SK1042003A3 - Imidazole derivatives - Google Patents

Abstract

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

Description

An imidazole derivative and a pharmaceutical composition thereof

Technical field

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 cyclin-dependent protein kinase 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 (glygocene synthase kinase-3).

BACKGROUND OF THE INVENTION

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

The cdk2 serine / threonine kinase is essential for normal cell cycling and plays a critical role in disorders caused by abnormal cell cycling, a general characteristic of many oncological disorders. Therefore, cdk2 inhibitors are useful in the treatment of various types of cancer and other diseases or conditions associated with abnormal cell growth (Meijer et al., Chemical Inhibitors of Cyclic-Dependent Kinases, Pharmacology & Therapeutics 82 (2-3), pp. 279-284, 1999; Sausville et al., Cyclic-Dependent Kinases: Initial Approaches to Exploit and 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, α and β, in vertebrates and is known to have a monomeric structure of 49kD and 47kD. Both isoforms phosphorylate muscle glycogen synthase (Cross et al., Biochemical Journal 303, 21-26, 1994). The amino acid identity between the homologues of GSK-3 species has been shown to be in excess of 98% within the catalytic domain (Plyte et al., Biochim. Biophys.

Acta 1114, p. 147-162, 1992). Given the remarkably high degree of conservation across the phylogenetic spectrum, the essential role of GSK-3 in cellular processes is highlighted.

GSK-3 is implicated in a number of different disease states and conditions. For example, Chen et al. (Diabetes 43, 1234-1241, 1994) believe that an increase in GSK-3 activity may be significant in type 2 diabetes. Increased expression of GSK-3 in diabetic muscles is also considered to contribute to the deleterious activity of glycogen synthase and insulin resistance in diabetes. skeletal muscle in type 2 diabetes (Nikoulina et al., Diabetes 49, 263-271, 2000). Also, increased type 1 proteinophosphatase activity, measured in immovable semen, was attributed to higher GSK-3 activity and was considered responsible for sperm motility in control (Vijayaraghavan et al., Biology of Reproduction 54, pp. 709-717, 1996). Vijayaraghavan et al. suggests that such results constitute a biochemical base 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 (WO 97/41854). In addition to other conditions, GSK-3 is also involved in hair loss, schizophrenia, and neurodegeneration, including chronic neurodegenerative disorder (such as Alzheimer's disease) and neurotrauma such as stroke, traumatic brain and spinal cord injury.

SUMMARY OF THE INVENTION

The present invention provides an imidazole derivative of the formula I

where it means

R ^{@ 1 is} a straight or branched chain alkyl group having from 1 to 8 carbon atoms, a straight or branched chain alkenyl group having from 2 to 8 carbon atoms, a straight or branched chain alkynyl group having from 2 to 8 carbon atoms, a cycloalkyl group of 3 to 8 C 4 -C 8 cycloalkenyl, C 3 -C 8 heterocycloalkyl, C 5 -C 11 bicycloalkyl, C 7 -C 11 bicycloalkenyl, 5- to 11-membered heterobicycloalkyl, C 6 -C 14 aryl or aryl of 6 to 14 carbon atoms 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 ⁸ , -nr ⁷ c (= o ) r ^8, -NR ⁷ C (= o) OR ^8, -NR ⁷ C (= o) nR ⁸ r ^9, -NR ⁷ s (= o) 2 r ^8, -NR ⁷ s (= o) 2 nR ⁸ r ⁹ , -or ⁷ , -oc (= o) r ⁷

-OC (= O) OR 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) ₂ R ⁷ ,

-S (= O) ₂ NR ⁷ R ⁸ , -OS (= O) 2 R ⁷ , -N 3 are ar ⁷ ,

R ² is H, F, methyl, CN, or -C (= O) OR ⁷ -,

R ³ is -C (= O) NR ⁹ C (= 0) 0-, -C (= 0) (CR ¹⁰ R ^{and L)} n- or - (CR ^^ R ¹¹⁾ n R ⁴ is alkyl straight or branched chain C 1 -C 8 alkenyl, straight or branched C 2 -C 8 alkenyl, straight or branched C 2 -C 8 alkynyl, C 3 -C 8 cycloalkyl, cycloalkenyl (C až-C 8), (C až-C troj), (C bic-C troj), (C až-C troj), (C,-C bic), (C až-C bic) bicycloalkyl, (C až-C bic) bicycloalkenyl, (C až-C heter) bicycloalkenyl, (C až-C 14) aryl; ⁴ optionally substituted with one to six substituents R ⁶ independently of one another selected from the group 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 C (= O) NR ⁸ R ⁹ , -nr ⁷ s (= o) 2r ⁸ , -nr ⁷ s (= o) 2 nr ⁸ r ⁹ , -or ⁷ , -OC (= O) R ⁷ ,

-OC (= O) OR 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) 2 R ⁷ , -S (= O) 2N R ⁷ R ⁸ and R ⁷ ,

R ( ⁷⁾ , R ( ⁸⁾ and R ( ⁹⁾ 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, bicycloalkyl of 5 to 11 carbon atoms, bicycloalkenyl of 7 to 11 carbon atoms, five to eleven-membered and eleven-membered, C 6 -C 14 or C 5 -C 14 heteroaryl, wherein R ⁷ , R ⁸ and R ^{9 are} optionally substituted independently of one another by one to six substituents on the series. including fluorine, chlorine, bromine and iodine, nitro, cyano, trifluoromethyl, -NR ¹⁰ R ¹¹ , -NR ¹⁰ C (= O) R ^{1: L} , -NR ¹⁰ C (= O) OR ¹¹ , -NR ¹⁰ C (= O) NR ^{i: L} R ¹² , -nr ¹⁰ s (= o) 2r ¹¹ , -nr ¹⁰ s (= o) 2nr ^{i: 1} r ¹² , -or ¹⁰ , -oc (= o) r ^10, -OC (= O) OR ^10, -OC (= O) NR ¹⁰ R ^{1: L,} -OC (= O) SR ^10, -SR ^10,

-S (= O) R ^10, -S (= O) 2 R ^10, -S (= O) 2 NR ¹⁰ R ^{i: l,} -C (= O) ^R10, -C (= O) OR ^10, - C (= O) NR ¹⁰ R ^{1: L} and R ¹⁰ , or when R ⁷ and R ⁸ is NR ⁷ R ⁸ , this group may optionally be linked to the nitrogen atom of NR ⁷ R ⁸ to which it is bound to form a 3- to 7-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 or branched chain alkyl of 1 to 8 carbon atoms, straight or branched chain alkenyl of 2 to 8 carbon atoms, 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 and eleven-membered, (C 6 -C 14) or (C 5 -C 14) heteroaryl;

ΊΊΠΊΊ 1 9>

R, R, and R are each optionally substituted with one to six substituents selected from fluorine, chlorine, bromine and iodine, 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 n r ¹⁴ r ¹⁵ , -or ¹³ , -oc (= o) r ¹³ , -OC (= 0) OR ¹³ ,. -OC (= 0) NR ¹³ R ^14, -OC (= O) 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 ^{( 14} ) 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, 2-8 alkynyl groups 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 elevenalkylene, five to elevenalkylene, 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 with one to six substituents from the group consisting of fluorine, chlorine, bromine and iodine, nitro, cyano, trifluoromethyl, -NR ¹⁶ R ¹⁷ , -NR ¹⁶ C (= O) R ¹⁷ , -NR ¹⁶ C (= O) OR ¹⁷ , -NR ¹⁶ C (= O) NR ¹⁷ R ¹⁸ , -NR ¹⁶ S (= O) 2R ¹⁷ , -nr ¹⁶ s (= o) 2nr ¹⁷ r ¹⁸ , -or ¹⁶ , -oc (= o) r ¹⁶ ,

-OC (= 0) OR ^16, -OC (= O) 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 (= 0) 0R ^16, -C ( = O) NR ¹⁶ R ¹⁷ and R ^16,

R ( ¹⁶⁾ , R ( ¹⁷⁾ and R ( ¹⁸⁾ 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, bicycloalkyl of 7 to 11 carbon atoms, bicycloalkenyl of 7 to 11 carbon atoms, five to eleven-membered and eleven-membered, having 6 to 14 carbon atoms or five to fourteen membered heteroaryl, n 0, 1, 2 or 3, wherein R ¹⁰ and R ¹¹ in the group -C (= O) (CR ¹⁰ R ¹¹ ) _n - are defined for each repetition of n independently of each other as above, and pharmaceutically acceptable salts thereof.

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

The term alkyl, in particular, unless otherwise indicated, refers to straight or branched chain saturated monovalent hydrocarbon groups. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, and tert-butyl.

The term alkenyl, unless otherwise stated, means alkyl groups having at least one double bond, alkyl being as defined above. Examples of alkenyl groups include, but are not limited to, ethenyl and propenyl groups.

The term alkynyl means, unless otherwise indicated, alkyl groups having at least one triple bond, alkyl being as defined above. Examples of alkynyl groups include, but are not limited to, ethynyl and 2-propynyl.

The term cycloalkyl, unless otherwise indicated, means non-aromatic saturated cyclic alkyl groups, wherein alkyl is as defined above. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. The term bicycloalkyl, unless otherwise indicated, means non-aromatic saturated carbocyclic groups with two rings, wherein such rings have one or two common carbon atoms. According to the invention, unless otherwise indicated, bicycloalkyl groups include spiro groups and fused cyclic groups.

Examples of bicycloalkyl groups include, but are not limited to, the bicyclo [3.1.0] hexyl, norbornyl, spiro [4.5] decyl, spiro [4.4] nonyl, spiro [4.3] octyl and spiro [4.2] heptyl groups. The term cycloalkenyl and bicycloalkenyl means, 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 linking the ring carbon atoms (endocyclic double bond) and / or one or more double bonds between two carbon atoms linking a ring carbon atom and an adjacent non-ring carbon atom (exocyclic double bond). Exemplary cycloalkenyl groups include, but are not limited to, cyclopentenyl and cyclobutenyl, and by way of example, not as any limitation of bicycloalkenyl groups, norbornenyl. Cycloalkyl, cycloalkenyl, bicycloalkyl, and bicycloalkenyl groups also include groups with one or more substituents. Examples of oxo groups include oxocyclopentyl, oxocyclobutyl oxocyclopentenyl and norgaphre.

The term aryl means, unless otherwise indicated, an organic group derived from aromatic hydrocarbons by removal of one hydrogen atom, such as phenyl, naphthyl, indenyl and fluorenyl.

For example, the term heterocyclic and heterocycloalkyl refers to non-aromatic cyclic groups containing one or more heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen. Heterobicycloalkyl refers to non-aromatic bicyclic groups whose rings have one or two common atoms and at least one ring contains a heteroatom (oxygen, sulfur or nitrogen). According to the invention, unless otherwise noted, heterobicycloalkyl groups include spiro groups and fused ring groups. In 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). The heterocyclic groups of the invention also include cyclic 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, thiomorpholinopyranyl, morpholino, morpholino, morpholino , indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl,

3-azabicyclo [3.1.0] hexanyl, 3-azabicyclo [4.1.0] heptanyl, quinolizinyl, quinuclidinyl, 1,4-dioxaspiro [4.5] decyl,

1,4-dioxaspiro [4.4] nonyl, 1,4-dioxaspiro [4.3] octyl and

1,4-dioxaspiro [4.2] heptyl group.

The term heteroaryl means aromatic cyclic groups containing one or more heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, preferably one to four heteroatoms. A multicyclic group containing one or more heteroatoms, wherein at least one such ring 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. Exemplary heteroaryl groups include pyridinyl, pyridazinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, quinolyl, isoquinolyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, indole, thiazolyl, indole, thiazolyl, indazol, , indolizinyl, phthalazinyl, triazinyl, isoindolyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzotriazolyl, benzothiazolyl, benzoixazolylová, quinazolinyl, quinoxalinyl, naphthyridinyl, dihydroquinolyl, tetrahydroquinolyl, dihydroisoquinolyl, tetradroizochinolylová, benzofuryl, furopyridinylová, pyrolopyrimidinylová and azaindolyl.

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

In one embodiment, the invention relates to compounds of formula I wherein R ^{3 is} -C (= O) NR ⁹ - or -C (= O) (CR ¹⁰ R ¹¹ ) n -. In another embodiment of R ¹⁰ and R ^{11, the} group -C (= O) (CR ¹⁰ R ¹¹ ) n - is each hydrogen n. In another embodiment, R ⁹ in the -C (= O) NR ^{9 group} is hydrogen. In another embodiment, R ^{3 is} -C (= O) NR ⁹ or -C (= O) (CR ¹⁰ R ¹¹ ) _R - and R ² is hydrogen.

In another embodiment, the invention relates to compounds of formula I wherein R is optionally substituted C 3 -C 8 cycloalkyl or optionally substituted C 5 -C 11 cycloalkyl. According to a preferred embodiment, R ^{1 is} cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or norbornyl, each optionally substituted as above (i.e. optionally with one to six S substituents R 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 ⁸ , -nr ⁷ c (= o) nr ⁸ r ^9, -NR ⁷ s (= o) 2 r ^8, -NR ⁷ s (= o) 2 NR ⁸ r ^9, -OR ^7, -OC (= o) r ^7, -OC (= o) OR ^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) 2 R ⁷ , -S (= O) 2 NR ⁷ R ⁸ and R ⁷ ). More preferably, R ^{x is} C 3 -C 8 cycloalkyl or optionally substituted C 5 -C 11 bicycloalkyl, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or norbornyl, each of which is optionally substituted with one to three substituents independently selected from the group of fluorine, chlorine, bromine and iodine, nitro, cyano, trifluoromethyl, -NR ⁷ R ⁸ , -NR ⁷ C (= O) R ⁸ , -OR ⁷ , -C (= O) OR ⁷ , -C (= O) R ⁷ and R ⁷ . More preferably, R ^{1 is} C 3 -C 8 cycloalkyl or optionally substituted C 5 -C 11 bicycloalkyl, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or norbornyl, wherein R ^{x is} substituted with -NR ⁷ C ( == O) R ⁸ , a 6 to 14 carbon atom, a 3- to 8-membered heterocycloalkyl or a 5- to 14-membered heteroaryl, and an aryl, heterocycloalkyl and heteroaryl group optionally substituted with one to six substituents independently selected from fluoro; , chlorine, bromine and iodine, nitro, cyano, trifluoromethyl, -NR ¹⁰ R ¹¹ , -NR ¹⁰ C (= O) R ¹³ , -NR ¹⁰ C (= O) OR ¹¹ ,

-NR ¹⁰ C (= O) NR ¹¹ R ¹² , -NR ¹⁰ S (= O) 2 R ^{1: L} , -NR ¹⁰ S (= O) 2N R ^{1, L} R ¹² , -OR ¹⁰ ,

-OC (= O) R ^10, -OC (= O) OR ^10, -OC (= O) NR ¹⁰ R ^11, -OC (= O) SR ^10, -SR ^10,

S (O) R ^10, -S (= O) 2 R ^10, -S (= O) 2 NR ¹⁰ R ^11, -C (= O) R ^10, -C (= O) OR ^10, -C ( = O) NR ¹⁰ R ^{1: 1} · and R ¹⁰ . In another embodiment of the invention, R ^{1 is} a bicyclo [3.1.0] hexyl group optionally substituted with the above substituents (i.e., optionally substituted 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 ⁸ , -nr ⁷ c (= o) nr ^{8 9} , -nr ⁷ s (= o) 2r ⁸ , -nr ⁷ s (= o) 2r ^{8, 9} , -OR ⁷ ,

-OC (= O) R ⁷ , -OC (= O) OR 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) 2 R ⁷ , -S (= O) 2 NR ⁷ R ^8, and R ⁷ ).

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

In yet another embodiment, the invention relates to compounds of formula I wherein R ² is hydrogen. In 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 having 6 to 14 carbon atoms or a 5- to 14-membered heteroaryl group, each of which is optionally substituted. According to a preferred embodiment, the invention relates to compounds of formula I wherein R ^{4 is an} optionally substituted phenyl or an optionally substituted pyridyl group. In another preferred embodiment, the invention relates to compounds of formula I wherein R ^{4 is} naphthyl, quinolyl or isoquinolyl, each 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.

