Spiros and related analogs for inhibiting YAP/TAZ-TEAD

1 . A compound of Formula II, Formula III or Formula IV:

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

R 1 is

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) C 3 -C 6 cycloalkyl,

(e) C 1 -C 6 haloalkyl,

(f) —OZ 1 , and

(g) 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 ,

Y is N—;

R 2 and R 3 are independently selected from the group consisting of hydrogen and C 1 -C 6 alkyl; or

R 2 and R 3 taken together with the carbon atom to which they are attached form a —C(═O)— group;

R 4 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 selected from the group consisting of:

(a) halogen,

(b) hydroxy,

(c) cyano,

(d) —OZ 1 ,

(e) —SZ 1 ,

(iii) —C(═O)Z 2

(iv) —C(═O)OZ 2 ,

(v) —C(═O)NZ 3 Z 4 ,

R 5 is selected from the group consisting of hydrogen and C 1 -C 6 alkyl;

R 6 is selected from the group consisting of:

(i) —C(═O)Z 2 ,

(ii) —C(═O)NZ 3 Z 4 ,

(iii) —S(═O) 2 Z 8 , and

(iv) —S(═O) 2 NZ 3 Z 4 ;

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 8 , —S(═O) 2 NZ 3 Z 4 , halogen and unsubstituted or substituted C 1 -C 6 alkyl, wherein one or more substituents are independently selected from the group consisting of —NZ 3 Z 4 and 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) C 1 -C 6 alkyl,

(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 8 , —S(═O) 2 NZ 3 Z 4 , halogen and unsubstituted or substituted C 1 -C 6 alkyl, wherein one or more substituents are independently selected from the group consisting of —NZ 3 Z 4 and 4- to 8-membered heterocycle,

(iii) C 2 -C 6 alkynyl,

(iv) C 3 -C 6 cycloalkyl,

(v) C 3 -C 6 cycloalkenyl, and

(vi) C 1 -C 6 haloalkyl;

each Z 3 is 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, —S(═O) 2 Z 8 , halogen, heteroaryl, and unsubstituted or substituted C 1 -C 6 alkyl, wherein one or more substituents are independently selected from the group consisting of 4- to 8-membered heterocycle,

(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 8 , halogen and unsubstituted or substituted C 1 -C 6 alkyl, wherein one or more substituents are independently selected from the group consisting of 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 4 is independently selected from the group consisting of:

(i) hydrogen,

(ii) C 1 -C 6 alkyl, and

(iii) C 3 -C 6 cycloalkyl;

each Z 8 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, halogen and unsubstituted or substituted C 1 -C 6 alkyl, wherein one or more substituents are independently selected from the group consisting of 4- to 8-membered heterocycle,

(iv) halogen, and

(v) hydroxy;

X is ═CR 7a —;

X 1 is ═CR 7b —;

X 2 is ═CR 7c —;

X 3 is selected from the group consisting of ═N— and ═CR 7d —; and

R 7a , R b , R 7c and R 7d , are independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —OZ 1 , and —NZ 3 Z 4 .

2 . The compound of claim 1 , wherein the compound is the compound of Formula II:

or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof.

3 . The compound of claim 2 , or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein:

R 6 is —S(═O) 2 Z 8 .

4 . The compound of claim 2 , or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein R 6 is —C(═O)Z 2 .

5 . The compound of claim 1 , wherein the compound is the compound of Formula III:

or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof.

6 . The compound of claim 5 , or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein R 6 is —C(═O)Z 2 .

7 . The compound of claim 1 , wherein the compound is the compound of Formula IV:

or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof.

8 . The compound of claim 7 , or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein R 6 is —C(═O)Z 2 .

9 . A compound selected from the group consisting of:

1-[6-(trifluoromethyl)-1-[4-(trifluoromethyl)phenyl]spiro[2,4-dihydroquinoline-3,3′-pyrrolidine]-1′-yl]prop-2-en-1-one;

1′-methylsulfonyl-6-(trifluoromethyl)-1-[4-(trifluoromethyl)phenyl]spiro[2,4-dihydroquinoline-3,3′-pyrrolidine];

and a stereoisomer, tautomer, pharmaceutically acceptable salt, and solvate thereof.

