OA12345A - Imidazole derivatives. - Google Patents

Abstract

The invention provides compounds of formula (1), wherein R<1>, R<2>, R<3>, and R<4> are as defined, and their pharmaceutically acceptable salts. Compounds of formula (1) are indicated to have activity inhibiting cdk5, cdk2, and GSK-3. Pharmaceutical compositions and methods comprising compounds of formula (1) for treating and preventing diseases and conditions comprising abnormal cell growth, such as cancer, and neurodegenerative diseases and conditions and those affected by dopamine neurotransmission. Also described are pharmaceutical compositions and methods comprising compounds of formula (1) for treating male fertility and sperm motility; diabetes mellitus; impaired glucose tolerance; metabolic syndrome or syndrome X; polycystic ovary syndrome; adipogenesis and obesity; myogenesis and frailty, for example age-related decline in physical performance; acute sarcopenia, for example muscle atrophy and/or cachexia associated with burns, bed rest, limb immobilization, or major thoracic, abdominal, and/or orthopedic surgery; sepsis; hair loss, hair thinning, and balding; and immunodeficiency.

Description

ο 1234 5 -1-

IMIDAZOLE DERIVATIVES

Field of the Invention

The subjeci invention relates to imidazole dérivatives, pharrnaceutical compositionscomprising such dérivatives and methods of using such dérivatives to treat abnormal cellgrowth and certain diseases and conditions of the central nervous system. The compounds ofthe présent invention act as inhibitors of cyclin-dependent protein kinase enzymes cdk5 ·(cyclin-dependent protein kinase 5) and cdk2 (cyclin-dependent protein kinase 2). Thecompounds of the présent invention also are inhibitors of the enzyme GSK-3 (glygocensynthase kinase-3) enzyme.

Background of the invention

The serine/threonine kinase cdk5 along with its cofactor p25 (or the longercofactor, p35) has been linked to neurodegerierative disorders, and inhibitors of cdk5/p25 (orcdk5/p35) are therefore useful for the treatment of neurodegenerative disorders such asAlzheimer’s disease, Parkinson’s disease, stroke, or Huntington's disease. Treatment of suchneurodegenerative disorders using cdk5 inhibitors is supported by the finding that cdk5 isinvoiv.ed in the phosphorylation of tau protein (J. Biochem, 117, 741-749 (1995)). cdk5 alsophosphorylâtes Dopamine and Cyclic AMP-Regulated Phosphorprotein (DARPP-32) atthreonine 75 and is thus indicated in having a rôle in dopaminergic neurotransmission(Nature, 402, 669-671 (1999)).

The serine/threonine kinase cdk2 is essential for normal cell cycling and plays acritical rôle in disorders arising from abnormal cell cycling, a common characteristic of manyoncological disorders. Inhibitors of cdk2 are therefore useful for the treatment of various typesof cancer and other diseases or conditions related to abnormal cell growth (Meijer, et al.,Properties and Potential-applications of Chemical Inhibitors of Cyclin-dependent Kinsases,

Pharmacofogy &amp; therapeutics, 82 (2-3), 279-284 (1999); Sausville, et al., Cyclin-dependentKinases: Initial Approaches to Exploit a Novel Therapeutic Target, Pharmacology &amp;therapeutics 82 (2-3) 285-292 (1999)). GSK-3 is a serine/threonine protein kinase. It is one of several protein kinases whichphosphorylate giycogen synthase (Embi, et al., Eur. J. Biochem. 107:519-527 (1980);Hemmings, et al., Eur. J. Biochem. 119:443-451 (1982)). GSK-3 exists in two isoforms, a andβ, in vertebrates, reported as having a monomeric structure of 49kD and 47kD respectively.Both isoforms phosphorylate muscle giycogen synthase (Cross, et al., Biochemical Journal303: 21-26 (1994)). The amino acid identity among GSK-3 species homologs has been 1indicated to be in excess of 98% within the catalytic domain (Plyte, et al., Biochim. Biophys. w Μ Λ 1 λ 012345

Acta 1114:147-162) (1992)). Due to a remarkably high degree of conservation across thephyiogenetic spectrum, a fundamenta! rôle of GSK-3 in cellular processes is suggested. GSK-3 has been implicated in numerous different disease states and conditions. Forexample, Chen, et al, Diabètes 43: 1234-1241 (1994) hâve suggestgd that an increase inGSK-3 activity can be important in Type 2 diabètes. Increased GSK-3 expression in diabeticmuscle is also though to contribute to the impaired glycogen synthase activity and skeletalmuscle insulin résistance présent in Type 2 diabètes (Nikoulina, et ai., Diabètes 49: 263-271(2000)). Also, a higher activity of a type 1 protein phosphatase measured in immotile spermwas attributed to higher GSK-3 activity and was indicated as responsibie for holding thesperm motility in check (Vijayaraghavan, et al. Biology of Reproduction 54: 709-718 (1996)).Vijayaraghavan et al. indicate that such results suggest a biochemical basis for thedevelopment and régulation of sperm motility and a possible physiological rôle for a proteinphosphatase 1/inhibitor 2/GSK-3 System. GSK-3 activity has aiso been associated withAizheimer’s disease and mood disorders such as bipolar disorder (WO 97/41854). Amongother conditions, GSK-3 has furthermore been implicated in hair loss, schizophrenia, andneurodegeneration, inciuding both chronic neurodegenerative diseases (such as Aizheimer’s,supra) and neurotrauma, for example stroke, traumatic brain injury, and spinal cord trauma.

Summary of the Invention

This invention provides compounds of the formula

wherein R’ is a straight chain or branched (C^-C^alkyl, a straight chain or branched (C2-CB)alkenyl, a straight Chain or branched (C2-C8)alkynyl, (C3-C8)cycloalkyl, (C4-C8)cycloalkenyl, (3-8 rnembered) heterocycloalkyl, (C5-Cn)bicycloalkyl, (Cy-C^jbicycloalkenyl, (5-11 membered)heterobicycioalkyl, (C6-C14) aryl, or (5-14 membered) heteroaryl; and wherein R1 is optionallysubstituted with from one to six substituents R5 independently selected from F, Cl, Br, I, nitro,cyano, -CF3, -NR7RB, -NR7C(=O)R8, -NR7C(=O)OR8, -NR7C(=O)NR8R9, -NR7S(=O)2Rs,-NR7S(=O)2NR8R9, -OR7, -OC(=O)R7, -OC(=O)OR7, -C(=O)OR7, -C(=O)R7, -C(=O)NR7RB,-OC(=O)NR7R8, -OC(=O)SR7, -SR7, -S(=O)R7, -S(=O)2R7, -S(=O)2NR7R8, -0-S(=O)2R7, -N3 andR7; R2 is H, F, CH3, CN, or C(=O)OR7; R3 is -C(=O)NR9-, -C(=O)O-, -C(=O)(CR10R11)n-, or -(CRwR11)n-; 012345 -3- R4 is a straight chain or a branched (C^C^alkyl, a straight chain or à branched (C2-C„)alkenyl, a straight chain or branched (C2-C8 alkynyl), (C3-CB)cycloalk5d, (C4-Ce)cycioalkenyl,(3-8 membered) heterocycloalkyl, (Cs-Clt)bicycloalkyl, (C7-Cn)bicycloalkenyl, (5-11 membered)heterobicycloalkyl, (C6-C14)aryl, or (5-14 membered) heteroaryi; and wherein R4 is optionaliysubstituted with from one to three substitutents R5 independently selected from F, Cl, Br, I, nitro,cyano, -CF3, -NR7R8, -NR7C(=O)R8, -NR7C(=O)OR8, -NR7C(=O)NR8R9, -NR7S(=O)2R8,-NR7S(=O)2NR8R9, -OR7, -OC(=O)R7, -OC(=O)OR7, -C(=O)OR7, -C(=O)R7, -C(=O)NR7R8,-OC(=O)NR7Rb, -OC(=O)SR7, -SR7, -S(=O)R7, -S(=O)2R7, -S(=O)2NR7R8, or R7; each R7, R8, and R9 is independently selected from H, straight chain or branched (C,-CB)alkyl, straight chain or branched (C2-C8)alkenyl, straight chain or branched (C2-C8 alkynyl),(C3-C8)cycloalkyl, (C4-CB)cycloaikenyl, (3-8 membered) heterocycloalkyl, (Cs-C^Jbicycloalkyl,(CrC-tJbicycloalkenyl, (5-11 membered) heterobicycloalkyl, (CB-C14)aryl, and (5-14 membered)heteroaryi, wherein R7, R8, and R9 are each independently optionaliy substituted with from one tosix substituents independently seiected from F, Cl, Br, I, NO2, -CN, -CF3, -NR10R11,-NR10C(=O)R11, -NR10C(=O)OR11, -NR10C(=O)NR11R12, -NR10S(=O)2R11, -NR10S(=O)2NR11R12,-OR10, OC(=O)R10, -OC(=O)OR10, -OC(=O)NR10R11, -OC(=O)SR10, -SR10, -S(=O)R10, -S(=O)2R10,-S(=Q)2NR1oR11, -C(=O)R10, -C(=O)OR10, -C(=O)NR10R11, and R10; or, when R7 and R8 are as in NR7R8, they may instead optionaliy be connected to formwith the nitrogen of NR7R8 to which they are attached a’heterocycloalkyl moiety of from three toseven ring members, said heterocycloalkyl moiety optionaliy comprising one or two furtherheteroatoms independently selected from N, O, and S; each R10, R11, and R12 is independently selected from H, straight chain or branched (C,-C8)alkyl, straight chain or branched (C2-C8)alkenyl, straight chain or branched (C2-C8 alkynyl),(C3-C8)cycloalkyl, (C4-C8)cycloalkenyl, (3-8 membered) heterocycloalkyl, (C5-Cn)bicycloalkyl,(Cy-C^bicycloatkenyi, (5-11 membered) heterobicycloalkyl, (C6-C14)aryl, and (5-14 membered)heteroaryi, wherein R10, R11, and R12 are each independently optionaliy substituted with from oneto six substituents independently selected from F, Cl, Br, I, NO2, -CN, -CF3, -NR13R14,-NR13C(=O)R14, -NR13C(=O)OR14, -NR13C(=O)NR14R15, -NR13S(=O)2R14, -NR13S(=O)2NR14R15,-OR13, -OC(=O)R13, -OC(=O)OR13, -OC(=O)NR13R14, -OC(=O)SR13, -SR13, -S(=O)R13, -S(=O)2R13, -S(=O)2NR13R14, -C(=O)R13, -C(=O)OR13, -C(=O)NR13R14, and R13; each R13, R14, and R15 is independently selected from H, straight chain or branched (C,-CB)alkyl, straight chain or branched (C2-CB)alkenyl, straight chain or branched (C2-CB alkynyl),(C3-Ce)cycloalkyi, (C4-C8)cycloalkenyl, (3-8 membered) heterocycloalkyl, (C5-C11)bicycloalkyl,(C7-C11)bicycloalkenyl, (5-11 membered) heterobicycloalkyl, (C6-C14)aryl, and (5-14 membered)heteroaryi, wherein R13, R14, and R15 are each independently optionaliy substituted with from oneto six substituents independently selected from F, Cl, Br, l, NO2, -CN, -CF3, -NR16R17, 012345 -4- -NR1SC(=O)R17, -NR16C(=O)OR17, -NR16C(=O)NR17R18, -NR16S(=O)2R17, -NR16S(=O)2NR17R18,-OR16, -OC(=O)R16, -OC(=O)OR16, -OC(=O)NR16R17, -OC(=O)SR16, -SR16, -S(=O)R16, -S(=O)2R16, -S(=O)2NR16Rî7, -C(=O)R18, -C(=O)OR16, -C(=O)NR16R17, and R15; each R16, R17, and R18 is independently selected from H, straight_chain or branched (CrC8)alkyl, straight chain or branched (C2-CB)alkenyl, straight Chain or branched (C2-CB alkynyl),(C3-C8)cycloalkyl, (C4-CB)cycioalkenyl, (3-8 membered) heterocycloalkyl, (Cj-C^bicycloalkyl,(Cy-C^bicycloalkenyl, (5-11 membered) heterobicycloalkyl, (Cs-C14)aryl, and (5-14 membered)heteroaryi; n is 0,1,2, or 3; wherein R10 and R11 in -C(=O)(CR10R11)n- and -(CR’°R11)n- are for each itération of ndefined independently as recited above; and pharmaceutically acceptable salts thereof.

Compounds of formula 1 of the invention are inhibitors of serine/threonine kinases,especiaily cyclin-dependent kinases such as cdk5 and cdk2, and are useful for the treatmentof neurodegenerative disorders and other CNS disorders, and of abnormal cell growth,including cancer. The compounds of formula 1 are particularly useful in inhibiting cdk5. Thecompounds of formula 1 are also useful as inhibitors of GSK-3.

The term “alkyl”, as used herein, unless otherwise indicated, includes saturatedmonovalent hydrocarbon radicals having straight or branched moieties. Examples of alkylgroups include, but are not limited to, methyl, ethyl, propyl, isopropyl, and f-butyl.

The term “alkenyl", as used herein, uniess otherwise indicated, includes alkyl moietieshaving at least one carbon-carbon double bond wherein alkyl is as defined above. Examplesof alkenyl include, but are not limited to, ethenyi and propenyl.

The term '‘alkynyl”, as used herein, unless otherwise indicated, includes alkyl moietieshaving at least one carbon-carbon triple bond wherein alkyl is as defined above. Examples ofalkynyl groups include, but are not limited to, ethynyl and 2-propynyl.

The term “cycloalkyl”, as used herein, unless otherwise indicated, includes non-aromatic saturated cyclic alkyl moieties wherein alkyl is as defined above. Examples ofcycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, andcycloheptyl. “Bicycloalkyl” groups are non-aromatic saturated carbocyclic groups consistingof two rings, wherein said rings share one or two carbon atoms. For purposes of the présentinvention, and unless otherwise indicated, bicycloalkyl groups include spiro groups and fusedring groups. Examples of bicycloalkyl groups include, but are not limited to, bicyclo-[3.1.0]-hexyl, norbornyl, spiro[4.5]decyl, spiro[4.4Jnonyl, spiro[4.3]octyl, and spiro[4.2]heptyl.“Cycloalkenyl” and “bicycloalkenyl” refer to non-aromatic carbocyclic cycloalkyl andbicycloalkyl moieties as defined above, except comprising one or more carbon-carbon double 012345 bonds connecting carbon ring members (an "endocyclic" double bond) and/or one or morecarbon-carbon double bonds connecting a carbon ring member and an adjacent non-ringcarbon (an “exocyclic" double bond). Examples of cycloalkenyl groups include, but are notlimited to, cyclopentenyl and cyclobutenyl, and a non-limiting examplè of a bicycloalkenylgroup is norbornenyl. Cycloalkyl, cycloalkenyl, bicycloalkyl, and bicycloalkenyl groups alsoinclude groups that are substituted with one or more oxo moieties. Examples of such groupswith oxo moieties are oxocyclopentyl, oxocyclobutyl, oxocyclopentenyl, and norcamphoryl.

The term “aryl”, as used herein, unless oiherwise indicated, includes an organicradical derived from an aromatic hydrocarbon by removal of one hydrogen, such as phenyl,naphthyl, indenyl, and fluorenyl.

The terms "heterocyclic", “heterocycloalkyl”, and like terms, as used herein, refer tonon-aromatic cyclic groups containing one or more heteroatoms, prefereably from one to fourheteroatoms, each selected from O, S and N. "Heterobicycloalkyl" groups are non-aromatic two-ringed cyclic groups, wherein said rings share one or two atoms, and wherein at least one of therings contains a heteroatom (O, S, or N). Heterobicycloalkyl groups for purposes of the présentinvention, and unless oiherwise indicated, include spiro groups and fused ring groups. In oneembodiment, each ring in the heterobicycloalkyl contains up to four heteroatoms (i.e. from zéroto four heteroatoms, provided that at ieast one ring contains al least one heteroatom). Theheterocyclic groups of this invention can also include ring Systems substituted with one or moreoxo moieties. Examples of non-aromatic heterocyclic groups are aziridinyi, azetidinyl,pyrrolidinyl, piperidinyl, azepinyl, piperazinyl, 1,2,3,6-tetrahydropyridinyl, oxiranyi, oxetanyl,tetrahydrofuranyl, tetrahydrothienyi, tetrahydropyranyl, tetrahydrothiopyranyi, morpholino,thiomorpholino, thioxanyl, pyrrolinyl, indoîinyi, 2H-pyranyl, 4H-pyrany!, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl,imidazoiinyl, imidazolidinyl, 3-azabicyclo[3.1 .Ojhexanyl, 3-azabicyclo[4.1.0]heptanyl,quinolizinyl, quinuclidinyl, 1,4-dioxaspiro[4.5]decyl, 1,4-dioxaspiro[4.4]nonyi, 1,4-dioxaspiro[4.3]octyl, and 1,4-dioxaspiro[4.2]heptyl. “Heteroaryl", as used herein, refers to aromatic groups containing one or moreheteroatoms (O, S, or N), preferabiy from one to four heteroatoms. A multicyclic groupcontaining 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 Systemssubstituted with one or more oxo moieties. Examples of heteroaryl groups are pyridinyl,pyridazinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, quinolyl, isoquinolyl,tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, indoiyl,benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyi, triazinyl,isoindolyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, 012345 -6- benzotriazolyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyi, naphthyridinyl,dihydroquinolyl, tetrahydroquinolyl, dihydroisoquinolyl, tetrahydroisoquinolyl, benzofuryl,furopyridinyl, pyrolopyrimidinyl, and azaindolyi.

The foregoing groups, as derived from the compounds listed above, may be C-attachedor 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 encompassail possible tautomers.

In one embodiment, this invention provides compounds of formula 1, wherein R3 is -C(=O)NR9- or -C(=O)(CR10R11)n-, In another embodiment, R10 and R11,of -C(=O)(CR10R11)n- areat each itération of n both hydrogen. In another embodiment, R9 of-C(=O)NR9- is hydrogen. Inanother embodiment, R3 is -C(=0)NR9- or -C(=O)(CR10R11)n- and R2 is hydrogen.

In another embodiment of the invention, a compound of formula 1 is provided whereinR1 is optionally substituted (C3-C8)cycloalkyl or optionally substituted (Cç-C^) bicycloalkyl.Prefemed embodiments are wherein R1 is cyclopropyl, cyclobutyl, cyciopentyl, cyclohexyl, ornorbornyl, each optionally substituted as recited above (i.e. optionally with from one to sixsubstituents R5 independently selected from F, Cl, Br, I, nitro, cyano, -CF3, -NR7R8,-NR7C(=O)R8, -NR7C(=O)ORb, -NR7C(=O)NRbR9, -NR7S(=O)2Rb, -NR7S(=O)2NRsR9, -OR7,-OC(=O)R7, -OC(=O)OR7, -C(=O)OR7, -C(=O)R7, -C(=O)NR7RB, -OC(=O)NR7R8, -OC(=O)SR7,-SR7, -S(=O)R7, -S(=0)2R7, -S(=O)2NR7Rb, and R7). In a more preferred embodiment, R1 is (C3-CB)cycloalkyl or optionally substituted (C5-C„) bicycloalkyl, for example cyclopropyl, cyclobutyl,cyciopentyl, cyclohexyl, or norbornyl, and is optionally substituted with from one to threesubstituents independently selected from F, Cl, Br, l, nitro, cyano, -CF3, -NR7R8, -NR7C(=O)RB,-OR7, -C(=O)OR7, -C(=O)R7, and R7. More preferably, R1 is (C3-C8)cycloalkyl or optionallysubstituted (C5-C,i) bicycloalkyl, for example cyclopropyl, cyclobutyl, cyciopentyl, cyclohexyl, ornorbornyl, and R1 is substituted with -NR7C(=O)R8, (C6-C14)aryl, (3-8 membered) heterocycloalkyl, or (5-14 membered) heteroaryl, and wherein said aryl, heterocycloalkyl, andheteroaryl are each optionally substituted with from one to six substituents independentlyselected from F, Cl, Br, I, NO2, -CN, -CF3, -NR10R11, -NR10C(=O)R11, -NR10C(=O)OR11,-NR10C(=O)NR11R12, -NR10S(=O)2R11, -NR10S(=O)2NR11R12, -OR10, -OC(=O)R10, -OC(=O)OR10,-OC(=O)NR10R11, -OC(=O)SR10, -SR10, -S(=O)R10, -S(=O)2R10, -S(=O)2NR1OR11, -C(=O)R10,-C(=O)OR10, -C(=O)NR10R11, and R10. In another embodiment of the invention, R1 is bicycio-[3.1.0]-hexyl and is optionally substituted as recited above (i.e. optionally substituted with fromone to six substituents R5 independently selected from F, Cl, Br, I, nitro, cyano, -CF3, -NR7R8,-NR7C(=O)RB, -NR7C(=O)ORB, -NR7C(=0)NRbR9, -NR7S(=O)2Rb, -NR7S(=O)2NRbR9, -OR7,-OC(=O)R7, -OC(=O)OR7, -C(=O)OR7, -C(=O)R7, -C(=O)NR7R8, -OC(=O)NR7RB, -OC(=O)SR7,-SR7, -S(=O)R7, -S(=O)2R7, -S(=O)2NR7Rb, and R7). 012345 -7-

In another embodiment of the invention, a compound of formula 1 is provided whereinR1 is optionaily substituted straight chain or branched (C,-Ce)alkyl or optionally substitutedstraight chain or branched (C2-Ce)alkenyl.

In another embodiment of the invention, compounds of formula 1 are provided, butwherein R2 is hydrogen. In a further embodiment, R2 is hydrogen, and R1 is as subdefined in thepreceding paragraphs.

In another embodiment, this invention provides a compound of formula 1 wherein R4 is ·(C6-C14)aryl or (5-14 membered) heteroaryl, each optionally substituted. In a preferredembodiment, R4 is optionally substituted phenyl or optionally substituted pyridyl. In anotherpreferred embodiment, R4 is naphthyl, quinolyl, or isoquinolyl, each optionally substituted. Inanother embodiment, R4 is napthyl, quinolyl, or isoquinolyl, and is unsubstituted. in another embodiment, compounds of formula 1 are provided, wherein R2 is specificallyhydrogen, and R4 is as subdefined in the preceding paragraph.

