US 11,884,672 B2
Modulators of alpha-1 antitrypsin
Upul Keerthi Bandarage, Lexington, MA (US); Cavan McKeon Bligh, Melrose, MA (US); Diane Boucher, South Hamilton, MA (US); Michael John Boyd, Sharon, MA (US); Michael Aaron Brodney, Newton, MA (US); Michael Philip Clark, Concord, MA (US); Veronique Damagnez, Boston, MA (US); Lev Tyler Dewey Fanning, San Marcos, CA (US); Robert Francis Fimognari, Brookline, MA (US); Gabrielle Simone Fleming, Boston, MA (US); Kevin James Gagnon, Burlington, MA (US); Pedro Manuel Garcia Barrantes, Melrose, MA (US); Robert Daniel Giacometti, Malden, MA (US); Simon Giroux, Cambridge, MA (US); Ronald Lee Grey, Jr., Mansfield, MA (US); Samantha Guido, Quincy, MA (US); Amy Beth Hall, Wellesley Hills, MA (US); Sarah Carol Hood, Worcester, MA (US); Dennis James Hurley, San Marcos, CA (US); Mac Arthur Johnson, Jr., Derry, NH (US); Peter Jones, Sharon, MA (US); Sarathy Kesavan, Quincy, MA (US); Mei-Hsiu Lai, Waltham, MA (US); Siying Liu, Malden, MA (US); Adam Looker, Newtonville, MA (US); Brad Maxwell, Holliston, MA (US); John Patrick Maxwell, Hingham, MA (US); Ales Medek, Winchester, MA (US); Philippe Marcel Nuhant, Dorchester, MA (US); Kirk Alan Overhoff, Lynn, MA (US); Setu Roday, Arlington, MA (US); Stefanie Roeper, Medford, MA (US); Steven M. Ronkin, Watertown, MA (US); Rupa Sawant, Wayland, MA (US); Yi Shi, Natick, MA (US); Muna Shrestha, Belmont, MA (US); Marisa Sposato, Cambridge, MA (US); Kathy Stavropoulos, Quincy, MA (US); Rebecca Jane Swett, Somerville, MA (US); Timothy Lewis Tapley, Cardiff, CA (US); Qing Tang, Boxborough, MA (US); Stephen Thomson, Del Mar, CA (US); Jinwang Xu, Framingham, MA (US); Mariam Zaky, Boston, MA (US); and Kevin Michael Cottrell, Cambridge, MA (US)
Assigned to Vertex Pharmaceuticals Incorporated, Boston, MA (US)
Filed by Vertex Pharmaceuticals Incorporated, Boston, MA (US)
Filed on May 13, 2020, as Appl. No. 15/931,256.
Claims priority of provisional application 63/004,813, filed on Apr. 3, 2020.
Claims priority of provisional application 62/847,562, filed on May 14, 2019.
Prior Publication US 2020/0361939 A1, Nov. 19, 2020
This patent is subject to a terminal disclaimer.
Int. Cl. C07D 487/04 (2006.01); A61K 9/16 (2006.01); A61K 31/4162 (2006.01); C07D 491/18 (2006.01); C07D 513/04 (2006.01); C07D 519/00 (2006.01); C07F 9/6561 (2006.01); C07H 15/26 (2006.01)
CPC C07D 487/04 (2013.01) [A61K 9/1635 (2013.01); A61K 9/1652 (2013.01); A61K 31/4162 (2013.01); C07D 491/18 (2013.01); C07D 513/04 (2013.01); C07D 519/00 (2013.01); C07F 9/6561 (2013.01); C07H 15/26 (2013.01); C07B 2200/13 (2013.01)] 11 Claims
 
