Linear dipeptidyl peptidase 1 inhibitors and uses thereof
Provided herein are compounds of Formula (I), or pharmaceutically acceptable salts or deuterated forms thereof, wherein R 1 , R 2 , R 3 , R 4 , L, n, m, R a , R b , R c , and R d are defined herein. Also provided herein are pharmaceutical compositions comprising a compound of Formula (I) or pharmaceutically acceptable salt or deuterated form thereof, and methods of using a compound of Formula (I) or pharmaceutically acceptable salt or deuterated form thereof, e.g., in the treatment of a disease that is treatable by administration of a DPP1 inhibitor.
1 . A compound of Formula (IX),
or a pharmaceutically acceptable salt, a stereoisomer or a deuterated form thereof, wherein:
R 1 is carbocyclyl, aryl, heterocyclyl or heteroaryl, wherein R 1 is optionally substituted with 1-5 groups independently selected from R 5 or R 6 ;
L is arylene, heterocyclylene, heteroarylene or cycloalkylene, wherein L is optionally substituted by 1-4 R 7 ;
each R 2 is independently H, halogen, —OH, —CN, —Oalkyl, -NH 2 , —SH, —C(═O)alkyl, -C(═O)NH 2 , alkyl, haloalkyl, -alkylene-OH, -alkylene-CH (COOH)(NH 2 ), alkenyl, alkynyl, -S(alkyl), —S(═O)alkyl, —S(═O) 2 alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, alkylene-aryl, alkylene-heteroaryl, alkylene-heterocyclyl or alkylene-carbocyclyl, wherein R 2 is optionally substituted with 1-4 R 2a , provided that at least one R 2 is not H;
or two R 2 together form (═O);
R 3 is H, alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -alkylene-OH, -alkylene-O-alkyl, -alkylene-carbocyclyl, -alkylene-heterocyclyl, -alkylene-aryl, -alkylene-heteroaryl, —C(═O)alkyl, —C(═O) cycloalkyl, —C(═O)aryl or -C(═O) heteroaryl, wherein R 3 is optionally substituted with 1-4 R 3a ;
R 4 is C 1-6 alkyl;
or R 3 and R 4 together with the nitrogen to which they are attached form a heterocyclyl, wherein the heterocyclyl is optionally substituted with 1-4 R 3a ;
each of R 2a and R 3a is independently alkyl, halogen, haloalkyl, —Oalkyl, —OH, —CN, -C(═O)OH, —NH 2 , —NH(alkyl), —NH(alkyl) 2 , cycloalkyl or heterocyclyl;
each R 5 is independently halogen, C 1-6 alkyl, —O (C 1-6 alkyl), C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, —CN, oxo, —OH, —NH 2 , —NHC 1-6 alkyl, —N(C 1-6 alkyl) 2 , -COOH, -C(═O)(C 1-6 alkyl), —C(═O)O (C 1-6 alkyl), —C(═O)NH(C 1-6 alkyl), C(═O)N (C 1-6 alkyl) 2 , NHC(═O)(C 1-6 alkyl), —S(═O) 2 (C 1-6 alkyl), -(C 1-6 alkylene)-cycloalkyl, —S(═O) 2 -cycloalkyl, -(C 1-6 alkylene)-heterocyclyl, —S(═O) 2 -heterocyclyl, -heterocyclylene-heterocyclyl or heterocyclyl, wherein each R 5 is optionally substituted with 1-3 groups selected from halogen, —CN, —OH, —NH 2 , C 1-6 alkyl, —O (C 1-6 alkyl), -COOH, cycloalkyl or heterocyclyl;
each R 6 is independently H, C 1-6 alkyl, -(C 1-6 alkylene)-O-(C 1-6 alkyl), -(C 1-6 alkylene)-NH 2 , -(C 1-6 alkylene)-NH(C 1-6 alkyl) 2 , -C 1-6 alkylene-N(C 1-6 alkyl) 2 , -C 1-6 alkylene-NH(C 1-6 alkylene-O-C 1-6 alkyl), -C 1-6 alkylene-N(C 1-6 alkylene-O-C 1-6 alkyl)(C 1-6 alkyl), -C 1-6 alkylene-heterocyclyl, C(═O)(C 1-6 alkyl), C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, -heterocyclylene-heterocyclyl or heterocyclyl, wherein each R 6 is optionally substituted with 1-3 groups selected from halogen, —CN, —OH, C 1-6 alkyl, —O (C 1-6 alkyl), —NH 2 , —NH(C 1-6 alkyl), —N(C 1-6 alkyl) 2 , cycloalkyl, aryl, heterocyclyl, heteroaryl or -COOH; and
each R 7 is independently ═O, halogen, C 1-6 alkyl, —O (C 1-6 alkyl), —S(C 1-6 alkyl), C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, —CN, —OH, —NH 2 , —NH(C 1-6 alkyl), —N(C 1-6 alkyl) 2 , -COOH, -C(═O)(C 1-6 alkyl), —C(═O)O (C 1-6 alkyl), —C(═O)N (C 1-6 alkyl) 2 , or —NHC(═O)(C 1-6 alkyl);
or one R 7 and one R 5 together form a carbocyclyl, aryl, heterocyclyl or heteroaryl ring, wherein the carbocyclyl, aryl, heterocyclyl, heteroaryl is optionally substituted with 1-4 groups selected from C 1-6 alkyl, halogen, —OC 1-6 alkyl, haloalkyl, —OH, —CN, or heterocyclyl.
