Compounds and Methods for Kinase Modulation, and Indications Therefor

• US 20090306087A1
• Filed: 06/08/2009
• Published: 12/10/2009
• Est. Priority Date: 06/10/2008
• Status: Active Grant

• Current Assignee: Plexxikon Inc (Daiichi Sankyo Company Limited)
• Original Assignee: Plexxikon Inc (Daiichi Sankyo Company Limited)
• Inventors: Spevak, Wayne, Ibrahim, Prabha N., Cho, Hanna
• Granted Patent: US 8,110,576 B2
• Time in Patent Office: Days
• US Class Current: 514/249
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• 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 35/00 Antineoplastic agents
• CPC Class Codes: C07D 487/04 Ortho-condensed systems

Abstract

Compounds and salts thereof, formulations thereof conjugates thereof, derivatives thereof, forms thereof and uses thereof are described. In certain aspects and embodiments, the described compounds or salts thereof, formulations thereof, conjugates thereof, derivatives thereof, forms thereof are active on at least one Raf protein kinase. Also described are methods of use thereof to treat diseases and conditions, including diseases and conditions associated with activity of Raf protein kinases, including melanoma, colorectal cancer, thyroid cancer, ovarian cancer, cholangiocarcinoma, pain or polycystic kidney disease.

Claims

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

2. The compound of claim 1, wherein:

R¹ is selected from the group consisting of lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl, lower alkenyl or lower alkynyl are optionally substituted with one or more substituents R⁶³, and wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents R⁶⁴;

R⁶³ at each occurrence is independently selected from the group consisting of —

OH, —

NH₂, —

C(O)—

OH, —

S(O)—

NH₂, —

S(O)₂—

NH₂, —

C(O)—

NH₂, —

O—

R⁶⁵, —

S—

R⁶⁵, —

N(R⁶⁶)—

R⁶⁵, —

N(R⁶⁶)—

C(O)—

R⁶⁵, —

N(R⁶⁶)—

S(O)—

R⁶⁵, —

N(R⁶⁶)—

S(O)₂—

R⁶⁵, —

C(O)—

N(R⁶⁶)—

R⁶⁵, —

C(O)—

O—

R⁶⁵, —

C(O)—

R⁶⁵, —

S(O)—

N(R⁶⁶)—

R⁶⁵, —

S(O)₂—

N(R⁶⁶)—

R⁶⁵, —

S(O)—

R⁶⁵, —

S(O)₂—

R⁶⁵, fluoro, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one or more substituents R⁶⁴;

R⁶⁴ at each occurrence is independently selected from the group consisting of —

OH, —

NH₂, —

NO₂, —

CN, —

C(O)—

OH, —

S(O)—

NH₂, —

S(O)₂—

NH₂, —

C(O)—

NH₂, —

O—

R⁶⁵, —

S—

R⁶⁵, —

N(R⁶⁶)—

R⁶⁵, —

N(R⁶⁶)—

C(O)—

R⁶⁵, —

N(R⁶⁶)—

S(O)—

R⁶⁵, —

N(R⁶⁶)—

S(O)₂—

R⁶⁵, —

S(O)—

R⁶⁵, —

S(O)₂—

R⁶⁵, —

C(O)—

R⁶⁵, —

C(O)—

O—

R⁶⁵, —

C(O)—

N(R⁶⁶)—

R⁶⁵, —

S(O)—

N(R⁶⁶)—

R⁶⁵, —

S(O)₂—

N(R⁶⁶)—

R⁶⁵, 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 R⁶⁴, or as substituents of lower alkyl, are optionally substituted with one or more substituents selected from the group consisting of —

OH, —

NH₂, —

NO₂, —

CN, —

C(O)—

OH, —

S(O)₂—

NH₂, —

C(O)—

NH₂, —

O—

R⁶⁷, —

S—

R⁶⁷, —

N(R⁶⁶)—

R⁶⁷, —

N(R⁶⁶)—

C(O)—

R⁶⁷, —

N(R⁶⁶)—

S(O)₂—

R⁶⁷, —

S(O)—

R⁶⁷, —

S(O)₂—

R⁶⁷, —

C(O)—

R⁶⁷, —

C(O)—

O—

R⁶⁷, —

C(O)—

N(R⁶⁶)—

R⁶⁷, —

S(O)₂—

N(R⁶⁶)—

R⁶⁷, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino;

R⁶⁵ at each occurrence is independently selected from the group consisting of 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 R⁶⁵ or as substituents of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of —

OH, —

NH₂, —

CN, —

NO₂, —

C(O)—

OH, —

S(O)₂—

NH₂, —

C(O)—

NH₂, —

O—

R⁶⁹, —

S—

R⁶⁹, —

N(R⁶⁸)—

R⁶⁹, —

N(R⁶⁸)—

C(O)—

R⁶⁹, —

N(R⁶⁸)—

S(O)₂—

R⁶⁹, —

C(O)—

R⁶⁹, —

S(O)—

R⁶⁹, —

S(O)₂—

R⁶⁹, —

C(O)—

O—

R⁶⁹, —

C(O)—

N(R⁶⁸)—

R⁶⁹, —

S(O)₂—

N(R⁶⁸)—

R⁶⁹, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino;

R⁶⁶ and R⁶⁸ at each occurrence are independently hydrogen, lower alkyl, or lower alkyl substituted with one or more substituents selected from the group consisting of fluoro, —

OH, —

NH₂, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, fluoro substituted mono-alkylamino, di-alkylamino, fluoro substituted di-alkylamino, and cycloalkylamino; and

R⁶⁷ and R⁶⁹ at each occurrence are independently selected from the group consisting of lower alkyl, heterocycloalkyl 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, and cycloalkylamino, and wherein heterocycloalkyl and heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, —

CN, lower alkyl, fluoro substituted lower alkyl, lower alkoxy and fluoro substituted lower alkoxy.

3. The compound of claim 2, wherein:

R¹ is selected from the group consisting of lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl, is optionally substituted with one or more substituents R⁶³, and wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents R⁶⁴;

R⁶³ at each occurrence is independently selected from the group consisting of —

OH, —

NH₂, —

O—

R⁶⁵, —

S—

R⁶⁵, —

N(R⁶⁶)—

R⁶⁵, —

N(R⁶⁶)—

C(O)—

R⁶⁵, —

N(R⁶⁶)—

S(O)—

R⁶⁵, —

N(R⁶⁶)—

S(O)₂—

R⁶⁵, —

C(O)—

R⁶⁵, —

S(O)—

R⁶⁵, —

S(O)₂—

R⁶⁵, fluoro, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one or more substituents R⁶⁴; and

R⁶⁴ at each occurrence is independently selected from the group consisting of —

OH, —

NH₂, —

NO₂, —

CN, —

O—

R⁶⁵, —

S—

R⁶⁵, —

N(R⁶⁶)—

R⁶⁵, —

N(R⁶⁶)—

C(O)—

R⁶⁵, —

N(R⁶⁶)—

S(O)—

R⁶⁵, —

N(R⁶⁶)—

S(O)₂—

R⁶⁵, —

C(O)—

R⁶⁵, —

S(O)—

R⁶⁵, —

S(O)₂—

R⁶⁵, 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 R⁶⁴, or as substituents of lower alkyl, are optionally substituted with one or more substituents selected from the group consisting of —

OH, —

NH₂, —

NO₂, —

CN, —

O—

R⁶⁷, —

S—

R⁶⁷, —

N(R⁶⁶)—

R⁶⁷, —

N(R⁶⁶)—

C(O)—

R⁶⁷, —

N(R⁶⁶)—

S(O)₂—

R⁶⁷, —

S(O)—

R⁶⁷, —

S(O)₂—

R⁶⁷, —

C(O)—

R⁶⁷, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino.

