COMPOUNDS AND METHODS FOR KINASE MODULATION, AND INDICATIONS THEREFOR

• US 20100190777A1
• Filed: 07/16/2008
• Published: 07/29/2010
• Est. Priority Date: 07/17/2007
• Status: Abandoned Application

• Current Assignee: Plexxikon Inc (Daiichi Sankyo Company Limited)
• Original Assignee: Plexxikon Inc (Daiichi Sankyo Company Limited)
• Inventors: Tsai, James, Wu, Guoxian, Artis, Dean R., Spevak, Wayne, Zhang, Jiazhong, Zhang, Chao, Ibrahim, Prabha N., Shi, Songyuan, Zhu, Yong-Liang
• Application Number:
  US12/669,450
• Publication Number:
  US 20100190777A1
• Time in Patent Office: Days
• US Class Current: 514/222.5
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
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• CPC Class Codes: A61K 31/42 Oxazoles
• CPC Class Codes: A61K 31/433 Thidiazoles
• CPC Class Codes: A61K 31/437 the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
• CPC Class Codes: A61K 31/44 Non condensed pyridines; Hydrogenated derivatives thereof
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• CPC Class Codes: A61K 31/4545 containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
• CPC Class Codes: A61K 31/47 Quinolines; Isoquinolines
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• CPC Class Codes: C07D 213/74 : Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
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• CPC Class Codes: C07D 213/76 : to which a second hetero atom is attached nitro radicals C07D213/61
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• CPC Class Codes: C07D 471/04 : Ortho-condensed systems

Abstract

Compounds of formula I 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. Formula (I) wherein Ar is optionally substituted heteroaryl; R² is hydrogen, lower alkyl or halogen; U is selected from the group consisting of —S(O)₂—, —C(X)—, —C(X)—N(R¹⁰)—, and —S(O)₂—N(R¹⁰)—; R³ is optionally substituted lower alkyl, optionally substituted C3.6 cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl or optionally substituted heteroaryl; and wherein R¹, R³, R⁴, m, L₁, X R¹⁰ are as described herein.

Claims

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

or a salt, a prodrug, a tautomer or an isomer thereof,

wherein:

Ar is optionally substituted heteroaryl;

R¹ at each occurrence is independently selected from the group consisting of halogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkenyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, —

NO₂, —

CN, —

O—

R⁵, —

N(R⁵)—

R⁶, —

C(X)—

N(R⁵)—

R⁶, —

C(X)—

R⁷, —

S(O)₂—

N(R⁵)—

R⁶, —

S(O)—

R⁷, —

O—

C(X)—

R⁷, —

C(X)—

O—

R⁵, —

C(NH)—

N(R⁸)—

R⁹, —

N(R⁵)—

C(X)—

R⁷, —

N(R⁵)—

S(O)₂—

R⁷, —

N(R⁵)—

C(X)—

N(R⁵)—

R⁶, and —

N(R⁵)—

S(O)₂—

N(R⁵)—

R⁶;

m is 0, 1, 2, 3, 4 or 5;

n is 0, 1 or 2;

R² is hydrogen, lower alkyl or halogen;

L₂ is selected from the group consisting of —

S(O)₂—

, —

C(X)—

, —

C(X)—

N(R¹⁹)—

, and —

S(O)₂—

N(R¹⁰)—

;

R³ is optionally substituted lower alkyl, optionally substituted C_3-6 cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl or optionally substituted heteroaryl;

L₁ is selected from the group consisting of a bond, —

N(R¹¹)—

, —

O—

, —

S—

, —

C(X)—

, —

C(R¹²R¹³)—

X—

, —

X—

C(R¹²R¹³)—

, —

C(R¹²R¹³)—

N(R¹¹)—

, —

N(R¹¹)—

C(R¹²R¹³)—

, —

O—

C(X)—

, —

C(X)—

O—

, —

C(X)—

N(R¹¹)—

, —

N(R¹¹)—

C(X)—

, —

S(O)—

, —

S(O)₂—

, —

S(O)₂—

N(R¹¹)—

, —

N(R¹¹)—

S(O)₂—

, —

C(NH)—

N(R¹¹)—

, —

N(R¹¹)—

C(NH)—

, —

N(R¹¹)—

C(X)—

N(R¹¹)—

, and —

N(R¹¹)—

S(O)₂—

N(R¹¹)—

;

X is O or S;

R⁴, R¹⁶ and each R¹¹ are independently hydrogen or lower alkyl, wherein lower alkyl is optionally 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 —

NR¹⁴R¹⁵;

R⁵, R⁶, R⁸, and R⁹ at each occurrence are independently selected from the group consisting of hydrogen, optionally substituted lower alkyl, optionally substituted C_3-6 alkenyl, optionally substituted C_3-6 alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl, or

R⁸ and R⁹ combine with the nitrogen to which they are attached to form a 5-7 membered optionally substituted nitrogen containing heterocycloalkyl or a 5 or 7 membered optionally substituted nitrogen containing heteroaryl;

R⁷ at each occurrence is independently selected from the group consisting of optionally substituted lower alkyl, optionally substituted C_3-6 alkenyl, optionally substituted C_3-6 alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;

R¹² and R¹³ are independently selected from the group consisting of hydrogen, fluoro, —

OH, —

NH₂, lower alkyl, lower alkoxy, lower alklylthio, mono-alkylamino, di-alkylamino, and —

