OA16903A - Substituted 4 - phenyl - pyridines for the treatment of NK-1 receptor related diseases. - Google Patents

Abstract

Disclosed are compounds, compositions and methods for the prevention and/or treatment of diseases which are pathophysiologically mediated by the neurokinin (NKj) receptor. The compounds have the general formula (I):

Description

The présent Invention relates to novel 4-phenyl-pyridine compounds, and medical uses thereof, particularly ln the prévention and/or treatment of medical conditions modulated by the neurokinin (NK|) receptor.

Description of Related Art

Substance P is an 11-amino acid neuropeptide présent reportedly involved in various pathological conditions including asthma, inflammation, pain, psoriasis, migraine, dyskinesia, cystitis, schizophrenia, emesis and anxiety, due to its localizations and fonctions. Substance P is an agonist for the NKl receptor, and causes Intracellular signal transduction through its interaction with the NKl receptor.

The NKl receptor has been reported to be implicated in various disorders and diseases, and various NK| antagonists hâve been developed for the purpose of treating or preventîng such disorders and diseases. For example, Kramer et al. (Science 281 (5383), 1640-1645, 1988) reports clinical trials for NK] receptor antagonists in the treatment of anxiety, dépression, psychosis, schizophrenia and emesis. Gesztesi et al. (Anestliesiology 93(4), 931-937, 2000) also reports the use of NK| receptor antagonists in the treatment of emesis

U.S. Patent No. 6,297,375 to Hoffmann-La Roche describes a class of 4-phenylpyridine compounds that are NK| antagonists which are useful for treating CNS disorders, such as dépression, anxiety or emesis. Netupitant is a sélective NKi receptor antagonist among these 4-phenyl-pyridine compounds, and is currently under clinical development in combination with palonosetron (a 5-HTj receptor antagonist) for the prévention of chemotherapy-induced-nausea and vomiting (CINV) by Helsinn Healthcare.

Mono-N-oxide denvatives of 4-phenyl-pyridine compounds are described in U.S. Patent No. 6,747,026 to Hoffmann-La Roche. These N-oxide dérivatives are reportedly intended to overcome limitations on the parent compounds that would otherwise limit their clinical usefulness, such as solubility or pharmacokïnetic limitations. However, no physicochemîcal or biological data of the mono-N-oxide dérivatives are reported in the ‘026 patent.

U.S. Patent No. 5,985,856 to the University of Kansas describes water soluble Nphosphoryloxymethyl dérivatives of secondary and tertiary amines, and the use of such dérivatives to improve the solubility profiles of loxapine and cïnnarizine. The *856 patent does not disclose how the N-phosphoryloxymethyl moiety would affect other critical attributes of the drug product, such as prodnig structure(s), prodrug stability, synthetic cost, and selectivity of the phosphorylox y méthylation protocol.

In view of the above, there is a need to find new dérivatives of and methods for making 4-phenyl-pyridine compounds that are effective NKi receptor antagonists, and that hâve enhanced physicochemîcal and/or biological properties.

SUMMARY

In view of the foregoing, the inventors hâve developed a novel class of 4-phenylpyridine dérivatives that are particularly well-suited for antagonizing the NK| receptor and that hâve the following general formula (I):

Formula (I) und pharmaceutically acceptable salts or adducts thereof.

Compounds of formula (1), also known as 4-phenyl-pyridine dérivatives, are particularly useful for preventing and/or treating diseases that are pathophysiologically rclated to the NK| receptor in a subject. Accordingly, in another embodiment the invention provides a method of treating a disease that is medialed by the NK| receptor, comprising

ZI924592V1

administering to said subject a therapeutîcally effective amount of a compound of formula (1), or a pharmaceutically acceptable sait or adduct thereof.

Also disclosed are pharmaceutical compositions for preventing and/or treating diseases which are pathophysiologically related to NK| receptor in a subject, comprising a 5 therapeutîcally effective amount of a compound of formula (1), or a pharmaceutically acceptable sait or adduct thereof, and one or more pharmaceutically acceptable excipients.

In one embodiment the invention is a compound of formula (I), or a pharmaceutically acceptable sait or adduct thereof,

(0)p

Formula (I) wherein:

R is selected from the group consisting of hydrogen, hydroxy, hydroxyalkyl, amino, allcyi, alkenyl, cycloalkyl, halogen, alkoxyalkyl, -OR¹⁰¹, -NR^,0lR¹⁰², -NR^,0lC(O)R¹⁰², C(O)R¹⁰¹, -C(O)OR¹⁰¹, -C(O)NR^l01R¹⁰², -alkylNR^I0IR¹⁰², -S(O)2R¹⁰² , -SR¹⁰¹. 15 S(O)2NR^l0lR^,02 _t aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl and heteroarylalkyl, each optionally independently substituted with one or more independent R¹⁰³ substituents;

Ri and R₂ are independently selected from the group consisting of hydrogen, hydroxy, hydroxyalkyl, amino, alkyl, alkenyl, cycloalkyl, halogen, alkoxyalkyl, -OR¹⁰¹, -NR^I0lR¹⁰², 20 NR^l0lC(O)R^,0ît -C(O)R¹⁰¹, -C(O)OR¹⁰¹, -C(O)NR^I0IR¹⁰², -alkylNR^,0,R^t02. -SiO^R¹⁰² , SR¹⁰¹, -S(O)2NR^l0lR^,02t aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl and heteroarylalkyl, each optionally independently substituted with one or more independent R^,oî substituents; or Ri together with the atoms and/or other substituent (s) on the same phenyl ring, form a fused or non-fused mono, bicyclic or tricyclic heterocyclic or carbocyclic 25 ring which is optionally independently substituted with one or more R¹⁰³ substituents; or R2 together with the atoms and/or other substituent(s) on the same phenyl ring, form a fused or non-fused mono, bicyclic or tricyclic heterocyclic or carbocyclic ring which is optionally independently substituted with one or more R¹⁰³ substituents;

2l924592vl

Rj and R4 are independently selected from the group consisting of hydrogen, hydroxy, hydroxyalkyl, amino, alkyl, alkenyl, cycloalkyl, halogen, alkoxyalkyl, -OR¹⁰¹, -NR^l0lR¹⁰², NR^l0lC(O)R^10î, -C(O)R'⁰¹, -C(O)OR¹⁰'. -C(O)NR^l0lR^t0î, -alkylNR^lolR¹⁰², -S(O)2R¹⁰² , SR¹⁰¹, -S(O)2NR^,0tR¹⁰², aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl and heteroarylalkyl, each optionally independently substituted with one or more independent R¹⁰³ substituents; or Rj and R4, together with the atoms connecting the same, form a fused or non-fused mono, bicyclic or tricyclic heterocyclic or carbocyclic ring which is optionally independently substituted with one or more R¹⁰³ substituents;

Rs and R$ are independently selected from the group consisting of hydrogen, hydroxy, 10 hydroxyalkyl, amino, alkyl, alkenyl, cycloalkyl, halogen, alkoxyalkyl, -OR¹⁰¹, -NR^lolR^to2, NR^,0,C(O)R¹⁰². -C(O)R¹⁰¹, -C(O)OR^l0‘, -C(O)NR^l0tR¹⁰², -aIkylNR^l01R¹⁰², -S(O)2R¹⁰² , SR¹⁰¹, -S(O)2NR^l0lR¹⁰², aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl and heteroarylalkyl, each optionally independently substituted with one or more independent R¹⁰³ substituents;

X is selected from the group consisting of -C(O)NR^10lR¹⁰², -alkylO, -allcylNR^l0lR¹⁰²,

-NR^,0lC(O) and -NR^l0lalkyl, each optionally Independently substituted with one or more independent R¹⁰³ substituents;

Y is selected from the group consisting of -NR^l0lR¹⁰², -NR^l0*alkylOH, NR^l0lS(O)2alkyl, -NR^l0lS(O)2phenyl, -N=CH-NR^l0,R^t02, heterocycloalkyl and 20 heterocycloalkylalkyl, each optionally independently substituted with one or more independent R¹⁰³ substituents;

Z is a structural formula selected from the group consisting of:

—0’	(ïa).	—OR100	(Ib).
0 —O-P-OR100 OR100*	(Ic),	0 -O-P-OR100 / ORiotr	(Id),
0 _o-U-or100	(fe).	0 -O-U-nrioorwo·	(if).
0 __U_Nr100r1M*	(Ig).	0 --U-OR100	(Ih) and

21934592,1

Ο ^1_OR100 ^ζ (Π).

where formula (la) refers to an oxide;

R¹⁰⁰, R¹⁰⁰, R¹⁰¹, R¹⁰² and R¹⁰³ are each Independently selected from the group consisting of hydrogen, cyano, -NO3, -OR¹⁰⁴, oxide, hydroxy, amino, alkyl, alkenyl, cycloalkyl, halogen, alkoxy, alkoxyalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylaikyl, -C(O)R^,W, -C(O)OR¹⁰⁴, -C(O)NR^IWR^,M, NR'^wR^l0î,-NR^,04S(O)2R^,M, -NR^iwC(0)R^im, -S(O)₃R^1w , -SR^,W and -SiOhNR^R¹⁰³, each optionaily independently substituted with one or more independent R¹⁰³ substituents; or R¹⁰¹, R¹⁰², together with the atoms connecting the same, form a fused or non-fused mono, bicyclîc or tricyclîc heterocyclic or carbocyclic ring which is optionaily independently substituted with one or more R^,OÎ substituents; or R¹⁰⁰, R¹⁰⁰, together with the atoms connecting the same, form a fused or non-fused mono, bicyclîc or tricyclîc heterocyclic or carbocyclic ring which is optionaily independently substituted with one or more R^,OÎ substituents;

R¹⁰⁴ and R^,M are each independently selected from the group consisting of hydrogen, cyano, -N0₃. hydroxy, oxide, hydroxyalkyl, amino, alkyl, alkenyl, cycloalkyl, halogen, alkoxy, alkoxyalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl and heteroarylaikyl;

m isO, 1,2,3, or 4;

nisO, 1,2,3,4 or 5;

pisOor I; and with a proviso that if a non-pyridine N-Oxide (Ν'—O*) is présent on the compound of Formula (I), then the total number of N-Oxide on the compound of Formula (I) is more than one.

In another embodiment the invention îs the use of a therapeutically effective amount of a compound of formula (I) as defined above or a pharmaceutically acceptable sait or adduct thereof, in the manufacture of a médicament which is able to treat emesis, bladder dysfonction, dépression or anxiety, in a patient in need thereof.

In an alternative embodiment the invention is a method of treating emesis, bladder dysfonction, dépression or anxiety, in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a compound of formula (I) as defined above.

21934592VI

In stîll another embodiment the invention is a compound selected from the group

consisting of:

OAl	* r-ΛΧ θ AJ HO-P-Ct 1 ™ I OH CFa	445-(2-(3,5bîs(lrifluoromethyl)phenyl)-N,2dimethylpropanamido)-4-(otolyl)pyridin-2-yl)-l-methyl-l((phosphonooxy)methyl)piperazin-1ium.
GA2	CFa	l4acetoxymeihyl)-445-(243,5bis(trinuoromethyl)phenyl)-N,2dimet hy lpropanamido)-44otoly l)pyridin-2-y 1)-1 -methy Ipipernzinl-iurn,
GA3	J CFj	445-(2-(3,5bis(trifluoromethyl)phenyl)-N,2dimethylpropanamîdo)-4-(otolyl)pyridin-2-yl)-l((butyryloxy)methyl)-lmethy 1 pi perazi η-1 - i um.
GA4		1454243.5bis(trifluoromethyl)phenyl)-N,2di methy lpropanamido)-4-(otolyl)pyridîn-2-yl)-4-methylpiperazme 1,4-dioxide,
GA5	0. CFj	1454243,5- bis( tri fluoro methy 1 )p heny l)-N,2dimet hy Iproponamido)-1 -oxido-44otolyl)pyridîn-2-yl)-4-methylpïpenizÎne 1-oxide,

31934592*1

GA6	Ô. CF3	4-(5-(2-(3,5bis(trifluoromethyl)phenyl)-N,2di methyl propanamido)-1 -ox ido-4-(otoly 1 )py ri di n-2-y 1 )-1 - methy Ipiperazi ne 1-oxide,
GA7	RxR 0. CF3	5-(2-(3^-bis(trinuoromethyl)phenyl)N,2-di methy lpropanamido)-2-{4mcthylpiperazin-l-yi)-4-(otolyljpyridine l-oxide, and
GAS	Rr ό-nRJ cf3	4-(5-(2-(3,5bis(trifluoromethy!)phenyi)-N,2d i methy !p ropanamido)-4-{otoly!)pyridin-2-yl)-l-methy!piperazine l-oxide.

or a pharmaceutically acceptable sali or adducl thereof.

In a further embodiment the invention is a compound of formula GAI, formula

GAI

4-(5-(2-(3,5bi s( tri Π uo romcthy 1 )phenyl)-N,2dimethylpropanamido)-4-(otoly l)pyridin-2-y l )-1 -methy I- i ((phosphonooxy )methy IJpiperazin-1 ium or a pharmaceutically acceptable sait or adduct thereof.

BRIEF DESCRIPTION OFTHE DRAWINGS

FIGURE I reproduces stability data for various salts of 4-(5-(2-(3^-bis(trifluoromethyl)phenyl)-N,2-dimcthylpropanamido)-4-(o-tolyl)pyridin-2-yl)-l-methyl-l-((phosphornooxyjmethyljpipcrazin-l-ium.

21924592VI

DETAILED DESCRIPTION

Before the présent compounds, compositions, articles, devices, and/or methods are disclosed and described, it is to be understood that they are not limited to spécifie synthetic methods or spécifie treatment methods unless otherwise specified, or to particular reagents 5 unless otherwise specified, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purposc of describing particular embodiments only and is not intended to be limiting.

