TRPML modulators
The present invention provides compounds, pharmaceutically acceptable compositions thereof, and methods of using the same.
1 . A compound of Formula IIb-1 or IId:
or a pharmaceutically acceptable salt thereof, wherein
L 1 is —C(O)—NR 3 —, —NR 3 —C(O)—, or an optionally substituted bivalent moiety selected from C 1-6 alkylenyl, —NR 3 -C 0-6 alkylenyl, —C(O)—C 0-6 alkylenyl, —C 1-6 alkylenyl-C(O)—, and —C 1-6 alkylenyl-O—C(O)—;
Z is 4- to 16-membered monocyclic or polycyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S, wherein Z is substituted with (R 2 ) q ;
each R a is independently H, halo, —CN, or an optionally substituted group selected from C 1-6 aliphatic, —C 3-6 cycloaliphatic, and —O—C 1-6 aliphatic;
each R 2 is independently selected from halo, oxo, —CN, —OH, —O—R 2a , —C(O)—R 2a , —C(O)O—R 2ª , and
an optionally substituted group selected from —C 1-6 aliphatic, —C 6-12 aryl, and 5- to 12-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S;
each R 2a is independently H or an optionally substituted group selected from C 1-6 aliphatic, C 3-12 cycloaliphatic, and 4- to 12-membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S;
each R 3 is independently selected from H and optionally substituted-C 1-6 aliphatic;
each R 5 is —N(R 3 ) 2 or an optionally substituted group selected from —C 1-6 aliphatic, —P(O)(C 1-6 aliphatic) 2 , —C 3-12 cycloaliphatic, and 5- to 12-membered monocyclic or polycyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S;
each R 6 is independently selected from halo, —SF 5 , —S(O)—R 5 , S(O) 2 —R 5 , —S(O)(NH)—R 5 , —S(O) 2 —(NH)—R 5 , —S(O)—N(R 5 ) 2 , —S(O) 2 —N(R 5 ) 2 , —CN, —C(O)—NH(R 5 ), —C(O)—N(R 5 ) 2 , —P(O)(R 5 ) 2 , —O—R 5 , or an optionally substituted group selected from —C 1-6 aliphatic, −S—C 1-6 aliphatic, —C 0-6 alkylenyl —C(O)—R 5 , —C 0-6 alkylenyl-C(O)O—R 5 , —C 6-12 aryl, —C 3-12 cycloaliphatic, and 4- to 7-membered monocyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S;
m is 0, 1, 2, 3, or 4; and
q is 2.
2 . The compound of claim 1 , wherein each R 6 is independently halo, —S(O)—R 5 , —S(O) 2 —R 5 , —S(O)(NH)—R 5 , or an optionally substituted —O—C 1-6 aliphatic.
3 . The compound of claim 1 , wherein R 6 is —S(O)—R 5 , —S(O) 2 —R 5 , or optionally substituted —C 1-6 aliphatic.
4 . A pharmaceutical composition comprising a compound of claim 1 , and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
5 . The compound of claim 1 , wherein the compound is selected from:
Structure
Compound No.
A-544
A-748
A-750
A-754
A-755
A-758
A-763
A-766
A-769
A-771
A-773
A-774
A-776
A-779
A-782
A-783
A-788
A-789
A-800
A-801
A-802
A-803
A-804
A-805
A-806
A-807
A-808
A-810
A-811
A-814
A-818
A-824
A-826
A-831
A-833
A-834
A-835
A-836
A-838
A-840
A-841
A-842
A-843
A-845
A-846
A-847
A-854
A-859
A-862
A-863
A-864
A-865
A-866
A-867
A-871
A-871A
A-871B
A-872
A-872A
A-872B
A-878
A-883
A-885
A-902
A-903
A-931
A-985
A-997
A-998
A-1001
or a pharmaceutically acceptable salt thereof.
6 . The compound of claim 1 , wherein Z is selected from:
7 . The compound of claim 1 , wherein m is 1.
8 . The compound of claim 3 , wherein R 6 is —S(O) 2 —R 5 .
9 . The compound of claim 1 , wherein L 1 is C 1-6 alkylenyl.
10 . The compound of claim 1 , wherein Z is 4- to 6-membered monocyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S.
11 . The compound of claim 1 , wherein R a is H.
12 . The compound of claim 1 , wherein each R 2 is —C 1-6 aliphatic.
13 . The compound of claim 1 , wherein R 5 is —N(R 3 ) 2 .
14 . The compound of claim 1 , wherein each R 3 is —C 1-6 aliphatic.
15 . A compound having the structure:
or a pharmaceutically acceptable salt thereof.
16 . A compound having the structure: