FUSED TETRAZOLES AS LRRK2 INHIBITORS
The present invention is directed to fused tetrazoles of formula (IA) which are inhibitors of LRRK2 and are useful in the treatment of CNS disorders.
1 . A compound of Formula IA:
or a pharmaceutically acceptable salt thereof, wherein:
W is O or S;
Q is selected from one of the following:
A 1 , A 2 , and A 3 are each independently selected from N and CR 6 , wherein no more than two of A 1 , A 2 , and A 3 in (a) are simultaneously N;
ring B is selected from:
R 1 , R 1A , and R 1B are each independently selected from H, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl, C 3-7 cycloalkyl-C 1-4 alkyl, 5-10 membered heteroaryl-C 1-4 alkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl, 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 ; wherein said Cue alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl, C 3-7 cycloalkyl-C 1-4 alkyl, 5-10 membered heteroaryl-C 1-4 alkyl, and 4-10 membered heterocycloalkyl-C 1-4 alkyl of R 1 are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Cy 1 , Cy 1 -C 1-4 alkyl, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, 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 ;
or R 1A and R 1B together form a C 3-7 cycloalkyl or 4-10 membered heterocycloalkyl ring, each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Cy 1 , Cy 1 -C 1-4 alkyl, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, 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 ;
R 1C and R 1D are each independently selected from H and C 1-3 alkyl;
R 2 is H or C 1-4 alkyl;
R 3A and R 3B are each independently selected from H, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl, C 3-7 cycloalkyl-C 1-4 alkyl, 5-10 membered heteroaryl-C 1-4 alkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl, CN, NO 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 , C(═NR e1 )R b1 , C(═NR e1 )NR c1 R d1 , NR c1 C(═NR e1 )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, C 2-6 alkynyl, C 1-6 haloalkyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl, C 3-7 cycloalkyl-C 1-4 alkyl, 5-10 membered heteroaryl-C 1-4 alkyl, and 4-10 membered heterocycloalkyl-C 1-4 alkyl of R 1 are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Cy 2 , Cy 2 -C 1-4 alkyl, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, CN, NO 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 , C(═NR e1 )R b1 , C(═NR e1 )NR c1 R d1 , NR c1 C(═NR e1 )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 ;
or R 3A and R 3B together form a C 3-7 cycloalkyl or 4-10 membered heterocycloalkyl ring, each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Cy 2 , Cy 2 -C 1-4 alkyl, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, CN, NO 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 , C(═NR e1 )R b1 , C(═NR e1 )NR c1 R d1 , NR c1 C(═NR e1 )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 ;
R 4 is H, C 1-4 alkyl, halo, C 1-4 haloalkyl, or CN;
R 5 is H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl, C 3-7 cycloalkyl-C 1-4 alkyl, 5-10 membered heteroaryl-C 1-4 alkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl, CN, NO 2 , 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 , C(═NR e2 )R b2 , C(═NR e2 )NR c2 R d2 , NR c2 C(═NR e2 )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, C 2-6 alkynyl, C 1-6 haloalkyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl, C 3-7 cycloalkyl-C 1-4 alkyl, 5-10 membered heteroaryl-C 1-4 alkyl, and 4-10 membered heterocycloalkyl-C 1-4 alkyl of R 1 are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Cy 3 , Cy 3 -C 1-4 alkyl, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, CN, NO 2 , OR a2 , SR 32 , 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 , C(═NR e2 )R b2 , C(═NR e2 )NR c2 R d2 , NR c2 C(═NR e2 )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 , or S(O) 2 NR c2 R d2 ;
each R 6 is independently selected from H, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, CN, NO 2 , OR a3 , SR a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , OC(O)R b3 , OC(O)NR c3 R d3 , NR c3 R d3 , NR c3 C(O)R b3 , NR c3 C(O)NR c3 R d3 , NR c3 C(O)OR a3 , C(═NR e3 )NR c3 R d3 , NR c3 C(═NR e3 )NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O) 2 R b3 , NR c3 S(O) 2 R b3 , NR c3 S(O) 2 NR c3 R d3 , and S(O) 2 NR c3 R d3 , wherein said C 1-6 alkyl, C 1-6 haloalkyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl of R 6 are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, CN, NO 2 , OR a3 , SR a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , OC(O)R b3 , OC(O)NR c3 R d3 , NR c3 R d3 , NR c3 C(O)R b3 , NR c3 C(O)NR c3 R d3 , NR c3 C(O)OR a3 , C(═NR e3 )NR c3 R d3 , NR c3 C(═NR e3 )NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O) 2 R b3 , NR c3 S(O) 2 R b3 , NR c3 S(O) 2 NR c3 R d3 , and S(O) 2 NR c3 R d3 ;
