US2023014730A1PendingUtilityA1
Phosphodiesterase inhibitors and use
Assignee: NANJING ZHENGXIANG PHARMACEUTICALS CO LTDPriority: Sep 23, 2019Filed: Sep 23, 2020Published: Jan 19, 2023
Est. expirySep 23, 2039(~13.2 yrs left)· nominal 20-yr term from priority
Inventors:Xiaolin Hao
C07D 498/04C07D 487/04C07D 471/04C07D 471/14
60
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Claims
Abstract
The invention provides compounds that may inhibits to ENPP1, and are accordingly useful for treatment disorders related to ENPP1. The invention further provides pharmaceutical compositions containing these compounds and methods of using these compounds to treat or prevent disorders related to ENPP1.
Claims
exact text as granted — not AI-modified1 . A compound of Formula (A):
or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof, wherein:
L 1 is a bond, O, CR 1 R 2 , NR 3 , or *CR 1 R 2 NR 3 , wherein * denotes the point of attachment to ring A;
L 2 is a bond, CR 1 R 2 , or C(═O);
Q 1 , Q 2 , Q 3 , Q 4 , and Q 5 are independently N, C or C-E;
A 2 , A 3 , A 4 and A 5 are independently N or CR 4 ;
X is S, O, CR 1 R 2 , C-E, N or NR 3 ;
Z is SO 2 NHR 5 , SO 2 R 5 , C(O)OH, C(O)NHR 5 , C(O)NHOR 5 , P(O)(OR 5 ) 2 , or B(OH) 2 ;
E is, independently at each occurrence, selected from the group consisting of hydrogen, deuterium, halogen, oxo, —CN, —OR 3 , —NO 2 , —NR 3 R 3 ′, —C(O)R 3 , —C(O)OR 3 , —C(O)NR 3 R 3 ′, —SO 2 R 3 , —SO 2 NR 3 R 3 ′, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 4 alkoxy, C 3 -C 8 cycloalkyl, and 3-8 membered heterocyclyl, wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, and 3-8 membered heterocyclyl are optionally substituted with one or more substituents selected from the group consisting of halogen, CN, OH, NH 2 , N(C 1 -C 6 alkyl) 2 , C 1 -C 3 alkyl, phenyl, C 1 -C 4 alkoxy, C 1 -C 3 haloalkyl, C 1 -C 3 haloalkoxy, 3-8 membered heterocyclyl, —C(O)—C 1 -C 4 alkoxy, —C(O)—NH 2 , and —S(O) 2 —C 1 -C 6 alkyl;
R 1 and R 2 are independently selected from the group consisting of hydrogen, deuterium, halogen, C 1 -C 6 alkyl, and C 3 -C 8 cycloalkyl, wherein the C 1 -C 6 alkyl, and C 3 -C 8 cycloalkyl are optionally substituted with one or more substituents selected from the group consisting of halogen, CN, OH, NH 2 , C 1 -C 3 alkyl, phenyl, C 1 -C 4 alkoxy, C 1 -C 3 haloalkyl, and C 1 -C 3 haloalkoxy, or R 1 and R 2 together form a C 3 -C 6 cycloalkyl;
R 3 and R 3 ′ are independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, 3-6 membered cycloalkyl, and 3-8 membered heterocyclyl, wherein the C 1 -C 6 alkyl, and C 3 -C 6 cycloalkyl are optionally substituted with one or more substituents selected from the group consisting of halogen, CN, OH, NH 2 , C 1 -C 3 alkyl, phenyl, C 1 -C 4 alkoxy, C 1 -C 3 haloalkyl, and C 1 -C 3 haloalkoxy;
R 4 is selected from the group consisting of hydrogen, deuterium, halogen, —CN, —OR 3 , —NO 2 , —NR 3 R 3 ′, —C(O)R 3 , —C(O)OR 3 , —C(O)NR 3 R 3 ′, —SO 2 R 3 , —SO 2 NR 3 R 3 ′, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, and 3-8 membered heterocyclyl, wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, and 3-8 membered heterocyclyl are optionally substituted with one or more substituents selected from the group consisting of halogen, CN, OH, NH 2 , C 1 -C 3 alkyl, phenyl, C 1 -C 4 alkoxy, C 1 -C 3 haloalkyl, and C 1 -C 3 haloalkoxy;
R 5 is, independently at each occurrence, selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, 3-8 membered heterocyclyl, and —C(═O)—C 1 -C 6 alkyl, wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, and 3-8 membered heterocyclyl are independently optionally substituted with one or more substituents selected from the group consisting of halogen, CN, OH, NH 2 , C 1 -C 3 alkyl, phenyl, C 1 -C 4 alkoxy, C 1 -C 3 haloalkyl, and C 1 -C 3 haloalkoxy;
ring A is C 3 -C 8 cycloalkyl, 3- to 12-membered heterocyclyl, C 6 -C 14 aryl, or 5- to 10-membered heteroaryl, wherein the C 3 -C 8 cycloalkyl, 3- to 12-membered heterocyclyl, C 6 -C 14 aryl, and 5- to 10-membered heteroaryl of ring A are optionally substituted with one or more substituents selected from the group consisting of halogen, CN, OH, NH 2 , C 1 -C 3 alkyl, and C 1 -C 4 alkoxy, wherein the C 1 -C 3 alkyl and C 1 -C 4 alkoxy are independently optionally substituted with one or more halogen; and
indicates that ring B is fully unsaturated, or partially unsaturated,
provided that the compound is not the following:
or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof.
