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WO2008065500A2 - Heteroaryl amides as type i glycine transport inhibitors

WO2008065500A2 - Heteroaryl amides as type i glycine transport inhibitors - Google PatentsHeteroaryl amides as type i glycine transport inhibitors Download PDF Info
Publication number
WO2008065500A2
WO2008065500A2 PCT/IB2007/003604 IB2007003604W WO2008065500A2 WO 2008065500 A2 WO2008065500 A2 WO 2008065500A2 IB 2007003604 W IB2007003604 W IB 2007003604W WO 2008065500 A2 WO2008065500 A2 WO 2008065500A2
Authority
WO
WIPO (PCT)
Prior art keywords
alkylene
membered
alkyl
zero
heterocycloalkyl
Prior art date
2006-11-30
Application number
PCT/IB2007/003604
Other languages
French (fr)
Other versions
WO2008065500A3 (en
Inventor
Iii John Adams Lowe
Subas Man Sakya
Mark Allen Sanner
Jotham Wadsworth Coe
Stanton Furst Mchardy
Original Assignee
Pfizer Products Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
2006-11-30
Filing date
2007-11-19
Publication date
2008-06-05
2007-11-19 Application filed by Pfizer Products Inc. filed Critical Pfizer Products Inc.
2008-06-05 Publication of WO2008065500A2 publication Critical patent/WO2008065500A2/en
2008-11-13 Publication of WO2008065500A3 publication Critical patent/WO2008065500A3/en
Links Classifications Definitions Landscapes Abstract

The present invention relates to a series of substituted heteroaryl amides of the Formula (I), wherein, R1-R12 groups are defined as in the specification, that exhibit activity as glycine transport inhibitors, their pharmaceutically acceptable salts, pharmaceutical compositions containing them, and their use for the enhancement of cognition and the treatment of the positive and negative symptoms of schizophrenia and other psychoses in mammals, Including humans, wherein HET is a 5 or 6 membered membered heteroaryl ring optionally substituted by one or more substituents selected from R5; X1 Is C(=O) Or SO2;. X2 Is -(Czero-C1O alkyleneXO)y-(Czero-C10 alkytene)-, or -(C3C10 cycloalkyl)-(Czero-C10 alkylene)-(O)y-(Czero H10 alkylene)-; wherein y is O or 1; X3 Is -(Czero-C1O alkylene)-NR1R2; -(C3-C10 alkylene)-NR1R2; -(Czero-C10alkylene)-X4 or (C3-C10 cycloalkyl)-(Czero-C10 alkylene)-X4; wherein said cycloalkyl is optional substituted by one or more -OH; X4 is a nitrogen containing (5-15 membered) heterocydoalkyi or a nitrogen containing (5-15 membered) heteroaryl, each optionally substituted by one or more substituents selected from R5; with the proviso that the 4-15 membered heterocydoalkyi of X4 is not a 3-aza-bicyclo{3.1.0]hex-6-yl group; Ring A Is a -(C5-C15) aryt, -(5-15 membered) heteroaryl or (5-15 membered) heterocydoalkyi.

Description

HETEROARYL AMIDES AS TYPE I GLYCINE TRANSPORT INHIBITORS

Background

The present invention relates to heteroaryl amides and to pharmaceutical compositions containing them and to their use in the treatment of central nervous system disorders, cognitive disorders, schizophrenia, dementia and other disorders in mammals, including humans. These compounds exhibit activity as inhibitors of the glycine type-1 transporter.

Schizophrenia, a progressive neurological disease, is manifested in its early stages as thought disorders such as hallucinations, paranoid delusions, and bizarre thought patterns, collectively known as positive symptoms. These easily recognizable symptoms gave the disease the historical name "madness". As the disease progresses, negative symptoms, such as social withdrawal and anhedonia, and cognitive symptoms such as dementia become more apparent. Only about one-third of schizophrenic patients can be treated successfully and returned to society, while the remainder is generally institutionalized. The burden on society of this devastating illness and the toll it takes on family members of affected patients make it one of the most costly of all CNS diseases.

Pharmacological treatment for schizophrenia has traditionally involved blockade of the dopamine system, which is thought to be responsible for its positive symptoms. Such treatment, however, ignores the negative and cognitive aspects of the disease. Another neurotransmitter system believed to play a role in schizophrenia is the glutamate system, the major excitatory transmitter system in the brain. This hypothesis is based on the observation that blockade of the glutamate system by compounds such as PCP ("angel dust") can replicate many of the symptoms of schizophrenia, including its positive, negative, and cognitive aspects. If schizophrenia involves a deficit of glutamatergic transmission, augmentation of the glutamate system, and specifically the NMDA receptor, may be beneficial. While glutamate is the principle agonist at NMDA receptors, glycine is required as a co-agonist to set the "tone" of the receptor for its response to glutamate. Enhancing this "tone" by increasing the effect of glycine would augment NMDA neurotransmission, and provide potential benefit in the treatment of schizophrenia.

A specific mechanism for augmenting the glycinergic "tone" of the NMDA receptor was disclosed recently by Bergeron, et al. (Proc. Natl. Acad. Sci. USA, 95, 15730, (1998)), which is hereby incorporated by reference. This group showed that a specific and potent inhibitor of the glycine type-1 transporter (GIyTI ) responsible for removing glycine from the synapse at the NMDA receptor, termed NFPS (WO 97/45115), could enhance NMDA receptor function. For example, NFPS increased the postsynaptic current driven by the NMDA receptor, an effect blocked by both a specific NMDA-site antagonist and a glycine-site antagonist. Even though glycine levels in the brain are high relative to the amount required to act as an NMDA receptor co-agonist, this work shows that GIyTI removes glycine efficiently at the synapse, and that inhibition of GIyTI can augment NMDA receptor function. The present invention provides GIyTI inhibitors as a treatment for disorders or conditions such as schizophrenia through its augmentation of glutamatergic neurotransmission.

Summary of the Invention The present invention relates to compounds of Formula I,

wherein HET is a 5 or 6 membered membered heteroaryl ring optionally substituted by one or more substituents selected from R

5

;

X1 is C(=O) or SO2;

X2 is -(CZero-Cio alkylene)-(O)y-(Czero-C10 alkylene)-, or -(C3-C10 cycloalkyl)-(Czera-Ci0 alkylene)-(O)y-(C2ero-C10 alkylene)-; wherein y is 0 or 1;

X3 is -(Czero-Cio alkylene)-NR1R2; -(C3-C10 cycloalky)-(Czero-C10 alkylene)-NR1R2; -(Czero-Ci0 alkylene)-X4 or -(C3-C10 cycloalkyl)-(Czero-C10 alkylene)-X4; wherein said cycloalkyl is optional substituted by one or more -OH;

X4 is a nitrogen containing (5-15 membered) heterocycloalkyl or a nitrogen containing (5-15 membered) heteroaryl, each optionally substituted by one or more substituents selected from R5; with the proviso that the 4-15 membered heterocycloalkyl of X4 is not a 3-aza- bicyclo{3.1.0]hex-6-yl group;

Ring A is a -(C6-C15) aryl, -(5-15 membered) heteroaryl or (5-15 membered) heterocycloalkyl, each optionally substituted by one or more substitutent selected from R5; each R1 and R2 are independently selected from -H, -C1-C12 alkyl, -C2-Ci2 alkenyl, - C2-C12 alkynyl, -C(=O)R3, -S(O)nR3, -C(=O)OR4, -C(=O)NR3R4, -S(O)2NR3R4, -(Czero-C4 alkylene)-(C3-C20 cycloalkyl), -(Czero-C4 alkylene)-(C4-C8 cycloalkenyl), -(Czero-C4 alkylene)- ((Cs-C-πJbi- or tricycloalkyi), -(Czero-C4 alkylene)-((C7-C1i)bi- or tricycloalkenyl), -(Czero-C4 alkylene)-((5-10 membered) heterocycloalkyl), -(Czero-C4 alkylene)-(C6-C10 aryl) and -(Czero-C4 alkylene)-((5-10 membered) heteroaryl, wherein said wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bi- or tricycloalkyi, bi- or tricycioalkenyl, heterocycloalkyl, aryl, and heteroaryl of R1 or R2 are each independently optionally substituted by one or more substitutents selected from R5; each R3 and R4 are independently selected from -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl and -(Czero-C4 alkylene)-(C3-C6 cycloalkyl), wherein said alkyl, alkenyl, alkynyl and cycloalkylof R3 or R4 are each optionally independently substituted with one or more substituents independently selected from -C1-C4 alkoxy, -OH and -S(Ci-C4 alkyl); wherein each R5 is independently selected from -OH, -CrC12 alkyl, -C2-C12 alkenyl, - C2-C12 alkynyl, -C1-C6 alkoxy, -C2-C6 alkenoxy, -C2-C6 alkynoxy, halogen, -CN, -NO2, -NR9R10, -C(O)NR9R10, -S(O)2NR9R10, -C(=O)R11, -OC(=O)R11, -S(O)nR11, -C(=O)OR12, -C3-C15 cycloalkyl, -C4-C15 cycloalkenyl, -(Cs-C-nJbi- or tricycloalkyl, -(Cr-Ci^bi- or tricycloalkenyl, -(4-20 membered) heterocycloalkyl, -C6-C15 aryl, -(5-15 membered) heteroaryl, -C6-Ci5 aryloxy and -(5- 15 membered) heteroaryloxy, wherein said alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, alkynoxy, cycloalkyl, cycloalkenyl, bi- or tricycloalkyl, bi- or tricycloalkenyl, heterocycloalkyl, aryl, heteroaryl, aryloxy and heteroaryloxy of R5 are each optionally independently substituted with one or more substituents independently selected from R6; wherein each R6 is independently selected from -OH, halogen, -C1-Ci2 alkyl, -C2-C12 alkenyl, -C2-C12 alkynyl, -C1-C6 alkoxy, -C2-C6 alkenoxy, -C2-C6 alkynoxy, -Cl, -Br, -I, -CN, - NO2, -NR9R10, -C(=O)NR9R10, -S(O)2NR9R10, -C(=0)R11, -0C(=0)R11, -S(O)nR11, -C(=0)0R12, -C3-C15 cycloalkyl, -C4-C15 cycloalkenyl, -(C5-C-,i)bi- or tricycloalkyl, -(Cy-C-nJbi- or tricycloalkenyl, -(4-20 membered) heterocycloalkyl, -C6-Ci5 aryl. -(5-15 membered) heteroaryl, -C6-C15 aryloxy and -(5-15 membered) heteroaryloxy, wherein said alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, alkynoxy, cycloalkyl, cycloalkenyl, bi- or tricycloalkyl, bi- or tricycloalkenyl, heterocycloalkyl, aryl, heteroaryl, aryloxy and heteroaryloxy of R6 are each optionally independently substituted with one or more substituents independently selected from the group

R6a wherein each R6a is independently selected from -OH, halogen, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -C1-C6 alkoxy, -C2-C6 alkenoxy, -C2-C6 alkynoxy, -C1-C6 hydroxyalkyl, -CN, -NO2, -NR9R10, -C(=O)NR9R10, -C(=0)R11, -S(O)2NR9R10, -S(O)nR11, -C6-C15 aryl, -(5-15 membered) heteroaryl, -C6-C15 aryloxy and -(5-15 membered) heteroaryloxy, wherein said alkyl, alkenyl and alkynyl, alkoxy, alkenoxy, alkynoxy, hydroxyalkyl, aryl, aryloxy, heteroaryl and heteroaryloxy of R6a are each optionally independently substituted with one or more subsitutents selected from halogens, -C1-C12 alkyl, -C1-C4 alkoxy, or -OH; each R9 and R10 are independently selected from -H, -C1-C12 alkyl, -C2-C12 alkenyl, - C2-C12 alkynyl, -CF3, -C(=O)R11, -S(O)nR11, -C(=O)OR12, -C(=O)NR11R12, -S(O)2NR11R12, - (Czero-C4 alkylene)-(C3-C20 cycloalkyl), -(Czera-C4 alkylene)-(C4-C8 cycloalkenyl), -(Czer0-C4 alkylene)-((C5-Cii)bi- or tricycloalkyl), -(Czero-C4 alkylene)-((C7-C11)bi- or tricycloalkenyl), -(Czera- C4 alkylene)-((5-10 membered) heterocycloalkyl), -(Czero-C4 alkylene)-(C6-C10 aryl) and -(Czero- C4 alkylene)-((5-10 membered) heteroaryl), wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bi-or tricycloalkyl, bi- or tricycloalkenyl, heterocycloalkyl, aryl and heteroaryl of R9 and R10 are each optionally independently substituted with one or more substituents independently selected from -OH, -C1-C12 alkyl, -C2-C12 alkenyl, -C2-Ci2 alkynyl, -C1-C6 alkoxy, -C2-C6 alkenoxy, -C2-C6 alkynoxy, -C1-C6 hydroxyalkyl, halogen, -CN, -NO2, -CF3, -NR11R12, -C(=O)NR11R12, -SO2NR11R12, -C(=O)H and -C(=O)OH; or NR9R10 may in each instance independently optionally form a -(4-10 membered) heterocycloalkyl or -(4-10 membered) heterocycloalkenyl, wherein said heterocycloaikyl and heterocycloalkenyl of NR9R10 each optionally independently contain from one to two further heteroatoms independently selected from N, O and S, and wherein said heterocycloalkyl and heterocycloalkenyl of NR9R10 are each optionally independently substituted with one or more substituents independently selected from -OH, -C1-C12 alkyl, -C2-C12 alkenyl, -C2-Ci2 alkynyl, - C1-C6 alkoxy, -C2-C6 alkenoxy, -C2-C6 alkynoxy, halogen, -NR11R12, -C(=O)NR11R12, - SO2NR11R12, C(=O)R11, SO2R11, (Czero-C4 alkylene)-(C6-C10 cycloalkyl), (Czero-C4 alkylene)-((5- 10 membered) heterocycloalkyl), (Czero-C4 alkylene)-(C6-C10 aryl) and (Czero-C4 alkylene)-((5- 10 membered) heteroaryl, each R11 and R12 are independently selected from -H, -C1-C15 alkyl, -C2-C15 alkenyl, - C2-C15 alkynyl, -(Czera-C4 alkylene)-(C3-C15 cycloalkyl), -(Czer0-C4 alkylene)-(C4-C8 cycloalkenyl), -(Czero-C4 alkylene)-((C5-C1i)bi- or tricycloalkyl), -(C^r0-C4 alkyleneJ-^Cy-C-i -,)bi- or tricycloalkenyl), -(Czer0-C4 alkylene)-((5-15 membered) heterocycloalkyl), -(Czera-C4 alkylene)- (C6-C15 aryl) and -(Czero-C4 alkylene)-((5-15 membered) heteroaryl), wherein said alkyl, alkenyl, alkynyl, cycloalkyi, cycloalkenyl, bi-or tricycloalkyl, bi- or tricycloalkenyl, heterocycloalkyl, aryl and heteroaryl of R11 and R12 are each optionally independently substituted with with one or more substituents independently selected from -OH, -C1-C12 alkyl, -C2-C12 alkenyl, -C2-Ci2 alkynyl, -C1-C6 alkoxy, -C2-C6 alkenoxy, -C2-C6 alkynoxy, -Ci-C6 hydroxyalkyl, halogen, -CN, -NO2, -CF3, -NH2, -NH(CrC6 alkyl), -N(Ci-C6 alkyl)2, -C(=O)NH2, - C(=O)NH(CrC6 alkyl), -C(=O)N(C,-C6 alkyl)2, -SO2NH2, -SO2NH(Ci-C6 alkyl), -SO2N(C1-C6 alkyl)2, -C(=O)H, -C(=O)OH and -C(=O)O(CrC6 alkyl), or NR11R12 may in each instance independently optionally form a -(4-10 membered) heterocycloalkyl or -(4-10 membered) heterocycloalkenyl, wherein said heterocycloalkyl and heterocycloalkenyl of NR9R10 each optionally independently contain from one to two further heteroatoms independently selected from N, O and S, and wherein said heterocycloalkyl and heterocycloalkenyl of NR9R10 are each optionally independently substituted with one or more substituents independently selected from -OH, -Ci-C12 alkyl, -C2-Ci2 alkenyl, -C2-Ci2 alkynyl, - C1-C6 alkoxy, -C2-C6 alkenoxy, -C2-C6 alkynoxy, halogen, -NR11R12, (Czer0-C4 alkylene)-(C6-Ci0 cycloalkyl), (Czer0-C4 alkylene)-((5-10 membered) heterocycloalkyl), (Czero-C4 alkylene)-(C6-C10 aryl) and (Czer0-C4 alkylene)-((5-10 membered) heteroaryl; n is O, 1 , or 2; or a pharmaceutically acceptable salt thereof.

Detailed Description of the Invention Unless otherwise indicated, as used herein, the terms "halogen" and "halo" include F, Cl, Br, and 1.

Unless otherwise indicated, as used herein, the term "alkyl" includes saturated monovalent hydrocarbon radicals having straight or branched moieties. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, butyl, pentyl, hexyl, cyclopropylmethylene (-CHa-cyclopropyl) and £-butyl.

Unless otherwise indicated, as used herein, the term "alkenyl" includes alkyl moieties having at least one carbon-carbon double bond wherein alkyl is as defined above. Examples of alkenyl include, but are not limited to, ethenyl and propenyl.

Unless otherwise indicated, as used herein, the term "alkynyl" includes alkyl moieties having at least one carbon-carbon triple bond wherein alkyl is as defined above. Examples of alkynyl groups include, but are not limited to, ethynyl and 2-propynyl.

Unless otherwise indicated, as used herein, the term "alkoxy", means "alkyl-O-", wherein "alkyl" is as defined above. Examples of "alkoxy" groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, pentoxy and allyloxy.

Unless otherwise indicated, as used herein, the term "aikoxyalkyl" means alkyl-O- alkyl-, wherein alkyl is defined above.

Unless otherwise indicated, as used herein, the term "hydroxyalkyl" means -alkyl-OH, wherein alkyl is defined above.

Unless otherwise indicated, as used herein, the term "alkenoxy", means "alkenyl-O-", wherein "alkenyl" is as defined above.

Unless otherwise indicated, as used herein, the term "alkynoxy", means "alkynyl-O-", wherein "alkynyl" is as defined above.

Unless otherwise indicated, as used herein, the term "cycloalkyl" includes non- aromatic saturated cyclic alkyl moieties wherein alkyl is as defined above. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. "Bicycloalkyl" and "tricycloalkyl" groups include non-aromatic saturated cyclic alkyl moieties consisting of two or three rings respectively, wherein said rings share at least one carbon atom. "Bicycloalkyl" and "tricycloalkyl" groups also include cyclic moieties consisting of two or three rings respectively, wherein one ring is aryl or heteroaryl and wherein said rings share two carbon atoms. For purposes of the present invention, and unless otherwise indicated, bicycloalkyl groups include spiro groups and fused ring groups. Examples of bicycloalkyl groups include, but are not limited to, bicyclo-[3.1.0]-hexyl, bicyclo — 2.2.1]-hept-1-yl, norbornyl, spiro[4.5]decyl, spiro[4.4]nonyl, spiro[4.3]octyl, spiro[4.2]heptyl, indan, teralene (1 ,2,3,4-tetrahydronaphlene) and 6, 7, 8, θ-tetrahydro-δH-benzocycloheptene. An example of a tricycloalkyl group is adamantanyl. Other cycloalkyl, bicycloalkyl, and tricycloalkyl groups are known in the art, and such groups are encompassed by the definitions "cycloalkyl", "bicycloalkyl" and "tricycloalkyl" herein. For purposes of this invention, the term "cycloalkyl" will also include multi-cyclic rings groups (e.g., bicycloalkyl, tricycloalkyl, etc.) "Cycloalkenyl", "bicycloalkenyl", and "tricycloalkenyl" refer to non-aromatic each cycloalkyl, bicycloalkyl, and tricycloalkyl moieties as defined above, except that they each include one or more carbon-carbon double bonds connecting carbon ring members (an "endocyclic" double bond) and/or one or more carbon-carbon double bonds connecting a carbon ring member and an adjacent non-ring carbon (an "exocyclic" double bond). Examples of cycloalkenyl groups include, but are not limited to, cyclopentenyl, cyclobutenyl, and cyclohexenyl. A non-limiting example of a bicycloalkenyl group is norbomenyl. Cycloaikyl, cycloalkenyl, bicycloalkyl, and bicycloalkenyl groups also include groups that are substituted with one or more oxo moieties. Examples of such groups with oxo moieties are oxocyclopentyl, oxocyclobutyl, oxocyclopentenyl and norcamphoryl. Other cycloalkenyl, bicycloalkenyl, and tricycloalkenyl groups are known in the art, and such groups are included within the definitions "cycloalkenyl", "bicycloalkenyl" and "tricycloalkenyl" herein.

Unless otherwise indicated, as used herein, the term "aryl" includes an organic radical derived from an aromatic hydrocarbon by removal of one hydrogen, such as phenyl (Ph), naphthyl, indenyl, indanyl and fluorenyl. "Aryl" encompasses fused ring groups wherein at least one ring is aromatic.

Unless otherwise indicated, as used herein, the terms "heterocyclic" and "heterocycloalkyl" refer to non-aromatic cyclic groups containing one or more heteroatoms, preferably from one to four heteroatoms, each selected from O, S and N. "Heterobicycloalkyl" groups include non-aromatic two-ringed cyclic groups, wherein said rings share one or two atoms, and wherein at least one of the rings contains a heteroatom (O, S, or N). "Heterobicycloalkyl" groups also include two-ringed cyclic groups, wherein said one ring is aryl or heteroaryl ring and wherein said rings share one or two atoms, and wherein at least one of the rings contains a heteroatom (O, S, or N). Unless otherwise indicated, for purposes of the present invention, heterobicycloalkyl groups include spiro groups and fused ring groups. In one embodiment, each ring in the heterobicycloalkyl contains up to four heteroatoms (i.e. from zero to four heteroatoms, provided that at least one ring contains at least one heteroatom). The heterocyclic groups of this invention can also include ring systems substituted with one or more oxo moieties. For purposes of this invention, the term "heterocycloalkyl" will include multi-cyclic rings groups (e.g., heterobicycloalkyl heterotricycloalkyl, etc.) Examples of non-aromatic heterocyclic groups are aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, azepinyl, piperazinyl, 1 ,2,3,6-tetrahydropyridinyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholino, thiomorpholino, thioxanyl, pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1 ,3-dioxolanyl, pyrazolinyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, quinolizinyl, quinuclidinyl, 1,4-dioxaspiro[4.5]decyl, 1 ,4-dioxaspiro[4.4]nonyl, 1 ,4- dioxaspiro[4.3]octyl, and 1 ,4-dioxaspiro[4.2]heptyl.

Unless otherwise indicated, as used herein, "heteroaryl" refers to aromatic groups containing one or more heteroatoms, preferably from one to four heteroatoms, selected from O, S and N. A multicyclic group containing one or more heteroatoms wherein at least one ring of the group is aromatic is a "heteroaryl" group. The heteroaryl groups of this invention can also include ring systems substituted with one or more oxo moieties. Examples of heteroaryl groups are pyridinyl, pyridazinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, quinolyl, isoquinolyl, 1 ,2,3,4-tetrahydroguinolyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, triazinyl, 1 ,2,4-trizainyl, 1 ,3,5-triazinyl, isoindolyl, 1-oxoisoindolyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzotriazolyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, dihydroquinolyl, tetrahydroquinolyl, dihydroisoquinolyl, tetrahydroisoquinolyl, benzofuryl, furopyridinyl, pyrolopyrimidinyl, and azaindolyl.

Unless otherwise indicated, as used herein, the term "cycloalkoxy", means "cycloalkyl-O-", wherein "cycloalkyl" is as defined above.

Unless otherwise indicated, as used herein, the term "aryloxy", means "aryl-O-", wherein "aryl" is as defined above.

Unless otherwise indicated, as used herein, the term "heterocycloalkoxy", means "heterocycloalkyl-O-", wherein "heterocycloalkyl" is as defined above.

Unless otherwise indicated, as used herein, the term "heteroaryloxy", means "heteroaryl-O", wherein "heteroaryl" is as defined above.

Unless otherwise indicated, all the foregoing groups derived from hydrocarbons may be optionally substituted by one or more halogen atoms (e.g., -CH2F, -CHF2 -CF3, -PhCI, etc.).

Unless otherwise indicated, the term "one or more" substituents, or "at least one" substituent as used herein, refers to from one to the maximum number of substituents possible based on the number of available bonding sites. (Examples of one or more or at least one substituent include, but are not limited to, 1 to 10 substituents, or 1 to 6 substituents or 1 to 3 substituents).

All the foregoing groups derived from hydrocarbons may have up to about 1 to about 20 carbon atoms (e.g. CrC2o alkyl, C2-C20 alkenyl, C3-C20 cycloalkyl, (3-20 membered)heterocycloalkyl, C6-C20 aryl, (5-20 membered)heteroaryl, etc.) or 1 to about 15 carbon atoms (e.g., C1-C15 alkyl, C2-Ci5 alkenyl, C3-Ci5 cycloalkyl, (3-15 membered)heterocycloalkyl, C6-C15 aryl, (5-15 membered)heteroaryl, etc.), or 1 to about 12 carbon atoms, or 1 to about 8 carbon atoms, or 1 to about 6 carbon atoms.

The foregoing groups, as derived from the compounds listed above, may be C- attached or N-attached where such is possible. For instance, a group derived from pyrrole may be pyrrol-1-yl (N-attached) or pyrrol-3-yl (C-attached). The terms referring to the groups also encompass all possible tautomers.

A 3-aza-bicyclo{3.1.0]hex-6-yl group has the following structure:.

A Czero alkylene means a direct bond. For example, when X3 is -(C2era alkylene)-X4, this mean that X4 is directed bonded to the tertiary nitrogen of Formula I.

In one aspect of the invention, in the compound of Formula I, HET is imidazolyl, thiazolyl or isoxazolyl.

