Aza-heteroaryl compounds as PI3K-gamma inhibitors
View Patent ↗The present invention provides aza-heteroaryl derivatives of Formula I: and pharmaceutically acceptable salts thereof, wherein X, Y, Z, A, W, R 4 , R 5 , and R 6 are defined herein, that inhibit the activity of phosphoinositide 3-kinases-gamma (PI3Kγ) and are useful in the treatment of diseases related to the activity of PI3Kγ including, for example, autoimmune diseases, cancer, cardiovascular diseases, and neurodegenerative diseases.
1. A compound of Formula I:
or a pharmaceutically acceptable salt thereof, wherein:
X is N or CR 1 ;
Y is N or CR 2 ;
Z is N or CR 3 ;
R 1 , R 2 , and R 3 are each independently selected from H, halo, CN, NO 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, Cy 2 , OR a1 , SR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , OC(O)R b1 , OC(O)NR c1 R d1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)OR a1 , NR c1 C(O)NR c1 R d1 , NR c1 S(O)R b1 , NR c1 S(O) 2 R b1 , NR c1 S(O) 2 NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O) 2 R b1 , and S(O) 2 NR c1 R d1 ; wherein said C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl are each optionally substituted with 1, 2 or 3 independently selected R 10 groups; or
alternatively, R 1 and R 2 , taken together with the carbon atoms to which they are attached, form a phenyl, C 3-6 cycloalkyl, or a 5-6-membered heteroaryl ring, which is optionally substituted by 1, 2, or 3 independently selected R 11 groups; or
alternatively, R 2 and R 3 , taken together with the carbon atoms to which they are attached, form a phenyl or a 5-6-membered heteroaryl ring, which is optionally substituted by 1, 2, or 3 independently selected R 11 groups;
A is O or S;
R 4 , R 5 , and R 6 are each independently selected from H, OH, NO 2 , CN, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, thio, C 1-6 alkylthio, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, carbamyl, C 1-6 alkylcarbamyl, di(C 1-6 alkyl)carbamyl, carboxy, C 1-6 alkylcarbonyl, C 1-6 alkoxycarbonyl, C 1-6 alkylcarbonylamino, C 1-6 alkylsulfonylamino, aminosulfonyl, C 1-6 alkylaminosulfonyl, di(C 1-6 alkyl)aminosulfonyl, aminosulfonylamino, C 1-6 alkylaminosulfonylamino, di(C 1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C 1-6 alkylaminocarbonylamino, and di(C 1-6 alkyl)aminocarbonylamino;
W is Cy;
Cy is phenyl, naphthyl, 5-10 membered heteroaryl, or 4-10 membered heterocycloalkyl, each of which is optionally substituted by 1, 2, 3, or 4 substituents independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, Cy 1 , —(C 1-4 alkylene)-Cy 1 , CN, NO 2 , OR a , SR a , P(O)R a R b , C(O)R b , C(O)NR c R d , C(O)OR a , OC(O)R b , OC(O)NR c R d , NR c R d , NR c C(O)R b , NR c C(O)OR a , NR c C(O)NR c R d , C(═NR e )R b , C(═NR e )NR c R d , NR c C(═NR e )NR c R d , NR c S(O)R b , NR c S(O) 2 R b , NR c S(O) 2 NR c R d , S(O)R b , S(O)NR c R d , S(O) 2 R b , and S(O) 2 NR c R d ; wherein the C 1-6 alkyl as the substituent of Cy is further substituted by 1 or 2 independently selected R g groups;
each R 10 is independently selected from halo, CN, NO 2 , Cy 2 , OR a1 , SR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , OC(O)R b1 , OC(O)NR c1 R d1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)OR a1 , NR c1 C(O)NR c1 R d1 , NR c1 S(O)R b1 , NR c1 S(O) 2 R b1 , NR c1 S(O) 2 NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O) 2 R b1 , and S(O) 2 NR c1 R d1 ;
each R 11 is independently selected from halo, CN, NO 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, OR a2 , SR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , OC(O)R b2 , OC(O)NR c2 R d2 , NR c2 R d2 , NR c2 C(O)R b2 , NR c2 C(O)OR a2 , NR c2 C(O)NR c2 R d2 , NR c2 S(O)R b2 , NR c2 S(O) 2 R b2 , NR c2 S(O) 2 NR c2 R d2 , S(O)R b2 , S(O)NR c2 R d2 , S(O) 2 R b2 , and S(O) 2 NR c2 R d2 ; wherein said C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl are each optionally substituted with 1, 2 or 3 independently selected R 12 groups;
each R 12 is independently selected from OH, NO 2 , CN, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, thio, C 1-6 alkylthio, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, carbamyl, C 1-6 alkylcarbamyl, di(C 1-6 alkyl)carbamyl, carboxy, C 1-6 alkylcarbonyl, C 1-6 alkoxycarbonyl, C 1-6 alkylcarbonylamino, C 1-6 alkylsulfonylamino, aminosulfonyl, C 1-6 alkylaminosulfonyl, di(C 1-6 alkyl)aminosulfonyl, aminosulfonylamino, C 1-6 alkylaminosulfonylamino, di(C 1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C 1-6 alkylaminocarbonylamino, and di(C 1-6 alkyl)aminocarbonylamino;