4. The compound of claim 3, wherein:

R² is selected from the group consisting of hydrogen, —

CN, —

O—

R⁷⁰, —

S—

R⁷⁰, —

N(R⁷¹)—

R⁷⁰, fluoro, and lower alkyl, 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, and cycloalkylamino;

R³ is selected from the group consisting of hydrogen, —

CN, —

O—

R⁷⁰, —

S—

R⁷⁰, —

N(R⁷¹)—

R⁷⁰, fluoro, and lower alkyl, 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, and cycloalkylamino;

R⁴ is hydrogen;

R⁷⁰ is lower alkyl 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, and cycloalkylamino; and

R⁷¹ is hydrogen or lower alkyl 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, and cycloalkylamino.

5. The compound of claim 1, having the chemical structure of Formula Ia,

6. The compound of claim 5, wherein;

R³¹ is selected from the group consisting of lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl, lower alkenyl or lower alkynyl are optionally substituted with one or more substituents R⁶³, and wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents R⁶⁴, wherein

R⁶³ at each occurrence is independently selected from the group consisting of —

OH, —

NH₂, —

C(O)—

OH, —

S(O)—

NH₂, —

S(O)₂—

NH₂, —

C(O)—

NH₂, —

O—

R⁶⁵, —

S—

R⁶⁵, —

N(R⁶⁶)—

R⁶⁵, —

N(R⁶⁶)—

C(O)—

R⁶⁵, —

N(R⁶⁶)—

S(O)—

R⁶⁵, —

N(R⁶⁶)—

S(O)₂—

R⁶⁵, —

C(O)—

N(R⁶⁶)—

R⁶⁵, —

C(O)—

O—

R⁶⁵, —

C(O)—

R⁶⁵, —

S(O)—

N(R⁶⁶)—

R⁶⁵, —

S(O)₂—

N(R⁶⁶)—

R⁶⁵, —

S(O)—

R⁶⁵, —

S(O)₂—

R⁶⁵, fluoro, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one or more substituents R⁶⁴;

R⁶⁴ at each occurrence is independently selected from the group consisting of —

OH, —

NH₂, —

NO₂, —

CN, —

C(O)—

OH, —

S(O)—

NH₂, —

S(O)₂—

NH₂, —

C(O)—

NH₂, —

O—

R⁶⁵, —

S—

R⁶⁵, —

N(R⁶⁶)—

R⁶⁵, —

N(R⁶⁶)—

C(O)—

R⁶⁵, —

N(R⁶⁶)—

S(O)—

R⁶⁵, —

N(R⁶⁶)—

S(O)₂—

R⁶⁵, —

S(O)—

R⁶⁵, —

S(O)₂—

R⁶⁵, —

C(O)—

R⁶⁵, —

C(O)—

O—

R⁶⁵, —

C(O)—

N(R⁶⁶)—

R⁶⁵, —

S(O)—

N(R⁶⁶)—

R⁶⁵, —

S(O)₂—

N(R⁶⁶)—

R⁶⁵, 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 R⁶⁴, or as substituents of lower alkyl, are optionally substituted with one or more substituents selected from the group consisting of —

OH, —

NH₂, —

NO₂, —

CN, —

C(O)—

OH, —

S(O)₂—

NH₂, —

C(O)—

NH₂, —

O—

R⁶⁷, —

S—

R⁶⁷, —

N(R⁶⁶)—

R⁶⁷, —

N(R⁶⁶)—

C(O)—

R⁶⁷, —

N(R⁶⁶)—

S(O)₂—

R⁶⁷, —

S(O)—

R⁶⁷, —

S(O)₂—

R⁶⁷, —

C(O)—

R⁶⁷, —

C(O)—

O—

R⁶⁷, —

C(O)—

N(R⁶⁶)—

R⁶⁷, —

S(O)₂—

N(R⁶⁶)—

R⁶⁷, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino;