Materials

A. Compounds

Disclosed are compounds and pharmaceutically acceptable salts or adducts thereof represented by formula (I):

Formula (I) wherein:

R is selected from the group consisting of hydrogen, hydroxy, hydroxyaikyl, amino, alkyl, alkenyl, cycloalkyl, halogen, alkoxy, alkoxyalkyl, -OR¹⁰¹, -NR^l0,R¹⁰², -NR^10lC(O)R¹⁰², -C(O)R¹⁰', -C(O)OR¹⁰¹, -C(O)NR^,0,R¹⁰². -alkylNR^l0lR¹⁰², -S(O)2R¹⁰² , -SR¹⁰¹. S(O)2NR^,0lR¹⁰², aryl, arylatkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl and 20 heteroarylalkyl, each optionally independently substituted with one or more independent R¹⁰³ substituents;

Ri and Rî arc independently selected from the group consisting of hydrogen, hydroxy, hydroxyaikyl, amino, alkyl, alkenyl, cycloalkyl, halogen, alkoxy, alkoxyalkyt, -OR¹⁰¹, NR^l0lR¹⁰², -NR^10lC(O)R¹⁰², -C(O)R¹⁰', -C(O)OR¹⁰¹, -C(O)NR^,0lR¹⁰². -a!kylNR^l0lR¹⁰², 25 S(OhR¹⁰², -SR¹⁰¹, -S(O)iNR^10lR¹⁰², aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl and heteroarylalkyl, each optionally independently substituted with one or more independent R¹⁰³ substituents; or R| together with the atoms and/or other substituent(s) on the same phenyl ring form a fused or non-fused mono, bicyclic or tricyclic heterocyclîc or

2l924S92vt

I

carbocyclic ring which is optionally independently substituted with one or more R¹⁰³ substituents; or Ri together with the atoms and/or other substituent(s) on the same phenyl ring form a fused or non-fused mono, bicyclic or tricyclic heterocyclic or carbocyclic ring which is optionally independently substituted with one or more R¹⁰¹ substituents;

R₃ and R» arc independently selected from the group consisting of hydrogen, hydroxy, hydroxyalkyl, amino, alkyl, alkenyl, cycloalkyl, halogen, alkoxy, alkoxyalkyl, -0R^wt, Nr101r^,02( .nR¹⁰¹C(O)R¹⁰², -C(O)R¹⁰¹, -C(O)OR¹⁰¹, -C(O)NR^,0lR¹⁰², -alkylNR^l0IR¹⁰², S(O):R¹⁰², -SR¹⁰¹, -S(O)iNR^I0IR^IQ2, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl and heteroarylalkyl, each optionally independently substituted with one or more 10 independent R¹⁰³ substituents; or R3 and R4, together with the atoms connecting the same form a fused or non-fused mono, bicyclic or tricyclic heterocyclic or carbocyclic ring which is optionally independently substituted with one or more R¹⁰³ substituents;

Rs and R« are independently selected from the group consisting of hydrogen, hydroxy, hydroxyalkyl, amino, alkyl, alkenyl, cycloalkyl, halogen, alkoxy, alkoxyalkyl, -OR¹⁰¹, 15 NR¹⁰¹^⁰², -NR^l0,C(O)R¹⁰². -C(O)R¹⁰¹, -C(O)OR¹⁰¹, -C(O)NR^,0IR¹⁰², -alkyINR^,olR¹⁰², S(O)îR^W2 , -SR¹⁰’, -S(O)2NR^l0lR¹⁰², aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl and heteroarylalkyl, each optionally independently substituted with one or more independent R¹⁰³ substituents;

X is selected from the group consisting of -C(O)NR¹⁰¹ R¹⁰², -alkylO, -aIkylNR^l0lR^IQ2, 20 -NR^10,C(O) and -NR^l0lalkyl, each optionally independently substituted with one or more independent R¹⁰³ substituents;

Y is selected from the group consisting of -NR^l0lR¹⁰², -NR^l0IalkylOH, NR^l0,S(O)2alkyl, -NR^l0lS(O)₂phenyl, -N=CH-NR^l0,R¹⁰², heterocycloalkyl and heterocycloalkylalkyl, each optionally Independently substituted with one or more 25 independent R¹⁰³ substituents;

Z îs a structural formula selected from the group consisting of:

—O	(h).	—OR100	(lb).
0 —O-P-OR100 OR100*	(Ic),	0 r-O-P-OR100 / ORioo·	(Id),
0 —o-W-OR100	de).	0 —O-U-NR10°R1Q<r	(ID.

ίο ο

—U-NR100R100· _(Ig)t

(Ih) and

OR¹⁰⁰ where formula (la) refers to an oxide;

R*⁰⁰, R¹⁰⁰, R¹⁰¹, R^,oî and R*⁰³ are each independently selected from the group consisting of hydrogen, cyano, -NO2, -OR¹⁰⁴, oxide, hydroxy, amino, alkyi, alkenyl, cycloalkyl, halogen, alkoxy, alkoxyalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyi, heteroaryl, heteroarylalkyl, -C(O)R^IM, -C(O)OR¹⁰⁴, -C(O)NR^ltMR’⁰⁵, NR^l04R^l0î,-NR^,04S(O)3R’⁰⁵. -NR^,mC(0)R’^os, -S(O)₂R^iw , -SR^,W and -S(O)2NR^,04R^,0î, each optionally independently substituted with one or more independent R¹⁰³ substituents; or R¹⁰’, R¹⁰², together with the atoms connecting the same, form a fused or non-fused mono, bicyclic or tricyclic heterocyclic or carbocyclic ring which is optionally independently substituted with one or more R¹⁰³ substituents; or R¹⁰⁰, R^,txr, together with the atoms connecting the same, form a fused or non-fused mono, bicyclic or tricyclic heterocyclic or carbocyclic ring which is optionally independently substituted with one or more R¹⁰³ substituents:

R¹⁰⁴ and R^IOÎ are each independently selected from the group consisting of hydrogen, cyano, -NO₃, hydroxy, oxide, hydroxyalkyl, amino, alkyi, alkenyl, cycloalkyl, halogen, alkoxy, alkoxyalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl and heteroarylalkyl;

m Is from 0 to 4; n is from 0 to 5; p is from 0 to 1; and with a proviso that if a nonpyridine N-Oxide (N*—O*) is présent on the compound of Formula (I), then the total number of N-Oxide on the compound of Formula (I) is more than one. In another embodiment, the invention excludes ail N-oxide forms.

In some forms, the compounds as presently disclosed are compounds of formula (I), or pharmaceutically acceptable salts or adducts thereof, wherein R, Ri, R₂, Rj, Rj, Rj and Re are each independently selected from the group consisting of hydrogen, hydroxy, amino, alkyi, alkenyl, cycloalkyl, halogen, cyano, -OR¹⁰¹ and CFj.

In some other forms, the compounds as presently disclosed are compounds of formula (I), or pharmaceutically acceptable salts or adducts thereof, wherein X is -NR^l0lC(O). In some other forms, the compounds as presently disclosed are compounds of formula (I), or pharmaceutically acceptable salts or adducts thereof, wherein Y is a heterocycloalkyl or 2l924392vl

1!

heterocycloalkylalkyl. In some still other forms, the compounds as presently disclosed are compounds of formula (I), or pharmaceutically acceptable salis or adducts thereof, wherein the compound of formula (1) has a structure of formula (Π):

Formula (II) where Q and R’ are each independently selected from the group consisting of C, O, S, and N, each optionally independently substituted with one or more independent R¹⁰³ substituents; R? is selected from the group selected from hydrogen, alkoxy, alkoxyalkyl, -OR¹⁰¹, hydroxy, hydroxyalkyl, amino, alkyl, alkenyl, cycloalkyl and halogen, each optionally independently substituted with one or more independent R¹⁰³ substituents; s is from 0 to 4; and ail other variables are defined as for formula (I).

In some forms, the compounds as presently disclosed are compounds of formula (I), or pharmaceutically acceptable salts or adducts thereof, wherein the compound of formula (I) has a structure of formula (ΠΙ):

Formula (III) where Rg is selected from the group consisting of hydrogen, alkyl, alkenyl and cycloalkyl, each optionally independently substituted with one or more independent R¹⁰³ substituents; R$ is alkyl or cycloalkyl, each optionally substituted with one or more independent R¹⁰³ substituents; and ail other radicals are defined as for formula (I) and formula (Π).

2l924S92vl

In some other forms, the compounds os presently disclosed are compounds of formula (I), or pharmaceutically acceptable salts oradducts thereof, wherein the compound of formula (I) has a structure of formula (TV):

Formula (TV) where p is independently 0 or 1; and ail other radicals are defined as for formula (1), formula (Π) and formula (III).

In some forms, the compounds as presently disclosed are compounds of formula (I), or pharmaceutically acceptable salts or adducts thereof, wherein the compound of formula (I) 10 has a structure of formula (V):

Formula (V) where p is independently 0 or I; and ail other radicals are defined as for formula (I), formula (II), formula (ΓΠ) and formula (IV).

In some other forms, the compounds as presently disclosed are compounds of formula (I), or pharmaceutically acceptable salts or adducts thereof, wherein the compound of formula (I) has a structure of formula (VI):

Îl924592vl

Formula (VI) where R200 and R 300 are each Independently selected from the group consisting of hydrogen, alkyl and cycloalkyl, each optionally independently substituted with one or more îndependent 5 R¹⁰³ substituents; or R200 and Rjoo are each independently an organic or inorgamc cation; p Is independently 0 or 1; and ail other radicals are defined according to formula (I), formula (Π), formula (ΠΙ), formula (IV) and formula (V).

In some forms, the compounds as presently disciosed are compounds of formula (I), or pharmaceutically acceptable salts or adducts thereof, wherein the compound of formula (I) 10 is a compound selected from the group consisting of:

GAI	Ho-h-o rp7 N t ôh cp3	4-(5-(2-(3,5bis(trinuoromethyl)phenyl)-N,2dîmethylpropanamido)-4-(otol y I )pyrid in-2-y 1 )-l -methy 1-1 ((phosphonooxy)methyl)piperazin-1 ium.
GA2	CF3	1 -(acetoxymethyl )-4-(5-(2-( 3,5bis(trinuoromethyl)pheny!)-N,2d i methy|propanamido)-4-(otoly 1 )pyridin-2-y 1 )-1 -methy 1 piperazl nl-ium.
GA3	X cf3	4-(5-(2-(3,5- bi s (t ri iluoromethy l)pheny 1 >N,2di methy lpropanamido)-4-(otolyl)pyridin-2-yl)-l((buty ty loxy) methyl )-1 methylp iperazin-1 -ium.

21924592vl

GA4	Ja 0-ίζ> CFj	1-(5-(2-(3,5bis(trifIuoromethyl)phenyl)-N,2dîmethylpropanamido)-4-(otolyl)pyridin-2-yl)-4-methy 1 piperazine 1,4-dioxide,
GA5	AV 0. CF3	1-(5-(2-(3,5bis(trifluoromethyl)phenyl)-N,2dimethylpropanamido)-1 -oxido-4-(otolyl)pyridin-2-y|)-4-methylpiperazine 1-oxide.
GA6		4-(5-(2-(3.5bis(trifluoromethy l)pheny l>N,2dimethylpropanamido)-1 -oxido-4-(otolyl)pyridin-2-yl)-l-methylpiperazine 1-oxide.
GA7	av cl cf3	5<2-(3,5-bis(trifluoromethyl)phenyl)N,2-dimethylpropanamido)-2-(4methylpiperuzin- |-yl)-4-(otoly l)pyridine 1-oxide, and
GA8	AV ·ο-Αζ> cf3	4-(5-(2-(3,5bis(trifluoromethyl)phenyl)-N,2dimethylpropanamido)-4-(otolyl)pyridin-2-yl)-l-methylpÎpcrazinc 1-oxide.

A particular preferred compound is the chloride hydrochloride HCl sait of GAI having the following chemical structure which, it has been found, ts tremendously résistant lo decoupling of the oxo-phosphonomethyl, nnd reversion of the active moiety to its parent state.

W24592vl

CF₃ .HCl cr _Λ ok^NçAiO OH

Salts and Adducts

The disclosed compositions and compounds can be used in the form of salts derived 5 from inorganic or organic acids. Depending on the particular compound, a sait of the compound can be advantageous due to one or more of the salt’s physical properties, such as enhanccd storage stabiüty in differing températures and humidities, or a désirable solubility in water or oil. In some instances, a sait of a compound also can be used as an aid In the isolation, purification, and/or resolution of the compound.

Where a sait is intended to be administered to a patient (as opposed to, for example, being used in an In vitro context), the sait preferably is pharmaceutically acceptable. The term pharmaceutically acceptable sait” refers to a sali prepared by combining a compound, such as the disclosed compounds, with an acid whose union, or a base whose cation is generally considered suitabie for human consumption. Pharmaceutically acceptable salts are 15 particularly useful as products of the disclosed methods because of their greater aqueous solubility relative to the parent compound. For use in medicine, the salts of the disclosed compounds arc non-toxtc pharmaceutically acceptable salts.” Salis encompassed within the term pharmaceutically acceptable salts refer to non-toxic salts of the disclosed compounds which are generally prepared by reacltng the free base with a suitabie organic or inorganic 20 acid.

Suitabie pharmaceutically acceptable acid addition salts of the disclosed compounds, when possible include those derived from inorganic acids, such as hydrochloric, hydrobromic, hydrofluoric, boric, fluoroboric, phosphoric, metaphosphoric, nitric, carbonic, sulfonic, and sut furie acids, and organic acids such as acetic, benzenesulfonic, benzoic, ci trie, 25 ethanesulfonic, fumaric, gluconic, glycolic, isothiontc, lactic, Jactobionic, maleic, malic, methanesulfonic, trifluoromethanesulfonic, succinic, toluenesulfonic, tartane, and trifluoroacetic acids. Suitabie organic acids generally include, for example, aliphatic.

2Ι924ί92ν) cycloaliphatic, aromatic, araliphatic, hctcrocyclylic, carboxylic, and sulfonïc classes of organic acids.

Spécifie examples of suitable organic acids include acetate, trifluoroacetate, formate, propionate, succinate, glycolate, gluconate, digluconate, lactate, malate, tartane acid, citrate, ascorbate, glucuronate, maleate, fumaratc, pyruvate, aspartate, glutamate, benzoate, anthranilic acid, mesylate, stéarate, salicylate, p-hydroxybenzoate, phcnylacetate, mandelate, embonate (pamoate), methanesulfonate, ethanesulfonate, benzencsulfonate, pantothenate, toluenesulfonate, 2-hydroxyethanesulfonate, sufanilate, cyclohexylaminosulfonate, algenic acid, β-hydroxybutyric acid, galactarate, galacturonate, adipate, alginate, butyrate, camphorate, camphorsulfonate, cyclopentanepropionate, dodccylsulfate, glycoheptanoatc, glycérophosphate, heptanoate, hexanoate, nicotinate, 2-naphthalesuJfonatc, oxalate, palmoatc, pectinate, 3-phenylpropionate, picrate, pivalate, thiocyanate, tosylate, and undecanoate.

Furthermore, where the disclosed compounds carry an acidic moiety, suitable pharmaceutically acceptable salts thereof can include alkali métal salts, e.g., sodium or potassium salts; alkaline earth métal salts, e.g., copper, calcium or magnésium salts; and salts formed with suitable organic ligands, e.g., quatemary ammonium salts. In some forms, base salts are formed from bases which form non-toxic salts, including aluminum, arginine, benzathîne, choline, diethylamine, diolamine, glycine, lysine, meglumine, olamine, tromethamine and zinc salts.

Organic salts can be made from secondary, tertiary or quatemary amine salts, such as tromethamine, diethylamine, N.N’-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucaminc), and procaine. Basic nitrogen-containing groups can be quatemized with agents such as lower alkyl (C1-C6) halides (e.g., methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides), dialky] sulfates (e.g., dimethyl, diethyl, dibuytl, and diamyl sulfates), long chain halides (e.g„ dccyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides), arylalkyl halides (e.g., benzyl and phcnethyl bromides), and others. In some forms, hemisalts of acids and bases can also be formed, for example, hemisulphate and hemicalcium salts. The disclosed compounds can exist in both unsolvated and solvated forms. A solvaté” as used herein is a nonaqueous solution or dispersion in which there is a noncovaJent or easily dispersible combination between solvent and soluté, or dispersion means and disperse phase.

The disclosed compositions and compounds can be used in the form of adducts derived by formation of Lewis pairs, covalently linked adducts e.g. between N atoms and 21924292vl carbonyl-containing reactants, hydrates and alcoholates, host-guest adducts containing molecular species not bonded or associated with the médicinal compound, and other clathrates.

Depending on the particular compound, an adduct of the compound can be advantageous due to one or more of lhe adduct's physical properties, such as enhanced pharmaceutical stability in differing températures and humidilies, or a désirable solubility in water or oil. In some instances, an adduct of a compound also can be used as an aid in the isolation, purification, and/or résolution of the compound.

Where an adduct is intended to be administered to a patient (as opposed to, for example, being used in an in vitro context), the adduct preferably is pharmaceutically acceptable. The term pharmaceutically acceptable adduct refers to an adduct prepared by combining a compound, such as the disclosed compounds, with a gas, water, solvent, Lewis base, carbonyl-conlaining molécule, or guest molécule that is generally considered suitable for human consumption. Pharmaceutically acceptable addition species are particularly useful as products of the disclosed methods because of their greater aqueous solubility relative to the parent compound. For use in medïcine, the adducts of the disclosed compounds are non-toxic pharmaceutically acceptable adducts.” Adducts encompassed within the term pharmaceutically acceptable salts” refer to non-toxic adducts of the disclosed compounds which are generally prepared by reactïng a compound of the invention with a suitable organic or inorganic addition species.

Suitable pharmaceutically acceptable adducts of the disclosed compounds, when possible, include those derived from Lewis bases such as boric acid, aluminum hydroxide, organic sulfoxides, organic sulfones, organic sulfonium salts, H3PO3, siloxanes, and other Lewis bases.