each R a , R c , and R d is independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-4 haloalkyl, Cy 1 , and —(C 1-4 alkylene)-Cy 1 ; wherein said C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl are each optionally substituted with 1, 2, 3, or 4 independently selected R g groups;
each R b is independently selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-4 haloalkyl, Cy 1 , and —(C 1-4 alkylene)-Cy 1 ; wherein said C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl are each optionally substituted with 1, 2, 3, or 4 independently selected R g groups; or
alternatively, any R c and R d attached to the same N atom, together with the N atom to which they are attached, form a 4-6 membered heterocycloalkyl group or a 5-6 membered heteroaryl group, each optionally substituted with 1, 2, or 3 independently selected R g groups;
each R e is independently selected from H, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkylthio, C 1-6 alkylsulfonyl, C 1-6 alkylcarbonyl, C 1-6 alkylaminosulfonyl, carbamyl, C 1-6 alkylcarbamyl, di(C 1-6 alkyl)carbamyl, aminosulfonyl, C 1-6 alkylaminosulfonyl, and di(C 1-6 alkyl)aminosulfonyl;
each R a1 , R c1 , and R d1 are independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-4 haloalkyl, and Cy 3 ; wherein said C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl are each optionally substituted with 1, 2 or 3 independently selected R 12 groups;
each R b1 is independently selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-4 haloalkyl, and Cy 3 ; wherein said C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl are each optionally substituted with 1, 2 or 3 independently selected R 12 groups; or
alternatively, any R c1 and R d1 attached to the same N atom, together with the N atom to which they are attached, form a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally substituted with 1, 2 or 3 independently selected R 12 groups;
each R a2 , R c2 , and R d2 is independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 1-4 haloalkyl; wherein said C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl are each optionally substituted with 1, 2 or 3 independently selected R 12 groups;
each R b2 is independently selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 1-4 haloalkyl; wherein said C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl are each optionally substituted with 1, 2 or 3 independently selected R 12 groups; or
alternatively, any R c2 and R d2 attached to the same N atom, together with the N atom to which they are attached, form a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally substituted with 1, 2 or 3 independently selected R 12 groups;
each Cy 1 is independently selected from phenyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl, and 4-6 membered heterocycloalkyl, each optionally substituted by 1, 2, 3, or 4 independently selected R g groups;
each Cy 2 is independently selected from phenyl, C 3-7 cycloalkyl, 5-6 membered heteroaryl, and 4-6 membered heterocycloalkyl; wherein said phenyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl, and 4-6 membered heterocycloalkyl are each optionally substituted with 1, 2 or 3 independently selected R 11 groups;
each Cy 3 is independently selected from phenyl, C 3-7 cycloalkyl, 5-6 membered heteroaryl, and 4-6 membered heterocycloalkyl; wherein said phenyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl, and 4-6 membered heterocycloalkyl are each optionally substituted with 1, 2 or 3 independently selected C 1-4 alkylene-R 12 or R 12 groups; and
each R g is independently selected from OH, NO 2 , CN, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, cyano-C 1-3 alkyl, HO—C 1-3 alkyl, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, thio, C 1-6 alkylthio, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, carbamyl, C 1-6 alkylcarbamyl, di(C 1-6 alkyl)carbamyl, carboxy, C 1-6 alkylcarbonyl, C 1-6 alkoxycarbonyl, C 1-6 alkylcarbonylamino, C 1-6 alkylsulfonylamino, aminosulfonyl, C 1-6 alkylaminosulfonyl, di(C 1-6 alkyl)aminosulfonyl, aminosulfonylamino, C 1-6 alkylaminosulfonylamino, di(C 1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C 1-6 alkylaminocarbonylamino, and di(C 1-6 alkyl)aminocarbonylamino.
