BG107469A - Imidazole derivatives - Google Patents

Abstract

The invention provides compounds of formula wherein R1, R2, R3 and R4 have the meanings given in the description, and their pharmaceutically acceptable salts. Compounds of formula (1) are indicated to have activity inhibiting cdk5, cdk2, GSK-3. Pharmaceutical compositions and methods comprising compounds of formula (1) for treating and preventing diseases as 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. 13 claims

Description

IMIDASOL PRODUCTS

TECHNICAL FIELD

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

BACKGROUND OF THE INVENTION

The serine / threonine kinase cdk5, together with its cofactor p25 (or the longer cofactor, p35), binds to neurodegenerative disorders, and thus inhibitors of cdk5 / p25 (or cdk5 / p35) are useful for treating neurodegenerative disorders, such such as Alzheimer's disease, Parkinson's disease, stroke, or Huntington's disease. Treatment of such neurodegenerative disorders using cdk5 inhibitors is supported by the fact that cdk5 is involved in the phosphorylation of tau protein (J. Biochem, 117, 741-749 (1995)). cdk5 also phosphorylates dopamine and cyclic AMP-regulated phosphoprotein (DARPP-32) in threonine 75, and thus has been shown to play a role in dopaminergic neurotransmission (Nature, 402, 669-671 (1999)).

Serine / threonine kinase cdk2 is essential for the normal cyclization of the cell, and plays a critical role in disorders caused by abnormal cell cycling, a common feature of many cancer disorders. Therefore, cdk2 inhibitors are useful for treating various types of cancer and other abnormal cell growth disorders (Meijer, et al., Properties and Potential Applications of Chemical Inhibitors of Cyclin-dependent Kinases, Pharmacology & Therapeutics, 82 (2-3), 279-284 (1999); Sausville, et al., Cyclin-dependent Kinases; Initial Approaches to Exploit a Novel Therapeutic Target, Pharmacology & Therapeutics, 82 (2-3), 285-292 (1999) )).

^w GSK-3 is a serine / threonine protein kinase. It is one of several protein kinases that phosphorylate glycogen synthase (Fmbi, et al., Eur. J. Biochem. 107: 519-527 (1980); Hemmings, et al., Eur. J. Biochem. 119: 443- 451 (1982). GSK-3 exists in two isoforms, a and β, in vertebreites considered as having the monomeric structure of 49kD and 47 kD, respectively. Both isoforms phosphorylate muscle glycogen synthase (Cross, et al., Biochemical Journal 303: 21-26 (1994)). The amino acid identity among the homologs of the GSK-3 species was reported to be in excess of 98% in catalytic dopamine (Plyte, et al.,

Biochim. Biophys. Acta 1114: 147-162 (1992). Due to the remarkably high level of storage across the phylogenetic spectrum, the fundamental role of GSK3 in cellular processes is suggested.

GSK-3 has been associated with many different diseases and conditions. For example, Chen, et al., Diabetes 43: 12341241 (1994) conclude that increased GSK3 activity may be important for type 2 diabetes. Increased GSK-3 expression in diabetic muscle is also thought to provoke impaired glycogen synthase activity and ^w-sectors resistances of skeletal muscles, are present in type 2 diabetes (Nikoulina, et al., diabetes 49: 263-271 (2000)). Also, the increased activity of type 1 protein phosphatase measured in immobile sperm is attributed to the increased activity of GSK-3 and is responsible for being an impediment to sperm motility (Vijayaraghavan, et al., Biology of Reproduction 54: 709-718 (1996). Vijayaraghavan, et al.shows that such results suggest a biological basis for the development and regulation of sperm motility, and a possible physiological role for the protein phosphatase 1 / inhibitor 2 / GSK-3 system. GSK-3 activity is also associated with Alzheimer's disease, and mood disorders such as bipolar disorder (WO 97/41854). Among other conditions, GSK-3 has also been associated with hair loss, schizophrenia, and neurodegenerative conditions, including chronic neurodegenerative diseases (such as Alzheimer's disease, supra), and neurotrauma, such as stroke, traumatic brain injury, and spinal cord injuries.

SUMMARY OF THE INVENTION

This invention relates to compounds of the formula

wherein R ¹ is straight or branched (C 1 -C 8) alkyl, (C 2 -C 8) straight or branched chain alkenyl, (C 2 -C 8) straight or branched alkynyl, (C 3 -C 8) ) cycloalkyl, (C4-C8) cycloalkenyl, (3-8 membered) heterocycloalkyl, (C5-C6) bicycloalkyl, (C1-C11) bicycloalkenyl, (5-11 membered) heterobicycloalkyl, (Ces-Caryl, or (5- And wherein R ¹ is optionally substituted by one to six R ⁵ substituents independently selected from the group consisting of F, Cl, Br, I, nitro, cyano, -CF 3, -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) 2NR 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 ;

R ² is H, F, CH ₃ , CN, or C (= O) OR ⁷ ;

R ³ is -C (= O) NR ⁹ -, -C (= O) O-, -C (= O) (CR ¹⁰ R ¹¹ ) _n -> or

- (CR ¹⁰ R ¹¹ ) _n -;

R ⁴ is straight or branched (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) straight or branched alkenyl, straight or branched (C ₂ -C ₈ ) -alkynyl, (C ₃ -C ₈ ) cycloalkyl, (C ₄ -C ₈ ) cycloalkenyl, (3-8 membered) heterocycloalkyl, (C ₅ -C ₆ ) bicycloalkyl, (C ₇ -C ₆ ) bicycloalkenyl, (5-11 membered) heterobicycloalkyl, (Ce -Staryl or (5-14 membered) heteroaryl; and • · · · · · · · · · · · · · · · · · · · · · · · · · · Wherein R ⁴ is optionally substituted by one to three R ⁵ substituents independently selected from the group consisting of F, Cl, Br, I, nitro, cyano, -CF ₃ , -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) 2NR 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 or R ⁷ ;

Each of R ^z , R ⁸ and R ⁹ is independently selected from the group consisting of H, (C 1 -C 8) straight or branched alkyl, straight or branched (C 2 -C 8) alkenyl, Straight or branched (C2-C8) alkynyl, (C3-C8) cycloalkyl, (C4-C8) cycloalkenyl, (3-8 membered) heterocycloalkyl, (C5-C6) bicycloalkyl, (C7-C6) bicycloalkenyl, (5-11 membered) heterobicycloalkyl, (C6-C14) aryl, and (5-14 membered) heteroaryl, wherein each of R ^z , R ⁸ and R ⁹ is independently optionally substituted with one to six substituents independently selected from the group consisting of F, Cl. Br, I, NO2, -CN, -CF ₃ , -NR ¹⁰ R ¹¹ , -NR ¹⁰ C (= O) R ¹¹ , -NR ¹⁰ C (= O) OR ¹¹ , -NR ¹⁰ C (= O) NR ¹¹ R ¹² ,

-NR ¹⁰ S (= O) 2R ¹¹ , -NR ¹⁰ S (= O) 2NR ¹¹ R ¹² , -OR ¹⁰ , OC (= O) R ^1c , -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 ¹¹ , and R ¹⁰ ;

or, when R ⁷ and R ⁸ are as in NR ⁷ R ⁸ , they may optionally be attached, forming with the nitrogen of NR ⁷ R ⁸ to which they are attached, a heterocycloalkyl residue having from three to seven ring members, wherein said heterocycloalkyl moiety optionally contains one or two other heteroatoms independently selected from the group consisting of N, O and S;

Each of R ¹⁰ , R ¹¹ and R ¹² is independently selected from the group consisting of H, (C ₁ -C ₈ ) straight or branched alkyl, (C ₂ -C ₈ ) straight or alkenyl branched chain, (C ₂ C ₈ ) straight or branched alkynyl, (C ₃ -C ₈ ) cycloalkyl, (C ₄ -C ₈ ) cycloalkenyl, (3-8 membered) heterocycloalkyl, (C ₅ -C) bicycloalkyl, (C ₇ -C ₄ ) bicycloalkenyl, (5-11 membered) heterobicycloalkyl, (C ₆ -C ₁₄ ) aryl, and (5-14 membered) heteroaryl, wherein each of R ¹⁰ , R ¹¹ and R ¹² has been replaced independently by

choice with one to six substituents independently selected from the group consisting of F, Cl. Br, I, NO ₂ , -CN, -CF ₃₁ -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) R ¹³ , -C (= O) OR ¹³ ,

-C (= O) NR ¹³ R ¹⁴ , and R ¹³ ;

Each of R ^1o; R ¹⁴ and R ¹⁵ are independently selected from the group consisting of H, (C 1 -C 8) straight or branched alkyl, (C ₂ -C ₈ ) straight or branched alkenyl, (C ₂ -C ₈ ) straight or branched chain alkynyl, (C ₃ -C ₈ ) cycloalkyl, (C ₄ -C ₈ ) cycloalkenyl, (3-8 membered) heterocycloalkyl, (C ₅ -C ₈ ) bicycloalkyl, (C ₇ -C ₃ ) bicycloalkenyl, (5-11 membered) heterobicycloalkyl, (C ₅ -C ₁₄ ) aryl, and (5-14 membered) heteroaryl, wherein each of R ³ , R ¹⁴ and R ¹⁵ is optionally substituted with from one to six substituents independently selected from the group consisting of F, Cl. Br, I, NO ₂ . -CN, -CF ₃ , -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 ^1s S (= O) 2NR ¹⁷ R ¹⁸ , -OR ¹⁶ OC (= O) R ¹⁶ , -C (= O) OR ¹⁶ , -OC (= O) NR ¹⁶ R ¹⁷ , -OC (= O) SR ¹³ , -SR ¹⁶ , -S (= O) R ¹⁶ , -S (= O) 2R 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 ;

Each of R ¹⁶ , R ¹⁷ and R ¹⁸ is independently selected from the group consisting of H, (C ₁ -C ₈ ) straight or branched chain alkyl, (C ₂ -C ₈ ) straight alkenyl, or branched chain, (C ₂ -C ₈ ) straight or branched alkynyl, (C 3 -C ₈ ) cycloalkyl, (C ₄ -C ₈ ) cycloalkenyl, (3-8 membered) heterocycloalkyl, (C ₅ -C ₈ ) ) bicycloalkyl, (C ₇ -C ₁₄ ) bicycloalkenyl, (5-11 membered) heterobicycloalkyl, (C ₆ -C ₁₄ ) aryl, and (5-14 membered) heteroaryl;

η is 0, 1, 2, or 3;

where each of R ¹⁰ and R ¹¹ in -C (= O) (CR ¹⁰ R ¹¹ ) n- and - (CR ¹⁰ R ¹¹ ) n- is a repetition of n, defined independently,

as indicated above;

and pharmaceutically acceptable salts thereof.

Compounds of formula I according to the invention are inhibitors of serine / threonine kinase, in particular cyclin-dependent kinase, such as cdk5 and cdk2, and are used to treat neurodegenerative disorders and other CNS disorders, and abnormal cell growth, including cancer. Compounds of formula I are particularly useful for inhibiting cdk5. Compounds of formula I are also particularly useful for inhibiting GSK-3.

The term "alkyl" as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight or branched moieties. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, and t-butyl.

The term "alkenyl" as used herein, unless otherwise indicated, includes alkyl residues having at least one carbon double bond, wherein alkyl is as defined above.

• ♦ · ·

· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · 9 9

Examples of alkenyl groups include, but are not limited to, ethenyl and propenyl.

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

The term "cycloalkyl" as used herein, unless otherwise indicated, includes non-aromatic saturated cyclic alkyl moieties having at least one carbon-carbon triple bond, where alkyl is as defined above. Examples of alkynyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. "Bicycloalkyl" groups are non-aromatic saturated carbocyclic groups consisting of two rings where said rings engage one or two carbon atoms. For the purposes of the present invention, and unless otherwise indicated, bicycloalkyl groups include spiro groups and fused ring groups. Examples of bicycloalkyl groups include, but are not limited to, bicyclo- [3.1.0] -hexyl, norbornyl, spiro [4.5] desyl, spiro [4.4] nonyl, spiro [4.3] octyl, and spiro [4.2] heptyl. &Quot; Cycloalkenyl " and " bicycloalkenyl " refers to non-aromatic carbocyclic cycloalkyl and bicycloalkyl residues as defined above, except for one or more carbon-carbon double bonds linking carbon atoms to ring members double bond) and / or one or more carbon-carbon double bonds linking a carbon atom to a ring member and adjacent non-ring carbon ("exocyclic" double bond). Examples of cycloalkenyl groups include, but are not limited to, cyclopentenyl and cyclobutenyl, and a non-limiting example of a bicycloalkenyl group is norbornenyl. Cycloalkyl, cycloalkenyl, bicycloalkyl, and bicyclocycloalkenyl groups also include groups which are substituted by one or more oxo moieties. Examples of such groups with oxo residues are oxocyclopentyl, oxocyclobutyl, oxocyclopentenyl, and norcamphoryl.

^w The term "aryl" as used herein, unless otherwise indicated, includes an organic radical derived from an aromatic hydrocarbon by removal of one hydrogen, such as phenyl, naphthyl, indenyl, and fluorenyl.

The terms "heterocyclic", "heterocycloalkyl", and similar terms as used herein, unless otherwise indicated, refer to non-aromatic cyclic groups containing one or more heteroatoms, preferably from one to four heteroatoms, each selected from the group consisting of 0, S, and N. "Heterobicycloalkyl" groups are non-aromatic two-ring cyclic groups wherein said rings engage one or two atoms, and wherein at least one of the rings contains a heteroatom (O, S, or N). Heterobicycloalkyl groups for the purposes of the present invention, and unless otherwise indicated, include spiro groups and fused ring groups. According to one embodiment of the invention, each ring in the heterobicycloalkyl group contains up to four heteroatoms (i.e., from zero to four heteroatoms, provided that at least one of the rings contains at least one heteroatom). The heterocyclic groups of this invention may also include ring systems substituted with one or more oxo moieties. Examples of non-aromatic heterocyclic groups are aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, azepinyl, piperazinyl, 1,2,3,6-tetrahydropyridinyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydrothiothiothiothiopyranopyran, tetrahydropyranyl, tetrahydropyranyl, , indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo [3.1.0] 3-hexacyl [3.1.0] 3-hexazibyl] ] 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.

"Heteroaryl" as used herein refers to groups containing one or more heteroatoms (O, S or N), preferably from one to four heteroatoms. Multicycle groups contain one or more heteroatoms, where at least one ring of the group is aromatic is a "heteroaryl" group. The heteroaryl groups of this invention may also include ring systems substituted with one or more oxo moieties. Examples of heteroaryl groups are pyridine; , phthalazinyl, triazinyl, isoindolyl, purinyl, oxadiazolyl, thiadiazolyl, • · · · · · · · »

furazanil, benzofurazil, benzothiophenyl, benzotriazolyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, dihydroquinolyl, tetrahydroquinolyl, tetrahydro, pyrrolidine

The groups mentioned above, as derivatives of the compounds listed above, may be C-attached or M-attached, where appropriate. For example, a pyrrole derivative group may be pyrrol-1-yl (N-attached) or pyrrole-

3-yl (C-attached). The terms referring to groups also encompass all possible tautomers.

In one embodiment, this invention provides compounds of formula 1 wherein R ³ is -C (= O) NR ⁹ -, or -C (= O) (CR ¹⁰ R ¹¹ ) n-. In another embodiment, R ¹⁰ and R ¹¹ of -C (= O) (CR ¹⁰ R ¹¹ ) n- for each repetition of η are both hydrogen. In another embodiment, R ⁹ of -C (= O) NR ⁹ is hydrogen. According to another embodiment, R ³ is -C (= O) NR ⁹ -, or -C (= O) (CR ¹⁰ R ¹¹ ) n - and R ² is hydrogen.

According to another embodiment of the invention, a compound of formula I is provided when R ¹ is optionally substituted (C 3 -C 8) cycloalkyl, or optionally substituted (C 5 -C 6) bicycloalkyl. Preferred embodiments are when R ¹ is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or norbornyl, each optionally substituted as indicated above (i.e., optionally, with one to six substituents R ⁵ independently selected from the group consisting of F, Cl, Br, I, nitro, cyano, -CF3, -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) 2NR ^with 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 , or R ^7. According to no12 • ·

a preferred embodiment, R ¹ is (C ₃ -C ₈ ) cycloalkyl, or optionally substituted (C ₅ -C ₈ ) bicycloalkyl, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or

norbornyl, and is optionally substituted by one to three substituents independently selected from the group consisting of F, Cl, Br, I, nitro, cyano, -CF ₃ , -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 8) bicycloalkyl, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or norbornyl, and R ¹ is substituted with -NR ⁷ C (= O) R ⁸ , (C 6 -C ₁₄ ) aryl, (3-8 membered) heterocycloalkyl, or (5-14 membered) heteroaryl, and wherein said aryl, heterocycloalkyl, and heteroaryl are each optionally substituted by from one to six substituents independently selected from the group consisting of F, Cl, Br, I, NO ₂₎ -CN, -CF ₃ , -NR ¹⁰ R ¹¹ , -NR ¹⁰ C (= O) R ¹¹ , -NR ¹⁰ C (= O) OR ¹¹ , -NR ¹⁰ C (= O) NR ¹¹ R ¹² ,

-NR ¹⁰ S (= O) 2R ¹¹ , -NR ¹⁰ S (= O) 2NR ¹¹ 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) 2R ¹⁰ , -S (= O) 2NR ^1g R ¹¹ , -C (= O) R ¹⁰ , -C (= O) OR ¹⁰ ,

-C (= O) NR ¹⁰ R ¹¹ , and R ¹⁰ . According to another embodiment of the invention, R ¹ is optionally glass- [3.1.0] -hexyl, and is optionally substituted as indicated above (i.e., optionally substituted with one to six substituents R ⁵ , independently selected from the group consisting of F, Cl, Br, I, nitro, cyano, -CF ₃ , -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) 2NR 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 ^? , -SR ⁷ ,

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

According to another embodiment of the invention, the compound of formula 1 is provided, when R ¹ is optionally substituted (C _d C ₈₎ straight or branched chain, or • · * · _l ··· · ·. · ·

• .....! · · · · · •• J ···

....... ... · .. · optionally substituted (C ₂ -C) alkenyl with straight or branched chain.

According to another embodiment of the invention, a compound of formula I is provided but when R ² is hydrogen. According to another embodiment of the invention, R ² is hydrogen and R ¹ is further defined in the preceding paragraph.

In another embodiment, this invention provides a compound of formula I when R ⁴ is (C ₆ -C ₁₄ ) aryl, or (5-14 membered) heteroaryl, each optionally substituted. According to a preferred embodiment, R ⁴ is optionally substituted phenyl or optionally substituted pyridyl. In another preferred embodiment, R ⁴ is naphthyl, quinolyl, or isoquinolyl, each of which is optionally substituted. In another embodiment, R ⁴ is naphthyl, quinolyl, or isoquinolyl, and is unsubstituted.

In another embodiment, a compound of formula I is provided when R ² is specifically hydrogen and R ⁴ is further defined in the preceding paragraph.