In another preferred embodiment, the invention relates to compounds of formula I wherein R ² is hydrogen and R ⁴ is as defined above.

Examples of preferred compounds of formula I include the following:

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

N- (1-cyclopentyl-1H-imidazol-4-yl) -2- (4-methoxyphenyl) acetamide, N- [1- (cis-3-phenylcyclobutyl-1H-imidazol-4-yl) -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- [ 1- (cis-3-aminocyclobutyl) -1H-imidazol-4-yl] -2-naphthalen-1-ylacetamide, {cis-3- [4- (2-naphthalen-1-ylacetylamino) imidazol-1-yl] 6-Methyl-pyridine-2-carboxylic acid cyclobutyl} amide {1H-imidazole-4-carboxylic acid {cis-3- [4- (2-naphthalen-1-ylacetylamino) -imidazol-1-yl] -cyclobutyl} -amide {cis 6-hydroxypyridine-2-carboxylic acid -3- [4- (2-naphthalen-1-ylacetylamino) imidazol-1-yl] cyclobutyl] amide, {cis-3- [4- (2-naphthalen-1-ylacetylamino) imidazole -1-yl] cyclobutyl} 3-methylpyridine-2-carboxylic acid amide, 2-pyridin-3-yltriazole {cis-3- [4- (2-naphthalen-1-ylacetylamino) imidazol-1-yl] cyclobutyl] amide 4-carboxylic acid 6- {cis-3- [4- (2-naphthalen-1-ylacetylamino) imidazol-yl] cyclobutylcarbamate methyl ester oyl} nicotinic acid, Pyrazin-2-carboxylic acid {cis -3- [4- (2-naphthalen-1-ylacetylamino) -imidazol-1-yl] -cyclobutyl) -amide,

N- (cis-3- [4- (2-naphthalen-1-ylacetylamino) imidazol-1-yl] cyclobutyl} benzamide, {cis-3- [4- (2-naphthalen-1-ylacetylamino) imidazole-1-] yl] 5-methylpyrazine-2-carboxylic acid {cis-3- [4- (2-naphthalen-1-ylacetylamino) imidazol-1-yl] cyclobutyl} amide, 5-methylpyrazine-2-carboxylic acid cyclobutyl jamide, {cis- Acid 3- [4- (2-naphthalen-1-ylacetylamino) imidazol-1-yl] cyclobutyl} isobutyramide, {cis-3- [4- (2-naphthalen-1-ylacetylamino) imidazol-1-yl] cyclobutyl} amide 6 quinoline-2-carboxylic acid {cis-3- [4- (2-naphthalen-1-ylacetylamino) imidazol-1-yl] cyclobutyl] amide, {cis-3- [4- (2-naphthalene) 1H-pyrrole-2-carboxylic acid-1-ylacetylamino) imidazol-1-yl] cyclobutyl} amide,

N- {cis-3- [4- (2-naphthalen-1-ylacetylamino) imidazol-1-yl] cyclobutyl} -2-m-tolylacetamide, {cis-3- [4- (2-naphthalen-1-ylacetylamino) pyridin-2-carboxylic acid imidazol-1-yl] cyclobutyl} amide,

2- (3-Hydroxyphenyl) -N- {cis-3- [4- (2-naphthalen-1-ylacetylamino) imidazol-1-yl] cyclobutyl} acetamide, {cis-3- [4- (2-naphthalene- piperidine-4-carboxylic acid 1-ylacetylamino) imidazol-1-yl] cyclobutyl} amide hydrochloride,

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

N- {cis-3- [4- (2-isoquinolin-5-ylacetylamino) imidazol-1-yl] cyclobutyl} benzamide and {cis-3- [4- (2-isoquinolin-5-ylacetylamino) imidazol-1] pyridyl-2-carboxylic acid amide and cyclically acceptable salts thereof, and pharmaceutically acceptable salts of said compounds.

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

cis-N- (1-bicyclo [3.1.0] hex-3-yl-1H-imidazol-4-yl) -2-quinolin-6-ylacetamide, cis-N- (1-trans-6- (pyridine- 2-carbonyl) bicyclo [3.1.0] hex-3-yl-lH-imidazol-4-yl) -2-quinolin-6-yl-acetamide,

N- {1- [cis-3- (2-methoxyphenyl) cyclobutyl] -lH-imidazol-4-yl} -2-quinolin-6-yl-acetamide,

N- {1- [cis-3- (2-fluorophenyl) cyclobutyl] -lH-imidazol-4-yl} -2-quinolin-6-yl-acetamide,

N- {1- [cis -3- (4-methoxyphenyl) cyclobutyl] -lH-imidazol-4-yl} -2-quinolin-6-yl-acetamide,

2-quinolin-6-yl-N- {1- [cis-3-p-tolyl-cyclobutyl] -lH-imidazol-4-yl} -acetamide,

N- {1- [cis-3- (2-ethoxyphenyl) cyclobutyl] -1H-imidazol-4-yl} -2-quinolin-6-ylacetamide,

N- {1- [cis-3- (3-methoxyphenyl) cyclobutyl] -1H-imidazol-4-yl} -2-quinolin-6-ylacetamide; and pharmaceutically acceptable salts of said compounds.

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

N- {1- [3- (2-hydroxyphenyl) cyclobutyl] -1 H-imidazole-4-y1} -2- (4-methoxyphenyl) acetamide,

N- {l- [3- (3-hydroxyphenyl) cyclobutyl] -lH-imidazol-4-yl} -2- (4-methoxyphenyl) acetamide,

N- {l- [3- (2-aminophenyl) cyclobutyl] -lH-imidazol-4-yl} -2- (4-methoxyphenyl) acetamide,

N- {1- [3- (3-aminophenyl) cyclobutyl] -lH-imidazol-4-yl} -2- (4-methoxyphenyl) acetamide,

N- {1- [3- (3-Aminomethyl-phenyl-cyclobutyl] -1H-imidazol-4-yl} -2- (4-methoxy-phenyl) -acetamide,

N- {1- [3- (3-dimethylaminomethyl-phenyl) cyclobutyl] -lH-imidazol-4-yl} -2- (4-methoxyphenyl) acetamide,

2- (4-Methoxyphenyl-N- {1- [3- (1-methyl-1H-pyrazol-3-yl) cyclobutyl] -1H-imidazol-4-yl} -acetamide and pharmaceutically acceptable salts of said compounds.

Salts of the compounds of formula (I) may be prepared using any of the 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-p-toluoyl tartaric, acetic, sulfuric, hydroiodic, almond, sodium, potassium, magnesium, calcium and lithium.

The compounds of formula I may have optical centers and therefore may be in different enantiomeric and other stereoisomeric configurations. The invention encompasses all of these enantiomers, diastereomers and other stereoisomers of the compounds of formula (I), as well as racemic and other mixtures thereof.

The invention also encompasses isotopes of labeled compounds which are identical to the compounds of formula I, but one or more of which is replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that may be included in the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, iodine, and chlorine, such as ³ H, ^{1 L} , ¹⁴ C, 18 ?. 123j _and 125j. the invention includes the compounds of the invention and the pharmaceutically acceptable salts of these compounds which contain the aforementioned isotopes and / or other isotopes of other atoms. Isotope-labeled compounds of the invention, for example compounds into which the ³ H and ¹⁴ C isotopes have been incorporated, are useful in drug testing and / or distribution in substrate tissue. Tritiated isotopes, i. and treated with carbon 14, i. ¹⁴ C isotopes are particularly suitable for their readiness and traceability. The isotopes ¹³ C and a ^{1 S} F are particularly suitable for ροζ itrónovú emission tomography (PET) isotopes ¹²⁵ and J are particularly suitable for single photon emission computerized tomography (SPECT), in each case for imaging of the brain. In addition, sub17 substitution with heavier isotopes such as deuterium, i. ² H, may provide certain therapeutic advantages due to its greater metabolic stability, for example, increased in vivo half-life or reduced dosage options, and therefore may be advantageous in certain circumstances. Isotope-labeled compounds of the formula I according to the invention can be prepared by the methods illustrated in the schemes and / or in the examples, by replacing the non-isotope-labeled reagent with a readily available isotope-labeled reagent.

The invention also relates to pharmaceutical compositions for treating a disease or condition comprising abnormal cell growth in a mammal comprising a compound of Formula I in an amount effective to inhibit abnormal cell growth in association with a pharmaceutically acceptable carrier.

The invention also relates to pharmaceutical compositions for the treatment of diseases or conditions comprising abnormal growth of mammalian cells comprising 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 comprising abnormal growth of mammalian cells, comprising administering a compound of Formula I in an amount effective to inhibit abnormal growth of cells.

The invention also relates to a method of treating diseases or conditions comprising abnormal growth of mammalian cells, comprising administering a compound of Formula I in an amount effective to inhibit cdk2 activity.

In a pharmaceutical composition or method of treating diseases or conditions of the invention comprising abnormal cell growth, the disease or condition exhibiting abnormal cell growth is in one embodiment cancer. The cancer may be a carcinoma, for example a carcinoma of the bladder, breast, colon, kidney, liver, lung, for example a small cell lung cell of esophagus, gall bladder, ovary, pancreas, stomach, cervix, thyroid, prostate or skin, for example flat cell carcinoma; a hematopoietic tumor of the lymphatic system, for example, leukemia, acute lymph 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 leukemias, 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; pigment xenoderoma; keratoktantóm; 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, neuro-fibromatosis, atherosclerosis, pulmonary fibrosis, arthritis, psoriasis, glomerulonephritis, restenosis, hypertrophic scarring, inflammatory bowel disease, fungal infections, and endotoxic graft rejection.

The invention also relates to pharmaceutical compositions for treating neurodegenerative diseases or conditions in a mammal, the composition comprising a compound of Formula I in an effective amount for treating such a disease or condition and a pharmaceutically acceptable carrier.

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

The invention also relates to a method of treating a neurodegenerative disease or condition in a mammal 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 a mammal 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, amyotropic lateral sclerosis, pain, virus-induced dementia or AIDS-induced dementia associated neurodegeneration, neurodegeneration , migraine, hypoglycaemia, urinary incontinence, cerebral ischemia, multiple sclerosis, Alzheimer's disease, senile dementia of the Alzheimer's type, mild disturbance of consciousness, age-related decline in consciousness, emesis, corticobasal degeneration, dementia pugilistic dystrophy, Noseia pugiloma, Downov , Pick's disease, prion disease with dizziness, progressive supranuclear paralysis, lower lateral sclerosis and subacute sclerotic panencephalitis.

The invention also relates to a pharmaceutical composition for the treatment of a disease or condition, the treatment of which can be influenced or alleviated by altering dopamine-mediated neurotransmission in a mammal, the composition comprising an 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 influenced or alleviated by altering dopamine-20 mediated neurotransmission in a mammal, the composition comprising an cdk5 inhibitor in an amount effective to inhibit cdk5 and a pharmaceutically acceptable carrier.

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

In one embodiment, the disease or condition treatable or ameliorated by altering mammalian dopamine-mediated neurotransmission is Parkinson's disease, schizophrenia, schizophreniform disorder, schizoaffective disorder, for example of the mirage type, or depressive type, psychosis-induced, psychosis-induced, psychosis-induced, , cannabis, cocaine, hallucinogens, inhalers, opiates, or phencyclidine; personality disorder of the paranoid type, personality disorder of the schizoid type; drug addiction, including addiction to narcotics (for example, heroin, opium and morphine), cocaine and alcohol; drug abstinence including narcotic, cocaine and alcohol abstinence; obsessive compulsive disorder, Tourette's syndrome; depression; major depressive episode manic or mixed mood episode, hypomanic episode episode, depressive episode with atypical signs or melancholic signs or catatonic signs, mood episode with delayed onset, stroke depression, major depressive disorder, dystic disorder, mild depressive disorder, mild depressive disorder, mild depressive disorder, mild depressive disorder, mild depressive disorder , post-psychotic depressive disorder schizophrenia, a major depressive disorder stacked into a psychotic disorder such as delusional disorder or schizophrenia, bipolar disorder such as bipolar I disorder, bipolar II disorder, cytotimic disorder, anxiety, attention deficit, and hyperactivity and disorder.

In another embodiment, the cdk5 inhibitor in a method of treating a disease or condition that can be treated 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 mediated 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 cdk5 activity.

It has also been found that compounds of Formula I inhibit GSK-3. It is expected that the compounds of Formula I may be effective in the treatment of diseases and conditions that may be affected or ameliorated by inhibition of GSK-3. Diseases and conditions that can be treated or ameliorated by inhibiting GSK-3 include neurodegenerative diseases and conditions. Neurodegenerative diseases and conditions are described above and include, but are not limited to, for example, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotropic lateral sclerosis, multiple sclerosis, stroke, cerebral ischemia, dementia derived from AIDS, neurodegenerative infections associated with bacterial neurodegeneration dementia, traumatic brain injury and spinal cord trauma. Therefore, the compounds can be of the general formula

Also effective in treating neurodegenerative diseases and conditions based on both cdk5 and GSK-3 activity.

Other diseases and conditions that may be treated or ameliorated by GSK-3 inhibition include psychotic disorders and conditions such as schizophrenia, schizophreniform disorder, schizoaffective disorder such as the delusional type, or depressive type, substance-induced psychosis disorder, for example, psychosis induced by alcohol, amphetamine, cannabis, cocaine, hallucinogens, inhalers, opiates, or phencyclidine; personality disorder of the paranoid type, personality disorder of the schizoid type. Treatment of such diseases and conditions can be accomplished or alleviated by altering dopamine-mediated neurotransmission. Therefore, the compounds of Formula I are effective in treating such diseases and conditions based on both cdk5 and GSK-3 activity.

Other diseases or conditions that can be treated or ameliorated by GSK-3 inhibition include mood disorders and mood episodes, such as major depressive episode, manic or mixed mood episode, hypomanic episode episode, atypical episode episode, or with melancholic sign, delayed mood episode, stroke depression, major depressive episode, dystimic episode, major depressive disorder, premenstrual dysphoric disorder, post-psychotic depressive disorder schizophrenia, major depressive disorder overlapped with schizophrenia for example, bipolar I disorder, bipolar II disorder, and cyclothymic disorder. The treatment of such mood disorders and events, for example depression, can also be performed or facilitated by altering dopamine-mediated neurotransmission. Therefore, the compounds of Formula I are effective in treating some mood disorders and mood events based on both cdk5 and GSK-3 activity.

Other disorders and conditions whose treatment can be accomplished or facilitated by inhibiting GSK-3 are male fertility and sperm motility, diabetes mellitus, impaired sugar tolerance, metabolic syndrome or syndrome X; polycystic ovarian syndrome; adipogenesis and obesity, myogenesis and brittle, for example age-related decline in physical performance; acute sarcopenia, such as muscle atrophy and / or cachexia associated with burns, bed restraint, limb immobilization or major chest, abdominal and / or orthopedic surgery; sepsis; hair loss, hair loss and baldness; immune deficiency and cancer.

The invention also relates to pharmaceutical compositions for the treatment of mammals, including humans, wherein the diseases or conditions are male fertility and sperm motility, diabetes mellitus, impaired sugar tolerance, metabolic syndrome or syndrome X; polycystic ovarian syndrome; adipogenesis and obesity, myogenesis and brittle, for example age-related decline in physical performance; acute sarcopenia, for example, muscle atrophy and / or cachexia associated with burns, bedding, limb immobilization or major chest, abdominal and / or orthopedic surgery; sepsis; hair loss, hair loss and baldness; immune deficiency, wherein the composition comprises a pharmaceutically acceptable carrier and an amount of a compound of Formula I effective in treating such diseases or conditions.

The invention also relates to pharmaceutical compositions for the treatment of mammals, including humans, wherein the diseases or conditions are male fertility and sperm motility, diabetes mellitus, impaired sugar tolerance, metabolic syndrome or syndrome X; polycystic ovarian syndrome; adipogenesis and obesity, myogenesis and brittle, for example age-related decline in physical performance; acute sarcopenia, for example, muscle atrophy and / or cachexia associated with burns, bedding, limb immobilization or major chest, abdominal and / or orthopedic surgery; sepsis; hair loss, hair loss and baldness; immune deficiency, wherein the composition comprises a pharmaceutically acceptable carrier and an amount of a compound of Formula I effective to inhibit GSK-3.