2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
X is N or CR 1 ;
Y is N or CR 2 ;
Z is N or CR 3 ;
R 1 , R 2 , and R 3 are each independently selected from H, halo, CN, NO 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, Cy 2 , OR a1 , SR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , OC(O)R b1 , OC(O)NR c1 R d1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)OR a1 , NR c1 C(O)NR c1 R d1 , NR c1 S(O)R b1 , NR c1 S(O) 2 R b , NR c1 S(O) 2 NR c1 R d1 , S(O)R b1 , S(O)NR c1 R dl , S(O) 2 R b1 , and S(O) 2 NR c1 R d1 ; wherein said C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl are each optionally substituted with 1, 2 or 3 independently selected R 10 groups; or
alternatively, R 1 and R 2 , taken together with the carbon atoms to which they are attached, form a phenyl or a 5-6-membered heteroaryl ring, which is optionally substituted by 1, 2, or 3 independently selected R 11 groups; or
alternatively, R 2 and R 3 , taken together with the carbon atoms to which they are attached, form a phenyl or a 5-6-membered heteroaryl ring, which is optionally substituted by 1, 2, or 3 independently selected R 11 groups;
A is O or S;
R 4 , R 5 , and R 6 are each independently selected from H, OH, NO 2 , CN, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, thio, C 1-6 alkylthio, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, carbamyl, C 1-6 alkylcarbamyl, di(C 1-6 alkyl)carbamyl, carboxy, C 1-6 alkylcarbonyl, C 1-6 alkoxycarbonyl, C 1-6 alkylcarbonylamino, C 1-6 alkylsulfonylamino, aminosulfonyl, C 1-6 alkylaminosulfonyl, di(C 1-6 alkyl)aminosulfonyl, aminosulfonylamino, C 1-6 alkylaminosulfonylamino, di(C 1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C 1-6 alkylaminocarbonylamino, and di(C 1-6 alkyl)aminocarbonylamino;
W is Cy;
Cy is phenyl, naphthyl, 5-10 membered heteroaryl, or 4-10 membered heterocycloalkyl, each of which is optionally substituted by 1, 2, 3, or 4 substituents independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, Cy 1 , —(C 1-4 alkylene)-Cy 1 , CN, NO 2 , OR a , SR a , C(O)R b , C(O)NR c R d , C(O)OR a , OC(O)R b , OC(O)NR c R d , NR c R d , NR c C(O)R b , NR c C(O)OR a , NR c C(O)NR c R d , C(═NR e )R b , C(═NR e )NR c R d , NR c C(═NR e )NR c R d , NR c S(O)R b , NR c S(O) 2 R b , NR c S(O) 2 NR c R d , S(O)R b , S(O)NR c R d , S(O) 2 R b , and S(O) 2 NR c R d ;
each R 10 is independently selected from halo, CN, NO 2 , Cy 2 , OR a1 , SR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , OC(O)R b1 , OC(O)NR c1 R d1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)OR a1 , NR c1 C(O)NR c1 R d1 , NR c1 S(O)R b1 , NR c1 S(O) 2 R b1 , NR c1 S(O) 2 NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O) 2 R b1 , and S(O) 2 NR c1 R d1 ;
each R 11 is independently selected from halo, CN, NO 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, OR a2 , SR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , OC(O)R b2 , OC(O)NR c2 R d2 , NR c2 R d2 , NR c2 C(O)R b2 , NR c2 C(O)OR a2 , NR c2 C(O)NR c2 R d2 , NR c2 S(O)R b2 , NR c2 S(O) 2 R b2 , NR c2 S(O) 2 NR c2 R d2 , S(O)R b2 , S(O)NR c2 R d2 , S(O) 2 R b2 , and S(O) 2 NR c2 R d2 ; wherein said C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl are each optionally substituted with 1, 2 or 3 independently selected R 12 groups;
each R 12 is independently selected from OH, NO 2 , CN, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, thio, C 1-6 alkylthio, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, carbamyl, C 1-6 alkylcarbamyl, di(C 1-6 alkyl)carbamyl, carboxy, C 1-6 alkylcarbonyl, C 1-6 alkoxycarbonyl, C 1-6 alkylcarbonylamino, C 1-6 alkylsulfonylamino, aminosulfonyl, C 1-6 alkylaminosulfonyl, di(C 1-6 alkyl)aminosulfonyl, aminosulfonylamino, C 1-6 alkylaminosulfonylamino, di(C 1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C 1-6 alkylaminocarbonylamino, and di(C 1-6 alkyl)aminocarbonylamino;
each R a , R c , and R d is independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-4 haloalkyl, Cy 1 , and —(C 1-4 alkylene)-Cy 1 ; wherein said C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl are each optionally substituted with 1, 2, 3, or 4 independently selected R g groups;
each R b is independently selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-4 haloalkyl, Cy 1 , and —(C 1-4 alkylene)-Cy 1 ; wherein said C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl are each optionally substituted with 1, 2, 3, or 4 independently selected R g groups; or
alternatively, any R c and R d attached to the same N atom, together with the N atom to which they are attached, form a 4-6 membered heterocycloalkyl group or a 5-6 membered heteroaryl group, each optionally substituted with 1, 2, or 3 independently selected R g groups;