R⁶⁵ at each occurrence is independently selected from the group consisting of 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 R⁶⁵ or as substituents of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of —

OH, —

NH₂, —

CN, —

NO₂, —

C(O)—

OH, —

S(O)₂—

NH₂, —

C(O)—

NH₂, —

O—

R⁶⁹, —

S—

R⁶⁹, —

N(R⁶⁸)—

R⁶⁹, —

N(R⁶⁸)—

C(O)—

R⁶⁹, —

N(R⁶⁸)—

S(O)₂—

R⁶⁹, —

C(O)—

R⁶⁹, —

S(O)—

R⁶⁹, —

S(O)₂—

R⁶⁹, —

C(O)—

O—

R⁶⁹, —

C(O)—

N(R⁶⁸)—

R⁶⁹, —

S(O)₂—

N(R⁶⁸)—

R⁶⁹, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino;

R⁶⁶ and R⁶⁸ at each occurrence are independently hydrogen, lower alkyl, or lower alkyl substituted with one or more substituents selected from the group consisting of fluoro, —

OH, —

NH₂, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, fluoro substituted mono-alkylamino, di-alkylamino, fluoro substituted di-alkylamino, and cycloalkylamino; and

R⁶⁷ and R⁶⁹ at each occurrence are independently selected from the group consisting of lower alkyl, heterocycloalkyl 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, and cycloalkylamino, and wherein heterocycloalkyl and heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, —

CN, lower alkyl, fluoro substituted lower alkyl, lower alkoxy and fluoro substituted lower alkoxy.

7. The compound of claim 6, wherein:

R³¹ is selected from the group consisting of lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl, is optionally substituted with one or more substituents R⁶³, and wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents R⁶⁴;

R⁶³ at each occurrence is independently selected from the group consisting of —

OH, —

NH₂, —

O—

R⁶⁵, —

S—

R⁶⁵, —

N(R⁶⁶)—

R⁶⁵, —

N(R⁶⁶)—

C(O)—

R⁶⁵, —

N(R⁶⁶)—

S(O)—

R⁶⁵, —

N(R⁶⁶)—

S(O)₂—

R⁶⁵, —

C(O)—

R⁶⁵, —

S(O)—

R⁶⁵, —

S(O)₂—

R⁶⁵, fluoro, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one or more substituents R⁶⁴; and

R⁶⁴ at each occurrence is independently selected from the group consisting of —

OH, —

NH₂, —

NO₂, —

CN, —

O—

R⁶⁵, —

S—

R⁶⁵, —

N(R⁶⁶)—

R⁶⁵, —

N(R⁶⁶)—

C(O)—

R⁶⁵, —

N(R⁶⁶)—

S(O)—

R⁶⁵, —

N(R⁶⁶)—

S(O)₂—

R⁶⁵, —

C(O)—

R⁶⁵, —

S(O)—

R⁶⁵, —

S(O)₂—

R⁶⁵, 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 R⁶⁴, or as substituents of lower alkyl, are optionally substituted with one or more substituents selected from the group consisting of —

OH, —

NH₂, —

NO₂, —

CN, —

O—

R⁶⁷, —

S—

R⁶⁷, —

N(R⁶⁶)—

R⁶⁷, —

N(R⁶⁶)—

C(O)—

R⁶⁷, —

N(R⁶⁶)—

S(O)₂—

R⁶⁷, —

S(O)—

R⁶⁷, —

S(O)₂—

R⁶⁷, —

C(O)—

R⁶⁷, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino.

