IP Library › Granted Patent US 7,041,669

Granted Patent B2

US 7,041,669 · App. 10/369,847 · Granted May 9, 2006

1,4-benzofused urea compounds useful in treating cytokine mediated diseases

Assignee: Boehringer Ingelheim Pharmaceuticals, Inc.

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Patent No.: US 7,041,669
App. No.: 10/369,847
Granted: May 9, 2006
Kind: B2

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Abstract

Disclosed are 1,4-disubstituted benzo-fused urea compounds of formula (I): wherein Ar, X, A, L, and Q of formula(I) are defined herein. The compounds inhibit production of cytokines involved in inflammatory processes and are thus useful for treating diseases and pathological conditions involving inflammation such as chronic inflammatory disease. Also disclosed are processes for preparing these compounds and pharmaceutical compositions comprising these compounds.

Claims (102)

1. A compound chosen from:

1-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-(4-{2-[2-(1-phenyl-ethylamino)-pyrimidin-4-yl]-ethoxy}-naphthalen-1-yl)-urea;

1-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-{4-[2-(cyclopropylmethyl-amino)-pyrimidin-4-yloxy]-naphthalen-1-yl}-urea;

1-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-(4-{2-[(tetrahydro-furan-2-ylmethyl)-amino]-pyrimidin-4-yloxy}-naphthalen-1-yl)-urea;

1-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-(4-{2-[(thiophen-2-ylmethyl)-amino]-pyrimidin-4-yloxy}-naphthalen-1-yl)-urea;

1-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-(4-{2-[2-(1-pyridin-2-yl-ethylamino)-pyrimidin-4-yl]-ethoxy}-naphthalen-1-yl)-urea;

4-(2-{4-[3-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-ureido]-naphthalen-1-yloxy}-ethyl)-pyridine-2-carboxylic acid ethylamide;

4-{4-[3-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-ureido]-naphthalen-1-yloxy}-pyridine-2-carboxylic acid diethylamide;

1-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-{4-[2-(2-piperidin-1-ylmethyl-pyridin-4-yl)-ethoxy]-naphthalen-1-yl}-urea;

4-(4-{3-[5-tert-Butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-ureido}-naphthalen-1-yloxy)-pyridine-2-carboxylic acid methyl-phenyl-amide;

1-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-(4-{2-[2-(1-phenyl-ethylamino)-pyrimidin-4-yloxy]-ethyl}-naphthalen-1-yl)-urea;

4-(2-{4-[3-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-ureido]-naphthalen-1-yloxy}-ethyl)-morpholine-2-carboxylic acid ethylamide;

1(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-{4-[2-(2-diethylaminomethyl-morpholin-4-yl)-ethoxy]-naphthalen-1-yl}-urea;

4-(2-{4-[3-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-ureido]-naphthalen-1-yloxy}-ethyl)-morpholine-2-carboxylic acid methyl-phenyl-amide;

1-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-3-(4-{2-[2-(1-phenyl-ethylamino)-pyrimidin-4-yl]-ethoxy}-naphthalen-1-yl)-urea;

1-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-3-{4-[2-(cyclopropylmethyl-amino)-pyrimidin-4-yloxy]-naphthalen-1-yl}-urea;

1-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-3-(4-{2-[(tetrahydro-furan-2-ylmethyl)-amino]-pyrimidin-4-yloxy}-naphthalen-1-yl)-urea;

1-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-3-(4-{2-[(thiophen-2-ylmethyl)-amino]-pyrimidin-4-yloxy}-naphthalen-1-yl)-urea;

1-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-3-(4-{2-[2-(1-pyridin-2-yl-ethylamino)-pyrimidin-4-yl]-ethoxy}-naphthalen-1-yl)-urea;

4-(2-{4-[3-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-ureido]-naphthalen-1-yloxy}-ethyl)-pyridine-2-carboxylic acid ethylamide;

4-{4-[3-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-ureido]-naphthalen-1-yloxy}-pyridine-2-carboxylic acid diethylamide;

1-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-3-{4-[2-(2-piperidin-1-ylmethyl-pyridin-4-yl)-ethoxy]-naphthalen-1-yl}-urea;

1-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-3-(4-{2-[2-(1-phenyl-ethylamino)-pyrimidin-4-yloxy]-ethyl}-naphthalen-1-yl)-urea;

4-(2-{4-[3(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-ureido]-naphthalen-1-yloxy}-ethyl)-morpholine-2-carboxylic acid ethylamide;

1-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-3-{4-[2-(2-diethylaminomethyl-morpholin-4-yl)-ethoxy]-naphthalen-1-yl}-urea;