each Cy 1 is independently selected from C 6-10 aryl, C 3-10 cycloalkyl, 5-14 membered heteroaryl, and 4-14 membered heterocycloalkyl, each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl, C 3-7 cycloalkyl-C 1-4 alkyl, 5-10 membered heteroaryl-C 1-4 alkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl, 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 C 6-10 aryl, C 3-10 cycloalkyl, 5-14 membered heteroaryl, and 4-14 membered heterocycloalkyl, each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl, C 3-7 cycloalkyl-C 1-4 alkyl, 5-10 membered heteroaryl-C 1-4 alkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl, CN, NO 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 , C(═NR e1 )R b1 , C(═NR e1 )NR c1 R d1 , NR c1 C(═NR e1 )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 Cy 3 is independently selected from C 6-10 aryl, C 3-10 cycloalkyl, 5-14 membered heteroaryl, and 4-14 membered heterocycloalkyl, each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl, C 3-7 cycloalkyl-C 1-4 alkyl, 5-10 membered heteroaryl-C 1-4 alkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl, CN, NO 2 , OR a2 , SR 32 , 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 , C(═NR e2 )R b2 , C(═NR e2 )NR c2 R d2 , NR c2 C(═NR e2 )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 ;
each R a , R b , R c , R d , R a1 , R b1 , R c1 , R d1 , R a2 , R b2 , R c2 , R d2 , R a3 , R b3 , R c3 , and R d3 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl, C 3-7 cycloalkyl-C 1-4 alkyl, 5-10 membered heteroaryl-C 1-4 alkyl, and 4-10 membered heterocycloalkyl-C 1-4 alkyl, wherein said CM alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl, C 3-7 cycloalkyl-C 1-4 alkyl, 5-10 membered heteroaryl-C 1-4 alkyl, and 4-10 membered heterocycloalkyl-CM alkyl of R a , R b , R c , R d , R a1 , R b1 , R c1 , R d1 , R a2 , R b2 , R c2 , R d2 , R a3 , R b3 , R c3 , or R d3 is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, CM alkyl, C 1-4 haloalkyl, CM haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, CN, OR a4 , SR a4 , C(O)R b4 , C(O)NR c4 R d4 , C(O)OR a4 , OC(O)R b4 , OC(O)NR c4 R d4 , NR c4 R d4 , NR c4 C(O)R b4 , NR c4 C(O)NR c4 R d4 , NR c4 C(O)OR a4 , C(═NR e4 )NR c4 R d4 , NR c4 C(═NR e4 )NR c4 R d4 , S(O)R b4 , S(O)NR c4 R d4 , S(O) 2 R b4 , NR c4 S(O) 2 R b4 , NR c4 S(O) 2 NR c4 R d4 , and S(O) 2 NR c4 R d4 ;
each R a4 , R b4 , R c4 , and R d4 are independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, wherein said CM alkyl, CM haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl are each optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, and C 1-6 haloalkoxy; and
each R e , R e1 , R e2 , R e3 , and R e4 is independently selected from H, CM alkyl, and CN;
with the proviso that the compound is other than:
2 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Q is
3 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Q is
4 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Q is (a) and A 1 , A 2 , and A 3 are each CR 6 .
5 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Q is (a) and A 1 is N, and A 2 and A 3 are each CR 6 .
6 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Q is (a) and A 1 and A 3 are each CR 6 , and A 2 is N.
7 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Q is (b) and A 1 and A 2 are each CR 6 .
8 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein W is O.
9 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein W is S.
10 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein ring B is selected from:
11 . The compound of claim 3 , or a pharmaceutically acceptable salt thereof, wherein ring B is selected from:
12 . The compound of claim 3 , or a pharmaceutically acceptable salt thereof, wherein ring B is
13 . The compound of claim 3 , or a pharmaceutically acceptable salt thereof, wherein ring B is
14 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein ring B is selected from:
15 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1A and R 1B are each independently selected from H and C 1-6 alkyl.
16 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1A and R 1B are each methyl.
17 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1A and R 1B are each H.
18 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1C and R 1D are each H.
19 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1C is C 1-3 alkyl.
20 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1C is methyl.
21 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1C is H.
22 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1D is C 1-3 alkyl.
23 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1D is methyl.
24 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1D is H.
25 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from H, halo, C 1-6 alkyl, C 6-10 aryl, 5-14 membered heteroaryl, C(O)R b , C(O)NR c R d , NR c R d , and NR c C(O)R b ; wherein said C 1-6 alkyl, C 6-10 aryl, and 5-14 membered heteroaryl are each optionally substituted with 1, 2, 3, 4, or substituents independently selected from Cy 1 , Cy 1 -C 1-4 alkyl, halo, C 1-6 alkyl and S(O) 2 NR c R d .
26 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from H, halo, C 1-6 alkyl, C 6-10 aryl, 4-14 membered heterocycloalkyl, 5-14 membered heteroaryl, C(O)R b , C(O)OR a , C(O)NR c R d , NR c R d , and NR c C(O)R b ; wherein said C 1-6 alkyl, C 6-10 aryl, 4-14 membered heterocycloalkyl, and 5-14 membered heteroaryl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Cy 1 , Cy 1 -C 1-4 alkyl, halo, C 1-6 alkyl and S(O) 2 NR c R d .
27 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is H.
28 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is halo.
29 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is Br.
30 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is C 1-6 alkyl.
31 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is methyl.
32 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is methyl or isopropyl.
33 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is C 6-10 aryl, optionally substituted with Cy 1 or SO 2 NH 2 .
34 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is phenyl.
35 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is 5-10 membered heteroaryl, optionally substituted with Cy 1 .
36 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is pyridinyl or pyrimidinyl.
37 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is pyridinyl, pyrimidinyl, or 1H-benzo[d]imidazolyl, each optionally substituted with Cy 1 .
38 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is 4-14 membered heterocycloalkyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Cy 1 , Cy 1 -C 1-4 alkyl, halo, C 1-6 alkyl and S(O) 2 NR c R d .
39 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is pyrrolidinyl.
40 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is NH 2 .
41 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is CONH 2 .
42 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is C(O)OR a .
43 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is NR c C(O)R b .
44 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is C(O)NR c R d .
45 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is H.
46 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is C 1-4 alkyl.
47 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is methyl.
48 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3A and R 3B are each independently selected from H, C 1-6 alkyl, C 6-10 aryl, and 5-14 membered heteroaryl, wherein said C 1-6 alkyl and 5-14 membered heteroaryl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Cy 2 , Cy 2 -C 1-4 alkyl, halo, C 1-6 alkyl, and OR a1 .
49 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3A and R 3B are each independently selected from H, methyl, ethyl, isopropyl, phenyl, and OH.
50 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3A is C 1-6 alkyl optionally substituted with OR a1 .
51 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3A and R 3B are each H.
52 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3A and R 3B are each methyl.
53 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3A is methyl and R 3B is H.
54 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3A and R 3B together form a C 3-7 cycloalkyl.
55 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3A and R 3B together form a cyclopentyl group.
56 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is H.
57 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is C 1-4 alkyl.
58 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is methyl.
59 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is ethyl.
60 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5 is H, C 1-6 alkyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl, CN, NO 2 , or C(O)NR c2 R d2 .
61 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5 is H, C 1-6 alkyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl, CN, NO 2 , C(O)NR c2 R d2 , or C(O)R b2 , wherein said C 1-6 alkyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, and 4-10 membered heterocycloalkyl-C 1-4 alkyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Cy 3 , Cy 3 -C 1-4 alkyl, halo, C 1-6 alkyl, C 1-6 haloalkyl, CN, NO 2 , 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 , and NR c2 R d2 .
62 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5 is H.
63 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5 is C 1-6 alkyl.
64 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5 is methyl.
65 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5 is ethyl.
66 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5 is C 6-10 aryl.
67 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5 is phenyl.
68 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5 is 4-10 membered heterocycloalkyl-C 1-4 alkyl.
69 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5 is morpholino-C 1-4 alkyl.
70 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5 is C(O)NR c2 R d2 .
71 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 6 is H, halo, OR a3 , C(O)NR c3 R d3 , C(O)OR a3 , or NR c3 R d3 .
72 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R 6 is independently selected from H, halo, OR a3 , C(O)NR c3 R d3 , C(O)OR a3 , and NR c3 R d3 .
73 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R 6 is independently selected from H, halo, OR a3 , C 1-6 alkyl, C 1-6 haloalkyl, C(O)NR c3 R d3 , C(O)OR a3 , and NR c3 R d3 .
74 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R 6 is independently selected from H, F, methyl, methoxy, and CF 3 .
75 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 6 is H.
76 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 6 is halo.
77 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R 6 is independently selected from H and halo.
78 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 6 is F.
79 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R 6 is independently selected from H and F.
80 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 6 is methoxy.
81 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R 6 is independently selected from H and methoxy.
82 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R 6 is independently selected from H, C(O)NR c3 R d3 , and NR c3 R d3 .
83 . The compound of claim 1 , having Formula II:
or a pharmaceutically acceptable salt thereof.
84 . The compound of claim 1 , having Formula III:
or a pharmaceutically acceptable salt thereof, wherein
X is oxo (═O) or CR 1A R 1B ; and
Z is oxo (═O) or CR 1A R 1B ,
wherein if X is CR 1A R 1B then Z is not CR 1A R 1B .
85 . The compound of claim 1 , having Formula IV:
or a pharmaceutically acceptable salt thereof.
86 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
W is O or S;
Q is selected from one of the following:
A 1 , A 2 , and A 3 are each independently selected from N and CR 6 , wherein no more than two of A 1 , A 2 , and A 3 in (a) are simultaneously N;
ring B is selected from:
R 1 , R 1A , and R 1B are each independently selected from H, halo, C 1-6 alkyl, C 6-10 aryl, 5-14 membered heteroaryl, C(O)R b , C(O)NR c R d , NR c R d , and NR c C(O)R b ; wherein said C 1-6 alkyl, C 6-10 aryl, and 5-14 membered heteroaryl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Cy 1 , Cy 1 -C 1-4 alkyl, halo, C 1-6 alkyl and S(O) 2 NR c R d ;
R 1C and R 1D are each independently selected from H and C 1-3 alkyl;
R 2 is H or C 1-4 alkyl;
R 3A and R 3B are each independently selected from H, C 1-6 alkyl, C 6-10 aryl, 5-14 membered heteroaryl, wherein said C 1-6 alkyl and 5-14 membered heteroaryl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Cy 2 , Cy 2 -C 1-4 alkyl, halo, C 1-6 alkyl, and OR a1 ;
or R 3A and R 3B together form a C 3-7 cycloalkyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Cy 2 , Cy 2 -C 1-4 alkyl, halo, C 1-6 alkyl, and OR a1 ;
R 4 is H or C 1-4 alkyl;
R 5 is H, C 1-6 alkyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl, CN, NO 2 , or C(O)NR c2 R d2 ;
R 6 is H, halo, C 1-6 alkyl, C 1-6 haloalkyl, OR a3 , C(O)NR c3 R d3 , C(O)OR a3 , or NR c3 R d3 ;
each Cy 1 is independently selected from 5-14 membered heteroaryl and 4-14 membered heterocycloalkyl;
each Cy 2 is independently selected from C 6-10 aryl, C 3-10 cycloalkyl, 5-14 membered heteroaryl, and 4-14 membered heterocycloalkyl;
each R b , R c , R d , R a1 , R c2 , R d2 , R a3 , R c3 , and R d3 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl, C 3-7 cycloalkyl-CM alkyl, 5-10 membered heteroaryl-C 1-4 alkyl, and 4-10 membered heterocycloalkyl-C 1-4 alkyl, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl, C 3-7 cycloalkyl-C 1-4 alkyl, 5-10 membered heteroaryl-C 1-4 alkyl, and 4-10 membered heterocycloalkyl-C 1-4 alkyl of R b , R c , R d , R a1 , R c2 , R d2 , R a3 , R c3 , or R d3 is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C 1-4 alkyl, C 1-4 haloalkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, CN, OR a4 , SR a4 , C(O)R b4 , C(O)NR c4 R d4 , C(O)OR a4 , OC(O)R b4 , OC(O)NR c4 R d4 , NR c4 R d4 , NR c4 C(O)R b4 , NR c4 C(O)NR c4 R d4 , NR c4 C(O)OR a4 , C(═NR e4 )NR c4 R d4 , NR c4 C(═NR e4 )NR c4 R d4 , S(O)R b4 , S(O)NR c4 R d4 , S(O) 2 R b4 , NR c4 S(O) 2 R b4 , NR c4 S(O) 2 NR c4 R d4 , and S(O) 2 NR c4 R d4 ;
each R a4 , R b4 , R c4 , and R d4 are independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, wherein said C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl are each optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, and C 1-6 haloalkoxy; and
each R e4 is independently selected from H, C 1-4 alkyl, and CN;
with the proviso that the compound is other than:
87 . The compound of claim 1 , having Formula I:
or a pharmaceutically acceptable salt thereof, wherein:
A 1 , A 2 , and A 3 are each independently selected from N and CR 6 , wherein no more than two of A 1 , A 2 , and A 3 are simultaneously N;
W is O or S;
the moiety
is selected from:
R 1 , R 1A , and R 1B are each independently selected from H, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl, C 3-7 cycloalkyl-C 1-4 alkyl, 5-10 membered heteroaryl-C 1-4 alkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl, 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 ; wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl, C 3-7 cycloalkyl-C 1-4 alkyl, 5-10 membered heteroaryl-C 1-4 alkyl, and 4-10 membered heterocycloalkyl-C 1-4 alkyl of R 1 are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Cy 1 , Cy 1 -C 1-4 alkyl, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, 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 ;
or R 1A and R 1B together form a C 3-7 cycloalkyl or 4-10 membered heterocycloalkyl ring, each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Cy 1 , Cy 1 -C 1-4 alkyl, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, 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 ;
R 2 is H or C 1-4 alkyl;
R 3A and R 3B are each independently selected from H, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl, C 3-7 cycloalkyl-C 1-4 alkyl, 5-10 membered heteroaryl-C 1-4 alkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl, CN, NO 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 , C(═NR e1 )R b1 , C(═NR e1 )NR c1 R d1 , NR c1 C(═NR e1 )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, C 2-6 alkynyl, C 1-6 haloalkyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl, C 3-7 cycloalkyl-C 1-4 alkyl, 5-10 membered heteroaryl-C 1-4 alkyl, and 4-10 membered heterocycloalkyl-C 1-4 alkyl of R 1 are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Cy 2 , Cy 2 -C 1-4 alkyl, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, CN, NO 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 , C(═NR e1 )R b1 , C(═NR e1 )NR c1 R d1 , NR c1 C(═NR e1 )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 ;
or R 3A and R 3B together form a C 3-7 cycloalkyl or 4-10 membered heterocycloalkyl ring, each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Cy 2 , Cy 2 -C 1-4 alkyl, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, CN, NO 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 , C(═NR e1 )R b1 , C(═NR e1 )NR c1 R d1 , NR c1 C(═NR e1 )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 ;
R 4 is H, C 1-4 alkyl, halo, C 1-4 haloalkyl, or CN;
R 5 is H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl, C 3-7 cycloalkyl-C 1-4 alkyl, 5-10 membered heteroaryl-C 1-4 alkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl, CN, NO 2 , 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 , C(═NR e2 )R b2 , C(═NR e2 )NR c2 R d2 , NR c2 C(═NR e2 )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, C 2-6 alkynyl, C 1-6 haloalkyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl, C 3-7 cycloalkyl-C 1-4 alkyl, 5-10 membered heteroaryl-C 1-4 alkyl, and 4-10 membered heterocycloalkyl-C 1-4 alkyl of R 1 are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Cy 3 , Cy 3 -C 1-4 alkyl, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, CN, NO 2 , OR a2 , SR 32 , 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 , C(═NR e2 )R b2 , C(═NR e2 )NR c2 R d2 , NR c2 C(═NR e2 )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 , or S(O) 2 NR c2 R d2 ;
each R 6 is independently selected from H, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, CN, NO 2 , OR a3 , SR a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , OC(O)R b3 , OC(O)NR c3 R d3 , NR c3 R d3 , NR c3 C(O)R b3 , NR c3 C(O)NR c3 R d3 , NR c3 C(O)OR a3 , C(═NR e3 )NR c3 R d3 , NR c3 C(═NR e3 )NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O) 2 R b3 , NR c3 S(O) 2 R b3 , NR c3 S(O) 2 NR c3 R d3 , and S(O) 2 NR c3 R d3 , wherein said C 1-6 alkyl, C 1-6 haloalkyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl of R 6 are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, CN, NO 2 , OR a3 , SR a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , OC(O)R b3 , OC(O)NR c3 R d3 , NR c3 R d3 , NR c3 C(O)R b3 , NR c3 C(O)NR c3 R d3 , NR c3 C(O)OR a3 , C(═NR e3 )NR c3 R d3 , NR c3 C(═NR e3 )NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O) 2 R b3 , NR c3 S(O) 2 R b3 , NR c3 S(O) 2 NR c3 R d3 , and S(O) 2 NR c3 R d3 ;
each Cy 1 is independently selected from C 6-10 aryl, C 3-10 cycloalkyl, 5-14 membered heteroaryl, and 4-14 membered heterocycloalkyl, each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl, C 3-7 cycloalkyl-C 1-4 alkyl, 5-10 membered heteroaryl-C 1-4 alkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl, 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 C 6-10 aryl, C 3-10 cycloalkyl, 5-14 membered heteroaryl, and 4-14 membered heterocycloalkyl, each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl, C 3-7 cycloalkyl-C 1-4 alkyl, 5-10 membered heteroaryl-C 1-4 alkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl, CN, NO 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 , C(═NR e1 )R b1 , C(═NR e1 )NR c1 R d1 , NR c1 C(═NR e1 )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 Cy 3 is independently selected from C 6-10 aryl, C 3-10 cycloalkyl, 5-14 membered heteroaryl, and 4-14 membered heterocycloalkyl, each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl, C 3-7 cycloalkyl-C 1-4 alkyl, 5-10 membered heteroaryl-C 1-4 alkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl, CN, NO 2 , OR a2 , SR 32 , 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 , C(═NR e2 )R b2 , C(═NR e2 )NR c2 R d2 , NR c2 C(═NR e2 )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 ;
each R a , R b , R c , R d , R a1 , R b1 , R c1 , R d1 , R a2 , R b2 , R c2 , R d2 , R a3 , R b3 , R c3 , and R d3 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl, C 3-7 cycloalkyl-C 1-4 alkyl, 5-10 membered heteroaryl-C 1-4 alkyl, and 4-10 membered heterocycloalkyl-C 1-4 alkyl, wherein said CM alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl, C 3-7 cycloalkyl-C 1-4 alkyl, 5-10 membered heteroaryl-C 1-4 alkyl, and 4-10 membered heterocycloalkyl-CM alkyl of R a , R b , R c , R d , R a1 , R b1 , R c1 , R d1 , R a2 , R b2 , R c2 , R d2 , R a3 , R b3 , R c3 , or R d3 is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected halo, C 1-4 alkyl, CM haloalkyl, CM haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, CN, OR a4 , SR a4 , C(O)R b4 , C(O)NR c4 R d4 , C(O)OR a4 , OC(O)R b4 , OC(O)NR c4 R d4 , NR c4 R d4 , NR c4 C(O)R b4 , NR c4 C(O)NR c4 R d4 , NR c4 C(O)OR a4 , C(═NR e4 )NR c4 R d4 , NR c4 C(═NR e4 )NR c4 R d4 , S(O)R b4 , S(O)NR c4 R d4 , S(O) 2 R b4 , NR c4 S(O) 2 R b4 , NR c4 S(O) 2 NR c4 R d4 , and S(O) 2 NR c4 R d4 ;
each R a4 , R b4 , R c4 , and R d4 are independently selected from H, CM alkyl, CM haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, wherein said CM alkyl, CM haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl are each optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, and C 1-6 haloalkoxy; and
each R e , R e1 , R e2 , R e3 , and R e4 is independently selected from H, C 1-4 alkyl, and CN;
with the proviso that the compound is other than:
88 . The compound of claim 1 selected from:
N-(1H-indazol-5-yl)-4,5,7-trimethyl-4H,7H-[1,2,3,4]tetrazolo[1,5-a]pyrimidine-6-carboxamide;
N-(1H-indazol-5-yl)-4,5,7-trimethyl-4H,7H-[1,2,3,4]tetrazolo[1,5-a]pyrimidine-6-carboxamide;
N-(1H-indazol-6-yl)-4,5-dimethyl-4H,7H-[1,2,3,4]tetrazolo[1,5-a]pyrimidine-6-carboxamide;
N-(1H-Indazol-5-yl)-5-methyl-4-[2-(morpholin-4-yl)ethyl]-4H,7H-[1,2,3,4]tetrazolo[1,5-a]pyrimidine-6-carboxamide;
5-Ethyl-N-(1H-indazol-5-yl)-4-methyl-4H,7H-[1,2,3,4]tetrazolo[1,5-a]pyrimidine-6-carb oxamide;
4,5-dimethyl-N-(3-(pyridin-4-yl)-1H-indazol-5-yl)-4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-carboxamide;
4,5-Dimethyl-N-(3-(2-morpholinopyridin-4-yl)-1H-indazol-5-yl)-4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-carboxamide;
7-Ethyl-N-(1H-indazol-5-yl)-4,5-dimethyl-4H,7H-[1,2,3,4]tetrazolo[1,5-a]pyrimidine-6-carboxamide;
4,5-Dimethyl-N-(3-(6-morpholinopyrimidin-4-yl)-1H-indazol-5-yl)-4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-carboxamide;
N-(3-Bromo-1H-indazol-5-yl)-4,5-dimethyl-4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-carboxamide;
4,5-Dimethyl-N-(3-(4-sulfamoylphenyl)-1H-indazol-5-yl)-4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-carboxamide;
N 6 -(1H-indazol-5-yl)-N 4 ,N 4 ,5-trimethyltetrazolo[1,5-a]pyrimidine-4,6(7H)-dicarboxamide;
N-(1H-indazol-5-yl)-5-methyl-4-phenyl-4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-carboxamide;
N-(4-fluoro-1H-indazol-5-yl)-4,5-dimethyl-4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-carboxamide;
N-(1H-indazol-5-yl)-4,5-dimethyl-4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-carbothioamide;
4,5,7-trimethyl-N-(2H-pyrazolo[3,4-b]pyridin-5-yl)-4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-carboxamide;
N-(6-methoxy-2H-indazol-5-yl)-4,5-dimethyl-4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-carboxamide;
N-(3-carbamoyl-2H-indazol-5-yl)-4,5-dimethyl-4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-carboxamide;
N-(6-fluoro-2H-indazol-5-yl)-4,5-dimethyl-4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-carboxamide;
N-(6-carbamoyl-2H-indazol-5-yl)-4,5-dimethyl-4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-carboxamide;
N-(6-amino-2H-indazol-5-yl)-4,5-dimethyl-4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-carboxamide;
(7R)—N-(3-bromo-2H-indazol-5-yl)-4,5,7-trimethyl-4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-carboxamide;
4,5,7-trimethyl-N-(1H-pyrazolo[3,4-c]pyridin-5-yl)-4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-carboxamide;
4,5,7-trimethyl-N-(3-(2-morpholinopyridin-4-yl)-1H-indazol-5-yl)-4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-carboxamide;
N-(6-amino-2H-indazol-5-yl)-4,5,7-trimethyl-4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-carboxamide;
N-(2H-indazol-5-yl)-4,5,7,7-tetramethyl-4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-carboxamide;
(R)-4,5,7-trimethyl-N-(3-(pyridin-4-yl)-1H-indazol-5-yl)-4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-carboxamide;
N-(3-acetamido-2H-indazol-5-yl)-4,5-dimethyl-4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-carboxamide;
4,5-dimethyl-N-(2-oxoindolin-5-yl)-4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-carboxamide;
4,5-dimethyl-N-(2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)-4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-carboxamide; and
4,5-dimethyl-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-carboxamide;
or a pharmaceutically acceptable salt thereof.
89 . The compound of claim 1 selected from:
4′,5′-dimethyl-N-(3-methyl-2H-indazol-5-yl)-4′H-spiro[cyclopentane-1,7′-tetrazolo[1,5-a]pyrimidine]-6′-carboxamide;
4,5-dimethyl-N-{3-[3-(morpholin-4-yl)phenyl]-1H-indazol-5-yl}-4H-spiro[[1,2,3,4]tetrazolo[1,5-a]pyrimidine-7,1′-cyclopentane]-6-carboxamide;
(R)—N-(3-(2-((2S,6R)-2,6-dimethylmorpholino)pyridin-4-yl)-1H-indazol-5-yl)-4,5,7-trimethyl-4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-carboxamide;
(R)-4,5,7-trimethyl-N-(3-(pyrrolidin-1-yl)-1H-indazol-5-yl)-4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-carboxamide;
(R)—N-(3-isopropyl-1H-indazol-5-yl)-4,5,7-trimethyl-4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-carboxamide;
trans-(7R)—N-(3-(2-(2,6-dimethyl morpholino)pyridin-4-yl)-1H-indazol-5-yl)-4,5,7-trimethyl-4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-carboxamide;
(7R)—N-(3-{2-[(2S,6S)-2,6-dimethylmorpholin-4-yl]pyridin-4-yl}-1H-indazol-5-yl)-4,5,7-trimethyl-4H,7H-[1,2,3,4]tetrazolo[1,5-a]pyrimidine-6-carboxamide;
(7R)—N-(3-{2-[(2R,6R)-2,6-dimethylmorpholin-4-yl]pyridin-4-yl}-1H-indazol-5-yl)-4,5,7-trimethyl-4H,7H-[1,2,3,4]tetrazolo[1,5-a]pyrimidine-6-carboxamide;
(R)—N-(3-(2-((3R,5S)-3,5-dimethylpiperidin-1-yl)pyridin-4-yl)-1H-indazol-5-yl)-4,5,7-trimethyl-4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-carboxamide;
(R)-4,5,7-trimethyl-N-(3-phenyl-1H-indazol-5-yl)-4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-carboxamide;
(R)—N-(3-(3-((2S,6R)-2,6-dimethylmorpholino)phenyl)-1H-indazol-5-yl)-4,5,7-trimethyl-4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-carboxamide;
4,5,7-trimethyl-N-(3-methyl-1H-indazol-5-yl)-4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-carboxamide;
(R)—N-(1-aminoisoquinolin-6-yl)-4,5,7-trimethyl-4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-carboxamide;
4,5,7,7-tetramethyl-N-(3-(2-morpholinopyridin-4-yl)-1H-indazol-5-yl)-4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-carboxamide;
4,5,7,7-tetramethyl-N-(3-(3-morpholinophenyl)-1H-indazol-5-yl)-4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-carboxamide;
N-(3-(3-((2S,6R)-2,6-dDimethylmorpholino)phenyl)-1H-indazol-5-yl)-4,5,7,7-tetramethyl-4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-carboxamide;
4,5,7,7-tetramethyl-N-(3-phenyl-1H-indazol-5-yl)-4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-carboxamide;
(R)-4,5,7-trimethyl-N-(3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-carboxamide;
(R)-4,5,7-trimethyl-N-(1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-carboxamide;
(R)—N-(3,3-dimethyl-1-oxoisoindolin-5-yl)-4,5,7-trimethyl-4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-carboxamide;
N-(1H-indazol-5-yl)-7-isopropyl-4,5-dimethyl-4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-carboxamide;
4-acetyl-N-(2H-indazol-5-yl)-5-methyl-4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-carboxamide;
N-(3-(2-(4-(dimethylamino)phenyl)acetamido)-2H-indazol-5-yl)-4,5-dimethyl-4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-carboxamide;
N-(4-methoxy-1H-indazol-5-yl)-4,5-dimethyl-4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-carboxamide;
4,5-dimethyl-N-(3-((6-methylpyridin-3-yl)carbamoyl)-2H-indazol-5-yl)-4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-carboxamide;
N-(3-(furan-2-carboxamido)-2H-indazol-5-yl)-4,5-dimethyl-4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-carboxamide;
N-(3-(cyclopropanecarboxamido)-2H-indazol-5-yl)-4,5-dimethyl-4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-carboxamide;
N-(3-butyramido-2H-indazol-5-yl)-4,5-dimethyl-4,7-dihydrotetrazolo[1,5-a]pyrimidine-b-carboxamide;
4,5-dimethyl-N-(3-methyl-2H-indazol-5-yl)-4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-carboxamide;
N-(3-(1H-benzo[d]imidazol-2-yl)-1H-indazol-5-yl)-4,5-dimethyl-4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-carboxamide;
4,5,7,7-tetramethyl-N-(3-methyl-2H-indazol-5-yl)-4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-carboxamide;
methyl 5-(4,5-dimethyl-4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-carboxamido)-2H-indazole-4-carboxylate;
4,5-dimethyl-N-(4-methyl-2H-indazol-5-yl)-4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-carboxamide;
4,5-dimethyl-N-(3-methyl-1H-indol-5-yl)-4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-carboxamide;
4,5-dimethyl-N-(1-methyl-1H-indazol-6-yl)-4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-carboxamide;
4,5-dimethyl-N-(3-methyl-6-(trifluoromethyl)-2H-indazol-5-yl)-4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-carboxamide; and
N-(3-benzamido-2H-indazol-5-yl)-4,5-dimethyl-4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-carboxamide;
or a pharmaceutically acceptable salt thereof.
90 . A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
91 . A method of inhibiting LRRK2 activity, said method comprising contacting a compound of claim 1 , or a pharmaceutically acceptable salt thereof with LRRK2.
92 . The method of claim 91 , wherein the LRRK2 is characterized by a G2019S mutation.
93 . The method of claim 91 , wherein the contacting comprises administering the compound to a patient.
94 . A method of treating a disease or disorder associated with elevated expression or activity of LRRK2, or functional variants thereof, said method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.
95 . The method of claim 94 , wherein the LRRK2 is characterized by a G2019S mutation.
96 . A method for treating a neurodegenerative disease in a patient, said method comprising: administering to the patient a therapeutically effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt thereof.
97 . The method of claim 96 , wherein said neurodegenerative disease is selected from Parkinson's disease, Parkinson disease with dementia, Parkinson's disease at risk syndrome, dementia with Lewy bodies, Lewy body variant of Alzheimer's disease, combined Parkinson's disease and Alzheimer's disease, multiple system atrophy, striatonigral degeneration, olivopontocerebellar atrophy, and Shy-Drager syndrome.
98 . The method of claim 96 , wherein said neurodegenerative disease is Parkinson's disease.
99 . The method of claim 96 , wherein the Parkinson's disease is characterized by a G2019S mutation in LRRK2.