Tetrahydropyrazolopyrimidines and Related Analogs for Inhibiting YAP/TAZ-TEAD
The present disclosure relates to novel compounds, to said compounds for use as a medicine, more in particular for the prevention or treatment of diseases mediated by activity of YAP/TAZ-TEAD transcription, yet more in particular for the prevention or treatment of cancer or fibrosis. The present disclosure also relates to a method for the prevention or treatment of said diseases comprising the use of the novel compounds.
1 . A compound of Formula I:
or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein:
Y is N, Y 1 is N, Y 2 is CR 3a , and Y 3 is CR 2 ; or
Y is N, Y 1 is N, Y 2 is CR 3a , and Y 3 is N ; or
Y is N, Y 1 is N, Y 2 is CH, and Y 3 is N ; or
Y is N, Y 1 is N, Y 2 is CH, and Y 3 is CR 2 ; or
Y is N, Y 1 is CR 3a , Y 2 is N, and Y 3 is CR 2 ; or
Y is N, Y 1 is CR 3a , Y 2 is N, and Y 3 is N; or
Y is N, Y 1 is CR 3a , Y 2 is CH, and Y 3 is CR 2 ; or
Y is N, Y 1 is CR 3a , Y 2 is CH, and Y 3 is N; or
Y is C, Y 1 is NR 3b , Y 2 is N, and Y 3 is CR 2 ; or
Y is C,Y 1 is NR 3b , Y 2 is N, and Y 3 is N; or
Y is C, Y 1 is NR 3b , Y 2 is CH, and Y 3 is CR 2 ; or
Y is C, Y 1 is NR 3b , Y 2 is CH, and Y 3 is N; or
Y is C, Y 1 is N, Y 2 is NR 3c , and Y 3 is CR 2 ; or
Y is C, Y 1 is N, Y 2 is NR 3c , and Y 3 is N; or
Y is C, Y 1 is N, Y 2 is CH, and Y 3 is CR 2 ; or
Y is C,Y 1 is N, Y 2 is CH, and Y 3 is N;
R 1 is selected from the group consisting of:
(i) Hydrogen,
(ii) —C(═O)Z 2
(iii) —S(═O) 2 Z 2 ,
(iv) unsubstituted or substituted C 1 -C 6 alkyl, wherein one or more substituents are independently selected from the group consisting of:
(a) unsubstituted or substituted C 6 -C 10 aryl, wherein one or more substituents are independently selected from the group consisting of:
(2) cyano,
(3) C 1 -C 6 alkyl,
(4) C 3 -C 6 cycloalkyl,
(5) C 1 -C 6 haloalkyl,
(6) —OZ 1 ,
(7) C 2 -C 6 alkenyl, and
(8) C 2 -C 6 alkynyl,
(b) unsubstituted or substituted C 3 -C 6 cycloalkyl, wherein one or more substituents are independently selected from the group consisting of:
(1) halogen,
(2) cyano,
(3) C 1 -C 6 alkyl,
(4) C 3 -C 6 cycloalkyl,
(5) C 1 -C 6 haloalkyl, and
(6) —OZ 1 ,
(c) C 2 -C 6 alkynyl,
(v) unsubstituted or substituted C 6 -C 10 aryl, wherein one or more substituents are independently selected from the group consisting of:
(a) halogen,
(b) cyano,
(c) C 1 -C 6 alkyl,
(d) unsubstituted or substituted C 3 -C 6 cycloalkyl, wherein one ore more substituents are independently selected from the group consisting of halogen, C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl, and —OZ 1 ,
(e) C 1 -C 6 haloalkyl,
(f) unsubstituted or substituted C 1 -C 6 alkyl, wherein one or more substituents are independently selected from the group consisting of halogen and alcohol,
(g) —OZ 1 ,
(h) —SZ 1 ,
(i) —SF 5 and
(j) unsubstituted or substituted C 6 -C 10 aryl, wherein one or more substituents are independently selected from the group consisting of halogen, C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl, and —OZ 1 ,
(vi) 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) C 1 -C 6 alkyl,
(d) C 3 -C 6 cycloalkyl,
(e) C 1 -C 6 haloalkyl,
(f) —OZ 1 ,
(g) oxo, and
(h) unsubstituted or substituted C 6 -C 10 aryl, wherein one or more substituents are independently selected from the group consisting of halogen, C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl, and —OZ 1 ,
(vii) unsubstituted or substituted C 3 -C 6 cycloalkyl, wherein one or more substituents are independently selected from the group consisting of:
(a) halogen,
(b) cyano,
(c) C 1 -C 6 alkyl,
(d) C 3 -C 6 cycloalkyl,
(e) C 1 -C 6 haloalkyl, and
(f) —OZ 1 ,
