BENZIMIDAZOLE DERIVATIVES

• US 20090005416A1
• Filed: 06/19/2008
• Published: 01/01/2009
• Est. Priority Date: 06/29/2007
• Status: Active Grant

• Current Assignee: Pfizer Inc.
• Original Assignee: Pfizer Inc.
• Inventors: Jones, Christopher S., La Greca, Susan D., Reiter, Lawrence A., Munchhof, Michael J., Li, Qifang
• Granted Patent: US 8,148,401 B2
• Time in Patent Office: Days
• US Class Current: 514/318
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 401/04 directly linked by a ring-member-to-ring-member bond
• 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 403/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 403/14 containing three or more hetero rings
• CPC Class Codes: C07D 405/14 containing three or more hetero rings
• CPC Class Codes: C07D 409/14 containing three or more hetero rings
• CPC Class Codes: C07D 413/14 containing three or more hetero rings
• CPC Class Codes: C07D 471/04 Ortho-condensed systems

Abstract

The present invention relates to a compound of the Formula I

or a pharmaceutically acceptable salt thereof, wherein R¹, R², R^3A, R^3B, R⁴, R⁵, X, m, and n are as defined herein. Such novel benzamidazole derivatives are useful in the treatment of abnormal cell growth, such as cancer, in mammals. This invention also relates to a method of using such compounds in the treatment of abnormal cell growth in mammals, especially humans, and to pharmaceutical compositions containing such compounds.

Claims

1. A compound of Formula II(a),

wherein:

each R¹ is independently halo, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, —

CF₃, —

CN, or —

NR¹⁶R¹⁷;

R² is hydrogen or (C₁-C₆)alkyl;

R^3B is hydrogen, (C₁-C₆)alkyl, —

(CH₂)_t(C₆-C₁₂)aryl, or —

(CH₂)_t(C₃-C₁₂)carbocyclyl;

R⁴ is hydrogen or (C₁-C₆)alkyl;

R¹⁰ is —

(CH₂)_t(C₆-C₁₂)aryl or —

(CH₂)_t(4 to 14 membered heterocyclyl), wherein each of said (C₆-C₁₂)aryl and (4 to 14 membered heterocyclyl) is optionally substituted with from 1 to 5 substituents each of which is independently selected from (C₁-C₆)alkyl, —

CN, halo, —

CF₃, —

OCF₃, —

NR¹⁶R¹⁷, (C₁-C₆)alkoxy, —

NO₂, —

(CH₂)_t(C₆-C₁₂)aryl, —

C(O)(C₁-C₆ alkyl), —

C(O)CF₃, azido, (4 to 12 membered heterocyclyl), and —

S((C₁-C₆)alkyl);

each R¹⁶ and R¹⁷ is independently selected from hydrogen and (C₁-C₆)alkyl;

n is 0, 1, 2, 3, or 4; and

each t is independently 0, 1, or 2;

or

a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1, wherein:

each R¹ is independently F, Cl, Br, —

CH₃, —

OCH₃, —

CF₃, —

CN, or —

NR¹⁶R¹⁷;

R² is hydrogen;

R^3B is hydrogen, —

CH₃, —

CH₂CH₃, —

CH₂CH₂CH₃, —

CH(CH₃)₂, —

CH₂CH₂CH₂CH₃, —

CH₂CH(CH₃)₂, or —

CH₂(phenyl);

R⁴ is hydrogen; and

R¹⁰ is phenyl, pyridyl, or 2,3-dihydro-1,4-benzodioxinyl, wherein each of said phenyl, pyridyl, and 2,3-dihydro-1,4-benzodioxinyl is optionally substituted with from 1 to 5 substituents each of which is independently selected from (C₁-C₆)alkyl, —

CN, halo, —

CF₃, —

OCF₃, —

NR¹⁶R¹⁷, (C₁-C₆)alkoxy, —

NO₂, —

(CH₂)_t(C₆-C₁₂)aryl, —

C(O)(C₁-C₆ alkyl), —

C(O)CF₃, azido, (4 to 12 membered heterocyclyl), and —

S((C₁-C₆)alkyl);

or

a pharmaceutically acceptable salt thereof.