Examples of preferred compounds of formula I are:

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-phenyl-cyclobutyl) -1H-imidazol-4-yl] -2quinolin-6-yl-acetamide;

(1-Cyclobutyl-1H-imidazol-4-yl) carbamic acid phenyl ester;

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

• ·

N- [1- (cis-3-amino-cyclobutyl) -1H-imidazol-4-yl] -2-naphthalen-1-yl-acetamide;

6-methyl-pyridine-2-carboxylic acid and {cis-3- [4- (2-naphthalen-1-yl-acetylamino) -imidazol-1-yl] cyclobutyl} -amide;

1H-imidazole-4-carboxylic acid {cis-3- [4- (2-naphthalen-1-yl-acetylamino) -imidazol-1-yl] cyclobutyl} -amide;

6-hydroxy-pyridine-2-carboxylic acid {cis-3- [4- (2-naphthalen-1-yl-acetylamino) -imidazol-1-yl] -cyclobutyl} amide;

3-methyl-pyridine-2-carboxylic acid {cis-3- [4- (2-naphthalen-1-yl-acetylamino) -imidazol-1-yl] -cyclobutyl} amide;

2-Pyridin-3-yl-thiazole-4-carboxylic acid {cis-3- [4 (2-naphthalen-1-yl-acetylamino) -imidazol-1-yl] -cyclobutyl} amide;

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

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

N- {cis-3- [4- (2-naphthalen-1-yl-acetylamino) -imidazol-1-yl] -cyclobutyl} benzamide;

5-methyl-pyrazine-2-carboxylic acid {cis-3- [4- (2-naphthalen-1-yl-acetylamino) -imidazol-1-yl] -cyclobutyl} -amide;

N- {cis-3- [4- (2-naphthalen-1-yl-acetylamino) -imidazol-1-yl] -cyclobutyl} -isobutyramide;

6-chloro-pyridine-2-carboxylic acid {cis-3- [4- (2-naphthalen-1-yl-acetylamino) -imidazol-1-yl] -cyclobutyl} amide;

• ^d ···· quinoline-2-carboxylic acid {cis-3- [4- (2-naphthalen-1-yl-acetylamino) -imidazol-1-yl] cyclobutyl} -amide;

1H-Pyrrole-2-carboxylic acid {cis-3- [4- (2-naphthalen-1-yl-acetylamino) -imidazol-1-yl] -cyclobutyl} -amide;

N- {cis-3- [4- (2-naphthalen-1-yl-acetylamino) -imidazol-1-yl] -cyclobutyl} -2-t-tolyl-acetamide;

Pyridine-2-carboxylic acid {cis-3- [4- (2-naphthalen-1-yl-acetylamino) -imidazol-1-yl] -cyclobutyl} -amide;

2- (3-hydroxy-phenyl) -N- {cis-3- [4- (2-naphthalen-1-ylacetylamino) -imidazol-1-yl] -cyclobutyl} -acetamide;

piperidine-4-carboxylic acid {cis-3- [4- (2-naphthalen-yl-acetylamino) -imidazol-1-yl] -cyclobutyl} -amide hydrochloride;

N- [1- (cis-3-acetylamino-cyclobutyl) -1H-imidazol-4-yl] 2-naphthalen-2-yl-acetamide;

N- (cis-3- [4- (2-isoquinolin-5-yl-acetylamino) -imidazol-1-yl] -cyclobutyl} -benzamide; and pyridine-2-carboxylic acid {cis-3- [4- (2- isoquinoline-

5-yl-acetylamino) -imidazol-1-yl] -cyclobutyl} -amide; and pharmaceutically acceptable salts of the above compounds.

Examples of other specific compounds of the invention of Formula 1 are:

Cis-N- (1-bicyclo [3.1,0] hex-3-yl-1H-imidazol-4-yl) -2quinolin-6-yl-acetamide;

Cis-N-flu - [trans-6- (pyridine-2-carbonyl) -bicyclo [3.1.0] hex-3-yl-1H-imidazol-4-yl} -2-quinolin-6-yl-acetamide;

N- {1- [cis-3- (2-methoxy-phenyl) -cyclobutyl] -1H-imidazole-

4-yl} -2-quinolin-6-yl-acetamide;

····

N- {1- [cis-3- (2-fluoro-phenyl) -cyclobutyl] -1H-imidazol4-yl} -2-quinolin-6-yl-acetamide;

N- {1- [cis-3- (4-methoxy-phenyl) -cyclobutyl] -1H-imidazol4-yl} -2-quinolin-6-yl-acetamide;

2-quinolin-6-yl-N- [1- (cis-3-p-tolyl-cyclobutyl) -1H-imidazol-4-yl] -acetamide;

N- {1- [cis-3- (2-ethoxy-phenyl) -cyclobutyl] -1H-imidazol-4-yl} -2-quinolin-6-yl-acetamide;

N- {1- [cis-3- (2-methoxy-phenyl) -cyclobutyl] -1H-imidazol4-yl} -2-quinolin-6-yl-acetamide; and pharmaceutically acceptable salts of the above compounds.

Other examples of specific compounds of formula 1 are:

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

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

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

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

N- {1- [3- (3-Aminomethyl-phenyl) -cyclobutyl] -1H-imidazol4-yl} -2- (4-methoxy-phenyl) -acetamide;

N- {1- [3- (3-dimethylaminomethyl-phenyl) -cyclobutyl] -1-imidazol-4-yl} -2- (4-methoxy-phenyl) -acetamide; and

2- (4-methoxy-phenyl) -1 N- {1- [3- (2-methyl-1H-pyrazol-3-yl) cyclobutyl] -1H-imidazol-4-yl} -acetamide;

and pharmaceutically acceptable salts of the above compounds.

• · · · ·

Salts of compounds of formula 1 can be prepared by forming salts with any acidic or basic group present in a compound of formula 1. Examples of pharmaceutically acceptable salts of compounds of formula 1 are hydrochloric acid salts, p -toluenesulfonic acid, fumaric acid, citric acid, succinic acid, salicylic acid, oxalic acid, hydrobromic acid, phosphoric acid, methanesulfonic acid, tartaric acid, maleic acid -p-toluoyl tartaric acid, acetic acid, sulfuric acid, hydriodic acid, mandelic acid, sodium, potassium, magnesium, calcium, and lithium.

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

The present invention also encompasses radioactive isotope compounds which are identical to those indicated for formula 1, but with the fact that one or more atoms are substituted by an atom having an atomic mass or mass other than the atomic mass, or the mass number that is commonly found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, iodine, and chlorine, such as ³ H, ¹¹ C, ¹⁴ C , ¹⁸ F, ¹²³ 1 and ¹²⁵ 1. Compounds of the present invention and pharmaceutically acceptable salts of the compounds, which contain the above isotopes and / or other isotopes of other atoms, are within the scope of this invention. Radioactive isotope compounds according to the present invention, for example those incorporating radioactive isotopes such as ³ H and ¹⁴ C, are used in the study of drug and / or substrate distribution in tissues. Tritium isotopes, i.e., ³ H, and carbon-14, i.e., ¹⁴ C, are particularly preferred because of their easy preparation and detectability. The ¹¹ C and ¹⁸ F isotopes are particularly useful for PET (positron emission tomography), and the ¹²⁵ C isotopes are particularly useful for SPECT (single photon emission computed tomography), all of which are useful for brain imaging. Moreover, substitution with heavier isotopes, such as deuterium, i.e. ² H, may provide some therapeutic benefits as a result of metabolic stability, for example, increased in vivo half-life, or reduced dosage requirements, and, therefrom may be preferred in some situations. Radiolabelled compounds of the formula I according to this invention can generally be prepared by following the procedures described in the schemes and / or examples below by replacing a readily available radioactive isotope reagent with a reagent that is not labeled with a radioactive isotope.

The present invention also provides a pharmaceutical composition for treating diseases or conditions comprising abnormal cell growth in a mammal comprising a compound of formula 1 in an amount effective to inhibit abnormal cell growth, and a pharmaceutically acceptable carrier.

• · · · · · ·: · · · ..... ·· · .. ··.

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

This invention also provides a method of treating diseases or conditions comprising abnormal cell growth in a mammal, comprising administering to the mammal a compound of formula 1 in an amount effective to inhibit abnormal cell growth.

This invention also provides a method of treating diseases or conditions comprising abnormal cell growth in a mammal comprising administering to a mammal a compound of formula 1 in an amount effective to inhibit cdk2 activity.

According to the pharmaceutical composition or method of this invention for treating a disease or condition containing abnormal cell growth, the disease, or a condition containing abnormal cell growth according to one embodiment, is a cancer. Cancer can be cancer, for example, cancer of the bladder, breast, colon, kidney, liver, lungs, for example, small cells of lung cancer, esophagus, gallbladder, ovaries, pancreas, stomach, neck, thyroid, prostate, or skin, for example, flaky cell carcinoma; haematopoietic (blood gland) tumor or lymphoid order, for example, leukemia, acute lymphocytic leukemia, B-cell lymphoma, T-cell ···· lymphoma, Hodgkins lymphoma, non-Hodgkin's lymphoma, lymphoma lymphoma, Burket; hematopoietic tumor or myeloid sequence, for example, acute and chronic myelogenous leukemias, myelodysplastic syndrome, or promyelocytic leukemia; a tumor of mesenchymal origin, for example, fibrosarcoma or rhabdomyosarcoma; a tumor of the central or peripheral nervous system, for example, an astrocytoma. neuroblastoma, glioma, or schwannomas; melanoma; seminomas; teratocarcinoma; osteosarcoma; pigment xenoderma; keratocanthoma; thyroid follicular cancer; or Kaposi's sarcoma.

According to another embodiment of the invention, the disease or condition containing abnormal cell growth is benign. Such diseases and conditions include benign prostatic hyperplasia, hereditary adenomatous polyps, neurofibromatosis, atherosclerosis, pulmonary fibrosis, arthritis, psoriasis, glomerulonephritis, restenosis, hypertensive cytotoxic formations, inflammation, inflammation, inflammation .

This invention also provides a pharmaceutical composition for treating neurodegenerative diseases or conditions in a mammal comprising a compound of formula 1 in an amount effective to treat said diseases or conditions, and a pharmaceutically acceptable carrier.

This invention also provides a pharmaceutical composition for treating neurodegenerative diseases or conditions in a mammal comprising a compound of formula 1 in an amount effective to inhibit cdk5 activity and a pharmaceutically acceptable carrier.

This invention also provides a method of treating neurodegenerative diseases or conditions in mammals comprising administering to a mammal a compound of Formula 1 in an amount effective to inhibit cdk5 activity.

This invention also provides a method of treating neurodegenerative diseases or conditions in mammals, comprising administering to a mammal a compound of formula 1 in an amount effective in treating said diseases or conditions.

According to one embodiment of the invention, the neurodegenerative disease or condition being treated is selected from the group consisting of Huntington's disease, stroke, spinal trauma, traumatic brain injury, multi-infarct dementia, epilepsy, amyotropic lateral sclerosis, dementia, eg AIDS-induced dementia, neurodegeneration associated with bacterial infection, migraine, hypoglycaemia, urinary incontinence (discharge), cerebral ischemia, multiple sclerosis, Alzheimer's disease, senile dementia Alzheimer's type, mild cognitive impairment, age-related cognitive decline, vomiting, corticobasal degeneration, pugilistica dementia, Dawn's syndrome, myotonic dystrophy, Niemann-Pick disease, Pik disease, prion supernatural disease, paracas disease -Lysis, weaker lateral sclerosis, and subacute sclerosing encephalitis.

This invention also provides a pharmaceutical composition for treating diseases, or conditions, the treatment of which may be affected or facilitated by changing the · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · for treating said disease or condition, and a pharmaceutically acceptable carrier.

This invention also provides a pharmaceutical composition for treating a disease or condition whose treatment can be efficiently effected or facilitated by altering the dopamine mediated neurotransmission in a mammal containing a cdk5 inhibitor in an amount effective to inhibit cdk5, and pharmaceutically acceptable carrier.

The present invention also provides a method of treating a disease, or condition, the treatment of which can be efficiently effected or facilitated by alteration of a dopamine mediated neurotransmission in a mammal comprising administering to the mammal a cdk5 inhibitor in an amount effective to inhibit cdk5 activity.

The present invention also provides a method of treating a disease, or condition, the treatment of which can be efficiently effected or facilitated by alteration of a dopamine mediated neurotransmission in a mammal comprising administering to the mammal a cdk5 inhibitor in an amount effective for treating said disease or condition.

According to one embodiment of the invention, the disease, or condition whose treatment can be efficiently effected or facilitated by dopamine mediated neurotransmission, is selected from the group consisting of Parkinson's disease; schizophrenia; schizophrenic disorder; schizoaffective disorder, for example, of the delusional type or the depressive type;

· · · · · · · · · · · · · · · · · · · · · · · · · · · · Delusional disorder; substance-induced psychiatric disorder, for example, alcohol-induced psychosis, amphetamine, cannabis, cocaine, hallucinogens, inhalants, opiates, or phencyclidine; personality disorders of the paratoid type; schizoid personality disorders; drug use, including drugs (eg, heroin, opium and morphine), cocaine and alcohol use; drug withdrawal, including drug, cocaine and alcohol withdrawal; obsessive manic disorder; Touret syndrome; depression; major depressive episode, manic or mixed episode of depression, hypomaniacal episode of depression, depressive episode with atypical features, or with melancholic features, or catatonic (motionless) features, episode with aftertreatment; post-stroke depression, classic depressive disorder, dysthymic disorder, mild depressive disorder, premenstrual dysphoric disorder, postpsychotic depressive disorder, or schizophrenia, a major depressive disorder caused by a psychotic disorder, such as crazy disorder, or schizophrenia, or schizophrenia, , bipolar II disorder, cyclothymic disorder; anxiety; disorder with lack of attention and overactivity; and attention deficit disorder.

According to another embodiment of the invention, the cdk5 inhibitor in the method or composition for treating a disease or condition whose treatment can be efficiently effected or facilitated by dopamine mediated neurotransmission modification is a compound of formula 1 , or a pharmaceutically acceptable salt thereof.

«· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·· ·· ··

This invention also provides a pharmaceutical composition for treating a disease or condition facilitated by cdk5 activity in a mammal, which composition comprises a compound of formula 1 in an amount effective to inhibit cdk5 activity, and a pharmaceutically acceptable carrier.

This invention also provides a method for treating a disease or condition facilitated by cdk5 activity in a mammal, which method comprises administering to the mammal a compound of formula 1 in an amount effective to inhibit cdk5 activity.

We have also found that the compounds of formula 1 have GSK-3 inhibitory activity. Therefore, it can be expected that the compounds of formula 1 are useful for treating diseases and conditions whose treatment can be efficiently effected or facilitated by inhibition of GSK-3. Diseases and conditions that can be effectively treated or facilitated by GSK3 inhibition include neurodegenerative diseases and conditions. Neurodegenerative diseases and conditions are discussed above and include, but are not limited to, for example, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotropic lateral sclerosis, multiple sclerosis, cerebral ischemia., Dementia associated with AIDS, bacteremia, infection, multi-infarct dementia, traumatic brain damage, and spinal cord injuries. Therefore, compounds of formula I are effective in treating neurodegenerative diseases and conditions based on both cbk5 activity and GSK-3 activity.

Other diseases and conditions that can be effectively treated or alleviated by inhibition of шшш '· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

GSK-3 include psychotic illnesses and conditions, for example, schizophrenia, schizophrenia-like disorder; schizoaffective disorder, for example, of the insane type or of the depressive type; disorder with lunacy; substance-induced psychiatric disorder, for example, alcohol-induced psychosis, amphetamine, cannabis, cocaine, hallucinogens, inhalants, opiates, or phencyclidine; personality disorders of the paratoid type; schizoid personality disorders. Treatment of such diseases and conditions may also be effected or facilitated by alteration of dopamine-mediated neurotransmission. Therefore, compounds of formula I are effective in treating such diseases and conditions based on both cd5 activity and GSK-3 activity.

Other disorders and conditions that can be effectively treated or facilitated by GSK-3 inhibition include obsessive manic disorder and an episode of intrusiveness, for example, major depressive episode, manic, or mixed episode of anxiety, hypothyroidism, hypothyroidism, hypothyroidism, , a depressive episode with atypical features, or with melancholic features, or with catatonic (immobility) features, an episode of postpartum depression; post-stroke depression, classic depressive disorder, dysthymic disorder, mild depressive disorder, premenstrual dysphoric disorder, postpsychotic depressive disorder, or schizophrenia, a major depressive disorder caused by a psychotic disorder, such as crazy disorder, or schizophrenia, or schizophrenia, , bipolar II disorder, cyclothymic disorder.

• · · ·

Treatment of such obsessive-manic disorders and episodes, for example, depression, may also be effected or facilitated by alteration of dopamine-mediated neurotransmission. Therefore, compounds of formula I are effective in the treatment of certain obsessive-manic diseases and obsessive-manic episodes based on both cd5 activity and GSK-3 activity.

Other diseases and conditions that can be effectively treated or facilitated by GSK-3 inhibition are male infertility and semen motility; diabetic melitus; impaired glucose tolerance; metabolic syndrome, or syndrome X; polycystic ovarian syndrome; adipogenesis and obesity; myogenesis and fragility, for example, age-related decline in physical characteristics; acute sarcopenia, for example, muscular atrophy and / or cachexia associated with burns, poor support, limb immobilization, or major thoracic, abdominal, and / or orthopedic surgery; sepsis; damage to the spinal cord; hair loss, thinning hair, and baldness; immune deficiency and cancer.

Accordingly, the present invention also provides a pharmaceutical composition for treating mammals, including humans, a disease, or a condition selected from the group consisting of male infertility and semen motility; diabetic melitus; impaired glucose tolerance; metabolic syndrome, or syndrome X; polycystic ovarian syndrome; adipogenesis and obesity; myogenesis and fragility, for example, age-related decline in physical characteristics; acute sarcopenia, for example, muscular atrophy and / or cachexia associated with burning, poor support, immobilization · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · На sepsis; hair loss, thinning hair, and baldness; and immune deficiency; which composition comprises a pharmaceutically acceptable carrier and an amount of a compound of formula I effective in treating said disease or condition.

The present invention further provides a pharmaceutical composition for treating mammals, including humans, a disease or condition selected from the group consisting of male infertility and sperm motility; diabetic melitus; impaired glucose tolerance; metabolic syndrome, or syndrome X; polycystic ovarian syndrome; adipogenesis and obesity; myogenesis and fragility, for example, age-related decline in physical characteristics; acute sarcopenia, for example, muscular atrophy and / or cachexia associated with burning, poor support, limb immobilization, or major thoracic, abdominal, and / or orthopedic surgery; sepsis; hair loss, thinning hair, and baldness; and immune deficiency; which composition comprises a pharmaceutically acceptable carrier and an amount of a compound of formula 1 effectively inhibiting GSK-3.

The present invention also provides a method of treating in a mammal, including a human, a disease or condition selected from the group consisting of male infertility and semen motility; diabetic melitus; impaired glucose tolerance; metabolic syndrome, or syndrome X; polycystic ovarian syndrome; adipogenesis and obesity; myogenesis and fragility, for example, age-related decline in physical characteristics; acute sarcopenia, for example, muscular atrophy and / or cachexia associated with burning, poor support, limb immobilization, or major thoracic, abdominal, and / or orthopedic surgery; sepsis; hair loss, thinning hair, and baldness; and immune deficiency; which method method comprises administering to said mammal an amount of a compound of formula I effective in treating said disease or condition.

The present invention also provides a method of treating in a mammal, including a human, a disease or condition selected from the group consisting of male infertility and sperm motility; diabetic melitus; low glucose tolerance; metabolic syndrome, or syndrome X; polycystic ovarian syndrome; adipogenesis and obesity; myogenesis and fragility, for example, age-related decline in physical characteristics; acute sarcopenia, for example, muscular atrophy and / or cachexia associated with burning, poor support, limb immobilization, or major thoracic, abdominal, and / or orthopedic surgery; sepsis; hair loss, thinning hair, and baldness; and immune deficiency; which method consists of administering to said mammal an amount of a compound of formula 1 effectively inhibiting GSK-3.

The present invention further provides a method of inhibiting GSK-3 in mammals, including a human, which comprises administering to said mammal an amount of a compound of formula 1 to effectively inhibit GSK-3.

The present invention further provides a pharmaceutical composition for the treatment of mammals of a disease selected from the group consisting of Alzheimer's disease, moderate impairment of cognitive abilities, and age-related impairment of cognitive abilities, • · · · · · · * · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · of cbcb and a COX-II inhibitor, in an amount effective to treat said disorder and a pharmaceutically acceptable carrier. In one embodiment of the invention, a cck5 inhibitor is a compound of formula I, or a pharmaceutically acceptable salt thereof.

The present invention further provides a method of treating in a mammal a disease selected from the group consisting of Alzheimer's disease, a moderate mean cognitive impairment, and an age-related cognitive impairment, which method comprises administering to said mammal a a cbk5 inhibitor and a COX-II inhibitor, wherein the combined amounts of cbk5 and a COX-II inhibitor are effective in treating said disorder. According to one embodiment of the invention, the cbcb inhibitor is a compound of formula 1, or a pharmaceutically acceptable salt thereof. The cck5 inhibitor and the COX-II inhibitor may be administered to the mammal at the same time and / or at different times. In addition, they may be administered together with a single pharmaceutical composition or with separate pharmaceutical compositions.

^w In addition, the cdK5 inhibitor, for example, a compound of formula I according to the invention, or a pharmaceutically acceptable salt of a compound of formula 1, may be administered or formulated in the form of a pharmaceutical composition with one or more anti- depressants or anxiolytic compounds for the treatment or prevention of depression and / or anxiety.

Accordingly, the present invention provides a pharmaceutical composition for treating depression or anxiety in a mammal comprising a cdk5 inhibitor and an NK-1 antagonist. ······················································································· The receptor together, in an amount effective to treat depression or anxiety. , and a pharmaceutically acceptable carrier. In one embodiment of the invention, the cbk5 inhibitor is a compound of formula I, or a pharmaceutically acceptable salt thereof.

The invention further provides a method of treating depression or anxiety in mammals, which method comprises administering to said mammal a cdk5 inhibitor and an NK-1 receptor antagonist, such as the combined amounts of a cdk5 inhibitor and an NK- antagonist The 1 receptors are effective in treating depression or anxiety. In one embodiment of the invention, the cdK5 inhibitor is a compound of formula I, or a pharmaceutically acceptable salt thereof. The cdk5 inhibitor and the NK-1 receptor antagonist may be administered to the mammal at the same time and / or at different times. In addition, they may be administered together with a single pharmaceutical composition or with separate pharmaceutical compositions.

