US2023265080A1PendingUtilityA1
Modulators of alpha-1 antitrypsin
Est. expiryOct 5, 2038(~12.2 yrs left)· nominal 20-yr term from priority
Inventors:Upul K. BandarageCavan Mckeon BlighMichael BoydDiane BoucherMichael Aaron BrodneyVeronique DamagnezLev Tyler Dewey FanningMary Elizabeth EcclesRobert Francis FimognariKevin GagnonPedro Manuel Garcia BarrantesSimon GirouxRonald Grey, Jr.Amy Beth HallSarah Carol HoodDennis James HurleyJoshua Kennedy HusseyMac Arthur Johnson, Jr.Peter JonesSarathy KesavanAdam LookerBrad D. MaxwellJohn Patrick MaxwellAles MedekMettachit NavamalPhilippe Marcel NuhantSetu RodayStefanie RoeperRupa SawantYi-Qun ShiRebecca Jane SwettQing TangTimothy Lewis TapleyStephen Andrew ThomsonMichael WaldoJinwang XuKevin Michael Cottrell
C07D 403/04C07D 519/00C07B 2200/05C07B 2200/13C07D 487/04C07D 487/14C07D 471/14A61P 11/00A61P 1/16A61K 31/4162A61K 31/5377A61K 31/496
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Claims
Abstract
Novel compounds, compositions, and methods of using and preparing the same, which may be useful for treating alpha-1 antitrypsin deficiency (AATD).
Claims
exact text as granted — not AI-modified1 - 42 . (canceled)
43 . A method of preparing a compound of formula I-3
a salt thereof, or a deuterated derivative of any of the foregoing, comprising an internal alkyne amine coupling reaction in a compound of Formula I-4
or a salt thereof,
wherein, in the compounds of Formula I-3 and compounds of Formula I-4:
(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 independently 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 independently 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 independently 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) 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;
(iv) each represents a single or double bond, provided that no more than one is a double bond;
(v) 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;
(vi) n is an integer chosen from 0, 1, 2, and 3; and
(vii) Z 1 , Z 2 , and Z 3 are independently chosen from carbon, nitrogen, sulfur, and oxygen, wherein when Z 1 , Z 2 , and/or Z 3 are carbon or nitrogen, the valences of carbon and nitrogen are completed with hydrogen atoms, C 1 -C 8 linear, branched, and cyclic alkyls, or cyano.
44 - 48 . (canceled)
49 . A method of preparing a compound of formula S3
a salt thereof, or a deuterated derivative of any of the foregoing, comprising reacting a compound of formula C4
with at least one acid.
50 . The method of claim 49 , wherein the compound of formula C4 is prepared by reacting a compound of formula C8
with 4-fluoroaniline in the presence of a palladium catalyst and at least one base.
51 . A method of preparing a compound of formula S6
a salt thereof, or a deuterated derivative of any of the foregoing, comprising heating a solution comprising a compound of formula C15
with at least one base.
52 . The method of claim 51 , further comprising reacting a compound of formula C14
with 4-fluoroaniline, at least one base, and at least one palladium precatalyst to prepare the compound of formula S6.
53 . A compound of formula I-2:
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 independently 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 independently 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) 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;
(iv) each represents a single or double bond, provided that no more than one is a double bond;
(v) 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 alkoxy groups are optionally substituted with 1-4 halogens;
(vi) n is an integer chosen from 0, 1, 2, and 3;
(vii) Z 1 , Z 2 , and Z 3 are independently chosen from carbon, nitrogen, sulfur, and oxygen, wherein when Z 1 , Z 2 , and/or Z 3 are carbon or nitrogen, the valences of carbon and nitrogen are completed with hydrogen atoms, C 1 -C 8 linear, branched, and cyclic alkyls, or cyano; and
(viii) PG is chosen from t-butyl carbamate (Boc), benzyl (Bn), tetrahydropyranyl (THP), 9-fluorenylmethyl carbamate (Fmoc) benzyl carbamate (Cbz), acetamide, trifluoroacetamide, triphenylmethylamine, benzylideneamine, and p-toluenesulfonamide with the proviso that at least one of Z 1 , Z 2 , or Z 3 is nitrogen.
54 . A compound of formula I-3:
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 independently 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 independently 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) 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;
(iv) each represents a single or double bond, provided that no more than one is a double bond;
(v) 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 alkoxy groups are optionally substituted with 1-4 halogens;
(vi) n is an integer chosen from 0, 1, 2, and 3; and
(vii) Z 1 , Z 2 , and Z 3 are independently chosen from carbon, nitrogen, sulfur, and oxygen, wherein when Z 1 , Z 2 , and/or Z 3 are carbon or nitrogen, the valences of carbon and nitrogen are completed with hydrogen atoms, C 1 -C 8 linear, branched, and cyclic alkyls, or cyano.
55 . A compound of formula I-4:
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 independently 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 independently 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 independently 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) 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;
(iv) each represents a single or double bond, provided that no more than one is a double bond;
(v) 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 alkoxy groups are optionally substituted with 1-4 halogens;
(vi) n is an integer chosen from 0, 1, 2, and 3; and
(vii) Z 1 , Z 2 , and Z 3 are independently chosen from carbon, nitrogen, sulfur, and oxygen, wherein when Z 1 , Z 2 , and/or Z 3 are carbon or nitrogen, the valences of carbon and nitrogen are completed with hydrogen atoms, C 1 -C 8 linear, branched, and cyclic alkyls, or cyano.
56 . A compound of formula I-5:
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 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 independently 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 independently 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;
(ii) 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;
(iii) each represents a single or double bond, provided that no more than one is a double bond;
(iv) 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 alkoxy groups are optionally substituted with 1-4 halogens;
(v) n is an integer chosen from 0, 1, 2, and 3;
(vi) Z 1 , Z 2 , and Z 3 are independently chosen from carbon, nitrogen, sulfur, and oxygen, wherein when Z 1 , Z 2 , and/or Z 3 are carbon or nitrogen, the valences of carbon and nitrogen are completed with hydrogen atoms, C 1 -C 8 linear, branched, and cyclic alkyls, or cyano; and
(vii) Y 1 is chosen from halogens.
57 . A compound of formula I-7:
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 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 independently 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 independently 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;
(ii) 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;
(iii) each represents a single or double bond, provided that no more than one is a double bond;
(iv) 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 alkoxy groups are optionally substituted with 1-4 halogens;
(v) n is an integer chosen from 0, 1, 2, and 3;
(vi) Z 1 , Z 2 , and Z 3 are independently chosen from carbon, nitrogen, sulfur, and oxygen, wherein when Z 1 , Z 2 , and/or Z 3 are carbon or nitrogen, the valences of carbon and nitrogen are completed with hydrogen atoms, C 1 -C 8 linear, branched, and cyclic alkyls, or cyano; and
(vii) Y 1 and Y 2 are independently chosen from halogens.
58 . A compound chosen from:
and tautomers thereof, deuterated derivatives of those compounds and tautomers, and salts of any of the foregoing.
59 . The compound of claim 58 , wherein the compound is chosen from:
and tautomers thereof, deuterated derivatives of those compounds and tautomers, and salts of any of the foregoing.
60 . The compound of claim 58 , wherein the compound is chosen from:
and tautomers thereof, deuterated derivatives of those compounds and tautomers, and salts of any of the foregoing.Join the waitlist — get patent alerts
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