Examples of preferred compounds of formula 1 are: N-{1-cyclobutyl-1H-imidazol-4-yl)-2-quinolin-6-yi-acetamide; /V-(1-cyclopentyl-1H-imidazol-4-yl)-2-(4-methoxy-phenyl)-acetamide; W-[1 -(c/s-3-phenyl-cyclobutyl)-1 H-imidazol-4-yl]-2-quinoIin-6-yI-acetamide; (1-cyclobutyi-1H-imidazol-4-yl)-carbamic acid phenyl ester; 1 -(1 -cyclobutyl-1 H-imidazol-4-yl)-3-isoquinoiin-5-yl-urea; W-[1 -(cfs-3-amino-cyclobutyl}-1 H-imidazoi-4-ylj-2-naphthalen-1 -yl-acetamide; 6-methyl-pyridine-2-carboxylic acid {c/'s-3-[4-(2-naphthalen-1-yl-acetyiamino)-imidazol-1-yl]-cyclobutyi}-amide; 1 H-imidazole-4-carboxylic acid {c/s-3-[4-(2-naphthalen-1-yl-acetylamino)-imidazol-1-yl]-cyclobutyl}-amide; 6-hydroxy-pyridine-2-carboxylicimidazol-1 -yl]-cyclobutyl}-amide; 3-methyl-pyridine-2-carboxylicimidazol-1-yl]-cyclobutyl}-amide; 2-pyridin-3-yl-thiazole-4-carboxylic acidimidazol-1-yl]-cyclobutyl}-amide; 6-{c/s-3-[4-(2-naphthaien-1-yl-acetylamino)-imidazo!-1-yl]-cyclobutylcarbamoyl}-nicotinic acid methyl ester; pyrazine-2-carboxylic acid {c/s-3-[4-(2-naphthaien-1-y!-acetyiamino)-imidazol-1-yll-cyciobutyl}-amide; N-{c/s-3-[4-(2-naphthaien-1-yl-acetylamino)-imidazol-1-y!]-cyclobutyl}-benzamide; acid {c/s-3-[4-(2-naphthalen-1-yl-acetylamino)- {c/s-3-[4-(2-naphthalen-1-yl-scetylamino)- {c/s-3-[4-(2-naphthalen-1-yl-acetylamino}- acid θ1234ζ 5- methyl-pyrazine-2-carboxylic acid {c/s-3-[4-(2-naphthalen-1-yl-acetylamino)- imidazol-1-yl]-cyclobutyl}-amide; N-{c/s-3-[4-(2-naphthalen-1-yl-acetylamino)-imidazol-1-yi]-cyclobutyl}-isobutyramide; 6- chioro-pyridine-2-carboxylic acid {c/s-3-[4-(2-naphthalen-1 -yl-a'cetylamino)-imidazol-1-y|]-cyclobutyi}-amide; quinoIine-2-carboxylic acid {c/s-3-[4-(2-naphthalen-1-yl-acetylamino)-imidazol-1-yI]-cyclobutyl}-amide; 1 H-pyrrole-2-carboxyiic acid {c/s-3-[4-(2-naphthalen-1 -yl-acetylamino)-imidazol-1 -yl]-cyclobutyl}-amide; N-{c/s-3-[4-(2-naphthalen-1-yI-acetylamino)-imidazol-1-yl]-cyclobuty!}-2-m-tolyl- acetamide; pyridine-2-carboxylic acid {c/s-3-[4-(2-naphthalen-1 -yl-acetylamino)~imidazol-1 -yl]-cyciobutyi}-amide; 2-(3-hydroxy-phenyl)-N-{c/s-3-[4-(2-naphthalen-1-yl-acety!amino)-imidazol-1-yI]- cyclobutyl}-acetamide; piperidine-4-carboxylic acid {c/'s-3-[4-(2-naphthalen-1 -yl-acetylamino)-imidazol-1 -yl]-cyclobutyl}-amide hydrochloride; N-[1-(c/s-3-acetylamino-cyclobutyl)-1H-imidazol-4-yl]-2-naphthalen-2-yl-acetamide;N-{c/s-3-[4-(2-isoquinoiin-5-yl-acetylamino)-imidazol-1-yl]-cycîobutyl}-benzamide; andpyridine-2-carboxyiic acid {c/s-3-[4-(2-isoquinolin-5-yl-acetylamino)-imidazol-1 -yl]- cyclobutyl}-amide; and pharmaceutically acceptable salts of the foregoing compounds.

Examples of other spécifie compound of the invention of formula 1 are:c/s-N-(1 -bicyclo[3.1.0]hex-3-yl-1 H-imidazol-4-yl)-2-quinolin-6-yl-acetamide;c/s-N-{1-[irans-6-(pyridine-2-carbonyl)-bicyclo[3.1.0]hex-3-yl]-1H-imidazol-4-yl}-2- quinolin-6-yl-acetamide; N-{1-[c/s-3-(2-methoxy-phenyl)-cyclobutyl]-1H-imidazol-4-yl}-2-quinolin-6-yl- acetamide; N-{1-[c/s-3-(2-fluoro-phenyl)-cyclobutyl]-1H-imidazol-4-y|}-2-quinolin-6-yl-acetamide; N-{1-[c/s-3-(4-methoxy-phenyl)-cyclobutyl]-1H-imidazol-4-yl}-2-quinolin-6-yl- acetamide; 2~quinolin-6-yl-N-[1-(c/s-3-p-tolyl-cyclobutyl)-1H-imidazo!-4-yl]-acetamide; N-{1-[c/s-3-(2-ethoxy-phenyl)-cyclobutyl]-1H-imidazol-4-yl}-2-quinoIin-6-yI-acetamide; N-{1-[c/s-3-(3-methoxy-phenyl)-cyclobutyl]-1H-imidazol-4-yl}-2-quinolin-6-yl- acetamide; and pharmaceutically acceptable salts of the foregoing compounds. 012345 -9-

Other examples of spécifie compounds of formula 1 are: N-{1-[3-(2-hydroxy-phenyl)-cyclobutyl]-1H-imidazol-4-yl}-2-(4-methoxy-phenyl)- acetamide; N-{1-[3-(3-hydroxy-phenyl)-cyciobutyl3-1H-imidazo!-4-yl}-2-(4~rnethoxy-phenyl)- acetamide; N-{1-[3-(2-amino-phenyl)-cyclobutyl]-1 H-imidazoi-4-yl}-2-(4-methoxy-phenyl)-acetamide; N-{1-[3-(3-amino-phenyl)-cyclobutyl]-1H-imidazol-4-yl}-2-(4-methoxy-phenyl)- acetamide; N-{1-[3-(3-aminomethyl-phenyl)-cyclobutyl]-1H-imidazo!-4-yl}-2-(4-methoxy-phenyl)- acetamide; N-{1-[3-(3-dimethylaminomethyl-phenyl)-cyclobutylJ-1H-imidazol-4-yi}-2-(4-methoxy-phenyl)-acetamide; and 2-(4-methoxy-phenyl)-N-{1 -[3-(1-methyl-1 H-pyrazol-3-yl)-cyclobutyl]-1 H-imidazol-4-yl}-acetamide; and pharmaceutically acceptable salts of the foregoing compounds.

Salts of compounds of formula 1 can be obtained by forming salts with any acidic orbasic group présent on a compound of formula 1. Examples of pharmaceutically acceptablesalts of the compounds of formula 1 are the salts of hydrochloric acid, p-toluenesulfonic acid,fumaric acid, citric acid, succinic acid, salicylic acid, oxalic acid, hydrobromic acid, phosphoricacid, methanesulfonic acid, tartane acid, maieic acid, di-p-toluoyl tartaric acid, acetic acid,sulfuric acid, hydroiodic acid, mandeiic acid, sodium, potassium, magnésium, calcium, andlithium.

The compounds of formula 1 may hâve optical centers and therefore may occur indifferent enantiomeric and other stereoisomeric configurations. The invention includes ailenantiomers, diastereomers, and other stereoisomers of such compounds of formula 1, aswell as racemic and other mixtures thereof.

The subject invention also includes isotopically-labeled compounds, which areidentical to those recited in formula 1, but for the fact that one or more atoms are repiaced byan atom having an atomic mass or mass number different from the atomic mass or massnumber usually found in nature. Examples of isotopes that can be incorporated intocompounds of the invention inciude isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorous, fluorine, iodine, and chiorine, such as 3H, 11C, 14C, 1BF, 123| and 12SI. Compoundsof the présent invention and pharmaceutically acceptable salts of said compounds thatcontain the aforementioned isotopes and/or other isotopes of other atoms are with in the scopeof this invention. Isotopically-labeled compounds of the présent invention, for example those 012345 -10- into which radioactive isotopes such as 3H and 14C are incorporated, are useful in drug and/orsubstrate tissue distribution assays. Tritiated, Le., 3H, and carbon-14, i.e., 14C, isotopes areparticularly preferred for their ease of préparation and detectabiiity. 11C and 18F isotopes areparticuiariy useful in PET (positron émission tomography), and ’25l isotopes are particularlyuseful in SPECT (single photon émission computerized tomography), ail useful in brainimaging. Further, substitution with heavier isotopes such as deuterium, i.e., 2H, can affordcertain therapeutic advantages resulting from greater metabolic stability, for exampleincreased in vivo haif-life or reduced dosage requirements and, hence, may be preferred insome circumstances.- Isotopically labeled compounds of formula 1 of this invention cangenerally be prepared by carrying out the procedures disclosed in the Schemes and/or in theExemples below, by substituting a readily available isotopically labeied reagent for a non-isotopically labeled reagent.

This invention also provides a pharmaceutical composition for treating a disease orcondition comprising abnormal cell growth in a mammal comprising a compound of formula 1in an amount effective in inhibiting abnormal cell growth, and a pharmaceutically acceptablecarrier.

This invention also provides a pharmaceutical composition for treating a diseases orcondition comprising abnormal cell growth in a mammai comprising a compound of formula 1in an amount effective to inhibit cdk2 activity, and a pharmaceutically acceptable carrier.

This invention also provides a method for treating a disease or condition comprisingabnormal cell growth in a mammal comprising administering to the mammal a compound offormula 1 in an amount effective in inhibiting abnormal cell growth.

This invention also provides a method for treating a diseases or condition comprisingabnormal cell growth in a mammal comprising administering to the mammal a compound offormula 1 in an amount effective to inhibit cdk2 activity.

In a pharmaceutical composition or method of this invention for treating a disease orcondition comprising abnormal cell growth, the disease or condition comprising abnormal cellgrowth is in one embodiment cancer. The cancer may be a carcinoma, for example carcinomaof the bladder, breast, colon, kidney, liver, lung, for example small cell lung cancer, esophagus,gall bladder, ovary, pancréas, stomach, cervix, thyroid, prostate, or skin, for example squarnouscell carcinoma; a hematopoietic tumor of lymphoid lineage, for example leukemia, acutelymphocytic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkins lymphoma, non-Hodgkinslymphorna, hairy cell lymphoma, or Burketfs lymphoma; a hematopoietic tumor of myeioidlineage, for example acute and chronic myelogenous leukemias, myelodysplastic syndrome, orpromyelocytic leukemia; a tumor of mesenchymal origin, for example fibrosarcoma orrhabdomyosarcome; a tumor of the central or peripheral nervous System, for example -11- 012345 astrocytoma, neuroblastome, glioma or schwannoma; melanoma; seminoma; teratocarcinoma;osteosarcoma; xenoderoma pigmentoum; keratoctanthoma; thyroid follicular cancer; or Kaposi'ssarcoma.

In another embodiment, the disease or condition comprising abnormal cell growth is5 benign. Such diseases and conditions include benign prostate hyperplasie, familialadenomatosis polyposis, neuro-fibromatosis, atherosclerosis, pulmonary fibrosis, arthritis, psoriasis, glomerulonephritis, restenosis, hypertrophie scar formation, inflammatory bowel ·disease, transplantation rejection, fungal infection, and endotoxic shock.

This invention also provides a pharmaceutical composition for treating a10 neurodegenerative disease or condition in a mammal comprising a compound of formula 1 inan amount effective in treating said disease or condition, and a pharmaceuticaily acceptable carrier.

This invention also provides a pharmaceutical composition for treating aneurodegenerative disease or condition in a mammal comprising a compound of formula 1 in 15 an arnount effective in inhibiting cdk5 activity, and a pharmaceuticaily acceptable carrier.

This invention also provides a method for treating a neurodegenerative disease orcondition in a mammal comprising administering to the mammal a compound of formula 1 inan amount effective in inhibiting cdk5 activity.

This invention also provides a method for treating a neurodegenerative disease or20 condition in a mammal comprising administering to the mammal a compound of formula 1 in an amount effective in treating said disease or condition.

In one embodiment of the invention, the neurodegenerative disease or conditionwhich is treated is selected from Huntington’s disease, stroke, spinal cord trauma, traumaticbrain injury, multiinfarct dementia, epilepsy, amyotrophie latéral sclerosis, pain, viral induced . 25 dementia for example AIDS induced dementia, neurodegeneration associated with bacterialinfection, migraine, hypoglycemia, urinary incontinece, brain ischemia, multiple sclerosis,Alzheimer’s disease, seniie dementia of the Alzheimer’s type, miid cognitive impairment, age-reialed cognitive décliné, emesis, corticobasal degeneration, dementia pugiiistica, Down’ssyndrome, myotonie dystrophy, Niemann-Pick disesse, Pick’s disease, prion disease with 30 tangies, progessive supranuclear paisy, lower latéral sclerosis, and subacute scierosingpanencephalistis.

This invention aiso provides a pharmaceutical composition for treating a disease orcondition the treatment of which can be effected or facilitated by altering dopamine mediatedneurotransmission in a mammal comprising a cdk5 inhibitor in an amount effective in treating 35 said disease or condition and a pharmaceuticaily acceptable carrier. 012345 -12-

This invention also provides a pharmaceutical composition for treating a disease orcondition the treatment of which can be effected or facilitated by altering dopamine mediatedneurotransmission in a mammal comprising a cdk5 inhibitor in an amount effective to irihibitcdk5 and a pharmaceutically acceptable carrier.

This invention also provides a method for treating a disease or condition the treatmentof which can be effected or facilitated by altering dopamine mediated neurotransmission in amammal comprising administering to the mammal a cdk5 inhibitor in an amount effective ininhibiting cdk5 activity.

This invention also provides a method for treating a disease or condition the treatmentof which can be effected or facilitated by altering dopamine mediated neurotransmission in amammal comprising administering to the mammal a cdk5 inhibitor in an amount effective intreating said disease or condition.

In one embodiment of the invention, the disease or condition the treatment of whichcan be effected or facilitated by altering dopamine mediated neurotransmission is selectedfrom Parkinson’s disease; schizophrenia; schizophreniform disorder; schizoaffective disorder,for example of the delusional type or the dépressive type; delusional disorder; substance-induced psychotic disorder, for example psychosis induced by alcohol, amphétamine,cannabis, cocaïne, hallucinogens, inhalants, opioids, or phencyclidine; personality disorder ofthe paranoid type; personality disorder of the schizoid -type; drug addiction, including narcotic(e.g. heroin, opium, and morphine), cocaïne and alcohol addiction; drug withdrawal, includingnarcotic, cocaïne and alcohol withdrawal; obsessive compulsive disorder; Tourette’ssyndrome; dépréssion; a major dépressive épisode, a manie or mixed mood épisode, ahypomanie mood épisode, a dépressive épisode with atypical features or with melanchoiicfeatures or catatonie features, a mood épisode with postpartum onset; post-stroke dépréssion,major dépressive disorder, dysthymie disorder, minor dépressive disorder, premenstrualdysphorie disorder, post-psychotic dépressive disorder of schizophrenia, a major dépressivedisorder superimposed on a psychotic disorder such as delusional disorder or schizophrenia,a bipolar disorder, for example bipolar I disorder, bipolar II disorder, cyclothymie disorder;anxiety; attention déficit and hyperactivity disorder; and attention déficit disorder.

In another embodiment, the cdk5 inhibitor in the method or composition for treating adisease or condition the treatment of which can be effected or facilitated by altering dopaminemediated neurotransmission is a compound of formula 1 or a pharmaceutically-acceptabiesait thereof.

This invention also provides a pharmaceutical composition for treating a disease orcondition facilitated by cdk5 activity in a mammal which composition comprises a compound 0/2345 -13- of formula 1 in an amount effective in inhibiting cdk5 activity and a pharmaceuticallyacceptable carrier.

This invention aiso provides a method for treating a disease or condition facilitated bycdk5 activity in a mammal which method comprises administering to the mammal a compoundof formula 1 in an amount effective in inhibiting cdk5 activity.

We hâve also found that the compounds of formula 1 hâve activity in inhibiting GSK-3. The compounds of formula 1 therefore can be expected to be useful in treating diseasesand conditions the treatment of which can be effected or facilitated by inhibition of GSK-3.Diseases and conditions the treatment of which can be effected or facilitated by inhibitingGSK-3 include neurodegenerative diseases and conditions. Neurodegenerative diseases andconditions are discussed above and include, but are not limited to, for example Alzheimer’sdisease, Parkinson’s disease, Huntington's disease, amyotrophie latéral sclerosis, multiplesclerosis, stroke, cérébral ischemia, AIDS-reiated dementia, neurodegeneration associatedwith bacterial infection, multiinfarct dementia, traumatic brain injury, and spinal cord trauma.Therefore, compounds of formula 1 are effective in treating neurodegenerative diseases andconditions based on both cdk5 activity and GSK-3 activity.

Other diseases and conditions the treatment of which can be effected or facilitated byinhibiting GSK-3 include psychotic disorders and conditions, for example schizophrenia,schizophreniform disorder; schizoaffective disorder, for example of the delusional type or thedépressive type; delusional disorder; substance-induced psychotic disorder, for examplepsychosis induced by alcohol, amphétamine, cannabis, cocaïne, hallucinogens, inhalants,opioids, or phencyciidine; personality disorder of the paranoid type; and personality disorderof the schizoid type. The treatment of such diseases and conditions can also be effected orfacilitated by altering dopamine mediated neurotransmission. Therefore, compounds offormula 1 are effective in treating such disorders and conditions based on both cdk5 activityand GSK-3 activity.

Other disorders and conditions the treatment of which can be effected or facilitated byinhibiting GSK-3 include mood disorders and mood épisodes, for example a major dépressiveépisode, a manie or mixed mood épisode, a hypomanie mood épisode, a dépressive épisodewith atypica! features or with melancholic features or catatonie features, a mood épisode withpostpartum onset; post-stroke dépréssion, major dépressive disorder, dysthymie disorder,minor dépressive disorder, premenstrual dysphorie disorder, post-psychotic dépressivedisorder of schizophrenia, a major dépressive disorder superimposed on a psychotic disordersuch as delusional disorder or schizophrenia, a bipolar disorder, for example bipolar Idisorder, bipolar II disorder, and cyclothymie disorder. The treatment of such mood disordersand épisodes, for example dépréssion, can also be effected or facilitated by altering dopamine 012345 -14- mediated neurotransmission. Therefore, compounds of formula 1 are effective in treatingcertain mood disorders and mood épisodes based on both cdk5 activity and GSK-3 activity.

Other disorders and conditions the treatment of which can be effected or facilitated byinhibiting GSK-3 are male fertility and sperm motiiity; diabètes mellitus; impaired glucosetolérance; metabolic syndrome or syndrome X; polycystic ovary syndrome; adipogenesis andobesity; myogenesis and frailty, for example age-related décliné in physical performance;acute sarcopenia, for example muscle atrophy and/or cachexia associated with burns, bedrest, limb immobilization, or major thoracic, abdominal, and/or orthopédie surgery; sepsis;spinal cord injury; hair loss, hair thinning, and balding; immunodeficiency; and cancer.

Accordingly, the présent invention also provides a pharmaceutical composition fortreating in a mammal, including a human, a disease or condition selected from male fertilityand sperm motiiity; diabètes mellitus; impaired glucose tolérance; metabolic syndrome orsyndrome X; polycystic ovary syndrome; adipogenesis and obesity; myogenesis and frailty,for example age-related décliné in physical performance; acute sarcopenia, for examplemuscle atrophy and/or cachexia associated with burns, bed rest, limb immobilization, or majorthoracic, abdominal, and/or orthopédie surgery; sepsis; hair loss, hair thinning, and balding;and immunodeficiency; which composition comprises a pharmaceutically acceptable carrierand an amount of a compound of formula 1 effective in treating said disease or condition.

The présent invention further provides a pharmaceutical composition for treating in amammal, including a human, a disease or condition selected from male fertility and spermmotiiity; diabètes mellitus; impaired glucose tolérance; metabolic syndrome or syndrome X;polycystic ovary syndrome; adipogenesis and obesity; myogenesis and frailty, for exampleage-related décliné in physical performance; acute sarcopenia, for example muscle atrophyand/or cachexia associated with burns, bed rest, limb immobilization, or major thoracic,abdominal, and/or orthopédie surgery; sepsis; hair loss, hair thinning, and balding; andimmunodeficiency; which composition comprises a pharmaceutically acceptable carrier andan amount of a compound of formula 1 effective in inhibiting GSK-3.

The présent invention also provides a method for treating in a mammal, including ahuman, a disease or condition selected from male fertility and sperm motiiity; diabètesmellitus; impaired glucose tolérance; metabolic syndrome or syndrome X; polycystic ovarysyndrome; adipogenesis and obesity; myogenesis and frailty, for example age-related déclinéin physical performance; acute sarcopenia, for example muscle atrophy and/or cachexiaassociated with burns, bed rest, limb immobilization, or major thoracic, abdominal, and/ororthopédie surgery; sepsis; hair loss, hair thinning, and balding; and immunodeficiency; whichmethod comprises administering to said mammal an amount of a compound of formula 1effective in treating said disease or condition. 012345 -15-

The présent invention also provides a method for treating in a mammal, including ahuman, a disease or condition selected from maie fertiiity and sperm motility; diabètesmellitus; impaired glucose tolérance; metabolic syndrome or syndrome X; polycystic ovarysyndrome; adipogenesis and obesity; myogenesis and frailty, for example age-related déclinéin physical performance; acute sarcopenia, for example muscle atrophy and/or cachexiaassociated with burns, bed rest, limb immobilization, or major thoracic, abdominal, and/ororthopédie surgery; sepsis; haïr loss, hair thinning, and balding; and immunodeficiency; which.method comprises administering to said mammal an amount of a compound of formula 1effective in inhibiting GSK-3.

The présent invention further provides a method for inhibiting GSK-3 in a mammal,including a human, which method comprises administering to said mammal an amount of acompound of formula 1 effective in inhibiting GSK-3.

The présent invention further provides a pharmaceutical composition for treating in amammal a disorder selected from Alzheimer’s disease, miid cognitive impairment, and age-reiated cognitive décliné comprising a cdk5 inhibitorand a COX-ll inhibitor together in an amounteffective in treating said disorder, and a pharmaceutically acceptable carrier, in oneembodiment, the cdk5 inhibitor is a compound of formula 1 or a pharmaceutically acceptable saitthereof.

This invention aiso provides a method for treating in a mammal a disorder selected fromAlzheimer’s disease, mild cognitive impariment, and age-related cognitive décliné which methodcomprises administering to said mammal a cdk5 inhibitor and a COX-ll inhibitor, wherein thecombined amounts of’the cdk5 inhibitor and the COX-ll inhibitor are effective in treating saiddisorder. In one embodiment, the cdk5 inhibitor is a compound of formula 1 or apharmaceutically acceptable sait thereof. The cdk5 inhibitor and the COX-ll inhibitor can beadministered to the mammal àt the same time and/or at different times. Moreover, they may beadministered together in a single pharmaceutical composition or in separate pharmaceuticalcompositions.

Moreover, a cdk5 inhibitor, for example a compound of formula 1 of the invention, or apharmaceutically acceptable sait of a compound of formula 1, can be administered or formulatedinto a pharmaceutical composition with one or more anti-depressants or anxioiytic compoundsfor treatment or prévention of dépréssion and/or anxiety.

Accordingiy, this invention also provides a pharmaceutical composition for treatingdépréssion or anxiety in a mammal comprising a cdk5 inhibitor and NK-1 receptor antagonisttogether in an amount effective in treating dépréssion or anxiety, and a pharmaceuticallyacceptable carrier, in one embodiment, the cdk5 inhibitor is a compound of formula 1 or apharmaceutically acceptable sait thereof. Q123 4 5 -16-

This invention further provides a method for treating dépréssion or anxiety in amammal which method comprises administering to said mammal a cdk5 inhibitor and an NK-1receptor antagonist, wherein the combined amounts of the cdk5 inhibitor and the NK-1receptor antagonist are effective in treating dépréssion or anxiety. In one embodiment, thecdk5 inhibitor is a compound of formula 1 or a pharmaceuticaily acceptable sait thereof. Thecdk5 inhibitor and the NK-1 receptor antagonist can be administered to the mammal at thesame time and/or at different times. Moreover, they may be administered together in a singiepharmaceutical composition or in separate pharmaceutical compositions.

This invention-also provides a pharmaceutical composition for treating dépréssion oranxiety in a mammal comprising a cdk5 inhibitor and a 5HT,0 receptor antagonist together inan amount effective in treating dépréssion or anxiety, and a pharmaceuticaily acceptablecarrier. In one embodiment, the cdk5 inhibitor is a compound of formula 1 or apharmaceuticaily acceptable sait thereof.

This invention further provides a method for treating dépréssion or anxiety in amammal which method comprises administering to said mammal a cdk5 inhibitor and a 5HT1Dreceptor antagonist, wherein the combined amounts of the cdk5 inhibitor and the 5HT1Dreceptor antagonist are effective in treating dépréssion or anxiety. in one embodiment, thecdk5 inhibitor is a compound of formula 1 or a pharmaceuticaily acceptable sait thereof. Thecdk5 inhibitor and the 5HT1D receptor antagonist can -be administered to the mammal at thesame time and/or at different times. Moreover, they may be administered together in a singlepharmaceutical cpmposition or in separate pharmaceutical compositions.

This invention also provides a pharmaceutical composition for treating dépréssion oranxiety in a mammal comprising a cdk5 inhibitor and a SSRI together in an amount effective intreating dépréssion or anxiety, and a pharmaceuticaily acceptable carrier. In oneembodiment, the cdk5 inhibitor is a compound of formula 1 or a pharmaceuticaily acceptablesait thereof.

This invention further provides a method for treating dépréssion or anxiety in amammal which method comprises administering to said mammal a cdk5 inhibitor and a SSRI,wherein the combined amounts of the cdk5 inhibitor and the SSRI are effective in treatingdépréssion or anxiety. In one embodiment, the cdk5 inhibitor is a compound of formula 1 or apharmaceuticaily acceptable sait thereof. The cdk5 inhibitor and the SSRI can beadministered to the mammal at the same time and/or at different times. Moreover, they maybe administered together in a single pharmaceutical composition or in separatepharmaceutical compositions.

This invention also provides a pharmaceutical composition for treating schizophrenia in a mammal comprising a cdk5 inhibitor and as antipsychotic selected from ziprasidone, 012345 -17- olanzapine, rispéridone, L-745870, sonepiprazoie, RP 62203, NGD 941, balaperidone,flesinoxan, and gepirone, together in an amount effective in treating schizophrenia, and apharmaceuticaliy acceptable carrier. In one embodiment, the cdk5 inhibitor is a compound offormula 1 or a pharmaceuticaliy acceptable sait thereof. 5 This invention further provides a method for treating schizophrenia in a mammal which method comprises administering to said mammal a cdk5 inhibitor and an antipsychoticselected from ziprasidone, olanzapine, rispéridone, L-745870, sonepiprazoie, RP 62203, NGD941, balaperidone, flesinoxan, and gepirone, wherein the combined amounts of the cdk5inhibitor and the antipsychotic are effective in treating schizophrenia. tn one embodiment, the 10 cdk5 inhibitor is a compound of formula 1 or a pharmaceuticaliy acceptable sait thereof. Thecdk5 inhibitor and the antipsychotic can be administered to the mammal at the same timeand/or at different times. Moreover, they may be administered together in a singlepharmaceutical composition or in separate pharmaceutical compositions.

This invention also provides a pharmaceutical composition for treating a disorder 15 selected from Alzheimer's disease, mild cognitive impairment, and age-related cognitivedécliné in a mammal comprising a cdk5 inhibitor and an acetyichoiinesterase inhibitor togetherin an amount effective in treating said disorder, and a pharmaceuticaliy acceptable carrier. Inone embodiment, the cdk5 inhibitor is a compound of formula 1 or a pharmaceuticaliyacceptable sait thereof. 20 This invention further provides a method for treating in a mammal a disorder selected from Alzheimer’s disease, mild cognitive impairment, and age-related cognitive décliné, whichmethod comprises administering to said mammal a cdk5 inhibitor and an acetyichoiinesteraseinhibitor, wherein the combined amounts of the cdk5 inhibitor and the acetyichoiinesteraseinhibitor are effective in treating said disorder. in one embodiment, the cdk5 inhibitor is a 25 compound of formula 1 or a pharmaceuticaliy acceptable sait thereof. The cdk5 inhibitor and theacetyichoiinesterase inhibitor can be administered to the mammal at the same time and/or atdifferent times.

This invention also provides a pharmaceutical composition for treating a disease orcondition selected from stroke, spinal cord trauma, traumatic brain injury, multiinfarct dementia, 30 epilepsy, pain, Alzheimer’s disease, and senile dementia comprising a cdk5 inhibitor and TPA(tissue plasminogen activator, for example ACTIVASE) together in an amount effective intreating said disorder, and a pharmaceuticaliy acceptable carrier. In one embodiment, the cdk5inhibitor is a compound of formula 1 or a pharmaceuticaliy acceptable sait thereof.

This invention further provides a method for treating in a mammal a disease or condition 35 selected from stroke, spinal cord trauma, traumatic brain injury, multiinfarct dementia, epilepsy,pain, Alzheimer's disease, and senile dementia, which method comprises administering to said 072345 -18- mammal a cdk5 inhibitor and TP A, wherein the combined amounts of the cdk5 in hibitor and theTPA are effective in treating said disease or condition. In one embodiment, the cdk5 inhibitor isa compound of formula 1 or a pharmaceutically acceptable sait thereof. The cdk5 inhibitor andthe TPA can be administered to the mammal at the same time and/or at different times.Moreover, they may be administered together in a single pharmaceutical composition or inseparate pharmaceutical compositions.

This invention also provides a pharmaceutical composition for treating a disease orcondition selected from stroke, spinal cord trauma, traumatic brain injury, multiinfarct dementia,epilepsy, pain, Aizheimer’s disease, and seniie dementia in a marpmal comprising a cdk5inhibitor and NIF (neutrophil inhibitory factor) together in an amount effective in treating saiddisorder, and a pharmaceutically acceptable carrier. In one embodiment, the cdk5 inhibitor is acompound of formula 1 or a pharmaceutically acceptable sait thereof.

This invention further provides a method for treating in a mammal a disease or conditionselected from stroke, spinal cord trauma, traumatic brain injury, multiinfarct dementia, epilepsy,pain, Aizheimer’s disease, and seniie dementia, which method comprises administering to saidmammal a cdk5 inhibitor and NIF, wherein the combined amounts of the cdk5 inhibitor and theNIF are effective in treating said disease or condition. In one embodiment, the cdk5 inhibitor is acompound of formula 1 or a pharmaceutically acceptable sait thereof. The cdk5 inhibitor and theNIF can be administered to the mammal at the same time and/or at different times. Moreover,they may be administered together in a single pharmaceutical composition or in separatepharmaceutical compositions.

This invention also provides a pharmaceutical composition for treating a disease orcondition selected from Huntington’s disease, stroke, spinal cord trauma, traumatic braininjury, multiinfarct dementia, epilepsy, amyotrophie latéral sclerosis, pain, viral induceddementia for example AIDS induced dementia, migraine, hypoglycemia, urinary incontinece,brain ischemia, multiple sclerosis, Aizheimer’s disease, seniie dementia of the Aizheimer’stype, mild cognitive impairment, age-related cognitive décliné, emesis, corticobasaldegeneration, dementia pugilistica, Down’s syndrome, myotonie dystrophy, Niemann-Pickdisease, Pick’s disease, prion disease with tangies, progessive supranuclear palsy, lowerlatéral sclerosis, and subacute sclerosing panencephalistis in a mammal comprising a cdk5inhibitor and an NMDA receptor antagonist together in an amount effective in treating saiddisorder, and a pharmaceutically acceptable carrier. In one embodiment, the cdk5 inhibitor isa compound of formula 1 or a pharmaceutically acceptable sait thereof.

This invention further provides a method for treating in a mammal a disease orcondition selected from Huntington’s disease, stroke, spinal cord trauma, traumatic braininjury, multiinfarct dementia, epilepsy, amyotrophie latéral sclerosis, pain, vira! induced 012345 -19- dementia for example AIDS induced dementia, migraine, hypoglycemia, urinary incontinece,brain ischemia, multiple sclerosis, Alzheimer’s disease, senile dementia of the Alzheimer'stype, mild cognitive impairment, age-related cognitive décliné, emesis, corticobasaldeaeneration, dementia pugilistica, Down’s syndrome, myotonie dystrophy, Niemann-Pickdisease, Pick’s disease, prion disease with tangles, progessive supranuciear palsy, lowerlatéral sclerosis, and subacute sclerosirig panencephalistis, which method comprisesadministering to said mammal a cdk5 inhibitor and an NMDA receptor antagonist, wherein the *combined amounts of the cdk5 inhibitor and the NMDA receptor antagonist are effective intreating said disease or condition. In one embodiment, the cdk5 inhibitor is a compound offormula 1 or a pharmaceutically acceptable sait thereof. The cdk5 inhibitor and the NMDAreceptor antagonist can be administered to the mammal at the same time and/or at differenttimes. Moreover, they may be administered together in a single pharmaceutical compositionor in separate pharmaceutical compositions.

This invention also provides a pharmaceutical composition for treating a disease orcondition selected from stroke, spinal cord trauma, traumatic brain injury, multiinfarctdementia, epilepsy, pain, Alzheimer's disease, and senile dementia in a mammal comprisinga cdk5 inhibitor and a potassium channel modulator together in an amount effective in treatingsaid disorder, and a pharmaceutically acceptable carrier. In one embodiment, the cdk5inhibitor is a compound of formula 1 or a pharmaceutically acceptable sait thereof.

This invention further provides a method for treating in a mammal a disease orcondition selected from stroke, spinal cord trauma, traumatic brain injury, multiinfarctdementia, epilepsy, pain, Alzheimer’s disease, and senile dementia, which method comprisesadministering to said mammal a cdk5 inhibitor and a potassium channel modulator, whereinthe combined amounts of the cdk5 inhibitor and the potassium channel modulator areeffective in treating said disease or condition. In one embodiment, the cdk5 inhibitor is acompound of formula 1 or a pharmaceutically acceptable sait thereof. The cdk5 inhibitor andthe potassium channel modulator can be administered to the mammal at the same time and/orat different times. Moreover, they may be administered together in a single pharmaceuticalcomposition or in separate pharmaceutical compositions.

The terms “treatment", “treating”, and the like, refers to reversing, aiieviating, orinhibiting the progress of the disease or condition to which such term appiies, or one or moresymptoms of such disease or condition. As used herein, these terms aiso encompass,depending on the condition of the patient, preventing the onset of a disese or condition, or ofsymptoms associated with a disease or condition, inciuding reducing the severity of a disease orcondition or symptoms associated therewith prior to affliction with said disease or condition.Such prévention or réduction prior to affliction refers to administration of the compound of the 012345 -20- invention to a subject.that is not at the time of administration afflicted with the disease orcondition. ‘‘Preventing" also encompasses preventing the récurrence of a disease or conditionor of symptoms associated therewith. “Mammal”, as used herein, and unless otherwise indicated, means any mammal. Theterm “mammar includes, for example and without limitation, dogs, cats, and humans. “Abnormal cell growth”, as used herein, refers to ceil growth, either malignant (e.g. asin cancer) or benign, that is independent of normal regulatory mechanisms {e.g., loss ofcontact inhibition). Examples of benign proliférative diseases are psoriasis,, benign prostatichypertrophy, human papilloma virus (HPV), and restinosis. “Neurodegenerative diseases and conditions”, as used herein, refers to diseases andconditions having associated therewith degeneration of neurons. Conditions and diseases thatare neurodegenerative in nature are generally known to those of ordinary skill in the art. Référencés herein to diseases and conditions “the treatment of which can be effected orfacilitated by altering dopamine mediated neurotransmission” mean a disease or condition that iscaused at least in part by dopamine neurotransmission, or a disease or condition that resuit inabnormal dopamine neurotransmission, thus contributing to symptoms or manifestations of thedisease or condition. Référencés herein to diseases and conditions “the treatment of which can be effected orfaciliatated by decreasing cdk5 activity” mean a disease or condition that is caused at least inpart by cdk5 activity, or a disease or condition that résulte in abnormal cdk5 activity thatcontributes to symptoms or manifestations of the disease or condition.

An “amount effective to inhibit cdk5 activity" as used herein refers to an amount of acompound sufficient to bind to the enzyme cdk5 with the effect of decreasing cdk5 activity.

An “amount effective to inhibit cdk2 activity” as used herein refers to an amount of acompound sufficient to bind to the enzyme cdk2 with the effect of decreasing cdk2 activity.

Detailed Description of the Invention

Compounds of the formula 1, above, and their pharmaceutically acceptable salts, canbe prepared according to the following reaction Schemes and discussion. Unless otherwiseindicated R1, R2, R3, and R4 are as defined above. Isolation and purification of the products isaccomplished by standard procedures which are known to a chemist of ordinary skill.

As used herein, the expression “réaction inert solvent” refers to a solvent System inwhich the components do not interact with starting materiais, reagents, or intermediates ofproducts in a manner which adversely affects the yield of the desired product.

During any of the following synthetic sequences it may be necessary and/or désirableto protect sensitive or réactivé groups on any of the molécules concerned. This may beachieved by means of conventional protecting groups, such as those described in T. W. 5 °1234 -21-

Greene, Protective Groups in Organic Chemistry, John Wiley &amp; Sons, 1981; and T. W.Greene and P. G. M. Wuts, Protective Groups in Organic Chemistry, John Wiley &amp; Sons,1991.

Scheme 1 illustrâtes methods suitable for preparing compounds of formula 1 whereinR3 is -C(=O)NH-, -C(=O)O-, or -C(=O)(CR10R1’)n-. Referring to Scheme 1, treatment of asolution of 1,4-dinitroimidazole (J. Phys. Chem. (1995) Vol. 99, pp. 5009-1015) indimethylsulfoxide (DMSO), pyridine-water, water, acetonitrile-water, an alcohol, or an alcohol-water solvent System, but preferably in a lower alcohol such as methanol, from about -20° Cto about 50° C, preferably from about -5° C to 35° C, with a primary alj^yl or aryl amine affords1-W-substituted-4-nitroimidazoles of formula 2. 1,4-Dinitroimidazole is a highly energetic, semi-stable substance and should be stored in a freezer- at ail times it is not in use.Thermodynamic measurements hâve shown that it can potentially generate enough energy at35 °C under adiabatic conditions to violently explode. Extrême caution should be exercised atail times using this material. Réduction of the nitro compound of formula 2 to the amine offormula 3 may be accompiished by exposing a mixture of a compound of formula 2 and anoble métal catalyst, in a solvent such as ethyl acetate, tetrahydrofuran, dioxane, or a mixturethereof, to an atmosphère of hydrogen gas at a pressure of about 1 to 100 atmosphères,where a preferred pressure of hydrogen gas is about one to about ten atmosphères.Palladium is the preferred noble métal catalyst. The métal may be conveniently suspendedon an inert solid support such as charcoal. After the compound of formula 2 has beenconsumed, the mixture is filtered and the resulting amine of formula 3 is reacted immediatelywith an acid chloride CIC(=O)(CR10R11)nR4, acid anhydride (R4(CR10R11)nC(=O))2O, or anactivated carboxylic acid dérivative XC(=O)(CR10R11)nR4, in the presence of a base, such astriethylamine, diisopropylethyiamine, pyridine, or 2,6-lutidine, from about -78 °C to 40 °C. 1-Propanephosphonic acid cyclic anhydride and triethylamine are a preferred combination. Theactivated carboxylic acid dérivative is prepared from the carboxylic acidHOC(=O)(CR10R1'l)nR'1 and a known activating reagent such as dicyclohexyl carbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochioride, carbonyi diimidazole, 1-propanephosphonic acid cyclic anhyrdide, alkyl or aryl chloroformate, bis(2-oxo-3-oxazolidinyl)phosphinic chloride, benzotriaza)-1-yloxy-tris(dimethylamino)phosphoniumhexafluorophosphate, or any other such standard iiterature reagents. This procedure affordsa compound of formula 1B where R3 is -C(=O)(CR10R1’)„-.

Alternativeiy, following filtration, the amine of formula 3 can be treated with a base,such as triethylamine, diisopropylethyiamine, pyridine, or 2,6-lutidine, and an alkyl- or aryl-chloroformate, from about -78 °C to 40 °C, where -78 °C to -40 °C are preferred, to afford acompound of formula 1A where R3 is -C(=O)O- and R4 is phenyi. Diisopropylethyiamine and 012345 -22-

phenyl chloroformate are a preferred combination. Subséquent treatment of phenylcarbamate of formula 1A with a primary or secondary amine in a solvent such as dioxane,dimethylformamide, or acetonitrile, at a température between about 40 °C and 90 °C, affordsthe corresponding urea product 1C where R3 is -C(=O)NRS- and R4 is phenyl or heteroaryl. A 5 1:1 mixture of dioxane - dimethylformamide and 70 °C are preferred.

Scheme 1 R1NH2

A method of preparing compounds of formula 1, wherein R1 is substituted with R5 and10 Rs is NHC(=O)R8, is shown in Scheme 2. Treating the compourid of formula 4 where R5 =OH, with an alkyl- or aryl-sulfonyl chloride, where p-toluenesulfonyl chloride (TosCI) ispreferred, in a reaction inert solvent such as tetrahydrofuran, methylene chloride or 012345 -23- chloroform, where methylene chloride is preferred, at a température from about -10° C toabout 30° C, in the presence of an amine base such as triethylamine, diisopropylethylamine,pyridine, or 2,6-lutidine, where triethylamine is preferred, and catalytic 4-N,W-dimethylaminopyridine, affords a compound of formula 5 wherein R5 is_CH3(C6H4)SO3 (TosO).Tieatment of the tosylate thus formed with an alkali métal sait of azide, wherein sodium azideis preferred, in a polar solvent such as dimethylformamide, dimethylsulfoxide, a lower alcohol,water, or a mixture of these solvents, wherein an ethanol-water mixture is preferred, at a -température from about 20° C to 130° C, where 90° C to 110° C are preferred, produces acompound of formula 6, wherein R5 is N3.

Treatment of the azide under sélective reducing conditions, such as triaikyl- ortriarylphosphine and water, wherein triphenyiphosphine is preferred, in a solvent such astetrahydrofuran, dioxane, acetonitrile, or a mixture thereof, where tetrahydrofuran is preferred,affords a compound of formula 7 where R5 is NH2. The primary amino group of the compoundof formula 7 thus formed (R5 = NH2) can be derivatized via reaction with a chioroformate,isocyanate, carbamoylyl chloride, acid chloride, acid anhydride, or an activated carboxyitcacid dérivative. The activated carboxylic acid dérivative is prepared from the carboxylic acidand a known activating reagent such as dicyclohexyl carbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, carbonyl diimidazoie, 1-propanephosphonic acidcyciic anhyrdide, alkyi chioroformate, bis(2-oxo-3-oxazolidinyl)phosphinic chloride,benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate, or any other suchstandard literature reagents in the presence of an amine base if necessary, such astriethylamine, diisopropylethylamine, pyridine, or 2,6-lutidine, wherein 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride is preferred, from about -78 °C to 80°C, where 0° C to 40° C is preferred. Tetrahydrofuran and methylene chloride are preferredsolvents.