Suitable pharmaceutically acceptable adducts of the disclosed compounds, when possible, also include those derived from covalent bonding between an oxygen, nitrogen or sulfur atom of the compound and carbon dioxide, low alkyl aldéhyde or ketone, vanillin, amino acid, or a nucleic acid.

Suitable pharmaceutically acceptable adducts of the disclosed compounds, when possible, also Include those derived from inclusion of an unbonded gas such as dioxygen, dinitrogen, carbon dioxide, nitrous oxide, ethyl ether, or other gas, contained within but not bonded to a crystalline or amorphous phase of the compound.

11924392*1

Suitable pharmaceutically acceptable adducts of the disclosed compounds, when possible, also inciude those derived from association of a molécule of the compound with water, a pharmaceutically acceptable lower alkyl alcohol, or another pharmaceutically acceptable solvent that is associated in a molecular ratio with the compound.

In one embodiment the adduct is optionally a clathrate.

General Synthetic Schemes

The compounds of the formula (I) (and other disclosed compounds), or their pharmaceutically acceptable salts or adducts, can be prepared by the methods as illustrated by examples described in the Examples” section, together with synthetic methods known in the art of organic chemistry, or modifications and derivatisations that are familiar to those of ordinary skill in the art. The starting materials used herein are commercially available or can be prepared by routine methods known in the art (such as those methods disclosed in standard reference books such as the Compendium of Organic Synthesis Methods, Vol. I-VI (published by Wiley-ïnterscience)). Preferred methods inciude, but are not limited to, those described below. During any of the following synthetic sequences it may be necessary and/or désirable to protect sensitive or reactive groups on any of the molécules concemed. This can bc achieved by means of conventional protecting groups, such as those described in T. W. Greene, Protective Groups in Organic Chemistry, John Wiley & Sons, 1981; T. W. Grecne and P. G. M. Wuts, Protective Groups in Organic Chemistry, John Wiley & Sons, 1991, T. W. Grecne and P. G. M. Wuts, Protective Groups in Organic Chemistry, John Wiley & Sons, 1999, and P. G. M. Wuts and T.W.Greene, Protective Groups in Organic Chemistry, John Wiley & Sons, 2006. Isolation and purification of the products is accomplished by standard procedures, which are known to a chemrst of ordinary skill.

The invention further provides methods for making suitable prodrugs of lhe 4-phenylpyridine dérivatives. In one embodiment the invention provides a one-step, acid-free synthesis for functionalizing tertiary amines by reaction with chloromethyl dialkyl phosphate esters to create (phosphooxy)methyl prodrugs that are substrates for phosphatase enzymes. By contrast the prior art had required multiple synthetic steps for comparable reactions, including requiring the use of proton scavengers during initial reaction and requiring strong acid to dcprotect the phosphate group in another step. In another embodiment the invention provides methods for making chloromethyl dialkyl phosphate esters having suitable purity and economy, because the quality of phosphate ester compositions from commercial sources 11914S91vl is too low to provide acceptable yields for réactions according to the invention. In on additional embodiment the invention provides a method to stabilize the (phosphooxy)methyl prodrugs according to the invention by combination with two équivalents of hydrochloric acid, because whereas the prior art preferred the use of dibasic salts of (phosphooxy)methyl substituents for quatemary ammonium salts in prodrugs, the présent invention had found that such salts are unstable and reform the underlying drug during storage.

Définition of Terms

The term alkyl” refers to a linear or branched-chain saturated hydrocarbyl substituent (i.e., a substituent obtained from a hydrocarbon by removal of a hydrogen) containing from one to twenty carbon atoms; in one embodiment from one to twelve carbon atoms; in another embodiment, from one to ten carbon atoms; in another embodiment, from one to six carbon atoms; and in another embodiment, from one to four carbon atoms. Examples of such substituents include methyl, ethyl, propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, sec-butyl and tert-butyl), pentyl, iso-amyl, hexyl and the like.

The term alkenyl” refers to a linear or branched-chain hydrocarbyl substituent containing one or more double bonds and from two to twenty carbon atoms; ln another embodiment, from two to twelve carbon atoms; in another embodiment, from two to six carbon atoms; and in another embodiment, from two to four carbon atoms. Examples of alkenyl include ethenyl (also known as vinyl), allyl, propenyl (including 1-propcnyl and 2propenyl) and butenyl (including l-butenyl, 2-butenyl and 3-butenyl). The term alkenyl” embraces substituents having ”cis” and trans” orientations, or altematively, “E” and Z” orientations.

The term benzyl” refers to methyl radical substituted with phenyl.

The term carbocyclic ring refers to a saturated cyclic, partially saturated cyclic, or aromatte ring containing from 3 to 14 carbon ring atoms (“ring atoms arc the atoms bound together to form the ring). A carbocyclic ring typically contains from 3 to 10 carbon ring atoms. Examples înclude cyclopropyl, cyclobutyl, cyclopentyl* cyclopentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, and phenyl. A carbocyclic ring System altematively may be 2 or 3 rings fused together, such as naphthalenyl, tetrahydronaphlhalenyl (also known as tetralinyl”), indenyl, isoindenyl, indonyl, bicyclodecanyl, anthraccnyl, phenanthrene. benzonaphthenyl (also known as phenalcnyl”), fluorenyl, and decalinyl.

2.1924593*1

The term “heterocyclic ring refers to a saturated cyclic, partially saturated cyclic, or aromatic ring containing from 3 to 14 ring atoms (“ring atoms are the atoms bound together to form the ring), in which at least one of the ring atoms is a heteroatom that is oxygen, nitrogen, or sulfur, with the remaining ring atoms being Independently selected from the 5 group consisting of carbon, oxygen, nitrogen, and sulfur.

The term cycloalkyl refers to a saturated carbocyclic substituent havtng three to fourteen carbon atoms. In one embodiment, a cycloalkyl substituent has three to ten carbon atoms. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

The term “cycloalkyl” also includes substituents that are fused to a Ce-Cjo aromatic 10 ring or to a 5-10-membered heteroaromatic ring, wherein a group having such a fused cycloalkyl group as a substituent Is bound to a carbon atom of the cycloalkyl group. When such a fused cycloalkyl group is substituted with one or more substituents, the one or more substituents, unless otherwise specified, arc each bound to a carbon atom of the cycloalkyl group. The fused Ce-Cio aromatic ring or to a 5-10-membered heteroaromatic ring may be 15 optionally substituted with halogen, C|-Ce alkyl, Cj-Cjo cycloalkyl, or=O.

The term cycloalkenyl refers to a partially unsaturated carbocyclic substituent having three to fourteen carbon atoms, typically three to ten carbon atoms. Examples of cycloalkenyl include cydobutenyl, cyclopentenyl, and cyclohexenyl.

A cycloalkyl or cycloalkenyl may be a single ring, which typically contains from 3 to 20 6 ring atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, and phenyl. Altematively, 2 or 3 rings may be fused together, such as bicyclodecanyl and decalinyl.

The term aryl” refers to an aromatic substituent containing one ring or two or three fused rings. The aryl substituent may hâve six to eighteen carbon atoms. As an example, the 25 aryl substituent may hâve six to fourteen carbon atoms. The term “aryl” may refer to substituents such as phenyl, naphthyl and anthracenyl. The term aryl” also includes substituents such as phenyl, naphthyl and anthracenyl that are fused to a C4-C10 carbocyclic ring, such as a Cs or a Ce carbocyclic ring, or to a 4-10-membered heterocyclic ring, wherein a group having such a fused aryl group as a substituent is bound to an aromatic carbon of the 30 aryl group. When such a fused aryl group is substituted with one more substituents, the one or more substituents, unless otherwise specified, are each bound to an aromatic carbon of the fused aryl group. The fused Q-Cæ carbocyclic or 4-10-membered heterocyclic ring may be optionally substituted with halogen, C|-Ce alkyl, Cj-C|₀ cycloalkyl, or =0. Examples of aryl

21924392*1 groups include accordingly phenyl, naphthalenyl, tetrahydronaphthalenyl (also known as “tetralinyl), indenyl, isoindenyl, Indanyl, anthracenyi, phenanthrenyl, benzonaphthenyi (also known as “phenalenyl), and fluorenyl.

In some instances, the number of carbon atoms in a hydrocarbyi substituent (e.g., alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl, etc.) Is Indicated by the prefix ”C_rC_r.‘’ wherein x is the minimum and y is the maximum number of carbon atoms in the substituent. Thus, for example, Ci-Ce-alkyl refers to an alkyl substituent containing from I to 6 carbon atoms. Ulustrating further, Cj-Ce-cycloalkyl refers to saturated cycloalkyl containing from 3 to 6 carbon ring atoms.

In some instances, the number of atoms in a cyclic substituent containing one or more heteroatoms (e.g., heteroaryl or heterocydoalkyl) is Indicated by the prefix ”X-Y-membered, wherein x is the minimum and y ls the maximum number of atoms forming the cyclic moiety of the substituent. Thus, for example, 5-8-membered heterocydoalkyl refers to a heterocydoalkyl containing from 5 to 8 atoms, including one or more heteroatoms. In the cyclic moiety of the heterocydoalkyl.

The term “hydrogen” refers to hydrogen substituent, and may be depicted as -H.

The term “hydroxy” refera to -OH. When used in combination with another term(s), the prefix “hydroxy” indicates that the substituent to which the prefix is attached is substituted with one or more hydroxy substituents. Compounds bearing a carbon to which one or more hydroxy substituents include, for example, alcohols, enols and phénol.

The term “hydroxyalkyl refera to an alkyl that is substituted with at least one hydroxy substituent. Examples of hydroxyalkyl include hydroxymethyl, hydroxyethyl, hydroxypropyl and hydroxybutyl.

The term nltro” means -NO2.

The term “cyano (also referred to as “nitrile) -CN.

The term “carbonyl” means -C(O)-.

The term “amino” refera to -NHi.

The term “alkylamino refera to an amino group, wherein at least one alkyl chain îs bonded to the amino nitrogen in place of a hydrogen atom. Examples of alkylamino substituents include monoalkylamino such as methylamino (exemplified by the formula -NH(CHj)), and dialkylamino such as dimethylamino.

The term “aminocarbonyl” means -C(0)-NH₂.

2l924592vl

The term “halogen” refers to fluorine (which may be depicted as -F), chlorine (which may be depicted as -Cl), bromine (which may be depicted as -Br), or iodine (which may be depicted as -I). In one embodiment, the halogen is chlorine. In another embodiment, the halogen is a fluorine.

The prefix “halo indicates that the substituent to which the prefix is attached is substituted with one or more independently selected halogen substituents. For example, haloalkyl refers to an alkyl that is substituted with at least one halogen substituent. The term “oxo” refers to =0.

The term “oxy” refers to an ether substituent, and may be depicted as -O-.

The term “alkoxy” refers to an alkyl linked to an oxygen, which may also be represented as -O-R, wherein the R représente the alkyl group. Examples of alkoxy include methoxy, ethoxy, propoxy and butoxy.

The term “alkylthio” means -S-alkyl. For example, methylthio” is -S-CHj. Other examples of alkylthio include ethylthio, propylthio, butylthio, and hexylthio.

The term “alkylcarbonyl” means -C(O)-alkyl. Examples of alkylcarbonyl include methylcarbonyl, propylcarbonyl, butylcarbonyl. pentylcabonyl, and hcxylcarbonyl.

The term “aminoalkylcarbonyl” means -C(O)-alkyl-NH2.

The term “alkoxycarbony!” means -C(O)-O-alkyl. Examples of alkoxycarbonyl include methoxycarbonyl, ethoxycarbonyl. propoxycarbonyl, butoxycarbony], pentoxycarbonyl. and hexyloxycorbonyl. In another embodiment, where the carbon atom of the carbonyl is attached to a carbon atom of a second alkyl, the resulting functional group Is an ester.

The terms “thîo” and “thia” mean a divalent sulfur atom and such a substituent may be depicted as -S-. For example, a thioether is represented as “alkyl-thio-alkyl” or, alternatively, alkyl-S-alkyl.

The term “thio!” refers to a sulfhydryl substituent, and may be depicted as -SH.

The term “thione” refers to =S.

The term “sulfony! refers to -S(O)i-, Thus, for example, “alkyl-sulfonyl-alkyl” refers to alkyl-S(O)2-alkyl. Examples of alkylsulfonyl include melhylsulfonyl, ethylsulfonyl, and propylsulfonyl.

The term “aminosulfony!” means -S(O)2-NH₂.

21914591»!

The term sulfinyl or “sulfoxido” means -S(O)-. Thus, for example, “alkylsulfinylalky!” or alkylsulfoxidoalkyr refers to alkyl-S(O)-alkyl. Exemplary alkylsulfiny! groups include methylsulfînyl, ethylsulfinyl, butylsulfinyl, and hexylsulfînyl.

The term “heterocycloalkyl” refers to a saturated or partially saturated ring structure containing a total of 3 to 14 ring atoms. At least one of the ring atoms is a heteroatom (i.e., oxygen, nitrogen, or sulfur), with the remaining ring atoms being independently selected from the group consisting of carbon, oxygen, nitrogen, and sulfur. A heterocycloalkyl altematively may comprise 2 or 3 rings fused together, wherein at least one such ring contains a heteroatom as a ring atom (e.g., nitrogen, oxygen, or sulfur). In a group that has a heterocycloalkyl substituent, the ring atom ofthe heterocycloalkyl substituent that is bound to the group may be the at least one heteroatom, or it may be a ring catbon atom, where the ring carbon atom may be in the same ring as the at least one heteroatom or where the ring catbon atom may be in a different ring from the at least one heteroatom. Similarfy, if the heterocycloalkyl substituent is in tum substituted with u group or substituent, the group or substituent may be bound to the at least one heteroatom, or it may be bound to a ring carbon atom, where the ring carbon atom may be in the same ring as the at least one heteroatom or where the ring carbon atom may be in a different ring from the at least one heteroatom.

Examples of heterocycloalkyl Include, but not limited to, azacyclobutane, 1,3diazatidine, pyrrolidine, 2-pyrroline, 3-pyrroline, 2-lmidazoline, imidazolidine, 2-pyrazoline, pyrazolidine, piperidine, 1,2-diazacyclohexane, 1,3-diazacyclohexanc, 1,4-diazacyclohexane, octahydroazocine, oxacydobutane, tetrahydrofuran, tetrahydropyran, 1,2-dioxacyclohexane,

1.3- dîoxacyclohexane, 1,4-dioxacydohexane, 1,3-dioxolane, thiacydobutane, thiocyclopentane, 1,3-dithiolane, thiacydohexane, 1,4-dîthiane, 1,3-oxathialane, morpholine,

1.4- thiaxane, 1,3,5-trithïane and thiomorpholine.

The term heterocycloalkyl” also includes substituents that are fused to a Cô-Cjo aromatic ring or to a 5-10-membered heteroaromatic ring, wherein a group having such a fused heterocycloalkyl group as a substituent is bound to a heteroatom of the heterocydocalkyl group or to a carbon atom of the heterocycloalkyl group. When such a fused heterocycloalkyl group is substituted with one more substituents, the one or more substituents, unless otherwise specifïed, are each bound to a heteroatom of the heterocydocalkyl group or to a carbon atom of the heterocycloalkyl group. The fused Ce-Cto aromatic ring or to a 5-IO-membered heteroaromatic ring may be optionally substituted with halogen, C_rCe alkyl, C3-C10 cycloalkyl, or =0.

21924592Vt

The term “heteroaryl” refers to an aromatic ring structure containing from 5 to 14 ring atoms In which at least one of the ring atoms is a heteroatom (i.e., oxygen, nitrogen, or sulfur), with the remaining ring atoms being independently selected from the group consisting of carbon, oxygen, nitrogen, and sulfur. A heteroaryl may be a single ring or 2 or 3 fused rings. Examples of heteroaryl substituents include 6-membered ring substituents such as pyridyl, pyrazyl, pyrimidinyl, and pyridazinyl; 5-membered ring substituents such as triozolyl, imidazolyl, furanyl, thiophenyl, pyrazolyl, oxazoiyl, isoxazoiyl, thiazolyl, 1,2,3-,

1.2.4- , 1,2,5-, or 1,3,4-oxadiazoIyl and isothiozolyl; 6/5-membcred fused ring substituents such as benzothiofuranyl, isobenzothiofuranyl, benzlsoxazolyl, benzoxazolyl, purinyl, and anthranilyl; and 6/6-membered fused rings such as quinoiinyl, isoquinolinyl, cinnoiinyl, quinazolinyl, and 1,4-benzoxazinyl. The term '‘heteroaryl also includes pyridyi N-oxides and groups containing a pyridine N-oxide ring.

