IP Library › Patent Application 18915226

Patent Application

App. No. 18/915,226

HETEROCYCLIC COMPOUNDS AS BET INHIBITORS

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Patent No.: US None
App. No.: 18/915,226

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Abstract

Novel bromodomain and extraterminal domain (BET) inhibitors and to therapeutic methods of treating conditions and diseases using these novel BET inhibitors are provided.

Claims (152)

1 - 23 . (canceled)

24 : A method of treating a disease mediated by bromodomain and extraterminal domain (BET) in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound of Formula (J),

or a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing,

wherein:

each is independently a single bond or double bond;

X is O or S;

R 1 is hydrogen, C 1 -C 3 alkyl, —(C 1 -C 3 alkylene)OH, C 1 -C 3 haloalkyl, or C 3 -C 4 cycloalkyl;

G 1 is CR a , wherein:

R a is hydrogen, halogen, or C 1 -C 4 alkyl;

Z 1 is C—W 1 —R c ; wherein:

each W 1 is independently —O— or —NR w1 —, wherein:

R w1 is hydrogen, C 3 -C 6 cycloalkyl, or C 1 -C 4 alkyl optionally substituted by oxo, —OH, or halogen, and

R c is independently C 3 -C 6 cycloalkyl, 4- to 6-membered heterocyclyl, C 6 -C 14 aryl, or 5- or 6-membered heteroaryl, each of which is independently optionally substituted by R o , wherein each R 1 is independently halogen, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, 3- to 6-membered heterocyclyl, cyano, oxo, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, C 1 -C 4 haloalkyl, —OR 10 , —NR 10 R 11 , —C(O)NR 10 R 11 , —NR 10 C(O)R 11 , —S(O) 2 R 10 , —NR 10 S(O) 2 R 11 , or —S(O) 2 NR 10 R 11 ;

Z 2 is C—W 2 —R d , wherein:

W 2 is —O—, —NR w2 —, or a bond, wherein:

R w2 is hydrogen, C 3 -C 6 cycloalkyl, or C 1 -C 4 alkyl optionally substituted by oxo, —OH, or halogen, and

R d is independently hydrogen, halogen, cyano, 3- to 6-membered heterocyclyl, or C 1 -C 4 alkyl;

Z 3 is C—R e , wherein:

R e is independently hydrogen, halogen, cyano, 3- to 6-membered heterocyclyl, or C 1 -C 4 alkyl:

M 1 is S or CR 1a ;

M 2 is S or CR 2a , provided that

(1) when M 1 is S, then the adjacent to M 1 is a single bond and the adjacent to M 2 is a double bond,

(2) when M 2 is S, then the adjacent to M 2 is a single bond and the adjacent to M 1 is a double bond, and

(3) either M 1 or M 2 is S;

R 1a and R 2a are each independently hydrogen, halogen, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, 3- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl, cyano, oxo, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, —OR 10 , —NR 10 R 11 , —C(O)OR 10 , —C(O)NR 10 R 11 , —NR 10 C(O)R 11 , —S(O) 2 R 10 , —NR 10 S(O) 2 R 11 or —S(O) 2 NR 1O R 11 , each of which is independently optionally substituted by R 12 ;

R 2 is hydrogen, halogen, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, 3- to 6-membered heterocyclyl, —(C 1 -C 3 alkylene)3- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl, cyano, oxo, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, —OR 10 , —NR 10 R 11 , —C(O)OR 10 , —C(O)NR 10 R 11 , —NR 10 C(O)R 11 , —S(O) 2 R 10 , —NR 10 S(O) 2 R 11 , or —S(O) 2 NR 10 R 11 each of which is independently optionally substituted by R 12 ;

R 3 is —(CH 2 ) m NR 13 S(O) 2 R 14 wherein m is 0, 1, 2 or 3; C 3 -C 6 cycloalkyl optionally substituted by halogen, oxo, —CN, or —OH; C 1 -C 4 alkyl substituted by halogen, oxo, —CN, or —OH; or C 1 -C 6 alkenyl;