The invention also provides a pharmaceutical composition for treating depression or anxiety in a mammal comprising a cdk5 inhibitor and a 5HT ₁₀ receptor antagonist together, in an amount effective to treat depression or anxiety, and a pharmaceutically acceptable carrier. According to one embodiment of the invention, the cdK5 inhibitor is a compound of formula I, or a pharmaceutically acceptable salt thereof.

This invention further provides a method of treating depression or anxiety in mammals, which method comprises administering to said mammal a cdk5 inhibitor and a 5HT ₁₀ receptor antagonist such as the combined amounts of the cdk5 inhibitor and 5HT ₁₀ receptor antagonists are effective in treating depression or anxiety. According to one embodiment of the invention, the cbcb inhibitor is a compound of formula 1, or a pharmaceutically acceptable salt thereof. The cdk5 inhibitor and the 5HT _1D receptor antagonist may be administered to the mammal at the same time and / or at different times. In addition, they may be administered together with a single pharmaceutical composition or with separate pharmaceutical compositions.

This invention also provides a pharmaceutical composition for treating depression or anxiety in a mammal comprising a cdk5 inhibitor and SSRI together, in an amount effective to treat depression or anxiety, and a pharmaceutically acceptable carrier. In one embodiment of the invention, the cdK5 inhibitor is a compound of formula I, or a pharmaceutically acceptable salt thereof.

This invention further provides a method of treating depression or anxiety in mammals, which method comprises administering to said mammal a cdk5 and SSRI inhibitor, the combined amounts of the cdk5 inhibitor and SSRI being effective for treating depression. or of concern. In one embodiment of the invention, the cdK5 inhibitor is a compound of formula I, or a pharmaceutically acceptable salt thereof. The cdk5 and SSRI inhibitor may be administered to the mammal at the same time and / or at different times. In addition, they may be administered together with a single pharmaceutical composition or with separate pharmaceutical compositions.

This invention also provides a pharmaceutical composition for the treatment of mammals schizophrenia comprising a cdk5 inhibitor and as an antipsychotic selected from the group consisting of cipazidone, olanzapine, risperidone, L-745870, sonepiprazole, RP 62203, NGD941, balanosidone, balanosidone, and gepirone, together, in an amount effective to treat schizophrenia, and a pharmaceutically acceptable carrier. According to an embodiment of the invention, the cbcb inhibitor is a compound of formula 1, or a pharmaceutical composition thereof.

liva salt.

This invention further provides a method of treating mammalian schizophrenia, which method comprises administering to said mammal a cdk5 inhibitor and an antipsychotic selected from the group consisting of cipazidone, olanzapine, risperidone, L-745870, sonepiprazole, RP 62203, NGD941, balaperidone, flesinoxane, and hepirone, where the combined amounts of the cdk5 inhibitor and the antipsychotic are effective in treating schizophrenia. In one embodiment of the invention, the cbk5 inhibitor is a compound of formula I, or a pharmaceutically acceptable salt thereof. The cdk5 inhibitor and antipsychotics may be administered to the mammal at the same time and / or at different times. In addition, they may be administered together with a single pharmaceutical composition or with separate pharmaceutical compositions.

This invention also provides a pharmaceutical composition for treating a disorder selected from the group consisting of Alzheimer's disease, moderate cognitive impairment, and age-related cognitive impairment in mammals containing • · · · a cdk5 inhibitor and an acetylcholinesterase inhibitor together, in an amount effective to treat said disorder, and a pharmaceutically acceptable carrier. According to one embodiment of the invention, the cbcb inhibitor is a compound of formula 1, or a pharmaceutically acceptable salt thereof.

This invention further provides a method of treating in a mammal a disease selected from the group consisting of Alzheimer's disease, moderate cognitive impairment, and age-related cognitive impairment, which method comprises administering to said mammal a a cdk5 inhibitor and an acetylcholinesterase inhibitor, the combined amounts of the cdk5 inhibitor and the acetylcholinesterase inhibitor being effective in treating said disorder. In one embodiment of the invention, the cbk5 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 at the same time and / or at different times. In addition, they may be administered together with a single pharmaceutical composition or with separate pharmaceutical compositions.

This invention also provides a pharmaceutical composition for treating a disease or condition selected from the group consisting of stroke, spinal cord injury, traumatic brain injury, multi-infarct dementia, epilepsy, pain, Alzheimer's disease, and senile dementia containing inhibitor of cdk5 and TPA (tissue plasminogen activator, e.g., ACTIVASE) together, in an amount effective to treat said disorder, and pharmaceutically acceptable. · · · · · · · · · · · · · · · · · · · · · · · · · · · · · carrier. In one embodiment of the invention, the cbk5 inhibitor is a compound of formula I, or a pharmaceutically acceptable salt thereof.

This invention further provides a method of treating in a mammal a disease or condition selected from the group consisting of stroke, spinal cord injury, traumatic brain injury, multi-infarct dementia, epilepsy, pain, Alzheimer's disease, and senile dementia, which method comprises administering to said mammal a cdk5 inhibitor and PTA the combined amounts of w of the cdk5 inhibitor and PTA being effective in treating said disease or condition. In one embodiment of the invention, the cbk5 inhibitor is a compound of formula I, or a pharmaceutically acceptable salt thereof. The cdk5 inhibitor and PTA may be administered to the mammal at the same time and / or at different times. In addition, they may be administered together with a single pharmaceutical composition or with separate pharmaceutical compositions.

This invention also provides a pharmaceutical composition for treating a disease or condition selected from the group consisting of stroke, spinal cord injury, traumatic brain injury, multi-infarct dementia, epilepsy, pain, Alzheimer's disease, and senile dementia in mammals containing a cdk5 inhibitor and NIF (neutrophil inhibitory factor) together, in an amount effective to treat said disorder, and a pharmaceutically acceptable carrier. According to one embodiment of the invention, the cbcb inhibitor is a compound of formula 1, or a pharmaceutically acceptable salt thereof.

tt · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

This invention further provides a method of treating in a mammal a disease or condition selected from the group consisting of stroke, spinal cord injury, traumatic brain injury, multi-infarct dementia, epilepsy, pain, Alzheimer's disease, and senile dementia, which method comprises administering to said cdk5 and NIF inhibitor mammal, the combined amounts of the cdk5 inhibitor and NIF being effective in treating said disease or condition. In one embodiment of the invention, the cbk5 inhibitor is a compound of formula I, or a pharmaceutically acceptable salt thereof. The cdk5 and NIF inhibitor may be administered to the mammal at the same time and / or at different times. In addition, they may be administered together with a single pharmaceutical composition or with separate pharmaceutical compositions.

This invention also provides a pharmaceutical composition for treating a disease or condition selected from the group consisting of Huntington's disease, stroke, spinal cord injury, traumatic brain injury, multi-infarct dementia, epilepsy, amyotrophic lateral sclerosis, pain, viral induced dementia, for example, AIDS-induced dementia, migraines, hypoglycemia, urinary incontinence, cerebral ischemia, multiple sclerosis, Alzheimer's disease, Alzheimer's type dementia, moderate cognitive impairment age-related cognitive impairment, vomiting, corticobasal degeneration, boxing dementia, Down syndrome, myotonic dystrophy, NiemannPick disease, Pick disease, prion confusion disease, progressive extracellular paralysis, more sclerosis, A mammalian subacute sclerosing panencephalitis comprising a cdk5 inhibitor and an NMDA receptor antagonist together, in an amount effective to treat said disease, and a pharmaceutically acceptable carrier. In one embodiment of the invention, the cdK5 inhibitor is a compound of formula I, or a pharmaceutically acceptable salt thereof.

This invention further provides a method of treating a mammal for a disease or condition selected from the group consisting of Huntington's disease, stroke, spinal cord injury, traumatic brain injury, multi-infarct dementia, epilepsy, amyotrophic lateral sclerosis, viral-induced dementia, for example, AIDS-induced dementia, migraines, hypoglycemia, urinary incontinence, cerebral ischemia, multiple sclerosis, Alzheimer's disease, Alzheimer's type dementia, moderate cognitive impairment and, age-related cognitive impairment, vomiting, corticobasal degeneration, boxing dementia, Down syndrome, myotonic dystrophy, NiemannPick disease, Pick disease, prion confusion disease, progressive extracellular paralysis, less sclerosis pancephalitis which method comprises administering to said mammal a cdk5 inhibitor and an NMDA receptor antagonist, the combined amounts of the cdk5 inhibitor and the NMDA receptor antagonist being effective in treating and the disease or condition indicated. In one embodiment of the invention, the cdK5 inhibitor is a compound of formula I, or a pharmaceutically acceptable salt thereof. The cdk5 inhibitor and the NMDA receptor antagonist may be administered to the mammal at the same time and / or at different times. In addition, they may be administered together with a single pharmaceutical composition or with separate pharmaceutical compositions.

This invention also provides a pharmaceutical composition for treating a disease or condition selected from the group consisting of stroke, spinal cord injury, traumatic brain injury, multi-infarct dementia, epilepsy, pain, Alzheimer's disease, and senile dementia in mammals containing a cdk5 inhibitor and a potassium channel modulator together, in an amount effective to treat said disorder, and a pharmaceutically acceptable carrier. In one embodiment of the invention, the cbk5 inhibitor is a compound of formula I, or a pharmaceutically acceptable salt thereof.

This invention further provides a method of treating in a mammal a disease or condition selected from the group consisting of stroke, spinal cord injury, traumatic brain injury, multi-infarct dementia, epilepsy, pain, Alzheimer's disease, and senile dementia, which method comprises administering to said mammal a cdk5 inhibitor and a potassium channel modulator, the combined amounts of the cdk5 inhibitor and the potassium channel modulator being effective in treating said disease or condition. In one embodiment of the invention, the cbk5 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 at the same time and / or at different times. In addition, they may be administered in conjunction with one of the following methods: A single pharmaceutical composition, or with separate pharmaceutical compositions.

The terms "treatment", "treatment", and the like, refer to reversing, ameliorating, or inhibiting the progression of the disease, or the condition to which such terms apply, or one or more symptoms of such disease, or state. As used herein, these terms also include, depending on the patient's condition, prevention of the onset of the disease or condition, or symptoms, association with the disease '*** no, or condition, including reduction of the severity of the disease, or a condition or symptoms associated with it prior to suffering from the said disease or condition. Such prevention or reduction prior to suffering relates to the administration of a compound of the invention to a subject who, during administration, does not suffer from a disease or condition or symptoms associated with them.

"Mammal" as used herein, and unless otherwise indicated, means any mammal. The term "mammal" includes, for example, and not limited to, dogs, cats, and humans.

"Abnormal cell growth" as used herein refers to cell growth, whether malignant (eg, as in cancer), or benign, which is independent of normal regulatory mechanisms (eg, inhibition in loss of contact). Examples of benign proliferative diseases are psoriasis, benign prostatic hypertrophy, human papillomavirus (HPV), and restinosis.

• · · · “Neurodegenerative diseases and conditions,” as used herein, refers to diseases and conditions associated with such neuronal degeneration. Conditions and diseases that are neurodegenerative in nature are generally known to those skilled in the art.

References to diseases and conditions "the treatment of which may be effective or facilitated by alteration of dopamine mediated neurotransmission" means a disease or condition caused at least in part by dopamine neurotransmission, or a disease or condition, resulting in abnormal dopamine neurotransmission, and thus leading to symptoms or manifestations of a disease or condition.

References here to diseases and conditions the treatment of which may be effective or facilitated by a decrease in cdk5 activity "means a disease or condition caused at least in part by the activity of cdk5, or a disease or condition that results in abnormal cdk5 activity leading to symptoms or manifestations of a disease or condition.

An "amount effective to inhibit cdk5 activity" as used herein refers to an amount of a compound sufficient to bind to the cdk5 enzyme with the effect of reducing cdk5 activity.

An "amount effective to inhibit cdk2 activity" as used herein refers to an amount of a compound sufficient to bind to the cdk2 enzyme with the effect of reducing cdk2 activity.

• • · • ··· * · • · • · • · • · · · · · · · ·· Ф4 • 4 ♦ · · • · ··

Detailed description of the invention

Compounds of formula I above and their pharmaceutically acceptable salts can be prepared according to the following reaction schemes and explanations. Unless otherwise stated, R ¹ , R ¹ , R ¹ , and R ¹ are as defined above. The isolation and purification of the products is carried out by standard procedures known to those skilled in the art.

As used herein, the term "reaction inert solvent" refers to a system of solvents in which the compounds do not interact with the starting materials, reagents, or intermediates of the products in a way that adversely affects the yield of the desired product.

Within any of the following synthetic sequences, it may be necessary and / or desirable to protect sensitive or reactive groups for any of the molecules in question. This can be accomplished by conventional protecting groups such as those described in T. W. Green, 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 1 illustrates methods suitable for the preparation of compounds of formula 1 wherein R ³ is -C (= O) NH, -C (= O) O-, or -C (= O) (CR ¹⁰ R ¹¹ ) _n - . According to Scheme 1, by reacting a solution of 1,4-dinitroimidazole (J.Phys. Chem. (1995) Vol. 99, pp. 5009-1015) in dimethyl sulfoxide (DMSO), a solvent system, pyridine-water, water, acetonitrile-water, alcohol, or alcohol-water, but preferably in a niche alcohol, such as methanol, at from at.

50 ° C, preferably from about -5 ° C to about 41

but 35 ° C, with primary alkyl or aryl amine, yields 1-Nsubstituted-4-nitroimidazole of formula 2. 1,4-dinitroimidazole is a highly energetic, semi-stable substance, and must be stored in the freezer at all times until used. Thermodynamic measurements indicate that it can potentially generate enough energy at 35 ° C under adiabatic conditions to cause a strong explosion. Extreme caution is required throughout the use of this product. The reduction of the nitro compound of formula 2 to the amine of formula 3 may be accompanied by the explosion of a mixture of the compound of formula 2 and a noble metal catalyst in a solvent such as ethyl acetate, tetrahydrofuran, dioxane, or a mixture thereof, in an atmosphere of hydrogen gas at a pressure in the range of about 1 to 100 atmospheres, where the preferred pressure of hydrogen gas is about one to about ten atmospheres. Palladium is the preferred precious metal catalyst. The metal may be suitably suspended in an inert solid carrier such as charcoal. After the compound of formula 2 is consumed, the mixture is filtered, and the resulting amine of formula ^w la 3 is reacted immediately with acid chloride

CIC (= O) (CR ¹⁰ R ¹¹ ) nR ⁴ , acid anhydride (R ⁴ (CR ¹⁰ R ¹¹ ) nC (= O)) ₂ O, or with an activated carboxylic acid derivative XC (= O) (CR ¹⁰ R ¹¹ ) nR ⁴ , in the presence of a base such as triethylamine, diisopropylethylamine, pyridine or 2,6-lutidine, from about -78 ° C to 40 ° C. A preferred combination is cyclic anhydride of 1-propanophosphoric acid and triethylamine. The activated carboxylic acid derivative is obtained from the carboxylic acid HOC (= O) (CR ¹⁰ R ¹¹ ) nR ⁴ , and a known activating reagent such as dicyclohexyl

carbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, carbonyl diimidazole, cyclic anhydride of 1-propan-phosphonic acid, alkyl, or aryl chloroformate, bis (2-oxo-3-oxazolidinyl) chloroformyl (dimethylamino) phosphonium hexafluorophosphate, or any such standard reagents known in the literature. This procedure yields a compound of formula 1B, wherein R ³ is -C (= O) (CR ¹⁰ R ¹¹ ) _n -.

Alternatively, after filtration, the amine of formula 3 may be treated with a base such as triethylamine, diisopropylethylamine, pyridine, 2,6-lutidine, and alkyl- or aryl-chloroformate, from about -78 ° C to 40 ° C. , -78 ° C to 40 ° C, with -78 ° C to 40 ° C being preferred to give a compound of formula 1 A, wherein R ³ is -C (= O) O- and R ⁴ is phenyl . Diisopropylethylamine and phenyl chloroformate are the preferred combination. Subsequent reaction of a phenyl carbamate of formula IA with a primary or secondary amine in a solvent such as dioxane, dimethylformamide or acetonitrile at a temperature of approximately 40 ° C and 90 ° C yields the corresponding urea product 1C, ^w where R ³ is -C (= O) NR ⁹ -, and R ⁴ is phenyl or heteroaryl. A mixture of 1: 1 dioxane-dimethylformamide at 70 ° C is preferred.

• · ·

Scheme 1 r ¹ nh ₂

1A

A process for the preparation of compounds of formula 1, wherein R ¹ is substituted with R ⁵ and R ⁵ is NHC (= O) R ⁸ , is shown in Scheme 2. When reacting the compound of formula 4, where R ⁵ is OH, with alkyl- or aryl-sulfonyl chloride, where p-toluenesulfonyl chloride (TosCI) is preferably in an inert reaction reagent.

a solvent such as tetrahydrofuran, methylene chloride, or chloroform, where methylene chloride is preferably at a temperature of about -10 ° C to about 30 ° C, in the presence of an amine base such as triethylamine, diisopropylethylamine, pyridine, or 2, 6-Lutidine, where triethylamine is preferred, and catalyst 4-N, N-dimethylaminopyridine, yields a compound of formula 5, wherein R ⁵ is CH 3 (C 6 H 4) SO 3 (TosO). Interaction of the tosylate thus formed with an alkali metal azide, preferably sodium azide, in a polar solvent such as dimethylformamide, dimethylsulfoxide, niche alcohol, water, or a mixture of these solvents, where an ethanol-water mixture is preferred, at a temperature of ca. 20 ° C to 130 ° C, preferably 90 ° C to 110 ° C, yields a compound of formula 6, wherein R ⁵ is N 3.

Interaction of the azide under selective reducing conditions such as trialkyl- or triarylphosphine and water, preferably triphenylphosphine, in a solvent such as tetrahydrofuran, dioxane, acetonitrile, or a mixture thereof, where tetrahydrofuran is preferred, to give a compound formula 7, wherein R ⁵ is 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, carbamoylyl chloride, acid chloride, acid anhydride, or an activated carboxylic acid derivative. The activated carboxylic acid derivative is obtained from a carboxylic acid and a known activating reagent such as dicyclohexyl carbodiimide, 1- (3-dimethylaminopropyl) -

3-ethylcarbodiimide, carbonyl diimidazole, cyclic 1-propanphosphonic acid anhydride, alkyl chloroformate, bis (245

• e

oxo-3-oxazolidinyl) phosphonic chloride, benzotriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate, or any other such standard reagents known in the literature, in the presence of an amine base, if necessary, such as triethylamine diisopropylethylamine, pyridine,

2,6-lutidine, where 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride is preferred, from about -78 ° C to 80 ° C, where 0 ° C to 40 ° C is preferred. Tetrahydrofuran and methylene chloride are preferred solvents.

Conversion of the compound thus obtained of formula 8, wherein R ⁵ is -NHC (= O) R ⁸ , to a compound of formula 1D (R ⁵ is NHC (= O) R ⁸ ; R ³ is C (= O) (CR ¹⁰ R ¹¹ ) 'R ⁴ ) may be carried out as a mixture of a compound of formula 8 and a noble metal catalyst, wherein palladium is the preferred catalyst for the parent metal, the metal being suitably suspended in an inert solid carrier such as activated carbon. in a solvent such as ethyl acetate, tetrahydrofuran, dioxane or a mixture thereof, hydrogen is exposed to a gas atmosphere at a pressure in the range of approximately 1 to 100 atm. ferric, where it is preferred pressure of hydrogen gas is in the range of about one to about ten atmospheres. After the compound of formula 8 is consumed, the mixture is filtered and the resulting amine acylated immediately by reacting with acid chloride, acid anhydride, or activated carboxylic acid derivative in the presence of an amine base, if appropriate, such as triethylamine. diisopropylethylamine, pyridine, 2,6-lutidine, wherein the preferred combination is cyclic anhydride of 1-propanophosphoric acid and triethylamine, from about -78 ° C to 40 ° C, to give the N-acylated product of formula 1D. The active carboxylic acid derivative is obtained from the carboxylic acid and a known activating reagent such as dicyclohexyl carbodiimide, 1- (3-dimethylaminopropyl) 3-ethylcarbodiimide, carbonyl diimidazole, cyclic anhydride of 1-propanoxosulfonic acid 3-oxazolidinyl) phosphine chloride, benzotriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate, or any other such standard reagent known in the literature.

