WO2009145718A1

WO2009145718A1 - Isoindoline derivatives comprising an additional heterocyclic group and their use in the treatment of pain disorders

Info

Publication number: WO2009145718A1
Application number: PCT/SE2009/050615
Authority: WO
Inventors: Per Arvidsson; Yevgeni Besidski; Gabor Csjernyik; Tim Lange; István MACSÁRI; Linda Nilsson
Original assignee: Astrazeneca Ab
Priority date: 2008-05-30
Filing date: 2009-05-29
Publication date: 2009-12-03
Also published as: AR071955A1; CL2009001329A1; UY31852A; TW201000461A; PE20091945A1

Abstract

Compounds of formula I are claimed, wherein R¹is hydrogen, C₁_₃alkyl, C₁_₃alkoxy, cyano, hydroxy or halo; wherein C_1-3alkyl may optionally be substituted by one or more substituents independently selected from hydroxy, C_1-3alkoxy orfluoro; and wherein Ci^alkoxy may optionally be substituted by one or more fluoro; m is 1 or 2; R² and R³ is each and independently selected from hydrogen, Ci_4haloalkyl, C₁_₄haloalkoxy, halo, C₁_₄alkoxy, C₁_₄alkyl and C₃_₇cycloalkyloxy; and wherein said C₃_₇cycloalkyloxy may optionally be substituted by one or more fluoro; and whereas both R²and R³ can not be hydrogen; Het is selected from any one of pyridinyl, pyrazinyl, isoxazolyl, pyrazolyl, indolyl, triazolyl and pyrimidinyl, wherein each such heteroaryl may optionally be substituted by one or more X⁴; X⁴is halo, C_1-3alkyl, C_1-3alkyl0C_1-3alkyl, -CH(CH₃)-O-C(CH₃)₃,C₁_₄alkoxy, cyano, or hydroxyl, or Ci_2hydroxyalkyl;; and wherein said C_1-3alkyl, C _1-3alkylOC_1-3alkyl, -CH(CH₃)-O-C(CH₃)₃, or C₁_₄alkoxy may each optionally be substituted by one or more fluoro; L₁ is C₁_₄alkylene, which may optionally be fluorinated or hydroxylated; and L₂ is C_1-3alkylene; with the exception of the compounds: 2-[1-(1,5-dimethyl-lH-pyrazol-4-yl)ethyl]-5,7-dimethoxy-3-oxo-N-[2-(trifluoromethyl)benzyl]isoindoline-1-carboxamide; N-(4-fluorobenzyl)-3-oxo-2-(-pyridin-4-yletyl)isoindoline-1-carboxamide and N-(2-chlorobenzyl)-2[2-(1H-indol-3-yl)-1-methyletyl]-3-oxoisoindoline-1-carboxamide; The invention further relates to pharmaceutical compositions containing said compounds and to the use of said compounds in therapy.

Description

Isoindoline derivatives comprising an additional heterocyclic group and their use in the treatment of pain disorders

FIELD OF THE INVENTION

The present invention relates to new compounds, to a pharmaceutical composition containing said compounds and to the use of said compounds in therapy. The present invention also relates to processes for the preparation of said compounds.

BACKGROUND

The current treatment regimes for pain conditions utilise compounds which exploit a very limited range of pharmacological mechanisms. One class of compounds, the opioids, stimulates the endogenous endorphine system; an example from this class is morphine. Compounds of the opioid class have several drawbacks that limit their use, e.g. emetic and constipatory effects and negative influence on respiratory capability. The second major class of analgesics, the non-steroidal antiinflammatory analgesics of the COX-I or COX-2 types, also have liabilities such as insufficient efficacy in severe pain conditions and at long term use the COX-I inhibitors cause ulcers of the mucosa. Mechanisms of analgesic effects of other currently used medicines are insufficiently characterized and/or have limited therapeutic potential.

Local anesthetics, that are known to block most types of sodium channels in nerves, are useful for relieving pain in small areas of the human body and for blocking nerve conduction from the periphery to the central nervous system. They can also be used in the last-mentioned way to block sensory signalling by instilling solutions of local anesthetics at the spinal cord. Due to their high toxicity, in particular heart toxicity, they can not, however, be used for systemic administration as generally useful analgesics. There remains thus a need for more selective modulators of sodium channels involved in pain signal conduction. Nine sodium channel subtypes have been cloned and functionally expressed to date. (Wood JN, Baker M.. Current Opinion in Pharmacology 2001, 1, 17-21). They are differentially expressed throughout muscle and nerve tissues and show distinct biophysical properties. All voltage-gated sodium channels (NaV:s) are characterized by a high degree of selectivity for sodium over other ions and by their voltage-dependent gating. By application of genetic analysis it has been shown that a mutation in the gene coding for sodium channel NaVl .7, making this protein non-functional, can make a human become almost insensitive to pain (Cox JJ et al. Nature 2006, 444, 894-898).

It is well known that the voltage-gated sodium channels in nerves play a critical role in neuropathic pain (Baker MD and Wood JN. Trends in Pharmacological Sciences 2001, 22, 27-31). Injuries of the peripheral nervous system often result in neuropathic pain persisting long after the initial injury resolves. Examples of neuropathic pain include, but are not limited to, postherpetic neuralgia, trigeminal neuralgia, diabetic neuropathy, chronic lower back pain, phantom limb pain, pain resulting from cancer and chemotherapy, chronic pelvic pain, complex regional pain syndrome and related neuralgias. It has been shown in human patients as well as in animal models of neuropathic pain, that damage to primary afferent sensory neurons can lead to neuroma formation and spontaneous activity, as well as evoked activity in response to normally innocuous stimuli. NaV 1.7 is expressed in human neuromas, which are swollen and hypersensitive nerves and nerve endings that are often present in chronic pain states {Acta Neurochirurgica 2002, 144, 803-810).

In rat models of peripheral nerve injury, ectopic activity in the injured nerve corresponds to the behavioral signs of pain. In these models, intravenous application of the sodium channel blocker and local anesthetic lidocaine can suppress the ectopic activity and reverse the tactile allodynia at concentrations that do not affect general behavior and motor function (Mao J and Chen LL, Pain, 2000, 87, 7-17).

In addition to neuropathic pain, sodium channel blockers have clinical uses in the treatment of epilepsy and cardiac arrhythmias. Recent evidence from animal models suggests that sodium channel blockers may also be useful for neuroprotection under ischaemic conditions caused by stroke or neural trauma and in patients with multiple sclerosis (MS). DISCLOSURE OF THE INVENTION

According to the invention there are provided compounds of formula I

wherein

R¹ is hydrogen, Ci_3alkyl, Ci_3alkoxy, cyano, hydroxy or halo; wherein may optionally be substituted by one or more substituents independently selected from hydroxy,

orfluoro; and wherein

may optionally be substituted by one or more fluoro;

m is 1 or 2;

R² and R³ is each and independently selected from hydrogen, Ci_₄haloalkyl, Ci_4haloalkoxy, halo, Ci_4alkoxy, Ci_4alkyl and C3-7cycloalkyloxy; and wherein said Cs.γcycloalkyloxy may optionally be substituted by one or more fluoro; and whereas both R² and R³ can not be hydrogen;

Het is selected from any one of pyridinyl, pyrazinyl, isoxazolyl, pyrazolyl, indolyl, triazolyl and pyrimidinyl, wherein each such heteroaryl may optionally be substituted by one or more Λ;

X⁴ is halo, Ci_₃alkyl, Ci_₃alkyl0Ci_₃alkyl, -CH(CH₃)-O-C(CH₃)₃, d_₄alkoxy, cyano, hydroxy, or C i_2hydroxyalkyl;

CisalkylOCisalkyl, -CH(CH₃)-O-C(CH₃)3, and

may each optionally be substituted by one or more fluoro;

Li is Ci_4alkylene, which may optionally be fluorinated or hydroxylated; and L₂ is Ci_₃alkylene;

with the exception of the compounds:

2-[l-(l,5-dimethyl-lH-pyrazol-4-yl)ethyl]-5,7-dimethoxy-3-oxo-N-[2- (trifluoromethyl)benzyl]isoindoline- 1 -carboxamide; N-(4-fluorobenzyl)-3-oxo-2-(2-pyridin-4-ylethyl)isoindoline-l -carboxamide; and

N-(2-chlorobenzyl)-2-[2-(lH-indol-3-yl)- 1 -methylethyl]-3-oxoisoindoline- 1 -carboxamide;

as well as a pharmaceutically acceptable salt, or isomer thereof, or a salt of said isomer.

One embodiment of the invention relates to compounds of formula I wherein:

R¹ is hydrogen, d_₃alkoxy, Ci_₃alkyl, chloro, fluoro, cyano or hydroxy; m is 1 or 2;

R² and R³ is each and independently selected from hydrogen, Ci_₄haloalkyl, Ci_4haloalkoxy, halo, Ci_4alkoxy and Ci_4alkyl, and whereas both R² and R³ can not be hydrogen;

Het is selected from any one of pyridinyl, pyrazinyl, isoxazolyl, pyrazolyl, indolyl, triazolyl and pyrimidinyl, wherein each such heteroaryl may optionally be substituted by one or more Λ ; X⁴ is Ci_₃alkyl, d_₃alkoxy or fluoro;

Li is Ci_₃alkylene; and

L₂ is Ci_₃alkylene.

One embodiment of the invention is related to a compound of formula I, wherein R¹ is hydrogen. A further embodiment of the invention is related to a compound of formula I, wherein R¹ is methoxy.

Yet an embodiment of the invention relates to a compound of formula I, wherein R¹ is methyl.

Yet an embodiment of the invention relates to a compound of formula I, wherein R¹ is cyano.

Yet an embodiment of the invention relates to a compound of formula I, wherein R¹ is hydroxy.

Still an embodiment of the invention relates to a compound of formula I, wherein R¹ is chloro.

Still an embodiment of the invention relates to a compound of formula I, wherein R¹ is fluoro.

Still an embodiment of the invention is related to a compound of formula I, wherein R² is selected from chloro, fluoro, and bromo.

One embodiment of the invention is a compound of formula I, wherein R² is -O-CF

Yet an embodiment of the invention is a compound of formula I, wherein R² is -0-CH₂-CF₃. .

Yet an embodiment of the invention is a compound of formula I, wherein R² is CF₃.

Yet an embodiment of the invention is a compound of formula I, wherein R² is -CH₂-CF₃.

One embodiment of the invention is a compound of formula I, wherein R² is methoxy. One embodiment of the invention is a compound of formula I, wherein R² is hydrogen.

Yet an embodiment of the invention is a compound of formula I, wherein R² is iso-propyl.

Yet an embodiment of the invention is a compound of formula I, wherein R³ is hydrogen.

Yet an embodiment of the invention is a compound of formula I, wherein R³ is fluoro.

Yet an embodiment of the invention is a compound of formula I, wherein R³ is chloro.

Yet an embodiment of the invention is a compound of formula I, wherein R³ is bromo.

One embodiment of the invention is a compound of formula I, wherein R³ is methyl.

Yet an embodiment of the invention is a compound of formula I, wherein R³ is CF3.

Yet an embodiment of the invention is a compound of formula I, wherein R³ is -OCF3.

One embodiment of the invention is a compound of formula I, wherein Li is methylene.

Yet an embodiment of the invention is a compound of formula I, wherein Li is ethylene.

Yet an embodiment of the invention is a compound of formula I, wherein Li is propylene.

One embodiment of the invention is a compound of formula I, wherein Li is -CH-(CHs)-CH₂-.

One embodiment of the invention is a compound of formula I, wherein Li is -CH-(CH3)-.

Yet an embodiment of the invention is a compound of formula I, wherein Li is -C(CH₃)₂-CH₂-. Yet an embodiment of the invention is a compound of formula I, wherein Li is -CH₂-CH(CH₃).

Yet an embodiment of the invention is a compound of formula I, wherein Li is -CH₂-C-(CH₃)₂-.

Yet an embodiment of the invention is a compound of formula I, wherein Li is

One embodiment of the invention is a compound of formula I, wherein L₂ is methylene.

Yet an embodiment of the invention is a compound of formula I, wherein L₂ is -CH-(CH₃)-.

Yet an embodiment of the invention is a compound of formula I, wherein L₂ is -cyclopropylene-.

One embodiment of the invention is a compound of formula I, wherein X⁴ is methoxy.

Yet an embodiment of the invention is a compound of formula I, wherein X⁴ is methyl.

Yet an embodiment of the invention is a compound of formula I, wherein X⁴ is cyano.

Yet an embodiment of the invention is a compound of formula I, wherein, wherein X⁴ is CF₃.

Yet an embodiment of the invention is a compound of formula I, wherein, wherein X⁴ is fluoro. Yet an embodiment of the invention is a compound of formula I, wherein, wherein X⁴ is -0-CH₂-CF₃.

Yet an embodiment of the invention is a compound of formula I, wherein X⁴ is -CH₂OH.

Yet an embodiment of the invention is a compound of formula I, wherein X⁴ is -CH(CH₃)-O-C(CH₃)₃.

One embodiment of the invention is a compound of formula I, selected from any one of:

N-[(4-Chlorophenyl)methyl]-3-oxo-2-(2-pyridin-2-ylethyl)-lH-isoindole-l-carboxamide;

3-Oxo-2-(2-pyridin-2-ylethyl)-N-[[4-(trifluoromethoxy)phenyl]methyl]-lH-isoindole-l- carboxamide;

3 -Oxo-2-(2-pyridin-2-ylethyl)-N- [ [4-(trifluoromethyl)phenyl]methyl]- 1 H-isoindole- 1 - carboxamide;

3 -Oxo-2-(pyridin-3 -ylmethyl)-N- [ [4-(trifluoromethoxy)phenyl]methyl] - 1 H-isoindole- 1 - carboxamide; N-[I -(4-Chlorophenyl)ethyl]-3-oxo-2-(2-pyridin-2-ylethyl)- 1 H-isoindole- 1 -carboxamide;

3-Oxo-2-(2-pyrazin-2-ylethyl)-N-[[4-(trifluoromethoxy)phenyl]methyl]-lH-isoindole-l- carboxamide;

2-[(2-Methoxypyridin-3-yl)methyl]-3-oxo-N-[[4-(trifluoromethoxy)phenyl]methyl]-lH- isoindole- 1 -carboxamide; 3-Oxo-2-(pyrazin-2-ylmethyl)-N-[[4-(trifluoromethoxy)phenyl]methyl]-lH-isoindole-l- carboxamide;

3-Oxo-2-(2-pyridin-2-ylethyl)-N-[l-[4-(2,2,2-trifluoroethoxy)phenyl]ethyl]-lH-isoindole-

1 -carboxamide;

2-[(5 -Methyl 1 ,2-oxazol-3 -yl)methyl] -3 -oxo-N-[ [4-(trifluoromethoxy)phenyl]methyl] - 1 H- isoindole-1 -carboxamide;

N-[(4-Chlorophenyl)methyl]-3-oxo-2-(2-pyrazin-2-ylethyl)-lH-isoindole-l -carboxamide; N-[ 1 -(4-Chlorophenyl)ethyl]-3-oxo-2-(2-pyrazin-2-ylethyl)- 1 H-isoindole- 1 -carboxamide;

N-[ 1 -(4-Chlorophenyl)ethyl]-3-oxo-2-(pyridin-3-ylmethyl)- lH-isoindole- 1 -carboxamide;

N-[(4-Fluorophenyl)methyl]-3-oxo-2-(2-pyridin-2-ylethyl)-lH-isoindole-l -carboxamide;

3-Oxo-2-(2-pyridin-2-ylethyl)-N-[[4-(2,2,2-trifluoroethoxy)phenyl]methyl]-lH-isoindole- 1 -carboxamide;

2- [3 -(3 -Methyl- 1 H-pyrazol- 1 -yl)propyl]-3 -oxo-N-[4-(trifluoromethoxy)benzyl] - isoindoline- 1 -carboxamide;

2-(l-Methyl-2-pyridin-2-ylethyl)-3-oxo-N-[4-(trifluoromethoxy)benzyl]isoindoline-l- carboxamide; 4-Methoxy-3-oxo-2-(2-pyridin-2-ylethyl)-Λ/-[4-(trifluoromethoxy)benzyl]isoindoline-l- carboxamide;

3-Oxo-2-(2-pyridin-4-ylethyl)-Λ/-[4-(trifluoromethoxy)benzyl]isoindoline-l -carboxamide;

3 -Oxo-2-(2-pyridin-3 -ylethyl)-//- [4-(trifluoromethoxy)benzyl]isoindo line- 1 -carboxamide;

2-( 1 -Methyl-2-pyridin-2-ylethyl)-3 -oxo-N- [4-(trifluoromethyl)benzyl]isoindoline- 1 - carboxamide;

Λ/-(4-Chlorobenzyl)-2-(l-methyl-2-pyridin-2-ylethyl)-3-oxoisoindoline-l -carboxamide;

2-[2-(lH-Indol-3-yl)ethyl]-3-oxo-Λ/-[4-(trifluoromethoxy)benzyl]isoindoline-l- carboxamide;

N-(4-Methoxybenzyl)-3-oxo-2-(2-pyridin-2-ylethyl)isoindoline-l -carboxamide; 4-Methoxy-2-( 1 -methyl-2-pyridin-2-ylethyl)-3 -oxo-N- [4 (trifluoromethoxy)benzyl] - isoindoline- 1 -carboxamide;

N-(4-Isopropylbenzyl)-2-( 1 -methyl-2-pyridin-2-ylethyl)-3-oxoisoindoline- 1 -carboxamide;

Λ/-[4-Fluoro-3-(trifluoromethyl)benzyl]-2-(l-methyl-2-pyridin-2-ylethyl)-3- oxoisoindoline- 1 -carboxamide; Λ/-[3-Fluoro-4-(trifluoromethyl)benzyl]-2-(l-methyl-2-pyridin-2-ylethyl)-3- oxoisoindoline- 1 -carboxamide;

2-( 1 -Methyl-2-pyridin-2-ylethyl)-3 -oxo-N- [3 -(trifluoromethoxy)benzyl]isoindoline- 1 - carboxamide;

N-[l-(3-Chlorophenyl)ethyl]-3-oxo-2-(2-pyridin-2-ylethyl)isoindoline-l -carboxamide; 2-(2-(5-Fluoropyrimidin-2-yl)ethyl)-3-oxo-Ν-(4-(trifluoromethoxy)benzyl)isoindoline- 1 - carboxamide; 2-(2-(4-Methylpyrimidin-2-yl)ethyl)-3 -oxo-N-(4-(trifluoromethoxy)benzyl)isoindoline- 1 - carboxamide;

3 -Oxo-2-(2-(pyrimidin-2-yl)ethyl)-N-(4-(trifluoromethoxy)benzyl)isoindoline- 1 - carboxamide; 2-(2-(2-Methylpyrimidin-5-yl)ethyl)-3-oxo-N-(4-(trifluoromethoxy)benzyl)isoindoline-l- carboxamide;

2-((6-Cy anopyridin-3 -yl)methyl)-3 -oxo-N-(4-(trifluoromethoxy)benzyl)isoindoline- 1 - carboxamide;

3-Oxo-N-(4-(trifluoromethoxy)benzyl)-2-((5-(trifluoromethyl)pyridin-2- yl)methyl)isoindoline- 1 -carboxamide;

3-Oxo-N-(4-(trifluoromethoxy)benzyl)-2-((6-(trifluoromethyl)pyridin-3- yl)methyl)isoindoline- 1 -carboxamide;

3-Oxo-2-((6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-N-(4-

(trifluoromethoxy)benzyl)isoindoline- 1 -carboxamide; 2-(l-(5-Fluoropyridin-2-yl)ethyl)-3-oxo-N-(4-(trifluoromethoxy)benzyl)isoindoline-l- carboxamide;

7-Chloro-3-oxo-2-(2-(pyridin-2-yl)ethyl)-N-(4-(trifluoromethoxy)benzyl)isoindoline-l- carboxamide;

7-Cyano-3-oxo-2-(2-(pyridin-2-yl)ethyl)-N-(4-(trifluoromethoxy)benzyl)isoindoline-l- carboxamide;

2-(2-Hydroxy-2-(pyridin-2-yl)ethyl)-3 -oxo-N-(4-(trifluoromethoxy)benzyl)isoindoline- 1 - carboxamide;

2-(2,2-Difluoro-2-(pyridin-2-yl)ethyl)-3-oxo-N-(4-(trifluoromethoxy)benzyl)isoindoline-l- carboxamide; 2-(2,2-Difluoro-2-(pyridin-2-yl)ethyl)-7-methyl-3-oxo-N-(4-

(trifluoromethoxy)benzyl)isoindoline- 1 -carboxamide;

3 -Oxo-2-(3 -(pyridin-2-yl)propyl)-N-(4-(trifluoromethoxy)benzyl)isoindoline- 1 - carboxamide;

7-Methoxy-3 -oxo-2-(2-(pyridin-2-yl)ethyl)-N-(4-(trifluoromethoxy)benzyl)isoindoline- 1 - carboxamide; 7-Hydroxy-3 -oxo-2-(2-(pyridin-2-yl)ethyl)-N-(4-(trifluoromethoxy)benzyl)isoindoline- 1 - carboxamide;

2-(2-Methyl- 1 -(pyridin-2-yl)propan-2-yl)-3-oxo-N-(4-

(trifluoromethoxy)benzyl)isoindoline- 1 -carboxamide; 7-Methyl-3-oxo-2-(2-(pyridin-2-yl)ethyl)-N-(4-(trifluoromethoxy)benzyl)isoindoline- 1 - carboxamide;

2-(2-Methyl-2-(pyridin-3-yl)propyl)-3-oxo-N-(4-(trifluoromethoxy)benzyl)isoindoline-l- carboxamide;

2-(2-Methyl-2-(pyridin-2-yl)propyl)-3-oxo-N-(4-(trifluoromethoxy)benzyl)isoindoline-l- carboxamide;

3-Oxo-2-((l-(pyridin-2-yl)cyclopropyl)methyl)-N-(4-

(trifluoromethoxy)benzyl)isoindoline- 1 -carboxamide;

3-Oxo-2-(2-(pyridin-2-yl)ethyl)-N-(l -(4-(trifluoromethoxy)phenyl)ethyl)isoindoline- 1 - carboxamide, ISOMER 4; 2-(2-(6-Methylpyridin-2-yl)ethyl)-3-oxo-N-(4-(trifluoromethoxy)benzyl)isoindoline- 1 - carboxamide;

2-(2-(6-(Hydroxymethyl)pyridin-2-yl)ethyl)-3-oxo-N-(4-

(trifluoromethoxy)benzyl)isoindoline- 1 -carboxamide;

2-(2-(4-(l -tert-Butoxy ethyl)- IH- 1 ,2,3-triazol- 1 -yl)ethyl)-3-oxo-N-(4- (trifluoromethoxy)benzyl)isoindoline- 1 -carboxamide;

4-Fluoro-3-oxo-2-(2-(pyridin-2-yl)ethyl)-N-(4-(trifluoromethoxy)benzyl)isoindoline-l- carboxamide;

7-Fluoro-3-oxo-2-(2-(pyridin-2-yl)ethyl)-N-(4-(trifluoromethoxy)benzyl)isoindoline-l- carboxamide; 2-(2-(3-Fluoropyridin-2-yl)ethyl)-3-oxo-N-(4-(trifluoromethoxy)benzyl)isoindoline- 1 - carboxamide;

4-Hydroxy-3-oxo-2-(l-(pyridin-2-yl)propan-2-yl)-N-(4-

(trifluoromethoxy)benzyl)isoindoline- 1 -carboxamide;

4-Hydroxy-3 -oxo-2-(2-(pyridin-2-yl)ethyl)-N-(4-(trifluoromethoxy)benzyl)isoindoline- 1 - carboxamide;

3-Oxo-2-(2-(pyridin-2-yl)ethyl)-N-(3 -(trifluoromethoxy)benzyl)isoindoline- 1 - carboxamide; N-(2-Methyl-4-(trifluoromethoxy)benzyl)-3 -oxo-2-(2-(pyridin-2-yl)ethyl)isoindoline- 1 - carboxamide;

N-(3-Bromobenzyl)-3-oxo-2-(2-(pyridin-2-yl)ethyl)isoindoline-l-carboxamide; N-(4-Bromobenzyl)-3-oxo-2-(2-(pyridin-2-yl)ethyl)isoindoline-l -carboxamide; N-(4-Bromobenzyl)-3-oxo-2-(2-(pyridin-2-yl)ethyl)isoindoline- 1 -carboxamide, ISOMER

1;

N-(3,4-Dichlorobenzyl)-3-oxo-2-(2-(pyridin-2-yl)ethyl)isoindoline-l -carboxamide; 3-Oxo-2-(2-(pyridin-3-yl)ethyl)-N-(l-(4-(trifluoromethyl)phenyl)cyclopropyl)isoindoline- 1 -carboxamide; and 3-Oxo-2-(2-(pyridin-2-yl)ethyl)-N-(4-(2,2,2-trifluoroethyl)benzyl)isoindoline- 1 - carboxamide.

For the avoidance of doubt it is to be understood that in this specification 'C_1-6' means a carbon containing group having 1, 2, 3, 4, 5 or 6 carbon atoms.

In this specification, unless stated otherwise, the term "alkyl" includes both straight and branched chain alkyl groups and may be, but are not limited to methyl, ethyl, n-propyl, i- propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, neo-pentyl, n-hexyl or i-hexyl. The term Ci_4alkyl as used herein is defined as a straight, branched or cyclic (cyclic where at least three carbon atoms are present) alkyl chain, having from 1 to 4 carbon atoms and may be but are not limited to methyl, ethyl, n-propyl, i-propyl, cyclopropyl, cyclobutyl or tert-butyl. The term Ci_3 alkyl as used herein is defined as a straight, branched or cyclic alkyl chain (cyclic when three carbon atoms are present), having from 1 to 3 carbon atoms, namely: methyl, ethyl, n-propyl, iso-propyl, or cyclopropyl.

The term Ci_4alkylene as used herein for I4 may be a straight, branched or cyclic alkylene group, and includes but is not limited to, a methylene, ethylene, n-propylene, i-propylene, cyclopropylene, n-butylene, iso-butylene, te/t-butylene, and a cyclobutylene hydrocarbon chain. The term Ci_₃alkylene as used herein for L₂ may be a straight, branched or cyclic alkylene group, and includes but is not limited to, a methylene, ethylene, n-propylene, i-propylene, and cyclopropylene hydrocarbon chain.

