Claims for Patent: 8,148,401

Summary for Patent: 8,148,401

Title:	Benzimidazole derivatives
Abstract:	The present invention relates to a compound of the Formula I ##STR00001## or a pharmaceutically acceptable salt thereof, wherein R.sup.1, R.sup.2, R.sup.3A, R.sup.3B, R.sup.4, R.sup.5, 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.
Inventor(s):	Munchhof; Michael J. (Salem, CT), Reiter; Lawrence A. (Mystic, CT), La Greca; Susan D. (Old Lyme, CT), Jones; Christopher S. (Gales Ferry, CT), Li; Qifang (Stonington, CT)
Assignee:	Pfizer Inc. (New York, NY)
Application Number:	12/142,119
Patent Claims:	1. A compound of Formula II(a), ##STR00198## wherein: each R.sup.1 is independently halo, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy, --CF.sub.3, --CN, or --NR.sup.16R.sup.17; R.sup.2 is hydrogen or (C.sub.1-C.sub.6)alkyl; R.sup.3B is hydrogen, (C.sub.1-C.sub.6)alkyl, --(CH.sub.2).sub.t(C.sub.6-C.sub.12)aryl, or --(CH.sub.2).sub.t(C.sub.3-C.sub.12)carbocyclyl; R.sup.4 is hydrogen or (C.sub.1-C.sub.6)alkyl; R.sup.10 is --(CH.sub.2).sub.t(C.sub.6-C.sub.12)aryl or --(CH.sub.2).sub.t(4 to 14 membered heterocyclyl), wherein each of said (C.sub.6-C.sub.12)aryl and (4 to 14 membered heterocyclyl) is optionally substituted with from 1 to 5 substituents each of which is independently selected from (C.sub.1-C.sub.6)alkyl, --CN, halo, --CF.sub.3, --OCF.sub.3, --NR.sup.16R.sup.17, (C.sub.1-C.sub.6)alkoxy, --NO.sub.2, --(CH.sub.2).sub.t(C.sub.6-C.sub.12)aryl, --C(O)(C.sub.1-C.sub.6 alkyl), --C(O)CF.sub.3, azido, (4 to 12 membered heterocyclyl), and --S((C.sub.1-C.sub.6)alkyl); each R.sup.16 and R.sup.17 is independently selected from hydrogen and (C.sub.1-C.sub.6)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 R.sup.1 is independently F, Cl, Br, --CH.sub.3, --OCH.sub.3, --CF.sub.3, --CN, or --NR.sup.16R.sup.17; R.sup.2 is hydrogen; R.sup.3B is hydrogen, --CH.sub.3, --CH.sub.2CH.sub.3, --CH.sub.2CH.sub.2CH.sub.3, --CH(CH.sub.3).sub.2, --CH.sub.2CH.sub.2CH.sub.2CH.sub.3, --CH.sub.2CH(CH.sub.3).sub.2, or --CH.sub.2(phenyl); R.sup.4 is hydrogen; and R.sup.10 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 (C.sub.1-C.sub.6)alkyl, --CN, halo, --CF.sub.3, --OCF.sub.3, --NR.sup.16R.sup.17, (C.sub.1-C.sub.6)alkoxy, --NO.sub.2, --(CH.sub.2).sub.t(C.sub.6-C.sub.12)aryl, --C(O)(C.sub.1-C.sub.6 alkyl), --C(O)CF.sub.3, azido, (4 to 12 membered heterocyclyl), and --S((C.sub.1-C.sub.6)alkyl); or a pharmaceutically acceptable salt thereof. 3. A compound according to claim 2, wherein: each R.sup.1 is independently F, Cl, --CH.sub.3, --OCH.sub.3, --CF.sub.3, --CN, or --N(CH.sub.3).sub.2; R.sup.3B is --CH.sub.3; and R.sup.10 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 (C.sub.1-C.sub.6)alkyl, --CN, halo, --CF.sub.3, --OCF.sub.3, --NR.sup.16R.sup.17, (C.sub.1-C.sub.6)alkoxy, --NO.sub.2, --(CH.sub.2).sub.t(C.sub.6-C.sub.12)aryl, --C(O)(C.sub.1-C.sub.6 alkyl), --C(O)CF.sub.3, azido, (4 to 12 membered heterocyclyl), and --S((C.sub.1-C.sub.6)alkyl); or a pharmaceutically acceptable salt thereof. 4. A compound according to claim 3, wherein R.sup.10 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 (C.sub.1-C.sub.6)alkyl, --CN, halo, --CF.sub.3, --OCF.sub.3, --NR.sup.16R.sup.17, (C.sub.1-C.sub.6)alkoxy, --NO.sub.2, --(CH.sub.2).sub.t(C.sub.6-C.sub.12)aryl, --C(O)(C.sub.1-C.sub.6 alkyl), --C(O)CF.sub.3, azido, (4 to 12 membered heterocyclyl), and --S((C.sub.1-C.sub.6)alkyl); or a pharmaceutically acceptable salt thereof. 5. A compound according to claim 4, wherein R.sup.10 is phenyl optionally substituted with from 1 to 5 substituents each of which is independently selected from (C.sub.1-C.sub.6)alkyl, --CN, halo, --CF.sub.3, --OCF.sub.3, --NR.sup.16R.sup.17, (C.sub.1-C.sub.6)alkoxy, --NO.sub.2, --(CH.sub.2).sub.t(C.sub.6-C.sub.12)aryl, --C(O)(C.sub.1-C.sub.6 alkyl), --C(O)CF.sub.3, azido, (4 to 12 membered heterocyclyl), and --S((C.sub.1-C.sub.6)alkyl); or a pharmaceutically acceptable salt thereof. 