each R e is independently selected from H, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkylthio, C 1-6 alkylsulfonyl, C 1-6 alkylcarbonyl, C 1-6 alkylaminosulfonyl, carbamyl, C 1-6 alkylcarbamyl, di(C 1-6 alkyl)carbamyl, aminosulfonyl, C 1-6 alkylaminosulfonyl, and di(C 1-6 alkyl)aminosulfonyl;
each R a1 , R c1 , and R d1 are independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-4 haloalkyl, and Cy 3 ; wherein said C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl are each optionally substituted with 1, 2 or 3 independently selected R 12 groups;
each R b1 is independently selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-4 haloalkyl, and Cy 3 ; wherein said C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl are each optionally substituted with 1, 2 or 3 independently selected R 12 groups; or
alternatively, any R c1 and R d1 attached to the same N atom, together with the N atom to which they are attached, form a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally substituted with 1, 2 or 3 independently selected R 12 groups;
each R a2 , R c2 , and R d2 is independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 1-4 haloalkyl; wherein said C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl are each optionally substituted with 1, 2 or 3 independently selected R 12 groups;
each R b2 is independently selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 1-4 haloalkyl; wherein said C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl are each optionally substituted with 1, 2 or 3 independently selected R 12 groups; or
alternatively, any R c2 and R d2 attached to the same N atom, together with the N atom to which they are attached, form a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally substituted with 1, 2 or 3 independently selected R 12 groups;
each Cy 1 is independently selected from phenyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl, and 4-6 membered heterocycloalkyl, each optionally substituted by 1, 2, 3, or 4 independently selected R g groups;
each Cy 2 is independently selected from phenyl, C 3-7 cycloalkyl, 5-6 membered heteroaryl, and 4-6 membered heterocycloalkyl; wherein said phenyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl, and 4-6 membered heterocycloalkyl are each optionally substituted with 1, 2 or 3 independently selected R 11 groups;
each Cy 3 is independently selected from phenyl, C 3-7 cycloalkyl, 5-6 membered heteroaryl, and 4-6 membered heterocycloalkyl; wherein said phenyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl, and 4-6 membered heterocycloalkyl are each optionally substituted with 1, 2 or 3 independently selected C 1-4 alkylene-R 12 or R 12 groups; and
each R g is independently selected from OH, NO 2 , CN, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, cyano-C 1-3 alkyl, HO—C 1-3 alkyl, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, thio, C 1-6 alkylthio, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, carbamyl, C 1-6 alkylcarbamyl, di(C 1-6 alkyl)carbamyl, carboxy, C 1-6 alkylcarbonyl, C 1-6 alkoxycarbonyl, C 1-6 alkylcarbonylamino, C 1-6 alkylsulfonylamino, aminosulfonyl, C 1-6 alkylaminosulfonyl, di(C 1-6 alkyl)aminosulfonyl, aminosulfonylamino, C 1-6 alkylaminosulfonylamino, di(C 1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C 1-6 alkylaminocarbonylamino, and di(C 1-6 alkyl)aminocarbonylamino.
3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is H, methyl, ethyl, cyclopropyl, phenyl, or a tetrahydrofuran ring.
4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is H, methyl, propyl, or phenyl.
5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 , together with the carbon atoms to which they are attached, form a phenyl ring or cyclohexene group, which is optionally substituted by 1, 2, or 3 independently selected R 11 groups.
6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 , together with the carbon atoms to which they are attached, form a phenyl ring, which is optionally substituted by 1, 2, or 3 R 11 groups independently selected from halo, C 1-6 alkyl, and C 1-6 haloalkyl.
7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is H.
8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 , R 5 , and R 6 are each H.
9. The compound of claim 1 , wherein Cy is a pyridine ring, which is optionally substituted by 1, 2, 3, or 4 substituents independently selected from halo, C 1-6 alkyl, C 1-6 haloalkyl, CN, OR a , NR c R d , NR c C(O)R b , NR c S(O) 2 R b , NR c S(O) 2 NR c R d , S(O) 2 R b , and S(O) 2 NR c R d .
10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein
is
11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein
is
12. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein
is
13. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein
is
14. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, where A is O.
15. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, where A is S.
16. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
is:
or
A is O or S;
R 1 and R 2 are each independently selected from H, OR a1 , NO 2 , CN, halo, C 1-6 alkyl, C 1-6 haloalkyl, and Cy 2 ;
R 3 is H, methyl, or ethyl;
or R 1 and R 2 , together with the carbon atoms to which they are attached, form a phenyl ring, which is optionally substituted by 1, 2, or 3 independently selected R 11 groups;
R 4 , R 5 , and R 6 are each H;
W is Cy;
Cy is 6-membered heteroaryl, which is optionally substituted by 1, 2, or 3 substituents independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, Cy 1 , —(C 1-4 alkylene)-Cy 1 , CN, NO 2 , OR a , SR a , C(O)R b , C(O)NR c R d , C(O)OR a , OC(O)R b , OC(O)NR c R d , NR c R d , NR c C(O)R b , NR c C(O)OR a , NR c C(O)NR c R d , C(═NR e )R b , C(═NR e )NR c R d , NR c C(═NR e )NR c R d , NR c S(O)R b , NR c S(O) 2 R b , NR c S(O) 2 NR c R d , S(O)R b , S(O)NR c R d , S(O) 2 R b , and S(O) 2 NR c R d ;
each Cy 2 is independently selected from phenyl, C 3-7 cycloalkyl, 5-6 membered heteroaryl, and 4-6 membered heterocycloalkyl;
each R 11 is independently selected from halo, C 1-6 alkyl, and C 1-6 haloalkyl;
each R a1 is independently selected from H, C 1-6 alkyl, and C 14 haloalkyl;
each R a , R c , and R d is independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-4 haloalkyl, Cy 1 , and —(C 1-4 alkylene)-Cy 1 ; wherein said C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl are each optionally substituted with 1, 2, 3, or 4 independently selected R g groups;
each R b is independently selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-4 haloalkyl, Cy 1 , and —(C 1-4 alkylene)-Cy 1 ; wherein said C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl are each optionally substituted with 1, 2, 3, or 4 independently selected R g groups;
or any R c and R d together with the N atom to which they are attached form a 4-6 membered heterocycloalkyl group or a 5-6 membered heteroaryl group, each optionally substituted with 1, 2, or 3 independently selected R g groups;
each R e is independently selected from H and C 1-6 alkyl;
each Cy 1 is independently selected from phenyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl, and 4-6 membered heterocycloalkyl, each optionally substituted by 1, 2, 3, or 4 independently selected R g groups; and
each R g is independently selected from OH, NO 2 , CN, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, cyano-C 1-3 alkyl, HO—C 1-3 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, thio, C 1-6 alkylthio, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, carbamyl, C 1-6 alkylcarbamyl, di(C 1-6 alkyl)carbamyl, carboxy, C 1-6 alkylcarbonyl, C 1-6 alkoxycarbonyl, C 1-6 alkylcarbonylamino, C 1-6 alkylsulfonylamino, aminosulfonyl, C 1-6 alkylaminosulfonyl, di(C 1-6 alkyl)aminosulfonyl, aminosulfonylamino, C 1-6 alkylaminosulfonylamino, di(C 1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C 1-6 alkylaminocarbonylamino, and di(C 1-6 alkyl)aminocarbonylamino.
17. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
is:
or
A is O or S;
R 1 is H, methyl, ethyl, cyclopropyl, phenyl, or a tetrahydrofuran ring;
R 2 is H, methyl, propyl, or phenyl; or
R 1 and R 2 , together with the carbon atoms to which they are attached, form a phenyl ring or cyclohexene ring, which is optionally substituted by 1 or 2 independently selected R 11 groups;
R 3 is H;
R 4 , R 5 , and R 6 are each H;
W is Cy;
Cy is a phenyl ring, a piperazine ring, a pyridine ring, a pyrimidine ring, an imidazole ring, an indazole ring, or a 1H-pyrazolo[4,3-b]pyridine ring, each of which is optionally substituted by 1 or 2 substituents independently selected from halo, C 1-6 alkyl, C 1-6 haloalkyl, Cy 1 , —(C 1-2 alkylene)-Cy 1 , CN, OR a , P(O)R a R b , NR c R d , NR c C(O)R b , NR c C(O)NR c R d , NR c S(O) 2 R b , NR c S(O) 2 NR c R d , S(O) 2 R b , and S(O) 2 NR c R d ;
each R 11 is independently selected from halo, C 1-6 alkyl, and C 1-6 haloalkyl;
each R a is independently selected from H and C 1-6 alkyl; wherein said C 1-6 alkyl is optionally substituted with 1, 2, 3, or 4 independently selected R g groups;
each R c and R d is independently selected from H, C 1-6 alkyl, and Cy 1 ; wherein said C 1-6 alkyl is optionally substituted with 1, 2, 3, or 4 independently selected R g groups;
each R b is independently selected from C 1-6 alkyl and Cy 1 ; wherein said C 1-6 alkyl is optionally substituted with 1, 2, 3, or 4 independently selected R g groups;
each Cy 1 is independently selected from phenyl and 6-membered heterocycloalkyl, each optionally substituted by 1 or 2 independently selected R g groups; and
each R g is, independently, OH, C 1-6 alkyl, C 1-4 haloalkyl, halo, or carboxy.
18. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, having Formula II:
or a pharmaceutically acceptable salt thereof.
19. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, having Formula III:
or a pharmaceutically acceptable salt thereof.
20. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, having Formula V:
or a pharmaceutically acceptable salt thereof.
21. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, having Formula VI:
or a pharmaceutically acceptable salt thereof.
22. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, having Formula VII:
or a pharmaceutically acceptable salt thereof.
23. The compound of claim 1 , or a pharmaceutically salt thereof, having Formula IIa, IIb, IIIa, or VIIa:
or a pharmaceutically acceptable salt thereof.
24. The compound of claim 1 , selected from:
2-(1H-imidazol-2-yl)-6-(5-methoxypyridin-3-yl)benzo[d]oxazole;
2-(1H-imidazol-5-yl)-6-(5-methoxypyridin-3-yl)benzo[d]oxazole;
6-(5-methoxypyridin-3-yl)-2-(1H-pyrrol-2-yl)benzo[d]oxazole;
2-(1H-benzo[d]imidazol-2-yl)-6-(5-methoxypyridin-3-yl)benzo[d]oxazole;
2-(1H-indol-2-yl)-6-(5-methoxypyridin-3-yl)benzo[d]oxazole;
2-(1H-benzo[d]imidazol-2-yl)-6-(5-methoxypyridin-3-yl)benzo[d]thiazole;
2-(6-bromo-1H-benzo[d]imidazol-2-yl)-6-(5-methoxypyridin-3-yl)benzo[d]oxazole;
2-(5-fluoro-1H-benzo[d]imidazol-2-yl)-6-(5-methoxypyridin-3-yl)benzo[d]oxazole;
6-(5-methoxypyridin-3-yl)-2-(5-methyl-1H-benzo[d]imidazol-2-yl)benzo[d]oxazole;
6-(5-methoxypyridin-3-yl)-2-(4-methyl-1H-benzo[d]imidazol-2-yl)benzo[d]oxazole;
5-(2-(1H-benzo[d]imidazol-2-yl)benzo[d]oxazol-6-yl)pyridin-3-ol;
2-(1H-benzo[d]imidazol-2-yl)-6-(5-isopropoxypyridin-3-yl)benzo[d]oxazole;
2-(1H-benzo[d]imidazol-2-yl)-6-(5-(difluoromethoxy)pyridin-3-yl)benzo[d]oxazole;
N-(5-(2-(1H-benzo[d]imidazol-2-yl)benzo[d]oxazol-6-yl)pyridin-3-yl)-4-fluorobenzenesulfonamide;
N-(5-(2-(1H-benzo[d]imidazol-2-yl)benzo[d]oxazol-6-yl)pyridin-3-yl)ethanesulfonamide;
N-(5-(2-(1H-benzo[d]imidazol-2-yl)benzo[d]oxazol-6-yl)pyridin-3-yl)-3-fluorobenzenesulfonamide;
N-(5-(2-(1H-benzo[d]imidazol-2-yl)benzo[d]oxazol-6-yl)pyridin-3-yl)piperidine-1-sulfonamide;
N′-{5-[2-(1H-benzimidazol-2-yl)-1,3-benzoxazol-6-yl]-pyridin-3-yl}-N,N-dimethylsulfamide;
N′-{5-[2-(1H-benzimidazol-2-yl)-1,3-benzoxazol-6-yl]-2-methylpyridin-3-yl}-N,N-dimethylsulfamide;