The term "alkoxy", unless stated otherwise, refers to radicals of the general formula -O-R, wherein R is selected from a hydrocarbon radical. The term "Ci-βalkoxy" may include, but is not limited to methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, isobutoxy,cyclopropylmethoxy, allyloxy or propargyloxy.

The term "C ₁-₃ alkoxy" as used herein may include, but is not limited to methoxy, ethoxy, or propoxy. The term "C1-4 alkoxy" as used herein may include, but is not limited to methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, isobutoxy.

In one embodiment of the invention, "C₁-₃ alkoxy" may be substituted by one or more fluoro atoms whereby one or more hydrogen atoms in the alkoxy group is replaced by one or more fluoro atoms such as -0-CH₂-CF₃; -0-CH₂-CH₂-CF₃; -0-CH-F₂.

The term "Ci_₃alkyl0Ci_₃alkyl", unless stated otherwise, refers to an ether group with the general formula R-O-R, wherein R is selected from a hydrocarbon radical. "Ci_₃alkyl0Ci_₃alkyl" may include, but is not limited to dimethylether, metylethylether, methylpropylether, diethylether, dipropylether or methylisopropylether.

In this specification, unless stated otherwise, the term "haloalkyl" means an alkyl group as defined above, which is substituted with halo as defined above. The term "Ci-4haloalkyl" may include, but is not limited to fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl or fluorochloromethyl.

In this specification, unless stated otherwise, the term "haloalkoxy" means an alkoxy group as defined above, which is substituted with halo as defined above. The term "Ci_4haloalkoxy" may include, but is not limited to fluoromethoxy, difluoromethoxy, trifluoromethoxy, fluoroethoxy or difluoroethoxy. The term "cycloalkyloxy-" refers to a cycloalkyl group attached to the rest of the molecule via the 0-atom of the oxy-group. Examples of C^.j cycloalkyloxy as used herein, are without limitation -O-cyclohexyl, -O-cyclopropyl, O-cyclobutyl, and -O-cyclopentyl.

In this specification, unless stated otherwise, the terms "halo" and "halogen" may be fluorine, iodine, chlorine or bromine.

It will be appreciated that throughout the specification, the number and nature of substituents on rings in the compounds of the invention will be selected so as to avoid sterically undesirable combinations.

For the avoidance of doubt it is to be understood that where in this specification a group is qualified by 'hereinbefore defined', 'defined hereinbefore' or 'defined above' the said group encompasses the first occurring and broadest definition as well as each and all of the particular definitions for that group.

The present invention relates to compounds of formula I as hereinbefore defined, as well as to pharmaceutically acceptable salts thereof. Salts for use in pharmaceutical formulations will be pharmaceutically acceptable salts.

Examples of useful pharmaceutically acceptable salts of a compound of the invention is, for example an acid-addition salt such as a salt formed with an inorganic or organic acid. A further example of useful salts is an alkali metal salt such as an alkaline earth metal salt; or a salt formed with an organic base. Examples of useful salts in accordance with the invention are an acetate, fumarate, maleate, tartrate, citrate, hydrochloride, hydrobromide, sulphate and phosphate salt.

Still other pharmaceutically acceptable salts useful in accordance with the invention and methods of preparing these salts may be found in, for example, Remington's Pharmaceutical Sciences (18^th Edition, Mack Publishing Co.). The compounds of the invention may exhibit tautomerism. All tautomeric forms and mixtures thereof are included within the scope of the invention. The wording "tautomerism" refers to a chemical equilibrium between a keto form and an enol form where the enol and keto forms are tautomers of each other.

The compounds of the invention may also contain one or more asymmetric carbon atoms and may therefore exhibit optical isomerism, such as one or more enantiomers and/or diastereoisomers. Diastereoisomers may be separated using conventional techniques, e.g. chromatography or fractional crystallisation. The various stereoisomers may be isolated by separation of a racemic or other mixture of the compounds using conventional, e.g. fractional crystallisation or HPLC, techniques. Alternatively the desired optical isomers may be made by reaction of the appropriate optically active starting materials under conditions which will not cause racemisation or epimerisation, or by derivatisation, for example with a homochiral acid followed by separation of the diastereomeric esters by conventional means (e.g. HPLC, chromatography over silica). All stereoisomers are included within the scope of the invention.

PHARMACEUTICAL COMPOSITIONS According to one embodiment of the present invention there is provided a pharmaceutical composition comprising as active ingredient a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, in association with one or more pharmaceutically acceptable diluents, excipients and/or inert carriers.

The pharmaceutical composition may be in a form suitable for oral administration, for example as a tablet, pill, syrup, powder, granule or capsule, for parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion) as a sterile solution, suspension or emulsion, for topical administration e.g. as an ointment, patch or cream or for rectal administration e.g. as a suppository. In general the above compositions may be prepared in a conventional manner using one or more conventional excipients, pharmaceutical acceptable diluents and/or inert carriers.

A suitable daily dose of a compound of the invention in the treatment of a mammal, in- eluding man, is approximately from 5 to 100 mg/kg bodyweight at peroral administration and from about 0.01 to 250 mg/kg bodyweight at parenteral administration.

The typical daily dose of the active ingredient varies within a wide range and will depend on various factors such as the relevant indication, severity of the illness being treated, the route of administration, the age, weight and sex of the patient and the particular compound being used, and may be determined by a physician.

MEDICAL USE Compounds according to the present invention are contemplated to be useful in therapy. Compounds of formula I as herein described and claimed, or a pharmaceutically acceptable salt thereof, as well as their corresponding active metabolites, exhibit a high degree of potency at the sodium channel NaVl .7 and also selectivity for this channel compared with other essential sodium channels. Accordingly, compounds of the present invention are expected to be useful in the treatment of conditions associated with upregulation of NaVl.7 and other sodium channels present in C-fϊbers.

Compounds of the invention may be used to produce an inhibitory effect of sodium channels in mammals, including man.

One embodiment of the invention relates to the use of a compound of formula I as hereinbefore defined, in the manufacture of a medicament for the treatment of NaV 1.7 mediated disorders.

Compounds of formula I according to the invention are expected to be useful for the treatment of a pain disorder such as: acute pain; chronic pain; neuropathic pain such as diabetic neuropathies; inflammatory pain associated with arthritis and rheumatoid diseases; low back pain; post-operative pain; pain associated with various conditions including cancer, angina, renal or billiary colic, menstruation, fibromyalgia, low back pain, post-operative pain, cancer pain, visceral pains such as chronic pelvic pain, cystitis, IBS, pancreatitis, ischeamic pain, or gout.

Still an aspect of the invention is the use of a compound of formula I, for the treatment of a vascular headache such as migraine.

Yet an aspect of the invention is the use of a compound of formula I, for the treatment of pain conditions related to erythermalgia, psoriasis, emesis, urinary incontinence and hyperactive bladder.

Still an embodiment of the present invention is the use of a compound of formula I, for the treatment of epilepsy.

One embodiment of the invention relates to the use of a compound of formula I as hereinbefore defined, for the treatment of pain conditions related to arthritis, fibromyalgia, low back pain, post-operative pain, cancer pain, visceral pains such as chronic pelvic pain, cystitis, IBS, pancreatitis or ischeamic pain.

One embodiment of the invention relates to the use of a compound of formula I as hereinbefore defined, in therapy.

Still an embodiment of the invention relates to the use of a compound of formula I as hereinbefore defined, for the manufacture of a medicament for the treatment of a pain disorder such as: acute pain; chronic pain; neuropathic pain such as diabetic neuropathies; inflammatory pain associated with arthritis and rheumatoid diseases; low back pain; post-operative pain; pain associated with various conditions including cancer, angina, renal or billiary colic, menstruation, fibromyalgia, low back pain, post-operative pain, cancer pain, visceral pains such as chronic pelvic pain, cystitis, IBS, pancreatitis, ischeamic pain, or gout. Still an aspect of the invention is the use of a compound of formula I, for the manufacture of a medicament for use in the treatment of a vascular headache such as migraine.

Yet an aspect of the invention is the use of a compound of formula I, for the manufacture of a medicament for use in the treatment of pain conditions related to erythermalgia, psoriasis, emesis, urinary incontinence and hyperactive bladder.

Still an embodiment of the present invention is the use of a compound of formula I, for the manufacture of a medicament for use in the treatment of of epilepsy.

Still an embodiment of the invention relates to a method for the treatment of any one of the following pain disorders such as: acute pain; chronic pain; neuropathic pain such as diabetic neuropathies; inflammatory pain associated with arthritis and rheumatoid diseases; low back pain; post-operative pain; pain associated with various conditions including cancer, angina, renal or billiary colic, menstruation, fibromyalgia, low back pain, post-operative pain, cancer pain, visceral pains such as chronic pelvic pain, cystitis, IBS, pancreatitis, ischeamic pain, or gout; whereby a compound of formula I as hereinbefore defined, is administered to a subject in need of such treatment.

Still an aspect of the invention is a method for the treatment of a vascular headache such as migraine, whereby a compound of formula I as hereinbefore defined, is administered to a subject in need of such treatment.

Yet an aspect of the invention is a method for the treatment of pain conditions related to erythermalgia, psoriasis, emesis, urinary incontinence and hyperactive bladder, whereby a compound of formula I as hereinbefore defined, is administered to a subject in need of such treatment. Still an embodiment of the present invention is a method for the treatment of epilepsy, whereby a compound of formula I as hereinbefore defined is administered to a subject in need of such treatment.

Yet an embodiment of the invention is a compound of formula I as hereinbefore defined, for use in the treatment of a pain disorder such as: acute pain; chronic pain; neuropathic pain such as diabetic neuropathies; inflammatory pain associated with arthritis and rheumatoid diseases; low back pain; post-operative pain; pain associated with various conditions including cancer, angina, renal or billiary colic, menstruation, fibromyalgia, low back pain, post-operative pain, cancer pain, visceral pains such as chronic pelvic pain, cystitis, IBS, pancreatitis, ischeamic pain, or gout.

Still an aspect of the invention is a compound of formula I as hereinbefore defined, for use in the treatment of a vascular headache such as migraine.

Yet an aspect of the invention is a compound of formula I as hereinbefore defined, for use in the treatment of pain conditions related to erythermalgia, psoriasis, emesis, urinary incontinence and hyperactive bladder.

Still an embodiment of the present invention is a compound of formula I as hereinbefore defined, for use in the treatment of epilepsy.

COMBINATIONS Pain treatment as defined herein may be applied as a sole therapy or may involve, in addition to a compound according to the invention, administration of other analgesics or adjuvant therapy. Such therapy may for example include in combination with a compound of the present invention, one or more of the following categories of pain-relieving ingredients: a) opioid analgesics, for example morphine, ketobemidone or fentanyl; b) analgesics of the NSAID or COX- 1/2 class, for example ibuprofene, naproxene, celecoxib or acetylsalicylic acid, and their analogues containing nitric oxide- donating groups; c) analgesic adjuvants such as amitriptyline, imipramine, duloxetine or mexiletine; d) NMDA antagonists for example ketamine or dextrometorfan; e) sodium channel blocking agents, for example lidocaine; f) anticonvulsants, for example carbamazepine, topiramate or lamotrigine; g) anticonvulsant/analgesic amino acids such as gabapentin or pregabalin; h) cannabinoids.

Each active compound of such a combination may be administered simultaneously, separately or sequentiallly.

EXAMPLES

Methods of Preparation

An aspect of the present invention provides a process for preparing a compound of formula I, or a salt thereof.

Throughout the following description of such processes it is understood that, where appropriate, suitable protecting groups will be added to, and subsequently removed from, the various reactants and intermediates in a manner that will be readily understood by one skilled in the art of organic synthesis. Conventional procedures for using such protecting groups as well as examples of suitable protecting groups are described, for example, in

"Green's Protective Groups in Organic Synthesis" P. G. M. Wuts, T.W. Green, Wiley, New York, 2007. References and descriptions of other suitable reactions are described in textbooks of organic chemistry, for example, "Advanced Organic Chemistry", March, 4^th ed. McGraw Hill (1992) or, "Organic Synthesis", Smith, McGraw Hill, (1994). For representative examples of heterocyclic chemistry see for example "Heterocyclic

Chemistry", J. A. Joule, K. Mills, G. F. Smith, 3^rd ed. Chapman and Hall (1995), p. 189- 224 and "Heterocyclic Chemistry", T. L. Gilchrist, 2^nd ed. Longman Scientific and Technical (1992), p. 248-282.

The term "room temperature" and "ambient temperature" shall mean, unless otherwise specified, a temperature between 16 and 25 ⁰C.

Abbreviations

DMF N,N-dimethylformamide

NaOH sodium hydroxide

HCl hydrochloric acid

M molar

PG protective group

One embodiment of the invention relates to processes for the preparation of the compound of formula I according to Methods A and B, wherein R¹, R², R³, L₁, L₂, Het and m, unless otherwise specified, are defined as in formula I.

Method A

A compound of formula I may be prepared by a 3-component Ugi reaction (Journal of Organic Chemistry (1999), 64(3), 1074-1076) using appropriately substituted 2- formylbenzoic acid, amine and isonitrile reacting in a protic solvent, for example methanol at ambient temperature.

+HeI-L₁-NH₂

Method B

A compound of formula I may be prepared by an amide coupling reaction using appropriately substituted indolone carboxylic acid II and amine III and a suitable activator, for example but not limited to, fluoro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate, O-benzotriazol- 1 -yl-N,N,N',N'-tetramethyluronium hexafluorophosphate or O-(7-azabenzotriazol- 1 -yl)-N,N,N',N'-tetramethyluronium hexafluoro-phosphate reacting in precence of an organic base such as triethylamine, N ,N- diisopropylamine or 4-(dimethylamino)pyridine in an aprotic solvent such as DMF, acetonitrile, tetrahydrofuran or dioxane at 0-45 ⁰C:

The carboxylic acids II are available via procedures described in the literature, for example: Othman, M. and Decroix, B., Synthetic communications 1996, 26 (15), 2803- 2809 and Othman, M. et. al, Tetrahedron 1998, 54 (30), 8737-8744 where a homophtalic ester is brominated by for example N-bromosuccinimide (NBS) in carbontetrachloride and then ring closed with an amine in precence of an organic base such as triethylamine, N₅N- diisopropylamine or 4-(dimethylamino)pyridine in a solvent such as acetonitrile at 0-25 ⁰C, as shown below.

EXAMPLES General Methods

Mass spectra were recorded on one of the following instruments:

A) A LC-MS system consisting of a Waters Alliance 2795 HPLC, a Waters PDA 2996 diode array detector, a Sedex 85 ELS detector and a ZQ single quadrupole mass spectrometer. The mass spectrometer was equipped with an electrospray ion source (ES) operated in positive or negative ion mode. The capillary voltage was set to 3.2 kV and the cone voltage to 30 V, respectively. The mass spectrometer scanned between m/z 100-700 with a scan time of 0.3 s. The diode array detector scanned from 200-400 nm. The temperature of the ELS detector was adjusted to 40 ⁰C and the pressure was set to 1.9 bars. Separation was performed on an X-Terra MS C8, 3.0 mm x 50 mm, 3.5 μm (Waters) run at a flow rate of 1 ml/min. A linear gradient was applied starting at 100 % A (A: 10 mM ammonium acetate in 5 % acetonitrile, or 8 mM formic acid in 5 % acetonitrile) ending at 100% B (B: acetonitrile). The column oven temperature was set to 40 ⁰C.

B) A LC-MS system consisting of a Waters sample manager 2111 C, a Waters 1525 μ binary pump, a Waters 1500 column oven, a Waters ZQ single quadrupole mass spectrometer, a Waters PDA 2996 diode array detector and a Sedex 85 ELS detector. The mass spectrometer was configured with an atmospheric pressure chemical ionisation

(APCI) ion source which was further equipped with atmospheric pressure photo ionisation (APPI) device. The mass spectrometer scanned in the positive mode, switching between APCI and APPI mode. The mass range was set to m/z 120-800 using a scan time of 0.3 s. The APPI repeller and the APCI corona were set to 0.86 kV and 0.80 μA, respectively. In addition, the desolvation temperature (300⁰C), desolvation gas (400 L/Hr) and cone gas (5 L/Hr) were constant for both APCI and APPI mode. Separation was performed using a Gemini column C 18, 3.0 mm x 50 mm, 3 μm, (Phenomenex) and run at a flow rate of 1 ml/min. A linear gradient was used starting at 100 % A (A: 10 mM ammonium acetated in 5 % methanol) and ending at 100% B (methanol). The column oven temperature was set to 40 ⁰C. C) A LC-MS system consisting of a Waters Alliance 2795 HPLC and a Waters Micromass ZQ detector operating at 120 ⁰C. The mass spectrometer was equipped with an electrospray ion source (ES) operated in a positive or negative ion mode. The mass spectrometer was scanned between m/z 100-1000 with a scan time of 0.3 s. The LC system used was 75 % acetonitrile and 25 % of a 0.1 % formic acid solution in water.

Preparative chromatography was run on one of the following instruments:

A) A Waters FractionLynx system with a Autosampler combined Automated Fraction Collector (Waters 2767), Gradient Pump (Waters 2525), Column Switch (Waters CFO) and PDA (Waters 2996). Column; XTerra® Prep MS C8 10 μm OBD™ 19 x 300 mm or XTerra® Prep MS C8 10 μm OBD™ 30 x 150 mm both with the guard column XTerra ® Prep MS C 8 10 μm 19 x 10 mm Cartridge. A gradient from 100 % A (95 % 0.1 M ammonium acetate in MiIIiQ water and 5 % acetonitrile) to 100 % B (100 % acetonitrile) was applied for LC-separation at flow rate 20 ml/min. The PDA was scanned from 210- 350 nm. UV triggering determined the fraction collection.

B) A Waters FractionLynx system with a Autosampler combined Automated Fraction Collector (Waters 2767), Gradient Pump (Waters 2525), Regeneration Pump (Waters 600), Make Up Pump (Waters 515), Waters Active Splitter, Column Switch (Waters CFO), PDA (Waters 2996) and Waters ZQ mass spectrometer. Column; XBridge™ Prep C8 5 μm OBD™ 19 x 100 mm, with guard column; XTerra ® Prep MS C8 10 μm 19 x 10 mm Cartridge. A gradient from 100 % A (95 % 0.1 M ammonium acetate in MiIIiQ water and 5 % acetonitrile) to 100 % B (100 % acetonitrile) was applied for LC-separation at flow rate 25 ml/min. The PDA was scanned from 210-350 nm. The ZQ mass spectrometer was run with ESI in positive mode. The Capillary Voltage was 3kV and the Cone Voltage was 30V. Mixed triggering, UV and MS signal, determined the fraction collection.'

Purity analyses were performed on one of the following instruments: A) An Agilent HPl 100 system consisting of a G1379A Micro Vacuum Degasser, a G1312A Binary Pump, a G1367 Well-Plate Autosampler, a G1316A Thermostatted Column Compartment and a G1315C Diode Array Detector. The column used was a Gemini Cl 8 3.0 x 50, 3 μm (Phenomenex) run at a flow rate of 1.0 ml/min. The purity method consisted of three parts: firstly a 3 -minute column wash was applied, secondly a blank run was performed and finally the sample was analysed. A linear gradient was used for both the blank and the sample, starting at 100 % A (A: 10 mM ammonium acetate in 5 % acetonitrile) and ending at 100 % B (B: acetonitrile) after 3.5 minutes. The blank run was subtracted from the sample run at the wavelengths 220 nm, 254 nm and 290 nm.

B) A Water Acquity system with PDA (Waters 2996) and Waters ZQ mass spectrometer. Column; Acquity UPLC™ BEH Cs 1.7 μm 2.1 x 50 mm. The column temperature was set to 65 ⁰C. A linear 2 min 15 sec gradient from 100 % A (A: 95 % 0.01 M ammonium acetate in MiIIiQ water and 5 % acetonitrile) to 100 % B (5 % 0.01 M ammonium acetate in MiIIiQ water and 95 % acetonitrile) was applied for LC-separation at flow rate 1.0 ml/min. The PDA was scanned from 210-350 nm and 25 4nm was extracted for purity determination. The ZQ mass spectrometer was run with ESI in pos/neg switching mode. The Capillary Voltage was 3kV and the Cone Voltage was 30V.

C) A Waters 600 Controller system with a Waters 717 Plus Autosampler and a Waters 2996 Photodiode Array Detector. The column used was an ACE C₁₈, 5 μm, 6O x 150 mm. A linear gradient was applied, starting at 95 % A (A: 0.1 % H₃PO₄ in water) and ending at 55 % B (B: acetonitrile) in 20 min run. The column was at ambient temperature with the flow rate of 1.0 mL/min. The Diode Array Detector was scanned from 200-400 nm.

NMR spectra were recorded on a Varian Mercury Plus 400 NMR Spectrometer, operating at 400 MHz and equipped with a Varian 400 ATB PFG probe; or on a Varian Unity+ 400 NMR Spectrometer, operating at 400 MHz for proton and 100 MHz for carbon-13, and equipped with a 5 mm BBO probe with Z-gradients; or on a Bruker av400 NMR spectrometer operating at 400 MHz for proton and 100 MHz for carbon-13, and equipped with a 3 mm flow injection SEI ¹HZD-¹³C probe head with Z-gradients, using a BEST 215 liquid handler for sample injection; or on a Bruker DPX400 NMR spectrometer, operating at 400 MHz for proton and 100 MHz for carbon- 13, and equipped with a 4-nucleus probe with Z-gradients. The following reference signals were used: TMS δ 0.00, or the residual solvent signal Of DMSO-J₆ δ 2.49, CD₃OD δ 3.31 or CDCl₃ δ 7.25 (unless otherwise indicated). Resonance multiplicities are denoted s, d, t, q, m and br for singlet, doublet, triplet, quartet, multiplet and broad, respectively.

Diastereomers may or may not be denoted in spectra depending upon ease of interpretation of spectra. Unless otherwise stated, chemical shifts are given in ppm with the solvent as internal standard.

Column chromatography was performed using Merck Silica gel 60 (0.040-0.063 mm), or employing a Combi Flash^® Companion^™ system using RediSep^™ normal-phase flash columns.

Compounds of the present invention have been named using ACD/Name, version 8.0 or 9.0, software from Advanced Chemistry Development, Inc. (ACD/Labs), Toronto ON, Canada, www.acdlabs.com, 2004; and ELN version 2.1 software from Cambridgesoft, ■^^■^l-.S^IJ.lb2idgeAQJl..com, 2008.

Preparation of intermediates

The invention will now be illustrated by the following non-limiting examples.

Example 1-1 Ethyl 3-oxo-2-(2-pyridin-2-ylethyl)-lH-isoindole-l-carboxylate

Intermediate 1

The solution of ethyl 2-(l-bromo-2-ethoxy-2-oxoethyl)benzoate (3.15 g, 10.0 mmol prepared according to Othman et al Synth. Comm. 1996, 26, 2803.) in acetonitrile (25 mL) was cooled to 0 ⁰C with ice-bath, and the atmosphere over the solution was exchanged to argon. Triethylamine (2.23 rnL, 16.0 mmol), and 2-(pyridin-2-yl)ethanamine (1.80 mL, 15.0 mmol) were added sequentially, and the reaction mixture was allowed to warm up to ambient temperature while stirred for 1 day. The reaction mixture was dissolved in ethyl acetate (100 mL) and washed with water, sat. sodium bicarbonate, and finally with brine. The organic layer was dried over magsesium sulfate and concentrated in vacuum. The crude was purified by column chromatography using a gradient of chloroform/methanol/7 M ammonia in methanol 90/9/1, in chloroform (0-60 %). The fractions containing the product were pooled and concentrated in vaccum to yield the title compound as yellow oil, 2.08 g (67 %).

¹H NMR (400 MHz, CDC13) δ ppm 8.48 - 8.54 (m, 1 H), 7.83 (d, 1 H), 7.61 (t, 1 H), 7.46 - 7.56 (m, 3 H), 7.25 (d, 1 H), 7.12 - 7.19 (m, 1 H), 5.09 (s, 1 H), 4.40 - 4.50 (m, 1 H), 4.17 - 4.32 (m, 2 H), 3.73 - 3.83 (m, 1 H), 3.17 - 3.29 (m, 2 H), 1.30 (t, 3 H); MS (ESI) m/z 311 [M+H], MS (ESI) m/z 309 [M-H].

Example 1-2 S-Oxo-l-d-pyridin-l-ylethyD-lH-isoindole-l-carboxylic acid

Intermediate 2

To a stirred solution of ethyl 3-oxo-2-(2-pyridin-2-ylethyl)-lH-isoindole-l-carboxylate (1.09 g, 3.50 mmol) in methanol (10 mL) was added 2M NaOH (3.5 mL, 7.0 mmol). The reaction mixture was stirred at ambient temperature for 15 minutes and then neutralized with 2 M HCl and concentrated to driness in vacuum. The obtained solid was solubilized in methanol/acetone, 1/1 mixture (25 mL) and the formed white solid was filtered off to yield a transparent yellow solution, which by evaporation yielded the title compound as a yellow solid, 0.97 g (98 %).

¹H NMR (400 MHz, DMSO-J₆) δ ppm 8.44 - 8.48 (m, 1 H), 7.58 - 7.70 (m, 3 H), 7.51 - 7.57 (m, 1 H), 7.45 (t, 1 H), 7.26 (d, 1 H), 7.17 - 7.22 (m, 1 H), 5.07 (s, 1 H), 4.13 - 4.24 (m, 1 H), 3.53 - 3.64 (m, 1 H), 2.95 - 3.14 (m, 2 H); MS (ESI) m/z 283 [M+H]. Example 1-3

Ethyl 3-oxo-2-(pyridin-3-ylmethyl)-lH-isoindole-l-carboxylate

Intermediate 3

The titled compound was synthesized according to the procedure described for intermediate 1 from ethyl 2-(l-bromo-2-ethoxy-2-oxoethyl)benzoate (0.95 g, 3.0 mmol), triethylamine (0.83 mL, 6.0 mmol) and pyridin-3-yl-methylamine (0.46 mL, 4.5 mmol) in acetonitrile (25 mL) to yield a yellow oil, 0.56 g (63%). 1H NMR (400 MHz, DMSO-J₆) δ ppm 8.52 - 8.55 (m, 1 H), 8.47 - 8.50 (m, 1 H), 7.76 - 7.80 (m, 1 H), 7.69 - 7.73 (m, 1 H), 7.65 - 7.69 (m, 1 H), 7.57 - 7.64 (m, 2 H), 7.33 - 7.38 (m, 1 H), 5.39 (s, 1 H), 5.02 (d, 1 H), 4.51 (d, 1 H), 4.07 - 4.18 (m, 2 H), 1.14 - 1.20 (m, 3 H); MS (ESI) m/z 297 [M+H], MS (ESI) m/z 295 [M-H].