Exemptes of singie-ring heteroaryls include furanyl, dihydrofurunyi, tctradydrofuranyl, thiophenyl (also known as “thiofuranyl), dihydrothiophenyl, tetrahydrothiophenyl, pyrrolyi, isopyrroiyl, pyrrolinyi, pyrrolidinyi, imldazoiyl, isoimidazolyl, imidazolinyl, imidazoiidinyl, pyrazolyi, pyrazolinyi, pyrazoiidinyl, triazoiyl, tetrazolyl, dithiolyl, oxathiolyl, oxazoiyl, isoxazoiyl, thiazolyl, isothîazoiyi, thiazoiinyl, isothiazolinyl, thiazolidinyl, isothiazolidinyl, thlaodiazolyl, oxathiazoiyi, oxadiazolyl (including oxadiazolyl,

1.2.4- oxadiazolyl (also known as “azoximyl), 1,2,5-oxadiazolyl (also known as furazanyl), or 1,3,4-oxadiazolyi), oxatriazolyl (including 1,2,3,4-oxatriazolyl or 1,2,3,5-oxatriazolyl), dioxazolyl (including 1,2,3-dîoxazolyl, 1,2,4-dioxazoiyl, 1,3,2-dioxozolyl, or

1.3.4- dioxazolyl), oxathiazoiyi, oxathiolyl, oxathîolanyl, pyranyl (including 1,2-pyranyl or

1.4- pyrunyl), dihydropyranyl, pyridinyl (also known as azinyi”), piperidinyl, dîazinyl (including pyridazinyl (also known as “1,2-diazinyl*’), pyrimidinyl (also known as “1,3-diazinyl or “pyrimidyl”), or pyrazinyl (also known as “1,4-diazinyl”)), piperazinyl, triazinyi (including s-triazinyl (also known as “1,3,5-triazinyi”), as-triazinyl (also known

1.2.4- triazinyl), and v-triazinyl (also known as “1,23-triazinyl)). oxazinyl (including 1,2,3-oxazinyi, 1,3,2-oxazinyi, 1,3,6-ox azinyi (also known as pentoxazoiyi”), 1,2,6-oxazinyl, or 1,4-oxazinyl), isoxazïnyl (including o-isoxazinyl or p-isoxazinyi), oxazolidinyi, isoxozoiidinyl, oxathiazinyl (including 1,2,5-oxathiazinyi or 1,2,6-oxathiazinyl), oxadiazinyl (including 1,4,2-oxadiazinyi or 1,3,5,2-oxadiazinyl), morpholinyl. azepinyl, oxepinyl, thîepinyl, and diazepinyl.

2l924592vl i j

Examples of 2-fused-ring heteroaryls include, indolizinyl, pyrindinyl, pyranopyrrolyl, 4H-quinolizinyl, purinyl, naphthyridînyl, pyridopyridiny) (including pyrido[3,4-bl-pyridinyl, pyrido[3,2-bl-pyridînyl, or pyrido[4,3-b]-pyridinyl), and pteridinyl, indoiyl, isoindoly), indoleninyl, isoindazolyl, benzaziny), phthalazinyl, quinoxoliny), quinazolinyl, benzodïazinyl, benzopyrany), benzothiopyranyl, benzoxazoiyl, indoxazînyl, anthranilyl, benzodioxolyl, benzodioxany), benzoxadiazolyl, benzofuranyl, isobenzofuranyl, benzothieny), isobenzothienyl, benzothiazolyl, benzothiadiazolyl, benzimidazolyl, benzotriazolyl, benzoxazinyi, benzisoxazinyl, and tetrahydroisoquinolinyl.

Examples of 3-fused-ring heteroaryls or heterocycloolkyls include 5,6-dihydro-4H-imidazo[4,5,l-ijlquino)ine, 4,5-dihydroimidazo[4,5,l-hilindo!e,

4,5,6,7-tetrahydroimidazo[4,5,l-jlc][l]benzazepïne, and dîbenzofuranyl.

The term “heteroaryl” also includes substituents such as pyridyl and quinoliny! that are fused to a C<-C|q carbocyclic ring, such as a Cj or a Ce carbocyclic ring, or to a 4-10membered heterocyclic ring, wherein a group having such a fused aryl group as a substituent is bound to an aromatic carbon of the heteroaryl group or to a heteroatom of the heteroaryl group. When such a fused heteroaryl group is substituted with one more substituents, the one or more substituents, unless otherwise specified, are each bound to an aromatic carbon of the heteroaryl group or to a heteroatom of the heteroaryl group. The fused C<-C_I0 carbocyclic or 4-10-membered heterocyclic ring may be optionally substituted with halogen, CpCs alkyl, C3-C10 cycloalkyl, or =0.

The term “ethylene” refera to the group -CHrCHi*. The term ethynelene·’ refera to the group -CH=CH- The term “propylene” refera to the group -CHj-CHrCHr. The term “butylène” refera to the group -CHî-CHi-CHrCHr. The term methylenoxy” refera to the group -CHi-O- The term “methylenethioxy” refera to the group -CHrS-, The term 25 “methylenamino” refera to the group -CHj-NfH)-. The term “cthylenoxy” refera to the group -CH2-CH2-O-. The term “ethylenethioxy” refera to the group - CHj-CHi-S·. The term “ethylenamino” refera to the group -CHî-CH2-N(H)A substituent is “substitutable” Jf it comprises at least one carbon, sulfur, oxygen or nitrogen atom thaï is bonded to one or more hydrogen atoms. Thus, for example, hydrogen, 30 halogen, and cyano do not fall within this définition. If a substituent is described as being substituted, a non-hydrogen substituent is in the place of a hydrogen substituent on a carbon, oxygen, sulfur or nitrogen of the substituent. Thus, for example, a substituted alkyl

21924392*1

substituent is un alkyl substituent wherein at least one non-hydrogen substituent is in the place of a hydrogen substituent on the alkyl substituent.

If a substituent is described as being “optionally substituted, the substituent may be either (1) not substituted, or (2) substituted. When a substituent is comprised of multiple 5 moieties, unless otherwise indicated, it is the intention for the final moiety to serve as the point of attachment to the remainder of the molécule. For example, in a substituent A-B-C, moiety C is attached to the remainder of the molécule. If substituents are described as being independently selected from a group, each substituent is selected independent of the other. Each substituent therefore may be identical to or different from the other substituent(s).

Pharmaceutical Compositions

Pharmaceutical compositions for preventing and/or treating a subject are further provided comprising a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable sait or adduct thereof, and one or more pharmaceutically 15 acceptable excipients.

A pharmaceutically acceptable excipient is one that is not biologically or otherwise undesirable, i.e., the material can be administered to a subject without causing any undesirable biological effects or interacting in a deleterious manner with any of the other components of the pharmaceutical composition in which it is contained. The carrier can be 20 selected to minimize any dégradation of the active ingrédient and to minimize any adverse side effects in the subject, as would be well known to one of skill in the art. The carrier can be a solid, a liquid, or both.

The disclosed compounds can be administered by any suitable route, preferably in the form of a pharmaceutical composition adapted to such a route, and in a dose effective for the 25 treatment or prévention intended. The active compounds and compositions, for example, can be administered orally, rectally, parenterally, ocularly, inhalationaly, or topically. In particular, administration can be epîcutaneous, inhalational, enema, conjunctival, eye drops, ear drops, alveolar, nasal, intranasal, vaginal, intruvaginal, transvaginal, ocular, intraocular, transocular, enterai, oral, intraoral, transoral, intestinal, rectal, intrarectal, transrectal, 30 injection, infusion, intravenous, intraarterial, intramuscular, intracérébral, intraventricular, intracerebroventricular, intracardiac, subcutaneous, intraosseous, intradermal, intrathecal, intraperitoneal, intravesical, intracavemosal, in trame du 11 ar, intraocular, intracranial,

21924592*1

transdermal, transmucosal, transnasal, in halation al, intracistemal, épidural, péridural, intravitreal, etc.

Suitabie carriers and their formulations are described in Remington: The Science and Practice of Phamtacy (19th ed.) ed. A.R. Gennaro, Mack Publishing Company, Easton, PA, 5 1995. Oral administration of a solid dose form can be, for example, presented in discrète units, such as hard or soft capsules, pills, cachets, lozenges, or tablets, each containing a predetermined amount of at least one of the disclosed compound or compositions. In some forms, the oral administration can be in a powder or granule form. In some forms, the oral dose form is sub-lingual, such as, for example, a lozenge. In such solid dosage forms, the 10 compounds of formula I are ordinarily combined with one or more adjuvants. Such capsules or tablets can contain a controlled-release formulation. In the case of capsules, tablets, and pills, the dosage forms also can comprise buffering agents or can be prepared with enteric coatings.

In some forms, oral administration can be in a liquid dose form. Liquid dosage forms 15 for oral administration include, for example, pharmaceutically acceptable émulsions, solutions, suspensions, syrups, and élixirs containing inert diluents commonIy used in the art (e.g., water). Such compositions also can comprise adjuvants, such as wetting, emulsifying, suspending, flavoring (e.g., sweetening), and/or perfuming agents.

In some forms, the disclosed compositions can comprise a parentéral dose form. 20 '‘Parentéral administration includes, for example, subcutaneous injections, intravenous injections, intraperitoneal!y, intramuscular injections, intrastemal injections, and infusion. Injectable préparations (e.g., stérile injectable aqueous or oleaginous suspensions) can be formulated according to the known art using suitabie dispersing, wetting agents, and/or suspending agents. Typically, an appropriate amount of a pharmaceutically acceptable carrier 25 is used in the formulation to render the formulation isotonie. Examples of the pharmaceutically acceptable carrier include, but are not limited to, saline, Ringer's solution and dextrose solution. Other acceptable excipients include, but are not limited to, thickeners, diluents, buffers, preservatives, surface active agents and the like.

Other carrier materials and modes of administration known in the pharmaceutical art 30 can also be used. The disclosed pharmaceutical compositions can be prepared by any of the well-known techniques of pharmacy, such as effective formulation and administration procedures. The above considérations in regard to effective formulations and administration procedures arc well known in the art and are described in standard textbooks. Formulation of

Î1924S9ÎVÎ

drugs is discussed in, for exampie, Hoover, John E., Remington’s Pharmaceutical Sciences,

Mack Publishing Co., Easton, Pennsylvania, 1975; Liberman, et al., Eds., Pharmaceutical

Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Kibbe, et al., Eds., Handbook of Pharmaceutical Excipients (3ⁿ⁾ Ed.)₍ American Pharmaceutical Association, Washington, 5 1999.

The disclosed compounds can be used, alone or in combination with other therapeutic agents, in the treatment or prévention of various conditions or disease states. The administration of two or more compounds “in combination’’ means that the two compounds arc administered cl ose I y enough in time that the presence of one alters the biological effects 10 of the other. The two or more compounds can be administered simultaneously, concurrently or sequentially.

Disclosed are pharmaceutical compositions comprising an effective amount of a compound of the invention or a pharmaceutically accepted sait, solvaté, dathrate, or prodrug thereof; and a pharmaceutically acceptable carrier or vehicle. These compositions may further 15 comprise additional agents. These compositions are useful for modulating the activity of the neurokinin (NKj) receptor, thus to improve the prévention and treatment of NKj receptor associated diseuses such as nausea and vomiting, bladder dysfonction, dépression or anxiety.

In some forms, disclosed are pharmaceutical compositions for preventing and/or treating a subject comprising a therapeutically effective amount of a compound according to 20 formula (I), and one or more pharmaceutically acceptable excipients. In some other forms, disclosed are pharmaceutical compositions, further comprising one or more therapeutic agents or a pharmaceutically acceptable sait thereof. In some forms, said therapeutic agent is a 5-HT3 antagonist, a NK| antagonist or dexamethasone. In some other forms, said 5-HT3 antagonist is ondansetron, palonosetron, granîsetron or tropisetron. or a pharmaceutically 25 acceptable sait thereof.

Methods

Ail of the methods of the invention may be practiced with a compound of the invention alone, or in combination with other agents.

Treating

The above-described compounds and compositions are useful for the inhibition, réduction, prévention, and/or treatment of dîseases which are pathophysiologically modulated

21924592*1 by the neurokinm (NK|) receptor. Accordingly, in some forms, disclosed are methods of preventing and/or treating diseases which are pathophysiologically modulated by the NK| receptor, comprising administering to a subject a therapeutically effective amount of a compound of formula (D os disclosed above, or a pharmaceutically acceptable sait or adduct thereof.

Suitable subjects can inciude mammalian subjects. Mammals inciude, but are not limited to, canine, féline, bovine, caprine, equine, ovine, porcine, rodents, lagomorphs, primates, and the like, and encompass mammals in utero. In some forms, humans are the subjects. Human subjects can be ofeither gender and at any stage ofdevelopment.

In some other forms, disclosed are methods of preventing and/or treating diseases which are pathophysiologically modulated by the NKj receptor, wherein said disease is nausea and vomiting, bladder dysfonction, dépréssion oranxiety.

In some other forms, disclosed are methods of preventing and/or treating diseases which are pathophysiologically modulated by the NKj receptor, wherein said nausea and vomiting is chemotherapy induced nausea and vomiting (CINV), radiation therapy induced nausea and vomiting (RINV), or post-operative nausea and vomiting (PONV).

In some other forms, disclosed are methods of preventing and/or treating diseases which are pathophysiologically modulated by the NK| receptor, wherein said nausea and vomiting is induced by moderately or highly emetogenic chemotherapy. In some other forms, disclosed are methods of preventing and/or treating diseases which are pathophysiologically modulated by the NKj receptor, wherein said nausea and vomiting is an acute and/or delayed phases of CINV.

Acute emesis refers to the first twenty-four hour period following an emesis-inducîng event. Delayed emesis refers to the second, third, fourth and fifth twenty-four hour periods following an emesis-inducing event. When a treatment is said to be effective during the delayed phase, it will be understood to mean that the effectiveness of the treatment is statistlcally significant during the en tire delayed phase, regardless of whether the treatment is effective during any particular twenty-four hour period of the delayed phase. It will also be understood that the method can be defined based upon its effectiveness during any one of the twenty-four hour periods of the delayed phase. Thus, unless otherwise specified, any of the methods of treating nausea and/or vomiting during the delayed phases, as described herein, could also bc practiced to treat nausea and/or vomiting during the second, third, fourth or fifth twenty-four hour periods following an emesis inducing event, or an combination thereof.

21924592vl

In some other forms, disclosed are methods of preventing and/or treating diseases which are pathophysîologically modulated by the NKj receptor, wherein said acute and/or delayed phases of CINV is induced by moderately or highly emetogenic chemotherapy. “Highly emetogenic chemotherapy refers to chemotherapy having a high degree of emetogenic potential, and includes chemotherapy based on carmustine, cisplatin, cyclophosphamide > 1500 mg/m², dacarbazine, dactinomycin, mechlorethamine, and streptozotocin. “Moderately emetogenic chemotherapy*' refers to chemotherapy having a moderato degree of emetogenic potential, and includes chemotherapy based on carboplatin, cyclophosphamide < 1500 mg/m², cytarabine > I mg/m², daunonibicin, doxorubicin, 10 epirubicin, idarubicin, ifosfamide, irinotecan, and oxal iplatin.