4-(2-{4-[3-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-ureido]-naphthalen-1-yloxy}-ethyl)-morpholine-2-carboxylic acid methyl-phenyl-amide;

4-(2-{4-[3-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-ureido]-naphthalen-1-yloxy}-ethyl)-morpholine-2-carboxylic acid methylamide;

4-(2-{4-[3-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-ureido]-naphthalen-1-yloxy}-ethyl)-morpholine-2-carboxylic acid dimemethylamide;

4-(2-{4-[3-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-ureido]-naphthalen-1-yloxy}-ethyl)-morpholine-2-carboxylic acid phenylamide;

2-[4-(2-{4-[3-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-ureido]-naphthalen-1-yloxy}-ethyl)-morpholin-2-yl]-N,N-dimethyl-acetamide;

1-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-{4-[2-(2-phenyl-morpholin-4-yl)-ethoxy]-naphthalen-1-yl}-urea;

1-{4-[2-(2-Benzyl-morpholin-4-yl)-ethoxy]-naphthalen-1-yl}-3-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-urea;

1-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-{4-[2-(2-phenethyl-morpholin-4-yl)-ethoxy]-naphthalen-1-yl}-urea;

1-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-{4-[2-(2-phenoxymethyl-morpholin-4-yl)-ethoxy]-naphthalen-1-yl}-urea;

1-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-(4-{2-[2-(1-phenyl-ethyl)-morpholin-4-yl]-ethoxy}-naphthalen-1-yl)-urea;

1-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-{4-[2-(2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl)-ethoxy]-naphthalen-1-yl}-urea;

1-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-{4-[2-(2-thiazol-2-yl -morpholin-4-yl)-ethoxy]-naphthalen-1-yl}-urea;

1-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-{4-[2-(2,3-dihydro-benzo[1,4]oxazin-4-yl)-ethoxy]-naphthalen-1-yl}-urea;

4-(2-{4-[3-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-ureido]-naphthalen-1-yloxy}-ethyl)-morpholine-2-carboxylic acid methylamide;

4-(2-{4-[3-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-ureido]-naphthalen-1-yloxy}-ethyl)-morpholine-2-carboxylic acid dimethylamide;

4-(2-{4-[3-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-ureido]-naphthalen-1-yloxy}-ethyl)-morpholine-2-carboxylic acid phenylamide;

2-[4-(2-{4-[3-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-ureido]-naphthalen-1-yloxy}-ethyl)-morpholine-2-yl]-N,N-dimethyl-acetamide;

1-(5-tert-Butyl-2-methyl-2H-pyrazol-3yl)-3-{4-[2-(2-phenyl-morpholin-4-yl)-ethoxy]-naphthalen-1-yl}-urea;

1-{4-[2-(2-Benzyl-morpholin-4-yl)-ethoxy]-naphthalen-1-yl}-3-(5-tert-butyl-2-methyl-2H-pyrazol-3-yl)-urea;

1-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-3-{4-[2-(2-phenethyl-morpholin-4-yl)-ethoxy]-naphthalen-1-yl}-urea;

1-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-3-{4-[2-(2-phenoxymethyl-morpholin-4-yl)-ethoxy]-naphthalen-1-yl}-urea;

1-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-3-(4-{2-[2-phenyl-ethyl)-morpholin-4-yl]-ethoxy}-naphthalen-1-yl)-urea;

1-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-3-{4-[2-(2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl)-ethoxy]-naphthalen-1-yl}-urea;

1-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-3-{4-[2-(2-thiazol-2-yl-morpholin-4-yl)-ethoxy]-naphthalen-1-yl}-urea;

1-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-3-{4-[2-(2,3-dihydro-benzo[1,4oxazin-4-yl)-ethoxy]-naphthalen-1-yl}-urea;

4-[2-(4-{3-[5-tert-Butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-ureido}-naphthalen-1-yloxy)-ethyl]-morpholine-2-carboxylic acid methylamide;

4-[2-(4-{3-[5-tert-Butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-ureido}-naphthalen-1-yloxy)-ethyl]-morpholine-2-carboxylic acid methyl-phenyl-amide;

4-[2-(4-{3-[5-tert-Butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-ureido}-naphthalen-1-yloxy)-ethyl]-morpholine-2-carboxylic acid dimethylamide;

4-[2-(4-{3-[5-tert-Butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-ureido}-naphthalen-1-yloxy)-ethyl]-morpholine-2-carboxylic acid phenylamide;

2-{4-[2-(4-{3-[5tert-Butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-ureido}-naphthalen-1-yloxy)-ethyl]-morpholine-2-yl}-N,N-dimethyl-acetamide;

1-[5-tert-Butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-{4-[2-(2-phenyl-morpholin-4-yl)-ethoxy]-naphthalen-1-yl}-urea;

1-{4-[2-(2-Benzyl-morpholin-4-yl)-ethoxy]-naphthalen-1-yl}-3-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-urea;

1-[5-tert-Butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-{4-[2-(2-phenethyl-morpholin-4-yl)-ethoxy]-naphthalen-1-yl}-urea;

1-[5-tert-Butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-{4-[2-(2-phenoxymethyl-morpholin-4-yl)-ethoxy]-naphthalen-1-yl}-urea;

1-[5-tert-Butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-(4-{2-[2-(1-phenyl-ethyl)-morpholin-4-yl]-ethoxy}-naphthalen-1-yl)-urea;

1-[5-tert-Butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-{4-[2-(2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl)-ethoxy]-naphthalen-1-yl}-urea;

1-[5-tert-Butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-{4-[2-(2-thiazol-2-yl-morpholin-4-yl)-ethoxy]-naphthalen-1-yl}-urea;

1-[5-tert-Butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-{4-[2-(2,3-dihydro-benzo[1,4]oxazin-4-yl)-ethoxy]-naphthalen-1-yl}-urea;

1-[5-tert-Butyl-2-(6-methoxy-pyridin-3-yl)-2H-pyrazol-3-yl]-3-{4-[2-(2-phenethyl-morpholin-4-yl)-ethoxy]-naphthalen-1-yl}-urea;

1-[5-tert-Butyl-2-(6-methoxy-pyridin-3-yl)-2H-pyrazol-3-yl]-3-{4-[2-(2-phenoxymethyl-morpholin-4-yl)-ethoxy]-naphthalen-1-yl}-urea;

1-[5-tert-Butyl-2-(6methoxy-pyridin-3-yl)-2H-pyrazol-3-yl]-3-(4-{2-[2-(1-phenyl-ethyl)-morpholin-4-yl)-ethoxy}-naphthalen-1-yl)-urea;

1-[5-tert-Butyl-2-(6-methoxy-pyridin-3-yl)-2H-pyrazol-3-yl]-3-{4-[2-(2-oxa-5aza-bicyclo[2.2.1]hept-5-yl)-ethoxy]-naphthalen-1-yl}-urea;

1-[5-tert-Butyl-2-(6-methoxy-pyridin-3-yl)-2H-pyrazol-3-yl]-3-{4-[2-(2-thiazol-2-yl-morpholin-4-yl)-ethoxy]-naphthalen-1-yl}-urea;

1-[5-tert-Butyl-2-(6-methoxy-pyridin-3-yl)-2H-pyrazol-3-yl]-3-{4-[2-(2,3-dihydro-benzo[1,4]oxazin-4-yl)-ethoxy]-naphthalen-1-yl}-urea;

1(5-tert-Butyl-2-(6-methoxy-pyridin-3-yl)-2H-pyrazol-3-yl)-3-{4-[2-(2,3-dihydro-benzo[1,4]oxazin-4-yl)-ethoxy]-naphthalen-1-yl }-urea;

1-(5-tert-Butyl -2-methyl-2H-pyrazol-3-yl)-3-{4-[2-(cyclopropylmethyl-amino)-6-methyl-pyrimidin-4-yloxy]-naphthalen-1-yl}-urea;

1-(5-tert-Butyl-2-{2-methyl-pyrimidin-5-yl)-3-{4-[2-(cyclopropylmethyl-amino)-pyrimidin-4-yloxy]-ethyl}-naphthalen-1-yl)-urea and

1-(5-tert-Butyl-2-{2-methyl-pyrimidin-5-yl)-3-{4-[2-(cyclopropylmethyl-amino)-6-methyl-pyrimidin-4-yloxy]-ethyl}-naphthalen-1-yl)-urea

or the pharmaceutically acceptable acids or salts thereof.