Example 1-4 S-Oxo-l-foyridin-S-ylmethvD-lH-isoindole-l-carboxylic acid

Intermediate 4

The titled compound was synthesized according to the procedure described for intermediate 2 from ethyl 3-oxo-2-(pyridin-3-ylmethyl)-lH-isoindole-l-carboxylate (0.56 g, 1.9 mmol) reacted with 1 M NaOH (5.7 mL, 5.7 mmol) in methanol (10 mL) to yield a white solid, 0.43 g (84 %).

¹H NMR (400 MHz, DMSO-J₆) δ ppm 13.68 (br. s., 1 H), 8.51 - 8.55 (m, 1 H), 8.48 (dd, 1 H), 7.76 (d, 1 H), 7.68 - 7.72 (m, 1 H), 7.62 - 7.68 (m, 2 H), 7.55 - 7.61 (m, 1 H), 7.35 (dd, 1 H), 5.24 (s, 1 H), 5.10 (d, 1 H), 4.44 (d, 1 H); MS (ESI) m/z 267 [M+H], MS (ESI) m/z 269 [M-H].

Example 1-5 Ethyl 2-d-methyl-2-pyridin-2-ylethyl)-3-oxoisoindoline-l-carboxylate

Intermediate 5

The titled compound was synthesized according to the procedure described for intermediate 1 from ethyl 2-(l-bromo-2-ethoxy-2-oxoethyl)benzoate (3.0 g, 9.5 mmol), 1- methyl-2-pyridin-2-yl-ethylamine (1.95 g, 14.3 mol) and triethylamine (2.13 mL, 15.3 mmol) in acetonitrile (25 mL) to yield the product, 1.9 g (62 %). 1H NMR (400 MHz, CDCl₃) δ ppm 8.52, 8.38 (d + d, 1 H), 7.76 - 7.81 (m, 1 H), 7.46 - 7.57 (m, 4 H), 7.20, 7.13 (d + d, 1 H), 7.04 - 7.10 (m, IH), 5.31, 4.72 (s + s, 1 H), 4.75 - 4.80, 4.09 - 4.30 (m + m, 3H), 3.63 - 3.69, 3.24 - 3.34, 3.10 (m + m + dd, 2 H), 1.67, 1.37 (d + d, 3 H), 1.29 (m, 3H); MS (ESI) m/z 325 [M+H].

Example 1-6 l-fl-methyl-l-pyridin-l-ylethyD-S-oxoisoindoline-l-carboxylic acid

Intermediate 6

The title compound was synthesized according to the procedure described for intermediate 2 from ethyl 2-(l-methyl-2-pyridin-2-ylethyl)-3-oxoisoindoline-l-carboxylate (0.97 g, 3.0 mmol) reacted with 1 M NaOH (9.0 mL, 9.0 mmol) in methanol (10 mL) to yield a yellow solid, 0.87 g (98 %). 1H NMR (400 MHz, CD₃OD) δ ppm 8.43 - 8.47, 8.34 - 8.38 (m + m, 1 H), 7.47 - 7.71 (m, 4 H), 7.37 - 7.46 (m, 1 H), 7.24 - 7.29 (m, 1 H), 7.15 - 7.24 (m, 1 H), 5.15, 4.55 (s + s, 1 H), 4.75 - 4.83, 4.22 - 4.31 (m + m, 1 H), 3.65, 3.08 (dd + dd, 1 H), 3.19 - 3.28 (m, 1 H), 1.64, 1.44 (d + d, 3 H); MS (APCI/APPI) m/z 297 [M+H].

Example 1-7 Ethyl 2-(2-ethoxy-2-oxoethyl)-6-methoxybenzoate

Interm ediate 7

Step l: A mixture of 3-hydroxyhomophthalic acid (2.90 g, 12.8 mmol), concentrated sulfuric acid (3 ml) in ethanol (20 ml) and toluene (30 ml) was refluxed over night under Dean-Starck conditions. The reaction mixture was allowed to cool to ambient temperature and was neutralized with 1 M NaOH. The ethanol was evaporated in vacuo and the remaining solution washed with brine. The reaction mixture was concentrated in vacuo and the crude was purified by column chromatography using a gradient of ethyl acetate in heptane (0-20 %), yielding a transparant oil, 0.56 mg (22 %).

Step 2:

A mixture of the ester product from the first step (0.56 g, 2.2 mmol) and potassium carbonate (0.77 g, 5.6 mmol, 2.5 equiv) in DMF (10 mL) was stirred at ambient temperature for 15 min. Methyl iodide (283 μL, 4.50 mmol, 2.0 equiv) was added, the atmosphere was changed to argon and the reaction mixture was heated to 60 ⁰C over night. The reaction mixture was allowed to reach ambient temperature, diluted with ethyl acetate and neutralized with 2 M HCl. The organic layer was dried over magnesium sulfate and the crude was purifed by column chromatography using a gradient of ethyl acetate in heptane (0-20 %) to yield a transparent oil, 0.54 g (91%).

¹H NMR (400 MHz, CDCl₃-;/) δ ppm 7.33 (t, 1 H), 6.84 - 6.93 (m, 2 H), 4.39 (q, 2 H), 4.14 (q, 2 H), 3.84 (s, 3 H), 3.66 (s, 2 H), 1.38 (t, 3 H), 1.25 (t, 3 H); MS (ESI) m/z 267 [M+H]. Example 1-8

Ethyl 2-(l-bromo-2-ethoxy-2-oxoethyl)-6-methoxybenzoate

Interm ed iate 8

A mixture of ethyl 2-(2-ethoxy-2-oxoethyl)-6-methoxybenzoate (3.1O g, 11.6 mmol), N- bromosuccinimide (3.00 g, 16.9 mmol, 1.5 equiv) and 2,2'-azobis(2-methylpropionitrile) (377 mg, 2.30 mmol, 0.2 equiv) in carbon tetrachloride (50 mL) was refluxed for 1.5 h. The reaction mixture was allowed to cool to ambient temperature, filtered and concentrated in vacuo. The crude was purified by column chromatography using a gradient of ethyl acetate in heptane (0-30 %) to yield a transparant oil, 3.54 g (89%).

¹H NMR (400 MHz, CDCl₃-;/) δ ppm 7.38 - 7.43 (m, 2 H), 6.90 - 6.95 (m, 1 H), 4.44 (q, 2 H), 4.17 - 4.31 (m, 2 H), 3.85 (s, 3 H), 1.74 (s, 1 H), 1.41 (t, 3 H), 1.27 (t, 3 H); MS (ESI) m/z 345, 347 [M+H].

Example 1-9

Ethyl 4-methoxy-3-oxo-2-f2-pyridin-2-ylethyl)isoindoline-l-carboxylate

Interm ed iate 9

The title compound was synthesized according to the procedure described for intermediate 1 from ethyl 2-(l-bromo-2-ethoxy-2-oxoethyl)-6-methoxybenzoate (2.50 g, 7.24 mmol), 2-pyridin-2-yl-ethylamine (1.50 g, 12.2 mol) and triethylamine (2.20 mL, 15.8 mmol) in acetonitrile (30 mL), to yield 1.21 g (49 %) of the product.

¹H NMR (400 MHz, CDCl₃) δ ppm 8.51 (d,l H), 7.58 (t, 1 H), 7.45 (t, H), 7.22 (d, 1 H), 7.06 - 7.17 (m, 2 H), 6.92 (d, 1 H), 4.95 (s, 1 H), 4.38 (dt, 1 H), 4.10 - 4.32 (m, 2 H), 3.96 (s, 3 H), 3.68 (dt, 1 H), 3.08 - 3.28 (m, 2H), 1.28, (t, 3 H); MS (ESI) m/z 341 [M+H]. Example I- 10 ^methoxy-S-oxo-l-d-pyridin-l-ylethyDisoindoline-l-carboxylic acid

Intermediate 10

The title compound was synthesized according to the procedure described for intermediate 2 from ethyl 4-methoxy-3-oxo-2-(2-pyridin-2-ylethyl)isoindoline-l-carboxylate (0.681 g, 2.00 mmol) reacted with 1 M NaOH (5.0 mL, 5.0 mmol) in methanol (10 mL) to yield a yellowish solid, 0.61O g (98 %). 1H NMR (400 MHz, MeOH) δ ppm 8.39 - 8.45 (m, 1 H), 7.71 (td, 1 H), 7.46 (t, 1 H), 7.33 (d, 1 H), 7.21 - 7.26 (m, 2 H), 6.97 (d, 1 H), 4.83 (s, 1 H), 4.30 - 4.41 (m, 1 H), 3.89 (s, 3 H), 3.54 - 3.68 (m, 1 H), 3.05 - 3.23 (m, 2 H); MS (ESI) m/z 313 [M+H].

Example I- 11 Ethyl 4-methoxy-2-fl-methyl-2-pyridin-2-ylethyl)-3-oxoisoindoline-l-carboxylate

Intermediate 11

The title compound was synthesized according to the procedure described for intermediate 1 from ethyl 2-(l-bromo-2-ethoxy-2-oxoethyl)-6-methoxybenzoate, l-methyl-2-pyridin-2- yl-ethylamine and triethylamine in acetonitrile, to yield 0.354 g of the product. 1H NMR (400 MHz, CDCl₃) δ ppm 8.51 (dd, IH), 7.39 - 7.69 (m, 2 H), 7.23 (dd, 1 H), 6.97 - 7.16 (m, 2 H), 6.90 (d, 1 H), 4.62 - 4.79 (m, 2 H), 4.07 -

4.36 (m, 3 H), 3.89 - 4.04 (m, 3 H), 3.19 - 3.39 (m, 1 H), 1.59 - 1.70 (m, 1 H), 1.17 - 1.39 (m, 5 H); MS (ESI) m/z 355 [M+H]. Example 1-12 4-Methoxy-2-fl-methyl-2-pyridin-2-ylethyl)-3-oxoisoindoline-l-carboxylic acid

Intermediate 12

The title compound was synthesized according to the procedure described for intermediate 2 from ethyl 4-methoxy-2-(l-methyl-2-pyridin-2-ylethyl)-3-oxoisoindoline-l-carboxylate (0.354 g, 1.00 mmol) reacted with 1 M NaOH (2.5 mL, 2.5 mmol) in methanol (10 mL) to yield a yellowish solid, 0.266 g (82 %). 1H NMR (400 MHz, DMSO-J₆) δ 8.41 - 8.51 (m, 1 H), 7.56 - 7.68 (m, 1 H), 7.29 - 7.37 (m, 1 H), 7.13 - 7.22 (m, 2 H), 7.06 (t, 1 H), 6.85 (d, 1 H), 4.73, 4.31 (s + s, 1 H), 4.39 - 4.51, 4.06 - 4.18 (m, 1 H), 3.80, 3.79(s + s, 3 H), 3.40 - 3.49, 3.05 - 3.26, 2.91 - 3.00 (m, 2 H), 1.37, 1.20 (d, 3 H); MS (ESI) m/z 327 [M+H].

Example 1-13 Ethyl 3-oxo-2-(2-pyridin-4-ylethyl)isoindoline-l-carboxylate

intermediate 13

The title compound was synthesized according to the procedure described for intermediate 1 from ethyl 2-(l-bromo-2-ethoxy-2-oxoethyl)benzoate (2.50 g, 7.90 mmol), 2-pyridin-4- yl-ethylamine (2.00 g, 16.3 mmol) and triethylamine (2.50 mL, 18.0 mmol) in acetonitrile (25 mL), to yield 1.42 g (58%) of the product.

¹H NMR (400 MHz, CDCl₃) δ ppm 8.51 (d, 2 H), 7.85 (d, 1 H), 7.46 - 7.61 (m, 3 H), 7.18 (d, 2 H), 4.94 (s, 1 H), 4.11 - 4.41 (m, 3 H), 3.46 - 3.61 (m, 1 H), 2.91 - 3.14 (m, 2 H), 1.30 (t, 3 H); MS (ESI) m/z 311 [M+H]. Example 1-14 3-Oxo-2-f2-pyridin-4-ylethyl)isoindoline-l-carboxylic acid

Intermediate 14

The title compound was synthesized according to the procedure for intermediate 2 from ethyl 3-oxo-2-(2-pyridin-4-ylethyl)isoindoline-l-carboxylate (0.621 g, 2.00 mmol) reacted with 1 M NaOH (4.0 mL, 4.0 mmol) in methanol (10 mL) to yield a white solid, 0.553 g (98 %). 1H NMR (400 MHz, MeOH) δ ppm 8.39 - 8.41 (m, 2 H), 7.68 - 7.73 (m, 2 H), 7.56 (td, 1 H), 7.46 (t, 1 H), 7.34 - 7.39 (m, 2 H), 5.00 (s, 1 H), 4.26 - 4.35 (m, 1 H), 3.57 - 3.66 (m, 1 H), 3.00 - 3.17 (m, 2 H); MS (ESI) m/z 283 [M+H].

Example 1-15

Ethyl 3-oxo-2-(2-pyridin-3-ylethyl)isoindoline-l-carboxylate

Intermediate 15

The title compound was synthesized according to the procedure described for intermediate 1 from ethyl 2-(l-bromo-2-ethoxy-2-oxoethyl)benzoate (2.10 g, 6.60 mmol), 2-pyridin-3- yl-ethylamine (1.80 g, 14.7 mol) and triethylamine (2.00 mL, 14.4 mmol) in acetonitrile (25 mL), to yield 1.29 g (63 %) of the product. 1H NMR (400 MHz, CDCl₃) δ ppm 8.51 (d, 2 H), 7.85 (d, 1 H), 7.46 - 7.61 (m, 3 H), 7.18 (d, 2 H), 4.94 (s, 1 H), 4.12 - 4.42 (m, 3 H), 3.47 - 3.60 (m, 1 H), 2.91 - 3.14 (m, 2 H), 1.30 (t, 3 H); MS (ESI) m/z 311 [M+H]. Example 1-16 S-Oxo-l-d-pyridin-S-ylethyDisoindoline-l-carboxylic acid

Intermediate 16

The title compound was synthesized according to the procedure described for intermediate 2 from ethyl 3-oxo-2-(2-pyridin-3-ylethyl)isoindoline-l-carboxylate (0.621 g, 2.00 mmol) reacted with 1 M NaOH (4.0 mL, 4.0 mmol) in methanol (10 mL) to yield a yellowish solid, 0.548 g (97 %). 1H NMR (400 MHz, MeOH) δ ppm 8.41 - 8.44 (m, 1 H), 8.36 (dd, 1 H), 7.76 - 7.82 (m, 1 H), 7.66 - 7.74 (m, 2 H), 7.53 - 7.58 (m, 1 H), 7.42 - 7.49 (m, 1 H), 7.31 - 7.38 (m, 1 H), 5.00 (s, 1 H), 4.23 - 4.32 (m, 1 H), 3.54 - 3.63 (m, 1 H), 2.98 - 3.17 (m, 2 H); MS (ESI) m/z 283 [M+H].

Example 1-17 2-Methyl-l-fpyridin-2-yl)propan-2-amine

Intermediate 17

2-Methyl-l-(pyridin-2-yl)propan-2-ol (197 mg, 1.3 mmol, prepared according to European Journal of Organic Chemistry 2000, 15, 2735) and trimethylsilyl cyanide (0.347 mL, 2.60 mmol) were mixed, set under N₂ atmosphere and cooled down to -15°C then concentrated sulfuric acid (0.21 mL, 3.90 mmol) was added slowly. The mixture was allowed to warm up to room temperature and stirred for 16 hours then poured onto ice, neutralized with 4M NaOH solution and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The crude is a mixture of formamide intermediate and olefin by-product. The crude was diluted with 6M HCl solution (5 mL) and refluxed for 16 hours. The pH was set to 7 by adding 4M NaOH solution and the mixture was purified by preparative HPLC. Colorless oil, 32 mg (16 %). ¹H NMR (400 MHz, CD₃OD) δ (ppm) 8.49 (dd, 1 H) 7.74 (td, 1 H) 7.23 - 7.32 (m, 2 H) 3.28 (s, 2 H) 3.01 (s, 2 H) 1.29 (s, 6 H). MS (ESI) m/z 151 [M+H].

Example 1-18 N-fl-f4-ftrifluoromethoxy)phenyl)ethyl)formamide

lntemBdate18

l-(4-(trifluoromethoxy)phenyl)ethanamine (0.352 g, 1.72 mmol) was dissolved in dichloromethane (4 niL), set under N₂ atmosphere and was cooled down to 0⁰C. Phenyl formate (0.187 mL, 1.72 mmol) was added dropwise and the mixture was stirred at room temperature for 16 hours. The solvent was removed in vacuo and the residue was purified on silica column using heptane : ethyl acetate = 100:0 to 0:100 as gradient. Colorless oil, 284 mg (71 %). 1H NMR (500 MHz, CDCl₃) δ (ppm) 8.20 (s, 1 H) 7.36 (d, 2 H) 7.17 - 7.22 (m, 2 H) 5.77 (br. s., 1 H) 5.24 (t, 1 H) 1.53 (d, 3 H). MS (ESI) m/z 234 [M+H].

Example 1-19 l-fl-Isocvanoethyl)-4-ftrifluoromethoxy)benzene

Intermediate 19

N-(l-(4-(Trifluoromethoxy)phenyl)ethyl)formamide (0.275 g, 1.18 mmol) was dissolved in dichloromethane (4 mL) and cooled to -15°C under N₂ atmosphere. N ,N- diisopropylethylamine (0.780 mL, 4.72 mmol) followed by phosphorus oxychloride (0.132 mL, 1.42 mmol) were added and the resulting mixture was allowed to slowly reach room temperature (3 hours). Then methanol (1.5 mL) was added to quench the reaction. The mixture was diluted with dichloromethane and washed twice with sat. NaHCO₃ solution. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated to give the product as a brown oil, 284 mg (112 %) which was used without further purification.

¹H NMR (500 MHz, CDCl₃) δ (ppm) 7.41 (d, 2 H) 7.24 - 7.29 (m, 2 H) 4.85 (q, 1 H) 1.70 (d, 2 H). MS (ESI) m/z 216 [M+H].

Example 1-20 6-(YTetrahvdro-2H-pyran-2-yloxy)methyl)picolinaldehyde

Intermediate 20

2.5M solution of butyl lithium (5.0 mL, 11.9 mmol) in diethyl ether was slowly added to a solution of 2-bromo-6-((tetrahydro-2H-pyran-2-yloxy)methyl)pyridine (3.0g, 11.0 mmol, prepared according to Journal of Organic Chemistry 1993, 58(16), 1993) in anhydrous tetrahydrofuran (15 ml) at -78°C under nitrogen. The reaction mixture was stirred for 1 hour then DMF (5 mL) was added. The mixture was allowed to warm up to room temperature during 2 hours then quenched with saturated solution of ammonium chloride and extracted with diethyl ether (2x30 mL). The ethereal layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography using hexane : ethyl acetate = 100:0 to 90:10 furnishing the desired compound, 1.25 g (54 %).

¹H NMR (400 MHz, CDCl₃) δ (ppm) 10.06 (s, 1 H) 7.88 (s, 2 H) 7.74 (d, 1 H) 4.99 (d, 1 H) 4.82 (br. s., 1 H) 4.73 (s, 1 H) 3.92 (d, 1 H) 3.57 (d, 1 H) 1.66 - 1.96 (m, 6 H).

Example 1-21 (E)-2-(2-Nitrovinyl)-6-(Ttetrahvdro-2H-pyran-2-yloxy)methyl)pyridine

Intermediate 21

Sodium hydroxide (0.282 g, 7.0 mmol) was dissolved in water (1.7 mL) and was slowly added to the stirred methanol (8 mL) solution of nitromethane (0.394 g, 6.47 mmol) and 6- ((tetrahydro-2H-pyran-2-yloxy)methyl)picolinaldehyde (1.3 g, 5.9 mmol) at 0⁰C. The reaction mixture was stirred for 2 hours and concentrated under reduced pressure. The residue was diluted with water (10 mL) and extracted with dichloromethane (2x10 mL). The organic extract was concentrated in vacuo to give 2-nitro-l-(6-((tetrahydro-2H-pyran- 2-yloxy)methyl)pyridin-2-yl)ethanol (1.21 g, 4.3 mmol), which was dissolved in dry dichloromethane (5 mL). To this mixture methanesulfonyl chloride (0.478 g, 4.3 mmol) in dry dichloromethane (5 mL) was added slowly at 0⁰C then stirred for 15 minutes. Thereafter N,N-diisopropylethylamine (0.58 g, 4.5 mmol) was added and the reaction mixture was stirred for an additional 1 hour, diluted with dichloromethane (10 mL) and washed with water (10 mL) and brine (10 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography using hexane : ethyl acetate = 100:0 to 90: 10 eluent affording the desired product, 750 mg (50 %).

¹H NMR (400 MHz, CDCl₃) δ (ppm) 8.02 (d, 1 H) 7.91 (d, 1 H) 7.79 (t, 1 H) 7.58 (d, 1 H) 7.36 (d, 1 H) 4.91 (d, 1 H) 4.80 (t, 1 H) 4.66 (d, 1 H) 3.80 - 4.00 (m, 1 H) 3.48 - 3.66 (m, 1 H) 1.77 - 1.93 (m, 6 H). MS (ESI) m/z 265 [M+H].

Example 1-22

2-f6-ffTetrahvdro-2H-pyran-2-yloxy)methyl)pyridin-2-yl)ethanamine

Intermediate 22

The tetrahydrofuran (10 mL) solution of (E)-2-(2-nitrovinyl)-6-((tetrahydro-2H-pyran-2- yloxy)methyl)pyridine (750 mg, 2.8 mmol) was added dropwise to lithium aluminum hydride (323 mg, 8.5 mmol) in diethyl ether (6 mL) at room temperature. The reaction mixture was refluxed for 2 hours, cooled to room temperature and stirred for 18 hours. The reaction mixture was quenched with 20% NaOH solution and extracted with diethyl ether (3x20mL). The combined ethereal layer was dried over anhydrous sodium sulfate, filtered and concentrated to give the desired compound, 380 mg (56 %). MS (ESI) m/z 237 [M+H].

Example 1-23

Ethyl 3-oxo-2-(^-(^-(Ytetrahydro-2H-pyran-2-yloxy)methyl)pyridin-2- yPethyDisoindoline-l-carboxylate

Intermediate 23

The title compound was synthesized according to the procedure described for intermediate 1 from ethyl 2-(l-bromo-2-ethoxy-2-oxoethyl)benzoate (504 mg, 1.6 mmol), 2-(6- ((tetrahydro-2H-pyran-2-yloxy)methyl)pyridin-2-yl)ethanamine (380 mg, 1.6 mmol ) and triethylamine (323 mg, 3.2 mmol) in acetonitrile (5 mL). Solid, 210 mg (30 %). MS (ESI) m/z 425 [M+H].

Example 1-24

3-Oxo-2-(2-(^-(|tetrahydro-2H-pyran-2-yloxy)methyl)pyridin-2-yl)ethyl)isoindoline-l- carboxylic acid

Intermeciate24

A solution of lithium hydroxide (14 mg, 0.58 mmol) in water (3 mL) was added to the stirred solution of ethyl 3-oxo-2-(2-(6-((tetrahydro-2H-pyran-2-yloxy)methyl)pyridin-2- yl)ethyl)isoindoline-l-carboxylate (0.210 g, 0.49 mmol) in tetrahydrofuran (10 mL) at room temperature. The reaction mixture was stirred for 3 hours then concentrated under reduced pressure. The crude residue was redissolved in water (10 mL) and acidified with saturated solution of citric acid and then extracted with ethyl acetate (3x40 mL). The combined organic extract was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to give the desired product as white solid, 180 mg (91 %). MS (ESI) m/z 397 [M+H].

Example 1-25

Ethyl 2-(2-(3-fluoropyridin-2-yDethyr)-3-oxoisoindoline-l-carboxylate

Intermediate 25

The title compound was synthesized according to the procedure described for intermediate 1 from ethyl 2-(l-bromo-2-ethoxy-2-oxoethyl)benzoate (492 mg, 1.6 mmol), 2-(3- fluoropyridin-2-yl)ethanamine (218 mg, 1.6 mmol) and triethylamine (323 mg, 3.2 mmol) in acetonitrile (5 mL). Solid, 160 mg (33.8 %).

¹H NMR (400 MHz, CDCl₃) δ (ppm) 8.26 (d, 1 H) 7.78 (d, 1 H) 7.37 - 7.47 (m, 2 H) 7.28 - 7.36 (m, 2 H) 7.02 - 7.15 (m, 1 H) 5.33 (s, 1 H) 4.13 - 4.26 (q, 2 H) 2.83 - 3.10 (m, 4 H) 1.38 (t, 3 H). MS (ESI) m/z 329 [M+H].

Example 1-26

2-(2-(3-Fluoropyridin-2-yl)ethyl)-3-oxoisoindoline-l-carboxylic acid

Intermediate 26

A solution of lithium hydroxide (10 mg, 0.41 mmol) in water (3 mL) was added to the stirred solution of ethyl 2-(2-(3-fluoropyridin-2-yl)ethyl)-3-oxoisoindoline-l-carboxylate (0.125 g, 0.38 mmol) in tetrahydrofuran (10 mL) at room temperature. The reaction mixture was stirred for 3 hours then concentrated under reduced pressure. The crude residue was redissolved in water (10 mL) and acidified with saturated solution of citric acid and then extracted with ethyl acetate (3x50 mL). The combined organic extract was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give the desired product as white solid, 85 mg (74 %).

¹H NMR (400 MHz, CDCl₃) δ (ppm) 8.24 (d, 1 H) 7.80 (d, 1 H) 7.27 - 7.35 (m, 2 H) 7.22 - 7.31 (m, 2 H) 7.02 - 7.10 (m, 1 H) 5.28 (s, IH) 2.92 - 3.12 (m, 4 H). MS (ESI) m/z 301 [M+H].

