IP Library › Granted Patent US 12,528,808
Granted Patent B2
US 12,528,808 · App. 17/612,638 · Granted Jan 20, 2026

Therapy for erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP)

Inventors: Xiaochao Ma (Sewickley, PA); Junjie Zhu (Pittsburgh, PA); Jie Lu (Wexford, PA)
Assignee: UNIVERSITY OF PITTSBURGH OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION
C07D471/14A61K31/4985A61P1/16A61P35/00C07K14/705C12N9/14C12Y306/03044
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Quick Facts
Patent No.
US 12,528,808
App. No.
17/612,638
Granted
Jan 20, 2026
Kind
B2
Abstract

Disclosed are novel compositions and methods of using the same for the treatment of Erythropoiefic protoporphyria (EPP) and X-linked protoporphyria (XLP). Disclosed are methods and compositions related to treating Erythropoietic protoporphyria and X-linked protoporphyria. Also described are therapeutic agents that can inhibit ABCG2. For example, provided herein are therapeutic agents defined by Formula I.

Claims (29)

1 . A compound defined by Formula IA below

wherein

n is an integer of from 0 to 6;

R 6 and R 7 are each independently selected from the group consisting of H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-4 haloalkyl, C 3-10 cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-4 haloalkyl, C 3-10 cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, are optionally substituted with 1, 2, 3, or 4 independently selected R A groups, or R 6 and R 7 , together with the N atom to which they are attached, form a 4-9 membered heterocycloalkyl group or a 5-6 membered heteroaryl group, each optionally substituted with 1, 2, or 3 independently selected R A groups; and

each R A is independently selected from OH, NO 2 , CN, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-4 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, cyano-C 1-3 alkyl, HO-C 1-3 alkyl, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, thio, C 1-6 alkylthio, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, carbamyl, C 1-6 alkylcarbamyl, di(C 1-6 alkyl) carbamyl, carboxy, C 1-6 alkylcarbonyl, C 1-6 alkoxycarbonyl, C 1-6 alkylcarbonylamino, C 1-6 alkylsulfonylamino, aminosulfonyl, C 1-6 alkylaminosulfonyl, di(C 1-6 alkyl)aminosulfonyl, aminosulfonylamino, C 1-6 alkylaminosulfonylamino, di(C 1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C 1-6 alkylaminocarbonylamino, and di(C 1-6 alkyl)aminocarbonylamino;

or a pharmaceutically acceptable salt, ester, or N-oxide thereof.

2 . A compound defined by Formula IB below

wherein

n is an integer of from 0 to 6;

R 8 and R 9 are independently selected from the group consisting of H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-4 haloalkyl, C 3-10 cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-4 haloalkyl, C 3-10 cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, are optionally substituted with 1, 2, 3, or 4 independently selected R A groups, or R 8 and R 9 , together with the atoms to which they are attached, form a 4-9 membered heterocycloalkyl group or a 5-6 membered heteroaryl group, each optionally substituted with 1, 2, or 3 independently selected R A groups; and

each R A is independently selected from OH, NO 2 , CN, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-4 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, cyano-C 1-3 alkyl, HO-C 1-3 alkyl, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, thio, C 1-6 alkylthio, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, carbamyl, C 1-6 alkylcarbamyl, di(C 1-6 alkyl) carbamyl, carboxy, C 1-6 alkylcarbonyl, C 1-6 alkoxycarbonyl, C 1-6 alkylcarbonylamino, C 1-6 alkylsulfonylamino, aminosulfonyl, C 1-6 alkylaminosulfonyl, di(C 1-6 alkyl)aminosulfonyl, aminosulfonylamino, C 1-6 alkylaminosulfonylamino, di(C 1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C 1-6 alkylaminocarbonylamino, and di(C 1-6 alkyl)aminocarbonylamino;

or a pharmaceutically acceptable salt, ester, or N-oxide thereof.