2. A compound chosen from:

1-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-(4-{2-[2-(1-phenyl-ethylamino)-pyrimidin-4-yl]-ethoxy}-naphthalen-1-yl)-urea;

1-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-{4-[2-(cyclopropylmethyl-amino)-pyrimidin-4-yloxy]-naphthalen-1-yl}-urea;

1-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-(4-{2-[(tetrahydro-furan-2-ylmethyl)-amino]-pyrimidin-4-yloxy}-naphthalen-1-yl)-urea;

1-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-(4-{2-[2-(1-pyridin-2-yl-ethylamino)-pyrimidin-4-yl]-ethoxy}-naphthalen-1-yl)-urea;

4-(2-{4-[3-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-ureido]-naphthalen-1-yloxy}-ethyl)-pyridne-2-carboxylic acid ethylamide;

4-{4-[3-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-ureido]-naphthalen-1-yloxy}-pyridine)-2-carboxylic acid diethylamide;

4-(4-{3-[5-tert-Butyl-2-(6methyl-pyridin-3yl)-2H-pyrazol-3-yl]-ureido}-naphthalen-1-yloxy)-pyridine-2-carboxylic acid methyl-phenyl-amide;

4-(2-{4-[3-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-ureido]-naphthalen-1-yloxy}-ethyl)-morpholine-2-carboxylic acid ethylamide;

4-(2-{4-[3-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-ureido]-naphthalen-1-yloxy}-ethyl)-morpholine-2-carboxylic acid methyl-phenyl-amide;

4-(2-{4-[3-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-ureido]-naphthalen-1-yloxy}-ethyl)-morpholine-2-carboxylic acid methylamide;

4-(2-{4-[3-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-ureido]-naphthalen-1-yloxy}-ethyl)-morpholine-2-carboxylic acid dimethylamide;

4-(2-{4-[3-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-ureido]-naphthalen-1-yloxy}-ethyl)-morpholine-2-carboxylic acid phenylamide;

4-[2-(4-{3-[5-tert-Butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-ureido}-naphthalen-1-yloxy)-ethyl]-morpholine-2-carboxylic acid methylamide;

4-[2-(4-{3-[5-tert-Butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-ureido}-naphthalen-1-yloxy)-ethyl]-morpholine-2-carboxylic acid methyl-phenyl-amide;

4-[2-(4-{3-[5-tert-Butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-ureido}-naphthalen-1-yloxy)-ethyl]-morpholine-2-carboxylic acid dimethylamide;

4-[2-(4-{3-[5-tert-Butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-ureido}-naphthalen-1-yloxy)-ethyl]-morpholine-2-carboxylic acid phenylamide;

1-{4-[2-(2-Benzyl-morpholin-4-yl)-ethoxy]-naphthalen-1-yl}-3-[5-tert-butyl-2(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-urea;

1-[5-tert-Butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-{4-[2-(2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl)-ethoxy]-naphthalen-1-yl}-urea;

1-[5-tert-Butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-{4-[2-(2,3-dihydro-benzo[1,4]oxazin-4-yl)-ethoxy]-naphthalen-1-yl}-urea;

1-[5-tert-Butyl-2-(6-methoxy-pyridin-3-yl)-2H-pyrazol-3-yl]-3-{4-[2-(2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl)-ethoxy]-naphthalen-1-yl}-urea;

1-[5-tert-Butyl-2-(6-methoxy-pyridin-3-yl)-2H-pyrazol-3-yl]-3-{4-[2-(2,3-dihydro-benzo[1,4]oxazin-4-yl)-ethoxy]-naphthalen-1-yl}-urea;

1-(5-tert-Butyl-2-{2-methyl-pyrimidin-5-yl)-3-{4-[2-(cyclopropylmethyl-amino)-pyrimidin-4-yloxy]-ethyl}-naphthalen-1-yl)-urea and

1-(5-tert-Butyl-2-{2-methyl-pyrimidin-5-yl)-3-{4-[2-(cyclopropylmethyl-amino)-6-methyl-pyrimidin-4-yloxy]-ethyl}-naphthalen-1-yl)-urea

or the pharmaceutically acceptable acids or salts thereof.

3. A pharmaceutical composition comprising a pharmaceutically effective amount of a compound according to claim 1 and one or more pharmaceutically acceptable carriers and/or adjuvants.

4. A method of treating a disease or condition selected from rheumatoid arthritis, inflammatory bowel disease, osteoarthritis, Crohn3s disease, ulcerative colitis, psoriasis, and chronic obstructive pulmonary disease, said method comprising administering to a patient a pharmaceutically effective amount of a compound according to claim 1 .

Assignments (1)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Feb 19, 2003

From: CIRILLO, PIER F.; HAMMACH, ABDELHAKIM; REGAN, JOHN ROBINSON

To: BOEHRINGER INGELHEIM PHARMACEUTICALS, INC.

Reel/Frame 013807/0394 →

Continuity (2)

Provisional Application 6035980900 · Feb 25, 2002

Related Publication 20030232865A1 · Dec 18, 2003