US 12,319,679 B2
Morpholinyl, piperazinyl, oxazepanyl and diazepanyl O-glycoprotein-2-acetamido-2-deoxy-3-d-glucopyranosidase inhibitors
Nathan Genung, Charlestown, MA (US); Kevin M. Guckian, Northborough, MA (US); Jeffrey Vessels, Marlborough, MA (US); Lei Zhang, Westford, MA (US); Ryan Gianatassio, Everett, MA (US); Edward Yin Shiang Lin, Ashland, MA (US); and Zhili Xin, Lexington, MA (US)
Assigned to BIOGEN MA INC., Cambridge, MA (US)
Appl. No. 17/311,232
Filed by BIOGEN MA INC., Cambridge, MA (US)
PCT Filed Dec. 4, 2019, PCT No. PCT/US2019/064514
§ 371(c)(1), (2) Date Jun. 4, 2021,
PCT Pub. No. WO2020/117961, PCT Pub. Date Jun. 11, 2020.
Claims priority of provisional application 62/775,558, filed on Dec. 5, 2018.
Prior Publication US 2022/0017506 A1, Jan. 20, 2022
Int. Cl. C07D 417/12 (2006.01); C07D 417/14 (2006.01)
CPC C07D 417/12 (2013.01) [C07D 417/14 (2013.01)] 18 Claims
 
1. A compound represented by the following structural formula:

OG Complex Work Unit Chemistry
or a pharmaceutically acceptable salt thereof, wherein:
Ar is an optionally substituted 5- to 10-membered aryl or an optionally substituted 5- to 10-membered heteroaryl, wherein Ar is not a 9-membered bicyclic heteroaryl having 1 to 4 nitrogen atoms when the sum of m and p is 1; wherein said 5- to 10-membered aryl or 5- to 10-membered heteroaryl represented by Ar is optionally substituted with one or more groups selected from C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, C3-C6 heterocyclyl, halo, —CN, —NO2, —ORz, —NRxRy, —S(O)iRx, —NRxS(O)iRy, —S(O)iNRxRy, —C(═O)ORx, —OC(═O)ORx, —C(═S)ORy, —O(C═S)Rx, —C(═O)NRxRy, —NRxC(═O)Ry, —C(═S)NRxRy, —NRxC(═S)Ry, —NRx(C═O)ORy, —O(C═O)NRxRy, —NRx(C═S)ORy, —O(C═S)NRxRy, —NRx(C═O)NRxRy, —NRx(C═S)NRxRy, —C(═S)Rx, —C(═O)Rx, phenyl and monocyclic heteroaryl;
wherein
the C1-C4 alkyl group substituent on Ar is optionally substituted with —CN, —NO2, —ORz, —NRxRy, —S(O)iRx, —NRxS(O)iRy, —S(O)iNRxRy, —C(═O)ORx, —OC(═O)ORx, —C(═S)ORx, —O(C═S)Rx, —C(═O)NRxRy, —NRxC(═O)Ry, —C(═S)NRxRy, —NRxC(═S)Ry, —NRx(C═O)ORy, —O(C═O)NRxRy, —NRx(C═S)ORy, —O(C═S)NRxRy, —NRx(C═O)NRxRy, —NRx(C═S)NRxRy, —C(═S)Rx, and —C(═O)Ry, C3-C6 cycloalkyl (optionally substituted with one or more groups selected from —CH3, halomethyl, halo, methoxy and halomethoxy), monocyclic heteroaryl (optionally substituted with one or more groups selected from —CH3, halomethyl, halo, methoxy or halomethoxy) and phenyl (optionally substituted with one or more groups selected from —CH3, halomethyl, halo, methoxy and halomethoxy);
the C3-C6 cycloalkyl, C3-C6 heterocyclyl, phenyl and monocyclic heteroaryl group substituent on Ar are optionally and independently substituted with C1-C4 alkyl, C1-C4 haloalkyl, halo, —CN, —NO2, —ORz, —NRxRy, —S(O)iRx, —NRxS(O)iRy, —S(O)iNRxRy, —C(═O)ORx, —OC(═O)ORx, —C(═S)ORx, —O(C═S)Ry, —C(═O)NRxRy, —NRxC(═O)Ry, —C(═S)NRxRy, —NRxC(═S)Ry, —NRx(C═O)ORy, —O(C═O)NRxRy, —NRx(C═S)ORy, —O(C═S)NRxRy, —NRx(C═O)NRxRy, —NRx(C═S)NRxRy, —C(═S)Rx, and —C(═O)Rx;
each Rx and each Ry is independently —H, C1-C4 alkyl, or C3-C8 cycloalkyl; wherein the C1-C4 alkyl or C3-C8 cycloalkyl represented by Rx or Ry is optionally substituted with one or more substituents selected from halo, hydroxyl, C3-C6 cycloalkyl and phenyl (optionally substituted with one or more groups selected from —CH3, halomethyl, halo, methoxy or halomethoxy);
Rz is —H, C1-C4 alkyl, C1-C4 alkoxy, C3-C8 cycloalkyl, or C3-C8 heterocyclyl; wherein the C1-C4 alkyl or C3-C8 cycloalkyl group represented by Rz is optionally substituted with one or more substituents selected from —CN, halo, hydroxyl, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl and phenyl (optionally substituted with one or more groups selected from —CH3, halomethyl, halo, methoxy and halomethoxy); and
i is 0, 1, or 2;
W is O or —NRd; when W is —NRd, then p is 0 and m is 1;
X is —CR2R2, —(CR2R2)2, —(CR2R2)O— or —O(CR2R2)—;
Y1 and Y2 are each CRc or N, wherein at least one of Y1 or Y2 is N;
Z is —CR2R2, —C(═O), —(CR2R2)2, or —CH2C(═O);
Rc is —H, halo, —C1-C4 alkyl, or —C1-C4 haloalkyl;
Rd is —H, C1-C4 alkyl, C1-C4 haloalkyl, or —C(═O)C1-C4 alkyl;
m is 1 or 2;
p is 0 or 1, provided that the sum of m and p is not 3;
n is 0 or an integer from 1 to 9;
when n is other than 0, R1, for each occurrence, is independently halo, —C1-C4 alkyl, —C1-C4 haloalkyl, or —C1-C4 alkoxy;
R2, for each occurrence, is independently —H, halo, —C1-C4 alkyl, —C1-C4 haloalkyl, —C3-C10 cycloalkyl, or —C3-C10 halocycloalkyl;
or alternatively two R2 together with the carbon atom to which they are attached form a —C3-C10 cycloalkyl;
R3 is —H or —C1-C4 alkyl; and
R4 is —H, —C1-C4 alkyl, —C1-C4 haloalkyl, or —C3-C6 cycloalkyl;
or alternatively R3 and R4 taken together with their intervening atoms form an optionally substituted 5- to 7-membered heterocyclyl.