3. A compound according to claim 2, wherein:

each R¹ is independently F, Cl, —

CH₃, —

OCH₃, —

CF₃, —

CN, or —

N(CH₃)₂;

R^3B is —

CH₃; and

R¹⁰ is phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, or 2,3-dihydro-1,4-benzodioxin-6-yl, wherein each of said phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, and 2,3-dihydro-1,4-benzodioxin-6-yl is optionally substituted with from 1 to 5 substituents each of which is independently selected from (C₁-C₆)alkyl, —

CN, halo, —

CF₃, —

OCF₃, —

NR¹⁶R¹⁷, (C₁-C₆)alkoxy, —

NO₂, —

(CH₂)_t(C₆-C₁₂)aryl, —

C(O)(C₁-C₆ alkyl), —

C(O)CF₃, azido, (4 to 12 membered heterocyclyl), and —

S((C₁-C₆)alkyl);

or

a pharmaceutically acceptable salt thereof.

4. A compound according to claim 3, wherein R¹⁰ is phenyl, 3-pyridyl, or 2,3-dihydro-1,4-benzodioxin-6-yl, wherein each of said phenyl, 3-pyridyl, and 2,3-dihydro-1,4-benzodioxin-6-yl is optionally substituted with from 1 to 5 substituents each of which is independently selected from (C₁-C₆)alkyl, —

CN, halo, —

CF₃, —

OCF₃, —

NR¹⁶R¹⁷, (C₁-C₆)alkoxy, —

NO₂, —

(CH₂)_t(C₆-C₁₂)aryl, —

C(O)(C₁-C₆ alkyl), —

C(O)CF₃, azido, (4 to 12 membered heterocyclyl), and —

S((C₁-C₆)alkyl);

or a pharmaceutically acceptable salt thereof.

5. A compound according to claim 4, wherein R¹⁰ is phenyl optionally substituted with from 1 to 5 substituents each of which is independently selected from (C₁-C₆)alkyl, —

CN, halo, —

CF₃, —

OCF₃, —

NR¹⁶R¹⁷, (C₁-C₆)alkoxy, —

NO₂, —

(CH₂)_t(C₆-C₁₂)aryl, —

C(O)(C₁-C₆ alkyl), —

C(O)CF₃, azido, (4 to 12 membered heterocyclyl), and —

S((C₁-C₆)alkyl);

or a pharmaceutically acceptable salt thereof.

6. A compound according to claim 5, wherein R¹⁰ is phenyl optionally substituted with from 1 to 5 substituents each of which is independently selected from —

CH₃, —

CN, —

F, —

Cl, —

Br, —

CF₃, —

OCF₃, —

NR¹⁶R¹⁷, —

OCH₃, and —

NO₂;

or a pharmaceutically acceptable salt thereof.

13. A compound according to claim 1, selected from:

1-[(2R,4R)-2-(1H-benzimidazol-2-yl)-1-methylpiperidin-4-yl]-3-(4-cyanophenyl)urea;

1-[(2R,4R)-2-(1H-benzimidazol-2-yl)-1-methylpiperidin-4-yl]-3-(4-chlorophenyl);

1-[(2R,4R)-2-(1H-benzimidazol-2-yl)-1-methylpiperidin-4-yl]-3-(6-fluoropyridin-3-yl)urea;

N-[(2R,4R)-2-(1H-benzimidazol-2-yl)-1-methylpiperidin-4-yl]chromane-6-carboxamide;

N-[(2R,4R)-2-(6-chloro-1H-benzimidazol-2-yl)-1-methylpiperidin-4-yl]-2,3-dihydro-1,4-benzodioxine-6-carboxamide;

1-{(2R,4R)-1-methyl-2-[5-(trifluoromethyl)-1H-benzimidazol-2-yl]piperidin-4-yl}-3-[6-(trifluoromethyl)pyridin-3-yl]urea;

1-[(2R,4R)-2-(1H-benzimidazol-2-yl)-1-methylpiperidin-4-yl]-3-(4-methoxyphenyl)urea;

N-[(2R,4R)-2-(6-methoxy-1H-benzimidazol-2-yl)-1-methylpiperidin-4-yl]-2,3-dihydro-1,4-benzodioxine-6-carboxamide;

1-[(2R,4R)-2-(1H-benzimidazol-2-yl)-1-isobutylpiperidin-4-yl]-3-(4-cyanophenyl)urea; and

1-[(2R,4R)-2-(1H-benzimidazol-2-yl)-1-methylpiperidin-4-yl]-3-(6-fluoro-5-methylpyridin-3-yl)urea;

or

a pharmaceutically acceptable salt thereof.

17. A pharmaceutical composition, comprising an effective amount of at least one compound according to claim 1, and a pharmaceutically acceptable carrier.

18. A method of treating abnormal cell growth in a mammal, comprising administering to said mammal an amount of a compound according to claim 1, or a pharmaceutically acceptable salt thereof.