(viii) unsubstituted or substituted C 3 -C 6 heterocycle, wherein one or more substituents are independently selected from the group consisting of:
(a) halogen,
(b) cyano,
(c) C 1 -C 6 alkyl,
(d) C 3 -C 6 cycloalkyl,
(e) C 1 -C 6 haloalkyl,
(f) —OZ 1 , and
(g) oxo,
(ix) —S(═O) 2 Z 2 , and
(x) —C(═O)Z 2 ;
R 2 is selected from the group consisting of:
(i) hydrogen,
(ii) unsubstituted or substituted C 1 -C 6 alkyl, wherein one or more substituents are independently unsubstituted or substituted C 6 -C 10 aryl, wherein one or more substituents are C 1 -C 6 haloalkyl
(iii) halogen, and
(iv) unsubstituted or substituted C 1 -C 6 alkynyl, wherein one or more substituents are independently selected from the group consisting of:
(a) unsubstituted or substituted C 6 -C 10 aryl, wherein one or more substituents are independently selected from the group consisting of:
(1) halogen,
(2) cyano,
(3) C 1 -C 6 alkyl,
(4) C 3 -C 6 cycloalkyl,
(5) C 1 -C 6 haloalkyl, and
(6) —OZ 1 , and
(b) unsubstituted or substituted C 3 -C 6 cycloalkyl, wherein one or more substituents are independently selected from the group consisting of:
(1) halogen,
(2) cyano,
(3) C 1 -C 6 alkyl,
(4) C 3 -C 6 cycloalkyl,
(5) C 1 -C 6 haloalkyl, and
(6) —OZ 1 ,
(v) unsubstituted or substituted C 6 -C 10 aryl, wherein one or more substituents are independently selected from the group consisting of halogen, C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl
R 3a , R 3b , and R 3c are independently selected from the group consisting of:
(i) hydrogen,
(ii) unsubstituted or substituted C 1 -C 6 alkyl, wherein one or more substituents are independently selected from the group consisting of cyano, C 3 -C 6 cycloalkyl and unsubstituted or substituted C 6 -C 10 aryl, wherein one or more substituents are independently selected from the group consisting of halogen, C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl, and —OZ 1 , and
(iii) C 3 -C 6 cycloalkyl;
R 4 , R 5 , R 8 , and R 9 are independently selected from the group consisting of hydrogen and C 1 -C 6 alkyl;
R 6 is selected from the group consisting of:
(i) —(CH 2 ) m —NR 10a R 10b ,
(ii) —C(═O)NZ 3 Z 4 , and
(iii) unsubstituted or substituted 4- to 8-membered heterocycle, wherein one or more substituents are selected from the group consisting of:
(a) C 1 -C 6 alkyl,
(b) —C(═O)Z 2
(c) —C(═O)OZ 2 ,
(d) —C(═O)NZ 3 Z 4 ,
(e) —S(═O) 2 Z 2 ,
(f) —S(═O) 2 NZ 3 Z 4 , and
(g) halogen,
(iv) —CH 2 —C(═O)OH
R 7 is selected from the group consisting of:
(i) hydrogen, and
(ii) unsubstituted or substituted C 1 -C 6 alkyl, wherein one or more substituents are independently selected from the group consisting of cyano and C 2 -C 6 alkynyl; or
R 6 and R 7 taken together with the carbon to which they are attached form a an unsubstituted or substituted 4- to 8-membered heterocycle, wherein one or more substituents are independently selected from the group consisting of C 1 -C 6 alkyl, —C(═O)Z 2 , —S(═O) 2 Z 2 , and oxo;
m is0or1;
R 10a is selected from the group consisting of:
(i) —C(═O)Z 2
(ii) —C(═O)OZ 2 ,
(iii) —C(═O)NZ 3 Z 4 ,
(iv) —S(═O) 2 Z 2 ,
(v) —S(═O) 2 NZ 3 Z 4 ,
(vi) —S(═O)(═NZ 5 )Z 2 ,
(vii) —S(═NZ 5 )(═NZ 6 )Z 2 ,
(viii) —S(═O)(═NZ 5 )NZ 3 Z 4
(ix) —CH 2 —C(═O)OH
(x) unsubstituted or substituted C 1 -C 6 alkyl, wherein one or more substituents are independently selected from the group consisting of cyano and C 2 -C 6 alkynyl; and,
(xi) unsubstituted or substituted C 2 -C 6 alkenyl, wherein one or more substituents are independently selected from the group consisting of cyano, —S(═O) 2 Z 1 , —S(═O) 2 NZ 3 Z 4 , halogen, —NZ 3 Z 4 , and —C(═O)OZ 2 ;
R 10a and R 10b taken together with the nitrogen to which they are attached form an unsubstituted or substituted 4- to 8-membered heterocycle;