Example 1-27

N-O-(T rifluoromethoxy)benzvDfbrmamide

Intermediate 27

The title compound was prepared according to the method described for example 18 using (3-(trifluoromethoxy)phenyl)methanamine (0.2 g, 1.05 mmol) and phenyl formate (0.117 mL, 1.05 mmol). Colorless oil, 120 mg (52 %).

¹H NMR (500 MHz, CDCl₃) δ (ppm) 8.31 (s, 1 H) 7.35 - 7.40 (m, 1 H) 7.22 - 7.26 (m, 1 H) 7.15 (br. s., 2 H) 5.92 (br. s., 1 H) 4.53 (d, 2 H). MS (ESI) m/z 220 [M+H].

Example 1-28 l-fIsocvanomethyl)-3-ftrifluoromethoxy)benzene

Intermediate 28

The title compound was prepared according to the method described for example 19 using N-(3-(trifluoromethoxy)benzyl)formamide (120 mg, 0.55 mmol), N ,N- diisopropylethylamine (0.362 mL, 2.19 mmol) and phosphorus oxychloride (0.061 mL, 0.66 mmol). Brown oil, 110 mg (100 %) which was used without further purification. ¹H NMR (500 MHz, CDCl₃) δ (ppm) 7.43 - 7.49 (m, 1 H) 7.31 (d, 1 H) 7.21 - 7.25 (m, 2 H) 4.69 (s, 2 H). MS (ESI) m/z 202 [M+H].

Example 1-29 N-f2-Methyl-4-ftrifluoromethoxy)benzyl)formamide

O H Intermediate 29

The title compound was prepared according to the method described for example 18 using (2-methyl-4-(trifluoromethoxy)phenyl)methanamine (0.35 g, 1.71 mmol) and phenyl formate (0.191 mL, 1.71 mmol). The crude was purified on silica column using dichloromethane : (dichloromethane/methanol/ammonia 90:10:1) = 100:0 to 30:70 as gradient. White solid, 252 mg (63 %).

¹H NMR (500 MHz, CDCl₃) δ (ppm) 8.28 (s, 1 H) 7.27 (t, 1 H) 7.06 (br. s., 2 H) 5.68 (br. s., 1 H) 4.49 (d, 2 H) 2.36 (s, 3 H). MS (ESI) m/z 232 [M-H].

Example 1-30 l-(Isocvanomethyl)-2-methyl-4-(trifluoromethoxy)benzene

Intermediate 30

The title compound was prepared according to the method described for example 19 using N-(2-methyl-4-(trifluoromethoxy)benzyl)formamide (0.250 g, 1.07 mmol), N₅N- diisopropylethylamine (0.742 mL, 4.29 mmol) and phosphorus oxychloride (0.120 mL, 1.29 mmol). Brown oil, 300 mg (130 %) which was used without further purification. MS (ESI) m/z 216 [M+H]. Example 1-31 4-f2,2,2-Trifluoroethyl)benzonitrile

Intermediate 31

To the DMF (25 niL) solution of l-bromo-4-(2,2,2-trifluoroethyl)benzene (2.15 g, 9.00 mmol) were zinc cyanide (2.11 g, 18.0 mmol) and Pd(PPh₃)₄ (0.828 g, 0.720 mmol) added. The mixture was heated at 100⁰C for 18 hours then cooled to room temperature, diluted with ethyl acetate (50 mL) and filtered through a short bed of celite. The filtrate was concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography using hexane : ethyl acetate = 90: 10 as eluent to give the title compound as a white solid, 800 mg (48%).

¹H NMR (400 MHz, CDCl₃) δ (ppm) 7.67 (d, 2 H) 7.43 (d, 2 H) 3.44 (q, 2 H). ¹⁹F NMR (400 MHz, CDCl₃) δ (ppm) -65.85, -65.88 and -65.91. MS (ESI) m/z 186 [M+H].

Example 1-32

(4-(2,2,2-Trifluor()ethyl)phenyl)methanamine

Intermediate 32

IM borane in tetrahydrofuran (9.40 mL, 9.40 mmol) was added to the tetrahydrofuran (15 mL) solution of 4-(2,2,2-trifluoroethyl)benzonitrile (0.580 g, 3.13 mmol). The mixture was heated at 6O⁰C for 18 hours, cooled to room temperature and concentrated under reduced pressure. The residue was redissolved in methanol (15 mL), refluxed for 2 hours and concentrated under reduced pressure. The crude residue was dissolved in dichloromethane (50 mL), washed with 2M NaOH solution (20 mL), brine (20 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give the title compound as a pale yellow oil, 600 mg (100 %). ¹H NMR (400 MHz, CDCl₃) δ (ppm) 7.27 - 7.34 (m, 4 H) 3.88 (s, 2 H) 3.36 (q, 2H) (NH₂ not shown). ¹⁹F NMR (400 MHz, CDCl₃) δ (ppm) -66.42, -66.45 and -66.48. MS (ESI) m/z 190 [M+H].

Example 1-33

N-f4-f2,2,2-Trifluoroethyl)benzyl)formamide

Intermediate 33

A solution of (4-(2,2,2-trifluoroethyl)phenyl)methanamine (0.650 g, 3.40 mmol) in ethylformate (5 mL) was refluxed for 18 hours. The reaction mixture was concentrated under reduced pressure and the crude residue was purified by silica gel column chromatography using hexane: ethyl acetate = 100:0 to 50:50 as eluent to afford the desired compound as a white solid, 620 mg (84%).

¹H NMR (400 MHz, CDCl₃) δ (ppm) 8.30 (s, 1 H) 7.29 (s, 4 H) 5.77 (m, 1 H) 4.51 (d, 2 H) 3.36 (q, 2 H). ¹⁹F NMR (400 MHz, CDCl₃) δ (ppm) -66.36, -66.39 and -66.41. MS (ESI) m/z 218 [M+H].

Example 1-34 l-Isocvanomethyl-4-f2,2,2-trifluoroethyl)benzene

Intermediate 34

Phosphorus oxychloride (0.320 mL, 3.43 mmol) was added dropwise to a solution of N-(4- (2,2,2-trifluoroethyl)benzyl)formamide (0.620 g, 2.86 mmol) and N₅N- diisopropylethylamine (1.97 mL, 11.4 mmol ) in dichloromethane (20 mL) at -2O⁰C. The mixture was slowly warmed to room temperature and stirred for 16 hours. Afterwards the reaction mixture was concentrated, the residue was dissolved in methanol (3 mL) and triethylamine (2.5 mL) was added. The reaction mixture was stirred for 5 minutes and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography using hexane: ethyl acetate = 100:0 to 80:20 as eluent yielding the title compound as a white solid, 442 mg (78%).

¹H NMR (400 MHz, CDCl₃) δ (ppm) 7.36 (s, 4 H) 4.66 (s, 2 H) 3.39 (q, 2 H). ¹⁹F NMR (400 MHz, CDCl₃) δ (ppm) -66.31, -66.34 and -66.37. MS (ESI) m/z 200 [M+H].

Example 1 (general procedure 1)

N-r^-ChlorophenvDmethyll-S-oxo-l-fl-pyridin-l-ylethyD-lH-isoindole-l- carboxamide

To a solution of 2-formylbenzoic acid (30 mg, 0.20 mmol) in methanol (2 mL) 2-(2- aminoethyl)pyridine (24 μL, 0.20 mmol) was added followed by addition of l-chloro-4- (isocyanomethyl)benzene (27 mg, 0.18 mmol). The reaction mixture was stirred over night at ambient temperature before it was filtered and purified using preparative liquid chromatography. The fractions containing the product were pooled, and the acetonitrile was removed in vacuum. The water solution was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated in vacuum to yield the title compound as white solid, 41 mg (51 %). 1H NMR (400 MHz, CDCl₃) δ ppm 8.95 - 9.04 (m, 1 H), 8.16 (d, 1 H), 7.64 - 7.72 (m, 3 H), 7.54 - 7.60 (m, 1 H), 7.44 - 7.50 (m, 1 H), 7.28 (s, 1 H), 7.11 - 7.21 (m, 3 H), 7.01 - 7.07 (m, 2 H), 5.04 (s, 1 H), 4.30 - 4.47 (m, 2 H), 4.03 - 4.13 (m, 1 H), 3.82 - 3.91 (m, 1 H), 3.12 - 3.23 (m, 1 H), 3.01 - 3.10 (m, 1 H); MS (ESI) m/z 406 [M+H]. Example 2 (general procedure 2)

3-Oxo-2-f2-pyridin-2-ylethyl)-N-[[4-ftrifluoromethoxy)phenyllmethyll-lH-isoindole-

1-carboxamide

To a solution of 3-oxo-2-(2-pyridin-2-ylethyl)-lH-isoindole-l-carboxylic acid (56 mg, 0.2 mmol) in DMF (1.5mL), triethylamine (84 μL, 0.6 mmol) and fluoro-N,N,N',N'- tetramethylformamidinium hexafluorophosphate (79 mg, 0.3 mmol) were added sequentially. The reaction mixture was stirred at ambient temperature for 5-10 minutes. A- Trifluoromethoxy-benzylamine (152 μL, 1 mmol) was added, and the mixture was stirred at 45 ⁰C for 2.5 h. The mixture was filtered and purified using preparative liquid chromatography. The fractions containing the product were pooled, and the acetonitrile was removed in vacuum. The water solution was basified with saturated solution of sodium bicarbonate and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated in vacuum to yield the title compound as white solid, 15 mg (16 %).

¹H NMR (400 MHz, CDCl₃) δ ppm 9.11 - 9.19 (m, 1 H), 8.13 (d, 1 H), 7.66 - 7.75 (m, 3 H), 7.54 - 7.60 (m, 1 H), 7.47 (t, 1 H), 7.31 (d, 1 H), 7.11 - 7.21 (m, 3 H), 7.03 - 7.09 (m, 2 H), 5.09 (s, 1 H), 4.35 - 4.51 (m, 2 H), 4.02 - 4.13 (m, 1 H), 3.83 - 3.94 (m, 1 H), 3.13 - 3.24 (m, 1 H), 3.03 - 3.13 (m, 1 H); MS (ESI) m/z 456 [M+H], MS (ESI) m/z 454 [M-H].

Example 3

3-Oxo-2-f2-pyridin-2-ylethyl)-N-[[4-ftrifluoromethoxy)phenyllmethyll-lH-isoindole- 1-carboxamide, ISOMER 1

ISOMER 1 a = unknown absolute

The enantiopure compound was obtained by chiral separation of the racemic compound 3- oxo-2-(2-pyridin-2-ylethyl)-N-[[4-(trifluoromethoxy)phenyl]methyl]-lH-isoindole-l- carboxamide using LaPrep system; Column: Chiralpak AD; 50 x 300 mm, 10 μm; Mobile phase: 40 % ethanol / 60 % heptane then 100 % ethanol after 9 min; Flowrate: 120 mL/min, 170 mg/inj. The fractions were collected according to retention times yielding ISOMER 1 as the first eluting fraction at 13.3 min. The fraction were evaporated at 23 - 25 ⁰C in order to avoid thermo racemisation, and handled separately. Analytical LC analysis were conducted using a Gilson system; Column: Chiralpak AD, 4.6x250 mm, lOμm; Mobilphase: 100 % ethanol; Flowrate: 1 mL/min. ISOMER 1 (5.5 min): 134 mg. Enantiopurity 99 %.

¹H NMR (400 MHz, DMSO-J₆) δ ppm 9.19 (t, 1 H), 8.43 - 8.47 (m, 1 H), 7.66 - 7.71 (m, 2 H), 7.57 - 7.63 (m, 1 H), 7.48 - 7.56 (m, 2 H), 7.35 - 7.40 (m, 2 H), 7.29 - 7.34 (m, 2 H), 7.26 (d, 1 H), 7.19 - 7.24 (m, 1 H), 5.24 (s, 1 H), 4.36 (d, 2 H), 4.15 - 4.25 (m, 1 H), 3.37 - 3.45 (m, 1 H), 3.04 - 3.14 (m, 1 H), 2.95 - 3.05 (m, 1 H); MS (APCI/APPI) m/z 456 [M+H]. Example 4

3-Oxo-2-(2-pyridin-2-ylethyl)-N-rr4-(trifluoromethyl)phenyllmethyll-lH-isoindole-l- carboxamide

The title compound was synthesized according to the general procedure 2, described in example 2, from 3-oxo-2-(2-pyridin-2-ylethyl)-lH-isoindole-l-carboxylic acid (56 mg, 0.2 mmol) and 4-trifluoromethyl-benzylamine (142 μL, 1 mmol). White solid, 17 mg (19 %). ¹H NMR (400 MHz, CDCl₃) δ ppm 9.28 - 9.35 (m, 1 H), 8.10 - 8.14 (m, 1 H), 7.66 - 7.73 (m, 3 H), 7.55 - 7.61 (m, 1 H), 7.44 - 7.51 (m, 3 H), 7.30 (d, 1 H), 7.20 (d, 2 H), 7.13 - 7.17 (m, 1 H), 5.07 (s, 1 H), 4.51 - 4.59 (m, 1 H), 4.37 - 4.45 (m, 1 H), 4.06 - 4.17 (m, 1 H), 3.81 - 3.89 (m, 1 H), 3.14 - 3.24 (m, 1 H), 3.02 - 3.11 (m, 1 H); MS (ESI) m/z 440 [M+H], MS (ESI) m/z 438 [M-H].

Example 5 3-Oxo-2-fpyridin-3-ylmethyl)-N-[[4-ftrifluoromethoxy)phenyllmethyll-lH-isoindole- 1-carboxamide

3-Oxo-2-(pyridin-3-ylmethyl)-lH-isoindole-l-carboxylic acid (268 mg, 1 mmol) was dissolved in a mixture of dichloromethane and DMF (15 mL and 2 mL). Triethylamine (556 μL, 4 mmol), N^'-dicyclohexylcarbodiimide (412 mg, 2 mmol), and 1- hydroxybenzotriazole (270 mg, 2 mmol) were added sequentially, and the mixture was stirred at ambient temperature for 5 min. 4-Trifluoromethoxy-benzylamine (152 μL, 1 mmol) was added, and the resulting mixture was stirred at ambient temperature for 24 h. The mixture was diluted with ethyl acetate (25 mL) and extracted with saturated solution of sodium bicarbonate and then brine. The organic layer was collected, dried over magnesium sulfate and concentrated. The crude product was purified by column chromatography on silica gel using a gradient of chloroform in methanol as an eluent to yield the title compound, 166 mg (38 %).

¹H NMR (400 MHz, CDCl₃) δ ppm 8.57 (br. s., 1 H), 8.54 (d, 1 H), 7.71 (d, 1 H), 7.62 - 7.67 (m, 1 H), 7.57 - 7.62 (m, 2 H), 7.46 - 7.51 (m, 1 H), 7.23 - 7.27 (m, 1 H), 7.09 - 7.16 (m, 4 H), 6.42 - 6.50 (m, 1 H), 5.28 (d, 1 H), 4.94 (s, 1 H), 4.36 - 4.40 (m, 2 H), 4.28 (d, 1 H); MS (ESI) m/z 442 [M+H], MS (ESI) m/z 440 [M-H].

Example 6

N-ri-H-ChlorophenvDethyll-S-oxo-l-α-pyridin-l-ylethvD-lH-isoindole-l- carboxamide

The title compound was synthesized according to the general procedure 1 , described in example 1, from 2-formylbenzoic acid (30 mg, 0.20 mmol), 2-(2-aminoethyl)pyridine (24 μL, 0.20 mmol), and l-chloro-4-(l-isocyanoethyl)benzene (30 mg, 0.18 mmol). White solid, 35 mg (41 %). 1H NMR (400 MHz, CDCl₃) δ ppm 8.56 - 8.82 (m, 1 H), 8.03 - 8.30 (m, 1 H), 7.57 - 7.65 (m, 2 H), 7.45 - 7.51 (m, 1 H), 7.42 - 7.45 (m, 1 H), 7.35 - 7.41 (m, 1 H), 7.20 - 7.26 (m, 1 H), 7.15 - 7.18 (m, 1 H), 7.06 - 7.14 (m, 1 H), 7.01 - 7.05 (m, 1 H), 6.77 - 6.83 (m, 1 H), 4.96 - 5.11 (m, 1 H), 4.91 (d, 1 H), 3.72 - 4.07 (m, 2 H), 2.84 - 3.29 (m, 2 H), 1.27 - 1.40 (m, 3 H); MS (ESI) m/z 420 [M+H]. Example 7

3-Oxo-2-( 2-pyrazin-2-ylethyl)-N- [ \4-( trifluoromethoxy)phenyll methyll - lH-isoindole-

1-carboxamide

The title compound was synthesized according to the general procedure 1 , described in example 1, from 2-formylbenzoic acid (75 mg, 0.50 mmol), 2-pyrazin-2-yl-ethylamine (61mg, 0.50 mmol) and l-(isocyanomethyl)-4-(trifluoromethoxy)benzene (100 mg, 0.50 mmol). White solid, 116 mg (50 %). 1H NMR (400 MHz, CDCl₃) δ ppm 8.58 (s, 1 H), 8.47 (s, 1 H), 8.18 (s, 1 H), 7.97 - 8.05 (m, 1 H), 7.68 (d, 1 H), 7.64 (d, 1 H), 7.56 - 7.62 (m, 1 H), 7.43 - 7.50 (m, 1 H), 7.10 - 7.17 (m, 2 H), 7.04 - 7.10 (m, 2 H), 5.10 (s, 1 H), 4.37 - 4.45 (m, 2 H), 3.91 - 4.08 (m, 2 H), 3.09 - 3.23 (m, 2 H), 1.90 (br. s., 1 H); MS (ESI) m/z 457 [M+H], MS (ESI) m/z 455 [M- H].

Example 8

2- \( 2-Methoxypyridin-3-yl)methyll -3-oxo-N- [ \4-( trifluoromethoxy)phenyll methyll - lH-isoindole-1-carboxamide

The title compound was synthesized according to the general procedure 1 , described in example 1, from 2-formylbenzoic acid (38 mg, 0.25 mmol), (2-methoxy-pyridin-3-yl)- methylamine (35 mg, 0.25 mmol, prepared according to WO2006/097489), and 1- (isocyanomethyl)-4-(trifluoromethoxy)benzene (50 mg, 0.25 mmol). White solid, 18 mg (15 %). ¹H NMR (400 MHz, DMSO-J₆) δ ppm 9.13 (t, 1 H), 8.08 - 8.13 (m, 1 H), 7.74 (d, 1 H), 7.59 - 7.65 (m, 1 H), 7.51 - 7.58 (m, 2 H), 7.44 - 7.50 (m, 1 H), 7.30 - 7.39 (m, 4 H), 6.90 - 6.97 (m, 1 H), 5.09 (s, 1 H), 4.97 (d, 1 H), 4.30 - 4.41 (m, 2 H), 4.17 (d, 1 H), 3.84 (s, 3 H); MS (ESI) m/z All [M+H], MS (ESI) m/z 470 [M-H].

Example 9

3-Oxo-2-( pyrazin-2-ylmethyl)-N- [ \4-( trifluoromethoxy)phenyll methyll - lH-isoindole-

1-carboxamide

The title compound was synthesized according to the general procedure 1 , described in example 1, from 2-formylbenzoic acid (75 mg, 0.50 mmol), pyrazin-2-yl-methylamine (72 mg, 0.50 mmol), and l-(isocyanomethyl)-4-(trifluoromethoxy)benzene (100 mg, 0.50 mmol). White solid, 20 mg (9 %).

¹H NMR (400 MHz, DMSO-J₆) δ ppm 9.17 - 9.23 (m, 1 H), 8.67 - 8.69 (m, 1 H), 8.54 - 8.57 (m, 2 H), 7.73 - 7.78 (m, 1 H), 7.61 - 7.67 (m, 1 H), 7.53 - 7.59 (m, 2 H), 7.29 - 7.38 (m, 4 H), 5.31 (s, 1 H), 5.24 (d, 1 H), 4.41 (d, 1 H), 4.34 (d, 2 H); MS (ESI) m/z 443 [M+H], MS (ESI) m/z 441 [M-H].

Example 10 3-Oxo-2-α-pyridin-2-ylethyl)-N-ri-r4-q,2,2-trifluoroethoxy)phenyllethyll-lH- isoindole-1-carboxamide

The titled compound was prepared according to the general procedure 2, described in example 2, from 3-oxo-2-(2-pyridin-2-ylethyl)-lH-isoindole-l-carboxylic acid (56 mg, 0.2 mmol) and l-[4-(2,2,2-trifluoro-ethoxy)-phenyl]-ethylamine (prepared according to WO 2007/073303, 150 mg, 0.60 mmol). White solid, 13 mg (13 %). 1H NMR (400 MHz, CDCl₃) δ ppm 8.64, 8.47 (d + d, 1 H), 8.36, 8.13 (d + d, 1 H), 7.42 - 7.73 (m, 5 H), 7.22 - 7.34 (m, 2 H), 7.11 - 7.22 (m, 1 H), 6.90 - 6.96 (m, 1 H), 6.82 - 6.88 (m, 1 H), 6.68 - 6.75 (m, 1 H), 5.04 - 5.17 (m, 1 H), 5.03, 4.95 (s + s, 1 H), 4.24 - 4.35 (m, 2 H), 4.01 - 4.11, 3.90 - 4.00, 3.81 - 3.90 (m + m +m, 2 H), 3.26 - 3.36, 3.03 - 3.14, 2.90 - 3.01 (m + m + m, 2 H), 1.47, 1.39 (d + d, 3 H); MS (ESI) m/z 484 [M+H], MS (ESI) m/z 482 [M-H].

Example 11

2-[f5-Methyll,2-oxazol-3-yl)methyll-3-oxo-N-[[4-ftrifluoromethoxy)phenyllmethyll- lH-isoindole-1-carboxamide

The title compound was synthesized according to the general procedure 1 , described in example 1, from 2-formylbenzoic acid (38 mg, 0.25 mmol), 5-methyl-isoxazol-3-yl- methylamine (29 mg, 0.25 mmol), and l-(isocyanomethyl)-4-(trifluoromethoxy)benzene (50 mg, 0.25 mmol). White solid, 41 mg (37 %).

¹H NMR (400 MHz, DMSO-J₆) δ ppm 9.21 (t, 1 H), 7.73 - 7.78 (m, 1 H), 7.61 - 7.67 (m, 1 H), 7.53 - 7.59 (m, 2 H), 7.35 - 7.40 (m, 2 H), 7.30 - 7.34 (m, 2 H), 6.17 - 6.21 (m, 1 H), 5.20 (s, 1 H), 5.13 (d, 1 H), 4.36 (d, 2 H), 4.17 (d, 1 H), 2.36 (s, 3 H); MS (ESI) m/z 446 [M+H], MS (ESI) m/z 444 [M-H]. Example 12

N-[f4-Chlorophenyl)methyll-3-oxo-2-f2-pyrazin-2-ylethyl)-lH-isoindole-l- carboxamide

The title compound was synthesized according to the general procedure 1 , described in example 1, from 2-formylbenzoic acid (30 mg, 0.20 mmol), 2-(pyrazin-2-yl)ethanamine (25 mg, 0.20 mmol), and l-chloro-4-(isocyanomethyl)benzene (27 mg, 0.18 mmol). White solid, 36 g (44 %).

¹H NMR (400 MHz, CDCl₃) δ ppm 8.55 (s, 1 H), 8.43 - 8.49 (m, 1 H), 8.18 - 8.23 (m, 1 H), 7.83 - 7.92 (m, 1 H), 7.62 - 7.71 (m, 2 H), 7.56 - 7.61 (m, 1 H), 7.44 - 7.50 (m, 1 H), 7.16 - 7.22 (m, 2 H), 7.00 - 7.05 (m, 2 H), 5.07 (s, 1 H), 4.38 (d, 2 H), 3.90 - 4.08 (m, 2 H), 3.07 - 3.22 (m, 2 H); MS (ESI) m/z 407 [M+H].

Example 13

N-ri-(4-Chlorophenyl)ethyll-3-oxo-2-(2-pyrazin-2-ylethyl)-lH-isoindole-l- carboxamide

The title compound was synthesized according to the general procedure 1 , described in example 1, from 2-formylbenzoic acid (30mg, 0.20 mmol), 2-(pyrazin-2-yl)ethanamine (25 mg, 0.20 mmol), and l-chloro-4-(l-isocyanoethyl)benzene (30 mg, 0.18 mmol). White solid, 50 mg (59 %).

¹H NMR (400 MHz, CDCl₃) δ ppm 8.59 (d, 1 H), 8.50 (br. s., 1 H), 8.27 (d, 1 H), 7.79 (d, 1 H), 7.65 - 7.71 (m, 1 H), 7.58 - 7.63 (m, 1 H), 7.54 - 7.58 (m, 1 H), 7.44 - 7.51 (m, 1 H), 7.25 - 7.27 (m, 2 H), 7.10 - 7.15 (m, 1 H), 6.84 - 6.90 (m, 1 H), 5.00 - 5.16 (m, 2 H), 3.82 - 4.13 (m, 2 H), 3.15 - 3.36 (m, 1 H), 3.03 - 3.13 (m, 1 H), 1.33 - 1.47 (m, 3 H); MS (ESI) m/z 421 [M+H].

Example 14 N-ri-H-ChlorophenvDethyll-S-oxo-l-fpyridin-S-ylmethvD-lH-isoindole-l- carboxamide

The title compound was synthesized according to the general procedure 1 , described in example 1, from 2-formylbenzoic acid (30 mg, 0.20 mmol), 3-(aminomethyl)pyridine (20 μL, 0.20 mmol), and l-chloro-4-(l-isocyanoethyl)benzene (33 g, 0.20 mmol). White solid,

35 mg (43 %).

