Tricyclic compounds

Patent metadata

Field	Value
Publication number	US-9365579-B2
Application number	US-201514610119-A
Country	US
Kind code	B2
Filing date	Jan 30, 2015
Priority date	Jun 10, 2008
Publication date	Jun 14, 2016
Grant date	Jun 14, 2016

Abstract

The invention provide a compound of Formula (I)

pharmaceutically acceptable salts, pro-drugs, biologically active metabolites, stereoisomer and isomer thereof wherein the variable are defined herein. The compound of the invention are useful for treating immunological and oncological conditions.

First claim

What is claimed:

1. A method of preparing a compound of Formula (Ia)

or pharmaceutically acceptable salts, stereoisomer or isomer thereof, comprising:
converting a compound of Formula 2

into the compound of (Ia), wherein
R p is a hydrogen, —SO 2 N(CH 3 ) 2 , —SO 2 (2,4,6-trimethylphenyl), —SO 2 phenyl, —SO 2 (4-butylphenyl), —SO 2 (4-methylphenyl), —SO 2 (4-methoxyphenyl), —C(O)OCH 2 CCl 3 , —C(O)OCH 2 CH 2 Si(CH 3 ) 3 , —C(O)OC(CH 3 ) 3 , —C(O)OC(CH 3 ) 2 (CCl 3 ), —C(O)O—1-adamantyl, —CH═CH 2 , —CH 2 CH 2 Cl, —CH(OCH 2 CH 3 )CH 3 , —CH 2 CH 2 -2-pyridyl, —CH 2 CH 2 -4-pyridyl, —Si(C(CH 3 ) 3 )(CH 3 ) 2 , —Si(CH(CH 3 ) 2 ) 3 , —CH 2 phenyl, —CH 2 (4-CH 3 O-phenyl), —CH 2 (3,4-di-methoxyphenyl), —CH 2 (2-Nitrophenyl), -(2,4-dinitrophenyl), —CH 2 C(O)phenyl, —C(phenyl) 3 , —CH(phenyl) 2 , —C(phenyl) 2 (4-pyridyl), —N(CH 3 ) 2 , —CH 2 OH, —CH 2 OCH 3 , —CH(OCH 2 CH 3 ) 2 , —CH 2 OCH 2 CH 2 Cl, —CH 2 OCH 2 CH 2 Si(CH 3 ) 3 , —CH 2 OC(CH 3 ) 3 , —CH 2 OC(O)C(CH 3 ) 3 , —CH 2 OCH 2 phenyl, -(2-tetrahydropyranyl), —C(O)H, or —P(S)(phenyl) 2 ;
R 1 , R 2 and R 5 are each independently hydrogen, deuterium, —N(R a )(R b ), halogen, —OR a , —SR a , —S(O)R a , —S(O) 2 R a , —NO 2 , —C(O)OR a , —CN, —C(O)N(R a )(R b ), —N(R a )C(O)(R b ), —C(O)R a , —C(OH)R a R b , —N(R a )S(O) 2 —R b , —S(O) 2 N(R a )(R b ), —CF 3 , —OCF 3 , optionally substituted (C 1 -C 6 )alkyl, optionally substituted (C 2 -C 6 )alkenyl, optionally substituted (C 2 -C 6 )alkynyl, optionally substituted (C 3 -C 10 )cycloalkyl, optionally substituted (C 1 -C 10 )heteroaryl, optionally substituted (C 1 -C 10 )heterocyclyl, or optionally substituted (C 6 -C 10 )aryl;
wherein in a moiety containing —N(R a )(R b ), the nitrogen, R a and R b may form a ring such that —N(R a )(R b ) represents an optionally substituted (C 2 -C 10 )heterocyclyl or optionally substituted (C 1 -C 10 )heteroaryl linked through a nitrogen;
R 3 is hydrogen, an optionally substituted bridged (C 5 -C 12 )cycloalkyl, optionally substituted bridged (C 2 -C 10 )heterocyclyl, optionally substituted (C 1 -C 8 )alkyl, optionally substituted (C 3 -C 10 )cycloalkyl, optionally substituted (C 3 -C 8 )cycloalkenyl, optionally substituted (C 6 -C 10 )aryl, optionally substituted (C 1 -C 10 )heteroaryl, optionally substituted (C 2 -C 10 )heterocyclyl; or
R 3 is -A-D-E-G, wherein:
A is a bond, —C(O)—, optionally substituted (C 1 -C 6 )alkylene, optionally substituted (C 2 -C 6 )alkenylene, optionally substituted (C 2 -C 6 )alkynylene, optionally substituted (C 3 -C 12 )cycloalkylene, optionally substituted (C 2 -C 6 )heterocyclylene, —C(O)N(R a )—R e —, —N(R a )C(O)—R e —, —O—R e —, —N(R a )—R e —, —S—R e —, —S(O) 2 —R e —, —S(O)R e —, —C(O—R a )(R b )—R e —, —S(O) 2 N(R a )—R e —, —N(R a )S(O) 2 —R e — or —N(R a )C(O)N(R b )—R e —;
D is an optionally substituted (C 1 -C 8 )alkylene, optionally substituted bridged (C 5 -C 12 )cycloalkylene, optionally substituted (C 3 C 10 ) cycloalkylene, optionally substituted bridged (C 5 -C 10 )cycloalkenylene, optionally substituted (C 3 -C 10 )cycloalkenylene, optionally substituted (C 6 -C 10 )arylene, optionally substituted (C 1 -C 10 )heteroarylene, optionally substituted bridged (C 2 -C 10 )heterocyclylene or an optionally substituted (C 2 -C 10 )heterocyclylene;
E is a bond, —R e —, —R e —C(O)—R e —, —R e —C(O)C(O)—R e —, —R e —C(O)O—R e —, —R e —C(O)C(O)N(R a )—R e —, —R e —N(R a )—C(O)C(O)—R e —, —R e —O—R e —, —R e —S(O) 2 —R e —, —R e —S(O)—R e —, —R e —S—R e —, —R e —N(R a )—R e —, —R e —N(R a )C(O)—R e —, —R e C(O)N(R a )R e —, —R e —OC(O)N(R a )—R e —, —R e —N(R a )C(O)OR e —, —R e —OC(O)—R e , —R e —N(R a )C(O)N(R b )—R e —, —R e —N(R a )S(O) 2 —R e —, or —R e —S(O) 2 N(R a )—R e —; or
E is