R 10b is selected from the group consisting of:
(i) hydrogen, and
(ii) unsubstituted or substituted C 1 -C 6 alkyl, wherein one or more substituents are independently selected from the group consisting of cyano, OZ 1 , and C 2 -C 6 alkynyl;
each Z 1 is independently selected from the group consisting of:
(i) hydrogen,
(ii) C 1 -C 6 alkyl,
(iii) unsubstituted or substituted C 2 -C 6 alkenyl, wherein one or more substituents are independently selected from the group consisting of cyano, —S(═O) 2 Z 1 , —S(═O) 2 NZ 3 Z 4 , halogen, —NZ 3 Z 4 , 4- to 8-membered heterocycle,
(iv) C 2 -C 6 alkynyl,
(v) C 3 -C 6 cycloalkyl,
(vi) C 3 -C 6 cycloalkenyl, and
(vii) C 1 -C 6 haloalkyl;
each Z 2 is independently selected from the group consisting of:
(i) unsubstituted or substituted C 1 -C 6 alkyl, wherein one or more substituents are independently selected from the group consisting of cyano and C 2 -C 6 alkynyl;
(ii) unsubstituted or substituted C 2 -C 6 alkenyl, wherein one or more substituents are independently selected from the group consisting of cyano, —S(═O) 2 Z 1 , —S(═O) 2 NZ 3 Z 4 , halogen, —NZ 3 Z 4 , 4- to 8-membered heterocycle, —OZ 1 , —C(═O)OZ 3 ,
(iii) C 2 -C 6 alkynyl,
(iv) C 3 -C 6 cycloalkyl,
(v) C 3 -C 6 cycloalkenyl,
(vi) C 1 -C 6 haloalkyl,
(vii) unsubstituted or substituted C 6 -C 10 aryl, wherein one or more substituents are independently selected from the group consisting of halogen, C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl, and —OZ 1 , and
(viii) unsubstituted or substituted C 3 -C 6 cycloalkyl, wherein one or more substituents are independently selected from the group consisting of halogen, C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl, and —OZ 1 ;
each Z 3 and Z 4 are independently selected from the group consisting of:
(i) hydrogen,
(ii) —S(═O) 2 Z 2 ,
(iii) unsubstituted or substituted C 1 -C 6 alkyl, wherein one or more substituents are independently selected from the group consisting of:
(a) unsubstituted or substituted C 6 -C 10 aryl, wherein one or more substituents are independently selected from the group consisting of:
(1) halogen,
(2) cyano,
(3) C 1 -C 6 alkyl,
(4) C 3 -C 6 cycloalkyl,
(5) C 1 -C 6 haloalkyl,
(6) —OZ 1 ,
(7) C 2 -C 6 alkenyl, and
(8) C2-C6alkynyl,
(b) unsubstituted or substituted C 3 -C 6 cycloalkyl, wherein one or more substituents are independently selected from the group consisting of:
(1) halogen,
(2) cyano,
(3) C 1 -C 6 alkyl,
(4) C 3 -C 6 cycloalkyl,
(5) C 1 -C 6 haloalkyl, and
(6) —OZ 1 ,
(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) C 1 -C 6 alkyl,
(4) C 3 -C 6 cycloalkyl,
(5) C 1 -C 6 haloalkyl,
(6) —OZ 1 ,
(7) C 2 -C 6 alkenyl, and
(8) C 2 -C 6 alkynyl,
(iii) C 2 -C 6 alkenyl,
(iv) C 2 -C 6 alkynyl,
(v) C 3 -C 6 cycloalkyl,
(vi) C 3 -C 6 cycloalkenyl, and
(vii) C 1 -C 6 haloalkyl; and
each Z 5 and Z 6 are independently selected from the group consisting of:
(i) hydrogen,
(ii) C 1 -C 6 alkyl, and
(iii) C 3 -C 6 cycloalkyl;
2 . A compound of Formula II:
or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein:
Y is N, Y 1 is N, and Y 2 is CR 3a ; or
Y is N, Y 1 is CR 3a , and Y 2 is N; or
Y is C, Y 1 is NR 3b , and Y 2 is N; or
Y is C, Y 1 is N, and Y 2 is NR 3c ;
R 1 is selected from the group consisting of:
(i) hydrogen,
(ii) —C(═O)Z 2
(iii) —S(═O) 2 Z 2 ,
(iv) unsubstituted or substituted C 1 -C 6 alkyl, wherein one or more substituents are independently selected from the group consisting of:
(a) unsubstituted or substituted C 6 -C 10 aryl, wherein one or more substituents are independently selected from the group consisting of:
(1) halogen,
(2) cyano,
(3) C 1 -C 6 alkyl,
(4) C 3 -C 6 cycloalkyl,