N′-{5-[2-(1H-benzimidazol-2-yl)-1,3-benzoxazol-6-yl]-2-fluoropyridin-3-yl}-N,N-dimethylsulfamide;
N-(5-(2-(1H-benzo[d]imidazol-2-yl)benzo[d]oxazol-6-yl)pyridin-3-yl)propane-2-sulfonamide;
N-(5-(2-(1H-benzo[d]imidazol-2-yl)benzo[d]oxazol-6-yl)-2-methylpyridin-3-yl)ethanesulfonamide;
N-(5-(2-(1H-benzo[d]imidazol-2-yl)benzo[d]oxazol-6-yl)-2-chloropyridin-3-yl)ethanesulfonamide;
N-(5-(2-(1H-benzo[d]imidazol-2-yl)benzo[d]oxazol-6-yl)-2-fluoropyridin-3-yl)ethanesulfonamide;
N-(5-(2-(1H-benzo[d]imidazol-2-yl)benzo[d]oxazol-6-yl)-2-methylpyridin-3-yl)-4-fluorobenzenesulfonamide;
N-(5-(2-(1H-benzo[d]imidazol-2-yl)benzo[d]oxazol-6-yl)-2-chloropyridin-3-yl)-4-fluorobenzenesulfonamide;
N-(5-(2-(1H-benzo[d]imidazol-2-yl)benzo[d]oxazol-6-yl)-2-fluoropyridin-3-yl)-4-fluorobenzenesulfonamide;
N-(5-(2-(1H-benzo[d]imidazol-2-yl)benzo[d]oxazol-6-yl)pyridin-3-yl)-4-methylpiperazine-1-sulfonamide;
N-(5-(2-(1H-benzo[d]imidazol-2-yl)benzo[d]oxazol-6-yl)-2-fluoropyridin-3-yl)-4-methylpiperazine-1-sulfonamide;
N-(5-(2-(1H-benzo[d]imidazol-2-yl)benzo[d]oxazol-6-yl)pyridin-3-yl)acetamide;
5-(2-(1H-benzo[d]imidazol-2-yl)benzo[d]oxazol-6-yl)-N,N-dimethylpyridin-3-amine;
5-(2-(1H-benzo[d]imidazol-2-yl)benzo[d]oxazol-6-yl)nicotinonitrile;
2-(1H-benzo[d]imidazol-2-yl)-6-(5-(methylsulfonyl)pyridin-3-yl)benzo[d]oxazole;
5-[2-(1H-benzimidazol-2-yl)-1,3-benzoxazol-6-yl]-N,N-dimethylpyridine-3-sulfonamide;
2-(1H-benzo[d]imidazol-2-yl)-6-(5-(morpholinosulfonyl)pyridin-3-yl)benzo[d]oxazole;
N-(5-(2-(1H-imidazol-2-yl)benzo[d]oxazol-6-yl)pyridin-3-yl)-4-fluorobenzenesulfonamide;
N-(5-(2-(1H-imidazol-2-yl)benzo[d]oxazol-6-yl)pyridin-3-yl)ethanesulfonamide;
N′-{5-[2-(1H-imidazol-2-yl)-1,3-benzoxazol-6-yl]pyridin-3-yl}-N,N-dimethylsulfamide;
2-(2-cyclopropyl-1H-imidazol-5-yl)-6-(5-methoxypyridin-3-yl)benzo[d]oxazole;
6-(5-methoxypyridin-3-yl)-2-(2-(tetrahydrofuran-3-yl)-1H-imidazol-5-yl)benzo[d]oxazole;
6-(5-methoxypyridin-3-yl)-2-(2-phenyl-1H-imidazol-5-yl)benzo[d]oxazole;
2-(2-ethyl-1H-imidazol-5-yl)-6-(5-methoxypyridin-3-yl)benzo[d]oxazole;
6-(5-methoxypyridin-3-yl)-2-(3-methyl-1H-pyrazol-5-yl)benzo[d]oxazole;
6-(5-methoxypyridin-3-yl)-2-(3-phenyl-1H-pyrazol-5-yl)benzo[d]oxazole;
or a pharmaceutically acceptable salt of any of the aforementioned.
25. The compound of claim 1 , selected from:
2-(1H-Benzimidazol-2-yl)-6-(1-benzyl-1H-pyrazol-4-yl)-1,3-benzoxazole;
2-(1H-Benzimidazol-2-yl)-6-(1H-indazol-5-yl)-1,3-benzoxazole;
2-(1H-Benzimidazol-2-yl)-6-(3-methyl-1H-indazol-5-yl)-1,3-benzoxazole;
2-(1H-Benzimidazol-2-yl)-6-(3,4-difluorophenyl)-1,3-benzoxazole;
6-[1-(Ethylsulfonyl)-1H-indazol-6-yl]-2-(1H-benzimidazol-2-yl)-1,3-benzoxazole;
2-(1H-Benzimidazol-2-yl)-6-(2-ethyl-2H-indazol-6-yl)-1, 3-benzoxazole;
2-(1H-Benzimidazol-2-yl)-6-(1-ethyl-1H-indazol-6-yl)-1, 3-benzoxazole;
2-(1H-Benzimidazol-2-yl)-6-(4-benzylpiperazin-1-yl)-1,3-benzoxazole;
5-[2-(1H-Benzimidazol-2-yl)-1,3-benzoxazol-6-yl]-3-(trifluoromethyl)pyridin-2-amine;
6-[2-(1H-Benzimidazol-2-yl)-1,3-benzoxazol-6-yl]-1-ethyl-1H-pyrazolo[4,3-b]pyridine;
1-({5-[2-(1H-Benzimidazol-2-yl)-1,3-benzoxazol-6-yl]pyridin-3-yl}sulfonyl)pyrrolidin-3-ol;
5-[2-(1H-Benzimidazol-2-yl)-1,3-benzoxazol-6-yl]-N-ethylpyridine-3-sulfonamide;
N-{5-[2-(1H-Benzimidazol-2-yl)-1,3-benzoxazol-6-yl]-2-fluorophenyl}ethanesulfonamide;
1-(5-(2-(1H-Imidazol-2-yl)benzo[d]oxazol-6-yl)pyridin-3-yl)-2, 2,2-trifluoroethanol;
2-(4, 5-Dimethyl-1H-imidazol-2-yl)-6-(5-(methylsulfonyl)pyridin-3-yl)benzo[d]oxazole;
N-(5-(2-(4,5-Dimethyl-1H-imidazol-2-yl)benzo[d]oxazol-6-yl)pyridin-3-yl)ethanesulfonamide;
N-(5-(2-(5-Methyl-4-propyl-1H-imidazol-2-yl)benzo[d]oxazol-6-yl)pyridin-3-yl)ethanesulfonamide;
N-(5-(2-(4,5-Dimethyl-1H-imidazol-2-yl)benzo[d]oxazol-6-yl)-2-methoxypyridin-3-yl)ethanesulfonamide;
N-(2-Methoxy-5-(2-(4, 5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)benzo[d]oxazol-6-yl)pyridin-3-yl)ethanesulfonamide;
1-(5-(2-(4, 5-Dimethyl-1H-imidazol-2-yl)benzo[d]oxazol-6-yl)pyridin-3-yl)-2, 2,2-trifluoroethanol;
2,2,2-Trifluoro-1-(5-(2-(4, 5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)benzo[d]oxazol-6-yl)pyridin-3-yl)ethanol;
2-(1H-Benzo[d]imidazol-2-yl)-6-(6-fluoro-5-methoxypyridin-3-yl)benzo[d]oxazole;
2-(1H-Benzo[d]imidazol-2-yl)-6-(2-fluoropyrimidin-5-yl)benzo[d]oxazole;
2-(5-(2-(1H-Benzo[d]imidazol-2-yl)benzo[d]oxazol-6-yl)pyridin-3-yl)acetic acid;
2-(1H-Benzo[d]imidazol-2-yl)-6-(5-(dimethylphosphoryl)pyridin-3-yl)benzo[d]oxazole;
N-(5-(2-(1H-Benzo[d]imidazol-2-yl)benzo[d]oxazol-6-yl)pyridin-3-yl)-N-methylethanesulfonamide;
1-(5-(2-(1H-Benzo[d]imidazol-2-yl)benzo[d]oxazol-6-yl)pyridin-3-yl)-2,2,2-trifluoroethanol;
N-(5-(2-(1H-Benzo[d]imidazol-2-yl)benzo[d]oxazol-6-yl)-2-fluoropyridin-3-yl)-2,2,2-trifluoroethanesulfonamide;
N-(5-(2-(1H-Benzo[d]imidazol-2-yl)benzo[d]oxazol-6-yl)-2-methylpyridin-3-yl)-2,2,2-trifluoroethanesulfonamide;
N-(5-(2-(1H-Benzo[d]imidazol-2-yl)benzo[d]oxazol-6-yl)pyridin-3-yl)-2,2,2-trifluoroethanesulfonamide;
N-(2-(2-(1H-Benzo[d]imidazol-2-yl)benzo[d]oxazol-6-yl)-5-fluoropyridin-4-yl)ethanesulfonamide;
N-(5-(2-(1H-Benzo[d]imidazol-2-yl)benzo[d]oxazol-6-yl)-2-methoxypyridin-3-yl)ethanesulfonamide; and
N-(5-(2-(1H-Benzo[d]imidazol-2-yl)benzo[d]oxazol-6-yl)-3-fluoro-2-methoxyphenyl)ethanesulfonamide;
or a pharmaceutically acceptable salt of any of the aforementioned.
26. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.