US2022213122A1PendingUtilityA1
Substituted 1,6-dihydropyridinones and 1,2-dihydroisoquinolinones as bet inhibitors
Est. expiryOct 30, 2038(~12.3 yrs left)· nominal 20-yr term from priority
C07D 498/04C07D 237/22C07D 513/04C07D 491/048C07D 471/04C07D 417/12C07D 411/10C07D 495/04C07D 239/90C07D 239/36C07D 409/12A61P 35/00C07D 213/89C07D 401/12
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Claims
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
exact text as granted — not AI-modified1 - 24 . (canceled)
25 : A method of treating 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 (I):
or a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing,
wherein:
X is O or S;
Y 1 is N or C;
Y 2 is N or C, provided that
(1) at least one of Y 1 and Y 2 is N, and
(2) when both Y 1 and Y 2 are N, then G 1 is CR a or CHR a ;
each is independently a single bond or a double bond, provided that
(i) when Y 2 is N and Y 1 is C, then the between G 1 and Y 1 is a double bond and the between G 1 and Y 2 is a single bond,
(ii) when Y 1 is N and Y 2 is C, then the between G 1 and Y 1 is a single bond and the between G 1 and Y 2 is a double bond, and
(iii) when both Y 1 and Y 2 are N, then the between G 1 and Y 1 and the between G 1 and Y 2 are both single bonds;
R 1 is hydrogen, cyano, halogen, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkyl optionally substituted by —OH, C 3 -C 6 cycloalkyl optionally substituted by C 1 -C 6 alkyl, —(CH 2 ) m N(R f )W 3 R g , —(CH 2 ) m N(R f )C(O)OR h , or —(CH 2 ) m W 3 R g , provided that when Y 1 is N and G 1 is N, then R 1 is cyano, halogen, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkyl optionally substituted by —OH, C 3 -C 6 cycloalkyl optionally substituted by C 1 -C 6 alkyl, —(CH 2 ) m N(R f )W 3 R g , —(CH 2 ) m N(R f )C(O)OR h , or —(CH 2 ) m W 3 R g ;
G 1 is CR a , CHR a or N, wherein:
R a is hydrogen, halogen, or C 1 -C 4 alkyl;
G 2 is CR b or N, wherein:
R b is hydrogen, halogen, cyano, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, 3- to 6-membered heterocyclyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, —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 ;
R 2 is hydrogen, halogen, cyano, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, 3- to 6-membered heterocyclyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, —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 ,
or R b and R 2 are taken together with the atoms to which they are attached to form a 5- or 6-membered C ring, which is optionally substituted by R 5 , wherein each R 5 is independently halogen, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, 3- to 6-membered heterocyclyl, C 6 -C 14 aryl, 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 optionally substituted by R 12 ;
indicates a saturated, partially unsaturated or fully unsaturated ring;
Z 1 is CH—W 1 —R c , C—W 1 —R c , C═O, NR c , or N, wherein:
each W 1 is independently —O—, —NR w1 —, or a bond, wherein:
R w1 is hydrogen, C 3 -C 6 cycloalkyl, or C 1 -C 4 alkyl optionally substituted by oxo, —OH, or halogen, and
each R c is independently hydrogen, halogen, cyano, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 4 haloalkyl, 3- to 6-membered heterocyclyl, C 6 -C 14 aryl, or 5- to 6-membered heteroaryl, wherein C 3 -C 6 cycloalkyl, 3- to 6-membered heterocyclyl, C 6 -C 14 aryl, and 5- to 6-membered heteroaryl of R c are 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 CH—W 2 —R d , C—W 2 —R d , C═O, NR d , or N, wherein:
each W 2 is independently —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
each R d is independently hydrogen, 3- to 6-membered heterocyclyl, or C 1 -C 4 alkyl;