R 10 and R 11 are each independently hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkenyl, C 3 -C 6 cycloalkyl, C 6 -C 14 aryl, 3- to 6-membered heterocyclyl, —(C 1 -C 3 alkylene)C 3 -C 6 cycloalkyl, —(C 1 -C 3 alkylene) 3- to 6-membered heterocyclyl, —(C 1 -C 3 alkylene) C 6 -C 14 aryl, —NR 15 R 16 or —C(O)R 12 , wherein each of R 10 and R 11 is independently optionally substituted by halogen, oxo, —CN, —CF 3 , —OH, —NR 13 R 14 , —C(O)NR 13 R 14 , or C 1 -C 4 alkyl optionally substituted by halogen, oxo, —CN, —CF 3 , or —OH,

or R 10 and R 11 are taken together with the atom or atoms to which they are attached to form a 3- to 6-membered heterocyclyl ring optionally substituted by halogen, oxo, —CN, —CF 3 , —OH, or C 1 -C 4 alkyl optionally substituted by halogen, oxo, —CN, or —OH:

each R 12 is independently halogen, cyano, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, —OR 15 , —NR 15 R 16 , —C(O)NR 15 R 16 , —NR 15 C(O)R 16 , —S(O) 2 R 15 , —NR 15 S(O) 2 R 16 , —S(O) 2 NR 15 R 16 , C 3 -C 6 cycloalkyl, 3- to 6-membered heterocyclyl, or C 1 -C 4 alkyl, each of which is independently optionally substituted by halogen, oxo, —CF 3 , —CN, —OH, —NR 13 R 14 , or —NR 13 C(O)R 14 ;

R 13 and R 14 are independently hydrogen, C 1 -C 4 alkyl C 3 -C 6 cycloalkyl, or 3- to 6-membered heterocyclyl, each of which is independently optionally substituted by halogen, oxo, —CN, or —OH,

or R 13 and R 14 are taken together with the atom or atoms to which they are attached to form a 3- to 6-membered heterocyclyl ring optionally substituted by halogen, oxo, —CN, —OH, or C 1 -C 4 alkyl optionally substituted by halogen, oxo, —CN, or —OH; and

or R 15 and R 16 are taken together with the atoms to which they are attached to form a 3- to 6-membered heterocyclyl ring optionally substituted by halogen, oxo, —CN, —OH, or C 1 -C 4 alkyl optionally substituted by halogen, oxo, —CN, or —OH.

25 : A method of treating cancer in an individual in need thereof comprising administering to the individual a therapeutically effective amount of a compound of Formula (J),

or a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing,

wherein:

each is independently a single bond or double bond;

X is O or S;

R 1 is hydrogen, C 1 -C 3 alkyl, —(C 1 -C 3 alkylene)OH, C 1 -C 3 haloalkyl, or C 3 -C 4 cycloalkyl;

G 1 is CR a , wherein:

R a is hydrogen, halogen, or C 1 -C 4 alkyl;

Z 1 is C-W 1 -R c wherein:

each W 1 is independently —O— or —NR w1 —, wherein:

R w1 is hydrogen, C 3 -C 6 cycloalkyl, or C 1 -C 4 alkyl optionally substituted by oxo, —OH, or halogen, and

R c is independently C 3 -C 6 cycloalkyl, 4- to 6-membered heterocyclyl, C 6 -C 14 aryl, or 5- or 6-membered heteroaryl, each of which is independently optionally substituted by R c , wherein each R 1 is independently halogen, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, 3- to 6-membered heterocyclyl, cyano, oxo, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, C 1 -C 4 haloalkyl, —OR 10 , —NR 10 R 11 , —C(O)NR 10 R 11 , —NR 10 C(O)R 11 , —S(O) 2 R 10 , —NR 10 S(O) 2 R 11 , or —S(O) 2 NR 10 R 11 ;

Z 2 is C—W 2 —R d , wherein:

W 2 is —O—, —NR w2 —, or a bond, wherein:

R w2 is hydrogen, C 3 -C 6 cycloalkyl, or C 1 -C 4 alkyl optionally substituted by oxo, —OH, or halogen, and

R d is independently hydrogen, halogen, cyano, 3- to 6-membered heterocyclyl, or C 1 -C 4 alkyl:

Z 3 is C—R e , wherein:

R e is independently hydrogen, halogen, cyano, 3- to 6-membered heterocyclyl, or C 1 -C 4 alkyl;

M 1 is S or CR 1a ;

M 2 is S or CR 2a , provided that

(1) when M 1 is S, then the adjacent to M 1 is a single bond and the adjacent to M 2 is a double bond,

(2) when M 2 is S, then the adjacent to M 2 is a single bond and the adjacent to M 1 is a double bond, and

(3) either M 1 or M 2 is S;

R 13 and R 14 are independently hydrogen, C 1 -C 4 alkyl C 3 -C 6 cycloalkyl, or 3- to 6-membered heterocyclyl, each of which is independently optionally substituted by halogen, oxo, —CN, or —OH,

26 : A method of inhibiting bromodomain and extraterminal domain (BET) in a cell, comprising administering to the cell a compound of Formula (J),

or a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing,

wherein:

each is independently a single bond or double bond;

X is O or S;

R 1 is hydrogen, C 1 -C 3 alkyl, —(C 1 -C 3 alkylene)OH, C 1 -C 3 haloalkyl, or C 3 -C 4 cycloalkyl;

G 1 is CR a , wherein:

R a is hydrogen, halogen, or C 1 -C 4 alkyl;

Z 1 is C—W 1 —R c ; wherein:

each W 1 is independently —O— or —NR w1 —, wherein:

R w1 is hydrogen, C 3 -C 6 cycloalkyl, or C 1 -C 4 alkyl optionally substituted by oxo, —OH, or halogen, and

R c is independently C 3 -C 6 cycloalkyl, 4- to 6-membered heterocyclyl, C 6 -C 14 aryl, or 5- or 6-membered heteroaryl, each of which is independently optionally substituted by R c1 , wherein each R c1 is independently halogen, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, 3- to 6-membered heterocyclyl, cyano, oxo, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, C 1 -C 4 haloalkyl, —OR 10 , —NR 10 R 11 , —C(O)NR 10 R 11 , —NR 10 C(O)R 11 , —S(O) 2 R 10 , —NR 10 S(O) 2 R 11 , or —S(O) 2 NR 10 R 11 ;

Z 2 is C—W 2 —R d , wherein:

W 2 is —O—, —NR w2 —, or a bond, wherein:

R w2 is hydrogen, C 3 -C 6 cycloalkyl, or C 1 -C 4 alkyl optionally substituted by oxo, —OH, or halogen, and

R d is independently hydrogen, halogen, cyano, 3- to 6-membered heterocyclyl, or C 1 -C 4 alkyl;

Z 3 is C—R e , wherein:

R e is independently hydrogen, halogen, cyano, 3- to 6-membered heterocyclyl, or C 1 -C 4 alkyl;

M 1 is S or CR 1a ;

M 2 is S or CR 2a , provided that

(1) when M 1 is S, then the adjacent to M 1 is a single bond and the adjacent to M 2 is a double bond,

(2) when M 2 is S, then the adjacent to M 2 is a single bond and the adjacent to M 1 is a double bond, and

(3) either M 1 or M 2 is S;

R 1a and R 2a are each independently hydrogen, halogen, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, 3- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl, cyano, oxo, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, —OR 10 , —NR 10 R 11 , —C(O)OR 10 , —C(O)NR 10 R 11 , —NR 10 C(O)R 11 , —S(O) 2 R 10 , —NR 10 S(O) 2 R 11 or —S(O) 2 NR 10 R 11 each of which is independently optionally substituted by R 12 ;

R 10 and R 11 are each independently hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkenyl, C 3 -C 6 cycloalkyl, C 6 -C 14 aryl, 3- to 6-membered heterocyclyl, —(C 1 -C 3 alkylene)C 3 -C 6 cycloalkyl, —(C 1 -C 3 alkylene) 3- to 6-membered heterocyclyl, —(C 1 -C 3 alkylene) C 6 -C 14 aryl, —NR 15 R 16 , or —C(O)R 12 , wherein each of R 10 and R 11 is independently optionally substituted by halogen, oxo, —CN, —CF 3 , —OH, —NR 13 R 14 , —C(O)NR 13 R 14 , or C 1 -C 4 alkyl optionally substituted by halogen, oxo, —CN, —CF 3 , or —OH,

R 13 and R 14 are independently hydrogen, C 1 -C 4 alkyl C 3 -C 6 cycloalkyl, or 3- to 6-membered heterocyclyl, each of which is independently optionally substituted by halogen, oxo, —CN, or —OH,

27 - 28 . (canceled)

29 : The method of claim 25 , wherein the compound is of Formula (I):

or a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein:

each is independently a single bond or double bond;

X is O or S;

R 1 is hydrogen, C 1 -C 3 alkyl, —(C 1 -C 3 alkylene)OH, C 1 -C 3 haloalkyl, or C 3 -C 4 cycloalkyl;

G 1 is CR a , wherein:

R a is hydrogen, halogen, or C 1 -C 4 alkyl;

Z 1 is C—W 1 —R c ; wherein:

each W 1 is independently —O— or —NR w1 —, wherein:

R w1 is hydrogen, C 3 -C 6 cycloalkyl, or C 1 -C 4 alkyl optionally substituted by oxo, —OH, or halogen, and

R c is independently 4- to 6-membered heterocyclyl, C 6 -C 14 aryl, or 5- or 6-membered heteroaryl, each of which is independently optionally substituted by R c , wherein each R c is independently halogen, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, 3- to 6-membered heterocyclyl, cyano, oxo, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, C 1 -C 4 haloalkyl, —OR 10 , —NR 10 R 11 , —C(O)NR 10 R 11 , —NR 10 C(O)R 11 , —S(O) 2 R 10 , —NR 10 S(O) 2 R 11 , or —S(O) 2 NR 10 R 11 ;

Z 2 is C—W 2 —R d , wherein:

W 2 is —O—, —NR w2 —, or a bond, wherein:

R w2 is hydrogen, C 3 -C 6 cycloalkyl, or C 1 -C 4 alkyl optionally substituted by oxo, —OH, or halogen, and

R d is independently hydrogen, halogen, cyano, 3- to 6-membered heterocyclyl, or C 1 -C 4 alkyl;

Z 3 is C—R e , wherein:

R e is independently hydrogen, halogen, cyano, 3- to 6-membered heterocyclyl, or C 1 -C 4 alkyl;

M 1 is S or CR 1a ;

M 2 is S or CR 2a , provided that

(1) when M 1 is S, then the adjacent to M 1 is a single bond and the adjacent to M 2 is a double bond,

(2) when M 2 is S, then the adjacent to M 2 is a single bond and the adjacent to M 1 is a double bond, and

(3) at least one of M 1 and M 2 is not S;

R 1a and R 2a are each independently hydrogen, halogen, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, 3- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl, cyano, oxo, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, —OR 10 , —NR 10 R 11 , —C(O)OR 10 , —C(O)NR 10 R 11 , —NR 10 C(O)R 11 , —S(O) 2 R 10 , —NR 10 S(O) 2 R 11 or —S(O) 2 NR 10 R 11 , each of which is independently optionally substituted by R 12 ;

R 2 is halogen, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, 3- to 6-membered heterocyclyl, —(C 1 -C 3 alkylene)3- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl, cyano, oxo, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, —OR 10 , —NR 10 R 11 , —C(O)OR 10 , —C(O)NR 10 R 11 , —NR 10 C(O)R 11 , —S(O) 2 R 10 , —NR 10 S(O) 2 R 11 , or —S(O) 2 NR 10 R 11 , each of which is independently optionally substituted by R 12 ;

R 3 is —(CH 2 ) m NR 13 S(O) 2 R 14 , C 3 -C 6 cycloalkyl, or C 1 -C 4 alkyl substituted by halogen, oxo, —CN, or —OH, wherein m is 0, 1, 2 or 3;

R 10 and R 11 are each independently hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkenyl, C 3 -C 6 cycloalkyl, 3- to 6-membered heterocyclyl, —(C 1 -C 3 alkylene)C 3 -C 6 cycloalkyl, —(C 1 -C 3 alkylene) 3- to 6-membered heterocyclyl, —NR 15 R 16 , or —C(O)R 12 , wherein each of R 10 and R 11 is independently optionally substituted by halogen, oxo, —CN, —CF 3 , —OH, —NR 13 R 14 , —C(O)NR 13 R 14 , or C 1 -C 4 alkyl optionally substituted by halogen, oxo, —CN, —CF 3 , or —OH,

R 13 and R 14 are independently hydrogen, C 1 -C 4 alkyl C 3 -C 6 cycloalkyl, or 3- to 6-membered heterocyclyl, each of which is independently optionally substituted by halogen, oxo, —CN, or —OH,

each R 15 and R 16 are independently hydrogen, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, or 3- to 6-membered heterocyclyl, each of which is independently optionally substituted by halogen, oxo, —CN, or —OH, or R 15 and R 16 are taken together with the atoms to which they are attached to form a 3- to 6-membered heterocyclyl ring optionally substituted by halogen, oxo, —CN, —OH, or C 1 -C 4 alkyl optionally substituted by halogen, oxo, —CN, or —OH.

30 : The method of claim 29 , wherein the compound is of Formula (II),

or a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

31 : The method of claim 29 , wherein the compound is of Formula (III),

or a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

32 : The method of claim 25 , wherein the compound is selected from the group consisting of: