Modulators of alpha-1 antitrypsin

Patent metadata

Field	Value
Publication number	US-11623924-B2
Application number	US-201916593118-A
Country	US
Kind code	B2
Filing date	Oct 4, 2019
Priority date	Oct 5, 2018
Publication date	Apr 11, 2023
Grant date	Apr 11, 2023

Abstract

Novel compounds, compositions, and methods of using and preparing the same, which may be useful for treating alpha-1 antitrypsin deficiency (AATD).

First claim

The invention claimed is:

1. A compound of formula (I):

a tautomer thereof, a pharmaceutically acceptable salt of the compound or the tautomer, or a deuterated derivative of the compound, the tautomer, or the pharmaceutically acceptable salt;
wherein:
(i) R 0 is chosen from
(a) C 1 -C 8 linear, branched, and cyclic alkyl groups, wherein the alkyl group is optionally substituted with 1-4 R A ; and
(b) 5- to 10-membered aromatic rings optionally substituted with 1-4 R A ,
wherein each R A is independently chosen from halogens, cyano, hydroxy, thiol, sulfonic acid, sulfonamide, sulfinamide, amino, amide, 5- to 10-membered aromatic rings, and C 1 -C 6 linear, branched, and cyclic groups, wherein the C 1 -C 6 linear, branched, and cyclic groups are chosen from alkyl, alkoxy, thioalkyl, alkylsulfoxide, alkylsulfonyl, alkylsulfonamide, alkylsulfinamide, aminoalkyl, and alkylamide, and wherein the 5- to 10-membered aromatic rings and C 1 -C 6 linear, branched, and cyclic groups are optionally substituted with 1-4 substituents chosen from halogens and methoxy;

(ii) R 1 is chosen from
(a) C 1 -C 8 linear, branched, and cyclic alkyl groups, wherein the alkyl group is optionally substituted with 1-4 substituents chosen from
halogens,
carboxylic acid,
cyano, and
C 1 -C 6 linear, branched, and cyclic groups, wherein the C 1 -C 6 linear, branched, and cyclic groups are chosen from alkyl and alkoxy groups, and wherein the C 1 -C 6 linear, branched, and cyclic groups are optionally substituted with 1-4 halogens,

(b) C 1 -C 8 linear, branched, and cyclic alkoxy groups optionally substituted with 1-4 substituents chosen from
halogens,
cyano, and
C 1 -C 6 linear, branched, and cyclic alkyl groups that are optionally substituted with 1-4 halogens;

(c) C 1 -C 8 heterocycles, and
(d) C 2 -C 6 linear, branched, and cyclic alkenyl groups;

(iii) R 2 is chosen from:
hydrogen,
cyano,
halogens,
alkylamide groups,
C 1 -C 8 linear, branched, and cyclic alkyl groups optionally substituted with one or more groups independently chosen from:
an oxo group,
a C 1 -C 8 linear, branched, and cyclic alkoxy group,
a 5- or 6-membered heteroaryl group,
a cyano group,
an amino group,
an aminoalkyl group,
an alkylamide group,
an alkylsulfonyl group,
an alkylsulfonamide group,
an alkylsulfoxide group,
a group

 wherein R B is chosen from amino groups, C 1 -C 8 linear, branched, and cyclic alkyl groups, and O—R C groups, wherein R C is chosen from C 1 -C 8 linear, branched, and cyclic alkyl groups substituted with an aryl group,
a group N—C(O)—R B wherein R B is chosen from amino groups, C 1 -C 8 linear, branched, and cyclic alkyl groups, and O—R C , wherein R C is chosen from C 1 -C 8 linear, branched, and cyclic alkyl groups substituted with an aryl group,
a

 group, wherein the Ring A is chosen from 4-8 membered rings optionally containing one or two heteroatoms in addition to the Ring A nitrogen, and
a carboxylic acid group esterified with a uronic acid,

C 2 -C 6 linear, branched, and cyclic alkenyl groups,
C 2 -C 6 linear, branched, and cyclic alkynyl groups,
A-CO 2 R 4 groups wherein A is optionally present and if present is chosen from
C 1 -C 8 linear, branched, and cyclic alkyl and alkoxy groups,
C 2 -C 6 linear, branched, and cyclic alkenyl groups,
C 3 -C 8 cycloalkyl linked to C 1 -C 8 linear or branched alkyl groups,
C 1 -C 8 linear or branched alkyl linked to C 3 -C 8 cycloalkyl groups,
C 3 -C 8 cycloalkyl linked to C 3 -C 8 cycloalkyl groups, and
C 1 -C 8 linear, branched, and cyclic alkyl linked to C 3 -C 8 cycloalkyl linked to a C 1 -C 8 linear, branched, and cyclic alkyl groups,
wherein up to 3 carbon atoms of A are optionally substituted with 1-4 halogens or 1-3 C 1 -C 4 linear, branched, or cyclic groups, wherein the C 1 -C 4 linear, branched, or cyclic groups are chosen from alkyl and alkoxy groups, and wherein the linear, branched, or cyclic C 1 -C 4 groups are optionally substituted with 1-4 halogens, and

wherein R 4 is chosen from hydrogen, C 1 -C 8 linear, branched, and cyclic alkyl groups, and C 2 -C 6 linear, branched, and cyclic alkenyl groups,

A-C(O)NH 2 groups wherein A is optionally present and if present is chosen from
C 1 -C 8 linear, branched, and cyclic alkyl and alkoxy groups,
C 2 -C 6 linear, branched, and cyclic alkenyl groups,
C 3 -C 8 cycloalkyl linked to C 1 -C 8 linear or branched alkyl groups,
C 1 -C 8 linear or branched alkyl linked to C 3 -C 8 cycloalkyl groups,
C 3 -C 8 cycloalkyl linked to C 3 -C 8 cycloalkyl groups, and
C 1 -C 8 linear, branched, and cyclic alkyl linked to C 3 -C 8 cycloalkyl linked to a C 1 -C 8 linear, branched, and cyclic alkyl groups,
wherein up to 3 carbon atoms of A are optionally substituted with 1-4 halogens or 1-3 C 1 -C 4 linear, branched, or cyclic groups, wherein the C 1 -C 4 linear, branched, or cyclic groups are chosen from alkyl and alkoxy groups, and wherein the linear, branched, or cyclic C 1 -C 4 groups are optionally substituted with 1-4 halogens, and

C(O)NR 6 R 7 wherein R 6 and R 7 are independently chosen from hydrogen,
C 1 -C 8 linear, branched, and cyclic alkyl groups,
C 2 -C 6 linear, branched, and cyclic alkenyl groups,
4- to 8-membered heterocycles optionally substituted by one or more substituents chosen from cyano and halogens,
C 1 -C 8 linear, branched, and cyclic alkyl groups, and
C 2 -C 6 linear, branched, and cyclic alkenyl groups,
or R 6 and R 7 together with the nitrogen to which they are attached form a 4-8 membered ring optionally containing one or two heteroatoms in addition to the nitrogen to which they are attached, and which 4-8 membered ring is optionally substituted with a substituent chosen from halogens, cyano, hydroxy, and C 1 -C 6 linear, branched, and cyclic alkyl groups, and

SO 2 R 5 groups wherein R 5 is chosen from C 1 -C 8 linear, branched, and cyclic alkyl groups, and C 2 -C 6 linear, branched, and cyclic alkenyl groups, and

 groups, wherein the Ring A is a 4-8 membered ring optionally containing one or two heteroatoms in addition to the Ring A nitrogen;

(iv) X 1 and X 2 are independently chosen from hydrogen, halogens, cyano, hydroxy, C 1 -C 6 linear, branched, and cyclic groups wherein the C 1 -C 6 linear, branched, and cyclic groups are chosen from alkyl, alkoxy, thioalkyl, and aminoalkyl groups, and wherein the C 1 -C 6 linear, branched, and cyclic groups are optionally substituted by 1-4 halogens;
(v) each represents a single or double bond, provided that no more than one is a double bond;
(vi) each R 3 is independently chosen from hydrogen, halogens, cyano, C 1 -C 6 linear, branched, and cyclic alkyl groups, and C 1 -C 6 linear, branched, and cyclic alkoxy groups, wherein the linear, branched, and cyclic alkyl and the linear, branched, and cyclic alkoxy groups are optionally substituted with 1-4 halogens;
(vii) n is an integer chosen from 0, 1, 2, and 3; and
(viii) Z 1 and Z 2 are nitrogen, and Z 3 is chosen from carbon and nitrogen, wherein the valences of carbon and nitrogen are completed with hydrogen

Assignees

• Vertex Pharma

Inventors

• Bandarage Upul Keerthi
• Bligh Cavan Mckeon
• Boyd Michael John
• Boucher Diane M
• Brodney Michael Aaron
• Damagnez Veronique
• Dewey Fanning Lev Tyler
• Eccles Mary Elizabeth
• Fimognari Jr Robert Francis
• Gagnon Kevin James
• Garcia Barrantes Pedro M
• Giroux Simon
• Grey Jr Ronald Lee
• Hall Amy Beth
• Hood Sarah Carol
• Hurley Dennis James
• Hussey Joshua Kennedy
• Johnson Jr Mac Arthur
• Jones Peter
• Kesavan Sarathy
• Looker Adam
• Maxwell Brad D
• Maxwell John Patrick
• Medek Ales
• Navamal Mettachit
• Nuhant Philippe Marcel
• Roday Setu
• Roeper Stefanie
• Sawant Rupa
• Shi Yi
• Swett Rebecca Jane
• Tang Qing
• Tapley Timothy Lewis
• Thomson Stephen A
• Waldo Michael
• Xu Jinwang
• Cottrell Kevin Michael

Classifications

• A61P1/16

  for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics · CPC title

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• C07D471/14

  Ortho-condensed systems · CPC title

• C07D403/04 Primary

  directly linked by a ring-member-to-ring-member bond · CPC title

• A61K31/4162

  condensed with heterocyclic ring systems · CPC title