where in all cases, E is linked to either a carbon or a nitrogen atom in D;
G is hydrogen, deuterium, —N(R a )(R b ), halogen, —OR a , —SR a , —S(O)R a , —S(O) 2 R a , —NO 2 , —C(O)OR a , —CN, —C(O)N(R a )(R b ), —N(R a )C(O)R b , —N(R a )C(O)OR b , —OC(O)N(R a ), —N(R a )C(O)N(R b ) 2 , —C(O-R a )(R b ) 2 , —C(O)R a , —CF 3 , —OCF 3 , —N(R a )S(O) 2 R b , —S(O) 2 N(R a )(R b ), —S(O) 2 N(R a )C(O)R b , an optionally substituted —(C 1 -C 6 )alkyl, an optionally substituted —(C 2 -C 6 )alkenyl, an optionally substituted —(C 2 -C 6 )alkynyl, an optionally substituted —(C 3 -C 10 )cycloalkyl, an optionally substituted —(C 1 -C 10 )heteroaryl, an optionally substituted —(C 1 -C 10 )heterocyclyl, an optionally substituted —(C 6 C 10 )aryl, an optionally substituted —(C 1 -C 6 )alkyl-(C 3 -C 10 )cycloalkyl, an optionally substituted —(C 1 -C 6 )alkyl-(C 6 -C 10 )aryl, an optionally substituted —(C 1 -C 6 )alkyl-(C 1 -C 10 )heteroaryl, or an optionally substituted —(C 1 -C 6 )alkyl-(C 1 -C 10 )heterocyclyl;
wherein in a moiety containing —N(R a )(R b ), the nitrogen, R a and R b may form a ring such that —N(R a )(R b ) represents an optionally substituted (C 2 -C 10 )heterocyclyl or an optionally substituted (C 1 -C 10 ) heteroaryl linked through a nitrogen;

