Compounds and methods for kinase modulation, and indications therefor

• US 7,872,018 B2
• Filed: 12/20/2007
• Issued: 01/18/2011
• Est. Priority Date: 12/21/2006
• Status: Expired due to Fees

• Current Assignee: Plexxikon Inc (Daiichi Sankyo Company Limited)
• Original Assignee: Plexxikon Inc (Daiichi Sankyo Company Limited)
• Inventors: Wu, Guoxian, Zhu, Hongyao, Zhang, Jiazhong, Hirth, Klaus-Peter, Zhang, Chao, Ibrahim, Prabha N., Bremer, Ryan
• Primary Examiner(s): Seaman; D. Margaret
• Assistant Examiner(s): Rahmani; Niloofar
• Application Number:
  US11/962,044
• Publication Number:
  US 20080221148A1
• Time in Patent Office: 1,125 Days
• Field of Search: 546/113, 514/300
• US Class Current: 514/300
• 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 11/02 Nasal agents, e.g. decongestants
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 11/08 Bronchodilators
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/04 Antipruritics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/08 for bone diseases, e.g. rachitism, Paget's disease
• CPC Class Codes: A61P 19/10 for osteoporosis
• 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 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 3/14 for calcium homeostasis vitamin D A61P3/02; parathyroid hormones A61P5/18; calcitonin A61P5/22; osteoporosis A61P19/10; bone metastasis A61P35/04
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 35/04 specific for metastasis
• CPC Class Codes: A61P 37/04 Immunostimulants
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 37/08 : Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/50 : for increasing or potentiating the activity of insulin
• CPC Class Codes: A61P 9/04 : Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• 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 471/04 : Ortho-condensed systems

Abstract

Compounds active on protein kinases are described, as well as methods of using such compounds to treat diseases and conditions associated with aberrant activity of protein kinases.

Claims

1. A compound having the chemical structure of Formula II,

2. The compound of claim 1, having the chemical structure of Formula IIa,

3. The compound of claim 2 wherein A₁ is —

CR⁴⁰R⁴¹—

or —

C(O)—

.

4. The compound of claim 3 wherein L₃ is —

NR⁴⁸CH(R⁴⁹)—

, —

SCH(R⁴⁹)—

, or —

OCH(R⁴⁹)—

.

5. The compound of claim 4 wherein R⁵³ and R⁵⁵ are independently selected from the group consisting of hydrogen, halogen, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, and fluoro substituted lower alkoxy.

6. The compound of claim 5, wherein:

R¹⁰⁰ is selected from the group consisting of hydrogen, —

OH, —

NH₂, —

CN, —

NO₂, —

C(O)OH, —

S(O)₂NH₂, —

C(O)NH₂, —

OR⁵⁷, —

SR⁵⁷, —

NR⁴⁸R⁵⁷, —

NR⁴⁸C(O)R⁵⁷, —

NR⁴⁸S(O)₂R⁵⁷, —

S(O)R⁵⁷, —

S(O)₂R⁵⁷, —

C(O)R⁵⁷, —

C(O)OR⁵⁷, —

C(O)NR⁴⁸R⁵⁷, —

S(O)₂NR⁴⁸R⁵⁷, halogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as R¹⁰⁰ or as substituents of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of —

OH, —

NH₂, —

CN, —

NO₂, —

S(O)₂NH₂, —

C(O)NH₂, —

OR⁵⁸, —

SR⁵⁸, —

NHR⁵⁸, —

NR⁴⁸R⁵⁸, —

NR⁴⁸C(O)R⁵⁸, —

NR⁴⁸S(O)₂R⁵⁸, —

S(O)₂R⁵⁸, —

S(O)₂NR⁴⁸R⁵⁸, —

C(O)R⁵⁸, —

C(O)NR⁴⁸R⁵⁸, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino.

7. The compound of claim 6 wherein A₁ is —

CH₂—

.

8. The compound of claim 7 wherein L₃ is —

OCH(R⁴⁹)—

.

9. The compound of claim 8 wherein:

Z₁₂ is CR⁵²;

Z₁₆ is CR⁵⁶;

R¹⁰⁰ is selected from the group consisting of hydrogen, —

CN, —

C(O)OH, —

C(O)OR⁵⁷, —

NR⁴⁸R⁵⁷, —

OR⁵⁷, —

S(O)₂R⁵⁷, fluoro, chloro, bromo, lower alkyl, fluoro substituted lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, —

NR⁴⁸R⁵⁸, —

OR⁵⁸ and —

S(O)₂R⁵⁸; and

R¹⁰¹ is selected from the group consisting of —

OH, —

NH₂, —

CN, —

NO₂, —

C(O)OH, —

C(O)NH₂, —

S(O)₂NH₂—

, C(O)OR⁵⁷, —

NR⁴⁸R⁵⁷, —

OR⁵⁷, —

S(O)₂R⁵⁷, —

C(O)NR⁴⁸R⁵⁷, —

S(O)₂NR⁴⁸R⁵⁷, halogen, lower alkyl, fluoro substituted lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, —

NR⁴⁸R⁵⁸, —

OR⁵⁸ and —

S(O)₂R⁵⁸.

