US20070093453A1 - Sulfonamide-substituted chalcone derivatives and their use to treat diseases - Google Patents

Sulfonamide-substituted chalcone derivatives and their use to treat diseases Download PDF

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US20070093453A1
US20070093453A1 US11/640,509 US64050906A US2007093453A1 US 20070093453 A1 US20070093453 A1 US 20070093453A1 US 64050906 A US64050906 A US 64050906A US 2007093453 A1 US2007093453 A1 US 2007093453A1
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group
heterocyclic
alkyl
alkoxy
lower alkyl
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US11/640,509
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Kimberly Worsencroft
Liming Ni
Zhihong Ye
Charles Meng
M. Weingarten
Jacob Simpson
James Sikorski
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Atherogenics Inc
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Atherogenics Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/18—Sulfonamides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/397—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having four-membered rings, e.g. azetidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4015—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine

Definitions

  • the present invention is in the field of novel chalcone derivatives, pharmaceutical compositions and methods for treating a variety of diseases and disorders, including inflammation and cardiovascular disease.
  • Adhesion of leukocytes to the endothelium represents a fundamental, early event in a wide variety of inflammatory conditions, autoimmune disorders and bacterial and viral infections.
  • Leukocyte recruitment to endothelium is mediated in part by the inducible expression of adhesion molecules on the surface of endothelial cells that interact with counterreceptors on immune cells.
  • Endothelial cells determine which types of leukocytes are recruited by selectively expressing specific adhesion molecules, such as vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and E-selectin.
  • VCAM-1 vascular cell adhesion molecule-1
  • ICAM-1 intercellular adhesion molecule-1
  • E-selectin E-selectin.
  • VCAM-1 binds to the integrin VLA-4 expressed on lymphocytes, monocytes, macrophages, eosinophils, and basophils but not neutrophils. This interaction facilitates the firm adhesion of these leukocytes to the endothelium.
  • VCAM-1 is an inducible gene that is not expressed, or expressed at very low levels, in normal tissues.
  • VCAM-1 is upregulated in a number of inflammatory diseases, including arthritis (including rheumatoid arthritis), asthma, dermatitis, psoriasis, cystic fibrosis, post transplantation late and chronic solid organ rejection, multiple sclerosis, systemic lupus erythematosis, inflammatory bowel diseases, autoimmune diabetes, diabetic retinopathy, rhinitis, ischemia-reperfusion injury, post-angioplasty restenosis, chronic obstructive pulmonary disease (COPD), glomerulonephritis, Graves disease, gastrointestinal allergies, conjunctivitis, atherosclerosis, coronary artery disease, angina and small artery disease.
  • arthritis including rheumatoid arthritis
  • asthma including rheumatoid arthritis
  • dermatitis including dermatitis, psoriasis, cystic fibrosis, post transplantation late and chronic solid organ rejection
  • multiple sclerosis systemic lupus ery
  • linoleic acid linolenic acid, arachidonic acid, linoleyl hydroperoxide (13-HPODE) and arachidonic hydroperoxide (15-HPETE) induce cell-surface gene expression of VCAM-1 but not ICAM-1 or E-selectin.
  • Saturated fatty acids such as stearic acid
  • monounsaturated fatty acids such as oleic acid
  • Chalcone (1,3-bis-aromatic-prop-2-en-1-ones) compounds are natural products related to flavonoids.
  • WO 99/00114 discloses the use of certain chalcones, 1,3-bis-aromatic-propan-1-ones (dihydrochalcones), and 1,3-bisaromatic-prop-2-yn-1-ones for the preparation of pharmaceutical compositions for the treatment of prophylaxis of a number of serious diseases including i) conditions relating to harmful effects of inflammatory cytokines, ii) conditions involving infection by Helicobacter species, iii) conditions involving infections by viruses, iv) neoplastic disorders, and v) conditions caused by microorganisms or parasites.
  • U.S. Pat. No. 4,085,135 to Kyogoku et al. discloses a process for preparation of 2′-(carboxymethoxy)-chalcones having antigastric and anti duodenal activities with low toxicity and high absorptive ratio in the body.
  • JP 63010720 to Nippon Kayaku Co., LTD discloses that chalcone derivatives of the following formula (wherein R 1 and R 2 are hydrogen or alkyl, and m and n are 0-3) are 5-lipoxygenase inhibitors and can be used in treating allergies.
  • JP 06116206 to Morinaga Milk Industry Co. Ltd, Japan discloses chalcones of the following structure as 5-lipoxygenase inhibitors, wherein R is acyl and R 1 -R 5 are hydrogen, lower alkyl, lower alkoxy or halo, and specifically that in which R is acyl and R 1 -R 5 are hydrogen.
  • VCAM-1 is a mediator of chronic inflammatory disorders
  • a more general goal is to identify selective compounds and methods for suppressing the expression of redox sensitive genes or activating redox sensitive genes that are suppressed.
  • An even more general goal is to identify selective compounds, pharmaceutical compositions and methods of using the compounds for the treatment of inflammatory diseases.
  • Another object of the invention is to provide compounds, compositions, and method of treating cardiovascular and inflammatory diseases.
  • Another object of the invention is to provide compounds, compositions and methods to treat rheumatoid arthritis.
  • the inventions compounds, compositions and methods are also suitable as disease modifying anti-rheumatoid arthritis drugs (DMARDs).
  • DMARDs disease modifying anti-rheumatoid arthritis drugs
  • COPD chronic obstructive pulmonary disease
  • an object of the present invention is to provide compounds, methods and compositions that can be used as adjunct or combination therapy both simultaneously, and and in series.
  • VCAM-1 vascular endothelial fibrosis
  • inflammatory disorders include, but are not limited to arthritis, asthma, dermatitis, cystic fibrosis, post transplantation late and chronic solid organ rejection, multiple sclerosis, systemic lupus erythematosis, inflammatory bowel diseases, autoimmune diabetes, diabetic retinopathy, diabetic nephropathy, diabetic vasculopathy, rhinitis, ocular inflammation, uveitis, ischemia-reperfusion injury, post-angioplasty restenosis, chronic obstructive pulmonary disease (COPD), glomerulonephritis, Graves disease, gastrointestinal allergies, conjunctivitis, atherosclerosis, coronary artery disease, angina and small artery disease.
  • COPD chronic obstructive pulmonary disease
  • the compounds disclosed herein can also be used in the treatment of inflammatory skin diseases that are mediated by VCAM-1, as well as human endothelial disorders that are mediated by VCAM-1, which include, but are not limited to psoriasis, dermatitis, including eczematous dermatitis, Kaposi's sarcoma, multiple sclerosis, as well as proliferative disorders of smooth muscle cells.
  • the compounds disclosed herein can be selected to treat anti-inflammatory conditions that are mediated by mononuclear leucocytes.
  • the compounds of the present invention are selected for the prevention or treatment of tissue or organ transplant rejection.
  • Treatment and prevention of organ or tissue transplant rejection includes, but is not limited to treatment of recipients of heart, lung, combined heart-lung, liver, kidney, pancreatic, skin, spleen, small bowel, or corneal transplants.
  • the compounds can also be used in the prevention or treatment of graft-versus-host disease, such as sometimes occurs following bone marrow transplantation.
  • the compounds described herein are useful in both the primary and adjunctive medical treatment of cardiovascular disease.
  • the compounds are used in primary treatment of, for example, coronary disease states including atherosclerosis, post-angioplasty restenosis, coronary artery diseases and angina.
  • the compounds can be administered to treat small vessel disease that is not treatable by surgery or angioplasty, or other vessel disease in which surgery is not an option.
  • the compounds can also be used to stabilize patients prior to revascularization therapy.
  • a further embodiment of the invention is to supply intermediates suitable for manufacturing compounds of the invention that may have independent therapeutic value.
  • Such intermediates having the formulas wherein
  • X is —C(O)H or —CH 2 OH
  • R 3 and R 4 are independently selected from the group consisting of hydroxy, alkoxy, lower alkoxy, —(O(CH 2 ) 2 ) 1-3 —O-lower alkyl, cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy, —OC(R 9 ) 2 C(O)N(R 9 ) 2 , and —OC(R 9 ) 2 C(O)NR 7 R 8 , wherein all substituents may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, haloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR 7 R 8
  • Y 1 , Y 2 , Y 3 , and Y 4 are independently selected from the group consisting of hydrogen, hydroxyl, halo, alkyl, lower alkyl, alkenyl, cycloalkyl, haloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR 7 R 8 , alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, heteroaryl, —C(O)NR 7 R 8 , and C(O)N(R 9 ) 2 , wherein all substituents, when possible may be optionally substituted by one or more selected from the group consisting of hydroxyl, halo, alkyl, lower alkyl, alkenyl, cycloalkyl, haloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR 7 R 8 , alkoxy
  • Y 5 is selected from the group consisting of hydrogen, alkyl, lower alkyl, acyl, and alkoxycarbonyl wherein all substituents, when possible may be optionally substituted by one or more selected from the group consisting of hydroxyl, halo, alkyl, lower alkyl, alkenyl, cycloalkyl, haloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR 7 R 8 , alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, heteroaryl, —C(O)NR 7 R 8 , and —C(O)N(R 9 ) 2 ;
  • R 9 is independently selected from the group consisting of alkyl, lower alkyl, carbocyclic, cycloalkyl, hydroxy, alkoxy, lower alkoxy, trialkylsilyloxy, cycloalkyloxy, cycloalkylalkoxy, heterocyclicoxy, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, acyl, alkoxycarbonyl, and heterocyclicalkyl, wherein all substituents may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, haloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR 7 R 8 , —NHR 9 , —N(R 9 ) 2 , alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, hetero
  • R 7 and R 8 are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 4- to 12-membered monocyclic, bicylic, tricyclic or benzofused ring, which may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, haloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR 7 R 8 , alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —C(O)NR 7 R 8 , and —C(O)N(R 9 ) 2 .
  • VCAM-1 VCAM-1-binding protein-1
  • compounds of the invention inhibit the expression of VCAM-1, and thus can be used to treat a patient with a disorder mediated by VCAM-1.
  • These compounds can be administered to a host as monotherapy, or if desired, in combination with another compound of the invention or another biologically active agent, as described in more detail below.
  • the invention is represented by Formula 1 or its pharmaceutically acceptable salt, wherein:
  • R 1 is selected from the group consisting of hydrogen, alkyl, lower alkyl, carbocyclic, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, acyl and heterocyclicalkyl, wherein all substituents may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, haloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR 7 R 8 , alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, heteroaryl, —C(O)NR 7 R 8 , and —C(O)N(R 2 ) 2 ;
  • R 2 is independently selected from the group consisting of alkyl, lower alkyl, carbocyclic, cycloalkyl, hydroxy, alkoxy, lower alkoxy, trialkylsilyloxy, cycloalkyloxy, cycloalkylalkoxy, heterocyclicoxy, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, acyl, alkoxycarbonyl, and heterocyclicalkyl, wherein all substituents may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, haloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR 7 R 8 , alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, heteroaryl, —C(O)NR 7 R 8 , —NR
  • R 1 and R 2 may be taken together to form a 4- to 12-membered saturated or unsaturated heterocyclic ring which can be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, haloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR 7 R 8 , alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —C(O)NR 7 R 8 , and —C(O)N(R 2 ) 2 ;
  • R 7 and R 8 are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 4- to 12-membered monocyclic, bicylic, tricyclic or benzofused ring, which may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, haloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR 7 R 8 , alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —C(O)NR 7 R 8 , and —C(O)N(R 2 ) 2 ;
  • R 3 and R 4 are independently selected from hydroxy, alkoxy, lower alkoxy, —(O(CH 2 ) 2 ) 1-3 —O-lower alkyl, cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy, —OC(R 1 ) 2 C(O)N(R 2 ) 2 , and —OC(R 1 ) 2 C(O)NR 7 R 8 , wherein all substituents may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, haloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR 7 R 8 , alkoxy,
  • R 5 is selected from the group consisting of a carbon-carbon linked heteroaryl and a carbon-carbon linked heterocyclic, which may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, haloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR 7 R 8 , alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —C(O)NR 7 R 8 , and C(O)N(R 2 ) 2 ;
  • R 5 cannot be 5-benzo[b]thien-2-yl.
  • the invention is represented by Formula 1 or its pharmaceutically acceptable salt, wherein:
  • R 1 is selected from the group consisting of hydrogen, alkyl, and lower alkyl, wherein all substituents may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, haloalkyl, heterocyclic, —NR 7 R 8 , alkoxy, carboxy, carboxyalkyl, alkoxycarbonyl and heteroaryl;
  • R 2 is independently selected from the group consisting of alkyl, lower alkyl, alkoxy, lower alkoxy, heteroaryl, heterocyclic, heteroarylalkyl, and heterocyclicalkyl, wherein all substituents may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, haloalkyl, heterocyclic, —NR 7 R 8 , alkoxy, carboxy, carboxyalkyl, alkoxycarbonyl and heteroaryl;
  • R 1 and R 2 may be taken together to form a 5- to 7-membered saturated or unsaturated heterocyclic ring which can be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, haloalkyl, heterocyclic, —NR 7 R 8 , alkoxy, carboxy, carboxyalkyl and alkoxycarbonyl;
  • R 7 and R 8 are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 5- to 10-membered monocyclic, bicylic or benzofused ring, which may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, haloalkyl, heterocyclic, —NR 7 R 8 , alkoxy, carboxy, carboxyalkyl and alkoxycarbonyl;
  • R 3 and R 4 are independently selected from hydroxy, alkoxy, lower alkoxy, —(O(CH 2 ) 2 ) 1-3 —O-lower alkyl, haloalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy, —OC(R 1 ) 2 C(O)N(R 2 ) 2 , and —OC(R 1 ) 2 C(O)NR 7 R 8 wherein all substituents may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, hydroxy, hydroxyalkyl, heterocyclic, —NR 7 R 8 , alkoxy, —C(O)NR 7 R 8 , and —C(O)N(R 2 ) 2 ;
  • R 5 is selected from the group consisting of a carbon-carbon linked heteroaryl and a carbon-carbon linked heterocyclic, which may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, haloalkyl, heterocyclic, —NR 7 R 8 and alkoxy.
  • the invention is represented by Formula 1 or its pharmaceutically acceptable salt, wherein:
  • R 1 is selected from the group consisting of hydrogen and lower alkyl
  • R 2 is independently selected from the group consisting of lower alkyl, lower alkoxy, heteroaryl, heterocyclic, heteroarylalkyl, and heterocyclicalkyl, wherein all substituents may be optionally substituted by one or more selected from the group consisting of halo, lower alkyl, haloalkyl, heterocyclic, —NR 7 R 8 and carboxy;
  • R 1 and R 2 may be taken together to form a 5- to 6-membered heterocyclic saturated ring which can be optionally substituted by one or more selected from the group consisting of halo, lower alkyl and carboxy;
  • R 7 and R 8 are independently selected from the group consisting of alkyl and alkenyl, and linked together forming a 5- to 7-membered monocyclic ring, which may be optionally substituted by one or more selected from the group consisting of halo, lower alkyl, haloalkyl, heterocyclic and carboxy;
  • R 3 and R 4 are independently selected from hydroxy, lower alkoxy, —(O(CH 2 ) 2 ) 1-3 —O-lower alkyl, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy, —OC(R 1 ) 2 C(O)N(R 2 ) 2 , and —OC(R 1 ) 2 C(O)NR 7 R 8 , wherein all substituents may be optionally substituted by one or more selected from the group consisting of hydroxy, hydroxyalkyl, heterocyclic, —NR 7 R 8 , —C(O)NR 7 R 8 , and —C(O)N(R 2 ) 2 ;
  • R 5 is selected from the group consisting of a carbon-carbon linked heteroaryl and a carbon-carbon linked heterocyclic, which may be optionally substituted by one or more lower alkyl.
  • the invention is represented by Formula 1 or its pharmaceutically acceptable salt, wherein:
  • R 1 is hydrogen
  • R 2 is independently selected from the group consisting of lower alkyl, heteroaryl, heteroarylalkyl, and heterocyclicalkyl, wherein all substituents may be optionally substituted by one or more selected from the group consisting of halo and lower alkyl;
  • R 1 and R 2 may be taken together to form a 5- to 6-membered heterocyclic saturated ring
  • R 7 and R 8 are independently alkyl and linked together forming a 5- to 7-membered saturated monocyclic ring
  • R 3 and R 4 are independently selected from hydroxy, lower alkoxy and heterocyclic lower alkoxy;
  • R 5 is selected from the group consisting of a carbon-carbon linked heteroaryl and a carbon-carbon linked heterocyclic, which may be optionally substituted by one or more lower alkyl.
  • the invention is represented by Formula 1 or its pharmaceutically acceptable salt, wherein:
  • R 1 is hydrogen
  • R 2 is independently selected from the group consisting of lower alkyl, heteroaryl, heteroarylalkyl, and heterocyclicalkyl, wherein all substituents may be optionally substituted by one or more selected from the group consisting of halo and lower alkyl;
  • R 3 and R 4 are independently selected from lower alkoxy and heterocyclic lower alkoxy
  • R 5 is a carbon-carbon linked heteroaryl, which may be optionally substituted by one or more lower alkyl.
  • the invention is represented by Formula 1 or its pharmaceutically acceptable salt, wherein the compound is selected from
  • the invention is represented by Formula III or its pharmaceutically acceptable salt, wherein:
  • R 1 is selected from the group consisting of hydrogen, alkyl, lower alkyl, carbocyclic, cycloalkyl, alkoxy, lower alkoxy, cycloalkyloxy, cycloalkylalkoxy, heterocyclicoxy, aryloxy, heteroaryloxy, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, —NR 7 R 8 , —NHR 2 , —N(R 2 ) 2 , acyl and heterocyclicalkyl, wherein all substituents may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, haloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR 7 R 8 , —NHR 2 , —N(R 2 ) 2 , alkoxy, oxo, cyano
  • R 2 is independently selected from the group consisting of hydrogen, alkyl, lower alkyl, carbocyclic, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, acyl, alkoxycarbonyl, and heterocyclicalkyl, wherein all substituents may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, haloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR 7 R 8 , alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, heteroaryl, —C(O)NR 7 R 8 , —NR 1 R 2 and —C(O)N(R 2 ) 2 ;
  • R 7 and R 8 are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 4- to 12-membered monocyclic, bicylic, tricyclic or benzofused ring, which may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, haloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR 7 R 8 , alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —C(O)NR 7 R 8 , and —C(O)N(R 2 ) 2 ;
  • R 3 , R 4 and R 5 are independently selected from hydrogen, hydroxy, alkoxy, lower alkoxy, —(O(CH 2 ) 2 ) 1-3 —O-lower alkyl, cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclic, heteroaryl, NR 7 R 8 , heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy, —OC(R 1 ) 2 C(O)N(R 2 ) 2 , and —OC(R 1 ) 2 C(O)NR 7 R 8 , wherein all substituents may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, haloalkyl, acyl, hydroxy, hydroxyalkyl, heterocycl
  • R 3 , R 4 or R 5 is an N-linked heteroaryl or —NR 7 R 8 .
  • the invention is represented by Formula III or its pharmaceutically acceptable salt, wherein:
  • R 1 is selected from the group consisting of hydrogen, alkyl, lower alkyl, alkoxy, lower alkoxy, cycloalkyloxy, cycloalkylalkoxy, heterocyclicoxy, aryloxy, heteroaryloxy, heterocyclic, heteroarylalkyl, acyl and heterocyclicalkyl, wherein all substituents may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, haloalkyl, heterocyclic, amino, aminoalkyl, —NR 7 R 8 , —NHR 2 , —N(R 2 ) 2 , alkoxy, carboxy, carboxyalkyl, alkoxycarbonyl, and heteroaryl;
  • R 2 is independently selected from the group consisting of alkyl, lower alkyl, heteroaryl, heterocyclic, heteroarylalkyl, acyl and heterocyclicalkyl, wherein all substituents may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, haloalkyl, heterocyclic, —NR 7 R 8 , alkoxy, carboxy, carboxyalkyl, alkoxycarbonyl and heteroaryl;
  • R 7 and R 8 are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 5- to 10-membered monocyclic, bicylic or benzofused ring, which may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, haloalkyl, heterocyclic, —NR 7 R 8 , alkoxy, carboxy, carboxyalkyl and alkoxycarbonyl;
  • R 3 , R 4 and R 5 are independently selected from hydrogen, hydroxy, alkoxy, lower alkoxy, —(O(CH 2 ) 2 ) 1-3 —O-lower alkyl, haloalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclic, heteroaryl, NR 7 R 8 , heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy, —OC(R 1 ) 2 C(O)N(R 2 ) 2 , and —OC(R 1 ) 2 C(O)NR 7 R 8 , wherein all substituents may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, hydroxy, hydroxyalkyl, heterocyclic, N-linked heteroaryl, —NR 7 R 8 , alkoxy, —C(O)NR 7 R 8 , and —C(O)N(R) 2 ;
  • R 3 , R 4 or R 5 is an N-linked heteroaryl or —NR 7 R 8 .
  • the invention is represented by Formula III or its pharmaceutically acceptable salt, wherein:
  • R 1 is selected from the group consisting of alkyl, lower alkyl, alkoxy, and lower alkoxy, wherein all substituents may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, amino, —NR 7 R 8 , NHR 2 , —N(R 2 ) 2 , aminoalkyl, alkoxy, carboxy, carboxyalkyl, alkoxycarbonyl, and heteroaryl;
  • R 2 is independently selected from the group consisting of lower alkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all substituents may be optionally substituted by one or more selected from the group consisting of halo, lower alkyl, haloalkyl, heterocyclic, —NR 7 R 8 and carboxy;
  • R 7 and R 8 are independently selected from the group consisting of alkyl and alkenyl, and linked together forming a 5- to 7-membered monocyclic ring, which may be optionally substituted by one or more selected from the group consisting of halo, lower alkyl, haloalkyl, heterocyclic and carboxy;
  • R 3 , R 4 and R 5 are independently selected from hydrogen, hydroxy, lower alkoxy, —(O(CH 2 ) 2 ) 1-3 —O-lower alkyl, heteroaryl lower alkoxy, heterocyclic, heteroaryl, NR 7 R 8 , heterocyclicoxy, heterocyclic lower alkoxy, —OC(R 1 ) 2 C(O)N(R 2 ) 2 , and —OC(R 1 ) 2 C(O)NR 7 R 8 , wherein all substituents may be optionally substituted by one or more selected from the group consisting of hydroxy, hydroxyalkyl, heterocyclic, N-linked heteroaryl, —NR 7 R 8 , —C(O)NR 7 R 8 , and —C(O)N(R 2 ) 2 ;
  • R 3 , R 4 or R 5 is an N-linked heteroaryl or —NR 7 R 8 .
  • the invention is represented by Formula III or its pharmaceutically acceptable salt, wherein:
  • R 1 is selected from the group consisting of lower alkyl, and lower alkoxy, wherein all substituents may be optionally substituted by one or more selected from the group consisting of alkoxy, —NR 7 R 8 , —NHR 2 , and —N(R 2 ) 2 ;
  • R 2 is lower alkyl
  • R 7 and R 8 are independently alkyl and linked together forming a 5- to 7-membered saturated monocyclic ring
  • R 3 , R 4 and R 5 are independently selected from hydrogen, hydroxy, lower alkoxy, heterocyclic, heteroaryl, NR 7 R 8 and heterocyclic lower alkoxy;
  • R 3 , R 4 or R 5 is an N-linked heteroaryl or —NR 7 R 8 .
  • the invention is represented by Formula III or its pharmaceutically acceptable salt, wherein:
  • R 1 is selected from the group consisting of lower alkyl, and lower alkoxy
  • R 7 and R 8 are independently alkyl and linked together forming a 5- to 7-membered saturated monocyclic ring
  • R 3 , R 4 and R 5 are independently selected from lower alkoxy, NR 7 R 8 and heterocyclic lower alkoxy;
  • R 3 , R 4 or R 5 is —NR 7 R 8 .
  • the invention is represented by Formula III or its the compound is N-Butyryl-4-[3E-(2,4-dimethoxy-5-pyrrolidin-1-ylphenyl)acryloyl]benzenesulfonamide.
  • the invention is represented by Formula III or its pharmaceutically acceptable salt, wherein:
  • R 1 is selected from the group consisting of hydrogen, alkyl, lower alkyl, carbocyclic, cycloalkyl, alkoxy, lower alkoxy, cycloalkyloxy, cycloalkylalkoxy, heterocyclicoxy, aryloxy, heteroaryloxy, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, —NR 7 R 8 , —NHR 2 , —N(R 2 ) 2 , acyl and heterocyclicalkyl, wherein all substituents may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, haloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR 7 R 8 , —NHR 2 , —N(R 2 ) 2 , alkoxy, oxo, cyano
  • R 2 is independently selected from the group consisting of hydrogen, alkyl, lower alkyl, carbocyclic, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, acyl, alkoxycarbonyl, and heterocyclicalkyl, wherein all substituents may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, haloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR 7 R 8 , alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, heteroaryl, —C(O)NR 7 R 8 , —NR 1 R 2 and —C(O)N(R 2 ) 2 ;
  • R 7 and R 8 are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 4- to 12-membered monocyclic, bicylic, tricyclic or benzofused ring, which may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, haloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR 7 R 8 , alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —C(O)NR 7 R 8 , and —C(O)N(R 2 ) 2 ;
  • R 3 and R 4 are independently selected from hydrogen, hydroxy, alkoxy, lower alkoxy, —(O(CH 2 ) 2 ) 1-3 —O-lower alkyl, cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy, —OC(R 1 ) 2 C(O)N(R 2 ) 2 , and —OC(R 1 ) 2 C(O)NR 7 R 8 , wherein all substituents may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, haloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, N-linked heteroaryl, —NR
  • R 5 is selected from the group consisting of a carbon-carbon linked heterocyclic and a carbon-carbon linked heteroaryl, which may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, haloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR 7 R 8 , alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —C(O)NR 7 R 8 , and —C(O)N(R 2 ) 2 ;
  • R 5 cannot be 5-benzo[b]thien-2-yl.
  • the invention is represented by Formula III or its pharmaceutically acceptable salt, wherein:
  • R 1 is selected from the group consisting of hydrogen, alkyl, lower alkyl, alkoxy, lower alkoxy, cycloalkyloxy, cycloalkylalkoxy, heterocyclicoxy, aryloxy, heteroaryloxy, heterocyclic, heteroarylalkyl, and heterocyclicalkyl, wherein all substituents may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, haloalkyl, heterocyclic, amino, aminoalkyl, —NR 7 R 8 , —NHR 2 , —N(R 2 ) 2 , alkoxy, carboxy, carboxyalkyl, alkoxycarbonyl, and heteroaryl;
  • R 2 is independently selected from the group consisting of alkyl, lower alkyl, heteroaryl, heterocyclic, heteroarylalkyl, and heterocyclicalkyl, wherein all substituents may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, haloalkyl, heterocyclic, —NR 7 R 8 , alkoxy, carboxy, carboxyalkyl, alkoxycarbonyl and heteroaryl;
  • R 7 and R 8 are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 5- to 10-membered monocyclic, bicylic or benzofused ring, which may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, haloalkyl, heterocyclic, —NR 7 R 8 , alkoxy, carboxy, carboxyalkyl and alkoxycarbonyl;
  • R 3 and R 4 are independently selected from hydroxy, alkoxy, lower alkoxy, —(O(CH 2 ) 2 ) 1-3 —O-lower alkyl, haloalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy, —OC(R 1 ) 2 C(O)N(R 2 ) 2 , and —OC(R 1 ) 2 C(O)NR 7 R 8 , wherein all substituents may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, hydroxy, hydroxyalkyl, heterocyclic, —NR 7 R 8 , alkoxy, —C(O)NR 7 R 8 , and —C(O)N(R 2 ) 2 ;
  • R 5 is selected from the group consisting of a carbon-carbon linked heteroaryl and a carbon-carbon linked heterocyclic, which may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, haloalkyl, heterocyclic, —NR 7 R 8 and alkoxy;
  • R 5 cannot be 5-benzo[b]thien-2-yl.
  • the invention is represented by Formula III or its pharmaceutically acceptable salt, wherein:
  • R 1 is selected from the group consisting of alkyl, lower alkyl, alkoxy, and lower alkoxy, wherein all substituents may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, amino, aminoalkyl, —NR 7 R 8 , —NHR 2 , —N(R 2 ) 2 , alkoxy, carboxy, carboxyalkyl, alkoxycarbonyl, and heteroaryl;
  • R 2 is independently selected from the group consisting of lower alkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all substituents may be optionally substituted by one or more selected from the group consisting of halo, lower alkyl, haloalkyl, heterocyclic, —NR 7 R 8 and carboxy;
  • R 7 and R 8 are independently selected from the group consisting of alkyl and alkenyl, and linked together forming a 5- to 7-membered monocyclic ring, which may be optionally substituted by one or more selected from the group consisting of halo, lower alkyl, haloalkyl, heterocyclic and carboxy;
  • R 3 and R 4 are independently selected from hydroxy, lower alkoxy, —(O(CH 2 ) 2 ) 1-3 —O-lower alkyl, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy, —OC(R 1 ) 2 C(O)N(R 2 ) 2 , and —OC(R 1 ) 2 C(O)NR 7 R 8 , wherein all substituents may be optionally substituted by one or more selected from the group consisting of hydroxy, hydroxyalkyl, heterocyclic, —NR 7 R 8 , —C(O)NR 7 R 8 , and —C(O)N(R 2 ) 2 ;
  • R 5 is selected from the group consisting of a carbon-carbon linked heteroaryl and a carbon-carbon linked heterocyclic, which may be optionally substituted by one or more lower alkyl;
  • R 5 cannot be 5-benzo[b]thien-2-yl.
  • the invention is represented by Formula III or its pharmaceutically acceptable salt, wherein:
  • R 1 is selected from the group consisting of lower alkyl, and lower alkoxy, wherein all substituents may be optionally substituted by one or more selected from the group consisting of alkoxy, —NR 7 R 8 , —NHR 2 , and —N(R 2 ) 2 ;
  • R 2 is lower alkyl
  • R 7 and R 8 are independently alkyl and linked together forming a 5- to 7-membered saturated monocyclic ring
  • R 3 and R 4 are independently selected from hydroxy, lower alkoxy and heterocyclic lower alkoxy;
  • R 5 is selected from the group consisting of a carbon-carbon linked heteroaryl and a carbon-carbon linked heterocyclic, which may be optionally substituted by one or more lower alkyl;
  • R 5 cannot be 5-benzo[b]thien-2-yl.
  • the invention is represented by Formula III or its pharmaceutically acceptable salt, wherein:
  • R 1 is selected from the group consisting of lower alkyl, and lower alkoxy
  • R 3 and R 4 are independently selected from lower alkoxy and heterocyclic lower alkoxy
  • R 5 is a carbon-carbon linked heteroaryl, which may be optionally substituted by one or more lower alkyl;
  • R 5 cannot be 5-benzo[b]thien-2-yl.
  • the invention is represented by Formula III or its pharmaceutically acceptable salt, wherein the compound is selected from the group consisting of
  • the invention is represented by Formula I or its pharmaceutically acceptable salt, wherein:
  • R 1 is selected from the group consisting of hydrogen, alkyl, lower alkyl, carbocyclic, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, acyl and heterocyclicalkyl, wherein all substituents may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, haloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR 7 R 8 , alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, heteroaryl, —C(O)NR 7 R 8 , and —C(O)N(R 2 ) 2 ;
  • R 2 is independently selected from the group consisting of alkyl, lower alkyl, carbocyclic, cycloalkyl, hydroxy, alkoxy, lower alkoxy, trialkylsilyloxy, cycloalkyloxy, cycloalkylalkoxy, heterocyclicoxy, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, acyl, alkoxycarbonyl, and heterocyclicalkyl, wherein all substituents may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, haloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR 7 R 8 , alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, heteroaryl, —C(O)NR 7 R 8 , —NR
  • R 1 and R 2 may be taken together to form a 4- to 12-membered saturated or unsaturated heterocyclic ring which can be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, haloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR 7 R 8 , alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —C(O)NR 7 R 8 , and —C(O)N(R 2 ) 2 ;
  • R 7 and R 8 are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 4- to 12-membered monocyclic, bicylic, tricyclic or benzofused ring, which may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, haloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR 7 R 8 , alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —C(O)NR 7 R 8 , and —C(O)N(R 2 ) 2 ;
  • R 3 and R 4 are independently selected from hydroxy, alkoxy, lower alkoxy, —(O(CH 2 ) 2 ) 1-3 —O-lower alkyl, cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy, —OC(R 1 ) 2 C(O)N(R 2 ) 2 , and —OC(R 1 ) 2 C(O)NR 7 R 8 , wherein all substituents may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, haloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR 7 R 8 , alkoxy,
  • R 5 is selected from the group consisting of a carbon-nitrogen linked heteroaryl and a carbon-nitrogen linked heterocyclic, which may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, haloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR 7 R 8 , alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —C(O)NR 7 R 8 , and —C(O)N(R 2 ) 2 .
  • the invention is represented by Formula I or its pharmaceutically acceptable salt, wherein:
  • R 1 is selected from the group consisting of hydrogen, alkyl, and lower alkyl, wherein all substituents may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, haloalkyl, heterocyclic, —NR 7 R 8 , alkoxy, carboxy, carboxyalkyl, alkoxycarbonyl and heteroaryl;
  • R 2 is independently selected from the group consisting of alkyl, lower alkyl, alkoxy, lower alkoxy, heteroaryl, heterocyclic, heteroarylalkyl, and heterocyclicalkyl, wherein all substituents may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, haloalkyl, heterocyclic, —NR 7 R 8 , alkoxy, carboxy, carboxyalkyl, alkoxycarbonyl and heteroaryl;
  • R 1 and R 2 may be taken together to form a 5- to 7-membered saturated or unsaturated heterocyclic ring which can be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, haloalkyl, heterocyclic, —NR 7 R 8 , alkoxy, carboxy, carboxyalkyl and alkoxycarbonyl;
  • R 7 and R 8 are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 5- to 10-membered monocyclic, bicylic or benzofused ring, which may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, haloalkyl, heterocyclic, —NR 7 R 8 , alkoxy, carboxy, carboxyalkyl and alkoxycarbonyl;
  • R 3 and R 4 are independently selected from hydroxy, alkoxy, lower alkoxy, —(O(CH 2 ) 2 ) 1-3 —O-lower alkyl, haloalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy, —OC(R 1 ) 2 C(O)N(R 2 ) 2 , and —OC(R 1 ) 2 C(O)NR 7 R 8 , wherein all substituents may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, hydroxy, hydroxyalkyl, heterocyclic, —NR 7 R 8 , alkoxy, —C(O)NR 7 R 8 , and —C(O)N(R 2 ) 2 ;
  • R 5 is selected from the group consisting of a carbon-nitrogen linked heteroaryl and a carbon-nitrogen linked heterocyclic, which may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, haloalkyl, heterocyclic, —NR 7 R 8 and alkoxy.
  • the invention is represented by Formula I or its pharmaceutically acceptable salt, wherein:
  • R 1 is selected from the group consisting of hydrogen and lower alkyl
  • R 2 is independently selected from the group consisting of lower alkyl, lower alkoxy, heteroaryl, heterocyclic, heteroarylalkyl, and heterocyclicalkyl, wherein all substituents may be optionally substituted by one or more selected from the group consisting of halo, lower alkyl, haloalkyl, heterocyclic, heteroaryl, —NR 7 R 8 and carboxy;
  • R 1 and R 2 may be taken together to form a 5- to 6-membered heterocyclic saturated ring which can be optionally substituted by one or more selected from the group consisting of halo, lower alkyl and carboxy;
  • R 7 and R 8 are independently selected from the group consisting of alkyl and alkenyl, and linked together forming a 5- to 7-membered monocyclic ring, which may be optionally substituted by one or more selected from the group consisting of halo, lower alkyl, haloalkyl, heterocyclic and carboxy;
  • R 3 and R 4 are independently selected from hydroxy, lower alkoxy, —(O(CH 2 ) 2 ) 1-3 —O-lower alkyl, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy, —OC(R 1 ) 2 C(O)N(R 2 ) 2 , and —OC(R 1 ) 2 C(O)NR 7 R 8 , wherein all substituents may be optionally substituted by one or more selected from the group consisting of hydroxy, hydroxyalkyl, heterocyclic, —NR 7 R 8 , —C(O)NR 7 R 8 , and —C(O)N(R 2 ) 2 ;
  • R 5 is selected from the group consisting of a carbon-nitrogen linked heteroaryl and a carbon-nitrogen linked heterocyclic, which may be optionally substituted by one or more lower alkyl.
  • the invention is represented by Formula I or its pharmaceutically acceptable salt, wherein:
  • R 1 is hydrogen
  • R 2 is independently selected from the group consisting of lower alkyl, heteroaryl, heteroarylalkyl, and heterocyclicalkyl, wherein all substituents may be optionally substituted by one or more selected from the group consisting of halo, heterocyclic, heteroaryl, and lower alkyl;
  • R 1 and R 2 may be taken together to form a 5- to 6-membered heterocyclic saturated ring
  • R 7 and R 8 are independently alkyl and linked together forming a 5- to 7-membered saturated monocyclic ring
  • R 3 and R 4 are independently selected from hydroxy, lower alkoxy and heterocyclic lower alkoxy;
  • R 5 is selected from the group consisting of a carbon-nitrogen linked heterocyclic, which may be optionally substituted by one or more lower alkyl.
  • the invention is represented by Formula I or its pharmaceutically acceptable salt, wherein:
  • R 1 is hydrogen
  • R 2 is independently selected from the group consisting of lower alkyl, heteroaryl, heteroarylalkyl, and heterocyclicalkyl, wherein all substituents may be optionally substituted by one or more selected from the group consisting of halo, heterocyclic, heteroaryl, and lower alkyl;
  • R 3 and R 4 are independently selected from lower alkoxy and heterocyclic lower alkoxy
  • R 5 is a carbon-nitrogen linked heterocyclic.
  • the invention is represented by Formula I, wherein the compound is selected from the group consisting of:
  • the invention is a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or 24, together with one or more pharmaceutically acceptable carrier.
  • the invention is represented by a method for the treatment or prophylaxis of an inflammatory disorder, comprising administering an effective amount of a compound of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or 24.
  • the invention is represented by embodiment 26, wherein the disorder is arthritis.
  • the invention is represented by embodiment 26, wherein the disorder is rheumatoid arthritis.
  • the invention is represented by embodiment 26, wherein the disorder is asthma.
  • the invention is represented by embodiment 26, wherein the treatment is disease modifying for the treatment of rheumatoid arthritis.
  • the invention is represented by embodiment 26, wherein the disorder is allergic rhinitis.
  • the invention is represented by embodiment 26, wherein the disorder is chronic obstructive pulmonary disease.
  • the invention is represented by embodiment 26, wherein the disorder is atherosclerosis.
  • the invention is represented by embodiment 26, wherein the disorder is restinosis.
  • the invention is represented by embodiment, the invention is represented by a method for inhibiting the expression of VCAM-1, comprising administering an effective amount of a compound of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or 24.
  • the invention is represented by intermediates used to make the final compounds of the invention.
  • Said intermediates are useful as starting materials for making the compounds of the invention as well as having pharmaceutical activity alone.
  • Particular intermediates include the ones represented by embodiment 36, represented by the formulas wherein
  • X is —C(O)H or —CH 2 OH
  • R 3 and R 4 are independently selected from the group consisting of hydroxy, alkoxy, lower alkoxy, —(O(CH 2 ) 2 ) 1-3 —O-lower alkyl, cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy, —OC(R 9 ) 2 C(O)N(R 9 ) 2 , and —OC(R 9 ) 2 C(O)NR 7 R 8 , wherein all substituents may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, haloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR 7 R 8
  • Y 1 , Y 2 , Y 3 , and Y 4 are independently selected from the group consisting of hydrogen, hydroxyl, halo, alkyl, lower alkyl, alkenyl, cycloalkyl, haloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR 7 R 8 , alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, heteroaryl, —C(O)NR 7 R 8 , and —C(O)N(R 9 ) 2 , wherein all substituents, when possible may be optionally substituted by one or more selected from the group consisting of hydroxyl, halo, alkyl, lower alkyl, alkenyl, cycloalkyl, haloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR 7 R 8 , al
  • Y 5 is selected from the group consisting of hydrogen, alkyl, lower alkyl, acyl, and alkoxycarbonyl wherein all substituents, when possible may be optionally substituted by one or more selected from the group consisting of hydroxyl, halo, alkyl, lower alkyl, alkenyl, cycloalkyl, haloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR 7 R 8 , alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, heteroaryl, —C(O)NR 7 R 8 , and —C(O)N(R 9 ) 2 ;
  • R 9 is independently selected from the group consisting of alkyl, lower alkyl, carbocyclic, cycloalkyl, hydroxy, alkoxy, lower alkoxy, trialkylsilyloxy, cycloalkyloxy, cycloalkylalkoxy, heterocyclicoxy, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, acyl, alkoxycarbonyl, and heterocyclicalkyl, wherein all substituents may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, haloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR 7 R 8 , —NHR 9 , —N(R 9 ) 2 , alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, hetero
  • R 7 and R 8 are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 4- to 12-membered monocyclic, bicylic, tricyclic or benzofused ring, which may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, haloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR 7 R 8 , alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —C(O)NR 7 R 8 , and —C(O)N(R 9 ) 2 .
  • the invention is represented by embodiment 36 wherein the compound is selected from
  • Another embodiment of the invention includes the process for making both the intermediates as well as the final compounds.
  • alkyl or “alk”, alone or in combination, unless otherwise specified, refers to a saturated straight or branched primary, secondary, or tertiary hydrocarbon from 1 to 10 carbon atoms, including, but not limited to methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, and sec-butyl.
  • lower alkyl alone or in combination refers to an alkyl having from 1 to 4 carbon atoms.
  • the alkyl group may be optionally substituted with any moiety that does not otherwise interfere with the reaction or that provides an improvement in the process, including but not limited to but limited to halo, haloalkyl, hydroxyl, carboxyl, acyl, aryl, acyloxy, amino, amido, carboxyl derivatives, alkylamino, dialkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, thiol, imine, sulfonyl, sulfanyl, sulfinyl, sulfamonyl, ester, carboxylic acid, amide, phosphonyl, phosphinyl, phosphoryl, phosphine, thioester, thioether, acid halide, anhydride, oxime, hydrazine, carbamate, phosphonic acid, phosphonate, either unprotected, or protected as necessary, as known
  • alkenyl means a non-cyclic alkyl of 2 to 10 carbon atoms having one or more unsaturated carbon-carbon bonds.
  • the alkenyl group may be optionally substituted with any moiety that does not otherwise interfere with the reaction or that provides an improvement in the process, including but not limited to but limited to halo, haloalkyl, hydroxyl, carboxyl, acyl, aryl, acyloxy, amino, amido, carboxyl derivatives, alkylamino, dialkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, thiol, imine, sulfonyl, sulfanyl, sulfinyl, sulfamonyl, ester, carboxylic acid, amide, phosphonyl, phosphinyl, phosphoryl, phosphine, thioester, thioether, acid hal
  • alkynyl means a non-cyclic alkyl of 2 to 10 carbon atoms having one or more triple carbon-carbon bonds, including but not limited to ethynyl and propynyl.
  • the alkynyl group may be optionally substituted with any moiety that does not otherwise interfere with the reaction or that provides an improvement in the process, including but not limited to but limited to halo, haloalkyl, hydroxyl, carboxyl, acyl, aryl, acyloxy, amino, amido, carboxyl derivatives, alkylamino, dialkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, thiol, imine, sulfonyl, sulfanyl, sulfinyl, sulfamonyl, ester, carboxylic acid, amide, phosphonyl, phosphinyl, phosphoryl,
  • alkoxycarbonyl and “carboalkoxy” are used interchangeably. Used alone or in combination, the terms mean refer to the radical —C(O)OR, wherein R is alkyl that can be optionally substituted as defined herein.
  • thio alone or in combination, means the radical —S—.
  • thiol alone or in combination, means the radical —SH.
  • hydroxy alone or in combination means the radical —OH.
  • sulfonyl alone or in combination means the radical —S(O) 2 —.
  • oxo refers to an oxygen attached by a double bond ( ⁇ O).
  • carbocycle and “carbocyclic”, alone or in combination, means any stable 3- to 7-membered monocyclic or bicyclic or 7- to 14-membered bicyclic or tricyclic or an up to 26-membered polycyclic carbon ring, any of which may be saturated, partially unsaturated, or aromatic.
  • carbocyles include, but are not limited to, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, biphenyl, naphthyl, indanyl, adamantyl, or tetrahydronaphthyl (tetralin).
  • cycloalkyl alone or in combination, means a saturated or partially unsaturated cyclic alkyl, having from 1 to 10 carbon atoms, including but not limited to mono- or bi-cyclic ring systems such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexenyl, and cyclohexyl.
  • aryl alone or in combination, means a carbocyclic aromatic system containing one, two or three rings wherein such rings may be attached together in a pendent manner or may be fused.
  • the “aryl” group can be optionally substituted with one or more of the moieties selected from the group consisting of alkyl, alkenyl, alkynyl, heteroaryl, heterocyclic, carbocycle, alkoxy, oxo, aryloxy, arylalkoxy, cycloalkyl, tetrazolyl, heteroaryloxy; heteroarylalkoxy, carbohydrate, amino acid, amino acid esters, amino acid amides, alditol, halogen, haloalkylthi, haloalkoxy, haloalkyl, hydroxyl, carboxyl, acyl, acyloxy, amino, aminoalkyl, aminoacyl, amido, alkylamino, dialkylamino, arylamino, nitro,
  • heterocyclic refers to a nonaromatic cyclic group that may be partially (containing at least one double bond) or fully saturated and wherein the ring contains at least one heteroatom selected from oxygen, sulfur, nitrogen, or phosphorus.
  • heteroaryl or “heteroaromatic”, alone or in combination, refer to an aromatic ring containing at least one heteroatom selected from sulfur, oxygen, nitrogen or phosphorus.
  • the heteroaryl or heterocyclic ring may optionally be substituted by one or more substituent listed as optional substituents for aryl.
  • heterocyclics and heteroaromatics are pyrrolidinyl, tetrahydrofuryl, tetrahydrofuranyl, pyranyl, purinyl, tetrahydropyranyl, piperazinyl, piperidinyl, morpholino, thiomorpholino, tetrahydropyranyl, imidazolyl, pyrrolinyl, pyrazolinyl, indolinyl, dioxolanyl, or 1,4-dioxanyl, aziridinyl, furyl, furanyl, pyridyl, pyridinyl, pyridazinyl, pyrimidinyl, benzoxazolyl, 1,2,4-o
  • Suitable protecting groups can include trimethylsilyl, dimethylhexylsilyl, t-butyldimethylsilyl, and t-butyldiphenylsilyl, trityl or substituted trityl, alkyl groups, acyl groups such as acetyl and propionyl, methanesulfonyl, and p-toluenesulfonyl.
  • thienyl and “thien”, alone or in combination, refers to a five member cyclic group wherein the ring contains one sulfur atom and two double bonds.
  • benzothienyl refers to a five member cyclic group wherein the ring contains one sulfur atom and two double bonds fused to a phenyl ring.
  • aryloxy refers to an aryl group bound to the molecule through an oxygen atom.
  • heteroaryloxy refers to a heteroaryl group bound to the molecule through an oxygen atom.
  • aralkoxy refers to an aryl group attached to an alkyl group which is attached to the molecule through an oxygen atom.
  • heterocyclearalkoxy refers to a heterocyclic group attached to an aryl group attached to an alkyl-O— group.
  • the heterocyclic, aryl and alkyl groups can be optionally substituted as described above.
  • halo and “halogen”, alone or in combination, refer to chloro, bromo, iodo and fluoro.
  • alkoxy or “alkylthio”, alone or in combination, refers to an alkyl group as defined above bonded through an oxygen linkage (—O—) or a sulfur linkage (—S—), respectively.
  • lower alkoxy or “lower alkylthio”, alone or in combination, refers to a lower alkyl group as defined above bonded through an oxygen linkage (—O—) or a sulfur linkage (—S—), respectively.
  • acyl refers to a group of the formula C(O)R′, wherein R′ is an alkyl, aryl, alkaryl or aralkyl group, or substituted alkyl, aryl, aralkyl or alkaryl, wherein these groups are as defined above.
  • acetyl alone or in combination, refers to the radical —C(O)CH 3 .
  • amino alone or in combination, denotes the radical —NH 2 or —NH—.
  • nitro alone or in combination, denotes the radical —NO 2 .
  • substituted means that one or more hydrogen on the designated atom or substituent is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and the that the substitution results in a stable compound.
  • substitutent is “oxo” (keto) (i.e., ⁇ O)
  • the term “patient” refers to warm-blooded animals or mammals, and in particular humans, who are in need of the therapy described herein.
  • the term “host”, as used herein, refers to a unicellular or multicellular organism, including cell lines and animals, and preferably a human.
  • the compounds of the present invention can be readily prepared by those skilled in the art of organic synthesis using commonly known methods, many of which are described by J, March, in Advanced Organic Chemistry, 4 th Edition (Wiley-Interscience, New York, 1992) and D. N. Dnar in The Chemistry of Chalcones and Related Compounds (Wiley-Interscience, New York, 1981), incorporated herein by reference.
  • Ex-1A 5-bromo-2,4-dimethoxybenzaldehyde (20.3 g, 83 mmol), thiophene-2-boronic acid (11.6 g, 91 mmol) and THF (200 mL) were sequentially charged into a clean reaction vessel fitted with a reflux condenser, mechanical stirrer and nitrogen inlet adapter. Nitrogen was bubbled into the resulting solution for 20 min followed by the sequential addition of KF (10.1 g, 174 mmol), and Pd( t Bu 3 P) 2 (0.424 g, 0.83 mmol). The solution was immediately heated to 60° C. and aged for 1.5 h.
  • the reaction was diluted with H 2 O (200 mL) and transferred to a separatory funnel containing EtOAc (200 mL) and H 2 O (200 mL). The layers were cut and the aqueous layer was extracted with EtOAc (100 mL). The combined organic cuts were filtered through a pre-washed pad of solka floc (5 g). The pad of solka floc and spent catalyst were washed with fresh EtOAc (200 mL) and this wash combined with the batch. The resultant filtrate was concentrated to dryness. The crude product was dissolved in THF (38 mL) and crystallized upon heptane (152 mL) addition.
  • Ex-1B To a solution of 3-amino-5-methylisoxazole (0.27 g, 2.75 mmol) in pyridine (1 mL) at 0° C. was added a solution of 4-acetylbenzenesulfonyl chloride (0.50 g, 2.29 mmol) in 1 mL pyridine dropwise to the reaction. The resulting solution was stirred at 0° C. for 30 min and then warmed to room temperature and stirred for an additional 18 h. The mixture was diluted with water (100 mL), cooled to 0° C., and stirred for 1 h. The resulting precipitate was collected on filter paper and rinsed with several portions of water.
  • the mixture was diluted with water (80 mL), acidified with a 1 N hydrochloric acid solution, and extracted with ethyl acetate (3 ⁇ 40 mL). The combined organic extracts were dried over sodium sulfate and evaporated to dryness.
  • the crude oil was taken up in ethanol (20 mL) and warmed to 60° C. to obtain complete dissolution and allowed to cool to room temperature. The resulting precipitate was collected on filter paper and dried in vacuo to yield 3.78 g (83%) of the title compound as an orange solid, mp 202-203° C.
  • Ex-3A 4-Acetyl-N-pyrimidin-2-ylbenzenesulfonamide was prepared in an analogous fashion as Ex-1B using 2-aminopyrimidine, 30% yield, pale yellow solid, mp>240° C. (dec).
  • HRMS (ESI) Calcd. for C 12 H 11 N 3 O 3 S: 278.0599 (M+H) + ; Found: 278.0608.
  • Ex-4A 4-Acetyl-N-(1-H-tetrazol-5-yl)benzenesulfonamide was prepared in an analogous fashion as Ex-1B using 5-aminotetrazole, 50% yield, off-white solid, mp 150-151° C.
  • HRMS (EI) Calcd. for C 9 H 9 N 5 O 3 S: 267.0426 (M + ); Found: 267.0425.
  • Ex-5A 4-Acetyl-N-pyridin-2-ylbenzenesulfonamide was prepared in an analogous fashion as Ex-1B using 2-aminopyridine, 77% yield, off-white solid, mp 198-199° C.
  • HRMS (EI) Calcd. for C 13 H 12 N 2 O 3 S: 276.0569 (M + ); Found: 276.0563.
  • Ex-6A 4-Acetyl-N-(1H-pyrazol-3-yl)benzenesulfonamide was prepared in an analogous fashion as Ex-1B using 3-aminopyrazole except that silica gel chromatography (ethyl acetate/hexanes, 1:1 to 3:1) was used, 15% yield, white solid.
  • HRMS (EI) Calcd. for C 11 H 11 N 3 O 3 S: 265.0521 (M + ); Found: 265.0526.
  • Ex-7A 4-Acetyl-N-isoxazol-3-ylbenzenesulfonamide was prepared in an analogous fashion as Ex-1B using 3-aminoisoxazole, 71% yield, off-white solid, mp 165-166° C.
  • HRMS EI
  • Ex-8A 4-Acetyl-N-thiazol-2-ylbenzenesulfonamide was prepared in an analogous fashion as Ex-1B using 2-aminothiazole, 68% yield, tan solid, mp 194-195° C.
  • HRMS (EI) Calcd. for C 11 H 10 N 2 O 3 S 2 : 282.0133 (M + ); Found: 282.0131.
  • Ex-9A 4-Acetyl-N-(3-methylisoxazol-5-yl)benzenesulfonamide was prepared in an analogous fashion as Ex-1B using 5-amino-3-methylisoxazole, 64% yield, tan solid, mp 144-145° C.
  • HRMS (EI) Calcd. for C 12 H 12 N 2 O 4 S: 280.0518 (M + ); Found: 280.0525.
  • Ex-10A 4-Acetyl-N-(5-chloropyridin-2-yl)benzenesulfonamide was prepared in an analogous fashion as Ex-1B using 2-amino-5-chloropyridine, 78% yield, tan solid, mp 181-182° C.
  • Ex-11A 4-Acetyl-N-(5-fluoropyridin-2-yl)benzenesulfonamide was prepared in an analogous fashion as Ex-1B using 2-amino-5-fluoropyridine, 91% yield, light red solid, mp 151-152° C.
  • HRMS (ESI) Calcd. for C 13 H 11 FN 2 O 3 S: 295.0552 (M+H) + ; Found: 295.0563.
  • Ex-12A 4-Acetyl-N-(5-trifluoromethylpyridin-2-yl)benzenesulfonamide was prepared in an analogous fashion as Ex-1B using 2-amino-5-(trifluoromethyl)pyridine, 75% yield, off-white solid, mp 179-180° C.
  • HRMS (ESI) Calcd. for C 14 H 11 F 3 N 2 O 3 S: 345.0520 (M+H) + ; Found: 345.0531.
  • Ex-13C 5-Bromo-2-hydroxy-4-methoxybenzaldehyde (Ex-13B, 1.5 g, 6.5 mmol) and thiophene-2-boronic acid (0.91 g, 7.1 mmol) were dissolved in tetrahydrofuran (15 mL). Nitrogen was bubbled into the solution for 10 min followed by the sequential addition of potassium fluoride (0.80 g, 14 mmol, spray-dried) and bis(tri-t-butylphosphine)palladium (0) (0.033 g, 0.065 mmol). The solution was immediately heated to 60° C. and aged for 1.5 h.
  • Ex-13D To a solution of 2-hydroxy-4-methoxy-5-thien-2-ylbenzaldehyde (Ex-13C, 0.10 g, 0.43 mmol) in N,N-dimethylformamide (3 mL) was added potassium carbonate (0.18 g, 1.3 mmol) and the resulting yellow slurry was heated to 80° C. Methanesulfonic acid 3-(tert-butyldimethylsilanyloxy)-2-(tert-butyldimethylsilanyloxymethyl)propyl ester (Ex-13A, 0.24 g, 1.3 mmol) was then added dropwise in three equal portions with stirring at 1 h intervals.
  • Ex-13E To a solution of 2-[3-(tert-butyldimethylsilanyloxy)-2-(tert-butyldimethylsilanyloxymethyl)propoxy]-4-methoxy-5-thien-2-ylbenzaldehyde (Ex-13D, 0.78 g, 1.41 mmol) in tetrahydrofuran (5 mL) was added tetrabutylammonium fluoride (1 M in tetrahydrofuran, 3.0 mL, 2.9 mmol) and the mixture was stirred at room temperature for 30 min.
  • Ex-14A 4-Methoxy-2-(2-morpholin-4-ylethoxy)-5-thien-2-ylbenzaldehyde was prepared in an analogous fashion as Ex-13D using 4-(2-chloroethyl)morpholine hydrochloride, 93% yield after silica gel chromatography (80 to 100% ethyl acetate/hexanes then 5% methanol/methylene chloride), off-white solid, mp 130-131° C.
  • the mixture was diluted with water (8.0 mL), acidified with a 1 N hydrochloric acid solution, and extracted with ethyl acetate:tetrahydrofuran (1:1, 3 ⁇ 20 mL). The combined organic extracts were evaporated to dryness.
  • the crude oil was taken up in ethanol (10 mL) and warmed to 60° C. to obtain complete dissolution and allowed to cool to room temperature. The resulting precipitate was collected on filter paper and dried in vacuo to yield 0.46 g (88%) of the title compound as a pale orange solid, mp>260° C.
  • Ex-18A 4-Acetyl-N-(2-morpholin-4-ylethyl)benzenesulfonamide was prepared in an analogous fashion as Ex-17A using 4-(2-aminoethyl)morpholine, 99% yield, off-white solid, mp 128-129° C.
  • Ex-21A 1-[4-(4-Methylpiperazine-1-sulfonyl)phenyl]ethanone was prepared in an analogous fashion as Ex-17A using 4-methylpiperazine, 99% yield, pale yellow solid, mp 118-119° C.
  • HRMS (EI) Calcd. for C 13 H 18 N 2 O 3 S: 282.1038 (M + ); Found: 282.1038.
  • Ex-22A 4-Acetyl-N-piperidin-1-ylbenzenesulfonamide was prepared in an analogous fashion as Ex-17A using 1-aminopiperidine, 98% yield, pale yellow solid, mp 137-139° C.
  • Ex-23A 4-Acetyl-N-(3-imidazol-1-ylpropyl)benzenesulfonamide was prepared in an analogous fashion as Ex-17A using 1-(3-aminopropyl)imidazole, 89% yield, white solid, mp 142-144° C.
  • Ex-24A 4-Acetyl-N-(2,2,2-trifluoroethyl)benzenesulfonamide was prepared in an analogous fashion as Ex-17A using 2,2,2-trifluoroethylamine hydrochloride and triethylamine in a tetrahydrofuran:water mixture (9:1), 73% yield, white solid, mp 180-181° C.
  • HRMS (EI) Calcd. for C 10 H 10 F 3 NO 3 S: 281.0333 (M + ); Found: 281.0342.
  • Ex-27A 2-(4-Acetylbenzenesulfonylamino)-2-methylpropionic acid was prepared in an analogous fashion as Ex-26A using 2-aminoisobutyric acid, 70% yield, white solid, mp 157-158° C.
  • Ex-28A 1-(4-Acetylbenzenesulfonyl)piperidine-2-carboxylic acid was prepared in an analogous fashion as Ex-26A using 2-pipecolinic acid, 67% yield, white foam.
  • HRMS (ESI) Calcd. for C 14 H 17 NO 5 S: 312.0905 (M+H) + ; Found: 312.0915.
  • Ex-31A 4-Acetyl-N,N-dimethylbenzenesulfonamide was prepared in an analogous manner as Ex-29A using dimethylamine, 93% yield, white solid.
  • Ex-32A 2-(5-Formyl-2,4-dimethoxyphenyl)indole-1-carboxylic acid tert-butyl ester was prepared from 5-bromo-2,4-dimethoxybenzaldehyde and N-Boc-indole-2-boronic acid in a similar manner as Ex-1A, 79% yield, yellow oil.
  • Ex-32B 2-(5-Formyl-2,4-dimethoxyphenyl)indole-1-carboxylic acid tert-butyl ester (Ex-32A, 2.0 g, 5.2 mmol) was dissolved in 100 ml of THF, and Bu 4 NF (6.86 g, 26 mmol) was added. The reaction mixture was stirred at room temperature overnight. No significant reaction occurred under these conditions by HPLC. Then, additional Bu 4 NF (6.86 g, 26 mmol) was added to the mixture, and the mixture was stirred at reflux for 4 days. The reaction reached about 50% completion (HPLC). The reaction mixture was poured into CH 2 Cl 2 , and washed with water and brine.
  • the crude product was further purified by recrystallization from THF/heptane (1:1) to give 5-iodo-2,4-dimethoxybenzaldehyde as an off-white solid (27.5 g, m.p 170-172° C.).
  • the mother liquid was concentrated to dryness.
  • the residual material was dissolved in EtOH (100 mL) and acetone (20 mL) followed by addition of water (20 mL) to give additional product (3.12 g, m.p. 169-171° C.). Overall isolated yield of this reaction was 87.5%.
  • Ex-35C To a solution of 5-iodo-2,4-dimethoxybenzaldehyde (Ex-35B, 11.7 g, 40 mmol) in 250 ml of THF, PdCl 2 (PPh 3 ) 2 (0.56 g, 0.8 mmol), CuI (0.3 g, 1.6 mmol), Et 3 N (6.06 g, 60 mmol), and 2-[(trimethylsilyl)ethynyl]aniline (7.92 g, 42 mmol) were added. The mixture was stirred to a homogeneous solution, and then TBAF (10.4 g, 40 mmol) was added. The reaction mixture was aged at room temperature for 4 h and then filtered.
  • PdCl 2 (PPh 3 ) 2 (0.56 g, 0.8 mmol
  • CuI 0.3 g, 1.6 mmol
  • Et 3 N 6.06 g, 60 mmol
  • Ex-35D 4- ⁇ 3E-[5-(2-Amino-phenylethynyl)-2,4-dimethoxyphenyl]acryloyl ⁇ benzenesulfonamide was prepared in a similar manner as Ex-1 using 4-acetylbenzenesulfonamide (Ex-35A) and 5-(2-amino-phenylethynyl)-2,4-dimethoxybenzaldehyde (Ex-35C), 82.6% yield, yellow solid, mp 167-169° C.
  • Ex-35E 4- ⁇ 3E-[5-(2-Aminophenylethynyl)-2,4-dimethoxyphenyl]acryloyl ⁇ benzenesulfonamide (Ex-35D, 0.91 g, 1.97 mmol) was dissolved in acetonitrile (100 ml), heated to reflux, and then PdCl 2 (0.035 g, 0.197 mmol) was added. The reaction mixture was kept at reflux for 10 min and cooled to room temperature. Upon cooling, the mixture was filtered to remove any solid material and the filtrate was treated with 3-mercaptopropyl-functionalized silica gel (1.0 g) under stirring for 0.5 h.
  • Ex-38A Method A: A mixture of 2,4-dimethoxyaniline (1.0 g, 6.53 mmol), 1,4-dibromobutane (1.41 g, 6.53 mmol) and potassium carbonate (3.61 g, 26.1 mmol) in N,N-dimethylformamide (70 mL) was heated at 150° C. overnight. The reaction mixture was concentrated under reduced pressure. The residue was taken up in a mixture of water and ethyl acetate. After the mixture was partitioned, the aqueous solution was extracted with ethyl acetate. The combined solution of ethyl acetate was washed with saturated sodium bicarbonate, brine, dried over sodium sulfate and concentrated.
  • Method B Sodium tert-butoxide was charged to a mixture of 1-bromo-2,4-dimethoxybenzene (3.03 g, 14.0 mmol), pyrrolidine (1.75 mL, 20.9 mmol), tris(dibenzylideneacetone)dipalladium (Pd 2 (dba) 3 ) (0.26 g, 0.28 mmol) and rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP) (0.35 g, 0.56 mmol) in degassed toluene (60 mL). The reaction mixture was heated at 100° C. under N 2 for 17 h.
  • Ex-38B To a solution of 1-pyrrolidin-1-yl-2,4-dimethoxybenzene (Ex-38A, 1.82 g, 8.78 mmol) and ⁇ , ⁇ -dichloromethyl methyl ether (1.6 mL, 17.6 mmol) in dichloromethane (50 mL) was added titanium tetrachloride (1.0 M in dichloromethane, 26.3 mL, 26.3 mmol) dropwise at 0° C. The solution was allowed to stir for 16 h at ambient temperature and poured into ice/water. The aqueous solution was extracted with dichloromethane.
  • the combined dichloromethane was washed with saturated sodium bicarbonate, brine, dried over sodium sulfate and concentrated to give a crude product (0.67 g).
  • the aqueous solution was further treated with solid sodium hydroxide to pH 8.
  • the suspension was mixed with ethyl acetate.
  • the insoluble solid was removed by filtering through a pad of Celite.
  • the filtrate was then partitioned.
  • the aqueous solution was further extracted with ethyl acetate.
  • the combined ethyl acetate was washed with saturated sodium bicarbonate, brine, dried over sodium sulfate and concentrated.
  • the combined crude product (1.71 g) was purified by flash chromatography.
  • Ex-39A A solution of 2-hydroxy-4-methoxy-5-thiophen-2-yl-benzaldehyde (Ex-13C, 500 mg, 2.13 mmol) in DMF (20 mL) was treated with potassium carbonate (589 mg, 4.26 mmol) followed by the addition of 3-bromo-propan-1-ol (356 mg, 2.56 mmol). The reaction mixture was heated to 80° C. for 2 h followed by another addition of potassium carbonate (294 mg, 2.13 mmol) and 3-bromo-propan-1-ol (296 mg, 2.13 mmol). The reaction mixture was stirred for an additional 45 minutes, quenched with water (15 mL), and extracted with ethyl acetate (2 ⁇ 25 ml).
  • Ex-48A To a solution of 4-acetylbenzenesulfonamide (Ex-35A, 0.13 g, 0.64 mmol) and 2,4-dimethoxy-5-pyrrolidin-1-yl-benzaldehyde (Ex-38B, 0.15 g, 0.64 mmol) in N,N-dimethylformamide (5 mL) was added lithium methoxide (1.0 M in methanol, 1.6 mL, 1.6 mmol). The solution was allowed to stir at ambient temperature for 13 h and then at 40° C. for 2 h. HPLC indicated no further change of starting materials. The reaction mixture was then diluted with water, acidified to pH 5.
  • Ex-50A A solution of 4-acetyl-N-(3-imidazol-1-ylpropyl)benzenesulfonamide (Ex-23A, 312 mg, 1.02 mmol) and 5-(2-amino-phenylethynyl)-2,4-dimethoxybenzaldehyde (Ex-35C, 287 mg, 1.02 mmol) in DMF (4.4 mL) and MeOH (1.9 mL) was treated with lithium methoxide (155 mg, 4.08 mmol). The reaction mixture was stirred at room temperature for 16 h under nitrogen. The reaction mixture was quenched with water (25 mL) and extracted with (3:1) ethyl acetate/THF (3 ⁇ 25 mL).
  • Ex-51A A solution (4-acetylbenzenesulfonylamino)acetic acid (Ex-26A, 238 mg, 1.01 mmol) in DMF (4.4 mL) and MeOH (1.9 mL) was treated with lithium methoxide (153 mg, 4.04 mmol), followed by the addition of 5-(2-amino-phenylethynyl)-2,4-dimethoxybenzaldehyde (Ex-35C, 300 mg, 1.07 mmol). The reaction mixture was stirred at room temperature for 23 h under nitrogen. It was quenched with water (10 mL) and extracted with ethyl acetate (25 mL).
  • the aqueous phase was acidified with 6N HCl to pH3 and was extracted with (3:1) ethyl acetate/THF (5 ⁇ 25 mL).
  • the organic phase was brined, dried over sodium sulfate, and concentrated to a yellow oil.
  • the crude material was purified by column chromatography (0-7.5% MeOH in dichloromethane) to give (4- ⁇ 3E-[5-(2-amino-phenylethynyl)-2,4-dimethoxyphenyl]acryloyl ⁇ benzenesulfonylamino)acetic acid (188 mg, 36%) as an orange solid.
  • Ex-53A A solution of 4-acetyl-benzenesulfonyl chloride (1.94 g, 8.89 mmol) and triethylamine (1.85 mL, 13.3 mmol) in anhydrous THF (15 mL) was treated with 2-(aminomethyl)pyridine (1.01 g, 9.34 mmol) at room temperature under nitrogen. The reaction mixture was stirred for 5 minutes and a precipitate formed. The reaction mixture was diluted with water (10 mL) and suction filtration gave 4-acetyl-N-pyridin-2-ylmethylbenzenesulfonamide as a yellow solid (1.36 g, 65%).
  • Ex-55A A chilled solution of 4-acetyl-benzenesulfonyl chloride (1.0 g, 4.57 mmol) and triethylamine (0.955 mL, 6.86 mmol) in anhydrous THF (5 mL) was treated with 1-(3-aminopropyl)-4-methylpiperazine (755 mg, 4.80 mmol) under nitrogen. The reaction mixture was stirred for 30 minutes, quenched with water (30 mL) and extracted with ethyl acetate (3 ⁇ 25 mL).
  • the aqueous phase was acidified with 6N HCl to pH 3 and was extracted with (3:1) ethyl acetate/THF (6 ⁇ 25 mL).
  • the organic phase was brined, dried over sodium sulfate, and concentrated to a red solid.
  • Precipitation from dichloromethane (5 mL) gave the title compound (33 mg, 8%) as a brown solid, mp 155-158° C.
  • Ex-57A A solution of 4-acetyl-N-pyridin-2-ylbenzenesulfonamide (Ex-5A, 451 mg, 1.63 mmol) and 5-(2-aminophenylethynyl)-2,4-dimethoxybenzaldehyde (Ex-35C, 459 mg, 1.63 mmol) in DMF (10.0 mL) and MeOH (5.0 mL) was treated with lithium methoxide (248 mg, 6.52 mmol). The reaction mixture was stirred at room temperature for 3 h under nitrogen, quenched with water (50 mL), and extracted with (3:1) ethyl acetate/THF (4 ⁇ 30 mL).
  • N-[2-(5-Formyl-2,4-dimethoxy-phenyl ethynyl)phenyl]acetamide (Ex-57E, 535 mg, 1.6 mmol) was added to 150 mL of DMF (nitrogen purged) at room temperature and the resulting solution was heated to 80° C. Palladium(II) chloride (22 mg) was added in one portion. After 6 h the reaction mixture was poured into water (50 mL) and EtOAc (50 mL), and the layers were cut. The organic layer was filtered through Celite, washed with brine, and concentrated to an orange solid.
  • N-[2-(5-Formyl-2,4-dimethoxy-phenylethynyl)phenyl]-2,2-dimethylpropionamide (Ex-57G, 19.86 g, 54.4 mmol) was dissolved in nitrogen-purged DMF (189 mL) and heated to 80° C., followed by the addition of palladium(II) chloride (754 mg). After 1 h, the reaction mixture was diluted with water (300 mL) and extracted with EtOAc (2 ⁇ 200 mL). The combined organic phase was brined, dried over sodium sulfate, and concentrated to brown oil.
  • the title compound could be prepared from 4-acetyl-N-pyridin-2-ylbenzenesulfonamide (Ex-5A) and 5-(1-acetyl-1H-indol-2-yl)-2,4-dimethoxybenzaldehyde (Ex-57F) or 5-(1H-indol-2-yl)-2,4-dimethoxybenzaldehyde (Ex-57D or Ex-57DD).
  • compounds of the present invention having a chiral center may exist in and be isolated in optically active and racemic forms. Some compounds may exhibit polymorphism. It is to be understood that the present invention encompasses any racemic, optically-active, diastereomeric, polymorphic, or stereoisomeric form, or mixtures thereof, of a compound of the invention, which possess the useful properties described herein, it being well known in the art how to prepare optically active forms (for example, by resolution of the racemic form by recrystallization techniques, by synthesis from optically-active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase).
  • optically active materials examples include at least the following.
  • pharmaceutically acceptable salts or “complexes” refers to salts or complexes that retain the desired biological activity of the compounds of the present invention and exhibit minimal undesired toxicological effects.
  • Examples of pharmaceutically acceptable salts are organic acid addition salts formed with acids, which form a physiological acceptable anion, for example, tosylate, methanesulfonate, acetate, citrate, malonate, tartarate, succinate, benzoate, ascorbate, ⁇ -ketoglutarate and ⁇ -glycerophosphate.
  • Suitable inorganic salts may also be formed, including, sulfate, nitrate, bicarbonate and carbonate salts.
  • the pharmaceutically acceptable salts may be made with sufficiently basic compounds such as an amine with a suitable acid affording a physiologically acceptable anion.
  • Alkali metal (for example, sodium, potassium or lithium) or alkaline earth metal (for example calcium) salts of carboxylic acids can also be made.
  • Nonlimiting examples of such salts are (a) acid addition salts formed with inorganic acids (for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like), and salts formed with organic acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, naphthalenedisulfonic acid, and polygalacturonic acid; (b) base addition salts formed with metal cations such as zinc, calcium, bismuth, barium, magnesium, aluminum, copper, cobalt, nickel, cadmium, sodium, potassium, and the like, or with a cation formed from ammonia, N,N-dibenzylethylenediamine, D-glucosamine, tetraethylammonium, or ethylene
  • quaternary salts known by those skilled in the art, which specifically include the quaternary ammonium salt of the formula —NR + A ⁇ , wherein R is as defined above and A is a counterion, including chloride, bromide, iodide, —O-alkyl, toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carboxylate (such as benzoate, succinate, acetate, glycolate, maleate, malate, citrate, tartrate, ascorbate, benzoate, cinnamoate, mandeloate, benzyloate, and diphenylacetate).
  • R is as defined above and A is a counterion, including chloride, bromide, iodide, —O-alkyl, toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carboxylate (such as benzoate, succ
  • approved anions include aceglumate, acephyllinate, acetamidobenzoate, acetate, acetylasparaginate, acetylaspartate, adipate, aminosalicylate, anhydromethylenecitrate, ascorbate, aspartate, benzoate, besylate, bicarbonate, bisulfate, bitartrate, borate, bromide, camphorate, camsylate, carbonate, chloride, chlorophenoxyacetate, citrate, closylate, cromesilate, cyclamate, dehydrocholate, dihydrochloride, dimalonate, edentate, edisylate, estolate, esylate, ethylbromide, ethylsulfate, fendizoate, fosfatex, fumarate, gluceptate, gluconate, glucuronate, glutamate, glycerophosphate, glycero
  • the approved cations include ammonium, benethamine, benzathine, betaine, calcium, carnitine, clemizole, chlorcyclizine, choline, dibenylamine, diethanolamine, diethylamine, diethylammonium diolamine, eglumine, erbumine, ethylenediamine, heptaminol, hydrabamine, hydroxyethylpyrrolidone, imadazole, meglumine, olamine, piperazine, 4-phenylcyclohexylamine, procaine, pyridoxine, triethanolamine, and tromethamine.
  • Metallic cations include, aluminum, bismuth, calcium lithium, magnesium, neodymium, potassium, rubidium, sodium, strontium and zinc.
  • a particular class of salts can be classified as organic amine salts.
  • the organic amines used to form these salts can be primary amines, secondary amines or tertiary amines, and the substituents on the amine can be straight, branched or cyclic groups, including ringed structures formed by attachment of two or more of the amine substituents.
  • organic amines that are substituted by one or more hydroxyalkyl groups, including alditol or carbohydrate moieties.
  • These hydroxy substituted organic amines can be cyclic or acyclic, both classes of which can be primary amines, secondary amines or tertiary amines.
  • a common class of cyclic hydroxy substituted amines are the amino sugars.
  • a particular class of acyclic organic amines are represented by the formula wherein Y and Z are independently hydrogen or lower alkyl or, may be taken together to form a ring, R is hydrogen, alkyl or hydroxyloweralkyl, and n is 1, 2, 3, 4, or 5.
  • Y and Z are independently hydrogen or lower alkyl or, may be taken together to form a ring
  • R is hydrogen, alkyl or hydroxyloweralkyl
  • n 1, 2, 3, 4, or 5.
  • n 1, 2, 3, 4, or 5.
  • the invention also includes pharmaceutically acceptable prodrugs of the compounds.
  • Pharmaceutically acceptable prodrugs refer to a compound that is metabolized, for example hydrolyzed or oxidized, in the host to form the compound of the present invention.
  • Typical examples of prodrugs include compounds that have biologically labile protecting groups on a functional moiety of the active compound.
  • Prodrugs include compounds that can be oxidized, reduced, aminated, deaminated, hydroxylated, dehydroxylated, hydrolyzed, dehydrolyzed, alkylated, dealkylated, acylated, deacylated, phosphorylated, dephosphorylated to produce the active compound.
  • any of the compounds described herein can be administered as a prodrug to increase the activity, bioavailability, stability or otherwise alter the properties of the compound.
  • a number of prodrug ligands are known. In general, alkylation, acylation or other lipophilic modification of the compound will increase the stability of the chalcone.
  • substituent groups that can replace one or more hydrogens on the compound are alkyl, aryl, steroids, carbohydrates, including sugars, 1,2-diacylglycerol and alcohols. Many are described in R. Jones and N. Bischofberger, Antiviral Research, 27 (1995) 1-17. Any of these can be used in combination with the disclosed compounds to achieve a desired effect.
  • the compounds of the present invention can be used to treat any disorder that is mediated by VCAM-1.
  • Inflammatory disorders that are mediated by VCAM-1 include, but are not limited to arthritis, asthma, dermatitis, psoriasis, cystic fibrosis, post transplantation late and chronic solid organ rejection, multiple sclerosis, systemic lupus erythematosis, inflammatory bowel diseases, autoimmune diabetes, diabetic retinopathy, diabetic nephropathy, diabetic vasculopathy, ocular inflammation, uveitis, rhinitis, ischemia-reperfusion injury, post-angioplasty restenosis, chronic obstructive pulmonary disease (COPD), glomerulonephritis, Graves disease, gastrointestinal allergies, conjunctivitis, atherosclerosis, coronary artery disease, angina and small artery disease.
  • COPD chronic obstructive pulmonary disease
  • the compounds disclosed herein can be used in the treatment of inflammatory skin diseases that are mediated by VCAM-1, and in particular, human endothelial disorders that are mediated by VCAM-1, which include, but are not limited to, psoriasis, dermatitis, including eczematous dermatitis, and Kaposi's sarcoma, as well as proliferative disorders of smooth muscle cells.
  • the compounds disclosed herein can be selected to treat anti-inflammatory conditions that are mediated by mononuclear leucocytes.
  • the compounds of the present invention can be selected for the prevention or treatment of tissue or organ transplant rejection.
  • Treatment and prevention of organ or tissue transplant rejection includes, but are not limited to treatment of recipients of heart, lung, combined heart-lung, liver, kidney, pancreatic, skin, spleen, small bowel, or corneal transplants. They are also indicated for the prevention or treatment of graft-versus-host disease, which sometimes occurs following bone marrow transplantation.
  • the compounds described herein are useful in both the primary and adjunctive medical treatment of cardiovascular disease.
  • the compounds are used in primary treatment of, for example, coronary disease states including atherosclerosis, post-angioplasty restenosis, coronary artery diseases and angina.
  • the compounds can be administered to treat small vessel disease that is not treatable by surgery or angioplasty, or other vessel disease in which surgery is not an option.
  • the compounds can also be used to stabilize patients prior to revascularization therapy.
  • the compounds can be used in compositions including pharmaceutical compositions for the treatment of diseases or disorders mediated by VCAM-1 wherein such compositions comprise a VCAM-1 inhibiting amount of a compound of the invention or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable carrier.
  • Another aspect of the invention provides a method for treating a disease or disorder mediated by VCAM-1 comprising administering to a patient a VCAM-1 inhibiting effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof.
  • the invention provides a method for treating cardiovascular and inflammatory disorders in a patient in need thereof comprising administering to said patient an VCAM-1 inhibiting effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof.
  • the invention provides a method and composition for treating asthma or arthritis in a patient in need thereof comprising administering to said patient an effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof.
  • Nonlimiting examples of arthritis include rheumatoid (such as soft-tissue rheumatism and non-articular rheumatism, fibromyalgia, fibrositis, muscular rheumatism, myofascil pain, humeral epicondylitis, frozen shoulder, Tietze's syndrome, fascitis, tendinitis, tenosynovitis, bursitis), juvenile chronic, spondyloarthropaties (ankylosing spondylitis), osteoarthritis, hyperuricemia and arthritis associated with acute gout, chronic gout and systemic lupus erythematosus.
  • rheumatoid such as soft-tissue rheumatism and non-articular rheumatism, fibromyalgia, fibrositis, muscular rheumatism, myofascil pain, humeral epicondylitis, frozen shoulder, Tietze's syndrome, fascitis
  • VCAM-1 Human endothelial disorders mediated by VCAM-1 include psoriasis, eczematous dermatitis, Kaposi's sarcoma, as well as proliferative disorders of smooth muscle cells.
  • the compounds disclosed herein can be selected to treat anti-inflammatory conditions that are mediated by mononuclear leucocytes.
  • the compounds of the present invention are selected for the prevention or treatment of tissue or organ transplant rejection.
  • Treatment and prevention of organ or tissue transplant rejection includes, but are not limited to treatment of recipients of heart, lung, combined heart-lung, liver, kidney, pancreatic, skin, spleen, small bowel, or corneal transplants.
  • the compounds can also be used in the prevention or treatment of graft-versus-host disease, such as sometimes occurs following bone marrow transplantation.
  • the compounds described herein are useful in both the primary and adjunctive medical treatment of cardiovascular disease.
  • the compounds are used in primary treatment of, for example, coronary disease states including atherosclerosis, post-angioplasty restenosis, coronary artery diseases and angina.
  • the compounds can be administered to treat small vessel disease that is not treatable by surgery or angioplasty, or other vessel disease in which surgery is not an option.
  • the compounds can also be used to stabilize patients prior to revascularization therapy.
  • MCP-1 monocyte chemoattractant protein-1
  • MCP-1 monocyte chemoattractant protein-1
  • MCP-1 is a chemoattractant protein produced by endothelial cells, smooth muscle cells as well as macrophages. MCP-1 promotes integrin activation on endothelial cells thereby facilitating adhesion of leukocytes to VCAM-1, and MCP-1 is a chemoattractant for monocytes. MCP-1 has been shown to play a role in leukocyte recruitment in a number of chronic inflammatory diseases including atherosclerosis, rheumatoid arthritis, and asthma.
  • MCP-1 expression is upregulated in these diseases and as such inhibition of MCP-1 expression represents a desirable property of anti-inflammatory therapeutics.
  • smooth muscle cell hyperplasia and resulting tissue remodeling and decreased organ function is yet another characteristic of many chronic inflammatory diseases including atherosclerosis, chronic transplant rejection and asthma. Inhibition of the hyperproliferation of smooth muscle cells is another desirable property for therapeutic compounds.
  • Any of the compounds disclosed herein can be administered in combination or alternation with a second biologically active agent to increase its effectiveness against the target disorder.
  • the efficacy of a drug can be prolonged, augmented, or restored by administering the compound in combination or alternation with a second, and perhaps third, agent that induces a different biological pathway from that caused by the principle drug.
  • a second, and perhaps third, agent that induces a different biological pathway from that caused by the principle drug.
  • the pharmacokinetics, biodistribution or other parameter of the drug can be altered by such combination or alternation therapy.
  • combination therapy is typically preferred over alternation therapy because it induces multiple simultaneous stresses on the condition.
  • alternation patterns include 1-6 weeks of administration of an effective amount of one agent followed by 1-6 weeks of administration of an effective amount of a second agent.
  • the alternation schedule can include periods of no treatment.
  • Combination therapy generally includes the simultaneous administration of an effective ratio of dosages of two or more active agents.
  • agents that can be used in combination or alternation with the compounds of the present invention are described below in regard to asthma and arthritis.
  • the agents set out below or others can alternatively be used to treat a host suffering from any of the other disorders listed above or that are mediated by VCAM-1 or MCP-1.
  • Illustrative second biologically active agents for the treatment of cardiovascular disease are also provided below.
  • the compounds of the present invention are administered in combination or alternation with heparin, frusemide, ranitidine, an agent that effects respiratory function, such as DNAase, or immunosuppressive agents, IV gamma globulin, troleandomycin, cyclosporin (Neoral), methotrexate, FK-506, gold compounds such as Myochrysine (gold sodium thiomalate), platelet activating factor (PAF) antagonists such as thromboxane inhibitors, leukotriene-D 4 -receptor antagonists such as Accolate (zafirlukast), Ziflo (zileuton), leukotriene C 1 or C 2 antagonists and inhibitors of leukotriene synthesis such as zileuton for the treatment of asthma, or an inducible nitric oxide synthase inhibitor.
  • an agent that effects respiratory function such as DNAase, or immunosuppressive agents
  • IV gamma globulin such as Tween,
  • the active compound is administered in combination or alternation with one or more other prophylactic agent(s).
  • prophylactic agents that can be used in alternation or combination therapy include but are not limited to sodium cromoglycate, Intal (cromolyn sodium, Nasalcrom, Opticrom, Crolom, Ophthalmic Crolom), Tilade (nedocromil, nedocromil sodium) and ketotifen.
  • the active compound is administered in combination or alternation with one or more other ⁇ 2 -adrenergic agonist(s) ( ⁇ agonists).
  • ⁇ 2 -adrenergic agonists ⁇ agonists
  • ⁇ agonists include but are not limited to albuterol (salbutamol, Proventil, Ventolin), terbutaline, Maxair (pirbuterol), Serevent (salmeterol), epinephrine, metaproterenol (Alupent, Metaprel), Brethine (Bricanyl, Brethaire, terbutaline sulfate), Tornalate (bitolterol), isoprenaline, ipratropium bromide, bambuterol hydrochloride, bitolterol meslyate, broxaterol, carbuterol hydrochloride, clenbuterol hydrochloride, clorprenaline hydrochloride, efirmo
  • the active compound is administered in combination or alternation with one or more other corticosteriod(s).
  • corticosteriods that can be used in alternation or combination therapy include but are not limited to glucocorticoids (GC), Aerobid (Aerobid-M, flunisolide), Azmacort (triamcinolone acetonide), Beclovet (Vanceril, beclomethasone dipropionate), Flovent (fluticasone), Pulmicort (budesonide), prednisolone, hydrocortisone, adrenaline, Alclometasone Dipropionate, Aldosterone, Amcinonide, Beclomethasone Dipropionate, Bendacort, Betamethasone (Betamethasone Acetate, Betamethasone Benzoate, Betamethasone Dipropionate, Betamethasone Sodium Phosphate, Betamethasone Valerate), Budesonide, Ciclomethasone, Ciprocinonide,
  • the active compound is administered in combination or alternation with one or more other antihistimine(s) (H 1 receptor antagonists).
  • antihistimines H 1 receptor antagonists
  • antihistimines include alkylamines, ethanolamines ethylenediamines, piperazines, piperidines or phenothiazines.
  • antihistamines are Chlortrimeton (Teldrin, chlorpheniramine), Atrohist (brompheniramine, Bromarest, Bromfed, Dimetane), Actidil (triprolidine), Dexchlor (Poladex, Polaramine, dexchlorpheniramine), Benadryl (diphenhydramine), Tavist (clemastine), Dimetabs (dimenhydrinate, Dramamine, Marmine), PBZ (tripelennamine), pyrilamine, Marezine (cyclizine), Zyrtec (cetirizine), hydroxyzine, Antivert (meclizine, Bonine), Allegra (fexofenadine), Hismanal (astemizole), Claritin (loratadine), Seldane (terfenadine), Periactin (cyproheptadine), Nolamine (phenindamine, Nolahist), Phenameth (promethazine, Phenergan),
  • the compound of the present invention may be administered in combination or alternation with
  • the compound of the present invention can also be administered in combination or alternation with apazone, amitriptyline, chymopapain, collegenase, cyclobenzaprine, diazepam, fluoxetine, pyridoxine, ademetionine, diacerein, glucosamine, hylan (hyaluronate), misoprostol, paracetamol, superoxide dismutase mimics, IL-1 receptor antagonists, IL-2 receptor antagonists, IL-6 receptor antagonists, TNF ⁇ receptor antagonists, TNF ⁇ antibodies, P38 MAP Kinase inhibitors, tricyclic antidepressents, cJun kinase inhibitors or immunosuppressive agents, IV gamma globulin, troleandomycin, cyclosporin (Neoral), methotrexate, FK-506, gold compounds such as Myochrysine (gold sodium thiomalate), platelet activating factor (PAF) antagonist
  • the active compound is administered in combination or alternation with one or more other corticosteriod(s).
  • corticosteriods that can be used in alternation or combination therapy include but are not limited to glucocorticoids (GC), Aerobid (Aerobid-M, flunisolide), Azmacort (triamcinolone acetonide), Beclovet (Vanceril, beclomethasone dipropionate), Flovent (fluticasone), Pulmicort (budesonide), prednisolone, hydrocortisone, adrenaline, Alclometasone Dipropionate, Aldosterone, Amcinonide, Beclomethasone Dipropionate, Bendacort, Betamethasone (Betamethasone Acetate, Betamethasone Benzoate, Betamethasone Dipropionate, Betamethasone Sodium Phosphate, Betamethasone Valerate), Budesonide, Ciclomethasone, Ciprocinonide,
  • the active compound is administered in combination or alternation with one or more other non-steroidal anti-inflammatory drug(s) (NSAIDS).
  • NSAIDS non-steroidal anti-inflammatory drug(s)
  • NSAIDS non-steroidal anti-inflammatory drug(s)
  • COX-2 cylcooxygenase-2
  • Some nonlimiting examples of COX-2 inhibitors are Celebrex (celecoxib), Bextra (valdecoxib), Dynastat (parecoxib sodium) and Vioxx (rofacoxib).
  • NSAIDS are aspirin (acetylsalicylic acid), Dolobid (diflunisal), Disalcid (salsalate, salicylsalicylate), Trisilate (choline magnesium trisalicylate), sodium salicylate, Cuprimine (penicillamine), Tolectin (tolmetin), ibuprofen (Motrin, Advil, Nuprin Rufen), Naprosyn (naproxen, Anaprox, naproxen sodium), Nalfon (fenoprofen), Orudis (ketoprofen), Ansaid (flurbiprofen), Daypro (oxaprozin), meclofenamate (meclofanamic acid, Meclomen), mefenamic acid, Indocin (indomethacin), Clinoril (sulindac), tolmetin, Voltaren (diclofenac), Lodine (etodolac), ketorolac, Butazolidin (phenylsalicylic
  • Compounds useful for combining with the compounds of the present invention for the treatment of cardiovascular disease encompass a wide range of therapeutic compounds.
  • IBAT inhibitors for example, are useful in the present invention, and are disclosed in patent application no. PCT/US95/10863, herein incorporated by reference. More IBAT inhibitors are described in PCT/US97/04076, herein incorporated by reference. Still further IBAT inhibitors useful in the present invention are described in U.S. application Ser. No. 08/816,065, herein incorporated by reference. More IBAT inhibitor compounds useful in the present invention are described in WO 98/40375, and WO 00/38725, herein incorporated by reference. Additional IBAT inhibitor compounds useful in the present invention are described in U.S. application Ser. No. 08/816,065, herein incorporated by reference.
  • the second biologically active agent is a statin.
  • Statins lower cholesterol by inhibiting of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, a key enzyme in the cholesterol biosynthetic pathway.
  • HMG CoA 3-hydroxy-3-methylglutaryl coenzyme A
  • the statins decrease liver cholesterol biosynthesis, which increases the production of LDL receptors thereby decreasing plasma total and LDL cholesterol (Grundy, S. M. New Engl. J. Med. 319, 24 (1988); Endo, A. J. Lipid Res. 33, 1569 (1992)).
  • statins may decrease plasma triglyceride levels and may increase HDLc.
  • statins on the market are lovastatin (Merck), simvastatin (Merck), pravastatin (Sankyo and Squibb) and fluvastatin (Sandoz).
  • a fifth statin, atorvastatin (Parke-Davis/Pfizer) is the most recent entrant into the statin market. Any of these statins or thers can be used in combination with the chalcones of the present invention.
  • MTP inhibitor compounds useful in the combinations and methods of the present invention comprise a wide variety of structures and functionalities. Some of the MTP inhibitor compounds of particular interest for use in the present invention are disclosed in WO 00/38725, the disclosure from which is incorporated by reference. Descriptions of these therapeutic compounds can be found in Science, 282, 23 Oct. 1998, pp. 751-754, herein incorporated by reference.
  • Cholesterol absorption antagonist compounds useful in the combinations and methods of the present invention comprise a wide variety of structures and functionalities. Some of the cholesterol absorption antagonist compounds of particular interest for use in the present invention are described in U.S. Pat. No. 5,767,115, herein incorporated by reference. Further cholesterol absorption antagonist compounds of particular interest for use in the present invention, and methods for making such cholesterol absorption antagonist compounds are described in U.S. Pat. No. 5,631,365, herein incorporated by reference.
  • phytosterols suitable for the combination therapies of the present invention are described by Ling and Jones in “Dietary Phytosterols: A Review of Metabolism, Benefits and Side Effects,” Life Sciences, 57 (3), 195-206 (1995). Without limitation, some phytosterols of particular use in the combination of the present invention are Clofibrate, Fenofibrate, Ciprofibrate, Bezafibrate, Gemfibrozil. The structures of the foregoing compounds can be found in WO 00/38725.
  • Phytosterols are also referred to generally by Nes ( Physiology and Biochemistry of Sterols , American Oil Chemists' Society, Champaign, Ill., 1991, Table 7-2). Especially preferred among the phytosterols for use in the combinations of the present invention are saturated phytosterols or stanols. Additional stanols are also described by Nes (Id.) and are useful in the combination of the present invention.
  • the phytosterol preferably comprises a stanol.
  • the stanol is campestanol.
  • the stanol is cholestanol.
  • the stanol is clionastanol.
  • the stanol is coprostanol. In another preferred embodiment the stanol is 22,23-dihydrobrassicastanol. In another embodiment the stanol is epicholestanol. In another preferred embodiment the stanol is fucostanol. In another preferred embodiment the stanol is stigmastanol.
  • the present invention encompasses a therapeutic combination of a compound of the present invention and an HDLc elevating agent.
  • the second HDLc elevating agent can be a CETP inhibitor.
  • Individual CETP inhibitor compounds useful in the present invention are separately described in WO 00/38725, the disclosure of which is herein incorporated by reference.
  • Other individual CETP inhibitor compounds useful in the present invention are separately described in WO 99/14174, EP818448, WO 99/15504, WO 99/14215, WO 98/04528, and WO 00/17166, the disclosures of which are herein incorporated by reference.
  • the second biologically active agent can be a fibric acid derivative.
  • Fibric acid derivatives useful in the combinations and methods of the present invention comprise a wide variety of structures and functionalities which have been reported and published in the art.
  • the compounds of the present invention may also be used in combination or alternation therapy with PPAR agonists including PPAR ⁇ / ⁇ dual agonists, PPAR ⁇ agonists, and PPAR ⁇ agonists.
  • the present invention encompasses a therapeutic combination of a compound of the present invention and an antihypertensive agent. Hypertension is defined as persistently high blood pressure.
  • the chalcone is administered in combination with an ACE inhibitor, a beta andrenergic blocker, alpha andrenergic blocker, angiotensin II receptor antagonist, vasodilator and diuretic.
  • Any host organism including a patient, mammal, and specifically a human, suffering from any of the above-described conditions can be treated by the administration of a composition comprising an effective amount of the compound of the invention or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier or diluent.
  • composition can be administered in any desired manner, including oral, topical, parenteral, intravenous, intradermal, intra-articular, intra-synovial, intrathecal, intra-arterial, intracardiac, intramuscular, subcutaneous, intraorbital, intracapsular, intraspinal, intrasternal, topical, transdermal patch, via rectal, vaginal or urethral suppository, peritoneal, percutaneous, nasal spray, surgical implant, internal surgical paint, infusion pump, or via catheter.
  • the agent and carrier are administered in a slow release formulation such as an implant, bolus, microparticle, microsphere, nanoparticle or nanosphere.
  • an effective dose for any of the herein described conditions can be readily determined by the use of conventional techniques and by observing results obtained under analogous circumstances. In determining the effective dose, a number of factors are considered including, but not limited to: the species of patient; its size, age, and general health; the specific disease involved; the degree of involvement or the severity of the disease; the response of the individual patient; the particular compound administered; the mode of administration; the bioavailability characteristics of the preparation administered; the dose regimen selected; and the use of concomitant medication.
  • Typical systemic dosages for all of the herein described conditions are those ranging from 0.1 mg/kg to 500 mg/kg of body weight per day as a single daily dose or divided daily doses.
  • Preferred dosages for the described conditions range from 5-1500 mg per day.
  • a more particularly preferred dosage for the desired conditions ranges from 25-750 mg per day.
  • Typical dosages for topical application are those ranging from 0.001 to 100% by weight of the active compound.
  • the compound is administered for a sufficient time period to alleviate the undesired symptoms and the clinical signs associated with the condition being treated.
  • the active compound is included in the pharmaceutically acceptable carrier or diluent in an amount sufficient to deliver to a patient a therapeutic amount of compound in vivo in the absence of serious toxic effects.
  • the concentration of active compound in the drug composition will depend on absorption, inactivation, and excretion rates of the drug as well as other factors known to those of skill in the art. It is to be noted that dosage values will also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that the dosage ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed composition.
  • the active ingredient may be administered at once, or may be divided into a number of smaller doses to be administered at varying intervals of time.
  • Oral compositions will generally include an inert diluent or an edible carrier. They may be enclosed in gelatin capsules or compressed into tablets.
  • the active compound can be incorporated with excipients and used in the form of tablets, troches or capsules. Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition.
  • the tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.
  • a binder such as microcrystalline cellulose, gum tragacanth or gelatin
  • an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch
  • a lubricant such as magnesium stearate or Sterotes
  • a glidant such as colloidal silicon dioxide
  • dosage unit form When the dosage unit form is a capsule, it can contain, in addition to material of the above type, a liquid carrier such as a fatty oil.
  • dosage unit forms can contain various other materials which modify the physical form of the dosage unit, for example, coatings of sugar, shellac, or other enteric agents.
  • the compound or its salts can be administered as a component of an elixir, suspension, syrup, wafer, chewing gum or the like.
  • a syrup may contain, in addition to the active compounds, sucrose as a sweetening agent and certain preservatives, dyes and colorings and flavors.
  • the compound can also be mixed with other active materials that do not impair the desired action, or with materials that supplement the desired action.
  • the compounds can also be administered in combination with nonsteroidal antiinflammatories such as ibuprofen, indomethacin, fenoprofen, mefenamic acid, flufenamic acid, sulindac.
  • nonsteroidal antiinflammatories such as ibuprofen, indomethacin, fenoprofen, mefenamic acid, flufenamic acid, sulindac.
  • the compound can also be administered with corticosteriods.
  • Solutions or suspensions used for parenteral, intradermal, subcutaneous, or topical application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose. pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide.
  • the parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.
  • preferred carriers are physiological saline, bacteriostatic water, Cremophor ELTM (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS).
  • physiological saline bacteriostatic water
  • Cremophor ELTM BASF, Parsippany, N.J.
  • PBS phosphate buffered saline
  • the active compounds are prepared with carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems.
  • a controlled release formulation including implants and microencapsulated delivery systems.
  • Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art. The materials can also be obtained commercially from Alza Corporation and Nova Pharmaceuticals, Inc.
  • Liposomal suspensions including liposomes targeted to infected cells with monoclonal antibodies to viral antigens
  • These may be prepared according to methods known to those skilled in the art, for example, as described in U.S.
  • liposome formulations may be prepared by dissolving appropriate lipid(s) (such as stearoyl phosphatidyl ethanolamine, stearoyl phosphatidyl choline, arachadoyl phosphatidyl choline, and cholesterol) in an inorganic solvent that is then evaporated, leaving behind a thin film of dried lipid on the surface of the container. An aqueous solution of the compound is then introduced into the container. The container is then swirled by hand to free lipid material from the sides of the container and to disperse lipid aggregates, thereby forming the liposomal suspension.
  • appropriate lipid(s) such as stearoyl phosphatidyl ethanolamine, stearoyl phosphatidyl choline, arachadoyl phosphatidyl choline, and cholesterol
  • Suitable vehicles or carriers for topical application can be prepared by conventional techniques, such as lotions, suspensions, ointments, creams, gels, tinctures, sprays, powders, pastes, slow-release transdermal patches, suppositories for application to rectal, vaginal, nasal or oral mucosa.
  • thickening agents include petrolatum, beeswax, xanthan gum, or polyethylene, humectants such as sorbitol, emollients such as mineral oil, lanolin and its derivatives, or squalene.
  • any of the compounds described herein for combination or alternation therapy can be administered as any derivative that upon administration to the recipient, is capable of providing directly or indirectly, the parent compound, or that exhibits activity itself.
  • Nonlimiting examples are the pharmaceutically acceptable salts (alternatively referred to as “physiologically acceptable salts”), and a compound which has been alkylated or acylated at an appropriate position.
  • physiologically acceptable salts alternatively referred to as “physiologically acceptable salts”
  • the modifications can affect the biological activity of the compound, in some cases increasing the activity over the parent compound. This can easily be assessed by preparing the derivative and testing its anti-inflammatory activity according to known methods.
  • HAEC human aortic
  • HPAEC pulmonary endothelial cells
  • HBS Hanks Balanced Salt Solution
  • PBS Phosphate buffered saline
  • IC 50 values the concentration (micromolar) of compound required to inhibit 50% of the maximal response of the control sample stimulated by TNF- ⁇ only). Compounds exhibiting IC 50 's of less than 5 micromolar are tabulated in Biological Table 1.

Abstract

The invention relates to compounds, pharmaceutical compositions and methods of using compounds of the general formula
Figure US20070093453A1-20070426-C00001
 or its pharmaceutically acceptable salt or ester, wherein the substituents are defined in the application.

Description

    CROSS REFERENCE TO RELATED APPLICATIONS
  • This application claims priority to U.S. provisional patent application Ser. No. 60/476,708 filed Jun. 6, 2003.
    • FIELD OF THE INVENTION
  • The present invention is in the field of novel chalcone derivatives, pharmaceutical compositions and methods for treating a variety of diseases and disorders, including inflammation and cardiovascular disease.
    • BACKGROUND OF THE INVENTION
  • Adhesion of leukocytes to the endothelium represents a fundamental, early event in a wide variety of inflammatory conditions, autoimmune disorders and bacterial and viral infections. Leukocyte recruitment to endothelium is mediated in part by the inducible expression of adhesion molecules on the surface of endothelial cells that interact with counterreceptors on immune cells. Endothelial cells determine which types of leukocytes are recruited by selectively expressing specific adhesion molecules, such as vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and E-selectin. VCAM-1 binds to the integrin VLA-4 expressed on lymphocytes, monocytes, macrophages, eosinophils, and basophils but not neutrophils. This interaction facilitates the firm adhesion of these leukocytes to the endothelium. VCAM-1 is an inducible gene that is not expressed, or expressed at very low levels, in normal tissues. VCAM-1 is upregulated in a number of inflammatory diseases, including arthritis (including rheumatoid arthritis), asthma, dermatitis, psoriasis, cystic fibrosis, post transplantation late and chronic solid organ rejection, multiple sclerosis, systemic lupus erythematosis, inflammatory bowel diseases, autoimmune diabetes, diabetic retinopathy, rhinitis, ischemia-reperfusion injury, post-angioplasty restenosis, chronic obstructive pulmonary disease (COPD), glomerulonephritis, Graves disease, gastrointestinal allergies, conjunctivitis, atherosclerosis, coronary artery disease, angina and small artery disease.
  • U.S. Pat. Nos. 5,750,351; 5,807,884; 5,811,449; 5,846,959; 5,773,231, and 5,773,209 to Medford, et al., as well as the corresponding WO 95/30415 to Emory University indicate that polyunsaturated fatty acids (“PUFAs”) and their hydroperoxides (“ox-PUFAs”), which are important components of oxidatively modified low density lipoprotein (LDL), induce the expression of VCAM-1, but not intracellular adhesion molecule-1 (ICAM-1) or E-selectin in human aortic endothelial cells, through a mechanism that is not mediated by cytokines or other noncytokine signals. This is a fundamental discovery of an important and previously unknown biological pathway in VCAM-1 mediated immune responses. As non-limiting examples, linoleic acid, linolenic acid, arachidonic acid, linoleyl hydroperoxide (13-HPODE) and arachidonic hydroperoxide (15-HPETE) induce cell-surface gene expression of VCAM-1 but not ICAM-1 or E-selectin. Saturated fatty acids (such as stearic acid) and monounsaturated fatty acids (such as oleic acid) do not induce the expression of VCAM-1, ICAM-1 or E-selectin.
  • Chalcone (1,3-bis-aromatic-prop-2-en-1-ones) compounds are natural products related to flavonoids. WO 99/00114 (PCT/DK98/00283) discloses the use of certain chalcones, 1,3-bis-aromatic-propan-1-ones (dihydrochalcones), and 1,3-bisaromatic-prop-2-yn-1-ones for the preparation of pharmaceutical compositions for the treatment of prophylaxis of a number of serious diseases including i) conditions relating to harmful effects of inflammatory cytokines, ii) conditions involving infection by Helicobacter species, iii) conditions involving infections by viruses, iv) neoplastic disorders, and v) conditions caused by microorganisms or parasites.
  • U.S. Pat. No. 4,085,135 to Kyogoku et al. discloses a process for preparation of 2′-(carboxymethoxy)-chalcones having antigastric and anti duodenal activities with low toxicity and high absorptive ratio in the body.
  • European Patent No 307762 assigned to Hofmann-La Roche discloses substituted phenyl chalcones.
  • Herencia, et al., in Synthesis and Anti-inflammatory Activity of Chalcone Derivatives, Bioorganic & Medicinal Chemistry Letters 8 (1998) 1169-1174, discloses certain chalcone derivatives with anti-inflammatory activity.
  • Hsieh, et al., Synthesis and Antiinflammatory Effect of Chalcones, J. Pharm. Pharmacol. 2000, 52; 163-171 describes that certain chalcones have potent antiinflammatory activity.
  • Zwaagstra, et al., Synthesis and Structure-Activity Relationships of Carboxylated Chalcones: A Novel Series of CysLT1 (LT4) Receptor Antagonists; J. Med. Chem., 1997, 40, 1075-1089 discloses that in a series of 2-, 3-, and 4-(2-quinolinylmethoxy)- and 3- and 4-[2-(2-quinolinyl)ethenyl]-substituted, 2′, 3′, 4′, or 5′ carboxylated chalcones, certain compounds are CysLT1 receptor antagonists.
  • JP 63010720 to Nippon Kayaku Co., LTD discloses that chalcone derivatives of the following formula (wherein R1 and R2 are hydrogen or alkyl, and m and n are 0-3) are 5-lipoxygenase inhibitors and can be used in treating allergies.
    Figure US20070093453A1-20070426-C00002
  • JP 06116206 to Morinaga Milk Industry Co. Ltd, Japan, discloses chalcones of the following structure as 5-lipoxygenase inhibitors, wherein R is acyl and R1-R5 are hydrogen, lower alkyl, lower alkoxy or halo, and specifically that in which R is acyl and R1-R5 are hydrogen.
    Figure US20070093453A1-20070426-C00003
  • U.S. Pat. No. 6,046,212 to Kowa Co. Ltd. discloses heterocyclic ring-containing chalcones of the following formula as antiallergic agents.
    Figure US20070093453A1-20070426-C00004
  • Reported bioactivies of chalcones have been reviewed by Dimmock, et al., in Bioactivities of Chalcones, Current Medicinal Chemistry 1999, 6, 1125-1149; Liu, et al., Antimalarial Alkoxylated and Hydroxylated Chalones: Structure-Activity Relationship Analysis, J. Med. Chem. 2001, 44, 4443-4452; Herencia et al, Novel Anti-inflammatory Chalcone Derivatives Inhibit the Induction of Nitric Oxide Synthase and Cyclooxygenase-2 in Mouse Peritoneal Macrophages, FEBS Letters, 1999, 453, 129-134; and Hsieh et al., Synthesis and Anti-inflammatory Effect of Chalcones and Related Compounds, Pharmaceutical Research, 1998, Vol. 15, No. 1, 39-46.
  • U.S. patent application Ser. No. 09/866,348, filed Jun. 20, 2001 and Ser. No. 10/324,987, filed Dec. 19, 2002 both assigned to AtheroGenics, Inc., and herein incorporated by reference, disclose particular derivatives of chalcones suitable to treat diseases mediated by VCAM-1.
  • Given that VCAM-1 is a mediator of chronic inflammatory disorders, it is a goal of the present work to identify new compounds, compositions and methods that can inhibit the expression of VCAM-1. A more general goal is to identify selective compounds and methods for suppressing the expression of redox sensitive genes or activating redox sensitive genes that are suppressed. An even more general goal is to identify selective compounds, pharmaceutical compositions and methods of using the compounds for the treatment of inflammatory diseases.
  • It is therefore an object of the present invention to provide new compounds for the treatment of disorders mediated by VCAM-1.
  • It is also an object to provide new pharmaceutical compositions for the treatment of diseases and disorders mediated by the expression of VCAM-1.
  • It is a further object of the invention to provide compounds, compositions, and methods of treating disorders and diseases mediated by VCAM-1, including cardiovascular and inflammatory diseases.
  • Another object of the invention is to provide compounds, compositions, and method of treating cardiovascular and inflammatory diseases.
  • It is another object of the invention to provide compounds, compositions and methods to treat arthritis.
  • Another object of the invention is to provide compounds, compositions and methods to treat rheumatoid arthritis. The inventions compounds, compositions and methods are also suitable as disease modifying anti-rheumatoid arthritis drugs (DMARDs).
  • It is yet another object of the invention to provide compounds, compositions and methods to treat asthma.
  • It is another object of the invention to provide compounds, methods and compositions to inhibit the progression of atherosclerosis.
  • It is still another object of the invention to provide compounds, compositions, and methods to treat or prevent transplant rejection.
  • It is a further object of the present invention to provide compounds, methods and compositions for the treatment of lupus.
  • It is a further object of the present invention to provide compounds, methods and compositions for the treatment of inflammatory bowel disease.
  • It is a further object of the present invention to provide compounds, methods and compositions for the treatment of autoimmune diabetes.
  • It is a further object of the present invention to provide compounds, methods and compositions for the treatment of multiple sclerosis.
  • It is a further object of the present invention to provide compounds, methods and compositions for the treatment of diabetic retinopathy.
  • It is a further object of the present invention to provide compounds, methods and compositions for the treatment of diabetic nephropathy.
  • It is a further object of the present invention to provide compounds, methods and compositions for the treatment of diabetic vasculopathy.
  • It is a further object of the present invention to provide compounds, methods and compositions for the treatment of rhinitis.
  • It is a further object of the present invention to provide compounds, methods and compositions for the treatment of ischemia-reperfusion injury.
  • It is a further object of the present invention to provide compounds, methods and compositions for the treatment of post-angioplasty restenosis.
  • It is a further object of the present invention to provide compounds, methods and compositions for the treatment of chronic obstructive pulmonary disease (COPD).
  • It is a further object of the present invention to provide compounds, methods and compositions for the treatment of glomerulonephritis.
  • It is a further object of the present invention to provide compounds, methods and compositions for the treatment of Graves disease.
  • It is a further object of the present invention to provide compounds, methods and compositions for the treatment of gastrointestinal allergies.
  • It is a further object of the present invention to provide compounds, methods and compositions for the treatment of conjunctivitis.
  • It is a further object of the present invention to provide compounds, methods and compositions for the treatment of dermatitis.
  • It is a further object of the present invention to provide compounds, methods and compositions for the treatment of psoriasis.
  • It is a further object of the present invention to provide compounds, methods and compositions for the treatment of ocular inflammation, including uveitis.
  • In a broader sense, an object of the present invention is to provide compounds, methods and compositions that can be used as adjunct or combination therapy both simultaneously, and and in series.
    • SUMMARY OF THE INVENTION
  • It has been discovered that particular sulfonamide substituted chalcone derivatives inhibit the expression of VCAM-1, and thus can be used to treat a patient with a disorder mediated by VCAM-1. Examples of inflammatory disorders that are mediated by VCAM-1 include, but are not limited to arthritis, asthma, dermatitis, cystic fibrosis, post transplantation late and chronic solid organ rejection, multiple sclerosis, systemic lupus erythematosis, inflammatory bowel diseases, autoimmune diabetes, diabetic retinopathy, diabetic nephropathy, diabetic vasculopathy, rhinitis, ocular inflammation, uveitis, ischemia-reperfusion injury, post-angioplasty restenosis, chronic obstructive pulmonary disease (COPD), glomerulonephritis, Graves disease, gastrointestinal allergies, conjunctivitis, atherosclerosis, coronary artery disease, angina and small artery disease.
  • The compounds disclosed herein can also be used in the treatment of inflammatory skin diseases that are mediated by VCAM-1, as well as human endothelial disorders that are mediated by VCAM-1, which include, but are not limited to psoriasis, dermatitis, including eczematous dermatitis, Kaposi's sarcoma, multiple sclerosis, as well as proliferative disorders of smooth muscle cells.
  • In yet another embodiment, the compounds disclosed herein can be selected to treat anti-inflammatory conditions that are mediated by mononuclear leucocytes.
  • In one embodiment, the compounds of the present invention are selected for the prevention or treatment of tissue or organ transplant rejection. Treatment and prevention of organ or tissue transplant rejection includes, but is not limited to treatment of recipients of heart, lung, combined heart-lung, liver, kidney, pancreatic, skin, spleen, small bowel, or corneal transplants. The compounds can also be used in the prevention or treatment of graft-versus-host disease, such as sometimes occurs following bone marrow transplantation.
  • In an alternative embodiment, the compounds described herein are useful in both the primary and adjunctive medical treatment of cardiovascular disease. The compounds are used in primary treatment of, for example, coronary disease states including atherosclerosis, post-angioplasty restenosis, coronary artery diseases and angina. The compounds can be administered to treat small vessel disease that is not treatable by surgery or angioplasty, or other vessel disease in which surgery is not an option. The compounds can also be used to stabilize patients prior to revascularization therapy.
  • Compounds of the present invention are of the formula
    Figure US20070093453A1-20070426-C00005
    or its pharmaceutically acceptable salt or ester, wherein the substituents are defined herein.
  • A further embodiment of the invention is to supply intermediates suitable for manufacturing compounds of the invention that may have independent therapeutic value. Such intermediates having the formulas
    Figure US20070093453A1-20070426-C00006
    wherein
  • X is —C(O)H or —CH2OH;
  • R3 and R4 are independently selected from the group consisting of hydroxy, alkoxy, lower alkoxy, —(O(CH2)2)1-3—O-lower alkyl, cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy, —OC(R9)2C(O)N(R9)2, and —OC(R9)2C(O)NR7R8, wherein all substituents may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, haloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —C(O)NR7R8, and —C(O)N(R9)2;
  • Y1, Y2, Y3, and Y4 are independently selected from the group consisting of hydrogen, hydroxyl, halo, alkyl, lower alkyl, alkenyl, cycloalkyl, haloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, heteroaryl, —C(O)NR7R8, and C(O)N(R9)2, wherein all substituents, when possible may be optionally substituted by one or more selected from the group consisting of hydroxyl, halo, alkyl, lower alkyl, alkenyl, cycloalkyl, haloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, heteroaryl, —C(O)NR7R8, and —C(O)N(R2)2.
  • Y5 is selected from the group consisting of hydrogen, alkyl, lower alkyl, acyl, and alkoxycarbonyl wherein all substituents, when possible may be optionally substituted by one or more selected from the group consisting of hydroxyl, halo, alkyl, lower alkyl, alkenyl, cycloalkyl, haloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, heteroaryl, —C(O)NR7R8, and —C(O)N(R9)2;
  • R9 is independently selected from the group consisting of alkyl, lower alkyl, carbocyclic, cycloalkyl, hydroxy, alkoxy, lower alkoxy, trialkylsilyloxy, cycloalkyloxy, cycloalkylalkoxy, heterocyclicoxy, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, acyl, alkoxycarbonyl, and heterocyclicalkyl, wherein all substituents may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, haloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR7R8, —NHR9, —N(R9)2, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, heteroaryl, —C(O)NR7R8, —NR9R9 and —C(O)N(R9)2;
  • R7 and R8 are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 4- to 12-membered monocyclic, bicylic, tricyclic or benzofused ring, which may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, haloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —C(O)NR7R8, and —C(O)N(R9)2.
    • DETAILED DESCRIPTION OF THE INVENTION
  • It has been discovered that compounds of the invention inhibit the expression of VCAM-1, and thus can be used to treat a patient with a disorder mediated by VCAM-1. These compounds can be administered to a host as monotherapy, or if desired, in combination with another compound of the invention or another biologically active agent, as described in more detail below.
  • In a 1st embodiment, the invention is represented by Formula 1
    Figure US20070093453A1-20070426-C00007
    or its pharmaceutically acceptable salt, wherein:
  • R1 is selected from the group consisting of hydrogen, alkyl, lower alkyl, carbocyclic, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, acyl and heterocyclicalkyl, wherein all substituents may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, haloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, heteroaryl, —C(O)NR7R8, and —C(O)N(R2)2;
  • R2 is independently selected from the group consisting of alkyl, lower alkyl, carbocyclic, cycloalkyl, hydroxy, alkoxy, lower alkoxy, trialkylsilyloxy, cycloalkyloxy, cycloalkylalkoxy, heterocyclicoxy, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, acyl, alkoxycarbonyl, and heterocyclicalkyl, wherein all substituents may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, haloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, heteroaryl, —C(O)NR7R8, —NR1R2 and —C(O)N(R2)2;
  • R1 and R2 may be taken together to form a 4- to 12-membered saturated or unsaturated heterocyclic ring which can be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, haloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —C(O)NR7R8, and —C(O)N(R2)2;
  • R7 and R8 are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 4- to 12-membered monocyclic, bicylic, tricyclic or benzofused ring, which may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, haloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —C(O)NR7R8, and —C(O)N(R2)2;
  • R3 and R4 are independently selected from hydroxy, alkoxy, lower alkoxy, —(O(CH2)2)1-3—O-lower alkyl, cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy, —OC(R1)2C(O)N(R2)2, and —OC(R1)2C(O)NR7R8, wherein all substituents may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, haloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —C(O)NR7R8, and —C(O)N(R2)2;
  • R5 is selected from the group consisting of a carbon-carbon linked heteroaryl and a carbon-carbon linked heterocyclic, which may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, haloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —C(O)NR7R8, and C(O)N(R2)2;
  • with the proviso that when R1 is hydrogen and R2 is 2-methyl propanoyl, then R5 cannot be 5-benzo[b]thien-2-yl.
  • In a 2nd embodiment, the invention is represented by Formula 1 or its pharmaceutically acceptable salt, wherein:
  • R1 is selected from the group consisting of hydrogen, alkyl, and lower alkyl, wherein all substituents may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, haloalkyl, heterocyclic, —NR7R8, alkoxy, carboxy, carboxyalkyl, alkoxycarbonyl and heteroaryl;
  • R2 is independently selected from the group consisting of alkyl, lower alkyl, alkoxy, lower alkoxy, heteroaryl, heterocyclic, heteroarylalkyl, and heterocyclicalkyl, wherein all substituents may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, haloalkyl, heterocyclic, —NR7R8, alkoxy, carboxy, carboxyalkyl, alkoxycarbonyl and heteroaryl;
  • R1 and R2 may be taken together to form a 5- to 7-membered saturated or unsaturated heterocyclic ring which can be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, haloalkyl, heterocyclic, —NR7R8, alkoxy, carboxy, carboxyalkyl and alkoxycarbonyl;
  • R7 and R8 are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 5- to 10-membered monocyclic, bicylic or benzofused ring, which may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, haloalkyl, heterocyclic, —NR7R8, alkoxy, carboxy, carboxyalkyl and alkoxycarbonyl;
  • R3 and R4 are independently selected from hydroxy, alkoxy, lower alkoxy, —(O(CH2)2)1-3—O-lower alkyl, haloalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy, —OC(R1)2C(O)N(R2)2, and —OC(R1)2C(O)NR7R8 wherein all substituents may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, hydroxy, hydroxyalkyl, heterocyclic, —NR7R8, alkoxy, —C(O)NR7R8, and —C(O)N(R2)2;
  • R5 is selected from the group consisting of a carbon-carbon linked heteroaryl and a carbon-carbon linked heterocyclic, which may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, haloalkyl, heterocyclic, —NR7R8 and alkoxy.
  • In a 3rd embodiment, the invention is represented by Formula 1 or its pharmaceutically acceptable salt, wherein:
  • R1 is selected from the group consisting of hydrogen and lower alkyl;
  • R2 is independently selected from the group consisting of lower alkyl, lower alkoxy, heteroaryl, heterocyclic, heteroarylalkyl, and heterocyclicalkyl, wherein all substituents may be optionally substituted by one or more selected from the group consisting of halo, lower alkyl, haloalkyl, heterocyclic, —NR7R8 and carboxy;
  • R1 and R2 may be taken together to form a 5- to 6-membered heterocyclic saturated ring which can be optionally substituted by one or more selected from the group consisting of halo, lower alkyl and carboxy;
  • R7 and R8 are independently selected from the group consisting of alkyl and alkenyl, and linked together forming a 5- to 7-membered monocyclic ring, which may be optionally substituted by one or more selected from the group consisting of halo, lower alkyl, haloalkyl, heterocyclic and carboxy;
  • R3 and R4 are independently selected from hydroxy, lower alkoxy, —(O(CH2)2)1-3—O-lower alkyl, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy, —OC(R1)2C(O)N(R2)2, and —OC(R1)2C(O)NR7R8, wherein all substituents may be optionally substituted by one or more selected from the group consisting of hydroxy, hydroxyalkyl, heterocyclic, —NR7R8, —C(O)NR7R8, and —C(O)N(R2)2;
  • R5 is selected from the group consisting of a carbon-carbon linked heteroaryl and a carbon-carbon linked heterocyclic, which may be optionally substituted by one or more lower alkyl.
  • In a 4th embodiment, the invention is represented by Formula 1 or its pharmaceutically acceptable salt, wherein:
  • R1 is hydrogen;
  • R2 is independently selected from the group consisting of lower alkyl, heteroaryl, heteroarylalkyl, and heterocyclicalkyl, wherein all substituents may be optionally substituted by one or more selected from the group consisting of halo and lower alkyl;
  • R1 and R2 may be taken together to form a 5- to 6-membered heterocyclic saturated ring;
  • R7 and R8 are independently alkyl and linked together forming a 5- to 7-membered saturated monocyclic ring;
  • R3 and R4 are independently selected from hydroxy, lower alkoxy and heterocyclic lower alkoxy;
  • R5 is selected from the group consisting of a carbon-carbon linked heteroaryl and a carbon-carbon linked heterocyclic, which may be optionally substituted by one or more lower alkyl.
  • In a 5th embodiment, the invention is represented by Formula 1 or its pharmaceutically acceptable salt, wherein:
  • R1 is hydrogen;
  • R2 is independently selected from the group consisting of lower alkyl, heteroaryl, heteroarylalkyl, and heterocyclicalkyl, wherein all substituents may be optionally substituted by one or more selected from the group consisting of halo and lower alkyl;
  • R3 and R4 are independently selected from lower alkoxy and heterocyclic lower alkoxy;
  • R5 is a carbon-carbon linked heteroaryl, which may be optionally substituted by one or more lower alkyl.
  • In a 6th embodiment, the invention is represented by Formula 1 or its pharmaceutically acceptable salt, wherein the compound is selected from
    • 4-[3E-(2,4-Dimethoxy-5-thien-2-yl-phenyl)acryloyl]-N-(5-methylisoxazol-3-yl)benzenesulfonamide;
    • 3E-(2,4-Dimethoxy-5-thien-2-ylphenyl)acryloyl]-N-(5-methylisoxazol-3-yl)benzenesulfonamide sodium salt;
    • 4-[3E-(2,4-Dimethoxy-5-thien-2-ylphenyl)acryloyl]-N-pyrimidin-2-ylbenzenesulfonamide;
    • 4-[3E-(2,4-Dimethoxy-5-thien-2-ylphenyl)acryloyl]-N-(1-H-tetrazol-5-yl)benzenesulfonamide;
    • 4-[3E-(2,4-Dimethoxy-5-thien-2-ylphenyl)acryloyl]-N-pyridin-2-ylbenzenesulfonamide;
    • 4-[3E-(2,4-Dimethoxy-5-thien-2-ylphenyl)acryloyl]-N-(1H-pyrazol-3-yl)benzenesulfonamide;
    • 4-[3E-(2,4-Dimethoxy-5-thien-2-ylphenyl)acryloyl]-N-isoxazol-3-ylbenzenesulfonamide;
    • 4-[3E-(2,4-Dimethoxy-5-thien-2-ylphenyl)acryloyl]-N-thiazol-2-ylbenzenesulfonamide;
    • 4-[3E-(2,4-Dimethoxy-5-thien-2-ylphenyl)acryloyl]-N-(3-methylisoxazol-5-ylbenzenesulfonamide;
    • N-(5-Chloropyridin-2-yl)-4-[3E-(2,4-dimethoxy-5-thien-2-ylphenyl)acryloyl]benzenesulfonamide;
    • 4-[3E-(2,4-Dimethoxy-5-thien-2-ylphenyl)acryloyl]-N-(5-fluoropyridin-2-yl)benzenesulfonamide;
    • 4-[3E-(2,4-Dimethoxy-5-thien-2-ylphenyl)acryloyl]-N-(5-trifluoromethylpyridin-2-yl)benzenesulfonamide;
    • 4-{3E-[2-(3-Hydroxy-2-hydroxymethylpropoxy)-4-methoxy-5-thien-2-ylphenyl]acryloyl}-N-(5-methylisoxazol-3-yl)benzenesulfonamide;
    • 4-{3E-[4-Methoxy-2-(2-morpholin-4-yl-ethoxy)-5-thien-2-ylphenyl]acryloyl}-N-(5-methyl-isoxazol-3-yl)benzenesulfonamide hydrochloride;
    • 4-{3E-[2,4-Dimethoxy-5-(1-methyl-1H-indol-2-yl)phenyl]acryloyl}-N-(5-methylisoxazol-3-yl)benzenesulfonamide;
    • 4-{3E-[2,4-Dimethoxy-5-(1-methyl-1H-indol-2-yl)phenyl]acryloyl}-N-(5-methylisoxazol-3-yl)benzenesulfonamide sodium salt;
    • 4-{3E-[2,4-Dimethoxy-5-(1-methyl-1H-indol-2-yl)phenyl]acryloyl}-N-pyridin-3-ylmethylbenzenesulfonamide;
    • 4-{3E-[2,4-Dimethoxy-5-(1-methyl-1H-indol-2-yl)phenyl]acryloyl}-N-(2-morpholin-4-yl-ethyl)benzenesulfonamide;
    • 4-[3E-(2,4-Dimethoxy-5-thien-2-ylphenyl)acryloyl]-N-pyridin-3-ylmethylbenzenesulfonamide
    • 4-[3E-(2,4-Dimethoxy-5-thien-2-ylphenyl)acryloyl]-N-(2-morpholin-4-yl-ethyl)benzenesulfonamide;
    • 3E-(2,4-Dimethoxy-5-thien-2-ylphenyl)-1-[4-(4-methylpiperazine-1-sulfonyl)phenyl]propenone;
    • 4-[3E-(2,4-Dimethoxy-5-thien-2-ylphenyl)acryloyl]-N-piperidin-1-ylbenzenesulfonamide;
    • 4-[3E-(2,4-Dimethoxy-5-thien-2-ylphenyl)acryloyl]-N-(3-imidazol-1-ylpropyl)benzenesulfonamide;
    • 4-[3E-(2,4-Dimethoxy-5-thien-2-ylphenyl)acryloyl]-N-(2,2,2-trifluoroethyl)benzenesulfonamide;
    • 4-[3E-(2,4-Dimethoxy-5-thien-2-ylphenyl)acryloyl]-N-(2,2,2-trifluoroethyl)benzenesulfonamide sodium salt;
    • {4-[3E-(2,4-Dimethoxy-5-thien-2-ylphenyl)acryloyl]benzenesulfonylamino}acetic acid;
    • 2-{4-[3E-(2,4-Dimethoxy-5-thien-2-yl-phenyl)acryloyl]benzenesulfonylamino}-2-methylpropionic acid;
    • 1-{4-[3E-(2,4-Dimethoxy-5-thien-2-ylphenyl)acryloyl]benzenesulfonyl}piperidine-2-carboxylic acid;
    • 4-{3E-[2,4-Dimethoxy-5-(1-methyl-1H-indol-2-yl)phenyl]acryloyl}-N-methyl-benzenesulfonamide;
    • 4-{3E-[2,4-Dimethoxy-5-(1-methyl-1H-indol-2-yl)phenyl]acryloyl}-N-methoxybenzenesulfonamide;
    • 4-{3E-[2,4-Dimethoxy-5-(1-methyl-1H-indol-2-yl)phenyl]acryloyl}-N,N-dimethylbenzenesulfonamide;
    • 4-{3E-[5-(1H-Indol-2-yl)-2,4-dimethoxyphenyl]acryloyl}-N,N-dimethylbenzenesulfonamide;
    • 4-{3E-[2,4-Dimethoxy-5-(1-methyl-1H-indol-2-yl)phenyl]acryloyl}-N-(tert-butyldimethylsiloxy)benzenesulfonamide;
    • 4-{3E-[2,4-Dimethoxy-5-(1-methyl-1H-indol-2-yl)phenyl]-acryloyl}-N-hydroxybenzenesulfonamide;
    • 4-{3E-[2,4-Dimethoxy-5-(1-methyl-1H-pyrol-2-yl)phenyl]acryloyl}-N-(5-methyl-isoxazol-3-yl)benzenesulfonamide;
    • 4-{3E-[2-(3-Hydroxy-propoxy)-4-methoxy-5-thien-2-ylphenyl]acryloyl}-N-(5-methylisoxazol-3-yl)benzenesulfonamide;
    • 4-{3E-[2,4-Dimethoxy-5-(1-methyl-1H-pyrol-2-yl)phenyl]acryloyl}-N-(5-methyl-isoxazol-3-yl)benzenesulfonamide;
    • N-(3-Imidazol-1-yl-propyl)-4-{3E-[5-(1H-indol-2-yl)-2,4-dimethoxy-phenyl]acryloyl}benzenesulfonamide;
    • (4-{3E-[5-(1H-Indol-2-yl)-2,4-dimethoxyphenyl]acryloyl}benzenesulfonylamino)acetic acid; and
    • 4-{3E-[5-(1H-Indol-2-yl)-2,4-dimethoxyphenyl]acryloyl}-N-pyridin-2-ylbenzenesulfonamide.
  • In a 7th embodiment, the invention is represented by Formula III
    Figure US20070093453A1-20070426-C00008
    or its pharmaceutically acceptable salt, wherein:
  • R1 is selected from the group consisting of hydrogen, alkyl, lower alkyl, carbocyclic, cycloalkyl, alkoxy, lower alkoxy, cycloalkyloxy, cycloalkylalkoxy, heterocyclicoxy, aryloxy, heteroaryloxy, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, —NR7R8, —NHR2, —N(R2)2, acyl and heterocyclicalkyl, wherein all substituents may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, haloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR7R8, —NHR2, —N(R2)2, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, heteroaryl, —C(O)NR7R8, and —C(O)N(R2)2;
  • R2 is independently selected from the group consisting of hydrogen, alkyl, lower alkyl, carbocyclic, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, acyl, alkoxycarbonyl, and heterocyclicalkyl, wherein all substituents may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, haloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, heteroaryl, —C(O)NR7R8, —NR1R2 and —C(O)N(R2)2;
  • R7 and R8 are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 4- to 12-membered monocyclic, bicylic, tricyclic or benzofused ring, which may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, haloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —C(O)NR7R8, and —C(O)N(R2)2;
  • R3, R4 and R5 are independently selected from hydrogen, hydroxy, alkoxy, lower alkoxy, —(O(CH2)2)1-3—O-lower alkyl, cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclic, heteroaryl, NR7R8, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy, —OC(R1)2C(O)N(R2)2, and —OC(R1)2C(O)NR7R8, wherein all substituents may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, haloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, N-linked heteroaryl, —NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —C(O)NR7R8, and —C(O)N(R2)2;
  • with the proviso that at least one of R3, R4 or R5 is an N-linked heteroaryl or —NR7R8.
  • In an 8th embodiment, the invention is represented by Formula III or its pharmaceutically acceptable salt, wherein:
  • R1 is selected from the group consisting of hydrogen, alkyl, lower alkyl, alkoxy, lower alkoxy, cycloalkyloxy, cycloalkylalkoxy, heterocyclicoxy, aryloxy, heteroaryloxy, heterocyclic, heteroarylalkyl, acyl and heterocyclicalkyl, wherein all substituents may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, haloalkyl, heterocyclic, amino, aminoalkyl, —NR7R8, —NHR2, —N(R2)2, alkoxy, carboxy, carboxyalkyl, alkoxycarbonyl, and heteroaryl;
  • R2 is independently selected from the group consisting of alkyl, lower alkyl, heteroaryl, heterocyclic, heteroarylalkyl, acyl and heterocyclicalkyl, wherein all substituents may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, haloalkyl, heterocyclic, —NR7R8, alkoxy, carboxy, carboxyalkyl, alkoxycarbonyl and heteroaryl;
  • R7 and R8 are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 5- to 10-membered monocyclic, bicylic or benzofused ring, which may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, haloalkyl, heterocyclic, —NR7R8, alkoxy, carboxy, carboxyalkyl and alkoxycarbonyl;
  • R3, R4 and R5 are independently selected from hydrogen, hydroxy, alkoxy, lower alkoxy, —(O(CH2)2)1-3—O-lower alkyl, haloalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclic, heteroaryl, NR7R8, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy, —OC(R1)2C(O)N(R2)2, and —OC(R1)2C(O)NR7R8, wherein all substituents may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, hydroxy, hydroxyalkyl, heterocyclic, N-linked heteroaryl, —NR7R8, alkoxy, —C(O)NR7R8, and —C(O)N(R)2;
  • with the proviso that at least one of R3, R4 or R5 is an N-linked heteroaryl or —NR7R8.
  • In a 9th embodiment, the invention is represented by Formula III or its pharmaceutically acceptable salt, wherein:
  • R1 is selected from the group consisting of alkyl, lower alkyl, alkoxy, and lower alkoxy, wherein all substituents may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, amino, —NR7R8, NHR2, —N(R2)2, aminoalkyl, alkoxy, carboxy, carboxyalkyl, alkoxycarbonyl, and heteroaryl;
  • R2 is independently selected from the group consisting of lower alkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all substituents may be optionally substituted by one or more selected from the group consisting of halo, lower alkyl, haloalkyl, heterocyclic, —NR7R8 and carboxy;
  • R7 and R8 are independently selected from the group consisting of alkyl and alkenyl, and linked together forming a 5- to 7-membered monocyclic ring, which may be optionally substituted by one or more selected from the group consisting of halo, lower alkyl, haloalkyl, heterocyclic and carboxy;
  • R3, R4 and R5 are independently selected from hydrogen, hydroxy, lower alkoxy, —(O(CH2)2)1-3—O-lower alkyl, heteroaryl lower alkoxy, heterocyclic, heteroaryl, NR7R8, heterocyclicoxy, heterocyclic lower alkoxy, —OC(R1)2C(O)N(R2)2, and —OC(R1)2C(O)NR7R8, wherein all substituents may be optionally substituted by one or more selected from the group consisting of hydroxy, hydroxyalkyl, heterocyclic, N-linked heteroaryl, —NR7R8, —C(O)NR7R8, and —C(O)N(R2)2;
  • with the proviso that at least one of R3, R4 or R5 is an N-linked heteroaryl or —NR7R8.
  • In a 10th embodiment, the invention is represented by Formula III or its pharmaceutically acceptable salt, wherein:
  • R1 is selected from the group consisting of lower alkyl, and lower alkoxy, wherein all substituents may be optionally substituted by one or more selected from the group consisting of alkoxy, —NR7R8, —NHR2, and —N(R2)2;
  • R2 is lower alkyl;
  • R7 and R8 are independently alkyl and linked together forming a 5- to 7-membered saturated monocyclic ring;
  • R3, R4 and R5 are independently selected from hydrogen, hydroxy, lower alkoxy, heterocyclic, heteroaryl, NR7R8 and heterocyclic lower alkoxy;
  • with the proviso that at least one of R3, R4 or R5 is an N-linked heteroaryl or —NR7R8.
  • In an 11th embodiment, the invention is represented by Formula III or its pharmaceutically acceptable salt, wherein:
  • R1 is selected from the group consisting of lower alkyl, and lower alkoxy;
  • R7 and R8 are independently alkyl and linked together forming a 5- to 7-membered saturated monocyclic ring;
  • R3, R4 and R5 are independently selected from lower alkoxy, NR7R8 and heterocyclic lower alkoxy;
  • with the proviso that at least one of R3, R4 or R5 is —NR7R8.
  • In the 12th embodiment, the invention is represented by Formula III or its the compound is N-Butyryl-4-[3E-(2,4-dimethoxy-5-pyrrolidin-1-ylphenyl)acryloyl]benzenesulfonamide.
  • In a 13th embodiment, the invention is represented by Formula III
    Figure US20070093453A1-20070426-C00009
    or its pharmaceutically acceptable salt, wherein:
  • R1 is selected from the group consisting of hydrogen, alkyl, lower alkyl, carbocyclic, cycloalkyl, alkoxy, lower alkoxy, cycloalkyloxy, cycloalkylalkoxy, heterocyclicoxy, aryloxy, heteroaryloxy, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, —NR7R8, —NHR2, —N(R2)2, acyl and heterocyclicalkyl, wherein all substituents may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, haloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR7R8, —NHR2, —N(R2)2, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, heteroaryl, —C(O)NR7R8, and —C(O)N(R2)2;
  • R2 is independently selected from the group consisting of hydrogen, alkyl, lower alkyl, carbocyclic, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, acyl, alkoxycarbonyl, and heterocyclicalkyl, wherein all substituents may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, haloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, heteroaryl, —C(O)NR7R8, —NR1R2 and —C(O)N(R2)2;
  • R7 and R8 are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 4- to 12-membered monocyclic, bicylic, tricyclic or benzofused ring, which may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, haloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —C(O)NR7R8, and —C(O)N(R2)2;
  • R3 and R4 are independently selected from hydrogen, hydroxy, alkoxy, lower alkoxy, —(O(CH2)2)1-3—O-lower alkyl, cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy, —OC(R1)2C(O)N(R2)2, and —OC(R1)2C(O)NR7R8, wherein all substituents may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, haloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, N-linked heteroaryl, —NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —C(O)NR7R8, and —C(O)N(R2)2;
  • R5 is selected from the group consisting of a carbon-carbon linked heterocyclic and a carbon-carbon linked heteroaryl, which may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, haloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —C(O)NR7R8, and —C(O)N(R2)2;
  • with the proviso that when R1 is isopropyl, R5 cannot be 5-benzo[b]thien-2-yl.
  • In a 14th embodiment, the invention is represented by Formula III or its pharmaceutically acceptable salt, wherein:
  • R1 is selected from the group consisting of hydrogen, alkyl, lower alkyl, alkoxy, lower alkoxy, cycloalkyloxy, cycloalkylalkoxy, heterocyclicoxy, aryloxy, heteroaryloxy, heterocyclic, heteroarylalkyl, and heterocyclicalkyl, wherein all substituents may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, haloalkyl, heterocyclic, amino, aminoalkyl, —NR7R8, —NHR2, —N(R2)2, alkoxy, carboxy, carboxyalkyl, alkoxycarbonyl, and heteroaryl;
  • R2 is independently selected from the group consisting of alkyl, lower alkyl, heteroaryl, heterocyclic, heteroarylalkyl, and heterocyclicalkyl, wherein all substituents may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, haloalkyl, heterocyclic, —NR7R8, alkoxy, carboxy, carboxyalkyl, alkoxycarbonyl and heteroaryl;
  • R7 and R8 are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 5- to 10-membered monocyclic, bicylic or benzofused ring, which may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, haloalkyl, heterocyclic, —NR7R8, alkoxy, carboxy, carboxyalkyl and alkoxycarbonyl;
  • R3 and R4 are independently selected from hydroxy, alkoxy, lower alkoxy, —(O(CH2)2)1-3—O-lower alkyl, haloalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy, —OC(R1)2C(O)N(R2)2, and —OC(R1)2C(O)NR7R8, wherein all substituents may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, hydroxy, hydroxyalkyl, heterocyclic, —NR7R8, alkoxy, —C(O)NR7R8, and —C(O)N(R2)2;
  • R5 is selected from the group consisting of a carbon-carbon linked heteroaryl and a carbon-carbon linked heterocyclic, which may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, haloalkyl, heterocyclic, —NR7R8 and alkoxy;
  • with the proviso that when R1 is isopropyl, R5 cannot be 5-benzo[b]thien-2-yl.
  • In 15th embodiment, the invention is represented by Formula III or its pharmaceutically acceptable salt, wherein:
  • R1 is selected from the group consisting of alkyl, lower alkyl, alkoxy, and lower alkoxy, wherein all substituents may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, amino, aminoalkyl, —NR7R8, —NHR2, —N(R2)2, alkoxy, carboxy, carboxyalkyl, alkoxycarbonyl, and heteroaryl;
  • R2 is independently selected from the group consisting of lower alkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all substituents may be optionally substituted by one or more selected from the group consisting of halo, lower alkyl, haloalkyl, heterocyclic, —NR7R8 and carboxy;
  • R7 and R8 are independently selected from the group consisting of alkyl and alkenyl, and linked together forming a 5- to 7-membered monocyclic ring, which may be optionally substituted by one or more selected from the group consisting of halo, lower alkyl, haloalkyl, heterocyclic and carboxy;
  • R3 and R4 are independently selected from hydroxy, lower alkoxy, —(O(CH2)2)1-3—O-lower alkyl, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy, —OC(R1)2C(O)N(R2)2, and —OC(R1)2C(O)NR7R8, wherein all substituents may be optionally substituted by one or more selected from the group consisting of hydroxy, hydroxyalkyl, heterocyclic, —NR7R8, —C(O)NR7R8, and —C(O)N(R2)2;
  • R5 is selected from the group consisting of a carbon-carbon linked heteroaryl and a carbon-carbon linked heterocyclic, which may be optionally substituted by one or more lower alkyl;
  • with the proviso that when R1 is isopropyl, R5 cannot be 5-benzo[b]thien-2-yl.
  • In a 16th embodiment, the invention is represented by Formula III or its pharmaceutically acceptable salt, wherein:
  • R1 is selected from the group consisting of lower alkyl, and lower alkoxy, wherein all substituents may be optionally substituted by one or more selected from the group consisting of alkoxy, —NR7R8, —NHR2, and —N(R2)2;
  • R2 is lower alkyl;
  • R7 and R8 are independently alkyl and linked together forming a 5- to 7-membered saturated monocyclic ring;
  • R3 and R4 are independently selected from hydroxy, lower alkoxy and heterocyclic lower alkoxy;
  • R5 is selected from the group consisting of a carbon-carbon linked heteroaryl and a carbon-carbon linked heterocyclic, which may be optionally substituted by one or more lower alkyl;
  • with the proviso that when R1 is isopropyl, R5 cannot be 5-benzo[b]thien-2-yl.
  • In a 17th embodiment, the invention is represented by Formula III or its pharmaceutically acceptable salt, wherein:
  • R1 is selected from the group consisting of lower alkyl, and lower alkoxy;
  • R3 and R4 are independently selected from lower alkoxy and heterocyclic lower alkoxy;
  • R5 is a carbon-carbon linked heteroaryl, which may be optionally substituted by one or more lower alkyl;
  • with the proviso that when R1 is isopropyl, R5 cannot be 5-benzo[b]thien-2-yl.
  • In a 18th embodiment, the invention is represented by Formula III or its pharmaceutically acceptable salt, wherein the compound is selected from the group consisting of
    • 4-{3E-[5-(1H-Indol-2-yl)-2,4-dimethoxyphenyl]acryloyl}-N-isobutyrylbenzenesulfonamide;
    • 4-{3E-[5-(1H-Indol-2-yl)-2,4-dimethoxyphenyl]acryloyl}-N-isobutyrylbenzenesulfonamide sodium salt;
    • N-Butyryl-4-{3E-[2,4-dimethoxy-5-(1-methyl-1H-indol-2-yl)phenyl]acryloyl}benzenesulfonamide;
    • N-Ethoxycarbonyl-4-{3E-[5-(1H-indol-2-yl)-2,4-dimethoxyphenyl]acryloyl}benzenesulfonamide potassium salt;
    • N-Ethoxycarbonyl-4-{3E-[5-(1H-indol-2-yl)-2,4-dimethoxyphenyl]acryloyl}benzenesulfonamide;
    • N-Acetyl-4-{3E-[5-(1H-indol-2-yl)-2,4-dimethoxyphenyl]acryloyl}benzenesulfonamide;
    • N-Acetyl-4-{3E-[5-(1H-indol-2-yl)-2,4-dimethoxyphenyl]acryloyl}benzenesulfonamide sodium salt;
    • 4-{3E-[5-(1H-Indol-2-yl)-2,4-dimethoxyphenyl]acryloyl}-N-propionyl-benzenesulfonamide;
    • 4-{3E-[5-(1H-Indol-2-yl)-2,4-dimethoxyphenyl]acryloyl}-N-propionylbenzenesulfonamide sodium salt;
    • N-Butyryl-4-{3E-[5-(1H-indol-2-yl)-2,4-dimethoxyphenyl]acryloyl}benzenesulfonamide; and
    • N-Butyryl-4-{3E-[5-(1H-indol-2-yl)-2,4-dimethoxyphenyl]acryloyl}benzenesulfonamide sodium salt.
  • In a 19th embodiment, the invention is represented by Formula I
    Figure US20070093453A1-20070426-C00010
    or its pharmaceutically acceptable salt, wherein:
  • R1 is selected from the group consisting of hydrogen, alkyl, lower alkyl, carbocyclic, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, acyl and heterocyclicalkyl, wherein all substituents may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, haloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, heteroaryl, —C(O)NR7R8, and —C(O)N(R2)2;
  • R2 is independently selected from the group consisting of alkyl, lower alkyl, carbocyclic, cycloalkyl, hydroxy, alkoxy, lower alkoxy, trialkylsilyloxy, cycloalkyloxy, cycloalkylalkoxy, heterocyclicoxy, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, acyl, alkoxycarbonyl, and heterocyclicalkyl, wherein all substituents may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, haloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, heteroaryl, —C(O)NR7R8, —NR1R2 and —C(O)N(R2)2;
  • R1 and R2 may be taken together to form a 4- to 12-membered saturated or unsaturated heterocyclic ring which can be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, haloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —C(O)NR7R8, and —C(O)N(R2)2;
  • R7 and R8 are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 4- to 12-membered monocyclic, bicylic, tricyclic or benzofused ring, which may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, haloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —C(O)NR7R8, and —C(O)N(R2)2;
  • R3 and R4 are independently selected from hydroxy, alkoxy, lower alkoxy, —(O(CH2)2)1-3—O-lower alkyl, cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy, —OC(R1)2C(O)N(R2)2, and —OC(R1)2C(O)NR7R8, wherein all substituents may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, haloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —C(O)NR7R8, and —C(O)N(R2)2;
  • R5 is selected from the group consisting of a carbon-nitrogen linked heteroaryl and a carbon-nitrogen linked heterocyclic, which may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, haloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —C(O)NR7R8, and —C(O)N(R2)2.
  • In a 20th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt, wherein:
  • R1 is selected from the group consisting of hydrogen, alkyl, and lower alkyl, wherein all substituents may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, haloalkyl, heterocyclic, —NR7R8, alkoxy, carboxy, carboxyalkyl, alkoxycarbonyl and heteroaryl;
  • R2 is independently selected from the group consisting of alkyl, lower alkyl, alkoxy, lower alkoxy, heteroaryl, heterocyclic, heteroarylalkyl, and heterocyclicalkyl, wherein all substituents may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, haloalkyl, heterocyclic, —NR7R8, alkoxy, carboxy, carboxyalkyl, alkoxycarbonyl and heteroaryl;
  • R1 and R2 may be taken together to form a 5- to 7-membered saturated or unsaturated heterocyclic ring which can be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, haloalkyl, heterocyclic, —NR7R8, alkoxy, carboxy, carboxyalkyl and alkoxycarbonyl;
  • R7 and R8 are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 5- to 10-membered monocyclic, bicylic or benzofused ring, which may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, haloalkyl, heterocyclic, —NR7R8, alkoxy, carboxy, carboxyalkyl and alkoxycarbonyl;
  • R3 and R4 are independently selected from hydroxy, alkoxy, lower alkoxy, —(O(CH2)2)1-3—O-lower alkyl, haloalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy, —OC(R1)2C(O)N(R2)2, and —OC(R1)2C(O)NR7R8, wherein all substituents may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, hydroxy, hydroxyalkyl, heterocyclic, —NR7R8, alkoxy, —C(O)NR7R8, and —C(O)N(R2)2;
  • R5 is selected from the group consisting of a carbon-nitrogen linked heteroaryl and a carbon-nitrogen linked heterocyclic, which may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, haloalkyl, heterocyclic, —NR7R8 and alkoxy.
  • In a 21st embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt, wherein:
  • R1 is selected from the group consisting of hydrogen and lower alkyl;
  • R2 is independently selected from the group consisting of lower alkyl, lower alkoxy, heteroaryl, heterocyclic, heteroarylalkyl, and heterocyclicalkyl, wherein all substituents may be optionally substituted by one or more selected from the group consisting of halo, lower alkyl, haloalkyl, heterocyclic, heteroaryl, —NR7R8 and carboxy;
  • R1 and R2 may be taken together to form a 5- to 6-membered heterocyclic saturated ring which can be optionally substituted by one or more selected from the group consisting of halo, lower alkyl and carboxy;
  • R7 and R8 are independently selected from the group consisting of alkyl and alkenyl, and linked together forming a 5- to 7-membered monocyclic ring, which may be optionally substituted by one or more selected from the group consisting of halo, lower alkyl, haloalkyl, heterocyclic and carboxy;
  • R3 and R4 are independently selected from hydroxy, lower alkoxy, —(O(CH2)2)1-3—O-lower alkyl, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy, —OC(R1)2C(O)N(R2)2, and —OC(R1)2C(O)NR7R8, wherein all substituents may be optionally substituted by one or more selected from the group consisting of hydroxy, hydroxyalkyl, heterocyclic, —NR7R8, —C(O)NR7R8, and —C(O)N(R2)2;
  • R5 is selected from the group consisting of a carbon-nitrogen linked heteroaryl and a carbon-nitrogen linked heterocyclic, which may be optionally substituted by one or more lower alkyl.
  • In a 22nd embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt, wherein:
  • R1 is hydrogen;
  • R2 is independently selected from the group consisting of lower alkyl, heteroaryl, heteroarylalkyl, and heterocyclicalkyl, wherein all substituents may be optionally substituted by one or more selected from the group consisting of halo, heterocyclic, heteroaryl, and lower alkyl;
  • R1 and R2 may be taken together to form a 5- to 6-membered heterocyclic saturated ring;
  • R7 and R8 are independently alkyl and linked together forming a 5- to 7-membered saturated monocyclic ring;
  • R3 and R4 are independently selected from hydroxy, lower alkoxy and heterocyclic lower alkoxy;
  • R5 is selected from the group consisting of a carbon-nitrogen linked heterocyclic, which may be optionally substituted by one or more lower alkyl.
  • In a 23rd embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt, wherein:
  • R1 is hydrogen;
  • R2 is independently selected from the group consisting of lower alkyl, heteroaryl, heteroarylalkyl, and heterocyclicalkyl, wherein all substituents may be optionally substituted by one or more selected from the group consisting of halo, heterocyclic, heteroaryl, and lower alkyl;
  • R3 and R4 are independently selected from lower alkoxy and heterocyclic lower alkoxy;
  • R5 is a carbon-nitrogen linked heterocyclic.
  • In a 24th embodiment, the invention is represented by Formula I, wherein the compound is selected from the group consisting of:
    • 4-[3E-(2,4-Dimethoxy-5-pyrrolidin-1-yl-phenyl)-acryloyl]-N-pyridin-2-yl-benzenesulfonamide;
    • 4-[3E-(2,4-Dimethoxy-5-pyrrolidin-1-ylphenyl)acryloyl]-N-pyridin-2-ylmethylbenzenesulfonamide;
    • 4-[3E-(2,4-Dimethoxy-5-pyrrolidin-1-ylphenyl)acryloyl]-N-(3-imidazol-1-ylpropyl)benzenesulfonamide;
    • 4-[3E-(2,4-Dimethoxy-5-pyrrolidin-1-ylphenyl)acryloyl]-N-[3-(4-methyl-piperazin-1-yl)propyl]benzenesulfonamide; and
    • {4-[3E-(2,4-Dimethoxy-5-pyrrolidin-1-ylphenyl)acryloyl]benzenesulfonylamino}acetic acid.
  • In a 25th embodiment, the invention is a pharmaceutical composition comprising a therapeutically effective amount of a compound of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or 24, together with one or more pharmaceutically acceptable carrier.
  • In a 26th embodiment, the invention is represented by a method for the treatment or prophylaxis of an inflammatory disorder, comprising administering an effective amount of a compound of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or 24.
  • In a 27th embodiment, the invention is represented by embodiment 26, wherein the disorder is arthritis.
  • In a 28th embodiment, the invention is represented by embodiment 26, wherein the disorder is rheumatoid arthritis.
  • In a 29th embodiment, the invention is represented by embodiment 26, wherein the disorder is asthma.
  • In a 30th embodiment, the invention is represented by embodiment 26, wherein the treatment is disease modifying for the treatment of rheumatoid arthritis.
  • In a 31st embodiment, the invention is represented by embodiment 26, wherein the disorder is allergic rhinitis.
  • In a 32nd embodiment, the invention is represented by embodiment 26, wherein the disorder is chronic obstructive pulmonary disease.
  • In a 33rd embodiment, the invention is represented by embodiment 26, wherein the disorder is atherosclerosis.
  • In a 34th embodiment, the invention is represented by embodiment 26, wherein the disorder is restinosis.
  • In a 35th embodiment, the invention is represented by embodiment, the invention is represented by a method for inhibiting the expression of VCAM-1, comprising administering an effective amount of a compound of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or 24.
  • In further embodiments, the invention is represented by intermediates used to make the final compounds of the invention. Said intermediates are useful as starting materials for making the compounds of the invention as well as having pharmaceutical activity alone. Particular intermediates include the ones represented by embodiment 36, represented by the formulas
    Figure US20070093453A1-20070426-C00011
    wherein
  • X is —C(O)H or —CH2OH;
  • R3 and R4 are independently selected from the group consisting of hydroxy, alkoxy, lower alkoxy, —(O(CH2)2)1-3—O-lower alkyl, cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy, —OC(R9)2C(O)N(R9)2, and —OC(R9)2C(O)NR7R8, wherein all substituents may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, haloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —C(O)NR7R8, and —C(O)N(R9)2;
  • Y1, Y2, Y3, and Y4 are independently selected from the group consisting of hydrogen, hydroxyl, halo, alkyl, lower alkyl, alkenyl, cycloalkyl, haloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, heteroaryl, —C(O)NR7R8, and —C(O)N(R9)2, wherein all substituents, when possible may be optionally substituted by one or more selected from the group consisting of hydroxyl, halo, alkyl, lower alkyl, alkenyl, cycloalkyl, haloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, heteroaryl, —C(O)NR7R8, and —C(O)N(R2)2.
  • Y5 is selected from the group consisting of hydrogen, alkyl, lower alkyl, acyl, and alkoxycarbonyl wherein all substituents, when possible may be optionally substituted by one or more selected from the group consisting of hydroxyl, halo, alkyl, lower alkyl, alkenyl, cycloalkyl, haloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, heteroaryl, —C(O)NR7R8, and —C(O)N(R9)2;
  • R9 is independently selected from the group consisting of alkyl, lower alkyl, carbocyclic, cycloalkyl, hydroxy, alkoxy, lower alkoxy, trialkylsilyloxy, cycloalkyloxy, cycloalkylalkoxy, heterocyclicoxy, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, acyl, alkoxycarbonyl, and heterocyclicalkyl, wherein all substituents may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, haloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR7R8, —NHR9, —N(R9)2, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, heteroaryl, —C(O)NR7R8, —NR9R9 and —C(O)N(R9)2;
  • R7 and R8 are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 4- to 12-membered monocyclic, bicylic, tricyclic or benzofused ring, which may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, haloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —C(O)NR7R8, and —C(O)N(R9)2.
  • In a 37th embodiment, the invention is represented by embodiment 36 wherein the compound is selected from
    Figure US20070093453A1-20070426-C00012
  • Another embodiment of the invention includes the process for making both the intermediates as well as the final compounds.
  • Definitions
  • A wavy line used as a bond “
    Figure US20070093453A1-20070426-P00900
    ”, denotes a bond which can be either the E- or Z-geometric isomer.
  • When not used as a bond, the wavy line indicates the point of attachment of the particular substituent.
  • The terms “alkyl” or “alk”, alone or in combination, unless otherwise specified, refers to a saturated straight or branched primary, secondary, or tertiary hydrocarbon from 1 to 10 carbon atoms, including, but not limited to methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, and sec-butyl. The term “lower alkyl” alone or in combination refers to an alkyl having from 1 to 4 carbon atoms. The alkyl group may be optionally substituted with any moiety that does not otherwise interfere with the reaction or that provides an improvement in the process, including but not limited to but limited to halo, haloalkyl, hydroxyl, carboxyl, acyl, aryl, acyloxy, amino, amido, carboxyl derivatives, alkylamino, dialkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, thiol, imine, sulfonyl, sulfanyl, sulfinyl, sulfamonyl, ester, carboxylic acid, amide, phosphonyl, phosphinyl, phosphoryl, phosphine, thioester, thioether, acid halide, anhydride, oxime, hydrazine, carbamate, phosphonic acid, phosphonate, either unprotected, or protected as necessary, as known to those skilled in the art, for example, as taught in Greene et al., Protective Groups in Organic Synthesis, John Wiley & Sons, Second Edition, 1991, hereby incorporated by reference. Specifically included are CF3 and CH2CF3.
  • The term “alkenyl”, alone or in combination, means a non-cyclic alkyl of 2 to 10 carbon atoms having one or more unsaturated carbon-carbon bonds. The alkenyl group may be optionally substituted with any moiety that does not otherwise interfere with the reaction or that provides an improvement in the process, including but not limited to but limited to halo, haloalkyl, hydroxyl, carboxyl, acyl, aryl, acyloxy, amino, amido, carboxyl derivatives, alkylamino, dialkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, thiol, imine, sulfonyl, sulfanyl, sulfinyl, sulfamonyl, ester, carboxylic acid, amide, phosphonyl, phosphinyl, phosphoryl, phosphine, thioester, thioether, acid halide, anhydride, oxime, hydrazine, carbamate, phosphonic acid, phosphonate, either unprotected, or protected as necessary, as known to those skilled in the art, for example, as taught in Greene et al., Protective Groups in Organic Synthesis, John Wiley & Sons, Second Edition, 1991, hereby incorporated by reference. Specifically included are CF3 and CH2CF3.
  • The term “alkynyl”, alone or in combination, means a non-cyclic alkyl of 2 to 10 carbon atoms having one or more triple carbon-carbon bonds, including but not limited to ethynyl and propynyl. The alkynyl group may be optionally substituted with any moiety that does not otherwise interfere with the reaction or that provides an improvement in the process, including but not limited to but limited to halo, haloalkyl, hydroxyl, carboxyl, acyl, aryl, acyloxy, amino, amido, carboxyl derivatives, alkylamino, dialkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, thiol, imine, sulfonyl, sulfanyl, sulfinyl, sulfamonyl, ester, carboxylic acid, amide, phosphonyl, phosphinyl, phosphoryl, phosphine, thioester, thioether, acid halide, anhydride, oxime, hydrazine, carbamate, phosphonic acid, phosphonate, either unprotected, or protected as necessary, as known to those skilled in the art, for example, as taught in Greene et al., Protective Groups in Organic Synthesis, John Wiley & Sons, Second Edition, 1991, hereby incorporated by reference. Specifically included are CF3 and CH2CF3.
  • The terms “carboxy”, “COOH” and “C(O)OH” are used interchangeably.
  • The terms “alkoxycarbonyl” and “carboalkoxy” are used interchangeably. Used alone or in combination, the terms mean refer to the radical —C(O)OR, wherein R is alkyl that can be optionally substituted as defined herein.
  • The term “thio”, alone or in combination, means the radical —S—.
  • The term “thiol”, alone or in combination, means the radical —SH.
  • The term “hydroxy”, alone or in combination means the radical —OH.
  • The term “sulfonyl”, alone or in combination means the radical —S(O)2—.
  • The term “oxo” refers to an oxygen attached by a double bond (═O).
  • The terms “carbocycle” and “carbocyclic”, alone or in combination, means any stable 3- to 7-membered monocyclic or bicyclic or 7- to 14-membered bicyclic or tricyclic or an up to 26-membered polycyclic carbon ring, any of which may be saturated, partially unsaturated, or aromatic. Examples of such carbocyles include, but are not limited to, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, biphenyl, naphthyl, indanyl, adamantyl, or tetrahydronaphthyl (tetralin).
  • The term “cycloalkyl”, alone or in combination, means a saturated or partially unsaturated cyclic alkyl, having from 1 to 10 carbon atoms, including but not limited to mono- or bi-cyclic ring systems such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexenyl, and cyclohexyl.
  • The term “aryl”, alone or in combination, means a carbocyclic aromatic system containing one, two or three rings wherein such rings may be attached together in a pendent manner or may be fused. The “aryl” group can be optionally substituted with one or more of the moieties selected from the group consisting of alkyl, alkenyl, alkynyl, heteroaryl, heterocyclic, carbocycle, alkoxy, oxo, aryloxy, arylalkoxy, cycloalkyl, tetrazolyl, heteroaryloxy; heteroarylalkoxy, carbohydrate, amino acid, amino acid esters, amino acid amides, alditol, halogen, haloalkylthi, haloalkoxy, haloalkyl, hydroxyl, carboxyl, acyl, acyloxy, amino, aminoalkyl, aminoacyl, amido, alkylamino, dialkylamino, arylamino, nitro, cyano, thiol, imide, sulfonic acid, sulfate, sulfonate, sulfonyl, alkylsulfonyl, aminosulfonyl, alkylsulfonylamino, haloalkylsulfonyl, sulfanyl, sulfinyl, sulfamoyl, carboxylic ester, carboxylic acid, amide, phosphonyl, phosphinyl, phosphoryl, thioester, thioether, oxime, hydrazine, carbamate, phosphonic acid, phosphate, phosphonate, phosphinate, sulfonamido, carboxamido, hydroxamic acid, sulfonylimide or any other desired functional group that does not inhibit the pharmacological activity of this compound, either unprotected, or protected as necessary, as known to those skilled in the art, for example, as taught in Greene, et al., “Protective Groups in Organic Synthesis,” John Wiley and Sons, Second Edition, 1999. In addition, adjacent groups on an “aryl” ring may combine to form a 5- to 7-membered saturated or partially unsaturated carbocyclic, aryl, heteroaryl or heterocyclic ring, which in turn may be substituted as above.
  • The term “heterocyclic”, alone or in combination, refers to a nonaromatic cyclic group that may be partially (containing at least one double bond) or fully saturated and wherein the ring contains at least one heteroatom selected from oxygen, sulfur, nitrogen, or phosphorus. The terms “heteroaryl” or “heteroaromatic”, alone or in combination, refer to an aromatic ring containing at least one heteroatom selected from sulfur, oxygen, nitrogen or phosphorus. The heteroaryl or heterocyclic ring may optionally be substituted by one or more substituent listed as optional substituents for aryl. In addition, adjacent groups on the heteroaryl or heterocyclic ring may combine to form a 5- to 7-membered carbocyclic, aryl, heteroaryl or heterocyclic ring, which in turn may be substituted as above. Nonlimiting examples of heterocyclics and heteroaromatics are pyrrolidinyl, tetrahydrofuryl, tetrahydrofuranyl, pyranyl, purinyl, tetrahydropyranyl, piperazinyl, piperidinyl, morpholino, thiomorpholino, tetrahydropyranyl, imidazolyl, pyrrolinyl, pyrazolinyl, indolinyl, dioxolanyl, or 1,4-dioxanyl, aziridinyl, furyl, furanyl, pyridyl, pyridinyl, pyridazinyl, pyrimidinyl, benzoxazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,3,4-thiadiazole, indazolyl, triazinyl, 1,3,5-triazinyl, thienyl, isothiazolyl, imidazolyl, tetrazolyl, pyrazinyl, benzofuranyl, quinolyl, isoquinolyl, benzothienyl, isobenzofuryl, pyrazolyl, indolyl, isoindolyl, benzimidazolyl, purinyl, carbazolyl, oxazolyl, thiazolyl, benzothiazolyl, isothiazolyl, 1,2,4-thiadiazolyl, isoxazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, pyrrolyl, quinazolinyl, quinoxalinyl, benzoxazolyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, xanthinyl, hypoxanthinyl, pyrazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, 1,2,3-oxadiazole, thiazine, pyridazine, triazolopyridinyl or pteridinyl wherein said heteroaryl or heterocyclic group can be optionally substituted with one or more substituent selected from the same substituents as set out above for aryl groups. Functional oxygen and nitrogen groups on the heteroaryl group can be protected as necessary or desired. Suitable protecting groups can include trimethylsilyl, dimethylhexylsilyl, t-butyldimethylsilyl, and t-butyldiphenylsilyl, trityl or substituted trityl, alkyl groups, acyl groups such as acetyl and propionyl, methanesulfonyl, and p-toluenesulfonyl.
  • The terms “thienyl” and “thien”, alone or in combination, refers to a five member cyclic group wherein the ring contains one sulfur atom and two double bonds.
  • The term “benzothienyl”, alone or in combination, refers to a five member cyclic group wherein the ring contains one sulfur atom and two double bonds fused to a phenyl ring.
  • The term “aryloxy”, alone or in combination, refers to an aryl group bound to the molecule through an oxygen atom.
  • The term “heteroaryloxy”, alone or in combination, refers to a heteroaryl group bound to the molecule through an oxygen atom.
  • The term “aralkoxy”, alone or in combination, refers to an aryl group attached to an alkyl group which is attached to the molecule through an oxygen atom.
  • The term “heterocyclearalkoxy” refers to a heterocyclic group attached to an aryl group attached to an alkyl-O— group. The heterocyclic, aryl and alkyl groups can be optionally substituted as described above.
  • The terms “halo” and “halogen”, alone or in combination, refer to chloro, bromo, iodo and fluoro.
  • The terms “alkoxy” or “alkylthio”, alone or in combination, refers to an alkyl group as defined above bonded through an oxygen linkage (—O—) or a sulfur linkage (—S—), respectively.
  • The terms “lower alkoxy” or “lower alkylthio”, alone or in combination, refers to a lower alkyl group as defined above bonded through an oxygen linkage (—O—) or a sulfur linkage (—S—), respectively.
  • The term “acyl”, alone or in combination, refers to a group of the formula C(O)R′, wherein R′ is an alkyl, aryl, alkaryl or aralkyl group, or substituted alkyl, aryl, aralkyl or alkaryl, wherein these groups are as defined above.
  • The term “acetyl”, alone or in combination, refers to the radical —C(O)CH3.
  • The term “amino”, alone or in combination, denotes the radical —NH2 or —NH—.
  • The term “nitro”, alone or in combination, denotes the radical —NO2.
  • The term “substituted”, means that one or more hydrogen on the designated atom or substituent is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and the that the substitution results in a stable compound. When a substitutent is “oxo” (keto) (i.e., ═O), then 2 hydrogens on the atom are replaced.
  • As used herein, the term “patient” refers to warm-blooded animals or mammals, and in particular humans, who are in need of the therapy described herein. The term “host”, as used herein, refers to a unicellular or multicellular organism, including cell lines and animals, and preferably a human.
  • Synthesis of the Active Compounds
  • The compounds of the present invention can be readily prepared by those skilled in the art of organic synthesis using commonly known methods, many of which are described by J, March, in Advanced Organic Chemistry, 4th Edition (Wiley-Interscience, New York, 1992) and D. N. Dnar in The Chemistry of Chalcones and Related Compounds (Wiley-Interscience, New York, 1981), incorporated herein by reference.
  • Compounds of the invention may be isolated as either mixtures of cis (Z) and trans (E) geometric isomers or pure trans (E) isomers. If desired, either the mixtures or the pure trans isomers may be isomerized to the corresponding predominantly cis (Z) iomers using methods well known in the literature.
  • The following schemes and examples will prove useful to those skilled in the art in manufacturing the compounds of the invention:
    Figure US20070093453A1-20070426-C00013
    Figure US20070093453A1-20070426-C00014
    Figure US20070093453A1-20070426-C00015
    Figure US20070093453A1-20070426-C00016
    • EXAMPLES
  • The following examples are understood to be illustrative only and are not intended to limit the scope of the present invention in any way. All intermediates and final products have been characterized by conventional proton NMR, mass spectral analyses and/or standard analytical methods known to those skilled in the art.
    • Example 1
  • Figure US20070093453A1-20070426-C00017
    • 4-[3E-(2,4-Dimethoxy-5-thien-2-yl-phenyl)acryloyl]-N-(5-methylisoxazol-3-yl)benzenesulfonamide
  • Ex-1A: 5-bromo-2,4-dimethoxybenzaldehyde (20.3 g, 83 mmol), thiophene-2-boronic acid (11.6 g, 91 mmol) and THF (200 mL) were sequentially charged into a clean reaction vessel fitted with a reflux condenser, mechanical stirrer and nitrogen inlet adapter. Nitrogen was bubbled into the resulting solution for 20 min followed by the sequential addition of KF (10.1 g, 174 mmol), and Pd(tBu3P)2 (0.424 g, 0.83 mmol). The solution was immediately heated to 60° C. and aged for 1.5 h. The reaction was diluted with H2O (200 mL) and transferred to a separatory funnel containing EtOAc (200 mL) and H2O (200 mL). The layers were cut and the aqueous layer was extracted with EtOAc (100 mL). The combined organic cuts were filtered through a pre-washed pad of solka floc (5 g). The pad of solka floc and spent catalyst were washed with fresh EtOAc (200 mL) and this wash combined with the batch. The resultant filtrate was concentrated to dryness. The crude product was dissolved in THF (38 mL) and crystallized upon heptane (152 mL) addition. The product was filtered and then dried to a constant weight in the vacuum oven (38° C., 20 in Hg) affording 19.32 g (94%) of the desired 2,4-dimethoxy-5-thien-2-ylbenzaldehyde as a light off-white solid, mp 125-126° C. 1H-NMR (300 MHz, CDCl3): 10.34 (s, 1H), 8.12 (s, 1H), 7.44 (dd, 1H, J=3.5 and 1.5 Hz), 7.31 (dd, 1H, J=5.2 and 1.5 Hz), 7.07 (dd, 1H, J=5.2 and 3.5 Hz), 6.51 (s, 1H), 4.02 (s, 3H), 3.99 (s, 3H). HRMS (EI) Calcd. for C13H12O3S: 248.0507 (M+); Found: 248.0504.
  • Ex-1B: To a solution of 3-amino-5-methylisoxazole (0.27 g, 2.75 mmol) in pyridine (1 mL) at 0° C. was added a solution of 4-acetylbenzenesulfonyl chloride (0.50 g, 2.29 mmol) in 1 mL pyridine dropwise to the reaction. The resulting solution was stirred at 0° C. for 30 min and then warmed to room temperature and stirred for an additional 18 h. The mixture was diluted with water (100 mL), cooled to 0° C., and stirred for 1 h. The resulting precipitate was collected on filter paper and rinsed with several portions of water. The filtrate was acidified with 3 N HCl and the resulting precipitate was collected and rinsed with water. The solids were combined and dried in vacuo to afford 0.50 g (80%) of 4-acetyl-N-(5-methylisoxazole-3-yl)benzenesulfonamide as a pale green solid, mp 189-190° C. 1H-NMR (300 MHz, DMSO-d6) δ 8.14 (d, 2H, J=8.1 Hz), 7.98 (d, 2H, J=8.1 Hz), 6.16 (s, 1H), 2.62 (s, 3H), 2.30 (s, 3H). HRMS (EI) Calcd. for C12H12N2O4S: 280.0518 (M+); Found: 280.0514. Anal. Calcd. for C12H12N2O4S: C, 51.42; H, 4.32; N, 9.99; S, 11.44; Found: C, 51.73; H, 4.39; N, 10.12; S, 11.30.
  • 4-Acetyl-N-(5-methylisoxazole-3-yl)benzenesulfonamide (Ex-1B, 2.50 g, 8.9 mmol) and 2,4-dimethoxy-5-thien-2-ylbenzaldehyde (Ex-1A, 2.20 g, 8.9 mmol) were dissolved in a dimethylformamide-methanol solution (55 mL, 7:3). After complete dissolution, lithium methoxide (1.35 g, 35.6 mmol) was added and the resulting orange slurry was stirred in the dark at room temperature for 1 h. Upon completion, as determined by HPLC, the mixture was diluted with water (80 mL), acidified with a 1 N hydrochloric acid solution, and extracted with ethyl acetate (3×40 mL). The combined organic extracts were dried over sodium sulfate and evaporated to dryness. The crude oil was taken up in ethanol (20 mL) and warmed to 60° C. to obtain complete dissolution and allowed to cool to room temperature. The resulting precipitate was collected on filter paper and dried in vacuo to yield 3.78 g (83%) of the title compound as an orange solid, mp 202-203° C. 1H-NMR (300 MHz, DMSO-d6)
    Figure US20070093453A1-20070426-P00901
    8.31 (d, 2H, J=8.1 Hz), 8.27 (s, 1H), 8.08 (d, 1H, J=15.9 Hz), 8.01 (d, 2H, J=8.1 Hz), 7.88 (d, 1H, J=15.9 Hz), 7.66 (d, 1H, J=3.3 Hz), 7.53 (d, 1H, J=5.1 Hz), 7.13 (dd, 1H, J=5.1, 3.3 Hz), 6.84 (s, 1H), 6.18 (s, 1H), 4.02 (s, 3H), 4.00 (s, 3H), 2.31 (s, 3H). Anal. Calcd. for C25H22N2O6S2: C, 58.81; H, 4.34; N, 5.49; S, 12.56; Found: C, 58.68; H, 4.40; N, 5.61; S, 12.62. HRMS (EI) Calcd. for C25H22N2O6S2: 511.0997 (M+); Found: 511.0983.
    • Example 2
  • Figure US20070093453A1-20070426-C00018
    • 4-[3E-(2,4-Dimethoxy-5-thien-2-ylphenyl)acryloyl]-N-(5-methylisoxazol-3-yl)benzenesulfonamide sodium salt
  • To a solution of 4-[3E-(2,4-dimethoxy-5-thien-2-ylphenyl)acryloyl]-N-(5-methyl-isoxazol-3-yl)benzenesulfonamide (Ex-1, 0.50 g, 0.98 mmol) in tetrahydrofuran (8 mL) was added sodium methoxide (0.061 g, 1.07 mmol) and the reaction was stirred in the dark at room temperature for 1 h. The resulting yellow solid was collected on filter paper and rinsed with fresh portions of THF. The wet filtercake was dried in a vacuum desiccator for 1 h then transferred to a flask and dried further in vacuo for 18 h. The crude orange solid was taken up in ethanol (6 mL) and stirred for 4 h at room temperature in the dark. The solid was collected on filter paper and dried in vacuo to yield 0.30 g (60%) of the title compound as a yellow solid, mp>260° C. 1H-NMR (300 MHz, DMSO-d6)
    Figure US20070093453A1-20070426-P00901
    8.26 (s, 1H), 8.11 (d, 2H, J=8.1 Hz), 8.04 (d, 1H, J=15.7 Hz), 7.88 (d, 1H, J=15.7 Hz), 7.80 (d, 2H, J=8.1 Hz), 7.69 (d, 1H, J=3.3 Hz), 7.51 (d, 1H, J=5.1 Hz), 7.13 (dd, 1H, J=5.1, 3.3 Hz), 6.83 (s, 1H), 5.80 (s,1H), 4.01 (s, 3H), 4.00 (s, 3H), 2.11 (s, 3H). Anal. Calcd. for C25H21N2NaO6S2.¼H2O: C, 55.91; H, 4.04; N, 5.22; S, 11.94; Found: C, 55.92; H, 3.98; N, 5.21; S, 11.95.
    • Example 3
  • Figure US20070093453A1-20070426-C00019
    • 4-[3E-(2,4-Dimethoxy-5-thien-2-ylphenyl)acryloyl]-N-pyrimidin-2-ylbenzenesulfonamide
  • Ex-3A: 4-Acetyl-N-pyrimidin-2-ylbenzenesulfonamide was prepared in an analogous fashion as Ex-1B using 2-aminopyrimidine, 30% yield, pale yellow solid, mp>240° C. (dec). 1H-NMR (300 MHz, DMSO-d6) δ 8.50 (d, 2H, J=4.8 Hz), 8.07-8.14 (m, 4H), 7.05 (t, 1H, J=4.5 Hz), 2.61 (s, 3H). HRMS (ESI) Calcd. for C12H11N3O3S: 278.0599 (M+H)+; Found: 278.0608.
  • The title compound was prepared in an analogous fashion as Ex-1 using 4-acetyl-N-pyrimidin-2-ylbenzenesulfonamide (Ex-3A), 70% yield, yellow solid, mp 215° C. (dec). 1H-NMR (300 MHz, DMSO-d6)
    Figure US20070093453A1-20070426-P00901
    8.27 (s, 1H), 8.12-8.16 (m, 4H), 8.06 (d, 1H, J=15.6 Hz), 7.95 (d, 2H, J=8.1 Hz), 7.90 (d, 1H, J=15.6 Hz), 7.68 (d, 1H, J=3.6 Hz), 7.52 (d, 1H, J=4.8 Hz), 7.12-7.15 (m, 1H), 6.84 (s, 1H), 6.50 (t, 1H, J=5.1 Hz), 4.02 (s, 3H), 4.00 (s, 3H). Anal. Calcd. for C25H21N3O5S2.3H2O: C, 53.46; H, 4.85; N, 7.48; S, 11.42; Found: C, 53.67; H, 4.71; N, 7.38; S, 11.76. HRMS (ESI) Calcd. for C25H21N3O5S2: 508.1001 (M+H)+; Found: 508.1005.
    • Example 4
  • Figure US20070093453A1-20070426-C00020
    • 4-[3E-(2,4-Dimethoxy-5-thien-2-ylphenyl)acryloyl]-N-(1-H-tetrazol-5-yl)benzenesulfonamide
  • Ex-4A: 4-Acetyl-N-(1-H-tetrazol-5-yl)benzenesulfonamide was prepared in an analogous fashion as Ex-1B using 5-aminotetrazole, 50% yield, off-white solid, mp 150-151° C. 1H-NMR (300 MHz, DMSO-d6) δ 8.98 (brs, 1H), 8.11 (d, 2H, J=8.1 Hz), 8.02 (d, 2H, J=8.1 Hz), 7.91 (brs, 1H), 2.64 (s, 3H). HRMS (EI) Calcd. for C9H9N5O3S: 267.0426 (M+); Found: 267.0425.
  • The title compound was prepared in an analogous fashion as Ex-1 using 4-acetyl-N-(1-H-tetrazol-5-yl)benzenesulfonamide (Ex-4A), 55% yield, dark yellow solid, mp 185-186° C. 1H-NMR (300 MHz, DMSO-d6) δ 8.29 (d, 2H, J=8.1 Hz), 8.27 (s, 1H), 8.07 (d, 1H, J=15.9 Hz), 8.03 (d, 2H, J=8.1 Hz), 7.88 (d, 1H, J=15.9 Hz), 7.66 (d, 1H, J=3.6 Hz), 7.52 (dd, 1H, J=5.4, 1.5 Hz), 7.13 (dd, 1H, J=5.4, 3.6 Hz), 6.85 (s, 1H), 4.02 (s, 3H), 4.00 (s, 3H). Anal. Calcd. for C22H19N5O5S2.¼EtOH: C, 53.09; H, 4.06; N, 13.76; S, 12.60; Found: C, 53.39; H, 3.95; N, 13.51; S, 12.72. HRMS (ESI) Calcd. for C22H19N5O5S2: 498.0906 (M+H)+; Found: 498.0920.
    • Example 5
  • Figure US20070093453A1-20070426-C00021
    • 4-[3E-(2,4-Dimethoxy-5-thien-2-ylphenyl)acryloyl]-N-pyridin-2-ylbenzenesulfonamide
  • Ex-5A: 4-Acetyl-N-pyridin-2-ylbenzenesulfonamide was prepared in an analogous fashion as Ex-1B using 2-aminopyridine, 77% yield, off-white solid, mp 198-199° C. 1H-NMR (300 MHz, DMSO-d6) δ 8.07 (d, 2H, J=8.1 Hz), 7.97 (d, 3H, J=8.1 Hz), 7.75-7.80 (m, 1H), 7.22 (d, 1H, J=8.7 Hz), 6.86 (t, 1H, J=6.9 Hz), 2.60 (s, 3H). HRMS (EI) Calcd. for C13H12N2O3S: 276.0569 (M+); Found: 276.0563.
  • The title compound was prepared in an analogous fashion as Ex-1 using 4-acetyl-N-pyridin-2-ylbenzenesulfonamide (Ex-5A), 54% yield, yellow solid, mp 141-143° C. 1H-NMR (300 MHz, DMSO-d6)
    Figure US20070093453A1-20070426-P00901
    8.26 (s, 1H), 8.24 (d, 2H, J=8.1 Hz), 8.06 (d, 1H, J=15.6 Hz), 8.01 (d, 2H, J=8.1 Hz), 7.96-7.99 (m, 1H), 7.87 (d, 1H, J=15.6 Hz), 7.75 (ddd, 1H, J=8.7, 6.7, 1.8 Hz), 7.66 (dd, 1H, J=3.5, 1.5 Hz), 7.52 (d, 1H, J=5.4 Hz), 7.21 (d, 1H, J=8.7 Hz), 7.13 (dd, 1H, J=5.4, 3.5 Hz), 6.82-6.86 (m, 2H), 4.02 (s, 3H), 4.00 (s, 3H). Anal. Calcd. for C26H22N2O5S2.½H2O: C, 60.78; H, 4.81; N, 5.35; S, 12.25; Found: C, 60.63; H, 4.55; N, 5.74; S, 12.32. HRMS (ESI) Calcd. for C26H22N2O5S2: 507.1048 (M+H)+; Found: 507.1051.
    • Example 6
  • Figure US20070093453A1-20070426-C00022
    • 4-[3E-(2,4-Dimethoxy-5-thien-2-ylphenyl)acryloyl]-N-(1H-pyrazol-3-yl)benzenesulfonamide
  • Ex-6A: 4-Acetyl-N-(1H-pyrazol-3-yl)benzenesulfonamide was prepared in an analogous fashion as Ex-1B using 3-aminopyrazole except that silica gel chromatography (ethyl acetate/hexanes, 1:1 to 3:1) was used, 15% yield, white solid. 1H-NMR (300 MHz, DMSO-d6) δ 10.60 (s, 1H), 8.09 (d, 2H, J=8.7 Hz), 7.90 (d, 2H, J=8.7 Hz), 7.56 (s, 1H), 5.98 (s, 1H), 2.61 (s, 3H). HRMS (EI) Calcd. for C11H11N3O3S: 265.0521 (M+); Found: 265.0526.
  • The title compound was prepared in an analogous fashion as Ex-1 using 4-acetyl-N-(1H-pyrazol-3-yl)benzenesulfonamide (Ex-6A), 40% yield, yellow solid, mp 142-145° C. 1H-NMR (300 MHz, DMSO-d6)
    Figure US20070093453A1-20070426-P00901
    10.60 (s, 1H), 8.25 (d, 3H, J=8.4 Hz), 8.08 (d, 1H, J=15.6 Hz), 7.93 (d, 2H, J=8.7 Hz), 7.87 (d, 1H, J=15.6 Hz), 7.67 (d, 1H, J=−3.6 Hz), 7.56 (d, 1H, J=2.1 Hz), 7.52 (d, 1H, J=5.4 Hz), 7.13 (dd, 1H, J=5.4, 3.6 Hz), 6.84 (s, 1H), 6.00 (d, 1H, J=1.8 Hz), 4.02 (s, 3H), 4.00 (s, 3H). HRMS (ESI) Calcd. for C24H21N3O5S2: 496.1001 (M+H)+; Found: 496.1022.
    • Example 7
  • Figure US20070093453A1-20070426-C00023
    • 4-[3E-(2,4-Dimethoxy-5-thien-2-ylphenyl)acryloyl]-N-isoxazol-3-ylbenzenesulfonamide
  • Ex-7A: 4-Acetyl-N-isoxazol-3-ylbenzenesulfonamide was prepared in an analogous fashion as Ex-1B using 3-aminoisoxazole, 71% yield, off-white solid, mp 165-166° C. 1H-NMR (300 MHz, DMSO-d6) δ 8.75 (d, 1H, J=1.5 Hz), 8.14 (d, 2H, J=8.1 Hz), 8.00 (d, 2H, J=8.1 Hz), 6.45 (d, 1H, J=1.5 Hz), 2.62 (s, 3H). Anal. Calcd. for C11H10N2O4S: C, 49.62; H, 3.79; N, 10.52; S, 12.04. Found: C, 49.58; H, 3.63; N, 10.45; S, 12.14. HRMS (EI) Calcd. for C11H10N2O4S: 266.0361 (M+); Found: 266.0365.
  • The title compound was prepared in an analogous fashion as Ex-1 using 4-acetyl-N-isoxazol-3-ylbenzenesulfonamide (Ex-7A), 77% yield, orange solid, mp 198-199° C. 1H-NMR (300 MHz, DMSO-d6)
    Figure US20070093453A1-20070426-P00901
    8.76 (d, 1H, J=2.7 Hz), 8.31 (d, 2H, J=8.1 Hz), 8.27 (s, 1H), 8.07 (d, 1H, J=15.6 Hz), 8.02 (d, 2H, J=8.1 Hz), 7.88 (d, 1H, J=15.6 Hz), 7.67 (d, 1H, J=3.6 Hz), 7.53 (d, 1H, J=5.4 Hz), 7.13 (dd, 1H, J=5.4, 3.6 Hz), 6.84 (s, 1H), 6.48 (d, 1H, J=2.7 Hz), 4.02 (s, 3H), 4.00 (s, 3H). Anal. Calcd. for C24H20N2O6S2: C, 58.05; H, 4.06; N, 5.64; S, 12.91; Found: C, 57.91; H, 4.16; N, 5.63; S, 12.71. HRMS (EI) Calcd. for C24H20N2O6S2: 496.0763 (M+); Found: 496.0770.
    • Example 8
  • Figure US20070093453A1-20070426-C00024
    • 4-[3E-(2,4-Dimethoxy-5-thien-2-ylphenyl)acryloyl]-N-thiazol-2-ylbenzenesulfonamide
  • Ex-8A: 4-Acetyl-N-thiazol-2-ylbenzenesulfonamide was prepared in an analogous fashion as Ex-1B using 2-aminothiazole, 68% yield, tan solid, mp 194-195° C. 1H-NMR (300 MHz, DMSO-d6) δ 8.08 (d, 2H, J=8.4 Hz), 7.92 (d, 2H, J=8.4 Hz), 7.29 (d, 1H, J=4.5 Hz), 6.87 (d, 1H, J=4.5 Hz), 2.60 (s, 3H). HRMS (EI) Calcd. for C11H10N2O3S2: 282.0133 (M+); Found: 282.0131.
  • The title compound was prepared in an analogous fashion as Ex-1 using 4-acetyl-N-thiazol-2-ylbenzenesulfonamide (Ex-8A), 83% yield, yellow solid, mp 220-221° C. 1H-NMR (300 MHz, DMSO-d6)
    Figure US20070093453A1-20070426-P00901
    8.24-8.26 (m, 3H), 8.06 (d, 1H, J=15.8 Hz), 7.95 (d, 2H, J=7.8 Hz), 7.88 (d, 1H, J=15.8 Hz), 7.66 (d, 1H, J=3.6 Hz), 7.52 (d, 1H, J=5.4 Hz), 7.29 (d, 1H, J=4.2 Hz), 7.13 (dd, 1H, J=5.4, 3.6 Hz), 6.88 (d, 1H, J=4.5 Hz), 6.84 (s, 1H), 4.02 (s, 3H), 4.00 (s, 3H). HRMS (ESI) Calcd. for C24H20N2O5S3: 513.0612 (M+H)+; Found: 513.0633.
    • Example 9
  • Figure US20070093453A1-20070426-C00025
    • 4-[3E-(2,4-Dimethoxy-5-thien-2-ylphenyl)acryloyl]-N-(3-methylisoxazol-5-ylbenzenesulfonamide
  • Ex-9A: 4-Acetyl-N-(3-methylisoxazol-5-yl)benzenesulfonamide was prepared in an analogous fashion as Ex-1B using 5-amino-3-methylisoxazole, 64% yield, tan solid, mp 144-145° C. 1H-NMR (300 MHz, DMSO-d6) δ 8.15 (d, 2H, J=8.7 Hz), 7.99 (d, 2H, J=8.7 Hz), 5.77 (s, 1H), 2.63 (s, 3H), 2.01 (s, 3H). HRMS (EI) Calcd. for C12H12N2O4S: 280.0518 (M+); Found: 280.0525.
  • The title compound was prepared in an analogous fashion as Ex-1 using 4-acetyl-N-(3-methylisoxazol-5-yl)benzenesulfonamide (Ex-9A), 30% yield, orange solid, mp 138-140° C. 1H-NMR (300 MHz, DMSO-d6)
    Figure US20070093453A1-20070426-P00901
    8.28-8.34 (m, 3H), 8.08 (d, 1H, J=15.3 Hz), 8.02 (d, 2H, J=8.1 Hz), 7.90 (d, 1H, J=15.3 Hz), 7.66 (d, 1H, J=−3.0 Hz), 7.51 (d, 1H, J=5.4 Hz), 7.13 (dd, 1H, J=5.4, 3.6 Hz), 6.85 (s, 1H), 5.80 (s, 1H), 4.02 (s, 3H), 4.00 (s, 3H), 2.11 (s, 3H). HRMS (ESI) Calcd. for C25H22N2O6S2: 510.0997 (M+H)+; Found: 511.0991.
    • Example 10
  • Figure US20070093453A1-20070426-C00026
    • N-(5-Chloropyridin-2-yl)-4-[3E-(2,4-dimethoxy-5-thien-2-ylphenyl)acryloyl]benzenesulfonamide
  • Ex-10A: 4-Acetyl-N-(5-chloropyridin-2-yl)benzenesulfonamide was prepared in an analogous fashion as Ex-1B using 2-amino-5-chloropyridine, 78% yield, tan solid, mp 181-182° C. 1H-NMR (300 MHz, DMSO-d6) δ 8.20 (d, 1H, J=3.3 Hz), 8.11 (d, 2H, J=8.4 Hz), 8.03 (d, 2H, J=8.4 Hz), 7.82 (dd, 1H, J=9.0, 3.3 Hz), 7.09 (d, 1H, J=9.0 Hz), 2.62 (s, 3H). Anal. Calcd. for C13H11ClN2O3S: C, 50.24; H, 3.57; Cl, 11.41; N, 9.01; S, 10.32. Found: C, 50.59; H, 3.62; Cl, 11.49; N, 9.34; S, 10.02. HRMS (ESI) Calcd. for C13H11ClN2O3S: 311.0257 (M+H)+; Found: 311.0264.
  • The title compound was prepared in an analogous fashion as Ex-1 using 4-acetyl-N-(5-chloropyridin-2-yl)benzenesulfonamide (Ex-10A), 85% yield, orange solid, mp 228-229° C. 1H-NMR (300 MHz, DMSO-d6)
    Figure US20070093453A1-20070426-P00901
    8.27-8.30 (m, 3H), 8.22 (d, 1H, J=2.4 Hz), 8.05-8.10 (m, 3H), 7.87 (d, 1H, J=16.0 Hz), 7.83 (dd, 1H, J=9.0, 2.4 Hz), 7.65 (d, 1H, J=3.6 Hz), 7.53 (d, 1H, J=5.4 Hz), 7.10-7.15 (m, 2H), 6.84 (s, 1H), 4.02 (s, 3H), 4.00 (s, 3H). Anal. Calcd. for C26H21ClN2O5S2.⅙H2O: C, 57.40; H, 3.95; Cl, 6.52; N, 5.15; S, 11.79. Found: C, 57.18; H, 4.05; Cl, 6.25; N, 5.51; S, 11.60. HRMS (ESI) Calcd. for C26H21ClN2O5S2: 541.0658 (M+H)+; Found: 541.0642.
    • Example 11
  • Figure US20070093453A1-20070426-C00027
    • 4-[3E-(2,4-Dimethoxy-5-thien-2-ylphenyl)acryloyl]-N-(5-fluoropyridin-2-yl)benzenesulfonamide
  • Ex-11A: 4-Acetyl-N-(5-fluoropyridin-2-yl)benzenesulfonamide was prepared in an analogous fashion as Ex-1B using 2-amino-5-fluoropyridine, 91% yield, light red solid, mp 151-152° C. 1H-NMR (300 MHz, DMSO-d6) δ 8.17 (d, 1H, J=3.0 Hz), 8.11 (d, 2H, J=8.4 Hz), 8.02 (d, 2H, J=8.4 Hz), 7.82 (dt, 1H, J=9.1, 3.3 Hz), 7.09 (dd, 1H, J=9.1, 3.3 Hz), 2.61 (s, 3H). HRMS (ESI) Calcd. for C13H11FN2O3S: 295.0552 (M+H)+; Found: 295.0563.
  • The title compound was prepared in an analogous fashion as Ex-1 using 4-acetyl-N-(5-fluoropyridin-2-yl)benzenesulfonamide (Ex-11A), 81% yield, an orange solid, mp 194-195° C. 1H-NMR (300 MHz, DMSO-d6)
    Figure US20070093453A1-20070426-P00901
    8.29-8.31 (m, 3H), 8.18 (d, 1H, J=2.1 Hz), 8.03-8.10 (m, 3H), 7.87 (d, 1H, J=15.6 Hz), 7.66-7.72 (m, 2H), 7.52 (d, 1H, J=3.0 Hz), 7.12-7.17 (m, 2H), 6.84 (s, 1H), 4.02 (s, 3H), 4.00 (s, 3H). Anal. Calcd. for C26H21FN2O5S2.⅕H2O: C, 59.12; H, 4.08; F, 3.60; N, 5.30; S, 12.14. Found: C, 59.07; H, 4.07; F, 3.55; N, 5.53; S, 12.17. HRMS (ESI) Calcd. for C26H21FN2O5S2: 525.0954 (M+H)+; Found: 525.0967.
    • Example 12
  • Figure US20070093453A1-20070426-C00028
    • 4-[3E-(2,4-Dimethoxy-5-thien-2-ylphenyl)acryloyl]-N-(5-trifluoromethylpyridin-2-yl)benzenesulfonamide
  • Ex-12A: 4-Acetyl-N-(5-trifluoromethylpyridin-2-yl)benzenesulfonamide was prepared in an analogous fashion as Ex-1B using 2-amino-5-(trifluoromethyl)pyridine, 75% yield, off-white solid, mp 179-180° C. 1H-NMR (300 MHz, DMSO-d6) δ 8.52 (brs, 1H), 8.06-8.14 (m, 5H), 7.23 (d, 1H, J=9.0 Hz), 2.61 (s, 3H). HRMS (ESI) Calcd. for C14H11F3N2O3S: 345.0520 (M+H)+; Found: 345.0531.
  • The title compound was prepared in an analogous fashion as Ex-1 using 4-acetyl-N-(5-trifluoromethylpyridin-2-yl)benzenesulfonamide (Ex-12A), 85% yield, orange solid, mp 228-229° C. 1H-NMR (300 MHz, DMSO-d6)
    Figure US20070093453A1-20070426-P00901
    8.54 (brs, 1H), 8.29 (d, 2H, J=8.4 Hz), 8.26 (s, 1H), 8.05-8.13 (m, 4H), 7.88 (d, 1H, J=15.9 Hz), 7.65 (d, 1H, J=3.6 Hz), 7.52 (d, 1H, J=5.1 Hz), 7.24 (d, 1H, J=8.7 Hz), 7.13 (dd, 1H, J=5.1, 3.6 Hz), 6.84 (s, 1H), 4.02 (s, 3H), 4.00 (s, 3H). Anal. Calcd. for C27H21F3N2O5S2.¼H2O: C, 56.00; H, 3.74; F, 9.84; N, 4.84; S, 11.07. Found: C, 55.90; H, 3.90; F, 9.81; N, 5.09; S, 11.08. HRMS (ESI) Calcd. for C27H21F3N2O5S2: 575.0922 (M+H)+; Found: 575.0925.
    • Example 13
  • Figure US20070093453A1-20070426-C00029
    • 4-{3E-[2-(3-Hydroxy-2-hydroxymethylpropoxy)-4-methoxy-5-thien-2-ylphenyl]acryloyl}-N-(5-methylisoxazol-3-yl)benzenesulfonamide
  • Ex-13A: To a solution of 3-(tert-butyldimethylsilanyloxy)-2-(tert-butyldimethylsilanyloxymethyl)propan-1-ol (25.0 g, 74.3 mmol) and triethylamine (22.6 g, 223 mmol) in dichloromethane (150 mL) at 0° C. was added methanesulfonyl chloride (12.8 g, 111 mmol) and the resulting slurry was stirred at 0° C. for 15 min and allowed to warm to room temperature. The solution was stirred for an additional 3 h at room temperature and diluted with water (130 mL) and ethyl acetate (350 mL). The layers were separated and the aqueous was extracted with ethyl acetate (150 mL). The combined organic extracts were washed with a saturated sodium bicarbonate (200 mL), a 50% sodium chloride solution (2×200 mL), dried over sodium sulfate and concentrated to afford 29.5 g (97%) of methanesulfonic acid 3-(tert-butyldimethylsilanyloxy)-2-(tert-butyldimethylsilanyloxymethyl)propyl ester as a yellow oil. 1H-NMR (300 MHz, CDCl3) δ 4.29 (d, 2H, J=5.7 Hz), 3.61-3.68 (m, 4H), 2.99 (s, 3H), 2.04-2.11 (m, 1H), 0.88 (s, 18H), 0.049 (s, 12H). HRMS (ESI) Calcd. for C17H40O5SSi2: 413.2213 (M+H)+; Found: 413.2226.
  • Ex-13B: 2-Hydroxy-4-methoxybenzaldehyde (6.0 g, 39 mmol) was dissolved in dichloromethane (50 mL) and cooled to 0° C. using an ice-water bath. Bromine (6.8 g, 43 mmol) in dichloromethane (2 mL) was added dropwise to the cooled solution and stirred for 2 h at 0° C. The mixture was warmed to room temperature and stirred for an additional 1 h and the resulting yellow precipitate was collected. Recrystallization (ethyl acetate/hexanes) yielded 7.1 g (80%) of 5-bromo-2-hydroxy-4-methoxybenzaldehyde as white needles, mp 63-64° C. 1H-NMR (300 MHz, CDCl3) δ 11.43 (s, 1H), 9.69 (s, 1H), 7.68 (s, 1H), 6.48 (s, 1H), 3.95 (s, 3H). Anal. Calcd. for C8H7BrO3: C, 41.59; H, 3.05; Found: C, 41.86; H, 3.05.
  • Ex-13C: 5-Bromo-2-hydroxy-4-methoxybenzaldehyde (Ex-13B, 1.5 g, 6.5 mmol) and thiophene-2-boronic acid (0.91 g, 7.1 mmol) were dissolved in tetrahydrofuran (15 mL). Nitrogen was bubbled into the solution for 10 min followed by the sequential addition of potassium fluoride (0.80 g, 14 mmol, spray-dried) and bis(tri-t-butylphosphine)palladium (0) (0.033 g, 0.065 mmol). The solution was immediately heated to 60° C. and aged for 1.5 h. Upon completion, as determined by HPLC, the reaction was diluted with water (25 mL) and extracted with ethyl acetate (3×30 mL). The combined organic extracts were dried over sodium sulfate and concentrated to a brown solid. Silica gel chromatography (ethyl acetate/hexanes, 1:3) gave 1.46 g (97%) of 2-hydroxy-4-methoxy-5-thien-2-ylbenzaldehyde as a yellow solid, mp 118-119° C. 1H-NMR (300 MHz, CDCl3) δ 11.48 (s, 1H), 9.79 (s, 1H), 7.72 (s, 1H), 7.37 (d, 1H, J=3.6 Hz), 7.31 (dd, 1H, J=5.1, 1.5 Hz), 7.08 (dd, 1H, J=5.1, 3.6 Hz), 6.54 (s, 1H), 3.98 (s, 3H). MS (ESI) m/z 235 ([M+H]+, 100%). Anal. Calcd. for C8H7O3S: C, 61.52; H, 4.30; S, 13.69; Found: C, 61.12; H, 4.34; S, 13.56.
  • Ex-13D: To a solution of 2-hydroxy-4-methoxy-5-thien-2-ylbenzaldehyde (Ex-13C, 0.10 g, 0.43 mmol) in N,N-dimethylformamide (3 mL) was added potassium carbonate (0.18 g, 1.3 mmol) and the resulting yellow slurry was heated to 80° C. Methanesulfonic acid 3-(tert-butyldimethylsilanyloxy)-2-(tert-butyldimethylsilanyloxymethyl)propyl ester (Ex-13A, 0.24 g, 1.3 mmol) was then added dropwise in three equal portions with stirring at 1 h intervals. After the last addition, the reaction was stirred for an additional 1 h at 80° C. and cooled to room temperature. The mixture was diluted with water (15 mL) and extracted with ethyl acetate (3×15 mL). The combined organic phase was sequentially washed with a saturated ammonium chloride solution (15 mL), water (15 mL), and brine (15 mL), dried over sodium sulfate, and concentrated to a brown oil. Silica gel chromatography (ethyl acetate/hexanes, 1:6) gave 0.78 g (90%) of 2-[3-(tert-butyldimethylsilanyloxy)-2-(tert-butyldimethylsilanyloxymethyl)propoxy]-4-methoxy-5-thien-2-ylbenzaldehyde as a pale green solid, mp 91-92° C. 1H-NMR (300 MHz, CDCl3) δ 10.34 (s, 1H), 8.13 (s, 1H), 7.41 (dd, 1H, J=3.6, 1.2 Hz), 7.28 (dd, 1H, J=5.1, 1.2 Hz), 7.05 (dd, 1H, J=5.1, 3.6 Hz), 6.54 (s, 1H), 4.22 (d, 2H, J=5.7 Hz), 3.96 (s, 3H), 3.80 (d, 4H, J=5.7 Hz), 2.33 (pentet, 1H, J=5.7 Hz), 0.88 (s, 18H), 0.012 (s, 12H). HRMS (EI) Calcd. for C28H46O5SSi2: 550.2604 (M+); Found: 550.2593.
  • Ex-13E: To a solution of 2-[3-(tert-butyldimethylsilanyloxy)-2-(tert-butyldimethylsilanyloxymethyl)propoxy]-4-methoxy-5-thien-2-ylbenzaldehyde (Ex-13D, 0.78 g, 1.41 mmol) in tetrahydrofuran (5 mL) was added tetrabutylammonium fluoride (1 M in tetrahydrofuran, 3.0 mL, 2.9 mmol) and the mixture was stirred at room temperature for 30 min. The reaction was diluted with ethyl acetate (50 mL) and washed sequentially with a 50% ammonium chloride solution (30 mL), water (2×30 mL), brine (30 mL), dried over sodium sulfate and concentrated to a crude yellow solid. Silica gel chromatography afforded 0.37 g (99%) of 2-(3-hydroxy-2-hydroxymethylpropoxy)-4-methoxy-5-thien-2-ylbenzaldehyde as a pale yellow solid, mp 144-145° C. 1H-NMR (300 MHz, CDCl3) δ 10.33 (s, 1H), 8.10 (s, 1H), 7.38 (dd, 1H, J=3.6, 1.5 Hz), 7.30 (dd, 1H, J=5.1, 1.5 Hz), 7.07 (dd, 1H, J=5.1, 3.6 Hz), 6.59 (s, 1H), 4.35 (d, 2H, J=6.0 Hz), 4.02 (t, 4H, J=4.8 Hz), 3.96 (s, 3H), 2.33 (pentet, 1H, J=6.0 Hz), 1.89 (t, 2H, J=4.8 Hz). Anal. Calcd. for C16H18O5S: C, 59.61; H, 5.63; S, 9.95; Found: C, 59.34; H, 5.75; S, 9.82.
  • The title compound was prepared in an analogous fashion as Ex-1 using 4-acetyl-N-(5-methylisoxazole-3-yl)benzenesulfonamide (Ex-13E), 57% yield, orange solid, mp 165-166° C. 1H-NMR (300 MHz, DMSO-d6)
    Figure US20070093453A1-20070426-P00901
    8.29 (d, 2H, J=8.7 Hz), 8.25 (s, 1H), 8.08 (d, 1H, J=15.9 Hz), 8.02 (d, 2H, J=8.7 Hz), 7.90 (d, 1H, J=15.9 Hz), 7.65 (d, 1H, J=3.6 Hz), 7.52 (d, 1H, J=5.1 Hz), 7.13 (dd, 1H, J=5.1, 3.6 Hz), 6.87 (s, 1H), 6.18 (s, 1H), 4.67 (brs, 2H), 4.23 (d, 2H, J=5.7 Hz), 4.01 (s, 3H), 3.57-3.59 (m, 4H), 2.31 (s, 3H), 2.11 (pentet, 1H, J=5.7 Hz). Anal. Calcd. for C28H28N2O8S2: C, 57.52; H, 4.83; N, 4.79; S, 10.97. Found: C, 57.58; H, 4.77; N, 4.67; S, 11.01. HRMS (ESI) Calcd. for C28H28N2O8S2: 585.1365 (M+H)+; Found: 585.1367.
    • Example 14
  • Figure US20070093453A1-20070426-C00030
    • 4-{3E-[4-Methoxy-2-(2-morpholin-4-yl-ethoxy)-5-thien-2-ylphenyl]acryloyl}-N-(5-methyl-isoxazol-3-yl)benzenesulfonamide hydrochloride
  • Ex-14A: 4-Methoxy-2-(2-morpholin-4-ylethoxy)-5-thien-2-ylbenzaldehyde was prepared in an analogous fashion as Ex-13D using 4-(2-chloroethyl)morpholine hydrochloride, 93% yield after silica gel chromatography (80 to 100% ethyl acetate/hexanes then 5% methanol/methylene chloride), off-white solid, mp 130-131° C. 1H-NMR (300 MHz, CDCl3) δ 10.36 (s, 1H), 8.12 (s, 1H), 7.44 (dd, 1H, J=3.6, 1.5 Hz), 7.30 (dd, 1H, J=5.1, 1.5 Hz), 7.07 (dd, 1H, J=5.1, 3.6 Hz), 6.53 (s, 1H), 4.27 (t, 2H, J=6.3 Hz), 4.00 (s, 3H), 3.72-3.76 (m, 4H), 2.89 (t, 2H, J=6.3 Hz), 2.60-2.63 (m, 4H). HRMS (EI) Calcd. for C18H21NO4S: 347.1191 (M+); Found: 347.1188.
  • 4-Acetyl-N-(5-methylisoxazole-3-yl)benzenesulfonamide (Ex-1B, 0.30 g, 0.86 mmol) and 4-methoxy-2-(2-morpholin-4-ylethoxy)-5-thien-2-ylbenzaldehyde (Ex-14A, 0.24 g, 0.86 mmol) were dissolved in a dimethylformamide-methanol solution (6.0 mL, 7:3). After complete dissolution, lithium methoxide (0.13 g, 3.4 mmol) was added and the resulting orange slurry was stirred in the dark at room temperature for 1 h. Upon completion, as determined by HPLC, the mixture was diluted with water (8.0 mL), acidified with a 1 N hydrochloric acid solution, and extracted with ethyl acetate:tetrahydrofuran (1:1, 3×20 mL). The combined organic extracts were evaporated to dryness. The crude oil was taken up in ethanol (10 mL) and warmed to 60° C. to obtain complete dissolution and allowed to cool to room temperature. The resulting precipitate was collected on filter paper and dried in vacuo to yield 0.46 g (88%) of the title compound as a pale orange solid, mp>260° C. 1H-NMR (300 MHz, DMSO-d6)
    Figure US20070093453A1-20070426-P00901
    8.34 (d, 2H, J=9.0 Hz), 8.32 (s, 1H), 8.12 (d, 1H, J=15.9 Hz), 8.03 (d, 2H, J=9.0 Hz), 7.93 (d, 1H, J=15.9 Hz), 7.69 (d, 1H, J=3.3 Hz), 7.56 (d, 1H, J=5.4 Hz), 7.15 (dd, 1H, J=5.4, 3.3 Hz), 6.92 (s, 1H), 6.18 (s, 1H), 4.65 (brs, 2H), 4.03 (s, 3H), 3.97 (brs, 4H), 3.69 (brs, 2H), 3.50-3.23 (brs, 4H), 2.31 (s, 3H). Anal. Calcd. for C30H32ClN3O7S2.H2O: C, 54.25; H, 5.16; N, 6.33; S, 9.66; Found: C, 54.10; H, 4.91; N, 6.39; S, 9.68. HRMS (ESI) Calcd. for C30H32ClN3O7S2: 610.1681 (—HCl) (M+H)+. Found: 610.1673.
    • Example 15
  • Figure US20070093453A1-20070426-C00031
    • 4-{3E-[2,4-Dimethoxy-5-(1-methyl-1H-indol-2-yl)phenyl]acryloyl}-N-(5-methylisoxazol-3-yl)benzenesulfonamide
  • Ex-15A: 1-Methylindole (5.0 g, 38.1 mmol) was dissolved in tetrahydrofuran (190 mL) and nitrogen was bubbled into the solution for 15 min. The solution was then cooled to 0° C. and tert-butyllithium (1.6 M solution in pentane, 23.5 mL, 40.0 mmol) was added dropwise and the mixture was stirred for 30 min at 0° C. and then warmed to room temperature and stirred for an additional 1 h. Triethylborane (1.0 M solution in THF, 45.7 mL, 45.7 mmol) was added, and the reaction mixture was stirred for 1 h at room temperature. To the crude indolylborate, generated in situ, was added 5-bromo-2,4-dimethoxybenzaldehyde (9.3 g, 38.1 mmol) and bis(tri-t-butylphosphine)palladium (0) (0.48 g, 0.95 mmol). The solution was immediately heated to 60° C. and aged for 30 min. Upon completion, as determined by HPLC, the reaction was treated with 10% aqueous sodium hydroxide (190 mL) and 30% hydrogen peroxide (38 mL) with ice-cooling for 20 min. The mixture was extracted with ethyl acetate (3×100 mL), and the combined organic extracts were washed with brine (2×75 mL), dried over sodium sulfate and concentrated to a brown oil. Silica gel chromatography (ethyl acetate/hexanes, 1:3 to 3:1) gave 7.69 g (77%) of 2,4-dimethoxy-5-(1-methyl-1H-indol-2-yl)benzaldehyde as a yellow solid, mp 153-153° C. 1H-NMR (300 MHz, CDCl3) δ 10.36 (s, 1H), 7.87 (s, 1H), 7.37 (d, 1H, J=7.5 Hz), 7.31 (d, 1H, J=9.0 Hz), 7.20-7.28 (m, 1H), 7.12 (t, 1H, J=6.8 Hz), 6.55 (s, 1H), 6.48 (s, 1H), 4.03 (s, 3H), 3.91 (s, 3H), 3.55 (s, 3H). Anal. Calcd. for C18H17NO3: C, 73.20; H, 5.80; N, 4.74; Found: C, 72.98; H, 5.89; N, 4.73.
  • The title compound was prepared in an analogous fashion as Ex-1 using 2,4-dimethoxy-5-(1-methyl-1H-indol-2-yl)benzaldehyde (Ex-15A), 66% yield, pale orange solid, mp 220° C. 1H-NMR (300 MHz, DMSO-d6)
    Figure US20070093453A1-20070426-P00901
    8.29 (d, 2H, J=8.7 Hz), 8.12 (d, 1H, J=15.8 Hz), 8.04 (s, 1H), 7.96 (d, 2H, J=8.7 Hz), 7.84 (d, 1H, J=15.8 Hz), 7.55 (d, 1H, J=7.5 Hz), 7.46 (d, 1H, J=8.1 Hz), 7.17 (t, 1H, J=7.5 Hz), 7.06 (t, 1H, J=7.8 Hz), 6.89 (s, 1H), 6.45 (s, 1H), 6.15 (s, 1H), 4.05 (s, 3H), 3.91 (s, 3H), 3.54 (s, 3H), 2.28 (s, 3H). Anal. Calcd. for C30H27N3O6S: C, 64.62; H, 4.88; N, 7.54; S, 5.75. Found: C, 64.42; H, 5.26; N, 7.46; S, 5.61. HRMS (ESI) Calcd. for C30H27N3O6S: 558.1699 (M+H)+; Found: 558.1685.
    • Example 16
  • Figure US20070093453A1-20070426-C00032
    • 4-{3E-[2,4-Dimethoxy-5-(1-methyl-1H-indol-2-yl)phenyl]acryloyl}-N-(5-methylisoxazol-3-yl)benzenesulfonamide sodium salt
  • The title compound was prepared in an analogous fashion as Ex-2 from 4-{3-[2,4-dimethoxy-5-(1-methyl-1H-indol-2-yl)phenyl]acryloyl}-N-(5-methylisoxazol-3-yl)benzenesulfonamide (Ex-15) as a yellow solid, mp 202-206° C. 1H-NMR (300 MHz, DMSO-d6)
    Figure US20070093453A1-20070426-P00901
    8.03-8.10 (m, 4H), 7.88 (d, 1H, J=15.9 Hz), 7.75 (d, 2H, J=8.1 Hz), 7.55 (d, 1H, J=7.5 Hz), 7.46 (d, 1H, J=8.4 Hz), 7.17 (t, 1H, J=7.5 Hz), 7.06 (t, 1H, J=7.8 Hz), 6.88 (s, 1H), 6.46 (s, 1H), 5.77 (s, 1H), 4.04 (s, 3H), 3.91 (s, 3H), 3.54 (s, 3H), 2.09 (s, 3H). Anal. Calcd. for C30H26N3NaO6S.H2O.⅓EtOH: C, 60.09; H, 4.93; N, 6.86; S, 5.23; Found: C, 59.86; H, 4.89; N, 6.80; S, 5.14.
    • Example 17
  • Figure US20070093453A1-20070426-C00033
    • 4-{3E-[2,4-Dimethoxy-5-(1-methyl-1H-indol-2-yl)phenyl]acryloyl}-N-pyridin-3-ylmethyl-benzenesulfonamide
  • Ex-17A: To a solution of 4-acetylbenzenesulfonyl chloride (0.50 g, 2.3 mmol) in tetrahydrofuran (10 mL) was added 3-(aminomethyl)pyridine (0.58 g, 5.7 mmol) and the reaction was stirred for 30 min at room temperature. The mixture was then diluted with water (30 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine (2×25 mL), dried over sodium sulfate, and the solvent was removed under reduced pressure. The resulting solid was dried in vacuo to afford 0.67 g (99%) of 4-acetyl-N-pyridin-3-ylmethylbenzenesulfonamide as a white solid, mp 143-144° C. 1H-NMR (300 MHz, CDCl3) δ 8.50-8.52 (m, 1H), 8.41 (d, 1H, J=2.7 Hz), 8.06 (d, 2H, J=8.7 Hz), 7.95 (d, 2H, J=8.4 Hz), 7.6-7.63 (m, 1H), 7.21-7.25 (m, 1H), 5.05 (brs, 1H), 4.22 (d, 2H, J=5.7 Hz), 2.66 (s, 3H). HRMS (EI) Calcd. for C14H14N2O3S: 290.0725 (M+); Found: 290.0726.
  • The title compound was prepared in an analogous fashion as Ex-1 using 4-acetyl-N-(5-methylisoxazole-3-yl)benzenesulfonamide (Ex-17A) and 2,4-dimethoxy-5-(1-methyl-1H-indol-2-yl)benzaldehyde (Ex-15A), 80% yield, yellow solid, mp 202-203° C. 1H-NMR (300 MHz, DMSO-d6)
    Figure US20070093453A1-20070426-P00901
    8.39-8.43 (m, 3H), 8.26 (d, 2H, J=8.0 Hz), 8.13 (d, 1H, J=15.9 Hz), 8.06 (s, 1H), 7.89 (d, 2H, J=8.0 Hz), 7.85 (d, 1H, J=15.9 Hz), 7.60-7.63 (m, 1H), 7.56 (d, 1H, J=6.9 Hz), 7.46 (d, 1H, J=8.1 Hz), 7.27 (dd, 1H, J=7.2, 4.2 Hz), 7.17 (t, 1H, J=7.2 Hz), 7.06 (t, 1H, J=8.1 Hz), 6.90 (s, 1H), 6.46 (s, 1H), 4.07 (s, 2H), 4.06 (s, 3H), 3.93 (s, 3H), 3.55 (s, 3H). Anal. Calcd. for C32H29N3O5S.¼H2O: C, 67.17; H, 5.20; N, 7.34; S, 5.60; Found: C, 67.39; H, 5.41; N, 7.38; S, 5.54. HRMS (ESI) Calcd. for C32H29N3O5S: 568.1906 (M+H)+; Found: 568.1895.
    • Example 18
  • Figure US20070093453A1-20070426-C00034
    • 4-{3E-[2,4-Dimethoxy-5-(1-methyl-1H-indol-2-yl)phenyl]acryloyl}-N-(2-morpholin-4-yl-ethyl)benzenesulfonamide
  • Ex-18A: 4-Acetyl-N-(2-morpholin-4-ylethyl)benzenesulfonamide was prepared in an analogous fashion as Ex-17A using 4-(2-aminoethyl)morpholine, 99% yield, off-white solid, mp 128-129° C. 1H-NMR (300 MHz, CDCl3) δ 8.08 (d, 2H, J=8.7 Hz), 7.98 (d, 2H, J=8.7 Hz), 5.28 (brs, 1H), 3.61-3.64 (m, 4H), 3.05 (t, 2H, J=5.4 Hz), 2.66 (s, 3H), 2.42 (t, 2H, J=5.7 Hz), 2.27-2.31 (m, 4H). HRMS (ESI) Calcd. for C14H20N2O4S: 313.1222 (M+H)+; Found: 313.1215.
  • The title compound was prepared in an analogous fashion as Ex-1 using 4-acetyl-N-(5-methylisoxazole-3-yl)benzenesulfonamide (Ex-18A) and 2,4-dimethoxy-5-(1-methyl-1H-indol-2-yl)benzaldehyde (Ex-15A), 80% yield, yellow solid, mp 167-168° C. 1H-NMR (300 MHz, DMSO-d6)
    Figure US20070093453A1-20070426-P00901
    8.29 (d, 2H, J=8.7 Hz), 8.14 (d, 1H, J=15.3 Hz), 8.06 (s, 1H), 7.93 (d, 2H, J=8.7 Hz), 7.86 (d, 1H, J=15.3 Hz), 7.77 (brs, 1H), 7.56 (d, 1H, J=7.2 Hz), 7.46 (d, 1H, J=8.1 Hz), 7.18 (t, 1H, J=7.8 Hz), 7.06 (t, 1H, J=7.2 Hz), 6.90 (s, 1H), 6.46 (s, 1H), 4.06 (s, 3H), 3.93 (s, 3H), 3.55 (s, 3H), 3.42-3.48 (m, 4H), 2.89 (t, 2H, J=7.5 Hz), 2.22-2.31 (m, 6H). Anal. Calcd. for C32H35N3O6S: C, 65.18; H, 5.98; N, 7.13; S, 5.44; Found: C, 65.05; H, 6.11; N, 7.09; S, 5.42. HRMS (ESI) Calcd. for C32H35N3O6S: 590.2325 (M+H)+; Found: 590.2334.
    • Example 19
  • Figure US20070093453A1-20070426-C00035
    • 4-[3E-(2,4-Dimethoxy-5-thien-2-ylphenyl)acryloyl]-N-pyridin-3-ylmethylbenzenesulfonamide
  • The title compound was prepared in an analogous fashion as Ex-1 using 4-acetyl-N-pyridin-3-ylmethylbenzenesulfonamide (Ex-17A), 85% yield, yellow solid, mp 167-168° C. 1H-NMR (300 MHz, DMSO-d6)
    Figure US20070093453A1-20070426-P00901
    8.47 (brs, 1H), 8.40-8.43 (m, 2H), 8.27 (d, 3H, J=8.4 Hz), 8.10 (d, 1H, J=15.6 Hz), 7.94 (d, 2H, J=8.4 Hz), 7.90 (d, 1H, J=15.6 Hz), 7.62-7.68 (m, 2H), 7.53 (d, 1H, J=5.4 Hz), 7.29 (dd, 1H, J=7.5, 4.8 Hz), 7.14 (dd, 1H, J=5.4, 3.6 Hz), 6.85 (s, 1H), 4.10 (s, 2H), 4.02 (s, 3H), 4.01 (s, 3H). Anal. Calcd. for C27H24N2O5S2: C, 62.29; H, 4.65; N, 5.38; S, 12.32; Found: C, 62.03; H, 4.87; N, 5.39; S, 12.10.
    • Example 20
  • Figure US20070093453A1-20070426-C00036
    • 4-[3E-(2,4-Dimethoxy-5-thien-2-ylphenyl)acryloyl]-N-(2-morpholin-4-yl-ethyl)benzenesulfonamide
  • The title compound was prepared in an analogous fashion as Ex-1 using 4-acetyl-N-(2-morpholin-4-ylethyl)benzenesulfonamide (Ex-18A), 90% yield, yellow solid, mp 171-172° C. 1H-NMR (300 MHz, DMSO-d6)
    Figure US20070093453A1-20070426-P00901
    8.31 (d, 2H, J=9.0 Hz), 8.28 (s, 1H), 8.09 (d, 1H, J=15.6 Hz), 7.97 (d, 2H, J=9.0 Hz), 7.91 (d, 1H, J=15.6 Hz), 7.80 (brs, 1H), 7.67 (d, 1H, J=3.6 Hz), 7.53 (d, 1H, J=5.4 Hz), 7.13 (dd, 1H, J=5.4, 3.6 Hz), 6.85 (s, 1H), 4.02 (s, 3H), 4.01 (s, 3H), 3.47-3.50 (m, 4H), 2.91 (t, 2H, J=7.2 Hz), 2.24-2.33 (m, 6H). Anal. Calcd. for C27H30N2O6S2: C, 59.76; H, 5.57; N, 5.16; S, 11.82; Found: C, 59.39; H, 5.65; N, 5.11; S, 11.53.
    • Example 21
  • Figure US20070093453A1-20070426-C00037
    • 3E-(2,4-Dimethoxy-5-thien-2-ylphenyl)-1-[4-(4-methylpiperazine-1-sulfonyl)phenyl]propenone
  • Ex-21A: 1-[4-(4-Methylpiperazine-1-sulfonyl)phenyl]ethanone was prepared in an analogous fashion as Ex-17A using 4-methylpiperazine, 99% yield, pale yellow solid, mp 118-119° C. 1H-NMR (300 MHz, CDCl3) δ 8.09 (d, 2H, J=9.3 Hz), 7.85 (d, 2H, J=9.3 Hz), 3.67 (t, 4H, J=4.8 Hz), 2.66 (s, 3H), 2.48 (t, 4H, J=4.8 Hz), 2.27 (s, 3H). HRMS (EI) Calcd. for C13H18N2O3S: 282.1038 (M+); Found: 282.1038.
  • The title compound was prepared in an analogous fashion as Ex-1 using 1-[4-(4-methylpiperazine-1-sulfonyl)phenyl]ethanone (Ex-21A), 30% yield after silica gel chromatography (methanol/methylene chloride, 1:10), dark yellow solid, mp 133-135° C. 1H-NMR (300 MHz, DMSO-d6)
    Figure US20070093453A1-20070426-P00901
    8.31 (d, 2H, J=8.7 Hz), 8.25 (s, 1H), 8.06 (d, 1H, J=15.0 Hz), 7.89 (d, 2H, J=8.7 Hz), 7.82 (d, 1H, J=15.0 Hz), 7.63 (d, 1H, J=3.9 Hz), 7.48 (d, 1H, J=5.4 Hz), 7.09 (dd, 1H, J=5.4, 3.9 Hz), 6.81 (s, 1H), 4.00 (s, 3H), 3.98 (s, 3H), 3.90 (brs, 4H), 2.32-2.34 (m, 4H), 2.07 (s, 3H). HRMS (EI) Calcd. for C26H28N2O5S2: 512.1440 (M+); Found: 512.1427.
    • Example 22
  • Figure US20070093453A1-20070426-C00038
    • 4-[3E-(2,4-Dimethoxy-5-thien-2-ylphenyl)acryloyl]-N-piperidin-1-ylbenzenesulfonamide
  • Ex-22A: 4-Acetyl-N-piperidin-1-ylbenzenesulfonamide was prepared in an analogous fashion as Ex-17A using 1-aminopiperidine, 98% yield, pale yellow solid, mp 137-139° C. 1H-NMR (300 MHz, CDCl3) δ 8.07 (s, 4H), 5.38 (brs, 1H), 2.67 (s, 3H), 2.54 (t, 4H, J=5.4 Hz), 1.47-1.55 (m, 4H), 1.30-1.33 (m, 2H). Anal. Calcd. for C13H18N2O3S: C, 55.30; H, 6.43; N, 9.92; S, 11.36; Found: C, 55.22; H, 6.40; N, 9.50; S, 11.38.
  • The title compound was prepared in an analogous fashion as Ex-1 using 4-acetyl-N-piperidin-1-ylbenzenesulfonamide (Ex-22A), 71% yield, orange solid, mp 174-176° C. 1H-NMR (300 MHz, DMSO-d6)
    Figure US20070093453A1-20070426-P00901
    8.94 (s, 1H), 8.32 (d, 2H, J=8.7 Hz), 8.29 (s, 1H), 8.10 (d, 1H, J=15.0 Hz), 8.00 (d, 2H, J=8.7 Hz), 7.93 (d, 1H, J=15.0 Hz), 7.67 (dd, 1H, J=3.6, 1.5 Hz), 7.53 (dd, 1H, J=5.4, 1.5 Hz), 7.14 (dd, 1H, J=5.4, 3.6 Hz), 6.85 (s, 1H), 4.02 (s, 3H), 4.01 (s, 3H), 2.44-2.47 (m, 4H), 1.38 (brs, 4H), 1.21-1.23 (m, 2H). Anal. Calcd. for C26H28N2O5S2: C, 60.92; H, 5.51; N, 5.46; S, 12.51; Found: C, 61.13; H, 5.71; N, 5.38; S, 12.35.
    • Example 23
  • Figure US20070093453A1-20070426-C00039
    • 4-[3E-(2,4-Dimethoxy-5-thien-2-ylphenyl)acryloyl]-N-(3-imidazol-1-ylpropyl)benzenesulfonamide
  • Ex-23A: 4-Acetyl-N-(3-imidazol-1-ylpropyl)benzenesulfonamide was prepared in an analogous fashion as Ex-17A using 1-(3-aminopropyl)imidazole, 89% yield, white solid, mp 142-144° C. 1H-NMR (300 MHz, DMSO-d6) δ 8.14 (d, 2H, J=8.1 Hz), 7.89 (d, 2H, J=8.1 Hz), 7.54 (s, 1H), 7.09 (s, 1H), 6.85 (s, 1H), 3.96 (t, 2H, J=7.2 Hz), 3.31 (s, 3H), 2.70 (t, 2H, J=7.8 Hz), 1.80 (pentet, 2H, J=7.8 Hz). HRMS (EI) Calcd. for C14H17N3O3S: 307.0991 (M+); Found: 307.0986.
  • The title compound was prepared in an analogous fashion as Ex-1 using 4-acetyl-N-(3-imidazol-1-ylpropyl)benzenesulfonamide (Ex-23A), 70% yield, yellow solid, mp 160-162° C. 1H-NMR (300 MHz, DMSO-d6)
    Figure US20070093453A1-20070426-P00901
    8.31 (d, 2H, J=8.7 Hz), 8.29 (s, 1H), 8.10 (d, 1H, J=15.9 Hz), 7.93 (d, 3H, J=8.7 Hz), 7.91 (d, 1H, J=15.9 Hz), 7.67 (dd, 1H, J=3.6, 1.5 Hz), 7.55 (s, 1H), 7.54 (d, 1H, J=5.4 Hz), 7.13 (dd, 1H, J=5.4, 3.6 Hz), 7.10 (s, 1H), 6.85 (s, 1H), 4.02 (s, 3H), 4.01 (s, 3H), 3.97 (t, 2H, J=6.3 Hz), 2.70-2.76 (m, 2H), 1.81 (pentet, 2H, J=6.3 Hz). Anal. Calcd. for C27H27N3O5S2: C, 60.32; H, 5.06; N, 7.82; S, 11.93; Found: C, 59.76; H, 5.06; N, 7.60; S, 12.00.
    • Example 24
  • Figure US20070093453A1-20070426-C00040
    • 4-[3E-(2,4-Dimethoxy-5-thien-2-ylphenyl)acryloyl]-N-(2,2,2-trifluoroethyl)benzenesulfonamide
  • Ex-24A: 4-Acetyl-N-(2,2,2-trifluoroethyl)benzenesulfonamide was prepared in an analogous fashion as Ex-17A using 2,2,2-trifluoroethylamine hydrochloride and triethylamine in a tetrahydrofuran:water mixture (9:1), 73% yield, white solid, mp 180-181° C. 1H-NMR (300 MHz, DMSO-d6) δ 8.85 (brs, 1H), 8.14 (d, 2H, J=8.1 Hz), 7.96 (d, 2H, J=8.1 Hz), 7.75 (q, 2H, J=10.0 Hz), 6.64 (s, 3H). HRMS (EI) Calcd. for C10H10F3NO3S: 281.0333 (M+); Found: 281.0342.
  • The title compound was prepared in an analogous fashion as Ex-1 using 4-acetyl-N-(2,2,2-trifluoroethyl)benzenesulfonamide (Ex-24A), 43% yield, yellow solid, mp 167-168° C. 1H-NMR (400 MHz, DMSO-d6)
    Figure US20070093453A1-20070426-P00901
    8.87 (s, 1H), 8.31 (d, 2H, J=5.6 Hz), 8.29 (s, 1H), 8.10 (d, 1H, J=10.4 Hz), 8.00 (d, 2H, J=5.6 Hz), 7.92 (d, 1H, J=10.4 Hz), 7.67 (d, 1H, J=2.8 Hz), 7.53 (d, 1H, J=3.6 Hz), 7.14 (dd, 1H, J=3.6, 2.8 Hz), 6.85 (s, 1H), 4.02 (s, 3H), 4.01 (s, 3H), 3.78 (q, 2H, J=6.8 Hz). HRMS (ESI) Calcd. for C23H20F3NO5S2: 512.0813 (M+H)+; Found: 512.0798.
    • Example 25
  • Figure US20070093453A1-20070426-C00041
    • 4-[3E-(2,4-Dimethoxy-5-thien-2-ylphenyl)acryloyl]-N-(2,2,2-trifluoroethyl)benzenesulfonamide sodium salt
  • The title compound was prepared in an analogous fashion as Ex-2, from 4-[3E-(2,4-Dimethoxy-5-thien-2-ylphenyl)acryloyl]-N-(2,2,2-trifluoroethyl)benzenesulfonamide (Ex-24, 45% yield, yellow solid, mp 160-170° C. 1H-NMR (300 MHz, DMSO-d6)
    Figure US20070093453A1-20070426-P00901
    8.27 (s, 1H), 8.10 (d, 2H, J=8.1 Hz), 8.05 (d, 1H, J=15.7 Hz), 7.90 (d, 1H, J=15.7 Hz), 7.71 (d, 3H, J=8.1 Hz), 7.52 (d, 1H, J=5.4 Hz), 7.13 (dd, 1H, J=3.3, 5.4 Hz), 6.84 (s, 1H), 4.02 (s, 3H), 4.01 (s, 3H), 3.28 (q, 2H, J=10.5 Hz). Anal. Calcd. for C23H19F3NNaO5S2.⅔H2O.⅓EtOH: C, 50.68; H, 4.01; N, 2.50; S, 11.43; Found: C, 50.88; H, 4.35; N, 2.49; S, 10.99.
    • Example 26
  • Figure US20070093453A1-20070426-C00042
    • {4-[3E-(2,4-Dimethoxy-5-thien-2-ylphenyl)acryloyl]benzenesulfonylamino}acetic acid
  • Ex-26A: To a solution of 4-acetylbenzenesulfonyl chloride (0.50 g, 2.3 mmol) in acetone (7.5 mL) was added a solution of glycine (0.42 g, 5.7 mmol) in 5% aqueous sodium hydroxide (2.5 mL) and the reaction was stirred for 30 min at room temperature. The mixture was diluted with water (10 mL), acidified with a 1 N hydrochloric acid solution, and extracted with ethyl acetate (3×15 mL). The combined organic layers were washed with brine (2×20 mL), dried over sodium sulfate, and the solvent was removed under reduced pressure. The resulting solid was dried in vacuo to afford 0.55 g (94%) of (4-acetylbenzenesulfonylamino)acetic acid as a white solid, mp 213-215° C. 1H-NMR (300 MHz, DMSO-d6) δ 8.28 (t, 1H, J=5.4 Hz), 8.12 (d, 2H, J=8.4 Hz), 7.92 (d, 2H, J=8.4 Hz), 3.64 (d, 2H, J=5.1 Hz), 2.64 (s, 3H). Anal. Calcd. for C10H11NO5S: C, 46.69; H, 4.31; N, 5.44; S, 12.46; Found: C, 46.76; H, 4.43; N, 5.39; S, 12.16.
  • The title compound was prepared in an analogous fashion as Ex-1 using (4-acetylbenzenesulfonylamino)acetic acid (Ex-26A), 82% yield, orange solid, mp 100-101° C. 1H-NMR (300 MHz, DMSO-d6)
    Figure US20070093453A1-20070426-P00901
    8.30 (d, 3H, J=8.1 Hz), 8.29(s, 1H), 8.10 (d, 1H, J=15.0 Hz), 7.96 (d, 2H, J=8.1 Hz), 7.92 (d, 1H, J=15.0 Hz), 7.67 (dd, 1H, J=3.6, 1.2 Hz), 7.53 (d, 1H, J=5.4 Hz), 7.14 (dd, 1H, J=5.4, 3.6 Hz), 6.85 (s, 1H), 4.02 (s, 3H), 4.01 (s, 3H), 3.66 (d, 2H, J=5.7 Hz). HRMS (ESI) Calcd. for C23H21NO7S2: 488.0837 (M+H)+; Found: 488.0847.
    • Example 27
  • Figure US20070093453A1-20070426-C00043
    • 2-{4-[3E-(2,4-Dimethoxy-5-thien-2-yl-phenyl)acryloyl]benzenesulfonylamino}-2-methylpropionic acid
  • Ex-27A: 2-(4-Acetylbenzenesulfonylamino)-2-methylpropionic acid was prepared in an analogous fashion as Ex-26A using 2-aminoisobutyric acid, 70% yield, white solid, mp 157-158° C. 1H-NMR (300 MHz, DMSO-d6) δ 8.21 (s, 1H), 8.10 (d, 2H, J=8.7 Hz), 7.92 (d, 2H, J=8.7 Hz), 3.63 (s, 3H), 1.27 (s, 6H). Anal. Calcd. for C12H15NO5S. 1/30H2O: C, 50.40; H, 5.31; N, 4.90; S, 11.21; Found: C, 50.12; H, 5.25; N, 5.15; S, 11.65. HRMS (ESI) Calcd. for C12H15NO5S: 286.0749 (M+H)+; Found: 286.0756.
  • The title compound was prepared in an analogous fashion as Ex-1 using 2-(4-acetylbenzenesulfonylamino)-2-methylpropionic acid (Ex-27A), 80% yield, yellow solid, mp 205° C. (dec). 1H-NMR (300 MHz, DMSO-d6)
    Figure US20070093453A1-20070426-P00901
    8.29 (d, 2H, J=8.4 Hz), 8.28(s, 1H), 8.23 (s, 1H), 8.10 (d, 1H, J=15.3 Hz), 7.96 (d, 2H, J=8.4 Hz), 7.92 (d, 1H, J=15.3 Hz), 7.67 (d, 1H, J=3.6 Hz), 7.53 (d, 1H, J=5.4 Hz), 7.14 (dd, 1H, J=5.4, 3.6 Hz), 6.85 (s, 1H), 4.02 (s, 3H), 4.01 (s, 3H), 1.30 (s, 6H). Anal. Calcd. for C25H25NO7S2.⅕H2O: C, 57.83; H, 4.93; N, 2.70; S, 12.35; Found: C, 57.81; H, 4.98; N, 3.08; S, 12.45.
    • Example 28
  • Figure US20070093453A1-20070426-C00044
    • 1-{4-[3E-(2,4-Dimethoxy-5-thien-2-ylphenyl)acryloyl]benzenesulfonyl}piperidine-2-carboxylic acid
  • Ex-28A: 1-(4-Acetylbenzenesulfonyl)piperidine-2-carboxylic acid was prepared in an analogous fashion as Ex-26A using 2-pipecolinic acid, 67% yield, white foam. 1H-NMR (300 MHz, CDCl3) δ 8.06 (d, 2H, J=8.4 Hz), 7.90 (d, 2H, J=8.4 Hz), 4.83 (d, 1H, J=3.9 Hz), 3.76-3.83 (m, 2H), 3.19 (dt, 1H, J=12.7, 3.0 Hz), 2.66 (s, 3H), 2.19-2.24 (m, 1H), 1.60-1.82 (m, 4H). HRMS (ESI) Calcd. for C14H17NO5S: 312.0905 (M+H)+; Found: 312.0915.
  • The title compound was prepared in an analogous fashion as Ex-1 using 1-(4-acetylbenzenesulfonyl)piperidine-2-carboxylic acid (Ex-28A), 66% yield, yellow foam. 1H-NMR (300 MHz, CDCl3)
    Figure US20070093453A1-20070426-P00901
    8.08 (d, 1H, J=15.6 Hz), 8.05 (d, 2H, J=8.7 Hz), 8.00 (s, 1H), 7.91 (d, 2H, J=8.7 Hz), 7.86 (s, 1H), 7.51 (d, 1H, J=15.7 Hz), 7.41 (d, 1H, J=3.6 Hz), 7.31 (d, 1H, J=5.7 Hz), 7.09 (dd, 1H, J=5.7, 3.6 Hz), 6.54 (s, 1H), 4.81 (d, 1H, J=4.2 Hz), 3.99 (s, 3H), 3.98 (s, 3H), 3.80-3.83 (m, 2H), 3.23 (dt, 1H, J=12.0, 2.1 Hz), 2.17-2.21 (m, 1H), 1.65-1.73 (m, 4H). HRMS (ESI) Calcd. for C27H27NO7S2: 542.1307 (M+H)+; Found: 542.1298.
    • Example 29
  • Figure US20070093453A1-20070426-C00045
    • 4-{3E-[2,4-Dimethoxy-5-(1-methyl-1H-indol-2-yl)phenyl]acryloyl}-N-methyl-benzenesulfonamide
  • Ex-29A: To a solution of 4-acetylbenzenesulfonyl chloride (1.1 g, 5.0 mmol) in 25 ml of THF, methylamine (0.44 ml of 40% solution in H2O, 5 mmol) was added dropwise, and the mixture was stirred for 30 min. The reaction mixture was poured into water, and the precipitate was filtered. Recrystallization from EtOAc/hexanes gave 0.67 g (62.6%) of 4-acetyl-N-methyl-benzenesulfonamide as a white solid. 1H-NMR (300 MHz, CDCl3) δ 8.09 (d, J=8 Hz, 2H), 7.96 (d, J=8 Hz, 2H), 4.48 (br, 1H), 2.70 (d, J=4 Hz, 1H), 2.66 (s, 3H).
  • The title compound was prepared using in an analogous way as Ex-1 using 4-acetyl-N-methyl-benzenesulfonamide (Ex-29A) and 2,4-dimethoxy-5-(1-methyl-1H-indol-2-yl)benzaldehyde (Ex-15A), 57% yield, yellow solid, mp 129-131° C. 1H-NMR (300 MHz, CDCl3) δ 8.17 (d, J=16 Hz, 1H), 8.10 (d, J=9 Hz, 2H), 7.95 (d, J=9 Hz, 2H), 7.68 (s, 1H), 7.64 (d, J=7 Hz, 1H), 7.47 (d, J=16 Hz, 1H), 7.36 (d, J=8 Hz, 1H), 7.22-7.26 (m, 1H), 7.14-7.16 (m, 1H), 6.59 (s, 1H), 6.51 (s, 1H), 4.42 (br s, 1H) 4.03 (s, 3H), 3.90 (s, 3H), 3.58 (s, 3H), 2.69 (d, J=6 Hz, 3H). HRMS (ESI) Calcd. for C27H26N2O5S: 491.1641 (M+H)+; Found: 491.1646.
    • Example 30
  • Figure US20070093453A1-20070426-C00046
    • 4-{3E-[2,4-Dimethoxy-5-(1-methyl-1H-indol-2-yl)phenyl]acryloyl}-N-methoxybenzenesulfonamide
  • Ex-30A: To a solution of 4-acetylbenzenesulfonyl chloride (2.18 g, 10.0 mmol) in 100 ml of THF at 0° C., Et3N (2.5 g, 25 mmol) was added followed by O-methyl hydroxyamine hydrochloride (0.84 g, 10 mmol). The mixture was stirred for 1 hr at room temperature and then poured into water, and the precipitate was filtered and dried. Recrystallization from THF/hexanes gave 1.5 g (65.8%) of 4-acetyl-N-methoxybenzenesulfonamide as a white solid. 1H-NMR (300 MHz, CDCl3) δ 8.10 (d, J=8 Hz, 2H), 8.03 (d, J=8 Hz, 2H), 7.23 (brs, 1H), 3.82 (s, 3H), 2.66 (s, 3H).
  • The title compound was prepared in an analogous way as Ex-1 using 4-acetyl-N-methoxy-benzenesulfonamide (Ex-30A) and 2,4-dimethoxy-5-(1-methyl-1H-indol-2-yl)benzaldehyde (Ex-15A), 94% yield, yellow solid, mp 214-216° C. 1H-NMR (300 MHz, CDCl3) δ 8.17 (d, J=16 Hz, 1H), 8.11 (d, J=8 Hz, 2H), 8.03 (d, J=8 Hz, 2H), 7.68 (s, 1H), 7.64 (d, J=7 Hz, 1H), 7.48 (d, J=16 Hz, 1H), 7.36 (d, J=8 Hz, 1H), 7.25-7.26 (m, 1H), 7.11-7.16 (m, 2H), 6.59 (s, 1H), 6.50 (s, 1H), 4.03 (s, 3H) 3.90 (s, 3H), 3.84 (s, 3H), 3.58 (s, 3H). MS m/z: 506 ([M]+, 30%), 476 (100%).
    • Example 31
  • Figure US20070093453A1-20070426-C00047
    • 4-{3E-[2,4-Dimethoxy-5-(1-methyl-1H-indol-2-yl)phenyl]acryloyl}-N,N-dimethylbenzenesulfonamide
  • Ex-31A: 4-Acetyl-N,N-dimethylbenzenesulfonamide was prepared in an analogous manner as Ex-29A using dimethylamine, 93% yield, white solid. 1H-NMR (300 MHz, CDCl3) δ 8.10 (d, J=8 Hz, 2H), 7.87 (d, J=8 Hz, 2H), 2.74 (s, 6H), 2.66 (s, 3H).
  • The title compound was prepared in an analogous manner as Ex-1 using 4-acetyl-N,N-dimethyl-benzenesulfonamide (Ex-31A) and 2,4-dimethoxy-5-(1-methyl-1H-indol-2-yl)benzaldehyde (Ex-15A), 64% yield, yellow solid, mp 120-122° C. 1H-NMR (300 MHz, CDCl3) δ 8.18 (d, J=16 Hz, 1H), 8.12 (d, J=8 Hz, 2H), 7.88 (d, J=8 Hz, 2H), 7.69 (s, 1H), 7.64 (d, J=8 Hz, 1H), 7.48 (d, J=16 Hz, 1H), 7.36 (d, J=8 Hz, 1H), 7.22-7.27 (m, 1H), 7.11-7.16 (m, 1H), 6.59 (s, 1H), 6.50 (s, 1H), 4.11 (s, 3H), 3.90 (s, 3H), 3.59 (s, 3H), 2.74 (s, 6H). HRMS (ESI) Calcd. for C28H28N2O5S: 505.1797 (M+H)+; Found: 505.1797.
    • Example 32
  • Figure US20070093453A1-20070426-C00048
    • 4-{3E-[5-(1H-Indol-2-yl)-2,4-dimethoxyphenyl]acryloyl}-N,N-dimethylbenzenesulfonamide
  • Ex-32A: 2-(5-Formyl-2,4-dimethoxyphenyl)indole-1-carboxylic acid tert-butyl ester was prepared from 5-bromo-2,4-dimethoxybenzaldehyde and N-Boc-indole-2-boronic acid in a similar manner as Ex-1A, 79% yield, yellow oil. 1H-NMR (300 MHz, CDCl3) δ 10.36 (s, 1H), 8.15 (d, J=8 Hz, 1H), 7.88 (s, 1H), 7.45 (d, J=8 Hz, 3H), 7.27-7.35 (m, 1H), 7.19-7.27 (m, 1H), 6.52 (s, 1H), 6.47 (s, 1H), 4.00 (s, 3H), 3.86 (s, 3H), 1.42 (s, 9H).
  • Ex-32B: 2-(5-Formyl-2,4-dimethoxyphenyl)indole-1-carboxylic acid tert-butyl ester (Ex-32A, 2.0 g, 5.2 mmol) was dissolved in 100 ml of THF, and Bu4NF (6.86 g, 26 mmol) was added. The reaction mixture was stirred at room temperature overnight. No significant reaction occurred under these conditions by HPLC. Then, additional Bu4NF (6.86 g, 26 mmol) was added to the mixture, and the mixture was stirred at reflux for 4 days. The reaction reached about 50% completion (HPLC). The reaction mixture was poured into CH2Cl2, and washed with water and brine. The organic phase was dried over MgSO4, and concentrated. The residue was purified by column chromatography (EtOAc/hexanes, 2:1) to give 0.45 g (30%) of 5-(1H-indol-2-yl)-2,4-dimethoxybenzaldehyde. 1H-NMR (300 MHz, CDCl3) δ 10.37 (s, 1H), 9.25 (br, 1H), 8.28 (s, 1H), 7.63(d, J=8 Hz, 1H), 7.39 (d, J=8 Hz, 1H), 7.08-7.20 (m, 2H), 6.92(d, J=2 Hz, 1H), 6.56 (s, 1H) 4.11(s, 3H), 4.00 (s, 3H). HMRS (EI) calcd. for C17H15NO3: 281.1052 (M+); Found: 281.1049.
  • The title compound was prepared in an analogous manner as Ex-1 using 5-(1H-indol-2-yl)-2,4-dimethoxybenzaldehyde (Ex-32B) and 4-acetyl-N,N-dimethylbenzenesulfonamide (Ex-31A), 12% yield after silica gel column chromatography (hexane/EtOAc, 2:1), yellow solid, mp 158-162° C. 1H-NMR (300 MHz, CDCl3) δ 9.39 (br, 1H), 8.15 (m, 2H), 8.08 (d, J=9 Hz, 2H), 7.91 (d, J=9 Hz, 2H), 7.64 (d, J=7 Hz, 1H), 7.57 (d, J=15 Hz, 1H), 7.42 (d, J=8 Hz, 1H), 7.09-7.21 (m, 2H), 6.87 (d, J=2 Hz, 1H), 6.60 (s, 1H), 4.10 (s, 3H), 4.01 (s, 3H), 2.76 (s, 6H). HRMS (ESI) Calcd. for C27H26N2O5S: 491.1641 (M+H)+; Found: 491.1638.
    • Example 33
  • Figure US20070093453A1-20070426-C00049
    • 4-{3E-[2,4-Dimethoxy-5-(1-methyl-1H-indol-2-yl)phenyl]acryloyl}-N-(tert-butyldimethylsiloxy)benzenesulfonamide
  • Ex-33A: To a solution of O-(tert-butyldimethylsilyl)hydroxylamine (0.74 g, 5 mmol) and triethylamine (1.01 g, 10 mmol) in 25 ml THF, 4-acetylbenzenesulfonyl chloride (1.1 g, 5 mmol) was added at 0° C. The mixture was stirred overnight and then poured into H2O. The precipitate was filtered, dried, and recrystallized from EtOAc/Hexene to give 1.3 g (76.8%) of 4-acetyl-N-(tert-butyldimethylsiloxy)benzenesulfonamide as a white solid. 1H-NMR (300 MHz, CDCl3) δ 8.11 (d, J=9 Hz, 2H), 8.01 (d, J=9 Hz, 2H), 6.59 (b, 1H), 2.67 (s, 3H), 0.89 (s, 9H), 0.20 (s, 6H).
  • The title compound was prepared in an analogous manner as Ex-1 using 4-acetyl-N-(tert-butyldimethylsiloxy)benzenesulfonamide (Ex-33A) and 2,4-dimethoxy-5-(1-methyl-1H-indol-2-yl)benzaldehyde (Ex-15A), 19% yield after preparative TLC (MeOH/CH2Cl2, 1:10), yellow solid, mp 129-131° C. 1H-NMR (300 MHz, CDCl3) δ 8.18 (d, J=15 Hz, 1H), 8.12 (d, J=8 Hz, 2H), 8.02 (d, J=8 Hz, 2H), 7.69 (s, 1H), 7.64 (d, J=8 Hz, 1H), 7.47 (d, J=15 Hz, 1H), 7.36 (d, J=7 Hz, 1H), 7.22-7.26 (m, 1H), 7.11-7.16 (m, 1H), 6.58 (s, 1H), 6.50-6.51 (m, 2H), 4.03 (s, 3H), 3.90 (s, 3H), 3.59 (s, 3H), 0.90 (s, 9H), 0.20 (s, 6H). HRMS (ESI) Calcd. for C32H39N2O6SSi: 607.2298 (M+H)+; Found: 607.2306.
    • Example 34
  • Figure US20070093453A1-20070426-C00050
    • 4-{3E-[2,4-Dimethoxy-5-(1-methyl-1H-indol-2-yl)phenyl]acryloyl}-N-hydroxybenzenesulfonamide
  • The title compound was obtained as a side product from Ex-33 (37% yield after preparative TLC) as a yellow solid, mp>260° C. 1H-NMR (300 MHz, CD3OD) δ 8.01-8.14 (m, 3H), 7.65-7.78 (m, 4H), 7.52 (d, J=7 Hz, 1H), 7.33 (d, J=8 Hz, 1H), 7.11-7.17 (m, 1H), 7.00-7.05 (m, 1H), 6.80(s, 1H), 6.40 (s, 1H), 4.05 (s, 3H), 3.91 (s, 3H), 3.55 (s, 3H). HRMS Calcd. for C26H24N2O6S: 492.1355 (M+); Found: 493.1423.
    • Example 35
  • Figure US20070093453A1-20070426-C00051
    • 4-{3E-[5-(1H-Indol-2-yl)-2,4-dimethoxyphenyl]acryloyl}-N-isobutyrylbenzenesulfonamide
  • Ex-35A: To a solution of 4-acetylbenzenesulfonyl chloride in acetone (30 mL) was added ammonia (28% in water, 8.2 mL, 57.3 mmol) dropwise at 0° C. The reaction mixture was allowed to stir at 0° C. for 30 min. The precipitate was filtered and the residue was washed with water and dried in vacuo to afford 4-acetylbenzenesulfonamide as a white solid (3.54 g, 93%), mp 176-177° C. 1H NMR (DMSO-d6) δ 8.10 (d, J=9 Hz, 2H), 8.03 (d, J=9 Hz, 2H), 4.86 (brs, 2H), 2.65 (s, 3H). HRMS Calcd. for C8H9NO3S: 199.0303 (M+); Found: 199.0300.
  • Ex-35B: To a solution of 2,4-dimethoxybenzaldehyde (20.0 g, 120.4 mmol) in methanol (550 mL) was added iodine monochloride (23.5 g in 60 mL methanol) dropwise over 20 min at ambient temperature. The solution was allowed to stir at this temperature. HPLC showed about 94% conversion after 3 hours. The reaction mixture was then poured into a solution of HCl (0.5M, 600 mL). The precipitate was collected by filtration, washed with water, dried in vacuo (40° C.) to give crude product of 33.02 g. The crude product was further purified by recrystallization from THF/heptane (1:1) to give 5-iodo-2,4-dimethoxybenzaldehyde as an off-white solid (27.5 g, m.p 170-172° C.). The mother liquid was concentrated to dryness. The residual material was dissolved in EtOH (100 mL) and acetone (20 mL) followed by addition of water (20 mL) to give additional product (3.12 g, m.p. 169-171° C.). Overall isolated yield of this reaction was 87.5%. 1H NMR (CDCl3) δ 10.20 (s, 1H), 8.22 (s, 1H), 6.39 (s, 1H), 3.97 (s, 3H), 3.95 (s, 3H). HRMS Calcd. for C9H9IO3: 291.9596 (M+); Found: 291.9602. Anal. Calcd. for C8H9NO3S: C, 37.01; H, 3.11; I, 43.33; Found: C, 37.12; H, 3.15; I, 43.33.
  • Ex-35C: To a solution of 5-iodo-2,4-dimethoxybenzaldehyde (Ex-35B, 11.7 g, 40 mmol) in 250 ml of THF, PdCl2(PPh3)2 (0.56 g, 0.8 mmol), CuI (0.3 g, 1.6 mmol), Et3N (6.06 g, 60 mmol), and 2-[(trimethylsilyl)ethynyl]aniline (7.92 g, 42 mmol) were added. The mixture was stirred to a homogeneous solution, and then TBAF (10.4 g, 40 mmol) was added. The reaction mixture was aged at room temperature for 4 h and then filtered. The filtrate was concentrated to about 50 ml, and the precipitate was filtered to give first portion of 5-(2-aminophenylethynyl)-2,4-dimethoxybenzaldehyde (8.5 g), as light yellow crystals. The filtrate was concentrated, and the residue was recrystallized from EtOAc/hexanes to give 1.85 g of additional product (total 10.35 g, 92%), mp 180-181° C. 1H-NMR (300 MHz, CDCl3) δ 10.30 (s, 1H), 7.99 (s, 1H), 7.36 (d, J=8 Hz, 1H), 7.11-7.17 (m, 1H), 6.69-6.75 (m, 2H), 6.46 (s, 1H), 4.41 (brs, 2H), 4.02 (s, 3H), 4.00 (s, 3H). HRMS Calcd. for C17H15NO3: 281.1052 (M+); Found: 281.1056. Anal. Calcd. for C17H15NO3: C, 72.58; H, 5.37; N, 4.98; Found: C, 72.74; H, 5.38; N, 4.93.
  • Ex-35D: 4-{3E-[5-(2-Amino-phenylethynyl)-2,4-dimethoxyphenyl]acryloyl}benzenesulfonamide was prepared in a similar manner as Ex-1 using 4-acetylbenzenesulfonamide (Ex-35A) and 5-(2-amino-phenylethynyl)-2,4-dimethoxybenzaldehyde (Ex-35C), 82.6% yield, yellow solid, mp 167-169° C. 1H-NMR (300 MHz, DMSO-d6) δ 8.27 (d, J=8 Hz, 2H), 8.20(s, 1H), 8.01 (d, J=16 Hz, 1H), 7.94 (d, J=8 Hz, 2H), 7.84 (d, J=16 Hz, 1H), 7.53 (s, 2H), 7.15-7.17 (m, 1H), 7.02-7.08 (m, 1H), 6.77 (s, 1H), 6.72 (d, J=8 Hz, 1H), 6.49-6.54 (m, 1H), 5.46 (br, 1H) 3.97 (s, 3H), 3.96 (s, 3H). MS m/z: 462 ([M+H]+, 100%).
  • Ex-35E: 4-{3E-[5-(2-Aminophenylethynyl)-2,4-dimethoxyphenyl]acryloyl}benzenesulfonamide (Ex-35D, 0.91 g, 1.97 mmol) was dissolved in acetonitrile (100 ml), heated to reflux, and then PdCl2 (0.035 g, 0.197 mmol) was added. The reaction mixture was kept at reflux for 10 min and cooled to room temperature. Upon cooling, the mixture was filtered to remove any solid material and the filtrate was treated with 3-mercaptopropyl-functionalized silica gel (1.0 g) under stirring for 0.5 h. The mixture was then filtered and concentrated to give crude product, which was recrystallized from EtOAc/hexanes to yield 0.75 g (83%) of 4-{3E-[5-(1H-indol-2-yl)-2,4-dimethoxyphenyl]acryloyl}benzenesulfonamide as a yellow solid, mp 185-187° C. 1H-NMR (DMSO-d6) δ 11.15 (brs, 1H), 8.33(s, 1H), 8.24 (d, J=8 Hz, 2H), 8.07 (d, J=15 Hz, 1H), 7.98 (d, J=8 Hz, 2H), 7.80 (d, J=15 Hz, 1H), 7.41-7.55 (m, 4H), 7.03-7.08 (m, 1H), 6.93-6.99 (m, 2H), 6.83 (s, 1H), 4.04 (s, 3H), 3.99(s, 3H), MS m/z: 463 [M+H]+.
  • To a suspension of 4-{3E-[5-(1H-indol-2-yl)-2,4-dimethoxyphenyl]acryloyl}benzenesulfonamide (Ex-35E, 1.84 g, 4 mmol) in 100 ml of THF, isobutyric anhydride (1.26 g, 8 mmol), triethylamine (0.42 g, 4.2 mmol) and N-dimethylaminopyridine (0.049 g, 0.4 mmol) were added. The mixture was aged at room temperature overnight and then poured into water (100 ml) and extracted with CH2Cl2 (3×100 ml). The combined organic phases were washed with 0.5 N HCl, H2O and brine, and concentrated. Recrystallization from EtOAc/hexanes gave 1.8 g (87%) of the title compound as a red solid, mp 243-245° C. (dec.). 1H-NMR (300 MHz, CD3COCD3) δ 10.54 (brs, 1H), 8.35(s, 1H), 8.27 (d, J=8 Hz, 2H), 8.18 (d, J=16 Hz, H), 8.15 (d, J=8 Hz, 2H), 7.90 (d, J=16 Hz, 1H), 7.52 (d, J=8 Hz, 1H), 7.38 (d, J=8 Hz, 1H), 6.91-7.07 (m, 4H), 4.10 (s, 3H), 4.05 (s, 3H), 2.58 (septet, J=6 Hz, 1H), 1.02 (d, J=6 Hz, 6H). HRMS (ESI) Calcd. for C29H28N2O6S: 533.1746 (M+H)+; Found: 533.1746.
    • Example 36
  • Figure US20070093453A1-20070426-C00052
    • 4-{3E-[5-(1H-Indol-2-yl)-2,4-dimethoxyphenyl]acryloyl}-N-isobutyrylbenzenesulfonamide sodium salt
  • To a solution of 4-{3E-[5-(1H-indol-2-yl)-2,4-dimethoxyphenyl]acryloyl}-N-isobutyrylbenzenesulfonamide (Ex-35, 2.44 g, 4.6 mmol) in 100 ml of THF, NaOMe (0.24 g, 4.4 mmol) was added. The mixture was stirred at room temperature overnight. The resulting thick yellow mixture was diluted with 150 ml of EtOAc/hexanes (1:1) and filtered. The yellow solid was then dried in vacuo to afford 2.35 g (93%) of the title compound as a red solid, mp 249-251° C. (dec.). 1H-NMR (300 MHz, DMSO-d6) δ 11.16 (brs, 1H), 8.32 (s, 1H), 8.05 (d, J=8 Hz, 2H), 8.04 (d, J=15 Hz, 1H), 7.84 (d, J=15 Hz, 1H), 7.83 (d, J=8 Hz, 2H), 7.49 (d, J=8 Hz, 1H), 7.42 (d, J=8 Hz, 1H), 7.02-7.07(m, 1H), 6.93-6.97 (m, 2H), 6.83(s, 1H), 4.03 (s, 3H), 3.99 (s, 3H), 2.10 (septet, J=8 Hz, 1H), 0.84 (d, J=8 Hz, 6H). HRMS (ESI) Calcd. for C29H27N2O6SNa: 531.1595 (M−Na)+; Found: 531.1611.
    • Example 37
  • Figure US20070093453A1-20070426-C00053
    • N-Butyryl-4-{3E-[2,4-dimethoxy-5-(1-methyl-1H-indol-2-yl)phenyl]acryloyl}benzenesulfonamide
  • Ex-37A: To a solution of 4-acetylbenzenesulfonamide (Ex-35A, 0.20 g, 1 mmol) and 2,4-dimethoxy-5-(1-methyl-1H-indol-2-yl)benzaldehyde (Ex-15A, 0.30 g, 1 mmol) in DMF (25 ml) was added lithium methoxide (4 ml, 1.0 M in methanol). The mixture was stirred at room temperature overnight. It was poured into water (50 ml) and acidified to pH=1 with 3 N HCl. The yellow precipitate was filtered, washed with water, and dried. Crystallization from EtOAc/hexanes gave 4-{3-[2,4-dimethoxy-5-(1-methyl-1H-indol-2-yl)phenyl]acryloyl}benzenesulfonamide (0.43 g, 90%) as a yellow solid, mp 148-150° C. 1H-NMR (300 MHz, CDCl3) δ 8.17 (d, J=16 Hz, 1H), 8.09 (d, J=9 Hz, 2H), 8.01 (d, J=9 Hz, 2H), 7.68 (s, 1H), 7.64 (d, J=8 Hz, 1H), 7.47 (d, J=16 Hz, 1H), 7.35 (d, J=8 Hz, 1H), 7.22-7.26 (m, 1H), 7.11-7.16 (m, 1H), 6.58 (s, 1H), 6.50 (s, 1H), 4.92 (brs, 2H), 4.02 (s, 3H), 3.90 (s, 3H), 3.58 (s, 3H). MS m/z=477 ([M+H]+, 100%).
  • To a suspension of 4-{3-[2,4-dimethoxy-5-(1-methyl-1H-indol-2-yl)phenyl]acryloyl}benzenesulfonamide (Ex-37A, 1.5 g, 3.15 mmol) in 100 ml of THF, butyric anhydride (1.0 g, 6.3 mmol), triethylamine (0.33 g, 3.3 mmol) and 4-dimethylaminopyridine (0.038 g, 0.32 mmol) were added. The mixture was aged at room temperature overnight. The mixture was poured into water (100 ml) and extracted with 3×100 ml of CH2Cl2. The combined organic phase was washed with 0.5 N HCl, H2O, and brine, and concentrated to give crude product. Crystallization from EtOAc/hexanes gave 0.95 g (55%) of the title compound as a yellow solid, mp 144-146° C. 1H-NMR (300 MHz, CD3COCD3) δ 8.27 (d, J=9 Hz, 2H), 8.21 (d, J=16 Hz, 1H), 8.10 (d, J=9 Hz, 2H), 7.89 (s, 1H), 7.87 (d, J=16 Hz, 1H), 7.54 (d, J=8 Hz, 1H), 7.37 (d, J=8 Hz, 1H), 7.13-7.18 (m, 1H), 7.01-7.06 (m, 1H), 6.91 (s, 1H), 6.41 (s, 1H), 4.08 (s, 3H), 3.94 (s, 3H), 3.57 (s, 3H), 2.27 (t, J=7 Hz, 2H), 1.45-1.53 (m, 2H), 0.79 (t, J=8 Hz, 3H). HRMS (ESI) Calcd. for C30H30N2O6S: 547.1903 (M+H)+; Found: 547.1905.
    • Example 38
  • Figure US20070093453A1-20070426-C00054
    • 4-[3E-(2,4-Dimethoxy-5-pyrrolidin-1-yl-phenyl)acryloyl]-N-(5-methyl-isozaxol-3-yl)benzenesulfonamide
  • Ex-38A: Method A: A mixture of 2,4-dimethoxyaniline (1.0 g, 6.53 mmol), 1,4-dibromobutane (1.41 g, 6.53 mmol) and potassium carbonate (3.61 g, 26.1 mmol) in N,N-dimethylformamide (70 mL) was heated at 150° C. overnight. The reaction mixture was concentrated under reduced pressure. The residue was taken up in a mixture of water and ethyl acetate. After the mixture was partitioned, the aqueous solution was extracted with ethyl acetate. The combined solution of ethyl acetate was washed with saturated sodium bicarbonate, brine, dried over sodium sulfate and concentrated. The residue was purified by flash chromatography. Elution with ethyl acetate and hexane (1:2, v/v) gave 1′-pyrrolidin-1-yl-2,4-dimethoxybenzene as a brown oil (0.85 g, 63%). 1H-NMR (300 MHz, CDCl3) δ 6.76 (d, J=8.9 Hz, 1H), 6.49 (d, J=2.7 Hz, 1H), 6.41 (dd, J=2.7, 8.9 Hz, 1H), 3.84 (s, 3H), 3.78 (s, 3H), 3.18-3.14 (m, 4H), 1.95-1.90 (m, 4H). Method B: Sodium tert-butoxide was charged to a mixture of 1-bromo-2,4-dimethoxybenzene (3.03 g, 14.0 mmol), pyrrolidine (1.75 mL, 20.9 mmol), tris(dibenzylideneacetone)dipalladium (Pd2(dba)3) (0.26 g, 0.28 mmol) and rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP) (0.35 g, 0.56 mmol) in degassed toluene (60 mL). The reaction mixture was heated at 100° C. under N2 for 17 h. After cooling to room temperature, the reaction mixture was diluted with water (60 mL) and partitioned. The aqueous solution was further extracted with ethyl acetate. The combined ethyl acetate and toluene was washed with saturated sodium bicarbonate, brine, dried over sodium sulfate and concentrated. The crude product was purified by flash chromatography with ethyl acetate and hexane (1:2, v/v) to give 1-pyrrolidin-1-yl-2,4-dimethoxybenzene as a brown oil (1.82 g, 63%).
  • Ex-38B: To a solution of 1-pyrrolidin-1-yl-2,4-dimethoxybenzene (Ex-38A, 1.82 g, 8.78 mmol) and α,α-dichloromethyl methyl ether (1.6 mL, 17.6 mmol) in dichloromethane (50 mL) was added titanium tetrachloride (1.0 M in dichloromethane, 26.3 mL, 26.3 mmol) dropwise at 0° C. The solution was allowed to stir for 16 h at ambient temperature and poured into ice/water. The aqueous solution was extracted with dichloromethane. The combined dichloromethane was washed with saturated sodium bicarbonate, brine, dried over sodium sulfate and concentrated to give a crude product (0.67 g). The aqueous solution was further treated with solid sodium hydroxide to pH 8. The suspension was mixed with ethyl acetate. The insoluble solid was removed by filtering through a pad of Celite. The filtrate was then partitioned. The aqueous solution was further extracted with ethyl acetate. The combined ethyl acetate was washed with saturated sodium bicarbonate, brine, dried over sodium sulfate and concentrated. The combined crude product (1.71 g) was purified by flash chromatography. Elution with ethyl acetate and hexane (1:1, v/v) gave 2,4-dimethoxy-5-pyrrolidin-1-yl-benzaldehyde as a brown oil (1.03 g, 50%): 1H-NMR (300 MHz, CDCl3) δ 10.25 (s, 1H), 7.26 (s, 3H), 6.44 (s, 1H), 3.93 (s, 3H), 3.89 (s, 3H), 3.20-3.16 (m, 4H), 1.93-1.89 (m, 4H). MS m/z: 235 (M+), 100%.
  • The title compound was prepared in a similar manner as Ex-1 using 4-acetyl-N-(5-methylisoxazol-3-yl)benzenesulfonamide (Ex-1B, 0.30 g, 1.07 mmol) and 2,4-dimethoxy-5-pyrrolidin-1-ylbenzaldehyde (Ex-38B, 0.25 g, 1.07 mmol) as a dark red solid, mp 164-165° C. 1H-NMR (300 MHz, CDCl3) δ 8.09-7.93 (m, 4H), 7.35 (d, J=15.3 Hz, 1H), 7.05 (s, 1H), 6.48 (s, 1H), 6.24 (s, 1H), 3.92 (s, 3H), 3.90 (s, 3H), 3.29-3.18 (m, 4H), 2.38 (s, 3H), 2.02-1.91 (s 4H). MS m/z: 498 (M+), 100%.
    • Example 39
  • Figure US20070093453A1-20070426-C00055
    • 4-{3E-[2-(3-Hydroxy-propoxy)-4-methoxy-5-thien-2-ylphenyl]acryloyl}-N-(5-methylisoxazol-3-yl)benzenesulfonamide
  • Ex-39A: A solution of 2-hydroxy-4-methoxy-5-thiophen-2-yl-benzaldehyde (Ex-13C, 500 mg, 2.13 mmol) in DMF (20 mL) was treated with potassium carbonate (589 mg, 4.26 mmol) followed by the addition of 3-bromo-propan-1-ol (356 mg, 2.56 mmol). The reaction mixture was heated to 80° C. for 2 h followed by another addition of potassium carbonate (294 mg, 2.13 mmol) and 3-bromo-propan-1-ol (296 mg, 2.13 mmol). The reaction mixture was stirred for an additional 45 minutes, quenched with water (15 mL), and extracted with ethyl acetate (2×25 ml). The organic phase was washed with brine, dried over sodium sulfate, and concentrated to a beige oil. The oil was purified by column chromatography (elution: 30, 50, and 80% ethyl acetate in hexane) to yield 240 mg (38%) of 2-(3-hydroxypropoxy)-4-methoxy-5-thiophen-2-ylbenzaldehyde as an off-white solid. 1H-NMR (300 MHz, CDCl3)
    Figure US20070093453A1-20070426-P00901
    10.21 (s, 1H), 8.02 (s, 1H), 7.41 (br d, 1H, J=3.9 Hz), 7.28 (d, 1H, J=5.10 Hz), 7.06 (dd, 1H, J=3.0, 5.7 Hz), 6.48 (s, 1H), 4.24 (t, 2H, J=7.0 Hz), 3.92 (s, 3H), 3.88 (br s, 2H), 2.11 (q, 2H, J=7.0 Hz).
  • The title compound was prepared in a analogous way as Ex-1 from 2-(3-hydroxypropoxy)-4-methoxy-5-thien-2-ylbenzaldehyde (Ex-39A), 78% yield, red solid, mp 178-182° C. 1H-NMR (300 MHz, DMSO-d6)
    Figure US20070093453A1-20070426-P00902
    11.63 (brs, 1H), 8.23 (m, 3H), 8.04 (d, 1H, J=16.0 Hz), 7.98 (d, 2H, J=9.0 Hz), 7.86 (d, 1H, J=16.0 Hz), 7.61 (d, 1H, J=4 Hz), 7.48 (d, 1H, J=5 Hz,), 7.09 (t, 1H), 6.81 (s, 1H), 6.14 (s, 1H), 4.62 (m, 1H), 4.62 (m, 1H), 4.24 (t, 2H), 3.96 (s, 3H), 3.59 (s, 2H), 2.27 (s, 3H), 1.95 (quintet, 2H). HRMS (ESI) Calcd. for C27H26N2O7S2: 555.1260 (M+H)+; Found: 555.1261.
    • Example 40
  • Figure US20070093453A1-20070426-C00056
    • N-Ethoxycarbonyl-4-{3E-[5-(1H-indol-2-yl)-2,4-dimethoxyphenyl]acryloyl}benzenesulfonamide potassium salt
  • To a solution of 4-{3E-[5-(1H-indol-2-yl)-2,4-dimethoxyphenyl]acryloyl}benzenesulfonamide (Ex-35E, 3.0 g, 6.5 mmol) in 250 mL of acetone were added ethyl chloroformate (0.93 g, 8.6 mmol) and K2CO3 (2.3 g, 16.7 mmol). The mixture was heated to reflux overnight. The yellow precipitate formed was filtered and washed with cold water to give 2.6 g (70%) of the title compound as a yellow solid, mp 220-222° C. 1H-NMR (300 MHz, DMSO-d6) δ 11.23 (br, 1H), 8.35 (s, 1H), 8.01-8.09 (m, 3H), 7.83-7.89 (m, 3H), 7.49 (d, J=7 Hz, 1H), 7.42 (d, J=8 Hz, 1H), 7.02-7.07(m, 1H), 6.92-6.97 (m, 2H), 6.83 (s, 1H), 4.03 (s, 3H), 3.99 (s, 3H), 3.67 (q, J=8 Hz, 2H), 0.98(t, J=8 Hz, 3H). HRMS Calcd for C28H25KN2O7S: 533.1382 ([M−K]+); Found: 533.1378. Anal. Calcd for C28H25KN2O7S: C, 58.72; H, 4.40; N, 4.89; S, 5.60; Found: C, 58.62; H, 4.34; N, 4.83; S, 5.62.
    • Example 41
  • Figure US20070093453A1-20070426-C00057
    • N-Ethoxycarbonyl-4-{3E-[5-(1H-indol-2-yl)-2,4-dimethoxyphenyl]acryloyl}benzenesulfonamide
  • To a solution of 4-{3E-[5-(1H-indol-2-yl)-2,4-dimethoxyphenyl]acryloyl}benzenesulfonamide (Ex-35E, 3.0 g, 6.5 mmol) in 250 mL of acetone were added ethyl chloroformate (0.93 g, 8.6 mmol) and K2CO3 (2.3 g, 16.7 mmol). The mixture was heated to reflux overnight. The yellow precipitate formed was filtered. The filtrate was acidified to pH=1 with 3N HCl and extracted with CH2Cl2. The organic phase was washed with water, dried over MgSO4, and concentrated. The residue was further purified by passing a short silica gel column eluted with EtOAc/hexenes (1:1) to give 30 mg of the title compound as a yellow solid, mp 165-175° C. 1H-NMR (300 MHz, CDCl3) δ 9.39 (br, 1H), 8.04-8.20 (m, 6H), 7.64 (d, J=7 Hz, 1H), 7.57 (d, J=15 Hz, 1H), 7.42 (d, J=8 Hz, 1H), 7.12-7.07(m, 2H), 6.87 (s, 1H), 6.59 (s, 1H), 4.16 (q, J=7 Hz, 2H), 4.10 (s, 3H), 4.01 (s, 3H), 1.24 (t, J=7 Hz, 3H).
    • Example 42
  • Figure US20070093453A1-20070426-C00058
    • N-Acetyl-4-{3E-[5-(1H-indol-2-yl)-2,4-dimethoxyphenyl]acryloyl}benzenesulfonamide
  • To a solution of 4-{3E-[5-(1H-indol-2-yl)-2,4-dimethoxyphenyl]acryloyl}benzenesulfonamide (Ex-35E, 0.462 g, 1 mmol), DMAP (0.012 g, 0.1 mmol), and Et3N (0.1 g, 1.05 mmol) in 50 ml of THF, was added Ac2O (0.204 g, 2 mmol). The reaction mixture was stirred at room temperature overnight. The yellow solid precipitated was filtered and redissolved in 50% ethanol in water (50 mL). The clear solution was then adjusted to pH 1, and the solid formed was filtered and washed with water to give 0.31 g (62%) the title compound as a red solid, mp 218-220° C. 1H-NMR (300 MHz, DMSO-d6) δ 12.26 (br, 1H), 11.15 (s, 1H), 8.32 (s, 1H), 8.25 (d, J=8 Hz, 2H), 8.04-8.09 (m, 3H), 7.83 (d, J=15 Hz, 1H), 7.49 (d, J=7 Hz, 1H), 7.42 (d, J=8 Hz, 1H), 7.02-7.07 (m, 1H), 6.93-6.97(m, 2H), 6.82 (s, 1H), 4.03 (s, 3H), 3.99 (s, 3H), 1.94 (s, 3H). HRMS (EI) Calcd for C27H24N2O6S: 504.1335 ([M]+); Found: 504.1365.
    • Example 43
  • Figure US20070093453A1-20070426-C00059
    • N-Acetyl-4-{3E-[5-(1H-indol-2-yl)-2,4-dimethoxyphenyl]acryloyl}benzenesulfonamide sodium salt
  • To a solution of N-acetyl-4-{3E-[5-(1H-indol-2-yl)-2,4-dimethoxyphenyl]acryloyl}benzenesulfonamide (Ex-42, 0.17 g, 0.34 mmol) in THF (30 mL) was added NaOMe (0.0174 g, 0.32 mmol). The solution was stirred overnight. The reaction mixture was concentrated to about 5 mL and filtered to give 0.17 g (96%) of the title compound as a red solid, mp 240-250° C. 1H-NMR (300 MHz, DMSO-d6) δ 11.17 (s, 1H), 8.30 (s, 1H), 8.00-8.06 (m, 3H), 7.80-7.86 (m, 3H), 7.49 (d, J=7 Hz, 1H), 7.42 (d, J=7 Hz, 1H), 7.02-7.04 (m, 1H), 6.93-6.96(m, 2H), 6.81 (s, 1H), 4.02 (s, 3H), 3.97 (s, 3H), 1.63 (s, 3H). Anal. Calcd for C27H23N2NaO6S. 5/4H2O: C, 59.06; H, 4.68; N, 5.10; S, 5.84; Found: C, 59.17; H, 4.86; N, 5.04; S, 5.54.
    • Example 44
  • Figure US20070093453A1-20070426-C00060
    • 4-{3E-[2,4-Dimethoxy-5-(1-methyl-1H-pyrol-2-yl)phenyl]acryloyl}-N-(5-methyl-isoxazol-3-yl)benzenesulfonamide
  • Ex-44A: A solution of 5-bromo-2,4-dimethoxybenzaldehyde (1.90 g, 7.77 mmol) and trans-dichlorobis(triphenylphosphine)palladium(II) in dioxane (150 mL) was treated with 1-methyl-2-(tributylstannyl)-1H-pyrrole and then refluxed for 68 h. The reaction mixture was quenched with 10% potassium fluoride/ether (300 mL/100 mL) and filtered through Celite. The organic phase was extracted with saturated ammonium chloride solution (4×25 mL), dried over magnesium sulfate, and concentrated to a brown solid. The solid was purified by column chromatography (30% ethyl acetate/hexane) to yield 0.87 g (46%) of 2,4-dimethoxy-5-(1-methyl-1H-pyrol-2-yl)benzaldehyde as a white solid. 1H-NMR (300 MHz, CDCl3) δ 10.34 (s, 1H), 7.78 (s, 1H), 6.72 (m, 1H), 6.51 (s, 1H), 6.20 (m, 1H), 6.13 (m,1H), 4.01 (s, 3H), 3.92 (s, 3H), 3.46 (s, 3H).
  • The title compound was prepared in a similar manner as Ex-1 using 2,4-dimethoxy-5-(1-methyl-1H-pyrol-2-yl)benzaldehyde (Ex-44A), yellow solid, mp 113-115° C. 1H-NMR (300 MHz, DMSO-d6) δ 8.13 (d, 1H, J=16.0 Hz), 8.05 (d, 2H, J=9.0 Hz), 7.95 (d, 2H, J=9.0 Hz), 7.57 (s, 1H), 7.41 (d, 1H, J=16.0 Hz,), 7.26 (s, 1H), 6.73 (t, 1H, J=3 Hz), 6.52 (s, 1H), 6.22 (m, 2H), 6.13 (m, 1H), 3.98 (s, 3H), 3.88 (s, 3H), 3.47 (s, 3H), 2.38 (s, 3H), HRMS (ESI) Calcd. for C26H25N3O6S: 507.1464 (M+H)+; Found: 507.1477.
    • Example 45
  • Figure US20070093453A1-20070426-C00061
    • 4-{3E-[5-(1H-Indol-2-yl)-2,4-dimethoxyphenyl]acryloyl}-N-propionyl-benzenesulfonamide
  • To a solution of 4-{3E-[5-(1H-indol-2-yl)-2,4-dimethoxyphenyl]acryloyl}benzenesulfonamide (Ex-35E, 0.462 g, 1 mmol), DMAP (0.012 g, 0.1 mmol) and Et3N (0.1 g, 1.05 mmol) in THF (50 mL) was added propionic anhydride (0.26 g, 2 mmol). The reaction mixture was stirred at room temperature overnight. The clear solution was poured into 100 ml of H2O and extracted with CH2Cl2. The combined organic phase was washed with water, dried over MgSO4, and concentrated to dryness. Recrystallization from EtOAc/hexenes gave 0.42 g (81%) of the title compound as a red solid, mp 223-225° C. 1H-NMR (300 MHz, Acetone-d6) δ 10.54 (br, 1H), 8.35 (s, 1H), 8.27 (d, J=9 Hz, 2H), 8.13-8.20 (m, 3H), 7.89 (d, J=15 Hz, 1H), 7.52 (d, J=7 Hz, 1H), 7.39 (d, J=8 Hz, 1H), 6.97-7.05(m, 3H), 6.90 (s, 1H), 4.09 (s, 3H), 4.04 (s, 3H), 2.35 (q, J=8 Hz, 2H), 0.97(t, J=8 Hz, 3H). HRMS (EI) Calcd for C28H26N2O6S: 518.1512 ([M]+); Found: 518.1516.
    • Example 46
  • Figure US20070093453A1-20070426-C00062
    • 4-{3E-[5-(1H-Indol-2-yl)-2,4-dimethoxyphenyl]acryloyl}-N-propionylbenzenesulfonamide sodium salt
  • To a solution of 4-{3E-[5-(1H-Indol-2-yl)-2,4-dimethoxyphenyl]acryloyl}-N-propionylbenzenesulfonamide (Ex-45, 0.39 g, 0.75 mmol) in THF (50 mL) was added NaOMe (0.039 g, 0.72 mmol). The solution was stirred overnight. The reaction mixture was concentrated to about 5 mL, and filtered to give 0.34 g (83%) of the title compound as a red solid, mp>250° C. 1H-NMR (300 MHz, DMSO6) δ 11.18 (s, 1H), 8.30 (s, 1H), 8.00-8.06 (m, 3H), 7.80-7.86 (m, 3H), 7.49 (d, J=7 Hz, 1H), 7.42 (d, J=8 Hz, 1H), 7.02-7.04 (m, 1H), 6.93-6.96(m, 2H), 6.81 (s, 1H), 4.02 (s, 3H), 3.97 (s, 3H), 1.90 (q, J=8 Hz, 2H), 0.82 (t, J=8 Hz, 3H). Anal. Calcd for C28H25N2NaO6S.¾H2O: C, 60.72; H, 4.78; N, 5.06; S, 5.79; Found: C, 60.63; H, 4.76; N, 5.03; S, 5.68.
    • Example 47
  • Figure US20070093453A1-20070426-C00063
    • N-Butyryl-4-{3E-[5-(1H-indol-2-yl)-2,4-dimethoxyphenyl]acryloyl}benzenesulfonamide
  • To a solution of 4-{3E-[5-(1H-indol-2-yl)-2,4-dimethoxyphenyl]acryloyl}benzenesulfonamide (Ex-35E, 0.92 g, 2 mmol), DMAP (0.024 g, 0.2 mmol) and Et3N (0.2 g, 2.1 mmol) in 100 ml of THF was added butyric anhydride (0.64 g, 4 mmol). The reaction mixture was stirred at room temperature overnight. The clear solution was then poured into 150 ml of H2O and extracted with CH2Cl2. The combined organic phase was washed with water, dried over MgSO4, and concentrated to dryness. Recrystallization from EtOAc/hexenes gave 0.80 g (75%) of the title compound as a red solid, mp 155-165° C. 1H-NMR (300 MHz, Acetone-d6) δ 10.55 (br, 1H), 8.35 (s, 1H), 8.27 (d, J=8 Hz, 2H), 8.13-8.20 (m, 3H), 7.89 (d, J=16 Hz, 1H), 7.52 (d, J=7 Hz, 1H), 7.39 (d, J=8 Hz, 1H), 7.02-7.07(m, 1H), 6.95-7.00 (m, 2H), 6.90 (s, 1H), 4.10 (s, 3H), 4.04 (s, 3H), 2.29 (t, J=8 Hz, 2H), 1.48-1.56 (m, 2H), 0.81(t, J=8 Hz, 3H).
    • Example 48
  • Figure US20070093453A1-20070426-C00064
    • N-Butyryl-4-[3E-(2,4-dimethoxy-5-pyrrolidin-1-ylphenyl)acryloyl]benzenesulfonamide
  • Ex-48A: To a solution of 4-acetylbenzenesulfonamide (Ex-35A, 0.13 g, 0.64 mmol) and 2,4-dimethoxy-5-pyrrolidin-1-yl-benzaldehyde (Ex-38B, 0.15 g, 0.64 mmol) in N,N-dimethylformamide (5 mL) was added lithium methoxide (1.0 M in methanol, 1.6 mL, 1.6 mmol). The solution was allowed to stir at ambient temperature for 13 h and then at 40° C. for 2 h. HPLC indicated no further change of starting materials. The reaction mixture was then diluted with water, acidified to pH 5. The resulting precipitate was collected by filtration, washed with water, dried in vacuo. The crude product was slurried in ethanol overnight. The solid was collected by filtration, washed with ethanol, dried in vacuo to give 4-[3E-(2,4-dimethoxy-5-pyrrolidin-1-ylphenyl)acryloyl]benzenesulfonamide (0.16 g, 59%) as a red solid, m.p. 220-222° C. 1H-NMR (300 MHz, DMSO-d6) δ 8.22 (d, J=8.7 Hz, 2H), 8.04 (d, J=16.1 Hz, 1H), 7.93 (d, J=8.7 Hz, 2H), 7.64 (d, J=16.1 Hz, 1H), 7.52 (s, 2H), 7.18 (s, 1H), 6.67 (s, 1H), 3.86 (s, 6H), 3.19-3.17 (m, 4H), 1.84-1.83 (m, 4H). HRMS Calcd for C21H24N2O5S: 416.1408 (M+); Found: 416.1408.
  • The title compound was synthesized by reacting 4-[3E-(2,4-dimethoxy-5-pyrrolidin-1-ylphenyl)acryloyl]benzenesulfonamide (Ex-48A, 137 mg, 0.33 mmol) with butyric anhydride (0.11 mL, 0.66 mmol) in the presence of triethylamine (0.048 mL, 0.35 mmol) and 4-(dimethylamino)pyridine (4 mg, 0.03 mmol) in a mixture of THF (5 mL) and DMF (0.7 mL) in a similar manner as Ex-35, dark red solid (98 mg, 61%), mp 193-195° C. 1H NMR (300 MHz, DMSO-d6) δ 12.23 (brs, 1H), 8.26 (d, J=8.5 Hz, 2H), 8.11-8.03 (m, 3H), 7.66 (d, J=15.2 Hz, 1H), 7.02 (s, 1H), 6.71 (s, 1H), 3.90 (s, 6H), 3.15-3.25 (m, 4H), 2.20 (t, J=7.6 Hz, 2H), 1.92-1.81 (m, 4H), 1.46-1.39 (m, 2H), 0.76 (t, J=7.3 Hz, 3H).
    • Example 49
  • Figure US20070093453A1-20070426-C00065
    • N-Butyryl-4-{3E-[5-(1H-indol-2-yl)-2,4-dimethoxyphenyl]acryloyl}benzenesulfonamide sodium salt
  • To a solution of N-butyryl-4-{3E-[5-(1H-indol-2-yl)-2,4-dimethoxyphenyl]acryloyl}benzenesulfonamide (Ex-47, 0.40 g, 0.75 mmol) in 50 ml THF, was added NaOMe (0.039 g, 0.72 mmol). The solution was stirred overnight. The reaction mixture was concentrated to about 5 mL and filtered to give 0.36 g (86%) of the title compound as a red solid, mp 191-193° C. 1H-NMR (300 MHz, DMSO6) δ 11.18 (s, 1H), 8.30 (s, 1H), 8.00-8.06 (m, 3H), 7.80-7.85 (m, 3H), 7.49 (d, J=7 Hz, 1H), 7.42 (d, J=8 Hz, 1H), 7.02-7.04 (m, 1H), 6.93-6.96(m, 2H), 6.81 (s, 1H), 4.02 (s, 3H), 3.97 (s, 3H), 1.86 (t, J=7 Hz, 2H), 1.31-1.39 (m, 2H), 0.73 (t, J=8 Hz, 3H). Anal. Calcd for C29H27N2NaO6S.2H2O: C, 58.97; H, 5.29; N, 4.74; S, 5.43; Found: C, 59.08; H, 5.52; N, 4.64; S, 5.16.
    • Example 50
  • Figure US20070093453A1-20070426-C00066
    • N-(3-Imidazol-1-yl-propyl)-4-{3E-[5-(1H-indol-2-yl)-2,4-dimethoxy-phenyl]acryloyl}benzenesulfonamide
  • Ex-50A: A solution of 4-acetyl-N-(3-imidazol-1-ylpropyl)benzenesulfonamide (Ex-23A, 312 mg, 1.02 mmol) and 5-(2-amino-phenylethynyl)-2,4-dimethoxybenzaldehyde (Ex-35C, 287 mg, 1.02 mmol) in DMF (4.4 mL) and MeOH (1.9 mL) was treated with lithium methoxide (155 mg, 4.08 mmol). The reaction mixture was stirred at room temperature for 16 h under nitrogen. The reaction mixture was quenched with water (25 mL) and extracted with (3:1) ethyl acetate/THF (3×25 mL). The organic phase was brined, dried over sodium sulfate, and concentrated to a yellow oil. The crude material was purified by column chromatography (0-7.5% MeOH in dichloromethane) to give 4-{3E-[5-(2-amino-phenylethynyl)-2,4-dimethoxy-phenyl]acryloyl}-N-(3-imidazol-1-ylpropyl)benzenesulfonamide (309 mg, 53%) as a yellow oil. 1H-NMR (300 MHz, DMSO-d6)
    Figure US20070093453A1-20070426-P00902
    8.28 (d, 2H, J=7.80), 8.20 (s, 1H), 8.01 (d, 1H, J=15.0 Hz), 7.86 (m, 5H), 7.51 (s, 1H), 7.16 (d, 1H, J=7.5 Hz), 7.23 (m, 2H), 6.79 (d, 2H, J=10.8 Hz), 6.72 (d, 1H, J=8.1 Hz), 6.52 (t, 1H, J=7.2 Hz), 5.45 (m, 1H), 3.97 (s, 3H), 3.96 (s, 3H), 3.92 (m, 4H), 1.77 (quintet, 2H, J=6.6 Hz).
  • A suspension of 4-{3E-[5-(2-amino-phenylethynyl)-2,4-dimethoxyphenyl]acryloyl}-N-(3-imidazol-1-ylpropyl)benzenesulfonamide (Ex-50A, 210 mg, 0.37 mmol) in acetonitrile (130 mL) was purged with nitrogen gas for 10 minutes. Palladium(II) chloride (5.0 mg, 0.029 mmol) was added to the reaction vessel. The reaction mixture was refluxed for 16 hrs. The cooled reaction mixture was stirred with 3-mercaptopropyl functionalized silica gel (500 mg) for 5 minutes. The filtrate was collected via suction filtration and concentrated to an orange solid to give 210 mg (100%) of the title compound, mp 197-200° C. 1H-NMR (300 MHz, DMSO-d6)
    Figure US20070093453A1-20070426-P00902
    11.19 (br s, 1H), 8.28 (m, 3H), 8.11 (m, 2H), 7.95 (m, 4H), 7.45 (m, 3H), 7.00 (m, 5H), 4.08 (s, 3H), 4.03 (s, 3H), 3.89 (m, 2H), 2.69 (br s, 2H), 1.78 (br s, 2H). HRMS (ESI) Calcd. for C31H30N4O5S: 571.2015 [(M+H)+]; Found: 571.2016.
    • Example 51
  • Figure US20070093453A1-20070426-C00067
    • (4-{3E-[5-(1H-Indol-2-yl)-2,4-dimethoxyphenyl]acryloyl}benzenesulfonylamino)acetic acid
  • Ex-51A: A solution (4-acetylbenzenesulfonylamino)acetic acid (Ex-26A, 238 mg, 1.01 mmol) in DMF (4.4 mL) and MeOH (1.9 mL) was treated with lithium methoxide (153 mg, 4.04 mmol), followed by the addition of 5-(2-amino-phenylethynyl)-2,4-dimethoxybenzaldehyde (Ex-35C, 300 mg, 1.07 mmol). The reaction mixture was stirred at room temperature for 23 h under nitrogen. It was quenched with water (10 mL) and extracted with ethyl acetate (25 mL). The aqueous phase was acidified with 6N HCl to pH3 and was extracted with (3:1) ethyl acetate/THF (5×25 mL). The organic phase was brined, dried over sodium sulfate, and concentrated to a yellow oil. The crude material was purified by column chromatography (0-7.5% MeOH in dichloromethane) to give (4-{3E-[5-(2-amino-phenylethynyl)-2,4-dimethoxyphenyl]acryloyl}benzenesulfonylamino)acetic acid (188 mg, 36%) as an orange solid. 1H-NMR (300 MHz, DMSO-d6)
    Figure US20070093453A1-20070426-P00902
    8.23 (d, 2H, J=8.7), 8.19 (s, 1H), 7.99 (d, 1H, J=15.9 Hz), 7.92 (d, 2H, J=7.80 Hz), 7.82 (d, 1H, J=16.5 Hz), 7.16 (d, 1H, J=6.6 Hz), 7.05 (t, 1H, J=8.1 Hz), 6.76 (s, 1H), 6.71 (d, 1H, J=7.8 Hz), 6.52 (t, 1H, J=7.2 Hz), 5.72 (s, 1H), 5.45 (br s, 1H), 3.96 (s, 3H), 3.95 (s, 3H), 3.41 (m, 2H).
  • A suspension of (4-{3E-[5-(2-amino-phenylethynyl)-2,4-dimethoxyphenyl]acryloyl}benzenesulfonylamino)acetic acid (Ex-51A, 153 mg, 0.294 mmol) in acetonitrile (130 mL) was purged with nitrogen gas for 10 minutes. Palladium (II) chloride (5.2 mg, 0.029 mmol) was added to the reaction vessel. The reaction mixture was refluxed for 2 h. The reaction mixture was gravity filtered and yielded a red solid. The crude was swished in ethanol to give 35 mg (23%) of the title compound as a red solid, mp 189-190° C. 1H-NMR (300 MHz, DMSO-d6)
    Figure US20070093453A1-20070426-P00902
    11.18 (br s, 1H), 8.25 (m, 3H), 8.06 (d, 1H, J=15.3 Hz), 7.89 (m, 5H), 7.49 (d, 1H, J=7.8 Hz), 7.41 (d, 1H, J=8.1 Hz), 7.03 (t, 1H, J=6.6 Hz), 6.96 (m, 1H), 6.83 (s, 1H), 4.04 (s, 3H), 3.99 (s, 3H). MS (ESI, for C27H24N2O7S) Found: 520 [(M+H)+].
    • Example 52
  • Figure US20070093453A1-20070426-C00068
    • 4-[3E-(2,4-Dimethoxy-5-pyrrolidin-1-yl-phenyl)-acryloyl]-N-pyridin-2-yl-benzenesulfonamide
  • A solution 4-acetyl-N-pyridin-2-ylbenzenesulfonamide (Ex-5A, 588 mg, 2.13 mmol) and 2,4-dimethoxy-5-pyrrolidin-1-yl-benzaldehyde (Ex-38B, 500 mg, 2.13 mmol) in DMF (9.3 mL) and MeOH (4.0 mL) was treated with lithium methoxide (243 mg, 6.39 mmol) and stirred for 20 h at room temperature under nitrogen. The reaction mixture was quenched with water (25 mL) and extracted ethyl acetate (3×50 mL). The product precipitated out of the organic phase to give 535 mg (51%) of the title compound as a red solid, mp 124-128° C. 1H-NMR (300 MHz, DMSO-d6)
    Figure US20070093453A1-20070426-P00902
    8.16 (d, 2H, J=8.7), 8.02 (d, 1H, J=15.9 Hz), 7.95 (m, 3H), 7.70 (t, 1H, J=7.80 Hz), 7.61 (d, 1H, J=16.2 Hz), 7.18 (d, 1H, J=8.70 Hz), 7.15 (s, 1H), 6.83 (t, 1H, J=6.0 Hz), 6.66 (s, 1H), 3.84 (s, 6H), 3.13 (m, 4H), 1.18 (m, 4H). HRMS (ESI) Calcd. for C26H27N3O5S: 494.1750 [(M+H)+]; Found: 494.1750.
    • Example 53
  • Figure US20070093453A1-20070426-C00069
    • 4-[3E-(2,4-Dimethoxy-5-pyrrolidin-1-ylphenyl)acryloyl]-N-pyridin-2-ylmethylbenzenesulfonamide
  • Ex-53A: A solution of 4-acetyl-benzenesulfonyl chloride (1.94 g, 8.89 mmol) and triethylamine (1.85 mL, 13.3 mmol) in anhydrous THF (15 mL) was treated with 2-(aminomethyl)pyridine (1.01 g, 9.34 mmol) at room temperature under nitrogen. The reaction mixture was stirred for 5 minutes and a precipitate formed. The reaction mixture was diluted with water (10 mL) and suction filtration gave 4-acetyl-N-pyridin-2-ylmethylbenzenesulfonamide as a yellow solid (1.36 g, 65%). 1H-NMR (300 MHz, DMSO-d6)
    Figure US20070093453A1-20070426-P00902
    8.38 (m, 3H), 8.06 (d, 2H, J=9.0 Hz), 7.87 (d, 2H, J=7.8 Hz), 7.58 (d, 1H, J=8.7 Hz), 7.25 (dd, 1H, J=5.4, 4.5 Hz), 4.04 (d, 2H, J=3.9 Hz), 2.60 (s, 3H).
  • A solution 4-acetyl-N-pyridin-2-ylmethyl-benzenesulfonamide (Ex-53A, 617 mg, 2.13 mmol) and 2,4-dimethoxy-5-pyrrolidin-1-yl-benzaldehyde (Ex-38B, 500 mg, 2.13 mmol) in DMF (9.3 mL) and MeOH (4.0 mL) was treated with lithium methoxide (162 mg, 4.26 mmol) and stirred for 20 h at room temperature under nitrogen. The reaction mixture was quenched with water (20 mL) and extracted ethyl acetate (3×50 mL). The organic phase was brined, dried over sodium sulfate, and concentrated to a red solid. Crystallization from hot ethanol (25 mL) and water (50 mL) gave the title compound as a red solid (626 mg, 58%), mp 112-116° C. 1H-NMR (300 MHz, DMSO-d6)
    Figure US20070093453A1-20070426-P00902
    8.40 (m, 3H), 8.19 (d, 2H, J=9.0 Hz), 8.05 (d, 1H, J=15.9 Hz), 7.89 (d, 2H, J=9.0 Hz), 7.62 (m, 2H), 7.25 (dd, 1H, J=4.5, 5.7 Hz), 7.17 (s, 1H), 6.67 (s, 1H), 4.05 (d, 2H, J=5.7 Hz), 3.86 (s, 3H), 3.85 (s, 3H), 3.16 (br s, 4H), 1.82 (br s, 4H). HRMS (ESI) Calcd. for C27H29N3O5S: 508.1906 [(M+H)+]; Found: 508.1902.
    • Example 54
  • Figure US20070093453A1-20070426-C00070
    • 4-[3E-(2,4-Dimethoxy-5-pyrrolidin-1-ylphenyl)acryloyl]-N-(3-imidazol-1-ylpropyl)benzenesulfonamide
  • A solution 4-acetyl-N-(3-imidazol-1-ylpropyl)benzenesulfonamide (Ex-23A, 653 mg, 2.13 mmol) and 2,4-dimethoxy-5-pyrrolidin-1-yl-benzaldehyde (Ex-38B, 500 mg, 2.13 mmol) in DMF (9.3 mL) and MeOH (4.0 mL) was treated with lithium methoxide (162 mg, 4.26 mmol) and stirred for 20 h at room temperature under nitrogen atmosphere. The reaction mixture was quenched with water (75 mL) and extracted ethyl acetate (3×50 mL). The organic phase was brined, dried over sodium sulfate, and concentrated to a red solid. Crystallization from hot ethanol (10 mL) and water (12 mL) gave 461 mg (41%) of the title compound as a red solid, mp 140-143° C. 1H-NMR (300 MHz, DMSO-d6)
    Figure US20070093453A1-20070426-P00902
    8.23 (d, 2H, J=8.7 Hz), 8.05 (d, 1H, J=15.3 Hz), 7.88 (d, 2H, J=9.3 Hz), 7.64 (d, 1H, J=15.3 Hz), 7.51 (s, 1H), 7.17 (s, 1H), 7.05 (s, 1H), 6.81 (s, 1H), 6.67 (s, 1H), 3.92 (t, 2H, J=6.9 Hz), 3.86 (s, 6H), 3.15 (m, 4H), 2.68 (t, 2H, J=6.3 Hz), 1.80 (m, 6H). HRMS (ESI) Calcd. for C27H32N4O5S: 525.2172 (M+H)+; Found: 525.2179.
    • Example 55
  • Figure US20070093453A1-20070426-C00071
    • 4-[3E-(2,4-Dimethoxy-5-pyrrolidin-1-ylphenyl)acryloyl]-N-[3-(4-methyl-piperazin-1-yl)propyl]benzenesulfonamide
  • Ex-55A: A chilled solution of 4-acetyl-benzenesulfonyl chloride (1.0 g, 4.57 mmol) and triethylamine (0.955 mL, 6.86 mmol) in anhydrous THF (5 mL) was treated with 1-(3-aminopropyl)-4-methylpiperazine (755 mg, 4.80 mmol) under nitrogen. The reaction mixture was stirred for 30 minutes, quenched with water (30 mL) and extracted with ethyl acetate (3×25 mL). The combined organic phase was brined, dried over sodium sulfate, and concentrated to 4-acetyl-N-[3-(4-methylpiperazin-1-yl)propyl]benzenesulfonamide as a brown solid (1.18 g, 76%). 1H-NMR (300 MHz, DMSO-d6)
    Figure US20070093453A1-20070426-P00902
    8.10 (d, 2H, J=8.1 Hz), 7.86 (d, 2H, J=8.4 Hz), 7.77 (br s, 1H), 2.74 (quartet, 2H, J=5.4 Hz), 2.60 (s, 3H), 2.20-2.13 (m, 10H), 2.09 (s, 3H), 1.45 (quintet, 2H, J=7.2 Hz).
  • A solution 4-acetyl-N-[3-(4-methylpiperazin-1-yl)propyl]benzenesulfonamide (Ex-55A, 830 mg, 2.44 mmol) and 2,4-dimethoxy-5-pyrrolidin-1-ylbenzaldehyde (Ex-38B, 575 mg, 2.44 mmol) in DMF (10.8 mL) and MeOH (4.4 mL) was treated with lithium methoxide (278 mg, 7.32 mmol) and stirred for 20 h at room temperature under nitrogen atmosphere. The reaction mixture was quenched with water (75 mL) and extracted ethyl acetate (3×50 mL). The combined organic phase was brined, dried over sodium sulfate, and concentrated to a red solid. Column chromatography (5% MeOH in dichloromethane) gave 772 mg (57%) of the title compound as a brown solid, mp 64-68° C. 1H-NMR (300 MHz, DMSO-d6)
    Figure US20070093453A1-20070426-P00902
    8.23 (d, 2H, J=8.7), 8.05 (d, 1H, J=15.3 Hz), 7.88 (d, 2H, J=7.5 Hz), 7.76 (t, 1H, J=4.8 Hz), 7.63 (d, 1H, J=15.3 Hz), 7.16 (s, 1H), 6.67 (s, 1H), 3.86 (s, 6H), 3.16 (br s, 4H), 2.76 (quartet, 2H, J=6.9 Hz), 2.15 (m, 10H), 2.06 (s, 3H), 1.80 (br s, 4H), 1.45 (quintet, 2H, J=6.9 Hz). HRMS (ESI) Calcd. for C29H40N4O5S: 557.2798 [(M+H)+]; Found: 557.2798.
    • Example 56
  • Figure US20070093453A1-20070426-C00072
    • {4-[3E-(2,4-Dimethoxy-5-pyrrolidin-1-ylphenyl)acryloyl]benzenesulfonylamino}acetic acid
  • A solution of (4-acetylbenzenesulfonylamino)acetic acid (Ex-26A, 226 mg, 0.878 mmol) and 2,4-dimethoxy-5-pyrrolidin-1-ylbenzaldehyde (Ex-38B, 216 mg, 0.922 mmol) in DMF (8.0 mL) and MeOH (3.6 mL) was treated with lithium methoxide (140 mg, 3.69 mmol) and stirred for 21 h at room temperature under nitrogen. The reaction mixture was quenched with water (10 mL) and extracted ethyl acetate (2×20 mL). The aqueous phase was acidified with 6N HCl to pH 3 and was extracted with (3:1) ethyl acetate/THF (6×25 mL). The organic phase was brined, dried over sodium sulfate, and concentrated to a red solid. Precipitation from dichloromethane (5 mL) gave the title compound (33 mg, 8%) as a brown solid, mp 155-158° C. 1H-NMR (300 MHz, DMSO-d6)
    Figure US20070093453A1-20070426-P00902
    12.06 (br s, 1), 8.22 (m, 3H), 8.04 (d, 1H, J=15.3 Hz), 7.89 (d, 2H, J=7.8 Hz), 7.64 (d, 1H, J=15.3 Hz), 7.18 (s, 1H), 6.67 (s, 1H), 3.86 (s, 6H), 3.29 (br s, 2H), 3.16 (br s, 4H), 1.82 (br s, 4H). HRMS (ESI) Calcd. for C23H26N2O7S: 475.1539 [(M+H)+]; Found: 475.1547.
    • Example 57
  • Figure US20070093453A1-20070426-C00073
    • 4-{3E-[5-(1H-Indol-2-yl)-2,4-dimethoxyphenyl]acryloyl}-N-pyridin-2-ylbenzenesulfonamide
  • Ex-57A: A solution of 4-acetyl-N-pyridin-2-ylbenzenesulfonamide (Ex-5A, 451 mg, 1.63 mmol) and 5-(2-aminophenylethynyl)-2,4-dimethoxybenzaldehyde (Ex-35C, 459 mg, 1.63 mmol) in DMF (10.0 mL) and MeOH (5.0 mL) was treated with lithium methoxide (248 mg, 6.52 mmol). The reaction mixture was stirred at room temperature for 3 h under nitrogen, quenched with water (50 mL), and extracted with (3:1) ethyl acetate/THF (4×30 mL). The combined organic phase was brined, dried over sodium sulfate, and concentrated to a yellow oil. The crude material was purified by column chromatography (2-5% MeOH in dichloromethane) to give 735 mg (65%) of 4-{3E-[5-(2-amino-phenylethynyl)-2,4-dimethoxyphenyl]acryloyl}-N-pyridin-2-yl-benzenesulfonamide as a yellow oil. 1H-NMR (300 MHz, DMSO-d6)
    Figure US20070093453A1-20070426-P00902
    8.21 (d, 2H, J=7.5), 8.18 (s, 1H), 8.00 (m, 4H), 7.81 (d, 1H, J=15.0 Hz), 7.74 (t, 2H, J=7.5 Hz), 7.17 (m, 2H), 7.05 (t, 2H, J=7.2 Hz), 6.80 (m, 3H), 6.52 (t, 1H, J=7.5 Hz), 5.43 (d, 1H, J=6.9 Hz), 3.96 (s, 3H), 3.95 (s, 3H).
  • Ex-57B:
    Figure US20070093453A1-20070426-C00074
  • A solution of 5-(2-aminophenylethynyl)-2,4-dimethoxybenzaldehyde (Ex-35C, 10.3 g, 36.7 mmol) in 500 ml of THF and 500 ml of MeOH was cooled to 0° C. with an ice bath. To this solution was added NaBH4 (2.8 g, 73.4 mmol) portion-wise. The mixture was stirred at 0° C. for 1 h. The reaction was quenched with 1N H2SO4 slowly until no gas bubbling was observed. The mixture was filtered and the filtrate was concentrated to about 100 ml. The precipitate was filtered to give 9.65 g (92.3%) of [5-(2-aminophenylethynyl)-2,4-dimethoxyphenyl]methanol as a white solid. 1H-NMR (300 MHz, Acetone-d6) δ 7.44 (s, 1H), 7.19 (dd, J=8, 1 Hz, 1H), 7.00-7.5 (m, 1H), 6.74 (d, J=8 Hz, 1H), 6.70 (s, 1H), 6.52-6.57 (m, 1H), 5.15 (br, 2H), 4.53 (d, J=5 Hz, 2H), 3.92 (s, 3H), 3.87 (s, 3H).
  • Ex-57C:
    Figure US20070093453A1-20070426-C00075
  • To a solution of [5-(2-aminophenylethynyl)-2,4-dimethoxyphenyl]methanol (Ex-57B, 9.65 g, 34 mmol) in 1 L of acetonitrile, was added PdCl2 (0.6 g, 3.4 mmol). The mixture was heated to reflux for about 0.5 h and the reaction was complete as indicated by HPLC. The mixture was cooled to room temperature and filtered. The filtrate was treated with 20 g of 3-mercaptopropyl functional silica gel with stirring for 30 min and then filtered. The filtrate was concentrated and the residue was recrystallized from EtOAc/hexanes to give 6.25 g (67.8%) of [5-(1H-indol-2-yl)-2,4-dimethoxyphenyl]methanol as off-white solid. 1H-NMR (Acetone-d6) δ 10 50 (br, 1H), 7.84 (s, 1H), 7.48 (d, J=7 Hz, 1H), 7.37 (d, J=8 Hz, 1H), 6.91-7.03 (m, 2H), 6.79 (d, J=2 Hz, 1H), 6.77 (s, 1H), 4.59 (s, 2H), 3.98 (s, 3H), 3.88 (s, 3H).
  • Ex-57D:
    Figure US20070093453A1-20070426-C00076
  • To a solution of [5-(1H-indol-2-yl)-2,4-dimethoxyphenyl]methanol (Ex-57C, 5.8 g, 20 mmol) in 250 ml of THF and 250 ml of CH2Cl2, was added MnO2 (1.8 g, 20 mmol). The mixture was heated to reflux. The reaction was pushed to completion by adding two more portions of MnO2 (1.8 g each) within 48 h. The mixture was then cooled to room temperature and filtered. The filtrate was concentrated and the residue was recrystallized from EtOAc/Hexane to give 5.1 g (88%) of 5-(1H-indol-2-yl)-2,4-dimethoxybenzaldehyde. 1H-NMR (300 MHz, DMSO-d6) δ 11.29 (br s, 1H), 10 24 (s, 1H), 8.10 (s, 1H), 7.47 (d, J=8 Hz, 1H), 7.37 (d, J=7 Hz, 1H), 7.01-7.05 (m, 1H), 6.91-6.95 (m, 1H), 6.85-6.86 (m, 2H), 4.06 (s, 3H), 3.99 (s, 3H). HRMS (EI) Calcd. for C17H15NO3: 281.1052 (M+); Found: 281.1046.
  • Ex-57DD:
    Figure US20070093453A1-20070426-C00077
  • A solution of PdCl2 (0.066 g, 0.373 mmol) in 200 ml of acetonitrile was heated to reflux. To this solution was added 5-(2-amino-phenylethynyl)-2,4-dimethoxybenzaldehyde (Ex-35C, 1.4 g, 5 mmol) portion by portion slowly so that no cloudiness of the solution occurred. After the addition, the reaction was kept at reflux for another 10 min. Then the mixture was cooled to room temperature and filtered. The filtrate was treated with 5 g of 3-mercaptopropyl functional silica gel with stirring for 30 min and filtered. The filtrate was concentrated and the residue was recrystallized from EtOAc/Hexane to give 0.84 g (60%) of 5-(1H-indol-2-yl)-2,4-dimethoxybenzaldehyde, analytical dada identical as in Ex-57D.
  • Ex-57E:
    Figure US20070093453A1-20070426-C00078
  • Pyridine (453 μL, 5.61 mmol) was added to a suspension of 5-(2-amino-phenylethynyl)-2,4-dimethoxybenzaldehyde (Ex-35C, 750 mg, 2.67 mmol) in anhydrous methylene chloride (20 mL) and chilled to 0° C. The reaction mixture was treated dropwise with acetyl chloride (9.25 mL, 75.1 mmol). Upon completion the reaction was quenched with 1N HCl (10 mL) and the layers were separated. The organic layer was washed with brine, dried over sodium sulfate, and concentrated to dryness. The crude solid was purified by silica gel chromatography (5% MeOH/CH2Cl2) to yield 671 mg (78%) of N-[2-(5-formyl-2,4-dimethoxyphenylethynyl)phenyl]acetamide as an off-white solid. 1H-NMR (300 MHz, DMSO-d6)
    Figure US20070093453A1-20070426-P00902
    10.15 (s, 1H), 9.23 (br s, 1H), 7.82 (m, 2H), 7.80 (s, 1H), 7.50 (dd, 1H, J=0.9, 7.8 Hz), 7.35 (dt, 1H, J=1.8, 9.3 Hz), 7.12 (t, 1H, J=7.8 Hz), 6.82 (s, 1H), 4.00 (s, 3H), 3.99 (s, 3H), 2.10 (s, 3H).
  • Ex-57F:
    Figure US20070093453A1-20070426-C00079
  • N-[2-(5-Formyl-2,4-dimethoxy-phenyl ethynyl)phenyl]acetamide (Ex-57E, 535 mg, 1.6 mmol) was added to 150 mL of DMF (nitrogen purged) at room temperature and the resulting solution was heated to 80° C. Palladium(II) chloride (22 mg) was added in one portion. After 6 h the reaction mixture was poured into water (50 mL) and EtOAc (50 mL), and the layers were cut. The organic layer was filtered through Celite, washed with brine, and concentrated to an orange solid. The crude was purified by silica gel chromatography (25% ethyl acetate/hexane) to yield 210 mg (39%) of 5-(1-acetyl-1H-indol-2-yl)-2,4-dimethoxybenzaldehyde as a white solid. 1H-NMR (300 MHz, DMSO-d6)
    Figure US20070093453A1-20070426-P00901
    10.22 (s, 1H), 8.13 (d, 1H, J=8.1 Hz), 7.71 (s, 1H), 7.55 (d, 1H, J=6.3 Hz), 7.25 (m, 2H, J=6.9 Hz), 6.84 (s, 1H), 6.64 (s, 1H), 4.01 (s, 3H), 3.87 (s, 3H), 2.13 (s, 3H).
  • Ex-57G:
    Figure US20070093453A1-20070426-C00080
  • Pyridine (12.6 mL, 156.24 mmol) was added to a suspension of 5-(2-aminophenylethynyl)-2,4-dimethoxybenzaldehyde (Ex-35C, 20.90 g, 74.4 mmol) in anhydrous methylene chloride (572 mL) and chilled to 0° C. The reaction mixture was treated dropwise with pivaloyl chloride (9.25 mL, 75.1 mmol) and then aged at room temperature for 2 h. The reaction was quenched with 1N HCl (200 mL) and the layers were cut. The organic layer was washed with brine, dried over sodium sulfate, and concentrated to dryness to afford 21.47 g (79%) of N-[2-(5-formyl-2,4-dimethoxyphenylethynyl)phenyl]-2,2-dimethylpropionamide as a light brown solid. 1H-NMR (300 MHz, DMSO-d6)
    Figure US20070093453A1-20070426-P00902
    10.14 (s, 1H), 8.74 (br s, 1H), 7.89 (d, 1H, J=8.1 Hz), 7.80 (s, 1H), 7.50 (dd, 1H, J=1.2, 7.8 Hz), 7.35 (dt, 1H, 1.8, 9.3 Hz), 7.12 (t, 1H, J=9.0 Hz), 6.82 (s, 1H), 3.99 (s, 3H), 3.98 (s, 3H), 1.23 (s, 9H).
  • Ex-57H:
    Figure US20070093453A1-20070426-C00081
  • N-[2-(5-Formyl-2,4-dimethoxy-phenylethynyl)phenyl]-2,2-dimethylpropionamide (Ex-57G, 19.86 g, 54.4 mmol) was dissolved in nitrogen-purged DMF (189 mL) and heated to 80° C., followed by the addition of palladium(II) chloride (754 mg). After 1 h, the reaction mixture was diluted with water (300 mL) and extracted with EtOAc (2×200 mL). The combined organic phase was brined, dried over sodium sulfate, and concentrated to brown oil. The oil was purified by silica gel chromatography (30 to 50% ethyl acetate/hexane) to yield 14.31 g (72%) of 5-[1-(2,2-dimethylpropionyl)-1H-indol-2-yl]-2,4-dimethoxybenzaldehyde as a light yellow solid. 1H-NMR (300 z, CDCl3)
    Figure US20070093453A1-20070426-P00901
    10.21 (s, 1H), 7.69 (s, 1H), 7.57 (d, 1H, J=37.8 Hz), 7.30 (d, 1H, J=8.10 Hz), 7.20 (t, 1H, J=6.9 Hz), 7.12 (t, 2H, J=6.9 Hz), 6.85 (s, 1H), 6.70 (s, 1H), 4.00 (s, 3H), 3.87 (s, 3H), 0.95 (s, 9H).
  • A suspension of 4-{3E-[5-(2-amino-phenylethynyl)-2,4-dimethoxyphenyl]acryloyl}-N-pyridin-2-ylbenzenesulfonamide (Ex-57A, 735 mg, 1.36 mmol) in acetonitrile (100 mL) was purged with nitrogen for 10 minutes. Palladium(II) chloride (24 mg, 0.14 mmol) was added and the reaction mixture was refluxed for 3.5 hrs. The cooled reaction mixture was stirred with 3-mercaptopropyl functionalized silica gel (500 mg) for 5 minutes, filtered, and concentrated. The crude material was purified by column chromatography (2% MeOH in dichloromethane) to give 320 mg (44%) of the title compound as a red solid, mp 206-208° C. 1H-NMR (300 MHz, DMSO-d6)
    Figure US20070093453A1-20070426-P00902
    11.13 (br s, 1H), 8.31 (s, 1H), 8.19 (d, 2H, J=7.80 Hz), 8.05 (m, 3H), 7.94 (br s, 1H), 7.82 (d, 1H, J=15.0 Hz), 7.74 (t, 2H, J=7.2 Hz), 7.49 (d, 1H, J=8.1 Hz), 7.41 (d, 1H, J=7.5 Hz), 7.21 (d, 1H, J=8.4 Hz), 7.05 (t, 1H, J=7.5 Hz), 6.95 (m, 2H), 6.82 (s, 2H), 4.03 (s, 3H), 3.98 (s, 3H). HRMS (ESI) Calcd. for C30H25N3O5S: 540.1593 (M+H)+; Found: 540.1576.
  • Alternatively, 4-Acetyl-N-pyridin-2-ylbenzenesulfonamide (Ex-5A, 1.52 g, 5.50 mmol), 5-[1-(2,2-dimethylpropionyl)-1H-indol-2-yl]-2,4-dimethoxybenzaldehyde (Ex-57H, 2.0 g, 5.47 mmol), MeOH (7 mL) and DMF (14 mL) were sequentially charged into a clean reaction vessel fitted with a stir bar and nitrogen inlet adapter. LiOMe (0.42 g, 11.1 mmol) was added and the resulting solution was aged for 45 min at room temperature. The reaction was diluted with sat. NH4Cl (25 mL) and transferred to a separatory funnel containing THF (50 mL), EtOAc (50 mL) and H2O (50 mL). The layers were cut and the organic layer was concentrated to dryness. The crude product was suspended in EtOH (50 mL), filtered and then dried under vacuum to afford 2.5 g (85% yield) of the title compound, analytical dada identical as above. Similarly, the title compound could be prepared from 4-acetyl-N-pyridin-2-ylbenzenesulfonamide (Ex-5A) and 5-(1-acetyl-1H-indol-2-yl)-2,4-dimethoxybenzaldehyde (Ex-57F) or 5-(1H-indol-2-yl)-2,4-dimethoxybenzaldehyde (Ex-57D or Ex-57DD).
  • Using one or more of the preceding procedures or methods, additional compounds of the inventions listed in the following Tables can be prepared by one skilled in the art.
    TABLE 1a
    Figure US20070093453A1-20070426-C00082
    Ex.
    No. R2B
    100
    Figure US20070093453A1-20070426-C00083
    101
    Figure US20070093453A1-20070426-C00084
    102
    Figure US20070093453A1-20070426-C00085
    103
    Figure US20070093453A1-20070426-C00086
    104
    Figure US20070093453A1-20070426-C00087
    105
    Figure US20070093453A1-20070426-C00088
    106
    Figure US20070093453A1-20070426-C00089
    107
    Figure US20070093453A1-20070426-C00090
    108
    Figure US20070093453A1-20070426-C00091
    109
    Figure US20070093453A1-20070426-C00092
    110
    Figure US20070093453A1-20070426-C00093
    111
    Figure US20070093453A1-20070426-C00094
    112
    Figure US20070093453A1-20070426-C00095
    113
    Figure US20070093453A1-20070426-C00096
    114
    Figure US20070093453A1-20070426-C00097
    115
    Figure US20070093453A1-20070426-C00098
    116
    Figure US20070093453A1-20070426-C00099
    117
    Figure US20070093453A1-20070426-C00100
    118
    Figure US20070093453A1-20070426-C00101
    119
    Figure US20070093453A1-20070426-C00102
    120
    Figure US20070093453A1-20070426-C00103
    121
    Figure US20070093453A1-20070426-C00104
    122
    Figure US20070093453A1-20070426-C00105
    123
    Figure US20070093453A1-20070426-C00106
    124
    Figure US20070093453A1-20070426-C00107
    125
    Figure US20070093453A1-20070426-C00108
    126
    Figure US20070093453A1-20070426-C00109
    127
    Figure US20070093453A1-20070426-C00110
    128
    Figure US20070093453A1-20070426-C00111
    129
    Figure US20070093453A1-20070426-C00112
  • TABLE 1b
    Figure US20070093453A1-20070426-C00113
    Ex.
    No. R4
    130
    Figure US20070093453A1-20070426-C00114
    131
    Figure US20070093453A1-20070426-C00115
    132
    Figure US20070093453A1-20070426-C00116
    133
    Figure US20070093453A1-20070426-C00117
    134
    Figure US20070093453A1-20070426-C00118
    135
    Figure US20070093453A1-20070426-C00119
    136
    Figure US20070093453A1-20070426-C00120
    137
    Figure US20070093453A1-20070426-C00121
    138
    Figure US20070093453A1-20070426-C00122
    139
    Figure US20070093453A1-20070426-C00123
    140
    Figure US20070093453A1-20070426-C00124
    141
    Figure US20070093453A1-20070426-C00125
    142
    Figure US20070093453A1-20070426-C00126
    143
    Figure US20070093453A1-20070426-C00127
    144
    Figure US20070093453A1-20070426-C00128
    145
    Figure US20070093453A1-20070426-C00129
    146
    Figure US20070093453A1-20070426-C00130
    147
    Figure US20070093453A1-20070426-C00131
    148
    Figure US20070093453A1-20070426-C00132
    149
    Figure US20070093453A1-20070426-C00133
    150
    Figure US20070093453A1-20070426-C00134
    151
    Figure US20070093453A1-20070426-C00135
    152
    Figure US20070093453A1-20070426-C00136
    153
    Figure US20070093453A1-20070426-C00137
    154
    Figure US20070093453A1-20070426-C00138
    155
    Figure US20070093453A1-20070426-C00139
    156
    Figure US20070093453A1-20070426-C00140
    157
    Figure US20070093453A1-20070426-C00141
    158
    Figure US20070093453A1-20070426-C00142
    159
    Figure US20070093453A1-20070426-C00143
  • TABLE 1c
    Figure US20070093453A1-20070426-C00144
    Ex.
    No. R5
    160
    Figure US20070093453A1-20070426-C00145
    161
    Figure US20070093453A1-20070426-C00146
    162
    Figure US20070093453A1-20070426-C00147
    163
    Figure US20070093453A1-20070426-C00148
    164
    Figure US20070093453A1-20070426-C00149
    165
    Figure US20070093453A1-20070426-C00150
    166
    Figure US20070093453A1-20070426-C00151
    167
    Figure US20070093453A1-20070426-C00152
    168
    Figure US20070093453A1-20070426-C00153
    169
    Figure US20070093453A1-20070426-C00154
    170
    Figure US20070093453A1-20070426-C00155
    171
    Figure US20070093453A1-20070426-C00156
    172
    Figure US20070093453A1-20070426-C00157
    173
    Figure US20070093453A1-20070426-C00158
    174
    Figure US20070093453A1-20070426-C00159
    175
    Figure US20070093453A1-20070426-C00160
    176
    Figure US20070093453A1-20070426-C00161
    177
    Figure US20070093453A1-20070426-C00162
    178
    Figure US20070093453A1-20070426-C00163
    179
    Figure US20070093453A1-20070426-C00164
    180
    Figure US20070093453A1-20070426-C00165
    181
    Figure US20070093453A1-20070426-C00166
    182
    Figure US20070093453A1-20070426-C00167
    183
    Figure US20070093453A1-20070426-C00168
    184
    Figure US20070093453A1-20070426-C00169
    185
    Figure US20070093453A1-20070426-C00170
    186
    Figure US20070093453A1-20070426-C00171
    187
    Figure US20070093453A1-20070426-C00172
    188
    Figure US20070093453A1-20070426-C00173
    189
    Figure US20070093453A1-20070426-C00174
  • TABLE 1d
    Figure US20070093453A1-20070426-C00175
    Ex.
    No. R5
    190
    Figure US20070093453A1-20070426-C00176
    191
    Figure US20070093453A1-20070426-C00177
    192
    Figure US20070093453A1-20070426-C00178
    193
    Figure US20070093453A1-20070426-C00179
    194
    Figure US20070093453A1-20070426-C00180
    195
    Figure US20070093453A1-20070426-C00181
    196
    Figure US20070093453A1-20070426-C00182
    197
    Figure US20070093453A1-20070426-C00183
    198
    Figure US20070093453A1-20070426-C00184
    199
    Figure US20070093453A1-20070426-C00185
    200
    Figure US20070093453A1-20070426-C00186
    201
    Figure US20070093453A1-20070426-C00187
    202
    Figure US20070093453A1-20070426-C00188
    203
    Figure US20070093453A1-20070426-C00189
    204
    Figure US20070093453A1-20070426-C00190
    205
    Figure US20070093453A1-20070426-C00191
    206
    Figure US20070093453A1-20070426-C00192
    207
    Figure US20070093453A1-20070426-C00193
    208
    Figure US20070093453A1-20070426-C00194
    209
    Figure US20070093453A1-20070426-C00195
    210
    Figure US20070093453A1-20070426-C00196
    211
    Figure US20070093453A1-20070426-C00197
    212
    Figure US20070093453A1-20070426-C00198
    213
    Figure US20070093453A1-20070426-C00199
    214
    Figure US20070093453A1-20070426-C00200
    215
    Figure US20070093453A1-20070426-C00201
    216
    Figure US20070093453A1-20070426-C00202
    217
    Figure US20070093453A1-20070426-C00203
    218
    Figure US20070093453A1-20070426-C00204
    219
    Figure US20070093453A1-20070426-C00205
  • TABLE 1e
    Figure US20070093453A1-20070426-C00206
    Ex.
    No. R5
    220
    Figure US20070093453A1-20070426-C00207
    221
    Figure US20070093453A1-20070426-C00208
    222
    Figure US20070093453A1-20070426-C00209
    223
    Figure US20070093453A1-20070426-C00210
    224
    Figure US20070093453A1-20070426-C00211
    225
    Figure US20070093453A1-20070426-C00212
    226
    Figure US20070093453A1-20070426-C00213
    227
    Figure US20070093453A1-20070426-C00214
    228
    Figure US20070093453A1-20070426-C00215
    229
    Figure US20070093453A1-20070426-C00216
    230
    Figure US20070093453A1-20070426-C00217
    231
    Figure US20070093453A1-20070426-C00218
    232
    Figure US20070093453A1-20070426-C00219
    233
    Figure US20070093453A1-20070426-C00220
    234
    Figure US20070093453A1-20070426-C00221
    235
    Figure US20070093453A1-20070426-C00222
    236
    Figure US20070093453A1-20070426-C00223
    237
    Figure US20070093453A1-20070426-C00224
    238
    Figure US20070093453A1-20070426-C00225
    239
    Figure US20070093453A1-20070426-C00226
    240
    Figure US20070093453A1-20070426-C00227
    241
    Figure US20070093453A1-20070426-C00228
    242
    Figure US20070093453A1-20070426-C00229
    243
    Figure US20070093453A1-20070426-C00230
    244
    Figure US20070093453A1-20070426-C00231
    245
    Figure US20070093453A1-20070426-C00232
    246
    Figure US20070093453A1-20070426-C00233
    247
    Figure US20070093453A1-20070426-C00234
    248
    Figure US20070093453A1-20070426-C00235
    249
    Figure US20070093453A1-20070426-C00236
  • TABLE 3f
    Figure US20070093453A1-20070426-C00237
    Ex.
    No. R2B
    250
    Figure US20070093453A1-20070426-C00238
    251
    Figure US20070093453A1-20070426-C00239
    252
    Figure US20070093453A1-20070426-C00240
    253
    Figure US20070093453A1-20070426-C00241
    254
    Figure US20070093453A1-20070426-C00242
    255
    Figure US20070093453A1-20070426-C00243
    256
    Figure US20070093453A1-20070426-C00244
    257
    Figure US20070093453A1-20070426-C00245
    258
    Figure US20070093453A1-20070426-C00246
    259
    Figure US20070093453A1-20070426-C00247
    260
    Figure US20070093453A1-20070426-C00248
    261
    Figure US20070093453A1-20070426-C00249
    262
    Figure US20070093453A1-20070426-C00250
    263
    Figure US20070093453A1-20070426-C00251
    264
    Figure US20070093453A1-20070426-C00252
    265
    Figure US20070093453A1-20070426-C00253
    266
    Figure US20070093453A1-20070426-C00254
    267
    Figure US20070093453A1-20070426-C00255
    268
    Figure US20070093453A1-20070426-C00256
    269
    Figure US20070093453A1-20070426-C00257
    270
    Figure US20070093453A1-20070426-C00258
    271
    Figure US20070093453A1-20070426-C00259
    272
    Figure US20070093453A1-20070426-C00260
    273
    Figure US20070093453A1-20070426-C00261
    274
    Figure US20070093453A1-20070426-C00262
    275
    Figure US20070093453A1-20070426-C00263
    276
    Figure US20070093453A1-20070426-C00264
    277
    Figure US20070093453A1-20070426-C00265
    278
    Figure US20070093453A1-20070426-C00266
    279
    Figure US20070093453A1-20070426-C00267
  • TABLE 1g
    Figure US20070093453A1-20070426-C00268
    Ex.
    No. R5
    280
    Figure US20070093453A1-20070426-C00269
    281
    Figure US20070093453A1-20070426-C00270
    282
    Figure US20070093453A1-20070426-C00271
    283
    Figure US20070093453A1-20070426-C00272
    284
    Figure US20070093453A1-20070426-C00273
    285
    Figure US20070093453A1-20070426-C00274
    286
    Figure US20070093453A1-20070426-C00275
    287
    Figure US20070093453A1-20070426-C00276
    288
    Figure US20070093453A1-20070426-C00277
    289
    Figure US20070093453A1-20070426-C00278
    290
    Figure US20070093453A1-20070426-C00279
    291
    Figure US20070093453A1-20070426-C00280
    292
    Figure US20070093453A1-20070426-C00281
    293
    Figure US20070093453A1-20070426-C00282
    294
    Figure US20070093453A1-20070426-C00283
    295
    Figure US20070093453A1-20070426-C00284
    296
    Figure US20070093453A1-20070426-C00285
    297
    Figure US20070093453A1-20070426-C00286
    298
    Figure US20070093453A1-20070426-C00287
    299
    Figure US20070093453A1-20070426-C00288
    300
    Figure US20070093453A1-20070426-C00289
    301
    Figure US20070093453A1-20070426-C00290
    302
    Figure US20070093453A1-20070426-C00291
    303
    Figure US20070093453A1-20070426-C00292
    304
    Figure US20070093453A1-20070426-C00293
    305
    Figure US20070093453A1-20070426-C00294
    306
    Figure US20070093453A1-20070426-C00295
    307
    Figure US20070093453A1-20070426-C00296
    308
    Figure US20070093453A1-20070426-C00297
    309
    Figure US20070093453A1-20070426-C00298
  • TABLE 2a
    Figure US20070093453A1-20070426-C00299
    Ex.
    No. R2B
    310
    Figure US20070093453A1-20070426-C00300
    311
    Figure US20070093453A1-20070426-C00301
    312
    Figure US20070093453A1-20070426-C00302
    313
    Figure US20070093453A1-20070426-C00303
    314
    Figure US20070093453A1-20070426-C00304
    315
    Figure US20070093453A1-20070426-C00305
    316
    Figure US20070093453A1-20070426-C00306
    317
    Figure US20070093453A1-20070426-C00307
    318
    Figure US20070093453A1-20070426-C00308
    319
    Figure US20070093453A1-20070426-C00309
    320
    Figure US20070093453A1-20070426-C00310
    321
    Figure US20070093453A1-20070426-C00311
    322
    Figure US20070093453A1-20070426-C00312
    323
    Figure US20070093453A1-20070426-C00313
    324
    Figure US20070093453A1-20070426-C00314
    325
    Figure US20070093453A1-20070426-C00315
    326
    Figure US20070093453A1-20070426-C00316
    327
    Figure US20070093453A1-20070426-C00317
    328
    Figure US20070093453A1-20070426-C00318
    329
    Figure US20070093453A1-20070426-C00319
    330
    Figure US20070093453A1-20070426-C00320
    331
    Figure US20070093453A1-20070426-C00321
    332
    Figure US20070093453A1-20070426-C00322
    333
    Figure US20070093453A1-20070426-C00323
    334
    Figure US20070093453A1-20070426-C00324
    335
    Figure US20070093453A1-20070426-C00325
    336
    Figure US20070093453A1-20070426-C00326
    33
    Figure US20070093453A1-20070426-C00327
    338
    Figure US20070093453A1-20070426-C00328
    339
    Figure US20070093453A1-20070426-C00329
  • TABLE 2b
    Figure US20070093453A1-20070426-C00330
    Ex.
    No. R4
    340
    Figure US20070093453A1-20070426-C00331
    341
    Figure US20070093453A1-20070426-C00332
    342
    Figure US20070093453A1-20070426-C00333
    343
    Figure US20070093453A1-20070426-C00334
    344
    Figure US20070093453A1-20070426-C00335
    345
    Figure US20070093453A1-20070426-C00336
    346
    Figure US20070093453A1-20070426-C00337
    347
    Figure US20070093453A1-20070426-C00338
    348
    Figure US20070093453A1-20070426-C00339
    349
    Figure US20070093453A1-20070426-C00340
    350
    Figure US20070093453A1-20070426-C00341
    351
    Figure US20070093453A1-20070426-C00342
    352
    Figure US20070093453A1-20070426-C00343
    353
    Figure US20070093453A1-20070426-C00344
    354
    Figure US20070093453A1-20070426-C00345
    355
    Figure US20070093453A1-20070426-C00346
    356
    Figure US20070093453A1-20070426-C00347
    357
    Figure US20070093453A1-20070426-C00348
    358
    Figure US20070093453A1-20070426-C00349
    359
    Figure US20070093453A1-20070426-C00350
    360
    Figure US20070093453A1-20070426-C00351
    361
    Figure US20070093453A1-20070426-C00352
    362
    Figure US20070093453A1-20070426-C00353
    363
    Figure US20070093453A1-20070426-C00354
    364
    Figure US20070093453A1-20070426-C00355
    365
    Figure US20070093453A1-20070426-C00356
    366
    Figure US20070093453A1-20070426-C00357
    367
    Figure US20070093453A1-20070426-C00358
    368
    Figure US20070093453A1-20070426-C00359
    369
    Figure US20070093453A1-20070426-C00360
  • TABLE 2c
    Figure US20070093453A1-20070426-C00361
    Ex.
    No. R5
    370
    Figure US20070093453A1-20070426-C00362
    371
    Figure US20070093453A1-20070426-C00363
    372
    Figure US20070093453A1-20070426-C00364
    373
    Figure US20070093453A1-20070426-C00365
    374
    Figure US20070093453A1-20070426-C00366
    375
    Figure US20070093453A1-20070426-C00367
    376
    Figure US20070093453A1-20070426-C00368
    377
    Figure US20070093453A1-20070426-C00369
    378
    Figure US20070093453A1-20070426-C00370
    379
    Figure US20070093453A1-20070426-C00371
    380
    Figure US20070093453A1-20070426-C00372
    381
    Figure US20070093453A1-20070426-C00373
    382
    Figure US20070093453A1-20070426-C00374
    383
    Figure US20070093453A1-20070426-C00375
    384
    Figure US20070093453A1-20070426-C00376
    385
    Figure US20070093453A1-20070426-C00377
    386
    Figure US20070093453A1-20070426-C00378
    387
    Figure US20070093453A1-20070426-C00379
    388
    Figure US20070093453A1-20070426-C00380
    389
    Figure US20070093453A1-20070426-C00381
    390
    Figure US20070093453A1-20070426-C00382
    391
    Figure US20070093453A1-20070426-C00383
    392
    Figure US20070093453A1-20070426-C00384
    393
    Figure US20070093453A1-20070426-C00385
    394
    Figure US20070093453A1-20070426-C00386
    395
    Figure US20070093453A1-20070426-C00387
    396
    Figure US20070093453A1-20070426-C00388
    397
    Figure US20070093453A1-20070426-C00389
    398
    Figure US20070093453A1-20070426-C00390
    399
    Figure US20070093453A1-20070426-C00391
  • TABLE 2d
    Figure US20070093453A1-20070426-C00392
    Ex.
    No. R5
    400
    Figure US20070093453A1-20070426-C00393
    401
    Figure US20070093453A1-20070426-C00394
    402
    Figure US20070093453A1-20070426-C00395
    403
    Figure US20070093453A1-20070426-C00396
    404
    Figure US20070093453A1-20070426-C00397
    405
    Figure US20070093453A1-20070426-C00398
    406
    Figure US20070093453A1-20070426-C00399
    407
    Figure US20070093453A1-20070426-C00400
    408
    Figure US20070093453A1-20070426-C00401
    409
    Figure US20070093453A1-20070426-C00402
    410
    Figure US20070093453A1-20070426-C00403
    411
    Figure US20070093453A1-20070426-C00404
    412
    Figure US20070093453A1-20070426-C00405
    413
    Figure US20070093453A1-20070426-C00406
    414
    Figure US20070093453A1-20070426-C00407
    415
    Figure US20070093453A1-20070426-C00408
    416
    Figure US20070093453A1-20070426-C00409
    417
    Figure US20070093453A1-20070426-C00410
    418
    Figure US20070093453A1-20070426-C00411
    419
    Figure US20070093453A1-20070426-C00412
    420
    Figure US20070093453A1-20070426-C00413
    421
    Figure US20070093453A1-20070426-C00414
    422
    Figure US20070093453A1-20070426-C00415
    423
    Figure US20070093453A1-20070426-C00416
    424
    Figure US20070093453A1-20070426-C00417
    425
    Figure US20070093453A1-20070426-C00418
    426
    Figure US20070093453A1-20070426-C00419
    427
    Figure US20070093453A1-20070426-C00420
    428
    Figure US20070093453A1-20070426-C00421
    429
    Figure US20070093453A1-20070426-C00422
  • TABLE 2e
    Figure US20070093453A1-20070426-C00423
    Ex.
    No. R5
    430
    Figure US20070093453A1-20070426-C00424
    431
    Figure US20070093453A1-20070426-C00425
    432
    Figure US20070093453A1-20070426-C00426
    433
    Figure US20070093453A1-20070426-C00427
    434
    Figure US20070093453A1-20070426-C00428
    435
    Figure US20070093453A1-20070426-C00429
    436
    Figure US20070093453A1-20070426-C00430
    437
    Figure US20070093453A1-20070426-C00431
    438
    Figure US20070093453A1-20070426-C00432
    439
    Figure US20070093453A1-20070426-C00433
    440
    Figure US20070093453A1-20070426-C00434
    441
    Figure US20070093453A1-20070426-C00435
    442
    Figure US20070093453A1-20070426-C00436
    443
    Figure US20070093453A1-20070426-C00437
    444
    Figure US20070093453A1-20070426-C00438
    445
    Figure US20070093453A1-20070426-C00439
    446
    Figure US20070093453A1-20070426-C00440
    447
    Figure US20070093453A1-20070426-C00441
    448
    Figure US20070093453A1-20070426-C00442
    449
    Figure US20070093453A1-20070426-C00443
    450
    Figure US20070093453A1-20070426-C00444
    451
    Figure US20070093453A1-20070426-C00445
    452
    Figure US20070093453A1-20070426-C00446
    453
    Figure US20070093453A1-20070426-C00447
    454
    Figure US20070093453A1-20070426-C00448
    455
    Figure US20070093453A1-20070426-C00449
    456
    Figure US20070093453A1-20070426-C00450
    457
    Figure US20070093453A1-20070426-C00451
    458
    Figure US20070093453A1-20070426-C00452
    459
    Figure US20070093453A1-20070426-C00453
  • TABLE 2f
    Figure US20070093453A1-20070426-C00454
    Ex.
    No. R2B
    460
    Figure US20070093453A1-20070426-C00455
    461
    Figure US20070093453A1-20070426-C00456
    462
    Figure US20070093453A1-20070426-C00457
    463
    Figure US20070093453A1-20070426-C00458
    464
    Figure US20070093453A1-20070426-C00459
    465
    Figure US20070093453A1-20070426-C00460
    466
    Figure US20070093453A1-20070426-C00461
    467
    Figure US20070093453A1-20070426-C00462
    468
    Figure US20070093453A1-20070426-C00463
    469
    Figure US20070093453A1-20070426-C00464
    470
    Figure US20070093453A1-20070426-C00465
    471
    Figure US20070093453A1-20070426-C00466
    472
    Figure US20070093453A1-20070426-C00467
    473
    Figure US20070093453A1-20070426-C00468
    474
    Figure US20070093453A1-20070426-C00469
    475
    Figure US20070093453A1-20070426-C00470
    476
    Figure US20070093453A1-20070426-C00471
    477
    Figure US20070093453A1-20070426-C00472
    478
    Figure US20070093453A1-20070426-C00473
    479
    Figure US20070093453A1-20070426-C00474
    480
    Figure US20070093453A1-20070426-C00475
    481
    Figure US20070093453A1-20070426-C00476
    482
    Figure US20070093453A1-20070426-C00477
    483
    Figure US20070093453A1-20070426-C00478
    484
    Figure US20070093453A1-20070426-C00479
    485
    Figure US20070093453A1-20070426-C00480
    486
    Figure US20070093453A1-20070426-C00481
    487
    Figure US20070093453A1-20070426-C00482
    488
    Figure US20070093453A1-20070426-C00483
    489
    Figure US20070093453A1-20070426-C00484
  • TABLE 2g
    Figure US20070093453A1-20070426-C00485
    Ex.
    No. R5
    490
    Figure US20070093453A1-20070426-C00486
    491
    Figure US20070093453A1-20070426-C00487
    492
    Figure US20070093453A1-20070426-C00488
    493
    Figure US20070093453A1-20070426-C00489
    494
    Figure US20070093453A1-20070426-C00490
    495
    Figure US20070093453A1-20070426-C00491
    496
    Figure US20070093453A1-20070426-C00492
    497
    Figure US20070093453A1-20070426-C00493
    498
    Figure US20070093453A1-20070426-C00494
    499
    Figure US20070093453A1-20070426-C00495
    500
    Figure US20070093453A1-20070426-C00496
    501
    Figure US20070093453A1-20070426-C00497
    502
    Figure US20070093453A1-20070426-C00498
    503
    Figure US20070093453A1-20070426-C00499
    504
    Figure US20070093453A1-20070426-C00500
    505
    Figure US20070093453A1-20070426-C00501
    506
    Figure US20070093453A1-20070426-C00502
    507
    Figure US20070093453A1-20070426-C00503
    508
    Figure US20070093453A1-20070426-C00504
    509
    Figure US20070093453A1-20070426-C00505
    510
    Figure US20070093453A1-20070426-C00506
    511
    Figure US20070093453A1-20070426-C00507
    512
    Figure US20070093453A1-20070426-C00508
    513
    Figure US20070093453A1-20070426-C00509
    514
    Figure US20070093453A1-20070426-C00510
    515
    Figure US20070093453A1-20070426-C00511
    516
    Figure US20070093453A1-20070426-C00512
    517
    Figure US20070093453A1-20070426-C00513
    518
    Figure US20070093453A1-20070426-C00514
    519
    Figure US20070093453A1-20070426-C00515
  • TABLE 3a
    Figure US20070093453A1-20070426-C00516
    Ex.
    No. R5
    730
    Figure US20070093453A1-20070426-C00517
    731
    Figure US20070093453A1-20070426-C00518
    732
    Figure US20070093453A1-20070426-C00519
    733
    Figure US20070093453A1-20070426-C00520
    734
    Figure US20070093453A1-20070426-C00521
    735
    Figure US20070093453A1-20070426-C00522
    736
    Figure US20070093453A1-20070426-C00523
    737
    Figure US20070093453A1-20070426-C00524
    738
    Figure US20070093453A1-20070426-C00525
    739
    Figure US20070093453A1-20070426-C00526
    740
    Figure US20070093453A1-20070426-C00527
    741
    Figure US20070093453A1-20070426-C00528
    742
    Figure US20070093453A1-20070426-C00529
    743
    Figure US20070093453A1-20070426-C00530
    744
    Figure US20070093453A1-20070426-C00531
    745
    Figure US20070093453A1-20070426-C00532
    746
    Figure US20070093453A1-20070426-C00533
    747
    Figure US20070093453A1-20070426-C00534
    748
    Figure US20070093453A1-20070426-C00535
    749
    Figure US20070093453A1-20070426-C00536
    750
    Figure US20070093453A1-20070426-C00537
  • TABLE 3b
    Figure US20070093453A1-20070426-C00538
    Ex.
    No. R5
    751
    Figure US20070093453A1-20070426-C00539
    752
    Figure US20070093453A1-20070426-C00540
    753
    Figure US20070093453A1-20070426-C00541
    754
    Figure US20070093453A1-20070426-C00542
    755
    Figure US20070093453A1-20070426-C00543
    756
    Figure US20070093453A1-20070426-C00544
    757
    Figure US20070093453A1-20070426-C00545
    758
    Figure US20070093453A1-20070426-C00546
    759
    Figure US20070093453A1-20070426-C00547
    760
    Figure US20070093453A1-20070426-C00548
    761
    Figure US20070093453A1-20070426-C00549
    762
    Figure US20070093453A1-20070426-C00550
    763
    Figure US20070093453A1-20070426-C00551
    764
    Figure US20070093453A1-20070426-C00552
    765
    Figure US20070093453A1-20070426-C00553
    766
    Figure US20070093453A1-20070426-C00554
    767
    Figure US20070093453A1-20070426-C00555
    768
    Figure US20070093453A1-20070426-C00556
    769
    Figure US20070093453A1-20070426-C00557
    770
    Figure US20070093453A1-20070426-C00558
    771
    Figure US20070093453A1-20070426-C00559
  • TABLE 3c
    Figure US20070093453A1-20070426-C00560
    Ex.
    No. R5
    772
    Figure US20070093453A1-20070426-C00561
    773
    Figure US20070093453A1-20070426-C00562
    774
    Figure US20070093453A1-20070426-C00563
    775
    Figure US20070093453A1-20070426-C00564
    776
    Figure US20070093453A1-20070426-C00565
    777
    Figure US20070093453A1-20070426-C00566
    778
    Figure US20070093453A1-20070426-C00567
    779
    Figure US20070093453A1-20070426-C00568
    780
    Figure US20070093453A1-20070426-C00569
    781
    Figure US20070093453A1-20070426-C00570
    782
    Figure US20070093453A1-20070426-C00571
    783
    Figure US20070093453A1-20070426-C00572
    784
    Figure US20070093453A1-20070426-C00573
    785
    Figure US20070093453A1-20070426-C00574
    786
    Figure US20070093453A1-20070426-C00575
    787
    Figure US20070093453A1-20070426-C00576
    788
    Figure US20070093453A1-20070426-C00577
    789
    Figure US20070093453A1-20070426-C00578
    790
    Figure US20070093453A1-20070426-C00579
    791
    Figure US20070093453A1-20070426-C00580
    792
    Figure US20070093453A1-20070426-C00581
  • TABLE 3d
    Figure US20070093453A1-20070426-C00582
    Ex.
    No. R5
    793
    Figure US20070093453A1-20070426-C00583
    794
    Figure US20070093453A1-20070426-C00584
    795
    Figure US20070093453A1-20070426-C00585
    796
    Figure US20070093453A1-20070426-C00586
    797
    Figure US20070093453A1-20070426-C00587
    798
    Figure US20070093453A1-20070426-C00588
    799
    Figure US20070093453A1-20070426-C00589
    800
    Figure US20070093453A1-20070426-C00590
    801
    Figure US20070093453A1-20070426-C00591
    802
    Figure US20070093453A1-20070426-C00592
    803
    Figure US20070093453A1-20070426-C00593
    804
    Figure US20070093453A1-20070426-C00594
    805
    Figure US20070093453A1-20070426-C00595
    806
    Figure US20070093453A1-20070426-C00596
    807
    Figure US20070093453A1-20070426-C00597
    808
    Figure US20070093453A1-20070426-C00598
    809
    Figure US20070093453A1-20070426-C00599
    810
    Figure US20070093453A1-20070426-C00600
    811
    Figure US20070093453A1-20070426-C00601
    812
    Figure US20070093453A1-20070426-C00602
    813
    Figure US20070093453A1-20070426-C00603
  • TABLE 3e
    Figure US20070093453A1-20070426-C00604
    Ex.
    No. R5
    814
    Figure US20070093453A1-20070426-C00605
    815
    Figure US20070093453A1-20070426-C00606
    816
    Figure US20070093453A1-20070426-C00607
    817
    Figure US20070093453A1-20070426-C00608
    818
    Figure US20070093453A1-20070426-C00609
    819
    Figure US20070093453A1-20070426-C00610
    820
    Figure US20070093453A1-20070426-C00611
    821
    Figure US20070093453A1-20070426-C00612
    822
    Figure US20070093453A1-20070426-C00613
    823
    Figure US20070093453A1-20070426-C00614
    824
    Figure US20070093453A1-20070426-C00615
    825
    Figure US20070093453A1-20070426-C00616
    826
    Figure US20070093453A1-20070426-C00617
    827
    Figure US20070093453A1-20070426-C00618
    828
    Figure US20070093453A1-20070426-C00619
    829
    Figure US20070093453A1-20070426-C00620
    830
    Figure US20070093453A1-20070426-C00621
    831
    Figure US20070093453A1-20070426-C00622
    832
    Figure US20070093453A1-20070426-C00623
    833
    Figure US20070093453A1-20070426-C00624
    834
    Figure US20070093453A1-20070426-C00625
  • TABLE 3f
    Figure US20070093453A1-20070426-C00626
    Ex.
    No. R5
    835
    Figure US20070093453A1-20070426-C00627
    836
    Figure US20070093453A1-20070426-C00628
    837
    Figure US20070093453A1-20070426-C00629
    838
    Figure US20070093453A1-20070426-C00630
    839
    Figure US20070093453A1-20070426-C00631
    840
    Figure US20070093453A1-20070426-C00632
    841
    Figure US20070093453A1-20070426-C00633
    842
    Figure US20070093453A1-20070426-C00634
    843
    Figure US20070093453A1-20070426-C00635
    844
    Figure US20070093453A1-20070426-C00636
    845
    Figure US20070093453A1-20070426-C00637
    846
    Figure US20070093453A1-20070426-C00638
    847
    Figure US20070093453A1-20070426-C00639
    848
    Figure US20070093453A1-20070426-C00640
    849
    Figure US20070093453A1-20070426-C00641
    850
    Figure US20070093453A1-20070426-C00642
    851
    Figure US20070093453A1-20070426-C00643
    852
    Figure US20070093453A1-20070426-C00644
    853
    Figure US20070093453A1-20070426-C00645
    854
    Figure US20070093453A1-20070426-C00646
    855
    Figure US20070093453A1-20070426-C00647
  • TABLE 3g
    Figure US20070093453A1-20070426-C00648
    Ex.
    No. R5
    856
    Figure US20070093453A1-20070426-C00649
    857
    Figure US20070093453A1-20070426-C00650
    858
    Figure US20070093453A1-20070426-C00651
    859
    Figure US20070093453A1-20070426-C00652
    860
    Figure US20070093453A1-20070426-C00653
    861
    Figure US20070093453A1-20070426-C00654
    862
    Figure US20070093453A1-20070426-C00655
    863
    Figure US20070093453A1-20070426-C00656
    864
    Figure US20070093453A1-20070426-C00657
    865
    Figure US20070093453A1-20070426-C00658
    866
    Figure US20070093453A1-20070426-C00659
    867
    Figure US20070093453A1-20070426-C00660
    868
    Figure US20070093453A1-20070426-C00661
    869
    Figure US20070093453A1-20070426-C00662
    870
    Figure US20070093453A1-20070426-C00663
    871
    Figure US20070093453A1-20070426-C00664
    872
    Figure US20070093453A1-20070426-C00665
    873
    Figure US20070093453A1-20070426-C00666
    874
    Figure US20070093453A1-20070426-C00667
    875
    Figure US20070093453A1-20070426-C00668
    876
    Figure US20070093453A1-20070426-C00669
  • TABLE 3h
    Figure US20070093453A1-20070426-C00670
    Ex.
    No. R5
    877
    Figure US20070093453A1-20070426-C00671
    878
    Figure US20070093453A1-20070426-C00672
    879
    Figure US20070093453A1-20070426-C00673
    880
    Figure US20070093453A1-20070426-C00674
    881
    Figure US20070093453A1-20070426-C00675
    882
    Figure US20070093453A1-20070426-C00676
    883
    Figure US20070093453A1-20070426-C00677
    884
    Figure US20070093453A1-20070426-C00678
    885
    Figure US20070093453A1-20070426-C00679
    886
    Figure US20070093453A1-20070426-C00680
    887
    Figure US20070093453A1-20070426-C00681
    888
    Figure US20070093453A1-20070426-C00682
    889
    Figure US20070093453A1-20070426-C00683
    890
    Figure US20070093453A1-20070426-C00684
    891
    Figure US20070093453A1-20070426-C00685
    892
    Figure US20070093453A1-20070426-C00686
    893
    Figure US20070093453A1-20070426-C00687
    894
    Figure US20070093453A1-20070426-C00688
    895
    Figure US20070093453A1-20070426-C00689
    896
    Figure US20070093453A1-20070426-C00690
    897
    Figure US20070093453A1-20070426-C00691
  • TABLE 3i
    Figure US20070093453A1-20070426-C00692
    Ex.
    No. R5
    898
    Figure US20070093453A1-20070426-C00693
    899
    Figure US20070093453A1-20070426-C00694
    900
    Figure US20070093453A1-20070426-C00695
    901
    Figure US20070093453A1-20070426-C00696
    902
    Figure US20070093453A1-20070426-C00697
    903
    Figure US20070093453A1-20070426-C00698
    904
    Figure US20070093453A1-20070426-C00699
    905
    Figure US20070093453A1-20070426-C00700
    906
    Figure US20070093453A1-20070426-C00701
    907
    Figure US20070093453A1-20070426-C00702
    908
    Figure US20070093453A1-20070426-C00703
    909
    Figure US20070093453A1-20070426-C00704
    910
    Figure US20070093453A1-20070426-C00705
    911
    Figure US20070093453A1-20070426-C00706
    912
    Figure US20070093453A1-20070426-C00707
    913
    Figure US20070093453A1-20070426-C00708
    914
    Figure US20070093453A1-20070426-C00709
    915
    Figure US20070093453A1-20070426-C00710
    916
    Figure US20070093453A1-20070426-C00711
    917
    Figure US20070093453A1-20070426-C00712
    918
    Figure US20070093453A1-20070426-C00713

    Stereoisomerism and Polymorphism
  • It is appreciated that compounds of the present invention having a chiral center may exist in and be isolated in optically active and racemic forms. Some compounds may exhibit polymorphism. It is to be understood that the present invention encompasses any racemic, optically-active, diastereomeric, polymorphic, or stereoisomeric form, or mixtures thereof, of a compound of the invention, which possess the useful properties described herein, it being well known in the art how to prepare optically active forms (for example, by resolution of the racemic form by recrystallization techniques, by synthesis from optically-active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase).
  • Examples of methods to obtain optically active materials are known in the art, and include at least the following.
      • i) physical separation of crystals—a technique whereby macroscopic crystals of the individual enantiomers are manually separated. This technique can be used if crystals of the separate enantiomers exist, i.e., the material is a conglomerate, and the crystals are visually distinct;
      • ii) simultaneous crystallization—a technique whereby the individual enantiomers are separately crystallized from a solution of the racemate, possible only if the latter is a conglomerate in the solid state;
      • iii) enzymatic resolutions—a technique whereby partial or complete separation of a racemate by virtue of differing rates of reaction for the enantiomers with an enzyme;
      • iv) enzymatic asymmetric synthesis—a synthetic technique whereby at least one step of the synthesis uses an enzymatic reaction to obtain an enantiomerically pure or enriched synthetic precursor of the desired enantiomer;
      • v) chemical asymmetric synthesis—a synthetic technique whereby the desired enantiomer is synthesized from an achiral precursor under conditions that produce asymmetry (i.e., chirality) in the product, which may be achieved using chiral catalysts or chiral auxiliaries;
      • vi) diastereomer separations—a technique whereby a racemic compound is reacted with an enantiomerically pure reagent (the chiral auxiliary) that converts the individual enantiomers to diastereomers. The resulting diastereomers are then separated by chromatography or crystallization by virtue of their now more distinct structural differences and the chiral auxiliary later removed to obtain the desired enantiomer;
      • vii) first- and second-order asymmetric transformations—a technique whereby diastereomers from the racemate equilibrate to yield a preponderance in solution of the diastereomer from the desired enantiomer or where preferential crystallization of the diastereomer from the desired enantiomer perturbs the equilibrium such that eventually in principle all the material is converted to the crystalline diastereomer from the desired enantiomer. The desired enantiomer is then released from the diastereomer;
      • viii) kinetic resolutions—this technique refers to the achievement of partial or complete resolution of a racemate (or of a further resolution of a partially resolved compound) by virtue of unequal reaction rates of the enantiomers with a chiral, non-racemic reagent or catalyst under kinetic conditions;
      • ix) enantiospecific synthesis from non-racemic precursors—a synthetic technique whereby the desired enantiomer is obtained from non-chiral starting materials and where the stereochemical integrity is not or is only minimally compromised over the course of the synthesis;
      • x) chiral liquid chromatography—a technique whereby the enantiomers of a racemate are separated in a liquid mobile phase by virtue of their differing interactions with a stationary phase. The stationary phase can be made of chiral material or the mobile phase can contain an additional chiral material to provoke the differing interactions;
      • xi) chiral gas chromatography—a technique whereby the racemate is volatilized and enantiomers are separated by virtue of their differing interactions in the gaseous mobile phase with a column containing a fixed non-racemic chiral adsorbent phase;
      • xii) extraction with chiral solvents—a technique whereby the enantiomers are separated by virtue of preferential dissolution of one enantiomer into a particular chiral solvent;
      • xiii) transport across chiral membranes—a technique whereby a racemate is placed in contact with a thin membrane barrier. The barrier typically separates two miscible fluids, one containing the racemate, and a driving force such as concentration or pressure differential causes preferential transport across the membrane barrier. Separation occurs as a result of the non-racemic chiral nature of the membrane which allows only one enantiomer of the racemate to pass through.
        Pharmaceutically Acceptable Salt Formulations
  • In cases where compounds are sufficiently basic or acidic to form stable nontoxic acid or base salts, administration of the compound as a pharmaceutically acceptable salt may be appropriate. The term “pharmaceutically acceptable salts” or “complexes” refers to salts or complexes that retain the desired biological activity of the compounds of the present invention and exhibit minimal undesired toxicological effects.
  • Examples of pharmaceutically acceptable salts are organic acid addition salts formed with acids, which form a physiological acceptable anion, for example, tosylate, methanesulfonate, acetate, citrate, malonate, tartarate, succinate, benzoate, ascorbate, α-ketoglutarate and α-glycerophosphate. Suitable inorganic salts may also be formed, including, sulfate, nitrate, bicarbonate and carbonate salts. Alternatively, the pharmaceutically acceptable salts may be made with sufficiently basic compounds such as an amine with a suitable acid affording a physiologically acceptable anion. Alkali metal (for example, sodium, potassium or lithium) or alkaline earth metal (for example calcium) salts of carboxylic acids can also be made.
  • Nonlimiting examples of such salts are (a) acid addition salts formed with inorganic acids (for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like), and salts formed with organic acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, naphthalenedisulfonic acid, and polygalacturonic acid; (b) base addition salts formed with metal cations such as zinc, calcium, bismuth, barium, magnesium, aluminum, copper, cobalt, nickel, cadmium, sodium, potassium, and the like, or with a cation formed from ammonia, N,N-dibenzylethylenediamine, D-glucosamine, tetraethylammonium, or ethylenediamine; or (c) combinations of (a) and (b); e.g., a zinc tannate salt or the like. Also included in this definition are pharmaceutically acceptable quaternary salts known by those skilled in the art, which specifically include the quaternary ammonium salt of the formula —NR+A−, wherein R is as defined above and A is a counterion, including chloride, bromide, iodide, —O-alkyl, toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carboxylate (such as benzoate, succinate, acetate, glycolate, maleate, malate, citrate, tartrate, ascorbate, benzoate, cinnamoate, mandeloate, benzyloate, and diphenylacetate).
  • Particular FDA-approved salts can be conveniently divided between anions and cations (Approved Drug Products with Therapeutic Equivalence Evaluations (1994) U.S. Department of Health and Human Services, Public Health Service, FDA, Center for Drug Evaluation and Research, Rockville, Md.; L. D. Bighley, S. M. Berge and D. C. Monkhouse, Salt Forms of Drugs and Absorption, Encyclopedia of Pharmaceutical Technology, Vol. 13, J. Swarbridk and J. Boylan, eds., Marcel Dekker, NY (1996)). Among the approved anions include aceglumate, acephyllinate, acetamidobenzoate, acetate, acetylasparaginate, acetylaspartate, adipate, aminosalicylate, anhydromethylenecitrate, ascorbate, aspartate, benzoate, besylate, bicarbonate, bisulfate, bitartrate, borate, bromide, camphorate, camsylate, carbonate, chloride, chlorophenoxyacetate, citrate, closylate, cromesilate, cyclamate, dehydrocholate, dihydrochloride, dimalonate, edentate, edisylate, estolate, esylate, ethylbromide, ethylsulfate, fendizoate, fosfatex, fumarate, gluceptate, gluconate, glucuronate, glutamate, glycerophosphate, glysinate, glycollylarsanilate, glycyrrhizate, hippurate, hemisulfate, hexylresorcinate, hybenzate, hydrobromide, hydrochloride, hydroiodide, hydroxybenzenesulfonate, hydroxybenzoate, hydroxynaphthoate, hyclate, iodide, isethionate, lactate, lactobionate, lysine, malate, maleate, mesylate, methylbromide, methyliodide, methylnitrate, methylsulfate, monophosadenine, mucate, napadisylate, napsylate, nicotinate, nitrate, oleate, orotate, oxalate, oxoglurate, pamoate, pantothenate, pectinate, phenylethylbarbiturate, phosphate, pacrate, plicrilix, polistirex, polygalacturonate, propionate, pyridoxylphosphate, saccharinate, salicylate, stearate, succinate, stearylsulfate, subacetate, succinate, sulfate, sulfosalicylate, tannate, tartrate, teprosilate, terephthalate, teoclate, thiocyante, tidiacicate, timonacicate, tosylate, triethiodide, triethiodide, undecanoate, and xinafoate. The approved cations include ammonium, benethamine, benzathine, betaine, calcium, carnitine, clemizole, chlorcyclizine, choline, dibenylamine, diethanolamine, diethylamine, diethylammonium diolamine, eglumine, erbumine, ethylenediamine, heptaminol, hydrabamine, hydroxyethylpyrrolidone, imadazole, meglumine, olamine, piperazine, 4-phenylcyclohexylamine, procaine, pyridoxine, triethanolamine, and tromethamine. Metallic cations include, aluminum, bismuth, calcium lithium, magnesium, neodymium, potassium, rubidium, sodium, strontium and zinc.
  • A particular class of salts can be classified as organic amine salts. The organic amines used to form these salts can be primary amines, secondary amines or tertiary amines, and the substituents on the amine can be straight, branched or cyclic groups, including ringed structures formed by attachment of two or more of the amine substituents. Of particular interest are organic amines that are substituted by one or more hydroxyalkyl groups, including alditol or carbohydrate moieties. These hydroxy substituted organic amines can be cyclic or acyclic, both classes of which can be primary amines, secondary amines or tertiary amines. A common class of cyclic hydroxy substituted amines are the amino sugars.
  • A particular class of acyclic organic amines are represented by the formula
    Figure US20070093453A1-20070426-C00714
    wherein Y and Z are independently hydrogen or lower alkyl or, may be taken together to form a ring, R is hydrogen, alkyl or hydroxyloweralkyl, and n is 1, 2, 3, 4, or 5. Among these hydroxylamines are a particular class characterized when n is 4. A representative of this group is meglumine, represented when Y is hydrogen, Z is methyl and R is methoxy. Meglumine is also known in the art as N-methylglucamine, N-MG, and 1-deoxy-1-(methylamino)-D-glucitol.
  • The invention also includes pharmaceutically acceptable prodrugs of the compounds. Pharmaceutically acceptable prodrugs refer to a compound that is metabolized, for example hydrolyzed or oxidized, in the host to form the compound of the present invention. Typical examples of prodrugs include compounds that have biologically labile protecting groups on a functional moiety of the active compound. Prodrugs include compounds that can be oxidized, reduced, aminated, deaminated, hydroxylated, dehydroxylated, hydrolyzed, dehydrolyzed, alkylated, dealkylated, acylated, deacylated, phosphorylated, dephosphorylated to produce the active compound.
  • Any of the compounds described herein can be administered as a prodrug to increase the activity, bioavailability, stability or otherwise alter the properties of the compound. A number of prodrug ligands are known. In general, alkylation, acylation or other lipophilic modification of the compound will increase the stability of the chalcone. Examples of substituent groups that can replace one or more hydrogens on the compound are alkyl, aryl, steroids, carbohydrates, including sugars, 1,2-diacylglycerol and alcohols. Many are described in R. Jones and N. Bischofberger, Antiviral Research, 27 (1995) 1-17. Any of these can be used in combination with the disclosed compounds to achieve a desired effect.
  • The compounds of the present invention can be used to treat any disorder that is mediated by VCAM-1. Inflammatory disorders that are mediated by VCAM-1 include, but are not limited to arthritis, asthma, dermatitis, psoriasis, cystic fibrosis, post transplantation late and chronic solid organ rejection, multiple sclerosis, systemic lupus erythematosis, inflammatory bowel diseases, autoimmune diabetes, diabetic retinopathy, diabetic nephropathy, diabetic vasculopathy, ocular inflammation, uveitis, rhinitis, ischemia-reperfusion injury, post-angioplasty restenosis, chronic obstructive pulmonary disease (COPD), glomerulonephritis, Graves disease, gastrointestinal allergies, conjunctivitis, atherosclerosis, coronary artery disease, angina and small artery disease.
  • The compounds disclosed herein can be used in the treatment of inflammatory skin diseases that are mediated by VCAM-1, and in particular, human endothelial disorders that are mediated by VCAM-1, which include, but are not limited to, psoriasis, dermatitis, including eczematous dermatitis, and Kaposi's sarcoma, as well as proliferative disorders of smooth muscle cells.
  • In yet another embodiment, the compounds disclosed herein can be selected to treat anti-inflammatory conditions that are mediated by mononuclear leucocytes.
  • In yet another embodiment, the compounds of the present invention can be selected for the prevention or treatment of tissue or organ transplant rejection. Treatment and prevention of organ or tissue transplant rejection includes, but are not limited to treatment of recipients of heart, lung, combined heart-lung, liver, kidney, pancreatic, skin, spleen, small bowel, or corneal transplants. They are also indicated for the prevention or treatment of graft-versus-host disease, which sometimes occurs following bone marrow transplantation.
  • In an alternative embodiment, the compounds described herein are useful in both the primary and adjunctive medical treatment of cardiovascular disease. The compounds are used in primary treatment of, for example, coronary disease states including atherosclerosis, post-angioplasty restenosis, coronary artery diseases and angina. The compounds can be administered to treat small vessel disease that is not treatable by surgery or angioplasty, or other vessel disease in which surgery is not an option. The compounds can also be used to stabilize patients prior to revascularization therapy.
  • In another aspect the invention the compounds can be used in compositions including pharmaceutical compositions for the treatment of diseases or disorders mediated by VCAM-1 wherein such compositions comprise a VCAM-1 inhibiting amount of a compound of the invention or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable carrier.
  • Another aspect of the invention provides a method for treating a disease or disorder mediated by VCAM-1 comprising administering to a patient a VCAM-1 inhibiting effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof.
  • In another aspect the invention provides a method for treating cardiovascular and inflammatory disorders in a patient in need thereof comprising administering to said patient an VCAM-1 inhibiting effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof.
  • In another aspect the invention provides a method and composition for treating asthma or arthritis in a patient in need thereof comprising administering to said patient an effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof.
  • Nonlimiting examples of arthritis include rheumatoid (such as soft-tissue rheumatism and non-articular rheumatism, fibromyalgia, fibrositis, muscular rheumatism, myofascil pain, humeral epicondylitis, frozen shoulder, Tietze's syndrome, fascitis, tendinitis, tenosynovitis, bursitis), juvenile chronic, spondyloarthropaties (ankylosing spondylitis), osteoarthritis, hyperuricemia and arthritis associated with acute gout, chronic gout and systemic lupus erythematosus.
  • Human endothelial disorders mediated by VCAM-1 include psoriasis, eczematous dermatitis, Kaposi's sarcoma, as well as proliferative disorders of smooth muscle cells.
  • In yet another embodiment, the compounds disclosed herein can be selected to treat anti-inflammatory conditions that are mediated by mononuclear leucocytes.
  • In one embodiment, the compounds of the present invention are selected for the prevention or treatment of tissue or organ transplant rejection. Treatment and prevention of organ or tissue transplant rejection includes, but are not limited to treatment of recipients of heart, lung, combined heart-lung, liver, kidney, pancreatic, skin, spleen, small bowel, or corneal transplants. The compounds can also be used in the prevention or treatment of graft-versus-host disease, such as sometimes occurs following bone marrow transplantation.
  • In an alternative embodiment, the compounds described herein are useful in both the primary and adjunctive medical treatment of cardiovascular disease. The compounds are used in primary treatment of, for example, coronary disease states including atherosclerosis, post-angioplasty restenosis, coronary artery diseases and angina. The compounds can be administered to treat small vessel disease that is not treatable by surgery or angioplasty, or other vessel disease in which surgery is not an option. The compounds can also be used to stabilize patients prior to revascularization therapy.
  • In addition to inhibiting the expression of VCAM-1, some of the compounds of the invention have the additional properties of inhibiting monocyte chemoattractant protein-1 (MCP-1) and/or smooth muscle proliferation. MCP-1 is a chemoattractant protein produced by endothelial cells, smooth muscle cells as well as macrophages. MCP-1 promotes integrin activation on endothelial cells thereby facilitating adhesion of leukocytes to VCAM-1, and MCP-1 is a chemoattractant for monocytes. MCP-1 has been shown to play a role in leukocyte recruitment in a number of chronic inflammatory diseases including atherosclerosis, rheumatoid arthritis, and asthma. Its expression is upregulated in these diseases and as such inhibition of MCP-1 expression represents a desirable property of anti-inflammatory therapeutics. Furthermore, smooth muscle cell hyperplasia and resulting tissue remodeling and decreased organ function is yet another characteristic of many chronic inflammatory diseases including atherosclerosis, chronic transplant rejection and asthma. Inhibition of the hyperproliferation of smooth muscle cells is another desirable property for therapeutic compounds.
  • Combination and Alternation Therapy
  • Any of the compounds disclosed herein can be administered in combination or alternation with a second biologically active agent to increase its effectiveness against the target disorder.
  • In combination therapy, effective dosages of two or more agents are administered together, whereas during alternation therapy an effective dosage of each agent is administered serially. The dosages will depend on absorption, inactivation and excretion rates of the drug as well as other factors known to those of skill in the art. It is to be noted that dosage values will also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens and schedules should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions.
  • The efficacy of a drug can be prolonged, augmented, or restored by administering the compound in combination or alternation with a second, and perhaps third, agent that induces a different biological pathway from that caused by the principle drug. Alternatively, the pharmacokinetics, biodistribution or other parameter of the drug can be altered by such combination or alternation therapy. In general, combination therapy is typically preferred over alternation therapy because it induces multiple simultaneous stresses on the condition.
  • Any method of alternation can be used that provides treatment to the patient. Nonlimiting examples of alternation patterns include 1-6 weeks of administration of an effective amount of one agent followed by 1-6 weeks of administration of an effective amount of a second agent. The alternation schedule can include periods of no treatment. Combination therapy generally includes the simultaneous administration of an effective ratio of dosages of two or more active agents.
  • Illustrative examples of specific agents that can be used in combination or alternation with the compounds of the present invention are described below in regard to asthma and arthritis. The agents set out below or others can alternatively be used to treat a host suffering from any of the other disorders listed above or that are mediated by VCAM-1 or MCP-1. Illustrative second biologically active agents for the treatment of cardiovascular disease are also provided below.
  • Asthma
  • In one embodiment, the compounds of the present invention are administered in combination or alternation with heparin, frusemide, ranitidine, an agent that effects respiratory function, such as DNAase, or immunosuppressive agents, IV gamma globulin, troleandomycin, cyclosporin (Neoral), methotrexate, FK-506, gold compounds such as Myochrysine (gold sodium thiomalate), platelet activating factor (PAF) antagonists such as thromboxane inhibitors, leukotriene-D4-receptor antagonists such as Accolate (zafirlukast), Ziflo (zileuton), leukotriene C1 or C2 antagonists and inhibitors of leukotriene synthesis such as zileuton for the treatment of asthma, or an inducible nitric oxide synthase inhibitor.
  • In another embodiment, the active compound is administered in combination or alternation with one or more other prophylactic agent(s). Examples of prophylactic agents that can be used in alternation or combination therapy include but are not limited to sodium cromoglycate, Intal (cromolyn sodium, Nasalcrom, Opticrom, Crolom, Ophthalmic Crolom), Tilade (nedocromil, nedocromil sodium) and ketotifen.
  • In another embodiment, the active compound is administered in combination or alternation with one or more other β2-adrenergic agonist(s) (β agonists). Examples of β2-adrenergic agonists (β agonists) that can be used in alternation or combination therapy include but are not limited to albuterol (salbutamol, Proventil, Ventolin), terbutaline, Maxair (pirbuterol), Serevent (salmeterol), epinephrine, metaproterenol (Alupent, Metaprel), Brethine (Bricanyl, Brethaire, terbutaline sulfate), Tornalate (bitolterol), isoprenaline, ipratropium bromide, bambuterol hydrochloride, bitolterol meslyate, broxaterol, carbuterol hydrochloride, clenbuterol hydrochloride, clorprenaline hydrochloride, efirmoterol fumarate, ephedra (source of alkaloids), ephedrine (ephedrine hydrochloride, ephedrine sulfate), etafedrine hydrochloride, ethylnoradrenaline hydrochloride, fenoterol hydrochloride, hexoprenaline hydrochloride, isoetharine hydrochloride, isoprenaline, mabuterol, methoxyphenamine hydrochloride, methylephedrine hydrochloride, orciprenaline sulphate, phenylephrine acid tartrate, phenylpropanolamine (phenylpropanolamine polistirex, phenylpropanolamine sulphate), pirbuterol acetate, procaterol hydrochloride, protokylol hydrochloride, psuedoephedrine (psuedoephedrine polixtirex, psuedoephedrine tannate, psuedoephedrine hydrochloride, psuedoephedrine sulphate), reproterol hydrochloride, rimiterol hydrobromide, ritodrine hydrochloride, salmeterol xinafoate, terbutaline sulphate, tretoquinol hydrate and tulobuterol hydrochloride.
  • In another embodiment, the active compound is administered in combination or alternation with one or more other corticosteriod(s). Examples of corticosteriods that can be used in alternation or combination therapy include but are not limited to glucocorticoids (GC), Aerobid (Aerobid-M, flunisolide), Azmacort (triamcinolone acetonide), Beclovet (Vanceril, beclomethasone dipropionate), Flovent (fluticasone), Pulmicort (budesonide), prednisolone, hydrocortisone, adrenaline, Alclometasone Dipropionate, Aldosterone, Amcinonide, Beclomethasone Dipropionate, Bendacort, Betamethasone (Betamethasone Acetate, Betamethasone Benzoate, Betamethasone Dipropionate, Betamethasone Sodium Phosphate, Betamethasone Valerate), Budesonide, Ciclomethasone, Ciprocinonide, Clobetasol Propionate, Clobetasone Butyrate, Clocortolone Pivalate, Cloprednol, Cortisone Acetate, Cortivazol, Deflazacort, Deoxycortone Acetate (Deoxycortone Pivalate), Deprodone, Desonide, Desoxymethasone, Dexamethasone (Dexamethasone Acetate, Dexamethasone Isonicotinate, Dexamethasone Phosphate, Dexamethasone Sodium Metasulphobenzoate, Dexamethasone Sodium Phosphate), Dichlorisone Acetate, Diflorasone Diacetate, Diflucortolone Valerate, Difluprednate, Domoprednate, Endrysone, Fluazacort, Fluclorolone Acetonide, Fludrocortisone Acetate, Flumethasone (Flumethasone Pivalate), Flunisolide, Fluocinolone Acetonide, Fluocinonide, Fluocortin Butyl, Fluocortolone (Fluocortolone Hexanoate, Fluocortolone Pivalate), Fluorometholone (Fluorometholone Acetate), Fluprednidene Acetate, Fluprednisolone, Flurandrenolone, Fluticasone Propionate, Formocortal, Halcinonide, Halobetasol Propionate, Halometasone, Hydrocortamate Hydrochloride, Hydrocortisone (Hydrocortisone Acetate, Hydrocortisone Butyrate, Hydrocortisone Cypionate, Hydrocortisone Hemisuccinate, Hydrocortisone Sodium Phosphate, Hydrocortisone Sodium Succinate, Hydrocortisone Valerate), Medrysone, Meprednisone, Methylprednisolone (Methylprednisolone Acetate, Methylprednisolone, Hemisuccinate, Methylprednisolone Sodium Succinate), Mometasone Furoate, Paramethasone Acetate, Prednicarbate, Prednisolamate Hydrochloride, Prednisolone (Prednisolone Acetate, Prednisolone Hemisuccinate, Prednisolone Hexanoate, Prednisolone Pivalate, Prednisolone Sodium Metasulphobenzoate, Prednisolone Sodium Phosphate, Prednisolone Sodium Succinate, Prednisolone Steaglate, Prednisolone Tebutate), Prednisone (Prednisone Acetate), Prednylidene, Procinonide, Rimexolone, Suprarenal Cortex, Tixocortol Pivalate, Triamcinolone (Triamcinolone Acetonide, Triamcinolone Diacetate and Triamcinolone Hexacetonide).
  • In another embodiment, the active compound is administered in combination or alternation with one or more other antihistimine(s) (H1 receptor antagonists). Examples of antihistimines (H1 receptor antagonists) that can be used in alternation or combination therapy include alkylamines, ethanolamines ethylenediamines, piperazines, piperidines or phenothiazines. Some non-limiting examples of antihistamines are Chlortrimeton (Teldrin, chlorpheniramine), Atrohist (brompheniramine, Bromarest, Bromfed, Dimetane), Actidil (triprolidine), Dexchlor (Poladex, Polaramine, dexchlorpheniramine), Benadryl (diphenhydramine), Tavist (clemastine), Dimetabs (dimenhydrinate, Dramamine, Marmine), PBZ (tripelennamine), pyrilamine, Marezine (cyclizine), Zyrtec (cetirizine), hydroxyzine, Antivert (meclizine, Bonine), Allegra (fexofenadine), Hismanal (astemizole), Claritin (loratadine), Seldane (terfenadine), Periactin (cyproheptadine), Nolamine (phenindamine, Nolahist), Phenameth (promethazine, Phenergan), Tacaryl (methdilazine) and Temaril (trimeprazine).
  • Alternatively, the compound of the present invention may be administered in combination or alternation with
    • (a) xanthines and methylxanthines, such as Theo-24 (theophylline, Slo-Phylline, Uniphyllin, Slobid, Theo-Dur), Choledyl (oxitriphylline), aminophylline;
    • (b) anticholinergic agents (antimuscarinic agents) such as belladonna alkaloids, Atrovent (ipratropium bromide), atropine, oxitropium bromide;
    • (c) phosphodiesterase inhibitors, including phosphodiesterase IV inhibitors such as zardaverine;
    • (d) calcium antagonists such as nifedipine;
    • (e) potassium activators such as cromakalim for the treatment of asthma;
    • (f) B-eotaxin chemokine receptor, CCR3, antagonists; or
    • (g) IL-5 antibodies, IL-13 antibodies, IL-13 antagonists, IL-4 receptor antagonists, and IgE antibodies.
      Arthritic Disorders
  • In one embodiment, the compound of the present invention can also be administered in combination or alternation with apazone, amitriptyline, chymopapain, collegenase, cyclobenzaprine, diazepam, fluoxetine, pyridoxine, ademetionine, diacerein, glucosamine, hylan (hyaluronate), misoprostol, paracetamol, superoxide dismutase mimics, IL-1 receptor antagonists, IL-2 receptor antagonists, IL-6 receptor antagonists, TNFα receptor antagonists, TNFα antibodies, P38 MAP Kinase inhibitors, tricyclic antidepressents, cJun kinase inhibitors or immunosuppressive agents, IV gamma globulin, troleandomycin, cyclosporin (Neoral), methotrexate, FK-506, gold compounds such as Myochrysine (gold sodium thiomalate), platelet activating factor (PAF) antagonists such as thromboxane inhibitors, MAPKAPK2 (MK2) Kinase inhibitors, CCR5 Receptor antagonists, Interleukin Converting Enzyme (ICE) inhibitors, IKB Kinase (IKK1, IKK2) inhibitors, TNF-α Convertase Enzyme (TACE) inhibitors, ICK Kinase inhibitors, Janus Kinase 3 (JAK3) inhibitors, Kinase insert domain-containing Receptor (KdR) Kinase inhibitors, and inducible nitric oxide synthase (iNOS) inhibitors.
  • In another embodiment, the active compound is administered in combination or alternation with one or more other corticosteriod(s). Examples of corticosteriods that can be used in alternation or combination therapy include but are not limited to glucocorticoids (GC), Aerobid (Aerobid-M, flunisolide), Azmacort (triamcinolone acetonide), Beclovet (Vanceril, beclomethasone dipropionate), Flovent (fluticasone), Pulmicort (budesonide), prednisolone, hydrocortisone, adrenaline, Alclometasone Dipropionate, Aldosterone, Amcinonide, Beclomethasone Dipropionate, Bendacort, Betamethasone (Betamethasone Acetate, Betamethasone Benzoate, Betamethasone Dipropionate, Betamethasone Sodium Phosphate, Betamethasone Valerate), Budesonide, Ciclomethasone, Ciprocinonide, Clobetasol Propionate, Clobetasone Butyrate, Clocortolone Pivalate, Cloprednol, Cortisone Acetate, Cortivazol, Deflazacort, Deoxycortone Acetate (Deoxycortone Pivalate), Deprodone, Desonide, Desoxymethasone, Dexamethasone (Dexamethasone Acetate, Dexamethasone Isonicotinate, Dexamethasone Phosphate, Dexamethasone Sodium Metasulphobenzoate, Dexamethasone Sodium Phosphate), Dichlorisone Acetate, Diflorasone Diacetate, Diflucortolone Valerate, Difluprednate, Domoprednate, Endrysone, Fluazacort, Fluclorolone Acetonide, Fludrocortisone Acetate, Flumethasone (Flumethasone Pivalate), Flunisolide, Fluocinolone Acetonide, Fluocinonide, Fluocortin Butyl, Fluocortolone (Fluocortolone Hexanoate, Fluocortolone Pivalate), Fluorometholone (Fluorometholone Acetate), Fluprednidene Acetate, Fluprednisolone, Flurandrenolone, Fluticasone Propionate, Formocortal, Halcinonide, Halobetasol Propionate, Halometasone, Hydrocortamate Hydrochloride, Hydrocortisone (Hydrocortisone Acetate, Hydrocortisone Butyrate, Hydrocortisone Cypionate, Hydrocortisone Hemisuccinate, Hydrocortisone Sodium Phosphate, Hydrocortisone Sodium Succinate, Hydrocortisone Valerate), Medrysone, Meprednisone, Methylprednisolone (Methylprednisolone Acetate, Methylprednisolone, Hemisuccinate, Methylprednisolone Sodium Succinate), Mometasone Furoate, Paramethasone Acetate, Prednicarbate, Prednisolamate Hydrochloride, Prednisolone (Prednisolone Acetate, Prednisolone Hemisuccinate, Prednisolone Hexanoate, Prednisolone Pivalate, Prednisolone Sodium Metasulphobenzoate, Prednisolone Sodium Phosphate, Prednisolone Sodium Succinate, Prednisolone Steaglate, Prednisolone Tebutate), Prednisone (Prednisone Acetate), Prednylidene, Procinonide, Rimexolone, Suprarenal Cortex, Tixocortol Pivalate, Triamcinolone (Triamcinolone Acetonide, Triamcinolone Diacetate and Triamcinolone Hexacetonide).
