6 alkyl; or
R2 and R3 taken together with the carbon atom to which they are attached form a —C(═O)— group;
R4 is selected from the group consisting of hydrogen and —NR10aR10b;
R5 is selected from the group consisting of hydrogen and C1-C6 alkyl;
each R6 and R7 is independently selected from the group consisting of hydrogen and C1-C6 alkyl;
R8 and R9 are independently selected from the group consisting of hydrogen and C1-C6 alkyl; or
R8 and R9 taken together with the carbon atom to which they are attached form a —C(═O)— group;
R10a is selected from the group consisting of:
(i) —C(═O)Z2
(ii) —C(═O)OZ2,
(iii) —C(═O)NZ3Z4,
(iv) —S(═O)2Z2,
(v) —S(═O)2NZ3Z4,
(vi) —S(═O)(═NZ)Z2,
(vii) —S(═NZ5)(═NZ6)Z2,
(viii) —S(═O)(═NZ5)NZ3Z4, and
(ix) unsubstituted or substituted C1-C6 alkyl, wherein one or more substituents are independently selected from the group consisting of:
(a) cyano,
(b) hydroxy,
(c) —OZ1,
(d) —C(═O)OH
(e) —C(═O)Z2
(f) —C(═O)OZ2,
(g) —C(═O)NZ3Z4,
(h) —S(═O)2Z2,
(i) —S(═O)2NZ3Z4,
(j) —S(═O)(═NZ5)Z2,
(k) —S(═NZ5)(═NZ6)Z2,
(l) —S(═O)(═NZ5)NZ3Z4, and
(m) —NZ3Z4,
R10b is selected from the group consisting of hydrogen and C1-C6 alkyl;
each Z1 is independently selected from the group consisting of:
(i) hydrogen,
(ii) C1-C6 alkyl,
(iii) unsubstituted or substituted C2-C6 alkenyl, wherein one or more substituents are independently selected from the group consisting of cyano, —S(═O)2Z2, —S(═O)2NZ3Z4, halogen, —NZ3Z4, and 4- to 8-membered heterocycle,
(iv) C2-C6 alkynyl,
(v) C3-C6 cycloalkyl,
(vi) C3-C6 cycloalkenyl, and
(vii) C1-C6 haloalkyl;
each Z2 is independently selected from the group consisting of:
(i) unsubstituted or substituted C1-C6 alkyl, wherein one or more substituents are independently selected from the group consisting of cyano and C2-C6 alkynyl;
(ii) unsubstituted or substituted C2-C6 alkenyl, wherein one or more substituents are independently selected from the group consisting of cyano, —S(═O)2Z2, —S(═O)2NZ3Z4, halogen, —NZ3Z4, 4- to 8-membered heterocycle,
(iii) C2-C6 alkynyl,
(iv) C3-C6 cycloalkyl,
(v) C3-C6 cycloalkenyl,
(vi) C1-C6 haloalkyl,
(vii) unsubstituted or substituted C6-C10 aryl, wherein one or more substituents are independently selected from the group consisting of halogen, C1-C6 alkyl, and C1-C6 haloalkyl, and —OZ1, and
(viii) unsubstituted or substituted C3-C6 cycloalkyl, wherein one or more substituents are independently selected from the group consisting of halogen, C1-C6 alkyl, and C1-C6 haloalkyl, and —OZ1;
each Z3 and Z4 are independently selected from the group consisting of:
(i) hydrogen;
(ii) unsubstituted or substituted C1-C6 alkyl, wherein one or more substituents are independently selected from the group consisting of:
(a) unsubstituted or substituted C6-C10 aryl, wherein one or more substituents are independently selected from the group consisting of:
(1) halogen,
(2) cyano,
(3) C1-C6 alkyl,
(4) C3-C6 cycloalkyl,
(5) C1-C6 haloalkyl,
(6) —OZ1,
(7) C2-C6 alkenyl, and
(8) C2-C6 alkynyl,
(b) unsubstituted or substituted C3-C6 cycloalkyl, wherein one or more substituents are independently selected from the group consisting of:
(1) halogen,
(2) cyano,
(3) C1-C6 alkyl,
(4) C3-C6 cycloalkyl,
(5) C1-C6 haloalkyl, and
(6) —OZ1,
(c) unsubstituted or substituted 5- to 9-membered heteroaryl, wherein one or more substituents are independently selected from the group consisting of:
(1) halogen,
(2) cyano,
(3) C1-C6 alkyl,
(4) C3-C6 cycloalkyl,
(5) C1-C6 haloalkyl,
(6) —OZ1,
(7) C2-C6 alkenyl, and
(8) C2-C6 alkynyl,
(d) cyano,
(e) hydroxy,
(f) —OZ1, and
(g) —NZ3Z4,
(iii) unsubstituted or substituted C2-C6 alkenyl, wherein one or more substituents are independently selected from the group consisting of cyano, —S(═O)2Z2, —S(═O)2NZ3Z4, halogen, —NZ3Z4, 4- to 8-membered heterocycle,
(iv) C2-C6 alkynyl,
(v) C3-C6 cycloalkyl,
(vi) C3-C6 cycloalkenyl, and
(vii) C1-C6 haloalkyl;
each Z5 and Z6 are independently selected from the group consisting of:
(i) hydrogen,
(ii) C1-C6 alkyl, and
(iii) C3-C6 cycloalkyl;
X is selected from the group consisting of —CR11a═ and —N═;
X1 is selected from the group consisting of —CR11b═ and —N═;
X2 is selected from the group consisting of —CR11c═ and —N═;
X3 is selected from the group consisting of —CR11d═ and —N═; and
each R11a, R11b, R11c, and R11d is independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, C1-C6 alkyl, C1-C6 haloalkyl, and —NZ3Z4.