SYNTHESIS OF QUATERNARY SALT COMPOUNDS

• US 20090112003A1
• Filed: 10/22/2008
• Published: 04/30/2009
• Est. Priority Date: 10/26/2007
• Status: Active Grant

• Current Assignee: Janssen Pharmaceuticals, Inc. (Johnson & Johnson), Janssen Pharmaceutica NV (Johnson & Johnson)
• Original Assignee: Janssen Pharmaceutica NV (Johnson & Johnson)
• Inventors: Li, Xun
• Granted Patent: US 8,093,428 B2
• Time in Patent Office: Days
• US Class Current: 549/424
• CPC Class Codes: C07C 231/12 by reactions not involving the formation of carboxamide groups
• CPC Class Codes: C07C 233/40 having the carbon atom of the carboxamide group bound to an acyclic carbon atom of a carbon skeleton containing six-membered aromatic rings
• CPC Class Codes: C07C 233/62 having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups
• CPC Class Codes: C07C 233/78 with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
• CPC Class Codes: C07D 209/42 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 295/135 with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
• CPC Class Codes: C07D 307/14 Radicals substituted by nitrogen atoms not forming part of a nitro radical
• CPC Class Codes: C07D 307/68 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
• CPC Class Codes: C07D 307/85 attached in position 2
• CPC Class Codes: C07D 309/04 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 309/14 Nitrogen atoms not forming part of a nitro radical
• CPC Class Codes: C07D 311/58 other than with oxygen or sulphur atoms in position 2 or 4
• CPC Class Codes: C07D 311/92 Naphthopyrans; Hydrogenated naphthopyrans
• CPC Class Codes: C07D 313/08 condensed with one six-membered ring
• CPC Class Codes: C07D 333/36 Nitrogen atoms
• CPC Class Codes: C07D 333/70 attached in position 2
• CPC Class Codes: C07D 335/02 not condensed with other rings
• CPC Class Codes: C07D 405/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 407/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/12 : linked by a chain containing hetero atoms as chain links

Abstract

The present invention is directed to a process, having a reduced environmental impact, for preparing phenylamino substituted quaternary salt compounds that are CCR2 antagonists.

Claims

1. A process for preparing a quaternary chloride salt compound of Formula (I):

2. The process of claim 1, wherein the reaction of Compound A1 and Compound A2 is carried out in a solvent such as CH₂Cl₂ and the like, followed by the stepwise addition of Et₃N and NaB(OAc)₃H.

3. The process of claim 1, wherein the reaction of Compound A3 uses a metallation reducing reagent such as SnCl₂.2H₂O in conc. HCl and the like in a solvent such as THF and the like.

4. The process of claim 1, wherein the reaction of Compound A4 and Compound A5 is carried out in a solvent mixture such as Et₃N in THF and the like.

5. The process of claim 1, wherein the reaction of Compound A4 and Compound A5 is carried out by adding Compound A7 to a solution of Compound A6 in a solvent mixture such as acetone and ACN and the like.

6. The process of claim 1, wherein the reaction of Compound A8 is carried out in an ion-exchange resin column in a solvent mixture such as MeOH and water having a solvent:

water ratio mix such as 1;

1.

7. The process of claim 1, further comprising the step of reacting Compound A6 with a chlorinated alkyl Compound Cl to provide the Compound A9, representative of the Compound of Formula (I):

8. The process of claim 1, wherein the compound of Formula (I) is selected from the group consisting of:

(4-{[3-(3-bromo-phenyl)-acryloylamino]-methyl}-benzyl)-cyclohexyl-dimethyl-ammonium chloride,

{4-[(3-bromo-benzoylamino)-methyl]-benzyl}-cyclohexyl-dimethyl-ammonium chloride,

cyclohexyl-dimethyl-{4-[(3-trifluoromethyl-benzoylamino)-methyl]-benzyl}-ammonium chloride,

(4-{[3-(3,4-dichloro-phenyl)-acryloylamino]-methyl}-benzyl)-dimethyl-(tetrahydro-pyran-4-yl)-ammonium chloride,

(4-{[3-(3-bromo-phenyl)-acryloylamino]-methyl}-benzyl)-dimethyl-(tetrahydro-pyran-4-yl)-ammonium chloride,