  • In another embodiment, the active compound is administered in combination or alternation with one or more other non-steroidal anti-inflammatory drug(s) (NSAIDS). Examples of NSAIDS that can be used in alternation or combination therapy are carboxylic acids, propionic acids, fenamates, acetic acids, pyrazolones, oxicans, alkanones, gold compounds and others that inhibit prostaglandin synthesis, preferably by selectively inhibiting cylcooxygenase-2 (COX-2). Some nonlimiting examples of COX-2 inhibitors are Celebrex (celecoxib), Bextra (valdecoxib), Dynastat (parecoxib sodium) and Vioxx (rofacoxib). Some non-limiting examples of NSAIDS are aspirin (acetylsalicylic acid), Dolobid (diflunisal), Disalcid (salsalate, salicylsalicylate), Trisilate (choline magnesium trisalicylate), sodium salicylate, Cuprimine (penicillamine), Tolectin (tolmetin), ibuprofen (Motrin, Advil, Nuprin Rufen), Naprosyn (naproxen, Anaprox, naproxen sodium), Nalfon (fenoprofen), Orudis (ketoprofen), Ansaid (flurbiprofen), Daypro (oxaprozin), meclofenamate (meclofanamic acid, Meclomen), mefenamic acid, Indocin (indomethacin), Clinoril (sulindac), tolmetin, Voltaren (diclofenac), Lodine (etodolac), ketorolac, Butazolidin (phenylbutazone), Tandearil (oxyphenbutazone), piroxicam (Feldene), Relafen (nabumetone), Myochrysine (gold sodium thiomalate), Ridaura (auranofin), Solganal (aurothioglucose), acetaminophen, colchicine, Zyloprim (allopurinol), Benemid (probenecid), Anturane (sufinpyrizone), Plaquenil (hydroxychloroquine), Aceclofenac, Acemetacin, Acetanilide, Actarit, Alclofenac, Alminoprofen, Aloxiprin, Aluminium Aspirin, Amfenac Sodium, Amidopyrine, Aminopropylone, Ammonium Salicylate, Ampiroxicam, Amyl Salicylate, Anirolac, Aspirin, Auranofin, Aurothioglucose, Aurotioprol, Azapropazone, Bendazac (Bendazac Lysine), Benorylate, Benoxaprofen, Benzpiperylone, Benzydamine, Hydrochloride, Bornyl Salicylate, Bromfenac Sodium, Bufexamac, Bumadizone Calcium, Butibufen Sodium, Capsaicin, Carbaspirin Calcium, Carprofen, Chlorthenoxazin, Choline Magnesium Trisalicylate, Choline Salicylate, Cinmetacin, Clofexamide, Clofezone, Clometacin, Clonixin, Cloracetadol, Cymene, Diacerein, Diclofenac (Diclofenac Diethylammonium Salt, Diclofenac Potassium, Diclofenac Sodium), Diethylamine Salicylate, Diethylsalicylamide, Difenpiramide, Diflunisal, Dipyrone, Droxicam, Epirizole, Etenzamide, Etersalate, Ethyl Salicylate, Etodolac, Etofenamate, Felbinac, Fenbufen, Fenclofenac, Fenoprofen Calcium, Fentiazac, Fepradinol, Feprazone, Floctafenine, Flufenamic, Flunoxaprofen, Flurbiprofen (Flurbiprofen Sodium), Fosfosal, Furprofen, Glafenine, Glucametacin, Glycol Salicylate, Gold Keratinate, Harpagophytum Procumbens, Ibufenac, Ibuprofen, Ibuproxam, Imidazole Salicylate, Indomethacin (Indomethacin Sodium), Indoprofen, Isamifazone, Isonixin, Isoxicam, Kebuzone, Ketoprofen, Ketorolac Trometamol, Lithium Salicylate, Lonazolac Calcium, Lomoxicam, Loxoprofen Sodium, Lysine Aspirin, Magnesium Salicylate, Meclofenamae Sodium, Mefenamic Acid, Meloxicam, Methyl Butetisalicylate, Methyl Gentisate, Methyl Salicylate, Metiazinic Acid, Metifenazone, Mofebutazone, Mofezolac, Morazone Hydrochloride, Morniflumate, Morpholine Salicylate, Nabumetone, Naproxen (Naproxen Sodium), Nifenazone, Niflumic Acid, Nimesulide, Oxametacin, Oxaprozin, Oxindanac, Oxyphenbutazone, Parsalmide, Phenybutazone, Phenyramidol Hydrochloride, Picenadol Hydrochloride, Picolamine Salicylate, Piketoprofen, Pirazolac, Piroxicam, Pirprofen, Pranoprofen, Pranosal, Proglumetacin Maleate, Proquazone, Protizinic Acid, Ramifenazone, Salacetamide, Salamidacetic Acid, Salicylamide, Salix, Salol, Salsalate, Sodium Aurothiomalate, Sodium Gentisate, Sodium Salicylate, Sodium Thiosalicylate, Sulindac, Superoxide Dismutase (Orgotein, Pegorgotein, Sudismase), Suprofen, Suxibuzone, Tenidap Sodium, Tenoxicam, Tetrydamine, Thurfyl Salicylate, Tiaprofenic, Tiaramide Hydrochloride, Tinoridine Hydrochloride, Tolfenamic Acid, Tometin Sodium, Triethanolamine Salicylate, Ufenamate, Zaltoprofen, Zidometacin and Zomepirac Sodium.
  • Cardiovascular Disease
  • Compounds useful for combining with the compounds of the present invention for the treatment of cardiovascular disease encompass a wide range of therapeutic compounds.
  • Ileal bile acid transporter (IBAT) inhibitors, for example, are useful in the present invention, and are disclosed in patent application no. PCT/US95/10863, herein incorporated by reference. More IBAT inhibitors are described in PCT/US97/04076, herein incorporated by reference. Still further IBAT inhibitors useful in the present invention are described in U.S. application Ser. No. 08/816,065, herein incorporated by reference. More IBAT inhibitor compounds useful in the present invention are described in WO 98/40375, and WO 00/38725, herein incorporated by reference. Additional IBAT inhibitor compounds useful in the present invention are described in U.S. application Ser. No. 08/816,065, herein incorporated by reference.
  • In another aspect, the second biologically active agent is a statin. Statins lower cholesterol by inhibiting of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, a key enzyme in the cholesterol biosynthetic pathway. The statins decrease liver cholesterol biosynthesis, which increases the production of LDL receptors thereby decreasing plasma total and LDL cholesterol (Grundy, S. M. New Engl. J. Med. 319, 24 (1988); Endo, A. J. Lipid Res. 33, 1569 (1992)). Depending on the agent and the dose used, statins may decrease plasma triglyceride levels and may increase HDLc. Currently the statins on the market are lovastatin (Merck), simvastatin (Merck), pravastatin (Sankyo and Squibb) and fluvastatin (Sandoz). A fifth statin, atorvastatin (Parke-Davis/Pfizer), is the most recent entrant into the statin market. Any of these statins or thers can be used in combination with the chalcones of the present invention.
  • MTP inhibitor compounds useful in the combinations and methods of the present invention comprise a wide variety of structures and functionalities. Some of the MTP inhibitor compounds of particular interest for use in the present invention are disclosed in WO 00/38725, the disclosure from which is incorporated by reference. Descriptions of these therapeutic compounds can be found in Science, 282, 23 Oct. 1998, pp. 751-754, herein incorporated by reference.
  • Cholesterol absorption antagonist compounds useful in the combinations and methods of the present invention comprise a wide variety of structures and functionalities. Some of the cholesterol absorption antagonist compounds of particular interest for use in the present invention are described in U.S. Pat. No. 5,767,115, herein incorporated by reference. Further cholesterol absorption antagonist compounds of particular interest for use in the present invention, and methods for making such cholesterol absorption antagonist compounds are described in U.S. Pat. No. 5,631,365, herein incorporated by reference.
  • A number of phytosterols suitable for the combination therapies of the present invention are described by Ling and Jones in “Dietary Phytosterols: A Review of Metabolism, Benefits and Side Effects,” Life Sciences, 57 (3), 195-206 (1995). Without limitation, some phytosterols of particular use in the combination of the present invention are Clofibrate, Fenofibrate, Ciprofibrate, Bezafibrate, Gemfibrozil. The structures of the foregoing compounds can be found in WO 00/38725.
  • Phytosterols are also referred to generally by Nes (Physiology and Biochemistry of Sterols, American Oil Chemists' Society, Champaign, Ill., 1991, Table 7-2). Especially preferred among the phytosterols for use in the combinations of the present invention are saturated phytosterols or stanols. Additional stanols are also described by Nes (Id.) and are useful in the combination of the present invention. In the combination of the present invention, the phytosterol preferably comprises a stanol. In one preferred embodiment the stanol is campestanol. In another preferred embodiment the stanol is cholestanol. In another preferred embodiment the stanol is clionastanol. In another preferred embodiment the stanol is coprostanol. In another preferred embodiment the stanol is 22,23-dihydrobrassicastanol. In another embodiment the stanol is epicholestanol. In another preferred embodiment the stanol is fucostanol. In another preferred embodiment the stanol is stigmastanol.
  • Another embodiment the present invention encompasses a therapeutic combination of a compound of the present invention and an HDLc elevating agent. In one aspect, the second HDLc elevating agent can be a CETP inhibitor. Individual CETP inhibitor compounds useful in the present invention are separately described in WO 00/38725, the disclosure of which is herein incorporated by reference. Other individual CETP inhibitor compounds useful in the present invention are separately described in WO 99/14174, EP818448, WO 99/15504, WO 99/14215, WO 98/04528, and WO 00/17166, the disclosures of which are herein incorporated by reference. Other individual CETP inhibitor compounds useful in the present invention are separately described in WO 00/18724, WO 00/18723, and WO 00/18721, the disclosures of which are herein incorporated by reference. Other individual CETP inhibitor compounds useful in the present invention are separately described in WO 98/35937 as well as U.S. Pat. Nos. 6,313,142, 6,310,075, 6,197,786, 6,147,090, 6,147,089, 6,140,343, and 6,140,343, the disclosures of which is herein incorporated by reference.
  • In another aspect, the second biologically active agent can be a fibric acid derivative. Fibric acid derivatives useful in the combinations and methods of the present invention comprise a wide variety of structures and functionalities which have been reported and published in the art.
  • The compounds of the present invention may also be used in combination or alternation therapy with PPAR agonists including PPARα/γ dual agonists, PPARα agonists, and PPARγ agonists.
  • In another embodiment the present invention encompasses a therapeutic combination of a compound of the present invention and an antihypertensive agent. Hypertension is defined as persistently high blood pressure. In another embodiment, the chalcone is administered in combination with an ACE inhibitor, a beta andrenergic blocker, alpha andrenergic blocker, angiotensin II receptor antagonist, vasodilator and diuretic.
  • Pharmaceutical Compositions
  • Any host organism, including a patient, mammal, and specifically a human, suffering from any of the above-described conditions can be treated by the administration of a composition comprising an effective amount of the compound of the invention or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier or diluent.
  • The composition can be administered in any desired manner, including oral, topical, parenteral, intravenous, intradermal, intra-articular, intra-synovial, intrathecal, intra-arterial, intracardiac, intramuscular, subcutaneous, intraorbital, intracapsular, intraspinal, intrasternal, topical, transdermal patch, via rectal, vaginal or urethral suppository, peritoneal, percutaneous, nasal spray, surgical implant, internal surgical paint, infusion pump, or via catheter. In one embodiment, the agent and carrier are administered in a slow release formulation such as an implant, bolus, microparticle, microsphere, nanoparticle or nanosphere. For standard information on pharmaceutical formulations, see Ansel, et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, Sixth Edition, Williams & Wilkins (1995).
  • An effective dose for any of the herein described conditions can be readily determined by the use of conventional techniques and by observing results obtained under analogous circumstances. In determining the effective dose, a number of factors are considered including, but not limited to: the species of patient; its size, age, and general health; the specific disease involved; the degree of involvement or the severity of the disease; the response of the individual patient; the particular compound administered; the mode of administration; the bioavailability characteristics of the preparation administered; the dose regimen selected; and the use of concomitant medication. Typical systemic dosages for all of the herein described conditions are those ranging from 0.1 mg/kg to 500 mg/kg of body weight per day as a single daily dose or divided daily doses. Preferred dosages for the described conditions range from 5-1500 mg per day. A more particularly preferred dosage for the desired conditions ranges from 25-750 mg per day. Typical dosages for topical application are those ranging from 0.001 to 100% by weight of the active compound.
  • The compound is administered for a sufficient time period to alleviate the undesired symptoms and the clinical signs associated with the condition being treated.
  • The active compound is included in the pharmaceutically acceptable carrier or diluent in an amount sufficient to deliver to a patient a therapeutic amount of compound in vivo in the absence of serious toxic effects.
  • The concentration of active compound in the drug composition will depend on absorption, inactivation, and excretion rates of the drug as well as other factors known to those of skill in the art. It is to be noted that dosage values will also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that the dosage ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed composition. The active ingredient may be administered at once, or may be divided into a number of smaller doses to be administered at varying intervals of time.
  • A preferred mode of administration of the active compound for systemic delivery is oral. Oral compositions will generally include an inert diluent or an edible carrier. They may be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches or capsules. Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition.
  • The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.
  • When the dosage unit form is a capsule, it can contain, in addition to material of the above type, a liquid carrier such as a fatty oil. In addition, dosage unit forms can contain various other materials which modify the physical form of the dosage unit, for example, coatings of sugar, shellac, or other enteric agents.
  • The compound or its salts can be administered as a component of an elixir, suspension, syrup, wafer, chewing gum or the like. A syrup may contain, in addition to the active compounds, sucrose as a sweetening agent and certain preservatives, dyes and colorings and flavors.
  • The compound can also be mixed with other active materials that do not impair the desired action, or with materials that supplement the desired action. The compounds can also be administered in combination with nonsteroidal antiinflammatories such as ibuprofen, indomethacin, fenoprofen, mefenamic acid, flufenamic acid, sulindac. The compound can also be administered with corticosteriods.
  • Solutions or suspensions used for parenteral, intradermal, subcutaneous, or topical application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose. pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide. The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.
  • If administered intravenously, preferred carriers are physiological saline, bacteriostatic water, Cremophor EL™ (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS).
  • In a preferred embodiment, the active compounds are prepared with carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art. The materials can also be obtained commercially from Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions (including liposomes targeted to infected cells with monoclonal antibodies to viral antigens) are also preferred as pharmaceutically acceptable carriers. These may be prepared according to methods known to those skilled in the art, for example, as described in U.S. Pat. No. 4,522,811 (which is incorporated herein by reference in its entirety). For example, liposome formulations may be prepared by dissolving appropriate lipid(s) (such as stearoyl phosphatidyl ethanolamine, stearoyl phosphatidyl choline, arachadoyl phosphatidyl choline, and cholesterol) in an inorganic solvent that is then evaporated, leaving behind a thin film of dried lipid on the surface of the container. An aqueous solution of the compound is then introduced into the container. The container is then swirled by hand to free lipid material from the sides of the container and to disperse lipid aggregates, thereby forming the liposomal suspension.
  • Suitable vehicles or carriers for topical application can be prepared by conventional techniques, such as lotions, suspensions, ointments, creams, gels, tinctures, sprays, powders, pastes, slow-release transdermal patches, suppositories for application to rectal, vaginal, nasal or oral mucosa. In addition to the other materials listed above for systemic administration, thickening agents, emollients and stabilizers can be used to prepare topical compositions. Examples of thickening agents include petrolatum, beeswax, xanthan gum, or polyethylene, humectants such as sorbitol, emollients such as mineral oil, lanolin and its derivatives, or squalene.
  • Any of the compounds described herein for combination or alternation therapy can be administered as any derivative that upon administration to the recipient, is capable of providing directly or indirectly, the parent compound, or that exhibits activity itself. Nonlimiting examples are the pharmaceutically acceptable salts (alternatively referred to as “physiologically acceptable salts”), and a compound which has been alkylated or acylated at an appropriate position. The modifications can affect the biological activity of the compound, in some cases increasing the activity over the parent compound. This can easily be assessed by preparing the derivative and testing its anti-inflammatory activity according to known methods.
  • Biological Activity of Active Compounds
  • The ability of a compound described herein to inhibit the expression of VCAM-1 or in the treatment of diseases in a host can be assessed using any known method, including that described in detail below.
  • In Vitro VCAM-1 Assay
  • Cell Culture and compound dosing: Cultured primary human aortic (HAEC) or pulmonary (HPAEC) endothelial cells were obtained from Clonetics, Inc., and were used below passage 9. Cells were seeded in 96 well plates such that they would reach 90-95% confluency by the following day. On the following day the cells were stimulated with TNF-α (1 ng/ml) in the presence or absence of compounds dissolved in DMSO such that the final concentration of DMSO is 0.25% or less. To establish a dose curve for each compound, four concentrations in 2- to 5-fold increments were used. Cells were exposed to TNF-α and compounds for approximately 16 hours. The next day the cells were examined under microscope to score for visual signs of toxicity or cell stress.
  • Following 16 hr exposure to TNF-α and compound the media was discarded and the cells were washed once with Hanks Balanced Salt Solution (HBSS)/Phosphate buffered saline (PBS) (1:1). Primary antibodies against VCAM-1 (0.25 μg/ml in HBSS/PBS+5% FBS) were added and incubated for 30-60 minutes at 37° C. Cells were washed with HBSS/PBS three times, and secondary antibody Horse Radish Peroxidase (HRP)-conjugated goat anti-mouse IgG (1:500 in HBSS/PBS+5% FBS) were added and incubated for 30 minutes at 37° C. Cells were washed with HBSS/PBS four time and TMB substrate were added and incubated at room temperature in the dark until there was adequate development of blue color. The length of time of incubation was typically 5-15 minutes. 2N sulfuric acid was added to stop the color development and the data was collected by reading the absorbance on a BioRad ELISA plate reader at OD 450 nm. The results are expressed as IC50 values (the concentration (micromolar) of compound required to inhibit 50% of the maximal response of the control sample stimulated by TNF-α only). Compounds exhibiting IC50's of less than 5 micromolar are tabulated in Biological Table 1.
    Biological TABLE 1
    VCAM-1
    Example IC50
    Number (μM)
    1 <5
    2 <5
    3 <5
    4 >10
    5 <5
    6 <5
    7 <5
    8 <5
    9 <10
    10 <10
    11 <5
    12 <10
    13 >10
    14 <5
    15 <5
    16 <5
    17 <10
    18 <10
    19 <5
    20 <5
    21 <10
    22 >10
    23 <5
    24 <5
    25 <5
    26 >10
    27 <10
    28 <10
    29 <5
    30 <10
    31 <10
    32 <5
    33 >10
    34 >10
    35 <5
    36 <5
    37 <5
    38 <5
    39 <5
    40 <5
    41 <5
    42 >10
    43 <5
    44 <5
    45 <5
    40 <5
    46 <5
    47 <5
    48 <5
    49 <5
    50 >10
    51 >10
    52 <5
    53 <5
    54 >5
    55 >10
    56 >10
    57 <5
  • Modifications and variations of the present invention relating to compounds and methods of treating diseases will be obvious to those skilled in the art from the foregoing detailed description of the invention. Such modifications and variations are intended to come within the scope of the appended claims.

Claims (37)

1. A compound of Formula I
Figure US20070093453A1-20070426-C00715
or its pharmaceutically acceptable salt, wherein:
R1 is selected from the group consisting of hydrogen, alkyl, lower alkyl, carbocyclic, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, acyl and heterocyclicalkyl, wherein all substituents may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, haloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, heteroaryl, —C(O)NR7R8, and —C(O)N(R2)2;
R2 is independently selected from the group consisting of alkyl, lower alkyl, carbocyclic, cycloalkyl, hydroxy, alkoxy, lower alkoxy, trialkylsilyloxy, cycloalkyloxy, cycloalkylalkoxy, heterocyclicoxy, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, acyl, alkoxycarbonyl, and heterocyclicalkyl, wherein all substituents may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, haloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, heteroaryl, —C(O)NR7R8, —NR1R2 and —C(O)N(R2)2;
R1 and R2 may be taken together to form a 4- to 12-membered saturated or unsaturated heterocyclic ring which can be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, haloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —C(O)NR7R8, and —C(O)N(R2)2;
R7 and R8 are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 4- to 12-membered monocyclic, bicylic, tricyclic or benzofused ring, which may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, haloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —C(O)NR7R8, and —C(O)N(R2)2;
R3 and R4 are independently selected from hydroxy, alkoxy, lower alkoxy, —(O(CH2)2)1-3—O-lower alkyl, cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy, —OC(R1)2C(O)N(R2)2, and —OC(R1)2C(O)NR7R8, wherein all substituents may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, haloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —C(O)NR7R8, and —C(O)N(R2)2;
R5 is selected from the group consisting of a carbon-carbon linked heteroaryl and a carbon-carbon linked heterocyclic, which may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, haloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —C(O)NR7R8, and —C(O)N(R2)2;
with the proviso that when R1 is hydrogen and R2 is 2-methyl propanoyl, then R5 cannot be 5-benzo[b]thien-2-yl.
2. The compound of claim 1 or its pharmaceutically acceptable salt, wherein:
R1 is selected from the group consisting of hydrogen, alkyl, and lower alkyl, wherein all substituents may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, haloalkyl, heterocyclic, —NR7R8, alkoxy, carboxy, carboxyalkyl, alkoxycarbonyl and heteroaryl;
R2 is independently selected from the group consisting of alkyl, lower alkyl, alkoxy, lower alkoxy, heteroaryl, heterocyclic, heteroarylalkyl, and heterocyclicalkyl, wherein all substituents may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, haloalkyl, heterocyclic, —NR7R8, alkoxy, carboxy, carboxyalkyl, alkoxycarbonyl and heteroaryl;
R1 and R2 may be taken together to form a 5- to 7-membered saturated or unsaturated heterocyclic ring which can be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, haloalkyl, heterocyclic, —NR7R8, alkoxy, carboxy, carboxyalkyl and alkoxycarbonyl;
R7 and R8 are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 5- to 10-membered monocyclic, bicylic or benzofused ring, which may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, haloalkyl, heterocyclic, —NR7R8, alkoxy, carboxy, carboxyalkyl and alkoxycarbonyl;
R3 and R4 are independently selected from hydroxy, alkoxy, lower alkoxy, —(O(CH2)2)1-3—O-lower alkyl, haloalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy, —OC(R1)2C(O)N(R2)2, and —OC(R1)2C(O)NR7R8, wherein all substituents may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, hydroxy, hydroxyalkyl, heterocyclic, —NR7R8, alkoxy, —C(O)NR7R8, and —C(O)N(R2)2;
R5 is selected from the group consisting of a carbon-carbon linked heteroaryl and a carbon-carbon linked heterocyclic, which may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, haloalkyl, heterocyclic, —NR7R8 and alkoxy.
3. The compound of claim 1 or its pharmaceutically acceptable salt, wherein:
R1 is selected from the group consisting of hydrogen and lower alkyl;
R2 is independently selected from the group consisting of lower alkyl, lower alkoxy, heteroaryl, heterocyclic, heteroarylalkyl, and heterocyclicalkyl, wherein all substituents may be optionally substituted by one or more selected from the group consisting of halo, lower alkyl, haloalkyl, heterocyclic, —NR7R8 and carboxy;
R1 and R2 may be taken together to form a 5- to 6-membered heterocyclic saturated ring which can be optionally substituted by one or more selected from the group consisting of halo, lower alkyl and carboxy;
R7 and R8 are independently selected from the group consisting of alkyl and alkenyl, and linked together forming a 5- to 7-membered monocyclic ring, which may be optionally substituted by one or more selected from the group consisting of halo, lower alkyl, haloalkyl, heterocyclic and carboxy;
R3 and R4 are independently selected from hydroxy, lower alkoxy, —(O(CH2)2)1-3—O-lower alkyl, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy, —OC(R1)2C(O)N(R2)2, and —OC(R1)2C(O)NR7R8, wherein all substituents may be optionally substituted by one or more selected from the group consisting of hydroxy, hydroxyalkyl, heterocyclic, —NR7R8, —C(O)NR7R8, and —C(O)N(R2)2;
R5 is selected from the group consisting of a carbon-carbon linked heteroaryl and a carbon-carbon linked heterocyclic, which may be optionally substituted by one or more lower alkyl.
4. The compound of claim 1 or its pharmaceutically acceptable salt, wherein:
R1 is hydrogen;
R2 is independently selected from the group consisting of lower alkyl, heteroaryl, heteroarylalkyl, and heterocyclicalkyl, wherein all substituents may be optionally substituted by one or more selected from the group consisting of halo and lower alkyl;
R1 and R2 may be taken together to form a 5- to 6-membered heterocyclic saturated ring;
R7 and R8 are independently alkyl and linked together forming a 5- to 7-membered saturated monocyclic ring;
R3 and R4 are independently selected from hydroxy, lower alkoxy and heterocyclic lower alkoxy;
R5 is selected from the group consisting of a carbon-carbon linked heteroaryl and a carbon-carbon linked heterocyclic, which may be optionally substituted by one or more lower alkyl.
5. The compound of claim 1 or its pharmaceutically acceptable salt, wherein:
R1 is hydrogen;
R2 is independently selected from the group consisting of lower alkyl, heteroaryl, heteroarylalkyl, and heterocyclicalkyl, wherein all substituents may be optionally substituted by one or more selected from the group consisting of halo and lower alkyl;
R3 and R4 are independently selected from lower alkoxy and heterocyclic lower alkoxy;
R5 is a carbon-carbon linked heteroaryl, which may be optionally substituted by one or more lower alkyl.
6. The compound of claim 1 or its pharmaceutically acceptable salt, wherein the compound is selected from the group consisting of:
4-[3E-(2,4-Dimethoxy-5-thien-2-yl-phenyl)acryloyl]-N-(5-methylisoxazol-3-yl)benzenesulfonamide;
3E-(2,4-Dimethoxy-5-thien-2-ylphenyl)acryloyl]-N-(5-methylisoxazol-3-yl)benzenesulfonamide sodium salt;
4-[3E-(2,4-Dimethoxy-5-thien-2-ylphenyl)acryloyl]-N-pyrimidin-2-ylbenzenesulfonamide;
4-[3E-(2,4-Dimethoxy-5-thien-2-ylphenyl)acryloyl]-N-(1-H-tetrazol-5-yl)benzenesulfonamide;
4-[3E-(2,4-Dimethoxy-5-thien-2-ylphenyl)acryloyl]-N-pyridin-2-ylbenzenesulfonamide;
4-[3E-(2,4-Dimethoxy-5-thien-2-ylphenyl)acryloyl]-N-(1H-pyrazol-3-yl)benzenesulfonamide;
4-[3E-(2,4-Dimethoxy-5-thien-2-ylphenyl)acryloyl]-N-isoxazol-3-ylbenzenesulfonamide;
4-[3E-(2,4-Dimethoxy-5-thien-2-ylphenyl)acryloyl]-N-thiazol-2-ylbenzenesulfonamide;
4-[3E-(2,4-Dimethoxy-5-thien-2-ylphenyl)acryloyl]-N-(3-methylisoxazol-5-ylbenzenesulfonamide;
N-(5-Chloropyridin-2-yl)-4-[3E-(2,4-dimethoxy-5-thien-2-ylphenyl)acryloyl]benzenesulfonamide;
4-[3E-(2,4-Dimethoxy-5-thien-2-ylphenyl)acryloyl]-N-(5-fluoropyridin-2-yl)benzenesulfonamide;
4-[3E-(2,4-Dimethoxy-5-thien-2-ylphenyl)acryloyl]-N-(5-trifluoromethylpyridin-2-yl)benzenesulfonamide;
4-{3E-[2-(3-Hydroxy-2-hydroxymethylpropoxy)-4-methoxy-5-thien-2-ylphenyl]acryloyl}-N-(5-methylisoxazol-3-yl)benzenesulfonamide;
4-{3E-[4-Methoxy-2-(2-morpholin-4-yl-ethoxy)-5-thien-2-ylphenyl]acryloyl}-N-(5-methyl-isoxazol-3-yl)benzenesulfonamide hydrochloride;
4-{3E-[2,4-Dimethoxy-5-(1-methyl-1H-indol-2-yl)phenyl]acryloyl}-N-(5-methylisoxazol-3-yl)benzenesulfonamide;
4-{3E-[2,4-Dimethoxy-5-(1-methyl-1H-indol-2-yl)phenyl]acryloyl}-N-(5-methylisoxazol-3-yl)benzenesulfonamide sodium salt;
4-{3E-[2,4-Dimethoxy-5-(1-methyl-1H-indol-2-yl)phenyl]acryloyl}-N-pyridin-3-ylmethyl-benzenesulfonamide;
4-{3E-[2,4-Dimethoxy-5-(1-methyl-1H-indol-2-yl)phenyl]acryloyl}-N-(2-morpholin-4-yl-ethyl)benzenesulfonamide;
4-[3E-(2,4-Dimethoxy-5-thien-2-ylphenyl)acryloyl]-N-pyridin-3-ylmethylbenzenesulfonamide
4-[3E-(2,4-Dimethoxy-5-thien-2-ylphenyl)acryloyl]-N-(2-morpholin-4-yl-ethyl)benzenesulfonamide;
3E-(2,4-Dimethoxy-5-thien-2-ylphenyl)-1-[4-(4-methylpiperazine-1-sulfonyl)phenyl]propenone;
4-[3E-(2,4-Dimethoxy-5-thien-2-ylphenyl)acryloyl]-N-piperidin-1-ylbenzenesulfonamide;
4-[3E-(2,4-Dimethoxy-5-thien-2-ylphenyl)acryloyl]-N-(3-imidazol-1-ylpropyl)benzenesulfonamide;
4-[3E-(2,4-Dimethoxy-5-thien-2-ylphenyl)acryloyl]-N-(2,2,2-trifluoroethyl)benzenesulfonamide;
4-[3E-(2,4-Dimethoxy-5-thien-2-ylphenyl)acryloyl]-N-(2,2,2-trifluoroethyl)benzenesulfonamide sodium salt;
{4-[3E-(2,4-Dimethoxy-5-thien-2-ylphenyl)acryloyl]benzenesulfonylamino}acetic acid;
2-{4-[3E-(2,4-Dimethoxy-5-thien-2-yl-phenyl)acryloyl]benzenesulfonylamino}-2-methylpropionic acid;
1-{4-[3E-(2,4-Dimethoxy-5-thien-2-ylphenyl)acryloyl]benzenesulfonyl}piperidine-2-carboxylic acid;
4-{3E-[2,4-Dimethoxy-5-(1-methyl-1H-indol-2-yl)phenyl]acryloyl}-N-methyl-benzenesulfonamide;
4-{3E-[2,4-Dimethoxy-5-(1-methyl-1H-indol-2-yl)phenyl]acryloyl}-N-methoxybenzenesulfonamide;
4-{3E-[2,4-Dimethoxy-5-(1-methyl-1H-indol-2-yl)phenyl]acryloyl}-N,N-dimethylbenzenesulfonamide;
4-{3E-[5-(1H-Indol-2-yl)-2,4-dimethoxyphenyl]acryloyl}-N,N-dimethylbenzenesulfonamide;
4-{3E-[2,4-Dimethoxy-5-(1-methyl-1H-indol-2-yl)phenyl]acryloyl}-N-(tert-butyldimethylsiloxy)benzenesulfonamide;
4-{3E-[2,4-Dimethoxy-5-(1-methyl-1H-indol-2-yl)phenyl]-acryloyl}-N-hydroxybenzenesulfonamide;
4-{3E-[2,4-Dimethoxy-5-(1-methyl-1H-pyrol-2-yl)phenyl]acryloyl}-N-(5-methyl-isoxazol-3-yl)benzenesulfonamide;
4-{3E-[2-(3-Hydroxy-propoxy)-4-methoxy-5-thien-2-ylphenyl]acryloyl}-N-(5-methylisoxazol-3-yl)benzenesulfonamide;
4-{3E-[2,4-Dimethoxy-5-(1-methyl-1H-pyrol-2-yl)phenyl]acryloyl}-N-(5-methyl-isoxazol-3-yl)benzenesulfonamide;
N-(3-Imidazol-1-yl-propyl)-4-{3E-[5-(1H-indol-2-yl)-2,4-dimethoxy-phenyl]acryloyl}benzenesulfonamide;
(4-{3E-[5-(1H-Indol-2-yl)-2,4-dimethoxyphenyl]acryloyl}benzenesulfonylamino)acetic acid; and
4-{3E-[5-(1H-Indol-2-yl)-2,4-dimethoxyphenyl]acryloyl}-N-pyridin-2-ylbenzenesulfonamide.
7. A compound of Formula III
Figure US20070093453A1-20070426-C00716
or its pharmaceutically acceptable salt, wherein:
R1 is selected from the group consisting of hydrogen, alkyl, lower alkyl, carbocyclic, cycloalkyl, alkoxy, lower alkoxy, cycloalkyloxy, cycloalkylalkoxy, heterocyclicoxy, aryloxy, heteroaryloxy, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, —NR7R8, —NHR2, —N(R2)2, acyl and heterocyclicalkyl, wherein all substituents may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, haloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR7R8, —NHR2, —N(R2)2, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, heteroaryl, —C(O)NR7R8, and —C(O)N(R2)2;
R2 is independently selected from the group consisting of hydrogen, alkyl, lower alkyl, carbocyclic, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, acyl, alkoxycarbonyl, and heterocyclicalkyl, wherein all substituents may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, haloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, heteroaryl, —C(O)NR7R8, —NR1R2 and —C(O)N(R2)2;
R7 and R8 are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 4- to 12-membered monocyclic, bicylic, tricyclic or benzofused ring, which may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, haloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —C(O)NR7R8, and —C(O)N(R2)2;
R3, R4 and R5 are independently selected from hydrogen, hydroxy, alkoxy, lower alkoxy, —(O(CH2)2)1-3—O-lower alkyl, cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclic, heteroaryl, NR7R8, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy, —OC(R1)2C(O)N(R2)2, and —OC(R1)2C(O)NR7R8, wherein all substituents may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, haloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, N-linked heteroaryl, —NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —C(O)NR7R8, and —C(O)N(R2)2;
with the proviso that at least one of R3, R4 or R5 is an N-linked heteroaryl or —NR7R8.
8. The compound of claim 7 or its pharmaceutically acceptable salt, wherein:
R1 is selected from the group consisting of hydrogen, alkyl, lower alkyl, alkoxy, lower alkoxy, cycloalkyloxy, cycloalkylalkoxy, heterocyclicoxy, aryloxy, heteroaryloxy, heterocyclic, heteroarylalkyl, acyl and heterocyclicalkyl, wherein all substituents may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, haloalkyl, heterocyclic, amino, aminoalkyl, —NR7R8, —NHR2, —N(R2)2, alkoxy, carboxy, carboxyalkyl, alkoxycarbonyl, and heteroaryl;
R2 is independently selected from the group consisting of alkyl, lower alkyl, heteroaryl, heterocyclic, heteroarylalkyl, acyl and heterocyclicalkyl, wherein all substituents may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, haloalkyl, heterocyclic, —NR7R8, alkoxy, carboxy, carboxyalkyl, alkoxycarbonyl and heteroaryl;
R7 and R8 are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 5- to 10-membered monocyclic, bicylic or benzofused ring, which may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, haloalkyl, heterocyclic, —NR7R8, alkoxy, carboxy, carboxyalkyl and alkoxycarbonyl;
R3, R4 and R5 are independently selected from hydrogen, hydroxy, alkoxy, lower alkoxy, —(O(CH2)2)1-3—O-lower alkyl, haloalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclic, heteroaryl, NR7R8, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy, —OC(R1)2C(O)N(R2)2, and —OC(R1)2C(O)NR7R8, wherein all substituents may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, hydroxy, hydroxyalkyl, heterocyclic, N-linked heteroaryl, —NR7R8, alkoxy, —C(O)NR7R8, and —C(O)N(R)2;
with the proviso that at least one of R3, R4 or R5 is an N-linked heteroaryl or —NR7R8.
9. The compound of claim 7 or its pharmaceutically acceptable salt, wherein:
R1 is selected from the group consisting of alkyl, lower alkyl, alkoxy, and lower alkoxy, wherein all substituents may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, amino, —NR7R8, —NHR2, —N(R2)2, aminoalkyl, alkoxy, carboxy, carboxyalkyl, alkoxycarbonyl, and heteroaryl;
R2 is independently selected from the group consisting of lower alkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all substituents may be optionally substituted by one or more selected from the group consisting of halo, lower alkyl, haloalkyl, heterocyclic, —NR7R8 and carboxy;
R7 and R8 are independently selected from the group consisting of alkyl and alkenyl, and linked together forming a 5- to 7-membered monocyclic ring, which may be optionally substituted by one or more selected from the group consisting of halo, lower alkyl, haloalkyl, heterocyclic and carboxy;
R3, R4 and R5 are independently selected from hydrogen, hydroxy, lower alkoxy, —(O(CH2)2)1-3—O-lower alkyl, heteroaryl lower alkoxy, heterocyclic, heteroaryl, NR7R8, heterocyclicoxy, heterocyclic lower alkoxy, —OC(R1)2C(O)N(R2)2, and —OC(R1)2C(O)NR7R8, wherein all substituents may be optionally substituted by one or more selected from the group consisting of hydroxy, hydroxyalkyl, heterocyclic, N-linked heteroaryl, —NR7R8, —C(O)NR7R8, and —C(O)N(R2)2;
with the proviso that at least one of R3, R4 or R5 is an N-linked heteroaryl or —NR7R8.
10. The compound of claim 7 or its pharmaceutically acceptable salt, wherein:
R1 is selected from the group consisting of lower alkyl, and lower alkoxy, wherein all substituents may be optionally substituted by one or more selected from the group consisting of alkoxy, —NR7R8, —NHR2, and —N(R2)2;
R2 is lower alkyl;
R7 and R8 are independently alkyl and linked together forming a 5- to 7-membered saturated monocyclic ring;
R3, R4 and R5 are independently selected from hydrogen, hydroxy, lower alkoxy, heterocyclic, heteroaryl, NR7R8 and heterocyclic lower alkoxy;
with the proviso that at least one of R3, R4 or R5 is an N-linked heteroaryl or —NR7R8.
11. The compound of claim 7 or its pharmaceutically acceptable salt, wherein:
R1 is selected from the group consisting of lower alkyl, and lower alkoxy;
R7 and R8 are independently alkyl and linked together forming a 5- to 7-membered saturated monocyclic ring;
R3, R4 and R5 are independently selected from lower alkoxy, NR7R8 and heterocyclic lower alkoxy;
with the proviso that at least one of R3, R4 or R5 is —NR7R8.
12. The compound of claim 7 or its pharmaceutically acceptable salt, wherein the compound is N-Butyryl-4-[3E-(2,4-dimethoxy-5-pyrrolidin-1-ylphenyl)acryloyl]benzenesulfonamide.
13. A compound of Formula III
Figure US20070093453A1-20070426-C00717
or its pharmaceutically acceptable salt, wherein:
R1 is selected from the group consisting of hydrogen, alkyl, lower alkyl, carbocyclic, cycloalkyl, alkoxy, lower alkoxy, cycloalkyloxy, cycloalkylalkoxy, heterocyclicoxy, aryloxy, heteroaryloxy, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, —NR7R8, —NHR2, —N(R2)2, acyl and heterocyclicalkyl, wherein all substituents may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, haloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR7R8, —NHR2, —N(R2)2, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, heteroaryl, —C(O)NR7R8, and —C(O)N(R2)2;
R2 is independently selected from the group consisting of hydrogen, alkyl, lower alkyl, carbocyclic, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, acyl, alkoxycarbonyl, and heterocyclicalkyl, wherein all substituents may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, haloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, heteroaryl, —C(O)NR7R8, —NR1R2 and —C(O)N(R2)2;
R7 and R8 are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 4- to 12-membered monocyclic, bicylic, tricyclic or benzofused ring, which may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, haloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —C(O)NR7R8, and —C(O)N(R2)2;
R3 and R4 are independently selected from hydrogen, hydroxy, alkoxy, lower alkoxy, —(O(CH2)2)1-3—O-lower alkyl, cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy, —OC(R1)2C(O)N(R2)2, and —OC(R1)2C(O)NR7R8, wherein all substituents may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, haloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, N-linked heteroaryl, —NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —C(O)NR7R8, and —C(O)N(R2)2;
R5 is selected from the group consisting of a carbon-carbon linked heterocyclic and a carbon-carbon linked heteroaryl, which may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, haloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —C(O)NR7R8, and C(O)N(R2)2;
with the proviso that when R1 is isopropyl, R5 cannot be 5-benzo[b]thien-2-yl.
14. The compound of claim 13 or its pharmaceutically acceptable salt, wherein:
R1 is selected from the group consisting of hydrogen, alkyl, lower alkyl, alkoxy, lower alkoxy, cycloalkyloxy, cycloalkylalkoxy, heterocyclicoxy, aryloxy, heteroaryloxy, heterocyclic, heteroarylalkyl, and heterocyclicalkyl, wherein all substituents may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, haloalkyl, heterocyclic, amino, aminoalkyl, —NR7R8, —NHR2, —N(R2)2, alkoxy, carboxy, carboxyalkyl, alkoxycarbonyl, and heteroaryl;
R2 is independently selected from the group consisting of alkyl, lower alkyl, heteroaryl, heterocyclic, heteroarylalkyl, and heterocyclicalkyl, wherein all substituents may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, haloalkyl, heterocyclic, —NR7R8, alkoxy, carboxy, carboxyalkyl, alkoxycarbonyl and heteroaryl;
R7 and R8 are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 5- to 10-membered monocyclic, bicylic or benzofused ring, which may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, haloalkyl, heterocyclic, —NR7R8, alkoxy, carboxy, carboxyalkyl and alkoxycarbonyl;
R3 and R4 are independently selected from hydroxy, alkoxy, lower alkoxy, —(O(CH2)2)1-3—O-lower alkyl, haloalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy, —OC(R1)2C(O)N(R2)2, and —OC(R1)2C(O)NR7R8, wherein all substituents may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, hydroxy, hydroxyalkyl, heterocyclic, —NR7R8, alkoxy, —C(O)NR7R8, and —C(O)N(R2)2;
R5 is selected from the group consisting of a carbon-carbon linked heteroaryl and a carbon-carbon linked heterocyclic, which may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, haloalkyl, heterocyclic, —NR7R8 and alkoxy;
with the proviso that when R1 is isopropyl, R5 cannot be 5-benzo[b]thien-2-yl.
15. The compound of claim 13 or its pharmaceutically acceptable salt, wherein:
R1 is selected from the group consisting of alkyl, lower alkyl, alkoxy, and lower alkoxy, wherein all substituents may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, amino, aminoalkyl, —NR7R8, —NHR2, —N(R2)2, alkoxy, carboxy, carboxyalkyl, alkoxycarbonyl, and heteroaryl;
R2 is independently selected from the group consisting of lower alkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all substituents may be optionally substituted by one or more selected from the group consisting of halo, lower alkyl, haloalkyl, heterocyclic, —NR7R8 and carboxy;
R7 and R8 are independently selected from the group consisting of alkyl and alkenyl, and linked together forming a 5- to 7-membered monocyclic ring, which may be optionally substituted by one or more selected from the group consisting of halo, lower alkyl, haloalkyl, heterocyclic and carboxy;
R3 and R4 are independently selected from hydroxy, lower alkoxy, —(O(CH2)2)1-3—O-lower alkyl, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy, —OC(R1)2C(O)N(R2)2, and —OC(R1)2C(O)NR7R8, wherein all substituents may be optionally substituted by one or more selected from the group consisting of hydroxy, hydroxyalkyl, heterocyclic, —NR7R8, —C(O)NR7R8, and —C(O)N(R2)2;
R5 is selected from the group consisting of a carbon-carbon linked heteroaryl and a carbon-carbon linked heterocyclic, which may be optionally substituted by one or more lower alkyl;
with the proviso that when R1 is isopropyl, R5 cannot be 5-benzo[b]thien-2-yl.
16. The compound of claim 13 or its pharmaceutically acceptable salt, wherein:
R1 is selected from the group consisting of lower alkyl, and lower alkoxy, wherein all substituents may be optionally substituted by one or more selected from the group consisting of alkoxy, —NR7R8, —NHR2, and —N(R2)2;
R2 is lower alkyl;
R7 and R8 are independently alkyl and linked together forming a 5- to 7-membered saturated monocyclic ring;
R3 and R4 are independently selected from hydroxy, lower alkoxy and heterocyclic lower alkoxy;
R5 is selected from the group consisting of a carbon-carbon linked heteroaryl and a carbon-carbon linked heterocyclic, which may be optionally substituted by one or more lower alkyl;
with the proviso that when R1 is isopropyl, R5 cannot be 5-benzo[b]thien-2-yl.
17. The compound of claim 13 or its pharmaceutically acceptable salt, wherein:
R1 is selected from the group consisting of lower alkyl, and lower alkoxy;
R3 and R4 are independently selected from lower alkoxy and heterocyclic lower alkoxy;
R5 is a carbon-carbon linked heteroaryl, which may be optionally substituted by one or more lower alkyl;
with the proviso that when R1 is isopropyl, R5 cannot be 5-benzo[b]thien-2-yl.
18. The compound of claim 13 or its pharmaceutically acceptable salt, wherein the compound is selected from the group consisting of:
4-{3E-[5-(1H-Indol-2-yl)-2,4-dimethoxyphenyl]acryloyl}-N-isobutyrylbenzenesulfonamide;
4-{3E-[5-(1H-Indol-2-yl)-2,4-dimethoxyphenyl]acryloyl}-N-isobutyrylbenzenesulfonamide sodium salt;
N-Butyryl-4-{3E-[2,4-dimethoxy-5-(1-methyl-1H-indol-2-yl)phenyl]acryloyl}benzenesulfonamide;
N-Ethoxycarbonyl-4-{3E-[5-(1H-indol-2-yl)-2,4-dimethoxyphenyl]acryloyl}benzenesulfonamide potassium salt;
N-Ethoxycarbonyl-4-{3E-[5-(1H-indol-2-yl)-2,4-dimethoxyphenyl]acryloyl}benzenesulfonamide;
N-Acetyl-4-{3E-[5-(1H-indol-2-yl)-2,4-dimethoxyphenyl]acryloyl}benzenesulfonamide;
N-Acetyl-4-{3E-[5-(1H-indol-2-yl)-2,4-dimethoxyphenyl]acryloyl}benzenesulfonamide sodium salt;
4-{3E-[5-(1H-Indol-2-yl)-2,4-dimethoxyphenyl]acryloyl}-N-propionyl-benzenesulfonamide;
4-{3E-[5-(1H-Indol-2-yl)-2,4-dimethoxyphenyl]acryloyl}-N-propionylbenzenesulfonamide sodium salt;
N-Butyryl-4-{3E-[5-(1H-indol-2-yl)-2,4-dimethoxyphenyl]acryloyl}benzenesulfonamide; and
N-Butyryl-4-{3E-[5-(1H-indol-2-yl)-2,4-dimethoxyphenyl]acryloyl}benzenesulfonamide sodium salt.
19. A compound of Formula I
Figure US20070093453A1-20070426-C00718
or its pharmaceutically acceptable salt, wherein:
R1 is selected from the group consisting of hydrogen, alkyl, lower alkyl, carbocyclic, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, acyl and heterocyclicalkyl, wherein all substituents may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, haloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, heteroaryl, —C(O)NR7R8, and —C(O)N(R2)2;
R2 is independently selected from the group consisting of alkyl, lower alkyl, carbocyclic, cycloalkyl, hydroxy, alkoxy, lower alkoxy, trialkylsilyloxy, cycloalkyloxy, cycloalkylalkoxy, heterocyclicoxy, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, acyl, alkoxycarbonyl, and heterocyclicalkyl, wherein all substituents may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, haloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, heteroaryl, —C(O)NR7R8, —NR1R2 and —C(O)N(R2)2;
R1 and R2 may be taken together to form a 4- to 12-membered saturated or unsaturated heterocyclic ring which can be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, haloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —C(O)NR7R8, and —C(O)N(R2)2;
R7 and R8 are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 4- to 12-membered monocyclic, bicylic, tricyclic or benzofused ring, which may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, haloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —C(O)NR7R8, and —C(O)N(R2)2;
R3 and R4 are independently selected from hydroxy, alkoxy, lower alkoxy, —(O(CH2)2)1-3—O-lower alkyl, cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy, —OC(R1)2C(O)N(R2)2, and —OC(R1)2C(O)NR7R8, wherein all substituents may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, haloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —C(O)NR7R8, and —C(O)N(R2)2;
R5 is selected from the group consisting of a carbon-nitrogen linked heteroaryl and a carbon-nitrogen linked heterocyclic, which may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, haloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —C(O)NR7R8, and —C(O)N(R2)2.
20. The compound of claim 19 or its pharmaceutically acceptable salt, wherein:
R1 is selected from the group consisting of hydrogen, alkyl, and lower alkyl, wherein all substituents may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, haloalkyl, heterocyclic, —NR7R8, alkoxy, carboxy, carboxyalkyl, alkoxycarbonyl and heteroaryl;
R2 is independently selected from the group consisting of alkyl, lower alkyl, alkoxy, lower alkoxy, heteroaryl, heterocyclic, heteroarylalkyl, and heterocyclicalkyl, wherein all substituents may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, haloalkyl, heterocyclic, —NR7R8, alkoxy, carboxy, carboxyalkyl, alkoxycarbonyl and heteroaryl;
R1 and R2 may be taken together to form a 5- to 7-membered saturated or unsaturated heterocyclic ring which can be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, haloalkyl, heterocyclic, —NR7R8, alkoxy, carboxy, carboxyalkyl and alkoxycarbonyl;
R7 and R8 are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 5- to 10-membered monocyclic, bicylic or benzofused ring, which may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, haloalkyl, heterocyclic, —NR7R8, alkoxy, carboxy, carboxyalkyl and alkoxycarbonyl;
R3 and R4 are independently selected from hydroxy, alkoxy, lower alkoxy, —(O(CH2)2)1-3—O-lower alkyl, haloalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy, —OC(R1)2C(O)N(R2)2, and —OC(R1)2C(O)NR7R8, wherein all substituents may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, hydroxy, hydroxyalkyl, heterocyclic, —NR7R8, alkoxy, —C(O)NR7R8, and —C(O)N(R2)2;
R5 is selected from the group consisting of a carbon-nitrogen linked heteroaryl and a carbon-nitrogen linked heterocyclic, which may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, haloalkyl, heterocyclic, —NR7R8 and alkoxy.
21. The compound of claim 19 or its pharmaceutically acceptable salt, wherein:
R1 is selected from the group consisting of hydrogen and lower alkyl;
R2 is independently selected from the group consisting of lower alkyl, lower alkoxy, heteroaryl, heterocyclic, heteroarylalkyl, and heterocyclicalkyl, wherein all substituents may be optionally substituted by one or more selected from the group consisting of halo, lower alkyl, haloalkyl, heterocyclic, heteroaryl, —NR7R8 and carboxy;
R1 and R2 may be taken together to form a 5- to 6-membered heterocyclic saturated ring which can be optionally substituted by one or more selected from the group consisting of halo, lower alkyl and carboxy;
R7 and R8 are independently selected from the group consisting of alkyl and alkenyl, and linked together forming a 5- to 7-membered monocyclic ring, which may be optionally substituted by one or more selected from the group consisting of halo, lower alkyl, haloalkyl, heterocyclic and carboxy;
R3 and R4 are independently selected from hydroxy, lower alkoxy, —(O(CH2)2)1-3—O-lower alkyl, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy, —OC(R1)2C(O)N(R2)2, and —OC(R1)2C(O)NR7R8, wherein all substituents may be optionally substituted by one or more selected from the group consisting of hydroxy, hydroxyalkyl, heterocyclic, —NR7R8, —C(O)NR7R8, and —C(O)N(R2)2;
R5 is selected from the group consisting of a carbon-nitrogen linked heteroaryl and a carbon-nitrogen linked heterocyclic, which may be optionally substituted by one or more lower alkyl.
22. The compound of claim 19 or its pharmaceutically acceptable salt, wherein:
R1 is hydrogen;
R2 is independently selected from the group consisting of lower alkyl, heteroaryl, heteroarylalkyl, and heterocyclicalkyl, wherein all substituents may be optionally substituted by one or more selected from the group consisting of halo, heterocyclic, heteroaryl, and lower alkyl;
R1 and R2 may be taken together to form a 5- to 6-membered heterocyclic saturated ring;
R7 and R8 are independently alkyl and linked together forming a 5- to 7-membered saturated monocyclic ring;
R3 and R4 are independently selected from hydroxy, lower alkoxy and heterocyclic lower alkoxy;
R5 is selected from the group consisting of a carbon-nitrogen linked heterocyclic, which may be optionally substituted by one or more lower alkyl.
23. The compound of claim 19 or its pharmaceutically acceptable salt, wherein:
R1 is hydrogen;
R2 is independently selected from the group consisting of lower alkyl, heteroaryl, heteroarylalkyl, and heterocyclicalkyl, wherein all substituents may be optionally substituted by one or more selected from the group consisting of halo, heterocyclic, heteroaryl, and lower alkyl;
R3 and R4 are independently selected from lower alkoxy and heterocyclic lower alkoxy;
R5 is a carbon-nitrogen linked heterocyclic.
24. The compound of claim 19 or its pharmaceutically acceptable salt, wherein the compound is selected from the group consisting of:
4-[3E-(2,4-Dimethoxy-5-pyrrolidin-1-yl-phenyl)-acryloyl]-N-pyridin-2-yl-benzenesulfonamide;
4-[3E-(2,4-Dimethoxy-5-pyrrolidin-1-ylphenyl)acryloyl]-N-pyridin-2-ylmethylbenzenesulfonamide;
4-[3E-(2,4-Dimethoxy-5-pyrrolidin-1-ylphenyl)acryloyl]-N-(3-imidazol-1-ylpropyl)benzenesulfonamide;
4-[3E-(2,4-Dimethoxy-5-pyrrolidin-1-ylphenyl)acryloyl]-N-[3-(4-methyl-piperazin-1-yl)propyl]benzenesulfonamide; and
{4-[3E-(2,4-Dimethoxy-5-pyrrolidin-1-ylphenyl)acryloyl]benzenesulfonylamino}acetic acid.
25. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or 24, together with one or more pharmaceutically acceptable carrier.
26. A method for the treatment or prophylaxis of an inflammatory disorder, comprising administering an effective amount of a compound of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or 24.
27. The method of claim 26, wherein the disorder is arthritis.
28. The method of claim 26, wherein the disorder is rheumatoid arthritis.
29. The method of claim 26, wherein the disorder is asthma.
30. The method of claim 26, wherein the treatment is disease modifying for the treatment of rheumatoid arthritis.
31. The method of claim 26, wherein the disorder is allergic rhinitis.
32. The method of claim 26, wherein the disorder is chronic obstructive pulmonary disease.
33. The method of claim 26, wherein the disorder is atherosclerosis.
34. The method of claim 26, wherein the disorder is restinosis.
35. A method for inhibiting the expression of VCAM-1, comprising administering an effective amount of a compound of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or 24.
36. A compound having the formula
Figure US20070093453A1-20070426-C00719
wherein
X is —C(O)H or —CH2OH;
R3 and R4 are independently selected from the group consisting of hydroxy, alkoxy, lower alkoxy, —(O(CH2)2)1-3—O-lower alkyl, cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy, —OC(R9)2C(O)N(R9)2, and OC(R9)2C(O)NR7R8, wherein all substituents may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, haloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —C(O)NR7R8, and —C(O)N(R9)2;
Y1, Y2, Y3, and Y4 are independently selected from the group consisting of hydrogen, hydroxyl, halo, alkyl, lower alkyl, alkenyl, cycloalkyl, haloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, heteroaryl, —C(O)NR7R8, and —C(O)N(R9)2, wherein all substituents, when possible may be optionally substituted by one or more selected from the group consisting of hydroxyl, halo, alkyl, lower alkyl, alkenyl, cycloalkyl, haloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, heteroaryl, —C(O)NR7R8, and —C(O)N(R2)2.
Y5 is selected from the group consisting of hydrogen, alkyl, lower alkyl, acyl, and alkoxycarbonyl wherein all substituents, when possible may be optionally substituted by one or more selected from the group consisting of hydroxyl, halo, alkyl, lower alkyl, alkenyl, cycloalkyl, haloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, heteroaryl, —C(O)NR7R8, and —C(O)N(R9)2;
R9 is independently selected from the group consisting of alkyl, lower alkyl, carbocyclic, cycloalkyl, hydroxy, alkoxy, lower alkoxy, trialkylsilyloxy, cycloalkyloxy, cycloalkylalkoxy, heterocyclicoxy, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, acyl, alkoxycarbonyl, and heterocyclicalkyl, wherein all substituents may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, haloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR7R8, —NHR9, —N(R9)2, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, heteroaryl, —C(O)NR7R8, —NR9R9 and —C(O)N(R9)2;
R7 and R8 are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 4- to 12-membered monocyclic, bicylic, tricyclic or benzofused ring, which may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, haloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —C(O)NR7R8, and —C(O)N(R9)2.
37. The compound of claim 36 wherein the compound is selected from
Figure US20070093453A1-20070426-C00720
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