or R c and R d are taken together with the atoms to which they are attached to form a 5- or 6-membered D ring, which is optionally substituted by R 6 , wherein each R 6 is independently halogen, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, 3- to 6-membered heterocyclyl, C 6 -C 14 aryl, 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)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 optionally substituted by R 12 ;
Z 3 is CH—R e , C—R e , C═O, NR e , or N, wherein:
each R e is independently hydrogen, halogen, cyano, 3- to 6-membered heterocyclyl, or C 1 -C 4 alkyl,
provided that
(1) when Z 2 is C═O, then Z 3 is NR e ,
(2) when Z 3 is C═O, then Z 2 is NR d , and
(3) no more than two of Z 1 , Z 2 , and Z 3 are N;
R 3 and R 4 are each independently hydrogen, halogen, cyano, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, —OR 13 , —NR 13 R 14 , —C(O)NR 13 R 14 , —NR 13 C(O)R 14 , —NR 13 C(O)NR 13 R 14 , —S(O) 2 R 13 , —NR 13 S(O) 2 R 14 , —NR 13 S(O) 2 NR 13 R 14 , —S(O) 2 NR 13 R 14 , —(CH 2 ) m N(R f )W 3 R g , —(CH 2 ) m N(R f )C(O)OR h , —(CH 2 ) m W 3 R g , or C 1 -C 4 alkyl optionally substituted by halogen, oxo, —CN or —OH,
provided that
(a) when Y 2 is C, then at least one of R 1 , R 3 and R 4 is —(CH 2 ) m N(R f )W 3 R g , —(CH 2 ) m N(R f )C(O)OR h , or —(CH 2 ) m W 3 R g , and
(b) when Y 2 is N, then
(i) at least one of R 1 , R 3 and R 4 is —(CH 2 ) m N(R f )W 3 R g , —(CH 2 ) m N(R f )C(O)OR h , or —(CH 2 ) m W 3 R g , or
(ii) R 4 is halogen, cyano, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, —OR 13 , —NR 13 R 14 , —C(O)NR 13 R 14 , —NR 13 C(O)R 14 , —NR 13 C(O)NR 13 R 14 , —S(O) 2 R 13 , —NR 13 S(O) 2 R 14 , —NR 13 S(O) 2 NR 13 R 14 , —S(O) 2 NR 13 R 14 , —(CH 2 ) m N(R f )W 3 R g , —(CH 2 ) m N(R f )C(O)OR h , —(CH 2 ) m W 3 R g , or C 1 -C 4 alkyl optionally substituted by halogen, oxo, —CN or —OH, and Z 1 is CH—W 1 —R c or C—W 1 —R c , wherein W 1 is —O— or —NR w — and R c is C 3 -C 6 cycloalkyl, 3- to 6-membered heterocyclyl, phenyl, or 5- to 6-membered heteroaryl, each of which is optionally substituted by R c1 ;
each m is independently 0, 1, 2, 3, or 4;
R f is hydrogen, C 1 -C 4 alkyl, or C 3 -C 6 cycloalkyl;
W 3 is —C(O)— or —S(O) 2 —;
R g is —CR g1 ═CH R g2 or —C≡CR g2 , wherein R g1 and R g2 are each independently hydrogen, cyano, or C 1 -C 4 alkyl optionally substituted by —OH, —OCH 3 , —NH 2 , —NHCH 3′ or —N(CH 3 ) 2 ,
or for R 4 , when R 4 is —(CH 2 ) m N(R f )W 3 R g and m is 0, the N, R f , W 3 and R g in —N(R f )W 3 R g may be taken together to form a 5- or 6-membered ring having at least one double bond and optionally substituted by R, wherein each R is independently C 1 -C 4 alkyl, oxo, halogen, or —CN;
R h is C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl;
R 10 and R 11 are each independently hydrogen, 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, C(O)R 12 , or C 1 -C 4 alkyl optionally substituted by halogen, oxo, —CN, —OH, —NR 13 R 14 , or —C(O)NR 13 R 14 ,
or R 10 and R 11 are taken together with the atoms to which they are attached to form a 3- to 6-membered heterocyclyl optionally substituted by halogen, oxo, —CN, —OH, or C 1 -C 4 alkyl optionally substituted by halogen, oxo, —CN, or —OH;
each R 12 is independently halogen, C 3 -C 6 cycloalkyl, 3- to 6-membered heterocyclyl, or C 1 -C 4 alkyl optionally substituted by halogen, oxo, —CN, —OH, —NR 13 R 14 or —NR 13 C(O)R 14 ;
R 13 and R 14 are independently hydrogen, C 3 -C 6 cycloalkyl, 3- to 6-membered heterocyclyl, or C 1 -C 4 alkyl optionally substituted by halogen, oxo, —CN, or —OH,
or R 13 and R 14 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.