Conversion of a compound of the formula 8 thus formed wherein R5 is -NHC(=O)RB toa compound of formula 1D (R5 is NHC(=O)R8; R3 is C(=O)(CR1DR11)„R4) may be accompiishedby exposing a mixture of the compound of formula 8 and a noble métal catalyst, whereinpalladium is a preferred noble métal catalyst, wherein the métal may be convenientiysuspended on an inert soiid support such as charcoal, in a solvent such as ethyl acetate,tetrahydrofuran, dioxane, or a mixture thereof, to an atmosphère of hydrogen gas at apressure of about 1 to 100 atmosphères, where a preferred pressure of hydrogen gas is aboutone to about ten atmosphères. After the compound of formula 8 has been consumed, themixture is filtered and the resulting amine is acylated immediately by reaction with acidchloride, acid anhydride, or an activated carboxylic acid dérivative, in the presence of anamine base if appropriate, such as triethylamine, diisopropylethylamine, pyridine, or 2,6-

0J234S -24- lutidine, wherein 1-propanephosphonic acid cyclic anhyrdide and triethylamine are a preferredcombination, from about-78 °C to 40 °C, to afford the /V-acylated product of formuia 1D. Theactivated carboxylic acid dérivative is prepared from the carboxylic acid and a knownactivating reagent such as dicyclohexyl carbodiimide, 1 -(3-dimethyIaminopropyl)-3- 5 ethylcarbodiimide, carbonyi diimidazoie, 1-propanephosphonic acid cyciic anhyrdide, alkylchloroformate, bis(2-oxo-3-oxazolidinyl)phosphinic chioride, benzotriazol-1-yloxy-tris(dimethy!amino)phosphonium hexafluorophosphate, or any other such standard iiteraturereagent.

If an aryl chloroformate or heteroaryl chloroformate is used, in the above acylation 10 instead of an acid chioride, acid anhydride, or an activated carboxylic acid dérivative, an arylcarbamate 1E results. the resulting aryl carbamate 1E (R3 is C(=O)O- and R4 is aryl orheteroaryl) can be treated with an amine in a solvent such as dioxane, dimethylformamide, oracetonitrile, where a 1 : 1 mixture of dioxane - dimethylformamide is preferred, at atempérature between about 40 °C and 90 °C, where 70 °C is preferred, to afford the 15 corresponding urea product of formula 1F (R3 is -C(=O)NR9-, R4 is aryl or heteroaryl).

Ο 123 4 Q -25-

Scheme 2

0 -26- Αη alternative method of preparing compounds of formula ,1, wherein, R5 is -NHC(=O)RB, is shown in Scheme 3. Treating compound 4 where R5 is OH, with an alkyl- oraryl-sulfonyl chloride, p-toluenesulfonyl chloride (TosC!) being preferred, in a reaction inertsolvent such as tetrahydrofuran, methylene chloride or chloroform, where methylene chlorideis preferred, at a température from about -10° C to about 30° C, in the presence of an aminebase such as triethylamine, diisopropylethytamine, pyridine, or 2,6-lutidine, and 4-N,N-dimethyiaminopyridine. affords a compound of formula 5 wherein R5 is CH3(C6H4)SO3 (TosO).Triethylamine is the preferred amine base. Conversion of a compound of formula 5 (R5 isTosO) to a compound of formula 1G (R5 is TosO, R3 is C(=O)(CR10R’1)nR4) may beaccomplished by exposing a mixture of the compound of formula 5 (R5 is TosO) and a noblemétal catalyst, in a solvent such as ethyl acetate, tetrahydrofuran, dioxane, or a mixturethereof, to an atmosphère of hydrogen gas at a pressure of about 1 to 100 atmosphères,where a preferred pressure of hydrogen gas is about one to about ten atmosphères.Palladium is a preferred noble métal catalyst. The métal may be conveniently suspended onan inert solid support such as charcoal. After the compound 5 has been consumed, themixture is filtered and the resulting amine is reacted immediately with acid chloride, acidanhydride, or an activated carboxylic acid dérivative,- in the presence of an amine base ifappropriate, such as triethylamine, diisopropylethylamine, pyridine, or 2,6-lutidine, wherein 1-propanephosphonic acid cyclic anhyrdide and triethylamine are a preferred combination, fromabout -78 °C to 40 °C, to afford the A/-acylated product of formula 1G. The activatedcarboxylic acid dérivative is prepared from the carboxylic acid and a known activating reagentsuch as dicyclohexyl carbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, carbonyldiimidazole, 1-propanephosphonic acid cyclic anhyrdide, alkyl chloroformate, bis(2-oxo-3-oxazolidinyl)phosphinic chloride, benzotriazol-1 -yloxy-tris(dimethyiamino)phosphoniumhexafluorophosphate, or any other such standard literature reagents.

Treatment of the compound of formula 1G (R5 is TosO, R3 is -C(=O)(CR10R11)n- withan alkali métal sait of azide, wherein sodium azide is preferred, in a polar solvent such asdimethylformamide, dimethylsulfoxide, a lower alcohoi, water, or a mixture of these solvents,wherein an ethanol-water mixture is preferred, at a température from about 20° C to 130° C,where 90° C to 110° C are preferred, can be used to produce a compound of formula 1H,wherein R5 is N3. Subséquent réduction of azide of formula 1H (R5 is N3) may beaccomplished by exposing a mixture of the compound of formula 1H (Rs is N3) and a noblemétal catalyst, wherein palladium is a preferred noble métal catalyst, wherein the meta! maybe conveniently suspended on an inert solid support such as charcoal, in a solvent such as Ο 72345 -27- ethyl acetate, tetrahydrofuran, dioxane, or a mixture thereof, to an atmosphère of hydrogengas at a pressure of about 1 to 100 atmosphères, where a preferred pressure of hydrogen gasis about one to about ten atmosphères.

Alternatively, réduction of the azide of formula 1H (Rs is N3) can be by treatment with 5 a trialkyl- or triarylphosphine and waier, wherein triphenylphosphine is preferred, in a solventsuch as tetrahydrofuran, dioxane, or acetonitrile, where tetrahydrofuran is preferred. Theprimary amino group of the compound of formula 11 (R5 is NH2) can be derivatized via reactionwith a chloroformate, isocyanate, carbamoylyi chioride, acid chloride, acid anhydride, or anactivated carboxylic acid dérivative, wherein the activated carboxylic acid dérivative is 10 prepared from the carboxylic acid and a known activating reagent such as dicyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, carbonyl diimidazole, 1-propanephosphonic acid cyclic anhyrdide, alkyl chloroformate, bis(2-oxo-3-oxazolidinyl)phosphinic chloride, benzotriazol-1 -yioxy-tris(dimethylamino)phosphoniumhexafluorophosphate, or any other such standard literature reagents is in the présence of an 15 amine base if necessary, such as triethylamine, diisopropylethylamine, pyridine, or 2,6-lutidine, wherein 1-(3-dimethylaminopropyl)-3-ethy [carbodiimide hydrochloride is preferred,from about -78 °C to 80 °C, where 0° C to 40° C is preferred. Tetrahydrofuran and methylenechloride are preferred solvents.

Compounds of formula 1, wherein R3 is -(CR10R11)n- may be prepared according toScheme 4. Referring to Scheme 4, treatment of a solution of 4-bromoimidazole with a base, θί2345 -29- such as sodium hydride, potassium hydride, lithium hydride, césium carbonate, sodiumhydroxide, potassium hydroxide, césium hydroxide, lithium diisopropyl amide, sodium amide,potassium hexamethyldisilazide, sodium hexamethyldisilazide, sodium feri-butoxide, orpotassium fert-butoxide, in a reaction inert solvent such as tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, dimethylsulfoxide, or toluene, from about -20 °C to 150 °C, where 20 °Cto 100 °C is preferred, in the absence or presence of a phase transfer catalyst, such as tetra-n-butylammonium chloride, fefra-n-butylammonium bromide, fefra-n-butylammonium iodide,_benzyltrimethyl ammonium chloride, benzyltrimethy! ammonium bromide, or benzyltrimethylammonium fluoride.-foliowed by the addition of an alkyl, allylic, or benzylic chloride, bromide,iodide, alkyl sulfonate, aryl sulfonate, or triflate, affords a mixture of 1-substituted-4-bromoimidazole (9) and 1-substituted-5-bromoimidazo!e (10), which can be separated usingmethods known to one skilled in the art.

Alternatively, treatment of 4-bromoimidazole with an allylic fluoride, chloride, bromide,iodide, acetate, or carbonate, where the allylic carbonate is preferred, in a reaction inertsolvent, such as tetrahydrofuran, 1,2-dichloroethane, 1,4-dioxane, dimethylsulfoxide, or N,N-dimethylformamide, where tetrahydrofuran is preferred, in the presence of a palladiumcatalyst, such as palladium (0) tetrakis(triphenylphosphine), palladium (II) acetate, aliylpalladium chloride dimer, tris(dibenzylideneacetone)dipalladium (0),tris(dibenzylideneacetone)dipailadium (0) chloroform adduct, palladium (li) chloride, wherepalladium tetrakis(triphenylphosine) or palladium (II) acetate are preferred, in the presence orabsence of a phosphine ligand, such as triphenylphosine, tri-o-tolylphosphine, tri-ferf-butylphosphine, 1,2-bis(diphenylphosphino)ethane, or 1,3-bis(diphenylphosphino)propane,from about 0 °C to 100 °C, where 50 DC to 80 °C is preferred, provides a mixture of 1-substituted-4-bromoimidazole (9) and 1-substituted-5-bromoimidazole (10).

Treatment of 1-substituted-4~bromoimidazole (9) with an intermediate of the formula-NH2(CR10R11)nR4 and a palladium catalyst such as palladium (il) acetate, aliyl palladiumchloride dimer, tris(dibenzyiideneacetone)dipalladium (0), tris(dibenzylideneacetone)dipaliadium (0) chioroform adduct, or palladium (II) chloride, wherepalladium (l!) acetate, tris(dibenzyiideneacetone)dipalladium (0), andtris(dibenzylideneacetone)dipa!ladium (0) chioroform adduct are preferred, and a phosphineligand, such as BINAP, 2-biphenyl dicyciohexylphosphine, 2-biphenyl di-ferf-butyiphosphine,or 2-N,N-dimethylamino-2’-diphenyiphosphino biphenyl, where 2-A/,/V-dirnethylarnino-2’~diphenylphosphino biphenyl is preferred, and a base, such as sodium fe/ï-butoxide, césiumcarbonate, or potassium phosphate (K3PO4), where potassium phosphate is preferred, in areaction inert solvent, such as toluene, 1,4-dioxane, or tetrahydrofuran, from about 0 °C to 150°C, where 20 °C to 110 °C is preferred, affords the coupled product 1. ο » ~t »

An alternative method for synthesizing compounds of formula 1, wherein R3 is 5 -C(=O)(CR1°R11)n- is illustrated in Scheme 5, below. Treatment of ethyl-2-isocyano-3-/V,N- dimethylamino acrylate (11) with a primary amine, R’-NH2, in a solvent such as n-butanol, n-propanol, /-propanol, or éthanol, or in the absence of solvent, where either π-propanol or nosolvent are preferred, from about 23 °C to about 200°C, where from about 60°C to about150°C is preferred, affords imidazoles of formula 12. Treatment of N, O-dimethyl hydroxyl 10 amine hydrochloride with trimethylaluminum in 1,2-dichloroethane followed by the addition of12 and heating at about 30 °C to about 80 °C, where a température of about 50 °C ispreferred, affords imidazole 13. Addition of an organometallic reagent M-(CR10R11)nR4, whereM may be either lithium or magnésium halide, where magnésium halide is preferred, to asolution of 13 in a solvent such as tetrahydrofuran, methylene chloride, or diethyl ether, from a 15 température about -50 °C to about 30 °C, where a range of about -20 °C to about 0 °C ispreferred, affords 14. Addition of 14 to a mixture of hydroxyl amine hydrochloride andpotassium acetate in a lower alcohol solvent, where éthanol is preferred, at about 23 °C, θ 7 2345 -31- yields oxime 15 as a mixture of isomers. Treatment of an acetone solution of oxime 15 atabout 0 °C with aqueous sodium hydroxide followed by paratoluenesuifony! chioride yields amixture of O-sulfonyl compounds following extractive workup. Dissolution of the crudemateriel in a non-polar solvent such as benzene, hexanes, or toiuene, where benzene is 5 preferred, and application to a column of alumina followed by elution with chloroform-methanol (about 10 : 1) after approximately five minutes provides a compound 1B and aregioisomer from the Beckmann rearrangement. 012345 -32-

Scheme 5

R,-nH II ^^^(οιϊ,λ,ιλ

IB

Compounds of formula 1J may also be prepared by the method illustrated in Scheme 5 6 below. A key starting matériel for this synthesis is the double-bond containing compound (a compound of formula X) substituted with the group ER5 and one to three groups selected fromR5 (X), where ER5 is defined as an electron-withdrawing group chosen from C(=O)R7,C(=O)OR7, C(=O)NR7RB, S(=O)2R7, S(=O)2NR7Rb, S(=O)2OR7, cyano, and heteroaryl.Additionally, compounds of formula X may be wherein ER5 is connected to one of the groups 10 R5 or directly to the carbon-carbon double bond to form a ring and thus includes compoundssuch as 2-cyclopentene-1-one and 2-cyclohexene-1-one. Alternative^, compounds offormula X where L is defined as Cl, Br, I, OC(=O)R7, or OS(=O)2R7 may be used as startingmaterials; examples of such compounds are 3-chloro-1-cyclopentanone, 3-acetoxy-1-cyclobutanone. Thus, referring to Scheme 6, treatment of a sait of 4 (5)-nitroimidazole, where 15 the sait is sodium, potassium, césium, 1,8-diazabicyclo [5.4.0]undec-7-ene (DBU) or tetraalkylammonium, where tetra n-butyiammonium and DBU are the preferred salts, withintermediates 16 or 17 in a solvent such as acetonitrile, methylene chloride, 1,2-dichloroethane, or chloroform, where acetonitrile is the preferred solvent, at a température 5 °^234 -33- from about -60 °C to about 50 °C, where -20 °C to 23 °C is the preferred range, affordsaddition products of formula 2A. Réduction of nitro compound 2A may be accompiished byexposing a mixture of 2A and a noble métal catalyst, wherein palladium is a preferred noblemétal catalyst, wherein the métal may be conveniently suspended on an inert soiid supportsuch as charcoal, in a solvent such as ethyl acetate, tetrahydrofuran, dioxane, or a mixturethereof, to an atmosphère of hydrogen gas at a pressure of about 1 to 100 atmosphères,where a preferred pressure of hydrogen gas is about one to about ten atmosphères. After 2A -has been consumed, the mixture is fiitered and the resulting amine is reacted immediatelywith an acid chloride C!C(=O)(CR10R11)nR4, acid anhydride (R4(CR10R11)nC(=O))2O, or anactivated carboxylic acid dérivative XC(=O)(CR1DR11)nR4, in the presence of a base, such astriethyîamine, diisopropylethylamine, pyridine, or 2,6-iutidine, wherein , 1-propanephosphonicacid cyciic anhyrdide and triethyiamine are a preferred combination, from about -78 °C toabout 40 °C, to afford IJ. The activated carboxylic acid dérivative is prepared from thecarboxylic acid HOC(=O)(CR10R11)nR4 and known activating reagents such as dicyclohexyicarbodiimide, 1-(3-dimethyiaminopropyl)-3-ethylcarbodiimide hydrochloride, carbonyidiimidazole, 1-propanephosphonic acid cyciic anhyrdide, alkyl or aryl chioroformate, bis(2-oxo-3-oxazolidinyl)phosphinic chloride, benzotriazo!-1-yloxy-tris(dimethy!amino)phosphoniumhexafiuorophosphate, or any other such standard literature reagents.

Alternatively, foliowing filtration, the intermediate amine can be treated with a base,such as triethyiamine, diisopropylethyiamine, pyridine, or 2,6-iutidine, and an alkyl- or aryi-chioroformate, where diisopropylethylamine and phenyl chioroformate are a preferredcombination, from about -78 °C to about 40 °C, where about -78 °C to about -40 °C areDreferred, to afford 1K.

Subséquent treatment of 1K with a primary or secondary amine in a solvent such asdioxane, dimethylformamide, or acetonitriie, where a 1 : 1 mixture of dioxane -dimethyiformamide is preferred, at a température between about 40 °C and about 90 °C,where about 70 °C is preferred, affords the corresponding urea product 1L.

Subséquent transformations of compounds 2A, U, 1K, and 1L using methods knownto one skiiled in the art may be carried out to provide further compounds of formuia 1 that aredescribed in this application.

Compounds of formuia 1 as described herein, wherein R2 is other than hydrogen canbe prepared by transformations of the compounds of formuia 1 described herein wherein R2 ishydrogen using methods that are weli known in the art. For example, compounds of formula 1wherein R2 is F can be prepared by treating compounds of formula 1 wherein R2 is hydrogen,for exampie compounds of formula 1A, IB, and IC rsferred to in Scheme 1, supra, with N-fluorobenzenesu'Tonimide in toluene, xyienes, or dioxane, from about room température ιοabout 150°C, preferably from about 100°C to about 120cC. -34-' 012345

Schisme 6

Pharmaceutically acceptable salts of a compound of formula 1 can be prepared in aconventional manner by treating a solution or suspension of the corresponding free base oracid with One Chemical équivalent of a pharmaceuticâlly acceptable acid or base.Conventional concentration or crystallization techniques can be employed to isoJate the salts.Illustrative of suitable acids are acetic, lactic, succinic, maleic, tartane, citric, giuconic,ascorbic, bôn2oic, einnamic, fumaric, sulfurlc, phosphorlc, hydrochiorïc, hydrobromic,hydroiodic, sulfamic, sulfonic acids such as methanesulfonic, benzene sulfonic, p-toluenesuifonic, and related acids. Illustrative bases are sodium, potassium, and calcium. A compound of this invention may be administered alone or in combination withpharmaceutlcaily acceptable carriers, in either single or multiple doses. Suitable pharmaceulicalcarriers include inert solld diluants or fillera, aterile aqueous solutions and varlous organicsolvents. The pharmaceutical compositions formed by combining a compound of formula 1 or apharmaceutically acceptable sait thereof can then be readily administered in a variety of dosageforms such as tablets, powders, lozenges, syrups, injectable solutions and the like. Thesepharmaceutical compositions can, if deslred, contaln additional ingrédients such as fiavorings.binders, excipients and the like. Thus, for purposes of oral administration, tablets containïngvarious excipients such as sodium citrate, calcium carbonate and calcium phosphate may beemployed along with various disintegrants such as starch, methylceilulose, alginic acid andcertain complex silicates, together with binding agents such as polyvinylpyrrolidone, sucrose,gelatin and acacia. Addiiionally, lubricoting agents such as magnésium stéarate, sodium laurylsulfate and talc are often usefu! for tabletüng purposes. Solid compositions of a similar type mayalso be employed as fillers in soft and hard filled gelatin capsules. Preferred matériels for this ' 1 '|l> I · · 012345 -3f include lactose or milk sugar and high molecular weight polyethylene glycols. When aqueoussuspensions or élixirs are desired for oral administration, the essential active ingrédient thereinmay be combined with various sweetening or flavoring agents, coloring matter or dyes and, ifdesired, emulsifying or suspending agents, together with diluents such as water, éthanol,propylene glycol, glycerin and combinations thereof.

For parenterat administration, solutions containing a compound of this invention or apharmaceutically acceptable sait thereof in sesame or peanut oil, aqueous propylene glycol, or.in stérile aqueous solution may be employed. Such aqueous solutions should be suitably.buffereti if necessary..and the liquid diluent First rendered isotonie with sufficient saline orglucose. These particular aqueous solutions are especially suitable for intravenous,intramuscular, subeutaneous and intraperitoneal administration. The stérile aqueous mediaemployed are ail readily available by standard techniques known to those skilled in the art. A compound of formula 1 or a pharmaceutically acceptable sait thereof can beadministered orally, transdermally (e.g., through the use of a patch), parenterally (e.g.intravenously), rectally, or topically. In general, the daily dosage for treating aneurodegenerative disease or condition or the disease or condition the treatment of which canbe effected or facilitated by altering dopamine mediated neurotransmissîon will generally rangefrom about 0.0001 to about 10.0 mg/kg body weight of the patient to be treated. The dailydosage for treating cancer or disease or condition învolving abnormal cell growth of a benignnature will also generally range from about 0.0001 to about 500 mg/kg body weight of the patientto be treated. As an example, a compound of the formula 1 or a pharmaceutically acceptablesait thereof can be administered for treatment of a neurodegenerative disorder to an adulthuman of average weight (about 70kg) in a dose ranging from about 0.01 mg up to about1000 mg per day, preferably from about 0.1 to about 500 mg per day, in single or divided (i.e.,multiple) portions. The daily dosage for treating diabètes, sperm motility, hair loss, or anyother disease or condition that can be treated by inhibiting GSK-3 will generally range fromabout 0.0001 to about 10.0 mg/kg body weight of the patient to be treated. Variations basedon the aforementioned dosage ranges may be made by a physicien of ordinary skill taking intoaccount known considérations such as the weight, âge, and condition of the person beingtreated, the severity of the affliction, and the particular route of administration chosen.

The compounds of formula 1 and their pharmaceutically acceptable salts canfurthermore also be administered or formulated into a pharmaceutical composition with anamount of one or more substances selected from anti-angiogenesis agents, signaltransduction inhibitors, and antiproliférative agents, which amounts are together effective ininhibiting abnormal cell growth. 01234$

Anti-angiogenesis agents, such as MMP-2 (matrix-metalloproteinase 2) inhibitors,MMP-9 (matrix-metalloproteinase 9) inhibitors, and COX-II (cyclooxygenase II) inhibitors, canbe used in conjunction with a compound of formula 1 in the methods and pharmaceuticalcompositions described herein for treatment of abnormal cell growth, including cancer.Examples of useful COX-II inhibitors include CELEBREX™ (celecoxib), valdecoxib, androfecoxib. Examples of useful matrix metalloproteinase inhibitors are described in WO96/33172 (published October 24, 1996), WO 96/27583 (published March 7, 1996), EuropeanPatent Application No. 97304971.1 (filed July 8, 1997), European Patent Application No.99308617.2 (filed October 29, 1999), WO 98/07697 (published February 26, 1998), WO98/03516 (published January 29, 1998), WO 98/34918 (published August 13, 1998), WO98/34915 (published August 13, 1998), WO 98/33768 (published August 6, 1998), WO 98/30566(published July 16, 1998), European Patent Publication 606,046 (published July 13, 1994),European Patent Publication 931,788 (published July 28, 1999), WO 90/05719 (published May331, 1990), WO 99/52910 (published October 21, 1999), WO 99/52889 (published October21,1999), WO 99/29667 (published June 17, 1999), PCT International Application No.PCT/IB98/01113 (filed July 21,1998), European Patent Application No. 99302232.1 (filed March25,1999), Great Britain patent application number 9912961.1 (filed June 3,1999), United StatesProvisional Application No. 60/148,464 (filed August 12, 1999), United States Patent 5,863,949(issued January 26, 1999), United States Patent 5,861,510 (issued January 19, 1999), andEuropean Patent Publication 780,386 (published June 25, 1997), ail of which are incorporatedherein in their entireties by reference. Preferred MMP-2 and MMP-9 inhibitors are those thathâve little or no activity inhibiting MMP-1. More preferred, are those that selectively inhibit MMP-2 and/or MMP-9 relative to the other matrix-metalloproteinases (i.e. MMP-1, MMP-3, MMP-4,MMP-5, MMP-6, MMP-7, MMP-8, MMP-10, MMP-11, MMP-12, and MMP-13).

Some spécifie examples of MMP inhibitors useful in the présent invention are AG-3340,RO 32-3555, RS 13-0830, and the compounds recited in the following list: 3-[[4-(4-fluoro-phenoxy)-benzenesulfonyl]-(1-hydroxycarbamoyl-cyclopentyl)-amino]-propionic acid; 3- exo-3-[4-(4-fluoro-phenoxy)-benzenesulfonylamino]-8-oxa-bicyclo[3.2.1]octane-3-carboxylic acid hydroxyamide; (2R, 3R) 1-[4-(2-chloro-4-fluoro-benzyloxy)-benzenesulfonyl]-3-hydroxy-3-methyl-piperidine-2-carboxylic acid hydroxyamide; 4- [4-(4-fluoro-phenoxy)-benzenesulfonylamino]-tetrahydro-pyran-4-carboxylicacid hydroxyamide; 3-[[4-(4-fiuoro-phenoxy)-benzenesulfonyl]-(1-hydroxycarbamoyl-cyclobutyl)- aminoj-propionic acid; 01234s -37- 4-[4-(4-chloro-phenoxy)-benzenesulfonylamino]-tetrahydro-pyran-4-carboxylicacid hydroxyamide; (R) 3-[4-(4-chloro-phenoxy)-benzenesulfonylamino]-tetrahydro-pyran-3-carboxylicacid hydroxyamide; (2R, 3R) 1-[4-(4-fluoro-2-methyl-benzyloxy)-benzenesulfonyl]-3-hydroxy-3- methyl-piperidine-2-carboxylic acid hydroxyamide; 3-[[4-(4.fluoro-phenoxy)-benzenesulionyl]-(1-hydroxycarbamoyl-1-methyl-ethyl)- ·amino]-propionic acid; 3-[[4-(4-fluoro-phenoxy)-benzenesulfonyl]-(4-hydroxycarbamoyl-tetrahydro-pyran-4-y!)-amino]-propionic acid; 3-exo-3-[4-(4-chloro-phenoxy)-benzenesulfonylamino]-8-oxa-bicyclo[3.2.1]octane-3-carboxylic acid hydroxyamide; 3-endo-3-(4-(4-fluoro-phenoxy)-benzenesulfonyIamino]-8-oxa-bicyclo[3.2.1]octane-3-carboxylic acid hydroxyamide; and (R) 3-[4-(4-fluoro-phenoxy)-benzenesulfonylamino]-tetrahydro-furan-3-carboxylicacid hydroxyamide; and pharmaceutically acceptable salts and solvatés of said compounds.

Other anti-angiogenesis agents, inciuding other COX-II inhibitors and other MMPinhibitors, can also be used in the présent invention.

The effective amount of a COX-ll inhibïtor in combination with a cdk5 inhibitor, forexample a compound of formula 1, can generally be determined by a person of ordinary skiil. Aproposed daiiy effective dose range for a COX-ll inhibitor in combination with a cdk5 inhibitor isfrom about 0.1 to about 25 mg/kg body weight. The effective daiiy amount of the cdk5 inhibitorgenerally will be between about 0.0001 to about 10 mg/kg body weight. In some instances theamount of COX-ll inhibitor and/or cdk5 inhibitor in the combination may be less than would berequired on an individual basis to achieve the same desired effect in inhibiting abnormal cellgrowth. A compound of formula 1 can aiso be used with signal transduction inhibitors, such asagents that can inhibit EGFR (epidermal growth factor receptor) responses, such as EGFRantibodies, EGF antibodies, and molécules that are EGFR inhibitors; VEGF (vascuiarendothélial growth factor) inhibitors; and erbB2 receptor inhibitors, such as organic moléculesor antibodies that bind to the erbB2 receptor, for example, HERCEPTIN™ (Genentech, Inc. ofSouth San Francisco, California, USA). Such combinations are useful for treating andpreventing abnormal cell growth, inciuding cancer, as described herein. EGFR inhibitors are described in, for example in WO 95/19970 (published July 27, 1995), WO 98/14451 (published April 9,1998), WO 98/02434 (published January 22, 1998), and 012345 -30-

United States Patent 5,747,498 (issued May 5, 1998), and such substances can be used in theprésent invention as described herein. EGFR-inhibiting agents include, but are not iimited to, themonoclonal antibodies C225 and anti-EGFR 22Mab (ImCIone Systems Incorporated of NewYork, New York, USA), the compounds ZD-1839 (AstraZeneca), BiBX-1382 (BoehringerIngelheim), MDX-447 (Medarex Inc. of Annandaie, New Jersey, USA), and OLX-103 (Merck &amp;Co. of Whitehouse Station, New Jersey, USA), VRCTC-310 (Ventech Research) and EGFfusion toxin (Seragen Inc. of Hopkinton, Massachusettes). These and other EGFR-inhibitingagents can be used in the présent invention. VEGF inhibitors, for example SU-5416 and SU-6668 (Sugen Inc. of South SanFrancisco, California, USA), can also be combined with a compound of formula 1. VEGFinhibitors are described in, for example in WO 99/24440 (published May 20, 1999), PCTInternational Application PCT/IB99/00797 (fiied May 3, 1999), in WO 95/21613 (publishedAugust 17,1995), WO 99/61422 (published December 2, 1999), United States Patent 5,834,504(issued November 10, 1998), WO 98/50356 (published November 12, 1998), United StatesPatent 5,883,113 (issued March 16, 1999), United States Patent 5,886,020 (issued March 23,1999), United States Patent 5,792,783 (issued August 11, 1998), WO 99/10349 (publishedMarch 4, 1999), WO 97/32856 (published September 12, 1997), WO 97/22596 (published June26, 1997), WO 98/54093 (published December 3, 1998), WO 98/02438 (published January 22, 1998) , WO 99/16755 (published April 8,1999), and WOO8/02437 (published January 22,1998),ail of which are incorporated herein in their entireties by référencé. Other examples of somespécifie VEGF inhibitors useful in the présent invention are IM862 (Cytran Inc. of Kirkland,Washington, USA); anti-VEGF monoclonal antibody of Genentech, inc. of South SanFrancisco, California; and angiozyme, a synthetic ribozyme ' from Ribozyme (Boulder,Colorado) and Chiron (Emeryviile, California). These and other VEGF inhibitors can be usedin the présent invention as described herein.

ErbB2 receptor inhibitors, such as GW-282974 (Glaxo Wellcome pic), and themonoclonai antibodies AR-209 (Aronex Pharmaceuticals inc. of The Woodiands, Texas, USA)and 2B-1 (Chiron), can also be combined with a compound of formula 1, for example thoseindicated in WO 98/02434 (published January 22, 1998), WO 99/35146 (published July 15, 1999) , WO 99/35132 (published July 15, 1999), WO 98/02437 (published January 22, 1998),WO 97/13760 (published April 17, 1997), WO 95/19970 (published July 27, 1995), United StatesPatent 5,587,458 (issued December 24, 1996), and United States Patent 5,877,305 (issuedMarch 2,1999), which are ail hereby incorporated herein in their entireties by reference. ErbB2receptor inhibitors useful in the présent invention are also described in United States ProvisionalApplication No. 60/117,341, fiied January 27,1999, and in United States Provisional ApplicationNo. 60/117,346, fiied January 27, 1999, both of which are incorporated in their entireties herein ° 72345 -7k by reference. The erbB2 receptor inhibitor compounds and substance described in theaforementioned PCT applications, U.S. patents, and U.S, provisionai applications, as well asother compounds and substances that inhibit the erbB2 receptor, can be used with a compoundof formula 1, in accordance with the présent invention. A compound of formula 1, can also be used with other agents useful in treatingabnormal cell growth or cancer, including, but not limited to, agents capable of enhancingantitumor immune responses, such as CTLA4 (cytotoxic lymphocite antigen 4) antibodies, and'other agents capable of blocking CTLA4; and anti-proliferative agents such as farnesyl proteintransferase inhibitors. Spécifie CTLA4 antibodies that can be used in the présent inventioninclude those described in United States Provisionai Application 60/113,647 (filed December23, 1998) which is incorporated by reference in its entirety, however other CTLA4 antibodiescan be used in the présent invention.

The compounds of formula 1 can also be administered in a method for inhibitingabnormal cell growth in a mammal in combination with radiation therapy. Techniques foradministering radiation therapy are known in the art, and these techniques can be used in thecombination therapy described herein. The administration of the compound of the invention inthis combination therapy can be.determined as described herein.

Cdk5 inhibitors, such as compounds of formula 1, can also be administered incombination with a COX-II inhibitor for treating JMzheimer’s disease, miid cognitiveimpairment, or age-related cognitive décliné. Spécifie examples of COX-II inhibitors useful inthis aspect of the invention are provided above, wherein use of a COX-II inhibitor incombination with a compound of formula 1 for treatment of abnormal cell growth is described.The effective amount of a COX-II inhibitor in combination with a cdk5 inhibitor, for example acompound of formula 1, can generally be determined by a person of ordinary skill. A proposedeffective daily dose range for a COX-II inhibitor in combination with a cdk5 inhibitor is from about0.1 to about 25 mg/kg body weight. The daily effective amount of the cdk5 inhibitor generally willbe between about 0.0001 to about 10 mg/kg body weight. In some instances the amount ofCOX-II inhibitor and/or the amount of çdk5 inhibitor in the combination may be less than wouldbe required on an individual basis to achieve frie same desired effect in treating Alzheimer’sdisease, miid cognitive impairment, or age-related cognitive décliné.

Cdk5 inhibitors, such as compounds of formula 1, can also be administered incombination with an NK-1 receptor antagonist for treatment of dépréssion or anxiety. An NK-1 receptor antagonist, as recited herein, is a substance that is able to antagonize NK-1receptors, thereby inhibiting tachykinin-mediated responses, such as responses mediated bysubstance P. Various NK-1 receptor antagoniste are known in the art, and any such NK-1receptor antagonist can be utilized in the présent invention as described above in combination 012345 -40- with a cdk5 inhibitor, for example a compound of formula 1. NK-1 receptor antagonists aredescribed in, for example, United States Patent 5,716,965 (issued February 10,1998); UnitedStates Patent 5,852,038 (issued December 22,1998); WO 90/05729 (International PublicationDate May 31, 1990); United States Patent 5,807,867 (issued September 15, 1998); UnitedStates Patent 5,886,009 (issued March 23, 1999); United States Patent 5,939,433 (issuedAugust 17, 1999); United States Patent 5,773,450 (issued June 30, 1998); United StatesPatent 5,744,480 (issued April 28, 1998); United States Patent 5,232,929 (issued August 3, 1993) ; United Stated Patent 5,332,817 (issued July 26, 1994); United States Patent 5,122,525(issued June 16, .1992),-United States Patent 5,843,966 (issued December 1, 1998); UnitedStates Patent 5,703,240 (issued December 30, 1997); United States Patent 5,719,147 (issuedFebruary 17, 1998); and United States Patent 5,637,699 (issued June 10, 1997). Each of theforegoing U.S. patents and the foregoing published PCT International Application areincorporated in their entireties herein by reference. The compounds described in saidréférencés having NK-1 receptor antagonizing activity can be used in the présent invention.However, other NK-1 receptor antagonists can also be used in this invention.

The effective amount of an NK-1 receptor antagonist in combination with a cdk5inhibitor, for example a compound of formula 1, can generally be determined by a person ofordinary skill. A proposed effective daily dose range for an NK-1 receptor antagonist incombination with a cdk5 inhibitor is from about 0.07 „to about 21 mg/kg body weight. Theeffective amount of the cdk5 inhibitor generally will be between about 0.0001 to about 10 mg/kgbody weight. In some instances the amount of NK-1 receptor antagonist and/or the amount ofcdk5 inhibitor in the combination may be less than would be required on an individual basis toachieve the same desired effect in treating dépréssion or anxiety.

The subject invention also provides combining a cdk5 inhibitor, such as a compoundof formula 1, with a 5HT10 receptor antagonist for treatment of dépression or anxiety. A 5HT1Dreceptor antagonist, as recited herein, is a substance that antagonizes the 5HT10 subtype ofserotonin receptor. Any such substance can be used in the présent invention as describedabove in combination with a cdk5 inhibitor, for example a compound of formula 1. Substanceshaving 5HT1D receptor antagonizing activity can be determined by those of ordinary skill in theart. For exampie, 5HT,D receptor antagonists are described in WO 98/14433 (InternationalPublication Date April 9, 1998); WO 97/36867 (International Publication Date October 9,1997); WO 94/21619 (International Publication Date September 29, 1994); United StatesPatent 5,510,350 (issued April 23, 1996); United States Patent 5,358,948 (issued October 25, 1994) ; and GB 2276162 A (published September 21, 1994). These 5HT10 receptorantagonists, as well as others, can be used in the présent invention. The aforementionedpublished patent applications and patents are incorporated herein by reference in their entireties.

The effective amount of a 5HT1D receptor antagonist in combination with a cdk5inhibitor, for example a compound of formula 1, can generally be determined by a person ofordinary skill. A proposed effective daily dose range for a 5HT1D receptor antagonist incombination with a cdk5 inhibitor is from about 0.01 to about 40 mg/kg body weight. Theeffective daily amount of the cdk5 inhibitor generally will be between about 0.0001 to about 10mg/kg body weight. In some instances the amount of 5HT10 receptor antagonist and/or theamount of cdk5 inhibitor in the combination may be less than would be required on an individualbasis to achieve the same desired effect in treating dépréssion or anxiety.

This invention also provides a pharmaceutical composition and method for treatingdépréssion or anxiety in a mammal comprising a cdk5 inhibitor, for example a compound offormula 1, and a SSRI. Examples of SSRIs that can be combined in a method orpharmaceutical composition with cdk5 inhibitors, for example compounds of formula 1 andtheir pharmaceutically acceptable salts include, but are not limited to, fluoxetine, paroxetine,sertraline, and fluvoxamine. Other SSRIs may be combined or administered in combinationwith a cdk5 inhibitor, for example a compound of formula 1 or a pharmaceutically acceptablesait thereof. Other antidepressants and/or anxiolytic agents with which a cdk5 inhibitor suchas a compound of formula 1 may be combined or administered include WELLBUTRIN,SERZONE and EFFEXOR.

The effective amount of a SSRI in combination with a cdk5 inhibitor, for exampie acompound of formula 1, can generally be determined by a person of ordinary skill. A proposedeffective daily dose range for a SSRI in combination with a cdk5 inhibitor is from about 0.01 toabout 500 mg/kg body weight. The effective daily amount of the cdk5 inhibitor generally will bebetween about 0.0001 to about 10 mg/kg body weight. In some instances the amount of SSRIand/or the amount of cdk5 inhibitor in the combination may be less than would be required on anindividual basis to achieve the same desired effect in treating dépréssion or anxiety. A cdk5 inhibitor, for example a compound of formula 1, or a pharmaceuticallyacceptable sait thereof, can also be combined with one or more antipsychotic agents, forexample a dopaminergic agent, for the treatment of diseases or conditions the treatment ofwhich can be effected or facilitated by altering dopamine neurotransmission, such asschizophrenia. Examples of antipsychotics with which a compound of the invention can becombined include ziprasidone (5-(2-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)ethyl)-6-chloro- 1,3-dihydro-2H-indol-2-one; U.S. Patent 4,831,031 and U.S. Patent 5,312,925); olanzapine (2-methyl-4-(4-methyi-1-piperazinyl-10H-thieno (2,3b) (1,5)benzodiazepine; U.S Patent 4,115,574 and U.S. Patent 5,229,382); rispéridone (3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1- piperidinyl]ethyl]6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one; U .S. Patent θ 12345 -4J2- 4,804,663); L-745870 (3-(4-(4-chlorophenyl)piperazin-1-yl)methyl-1H-pyrrolo(2,3-b)pyridine;U.S. Patent 5,432,177); sonepiprazole (S-4-(4-(2-(isochroman-1-yl)ethyl)piperazin-1-yl)benzenesulfonamide; U.S. Patent 5,877,317); RP 62203 (fananserin; 2-(3-(4-(4-fluorophenyl)-1-piperazinyl)propyl)naphtho(1,8-c,d)isothiazole-1,1-diox(de; U.S. Patent5,021,420); NGD 941 (U.S. Patent 5,633,376 and U.S. Patent 5,428,165); balaperidone((1a,5a,6a)-3-(2-(6-(4-fluorophenyl)-3-azabicyc!o(3.2.0)hept-3-yl)ethyl)-2,4(1H,3H)-quinazolinedione; U.S. Patent 5,475,105); flesinoxan ((+)-4-fluoro-N-[2-[4-5-(2-hydroxymethyl- 1,4-benzodioxanyl)]-1-piperazinyl]ethyl]benzamide; U.S. Patent 4,833,142); and gepirone(4l4-dimethyl-1-(4-(4-(2-pyrimidinyl)-1-piperazinyl)butyl)-2,6-piperidinedïone; U.S. Patent4,423,049). The patents recited above in this paragraph are each incorporated herein byréférencé in their entireties. The effective daily amount of the cdk5 inhibitor generally will bebetween about 0.0001 to about 10 mg/kg body weight. The amount of any of theaforementioned antipsychotic agents contemplated for use in combination with a cdk5inhibitor, for example a compound of formula 1, is generally the amount known in the art to beuseful for treating psychotic conditions. However, in some instances, the amount of theantipsychotic and/or the amount of cdk5 inhibitor in the combination may be less than would berequired on an individual basis to achieve the same desired effect in treating dépression oranxiety. It is furthermore to be understood that the présent invention also encompassescombining a cdk5 inhibitor, for example a compound of formula 1 with antipsychotic ordopaminergic other than those in the aforementioned list. A proposed amount for sonepiprazole in the above-described combination with a cdk5inhibitor, for example a compound of formula 1, is from about 0.005 to about 50 mg/kg bodyweight of the patient per day. A proposed amount of RP 62203 in such combination is fromabout 0.20 to about 6 mg/kg body weight of the patient per day. A proposed amount of NGD 941in such combination is from about 0.1 to about 140 mg/kg of body weight per day. A proposedamount of balaperidone in such combination is from about 1 to about 100 mg/kg body weight perday. A proposed amount of flesinoxan in such combination is from about 0.02 to about 1.6mg/kg body weight per day. A proposed amount for gepirone in such combination is from about.01 to about 2 mg/kg body weight per day. A proposed amount of L-745870 in such combinationis from about 0.01 to about 250 mg/kg body weight per day, preferably from about 0.05 to about100 mg/kg body weight per day. A proposed amount of rispéridone in such combination is fromabout 0.05 to about 50 mg/kg body weight per day. A proposed amount of olanzapine in suchcombination is from about 0.0005 to about 0.6 mg/kg body weight per day. A proposed amountof ziprasidone in such combination is from about 0.05 to about 10 mg/kg body weight per day. Insome instances for each of the aforementioned combinations, however, the amount of each WO 02/10141 θ 23 4q -4J- l’CT/IBOl /01335 spécifie ingrédient in the combination may be less tlian would be required on an individual basisto achieve the same desired effect in treating a psychotic condition.

This invention also provides a pharmaceutical composition and method for treatingAlzheimer’s disease, mild cognitive impairment, or age-related cognitive décliné comprising a 5 cdk5 inhibitor, for example a compound of formula 1, and an acetylcholinesterase inhibitor.Acetylcholinesterase inhibitors are known in the art, and any such acetylcholinesteraseinhibitor can be used in the above-described pharmaceutical composition or method.·Examples of acetylcholinesterase inhibitors that can be used in this invention are ARICEPT(donepezil; U.S. - Patent 4,895,841); EXELON (rivastigmine ((SHN-ethyl-3-[1- 10 (dimethylamino)ethyljphenyl carbamate); U.S. Patent 5,603,176 and U.S. Patent 4,948,807);metrifonate ((2,2,2-trichloro-1-hydroxyethyl)phosphonic acid dimethyl ester; U.S. Patent2,701,225 and U.S. Patent 4,950,658); galantamine (U.S. Patent 4,663,318); physostigmine(Forest, USA); tacrine (1,2,3,4-tetrahydro-9-acridinamine; U.S. Patent 4,816,456); huperzine A(5R-(5a,9p,11E))-5-amino-11-ethylidene-5,6,9,10-tetrahydro-7-methyl-5,9- 15 methaneocycloocta(b)pyridin-2-(1H)-one); and icopezil (5,7-dihydro-3-(2-(1-(phenylmethy!)-4-piperidinyl)ethyl)-6H-pyrrolo(3,2-f)-1,2-benzisoxazol-6-one; U.S. Patent 5,750,542 and WO92/17475). The patents and patent applications recited above in this paragraph are hereinincorporated by reference in their entireties.

The effective amount of an acetylcholinesterase inhibitor in combination with a cdk5 20 inhibitor, for example a compound of formula 1, can generally be determined by a person ofordinary skill. A proposed effective daily dose range for an acetylcholinesterase inhibitor incombination with a cdk5 inhibitor is from about 0.01 to about 10 mg/kg body weight Theeffective daily amount of the cdk5 inhibitor generally will be between about 0.0001 to about 10mg/kg body weight. In some instances the amount of acetylcholinesterase inhibitor and/or the 25 amount of cdk5 inhibitor in the combination may be less than would be required on an individualbasis to achieve the same desired effect in treating Alzheimer’s disease, mild cognitiveimpairment, or age-related cognitive décliné.

The présent invention also provides for combining a cdk5 inhibitor withneuroprotectants, for exampie NMDA receptor antagoniste, for treatment of Huntington’s 30 disease, stroke, spinal cord trauma, traumatic brain injury, muitiinfarct dementia, epilepsy,amyotrophie latéral sclerosis, pain, viral induced dementia for example AIDS induceddementia, migraine, hypoglycémie, urinary incontinece, brain ischemia, multiple sclerosis,Alzheimer’s disease, senile dementia of the Alzheimer’s type, mild cognitive impairment, age-related cognitive décliné, emesis, corticobasal degeneration, dementia pugilistica, Down’s 35 syndrome, myotonie dystrophy, Niemann-Pick disease, Pick’s disease, prion disease with tangles, progessive supranuciear palsy, lower latéral sclerosis, or subacute sclerosing <”2345 panencephalistis. Examples of NMDA receptor antagoniste that can be used in the présentinvention include (1S,2S)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidin-1-yl)-1-propanol (U.S. Patent 5,272,160), eliprodil (U.S. Patent 4,690,931), and gavestenel (U.S.Patent 5,373,018). Other NMDA receptor antagonists, which can also be used in the présentinvention, are described in U.S. Patent 5,373,018; U.S. Patent 4,690,931; U.S. Patent5,272,160; U.S. Patent 5,185,343; U.S. Patent 5,356,905; U.S. Patent 5,744,483; WO97/23216; WO 97/23215; WO 97/23214; WO 96/37222; WO 96/06081; WO 97/23458; WO97/32581; WO 98/18793; WO 97/23202; and U.S. Serial No. 08/292,651 (filed August 18,1994). The aforementioned patents and patent applications are each hereby incorporated byreference in their entireties.

The effective daily amount of the cdk5 inhibitor in the combination with an NMDAreceptor antagonist generally will be between about 0.0001 to about 10 mg/kg body weight. Theamount of the NMDA receptor antagonist contemplated for use in combination with a cdk5inhibitor, for example a compound of formula 1, for treatment of any of the aforementioneddisorders, for example Alzheimer’s disease, is generally within the range of from about 0.02mg/kg/day to about 10 mg/kg/day. However, in some instances, the amount of the NMDAantagonist and/or the amount of cdk5 inhibitor in the combination may be less than would berequired on an individual basis to achieve the same desired effect in treating said disorders.

The subject invention also provides for combining a cdk5 inhibitor with certainsubstances capable of treating a stroke or traumatic brain injury, such as TPA, NIF, orpotassium channel modulators, for example BMS-204352. Such combinations are useful fortreating neurodegenerative disorders such as stroke, spinal cord trauma, traumatic braininjury, multiinfarct dementia, epilepsy, pain, Alzheimer’s disease, and senile dementia, forexample.

For the above-described combination thérapies and pharmaceutical compositions, theeffective amounts of the compound of the invention and of the other agent can generally bedetermined by those of ordinary skill in the art, based on the effective amounts for thecompounds described herein and those known or described for the other agent known in theart, for example the amounts described in the above-recited patents and patent applicationincorporated herein. The formulations and routes of administration for such thérapies andcompositions can be based on the information described herein for compositions andthérapies comprising a compound of the invention as the sole active agent and on informationprovided for the other agent in combination therewith. A spécifie compound of formula 1 can be determined to inhibit cdk2, cdk5, or GSK-3using biological assays known to those of ordinary skill in the art, for example the assaysdescribed below. 0)2345 -45-

The spécifie activity of a compound of formula 1 for inhibition of cdk5 or cdk2 can, forexample, be ascertained by means of the following assays using materials available to those ofordinary skill in the art:

Enzyme activities can be assayed as the incorporation of [33P] from the gammaphosphate of [33P]ATP (Amersham, cat. no. AH-9968) into biotinylated peptide substratePKTPKKAKKL. In such an assay, réactions are carried out in a buffer containing 50mM Tris-HCI, pH 8.0; 10mM MgCI2, 0.1 mM Na3VO4, and 1mM DTT. The final concentration of ATP is.about 0.5uM (final spécifie radioactivity of 4uCi/nmol), and the final concentration of substrate0.75uM. Reactions, initiated by the addition of either cdk5 and activator protein p25 or cdk2and activator cyclin E, may be carried out at room température for about 60 minutes.Reactions are stopped by addition of 0.6 volume of buffer containing (final concentrations):2.5mM EDTA, 0.05%Triton-X 100, 100uM ATP, and 1.25 mg/ml streptavidin coated SPAbeads (Amersham cat. no. RPNQ0007). Radioactivity associated with the beads is quantifiedby scintillation counting.

The spécifie activity of a compound of formula 1 for inhibition of GSK-3 can bedetermined in both cell-fee and cell-based assays, both of which are described in the art (see,for exampie, WO 99/65897). A cell-free assay can be carried out in general by incubatingGSK-3 with a peptide substrate, radiolabeled ATP (such as, for example, y33?- or γ32-Ρ-ΑΤΡ,both available from Amersham, Arlington Heights,· Illinois), magnésium ions, and thecompound to be assayed. The mixture is incubated for a period of time to allow incorporationof radiolabeld phosphate into the peptide substrate by GSK-3 activity. The reaction mixture iswashed to remove unreacted radiolabeled ATP, typically after first transferring ail or a portionof the enzyme reaction mixture to a well that contains a uniform amount of a ligand that iscapable of binding to,the peptide substrate. The amount of 33P or 32P remaining in each wellafter washing is then quantified to détermine the amount of radiolabeled phosphateincorporated into the peptide substrate. Inhibition is observed as a réduction, relative to acontrol, in the incorporation of radioiabeled phosphate into the peptide substrate. An exampieof a suitable GSK-3 peptide substrate for an assay is the SGSG-linked CREB peptidesequence, derived from the CREB DNA binding protein, described in Wang, et al., Anal.Biochem., 220:397-402 (1994). Purifîed GSK-3 for an assay may, for example, be obtainedfrom cells transfected with a human GSK-3P expression plasmid as described in, for exampieStambolic, et al., Current Biology 6:1664-68 (1996). WO 99/65897; Wang, et al., andStambolic, et al. are incorporated in their entireties herein by reference.

Another example of a GSK-3 assay, similar to the one described in the precedingparagraph is as follows: Enzyme activities are assayed as the incorporation of [33P] fromgamma phosphate of [33PJATP (Amersham, cat. No. AH-9968) into biotinylated peptide 012345 substrate PKTPKKAKKL. Reactions are carried out in a buffer containing 50mM Tris-HCI, pH8.0; 10mM MgClz, 0.1mM Na3VO4, and 1mM DTT. The final concentration of ATP is 0.5μΜ(final spécifie radioactivity of 4pCi/nmol), and the final concentration of substrate is 0.75μΜ.Reactions, initiated by the addition of enzyme, are carried out at room température for about60 minutes. Reactions are stopped by addition of 0.6 volume of buffer containing (finalconcentrations): 2.5mM EDTA, 0.05%Triton-X 100, 100μΜ ATP, and 1.25 mg/ml streptavidincoated SPA beads (Amersham cat. No. RPNQ0007). Radioactivity associated with the beadsis quantified by scintillation counting. AH of the title compounds of the foilowing Examples had an IC^ inhibiting peptidesubstrate phosphorylation of less than about 50 μΜ when assayed for cdk5 inhibition accordingto the preceding assay.

Several of the title compounds of the foilowing Examples were assayed for GSK-3inhibition using an assay such as that described above, and ali tested had an ICM for inhibition ofGSK-3p of less than about 50 μΜ .

The foilowing Examples illustrate the présent invention. It is to be understood, however,that the invention, as fully described herein and as recited in the daims, is not intended to beiimited by the details of the foilowing Exarriples.

EXAMPLES

Préparation 1 1 -Cyclobutyl-4-nitro-1 H-imidazole 1,4-Dinitroimidazole (237 mg, 1.5 mmol, J. Phys. Chem. 1995, 99, 5009-5015) wasadded to a solution of cydobutylamine (107 mg, 1.5 mmol) in methanol (10 mL) at 23 °C. Thereaction mixture was stirred for 16 h, then the solvent was removed in vacuo and the resultingresidue was purified by silica gel chromatography (1:1 hexanes-ethyl acetate) to afford 230mg (92% yield) of 1-cyclobutyl-4-nitro-1 H-imidazole; 1H NMR (400 MHz, CDCI3) δ 7.81 (s,1H), 7.45 (s, 1H), 4.64 (m, 1H), 2.6 (m, 2H), 2.4 (m, 2H), 2.0 (m, 2H); MS (AP/CI): 168.2(M+H)+. Note: 1,4-Dinitroimidazole is a highly energetic, semi-stable substance and shouldbe stored in a freezer at ail times it is not in use. Thermodynamic measurements hâve shownthat it can potentially generate enough energy at 35 °C under adiabatic conditions to violentlyexplode. Extrême caution should be exercised at ail times using this material.

Préparation 2 1-Cyciopentyl-4-nitro-1 H-imidazole

This réaction was carried out using the procedure for Préparation 1 with cyclopentylamine and 1,4-dinitroimidazole to afford 205 mg (75% yield) of 1-cyclopentyl-4-nitro-1H- 0)2345 -41- imidazole; 1H NMR (400 MHz, CDCI3) δ 7.77 (s, 1H), 7.45 (s, 1H), 4.49 (m, 1H), 2.25 (m, 2H),2.0-1.7 (m, 6H); MS (AP/CI): 182.2 (M+H)+.

Préparation 3 4-Nitro-1-(c/'s-3-phenyl-cyclobutyl)-1H-imidazole

This reaction was carried out using the procedure for Préparation 1 with c/s-3-phenylcyclobutylamine (J. Med. Pharm. Chem 1960, 2, 687-691; ACIEE 1981, 20, 879-880)and 1,4-dinitroimidazole to afford 46 mg (46% yield) of 4-nitro-1-(c/s-3-phenyl-cyclobutyl)-1H-imidazole; 1H NMR (300 MHz, CDCI3) δ 7.9 (s, 1H), 7.55 (s, 1H), 7.4-7.2 (m, 5H), 4.73 (m,1H), 3.48 (m, 1H), 3.12 (m, 2H), 2.54 (m, 2H); MS (AP/CI): 244 (M+H)\

Example 1 /V-(1-CyclobutyMH-imidazol-4-yl)-2-quinolin-6-yl-acetamide

To a Parr hydrogénation bottle was added 1-cyclobutyl-4-nitro-1H-imidazoie(Préparation 1, 150 mg, 0.9 mmol) and ethyl acetate (10 mL), followed by 10% Pd on carbon(250 mg). The reaction mixture was placed on a Parr hydrogénation apparatus and wasreacted for 6 h under 50 psi H2at 23 °C.The contents of the bottle were filtered through a shortpad of celite and were rinsed with dry methylene chloride (25 mL) into a flame-dried flaskunder nitrogen. Et3N (626 uL, 4.5 mmol) was added and the reaction solution was cooled to -10 °C. 6-Quinolylacetic acid (168 mg, 0.9 mmol) and tripropylphosphonic anhydride (530 uL,1.7 M solution in ethyl acetate) were then added and the mixture was stirred at -10 °C for 2 h.The solution was diluted with methylene chloride (50 mL) and washed with water (2x). Theaqueous layer was extracted with methylene chloride (3x) and the organic layers werecombined and washed with brine (1x). The solvent was removed in vacuo, the residue wasadsorbed onto silica gel and chromatographed using the Biotage Flash 12 System with SIMattachment (40:1 methylene chloride - methanol) to afford 130 mg (47% yield) of W-(1-cyclobutyl-1H-imidazol-4-yl)-2-quinolin-6-yl-acetamide (the title compound); 1H NMR (300MHz, CDCI3) δ 9.48 (s, 1H), 8.87 (dd, J = 1.6, 4.3 Hz, 1 H), 8.11 (m, 2H), 7.76 (d, J = 1.8 Hz,1H), 7.67 (dd, J = 2.0, 8.7 Hz, 1H), 7.44 (d, J = 1.6 Hz, 1H), 7.38 (m, 1H), 7.25 (d, J = 1.6 Hz,1H), 4.5 (m, 1H), 3.90 (s, 2H), 2.4 (m, 2H), 2.3 (m, 2H), 1.85 (m, 2H); MS (AP/CI): 307.1(M+H)+.

Example 2 /V-(1-Cyclopentyl-1H-imidazol-4-y|)-2-(4-methoxy-phenyl)-acetamide

The procedure for Example 1 was carried out with para-methoxy-phenylacetic acidand 1-cyclopentyl-4-nitro-1H-imidazole (Préparation 2) to préparé N-(1-cyclopentyl-1H-imidazol-4-yl)-2-(4-methoxy-phenyl)-acetamide in 32% yield (26.5 mg); 1H NMR (400 MHz,CDCI3) δ 8.54 (s, 1H), 7.35 (s, 1H), 7.24 (m, 2H), 6.87 (d, J = 1.7 Hz), 4.36 (m, 1H), 3.78 (s,3H), 3.64 (s, 2H), 2.1 (m, 2H), 1.8 (m, 4H), 1.6 (m, 2H); MS (AP/CI): 300.3 (M+H)+. 012345 -48-

Example 3 <V-[1 -(c/s-3-Phenyl-cyclobutyl)-1H-imidazol-4-yl]-2-quinolin-6-yl-acetamiàe

The procedure for Exampie 1 was carried out with 6-quinolylacetic acid and 4-nitro-1-(c/s-3-phenylcylobutyl)-1H-imidazoie (Préparation 3) to préparé /V-[1-(c/s-3-phenyl-cyclobutyl)-1H-imidazol-4-yl]-2-quinolin-6-yl-acetamide in 38% yield; 1H NMR (300 MHz, CDCI3) δ 8.93(m, 1H), 8.12 (m, 2H), 7.79 (d, J = 1.5 Hz, 1H), 7.71 (m, 1H), 7.55 (d, J = 1.5 Hz, 1H), 7.41(dd, J = 4.3, 8.4 Hz, 1H), 7.37-7.22 (m, 5H), 4.57 (m, 1H), 3.96 (s, 2H), 3.33 (m, 1H), 2.95 (m,2H), 2.49 (m, 2H); MS (AP/CI): 383.0 (M+H)+.

Example 4 (1-Cyclobutyl-1H-imidazol-4-yl)-carbamic acid phenyl ester A Parr hydrogénation bottle was charged with 1-cyclobutyl-4-nitro-1H-imidazole(Préparation 1,3g, 18 mmol) and ethyl acetate (70 mL) followed by 10% Pd on carbon (1.2 g)under a nitrogen atmosphère. The mixture was hydrogenated for 6 h under 50 psi Hz at 23 °C.The mixture was then filtered through a pad of celite which was rinsed with dry methylenechloride (140 mL) into a flame-dried flask. The resulting solution was cooled to -78 °C anddiisopropylethylamine (2.3g, 18 mmol) was added followed by the dropwise addition ofphenylchloroformate (2.5 g, 16.2 mmol). After 30 min, methanol (9 mL) containing acetic acid(1.8 mmol) was added. The réaction mixture was transferred to a separatory funnel, wasdiluted with ethyl acetate (200 mL), and was washed with water (2x). The aqueous layerswere extracted with ethyl acetate (2x10 mL). The organic layers were combined, werewashed with brine (2x), and were then dried (MgSO4), filtered, and concentrated in vacuo.The crude product was adsorbed onto silica gel and was purified by silica gel chromatography(1:1 hexanes-ethyl acetate) to afford 3 g (65% yield) of (1-cyclobutyl-1 H-imidazol-4-yl)-carbamic acid phenyl ester, 1H NMR (400 MHz, CDCI3) δ 7.4-7.3 (m, 2H), 7.22-7.18 (m, 3H), 4.5 (m, 1H), 2.46-2.30 (m, 4H), 1.83 (m, 2H); MS (AP/CI): 258.2 (M+H)+.

Example 5 1 -(1 -Cyclobutyl-1 H-imidazol-4-yl)-3-isoquinolin-5-yl-urea

To a 1 dram vial with septa screw cap was added (1-cyclobutyl-1 H-imidazol-4-yl)-carbamic acid phenyl ester (Example 4, 50 mg, 0.19 mmol), 5-aminoisoquinoline (30 mg, 0.21mmol), and 1:1 dioxane-DMF (1 mL). The reaction mixture was heated at 70 °C for 2 h. Thereaction mixture was adsorbed onto silica gel and was purified by silica gel chromatography(40:1 chloroform-methanol) to afford 30 mg (52% yield) of 1-(1 -cyclobutyl-1 H-imidazol-4-yl)-3-isoquinolin-5-yl-urea; 1H NMR (400 MHz, CD3OD) δ 9.21 (d, J= 1.7 Hz, 1H), 8.45 (d, 7 = 6.2Hz, 1H), 8.24 (d, J = 7.5 Hz, 1H), 7.98 (d, J = 5.4 Hz, 1H), 7.84 (dd, J = 2.3, 8.3 Hz, 1H), 7.66(m, 1H), 7.54 (s, 1H), 7.12 (brs, 1H), 4.66 (m, 1H), 2.5-2.3 (m, 4H), 1.9 (m. 2H); MS (AP/CI):308.0 (M+H)+. θT 234ζ H-'

Préparation 4 A/-[1-(c/s-3-Azido-cyclobutyl)-1H-imidazol-4-yl]-2-naphthalen-1 -yl-acetamide

Step 1 3-Benzyloxycyclobutylamine (43.4 g, 245 mmol, Chem. Ber. 1957, 90, 1424-1432)was dissolved in methanolic hydrogen chloride (saturated, 450 mL), then 10% Pd on carbon(4 g) was added. The mixture was hydrogenated at 50 psi H2 for 6 h. The mixture was filteredand concentrated in vacuo to give ca. 35 g of an oil. The oil was taken up in methanol (600.mL), was cooled to 0 °C, and was treated with potassium hydroxide (13.7 g, 245 mmol).When the pH = 10, a solution of 1,4-dinitroimidazole (42.7 g, 270 mmol) in methano! (200 mL)(prepared by dissoiving 1,4-dinitroimidazole in methanol at 0 °C) was added. (Note: 1,4-Dinitroimidazole is a highly energetic, semi-stable substance and should be stored in afreezer at ail times it is not in use. Thermodynamic measurements hâve shown that it canpotentially generate enough energy at 35 °C under adiabatic conditions to violently explode.Extrême caution should be exercised at ail times using this material.) The resulting orangesuspension was then allowed to slowly warm to 23 °C overnight. The solvent was removed invacuo and the resulting residue was purified by passage through a large plug of silica gel(20:1 chloroform-methanol) to afford 19 g (42% yield) of 3-(4-nitro-imidazol-1-yl)-cyc!obutanolas a 1:1 mixture of cis-trans isomers; 1H NMR (400 MHz, CD3OD) δ 8.29 (s, 1H), 8.27 (s, 1H),7.84 (s, 1H), 7.81 (s, 1H), 5.02 (m, 1H), 4.53 (m, 1H-), 4.37 (m, 1H), 4.10 (m, 1H), 2.95 (m,2H), 2.7 (m, 2H), 2.5 (m, 2H), 2.3 (m, 2H); MS (AP/CI): 184.0 (M+H)+.

Step 2 3-(4-nitro-imidazol-1-yl)-cyclobutanoI (Préparation 4, Step 1; 4g, 22 mmol) wastreated with Et3N (7.7 mL, 55 mmol) in methylene chloride (150 mL) followed by p-toluenesulfonyl chloride (TsCI) (5g, 26.4 mmol) and 4-W,N-dimethylaminopyridine (DMAP)(268 mg, 2.2 mmol). The resulting mixture was stirred at room température for 24 h. Analysisby thin layer chromatography showed two new spots. The reaction mixture was diluted withmethylene chloride and was washed with water (1x) and brine (1x). The organic layer wasdried (MgSO4), filtered, and concentrated in vacuo. Purification by silica gel chromatography(1:1 to 2:1 hexanes-ethyl acetate) allowed for séparation of the trans and cis diastereomers.The first spot to elute (high Rf) was the frans-isomer, frans-toluene-4-sulfonic acid 3-(4-nitro-imidazol-1-yl)-cyclobutyl ester (2.7 g, 37% yield); 1H NMR (400 MHz, CDCI3) δ 7.79 (s, 1H),7.77 (m, 2H), 7.44 (d, J = 1.7 Hz, 1H), 7.36 (dd, J = 0.5, 8.0 Hz, 2H), 5.034 (m, 1H), 4.94 (m,1H), 2.9 (m, 2H), 2.7 (m, 2H); MS (AP/CI): 338.1 (M+H)+. The second spot to elute was thec/s-isomer, c/s-toluene-4-sulfonic acid 3-(4-nitro-imidazol-1-yl)-cyclobutyl ester (2.9 g, 39%yield); 1H NMR (400 MHz, CDCI3) δ 7.8 (m, 3H), 7.43 (d, J = 1.4 Hz, 1H), 7.36 (dd, J = 0.6,

8.5 Hz, 2H), 4.74 (m, 1H), 4.30 (m, 1H), 3.05 (m, 2H), 2.6-2.5 (m, 2H), 2.45 (s, 3H); MS Q1234ζ -50 (APZCI): 338.1 (M+H)+. Relative configurations were determined by the rneasurement ofnuciear Overhauser effects.

Step 3 frans-Toiuene-4-sulfonic acid 3-(4-nitro-imidazol-1-yl)-cyclobutyl ester (Préparation 4,Step 2; 590 mg, 1.75 mmol) was mixed with 10% Pd on carbon (500 mg) in ethyl acetate (30mL). The mixture was then reacted under 50 psi H2 at room température for 6 h. The mixturewas filtered through celite into a flame-dried fiask which was kept under a nitrogenatmosphère. Et3N (1.22 mL, 8.75 mmol) was added followed by 1-naphthylacetic acid (326mg, 1.75 mmol) and tripropylphosphonic anhydride (1.1 mL, 1.7 M solution in ethyl acetate, 1.75 mmol). The mixture was stirred at room température for 1 h and was then diluted withethyl acetate and was washed with water and brine. The organic layer was dried (MgSO4),was filtered, and was concentrated in vacuo. The resulting residue was purified by silica gelchromatography (50:1 chloroform-methanol) to afford 600 mg (72% yield) of frans-toluene-4-sulfonic acid 3-[4-(2-naphthalen-1-yl-acetylamino)-imidazol-1-yl)-cyclobutyl ester; 1H NMR(400 MHz, CDCI3) δ 7.9 (m, 2H), 7.85 (m, 2H), 7.76 (d, J = 8.3 Hz, 2H), 7.48 (m, 2H), 7.42 (m,2H), 7.33 (m, 2H), 7.04 (s, 1H), 4.96 (m, 1H), 4.73 (m, 1H), 2.7 (m, 4H), 2.44 (s, 3H); MS(AP/CI): 476.2 (M+H)+.

Step 4 frans-Toluene-4-sulfonic acid 3-[4-(2-naphthalen-1-yl-acetylamino)-imidazol-1-yl]-cyclobutyl ester (Préparation 4, Step 3; 593 mg, 1.25 mmol) was mixed with sodium azide(813 mg, 12.5 mmol) in éthanol (15 mL), water (5 mL), and chloroform (5 mL). The mixturewas then heated at reflux with stirring for 96 h. The solvent was removed in vacuo and theresidue was diluted with water and was extracted with methylene chloride. The organic layerwas dried (MgSO4), filtered, and was concentrated in vacuo. Purification by silica gelchromatography (50:1 chloroform-methanol) afforded 340 mg (79% yield) of N-[1-(c/s-3-azido-cyclobutyl)-1H-Îmidazol-4-yl]-2-naphthalen-1-yl-acetamide; 1H NMR (400 MHz, CDCI3) δ 8.41(s, 1H), 7.98 (d, J = 6.4 Hz, 1H), 7.87 (m, 1H), 7.82 (m, 1H), 7.5 (m, 2H), 7.45 (m, 3H), 7.08(d, J = 1.7 Hz, 1H), 4.2 (m, 3H), 3.75 (m, 1H), 2.85 (m, 2H), 2.35 (m, 2H); MS (APZCI): 347.2(M+H)+.

Example 6 N-[1 -(c/s-3-Amino-cyclobutyl)-1 H-imidazol-4-yl]-2-naphthalen-1 -yl-acetamide A/-[1 -(c/s-3-azido-cyclobutyl)-1 H-imidazol-4-yl]-2-naphthalen-1 -yl-acetamide(Préparation 4, Step 4; 330 mg, 0.95 mmol) was treated with triphenylphosphine (301 mg,1.15 mmol) in tetrahydrofuran (10 mL) and water (1 mL) at 23 °C. The solution was stirred atroom température for 18 h. The solvent was removed in vacuo and the resulting residue waspurified by silica gel chromatography (20:1:0.5 chloroform-methanol-ammonium hydroxide) to I” 012345 «_< 1 afford 289 mg (95% yield) of A/-[1-(c/s-3-amino-cyclobutyl)-1H-imidazol-4-yl]-2-naphthalen-1-yl-acetamide; 1H NMR (400 MHz, CD3OD) δ 8.05 (d, J = 7.5 Hz, 1H), 7.87 (d, J = 7.9 Hz, 1H),7.79 (d, J = 9.0 Hz, 1H), 7.45 (m, 5H), 7.35 (s, 1H), 4.26 (m, 1H), 4.16 (s, 2H), 3.29 (m, 2H),3.16 (m, 1H), 2.75 (m, 2H), 2.1 (m, 2H); MS (AP/CI): 321.3 (M+H)+.

Example 7a 6-Methyl-pyridine-2-carboxylic acid {c/s-3-[4-(2-naphthalen-1-yl-acetylamino)- imidazol-1-yl]-cyclobutyl}-amide A solution of 6-methylpicolinic acid (9.4 mg, 0.07 mmol) in methylene chloride wastreated with 1 -(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (84 mg) and DMAP(2 mg) at 23 °C. After stirring for 10 min, N-[1-(c/s-3-amino-cyclobutyl)-1H-imidazol-4-yl]-2-naphthalen-1-yl-acetamide (Example 6, 20 mg, 0.06 mmol), was added. The resulting mixturewas then stirred for 3 h. Water was added, the solution was made neutral with aqueousNaOH and was extracted with ethyl acetate. The organic layer was dried (MgSO4), filtered,and concentrated in vacuo. Purification by silica gel chromatography (20 : 1 CHCI3 - MeOH)gave 26 mg (95% yield) of 6-methyl-pyridine-2-carboxylic acid {3-(4-(2-naphthalen-1-yl-acetylamino)-imidazol-1-yl]-cyclobutyl}-amide; 1H NMR (400 MHz, CDCI3) δ 9.15 (s, 1H), 8.28(d, J - 8.3 Hz, 1H), 8.01 (d, J = 7.5 Hz, 1H), 7.96 (d, J = 7.5 Hz, 1H), 7.97 (d, J 7.5 Hz, 1H),7.81 (dd, J = 2.4, 6.6 Hz, 1H), 7.72 (m, 1H), 7.5 (m, 5H), 7.2 (m, 1H), 7.16 (s, 1H), 4.45 (m,1H), 4.25 (m, 1H), 4.18 (s, 2H), 2.98 (m, 2H), 2.60 (s; 3H), 2.40 (m, 2H); MS (AP/CI): 440.3(M+H)+.

Example 7b 1H-lmidazole-4-carboxylic acid {c/s-3-[4-(2-naphthalen-1-yl-acetylamino)- imidazol-1-yl]-cyclobutyl}-amide

The title compound was prepared analogously to Example 7a; 1H NMR (400 MHz,CD3OD) δ 8.06 (d, J = 7.9 Hz, 1H), 7.87 (m, 1H), 7.80 (d, J = 7.5 Hz, 1H), 7.7 (s, 1H), 7.64 (s,1H), 7.5 (m, 6H), 4.44 (m, 1H). 4.32 (m, 1H), 4.18 (s, 2H), 2.9 (m, 2H), 2.45 (m, 2H); MS(AP/CI): 415.3 (M+H)+.

Example 7c 6-Hydroxy-pyridine-2-carboxylic acid {c/s-3-[4-(2-naphthalen-1 -yl-acetylamino)- imidazol-1-yl]-cyclobutyl}-amide

The title compound was prepared analogously to Example 7a; 1H NMR (400 MHz,CD3OD) δ 8.02 (d, J = 7.9 Hz, 1H), 7.84 (d, J = 7.9 Hz, 1H), 7.79 (d, J = 7.5 Hz, 1H), 7.65 (s,1H), 7.60 (m, 1H), 7.45 (m, 6H), 7.14 (brs, 1H), 6.71 (d, J = 8.7 Hz, 1H), 4.4 (m. 1H), 4.32 (m,1H), 4.17 (s, 2H), 2.93 (m, 2H), 2.5 (m, 2H); MS (AP/CI): 442.3 (M+H)+.

Example 7d 0 Ί 23 4 5 -52’ 3-Methyl-pyridine-2-carboxylic acid {c/s-3-[4-(2-naphthalen-1-yl-acetylamino)- imidazol-1-yl]-cyclobutyl}-amide

The title compound was prepared analogously to Example 7a; 1H NMR (CD3OD, 400MHz) δ 8.39 (d, J = 4.2 Hz, 1 H), 8.06 (d, J = 8.3 Hz, 1 H), 7.87 (d, J = 7.5 Hz, 1 H), 7.80 (d, J - 7.5 Hz, 1H), 7.69 (d, J = 7.9 Hz, 1H), 7.5 (m, 7H), 4.5 (m, 1H),4.3 (m, 1H), 4.17 (s, 2H), 2.92(m, 2H), 2.54 (s, 3H), 2.46 (m, 2H); MS (AP/CI): 440.3 (M+H)+.

Example 7e 2-Pyridin-3-yl-thiazole-4-carboxylic_acid_{c/s-3-[4-(2-naphthalen-1-yl- acetylamino)-imidazol-1-yl]-cyclobutyl}-amide

The title compound was prepared analogously to Example 7a; 1H NMR (400 MHz,CD3OD) 9.21 (d, J = 2.5 Hz, 1H), 8.61 (d, J =5.0 Hz, 1 H), 8.41 (dd, J = 1.7, 7.9 Hz, 1 H), 8.26(s, 1 H), 8.06 (d, J = 7.9 Hz, 1 H), 7.86 (d, J = 7.5 Hz, 1 H), 7.79 (d, J = 7.9 Hz, 1 H), 7.5 (m, 7H),4.44 (m, 2H), 4.17 (s, 2H), 2.9 (m, 2H), 2.6 (m, 2H); MS (AP/CI): 509.3 (M+H)+.

Example 7f 6-{c/s-3-[4-(2-Naphthalen-1-yl-acetylarnino)-imidazol-1-yl]-cyclobutylcarbamoyl}- nicotinic acid methyl ester

The title compound was prepared analogously to Example 7a; -1H NMR (400 MHz,CD3OD / CDCI3) δ 9.15 (d, J = 1.6 Hz. 1H), 9.12 (d, J = 8.0 Hz, 1H), 8.45 (dd, J = 2.0, 8.4 Hz,1H), 8.16 (d, J = 8.0 Hz, 1H), 8.02 (d, J = 8.4 Hz, 1H), 7.85 (d, J = 8.0 Hz, 1H), 7.80 (d, J = 7.8Hz, 1H), 7.48 (m, 6H), 4.45 (m, 2H), 3.96 (s, 3H), 2.94 (m, 2H), 2.58 (m, 2H); MS (AP/CI):484.3 (M+H)+.

Example 7g

Pyrazine-2-carboxylic acid {c/s-3-[4-(2-naphthalen-1 -yl-acetylamino)-imidazol-1- yl]-cyclobutyl}-amide

The title compound was prepared analogously to Example 7a; 1H NMR (400 MHz,CD3OD) δ 9.23 (d, J = 2.0 Hz, 1H), 9.03 (d, J = 8.0 Hz, 1H), 8.73 (d, J = 2.4 Hz, 1H), 8.63 (d,J = 1.6, 2.4 Hz, 1 H), 8.02 (d, J = 8.4 Hz, 1 H), 7.85 (d, J = 8.0 Hz, 1 H), 7.79 (d, J = 8.0 Hz, 1 H),7.49 (m, 6H), 4.44 (m, 2H), 4.16 (s, 2H), 2.95 (m, 2H), 2.56 (m, 2H); MS (AP/CI): 427.3(M+H)+.

Example 7h N-{c/'s-3-[4-(2-Naphthalen-1-yl-acetylamino)-imidazol-1-yl]-cyclobutyl}- benzamide

The title compound was prepared analogously to Example 7a; 1H NMR (400 MHz,CD3OD) δ 8.05 (d, J = 8.3 Hz, 2H), 7.99 (d, J = 7.1 Hz, 1 H), 7.86 (d, J = 7.5 Hz, 1 H), 7.80 (J = -5.3- 7.1 Hz, 2Η), 7.45 (m, 8H), 4.47 (m, 1H), 4.37 (m, 1H), 4.17 (s, 2H), 2.90 (m, 2H), 2.47 (m, 2H);MS (AP/CI): 425.0 (M+H)+.

Example 7i 5- IVlethyl-pyrazine-2-carboxylic acid {c/s-3-[4-(2-naphthalen-1-yl-acetylamino)- imiàazol-1-yl]-cyclobutyl}-amide

The title compound was prepared analogously to Example 7a; 1H NMR (400 MHz,CD3OD) δ 9.07 (d, J = 1.2 Hz, 1 H), 8.5 (d, J = 0.8 Hz, 1 H), 8.02 (d, J = 8.0 Hz, 1 H), 7.85 (d, J= 7.6 Hz, 1H), 7.79 (d, J = 7.6 Hz, 1H), 7.45 (m, 6H), 4.40 (m, 2H), 4.16 (s, 2H), 2.93 (m, 2H),2.61 (s, 3H), 2.54 (m, 2H); MS (APZCI): 441.3 (M+H)+.

Example 7j N-{c/s-3-[4-(2-Naphthalen-1-yl-acetylamino)-imidazol-1-yl]-cyclobutyl}- isobutyramide

The title compound was prepared analogously to Example 7a; 1H NMR (400 MHz,CD3OD) δ 8.01 (d, J = 7.9 Hz, 1H), 7.84 (d, J = 7.5 Hz, 1H), 7.78 (d, J = 7.5 Hz, 1H), 7.45 (m,6H), 4.35 (m, 1H), 4.15 (s, 2H), 4.11 (m, 2H), 2.84 (m, 2H), 2.35 (m, 1H), 2.28 (m, 2H), 1.06(d, J = 6.6 Hz, 6H); MS (AP/CI): 391.1 (M+H)+.

Example 7k 6- Chloro-pyridine-2-carboxylic acid {c/s-3-[4-(2-naphthalen-1 -yl-acetylamino)- imidazol-1-yl]-cyclobutyl}-amide

The title compound was prepared analogously to Example 7a; 1H NMR (400 MHz,CD3OD) δ 8.07 (d, J = 7.9 Hz, 1 H), 8.03 (d, J = 7.5 Hz, 1 H), 7.94 (m, 1 H), 7.87 (d, J = 7.9 Hz,1H), 7.81 (d, J = 7.9 Hz, 1H), 7.61 (d, J = 7.1 Hz, 1H), 7.58 (s, 1H), 7.5 (m, 5H), 4.45 (m, 1H),4.39 (m, 1H), 4.18 (s, 2H), 2.89 (m, 2H), 2.63 (m, 2H); MS (AP/CI): 460.2, 462.2 (M+H)+.

Example 8

Acylation of A/-[1-(c/s-3-amino-cyclobutyl)-1 H-imidazol-4-yI]-2-naphthalen-1-yl-acetamide (Example 6) with various carboxylic acids and subséquent purification wascarried out according to the following procedure: To the carboxylic acid (RCO2H, 1 equiv,0.075 mmol) in 1 dram screw cap vials was added a solution of N-[1-(c/s-3-amino-cyclobutyl)-1H-imidazol-4-yl]-2-naphthalen-1-yl-acetamide (0.33 equiv, 8 mg, 0.025 mmol) in methylenechloride (1 mL). Next, PS-carbodiimide (Argonaut Technologies, 0.5 equiv, 39 mg, 0.038mmol, 1 mmol/g) was added. The mixtures were shaken at 23 °C for 24 h. Note: If the acidwas insoluble in methylene chloride, W,W-dimethylformamide (0.5 mL) was added. Eachreaction mixture was transferred with methylene chloride (0.5 mL) to a 3 mL SPE cartridge (20micron frit) with a tared 2 dram viat to collect solvent. The solvent was forced through the fritand the polymer was washed with THF (0.5 mL), methylene chloride (0.5 mL), THF (0.5 mL), 012345 and methylene chloride (0.5 mL). The solutions were concentrated under a stream of nitrogenand the crude products were analyzed by LCMS (Column: 3.9 x 150 mm Waters SymmetryC18, 5 uM; flow = 1.0 ml/min; solvent System: A = 0.1% aqueous TFA; B = acetonitrile; lineargradient of 10-100% B over 10 min). If the desired parent ion (M+H) was observed, the crudereaction mixture was purified by préparative HPLC (Column: 30 x 150 mm Waters SymmetryC1S 5uM; flow = 20 mL/min; solvent System: A = 0.1% aqueous TFA; B = acetonitrile; lineargradient of 0-100% B over 15 min) with the appropriate fractions determined by an in-linemass spectrometer. The purity of the chromatographed compound was determined byanalytic HPLC (Column: 2.1 x 150 mm Waters Symmetry C18 5 uM; Flow: 0.5 mL/min; solventSystem: A = 0.1% aqueous TFA; B = acetonitrile; linear gradient of 0-100% B over 10 min)using UV: 254 nM and diode array for détection.

The following compounds were prepared by the above-described method.Their mass spectral data and chromatographie rétention times are listed in Table 1:

Example 8a: Quinoline-2-carboxylic acid {c/s-3-[4-(2-naphthalen-1-yl-acetylamino)-imidazol-1-yl]-cyclobutyl}-amide

Example 8b: 1 H-Pyrrole-2-carboxylic acid {c/s-3-[4-(2-naphthalen-1-yl-acetylamino)-imidazol-1 -yl]-cyclobutyl}-amide

Example 8c: N-{c/s-3-[4-(2-Naphthalen-1 -yl-acetylamino)-imidazol-1 -yl]-cyclobutyl}-2-m-tolyl-acetamide

Example 8d: Pyridine-2-carboxylic acid {c/s-3-[4-(2-naphthalen-1-yl-acetylamino)-imidazol-1-yl]-cyclobutyl}-amide

Example 8e: 2-(3-Hydroxy-phenyl)-N-{c/s-3-[4-(2-naphthalen-1-yl-acetylamino)-imidazol-1-yl]-cyclobutyl}-acetamide

Table 1.

Acylated Products, Associated Rétention Times, and Mass Spectral Data Rétention Times

Example Analytical HPLC (min) LCMS (min) (M+H) 8a 7.68 8.79 476.2 8b 6.97 7.96 414.2 8c 7.45 8.56 453.2 8d 6.84 6.68 426.2 8e 6.75 7.77 455.2 012345 55-

Préparation 5 4-[3.[4-(2-Naphthalen-1-yl-acetylamino)-imidazol-1-yl]-cyclobutylcarbamoyl}- piperidine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester

Step 1 4-Piperidine carboxylic acid (129 mg, 1 mmol) was treated with sodium hydroxide (80mg, 2 mmol) in water/dioxane (1:1, 10 mL). After 30 min of stirring at room température, 9-fiuorenylmethyl chloroformate (259 mg, 1 mmol) in dioxane (2 mL) was added dropwise and·then the reaction solution was stirred for 4 h. The solvent was removed in vacuo and wasdiluted with water. The pH was adjusted to 1 with HCl (1 N) and the aqueous solution wasextracted with ethyl acetate. The organic layer was dried (MgSO4), filtered, and concentratedin vacuo. Purification by silica gel chromatography (50:1:0.5 chloroform-methanol-acetic acid)afforded 340 mg (97% yield) of /V-1-(fluorenylmethyloxycarbonyl)-4-piperidinylcarboxylic acid;1H NMR (400 MHz, CDCi3) d 7.75 (d, J = 7.1 Hz, 2H), 7.55 (d, J = 7.5 Hz, 2H), 7.39 (m, 2H),7.30 (m, 2H), 4.4 (brs, 2H), 4.23 (t, J = 6.5 Hz, 1H), 3.9 (brd, 2H), 2.9 (brs, 2H), 2.52 (m, 1H),1.90 (brs, 2H), 1.62 (brs, 2H); MS (AP/CI): 352.0 (M+H)+.

Step 2 A solution of N-1-(fluorenylmethyloxycarbonyl)-4-piperidinylcarboxylic acid(Préparation 5, Step 1; 77 mg) in methylene chloride was treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (84 mg) and DMAP (5 mg). Afterstirring for 30 min, A/-[1-(c/s-3-amino-cyclobutyl)-1H-imidazol-4-yl]-2-naphthalen-1-yl-acetamide (Example 6), was added. The resulting mixture was then stirred for 4 h. Waterwas added, the solution was made neutral, and was extracted with ethyl acetate. The organiclayer was dried (MgSO4), filtered, and concentrated in vacuo. Purification by silica gelchromatography (20:1 chloroform-methanol) gave 101 mg (77% yield) of 4-{3-[4-(2-Naphthalen-1 -yl-acetylamino)-imidazol-1 -yl]-cyclobutylcarbamoyl}-piperidine-1-carboxylic acid9H-fluoren-9-ylmethyl ester; 1H NMR (400 MHz, CD3OD) δ 8.0 (d, J = 8.3 Hz, 1H), 7.83 (m,1H), 7.78 (dd, J = 2.07, 7.5 Hz, 1H), 7.73 (d, J = 7.5 Hz, 2H), 7.53 (d, J = 6.6 Hz, 2H), 7.44 (m,5H), 7.35 (m, 3H), 7.27 (m, 2H), 4.4 (brs, 2H), 4.2 (m, 1H), 4.15 (m, 5H), 2.85 (m, 4H), 2.25(m, 3H), 1.7 (brs, 2H), 1.5 (brs, 2H); MS (AP/CI): 654.8 (M+H)+.

Example 9

Piperidine-4-carboxylic acid {c/s-3-[4-(2-naphthalen-1-yl-acetylamino)-imidazol- 1 -ylj-cyclobutyl}-amide hydrochloride 4-{3-[4-(2-Naphthalen-1-yl-acetylamino)-imidazo!-1-yl]-cyclobutylcarbamoyl}-piperidine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester (Préparation 5,100 mg, 0.15 mmol) inDMF (5 mL) was treated with piperidine (0.5 mL) and stirred at room température for 2 h. Thesolvent was removed in vacuo and the residue was purified by silica gel chromatography 012345 -56- (4:1:0.08 chloroform-methanol-ammonium hydroxide) to afford the free base. The free basewas dissolved in diethyl ether and treated with 1N HCl in methanol to afford the HCl sait (64mg, 91% yield), piperidine-4-carboxylic acid (c/s-3-[4-(2-naphthalen-1-yi-acetylamino)-imidazol-1-yl]-cyclobutyl}-amide hydrochloride; 1H NMR (400 MHz, CD3OD) δ 8.01 (d, J - 8.0Hz, 1H), 7.84 (d, J = 8.2 Hz, 1H), 7.78 (d, J = 7.8 Hz, 1H), 7.43 (m, 4H), 7.36 (s, 2H), 4.34 (m,1H), 4.15 (s, 2H), 4.10 (m, 1H), 3.03 (m, 2H), 2.83 (m, 2H), 2.54 (m, 2H), 2.24 (m, 3H), 1.69(m, 2H), 1.55 (m, 2H); MS (AP/Cl): 432 (M+H)+.

Préparation 6lsoquinolin-5-yl-acetic acid

Step 1 5-Aminoisoquinoline (5.0g, 34.7 mmol) was mixed with 48% aqueous HBr (65 mL) at-78 °C for 15 min. Sodium nitrite (3.1 g, 45 mmol) in water (6 mL) was then added dropwise.After stirring for 15 min at -78 °C, the mixture was warmed to 0 °C. Copper powder (0.3 g)was added very slowly to avoid excessive foaming. After addition was completed, thereaction vessel was fitted with a reflux condensor and the mixture was heated to 100 °C for 4h. The mixture was poured onto ice (ca. 200 g) and was made basic (pH = 10) with KOH.The aqueous mixture was extracted with ethyl acetate, the combined organic layers werewashed with brine, were dried (MgSO4), were filtered, and were concentrated in vacuo.Purification by silica gel chromatography (10:1 hexanes - ethyl acetate) afforded 3.8 g (53%yield) of 5-bromoisoquinoline; 1H NMR (400 MHz, CD3OD) δ 9.25 (s, 1H), 8.57 (d, J = 6.2Hz, 1H), 8.1 (m, 3H), 7.60 (m, 1H); MS (AP/Cl): 208.0, 210.0 (M+H)+.

Step 2 5-Bromoisoquinoline (Préparation 6, Step 1, 1.04 g, 5.0 mmol) was mixed withallyltributyltin (1.7 mL, 5.5 mmol) and dichloropalladium bis(triphenylphosphine) (176 mg, 0.25mmol) in toluene (20 mL) under a nitrogen atmosphère. The mixture was heated at reflux for16 h. After cooling to room température, a saturated aqueous solution of potassium fluoride(20 mL) was added with stirring, resulting in the formation of a precipitate. Following 15 minof stirring, the mixture was filtered and the organic layer was separated from the aqueouslayer, was concentrated in vacuo and was purified by silica gel chromatography (6 : 1hexanes - ethyl acetate) to give 778 mg (92% yield) of 5-allylisoquinoline; 1H NMR (400 MHz,CDCI3) δ 9.25 (s, 1 H), 8.54 (d, J= 5.8 Hz, 1H), 7.85 (m, 1H), 7.79 (d, J= 5.8 Hz, 1 H), 7.56 (m,2H), 6.1 (m, 1H), 5.15 (m, 1H), 5.05 (m, 1H), 3.81 (d, J = 6.2 Hz, 2H); MS (AP/Cl): 170.1(M+H)+.

Step 3 5-Allylisoquinoline (Préparation 6, Step 2; 169 mg, 1.0 mmol) in methylene chloride (2mL), acetic acid (0.5 mL), and water (0.5 mL) was treated with dimethyl polyethylene glycol 012345 - S?" (Μη ca. 500, 95 uL, 100 mg, 0.2 mmol) in methylene chloride (1 mL) at 23 °C. The mixturewas cooied to 0 °C and powdered KMnO4 (521 mg, 3.3 mmol) was added portionwise,maintaining the température below 30 °C. Following vigorous stirring for 18 h, the solvent wasremoved in vacuo and methanolic hydrogen chloride (10 mL, 1N) was added, and the mixturewas refluxed for 4 h. The methanol was removed in vacuo, the residue was diluted withwater, and the mixture was made basic with Na2CO3 (pH = 9). The mixture was extracted withethyl acetate, the resulting organic layer was washed with brine, was dried (MgSO4), wasfiltered, was concentrated in vacuo, and was purified by silica gel chromatography (2 : 1hexanes - ethyl acetate) to afford isoquinolin-5-yl-acetic acid methyl ester; 1H NMR (400MHz, CDC13) δ 9.28 (brs, 1H), 8.58 (d, J = 6.2 Hz, 1H), 7.95 (d, J = 7.9 Hz, 1H), 7.80 (d. J =5.8 Hz, 1H), 7.66 (d, J = 5.8 Hz, 1H), 7.59 (t, J = 7.6 Hz, 1H), 4.06 (s, 2H), 3.70 (s, 3H); MS(AP/Cl): 202.1 (M+H)+. Note: An impurity of 5-isoquinolylcarboxaldehyde was présentfollowing silica gel chromatography (ca. 20%).

Step4 lsoquinolin-5-yl-acetic acid methyl ester (Préparation 6, Step 3; 90 mg, 0.448 mmol)was treated with aqueous sodium hydroxide (4N, 3 mL) and the solution was heated at 50 °Cfor 4 h. The solution was cooied to 0 °C and acetic acid (2 mL) was added dropwise, whichresulted in the formation of a precipitate. The mixture was kept at 0 °C overnight (ca. 15 h)and the precipitate was removed via filtration and was washed with water. The solid wasdried in air to afford 35 mg (47% yield) of isoquinolin-5-yl-acetic acid; 1H NMR (400 MHz,CD3OD) δ 9.24 (s, 1H), 8.47 (d, J = 6.2 Hz, 1H), 8.04 (d, J = 7.9 Hz, 1H), 7.96 (d, J = 6.2 Hz,1H), 7.74 (d, J = 6.6 Hz, 1H), 7.66 (t, J = 7.6 Hz, 1H), 4.11 (s, 2H); MS (AP/Cl): 188.3(M+H)+.

Préparation 7 /tf-[c/s-3-(4-Nitro-imidazol-1H-yi)cyclobutyl]acetamide

Step 1 fzans-Toluene-4-sulfonic acid 3-(4-nitro-imidazol-1-yl)-cyclobutyl ester (Préparation 1,Step 2; 3.6 g, 10.7 mmol) was mixed with sodium azide (7g, 107 mmol) in éthanol (100 mL),water (35 mL), and chloroform (20 mL). The mixture was heated at reflux for 24 h. Theéthanol and chloroform were removed in vacuo and resulting mixture was diluted with waterand was extracted with ethyi acetate. The organic layer was washed with brine, was dried(MgSO4), filtered, and concentrated in vacuo. Purification by silica gel chromatography (1:1 to3:1 ethyl acetate - hexanes) gave 2.2 g (99%) of 1-(3-c/s-azido-cyclobutyl)-4-nitro-1H-imidazole; 1H NMR (400 MHz, CDCI3) δ 7.85 (s, 1H), 7.49 (s, 1H), 4.42 (m, 1H), 3.91 (m, 1H),3.07 (m, 2H), 2.43 (m, 1 H); MS (AP/Cl): 208.5 (M+H)+.

Step 2 012345 -5'δ' 1-(3-c/s-Azido-cyclobutyl)-4-nitro-1H-imidazole (Préparation 7, Step 1; 2.2 g, 10.7mmol) in THF (100 mL) was treated with triphenylphosphine (3.36 g, 12.8 mmol) and water(10 mL). The solution was stirred at room température for 18 h. The solvent was removed invacuo and the residue was purified by silica gel chromatography_ (20:1:0.4 chloroform-methanol-ammonium hydroxide) to give 1.95 g (100% yield) of 1-(3-c/s-amino-cyclobutyI)-4-nitro-1 H-imidazole; 1H NMR (400 MHz, CD3OD) δ 8.32 (s, 1H), 7.81 (s, 1H), 4.46 (m, 1H),3.29 (m, 1H), 2.87 (m, 2H), 2.17 (m, 2H); MS (AP/CI): 183.1 (M+H)+.

Step 3 1-(3-c/s-amino-cyclobutyl)-4-nitro-1H-imidazole (Préparation 7, Step 2; 500 mg, 2.75mmol) was coupled with acetic acid and purified as in Example 7 to afford 594 mg (96% yield)of W-[c/s-3-(4-nitro-imidazol-1 H-yl)cyc!obutyl]acetamide; 1H NMR (400 MHz, CD3OD) δ 8.30(s, 1H), 7.82 (s, 1H), 4.58 (m, 1H), 4.17 (m, 1H), 2.95 (m, 2H), 2.39 (m, 2H), 1.93 (s, 3H); MS(AP/CI): 225.1 (M+H)+.

Préparation 8 N-[c/s-3-(4-Nitro-imidazol-1-yl)-cyclobutyl)-benzamide N-[c/s-3-(4-Nitro-imidazol-1-yl)-cyclobutyl]-benzamide was prepared analogously tothe product of Préparation 7; 1H NMR (400 MHz, CD3OD) δ 8.36 (s, 1H), 7.85 (m, 3H), 7.55(m, 1H), 7.47 (m, 2H), 4.65 (m, 1H), 4.44 (m, 1H), 3.05 (m, 2H), 2.60 (m, 2H); MS (AP/CI):287.3 (M+H)+.

Préparation 9

Pyridine-2-carboxylic acid [c/s-3-(4-nitro-imidazol-1 -yl)-cyclobutyl]-amide

Pyridine-2-carboxylic acid [c/s-3-(4-nitro-imidazol-1-yl)-cyclobutyI]-amide wasprepared analogously to the product of Préparation 7; 1H NMR (400 MHz, CDCI3): δ 8.55 (m,1 H), 8.35 (d, J = 7.0 Hz, 1 H), 8.19 (d, J = 7.9 Hz, 1 H), 8.01 (s, 1 H), 7.88 (td, J = 1.65, 7.9 Hz;1H), 7.57 (s, 1H), 7.47 (m, 1H), 4.5 (m, 2H), 3.17 (m, 2H), 2.72 (m, 2H); MS (AP/CI): 288.1(M+H)+.

Example 9a N-[1-(cf's-3-acetylamino-cyclobutyl)-1H-imidazol-4-yl]-2-naphthalen-2-yl- acetamide N-[c/s-3-(4-Nitro-imidazol-1H-yl)cyclobutyl]acetamide (Préparation 7; 50 mg, 0.22mmol) was hydrogenated and acylated with 2-naphthyl acetic acid as in Example 1 to afford35 mg (44% yield) of N-[1-(c/s-3-acetylamino-cyclobutyl)-1H-imidazol-4-yl]-2-naphthalen-2-yl-acetamide; 1H NMR (400 MHz, CD3OD) δ 8.05 (d, J = 8.0 Hz, 1H), 7.87 (d, J = 7.6 Hz, 1H),7.81 (d, J = 6.4 Hz, 1H), 7.46 (m, 5H), 7.37 (s, 1H), 4.41 (m, 1H), 4.17 (s, 2H), 4.12 (m, 1H),2.84 (m, 2H), 2.27 (m, 2H), 1.89 (s, 3H); MS (AP/CI): 363.3 (M+H)+.

Example 9b 012345 N-{c/s-3-[4-(2-lsoquinolin-5-yl-acetylamino)-imidazol-1-yl]-cyclobutyl}- benzamide

The title compound was prepared analogously to Example 9a, using Préparation 8and isoquinolin-5-yl acetic acid (Préparation 6); 1H NMR (400 MHz, CD3OD) δ 9.24 (s, 1H),8.45 (d, J = 6.2 Hz, 1H), 8.05 (d, J = 7.9 Hz, 1H), 8.02 (J = 6.2 Hz, 1H), 7.82 (m, 3H), 7.67 (m,1H), 7.52 (m, 2H), 7.45 (m, 3H), 4.5 (m, 1H), 4.4 (m, 1H), 4.21 (s, 2H), 2.95 (m, 2H), 2.50 (m,2H); MS (AP/CI): 426.3 (M+H)+.

Example 9c

Pyridine-2-carboxylic acid {c/s-3-[4-(2-isoquinolin-5-yl-acetylamino)-imidazol-1 - yl]-cyclobutyl)-amide

The titie compound was prepared analogously to Example 9a, using Préparation 9and isoquinolin-5-yl acetic acid (Préparation 6); 1H NMR (400 MHz, CD3OD) δ 9.23 (s, 1H),8.60 (m, 1H), 8.44 (d, J = 5.8 Hz, 1H), 8.03 (m, 3H), 7.92 (dt, J = 1.7, 7.5 Hz, 1H), 7.78 (d, J =7.1 Hz, 1H), 7.66 (m, 1H), 7.58 (s, 1H), 7.5 (m, 1H), 7.46 (s, 1H), 4.45 (m, 1H), 4.40 (m, 1H),4.20 (s, 2H), 2.85 (m, 2H), 2.6 (m, 2H); MS (AP/CI): 427.2 (M+H)+.

Example 10 N-{cJS-3-I4-(3-naphthalen-1-yl-ureido)-imidazol-1-yll-cyclobutyl}-acetamide N-[c/'s-3-(4-nitro-imidazoi-1 H-yl)cyclobutyl)acetamide (Préparation 7, 50 mg, 0.22mmol) was reacted with phenyl chloroformate as described in Example 4. This afforded aninséparable mixture of mono- and bis-phenyl carbamate products following silica gelchromatography (20:1:0.2 chloroform-methanol-ammonium hydroxide) that were dissolved in1:1 DMF/dioxane (500 uL). 1-Naphthylamine (31 mg, 0.22 mmol) was added and the mixturewas heated at 70 °C for 16 h. Purification twice by silica gel chromatography (20:1:0.02chloroform-methanol-ammonium hydroxide) gave 4.4 mg (5 % yieid) of N-{as-37[4-(3-naphtha!en-1-yl-ureido)-imidazol-1-yl]-cyclobutyl}-acetamide; 1H NMR (400 MHz, CD3OD) δ8.06 (d, J = 8.0 Hz, 1H), 7.97 (d, J = 8.8 Hz, 1H), 7.83 (d, J = 7.6 Hz, 1H), 7.66 (d, J = 8.4 Hz, 1 H), 7.51 (m, 4H), 7.16 (s, 1 H), 4.46 (m, 1H),4.15(m, 1 H), 2.89 (m, 2H), 2.33 (m, 2H), 1.92(s, 3H); MS (AP/CI): 364.0 (M+H)+.

Claims (13)

1. 012345 -6d>- CLAIMS What is claimed is:
2. 2. A compound according to claim 1, wherein R3 is -C(=O)NH- or - C(=O)(CR10R11)n-. 012345 «
3. 3. A compound according to claim 1, wberein R1 is optionally substituted(C3-C8)cycloalkyl or optionally substituted (Cs-C,,) bicycloalkyl.
4. 4. A compound according to claim 4, wherein R1 is cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, norbornyl, or bicyclo-[3.1.0]-hexyl, each optionallysubstituted.
5. 5. A compound according to claim 1, wherein R1 is optionally substitutedstraight Chain or branched (C,-C8)alkyl or optionally substituted straight chain or branched (C2-C8)alkenyl.
6. 6. A compound according to claim 1, wherein R4 is (C6-Cu)aryl or (5-14membered) heteroaryl, each optionally substituted.
7. 7. A compound according to claim 6, wherein R4 is phenyl, pyridyl,naphthyl, quinolyl, or isoquinolyl, each optionally substituted.
8. 8. A compound according to any of daims 1-7, wherein R2 is hydrogen.
9. 9. A compound of claim 1, seiected from the group consisting of: Λ/-(1 -cyclobutyl-1 H-imidazol-4-yl)-2-quinolin-6-yl-acetamide;A/-(1-cyclopentyl-1H-imidazol-4-yl)-2-(4-methoxy-phenyI)-acetamide; Λ/-[1 -(c/s-3-phenyl-cyclobutyl)-1 H-imidazol-4-yl]-2-quinoIin-6-yl-acetamide;(1-cyclobutyl-1H-imidazol-4-yl)-carbamic acid phenyl ester; 1- (1-cyclobutyl-1 H-imidazol-4-yi)-3-isoquinolin-5-yl-urea; N-[\ -(c;s-3-amino-cyclobutyl)-1 H-imidazol-4-yl]-2-naphthalen-1 -yl-acetamide; 6-methyl-pyridine-2-carboxylic acid {c/s-3-[4-(2-naphthalen-1-yl-acetylamino)- imidazol-1 -yl]-cyclobutyl}-amide; 1 H-imidazole-4-carboxylic acid {cZs-3-[4-(2-naphthalen-1-yI-acetylamino)-imidazol-1-yl]-cyclobutyl}-amide; 6-hydroxy-pyridine-2-carboxylic acidimidazol-1 -yl]-cyclobutyl}-amide; 3-methyl-pyridine-2-carboxylic acidimidazol-1-yi]-cyclobutyl}-amide; 2- pyridin-3-yl-thiazole-4-carboxylic acid {c/s-3-[4-(2-naphthalen-1 -yl-acetylamino)- imidazol-1-yl]-cyclobutyl}-amide; 6-{c/s-3-[4-(2-naphthalen-1-yl-acetylamino)-imidazol-1-yl]-cyclobutylcarbamoyl}- nicotinic acid methyl ester; pyrazine-2-carboxylic acid {c/s-3-[4-(2-naphthalen-1-yl-acetylamino)-imidazol-1-yl]- cyclobutyl}-amide; N-{c/s-3-[4-(2-naphthalen-1-yl-acetylamino)-imidazol-1-yl]-cyclobutyl}-benzamide; {c/s-3-[4-(2-naphthalen-1-yl-acetylamino)- {c/s-3-[4-(2-naphthalen-1-yl-acetylamino)- 0)2345 -63- 5- methyl-pyrazine-2-carboxylic acid {c/s-3-[4-(2-naphthalen-1-yl-acetylamino)- imidazol-1 -yl]-cyclobutyl}-amide; N-{c/'s-3-[4-(2-naphthalen-1-yl-acetylamino)-imidazol-1-yl]-cyclobutyl}-isobutyramide; 6- chloro-pyridine-2-carboxylic acid {c/s-3-[4-(2-naphthalen-1-yl-acetylamino)-imidazol-1 -yl]-cyclobutyl}-amide; quinoIine-2-carboxylic acid {c/s-3-[4-(2-naphthalen-1 -yl-acetylamino)-imidazol-1 -ylj-cyclobutyl}-amide; 1 H-pyrrole-2-carboxyiic acid {ci's-3-[4-(2-naphthalen-1-yl-acetylamino)-imidazol-1-yl]-cyclobutyl}-amide; N-{c/s-3-[4-(2-naphthalen-1-yl-acetylamino)-imidazol-1-yl]-cyclobutyl}-2-m-tolyl- acetamide; pyridine-2-carboxylic acid {c/s-3-[4-(2-naphthalen-1 -yl-acetylamino)-imidazol-1-yl]-cyclobutylj-amide; 2-(3-hydroxy-phenyl)-N-{c/s-3-[4-(2-naphthalen-1-yl-acetylamino)-imidazol-1-yI]- cyclobutylj-acetamide; piperidine-4-carboxylic acid {c/s-3-[4-(2-naphthalen-1-yl-acetylamino)-imidazol-1-yl]-cyclo.butyl}-amide hydrochloride; N-[1-(c/s-3-acetylamino-cyclobutyl)-1H-imidazol-4-yl]-2-naphthalen-2-yl-acetamide;N-{c/s-3-[4-(2-isoqijinolin-5-yl-acetylamino)-imidazo!-1-yl]-cyclobutyl}-benzamide; andpyridine-2-carboxylic acid {c/s-3-[4-(2-isoquinolin-5-yl-acetylamino)-imidazol-1 -yl]- cyclobutylj-amide; and pharmaceutically acceptable salts of the foregoing compounds.
10. 10. A pharmaceutical composition for treating a disease or conditioncomprising abnormal cell growth or a neurodegenerative disease or condition in a mammaicomprising a compound of claim 1 in an amount effective in treating said disease or condition,and a pharmaceutically acceptable carrier.
11. 11. A pharmaceutical composition for treating a disease or condition in amammai the treatment of which can be effected or facilitated by altering dopamine mediatedneurotransmission comprising a cdk5 inhibitor in an amount effective in treating said diseaseor condition or in an amount effective to inhibit cdk5 activity, and a pharmaceuticallyacceptable carrier.
12. 12. A pharmaceutical composition for treating in a mammai a disease orcondition selected from male fertility and sperm motiiity; diabètes mellitus; impaired glucosetolérance; metabolic syndrome or syndrome X; poiycystic ovary syndrome; adipogenesis andobesity; myogenesis and frailty, for example age-related décliné in physical performance;acute sarcopenia, for example muscle atrophy and/or cachexia associated with burns, bed 012345 « rest, limb immobilization, or major thoracic, abdominal, and/or orthopédie surgery; sepsis; hairloss, hair thinning, and baiding; and immunodeficiency, comprising a compound of claim 1 inan amount effective in treating said disease or condition, and a pharmaceutically acceptablecarrier. 5
13. 13. A pharmaceuticai composition comprising a cdk5 inhibitor and a second member selected from the group consisting of an SSRI, an NK-1 receptor antagonist, a 5HT1Dantagonist, ziprasidone, olanzapine, rispéridone, L-745870, sonepiprazole, RP 62203, NGD941, balaperidone, flesinoxan, gepirone, an acetylcholinesterase inhibitor, TP A, NIF, apotassium channel modulator such as BMS-204352, and an NMDA receptor antagonist, 10 wherein the cdk5 inhibitor and the second member are together in an effective amount, and apharmaceutically acceptable carrier.