(4-benzoylamino-benzyl)-dimethyl-(tetrahydro-pyran-4-yl)-ammonium chloride,

[3-(3,4-dichloro-benzoylamino)-benzyl]-dimethyl-(tetrahydro-pyran-4-yl)-ammonium chloride,

[3-(3-bromo-benzoylamino)-benzyl]-dimethyl-(tetrahydro-pyran-4-yl)-ammonium chloride,

[4-(2,3-dichloro-benzoylamino)-benzyl]-dimethyl-(tetrahydro-pyran-4-yl)-ammonium chloride,

[4-(2,4-dichloro-benzoylamino)-benzyl]-dimethyl-(tetrahydro-pyran-4-yl)-ammonium chloride,

[4-(2,5-dichloro-benzoylamino)-benzyl]-dimethyl-(tetrahydro-pyran-4-yl)-ammonium chloride,

[4-(2,6-dichloro-benzoylamino)-benzyl]-dimethyl-(tetrahydro-pyran-4-yl)-ammonium chloride,

[4-(2-chloro-benzoylamino)-benzyl]-dimethyl-(tetrahydro-pyran-4-yl)-ammonium chloride,

bicyclo[2.2.1]hept-2-yl-[4-(3,4-dichloro-benzoylamino)-benzyl]-dimethyl-ammonium chloride,

(2S)-[4-(3,4-dichloro-benzoylamino)-benzyl]-dimethyl-(tetrahydro-furan-2-ylmethyl)-ammonium chloride,

(2R)-[4-(3,4-dichloro-benzoylamino)-benzyl]-dimethyl-(tetrahydro-furan-2-ylmethyl)-ammonium chloride,

[4-(3,4-dichloro-benzoylamino)-benzyl]-dimethyl-(tetrahydro-pyran-4-ylmethyl)-ammonium chloride,

[4-(3,4-dichloro-benzoylamino)-benzyl]-dimethyl-(tetrahydro-thien-3-yl)-ammonium chloride,

[4-(3,4-dichloro-benzoylamino)-benzyl]-dimethyl-(tetrahydro-thiopyran-4-yl)-ammonium chloride,

[4-(3,4-dichloro-benzoylamino)-benzyl]-ethyl-methyl-(tetrahydro-pyran-4-yl)-ammonium chloride,

[4-(3,4-dichloro-benzoylamino)-benzyl]-methyl-propyl-(tetrahydro-pyran-4-yl)-ammonium chloride,

[4-(3,5-dichloro-benzoylamino)-benzyl]-dimethyl-(tetrahydro-pyran-4-yl)-ammonium chloride,

[4-(3-bromo-benzoylamino)-benzyl]-dimethyl-(tetrahydro-pyran-4-yl)-ammonium chloride,

[4-(3-chloro-2-methyl-benzoylamino)-benzyl]-dimethyl-(tetrahydro-pyran-4-yl)-ammonium chloride,

[4-(3-chloro-4-fluoro-benzoylamino)-benzyl]-dimethyl-(tetrahydro-pyran-4-yl)-ammonium chloride,

[4-(3-chloro-4-methoxy-benzoylamino)-benzyl]-dimethyl-(tetrahydro-pyran-4-yl)-ammonium chloride,

[4-(3-chloro-4-methyl-benzoylamino)-benzyl]-dimethyl-(tetrahydro-pyran-4-yl)-ammonium chloride,

[4-(3-chloro-benzoylamino)-benzyl]-dimethyl-(tetrahydro-pyran-4-yl)-ammonium chloride,

[4-(3-cyano-benzoylamino)-benzyl]-dimethyl-(tetrahydro-pyran-4-yl)-ammonium chloride,

[4-(3-methoxy-benzoylamino)-benzyl]-dimethyl-(tetrahydro-pyran-4-yl)-ammonium chloride,

[4-(4-chloro-2-methyl-benzoylamino)-benzyl]-dimethyl-(tetrahydro-pyran-4-yl)-ammonium chloride,

[4-(4-chloro-3-trifluoromethyl-benzoylamino)-benzyl]-dimethyl-(tetrahydro-pyran-4-yl)-ammonium chloride,

[4-(4-chloro-benzoylamino)-benzyl]-dimethyl-(tetrahydro-pyran-4-yl)-ammonium chloride,