2 . The compound of claim 1 , or a pharmaceutically acceptable salt, a stereoisomer or a deuterated form thereof, wherein R 1 is 8-10 membered fused bicyclic heteroaryl containing 1-3 heteroatoms selected from N, S or O, wherein the heteroaryl is optionally substituted with 1-4 groups independently selected from R 5 or R 6 .
3 . The compound of claim 1 , or a pharmaceutically acceptable salt, a stereoisomer or a deuterated form thereof, wherein:
R 1 is
q is 0, 1, 2 or 3; and
Y is NH, O, S, CH 2 , CHF, or CF 2 .
4 . The compound of claim 1 , or a pharmaceutically acceptable salt, a stereoisomer or a deuterated form thereof, wherein R 1 is
5 . The compound of claim 1 , or a pharmaceutically acceptable salt, a stereoisomer or a deuterated form thereof, wherein L is arylene optionally substituted by 1-4 R 7 .
6 . The compound of claim 1 , or a pharmaceutically acceptable salt, a stereoisomer or a deuterated form thereof, wherein L is
wherein p is 0, 1, 2, 3 or 4.
7 . The compound of claim 1 , or a pharmaceutically acceptable salt, a stereoisomer or a deuterated form thereof, wherein L is
wherein R 7 is a halogen.
8 . The compound of claim 1 , or a pharmaceutically acceptable salt, a stereoisomer or a deuterated form thereof, wherein one of R 2 is H, and the other R 2 is —F, —Cl, —Br, —OH, —CN, —OCH 3 , —OCH 2 CH 3 , —OCH 2 CH 2 CH 3 , —SH, —NH 2 , —CH 3 , —CH 2 CH 3 , —CH 2 (CH 3 ) 2 ,
—CH 2 F, —CHF 2 , —CH 2 Cl, —CH (COOH)NH 2 , —CH 2 CH 2 CH 2 F,
9 . The compound of claim 1 , or a pharmaceutically acceptable salt, a stereoisomer or a deuterated form thereof, wherein one of R 2 is H, and the other R 2 is —F, —Cl, —Br, —OH, —CN, —OCH 3 , —OCH 2 CH 3 , —OCH 2 CH 2 CH 3 , —SH, —NH 2 , —CH 3 , —CH 2 CH 3 , —CH 2 (CH 3 ) 2 ,
—CH 2 F, —CHF 2 , —CH 2 Cl, —CH (COOH)NH 2 , —CH 2 CH 2 CH 2 F,
10 . The compound of claim 1 , or a pharmaceutically acceptable salt, a stereoisomer or a deuterated form thereof, wherein one of R 2 is H, and the other R 2 is —OH or —OCH 3 .
11 . The compound of claim 1 , or a pharmaceutically acceptable salt, a stereoisomer or a deuterated form thereof, wherein R 3 is H or -C 1-6 alkyl.
12 . The compound of claim 1 , or a pharmaceutically acceptable salt, a stereoisomer or a deuterated form thereof, wherein the compound has the structure of Formula (IX-A),
or a pharmaceutically acceptable salt, a stereoisomer or a deuterated form thereof, wherein:
q is 0, 1, 2 or 3;
Y is NR 6 , O, CR 8 R 9 , S, S(O) or S(O) 2 ; and
R 8 and R 9 are each independently H, halogen, C 1-6 alkyl, —O (C 1-6 alkyl), C 1-6 haloalkyl, C 3-6 cycloalkyl or heterocyclyl;
or R 8 and R 9 form-O.
13 . The compound of claim 1 , or a pharmaceutically acceptable salt, a stereoisomer or a deuterated form thereof, wherein the compound has the structure of Formula (IX-C),
or a pharmaceutically acceptable salt, a stereoisomer or a deuterated form thereof, wherein:
p is 0, 1, 2, 3 or 4;
q is 0, 1, 2 or 3;
Y is NR 6 , O, CR 8 R 9 , S, S(O) or S(O) 2 ; and
R 8 and R° are each independently H, halogen, C 1-6 alkyl, —O (C 1-6 alkyl), C 1-6 haloalkyl, C 3-6 cycloalkyl or heterocyclyl;
or R 8 and R 9 form ═O.