10 . A compound selected from the group consisting of:

1-(1′-(4-(trifluoromethyl)phenyl)-1′,4′-dihydro-2′H-spiro[pyrrolidine-3,3′-quinolin]-1-yl)propan-1-one;

1-(methylsulfonyl)-1′-(4-(trifluoromethyl)phenyl)-1′,4′-dihydro-2′H-spiro[pyrrolidine-3,3′-quinoline];

1-(1′-(4-(trifluoromethyl)phenyl)-1′,4′-dihydro-2′H-spiro[piperidine-4,3′-quinolin]-1-yl)prop-2-en-1-one;

1-(1′-(4-(trifluoromethyl)phenyl)-1′,4′-dihydro-2′H-spiro[pyrrolidine-3,3′-quinolin]-1-yl)prop-2-en-1-one;

1-(1′-(4-(trifluoromethyl)phenyl)-1′,4′-dihydro-2′H-spiro[azetidine-3,3′-quinolin]-1-yl)prop-2-en-1-one;

1-(1′-(4-(trifluoromethyl)phenyl)-1′,4′-dihydro-2′H-spiro[azetidine-3,3′-quinolin]-1-yl)propan-1-one;

1-acryloyl-1′-(4-(trifluoromethyl)phenyl)-1′,4′-dihydro-2′H-spiro[piperidine-4,3′-quinolin]-2′-one;

and a stereoisomer, tautomer, pharmaceutically acceptable salt, and solvate thereof.

11 . A pharmaceutical composition comprising the compound of claim 1 , or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, and a pharmaceutically acceptable carrier.

12 . A compound selected from the group consisting of

(R)-1-(1′-(4-(trifluoromethyl)phenyl)-1′,4′-dihydro-2′H-spiro[pyrrolidine-3,3′-quinolin]-1-yl)propan-2-en-1-one;

(S)-1-(1′-(4-(trifluoromethyl)phenyl)-1′,4′-dihydro-2′H-spiro[pyrrolidine-3,3′-quinolin]-1-yl) propan-2-en-1-one;

(R)-1-(1′-(4-(trifluoromethyl)phenyl)-1′,4′-dihydro-2′H-spiro[pyrrolidine-3,3′-quinolin]-1-yl)propan-1-one;

(S)-1-(1′-(4-(trifluoromethyl)phenyl)-1′,4′-dihydro-2′H-spiro[pyrrolidine-3,3′-quinolin]-1-yl)propan-1-one;

(R)-1-(methylsulfonyl)-1′-(4-(trifluoromethyl)phenyl)-1′,4′-dihydro-2′H-spiro[pyrrolidine-3,3′-quinoline];

(S)-1-(methylsulfonyl)-1′-(4-(trifluoromethyl)phenyl)-1′,4′-dihydro-2′H-spiro[pyrrolidine-3,3′-quinoline];

N-[1-(2-pyridyl)ethyl]-1-[4-(trifluoromethyl)phenyl]spiro [2,4-dihydroquinoline-3,3′-pyrrolidine]-1′-carboxamide;

1-[6-(trifluoromethyl)-1-[4-(trifluoromethyl)phenyl]spiro[2,4-dihydroquinoline-3,3′-pyrrolidine]-1′-yl]ethenone;

1-(methylsulfonyl)-1′-(4-(trifluoromethyl)phenyl)-1′,4′-dihydro-2′H-spiro[pyrrolidine-3,3′-[1,5]naphthyridine];

N-methyl-1′-(4-(trifluoromethyl)phenyl)-1′,4′-dihydro-2′H-spiro[pyrrolidine-3,3′-[1,5]naphthyridine]-1-sulfonamide;

1′-(4-(trifluoromethyl)phenyl)-1′,4,4′,5-tetrahydro-2H,2′H-spiro[thiophene-3,3′-[1,5]naphthyridine]1,1-dioxide;

1′-(4-(trifluoromethyl)phenyl)-1′,4′-dihydro-2′H-spiro[isothiazolidine-4,3′-[1,5]naphthyridine]1,1-dioxide;

and a stereoisomer, tautomer, pharmaceutically acceptable salt, and solvate thereof.

13 . The compound of claim 2 , wherein R 1 is

14 . The compound of claim 5 , wherein R 1 is

15 . The compound of claim 7 , wherein R 1 is