[4-(5-chloro-2-methyl-benzoylamino)-benzyl]-dimethyl-(tetrahydro-pyran-4-yl)-ammonium chloride,

{2-[4-(3,4-dichloro-benzoylamino)-phenyl]-ethyl}-dimethyl-(tetrahydro-pyran-4-yl)-ammonium chloride,

{2-[4-(3-bromo-benzoylamino)-phenyl]-ethyl}-dimethyl-(tetrahydro-pyran-4-yl)-ammonium chloride,

{3-[3-(3-bromo-phenyl)-acryloylamino]-benzyl}-dimethyl-(tetrahydro-pyran-4-yl)-ammonium chloride,

{4-[(3,4-dichloro-benzoylamino)-methyl]-benzyl}-dimethyl-(tetrahydro-pyran-4-yl)-ammonium chloride,

{4-[3-(3,4-dichloro-phenyl)-acryloylamino]-benzyl}-dimethyl-(tetrahydro-pyran-4-yl)-ammonium chloride,

{4-[3-(3,4-dichloro-phenyl)-acryloylamino]-benzyl}-dimethyl-(tetrahydro-thiopyran-4-yl)-ammonium chloride,

{4-[3-(3,5-difluoro-phenyl)-acryloylamino]-benzyl}-dimethyl-(tetrahydro-pyran-4-yl)-ammonium chloride,

{4-[3-(3-bromo-phenyl)-acryloylamino]-benzyl}-dimethyl-(tetrahydro-pyran-4-yl)-ammonium chloride,

{4-[3-(3-bromo-phenyl)-acryloylamino]-benzyl}-dimethyl-(tetrahydro-thiopyran-4-yl)-ammonium chloride,

{4-[3-(3-chloro-phenyl)-acryloylamino]-benzyl}-dimethyl-(tetrahydro-pyran-4-yl)-ammonium chloride,

{4-[3-(3-fluoro-phenyl)-acryloylamino]-benzyl}-dimethyl-(tetrahydro-pyran-4-yl)-ammonium chloride,

{4-[3-(4-bromo-phenyl)-acryloylamino]-benzyl}-dimethyl-(tetrahydro-pyran-4-yl)-ammonium chloride,

1-(4-{[3-(3,4-dichloro-phenyl)-acryloylamino]-methyl}-benzyl)-1-methyl-piperidinium chloride,

1-(4-{[3-(3-bromo-phenyl)-acryloylamino]-methyl}-benzyl)-1-methyl-piperidinium chloride,

1-[4-(3,4-dichloro-benzoylamino)-benzyl]-1-methyl-piperidinium chloride,

1-[4-(3,4-dichloro-benzoylamino)-benzyl]-1-methyl-pyrrolidinium chloride,

1-{3-[3-(3-bromo-phenyl)-acryloylamino]-benzyl}-1-methyl-piperidinium chloride,

1-{4-[3-(3,4-dichloro-phenyl)-acryloylamino]-benzyl}-1-methyl-piperidinium chloride,

1-{4-[3-(3,4-dichloro-phenyl)-acryloylamino]-benzyl}-4-(2-methoxy-phenyl)-1-methyl-piperazin-1-ium chloride,

1-{4-[3-(3-bromo-phenyl)-acryloylamino]-benzyl}-1-methyl-piperidinium chloride,

1-methyl-1-[3-(3-trifluoromethyl-benzoylamino)-benzyl]-piperidinium chloride,

1-methyl-1-{4-[3-(3-trifluoromethyl-phenyl)-acryloylamino]-benzyl}-piperidinium chloride,

4-(4-{[3-(3,4-dichloro-phenyl)-acryloylamino]-methyl}-benzyl)-4-methyl-morpholin-4-ium chloride,

4-[4-(3,4-dichloro-benzoylamino)-benzyl]-4-methyl-morpholin-4-ium chloride,

4-{4-[3-(3,4-dichloro-phenyl)-acryloylamino]-benzyl}-4-methyl-morpholin-4-ium chloride,

4-{4-[3-(3-bromo-phenyl)-acryloylamino]-benzyl}-4-methyl-morpholin-4-ium chloride,

