Tetrahydrobenzoazepinones 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:
p is 0, 1, or 2;
R 1 is 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:
(a) 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)
—OZ 1 ,
(6) C 2 -C 6 alkenyl, and
(7) 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,
(ii) 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) 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 ,
(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) 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 ,
(iv)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 ,
(v) 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, and
(f) —OZ 1 ,
(vi) —S(═O) 2 Z 2 , and
(vii) —C(═O)Z 2 ;
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 hydrogen and —NR 10a R 10b ;
R 5 is selected from the group consisting of hydrogen and C 1 -C 6 alkyl;
each R 6 and R 7 is independently selected from the group consisting of hydrogen and C 1 -C 6 alkyl;
R 8 and R 9 are independently selected from the group consisting of hydrogen and C 1 -C 6 alkyl; or
R 8 and R 9 taken together with the carbon atom to which they are attached form a —C(═O)— group;
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)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:
(a) cyano,
(b) hydroxy,
(c) —OZ 1 ,
(d) —C(═O)OH
(e) —C(═O)Z 2
(f) —C(═O)OZ 2 ,
(g) —C(═O)NZ 3 Z 4 ,
(h) —S(═O) 2 Z 2 ,
(i) —S(═O) 2 NZ 3 Z 4 ,
(j) —S(═O)(═NZ 5 )Z 2 ,
(k) —S(═NZ 5 )(═NZ 6 )Z 2 ,
(l) —S(═O)(═NZ 5 )NZ 3 Z 4 , and
(m) —NZ 3 Z 4 ,
R 10b is selected from the group consisting of hydrogen and C 1 -C 6 alkyl;
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 2 , —S(═O) 2 NZ 3 Z 4 , halogen, —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) 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 2 , —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:
(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) 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,
(d) cyano,
(e) hydroxy,
(f) —OZ 1 , and
(g) —NZ 3 Z 4 ,
(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 2 , —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 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;
X is selected from the group consisting of —CR 11a ═ and —N═;
X 1 is selected from the group consisting of —CR 11b ═ and —N═;
X 2 is selected from the group consisting of —CR 11c ═ and —N═;
X 3 is selected from the group consisting of —CR 11d ═ and —N═; and
each R 11a , R 11b , R 11c , and R 11d is independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and —NZ 3 Z 4 .
2. The compound of claim 1 of Formula II:
or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof.
3. The compound of claim 1 , or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein R 10a is selected from the group consisting of —C(═O)Z 2 and unsubstituted or substituted C 1 -C 6 alkyl; and
Z 2 is selected from the group consisting of:
(i) C 1 -C 6 alkyl; and
(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 2 , —S(═O) 2 NZ 3 Z 4 , halogen, —NZ 3 Z 4 , 4- to 8-membered heterocycle.
4. The compound of claim 1 , or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein R 2 and R 3 taken together with the carbon atom to which they are attached form a —C(═O)— group.
5. The compound of claim 1 , or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein R 2 and R 3 are hydrogen.
6. The compound of claim 1 , or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein:
X is —CR 11a ═;
X 1 is —CR 11b ═;
X 2 is —CR 11c ═; and
X 3 is —CR 11d ═.
7. The compound of claim 1 of Formula III:
or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof.
8. The compound of claim 1 , or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein Z 3 is unsubstituted or substituted C 1 -C 6 alkyl.
9. The compound of claim 8 , or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein:
X is —CR 11a ═;
X 1 is —CR 11b ═; and
X 3 is —CR 11d ═.
10. The compound of claim 1 , or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein R1 is substituted C6-C10 aryl, wherein one or more substituents are independently selected from the group consisting of halogen, hydroxy, cyano, C1-C6 alkyl, and —OZ1.
