# US 8,772,507 B2 · Imidazole-benzamide anti-cancer agents

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- Number: US 8,772,507 B2
- Document ID: US8772507B2
- Status: Granted
- Kind: B2
- Application number: 13/612,690
- Filed: 2012-09-12
- Published: 2013-04-18
- Granted: 2014-07-08
- Earliest claimed: 2004-05-06
- Assignees: Cytokinetics, Inc.
- Applicants: Xiangping Qian; Andrew I. McDonald; Han-Jie Zhou; Luke W. Ashcraft; Bing Yao; Hong Jiang; Jennifer Kuo Chen Huang; Jianchao Wang; David J. Morgans, Jr.; Bradley P. Morgan; Gustave Bergnes; Dashyant Dhanak; Steven D. Knight; Nicholas D. Adams; Cynthia A. Parrish; Kevin Duffy; Duke Fitch; Rosanna Tedesco
- Inventors: Xiangping Qian; Andrew I. McDonald; Han-Jie Zhou; Luke W. Ashcraft; Bing Yao; Hong Jiang; Jennifer Kuo Chen Huang; Jianchao Wang; David J. Morgans, Jr.; Bradley P. Morgan; Gustave Bergnes; Dashyant Dhanak; Steven D. Knight; Nicholas D. Adams; Cynthia A. Parrish; Kevin Duffy; Duke Fitch; Rosanna Tedesco
- Web page: https://patentgrep.com/patent/US8772507B2

## CPC

- C07D 233/64: with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 31/10: Antimycotics
- A61P 35/00: Antineoplastic agents
- A61P 37/00: Drugs for immunological or allergic disorders
- C07C 235/48: having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
- C07C 235/50: having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by nitrogen atoms not being part of nitro or nitroso groups
- C07C 235/52: having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups
- C07C 237/22: having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated (peptides C07K)
- C07C 255/57: containing cyano groups and carboxyl groups, other than cyano groups, bound to the carbon skeleton
- C07C 255/59: the carbon skeleton being further substituted by singly-bound oxygen atoms
- C07C 255/60: at least one of the singly-bound nitrogen atoms being acylated
- C07C 257/08: having carbon atoms of imino-carboxyl groups bound to carbon atoms of six-membered aromatic rings
- C07C 257/18: having carbon atoms of amidino groups bound to carbon atoms of six-membered aromatic rings
- C07C 259/18: having carbon atoms of hydroxamidine groups bound to carbon atoms of six-membered aromatic rings
- C07C 271/20: to carbon atoms of hydrocarbon radicals substituted by nitrogen atoms not being part of nitro or nitroso groups
- C07C 271/24: with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a ring other than a six-membered aromatic ring
- C07C 271/28: to a carbon atom of a non-condensed six-membered aromatic ring
- C07C 275/26: having nitrogen atoms of urea groups bound to carbon atoms of rings other than six-membered aromatic rings
- C07C 275/40: being further substituted by nitrogen atoms not being part of nitro or nitroso groups
- C07C 275/42: being further substituted by carboxyl groups
- C07C 281/06: Compounds containing any of the groups [IMAGE cpc-sch-C07C-0973.gif], e.g. semicarbazides
- C07C 307/10: having nitrogen atoms of the sulfamide groups bound to carbon atoms of six-membered aromatic rings
- C07C 311/37: having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
- C07C 311/46: Y being a hydrogen or a carbon atom
- C07D 207/273: with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms
- C07D 211/34: with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D 211/76: attached in position 2 or 6
- C07D 213/30: Oxygen atoms
- C07D 231/12: with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D 231/14: with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D 233/61: with hydrocarbon radicals, substituted by nitrogen atoms not forming part of a nitro radical, attached to ring nitrogen atoms
- C07D 233/70: One oxygen atom
- C07D 235/06: with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
- C07D 235/16: Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D 235/18: with aryl radicals directly attached in position 2
- C07D 235/26: Oxygen atoms
- C07D 239/36: as doubly bound oxygen atom or as unsubstituted hydroxy radical
- C07D 249/08: 1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
- C07D 257/04: Five-membered rings
- C07D 261/08: with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D 263/10: with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D 263/12: with radicals containing only hydrogen and carbon atoms
- C07D 263/32: with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D 271/06: 1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
- C07D 271/07: with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
- C07D 271/10: 1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles
- C07D 271/113: with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
- C07D 277/30: Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D 277/42: Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
- C07D 277/56: Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D 285/02: Thiadiazoles; Hydrogenated thiadiazoles
- C07D 285/125: with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
- C07D 295/145: with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D 295/155: with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
- C07D 333/38: Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D 403/10: linked by a carbon chain containing aromatic rings
- C07D 403/12: linked by a chain containing hetero atoms as chain links
- C07D 413/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 471/04: Ortho-condensed systems
- C07D 498/04: Ortho-condensed systems
- C07F 9/6506: having the nitrogen atoms in positions 1 and 3
- C07F 9/6561: containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
- C07C 2601/02: with a three-membered ring
- C07C 2601/14: The ring being saturated
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07F: ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM (metal-containing porphyrins C07D487/22)

## Abstract

Compounds useful for treating cellular proliferative diseases and disorders by modulating the activity of one or more mitotic kinesins are disclosed.

## Claims

### Claim 1

A compound of Formula V:
or a pharmaceutically acceptable salt thereof, wherein
R2 is selected from hydrogen and lower alkyl;
R3 is selected from lower alkyl substituted with hydroxy and lower alkyl substituted with optionally substituted amino;
R11 is selected from hydrogen, cyano, nitro and halo;
R12 is optionally substituted lower alkoxy;
R13 is hydrogen;
R14 is 1H-imidazol-4-yl substituted with one, two or three groups selected from optionally substituted lower alkyl, halo, acyl, sulfonyl, cyano, nitro, optionally substituted amino, and optionally substituted heteroaryl; and
R15 is selected from hydrogen, halo, hydroxy, and lower alkyl.

### Claim 2 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R3 is lower alkyl substituted with hydroxy.

### Claim 3 (depends on 2)

The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein R3 is 2-hydroxyethyl.

### Claim 4 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R3 is lower alkyl substituted with optionally substituted amino.

### Claim 5 (depends on 4)

The compound of claim 4, or a pharmaceutically acceptable salt thereof, wherein R3 is lower alkyl substituted with 2-dimethylamino-acetylamino.

### Claim 6 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R11 is halo.

### Claim 7 (depends on 6)

The compound of claim 6, or a pharmaceutically acceptable salt thereof, wherein R11 is chloro.

### Claim 8 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R12 is optionally substituted isopropoxy.

### Claim 9 (depends on 8)

The compound of claim 8, or a pharmaceutically acceptable salt thereof, wherein R12 is 2,2,2-trifluoro-1-methyl-ethoxy.

### Claim 10 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R11 is chloro and R12 is 2,2,2-trifluoro-1-methyl-ethoxy.

### Claim 11 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R14 is selected from 1-methyl-1H-imidazol-4-yl and 1-ethyl-1H-imidazol-4-yl, each optionally substituted with optionally substituted lower alkyl.

### Claim 12 (depends on 11)

The compound of claim 11, or a pharmaceutically acceptable salt thereof, wherein R14 is selected from 1-methyl-1H-imidazol-4-yl and 1-ethyl-1H-imidazol-4-yl, each optionally substituted with 1-hydroxy-1-methyl-ethyl.

### Claim 13 (depends on 11)

The compound of claim 11, or a pharmaceutically acceptable salt thereof, wherein R14 is selected from 1-methyl-1H-imidazol-4-yl and 1-ethyl-1H-imidazol-4-yl, each optionally substituted with 1-acetylamino-ethyl.

### Claim 14 (depends on 1)

The compound of claim 1 selected from N-(1-{4-[2-(1-acetylamino-ethyl)-1-ethyl-1H-imidazo-4-yl]-benzyl}-3-hydroxy-propyl)-3-chloro-4-(2,2,2-trifluoro-1-methyl-ethoxy)-benzamide, or a pharmaceutically acceptable salt thereof.

### Claim 15 (depends on 1)

The compound of claim 1 selected from N-(1-{4-[2-(1-methyl-1-hydroxy-ethyl)-1-ethyl-1H-imidazo-4-yl]-benzyl}-3-hydroxy-propyl)-3-chloro-4-(2,2,2-trifluoro-1-methyl-ethoxy)-benzamide, or a pharmaceutically acceptable salt thereof.

### Claim 16 (depends on 1)

The compound of claim 1 selected from N-(1-{4-[2-(1-hydroxy-1-methyl-ethyl)-1-methyl-1H-imidazo-4-yl]-benzyl}-3-hydroxy-propyl)-3-chloro-4-(2,2,2-trifluoro-1-methyl-ethoxy)-benzamide, or a pharmaceutically acceptable salt thereof.

### Claim 17 (depends on 1)

The compound of claim 1 having the structure:
or a pharmaceutically acceptable salt thereof.

### Claim 18 (depends on 1)

The compound of claim 1 having the structure:
or a pharmaceutically acceptable salt thereof.

### Claim 19 (depends on 1)

The compound of claim 1 having the structure:
or a pharmaceutically acceptable salt thereof.