26 : 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 (I):
or a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing,
wherein:
X is O or S;
Y 1 is N or C;
Y 2 is N or C, provided that
(1) at least one of Y 1 and Y 2 is N, and
(2) when both Y 1 and Y 2 are N, then G 1 is CR a or CHR a ;
each is independently a single bond or a double bond, provided that
(i) when Y 2 is N and Y 1 is C, then the between G 1 and Y 1 is a double bond and the between G 1 and Y 2 is a single bond,
(ii) when Y 1 is N and Y 2 is C, then the between G 1 and Y 1 is a single bond and the between G 1 and Y 2 is a double bond, and
(iii) when both Y 1 and Y 2 are N, then the between G 1 and Y 1 and the between G 1 and Y 2 are both single bonds;
R 1 is hydrogen, cyano, halogen, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkyl optionally substituted by —OH, C 3 -C 6 cycloalkyl optionally substituted by C 1 -C 6 alkyl, —(CH 2 ) m N(R f )W 3 R g , —(CH 2 ) m N(R f )C(O)OR h , or —(CH 2 ) m W 3 R g , provided that when Y 1 is N and G 1 is N, then R 1 is cyano, halogen, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkyl optionally substituted by —OH, C 3 -C 6 cycloalkyl optionally substituted by C 1 -C 6 alkyl, —(CH 2 ) m N(R f )W 3 R g , —(CH 2 ) m N(R′)C(O)OR h , or —(CH 2 ) m W 3 R g ;
G 1 is CR a , CHR a or N, wherein:
R a is hydrogen, halogen, or C 1 -C 4 alkyl;
G 2 is CR b or N, wherein:
R b is hydrogen, halogen, cyano, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, 3- to 6-membered heterocyclyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, —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 ;
R 2 is hydrogen, halogen, cyano, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, 3- to 6-membered heterocyclyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, —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 ,
or R b and R 2 are taken together with the atoms to which they are attached to form a 5- or 6-membered C ring, which is optionally substituted by R 5 , wherein each R 5 is independently halogen, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, 3- to 6-membered heterocyclyl, C 6 -C 14 aryl, 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 optionally substituted by R 12 ;
indicates a saturated, partially unsaturated or fully unsaturated ring;
Z 1 is CH—W 1 —R c , C—W 1 —R c , C═O, NR c , or N, wherein:
each W 1 is independently —O—, —NR w1 —, or a bond, wherein:
R w1 is hydrogen, C 3 -C 6 cycloalkyl, or C 1 -C 4 alkyl optionally substituted by oxo, —OH, or halogen, and
each R c is independently hydrogen, halogen, cyano, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 4 haloalkyl, 3- to 6-membered heterocyclyl, C 6 -C 14 aryl, or 5- to 6-membered heteroaryl, wherein C 3 -C 6 cycloalkyl, 3- to 6-membered heterocyclyl, C 6 -C 14 aryl, and 5- to 6-membered heteroaryl of R c are 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 CH—W 2 —R d , C—W 2 —R d , C═O, NR d , or N, wherein:
each W 2 is independently —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
each R d is independently hydrogen, 3- to 6-membered heterocyclyl, or C 1 -C 4 alkyl;
or R c and R d are taken together with the atoms to which they are attached to form a 5- or 6-membered D ring, which is optionally substituted by R 6 , wherein each R 6 is independently halogen, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, 3- to 6-membered heterocyclyl, C 6 -C 14 aryl, 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)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 optionally substituted by R 12 ;