In another aspect, X3 is -(C3-C10 cycloalky)-NR1R2. In yet another aspect, cycloalkyl is selected from cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. In another aspect, R1 and/or R2 are hydrogen.

In another aspect, X3 is -(C2Sr0-C1 alkylene)-X4 and X4 is nitrogen containing (5-15 membered) heterocycloalkyl. In another aspect, the nitrogen containing heterocyloalkyl is azepanyl, pyrrolidinyl, azabicycloheptyl, azabicyclononyl or azabicyclodecyl

In another aspect, X1 is -C(=O)-.

In another aspect, the present invention relates to a compound of Formula I

wherein HET is imidazolyl optionally substituted by one or more substituents selected from

R5;

X1 is -C(=O)- or SO2;

X2 is -(Czero-C10 alkylene)

X3 is -(Czero-C-,0 alky)ene)-X4, -(C3-C10 cycloalky)-NR1R2 or -(C3-C10 cycloalkyl)-X4; wherein said cycloalkyl is optional substituted by one or more -OH;

X4 is a nitrogen containing (4-15 membered) heterocycloalkyl or a nitrogen containing (5-15 membered) heteroaryl, each optionally substituted by one or more substituents selected from R5; with the proviso that the 4-15 membered heterocycloalkyl of X4 is not a 3-aza- bicyclo{3.1.0]hex-6-yl group

Ring A is a -C

6

-C

15

aryl, -(5-15 membered) heteroaryl or (4-15 membered) heterocycloalkyl, each optionally substituted by one or more substitutent selected from R

5

; each R

1

and R

2

are independently selected from -H, -C

1

-Ci

2

alkyl, -C

2

-Ci

2

alkenyl, - C

2

-C

12

alkynyl, -C(=O)R

3

, -S(O)

n

R

3

, -C(=O)OR

4

, -C(=O)NR

3

R

4

, -S(O)

2

NR

3

R

4

, -(C

2ero

-C

4

alkylene)-(C

3

-C

20

cycloalkyl), -(C

zero

-C

4

alkylene)-(C

4

-C

8

cycloalkenyl), -(C

2ero

-C

4

alkylene)- ((C

5

-Cn)bi- or tricycloalkyl), -(C

zero

-C

4

alkylene)-((C

7

-C

11

)bi- or tricycloalkenyl), -(Cz

S

r

0

-C

4

alkylene)-((5-10 membered) heterocycloalkyl), -(C

zero

-C

4

alkylene)-(C

6

-Ci

0

aryl) and -(C

Ze

r

o

-C

4

alkylene)-((5-10 membered) heteroaryl, wherein said wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bi- or tricycloalkyl, bi- or tricycloalkenyl, heterocycloalkyl, aryl, and heteroaryl of R

1

or R

2

are each independently optionally substituted by one or more substitutents selected from R

5

; each R

3

and R

4

are independently selected from -C

1

-C

6

alkyl, -C

2

-C

6

alkenyl, -C

2

-C

6

alkynyl and -(C

zero

-C

4

alkylene)-(C

3

-C

6

cycloalkyl), wherein said alkyl, alkenyl, alkynyl and cycloalkylof R

3

or R

4

are each optionally independently substituted with one or more substituents independently selected from -C

1

-C

4

alkoxy, -OH and -S(C

1

-C

4

alkyl); wherein each R

5

is independently selected from -OH, -C

1

-C

12

alkyl, -C

2

-C

12

alkenyl, - C

2

-C

12

alkynyl, -C

1

-C

6

alkoxy, -C

2

-C

6

alkenoxy, -C

2

-C

6

alkynoxy, halogen, -OR

11

, -CN, -NO

2

, - NR

9

R

10

, -C(=O)NR

9

R

10

, -S(O)

2

NR

9

R

10

, -C(=0)R

11

, -OC(=O)R

11

, -S(O)

n

R

11

, -C(=O)OR

12

, -C

3

- C

15

cycloalkyl, -C

4

-C

15

cycloalkenyl,

or tricycloalkyl, -(C

7

-C

11

JbJ- or tricycloalkenyl, - (4-20 membered) heterocycloalkyl, -C

6

-Ci

5

aryl, -(5-15 membered) heteroaryl, -C

6

-Ci

5

aryloxy and -(5-15 membered) heteroaryloxy, wherein said alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, alkynoxy, cycloalkyl, cycloalkenyl, bi- or tricycloalkyl, bi- or tricycloalkenyl, heterocycloalkyl, aryl, heteroaryl, aryloxy and heteroaryloxy of R

5

are each optionally independently substituted with one or more substituents independently selected from R

6

; wherein each R

6

is independently selected from -OH, halogen, -C

1

-C

12

alkyl, -C

2

-Ci

2

alkenyl, -C

2

-C

t2

alkynyl, -C

1

-C

6

alkoxy, -C

2

-C

6

alkenoxy, -C

2

-C

6

alkynoxy, -Cl, -Br, -I, -CN, - NO

2

, -NR

9

R

10

, -C(=O)NR

9

R

10

, -S(O)

2

NR

9

R

10

, -C(=0)R

11

, -0C(=0)R

11

, -S(O)

n

R

11

, -C(O)OR

12

, -C

3

-C

15

cycloalkyl, -C

4

-C

15

cycloalkenyl, -(C

5

-Cn)bi- or tricycloalkyl, -(C

7

-Cn)bi- or tricycloalkenyl, -(4-20 membered) heterocycloaikyl, -C

6

-C

15

aryl, -(5-15 membered) heteroaryl, -C

6

-C

15

aryloxy and -(5-15 membered) heteroaryloxy, wherein said alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, alkynoxy, cycloalkyl, cycloalkenyl, bi- or tricycloalkyl, bi- or tricycloalkenyl, heterocycloalkyl, aryl, heteroaryl, aryloxy and heteroaryloxy of R

6

are each optionally independently substituted with one or more substituents independently selected from the group R

6a

; wherein each R

6a

is independently selected from -OH

1

halogen, -C

1

-C

6

alkyl, -C

2

-C

6

alkenyl, -C

2

-C

6

alkynyl, -C

1

-C

6

alkoxy, -C

2

-C

6

alkenoxy, -C

2

-C

6

alkynoxy, -C

1

-C

6

hydroxyalkyl, -CN, -NO

2

, -NR

9

R

10

, -C(=O)NR

9

R

10

, -C(=O)R

11

, -S(O)

2

NR

9

R

10

, -S(O)

n

R

11

, -C

6

-C

15

aryl, -(5-15 membered) heteroaryl, -C

6

-C

15

aryloxy and -(5-15 membered) heteroaryloxy, wherein said aikyl, alkenyl and alkynyl, alkoxy, alkenoxy, alkynoxy, hydroxyalkyl, aryl, aryloxy, heteroaryl and heteroaryloxy of R

6a

are each optionally independently substituted with one or more subsitutents selected from halogens, -C

1

-C

12

alkyl, -C

1

-C

4

alkoxy, or -OH; each R

9

and R

10

are independently selected from -H, -Ci-Ci

2

alkyl, -C

2

-Ci

2

alkenyl, - C

2

-Ci

2

alkynyl, -CF

3

, -C(=O)R

11

, -S(O)

n

R

11

, -C(=O)OR

12

, -C(=0)NR

11

R

12

, -S(O)

2

NR

11

R

12

, - (C

zera

-C

4

alkylene)-(C

3

-C

20

cycloalkyl), -(C

ze

r

o

-C

4

alkylene)-(C

4

-C

8

cycloalkenyl), -(C

zero

-C

4

alkylene)-((C

5

-Cn)bi- or tricycloalkyl), -(C

zera

-C

4

alkylene)-((C

7

-Cn)bi- or tricycloalkenyl), -(C

zero

- C

4

alkylene)-((5-10 membered) heterocycloalkyl), -(C

zero

-C

4

alkylene)-(C

6

-C

10

aryl) and -(C

zero

- C

4

alkylene)-((5-10 membered) heteroaryl), wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bi-or tricycloalkyl, bi- or tricycloalkenyl, heterocycloalkyl, aryl and heteroaryl of R

9

and R

10

are each optionally independently substituted with one or more substituents independently selected from -OH, -C

r

Ci

2

alkyl, -C

2

-Ci

2

alkenyl, -C

2

-Ci

2

alkynyl, -C

1

-C

6

alkoxy, -C

2

-C

6

alkenoxy, -C

2

-C

6

alkynoxy, -C

1

-C

6

hydroxyalkyl, halogen, -CN, -NO

2

, -CF

3

, -NR

11

R

12

, -C(=0)NR

11

R

12

, -SO

2

NR

11

R

12

, -C(=O)H and -C(=O)OH; or NR

9

R

10

may in each instance independently optionally form a -(4-10 membered) heterocycloalkyl or -(4-10 membered) heterocycloalkenyl, wherein said heterocycloalkyl and heterocycloalkenyl of NR

9

R

10

each optionally independently contain from one to two further heteroatoms independently selected from N, O and S, and wherein said heterocycloalkyl and heterocycloalkenyl of NR

9

R

10

are each optionally independently substituted with one or more substituents independently selected from -OH, -C

1

-C

12

alkyl, -C

2

-C

12

alkenyl, -C

2

-C

12

alkynyl, - C

1

-C

6

alkoxy, -C

2

-C

6

alkenoxy, -C

2

-C

6

alkynoxy, halogen, -NR

11

R

12

, -C(=O)NR

11

R

12

, - SO

2

NR

11

R

12

, C(=O)R

11

, SO

2

R

11

, (C

zero

-C

4

alkylene)-(C

6

-C

10

cycloalkyl), (C

zero

-C

4

alkylene)-((5- 10 membered) heterocycloalkyl), (C

zer

o-C

4

alkylene)-(C

6

-C

10

aryl) and (C

zero

-C

4

alkylene)-((5- 10 membered) heteroaryl, each R

11

and R

12

are independently selected from -H, -Ci-C

15

alkyl, -C

2

-Ci

5

alkenyl, - C

2

-C

15

alkynyl, -(C

zero

-C

4

alkylene)-(C

3

-C

15

cycloalkyl), -(C

zero

-C

4

alkylene)-(C

4

-C

8

cycloalkenyl), -(C

zero

-C

4

alkylene)-((C

5

-C

11

)bi- or tricycloalkyl), -(C

zero

-C

4

alkylene)-((C

7

-C

1

i)bi- or tricycloalkenyl), -(C

ZΘro

-C

4

alkylene)-((5-15 membered) heterocycloalkyl), -(C

zero

-C

4

alkylene)- (C

6

-Ci

5

aryl) and -(C

zero

-C

4

alkylene)-((5-15 membered) heteroaryl), wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bi-or tricycloalkyl, bi- or tricycloalkenyl, heterocycloalkyl, aryl and heteroaryl of R

11

and R

12

are each optionally independently substituted with with one or more substituents independently selected from -OH, -C

1

-C

12

alkyl, -C

2

-C

12

alkenyl, -C

2

-C

12

alkynyl, -C

1

-C

6

alkoxy, -C

2

-C

6

alkenoxy, -C

2

-C

6

alkynoxy, -C

1

-C

6

hydroxyalkyl, halogen, -CN, -NO

2

, -CF

3

, -NH

2

, -NH(C

1

-C

6

alky!), -N(C

1

-C

6

alkyl)

2

, -C(=O)NH

2

, - C(=O)NH(C

r

C

β

alkyl), -C(=O)N(C

r

C

6

alkyl)

2

, -SO

2

NH

2

, -SO

2

NH(C

1

-C

6

alkyl), -SO

2

N(C

1

-C

6

alkyl)

2>

-C(=O)H, -C(=O)OH and -C(=0)0(C

r

C

6

alkyl), or NR

11

R

12

may in each instance independently optionally form a -(4-10 membered) heterocycloalkyl or -(4-10 membered) heterocycloalkenyl, wherein said heterocycloalkyl and heterocycloalkenyl of NR

9

R

10

each optionally independently contain from one to two further heteroatoms independently selected from N, O and S, and wherein said heterocycloalkyl and heterocycloalkenyl of NR

9

R

10

are each optionally independently substituted with one or more substituents independently selected from -OH, -Ci-C

12

alkyl, -C

2

-Ci

2

alkenyl, -C

2

-Ci

2

alkynyl, - Ci-C

6

alkoxy, -C

2

-C

6

alkenoxy, -C

2

-C

6

alkynoxy, halogen, (C

zer0

-C

4

alkylene)-(C

6

-C

10

cycloalkyl), (C

ze

r

o

-C

4

alkylene)-((5-10 membered) heterocycloalkyl), (C

2ero

-C

4

alkylene)-(C

6

-C

10

aryl) and (C

zero

-C

4

alkylene)-((5-10 membered) heteroaryl; n is 0, 1 , or 2; or a pharmaceutically acceptable salt thereof.

In another aspect of this invention X3 is X4 and X4 is

In another aspect X3 is -(CrC2 alkylene)-X4 wherein X4 is

In another aspect, X3 is -(C3-C10 cycloalky)-NR1R2 or -(C3-CI0 cycloalkyl)-X4; wherein the cycloalkyl is cyclopentyl or cyclohexyl.

In another aspect, X4 is azetidinyl or pyrrolidinyl

In another aspect, R1 and R2 are each independently hydrogen or C1-C6 alkyl.

In another aspect, X2 is -CH2- and ring A is phenyl.

In another aspect, ring A is phenyl and optionally substituted by one or more -OH, - C1-C6 alkyl, -Ci-C6 alkoxy, -C3-C8 cycloalkoxy, -C1-C6 haloalkyl, halogen, -C1-C6 haloalkyloxy or -C3-C8 cycloalkyl.

In another aspect, ring A is phenyl and optionally substituted by one or more -OH, - CF3, -OCF3 or Halogen In another aspect, Het is

Specific embodiments of the present invention are shown in the Examples below.

Compounds of the Formula I may have optical centers and therefore may occur in different enantiomeric and diastereomeric configurations. The present invention includes all enantiomers, diastereomers, and other stereoisomers of such compounds of the Formula I, as well as racemic compounds and racemic mixtures and other mixtures of stereoisomers thereof.

Pharmaceutically acceptable salts of the compounds of Formula I include the acid addition and base salts thereof.

Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include, but are not limited to, the acetate, adipate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mandelates mesylate, methylsulphate, naphthylate, 2- napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, pyroglutamate, salicylate, saccharate, stearate, succinate, sulfonate, stannate, tartrate, tosylate, trifluoroacetate and xinofoate salts.

Suitable base salts are formed from bases which form non-toxic salts. Examples include, but are not limited to, the aluminium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts.

Hemisalts of acids and bases may also be formed, for example, hemisulphate and hemicalcium salts.

For a review on suitable salts, see Handbook of Pharmaceutical Salts: Properties, Selection, and Use by Stahl and Wermuth (Wiley-VCH, 2002).

Pharmaceutically acceptable salts of compounds of Formula I may be prepared by one or more of three methods:

(i) by reacting the compound of Formula I with the desired acid or base; (ii) by removing an acid- or base-labile protecting group from a suitable precursor of the compound of Formula I or by ring-opening a suitable cyclic precursor, for example, a lactone or lactam, using the desired acid or base; or

(iii) by converting one salt of the compound of Formula I to another by reaction with an appropriate acid or base or by means of a suitable ion exchange column.

All three reactions are typically carried out in solution. The resulting salt may precipitate out and be collected by filtration or may be recovered by evaporation of the solvent. The degree of ionization in the resulting salt may vary from completely ionised to almost non-ionised.

The compounds of the invention may exist in a continuum of solid states ranging from fully amorphous to fully crystalline. The term 'amorphous' refers to a state in which the material lacks long range order at the molecular level and, depending upon temperature, may exhibit the physical properties of a solid or a liquid. Typically such materials do not give distinctive X-ray diffraction patterns and, while exhibiting the properties of a solid, are more formally described as a liquid. Upon heating, a change from solid to liquid properties occurs which is characterised by a change of state, typically second order ('glass transition')- The term 'crystalline' refers to a solid phase in which the material has a regular ordered internal structure at the molecular level and gives a distinctive X-ray diffraction pattern with defined peaks. Such materials when heated sufficiently will also exhibit the properties of a liquid, but the change from solid to liquid is characterised by a phase change, typically first order ('melting point').

The compounds of the invention may also exist in unsolvated and solvated forms. The term 'solvate' is used herein to describe a molecular complex comprising the compound of the invention and one or more pharmaceutically acceptable solvent molecules, for example, ethanol. The term 'hydrate' is employed when said solvent is water.

A currently accepted classification system for organic hydrates is one that defines isolated site, channel, or metal-ion coordinated hydrates - see Polymorphism in Pharmaceutical Solids by K. R. Morris (Ed. H. G. Brittain, Marcel Dekker, 1995). Isolated site hydrates are ones in which the water molecules are isolated from direct contact with each other by intervening organic molecules. In channel hydrates, the water molecules lie in lattice channels where they are next to other water molecules. In metal-ion coordinated hydrates, the water molecules are bonded to the metal ion.

When the solvent or water is tightly bound, the complex will have a well-defined stoichiometry independent of humidity. When, however, the solvent or water is weakly bound, as in channel solvates and hygroscopic compounds, the water/solvent content will be dependent on humidity and drying conditions. In such cases, non-stoichiometry will be the norm. The compounds of the invention may also exist in a mesomorphic state (mesophase or liquid crystal) when subjected to suitable conditions. The mesomorphic state is intermediate between the true crystalline state and the true liquid state (either melt or solution). Mesomorphism arising as the result of a change in temperature is described as 'thermotropic' and that resulting from the addition of a second component, such as water or another solvent, is described as 'lyotropic'. Compounds that have the potential to form lyotropic mesophases are described as 'amph philic' and consist of molecules which possess an ionic (such as -COO"Na+, -COO"K+, or -SO3-Na+) or non-ionic (such as -N"N+(CH3)3) polar head group. For more information,! see Crystals and the Polarizing Microscope by N. H. Hartshorne and A. Stuart, 4th Edition (Edward Arnold, 1970).

Hereinafter all references to compounds of Formula I include references to salts, solvates, multi-component complexes and liquid crystals thereof and to solvates, multi- component complexes and liquid crystals of salts thereof.

The compounds of the invention include compounds of Formula I as hereinbefore defined, including all polymorphs and crystal habits thereof, prodrugs and isomers thereof (including optical, geometric and tautomeric isomers) as hereinafter defined and isotopically- labeled compounds of Formula I.

As indicated, so-called 'prodrugs' of the compounds of Formula I are also within the scope of the invention. Thus certain derivatives of compounds of Formula I which may have little or no pharmacological activity themselves can, when administered into or onto the body, be converted into compounds of Formula I having the desired activity, for example, by hydrolytic cleavage. Such derivatives are referred to as 'prodrugs'. Further information on the use of prodrugs may be found in Pro-drugs as Novel Delivery Systems, Vol. 14, ACS Symposium Series (T. Higuchi and W. Stella) and Bioreversible Carriers in Drug Design, Pergamon Press, 1987 (Ed. E. B. Roche, American Pharmaceutical Association). '

Prodrugs in accordance with the invention can, for example, be produced by replacing appropriate functionalities present in the compounds of Formula I with certain moieties known to those skilled in the art as 'pro-moieties' as described, for example, in Design of Prodrugs by H. Bundgaard (Elsevier, 1985).

Some examples of prodrugs in accordance with the invention include, but are not limited to,

(i) where the compound of Formula I contains a carboxylic acid functionality

(-COOH), an ester thereof, for example, a compound wherein the hydrogen of the carboxylic acid functionality of the compound of Formula (I) is replaced by (CrC8)alkyl;

(ii) where the compound of Formula I contains an alcohol functionality (-OH)1 an ether thereof, for example, a compound wherein the hydrogen of the alcohol functionality of the compound of Formula I is replaced by (CrC6)alkanoyloxymethyl; and (iii) where the compound of Formula I contains a primary or secondary amino functionality (-NH2 or -NHR where R ≠ H), an amide thereof, for example, a compound wherein, as the case may be, one or both hydrogens of the amino functionality of the compound of Formula I is/are replaced by ((-VCioJalkanoyl.

Further examples of replacement groups in accordance with the foregoing examples and examples of other prodrug types may be found in the aforementioned references.

Moreover, certain compounds of Formula I may themselves act as prodrugs of other compounds of Formula I.

Also included within the scope of the invention are metabolites of compounds of Formula I, that is, compounds formed in vivo upon administration of the drug. Some examples of metabolites in accordance with the invention include, but are not limited to,

(i) where the compound of Formula I contains a methyl group, an hydroxymethyl derivative thereof (-CH3 -> -CH2OH):

(ii) where the compound of Formula I contains an alkoxy group, an hydroxy derivative thereof (-OR -> -OH);

(iii) where the compound of Formula I contains a tertiary amino group, a secondary amino derivative thereof (-NR1R2 -> -NHR1 or -NHR2);

(iv) where the compound of Formula I contains a secondary amino group, a primary derivative thereof (-NHR1 -> -NH2);

(v) where the compound of Formula I contains a phenyl moiety, a phenol derivative thereof (-Ph -> -PhOH); and

(vi) where the compound of Formula I contains an amide group, a carboxylic acid derivative thereof (-CONH2 -> COOH).

Compounds of Formula I containing one or more asymmetric carbon atoms can exist as two or more stereoisomers. Where a compound of Formula I contains an alkenyl or alkenylene group, geometric cis/trans (or Z/E) isomers are possible. Where structural isomers are interconvertible via a low energy barrier, tautomeric isomerism ('tautomerism') can occur. This can take the form of proton tautomerism in compounds of Formula I containing, for example, an imino, keto, or oxime group, or so-called valence tautomerism in compounds which contain an aromatic moiety. It follows that a single compound may exhibit more than one type of isomerism.

Included within the scope of the present invention are all stereoisomers, geometric isomers and tautomeric forms of the compounds of Formula I, including compounds exhibiting more than one type of isomerism, and mixtures of one or more thereof. Also included are acid addition or base salts wherein the counterion is optically active, for example, d-lactate or /-lysine, or racemic, for example, (//-tartrate or d/-arginine. Cisltrans isomers may be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallisation.

Conventional techniques for the preparation/isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC). -

Alternatively, the racemate or racemic mixture (or a racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where the compound of Formula I contains an acidic or basic moiety, a base or acid such as 1-phenylethylamine or tartaric acid. The resulting diastereomeric mixture may be separated by chromatography and/or fractional crystallization and one or both of the diastereoisomers converted to the corresponding pure enantiomer(s) by means well known to a skilled person.

Chiral compounds of the invention (and chiral precursors thereof) may be obtained in enantiomerically-enriched form using chromatography, typically HPLC, on an asymmetric resin with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50% by volume of isopropanol, typically from 2% to 20%, and from 0 to 5% by volume of an alkylamine, typically 0.1 % diethylamine. Concentration of the eluate affords the enriched mixture.

When any racemate crystallises, crystals of two different types are possible. The first type is the racemic compound (true racemate) referred to above wherein one homogeneous form of crystal is produced containing both enantiomers in equimolar amounts. The second type is the racemic mixture or conglomerate wherein two forms of crystal are produced in equimolar amounts each comprising a single enantiomer.

While both of the crystal forms present in a racemic mixture have identical physical properties, they may have different physical properties compared to the true racemate. Racemic mixtures may be separated by conventional techniques known to those skilled in the art - see, for example, Stereochemistry of Organic Compounds by E. L. ENeI and S. H. Wilen (Wiley, 1994).

The present invention includes all pharmaceutically acceptable isotopically-labelled compounds of Formula I wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number which predominates in nature.

Examples of isotopes suitable for inclusion in the compounds of the invention include, but are not limited to, isotopes of hydrogen, such as 2H and 3H, carbon, such as 11C, 13C and 14C, chlorine, such as 36CI, fluorine, such as 18F, iodine, such as 123I and 125I, nitrogen, such as

13:

1N and 15N, oxygen, such as 150, 17O and 18O, phosphorus, such as 32P, and sulphur, such as 35S. Certain isotopically-labelled compounds of Formula I, for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies. The radioactive isotopes tritium, i.e. 3H, and carbon-14, i.e. 14C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.

Substitution with heavier isotopes such as deuterium, i.e. 2H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.

Substitution with positron emitting isotopes, such as 11C, 18F, 15O and 13N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.

Isotopically-labeled compounds of Formula I can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically- labeled reagent in place of the non-labeled reagent previously employed.

Pharmaceutically acceptable solvates in accordance with the invention include those wherein the solvent of crystallization may be isotopically substituted, e.g. D2O, d6-acetone, d6- DMSO.

When preparing compounds of Formula I in accordance with the invention, it is open to a person skilled in the art to routinely select the form of compound of Formula Il which provides the best combination of features for this purpose. Such features include, but are not limited to, the melting point, solubility, processability and yield of the intermediate form and the resulting ease with which the product may be purified on isolation.

This invention also relates to a method of treating a disorder or condition selected from psychosis, schizophrenia, conduct disorder, disruptive behavior disorder, bipolar disorder, psychotic episodes of anxiety, anxiety associated with psychosis, psychotic mood disorders such as severe major depressive disorder; mood disorders associated with psychotic disorders such as acute mania or depression associated with bipolar disorder and mood disorders associated with schizophrenia, behavioral manifestations of mental retardation, conduct disorder and autistic disorder; movement disorders such as Tourette's syndrome, akinetic-rigid syndrome, movement disorders associated with Parkinson's disease, tardive dyskinesia and other drug induced and neurodegeneration based dyskinesias; attention deficit hyperactivity disorder; cognitive disorders such as dementias (including age related dementia, and senile dementia of the Alzheimer's type) and memory disorders in a mammal, including a human, comprising administering to a mammal in need of such treatment an amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof, that is effective in treating such condition or disorder. This invention also relates to a pharmaceutical composition for treating a disorder or condition selected from psychosis, schizophrenia, conduct disorder, disruptive behavior disorder, bipolar disorder, psychotic episodes of anxiety, anxiety associated with psychosis, psychotic mood disorders such as severe major depressive disorder; mood disorders associated with psychotic disorders such as acute mania or depression associated with bipolar disorder and mood disorders associated with schizophrenia, behavioral manifestations of mental retardation, conduct disorder and autistic disorder; movement disorders such as Tourette's syndrome, akinetic-rigid syndrome, movement disorders associated with Parkinson's disease, tardive dyskinesia and other drug induced and neurodegeneration based dyskinesias; attention deficit hyperactivity disorder; cognitive disorders such as dementias (including age related dementia and senile dementia of the Alzheimer's type) and memory disorders in a mammal, including a human, comprising a compound of the formula I1 or a pharmaceutically acceptable salt thereof, in an amount that is effective for treating such disorder or condition.

This invention also relates to a method of treating a disorder or condition selected from psychosis, schizophrenia, conduct disorder, disruptive behavior disorder, bipolar disorder, psychotic episodes of anxiety, anxiety associated with psychosis, psychotic mood disorders such as severe major depressive disorder; mood disorders associated with psychotic disorders such as acute mania or depression associated with bipolar disorder and mood disorders associated with schizophrenia, behavioral manifestations of mental retardation, conduct disorder and autistic disorder; movement disorders such as Tourette's syndrome, akinetic-rigid syndrome, movement disorders associated with Parkinson's disease, tardive dyskinesia and other drug induced and neurodegeneration based dyskinesias; attention deficit hyperactivity disorder; cognitive disorders such as dementias (including age related dementia and senile dementia of the Alzheimer's type) and memory disorders in a mammal, including a human, comprising administering to a mammal in need of such treatment a glycine transport-inhibiting amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof.

This invention also relates to a pharmaceutical composition for treating a disorder or condition selected from psychosis, schizophrenia, conduct disorder, disruptive behavior disorder, bipolar disorder, psychotic episodes of anxiety, anxiety associated with psychosis, psychotic mood disorders such as severe major depressive disorder; mood disorders associated with psychotic disorders such as acute mania or depression associated with bipolar disorder and mood disorders associated with schizophrenia, behavioral manifestations of mental retardation, conduct disorder and autistic disorder; movement disorders such as Tourette's syndrome, akinetic-rigid syndrome, movement disorders associated with Parkinson's disease, tardive dyskinesia and other drug induced and neurodegeneration based dyskinesias; attention deficit hyperactivity disorder; cognitive disorders such as dementias (including age related dementia and senile dementia of the Alzheimer's type) and memory disorders in a mammal, including a human, comprising a compound of the formula I, or a pharmaceutically acceptable salt thereof, in a glycine transport-inhibiting amount.

As used herein, the term "treating" refers to reversing, alleviating or inhibiting the progress of a disease, disorder or condition, or one or more symptoms of such disease, disorder or condition, to which such term applies. As used herein, "treating" may also refer to decreasing the probability or incidence of the occurrence of a disease, disorder or condition in a mammal as compared to an untreated control population, or as compared to the same mammal prior to treatment. For example, as used herein, "treating" may refer to preventing a disease, disorder or condition, and may include delaying or preventing the onset of a disease, disorder or condition, or delaying or preventing the symptoms associated with a disease, disorder or condition. As used herein, "treating" may also refer to reducing the severity of a disease, disorder or condition or symptoms associated with such disease, disorder or condition prior to a mammal's affliction with the disease, disorder or condition. Such prevention or reduction of the severity of a disease, disorder or condition prior to affliction relates to the administration of the composition of the present invention, as described herein, to a subject that is not at the time of administration afflicted with the disease, disorder or condition. As used herein "treating" may also refer to preventing the recurrence of a disease, disorder or condition or of one or more symptoms associated with such disease, disorder or condition. The terms "treatment" and "therapeutically," as used herein, refer to the act of treating, as "treating" is defined above.

The compounds of the present invention exhibit glycine transport inhibiting activity and therefore are of value in the treatment of a wide variety of clinical conditions that are characterized by the deficit of glutamateric neurotransmission in mammalian subjects, especially humans. Such conditions include the positive and negative symptoms of schizophrenia and other psychoses, and cognitive deficits.

The compounds of this invention can be administered via either the oral, parenteral (such as subcutaneous, intraveneous, intramuscular, intrasternal and infusion techniques), rectal, intranasal or topical routes to mammals. In general, these compounds are most desirably administered to humans in doses ranging from about 1mg to about 2000 mg per day, although variations will necessarily occur depending upon the weight and condition of the subject being treated and the particular route of administration chosen. However, a dosage level that is in the range of from about 0.1 mg to about 20 mg per kg of body weight per day is most desirably employed. Nevertheless, variations may still occur depending upon the species of animal being treated and its individual response to said medicament, as well as on the type of pharmaceutical formulation chosen and the time period and interval at which such administration is carried out. In some instances, dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effects provided that such higher dose levels are first divided into several small doses for administration throughout the day.

In one embodiment, the compounds of this invention are administered as adjunctive therapy with known antipsychotics such as Ziprasidone (Geodon), Clozapine, Molindone, Loxapine, Pimozide, Risperidone, Olanzapine, Remoxipride, Sertindole, Amisulpride, Quetiapine, Prochlorperazine, Fluphenazine, Trifluoroperazine, Thioridazine, Haloperidol, Chloropromazine, Flupentixol and Pipotiazine.

In another embodiment, the compounds of the present invention may also be used in combination with CNS agents such as antidepressants (such as sertraline), anti-Parkinsonian drugs (such as deprenyl, L-dopa, Requip, Mirapex, MAOB inhibitors such as selegine and rasagiline, comP inhibitors such as Tasmar, A-2 inhibitors, dopamine reuptake inhibitors, NMDA antagonists, Nicotine agonists, Dopamine agonists and inhibitors of neuronal nitric oxide synthase), anti-Alzheimer's drugs such as donepezil, tacrine, σ2<5 inhibitors, COX-2 inhibitors, gaba pentenoids, propentofylline or metryfonate, and antipyschotics such as PDE10 inhibitors, 5HT2C agonists, alpha 7 nicotinic receptor agonists, CB1 antagonists and compounds having activity antagonizing dopamine D2 receptors.

The compounds of the present invention may be administered alone or in combination with pharmaceutically acceptable carriers or diluents by either of the above routes previously indicated, and such administration can be carried out in single or multiple doses. More particularly, the novel therapeutic agents of the invention can be administered in a wide variety of different dosage forms, i.e., they may be combined with various pharmaceutically acceptable inert carriers in the form of tablets, capsules, lozenges, troches, hard candies, powders, sprays, creams, salves, suppositories, jellies, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs, syrups, and the like. Such carriers include solid diluents or fillers, sterile aqueous media and various non-toxic organic solvents, etc. Moreover, oral pharmaceutical compositions can be suitably sweetened and/or flavored. In general, the therapeutically effective compounds of this invention are present in such dosage forms at concentration levels ranging about 5.0% to about 70% by weight.

For oral administration, tablets containing various excipients such as microcrystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine may be employed along with various disintegrants such as starch and preferably corn, potato or tapioca starch, alginic acid and certain complex silicates, together with granulation binders like polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for tabletting purposes. Solid compositions of a similar type may also be employed as fillers in gelatine capsules; preferred materials in this connection also include lactose or milk sugar as well as high molecular weight polyethylene glycols. When aqueous suspensions and/or elixirs are desired for oral administration, the active ingredient may be combined with various sweetening or flavoring agents, coloring matter or dyes, and, if so desired, emulsifying and/or suspending agents as well, together with such diluents as water, ethanol, propylene glycol, glycerin and various like combinations thereof.

For parenteral administration, solutions of a compound of the present invention in either sesame or peanut oil or in aqueous propylene glycol may be employed. The aqueous solutions should be suitably buffered (preferably pH>8) if necessary and the liquid diluent first rendered isotonic, These aqueous solutions are suitable for intravenous injection purposes. The oily solutions are suitable for intra-articular, intra-muscular and subcutaneous injection purposes. The preparation of all these solutions under sterile conditions is readily accomplished by standard pharmaceutical techniques well-known to those skilled in the art. Additionally, it is also possible to administer the compounds of the present invention topically when treating inflammatory conditions of the skin and this may preferably be done by way of creams, jellies, gels, pastes, ointments and the like, in accordance with standard pharmaceutical practice.

The compounds of the present invention were assayed utilizing the GIyTI radioligand binding assay described below:

Test compound preparation: Compounds are dissolved in DMSO, sonicated if necessary, diluted to a concentration of 0.2 mM in DMSO and then diluted with de-ionized water to a concentration of 10 uM.

Tissue preparation: The GIyTIc transporter is expressed in HEK-293 cells and the frozen cell pellet weighed and polytroned, with 1 gram cell pellet in 30 ml_ assay buffer (50 mM Tris base, 120 mM NaCI, and 5 mM KCI, pH'd to 7.4 with 6N HCI). The mixture is centrifuged at 40000 G for 10 min., the supernatant decanted, and the pellet resuspended at 1 mg wet weight per 25 uL assay buffer.

Assay: The assay incubation is carried out for 60 min. at room temperature in 96 well plates (Beckman 2 mL polypropylene), which are vortexed upon addition of the tissue preparation. To each well is added 25 uL test drug solution or control, 200 uL of 0.7 nM [3H]- NPTS (Lowe, John A.; Drozda, Susan E.; Fisher, Katherine; Strick, Christine; Lebel, Lorraine; Schmidt, Christopher; Hiller, Donna; Zandi, Kathleen S. [3H]-(R)-NPTS, a radioligand for the type 1 glycine transporter. Bioorganic & Medicinal Chemistry Letters (2003), 13(7), 1291- 1292.), and 25 uL tissue. The plates are filtered using a Brandel cell harvester with GF/B filters, the filters are washed with 3 X 1.5 mL assay buffer, air-dried overnight, and counted on a LKB beta plate counter the next day. Compounds of the invention analyzed by this assay have been found to have significant activity in inhibiting glycine reuptake in synaptosomes, having greater than 20% inhibition at 1 μM.

The compounds of the Formula I may be prepared by the methods described below, together with synthetic methods known in the art of organic chemistry, or modifications and derivatisations that are familiar to those of ordinary skill in the art. Preferred methods include, but are not limited to, those described below.

During any of the following synthetic sequences it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This can be achieved by means of conventional protecting groups, such as those described in T. W. Greene, Protective Groups in Organic Chemistry, John Wiley & Sons, 1981 ; and T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Chemistry, John Wiley & Sons, 1991 , which are hereby incorporated by reference.

Compounds of formula I or their pharmaceutically acceptable salts, can be prepared according to the following reaction Schemes 1 through 17 as discussed herein below. Isolation and purification of the products is accomplished by standard procedures, which are known to a chemist of ordinary skill.

The following schemes and examples are exemplary of the processes for making compounds of formula I. It is to be understood, however, that the invention, as fully described herein and as recited in the claims, is not intended to be limited by the details of the following examples.

EXAMPLES

The invention is illustrated in the following non-limiting examples in which, unless stated otherwise: all operations were carried out at room or ambient temperature, that is, in the range of 18-250C; evaporation of solvent was carried out using a rotary evaporator under reduced pressure with a bath of up to 6O0C; reactions were monitored by thin layer chromatography (tic) and reaction times are given for illustration only; melting points (m.p.) given are uncorrected (polymorphism may result in different melting points); structure and purity of all isolated compounds were assured by at least one of the following techniques: tic (Merck silica gel 60 F-254 precoated plates),high performance liquid chromatography (HPLC), mass spectrometry, nuclear magnetic resonance (NMR) or infrared spectroscopy (IR). Yields are given for illustrative purposes only. Flash column chromatography was carried out using Merck silica gel 60 (230-400 mesh ASTM). Low-resolution mass spectral data (El) were obtained on a Automass 120 (JEOL) mass spectrometer. Liquid Chromatography data was collected on a Hewlett Packard 1100 Liquid Chromatography/ Mass Selective Detector (LC/MSD). Analysis was performed on a Luna C-18 column with dimensions of 3.0x150 mm. The flow rate was 0.425 ml/minute running a gradient of 50% 0.1% aqueous formic acid and 50% acetonitrile to 100% acetonitrile in 15 minutes. The ionization type for the mass detector of the Mass Spectrophotometer was atmospheric pressure electrospray in the positive ion mode with a fragmentor voltage of 50 volts. NMR data was determined at 270 MHz (JEOL JNM-LA 270 spectrometer) using deuterated chloroform (99.8% D), methanol (99.8% D) or dimethylsulfoxide (99.9% D) as solvent unless indicated otherwise, relative to tetramethylsilane (TMS) as internal standard in parts per million (ppm); conventional abbreviations used are: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad, etc.

The following abbreviations are used:

THF: tetrahydrofuran

CH2CI2: dichloromethane

NaHCO3: sodium bicarbonate

HCI: hydrogen chloride

MgSO4 : magnesium sulfate

Na2SO4 : sodium sulfate

DME: dimethoxyethane n-BuLi: n-butyllithium

DMF: dimethylformamide

Scheme 1.

Referring to Scheme 1 above, a compound of the formula 1 is reacted with 1 ,4- cyclohexanedionemonoethylene ketal in the presence of a reducing agent such as an alkaline borohydride, such as sodium borohydride, sodium cyanoborohydride, (method b) or sodium triacetoxyborohydride (method A), with an optional additive such as acetic acid or triethylamine, in a solvent such as 1 ,2-dichloroethane, tetrahydrofuran, or methanol at a temperature from room temperature to 100°C for a time from 1 hour to 72 hours. The resulting compound, 2, is treated with a compound of the formula 3 in the presence of a base, such as an organic amine such as triethylamine or diisopropylethylamine, in a solvent such as tetrahydrofuran, acetonitrile, dimethylformamide, or N-methylpyrrolidinone, at a temperature from 0° C to 100°C for a time from 1 hour to 72 hours. The resulting compound, 4, is hydrolyzed using, for example, acidic conditions such as aqueous HCI in a solvent such as ethyl acetate or tetrahydrofuran, or aqueous trifluoroacetic acid in dichloromethane, at a temperature from room temperature to 1000C for a time from 1 hour to 72 hours. The resulting intermediate 5 is treated with a primary and secondary amines, such as morpholine shown, in the presence of a reducing agent such as an alkaline borohydride, such as sodium borohydride, sodium cyanoborohydride, or sodium triacetoxyborohydride, with an optional additive such as acetic acid or triethylamine, in a solvent such as 1 ,2-dichloroethane, tetrahydrofuran, or methanol at a temperature from room temperature to 1000C for a time from 1 hour to 72 hours. Example 1. N-f3-(trifluoromethoxy)benzvn-1 ,4-dioxaspiroF4.51decan-8-amine: A solution of the 1 ,4-dioxaspiro[4.5]decan-8-one (6.0 g, 38.7 mmol) in dry THF (200 ml) at room temperature was added 3-trifluoromethoxy benzylamine (1 equiv, 7.4 g, 38.7 mmol), sodium acetoxyborohydride (1.5 equiv, 12.3 g, 58.1 mmol) and acetic acid (10 ml) and the resulting slurry was stirred at room temperature overnight. The reaction mixture was diluted with 1 N NaOH and extracted with EtOAc. The organic layer was dried (Na2SO4) and concentrated to give the title amine product (13 g, 100%) as viscous oil, which was clean enough to be taken to the next step as is. 1H NMR (400MHz, CDCI3) δ 7.35 (t, 1 H), 7.27 (d, 1 H), 7.23 (s, 1 H), 7.08 (d, 1H), 3.94 (s, 4H), 3.83 (s, 2H), 2.59 (m, 1H), 1.88 (m, 2H), 1.80 (m, 2H), 1.58-1.43 (m, 4H); LCMS (m/z) 332.0 (M+H). RT (Method A, std LCMS method), 1.0 min.

Example 2. i-methyl-IH-imidazole-4-carbonyl chloride: A slurry of the 1 -methyl imidazol-4-yl acid (10 g, 79.3 mmol) iin dry DCM (100 ml) at room temperature was treated with dropwise addition of oxalyl chlodide ( 12 ml, mmol) and catalytic DMF ( pipette drops). The reaction bubbled immediately and the slurry was stirred for 1 hr. Removal of the solvent in vacuo followed by drying under high vacuum gave the title compound (9.1 g) as a tan white solid. 1H NMR (400MHz, MD3OD) δ. 9.09 (s, 1H), 8.24 (s, 1H), 3.98 (s, 3H).

Example 3. N-1 ,4-dioxaspiror4.51dec-8-yl-1 -methyl-N-f3-trifluoromethoxybenzvn -1 H-imidazole-4-carboxamide: A solution of the 2 (65815-162) (5.7 g, 17.22 mmol) and triethylamine (2.5 equiv, 6.0 ml) in dry DCM (50 ml) under nitrogen was added 3 (1.4 equiv, 3.5 g). The reaction, which warmed up as the acid chloride was added, was stirred at room temperature until reaction was complete. The reaction mixture was diluted with water and extracted with DCM, dried (Na2SO4), and concentrated to provide the title compound as viscous yellow foam (6.5 g, 86%) which was clean enough for next step. LCMS (m/z) 440.0 (M+H); RT (Method A, std LCMS method), 2.0 min.

Example 4. 1 -methyl-N-(4-oxocvclohexyl)-N-r3-(trif luoromethoxy)benzvπ-1 H- imidazole-4-carboxamide: A solution of 4 in THF (50 ml) was added 80 ml of 1 N HCI and heated to 7O0C for 48 hr. Added additional 2N HCI and stirred at room temperature for another 48hr. The reaction was neutralized with slow addition of potassium carbonate (vigorous foaming) and extracted with ethylacetate. The organics were dried (MgSO4) and concentrated to give the title compound (4.6g, 79%), which was taken forward as is. 1H NMR (400MHz, CDCI3) δ 7.06 - 7.72 (m, 6H), 5.85 (br s, 1 H), 5.31 (br s, 1 H), 4.70-4.84 (br d, 2 H), 3.74 (3H), 1.84 -2.40 (m, 8H) ;LCMS (m/z) 396.0 (M+H); RT (Method A, std LCMS method), 2.0 min.

Example 5. 1 -methyl-N-fcis^-azetidin^-ylcyclohexyD-N-fS-ftrif luoromethoxy) benzvπ-IH-imidazole-4-carboxamide: A solution of 5 (285 mg, 0.72 mmol) in dry DCM (2 ml) at room temperature was added azetidine hydrochloride (1 equiv, 67.5 mg, 0.72 mmol) and triethylamine (0.15 ml, 1.08 mmol) and stirred the reaction for 20 min. Then sodiumacetoxyborohydride (1.5 equiv, 214 mg, 1.08 mmol) was added and the resulting slurry was stirred at room temperature (6 hr). The reaction mixture was diluted with saturated bicarbonate and extracted with DCM. The organic layer was dried (Na2SO4) and concentrated to give crude amine, which was purified by ISCO chromatography system to provide with the cis isomer (151 mg), colorless oil, as the top stop and the trans isomer (105 mg), colorless oil, as the bottom spot, The cis and trans products were converted to the HCL salt by adding 4N HCI/Dioxane to a solution of the free base in methyline chloride and removing the solvent in vauo to obtain the salt as a white solid. (NMR of cis isomer as free base form) 1H NMR (400MHz, CDCI3) δ 7.61 (s, 1H), 7.00 - 7.39 (m, 5H), 5.36 (br s, 1H) 5.9 (br s, 1 H), 4.68 - 4.83 (br d, 2H), 3.71 (s, 3H, N-Me), 2.45 (br s, 3H), 2.38 (br d, 3H), 1.61-2.11 (m, 8H), 1.80 (m, 2H), 1.58-1.43 (m, 4H); LCMS (HCI salt) (m/z) 437.1 (M+H). RT (Method A, std LCMS method), 1.0 min.

Scheme 2.

Referring to Scheme 2 above, a compound of the formula 2, is hydrolyzed using, for example, acidic conditions such as aqueous HCI in a solvent such as ethyl acetate or tetrahydrofuran, or aqueous trifluoroacetic acid in dichloromethane, at a temperature from room temperature to 1000C for a time from 1 hour to 72 hours. The resulting compound, 7, is treated with a compound of the formula 3 in the presence of a base, such as an organic amine such as triethylamine or diisopropylethylamine, in a solvent such as tetrahydrofuran, acetonitrile, dimethylformamide, or N-methylpyrrolidinone, at a temperature from 0° C to 1000C for a time from 1 hour to 72 hours to provide intermediate 5 from Scheme 1. Alternatively, intermediate 7 is treated with a primary and secondary amines, such as morpholine shown, in the presence of a reducing agent such as an alkaline borohydride, such as sodium borohydride, sodium cyanoborohydride, or sodium triacetoxyborohydride, with an optional additive such as acetic acid or triethylamine, in a solvent such as 1 ,2-dichloroethane, tetrahydrofuran, or methanol at a temperature from room temperature to 1000C for a time from 1 hour to 72 hours to provide diamine intermediate 8. This intermediate can then be acylated as mentioned to make intermediate 5.

Example 6. 4-fr3-(trifluoromethoxy)benzyl1amino}cvclohexanone: A solution of the ketal 2 (3.5g, 10.6 mmol) in THF (25 ml) was treated with 2 N HCI (30 ml) and heated to 8O0C (72 h). The reaction was cooled to room temperature and neutralized (pH-7.5-8) with 1N NaOH and extracted with EtOAc. The organic layer was dried and concentrated in vacuo and concentrated to give the title ketone 7 (2.9 g) as a brown oil. 1H NMR (400MHz, CDCI3) δ 7.36 (t, 1 H), 7.29 (d, 1 H), 7.24 (s, 1 H), 7.12 (d, 1H), 3.88 (s, 2H), 3.01 (m, 1H), 2.54 (m, 2H), 2.11 (m, 2H), 1.75 (m, 2H) ; LCMS (m/z) 288.0 (M+H); RT (Method A, std LCMS method), 0.6 min.

Example 7. 1 -methyl-N-(4-oxocvclohexyl)-N-r3-(trifluoromethoxy)ben2vπ-1 H- im idazole-4-carboxam ide : Prepared using example 4. 1H NMR (400MHz, CDCI3) δ 7.06 - 7.72 (m, 6H), 5.85 (br s, 1H), 5.31 (br s, 1H), 4.70-4.84 (br d, 2 H), 3.74 (3H), 1.84 -2.40 (m, 8H) ;LCMS (m/z) 396.0 (M+H); RT (Method A, std LCMS method), 2.0 min.

Example 8. 4-morpholin-4-yl-N-r3-(trifluoromethoxy)benzyllcyclohexanamine: Prepared using example 1 procedure to make cis 8 (454.9 mg) and trans 8 (269 mg). Cis-8: 1H NMR (400MHz, CDCI3) δ 1H NMR (400MHz, CDCI3) δ 7.33 (t, 1H), 7.26 (d, 1 H), 7.21 (s, 1H), 7.09 (d, 1H), 3.78 (s, 2H), 3.73 (app t, 4H), 2.75 (m, 1H), 2.54 (s, 4H), 2.19 (br s, 1H), 1.67 - 1.74 (m, 4H), 1.46 - 1.58 (m, 4H); LCMS (m/z) 359.0 (M+H); RT (Method A, std LCMS method), 0.3 min.

Example 9. 1 -methyl-N-fcis^-morpholin^-vIcvclohexyD-N-rS-ftrif luoromethoxy) benzvπ-1H-pyrazole-3-carboxamide: Prepared using example 3 to make 144 mg of title compound 9. 1H NMR (400MHz, CDCI3) δ 1H NMR (400MHz, CDCI3) δ 7.21-7.37 (m, 3H), 7.17 (s, 1 H), 7.05 (d, 1 H), 6.64 (d, 1 H), 5.04 (s, 1 H), 4.73 (s, 1 H), 4.66-4.84 (m, 1 H), 3.94 (s, 1 H), 3.78 (s, 1 H), 3.70 (s, 3H), 3.64 (s, 1 H), 2.35 (br s, 4H), 2.54 (s, 4H), 2.07 (br s, 1 H), 1.96 (d, 2H), 1.71-1.84 (3H), 1.42-1.45 (m, 3HH), 1.23-1.32 (m, 1 H); LCMS (m/z) 467.0 (M+H); RT (Method A, std LCMS method), 1.4 min.

Referring to Scheme 3 above, a compound of the formula 10 and 11, can be prepared according to process in Scheme 1 , preparation of 2 and 4. The resulting compound,

11 is deblocked using, for example, acidic conditions such as HCI in a solvent such as ethyl acetate or tetrahydrofuran, or trifluoroacetic acid in dichloromethane, at a temperature from room temperature to 10O0C for a time from 1 hour to 72 hours. The resulting intermediate salt

12 is treated with a ketones and aldehydes, such as cyclobutanone shown, in the presence of a reducing agent such as an alkaline borohydride, such as sodium borohydride, sodium cyanoborohydride, or sodium triacetoxyborohydride, with an optional additive such as acetic acid or triethylamine, in a solvent such as 1 ,2-dichloroethane, tetrahydrofuran, or methanol at a temperature from room temperature to 10O0C for a time from 1 hour to 72 hours. The resulting secondary amine can further be reacted with aldehydes and amines under similar conditions. tert-butyl (cis-4-(f3-(trifluoromethoxy)benzvπamino)cvclohexy0carbamate (1 oγ Prepared according to example 1. 1H NMR (400MHz, CD3OD) δ 7.41 (t, 1 H), 7.34 (d, 1 H), 7.30 (s, 1H)1 7.16 (d, 1 H), 3.80 (s, 2H), 3.57 (s, 1 H), 2.57 (br s, 1 H), 1.69 (m, 4H), 1.53 (m, 4H), 1.43 (s, 9H); LCMS (m/z) 389.0 (M+H, 100). RT (Method A, std LCMS method), 1.6 min. tert-butyl(cis-4-(f(1 -methyl-1 H-imidazol-4-vncarbonvflr3 (trifluoromethoxy)benzyl] amino} cvclohexyDcarbamate (11): . Prepared according to example 3. 1H NMR (400MHz, CDCI3) δ 7.52 (br s, 1H), 7.36 (br s, 1H), 7.22 (d, 1H), 7.21 (d, 1H), 7.14 (s, 1H), 7.05 (d, 1H), 5.28 (br s, 1 H), 5.16 (br s, 1 H), 4.75 br d, 2H)1 3.78 (br s, 1 H), 3.69 (s, 3H), 1.84 - 1.58 (m, 8H), 1.42 (s, 9H; LCMS (m/z) 497.1 (M+H, 100). RT (Method A, std LCMS method), 2.5 min.