In a preferred embodiment, the methods of the présent invention are effective to treat acute and delayed emesis resulting from moderately and highly emetogenic chemotherapy, from a single dose of the netupitant dérivative administered prior to chemotherapy, optionally in combination with other active Ingrédients.

i5 A particularly preferred regimen for treating emesis, especially emesis induced by chemotherapy, involves a netupitant dérivative of the présent invention, a 5-HT3 antagonist such as palonosetron or a pharmaceutically acceptable sait thereof, and a cortlcosteroid such as dexamethasone. A suitable fixed regimen for treating acute and delayed CINV includes a single administration of the netupitant dérivative on day one (preferably before 20 chemotherapy), a single administration of the 5-HT3 antagonist on day I (preferably before chemotherapy). A cortîcosteroid is optionally added to the combination on day one and, when highly emetogenic chemotherapy is administered, on days 2, 3 and 4 as well. A preferred intravenous dose of palonosetron HCl is 0.25 mg based on the weight of the free base. Preferred dexamethasone doses are 12 mg. orally on day I, foliowedby 8 mg. orally on 25 days 2,3 and 4 for highly emetogenic chemotherapy.

In some other forms, disclosed are methods of preventing and/or treating diseases which are pathophysîologically modulated by the NKi receptor, wherein said bladder dysfonction is selected from urgency, frequency, pollakiuria, nocturia, iow deferment time, suboptimal volume threshold, and neurogenic bladder, or a combination thereof.

In some other forms, disclosed are methods of preventing and/or treating diseases which are pathophysîologically modulated by the NKi receptor, wherein said compound or a pharmaceutically acceptable sait or adduct thereof, is administered by one or more routes selected from the group consisting of rectal, buccal, sublingual, intravenous, subcutaneous,

2l924î92vl

intradermal, transdermal, intraperitoneal, oral, eye drops, parentéral and topical administration.

In some other forms, disclosed are methods of preventing and/or treating diseases which are pathophysiologically modulated by the NK) receptor, wherein said administration 5 is accomplished by intravenously admînistering a liquid form of said compound or a pharmaceutically acceptable sait or adduct thereof.

In some other forms, disclosed are methods of preventing and/or treating diseases which are pathophysiologically modulated by the NK| receptor, particularly by dérivatives of netupitant, wherein said administration is accomplished by orally admînistering said 10 compound or a pharmaceutically acceptable sait or adduct thereof. In some other forms, disclosed are methods of preventing and/or treating discases which are pathophysiologically modulated by the NK) receptor, wherein said netupitant dérivative is orally administered at a dosage of from about 50 mg to about 500 mg, from about 100 mg to about 400 mg, from about 150 mg to about 350 mg, or about 300 mg, based on the weight of the netupitant 15 component of the molécule.

In some other forms, disclosed are methods of preventing and/or treating diseases which are pathophysiologically modulated by the NKt receptor, particularly by dérivatives of netupitant, wherein said compound or a pharmaceutically acceptable sait or adduct thereof is intravenously administered at a dosage of from about 10 mg to about 200 mg, from about 50 20 mg to about 150 mg, from about 75 mg to about 125 mg, or about 100 mg, based on the weight of the netupitant component of the molécule.

In some other forms, disclosed are methods of preventing and/or treating diseases which are pathophysiologically modulated by the NKi receptor, particularly by dérivatives of netupitant, wherein said compound or a pharmaceutically acceptable sait or adduct thereof, is 25 formulated to hâve a concentration of from about ! to about 20 mg/ml, from about 5 to about 15 mg/ml, from about 7 to about 2 mg/ml, or about 10 mg/ml, based on the weight of the netupitant component of the molécule.

In some other forms, disclosed are methods of preventing and/or treating discases which are pathophysiologically modulated by the NKi receptor, wherein said compound or a 30 pharmaceutically acceptable sait or adduct thereof, Is administered in a single dosage per day, a single dosage during a multi-day course of therapy (e.g„ a five-day therapeutic regimen for delayed emesis), or in multiple dosages per day. In some other forms, disclosed are methods

31924592*1

of preventing and/or treating diseases which are pathophysiologically modulated by the NKi receptor, wherein said multiple dosages are from 2 to 4 dosages per day.

In some other forms, disclosed are methods of preventing and/or treating diseases which are pathophysiologically modulated by the NK| receptor, further comprising 5 administering one or more therapeutic agents or a pharmaceutically acceptable sait thereof. In some other forms, said therapeutic agent is a S-HTj antagonist, a NK] antagonist or dexamethasone. In some other forms, said 5-HT3 antagonist Is ondansetron, palonosetron, granîsetron or tropisetron, or a pharmaceutically acceptable sait thereof. In some still other forms, said 5-HTj antagonist is palonosetron or a pharmaceutically acceptable sait thereof. In 10 some other forms, the oral dosage of palonosetron or a pharmaceutically acceptable sait thereof is from about 0.1 mg to about 2.0 mg, from about 0.25 mg to about 1.0 mg, from about 0.5 mg to about 0.75 mg. or about 03 mg. In some other forms, the intravenous dosage of palonosetron or a pharmaceutically acceptable sait thereof is from about 0.05 mg to about 2.0 mg, from about 0.075 mg to about 1.5 mg, from about 0.1 mg to about 1.0 mg, from 15 about 0.25 mg to about 0.75 mg, or about 0.25 mg. In some other forms, said palonosetron or a pharmaceutically acceptable sait thereof is formulated to hâve a concentration of about 0.25 mg/5 mL.

In some other forms, disclosed are methods of preventing and/or treating diseases which are pathophysiologically modulated by the NK] receptor, further comprising 20 administering one or more therapeutic agents or a pharmaceutically acceptable sait thereof, wherein said therapeutic agent is a NKi antagonist which is 2-(3,5bis(trinuoromethyl)phenyl)-N,2-dimethyl-N-(6-(4-niethylpÎperazin-I-yl)-4-(o-tolyl)pyridin3-yl)propanamide (netupitant). In one embodiment, the netupitant is administered in combination with GAS, and the ratio of GAS to netupitant is greater than 1:200 or 1:100.

In some other forms, disclosed are methods of preventing and/or treating diseases which are pathophysiologically modulated by the NK] receptor, wherein the subject is a human. In some other forms, disclosed are methods of preventing and/or treating diseases which are pathophysiologically modulated by the NKi receptor, wherein the subject has been identified as needing treatment for the disease or the administration.

One of ordinary skill in the art of treating such diseases will be able, without undue expérimentation and in reliance upon personal knowledge and the disclosure of this application, to ascertain a therapeutically effective amount of a compound of Formula I for a

21924592*1 given disease. In some other forms, disclosed are methods of prcventing and/or treating a subject, further comprising one or more therapeutic agents.

More Définitions of Terms

1. A, an, the

As used in the spécification and the appended ciaims, the singular forms “a,” “an” and “the include plural référents unless the context clearly dictâtes otherwise. Thus, for example, référencé to “a pharmaceutical carrier includes not only single carriers but also mixtures of two or more such carriers, and the like.

2. Abbrcviations

Abbrcviations, which are well known to one of ordinary ski 11 in the art, may be used (e.g., “h or “hr for hour or hours, “g or gm for gram(s), “mL for milliliters, and “rt for room température, “nm for nanometers. “M for molar, and like abbrcviations).

3. About

The term “about, when used to modify the quantity of an ingrédient in a composition, concentrations, volumes, process température, process time, yields, flow rates, pressures, and like values, and ranges thereof, employed in describing the embodiments of the disclosure, refers to variation In the numcrical quantity that can occur, for example, through typical measuring and handling procedures used for making compounds, compositions, concentrâtes or use formulations; through inadvertent error in these procedures; through différences in the manufacture, source, or purity of starting materials or Ingrédients used to carry out the methods; and like considérations. The term about also encompasses amounts that differ due to aging of a composition or formulation with a particular initial concentration or mixture, and amounts that differ due to mixïng or processing a composition or formulation with a particular initial concentration or mixture. Whether modified by the term about the ciaims appended hereto include équivalents to these quantitics.

4. Comprise

Throughout the description and ciaims of this spécification, the word “comprise and variations of the word, such as “comprising nnd comprises, means including but not limited to, and is not intended to exclude, for example, other additives, components, întegers or steps.

2l924592vl

Publications

Throughout this application, various publications arc referenced. In order to more fully document the state of the art to which this invention pertains, the dîsclosures of these publications are to be consîdered as being referenced individually, specifically and in their 5 entiretles for the material contained in them that is dîscussed In the sentence in which the reference ts relied upon.

6. Subject

As used throughout, by a subject” is meant an individual. Thus, the subject” can include, for example, domesticated animais, such as cats, dogs, etc., livestock (e.g., cattle, 10 horses, pigs, sheep, goats, etc.), laboratory animais (e.g., mouse, rnbbit, rat, guinea pig, etc.) mammals, non-human mammals, primates, non-human primates, rodents, birds, reptiles, amphibians, fish, and any other animal. The subject can be a mammal such as a primate or a human. The subject can also be a non-human.

EXAMPLES

The following examples are put forth so as to provide those of ordinary skill in the art with a complété disclosure and description of how the compounds, compositions, articles, devices and/or methods claimed herein are made and evaluatcd, and are intended to be purely exemplary and are not intended to limit the disclosure. Efforts hâve been made to ensure 20 accuracy with respect to numbers (e.g., amounts, température, etc.), but some errors and déviations should be accounted for. Unless indicated otherwise, parts are parts by weight, température is in °C or is at ambient température, and pressure is at or near atmospheric.

Example 1

Préparation of compounds of formula (I)

The following are examples of préparation of compounds of formula (I). This example is intended to be purely exemplary and is not intended to limit the disclosure.

319Î4391V1

General Scheme of Preparing Compounds of Formula (I)

Scheme 1

Other general procedures of preparing similar compounds to intermediate 1 of Scheme 1 arc also disclosed in U.S. Patent Nos. 6,303,790, 6,531,597, 6,297375 and 6,479,483, which are referenced individually, specifically and in their entireties for the 10 material contaîned In them that is relevant to the préparation of intermediate I.

21924592»!

Synthesis of methyl-[6-(4-meihyl-piperazin-]-yl)-4-o-to]yl-pyridin-3-yl]-amine

Step 1:

13.0 g (82.5 mMoI) 6-Chloro-nicotinic acid in 65 ml THF were cooled to 0°C and

206.3 ml (206.3 mMol) o-tolylmagnesium chloride solution (IM in THF) were added over 45 minutes. The solution obtained was further stirred 3 hours at 0°C and overnight at room température. Il was cooled to -60°C and 103.8 ml (1.8 Mol) acetic acid were added, followed 10 by 35 ml THF and 44.24 g (165 mMol) manganese(III) acetate dihydrate. After 30 minutes at

-60°C and one hour at room température, the reaction mixture was filtered and THF removed under reduced pressure. The residue was partitioned between water and dichloromethane and extracted. The crude product was filtered on silica gel (eluent: ethyl acetate/toluene/formic acid 20:75:5) then partitioned between 200 ml aqueous half-saturated sodium carbonate 15 solution and 100 ml dichloromethane. The organic phase was washed with 50 ml aqueous half-saturated sodium carbonate solution. The combined aqueous phases were acidified with 25 ml aqueous HCI 25% and extracted with dichloromethane. The organic extracts were dried (Na₂SO4) and concentrated under reduced pressure to yield 10.4 g (51%) of 6-chloro-4o-tolvl-nicotinic add as a yellow foam. MS (1SN): 246 (M-H, 100), 202 (M-CO₂H, 85), 166 20 (36).

Step 2:

To a solution of 8.0 g (32.3 mMol) 6-chloro-4-o-tolyl-nicotinic acid in 48.0 ml THF were added 3.1 ml (42.0 mMol) thionylchloride and 143 .mu.l (1.8 mMol) DMF. After 2 hours at 50°C, the reaction mixture was cooled to room température and added to a solution 25 of 725 ml aqueous ammonium hydroxide 25% and 96 ml water cooled to 0°C. After 30 minutes at 0°C, THF was removed under reduced pressure and the aqueous layer was extracted with ethyl acetate. Removal of the solvent yielded 7.8 g (98%) 6-ch!oro-4-o-tolvlnicotinamide as a beige crystalline foam. MS (ISP): 247 (M+H⁺, 100).

21924592*1

Step 3:

1.0 g (4.05 mMol) 6-Chloro-4-o-tolyl-nÎcotinarnide in 9.0 ml 1-methyl-piperazine was heated to 100°C for 2 hours. The excess N-methyl-piperazine was removed under high vacuum and the residue was filtered on silica gel (eluent: dichloromethane) to yield 1.2 g 5 (95%) 6-Î4-methvl-piperazin-I-vl)-4-o-tolyl-nicotmamlde ns a light yellow crystalline foam.

MS (ISP): 311 (M+H*, 100), 254 (62).

Step 4:

A solution of 0.2 g (0.6 mMoI) 6-(4-methyl-piperazin-l-yl)-4-o-tolyl-nicotinaniide in 1.0 ml methanol was added to a solution of 103 mg (2.6 mMol) sodium hydroxide in 1.47 ml 10 (3.2 mMol) NaOCl (13%) and heated for 2 hours at 70°C. After removal of methanol, the aqueous layer was extracted with ethyl acetate. The combined organic extracts were dried (Na₂SO₄), concentrated under reduced pressure and the residue filtered on silica gel (eluent: dichloromethane/methanol 4:1) to yield 100 mg (70%) 6-(4-methvl-piperazinJ-vl)-4-o-tolvlpyridin-3-ylamlne as a brown resin. MS (ISP): 283 (M+H*, 100), 226 (42).

Step 5:

2.15 ml (11.6 mMol) Sodium methoxide in methanol were added over 30 minutes to a suspension of 0.85 g (4.6 mMol) N-bromosuccinimide in 5.0 ml dichloromethane cooled to 5”C. The reaction mixture was stirred 16 hours at -5°C. Still at this température, a solution of 1.0 g (3.1 mMol) 6-(4-methyl-piperazin-l-yl)-4-o-tolyl-nicotinamide in 5.0 ml methanol was 20 added over 20 minutes and stirred for 5 hours. 7.1 ml (7.1 mMol) Aqueous HCl 1N and 20 ml dichloromethane were added. The phases were separated and the organic phase was washed with deionîzed water. The aqueous phases were extracted with dichloromethane, brought to pH=8 with aqueous NaOH IN and further extracted with dichloromethane. The latter organic extracts were combined, dried (Na₂SO₄) and concentrated to yield 1.08 g (quant) 16-14· 25 methvl-niperazin‘l-vl)-4‘O-tolvl-pvridin-3-vl1-carhamic acid methyl ester as a grey foam.

MS (ISP): 341 (M+H*, 100), 284 (35).

Step 6:

A solution of 0.5 g (1.4 mMol) [6-(4-methy!-piperazin-l-yl)-4-o-tolyl-pyridin-3-ylJcarbamic acid methyl ester in 3.0 ml dichloromethane was added over 10 minutes to a 30 solution of 1.98 ml (6.9 mMol ) Red-Al.RTM. (70% in toluene) and 2.5 ml toluene (exothermie, cool with a water bath to avoid température to go >50°C). The reaction mixture was stirred 2 hours at 50°C in CH₂C1₂, extracted with ethyl acetate and cooled to 0°C. 4 ml Aqueous NaOH IN were carefully (exothermie) added over 15 minutes, followed by 20 ml

2I92-I592vl

ethyl acetate. The phases were separated and the aqueous phase was extracted with ethyl acetate. The combined organic extracis were washed with deionized water and brine, dried (NaiSCh) and concentrated under reduced pressure to yield 0.37 g (89%) methvbf6-(4methvl’niperazin-l-vl)-4-o-!olvl-pvridin-3-vU-amine as an orange resin. MS (ISP): 297 (M+H*, 100).