Z 3 is CH—R e , C—R e , C═O, NR e , or N, wherein:
each R e is independently hydrogen, halogen, cyano, 3- to 6-membered heterocyclyl, or C 1 -C 4 alkyl,
provided that
(1) when Z 2 is C═O, then Z 3 is NR e ,
(2) when Z 3 is C═O, then Z 2 is NR d , and
(3) no more than two of Z 1 , Z 2 , and Z 3 are N;
R 3 and R 4 are each independently hydrogen, halogen, cyano, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, —OR 13 , —NR 13 R 14 , —C(O)NR 13 R 14 , —NR 13 C(O)R 14 , —NR 13 C(O)NR 13 R 14 , —S(O) 2 R 13 , —NR 13 S(O) 2 R 14 , —NR 13 S(O) 2 NR 13 R 14 , —S(O) 2 NR 13 R 14 , —(CH 2 ) m N(R f )W 3 R g , —(CH 2 ) m N(R f )C(O)OR h , —(CH 2 ) m W 3 R g , or C 1 -C 4 alkyl optionally substituted by halogen, oxo, —CN or —OH,
provided that
(a) when Y 2 is C, then at least one of R 1 , R 3 and R 4 is —(CH 2 ) m N(R f )W 3 R g , —(CH 2 ) m N(R f )C(O)OR h , or —(CH 2 ) m W 3 R g , and
(b) when Y 2 is N, then
(i) at least one of R 1 , R 3 and R 4 is —(CH 2 ) m N(R f )W 3 R g , —(CH 2 ) m N(R f )C(O)OR h , or —(CH 2 ) m W 3 R g , or
(ii) R 4 is halogen, cyano, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, —OR 13 , —NR 13 R 14 , —C(O)NR 13 R 14 , —NR 13 C(O)R 14 , —NR 13 C(O)NR 13 R 14 , —S(O) 2 R 13 , —NR 13 S(O) 2 R 14 , —NR 13 S(O) 2 NR 13 R 14 , —S(O) 2 NR 13 R 14 , —(CH 2 ) m N(R f )W 3 R g , —(CH 2 ) m N(R f )C(O)OR h , —(CH 2 ) m W 3 R g , or C 1 -C 4 alkyl optionally substituted by halogen, oxo, —CN or —OH, and Z 1 is CH—W 1 —R c or C—W 1 —R c , wherein W 1 is —O— or —NR w — and R c is C 3 -C 6 cycloalkyl, 3- to 6-membered heterocyclyl, phenyl, or 5- to 6-membered heteroaryl, each of which is optionally substituted by R c1 ;
each m is independently 0, 1, 2, 3, or 4:
R f is hydrogen, C 1 -C 4 alkyl, or C 3 -C 6 cycloalkyl;
W 3 is —C(O)— or —S(O) 2 —;
R g is —CR g1 ═CH R g2 or —C≡CR g2 , wherein R g1 and R g2 are each independently hydrogen, cyano, or C 1 -C 4 alkyl optionally substituted by —OH, —OCH 3 , —NH 2 , —NHCH 3′ or —N(CH 3 ) 2 ,
or for R 4 , when R 4 is —(CH 2 ) m N(R f )W 3 R g and m is 0, the N, R f , W 3 and R g in —N(R f )W 3 R g may be taken together to form a 5- or 6-membered ring having at least one double bond and optionally substituted by R, wherein each R is independently C 1 -C 4 alkyl, oxo, halogen, or —CN;
R h is C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl;
R 10 and R 11 are each independently hydrogen, 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, C(O)R 12 , or C 1 -C 4 alkyl optionally substituted by halogen, oxo, —CN, —OH, —NR 13 R 14 , or —C(O)NR 13 R 14 ,
or R 10 and R 11 are taken together with the atoms to which they are attached to form a 3- to 6-membered heterocyclyl optionally substituted by halogen, oxo, —CN, —OH, or C 1 -C 4 alkyl optionally substituted by halogen, oxo, —CN, or —OH;
each R 12 is independently halogen, C 3 -C 6 cycloalkyl, 3- to 6-membered heterocyclyl, or C 1 -C 4 alkyl optionally substituted by halogen, oxo, —CN, —OH, —NR 13 R 14 or —NR 13 C(O)R 14 ;
R 13 and R 14 are independently hydrogen, C 3 -C 6 cycloalkyl, 3- to 6-membered heterocyclyl, or C 1 -C 4 alkyl optionally substituted by halogen, oxo, —CN, or —OH,
or R 13 and R 14 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.