4-methyl-4-(4-{[3-(3-trifluoromethyl-phenyl)-acryloylamino]-methyl}-benzyl)-morpholin-4-ium chloride,

allyl-{4-[3-(3-bromo-phenyl)-acryloylamino]-benzyl}-methyl-(tetrahydro-thiopyran-4-yl)-ammonium chloride,

dimethyl-(tetrahydro-pyran-4-yl)-(4-{[3-(3-trifluoromethyl-phenyl)-acryloylamino]-methyl}-benzyl)-ammonium chloride,

dimethyl-(tetrahydro-pyran-4-yl)-[3-(3-trifluoromethyl-benzoylamino)-benzyl]-ammonium chloride,

dimethyl-(tetrahydro-pyran-4-yl)-[4-(3-m-tolyl-acryloylamino)-benzyl]-ammonium chloride,

dimethyl-(tetrahydro-pyran-4-yl)-[4-(3-trifluoromethyl-benzoylamino)-benzyl]-ammonium chloride,

dimethyl-(tetrahydro-pyran-4-yl)-{4-[3-(3-trifluoromethyl-phenyl)-acryloylamino]-benzyl}-ammonium chloride,

dimethyl-[4-(3-methyl-benzoylamino)-benzyl]-(tetrahydro-pyran-4-yl)-ammonium chloride,

cycloheptyl-[4-(3,4-dichloro-benzoylamino)-benzyl]-dimethyl-ammonium chloride,

cyclohexyl-{4-[3-(3,4-dichloro-phenyl)-acryloylamino]-benzyl}-dimethyl-ammonium chloride,

{4-[3-(3-bromo-phenyl)-acryloylamino]-benzyl}-cyclohexyl-dimethyl-ammonium chloride,

[4-(3-bromo-benzoylamino)-benzyl]-cyclohexyl-dimethyl-ammonium chloride,

cyclohexyl-dimethyl-[4-(3-trifluoromethyl-benzoylamino)-benzyl]-ammonium chloride,

cyclohexyl-[4-(3,4-dichloro-benzoylamino)-benzyl]-dimethyl-ammonium chloride,

[4-(3-chloro-4-fluoro-benzoylamino)-benzyl]-cyclohexyl-dimethyl-ammonium chloride,

cyclohexyl-[4-(2,3-dichloro-benzoylamino)-benzyl]-dimethyl-ammonium chloride,

cyclohexyl-[4-(2,6-dichloro-benzoylamino)-benzyl]-dimethyl-ammonium chloride,

[4-(3-chloro-4-methoxy-benzoylamino)-benzyl]-cyclohexyl-dimethyl-ammonium chloride,

[4-(3-chloro-4-methyl-benzoylamino)-benzyl]-cyclohexyl-dimethyl-ammonium chloride,

cyclohexyl-[4-(2,5-dichloro-benzoylamino)-benzyl]-dimethyl-ammonium chloride,

cyclopentyl-[4-(3,4-dichloro-benzoylamino)-benzyl]-dimethyl-ammonium chloride,

cyclohexyl-{3-[3-(3,4-dichloro-phenyl)-acryloylamino]-benzyl}-dimethyl-ammonium chloride,

cyclohexyl-{3-[3-(4-fluoro-phenyl)-acryloylamino]-benzyl}-dimethyl-ammonium chloride,

dimethyl-(tetrahydro-pyran-4-yl)-{4-[(4′

-trifluoromethyl-biphenyl-3-carbonyl)-amino]-benzyl}-ammonium chloride,

cyclohexyl-dimethyl-{4-[(4′

-methyl-biphenyl-3-carbonyl)-amino]-benzyl}-ammonium chloride,

dimethyl-{4-[(4′

-methyl-biphenyl-3-carbonyl)-amino]-benzyl}-(tetrahydro-pyran-4-yl)-ammonium chloride,

{4-[(biphenyl-4-carbonyl)-amino]-benzyl}-dimethyl-(tetrahydro-pyran-4-yl)-ammonium chloride,

dimethyl-{4-[(naphthalene-1-carbonyl)-amino]-benzyl}-(tetrahydro-pyran-4-yl)-ammonium chloride,

dimethyl-{4-[(naphthalene-2-carbonyl)-amino]-benzyl}-(tetrahydro-pyran-4-yl)-ammonium chloride,

ethyl-methyl-{4-[(naphthalene-2-carbonyl)-amino]-benzyl}-(tetrahydro-pyran-4-yl)-ammonium chloride,

methyl-{4-[(naphthalene-2-carbonyl)-amino]-benzyl}-propyl-(tetrahydro-pyran-4-yl)-ammonium chloride,

{4-[(7-bromo-naphthalene-2-carbonyl)-amino]-benzyl}-dimethyl-(tetrahydro-pyran-4-yl)-ammonium chloride,

{4-[(7-bromo-naphthalene-2-carbonyl)-amino]-benzyl}-cyclohexyl-dimethyl-ammonium chloride,

{4-[(6-bromo-2H-chromene-3-carbonyl)-amino]-benzyl}-dimethyl-(tetrahydro-pyran-4-yl)-ammonium chloride,

{4-[(6-chloro-2H-chromene-3-carbonyl)-amino]-benzyl}-dimethyl-(tetrahydro-pyran-4-yl)-ammonium chloride,

{4-[(6-bromo-2H-chromene-3-carbonyl)-amino]-benzyl}-cyclohexyl-dimethyl-ammonium chloride,

{4-[(6-chloro-2H-chromene-3-carbonyl)-amino]-benzyl}-cyclohexyl-dimethyl-ammonium chloride,

(4-{[(6-bromo-2H-chromene-3-carbonyl)-amino]-methyl}-benzyl)-dimethyl-(tetrahydro-pyran-4-yl)-ammonium chloride,

{4-[(5,7-dichloro-2H-chromene-3-carbonyl)-amino]-benzyl}-dimethyl-(tetrahydro-pyran-4-yl)-ammonium chloride,

cyclohexyl-{4-[(5,7-dichloro-2H-chromene-3-carbonyl)-amino]-benzyl}-dimethyl-ammonium chloride,

{4-[(6,8-dichloro-2H-chromene-3-carbonyl)-amino]-benzyl}-dimethyl-(tetrahydro-pyran-4-yl)-ammonium chloride,

dimethyl-{4-[(6-methyl-2H-chromene-3-carbonyl)-amino]-benzyl}-(tetrahydro-pyran-4-yl)-ammonium chloride,

{4-[(6-methoxy-2H-chromene-3-carbonyl)-amino]-benzyl}-dimethyl-(tetrahydro-pyran-4-yl)-ammonium chloride,

cyclohexyl-dimethyl-{4-[(6-methyl-2H-chromene-3-carbonyl)-amino]-benzyl}-ammonium chloride,

cyclohexyl-{4-[(6-methoxy-2H-chromene-3-carbonyl)-amino]-benzyl}-dimethyl-ammonium chloride,

cyclohexyl-{4-[(6,8-dichloro-2H-chromene-3-carbonyl)-amino]-benzyl}-dimethyl-ammonium chloride,

(2R)-{4-[(6-chloro-2H-chromene-3-carbonyl)-amino]-benzyl}-dimethyl-(tetrahydro-furan-2-ylmethyl)-ammonium chloride,

(2S)-{4-[(6-chloro-2H-chromene-3-carbonyl)-amino]-benzyl}-dimethyl-(tetrahydro-furan-2-ylmethyl)-ammonium chloride,

(2S)-bicyclo[2.2.1]hept-2-yl-{4-[(6-chloro-2H-chromene-3-carbonyl)-amino]-benzyl}-dimethyl-ammonium chloride,

bicyclo[2.2.1]hept-2-yl-{4-[(6,8-dichloro-2H-chromene-3-carbonyl)-amino]-benzyl}-dimethyl-ammonium chloride,

dimethyl-{4-[(8-methyl-2H-chromene-3-carbonyl)-amino]-benzyl}-(tetrahydro-pyran-4-yl)-ammonium chloride,

cyclohexyl-dimethyl-{4-[(8-methyl-2H-chromene-3-carbonyl)-amino]-benzyl}-ammonium chloride,

{4-[(6-chloro-8-methyl-2H-chromene-3-carbonyl)-amino]-benzyl}-cyclohexyl-dimethyl-ammonium chloride,

{4-[(6-chloro-8-methyl-2H-chromene-3-carbonyl)-amino]-benzyl}-dimethyl-(tetrahydro-pyran-4-yl)-ammonium chloride,

cyclohexyl-{4-[(7,8-dichloro-2H-chromene-3-carbonyl)-amino]-benzyl}-dimethyl-ammonium chloride,

bicyclo[2.2.1]hept-2-yl-{4-[(6-chloro-8-methyl-2H-chromene-3-carbonyl)-amino]-benzyl}-dimethyl-ammonium chloride,

{4-[(6-chloro-8-methyl-2H-chromene-3-carbonyl)-amino]-benzyl}-cycloheptyl-dimethyl-ammonium chloride,

{4-[(6-chloro-8-methyl-2H-chromene-3-carbonyl)-amino]-benzyl}-cyclopentyl-dimethyl-ammonium chloride,

{4-[(6-chloro-8-methyl-2H-chromene-3-carbonyl)-amino]-benzyl}-dimethyl-(tetrahydro-thiophen-3-yl)-ammonium chloride,

(4-{[(6-chloro-8-methyl-2H-chromene-3-carbonyl)-amino]-methyl}-benzyl) -dimethyl-(tetrahydro-pyran-4-yl)-ammonium chloride,

{4-[(6,8-dichloro-2H-chromene-3-carbonyl)-amino]-benzyl}-dimethyl-(tetrahydro-thiophen-3-yl)-ammonium chloride,

cyclohexyl-{4-[(6-fluoro-2H-chromene-3-carbonyl)-amino]-benzyl}-dimethyl-ammonium chloride,

cyclohexyl-{4-[(5-fluoro-2H-chromene-3-carbonyl)-amino]-benzyl}-dimethyl-ammonium chloride,

cyclohexyl-dimethyl-{4-[(6-trifluoromethyl-2H-chromene-3-carbonyl)-amino]-benzyl}-ammonium chloride,

cyclohexyl-{4-[(8-fluoro-2H-chromene-3-carbonyl)-amino]-benzyl}-dimethyl-ammonium chloride,

cyclohexyl-dimethyl-{4-[(7-methyl-2H-chromene-3-carbonyl)-amino]-benzyl}-ammonium chloride,

cyclohexyl-{4-[(7-methoxy-2H-chromene-3-carbonyl)-amino]-benzyl}-dimethyl-ammonium chloride,

{4-[(6-tert-butyl-2H-chromene-3-carbonyl)-amino]-benzyl}-cyclohexyl-dimethyl-ammonium chloride,

dimethyl-(tetrahydro-thiophen-3-yl)-{4-[(6-trifluoromethyl-2H-chromene-3-carbonyl)-amino]-benzyl}-ammonium chloride,

{4-[(5-fluoro-2H-chromene-3-carbonyl)-amino]-benzyl}-dimethyl-(tetrahydro-thiophen-3-yl)-ammonium chloride,

{4-[(6-fluoro-2H-chromene-3-carbonyl)-amino]-benzyl}-dimethyl-(tetrahydro-thiophen-3-yl)-ammonium chloride,

cyclohexyl-dimethyl-{4-[(5-trifluoromethyl-2H-chromene-3-carbonyl)-amino]-benzyl}-ammonium chloride,

cyclohexyl-dimethyl-{4-[(8-trifluoromethyl-2H-chromene-3-carbonyl)-amino]-benzyl}-ammonium chloride,

{4-[(3H-benzo [f]chromene-2-carbonyl)-amino]-benzyl}-dimethyl-(tetrahydro-pyran-4-yl)-ammonium chloride,

1-{4-[(3H-benzo[f]chromene-2-carbonyl)-amino]-benzyl}-1-methyl-pyrrolidinium chloride,

{4-[(3H-benzo[f]chromene-2-carbonyl)-amino]-benzyl}-cyclohexyl-dimethyl-ammonium chloride,

{4-[(3H-benzo[f]chromene-2-carbonyl)-amino]-benzyl}-dimethyl-(tetrahydro-thiopyran-4-yl)-ammonium chloride,

4-{4-[(3H-benzo[f]chromene-2-carbonyl)-amino]-benzyl}-4-methyl-morpholin-4-ium chloride,

{4-[(3H-benzo[f]chromene-2-carbonyl)-amino]-benzyl}-dimethyl-(tetrahydro-pyran-4-ylmethyl)-ammonium chloride,

