Tricyclic sulfonamide compounds and methods of making and using same

Patent metadata

Field	Value
Publication number	US-9359369-B2
Application number	US-201314372893-A
Country	US
Kind code	B2
Filing date	Jan 17, 2013
Priority date	Jan 18, 2012
Publication date	Jun 7, 2016
Grant date	Jun 7, 2016

Abstract

The invention provides tricyclic sulfonamide compounds and their use in treating medical disorders, such as obesity. Pharmaceutical compositions and methods of making various tricyclic compounds are provided. The compounds are contemplated to have activity against methionyl aminopeptidase 2.

First claim

What is claimed is:

1. A tricyclic compound represented by:

wherein:
T, Y and Z are independently selected from the group consisting of: CH or N, and wherein one or two of T, Y and Z is nitrogen;
D is a 5-6 membered heterocyclic, carbocyclic or heteroaromatic ring;
X is selected from the group consisting of: + —W 1 —*, + —W 2 —C(R D3 R D4 )—*, + —W 2 —C(O)—*, + —C(R D1 R D2 )—W 3 —*, in which the attachment points are indicated by + and * in X and in Formula I;
W 1 is selected from the group consisting of: O, N(R N1 ) or S;
W 2 is selected from the group consisting of: O or N(R N2 );
W 3 is selected from the group consisting of: O or N(R N3 );
A is a ring selected from the group consisting of: phenyl, a 5-6 membered heteroaryl having 1, 2 or 3 heteroatoms each selected from S, N or O, and a 4-7 membered heterocycle having 1, 2 or 3 heteroatoms each selected from N or O;
R A1 is selected, independently for each occurrence, from the group consisting of: hydrogen, hydroxyl, cyano, halogen, C 1-4 alkyl or C 1-3 alkoxy; wherein C 1-4 alkyl, or C 1-3 alkoxy may be optionally substituted by one or more fluorines;
n is 1 or 2;
R A2 is selected from the group consisting of: hydrogen, R i R j N—, heterocyclyl, heterocyclyloxy, 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-, 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-, 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 D1 and R D2 are each independently selected from the group consisting of: hydrogen, fluorine, hydroxyl, C 1-2 alkyl or C 1-2 alkoxy; wherein the C 1-2 alkyl and C 1-2 alkoxy may optionally be substituted by one or more fluorine atoms or a group selected from cyano or hydroxyl;
R D3 and R D4 are each independently selected from the group consisting of: hydrogen, fluorine, hydroxyl, cyano, C 1-2 alkyl or C 1-2 alkoxy; wherein the C 1-2 alkyl and C 1-2 alkoxy may optionally be substituted by one or more fluorine atoms or a group selected from cyano, hydroxyl or N(R a R b );
R N1 is selected from the group consisting of: hydrogen or C 1-2 alkyl;
R N2 is selected from the group consisting of: hydrogen or C 1-2 alkyl;
R N3 is selected from the group consisting of: hydrogen, C 1-3 alkyl or C 1-2 alkylcarbonyl; wherein the C 1-3 alkyl and C 1-2 alkylcarbonyl may optionally be substituted by one or more fluorine atoms or a group selected from cyano, hydroxyl or 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, or N; and 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 or 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 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 )—; C 1-6 alkoxycarbonyl-N(R a )—; and wherein C 1-6 alkyl, C 3-6 cycloalkyl, 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 )—, 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 )—, 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 alkylcarbonyl-N(R a )—, 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-, 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 —, C 1-6 alkylcarbonyl- 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 and C 3-6 cycloalkyl; 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-, C 1-3 alkoxy;
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, 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 —, R a R b N-carbonyl-; and wherein said C 1-6 alkyl or C 1-6 alkoxy may optionally be substituted by fluorine, hydroxyl or cyano; and optionally substituted on nitrogen by one or more substituents selected from the group consisting of: C 1-6 alkyl, R a R b N-carbonyl-; and wherein said C 1-6 alkyl may be optionally substituted by fluorine, hydroxyl, 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-carbonyl-, R i R j N—SO 2 —, R i R j N-carbonyl-N(R a )—;
and pharmaceutically acceptable salts, stereoisomers, esters and prodrugs thereof.

2. The tricyclic compound of claim 1 , wherein X is selected from the group consisting of + —O—C(R D3 R D4 )—* or + —N(R N2 )—C(R D3 R D4 )—*.

Assignees

• Zafgen Inc

Inventors

• Pallin Thomas D
• Dyke Hazel J
• Cramp Susan M
• Zahler Robert

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• C07D491/052 Primary

  the oxygen-containing ring being six-membered · CPC title

• A61P3/04

  Anorexiants; Antiobesity agents · CPC title

• C07D487/04

  Ortho-condensed systems · CPC title