US 12,281,102 B2
Inhibitors of APOL1 and methods of using same
Leslie A. Dakin, Framingham, MA (US); Timothy J. Senter, Arlington, MA (US); Jingrong Cao, Newton, MA (US); Jon H. Come, Cambridge, MA (US); Francois Denis, St-Lazare (CA); Warren A. Dorsch, Waltham, MA (US); Anne Fortier, Jamaica Plain, MA (US); Martine Hamel, Laval (CA); Elaine B. Krueger, Milton, MA (US); Brian Ledford, Norton, MA (US); Francois Maltais, Stoneham, MA (US); Suganthini S. Nanthakumar, Newton, MA (US); Olivier Nicolas, Montreal (CA); Camil E. Sayegh, Belmont, MA (US); Tiansheng Wang, Concord, MA (US); Stephanie Dorich, Pointe-Claire (CA); Lee Fader, Hawkesbury (CA); Claudio Sturino, Ile Bizard (CA); and Janek Szychowski, Montreal (CA)
Assigned to Vertex Pharmaceuticals Incorporated, Boston, MA (US)
Filed by Vertex Pharmaceuticals Incorporated, Boston, MA (US)
Filed on Jun. 11, 2021, as Appl. No. 17/345,268.
Claims priority of provisional application 63/040,183, filed on Jun. 17, 2020.
Claims priority of provisional application 63/038,275, filed on Jun. 12, 2020.
Prior Publication US 2023/0011118 A1, Jan. 12, 2023
This patent is subject to a terminal disclaimer.
Int. Cl. C07D 209/14 (2006.01); C07D 401/12 (2006.01); C07D 403/08 (2006.01); C07D 403/12 (2006.01); C07D 405/12 (2006.01); C07D 409/12 (2006.01); C07D 413/12 (2006.01); C07D 417/12 (2006.01); C07D 471/04 (2006.01)
CPC C07D 403/12 (2013.01) [C07D 209/14 (2013.01); C07D 401/12 (2013.01); C07D 403/08 (2013.01); C07D 405/12 (2013.01); C07D 409/12 (2013.01); C07D 413/12 (2013.01); C07D 417/12 (2013.01); C07D 471/04 (2013.01); C07B 2200/05 (2013.01)] 38 Claims
 
1. A compound, deuterated derivative, or pharmaceutically acceptable salt selected from compounds of Formula I:

OG Complex Work Unit Chemistry
deuterated derivatives thereof, and pharmaceutically acceptable salts of any of the foregoing, wherein
(i) R is selected from —NR3R4, —C(O)R3, —OR3, —NRSC(O)R3, —NRSC(O)OR3, —NR5SO2R3, and —NR5SO2NR3R4, wherein, when R is —C(O)R3, X is N or R3 is not bonded to the rest of the molecule through a nitrogen atom;
(ii) X is selected from N and CRX;
(iii) RX is absent or is selected from hydrogen, hydroxy, halogen, and C1-C3 linear and branched alkyl groups, wherein, when RX is absent, X is a bridgehead atom;
(iv) Ring A is a 4- to 7-membered cyclic alkyl or heterocycle, wherein the 4- to 7-membered heterocycle has one heteroatom and wherein the heteroatom is a nitrogen atom;
(v) each n is independently selected from 1, 2, and 3;
(vi) each R1 is independently selected from:
halogen,
amino, and
C1-C6 linear and branched haloalkyl groups;
(vii) each R2 is independently selected from:
halogen,
hydroxy,
amino,
cyano,
C1-C4 linear, branched, and cyclic alkyl groups,
C1-C4 linear, branched, and cyclic hydroxyalkyl groups,
C1-C4 linear, branched, and cyclic alkoxy groups,
C1-C4 linear, branched, and cyclic haloalkyl groups, and
C1-C4 linear, branched, and cyclic haloalkoxy groups;
(viii) R3 and R4 are independently selected from:
hydrogen,
C1-C6 linear and branched alkylsulfonyl groups optionally substituted with amino,
C1-C6 linear and branched alkoxy optionally substituted with 1-4 groups independently selected from hydroxy, amino, halogen, and oxo,
C1-C3 linear and branched aminoalkyl groups optionally substituted with 1-2 groups independently selected from amido,
C3-C6 cycloalkyl optionally substituted with 1-2 groups independently selected from:
halogen,
hydroxy,
oxo,
amido,
amino substituted with 1-2 groups independently selected from C1-C6 linear, C3-C6 branched, and C3-C6 cyclic alkyl groups,
aryl optionally substituted with 1-2 groups independently selected from halogen,
C1-C6 linear and branched alkoxy groups,
carbamate optionally substituted with C1-C6 linear or branched alkyl,
C1-C6 linear, C3-C6 branched, and C3-C6 cyclic alkyl groups optionally substituted with 1-3 groups independently selected from hydroxy, oxo, halogen, C1-C6 linear and branched alkoxy groups, and carbamate optionally substituted with 1-3 groups independently selected from C1-C6 linear and branched alkyl groups, and
C1-C3 hydroxyalkyl,
3- to 6-membered heterocyclyl optionally substituted with 1-3 groups independently selected from:
halogen,
oxo,
hydroxy,
C1-C6 linear and branched alkoxy groups optionally substituted with oxo,
C1-C6 linear, C3-C6 branched, and C3-C6 cyclic alkyl groups optionally substituted with 1-2 groups independently selected from hydroxy, oxo, and C1-C6 linear and branched alkoxy groups,
C1-C3 hydroxyalkyl and C1-C3 haloalkyl groups, and
carbamate optionally substituted with 1-2 groups independently selected from C1-C6 linear, C3-C6 branched, and C3-C6 cyclic alkyl groups,
aryl optionally substituted with 1-4 groups independently selected from halogen, hydroxy, and C1-C6 linear and branched alkyl groups optionally substituted with 1-2 groups independently selected from hydroxy and C1-C6 linear and branched alkoxy groups,
3- to 10-membered heteroaryl optionally substituted with 1-2 groups independently selected from amino, hydroxy, oxo, and C1-C6 linear alkyl optionally substituted with 1-3 groups independently selected from halogen and amino,
C1-C6 linear and branched alkyl groups optionally substituted with 1-4 groups independently selected from:
C1-C4 alkyl groups,
amino optionally substituted with 1-2 groups independently selected from C1-C6 linear and branched alkylsulfonyl groups and C1-C6 linear, C3-C6 branched, and C3-C6 cyclic alkyl groups (optionally substituted with 1-2 groups independently selected from oxo, hydroxy, amido, and C1-C6 linear and branched alkylsulfonyl groups),
hydroxy,
oxo,
cyano,
carboxylic acid,
carbamate optionally substituted with 1-2 groups independently selected from C1-C6 linear, C3-C6 branched, and C3-C6 cyclic alkyl groups,
halogen,
amido optionally substituted with 1-2 groups independently selected from C1-C6 linear, C3-C6 branched, and C3-C6 cyclic alkyl groups and C1-C6 linear, C3-C6 branched, and C3-C6 cyclic hydroxyalkyl groups,
C3-C6 cyclic alkyl optionally substituted with 1-2 groups independently selected from amino, halogen, hydroxy, oxo, C1-C3 alkyl, C1-C6 linear and branched alkoxy groups, and carbamate (which may be further substituted with C1-C4 linear or branched alkyl),
C1-C6 linear and branched alkoxy groups optionally substituted with hydroxy,
C1-C6 linear and branched alkylsulfonyl groups,
aryl optionally substituted with 1-2 groups independently selected from halogen, hydroxy, and C1-C6 linear and branched alkyl groups optionally substituted with 1-2 groups independently selected from hydroxy and C1-C6 linear and branched alkoxy groups,
4- to 10-membered heterocyclyl optionally substituted with 1-2 groups independently selected from halogen groups, oxo, hydroxy, amido optionally substituted with C1-C3 alkyl, and C1-C6 linear and branched alkyl groups optionally substituted with 1-2 groups independently selected from hydroxy and C1-C6 linear and branched alkoxy groups, and
4- to 10-membered heteroaryl optionally substituted with 1-3 groups independently selected from halogen groups, oxo, hydroxy, C1-C6 linear, C3-C6 branched, or C3-C6 cyclic alkyl optionally substituted with 1-3 groups independently selected from halogen, hydroxy, and C1-C6 linear and branched alkoxy groups, and amido groups optionally substituted with 1-2 groups independently selected from C1-C6 linear, C3-C6 branched, or C3-C6 cyclic alkyl,
or R3 and R4, together with the nitrogen atom to which they are attached, form a 3- to 10-membered heterocyclyl or heteroaryl optionally substituted with 1-3 groups independently selected from:
amino optionally substituted with 1-2 groups independently selected from C1-C6 linear, C3-C6 branched, and C3-C6 cyclic alkyl groups, which are optionally substituted with oxo,
halogen,
hydroxy,
oxo,
C1-C6 linear, C3-C6 branched, and C3-C6 cyclic alkyl groups optionally substituted with 1-2 groups independently selected from hydroxy, amino, and C1-C6 linear and branched alkoxy groups,
C1-C3 linear or branched hydroxyalkyl, and
amide optionally substituted with 1-2 groups independently selected from C1-C6 linear, C3-C6 branched, and C3-C6 cyclic alkyl groups; and
(ix) R5 is selected from hydrogen, hydroxy, halogen, and C1-C3 linear and branched alkyl groups.