8. The compound of claim 7, wherein:

R³² is selected from the group consisting of hydrogen, —

CN, —

O—

R⁷⁰, —

S—

R⁷⁰, —

N(R⁷¹)—

R⁷⁰, fluoro, and lower alkyl, 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, and cycloalkylamino;

R³³ is selected from the group consisting of hydrogen, —

CN, —

O—

R⁷⁰, —

S—

R⁷⁰, —

N(R⁷¹)—

R⁷⁰, fluoro, and lower alkyl, 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, and cycloalkylamino;

R³⁴ is hydrogen;

R⁷⁰ is lower alkyl 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, and cycloalkylamino; and

R⁷¹ is hydrogen or lower alkyl 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, and cycloalkylamino.

9. The compound of claim 2, having the chemical structure of formula Ib,

10. The compound of claim 9, wherein:

R⁵⁷ is selected from the group consisting of lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl, lower alkenyl or lower alkynyl are optionally substituted with one or more substituents R⁶³, and wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents R⁶⁴, wherein

R⁶³ at each occurrence is independently selected from the group consisting of —

OH, —

NH₂, —

C(O)—

OH, —

S(O)—

NH₂, —

S(O)₂—

NH₂, —

C(O)—

NH₂, —

O—

R⁶⁵, —

S—

R⁶⁵, —

N(R⁶⁶)—

R⁶⁵, —

N(R⁶⁶)—

C(O)—

R⁶⁵, —

N(R⁶⁶)—

S(O)—

R⁶⁵, —

N(R⁶⁶)—

S(O)₂—

R⁶⁵, —

C(O)—

N(R⁶⁶)—

R⁶⁵, —

C(O)—

O—

R⁶⁵, —

C(O)—

R⁶⁵, —

S(O)—

N(R⁵⁶)—

R⁶⁵, —

S(O)₂—

N(R⁶⁶)—

R⁶⁵, —

S(O)—

R⁶⁵, —

S(O)₂—

R⁶⁵, fluoro, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one or more substituents R⁶⁴;

R⁶⁴ at each occurrence is independently selected from the group consisting of —

OH, —

NH₂, —

NO₂, —

CN, —

C(O)—

OH, —

S(O)—

NH₂, —

S(O)₂—

NH₂, —

C(O)—

NH₂, —

O—

R⁶⁵, —

S—

R⁶⁵, —

N(R⁶⁶)—

R⁶⁵, —

N(R⁶⁶)—

C(O)—

R⁶⁵, —

N(R⁶⁶)—

S(O)—

R⁶⁵, —

N(R⁶⁶)—

S(O)₂—

R⁶⁵, —

S(O)—

R⁶⁵, —

S(O)₂—

R⁶⁵, —

C(O)—

R⁶⁵, —

C(O)—

O—

R⁶⁵, —

C(O)—

N(R⁶⁶)—

R⁶⁵, —

S(O)—

N(R⁶⁶)—

R⁶⁵, —

S(O)₂—

N(R⁶⁶)—

R⁶⁵, 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 R⁶⁴, or as substituents of lower alkyl, are optionally substituted with one or more substituents selected from the group consisting of —

OH, —

NH₂, —

NO₂, —

CN, —

C(O)—

OH, —

S(O)₂—

NH₂, —

C(O)—

NH₂, —

O—

R⁶⁷, —

S—

R⁶⁷, —

N(R⁶⁶)—

R⁶⁷, —

N(R⁶⁶)—

C(O)—

R⁶⁷, —

N(R⁶⁶)—

S(O)₂—

R⁶⁷, —

S(O)—

R⁶⁷, —

S(O)₂—

R⁶⁷, —

C(O)—

R⁶⁷, —

C(O)—

O—

R⁶⁷, —

C(O)—

N(R⁶⁶)—

R⁶⁷, —

S(O)₂—

N(R⁶⁶)—

R⁶⁷, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino;

R⁶⁵ at each occurrence is independently selected from the group consisting of 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 R⁶⁵ or as substituents of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of —

