Mitotic kinesin inhibitors

• US 7,060,705 B2
• Filed: 11/01/2002
• Issued: 06/13/2006
• Est. Priority Date: 11/07/2001
• Status: Expired due to Fees

• Current Assignee: Merck & Co., Inc.
• Original Assignee: Merck & Co., Inc.
• Inventors: Fraley, Mark E., Hoffman, William F.
• Primary Examiner(s): Balasubramanian, Venkataraman
• Application Number:
  US10/494,899
• Publication Number:
  US 20040259826A1
• Time in Patent Office: 1,320 Days
• Field of Search: 544/287, 544/62, 544/105, 544/82, 544/60, 540/460, 540/506, 540/480, 540/485, 540/492, 514/221, 514/224.8, 514/233.5, 514/266.2, 514/331, 514/266.22, 514/212.08, 514/227.8, 514/230.5
• US Class Current: 514/266.2
• 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 35/00 Antineoplastic agents
• 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 9/04 Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• CPC Class Codes: A61P 9/08 Vasodilators for multiple indications
• CPC Class Codes: C07D 239/88 Oxygen atoms
• CPC Class Codes: C07D 401/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 403/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 403/14 containing three or more hetero rings
• CPC Class Codes: C07D 471/04 Ortho-condensed systems
• CPC Class Codes: C07D 487/10 Spiro-condensed systems

Abstract

The present invention relates to quinazolinone compounds that are useful for treating cellular proliferative diseases, for treating disorders associated with KSP kinesin activity, and for inhibiting KSP kinesin. The invention also related to compositions which comprise these compounds, and methods of using them to treat cancer in mammals.

Claims

1. A compound of Formula I:

2. The compound according to claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

a is 0 or 1;

b is 0 or 1;

m is 0, 1, or 2;

n is 0 to 4;

R¹ is benzyl, optionally substituted with one or more substituents selected from R⁵;

R² is C₂–

C₆ alkyl;

R³ is H;

R⁴ is independently selected from;

1) (C═

O)_aO_bC₁–

C₁₀ alkyl,

2) (C═

O)_aO_baryl,

3) CO₂H,

4) halo,

5) OH,

6) O_bC₁–

C₆ perfluoroalkyl,

7) (C═

O)_aNR⁷R⁸,

8) CN,

9) (C═

O)_aO_bheterocyclyl,

10) SO₂NR⁷R⁸, and

11) SO₂C₁–

C₁₀ alkyl,

said alkyl, aryl, cycloalkyl, and heterocyclyl is optionally substituted with one or more substituents selected from R⁵;

R⁵ is;

1) (C═

O)_aO_bC₁–

C₁₀ alkyl,

2) (C═

O)_aO_baryl,

3) C₂–

C₁₀ alkenyl,

4) C₂–

C₁₀ alkynyl,

5) (C═

O)_aO_b heterocyclyl,

6) CO₂H,

7) halo,

8) CN,

9) OH,

10) O_bC₁–

C₆ perfluoroalkyl,

11) Oa(C═

O)_bNR⁷R⁸,

12) oxo,

13) CHO,

14) (N═

O)R⁷R⁸, or

15) (C═

O)_aO_bC₃–

C₈ cycloalkyl,

said alkyl, aryl, alkenyl, alkynyl, heterocyclyl, and cycloalkyl optionally substituted with one or more substituents selected from R⁶;

R⁵′

is;

1) H,

2) C₁–

C₁₀ alkyl,

3) aryl,

4) C₂–

C₁₀ alkenyl,

5) C₂–

C₁₀ alkynyl,

6) heterocyclyl,

7) OH,

8) C₁–

C₆ perfluoroalkyl,

9) C₃–

C₈ cycloalkyl;

said alkyl, aryl, alkenyl, alkynyl and heterocyclyl, and cycloalkyl optionally substituted with one or more substituents selected from R⁶;

R⁶ is selected from;

1) (C═

O)_rO_s(C₁–

C₁₀)alkyl, wherein r and s are independently 0 or 1,

2) O_r(C₁–

C₃)perfluoroalkyl, wherein r is 0 or 1,

3) oxo,

4) OH,

5) halo,

6) CN,

7) (C₂–

C₁₀)alkenyl,

8) (C₂–

C₁₀)alkynyl,

9) (C═

O)_rO_s(C₃–

C₆)cycloalkyl,

10) (C═

O)_rO_s(C₀–

C₆)alkylene-aryl,

11) (C═

O)_rO_s(C₀–

C₆)alkylene-heterocyclyl,

12) (C═

O)_rO_s(C₀–

C₆)alkylene-N(R^b)₂,

13) C(O)R^a,

14) (C₀–

C₆)alkylene-CO₂R^a,

15) C(O)H,

16) (C₀–

C₆)alkylene-CO₂H, and

17) C(O)N(R^b)₂,

said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl is optionally substituted with up to three substituents selected from R^b, OH, (C₁–

C₆)alkoxy, halogen, CO₂H, CN, O(C═

O)C₁–

C₆ alkyl, oxo, and N(R^b)₂;

R⁷ and R⁸ are independently selected from;