Example 9a: N-(cis-4-amι'nocyclohexyO-1 -methyl-N-f3-(trif luoromethoxy) benzvπ-IH-imidazole-4-carboxamide: A solution of 11 (1.74g) in dry dichloromethane (10 ml) was added 4N HCI/dioxane at room temperature and stirred until reaction was complete (1-2 hrs). The resulting slurry was diluted with ether and filtered off to obtain the desired product as a white solid. 1H NMR (400MHz, CD3OD) δ 9.05 (s, 1 H), 8.08 (br s, 1 H), 7.45 (br s, 1H), 7.37 (d, 1H), 7.26 (s, 1 H), 7.18 (s, 1H), 5.01 (br s, 2H), 4.40 (br d, 1H), 3.84 (br, d, 3H), 3.65 (s, 3H)1 3.60 (s, 1 H), 2.70 (s, 1 H), 1.14 - 1.97 (m, 5H), 1.75 (s, 2H; LCMS (m/z) 397.1 (M+H, 50), 219.7 (M-177, 100). RT (Method A, std LCMS method), 1.0 min.

N-(3-(trifluoromethoxy)benzyl)-N-((1s,4s)-4-(cvclobutylamino)cvclohexyl)-1-methyl- 1 H-imidazole-4-carboxamide (13): Prepared according to example 3.1H NMR (400MHz, CD3OD) δ 8.92 (s, 1 H), 8.04 (br s, 1 H), 7.45 (br s, 1 H), 7.37 (d, 1H), 7.26 (s, 1 H), 7.19 (br s, 1H), 5.01 (br s, 2H), 4.42 (br s, 1H), 3.88 (m, 1H), 3.87 (s, 3H), 2.36 - 2.24 (m, 4H), 2.15 (m, 2H), 1.95 -1.75 (m, 7H); LCMS (m/z) 451.1 (M+H, 80), 226.2 (M-225, 100). RT (Method A, std LCMS method), 1.1 min.

N-(3-(trifluoromethoxy)benzvπ-N-((1s.4s)-4-(N-cvclobutyl-N-methylamino)cyclohexyl)- 1 -methyl-1 H-imidazole-4-carboxamide (14): Prepared according to example 3. 1H NMR (400MHz1 CD3OD) δ 9.00 (s, 1H)1 7.70 (br s, 1 H)1 7.46 (m, 1 H), 7.38 (d, 1 H)1 7.28 (s, 1 H), 7.20 (br d, 1H), 5.09 (br s, 2H), 4.44 (br s, 1H)1 3.90 (m, 3H)1 3.65 (s, 3H)1 2.71 (s, 3H), 2.54 (m, 2H)1 2.24 (m, 4H), 2.06 (m, 2H), 1.95 -1.75 (m, 6H); LCMS (m/z) 465.0 (M+H, 50), 233.2 (M-232, 100). RT (Method A1 std LCMS method), 1.3 min.

Referring to Scheme 4 above, a compound of the formula 18 and the intermediates to make 18 can also be done by starting with protected ketone following procedures used in Schemes 1 , 2, and 3. tert-butyl rcis-4-(dimethylamino)cyclohexyncarbamate (15): Prepared according to Example 1, Scheme 1. 1H NMR (400MHz, CD3OD) δ 9.00 (s, 1 H), 7.70 (br s, 1 H), 7.46 (m, 1H), 7.38 (d, 1 H), 7.28 (s, 1H), 7.20 (br d, 1 H), 5.09 (br s, 2H), 4.44 (br s, 1H), 3.90 (m, 3H), 3.65 (s, 3H), 2.71 (s, 3H), 2.54 (m, 2H), 2.24 (m, 4H), 2.06 (m, 2H), 1.95 -1.75 (m, 6H); LCMS (m/z) 465.0 (M+H, 50), 233.2 (M-232, 100). RT (Method A, std LCMS method), 1.3 min. cis-N,N-dimethylcyclohexane-1,4-diamine (16): Prepared according to example 9a. 1 H NMR (400 MHz, METHANOL-^) D ppm 1.94 (s, 8 H) 2.03 (s, 8 H) 2.83 (s, 1 H)12.88 (s, 6 H) 3.52 (m, 1 H); MS (m/z) 143.2 (M+H) cis-N.N-dimethyl-N'-rs-^rifluoromethoxyfeenzyllcyclohexane-I Λ-diamine (17):

Prepared according to Example 1. MS (m/z) 315.2 (M-H), 317.2 (M+1).

N-[cis-4-(dimethylamino)cvclohexyn-1-methyl-N-r3-(trifluoromethoxy)benzyll-1H- imidazole-4-carboxamide (18): Prepared according to example 3. 1H NMR (400 MHz, METHANOL-^) D ppm 1.77 (m, 2 H) 1.94 (s, 4 H) 2.31 (d, 2 H) 2.89 (s, 6 H) 3.89 (br s, 2 H) 4.53 (br s, 1 H) 5.07 (br s, 2 H) 7.18 (s, 1 H) 7.26 (s, 1 H) 7.42 (s, 3 H) 8.89 (s, 1 H); MS (m/z) 425.1 (M+H).

Referring to Scheme 5 above, a compound of the formula 19 can also be made by reacting amine 12, made according to scheme 3, with di-halides or sulfonates (any suitable leaving groups) in a suitable solvent such as dichloromethane, DMF, THF or alcoholic solvents such as methanol, ethanol, and like at temperatures ranging from 0° C to 1000C.

Example 9b. i-methyl-N-fcis^-morpholin-^ylcyclohexyO-N-re-

(trif luoromethoxy) benzyl] -1 H-imidazole-4-carboxamide: A mixture of amine 12 (129 mg, 0.3 mmol) from Scheme 3, dibromoethylether (1.1 equiv, 92 mg, 0.36 mmol) and cesium carbonate (6 equiv, 636 mg, 1.95 mmol) in dry THF (3 ml) was heated 70oC overnight. Another 1 equiv of dibromide added and refluxed for 5 days. The reaction was poured in saturated bicarbonate (25 ml) and extracted with ethyl acetate (2 X 25 ml), dried with Na2SO4 and concentrated to give crude product. Purification using 12 g column in ISCO provided the desired product 19 (125 mg, 82%) as a white solid.

1H NMR (400 MHz, CHLOROFORM-of) δ ppm 1.40 (s, 3 H) 1.50 (s, 1 H) 1.58 (s, 2 H) 1.79 (s, 2 H) 1.96 (s, 2 H) 2.07 (s, 1 H) 2.34 (s, 3 H) 3.68 (s, 6 H) 4.68 (s, 1 H) 5.33 (s, 2 H) 7.03 (s, 1 H) 7.15 (s, 1 H) 7.25 (s, 4 H) 7.53 (s, 1 H): LCMS RT: 1.5 min; MS: 467 (M+H).

Scheme 6.

3-oxocvclobutanecarboxylic acid (20): Prepared according to literature reference: J. Org. Chem. 1988, 53, 3841.

Referring to Scheme 6 above, a compound of the formula 20 (prepared according to literature reference: J. Orp. Chem. 1988, 53, 3841) is esterified and protected as a ketal 21 by reacting with an alcohol such as methanol with catalytic acid such as p-toluene sulfonic acid, HCI, H2SO4, etc. The ester 21, can be reduced with a suitable reducing agent such as LAH, NaBH4, Dibal, etc to provide the alcohol 22. Preparation of 22 has also been reported in the literature Antiviral Chemistry & Chemotherapy 2002, 73(4), 251-262. Oxidation of the alcohol using standard Swern conditions (oxalyl chloride, DMSO, Et3N) known to chemists provides the aldehyde 23. Reaction of the aldehyde 23 with (cis)-tert-butyl 4- aminocyclohexylcarbamate_in the presence of a reducing agent such as an alkaline borohydride, such as sodium borohydride, sodium cyanoborohydride, or sodium triacetoxyborohydride, with an optional additive such as acetic acid or triethylamine, in a solvent such as 1 ,2-dichloroethane, tetrahydrofuran, or methanol at a temperature from room temperature to 100°C for a time from 1 hour to 72 hours. The resulting amine can be acylated with acid chlorides such as N-methyl imidazolyl acid chloride in the presense of suitable base such as triethyl amine or organic and inorganic bases in suitable solvents such as dichloromethane or THF at temperatures ranging from 0° C to 100° C. The ketal of the resulting amide 25 can be be hydrolyzed with suitable acid such as pTsOH or other aqueous and organic acids in suitable solvent such as acetone and water mixtures at appropriate temperatures ranging from room temperature to 100° C. The resulting ketone can be reduced to the alcohol with suitable reducing agents such as sodium borohydride and other agents well known to practicing chemists under suitable solvents such as methanol and ethanol at 0° C to 100° C. The resulting alcohol can then be reacted with appropriate phenols such as 3- chlorophenol under what's known in the chemistry community as Mitsunobu condition with activating reagents such as DEAD or DIAD and triphenylphosphine or trialkyl phospine in appropriate solvents such as THF at temperatures ranging from 0° C to 100° C. The resulting ether 28 can be deprotected of the protecting group such as BOC using acidic condition using acids such as acetic acid or HCL or sulfuric acid or trifluoroacetic acid in solvents such as dichloromethane or ether solvents at room temperatures to 100° C. The resulting amine can then be reacted under reductive amination conditions as described previously using suitable aldehydes and ketones.

Example 9c. methyl S^-dimethoxycyclobutanecarboxylate (21): A solution of 3- oxocyclobutanecarboxylic acid (20) (3.5 g, 31 mmol) and p-toluenesulfonic acid (0.04 equiv, 233 mg, 1.2 mmol) in MeOH (100 ml) was refluxed overnight. The reaction mixture was concentrated down to a small volume and diluted with water and extracted with dichloromethane. The orgnic layer was dried and concentrated down to provide the title compound (5.03 g) as a colorless oil. 1H NMR (400MHz, CDCI3) δ 3.69 (s, 3H, CO2Me), 3.16 (S, 3H), 3.14 (s, 3H), 2.88 (p, 1 H), 2.43 (m, 4H)

Example 9d. (3,3-dimethoxycvclobutyl)methanol (22): A solution of the methyl 3,3-dimethoxycyclobutane carboxylate (21) (5.03 g, 28.9 mmol) in anhydrous THF (50 ml) was cooled in an ice bath and 1 M solution of lithium aluminum hydride (LAH) in THF (30.4 ml, 30.4 mmol) was added dropwise. After complete addition, the ice bath was removed and the reaction stirred at room temperature for 1 hr. The reaction was quenched with water (2.2 ml) and 10 g celite was added and stirred vigorously. The resulting slurry was filtered through celite pad and washed with ethyl acetate (EtOAc). Concentration of the organics gave the desire title compound 22 (3.64 g, 86%) as a colorless liquid. 1H NMR (400MHz, CDCI3) δ 3.56 (d, 2H), 3.16 (s, 3H), 3.14 (s, 3H), 2.29 (m, 3H), 1.90 (m, 2H).

Example 9e. S.S-dimethoxycvclobutanecarbaldehvde (23): A solution of oxalyl chloride (0.33 ml, 3.8 mmol) in dichloromethane (8 ml) was cooled to -780C and DMSO (0.54 ml, 7.5 mmol) added dropwise and stirred for 30 min. A solution of (3,3- dimethoxycyclobutyl)methanol (500 mg, 3.4 mmol) in DCM (5 ml) was added to the reaction mixture and stirred for 30 min. Then triethylamine (2.39 ml, 17.1 mmol) was added dropwise to the reaction mixture and stirred for 1 hr. The reaction mixture was poured into water and extracted with DCM. The DCM layer was washed with water, dried and concentrated to give crude oil which was purified by passing through a plug of silica to provide the title compound 23 (555 mg) as a pale yellow oil. 1H NMR (400MHz, CDCI3) δ 9.73 (s, 1 H1CHO), 3.16 (s, 3H),

3.13 (s, 3H), 2.90 (m, 1H), 2.36 (d, 4H). tert-butyl (cis-4-([(3,3-dimethoxycvclobutyl)methvπamino)cvclohexy0carbamate (24): Prepared according to procedure for example 1 using tert-butyl (1s,4s)-4- aminocyclohexylcarbamate (751 mg) and 3,3-dimethoxycyclobutanecarbaldehyde (1.1 eqiv, 555 mg, 3.85 mmol) to give the title compound (1.25 g) as a viscous oil; 1H NMR (400MHz, CDCI3) δ 4.76 (br s, 1 H), 3.73 (s, 2H), 3.67 (br s, 1H), 3.14 (s, 3H), 3.12 (s, 3H), 2.73 (d, 2H), 2.65 (br s, 1H), 2.30 (m, 2H), 2.25 (br s, 1H), 1.80 -1.48 (m, 8H), 1.43 (s, 9H, BOC); LCMS (m/z) 343.0 (M+H, 100); RT (Method A, std LCMS method), 1.0 min (not UV active). tert-butyl (cis^-fflS.S-dimethoxycvclobutvDmethvnfd-methyl-IH-imidazol^-yl) carbonyliamino} cvclohexyDcarbamate (25): Prepared according to procedure for example 3 using 24 (5.0 mg, 14.6 mmol) and i-methyl-IH-imidazole-4-carbonyl chloride (1.1 eqiv, 16.1 mmol) in acetonitrile to give the title compound (6.04 g, 83%) as a viscous oil; 1H NMR (400MHz, CDCI3) δ 7.46 (s, 1 H), 7.38 (s, 1 H), 4.89 (br s, 1H), 3.82 (br s, 1H), 3.72 (s, 3H),

3.14 (s, 6H), 2.43 (br s, 1 H), 2.30 (br s, 2H), 1.89 (d, 3H), 1.75 -1.48 (m, 8H), 1.43 (s, 9H, BOC); LCMS (m/z) 451.1 (M+H, 100); RT (Method A, std LCMS method), 1.8 min.

Example 9f. tert-butyl (cis-4-fr(1-methyl-1H-imidazol-4-yl)carbonvnr(3- oxocyclobutvDmethvπamino} cvclohexyDcarbamate (26): A mixture of 25 (1.23 g, 2.7 mmol) and p-toluenesufonic acid (0.2 equiv, 104 mg, 0.54 mmol) in acetone:water (2:1 :15 ml) was stirred at 5O0C (6 h) and overnight at room temperature. The reaction was poured into aqueous bicarbonate and extracted with ethyl acetate. The organic layer was dried and concentrated to give the title compound (1.08 g) as viscous oil. 1H NMR (400MHz, CDCI3) δ 7.48 (s, 1 H), 7.38 (s, 1H), 4.89 (br s, 1 H), 3.82 (br s, 1 H), 3.69 (s, 3H), 3.14 - 2.90 (m, 4H), 2.80 (br s, 1H), 1.89 (d, 3H), 1.75 -1.55 (m, 6H), 1.44 (s, 9H, BOC); LCMS (m/z) 405.0 (M+H, 100); RT (Method A, std LCMS method), 1.6 min. Example 9g. tert-butyl (cis-^irO-hvdroxycvclobutvDmethvnFd-methyl-IH- imidazol-4-yl)carbonvπ amino} cyclohexyl) carbamate (27): A solution of 26 (3.04 g, 7.5 mmol) in anhydrous methanol (100 ml) at O0C was treated with slow addition of sodium borohydride (400 mg, 10.5 mmol). After stirring it at 00C for 10 min, the reaction was warmed to room temperature and stirred for 1.5 hr. The reaction was quenched with water and methanol removed via rotary evaporation. The aqueous layer was extracted with ethyl acetate, dried and concentrated down. The crude mixture was purified by chromatography to give the title compound 27 (2.98 g, 98%) as a oil. 1H NMR (400MHz, CDCI3) δ 7.41 (s, 1 H), 7.35 (s, 1 H), 5.20 (br s, 1 H), 5.05 (br s, 1 H), 3.85 (br s, 2H), 3.69 (s, 3H), 3.63 (s, 2H), 3.46 (s, 1H), 2.40 (br s, 1 H), 2.25 (br m, 3H), 2.05 (br s, 1 H), 1.89 (d, 3H), 1.57 (m, 6H), 1.45 (s, 9H, BOC); LCMS (m/z) 407.1 (M+H, 100); RT (Method A, std LCMS method), 1.4 min.

Example 9h. tert-butyl (cis-4-{{r3-(3-chlorophenoxy)cvclobutvnmethyl>f(1- methyl-1H-imidazol-4-yl)carbonvnamino>cvclohexyπcarbamate (28): The alcohol 27 (250 mg, 0.62 mmol), 3-chlorophenol (2.5 equiv, 198.1 mg, 1.54 mmol), and triphenyl phosphine was mixed in THF (3 ml) in a microwave tube and warmed (40°C)until the mixture went into solution. To this solution at room temperature was added dropwise diisopropyl azodicarboxylate (DIAD) (2.5 equiv, 0.30 ml, 1.54 mmol). The resulting solution was microwaved at 12O0C at 300W for 10 min after a ramptime of 2 min. The reaction was run 5 times at 250mg scale and the reactions combined, concentrated and purified by chromatography to provide the title compound (872 mg) as foam. 1H NMR (400MHz, CDCI3) δ 7.41 (s, 1 H), 7.35 (s, 1 H), 5.20 (br s, 1 H), 5.05 (br s, 1 H), 3.85 (br s, 2H), 3.69 (s, 3H), 3.63 (s, 2H), 3.46 (s, 1 H), 2.40 (br s, 1 H), 2.25 (br m, 3H), 2.05 (br s, 1 H), 1.89 (d, 3H), 1.57 (m, 6H), 1.45 (s, 9H, BOC); LCMS (m/z) 407.1 (M+H, 100); RT (Method A, std LCMS method), 1.4 min.

Example 9i N-(cis-4-aminocvclohexyl)-N-{T3-(3-chlorophenoxy)cvclobutyll methyl>-1-methyl-1H-imidazole-4-carboxamide (29): A solution of 28 (872 mg, 1.91 mmol) in DCM (3 ml) at room temperature was added 4N HCI/dioxane (3 ml) and stirred until reaction was complete (~ 2hr). The reaction was concentrated down and the residue taken up in ether and the solid precipitate filtered to obtain the title compound (937 mg) as a white solid. 1H NMR (400MHz, CDCI3) δ 7.41 (s, 1 H), 7.35 (s, 1 H), 5.20 (br s, 1 H), 5.05 (br s, 1 H), 3.85 (br s, 2H), 3.69 (s, 3H), 3.63 (s, 2H), 3.46 (s, 1 H), 2.40 (br s, 1 H), 2.25 (br m, 3H), 2.05 (br s, 1H), 1.89 (d, 3H), 1.57 (m, 6H), 1.45 (s, 9H, BOC); LCMS (m/z) 407.1 (M+H, 100); RT (Method A, std LCMS method), 1.4 min.

N-(r3-(3-chlorophenoxy)cyclobutyl'|methyl)-N-rcis-4-(dimethylamino)cvclohexylV1- methyl-1 H-imidazole-4-carboxamide (30): Prepared according to Example 1. 1H NMR (400 MHz, METHANOL-^) δ ppm 1.77 (s, 2 H) 1.94 (s, 4 H) 2.31 (s, 2 H) 2.89 (s, 6 H) 3.89 (s, 2 H) 4.53 (s, 1 H) 5.07 (s, 2 H) 7.18 (s, 1 H) 7.26 (s, 1 H) 7.42 (s, 3 H) 8.89 (s, 1 H); MS (m/z) 425.1 (M+H).

Scheme 7.

Referring to Scheme 7 above, a compound of the formula 21 (prepared according to literature reference: J. Org. Chem. 1988, 53, 3841 and scheme 6 hydrolyzed with suitable acid such as pTsOH or other aqueous and organic acids in suitable solvent such as doxane or acetone and water mixtures at appropriate temperatures ranging from room temperature to 100° C. The keto ester 31 can be reacted with (cis)-tert-butyl 4-aminocyclohexylcarbamate in the presence of a reducing agent such as an alkaline borohydride, such as sodium borohydride, sodium cyanoborohydride, or sodium triacetoxyborohydride, with an optional additive such as acetic acid or triethylamine, in a solvent such as 1 ,2-dichloroethane, tetrahydrofuran, or methanol at a temperature from room temperature to 10O0C. The resulting amine 32 can be acylated with acid chlorides such as N-methyl imidazolyl acid chloride in the presense of suitable base such as triethyl amine or organic and inorganic bases in suitable solvents such as dichloromethane or THF at temperatures ranging from 0° C to 100° C. for a time from 1 hour to 72 hours. The methyl ester of 33 can be reduced with a suitable reducing agent such as LAH1 NaBH4, Dibal, or LiBH4 etc in alcoholic solvents or non-alcoholics solvents such as methanol and THF at rom temperature to 100° C to provide the alcohol 34. The alcohol 34 can then be reacted with appropriate phenols such as 4-fluorophenol under what's known in the chemistry community as Mitsunobu condition with activating reagents such as DEAD or DIAD and triphenylphosphine or trialkyl phospine in appropriate solvents such as THF at temperatures ranging from 0° C to 100° C. The resulting ether 35 can be deprotected of the protecting group such as BOC using acidic condition using acids such as acetic acid or HCL or sulfuric acid or trifluoroacetic acid in solvents such as dichloromethane or ether solvents at room temperatures to 100° C. methyl S-oxocyclobutanecarboxylate (31): Prepared according to example 9f. MS (m/z) 130.0 (M+H). methyl 3-({cis-4-r(tert-butoxycarbonyl)amino1cvclohexylfømino) cyclobutanecarboxylate (32V Prepared according to example 1. 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.39 (s, 11 H) 1.61 (s, 6 H) 1.94 (s, 2 H) 2.52 (s, 2 H) 2.62 (s, 1 H) 2.74 (s, 1 H) 3.24 (s, 1 H) 3.64 (s, 4 H) 4.58 (s, 1 H).; LCMS (m/z) 327.1 (M+H)

Example 9j: methyl 3-Ucis-4-r(tert-butoxycarbonyl)amino1cvcloh6xyl}f(1-methyl- 1H-imidazol-4-yl)carbonvnamino> cvclobutanecarboxylate (33): A mixture of the amine 32 (500 mg, 1.5 mmol), N-methyl-imidazol-4-yl carboxylic acid ( 212 mg, 1.7 mmol), HOBT (218 mg, 1.6 mmol), DCC (353 mg, 1.8 mmol) and triethyl amine (0.64 ml, 4.6 mmol) in dry dichloromethane (15 ml) was stirred at room temperature for 5 days. The reaction mixture was poured into ethyl acetate and washed with 1 N NaOH (1 X), brine (1 X), dried and concentrated. The crude product was purified by chromatography using the ISCO purification system to provide the desired product 33 (590 mg) as a solid. 1H NMR (400 MHz, CHLOROFORM-d) δppm 1.25 (s, 2 H) 1.43 (s, 8 H) 1.58 (s, 5 H) 1.85 (s, 2 H) 2.01 (s, 1 H) 2.14 (s, 1 H) 2.50 (s, 3 H) 2.58 (s, 1 H) 2.74 (s, 1 H) 3.69 (s, 5 H) 3.88 (s, 1 H) 5.18 (s, 1 H) 7.25 (S, 2 H) 7.40 (s, 2 H); LCMS (m/z) 435.0 (M+H).

Example 9k: tert-butyl (cis^-ire-fhvdroxymethvDcvclobutyllKI-rnethyl-IH- imidazol-4-yl)carbonvπ amino}cvclohexyl)carbamate (34): A solution of ester 33 (488mg, 1.1 mmol) in THF (3 ml) was cooled to 0° C and added lithium borohydride (5.6 ml, 2 M in THF) slowly. The mixture was brought to room temperature and stirred for 5 day. The reaction was poured into 1 N NaOH and extracted with ehtylacetate. The organic layer was washed with brine, dried and concentrated to provide the alcohol (416 mg, 91%) as oily solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.43 (s, 9 H) 1.58 (s, 4 H) 1.77 (s, 2 H) 1.87 (s, 2 H) 2.17 (s, 1 H) 2.37 (s, 4 H) 2.65 (s, 1 H) 3.69 (s, 4 H) 3.92 (s, 3 H) 5.15 (s, 1 H) 6.84 (s, 2 H) 6.95 (s, 2 H) 7.40 (s, 2 H); LCMS (m/z) 407.1 (M+H).

Example 9L: tert-butyl (cis^-US-rtø-fluorophenoxylmethvπcvclobutylWI- methyl-1 H-imidazol-4-yl)carbonvπamino}cvclohexyl)carbamate (35): The reaction was set up and worked up as in example 17 but reaction run at room temperature to provide the desired product. LCMS (m/z) 501.0 (M+H).

N-(cis-4-aminocvclohexyl)-N-(3-f(4-fluorophenoxy)methvncyclobutyl>-1-methyl-1 H- imidazole-4-carboxamide (36): Prepared according to example 9i. 1 H NMR (400 MHz, METHANOL-d4) δ ppm 1.72 (s, 1 H) 2.00 (s, 2 H) 2.41 (s, 1 H) 3.29 (s, 7 H) 3.56 (s, 1 H) 3.77 (s, 1 H) 4.02 (s, 3 H) 4.91 (s, 9 H) 6.92 (s, 1 H) 7.01 (s, 1 H) 7.92 (s, 1 H); Scheme δ.

Referring to Scheme 8 above, a commercially available 1 ,3-diaminocyclohexane can be reacted with a protecting group tert-butyldicarbonate (BOC2O) in a solvent such as THF at OoC to 80° C for 1 hr to 72 h to provide the monoprotected compound 37. The amine of 37 can be reacted with aldehydes such as 3-trifluoromethoxy benzaldehyde in the presence of a reducing agent such as an alkaline borohydride, such as sodium borohydride, sodium cyanoborohydride, (method b) or sodium triacetoxyborohydride with an optional additive such as acetic acid or triethylamine, in a solvent such as 1 ,2-dichloroethane, tetrahydrofuran, or methanol at a temperature from room temperature to 1000C for a time from 1 hour to 72 hours. The resulting amine 38 can be treated with acid chlorides such as N-methyl imidazolyl acid chloride in the presense of suitable base such as triethyl amine or organic and inorganic bases in suitable solvents such as dichloromethane or THF at temperatures ranging from O0C to 100° C. for a time from 1 hour to 72 hours. The resulting product 39 can be deprotected of the BOC protecting group using acids such as acetic acid or HCL or sulfuric acid or trifluoroacetic acid in solvents such as dichloromethane or ether solvents at room temperatures to 100° C. The amine of 40 can be reacted with aldehydes such as cyclopropane carboxaldehyde in the presence of a reducing agent such as an alkaline borohydride, such as sodium borohydride, sodium cyanoborohydride, (method b) or sodium triacetoxyborohydride with an optional additive such as acetic acid or triethylamine, in a solvent such as 1 ,2-dichloroethane, tetrahydrofuran, or methanol at a temperature from room temperature to 1000C for a time from 1 hour to 72 hours.

Example 9m: tert-butyl O-aminocvclohexyQcarbamate (37): Prepared according to US 2004019058 A1: A solution of the 1 ,3-diaminocyclohexane (5.0 g, 43.7mmol) in dry chloroform (100 ml) under nitrogen was treated with a solution of di-t-butylcarbonate (0.5 equiv, 21.8 mmol) in dry chloroform (60 ml) over a period of several hours and stirred the reaction slurry overnight at room temperature. After complete reaction, the solid precipitate was filtrated and washed with dichloromethane. After concentration down to crude mixture, it was purified by chromatography to provide the title compound 37 (3.1 g) as viscous oil. 1H NMR (400MHz, CDCI3) δ 4.56 (br s, 1H), 2.80 (br s, 1 H), 2.10 (br d, 1H), 1.78 (br d, 1 H), 1.75 (m, 6H), 1.44 (s, 9H), 1.00 (m, 2H); LCMS (m/z) 215.2 (M+H, 100); RT (Method A, std LCMS method), 1.2 min. tert-butyl (3-{f3-(trifluoromethoxy)benzvnamino}cvclohexyl)carbamate (38): The intermediate 37 (3.18g, 14.86mmol) was reacted with 3-trifluoromethoxybenzaldehyde according to example 1 using dichloromethane (60 ml) as solvent to give the title compounds as cis 38 (1.62g) and mixed isomer (2.68 g). (cis 38) 1H NMR (400MHz, CDCI3) δ 7.36 (t, 1H),

7.28 (d, 1 H), 7. 23 (s, 1 H), 7.14 (d, 1 H), 7.12 (br s, 1 H, NH), 4.73 (br s, 1 H), 3.88 (app. q, 2H), 3.46 (br s, 1 H), 2.70 (br s, 1 H), 2.22 (br d, 1 H), 1.95 (br m, 2H), 1.83 - 1.77 (m, 1 H), 1.43 (s, 9H), 1.42-1.07 (m, 4H); LCMS (m/z) 389.1 (M+H, 100); RT (Method A, std LCMS method), 1.7 min. tert-butyl (3-(|T1 -methyl-1 H-imidazol-4-yl)carbonyri|'3 (trifluoromethoxy)benzvπamino} cvclohexyDcarbamate (39): The mixed isomer intermediate 38 (2.68 g, 6.90 mmol) was reacted with N-methyl 4-carbonyl chloride salt (1.4Og, 20.7 mmol) according to example 2 to provide the title compound. The cis (1.43 g) and trans 39 (1.12 g) were isolated along with mixture of isomer (640 mg).(fra/is 39): 1H NMR (400MHz, CDCI3) δ 7.70 (s, 1 H), 7.45 (s, 1 H),

7.29 (t, 1H), 7.20 (d, 1H), 7. 10 (d, 1H), 7.05 (d, 1 H), 5.44 (br t, 1 H), 4.78 (d, 1H), 4.57 (d, 1 H), 3.89 (br s, 1H), 3.76 (s, 3H, N-CH3), 2.04 (br s, 2H), 1.68 - 1.59 (m, 4H), 1.48 (s, 9H), 1.42 (m, 1 H), 1.25 (m, 1H); LCMS (m/z) 497.0 (M+H, 100); RT (Method A, std LCMS method), 2.9 min. cis 39: 1H NMR (400MHz, CDCI3) δ 7.52 (s, 2H), 7.29 (t, 1 H), 7.22 (d, 1H), 7. 11 (s, 1 H), 7.05 (d, 1 H), 5.23 (br s, 1 H), 4.69 (br d, 1 H), 4.36 (br d, 1 H), 3.77 (br s, 3H, N-CH3), 3.48 (br s, 1H), 2.06 (br s, 1H), 1.91 (d, 1H), 1.74 (br d, 1H), 1.40 (s, 9H), 1.38 - 1.24 (1H), 0.93 (m, 1 H); LCMS (m/z) 497.0 (M+H, 100); RT (Method A, std LCMS method), 2.9 min. N-O-aminocvclohexyD-i-methyl-N-rS-αrifluoromethoxy^benzvn-IH-imidazole^- carboxamide (40): The trans 39 (1.10 g, 2.22 mmol) reacted with 4N HCI/dioxane according to example 9m to provide the title compound 40 (1.12 g) as HCI salt: trans 40. 1H NMR (400MHz, CD3OD) δ 9.02 (s, 1H), 8.20 (br s, 1H), 7.47 (br s, 1H), 7.34 (d, 1 H), 7.24 (s, 1H), 7. 20 (br s, 1 H), 4.63 (br s, 1 H), 3.88 (br d, 3H), 3.69 (s, 1 H), 3.65 (s, 3H, N-CH3), 2.14 (td, 1H), 2.06 (br d, 1H), 1.83 - 1.59 (m, 6H); LCMS (m/z) 397.0 (M+H, 40), 219.7 (M-177, 100); RT (Method A1 std LCMS method), 1.6 min.

The cis isomer of 40 was prepared in similar manner: 1H NMR (400MHz, CD3OD) δ 9.05 (s, 1H), 8.15 (br s, 1H), 7.46 (br s, 1H), 7.35 (d, 1H), 7.25 (s, 1H), 7. 20 (br s, 1H), 4.33 (br t, 1 H), 4.10 -3.80 (br d, 3H), 3.65 (s, 3H, N-CH3), 3.38 (br d, 1 H), 2.17 (d, 1 H), 1.95 (dd, 2H), 1.89 - 1.60 (m, 3H), 1.50 (br s, 1 H), 1.32 (m, 1H); LCMS (m/z) 397.0 (M+H, 60), 219.6 (M-177, 100); RT (Method A, std LCMS method), 1.2 min

Example 9n: N-f3-r(cvclopropylmethyl)amino1cyclohexyl>-1-methyl-N-r3- (trifluoro methoxy)benzvπ-1H-imidazole-4-carboxamide (41): The trans 40 hydrochlride salt (100 mg, 0.25 mmol) was reacted with the cyclopropane carboxaldehyde (1.5 equiv, 0.028 ml, 0.38 mmol) and diisopropyl ethyl amine in anhydrous methanol (2 ml) at 4O0C overnight. The resulting imine was cooled down to O0C and NaBH4 (1.5 equiv., 14 mg) was added slowly and the reaction warmed to room temperature. After two hrs, the reaction was quenched with saturated aueous bicarbonate and extracted with dichloromethane. The organic layer was dried, concentrated and the crude product purified by chromatography to provide the title compound 41 (75.2 mg) as colorless oil. The product was isolated as the HCI salt by treating a DCM solution of 41 with 4N HCI/dioxane. 1H NMR (400MHz, CD3OD) δ 8.95 (s, 1 H), 7.59 (br s, 1H), 7.48 (br s, 1 H), 7.35 (d, 1 H), 7.24 (s, 2H), 4.64 (br s, 1H), 4.00 -3.80 (br s, 3H), 3.65 (s, 3H, N-CH3), 2.95 (d, 2H), 2.13 (m, 2H), 1.97 (d, 1 H), 1.78 (br m, 4H), 1.17 (t, 2H), 0.72 (d, 2H), 0.42 (s, 2H); LCMS (m/z) 451.0 (M+, 100) RT (Method A, std LCMS method), 1.4 min

Scheme 9.

Referring to Scheme 9 above, 3-oxocyclobutane carboxylic acid 20 can subjected to Curtius rearrangement with diphenylphosphoryl azide in the presence of base such as triethyl amine or diisopropylethyl amine at temperatures ranging from 0° C to 110° C in appropriate solvent such as toluene and after the initial conversion to the intermediate add benzyl alcohol to trap the isocyanate generated to provide the protected product 42 (Reference: EP1256578 A1, p22). The ketone 42 can be reacted with amines such as 2-chlorophenyl ethyl amine in the presence of a reducing agent such as an alkaline borohydride, such as sodium borohydride, sodium cyanoborohydride, or sodium triacetoxyborohydride, with an optional additive such as acetic acid or triethylamine, in a solvent such as 1 ,2-dichloroethane, tetrahydrofuran.'or methanol at a temperature from room temperature to 1000C. The resulting amine 43 can be sulfonylated with sulfonyl chlorides such as N-meyl-4-sulfonylchloride in the presence of base such as dimethylamino pyridine in appropriate solvent such as dichloroethane at temperatures ranging from room temperature to 100° C for periods ranging from 1 hr to 72 hr. The resulting sulfonamide 44 can be reacted under acidic condition such as hydrogen bromide in acetic acid at temperatures ranging from room temperature to 100° C for period ranging from 1 hr to 72 hr to give the amine product 45.

{3-f2-(2-Chloro-phenylVethylamino1-cvclobutyl>-carbamic acid benzyl ester (43): Synthesized according to example 1, Scheme 1 using dichloroethane as solvent . 71 %; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.26 (s, 1 H) 1.42 (s, 1 H) 2.14 (s, 4 H) 2.78 (s, 2 H) 2.90 (s, 2 H) 3.44 (s, 1 H) 4.22 (s, 1 H) 4.93 (s, 1 H) 5.08 (s, 2 H) 7.20 (s, 3 H) 7.33 (s, 5 H); LCMS (m/z) 359.0 (M+H).

Example 9o: (3-rr2-(2-Chloro-phenyl)-βthvπ-(1-methvMHwmidazole-4-sulfonyl)- aminoi-cvclobutyll-carbamic acid benzyl ester (44): A mixture of the amine 43 (115 mg, 0.32 mmol), N-methyl-IH-imidazole-4-sulfonylchloride (75 mg, 0.42 mmol) and dimethylaminopyridine (51 mg, 0.42 mmol) in dry dichloroethane (2.5 ml) was heated at reflux for 16 hr.The reaction mixture was added methylene chloride and washed with water. The organil layer was dried and concentrated to give crude sulfonamide. Purification by chromatography gave the desired product 44 (165 mg) as a solid. 1H NMR (400 MHz, CHLOROFORM-cQ δ ppm 1.59 (s, 1 H) 2.05 (s, 1 H) 2.34 (s, 1 H) 3.11 (s, 2 H) 3.37 (s, 2 H) 3.75 (s, 2 H) 3.91 (s, 1 H) 4.52 (s, 1 H) 4.93 (s, 1 H) 5.06 (s, 2 H) 7.18 (s, 1 H) 7.25 (s, 2 H) 7.34 (s, 4 H) 7.42 (s, 1 H); LCMS (m/z) 546.8 (M+H).

Example 9p: i-MethvHH-imidazole-4-sulfonic acid (3-amino-cvclobutyl)-r2-(2- chloro-phenyQ-ethvπ-amide (45): A solution of 44 (73 mg) in acetic acid ( 1 ml) was added 30% HBr/acetic acid (2 ml) and the resulting mixture was stirred at room temperature for 1 hr. The mixture was concentrated down and 1 N NaOH added and extracted with dichloromethane (2X), dried and concentrated to give crude residue. Purified by chromatography to provide the desired product 45 (16 mg) as a solid. The product was taken up in dichloromethane and made acidic with 4N HCI/dioxane and the HCI salt of 45 was collected by adding ether and filtering the solid salt precipitate. 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.24 (s, 1 H) 1.52 (s, 2 H) 1.87 (s, 2 H) 2.26 (s, 2 H) 3.15 (s, 2 H) 3.44 (s, 3 H) 3.75 (s, 2 H) 4.49 (s, 1 H) 5.26 (s, 1 H) 7.16 (s, 2 H) 7.31 (s, 3 H) 7.42 (s, 1 H); LCMS (m/z) 368.9 (M+H).

Scheme 9A.

Referring to Scheme 9A above, a commericially available compound methyl 3- oxocyclohexanecarboxylate is reacted with amines such as 3-trifluoromethoxy benzyl amine in the presence of a reducing agent such as an alkaline borohydride, such as sodium borohydride, sodium cyanoborohydride, (scheme 1 , method b) or sodium triacetoxyborohydride (scheme 1 , method A), with an optional additive such as acetic acid or triethylamine, in a solvent such asdichloromethane, 1 ,2-dichloroethane, tetrahydrofuran, or methanol at a temperature from room temperature to 10O0C for a time from 1 hour to 72 hours. The resulting ester 1 can be reduced to the alcohol with reducing agents such as DIBAL1 LAH, LiBH4, etc. in solvent such as THF, ether, and so on at temperatures ranging from -60° C to 100° C. The amino alcohol 2 can be separated using chiral separation or other chiral salt formation to get the pure cis and trans diastereomers 3 and 4.The aminoalcohol 3 or 4 can then be acylated independently with acid chlorides such as N-methylimidazo-4-yl carbonylchloride in the presence of a base, such as an organic amine such as triethylamine or diisopropylethylamine, in a solvent such as tetrahydrofuran, acetonitrile, dimethylformamide, or N-methylpyrrolidinone, at a temperature from 0° C to 1000C for a time from 1 hour to 72 hours. The resulting alcohol 5 can then be oxidized with various reagents, such as Dess-Martin periodinane, MnO2, Swern oxidation conditions, etc. at temperatures ranging from 0° C to 1000C for a time from 1 hour to 72 hours. The resulting aldehyde 6 can be treated with either primary or secondary amines, such as azetidine shown, in the presence of a reducing agent such as an alkaline borohydride, such as sodium borohydride, sodium cyanoborohydride, or sodium triacetoxyborohydride, with an optional additive such as acetic acid or triethylamine, in a solvent such as 1 ,2-dichloroethane, tetrahydrofuran, or methanol at a temperature from room temperature to 1000C for a time from 1 hour to 72 hours to give the desired amine 7. Using this approach, one can generally isolate all isomeric compounds in pure form.

Methyl 3-(3-(trifluoromethoxy)benzylamino)cyclohexanecarboxylate (1): Prepared according to Example 1. 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.08 (s, 1 H) 1.29 (s, 3 H) 1.84 (s, 1 H) 1.94 (s, 2 H) 2.24 (s, 1 H) 2.31 (s, 1 H) 2.50 (s, 1 H) 3.66 (s, 3 H) 3.85 (s, 2 H) 7.09 (s, 1 H) 7.24 (s, 2 H) 7.33 (s, 1 H); LCMS (m/z) 332.0

Example 9q. (3-(3-(trifluoromethoxy)benzylamino)cvclohexyl)methanol: A solution of the ester 1 (14.4g, 41.7 mmol) in dry THF at -780C under N2 atmosphere was added DIBAL (8.4 ml of 1 M in cyclohexane, 83.4 mmol) via dropwise addition and the resulting solution was allowed to warm to room temperature and stirred for 3 hr. The reaction mixture was quenched with sodium sulfate decahydrate and stirred at room temperature for a while and the resulting solids filtered out. Concentration of the filtrate gave crude residure which was purified by chromatography to give the desired product (5.7g) as a yellow oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.13 (s, 1 H) 1.23 (s, 2 H) 1.36 (s, 1 H) 1.49 (s, 3 H) 1.68 (s, 2 H) 1.91 (s, 1 H) 2.88 (s, 1 H) 3.45 (s, 2 H) 3.72 (s, 1 H) 3.79 (s, 2 H) 7.09 (s, 1 H) 7.22 (s, 1 H) 7.30 (s, 2 H); LCMS (m/z) 304.2 (M+H).

N-(3-(trifluoromethoxy)benzvπ-N-(3-(hvdroxymethyl)cyclohexyl)-1-methyl-1 H- imidazole-4-carboxamide: Prepared according Example 3. 1 H NMR (400 MHz, CHLOROFORM-cQ δ ppm 1.40 (s, 5 H) 1.58 (s, 3 H) 2.16 (s, 1 H) 2.33 (s, 1 H) 3.51 (s, 1 H) 3.74 (s, 4 H) 4.53 (s, 1 H) 4.85 (s, 1 H) 5.04 (s, 1 H) 7.04 (s, 1 H) 7.13 (s, 1 H) 7.21 (s, 1 H) 7.28 (s, 1 H) 7.48 (s, 1 H) 7.63 (s, 1 H); LCMS (m/z) 412.0 (M+H).

N-(3-(trifluoromethoxy)benzyl)-N-(3-formylcvclohexyl)-1-methyl-1 H-imidazole-4- carboxamide: Prepared according to Example 9e. 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.07 (S, 1 H) 1.37 (s, 3 H) 1.66 (s, 1 H) 1.74 (s, 1 H) 1.89 (s, 2 H) 2.12 (s, 1 H) 2.42 (s, 1 H) 2.57 (s, 1 H) 3.70 (s, 4 H) 4.72 (s, 1 H) 7.05 (s, 1 H) 7.14 (s, 1 H) 7.26 (s, 3 H) 7.55 (s, 1 H); LCMS (m/z) 410.0 (M+H).

N-(3-(trifluoromethoxy)benzyl)-N-((1R,3S)-3-(azetidin-1-ylmethyl)cvclohexyl)-1- methyl-1H-imidazole-4-carboxamide: Prepared according to Example 1. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.70 (s, 1 H) 1.06 (s, 1 H) 1.28 (s, 2 H) 1.45 (s, 1 H) 1.68 (s, 3 H) 1.80 (s, 1 H) 1.99 (s, 2 H) 2.19 (s, 2 H) 2.68 (br s, 1 H) 3.08 (s, 4 H) 3.66 (br m, 3 H) 4.49 (br s, 1 H) 4.58 (d, 1 H) 4.70 (d, 1 H) 5.16 (s, 1 H) 5.41 (br s, 1 H) 7.01 (s, 1 H) 7.09 (s, 1 H) 7.22 (s, 3 H) 7.48 (s, 1 H); LCMS (m/z) 451.2 (M+H). Scheme 10.

Referring to Scheme 10 above, a compound of the formula Il is reacted with N-t- butylcarboxy-octahydro-cyclopenta[c]pyrrol-5-one)-amine in the presence of a reducing agent such as an alkaline borohydride, such as sodium borohydride, sodium cyanoborohydride, or sodium triacetoxyborohydride, with an optional additive such as acetic acid or triethylamine, in a solvent such as 1 ,2-dichloroethane, tetrahydrofuran, or methanol at a temperature from room temperature to 1000C for a time from 1 hour to 72 hours. The resulting compound, III, is treated with a compound of the formula IV in the presence of a base, such as an organic amine such as triethylamine or diisopropylethylamine, in a solvent such as tetrahydrofuran, acetonitrile, dimethylformamide, or N-methylpyrrolidinone, at a temperature from room temperature to 100°C for a time from 1 hour to 72 hours. The resulting compound, V, is deblocked using, for example, acidic conditions such as HCI in a solvent such as ethyl acetate or tetrahydrofuran, or trifluoroacetic acid in dichloromethane, at a temperature from room temperature to 1000C for a time from 1 hour to 72 hours. The resulting intermediate is treated with a compound of the formula Vl in the presence of a reducing agent such as an alkaline borohydride, such as sodium borohydride, sodium cyanoborohydride, or sodium triacetoxyborohydride, with an optional additive such as acetic acid or triethylamine, in a solvent such as 1 ,2-dichloroethane, tetrahydrofuran, or methanol at a temperature from room temperature to 1000C for a time from 1 hour to 72 hours.

Example 10. i-Methyl-IH-imidazole-4-carboxylic acid (3-chloro-benzyl)-(2- methyl-octahvdro-cvclopentaMpyrrol-5-yl)-amide:

A. N-(t-ButylcarboxyM3-chloro-benzylMoctahvdro-cvclopentafcipyrrol-5-yl)-arnine (referring to Scheme 10): To a 125 mL round-bottomed flask equipped with N2 inlet were added 1.02 g (4.53 mmol) N-t-butylcarboxy-octahydro-cyclopenta[c]pyrrol-5-one)-amine (preared as described in Becker, Daniel P.; Flynn, Daniel L. Synthesis of N-BOC-3- azabicyclo[3.3.0]octan-7-one via reductive Pauson-Khand cyclization and subsequent conversion to a novel diazatricyclic ring system. Tetrahedron (1993), 49(23), 5047-54.), 554 uL (4.53 mmol) 3-chlorobenzylamine, 259 uL (4.53 mmol) acetic acid, 1.44 g (4.16 mmol) sodium triacetoxy borohydride, and 20 mL dry 1 ,2-dichloroethane. The reaction was stirred at room temperature for 15 hours, diluted with ethyl acetate, washed with aqueous sodium bicarbonate solution and brine, dried over sodium sulfate, and evaporated to an oil The residue was chromatographed on silica gel using methanol/ethyl acetate as eluant to afford 1.59 g (100%) of an oil.

13C-NMR (δ, CDCI3): 13.11 , 16.47, 25.97, 28.74, 39.30, 40.97, 52.48, 60.74, 79.31 , 108.55, 112.49, 126.43, 127.35, 128.41 , 129.89, 134.47, 142.66, 154.90. MS: 351/353 (parent+1 for MW = 350.5, C19H27N2O2CI).

B. 1-Methyl-1 H-imidazole-4-carboxylic acid (3-chloro-benzylHN-t-butoxycarboxy- octahvdro-cvclopentarclPyrrol-5-yl)-amide. To a 125 mL round-bottomed flask equipped with N2 inlet were added 200 mg (599 umol) N-(t-butylcarboxy)-(3-chloro-benzyl)-(octahydro- cyclopenta[c]pyrrol-5-yl)-amine, 1.2 g (6.75 mmol) N-methylimidazole-4-carbonyl chloride hydrochloride, 1.96 mL (13.5 mmol) diisopropylethylamine, and 10 mL dry acetonitrile. The reaction was heated at 4O0C for 16 hours, cooled, diluted with ethyl acetate, washed with aqueous sodium bicarbonate solution and brine, dried over sodium sulfate, and evaporated to an oil. The residue was chromatographed on silica gel using methanol/ethyl acetate/ammonium hydroxide as eluant to afford 1.33 g (64%) of the cis isomer as an oil.

13C-NMR (δ, CDCI3): 28.71 , 33.82, 34.66, 39.64, 40.65, 51.77, 79.41, 124.83, 126.57, 126.75, 127.05, 129.82, 134.48, 136.85, 138.59, 154.87, 164.75. MS: 459/461 (parent+1 for MW = 458.5, C24H3IN4O3CI).

C. 1 -Methyl-1 H-imidazole-4-carboxylic acid (3-chloro-benzyl)-(octahvdro- cvclopentarclPyrrol-5-vD-amide. To a 125 ml_ round-bottomed flask equipped with N2 inlet were added 1.33 g (2.9 mmol) i-methyl-I H-imidazole-4-carboxylic acid (3-chloro-benzyl)-(N-t- butoxycarboxy-octahydro-cyclopenta[c]pyrrol-5-yl)-amide and 50 mL dry ethyl acetate. The reaction was saturated with HCI and stirred at room temperature for 3 hours. It was then evaporated to a white solid, 1.17 g (94%).

13C-NMR (δ, CDCI3): 17.21 , 35.59, 38.76, 50.77, 57.13, 123.82, 124.77, 126.37, 130.11 , 137.16, 140.41 , 159.22.

MS: 359/361 (parent+1 for MW = 358.5, C19H23N4OCI).

D. 1 -Methyl-1 H-imidazole-4-carboxylic acid (3-chloro-benzyl)-(2-methyl-octahvdro- cvclopentarclPyrrol-5-vO-amide: To a 125 mL round-bottomed flask equipped with N2 inlet were added 161 mg (448 umol) 1-methyl-1H-imidazole-4-carboxylic acid (3-chloro-benzyl)- (octahydro-cyclopenta[c]pyrrol-5-yl)-amide, 75 uL (896 umol) formalin solution (33% formaldehyde in water), 26 uL (448 umol) acetic acid, 142 mg (672 umol) sodium triacetoxy borohydride, and 5 mL dry 1 ,2-dichloroethane. The reaction was stirred at room temperature for 2 hours, diluted with ethyl acetate, washed with aqueous sodium bicarbonate solution and brine, dried over sodium sulfate, and evaporated to an oil The residue was chromatographed on silica gel using methanol/dichloromethane/ammonium hydroxide as eluant to afford 124 mg (74%) of an oil.

13C-NMR (δ, CDCI3): .

MS: 373/375 (parent+1 for MW = 372.5, C20H25N4OCI).

Anal. CaICd. for C2OH25N4OOI^HCM .75H2O: C 50.32, H 6.44, N 11.74. Found: C 50.29, H 6.55, N 11.60.

Scheme H.

Referring to Scheme 11 above, a compound of the formula H is reacted with 4- benzyloxy-butylamine in the presence of a reducing agent such as an alkaline borohydride, such as sodium borohydride, sodium cyanoborohydride, or sodium triacetoxyborohydride, with an optional additive such as acetic acid or triethylamine, in a solvent such as 1 ,2- dichloroethane, tetrahydrofuran, or methanol at a temperature from room temperature to 10O0C for a time from 1 hour to 72 hours. The resulting compound, III, is treated with a compound of the formula IV in the presence of a base, such as an organic amine such as triethylamine or diisopropylethylamine, in a solvent such as tetrahydrofuran, acetonitrile, dimethylformamide, or N-methylpyrrolidinone, at a temperature from room temperature to 10O0C for a time from 1 hour to 72 hours. The resulting compound, V, is debenzylated using, for example, hydrogen gas in the presence of a palladium or other noble metal catalyst, at a pressure from 1 to 10 atmospheres, at a temperature from room temperature to 1000C, for 1 to 72 hours. Alternatively, a hydrogen source such as ammonium formate or 1- methylcyclohexadiene may be used, typically in an alcohol solvent such as ethanol, with the above palladium catalyst, at room temperature to reflux for 1 to 24 hours. The resulting intermediate is converted to compound Vl by oxidation using any of a wide range of standard conditions. For examples, Vl may be treated with oxalyl chloride and DMSO in methylene chloride, followed by addition of an organic base such as triethylamine or diisopropylamine, at -700C to reflux, for 1 to 24 hours. The resulting intermediate Vl is treated with a compound of the formula VII in the presence of a reducing agent such as an alkaline borohydride, such as sodium borohydride, sodium cyanoborohydride, or sodium triacetoxyborohydride, with an optional additive such as acetic acid or triethylamine, in a solvent such as 1,2-dichloroethane, tetrahydrofuran, or methanol at a temperature from room temperature to 1000C for a time from 1 hour to 72 hours.

Example 11. Methyl-IH-imidazole-4-carboxylic acid r4-(3-methyl-bu.ylamino)- butyll-(3-trifluoromethoxy-benzyl)-amide:

A. r4-(Benzyloxy)-butvπ-(3-trifluoromethoxy-benzyl)-amine (referring to Scheme 11): To a 125 mL round-bottomed flask equipped with N2 inlet were added 646 mg (3 mmol) 4- benzyloxy-butylamine, 429 uL (3 mmol) 3-(trifluoromethoxy)benzaldehyde, 172 uL (3 mmol) acetic acid, 1.27 g (6 mmol) sodium triacetoxy borohydride, and 10 mL dry 1 ,2- dichloroethane. The reaction was stirred at room temperature for 2 hours, diluted with ethyl acetate, washed with aqueous sodium bicarbonate solution and brine, dried over sodium sulfate, and evaporated to an oil, 920 mg (87%).

13C-NMR (δ, CDCI3): 23.92, 26.31, 26.40, 26.54, 27.62, 48.75, 48.81 , 52.88, 53.17, 64.15, 64.42, 70.27, 72.32, 73.05, 73.13, 119.31, 119.58, 119.77, 119.88, 120.88, 121.06, 122.57 (q, J=123), 125.06, 126.77, 126.93, 127.10, 127.80, 127.88, 128.01 , 128.59, 128.79, 128.94, 129.35, 129.71 , 130.00, 138.45, 138.63, 141.41 , 142.09, 142.44, 149.60.

MS: 354 (parent+1 for MW = 353, C19H22NO3F3).

B. 1-Methyl-1 H-imidazole-4-carboxylic acid r4-(benzyloxy')-butyl'|-(3-trifluoromethoxy- benzvP-amide. To a 125 mL round-bottomed flask equipped with N2 inlet were added 920 mg (2.61 mmol) [4-(benzyloxy)-butyl]-(3-trifluoromethoxy-benzyl)-amine, 543 mg (3 mmol) N- methylimidazole-4-carbonyl chloride hydrochloride, 1045 uL (6 mmol) diisopropylethylamine, and 10 mL dry acetonitrile. The reaction was heated at 400C for 24 hours, cooled, diluted with ethyl acetate, washed with aqueous sodium bicarbonate solution and brine, dried over sodium sulfate, and evaporated to an oil. The residue was chromatographed on silica gel using methanol/dichloromethane as eluant to afford 1050 mg (76%) of the product as an oil.

13C-NMR (δ, CDCI3): 21.13, 24.20, 25.86, 27.38, 33.76, 46.20, 47.99, 49.05, 51.23, 64.18, 64.33, 65.26, 70.18, 73.06, 119.30, 119.61 , 120.29, 120.88, 121.32, 125.97, 126.57, 127.70, 127.80, 128.54, 129.98, 130.04, 130.07, 130.12, 136.84, 138.72, 139.02, 141.25, 149.59, 163.95, (OCF3 group not visible in this scan, amide rotamers double many of the carbon lines).

MS: 462 (parent+1 for MW = 461 C24H26N3O3F3).

C. 1-Methyl-1 H-imidazole-4-carboxylic acid r4-hvdroxybutvπ-(3-trifluoromethoxy- benzvO-amide. To a 125 mL round-bottomed flask equipped with N2 inlet were added 1050 mg (2.28 mmol) 1-methyl-1 H-imidazole-4-carboxylic acid [4-(benzyloxy)-butyl]-(3- trifluoromethoxy-benzyl)-amide, 4.19 g (45.5 mmol) 1-methylcyclohexadiene, 170 mg of 20% palladium hydroxide on carbon, and 50 ml_ ethanol. The reaction was refluxed 2 hours, cooled, and filtered through Celite. The filtrate was evaporated to an oil, 800 mg (72%).

13C-NMR (δ, CDCI3): 23.80, 24.71, 25.81 , 26.29, 28.64, 29.79, 33.76, 33.93, 46.03, 47.04, 49.41, 51.31, 62.31 , 64.00, 64.30, 65.24, 76.99, 77.31 , 77.63, 119.25, 119.33, 119.63, 120.39, 120.63, 120.85, 121.89, 125.06, 125.98, 126.18, 126.68, 127.72, 129.81 , 130.02, 136.93, 137.42, 137.67, 138.19, 139.08, 140.55, 141.09, 144.36, 149.59, 163.42, (OCF3 group not visible in this scan, amide rotamers double many of the carbon lines).

MS: 372 (parent+1 for MW = 371 , C17H20N3O3F3).

D. 1-Methyl-1 H-imidazole-4-carboxylic acid f4-(3-methyl-butylamino)-butyl]-(3- trifluoromethoxy-benzvD-amide. i-Methyl-I H-imidazole-4-carboxylic acid [4-hydroxybutyl]-(3- trif!uoromethoxy-benzyl)-amide was converted to the corresponding aldehyde by Swern oxidation by dissolving 226 uL (2.54 mmol) oxalyl chloride in 15 ml_ dry dichloromethane, cooling to -700C, and adding 398 uL (5.61 mmol) dry DMSO. The reaction was stirred at - 700C for 10 minutes, then a solution of the alcohol in 7 ml_ dry dichloromethane was added, and stirring continued for 30 minutes. Then 1.88 ml_ (10.7 mmol) dry diisopropylethylamine was added, and the reaction warmed and stirred at 00C for 50 minutes. The reaction was washed with aqueous sodium bicarbonate solution, dried over sodium sulfate, and evaporated, and the residue used immediately in the following step: To a 125 mL round- bottomed flask equipped with N2 inlet were added 200 mg (540 umol) the aldehyde, 63 uL (540 umol) 3-methyl-butylamine, 31 uL (540 umol) acetic acid, 229 mg (1.08 mmol) sodium triacetoxy borohydride, and 5 mL dry 1 ,2-dichloroethane. The reaction was stirred at room temperature for 2 hours, diluted with ethyl acetate, washed with aqueous sodium bicarbonate solution and brine, dried over sodium sulfate, and evaporated to an oil, which was chromatographed on silica gel using methanol/dichloromethane as eluant to afford 100 mg (42%) of the product as an oil.

13C-NMR (δ, CDC13): 22.84, 22.91 , 25.19, 26.36, 26.67, 27.05, 27.65, 33.77, 39.33, 46.33, 48.01 , 48.15, 48.30, 49.14, 49.48, 49.90, 51.32, 119.60, 120.32, 125.98, 126.25, 126.60, 129.97, 136.83, 138.50, 141.26, 149.59, 163.90 (OCF3 group not visible in this scan).

MS: 441 (parent+1 for MW = 440, C22H31N4O2F3).

Anal. Calc'd. for C

22

H

3

iN

4

O

2

F

3

-2HC|-1/2H

2

O: C 50.58, H 6.56, N 10.72. Found: C 50.80, H 6.47, N 10.67.

Referring to Scheme 12, a compound of the formula Il is reacted with N-t- butoxycarbonylazepan-4-one in the presence of a reducing agent such as an alkaline borohydride, such as sodium borohydride, sodium cyanoborohydride, or sodium triacetoxyborohydride, with an optional additive such as acetic acid or triethylamine, in a solvent such as 1 ,2-dichloroethane, tetrahydrofuran, or methanol at a temperature from room temperature to 10O0C for a time from 1 hour to 72 hours. The resulting compound, III, is treated with a compound of the formula IV in the presence of a base, such as an organic amine such as triethylamine or diisopropylethylamine, in a solvent such as tetrahydrofuran, acetonitrile, dimethylformamide, or N-methylpyrrolidinone, at a temperature from room temperature to 10O0C for a time from 1 hour to 72 hours. The resulting compound, V, is deblocked using, for example, acidic conditions such as HCI in a solvent such as ethyl acetate or tetrahydrofuran, or trifluoroacetic acid in dichloromethane, at a temperature from room temperature to 1000C for a time from 1 hour to 72 hours. The resulting intermediate Vl is treated with a compound of the formula VII in the presence of a reducing agent such as an alkaline borohydride, such as sodium borohydride, sodium cyanoborohydride, or sodium triacetoxyborohydride, with an optional additive such as acetic acid or triethylamine, in a solvent such as 1 ,2-dichloroethane, tetrahydrofuran, or methanol at a temperature from room temperature to 1000C for a time from 1 hour to 72 hours.

Example 12. i-Methyl-IH-imidazole-4-carboxylic acid azepan-4-yl-(3- trifluoromethoxy-benzvD-amide:

A. (N-t-Butoxycarbonyl-azepan-4-yl-(3-trifluoromethoxy-benzyl)-amide (referring to Scheme 12): To a 125 ml_ round-bottomed flask equipped with N2 inlet were added 426 mg (2 mmol) N-t-butoxycarbonylazepan-4-one (prepared in analogy with the procedure given in Jour. Med. Chem., 23, 895 (1980), starting from N-t-butoxycarbonyl-piperidin-4-one, ethyl diazoacetate, and boron trifluoride etherate), 320 uL (2 mmol) 3- (trifluoromethoxy)benzylamine, 114 uL (2 mmol) acetic acid, 848 mg (4 mmol) sodium triacetoxy borohydride, and 10 mL dry 1 ,2-dichloroethane. The reaction was stirred at room temperature for 18 hours, diluted with ethyl acetate, washed with aqueous sodium bicarbonate solution and brine, dried over sodium sulfate, and evaporated to an oil, 830 mg (100%).

13C-NMR (δ, CDCI3): 24.39, 24.72, 28.52, 28.64, 32.86, 33.43, 34.90, 35.27, 42.78,

43.27, 43.63, 44.19, 46.15, 46.82, 50.92, 50.99, 57.30, 57.52, 60.57, 76.94, 77.26, 77.57, 79.34, 119.38, 119.50, 119.64, 119.80, 120.65, 126.52, 129.89, 143.14, 149.58, 155.71, (amide rotamers double many of the carbon lines).

MS: 389 (parent+1 for MW = 388, C19H27N2O3F3).

B. (N-t-Butoxycarbonyl)-1-methyl-1 H-imidazole-4-carboxylic acid azepan-4-yl-(3- trifluoromethoxy-benzvD-amide. To a 125 mL round-bottomed flask equipped with N2 inlet were added 830 mg (2 mmol) (N-t-butoxycarbonyl-azepan-4-yl-(3-trifluoromethoxy-benzyl)- amide, 362 mg (2 mmol) N-methylimidazole-4-carbonyl chloride hydrochloride, 697 uL (4 mmol) diisopropylethylamine, and 10 mL dry acetonitrile. The reaction was heated at 400C for 24 hours, cooled, diluted with ethyl acetate, washed with aqueous sodium bicarbonate solution and brine, dried over sodium sulfate, and evaporated to an oil. The residue was chromatographed on silica gel using methanol/dichloromethane as eluant to afford 880 mg (89%) of the product as an oil.

13C-NMR (δ, CDCI3): 25.20, 26.27, 28.46, 28.53, 31.68, 32.33, 32.81 , 33.65, 33.86, 34.26, 42.32, 42.82, 43.21 , 43.58, 43.98, 45.51 , 46.07, 46.68, 47.00, 49.72, 58.10, 58.59,

79.28, 118.93, 119.30, 119.43, 119.66, 120.13, 120.26, 122.55 (q, J=141 ), 124.41 , 125.40, 125.79, 126.12, 126.25, 129.73, 130.05, 136.82, 137.53, 138.33, 138.77, 141.41 , 142.52, 149.39, 155.54, 162.70, 163.99, 164.55 (amide rotamers double many of the carbon lines). MS: 497 (parent+1 for MW = 496 C24H31N4O4F3).

C. 1-Mβthyl-1 H-imidazole-4-carboxylic acid azepan-4-yl-(3-trifluoromethoxy-benzyl)- amide. To a 125 mL round-bottomed flask equipped with N2 inlet were added 880 g (1.77 mmol) (N-t-butoxycarbonylH-methyl-I H-imidazole^-carboxylic acid azepan-4-yl-(3- trifluoromethoxy-benzyl)-amide and 50 mL dry ethyl acetate. The reaction was saturated with HCI and stirred at room temperature for 14 hours. It was then evaporated to a white solid, 610 mg (77%).

13C-NMR (δ, CDCI3): 27.36, 28.16, 31.62, 32.96, 33.52, 33.72, 35.11 , 36.88, 42.22, 45.52, 45.70, 46.19, 48.75, 49.78, 50.32, 54.38, 58.32, 59.06, 118.74, 119.25, 119.52, 119.61 , 120.14, 122.52 (q, J=142), 124.37, 125.36, 125.91 , 126.03, 126.24, 127.50, 129.62, 129.97, 130.11, 136.81 , 138.33, 139.23, 142.36, 142.66, 143.31 , 149.27, 151.95, 163.88, 164.63 (amide rotamers double many carbon lines).

MS: 397 (parent+1 for MW = 396, C19H23N4O2F3).

Anal. Calc'd. for C19H23N4O2F32HC|-3H2O: C 43.60, H 5.97, N 10.70. Found: C 43.78, H 5.96, N 10.44.

Scheme 13.

Referring to Scheme 13, a compound of the formula Il is reacted with N-t- butoxycarbonyl-(2-aza-bicyclo[3.3.1]non-6-one), which is prepared according to a method reported in Tetrahedron Letters, 23 (44), 4559 (1982) using a t-BOC group instead of a methyl carbamate group, in the presence of a reducing agent such as an alkaline borohydride, such as sodium borohydride, sodium cyanoborohydride, or sodium triacetoxyborohydride, with an optional additive such as acetic acid or triethylamine, in a solvent such as 1 ,2-dichloroethane, tetrahydrofuran, or methanol at a temperature from room temperature to 10O0C for a time from 1 hour to 72 hours. The resulting compound, III, is treated with a compound of the formula IV in the presence of a base, such as an organic amine such as triethylamine or diisopropylethylamine, in a solvent such as tetrahydrofuran, acetonitrile, dimethylformamide, or N-methylpyrrolidinone, at a temperature from room temperature to 1000C for a time from 1 hour to 72 hours. The resulting compound, V, is deblocked using, for example, acidic conditions such as HCI in a solvent such as ethyl acetate or tetrahydrofuran, or trifluoroacetic acid in dichloromethane, at a temperature from room temperature to 1000C for a time from 1 hour to 72 hours. The resulting intermediate Vl is treated with a compound of the formula VII in the presence of a reducing agent such as an alkaline borohydride, such as sodium borohydride, sodium cyanoborohydride, or sodium triacetoxyborohydride, with an optional additive such as acetic acid or triethylamine, in a solvent such as 1 ,2-dichloroethane, tetrahydrofuran, or methanol at a temperature from room temperature to 1000C for a time from 1 hour to 72 hours.

Example 13. 1-Methyl-1H-imidazole-4-sulfonic acid (2-aza-bicvclor3.3.πnon-6- v0-(3-trifluoromethoxy-benzyl)-amide:

A. N-t-Butoxycarbonyl-(2-aza-bicvclof3.3.11non-6-yl)-(3-trifluoromethoxy-ben2vπ- amine: (referring to Scheme 13): To a 125 mL round-bottomed flask equipped with N2 inlet were added 500 mg (2.09 mmol) N-t-butoxycarbonyl-(2-aza-bicyclo[3.3.1]non-6-one) (prepared according to a method reported in Tetrahedron Letters, 23 (44), 4559 (1982) using a t-BOC group instead of a methyl carbamate group), 600 uL (3.14 mmol) 3- (trifluoromethoxy)benzylamine, 500 uL acetic acid, 1.33 g (6.28 mmol) sodium triacetoxy borohydride, and 20 mL dry 1,2-dichloroethane. The reaction was stirred at room temperature for 15 hours, diluted with ethyl acetate, washed with aqueous sodium bicarbonate solution and brine, dried over sodium sulfate, and evaporated to an oil The residue was chromatographed on silica gel using methanol/ethyl acetate as eluant to afford 607 mg (70%) of a mixture of isomers as an oil.

13C-NMR (δ, CDCI3): 22.19, 22.59, 23.33, 26.61, 27.09, 27.26, 28.16, 28.54, 28.69, 29.67, 30.41 , 31.10, 31.29, 39.21, 40.33, 43.15, 45.91 , 46.84, 50.40, 50.50, 51.33, 58.46, 76.95, 77.26, 77.58, 79.28, 119.41 , 119.93, 120.32, 120.59, 121.95, 126.20, 126.43, 129.82, 130.18, 141.11 , 143.66, 149.57 (as a mixture of isomers).

MS: 416 (parent+1 for MW = 415, C21H29N2O3F3).

HRMS Calc'd. for C21H30N2O3F3: 415.2209. Found: 415.2207 (-0.3 ppm).

B. N-(t-Butoxycarbonyl)-1-methyl-1 H-imidazole-4-sulfonic acid (2-aza- bicvclof3.3.nnon-6-yl)-(3-trifluoromethoxy-benzyl)-amide: To a 125 mL round-bottomed flask equipped with N2 inlet were added 302 mg (730 umol) N-t-butoxycarbonyl-(2-aza- bicyclo[3.3.1]non-6-yl)-(3-trifluoromethoxy-benzyl)-amine, 197 mg (1.09 mmol) N- methylimidazole-4-carbonyl chloride hydrochloride, 141 mg (1.09 mmol) diisopropylethylamine, and 10 mL dry acetonitrile. The reaction was heated at 800C for 72 hours, cooled, diluted with ethyl acetate, washed with aqueous sodium bicarbonate solution and brine, dried over sodium sulfate, and evaporated to an oil. The residue was chromatographed on silica gel using hexane/ethyl acetate as eluant to afford 198 mg (49%) of a mixture of isomers as an oil.

13C-NMR (δ, CDCI3): 21.45, 24.04, 24.23, 24.31 , 24.58, 25.45, 27.24, 28.08, 28.60, 28.63, 30.59, 31.09, 31.22, 31.58, 32.63, 32.89, 33.72, 34.11 , 37.87, 39.38, 40.31, 42.85, 44.96, 46.02, 48.71, 48.98, 57.49, 61.47, 61.90, 79.51, 119.35, 119.58, 119.68, 119.80, 120.00, 120.16, 121.91 , 124.14, 125.56, 125.80, 126.02, 129.81 , 139.19, 141.11 , 142.03, 149.48, 155.55, 155.78 (a mixture of isomers).

MS: 559 (parent+1 for MW = 558, C25H33N4O5SF3).

HRMS Calc'd. for C25H34N4O5SF3: 559.2202. Found: 559.2178 (-4.3 ppm).

C. 1-Methyl-1 H-imidazole-4-sulfonic acid (2-aza-bicvclof3.3.nnon-6-yl)-(3- trifluoromethoxy-benzvO-amide: To a 125 mL round-bottomed flask equipped with N2 inlet were added 198 mg (355 umol) N-(t-butoxycarbonyl)-1-methyl-1 H-imidazole-4-sulfonic acid (2-aza-bicydo[3.3.1]non-6-yl)-(3-trifluoromethoxy-benzyl)-arnide and 50 mL dry ethyl acetate. The reaction was saturated with HCI and stirred at room temperature for 14 hours. It was then evaporated to a white solid, which was triturated with ethyl ether, 133 mg (70%).

13C-NMR (δ, CDCI3): 15.28, 22.49, 25.18, 26.76, 30.73, 31.01 , 36.62, 39.48, 46.17, 48.87, 49.08, 49.30, 49.51 , 49.73, 49.94, 50.15, 50.46, 61.97, 119.28, 120.56, 120.81 , 121.83, 125.81, 126.62, 130.45, 135.28, 139.34, 140.13, 149.59.

MS: 459 (parent+1 for MW = 458, C20H24N4O3SF3).

Anal. Calc'd. for C2OH24N4O3SF3 ^HCI (IMC4H1OO2): C 45.86, H 5.41 , N 10.19. Found: C 45.80, H 5.27, N 10.53.

Example 14. i-Methyl-IH-imidazole-4-carboxyli'c acid (7-aza-bicyclor4.3.πdec-2- yl)-(4-fluoro-3-trifluoromethyl-benzyl)-amide:

This is a ring-expanded analogue of Example 1, prepared in analogy with Example 1, with the starting ketone treated with ethyl diazoacetate and boron trifluoride etherate to produce a mixture of four isomers, each of which was converted to final product, one of which gave the following characterization:

13C-NMR (δ, CDCI3): 13.33, 19.40, 19.77, 22.52, 26.37, 29.42, 30.96, 35.71 , 37.04, 50.60, 64.56, 117.53, 122.64 (q, J=226), 124.21 , 125.45, 127.19, 132.50, 134.30, 137.18, 158.63 (d, J=240).

MS: 439 (parent+1 for MW = 438, C22H26N4OF4).

Anal. Caic'd. for C22H26N4OF42HCM .75H2O: C 48.67, H 5.85, N 10.32. Found: C 48.69, H 5.80, N 10.04. Scheme 14.

Referring to Scheme 14 above, a compound of the formula Il is reacted with 4-t- butoxamido-cycloheptanone in the presence of a reducing agent such as an alkaline borohydride, such as sodium borohydride, sodium cyanoborohydride, or sodium triacetoxyborohydride, with an optional additive such as acetic acid or triethylamine, in a solvent such as 1,2-dichloroethane, tetrahydrofuran, or methanol at a temperature from room temperature to 10O0C for a time from 1 hour to 72 hours. The resulting compound, III, is treated with a compound of the formula IV in the presence of a base, such as an organic amine such as triethylamine or diisopropylethylamine, in a solvent such as tetrahydrofuran, acetonitrile, dimethylformamide, or N-methylpyrrolidinone, at a temperature from room temperature to 10O0C for a time from 1 hour to 72 hours. The resulting compound, V, is deblocked using, for example, acidic conditions such as HCI in a solvent such as ethyl acetate or tetrahydrofuran, or trifluoroacetic acid in dichloromethane, at a temperature from room temperature to 1000C for a time from 1 hour to 72 hours. The resulting intermediate Vl is treated with a compound of the formula VII in the presence of a reducing agent such as an alkaline borohydride, such as sodium borohydride, sodium cyanoborohydride, or sodium triacetoxyborohydride, with an optional additive such as acetic acid or triethylamine, in a solvent such as 1 ,2-dichloroethane, tetrahydrofuran, or methanol at a temperature from room temperature to 1000C for a time from 1 hour to 72 hours.

Example 15. i-Methyl-IH-imidazole-4-carboxylic acid (4-amino-cycloheptyl)-(3- trifluoromethoxy-benzvD-amide:

A. (4-t-Butoxamido-cvcloheptyl)-(3-trifluoromethoxy-benzyl)-amine (referring to Scheme 14): To a 125 ml. round-bottomed flask equipped with N2 inlet were added 454 mg (2 mmol) 4-t-butoxamido-cycloheptanone (prepared in analogy with the procedure given in Jour. Med. Chem.. 23, 895 (1980), starting from 4-t-butoxamido-cyclohexanone, ethyl diazoacetate, and boron trifluoride etherate), 320 uL (2 mmol) 3- (trifluoromethoxy)benzylamine, 114 uL (2 mmol) acetic acid, 848 mg (4 mmol) sodium triacetoxy borohydride, and 10 mL dry 1 ,2-dichloroethane. The reaction was stirred at room temperature for 18 hours, diluted with ethyl acetate, washed with aqueous sodium bicarbonate solution and brine, dried over sodium sulfate, and evaporated to an oil, 1.02 g (100%) of a mixture of cis/trans isomers as an oil.

13C-NMR (δ, CDCI3): 20.24, 28.62, 28.64, 29.41 , 30.18, 30.99, 32.00, 32.18, 34.38, 35.00, 35.41, 35.95, 41.39, 43.23, 43.63, 50.90, 51.18, 56.96, 58.06, 119.47, 119.86, 120.69, 121.95, 125.77, 126.23, 126.54, 129.86.

MS: 403 (parent+1 for MW = 402, C20H29N2O3F3).

B. 1-Methyl-1 H-imidazole-4-carboxylic acid (4-t-butoxamido-cvcloheptyl)-(3- trifluoromethoxy-benzvD-amide. To a 125 mL round-bottomed flask equipped with N2 inlet were added 100 mg (250 umol) (4-t-butoxamido-cycloheptyl)-(3-trifluoromethoxy-benzyl)- amine, 45 mg (250 umol) N-methylimidazole-4-carbonyl chloride hydrochloride, 87 uL (500 umol) diisopropylethylamine, and 5 mL dry acetonitrile. The reaction was heated at room temperature for 3 days, cooled, diluted with ethyl acetate, washed with aqueous sodium bicarbonate solution and brine, dried over sodium sulfate, and evaporated to an oil. The residue was chromatographed on silica gel using methanol/dichloromethane as eluant to afford 90 mg (71 %) of the product as a cis/trans mixture of isomers as an oil.

13C-NMR (δ, CDCI3): 22.18, 23.06, 28.59, 30.75, 31.85, 32.96, 33.77, 34.30, 35.32, 45.75, 50.42, 58.67, 79.22, 118.93, 119.64, 125.28, 126.18, 126.53, 129.78, 136.80, 142.20, 149.44, 163.97, 173.83.

MS: 511 (parent+1 for MW = 510 C25H33N4O4F3).

C. 1-Methyl-1 H-imidazole-4-carboxylic acid (4-amino-cycloheptyl)-(3-trifluoromethoxy- benzvP-amide. To a 125 mL round-bottomed flask equipped with N2 inlet were added 1.33 g (2.9 mmol) i-methyl-IH-imidazole^-carboxylic acid (4-t-butoxamido-cycloheptyl)-(3- trifluoromethoxy-benzyl)-amide and 50 mL dry ethyl acetate. The reaction was saturated with HCI and stirred at room temperature for 22 hours. It was then evaporated to a white solid, 58 g (48%).

13C-NMR (δ, CDCI3): 13.29, 20.14, 29.14, 31.24, 35.69, 51.92, 60.33, 119.42, 123.58, 125.66, 130.06, 137.15, 148, 158.75 (not all peaks visible n this scan).

MS: 411 (parent+1 for MW = 410, C20H25N4O2F3).

Anal. Calc'd. for C20H25N4O4F3^HCm2O: C 47.91 , H 5.83, N 11.17. Found: C 47.96, H 5.70, N 10.89.

Scheme 15.

Referring to Scheme 15 above, a compound of the formula Il is reacted with a compound of the formula III in the presence of a reducing agent such as an alkaline borohydride, such as sodium borohydride, sodium cyanoborohydride, or sodium triacetoxyborohydride, with an optional additive such as acetic acid or triethylamine, in a solvent such as 1 ,2-dichloroethane, tetrahydrofuran, or methanol at a temperature from room temperature to 1000C for a time from 1 hour to 72 hours. The resulting compound, IV, is treated with a compound of the formula V in the presence of a base, such as an organic amine such as triethylamine or diisopropylethylamine, in a solvent such as tetrahydrofuran, acetonitrile, dimethylformamide, or N-methylpyrrolidinone, at a temperature from room temperature to 1000C for a time from 1 hour to 72 hours. The resulting compound, Vl, is deblocked to compound VII, using, for example, acidic conditions such as HCI in a solvent such as ethyl acetate or tetrahydrofuran, or trifluoroacetic acid in dichloromethane, at a temperature from room temperature to 1000C for a time from 1 hour to 72 hours. A carbobenzyloxy group may be used as a protecting group, in which case the deprotection is carried out by hydrogenolytic cleavage using hydrogen at a pressure form atmospheric to 10 atmospheres, and a catalyst consisting of a noble metal such as palladium on carbon, or HBr in acetic acid, at a temperature from room temperature to 1000C for a time from 1 hour to 72 hours.

Example 16. c/s-i-Methyl-IH-imidazole-4-sulfonic acid (4-amino-cvclohexyl)-(2- phenoxy-ethvQ-amide: '

A. c/s-(4-t-Butylcarboxamido-cvclohexylH2-phenoxy-ethvO-amide (referring to Scheme 15): To a 125 mL round-bottomed flask equipped with N2 inlet were added 445 mg (2.08 mmol) c/s-4-t-butylcarboxamido-cyclohexylamine, 283 mg (2.08 mmol) phenxoyacetaldehyde, 119 uL (2.08 mmol) acetic acid, 881 mg (4.16 mmol) sodium triacetoxy borohydride, and 10 mL dry 1 ,2-dichloroethane. The reaction was stirred at room temperature for 5 hours, diluted with ethyl acetate, washed with aqueous sodium bicarbonate solution and brine, dried over sodium sulfate, and evaporated to an oil The residue was chromatographed on silica gel using methanol/ethyl acetate as eluant to afford 200 mg (29%) of an oil.

13C-NMR (δ, CDCI3): 28.53, 28.61 , 46.21, 46.96, 53.91 , 67.67, 79.09, 114.68, 121.00, 129.63, 155.39, 158.99.

MS: 335 (parent+1 for MW = 334, C19H30N2O3).

B. c/s-1-methyl-1 H-imidazole-4-sulfonic acid (4-t-butylcarboxamido-cyclohexyl)-(2- phenoxy-ethvP-amide. To a 125 m L round-bottomed flask equipped with N2 inlet were added 200 mg (599 umol) c/s-(4-t-butylcarboxamido-cyclohexyl)-(2-phenoxy-ethyl)-amide, 108 mg (599 umol) N-methylimidazole-4-sulfonyl chloride, 104 uL (599 umol) diisopropylethylamine, and 10 mL dry acetonitrile. The reaction was heated at 700C for 40 hours, cooled, diluted with ethyl acetate, washed with aqueous sodium bicarbonate solution and brine, dried over sodium sulfate, and evaporated to an oil. The residue was chromatographed on silica gel using methanol/dichloromethane as eluant to afford 245 mg (86%) of an oil.

13C-NMR (δ, CDCI3): 26.16, 28.61 , 30.13, 34.10, 43.17, 44.33, 57.81 , 68.19, 79.42, 114.53, 121.12, 123.96, 129.74, 139.22, 140.97, 155.43, 158.50. MS: 479 (parent+1 for MW = 478, C23H34N4O5S).

C. c/s-1 -Methyl-1 H-imidazole-4-sulfonic acid (4-amino-cvclohexyl)-(2-prιenoxy-ethyl)- amide. To a 125 mL round-bottomed flask equipped with N2 inlet were added 245 mg (513 umol) c/s-1 -methyl-1 H-imidazole-4-sulfonic acid (4-t-butylcarboxamido-cyclohexyl)-(2- phenoxy-ethyl)-amide and 50 mL dry ethyl acetate. The reaction was saturated with HCI and stirred at room temperature for 4 hours. It was then evaporated to a white solid.

1H-NMR (δ, CDCI3): 1.7-1.8 (m, 2H), 1.8-2.0 (m, 6H), 3.28 (m, 2H), 3.48 (m, 1 H), 3.72 (s, 3H), 3.96 (m, 1H), 4.14 (t, J=6, 2H), 6.83 (d, J=8, 2H), 6.92 (t, J=8, 1 H), 7.25 (t, J=8, 2H), 8.06 (S1 1H), 8.72 (s, 1H). 13C-NMR (δ, CDCI3): 24.88, 27.69, 35.14, 43.08, 45.73, 57.54, 66.12, 114.08, 120.98, 125.65, 129.49, 134.71, 138.79, 158.53.

MS: 379 (parent+1 for MW = 378, C18H26N4O3S).

Anal. Calc'd. for C18H26N4O3S^HCI: C 47.89, H 6.25, N 12.41. Found: C 47.88, H 6.19, N 12.43.

Scheme 16.

Referring to Scheme 16 above, a compound of the formula VIII is reacted with cyclohexanone ethyleneketal in the presence of a reducing agent such as an alkaline borohydride, such as sodium borohydride, sodium cyanoborohydride, or sodium triacetoxyborohydride, with an optional additive such as acetic acid or triethylamine, in a solvent such as 1,2-dichloroethane, tetrahydrofuran, or methanol at a temperature from room temperature to 10O0C for a time from 1 hour to 72 hours. The resulting compound, IX, is treated with a compound of the formula V in the presence of a base, such as an organic amine such as triethylamine or diisopropylethylamine, in a solvent such as tetrahydrofuran, acetonitrile, dimethylformamide, or N-methylpyrrolidinone, at a temperature from room temperature to 10O0C for a time from 1 hour to 72 hours. The resulting compound, X, is deblocked using, for example, a mineral acid such as hydrochloric acid, in acetone at a temperature from room temperature to 1000C for a time from 1 hour to 72 hours. Compound X is converted to compound XII using a compound of the formula Xl in the presence of a reducing agent such as an alkaline borohydride, such as sodium borohydride, sodium cyanoborohydride, or sodium triacetoxyborohydride, with an optional additive such as acetic acid or triethylamine, in a solvent such as 1 ,2-dichloroethane, tetrahydrofuran, or methanol at a temperature from room temperature to 1000C for a time from 1 hour to 72 hours. Example 17. c/s-i-MethyMH-imidazole^-carboxylic acid F4-(2,2,2-trifluoro- ethylamino)-cvclohexyπ-(3-trifluoromethoxy-benzyl)-amide:

A. (4-(3-Trifluoromethoxybenzyl)amino)-cvclohexanone ethylene ketal (referring to Scheme 16): To a 125 mL round-bottomed flask equipped with N2 inlet were added 469 mg (3 mmol) cyclohexane-1,4-dione monoethylene ketal, 478 mg (3 mmol) 3-trifluoromethoxy benzylamine, 172 uL (3 mmol) acetic acid, 1.27 g (6 mmol) sodium triacetoxy borohydride, and 15 mL dry 1 ,2-dichloroethane. The reaction was stirred at room temperature for 21 hours, diluted with ethyl acetate, washed with aqueous sodium bicarbonate solution and brine, dried over sodium sulfate, and evaporated to an oil The residue, 1.36 g, was used directly.

13C-NMR (δ, CDCI3): 30.33, 33.00, 50.77, 54.64, 64.44, 108.82, 119.42, 120.64, 126.48, 129.83, 143.53, 149.58.

MS: 332 (parent+1 for MW = 331 , Ci6H20NO3F).

B. i-Methyl-I H-imidazole-4-carboxylic acid [4-ethylene ketal-cyclohexylH3- trifluoromethoxy-benzvP-amide. To a 125 mL round-bottomed flask equipped with N2 inlet were added 299 mg (750 umol) (4-(3-trifluoromethoxybenzyl)amino)-cyclohexanone ethylene ketal, 141 mg (750 umol) N-methylimidazole-4-carbonyl chloride hydrochloride, 262 uL (1.5 mmol) diisopropylethylamine, and 5 mL dry acetonitrile. The reaction was heated at 4O0C for 16 hours, cooled, diluted with ethyl acetate, washed with aqueous sodium bicarbonate solution and brine, dried over sodium sulfate, and evaporated to an oil. The residue was chromatographed on silica gel using methanol/dichloromethane as eluant to afford 460 mg (100%) of an oil.

13C-NMR (δ, CDCI3): 27.45, 28.88, 34.06, 45.06, 47.325, 53.65, 55.885, 107.81 , 118.86, 119.57, 122.57 (q, J=144), 125.28, 126.28, 129.60, 136.85, 138.48, 142.34, 149.32, 164.94.

MS: 440 (parent+1 for MW = 439, C21H24N3O4F3).

This material was de-ketalized with 5 mL 3N aqueous hydrochloric acid in 20 mL acetone at room temperature for 18 hours to give 350 mg of an oil that was used directly in the next step. It gave:

13C-NMR (δ, CDCI3): 29.38, 31.09, 33.70, 40.14, 45.03, 48.35, 53.92, 55.05, 119.28, 119.64, 120.13, 120.26, 122.56 (q, J=145) 125.40, 126.92, 129.85, 136.98, 137.56, 138.31, 149.44, 164.59, 209.84.

MS: 396 (parent+1 for MW = 395, C19H20N3O3F3).

C. c/s-1 -Methyl-1 H-imidazole-4-carboxylic acid f4-(2,2,2-trifluoro-ethylaminoV cycloh exyll-O-trif I uorom ethoxy-benzvP-am ide. To a 125 mL round-bottomed flask equipped with N2 inlet were added 148 mg (375 umol) i-methyl-IH-imidazole-4-carboxylic acid [4-keto- cyclohexyl]-(3-trifluoromethoxy-benzyl)-amide, 52 uL (750 umol) 2,2,2-trifluoroethylamine, 21 uL (375 umol) acetic acid, 159 mg (750 umol) sodium triacetoxy borohydride, and 4 ml_ dry 1 ,2-dichloroethane. The reaction was stirred at room temperature for 21 hours, diluted with ethyl acetate, washed with aqueous sodium bicarbonate solution and brine, dried over sodium sulfate, and evaporated to an oil. The residue was chromatographed on silica gel using methanol/dichloromethane as eluant to afford 78 mg (44%) of the cis-isomer as the less polar spot, as an oil.

1H-NMR (δ, CDCI3): 1.4-1.6 (m, 4H), 1.6-1.8 (m, 4H), 2.875 (m, 1H), 3.05 (q, J=9, 2H), 3.675 (s, 3H), 4.4 (m, 1 H), 4.7 and 5.3 (m, 2H), 7.0-7.5 (m, 4H), 7.235 (s, 1 H), 7.47 (s, 1H).

13C-NMR (δ, CDCI3): 23.86, 25.34, 29.63, 33.74, 33.99, 42.46, 43.10, 45.25, 47.913 (q, J=32), 49.63, 55.26, 56.94, 118.93, 119.81 , 120.38, 123.915 (q, J=118), 125.52, 126.18, 126.28, 127.28, 129.63, 130.13, 136.81 , 137.53, 149.41 , 164.90. The aliphatic CF3 group was not visible in this scan.

MS: 478 (parent+1 for MW = 477, C21H24N4O2F6).

Conversion to the HCI salt gave: Anal. Calc'd. for C21H24N4O2F6^HCI H2O: C 44.30, H 4.96, N 9.84. Found: C 44.41 , H 4.89, N 9.62.

Scheme 17.

Referring to Scheme 17 above, a compound of the formula Il is reacted with 1 ,4- epoxy-1 ,2,3,4-tetrahydronaphthalene according to a method reported in Jour. Org. Chem., 52, 1680-1686, (1987), using dimethyl boronbromide in the presence of triethylamine, in a solvent such as 1 ,2-dichloroethane, tetrahydrofuran, or methanol at a temperature from -700C to 100°C for a time from 1 hour to 72 hours. The resulting compound, III, is treated with a compound of the formula IV in the presence of a base, such as an organic amine such as triethylamine or diisopropylethylamine, in a solvent such as tetrahydrofuran, acetonitrile, dimethylformamide, or N-methylpyrrolidinone, at a temperature from room temperature to 10O0C for a time from 1 hour to 72 hours. The resulting compound, V, is treated with triphenylphosphine and an azodicarboxylate ester, such as diethyl or diisopropyl azodicarboxylate, and diphenylphosphoryl azide in a solvent such as tetrahydrofuran, ether, toluene, or benzene at a temperature from room temperature to 10O0C for a time from 1 hour to 72 hours. The resulting compound, Vl, was treated with triphenyl phosphine and water in a solvent such as tetrahydrofuran, dimethylformamide, N-methylpyrrolidinone, or acetonitrile at a temperature from room temperature to 10O0C for a time from 1 hour to 72 hours. Example 18. i-Methyl-IH-imidazole-4-sulfonic acid (4-amino-1,2,3,4-tetrahvdro- naphthalen-1-yl)-(3-trifluoronnethoxy-benzyl)-amide:

A. (4-Hvdroxy-1.2.3.4-tetrahvdro-naphthalen-1-vπ-(3-trifluoromethoxy-benzyl)-amine: (referring to Scheme 17, prepared according to a method reported in Jour. Orq. Chem.. 52, 1680-1686, (1987)): To a 125 ml_ round-bottomed flask equipped with N2 inlet were added 813 mg (5.57 mmol) 1 ,4-epoxy-1 ,2,3,4-tetrahydronaphthalene (prepared as reported in Chem. Ber., 89, 1334 (1956)) and 20 mL dry dichloromethane. The solution was cooled to O0C, and a solution of 83 uL (596 umol) dimethylboronbromide in 5 mL dry dichloromethane. The reaction was stirred 15 minutes at 0°C, then 3.5 mL (22.28 mmol) 3- trifluoromethoxybenzylamine was added, and the reaction warmed to room temperature and stirred 14 hours. It was then quenched with 1 N aqueous hydrochloric acid and washed with dichloromethane. The aqueous layer was basified with aqueous sodium hydroxide and extracted with dichloromethane. The organic layer was dried over magnesium sulfate and evaporated. The residue was chromatographed on silica gel using hexane/ethyl acetate to afford 1.37 g (73%) of an oil.

13C-NMR (δ, CDCI3): 24.27, 25.42, 28.68, 28.83, 50.69, 50.85, 54.79, 56.00, 67.94, 69.04, 119.55, 119.82, 120.72, 120.86, 126.58, 126.70, 127.74, 127.90, 128.08, 128.41 , 128.48, 128.73, 128.82, 129.85, 130.10, 138.49, 138.94, 139.39, 141.29, 142.21, 143.54, 149.61 (as a mixture of isomers).

MS = 338 parent+1 for MW = 337 C18H18NO2F3).

B. 1-Methyl-1 H-imidazole-4-sulfonic acid (4-hvdroxy-1 ,2,3,4-tetrahvdro-naphthalen-1- ylH3-trifluoromethoxy-benzyl)-amide: To a 125 mL round-bottomed flask equipped with N2 inlet were added 198 mg (587 umol) N-t-butoxycarbonyl-(2-aza-bicyclo[3.3.1]non-6-yl)-(3- trifluoromethoxy-benzyl)-amine, 106 mg (587 umol) N-methylimidazole-4-sulfonyl chloride hydrochloride, 103 uL (593 mmol) diisopropylethylamine, and 5 mL dry acetonitrile. The reaction was heated at 800C for 8 hours, cooled, diluted with ethyl acetate, washed with aqueous sodium bicarbonate solution and brine, dried over sodium sulfate, and evaporated to an oil. The residue was chromatographed on silica gel using hexane/ethyl acetate as eluant to afford 150 mg (53%) of a mixture of isomers as an oil.

13C-NMR (δ, CDCI3): 23.37, 27.86, 30.17, 32.60, 34.02, 34.09, 48.19, 48.60, 57.99, 58.14, 67.03, 68.57, 119.30, 119.64, 119.72, 121.21 , 121.44, 124.23, 124.41, 127.13, 127.31, 127.65, 127.96, 128.40, 128.64, 128.92, 129.34, 129.49, 129.79, 133.82, 134.92, 139.17, 139.28, 139.61, 140.46, 140.55, 141.29, 141.49, 141.84, 149.09 (a mixture of isomers).

MS: 482 (parent+1 for MW = 481 , C22H22N3O4SF3).

C. 1-Methyl-1 H-imidazole-4-sulfonic acid (4-azido-1.2.3.4-tetrahvdro-naphthalen-1- ylH3-trifluoromethoxy-benzyl)-amide: To a 125 mL round-bottomed flask equipped with N2 inlet were added 150 mg (311 umol) 1-methyl-1 H-imidazole-4-sulfonic acid (4-hydroxy- 1 ,2,3,4-tetrahydro-naphthalen-1-y!)-(3-trifluoromethoxy-ben2yl)-amide, 102 mg (389 umol) triphenylphosphine, and 5 mL dry tetrahydrofuran. The reaction was cooled to -50C, and 80 uL (389 umol) diisopropylazodicarboxylate added, followed by 84 uL (389 umol) diphenylphosphoryl azide. The reaction was warmed to room temperature and stirred 14 hours, then concentrated and used directly in the next step.

D. 1-MethyH H-imidazole-4-sulfonic acid (4-amino-1 ,2,3,4-tetrahvdro-naphthalen-1- ylM3-trifluoromethoxy-benzvO-amide: To a 125 mL round-bottomed flask equipped with N2 inlet were added the above residue of 1-methyl-1 H-imidazole-4-sulfonic acid (4-azido-1 ,2,3,4- tetrahydro-naphthalen-1-yl)-(3-trifluoromethoxy-benzyl)-amide, 5 mL tetrahydrofuran, 197 mg (311 umol) triphenylphosphine, and 1 mL water. The reaction was stirred at room temperature for 24 hours, 3 mL 1 N aqueous hydrochloric acid added, and stirring continued for 4 days. The reaction was diluted with ethyl acetate, extracted into dilute hydrochloric acid, and the aqueous layer basified with aqueous sodium hydroxide solution and extracted into ethyl acetate. The organic phase was dried over sodium sulfate and evaporated, and the residue (40 mg, 27%) converted to the HCI salt, mp 65-810C.

13C-NMR (δ, CDCI3): 17.83, 22.14, 23.90, 28.60, 30.23, 30.87, 33.32, 34.06, 48.18, 48.39, 49.90, 58.20, 76.93, 77.25, 77.57, 119.66, 121.21, 121.42, 124.26, 124.35, 127.05, 127.12, 127.28, 127.52, 127.90, 128.65, 128.78, 128.91 , 129.44, 132.20, 132.30, 133.97, 134.27, 139.16, 139.23, 140.61 , 149.09 (mixture of isomers).

MS: 481 (parent+1 for MW = 480, C22H23N4O3SF3).

Scheme 18.

Example 19. N-(3-(trifluoromethoxy)benzyl)-N-((1 R,3S)-3-(dimethylamino) cyclopen tyl)-1 -methyl-1 H-imidazole-4-carboxamide:

Referring to scheme 18 above:

Preparation of 1: To a solution of fe/t-butyl carbazate (75 g, 567 mmol) in methylene chloride (2.0 L) at 0°C was added benzyl chloroformate over -45 minutes. After the addition was complete the reaction was stirred overnight coming to rt as the ice bath was depleted. The reaction was carefully poured into saturated sodium bicarbonate (1L) and extracted. The organic layer was washed with water, and dried over sodium sulfate. Removal of the solvent in vacuo gave the desired product (148 g, 556 mmol, 98% crude yield) as a viscous oil. The material was judged to be of satisfactory purity without further purification.

Preparation of 2: Crude 1 (148 g, 556 mmol) was dissolved in methylene chloride (1.5L) and pyridine (46 mL). The solution was cooled to O0C, and NBS (10Og, 561 mmol) was added in one portion. The reaction was allowed to warm to rt, and stirred ~2h at this temperature. The solution was then extracted with water (2 x 50OmL) and the pooled aqueous washes were back extracted with methylene chloride (250 mL). The pooled organic layers were dried over sodium sulfate then filtered. The crude solution was utilized in the next step without further manipulation.

Preparation of 3: The crude reaction mixture containing 2 in methylene chloride (-2 L) was chilled to O0C with and ice salt bath. The reaction was mechanically stirred under nitrogen, and freshly cracked cyclopentadiene (75 g, 1.14 mol) was added in one portion. A slow exotherm brought the reaction temperature to 13°C before the temperature began to retreat. At this point the cooling bath was removed and the reaction was stirred at rt overnight. The material was washed with Vz saturated sodium bicarbonate (3 x 1 L) then dried over sodium sulfate. Removal of the solvent in vacuo gave 3 as a light yellow oil.

Preparation of 4: A mixture of 3 (97 g, 294 mmol), acetic acid (15.8 mL, 294 mmol) and Pd(OH)2 (20%/C, 4 g) in 350 mL of methanol was shaken under H2 (45 psi) at rt for 16h. The catalyst was removed by filtration. The filtrated was concentrated. The oil residue was resuspended in DCM (2.5 L) and washed with sat. NaHCO3 (2 x 500 mL), dried (Na2SO4) and concentrated to give on light yellow oil. Chromatography on Biotage 75 with 10% MeOH/DCM gave 58 g (99.5%) of 4 as a light yellow oil.

Preparation of 5: A mixture of 4 (48 g, 242 mmol) and Raney Ni 2800 (slurry in water, 30 g) in 400 mL of methanol was sealed under H2 (180 psi) at rt. The mixture then was heated to 60 0C and stirred at 60 °C for 24 h. After cooling to rt, the mixture was filtered. The filtrate was concentrated to give a light yellow oil. Chromatography on Biotage 75 with 10% MeOH/DCM (0.5% NH4OH) gave 42.7 g (88.1 %) of 5 as waxy solid.

Preparation of 6: A slurry of 5 (6.45 g, 32.2 mmol) and NaBH(OAc)3 (10.92 g, 51.5 mmol) in dichloroethane (150 mL) was stirred 15 min. then treated with m-trifluoro- methoxybenzaldehyde (4.6 mL, 32.2 mmol) and additional dichloroethane (60 mL). After 4 h the reaction was quenched with water, the layers were separated and the aqueous layer was extracted with dichloromethane (2x). The combined organic layer was washed with brine and filtered through a cotton plug. Some solids were dissolved and rinsed through with sat. ammonia CHCI3 and solution was concentrated to an oil. Trituration provided 3.08 g of 6 as white solids and the filtrate was concentrated to 10.37 g of a yellow oil.

Preparation of 7: 1.60 (3.92 mmol) of 6 in acetonitrile (20 mL) was treated with triethylamine (1.64 mL, 11.76 mmol) and 1-methylimidazole-4-carboxylic acid chloride (851 mg, 4.70 mmol). The mixture was stirred for 2 h at room temperature, quenched with H2O and extracted with EtOAc (3x). The organic layer was washed with brine and dried over NaSO4, decanted and concentrated to 2.08 g of 7. Preparation of 8: 1.2 g (2.57 mmo!) of 7 in EtOAc (10 mL) was treated with 2.7N HCI in EtOAc (8 mL) and stirred at 60 0C for 24 h. Cooled and filtered the solids to give 1.12 g of 8.

Preparation of 9: A solution of 8 (0.112 g, 0.245 mmol), aq. formaldehyde (0.055 mL, 0.735 mmol of a 37%wt. SoIn. 1.083 g/mL) and triethylamine (0.075 mL, 0.54 mmol) in dichloroethane (2 mL) were treated with NaBH(OAc)3 (0.17 g, 0.78 mmol) then. After 60 h, the reaction was quenched with sat. aq. NaHCO3 solution, the layers were separated and the aqueous layer was extracted with methylene chloride (4x). The organic extracts were washed with brine (1x) and dried through a cotton plug and concentrated. The material was purified by chromatography on silica gel eluting with 3% methanol/methylene chloride then dissolved in methylene chloride and treated with excess 2.7N HCI in EtOAc. Concentration provided and crystallization from methylene chloride and isopropylether yielded 0.10 g of 9.

The following Examples may be prepatred by the methods disclosed in Schemes 1 to 18 above:

Table 1

Melting points were taken with a Buchi micro melting point apparatus and uncorrected. Infrared Ray absorption spectra (IR) were measured by a Shimazu infrared spectrometer (lR-470). 1H and 13C nuclear magnetic resonance spectra (NMR) were measured in CDCI3 by a Varian NMR spectrometer (Unity, 400MHz for 1H, 100MHz for 13C) unless otherwise indicated and peak positions are expressed in parts per million (ppm) downfield from tetramethylsilane (δ). The peak shapes are denoted as follows: s, singlet; d, doublet; t, triplet; m, multiplet; br, broad. The invention described and claimed herein is not to be limited in scope by the specific embodiments herein disclosed, since these embodiments are intended as illustrations of several aspects of the invention. Any equivalent embodiments are intended to be within the scope of this invention. Indeed, various modifications of the invention in addition to those shown and described herein will become apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims.

Claims CLAIMSWhat is claimed is:

1. A compound of the Formula I

wherein HET is a 5 or 6 -membered membered heteroaryl ring optionally substituted by one or more substituents selected from R

5

;

X1 is -C(=O)- or SO2;

X2 is -(Czero-Cio alkylene)-(0)y-(CZero-Cio alkylene)-, or -(C3-C10 cycloalkyl)-(Czero-C-ιo alkylene)-(O)y-(Czero-C10 alkylene)-; wherein y is 0 or 1 ;

X3 is -(Czero-Cio alkylene)-NR1R2; -(C3-Ci0 cycloalky)-(Czero-C10 alkylene)-NR1R2; -(CZero-Ci0 alkylene)-X4 or -(C3-C10 cycloalkyl)-(Czera-C10 alkylene)-X4; wherein said cycloalkyl is optional substituted by one or more -OH;

X4 is a nitrogen containing (4-15 membered) heterocycloalkyl or a nitrogen containing (5-15 membered) heteroaryl, each optionally substituted by one or more substituents selected from R5; with the proviso that the 4-15 membered heterocycloalkyl of X4 is not a 3-aza- bicyclo{3.1.0]hex-6-yl group;

Ring A is a -C6-C15 aryl, -(5-15 membered) heteroaryl or (4-15 membered) heterocycloalkyl, each optionally substituted by one or more substitutent selected from R5; each R1 and R2 are independently selected from -H, -C1-C12 alkyl, -C2-C12 alkenyl, -

C2-C12 alkynyl, -C(=O)R3, -S(O)nR3, -C(=O)OR4, -C(=O)NR3R4, -S(O)2NR3R4, -(C261-O-C4 alkylene)-(C3-C20 cycloalkyl), -(Czero-C4 alkylene)-(C4-C8 cycloalkenyl), -(Czero-C4 alkylene)- ((Cs-Ci1JbJ- or tricycloalkyl), -(C26TO-C4 alkylene)-((C7-C11)bi- or tricycloalkenyl), -(C2ero-C4 alkylene)-((5-10 membered) heterocycloalkyl), -(Czero-C4 alkylene)-(C6-C10 aryl) and -(C2ero-C4 alkylene)-((5-10 membered) heteroaryl, wherein said wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bi- or tricycloalkyl, bi- or tricycloalkenyl, heterocycloalkyl, aryl, and heteroaryl of R1 or R2 are each independently optionally substituted by one or more substitutents selected from R5; each R3 and R4 are independently selected from -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl and -(Czero-C4 alkylene)-(C3-C6 cycloalkyl), wherein said alkyl, alkenyl, alkynyl and cycloalkylof R3 or R4 are each optionally independently substituted with one or more substituents independently selected from -C1-C4 alkoxy, -OH and -S(CrC4 alkyl); wherein each R5 is independently selected from -OH, -C1-C12 alkyl, -C2-Ci2 alkenyl, - C2-C12 alkynyl, -Ci-C6 alkoxy, -C2-C6 alkenoxy, -C2-C6 alkynoxy, halogen, -OR11, -CN, -NO2, - NR9R10, -C(=O)NR9R10, -S(O)2NR9R10, -C(=O)R11, -OC(=O)R11, -S(O)nR11, -C(=O)OR12, -C3- C15 cycloalkyl, -C4-C15 cycloalkenyl, -(C5-Cn)bi- or tricycloalkyl, -(Cγ-C^bi- or tricycloalkenyl, - (4-20 membered) heterocycloalkyl, -C6-Ci5 aryl, -(5-15 membered) heteroaryl, -C6-C15 aryloxy and -(5-15 membered) heteroaryloxy, wherein said alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, alkynoxy, cycloalkyl, cycloalkenyl, bi- or tricycloalkyl, bi- or tricycloalkenyl, heterocycloalkyl, aryl, heteroaryl, aryloxy and heteroaryloxy of R5 are each optionally independently substituted with one or more substituents independently selected from R6; wherein each R6 is independently selected from -OH, halogen, -C1-Ci2 alkyl, -C2-C12 alkenyl, -C2-C12 alkynyl, -C1-C6 alkoxy, -C2-C6 alkenoxy, -C2-C6 alkynoxy, -Cl, -Br, -I, -CN, - NO2, -NR9R10, -C(=O)NR9R10, -S(O)2NR9R10, -C(=O)R11, -OC(=O)R11, -S(O)nR11, -C(O)OR12, -C3-C15 cycloalkyl, -C4-C15 cycloalkenyl, -(Cs-C^Jbi- or tricycloalkyl, ' -(C7-C1ObJ- or tricycloalkenyl, -(4-20 membered) heterocycloalkyl, -C6-C15 aryl, -(5-15 membered) heteroaryl, -C6-C15 aryloxy and -(5-15 membered) heteroaryloxy, wherein said alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, alkynoxy, cycloalkyl, cycloalkenyl, bi- or tricycloalkyl, bi- or tricycloalkenyl, heterocycloalkyl, aryl, heteroaryl, aryloxy and heteroaryloxy of R6 are each optionally independently substituted with one or more substituents independently selected from the group R6a; wherein each R6a is independently selected from -OH, halogen, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -C1-C6 alkoxy, -C2-C6 alkenoxy, -C2-C6 alkynoxy, -C1-C6 hydroxyalkyl, -CN, -NO2, -NR9R10, -C(=O)NR9R10, -C(=0)R11, -S(O)2NR9R10, -S(O)nR11, -C6-C15 aryl, -(5-15 membered) heteroaryl, -C6-C15 aryloxy and -(5-15 membered) heteroaryloxy, wherein said alkyl, alkenyl and alkynyl, alkoxy, alkenoxy, alkynoxy, hydroxyalkyl, aryl, aryloxy, heteroaryl and heteroaryloxy of R6a are each optionally independently substituted with one or more subsitutents selected from halogens, -C1-C12 alkyl, -C1-C4 alkoxy, or -OH; each R9 and R10 are independently selected from -H, -C1-C12 alkyl, -C2-C12 alkenyl, -

C2-C12 alkynyl, -CF3, -C(=0)R11, -S(O)nR11, -C(=O)OR12, -C(=O)NR11R12, -S(O)2NR11R12, - (C2ero-C4 alkylene)-(C3-C20 cycloalkyl), -(Czero-C4 alkylene)-(C4-C8 cycloalkenyl), -(C2ero-C4 alkylene)-((C5-Ci1)bi- or tricycloalkyl), -(Czero-C4 alkylene^Cy-C^bi- or tricycloalkenyl), -(Czer0- C4 alkylene)-((5-10 membered) heterocycloalkyl), -(Czero-C4 alkylene)-(C6-C10 aryl) and -(Czera- C4 alkylene)-((5-10 membered) heteroaryl), wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bi-or tricycloalkyl, bi- or tricycloalkenyl, heterocycloalkyl, aryl and heteroaryl of R9 and R10 are each optionally independently substituted with one or more substituents independently selected from -OH, -C1-Ci2 alkyl, -C2-C12 alkenyl, -C2-Ci2 alkynyl, -Ci-C6 alkoxy, -C2-C6 alkenoxy, -C2-C6 alkynoxy, -C1-C6 hydroxyalkyl, halogen, -CN, -NO2, -CF3, -NR11R12, -C(=O)NR11R12, -SO2NR11R12, -C(=O)H and -C(=O)OH; or NR9R10 may in each instance independently optionally form a -(4-10 membered) heterocycloalkyl or -(4-10 membered) heterocycloalkenyl, wherein said heterocycloalkyl and heterocycloalkenyl of NR9R10 each optionally independently contain from one to two further heteroatoms independently selected from N, O and S, and wherein said heterocycloalkyl and heterocycloalkenyl of NR9R10 are each optionally independently substituted with one or more substituents independently selected from -OH, -C1-C12 alkyl, -C2-C12 alkenyl, -C2-C12 alkynyl, - C1-C6 alkoxy, -C2-C6 alkenoxy, -C2-C6 alkynoxy, halogen, -NR11R12, -C(=O)NR11R12, - SO2NR11R12, C(=O)R11, SO2R11, (Czero-C4 alkylene)-(C6-C10 cycloalkyl), (Czer0-C4 alkylene)-((5- 10 membered) heterocycloalkyl), (Czero-C4 alkylene)-(C6-C10 aryl) and (Czero-C4 alkylene)-((5- 10 membered) heteroaryl, each R11 and R12 are independently selected from -H, -Ci-C15 alkyl, -C2-C15 alkenyl, - C2-C15 alkynyl, -(Czero-C4 alkylene)-(C3-C15 cycloalkyl), -(Czero-C4 alkylene)-(C4-C8 cycloalkenyl), -(Czero-C4 alkylene)-((C5-C11)bi- or tricycloalkyl), -(C761-O-C4 alkylene)-((C7-C1i)bi- or tricycloalkenyl), -(Czero-C4 alkylene)-((5-15 membered) heterocycloalkyl), -(Czero-C4 alkylene)- (C6-C15 aryl) and -(Czer0-C4 alkylene)-((5-15 membered) heteroaryl), wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bi-or tricycloalkyl, bi- or tricycloalkenyl, heterocycloalkyl, aryl and heteroaryl of R11 and R12 are each optionally independently substituted with with one or more substituents independently selected from -OH, -C1-C12 alkyl, -C2-C12 alkenyl, -C2-C12 alkynyl, -C1-C6 alkoxy, -C2-C6 alkenoxy, -C2-C6 alkynoxy, -C1-C6 hydroxyalkyl, halogen, -CN, -NO2, -CF3, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -C(O)NH2, - C(=O)NH(CrC6 alkyl), -C(=O)N(CrC6 alkyl)2, -SO2NH2, -SO2NH(C1-C6 alkyl), -SO2N(C1-C6 alkyl)2, -C(=O)H, -C(=O)OH and -C(O)O(C1-C6 alkyl), or NR11R12 may in each instance independently optionally form a -(4-10 membered) heterocycloalkyl or -(4-10 membered) heterocycloalkenyl, wherein said heterocycloalkyl and heterocycloalkenyl of NR9R10 each optionally independently contain from one to two further heteroatoms independently selected from N, O and S, and wherein said heterocycloalkyl and heterocycloalkenyl of NR9R10 are each optionally independently substituted with one or more substituents independently selected from -OH, -C1-C12 alkyl, -C2-Ci2 alkenyl, -C2-C12 alkynyl, - Ci-C6 alkoxy, -C2-C6 alkenoxy, -C2-C6 alkynoxy, halogen, (C2ero-C4 alkylene)-(C6-Ci0 cycloalkyl), (Czero-C4 alkylene)-((5-10 membered) heterocycloalkyl), (Czera-C4 alkylene)-(C6-Ci0 aryl) and (Czero-C4 alkylene)-((5-10 membered) heteroaryl; n is O, 1 , or 2; or a pharmaceutically acceptable salt thereof.

2. A compound of the Formula I

Formula I wherein HET is imidazolyl optionally substituted by one or more substituents selected from

R5;

X1 is -C(=O)- or SO2; X2 is -(Czero-Cio alkyiene)

X3 is -(Czero-C10 alkylene)-X4, -(C3-C10 cycloalky)-NR1R2 or -(C3-C10 cycloalkyl)-X4; wherein said cycloalkyl is optional substituted by one or more -OH;

X4 is a nitrogen containing (4-15 membered) heterocycloalkyl or a nitrogen containing (5-15 membered) heteroaryl, each optionally substituted by one or more substituents selected from R5; with the proviso that the 4-15 membered heterocycloalkyl of X4 is not a 3-aza- bicyclo{3.1.0]hex-6-yl group

Ring A is a -C6-C15 aryl, -(5-15 membered) heteroaryl or (4-15 membered) heterocycloalkyl, each optionally substituted by one or more substitutent selected from R5; each R1 and R2 are independently selected from -H, -C1-C12 alky], -C2-C12 alkenyl, - C2-C12 alkynyl, -C(=O)R3, -S(O)nR3, -C(=O)OR4, -C(O)NR3R4, -S(O)2NR3R4, -(Czero-C4 alkylene)-(C3-C20 cycloalkyl), -(Czero-C4 alkylene)-(C4-C8 cycloalkenyl), -(Czero-C4 alkylene)-

((C5-C1 Obi- or tricycloalkyl), -(Czero-C4 alkylene)-((C7-C11)bi- or tricycloalkenyl), -(Czero-C4 alkylene)-((5-10 membered) heterocycloalkyl), -(Czero-C4 alkylene)-(C6-C10 aryl) and -(Czero-C4 alkylene)-((5-10 membered) heteroaryl, wherein said wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bi- or tricycloalkyl, bi- or tricycloalkenyl, heterocycloalkyl, aryl, and heteroaryl of R1 or R2 are each independently optionally substituted by one or more substitutents selected from R5; each R3 and R4 are independently selected from -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl and -(Czsro-C4 alkylene)-(C3-C6 cycloalkyl), wherein said alkyl, alkenyl, alkynyl and cycloalkylof R3 or R4 are each optionally independently substituted with one or more substituents independently selected from -C1-C4 alkoxy, -OH and -S(C1-C4 alkyl); wherein each R5 is independently selected from -OH, -C1-C12 alkyl, -C2-C12 alkenyl, -

C2-C12 alkynyl, -C1-C6 alkoxy, -C2-C6 alkenoxy, -C2-C6 alkynoxy, halogen, -OR11, -CN, -NO2, -

NR9R10, -C(=O)NR9R10, -S(O)2NR9R10, -C(=O)R11, -OC(=O)R11, -S(O)nR11, -C(=0)0R12, -C3- C15 cycloalkyl, -C4-C15 cycloalkenyl, -(Cs-C^bi- or tricycloalkyl, -(Cy-C^bi- or tricycloalkenyl, -

(4-20 membered) heterocycloalkyl, -C6-Ci5 aryl. -(5-15 membered) heteroaryl, -C6-C15 aryloxy and -(5-15 membered) heteroaryloxy, wherein said alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, alkynoxy, cycloalkyl, cycloalkenyl, bi- or tricycloalkyl, bi- or tricycloalkenyl, heterocycloalkyl, aryl, heteroaryl, aryloxy and heteroaryloxy of R5 are each optionally independently substituted with one or more substituents independently selected from R6; wherein each R6 is independently selected from -OH, halogen, -C1-C12 alkyl, -C2-Ci2 alkenyl, -C2-C12 alkynyl, -C1-C6 alkoxy, -C2-C6 alkenoxy, -C2-C6 alkynoxy, -Cl, -Br, -I, -CN, - NO2, -NR9R10, -C(=O)NR9R10, -S(O)2NR9R10, -C(=O)R11, -OC(=O)R11, -S(O)nR11, -C(=O)OR12, -C3-C15 cycloalkyl, -C4-C15 cycloalkenyl, -(C5-C1ObJ- or tricycloalkyl, -(Cy-C^bi- or tricycloalkenyl, -(4-20 membered) heterocycloalkyl, -C6-C15 aryl, -(5-15 membered) heteroaryl, -C6-C15 aryloxy and -(5-15 membered) heteroaryloxy, wherein said alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, alkynoxy, cycloalkyl, cycloalkenyl, bi- or tricycloalkyl, bi- or tricycloalkenyl, heterocycloalkyl, aryl, heteroaryl, aryloxy and heteroaryloxy of R6 are each optionally independently substituted with one or more substituents independently selected from the group R6a; wherein each R6a is independently selected, from -OH, halogen, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -Ci-C6 alkoxy, -C2-C6 alkenoxy, -C2-C6 alkynoxy, -C1-C6 hydroxyalkyl, -CN, -NO2, -NR9R10, -C(=O)NR9R10, -C(=O)R11, -S(O)2NR9R10, -S(O)nR11, -C6-C15 aryl, -(5-15 membered) heteroaryl, -C6-Ci5 aryloxy and -(5-15 membered) heteroaryloxy, wherein said alkyl, alkenyl and alkynyl, alkoxy, alkenoxy, alkynoxy, hydroxyalkyl, aryl, aryloxy, heteroaryl and heteroaryloxy of R6a are each optionally independently substituted with one or more subsitutents selected from halogens, -C1-C12 alkyl, -Ci-C4 alkoxy, or -OH; each R9 and R10 are independently selected from -H, -C1-Ci2 alkyl, -C2-Ci2 alkenyl, - C2-C12 alkynyl, -CF3, -C(=O)R11, -S(O)nR11, -C(=O)OR12, -C(=O)NR11R12, -S(O)2NR11R12, - (C2ero-C4 alkylene)-(C3-C20 cycloalkyl), -(Czero-C4 alkylene)-(C4-C8 cycloalkenyl), -(Czera-C4 alkylene)-((C5-C11)bi- or tricycloalkyl), -(Czero-C4 alkylene)-((C7-Cn)bi- or tricycloalkenyl), -(Czero- C4 alkylene)-((5-10 membered) heterocycloalkyl), -(Czero-C4 alkylene)-(C6-C10 aryl) and -(Czero- C4 alkylene)-((5-10 membered) heteroaryl), wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bi-or tricycloalkyl, bi- or tricycloalkenyl, heterocycloalkyl, aryl and heteroaryl of R9 and R10 are each optionally independently substituted with one or more substituents independently selected from -OH, -Ci-Ci2 alkyl, -C2-Ci2 alkenyl, -C2-C12 alkynyl, -C1-C6 alkoxy, -C2-C6 alkenoxy, -C2-C6 alkynoxy, -C1-C6 hydroxyalkyl, halogen, -CN, -NO2, -CF3, -NR11R12, -C(O)NR11R12, -SO2NR11R12, -C(=O)H and -C(=0)0H; or NR9R10 may in each instance independently optionally form a -(4-10 membered) heterocycloalkyl or -(4-10 membered) heterocycloalkenyl, wherein said heterocycloalkyl and heterocycloalkenyl of NR9R10 each optionally independently contain from one to two further heteroatoms independently selected from N, O and S, and wherein said heterocycloalkyl and heterocycloalkenyl of NR9R10 are each optionally independently substituted with one or more substituents independently selected from -OH, -C1-C12 alkyl, -C2-Ci2 alkenyl, -C2-C12 alkynyl, - C1-C6 alkoxy, -C2-C6 alkenoxy, -C2-C6 alkynoxy, halogen, -NR11R12, -C(=0)NR11R12, - SO2NR11R12, C(=0)R11, SO2R11, (Czero-C4 alkylene)-(C6-C10 cycloalkyl), (Czero-C4 alkylene)-((5- 10 membered) heterocycloalkyl), (Czero-C4 alkylene)-(C6-Ci0 aryl) and (Czero-C4 alkylene)-((5- 10 membered) heteroaryl, each R11 and R12 are independently selected from -H, -CrC15 alkyl, -C2-C15 alkenyl, - C2-C15 alkynyl, -(Czero-C4 al Ky^e)-(C3-C15 cycloalkyl), -(C2ero-C4 alkylene)-(C4-C8 cycloalkenyl), -(Czero-C4 alkylene)-((C5-C11)bi- or tricycloalkyl), -(Czero-C4 alkylene)-((C7-C11)bi- or tricycloalkenyl), -(Czero-C4 alkylene)-((5-15 membered) heterocycloaikyl), -(Czera-C4 alkylene)- (C6-Ci5 aryl) and -(C2er0-C4 alkylene)-((5-15 membered) heteroaryl), wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bi-or tricycloalkyl, bi- or tricycloalkenyl, heterocycloaikyl, aryl and heteroaryl of R11 and R12 are each optionally independently substituted with with one or more substituents independently selected from -OH, -C1-C12 alkyl, -C2-C12 alkenyl, -C2-C12 alkynyl, -C1-C6 alkoxy, -C2-C6 alkenoxy, -C2-C6 alkynoxy, -C1-C6 hydroxyalkyl, halogen, -CN, -NO2, -CF3, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -C(O)NH2, - C(=O)NH(CrC6 alkyl), -C(O)N(C1-C6 alkyl)2, -SO2NH2, -SO2NH(P1-C6 alkyl), -SO2N(C1-C6 alkyl)2, -C(O)H, -C(O)OH and -C(O)O(C1-C6 alkyl), or NR11R12 may in each instance independently optionally form a -(4-10 membered) heterocycloaikyl or -(4-10 membered) heterocycloalkenyl, wherein said heterocycloaikyl and heterocycloalkenyl of NR9R10 each optionally independently contain from one to two further heteroatoms independently selected from N, O and S, and wherein said heterocycloaikyl and heterocycloalkenyl of NR9R10 are each optionally independently substituted with one or more substituents independently selected from -OH, -C1-C12 alkyl, -C2-C12 alkenyl, -C2-C12 alkynyl, -

C1-C6 alkoxy, -C2-C6 alkenoxy, -C2-C6 alkynoxy, halogen, (Czero-C4 alkylene)-(C6-Ci0 cycloalkyl), (Czero-C4 alkylene)-((5-10 membered) heterocycloaikyl), (Czero-C4 alkylene)-(C6-C10 aryl) and (Czero-C4 alkylene)-((5-10 membered) heteroaryl; n is O, 1 , or 2; or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1, wherein said HET is imidazolyl, thiazolyl or isoxazolyl.

4. The compound of claim 1 , wherein X3 is -(C3-C10 cycloalky)-NR1R2.

5. The compound of claim 4, wherein said cycloalkyl is selected from cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

6. The compound of claim 2, wherein X3 is X4 and wherein X4 is

X3 is -(C1-C2 alkylene)-X4 wherein X4 is

7. The compound of Claim 2 wherein X3 is -(C3-C10 cycloalky)-NR1R2 or -(C3-C10 cycloalkyl)-X4; wherein said cycloalkyl is cyclopentyl or cyclohexyl.

8. The compound of Claim 7, wherein X4 is azetidinyl or pyrrolidinyl;

9 The compound of Claim 7 wherein R1 and R2 are each independently hydrogen or C1-C6 alkyl.

10. The compound of claim 2, wherein X2 is -CH2- and ring A is phenyl.

11. The compound of Claim 2, wherein X1 is -C(=O)-.

12. A pharmaceutical composition for treating a disorder or condition selected from psychosis, schizophrenia, conduct disorder, disruptive behavior disorder, bipolar disorder, psychotic episodes of anxiety, anxiety associated with psychosis, psychotic mood disorders; behavioral manifestations of mental retardation, conduct disorder and autistic disorder; movement disorders associated with Tourette's syndrome, akinetic-rigid syndrome, movement disorders associated with Parkinson's disease, tardive dyskinesia and other drug induced and neurodegeneration based dyskinesias; attention deficit hyperactivity disorder; cognitive disorders and memory disorders in a mammal, comprising a compound of formula I according to claim 1 or a pharmaceutically acceptable salt thereof, in an amount that is effective for treating such disorder or condition.

13. A pharmaceutical composition for treating central nervous system disorders, cognitive disorders, schizophrenia, dementia and other disorders in a mammal, comprising a compound of formula I according to claim 1 and at least one anti-psychotic selected from the group consisting of: Ziprasidone (Geodon), Clozapine, Molindone, Loxapine, Pimozide, Risperidone, Olanzapine, Remoxipride, Sertindole, Amisulpride, Quetiapine, prochlorperazine, Fluphenazine, Trifluoroperazine, Thioridazine, Haloperidol, Chloropromazine, Flupentixol, and Pipotiazine /

14. A method of treating a disorder or condition selected from psychosis, schizophrenia, conduct disorder, disruptive behavior disorder, bipolar disorder, psychotic episodes of anxiety, anxiety associated with psychosis, psychotic mood disorders; behavioral manifestations of mental retardation, conduct disorder and autistic disorder; movement disorders associated with Tourette's syndrome, akinetic-rigid syndrome, movement disorders associated with Parkinson's disease, tardive dyskinesia and other drug induced and neurodegeneration based dyskinesias; attention deficit hyperactivity disorder; cognitive disorders and memory disorders in a mammal, including a human, comprising administering to a mammal in need of such treatment an amount of a compound of formula I according to claim 1, or a pharmaceutically acceptable salt thereof, that is effective in treating such condition or disorder.

15. A method of treating a disorder or condition selected from psychosis, schizophrenia, conduct disorder, disruptive behavior disorder, bipolar disorder, psychotic episodes of anxiety, anxiety associated with psychosis, psychotic mood disorders; behavioral manifestations of mental retardation, conduct disorder and autistic disorder; movement disorders associated with Tourette's syndrome, akinetic-rigid syndrome, movement disorders associated with Parkinson's disease, tardive dyskinesia and other drug induced and neurodegeneration based dyskinesias; attention deficit hyperactivity disorder; cognitive disorders and memory disorders in a mammal, including a human, comprising administering to a mammal in need of such treatment an amount of a compound of formula I according to claim 1 and at least one anti-psychotic selected from the group consisting of: Ziprasidone (Geodon), Clozapine, Molindone, Loxapine, Pimozide, Risperidone, Olanzapine, Remoxipride, Sertindole, Amisulpride, Quetiapine, Prochlorperazine, Fluphenazine, Trifluoroperazine, Thioridazine, Haloperidol, Chloropromazine, Flupentixol and Pipotiazine.

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