¹H NMR (400 MHz, DMSO-J₆) δ ppm 9.04 - 9.17 (m, 1 H), 8.49 - 8.54 (m, 1 H), 7.71 -

7.78 (m, 1 H), 7.62 - 7.70 (m, 1 H), 7.49 - 7.61 (m, 3 H), 7.38 - 7.45 (m, 2 H), 7.32 - 7.38 (m, 3 H), 7.27 - 7.31 (m, 1 H), 5.08 - 5.15 (m, 1 H), 5.02 - 5.06 (m, 1 H), 4.84 - 4.94 (m, 1

H), 4.00 - 4.20 (m, 1 H), 1.34 - 1.41 (m, 3 H); MS (ESI) m/z 406 [M+H]. Example 15

N-[f4-Fluorophenyl)methyll-3-oxo-2-f2-pyridin-2-ylethyl)-lH-isoindole-l- carboxamide

The title compound was synthesized according to the general procedure 2, described in example 2, from 3-oxo-2-(2-pyridin-2-ylethyl)-lH-isoindole-l-carboxylic acid (56 mg, 0.2 mmol) and 4-fluoro-benzylamine (165 μL, 2 mmol). Yellowish solid, 13 mg (16 %). 1H NMR (400 MHz, CDCl₃) δ ppm 8.76 - 8.85 (m, 1 H), 8.16 (d, 1 H), 7.70 (d, 2 H), 7.63 - 7.68 (m, 1 H), 7.54 - 7.59 (m, 1 H), 7.47 (t, 1 H), 7.23 - 7.26 (m, 1 H), 7.10 - 7.16 (m, 1 H), 7.04 - 7.10 (m, 2 H), 6.86 - 6.92 (m, 2 H), 5.02 (s, 1 H), 4.35 - 4.41 (m, 2 H), 4.01 - 4.11 (m, 1 H), 3.84 - 3.93 (m, 1 H), 3.12 - 3.21 (m, 1 H), 3.00 - 3.08 (m, 1 H); MS (ESI) m/z 390 [M+H], MS (ESI) m/z 388 [M-H].

Example 16

3-Oxo-2-α-pyridin-2-ylethyl)-N-rr4-q,2,2-trifluoroethoxy)phenyllmethyll-lH- isoindole-1-carboxamide

The title compound was synthesized according to the general procedure 2, described in example 2, from 3-oxo-2-(2-pyridin-2-ylethyl)-lH-isoindole-l-carboxylic acid (67 mg, 0.24 mmol) and (4-(2,2,2-trifluoroethoxy)phenyl)methanamine (73 mg, 0.36 mmol). Yellowish solid, 11 mg (10 %). ¹H NMR (400 MHz, DMSO-J₆) δ ppm 9.11 (t, 1 H), 8.43 - 8.49 (m, 1 H), 7.62 - 7.72 (m, 2 H), 7.54 - 7.63 (m, 1 H), 7.47 - 7.55 (m, 2 H), 7.17 - 7.26 (m, 4 H), 6.95 - 7.03 (m, 2 H), 5.22 (s, 1 H), 4.72 (q, 2 H), 4.28 (d, 2 H), 4.14 - 4.25 (m, 1 H), 3.35 - 3.46 (m, 1 H), 2.93 - 3.12 (m, 2 H); MS (ESI) m/z 470 [M+H], MS (ESI) m/z 468 [M-H].

Example 17

2-[3-f3-Methyl-lH-pyrazol-l-yl)propyll-3-oxo-N-[4- (trifluoromethoxy)benzyllisoindoline -1-carboxamide

The title compound was synthesized according to the general procedure 1 , described in example 1, from 2-formylbenzoic acid (30 mg, 0.20 mmol), 3-(3-methyl-lH-pyrazol-l- yl)propan-l -amine (28 mg, 0.20 mmol), and l-(isocyanomethyl)-4- (trifluoromethoxy)benzene (40 mg, 0.20 mmol). Solid, 44 mg (47 %). 1H NMR (400 MHz, OMSO-d6) δ ppm 9.14 - 9.22 (m, 1 H), 7.67 - 7.73 (m, 1 H), 7.58 - 7.65 (m, 1 H), 7.49 - 7.58 (m, 3 H), 7.29 - 7.38 (m, 4 H), 5.95 (d, 1 H), 5.32 (s, 1 H), 4.34 (d, 2 H), 3.99 - 4.06 (m, 2 H), 3.73 - 3.84 (m, 1 H), 2.97 - 3.08 (m, 1 H), 2.10 (s, 3 H), 1.94 - 2.08 (m, 2 H); MS (ESI) m/z 473 [M+H], MS (ESI) m/z 471 [M-H].

Example 18

2-fl-Methyl-2-pyridin-2-ylethyl)-3-oxo-N-[4-ftrifluoromethoxy)benzyllisoindoline-l- carboxamide

The title compound was prepared according to the general procedure 2, described in example 2, from 2-(l-methyl-2-pyridin-2-ylethyl)-3-oxoisoindoline-l-carboxylic acid (89 mg, 0.30 mmol) and (4-(trifluoromethoxy)phenyl)methanamine (172 mg, 0.90 mmol). Solid, 77 mg (55%).

¹H NMR (400 MHz, DMSO-J₆) δ ppm 9.32, 9.25 (t + t, 1 H), 8.45 - 8.48, 8.32 - 8.36 (m + m, 1 H), 7.54 - 7.70 (m, 3 H), 7.43 - 7.54 (m, 2 H), 7.41 (dd, 2 H), 7.28 - 7.36 (m, 2 H), 7.12 - 7.24 (m, 2 H), 5.41, 5.04 (s + s, 1 H), 4.62 - 4.72, 4.26 - 4.44, 4.07 - 4.15 (m + m + m, 3 H), 3.26 - 3.33, 2.88 (m + dd, 2 H), 3.12 (d, 1 H), 1.33, 1.14 (d + d, 3 H); MS (APCI/APPI) m/z 470 [M+H].

Example 19

2-fl-Methyl-2-pyridin-2-ylethyl)-3-oxo-N-[4-ftrifluoromethoxy)benzyllisoindoline-l- carboxamide, ISOMER 3

ISOMER 3 f = unknown absolute e = unknown absolute The enantiopure compound was obtained by chiral separation of the racemic compound 2- (1 -methyl-2-pyridin-2-ylethyl)-3-oxo-N-[4-(trifluoromethoxy)benzyl]isoindoline- 1 - carboxamide using SFC Berger Multigram II system; Column: Chiralpak AD, 20 x 250 mm, 10μm; Mobile phase: 25 % isopropyl alcohol + diethylamine / 75 % CO₂; Flowrate: 50 niL/min, 15 mg/inj. The fractions were collected accordind to retention times yielding ISOMER 3 as the third fraction eluting at 6.1 min. The fraction were evaporated at 23 - 25 ⁰C in order to avoid thermo racemisation and handled separately. Analytical LC analysis were conducted using Berger SFC Analytix; Column: Chiralpak AD, 4.6 x 250 mm, 10 μm; Mobile phase: 30 % isopropyl alcohol + diethylamine / 70 % CO₂; Flowrate: 2 mL/min; ISOMER 3 (5.43 min), 13 mg, enantiopurity: 99 %.

¹H NMR (400 MHz, COCh-d) δ ppm 8.66 - 8.75 (m, 1 H), 8.02 (d, 1 H), 7.74 (d, 1 H), 7.67 (d, 1 H), 7.58 - 7.64 (m, 1 H), 7.55 (td, 1 H), 7.45 (t, 1 H), 7.32 (d, 1 H), 7.12 - 7.17 (m, 2 H), 7.06 - 7.10 (m, 2 H), 6.98 - 7.05 (m, 1 H), 5.20 (s, 1 H), 4.45 - 4.51 (m, 1 H), 4.39 - 4.45 (m, 1 H), 4.31 - 4.39 (m, 1 H), 4.09 (dd, 1 H), 3.20 (dd, 1 H), 1.44 (d, 3 H); MS (ESI) m/z 470 [M+H], MS (ESI) m/z 468 [M-H].

Example 20

2-fl-Methyl-2-pyridin-2-ylethyl)-3-oxo-N-[4-ftrifluoromethoxy)benzyllisoindoline-l- carboxamide, ISOMER 4

ISOMER 4 h = unknown absolute g = unknown absolute

The enantiopure compound was obtained by chiral separation of the racemic compound 2- (1 -methyl-2-pyridin-2-ylethyl)-3-oxo-N-[4-(trifluoromethoxy)benzyl]isoindoline- 1 - carboxamide using the method in the previous example. The fractions were collected according to retention times yielding ISOMER 4 as the fourth fraction eluting at 6.5 min. Analytical LC analysis were conducted as above: ISOMER 4 (6.09 min), 14 mg, enantiopurity: 98 %.

¹H NMR (400 MHz, COCh-d) δ ppm 10.72 (t, 1 H), 7.82 - 7.88 (m, 1 H), 7.70 - 7.73 (m, 1 H), 7.65 - 7.70 (m, 1 H), 7.61 - 7.65 (m, 1 H), 7.56 (td, 1 H), 7.46 (t, 1 H), 7.29 - 7.33 (m, 1 H), 7.04 - 7.11 (m, 3 H), 6.98 - 7.04 (m, 2 H), 5.19 (s, 1 H), 4.64 - 4.74 (m, 1 H), 4.53 (dd, 1 H), 4.31 (dd, 1 H), 3.02 (dd, 1 H), 2.86 (dd, 1 H), 1.50 (d, 3 H); MS (ESI) m/z 470 [M+H], MS (ESI) m/z 468 [M-H].

Example 21 4-Methoxy-3-oxo-2-f2-pyridin-2-ylethyl)-7V-[4-ftrifluoromethoxy)benzyllisoindoline-l- carboxamide

The title compound was prepared according to the general procedure 2, described in example 2, from 4-methoxy-3-oxo-2-(2-pyridin-2-ylethyl)isoindo line- 1-carboxylic acid (0.468 g, 1.50 mmol) and (4-(trifluoromethoxy)phenyl)methanamine (0.717 g, 3.75 mmol) but stirred at ambient temperature for 40 min. Purification by preparative liquid chromatography or column chromatography using a gradient of chloroform/methanol/ammonia (7 M in methanol) 90/9/1, in chloroform (0-100 %) yielded a solid, 0.491 g (67 %). 1H NMR (400 MHz, DMSO-J₆) δ ppm 9.13 (t, 1 H), 8.42 - 8.47 (m, 1 H), 7.69 (td, 1 H), 7.51 (t, 1 H), 7.33 - 7.39 (m, 2 H), 7.27 - 7.33 (m, 2 H), 7.18 - 7.26 (m, 2 H), 7.05 (d, 2 H), 5.11 (s, 1 H), 4.34 (d, 2 H), 4.08 - 4.18 (m, 1 H), 3.83 (s, 3 H), 3.27 - 3.36 (m, 1 H), 3.00 - 3.09 (m, 1 H), 2.88 - 2.99 (m, 1 H); MS (ESI) m/z 486 [M+H], MS (ESI) m/z 484 [M-H]. Example 22

3-Oxo-2-f2-pyridin-4-ylethyl)-7V-[4-ftrifluoromethoxy)benzyllisoindoline-l- carboxamide

The title compound was prepared according to the general procedure 2, described in example 2, from 3-oxo-2-(2-pyridin-4-ylethyl)isoindoline-l-carboxylic acid (56 mg, 0.20 mmol) and (4-(trifluoro- methoxy)phenyl)methanamine (76 mg, 0.40 mmol) to yield a solid, 19 mg (21 %). 1H NMR (400 MHz, DMSO-J₆) δ ppm 9.17 (t, 1 H), 8.37 - 8.47 (m, 2 H), 7.67 (d, 1 H), 7.58 - 7.63 (m, 1 H), 7.49 - 7.56 (m, 2 H), 7.30 - 7.40 (m, 4 H), 7.20 - 7.24 (m, 2 H), 5.19 (s, 1 H), 4.36 (d, 2 H), 4.09 - 4.19 (m, 1 H), 3.22 - 3.32 (m, 1 H), 2.92 - 3.01 (m, 1 H), 2.82 - 2.91 (m, 1 H); MS (ESI) m/z 456 [M+H], MS (ESI) m/z 454 [M-H].

Example 23 3-Oxo-2-f2-pyridin-3-ylethyl)-7V-[4-ftrifluoromethoxy)benzyllisoindoline-l- carboxamide

The title compound was prepared according to the general procedure 2, described in example 2, from 3-oxo-2-(2-pyridin-3-ylethyl)isoindoline-l-carboxylic acid (56 mg, 0.20 mmol) and (4-(trifluoro- methoxy)phenyl)methanamine (76 mg, 0.40 mmol) to yield a solid, 13 mg (14 %). ¹H NMR (400 MHz, DMSO-J₆) δ ppm 9.18 (t, 1 H), 8.36 - 8.45 (m, 2 H), 7.66 (d, 1 H), 7.58 - 7.64 (m, 2 H), 7.48 - 7.56 (m, 2 H), 7.31 - 7.41 (m, 4 H), 7.28 (dd, 1 H), 5.22 (s, 1 H), 4.30 - 4.42 (m, 2 H), 4.07 - 4.17 (m, 1 H), 3.20 - 3.29 (m, 1 H), 2.92 - 3.01 (m, 1 H), 2.80 - 2.91 (m, 1 H); MS (ESI) m/z 456 [M+H], MS (ESI) m/z 454 [M-H].

Example 24

2-fl-Methyl-2-pyridin-2-ylethyl)-3-oxo-7V-[4-ftrifluoromethyl)benzyllisoindoline-l- carboxamide

The title compound was prepared according to the general procedure 2, described in example 2, from 2-(l-methyl-2-pyridin-2-ylethyl)-3-oxoisoindoline-l-carboxylic acid (30 mg, 0.10 mmol) and (4-(trifluoromethyl)phenyl)methanamine (44 mg, 0.25 mmol) to yield 14 mg (30 %).

¹H NMR (600 MHz, DMSO-J₆) δ ppm 9.34, 9.27 (t + 1, 1 H), 8.46, 8.33 (dd + dd, 1 H), 7.67 - 7.70 (m, 2 H), 7.56 - 7.67 (m, 3 H), 7.43 - 7.53 (m, 4 H), 7.18 - 7.23 (m, 1 H), 7.11 - 7.16 (m, 1 H), 5.41, 5.04 (s + s, 1 H), 4.63 - 4.70, 4.29 - 4.36 (m + m, 1 H), 4.40 - 4.47 (m, 2 H), 3.26 - 3.30, 3.12, 2.86 (m + d + dd, 2 H), 1.33, 1.15 (d + d, 3 H); MS (ESI) m/z 454 [M+H]. Example 25 TV-^-ChlorobenzvD-l-fl-methyl-l-pyridin-l-ylethvD-S-oxoisoindoline-l-carboxamide

The title compound was prepared according to the general procedure 2, described in example 2, from 2-(l-methyl-2-pyridin-2-ylethyl)-3-oxoisoindoline-l-carboxylic acid (30 mg, 0.10 mmol) and (4-chlorophenyl)methanamine (35 mg, 0.25 mmol) to yield 10 mg (23 %).

¹H NMR (600 MHz, DMSO-J₆) δ ppm 9.27, 9.21 (t + 1, 1 H), 8.46, 8.34 (dd + dd, 1 H), 7.54 - 7.68 (m, 3 H), 7.40 - 7.52 (m, 2 H), 7.36 - 7.40 (m, 2 H), 7.27 - 7.32 (m, 2 H), 7.17 - 7.21 (m, 1 H), 7.12 - 7.16 (m, 1 H), 5.39, 5.02 (s + s, 1 H), 4.63 - 4.69, 4.28 - 4.38 (m, 3 H), 3.26 - 3.30, 3.11, 2.87 (m + d + dd, IH), 1.33, 1.14 (d + d, 3 H); MS (ESI) m/z 420 [M+H].

Example 26

2-r2-αH-Indol-3-yl)ethyll-3-oxo-7V-r4-qrifluoromethoxy)benzyllisoindoline-l- carboxamide

The title compound was synthesized according to the general procedure 1 , described in example 1, from 2-formylbenzoic acid (35 mg, 0.23 mmol), 2-(lΗ-indol-3-yl)ethanamine (37 mg, 0.23 mmol) and l-(isocyanomethyl)-4-(trifluoromethoxy)benzene (47 mg, 0.23 mmol) to yield 41 mg (35 %). ^1H NMR (600 MHz, DMSO-J₆) δ ppm 9.16 (t, 1 H), 7.71 (d, 1 H), 7.59 - 7.62 (m, 1 H), 7.50 - 7.56 (m, 3 H), 7.32 - 7.37 (m, 3 H), 7.26 - 7.30 (m, 2 H), 7.14 (d, 1 H), 7.05 - 7.09 (m, 1 H), 6.93 - 6.97 (m, 1 H), 5.29 (s, 1 H), 4.32 - 4.39 (m, 2 H), 4.13 - 4.19 (m, 1 H), 3.25 - 3.30 (m, 1 H), 3.03 - 3.09 (m, 1 H), 2.92 - 3.00 (m, 1 H); MS (ESI) m/z 494 [M+H].

Example 27 7V-f4-Methoxybenzyl)-3-oxo-2-f2-pyridin-2-ylethyl)isoindoline-l-carboxamide

The title compound was synthesized according to the general procedure 1 , described in example 1, from 2-formylbenzoic acid (35 mg, 0.23 mmol), 2-(2-aminoethyl)pyridine (28 mg, 0.23 mmol) and l-(isocyanomethyl)-4-methoxybenzene (31 mg, 0.21 mmol) to yield

20 mg (22 %).

¹H NMR (600 MHz, DMSO-J₆) δ ppm 9.08 (t, 1 H), 8.45 - 8.47 (m, 1 H), 7.64 - 7.71 (m, 2

H), 7.59 (td, 1 H), 7.48 - 7.53 (m, 2 H), 7.24 (d, 1 H), 7.19 - 7.23 (m, 1 H), 7.16 - 7.20 (m, 2 H), 6.85 - 6.89 (m, 2 H), 5.22 (s, 1 H), 4.26 (d, 2 H), 4.17 - 4.23 (m, 1 H), 3.72 (s, 3 H),

3.37 - 3.43 (m, 1 H), 3.06 - 3.12 (m, 1 H), 2.96 - 3.02 (m, 1 H); MS (ESI) m/z 402 [M+H].

Example 28

4-Methoxy-2-fl-methyl-2-pyridin-2-ylethyl)-3-oxo-7V-[4-ftrifluoromethoxy)benzyll- isoindoline-1-carboxamide

The title compound was prepared according to the general procedure 2, described in example 2, from 4-methoxy-2-(l-methyl-2-pyridin-2-ylethyl)-3-oxoisoindoline-l- carboxylic acid (82 mg, 0.25 mmol) and (4-(trifluoromethoxy)phenyl)methanamine (239 mg, 1.25 mmol) to yield 38 mg (30 %). 1H NMR (400 MHz, DMSO-J₆) δ ppm 9.22, 9.15 (t + 1, 1 H), 8.44 - 8.50, 8.35 - 8.38 (m, 1 H), 7.65 (tt, 1 H), 7.45 - 7.51 (m, 1 H), 7.36 - 7.40 (m, 2 H), 7.27 - 7.34 (m, 2 H), 7.12 - 7.22 (m, 2 H), 7.03 (t, 1 H), 6.96 (dd, 1 H), 5.27, 4.93 (s + s, 1 H), 4.56 - 4.65, 4.25 - 4.41 (m + m, 3 H), 3.84, 3.81 (s + s, 3 H), 3.23, 2.80 (dd + dd, 1 H), 3.06 (d, 1 H), 1.26, 1.08 (d + d, 3 H); MS (ESI) m/z 500 [M+H].

Example 29

7V-f4-Isopropylbenzyl)-2-fl-methyl-2-pyridin-2-ylethyl)-3-oxoisoindoline-l- carboxamide

The title compound was prepared according to the general procedure 2, described in example 2, from 2-(l-methyl-2-pyridin-2-ylethyl)-3-oxoisoindoline-l-carboxylic acid (30 mg, 0.10 mmol) and (4-isopropylphenyl)methanamine (37 mg, 0.25 mmol) to yield 11 mg (27 %). 1H NMR (600 MHz, DMSO-J₆) δ ppm 9.20, 9.14 (t + 1, 1 H), 8.44 - 8.47, 8.33 - 8.36 (m + m, 1 H), 7.59 - 7.67 (m, 2 H), 7.57 (td, 1 H), 7.41 - 7.52 (m, 2 H), 7.17 - 7.22 (m, 5 H), 7.13 - 7.16 (m, 1 H), 5.39, 5.04 (s + s, 1 H), 4.64 - 4.70, 4.24 - 4.36 (m, 3 H), 3.27 - 3.30, 3.11, 2.82 - 2.91 (m + d + m, 3 H), 1.31 - 1.36, 1.15 - 1.20 (m + m, 9 H); MS (ESI) m/z 428 [M+H]. Example 30

7V-r4-Fluoro-3-(trifluoromethyl)benzyll-2-α-methyl-2-pyridin-2-ylethyl)-3- oxoisoindoline -1-carboxamide

The title compound was prepared according to the general procedure 2, described in example 2, from 2-(l-methyl-2-pyridin-2-ylethyl)-3-oxoisoindoline-l-carboxylic acid (30 mg, 0.10 mmol) and (4-fluoro-3-(trifluoromethyl)phenyl)methanamine (48 mg, 0.25 mmol) to yield 3 mg (7 %).

¹H NMR (600 MHz, DMSO-J₆) δ ppm 9.31, 9.24 (t + 1, 1 H), 8.44 - 8.46, 8.31 - 8.33 (m + m, 1 H), 7.58 - 7.68 (m, 4 H), 7.53 - 7.57 (m, 1 H), 7.40 - 7.52 (m, 3 H), 7.17 - 7.21 (m, 1 H), 7.12 - 7.16 (m, 1 H), 5.40, 5.03 (s + s, 1 H), 4.64 - 4.71, 4.27 - 4 .34 (m + m, 1 H), 4.36 - 4.45 (m, 2 H), 3.26 - 3.30, 3.09, 2.86 (m + d + dd, 2 H), 1.32, 1.12 (d + d, 3 H); MS (ESI) m/z 472 [M+H].

Example 31

7V-[3-Fluoro-4-ftrifluoromethyl)benzyll-2-fl-methyl-2-pyridin-2-ylethyl)-3- oxoisoindoline -1-carboxamide

The title compound was prepared according to the general procedure 2, described in example 2, from 2-(l-methyl-2-pyridin-2-ylethyl)-3-oxoisoindoline-l-carboxylic acid (30 mg, 0.10 mmol) and (3-fluoro-4-(trifluoromethyl)phenyl)methanamine (48 mg, 0.25 mmol) to yield 10 mg (20 %). 1H NMR (600 MHz, DMSO-J₆) δ ppm 9.35, 9.27 (t + t, 1 H), 8.45 - 8.48, 8.32 - 8.34 (m + m, 1 H), 7.74 (t, 1 H), 7.56 - 7.69 (m, 3 H), 7.44 - 7.53 (m, 2 H), 7.28 - 7.34 (m, 2 H), 7.18 - 7.23 (m, 1 H), 7.13 - 7.17 (m, 1 H), 5.42, 5.05 (s + s, 1 H), 4.63 - 4.70, 4.29 - 4.37 (m + m, 1 H), 4.39 - 4.46 (m, 2 H), 3.27 - 3.30, 3.13, 2.87 (m + d + dd, 2 H), 1.33, 1.16 (d + d, 3 H); MS (ESI) m/z 472 [M+H].

Example 32

2-fl-Methyl-2-pyridin-2-ylethyl)-3-oxo-7V-[3-ftrifluoromethoxy)benzyllisoindoline-l- carboxamide

The title compound was prepared according to the general procedure 2, described in example 2, from 2-(l-methyl-2-pyridin-2-ylethyl)-3-oxoisoindoline-l-carboxylic acid (30 mg, 0.10 mmol) and 3-(trifluoromethoxy)benzylamine (48 mg, 0.25 mmol) to yield 13 mg

(28 %).

¹H NMR (600 MHz, DMSO-J₆) δ ppm 9.34, 9.26 (t + t, 1 H), 8.41 - 8.48, 8.30 - 8.35 (m + m, 1 H), 7.58 - 7.68 (m, 2 H), 7.53 - 7.58 (m, 1 H), 7.41 - 7.52 (m, 3 H), 7.28 - 7.32 (m, 1

H), 7.22 - 7.26 (m, 1 H), 7.17 - 7.22 (m, 2 H), 7.12 - 7.17 (m, 1 H), 5.41, 5.04 (s + s, 1 H),

4.65 - 4.71, 4.27 - 4.35 (m, 01 H), 4.36 - 4.43 (m, 2 H), 3.27 - 3.30, 3.10, 2.90 (m + d + dd, 2 H), 1.34, 1.14 (d + d, 3 H); MS (ESI) m/z 470 [M+H]. Example 33 TV-ri-fS-ChlorophenvDethyll-S-oxo-l-fl-pyridin-l-ylethvDisoindoline-l-carboxamide

The title compound was synthesized according to the general procedure 1 , described in example 1, from 2-formylbenzoic acid (35 mg, 0.23 mmo), 2-(pyridin-2-yl)ethanamine (28 mg, 0.23 mmol) and l-chloro-3-(l-isocyanoethyl)benzene (35 mg, 0.21 mmol) to yield 33 mg (34 %).

¹H NMR (600 MHz, DMSO-J₆) δ ppm 9.17, 9.16 (s + s, 1 H), 8.46 - 8.48, 8.44 - 8.46 (m, 1 H), 7.46 - 7.72 (m, 5 H), 7.19 - 7.40 (m, 6 H), 5.25, 5.24 (s + s, 1 H), 4.91 - 4.97 (m, 1 H), 4.12 - 4.23 (m, 1 H), 3.37 - 3.44, 3.28 - 3.30, 2.95 - 3.13 (m + m + m, 3 H), 1.43, 1.42 (d + d, 3 H); MS (ESI) m/z 420 [M+H].

Example 34

2-f2-f5-Fluoropyrimidin-2-yl)ethyl)-3-oxo-N-f4-ftrifluoromethoxy)benzyl)isoindoline- 1-carboxamide

2-(5-Fluoropyrimidin-2-yl)ethanamine hydrochloride (59.2 mg, 0.33 mmol) was dissolved in methanol (2 mL) and triethylamine (0.093 mL, 0.67 mmol) was added and the mixture was stirred at room temperature for 45 minutes. Afterwards 2-formylbenzoic acid (50 mg, 0.33 mmol) and l-(isocyanomethyl)-4-(trifluoromethoxy)benzene (0.067 mL, 0.33 mmol) were added and the mixtrue was stirred at 45°C for 16 hours before it was filtered and purified using preparative liquid chromatography. The fractions containing the product were pooled, and the acetonitrile was removed in vacuum. The water solution was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated to yield the title compound as yellow semisolid, 18 mg (11 %). 1H NMR (400 MHz, CDCl₃) δ (ppm) 8.35 (s, 2 H) 8.16 (br. s., 1 H) 7.69 (d, 1 H) 7.51 - 7.63 (m, 2 H) 7.43 (t, 1 H) 7.14 (m, 2 H) 7.07 (m, 2 H) 5.10 (s, 1 H) 4.36 - 4.48 (m, 2 H) 3.91 - 4.16 (m, 2 H) 3.15 - 3.39 (m, 2 H). MS (ESI) m/z 475 [M+H].