1) H,

2) (C═

O)O_bC₁–

C₁₀ alkyl,

3) (C═

O)O_bC₃–

C₈ cycloalkyl,

4) (C═

O)O_baryl,

5) (C═

O)O_bheterocyclyl,

6) C₁–

C₁₀ alkyl,

7) aryl,

8) C₂–

C₁₀ alkenyl,

9) C₂–

C₁₀ alkynyl,

10) heterocyclyl,

11) C₃–

C₈ cycloalkyl,

12) SO₂R^a, and

13) (C═

O)NR^b₂,

said alkyl, cycloalkyl, aryl, heterocylyl, alkenyl, and alkynyl is optionally substituted with one or more substituents selected from R⁶, or

R⁷ and R⁸ can be taken together with the nitrogen to which they are attached to form a monocyclic or bicyclic heterocycle with 5–

7 members in each ring and optionally containing, in addition to the nitrogen, one or two additional heteroatoms selected from N, O and S, said monocylcic or bicyclic heterocycle optionally substituted with one or more substituents selected from R⁶;

R^a is (C₁–

C₆)alkyl, (C₃–

C₆)cycloalkyl, aryl, or heterocyclyl; and

R^b is H, (C₁–

C₆)alkyl, aryl, heterocyclyl, (C₃–

C₆)cycloalkyl, (C═

O)OC₁–

C₆ alkyl, (C═

O)C₁–

C₆ alkyl or S(O)₂R^a.

7. A pharmaceutical composition that is comprised of a compound in accordance with claim 1 and a pharmaceutically acceptable carrier.

8. A method of treating cancer in a mammal in need of such treatment that is comprised of administering to said mammal a therapeutically effective amount of a compound of claim 1 wherein the cancer is selected from histiocytic lymphoma, lung adenocarcinoma, small cell lung cancer, pancreatic cancer, glioblastoma and breast carcinoma.

3. A compound of Formula I:

9. A pharmaceutical composition that is comprised of a compound in accordance with claim 3 and a pharmaceutically acceptable carrier.

10. A method of treating cancer in a mammal in need of such treatment that is comprised of administering to said mammal a therapeutically effective amount of a compound of claim 3 wherein the cancer is selected from histiocytic lymphoma, lung adenocarcinoma, small cell lung cancer, pancreatic cancer, glioblastoma and breast carcinoma.

4. A compound selected from:

3-benzyl-2-[1-(4-methylpiperazin-1-yl)propyl]quinazolin-4(3H)-one;

3-benzyl-2-{1-[4-(2-hydroxyethyl)piperazin-1-yl]propyl}quinazolin-4(3H)-one;

3-benzyl-2-(1-{4-[2-(2-hydroxyethoxy)ethyl]-piperazin-1-yl}propyl)quinazolin-4(3H)-one;

3-benzyl-2-[1-(4-benzylpiperazin-1-yl)propyl]quinazolin-4(3H)-one;

3-benzyl-2-{1-[4-(2-morpholin-4-yl-2-oxoethyl)piperazin-1-yl]propyl}quinazolin-4(3H)-one;

3-benzyl-2-{1-[4-(2-oxo-2-pyrrolidin-1-ylethyl)piperazin-1-yl]propyl}quinazolin-4(3H)-one;

3-benzyl-2-{1-[4-(pyridin-2-ylmethyl)piperazin-1-yl]propyl}quinazolin-4(3H)-one;

3-benzyl-2-(1-{3-[(dimethylamino)methyl]-piperidin-1-yl}propyl)quinazolin-4(3H)-one;

3-benzyl-2-(1-piperazin-1-ylpropyl)quinazolin-4(3H)-one;

3-benzyl-2-[1-(2,5-dimethylpiperazin-1-yl)propyl]quinazolin-4(3H)-one;

4-[1-(3-benzyl-4-oxo-3,4-dihydroquinazolin-2-yl)propyl]piperazine-2-carboxamide;

or a pharmaceutically acceptable salt or stereoisomer thereof.

5. A compound according to claim 4 selected from:

3-benzyl-2-[1-(4-methylpiperazin-1-yl)propyl]quinazolin-4(3H)-one;

3-benzyl-2-{1-[4-(2-hydroxyethyl)piperazin-1-yl]propyl}quinazolin-4(3H)-one;

3-benzyl-2-[1-(4-benzylpiperazin-1-yl)propyl]quinazolin-4(3H)-one;

3-benzyl-2-{1-[4-(2-morpholin-4-yl-2-oxoethyl)piperazin-1-yl]propyl}quinazolin-4(3H)-one;

3-benzyl-2-(1-{3-[(dimethylamino)methyl]-piperidin-1-yl}propyl)quinazolin-4(3H)-one;

or a pharmaceutically acceptable salt or stereoisomer thereof.

6. A TFA salt of a compound selected from:

3-benzyl-2-[1-(4-methylpiperazin-1-yl)propyl]quinazolin-4(3H)-one;

3-benzyl-2-{1-[4-(pyridin-2-ylmethyl)piperazin-1-yl]propyl}quinazolin-4(3H)-one;

3-benzyl-2-(1-{3-[(dimethylamino)methyl]-piperidin-1-yl}propyl)quinazolin-4(3H)-one;

3-benzyl-2-(1-piperazin-1-ylpropyl)quinazolin-4(3H)-one;

3-benzyl-2-[1-(2,5-dimethylpiperazin-1-yl)propyl]quinazolin-4(3H)-one; and

4-[1-(3-benzyl-4-oxo-3,4-dihydroquinazolin-2-yl)propyl]piperazine-2-carboxamide

or a stereoisomer thereof.