Methods of treating liver diseases

Patent metadata

Field	Value
Publication number	US-10064839-B2
Application number	US-201615385248-A
Country	US
Kind code	B2
Filing date	Dec 20, 2016
Priority date	Nov 5, 2012
Publication date	Sep 4, 2018
Grant date	Sep 4, 2018

Abstract

The invention provides tricyclic compounds and their use in treating liver disorders, such as non-alcoholic steatohepatitis and related disorders (e.g., fibrosis). The compounds are contemplated to have activity against methionyl aminopeptidase 2.

First claim

What is claimed is:

1. A method of reducing hepatic fat in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound represented by:

wherein:
X 2 is + —W 2 —C(R D5 R D6 )—*; wherein the + and * indicate the attachment points of X 2 as indicated in Formula IV;
R B1 is selected from the group consisting of H, F, OH, CN, C 1-2 alkoxy and C 1-3 alkyl; wherein C 1-3 alkyl and C 1-2 alkoxy are optionally substituted by a group selected from OH, C 1-2 alkoxy, CN and one or more fluorine atoms;
R A1 is selected, independently for each occurrence, from the group consisting of hydrogen, hydroxyl, cyano, halogen, C 1-4 alkyl and C 1-3 alkoxy; wherein C 1-4 alkyl, and C 1-3 alkoxy may be optionally substituted by one or more fluorines;
n is 0, 1, or 2;
R A2 is selected from the group consisting of hydrogen, R i R j N—, heterocyclyl, heterocyclyloxy and heterocyclyl-(NR a )—; wherein said heterocyclyl may optionally be substituted by one or more substituents selected from R g and wherein if said heterocyclyl contains a —NH moiety that nitrogen may optionally be substituted by one or more groups R h ; or
R A2 is selected from the group consisting of: C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 3-6 alkenyloxy, C 3-6 alkynyloxy, C 3-6 cycloalkoxy, C 1-6 alkyl-S(O) w — (wherein w is 0, 1 or 2), C 1-6 alkyl-N(R a )—, C 1-6 alkyl-N(R a )-carbonyl-, C 1-6 alkylcarbonyl-N(R a )—, C 1-6 alkyl-N(R a )-carbonyl-N(R a )—, C 1-6 alkyl-N(R a )—SO 2 —, C 1-6 alkyl-SO 2 —N(R a )—, C 1-6 alkoxycarbonyl-N(R a )—, C 1-6 alkylcarbonyl-N(R a )—C 1-6 alkyl-, C 1-6 alkyl-N(R a )-carbonyl-C 1-6 alkyl-, and C 1-6 alkoxyC 1-6 alkyl-; wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 3-6 alkenyloxy, C 3-6 alkynyloxy, C 3-6 cycloalkoxy, C 1-6 alkyl-S(O) w —, C 1-6 alkyl-N(R a )—, C 1-6 alkyl-N(R a )-carbonyl-, C 1-6 alkylcarbonyl-N(R a )—, C 1-6 alkyl-N(R a )-carbonyl-N(R a )—, C 1-6 alkyl-N(R a )—SO 2 —, C 1-6 alkyl-SO 2 —N(R a )—, C 1-6 alkoxycarbonyl-N(R a )—, C 1-6 alkylcarbonyl-N(R a )C 1-6 alkyl-, C 1-6 alkyl-N(R a )-carbonyl-C 1-6 alkyl-, and C 1-6 alkoxy-C 1-6 alkyl may optionally be substituted by R P , phenyl, phenoxy, heteroaryl, heteroaryloxy, heteroaryl-(NR a )—, heterocyclyl, heterocyclyloxy or heterocyclyl-N(R a )—; and wherein said heteroaryl or phenyl may optionally be substituted with one or more substituents selected from R f ; and wherein said heterocyclyl may optionally be substituted by one or more substituents selected from R g ; and wherein if said heterocyclyl contains a —NH moiety that nitrogen may optionally be substituted by one or more groups R h ;
R D5 and R D6 are each independently selected from the group consisting of hydrogen, fluorine, hydroxyl, cyano, C 1-2 alkyl and C 1-2 alkoxy; wherein the C 1-2 -alkyl and C 1-2 alkoxy may optionally be substituted by a substituent or substituents selected from the group consisting of: one or more fluorine atoms, cyano, hydroxyl and N(R a R b );
R a and R b are independently selected, for each occurrence, from the group consisting of hydrogen and C 1-3 alkyl; wherein C 1-3 alkyl may optionally be substituted by one or more substituents selected from fluorine, cyano, oxo and hydroxyl;
or R a and R b , together with the nitrogen to which they are attached, may form a 4-6 membered heterocyclic ring, which may have an additional heteroatom selected from O, S, and N; wherein the 4-6 membered heterocyclic ring may optionally be substituted by one or more substituents selected from the group consisting of fluorine, cyano, oxo and hydroxyl;