(5) C 1 -C 6 haloalkyl,
(6) —OZ 1 ,
(7) C 2 -C 6 alkenyl, and
(8) C 2 -C 6 alkynyl,
(b) unsubstituted or substituted C 3 -C 6 cycloalkyl, wherein one or more substituents are independently selected from the group consisting of:
(1) halogen,
(2) cyano,
(3) C 1 -C 6 alkyl,
(4) C 3 -C 6 cycloalkyl,
(5) C 1 -C 6 haloalkyl, and
(6) —OZ 1 ,
(c) C 2 -C 6 alkynyl,
(v) unsubstituted or substituted C 6 -C 10 aryl, wherein one or more substituents are independently selected from the group consisting of:
(a) halogen,
(b) cyano,
(c) C 1 -C 6 alkyl,
(e) C 1 -C 6 haloalkyl,
(f) —OZ 1 ,
(g) —SZ 1 ,
(h) —SF 5 and
(i) unsubstituted or substituted C 6 -C 10 aryl, wherein one or more substituents are independently selected from the group consisting of halogen, C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl, and —OZ 1 ,
(vi) 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) C 1 -C 6 alkyl,
(d) C 3 -C 6 cycloalkyl,
(e) C 1 -C 6 haloalkyl,
(f) —OZ 1 ,
(g) oxo, and
(h) unsubstituted or substituted C 6 -C 10 aryl, wherein one or more substituents are independently selected from the group consisting of halogen, C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl, and —OZ 1 ,
(vii) unsubstituted or substituted C 3 -C 6 cycloalkyl, wherein one or more substituents are independently selected from the group consisting of:
(a) halogen,
(b) cyano,
(c) C 1 -C 6 alkyl,
(d) C 3 -C 6 cycloalkyl,
(e) C 1 -C 6 haloalkyl, and
(f) —OZ 1 ,
(viii) unsubstituted or substituted C 3 -C 6 heterocycle, wherein one or more substituents are independently selected from the group consisting of:
(a) halogen,
(b) cyano,
(c) C 1 -C 6 alkyl,
(d) C 3 -C 6 cycloalkyl,
(e) C 1 -C 6 haloalkyl,
(f) —OZ 1 , and
(g) oxo,
(ix) —S(═O) 2 Z 2 , and
(x) —C(═O)Z 2 ;
R 2 is selected from the group consisting of:
(i) hydrogen,
(ii) C 1 -C 6 alkyl,
(iii) halogen, and
(iv) unsubstituted or substituted C 1 -C 6 alkynyl, wherein one or more substituents are independently selected from the group consisting of:
(a) unsubstituted or substituted C 6 -C 10 aryl, wherein one or more substituents are independently selected from the group consisting of:
(1) halogen,
(2) cyano,
(3) C 1 -C 6 alkyl,
(4) C 3 -C 6 cycloalkyl,
(5) C 1 -C 6 haloalkyl, and
(6) —OZ 1 , and
(b) unsubstituted or substituted C 3 -C 6 cycloalkyl, wherein one or more substituents are independently selected from the group consisting of:
(1) halogen,
(2) cyano,
(3) C 1 -C 6 alkyl,
(4) C 3 -C 6 cycloalkyl,
(5) C 1 -C 6 haloalkyl, and
(6) —OZ 1 ,
R 3a , R 3b , and R 3c are independently selected from the group consisting of:
(i) hydrogen,
(ii) unsubstituted or substituted C 1 -C 6 alkyl, wherein one or more substituents are independently selected from the group consisting of cyano, C 3 -C 6 cycloalkyl and unsubstituted or substituted C 6 -C 10 aryl, wherein one or more substituents are independently selected from the group consisting of halogen, C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl, and —OZ 1 , and
(iii) C 3 -C 6 cycloalkyl;
R 4 , R 5 , R 8 , and R 9 are independently selected from the group consisting of hydrogen and C 1 -C 6 alkyl;
R 6 is selected from the group consisting of:
(i) —(CH 2 ) m —NR 10a R 10b ,
(ii) —C(═O)NZ 3 Z 4 , and
(iii) unsubstituted or substituted 4- to 8-membered heterocycle, wherein one or more substituents are selected from the group consisting of:
(a) C 1 -C 6 alkyl,
(b) —C(═O)Z 2
(c) —C(═O)OZ 2 ,
(d) —C(═O)NZ 3 Z 4 ,
(e) —S(═O) 2 Z 2 ,
(f) —S(═O) 2 NZ 3 Z 4 , and
(g) halogen,
R 7 is selected from the group consisting of:
(i) hydrogen, and
(ii) unsubstituted or substituted C 1 -C 6 alkyl, wherein one or more substituents are independently selected from the group consisting of cyano and C 2 -C 6 alkynyl; or
R 6 and R 7 taken together with the carbon to which they are attached form an unsubstituted or substituted 4- to 8-membered heterocycle, wherein one or more substituents are independently selected from the group consisting of C 1 -C 6 alkyl, —C(═O)Z 2 , —S(═O) 2 Z 2 , and oxo;
m is 0or 1;
R 10a is selected from the group consisting of:
(i) —C(═O)Z 2
(ii) —C(═O)OZ 2 ,
(iii) —C(═O)NZ 3 Z 4 ,
(iv) —S(═O) 2 Z 2 ,
(v) —S(═O) 2 NZ 3 Z 4 ,
(vi) —S(═O)(═NZ 5 )Z 2 ,
(vii) —S(═NZ 5 )(═NZ 6 )Z 2 ,
(viii) —S(═O)(═NZ 5 )NZ 3 Z 4 , and
(ix) unsubstituted or substituted C 1 -C 6 alkyl, wherein one or more substituents are independently selected from the group consisting of cyano and C 2 -C 6 alkynyl;
R 10b is selected from the group consisting of:
(i) hydrogen, and
(ii) unsubstituted or substituted C 1 -C 6 alkyl, wherein one or more substituents are independently selected from the group consisting of cyano and C 2 -C 6 alkynyl;
each Z 1 is independently selected from the group consisting of:
(i) hydrogen,
(ii) C 1 -C 6 alkyl,
(iii) unsubstituted or substituted C 2 -C 6 alkenyl, wherein one or more substituents are independently selected from the group consisting of cyano, —S(═O) 2 Z 1 , —S(═O) 2 NZ 3 Z 4 , halogen, —NZ 3 Z 4 , 4- to 8-membered heterocycle,
(iv) C 2 -C 6 alkynyl,
(v) C3-C6cycloalkyl,
(vi) C 3 -C 6 cycloalkenyl, and
(vii) C 1 -C 6 haloalkyl;
each Z 2 is independently selected from the group consisting of:
(i) unsubstituted or substituted C 1 -C 6 alkyl, wherein one or more substituents are independently selected from the group consisting of cyano and C 2 -C 6 alkynyl;
(ii) unsubstituted or substituted C 2 -C 6 alkenyl, wherein one or more substituents are independently selected from the group consisting of cyano, —S(═O) 2 Z 1 , —S(═O) 2 NZ 3 Z 4 , halogen, —NZ 3 Z 4 , 4- to 8-membered heterocycle,
(iii) C 2 -C 6 alkynyl,
(iv) C 3 -C 6 cycloalkyl,
(v) C 3 -C 6 cycloalkenyl,
(vi) C 1 -C 6 haloalkyl,
(vii) unsubstituted or substituted C 6 -C 10 aryl, wherein one or more substituents are independently selected from the group consisting of halogen, C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl, and —OZ 1 , and
(viii) unsubstituted or substituted C 3 -C 6 cycloalkyl, wherein one or more substituents are independently selected from the group consisting of halogen, C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl, and —OZ 1 ;
each Z 3 and Z 4 are independently selected from the group consisting of:
(ii) —S(═O) 2 Z 2 ,
(iii) unsubstituted or substituted C 1 -C 6 alkyl, wherein one or more substituents are independently selected from the group consisting of:
(a) unsubstituted or substituted C 6 -C 10 aryl, wherein one or more substituents are independently selected from the group consisting of:
(1) halogen,
(2) cyano,
(3) C 1 -C 6 alkyl,
(4) C 3 -C 6 cycloalkyl,
(5) C 1 -C 6 haloalkyl,
(6) —OZ 1 ,
(7) C 2 -C 6 alkenyl, and
(8) C 2 -C 6 alkynyl,
(b) unsubstituted or substituted C 3 -C 6 cycloalkyl, wherein one or more substituents are independently selected from the group consisting of:
(1) halogen,
(2) cyano,
(3) C 1 -C 6 alkyl,
(4) C 3 -C 6 cycloalkyl,
(5) C 1 -C 6 haloalkyl, and
(6) —OZ 1 ,
(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) C 1 -C 6 alkyl,
(4) C 3 -C 6 cycloalkyl,
(5) C 1 -C 6 haloalkyl,
(6) —OZ 1 ,
(7) C 2 -C 6 alkenyl, and
(8) C 2 -C 6 alkynyl,
(iv) C 2 -C 6 alkenyl,
(v) C 2 -C 6 alkynyl,
(vi) C 3 -C 6 cycloalkyl,
(vii) C 3 -C 6 cycloalkenyl, and
(viii) C 1 -C 6 haloalkyl; and
each Z 5 and Z 6 are independently selected from the group consisting of:
(i) hydrogen,
(ii) C 1 -C 6 alkyl, and
(iii) C 3 -C 6 cycloalkyl;
3 . The compound of claim 1 of Formula III:
or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof.
4 . The compound of claim 1 , or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein R 3a is selected from the group consisting of hydrogen and C 1 -C 6 alkyl.
5 . The compound of claim 1 or 2 of Formula IV:
or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof.
6 . The compound of claim 1 , or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein R 3b is selected from the group consisting of hydrogen and C 1 -C 6 alkyl.
7 . The compound of claim 1 of Formula V:
or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof.
8 . The compound of any one of claim 1 , or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein R 3c is selected from the group consisting of hydrogen and C 1 -C 6 alkyl.
9 . The compound of claim 1 , or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein:
R 6 is —(CH 2 ) m —NR 10a R 10b ;
m is 1;
R 7 is hydrogen, and
R 10b is hydrogen.
10 . The compound of claim 1 , or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein R 10a is —C(═O)Z 2 .
11 . The compound of claim 1 , or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein Z 2 is unsubstituted or substituted C 2 -C 6 alkenyl, wherein one or more substituents are independently selected from the group consisting of halogen, —NZ 3 Z 4 , 4- to 6-membered heterocycle.
12 . The compound of claim 11 , or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein Z 2 is unsubstituted C 2 -C 6 alkenyl.
13 . The compound of claim 1 , or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein R 1 is unsubstituted or substituted C 6 -C 10 aryl.
14 . The compound of claim 13 , or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein R 1 is unsubstituted or substituted phenyl, wherein one or more substituents are independently selected from the group consisting of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and —OZ 1 .
15 . The compound of claim 1 , or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein Y 3 is a nitrogen.
16 . The compound of claim 15 , or a tautomer, pharmaceutically acceptable salt, or solvate thereof, selected from the group consisting of:
N-((2-methyl-4-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)methyl)acrylamide;
(R)—N-((2-methyl-4-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)methyl)acrylamide;
(S)—N-((2-methyl-4-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)methyl)acrylamide;
N-((4-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)methyl)acrylamide;
(R)—N-((4-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)methyl)acrylamide;
(S)—N-((4-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)methyl)acrylamide;
N-((4-(4-(trifluoromethoxy)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)methyl)acrylamide;
(R)—N-((4-(4-(trifluoromethoxy)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)methyl)acrylamide; and
(S)—N-((4-(4-(trifluoromethoxy)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)methyl)acrylamide.
17 . A pharmaceutical composition comprising a compound of claim 1 , or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, and a pharmaceutically acceptable carrier.
18 - 22 . (canceled)
23 . A method for the prevention or treatment of a YAP/TAZ-TEAD activation mediated disorders in an animal, mammal or human comprising administering to said animal, mammal or human in need for such prevention or treatment an effective dose of the compound of claim 1 .
24 . The method claim 23 further comprising administering to said animal, mammal or human one or more other medicines selected from the group consisting of EGFR inhibitors, MEK inhibitors, AXL inhibitors, B-RAF inhibitors, and RAS inhibitors.