(4-{[(3H-benzo[f]chromene-2-carbonyl)-amino]-methyl}-benzyl)-dimethyl-(tetrahydro-pyran-4-yl)-ammonium chloride,

(4-{[(3-bromo-8,9-dihydro-7H-benzocycloheptene-6-carbonyl)-amino]-methyl}-benzyl)-dimethyl-(tetrahydro-pyran-4-yl)-ammonium chloride,

{4-[(3-bromo-8,9-dihydro-7H-benzocycloheptene-6-carbonyl)-amino]-benzyl}-dimethyl-(tetrahydro-pyran-4-yl)-ammonium chloride,

{4-[(3-bromo-8,9-dihydro-7H-benzocycloheptene-6-carbonyl)-amino]-benzyl}-cyclohexyl-dimethyl-ammonium chloride,

1-{4-[(8,9-dihydro-7H-benzocycloheptene-6-carbonyl)-amino]-benzyl}-methyl-pyrrolidinium chloride,

cyclohexyl-{4-[(8,9-dihydro-7H-benzocycloheptene-6-carbonyl)-amino]-benzyl}-dimethyl-ammonium chloride,

{4-[(8,9-dihydro-7H-benzocycloheptene-6-carbonyl)-amino]-benzyl}-dimethyl-(tetrahydro-pyran-4-yl)-ammonium chloride,

(4-{[(8,9-dihydro-7H-benzocycloheptene-6-carbonyl)-amino]-methyl}-benzyl)-dimethyl-(tetrahydro-pyran-4-yl)-ammonium chloride,

dimethyl-(4-{[(2-methyl-5-phenyl-furan-3-carbonyl)-amino]-methyl}-benzyl)-(tetrahydro-pyran-4-yl)-ammonium chloride,

[4-({[5-(4-chloro-phenyl)-2-methyl-furan-3-carbonyl]-amino}-methyl)-benzyl]-dimethyl-(tetrahydro-pyran-4-yl)-ammonium chloride,

dimethyl-{4-[(2-methyl-5-phenyl-furan-3-carbonyl)-amino]-benzyl}-(tetrahydro-pyran-4-yl)-ammonium chloride,

{4-[(benzofuran-2-carbonyl)-amino]-benzyl}-dimethyl-(tetrahydro-pyran-4-yl)-ammonium chloride,

(4-{[5-(4-chloro-phenyl)-2-trifluoromethyl-furan-3-carbonyl]-amino}-benzyl)-dimethyl-(tetrahydro-pyran-4-yl)-ammonium chloride,

(4-{[5-(4-chloro-phenyl)-2-trifluoromethyl-furan-3-carbonyl]-amino}-benzyl)-cyclohexyl-dimethyl-ammonium chloride,

{4-[(5-chloro-benzofuran-2-carbonyl)-amino]-benzyl}-dimethyl-(tetrahydro-pyran-4-yl)-ammonium chloride,

{4-[(5-chloro-benzofuran-2-carbonyl)-amino]-benzyl}-cyclohexyl-dimethyl-ammonium chloride,

{4-[(benzofuran-2-carbonyl)-amino]-benzyl}-cyclohexyl-dimethyl-ammonium chloride,

dimethyl-{4-[(1-methyl-1H-indole-2-carbonyl)-amino]-benzyl}-(tetrahydro-pyran-4-yl)-ammonium chloride,

{4-[(5-chloro-1H-indole-2-carbonyl)-amino]-benzyl}-dimethyl-(tetrahydro-pyran-4-yl)-ammonium chloride,

{4-[(5-bromo-1H-indole-2-carbonyl)-amino]-benzyl}-dimethyl-(tetrahydro-pyran-4-yl)-ammonium chloride,

dimethyl-{4-[(1-methyl-1H-indole-3-carbonyl)-amino]-benzyl}-(tetrahydro-pyran-4-yl)-ammonium chloride,

{4-[(1-benzyl-1H-indole-3-carbonyl)-amino]-benzyl}-dimethyl-(tetrahydro-pyran-4-yl)-ammonium chloride,

cyclohexyl-dimethyl-{4-[(1-methyl-1H-indole-2-carbonyl)-amino]-benzyl}-ammonium chloride,

{4-[(5-chloro-1H-indole-2-carbonyl)-amino]-benzyl}-cyclohexyl-dimethyl-ammonium chloride,