If aryl chloroformate or heteroaryl chloroformate is used in the above acylation, instead of acid chloride, acid anhydride, or activated carboxylic acid derivative, aryl carbamate 1E is obtained. The resulting aryl carbamate 1E (R ³ is C (= O) - and R ⁴ is aryl or heteroaryl) can be treated with an amine in a solvent such as dioxane, dimethylformamide, or acetonitrile, where a mixture of dioxane dimethylformamide 1: 1 is preferably at a temperature of about 40 ° C and 90 ° C, where 70 ° C is preferred, to give the corresponding urea product of formula 1F (R ³ is -C (= O) NR ⁹ -, R ⁴ is aryl or heteroaryl).

Scheme 2

1F

Η • · ·

An alternative method for the preparation of compounds of formula 1 wherein R ⁵ is -NHC (= O) R ⁸ is shown in Scheme 3. In reaction of compound 4, where R ⁵ is OH, with alkyl- or aryl-sulfonyl chloride , p-toluenesulfonyl chloride (TosCI) is preferably in a reaction inert solvent such as tetrahydrofuran, methylene chloride, or chloroform, where methylene chloride is preferably at a temperature of about -10 ° C to about 30 ° C, in the presence of an amine base such as triethylamine, diisopropylethylamine, pyridine or 2,6-lutidine, and 4-N, N-dimethylaminopyrides , To give a compound of formula 5 wherein R ⁵ is CH3 (C6H4) SO3 (TosO) . Triethylamine is the preferred amine base. Conversion of a compound of formula 5 wherein R ⁵ is TosO) to a compound of formula 1G (R ⁵ is TosO, R ³ is C (= O) (CR ¹⁰ R ¹¹ ) nR ⁴ ) can be carried out as a mixture of a compound of formula 5 (R ⁵ is TosO), and a noble metal catalyst, in a solvent such as ethyl acetate, tetrahydrofuran, dioxane, or a mixture thereof, is exposed to a hydrogen gas atmosphere at a pressure in the range of approximately 1 to 100 atmospheres where the preferred pressure of hydrogen gas is in the range of about one to about ten atmospheres. Palladium is a preferred precious metal catalyst. The metal may be suitably suspended in an inert solid carrier such as activated carbon. After the compound of formula 5 is consumed, the mixture is filtered, and the resulting amine is reacted immediately with acid chloride, acid anhydride, or activated carboxylic acid derivative in the presence of an amine base, such as triethylamine, diisopropylethylamine, pyridine, if necessary. , or 2,6-lutidine, where the preferred combination is cyclic anhydride of 1-propanphosphoric acid and triethylamine, from about -78 ° C to 40 ° C, to give the N-acylated product of formula 1G. The activated carboxylic acid derivative is obtained from the carboxylic acid and a known activating reagent, such as dicyclohexyl carbodiimide, 1- (3-dimethylaminopropyl) 3-ethylcarbodiimide, carbonyl diimidazole, cyclic anhydride of 1-propanoxosulfonic acid (3-hydroxyphosphonic) -oxazolidinyl) phosphine chloride, benzotriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate, or any such standard reagent known in the literature.

The reaction of the compound of formula 1G (R ⁵ is TosO, R ³ is -C (= O) (CR ¹⁰ R ¹¹ ) n-) with an alkali metal azide, preferably sodium azide, in a polar solvent such as dimethylformamide, dimethyl sulfoxide, niche alcohol, water, or a mixture of these solvents, where a mixture of ethanol is preferred, at a temperature of from about 20 ° C to 130 ° C, preferably 90 ° C to 110 ° C, can be used to prepare a compound of formula 1H, wherein R ⁵ is N 3.

Subsequent reduction of the azide of formula 1H (R ⁵ is N3) may be carried out as a mixture of a compound of formula 1H (R ⁵ is N3), and a noble metal catalyst, wherein palladium is a preferred noble metal catalyst, as the metal may suitably be suspended in an inert solid carrier such as activated carbon, in a solvent such as ethyl acetate, tetrahydrofuran, dioxane, or a mixture thereof, is exposed to a gas atmosphere of hydrogen at a pressure in the order of about 1 to 100 atmospheres, where preferred hydrogen gas pressure is in the order of approx a sizable one to about ten atmospheres.

Alternatively, reducing the azide of formula 1H (R ⁵ is N 3) may be reacted with trialkyl-1 or triarylphosphine and water, such as triphenylphosphine, preferably in a solvent such as tetrahydrofuran, dioxane, or acetonitrile, preferably tetrahydrofuran. The primary amino group of the compound of formula 11 (R ⁵ is NH 2) can be derivatized by reaction with chloroformate, isocyanate, carbamoylyl chloride, acid chloride, acid anhydride, or an activated carboxylic acid derivative, to give the activated carboxylic acid derivative carboxylic acid and a known activating reagent such as dicyclohexyl carbodiimide, 1- (3-dimethylaminopropyl) 3-ethylcarbodiimide, carbonyl diimidazole, cyclic anhydride of 1-propanephosphonic acid, alkyl chloroformate, bis (2-oxo-oxides nil) phosphonic chloride, benzotriazol-1yloxy-tris (dimethylamino) phosphonium hexafluorophosphate, or any other such standard reagents known from the literature, in the presence of an amine base, if necessary, such as triethylamine, diisopropylethylamine, or diisopropylethylamine, or 6-lutidine, where 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride is preferred, from about -78 ° C to 80 ° C, with 0 ° C to 40 ° C being preferred. Tetrahydrofuran and methylene chloride are preferred solvents.

Scheme 3

• · · ·

• ·

N — R ³ —R ⁴ I

H

Compounds of formula 1 wherein R ³ is - (CR ¹⁰ R ¹¹ ) _n - can be prepared according to Scheme 4. According to Scheme 4, reaction of a solution of 4-bromimidazole with a base such as sodium hydride, potassium hydride, lithium hydride , cesium carbonate, sodium hydroxide, potassium hydroxide, cesium hydroxide, lithium diisopropyl amide, sodium amide, potassium hexamethyldisilazide, sodium hexamethyldisilazide, sodium tert-butoxide, or potassium tertiary tartrate, and tertiary tertiary -dioxane, N, N-dimethylformamide, dimethyl sulfoxide, or oluene, from about -20 ° C to 150 ° C, preferably 20 ° C 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, benzyltrimethyl ammonium chloride, benzyltrimethyl ammonium bromide, or benzyltrimethyl ammonium fluoride, followed by the addition of alkyl, allyl or benzyl chloride, bromide, iodide, alkylnitanyl, sulfonyl, sulfonyl a mixture of 1-substituted-4-bromimidazole (9) and 1-substituted-5-bromimidazole (10), which empowered to separate, by using methods known to those skilled in the art.

Alternatively, the reaction of 4-bromimidazole with allyl fluoride, chloride, bromide, iodide, acetate or carbonate, preferably allyl carbonate, in a reaction inert solvent such as tetrahydrofuran, 1,2-dichloroethane, 1,4 dioxane, Ν, N-dimethylformamide, preferably tetrahydrofuran, in the presence of a palladium catalyst, such as palladium (O) tetrakis (triphenylphosphine), palladium (II) acetate, allyl palladium chloride dimer, tris (dibenzylideneacetone) dipalladium (0), trisene (dicene) dipalladium (0) • chloroform adduct, palladium (II) chloride, as prefer palladium (O) tetrakis (triphenylphosphine) or palladium (II) acetate, I presence, or in the absence of a phosphine ligand such as triphenylphosphine, tri-o-tolylphosphine, tri-tertbutylphosphine, 1,2-bis (diphenylphosphine) , or 1,3-bis (diphenylphosphino) propane, from about 0 ° C to 100 ° C, preferably 50 ° C to 80 ° C, produces a mixture of 1-substituted-4-bromimidazole (9) and 1- substituted-5-bromimidazole (10).

By reacting 1-substituted-4-bromimidazole (9) with an intermediate of formula -NH ₂ (CR ¹⁰ R ¹¹ ) nR ⁴ and a palladium catalyst such as palladium (II) acetate, allyl palladium dimer, tris (dibenzylideneacetone) dipaladium (0), tris (dibenzylideneacetone) dipaladium (0) chloroform adduct, or palladium (II) chloride, preferably palladium (II) acetate, tris (dibenzylideneacetone) dipaladium (0), and tris (dibenzylideneacetone) dipaladium (0) a chloroform adduct, and a phosphine ligand such as BINAP, 2-biphenyl dicyclohexylphosphine, 2-biphenyl di-tert-butylphosphine, or 2-N, N-dimethylamino-2'-di phenylphosphino biphenyl such as 2-N, N-dimethylamino-2'-diphenylphosphino biphenyl is preferred, and a base such as sodium tert-butoxide, cesium carbonate, or potassium phosphate (K3PO ₄ ), preferably potassium phosphate, in inert inert the reaction of a solvent such as 1,4-dioxane or tetrahydrofuran from about 0 ° C to 150 ° C, preferably 20 ° C to 110 ° C, yields the conjugated product 1.

• ··

Scheme 4

Chvi * '

An alternative method for synthesizing compounds of formula 1 wherein R ³ is -C (= O) (CR ¹⁰ R ¹¹ ) n- is illustrated in Scheme 5 below. By reacting ethyl 2-isocyano-3 ', N-dimethylaminoacrylate (11) with a primary amine, R ¹ -NH 2, in a solvent such as n-butanol, n-propanol, 1-propanol, or in the absence of a solvent such as preferably n-propanol, or in the absence of a solvent, from about 23 ° C to 200 ° C, preferably from about 60 ° C to about 150 ° C, imidazoles of formula 12 are obtained. : · *. :::::; · Interaction of N, O-dimethyl hydroxyl amine hydrochloride with trimethylaluminum in 1,2-dichloroethane, followed by the addition of 12 and heating at approximately 30 ° C to 80 ° C, preferably a temperature of approximately 50 ° C, to produce the imidazole 13. addition of an organometallic reagent M- (CR ¹⁰ R ¹¹⁾ _n R ^4, wherein M may be either lithium or magnesium halide, preferably magnesium halide, to a solution of 13 in a solvent, such as tetrahydrofuran, methylene chloride, or diethyl ether, at a temperature of about -50 ° C to riblizitelno 30 ° C, preferably range

J ** '· in the range of about -20 ° C to about 0 ° C results in 14. The addition of 14 to a mixture of hydroxyl amine hydrochloride and potassium acetate in a solvent niche alcohol, preferably ethanol, at about 23 ° C, yields oxime 15, in the form of a mixture of isomers. Reaction of acetone solution of oxime 15 at approximately 0 ° C with aqueous sodium hydroxide solution and then with paratoluenesulfonyl chloride results in a mixture of O-sulfonyl compounds followed by extraction. After dissolving the crude product in a non-fields ^w ren solvent such as benzene, hexanes, or toluene, preferably benzene, and passing through a column of alumina followed by elution with chloroform-methanol (about 10: 1), then for approximately five minutes, compound 1B and regioisomers of Beckmann rearrangement were obtained.

Scheme 5 ····

IB

Compounds of formula IJ may also be prepared according to the method illustrated in Scheme 6 below. A key starting point for this synthesis is the double bond compound (compound of formula X) substituted with the ER ⁵ group and one to three groups selected from the group consisting of R ⁵ (X), where ER ⁵ is defined as an electron- extraction group selected from the group consisting of C (= O) R ⁷ , C (= O) OR ⁷ , C (= O) NR ⁷ R ⁸ , C (= O) 2R ⁷ , S (= O) 2R ⁷ R ⁸ , S (= O) ₂ R ⁷ , cyano, and heteroaryl. In addition, compounds of formula X may be those in which ER ⁵ is attached to one of the groups R ⁵ , or directly to the carbon-carbon double bond to form a ring, and thus includes compounds such as 2-cyclopentene-1 -one and 2cyclohexen-1-one. Alternatively, compounds of formula X, wherein L is defined as Cl, Br, I, OC (= O) OR ⁷ , or S (= O) 2R ⁷ , can be used as starting materials; examples of such compounds are 3-chloro-1-cyclopentanone, 3-acetoxy-1-cyclobutanone. Thus, according to Scheme 6, when a salt of 4 (5) -nitroimidazole is reacted, where the salt is sodium, potassium, cesium, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), or tetraalkyl ammonium, wherein tetra n-butylammonium and DBU are the preferred salts, with intermediates 16 or 17, in a solvent such as acetonitrile, methylene chloride, 1,2-dichloroethane, or chloroform, where acetonitrile is the preferred solvent, at a temperature of about -60 ° C to about 50 ° C, preferably -20 ° C to 23 ° C, yields a coupling product of formula 2A. Reduction of nitro compound 2A can be accomplished as a mixture of 2A and a noble metal catalyst, wherein palladium is a preferred noble metal catalyst, the metal being suitably suspended in an inert solid carrier such as activated carbon in a solvent such as ethyl acetate, tetrahydrofuran, dioxane, or a mixture thereof, is exposed to a hydrogen gas atmosphere at a pressure in the range of about 1 to 100 atmospheres, where the preferred hydrogen gas pressure is in the order of about one to about ten atmospheres. After 2A was consumed, the mixture was filtered, and the resulting amine was reacted immediately with acid chloride CIC (= O) (CR ¹⁰ R ¹¹ ) nR ⁴ , acid anhydride (R ⁴ (CR ¹⁰ R ¹¹ ) nC (= O)) ₂ O, or activated carboxylic acid strong acid derivative XC (= O) (CR ¹⁰ R ¹¹ ) nR ⁴ , in the presence of an amine base such as triethylamine, diisopropylethylamine, pyridine, 2,6-lutidine, where cyclic anhydride is preferred 1-propanophosphoric acid and triethylamine, from about -78 ° C to 40 ° C, to give 1J. The activated carboxylic acid derivative is obtained from the carboxylic acid HOC (= O) (CR ¹⁰ R ¹¹ ) nR ⁴ , and a known activating reagent such as dicyclohexyl carbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, carbonyl diimide, carbonyl diimide cyclic anhydride of 1-propan-phosphonic acid, alkyl or aryl chloroformate, bis- (2-oxo-3-oxazolidinyl) phosphine chloride, benzotriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate, or such standard or any such standard.

Alternatively, after filtration, the intermediate amine may be reacted with a base such as triethylamine, diisopropylethylamine, pyridine or 2,6-lutidine, and alkyl- or aryl chloroformate, where diisopropylethylamines and phenyl chloroformate are preferred combinations of about -78 ° C. to about 40 ° C, preferably about -78 ° C to about -40 ° C, 1K is obtained.

Subsequent reaction of 1K with a primary or secondary amine in a solvent such as dioxane, dimethylformamide or acetonitrile, where a dioxane-dimethylformamide 1: 1 mixture is preferred at a temperature between about 40 ° C and about 90 ° C, preferably ca. 70 ° C, yields the corresponding urea product 1L.

• · · ·

Further transformation of compounds 2A, 1 J, 1K and 1L, using methods known to those skilled in the art, can be carried out to obtain the more compounds of formula I described in this application.

Compounds of formula 1 as described herein where R ² is other than hydrogen may be prepared by conversion of compounds of formula 1 described herein wherein R ² is hydrogen using methods well known to those skilled in the art of the technique. For example, compounds of formula 1 where R ² is F can be prepared by acting on compounds of formula 1 where R ² is hydrogen, for example, compounds of formula 1A, 1B and 1C according to Scheme 1, supra, c N-fluorobenzenesulfonamide in toluene, xylene, or dioxane, at a temperature from about room temperature to about 150 ° C, preferably from about 100 ° C to about 120 ° C.

Figure 6

· · · · · · · · · · · · · · · · · · · · · ·

Pharmaceutically acceptable salts of compounds of formula I may be prepared in a conventional manner by acting in solution or suspension of the corresponding free base or acid with one chemical equivalent of a pharmaceutically acceptable acid or base. Conventional concentration or crystallization techniques may be used to isolate the salts. Illustrations of suitable acids are acetic, lactic, succinic, maleic, tartaric, citric, gluconic, ascorbic, benzoic, cinnamon, fumaric, sulfuric, phosphoric, hydrochloric, hydrobromic, hydrofluoric, sulfamic, sulfonic acid, sulphonosulfonic acids, and related acids. The basics illustrations are sodium, potassium, and calcium.

Compounds of this invention may be administered alone or in combination with pharmaceutically acceptable carriers, or in single or multiple doses. Suitable pharmaceutical carriers include, inert solid solvents or excipients, sterile aqueous solutions, and various organic solvents. The pharmaceutical compositions formed by combining a compound of formula I, or a pharmaceutically acceptable salt thereof, can be readily administered in a variety of single unit dosage forms, such as tablets, powders, candies, syrups, injectable solutions and the like. These pharmaceutical compositions may optionally contain additional constituents, such as flavoring agents, binders, excipients, and the like. Thus, for oral administration, tablets containing various excipients such as sodium citrate, calcium carbonate, and calcium phosphate may be used in conjunction with various disintegrants such as starch, methylcellulose, alginic acid, and some complex silicates together with binders such as polyvinylpyrrolidone, sucrose, gelatin and acacia. In addition, oily effects such as magnesium stearate, sodium lauryl sulfate, and talc are often used for tabletting purposes. Solid compositions of this kind can also be used as fillers in soft and hard gelatin capsules. Preferred products for this include milk sugar and high molecular weight polyethylene glycols. When aqueous suspensions or elixirs for oral administration are desired, the main constituent therein may be combined with various sweeteners or flavoring agents, coloring products or dyes, and, if desired, emulsifiers or suspending agents, together with diluents such as water, ethanol, propylene glycol, glycerin and combinations thereof.

For parenteral administration, solutions containing a compound of this invention, or a pharmaceutically acceptable salt thereof, in sesame or peanut oil, ethylene glycol in water, or in sterile aqueous solutions, may be used. Such aqueous solutions could be suitably buffered, if necessary, and the liquid solvent first rendered isotonic with sufficient saline or glucose. These particular aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. The sterile aqueous media used are readily available through standard techniques well known to those skilled in the art.

A compound of formula I, or a pharmaceutically acceptable salt thereof, may be administered orally, transdermally, (e.g., using patches), parenterally, (e.g., intravenously), rectally, or topically. Typically, the daily dose for treating a neurodegenerative disease, or condition, or disease, or condition whose treatment can be effectively or facilitated by alteration of dopamine-mediated neurotransmission, should generally be in the range of approximately 0.0001 to approximately 10.0 mg / kg body weight of the patient to be treated. The daily dose for the treatment of cancer or disease or condition involving abnormal growth of cells of malignant nature is also generally in the range of approximately 0.0001 to about 500 mg / kg body weight of the patient to be treated. As an example, a compound of formula 1, or a pharmaceutically acceptable salt thereof, can be used to treat a neurodegenerative disorder in a middle-aged adult (approximately 70 kg with a dose in the range of about 0.01 mg to about 1000 mg per day, for preferably from about 0.1 to about 500 mg per day, per dose, or divided (i.e., into multiple) doses The daily dose for the treatment of diabetes, sperm motility, hair loss, or any other disease or condition , which can be treated by inhibiting n GSK-3 should generally be in the range of about 0.0001 to about 10.0 mg / kg body weight of the patient to be treated. Various changes based on the above dosage ranges may are made by the treating physician or by a person skilled in the art, having regard to known factors such as weight, age, and condition of the person to be treated, how severely affected, and the particular mode of treatment. the application that is selected.

The compounds of formula I and their pharmaceutically acceptable salts may further be administered or prepared in the form of pharmaceutical compositions with known amounts of one or more substances selected from the group consisting of anti-angiogenesis agents , signal transduction inhibitors, and antiproliferative agents, which, together, are effective in inhibiting abnormal cell growth.

Anti-angiogenic agents such as MMP-2 (matrix metalloprotein 2) inhibitors, MM-9 (matrix metalloprotein 9) inhibitors, and COX-II (cyclooxygenase II) inhibitors can be used in conjunction with a compound of formula 1 in methods and in the pharmaceutical compositions described herein for the treatment of abnormal cell growth, including cancer. ^w 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 October 24, 1996), WO 96/27583 (published March 7, 1996), European Patent Application No. 4/18.

97304971.1 (filed July 8, 1997), European Patent Application No. 4/2007

99308617.2 (filed October 29, 1999), WO 98/07697 (published February 26, 1998), WO 98/03516 (published January 29, 1998), WO 98/34918 (published August 13, 1998), WO 98/34915 ( published August 13, 1998), WO 98/33768 (published August 6, · · · ·

1998), WO 98/30566 (published July 16, 1998), WO 98/34918 (published August 13, 1998), European Patent Publication 606,046 (published July 13, 1994), European Patent Publication 931,788 (published July 28, 1999) , WO 90/05719 (published May 331, 1990), WO 99/52910 (published October 21, 1999), WO 99/52889 (published October 21, 1999), WO 99/29667 (published June 17,

1999), PCT International Application No. PCT / IB98 / 01113 (filed July

European Patent Application No. 21, 1998). 99302232.1 (filed March 25, 1999), United Kingdom patent application number

9912961.1 (filed June 3, 1999), United States 60 / 148,464 (filed August 12, 1999), United States Patent 5, 863,949 (issued January 26, 1999), Unated States Patent 5, 861,510 (issued January 19, 1999), and European Patent Publication 780,336 (published June 25, 1997 ), all of which are incorporated herein by reference in their entirety. Preferred MMP-2 and MMP-9 inhibitors are those that have little or no activity to inhibit MMP-1. More selectively those that inhibit MMP-2 and / or MMP-9 selectively than other matrix metalloproteinases (i.e., MMP-1, MMP-3, MMP-4, MMP-5, MMP-6, MMP) -7, MMP-8, MMP-10, MMP-11, MMP-12, and MMP-13).