The invention also relates to a method of treating mammals, including humans, wherein the diseases or conditions are male fertility and sperm motility, diabetes mellitus, impaired sugar tolerance, metabolic syndrome or syndrome X; polycystic ovarian syndrome; adipogenesis and obesity, myogenesis and brittle, for example age-related decline in physical performance; acute sarcopenia, for example, muscle atrophy and / or cachexia associated with burns, bedding, limb immobilization or major chest, abdominal and / or orthopedic surgery; sepsis; hair loss, hair loss and baldness; immune deficiency, wherein the mammal is administered a compound of Formula I in an amount effective to treat such diseases or conditions.

The invention also relates to a method of treating mammals, including humans, wherein the diseases or conditions are male fertility and sperm motility, diabetes mellitus, impaired sugar tolerance, metabolic syndrome or syndrome X; polycystic ovarian syndrome; adipogenesis and obesity, myogenesis and brittle, for example age-related decline in physical performance; acute sarcopenia, for example, muscle atrophy and / or cachexia associated with burns, bedding, limb immobilization or major chest, abdominal and / or orthopedic surgery; sepsis; hair loss, hair loss and baldness; immune deficiency, wherein the mammal is administered a compound of formula I in an amount effective to inhibit GSK-3.

The invention further relates to a method of inhibiting GSK-3 in a mammal, including a human, comprising administering to said mammal 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 mammalian disorders, wherein said disorders are selected from the group consisting of Alzheimer's disease, mild deterioration of consciousness and age-related decline in consciousness, comprising a cdk5 inhibitor and a COX-II inhibitor 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 the treatment of mammalian disorders, wherein the disorders are selected from the group consisting of Alzheimer's disease, mild deterioration of consciousness and age-related decrease in consciousness, wherein the mammal is administered a cdk5 inhibitor and a COX-II inhibitor in an amount effective to treat such diseases. 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 of the invention, or a pharmaceutically acceptable salt of a compound of formula I, may be administered or incorporated into a pharmaceutical composition with one or more antidepressant or anxiolytic compounds for treating or preventing depression and / or anxiety.

The invention also relates to a pharmaceutical composition for treating depression and anxiety in a mammal, 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 a mammal comprising administering to the mammal a cdk5 inhibitor and an NK-1 receptor antagonist in an amount of a cdk5 inhibitor and an NK-1 receptor antagonist effective in 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 NK-1 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 a mammal comprising a cdk5 inhibitor and a 5HT _1D 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 further relates to a method of treating depression and anxiety in a mammal comprising administering to said mammal a cdk5 inhibitor and a 5HT _1D receptor antagonist in an amount of a cdk5 inhibitor and a 5HT _1D receptor antagonist effective in 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 5HT _1D 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 a mammal, comprising a cdk5 inhibitor and an SSRI 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 a mammal comprising administering to said mammal a cdk5 inhibitor and an SSRI in an amount of a cdk5 inhibitor and an SSRI effective in 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 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 mammalian schizophrenia comprising a cdk5 inhibitor and antipsychotics selected from the group consisting of ziprasidone, olanzapine, risperidone, L-745870, sonepiprazole, RP 62203, NGD 941, balaperidone, flesinoxan, and gepirnie, and geprophenia 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 schizophrenia in a mammal, comprising administering to said mammal a cdk5 inhibitor and antipsychotics selected from the group consisting of ziprasidone, olanzapine, risperidone, L-745870, sonepiprazole, RP 62203, NGD 941, balaperanone and gepinoxidone and antipsychotics effective in the treatment of schizophrenia. In one embodiment, the cdk5 inhibitor is a compound of Formula I or a pharmaceutically acceptable salt thereof. The cdk5 inhibitor and antipsychotics 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 of the Alzheimer &apos; s disease, a slight deterioration of consciousness and an age-related decrease in consciousness comprising a cdk5 inhibitor and an acetylcholinesterase inhibitor together 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 also relates to a method of treating a mammal disorder of the Alzheimer's disease, a mild deterioration of consciousness and an age-related decrease in consciousness, comprising administering to said mammal a cdk5 inhibitor and an acetylcholinesterase inhibitor in an amount of cdk5 inhibitor and acetylcholinesterase inhibitor effective in treating schiz. 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 plasminogen tissue activator (TPA e.g. ANTIVASE). 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 also relates to a method of treating a mammal 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 plasminogen tissue activator in an amount and cdk5 inhibitor. plasminogen tissue effective in the treatment of said diseases and disorders.

In one embodiment, the cdk5 inhibitor is a compound of Formula I or a pharmaceutically acceptable salt thereof. The cdk5 inhibitor and plasminogen tissue 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, multiinfarct dementia, epilepsy, pain, Alzheimer's disease and senile dementia, comprising a cdk5 inhibitor and a neurophilic inhibitory factor (NIF) in an amount effective in 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 also relates to a method of treating a mammal disorder from the group of stroke, spinal cord trauma, traumatic brain damage, multiinfarct dementia, epilepsy, pain, Alzheimer's disease and senile dementia, wherein said mammals are administered a cdk5 inhibitor and a neurophilic inhibitory factor an inhibitory factor effective in the treatment of such diseases. In one embodiment, the cdk5 inhibitor is a compound of Formula I or a pharmaceutically acceptable salt thereof. The cdk5 inhibitor and neurophilic inhibitory factor may 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 a disorder or condition selected from Huntington's disease, stroke, spinal cord trauma, traumatic brain injury, multi-infarct dementia, epilepsy, amyotropic lateral sclerosis, pain, virus-induced dementia such as AIDS-induced dementia, migraines, hypoglycemia, urinary incontinence, cerebral ischemia, multiple sclerosis, Alzheimer's disease and senile dementia of the Alzheimer's type, mild deterioration of consciousness, age-related decline in consciousness, emesis, corticobasal degeneration, dementia ougilistica, Down's syndrome, Nidia, Pickonic dystrophy, myotic dystrophy dizziness, progressive supranuclear paralysis, lower lateral sclerosis and subacute sclerotic panencephalitis in mammals, comprising a cdk5 inhibitor and an NMDA receptor antagonist in an amount effective in 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 also relates to a method of treating mammal disorders of the group Huntington's disease, stroke, spinal cord trauma, traumatic brain injury, multi-infarct dementia, epilepsy, amyotropic lateral sclerosis, pain, virus-induced dementia, for example AIDS-induced dementia, migraine, hypoglycemia, urine cerebral ischemia, multiple sclerosis, Alzheimer's disease and senile dementia of the Alzheimer's type, mild deterioration of consciousness, age-related decrease in consciousness, emesis, corticobasal degeneration, ementine ementia, Down syndrome, myotic dystrophy, suppressive disorders, NiemanPick's disease, NiemanPick paralysis, lower lateral sclerosis, and subacute sclerotic panencephalitis in mammals, wherein the mammal is administered a cdk5 inhibitor and an NMDA receptor antagonist in an amount effective to treat 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 NMDA 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 the treatment of 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 for treatment. 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 also relates to a method of treating a mammal disorder from the group of stroke, spinal cord trauma, traumatic brain injury, multi-infarct dementia, epilepsy, pain, Alzheimer's disease and senile dementia in mammals, administering to the mammal a cdk5 inhibitor and potassium channel modulator in effective amounts. 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 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 treatment and treatment means averting, cradling or preventing the progression of the disease or condition to which the term treatment and treatment refers, or one or more symptoms of such disease or condition.

The term also encompasses, depending on the condition of the patient, the perception of the onset of the disease or condition, or the symptoms associated with the disease or condition, including reducing the severity of the disease or condition or symptoms associated therewith before affecting said disease or condition. Such prevention or reduction prior to affliction consists in administering a compound of formula I to a subject who is not affected by 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, unless otherwise noted, the term mammal means any mammal. For example, the term mammal includes, but is not limited to, dogs, cats, and humans.

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

As used herein, the terms neurodegenerative diseases and conditions refer to diseases and conditions associated with neuronal degeneration. Conditions and diseases of a neurodegenerative nature are well known to those skilled in the art.

References herein to treatment that may be affected or facilitated by a variable dopamine-mediated neurotransmission is 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 may be performed and / or facilitated by reducing cdk5 activity means 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 to be understood an amount of a compound sufficient to bind cdk2 to reduce cdk2 activity.

The invention is illustrated in more detail by the following detailed description.

The compounds of formula I and their pharmaceutically acceptable salts can be prepared according to the following schemes and procedures. Unless otherwise stated, the symbols R ^1, R ^2, R ³ and R ⁴ as defined above. Isolation and purification of the products is accomplished by methods known to those skilled in the art.

As used herein, solvent inert to the reactants means a solvent system in which the components do not react with the starting materials, reagents 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 of the molecules involved. This can be achieved 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 process for preparing compounds of formula I wherein R ^{3 is} -C (= O) NH, -C (= O) O- or -C (= O) (CR ³ R ³ R ³ ) _n -. Scheme I treats a solution of 1,4-dinitroimidazole (J. Phys. Chem. 99: 1009-1015, 1995) in dimethylsulfoxide (DMSO), in pyridine-water, in water in an acetonitrile-water solvent system, alcohol or alcohol-water, but preferably in a lower alcohol such as methanol, 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, thereby 1,4-Dinitroimidazole is a high-energy, semi-stable compound that must be stored in the freezer when not in use. Thermodynamic measurements have shown that it potentially generates enough energy at 35 ° C under adiabatic conditions to a violent explosion. Particular caution must be exercised when using this compound. The reduction of the nitro compound of the formula 2 to the amine of the formula 3 is possible by reducing the compound of the formula 2 in the presence of a noble metal catalyst, in a solvent such as ethyl acetate, tetrahydrofuran, dioxane or a mixture thereof with hydrogen gas at a pressure. a pressure of about 10 bar is preferred. The preferred noble metal is palladium. The metal is to be suspended on an inert solid support such as coal. After consumption of the compound of formula 2, the mixture was filtered and the resulting amine of formula 3 is immediately reacted with an acid chloride of the formula C1C (= O) ^(OR1 CR ¹ ·· -) R ⁴ -, with an anhydride of formula (R ⁴ (CR ¹⁰ R ¹¹ ) n C (= O)) 2 O or an activated carboxylic acid derivative of formula XC (= O) (CR ¹⁰ R ¹¹ ) n R ⁴ in the presence of a base such as triethylamine, diisopropylethylamine, pyridine or 2,6 -lutidine, at a temperature in the range of about -78 to about 40 ° C. 1-Propanephosphonic acid cyclic anhydride and triethylamine are a preferred combination. The activated carboxylic acid derivative is prepared from the carboxylic acid HOC (= O) (CR-LOr ¹¹ ) _n R ⁴ and a known activating agent such as dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, carbonyldiimidazole, cyclic anhydride 1-propanephosphonic acid, alkyl chloroformate, aryl chloroformate, bis (2-oxo-3-oxazolidinyl) phosphinic acid chloride, benzotriazol-1-yloxy-tris (di 35 methylamino) phosphonium hexafluorophosphate, or any other reagent known in the standard literature. This gives a compound of formula IB wherein R ³ is -C (= 0) (CR ¹⁰ R ^{and L)} _n -.

Alternatively, the amine of formula 3, after filtration, may be treated 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, preferably -78 to -40C to give a compound of formula IA, wherein R ³ is -C (= 0) 0 and R ⁴ is phenyl. Diisopropylethylamine and phenyl chloroformate are the preferred combinations. Subsequent treatment of the phenylcarbamate 1A with a primary or secondary amine in a solvent such as dioxane, dimethylformamide or acetonitrile at a temperature in the range of about 40 ° C to about 90 ° C gives the corresponding urea derivative of formula IC wherein R ^{3 is} -C (= O) NR ⁹ - and R ⁴ phenyl or heteroaryl. For this reaction, a 1: 1 dioxane-dimethylformamide system and a temperature of 70 ° C are preferred.

Scheme 1 R 2 NH ₂

R / N =

N

O í!

R ', R

R ¹ —Ν '/ ^ N

R

1G

A process for preparing compounds of formula I wherein R ^{1 is} substituted with R ⁵ and R ⁵ is NHC (= O) R ⁸ is illustrated in Scheme 2. Preferred is the treatment of a compound of Formula 4 wherein R ^{5 is a} hydroxyl group, alkylsulfonyl chloride or arylsulfonyl chloride, wherein p-toluenesulfonyl chloride (TosCl) in a reaction inert solvent such as tetrahydrofuran, methylene chloride or chloroform is preferred, methylene chloride is preferred, at a temperature 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, with triethylamine being preferred, and a catalytic amount of 4-N, N-dimethylaminopyridine to give a compound of formula 5 wherein R ^{5 is} CH 3 (C 6 H 4) SO 3 (TosO) ). Treatment of the tosylate thus obtained with an alkali metal azide salt, preferably sodium azide, in a polar solvent such as dimethylformamide, dimethylsulfoxide, lower alcohol, water, and mixtures of these solvents, preferably ethanol-water, at a temperature in the range of about 20 to about 130C, preferably at a temperature of 90 to 110 ° C, provides a compound of formula 6 wherein R ⁵ is N 3.

Treatment of the azide under selective reducing conditions, such as using a trialkylphosphine or triarylphosphine system and water, preferably triaphenylphosphine, in a solvent such as tetrahydrofuran, dioxane, acetonitrile, or a mixture thereof, preferably tetrahydrofuran, yields a compound of formula 7 wherein: NH ₂ · The primary amino group of the compound of formula 7 thus obtained (R ⁵ = NH ₂ ) 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 a 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-3-bis (oxo) bis (3-chloroformate) -oxazolidinyl) phosphinic acid, benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate or any other reagent known in the standard literature, optionally in the presence of a base such as triethylamine, diisopropylethylamine, pyridine and 2,6-lutidine, 1- (3) is preferred. dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride at a temperature of about -78 to about 80 ° C, preferably 0 to 40 ° C. Preferred solvents are tetrahydrofuran and methylene chloride.

Conversion of a compound of formula 8 so obtained wherein R ^{5 is} -NHC (= O) R ⁸ to a compound of formula ID (wherein R ^{5 is} -NHC (= O) R ⁸ and R ^{3 is} C (= O) (CR ¹⁰ R ¹¹ ) _n R ⁴ ) may be carried out by reducing the compound of formula 8 in the presence of a noble metal catalyst, the preferred noble metal being palladium, and the noble metal may be suspended, as usual, on an inert solid support such as is carbon, in a solvent such as ethyl acetate, tetrahydrofuran, dioxane or a mixture thereof, with hydrogen gas at a pressure of about 1 to about 10 MPa, with a pressure of about about 1 to about 1 MPa being preferred. After the compound of 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. wherein the preferred combination is 1-propanephosphonic acid cyclic anhydride and triethylamine at a temperature in the range of about -78 to about 40C to give the N-acylated product of Formula ID. The activated carboxylic acid derivative is prepared from a carboxylic acid and from a known activating agent such as dicyclohexylcarbodiimide, 1- (3-dimethyl aminopropyl) -3-ethylcarbodiimide hydrochloride, carbonyldiimidazole, cyclic 1-propanephosphonic anhydride, alkyl chloroformate, bis bis (oxo) bis 3-oxazolidinyl) phosphinic acid, benzotriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate or any other reagent known in the standard literature.

When an aryl chloroformate or heteroaryl chloroformate is used in the above acylation reaction in place of the acid chloride, acid anhydride or activated carboxylic acid derivative, the aryl carbamate of formula IE is obtained. The obtained arylcarbamate of formula IE (R ³ = C (= O) O- and R ⁴ represents an aryl or heteroaryl group) can be treated with an amine in a solvent such as dioxane, dimethylformamide or acetonitrile, a 1: 1 dioxane-dimethylformamide system being preferred. , at a temperature of about 40 to about 90 ° C, preferably at 70 ° C, to give the corresponding urea derivative of formula IF (R ³ = C (= O) NR ⁹ and R ⁴ is aryl or heteroaryl).

Scheme 2

in

R ⁷ /

N__ _R 4

An alternative method of preparing compounds of formula

C Q

I, where R is NHC (= O) R 0, is illustrated in Scheme 3. Treatment of a compound of formula 4 wherein R ^{5 is} hydroxyl, alkylsulfonyl chloride or arylsulfonyl chloride, p-toluenesulfonyl chloride (TosCl) in a solvent inert to a reaction such as tetrahydrofuran, methylene chloride or chloroform, wherein methylene chloride is preferred, at a temperature 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, and -N, N-dimethylaminopyridine, gives a compound of formula 5 wherein R ^{5 is} CH 3 (C 8 H 4) SO 3 (TosO). A preferred amine base is triethylamine. Conversion of a compound of formula 5 (R ⁵ is TosO) to a compound of formula IG (R ⁵ is TosO, R ³ -C (= O) (CR ¹⁰ R ¹¹ ) n R ⁴ ) can be accomplished by reducing the compound of formula 5 (R @ 4 is TosO) in the presence of a noble metal catalyst, in a solvent such as ethyl acetate, tetrahydrofuran, dioxane or a mixture thereof, with hydrogen gas at a pressure of about 1 to about 10 bar, with a pressure of about 0.1 to about 1 bar. The preferred noble metal is palladium. The noble metal may be suspended, as usual, on an inert solid support such as coal. After the compound of formula 5 has been consumed, the mixture is filtered and the amine obtained is immediately acylated by treatment 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. are a preferred combination of 1-propanephosphonic acid cyclic anhydride and triethylamine, at a temperature in the range of about -78 to about 40 ° C to give the N-acylated product of general 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- (bis-) -oxide. 3-oxazolidinyl) phosphinic acid, benzotriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate or any other reagent known in the standard literature.

Treatment of the compound of formula IG thus obtained (R ⁵ is TosO, R ³ is -C (= O) (CR 4 -Or ¹¹ ) -) 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 ethanol-water, at a temperature in the range of about 20 to about 130 ° C, preferably at 90 to 110 ° C, to provide a compound of formula IH wherein R ⁵ is N 3 . Subsequent reduction of the azide of formula IH (R ⁵ = N 3) may be accomplished by reduction of the azide of formula IH (R ⁵ = N ₃ ) in the presence of a noble metal catalyst, the preferred noble metal being palladium, and the noble metal may be as usual suspended in an inert solid support such as coal in a solvent such as ethyl acetate, tetrahydrofuran, dioxane or a mixture thereof with hydrogen gas at a pressure of about 1 to about 10 MPa, with a pressure of about 0.1 to about 1 MPa being preferred.

Alternatively, the reduction of the azide of formula IH (R ⁵ = N 3) may be carried out by treatment with a trialkylphosphine or triarylphosphine and water system, preferably triarylphosphine, in a solvent such as tetrahydrofuran, dioxane or acetonitrile, with tetrahydrofuran being preferred. The primary amino group of the compound of formula (Ii) thus obtained (R ⁵ = NH 2) 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-propanephosphonic anhydride, alkyl chloroformate, bis-3-chloro-3-formate. -oxazolidinyl) phosphinic acid, benzotriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate or any other reagent known in the standard literature, optionally in the presence of a base such as triethylamine, diisopropylethylamine, pyridine and 2,6-lutidine, 1- is preferred (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, at a temperature of about -78 to about 80 ° C, preferably 0 to 40 ° C. Preferred solvents are tetrahydrofuran and methylene chloride.

Scheme 3

Compounds of formula I where R ³ - (CR ¹⁰ R ¹¹ ) _n may be prepared as outlined 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 ammonium hexamethyldisilazide, sodium hexamethyldisilazide, sodium tert-butoxide, or potassium tert-butoxide, in a reaction-inert solvent, such as tetrahydrofuran, N, 1,4-tetrahydrofuran, 1,4-tetrahydrofuran, dimethyl sulfoxide or toluene, at a temperature of about -20 to about 150 ° C, preferably at 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 addition of alkyl chloride, allyl chloride or benzylc chloride, alkyl bromide, allyl bromide or benzyl bromide, alkyl iodide, allyl iodide or benzyl iodide, alkylsulfonate, arylsulfonate or triflate to give a mixture of 1-substituted 4-bromoimidazole (Formula 9) and 1-substituted 5-bromoimidazole (Formula 10) and both the compounds are separated by methods known to those skilled in the art.

Or, 4-bromoimidazole is treated with allyl fluoride, allyl chloride, allyl bromide, allyl iodide, allyl acetate or allyl carbonate, wherein allyl carbonate is preferred in a reaction-inert solvent such as tetrahydrofuran, 1,2-dichloroethane,

1,4-dioxane, dimethylsulfoxide or N, N-dimethylformamide, the preferred solvent being tetrahydrofuran, in the presence of a palladium catalyst such as palladium (0) tetrakis (triphenylphosphine), palladium (II) acetate, allyl palladium chloride dimer, tris (dibenzylidene acetone) (O), tris (dibenzylideneacetone) dipalladium (0) chloroform adduct, palladium (II) chloride, preferably palladium (0) tetrakis (triphenylphosphine), palladium (II) acetate, in the absence or presence of a phosphine ligand such as triphenylphosphine , tri-o-tolylphosphine, tri-tert-butylphosphine, 1,245

-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 (Formula 9) and 1-substituted 5-bromoimidazole (10).

Treatment of 1-substituted 4-bromoimidazole (9) with an intermediate of formula NH ₂ (CR ^{10 11} * ¹¹ ) n R ⁴ in the presence of a palladium catalyst such as palladium (II) acetate, allyl palladium chloride dimer, tris (dibenzylideneacetone) dipalladium (O) , tris (dibenzylideneacetone) dipalladium (0) chloroform adduct or palladium (II) chloride, preference being given to palladium (II) acetate, tris (dibenzylideneacetone) dipalladium (0), tris (dibenzylideneacetone) dipalladium (0) chloroform adduct, and phosphine adduct such as BINAP, 2-biphenyldicyclohexylphosphine, 2-biphenyldi-tert-butylphosphine or 2-N, N-dimethylamino-2'-diphenylphosphinobiphenyl, with 2-N, N-dimethylamino-2'-diphenylphosphinobiphenyl being preferred, and bases such as sodium tert-butoxide, cesium carbonate or potassium phosphate (K ₃ PO ₄ ), preferably potassium phosphate, in a reaction inert solvent such as toluene, 1,4-dioxane or tetrahydrofuran at a temperature of about 0 to about 150 ° C s preferably at 20-110 ° C, the coupled product 1 is obtained.

Scheme 4

HN ^ N

R '

N ^ N

M

R ¹

N ^ N

br

- (CR

IO ^ hV ~ R

An alternative process for the preparation of compounds of formula I wherein R ^{3 is} -C (= O) (CR ¹⁰ R ¹¹ ) _n - is illustrated in the Scheme.

5. Treatment of ethyl 2-isocyanano-N, N-dimethylaminoacrylate (11) with a primary amine, R ¹ -NH ₂ , in a solvent such as n-butanol, n-propanol, isopropanol or ethanol, or in the absence of a solvent, wherein n-propanol or a solvent-free reaction at a temperature in the range of about 23 ° C to about 200 ° C, preferably about 60 ° C to about 150 ° C is preferred, to provide imidazoles of formula 12. Treatment of N, O-dimethylhydroxylamine hydrochloride with trimethylaluminium in 1; 2-dichloroethane followed by the addition of a compound of formula 12 and at a temperature in the range of about 30 to about 80 ° C, preferably about 50, provides the imidazole of formula

13. Addition of an organometallic reagent M- (CR ¹⁰ R ¹¹ ) _n -R ⁴ , where M is a lithium halide or a magnesium halide, a magnesium halide being preferred, to a solution of a compound of Formula 13 in a solvent such as tetrahydrofuran, methylene chloride or diethyl ether at range approximately

-47 to about 30 ° C, preferably about -20 to about 0 ° C, to obtain a compound of Formula 14. Addition of a compound of Formula 14 to a mixture of hydroxylamine hydrochloride and potassium acetate in a lower alcohol solvent, the preferred solvent being ethanol at A temperature of about 23 ° C gives the oxime 15 as a mixture of isomers. Treatment of the acetone solution of the oxime of formula 15 at about 0 ° C with an aqueous sodium hydroxide solution followed by paratoluenesulfonyl chloride provides a mixture of O-sulfonyl compounds after extraction. Dissolving the crude product in a nonpolar solvent such as benzene, hexanes or toluene, with benzene being the preferred solvent, and loading onto an alumina column eluting with a chloroform-methanol (approximately 10: 1) system yields a compound of formula IB after about five minutes and Beckmann rearrangement regioisomer.

Scheme 5

ABOUT

IB

Compounds of formula IJ may also be prepared as outlined in Scheme 6. A key starting material for this preparation is a double bond containing a compound (compound of formula 10) substituted with ER ⁵ and one to three R ⁵ groups (formula 10), where ER ^{5 an} electron withdrawing group from the group consisting of -C (= O) R ⁷ , -C (= O) OR ⁷ , -C (= O) NR ⁷ R ⁸ , -S (= O) 2 R ⁷ , -S (= O) 2NR ⁷ R ⁸ , -S (= O) 2 OR ⁷ , cyano and heteroaryl. Additionally, the compound of formula 10 may be a compound in which the ER ⁵ group is bound to one of the R ⁵ groups or directly to a carbon-carbon double bond to form a cycle, including compounds such as 2-cyclopenten-1-one and 2-cyclohexene- l-one. Or may be used a compound of formula 10, wherein L is Cl, Br, I, -OC (= O) R ^7, or -OS (= O) 2 R ^7, as starting materials. Examples of such starting materials include 3-chloro-1-cyclopentanone a

3-acetoxy-l-cyclobutanone. In the method of Scheme 6, the salt of 4 (S) -nitroimidazole is treated with sodium, potassium or cesium, 1,8-diazabicyclo [5.4.0] undec-7-ene, (DBU) or tetraalkylammonium salt, with preference tetra-n-butylammonium salt or DBU, intermediates of formula 16 or 17 in a solvent such as acetonitrile, methylene chloride, 1,2-dichloroethane or chloroform, the preferred solvent being acetonitrile at a temperature in the range of about -60 to about 50 ° C , preferably about -20 to about 23 ° C, to obtain the addition product of formula IIA. The reduction of the nitro compound of formula (IIA) can be carried out in the presence of a noble metal catalyst, the preferred noble metal being palladium, and the noble metal can be suspended, as usual, on an inert solid support such as coal in a solvent such as ethyl acetate, tetrahydrofuran, dioxane, or a mixture thereof, with hydrogen gas at a pressure of about 1 to about 10 MPa, with a pressure of about 0.1 to about 1 MPa being preferred. 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 formula C1C (= O) (CR 4 R ¹¹ ) _n R ⁴ , with an acid anhydride of formula R ⁴ (CR ¹⁰ R ¹¹ ) n C (= o)) 20, or with an activated carboxylic acid derivative of the formula XC (= O) (CR ¹⁰ R ¹¹ ) n R ⁴ optionally in the presence of an amine base such as triethylamine, diisopropylethylamine, pyridine or

2,6-lutidine, a preferred combination of 1-propanephosphonic acid cyclic anhydride and triethylamine, at a temperature in the range of about -78 to about 40 ° C, to provide compounds of Formula IJ. The activated carboxylic acid derivative is prepared from a carboxylic acid of the formula HOC (= O) (CR ^b R 6 ^b 4) _n R ⁴ and a known activating agent such as dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, carbonyldiimidazole, 1-propanephosphonic acid cyclic anhydride, alkyl chloroformate, aryl chloroformate, bis (2-oxo-3-oxazolidinyl) fisphonic acid chloride, benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate, or any other reagent known from the standard literature.

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

Subsequent treatment of the compound of formula IK with a primary or secondary amine in a solvent such as dioxane, dimethylformamide or acetonitrile, wherein the 1: 1 dioxane-dimethylformamide system is a preferred solvent at a temperature in the range of about 40 to about 90 ° C, preferably about 70 ° C to obtain the corresponding urea derivative of formula IL.

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 other compounds of Formula I described herein.

Compounds of formula (I) of the invention wherein R is m is hydrogen can be prepared by the described transformations of compounds of formula (I) wherein R is hydrogen by known methods. For example, compounds of formula I wherein R ² is fluorine can be prepared by treating compounds of formula I wherein R ² is hydrogen, for example, compounds of formula IA,

IB and IC of Scheme 1 with n-fluorobenzenesulfonamide in a solvent such as toluene, xylenes or dioxane at a temperature ranging from about room temperature to about 150 ° C, preferably about 100 to about 120 ° C.

Scheme 6

Pharmaceutically acceptable salts of the compounds of formula

I may be prepared by known methods by treating a solution or suspension of the free base or acid with a chemical equivalent of a pharmaceutically acceptable acid or base. Conventional concentration or crystallization methods may be used to isolate the salt. Examples of suitable acids are acetic, lactic, succinic, maleic, tartaric, citric, gluconic, ascorbic, benzoic, cinnamon, fumaric, sulfuric, phosphoric, hydrochloric, hydrobromic, hydroiodic, sulfamic, sulfonic, such as methanesulfonic, methanesulfonic, methanesulfonic, methanesulfonic. toluenesulfonic acid and the like. Sodium, potassium and calcium bases are exemplified.

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, for example, diluents and fillers, sterile aqueous solutions and various organic solvents. Pharmaceutical compositions made from a mixture of a compound of Formula I or a pharmaceutically acceptable salt thereof can be readily 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 tableting purposes. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules. Lactose or milk sugar and high molecular weight polyethylene glycols are preferred for this purpose. Where aqueous suspensions or elixirs are desired for oral administration, the active ingredient of the invention may be combined with various sweetening or flavoring agents, coloring agents and optionally emulsifying or suspending agents together with diluents such as water, ethanol, propylene glycol, glycine or their mixture.

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

The compounds of formula (I) or pharmaceutically acceptable salts thereof may be administered orally, transdermally (e.g. using patches), parenterally (e.g. intravenously), rectally or topically. Generally, the daily dose for treating a neurodegenerative disease or condition, or for treating a disease or condition susceptible to or amenable to alteration in dopamine-mediated neurotransmission, is in the range of about 0.001 to about 10.0 mg / kg body weight of the subject to be treated. The daily dose for treating a cancer or disease or condition involving abnormal growth of benign cells is also in the range of about 0.001 to about 10.0 mg / kg body weight of the subject to be treated. For example, a compound of Formula I, or a pharmaceutically acceptable salt thereof, may be administered to treat an adult neurodegenerative disorder with an average weight (about 70 kg) in an amount ranging from about 0.01 to about 1000 mg per day, preferably ranging from about 0.1. up to about 500 mg per day at once or in divided doses. The daily dose for the treatment of diabetes, sperm mobility, hair loss or other diseases or conditions that can be treated by inhibiting GSK-3 is generally in the range of about 0.0001 to about 10.0 mg / kg body weight of the subject to be treated. Variations in these doses are possible at the discretion of the physician or attending practitioner according to the weight, age and condition of the subject being treated, the severity of the disease and, in particular, the proportion of the route of administration chosen.

The 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 substances selected from the group consisting of anti-angiogenic agents, signal transduction inhibitors and antiproliferative agents in an amount effective to inhibit abnormal cell growth.