R a and R b are each independently hydrogen, deuterium, an optionally substituted (C 1 -C 10 )alkyl, an optionally substituted (C 2 -C 10 )alkenyl, an optionally substituted (C 2 -C 10 )alkynyl, an optionally substituted (C 1 -C 10 )alkyl-O—(C 1 -C 10 )alkyl, an optionally substituted (C 3 -C 10 )cycloalkyl, an optionally substituted (C 6 -C 10 )aryl, an optionally substituted (C 1 -C 10 )heteroaryl, an optionally substituted (C 1 -C 10 )heterocyclyl, an optionally substituted —(C 1 -C 6 )alkylene-(C 3 -C 10 )cycloalkyl, an optionally substituted —(C 1 -C 6 )alkylene-(C 6 -C 10 )aryl, an optionally substituted —(C 1 -C 6 )alkylene-(C 1 -C 10 )heteroaryl, or an optionally substituted —(C 1 -C 6 )alkylene-(C 1 -C 10 )heterocyclyl; and
R e for each occurrence is independently a bond, an optionally substituted (C 1 -C 10 )alkylene, an optionally substituted (C 2 -C 10 )alkenylene, an optionally substituted (C 2 -C 10 )alkynylene, an optionally substituted —(C 1 -C 10 )alkylene-O—(C 1 -C 10 )alkylene group, an optionally substituted (C 3 -C 10 )cycloalkylene, an optionally substituted (C 6 -C 10 )arylene, an optionally substituted (C 1 -C 10 )heteroarylene, or an optionally substituted (C 1 -C 10 )heterocyclylene.

2. The method of claim 1 , comprising converting the compound of Formula 2 to compound 6 of the following structure:

and further comprising converting compound 6 to the compound of Formula (Ia), wherein
RP i—SO 2 N(CH 3 ) 2 , —SO 2 (2,4,6-trimethylphenyl), —SO 2 phenyl, —SO 2 (4-butylphenyl), —SO 2 (4-methylphenyl), —SO 2 (4-methoxyphenyl), —C(O)OCH 2 CCl 3 , —C(O)OCH 2 CH 2 Si(CH 3 ) 3 , —C(O)OC(CH 3 ) 3 , —C(O)OC(CH 3 ) 2 (CCl 3 ), —C(O)O—1-adamantyl, —CH═CH 2 , —CH 2 CH 2 Cl, —CH(OCH 2 CH 3 )CH 3 , —CH 2 CH 2 -2-pyridyl, —CH 2 CH 2 -4-pyridyl, —Si(C(CH 3 ) 3 )(CH 3 ) 2 , —Si(CH(CH 3 ) 2 ) 3 , —CH 2 phenyl, —CH 2 (4-CH 3 O-phenyl), —CH 2 (3,4-di-methoxyphenyl), —CH 2 (2-nitrophenyl), -(2,4-dinitrophenyl), —CH 2 C(O)phenyl, —C(phenyl) 3 , —CH(phenyl) 2 , —C(phenyl) 2 (4-pyridyl), —N(CH 3 ) 2 , —CH 2 OH, —CH 2 OCH 3 , —CH(OCH 2 CH 3 ) 2 , —CH 2 OCH 2 CH 2 Cl, —CH 2 OCH 2 CH 2 Si(CH 3 ) 3 , —CH 2 OC(CH 3 ) 3 , —CH 2 OC(O)C(CH 3 ) 3 , —CH 2 OCH 2 phenyl, -(2-tetrahydropyranyl), —C(O)H, or —P(S)(phenyl) 2 .

3. The method of claim 2 , wherein R P is —SO 2 N(CH 3 ) 2 , —SO 2 (2,4,6-trimethylphenyl), —SO 2 phenyl, —SO 2 (4-butylphenyl), —SO 2 (4-met

Assignees

• Abbvie Inc

Inventors

• Wishart Neil
• Argiriadi Maria A
• Calderwood David J
• Ericsson Anna M
• Fiamengo Bryan A
• Frank Kristine E
• Friedman Michael M
• George Dawn M
• Goedken Eric R
• Josephsohn Nathan S
• Li Biqin C
• Morytko Michael J
• Stewart Kent D
• Voss Jeffrey W
• Wallace Grier A
• Wang Lu
• Woller Kevin R

Classifications

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P9/04

  Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure · CPC title

• A61P37/08

  Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14) · CPC title

• A61P9/12

  Antihypertensives · CPC title

• A61P43/00

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