6. A compound according to claim 5, wherein R.sup.10 is phenyl optionally substituted with from 1 to 5 substituents each of which is independently selected from --CH.sub.3, --CN, --F, --Cl, --Br, --CF.sub.3, --OCF.sub.3, --NR.sup.16R.sup.17, --OCH.sub.3, and --NO.sub.2; or a pharmaceutically acceptable salt thereof. 7. A compound of Formula III(a), ##STR00199## wherein: each R.sup.1 is independently halo, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy, --CF.sub.3, --CN, or --NR.sup.16R.sup.17; R.sup.2 is hydrogen or (C.sub.1-C.sub.6)alkyl; R.sup.3B is hydrogen, (C.sub.1-C.sub.6)alkyl, --(CH.sub.2).sub.t(C.sub.6-C.sub.12)aryl, or --(CH.sub.2).sub.t(C.sub.3-C.sub.12)carbocyclyl; R.sup.4 is hydrogen or (C.sub.1-C.sub.6)alkyl; R.sup.11 is --(CH.sub.2).sub.t(C.sub.6-C.sub.12)aryl or --(CH.sub.2).sub.t(4 to 14 membered heterocyclyl), wherein each of said (C.sub.6-C.sub.12)aryl and (4 to 14 membered heterocyclyl) is optionally substituted with from 1 to 5 substituents each of which is independently selected from (C.sub.1-C.sub.6)alkyl, --CN, halo, --CF.sub.3, --OCF.sub.3, --NR.sup.16R.sup.17, (C.sub.1-C.sub.6)alkoxy, --NO.sub.2, --(CH.sub.2).sub.t(C.sub.6-C.sub.12)aryl, --C(O)(C.sub.1-C.sub.6 alkyl), --C(O)CF.sub.3, azido, (4 to 12 membered heterocyclyl), and --S((C.sub.1-C.sub.6)alkyl); each R.sup.16 and R.sup.17 is independently selected from hydrogen and (C.sub.1-C.sub.6)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) ##STR00200## wherein: each R.sup.1 is independently halo, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy, --CF.sub.3, --CN, or --NR.sup.16R.sup.17; R.sup.2 is hydrogen or (C.sub.1-C.sub.6)alkyl; R.sup.3B is hydrogen, (C.sub.1-C.sub.6)alkyl, --(CH.sub.2).sub.t(C.sub.6-C.sub.12)aryl, or --(CH.sub.2).sub.t(C.sub.3-C.sub.12)carbocyclyl; R.sup.4 is hydrogen or (C.sub.1-C.sub.6)alkyl; each R.sup.12 is independently selected from --(CH.sub.2).sub.t(C.sub.6-C.sub.12)aryl, --(CH.sub.2).sub.t(4 to 14 membered heterocyclyl), (C.sub.1-C.sub.6)alkyl, --CN, halo, --CF.sub.3, --OCF.sub.3, --NR.sup.16R.sup.17, (C.sub.1-C.sub.6)alkoxy, --NO.sub.2, --(CH.sub.2).sub.t(C.sub.6-C.sub.12)aryl, --C(O)(C.sub.1-C.sub.6 alkyl), --C(O)CF.sub.3, azido, (4 to 12 membered heterocyclyl), and --S((C.sub.1-C.sub.6)alkyl); each R.sup.16 and R.sup.17 is independently selected from hydrogen and (C.sub.1-C.sub.6)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: R.sup.2 is hydrogen; R.sup.3B is --CH.sub.3; R.sup.4 is hydrogen; and each R.sup.12 is independently selected from --CN, --F, --Cl, --Br, --CF.sub.3, --OCF.sub.3, --NR.sup.16R.sup.17, --OCH.sub.3, and --NO.sub.2; or a pharmaceutically acceptable salt thereof. 10. A compound according to claim 9, wherein: each R.sup.1 is independently halo, --CH.sub.3, --OCH.sub.3, --CF.sub.3, --CN, or --N(CH.sub.3).sub.2; R.sup.12 is --CN, --F, --Cl, --Br, --CF.sub.3, --OCF.sub.3, --OCH.sub.3, or --NO.sub.2; and z is 1; or a pharmaceutically acceptable salt thereof. 11. A compound according to claim 10, wherein: R.sup.12 is --CN, --F, --Cl, --Br, or --CF.sub.3; and n is 0; or a pharmaceutically acceptable salt thereof. 12. A compound according to claim 11, wherein R.sup.12 is --CN, or a pharmaceutically acceptable salt thereof. 13. A compound selected from: 1-[(2R,4R)-2-(1H-benzimidazol-2-yl)-1-methylpiperidin-4-yl]-3-(4-cyanophe- nyl)urea; 1-[(2R,4R)-2-(1H-benzimidazol-2-yl)-1-methylpiperidin-4-yl]-3-(4- -chlorophenyl)urea; 1-[(2R,4R)-2-(1H-benzimidazol-2-yl)-1-methylpiperidin-4-yl]-3-(6-fluoropy- ridin-3-yl)urea; N-[(2R,4R)-2-(1H-benzimidazol-2-yl)-1-methylpiperidin-4-yl]chromane-6-car- boxamide; 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-methoxyp- henyl)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-cyanop- henyl)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. 14. A compound which is ##STR00201## or a pharmaceutically acceptable salt thereof. 15. A compound which is ##STR00202## or a pharmaceutically acceptable salt thereof. 16. A compound which is ##STR00203## 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.