Some specific examples of MMP inhibitors useful according to the present invention are AG-3340, RO 32-2555, RS 13-0830, and the compounds listed in the following list:

3 [[[4_ (4-Fluoro-phenoxy) -benzenesulfonyl] - (1-hydroxycarbamoyl-cyclopentyl) -amino] -propionic acid;

3-Exo-3- [4- (4-fluoro-phenoxy) -benzenesulfonylamino] -8-oxa-bicyclo [3.2.1] octane-3-carboxylic acid hydroxyamide;

• ·

(2R, 3R) 1 [4- (2-Chloro-4-fluoro-benzyloxy) -benzenesulfonyl] -3-hydroxy-3-methyl-piperidine-2-carboxylic acid hydroxyamide;

4- [4- (4-Fluoro-phenoxy) -benzenesulfonylamino] -tetrahydro-pyran-4-carboxylic acid hydroxyamide;

3 - [[4- (4-fluoro-phenoxy) -benzenesulfonyl] - (1-hydroxycarbamoyl-cyclobutyl) -amino] -propionic acid;

4- [4- (4-Chloro-phenoxy) -benzenesulfonylamino] -tetrahydro-pyran-4-carboxylic acid hydroxyamide;

(R) 4- [4- (4-Chloro-phenoxy) -benzenesulfonylamino] -tetrahydro-pyran-3-carboxylic acid hydroxyamide;

(2R, 3R) 1- [4- (4-Fluoro-2-methyl-benzyloxy) -benzenesulfonyl] -3-hydroxy-3-methyl-piperidine-2-carboxylic acid hydroxyamide;

3 - [[4- (4-fluoro-phenoxy) -benzenesulfonyl] - (1-hydroxycarbamoyl-1-methyl-ethyl) -amino] -propionic acid;

3 - [[4- (4-fluoro-phenoxy) -benzenesulfonyl] - (4-hydroxycarbamoyl-tetrahydro-pyran-4-yl) -amino] -propionic acid;

3-Exo-3- [4- (4-chloro-phenoxy) -benzenesulfonylamino] -8-oxa-bicyclo [3.2.1] octane-3-carboxylic acid hydroxyamide;

3-endo-3- [4- (4-fluoro-phenoxy) -benzenesulfonylamino] -8-oxa-bicyclo [3.2.1] octane-3-carboxylic acid hydroxyamide; and (R) 3- [4- (4-fluoro-phenoxy) -benzenesulfonylamino] tetrahydro-furan-3-carboxylic acid hydroxyamide;

and pharmaceutically acceptable salts and solvates of said compounds.

Other anti-angiogenic agents including other COX-II inhibitors and other MMP inhibitors may be used according to the present invention.

The effective amount of a COX-II inhibitor in combination with a cdk5 inhibitor, for example a compound of formula 1, can usually be determined by one of ordinary skill in the art. The proposed daily effective 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. The effective daily amount of the cdk5 inhibitor is typically between about 0.001 to about 10 mg / kg body weight. Sometimes the amount of COX-II inhibitor and / or cdk5 inhibitor in the combination may be lower than what would be required on an individual basis to achieve the same desired effect of inhibiting abnormal cell growth.

A compound of formula 1 can also be used with signal transduction inhibitors, such as agents that can inhibit EGFR (epidermal growth factor receptor) responses, such as EGFR antibodies, EGF antibodies, and molecules that are EGFR inhibitors; VEGF (vascular endothelial growth factor) inhibitors; and inhibitors of the erb2 receptor, such as organic molecules, or antibodies that bind to the erb2 receptor, for example, HERCEPTIN ™ (Genenthech, Inc. of South San Francisco, California, USA). Such combinations are useful for treating and preventing abnormal cell growth, including cancer, as described herein.

EGFR inhibitors are described, for example, in

WO 95/19970 (published July 27, 1995), WO 98/14451 (published • · · ·

Apri 9, 1998), WO 98/02434 (published January 22, 1998), and Unated States Patent 5,747,498 (issued May 5, 1998), and such substances can be used according to the present invention as described herein. EGFR-inhibiting agents include, but are not limited to, monoclonal antibodies C225 and anti-EGFR 22Mab (ImClone Systeme Incorporated of New York, NY), compounds ZD-1839 (AstraZeneca), BIBX-1382 (Boehringer Ingelheim), MDX -447 (Medarex Inc. of Annandale, New Jersey, USA), and OLX-103 (Merck & Co. of Whitehouse Station, New Jersey, USA), VRCTC-310 (Ventech Research) and EGF fusion toxin (Seragen Inc. of Hopkinton, Massachusettes). These and other EGFR-inhibiting agents can be used according to the present invention.

VEGF inhibitors, for example, SU-5416 and SU-6668 (Sugen Inc. of South San Francisco, California, USA), can also be combined with a compound of formula 1. VEGF inhibitors are described, for example, in WO 99/24440 ( published May 20, 1999), PCT International Application PCT / IB99 / 00797 (filed May 3, 1999), in WO 95/21613 (published August 17, 1995), WO 99/61422 (published December 2, 1999), Unated States Patent 5,834,504 (issued November 10, 1998), WO 98/50356 (published November 12, 1998), United States Patent 5,883,113 (issued March 16, 1999), United States Patent 5,886,020 (issued March 23, 1999), Unated States Patent 5,797,783 (issued August 11,

1998), WO 99/10349 (published March 4, 1999), WO 97/32856 12, (published September 12, 1997), WO 97/22596 (published June 26, 1997), WO 98/54093 (published December 3, 1998), WO 98/02438 (published January 22, 1998), WO 99/16755 (published April 8,

1999), and WO 98/02437 (published January 22, 1998), all of which are incorporated herein by reference in their entirety. Other examples of some specific VEGF inhibitors useful in the present invention are IM862 (Cytran Inc. of Kirkland, Washington, USA); Genentech, Inc. anti-VEGF monoclonal antibody of South San Francisco, California; and angiosim synthetic ribozyme from Ribozome (Boulder, Colorado) and Chiron (Emeryville, California). These and other VEGF inhibitors can be used according to the present invention as described herein.

EgbB2 inhibitors, such as GW-282974 (Glaxo Wellcome pic), and the monoclonal antibodies AR-209 (Agopeh Pharmaceutical Inc. of The Woodlands, Texas, USA), and 2B-1 (Chiron), can also be combined with a compound of formula 1, for example, those specified in WO 98/02434 (published January 22, 1998), WO 99/35146 (published July 15, 1999), WO 99/35132 (published July 15, 1999), WO 98 / 02437 (published January 22, 1998), WO 97/13760 (published April 17, 1997), WO 95/19970 (published July 27, 1995), United States Patent 5,587,458 (issued December 24, 1996), and Unated States Patent 5,877,305 (issued March 2, 1999), all of which are incorporated herein by reference in their entirety. ErbB2 receptor inhibitors useful according to the present invention are also described in Unated States Provisional Application No. 5 60 / 117,341, filed Jan. 27, 1999, and Unated States Provisional Application No. 60 / 117,346 filed January 27, 1999, both of which are hereby incorporated by reference in their entirety. The compounds of inhibitors of the erbB2 receptor and the substance described in the above-mentioned PCT application, US pdtents, and US provisional application, as well as other compounds and substances that inhibit the erbB2 receptor can be used with a compound of formula I according to the present invention.

• · · · · · · · · · · · · · · · · · · · · · · · ·

The compound of formula 1 may also be used with other agents useful for treating abnormal cell growth or cancer, including, but not limited to, agents capable of enhancing antitumor immune responses, such as CTLA4 (cytotoxic lymphocyte antigen 4) antibodies, and other agents capable of blocking CTLA4; and antiproliferative agents such as farnesyl protein transferase inhibitors. Specific CTLA4 antibodies that can be used according to the present invention include those described in Unated States Provisional Application No. 5 60 / 113,647, (filed December 23, 1998), which is incorporated herein by reference in its entirety, however CTLA4 antibodies can be used according to the present invention.

Compounds of formula I may also be administered according to methods for inhibiting abnormal cell growth in mammals in combination with radiation therapy. Techniques for administering radiation therapy are known in the art, and these techniques can be used in the combination therapy described herein. The use of the compound of this invention in this combination therapy can be determined as described herein.

Cdk5 inhibitors, such as a compound of formula 1, may also be administered in combination with COX-II for the treatment of Alzheimer's disease, middle cognitive impairment, or age-related cognitive decline. Specific examples of COX-II inhibitors useful in this aspect of the invention are provided above, which describes the use of COX-II inhibitors in combination with a compound of formula 1 for the treatment of abnormal cell growth. The effective amount of a COX-II inhibitor, in combination with a cdk5 inhibitor, for example a compound of formula 1, can typically be determined by one of ordinary skill in the art. The proposed effective 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. The daily effective amount of a cdk5 inhibitor is typically between about 0.0001 to about 10 mg / kg body weight. Occasionally, the amount of COX-II inhibitor and / or the amount of cdk5 inhibitor in combination may be lower than necessary on an individual basis to exert the same desired effect in treating Alzheimer's disease of moderate cognitive impairment. , or age-related impairment of cognitive abilities.

Cdk5 inhibitors, such as compounds of formula 1, may also be administered in combination with an NK-1 receptor antagonist for the treatment of depression or anxiety. An NK-1 receptor antagonist, as referred to herein, is a substance that is capable of acting as an antagonist against NK-1 receptors and therefore inhibiting tashikinin mediated responses, such as substance P. mediated responses. -1 receptor are known in the art, and any NK-1 receptor antagonists can be used according to the present invention, as described above, in combination with a cdk5 inhibitor, for example, a compound of formula 1. Antagonists of the NK-1 receptor are described, for example, United States Patent 5,716,965 (issued February 10, 1998); United States Patent 5,852,038 (issued December 22, 1998); WO 90/05729 (International • · · · · · · (· · · · · · · · · · · · · · ·

Publication Date May 31, 1990); United States Patent 5,807,867 (issued September 15, 1998); United States Patent 5,886,009 (issued March 23, 1999); United States Patent 5,939,433 (issued August 17, 1999); United States Patent 5,773450,504 (issued June 30, 1998); United States Patent 5,744,480 (issued April 28, 1998); United States Patent 5,232,929 (issued August 3, 1993); United States Patent 5,332,817 (issued July 26, 1994); United States Patent 5,122,525 (issued June 16, 1992); United States Patent 5,843,966 (issued December 1, 1998); United States Patent 5,703,240 (issued December 30, 1997); United States Patent 5,719,147 (issued February 17, 1998); and United States Patent 5,637,699 (issued June 10, 1997). All of the above U. S. patents and the aforementioned published PCT International Application are incorporated herein by reference in their entirety. The compounds described in these references, having NK-1 receptor antagonist activity, can be used according to the present invention. However, other NK-1 receptor antagonists may also be used in accordance with this invention.

The effective amount of an NK-1 receptor antagonist in combination with a cdk5 inhibitor, for example a compound of formula 1, can generally be determined by one of ordinary skill in the art. The proposed effective daily dose of NK-1 receptor antagonist, in combination with a cdk5 inhibitor, is in the range of approximately 0.07 to approximately 21 mg / kg body weight. The daily effective amount of a cdk5 inhibitor is typically between about 0.0001 to about 10 mg / kg body weight. Sometimes the amount of NK-1 receptor antagonist and / or the amount of cdk5 inhibitor in the combination may be greater

Whose »· ··· · · · · · · · ···· · · · ·· * ······ · · · · · 72 ♦! · *» · * ’··’ »ί · * ·· ·· lower than necessary on an individual basis to exert the same desired effect in the treatment of depression or anxiety.

The present invention also provides a combination of a cdk5 inhibitor, such as a compound of formula 1, with a 5HT ₁₀ receptor antagonist for the treatment of depression or anxiety. The 5HT _1D receptor antagonist, as referred to herein, is a substance that acts as an antagonist against the 5HT _1D subtype of the serotonin receptor. Any such substance can be used according to the present invention, as described above, in combination with a cdk5 inhibitor, for example, a compound of formula 1. Substances having antagonistic activity against the 5HT 10 receptor can be determined by those skilled in the art the field of technology. For example, 5HT ₁₀ receptor antagonists are described in WO 98/14433 (International Publication Date April 9, 1998); WO 97/36867 (International Publication Date October 9, 1997); WO 94/21619 (International Publication Date September 29, 1994); United States Patent 5,510,350 (issued April 23, 1996); United States Patent 5,358,948 (issued October 25, 1994); and GB 2276162 A (publiahed September 21, 1994). These 5HT _1D receptor antagonists, as well as others, can be used according to the present invention. The above-mentioned published patent applications and patents are incorporated herein by reference in their entirety.

The effective amount of a 5HT _1D receptor antagonist in combination with a cdk5 inhibitor, for example a compound of formula 1, can generally be determined by those skilled in the art. The proposed effective daily dose of a 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. The daily effective amount of a cdk5 inhibitor is typically between about 0.0001 to about 10 mg / kg body weight. Sometimes the amount of 5HT ₁₀ receptor antagonist and / or the amount of cdk5 inhibitor in the combination may be lower than necessary on an individual basis to exert the same desired effect in the treatment of depression or anxiety.

This invention also provides a pharmaceutical composition and method for treating depression or anxiety in a mammal comprising a cdk5 inhibitor, for example a compound of formula 1, and SSRI. Examples of SSRIs that can be combined according to the method or pharmaceutical composition with cdk5 inhibitors, for example compounds of formula 1, and their pharmaceutically acceptable salts include, but are not limited to, fluoxetine, paroxetine, sertraline, and fluvoxamine. Other SSRIs may be combined or administered in combination with a cdk5 inhibitor, for example a compound of formula I, or a pharmaceutically acceptable salt thereof. Other antidepressants and / or anxiolytic agents with which a cdk5 inhibitor, such as a compound of formula 1, may be combined or administered include WELLBUTRIN, SERZONE and EFFEXOR.

The effective amount of SSRI in combination with a cdk5 inhibitor, for example a compound of formula 1, can generally be determined by those skilled in the art. The proposed effective daily dose of SSRI, in combination with a cdk5 inhibitor, is in the range of about 0.01 to about 500 mg / kg body weight. The daily effective amount of a cdk5 inhibitor is typically between about 0.0001 to about 10 mg / kg body weight. Sometimes the amount of SSRIs and / or the amount of cdk5 inhibitor in the combination may be lower than necessary on an individual basis to exert the same desired effect in the treatment of depression or anxiety.

The cdk5 inhibitor, for example compounds of formula 1, or a pharmaceutically acceptable salt thereof, may also be combined with one or more antipsychotic agents, for example, a dopaminergic agent, for treating diseases or conditions that can be treated efficiently, or facilitated, by altering dopamine neurotransmission, such as schizophrenia. Examples of antipsychotics with which a compound of the invention may be combined include cyprazidone (5- (2- (4- (1,2-benzisothiazol-3-yl) -1-piperazinyl) -6-chloro-1,3-dihydro -2Nindol-2-one; US Patent 4,831,031 and US Patent 5,312,925); olanzapine (2-methyl-4- (4-methyl-1-piperazine-10T-thieno (2, 3b) (1,5) benzodiazepine; US Patent 4,115,574 and US Patent 5,229,382); risperidone (3- [2- [4- (6-fluoro-1,2-benzisoxazol-3yl) -1-piperadinyl] ethyl] 6,7,8,9-tetrahydro-2-methyl -4H-pyrido [1,2-a] pyrimidin-4-one; US Patent 4,804,663); L-745870 (3- (4- (4-chlorophenyl) piperazin-1-yl) methyl-1H-pyrrolo (2,3 -B) Pyridine, US Patent 5,432,177; Sonepiperazole (5-4- (4- (2- ( isochroman-1-yl) ethyl) piperazin-1-yl) -benzenesulfonamide; US Patent 5,877,317); RP 62203 (fananzerine; 2- (3- (4- (4-fluorophenyl) -1-piperazinyl) naphtho (1,8-c, 6) ) isothiazole-1,1-dioxide; US Patent 5,021,420); NGD 941 (US Patent 5,633,376 and US Patent 5,428,165); balaperidone ((1α, 5α, 6a) -3- (2- (6- (4-fluorophenyl) - 3azabicyclo (3.2.0) hept-3-yl) -ethyl-2,4 (1H, 3H) -quinazoline;

• · · · · • · · · · · · · · · · ··· * U. S. Patent 5,475,105); flezinoxane ((+) - 4-fluoro-N- [2- [4-5- (2hydroxymethyl-1,4-benzodioxanyl)] -1-piperazinyl] ethyl] -benzamide; U. S. Patent 4,833,142); and hepirone (4,4-dimethyl-1- (4- (4- (2-pyrimidinyl) -1-piperazinyl) butyl) -2,6-piperidinedione; U. S. Patent 4,423,049). All patents referred to in this paragraph are fully incorporated by reference herein. The effective daily amount 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 abovementioned antipsychotics that is believed to be used in combination with a cdk5 inhibitor, for example a compound of formula 1, is generally the amount known in the art, that it is useful for treating psychotic conditions. However, sometimes the amount of antipsychotics and / or the amount of cdk5 inhibitor in the combination may be lower than necessary on an individual basis to achieve the same desired effect in the treatment of depression or anxiety. Furthermore, it should be understood that the present invention also encompasses combining a cdk5 inhibitor, for example a compound of formula 1, with an antipsychotic, or dopaminergic other than those in the above list.

The amount proposed for sonepiperazole in combination with the cdk5 inhibitor described above, for example, a compound of formula 1 is from about 0.005 to about 50 mg / kg body weight per patient per day. The suggested amount for RP 62203 in such combination is from about 0.20 to about 6 mg / kg of patient body weight per day. The suggested amount for NGD 941 in such a combination is from about 0.1 to about 140 mg / kg body weight per day. The amount suggested for balaperidone in

such a combination is from about 1 to about

100 mg / kg body weight per day. The amount suggested for flesinoxane in such combination is from about 0.02 to about 1.6 mg / kg body weight per patient per day. The suggested amount for gepirone in such a combination is from about 0.01 to about 2 mg / kg of patient body weight per day. The amount proposed for L-745870 in such combination is from about 0.01 to about

250 mg / kg patient body weight per day, preferably from about 0.05 to about 100 mg / kg patient body weight per day. The suggested amount for rice peridone in such combination is from about 0.05 to about 50 mg / kg of patient body weight per day. The suggested amount for olanzapine in such a combination is from '' W '' approximately 0.0005 to approximately 0.6 mg / kg body weight per patient per day. The suggested amount for ciprazidone in such combination is from about 0.05 to about 10 mg / kg body weight per patient per day. Sometimes, however, for each of the above combinations, the amount of each specific constituent in the combination may be lower than necessary on an individual basis to exert the same desired effect in the treatment of a psychotic condition.

This invention also provides a pharmaceutical composition and method for treating Alzheimer's disease, an average cognitive impairment, or age-related cognitive impairment comprising a cdk5 inhibitor, for example a compound of formula 1, and an acetylcholinesterase inhibitor. Acetylcholinesterase inhibitors are known in the art, and any such acetylcholinesterase inhibitor can be used in the pharmaceutical compositions described above. or method. Examples of acetylcholinesterase inhibitors that can be used according to this invention are ARICEPT (donepezil; U.S. Patent 4,895,841); EXELON (rivastigmine ((S- [N-eTnn-3- [1 (dimethylamino) ethyl] phenyl carbamate); US Patent 5,603,176 and US Patent 4,948,807); ((2,2,2trichloro-1-hydroxyethyl) methrifonate phosphoric acid; US Patent 2,701,225 and US Patent 4,950,656); Galantamine (US Patent 4,663,318); Physostigmine (Forest, USA); Tacrine (1,2,3,4-tetrahydro-9-acridinamine; US Patent 4,816,456); Hyperzine A ( 5R5α, 9β, 11E) -5-amino-11-ethylidene-5,6,9,10-tetrahydro-7-methyl5,9-methanocycloocta (b) pyridin-2- (1H) -one; and icopesil (5,7-dihydro-3- (2- (1- (phenylmethyl) -4-piperidinyl) -6H-pyrrolo (3,2-01,2-benzisoxazol-6-one; US Patent 5,750,542 and WO 92 / 17475) The patents and pdtent applications cited above in this paragraph are incorporated herein by reference in their entirety.

