US 12,030,866 B2
2-pyrazole anilines and related analogs for inhibiting YAP/TAZ-TEAD
Bart Vanderhoydonck, Diest (BE); Arnaud Marchand, Bierbeek (BE); Stephen L. Gwaltney, Stamford, CT (US); Stéphane Spieser, Munster (FR); Wim Smets, Rotselaar (BE); Aurélie Candi, Werchter (BE); Matthias Versele, Kessel-Lo (BE); and Georg Halder, Herent (BE)
Assigned to SPRINGWORKS THERAPEUTICS, INC., Stamford, CT (US); KATHOLIEKE UNIVERSITEIT LEUVEN, Leuven (BE); and VIB VZW, Ghent (BE)
Filed by THE KATHOLIEKE UNIVERSITEIT LEUVEN, Maams-Brabant Leuven (BE); SpringWorks Therapeutics, Inc., Stamford, CT (US); and VIB vzw, Ghent (BE)
Filed on Dec. 23, 2022, as Appl. No. 18/145,909.
Claims priority of provisional application 63/293,531, filed on Dec. 23, 2021.
Prior Publication US 2023/0278982 A1, Sep. 7, 2023
Int. Cl. C07D 401/10 (2006.01); C07D 213/16 (2006.01); C07D 231/12 (2006.01); C07D 255/02 (2006.01); C07D 257/04 (2006.01); C07D 401/04 (2006.01); C07D 401/06 (2006.01); C07D 401/14 (2006.01); C07D 403/04 (2006.01); C07D 403/10 (2006.01); C07D 403/14 (2006.01); C07D 405/04 (2006.01); C07D 405/06 (2006.01); C07D 405/14 (2006.01); C07D 409/14 (2006.01); C07D 413/04 (2006.01); C07D 413/14 (2006.01); C07D 417/04 (2006.01); C07D 471/04 (2006.01); C07D 471/08 (2006.01)
CPC C07D 401/10 (2013.01) [C07D 213/16 (2013.01); C07D 231/12 (2013.01); C07D 255/02 (2013.01); C07D 257/04 (2013.01); C07D 401/04 (2013.01); C07D 401/06 (2013.01); C07D 401/14 (2013.01); C07D 403/04 (2013.01); C07D 403/10 (2013.01); C07D 403/14 (2013.01); C07D 405/04 (2013.01); C07D 405/06 (2013.01); C07D 405/14 (2013.01); C07D 409/14 (2013.01); C07D 413/04 (2013.01); C07D 413/14 (2013.01); C07D 417/04 (2013.01); C07D 471/04 (2013.01); C07D 471/08 (2013.01); C07B 2200/09 (2013.01)] 21 Claims
 
1. A compound of Formula I:

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or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein:

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is selected from the group consisting of:

OG Complex Work Unit Chemistry
wherein the bond marked with an “*” is attached to R2;
X is selected from the group consisting of —CR10a— and —N═; and X1 is CR1; or
X is CR1; and X1 is selected from the group consisting of —CR10b═ and —N═; or
X is selected from the group consisting of —CR10a— and —N═; and X1 is selected from the group consisting of —CR10b═ and —N═;
X2 is selected from the group consisting of —CR10c═ and —N═;
X3 is selected from the group consisting of —CR10d═ and —N═;
L1 is selected from the group consisting of —NH— and —(CH2)p—;
p is 0 or 1;
R1 is selected from the group consisting of:
(i) hydrogen,
(ii) -L2-NR4aR4b, and
(iii) unsubstituted or substituted 4- to 8-membered heterocycle, wherein one or more substituents are selected from the group consisting of:
(a) C1-C6 alkyl,
(b) —C(═O)Z2
(c) —C(═O)OZ2,
(d) —C(═O)NZ3Z4,
(e) —S(═O)2Z8,
(f) —S(═O)2NZ3Z4,
(g) cyano,
(h) —OZ1, and
(i) halogen;
(iv) unsubstituted or substituted C6-C10 aryl, wherein one or more substituents are independently selected from the group consisting of —OZ1, —C(═O)Z2, halogen, C1-C6 alkyl, cyano, hydroxy, and C1-C6 haloalkyl;

OG Complex Work Unit Chemistry
L2 is selected from the group consisting —(CH2)n— and C3-C6 cycloalkylenyl
n is 0 or 1;
R2 is selected from the group consisting of:

OG Complex Work Unit Chemistry

OG Complex Work Unit Chemistry

OG Complex Work Unit Chemistry

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R3a is selected from the group consisting of:
(i) hydrogen,
(ii) halogen,
(iii) cyano,
(iv) —OZ1,
(v) —C(═O)NZ3Z4,
(vi) —NZ3Z4,
(vii) unsubstituted or substituted C1-C6 alkyl, wherein one or more substituents are independently selected from the group consisting of:
(a) cyano,
(b) —C(═O)NZ3Z4,
(c) —OZ1,
(d) —NZ3Z4
(e) unsubstituted or substituted C6-C10 aryl, wherein one or more substituents are independently selected from the group consisting of:
 (1) halogen,
 (2) cyano,
 (3) unsubstituted or substituted C1-C6 alkyl, wherein one or more substituents are independently selected from the group consisting of hydroxy, —OZ1, and —NZ3Z4,
 (4) C1-C6 haloalkyl,
 (5) C3-C6 cycloalkyl, wherein one or more substituents are independently selected from the group consisting of C1-C6 alkyl, hydroxy, and —NZ3Z4,
 (6) —C(═O)NZ3Z4,
 (7) —NZ3Z4,
 (8) unsubstituted or substituted C2-C6 alkenyl, wherein one or more substituents are independently selected from the group consisting of halogen and unsubstituted or substituted C1-C6 alkyl, wherein one or more substituents are independently selected from the group consisting of —NZ3Z4 and 4- to 8-membered heterocycle,
 (9) unsubstituted or substituted C6-C10 aryl, wherein one or more substituents are independently selected from the group consisting of halo, —OZ1, C1-C6 alkyl, cyano, hydroxy, and C1-C6 haloalkyl,
 (10) unsubstituted or substituted 4- to 10-membered heterocycle, wherein one or more substituents are independently selected from the group consisting of C1-C6 alkyl, and C1-C6 haloalkyl,
 (11) —OZ1,
 (12) —C(═O)OH,
 (13) hydroxy,
 (14) —NZ5C(═O)Z2,
 (15) —NZ5S(═O)2Z2, and
 (16) —NZ5S(═O)2NZ3Z4,
(f) unsubstituted or substituted C3-C6 cycloalkyl, wherein one or more substituents are independently selected from the group consisting of:
 (1) C1-C6 alkyl, and
 (2) C1-C6 haloalkyl,
(g) unsubstituted or substituted 5- to 10-membered heteroaryl, wherein one or more substituents are independently selected from the group consisting of:
 (1) halogen,
 (2) cyano,
 (3) unsubstituted or substituted C1-C6 alkyl, wherein one or more substituents are independently selected from the group consisting of hydroxy, —OZ1, and —NZ3Z4,
 (4) C1-C6 haloalkyl,
 (5) C3-C6 cycloalkyl, wherein one or more substituents are independently selected from the group consisting of C1-C6 alkyl, hydroxy, and —NZ3Z4,
 (6) —C(═O)NZ3Z4,
 (7) —NZ3Z4,
 (8) unsubstituted or substituted C2-C6 alkenyl, wherein one or more substituents are independently selected from the group consisting of halogen and unsubstituted or substituted C1-C6 alkyl, wherein one or more substituents are independently selected from the group consisting of —NZ3Z4,
 (9) unsubstituted or substituted C6-C10 aryl, wherein one or more substituents are independently selected from the group consisting of halo, —OZ1, C1-C6 alkyl, cyano, hydroxy, and C1-C6 haloalkyl,
 (10) unsubstituted or substituted 4- to 10-membered heterocycle, wherein one or more substituents are independently selected from the group consisting of C1-C6 alkyl, and C1-C6 haloalkyl,
 (11) —OZ1,
 (12) —C(═O)OH,
 (13) hydroxy, and
 (14) —NZ5C(═O)Z2,
(viii) C1-C6 haloalkyl,
(ix) unsubstituted or substituted C3-C6 cycloalkyl, wherein one or more substituents are independently selected from the group consisting of halogen and C1-C6 alkyl;
(x) unsubstituted or substituted 4- to 10-membered heterocycle, wherein one or more substituents are independently selected from the group consisting of:
(a) C1-C6 alkyl,
(b) —C(═O)Z2, and
(c) —S(═O)2Z8,
(xi) unsubstituted or substituted 5- to 10-membered heteroaryl, wherein one or more substituents are independently selected from the group consisting of:
(a) halogen,
(b) cyano,
(c) unsubstituted or substituted C1-C6 alkyl, wherein one or more substituents are independently selected from the group consisting of hydroxy, —OZ1, and —NZ3Z4,
(d) C1-C6 haloalkyl,
(e) unsubstituted or substituted C3-C6 cycloalkyl, wherein one or more substituents are independently selected from the group consisting of C1-C6 alkyl, hydroxy, and —NZ3Z4,
(f) —C(═O)NZ3Z4,
(g) —NZ3Z4,
(h) unsubstituted or substituted C2-C6 alkenyl, wherein one or more substituents are independently selected from the group consisting of halogen and unsubstituted or substituted C1-C6 alkyl, wherein one or more substituents are independently selected from the group consisting of —NZ3Z4 and 4- to 8-membered heterocycle,
(i) unsubstituted or substituted C6-C10 aryl, wherein one or more substituents are independently selected from the group consisting of halo, —OZ1, C1-C6 alkyl, cyano, hydroxy, and C1-C6 haloalkyl,
(j) unsubstituted or substituted 4- to 10-membered heterocycle, wherein one or more substituents are independently selected from the group consisting of C1-C6 alkyl, and C1-C6 haloalkyl,
(k) —OZ1,
(l) —C(═O)OH,
(m) hydroxy, and
(n) —NZ5C(═O)Z2;
R3b, R3c, and R3d are independently selected from the group consisting of:
(i) hydrogen,
(ii) halogen,
(iii) cyano,
(iv) —C(═O)NZ3Z4,
(v) unsubstituted or substituted C1-C6 alkyl, wherein one or more substituents are independently selected from the group consisting of hydroxy, —OZ1, and —NZ3Z4,
(vi) C1-C6 haloalkyl,
(vii) C3-C6 cycloalkyl, and
(viii) OZ1,
q is 0, 1, or 2;
R4a is 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) halogen,
(b) hydroxy,
(c) cyano,
(d) —OZ1,
(e) —SZ1,
(f) —NZ3Z4,
(g) —C(═O)Z2,
(h) —C(═O)OH,
(i) —C(═O)OZ2,
(j) —C(═O)NZ3Z4,
(k) —NZ5C(═O)Z2,
(l) —NZ5C(═O)OZ2,
(m) —NZ5C(═O)NZ3Z4,
(n) —S(═O)2Z8,
(o) —S(═O)2NZ3Z4,
(p) —S(═O)(═NZ6)Z2,
(q) —S(═Z6)(═NZ7)Z2,
(r) —S(═O)(═NZ6)NZ3Z4,
(s) —NZ5S(═O)2Z2,
(t) —NZ5S(═O)2NZ3Z4,
(u) —NZ5S(═O)(═NZ6)Z2,
(v) —NZ5S(═NZ6)(═NZ7)Z2, and
(w) —NZ5S(═O)(═NZ6)NZ3Z4,
(iii) unsubstituted or substituted 4- to 10-membered heterocycle, wherein one or more substituents are independently selected from the group consisting of:
(a) halogen,
(b) hydroxy,
(c) cyano,
(d) —OZ1,
(e) —SZ1,
(f) —NZ3Z4,
(g) —C(═O)Z2
(h) C(═O)OH,
(i) —C(═O)OZ2,
(j) —C(═O)NZ3Z4,
(k) —NZ5C(═O)Z2,
(l) —NZ5C(═O)OZ2,
(m) —NZ5C(═O)NZ3Z4,
(n) —S(═O)2Z8,
(o) —S(═O)2NZ3Z4,
(p) —S(═O)(═NZ6)Z2,
(q) —S(═Z6)(═NZ7)Z2,
(r) —S(═O)(═NZ6)NZ3Z4,
(s) —NZ5S(═O)2Z2,
(t) —NZ5S(═O)2NZ3Z4,
(u) —NZ5S(═O)(═NZ6)Z2,
(v) —NZ5S(═NZ6)(═NZ7)Z2,
(w) —NZ5S(═O)(═NZ6)NZ3Z4,
(x) C1-C6 alkyl,
(y) C1-C6 haloalkyl, and
(z) C3-C6 cycloalkyl,
(iv) unsubstituted or substituted C2-C6 alkenyl, wherein one or more substituents are independently selected from the group consisting of —C(═O)OZ2, halogen, and unsubstituted or substituted C1-C6 alkyl, wherein one or more substituents are independently selected from the group consisting of —NZ3Z4 and 4- to 8-membered heterocycle,
(v) —C(═O)Z2
(vi) —C(═O)OZ2,
(vii) —C(═O)NZ3Z4,
(viii) —S(═O)2Z8,
(ix) —S(═O)2NZ3Z4,
(x) —S(═O)(═NZ6)Z2,
(xi) —S(═Z6)(═NZ7)Z2, and
(xii) —S(═O)(═NZ6)NZ3Z4,
R4b is selected from the group consisting of:
(i) hydrogen, and
(ii) 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 halogen and unsubstituted or substituted C1-C6 alkyl, wherein one or more substituents are independently selected from the group consisting of —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) 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 halogen and unsubstituted or substituted C1-C6 alkyl, wherein one or more substituents are independently selected from the group consisting of —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 Z3 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 halogen and unsubstituted or substituted C1-C6 alkyl, wherein one or more substituents are independently selected from the group consisting of —NZ3Z4 and 4- to 8-membered heterocycle,
(iv) C2-C6 alkynyl,
(v) C3-C6 cycloalkyl,
(vi) C3-C6 cycloalkenyl,
(vii) C1-C6 haloalkyl,
(viii) cyano, and
(ix) —C(═O)Z2;
each Z4, Z5, Z6 and Z7 is independently selected from the group consisting of:
(i) hydrogen,
(ii) C1-C6 alkyl, and
(iii) C3-C6 cycloalkyl;
each Z8 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 halogen and unsubstituted or substituted C1-C6 alkyl, wherein one or more substituents are independently selected from the group consisting of —NZ3Z4 and 4- to 8-membered heterocycle,
(iv) halogen, and
(v) hydroxy;
R3b and R3c are independently selected from the group consisting of:
(i) hydrogen,
(ii) C1-C6 alkyl,
(iii) C1-C6 haloalkyl, and
(iv) C3-C6 cycloalkyl;

OG Complex Work Unit Chemistry
is selected from the group consisting of:
(i) C3-C6 cycloalkyl,
(ii) 4- to 10-membered heterocycle,
(iii) C6-C10 aryl, and
(iv) 5- to 10-membered heteroaryl;
each R5 is independently selected from the group consisting of:
(i) halogen,
(ii) hydroxy,
(iii) cyano,
(iv) —OZ1,
(v) —SZ1,
(vi) —NZ3Z4,
(vii) —C(═O)Z2
(viii) —C(═O)OH,
(ix) —C(═O)OZ2,
(x) —C(═O)NZ3Z4,
(xi) —NZ5C(═O)Z2,
(xii) —NZ5C(═O)OZ2,
(xiii) —NZ5C(═O)NZ3Z4,
(xiv) —S(═O)2Z8,
(xv) —S(═O)2NZ3Z4,
(xvi) —S(═O)(═NZ6)Z2,
(xvii) —S(═Z6)(═NZ7)Z2,
(xviii) —S(═O)(═NZ6)NZ3Z4,
(xix) —NZ5S(═O)2Z2,
(xx) —NZ5S(═O)2NZ3Z4,
(xxi) —NZ5S(═O)(═NZ6)Z2,
(xxii) —NZ5S(═NZ6)(═NZ7)Z2,
(xxiii) —NZ5S(═O)(═NZ6)NZ3Z4,
(xxiv) unsubstituted or substituted C1-C6 alkyl, wherein one or more substituents are independently selected from the group consisting of hydroxy, —OZ1, and —NZ3Z4,
(xxv) C1-C6 haloalkyl,
(xxvi) C3-C6 cycloalkyl, wherein one or more substituents are independently selected from the group consisting of C1-C6 alkyl, hydroxy, and —NZ3Z4,
(xxvii) unsubstituted or substituted C2-C6 alkenyl, wherein one or more substituents are independently selected from the group consisting of halogen and unsubstituted or substituted C1-C6 alkyl, wherein one or more substituents are independently selected from the group consisting of —NZ3Z4 and 4- to 8-membered heterocycle,
(xxviii) unsubstituted or substituted C6-C10 aryl, wherein one or more substituents are independently selected from the group consisting of halo, —OZ1, C1-C6 alkyl, cyano, hydroxy, and C1-C6 haloalkyl, and
(xxix) unsubstituted or substituted 4- to 10-membered heterocycle, wherein one or more substituents are independently selected from the group consisting of C1-C6 alkyl and C1-C6 haloalkyl,
R6a is selected from the group consisting of:
(i) hydrogen, and
(ii) C1-C6 alkyl;
R6b is selected from the group consisting of:
(i) hydrogen, and
(ii) C1-C6 alkyl,
m is 0, 1, 2, 3, or 4,
R10a, R10b, R10c, and R10d are independently selected from the group consisting of:
(i) hydrogen,
(ii) cyano,
(iii) hydroxy
(iv) —OZ1,
(v) —SZ1,
(vi) —NZ3Z4,
(vii) C1-C6 alkyl, and
(viii) C1-C6 haloalkyl.