Example 35

2-f2-f4-Methylpyrimidin-2-yl)ethyl)-3-oxo-N-f4-ftrifluoromethoxy)benzyl)isoindoline-

1-carboxamide

The title compound was prepared according to the method described for example 34 using 2-(4-methylpyrimidin-2-yl)ethanamine hydrochloride (121 mg, 0.70 mmol), triethylamine (0.195 mL, 1.40 mmol) and 2-formylbenzoic acid (105 mg, 0.7 mmol) and 1- (isocyanomethyl)-4-(trifluoromethoxy)benzene (0.141 mL, 0.70 mmol). Orange oil, 80 mg (24 %).

¹H NMR (500 MHz, CDCl₃) δ (ppm) 8.85 (br. s., 1 H) 8.31 (d, 1 H) 7.70 (dd, 2 H) 7.58 (t, 1 H) 7.48 (t, 1 H) 7.07 - 7.14 (m, 2 H) 7.02 - 7.07 (m, 2 H) 7.00 (d, 1 H) 5.11 (s, 1 H) 4.43 - 4.58 (m, 1 H) 4.31 - 4.42 (m, 1 H) 4.20 (d, 1 H) 3.87 (d, 1 H) 3.14 - 3.29 (m, 2 H) 2.28 (s, 3 H). MS (ESI) m/z All [M+H].

Example 36

3-Oxo-2-f2-fpyrimidin-2-yl)ethyl)-N-f4-ftrifluoromethoxy)benzyl)isoindoline-l- carboxamide

The title compound was prepared according to the method described for example 34 using 2-(pyrimidin-2-yl)ethanaminium chloride (0.106 g, 0.67 mmol), triethylamine (0.186 mL, 1.33 mmol), 2-formylbenzoic acid (0.10 g, 0.67 mmol) and l-(isocyanomethyl)-4- (trifluoromethoxy)benzene (0.134 g, 0.67 mmol). The mixture was stirred for 2 days at room temperature. The solvent was removed in vacuo and the residual oil was taken up in ethyl acetate and washed with water, dried over anhydrous sodium sulfate, filtered and concentrated. The crude was purified by silica gel chromatography using dichloromethane : (dichloromethane/methanol 90:10) = 100:0 to 60:40 as gradient. Yellowish solid, 87 mg (28 %). 1H NMR (500 MHz, CDCl₃) δ (ppm) 8.56 (d, 2 H) 7.67 (t, 2 H) 7.58 (t, 1 H) 7.47 (t, 1 H) 7.22 - 7.27 (m, 2 H) 7.16 (d, 2 H) 7.06 (d, 2 H) 5.15 (s, 1 H) 4.40 - 4.49 (m, 2 H) 4.13 - 4.19 (m, 1 H) 3.94 - 3.98 (m, 1 H) 3.30 - 3.36 (m, 2 H). MS (ESI) m/z 457 [M+H].

Example 37 2-f2-f2-Methylpyrimidin-5-yl)ethyl)-3-oxo-N-f4-ftrifluoromethoxy)benzyl)isoindoline- 1-carboxamide

The title compound was prepared according to the method described for example 34 using 2-(2-methylpyrimidin-5-yl)ethanaminium chloride (0.035 g, 0.20 mmol), triethylamine (0.056 mL, 0.40 mmol), 2-formylbenzoic acid (0.030 g, 0.20 mmol) and 1-

(isocyanomethyl)-4-(trifluoromethoxy)benzene (0.040 g, 0.20 mmol). The mixture was stirred for 16 hours at room temperature. Colorless oil, 27 mg (28 %). 1H NMR (400 MHz, CDCl₃) δ (ppm) 8.44 (s, 2 H) 7.59 - 7.65 (m, 1 H) 7.52 - 7.59 (m, 1 H) 7.32 (t, 1 H) 7.23 - 7.28 (m, 1 H) 7.11 - 7.18 (m, 2 H) 7.05 - 7.11 (m, 3 H) 5.06 (s, 1 H) 4.31 - 4.49 (m, 2 H) 4.11 - 4.26 (m, 1 H) 3.36 (ddd, 1 H) 2.76 - 3.00 (m, 2 H) 2.69 (s, 3 H). MS (ESI) m/z 471 [M+H]. Example 38

2-ff6-Cvanopyridin-3-yl)methyl)-3-oxo-N-f4-ftrifluoromethoxy)benzyl)isoindoline-l- carboxamide

The title compound was synthesized according to the general procedure 1 , described in example 1, from 2-formylbenzoic acid (0.030 g, 0.20 mmol), 5- (aminomethyl)picolinonitrile (0.027 g, 0.20 mmol) and l-(isocyanomethyl)-4- (trifluoromethoxy)benzene (0.040 g, 0.20 mmol). Yellowish oil, 3.7 mg (4 %). 1H NMR (500 MHz, CDCl₃) δ (ppm) 8.65 (d, 1 H) 7.76 (dd, 1 H) 7.61 - 7.66 (m, 2 H) 7.57 - 7.61 (m, 2 H) 7.48 (t, 1 H) 7.10 - 7.17 (m, 4 H) 6.49 (t, 1 H) 5.32 (d, 1 H) 4.92 (s, 1 H) 4.31 - 4.46 (m, 3 H). MS (ESI) m/z 467 [M+H].

Example 39

3-Oxo-N-(4-(ϊrifluoromethoxy)benzyl)-2-(ϊ5-(ϊrifluoromethyr)pyridin-2- yl)methyl)isoindoline-l-carboxamide

The title compound was prepared according to the method described for example 34 using (5-(trifluoromethyl)pyridin-2-yl)methanamine hydrochloride (42.5 mg, 0.20 mmol), triethylamine (0.084 ml, 0.60 mmol), 2-formylbenzoic acid (30 mg, 0.20 mmol) and 1- (isocyanomethyl)-4-(trifluoromethoxy)benzene (0.040 ml, 0.20 mmol). The solution was stirred for 2 hours at ambient temperature followed by heating to 5O⁰C for 16 hours. Brown semisolid, 12.8 mg (12.6 %).

¹H NMR (400 MHz, CDCl₃) δ (ppm) 9.49 (t, 1 H) 8.16 (s, 1 H) 7.94 (d, 1 H) 7.87 (d, 1 H) 7.79 (d, 1 H) 7.61 - 7.69 (m, 1 H) 7.47 - 7.61 (m, 2 H) 7.12 - 7.20 (m, 2 H) 7.04 - 7.12 (m, 2 H) 5.27 (s, 1 H) 4.91 (d, 1 H) 4.66 - 4.81 (m, 1 H) 4.31 - 4.52 (m, 2 H). MS (ESI) m/z 510 [M+H].

Example 40

3-Oxo-N-(4-(trifluoromethoxy)benzyl)-2-α6-(trifluoromethyl)pyridin-3- yl)methyl)isoindoline-l-carboxamide

The title compound was synthesized according to the general procedure 1, described in example 1, from 2-formylbenzoic acid (30 mg, 0.20 mmol), (6-(trifluoromethyl)pyridin-3- yl)methanamine (45.3 mg, 0.26 mmol) and l-(isocyanomethyl)-4- (trifluoromethoxy)benzene (0.040 mL, 0.20 mmol). The crude was purified by silica gel chromatography using heptane : ethyl acetate = 100:0 to 50:50 as a gradient yielding the title compound as a white solid, 25 mg (24.6 %).

¹H NMR (500 MHz, CDCl₃) δ (ppm) 8.66 - 8.73 (m, 1 H) 7.80 - 7.93 (m, 2 H) 7.49 - 7.67 (m, 4 H) 7.12 (m, 4 H) 6.01 (t, 1 H) 5.35 (d, 1 H) 4.92 (s, 1 H) 4.29 - 4.45 (m, 3 H). MS (ESI) m/z 510 [M+H]. Example 41

3-Oxo-2-α6-α,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-N-(4-

(trifluoromethoxy)benzvDisoindoline-l-carboxamide

The title compound was synthesized according to the general procedure 1 , described in example 1, from 2-formylbenzoic acid (30 mg, 0.20 mmol), (6-(2,2,2- trifluoroethoxy)pyridin-3-yl)methanamine (45.3 mg, 0.22 mmol) and l-(isocyanomethyl)- 4-(trifluoromethoxy)benzene (0.040 mL, 0.20 mmol). The crude was purified by silica gel chromatography using heptane : ethyl acetate = 100:0 to 50:50 as a gradient yielding the title compound as a white solid, 45 mg (42 %).

¹H NMR (500 MHz, DMSO-J₆) δ (ppm) 9.13 (t, 1 H) 8.04 - 8.17 (m, 1 H) 7.73 - 7.80 (m, 1 H) 7.67 (dd, 1 H) 7.59 - 7.65 (m, 1 H) 7.52 - 7.59 (m, 1 H) 7.46 - 7.52 (m, 1 H) 7.35 (s, 4 H) 6.95 (d, 1 H) 5.02 - 5.11 (m, 2 H) 4.97 (q, 2 H) 4.24 - 4.41 (m, 2 H) 4.16 (d, 1 H). MS (ESI) m/z 540 [M+H].

Example 42

2-fl-f5-Fluoropyridin-2-yl)ethyl)-3-oxo-N-f4-ftrifluoromethoxy)benzyl)isoindoline-l- carboxamide

The title compound was synthesized according to the general procedure 1 , described in example 1, from 2-formylbenzoic acid (30 mg, 0.20 mmol), l-(5-fluoropyridin-2- yl)ethanamine (28 mg, 0.2 mmol) and l-(isocyanomethyl)-4-(trifluoromethoxy)benzene (0.036 mL, 0.18 mmol). White solid, 27 mg (29 %), 1 :1 mixture of diastereomers, integration was set to 1 proton corresponding to 1 proton in one of diastereomers.

¹H NMR (400 MHz, DMSO-J₆) δ (ppm) 9.24 (t, 2 H) 8.39 (d, 1 H) 8.29 (d, 1 H) 7.49 - 7.71 (m, 12 H) 7.29 - 7.40 (m, 8 H) 5.44 (d, 1 H) 5.39 (s, 2 H) 5.23 (d, 1 H) 4.33 (dd, 2 H) 4.17 (dd, 2 H) 1.66 (d, 3 H) 1.53 (d, 3 H). MS (ESI) m/z 474 [M+H].

Example 43

T-Chloro-S-oxo-l-^-fpyridin-l-vDethvD-N-^-ftrifluoromethoxy^enzvDisoindoline-l- carboxamide

The title compound was synthesized according to the general procedure 1, described in example 1, from 4-chloro-3-hydroxyisobenzofuran-l(3H)-one (220 mg, 1.19 mmol, prepared according to Journal of Organic Chemistry 2003, 68, 2030), 2-(pyridin-2- yl)ethanamine (146 mg, 1.19 mmol) and l-(isocyanomethyl)-4-(trifluoromethoxy)benzene (0.24 mL, 1.19 mmol). The crude was subjected to silica gel chromatography using heptane : ethyl acetate 100:0 to 0:100 as gradient to give the product as a white solid, 355 mg (61 %).

¹H NMR (500 MHz, DMSO-J₆) δ (ppm) 9.57 (t, 1 H) 8.47 (m, 1 H) 7.62 - 7.76 (m, 3 H) 7.56 (t, 1 H) 7.42 - 7.50 (m, 2 H) 7.27 - 7.35 (m, 2 H) 7.15 - 7.27 (m, 2 H) 5.40 (s, 1 H) 4.31 - 4.50 (m, 2 H) 4.04 - 4.21 (m, 1 H) 3.26 - 3.33 (m, 1 H) 3.05 - 3.22 (m, 1 H) 2.89 - 3.05 (m, 1 H). MS (ESI) m/z 491, 493 [M+H]. Example 44 7-Cvano-3-oxo-2-f2-fpyridin-2-yl)ethyl)-N-f4-ftrifluoromethoxy)benzyl)isoindoline-l-

7-Chloro-3-oxo-2-(2-(pyridin-2-yl)ethyl)-N-(4-(trifluoromethoxy)benzyl)isoindoline- 1 - carboxamide (83 mg, 0.17 mmol), palladium dibenzylidenacetone (7.76 mg, 0.0085 mmol), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (6.96 mg, 0.02 mmol) and zinc cyanide (0.012 mL, 0.19 mmol) were mixed in DMF (2.5 mL) and water (0.1 mL). The air was exhanged to nitrogen before heating to 130⁰C in microwave oven for 75 minutes. The mixture was filtered through celite and washed with ethylacetate. To the filtrate 6 % NaOH (10 mL) and brine (5 mL) were added. The organic phase was separated, dried with anhydrous magnesium sulfate and concentrated. The crude material was purified by prep- HPLC yielding the title compound as a white solid, 44 mg (54 %). 1H NMR (500 MHz, CDCl₃) δ (ppm) 8.36 (br. s., 1 H) 8.27 (dt, 1 H) 7.98 - 8.06 (m, 1 H) 7.83 (dd, 1 H) 7.70 - 7.80 (m, 1 H) 7.61 (t, 1 H) 7.37 - 7.44 (m, 2 H) 7.30 - 7.36 (m, 1 H) 7.21 - 7.26 (m, 1 H) 7.11 - 7.19 (m, 2 H) 5.32 (br. s., 1 H) 4.47 - 4.67 (m, 2 H) 4.23 - 4.35 (m, 1 H) 3.82 (ddd, 1 H) 3.23 (t, 2 H). MS (ESI) m/z 480 [M+H].

Example 45 2-f2-Hvdroxy-2-fpyridin-2-yl)ethyl)-3-oxo-N-f4-ftrifluoromethoxy)benzyl)isoindoline- 1-carboxamide

The title compound was synthesized according to the general procedure 1 , described in example 1, from 2-formylbenzoic acid (45 mg, 0.30 mmol), 2-amino-l-(pyridin-2- yl)ethanol (42 mg, 0.30 mmol) and l-(isocyanomethyl)-4-(trifluoromethoxy)benzene (60.3 mg, 0.30 mmol). The crude was purified by silica gel column chromatography using dichloromethane : methanol = 100:0 to 95:5 eluent. White solid, 74 mg (52 %), 1 :1 mixture of diastereomers, integration was set to 1 proton corresponding to 1 proton in one of the diastereomers.

¹H NMR (400 MHz, CDCl₃) δ (ppm) 8.64 (m, 1 H) 8.55 (d, 1 H) 8.33 (d, 1 H) 7.46 - 7.80 (m, 11 H) 7.39 (d, 1 H) 7.20 - 7.29 (m, 4 H) 7.04 - 7.18 (m, 6 H) 6.76 (m, 1 H) 5.55 (m, 1 H) 5.43 (s, 1 H) 5.11 (d, 1 H) 5.10 (s, 1 H) 4.98 (m, 1 H) 4.82 (d, 1 H) 4.53 (dd, 1 H) 4.40 (d, 2 H) 4.38 (dd, 1 H) 4.16 (dd, 1 H) 3.94 (dd, 1 H) 3.69 (dd, 1 H), 3.57 (dd, 1 H). ¹⁹F NMR (400 MHz, CDCl₃) δ (ppm) -58.30 and -58.35. MS (ESI) m/z All [M+H].

Example 46 2-α,2-Difluoro-2-(pyridin-2-ylkthyl)-3-oxo-N-(4- (trifluoromethoxy)benzvDisoindoline-l-carboxamide

The title compound was synthesized according to the general procedure 1 , described in example 1, from 2-formylbenzoic acid (30 mg, 0.20 mmol), 2,2-difluoro-2-(pyridin-2- yl)ethanamine (31.6 mg, 0.20 mmol) and l-(isocyanomethyl)-4-

(trifluoromethoxy)benzene (40.2 mg, 0.20 mmol). The mixture was stirred for 16 hours at

50⁰C. Yellowish oil, 54 mg (55 %).

¹H NMR (400 MHz, CDCl₃) δ (ppm) 8.28 (d, 1 H) 8.13 (t, 1 H) 7.83 (td, 1 H) 7.68 (dd, 2

H) 7.52 - 7.62 (m, 1 H) 7.43 - 7.50 (m, 1 H) 7.31 - 7.42 (m, 2 H) 7.17 (d, 2 H) 7.06 (d, 2 H) 5.26 (s, 1 H) 4.43 - 4.58 (m, 2 H) 4.36 (dd, 1 H) 4.17 - 4.31 (m, 1 H). MS (ESI) m/z 492

[M+H]. Example 47

2-q,2-Difluoro-2-(pyridin-2-yl)ethyl)-7-methyl-3-oxo-N-(4-

(trifluoromethoxy)benzvDisoindoline-l-carboxamide

The title compound was synthesized according to the general procedure 1 , described in example 1, from 3-hydroxy-4-methylisobenzofuran-l(3H)-one (30 mg, 0.18 mmol, prepared according to the procedure described in Tetrahedron Letters 2002, 43, 7315 for the unsubstituted analog), 2,2-difluoro-2-(pyridin-2-yl)ethanamine (28.9 mg, 0.18 mmol) and l-(isocyanomethyl)-4-(trifluoromethoxy)benzene (36.8 mg, 0.18 mmol). The mixture was stirred for 60 hours at 50⁰C. Light brown oil, 18 mg (19 %).

¹H NMR (500 MHz, CDCl₃) δ (ppm) 8.47 (d, 1 H) 7.85 (t, 1 H) 7.69 (d, 1 H) 7.55 (br. s., 1 H) 7.35 - 7.42 (m, 3 H) 7.19 (m, 2 H) 7.10 (m, 2 H) 6.95 (br. s., 1 H) 5.32 (s, 1 H) 4.61 - 4.78 (m, 1 H) 4.50 (dd, 1 H) 4.37 (dd, 1 H) 3.98 - 4.14 (m, 1 H) 2.41 (s, 3 H). MS (ESI) m/z 506 [M+H].

Example 48 3-Oxo-2-(3-(pyridin-2-yl)propyl)-N-(4-(ϊrifluoromethoxy)benzyl)isoindoline-l- carboxamide

The title compound was prepared according to the method described for example 34 using 2-(3-ammoniopropyl)pyridinium chloride (41.8 mg, 0.20 mmol), triethylamine (0.070 mL, 0.50 mmol), 2-formylbenzoic acid (30 mg, 0.20 mmol) and l-(isocyanomethyl)-4- (trifluoromethoxy)benzene (40.2 mg, 0.20 mmol). Brown oil, 43 mg (46 %). 1H NMR (400 MHz, CDCl₃) δ (ppm) 8.41 (d, 1 H) 7.58 - 7.64 (m, 1 H) 7.49 - 7.57 (m, 2 H) 7.29 - 7.40 (m, 3 H) 7.13 - 7.18 (m, 2 H) 7.11 (d, 1 H) 7.02 - 7.09 (m, 3 H) 5.16 (s, 1 H) 4.32 - 4.50 (m, 2 H) 4.04 (ddd, 1 H) 3.17 - 3.28 (m, 1 H) 2.71 - 2.87 (m, 2 H) 2.04 - 2.16 (m, 2 H). MS (ESI) m/z 470 [M+H].

Example 49

7-Methoxy-3-oxo-2-f2-fpyridin-2-yl)ethyl)-N-f4-ftrifluoromethoxy)benzyl)isoindoline- 1-carboxamide

The title compound was synthesized according to the general procedure 1 , described in example 1, from 3-hydroxy-4-methoxyisobenzofuran-l(3H)-one (60 mg, 0.33 mmol, prepared according to Journal of Organic Chemistry 2007, 72, 3419), 2-(pyridin-2- yl)ethanamine (57 mg, 0.47 mmol) and l-(isocyanomethyl)-4-(trifluoromethoxy)benzene (0.067 mL, 0.33 mmol). The mixture was stirred for 4 hours at 50⁰C. White solid, 119 mg (73 %).

¹H NMR (500 MHz, DMSO-J₆) δ (ppm) 9.24 - 9.41 (m, 1 H) 8.37 - 8.53 (m, 1 H) 7.68 (td, 1 H) 7.39 - 7.52 (m, 3 H) 7.28 - 7.39 (m, 2 H) 7.09 - 7.28 (m, 4 H) 5.28 (s, 1 H) 4.52 (dd, 1 H) 4.31 (dd, 1 H) 4.05 - 4.20 (m, 1 H) 3.80 (s, 3 H) 3.20 - 3.32 (m, 1 H) 3.10 (ddd, 1 H) 2.88 - 3.04 (m, 1 H). MS (ESI) m/z 484 [M+H]. Example 50

7-Hvdroxy-3-oxo-2-f2-fpyridin-2-yl)ethyl)-N-f4-ftrifluoromethoxy)benzyl)isoindoline-

1-carboxamide

Over the dichloromethane (5 rnL) solution of 7-methoxy-3-oxo-2-(2-(pyridin-2-yl)ethyl)- N-(4-(trifluoromethoxy)benzyl)isoindoline-l-carboxamide (136 mg, 0.28 mmol) the atmosphere was exchanged to nitrogen. The mixture was cooled down to -78⁰C, and boron tribromide (0.105 mL, 1.11 mmol) was added via a syringe. The mixture was stirred at - 78⁰C for 2 hours and then was allowed to warm up to 10⁰C gradually over night. The crude was cooled down to O⁰C with ice, and quenched with water (~1 mL) which was added dropwise. The reaction mixture was diluted with dichloromethane (5 mL) and extracted with brine. The water phase was extracted with ethyl acetate and the organic phases were combined, dried over anhydrous magnesium sulfate and evaporated in vacuo. The crude was purified with preparative HPLC. The fractions containing the compound were combined and the acetonitrile was removed in vacuum. The aqueous solution was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated to yield the title compound as a light brown solid, 96 mg (73 %). ¹H NMR (500 MHz, DMSO-J₆) δ (ppm) 10.27 (s, 1 H) 9.30 (t, 1 H) 8.57 (d, 1 H) 7.26 - 7.50 (m, 9 H) 7.06 - 7.12 (m, 1 H) 6.95 - 7.04 (m, 1 H) 5.29 (s, 1 H) 4.42 - 4.49 (m, 1 H) 4.33 - 4.42 (m, 1 H) 4.12 (ddd, 1 H) 3.09 - 3.23 (m, 2 H) 3.06 (d, 1 H). MS (ESI) m/z 472 [M+H]. Example 51

2-(7-Methyl-l-(pyridin-2-yl)propan-2-yl)-3-oxo-N-(4-

(trifluoromethoxy)benzvDisoindoline-l-carboxamide

The title compound was synthesized according to the general procedure 1 , described in example 1, from 2-formylbenzoic acid (30 mg, 0.20 mmol), 2-methyl-l-(pyridin-2- yl)propan-2-amine (30 mg, 0.20 mmol) and l-(isocyanomethyl)-4- (trifluoromethoxy)benzene (40.2 mg, 0.20 mmol). Brown oil, 5 mg (5 %). 1H NMR (400 MHz, CDCl₃) δ (ppm) 8.52 (t, 1 H) 8.02 - 8.10 (m, 1 H) 7.71 (d, 1 H) 7.61 - 7.64 (m, 1 H) 7.51 - 7.58 (m, 2 H) 7.47 (t, 1 H) 7.21 (d, 1 H) 6.99 - 7.05 (m, 3 H) 6.92 - 6.99 (m, 2 H) 5.08 (s, 1 H) 4.40 (dd, 1 H) 4.13 (dd, 1 H) 3.71 (d, 1 H) 3.22 (d, 1 H) 1.59 (d, 6 H). MS (ESI) m/z 484 [M+H].

Example 52

7-Methyl-3-oxo-2-f2-fpyridin-2-yl)ethyl)-N-f4-ftrifluoromethoxy)benzyl)isoindoline-l- carboxamide

The title compound was synthesized according to the general procedure 1 , described in example 1, from 3-hydroxy-4-methylisobenzofuran-l(3H)-one (220 mg, 1.34 mmol, prepared according to the procedure described in Tetrahedron Letters 2002, 43, 7315 for the unsubstituted analog), 2-(pyridin-2-yl)ethanamine (164 mg, 1.34 mmol) and 1- (isocyanomethyl)-4-(trifluoromethoxy)benzene (0.270 niL, 1.34 mmol). The solution was stirred for 60 hours at 45°C. The crude was subjected to silica gel chromatography using heptane : ethyl acetate = 100:0 to 0:100 as gradient to give the product as a white solid, 420 mg (67 %). 1H NMR (500 MHz, DMSO-J₆) δ (ppm) 9.39 (t, 1 H) 8.44 - 8.53 (m, 1 H) 7.69 (td, 1 H) 7.48 (ddd, 1 H) 7.34 - 7.45 (m, 4 H) 7.27 - 7.34 (m, 2 H) 7.19 - 7.26 (m, 2 H) 5.31 (s, 1 H) 4.32 - 4.47 (m, 2 H) 4.10 - 4.21 (m, 1 H) 3.27 (ddd, 1 H) 3.12 (ddd, 1 H) 2.92 - 3.03 (m, 1 H) 2.24 (s, 3 H). MS (ESI) m/z 470 [M+H].

Example 53

2-f2-Methyl-2-fpyridin-3-yl)propyl)-3-oxo-N-f4-ftrifluoromethoxy)benzyl)isoindoline- 1-carboxamide

The title compound was synthesized according to the general procedure 1 , described in example 1, from 2-formylbenzoic acid (44 mg, 0.29 mmol), 2-methyl-2-(pyridin-3- yl)propan-l -amine (44 mg, 0.29 mmol) and l-(isocyanomethyl)-4- (trifluoromethoxy)benzene (58.9 mg, 0.29 mmol). Colorless oil, 84 mg (59 %). 1H NMR (400 MHz, CDCl₃) δ (ppm) 8.51 (d, 1 H) 8.41 (d, 1 H) 7.59 (ddd, 1 H) 7.46 - 7.53 (m, 1 H) 7.37 - 7.44 (m, 2 H) 7.30 - 7.36 (m, 1 H) 7.08 - 7.24 (m, 6 H) 4.44 (s, 1 H) 4.28 - 4.43 (m, 2 H) 4.25 (d, 1 H) 3.26 (d, 1 H) 1.35 (d, 6 H). MS (ESI) m/z 484 [M+H].