3 . A compound defined by Formula IC below

wherein

n is an integer of from 0 to 6;

R 6 and R 7 are each independently selected from the group consisting of H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-4 haloalkyl, C 3-10 cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-4 haloalkyl, C 3-10 cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, are optionally substituted with 1, 2, 3, or 4 independently selected R A groups, or R 6 and R 7 , together with the N atom to which they are attached, form a 4-9 membered heterocycloalkyl group or a 5-6 membered heteroaryl group, each optionally substituted with 1, 2, or 3 independently selected R A groups; and

each R A is independently selected from OH, NO 2 , CN, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-4 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, cyano-C 1-3 alkyl, HO-C 1-3 alkyl, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, thio, C 1-6 alkylthio, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, carbamyl, C 1-6 alkylcarbamyl, di(C 1-6 alkyl) carbamyl, carboxy, C 1-6 alkylcarbonyl, C 1-6 alkoxycarbonyl, C 1-6 alkylcarbonylamino, C 1-6 alkylsulfonylamino, aminosulfonyl, C 1-6 alkylaminosulfonyl, di(C 1-6 alkyl)aminosulfonyl, aminosulfonylamino, C 1-6 alkylaminosulfonylamino, di(C 1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C 1-6 alkylaminocarbonylamino, and di(C 1-6 alkyl)aminocarbonylamino;

or a pharmaceutically acceptable salt, ester, or N-oxide thereof.

4 . A compound defined by Formula ID below

wherein

n is an integer of from 0 to 6;

X is selected from the group consisting of CH 2 , O and S;

R 10 is selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-4 haloalkyl, C(O)R b , C 3-10 cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-4 haloalkyl, C 3-10 cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, are optionally substituted with 1, 2, 3, or 4 independently selected R A groups; and

each R A is independently selected from OH, NO 2 , CN, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-4 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, cyano-C 1-3 alkyl, HO-C 1-3 alkyl, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, thio, C 1-6 alkylthio, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, carbamyl, C 1-6 alkylcarbamyl, di(C 1-6 alkyl) carbamyl, carboxy, C 1-6 alkylcarbonyl, C 1-6 alkoxycarbonyl, C 1-6 alkylcarbonylamino, C 1-6 alkylsulfonylamino, aminosulfonyl, C 1-6 alkylaminosulfonyl, di(C 1-6 alkyl)aminosulfonyl, aminosulfonylamino, C 1-6 alkylaminosulfonylamino, di(C 1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C 1-6 alkylaminocarbonylamino, and di(C 1-6 alkyl)aminocarbonylamino;

or a pharmaceutically acceptable salt, ester, or N-oxide thereof.

5 . A method of treating multidrug resistance in a tumor or cancer in a subject in need thereof by inhibiting ABCG2 transporter activity, reducing resistance of a tumor or cancer to a chemotherapeutic agent by inhibiting ABCG2 in a mammal, enhancing the chemotherapeutic treatment of tumor or cancer with a chemotherapeutic agent or increasing the bioavailability of an ABCG2 substrate drug in a mammal, the method comprising administering to the subject a therapeutically effective amount of a compound of claim 1 .

6 . A method of treating multidrug resistance in a tumor or cancer in a subject in need thereof by inhibiting ABCG2 transporter activity, reducing resistance of a tumor or cancer to a chemotherapeutic agent by inhibiting ABCG2 in a mammal, enhancing the chemotherapeutic treatment of tumor or cancer with a chemotherapeutic agent, or increasing the bioavailability of an ABCG2 substrate drug in a mammal, the method comprising administering to the subject a therapeutically effective amount of a compound of claim 2 .

7 . A method of treating multidrug resistance in a tumor or cancer in a subject in need thereof by inhibiting ABCG2 transporter activity, reducing resistance of a tumor or cancer to a chemotherapeutic agent by inhibiting ABCG2 in a mammal, enhancing the chemotherapeutic treatment of tumor or cancer with a chemotherapeutic agent, or increasing the bioavailability of an ABCG2 substrate drug in a mammal, the method comprising administering to the subject a therapeutically effective amount of a compound of claim 3 .

8 . A method of treating multidrug resistance in a tumor or cancer in a subject in need thereof by inhibiting ABCG2 transporter activity, reducing resistance of a tumor or cancer to a chemotherapeutic agent by inhibiting ABCG2 in a mammal, enhancing the chemotherapeutic treatment of tumor or cancer with a chemotherapeutic agent, or increasing the bioavailability of an ABCG2 substrate drug in a mammal, the method comprising administering to the subject a therapeutically effective amount of a compound of claim 4 .

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Dec 16, 2021
From: MA, XIAOCHAO; ZHU, JUNJIE; LU, JIE
To: UNIVERSITY OF PITTSBURGH-OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION
Reel/Frame 058411/0344 →
Continuity (2)
Provisional Application 62850061 · May 20, 2019
Related Publication 20220249473A1 · Aug 11, 2022
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