The effective amount of an acetylcholinesterase inhibitor in combination with a cdk5 inhibitor, for example a compound of formula 1, can typically be determined by one of ordinary skill in the art. The proposed effective 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. The daily effective amount of a cdk5 inhibitor is typically between about 0.01 to about 10 mg / kg body weight. Occasionally, the amount of acetylcholinesterase inhibitor and / or the amount of cdk5 inhibitor in the combination may be lower than necessary on an individual basis to exert the same desired effect in treating Alzheimer's disease, a mediocre cognitive impairment, or age-related decline in cognitive ability.

The present invention also provides for the combination of a cdk5 inhibitor with neuroprotectors, e.g., NMDA receptor antagonists, for the treatment of Huntington's disease, stroke, and spinal cord injury, traumatic brain injury, multi-infarct dementia, epilepsy, amyotropic lateral, induced dementia, eg AIDS induced dementia, migraine, hypoglycemia, urinary incontinence (leakage), cerebral ischemia, multiple sclerosis, Alzheimer's disease, Alzheimer's type dementia, middle disorder n and age-related cognitive decline, vomiting, corticobasal degeneration, pugilistica dementia, Dawn syndrome, myotonic dystrophy, Niemann-Pick disease, Pik disease, prion confusion disease, progressive supranuclear sclerosis, and subacute sclerosing pan-encephalitis. Examples of NMDA receptor antagonists that can be used according to the present invention are (1S, 2S) -1- (4-hydroxy-4-phenylpiperidin-1-yl) -1-propanol U. S. Patent 5,272,160), eliprodil (U. S. Patent 4,690,931), and gavestenil (U. S. Patent 5,373,018). Other NMDA receptor antagonists that may be used according to the present invention are described in U.S. Patent 5,373,018; U. S. Patent 4,690,931; U. S. Patent 5,272,160; U. S. Patent 5,185,343; U. S. Patent 5,356,905; U. S. Patent 5,744,583; 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 97/23202; and the U. S.

• · · · · · · · · · · · · · · · · · · ·

Patent Serial No. 1 No. 08 / 292,651 (filed August 18, 1994). All patents and patemt applications mentioned above are fully incorporated by reference herein.

The effective daily amount of a cdk5 inhibitor in combination with an NMDA receptor antagonist is typically between about 0.0001 to about 10 mg / kg body weight. The amount of NMDA receptor antagonist intended for use in combination with a cdk5 inhibitor, e.g., a compound of formula 1, for the treatment of any of the above disorders, e.g., Alzheimer's disease, is generally in the range of approximately 0.02 mg / kg / day to approximately 10 mg / kg / day. However, sometimes the amount of the NMDA receptor antagonist and / or the amount of cdk5 inhibitor in the combination may be lower than necessary on an individual basis to exert the same desired effect in the treatment of said disorders.

The present invention also provides for the combination of a cdk5 inhibitor with certain agents capable of treating stroke or traumatic brain damage such as TRAP NIF or potassium channel modulators, for example, BMS204352. Such combinations are useful for treating neurodegenerative disorders such as stroke, spinal cord trauma, traumatic brain injury, multi-infarct dementia, epilepsy, pain, Alzheimer's disease, and senile dementia, for example.

For the combination therapies and pharmaceutical compositions described above, the effective amounts of the compounds according to the invention and the other agent can usually be determined by those skilled in the art,

''

Based on the effective amounts of the compounds described herein and those known or described for the other agent known in the art, for example, the amounts described in the references cited the above patents and patent applications included here. The dosage forms and routes of administration for such therapies and compositions may be based on the information described herein for compositions and therapies comprising a compound of the invention as the sole active agent, and information provided for another agent in combination with it.

A specific compound of formula I may be found to inhibit cdk2, cdk5, or GSK-3 using biological studies known to those skilled in the art, for example, the study described below.

The specific activity of a compound of formula I for inhibiting cdk5 or cdk2 can, for example, be verified by the following studies using products available to those skilled in the art:

Enzymatic activity can be assayed by incorporating [3P] from the gamma phosphate of [3P] ATP (Amersham, cat. No. AN-9968) into the biotinylated peptide substrate PKTPKKAKKL. In this study, the reactions were run in buffer containing 50 mM TpncHCI, pH 8.0; 10 mM MgCl 2, 0.1 mM Na3VO4, and 1 mM DTT. The final ATP concentration is approximately 0.5 µM (final specific radioactivity 4 µM / nmol) and the final, substrate concentration is 0.75 µM. Reactions initiated by the addition of either cdk5 and activator protein p25, or cdk2 and activator cyclin E may proceed at room temperature for approx. 81 · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · But 60 minutes. Reactions were stopped by the addition of 0.6 volumes of buffer containing (final concentrations): 2.5 mM EDTA, 0.05% Triton-X 100, 100 μM ATP, and 1.25 mg / ml streptavidin-coated SPA beads ( Amersham, cat. No. RPNQ0007). The radioactivity associated with the beads is quantified by scintillation counting.

The specific activity of a compound of formula I for GSK inhibition can be determined in both a cell-free and cell-based assay, both described in the art (see, e.g., WO 99/65897). Cell-free assays can usually be performed by incubating GSK-3 with a peptide substrate labeled with radioactive isotope ATP (such as, for example, γ ³³ Ρ- or γ ³³ Ρ-ΑΤΡ, both supplied by Amersham, Arlington Heights, Illinois), magnesium ions, and the compound to be tested. The mixture was incubated for a period of time enabling the incorporation of radiolabelled phosphate into the peptide substrate by GSK-3 activity. The reaction mixture is washed to remove the unreacted ATP, typically after the first transfer of all or part of the enzyme into the reaction mixture into a well containing a uniform amount of ligand capable of binding to the peptide substrate. . The amount of ³³ P or ³² P remaining in each well after washing is then quantified to determine the amount of radiolabelled phosphate in the peptide substrate. Inhibition was observed as a decrease, compared to control, of the incorporation of radiolabelled phosphate into the peptide

• · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · substrate. An example of a suitable GSK-3 peptide substrate for assay is the GSSG-linked CREB peptide sequence derived from the CREB DNA binding protein described in Wang, et al., Anal. Biochem., 220: 397-402 (1994). Purified GSK-3 for analysis can, for example, be obtained from cells transfected with human GSK-3β expressed plasmid, as described, for example, in Stambolic, et al., Current Biology 6: 166468 (1996). WO 99/65897; Wang et al., And Stambolic, et al. are fully included here for reference.

Another example of the GSK-3 assay similar to the one described in the preceding paragraph is as follows: Enzyme activities are examined as the incorporation of [3P] from gamma phosphate of [3P] ATP (Amersham, cat. No. AN-9968) into biotinylated peptide substrate PKTPKKAKKL. The reactions were carried out in buffer containing 50 mM TpncHCI, pH 8.0; 10 mM MgCl ₂ , 0.1 mM Na ₃ VO ₄ , and 1 mM DTT. The final ATP concentration is 0.5 μΜ (final specific radioactivity 4 pCi / nmol) and the final substrate concentration is 0.75 μΜ. Reactions initiated by the addition of the enzyme proceed at room temperature for approximately 60 minutes. The reactions were stopped by the addition of 0.6 volumes of buffer containing (final concentrations): 2.5 mM EDTA, 0.05% Triton-X 100, 100 μΜ ATP, and

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

All of the compounds according to the titles in the following examples have an IC ₅₀ o peptide inhibiting substrate phosphorylation of less than approximately 50 μΜ when tested for inhibition of cdk5 according to the previous study.

• · ♦ * · * ♦ ···· ·· · · · · · · f • ··· · · · · · · ··· ·· · ♦ «·· · · · *

Several of the title compounds in the following examples were tested for GSK-3 inhibition using a assay such as the one described above, and all tested have an IC ₅₀ for inhibition of GSK-3p less than approximately 50 μΜ.

The following examples illustrate the present invention. It should be understood, however, that the invention, as fully described herein, and as cited in the claims, should not be construed to be limited by the particulars in the foregoing examples.

EXAMPLES FOR THE IMPLEMENTATION OF THE INVENTION

Preparation of 1 1-cyclobutyl-4-nitro-1 H-imidazole

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

1995, 99, 5009-5015) was added to a solution of cyclobutylamine (237 mg, 1.5 mmol) in methanol (10 mL) at 23 ° C. The reaction mixture was stirred for 16 hours, then the solvent was removed in vacuo and the resulting residue was purified by silica gel chromatography (1: 1 hexane-ethyl acetate) to give 230 mg (92% yield) of 1-cyclobutyl-4-nitro-1H-imidazole; 1 H NMR (400 MHz, CDCI ₃ ) δ 7.81 (s, 1 Η), 7.45 (s, 1Η), 4.64 (m, 1H), 2.6 (m, 2H), 2.4 (m, 2H), 2.0 (m, 2H); MS (AP / CI):

168.2 (M + H) ⁺ . Note: 1,4-dinitroimidazole is a high-energy, semi-stable substance, and should be stored in the freezer at all times when not in use. Thermodynamic studies have shown that it can potentially generate enough energy at 35 ° C under adiabatic conditions for a powerful explosion. All the time, when · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·· Works with this product, extreme precautions must be taken.

Receipt 2

-cyclopentyl-4-nitro-1H-imidazole

This reaction was carried out using the procedure for preparation of 1 with cyclopentylamine and 1,4-dinitroimidazole to give 205 mg (75% yield) of 1-cyclopentyl-4nitro-1H-imidazole; 1 H NMR (400 MHz, CDCl ₃ ) δ 7.77 (s, 1H),

7.45 (s, 1 Η), 4.49 (m, 1 Η), 2.25 (m, 2Η), 2.0-1.7 (m, 6H); MS (AP / CI): 168.2 (M + H) ⁺ .

• 4 ^w Receive 3

4-nitro-1- (cis-3-phenyl-cyclobutyl) -1H-imidazole

This reaction was carried out using the procedure for the preparation of 1 with cis-3-phenylcyclobutylamine (J. Med. Chem. 1960, 2, 687-691; ACIEE 1981, 20, 879-880) and 1,4-dinitroimidazole, wherein yielding 46 mg (46% yield) of 4-nitro-1- (cis-3-phenyl-cyclobutyl) -1H-imidazole; 1 H NMR (300 MHz, CDCl 3) δ 7.9 (s, 1 Η), 7.55 (s, 1 Η), 7.4 - 7.2 (m, 5Η), 4.73 (m, 1H) , 3.48 (m, 1H), 3.12 (m, 2H), 2.54 (m, 2H); MS (AP / CI): 244 (m + no.

Example 1

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

To a hydrogenated Pair bottle was added 1-cyclobutyl-4-nitro-1H-imidazole (preparation 1, 150 mg, 0.9 mmol) and ethyl acetate (10 mL), then 10% Pd on charcoal. (250 mg). The reaction mixture was placed in a hydrogenated Rag apparatus and reacted for 6 hours at 50 psi H ₂ at 23 ° C. The contents of the cartridge are filtered through a pad of celite and rinsed with dry methylene

• · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · Chloride (1250 mL) in a flame-dried flask under a nitrogen atmosphere. Et ₃ N (626 µL, 4.5 mmol) was added and the reaction mixture was cooled to -10 ° C. 6-quinolylacetic acid (168 mg, 0.9 mmol) and tripropylphosphonium anhydride (530 µL, 1.7 M solution in ethyl acetate) were then added, and the mixture was stirred at -10 ° C for 2 hours. The solution was diluted with methylene chloride (50 mL), and washed with water (2x). The aqueous layer was extracted with methylene chloride (3x), and the organic layers combined and washed with brine (1x). The solvent was removed in vacuo, the residue was adsorbed in silica gel, and chromatographed using a Biotage Flash 12 system with SIM attachment (40; 1 methylene methanol chloride) to give 130 mg (47% yield) of N- (1cyclobutyl). -1H-imidazol-4-yl) -2-quinolin-6-yl-acetamide (the title compound); 1 H NMR (300 MHz, CDCI ₃ ) δ 9.48 (s, 1 Η), 8.87 (dd, J = 1.6, 4.3 Hz, 1H), 8.11 (m, 2H), 7 , 76 (d, J = 1.8 Hz, 1H), 7.67 (dd, J = 2.0, 8.7 Hz, 1H), 7.44 (d, J = 1.6 Hz, 1H) , 7.38 (m, 1H), 7.25 (d, J = 1.6 Hz, 1H), 4.5 (m, 1H), 3.90 (s, 2H), 2.4 (m, 2H), 2.3 (m, 2H), 1.85 (m, 2H); MS (AP / CI);

307.1 (M + H) ⁺ .

Example 2

N- (1-cyclobutyl-1H-imidazol-4-yl) -2- (4-methoxy-phenyl) acetamide

The procedure of Example 1 was carried out with para-methoxyphenylacetic acid and 1-cyclopentyl-4-nitro-1H-imidazole (preparation 2) to give N- (1-cyclobutyl-1H-imidazol4-yl) -2- ( 4-methoxy-phenyl) -acetamide 6 32% yield (26.5 mg); 1 H NMR (400 MHz, CDCl ₃ ) δ 8.54 (s, 1H), 7.35 (s, 1H), 7.24 (m, 2H), 6.87 (d, J = 1.7 Hz, 1H), 4.36 (m, 1H), 3.78 (s, 3H), 3.64 (s, • · ·

2H), 2.1 (m, 2H),

300.3 (M + H) ⁺ .

1.8 (m, 4H),

1.6 (m, 2H); MS (AP / CI):

Example 3

N- [1- (cis-triphenyl-cyclobutyl) -1H-imidazol-4-yl] -2-quinolin6-yl-acetamide

The procedure of Example 1 was carried out with 6-quinolylacetic acid and 4-nitro-1- (cis-3-phenylcyclobutyl) -1Nimidazole (Preparation 3) to give N- [1- (cis-triphenylcyclobutyl) -1H- imidazol-4-yl] -2-quinolin-6-yl-acetamide 38% yield; 1 H NMR (300 MHz, CDCI ₃ ) δ 8.93 (m, 1 Η), 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), 7.3 - 7.22 (m, 5H), 4.57 (m, 1H), 3.96 (s, 2H), 3.33 (m, 1H), 2.95 (m, 2H), 2.49 (m, 2H); MS (AP / CI): 383.0 (M + H) < ⁺ & gt ^; .

Example 4 (1-Cyclobutyl-1H-imidazol-4-yl) -carbamic acid phenyl ester

In a Parr hydrogenated bottle, 1-cyclobutyl4-nitro-1H-imidazole (obtain 1, 3 g, 18 mmol) and ethyl acetate (70 mL) were then added and then 10% Pd on charcoal (1.2 g). in a nitrogen atmosphere. The mixture was hydrogenated for 6 hours at 50 psi H ₂ at 23 ° C. The mixture was then filtered through a pad of celite, which was washed with dry methylene chloride (140 mL) in a flame-dried flask. The resulting solution was cooled to -78 ° C and diisopropylethylamine (2.3 g, 8 mmol) was added dropwise followed by phenyl chloroformate (2.5 mg, 16.2 mmol). After 30 minutes, methanol (9 mL) containing acetic acid (1.8 mmol) was added. The reaction mixture was transferred to a separatory funnel, diluted with ethyl acetate (200 mL), and washed with water (2x). The aqueous layer was extracted with

ethyl acetate (2 x 10 mL). The organic layers were combined, washed with brine (2x) and dried (Mg ₂ SO ₄ ), filtered and concentrated in vacuo. The crude product was adsorbed on silica gel, and purified by silica gel chromatography (1: 1 hexane-ethyl acetate) to give 3 g (65% yield) of (1-cyclobutyl-1H-imidazol-4 phenyl ester) -yl) -carbamic acid; 1 H NMR (400 MHz, CDCl ₃ ) δ 7.4 - 7.3 (m, 2H), 7.22 - 7.18 (m, 3H), 4.5 (m, 1H), 2.46-2 , 30 (m, 4H), 1.83 (m, 2H); MS (AP / CI): 258.2 (M + H) ⁺ . Example 5

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

To a 1 dram vial with screw cap was added (1-Cyclobutyl-1H-imidazol-4-yl) -carbamic acid phenyl ester (Example 4, 50 mg, 0.19 mmol), 5-aminoisoquinoline (30 mg, 0.21 mmol) and 1: 1 dioxane-DMF (1 mL). The reaction mixture was heated at 70 ° C for 2 hours. The reaction mixture was adsorbed on silica gel, and purified by silica gel chromatography (40: 1 chloroform-methanol) to give 30 mg (52% yield) of 1- (1-cyclobutyl-1H-imidazol-4-yl) -3-isoquinolin-5-yl-urea;

1 H NMR (400 MHz, CDCl 3) δ 9.21 (d, J = 1.7 Hz, 1H), 8.45 (d, J = 6.2 Hz, 1H), 8.24 (d, J = 7 , 5 Hz, 1H), 7.98 (d, J = 5.4 Hz, 1H), 7.84 67 (dd, J = 2.3, 8.3 Hz, 1H), 7.66 (m, 1H), 7.54 (s, 1H),

7.12 (brs, 1H), 4.66 (m, 1H), 2.5-2.3 (m, 4H), 1.9 (m, 2H); MS (AP / CI): 308.0 (M + H) < ⁺ & gt ^; .

Example 4

N- [1- (cis-3-azido-cyclobutyl) -1H-imidazol-4-yl] -2-naphthalen-1-yl-acetamide

Stage 1

3-Benzyloxycyclobutylamine (43.4 mg, 245 mmol, Chem. Ber. 1957p 90p 1424-1432) was dissolved in acidic methanol chloride (saturated, 450 mL), then 10% Pd on carbon (4 g) was added. The mixture was hydrogenated at 50 psi H ₂ for 6 hours. The mixture was filtered and concentrated in vacuo to give co. 35 g butter. The oil was dissolved in methanol (600 mL), cooled to 0 ° C and treated with a potassium base (13.7 g, 245 mmol). When pH = 10, a solution of 1,4-dinitroimidazole (42.7 g, 270 mmol) in methanol (200 mL) (obtained by dissolving 1,4-dinitroimidazole in methanol at 0 ° C) was added. (note: 1,4-dinitroimidazole is a high-energy, semi-stable substance, and should be stored in the freezer at all times when not in use. Thermodynamic studies have shown that it can potentially generate enough energy at 35 ° C at adiabatic conditions for high explosion. Extreme precautions should be taken throughout the handling of this product). The resulting orange suspension was then allowed to warm slowly to 23 ° C overnight, and the resulting residue was purified by passing through a thick pad of silica gel (20: chloroform-methanol) to give 19 g (42% yield) of 3- (4-nitro-imidazol-1-yl) cyclobutanol as a 1: 1 mixture of cis-trans. isomers; 1 H NMR (400 MHz, CDCI ₃ ) δ 8.29 (S, 1 Η), 8.27 (s, 1 Η), 7.84 (s, 1 Η), 7.81 (s, 1Η), 5 , 02 (m, 1H), 4.53 (m, 1H), 4.37 (m, 1Η), 4.10 (m, 1Η), 2.95

(m, 2H), 2.7 (m, 2H), 2.5 (m, 2H), 2.5 (m, 2H), 2.3 (m, 2H), 2.3 (m, 2H) ; MS (AP / CI): 184.0 (M + H) < ⁺ & gt ^; .

Stage 2

'* w

Ha 3- (4-Nitro-imidazol-1-yl) -cyclobutanol (Preparation 4, Step 1; 4 g, 22 mmol) was treated with Et ₃ N (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. temperature for 24 hours Analysis by thin layer chromatography revealed two new spots The reaction mixture was diluted with methylene chloride and washed with water (1x) and brine (1x), the organic layer was dried (MgSO ₄ ), filtered and concentrated in vacuo Chromate purification silica gel (1: 1 to 2: 1 hexane-ethyl acetate) screening allows the separation of trans and cis diastereomers The first eluting spot (high Rf) is the trans isomer, trans-toluene-4-sulfonic acid 3- ( 4-Nitroimidazol-1-yl) -cyclobutyl ester (2.7 g 37% yield); 1 H NMR (400 MHz, CDCl 3) δ 7.79 (s, 1H), 7.77 (m, 2H), 7, 44 (d, J = 1.7 Hz, 1H), 7.36 (dd, J = 0.5, 8.0 Hz, 2H), 5.034 (m, 1H), 4.94 (m, 1H). 2.9 (m, 2H), 2.7 (m, 2H); MS (AP / CI): 338.1 (M + H) < ⁺ & gt ^; . The second eluting spot is the cis-isomer, cis-toluene-4-sulfonic acid 3- (4-nitro-imidazol-1-yl) -cyclobutyl ester (2.9 g 39% yield); 1 H NMR (400 MHz, CDCl 3) 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 / CI): 338.1 (M + H) < ⁺ & gt ^; . The relative configurations are determined by measuring the nuclear Overhauser effects.