Example 54

2-f2-Methyl-2-fpyridin-2-yl)propyl)-3-oxo-N-f4-ftrifluoromethoxy)benzyl)isoindoline-

1-carboxamide

The title compound was synthesized according to the general procedure 1 , described in example 1, from 2-formylbenzoic acid (30 mg, 0.20 mmol), 2-methyl-2-(pyridin-2- yl)propan-l -amine (30 mg, 0.20 mmol) and l-(isocyanomethyl)-4- (trifluoromethoxy)benzene (40.2 mg, 0.20 mmol). Brown oil, 22 mg (22 %). 1H NMR (400 MHz, CDCl₃) δ (ppm) 8.52 - 8.58 (m, 1 H) 7.64 (td, 1 H) 7.53 (d, 1 H) 7.42 - 7.50 (m, 2 H) 7.33 - 7.40 (m, 1 H) 7.26 - 7.30 (m, 2 H) 7.24 (d, 1 H) 7.19 (ddd, 1 H) 7.13 (d, 2 H) 6.86 (t, 1 H) 4.50 (dd, 1 H) 4.32 (dd, 1 H) 4.05 - 4.21 (m, 3 H) 1.32 (s, 6 H). MS (ESI) m/z 484 [M+H].

Example 55

3-Oxo-2-(Yl-(pyridin-2-yl)cvclopropyl)methyl)-N-(4- (ϊrifluoromethoxy)benzyl)isoindoline-l-carboxamide

The title compound was synthesized according to the general procedure 1, described in example 1, from 2-formylbenzoic acid (30 mg, 0.20 mmol), (l-(pyridin-2- yl)cyclopropyl)methanamine (29.6 mg, 0.20 mmol) and l-(isocyanomethyl)-4- (trifluoromethoxy)benzene (40.2 mg, 0.20 mmol). Yellow solid, 36 mg (37 %). 1H NMR (400 MHz, CDCl₃) δ (ppm) 8.54 (t, 1 H) 8.08 - 8.14 (m, 1 H) 7.65 (dd, 2 H) 7.59 (td, 1 H) 7.55 (td, 1 H) 7.43 (t, 1 H) 7.30 (d, 1 H) 7.02 - 7.14 (m, 5 H) 5.06 (s, 1 H) 4.51 (dd, 1 H) 4.30 (d, 1 H) 4.25 (dd, 1 H) 3.54 (d, 1 H) 1.19 - 1.25 (m, 1 H) 0.94 - 1.03 (m, 3 H). MS (ESI) m/z 482 [M+H]. Example 56

3-Oxo-2-f2-fpyridin-2-yl)ethyl)-N-fl-f4-ftrifluoromethoxy)phenyl)ethyl)isoindoline-l- carboxamide, ISOMER 4

The title compound was synthesized according to the general procedure 1 , described in example 1, from 2-formylbenzoic acid (0.105 g, 0.70 mmol), 2-(2-aminoethyl)pyridine (0.084 mL, 0.70 mmol) and l-(l-isocyanoethyl)-4-(trifluoromethoxy)benzene (0.151 g, 0.70 mmol).

The resulted white solid (0.112 g, 34 % yield) was subjected to enantiomeric separation by chiral chromatography, which was performed on LaPrep system 1, Column: Chiralpak AD; 50*300 mm; lOμm. Mobilephase: 0-23 minutes: 5/5/90 methanol:ethanol:heptane, 23-35 minutes: 10/10/80 methanol:ethanol:heptane, 35-45 minutes: 15/15/70 methanol:ethanol:heptane; Flow: 120 niL/minute. The four separated isomers were eluted at 17 minutes (ISOMER 1) at 26 minutes (ISOMER 2) at 32 minutes (ISOMER 3) and at 38 minutes as ISOMER 4. The separated isomers were collected, concentrated and handled separately. The samples were analyzed by HPLC using GILSON HPLC System; Column: Reprosil-AM (AD); 4.6*250 mm; 5μm; Mobilephase: 7/3/90 methanol:ethanol:heptane; Flow: 0.8 niL/minute, ISOMER 4 (22 minutes), 21 mg, enatiomeric purity: 99 %. 1H NMR (500 MHz, DMSO-J₆) δ (ppm) 9.21 (d, 1 H), 8.47 (d, 1 H), 7.70 (td, 1 H), 7.63 (d, 1 H), 7.55 (m, 1 H), 7.48 (m, 4 H), 7.30 (m, 3 H), 7.22 (dd, 1 H), 5.23 (s, 1 H), 4.97 (m, 1 H), 4.20 (ddd, 1 H), 3.10 (m, 1 H), 3.01 (m, 1 H), 1.43 (d, 3 H). MS (ESI) m/z 470 [M+H]. Example 57

2-f2-f6-Methylpyridin-2-yl)ethyl)-3-oxo-N-f4-ftrifluoromethoxy)benzyl)isoindoline-l- carboxamide

The title compound was synthesized according to the general procedure 1 , described in example 1, from 2-formylbenzoic acid (100 mg, 0.67 mmol), 2-(6-methylpyridin-2- yl)ethanamine (90.5mg, 0.67 mmol) and l-(l-isocyanoethyl)-4-(trifluoromethoxy)benzene (134 mg, 0.67 mmol). Solid, 200 mg (64.5 %).

¹H NMR (400 MHz, CDCl₃) δ (ppm) 9.33 (br. s., 1 H) 7.67 (d, 1 H) 7.46 - 7.60 (m, 3 H) 7.40 (t, 1 H) 7.06 - 7.17 (m, 2 H) 6.88 - 7.06 (m, 4 H) 5.04 (s, 1 H) 4.29 - 4.54 (m, 2 H) 3.92 - 4.12 (m, 1 H) 3.84 (dt, 1 H) 2.99 - 3.20 (m, 1 H) 2.93 (dt, 1 H) 2.13 (s, 3 H). MS (ESI) m/z 470 [M+H].

Example 58

2-(2-(6-(Hvdroxymethyl)pyridin-2-yl)ethyl)-3-oxo-N-(4- ftrifluoromethoxy)benzyl)isoindoline-l-carboxamide

l-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (130 mg, 0.67 mmol) and

1-hydroxybenzotriazole hydrate (80 mg, 0.59 mmol) were added to the tetrahydrofuran (10 mL) solution of 3-oxo-2-(2-(6-((tetrahydro-2H-pyran-2-yloxy)methyl)pyridin-2- yl)ethyl)isoindoline-l-carboxylic acid (180 mg, 0.45 mmol). After 10 minutes (4- (trifluoromethoxy)phenyl)methanamine (160 mg, 0.9 mmol) was added. The reaction mixture was stirred for 16 hours at room temperature, concentrated under reduced pressure and the crude residue redissolved in ethyl acetate (30 mL). The ethyl acetate layer was extracted with water (20 mL) and brine (20 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography by using hexane : ethyl acetate = 50:50 to 30: 70. The product was obtained as solid, 110 mg (43 %). MS (ESI) m/z 570 [M+H].

Step 2:

Pyridinium-p-toluenesulfonate (44 mg, 0.177 mmol) was added to the methanol (2 mL) solution of 3-oxo-2-(2-(6-((tetrahydro-2H-pyran-2-yloxy)methyl)pyridin-2-yl)ethyl)-N-(4- (trifluoromethoxy)benzyl)isoindoline-l-carboxamide (84 mg, 0.148 mmol) and the reaction mixture was stirred for 40 minutes at room temperature then concentrated under reduced pressure, diluted with water (5 mL) and extracted with dichloromethane (2x5 mL). The organic extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using hexane : ethyl acetate = 100:0 to 40:60 as eluent. White solid, 42 mg (60 %). 1H NMR (400 MHz, CDCl₃) δ (ppm) 8.00 (br. s., 1 H) 7.47 - 7.71 (m, 3 H) 7.21 - 7.39 (m, 2 H) 6.93 - 7.21 (m, 6 H) 5.01 (s, 1 H) 4.53 (s, 2 H) 4.43 (m, 2 H) 4.15 - 4.31 (m, 1 H) 3.84 (dt, 1 H) 3.66 (br. s., 1 H) 2.92 - 3.16 (m, 2 H). MS (ESI) m/z 486 [M+H].

Example 59

2-α-(4-α-tert-Butoxyethyl)-lH-l,2,3-triazol-l-yl)ethyl)-3-oxo-N-(4-

(ϊrifluoromethoxy)benzyl)isoindoline-l-carboxamide

Step 1:

2-(2-Chloroethyl)-3 -oxo-N-(4-(trifluoromethoxy)benzyl)isoindoline- 1 -carboxamide was prepared according to the method described for example 34 using 2- chloroethanaminium chloride (309 mg, 2.66 mmol), triethylamine (0.334 mL, 2.40 mmol), 2-formylbenzoic acid (400 mg, 2.66 mmol) and l-(isocyanomethyl)-4- (trifluoromethoxy)benzene (0.482 mL, 2.40 mmol). The crude was purified by silica gel chromatography using heptane : ethyl acetate = 90:10 to 50:50 as a gradient affording the chloride intermediate as a dry film, 250 mg (23 %). 1H NMR (400 MHz, CDCl₃) δ (ppm) 7.65 (d, 1 H) 7.60 (d, 1 H) 7.50 (d, 1 H) 7.41 (t, 1 H) 7.16 (d, 2 H) 7.10 (d, 2 H) 6.83 (br.s., 1 H) 5.32 (s, 1 H) 4.42 (d, 2 H) 4.22 - 4.29 (dt, 1 H) 3.78 (t, 2 H) 3.55 - 3.60 (dt, 1 H). MS (ESI) m/z 413, 415 [M+H].

Step 2: 2-(2-Chloroethyl)-3-oxo-N-(4-(trifluoromethoxy)benzyl)isoindoline- 1 -carboxamide (100 mg, 0.24 mmol) was dissolved in dry DMF. Sodium azide (20 mg, 0.31 mmol) was added and the resulting solution was stirred at 60⁰C for 48 hours. The solution was cooled to room temperature then water (2 mL) ethyl acetate (2 mL) and toluene (2 mL) were added and the resulting two-phase mixture was stirred vigourously for 10 minutes. The layers were separated and the organic phase was washed with water (2 mL) and concentrated (to approx. 2 mL), which was used directly in the next step without isolation. Step 3:

To 2-(2-azidoethyl)-3-oxo-N-(4-(trifluoromethoxy)benzyl)isoindoline- 1 -carboxamide (50 mg, 0.12 mmol) in toluene (1 mL) 3-tert-butoxybut-l-yne (0.023 niL, 0.18 mmol) and cuprous iodide (15 mg, 0.08 mmol) were added. The resulting mixture was stirred vigourously at room temperature for 60 hours. Thereafter methanol (0.10 mL) and more 3- tert-butoxybut-1-yne (0.023 mL, 0.18 mmol) were added and the temperature was increased to 55⁰C and stirred for 24 hours. Afterwards ethyl acetate (3 mL) and water (2 mL) were added and the phases were separated. The organic layer was concentrated and the residue was subjected to preparative HPLC purification. The fractions containing the compound were combined and the acetonitrile was removed in vacuum. The aqueous solution was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated to yield the title compound as a dry film solid, 14 mg (21 %), 1 : 1 mixture of diastereomers, integration was set to 1 proton corresponding to 1 proton in one of the diastereomers.

¹H NMR (400 MHz, CDCl₃) δ (ppm) 7.55 (t, 2 H) 7.52 (d, 6 H) 7.38 - 7.48 (m, 4 H) 7.20

(d, 4 H) 7.09 (d, 4 H) 4.86 (s, 1 H) 4.79 - 4.86 (m, 2 H) 4.76 (s, 1 H) 4.57 - 4.70 (m, 4 H) 4.35 - 4.49 (m, 4 H) 4.18 - 4.26 (m, 2 H) 3.82 - 3.89 (m, 2 H) 1.40 (d, 3 H) 1.36 (d, 3 H) 1.16 (s, 9 H) 1.09 (s, 9 H). MS (ESI) m/z 546 [M+H].

Example 60

4-Fluoro-3-oxo-2-f2-fpyridin-2-yl)ethyl)-N-f4-ftrifluoromethoxy)benzyl)isoindoline-l- carboxamide

The title compound was synthesized according to the general procedure 1 , described in example 1, from 7-fluoro-3-hydroxyisobenzofuran-l(3H)-one (35 mg, 0.21 mmol), 2- (pyridin-2-yl)ethanamine (0.025 mL, 0.21 mmol) and l-(isocyanomethyl)-4- (trifluoromethoxy)benzene (0.042 mL, 0.21 mmol). White solid, 36 mg (36 %). 1H NMR (400 MHz, CDCl₃) δ (ppm) 9.22 (br.s., 1 H) 8.17 (d, 1 H) 7.68 (t, 1 H) 7.50 - 7.55 (m, 1 H) 7.45 (d, 1 H) 7.26 (d, 1 H) 7.17 (m, 2 H) 7.08 (m, 2 H) 5.07 (s, 1 H) 4.37 - 4.49 (m, 2 H) 3.97 - 4.07 (m, 1 H) 3.80 - 3.91 (m, 1 H) 3.00 - 3.20 (m, 2 H). MS (ESI) m/z 474 [M+H].

Example 61 7-Fluoro-3-oxo-2-f2-fpyridin-2-yl)ethyl)-N-f4-ftrifluoromethoxy)benzyl)isoindoline-l- carboxamide

The title compound was synthesized according to the general procedure 1 , described in example 1, from 4-fluoro-3-hydroxyisobenzofuran-l(3H)-one (40mg, 0.24 mmol), 2- (pyridin-2-yl)ethanamine (0.029 mL, 0.24 mmol) and l-(isocyanomethyl)-4- (trifluoromethoxy)benzene (0.048 mL, 0.24 mmol). White solid, 36 mg (32 %). 1H NMR (400 MHz, CDCl₃) δ (ppm) 8.29 (d, 1 H) 8.06 (d, 1 H) 7.67 (dt, 1 H) 7.50 (d, 1 H) 7.43 (m, 1 H) 7.12 - 7.28 (m, 7 H) 5.22 (s, 1 H) 4.49 (d, 2 H) 4.14 - 4.22 (m, 1 H) 3.80 3.91 (m, 1 H) 3.11 - 3.20 (m, 2 H). MS (ESI) m/z 474 [M+H].

Example 62 2-f2-f3-Fluoropyridin-2-yl)ethyl)-3-oxo-N-f4-ftrifluoromethoxy)benzyl)isoindoline-l- carboxamide

l-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (76 mg, 0.39 mmol) and 1- hydroxybenzotriazole hydrate (46 mg, 0.34 mmol) were added to the tetrahydrofuran (10 mL) solution of 2-(2-(3-fluoropyridin-2-yl)ethyl)-3-oxoisoindoline-l-carboxylic acid (80 mg, 0.26 mmol). After 10 minutes (4-(trifluoromethoxy)phenyl)methanamine (70 mg, 0.37 mmol) was added. The reaction mixture was stirred for 16 hours at room temperature, concentrated under reduced pressure and the crude residue redissolved in ethyl acetate (30 mL). The ethyl acetate layer was extracted with water (20 mL) and brine (20 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography by using hexane : ethyl acetate = 50:50 to 30:70. The title compound was obtained as solid, 51 mg (40 %). 1H NMR (400 MHz, CDCl₃) δ (ppm) 8.77 (br. s., 1 H) 7.92 (d, 1 H) 7.68 (d, 1 H) 7.47 - 7.61 (m, 3 H) 7.32 - 7.47 (m, 3 H) 7.09 - 7.23 (m, 2 H) 6.97 - 7.09 (m, 1 H) 5.09 (s, 1 H) 4.31 - 4.57 (m, 2 H) 3.98 - 4.13 (m, 1 H) 3.90 (dt, 1 H) 3.16 - 3.34 (m, 1 H) 3.06 (dt, 1 H). MS (ESI) m/z 474 [M+H].

Example 63

4-Hvdroxy-3-oxo-2-Q-(pyridin-2-yl)propan-2-yl)-N-(4- ftrifluoromethoxy)benzyl)isoindoline-l-carboxamide

The title compound was prepared according to the method described for example 50 using 4-methoxy-3-oxo-2-(l-(pyridin-2-yl)propan-2-yl)-N-(4-

(trifluoromethoxy)benzyl)isoindoline-l-carboxamide (50 mg, 0.10 mmol) and boron tribromide (0.142 mL, 1.50 mmol). White solid, 17 mg (35 %).

¹H NMR (400 MHz, DMSO-J₆) δ (ppm) 9.67 (br. s., 1 H) 9.21 (t, 1 H) 8.43 - 8.51 (m, 1 H) 7.62 - 7.69 (m, 1 H) 7.35 - 7.41 (m, 2 H) 7.29 - 7.34 (m, 3 H) 7.17 - 7.22 (m, 1 H) 7.15 (d, 1 H) 6.79 - 6.85 (m, 2 H) 4.94 (s, 1 H) 4.35 (d, 2 H) 4.22 - 4.31 (m, 1 H) 3.22 - 3.29 (m, 1 H) 2.79 - 2.88 (m, 1 H) 1.29 (d, 3 H). MS (ESI) m/z 486 [M+H].

Example 64 4-Hvdroxy-3-oxo-2-f2-fpyridin-2-yl)ethyl)-N-f4-ftrifluoromethoxy)benzyl)isoindoline- 1-carboxamide

The title compound was prepared according to the method described for example 50 using 4-methoxy-3 -oxo-2-(2-(pyridin-2-yl)ethyl)-N-(4-(trifluoromethoxy)benzyl)isoindoline- 1 - carboxamide (0.121 g, 0.25 mmol) and boron tribromide (0.236 mL, 2.50 mmol). White solid, 56 mg (47 %).

¹H NMR (400 MHz, CDCl₃) δ (ppm) 9.32 - 9.39 (m, 1 H) 8.16 (s, 1 H) 8.10 (d, 1 H) 7.64 - 7.73 (m, 1 H) 7.40 - 7.48 (m, 1 H) 7.27 - 7.31 (m, 1 H) 7.11 - 7.21 (m, 4 H) 7.04 - 7.09 (m, 2 H) 6.88 (d, 1 H) 5.05 (s, 1 H) 4.32 - 4.54 (m, 2 H) 4.00 - 4.12 (m, 1 H) 3.70 - 3.81 (m, 1 H) 3.09 - 3.20 (m, 1 H) 2.97 - 3.07 (m, 1 H). MS (ESI) m/z All [M+H].

Example 65

3-Oxo-2-(2-(pyridin-2-yl)ethyl)-N-(3-(trifluoromethoxy)benzyl)isoindoline-l- carboxamide

The title compound was synthesized according to the general procedure 1 , described in example 1, from 2-formylbenzoic acid (0.446 g, 2.97 mmol), 2-(2-aminoethyl)pyridine (0.355 niL, 2.97 mmol) and l-(isocyanomethyl)-3-(trifluoromethoxy)benzene (0.597 g, 2.97 mmol). White solid, 450 mg (33 %).

¹H NMR (500 MHz, DMSO-J₆) δ (ppm) 9.22 (t, 1 H) 8.45 (d, 1 H) 7.72 - 7.65 (m, 2 H) 7.59 (dt, 1 H) 7.56 - 7.50 (m, 2 H) 7.44 (t, 1 H) 7.31 - 7.19 (m, 4 H) 7.17 (s, 1 H) 5.25 (s, 1 H) 4.38 (d, 2 H) 4.22 (m, 1 H) 3.41 (m, 1 H) 3.14 - 3.06 (m, 1 H) 3.06 - 2.97 (m, 1 H). MS (ESI) m/z 456 [M+H].

Example 66

N-f2-Methyl-4-ftrifluoromethoxy)benzyl)-3-oxo-2-f2-fpyridin-2-yl)ethyl)isoindoline-l- carboxamide

The title compound was synthesized according to the general procedure 1 , described in example 1, from 2-formylbenzoic acid (37.5 mg, 0.25 mmol), 2-(2-aminoethyl)pyridine (0.030 mL, 0.25 mmol) and l-(isocyanomethyl)-2-methyl-4-(trifluoromethoxy)benzene (53.8 mg, 0.25 mmol). White solid, 1.6 mg (1.3 %).

¹H NMR (500 MHz, CD₃OD) δ (ppm) 7.79 (d, 1 H), 7.62 (m, 1 H), 7.56 (t, 1 H), 7.49 (d, 1 H), 7.30 (d, 1 H), 7.13 (s, 1 H), 7.06 (d, 1 H), 5.30 (s, 1 H), 4.44 (m, 2 H), 4.29 (m, 1 H), 4.00 (dd, 1 H), 3.93 (m, 1 H), 3.49 (m, 2 H), 2.38 (s, 3 H), 1.97 (qd, 1 H), 1.82 (m, 3 H). MS (ESI) m/z 470 [M+H].

Example 67 N-O-BromobenzvD-S-oxo-l-fl-fpyridin-l-vDethvDisoindoline-l-carboxamide

The title compound was synthesized according to the general procedure 1 , described in example 1, from 2-formylbenzoic acid (35 mg, 0.23 mmol), 2-(pyridin-2-yl)ethanamine (28.5 mg, 0.23 mmol) and l-bromo-3-(isocyanomethyl)benzene (0.041 mL, 0.21 mmol). White solid, 53 mg (50 %).

¹H NMR (500 MHz, CDCl₃) δ (ppm) 9.04 (t, 1 H) 8.18 (ddd, 1 H) 7.62 - 7.75 (m, 3 H) 7.58 (tt, 1 H) 7.46 (t, 1 H) 7.28 - 7.36 (m, 2 H) 7.20 (t, 1 H) 7.11 - 7.17 (m, 1 H) 6.95 - 7.11 (m, 2 H) 5.06 (s, 1 H) 4.48 (dd, 1 H) 4.31 (dd, 1 H) 4.01 - 4.14 (m, 1 H) 3.81 - 3.98 (m, 1 H) 3.13 - 3.27 (m, 1 H) 2.96 - 3.13 (m, 1 H). MS (ESI) m/z 451 [M+H].

Example 68 N-f4-Bromobenzyl)-3-oxo-2-f2-fpyridin-2-yl)ethyl)isoindoline-l-carboxamide

The title compound was synthesized according to the general procedure 1 , described in example 1, from 2-formylbenzoic acid (0.113 g, 0.75 mmol), 2-(pyridin-2-yl)ethanamine (0.090 mL, 0.75 mmol) l-bromo-4-(isocyanomethyl)benzene (0.140 g, 0.71 mmol). White solid, 151 mg (45 %).

¹H NMR (400 MHz, DMSO-J₆) δ (ppm) 9.19 (t, 1 H) 8.44 - 8.48 (m, 1 H) 7.64 - 7.72 (m, 2 H) 7.57 - 7.63 (m, 1 H) 7.47 - 7.55 (m, 4 H) 7.25 (d, 1 H) 7.18 - 7.23 (m, 3 H) 5.23 (s, 1 H) 4.30 (d, 2 H) 4.14 - 4.25 (m, 1 H) 3.35 - 3.44 (m, 1 H) 3.04 - 3.14 (m, 1 H) 2.93 - 3.04 (m, 1 H). MS (ESI) m/z 451 [M+H].

Example 69 N-^-BromobenzvD-S-oxo-l-fl-fpyridin-l-vDethvDisoindoline-l-carboxamide., ISOMER 1

ISOMER 1 a = unknown absolute

The preparative separation of N-(4-bromobenzyl)-3-oxo-2-(2-(pyridin-2- yl)ethyl)isoindoline-l-carboxamide (151 mg, 0.34 mmol) was performed on Berger

Multigram II system Column: Chiralpak AD; 21.2*250 mm; Mobilphase: 40% ethanol and 60% CO₂; Flow: 50 niL/minute, provided two separeted isomers eluting at 5.4 minutes as ISOMER 1 and at 8.7 minutes as ISOMER 2. The separated isomers were collected, evaporated and handled separately. The analysis was performed by HPLC using SFC Berger Analytix Column: Reprosil-AM (AD); 4.6*250 mm, 5μm; Mobilphase: 40% ethanol and 60% CO₂, Flow: 2 mL/minute, resulting the separation of the two isomers, as the first eluting isomer /ISOMER 1/ at 5.9 minutes and the second eluting isomer /ISOMER 2/ at 8.4 minutes. ISOMERl : white solid, 46 mg, enantiomeric purity: 99 %. ¹H NMR (400 MHz, DMSO-J₆) δ (ppm) 9.19 (t, 1 H) 8.44 - 8.48 (m, 1 H) 7.64 - 7.72 (m, 2 H) 7.57 - 7.63 (m, 1 H) 7.47 - 7.55 (m, 4 H) 7.25 (d, 1 H) 7.18 - 7.23 (m, 3 H) 5.23 (s, 1 H) 4.30 (d, 2 H) 4.14 - 4.25 (m, 1 H) 3.35 - 3.44 (m, 1 H) 3.04 - 3.14 (m, 1 H) 2.93 - 3.04 (m, 1 H). MS (ESI) m/z 451 [M+H]. Example 70 N-O^-DichlorobenzvD-S-oxo-l-fl-fpyridin-l-vDethvDisoindoline-l-carboxamide

The title compound was synthesized according to the general procedure 1 , described in example 1, from 2-formylbenzoic acid (35 mg, 0.23 mmol), 2-(pyridin-2-yl)ethanamine (28.5 mg, 0.23 mmol) and l,2-dichloro-4-(isocyanomethyl)benzene (0.039 mL, 0.21 mmol). White solid, 36 mg (35 %).

¹H NMR (500 MHz, CDCl₃) δ (ppm) 9.42 (t, 1 H) 8.17 (dd, 1 H) 7.64 - 7.86 (m, 3 H) 7.53 - 7.64 (m, 1 H) 7.44 - 7.53 (m, 1 H) 7.34 (d, 1 H) 7.13 - 7.24 (m, 2 H) 6.83 - 7.02 (m, 1 H) 5.31 (s, 1 H) 5.09 (br. s., 1 H) 4.46 (dd, 1 H) 4.29 (dd, 1 H) 4.12 (br. s., 1 H) 3.84 (d, 1 H) 3.13 - 3.29 (m, 1 H) 3.09 (d, 1 H). MS (ESI) m/z 440, 442 [M+H].