Synthesis of

2-(33-bis-TrifluoromethyI-phenyI)-2-methyI-propionyl Chloride

fAf

15.0 g (50 mmol) 2-(3₍5-bis-trifluoromethyl-phenyl)-2-methyl-propionic acid were dissolved in 127.5 ml dichloromethane in the presence of 0.75 ml DMF. 8.76 ml (2 eq.) Oxalyl chloride were added and after 4.5 hours, the solution was rotary evaporated to dryness.

ml Toluene were added and the resulting solution was again rotary evaporated, then dried under high vacuum yielding 16.25 g (quant) of 2d3.5’bls-trifluoromethvl-Dhenvl)-2’methvl15 proplonvl chloride as a yellow oil of 86% purity according to HPLC analysis. NMR (250 MHz, CDClj): 7.86 (br s, 1 H); 7.77, (br s, 2H, 3 H_amm); 1.77 (s. 6H, 2 CH₃).

Synthesis of

2-(3,5-bis(trifluoromethyl)phenyl)-N,2-dimethyI-N-(6-(4’methylpiperazin-l-yl)-4-(o20 tolyl)pyridin-3-yl)propanamide (Netupitant)

A solution of 20 g (673 mmol) methyl-[6-(4-methyl-piperuzin-l-yI)-4-o-tolyl· pyridin-3-yll-amine and 17.5 ml (101 mmol) N-ethyldiisopropylamine in 200 ml

2l924592vl dichloromethane was cooled in an ice bath and a solution of 24 g (75 mmol)2-(3,5-bistrifluoromethyl-phenyl)-2-methyl-propionyl chloride in 50 ml dichloromethane was added dropwise. The reaction mixture was warmed to 35-40°C for 3 h, cooled to room température again and was stirred with 250 ml saturated sodium bicarbonate solution. The organic layer was separated and the aqueous phase was extracted with dichloromethane. The combined organic layers were dried (magnésium sulfate) and evaporated. The residue was purified by flash chromatography to give 31.6 g (81%) of 2-(3,5-bis(trifluoromethyl)phenyl)-N,2· dimethyl-N-(6-(4-methylpiperazin-I•yl)-4'(o-toly!)pyridin-3-yl)propanamide as white crystals. M.P. 155-I57°C; MS m/e (%): 579 (M+H*, 100).

Synthesis of

5-(2-(3,5-bis(trifluoromethyl)phenyl)-N,2-dimethylpropanamido)-2-(4-methylpiperazin-lyl)-4-(o-tolyl)pyridine 1-oxide

Scheme 2

Step I:

The solution of 6-chloropyridin-3-amine (115 g, 0.898 mol) and (Boc)iO (215.4 g, 0.988 mol) in 900 mL of dîoxane was refluxed overnight The resulting solution was poured 21924592*1

into 1500 mL of water. The resulting solid was collected, washed with water and recrystallized from EtOAc to afford 160 g tert-butyl (6-chloropyridin-3-yl)carbamate as a white solid (Yield: 78.2%).

Step 2:

To the solution of tert-butyl (6-chloropyridin-3-yl)carbamate (160 g, 0.7 mol) in 1 L of anhydrous THF was added n-BuLi (600 mL, 1.5 mol) at -78°C under Ni atmosphère. After the addition was finished, the solution was stirred at -78°C for 30 min, and the solution of Ij ( 177.68 g, 0.7 mol) in 800 mL of anhydrous THF was added. Then the solution was stirred at -78°C for 4 hrs. TLC indicated the reaction was over. Water was added for quench. and 10 EtOAc was added to extract twice. The combined organic phases were washed with brine, dried over NaiSO^, filtered and purified by flash chromatography to afford 80 g of tert-butyl (6-chloro-4-lodopyridin-3-yl)carbamate as a yellow solid (32.3%).

Step 3:

To the solution of tert-butyl (6-chloro-4-«odopyridin-3-yl)carbamate (61 g, 0.172 mol) 15 in 300 mL of anhydrous THF was added 60% NaH (7.6 g, 0.189 mol) at 0°C under Ni atmosphère. After the addition was finished, the solution was stirred for 30 min, and then the solution of Mel (26.92 g, 0.189 mol) in 100 mL of dry THF was added. Then the solution was stirred at 0°C for 3 hrs. TLC indicated the reaction was over. Water was added for quench, and EtOAc was added to extract twice. The combined organic phases were washed 20 with brine, dried over NaiSOj, filtered and concentrated to afford 63 g of crude tert-butyl (6chloro-4-lodopyridin-3-yl)(meihyl)carbaniate used into the following de-protection without the further purification.

Step 4:

To the solution of tert-butyl (6-chloro-4-iodopyridin-3-yl)(methyl)carbamate (62.5 g, 25 0.172 mol) in 500 mL of anhydrous DCM was added 180 mL of TFA. Then the solution was stirred at room température for 4 hrs. Concentrated to remove the solvent, and purified by flash chromatography to afford 45.1 g 6-chloro-4-iodo-N-methylpyridin-3-amine as a yellow soüd (Yield: 97.3%).

21924592*1

Step 5:

To the solution of 6-chloro-4-iodo-N-methylpyridin-3-amine (40.3 g, 0.15 mol) and 2-methylbenzene boric acid (24.5 g, 0.18 mol) in 600 mL of anhydrous toluene was added 5 400 mL of 2 N aq. Na₂CO₃ solution, Pd(OAc)₂ (3.36 g, 15 mmol) and PPh₃ (7.87 g, 0.03 mmol). The solution was stirred at 100°C for 2 hrs. Cooled to room température, and diluted with water. EtOAc was added to extract twice. The combined organic phases were washed with water and brine consecutively, dried over Na₃SO4, concentrated and purified by flash chromatography to afford 19 g 6-chloro-N-methyl-4-(o-tolyl)pyridin-3-amine as a white solid 10 (Yield: 54.6%).

Step 6:

To the solution of 6-chloro-N-methyl-4-(o-tolyl)pyridin-3-amine (18.87 g, 81.3 mmol) and DMAP (29.8 g, 243,9 mmol) in 200 mL of anhydrous toluene was added the solution of

2- (3,5·bίs-trifluoromethyl-phenyl)-2-methyl·propionyl chloride (28.5 g, 89.4 mmol) in 15 toluene under N₂ atmosphère. The solution was heated at I2O°C for 23 hrs. Cooled to room température, poured into 1 L of 5% aq. NaHCO₃ solution, and extracted with EtOAc twice. The combined organic phases were washed by water and brine consecutively, dried over Na₃SO₄, filtered and purified by flash chromatography to afford 35 g 2-(3.5bis(trifluoromethyl)phenyl)-N-(6-cltloro-4-(o-toiyl)pyrÎdin-3-yl)-N,2-dimethylpropanamide as 20 a white solid (Yield: 83.9%).

Step 7:

To the solution of 2-(3,5-bis(trifluoromethyl)phenyl)-N-(6-chloro~4-(o-tolyl)pyridin-

3- yl)-N,2-dimethylpropanamide (5.14 g, 10 mmol) in 60 mL of DCM was added rn-CPBA (6.92 g, 40 mmol) at 0 °C under Nj atmosphère. Then the solution was stirred overnight at room température. 1 N aq. NaOH solution was added to wash twice for removing the excess m-CPBA and a side product. The organic phase was washed by brine, dried over Na₂SO₄, filtered and concentrated to afford 5.11 g of crude 5-(2-(3,5-bis(trifluoromethyl)phenyl)-N,2dimethylpropanamido)-2-chloro-4-(o-tolyl)pyridine 1-o.xtde as a while solid (Yield: 96.4%).

Step 8:

To the solution of crude 5-(2-(3,5-bis(trinuoromethyl)phenyl)-N,2dimethylpropanamido)-2-chloro-4-(o-lolyl)pyridine 1-oxide (5.1 g, 9.62 mmol) in 80 mL of n-BuOH was added N-methylpîperazine (7.41 g, 74.1 mmol) under N₂ atmosphère. Then the solution was stirred at 80°C overnight. Concentrated and purified by flash chromatography to

21914J92vl afford 4.98 g 5-(2-(3,5-bis(triJltioromethyl)phenyl)-N,2-dimethylpropanamido)-2-(4methylplperazin-l-yl)-4-(o-!olyl)pyridine 1-oxide as a white solid (Yield: 87.2%). ’HNMR (CDCI3,400MHz) δ 8.15 (s, IH), 7.93 (s, IH), 7.78 (s. 2H), 7.38 (m, 2H), 7.28 (m, IH). 7.17 (m, IH), 7.07 (s. IH), 5.50 (s, 3H), 2.72 (d, J = 4.4Hz, 4H), 2.57 (m, 3H), 2.40 (s, 3H), 2.23 (s, 3H), 1.45-1.20 (m,6H).

Synthesis of

4-(5-(2-(3,5-bis(trifluoromethyl)phenyl)-N,2-dimethylpropanamido)-l-oxido-4-(otolyl)pyridin-2-y))-l-methylpiperazine 1-oxide

CF₃

To a solution of 5-(2-(3,5-bis(trifluoromethyl)phenyl)-NÎ-dimethylpropanamido)-2(4-methylpiperazin-l-yl)-4-(o-tolyl)pyridine 1-oxide (3 g, 5.05 mmol) and NaHCO₃ (0.354 g, 12.66 mmol) in 60 mL of MeOH and 15 mL of H₂O were added potassium monopersulfate triple sait (1.62 g, 26.25 mmol) at room température during 15 min. After stirring for 4 hrs at room température under N₂ atmosphère, the reaction mixture was concentrated in vacuo and purified by flash chromatography (eluent: MeOH). The product was dissolved into DCM, the formed solid was filtered off, and the solution was concentrated under reduced pressure to afford 1.77 g 4-(5-(2-(3,5-bîs(trifluoromethyl)phenyl)-N,2-dimethylpropanamido)-l-oxido-4(o-tolyl)pyridin-2-yl)-l-methylplperazine 1-oxide as a white solid (Yield: 57.4%). *HNMR (CDCI3,400MHz)δ 8.06 (s, IH),7.78 (s, IH),7.60(s,2H), 7.37-7.20(m,4H),6.81 (s, IH), 3.89 (s, 2H), 3.74 (m, 4H), 3.31 (m, 5H), 2.48 (s, 3H), 2.18 (s, 3H), 1.36 (s, 6H).

Îl924591vl

Synthesis of

I -(5-(2-(3,5-bis(trifluoromethyl)phenyl)-N,2-dime thylpropanamido)-4 -(o-tolyl)pyridin-2-yl)4-methylpîperazine 1,4-dioxide

Scheme 4

To the solution of 2-(3,5-bis(trifluoromethyl)phenyl)-N,2-dimethyl-N-(6-(410 methylpiperazin-l-yl)-4-(o-tolyl)pyridin-3-yl)propanamide (11.1 g, 19.2 mmol) in 75 ml of Methanol was added sodium bicarbonate (3.38 g, 40.3 mmol) dissolved in 20 ml of water. Then Oxone (14.75 g, 48.0 mmol) was added to the stirred solution at room température in 34 portions. The suspension was heated for 4 h at 50 “C. After filtration of the salts (washed with 3 x 8 ml of methanol), the solvent has been evaporated under reduced pressure and 15 substituted by DCM (30 ml). The organic phase was washed with water (5 x 30 ml), dried over Na₂SO4, filtered, concentrated and purified by précipitation in toluene to afford 9.3 g 7(5-(2-( 3,5-bis( trifluoromethyl)pltenyl)-N, 2-dîmethylpropanamido)-4-(o-tolyl)pyridin-2-yl)-4methylpiperazine 1,4-dioxîde as a white solid (Yield: 80%). ’H-NMR (CDC13, 400MHz, at 333K) δ 8.27 (s, 2H), 7.75 (s, IH), 7.63 (s, 2H),7.26-7.19 (m, 2H), 7.14 (t, 1H, J-ΊΑ Hz), 20 7.09 (d, 1H, J = 7.4 Hz), 4.93 (t, 2H, J = 11.6 Hz), 4.70 (t, 2H, J - 11.6 Hz), 4.12 (d, 2H, J 10.7 Hz). 3.84 (s, 3H), 3.50 (d, 2H, J - 10.3 Hz), 2.47 (s, 3H), 2.12 (s, 3H), 1.40 (s, 6H).

2l924392vl

Synthesis (A) of di-tert-butyl (chloromethyl) phosphate

HCl methanol

NMe^OH methanol

O

CH_ZICI t2-dlmethoxye thane

Scheme 5

Di-tert-butyl phospohite (40.36 mmole) was combined with potassium bicarbonate (24.22 mmole) in 35 ml of water. The solution was stirred in an ice bath and potassium permanganate (28.25 mmole) was added in three equal portions over one hour's time. The reaction as then allowed to continue at room température for an additional half hour. Decolorizing carbon (600 mg) was then incorporated as the reaction was heated to 60°C for 15 minutes. The .reaction was then vacuum filtered to remove solid magnésium dioxide. The solid was washed several times with water. The filtrate was then combined with one gram of decolorizing carbon and heated at 60°C for on additional twenty minutes. The solution was again filtered to yield a colorless solution, which was then evaporated under vacuum to afford crude Di-tert-butyl phosphate potassium sait. Dl-tert-buty! phosphate potassium sait (5 g, 20.14 mmole) was dissolved in methanol (15 g): to this solution at 0 °C a slight excess of concentrated HCl is slowly added with efficient stirring at 0 °C The addition of acid causes the précipitation of potassium chloride. The solid is then filtered and washed with methanol. The compound in the mother liquor is then converted to the ammonium form by adding un equal molar amount of tétraméthylammonium hydroxide (3.65 g, 20.14 mmole) while keeping the reaction cooled by a salt/icc bath with efficient stirring. The resulting clear solution is placed under redueed pressure to give the crude product. To the tétraméthylammonium di-tert-butyl-phosphate dissolved in refluxing dimethoxyethane is then

11914592vl

added 4.3 grams of chloroiodomethane (24.16 mmole) and stirred for 1-2 hours. The reaction is then filtered and the filtrate is placed under reduced pressure to concentrate the solution in

DME. The chloromethyl di-tert-butyl phosphate 12-16% In DME is used in the synthesis of 4-(5-(2-(3,5-bis( tri fluoromethyl)phenyl)-N,2-dimethylpropanamido)-4-(o-tolyl)pyridin-2-yl)5 l-methyl-l-((phosphonooxy)methyi)piperazin-l-îum without further purifications (60% yield): ^1HNMR (CDjOD, 300 MHz) δ 1.51 (s, 12H), 5.63 (d, 2H, J=14.8). ^3IP-NMR (CD₃0D, 300 MHz) δ-i 1.3 (s, 1 P).

Synthesis (B) of di-tert-butyl (chloromethyl) phosphate

HCl methanol

O

U tBuO** Ç**OH OtBu

NBmOH methanol

O

L'. ♦ tBuO-^ÇO NBu«

OtBu

Ace tone

CH2ICI

Scheme 5A

Di-tert-butyl phosphate potassium sait (5 g, 20.14 mmole) is dissolved in methanol (15 g): to this solution at 0 °C a slight excess of concentrated HCl is slowly added with 15 efficient stirring at 0 °C. The addition of acid causes the précipitation of potassium chloride. The solid is then filtered and washed with methanol. The compound in the mother liquor is then converted to the ammonium form by adding an equal molar amount of tetrabuthylammonium hydroxide 1 M in methanol (20.14 mmole) while keeping the reaction cooled at 0 °C with efficient stirring. The resulting clear solution is placed under reduced 20 pressure to give the intermediate product. The tetrabuthylammonium di-tert-butyl-phosphate dissolved in acctone is then added dropwise to 53.3 grams of chloroiodomethanc (302.1 mmole) and stirred at 40 °C for !-2 hours. The solvent and excess of chloroiodomethane are distilled off, the reaction mass suspended in TBME and then filtered. The filtrate is washed by a saturated solution of sodium bicarbonate and water and then placed under reduced 25 pressure to substitute the solvent by acetone, i.e., to remove the solvent after which it is

2.1924592 vl replacée! with acetone. The chloromethyl di-tert-butyl phosphate 7-20% in acetone is used in the next step without further purifications (70-80% yield): ’H-NMR (CDjOD, 300 MHz) δ 1.51 (s, 12H), 5.63 (d, 2H. J= 14.8). ^3,P-NMR (CD3OD, 300 MHz) δ -11.3 (s, IP).