R f is independently selected, for each occurrence, from the group consisting of R P , hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkyl-S(O) w —, (wherein w is 0, 1 or 2), C 1-6 alkylcarbonyl-N(R a )— and C 1-6 alkoxycarbonyl-N(R a )—; wherein C 1-6 alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkyl-S(O) w —, C 1-6 alkylcarbonyl-N(R a )—, and C 1-6 alkoxycarbonyl-N(R a )— may be optionally substituted by one or more substituents selected from R P ;
R g is independently selected for each occurrence from the group consisting of R P , hydrogen, oxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 alkyl-S(O) w —, (wherein w is 0, 1 or 2), C 1-6 alkylcarbonyl-N(R a )— and C 1-6 alkoxycarbonyl-N(R a )—; wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 alkyl-S(O) w —, C 1-6 alkylcarbonyl-N(R a )—, and C 1-6 alkoxycarbonyl-N(R a )— may be optionally substituted by one or more substituents selected from R P ;
R h is independently selected for each occurrence from the group consisting of hydrogen, C 1-6 alkyl, C 3-6 alkenyl, C 3-6 alkynyl, C 3-6 cycloalkyl, C 1-6 alkyl-S(O) 2 —, C 1-6 alkoxycarbonyl-, R i R j N-carbonyl- and R i R j —N—SO 2 —; wherein C 1-6 alkyl, C 3-6 alkenyl, C 3-6 alkynyl, C 3-6 cycloalkyl C 1-6 alkyl-S(O) 2 —, and C 1-6 alkoxycarbonyl- may optionally be substituted by one or more substituents selected from R P ;
R i and R j are selected independently for each occurrence from the group consisting of hydrogen, C 1-4 alkyl, C 3-6 cycloalkyl, heterocyclyl and heterocyclylcarbonyl; wherein C 1-4 alkyl and C 3-6 cycloalkyl may be optionally substituted by one or more substituents selected from fluorine, hydroxyl, cyano, R a R b N—, R a R b N-carbonyl- and C 1-3 alkoxy and wherein heterocyclyl and heterocyclylcarbonyl may be optionally substituted by one or more substituents selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 1-6 alkoxy, halo-C 1-6 -alkyl, hydroxyl-C 1-6 -alkyl, R a R b N—C 1-6 alkyl- and C 1-6 -alkoxy-C 1-6 -alkyl group; and wherein if said heterocyclyl or heterocyclylcarbonyl contains a —NH moiety that nitrogen may optionally be substituted by one or more groups selected from C 1-6 alkyl, C 3-6 alkenyl, C 3-6 alkynyl, C 3-6 cycloalkyl, C 1-6 alkyl-S(O) 2 — and C 1-6 -alkylcarbonyl; or R i and R j taken together with the nitrogen to which they are attached form a 4-7 membered heterocyclic ring, which may have an additional heteroatom selected from O, S, or N; wherein the 4-7 membered heterocyclic ring may be optionally substituted on carbon by one or more substituents selected from the group consisting of fluorine, hydroxyl, oxo, cyano, C 1-6 alkyl, C 1-6 alkoxy, R a R b N—, R a R b N—SO 2 — and R a R b N-carbonyl-; wherein said C 1-6 alkyl or C 1-6 alkoxy may optionally be substituted by fluorine, hydroxyl or cyano; and wherein the 4-7 membered heterocyclic ring may be optionally substituted on nitrogen by one or more substituents selected from the group consisting of C 1-6 alkyl and R a R b N-carbonyl-; and wherein said C 1-6 alkyl may be optionally substituted by one or more substituents selected from the group consisting of fluorine, hydroxyl, and cyano;
R P is independently selected, for each occurrence, from the group consisting of halogen, hydroxyl, cyano, C 1-6 alkoxy, R i R j N—, R i R j N-carbonyl-, R i R j N—SO 2 — and R i R j N-carbonyl-N(R a )—; and pharmaceutically acceptable salts and stereoisomers thereof.

2. The method of claim 1 , wherein the patient is suffering from a fatty liver disease selected from the group consisting of: non-alcoholic steatohepatitis, liver cirrhosis, focal fatty liver, and hepatocellular carcinoma.

3. The method of claim 1 , wherein the patient is a human.

4. The method of claim 1 , wherein the compound is administered orally.

5. A method of reducing hep

Assignees

• Zafgen Inc

Inventors

• Hughes Thomas E
• Vath James E

Classifications

• A61P3/06

  Antihyperlipidemics · CPC title

• A61P31/06

  for tuberculosis · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P7/00

  Drugs for disorders of the blood or the extracellular fluid · CPC title