NOVEL, REVERSIBLE DPP1 INHIBITORS AND USES THEREOF
Provided herein are compounds of Formula (I), or pharmaceutically acceptable salts or deuterated forms thereof, wherein R 0 , L and R 1 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 (I)
or a pharmaceutically acceptable salt or deuterated form thereof,
wherein:
R 0 is
X 1 and X 2 are independently O, S, NH, N(C 1-6 alkyl), or CR 12 R 13 , wherein at least one of X 1 and X 2 are not CR 12 R 13 ;
X 3 is O, S, NH, N(C 1-6 alkyl), or CH 2 O;
R A is H, C 1-6 alkyl, C 1-6 alkylene-carbocyclyl, C 1-6 alkylene-heteroaryl, heteroaryl, or carbocyclyl; and
R B is C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkyl-OH, C 2-6 alkenyl, cycloalkyl, C 1-6 alkylene-carbocyclyl, C 1-6 alkylene-aryl, C 1-6 alkylene-heteroaryl, heteroaryl, or carbocyclyl; or
R A and R B are taken together to form a heterocyclyl;
L is aryl, heterocyclyl, heteroaryl, or
wherein L is independently substituted by 0-4 R 10 and wherein ring B is a carbocycle, or a heterocycle;
R 1 is
R 2 is H, F, Cl, Br, OSO 2 C 1-6 alkyl, or C 1-6 alkyl;
R 3 is H, F, Cl, Br, CN, C 1-6 haloalkyl, SO 2 C 1-6 alkyl, CONH 2 , or SO 2 NR 4 R 5 , wherein R 4 and R 5 together with the nitrogen atom to which they are attached form a heterocyclyl;
X is O, S, CHF, or CF 2 ;
Y is O, S, or CH 2 ;
Q is CH or N;
R 6 is C 1-6 alkyl optionally substituted by 1, 2 or 3 F, or optionally substituted by OH, OC 1-6 alkyl, N(C 1-6 alkyl) 2 , N(C 1-6 alkyl)(C 1-6 alkylene-O—C 1-6 alkyl), cycloalkyl, or heterocyclyl;
R 7 is H, F, Cl, Br, or C 1-6 alkyl;
each R 8 and R 12 are independently H, OH, halogen, NH 2 , COOH, C 1-6 alkyl, C 1-6 alkyl-OH, C 2-6 alkenyl, C 1-6 alkoxy, O-cycloalkyl, cycloalkyl, C 1-6 alkylene-carbocyclyl, C 1-6 alkylene-heteroaryl, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, heteroaryl, or carbocyclyl;
each R 13 is independently H, F, Cl, Br, I, or C 1 -C 6 alkyl;
each R 10 is independently oxo, halogen, C 1-6 alkyl, C 1-6 alkoxy, S—C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, cyano, hydroxy, NH 2 , —NH—C 1-6 alkyl, N(C 1-6 alkyl) 2 , COOH, COC 1-6 alkyl, COOC 1-6 alkyl, CON 1-6 alkyl, CON(C 1-6 alkyl) 2 , NHCOC 1-6 alkyl, or heterocycle; wherein each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, and heterocycle are independently optionally substituted with 1-3 substituents selected from halogen, cyano, hydroxy, NH 2 , and COOH;
W, X 4 , and Y 2 are each independently CH or N, provided that a maximum of one of W, X 4 , and Y 2 can be N;
D-E is N(H)—C(O), N(C 1-6 alkyl)-C(O), CH 2 CH 2 , C(O)—O, or CH 2 —O;
R 11 is H, C 1-6 alkyl, alkylene-O-alkyl, or heterocyclyl; and
i and j are each independently 1, 2 or 3, provided that the sum of i+j is 2, 3, or 4.
2 . (canceled)
3 . The compound of claim 1 , wherein the compound is of Formula (II):
or a pharmaceutically acceptable salt or deuterated form thereof, wherein n is 0, 1, or 2, and R 10 is halogen.
4 . The compound of claim 3 , or a pharmaceutically acceptable salt thereof or deuterated form thereof, wherein the halogen is F.