19. A method according to claim 18, wherein said abnormal cell growth is cancer.

20. A method according to claim 19, wherein said cancer is selected from the group consisting of basal cell cancer, medulloblastoma cancer, liver cancer, rhabdomyosarcoma, lung cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head, cancer of the neck, cutaneous melanoma, intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, colon cancer, breast cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin'"'"'s disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, prostate cancer, chronic or acute leukemia, lymphocytic lymphomas, cancer of the bladder, cancer of the kidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis, neoplasms of the central nervous system (CNS), primary CNS lymphoma, spinal axis tumors, brain stem glioma, and pituitary adenoma.

7. A compound of Formula III(a),

wherein:

each R¹ is independently halo, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, —

CF₃, —

CN, or —

NR¹⁶R¹⁷;

R² is hydrogen or (C₁-C₆)alkyl;

R^3B is hydrogen, (C₁-C₆)alkyl, —

(CH₂)_t(C₆-C₁₂)aryl, or —

(CH₂)_t(C₃-C₁₂)carbocyclyl;

R⁴ is hydrogen or (C₁-C₆)alkyl;

R¹¹ is —

(CH₂)_t(C₆-C₁₂)aryl or —

(CH₂)_t(4 to 14 membered heterocyclyl), wherein each of said (C₆-C₁₂)aryl and (4 to 14 membered heterocyclyl) is optionally substituted with from 1 to 5 substituents each of which is independently selected from (C₁-C₆)alkyl, —

CN, halo, —

CF₃, —

OCF₃, —

NR¹⁶R¹⁷, (C₁-C₆)alkoxy, —

NO₂, —

(CH₂)_t(C₆-C₁₂)aryl, —

C(O)(C₁-C₆ alkyl), —

C(O)CF₃, azido, (4 to 12 membered heterocyclyl), and —

S((C₁-C₆)alkyl);

each R¹⁶ and R¹⁷ is independently selected from hydrogen and (C₁-C₆)alkyl;

n is 0, 1, 2, 3, or 4; and

each t is independently 0, 1, or 2;

or

a pharmaceutically acceptable salt thereof.

8. A compound of Formula IV(a)

wherein:

each R¹ is independently halo, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, —

CF₃, —

CN, or —

NR¹⁶R¹⁷;

R² is hydrogen or (C₁-C₆)alkyl;

R^3B is hydrogen, (C₁-C₆)alkyl, —

(CH₂)_t(C₆-C₁₂)aryl, or —

(CH₂)_t(C₃-C₁₂)carbocyclyl;

R⁴ is hydrogen or (C₁-C₆)alkyl;

each R¹² is independently selected from —

(CH₂)_t(C₆-C₁₂)aryl, —

(CH₂)_t(4 to 14 membered heterocyclyl), (C₁-C₆)alkyl, —

CN, halo, —

CF₃, —

OCF₃, —

NR¹⁶R¹⁷, (C₁-C₆)alkoxy, —

NO₂, —

(CH₂)_t(C₆-C₁₂)aryl, —

C(O)(C₁-C₆ alkyl), —

C(O)CF₃, azido, (4 to 12 membered heterocyclyl), and —

S((C₁-C₆)alkyl);

each R¹⁶ and R¹⁷ is independently selected from hydrogen and (C₁-C₆)alkyl;

n is 0, 1, 2, 3, or 4;

each t is independently 0, 1, or 2; and

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

or

a pharmaceutically acceptable salt thereof.

9. A compound according to claim 8, wherein:

R² is hydrogen;

R^3B is —

CH₃;

R⁴ is hydrogen; and

each R¹² is independently selected from —

CN, —

F, —

Cl, —

Br, —

CF₃, —

OCF₃, —

NR¹⁶R¹⁷, —

OCH₃, and —

NO₂;

or

a pharmaceutically acceptable salt thereof.

10. A compound according to claim 9, wherein:

each R¹ is independently halo, —

CH₃, —

OCH₃, —

CF₃, —

CN, or —

N(CH₃)₂;

R¹² is —

CN, —

F, —

Cl, —

Br, —

CF₃, —

OCF₃, —

OCH₃, or —

NO₂; and

z is 1;

or

a pharmaceutically acceptable salt thereof.

11. A compound according to claim 10, wherein:

R¹² is —

CN, —

F, —

Cl, —

Br, or —

CF₃; and

n is 0;

or

a pharmaceutically acceptable salt thereof.

12. A compound according to claim 11, wherein R¹² is —

CN, or a pharmaceutically acceptable salt thereof.

14. A compound which is

or a pharmaceutically acceptable salt thereof.

15. A compound which is

or a pharmaceutically acceptable salt thereof.

16. A compound which is

or a pharmaceutically acceptable salt thereof.