Step 3 Trans-toluene-4-sulfonic acid 3- (4-nitro-imidazol-1-yl) -cyclobutyl ester (Preparation 4, Step 2; 590 mg, 1.75 mmol) was mixed with 10% Pd on carbon (500 mg ) in ethyl acetate (30 mL). The mixture was then reacted at 50 psi H ₂ at room temperature for 6 hours. The mixture was filtered through celite in a flame-dried flask, which was stored in a nitrogen atmosphere. Et ₃ N (1.22 mL, 8.75 mmol) was added followed by 1-naphthylacetic acid (326 mg, 1.75 mmol) and tripropylphosphonium anhydride (1.1 mL, 1.7 M solution in ethyl) acetate, 1.75 mmol). The mixture was stirred at room temperature for 1 hour, then diluted with ethyl acetate, and washed with water and brine. The organic layer was dried (MgSO ₄ ), filtered, and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (50: 1 chloroform-methanol) to give 600 mg (72% yield) of trans-toluene-4-sulfonic acid 3- [4- (2-naphthalene-1 - yl) -acetylamino) -imidazol-1-yl] -cyclobutyl ester; 1 H NMR (400 MHz, CDCl ₃ ) δ 7.9 (m, 2H), 7.85 (m, 2H), 7.85 (m, 2H), 7.76 (d, J = 8.3 Hz, 2H), 7.48 (m, 2H), 7.42 (m, 2H), 7.33 (m, 2H), 7.04 (s, 1H), 4.96 (m, 1H), 4. 73 (m, 1H), 2.7 (m, 4H), 2.44 (s, 3H); MS (AP / CI): 476.2 (M + H) ⁺ .

Step 4 Trans-toluene-4-sulfonic acid 3- [4- (2-naphthalen-1-yl) -acetylamino) -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 then heated to reflux with stirring for 96 hours. The solvent was removed in vacuo and the residue was removed

dilute with water and extract with methylene chloride. The organic layer was dried (MgSO ₄ ), filtered, and concentrated in vacuo. Purification by silica gel chromatography (50: 1 chloroform-methanol) yielded 340 mg (79% yield) of N- [1- (cis-3-azido-cyclobutyl) -1H-imidazol-4-yl] - 2naphthalen-1-yl-acetamide; 1 H NMR (400 MHz, CDCl ₃ ) δ 8.41 (s, 1H), 7.98 (d, J = 6.4 Hz, 2H), 7.87 (m, 1H), 7.82 (m, 1H), 7.5 (m, 2H), 7.45 (m, 3H), 7.08 (d, J = 1.7 Hz, 1H), 4.2 (m, 3H), 3.75 ( m, 1H), 2.85 (m, 2H), 2.35 (m, 2H); MS (AP / CI): 347.2 (M + H) ⁺ .

Example 6

N- [1- (cis-3-amino-cyclobutyl) -1H-imidazol-4-yl] -2-naphthalen-1-yl-acetamide

N- [1- (cis-3-azido-cyclobutyl) -1H-imidazol-4-yl] -2-naphthalen-1-yl-acetamide (Preparation 4, Step 4; 330 mg, 0.95 mmol) 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 resulting residue was purified by silica gel chromatography (20: 1: 0.5 chloroform-methanol-ammonium hydroxide) to give 289 mg (95% yield) of N- [1- ( cis-3-amino-cyclobutyl) -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, 2H), 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) < ⁺ & gt ^; .

• ·

Example 7a

6-Methyl-pyridine-2-carboxylic acid {cis-3- [4- (2-naphthalen-1-yl-acetylamino) -imidazol-1-yl] -cyclobutyl} -amide 6-methylpicolic acid solution (9,4 mg, 0.07 mmol) in methylene chloride was treated with 1- (dimethylaminopropyl) -3-atilcarbodiimide hydrochloride (84 mg) and DMAP (2 mg) at 23 ° C. After stirring for 10 minutes, N- [1- (cis-3-amino-cyclobutyl) -1H-imidazol-4-yl] -2naphthalen-1-yl-acetamide was added (Example 6, 20 mg, 0.06 mmol). The resulting mixture was then stirred for 3 hours. Water was added, the solution neutralized with aqueous NaOH and extracted with ethyl acetate. The organic layer was dried (MgSO ₄ ), filtered, and concentrated in vacuo. Purification by flash gel chromatography (20: 1 CHCl ₃ - MeOH) gave 26 mg (95% yield) of 6-methyl-pyridine-2-carboxylic acid {3- (4- (2-naphthalene-1 - yl-acetylamino) -imidazol-1-yl] -cyclobutyl} amide; 1 H NMR (400 MHz, CDCl ₃ ) δ 9.15 (s, 1 Η), 8.28 (d, J = 8.3 Hz, 1H ), 8.01 (d, J = 7.5 Hz, 1H), 7.96 (d, J = 7.5 Hz, 1H), 7.97 (d, J = 7.5 Hz, 1H), 7.81 (dd, J = 2.4, 6.6 Hz, 1H), 7.72 (m, 1H), 7.5 (m, 5H), 7.2 (m, 1H), 7.16 (s, 1H), 4.45 (m, 1H), 4.25 (m, 1H), 4.18 (s, 2H), 2.98 (m, 2H), 2.60 (s, 3H) , 2.40 (m, 2H); MS (AP / CI):

440.3 (M + H) ⁺ .

Example 7b

N-imidazole-4-carboxylic acid {cis-3- [4- (2-naphthalen-1-yl-acetylamino) -imidazol-1-yl] -cyclobutyl} -amide The title compound was prepared analogously 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). 7.7 (s,

Η), 7.64 (s, 1Η), 7.5 (m, 6H), 4.44 (m, 1H), 4.32 (m, 1H), 4.18 (s, 2H), 2. 9 (m, 2H), 2.45 (m, 2H); MS (AP / CI): 415.3 (M + H) ⁺ .

Example 7c

6-Hydroxy-pyridine-2-carboxylic acid {cis-3- [4- (2-naphthalen-1-yl-acetylamino) -imidazol-1-yl] -cyclobutyl} -amide The title compound was prepared analogously to Example 7a; 1 H NMR (400 MHz, CD 3 OD) δ 8.02 (d, J = 7.9 Hz, 1H), 7.84 (d, J = 7.9 Hz, 1H), 7.79 (d, J = 7 , 5 Hz, 1H), 7.65 (s, 1H), 7.60 (m, 1H), 7.45 (m, 6H), 7.14 (brs, 1H), 6.71 (d, J) = 8.7 Hz, 2H), 4.4 (m, 1H), 4.32 (m, 1H), 4.17 (s, 2H), 2.93 (m, 2H), 2.5 (m , 2H); MS (AP / CI): 442.3 (M + H) < ⁺ & gt ^; .

Example 7d

3-methyl-pyridine-2-carboxylic acid {cis-3- [4- (2-naphthalen-1-yl-acetylamino) -imidazol-1-yl] -cyclobutyl} -amide The title compound was prepared analogously to Example 7a; 1 H NMR (400 MHz, CD 3 OD) δ 8.39 (d, J = 4.2 Hz, 1H), 8.06 (d, J = 8.3 Hz, 1H), 7.87 (d, J = 7 , 5 Hz, 1H), 7.80 (d, J = 7.5 Hz, 1H), 7.69 (d, J = 7.9 Hz, 2H), 7.5 (m, 7H),

4.5 (m, 1H), 4.3 (m, 1H), 4.17 (s, 2H), 2.92 (m, 2H), 2.54 (s, 3H),

2.46 (m, 2H); MS (AP / CI): 440.3 (M + H) < ⁺ & gt ^; .

Example 7e

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

The title compound was prepared analogously to Example 7a; 1 H NMR (400 MHz, CD 3 OD) δ 9.21 (d, J = 2.5 Hz, 1H), 8.61 (d, J = 5.0 Hz, 1H), 8.41 (dd, J = 1 , 7, 7.9 Hz, 1H), 8.26 (s, 1H), 8.06 (d, J = 7.9 Hz, 1H), 7.86 (d, J = 7.5 Hz, 1H) ), 7.79 (d, J = 7.9 Hz, 1H), 7.5 (m, 7H), 4.44 (m, • · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

2H), 4.17 (s, 2H), 2.9 (m, 2H), 2.6 (m, 2H); MS (AP / CI):

509.3 (M + H) < ⁺ & gt ^; .

Example 7f

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

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

484.3 (M + H) < ⁺ & gt ^; .

Example 7g

Pyrazine-2-carboxylic acid {cis-3- [4- (2-naphthalen-1-yl-acetylamino) -imidazol-1-yl] -cyclobutyl} -amide The title compound was prepared analogously to Example 7a; 1 H NMR (400 MHz, CD 3 OD / CDCl ₃ ) δ 9.23 (d, J = 2.0 Hz, 1H), 9.03 (d, J = 8.0 Hz, 1H), 8.73 (d. J = 2.4 Hz, 1H), 8.63 (d, J = 1.6, 2.4 Hz, 1H), 8.02 (d, J = 8.4 Hz, 1H), 7.85 ( d, J = 8.0 Hz, 1H), 7.79 (d, J = 8.0 Hz, 1H), 7.49 (m, 6H), 4.44 (m, 2H), 4.16 ( s, 2H), 2.95 (m, 2H), 2.56 (m, 2H); MS (AP / CI):

427.3 (M + H) < ⁺ & gt ^; .

Example 7h

N- {cis-3- [4- (2-naphthalen-1-yl-acetylamino) -imidazol-1-yl] -cycobutyl} -benzamide

The title compound was prepared analogously 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) , 5 Hz, • · · ·

Η), 7.80 (J = 7.1 Hz, 1 Η), 7.45 (m, 8H), 4.47 (m, 1 Η), 4.17 (s, 2H).

2.90 (m, 2H), 2.47 (m, 2H); MS (AP / CI): 425.0 (M + H) ⁺ .

Example 7i

5-Methyl-pyrazine-2-carboxylic acid {cis-3- [4- (2-naphthalen-1-yl-acetylamino) -imidazol-1-yl] -cyclobutyl} -amide

The title compound was prepared analogously to Example 7a; 1 H NMR (400 MHz, CD 3 OD) δ 9.07 (d, J = 1.2 Hz, 1H), 8.5 (d, J = 0.8, 2.4 Hz, 1H), 8.02 (d , J = 8.0 Hz, 1H), 7.85 (d, J = 7.6 Hz, 1H), 7.79 (d, J = 7.6 Hz, 1H), 7.45 (m, 6H ),

4.40 (m, 2H), 4.16 (s, 2H), 2.93 (m, 2H), 2.61 (s, 3H), 2.54 (m, 2H), C MS (AP / CI): 441.3 (M + H) +.

Example 7j

N- {cis-3- [4- (2-naphthalen-1-yl-acetylamino) -imidazol-1-yl] -cycobutyl} -isobutyramide

The title compound was prepared analogously to Example 7a; 1 H NMR (400 MHz, CD 3 OD) δ 8.01 (d, J = 7.9 Hz, 2H), 7.84 (d, J = 7.5 Hz, 1H), 7.78 (J = 7.5 Hz, 1H), 7.45 (m, 6H), 4.35 (m, 1H), 4.15 (s, 2H), 4.11 (m, 2H), 2.84 (m, 2H). 2.35 (m, 1H), 2.28 (m, 2H), 1.06 (d, J = 6.6 Hz, 6H); MS (AP / CI):

391.1 (M + H) ⁺ .

Example 7k

6-Chloro-pyridine-2-carboxylic acid {cis-3- [4- (2-naphthalen-1-yl-acetylamino) -imidazol-1-yl] -cyclobutyl} -amide

The title compound was prepared analogously to Example 7a; 1 H NMR (400 MHz, CD 3 OD) δ 8.07 (d, J = 7.9 Hz, 1H), 8.03 (d, J = 7.5 Hz, 1H), 7.94 (m, 1H). 7.87 (d, J = 7.9 Hz, 1H), 7.81 (d, J = 7.9 Hz, 1H), 7.61 (d, J = 7.1 Hz, 2H), 7. 58 (s, 1H), 7.5 (m, 5H), 7.45 (m, 1H), 4.39 (m, 1H), 4.18 (s, 2H), 2.89 (m, 2H) ), 2.63 (m, 2H); MS (AP / CI): 460.2 (M + H) < ⁺ & gt ^; .

• · · ·

Example 8

Acylation of N- [1- (cis-3-amino-cyclobutyl) -1H-imidazol-4-yl] -2-naphthalen-1-yl-acetamide (Example 6) with various carboxylic acids and further purification is purified according to the following procedure: To a carboxylic acid (RCO ₂ H, 1 equivalent, 0.075 mmol) in 1 screw-plugged dram bottle was added a solution of N- [1- (cis-3amino-cyclobutyl) -1H-imidazole-4- yl] -2-naphthalen-1-yl-acetamide (0.33 equivalents, 8 mg, 0.025 mmol) in methylene chloride (1 mL). PC-carbodiimide (Argonaut Technologies, (0.5 equivalents, 39 mg, 0.038 mmol, 1 mmol / g) was then added. The mixture was shaken at 23 ° C for 24 hours. Note: If the acid is insoluble in methylene chloride, N, N-dimethylformamide (0.5 mL) was added Each reaction mixture was transferred with methylene chloride (0.5 mL) in 3 mL SPE filler (20 micron frits) with a tare 2 dram solvent collection vessel The solution was forced through a frit, and the polymer was washed with THF (0.5 mL), methylene chloride (0.5 mL), THF (0.5 mL), and methylene chloride (0.5 mL). in a stream of nitrogen, and the crude products are analyzed by LCM (column:

3.9 x 150 mm Waters Symmetry _C18, 5 uM; flow = 1.0 ml / min; solvent system: A = 0.1% aqueous THF solution; B = acetonitrile; linear gradient of 10-100% B for 10 minutes). If the desired base ion (M + H) is observed, the crude reaction mixture is purified by preparative HPLC (column: 30 x 150 mm Waters Symmetry C ₁₈ , 5 µM; flow = 20 ml / min; solvent system: A = 0.1 % aqueous THF solution; B = acetonitrile; linear gradient of 0-100% B for 15 minutes) with appropriate fractions determined by an in-line mass spectrometer. The purity of the chromatograph-

Firat compound was determined by analytical HPLC (Column: 2.1 x 150 mm Waters Symmetry _C18, 5 uM; flow = 0,5 ml / min; solvent system: A = 0.1% aqueous solution of THF; B = acetonitrile ; linear gradient from 0 - 100% B for 10 minutes) using UV: 254 nM and a diode detector system.

The following compounds were prepared by the method described above. Their retention times by mass spectroscopy and chromatography are listed in Table 1:

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

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

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

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

Example 8e: 2- (3-Hydroxy-phenyl) -N- {cis-3- [4- (2-naphthalen-yl-acetylamino) -imidazol-1-yl] -cyclobutyl} -amide

Table 1

Acetylated Products, Associated Retention Times, and Mass Spectroscopy Data

Retention times

An example Analytical HPLC (min) LCMS (min) (M + H) 8a 7.68 8.79 476,2 8b 6.97 7.96 414,2

• · «♦

8s 7.45 8.56 453,2 8d 6.84 6.68 426,2 8f 6.75 7.77 455,2

Receipt 5

4 - {- [4- (2-Naphthalen-1-ylacetylamino) -imidazol-1-yl] -cyclobutylcarbamoyl} piperidine-1-carboxylic acid 9H-fluoro-9-ylmethyl ester

Stage 1

The 4-piperidine carboxylic 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, 15 mmol) in dioxane (2 mL) was added dropwise, and the reaction mixture was then stirred for 4 hours. The solvent was removed in vacuo and diluted with water. The pH was adjusted to 1 with HCl (1N), and the aqueous solution was extracted with ethyl acetate. The organic layer was dried (MgSO ₄ ), filtered, and concentrated in vacuo. Purification by silica gel chromatography (50: 1: 0.5 chloroform-methanol-acetic acid) afforded 340 mg (97% yield) of N-1 (fluorenylmethyloxycarbonyl) -4-piperidinylcarboxylic acid; 1 H NMR (400 MHz, CDCl ₃ ) δ 7.75 (d, J = 7.1 Hz, 2H), 7.55 (d, J = 7.5 Hz, 2H), 7.39 (m, 2H) , 7.30 (m, 2H), 4.4 (brs, 2H), 4.23 (t, J = 6.5 Hz, 1H), 3.9 (brd, 2H), 2.9 (brs, 2H), 2.52 (m, 1H), 1.90 (brs, 2H), 1.62 (brs, 2H); MS (AP / CI): 352.0 (M + H) ⁺ .

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-dimethylamino99) · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

propyl) -3-ethylcarbodiide hydrochloride (84 mg) and DMAP (5 mg). After stirring for 30 minutes, N- [1- (cis-3-amino-cyclobutyl) -1H-imidazol-4-yl] -2naphthalen-1-yl-acetamide was added (Example 6). The resulting mixture was then stirred for 4 hours. Water was added, the solution was made neutral, and extracted with ethyl acetate. The organic layer was dried (MgSO ₄ ), filtered, and concentrated in vacuo. Purification by silica gel chromatography (20: 1 chloroform-methanol) afforded 101 mg (77% yield) of 4- {3 [4- (2-naphthalen-1-yl) 9H-fluoro-9-ylmethyl ester. acetylamino) -imidazol-1-yl] -cycobutylcarbamoyl} -piperidine-1-carboxylic acid;

1 H NMR (400 MHz, CD 3 OD) δ 8.0 (d, J = 8.3 Hz, 1H), 7.83 (m, 1H), 7.78 (dd, J = 2.07, 7.5 Hz) , 1H), 7.73 (d, J = 7.5 Hz, 2H), 7.53 (d, J = 6.6 Hz, 2H), 7.44 (m, 5H), 7.35 (m , 3H), 7.27 (m, 2H), 4.4 (brs, 2H), 4.2 (m, 1H), 4.15 (m, 5H), 2.85 (m, 4H), 2 , 25 (m, 3H), 1.7 (brs, 2H), 1.5 (brs, 2H); MS (AP / CI): 654.8 (M + H) ⁺ .

Example 9

Pyridine-4-carboxylic acid {cis-3- [4- (2-naphthalen-1-yl-acetylamino) -imidazol-1-yl] -cyclobutyl} -amide hydrochloride

4- {3- [4- (2-Naphthalen-1-yl-acetylamino) -imidazol-1-yl] -cyclobutylcarbamoyl} piperidine-1-carboxylic acid 9H-fluoro-9-ylmethyl ester (obtain 5, 100 mg, 0.15 mmol) in DMF (5 mL), treated with piperidine (0.5 mL), and stirred at room temperature for 2 hours. The solvent was removed in vacuo and the residue was purified by silica gel chromatography (4: 1: 0.08 chloroform-methanol-ammonium hydroxide) to give the free base. The free base is dissolved in

100 Diethyl ether, and is treated with 1N HCl in methanol. to give the HCl salt (64 mg, 91% yield), piperidine-4-carboxylic acid {cis-3- [4- (2-naphthalen-1-yl-acetylamino) -imidazol-1-yl] -cyclobutyl} - amide hydrochloride; 1 H NMR (400 MHz, CD 3 OD) δ 8.01 (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,

1H), 4.15 (s, 2H), 4.10 (m, 1H), 3.03 (m, 2H), 2.83 (m, 2H), 2.54 (m, 1H).

2H), 2.24 (m, 3H), 1.69 (m, 2H), 1.55 (m, 2H); MS (AP / CI): 432 (M + H) < ⁺ & gt ^; .

Receipt 6

Isoquinolin-5-yl-acetic acid

Stage 1

5-aminoisoquinoline (5.0 g, 34.7 mmol) was mixed with 38% aqueous HBr (65 mL) at -78 ° C for 15 minutes. Sodium nitrite (3.1 g, 45 mmol) in water (6 mL) was then added dropwise. After stirring for 15 minutes at -78 ° C, the mixture was heated to 0 ° C. Copper powder (0.3 g) was added very slowly to avoid excessive foaming. After the addition was complete, the reaction vessel was equipped with a reflux condenser, and the mixture was heated to 100 ° C for 4 hours. The mixture was poured into ice (ca. 200 g) and made alkaline (pH = 10) with KOH. The aqueous mixture was extracted with ethyl acetate, the combined organic layers were washed with brine, dried (MgSO ₄ ), filtered, and concentrated in vacuo. Purification by silica gel chromatography (10: 1 hexane-ethyl acetate) gave 3.8 g (53% yield) of 5-bromoisoquinoline; 1 H NMR (400 MHz, CD 3 OD) δ 9.25 (s, 1H), 8.57 (d, J = 6.2 Hz, 1H), 8.1 (m, 3H), 7.60 (m, 1H) ); MS (AP / CI): 208.0, 210.0 (M + H) ⁺ .