5 . The compound of claim 3 , or a pharmaceutically acceptable salt thereof or deuterated form thereof, wherein n is 0 or 1.
6 . (canceled)
7 . The compound of claim 1 , or a pharmaceutically acceptable salt or deuterated form thereof, wherein,
R 1 is
X is O, S, or CF 2 ;
Y is O or S;
Q is CH or N;
R 6 is C 1-3 alkyl, wherein said C 1-3 alkyl is optionally substituted by 1, 2 or 3 F, OH, OC 1-3 alkyl, N(C 1-3 alkyl) 2 , N(C 1-3 alkyl)(C 1-3 alkylene-O—C 1-3 alkyl), cyclopropyl, or tetrahydropyran;
R 7 is H, F, Cl, or CH 3 ; and
R 11 is H, C 1-6 alkyl, alkylene-O-alkyl, or heterocyclyl.
8 .- 11 . (canceled)
12 . The compound of claim 1 , or a pharmaceutically acceptable salt or deuterated form thereof, wherein,
R 1 is
X is O;
R 6 is C 1-3 alkyl; and
R 7 is H.
13 .- 16 . (canceled)
17 . The compound of claim 3 , or a pharmaceutically acceptable salt or deuterated form thereof, wherein R 6 is methyl.
18 .- 19 . (canceled)
20 . The compound of claim 3 , or a pharmaceutically acceptable salt or deuterated form thereof, wherein R 1 is
21 .- 24 . (canceled)
25 . The compound of claim 1 , wherein the compound is of Formula (II):
or a pharmaceutically acceptable salt or deuterated form thereof, wherein n is 0 or 1.
26 .- 28 . (canceled)
29 . The compound of claim 1 , wherein the compound is of Formula (III-B):
or a pharmaceutically acceptable salt or deuterated form thereof, wherein R 10 is —F.
30 . (canceled)
31 . The compound of claim 29 , or a pharmaceutically acceptable salt or deuterated form thereof, wherein X is O.
32 .- 71 . (canceled)
72 . The compound of claim 1 , or a pharmaceutically acceptable salt or deuterated form thereof, wherein R 0 is
73 . The compound of claim 72 , or a pharmaceutically acceptable salt or deuterated form thereof, wherein R 0 is
74 . The compound of claim 1 , or a pharmaceutically acceptable salt or deuterated form thereof, wherein R A is H or C 1-6 alkyl.
75 . The compound of claim 74 , or a pharmaceutically acceptable salt or deuterated form thereof, wherein R A is H, methyl, butyl, or isopropyl.
76 .- 78 . (canceled)
79 . The compound of claim 1 , or a pharmaceutically acceptable salt or deuterated form thereof, wherein R B is C 1-6 alkyl, C 2-6 alkenyl, C 1-6 alkylene-carbocyclyl, or C 1-6 alkylene-heteroaryl.
80 . The compound of claim 1 , or a pharmaceutically acceptable salt or deuterated form thereof, wherein R A and R B are taken together to form an oxetanyl, thietanyl, or tetrahydrofuranyl.
81 . (canceled)
82 . The compound of claim 72 , or a pharmaceutically acceptable salt or deuterated form thereof, wherein R 0 is
83 .- 84 . (canceled)
85 . The compound of claim 82 , or a pharmaceutically acceptable salt or deuterated form thereof, wherein R B is methyl or ethyl.
86 . (canceled)
87 . The compound of claim 73 , or a pharmaceutically acceptable salt or deuterated form thereof, wherein R 0 is
88 .- 89 . (canceled)
90 . The compound of claim 87 , or a pharmaceutically acceptable salt or deuterated form thereof, wherein R B is methyl, ethyl, isopropyl,
CF 3 , —CH═CH 2 , —CH 2 OH, —CH 2 —CH═CH 2 , or n-propyl.
91 .- 175 . (canceled)
176 . The compound of claim 72 , or a pharmaceutically acceptable salt or deuterated form thereof, wherein R 8 is H or methyl.
177 . A compound having the structure:
or a pharmaceutically acceptable salt thereof.