Anti-angiogenesis agents such as matrix metalloproteinase 2 (MMP-2) inhibitors, matrix metalloproteinase 9 (MMP-9) inhibitors, cyclooxygenase II (COX-II) inhibitors may be used together with the compounds of formula I in treatment methods and pharmaceutical compositions according to the invention. of the invention for treating 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 WO 96/33172 (published Oct. 24, 1996), WO 96/27583 (published Mar. 7, 1996), European Patent Application No. 97304971.1 (filed 8; European Patent Application No. 99308617.2 (filed October 29, 1999), World Patent Publication No. WO 98/07697 (published February 26, 1998), and World Patent Publication No. WO 98/03516 (published January 29, 1997). 1998), WO 98/34918 (published August 13, 1998), WO 98/34915 (published August 13, 1998), and WO 98/33768 (published June 6, 1998). World Patent Application No. WO 98/30566 (published June 16, 1998); European Patent Application No. EP 606046 (Published July 13, 1994); No. 931788 (published Jul. 28, 1999);

No. 90/05719 (published May 31, 1990), WO 99/52910 (published October 21, 1999), and WO 99/52889 (Published

On October 21, 1999), WO 99/29667 (published June 17, 1999), International Patent Application No. PCT / IB98 / 01113 (filed July 21, 1998), European Patent Application No. 99302232.1 (filed May 25, 1999). U.S. Patent Application Serial No. 9912961.1 (filed June 3, 1999); U.S. Patent Application Serial No. 60 / 148,464 (filed August 12, 1999); U.S. Patent No. 5,869,449 (issued January 26, 1999); , U.S. Pat. No. 5,886,110 (issued Jan. 19, 1999) and European Patent Publication No. EP 780386 (published June 25, 1997). Preferred MMP-2 and MMP-9 inhibitors are those that have little or no MMP-1 activity. More preferred are inhibitors that selectively inhibit MMP-2 and / or MMP-9 over 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) benzenesulfonyl] - (1-hydroxycarbamoylcyclopentyl) amino] propionic acid, 3-exo-3- [4- (4-fluorophenoxy) benzenesulfonylamino] -8-oxabicyclo [3.2.1] hydroxyamide octane-3-carboxylic acid, (2R, 3R) -1- [4- (2-chloro-4-fluoro-benzyloxy) benzenesulfonyl] -3-hydroxy-3-methylpiperidine-2-carboxylic acid hydroxyamide, hydroxyamide 4- [ 4- (4-fluorophenoxy) benzenesulfonylamino] tetrahydro-pyran-4-carboxylic acid,

3 - [[4- (4-fluorophenoxy) benzenesulfonyl] - (1-hydroxycarbamoylcyclobutyl) amino] propionic acid, 4- [4- (4-chlorophenoxy) benzenesulfonylamino] tetrahydro-pyran-4-carboxylic acid hydroxyamide, hydroxyamide (R) -3- [4- (4-chlorophenoxy) benzenesulfonylamino] tetrahydropyran-3-carboxylic acid, (2R, 3R) -1- [4- (4-fluoro-2-methylbenzyloxy) benzenesulfonyl] -3-hydroxy-3 hydroxyamide - methylpiperidine-2-carboxylic acid,

3 - [[4- (4-fluorophenoxy) benzenesulfonyl] - (1-hydroxycarbamoyl-1-methylethyl) amino] propionic acid,

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

Other anti-angiogenesis agents, including other COX-II inhibitors and other MMP inhibitors, may also be used according to the invention.

An 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 of skill in the art. The recommended daily dose 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. An 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 the COX-II inhibitor and / or the cdk5 inhibitor in combination may be less than would be required using these compounds individually to achieve the same desired effect in inhibiting abnormal cell growth.

Compounds of Formula I may also be used with signal transduction inhibitors, such as agents that inhibit epidermal growth factor receptor (EGFR) response, 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, for example, HERCEPTIN ™ (Genentech, Inc., South San Francisco, California, USA). Such combinations are useful in the treatment and prevention of abnormal cell growth, including cancer.

EGFR inhibitors are described, for example, in WO 95/19970 (published July 27, 1995), in WO 98/14451 (published April 9, 1998), and in WO 98/02434 (published April 9, 1998). On Jan. 22, 1998) and U.S. Pat. EGFR inhibitory agents include, by way of example and not limitation, monoclonal antibodies C225 and anti-EGFR 22 Mab (ImClone Systems Incorporated, New York, USA), ZD-1839 (Astra Zeneca), BIBX-1382 (Bohringer 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) may be combined with compounds of Formula I. VEGF inhibitors are described, for example, in WO 99/24440 (published Jun. PCT / IB99 / 00797 (filed May 3, 1999); WO 95/21613 (published Aug. 17, 1995); WO 99/61422 ( published December 2, 1999), U.S. Pat

U.S. Patent No. 5,834,504 (issued November 10, 1998), WO 98/50356 (published November 12, 1998), U.S. Patent No. 5,883,113 (issued March 16, 1999), U.S. Pat. U.S. Pat. No. 5,888,020 (issued Mar. 23, 1999), U.S. Pat. No. 5,792,783 (issued August 11, 1998), World Patent Publication No. WO 99/10349 (published Mar. 4, 1999); WO 97/32856 (published September 12, 1997), WO 97/22596 (published June 26, 1997), WO 98/54093 (published December 3, 1998), worldwide patent publication WO 98/02438 (published Jan. 22, 1998), WO 99/16755 (published Apr. 8, 1999) and WO 98/02437 (published Jan. 22, 1998). Other examples of some specific VEGF inhibitors useful for the purposes of the invention are IM862 (Cytran Inc., Kirland, Washington, USA); anti-VEGF monoclonal antibody (Genentech, Inc., South San Francisco, California, USA); and angiozyme, synthetic ribozyme (Ribozyme, Boulder, Colorado, USA) and Chiron (Emeryville, California, USA). These and other VEGF inhibitors may be used for the purposes of the invention.

ErbB2 receptor inhibitors such as GW-282974 (Glaxo Wellcome plc) and AR-209 monoclonal antibodies (Aronex Pharmaceuticals Inc. of The Woodlands, Texas) and 2B-1 (Chiron) may also be combined with compounds of Formula I. for example, the compounds described in WO 98/02434 (published January 22, 1998), WO 99/35146 (published July 15, 1999), WO 99/35132 ( World Patent Publication No. WO 98/02437 (published Jan. 22, 1998); World Patent Publication No. WO 97/13760 (published April 17, 1997); 19970 (published Jul. 27, 1995), U.S. Patent No. 5,587,458 (issued December 24, 1996), and U.S. Patent No. 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 Serial No. 60 / 117,346 (filed Jan. 27, 1999). The compounds and substances of the ErbB2 receptor inhibitor disclosed in the above PCT applications, US patents and US 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.

Compounds of formula I may also be used with other agents effective in the treatment of abnormal cell growth or cancer, including but not limited to, agents capable of promoting an anti-tumor immune response, such as cytotoxic lymphocyte antigen 4 (CTLA4) and other agents capable of blocking CTLA4. ; and antiproliferative agents such as farnesyprotein transferase inhibitors. Specific CTLA4 antibodies that are suitable for the purpose of the invention are described in U.S. Patent Application Serial No. 60 / 113,647 (filed December 22, 1998), but other CTLA4 antibodies may also be used for the purposes of the invention.

The compounds of formula I may also be administered in a method of inhibiting abnormal growth of mammalian cells in combination with radiation therapy. Methods of radiation therapy are known to those skilled in the art and can be used in combination with the methods of the invention. Administration of the 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, a slight decrease in perception and a decrease in perception associated with aging. Specific examples of COX-II for this purpose are described above, wherein the use of a COX-II inhibitor in combination with compounds of Formula I for treating excessive cell growth is described herein. An effective amount of a COX-II 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 dose 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. A 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 the COX-II inhibitor and / or the cdk5 inhibitor combined with each other may be less than would be required using these compounds individually to achieve the same desired effect in the treatment of Alzheimer's disease, slight impairment of perception and decreased perception associated with aging.

Cdk5 inhibitors, such as compounds of formula I, can also be administered in combination with an NK-1 receptor antagonist in the treatment of depression and anxiety.

The NK-1 receptor antagonist is a compound 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 each such NK-1 receptor antagonist is known. 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. Pat. U.S. Pat. No. 5,858,038 (issued December 22, 1998), World Patent Publication No. WO 90/05729 (International Publication May 31, 1990), U.S. Pat. No. 5,807867 (issued September 15, 1998), U.S. Pat. U.S. Pat. No. 5,886,600 (issued Mar. 23, 1999); U.S. Pat. No. 5,939,433 (issued Aug. 17, 1999); US Patent No. 5,773,450 (issued June 30, 1998), US Patent No. 5,744,480 (filed April 28, 1998), US Patent No. 5,232,929 (issued August 3, 1999); 1993), U.S. Patent No. 5,328,117 (issued July 26, 1994), U.S. Patent No. 5,125,225 (issued June 16, 1992), and U.S. Patent No. 5,839,366 (issued December 1, 1998). , U.S. Patent No. 5,702,140 (issued December 30, 1997), U.S. Patent No. 5,719,147 (issued February 17, 1998), and U.S. Patent No. 5,637,699 (issued June 10, 1997). The compounds described in the above publications having NK-1 receptor antagonist activity can be used for the purposes of the invention. However, other NK-1 receptor antagonists may also be used for the purposes of the invention.

An effective amount of a NK-1 receptor antagonist in combination with a cdk5 inhibitor, for example a compound of formula I, can generally be determined by one of skill in the art or by a person skilled in the art. The recommended daily dose of the 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. A 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 NK-1 receptor antagonist and / or cdk5 inhibitor in combination with each other may be less than would be required using these compounds individually to achieve the same desirable effect in treating depression and anxiety.

The invention also relates to the combination of a cdk5 inhibitor, such as a compound of formula I, with a 5HT _1D receptor antagonist for the treatment of depression and anxiety. The 5HT _1D receptor antagonist is a compound that is capable of antagonizing the 5HT _1D serotonin receptor subtype. Any substance described above may be used in combination with a cdk5 inhibitor, for example a compound of formula I. Those skilled in the art are able to determine substances having a 5HT _1D receptor antagonist activity. For example, 5HT _1D receptor antagonists are described in WO 98/14433 (International Publication on April 9, 1998), WO 97/36867 (International Publication)

On October 9, 1997), WO 94/21619 (International Publication September 29, 1994), U.S. Pat. No. 5,510,350 (issued April 23, 1996), U.S. Pat. No. 5,359,448 (U.S. Pat. On October 25, 1994) and British Patent Specification 2 276162 A (published September 21, 1994). Said δΗΤ-β receptor antagonists, like other such antagonists, can be used for the purposes of the invention.

An effective amount of a 5HT _1D receptor antagonist in combination with a cdk5 inhibitor, for example a compound of formula I, can generally be determined by one of skill in the art or by a person skilled in the art. The recommended daily dose of the 5HT _1D receptor antagonist in combination with a cdk5 inhibitor is in the range of about 0.01 to about 40 mg / kg body weight. A 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 instances, the amount of 5HT _1D receptor antagonist and / or cdk5 inhibitor in combination may be less than would be required using these compounds individually to achieve the same desirable effect in treating depression and anxiety.

The invention also relates to a pharmaceutical composition and method for treating depression and anxiety in a mammal by administering to a mammal a cdk5 inhibitor, for example a compound of formula I, and an SSRI. Examples of SSRIs that may be combined in a method or pharmaceutical composition with a cdk5 inhibitor, for example a compound of formula I and a pharmaceutically acceptable salt thereof, include, but are not limited to, fluoxetine, paroxetine, sertraline, and fluvoxamine. Also other SSRIs may be combined or po62 administered in combination with a cdk5 inhibitor, for example a compound of formula I and a pharmaceutically acceptable salt thereof. As other antidepressants and / or anxiolytic agents with a cdk5 inhibitor, for example a compound of formula I, WELLBUTRIN, SERZONE and EFFEXOR may be combined or administered.

An effective amount of an SSRI 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 dose of SSRIs in combination with a cdk5 inhibitor is in the range of about 0.01 to about 500 mg / kg body weight. A 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 SSRI and / or cdk5 inhibitor in combination may be less than would be required using these compounds individually to achieve the same desired effect in the treatment of depression and anxiety.

A cdk5 inhibitor, for example a compound of formula I, or a pharmaceutically acceptable salt thereof, may also be combined with one or more antipsychotic agents, for example, a dopaminergic, for the treatment of diseases or conditions, such treatment may affect or facilitate alteration of dopamine neurotransmission. schizophrenia. Examples of antipsychotic compounds include ziprasidone (5- (2- (4-1,2-benzisothiazol-3-yl) -1-piperazinyl) ethyl) -6-chloro-1,3-dihydro-2H-indole-2- he, U.S. Pat. No. 4,883,1031 and U.S. Pat. No. 5,329,225); olanzapi (2-methyl-4- (4-methyl-1-piperazinyl-10H-thieno (2,3b) (1,5) benzodiazepine, U.S. Pat. No. 4,15574 and U.S. Pat. No. 5,229,382); risperidone (3- [2- [4- (6-fluoro-1,2-benzisoxazol-3-yl) -1-piperidinyl] ethyl] -6,78,9-tetrahydro-2-methyl-4H-pyrido [1, 2-a] pyrimidin-4-one, U.S. Pat. No. 5,484,466; L-745870 (3- (4- (4-chlorophenylpiperazin-1-yl) methyl-1H-pyrrolo (2,3-b) pyridine) sonepiprazole (S- (4- (4- (2-isochroman-1-yl) ethyl) piperazin-1-yl) benzenesulfonamide, U.S. Pat. No. 5,877,317); 62203 (Fananserin, 2- (3- (4- (4-fluorophenyl) -1-piperazinyl) propyl) naphtho (1,8-cd) isothiazole-1,1-dioxide, U.S. Pat. No. 5,022,120) NGD 941 U.S. Patent No. 5,633,376 and U.S. Patent No. 5,428,165) balaperidone (1α, 5α, 6α) -3- (2- (6- (4-fluorophenyl) -3-azabicyclo (3.2.O) hept) -3-yl) ethyl-2,4 (1H, 3H) quinazolinedione of US patents U.S. Pat. No. 4,475,105) flesinoxane ((+) - 4-fluoro-N- [2- [4,5- (2-hydroxymethyl-1,4-benzodioxanyl) -1-piperazinylethyl] benzamide, U.S. Pat. 4,833,142); and gepirone (4,4-dimethyl-1- (4- (2-pyrimidinyl) -1-piperazinyl) butyl) -2,6-piperidinedione, U.S. Pat. No. 4,430,449). An 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 aforementioned 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 the treatment of 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 using these compounds individually to achieve the same desirable effect in treating depression and anxiety.

The invention also encompasses combinations of a cdk5 inhibitor, for example a compound of formula I, with another antipsychotic or dopaminergic agent as described above.

The recommended daily dose of sonepiprazole in the combination described above with a cdk5 inhibitor, for example a compound of 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 balape64 ridon in such a combination is in the range of about 1 to about 100 mg / kg body weight. The recommended daily dose of flesinoxane 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 combination is in the range of about 0.01 to about 250 mg / kg body weight, preferably in the range of about 0.05 to about 100 mg / kg 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 body weight. The recommended daily dose of olanzapine in such combination is in the range of about 0.0005 to about 0.6 mg / kg 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 body weight. However, in some cases of the above combinations, the amount of each specific agent in combination with each other may be less than would be required using these compounds individually to achieve the same desired effect in the treatment of a psychotic condition.

The invention also relates to a pharmaceutical composition and a method of treating disorders of the Alzheimer's disease, a slight deterioration of consciousness and an age-related decrease in consciousness, wherein a cdk5 inhibitor, for example a compound of formula I, and an acetylcholinesterase inhibitor are administered to mammals. 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 may be used for the purposes of the invention include, but are not limited to, ARICEPT (donepezil, U.S. Pat.

895 841); EXELON (rivastigmine, (S) - [N-ethyl-3- [1- (dimethylamino) ethyl] phenyl) carbamate, U.S. Pat.

603176 and U.S. Pat. No. 4,948807); phosphonate (2,2,2-trichloro-1-hydroxyethyl) phosphonic acid dimethyl ester, U.S. Pat. No. 2,701,225 and U.S. Pat. No. 4,950,658); galantamine, U.S. Patent No. 4,666,118); physostigmine (Forest, USA); tacrine (1,2,3,4-tetrahydro-9-acridinamine, U.S. Pat. No. 4,816456); huperzine A (5R- (5a, 9β, 11E)) -5-amino-11-ethylidene-5,6,9,10-tetrahydro-7-methyl-5,9-methanocycloocta (b) pyridine-2- (H) ) on); 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 Publication No. WO 92/17475).

An 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 dose 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. A 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 the acetylcholinesterase inhibitor and / or the cdk5 inhibitor in combination may be less than would be required using these compounds individually to achieve the same desired effect in the treatment of Alzheimer's disease, mild deterioration of consciousness and age-related decline in consciousness.

The invention also relates to combinations of 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, amyotropic lateral sclerosis or pain, pain, pain, pain AIDS-induced dementia, migraine, hypoglycaemia, urinary incontinence, cerebral ischemia, multiple sclerosis, Alzheimer's disease, senile dementia of the Alzheimer's type, mild disturbance of consciousness, s; age-related decline in consciousness, emesis, corticobasal dege66 do not revert, pugilistica dementia, Down's syndrome, myotonic dystrophy, Niemann-Pick disease, Pick's disease, prion disease with dizziness, progressive supranuclear paralysis, lower lateral sclerosis and subacuteence. Examples of NMDA receptor antagonists that can be used in the present invention include (1S, 2S) -1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenylpiperidin-1-yl) -1-propanol (U.S. Pat. U.S. Pat. No. 5,271,260); eliprodil (U.S. Patent 4,690,931); and gavestenel (U.S. Pat. No. 5,373,018). Other NMDA receptor antagonists which can 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. 5,227,260; U.S. Patent No. 5,185,343; U.S. Patent No. 5,356,905; U.S. Patent No. 5,744,483; WO 97/23216; WO 97/23215; WO 97/23214; WO 96/37222; WO 96/06081; WO 97/23458; WO 97/32581; WO 98/18793; WO 97/22202; No. 08/292651 (filed Aug. 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, for example a compound of Formula I, for the treatment of the above disorders, for example 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 using these compounds individually to achieve the same desired effect in the treatment of the above disorders.

The invention also relates to the combination of a cdk5 inhibitor with certain substances suitable for the treatment of stroke or traumatic brain injury, such as TPA, NIF or potassium channel modulators, for example BMS-204352. Such combinations are useful in the treatment of neurodegenerative disorders such as stroke, spinal cord trauma, traumatic brain injury, multi-infarct dementia, epilepsy, pain, Alzheimer's disease and senile dementia.

For the aforementioned 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 aforementioned compounds and other known or described agents described in the aforementioned patent literature. The compositions and routes of administration for such therapies and compositions are based on the compositions and therapies information described herein 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 may be assessed with respect to inhibition of cdk2, cdk5 or GSK-3 by bioassays known to those skilled in the art and, for example, by the assays described below.

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

Enzyme activity can be assessed as incorporation of [ ³³ P] from gamma phosphate [ ³³ P] ATP (Amersham, Cat. No. AH-9968) into the biotinylated peptide substrate PKTPKKAKKL. In such a test, the reactions are carried out in a buffer containing 50 mM

Tris-HCl, pH 8.0; 10 mM magnesium chloride, 0.1 mM Na ₃ VO ₄ and 1 mM DTT. The final ATP concentration is approximately 0.5 μΜ (final specific radioactivity 4μ0ί / ηιηο1) 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 performed 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% tritone-X 100, 100 μΜ ATP and 1.25 mg / ml streptavidin-coated SPA beads (Amersham, Cat. RPNQ0007). The radioactivity associated with the beads is quantified by scintillation counting.

The specific activity of the compounds of formula I for inhibiting GSK-3 can be determined from cell-based and cell-based assays. Cell-free assays can be performed generally by incubating GSK-3 with a peptide substrate, with radiolabeled ATP (e.g., gamma ³³ P- or gamma ^32- P-ATP, commercial products of the company (Amersham, Arlington Heights, Illinois), with magnesium ions and The mixture is incubated for the time required to incorporate radiolabeled phosphate into the peptide substrate by GSK-3 activity, and the reaction mixture is washed to remove unreacted radiolabeled ATP as a rule after transferring all or part of the enzyme reaction mixture to a well containing uniform amounts of Uganda. The amount of ³³ P or ³² P remaining in the well after washing is then quantitated to determine the amount of radiolabeled phosphate in the peptide substrate Inhibition is observed as a decrease, with respect to control, incorporation of radiolabeled phosphate into the peptide substrate. An example of a suitable GSK-3 peptide substrate for the assay is the SGSG-linked CREB peptide sequence derived from the Creb DNA-bound protein (Wang et al., Anal. Biochem. 220, p. 397-402, 1994). For example, purified GSK-3 for the assay can be obtained from cells transfected with a human GSK-3β expression plasmid (e.g., Stambolic et al., Current Biology 6, pp. 1664-1668, 1996; WO 99/65897).

Another example of the GSK-3 assay is similar to that described above. Enzyme activities were assessed as incorporation of [ ³³ P] from gamma phosphate [ ³³ P] ATP (Amersham, Cat. No. AH-9968) into the biotinylated peptide substrate PKTPKKAKKL. In such a test, the reactions are carried out in a buffer containing 50 mM Tris-HCl, pH 8.0; 10 mM magnesium chloride, 0.1 mM Na ₃ VO ₄ and 1 mM DTT. The final ATP concentration is approximately 0.5 μΜ (final specific radioactivity 4μΟΐ / ηιηο1) and the final substrate concentration is 0.75 μΜ. The reaction initiated by the addition of the enzyme 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% tritoneX 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.

All compounds of the following examples have an IC ₅₀ inhibiting peptide substrate phosphorylation of less than about 50 μΜ according to the cdk5 inhibition assays described above.

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

The following examples illustrate the invention but do not limit it in any way.

DETAILED DESCRIPTION OF THE INVENTION

Preparation 11 1-Cyclobutyl-4-nitro-1H-imidazole

1,4-Dinitroimidazole (237 mg, 1.5 mmol) (J. Phys. Chem.

99, p. 5009-5015 (1995) was added to a solution of cyclobutylamine (107 mg, 1.5 mmol) in methanol (10 mL) at 23 ° C. The reaction mixture was stirred for 16 hours, the solvent was removed in vacuo and the residue was purified by silica gel chromatography (1: 1 hexanes-ethyl acetate) to give 230 mg (92% yield) of 1-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) &lt; ^{+ &gt};.

Note: 1,4-Dinitroimidazole is a high-energy, semi-stable substance and should be stored in the freezer when not in use. Thermodynamic measurements have shown that it can potentially generate enough energy at 35 ° C under adiabatic explosion conditions. When using 1,4-dinitroimidazole, extreme caution must always be exercised!

Preparation 2 1-Cyclopentyl-4-nitro-1H-imidazole

This compound was prepared by 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 δ 7.77 (s, 1H), 7.45 (s, 1H), 4.49 (m, 1H), 2.25 (m, 2H) 2.0 to 1, MS (AP / Cl): 182.2 (M + H) &lt; ^{+ &gt};.

Preparation

4-Nitro-l- (cis-3-phenyl-cyclobutyl) -lH-imidazole

This compound was prepared by the method of Preparation 1 using cis-3-phenylcyclobutylamine (J. Med. Pharm. Chem.

2, p. 687-691, 1960; ACIEE 20, p. 879-880 (1981) and 1,4-dinitroimidazole to give 46 mg (46% yield) of 4-nitro-1- (cis-3-phenylcyclobutyl) -1H-imidazole. 1 H NMR (300 MHz, CDCl ₃ ) 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). WCH (AP / C1):

244 (M + H) &lt; ^{+ &gt};.

Example 1

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

To a Parr hydrogenation flask was charged 1-cyclobutyl-4-nitro-im-imidazole (Preparation 1, 150 mg, 0.9 mmol) and ethyl acetate (10 mL) followed by 10% palladium on carbon (250 mg). The reaction mixture was charged to a Parr hydrogenation unit and allowed to react for 6 hours under 50 psi of hydrogen at 23 ° C. Filter the contents of the flask through a thin pad of celite and rinse 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. Add 6-quinolylacetic acid (168 mg, 0.9 mmol) and tripropylphosphonic anhydride (530 μΐ, 1.7 M in ethyl acetate) and stir at -10 ° C for two hours. 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 connection (40: 1 methylene chloride-methanol system) to give 130 mg (47% yield) of N- (1-cyclobutyl). imidazol-4-yl) -2-quinolin-6-yl-acetamide.

1 H NMR (300 MHz, CDCl ₃ )? 5 Hz, 1H), 8.11 (m, 2H), 7.76

8.7 Hz, 1H), 7.44 (d, J = 1.6)

Hz, 1H), 4.5 (m, 1H), 3.90 MS (AP / C1): 307.1 (M + H) &lt; ^{+ &gt};

9.48 (s, 1H), 8.87 (dd, J = 1.6, 4.3, d, J = 1.8 Hz, 1H), 7.67 (dd, J = 2.0, Hz) 1H, 7.38 (m, 1H), 7.25 (d, J = 1.6 (s, 2H), 2.5 (m, 2H), 1.85 (m, 2H);

Example 2

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

This compound was prepared according to the procedure for 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). 1 H NMR (400 MHz, δ 8.54 (s, 1H), 7.35 (s, 1H),

7.24 (m, 2H), 6.87 (d, J = 1.7 Hz), 4.36 (m, 1H), 3.78 (s, 3H),

3.64 (s, 2H), 2.2 (m, 2H), 1.8 (m, 4H), 1.6 (m, 2H);

MS (AP / Cl): 300.3 (M + H) &lt; ^{+ &gt};. _____ _________

Example 3

N- [1- (cis-3-Phenylcyclobutyl) -lH-imidazol-4-yl] -2-quinolin-6ylacetamid

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 (3% yield); 1 H NMR (300 MHz, CDCl ₃ )? 8.93 cm 3, 1H), 8.12 (m, 2H), 7.79 (d, J = 1.5 Hz, 1H), 7.71 (m, 1H) 7.55 (d, J = 1.5 Hz, 1H), 7.41 (dd, J = 4.3, 8.4 Hz, 1H), 7.37-7.22 (m, 5H) 4.57 (m, 1H); 3.96 (s, 2H); 3.33 (m, 1H); 2.95 (m, 2H); 2.49 (m, 2H);

MS (AP / Cl): 383.0 (M + H) &lt; ^{+ &gt};.

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

A Parr hydrogenation flask was charged with 1-cyclobutyl-4-nitro-1H-imidazole (Preparation 1.3 g, 18 mmol) and ethyl acetate (70 mL) followed by 10% palladium on carbon (1.2 g) under nitrogen. The reaction mixture is hydrogenated at 23 ° C for 6 hours under hydrogen pressure. Filter the mixture through a celite pad and rinse with dry methylene chloride (140 mL) into a flame dried flask. The resulting solution was cooled to -78 ° C and diisopropylethylamine (2.3 g, 18 mmol) and phenyl chloroformate (2.5 g, 16.2 mmol) were added dropwise. After 30 minutes, 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 (2 x 10 mL). Combine the organic layer, wash with brine (2x), dry over magnesium sulfate, filter, and concentrate in vacuo. The crude product was adsorbed onto silica gel and purified by silica gel chromatography (1: 1 hexanes-ethyl acetate system) to give 3 g (65% yield) of carbamic acid (1-cyclobutyl-1H-imidazol-4-yl) -phenyl ester. 1 H NMR (400 MHz, CDCl ₃ ), δ 7.4-7.3 (m, 2H), 7.227.18 (m, 4H), 4.5 (m, 1H), 2.46-2.30 ( m, 4H), 1.83 (m, 2H); MS (AP / Cl): 258.2 (M + H) &lt; ^{+ &gt};.

Example 5

1- (l-cyclobutyl-lH-imidazol-4-yl) -3-isoquinolin-5-yl-urea

To a 1 gram screw cap vial 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 1: 1 dioxane-dimethylformamide (1 mL). The reaction mixture was maintained at 10 ° 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-yl-urea.

1 H NMR (400 MHz, CD ₃ OD), δ 9.21 (d, J = 1.7 Hz, 1H), 8.45 (d, J = 6.2)

Hz, 1 H), 8.24 (d, J = 7.5 Hz, 1 H), 7.98 (d, J = 5.4 Hz, 1 H), 7.84 (dd, J = 2, 3.8 (1H, 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-Azidocyklobutyl) -lH-imidazol-4-yl] -2-naphthalen-l-yl-acetamide

Stage 1

3-Benzylaxycyclobutylamine (43.4 g, 245 mmol), Chem. 90, p. 1424-1432 (1957) was dissolved in a saturated methanolic hydrogen chloride solution (450 mL), then 10% palladium on carbon (4 g) was added. The mixture was hydrogenated for 6 hours under 50 psi of hydrogen. The mixture was filtered and concentrated in vacuo to give about 35 g of an oil. The oil was taken up in methanol (600 mL), cooled to 0 ° C and treated with potassium hydroxide (13.7 g, 245 mmol). When it reaches pH 10, a solution of 1,4-dinitroimidazole (42.7 g, 270 mmol) in methanol (200 mL) (prepared by dissolving 1,4-dinitroimidazole in methanol at 0'C) is added.

Note: 1,4-Dinitroimidazole is a high-energy, semi-stable substance and should be stored in the freezer when not in use. Thermodynamic measurements have shown that it can potentially generate enough energy at 35 ° C under adiabatic explosion conditions. Always use extreme caution when using 1,4-dinitroimidazole.

The resulting orange suspension was allowed to warm slowly to 23 ° C overnight. The solvent was removed in vacuo and the resulting residue was purified by passing through a large pad of silica gel (20: 1 chloroform-methanol system) to give 19 g (42% yield) of 3- (4-nitroimidazol-1-yl) cyclobutanol as a 1: 1 cis-transisomers. 1 H NMR (400 MHz, CD ₃ OD), 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 hours. Thin layer analysis showed two new spots. The reaction mixture was diluted with methylene chloride and washed with water (1x) and brine (1x). 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) allows separation of the trans- and cis-diastereomers. The first elution spot (high Rf) is the trans-isomer, trans-toluene-4-sulfonic acid 3- (4-nitroimidazol-1-yl) cyclobutyl ester (2.7 g, 37% yield). 1 H NMR (400 MHz, CD 3 OD), 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.

Stage 3

Mix trans -toluene-4-sulfonic acid 3- (4-nitroimidazol-1-yl) cyclobutyl ester (Preparation 4, Step 2, 590 mg,

1.75 mmol) with 10% palladium on carbon (500 mg) in ethyl acetate (30 mL). The mixture was reacted under a hydrogen pressure of 50 psi for six hours at room temperature. The mixture was filtered through celite into a flame-dried flask maintained under nitrogen. Add triethylamine (1.22 mL, 8.75 mmol) followed by 1-naphthylacetic acid (326 mg, 1.75 mmol) and tripropylphosphonic acid amide 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 resulting residue was purified by silica gel chromatography (50: 1 chloroform-methanol system) to give 600 mg (72% yield) of 3- [4- (2-naphthalen-1-ylacetylamino) imidazol-1-yl] cyclobutyl ester trans-toluene- Of 4-sulfonic acid. 1 H NMR (400 MHz, CDCl ₃ ) δ 7.9 (m, 2H), 7.85 (m, 2H), 7.7.6 (d, J = 8.3 Hz, 2H), 7.48 (m. 2H). 7.42 (m,

2H), 7.33 (m, 2H), 7.04 (s, 1H). 4.98 (m, 1H), 4.73 (m, 1H), 2.7 (m, 4H). 2.44 (s, 3H); MS (AP / CI): 476.2 (M + H) &lt; + &gt;. Step 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 maintained at reflux for 96 hours with stirring. 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 obtained residue was purified by silica gel chromatography (50: 1 chloroform-methanol system) to obtain 340 mg (yield 79%).

N- [1-cis-3-azidocyclobutyl] -1H-imidazol-4-yl] -2-naphthalen-177

ylacetamide. 1 H NMR (400 MHz, CDCl ₃ ) δ 8.41 (s, 1H), 7.98 (d, J = 6.4 Hz, 1H), 7.87 (m, 1H), 7.82 (m, 1H), 7.5 (m, 2H), 7.45 (m, 3H), 7.08 (d, J = 1.7Hz, 1H), 4.2 (m, 3H), 3.75 (m / z), 2.85 (m, 2H), 2.35 (m, 2H); MS (AP / CI): 347.2 (M + H) &lt; + &gt;;'

Example 6

N- [l-cis-3-aminocyclobutyl) -lH-imidazol-4-YLJ-2-naphthalen-l-yl-acetamide

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

1 H NMR (400 MHz, CD 3 OD) δ 8.05 (d, J = 7.5 Hz, 1H), 7.87 (d, J = 7.9 Hz, 1H),

7.79 (d, J = 9.0 Hz, 1H), 7.45 (m, 5H), 7.35 (s, 1H), 4.26 (m, 1H), 4.16. (s, 2H); 3.29 (m, 2H);

3.16 (m, 1H), 2.75 (m, 2H), 2.1 (m, 2H); MS (AP / CI): 321.3 (M + H) &lt; + &gt;.

Example 7a 6-Methyl-pyridine-2-carboxylic acid {cis-3- [4- (2-naphthalen-1-ylacetylamino) -imidazol-1-yl] -cyclobutyl} -amide

A solution of 6-methyl-picolinic 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 23 ° C. After stirring for 10 minutes, N- [1-cis-3-aminocyclobutyl) -1H-imidazol-4-yl] -2-naphthalen-1-yl-acetamide (Example 6, 20 mg, 0.06 mmol) was added. 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 (MgSO 4), filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (20: 1 chloroform-methanol) to give 26 mg (yield 95%) of {cis-3- [4- ( 6-Methyl-pyridine-2-carboxylic acid 2-naphthalen-1-yl-acetylamino) -imidazol-1-yl] -cyclobutyl-amide.

1 H NMR (400 MHz, CDCl ₃ ) δ 9.15 (s, 1H), 8.28 (d, J = 8.3 Hz, 1H), 8.01 (d, J = 7.5 Hz, 1H) 7.96 (d, J = 7.5 Hz, 1H), 7.97 (d, J 7.5 Hz, 1H), 7.81 (dd, J = 2.4, 6.6 Hz, 1H), 7.72 (m, 1H), 7.5 (m, 5H), 7.2 (m, 1H), 7.16 (s, 1H), 4.45 (m, 1H), 4, 25 (m, 1H); 4.18 (s, 2H); 2.98 (m, 2H); 2.60 (s; 3H); 2.40 (m, 2H); MS (AP / Cl): 440.3 (M + H) &lt; + &gt;.

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

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

CD 3 OD) δ 8.06 (d, J = 7.9 Hz, 1H), 7.87 (m, 1H), 7.80 (d, J = 7.5 Hz, 1H), 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) &lt; + &gt;.

Example 7c 6-Hydroxypyridine-2-carboxylic acid {cis-3- [4- (2-naphthalen-1-ylacetylamino) -imidazol-1-yl] -cyclobutyl} -amide

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

CD3OD) δ 8.12 (d, J = 7.9 Hz, 1H), 7.84 (d, J = 7.9 Hz, 1H). 7.79 (d, J = 7.5Hz, 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,

H, 4.17 (s, 2H), 2.93 (m, 2H), 2.5 (m, 2H); MS (AP / CI): 442.3 (M + H) &lt; + &gt;.

Example 7d 3-Methyl-pyridine-2-carboxylic acid {cis-3- [4- (2-naphthalen-1-ylacetylamino) -imidazol-1-yl] -cyclobutyl] -amide

Prepared in analogy to Example 7a; 1 H NMR (CD ₃ OD 400 MHz) δ 8.39 (d, J = 4.2 Hz, 1H), 8.06 (d, J = 8.3 Hz, 1H), δ 17 (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) 4/7 (s, 2H), 2.92 (m, 2H), 2.54 (s, 3H), 2.46 (m, 2H); MS (AP / Cl): 440.3 (M + H) &lt; + &gt;.

Example 7e 2-Pyridin-3-yl-thiazole-4-carboxylic acid {cis-3- [4- (2-naphthalen-1-ylacetylamino) -imidazol-1-yl] -cyclobutyl} -amide

Prepared in analogy to Example 7a; 1 H NMR (400 MHz, CD 3 OD) 9.21 (d, J = 2 H, 1 H), 8.61 (d, J = 5.0 Hz, 1 H), 8.41 (dd, J = 1) 7.7 (7.9, 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), 4/4 (m, 2H), 4.17 (s, 2H), 2.9 (m, 2H) 2.6 (m, 2H); MS (AP / CI): 509.3 (M + H) &lt; + &gt;.

Example 7f

6- {cis-3- [4- (2-Naphthalen-1-ylacetylamino) imidazol-yl] cyclobutylcarbamoyl} nicotinic acid methyl ester

Prepared in analogy to Example 7a; 1 H NMR (400 MHz, CD 3 OD) 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) .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), 7/9 (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) m, 2H); MS (AP / CI): 427.3 (M + H) &lt; + &gt;.

Example 7g Pyrazine-2-carboxylic acid {cis-3- [4- (2-naphthalen-1-ylacetylamino) -imidazol-1-yl] -cyclobutyl] -amide

Prepared in analogy to Example 7a; 1 H NMR (400 MHz

CD3OD / CDCl ₃ ) δ 9.15 (d, J = 1.5 Hz, 1H), 9.12 (d, J = 8.0 Hz, 1H), 8.45 (dd, J = 2.0, 8, 4 Hz, 1H), 8.16 (d, J = 8.0 Hz, 1H), 8.02 (d, J = 8.4 Hz, 1H), 7.85 (d, J = 8.0 Hz) 1 H), 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) &lt; + &gt;.

Example 7h

N- {cis-3- [4- (2-Naphthalen-1-ylacetylamino) imidazol-1-yl] cyclo butyl} benzamide

Prepared in analogy to Example 7a; 1 H NMR (400 MHz CD 3 OD) δ 8.05 (d, J = 8.3 Hz, 2H), 7.99 (d, J = 7.1 Hz, 1H), 7.86 (d, J = 7) 1.5 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-Methyl-pyrazine-2-carboxylic acid {cis -3- [4- (2-naphthalen-1-ylacetylamino) -imidazol-1-yl] -cyclobutyl} -amide

Prepared in analogy to Example 7a; 1 H NMR (400 MHz

CD 3 OD) δ 9.07 (d, J = 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, 1 H), 7.79 (d, J = 7.6 Hz, 1 H), 7.45 (m, 6 H), 4.40 (m, 2 H), 4.16 (s, 2 H) 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-Naphthalen-1-ylacetylamino) imidazol-1-yl] cyclobutyl} i z obutyramide

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

CD 3 OD) 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 = 6.6Hz, 6H); MS (AP / CI): 391.1 (M + H) &lt; + &gt;.

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

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

CD3OD) δ 8.07 (d, J = 7.9Hz, 1H), 8.03 (d, J = 7.5Hz, 1H), 7.94 (m; 1H), 7.87 (d, J = 7.9) · Hz, 1 H, 7.81 (d, J = 7.9 Hz, 1H), 7.61 (d, J = 7.1 Hz, 1H), 7.58 (s, 1H). Δ> 5 (m, 5H), 4.45 (m, 1H),

4.39 (m, 1 H), 4.18 (s, 2 H), 2.89 (m, 2 H), 2.63 (m, 2 H); MS (AP / CI): 460.2 / 462.2 (M + H) &lt; + &gt;.

Example 8

N- [1- (cis-3-Aminocyclobutyl) -1H-imidazol-4-yl] -2-naphthalen-1-ylacetamide (Example 6) is acylated with various carboxylic acids and the products purified in this way;

A solution of N- [1- (cis-3-aminocyclobutyl) -1H-imidazol-4-yl] -2-naphthalene is added to a carboxylic acid (RCO ₂ H, 1 eq, 0.075 mmol) in a 1 gram screw vial. 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 at 23 ° C for 24 hours. Note: If the acid is not soluble in methylene chloride, add N, N-dimethylformamide (0.5 ml).

Each reaction mixture was transferred with methylene chloride (0.5 mL) into a 3 mL SPE capsule (20 micron frit) with a tared 2 gram solvent vial. The solvent was passed through a 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 in a stream of nitrogen and the crude product was analyzed by LCMS (column: 3.9x150 mm Waters Symmetry C ₁₈ 5 μΜ; flow rate 10 ml / min; solvent system: A = 0.1% aqueous trifluoroacetic acid;

B = acetonitrile; linear gradient of 10 to 100% B over 10 minutes). Once the mother ion (M + H) appears, the crude reaction mixture is purified by preparative HPLC (column: 30x150 mm Waters Symmetry C ₁₈ 5 μΜ; flow rate 20 ml / min; solvent system: A = 0.1% aqueous trifluoroacetic acid) acid: B = acetonitrile; linear gradient 0 to 100% B over 15 minutes) and the appropriate fractions are determined in-line by mass spectrometer. The purity of the chromatographed compound is determined by analytical HPLC (column: 2.1x150 mm Waters Symmetry C ₁₈ 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 a diode beam for detection.

The following compounds were prepared as described and their mass spectrometry data and chromatographic retention times are shown in Table I:

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

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

Example 8c: N- {cis-3- [4- (2-naphthalen-1-ylacetylamino) imidazol-1-yl] cyclobutyl} -2-m-tolyl acetamide.

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] cyclobutyl} acetamide.

Table I

Acylated products, associated retention times and mass spectrometry values

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

Preparation

4- {3- [4- (2-Naphthalen-1-ylacetylamino) imidazol-1-yl] cyclobutylcarbamoyl} piperidine-1-carboxylic acid 9H-fluoren-9-ylmethyl 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 minutes, 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 (system 50: 1: 0.5 chloroform-methanol-acetic acid) to give 340 mg (yield 97%) of N- (1-fluorenylmethyloxycarbonyl) -4-piperidinylcarboxylic acid.

1 H NMR (400 MHz, CDCl ₃ ) d 7.75 (d, J = 7.1 Hz, 2H), 7.55 (d, J = 7.5 Hz, 2H), 7.39 (m, 2H) .

7/0 (m, 2H), 4.4 (brs, 2H), 4.23 (t, J = 6.5 Hz, 1H), 3.9 (brd, 2H), 2.9 (brs, 2H), 2.52 (m, IH);

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

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) -9H-fluoro-9-ylmethyl ester. ) -imidazol-l-yl] cyclobutylcarbamoyl} -piperidine-l-carboxylic acid.

1 H NMR (400 MHz, CD 3 OD) δ 8.0 (d, J = 8.3 Hz, 1H), 7.83 (m,

H), 7.78 (dd, J = 2.07, 7.5 Hz, 1H), 7.73 (d, J = 7.5 Hz, 2H), 7.53 (d, J = 6, 6 Hz, 2H), 7.44 (m,

5H), 7.35 (m, 3H), 7.27 (m, 2H), 4.4 (brs, 2H), 4.2 (m, 1H), 4.15 (m, 5H), 2 85 (m, 4H), 2/5 (m, 3H), 1.7 (brs, 2H), 1.5 (brs, 2H); MS (AP / Cl); 65-8 (M + H) +.

Example 9 Piperidine-4-carboxylic acid {cis -3- [4- (2-naphthalen-1-ylacetylamino) imidazol-1-yl] cyclobutyl] amide hydrochloride

4- {3- [4- (2-Naphthalen-1-ylacetylamino) imidazol-1-yl] cyclobutylcarbamoyl} piperidine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester (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 obtained residue was purified by silica gel chromatography (4: 1: 0.08 chloroform-methanol-ammonium hydroxide system) 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-one]. yl] cyclobutyl} amide piperidine-4-carboxylic acid hydrochloride.

¹ H NMR (400MHz, CD 3 OD) δ8.01 (d, J = 8.0)

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 ,.

H, 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 _{out of} 69 (m, 2H), 1.55 (m, 2H); MS (AP / Cl): 432 (M + H) &lt; + &gt;.

Preparation 6

Isoquinolin-5-ylacetic acid

Stage 1

5-Aminoisoquinoline (5.0 g, 34.7 mmol) was stirred with 48% aqueous hydrogen bromide (65 mL) at -78 ° C for 15 min. Sodium nitrite (3.1 g, 45 mmol) in water (6 mL) was added dropwise. After stirring at -78 ° C for 15 minutes, the mixture was allowed to warm to 0 ° C. Copper powder (0.3 g) is added very slowly to prevent excessive foaming. After addition, the reaction vessel was equipped with a reflux condenser and held at 100 ° C for four hours. The mixture was poured onto ice (about 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 (yield 53%) of 5-bromoisoquinoline. 1 H NMR (400 MHz, CD ₃ OD) &

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) &lt; ^{+ &gt};.

Stage 2

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

CDCl ₃ ) δ 9.25 (s, 1H), 8.54 (d, J = 5.8 Hz, ΪΗ), 7.85 (m, 1H), 7.79 (d, J = 5, 8 Hz, 1H), 7.56 (m,

2H), 6.1 (m, 1H), 5/15 (m, 1H), 595 (m, 1H), 3.81 (d, J = 6 / 2Hz, 2H); MS (AP / Cl): 170.1 (M + H) &lt; + &gt;.

Stage 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) were treated with dimethylpolyethylene glycol (Mn approximately 500, 95) μΐ, 100 mg, 0.2 mmol) in methylene chloride (1 mL) at 23 ° C. The mixture was cooled to 0 ° C and powdered potassium permanganate (521 mg, 3.3 mmol) was added in portions keeping the temperature below 30 ° C. After stirring vigorously for 18 hours, 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 basified with sodium carbonate (pH = 9). Extract the mixture with ethyl acetate, wash the resulting organic layer with brine, dry with magnesium sulfate, filter, and concentrate in vacuo. The residue was purified by silica gel chromatography (2: 1 hexanes-ethyl acetate system) to give isoquinolin-5-ylacetic acid methyl ester.

@ 1 H 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 5.8 Hz, 1H), 7.66 (d, J = 5.8 Hz, 1H), 7.59 (t, J = 7, B-Hz, 1H), 4.06 ( s, 2H), 3.70 (s, 3H); MS (AP / Cl): 202.1 (M + H) &lt; + &gt;. .....

Note: After chromatography on silica gel, the product contains approximately 20% 5-isoquinolylcarboxaldehyde as an impurity.

Stage 4

Isoquinolin-5-ylacetic acid methyl ester (Preparation 6, Step 3, 90 mg, 0.448 mmol) was treated with aqueous sodium hydroxide solution (4N, 3 mL) and held 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 0 ° C overnight (about 15 hours) and the precipitate was filtered off and washed with water, and the solid was air dried to give 35 mg (47% yield) of isoquinolin-5-ylacetic acid. 1 H NMR (400 MHz,

CD 3 OD) 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 = 6.6Hz, 1H). 7.66 (t, J = 7.6Hz, 1H), 4.11 (s, 2H); MS (AP / Cl). 188.3 '(M + H) +.

Preparation 7

N- [cis -3- (4-nitro-lH-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 mixed with sodium azide (7g, 107 mmol) in the system. ethanol (100 mL), water (35 mL) and chloroform (20 mL). The mixture is maintained at reflux for 24 hours. 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 (yield 99%) of 1- (3-cis-azidocyclobutyl) -4-nitro-1H-imidazole. 1 H NMR (400 MHz, CDCl ₃ ) δ 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) &lt; ^{+ &gt};.

Step 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 at room temperature for 18 hours. The solvent was removed in vacuo and the residue was purified by silica gel chromatography (20: 1: 0.4 chloroform-methanol-ammonium hydroxide system) to give 1.95 g (yield 100%) of 1- (3-cis-aminocyclobutyl). ) -4-nitro-lH-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) &lt; ^{+ &gt};.

Step 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 (yield 96%)

N- [cis -3- (4-nitro-lH-yl) cyclobutyl] acetamide.

1 H NMR (400 MHz, CD ₃ OD) 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) &lt; ^{+ &gt};.

Preparation

N- [cis -3- (4-nitro-imidazol-l-yl) cyclobutyl] -benzamide

N- [cis-3- (4-nitroimidazol-1-yl) cyclobutyl] benzamide was prepared in analogy to Preparation 7;

1 H NMR (400 MHz, CD 3 OD) δ 8.36 (s, 1H), 7.85 (ni, 3H), 7.p5 (m, 1H), 7.47 (m, 2H), 4.65 (s) m, 1H), 4.44 (m, 1H), 3.05 (m, 2H), 2.60 (m, 2H), MS (AP / Cl):

287.3 (M + H) &lt; + &gt;.

Preparation 9 Pyridine-2-carboxylic acid [cis-3- (4-nitroimidazol-1-yl) cyclobutyl] amide [c is -3- (4-Nitroimide from o1-ΙΗ-yl) cyclobutyl] mid] pyridine acids -2-carboxylic acid was prepared analogously to Preparation 7;

1 H 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 / (M + H) &lt; + &gt;.

Example 9a

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

N- [cis-3- (4-nitroimidazol-1H-yl) cyclobutyl] acetamide (Preparation 7, 50 mg, 0.22 mmol) was hydrogenated and acylated

2-naphthylacetic acid as in Example 1 to give 35 mg (yield 44%) of N- [1- (cis-3-acetylaminocyclobutyl) -1H-imidazol-4-yl] -2-naphthalen-2-ylacetamide.

. @ 1 H NMR (400 MHz, CD3 OD) .delta. 8.05 (d, J = 6 Hz, 1H), 7.87 (d, J = 7.6 Hz, 1H), 7 _; 81 (d, J = 6.4 Hz, 1 H), 7.48 (m, 5 H), 7/7 (s, 1 H), 4.41 '(m, 1 H), 4/7 (s, 2 H) 4.12 (m, 1H); 2.84 (m, 2H); 2.27 (m, 2H); 1.89 (s, 3H); MS (AP / CI): 363.3 (M + H) &lt; + &gt;.

Example 9b

N- {cis-3- [4- (2-isoquinolin-5-ylacetylamino) imidazol-1-yl] cyclobutyl} benzamide

This compound was prepared analogously to Example 9a using Preparation 8 and isoquinolin-5-yl-acetic acid (Preparation 6). 1 H NMR (400 MHz, CD ₃ OD) 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 / Cl): 426 / (M + H) &lt; + &gt;.

Example 9c Pyridine-2-carboxylic acid {cis -3- [4- (2-isoquinolin-5-ylacetylamino) imidazol-1-yl] cyclo butyl} amide

This compound was prepared analogously to Example 9a using Preparation 9 and isoquinolin-5-yl-acetic acid (Preparation 6). 1 H NMR (400 MHz, CD ₃ OD) δ 9.23 (s, 1H),

8.60 (m, 1H), 8.44 (d, J = 5.8 Hz, 1H), 8.03 (m, 3H), 7.92 (dt, J = 1.7, 7.5 Hz) (1H), 7.78 (d, J =

7.1 Hz, 1 H), _7? 66 (m, 1H), 7.58 (s, 1H), 7.5 (m, 1H), 7.46 (s, 1H), 4.45 (m, 1H), 4.40 (m, 1H) )

4.20 (s, 2H); 2.85 (m, 2H); 2.6 (m, 2H); MS (AP / CI): 427.2 (M + H) &lt; + &gt;.

Example 10

N- {cis-3- [4- (3-naphthalen-l-yl-ureido) -imidazol-l-yl] cyclobutyl} acetamide

N- [cis-3- (4-Nitroimidazol-1H-yl) cyclobutyl] acetamide (Preparation 7, 50 mg, 0.22 mmol) was reacted with phenyl chloroformate as described in Example 4. This gave an inseparable mono - and the bis-phenylcarbamate products after chromatography on silica gel (20: 1: 0.2 chloroform-methanol-ammonium hydroxide system) which is dissolved in a 1: 1 dimethylformamide-dioxane system (500 μΐ). 1-Naphthylamine (31 mg, 0.22 mmol) was added and the mixture was kept at 70 ° C for 16 h. The product was purified by double chromatography on silica gel (20: 1: 0.2 chloroform-methanol-ammonium hydroxide system) to give 4.4 mg (5% yield).

N- {cis-3- [4- (3-naphthalen-l-yl-ureido) -imidazol-l-yl] cyclobutyl) -acetamide. 1 H NMR (400 MHz, CD ₃ OD) δ

8.06 (d, J = 8.0 Hz, 1H), 7.97 (d, J = 8.8 Hz, 1H), 7.83 (d, J = 7.6 Hz, 1H), 7 66 (d; J = 8.4 Hz, 1H), 7.51 (m, 4H), 706 (b, 1H), 4.46 (m, 1H), 4.15 (m, 1H) 2.89 (m, 2H); 2.33 (m, 2H); 1.92 (s, 3H); MS (AP / CI): 364.0 (M + H) &lt; + &gt;. Industrial usability

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.

Claims (13)

PATENT CLAIMS An imidazole derivative of the formula I H • N — R — R ⁴ (I) wherein 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 having from 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 7 to 11 carbon atoms, bicycloalkenyl of 7 to 11 carbon atoms, five to eleven-membered and 11-membered, C 6 -C 14 or C 5 -C 14 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 ⁸ , -NR ⁷ C (= O) R ⁸ , -NR ⁷ C (= O) OR ⁸ , -NR ⁷ C (= O) NR ⁸ R ⁹ , -NR ⁷ S (= O) 2 R ⁸ , - NR ⁷ S (= O) 2 NR ⁸ R ⁹ , "OR ^7, -OC (= O) R ^7, -OC (= O) OR 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) 2 R ^7, -S (= O) 2 NR ⁷ r ⁸ , -os (= o) 2 r ⁷ , -n 3 and R ⁷ , hydrogen, fluoro, methyl, cyano, or -C (= O) OR ⁷ -, -C (= O) NR ⁹ , -O (= O) O-, -C (= O) (CR ¹⁰ R ¹¹ ) _n - or R ⁴ is straight or branched chain alkyl of 1 to 8 carbon atoms, straight chained or branched alkenyl of 2 to 8 carbon atoms, straight chained or branched alkynyl of 2 to 8 carbon atoms, cycloalkyl of 3 to 8 carbon atoms C 4 -C 8 cycloalkenyl, C 3 -C 8 heterocycloalkyl, C 5 -C 11 bicycloalkyl, C 7 -C 11 bicycloalkenyl, 5 to 11-membered heterobicycloalkyl, aryl of 6 to 14 carbon atoms, or 6 to 14 carbon atoms, 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 ⁸ , -NR ⁷ C (= O) R ⁸ , -NR ⁷ C (= O) OR ⁸ , -NR ⁷ C (= O) NR ⁸ R ⁹ , -NR ⁷ S (= O) 2 R ⁸ , -NR ⁷ S (= O) 2 NR ⁸ R ⁹ , -or ⁷ , -oc (= o) r ⁷ , -OC (= O) OR 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) 2 R ⁷ , -S (= O) 2N R ⁷ R ⁸ and R ⁷ , R ( ⁷⁾ , R ( ⁸⁾ and R ( ⁹⁾ 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, bicycloalkyl of 7 to 11 carbon atoms, bicycloalkenyl of 7 to 11 carbon atoms, five to eleven-membered and eleven-membered, of 6 to 14 carbon atoms or five to 14-membered heteroaryl, Wherein Q, R, and R are optionally substituted independently of one another by one to six of fluoro, chloro, bromo and iodo, nitro, cyano, trifluoromethyl, -NR ¹ , R ¹¹ , -nr ¹⁰ c (= o) r ^1: -NR ¹⁰ C (= O) OR ¹¹ -NR ¹⁰ C (= O) NR ¹¹ R ¹² z -NR ¹⁰ S (= O) 2 R ^11, -NR ^{1 °} p (= O) 2 NR ¹¹ R ^12, -OR ^10, -OC (= O) R ^10, -OC (= O) OR ¹⁰ , -OC (= O) NR ¹⁰ R ^{1: L} , -OC (= O) SR ¹⁰ , -SR ¹⁰ , -S (= O) R ^10, -S (= O) 2 R ^10, -S (= O) 2 NR ¹⁰ R ^11, -C (= O) R ^10, -C (= O) OR ¹⁰ , -C (= O) NR ¹⁰ R ^{11: L} and R ¹⁰ , or when R ⁷ and R ⁸ are NR ⁷ R ⁸ , this may optionally be associated with a nitrogen atom of NR ⁷ R ⁸ to which it is attached to form a three to seven membered heterocycloalkyl moiety optionally containing one or two additional heteroatoms from nitrogen, oxygen and sulfur; R ( ¹⁰⁾ , R ( ¹¹⁾ and R ( ¹²⁾ 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, 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 7 to 11 carbon atoms, bicycloalkenyl of 7 to 11 carbon atoms, five to eleven-membered and eleven-membered, (C 6 -C 14) or (C 5 -C 14) heteroaryl, wherein R, R, and R are each optionally substituted with one to six substituents selected from fluorine, chlorine, bromine and iodine, 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) 2r ¹⁴ , -nr ¹³ s (= o) 2nr ¹⁴ r ¹⁵ , -OR ¹³ , -OC (= O) R ¹³ , -OC (= O) OR ¹³ , -OC (= O) NR ¹³ R ¹⁴ , -OC (= O) SR ¹³ , -SR ¹³ -S (= O) R ^13, -S (= O) 2 R ^13, -S (= O) 2 NR ¹³ R ^14, -C (= O) ^R13, -C (= 0) 0R ^13, -C ( = O) NR ¹³ R ¹⁴ and R ^13, R ( ¹³⁾ , R ( ¹⁴⁾ and R ( ¹⁵⁾ 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, bicycloalkyl of 7 to 11 carbon atoms, bicycloalkenyl of 7 to 11 carbon atoms, five to eleven-membered and eleven-membered, (C 6 -C 14) or (C 5 -C 14) heteroaryl, wherein R ¹³ , R ¹⁴ and R ^{15 are} optionally substituted independently of one another by one to six of fluoro, chloro, bromo and iodo, nitro, cyano, trifluoromethyl , -NR ¹⁶ R ¹⁷ , -NR ¹⁶ C (= O) R ¹⁷ , -nr ¹⁶ c (= o) or ¹⁷ , -nr ¹⁶ c (= o) nr ¹⁷ r ¹⁸ , -nr ¹⁶ s (= o) ) 2 R ^17, -NR ¹⁶ S (= O) 2 NR ¹⁷ R ^18, -OR ^16, -OC (= O) R ^16, -OC (= O) OR ^16, -OC (= O) 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 ( ¹⁸⁾ 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, bicycloalkyl of 7 to 11 carbon atoms, bicycloalkenyl of 7 to 11 carbon atoms, five to eleven-membered and eleven-membered, having 6 to 14 carbon atoms or five to fourteen-membered heteroaryl, n 0,1,2 or 3, wherein R ¹⁰ and R ¹¹ in the -C (= O) group (CR ¹ R ¹¹ -a - (CR ¹⁰ R ¹¹ )) _n are independently defined for each repetition of n as defined above and its pharmaceutically acceptable salts. An imidazole derivative according to claim 1, wherein R ^{3 is} -C (= O) NH- or -C (= O) (CR ^{9 10} R ¹¹ ) _n -. 3. A derivative according to claim 1 of formula I, wherein R ¹ represents an optionally substituted cycloalkyl of 3 to 8 carbon atoms or an optionally substituted bicycloalkyl of 5 to 11 carbon atoms. The imidazole derivative 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. A compound according to claim 1, 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. The imidazole derivative according to claim 1, wherein R ^{4 is} a C 6 -C 14 aralkyl group or a 5- to 14-membered heteroaryl group, each of which is optionally substituted. An imidazole derivative according to claim 6, wherein R ^{4 is} phenyl, pyridyl, naphthyl, quinolyl or isoquinolyl, each of which is optionally substituted. 8. A derivative according to claim 1 to 7 of formula I in which R ² is hydrogen. 9. An imidazole derivative according to claim 1 of the formula I N- (1-cyclobutyl-1H-imidazol-4-yl) -2-quinolin-6-ylacetamide, N- (1-cyclopentyl-1H-imidazol-4-yl) -2- (4-methoxyphenyl) acetamide, N- [1- (cis-3-phenylcyclobutyl-1H-imidazol-4-yl) -2-quinoline 6-Ylacetamide, (1-cyclobutyl-1H-imidazol-4-yl) carbamic acid phenyl ester, 1- (1-cyclobutyl-1H-imidazol-4-yl) -3-isoquinolin-5-ylurea, N- [1 - (cis-3-aminocyclobutyl) -1H-imidazol-4-yl] -2-naphthalen-1-ylacetamide, {cis-3- [4- (2-naphthalen-1-ylacetylamino) imidazol-1-yl] cyclobutyl 6H-Imidazole-4-carboxylic acid {cis-3- [4- (2-naphthalen-1-ylacetylamino) -imidazol-1-yl] -cyclobutyl] -amide, {cis-3- [} 6-Hydroxypyridine-2-carboxylic acid 4- (2-naphthalen-1-ylacetylamino) imidazol-1-yl] cyclobutyl iamide, {cis-3- [4- (2-naphthalen-1-ylacetylamino) imidazol-1-yl] 3-Methyl-pyridine-2-carboxylic acid cyclobutyl} amide 2-Pyridin-3-yl-thiazole-4-carboxylic acid {cis-3- [4- (2-naphthalen-1-ylacetylamino) -imidazol-1-yl] -cyclobutyl} -amide , 6- {cis-3- [4- (2-Naphthalen-1-ylacetylamino) imidazol-yl] cyclobutylcarbamoyl} nicotinic acid methyl ester, Pyrazine-2-carboxylic acid {cis-3- [4- (2-naphthalen-1-ylacetylamino) -imidazol-1-yl] -cyclobutyl} -amide, N- (cis-3- {4- (2-naphthalen-1-ylacetylamino) imidazol-1-yl] cyclobutyl} benzamide, {cis -3- [4- (2-naphthalen-1-ylacetylamino) imidazol-1-yl] - yl] cyclobutyl} 5-methylpyrazine-2-carboxylic acid amide, N- {cis-3- [4- (2-naphthalen-1-ylacetylamino) imidazol-1-yl] cyclobutyl} isobutyramide, {cis-3- [4- (2-naphthalen-1-ylacetylamino) imidazol-1-yl] yl] cyclobutyl} 6-chloropyridine-2-carboxylic acid amide {cis-3- [4- (2-naphthalen-1-ylacetylamino) imidazol-1-yl] cyclobutyl} quinoline-2-carboxylic acid amide, {cis-3 1H-pyrrole-2-carboxylic acid [4- (2-naphthalen-1-ylacetylamino) -imidazol-1-yl] -cyclobutyl} -amide, N- {cis-3- [4- (2-naphthalen-1-ylacetylamino) imidazol-1-yl] cyclobutyl} -2-m-tolylacetamide, {cis-3- [4- (2-naphthalen-1-ylacetylamino) pyridin-2-carboxylic acid imidazol-1-yl] cyclobutyl} amide, 2- (3-Hydroxyphenyl) -N- {cis-3- [4- (2-naphthalen-1-ylacetylamino) imidazol-1-yl] cyclobutyl} acetamide, {cis-3- [4- (2-naphthalene- piperidine-4-carboxylic acid 1-ylacetylamino) imidazol-1-yl] cyclobutyl} amide hydrochloride, N- [1- (cis-3-acetylaminocyklobutyl) -lH-imidazol-4-yl] -2naftalen-2-yl-acetamide, N- {cis-3- [4- (2-isoquinolin-5-ylacetylamino) imidazol-1-yl] cyclobutyl} benzamide; and {cis-3- [4- (2-isoquinolin-5-ylacetylamino) imidazol-1-yl] - yl] cyclobutyl} pyridine-2-carboxylic acid amide 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 according to claim 1 in an effective amount for the treatment of such disease or condition and a pharmaceutically acceptable carrier. A pharmaceutical composition for the treatment of diseases or conditions in mammals which may be affected or ameliorated by altering dopamine-mediated neurotransmission, comprising a cdk5 inhibitor in an effective amount for treating such a disease or condition or an effective amount for inhibiting 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, glucose tolerance, metabolic syndrome or syndrome X, polycystic ovarian syndrome, adipogenesis and obesity, myogenesis and poor health, e.g. 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, characterized by 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 agent selected from SSRI, NK-1 receptor antagonist, 5HT _1D 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.