14 . The compound of claim 1 , or a pharmaceutically acceptable salt, a stereoisomer or a deuterated form thereof, wherein the compound has the structure of Formula (IX-B),
or a pharmaceutically acceptable salt, a stereoisomer or a deuterated form thereof, wherein q is 0, 1, 2 or 3.
15 . The compound of claim 1 , or a pharmaceutically acceptable salt, a stereoisomer or a deuterated form thereof, wherein the compound has the structure of Formula (IX-D),
or a pharmaceutically acceptable salt, a stereoisomer or a deuterated form thereof, wherein:
p is 0, 1, 2, 3 or 4; and
q is 0, 1, 2 or 3.
16 . The compound of claim 1 , or a pharmaceutically acceptable salt, a stereoisomer or a deuterated form thereof, wherein the compound has the structure of Formula (X),
or a pharmaceutically acceptable salt, a stereoisomer or a deuterated form thereof.
17 . The compound of claim 16 , or a pharmaceutically acceptable salt, a stereoisomer or a deuterated form thereof, wherein R 1 is
18 . The compound of claim 16 , or a pharmaceutically acceptable salt, a stereoisomer or a deuterated form thereof, wherein R 1 is
19 . The compound of claim 16 , or a pharmaceutically acceptable salt, a stereoisomer or a deuterated form thereof, wherein:
L is
R 7 is a halogen; and
p is 0 or 1.
20 . The compound of claim 16 , or a pharmaceutically acceptable salt, a stereoisomer or a deuterated form thereof, wherein R 2 is —F, —Cl, -Br, —OH, —CN, —OCH 3 , -OCH 2 CH 3 , —OCH 2 CH 2 CH 3 , —SH, —NH 2 , —CH 3 , —CH 2 CH 3 , —CH 2 (CH 3 ) 2 ,
—CH 2 F, —CHF 2 , —CH 2 Cl, —CH(COOH)NH 2 , —CH 2 CH 2 CH 2 F,
21 . The compound of claim 16 , or a pharmaceutically acceptable salt, a stereoisomer or a deuterated form thereof, wherein R 2 is —OH or —O(C 1-6 alkyl).
22 . The compound of claim 16 , or a pharmaceutically acceptable salt, a stereoisomer or a deuterated form thereof, wherein R 2 is —OH or —OCH 3 .
23 . The compound of claim 16 , or a pharmaceutically acceptable salt, a stereoisomer or a deuterated form thereof, wherein R 3 is H or —C 1-6 alkyl.
24 . The compound of claim 16 , or a pharmaceutically acceptable salt, a stereoisomer or a deuterated form thereof, wherein R 3 is H, CH 3 , CH 2 CH 3 or CH 2 CH 2 CH 3 and R 4 is CH 3 , CH 2 CH 3 or CH 2 CH 2 CH 3 .
25 . The compound of claim 16 , or a pharmaceutically acceptable salt, a stereoisomer or a deuterated form thereof, wherein:
L is
wherein the asterisk (*) represents the point of attachment to R 1 ;
R 1 is
R 5 is halogen, —CN, C 1-6 alkyl, C 1-6 haloalkyl, or —O(C 1-6 alkyl);
R 6 is H or C 1-6 alkyl;
R 7 is halogen;
Y is O or CH 2 ; and
q is 0, 1, 2 or 3.
26 . The compound of claim 16 , or a pharmaceutically acceptable salt, a stereoisomer or a deuterated form thereof, wherein:
L is
wherein the asterisk (*) represents the point of attachment to R 1 ;
R 1 is
R 2 is —OH or —OCH 3 ;
R 3 is H or C 1-6 alkyl; and
R 7 is halogen.
27 . The compound of claim 16 , or a pharmaceutically acceptable salt, a stereoisomer or a deuterated form thereof, wherein the compound has the structure of Formula (X-A),
or a pharmaceutically acceptable salt, a stereoisomer or a deuterated form thereof, wherein:
Y is O or CH 2 ;
R 2 is —OH or —OCH 3 ;
R 3 is H or C 1-6 alkyl;
R 5 is halogen, —CN, C 1-6 alkyl, C 1-6 haloalkyl, or —O(C 1-6 alkyl);
R 6 is H or C 1-6 alkyl;
R 7 is halogen;
p is 0 or 1; and
q is 0 or 1.
28 . A pharmaceutical composition comprising the compound of claim 1 , or a pharmaceutically acceptable salt, a stereoisomer or a deuterated form thereof, and a pharmaceutically acceptable adjuvant, diluent or carrier.
29 . A compound selected from:
or a pharmaceutically acceptable salt, a stereoisomer, a racemic form, or a deuterated form thereof.
30 . A pharmaceutical composition comprising the compound of claim 29 , or a pharmaceutically acceptable salt, a stereoisomer or a deuterated form thereof, and a pharmaceutically acceptable adjuvant, diluent or carrier.