OH, —

NH₂, —

CN, —

NO₂, —

C(O)—

OH, —

S(O)₂—

NH₂, —

C(O)—

NH₂, —

O—

R⁶⁹, —

S—

R⁶⁹, —

N(R⁶⁸)—

R⁶⁹, —

N(R⁶⁸)—

C(O)—

R⁶⁹, —

N(R⁶⁸)—

S(O)₂—

R⁶⁹, —

C(O)—

R⁶⁹, —

S(O)—

R⁶⁹, —

S(O)₂—

R⁶⁹, —

C(O)—

O—

R⁶⁹, —

C(O)—

N(R⁶⁸)—

R⁶⁹, —

S(O)₂—

N(R⁶⁸)—

R⁶⁹, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino;

R⁶⁶ and R⁶⁸ at each occurrence are independently hydrogen, lower alkyl, or lower alkyl substituted with one or more substituents selected from the group consisting of fluoro, —

OH, —

NH₂, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, fluoro substituted mono-alkylamino, di-alkylamino, fluoro substituted di-alkylamino, and cycloalkylamino; and

R⁶⁷ and R⁶⁹ at each occurrence are independently selected from the group consisting of lower alkyl, heterocycloalkyl 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, and cycloalkylamino, and wherein heterocycloalkyl and heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, —

CN, lower alkyl, fluoro substituted lower alkyl, lower alkoxy and fluoro substituted lower alkoxy.

11. The compound of claim 10, wherein:

R⁵⁷ is selected from the group consisting of lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl, is optionally substituted with one or more substituents R⁶³, and wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents R⁶⁴;

R⁶³ at each occurrence is independently selected from the group consisting of —

OH, —

NH₂, —

O—

R⁶⁵, —

S—

R⁶⁵, —

N(R⁶⁶)—

R⁶⁵, —

N(R⁶⁶)—

C(O)—

R⁶⁵, —

N(R⁶⁶)—

S(O)—

R⁶⁵, —

N(R⁶⁶)—

S(O)₂—

R⁶⁵, —

C(O)—

R⁶⁵, —

S(O)—

R⁶⁶, —

S(O)₂—

R⁶⁵, fluoro, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one or more substituents R⁶⁴; and

R⁶⁴ at each occurrence is independently selected from the group consisting of —

OH, —

NH₂, —

NO₂, —

CN, —

O—

R⁶⁵, —

S—

R⁶⁵, —

N(R⁶⁶)—

R⁶⁵, —

N(R⁶⁶)—

C(O)—

R⁶⁵, —

N(R⁶⁶)—

S(O)—

R⁶⁵, —

N(R⁶⁶)—

S(O)₂R⁶⁵, —

C(O)—

R⁶⁵, —

S(O)—

R⁶⁵, —

S(O)₂—

R⁶⁵, 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 R⁶⁴, or as substituents of lower alkyl, are optionally substituted with one or more substituents selected from the group consisting of —

OH, —

NH₂, —

NO₂, —

CN, —

O—

R⁶⁷, —

S—

R⁶⁷, —

N(R⁶⁶)—

R⁶⁷, —

N(R⁶⁶)—

C(O)—

R⁶⁷, —

N(R⁶⁶)—

S(O)₂—

R⁶⁷, —

S(O)—

R⁶⁷, —

S(O)₂—

R⁶⁷, —

C(O)—

R⁶⁷, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino.

12. The compound of claim 11, wherein:

R⁵⁸ is selected from the group consisting of hydrogen, —

CN, —

O—

R⁷⁰, —

S—

R⁷⁰, —

N(R⁷¹)—

R⁷⁰, fluoro, and lower alkyl, 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, and cycloalkylamino;

R⁵⁹ is selected from the group consisting of hydrogen, —

CN, —

O—

R⁷⁰, —

S—

R⁷⁰, —

N(R⁷¹)—

R⁷⁰, fluoro, and lower alkyl, 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, and cycloalkylamino;

R⁶⁰ is hydrogen;

R⁷⁰ is lower alkyl 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, and cycloalkylamino; and

R⁷¹ is hydrogen or lower alkyl 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, and cycloalkylamino.