Example 71

3-Oxo-2-(2-(pyridin-3-ylkthyl)-N-q-(4-

(ϊrifluoromethvDphenvDcyclopropyDisoindoline-l-carboxamide

l-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (150 mg, 0.78 mmol) and 1-hydroxybenzotriazole hydrate (100 mg, 0.74 mmol) were added to the tetrahydrofuran (10 mL) solution of 3-oxo-2-(2-pyridin-3-ylethyl)isoindoline-l-carboxylic acid (0.125 g, 0.443 mmol) and after 10 minutes l-(4-trifluoromethyl-phenyl)-cyclopropylamine (106.9 mg, 0.527 mmol). The reaction mixture was stirred for 16 hours at room temperature, concentrated under reduced pressure and the crude residue redissolved in ethyl acetate (30 mL). The ethyl acetate layer was extracted with water (20 mL) and brine (20 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography by using hexane : ethyl acetate = 50:50 to 30:70 as gradient. The title compound was obtained as solid, 45 mg (24.7 %). ¹H NMR (400 MHz, CDCl₃) δ (ppm) 8.30 - 8.50 (m, 2 H) 7.83 (s, 1 H) 7.52 - 7.69 (m, 2 H) 7.32 - 7.52 (m, 5 H) 7.17 (dd, 1 H) 7.06 (d, 2 H) 5.00 (s, 1 H) 4.12 - 4.36 (m, 1 H) 3.26 - 3.45 (m, 1 H) 2.78 - 3.04 (m, 2 H) 1.27 - 1.46 (m, 2 H) 1.13 - 1.27 (m, 2 H). MS (ESI) m/z 466 [M+H].

Example 72 3-Oxo-2-f2-fpyridin-2-yl)ethyl)-N-f4-f2,2,2-trifluoroethyl)benzyl)isoindoline-l- carboxamide

The title compound was synthesized according to the general procedure 1 , described in example 1, from 2-formylbenzoic acid (30 mg, 0.20 mmol), 2-(pyridin-2-yl)ethanamine (24.4 mg, 0.20 mmol) and l-isocyanomethyl-4-(2,2,2-trifluoroethyl)benzene (40 mg, 0.20 mmol). Pale yellow solid, 58 mg (64 %).

¹H NMR (400 MHz, CDCl₃) δ (ppm) 8.90 (m, 1 H) 8.06 (d, 1 H) 7.67 - 7.72 (m, 2 H) 7.53 - 7.66 (m, 2 H) 7.46 (dd, 1 H) 7.23 (d, 1 H) 7.04 - 7.15 (m, 5 H) 5.02 (s, 1 H) 4.32 - 4.49 (m, 2 H) 4.02 - 4.12 (m, 1 H) 3.83 - 3.91 (m, 1 H) 3.23 - 3.34 (m, 2 H) 3.11 - 3.21 (m, 1 H) 2.98 - 3.06 (m, 1 H). ¹⁹F NMR (400 MHz, CDCl₃) δ (ppm) -66.35, -66.37 and -66.40. MS (ESI) m/z 454 [M+H]. BIOLOGICAL TESTS

Expression of voltage-gated sodium channel in cell lines:

Gene(s) encoding the full-length protein of the voltage-gated sodium channel of interest are cloned and expressed under a suitable promoter in a suitable cell line, as well known in the art. The so constructed stable cell lines are used in screening assays to identify suitable compounds active on voltage-gated sodium channels. Suitable screening assays are as follows.

Li+ influx assay

The cell line expressing the voltage-gated sodium channel of interest is plated in conventional 96 or 384 well tissue plates at a suitable cell density (for example 40000 cells/well in 96 well plate, or 20000 cells/well in 384 well plate). The cells are then repeatedly washed with a suitable Na free buffer using a suitable commercially available washer (for example EL-405 washer) until all tissue culture medium is removed from the wells. A suitable Na- free buffer could have the composition (mM) Choline chloride 137, KCl 5.4, MgSO₄ 0.81, CaCl₂ 0.95, glucose 5.55 and HEPES 25 at pH 7.4, but may also have other suitable composition. After completion of all wash steps, cells are incubated in the suitable Na free buffer for 15 min. Then, the Na free buffer is removed and cells are incubated with a buffer rich in LiCl for 60 min at 37⁰C. The LiCl buffer is also enriched in potassium ions, causing a depolarizing stimulus to the cells. Such a buffer may have the composition (mM): LiCl 100, KCl 50, MgSO₄ 0.81, CaCl₂ 0.95, glucose 5.55 and HEPES 25 at pH 7.4, but may also have other suitable composition. To enhance signal-to-noise ratio, an effective concentration (for example 100 μM) of the voltage-gated sodium channel opener veratridine, or any other suitable voltage-gated sodium channel opener, may be added to the medium to enhance signal detection. Furthermore, and also to enhance signal-to-noise ratio, an effective concentration (for example 10 μg/ml) of suitable scorpion venom may also be added to the medium to delay channel inactivation. In order to find a modulator of the voltage-gated sodium channel of interest, the assay can be complemented with compounds from a compound library. Compounds of interest are added to the Li-rich solution, one in each well. At the end of the incubation period cells are repeatedly washed with Na free buffer until all extracellular LiCl is removed. Cell lysis is obtained through incubation of cells with triton (1%) for 15 min, or any other suitable method. The resulting cell lysate is then introduced into an atomic absorption spectrophotometer, thus quantifying the amount of Li-influx during the procedure described above.

The described assay can be run with any atomic absorption spectrophotometer using plates of 96-well format, 384-well format, or any other conventional plate format. The described assay can be applied to cell lines expressing any given one or more of the voltage-gated sodium channel alpha subunits, as well as any given combination of one of the voltage- gated alpha subunits with any one or more beta subunit.

If needed the cell line of choice can be further hyperpolarised by expression of a suitable potassium leak ion channel, for example TREK-I, either by transient co-trans fection or through establishment of a stable co-transfected cell line. The successful expression of a leak K current can be verified using traditional intracellular electrophysiology, either in whole cell patch-clamp, perforated patch-clamp or conventional two-electrode voltage- clamp. A cell line of choice modified to successfully express a voltage-gated sodium channel of interest together with a suitable potassium leak ion channel transfected can then be used for screening using atomic absorptions spectrometry, as described above.

Whole-cell voltage clamp electrophysiology assay

Electrophysiological recordings of sodium currents in cells stably expressing the voltage- gated sodium channel of interest confirms activity and provides a functional measure of the potency of compounds that specifically affect such channels.

Electrophysiological studies can be performed using automated patch-clamp electrophysiology platforms, like Ion Works HT, Ion Works Quattro, PatchXpress, or any other suitable platform. The cell line expressing the voltage-gated sodium channel of interest is plated in appropriate well tissue plates, as provided by the manufacturer of the automated patch-clamp platforms. Suitable extracellular and intracellular buffer for such experiments are applied according to the instructions given by the manufacturer of the automated patch-clamp platforms. Cells that express the voltage-gated sodium channel protein of interest are exposed to drugs through the pipetting system integrated in the platforms. A suitable voltage stimulus protocol is used to activate the voltage-gated sodium channel proteins of interest. A suitable stimulus protocol may consist of eight voltage pulses, each to -20 mV and 50 ms in length, and separated from each other by 330 ms intervals at a potential of -90 mV or -65 mV, but may also have other suitable parameters.

Electrophysiological studies can also be performed using the whole cell configuration of the standard patch clamp technique as described in the literature. In this assay, cells that express the human voltage-gated sodium channel protein of interest are exposed to the drugs by conventional microperfusion systems and a suitable voltage stimulus protocol is used to activate the voltage-gated sodium channels.

In vivo experiments A compound of the invention when given by systemic injection to mice or rats, may specifically reduce pain behavior in the formalin test. This test is an accepted model of clinical pain in man, involving elements of nociceptor activation, inflammation, peripheral sensitization and central sensitization (A Tjølsen et al. Pain 1992, 51, 5/ It can therefore be inferred that a compound of the present invention is usefulas a therapeutic agent to relieve pain of various origins.

Compounds of formula I may showin analgesic activity in the intraarticular FCA (Freund's complete adjuvant) test in the rat, a model of inflammatory pain (Iadarola et al. Brain Research 1988, 455, 205-12) and in the Chung nerve lesion test in the rat, a model for neuropathic pain (Kim and Chung. Pain 1992, 50, 355). The analgesic effects in the animal models may be obtained after doses that do not produce tissue concentrations leading to conduction block in nerve fibers. Thus, the analgesic effects can not be explained by the local anesthetic properties of the compounds mentioned in the publication by Kornet and Thio. Analgesic efficacy after systemic administration is not a general property of drugs with local anesthetic effects (Scott et al. British Journal of Anaesthesia 1988, 61, 165-8). Generally, compounds of the invention are active in the Whole-cell voltage clamp electrophysiology assay above with IC₅₀ values less than 10 μM. In one aspect of the invention, the IC₅₀ value is less than 1 μM.

Title compounds of the above Examples were tested in the Whole-cell voltage clamp electrophysiology assay mentioned above. IC50 represents the compound concentration required for 50% inhibition. Specimen results are shown in the following table as pIC50 values, i.e. -log (IC50). Thus the larger the pIC50 the more potent the compound. For example, a pIC50 of 6.6 indicates an IC50 of 10 ^' M.

Claims

1. A compound of formula I

wherein

orfluoro; and wherein

may optionally be substituted by one or more fluoro;

m is 1 or 2;

Het is selected from any one of pyridinyl, pyrazinyl, isoxazolyl, pyrazolyl, indolyl, triazolyl and pyrimidinyl, wherein each such heteroaryl may optionally be substituted by one or more Λ; X⁴ is halo, C_1-3alkyl, Ci.₃alkyl0Ci.₃alkyl, -CH(CH₃)-O-C(CH₃)₃, d_₄alkoxy, cyano, hydroxy, or Ci_2hydroxyalkyl; ; and wherein said Cisalkyl,

-CH(CHi)-O-C(CHi) i and

may each optionally be substituted by one or more fluoro;

5

with the exception of the compounds: o 2-[l-(l,5-dimethyl-lH-pyrazol-4-yl)ethyl]-5,7-dimethoxy-3-oxo-N-[2- (trifluoromethyl)benzyl]isoindoline- 1 -carboxamide;

N-(4-fluorobenzyl)-3-oxo-2-(2-pyridin-4-ylethyl)isoindoline-l-carboxamide; and N-(2-chlorobenzyl)-2-[2-(lH-indol-3-yl)- 1 -methylethyl]-3-oxoisoindoline- 1 -carboxamide; s as well as a pharmaceutically acceptable salt or isomer thereof, or a salt of said isomer.

2. A compound according to claim 1, wherein

R¹ is hydrogen, Ci_₃alkoxy, Ci_₃alkyl, chloro, fluoro, cyano or hydroxy; 0 m is 1 or 2;

R² and R³ is each and independently selected from hydrogen, C^haloalkyl,

Ci_4haloalkoxy, halo, Ci_4alkoxy and Ci_4alkyl, and whereas both R² and R³ can not be hydrogen;

Het is selected from any one of pyridinyl, pyrazinyl, isoxazolyl, pyrazolyl, indolyl,5 triazolyl and pyrimidinyl, wherein each such heteroaryl may optionally be substituted by one or more X⁴;

X⁴ is Ci_₃alkyl, Ci_₃alkoxy or fluoro;

Liis Ci_₃alkylene; and

L₂ is Ci_₃alkylene. o

3. A compound according to claim 1 or 2, wherein R¹ is hydrogen.

4. A compound according to claim 1 or 2, wherein R¹ is methoxy.

5. A compound according to claim 1 or 2, wherein R¹ is methyl.

5 6. A compound according to claim 1 or 2, wherein R¹ is cyano.

7. A compound according to claim 1 or 2, wherein R¹ is hydroxy.

8. A compound according to claim 1 or 2, wherein R¹ is chloro. 0

9. A compound according to claim 1 or 2, wherein R¹ is fluoro.

10. A compound according to any one of claims 1-9, wherein R² is chloro, fluoro or bromo. 5

11. A compound according to any one of claims 1 -9, wherein R² is -O-CF₃ or -0-CH₂-CF₃.

12. A compound according to any one of claims 1-9, wherein R² is CF₃ or -CH₂-CF₃.0

13. A compound according to any one of claims 1-9, wherein R² is methoxy.

14. A compound according to any one of claims 1-9, wherein R² is hydrogen. 5

15. A compound according to any one of claims 1-9, wherein R² is iso-propyl.

16. A compound according to any one of claims 1-15, wherein R³ is hydrogen.

17. A compound according to any one of claims 1-15, wherein R³ is fluoro, chloro oro bromo.

18. A compound according to any one of claims 1-15, wherein R³ is methyl.

19. A compound according to any one of claims 1-15, wherein R³ is CF3.

20. A compound according to any one of claims 1-15, wherein R³ is -OCF3.

21. A compound according to any one of claims 1-20, wherein Li is selected from methylene, ethylene and propylene.

22. A compound according to any one of claims 1-20, wherein Li is selected from -CH-(CHs)-CH₂-; -CH-(CH₃)-; -C(CH₃)₂-CH₂-; -CH₂-CH(CH₃);

-CH₂-C-(CH₃)₂-; and

23. A compound according to any one of claims 1-22 wherein L₂ is methylene.

24. A compound according to any one of claims 1-22 wherein L₂ is -CH-(CH₃)-.

25. A compound according to any one of claims 1-22, wherein L₂ is -cy clopropy lene- .

26. A compound according to any one of claims l-25,wherein X⁴ is methoxy.

27. A compound according to any one of claims 1-25, wherein X⁴ is methyl.

28. A compound according to any one of claims 1-25, wherein, wherein X is cyano.

29. A compound according to any one of claims 1-25, wherein, wherein X⁴ is CF₃.

30. A compound according to any one of claims 1-25, wherein, wherein X⁴ is fluoro.

31. A compound according to any one of claims 1-25, wherein, wherein X⁴ is -0-CH₂-CF₃.

32. A compound according to any one of claims 1-25, wherein, wherein X⁴ is methyl.

33. A compound according to any one of claims 1-25, wherein, wherein X⁴ is -CH₂OH.

34. A compound according to any one of claims 1-25, wherein, wherein X⁴ is -CH(CH₃)-O-C(CH₃)₃.

35. A compound according to any one of the preceding claims, selected from any one of:

N-[(4-Chlorophenyl)methyl]-3-oxo-2-(2-pyridin-2-ylethyl)-lH-isoindole-l- carboxamide;

3 -Oxo-2-(2-pyridin-2-ylethyl)-N- [ [4-(trifluoromethoxy)phenyl]methyl] - 1 H-isoindole-

1-carboxamide;

3 -Oxo-2-(2-pyridin-2-ylethyl)-N- [ [4-(trifuoromethyl)phenyl]methyl]- 1 H-isoindole- 1 - carboxamide;

3-Oxo-2-(pyridin-3-ylmethyl)-N-[[4-(trifluoromethoxy)phenyl]methyl]-lH-isoindole-

1 -carboxamide;

N- [ 1 -(4-Chlorophenyl)ethyl] -3 -oxo-2-(2-pyridin-2-ylethyl)- 1 H-isoindole- 1 - carboxamide; 3-Oxo-2-(2-pyrazin-2-ylethyl)-N-[[4-(trifluoromethoxy)phenyl]methyl]-lH-isoindole-

1 -carboxamide;

2- [(2-Methoxypyridin-3 -yl)methyl] -3 -oxo-N- [ [4-(trifluoromethoxy)phenyl]methyl] -

1 H-isoindole- 1 -carboxamide;

3 -Oxo-2-(pyrazin-2-ylmethyl)-N- [ [4-(trifluoromethoxy)phenyl]methyl] - 1 H-isoindole- 1 -carboxamide; 3-Oxo-2-(2-pyridin-2-ylethyl)-N-[l-[4-(2,2,2-trifluoroethoxy)phenyl]ethyl]-lH- isoindole- 1 -carboxamide;

2- [(5 -Methyl 1 ,2-oxazol-3 -yl)methyl] -3 -oxo-N- [[4-(trifluoromethoxy)phenyl]methyl]-

1 H-isoindole- 1 -carboxamide; N- [(4-Chlorophenyl)methyl] -3 -oxo-2-(2-pyrazin-2-ylethyl)-l H-isoindole- 1- carboxamide;

N- [ 1 -(4-Chlorophenyl)ethyl] -3 -oxo-2-(2-pyrazin-2-ylethyl)- 1 H-isoindole- 1 - carboxamide;

N- [l-(4-Chlorophenyl)ethyl] -3 -oxo-2-(pyridin-3-ylmethyl)-l H-isoindole- 1- carboxamide;

N- [(4-Fluorophenyl)methyl] -3 -oxo-2-(2-pyridin-2-ylethyl)-l H-isoindole- 1- carboxamide;

3-Oxo-2-(2-pyridin-2-ylethyl)-N-[[4-(2,2,2-trifluoroethoxy)phenyl]methyl]-lH- isoindole- 1 -carboxamide; 2- [3 -(3 -Methyl- 1 H-pyrazol- 1 -yl)propyl] -3 -oxo-N- [4-(trifluoromethoxy)benzyl] - isoindoline- 1 -carboxamide;

2-(l -Methyl-2-pyridin-2-ylethyl)-3-oxo-N-[4-(trifluoromethoxy)benzyl]isoindoline- 1 ^■ carboxamide;

4-Methoxy-3-oxo-2-(2-pyridin-2-ylethyl)-7V-[4-(trifluoromethoxy)benzyl]isoindoline- 1 -carboxamide;

3-Oxo-2-(2-pyridin-4-ylethyl)-N-[4-(trifluoromethoxy)benzyl]isoindoline-l- carboxamide;

3-Oxo-2-(2-pyridin-3-ylethyl)-N-[4-(trifluoromethoxy)benzyl]isoindoline-l- carboxamide; 2-(l-Methyl-2-pyridin-2-ylethyl)-3-oxo-N-[4-(trifluoromethyl)benzyl]isoindoline-l- carboxamide;

Λ/-(4-Chlorobenzyl)-2-(l-methyl-2-pyridin-2-ylethyl)-3-oxoisoindoline-l- carboxamide;

2-[2-(lH-Indol-3-yl)ethyl]-3-oxo-N-[4-(trifluoromethoxy)benzyl]isoindoline-l- carboxamide;

Λ/-(4-Methoxybenzyl)-3-oxo-2-(2-pyridin-2-ylethyl)isoindoline-l -carboxamide; 4-Methoxy-2-(l-methyl-2-pyridin-2-ylethyl)-3-oxo-iV-[4 (trifluoromethoxy)benzyl]- isoindoline- 1 -carboxamide;

Λ/-(4-Isopropylbenzyl)-2-(l-methyl-2-pyridin-2-ylethyl)-3-oxoisoindoline-l- carboxamide; N- [4-Fluoro-3 -(trifluoromethyl)benzy 1] -2-( 1 -methyl-2-pyridin-2-ylethyl)-3 - oxoisoindoline- 1 -carboxamide;

N- [3 -Fluoro-4-(trifluoromethyl)benzy 1] -2-( 1 -methyl-2-pyridin-2-ylethyl)-3 - oxoisoindoline- 1 -carboxamide;

2-(l -Methyl-2-pyridin-2-ylethyl)-3-oxo-N-[3-(trifluoromethoxy)benzyl]isoindoline- 1 - carboxamide;

N-[I -(3-Chlorophenyl)ethyl]-3-oxo-2-(2-pyridin-2-ylethyl)isoindoline- 1 -carboxamide;

2-(2-(5-Fluoropyrimidin-2-yl)ethyl)-3-oxo-N-(4-

(trifluoromethoxy)benzyl)isoindoline- 1 -carboxamide;

2-(2-(4-Methylpyrimidin-2-yl)ethyl)-3-oxo-N-(4- (trifluoromethoxy)benzyl)isoindoline- 1 -carboxamide;

3 -Oxo-2-(2-(pyrimidin-2-yl)ethyl)-N-(4-(trifluoromethoxy)benzyl)isoindoline- 1 - carboxamide;

2-(2-(2-Methylpyrimidin-5-yl)ethyl)-3-oxo-N-(4-

(trifluoromethoxy)benzyl)isoindoline- 1 -carboxamide; 2-((6-Cyanopyridin-3-yl)methyl)-3-oxo-N-(4-(trifluoromethoxy)benzyl)isoindoline- 1 - carboxamide;

3-Oxo-2-((6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-N-(4-

(trifluoromethoxy)benzyl)isoindoline- 1 -carboxamide;

2-(l -(5-Fluoropyridin-2-yl)ethyl)-3-oxo-N-(4-(trifluoromethoxy)benzyl)isoindoline- 1 - carboxamide; 7-Chloro-3-oxo-2-(2-(pyridin-2-yl)ethyl)-N-(4-(trifluoromethoxy)benzyl)isoindoline-

1 -carboxamide; 7-Cyano-3-oxo-2-(2-(pyridin-2-yl)ethyl)-N-(4-(trifluoromethoxy)benzyl)isoindoline-

1-carboxamide;

2-(2-Hydroxy-2-(pyridin-2-yl)ethyl)-3-oxo-N-(4-

(trifluoromethoxy)benzyl)isoindoline- 1 -carboxamide; 2-(2,2-Difluoro-2-(pyridin-2-yl)ethyl)-3-oxo-N-(4-

(trifluoromethoxy)benzyl)isoindoline- 1 -carboxamide;

2-(2,2-Difluoro-2-(pyridin-2-yl)ethyl)-7-methyl-3-oxo-N-(4-

(trifluoromethoxy)benzyl)isoindoline- 1 -carboxamide;

7-Methoxy-3-oxo-2-(2-(pyridin-2-yl)ethyl)-N-(4-

(trifluoromethoxy)benzyl)isoindoline- 1 -carboxamide;

7-Hydroxy-3-oxo-2-(2-(pyridin-2-yl)ethyl)-N-(4-

(trifluoromethoxy)benzyl)isoindoline- 1 -carboxamide; 2-(2-Methyl- 1 -(pyridin-2-yl)propan-2-yl)-3-oxo-N-(4-

(trifluoromethoxy)benzyl)isoindoline- 1 -carboxamide;

7-Methyl-3-oxo-2-(2-(pyridin-2-yl)ethyl)-N-(4-(trifluoromethoxy)benzyl)isoindoline-

1 -carboxamide;

2-(2-Methyl-2-(pyridin-3-yl)propyl)-3-oxo-N-(4- (trifluoromethoxy)benzyl)isoindoline- 1 -carboxamide;

2-(2-Methyl-2-(pyridin-2-yl)propyl)-3-oxo-N-(4-

(trifluoromethoxy)benzyl)isoindoline- 1 -carboxamide;

3-Oxo-2-((l-(pyridin-2-yl)cyclopropyl)methyl)-N-(4-

(trifluoromethoxy)benzyl)isoindoline- 1 -carboxamide; 3-Oxo-2-(2-(pyridin-2-yl)ethyl)-N-(l-(4-(trifluoromethoxy)phenyl)ethyl)isoindoline-

1 -carboxamide, ISOMER 4;

2-(2-(6-Methylpyridin-2-yl)ethyl)-3-oxo-N-(4-(trifluoromethoxy)benzyl)isoindoline-

1 -carboxamide;

2-(2-(6-(Hydroxymethyl)pyridin-2-yl)ethyl)-3-oxo-N-(4- (trifluoromethoxy)benzyl)isoindoline- 1 -carboxamide;

2-(2-(4-( 1 -tert-Butoxy ethyl)- IH-1 ,2,3 -triazol- 1 -yl)ethyl)-3 -oxo-N-(4-

(trifluoromethoxy)benzyl)isoindoline- 1 -carboxamide; 4-Fluoro-3-oxo-2-(2-(pyridin-2-yl)ethyl)-N-(4-(trifluoromethoxy)benzyl)isoindoline-

1-carboxamide;

7-Fluoro-3-oxo-2-(2-(pyridin-2-yl)ethyl)-N-(4-(trifluoromethoxy)benzyl)isoindoline-

1-carboxamide; 2-(2-(3-Fluoropyridin-2-yl)ethyl)-3-oxo-N-(4-(trifluoromethoxy)benzyl)isoindoline- 1 - carboxamide;

4-Hydroxy-3-oxo-2-(l-(pyridin-2-yl)propan-2-yl)-N-(4-

(trifluoromethoxy)benzyl)isoindoline- 1 -carboxamide;

4-Hydroxy-3-oxo-2-(2-(pyridin-2-yl)ethyl)-N-(4- (trifluoromethoxy)benzyl)isoindoline- 1 -carboxamide;

3-Oxo-2-(2-(pyridin-2-yl)ethyl)-N-(3-(trifluoromethoxy)benzyl)isoindoline-l- carboxamide;

N-(2-Methyl-4-(trifluoromethoxy)benzyl)-3-oxo-2-(2-(pyridin-2-yl)ethyl)isoindoline-

1 -carboxamide; N-(3-Bromobenzyl)-3-oxo-2-(2-(pyridin-2-yl)ethyl)isoindoline- 1 -carboxamide;

N-(4-Bromobenzyl)-3-oxo-2-(2-(pyridin-2-yl)ethyl)isoindoline-l -carboxamide;

N-(4-Bromobenzyl)-3-oxo-2-(2-(pyridin-2-yl)ethyl)isoindoline-l -carboxamide,

ISOMER 1;

N-(3,4-Dichlorobenzyl)-3-oxo-2-(2-(pyridin-2-yl)ethyl)isoindo line- 1 -carboxamide; 3-Oxo-2-(2-(pyridin-3-yl)ethyl)-N-(l-(4-

(trifluoromethyl)phenyl)cyclopropyl)isoindoline- 1 -carboxamide; and

3-Oxo-2-(2-(pyridin-2-yl)ethyl)-N-(4-(2,2,2-trifluoroethyl)benzyl)isoindoline-l- carboxamide.

36. A compound according to any one of the preceding claims, for use in therapy.

37. Use of a compound according to any one of claims 1-35, for the manufacture of a medicament for use in the treatment of a pain disorder.

38. A method for the treatment of a pain disorder, whereby a compound according to any one of claims 1-35 is administered to a subject in need of such pain treatment.

39. A compound according to any one of claims 1-35, for use in the treatment of a pain disorder.

40. A pharmaceutical composition comprising a compound according to any one of claims 1-35, in admixture with a pharmaceutically and pharmacologically acceptable excipient.