27 : A method of inhibiting bromodomain and extraterminal domain (BET) in a cell, comprising administering to the cell a compound of Formula (I):
or a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing,
wherein:
X is O or S;
Y 1 is N or C;
Y 2 is N or C, provided that
(1) at least one of Y 1 and Y 2 is N, and
(2) when both Y 1 and Y 2 are N, then G 1 is CR a or CHR a ;
each is independently a single bond or a double bond, provided that
(i) when Y 2 is N and Y 1 is C, then the between G 1 and Y 1 is a double bond and the between G 1 and Y 2 is a single bond,
(ii) when Y 1 is N and Y 2 is C, then the between G 1 and Y 1 is a single bond and the between G 1 and Y 2 is a double bond, and
(iii) when both Y 1 and Y 2 are N, then the between G 1 and Y 1 and the between G 1 and Y 2 are both single bonds;
R 1 is hydrogen, cyano, halogen, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkyl optionally substituted by —OH, C 3 -C 6 cycloalkyl optionally substituted by C 1 -C 6 alkyl, —(CH 2 ) m N(R f )W 3 R g , —(CH 2 ) m N(R f )C(O)OR h , or —(CH 2 ) m W 3 R g , provided that when Y 1 is N and G 1 is N, then R 1 is cyano, halogen, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkyl optionally substituted by —OH, C 3 -C 6 cycloalkyl optionally substituted by C 1 -C 6 alkyl, —(CH 2 ) m N(R f )W 3 R g , —(CH 2 ) m N(R′)C(O)OR h , or —(CH 2 ) m W 3 R g ;
G 1 is CR a , CHR a or N, wherein:
R a is hydrogen, halogen, or C 1 -C 4 alkyl;
G 2 is CR b or N, wherein:
R b is hydrogen, halogen, cyano, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, 3- to 6-membered heterocyclyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, —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 ;
R 2 is hydrogen, halogen, cyano, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, 3- to 6-membered heterocyclyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, —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 ,
or R b and R 2 are taken together with the atoms to which they are attached to form a 5- or 6-membered C ring, which is optionally substituted by R 5 , wherein each R 5 is independently halogen, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, 3- to 6-membered heterocyclyl, C 6 -C 14 aryl, 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 optionally substituted by R 12 ;
indicates a saturated, partially unsaturated or fully unsaturated ring;
Z 1 is CH—W 1 —R c , C—W 1 —R c , C═O, NR c , or N, wherein:
each W 1 is independently —O—, —NR w1 —, or a bond, wherein:
R w1 is hydrogen, C 3 -C 6 cycloalkyl, or C 1 -C 4 alkyl optionally substituted by oxo, —OH, or halogen, and
each R c is independently hydrogen, halogen, cyano, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 4 haloalkyl, 3- to 6-membered heterocyclyl, C 6 -C 14 aryl, or 5- to 6-membered heteroaryl, wherein C 3 -C 6 cycloalkyl, 3- to 6-membered heterocyclyl, C 6 -C 14 aryl, and 5- to 6-membered heteroaryl of R c are 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 CH—W 2 —R d , C—W 2 —R d , C═O, NR d , or N, wherein:
each W 2 is independently —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
each R d is independently hydrogen, 3- to 6-membered heterocyclyl, or C 1 -C 4 alkyl;
or R c and R d are taken together with the atoms to which they are attached to form a 5- or 6-membered D ring, which is optionally substituted by R 6 , wherein each R 6 is independently halogen, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, 3- to 6-membered heterocyclyl, C 6 -C 14 aryl, 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)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 optionally substituted by R 12 ;
