CZ2003225A3 - Imidazole derivative and pharmaceutical composition in which the derivative is comprised - 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

Technical area

The invention relates to imidazole derivatives, pharmaceutical compositions containing such derivatives and their use for influencing abnormal cell growth and certain diseases and conditions of the central nervous system. The compounds of the invention act as inhibitors of the cyclin-dependent protein kinase enzymes cdk5 (cyclin dependent protein kinase 5) and cdk2 (cyclic dependent protein kinase 2). The compounds of the invention are also inhibitors of the enzyme GSK-3 (glycogen synthase kinase-3).

State of the art

The serine/threonine kinase cdk5, together with the cofactor p25 (or the longer cofactor, p35), has been associated with neurodegenerative disorders, and inhibitors of cdk5/p25 (or cdk5/p35) are therefore useful for the treatment of neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, stroke, or Huntington's disease. The treatment of such neurodegenerative disorders with cdk5 inhibitors is supported by the finding that cdk5 is involved in the phosphorylation of tau protein (J. Biochem 117, pp. 741-749, 1995). The enzyme cdk5 also phosphorylates dopamine and cyclic AMP-regulated phosphoprotein (DARPP-32) at threonine 75 and is therefore important in dopaminergic neurotransmission (Nature 402, pp. 669-671, 1999).

The serine/threonine kinase cdk2 is essential for normal cell cycling and plays a critical role in disorders caused by abnormal cell cycling, which is a common feature of many oncological disorders. Inhibitors of cdk2 are therefore useful for the treatment of various types of cancer and other diseases or conditions associated with abnormal cell growth (Meijer et al., Properties and Potential-applications of Chemical Inhibitors of Cyclic-dependent Kinases, Pharmacology & Therapeutics 82 (2-3), pp. 279-284, 1999; Sausville et al., Cyclic-dependent Kinases: lnitial ftpproaches to Exploit a novel Therapeutic Target, Pharmacology & Therapeutics 82, (2-3), pp. 285-292, 1999).

GSK-3 is a serine/threonine protein kinase. It is one of several protein kinases that phosphorylate glycogen synthase (Embi et al., Eur. J. Biochem. 107, pp. 519-527, 1980; Hemmings et al., Eur. J. Biochem. 119, pp. 443-451, 1982). GSK-3 exists in two isoforms, a and b, in vertebrates and is known to have a monomeric structure of 49kD and 47kD, respectively. Both isoforms phosphorylate muscle glycogen synthase (Cross et al., Biochemical Journal 303, pp. 21-26, 1994). The amino acid identity between species homologues of GSK-3 has been shown to be in excess of 98% within the catalytic domain (Plyte et al., Biochim. Biophys. Acta 1114, pp. 147-162, 1992). Given the remarkably high degree of conservation across the phylogenetic spectrum, it is suggested that GSK-3 plays an essential role in cellular processes.

GSK-3 has been implicated in a number of different disease states and conditions. For example, Chen et al. (Diabetes 43, pp. 1234-1241, 1994) suggested that increased GSK-3 activity may be important in type 2 diabetes. Increased expression of GSK-3 in diabetic muscle is also thought to contribute to the deleterious glycogen synthase activity and insulin resistance in skeletal muscle in type 2 diabetes (Nikoulina et al., Diabetes 49, pp. 263-271, 2000). Also, increased protein phosphatase type 1 activity measured in non-motile sperm has been attributed to higher GSK-3 activity and is thought to be responsible for the motility of sperm in controls (Vijayaraghavan et al., Biology of Reproduction 54, pp. 709-717, 1996). Vijayaraghavan et al. suggests that such results provide a biochemical basis for the development and regulation of sperm motility and a possible physiological role for the phosphatase 1/inhibitor 2/GSK-3 system. GSK-3 activity has also been associated with Alzheimer's disease and mood disorders such as bipolar disorder (World Patent Publication No. WO 97/41854). In addition to other conditions, GSK-3 has also been implicated in hair loss, schizophrenia, and neurodegeneration, including chronic neurodegenerative disorders (such as Alzheimer's disease) and neurotrauma, such as stroke, traumatic brain injury, and spinal cord injury.

The essence of the invention

The essence of the invention is an imidazole derivative of general formula I

R ¹ —N

-R—R ⁴ ( I) where means

R ¹ is a straight-chain or branched alkyl group with 1 to 8 carbon atoms, a straight-chain or branched alkenyl group with 2 to 8 carbon atoms, a straight-chain or branched alkynyl group with 2 to 8 carbon atoms, a cycloalkyl group with 3 to 8 carbon atoms, a cycloalkenyl group with 4 to 8 carbon atoms, a three- to eight-membered heterocycloalkyl group, a bicycloalkyl group with 5 to 11 carbon atoms, a bicycloalkenyl group with 7 to 11 carbon atoms, a five- to eleven-membered heterobicycloalkyl group, an aryl group with 6 to 14 carbon atoms or a five- to fourteen-membered heteroaryl group, wherein the group R ¹ is optionally substituted with one to six substituents R ⁵ independently selected from the group comprising a fluorine, chlorine, bromine and iodine, nitro group, cyano group, trifluoromethyl group, -NR ⁷ R ^S , -NR ⁷ C(=0)R ^s , -NR ⁷ C(=0)0R ^s , -NR ⁷ C(=0)NR ^S R ⁹ ,

-NR ⁷ S(=0) ₂ R ^s , -OC(=O)OR ⁷ ,

-NR ⁷ S(=0> ₂ NR ⁸ R ⁹ , -OR ⁷ , -OC(=O)R ⁷ ,

-C(=O)OR ⁷ , -C(=O)R ⁷ , -C(=O)NR ⁷ R ⁸ ,

-OC( =O)NR ⁷ R ⁸ , -OC(=O)SR ⁷ , -SR ⁷ , -S(=O)R ⁷ , -S(=O)2R ⁷ ,

-S(=O>2NR ⁷ R ^s , -OS(=O)2R ⁷ , -N3 and R ⁷ ,

R ² is a hydrogen atom, fluorine, methyl group, cyano group, or -C(=O)OR ⁷ - group,

R ³ the group -C(=O)NR ⁹ , -C(=0)0-, -C(=0)(CR ^1O R ¹¹ ) _n * or

-(CR ^1O R ¹¹ ) _n R ⁴ is a straight-chain or branched alkyl group of 1 to 8 carbon atoms, a straight-chain or branched alkenyl group of 2 to 8 carbon atoms, a straight-chain or branched alkynyl group of 2 to 8 carbon atoms, a cycloalkyl group of 3 to 8 carbon atoms, a cycloalkenyl group of 4 to 8 carbon atoms, a three- to eight-membered heterocycloalkyl group, a bicycloalkyl group of 5 to 11 carbon atoms, a bicycloalkenyl group of 7 to 11 carbon atoms, a five- to eleven-membered heterobicycloalkyl group, aryl group of 6 to 14 carbon atoms or a five- to fourteen-membered heteroaryl group, wherein the R ⁴ group is optionally substituted with one to six substituents R ⁶ independently of one another selected from the group consisting of fluorine, chlorine, bromine and iodine, nitro, cyano, trifluoromethyl, -NR ⁷ R ⁸ , -NR ⁷ C(=O)R ⁸ , -NR ⁷ C(=O)OR ⁸ , -NR ⁷ CÍ=O)NR ⁸ R ⁹ ,

-NR ⁷ S(=0)2R ^with , -NR ⁷ S(=O)2NR ^with R ⁹ , -OR ⁷ , -OC(=O)R ⁷ ,

-C(=0)0R ⁷ , -C(=0)R ⁷ , -C(=0)NR ⁷ R ⁸ ,

-0C(=0)SR ⁷ , -SR ⁷ , -S(=0)R ⁷ , -S(=0)2R ⁷ ,

-0C(=0)0R ⁷ , -0C(=0)NR ⁷ R ⁸ ,

-S(=0) ₂ NR ⁷ R ⁸ and R ⁷ ,

R ⁷ , R ⁸ and R ⁹ independently of each other are a hydrogen atom, a straight-chain or branched alkyl group with 1 to 8 carbon atoms, a straight-chain or branched alkenyl group with 2 to 8 carbon atoms, a straight-chain or branched alkynyl group with 2 to 8 carbon atoms, a cycloalkyl group with 3 to 8 carbon atoms, a cycloalkenyl group with 4 to 8 carbon atoms, a three- to eight-membered heterocycloalkyl group, a bicycloalkyl group with 5 to 11 carbon atoms, a bicycloalkenyl group with 7 to 11 carbon atoms, a five- to eleven-membered heterobicycloalkyl group, an aryl group with 6 to 14 carbon atoms or a five- to fourteen-membered heteroaryl group, wherein the group R ⁷ , R ⁸ and R ⁹ is optionally substituted independently of each other with one to six substituents from the group consisting of fluorine, chlorine, bromine and iodine atoms, nitro group, cyano group, trifluoromethyl group, -NR ^1O R ¹¹ ,

-NR ^1O C(=0)R ¹¹ , -NR ^1O C(=0)OR ¹¹ , -NR ¹ °C(=0)NR ¹¹ R ¹² ,

-NR ^1O S(=0)2R ¹¹ , -NR ^1O S(=0)2NR ¹ tR ¹² , -OR ¹⁰ , -OC(=O)R ¹⁰ , -OC(=O)OR ¹⁰ , -OC(=0)NR ^1O R ¹¹ , -OC(=O)SR ¹⁰ , -SR ¹⁰ ,

-S(=0)R ¹⁰ , -S(=0)2R ¹⁰ , -S(=0)2NR ^1o R ¹¹ , -C(=0)R ¹⁰ ,

-C(=O)OR ¹⁰ , -C<=O)NR ¹ °R ¹¹ and R ¹⁰ , or if R ⁷ and R ⁸ represent the group NR ⁷ R ⁸ , this group may optionally be combined with the nitrogen atom of the group NR ⁷ R ⁸ to which it is attached to form a three- to seven-membered heterocycloalkyl moiety, which optionally contains one or two additional heteroatoms from the group consisting of nitrogen, oxygen and sulfur,

R ¹⁰ , R ¹¹ and R ¹² independently of each other are hydrogen, straight or branched chain alkyl of 1 to 8 carbon atoms, straight or branched chain alkenyl of 2 to 8 carbon atoms, straight or branched chain alkynyl of 2 to 8 carbon atoms, straight or branched chain cycloalkyl of 3 to 8 carbon atoms, cycloalkenyl of 4 to 8 carbon atoms, three to eight membered heterocycloalkyl, bicycloalkyl of 5 to 11 carbon atoms, bicycloalkenyl of 7 to 11 carbon atoms, five to eleven membered heterobicycloalkyl, aryl of 6 to 14 carbon atoms or five to fourteen membered heteroaryl, wherein the group R ¹⁰ , R ¹¹ , and R ¹² is optionally independently substituted with one to six substituents from the group consisting of fluorine, chlorine, bromine and iodine, nitro, cyano, trifluoromethyl, -NR ¹³ R ¹⁴ , -NR ¹³ C(=0)R ¹⁴ , -NR ¹³ C(=0)OR ¹⁴ , -NR ¹³ C(=0)NR ¹⁴ R ¹⁵ , -NR ¹³ S(=0) ₂ R ¹⁴ , -NR ¹³ S(=0>2KR ¹⁴ R ¹⁵ , -OR ¹³ , -OCC=O)R ¹³ ,

OC(=O)OR ¹³ , -0C(=0)NR ¹³ E ¹⁴ , -0C(=0)SR ¹³ , -SR ¹³ ,

-S(=0)R ¹³ , -S(=0) ₂ R ¹³ ,

-C(=0)0R ¹³ , -C(=0)NR ¹³ R ¹⁴ and

-S(=0) ₂ NR ¹³ R ¹⁴ , R ¹³ ,

-C(=O)R ¹³ ,

R ¹³ , hydrogen atom, straight or branched chain alkyl group of 8 carbon atoms, straight non-alkynyl with 2 to 8 carbon atoms, cycloalkylcycloalkenyl with 4 to 8 carbon atoms, bicycloalkenyl, five to eleven membered heterocycloalkyl, with 6 to 14 carbon atoms, heteroaryl, optionally substituted with substituents from the group consisting of bromine and iodine, nitro group, fluoromethyl, -NR ¹⁶ R ¹⁷ j)OR ¹⁷ , -NR ¹⁶ C(=0)NR ¹⁷ R ¹⁸

NR ¹⁷ R ¹⁸ , -0R ¹⁶ , -0C(=0)R ^{16 17} , -0C(=0)SR ¹⁶ , -SR ¹⁶ ~S(=0) ₂ NR ¹⁶ R ¹⁷ , -C(=0)R ¹⁶

^R16 ,

R ¹⁴ and R ¹⁵ are independently one of 1 to 8 carbon atoms, 2 to 3 branched chain alkenyl, straight or branched chain alkenyl, 3 to 8 carbon atoms, 3 to 8 bicycloalkyl, 5 to 11 carbon atoms, 7 to 11 carbon atoms, heterobicycloalkyl, aryl, or a five to fourteen membered group R ¹³ , R ¹⁴ and R ¹⁵ are independently one to six membered fluorine, chlorine, cyano, -NR ¹⁶ C(=O)R ¹⁷ , -NR ¹⁶ C(=

-NR ¹⁶ S(=0)3R ¹⁷ , -NR ¹⁶ S(=0)

-OC(=0)OR ¹⁶ , -OC(=0)NR ¹⁶ fc

-S(=0)R ¹⁶ , -S(=0) ₂ R ¹⁶ ,

-C(=0)0R ¹⁶ , -C(=0)NR ¹⁶ R ¹⁷ and

R ¹⁶ , R ¹⁷ and R ^1S independently of each other are a hydrogen atom, a straight-chain or branched alkyl group with 1 to 8 carbon atoms, a straight-chain or branched alkenyl group with 2 to 8 carbon atoms, a straight-chain or branched alkynyl group with 2 to 8 carbon atoms, a cycloalkyl group with 3 to 8 carbon atoms, a cycloalkenyl group with 4 to 8 carbon atoms, a three- to eight-membered heterocycloalkyl group, a bicycloalkyl group with 5 to 11 carbon atoms, a bicycloalkenyl group with 7 to 11 carbon atoms, a five- to eleven-membered heterobicycloalkyl group, an aryl group with 6 to 14 carbon atoms or a five- to fourteen-membered heteroaryl group, η 0, 1, 2 or 3, where R ¹⁰ and R ¹¹ in the group -C<=O)(CR ¹⁰ R ¹¹ )n- and -(CR ¹⁰ R ¹¹ )n are defined independently of each other for each repetition n as defined above, and pharmaceutically acceptable salts thereof.

The compounds of formula I according to the invention are inhibitors of serine/threonine kinases, particularly cyclin-dependent kinases such as cdk5 and cdk2, and are useful for the treatment of neurodegenerative disorders and other disorders of the central nervous system and abnormal cell growth, including cancer. The compounds of formula I according to the invention are particularly useful for inhibiting cdk5. The compounds of formula I according to the invention are also useful as GSK-3 inhibitors.

The term alkyl is particularly intended, unless expressly stated otherwise, to mean saturated monovalent straight-chain or branched hydrocarbon groups. Examples of alkyl groups include, without any intention of limitation, methyl, ethyl, propyl, isopropyl and tert-butyl.

The term "alkenyl" refers, unless expressly stated otherwise, to alkyl groups having at least one double bond, wherein alkyl has the meaning given above. Examples of alkenyl groups include, without any intention of limitation, ethenyl and propenyl.

The term "alkynyl" refers, unless expressly stated otherwise, to alkyl groups having at least one triple bond, wherein alkyl has the meaning given above. Examples of alkynyl groups include, without any intention of limitation, ethynyl and 2-propynyl.

The term "cycloalkyl" refers, unless expressly stated otherwise, to non-aromatic saturated cyclic alkyl groups, wherein alkyl has the meaning given above. Examples of cycloalkyl groups include, without any intention of limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. The term "bicycloalkyl" refers, unless expressly stated otherwise, to non-aromatic saturated carbocyclic groups with two rings, such rings having one or two carbon atoms in common. According to the invention, unless otherwise stated, bicycloalkyl groups include spiro groups and fused cyclic groups. Examples of bicycloalkyl groups include, without any intention of limitation, bicyclo[3.1.Olhexyl, norbornyl, spiro[4.4.5]decyl, spiro[4.4.3nonyl, spiro[4.3.3octyl and spiro[4.2]heptyl. The terms "cycloalkenyl" and "bicycloalkenyl" mean, unless expressly stated otherwise, non-aromatic carbocyclic cycloalkyl and bicycloalkyl groups as defined above, but containing one or more double bonds between two carbon atoms connecting carbon atoms in a ring ("endocyclic double bond") and/or one or more double bonds between two carbon atoms connecting a carbon atom in a ring and an adjacent non-cyclic carbon atom (exocyclic double bond). Examples of cycloalkenyl groups include, without any intention of limitation, cyclopentenyl and cyclobutenyl, and examples of bicycloalkenyl groups include norbornenyl. The cycloalkyl, cycloalkenyl, bicycloalkyl, and bicycloalkenyl groups also include groups with one or more substituents. Examples of groups with oxo groups include oxocyclopentyl, oxocyclobutyl, oxocyclopentenyl and norcamphor.

The term aryl, unless expressly stated otherwise, refers to an organic group derived from aromatic hydrocarbons by the removal of one hydrogen atom, such as phenyl, naphthyl, indenyl and fluorenyl.

For example, the terms “heterocyclic” and heterocycloalkyl refer to non-aromatic cyclic groups containing one or more heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen. The term heterobicycloalkyl refers to non-aromatic bicyclic groups whose rings share one or two atoms in common and whose at least one ring contains a heteroatom (oxygen, sulfur, or nitrogen). According to the invention, unless otherwise indicated, heterobicycloalkyl groups include spiro groups and fused cyclic groups. According to one embodiment, each ring in a heterobicycloalkyl group contains up to four heteroatoms (i.e., from zero to four heteroatoms, provided that at least one ring contains at least one heteroatom). Heterocyclic groups according to the invention also include ring systems substituted with one or more oxo groups. Examples of non-aromatic heterocyclic groups include aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, azepinyl, piperazinyl, 1,2,3,6-tetrahydropyridinyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholino, thiomorpholino, thioxanyl, pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, quinolizinyl, quinuclidinyl, 1,4-dioxaspiro[4.53decyl, 1,4-dioxaspiroC4.43nonyl, 1,4-dioxaspiro[4.33octyl and 1,4-dioxaspiro10[4.2]heptyl groups.

The term heteroaryl refers to aromatic cyclic groups containing one or more heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, preferably one to four heteroatoms. A polycyclic group containing one or more heteroatoms, at least one of which is aromatic, is referred to herein as heteroaryl. The heteroaryl groups of the invention may also include ring systems substituted with one or more oxo groups. Examples of heteroaryl groups include pyridinyl, pyridazinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, quinolyl, isoquinolyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, triazinyl, purinyl, oxadiazolyl, thiadiazolyl, benzofurazanyl, benzothiophenyl, benzotriazolyl, benzothiazolyl, benzoixazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, dihydroquinolyl, tetrahydroquinolyl, dihydroisoquinolyl, tetradroisoquinolyl, benzofuryl, furopyridinyl, pyrrolopyrimidinyl and an azaindolyl group.

i so i ndolyl, furazane1,

The above groups derived from the above compounds may optionally be attached to a carbon or nitrogen atom. For example, a group derived from pyrrole may be pyrrol-1-yl (N-attached) or pyrrol-3-yl (C-attached). The invention also includes all possible tautomers.

In one embodiment, the invention relates to compounds of formula I, wherein ^R3 is -C(=O) ^NR9- or -C(=O)( ^CR10R11 ) ^n- . In another embodiment ^{, R10} and ^R11 of the -C(=O)( ^CR10R11 )n- group are each hydrogen at each occurrence of n.

• · · · · • · · · •··· ··· ··· ···

In another embodiment, R ⁹ in the group -C(=O)NR ⁹ - represents a hydrogen atom. In another embodiment, R ³ represents a group -C(=O)NR ⁹ or a group -C(=O)(CR ¹⁰ R ¹¹ )n~ and R ² represents a hydrogen atom.

In another embodiment, the invention relates to compounds of formula I, wherein R ¹ is an optionally substituted cycloalkyl group of 3 to 8 carbon atoms or an optionally substituted bicycloalkyl group of 5 to 11 carbon atoms. In a preferred embodiment, R ¹ is a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or norbornyl group, each of which is optionally substituted as defined above (i.e., optionally with one to six R ⁵ substituents independently selected from the group consisting of fluorine, chlorine, bromine and iodine, nitro, cyano, trifluoromethyl, -NR ⁷ R ⁸ , -NR ⁷ C(=O)R ⁸ ,

-NR ⁷ C(=O)OR ^S , -NR ⁷ C(=0)NR ^S R ⁹ , -NR ⁷ S(=0)3R ^S , -NR ⁷ S(=0>2NR ^with R ⁹ ,

-OR ⁷ , -0C(=0)R ⁷ , -0C(=0)0R ⁷ , -C(=0)OR ⁷ , -C(=0)R ⁷ , -C(=O)NR ⁷ R ^S , -0C(=O)NR ⁷ R ^S , -OC(=O)SR ⁷ , -SR ⁷ , -S(=O)R ⁷ , -S(=0) ₂ R ⁷ ,

-S(=0>2NR ⁷ R ^s and R ⁷ ). According to a more preferred embodiment, R ¹ represents a cycloalkyl group with 3 to 8 carbon atoms or an optionally substituted bicycloalkyl group with 5 to 11 carbon atoms, for example a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or norbornyl group, each of these groups being optionally substituted with one to three substituents independently selected from the group comprising a fluorine, chlorine, bromine and iodine atom, a nitro group, a cyano group, a trifluoromethyl group, a -NR ⁷ R ^S group, -NR ⁷ C(=O)R ^s , -OR ⁷ ,

-C(=O)0R ⁷ , -C(=O)R ⁷ and R ⁷ . According to an even more preferred embodiment, R ¹ represents a cycloalkyl group with 3 to 8 carbon atoms or an optionally substituted bicycloalkyl group with 5 to 11 carbon atoms, for example a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or norbornyl group, wherein the R ¹ group is substituted by a -NR ⁷ C(=O)R ^S group, an aryl group with 6 to 14 carbon atoms, a three- to eight-membered heterocycloalkyl group or a five- to fourteen-membered heteroaryl group and the aryl, heterocycloalkyl and heteroaryl groups are optionally substituted by one to six substituents independently selected from the group comprising a fluorine, chlorine, bromine and iodine atom, a nitro group, a cyano group, a trifluoromethyl, -NR ^1O R ¹¹ , -NR ^1O C(=0)R ⁴¹ ,

-NR ^1O C(=0)OR ¹¹ , -NR ^1O C(=O)NR ¹¹ R ¹² , -NR ^1O S(=0) ₂ R' ¹ .

-NR ¹ °S(=0)2NR ¹¹ R ¹² , -OR ¹⁰ , -OC(=O)R ¹⁰ , -OC(=O)OR ¹⁰ ,

-0C(=0)NR ^1O R ¹¹ , -OC(=O)SR ¹⁰ , -SR ¹⁰ , -S(=0)R ¹⁰ , -S(=O)2R ¹⁰ , -S(=O)2NR ¹ °R ¹¹ , -C(=O)R ¹⁰ , -C(=O)OR ¹⁰ , -C(=O)NR ¹ °R ¹¹ and ^R10 . According to another embodiment of the invention, R ¹ represents a bicyclo[3.1.0]hexyl group, which is optionally substituted by the above-mentioned substituents, i.e. optionally substituted by one to six substituents R ⁵ independently selected from the group consisting of fluorine, chlorine, bromine and iodine atoms, a nitro group, a cyano group, a trifluoromethyl group, a group -NR ⁷ R ⁸ , -NR ⁷ C(=0)R ⁸ , -NR ⁷ C(=0)OR ⁸ , -NR ⁷ C(=0)NR ^S R ⁹ , -NR ⁷ S<=0) 2R ^S , -NR ⁷ S(=O)2NR ⁸ R°, -OR ⁷ , -OC(=0)R ⁷ , -OC(=0)OR ⁷ , -C(=0)OR ⁷ , -C(=0)R ⁷ , -C(=0)NR ⁷ R ^s , -0C(=O)NR ⁷ R ⁸ , -0C(=0)SR ⁷ , -SR ⁷ , -S(=O)R ⁷ , -S(=0)2R ⁷ , -S(=0)2NR ⁷ R ^s and R ⁷ ).

According to yet another embodiment, the invention relates to compounds of formula I, wherein R ¹ is an optionally substituted straight or branched chain alkyl group having 1 to 8 carbon atoms or an optionally substituted straight or branched chain alkenyl group having 2 to 8 carbon atoms.

According to yet another embodiment, the invention relates to compounds of formula I, wherein R ² is hydrogen. According to yet another embodiment, the invention relates to compounds of formula I, wherein R ² is hydrogen and R ¹ is as defined above.

In yet another embodiment, the invention relates to compounds of formula I, wherein R ⁴ is an aryl group of 6 to 14 carbon atoms or a 5 to 14 membered heteroaryl group, each of which is optionally substituted. In a preferred embodiment, the invention relates to compounds of formula I, wherein R ⁴ is an optionally substituted phenyl group or an optionally substituted pyridyl group. In another preferred embodiment, the invention relates to compounds of formula I, wherein R ⁴ is a naphthyl, quinolyl or isoquinolyl group, each of which is optionally substituted. In another preferred embodiment, the invention relates to compounds of formula I, wherein R ⁴ is an unsubstituted naphthyl, quinolyl or isoquinolyl group.

According to another preferred embodiment, the invention relates to compounds of general formula I, wherein R ³ represents a hydrogen atom and R ⁴ has the meaning given above.

The following compounds are examples of preferred compounds of general formula I:

N-(1-cyclobutyl-1H-imidazol-4-yl)-2-quinolin-6-ylacetamide,

N - ( 1 -cyclopentyl - IE - imidazol - 4-yl) -2-(.4-methoxyphenyl) acetamide, N -[1 - ( cis -3-phenylcyclobutyl-1H-imidazol-4-yl3-2-quinolin-6-ylacetamide, (1-cyclobutyl-1H-imidazol-4-yl)carbamic acid phenyl ester,

1-(1-Cyclobutyl-1H-imidazol-4-yl)-3-isoquinolin-5-ylurea, N-C1-(cis-3-aminocyclobutyl)-1H-imidazol-4-yl3-2-naphthalen-1-ylacetamide, <cis-3-[4-(2-naphthalen-1-ylacetylamino)imidazol-1-yl]cyclobutyl 6-methylpyridine-2-carboxylic acid amide, cis-3-[4-(2-naphthalen-1-ylacetylamino)imidazol-1-yl3-cyclobutyl) 1H-imidazole-4-carboxylic acid amide, cis-3-[4-(2-naphthalen-1-ylacetylamino)imidazol-1-yl3 cyclobutyl)amide 6-hydroxypyridine-2-carboxylic acid, cis-3-[4-(2-naphthalen-1-ylacetylamino)imidazole Acid 1-yl3-cyclobutylamide 3-methylpyridine-2-carboxylic,

2-Pyridin-3-yltriazole-4-carboxylic acid (cis-3-[4-(2-naphthalen-1-ylacetylamino)imidazol-1-yl)cyclobutylamide, 6-cis-3-[4-(2-naphthalen-1-ylacetylamino)imidazol-1-yl]cyclobutylcarbamoyl)nicotinic acid methyl ester, (cis-3-[4-(2-naphthalen-1-ylacetylamino)imidazol-1-yl)cyclobutylamide pyrazine-2-carboxylic,

5-Methylpyrazine-2-carboxylic acid N-(cis-3-[4-(2-naphthalen-1-ylacetylamino)imidazol-1-ylIcyclotyltyl)benzamide, 5-methylpyrazine-2-carboxylic acid cis-3-[4-(2-naphthalen-1-ylacetylamino)imidazol-1-yl]cyclobutylamide 5-Methylpyrazine-2-carboxylic acid, cis-3-[4-(2-Naphthalen-1-ylacetylamino)imidazol-1-ylIcyclobutyl)isobutyramide, cis-3-[4-(2-Naphthalen-1-ylacetylamino)imidazol-1-yl1cyclobutylamide quinoline-2-carboxylic, 1H-pyrrole-2-carboxylic acid cis-3-[4-(2-naphthalen-1-ylacetylamino)imidazol-1-yl1-cyclobutylamide,

N-cis-3-[4-(2-naphthalen-1-ylacetylamino)imidazol-1-yl1cyclobutyl)-2-ra-tolylacetamide, pyridin-2-carboxylic acid cis-3-[4-(2-naphthalen-1-ylacetylamino)imidazol-1-yl1cyclobutylamide,

2-(3-Hydroxyphenyl)-N-cis-3-[4-(2-naphthalen-1-ylacetylamino)imidazol-1-ylcyclobutylacetamide, piperidine-4-carboxylic acid cis-3-[4-(2-naphthalen-1-ylacetylamino)imidazol-1-ylcyclobutylamide hydrochloride,

N-[1-(cis-3-acetylaminocyclobutyl)-1H-imidazol-4-yl]-2-naphthalen-2-ylacetamide,

N-cis-3-[4-(2-isoquinolin-5-ylacetylamino)imidazol-1-ylcyclobutyl}benzamide and cis-3-[4-(2-isoquinolin-5-ylacetylamino)imidazol-1-ylcyclobutylamide of pyridine-2-carboxylic acid and pharmaceutically acceptable salts of said compounds.

Examples of other specific compounds of general formula I according to the invention are:

c is-N-(1-bicycloE 3.1.01hex-3-yl-1H-imidazol-4-yl 3-2-quinolin-6-ylacetamide, cis-N-Cl-trans-6-(pyridine-2-carbony13b icycloE 3.1.01hex-3-yl-1H-i midazol-4-yl3-2-quinolin-6-ylacetamide,

N-El-Ecis-3-(2-Methoxyphenyl-3-cyclobutyl]-1H-1-midazol-4-yl1-2-quinolin-6-ylacetamide,

N-El-Ecis-3-(2-Fluorophenyl)cyclobutyl1-1H-imidazol-4-yl3-2-quinolin-6-ylacetamide,

M-yl-Ecis-3-(4-methoxyphenyl-3-cyclobutyl]-1H-imidazol-4-yl3-2-quinolin-6-ylacetaroid,

2-quinolin-6-yl-N-1-E cis-3-p-tolylcyclobutyl1-1H-imidazol-4-yl3-acetamide,

N-yl-Ecis-3-(2-ethoxyphenyl)cyclobutyl-3-1H-imidazol-4-ylJ-2quinolin-6-ylacetamide,

N-1-E cis -3-(3-methoxyphenyl)cyclobutyl-1-1H-imidazol-4-yl-3-2-quinolin-6-ylacetamide and pharmaceutically acceptable salts thereof.

Examples of other specific compounds of general formula I according to the invention are:

N-yl-E3-(2-hydroxyphenyl3cyclobutyl]-1H-imidazol-4-yl1-2-(4methoxyphenyl3acetamide,

N-E1-E3-(3-Hydroxyphenyl3cyclobutyl]-1H-imidazol-4-yl3-2-(4methoxyphenyl)acetamide,

N-yl-E3-(2-aminophenyl-3-cyclobutyl-1-1H-imidazol-4-yl3-2-(4-methoxyphenyl-3-acetamide),

N-11-E3-C 3-aminophenyl-3-cyclobutyl-1-1H-imidazol-4-yl 3-2-(4-methoxyphenyl-3-acetamide,

N-yl-E3-(3-aminomethyl-1-phenylcyclobutyl-3-1H-imidazol-4-yl)-2-(4-methoxy-phenyl-3-acetam i d,

N-Í1-E3-Í 3-dimethylaminomethylphenyl-3-cyclobutyl-3-1H-imidazol-4-yl3-2-(4-methoxyphenyl-3-acetamide, « « • ·

99 • · · · Λ • · ·

2-(4-methoxyphenyl-N-[1-[3-[1-methyl-1H-pyrazol-3-yl)cyclobutyl]-1H-imidazol-4-yl]-acetamide and pharmaceutically acceptable salts thereof

Salts of the compounds of formula I can be prepared using any acidic or basic groups of the compounds of formula I. Examples of pharmaceutically acceptable salts include salts of the compounds of formula I with hydrochloric, p-toluenesulfonic, fumaric, citric, succinic, salicylic, oxalic, hydrobromic, phosphoric, methanesulfonic, tartaric, maleic, di-ρ-toluoyltartaric, acetic, sulfuric, hydroiodic, mandelic, sodium, potassium, magnesium, calcium and lithium acids.

The compounds of formula I may have optical centers and therefore may exist in different enantiomeric and other stereoisomeric configurations. The invention includes all such enantiomers, diastereomers and other stereoisomers of the compounds of formula I, as well as racemic and other mixtures thereof.

The invention also includes isotopically labeled compounds which are identical to the compounds of formula I but in which one or more atoms have been replaced by an atom having an atomic mass or mass number different from that usually found in nature. Examples of isotopes which may be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, iodine and chlorine, such as ³ H, ^1X O, ¹⁴ C, ^1S F, ¹²³ I and ¹²⁵ I. The invention includes compounds of the invention and pharmaceutically acceptable salts thereof which contain the above-mentioned isotopes and/or other isotopes of other atoms. Isotope labeled compounds of the invention, for example compounds into which ³ H and ¹⁴ C have been incorporated, are useful for drug testing and/or for distribution in substrate tissue. Tritiated isotopes, i.e. ³ H and carbon-14-doped, i.e. ¹⁴ C, are particularly suitable for their ease of preparation and detection. The isotopes ¹¹ C and ¹⁵ F are particularly suitable for positron emission tomography (PET) and the isotopes ¹³⁵ J are particularly suitable for single-photon emission computed tomography (SPECT), a brain imaging technique. In addition, substitution with heavier isotopes such as deuterium, i.e. ² H, may provide certain therapeutic advantages due to its greater metabolic stability, for example, increased in vivo half-life or the possibility of reduced dosage, and may therefore be advantageous in certain circumstances. The isotopically labeled compounds of formula I according to the invention may be prepared by the methods illustrated in the Schemes and/or in the Examples, by replacing the non-isotopically labeled reagent with a readily available isotopically labeled reagent.

The invention also relates to pharmaceutical compositions for the treatment of a disease or condition involving abnormal cell growth in mammals, which comprise a compound of formula I in an amount effective to inhibit abnormal cell growth together with a pharmaceutically acceptable carrier.

The invention also relates to pharmaceutical compositions for the treatment of a disease or condition involving abnormal cell growth in mammals, which comprise a compound of formula I in an amount effective to inhibit cdk2 activity together with a pharmaceutically acceptable carrier.

The invention also relates to a method of treating a disease or condition involving abnormal cell growth in a mammal, comprising administering a compound of formula I in an amount effective to inhibit abnormal cell growth.

The invention also relates to a method of treating a disease or condition involving abnormal cell growth in a mammal, comprising administering a compound of formula I in an amount effective to inhibit cdk2 activity.

In the pharmaceutical composition or method of treating diseases or conditions of the invention involving abnormal cell growth, the disease or condition exhibiting abnormal cell growth is, in one embodiment, cancer. The cancer may be a carcinoma, for example, bladder, breast, colon, kidney, liver, lung, for example, small cell lung cancer, esophagus, gallbladder, ovary, pancreas, stomach, cervix, thyroid, prostate, or skin, for example, squamous cell carcinoma; a hematopoietic tumor of the lymphatic system, for example, leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, capillary lymphoma, or Burkett's lymphoma; a hematopoietic tumor of the myeloid system, for example, acute and chronic myeloid leukemia, myelodysplastic syndrome, or promyelocytic leukemia; a tumor of mesenchymal origin, for example fibrosarcoma, or rhabdomyosarcoma; a tumor in the central or peripheral nervous system, for example astrocytoma, neuroblastoma, glioma or schwannoma; melanoma; seminoma; teratocarcinoma; osteosarcoma; pigmented xenoderma; keratoctantoma; thyroid follicular cancer or Kaposi's sarcoma.

In another embodiment, the disease or condition involving abnormal cell growth is benign. Such diseases and conditions include benign prostatic hyperplasia, familial adenomatosis polyposis, neurofibromatosis, atherosclerosis, pulmonary fibrosis, arthritis, psoriasis, glomerulonephritis, restenosis, hypertrophic scarring, inflammatory bowel disease, transplant rejection, fungal infections, and endotoxic shock.

The invention also provides pharmaceutical compositions for the treatment of neurodegenerative diseases or conditions in mammals, the composition comprising a compound of formula I in an effective amount for the treatment of such disease or condition and a pharmaceutically acceptable carrier.

The invention also provides pharmaceutical compositions for treating neurodegenerative diseases or conditions in mammals, the composition comprising a compound of formula I in an amount effective to inhibit cdk5 activity and a pharmaceutically acceptable carrier.

The invention also relates to a method of treating a neurodegenerative disease or condition in mammals, comprising administering to the mammal a compound of formula I in an amount effective to inhibit cdk5 activity.

The invention also relates to a method of treating a neurodegenerative disease or condition in mammals, comprising administering to the mammal a compound of formula I in an amount effective to treat the disease or condition.

In one embodiment of the invention, the neurodegenerative disease or condition to be treated is Huntington's disease, stroke, spinal cord trauma, traumatic brain injury, multi-infarct dementia, epilepsy, amyotrophic lateral sclerosis, pain, viral or AIDS-related dementia, neurodegeneration associated with bacterial infection, migraine, hypoglycemia, urinary incontinence, cerebral ischemia, multiple sclerosis, Alzheimer's disease, senile dementia of the Alzheimer type, mild cognitive impairment, age-related decline in consciousness, emesis, corticobasal degeneration, dementia pugilistica, Down syndrome, myotonic dystrophy, Niemann-Pick disease, Pick's disease, prion disease with vertigo, progressive supranuclear palsy, inferior lateral sclerosis, and subacute sclerotic virginia fali t i da.

The invention also relates to a pharmaceutical composition for treating a disease or condition whose treatment can be affected or facilitated by altering dopamine-mediated neurotransmission in mammals, the composition comprising a cdk5 inhibitor in an amount effective to treat such disease or condition and a pharmaceutically acceptable carrier.

The invention also relates to a pharmaceutical composition for treating a disease or condition, the treatment of which can be affected or facilitated by altering dopamine-mediated neurotransmission in mammals, comprising a cdk5 inhibitor in an amount effective to inhibit cdk5 and a pharmaceutically acceptable carrier.

The invention further relates to a method of treating a disease or condition, or facilitating the alteration of dopamine-mediated neurotransmission in mammals, by administering an amount effective to inhibit cdk5 activity.

The invention also relates to a method of treating a disease or condition, the treatment of which can be affected or facilitated by altering dopamine-mediated neurotransmission in mammals by administering a cdk5 inhibitor in an amount effective to treat such disease or condition.

In one embodiment, the disease or condition whose treatment can be influenced or facilitated by altering dopamine-mediated neurotransmission in mammals is Parkinson's disease, schizophrenia, schizophreniform disorder, schizoaffective disorder, e.g., delusional type, or depressive type, substance-induced psychotic disorder, e.g., alcohol, amphetamine, cannabis, cocaine, hallucinogens, inhalants, opiates, or phencyclidine-induced psychosis; paranoid personality disorder, schizoid personality disorder; drug addiction, including addiction to narcotics (e.g., heroin, opium, and morphine), cocaine, and alcohol; drug withdrawal including narcotic, cocaine, and alcohol withdrawal; obsessive-compulsive disorder, Tourette's syndrome; depression; major depressive episode, manic or mixed mood episode, hypomanic mood episode, depressive episode with atypical features, or melancholy.

lic features or catatonic features, delayed-onset mood episode, post-stroke depression, major depressive disorder, dysthymic disorder, minor depressive disorder, premenstrual dysphoric disorder, post-psychotic depressive disorder schizophrenia, major depressive disorder superimposed on a psychotic disorder such as delusional disorder or schizophrenia, bipolar disorder, e.g., bipolar I disorder, bipolar II disorder, cytothymic disorder, anxiety, attention deficit hyperactivity disorder, and attention deficit disorder.

In another embodiment, the cdk5 inhibitor in a method of treating a disease or condition whose treatment can be affected or facilitated by altering dopamine-mediated neurotransmission is a compound of formula I or a pharmaceutically acceptable salt thereof.

The invention also relates to a pharmaceutical composition for treating a disease or condition facilitated by cdk5 activity in a mammal, the composition comprising a compound of formula I in an amount effective to inhibit cdk5 activity and a pharmaceutically acceptable carrier.

The invention also relates to a method of treating a disease or condition mediated by cdk5 activity in a mammal, comprising administering to the mammal a compound of formula I in an amount effective to inhibit the activity of cdk5.

It has also been found that the compounds of formula I have inhibitory effects on GSK-3. It is expected that the compounds of formula I may be effective in treating diseases and conditions that may be affected or alleviated by inhibition of GSK-3. Diseases and conditions whose treatment may be effected or alleviated by inhibition of GSK-3 include neurodegenerative diseases and conditions. Neurodegenerative diseases and conditions are described above and include, without any intention of limitation, for example, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, stroke, cerebral ischemia, AIDS-related dementia, neurodegeneration associated with bacterial infection, multi-infarct dementia, traumatic brain injury and spinal cord trauma. Therefore, the compounds of formula I may be effective in treating neurodegenerative diseases and conditions based on the activity of both cdk5 and GSK-3.

Other diseases and conditions whose treatment may be influenced or alleviated by inhibition of GSK-3 include psychotic disorders and conditions, such as schizophrenia, schizophreniform disorder, schizoaffective disorder, e.g. delusional type or depressive type, substance-induced psychotic disorder, e.g. alcohol, arafetamine, cannabis, cocaine, hallucinogens, inhalants, opiates or phencyclidine-induced psychosis: paranoid personality disorder, schizoid personality disorder. Treatment of such diseases and conditions may be effected or facilitated by altering dopamine-mediated neurotransmission. Therefore, compounds of formula I are effective in treating such diseases and conditions based on the activity of both cdk5 and GSK-3.

Other diseases or conditions that may be treated or alleviated by GSK-3 inhibition include mood disorders and mood episodes, such as major depressive episode, manic or mixed mood episode, hypomanic mood episode, depressive episode with atypical features or with melancholic features, delayed onset mood episode, post-stroke depression, major depressive episode, dysthymic episode, major depressive disorder, premenstrual dysphoric disorder, post-psychotic depressive disorder, schizophrenia, major depressive disorder overlaid with a psychotic disorder such as delusional disorder or schizophrenia, such as bipolar I disorder, bipolar II disorder, and cyclothymic disorder. Treatment of such mood disorders and episodes, such as depression, may also be treated or facilitated by altering dopamine-mediated neurotransmission. Therefore, compounds of general formula I are effective in treating certain mood disorders and mood episodes based on the activity of both cdk5 and GSK-3.

Other disorders and conditions whose treatment may be achieved or facilitated by GSK-3 inhibition include male fertility and sperm motility, diabetes mellitus, impaired glucose tolerance, metabolic syndrome or syndrome X; polycystic ovary syndrome; adipogenesis and obesity, myogenesis and frail, e.g. age-related decline in physical performance; acute sarcopenia, e.g. 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 baldness: immune deficiency; and cancer.

The invention also relates to pharmaceutical compositions for the treatment of mammals, including humans, for diseases or conditions selected from the group consisting of male fertility and sperm motility, diabetes mellitus, impaired glucose tolerance, metabolic syndrome or syndrome X; polycystic ovary syndrome; adipogenesis and obesity, myogenesis and frail, e.g. age-related decline in physical performance; acute sarcopenia, e.g. 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 baldness; immune deficiency, the composition comprising a pharmaceutically acceptable carrier and an amount of a compound of general formula I effective in treating such diseases or conditions.

The invention also relates to pharmaceutical compositions for the treatment of mammals, including humans, for diseases or conditions selected from the group consisting of male fertility and sperm motility, diabetes mellitus, impaired glucose tolerance, metabolic syndrome or metabolic syndrome.

X; polycystic ovary syndrome; adipogenesis and obesity, myogenesis and frail, e.g. age-related decline in physical performance; acute sarcopenia, e.g. 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 baldness; immune deficiency, wherein the composition comprises a pharmaceutically acceptable carrier and an amount of a compound of general formula I effective for inhibiting GSK-3.

The invention also relates to a method of treating mammals, including humans, for diseases or conditions selected from the group consisting of male fertility and sperm motility, diabetes mellitus, impaired glucose tolerance, metabolic syndrome or syndrome X; polycystic ovary syndrome; adipogenesis and obesity, myogenesis and frail, e.g. age-related decline in physical performance; acute sarcopenia, e.g. 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 baldness; immune deficiency, wherein the compound of general formula I is administered to the mammal in an amount effective for treating such diseases or conditions.

The invention also relates to a method of treating mammals, including humans, for diseases or conditions selected from the group consisting of male fertility and sperm motility, diabetes mellitus, impaired glucose tolerance, metabolic syndrome or syndrome X; polycystic ovary syndrome; adipogenesis and obesity, myogenesis and frail, e.g. age-related decline in physical performance; acute sarcopenia, e.g. 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 baldness; immune deficiency, wherein the mammal is administered a compound of the general

9 • 9 · · • · 99 9 9 9 *· • 9 · · ·

of formula I in an amount effective to inhibit GSK-3.

The invention further relates to a method of inhibiting GSK-3 in mammals, including humans, which method comprises administering to said mammals an amount of a compound of formula I effective to inhibit GSK-3.

The invention further relates to a pharmaceutical composition for the treatment of disorders in mammals, wherein the disorders are selected from the group consisting of Alzheimer's disease, mild cognitive impairment and age-related cognitive decline, and the compositions comprise a cdk5 inhibitor and a COX-II inhibitor in an amount effective to treat such disorders and a pharmaceutically acceptable carrier. In one embodiment, the cdk5 inhibitor is a compound of formula I or a pharmaceutically acceptable salt thereof.

The invention further relates to the treatment of disorders in mammals, wherein the disorders are selected from the group consisting of Alzheimer's disease, mild cognitive impairment and age-related cognitive decline, by administering to the mammal an amount of a cdk5 inhibitor and a COX-II inhibitor effective in treating such disorders. In one embodiment, the cdk5 inhibitor is a compound of formula I or a pharmaceutically acceptable salt thereof. The cdk5 inhibitor and the COX-II inhibitor may be administered to the mammal simultaneously and/or at separate time intervals. In addition, they may be administered together in a single pharmaceutical composition or in separate pharmaceutical compositions.

In addition, a cdk5 inhibitor, for example a compound of formula I according to the invention, or a pharmaceutically acceptable salt of a compound of formula I, can be administered or incorporated into a pharmaceutical composition with one or more anti-depressant or anxiolytic compounds to treat or prevent depression and/or anxiety.

The invention also relates to a pharmaceutical composition for the treatment of • 9 »»·

999· 999 999 depression and anxiety in mammals, the composition comprising a cdk5 inhibitor and an NK-1 receptor antagonist in an amount effective to treat depression or anxiety and a pharmaceutically acceptable carrier. In one embodiment, the cdk5 inhibitor is a compound of formula I or a pharmaceutically acceptable salt thereof.

The invention also relates to a method of treating depression and anxiety in mammals, comprising administering to the mammal a cdk5 inhibitor and an NK-1 receptor antagonist in an amount of the cdk5 inhibitor and the NK-1 receptor antagonist effective to treat depression and anxiety.

In one embodiment, the cdk5 inhibitor is a compound of Formula I or a pharmaceutically acceptable salt thereof. The cdk5 inhibitor and the NK-1 receptor antagonist can be administered to the mammal simultaneously and/or at separate time intervals. In addition, they can be administered together in a single pharmaceutical composition or in separate pharmaceutical compositions.

The invention also relates to a pharmaceutical composition for the treatment of depression and anxiety in mammals, comprising a cdk5 inhibitor and a 5HT11 receptor antagonist in an amount effective for treating depression or anxiety and a pharmaceutically acceptable carrier.

In one embodiment, the cdk5 inhibitor is a compound of formula I or a pharmaceutically acceptable salt thereof.

The invention further relates to a method of treating depression and anxiety in mammals, comprising administering to said mammal a cdk5 inhibitor and a 5HT11 receptor antagonist in an amount of cdk5 inhibitor and 5HT11 receptor antagonist effective to treat depression and anxiety. In one embodiment, the cdk5 inhibitor is a compound of formula I or a pharmaceutically acceptable salt thereof. The cdk5 inhibitor and the 5HT11 receptor antagonist may be administered to the mammal simultaneously and/or at separate time intervals. In addition, they may be administered together in a single pharmaceutical composition or in separate pharmaceutical compositions.

The invention also relates to a pharmaceutical composition for treating depression and anxiety in mammals, comprising a cdk5 inhibitor and an SSRI in an amount effective for treating depression or anxiety and a pharmaceutically acceptable carrier. In one embodiment, the cdk5 inhibitor is a compound of formula I or a pharmaceutically acceptable salt thereof.

The invention further relates to a method of treating depression and anxiety in mammals, comprising administering to said mammal a cdk5 inhibitor and an SSRI in an amount of the cdk5 inhibitor and an SSRI effective for treating depression and anxiety. In one embodiment, the cdk5 inhibitor is a compound of formula I or a pharmaceutically acceptable salt thereof. The cdk5 inhibitor and the SSRI may be administered to the mammal simultaneously and/or at separate time intervals. In addition, they may be administered together in a single pharmaceutical composition or in separate pharmaceutical compositions.

The invention also relates to a pharmaceutical composition for the treatment of schizophrenia in mammals, comprising a cdk5 inhibitor and an antipsychotic selected from the group consisting of ziprasidone, olanzapine, risperidone, L-745870, sonepiprazole, RP 62203, NGD 941, balaperidone, flesinoxane and gepirone in an amount effective for treating schizophrenia and a pharmaceutically acceptable carrier. In one embodiment, the cdk5 inhibitor is a compound of formula I or a pharmaceutically acceptable salt thereof.

The invention further relates to a method of treating schizophrenia in mammals, comprising administering to said mammal a cdk5 inhibitor and an antipsychotic selected from the group consisting of ziprasidone, olanzapine, risperidone, L-74587O, sonepiprazole, RP 62203, NGD 941, balaperidone, flesinoxane and gepirone in an amount of the cdk5 inhibitor and the antipsychotic effective for treating schizophrenia. In one embodiment, the cdk5 inhibitor is a compound of formula I or a pharmaceutically acceptable salt thereof. The cdk5 inhibitor and the antipsychotic can be administered to the mammal simultaneously and/or at separate time intervals. In addition, they can be administered together in a single pharmaceutical composition or in separate pharmaceutical compositions.

The invention also relates to a pharmaceutical composition for the treatment of disorders from the group of Alzheimer's disease, mild cognitive impairment and age-related cognitive decline, comprising a cdk5 inhibitor and an acetylcholinesterase inhibitor together in an amount effective for the treatment of such diseases and a pharmaceutically acceptable carrier.

In one embodiment, the cdk5 inhibitor is a compound of formula I or a pharmaceutically acceptable salt thereof.

The invention further relates to a method of treating a mammalian disorder selected from the group consisting of Alzheimer's disease, mild cognitive impairment and age-related cognitive decline, comprising administering to said mammal a cdk5 inhibitor and an acetylcholinesterase inhibitor in an amount of a cdk5 inhibitor and an acetylcholinesterase inhibitor effective for treating schizophrenia. In one embodiment, the cdk5 inhibitor is a compound of formula I or a pharmaceutically acceptable salt thereof. The cdk5 inhibitor and the acetylcholinesterase inhibitor may be administered to the mammal simultaneously and/or at separate time intervals. In addition, they may be administered together in a single pharmaceutical composition or in separate pharmaceutical compositions.

The invention also relates to a pharmaceutical composition for the treatment of disorders selected from the group consisting of stroke, spinal cord trauma, traumatic brain injury, multi-infarct dementia, epilepsy, pain, Alzheimer's disease and senile dementia comprising a cdk5 inhibitor and a tissue plasminogen activator (TPA e.g. ANTIVASE) in an amount effective to treat such diseases and a pharmaceutically acceptable carrier. In one embodiment, the cdk5 inhibitor is a compound of formula I or a pharmaceutically acceptable salt thereof.

The invention further relates to a method of treating a mammalian disorder selected from the group consisting of stroke, spinal cord trauma, traumatic brain injury, multi-infarct dementia, epilepsy, pain, Alzheimer's disease and senile dementia, comprising administering to said mammal a cdk5 inhibitor and a tissue plasminogen activator in an amount of cdk5 inhibitor and tissue plasminogen activator effective to treat said disease or disorder. In one embodiment, the cdk5 inhibitor is a compound of formula I or a pharmaceutically acceptable salt thereof. The cdk5 inhibitor and the tissue plasminogen activator may be administered to the mammal simultaneously and/or at separate time intervals. In addition, they may be administered together in a single pharmaceutical composition or in separate pharmaceutical compositions.

The invention also relates to a pharmaceutical composition for the treatment of disorders selected from the group consisting of stroke, spinal cord trauma, traumatic brain injury, multi-infarct dementia, epilepsy, pain, Alzheimer's disease and senile dementia comprising a cdk5 inhibitor and a neurophil inhibitory factor (NIF) in an amount effective to treat such diseases and a pharmaceutically acceptable carrier. In one embodiment, the cdk5 inhibitor is a compound of formula I or a pharmaceutically acceptable salt thereof.

The invention further relates to a method of treating a mammalian disorder selected from the group consisting of stroke, spinal cord trauma, traumatic brain injury, multi-infarct dementia, epilepsy, pain, Alzheimer's disease and senile dementia, comprising administering to said mammal a cdk5 inhibitor and a neurophilic inhibitory factor in an amount of cdk5 inhibitor and neurophilic inhibitory factor effective to treat such disorders. In one embodiment, the cdk5 inhibitor is a compound of formula I or a pharmaceutically acceptable salt thereof. The cdk5 inhibitor and the neurophilic inhibitory factor may be administered to the mammal simultaneously and/or at separate time intervals. In addition, they may be administered together in a single pharmaceutical composition or in separate pharmaceutical compositions.

from

- 30 The invention also relates to a pharmaceutical composition for treating disorders or conditions selected from the group consisting of Huntington's disease, stroke, spinal cord trauma, traumatic brain injury, multi-infarct dementia, epilepsy, amyotrophic lateral sclerosis, pain, viral-induced dementia, for example AIDS-induced dementia, migraines, hypoglycemia, urinary incontinence, cerebral ischemia, multiple sclerosis, Alzheimer's disease and senile dementia of the Alzheimer type, mild cognitive impairment, age-related decline in consciousness, emesis, corticobasal degeneration, dementia ougilistica, Down syndrome, myotic dystrophies, Nieman-Pick disorders, Pick's diseases, prion diseases with vertigo, progressive supranuclear palsy, inferior lateral sclerosis and subacute sclerotic panencephalitis in mammals, comprising a cdk5 inhibitor and an NMDA receptor antagonist in an amount effective for treating such diseases and a pharmaceutically acceptable carrier.

In one embodiment, the cdk5 inhibitor is a compound of formula I or a pharmaceutically acceptable salt thereof.

The invention further relates to a method of treating a mammalian disorder selected from the group consisting of Huntington's disease, stroke, spinal cord trauma, traumatic brain injury, multi-infarct dementia, epilepsy, amyotrophic lateral sclerosis, pain, virally induced dementia, e.g. AIDS-induced dementia, migraines, hypoglycemia, urinary incontinence, cerebral ischemia, multiple sclerosis, Alzheimer's disease and senile dementia of the Alzheimer type, mild cognitive impairment, age-related decline in consciousness, emesis, corticobasal degeneration, dementia ougilistica, Down syndrome, myotic dystrophies, Nieman-Pick disorders, Pick's diseases, prion diseases with vertigo, progressive supranuclear palsy, inferior lateral sclerosis and subacute sclerotic panencephalitis in mammals, comprising administering to the mammal an amount of a cdk5 inhibitor and an NMDA receptor antagonist effective for treating such diseases or conditions. In one embodiment, the cdk5 inhibitor is a compound of formula I or a pharmaceutically acceptable salt thereof. The cdk5 inhibitor and the NMDA receptor antagonist may be

may be administered to mammals simultaneously and/or at separate time intervals. In addition, they may be administered together in a single pharmaceutical composition or in separate pharmaceutical compositions.

The invention also relates to a pharmaceutical composition for treating disorders or conditions selected from the group consisting of stroke, spinal cord trauma, traumatic brain injury, multi-infarct dementia, epilepsy, pain, Alzheimer's disease and senile dementia in mammals comprising a cdk5 inhibitor and a potassium channel modulator in an amount effective to treat such diseases and a pharmaceutically acceptable carrier. In one embodiment, the cdk5 inhibitor is a compound of formula I or a pharmaceutically acceptable salt thereof.

The invention further relates to a method of treating a mammalian disorder selected from the group consisting of stroke, spinal cord trauma, traumatic brain injury, multi-infarct dementia, epilepsy, pain, Alzheimer's disease and senile dementia in a mammal, comprising administering to the mammal an amount of a cdk5 inhibitor and a potassium channel modulator effective to treat such disease or condition. In one embodiment, the cdk5 inhibitor is a compound of formula I or a pharmaceutically acceptable salt thereof. The cdk5 inhibitor and the potassium channel modulator may be administered to the mammal simultaneously and/or at separate time intervals. In addition, they may be administered together in a single pharmaceutical composition or in separate pharmaceutical compositions.

For example, the term "treating" means reversing, alleviating, or preventing the progression of a disease or condition to which the term "treating" refers, or one or more symptoms of such a disease or condition. The term also includes, depending on the condition of the patient, preventing the onset of the disease or condition, or symptoms associated with the disease or condition, including reducing the severity of the disease or condition or symptoms associated therewith prior to the onset of said disease or condition. Such prevention or reduction prior to onset consists in administering a compound of formula I to a subject who is not suffering from the disease or condition at the time of administration. The term "prevention" also means preventing the recurrence of the disease or condition or symptoms associated therewith.

As used herein, the term "mammal," unless otherwise specified, generally means any mammal. The term mammal includes, for example, without intending any limitation, dogs, cats, and 1 idi .

The term "abnormal cell growth" refers to cell growth that is either malignant (such as in cancer) or benign and independent of normal regulatory mechanisms (such as loss of contact inhibition). Examples of benign proliferative diseases include psoriasis, benign prostatic hypertrophy, human papillomavirus (HPV), and restinosis.

As used herein, the term neurodegenerative diseases and conditions refers to diseases and conditions associated with neuronal degeneration. Conditions and diseases that are neurodegenerative in nature are generally known to those skilled in the art.

References herein to "treatments that can affect or facilitate altered dopamine-mediated neurotransmission" mean a disease or condition that results in abnormal dopamine neurotransmission contributing to the syndromes or manifestations of the disease or condition.

References herein to diseases or conditions whose treatment can be accomplished or facilitated by reducing cdk5 activity mean a disease or condition that results in abnormal cdk5 activity that contributes to the symptoms or manifestations of the disease or condition.

An amount effective to inhibit cdk2 activity is intended to be an amount of compound sufficient to bind the cdk2 enzyme to reduce cdk2 activity.

The invention is further elucidated by the following detailed description.

Compounds of formula I and their pharmaceutically acceptable salts may be prepared according to the following schemes and discussions. Unless otherwise indicated, the symbols R ¹ , R ² , R ³ and R ⁴ have the meanings given above. Isolation and purification of the products are carried out by methods known to chemists skilled in the art.

As used herein, the term solvent inert to the reactants means a solvent system in which the components do not react with the starting materials, reactants, or intermediates in a manner that adversely affects the yield of the desired product.

During any subsequent synthetic sequence it may be necessary and/or desirable to protect sensitive or reactive groups on any molecules involved. This may be accomplished using conventional protecting groups such as those described in T.W. Greene Protective Groups in Organic Chemistry, John Wiley & Sons 1981 and T.W. Green and P.G.M. Wuts Protective Groups in Organic Chemistry, John Wiley & Sons 1991.

Scheme I illustrates a method for preparing compounds of general formula I, where ^R3 represents the group -C(=O)NH, -C(=0)0- or -C(=0)( ^CR10R11 )«-- According to Scheme I ^, a solution of 1,4-dinitroimidazole (J. Phys. Chem. 99, pp. 1009 to 1015, 1995) in dimethylsulfoxide (DMSO), in the pyridine-water system, in water, in the acetonitrile-water solvent system, alcohol or alcohol-water, but preferably in a lower alcohol such as methanol, β

at a temperature in the range of about -20 to about 50 C, preferably at a temperature in the range of about -5 to about 35 C, with a primary alkylamine or arylamine, to give 1-N-substituted 4-nitroimidazoles of the general formula 2. 1,4-Dinitroimidazole is a highly energetic, semi-stable compound that must be kept in a freezer whenever not in use. Thermodynamic measurements have shown that it can potentially generate enough energy at 35 C under adiabatic conditions to cause a violent explosion. Extreme caution must be exercised when using this compound. The reduction of the nitro compound of formula 2 to the amine of formula 3 is possible by reducing the compound of formula 2 in the presence of a noble metal as a catalyst, in a solvent such as ethyl acetate, tetrahydrofuran, dioxane or a mixture thereof, with hydrogen gas at a pressure of 0.1 to 10 MPa, preferably a pressure of about 1 MPa. The noble metal is preferably palladium. The metal should be suspended on an inert solid support such as carbon. After the compound of general formula 2 has been consumed, the mixture is filtered and the obtained amine of general formula 3 is immediately reacted with an acid chloride of general formula with an anhydride of general formula or an activated carboxylic acid derivative of general formula C1C(=0)(CR ^1O R ¹¹ )nR ⁴ -, (R ⁴ (CR ^lo R ⁱ¹ ) _n C(= ⁰ )) ₂ ⁰ in the presence of a base such as triethylamine, diisopropylethylamine, pyridine or 2,6-lutidine, at a temperature in the range ^of about -78 o

to about 40 C. Cyclic 1-propanephosphonic anhydride and triethylamine are a preferred combination. The activated carboxylic acid derivative is prepared from the carboxylic acid HOC(=O)(CR ¹⁰ R ¹¹ )nR ⁴ and a known activating agent such as dicyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, carbonyldiimidazole, cyclic 1-propanephosphonic anhydride, alkyl chloroformate, aryl chloroformate, bis(2-oxo-3-oxazolidinyl)phosphinic acid chloride, benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate or any other agent known from the standard literature. In this way, compounds of the general formula IB are obtained, where R ³ represents the group -C(=O)(CR ¹⁰ R ¹¹ )n-.

Alternatively, the amine of formula 3 may be treated after filtration with a base such as triethylamine, diisopropylethylamine, pyridine, and 2,6-lutidine, and an alkyl chloroformate or aryl chloroformate at a temperature in the range of about -78 to about 40°C,

wherein the preferred temperature is -78 to -40 C to obtain a compound of formula IA, wherein R ³ is -C(=O)O- and R ⁴ is phenyl. Diisopropylethylamine and phenyl chloroformate are preferred combinations. Subsequent treatment of the phenyl carbamate of formula IA with a primary or secondary amine in a solvent such as dioxane, dimethylformamide or acetonitrile,

B at a temperature in the range of about 40 to about 90 C provides the corresponding urea derivative of the general formula IC, where R ³ represents the group -C(=O)NR ⁹ - and R ⁴ represents a phenyl or heteroaryl group. The system 1:1 dioxane-dimethylformamide and the temperature 70 C are preferred for this reaction.

Scheme 1 R^NH ₂

no ₂

• ·

The method for preparing compounds of formula I, where R ¹ is substituted by R ⁵ and R ⁵ is NHC(=O)R ^S , is illustrated in Scheme 2. It is preferred to treat a compound of formula 4, where R ⁵ is a hydroxyl group, with an alkylsulfonyl chloride or an arylsulfonyl chloride, preferably p-toluenesulfonyl chloride (TosCl), in a reaction-inert solvent such as tetrahydrofuran, methylene chloride or chloroform, preferably methylene chloride, at a temperature of

in the range of about -10 to about 30 C, in the presence of an amine base such as triethylamine, diisopropylethylamine, pyridine or 2,6-lutidine, triethylamine being preferred, and a catalytic amount of 4-N,N-dimethylaminopyridine, thereby obtaining a compound of general formula 5, wherein R ⁵ represents the group CH3(C6H4>SO3(TosO). By treating the thus obtained tosylate with an alkali metal azide salt, sodium azide being preferred, in a polar solvent such as dimethylformamide, dimethylsulfoxide, a lower alcohol, water and mixtures of these solvents, the ethanol-water system being preferred, at a temperature in the range of β

about 20 to about 130 C, preferably at a temperature of 90 to 110 C, a compound of general formula 6 is obtained, where R ⁵ is N ₃ .

Treatment of the azide under selective reducing conditions, such as using a trialkylphosphine or triarylphosphine and water system, preferably triaphenylphosphine, in a solvent such as tetrahydrofuran, dioxane, acetonitrile or a mixture thereof, preferably tetrahydrofuran, provides a compound of formula 7, wherein ^R5 is an NH2 group. The primary amino group of the compound of formula 7 thus obtained ( ^R5 =NHa) can be derivatized by reaction with chloroformate, isocyanate, carbamoyl chloride, acid chloride, acid anhydride or an activated carboxylic acid derivative. The activated carboxylic acid derivative is prepared from the carboxylic acid by reaction with known activating agents such as dicyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, carbonyldiimidazole, cyclic 1-propanephosphinic anhydride, alkyl chloroformate, bis(2-oxo-3-oxazolidinyl)phosphinic chloride, benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate or any other agent known from the standard literature, optionally in the presence of a base such as triethylamine, diisopropylethylamine, pyridine and 2,6-lutidine, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride being preferred at a temperature of about -78 to about 80°C, preferably 0 to 40°C. Preferred solvents are tetrahydrofuran and methylene chloride.

The conversion of the compound of formula 8 thus obtained, where R 5 represents the ^group -NHC(=O)R ^S, to the compound of formula ID (where R ⁵ represents the group -NHC(=O)R ^S and R ³ represents the group C(=O)(CR ¹⁰ R ¹¹ )nR ⁴ ), can be carried out by reducing the compound of formula 8 in the presence of a noble metal as a catalyst, the preferred noble metal being palladium, and the noble metal can, as usual, be suspended on an inert solid support such as carbon, in a solvent such as ethyl acetate, tetrahydrofuran, dioxane or a mixture thereof, with hydrogen gas at a pressure of 0.1 to 10 MPa, the preferred pressure being about 0.1 to about 1 MPa. After the compound of general formula 8 has been consumed, the mixture is filtered and the amine obtained is immediately acylated by reaction with an acid chloride, an acid anhydride or an activated carboxylic acid derivative, optionally in the presence of an amine base, such as triethylamine, diisopropylethylamine, pyridine or 2,6-lutidine, the preferred combination being cyclic 1-propanephosphonic anhydride and triethylamine, at a temperature in the range of about

-78 to about 40° C. to give the N-acylated product of formula ID. The activated carboxylic acid derivative is prepared from the carboxylic acid and a known activating agent such as dicyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, carbonyldiimidazole, 1-propanephosphonic acid cyclic anhydride, alkyl38 chloroformate, bis(2-oxo-3-oxazolidinyl)phosphinic acid chloride, benzotriazol-1-yloxy-tris(dimethylamino)phosphonium Hexafluorophosphate or any other agent known from standard literature.

If an aryl chloroformate or heteroaryl chloroformate is used in the above acylation reaction instead of an acid chloride, acid anhydride or activated carboxylic acid derivative, an aryl carbamate of formula IE is obtained. The obtained aryl carbamate of formula IE ( ^R3 = C(=O)0- and ^R4 represents an aryl or heteroaryl group) can be treated with an amine in a solvent such as dioxane, dimethyl formamide or acetonitrile, with a 1:1 dioxane-dimethyl formamide system being preferred, at a temperature of about 40 to about 90°C, preferably at

at a temperature of 70 C, thereby obtaining the corresponding urea derivative of the general formula IF (R ³ = C(=O)NR ⁹ and R ⁴ represents an aryl or heteroaryl group).

Scheme 2

1F • · · ·

An alternative method for preparing compounds of formula I, wherein ^R5 is NHC(=O) ^R5 , is illustrated in Scheme 3. By treating a compound of formula 4, wherein ^R5 is hydroxyl, with an alkylsulfonyl chloride or an arylsulfonyl chloride, preferably p-toluenesulfonyl chloride (TosCl), in a reaction-inert solvent such as tetrahydrofuran, methylene chloride or chloroform, preferably methylene chloride, at a temperature in the range of about -10 to about 30°C.

C, in the presence of an amine base such as triethylamine, diisopropyl ethyl amine, pyridine or 2,6-lutidine, and in the presence of 4-N,N-dimethylaminopyridine, a compound of formula 5 is obtained, where R ⁵ represents a group CH3<C6H4)SO3(TosO). A preferred amine base is triethylamine. The conversion of a compound of formula 5 (R ⁵ represents a group TosO) to a compound of formula IG (R ⁵ represents a group TosO, R ³ represents a group -C(=O)(CR ^1O R ¹¹ ) _n R ⁴ ) can be carried out by reducing a compound of formula 5 (R ⁵ represents a group TosO) in the presence of a noble metal as a catalyst, in a solvent such as ethyl acetate, tetrahydrofuran, dioxane or a mixture thereof, with hydrogen gas at a pressure of 0.1 to 10 MPa, with a pressure of about 0.1 to about 1 MPa being preferred. The preferred noble metal is palladium. The noble metal may be suspended on an inert solid support such as carbon, as is conventional. After the compound of formula 5 has been consumed, the mixture is filtered and the amine obtained is immediately acylated by reaction with an acid chloride, an acid anhydride or an activated carboxylic acid derivative, optionally in the presence of an amine base such as triethylamine, diisopropylethylamine, pyridine or 2,6-lutidine, the preferred combination being cyclic 1-propanephosphonic anhydride and triethylamine, at a temperature in the range of about -78 to about 40° C. to give the N-acylated product of formula IG. The activated carboxylic acid derivative is prepared from a carboxylic acid and a known activating agent, such as dicyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, carbonyldiimidazole, cyclic 1-propanephosphonic anhydride, alkyl chloroformate, bis(2-oxo-3-oxazolidinyl)phosphinic acid chloride, benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate, or any other agent known from standard literature.

By treating the thus obtained compound of general formula IG (R ⁵ represents TosO, R ³ represents -C(=O)(CR ¹⁰ R ¹¹ )n-) with an alkali metal azide, preferably sodium azide, in a polar solvent such as dimethylformamide, dimethylsulfoxide, lower alcohol, water and mixtures of these solvents, preferably the ethanol-water system, at a temperature in the range of about 20 to about 130 C, preferably at a temperature of 90 to 110 C, a compound of general formula IH is obtained, where R ⁵ represents N3. The subsequent reduction of the azide of the general formula IH ( ^R5 = N3) can be carried out by reducing the azide of the general formula IH ( ^R5 = N3) in the presence of a noble metal as a catalyst, the preferred noble metal being palladium, and the noble metal can, as usual, be suspended on an inert solid support such as carbon, in a solvent such as ethyl acetate, tetrahydrofuran, dioxane or a mixture thereof, with hydrogen gas at a pressure of 0.1 to 10 MPa, preferably 11 to about 0.1 to about 1 MPa.

Alternatively, the reduction of the azide of formula IH ( ^R5 = N3) can be carried out by treatment with a trialkylphosphine or triarylphosphine and water, preferably triarylphosphine, in a solvent such as tetrahydrofuran, dioxane or acetonitrile, preferably tetrahydrofuran. The primary amino group of the compound of formula II thus obtained ( ^R5 = NH2) can be derivatized by reaction with chloroformate, isocyanate, carbamoyl chloride, acid chloride, acid anhydride or activated carboxylic acid derivative. The activated carboxylic acid derivative is prepared from the carboxylic acid by reaction with known activating agents such as dicyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, carbonyldiimidazole, cyclic 1-propanephosphonic anhydride, alkyl chloroformate, bis(2-oxo-3-oxazolidinyl)phosphinic acid chloride, benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate or any other agent known from the standard literature, optionally in the presence of a base such as triethylamine, diisopropylethylamine, pyridine and 2,6-lutidine, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride being preferred, at a temperature of about -78 to about 80°C, preferably 0 to 40°C. Preferred solvents are tetrahydrofuran and methylene chloride.

Scheme 3

H

Compounds of formula I wherein R ³ is -(CR ¹⁰ R ¹¹ ) n can be prepared by the method illustrated in Scheme 4. In this method, a solution of 4-bromoimidazole is treated with a base such as sodium hydride, potassium hydride, lithium hydride, cesium carbonate, sodium hydroxide, potassium hydroxide, cesium hydroxide, lithium diisopropylamide, sodium amide potassium hexamethyldisilazide, sodium hexamethyldisilazide, sodium tert-butoxide, or potassium tert-butoxide, in a reaction-inert solvent such as tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, dimethylsulfoxide, or toluene, at a temperature of about -20 to about eo

150 C, preferably at a temperature of 20 to 100 C, in the absence or presence of a phase transfer catalyst such as tetra-n-butylammonium chloride, tetra-n-butylammonium bromide, tetra-n-butylammonium iodide, benzyltrimethylammonium chloride, benzyltrimethylammonium bromide or benzyltrimethylammonium fluoride, followed by the addition of an alkyl chloride, allyl chloride or benzyl chloride, an alkyl bromide, allyl bromide or benzyl bromide, an alkyl iodide, allyl iodide or benzyl iodide, an alkyl sulfonate, aryl sulfonate or triflate, thereby obtaining a mixture of 1-substituted 4-bromoimidazole (general formula 9) and 1-substituted 5-bromoimidazole (general formula 10), and both of these compounds are separated by methods known to those skilled in the art.

Alternatively, 4-bromoimidazole is treated with allyl fluoride, allyl chloride, allyl bromide, allyl iodide, allyl acetate or allyl carbonate, allyl carbonate being preferred, in a reaction-inert solvent such as tetrahydrofuran, 1,2-dichloroethane, 1,4-dioxane, dimethyl sulfoxide or N,N-dimethylformamide, tetrahydrofuran being the preferred solvent, in the presence of a palladium catalyst such as palladium(O)tetrakis(triphenylphosphine), palladium(II)acetate, allylpalladium chloride dimer, tris(dibenzylideneacetone)dipalladium(O), tris(dibenzylideneacetone)dipalladium(O)chloroform adduct, palladium(II) chloride, palladium(II)acetate being preferred, in the absence or presence of • · · · ··· · ··· · ··· ··· ··· ··· ··· in the presence of a phosphine ligand, such as triphenylphosphine, tri-o-tolylphosphine, tri-tert-butylphosphine, 1,2-bis(diphenylphosphine)ethane or 1,3-bis(diphenylphosphine)propane, at a temperature of about 0 to about 100 C, preferably 50 to 80 C, to give a mixture of 1-substituted 4-bromoimidazole (general formula 9) and 1-substituted 5-bromoimidazole (general formula 10).

By treating 1-substituted 4-bromoimidazole (of general formula ⁹ ) with ^{an intermediate of general formula NH2CR10R11)nR4 in} _the presence of a palladium catalyst such as palladium(II)acetate, allylpalladium chloride dimer, tris(dibenzylideneacetone)dipalladium(0), tris(dibenzylideneacetone)dipalladium(0)chloroform adduct or palladium(II)chloride, with palladium(II)acetate, tris(dibenzylideneacetone)dipalladium(0), tris(dibenzylideneacetone)dipalladium(0)chloroform adduct being preferred and a phosphine ligand such as BINAP, 2-biphenyldicyclohexylphosphine, 2-biphenyldi-tert-butylphosphine or 2-N,N-dimethylamino-2'-diphenylphosphinobiphenyl being preferred, and a base such as sodium tert-butoxide, cesium carbonate or potassium phosphate (K3PO4), with potassium phosphate being preferred, in a reaction-inert solvent such as toluene, 1,4-dioxane or tetrahydrofuran, at a temperature of about 0 to about 150°C, preferably 20 to 110°C, to give the coupled product 1.

Scheme 4

HN^N

N^N

Br

Br

R

N^N

N—(^ ^R 10 ^R 1l)n R ⁴ a

An alternative method for preparing compounds of formula I, wherein ^R3 is -C(=O)( ^{CR1O R11} ) _n- is illustrated in Scheme 5. Treatment of ethyl-2-isocyano-N,N-dimethylaminoacrylate (formula 11) with a primary amine, ^R1 -NH2, in a solvent such as n-butanol, n-propanol, isopropanol or ethanol, or in the absence of a solvent, preferably n-propanol or a solvent-free reaction, at a temperature in the range of about 23 to about 200°C, preferably about 60 to about 150°C, provides imidazoles of formula 12. Treatment of N,O-dimethylhydroxylamine hydrochloride with trimethylaluminum in 1,2-dichloroethane followed by addition of a compound of formula 12 at a temperature in the range of about 30 to about 80°C

C, preferably about 50, gives the imidazole of general formula 13. Adding an organometallic reagent M-(CR^R ¹¹ )nR ⁴ , where M 1 is lithium halide or magnesium halide, magnesium halide being preferred, to a solution of a compound of general formula 13 in a solvent such as tetrahydrofuran, methylene chloride or diethyl ether, at a temperature in the range of about -50 to about 30 C, preferably about -20 to about OC, gives the compounds of general formula 14. Adding a compound of general formula 14 to a mixture of hydroxylamine hydrochloride and potassium acetate in a lower alcohol as a solvent, the preferred solvent being ethanol, at a temperature in the range of about 23 C, gives the oxime of general formula 15 as a mixture of isomers. Treatment of an acetone solution of an oxime of general formula e

at a temperature of about 0 C with an aqueous solution of sodium hydroxide and subsequently with paratoluenesulfonyl chloride 0-sulfonyl compounds after extractive work-up of the product in a nonpolar solvent, such as benzene, hexanes or toluene, benzene being the preferred solvent, eluting with a chloroform-methanol (approximately 10=1) system after about five minutes on an alumina column, gives the compound of general formula IB and a Beckmann rearrangement of the regioisomer.

Schena

R—NH ₂

/==N

( ^CR 10 ^R 1l) _n ^R 4 /=rN 0 a

N <CR, ₀ R„)„R,

IB » · · · · ♦

Compounds of formula IJ can also be prepared as illustrated in Scheme 6. The key starting material for this preparation is a double bond-containing compound (compound of formula 10) substituted with an ER ⁵ group and one to three R ⁵ groups (of formula 10), where ER ⁵ represents an electron-withdrawing group selected from the group consisting of -C(=O)R ⁷ , -C(=O)OR ⁷ , -C(=0)NR ⁷ R ^S , -S(=0)2R ⁷ , -S(=0)2NR ⁷ R ^s , -S(=0) ₂ 0R ⁷ , cyano and heteroaryl. Additionally, the compound of formula 10 may be a compound in which the ER ⁵ group is bonded to one of the R ⁵ groups or directly to a carbon-carbon double bond to form a ring, including compounds such as 2-cyclopenten-1-one and 2-cyclohexen-1-one. Alternatively, compounds of formula 10 in which L is chlorine, bromine or iodine, -OC(=O)R ⁷ or -OS(=O) ₂ R ⁷ may be used as starting materials. Examples of such starting materials include 3-chloro-1-cyclopentanone and 3-acetoxy-1-cyclobutanone. In the process of Scheme 6, a salt of 4(5)-nitroimidazole, which is a sodium, potassium or cesium salt, 1,8-diazabicyclo[5.4.0]undec-7-ene, (DBU) or tetraalkylammonium salt, with the tetra-n-butylammonium salt or DBU being preferred, is treated with intermediates of formula 16 or 17 in a solvent such as acetonitrile, methylene chloride, 1,2-dichloroethane or chloroform, with acetonitrile being the preferred solvent, at a temperature in the range of about -60 to about 50°C, preferably about -20 to about 23°C, to provide an adduct of formula IIA. The reduction of the nitro compound of general formula IIA can be carried out in the presence of a noble metal as a catalyst, the preferred noble metal being palladium, and the noble metal can be, as usual, suspended on an inert solid support such as carbon, in a solvent such as ethyl acetate, tetrahydrofuran, dioxane or a mixture thereof, with hydrogen gas at a pressure of 0.1 to 10 MPa, the preferred pressure being about 0.1 to about 1 MPa. After consumption of the compound of formula IIA, the mixture is filtered and the amine obtained is immediately acylated by reaction with an acid chloride of the formula ClC(=O)(CR ¹⁰ R ⁴¹ )nR ⁴ , with an acid anhydride of the formula R ⁴ (CR ¹⁰ R ⁴¹ )nC(=O))20, or with an activated carboxylic acid derivative of the formula XC(=O)(CR ¹⁰ R ¹¹ )nR ⁴ optionally in the presence of an amine base such as triethylamine, diisopropylethylamine, pyridine or 2,6-lutidine, the preferred combination being cyclic 1-propanephosphonic anhydride and triethylamine, at a temperature in the range of about -78 to about 40 C to obtain compounds of formula 1J. The activated carboxylic acid derivative is prepared from a carboxylic acid of the general formula HOC(=O)(CR ^1O R ¹¹ ) n R ⁴ and a known activating agent, such as dicyclohexylcarbodiimide,

-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, carbonyldiimidazole, cyclic 1-propanephosphonic anhydride, alkyl chloroformate, aryl chloroformate, bis(2-oxo-3-oxazolidinyl)phosphonic acid chloride, benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate or any other reagent known from the standard literature.

Alternatively, after filtration, the intermediate amine may be treated with a base such as triethylamine, diisopropylethylamine, pyridine or 2,6-lutidine and an alkyl chloroformate or aryl chloroformate, preferably diisopropylamine and phenyl chloroformate, at a temperature in the range of about -78 to about 40°C, preferably about -78 to about -40°C, to give a compound of formula IK.

By subsequent treatment of the compound of general formula IK with a primary or secondary amine in a solvent such as dioxane, dimethylformamide or acetonitrile, the dioxane-dimethylformamide system 1:1 being the preferred solvent, at a temperature of

in the range of about 40 to about 90 C, preferably about

B

C the corresponding urea derivative of the general formula IL is obtained

The following transformations of compounds of formula IIA, IJ, IK and IL using methods known to those skilled in the art can be carried out to obtain additional compounds of formula I as described herein.

Compounds of formula I according to the invention, where the symbol R ² represents a group other than hydrogen, can be prepared by the described transformations of compounds of formula I, where R ² represents a hydrogen atom, in known methods. For example, compounds of formula I, where R ² represents a fluorine atom, can be prepared by treating compounds of formula I, where R ² represents a hydrogen atom, for example compounds of formula IA, IB and IC according to scheme 1, with n-fluorobenzenesulfonamide in a solvent such as toluene, xylenes or dioxane, at a temperature in the range

D approximately room temperature to approximately 150 C, preferably

At approximately 100 to approximately 120 C.

Scheme 6

Pharmaceutically acceptable salts of the compounds of formula I may be prepared by methods known per se by treating a solution or suspension of the free base or acid with a chemical equivalent of a pharmaceutically acceptable acid or base. They may be

Conventional concentration or crystallization methods can be used to isolate the salt. Examples of suitable acids include acetic, lactic, succinic, maleic, tartaric, citric, gluconic, ascorbic, benzoic, cinnamic, fumaric, sulfuric, phosphoric, hydrochloric, hydrobromic, hydroiodic, sulfamic, sulfonic, such as methanesulfonic, benzenesulfonic, p-toluenesulfonic, and the like. Examples of bases include sodium, potassium, and calcium bases.

The compounds of the invention may be administered alone or in combination with pharmaceutically acceptable carriers, either as a single dose or as multiple doses. Pharmaceutically acceptable carriers include diluents and excipients, sterile aqueous solutions and various organic solvents. Pharmaceutical compositions prepared from a mixture of a compound of formula I or a pharmaceutically acceptable salt thereof may be conveniently administered in various dosage forms, such as tablets, powders, pills, syrups, and injectable solutions. The pharmaceutical compositions may optionally contain additional ingredients, such as flavoring agents, binders and excipients. For example, for oral administration, tablets contain various excipients, such as sodium citrate, calcium carbonate and calcium phosphate, together with various disintegrants, such as starch, methylcellulose, alginic acid and certain complex silicates, together with binders, such as polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally, lubricants such as magnesium stearate, sodium lauryl sulfate and talc are often useful for tabletting purposes. Solid agents of a similar type can also be used as fillings for soft and hard gelatin capsules. Lactose or milk sugar and high molecular weight polyethylene glycols are preferred for this purpose. If aqueous suspensions or elixirs are desired for oral administration, the active ingredient according to the invention can be combined with various sweetening or separating agents, with colorants and optionally with emulsifying or suspending agents, together with diluents such as water, ethanol, propylene glycol, glycerin or mixtures thereof.

For parenteral administration, solutions contain a compound of formula I according to the invention or a pharmaceutically acceptable salt thereof in sesame or peanut oil, in aqueous propylene glycol or in sterile aqueous solutions. Such aqueous solutions should optionally be suitably buffered and the isotonicity of the liquid diluents is first adjusted with a sufficient amount of saline or glucose. Such aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. Sterile aqueous media are readily available using methods known to those skilled in the art.

The compounds of formula I or their pharmaceutically acceptable salts may be administered orally, transdermally (e.g., by patch), parenterally (e.g., intravenously), rectally, or topically. In general, the daily dose for the treatment of a neurodegenerative disease or condition or for the treatment of a disease or condition susceptible to or ameliorated by an alteration in dopamine-mediated neurotransmission is in the range of about 0.001 to about 10.0 mg/kg of body weight of the patient being treated. The daily dose for the treatment of cancer or a disease or condition involving abnormal cell growth of a benign nature is also in the range of about 0.001 to about 10.0 mg/kg of body weight of the patient being treated. For example, a compound of formula I or a pharmaceutically acceptable salt thereof may be administered to an average adult (approximately 70 kg) in an amount ranging from about 0.01 to about 1000 mg per day, preferably from about 0.1 to about 500 mg per day, in single or divided doses. The daily dose for the treatment of diabetes, sperm motility, hair loss, or other diseases or conditions that can be treated by inhibition of GSK-3 is generally in the range of about 0.0001 to about 10.0 mg/kg of body weight of the patient being treated. These dosages may be varied at the discretion of the physician or treating expert according to the weight, age, and condition of the individual being treated, the severity of the disease, and particularly the route of administration chosen.

Compounds of formula I or pharmaceutically acceptable salts thereof may also be administered or formulated as pharmaceutical compositions with an amount of one or more agents selected from the group consisting of antiangiogenic agents, signal transduction inhibitors and antiproliferative agents in an amount effective to inhibit abnormal cell growth.

Antiangiogenic agents such as matrix metalloproteinase 2 (MMP-2) inhibitors, matrix metalloproteinase 9 (MMP-9) inhibitors, cyclooxygenase II (COX-II) inhibitors can be used in conjunction with the compounds of formula I in the methods of treatment and pharmaceutical compositions of the invention for the treatment of abnormal cell growth, including cancer. Examples of useful COX-II inhibitors include CELEBREX™ (celecoxib), valdecoxib, and rofecoxib. Examples of useful matrix metalloproteinase inhibitors are described in World Patent Application No. WO 96/33172 (published October 24, 1996), World Patent Application No. WO 96/27583 (published March 7, 1996), European Patent Application No. 97304971.1 (filed July 8, 1997), European Patent Application No. 99308617.2 (filed October 29, 1999), World Patent Application No. WO 98/07697 (published February 26, 1998), World Patent Application No. WO 98/03516 (published January 29, 1998), World Patent Application No. WO 98/34918 (published August 13, 1998), and World Patent Application No. WO 98/34918 (published August 13, 1998). 1998), in World Patent Application No. WO 98/34915 (published August 13, 1998), in World Patent Application No. WO 98/33768 (published August 6, 1998), in World Patent Application No. WO 98/30566 (published July 16, 1998), in European Patent Application No. EP 606046 (published July 13, 1994), in European Patent Application No. 54

in EP 931788 (published July 28, 1999), in World Patent Application No. WO 90/05719 (published May 31, 1990), in World Patent Application No. WO 99/52910 (published October 21, 1999), in World Patent Application No. WO 99/52889 (published October 21, 1999), in World Patent Application No. WO 99/29667 (published June 17, 1999), in International Patent Application No. PCT/IB98/01113 (filed July 21, 1998), in European Patent Application No. 99302232.1 (filed March 25, 1999), in British Patent Application No. 9912961.1 (filed June 3, 1999), U.S. Patent Application Serial No. 60/148,464 (filed August 12, 1999), U.S. Patent No. 5,863,949 (issued January 26, 1999), U.S. Patent No. 5,861,510 (issued January 19, 1999), and European Patent No. EP 780,386 (published June 25, 1997). Preferred MMP-2 and MMP-9 inhibitors are those that have little or no activity against MMP-1. More preferred are inhibitors that selectively inhibit MMP-2 and/or MMP-9 compared to 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).

Specific examples of MMP inhibitors useful in the present invention include AG-3340, RO 32-3555, RS 13-0830 and the following compounds:

3-[[4-(4-fluorophenoxy)benzenesulfonyl1-(1-hydroxycarbamoylcyclopentyl)amino]propionic acid, 3-exo-3-[4-(4-fluorophenoxy)benzenesulfonylamino1-8-oxabicyclo[3.2.1]octane-3-carboxylic acid hydroxyamide, (2R,3R)-1-[4-(2-chloro-4-fluorobenzyloxy)benzenesulfonyl]-3-hydroxy-3-methylpiperidine-2-carboxylic acid hydroxyamide, 4-[4-(4-fluorophenoxy)benzenesulfonylamino1tetrahydropyran-4-carboxylic acid hydroxyamide,

3-[[4-(4-fluorophenoxy)benzenesulfonyl3-(1-hydroxycarbamoylcyclo55 • · · ·>

butyl)amino]propionic acid, 4-[4-(4-chlorophenoxy)benzenesulfonylamino]tetrahydropyran-4-carboxylic acid hydroxyamide, (R)-3-[4-(4-chlorophenoxy)benzenesulfonylamino]tetrahydropyran-3-carboxylic acid hydroxyamide, (2R,3R)-1-[4-(4-fluoro-2-methylbenzyloxy)benzenesulfonyl]-3-hydroxy-3-methylpiperidine-2-carboxylic acid hydroxyamide, 3-[[4-(4-fluorophenoxy)benzenesulfonyl]-(1-hydroxycarbamoyl - 1-methyl ethyl )amino]propionic acid,

3-[[4-(4-fluorophenoxy)benzenesulfonyl-3-(4-hydroxycarbamoyltetrahydropyran-4-ylamino]propionic acid, 3-exo-3-[4-(4-chlorophenoxy)benzenesulfonylamino]-8-oxabicyclo[3.2.1]octane-3-carboxylic acid hydroxyamide, 3-endo-3-[4-(4-fluorophenoxy)benzenesulfonylamino]-8-oxabicyclo[3.2.1]octane-3-carboxylic acid hydroxyamide, (R)-3-[4-(4-fluorophenoxy)benzenesulfonylamino]tetrahydrofuran-3-carboxylic acid hydroxyamide, and pharmaceutically acceptable salts and solvates of these compounds.

Other antiangiogenic agents, including other COX-II inhibitors and other MMP inhibitors, may also be used in accordance with the invention.

The effective amount of a COX-II inhibitor in combination with a cdk5 inhibitor, for example a compound of formula I, can be determined by one skilled in the art. The recommended daily dosage for a COX-II inhibitor in combination with a cdk5 inhibitor is in the range of about 0.1 to about 25 mg/kg body weight. The effective daily amount of a cdk5 inhibitor is generally in the range of about 0.0001 to about 10 mg/kg body weight. In some cases, the amount of a COX-II inhibitor and/or a cdk5 inhibitor in combination with each other may be less than would be required if these compounds were administered individually to achieve the same desired effect in inhibiting abnormal cell growth.

Compounds of formula I can also be used with signal transduction inhibitors, such as agents that inhibit epidermal growth factor receptor (EGFR) responses, such as EGFR antibodies, EGF antibodies, and molecules that are EGFR inhibitors; vascular endothelial growth factor (VEGF) inhibitors; and erb2 receptor inhibitors, such as organic molecules or antibodies that bind to the erbB2 receptor, such as HERCEPTIN™ (Genentech, Inc., South San Francisco, California, USA). Such combinations are useful for the treatment and prevention of abnormal cell growth, including cancer.

EGFR inhibitors are described, for example, in World Patent Application No. WO 95/19970 (published July 27, 1995), World Patent Application No. WO 98/14451 (published April 9, 1998), World Patent Application No. WO 98/02434 (published January 22, 1998), and U.S. Patent No. US 5,747,498 (issued May 5, 1998), and these compounds may be used for the purposes of the invention. EGFR inhibitory agents include, by way of example and without limitation, the monoclonal antibodies C225 and anti-EGFR 22 Mab (ImClone Systems Incorporated New York, New York, USA), the compounds ZD-1839 (Astra Zeneca), BIBX-1382 (Bobringer Ingelheim), MDX-447 (Medarex Inc., Annandale, New Jersey, USA), OLX-103 (Merck & Co., Whitehouse Station, New Jersey, USA), VRCTC-310 (Ventech Research), and EGF fusion toxin (Seragen Inc., Hopkinton, Massachusettes). These and other EGFR inhibitors may be used for the purposes of the invention.

VEGF inhibitors, such as SU-5416 and SU-6668 (Sugen Inc., South San Francisco, California, USA), can be combined with compounds of formula I. VEGF inhibitors are described, for example, in World Patent Application No. WO 99/24440 (published May 20, 1999), in International Patent Application No. PCT/IB99/00797 (filed May 3, 1999), in World Patent Application No. WO 95/21613 (published August 17, 1995), in World Patent Application No. WO 99/61422 (published December 2, 1999), in United States Patent Application No. U.S.

834504 (issued November 10, 1998), in World Patent Application No. WO 98/50356 (published November 12, 1998), in U.S. Patent Application No. US 5,883,113 (issued March 16, 1999), in U.S. Patent Application No. US 5,886,020 (issued March 23, 1999), in U.S. Patent Application No. US 5,792,783 (issued August 11, 1998), in World Patent Application No. WO 99/10349 (published March 4, 1999), in World Patent Application No. WO 97/32856 (published September 12, 1997), in World Patent Application No. WO 97/22596 (published June 26, 1997), World Patent Application No. WO 98/54093 (published December 3, 1998), World Patent Application No. WO 98/02438 (published January 22, 1998), World Patent Application No. WO 99/16755 (published April 8, 1999), and World Patent Application No. WO 98/02437 (published January 22, 1998). Other examples of some specific VEGF inhibitors useful for the purposes of the invention are IM862 (Cytran Inc., Kirland, Wash., USA); anti-VEGF monoclonal antibody (Genentech, Inc., South San Francisco, Calif., USA); and Angiozyme, a synthetic ribozyme (Ribozyme, Boulder, Colorado, USA) and Chiron (Emeryville, Calif., USA). These and other VEGF inhibitors can be used for the purposes of the invention.

ErbB2 receptor inhibitors, such as GW-282974 (Glaxo Wellcome plc) and the monoclonal antibodies AR-209 (Aronex Pharmaceuticals Inc., The Woodlands, Texas, USA) and 2B-1 (Chiron) can also be combined with compounds of general formula I. Thus, for example, compounds described in World Patent Application No. WO 98/02434 (published January 22, 1998), in World Patent Application No. WO 99/35146 (published July 15, 1999), in World Patent Application No. WO 99/35132 (published July 15, 1999), in World Patent Application No. WO 98/02437 (published January 22, 1998), in World Patent Application No. WO 97/13760 can be used. (published April 17, 1997), World Patent Application No. WO 95/19970 (published July 27, 1995), U.S. Patent Application No. U.S. 5,587,458 (issued December 24, 1996), and U.S. Patent Application No. U.S. 5,877,305 (issued March 2, 1999). ErbB2 receptor inhibitors useful for the purposes of the invention are also described in U.S. Patent Application No. 60/117,346 (filed January 27, 1999). ErbB2 receptor inhibitor compounds and substances described in the above-mentioned PCT applications, U.S. patents, and U.S. applications, as well as other compounds and substances that inhibit the erbB2 receptor, can be used with the compounds of Formula I of the invention.

are CTLA4 inhibitor antibodies

Compounds of formula I can also be used with other agents effective in treating abnormal cell growth or cancer, including but not limited to agents capable of promoting antitumor immune responses, such as cytotoxic lymphocyte antigen 4 (CTLA4) and other agents capable of blocking CTLA4; and antiproliferative agents, such as farnesyprotein transferases. Specific ones suitable for the purposes of the invention are described in U.S. Patent Application Serial No. 60/113,647 (filed December 22, 1998), but other CTLA4 antibodies can also be used for the purposes of the invention.

Compounds of formula I can also be administered in a method of inhibiting abnormal growth of mammalian cells in combination with radiation therapy. Radiation therapy methods are known to those skilled in the art and can be used in combination with the methods of the invention. Administration of compounds of the invention in combination with radiation therapy is described herein.

Cdk5 inhibitors, such as compounds of Formula I, can also be administered in combination with a COX-II inhibitor for the treatment of Alzheimer's disease, mild cognitive impairment, and age-related cognitive decline. Specific examples of COX-II for this purpose are described above, and the use of a COX-II inhibitor in combination with compounds of Formula I for the treatment of excessive cell growth is described herein. The effective amount of a COX-II inhibitor in combination with a cdk5 inhibitor, such as a compound of Formula I, can generally be determined by one of ordinary skill in the art or by a person skilled in the art. The recommended daily dosage of a COX-II inhibitor in combination with a cdk5 inhibitor is in the range of about 0.1 to about 25 mg/kg body weight. The daily effective amount of a cdk5 inhibitor is generally in the range of about 0.0001 to about 10 mg/kg body weight.

In some cases, the amount of COX-II inhibitor and/or cdk5 inhibitor in combination with each other may be less than would be necessary when using these compounds individually to achieve the same desired effect in the treatment of Alzheimer's disease, mild cognitive impairment, and age-related cognitive decline.

Cdk5 inhibitors, such as compounds of formula I, can also be administered in combination with an NK-1 receptor antagonist for the treatment of depression and anxiety. An NK-1 receptor antagonist is a compound that is capable of antagonizing NK-1 receptors and thereby inhibiting a tachykinin-mediated response, such as a substance P-mediated response. Various NK-1 receptor antagonists are known in the art, and any such NK-1 receptor antagonist can be used for the purposes of the invention, as described above, in combination with a cdk5 inhibitor, for example, a compound of formula I. NK-1 receptor antagonists are described, for example, in U.S. Patent No. 5,716,965 (issued February 10, 1998), U.S. Patent No. 5,852,038 (issued December 22, 1998), World Patent No. WO 90/05729 (international publication May 31, 1990), U.S. Patent No. 5,807,867 (issued September 15, 1998), and U.S. Patent No. 5,807,867 (issued September 15, 1998). 1998), • · · · » ···*· · ··· · · · · · · · · · · · · « • · · · · ··· · No. 332817 (issued July 26, 1994), U.S. Patent No. 5,122525 (issued June 16, 1992), U.S. Patent No. 5,843966 (issued December 1, 1998), U.S. Patent No. 5,703240 (issued December 30, 1997), U.S. Patent No. 5,719147 (issued February 17, 1998), and U.S. Patent No. 5,637699 (issued June 10, 1997). Compounds described in the above publications having NK-1 receptor antagonizing activity may be used for the purposes of the invention. However, other NK-1 receptor antagonists may also be used for the purposes of the invention.

The effective amount of an NK-1 receptor antagonist in combination with a cdk5 inhibitor, for example a compound of formula I, can generally be determined by one of ordinary skill in the art or by a person skilled in the art. The recommended daily dosage of an NK-1 receptor antagonist in combination with a cdk5 inhibitor is in the range of about 0.07 to about 21 mg/kg body weight. The daily effective amount of a cdk5 inhibitor is generally in the range of about 0.0001 to about 10 mg/kg body weight. In some cases, the amount of an NK-1 receptor antagonist and/or a cdk5 inhibitor in combination with each other may be less than would be required when these compounds are used individually to achieve the same desired effect in the treatment of depression and anxiety.

The invention also relates to the combination of a cdk5 inhibitor, such as compounds of formula I, with a 5HT11 receptor antagonist for the treatment of depression and anxiety. A 5HT11 receptor antagonist is a compound that is capable of antagonizing the 5HT11 subtype of the serotonin receptor. Any of the substances described above can be used in combination with a cdk5 inhibitor, such as a compound of formula I. Those skilled in the art will be able to determine substances having 5HT11 receptor antagonist activity. For example, 5HT1 receptor antagonists are described in World Patent Application No. WO 98/14433 (International Publication April 9, 1998), World Patent Application No. WO 97/36867 (International Publication October 9, 1997), World Patent Application No. WO 94/21619 (International Publication September 29, 1994), U.S. Patent Application No. U.S. 5,510,350 (issued April 23, 1996), U.S. Patent Application No. U.S. 5,358,948 (issued October 25, 1994), and British Patent Application No. 2,276,162 A (published September 21, 1994). The aforementioned 5HT1 receptor antagonists, as well as other such antagonists, may be used for the purposes of the invention.

The effective amount of a 5HT11 receptor antagonist in combination with a cdk5 inhibitor, for example a compound of formula I, can generally be determined by one of ordinary skill in the art or by a person skilled in the art. The recommended daily dosage of a 5HT11 receptor antagonist in combination with a cdk5 inhibitor is in the range of about 0.01 to about 40 mg/kg body weight. The daily effective amount of a cdk5 inhibitor is generally in the range of about 0.0001 to about 10 mg/kg body weight. In some cases, the amount of a 5HT11 receptor antagonist and/or a cdk5 inhibitor in combination with each other may be less than would be required when using these compounds individually to achieve the same desired effect in the treatment of depression and anxiety.

The invention also relates to a pharmaceutical composition and method for treating depression and anxiety in mammals, comprising administering to the mammal a cdk5 inhibitor, e.g., a compound of formula I, and an SSRI. Examples of SSRIs that may be combined in the method or pharmaceutical composition with a cdk5 inhibitor, e.g., a compound of formula I and a pharmaceutically acceptable salt thereof, include, but are not limited to, fluoxetine, paroxetine, sertraline, and fluvoxamine. Other SSRIs may also be combined or administered in combination with a cdk5 inhibitor, e.g., a compound of formula I and a pharmaceutically acceptable salt thereof. Other antidepressants and/or anxiolytic agents may be combined or administered with a cdk5 inhibitor, e.g., a compound of formula I.

The effective amount of an SSRI in combination with a cdk5 inhibitor, for example a compound of formula I, can generally be determined by one of ordinary skill in the art or by a person skilled in the art. The recommended daily dosage of an SSRI in combination with a cdk5 inhibitor is in the range of about 0.01 to about 500 mg/kg body weight. The daily effective amount of a cdk5 inhibitor is generally in the range of about 0.0001 to about 10 mg/kg body weight. In some cases, the amount of an SSRI and/or a cdk5 inhibitor in combination with each other may be less than would be required when these compounds are used individually to achieve the same desired effect in the treatment of depression and anxiety.

A cdk5 inhibitor, e.g., a compound of formula I or a pharmaceutically acceptable salt thereof, may also be combined with one or more antipsychotic agents, e.g., a dopaminergic agent, for the treatment of diseases or conditions wherein such treatment may affect or facilitate alteration of dopamine neurotransmission, such as schizophrenia. Examples of antipsychotic compounds 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 No. 4,831,031 and U.S. Patent No. 5,312,925): olanzapine (2-methyl-4-(4-methyl-1-piperazinyl-10H-thieno(2,3b)(1,5)benzodiazepine, U.S. Patent No. 4,115,574 and U.S. Patent No. 5,229,382): risperidone (3-[263

- [4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl-3-ethyl-3-6,78,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one, US Patent No. 5,4804,663); L-745870 (3-(4-(4-chlorophenylpiperazin-1-yl)methyl-1H-pyrrolo(2,3-b)pyridine, US Patent No. 5,432,177); sonepiprazole (S-(4-(4-(2-isochroman-1-yl)ethyl)piperazin-1-yl)benzenesulfonamide, US Patent No. 5,877,317): RP 62203 (phananserin, 2-(3-(4-(4-fluorophenyl)-1-piperazinyl)propyl)naphtho(1,8-cd)isothiazole-1,1-dioxide, US Patent No. 5,021,420); NGD 941, US Patent No. 5,633,376 and US Patent No. 5,428,165): balaperidone (loc, 5t1, 6cr) - 3-(2-(6-(4-fluorophenyl)-3-azabicyclo(3.2.0)hept-3-yl)ethyl-2,4(1H,3H)quinazolinedione, U.S. Patent No. 4,475,105); flesinoxan ((+)-4-fluoro-N-[2-[4,5-(2-hydroxymethyl-1,4-benzodioxanyl3-1-piperazinylethylbenzamide, U.S. Patent No. 4,833,142); and gepirone (4,4-dimethyl-1-(4-(2-pyrimidinyl)-1-piperazinyl)butyl)-2,6-piperidindione, U.S. Patent No. 4,423,049). The effective daily dose of a cdk5 inhibitor is generally in the range of about 0.0001 to about 10 mg/kg body weight. The amount of any of the above antipsychotic agents contemplated for use in combination with a cdk5 inhibitor, for example, a compound of formula I, is generally known as an amount for treating psychotic conditions. In some cases, the amount of antipsychotic agent and/or cdk5 inhibitor in combination with each other may be less than would be required when these compounds are used individually to achieve the same desired effect in the treatment of depression and anxiety. The invention also encompasses combinations of a cdk5 inhibitor, for example, a compound of formula I, with an antipsychotic or dopaminergic agent other than those described above.

The recommended daily dose of sonepiprazole in the above-described combination with a cdk5 inhibitor, for example a compound of general formula I, is in the range of about 0.005 to about 50 mg/kg • · · · · ·

• ·· · ···· · • · · · · ··· · ··· · ··· ··· ··· ··· ,, body weight. The recommended daily dose of RP 62203 in such a combination is in the range of about 0.20 to about 6 mg/kg body weight. The recommended daily dose of NGD 941, in such a combination is in the range of about 0.10 to about 140 mg/kg body weight. The recommended daily dose of balaperidone in such a combination is in the range of about 1 to about 100 mg/kg body weight. The recommended daily dose of flesinoxan in such a combination is in the range of about 0.02 to about 1.6 mg/kg body weight. The recommended daily dose of gepirone in such a combination is in the range of about 0.01 to about 2 mg/kg body weight. The recommended daily dose of L-745870 in such a combination is in the range of about 0.01 to about 250 mg/kg of body weight, preferably in the range of about 0.05 to about 100 mg/kg of body weight. The recommended daily dose of risperidone in such a combination is in the range of about 0.05 to about 50 mg/kg of body weight. The recommended daily dose of olanzapine in such a combination is in the range of about 0.0005 to about 0.6 mg/kg of body weight. The recommended daily dose of ziprasidone in such a combination is in the range of about 0.05 to about 10 mg/kg of body weight. In some cases of such combinations as set forth above, however, the amount of each specific agent in combination with each other may be less than would be required when these compounds are used individually to achieve the same desired effect in the treatment of a psychotic condition.

The invention also relates to a pharmaceutical composition and method for treating disorders selected from the group consisting of Alzheimer's disease, mild cognitive impairment and age-related cognitive decline, comprising administering to mammals a cdk5 inhibitor, for example a compound of formula I, and an acetylcholinesterase inhibitor. Acetylcholinesterase inhibitors are known in the art and such acetylcholinesterase inhibitors can be used in the above-described compositions and methods of treatment. Examples of acetylcholinesterase inhibitors that can be used for the purposes of the invention include, without limitation, the following:

ARICEPT (donepezil, US Patent No. 4,895,841); EXELON (rivastigmine, (S)-tN-ethyl-3-[1-(dimethylamino)ethyl 1-phenyl]carbamate, US Patent No. 5,603,176 and US Patent No. 4,948,807); metrifonate (2,2,2-trichloro-1-hydroxyethyl)phosphonic acid dimethyl ester, US Patent No. 2,701,225 and US Patent No. 4,950,658); galantamine, US Patent No. 4,663,318); physostigmine (Forest, USA); tacrine (1,2,34-tetrahydro-9-acridinamine, US Patent No. 4,816,456); huperzine A (5R-(5α,9β,11E))-5-amino-11-ethylidene-5,6,9,10-tetrahydro-7-methyl-5,9-methanocycloocta(b)pyridin-2-(H)one); and icopezil (5,7-dihydro-3-(2-(1-(phenylmethyl)-4-piperidinyl)ethyl)-6H-pyrrolo-(3,2-f)-1,2-benzisoxazol-6-one, U.S. Patent No. 5,750,542 and World Patent No. WO 92/17475).

The effective amount of an acetylcholinesterase inhibitor in combination with a cdk5 inhibitor, for example a compound of formula I, can generally be determined by one skilled in the art or by a person skilled in the art. The recommended daily dosage of an acetylcholinesterase inhibitor in combination with a cdk5 inhibitor is in the range of about 0.01 to about 10 mg/kg body weight. The daily effective amount of a cdk5 inhibitor is generally in the range of about 0.0001 to about 10 mg/kg body weight. In some cases, the amount of an acetylcholinesterase inhibitor and/or a cdk5 inhibitor in combination with each other may be less than would be required when these compounds are used individually to achieve the same desired effect in the treatment of Alzheimer's disease, mild cognitive impairment, and age-related cognitive decline.

The invention also relates to combining a cdk5 inhibitor with neuroprotective agents, for example, NHDA receptor antagonists, for the treatment of diseases and conditions such as Huntington's disease, stroke, spinal cord trauma, traumatic brain injury, multi-infarct dementia, epilepsy, amyotrophic lateral sclerosis, pain, viral or AIDS-related dementia, migraine, hypoglycemia, urinary incontinence, cerebral ischemia, multiple sclerosis, Alzheimer's disease, senile dementia of the Alzheimer type, mild cognitive impairment, age-related decline in consciousness, emesis, corticobasal degeneration, dementia pugilistica, Down syndrome, myotonic dystrophy, Bieann-Pick disease, Pick's disease, prion disease with vertigo, progressive supranuclear palsy, inferior lateral sclerosis, and subacute sclerotic panencephalitis. Examples of NMDA receptor antagonists that may be used in accordance with the invention include (1S,2S)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidin-1-yl)-1-propanol (U.S. Patent No. 5,272,160); eliprodil (U.S. Patent No. 4,690,931); and gavestenel (U.S. Patent No. 5,373,018). Other NMDA receptor antagonists that may also be used for the purposes of the invention are described in the following patent literature: U.S. Patent No. 5,373,018; U.S. Patent No. 4,690,931; U.S. Patent No. 5,272,160; U.S. Patent No. 5,185,343; U.S. Patent No. 5,356,905; US Patent No. 5,744,483: World Patent No. WO 97/23216; World Patent No. WO 97/23215; World Patent No. WO 97/23214; World Patent No. WO 96/37222; World Patent No. WO 96/06081; World Patent No. WO 97/23458; World Patent No. WO 97/32581; World Patent No. WO 98/18793; World Patent No. WO 97/23202; US Patent Application No. 08/292,651 (filed August 18, 1994).

An effective daily amount of a cdk5 inhibitor in combination with an NMDA receptor antagonist is in the range of about 0.0001 to about 10 mg/kg body weight. The amount of NMDA receptor antagonist contemplated for use in combination with a cdk5 inhibitor, e.g., a compound of Formula I, for the treatment of the above disorders, e.g., Alzheimer's disease, is generally in the range of about 0.02 to about 10 mg/kg/day. In some cases, the amount of NMDA receptor antagonist and/or cdk5 inhibitor in combination with each other may be less than would be required when these compounds are used individually to achieve the same desired effect in the treatment of the above disorders.

The invention also relates to combining a cdk5 inhibitor with certain substances useful for the treatment of stroke or traumatic brain injury, such as TPA, NIF or potassium channel modulators, for example BMS-2O4352. Such combinations are useful for the treatment of neurodegenerative disorders, such as stroke, spinal cord injury, traumatic brain injury, multi-infarct dementia, epilepsy, pain, Alzheimer's disease and senile dementia.

For the above combination therapies and pharmaceutical compositions, effective amounts of the compound of the invention and other agents are generally determined by those skilled in the art based on effective amounts of the above compounds and other known or disclosed agents described in the above patent literature. The compositions and routes of administration for such therapies and compositions are based on the information described herein for compositions and therapies for the compound of the invention as the sole active agent and for use in combination with another active agent.

Specific compounds of formula I can be assessed for inhibition of cdk2, cdk5 or GSK-3 by biological assays known to those skilled in the art, such as those described below.

The specific activity of the compounds of formula I with respect to the inhibition of cdk5 or cdk2 can be assessed, for example, by the following assays using materials available to those skilled in the art.

Enzyme activity can be assessed by incorporation of [ ³³ P] from gamma phosphate [ ³³ P1ATP (Amersham, cat. no. AH-9968) into the biotinylated peptide substrate PKTPKKAKKL. In such an assay, reactions are carried out in a buffer containing 50 mM Tris-HCl, pH 8.0; 10 mM magnesium chloride, 0.1 mM Na3VO4 and 1 mM DTT. The final ATP concentration is approximately 0.5 μΜ (final specific radioactivity 4pCi/nmol) and the final substrate concentration is 0.75 μΜ. The reaction, initiated by the addition of either cdk5 and the p25 protein activator or cdk2 and the cyclin E activator, can be carried out at room temperature for 60 minutes. The reaction is terminated by adding 0.6 volumes of buffer containing (final concentration): 2.5 mM EDTA, 0.05% Triton-X 100, 100 μΜ ATP and

1.25 mg/ml streptavidin-coated SPA beads (Amersham, cat. no. RPNQ0007). The radioactivity associated with the beads is quantified by scintillation counting.

The specific activity of compounds of formula I for inhibiting GSK-3 can be determined based on cell-free and cell-based assays. Cell-free assays can generally be performed by incubating GSK-3 with a peptide substrate, with radiolabeled ATP (e.g., gamma ³³ P- or gamma ³² P-ATP, commercially available from Amersham, Arlington Heights, Illinois), with magnesium ions, and with a test compound. The mixture is incubated for a period of time sufficient for incorporation of the radiolabeled phosphate into the peptide substrate by GSK-3 activity. The reaction mixture is washed to remove unreacted radiolabeled ATP, typically after transferring all or a portion of the enzyme reaction mixture to a well containing a uniform amount of ligand capable of binding to the peptide substrate. The amount of ³³ P or ³² P remaining in the well after washing is then quantified to determine the amount of radiolabeled phosphate into the peptide substrate. Inhibition is observed as a decrease, relative to control, in incorporation of the radiolabeled phosphate into the peptide substrate. An example of a suitable GSK-3 peptide is The substrate for the assay is the SGSG-bound CREB peptide sequence, derived from the Creb DNA binding protein (Wang et al., Anal. Biochem. 220, pp. 397-402, 1994). For example, purified GSK-3 for the assay can be obtained from cells transfected with a human GSK-30 expression plasmid (e.g., Stambolic et al., Current Biology 6, pp. 1664-1668, 1996; World Patent Publication No. WO 99/65897).

Another example of a GSK-3 assay is similar to that described above. Enzyme activities are assessed as the incorporation of [ ³³ P] from gamma phosphate [ ³³ P1ATP (Amersham, cat. no. AH-9968) into the biotinylated peptide substrate PKTPKKAKKL. In such an assay, reactions are carried out in a buffer containing 50 mM Tris-HCl, pH 8.0; 10 mM magnesium chloride, 0.1 mM Na3VO4, and 1 mM DTT. The final ATP concentration is approximately 0.5 pM (final specific radioactivity 4 pCi/nmol) and the final substrate concentration is 0.75 pM. The reaction, initiated by the addition of the enzyme, can be carried out at room temperature for 60 minutes. The reaction is terminated by the addition of 0.6 volumes of buffer containing (final concentration): 2.5 mM EDTA, 0.05% Triton-X 100, 100 pM ATP and 1.25 mg/ml streptavidin-coated SPA beads (Amersham, cat. no. RPNQ0007). The radioactivity associated with the beads is quantified by scintillation counting.

All compounds of the following examples have IC 50s inhibiting peptide substrate phosphorylation of less than about 50 pM in the cdk5 inhibition assays described above.

Some of the compounds of the following examples were tested for GSK-3 inhibition using the assay described above, with all compounds tested having an IC50 for inhibiting GSK-3β of less than 50 pM.

The following practical examples illustrate the invention in more detail, but do not limit it in any way.

Examples of embodiments of the invention

Preparation 1

1-Cyclobutyl-4-nitro-1H-imidazole

1,4-Dinitroimidazole (237 mg, 1.5 mmol) (J. Phys. Chem. 99, pp. 5009-5015, 1995) was added to a solution of β-cyclobutylamine

(107 mg, 1.5 mmol) in methanol (10 mL) at 23 C. The reaction mixture was stirred for 16 h, the solvent was removed in vacuo, and the resulting residue was purified by silica gel chromatography (1:1 hexanes-ethyl acetate) to give 230 mg (92% yield).

-cyclobutyl-4-nitro-1H-imidazole. 1 H NMR (400 MHz, CDCl 3 ), 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/Cl): 168.2 (M+H) ⁺ .

Note: 1,4-Dinitroimidazole is a highly energetic, semi-stable substance and should be stored in a freezer when not in use. Thermodynamic measurements have shown that it can potentially

B generate enough energy at 35 C under adiabatic conditions to cause a violent explosion. Extreme caution is always required when using 1,4-Dinitroimidazole.

Preparation 2

1-Cyclopentyl-4-nitro-1H-imidazole

This compound was prepared according to the method of Preparation 1 using cyclopentylamine and 1,4-dinitroimidazole to give 205 mg (75% yield) of 1-cyclopentyl-4-nitro-1H-imidazole.

1 H NMR (400 MHz, CDCl ₃ 6 7.77 (s,1H), 7.45 (s,1H), 4.49 (m,1H), 2.25 (m,2H) 2.0 to 1.7 (m,6H). MS (AP/Cl): 182.2 (M+H) ⁺ .

Preparation 3

4-Nitro-1-(cis-3-phenylcyclobutyl)-1H-imidazole

This compound was prepared according to the method of Preparation 1 using cis-3-phenylcyclobutylamine (J. Med. Pharm. Chem. 2, pp. 687-691, 1960; ACIEE 20, pp. 879-880, 1981) and 1,4-dinitroimidazole to give 46 mg (yield 46%) of 4-nitro-1-(cis-3-phenylcyclobutyl)-1H-imidazole. 1H NMR (300 MHz, CDCl3) δ 7.9 (s,1H), 5.55 (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/Cl): 244 (M+H) ⁺ .

Example 1

Ν - (1-Cyclobutyl-1H-imidazol-4-yl)-2-quinolin-6-yl-acetamide

1-Cyclobutyl-4nitro-1H-imidazole (Preparation 1, 150 mg, 0.9 mmol) and ethyl acetate (10 mL) were placed in a Parr hydrogenation flask, followed by 10% palladium on carbon (250 mg). The reaction mixture was placed in a Parr hydrogenation unit and allowed to react for six hours under a hydrogen pressure of 345 kPa at 23°C. The contents of the flask were filtered through a thin pad of celite and rinsed with dry methylene chloride (25 mL) into a flame-dried flask under nitrogen. Triethylamine (626 μΐ, 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 µl, 1.7 M solution in ethyl acetate) were added and the mixture was stirred for two hours.

hours at -10 C. The solution was diluted with methylene chloride (50 mL) and washed with water (2x). The aqueous layer was extracted with methylene chloride (3x), the organic layers were combined and washed with brine (1x). The solvent was removed in vacuo, the residue was adsorbed onto silica gel and purified by chromatography using a Biotage Flash 12 system with SIM attachment (40:1 methylene chloride-methanol system) to give 130 mg (47% yield) of N-(1-cyclobutyl-1H-imidazol-4-yl)-2-quinolin-6-yl-acetamide.

9.48 (s, 1H), 8.87 (dd, J=1.6, 4.3 (d, J=1.8 Hz, 1H), 7.67 (dd, J=2, O, Hz, 1H), 7.38 (m,1H), 7.25 (d,J=1.6 (s,2H), 2.5 (m,2H), 1.85 (m,2H);

1 H NMR (300 MHz, CDCl 3 ) <S Hz, 1H) , 8.11 (m,2H), 7.76 8.7 Hz,1H), 7.44 (d, J=1.6 Hz, 1H), 4.5 (tt,1H), 3.90 MS (AP/C1): 307.1 (M+H) ⁺ Example 2

N-(1-Cyclopentyl-1H-imidazol-4-yl)-2-(4-methoxyphenyl)acetamide

This compound was prepared according to the method of Example 1 using paramethoxyphenylacetic acid and 1-cyclopentyl-4-nitro-1H-imidazole (Preparation 2) to give 26.5 mg of N-(1-cyclopentyl-1H-imidazol-4-yl)-2-(4-methoxyphenyl)acetamide (32% yield). 1H NMR (400 MHz, CDCl3) <5 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), 2.2 (m,2H), 1.8 (m,4H), 1.6 (m,2H);

MS (AP/Cl): 300.3 (M+H) ⁺ .

Example 3

N-[1-(cis-3-Phenylcyclobutyl)-1H-imidazol-4-yl1-2-quinoline-6-ylacetamide

This compound is prepared according to the method of Example 1 using 6-quinolylacetic acid and 4-nitro-1-(cis-3-phenylcyclobutyl)-1H-imidazole (Preparation 3) to give N-[1-(cis-3-phenylcyclobutyl)-1H-imidazol-4-yl]-2-quinolin-6-ylacetamide

(yield 3%); 1H NMR (300 MHz, CDCl3) 6 8.93 (m, 1H) , 8, 12 (m, 2H) , 7, 79 (d, J = 1.5 Hertz, 1H) , 7.71 (m.lH), 7.55 (d. J=1, 5 Hertz, 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/Cl): 383.0 (M+H) ⁺ .

Example 4 Carbamic acid (1-cyclobutyl-1H-imidazol-4-yl)phenyl ester

In a Parr hydrogenation flask, 1-cyclobutyl-4nitro-1H-imidazole (Preparation 1, 3 g, 18 mmol) and ethyl acetate (70 mL) were added, followed by 10% palladium on carbon (1.2 g) under nitrogen. The reaction mixture was hydrogenated for six hours under a hydrogen pressure of 345

O kPa at 23 C. The mixture is filtered through a thin pad of celite and rinsed with dry methylene chloride (140 ml) into a flame-dried flask. The resulting solution is cooled to a temperature of

-78 C and diisopropylethylamine (2.3 g, 18 mmol) and phenylchloroformate (2.5 g, 16.2 mmol) were added dropwise. After 30 min, methanol (9 mL) containing acetic acid (1.8 mmol) was added. The reaction mixture was transferred to a separate flask, diluted with ethyl acetate (200 mL) and washed with water (2x). The aqueous layers were extracted with ethyl acetate (2x10 mL). The organic layers were combined, washed with brine (2x), dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product was adsorbed onto silica gel and purified by silica gel chromatography (1:1 hexanes-ethyl acetate) to give 3 g (65% yield) of (1-cyclobutyl-1H-imidazol-4-yl)phenylcarbamic acid ester. 1 H NMR (400 MHz, CDCl ₃ ), δ 7.4-7.3 (m,2H), 7.22-7.18 (m,4H), 4.5 (m,1H), 2.46-2.30 (m,4H), 1.83 (m,2H); MS (AP/C1): 258.2 (M+H)*·

Example 5

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

Into a 1 dram vial with a septa screw cap was added (1-cyclobutyl-1H-imidazol-4-yl)carbamic acid phenyl ester (Example 4, 50 g, 0.19 mmol), 5-aminoisoquinoline (30 mg, 0.21 mmol) and the 1=1 dioxane-dimethylformamide system (1 mL). Reaction • · · · · ♦ · · ··· ··· ··· ··· « · ·· o

The mixture was kept at 70°C for two hours. The reaction mixture was adsorbed onto silica gel and purified by silica gel chromatography (40:1 chloroform-methanol system) to give 30 mg (52% yield) of 1-(1-cyclobutyl-1H-imidazol-4-yl)-3-isoquinolin-5-ylurea. 1H NMR (400 MHz, CD3OD), δ 9.21(0.7=1.7 131.11-1),8.45(0../ = 6.2

Hz, 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/Cl): 308.0 (M+H) ⁺ .

Preparation 4

N-[1-(cis-Azidocyclobutyl)-1H-imidazol-4-yl]-2-naphthalen-1-ylacetamide

Stage 1

3-Benzyloxycyclobutylamine (43.4 g, 245 mmol), Chem.Ber. 90, pp. 1424-1432, 1957) was dissolved in saturated methanolic hydrogen chloride (450 ml) and 10% palladium on carbon (4 g) was added. The mixture was hydrogenated for six hours under 345 KPa of hydrogen. The mixture was filtered and concentrated in vacuo to give approximately 35 g of an oil. The oil was taken up in methanol at

(600 ml), cooled to 0 C and treated with potassium hydroxide (13.7 g, 245 mmol). When pH 10 is reached, a solution of 1,4-dinitroimidazole (42.7 g, 270 mmol) in methanol (200 ml) (prepared by dissolving 1,4-dinitroimidazole β

in methanol at 0 C).

Note: 1,4-Dinitroimidazole is a highly energetic, semi-stable substance and should be kept in the freezer when not in use. Thermodynamic measurements have shown that it can potentially

generate enough energy at 35 C under adiabatic conditions to cause a violent explosion. Extreme caution is always required when using 1,4-Dinitroimidazole.

The resulting orange suspension is allowed to slowly warm overnight to β

temperature 23 C. The solvent was removed in vacuo and the resulting residue was purified by passage through a large plug of silica gel (system 20=1 chloroform-methanol) to give 19 g (yield 42%) of 3-(4-nitroimidazol-1-yl)cyclobutanol as a mixture of 1=1 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/Cl): 184.0 (M+H) ⁺ .

Stage 2

3-(4-Nitroimidazol-1-yl)cyclobutanol (Preparation 4, step 1; 4 g (22 mmol) was treated with triethylamine (7.7 mL, 55 mmol) in methylene chloride (150 mL) followed by p-toluenesulfonyl chloride (TsCl) (5 g, 26.4 mmol) and 4-N,N-dimethylaminopyridine (DMAP) (268 mg, 2.2 mmol). The resulting mixture was stirred at room temperature for 24 h. Thin layer chromatography analysis showed two new spots. The reaction mixture was diluted with methylene chloride and washed with water (1x) and brine (ix). The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. Purification by silica gel chromatography (1:1 to 2:1 hexanes-ethyl acetate system) allowed the separation of the trans- and cis-diastereomers. The first The eluting spot (high Rf) is the trans-isomer, trans-toluene-4-sulfonic acid 3-(4-nitroimidazol-1-yl)cyclobutyl ester (2.7 g, 37% yield). 1H NMR (400 MHz, CD3OD), 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 (rn,1H), 2.9 (m,2H), 2.7 (m,2H); MS (AP/Cl): 338.1 (M+H) ⁺ . The second eluted spot is the cis-isomer, cis-toluene-4-sulfonic acid 3-(4-nitroimidazol-1-yl)cyclobutyl ester (2.97 g, 39% yield). 1H NMR (400 MHz, CD3OD) , 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 (AP/Cl): 338.1 (M+H) ⁺ .

The relative configuration is determined by measuring nuclear Overhauser effects.

Level 3

Trans-toluene-4-sulfonic acid 3-(4-nitroimidazol-1-yl)cyclobutyl ester (Preparation 4, Step 2, 590 mg, 1.75 mmol) was mixed with 10% palladium on carbon (500 mg) in ethyl acetate (30 mL). The mixture was reacted under 345 KPa of hydrogen pressure for six hours at room temperature. The mixture was filtered through celite into a flame-dried flask maintained under nitrogen. Triethylamine (1.22 mL, 8.75 mmol) was added, followed by 1-naphthylacetic acid (326 mg, 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 temperature for one hour, diluted with ethyl acetate and washed with water and brine. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (50:1 chloroform-methanol system) to give 600 mg (72% yield) of trans-toluene-4-sulfonic acid 3-[4-(2-naphthalen-1-ylacetylamino)imidazol-1-yl]cyclobutyl ester. 1H NMR (400 MHz, CDCl ₃ ) 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/Cl): 476.2 (M+H) + .

Grade 4

Trans-toluene-4-sulfonic acid 3-[4-(2-Naphthalen-1-ylacetylamino)imidazol-1-yl]cyclobutyl ester (Preparation 4, step 3, 593 mg, 1.25 mmol) was mixed with sodium azide (813 mg, 12.5 mmol) in ethanol (15 mL), water (5 mL) and chloroform (5 mL). The mixture was stirred at reflux for 96 h. The solvent was removed in vacuo, the residue was diluted with water and extracted with methylene chloride. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue obtained was purified by chromatography on silica gel (50:1 chloroform-methanol system) to give 340 mg (79% yield).

N -[1-cis-3-azidocyclobutyl)-1H-imidazol-4-yl3-2-naphthalen-1-ylacetamide. 1H NMR (400 MHz, CDCl 3 ) S 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 (AP/Cl): 347.2 (M+H) + .

Example 6

N - C 1 -cis-3-Aminocyclobutyl)-1H-imidazol-4-yl3-2-naphthalen-1-yl acetam i d

N - [1-cis-3-Azidocyclobutyl)-1H-imidazol-4-yl3-2-naphthalen-1-ylacetamide (Preparation 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 for 18 hours at room temperature. The solvent was removed in vacuo and the residue was purified by silica gel chromatography (20 × 1:0.5 chloroform-methanol-ammonium hydroxide system) to give 289 mg (95% yield) of N-[1-cis-3-aminocyclobutyl)-1H-imidazol-4-yl3-2-naphthalen-1-ylacetamide.

1H NMR (400 MHz, CD3OD) δ 8.05 (d, J = 7.5 Hz/IH), 7 _Z 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/Cl): 321.3 (M+H) + .

Example 7a 6-Methylpyridine-2-carboxylic acid (cis-3-[4-(2-Naphthalen-1-ylacetylamino)imidazol-1-yl]cyclobutyl)amide

A solution of 6-methylpicolinic acid (9.4 mg, 0.07 mol) in methylene chloride was treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (84 mg) and DMAP (2 mg) at room temperature.

C. After stirring for 10 minutes, N-[1-cis-3-aminocyclo78

butyl)-1H-imidazol-4-yl1-2-naphthalen-1-yl-acetamide (Example 6, 20 mg, 0.06 mmol). The resulting mixture was stirred for three hours. Water was added and the solution was neutralized with aqueous sodium hydroxide solution and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (system 20=1 chloroform-methanol) to give 26 mg (yield 95%) of cis-3-[4-(2-naphthalen-1-yl-acetylamino)imidazol-1-yl]cyclobutylamide of 6-methylpyridine-2-carboxylic acid.

1H NMR (400 MHz, CDCi ₃ ) δ 9.15 (s, 1H), 8.23 (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), 7th (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/Cl): 440.3 (M+H) + .

Example 7b 1H-imidazole-4-carboxylic acid (cis-3-[4-(2-Naphthalen-1-ylacetylamino)imidazol-1-yl]cyclobutyl)amide

Prepared similarly 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£ 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 (cis-3-[4-(2-Naphthalen-1-ylacetylamino)imidazol-1-yl]cyclobutylamide of 6-hydroxypyridi ₍ n-2-carboxylic acid)

Prepared similarly 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/Cl): 442.3 (M+H) + .

Example 7d cis-3-[4-(2-Naphthalen-1-ylacetylamino)imidazol-1-yl]cyclobutyl 1) 3-methylpyridine-2-carboxylic acid amide

Prepared similarly to Example 7a; 1H NMR (CD30D 400 MHz) δ 8.39 (d, J = 4.2 Hz, 1H), 8.06 (d, J = 8.3 Hz, 1H), 7.87 (d, J = 7/ Hz, 1H), 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 _f 54 (s, 3H), 2.46 (m, 2H); MS (AP/Cl): 440.3 (M+H) + .

Example 7e 2-Pyridin-3-ylthiazole-4-carboxylic acid (cis-3-[4-(2-Naphthalen-1-ylacetylamino)imidazol-1-yl]cyclobutylamide

Prepared similarly to Example 7a; 1H NMR (400 MHz, CD3OD) 9.21 (d, J = 2.5 Hz, 1H), 8.61 (d, J = 5.0 Hz, 1H), 8.41 (dd, J = 1.7, 7.9 Hz, 1H), 8.26 (s, 1H), 8.06 (d, J = 7.9 Hz, 1H), 7.86 (d, J = 7.5 Hz, 1H), 7.79 (d, J = 7.9 Hz, 1H), 7.5 (m, 7H),

4.44 (m, 2H), 4.17 (s, 2H), 2.9 (m, 2H), 2.6 (m, 2H); MS (AP/Cl): 509.3 (M+H) + .

Example 7f

6-(cis-3-[4-(2-naphthalen-1-ylacetylamino)imidazol1-yl3cyclobutylcarbamoyl]nicotinic acid methyl ester

Prepared similarly 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, 1H), 8.02 (d, J = 8.4 Hz, 1H), 7.85 (d, J = 8.0 Hz, 1H), 7.79 (d, J - 8.0 Hz, 1H),

7.49 (m, 6H), 4.44 (m, 2H), 4.16 (s, 2H), 2.95 (m, 2H), 2.56 (m, 2H); MS (AP/Cl): 427.3 (M+H) + . '

Example 7g Pyrazine-2-carboxylic acid (cis-3-[4-(2-Naphthalen-1-ylacetylamino)imidazol-1-ylcyclobutyl)amide

Prepared similarly to Example 7a; 1H NMR (400 MHz,

CD3OD / CDCI ₃ ) δ 9/ 5 (d, J = 1 £ Hz, 1 Η), 9 _χ 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 = 7.8 Hz, 1H), 7.48 (m, 6H), 4.45 (m, 2H), 3.96 (s, 3H), 2.94 (m, 2H), 2.58 (m, 2H); MS (AP/Cl): 484.3 (M+H) + .

Example 7h

N-(cis-3-[4-(2-Naphthalen-1-ylacetylamino)imidazol-1-yl1-cyclobutyl)benzamide **

Prepared similarly to Example 7a; 1H NMR (400 MHz,

CD3OD) δ 8.05 (d, J = 8.3 Hz, 2H), 7.99 (d, J = 7.1 Hz, 1H), 7^86 (d, J?7.5 Hz, 1H), 7.80 (J =

7.1 Hz, 2H), 7.45 (m, 8H), 4.47 (m, 1H), 4.37 (m, 1H), 4.17 (s, 2H), .90 (m, 2H), 2.47 (m, 2H); MS (AP/Cl): 425.0 (M+H) + .

Example 7i 5-Methylpyrazine-2-carboxylic acid (cis-3-[4-(2-Naphthalen-1-ylacetylamino)imidazol-1-yl]-cyclobutylamide

Prepared similarly to Example 7a; 1H NMR (400 MHz,

CD3OD) δ 9.07 (d, J = 1.2 Hz, 1H), 8.5 (d, J = 0.8 Hz, 1H), 8.02 (d, J = 8.0 Hz, 1H), 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 (AP/Cl): 441.3 (M+H) + .

Example 7j

N-(cis-3-[4-(2-Naphbalen-1-ylacetylamino)imidazol-1-yl1cyclobutyl)isobutyramide

Prepared similarly to Example 7a; 1H NMR (400 MHz,

CD30D) 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/Cl): 391.1 (M+H) + .

Example 7k 6-Chloropyridine-2-carboxylic acid (cis-3-[4-(2-Naphthalen-1-ylacetylamino)imidazol-1-yl]cyclobutyl)amide

Prepared similarly to Example 7a; 1H NMR (400 MHz,

CD3OD) δ 8.07 (d, J = 7.9 Hz, 1H), 8.03 (d, J = 7.5 Hz, 1H), 7.94 (m, <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/ (m, 5H), 4.45 (m, 1H), 4.39 (m, 1H), 4.18 (s, 2H), 2.89 (m, 2H), 2.63 (m, 2H); MS (AP/Cl): 460.2, 462.2 (M+H) + .

Example 8

N-[1-(cis-3-Aminocyclobutyl)-1H-imidazol-4-yl]-2-naphtalen-1-ylacetamide (Example 6) is acylated with various carboxylic acids and the products are purified as follows:

To the carboxylic acid (RCO2H, 1 eq, 0.075 mmol) in a 1 dram screw-capped vial was added a solution of N-1-(cis-3-aminocyclobutyl)-1H-imidazol-4-yl3-2-naphthalen-1-ylacetamide (0.33 eq, 8 mg, 0.025 mmol) in methylene chloride (1 mL). PS-carbodiimide (Argonaut Technologies, 0.5 eq, 39 mg, 0.038 mmol, 1 mmol/g) was added. The mixtures were shaken for 24 h at 23°C. Note: If the acid was not soluble in methylene chloride, N,N-dimethylformamide (0.5 mL) was added. Each reaction mixture was transferred with methylene chloride (0.5 mL) to a 3 mL SPE cartridge (20 micron frit) with a tared 2 dram vial to collect the solvent. The solvent was forced through the frit and the polymer was washed with tetrahydrofuran (0.5 mL), methylene chloride (0.5 mL), tetrahydrofuran (0.5 mL), and methylene chloride (0.5 mL). The solutions were concentrated under a stream of nitrogen and the crude product was analyzed by LCMS (column: 3.9x150 mm Waters Symmetry Cis 5 μΜ; flow rate 10 mL/min: solvent system: A = 0.1% aqueous trifluoroacetic acid; B = acetonitrile: linear gradient 10 to 100% B over 10 minutes). Once the parent ion (M+H) appears, the crude reaction mixture is purified by preparative HPLC chromatography (column: 30x150 mm Waters Symmetry Cis 5 μΜ; flow rate 20 ml/min: solvent system: A = 0.1% aqueous trifluoroacetic acid: B = acetonitrile: linear gradient 0 to 100% B over 15 minutes) and the relevant fractions are determined in line by mass spectrometry. The purity of the chromatographed compound is determined by analytical HPLC chromatography (column: 2.1x150 mm Waters Symmetry Cis 5 μΜ: flow rate 0.5 ml/min; solvent system: a = 0.1% aqueous trifluoroacetic acid; B = acetonitrile; linear gradient 0 to 100% B over 10 minutes) using UV 254 nM and diode beam for detection.

The following compounds were prepared using the described method and their mass spectrometric data and chromatographic retention times are given in Table I:

Example 8a: Quinoline-2-carboxylic acid (cis-3-[4-(2-naphthalen-1-ylacetylamino)imidazol]-yl]cyclobutylamide.

• · · ·

Example 8b: {cis-3-[4-(2-naphthalen-1-ylacetylamino)imidazol]-yl}cyclobutyl] 1H-pyrrole-2-carboxylic acid amide.

Example 8c= N-(cis-3-[4-(2-naphthalen-1-ylacetylamino)imidazol]-yl)cyclobutyl]-2-m-tolylacetamide.

Example 8d: Pyridine-2-carboxylic acid cis-3-[4-(2-naphthalen-1-ylacetylamino)imidazol-1-yl]cyclobutyl}amide.

Example 8e: 2-(3-hydroxyphenyl)-N-(cis-3-[4-(2-naphthalen-1-ylacetylamino)imidazol-1-yl]cyclobutylacetamide.

Table I

Acylated products, associated retention times and mass spectrometer values

Retention times

Example Analytical HPLC (min) LCMS (min) (M+H) 8<a 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

Preparation 5

9H-Fluoren-9-yl methyl ester 4-(3-[4-(2-naphthalen-1-ylacetylamino)imidazol-1-yl-3-cyclobutylcarbamoyl]piperidin-1-carboxyl ester

Stage 1

4-Piperidinecarboxylic acid (129 mg, 1 mmol) was treated with sodium hydroxide (80 mg, 2 mmol) in water-dioxane (1·· 1, 10 mL). After stirring at room temperature for 30 min, 9-fluorenylmethyl chloroformate (259 mg, 1 mmol) in dioxane (2 mL) was added dropwise and the reaction solution was stirred for four hours. The solvent was removed in vacuo and the reaction solution was diluted with water. The pH was adjusted to 1 with hydrochloric acid (1N) and the aqueous solution was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (50:1:0.5 chloroform-methanol-acetic acid system) to give 340 mg (97% yield) of N-(1-fluorenylmethyloxycarbonyl)-4-piperidinylcarboxylic acid.

1H NMR (400 MHz, CDCl ₃ ) d 7/5 (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.Q (brs, 2H), 2.52 (m, 1H),

1.90 (brs, 2H), 1.62 (brs, 2H); MS (AP/Cl): 352.0 (M+H) + .

Stage 2

A solution of N-(1-fluorenylmethyloxycarbonyl)-4-piperidinylcarboxylic acid (Preparation 5, Step 1, 77 mg) in methylene chloride was treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (84 mg) and DMAP (5 mg). After stirring for 30 minutes, N-(1-cis-3-aminocyclobutyl)-1H-imidazol-4-yl)-2-naphthalen-1-ylacetamide (Example 6) was added. The resulting mixture was stirred for four hours. Water was added, the mixture was neutralized, and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (20:1 chloroform-methanol system) to give 101 mg (77% yield) of 4-(3-[4-(2-naphthalen-1-ylacetylamino)imidazol-1-yl]cyclobutylcarbamoylpiperidine-1-carboxylic acid 9H-fluoren-9-yl methyl 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 _f 53 (d, J = 6.6 Hz, 2H), 7.44 (m _r 5H), 7.35 (m, 3H), 7.27 (m, 2H), 4A (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/Cl): 654.8 (M+H) + . ^?

Example 9 (cis-3-[4-(2-Naphthalen-1-ylacetylamino)imidazoΓ-1-yl]cyclobutyl)amide hydrochloride of piperidine-4-carboxylic acid

9H-Fluoren-9-ylmethyl ester of 4-(3-[4-(2-naphthalen-1-ylacetylamino)imidazol-1-yl]cyclobutylcarbamoylpiperidine-1-carboxylic acid (Preparation 5, 100 mg, 0.15 mmol) in dimethylformamide (5 mL) was treated with piperidine (0.5 mL) and stirred at room temperature for two hours. The solvent was removed in vacuo and the resulting residue was purified by silica gel chromatography (system 4=1:0.08 chloroform-methanol-ammonium hydroxide) to give the free base. The free base was dissolved in diethyl ether and treated with 1N hydrochloric acid in methanol to give the hydrochloride salt (64 mg, 91% yield), cis-3-[4-(2-naphthalen-1-ylacetylamino)imidazol-1-yl]cyclobutylamide hydrochloride of piperidine-4-carboxylic acid.

_ 1H NMR (400 MHz, CD3OD) δ 8.01 (d, J = 8 _of 0 Hz, 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 _Z 69 (m, 2H), 1.55 (m, 2H); MS (AP/Cl): 432 (M+H) + .

Preparation 6

Isoquinolin-5-ylacetic acid

Stage 1

5-Aminoisoquinoline (5.0 g, 34.7 mmol) was mixed with

48% aqueous hydrogen bromide (<65 ml) at -78 C. Sodium nitrite (3.1 g, 45 mmol) in water (6 ml) was added dropwise. After 15 minutes and

stirring at a temperature of -78 C, the mixture is allowed to warm to a temperature of O o

C. Copper powder (0.3 g) was added very slowly to prevent excessive foaming. After the addition was complete, the reaction vessel was fitted with a condenser and the mixture was maintained at 100 C for four hours. The mixture was poured onto ice (approximately 200 g) and basified (pH=10) with potassium hydroxide. The aqueous mixture was extracted with ethyl acetate, the combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (10:1 hexanes-ethyl acetate) to give 3.8 g (53% yield) of 5-bromoisoquinoline. 1H NMR (400 MHz, CD 3 OD) δ 9.25 (s, 1H), 8.57 (d, J = 6.2 Hz, 1H), 8.1 (m, 3H), 7.60 (m, 1H); MS (AP/Cl):

208.0, 210.0 (M+H) ⁺ .

Stage 2

5-Bromoisoquinoline (Preparation 6, step 1, 1.04 g, 5.0 mmol) was mixed with allyltributyltin (1.7 mL, 5.5 mmol) and dichloropalladiumbis(triphenylphosphine) (176 mg, 0.25 mmol) in toluene (20 mL) under nitrogen. The mixture was refluxed for 16 h. After cooling to room temperature, saturated aqueous potassium fluoride (20 mL) was added with stirring to form a precipitate. After stirring for 15 min, the mixture was filtered, the organic layer was separated from the aqueous layer, concentrated in vacuo, and the residue was purified by silica gel chromatography (6:1 hexane-ethyl acetate) to give 778 mg (92% yield) of 5-allylisoquinoline. 1H NMR (400 MHz,

CDCl ₃ ) δ 9.25 (s, 1H), 8.54 (d, J = 5.8 Hz, 1H), 7 _; 85 (m, 1H), 7.79 (d, J = 5.8 Hz, 1H), 7.56 (m,

2H), 6.1 (m, 1H), 5/5 (m, 1H), 5/5 (m, 1H),*3/1 (d, J = 6.2 Hz, 2H); MS (AP/Cl): 170.1 (M+H) + .

Level 3

5-Allylisoquinoline (Preparation 6, step 2, 169 mg, 1.0 mmol) in methylene chloride (2 mL), acetic acid (0.5 mL), and water (0.5 mL) was treated with dimethyl polyethylene glycol (Mn approximately 500, 95 μl, 100 mg, 0.2 mmol) in methylene chloride (100 mL) at 23°C. The mixture was cooled to 0°C and powdered potassium permanganate (521 mg, 3.3 μl) was added portionwise.

mmol) while maintaining the temperature below 30 C. After 18 hours of vigorous stirring, the solvent was removed in vacuo and methanolic hydrogen chloride (10 ml, 1N) was added and the mixture was refluxed for four hours. The methanol was removed in vacuo, the residue was diluted with water and the mixture was basified with sodium carbonate (pH=9). The mixture was extracted with ethyl acetate, the resulting organic layer was washed with brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel (2'·1 hexanes-ethyl acetate system) to give isoquinolin-5-ylacetic acid methyl ester.

1H NMR (400

MHz, CDCl ₃ ) 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 _r 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: After chromatography on silica gel, the product contains approximately 20% 5-isoquinolylcarboxaldehyde as an impurity.

Grade 4

Isoquinolin-5-ylacetic acid methyl ester (Preparation 6, step 3, 90 mg, 0.448 mmol) was treated with aqueous sodium hydroxide (4N, 3 mL) and the solution was kept at 50°C for four hours. The solution was cooled to 0°C and acetic acid (2 mL) was added dropwise to form a precipitate. The mixture was kept at 50°C for four hours.

at 0 C overnight (approximately 15 hours) and the precipitate was filtered off and washed with water. The solid was air dried to give 35 mg (47% yield) of isoquinolin-5-ylacetic acid. 1H NMR (400 MHz,

CD30D) 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) + .

Preparation 7

N-[cis-3-(4-nitroimidazol-1H-yl)cyclobutyl]acetamide

Stage 1

Trans-toluene-4-sulfonic acid 3-(4-Nitroimidazol-1-yl)cyclobutyl ester (Preparation 1, Step 2, 3.6 g, 10.7 mmol) was combined with sodium azide (7 g, 107 mmol) in a system of ethanol (100 ml), water (35 ml), and chloroform (20 ml). The mixture was refluxed for 24 hours. The ethanol and chloroform were removed in vacuo, and the resulting mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (1:1 to 3:1 ethyl acetate-hexanes) to give 2.2 g (99% yield) of 1-(3-cis-azidocyclobutyl)-4-nitro-1H-imidazole. 1 HNMR (400 MHz, CDCl 3 ) <5 7.85 (s,1H), 7.49 (s,1H), 4.42 (m,1H), 3.91 (m,1H), 3.07 (m,2H), 2.43 (m,1H); MS (AP/Cl): 208.5 (M+H) ⁺ .

Stage 2

1-(3-cis-Azidocyclobutyl)-4-nitro-1H-imidazole (Preparation 7 step 1, 2.2 g, 10.7 mmol). in tetrahydrofuran (100 ml) was treated with triphenylphosphine (3.36 g, 12.8 mmol) and water (10 ml). The solution was stirred for 18 hours at room temperature. The solvent was removed in vacuo and the residue was purified by chromatography on silica gel (system 20'· 1:0, 4 chloroform-methanol-ammonium hydroxide), to give 1.95 g (yield 100%) of 1-(3-cis-aminocyclobutyl)-4-nitro-1H-imidazole. 1 H NMR (400 MHz, CD 3 OD) 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/Cl): 183.1 (M+H) ⁺ .

Level 3

1-(3-cis-Aminocyclobutyl)-4-nitro-1H-imidazole (Preparation 7, step 2, 500 mg, 2.75 mmol) was coupled with acetic acid and purified as in Example 7 to give 594 mg (96% yield) of N-[cis-3-(4-nitroimidazol-1H-yl)cyclobutyl]acetamide.

1H NMR (400 MHz, CD30D) 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 (m,2H); MS (AP/Cl):

225.1 (M+H) ⁺ .

Preparation 8

N-[ois-3-(4-nitroimidazol-1-yl)cyclobutyl]benzamide

N-[cis-3-(4-nitroimidazol-1-yl)cyclobutyl]benzamide was prepared analogously to Preparation 7:

1H NMR (400 MHz, CD30D) δ 8.36 (s, 1H), 7.85 (m, 3H), 7.5 (m, 1H), 7.47 (m, 2H), 4.65 (m, 1H), 4.44 (m, 1H), 3.05 (m, 2H), 2.60 (m, 2H); MS (AP/Cl):

287.3 (M+H)+.

Preparation 9 [cis-3-(4-Nitroimidazol-1-yl)cyclobutyl]amide of pyridine-2-carboxylic acid [cis-3-(4-Nitroimidazol-1H-yl)cyclobutyl]amide of pyridine-2-carboxylic acid is prepared analogously to Preparation 7;

1H NMR (400 MHz, CDCl ₃ ): δ 8.55 (m,

1H), 8.35 (d, J = 7.0 Hz, 1H), 8.19 (d, J = 7.9 Hz, 1H), 8.01 (s, 1H), 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/Cl): 288.1 (M+H) + . '

9

Example 9a

Ν-[1-(cis-3-Acetylaminocyclobutyl)-1H-imidazol-4-yl3-2-naphthalen-2-yl acetamide

N-[cis-3-(4-nitroimidazol-1H-yl)cyclobutylacetamide (Preparation 7, 50 mg, 0.22 mmol) was hydrogenated and acylated with 2-naphthyl acetic acid as in Example 1 to give 35 mg (44% yield) of N-[1-(cis-3-acetylaminocyclobutyl)-1H-imidazol-4-yl]-2-naphthalen-2-ylacetamide.

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/Cl): 363.3 (M+H) + .

Example 9b

N-(ci,s-3-C4-(2-Isoquinol xn-5-ylacetylamino)imidazole-1-y13cyclobutyl)benzamid

This compound was prepared analogously to Example 9a using Preparation 8 and isoquinol-5-yl-acetic acid (Preparation 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° (M+H)+.

Example 9c (cis-3-[4-(2-Isoquinolin-5-ylacetylamino)imidazol-1-yl]cyclobutyl)pyridine-2-carboxylic acid amide

This compound was prepared analogously to Example 9a, using Preparation 9 and isoquinolin-5-yl-acetic acid (Preparation 9).

rights 6). 1 H NMR (400 MHz, CD 3 OD) S 9, 23 (s, 1 H),

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), 4/0 (m, 1H), 4.20 (s, 2H), 2.85 (m, 2H), 2.6 (m, 2H); MS (AP/Cl): 427.2 (M+H) + .

Example 10

N-(cis-3-[4-(3-Naphthalen-1-ylureido)imidazol-1-yl1cyclobutyl)acetam i d

N-[cis-3-(4-Nitroimidazol-ΙΗ-yl)cyclobutyl]acetamide (Preparation 7, 50 mg, 0.22 mmol) was reacted with phenyl chloroformate as described in Example 4. This gave an unseparated mixture of mono- and bis-phenylcarbamate products after silica gel chromatography (20:1:0.2 chloroform-methanol-ammonium hydroxide system), which was dissolved in 1:1 dimethylformamide-dioxane system (500 μΐ). 1-Naphthylamine (31 mg, 0.22 mmol) was added and the mixture was stirred for 1 h.

is kept at 70 C for 16 hours. The product is purified by double chromatography on silica gel (system 20:1=0.2 chloroform-methanol-ammonium hydroxide), which gives 4.4 mg (yield 5%) of N-cis-3-C4-(3-naphthalen-1-ylureido)imidazol-1-yl]cyclobutyl)acetamide. 1H NMR (400 MHz, CD3OD) 6

(s, 3H); MS (AP/Cl): 364.0 (M+H) + .

Industrial applicability

An imidazole derivative suitable for the manufacture of pharmaceutical compositions for the treatment of diseases or conditions involving abnormal cell growth or for the treatment of neurodegenerative diseases or conditions in mammals.

PATENT ίΐΟΟΛ,-ΑΖΛ

Claims (13)

Claims An imidazole derivative of the formula I wherein R ¹ represents N - R - R ⁴ (I) straight or branched chain alkyl of 1 to 8 carbon atoms, straight or branched chain alkenyl of 2 to 8 carbon atoms, straight chain or branched alkynyl of 2 to 8 carbon atoms branched chain, cycloalkyl of 3 to 8 carbon atoms, cycloalkenyl of 4 to 8 carbon atoms, three to eight membered heterocycloalkyl, bicycloalkyl of 5 to 11 carbon atoms, bicycloalkenyl of 7 to 11 carbon atoms, five to eleven membered 6-membered and 14-membered cycloalkyls carbon atoms or five to fourteen membered heteroaryl, wherein R ^{1 is} optionally substituted with one to six R ⁵ substituents independently selected from fluoro, chloro, bromo and iodo, nitro, cyano, trifluoromethyl, -NR ⁷ R ⁵ , -NR ⁷ C (= O) R ^s , -NR ⁷ C (= O) OR ^s , -NR ⁷ C (= O) NR ⁸ R ⁹ , -NR ⁷ S (= O) 2 R ^s , -NR ⁷ S (= 0) 2 NR ^a R ^9, -OR ^7, -OC (= O) R ^7, -C (= 0) 0R ^7, -C (= 0) ^R7, -C (= O) NR ⁷ R ^S, -0C (= 0) SR ^7, -SR ^7, -S (= 0) R ^7, -S (= 0) ₂ R ^7, OS (= O) ₂ R ⁷ , -N 3 and R ⁷ , -0C (= O) OR ⁷ , -0C (= O) NR ⁷ R ^S , -S (= O) ₂ NR ⁷ R ^S , R ² R ³ is hydrogen, fluorine, methyl, cyano or -C (= 0) 0R ⁷ -, -C (= O) NR ⁹ -C (= 0) 0-, - C (= 0) ( CR ¹¹ R ¹¹ ) _n - or - (CRWAn93 -. R ^{4 is} a straight or branched chain alkyl group having from 1 to 8 carbon atoms, a straight chained or branched alkenyl group having from 2 to 8 carbon atoms, a straight chain or branched alkynyl group having from 2 to 8 carbon atoms, a cycloalkyl group of from 3 to 8 carbon atoms, cycloalkenyl of 4 to 8 carbon atoms, three to eight-membered heterocycloalkyl, bicycloalkyl of 5 to 11 carbon atoms, bicycloalkenyl of 7 to 11 carbon atoms, five to eleven-membered heterobicycloalkyl, aryl of 6 to 14 carbon atoms or 5 to 14 carbon atoms or 5 to 14 carbon atoms; heteroaryl, wherein R ^{4 is} optionally substituted with one to six R ⁶ substituents independently selected from fluoro, chloro, bromo and iodo, nitro, cyano, trifluoromethyl, -NR ⁷ R ^S , -NR ⁷ C ( = 0) ^R, -NR ⁷ C (= 0) 0R ^8, - NR ⁷ C (= 0) NR ⁸ R ^9, -NR ⁷ S (= 0) 2 R ^8, -NR ⁷ S (= O) 2 NR ^a R ^9, -OR ^7, -0C (= 0) R ^7, -C (= O) OR ⁷ , -C (= O) R ⁷ , -C (= O) NR ⁷ R ⁸ , OC (= O) SR ⁷ , -SR ⁷ , -S (= O) R ⁷ , -S (= O) ₂ R ⁷ , -OC (= 0) ^OR7, -0C (= O) NR ^{7 R,} -S (= O) ₂ NR ⁷ R ⁸ and R ⁷ , R ( ⁷⁾ , R ( ⁸⁾ and R ( ⁹⁾ independently of one another are hydrogen, straight chained or branched chain alkyl of 1 to 8 carbon atoms, straight chained or branched alkenyl of 2 to 8 carbon atoms, alkynyl of 2 to 8 atoms straight or branched chain carbon, cycloalkyl of 3 to 8 carbon atoms, cycloalkenyl of 4 to 8 carbon atoms, three to eight membered heterocycloalkyl, bicycloalkyl of 5 to 11 carbon atoms, bicycloalkenyl of 7 to 11 carbon atoms, five to eleven membered heterocycles cyclic, aryl of 6 to 14 carbon atoms or five to 14 membered heteroaryl, wherein R ⁷ , R ⁸ and R ^{9 are each} optionally substituted with one to six substituents independently selected from fluoro, chloro, bromo and iodo , nitro, cyano, trifluoromethyl, -NR ¹¹ R ^1O, • · '· · -NR ¹⁰ C (= O) R ¹¹ , -NR ¹⁰ C (= O) OR ¹¹ , -NR ¹⁰ C (= O) NR ¹¹ R ¹² , ^1O -NR S (= 0) 2 R ^11, -NR ^1O S (= 0) ₂ NR * ¹ R ^12, -OR ^10, -OC (= O) R ^10, -OC (= O) OR ^10, -0C (= 0) NR R ^11, -0C (= O) SR ^10, -SR ^10, -S (= 0) ^R10, -S (= 0) 2R ^10, -S (= 0) 2 NR ^1o R ^11, -C (= 0) ^R10, -C (= O) OR ^10, -C (= 0) NR ¹¹ R ^1O and R ^10, or when R ⁷ and ^R represents a group NR @ ⁷ R ^S, this group may be optionally linked to the nitrogen atom of NR ⁷ R ^S to which it is attached to form a three to seven membered heterocycloalkyl moiety optionally containing one or two additional heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, R ( ¹⁰⁾ , R ( ¹¹⁾ and R ( ¹²⁾ independently of one another are hydrogen, straight chained or branched alkyl having 1 to 8 carbon atoms, straight chained or branched alkenyl having 2 to 8 carbon atoms, alkynyl having 2 to 8 carbon atoms straight or branched chain, cycloalkyl of 3 to 8 carbon atoms, cycloalkenyl of 4 to 8 carbon atoms, three to eight membered heterocycloalkyl, bicycloalkenyl of 5 to 11 carbon atoms, bicycloalkenyl of 7 to 11 carbon atoms, five to eleven membered heterobicycloalkyl, C 6 -C 14 or C 5 -C 14 heteroaryl, wherein R ¹⁰ , R ¹¹ , and R ^{12 are} optionally independently substituted with one to six of fluoro, chloro, bromo and iodo, nitro, cyano, trifluoromethyl, -NR ¹³ R ¹⁴ , -NR ¹³ C (= O) R ¹⁴ , -NR ¹³ C (= O) OR ¹⁴ , -NR ¹³ C (= O) NR ¹⁴ R ¹⁵ , -NR ¹³ S (= O) 2 R ¹⁴ , -NR ¹³ S (= O) ₂ NR ¹⁴ R ¹⁵ , -OR ¹³ , -OC (= O) R ¹³ , -0C (= 0) OR ¹³ , -OC (= O) NR ¹³ R ¹⁴ , -0C (= 0) SR ¹³ , -SR ¹³ , -S (= O) R ¹³ , -S (= O) 2 R ¹³ , -S (= O) 2 NR ¹³ R ¹⁴ , -C (= O) R ¹³ , -C (= O) OR ¹³ , -C (= O) NR ¹³ R ¹⁴ and R ¹³ , R ( ¹³⁾ , R ( ¹⁴⁾ and R ( ¹⁵⁾ independently of one another are hydrogen, straight or branched chain alkyl of 1 to 8 carbon atoms, straight or branched chain alkenyl of 2 to 8 carbon atoms, 2-8 alkynyl straight or branched chain carbon atoms, cycloalkyl of 3 to 8 carbon atoms, cycloalkenyl of 4 to 8 carbon atoms, three to eight membered heterocycloalkyl, bicycloalkenyl of 5 to 11 carbon atoms, bicycloalkenyl of 7 to 11 carbon atoms, five to eleven membered heterocycloalkyl, aryl of 6 to 14 carbon atoms or five to 14 membered heteroaryl, wherein R ¹³ , R ¹⁴ and R ^{15 are} optionally substituted independently of one another with one to six substituents selected from fluoro, chloro, bromo and iodo, nitro, cyano, trifluoromethyl, -NR ¹⁶ R ^17, -NR ¹⁶ C (= 0) R ^17, -NR ¹⁶ C (= 0) 0R ^{1 '7>,} -NR ¹⁶ C (= 0) NR ¹⁷ R ^1S, -NR ¹⁶ S (= 0) 2 R ^17, -NR ¹⁶ S (= O) ₂ NR ¹⁷ R ^1s, -OR ^16, -OC (= O) R ^16, -OC (= O) ^OR16, -0C (= 0) NR ¹⁶ R ^17, -OC (= O) SR ^16, -SR ^16, -S (= O) R ¹⁶ , -S (= O) 2 R ¹⁶ , -s (= O) 2 NR ¹⁶ R ¹⁷ , -C (= O) R ¹⁶ , -C (= O) OR ¹⁶ , -C (= O) NR ¹⁶ R ¹⁷ and R ¹⁶ , R ^16, R ^17, and R ^{1 S} are independently hydrogen, alkyl having 1-8 carbon atoms, straight or branched chain alkenyl having 2 to 8 carbon atoms, straight or branched chain alkynyl having 2 to 8 carbon atoms straight or branched chain, cycloalkyl of 3 to 8 carbon atoms, cycloalkenyl of 4 to 8 carbon atoms, three to eight-membered heterocycloalkyl, bicycloalkenyl of 5 to 11 carbon atoms, bicycloalkenyl of 7 to 11 carbon atoms, five to eleven membered heterobicycloalkyl, aryl having 6 to 14 carbon atoms or five to fourteen-membered heteroaryl, η, 1, 2 or 3, wherein R ^Q1 and R ¹¹ -C (= 0) (CR ¹ R ^1O ^ n and R ¹ ° -CCR ¹¹ ) _n for each repetition of n is defined independently of each other, as mentioned above, and pharmaceutically acceptable salts thereof. A compound according to claim 1, wherein R ³ is -C (= Q) NH- or -C (= O) (CR ¹⁰ R ¹¹ ) n-. Third derivative according to claim 1 of formula I wherein R ¹ represents an optionally substituted cycloalkyl having 3 to 8 carbon atoms or an optionally substituted bicycloalkyl group having 5 to 11 carbon atoms. A compound according to claim 1, wherein R ¹ is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl or bicyclo [3.1.0] hexyl, each of which is optionally substituted 5th derivative according to claim 1 of formula I wherein R ¹ represents an optionally substituted alkyl group with straight or branched alkyl chain having 1 to 8 carbon atoms or optionally substituted alkenyl group, straight or branched chain having 2-8 carbon atoms. 6. An imidazole derivative according to claim 1, wherein R &lt; ^{4 &gt}; is a (C6-C14) -aryl or 5- to 14-membered heteroaryl group, each of which is optionally substituted. 7. An imidazole derivative according to claim 6, wherein R &lt; ^{4 &gt}; is phenyl, pyridyl, naphthyl, quinolyl or isoquinolyl, each optionally substituted. 8th derivative according to claim 1 to 7 of formula I wherein R ² is hydrogen. 9. The compound according to claim 1 of formula (I) N- (1-cyclobutyl-1H-imidazol-4-yl) -2-quinolin-6-ylacetamide, N- (1-cyclopentyl-1H-imidasol-4-yl) -2- (4-methoxyphenyl) acetamide, N- [1- (cis-3-phenylcyclobutyl-1H-imidasol-4-yl) -2-quinolin-6 -ylacetamide, (1-cyclobutyl-1H-imidazol-4-yl) carbamic acid phenyl ester, - (1-cyclobutyl-1H-imidasol-4-yl) -3-isoquinolin-5-ylurea, N- [1- (cis-3-aminocyclobutyl) -1H-imidasol-4-yl-3-naphthalene-1- 6-Methyl-pyridine-2-carboxylic acid cis-3- [4- (2-naphthalen-1-ylacetylamino) -isyl-1-yl] -cyclobutyl-lamide; 1H-Imidasol-4-carboxylic acid, cis-3- [4- (2-naphthalen-1-yl-acetylamino) -imidazol-1-yl-3-cyclobutyl] -amide 6-hydroxypyrimidoyl-1-yl] -cyclobutyl-amide 3-methylpyridine-2-carboxylic acid, cis-3- [4- (2-naphthalen-1-ylacetylamino) imidazol-1-yl] cyclobutyl lamide, cis-3- [4- (2-naphthalene-) 2-Pyridin-3-ylthiazole-4-carboxylic acid 1-ylacetylamino) imidasol-1-yl-3-cyclobutyl lamide 6-Isis-3- [4- (2-naphthalen-1-ylacetylamino) -imidazol-1-yl] -cyclobutylcarbamoyl-nicotinic acid methyl ester 3- [4- (2-Naphthalen-1-ylacetylamino) imidasol-1-yl] -cyclobutyl-pyrazine-2-carboxylic acid lamide, N- (cis-3- [4- (2-naphthalen-1-ylacetylamino) imidazol-1-yl) 3-cyclopropylthylbenzamido] -3- [4- (2-naphthalen-1-ylacetylamino) imidazol-1-yl] cyclobutyl lamide 5-Methyl-pyrazine-2-carboxylic acid, N-cis-3- [4- (2-naphthalen-1-ylacetylamino) imidazol-1-yl-3-cyclobutyl) isobutyraid, cis-3- [4- (2-naphthalen-1-ylacetylamino)] 6-Chloro-pyridine-2-carboxylic acid imidazol-1-yl-3-cyclobutyl-cis-3- [4- (2-naphthalen-1-ylacetylamino) -imidazol-1-yl-3-cyclobutyl-quinoline-2-carboxylic acid-imidazol-1-yl [4] - 1H-pyrrole-2-carboxylic acid (2-naphthalen-1-ylacetylamino) imidazol-1-yl (cyclo98 butyl) amide, N-icis-3- [4- (2-naphthalen-1-ylacetylamino) imidazol-1-yl-3-cyclobutyl) -2-m-tolylacetamide; cis-3- [4- (2-naphthalen-1-ylacetylamino) imidazole-1] -yl] cyclobutyl) pyridine-2-carboxylic acid amide, 2- (3-Hydroxyphenyl) -N-cis-3- [4- (2-naphthalen-1-ylacetylamino) imidazol-1-yl] cyclobutyl acetamide; cis-3- [4- (2-naphthalen-1-ylacetylamino)] Piperidine-4-carboxylic acid imidazol-1-ylcyclobutyl) amine hydrochloride, N- [1- (cis-3-acetylaminocyclobutyl) -1H-imidazol-4-yl] -2-naphthalen-2-ylacetamide, Pyridine-3- [4- (2-isoquinolin-5-ylacetylamino) imidazol-1-yl] cyclobutyllbenzamide, and cis-3- [4- (2-isoquinolin-5-ylacetylamino) imidazol-1-yl] cyclobutyl amide; 2-carboxylic and pharmaceutically acceptable salts of said compounds. A pharmaceutical composition for the treatment of diseases or conditions comprising abnormal cell growth or for the treatment of neurodegenerative diseases or conditions in mammals, comprising a compound of claim 1 in an effective amount for treating such disease or condition and a pharmaceutically acceptable carrier. 11. A pharmaceutical composition for the treatment of diseases or conditions of mammals which may be affected or alleviated by a change in dopamine-mediated neurotransmission, comprising a cdk5 inhibitor in an effective amount for treating such a disease or condition or an effective amount to inhibit cdk5 activity and a pharmaceutically acceptable carrier. A pharmaceutical composition for the treatment of diseases or conditions of mammals selected from the group consisting of male fertility and sperm mobility, diabetes mellitus, poor glucose tolerance, meta99 holic syndrome or syndrome X, polycystic ovarian syndrome, adipogenesis and obesity, myogenesis and poor health, for example age-related decreased physical performance, acute sarcopenia such as muscle atrophy and / or cachexia associated with burns, bed rest, limb immobility or major chest, abdominal and / or orthopedic surgery, sepsis, hair loss, hair loss and baldness, immunodeficiency. comprising a compound of claim 1 in an effective amount for treating such a disease or condition and a pharmaceutically acceptable carrier. 13. A pharmaceutical composition comprising a cdk5 inhibitor and another active ingredient selected from the group consisting of SSRI, NK-1 receptor antagonist, 5HTid antagonist, ziprasidone, olazapine, risperidone, L-745870, sonepiprazole, RP 62203, NGD941, balaperidone , flesinoxan, gepirone, an acetylcholinesterase inhibitor, TPA, NIF, a potassium channel modulator such as BMS-204352, and an NMDA receptor antagonist in an effective amount of both a cdk5 inhibitor and other active agents, and a pharmaceutically acceptable carrier.