2 . The compound of claim 1 , or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof, wherein the compound is of Formula (I):
provided that the compound is not the following:
or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof.
3 . The compound of claim 1 , or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof, wherein the compound is of Formula (II):
provided that the compound is not the following:
or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof.
4 . The compound of claim 1 , or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof, wherein the compound is of Formula (III):
wherein Q 3 is N or CH,
provided that the compound is not the following:
or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof.
5 . The compound of claim 1 , or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof, wherein the compound is of Formula (IV):
6 . The compound of claim 1 , or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof, wherein the compound is of Formula (V):
wherein X is N or C-E.
7 . The compound of claim 1 , or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof, wherein the compound is of Formula (VI):
wherein X is N or C-E.
8 . The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein L 1 is a bond and L 2 is CR 1 R 2 .
9 . The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein L 1 is NR 3 and L 2 is a bond or CR 1 R 2 .
10 . The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein L 1 is CR 1 R 2 , wherein R 1 is H or methyl and R 2 is H or methyl.
11 . The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein Q 1 is N or CH.
12 . The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein ring A is 3- to 12-membered heterocyclyl, C 6 -C 14 aryl, or 5- to 10-membered heteroaryl, wherein the 3- to 12-membered heterocyclyl, C 6 -C 14 aryl, and 5- to 10-membered heteroaryl of ring A are optionally substituted with one or more substituents selected from the group consisting of halogen, CN, OH, NH 2 , and C 1 -C 3 alkyl.
13 . The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein each E is independently H, deuterium, halogen, CN, methyl, or —NR 3 R 3 ′.
14 . The compound of claim 13 , or a pharmaceutically acceptable salt, solvate, wherein, when E is —NR 3 R 3 ′, R 3 and R 3 ′ are both hydrogen.
15 . The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein A 2 , A 3 , A 4 , and A 5 are independently N or CR 4 , and R 4 is hydrogen, deuterium, halogen, —CN, —OR 3 , or C 1 -C 6 alkyl, wherein the C 1 -C 6 alkyl optionally substituted with one or more halogen.
16 . The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein:
A 2 and A 5 are independently CH or N, A 3 and A 4 are independently N or CR 4 , wherein R 4 is hydrogen, deuterium, F, C 1 , Br, CN, OMe, or CF 3 , and Z is SO 2 NH 2 .
17 . The compound of claim 1 , or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof, wherein the compound is selected from the group consisting of those listed in Table 1.
18 . The compound of claim 2 , or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof, wherein the compound is selected from the group consisting of:
or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof.
19 . The compound of claim 3 , or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof, wherein the compound is selected from the group consisting of:
or a pharmaceutically acceptable salt,
stereoisomer, solvate, or prodrug thereof.
20 . The compound of claim 4 , or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof, wherein the compound is selected from the group consisting of:
or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof.
21 . The compound of claim 5 , or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof, wherein the compound is selected from the group consisting of:
or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof.
22 . The compound of claim 6 , or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof, wherein the compound is selected from the group consisting of:
or pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof.
23 . The compound of claim 7 , or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof, wherein the compound is:
or pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof.
24 . A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof, and one or more pharmaceutically acceptable carriers.
25 . A method of treating a disorder of uncontrolled cellular proliferation related to ENPP1, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1 .
26 . A method of treating skeletal and soft tissue mineralization related disorders, the method comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1 .
27 . A method of treating disorders related to ENPP1 genetic changes, including Cole disease, generalized arterial calcification of infancy and hypophosphatemic rickets, the method comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1 .
28 . A method of treating a subject with a viral infection, the method comprising the step of administering to the subject a therapeutically effective amount of a compound of claim 1 .
29 - 31 . (canceled)
32 . A methods of treating a subject with a bacterial infection, the method comprising the step of administering to the subject a therapeutically effective amount of a compound of claim 1 .
33 . (canceled)
34 . (canceled)
35 . A method of treating a cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1 .
36 - 43 . (canceled)Join the waitlist — get patent alerts
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