COMPOUNDS AS TYROSINE KINASE MODULATORS

• US 20110053905A1
• Filed: 09/03/2010
• Published: 03/03/2011
• Est. Priority Date: 09/03/2009
• Status: Active Grant

• Current Assignee: Allergan, Inc. (Canada) (Abbvie Incorporated)
• Original Assignee: Allergan, Inc. (Canada) (Abbvie Incorporated)
• Inventors: Guo, Xialing, Zhu, Zhen
• Granted Patent: US 8,614,234 B2
• Time in Patent Office: Days
• US Class Current: 514/210.18
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 27/00 Drugs for disorders of the senses
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 27/06 Antiglaucoma agents or miotics
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07D 401/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 401/14 : containing three or more hetero rings
• CPC Class Codes: C07D 405/00 : Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
• CPC Class Codes: C07D 405/14 : containing three or more hetero rings
• CPC Class Codes: C07D 409/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 409/14 : containing three or more hetero rings
• CPC Class Codes: C07D 413/14 : containing three or more hetero rings

Abstract

The present invention is directed to novel compounds of Formula I. The compounds of the present invention are potent tyrosine kinase modulators, and are suitable for the treatment and prevention of diseases and conditions related to abnormal activities of tyrosine kinase receptors.

Claims

1. A compound represented by Formula I:

2. The compound according to claim 1, wherein X is NH.

3. The compound according to claim 1, wherein X is S.

4. The compound according to claim 1, wherein Ring A and Ring B are independently selected from the group consisting of

5. A compound according to claim 1 selected from the group consisting of:

(1′

) [({5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrol-3-yl}carbonyl)amino]acetic acid;

(2′

) methyl [({5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrol-3-yl}carbonyl)amino]acetate;

(3′

) ({[5-(4-{3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrol-3-yl]carbonyl}amino)acetic acid;

(4′

) methyl({[5-(4-{3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrol-3-yl]carbonyl}amino)acetate;

(5′

) 5-[4-({3-[(3-methyl-2-furoyl)amino]phenyl}amino)pyridin-2-yl]-1H-pyrrole-3-carboxylic acid;

(6′

) methyl 5-[4-({3-[(3-methyl-2-furoyl)amino]phenyl}amino)pyridin-2-yl]-1H-pyrrole-3-carboxylate;

(7′

) 5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-N-hydroxy-1H-pyrrole-3-carboxamide;

(8′

) 4-fluoro-N-(2-fluoro-5-methylphenyl)-3-[(2-{4-[3-hydroxypiperidin-1-yl)carbonyl]-1H-pyrrol-2-yl}pyridin-4-yl)oxy]benzamide;

(9) N-(2,3-dihydroxypropyl)-5-[4-(3-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrole-3-carboxamide;

(10) N-(2-fluoro-5-methylphenyl)-3-[(2-{4-[(3-hydroxypyrrolidin-1-yl)carbonyl]-1H-pyrrol-2-yl}pyridin-4-yl)oxy]benzamide;

(11′

) 5-[4-(3-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-N-hydroxy-1H-pyrrole-3-carboxamide;

(12′

) methyl 5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrole-3-carboxylate;

(13′

) 5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrole-3-carboxylic acid;

(14′

) N-ethyl-5-(4-{3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrole-3-carboxamide;

(15′

) N-(2,3-dihydroxypropyl)-5-(4-{3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrole-3-carboxamide;

(16′

) 5-(4-{3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrole-3-carboxamide;

(17′

) N-hydroxy-5-(4-{3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrole-3-carboxamide;

(18′

) N-(3-{[2-(4-{[(3R)-3-hydroxypyrrolidin-1-yl]carbonyl}-1H-pyrrol-2-yl)pyridin-4-yl]oxy}phenyl)-3-methyl-2-furamide;

(19′

) 5-[4-(3-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrole-3-carboxylic acid;

(20′

) methyl 5-[4-(3-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrole-3-carboxylate;

(21′

) 2,3-dihydroxypropyl 5-(4-{3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrole-3-carboxylate;

(22′

) 5-[4-(3-{[(3-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrole-3-carboxylic acid;

(23′

) methyl 5-[4-(3-{[(3-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrole-3-carboxylate;

(24′

) 2-hydroxyethyl 5-[4-(3-{[(3-methyl-2-thienyl)carbonyl]amino}phenoxy)pyridin-2-yl]-1H-pyrrole-3-carboxylate;

(25′

) 2-hydroxyethyl 5-(4-{3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrole-3-carboxylate;

(26′

) 5-[4-(3-{[(3-methyl-2-thienyl)carbonyl]amino}phenoxy)pyridin-2-yl]-1H-pyrrole-3-carboxylic acid;

(27′

) methyl 5-[4-(3-{[(3-methyl-2-thienyl)carbonyl]amino}phenoxy)pyridin-2-yl]-1H-pyrrole-3-carboxylate;

(28′

) 5-(4-{4-fluoro-3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrole-3-carboxylic acid;

(29′

) methyl 5-(4-{4-fluoro-3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrole-3-carboxylate;

(30′

) N-[dimethyl(oxido)-lambda˜

4˜

-sulfanylidene]-5-(4-{3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrole-3-carboxamide;

(31′

) N-(3-{[2-(4-{[(3S)-3-hydroxypyrrolidin-1-yl]carbonyl}-1H-pyrrol-2-yl)pyridin-4-yl]oxy}phenyl)-3-methyl-2-furamide;

(32′

) 5-(4-{3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrole-3-carboxylic acid;

(33′

) methyl 5-(4-{3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrole-3-carboxylate;

(34′

) 3-methyl-N-(3-{[2-(1H-pyrrol-2-yl)pyridin-4-yl]oxy}phenyl)-2-furamide;

(35′

) methyl 4-(4-{3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrole-2-carboxylate;

(36′

) 2-fluoro-5-methyl-N-(4-{[2-(1H-pyrrol-2-yl)pyridin-4-yl]oxy}phenyl)benzamide;

and (37′

) 3-methyl-N-(4-{[2-(1H-pyrrol-2-yl)pyridin-4-yl]oxy}phenyl)-2-furamide.

6. The compound according to claim 1 provided that when Ring B is pyrazole, R^IV is not a phenyl or substituted phenyl.

7. A compound according to claim 6, wherein Y is selected from the group consisting of

(1′

) —

(CH₂)g-O—

(CH₂)h-;

(2′

) —

(CH₂)g-NR¹—

(CH₂)h-;

(3′

) —

(CH₂)g-S(O)_n—

(CH₂)h-;

(4′

) —

(CH₂)g-SO₂N R²—

(CH₂)h-;

(5′

) —

(CH₂)g-NR²SO₂—

(CH₂)h-;

(6′

) —

(CH₂)g-CO—

(CH₂)h-;

(7′

) —

(CH₂)g-C(O)NR²—

(CH₂)h-;

(8′

) —

(CH₂)g-NR²C(O)—

(CH₂)h-;

(9′

) —

(CH₂)g-NR²C(O)NR³—

(CH₂)h-;

and (10′

) a single bond.

8. The compound according to claim 1, wherein X is S.

9. The compound according to claim 1, wherein X is NH.

10. A compound according to claim 1 selected from the group consisting of

16. The compounds of claims 1 for use as a tyrosine kinase inhibitor.

17. The compound according to claim 1 which is used for the treatment of one of the diseases or conditions selected from the group consisting of colorectal cancer, lung cancer, hematological cancer, renal cancer, liver cancer, breast cancer, diabetic retinopathy, macular degeneration, age-related macular degeneration, retinopathy of prematurity, ocular angiogenesis, retinal edema, retinal ischemia, diabetic macular edema, cystoid macular edema, retinal vein occlusion, branch vein occlusion, preretinal neovascularization, laser-induced choroidal neovascularization, neovascularization associated with keratoplasty, glaucoma and ocular tumors, arthritis, restenosis, hepatic cirrhosis, atherosclerosis, psoriasis, diabetes mellitus, wound healing, inflammation, neurodegenerative diseases and immune disorders in the human being.

18. A pharmaceutical composition comprising of a therapeutic effective amount of the compounds of claim 1, together with a pharmaceutically acceptable carrier therefor.

19. The pharmaceutical composition of claim 18, wherein the composition comprises of tablets, capsules, intravenous injections, intramuscular injections, local injections, topical creams, gels and ointments, eye drops, eye ointments, eye sprays, ophthalmic suspensions, ophthalmic emulsions, intravitreal injections, subtenon injections, ophthalmic biodrodible implant, and non-bioeordible ophthalmic inserts and depots.

11. A compound represented by Formula II:

12. The compound of claim 12, wherein Z is selected from the group consisting of (CH₂)_iN(R⁷)C(O), C(O)N(R⁸)(CH₂)_j, (CH₂)_iN(R⁷)C(O)N(R⁸)(CH₂)_j and (CH₂)_iN(R⁷)C(S)N(R⁸)(CH₂)_j.

13. The compound of claim 12, wherein Y is selected from the group consisting of

(1′

) —

(CH₂)g-O—

(CH₂)h-;

(2′

) —

(CH₂)g-NR¹—

(CH₂)h-;

(3′

) —

(CH₂)g-S(O)_n—

(CH₂)h-;

(4′

) —

(CH₂)g-SO₂N R²—

(CH₂)h-;

(5′

) —

(CH₂)g-NR²SO₂—

(CH₂)h-;

(6′

) —

(CH₂)g-CO—

(CH₂)h-;

(7′

) —

(CH₂)g-C(O)NR²—

(CH₂)h-;

(8′

) —

(CH₂)g-NR²C(O)—

(CH₂)h-;

(9′

) —

(CH₂)g-C≡

C—

(CH₂)h-;

(10′

) —

(CH₂)g-NR²C(O)NR³—

(CH₂)h-;

and (11′

) a single bond.

14. The compound of claim 12, wherein W is C.

15. The compound of claim 12, wherein Ring A and Ring B are independently selected from the group consisting of