10. The compound of claim 9, wherein the compound is selected from the group consisting of:

2-[5-Chloro-4-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-2-fluoro-phenoxymethyl]-1H-benzoimidazole,

2-[4-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-2,5-difluoro-phenoxymethyl]-1H-benzoimidazole,

2-[2,5-Difluoro-4-(5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-phenoxymethyl]-1H-benzoimidazole,

2-[3,5-Difluoro-4-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-phenoxymethyl]-1H-benzoimidazole,

2-[5-Chloro-2-methoxy-4-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-phenoxymethyl]-1H-benzoimidazole,

2-[5-Chloro-4-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-2-methoxy-phenoxymethyl]-1H-benzoimidazole,

2-[4-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-3,5-difluoro-phenoxymethyl]-1H-benzoimidazole,

2-[4-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-5-fluoro-2-methoxy-phenoxymethyl]-1-methyl-1H-benzoimidazole,

2-[4-(5-Bromo-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-2,5-difluoro-phenoxymethyl]-1H-benzoimidazole,

2-{2,5-Difluoro-4-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl]-phenoxymethyl}-1H-benzoimidazole,

2-{5-Chloro-2-fluoro-4-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl]-phenoxymethyl}-1H-benzoimidazole,

2-{1-[4-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-5-fluoro-2-methoxy-phenoxyl]-ethyl}-1H-benzoimidazole,

6-Chloro-2-[4-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-5-fluoro-2-methoxy-phenoxymethyl]-1H-benzoimidazole,

6-Chloro-2-[5-fluoro-2-methoxy-4-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-phenoxymethyl]-1H-benzoimidazole,

2-[5-Fluoro-2-methoxy-4-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-phenoxymethyl]-6-methoxy-1H-benzoimidazole,

2-[5-Chloro-2-fluoro-4-(5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-phenoxymethyl]-1H-benzoimidazole,

2-[5-Fluoro-4-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-2-methoxy-phenoxymethyl]-1H-benzoimidazole,

2-[2-Chloro-5-fluoro-4-(5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-phenoxymethyl]-1H-benzoimidazole,

2-{2-Chloro-5-fluoro-4-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl]-phenoxymethyl}-1H-benzoimidazole,

2-{4-[(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-methoxy-methyl]-5-fluoro-2-methoxy-phenoxymethyl}-1H-benzoimidazole,

[4-(1H-Benzoimidazol-2-ylmethoxy)-2-fluoro-5-methoxy-phenyl]-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone,

2-[2,5-Difluoro-4-(5-methanesulfonyl-1H-pyrrolo[2, 3-b]pyridin-3-ylmethyl)-phenoxymethyl]-1H-benzoimidazole,

3-[4-(1H-Benzoimidazol-2-ylmethoxy)-2-fluoro-5-methoxy-benzyl]-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile,

5,6-Dichloro-2-[4-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-5-fluoro-2-methoxy-phenoxymethyl]-1H-benzoimidazole,

2-[4-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-5-fluoro-2-methoxy-phenoxymethyl]-1H-benzoimidazole-5-sulfonic acid dimethylamide,

3-[4-(1H-Benzoimidazol-2-ylmethoxy)-2-fluoro-5-methoxy-benzyl]-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid methyl ester,

3-[4-(1H-Benzoimidazol-2-ylmethoxy)-2-fluoro-5-methoxy-benzyl]-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid,

2-{2,5-Difluoro-4-[5-(2-methoxy-ethoxy)-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl]-phenoxymethyl}-1H-benzoimidazole,

2-[4-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-5-fluoro-2-methoxy-phenoxymethyl]-1-ethyl-1H-benzoimidazole,

2-[4-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-5-fluoro-2-methoxy-phenoxymethyl]-5-trifluoromethyl-1H-benzoimidazole,

2-[4-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-5-fluoro-2-methoxy-phenoxymethyl]-5-fluoro-1H-benzoimidazole,

2-{2-[4-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-5-fluoro-2-methoxy-phenoxy]-ethyl}-1H-benzoimidazole,

2-[4-(5-Bromo-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-5-fluoro-2-methoxy-phenoxymethyl]-1H-benzoimidazole,

2-[4-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-5-fluoro-2-methoxy-phenoxymethyl]-5-methoxy-1H-benzoimidazole,

5-Chloro-2-[5-fluoro-2-methoxy-4-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-phenoxymethyl]-1-benzoimidazole,

3-[4-(1H-Benzoimidazol-2-ylmethoxy)-2,5-difluoro-benzyl]-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile,

2-[5-Fluoro-4-(5-methanesulfonyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-2-methoxy-phenoxymethyl]-1H-benzoimidazole, and

all salts, tautomers, and isomers thereof.

11. A composition comprising:

a pharmaceutically acceptable carrier; and

a compound according to claim 1.

12. A kit comprising a compound according to claim 1.