(2S)-{4-[(5-chloro-1H-indole-2-carbonyl)-amino]-benzyl}-dimethyl-(tetrahydro-furan-2-ylmethyl)-ammonium chloride,

bicyclo[2.2.1]hept-2-ylmethyl-{4-[(5-chloro-1H-indole-2-carbonyl)-amino]-benzyl}-dimethyl-ammonium chloride,

{4-[(7,8-dichloro-2,3-dihydro-benzo[b]oxepine-4-carbonyl)-amino]-benzyl}-dimethyl-(tetrahydro-pyran-4-yl)-ammonium chloride,

cyclohexyl-{4-[(7,8-dichloro-2,3-dihydro-benzo[b]oxepine-4-carbonyl)-amino]-benzyl}-dimethyl-ammonium chloride,

bicyclo[2.2.1]hept-2-yl-{4-[(7,8-dichloro-2,3-dihydro-benzo[b]oxepine-4-carbonyl)-amino]-benzyl}-dimethyl-ammonium chloride,

(4-{[(7,8-dichloro-2,3-dihydro-benzo[b]oxepine-4-carbonyl)-amino]-methyl}-benzyl)-dimethyl-(tetrahydro-pyran-4-yl)-ammonium chloride,

{4-[(7,8-dichloro-2,3-dihydro-benzo[b]oxepine-4-carbonyl)-amino]-benzyl}-dimethyl-(tetrahydro-thiophen-3-yl)-ammonium chloride,

{4-[(5-bromo-pyridine-3-carbonyl)-amino]-benzyl}-dimethyl-(tetrahydro-pyran-4-yl)-ammonium chloride,

{4-[(2-chloro-pyridine-4-carbonyl)-amino]-benzyl}-dimethyl-(tetrahydro-pyran-4-yl)-ammonium chloride,

{4-[(3-chloro-benzo [b]thiophene-2-carbonyl)-amino]-benzyl}-dimethyl-(tetrahydro-pyran-4-yl)-ammonium chloride,

{4-[(2,5-dichloro-thiophene-3-carbonyl)-amino]-benzyl}-dimethyl-(tetrahydro-pyran-4-yl)-ammonium chloride,

{4-[(benzo[b]thiophene-2-carbonyl)-amino]-benzyl}-dimethyl-(tetrahydro-pyran-4-yl)-ammonium chloride,

{4-[(benzo[b]thiophene-2-carbonyl)-amino]-benzyl}-cyclohexyl-dimethyl-ammonium chloride, and

{4-[(3-chloro-benzo[b]thiophene-2-carbonyl)-amino]-benzyl}-cyclohexyl-dimethyl-ammonium chloride.

9. A process for preparing a quaternary chloride salt compound of Formula (Ia):

10. The process of claim 9, further comprising the step of reacting Compound B6 with a chlorinated methyl Compound D1 to provide the compound of Formula (Ia):

11. The process of claim 9, wherein Compound B6 may be recrystallized in Step C. or Step D. using a solvent selected from EtOAc, MeCN, hexanes or EtOH and mixtures thereof.

12. The process of claim 9, wherein the compound of Formula (Ia) may be recrystallized in Step D. using EtOH.

13. The process of claim 9, wherein the reaction of Compound B6 and Compound B7 is carried out by adding Compound B7 to a solution of Compound B6 in a solvent under pressure and at an elevated temperature.

14. The process of claim 9, wherein the solvent used in Step D. is selected from the group consisting of n-BuOH, toluene, IPA, EtOH, acetone, MeCN, DMF, THF and the like and mixtures thereof, wherein the reaction conditions include an elevated temperature and pressure.

15. The process of claim 9, wherein the solvent used in Step D. is selected from the group consisting of n-BuOH and toluene.

16. The process of claim 9, wherein the reaction pressure used in Step D. may be in a range of from about 10 psi to about 200 psi, or from about 10 psi to about 100 psi, or from about 10 psi to about 50 psi, or from about 10 psi to about 25 psi, or from about 20 psi to about 25 psi, or about 22 psi.

17. The process of claim 9, wherein the molar ratio of Compound B6:

Compound B7 is from about 1;

3 to about 1;

8;

or, from about 1;

3 to about 1;

5;

or, about 1;

3.