13. A composition comprising a pharmaceutically acceptable carrier;

and a compound according to claim 1.

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

15. A kit comprising a composition according to claim 13.

16. A method for treating a subject suffering from or at risk of a Raf kinase-mediated disease or condition, comprising administering to the subject an effective amount of a compound of claim 1.

17. The method of claim 16, wherein the disease or condition is selected from the group consisting of multi-infarct dementia, head injury, spinal cord injury, Alzheimer'"'"'s disease, Parkinson'"'"'s disease, seizures and epilepsy, melanoma, glioma, sarcoma, gastrointestinal carcinoma, liver carcinoma, cholangiocarcinoma, colorectal carcinoma, lung carcinoma, breast carcinoma, pancreatic carcinoma, thyroid carcinoma, renal carcinoma, ovarian carcinoma, prostate carcinoma, histiocytic lymphoma, neurofibromatosis, acute myeloid leukemia, myelodysplastic syndrome, leukemia, tumor angiogenesis, medullary thyroid cancer, carcinoid, small cell lung cancer, Kaposi'"'"'s sarcoma, pheochromocytoma, acute pain, chronic pain, cancer-related pain, migraine, heart failure, ischemic stroke, cardiac hypertrophy, thrombosis, atherosclerosis, reperfusion injury, psoriasis, eczema, arthritis, osteoarthritis, endometriosis, scarring, vascular restenosis, fibrotic disorders, rheumatoid arthritis, inflammatory bowel disease, organ transplant rejection, graft versus host disease, Kaposi'"'"'s sarcoma associated with HIV, diabetic nephropathy, polycystic kidney disease, nephrosclerosis, glomerulonephritis, prostate hyperplasia, polycystic liver disease, tuberous sclerosis, Von Hippel Lindau disease, medullary cystic kidney disease, nephronophthisis, cystic fibrosis, obesity, infection of Helicobacter pylori, Hepatitis and Influenza viruses, fever, HIV, sepsis, chronic obstructive pulmonary disease, acute respiratory distress syndrome, Noonan'"'"'s syndrome, Costello syndrome, LEOPARD syndrome, cardio-faciocutaneous syndrome, neural crest syndrome abnormalities causing cardiovascular, skeletal, intestinal, skin, hair and endocrine diseases, sarcopenia, Duchenne muscular dystrophy, Becker muscular dystrophy, Emery-Dreifuss muscular dystrophy, Limb-Girdle muscular dystrophy, Facioscapulohumeral muscular dystrophy, Myotonic muscular dystrophy, Oculopharyngeal muscular dystrophy. Distal muscular dystrophy and Congenital muscular dystrophy, amyotrophic lateral sclerosis, infantile progressive spinal muscular atrophy, intermediate spinal muscular atrophy, juvenile spinal muscular atrophy, spinal bulbar muscular atrophy, adult spinal muscular atrophy, dermatomyositis, polymyositis, inclusion body myositis, myasthenia gravis, Lambert-Eaton syndrome, congenital myasthenic syndrome, hyperthyroid myopathy, hypothyroid myopathy, Charcot-Marie-Tooth disease, Dejerine-Sottas disease, Friedreich'"'"'s ataxia, myotonia congenita, paramyotonia congenita, central core disease, nemaline myopathy, myotubular myopathy, periodic paralysis, phosphorylase deficiency, acid maltase deficiency, phosphofructokinase deficiency, debrancher enzyme deficiency, mitochondrial myopathy, carnitine deficiency, carnitine palmatyl transferase deficiency, phosphoglycerate kinase deficiency, phosphoglycerate mutase deficiency, lactate dehydrogenase deficiency, and myoadenylate deaminase deficiency.