NR¹⁴R¹⁵, wherein the alkyl chain(s) of lower alkyl, lower alkoxy, lower alkylthio, mono-alkylamino, or di-alkylamino are optionally 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, di-alkylamino, and cycloalkylamino;

or

R¹² and R¹³ combine with the carbon to which they are attached to form a 3-7 membered monocyclic cycloalkyl or 5-7 membered monocyclic heterocycloalkyl, wherein the monocyclic cycloalkyl or monocyclic heterocycloalkyl are optionally substituted with one or more substituents selected from the group consisting of halogen, —

OH, —

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

R¹⁴ and R¹⁵ at each occurrence independently combine with the nitrogen to which they are attached to form a 5-7 membered heterocycloalkyl or 5-7 membered heterocycloalkyl substituted with one or more substituents selected from the group consisting of fluoro, —

OH, —

NH₂, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, and fluoro substituted lower alkylthio,

provided, however, that when L₁ is a bond, —

NR¹¹—

, —

O—

, —

S—

, —

C(X)—

, —

S(O)—

, or —

S(O)₂—

, Ar is not 1H-pyrrolo[2,3-b]pyridine-3-yl, 1H-pyrazolo[3,4-b]pyridine-3-yl, 5H-pyrrolo[2,3-b]pyrazine-7-yl, 7H-pyrrolo[2,3-d]pyrimidine-5-yl, or 7H-pyrrolo[2,3-c]pyridazine-5-yl, i.e. is not

indicates the attachment point to L₁.

2. The compound of claim 1, wherein L₁ is a bond, —

N(R¹¹)—

, —

N(R¹¹)—

C(X)—

, —

N(R¹¹)—

S(O)₂—

, —

N(R¹¹)—

C(NH)—

, —

N(R¹¹)—

C(X)—

N(R¹¹)—

, or —

N(R¹¹)—

S(O)₂—

N(R¹¹)—

, and R² is hydrogen, fluoro, or chloro.

3. The compound of claim 2, wherein L₁ is —

N(R¹¹)—

, —

N(R¹¹)—

C(X)—

, or —

N(R¹¹)—

S(O)₂—

.

4. The compound of claim 3, wherein L₁ is —

N(R¹¹)—

C(O)—

.

5. The compound of claim 1, wherein L₁ is —

C(X)—

N(R¹¹)—

, —

C(R¹²R¹³)—

X—

, —

X—

C(R¹²R¹³)—

, —

C(R¹²R¹³)—

N(R¹¹)—

, or —

N(R¹¹)—

C(R¹²R¹³)—

, and R² is hydrogen, fluoro, or chloro.

8. A composition comprising a pharmaceutically acceptable carrier and a compound according to claim 4.

9. A kit comprising a compound according to claim 4.

10. A kit comprising a composition according to claim 8.

11. A method for treating a subject suffering from or at risk of a Raf mediated disease or condition, comprising administering to the subject an effective amount of a compound of claim 4.

12. A method for treating a subject suffering from or at risk of a Raf mediated disease or condition, comprising administering to the subject an effective amount of a composition according to claim 8.

6. The compound of 4, wherein

is selected from the group consisting of,

indicates the attachment point of the Ar ring to L₁;

p is 0, 1, 2 or 3;

R¹⁶ at each occurrence is independently selected from the group consisting of —

OH, —

NH₂, —

CN, —

NO₂, —

C(O)—

OH, —

S(O)₂—

NH₂, —

C(O)—

NH₂, —

O—

R¹⁷, —

S—

R¹⁷, —

N(R¹⁹)—

R¹⁷, —

N(R¹⁹)—

C(O)—

R¹⁷, —

N(R¹⁹)—

S(O)₂—

R¹⁷, —

S(O)₂—

R¹⁷, —

C(O)—

R¹⁷, —

C(O)—

O—

R¹⁷, —

C(O)—

N(R¹⁹)—

R¹⁷, —

S(O)₂—

N(R¹⁹)—

R¹⁷, 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, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as R¹⁶, 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—

R¹⁸, —

S—

R¹⁸, —

N(R¹⁹)—

R¹⁸, —

N(R¹⁹)—

C(O)—

R¹⁸, N(R¹⁹)—

S(O)₂—

R¹⁸, —

S(O)₂—

R¹⁸, —

C(O)—

R¹⁸, —

C(O)—

O—

R¹⁸, —

C(O)—

N(R¹⁹)—

R¹⁸, —

S(O)₂—

N(R¹⁹)—

R¹⁸, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino;

R¹⁷ 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, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as R¹⁷ 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—

R¹⁸, —

S—

R¹⁸, —

N(R¹⁹)—

R¹⁸, —

N(R¹⁹)—

(O)—

R¹⁸, —

N(R¹⁹)—

S(O)₂—

R¹⁸, —

S(O)₂—

R¹⁸, —

C(O)—

R¹⁸, —

C(O)—

O—

R¹⁸, —

C(O)—

N(R¹⁹)—

R¹⁸, —

S(O)₂—

N(R¹⁹)—

R¹⁸, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino;

R¹⁸ at each occurrence is 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

R¹⁹ at each occurrence is independently hydrogen or 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, and fluoro substituted lower alkylthio.

7. The compound of claim 6, wherein L₂ is —

S(O)₂—

.

13. A composition comprising a pharmaceutically acceptable carrier and a compound according to claim 7.

14. A kit comprising a compound according to claim 7.

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 mediated disease or condition, comprising administering to the subject an effective amount of a compound of claim 7.

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