1. A compound of formula (I):

OG Complex Work Unit Chemistry
a tautomer, a pharmaceutically acceptable salt, or a deuterated derivative thereof;
wherein:
(i) R0 is
(a) a C1-C8 linear, branched, or cyclic alkyl group, wherein the alkyl group is optionally substituted with 1-4 RA; or
(b) a 5- to 14-membered aromatic ring optionally substituted with 1-4 RA;
wherein each RA is independently a halogen, cyano, hydroxy, thiol, sulfonic acid, sulfonamide, sulfinamide, amino, amide, carboxylic acid, 5- to 10-membered aromatic ring, or a C1-C6 linear, branched, or cyclic group,
wherein the amide nitrogen atom in the amide of RA is optionally substituted with a heterocyclyl group that is optionally further substituted with oxo,
wherein each C1-C6 linear, branched, or cyclic group is, independently, an alkyl, alkoxy, thioalkyl, alkylsulfoxide, alkylsulfonyl, alkylsulfonamide, alkylsulfinamide, aminoalkyl, or alkylamide,
wherein each 5- to 10-membered aromatic ring or C1-C6 linear, branched, or cyclic group, independently, is optionally substituted with 1-4 substituents, wherein each substituent, independently, is a halogen, a C1-C6 linear, branched, or cyclic group, or a methoxy, or
wherein an RA group is optionally linked to an RB group or to an R2 group;
(ii) R1 is
(a) a hydrogen,
(b) a C1-C8 linear, branched, or cyclic alkyl group, wherein the alkyl group is optionally substituted with 1-4 substituents, wherein each substituent, independently, is a
halogen,
cyano,
cyanoalkyl,
hydroxy,
alkylsulfonyl, or
C1-C6 linear, branched, or cyclic group, wherein the C1-C6 linear, branched, or cyclic group is an alkyl or alkoxy group, and wherein the C1-C6 linear, branched, or cyclic group is optionally substituted with 1-4 substituents, wherein each substituent, independently, is a
halogen,
hydroxy, or
C1-C6 linear, branched, or cyclic alkoxy group,
(c) a C1-C8 linear, branched, or cyclic alkoxy or cyclic thioalkyl group optionally substituted with 1-4 substituents, wherein each substituent independently is a
halogen,
cyano,
cyanoalkyl;
sulfone,
sulfonamide,
hydroxy, or
a C1-C6 linear, branched, or cyclic alkyl group optionally substituted with 1-4 halogens or alkoxy groups;
(d) a C1-C6 linear, branched, or cyclic alkylsulfonyl group optionally substituted with C1-C6 linear or branched alkyl groups;
(e) an aminosulfonyl group, optionally substituted with 1 or 2 substituents, wherein each substituent independently is a
C1-C6 linear, branched, or cyclic alkyl group;
(f) a C1-C6 linear, branched, or cyclic alkylsulfonyl amino group;
(g) a phosphine oxide group, optionally substituted with 1 or 2 substituents, wherein each substituent, independently, is a
C1-C6 linear, branched, or cyclic alkyl group;
(h) a C1-C6 linear, branched, or cyclic trialkylsilyl group; or
(i) a C1-C6 alkylamide;
(iii) R2 is

OG Complex Work Unit Chemistry
(iv) each of X1 and X2, independently, is a hydrogen, halogen, cyano, hydroxy, C1-C6 linear, branched, or cyclic group, wherein each C1-C6 linear, branched, or cyclic group, independently, is an alkyl, alkoxy, thioalkyl, or aminoalkyl group, and wherein each C1-C6 linear, branched, or cyclic group is optionally substituted by 1-4 independently chosen halogens;
(v) each of W1 and W2 independently is a C or N;
(vi) each

OG Complex Work Unit Chemistry
 is a single or double bond, provided that no more than one

OG Complex Work Unit Chemistry
 is a double bond;
(vii) each R3 independently, is a hydrogen, halogen, cyano, C1-C6 linear, branched, or cyclic alkyl group, or C1-C6 linear, branched, or cyclic alkoxy group, wherein the C1-C6 linear, branched, or cyclic alkyl group and the C1-C6 linear, branched, or cyclic alkoxy group is optionally substituted with 1-4 substituents, wherein each substituent, independently, is a halogen, hydroxy or carboxylic acid;
(viii) n is 0, 1, 2, or 3; and
(ix) two of Z1, Z2, and Z3 are nitrogen, and the third is carbon or nitrogen, wherein the valences of carbon or nitrogen are completed with hydrogen, halogen, C1-C6 linear, branched, or cyclic alkyl groups, or C1-C6 linear, branched, or cyclic alkoxy groups, wherein the C1-C6 linear, branched, or cyclic alkyl groups and the C1-C6 linear, branched, or cyclic alkoxy groups are optionally substituted with 1-4 substituents, wherein each substituent, independently, is halogen, hydroxy, or carboxylic acid.