Z 3 is CH—R e , C—R e , C═O, NR e , or N, wherein:
each R e is independently hydrogen, halogen, cyano, 3- to 6-membered heterocyclyl, or C 1 -C 4 alkyl,
provided that
(1) when Z 2 is C═O, then Z 3 is NR e ,
(2) when Z 3 is C═O, then Z 2 is NR d , and
(3) no more than two of Z 1 , Z 2 , and Z 3 are N;
R 3 and R 4 are each independently hydrogen, halogen, cyano, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, —OR 13 , —NR 13 R 14 , —C(O)NR 13 R 14 , —NR 13 C(O)R 14 , —NR 13 C(O)NR 13 R 14 , —S(O) 2 R 13 , —NR 13 S(O) 2 R 14 , —NR 13 S(O) 2 NR 13 R 14 , —S(O) 2 NR 13 R 14 , —(CH 2 ) m N(R f )W 3 R g , —(CH 2 ) m N(R f )C(O)OR h , —(CH 2 ) m W 3 R g , or C 1 -C 4 alkyl optionally substituted by halogen, oxo, —CN or —OH,
provided that
(a) when Y 2 is C, then at least one of R 1 , R 3 and R 4 is —(CH 2 ) m N(R f )W 3 R g , —(CH 2 ) m N(R f )C(O)OR h , or —(CH 2 ) m W 3 R g , and
(b) when Y 2 is N, then
(i) at least one of R 1 , R 3 and R 4 is —(CH 2 ) m N(R f )W 3 R g , —(CH 2 ) m N(R f )C(O)OR h , or —(CH 2 ) m W 3 R g , or
(ii) R 4 is halogen, cyano, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, —OR 13 , —NR 13 R 14 , —C(O)NR 13 R 14 , —NR 13 C(O)R 14 , —NR 13 C(O)NR 13 R 14 , —S(O) 2 R 13 , —NR 13 S(O) 2 R 14 , —NR 13 S(O) 2 NR 13 R 14 , —S(O) 2 NR 13 R 14 , —(CH 2 ) m N(R f )W 3 R g , —(CH 2 ) m N(R f )C(O)OR h , —(CH 2 ) m W 3 R g , or C 1 -C 4 alkyl optionally substituted by halogen, oxo, —CN or —OH, and Z 1 is CH—W 1 —R c or C—W 1 —R c , wherein W 1 is —O— or —NR w — and R c is C 3 -C 6 cycloalkyl, 3- to 6-membered heterocyclyl, phenyl, or 5- to 6-membered heteroaryl, each of which is optionally substituted by R c1 ;
each m is independently 0, 1, 2, 3, or 4;
R f is hydrogen, C 1 -C 4 alkyl, or C 3 -C 6 cycloalkyl;
W 3 is —C(O)— or —S(O) 2 —;
R g is —CR g1 ═CH R g2 or —C≡CR g2 , wherein R g1 and R g2 are each independently hydrogen, cyano, or C 1 -C 4 alkyl optionally substituted by —OH, —OCH 3 , —NH 2 , —NHCH 3′ or —N(CH 3 ) 2 ,
or for R 4 , when R 4 is —(CH 2 ) m N(R f )W 3 R g and m is 0, the N, R f , W 3 and R g in —N(R f )W 3 R g may be taken together to form a 5- or 6-membered ring having at least one double bond and optionally substituted by R, wherein each R is independently C 1 -C 4 alkyl, oxo, halogen, or —CN;
R h is C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl;
R 10 and R 11 are each independently hydrogen, 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, C(O)R 12 , or C 1 -C 4 alkyl optionally substituted by halogen, oxo, —CN, —OH, —NR 13 R 14 , or —C(O)NR 13 R 14 ,
or R 10 and R 11 are taken together with the atoms to which they are attached to form a 3- to 6-membered heterocyclyl optionally substituted by halogen, oxo, —CN, —OH, or C 1 -C 4 alkyl optionally substituted by halogen, oxo, —CN, or —OH;
each R 12 is independently halogen, C 3 -C 6 cycloalkyl, 3- to 6-membered heterocyclyl, or C 1 -C 4 alkyl optionally substituted by halogen, oxo, —CN, —OH, —NR 13 R 14 or —NR 13 C(O)R 14 ;
R 13 and R 14 are independently hydrogen, C 3 -C 6 cycloalkyl, 3- to 6-membered heterocyclyl, or C 1 -C 4 alkyl optionally substituted by halogen, oxo, —CN, or —OH,
or R 13 and R 14 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.
28 - 29 . (canceled)
30 : The method of claim 25 , wherein the compound is of Formula (Ib):
wherein:
Z 1 is C—W 1 —R c or N;
Z 2 is C—W 2 —R d or N; and
Z 3 is C—R e or N.
31 : The method of claim 25 , wherein the compound is of Formula (III):
wherein:
Z 1 is C—W 1 —R c or N;
Z 2 is C—W 2 —R d or N; and
Z 3 is C—R e or N.
32 : The method of claim 25 , wherein X is O.