18. The method of claim 16, wherein the disease or condition is selected from the group consisting of melanoma, colorectal cancer, thyroid cancer, ovarian cancer, cholangiocarcinoma, pain and polycystic kidney disease.

19. A method for treating a subject suffering from or at risk of a Raf kinase-mediated disease or condition, comprising administering to the subject an effective amount of a composition of claim 13.

20. The method of claim 19, wherein the disease or condition is selected from the group consisting of multi-infarct dementia, head injury, spinal cord injury, Alzheimer'"'"'s disease, Parkinson'"'"'s disease, seizures and epilepsy, melanoma, glioma, sarcoma, gastrointestinal carcinoma, liver carcinoma, cholangiocarcinoma, colorectal carcinoma, lung carcinoma, breast carcinoma, pancreatic carcinoma, thyroid carcinoma, renal carcinoma, ovarian carcinoma, prostate carcinoma, histiocytic lymphoma, neurofibromatosis, acute myeloid leukemia, myelodysplastic syndrome, leukemia, tumor angiogenesis, medullary thyroid cancer, carcinoid, small cell lung cancer, Kaposi'"'"'s sarcoma, pheochromocytoma, acute pain, chronic pain, cancer-related pain, migraine, heart failure, ischemic stroke, cardiac hypertrophy, thrombosis, atherosclerosis, reperfusion injury, psoriasis, eczema, arthritis, osteoarthritis, endometriosis, scarring, vascular restenosis, fibrotic disorders, rheumatoid arthritis, inflammatory bowel disease, organ transplant rejection, graft versus host disease, Kaposi'"'"'s sarcoma associated with HIV, diabetic nephropathy, polycystic kidney disease, nephrosclerosis, glomerulonephritis, prostate hyperplasia, polycystic liver disease, tuberous sclerosis, Von Hippel Lindau disease, medullary cystic kidney disease, nephronophthisis, cystic fibrosis, obesity, infection of Helicobacter pylori, Hepatitis and Influenza viruses, fever, HIV, sepsis, chronic obstructive pulmonary disease, acute respiratory distress syndrome, Noonan'"'"'s syndrome, Costello syndrome, LEOPARD syndrome, cardio-faciocutaneous syndrome, neural crest syndrome abnormalities causing cardiovascular, skeletal, intestinal, skin, hair and endocrine diseases, sarcopenia. Duchenne muscular dystrophy, Becker muscular dystrophy, Emery-Dreifuss muscular dystrophy, Limb-Girdle muscular dystrophy, Facioscapulohumeral muscular dystrophy, Myotonic muscular dystrophy, Oculopharyngeal muscular dystrophy, Distal muscular dystrophy and Congenital muscular dystrophy, amyotrophic lateral sclerosis, infantile progressive spinal muscular atrophy, intermediate spinal muscular atrophy, juvenile spinal muscular atrophy, spinal bulbar muscular atrophy, adult spinal muscular atrophy, dermatomyositis, polymyositis, inclusion body myositis, myasthenia gravis, Lambert-Eaton syndrome, congenital myasthenic syndrome, hyperthyroid myopathy, hypothyroid myopathy, Charcot-Marie-Tooth disease, Dejerine-Sottas disease, Friedreich'"'"'s ataxia, myotonia congenita, paramyotonia congenita, central core disease, nemaline myopathy, myotubular myopathy, periodic paralysis, phosphorylase deficiency, acid maltase deficiency, phosphofructokinase deficiency, debrancher enzyme deficiency, mitochondrial myopathy, carnitine deficiency, carnitine palmatyl transferase deficiency, phosphoglycerate kinase deficiency, phosphoglycerate mutase deficiency, lactate dehydrogenase deficiency, and myoadenylate deaminase deficiency.

21. The method of claim 19, wherein the disease or condition is selected from the group consisting of melanoma, colorectal cancer, thyroid cancer, ovarian cancer, cholangiocarcinoma, pain and polycystic kidney disease.