Stability studies of

4-(5-(2-(3,5-bis(trifluoromethyl)pheny!)-N,2-dîmethylpropanamido)-4-(o-toly!)pyridin-2-y|)I - methyl-1 -((phosphonooxy) methyl Jpiperazîn-1 -lu m salts

In order to further improve the stability and solubility of 4-(5-(2-(3,5bîs(trifluoro methy!)pheny l)-N,2-di methylpropanamido)-4-(o-tolyl)pyridin-2-yl)-1 - methyl-1 ((phosphonooxy)methyl)piperazin-l-ium, a variety of its dérivative salts were synthesized and tested. Their synthesis employed either a) neutralization of the dried diacid phosphate species and îts corresponding base salts or b) a direct acid deproteetton starting from the dried di(A?ri-butyl)-protected phosphate species. Neutralization was performed with L-histidine, magnésium sait, N-methyl-D-glucamine (dimeglumine), and L-lysine. Both procedures were tried in the synthesis of citric dérivatives whereas with other acids the direct deprotection réaction was used. The figures below show the most relevant structures.

Parent acid species

Diacid phosphate species

11914392*1

When the parent acid species was not stored in dry condition it was found to undergo over 8% dégradation in the first week and over 65% dégradation in the first six months. When the dried parent acid species was held at 30 °C in air it underwent 0.05% dégradation 5 in the first 7 days and at total of 7.03% dégradation in six months. When the dried parent acid species was held under argon at room température it underwent up to 0.13% dégradation în the first 7 days but then was essentîally stable for six months. Results for various dérivative salts are shown in Table 1 below.

Table I: Représentative Dégradation Results forSalts

Solvents	j ' Addltives / ' s ‘	Yield ’ % y	Purity A% HPLC	*2 7 Commenta ,. - * ' 1 1 , - 1
MeOH	L-Histidine, 2 eq.	26.6%	95.94%	Dégradation: +0.70% in 6 days (în air) +0.46% in 6 days (in argon)
MeOH	Mg(OH)î, 2eq.	48.6%	94.11%	Dégradation: +0.81% in 6 days (in air) +0.29% in 6 days (in argon)
MeOH + DCM. 1:1	Citric acid, 2 eq.	N.A.	94.40%	From protected species.
MeOH	1. HCl dioxane, 4 eq. 2. Ca(OH)i	>90%	94.50%	From protected species.
MeOH	HjPO4, 85%, 2 eq.	>90%	98.81%	From protected species and retains 0.39% of that species.
MeOH	HBr, 48%, 4 eq.	84.6%	96.11%	From protected species. Product dégrades rapidly.
MeOH + DCM, 1:4	CHjSOjH	N.A.	61.54%	From protected species. Product NOT stable: contains 32.45% décomposition species.
MeOH	NaHiPO.}, 4 eq.	N.A.	n.d.	Only 1.27 of parent species formed. Poor réaction.
MeOH	N-methyl-Dglucamine	N.A.	96.88%	Dégradation: +0.87% in 6 days (in air)

2l924392vl

	(Meglumine), 2 eq.			+1.52% in 11 days (in argon)
MeOH	N-methyl-Dglucamine (Meglumine), 1 eq.	>99%	97.42%	Dégradation: +0.77% in 6 days (in air) +0.83% in 7 days (in argon)
MeOH + DCM, 5:2	1. NaOH, 3 eq 2. Citric acid, 1 eq.	96.5%	97.49%	Dégradation: +0.09% in 2 days (in argon) +0.59% in 89 days (in argon)
MeOH + DCM, 5:2	l.NaOH, 3eq. 2. Fumarie acid, 1 eq.	93.8%	97.46%	Dégradation: +1.95% in 14 days (in air) +1.80% in 12 days (ln argon)
MeOH	L-lysine, 1 eq.	>99%	97.62%	Dégradation: +0.69% in 14 days (in air) +0.48% in 12 days (in argon)

A more comprehensive showing of stability results is given in Fig. h where the horizontal axis represents number of days of testing and the vertical axis represents the mass percent of dégradation. Alphabetical letters are used to dénoté data points on the graph that 5 correspond to dégradation percentage values over time for respective salts of the same parent compound as just described above and in Table 2 below. The drawn lines correspond to general (rends over periods of days for the benchmark sait (the disodium sait) and for the few salts that manifested more désirable results than the disodium sait.

Table 2: Identity Codes for Salts and Gases ln Figure 1.

Letter Code	Sait	Ambient gas for storage
a	2 Di meglumine	Air
b	2 Dimeglumine	Argon
c	Dimeglumine	Air
d	Dimeglumine	Argon
e	Lysine	Air
f	Lysine	Argon
ε	Fumarate	Air
h	Fumarate	Argon
i	Citrate	Air
j	Citrate	Argon
k	Bromide	Air
1	Bromide	Argon
m	Mesylate	Nitrogen
n	Phosphate	Air
0	Phosphate	Argon
P	Citrate	Nitrogen
q	Calcium	Air
r	Calcium	Argon

21924592*1

s	Chloride hydrochloride, anhydrous	Air
t	Chloride hydrochloride, anhydrous	Argon
u	Disodium sait	Air
v	Histidine	Air
w	Histidine	Argon
X	Magnésium	Air
y	Magnésium	Argon

Synthesis (A) of

4-(5-(2-(3,5-bis(trifluorome thyl)phenyl)-N, 2-di methyl propanamido)-4 -(o-tolyl)pyridin-2-yl)1-methyl-l-((phosphonooxy)methyl)piperazin-l-ium chloride hydrochloride

Scheme 6

The solution of chloromethyl di-tert-butyl phosphate in DME (250 g from a 10% solution, 96.64 mmole) was evaporated under reduced pressure until the formation of pale 10 yellow oil, dissolved then at 50 °C with 318 ml of Acetonitrile. 17.2 g (80.54 mmole) of 1.8bis(dimethylamino)naphtalene and 46.6 g (80.54 mmole) of 2-(3,5bis(trifluoromethyl)phenyl)-N,2-dimethyl-N-(6-(4-methylpiperazin-l-yl)-4-(o-tolyl)pyridin3-yl)propanamidc were added and the solution heated at 90 °C for at least I2h. After the addition of 75 g of isopropylether, the precipitated crude product was cooled at room 15 température, filtered and washed with acetonitrile, isopropylether/acetone, 3:1 and isopropylether, and dried under reduced pressure to afford 20-33 g of the 4-(5-/2-/5,5bÎs(trifliioromethyl)phenyl]-N,2-dÎmet!iylpropanamldo}-4-(otolyl)pyridin-2-yl)-l-inelhyl-I21924592vt [[(fert-butoxy)phosphoryl]oxymefhyl}pîperazin-l-him as white solid (Yield: 30-50%). ΉNMR (CDjOD, 400 MHz) δ 7.98 (s, IH), 7.86 (s, IH), 7.76 (s, 2H), 7.33-7.10 (m. 4H). 6.80 (s. IH), 5.03 (d, 2H. J pu = 8.5 Hz). 4.52 (s, 2H), 4.13 (m. 2H), 3.83 (m. 2H). 3.69 (m, 2H). 3.52 (m. 2H). 3.23 (s, 3H). 2.53 (s, 3H), 2.18 (s, 3H), 1.46 (s, 18H), 1.39 (s, 6H). ^3,P-NMR (CDjOD, 161 MHz) δ -5.01 (s, IP). To 20 g (23.89 mmole) of the 4-(5-(2-(3,5bis(trifluoromethyl)phcnyl]-N,2-dimcthylprDpanamido}-4-(o-tolyl)pyrtdin-2-yl)-l-methyl-l([(tert-butoxy)phosphoryll oxymethyl)piperazin-l-ium dissolved in 180 g of methanol and 400 g of dichloromethane was added HCl 4M in dioxane (18.8 g, 71.66 mmole) and the solution was heated for 3 h at reflux. After the addition of 200 g of dioxane, DCM and methanol were dîstllled under reduced pressure until précipitation of the product, which was filtered and washed with isopropylether (100 g), acetone (30 g) and pentane (2 x 60 g). The product was finally dried under reduced pressure ut 55 °C to afford 15-17 g of 4-(5-(2-(3,5bis(trifliioromethyl)phenyl)-N,2-diinethylpropanamido)-4-(o-tolyl)pyridin-2-yl)-l -methyl-1((phosphonooxy)methy!)piperazin-l-him chloride hydrochloride as white solid (Yield: 8893%). 'H-NMR (CD3OD, 400 MHz) δ 7.02 (s, IH), 7.87 (s, IH), 7.74 (s, 2H), 7.33-7.40 (m. 2H), 7.27 (m, IH), 7.21 (s, IH), 7.16 (d, IH, J = 8.2 Hz), 5.27 (d. 2H, J pu = 7.9 Hz), 4.29 (m, 2H), 4.05 (m, 2H), 3.85 (m, 2H), 3.74 (m, 2H), 3.35 (s, 3H), 2.62 (s, 3H), 2.23 (s. 3H). 1.38 (s, 6H). ^3,P-NMR (CDjOD, 161 MHz) δ -2.81 (t, IP, J_w= 7.9 Hz).

219Z459’vl

Synthesis (B) of

4-(5-(2-(3,5-bis(trifluoromethyl)phenyl)-N,2-dimethylpropanamido)-4-(o-tolyl)pyridin-2-yl)l-methyl-l-((phosphonooxy)methyl)piperazin-l-ium chloride hydrochloride

Scheme 6A

To the solution of chloromethyl di-tert-butyl phosphate in Acetone (22.1 g from a

10% solution, 85.58 mmole), 15.5 g (103.24 mmole) of sodium îodide and 33.0 g (57.00 mmole) of netupitant were added and the solution heated at 50 °C for at 6-16 h. The precipîtated salts were fiitered off, the acetone distilled under reduced pressure and the crude product dissolved in 43.0 g of methanol and 43.0 g 1,4-dioxane. 12.6 g of HCl 4M in dioxane (113.85 mmole) were added, and then methanol is distilled off at 40 C under reduced pressure. The solution îs cooled at 5 °C and stirred at 5 °C for at least 2 h al 5 °C The product was isolated by filtration, purified by additional slurry in acetone (238 g), and fiitered and washed with acetone (47 g) and pentane (2 x 72 g).

The product was finally dried under reduced pressure at 60 °C to afford 22-30 g of white-yellowish solid (Yield: 50-70%) ‘H-NMR (CDjOD, 400 MHz) δ 7.02 (s, IH), 7.87 (s, IH), 7.74 (s, 2H), 7.33-7.40 (m,

2H), 7.27 (m, IH), 7.21 (s, IH), 7.16 (d, IH, J = 8.2 Hz), 5.27 (d, 2H, Jpn = TS Hz), 4.29 (m,

21924592*1

2H), 4.05 (m, 2H), 3.85 (m, 2H), 3.74 (m, 2H), 3.35 (s, 3H), 2.62 (s, 3H), 2.23 (s, 3H), 1.38 (s, 6H). ^3lP-NMR (CDjOD, 161 MHz) Ô -2.81 (t. IP, J_FH = 1.9 Hz).

It is to be understood that the product shown in Scheme 6A is illustrative, being just one of several permutations in which the acidic protons bond to various atoms in an 5 equilibrium. For instance depiction of other permutations would show a proton bound to one or more of the N atoms while one or more of the O atoms bound to the P atom wouid bear an anionic charge. The invention comprises ali of the molecular species within that equilibrium and the product shown in the figure is intended to represent ail of them in a generic fashion.

7. Evaluation of Représentative Compounds of Formula (1)

1. Chemical Stability and Solubility

The chemical stability and aqueous solubility of some représentative compounds of Formula (I), compared to some reference compounds, are reproduced in Table 3 below. Stability was tested according to ICH guidelînes under accelerated conditions (40° C).

Table 3: Chemical Stability and Solubility of Représentative Compounds

Compound No.	Compound Structure	Chemical Stability	Solubility (neutre! pH)
1	WW OH CFs	medium	10-15 mg/ml
2	JW Ο-Νζ> o. cf3	high	> 10 mg/ml

2I924592vl

3	'O-NtY CFa	high	> 10 mg/ml
4	0 ψ /Νχ> 0. CF3	medium	- 0.6 mg/ml
5’	. X%XvCF3 HîV CF3	medium	-1 mg/ml
6	Oy^y^yCF3 ra IÇJ 0. CFj	low	N/A
Ί	XÀXx^xCF» ° JL IT o U JT ILo fW 0 V Af,	low	insoluble
8	YVC^, o JL II S 1 J Ά-μ^ τ	Low	insoluble

31934392*1

		rZi
9’	JO	T i v Γ II n 11 T JJ O cf3		0.25

* Référence Compound ii. Local Tolérance

In contrast to netupitant (compound no. 9 In the above table), seven-day local tolerability study of three compounds (e.g.. compound nos. 1-3 of the above Table 1) on rat was conducted. Ail three compounds exhibited good local tolerability which is demonstrated by the below findings:

• There were minimal signs of inflammation at injection site and there was 1 ittle edema;

«No later stage thrombus was found in any animal studied;

• Severity of inflammation was similar in compound and vehicle-treated animais;

• No tissue necrosîs was observed in any of the taiis; and • The inflammation and palethrombus were caused by the needie injection through blood vcssels.

iii. Pharmacokinetic Studies

The pharmacokinetics (PKs) study of three compounds (e.g.. compound nos. 1-3 of the above Table 3), as compared to a référencé compound - netupitant (orally administered), on rat and dog was conducted.

Rat PKs Study: The rats tested in the study were Wistar rats, maie, body weight 220 240 g, and 5 rats per group. The dose was 10 mg/kg administered by intravenous (IV) slow bolus injection into the tail vein at a rate of 1 ml/min. The dose was administered to each animal at a dose volume of 5 ml/kg (the pre-formulation is 5% Glucose solution). Control animais received the vehîcle alone. The dose was administered to each animal on the basis of the most recently recorded body weight and the volume administered was recorded for each animal. Before administration, rats were fasted 12 hr, water ad libitum. After 240 min time point blood was collected. rats were fcd. 0.2-0.3 ml blood was collected in tubes contained EDTA/NaF as anticoagulant and stabîlizer at pre-dosc and at 0.05,0.25,0.5, 1, 2, 4, 6, 8, 24 21924392* I and 48 hrs after intravenous administration. After centrifugation, plasma was removed and stored deep-frozen approximately -20 ’C until analysis, Prepared quantification standard curve at 2, 10, 40, 100, 200, 1000 and 2000 ng/ml (diluted from methanol stock with methanol containing 1% formic acid). Aliquot 50 ul of standard solution and sptked into 50 ul of blank rat plasma samples either for standard curve or for QC samples, followed by adding 100 ul of acetonitrile (with IS). 50 ul of methanol replaced the compound standard methanol solution was used to spike 50 ul of rat plasma samples, and added 100 ul of acetonitrile (with IS), for the détermination of rat plasma samples. Plasma samples of time points 3, 15 and 30 min after intravenous administration were diluted 10 or 5 fold with blank rat plasma, respectively. Plasma was pre-prepared with acetonitrile using protein preclpitate (PPP). Rat plasma samples were analyzed by using an API4000 MS coupled with HPLC. Repaglinide was used as internai standard. Using an internai calibration method for compound 1 of the above Table 1 or Netupitant quantitation, the LLOQ and the linear range of standard curve were 2 ng/ml and 2 - 2000 ng/ml, respectively.