11. A compound, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, selected from the group consisting of:
N-(2-oxo-1-(4-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)acrylamide;
3-amino-1-(4-(trifluoromethyl)phenyl)-1,3,4,5-tetrahydro-2H-benzo[b]azepin-2-one;
3-((3-hydroxypropyl)amino)-1-(4-(trifluoromethyl)phenyl)-1,3,4,5-tetrahydro-2H-benzo[b]azepin-2-one;
2-((1-(4-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)amino)ethan-1-ol;
7-((2-hydroxyethyl)amino)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-5H-benzo[b]azepin-5-one;
7-((3-hydroxypropyl)amino)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-5H-benzo[b]azepin-5-one;
N-(1-(4-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)acrylamide
3-((2-hydroxyethyl)amino)-1-(4-(trifluoromethyl)phenyl)-1,3,4,5-tetrahydro-2H-benzo[b]azepin-2-one;
3-((1-(4-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)amino)propan-1-ol;
3-((1-(4-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)amino)propanoic acid;
1-(4-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-amine;
N-(1-(4-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)propionamide;
N-(2-oxo-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinolin-3-yl)acrylamide;
N-(5-fluoro-2-oxo-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinolin-3-y1)acrylamide; and
N-(2-oxo-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,6-naphthyridin-3-y1)acrylamide.
12. A pharmaceutical composition comprising the compound of claim 1 , and a pharmaceutically acceptable carrier.
13. 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 a compound of claim 1 .
14. The method of claim 13 , further comprising administering one or more other medicines selected from the group consisting of EGFR inhibitors, MEK inhibitors, AXL inhibitors, B-RAF inhibitors, and RAS inhibitors.
15. A pharmaceutical composition comprising a compound of claim 11 , and a pharmaceutically acceptable carrier.
16. 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 a compound of claim 11 .
17. The method of claim 16 , further comprising administering one or more other medicines selected from the group consisting of EGFR inhibitors, MEK inhibitors, AXL inhibitors, B-RAF inhibitors, and RAS inhibitors.
18. A compound of Formula I:
or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein:
p is 1 or 2;
R 1 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) 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,
(iii) 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) 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 ,
(iv) 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 , 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 ,
(v) 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 ,
(vi) 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, and
(f) —OZ 1 ,
(vii) —S(═O) 2 Z 2 , and
(viii) —C(═O)Z 2 ;
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 hydrogen and —NR 10a R 10b ;
R 5 is selected from the group consisting of hydrogen and C 1 -C 6 alkyl;
each R 6 and R 7 is independently selected from the group consisting of hydrogen and C 1 -C 6 alkyl;
R 8 and R 9 are independently selected from the group consisting of hydrogen and C 1 -C 6 alkyl;
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)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:
(a) cyano,
(b) hydroxy,
(c) —OZ 1 ,
(d) —C(═O)OH
(e) —C(═O)Z 2
(f) —C(═O)OZ 2 ,
(g) —C(═O)NZ 3 Z 4 ,
(h) —S(═O) 2 Z 2 ,
(i) —S(═O) 2 NZ 3 Z 4 ,
(j) —S(═O)(═NZ 5 )Z 2 ,
(k) —S(═NZ 5 )(═NZ 6 )Z 2 ,
(l) —S(═O)(═NZ 5 )NZ 3 Z 4 , and
(m) —NZ 3 Z 4 ,
R 10b is selected from the group consisting of hydrogen and C 1 -C 6 alkyl;
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 2 , —S(═O) 2 NZ 3 Z 4 , halogen, —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) 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 2 , —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:
(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) 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,
(d) cyano,
(e) hydroxy,
(f) —OZ 1 , and
(g) —NZ 3 Z 4 ,
(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 2 , —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 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;
X is selected from the group consisting of —CR 11a ═ and —N═;
X 1 is selected from the group consisting of —CR 11b ═ and —N═;
X 2 is selected from the group consisting of —CR 11d ═ and —N═;
X 3 is selected from the group consisting of —CR 11d ═ and —N═; and
each R 11a , R 11b , R 11c , and R 11d is independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and —NZ 3 Z 4 .
19. A compound of claim 11 , or a pharmaceutically acceptable salt thereof, selected from the group consisting of:
(S)-2-((1-(4-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydro-1H-benzo [b]azepin-3-yl)amino)ethan-1-ol;
(R)-2-((1-(4-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydro-1H-benzo [b]azepin-3-yl)amino)ethan-1-ol;
(S)-N-(1-(4-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydro-1H-benzo [b]azepin-3-yl)acrylamide; and
(R)-N-(1-(4-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydro-1H-benzo [b]azepin-3-yl)acrylamide.