33 : The method of claim 25 , wherein R 1 is hydrogen, C 1 -C 4 alkyl optionally substituted by —OH, C 3 -C 6 cycloalkyl optionally substituted by C 1 -C 6 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, —CN, —(CH 2 ) m N(R f )W 3 R g , or —(CH 2 ) m W 3 R g .
34 : The method of claim 25 , wherein R 1 is C 1 -C 4 alkyl optionally substituted by —OH.
35 : The method of claim 25 , wherein R 3 is hydrogen, —(CH 2 ) m N(R f )W 3 R g , or —(CH 2 ) m W 3 R g .
36 : The method of claim 25 , wherein R 4 is hydrogen, —NR 13 C(O)R 14 , —NR 13 S(O) 2 R 14 , —NR 13 C(O)NR 13 R 14 , —NR 13 S(O) 2 NR 13 R 14 , —(CH 2 ) m N(R f )W 3 R g , —(CH 2 ) m W 3 R g , or C 1 -C 4 alkyl optionally substituted by halogen, oxo, —CN or —OH.
37 : The method of claim 25 , wherein G 1 is N.
38 : The method of claim 25 , wherein G 1 is CR a , wherein R a is hydrogen.
39 : The method of claim 25 , wherein G 2 is N.
40 : The method of claim 25 , wherein G 2 is CR b , wherein R b is hydrogen, —NR 10 R 11 , —C(O)NR 10 R 11 , or —NR 10 C(O)R 11 .
41 : The method of claim 25 , wherein R 2 is hydrogen, halogen, cyano, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, or C 1 -C 4 haloalkoxy.
42 : The method of claim 25 , wherein R b and R 2 are taken together with the atoms to which they are attached to form a 5- or 6-membered C ring, which is optionally substituted by R 5 .
43 : The method of claim 25 , wherein the compound is of Formula (Ic),
wherein:
Z 1 is C—W 1 —R c or N;
Z 2 is C—W 2 —R d or N;
Z 3 is C—R e or N;
M 1 is O, S, N, NR 1a , CR 1a , or CR 1a R 1b ;
M 2 is N, NR 2a , CR 2a , or CR 2a R 2b ;
M 3 is N, NR 3a , CR 3a , CR 3a R 3b or absent;
M 4 is O, S, N, NR 4a , CR 4a , or CR 4a R 4b ,
provided that
(1) no more than three of M 1 , M 2 , M 3 and M 4 are N or N substituted by R 1a , R 2a , R 3a , or R 4a , and
(2) if M 3 is absent, then at least one of M 1 and M 4 is not O or S; and
R 1a , R 1b , R 2a , R 2b , R 3a , R 3b , R 4a , and R 4b are each independently hydrogen, halogen, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, 3- to 6-membered heterocyclyl, C 6 -C 14 aryl, 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 .
44 : The method of claim 25 , wherein the compound is of Formula (V):
or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein:
Z 1 is C—W 1 —R c or N;
Z 2 is C—W 2 —R d or N;
Z 3 is C—R e or N;
M 1 is O, S, N, NR 1a , CR 1a , or CR 1a R 1b ;
M 2 is N, NR 2a , CR 2a , or CR 2a R 2b ;
M 3 is N, NR 3a , CR 3a , CR 3a R 3b or absent;
M 4 is O, S, N, NR 4a , CR 4a , or CR 4a R 4b , provided that
(1) no more than three of M 1 , M 2 , M 3 and M 4 are N or N substituted by R 1a , R 2a , R 3a , or R 4a , and
(2) if M 3 is absent, then at least one of M 1 and M 4 is not O or S; and
R 1a , R 1b , R 2a , R 2b , R 3a , R 3b , R 4a , and R 4b are each independently hydrogen, halogen, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, 3- to 6-membered heterocyclyl, C 6 -C 14 aryl, 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 .
45 : The method of claim 25 , wherein Z 1 is C—W 1 —R c .
46 : The method of claim 25 , wherein W 1 is O and R c is phenyl optionally substituted by R c1 .
47 : The method of claim 25 , wherein Z 2 is CH.
48 : The method of claim 25 , wherein Z 3 is CH.
49 : The method of claim 25 , wherein the compound is selected from the group consisting of the compounds in Table 1.Join the waitlist — get patent alerts
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