Dog PKs Study: the dogs tested in the study were Beagle dogs, body weight 8-10 kg, and 3 male dogs per group. The four PK experiments were performed in 12 naïve dogs. The dose was 3 mg/kg administered via intravenous (IV) slow injection into the left and right cephalic or left and right saphenous veins used In rotation. The dose volume was 2 ml/kg in glucose 5% v/v solution at a fixed injection rate of 4 ml/mtn using an infusion pump (KDS 220, KD Scicntific). The dose was administered to each anima! on the basis of the most recently recorded body weight and the volume administered was recorded for each animal. Netupitant 3 mg/kg dose was tested at 2 ml/kg in vchicle (DMSO: Ethanol: Tween80 solution=5:4:1:90, v/v), dependence on its solubtlity, Dose was freshly prepared before each single PK experiment. Before administration, dqgs were fasted 12 hr, water ad libitum. After 480 min time point blood was collected, dogs were fed. 0.5 mi blood was collected în heparinised tubes at pre-dose and at 2, 5. 15, 30 min, l, 2,4, 6, 8, 12, 24, 36,48 and 72 hr after intravenous administration. Plasma samples would bc kept at -20 degree till analysis. After 2 weeks washout, the same group (IV for Netupitant ) was dosed Netupitant 3 mg/kg by gavage administration, the dose volume was 4 ml/kg in vehicle (Hypromellose 0.5%, Tween80 0.1%, Sodium Chloride 0.9% in distilled water). Prepared quantification standard curve at 2, 10, 40, 100, 200, 1000 and 2000 ng/ml (diluted from methanol stock with methanol containing 1% formic acid). Aliquot 50 ul of standard solution and sptked into 50 ul of blank dog plasma samples either for standard curve or for QC samples, followed by adding 100 ul 21924592*1

of acetonitrile (with IS). 50 ul of methanol replaced the compound standard methanol solution was used to spike 50 ul of dog plasma samples, and added 100 ul of acetonitrile (with IS), for the détermination of dog plasma samples. Plasma samples of time points 2, 5, 15 and 30 min after intravenous administration were diluted 5 or 2 folds with blank dog 5 plasma, respectively. Plasma was pre-prepared with acetonitrile using protein precipîtate (PPP). Dog plasma samples were analyzed by using an API4000 MS coupled with HPLC. MRM(+) was used to scan for Netupitant and compound nos. 1-3 of the above Table 3, respectively. Repaglînide was used as internai standard.

It was found that ail three compounds, when intravenously administered at a dosage 10 of 3 mg/kg, were efficiently converted to netupitant in rats and dogs. It was also found that compound no. 1 is bioequivalent to oral netupitant at the same dose in dog. The data of the comparative bioequivalence study is reproduced in below Table 4:

Table 4: Comparative Bioequivalence Studies ofNetupitant and Related Compounds

	IV	PO
	Compound I	Compound 2	Compound 3	Netupitant*
Dose (mg/kg)	3	3	3	3
Dose (mg/kg, équivalent to netupitant)	2.31	2.84	2.84	3
Mean AUCo.t (ng.min/ml)	315627	88732	192730	307285
Bioequivalence (%)	103	29	63

*Reference Compound

Throughout this application, various publications are referenced. The disclosures of these publications in their entireties are hereby referenced individually and specifically for the material contained in them that is discussed in the sentence in which the reference is relied upon. Jt will be apparent to those skilled in the art that various modifications and 20 variations can be made in the présent invention without departing from the scope or spirit of the invention. Other embodiments of the invention will be apparent to those skilled tn the art from considération of the spécification and practice of the invention disclosed herein. It is

21924592vl

intended that the spécification and examples be considered as exemplary only, with a true scope and spirit of the Invention being indicated by the following claims.

Claims (18)

1. A compound selected from the group consisting of:

□At «-f-⁰ JÛ jOô CF, .CF» 44MÎX34bl»(lritîi>orDined>yl)phaiyt>-N2dimetbylpn>pu«nûJo)M.{o. lotyOpyridln-l-yD-t -methyi· 1 ((phosphonooiy}meihy{)plpauÎn-l· lum. ÜA2 Hac(<tMyn>«thyl)-4-(5-(2(3,}. U bii(lrlfluawiahyl)phenytÿ-N.l. 1 A ' =F» dimethyJprapanaimdoHXo* Λ Ljj o ΚΓ •olyljpyridln-î.yl)· 1 -methylplpenrio- cFj 1-iutn, CtAJ 4(5(Î(JJ- W blc(trillu<wmneibyl)phcnyl).N4- X< CFj duncÜiyfpnifvinKniduMXa* ο _Λ y I ΊΟ loly1)pyridin-2-y1)-|- CFj ((hulyrylo«y)mtthy1)-l. ntethylpipenoio-l -lum. GA4 HMHU. j bb(triÎluDrorr>clhyl)pbctiyl}-N,2- 1 \/ J gl dimethylproptniiiildn)-4(»- <n xj tolyOpyridln-2-yl)-4-<»cthylpipenuin· ·ο-Νζ> CF3 l,44lwijde,

4-(5-(

2(3,5bii(trilhioromethyt)phenyl)-N2* dimelhylpropanatnido). l-atido-4-(o. tolyl)pyridin-2-yl)-l-methy!pipeniine I-oxide, or a pharmaceutically acceptable sait thereof.

10 2. A compound according to daim 1 for use In a method of treating emesis, bladder dysfunctlon, dépréssion or anxlety, In a patient In need thereof.

3. The compound for the use according to claim 2, wherein sald emesls comprises chemotherapy induced nausea and vomltlng (CINV), radiation therapy Induced nausea and vomltlng (RINV), or

15 post-operath/e nausea and vomlting (PONV).

4. The compound for the use according to either ofclaims 2-3, wherein said emesls Is Induced by moderately or highly emetogenlc chemotherapy.

5. The compound for the use according to any of daims 2-4, wherein emesls Is acute and delayed emesls Induced by modéra tely or hlghîy emetogenlc chemotherapy.

6. The compound for the use according to any of daims 2-5, wherein said bladder dysfunction is selected from urgency, frequency, pollakiurie, nocturia, low de ferment time, suboptimal volume threshold, and neurogenfc bladder, or a combination thereof.

7. The compound for the use according to any of daims 2-6, wherein said compound or a pharmaceutically acceptable sait or adduct thereof, Is administered by one or more routes selected from the group consisting of rectal, buccal, sublingual, Intravenous, subcutaneous, Intradermal, transdermai, Intraperitoneal, oral, eye drops, parentéral and topical administration.

8. The compound for the use according to any of daims 2-7, wherein said compound or a pharmaceutically acceptable sait or adduct thereof, Is Intravenously administered at a dosage of from about 10 mg to about 200 mg.

9. The compound for the use according to any of daims 2-8, wherein said emesls Is acute and delayed emesls induced by moderately or high ly emetogenic chemotherapy, further comprising admlnlstering a 5-HT₃ antagonist and cortlcosterold.

10. The compound for the use according to daim 9, wherein said 5-HTj antagonist Is ondansetron, paionosetron, granisetron or troplsetron, or a pharmaceutically acceptable sait thereof.

11. The compound for the use according to any of daims 2-10, further comprising admlnlstering 2-(3,5bis ( t ri fl uo romethyl}phenyl)-N,2-d Imethyi-N -( 6-(4-methylplperazln-l.yl)-4-(o-to ly!} py ridin-3-yl) propanamide (netupitant).

12. The compound for the use according ta any of daims 2Ί1, wherein the su b je et Is a human.

13. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to daim 1, and one or more pharmaceutically acceptable excipients.

14. The compound of daim 1, as a chloride hydrochloride sait having the following chemicai formula:

15. A process of making a compound of formula (I):

Formula (D

5 wherein:

R Is selected from the group consisting of hydrogen, hydroxy, hydroxyalkyi, amino, alkyi, alkenyl, cycloalkyl, halogen, alkoxyalkyl, -OR¹⁰¹, -NR^WÎR¹⁰², -NR¹⁰¹qo)R^xra, -CiOjR¹⁰¹, -C(O)OR^x0x, C(O)NR^l01R¹⁰¹, -alkylNR¹⁰^¹⁰*, -5(0)aR^toa, -SR¹⁰¹, -5(0)lNR¹R^,M, aryl, arylalkyl, heterocycloalkyl, heterocydoalkylalkyl, heteroaryl and heteroarylalkyl, each optionally Independently substituted 10 with one or more Independent R^MÎ substituents;

R_t and Ri are Independently selected from the group consisting of hydrogen, hydroxy, hydroxyalkyi, amino, alkyi, alkenyl, cycloalkyl, halogen, alkoxyalkyl, -0R“‘, -NR^X0XR¹⁰¹, -NR^qojR¹⁰¹, -C(0)R^XOX, C(O)OR“^X, -C(O)NR^10JR¹⁰², -alkylNR^XOIR^XOÎ, -5(0>ιΚ^ωϊ , -SR¹⁰¹, -S(O)₁NR^xelR^I“ aryl, arylalkyl, heterocycloalkyl, heterocydoalkylalkyl, heteroaryl and heteroarylalkyl, each optionally 15 Independently substituted with one or more Independent R^U1 substituents; or Ri together with the atoms and/or other substituent(s) on the same phenyl ring, form a fused or non-fused mono, blcydic or tricyclic heterocyclic or carbocyclic ring which Is optionally Independently substituted with one or more R¹⁰¹ substituents; or Ri together with the atoms and/or other substltuent(s) on the same phenyl ring, form a fused or non-fused mono, blcydic or tricyclic heterocyclic or 20 carbocyclic ring which Is optionally Independently substituted with one or more R¹⁰’ substituents;

Rj and R4 are Independently selected from the group consisting of hydrogen, hydroxy, hydroxyalkyi, amino, alkyi, alkenyl, cycloalkyl, halogen, alkoxyalkyl, -OR¹⁰¹, -NR’^R¹⁰², -NR^xoxqo)R^,oî, -qojR¹⁰¹, qo}OR“^x, -C(O)NR^X0IR^10î, -alkylNR^I0XR^xw, -SfOJjR¹⁰¹ , -SR¹⁰¹, -S(O}iNR^10IR^x“ aryl, arylalkyl, heterocycloalkyl, heterocydoalkylalkyl, heteroaryl and heteroarylalkyl, each optionally 25 Independently substituted with one or more independent R^U1 substituents; or Rj and R*, together with the atoms connecting the same, form a fused or non-fused mono, blcydic or tricyclic heterocyclic or carbocyclic ring which Is optionally independently substituted with one or more R¹⁰¹ substituents;

R_s and R« are Independently selected from the group consisting of hydrogen, hydroxy, hydroxyalkyi, 30 amino, alkyi, alkenyl, cycloalkyl, halogen, alkoxyalkyl, -OR^UX, -NR^WXR^XOÏ, -NR^qojR¹⁰¹, -C(O)R^x0x, qojOR¹⁰¹, -C(O)NR^xaiR^xox, -alkylNR^xoxR^loî, -5(0)^“’ , -SR^Ux, -S(O)iNR^10xR^10î, aryl, arylalkyl, heterocycloalkyl, heterocydoalkylalkyl, heteroaryl and heteroarylalkyl, each optionally Independently substituted with one or more independent R¹⁰⁵ substituents;

X Is selected from the group consisting of -C(O)NR^X0IR¹⁰¹, -alkylO, -aikylNR^R¹⁰², -NR“^xqo) and 35 NR^uxaikyl, each optionally Independently substituted with one or more independent R¹⁰’ substituents;

Y Is selected from the group consisting of -NR^R¹⁰¹, -NR^xoxalkylOH, -NR^I0xS(O)iaikyl, NR^10IS(O)iphenyi, -N=CH-NR^l01R¹⁰², heterocydoalkyi and heterocydoalkylalkyl, each optionally Independently substituted with one or more Independent R^W1 substituents;

Z is a structural formula selected from the group consisting of

—O’ (la), —OR¹⁰⁰ (lb>. 0 —O-P-OR¹⁰⁰ OR¹⁰⁰* (le), O y—O-P-OR^{100 7} OR¹⁰⁰* (Id), 0 —O-U-OR¹⁰⁰ (le), 0 _O-Ü-nrworioo· (If), O __IL-NRlOORtOO· (Ig), O —U-OR¹⁰⁰ (Ih)and

O y-^-OR^{100 7} («b where formula (la) refers to an oxide;

R¹⁰⁰, R¹⁰⁰, R^lOÎ, R¹⁰¹ and R“³ are each Independently selected from the group consisting of hydrogen, cyano, -N0₂, -0R^1M, oxide, hydroxy, amino, alkyl, alkenyl, cycloalkyl, halogen, alkoxy, 5 alkoxyalkyl, aryl, arytalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, ·

C(0) R^1M, -C(O)OR^1m, -ίίΟίΝΗ¹⁰^¹⁰⁵, -NR^R^-NR^SjOhR¹⁰¹, -NR^1MC(O)R¹⁰¹, -SfO^R¹⁰⁴, -SR^1W and -S(O)jNR^1mR^10S, each optionally Independently substituted with one or more Independent R¹⁰¹ substituents; or R¹⁰¹, R¹⁰¹, together with the atoms connecting the same, form a fused or non-fused mono, bicyclic or tricyclic heterocyclîc or carbocycllc ring which Is optionally Independently 10 substituted with one or more R¹⁰³ substituents; or R¹⁰⁰, R^î0<r, together with the atoms connecting the same, form a fused or non-fused mono, bicyclic or tricyclic heterocyclîc or carbocycllc ring which Is optionally Independently substituted with one or more R¹⁰³ substituents;

R³⁰* and R^I0S are each Independently selected from the group consisting of hydrogen, cyano, -NOj, hydroxy, oxide, hydroxyaikyl, amino, alkyl, alkenyl, cycloalkyl, halogen, alkoxy, alkoxyalkyl, aryl, IS arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl and heteroarylalkyl;

mis 0,1,2,3, or 4;

n Is 0,1,2,3,4 or 5;

plsOorl; and with a provlso that If a non-pyrldine N-Oxide (Ν'—Ό*) Is présent on the compound of Formula (I), 20 then the total number of N-Oxlde on the compound of Formula (I) Is more than one.

said process comprising:

a) providing a compound of formula (I) wherein Y Is a 4-N-methyl-plperazlne group and Z Is not présent;

25 b) providing a dlalky l(ha Iomethyl)p hos phate;

c) reactlng an N atom of the plperazlne group with the dlalkyl(halomelhyl)phosphate to obtain a quatemary ammonium methyl ene phosphate compound.

) where sala process Is perfonned to obtain the compound GA-1 according to daim 1.

16. The process of daim 15, wherein the reaction Is carried out In the presence of an lodlde sait and In the absence of a proton scavenger.

17. The process of either of daims 15-16, wherein the reaction Is carried out In the substantiel absence ofalranddloxygen.

16. The process of any of daims 15-17, wherein the quaternary ammonium methylene phosphate compound Is obtained with a (phosphooxy)methyl group In dealkylated form without addifylng the reaction or the product.

19. A process ofmaklng a compound of formula (V):

r LJ -(Rl)m V ^Re, (0)p ril ^^V^CF· Gl T (Ô)p ^sRs° CF,

(O)_P (Rt).

Formula (V) where:

Rt Is selected from the group selected from hydrogen, alkoxy, alkoxyalkyl, -OR¹⁰¹, hydroxy, hydroxyalkyl, amino, alkyl, alkenyl, cycloalkyl and halogen, each optionally Independently substituted with one or more Independent R¹⁰’ substituents;

and ail other radlcals are defined according to formula (I) In daim 15, comprising:

contacting a compound of formula V wherein p Is 0 for the methylated 4-N atom of the plperazlnyl ring, with a compound of formula VII In the presence of an lodide sait, for a period of time sufficlent to functlonallze the methylated 4-N atom on the compound of formula V with the compound of formula VII and to dealkylate the compound of formula VII:

(H₃ChC-O-P-O-CH₂CI

O-C(CH₃h

Formula (VII).

where said process Is performed to obtain the compound GA-1 according to daim 1.

Fia i/ι

Dégradation ofVarfou» Nrtupîtant Sait· a· a Functlon ofTlme

Mm) lysine saX (underAsi caldum sait osooMfti _f wjtferârj / (under Ar) phosphate sait (under aq

..···“ ..···· chtofxte hytfrochkjfxfe sai (underar^. · -s • -s chloride hydrochloride sat (under Af)

----I---_Λ

Ί

Έϋ----70----SO