101 • · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·· ·· ··

Stage 2

5-bromoisoquinoline (Preparation 6, Step 1, 1.04 g,

5.0 mmol) was mixed with allyl tributyltin (1.7 mL, 5.5 mmol) and dichloropalladium bis (triphenylphosphine) (176 mg, 0.25 mmol) in toluene (20 mL) in a nitrogen atmosphere. The mixture was heated at reflux for 16 hours. After cooling to room temperature, saturated aqueous potassium fluoride solution (20 mL) was added with stirring, which formed a precipitate. After stirring for 15 minutes, the mixture was filtered, and the organic layers were separated from the aqueous layer, concentrated in vacuo and purified by silica gel chromatography (6: 1 hexane-ethyl acetate) to give 778 mg (92% yield) of 5-allylisoquinoline; 1 H NMR (400 MHz, CD 3 OD) δ 9.25 (s, 1 Η), 8.54 (d, J = 5.8 Hz, 1H), 7.79 (d, J = 5.8 Hz, 2H) , 7.56 (m, 2H), 6.1 (m, 1H), 5.15 (m, 1H), 5.05 (m, 1H), 3.81 (d, J = 6.2 Hz). 2H); MS (AP / CI): 170.2 (M + H) < ⁺ & gt ^; .

Stage 3

Ha 5-allylisoquinoline (Preparation 6, Step 2; 169 mg, 1.0 mmol) in methylene chloride (2 mL), acetic acid (0.5 mL) and water (0.5 mL) was treated with dimethyl polyethylene glycol ( Mp: 95 µL, 100 mg, 0.2 mmol) in methylene chloride (1 mL) at 23 ° C. The mixture was cooled to 0 ° C, and a portion of the powder of KMpO ₄ (521 mg, 3.3 mmol) was added in portions, keeping the temperature below 30 ° C. After vigorous stirring for 18 hours, the solvent was removed in vacuo, and acidic methanol chloride (10 mL, 1 N) was added, and the mixture was refluxed for 4 hours. The methanol was removed in vacuo, the residue diluted with water, and the mixture made alkaline with Na ₂ CO ₃ (pH = 9).

102 ·· · · · «I ···· • · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

The mixture was extracted with ethyl acetate, the resulting organic layer was washed with brine, dried (MgSO ₄ ), filtered, and concentrated in vacuo and purified by silica gel chromatography (2: 1 hexane-ethyl acetate), to give isoquinolin-5-yl-acetic acid methyl ester; 1 H NMR (400 MHz, CDCI ₃ ) δ 9.28 (brs, 1 Η), 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 (d, J = 7.6 Hz, 1H), 4.06 (s, 2H),

3.70 (s, 3H); MS (AP / CI): 202.1 (M + H) < ⁺ & gt ^; . Note: Contaminants of 5-isoquinolylcarboxaldehyde are presented after silica gel chromatography (ca. 20%).

Stage 4

Isoquinolin-5-yl-acetic acid methyl ester (Preparation 6, Step 3; 90 mg, 0.448 mmol) was treated with aqueous sodium hydroxide solution (4N, 3 mL), the solution was heated at 50 ° C for at 4 o'clock. The solution was cooled to 0 ° C, and acetic acid (2 mL) was added dropwise, resulting in a precipitate. The mixture was kept at 0 ° C overnight (ca. 15 hours), and the precipitate was removed by filtration and washed with water. The solid was air-dried to give 35 mg (47% yield) of isoquinolin-5-yl-acetic acid; 1 H NMR (400 MHz, CD 3 OD) δ 9.24 (s, 1 Η), 8.47 (d, J = 6.2 Hz, 1H), 8.04 (d, J = 7.9 Hz, 1H) , 7.96 (d, J = 6.2 Hz, 1H), 7.74 (d, J = 6.6 Hz, 1H), 7.66 (d, J = 7.6 Hz, 1H), 4 , 11 (s, 2H); MS (AP / CI): 188.3 (M + H) < ⁺ & gt ^; .

Receipt 7

N- [cis-3- (4-nitro-imidazol-1H-yl) cyclobutyl] acetamide Step 1

Transtoluene-4-sulfonic acid 3- (4-nitro-imidazol-1-yl) -cyclobutyl ester (Preparation 1, Step 2; 3.6 g,

103

10.7 mmol) was combined with sodium azide (7 g, 107 mmol) in ethanol (100 mL), water (35 mL), and chloroform (20 mL). The mixture was heated 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 (MgSO ₄ ), filtered, and concentrated in vacuo. Purification by silica gel chromatography (3: 1 ethyl acetate-hexane) gave 2.2 mg (99% yield) of 1- (3-cis-azido-cyclobutyl) -4-nitro-1H-imidazole; 1 H NMR (400 MHz, CDCl ₃ ) δ 7.85 (s, 1H), 7.49 (s, 1 Η), 4.42 (m, 1Η), 3.91 (m, 1H), 3.07 (m, 2H), 2.43 (m, 1H); MS (AP / CI): 208.5 (M + H) ⁺ .

Stage 2

1- (3-Cis-azido-cyclobutyl) -4-nitro-1H-imidazole (Preparation 7, Step 1; 2.2 g, 10.7 mmol) in THF (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 purified by silica gel chromatography (20: 1: 0.4 chloroform-methanol-ammonium hydroxide) to give 1.95 g (100% yield) of 1- (3- cis-aminocycobutyl) -4-nitro-1H-imidazole; 1 H NMR (400 MHz, CD 3 OD) δ 8.32 (s, 1H), 7.81 (s, 1 Η), 4.46 (m, 1H), 3.29 (m, 1H), 2.87 ( m, 2H), 2.17 (m, 2H); MS (AP / CI): 183.1 (M + H) < ⁺ & gt ^; .

Stage 3

1- (3-cis-amino-cyclobutyl) -4-nitro-1H-imidazole (Preparation 7, Step 2; 500 mg, 2.75 mmol) was combined with acetic acid and purified as in Example 7. yielding 594 mg (96% yield) of N- [cis-3- (4-nitro-imidazol-1H) cyclobutyl] acetamide; 1 H NMR (400 MHz, CD 3 OD) δ 8.30 (s, 1 Η), 7.82

104 ··· ···· · · · · · · · · · · · · (s, 1 Η), 4.58 (m, 1 Η), 4.17 (m, 1 Η), 2. 95 (m, 2H), 2.39 (m, 2H), 1.93 (s, 3H); MS (AP / CI): 225.1 (M + H) < ⁺ & gt ^; .

Receipt 8

N- [cis-3- (4-nitro-imidazol-1-yl) -cyclobutyl] -benzamide N- [cis-3- (4-nitro-imidazol-1-yl) -cyclobutyl] -benzamide is obtained analogously to product from receipt 7; 1 H NMR (400 MHz, CD 3 OD) δ 8.36 (s, 1H), 7.85 (m, 3H), 7.55 (m, 1 Η), 7.47 (m, 2Η), 4.65 ( m, 1H), 4.44 (m, 1Η), 3.05 (m, 2Η), 2.60 (m, 2H); MS (AP / CI): 287.3 (M + H) ⁺ .

Receipt 9

Pyridine-2-carboxylic acid [cis-3- (4-nitroimidazol-1-yl) -cyclopentyl] -amide

Pyridine-2-carboxylic acid [cis-3- (4-nitro-imidazol-1-yl) -cyclobutyl] -amide was prepared analogously to the product of Preparation 7; 1 H NMR (400 MHz, CDCI ₃ ) δ 8.55 (m, 1 Η), 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 / CI): 288.1 (M + H) < ⁺ & gt ^; .

Example 9a

N- [1- (cis-3-acetylamino-cyclobutyl) -1H-imidazol-4-yl] 2-naphthalen-2-yl-acetamide

N- [cis-3- (4-nitro-imidazol-1-yl) -cyclobutyl] -acetamide Preparation 7; 50 mg, 0.22 mmol) was hydrogenated and acylated with 2-naphthyl acetic acid as in Example 1 to give 35 mg (44% yield) of N- [1- (cis-3-acetylaminocyclobutyl) - 1H-imidazol-4-yl] -2-naphthalen-2-yl-acetamide; 1 H NMR (400 MHz, CD 3 OD) δ 8.05 (d, J = 8.0 Hz, 1H), 7.87 (d, J = 7.6 Hz, 1H), 7.81 (d, J = 6 , 4 Hz, 2H), 7.46 (m, 5H), 7.37 (s, 1H), 4.41 (m, 1H), 4.17 (s, 2H), 4.12 (m, 1H) ), 2.84 (m, 2H), 2.27 (m, 2H), 1.89 (s, 3H); MS (AP / CI); 363.3 (M + H) ⁺ .

105

Example 9b

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

The title 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, 1 Η), 8.45 (d, J = 6.2 Hz, 1H), 8.05 (d, J = 7.9 Hz, 1H) , 8.02 (d, J = 6.2 Hz, 1H), 7.82 (m, 3H), 7.67 (m, 1H), 7.52 (m, 2H), 7.45 (m, 3H), 4.5 (m, 1H), 4.4 (m, 1H), 4.21 (s, 2H), 2.95 (m, 2H), 2.50 (m, 2H); MS (AP / CI): 426.3 (M + H) ⁺ .

Example 9c

Pyridine-2-carboxylic acid {cis-3- [4- (2-isoquinolin-5-yl-acetamino) -imidazol-1-yl] -cyclobutyl} -amide

The title compound was prepared analogously to Example 9a and isoquinolin-5-yl acetic acid (Preparation 6); 1 H NMR (400 MHz, CD 3 OD) δ 9.23 (s, 1 Η), 8.60 (m, 1 Η),

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

7.78 (d, J = 7.1 Hz, 1H), 7.66 (m, 1H), 7.58 (s, 1H), 7.5 (m, 1H),

7.46 (s, 1H), 4.45 (m, 1H), 4.40 (m, 1H), 4.20 (s, 2H), 2.85 (m, 2H),

2.6 (m, 2H); MS (AP / CI): 427.2 (M + H) ⁺ .

Example 10

N- {cis-3- [4- (3-naphthalen-1-yl-ureido) -imidazol-1-yl] cyclobutyl} -acetamide

N- [cis-3- (4-nitro-imidazol-1H) cyclobutyl] acetamide (obtain 7, 50 mg, 0.22 mmol) was reacted with phenyl chloroformate as described in example 4. This gave an inseparable mixture of mono- and bis-phenyl carbamate products, after silica gel chromatography (20: 1: 0.2 chloroform-methanol-ammonium hydroxide), which was dissolved in 1: 1 DMF / dioxane (500 µL). 1-Naphthylamine (31 mg,

106

0.22 mmol), and the mixture was heated at 70 ° C for 16 hours. Purification twice by silica gel chromatography (20: 1: 0.2 chloroform-methanol-ammonium hydroxide) yielded 4.4 mg (5% yield) of N- {unc-3- [4- (3 naphthalene-1) -yl-ureido) -imidazol-1-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, 2H), 7.51 (m, 4H), 7.16 (s, 1H), 4.46 (m, 1H). 4.15 (m, 1H), 2.89 (m, 2H), 2.33 (m, 2H), 192 (s, 3H); MS (AP / CI): 364.0 (M + H) < ⁺ & gt ^; .

107

Claims (13)

Patent Claims A compound of the formula wherein R ¹ is straight or branched (C ¹ -C 8) alkyl, straight or branched (C 2 -C 8) alkenyl, straight or branched (C 2 -C 8) alkynyl, ( C3-C8) cycloalkyl, (C4-C8) cycloalkenyl, (3-8 membered) heterocycloalkyl, (C5-C6) bicycloalkyl, (C7-C6) bicycloalkenyl, (5-11 membered) heterobicycloalkyl, (C6-C14) aryl, or (5-14 membered) heteroaryl; and wherein R ¹ is optionally substituted by one to six R ⁵ substituents independently selected from the group consisting of F, Cl. Br, I, nitro, cyano, -CF3, -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) 2NR 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 ; R ² is H, F, CH ₃ , CN, or C (= O) OR ⁷ ; R ³ is -C (= O) NR ⁹ -, -C (= O) O-, -C (= O) (CR ¹⁰ R ¹¹ ) _n -, or - (CR ¹⁰ R ¹¹ ) n-; R ⁴ is (C _C8) alkyl, c straight or branched c, (C ₂ -C ₈₎ alkenyl linear or branched (C ₂ -C ₈₎ alkynyl of straight or branched chain (C ₃ -C ₈ ) cycloalkyl, (C ₄ -C ₈ ) cycloalkenyl, (3-8 membered) heterocycloalkyl, (C ₅ -C ₆ ) bicycloalkyl, (C ₇ -C ₆ ) bicycloalkenyl, (5-11 membered) heterobicycloalkyl, (C ₆ -C ₁₄ ) aryl or (5-14 membered) heteroaryl; and 108 • · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · Wherein R ⁴ is optionally substituted by one to three R ⁸ substituents independently selected from the group consisting of F, Cl. Br, I, nitro, cyano, -CF ₃ , -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) 2NR 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 or R ⁷ ; Each of R ⁷ , R ⁸ and R ⁹ is independently selected from the group consisting of H, (C 1 -C 8) straight or branched chain alkyl, (C 2 -C 8) straight or branched alkenyl, (C 2 -C8) straight or branched-chain alkynyl, (C3-C8) cycloalkyl, (C4-C8) cycloalkenyl, (3-8 membered) heterocycloalkyl, (C5-C6) bicycloalkyl, (C7-C6) bicycloalkenyl, (5 -11 membered) heterobicycloalkyl, (C6-C14) aryl, and (5-14 membered) heteroaryl, wherein each of R ⁷ , R ⁸ and R ⁹ is independently optionally substituted with one to six substituents independently selected from the group consisting of F, Cl. Br, I, NO2, -CN, -CF ₃ , -NR ¹⁰ R ¹¹ , -NR ¹⁰ C (= O) R ¹¹ , -NR ¹⁰ C (= O) OR ¹¹ , -NR ¹⁰ C (= O) NR ¹¹ R ¹² , -NR ¹⁰ S (= O) 2R ¹¹ , -NR ¹⁰ S (= O) 2NR ¹¹ 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) 2R ¹⁰ , -S (= O) 2NR ¹⁰ R ¹¹ , -C (= O) R ¹⁰ , -C (= O) OR ¹⁰ , -C (= O) NR ¹⁰ R ¹¹ , and R ¹⁰ ; or, when R ⁷ and R ⁸ are as in NR ⁷ R ⁸ , they may instead optionally be attached, forming with the nitrogen of NR ⁷ R ⁸ to which they are attached, a heterocycloalkyl residue of three to seven members on the ring, said heterocycloalkyl residue optionally containing one or two other heteroatoms independently selected from the group consisting of N, O and S; Each of R ¹⁰ , R ¹¹ and R ¹² is independently selected from the group consisting of H, (C ₁ -C ₈ ) alkyl, straight or branched 109 · «·· • · · ·· · ·· ··· · 4 f · ·· ···· · · e 4 · 4 * 4 ♦ · 4 4 ♦ 4 l «« «4» · * · 44 «·· the chain, (C ₂ -C ₈ ) alkenyl on the right or branched chain, (C ₂ C ₈ ) alkynyl on the right, or branched chain, (C ₃ -C ₈ ) cycloalkyl, (C ₄ -C ₈ ) cycloalkenyl, (3-8 membered) hetero-cycloalkyl, (C ₅ -C ₆ ) bicycloalkyl, (C ₇ -C ₈ ) bicycloalkenyl, ( 5-11 membered) heterobicycloalkyl, (C ₆ -C- | ₄ ) aryl, and (5-14 membered) heteroaryl, wherein each of R ¹⁰ , R ¹¹ and R ¹² is optionally substituted by one to one six substituents independently selected from the group consisting of F, Cl. Br, I, NO ₂ , -CN, -CF ₃ , -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) R ¹³ , -C (= O) OR ¹³ , -C (= O) NR ¹³ R ¹⁴ , and R ¹³ ; Each of R ³ , R ¹⁴ and R ¹⁵ is independently selected from the group consisting of H, (C 1 -C 8) straight or branched alkyl, straight or branched (C 2 -C 8) alkenyl, Straight or branched (C2-C8) alkynyl, (C3-C8) cycloalkyl, (C4-C8) cycloalkenyl, (3-8 membered) heterocycloalkyl, (C5-C6) bicycloalkyl, (C6-C6cycloalkenyl, (5 -11 membered) heterobicycloalkyl, (C6-C14) aryl, and (5-14 membered) heteroaryl, wherein each of R ¹³ , R ¹⁴ and R ¹⁵ is independently optionally substituted with one to six substituents independently selected from the group consisting of F, Cl, Br, I, NO2, -CN, -CF ₃ , -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 (= O) OR ¹⁶ , -OC (= O) NR ¹⁶ R ¹⁷ , -OC (= O) SR ¹⁶ , -SR ¹⁶ , -S (= O) R ¹⁶ , -S (= O) 2R ¹⁶ , -S (= O) 2NR ¹⁶ R ¹⁷ , -C (= O) R ¹⁶ , -C (= O) OR ¹⁶ , -C (= O) NR ¹⁶ R ¹⁷ , and R ¹⁶ ; Each of R ¹⁶ , R ¹⁷ and R ¹⁸ is independently selected from the group consisting of H, (C ₁ -C ₈ ) alkyl, straight or branched 110 chain, (C ₂ -C ₈ ) straight or branched chain alkenyl, (C ₂ -C ₈ ) straight or branched alkynyl, (C ₃ -C ₈ ) cycloalkyl, (C ₄ -C ₈ ) cycloalkenyl, (3-8 membered) hetero-cycloalkyl, (C ₅ -C ₆ ) bicycloalkyl, (C ₇ -C ₈ ) ) bicycloalkenyl, (5-11 membered) heterobicycloalkyl, (C ₆ -C 1 ₃₎ aryl, and (5-14 membered) heteroaryl; η is 0.1, 2, or 3; wherein each of R ¹⁰ and R ¹¹ in -C (= O) (CR ¹⁰ R ¹¹ ) n- and - (CR ¹⁰ R ¹¹ ) n- is a repetition of n, defined independently as indicated above; and pharmaceutically acceptable salts thereof. A compound according to claim 1, wherein R ³ is -C (= O) NH- or -C (= O)) (CR ¹⁰ R ¹¹ ) _n -. A compound according to claim 1, wherein R ¹ is optionally substituted (C ₃ -C ₈ ) cycloalkyl, or optionally substituted (C ₅ -C ₆ ) bicycloalkyl. A compound according to claim 1 wherein R ¹ is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl, or bicyclo- [3.1.0] -hexyl, each optionally substituted. A compound according to claim 1, wherein R ¹ is optionally substituted (C ₁ -C ₈ ) straight or branched chain alkyl, or optionally substituted straight or branched chain (C ₂ -C ₈ ) alkenyl. A compound according to claim 1, wherein R ⁴ is optionally (C ₆ -C ₁₄ ) aryl, or (5-14 membered) heteroaryl, each optionally substituted. A compound according to claim 6 wherein R ⁴ is phenyl, pyridyl, naphthyl, quinolyl or isoquinolyl, each optionally substituted. 111 • · · · A compound according to any one of claims 1-7, wherein R ² is hydrogen. A compound according to claim 1 selected from the group consisting of: N- (1-cyclobutyl-1H-imidazol-4-yl) -2-quinolin-6-yl-acetamide; N- (1-cyclopentyl-1H-imidazol-4-yl) -2- (4-methoxyphenyl) acetamide; N- [1- (cis-3-phenyl-cyclobutyl) -1H-imidazol-4-yl] -2quinolin-6-yl-acetamide; (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-amino-cyclobutyl) -1H-imidazol-4-yl] -2-naphthalen-1-yl-acetamide; 6-methyl-pyridine-2-carboxylic acid and {cis-3- [4- (2-naphthalen-1-yl-acetylamino) -imidazol-1-yl] cyclobutyl} -amide; 1H-imidazole-4-carboxylic acid {cis-3- [4- (2-naphthalen-1-yl-acetylamino) -imidazol-1-yl] cyclobutyl} -amide; 6-hydroxy-pyridine-2-carboxylic acid {cis-3- [4- (2-naphthalen-1-yl-acetylamino) -imidazol-1-yl] -cyclobutyl} amide; 3-methyl-pyridine-2-carboxylic acid {cis-3- [4- (2-naphthalen-1-yl-acetylamino) -imidazol-1-yl] -cyclobutyl} amide; 2-Pyridin-3-yl-thiazole-4-carboxylic acid {cis-3- [4 (2-naphthalen-1-yl-acetylamino) -imidazol-1-yl] -cyclobutyl} amide; 112 • · · · 6- {cis-3- [4- (2-naphthalen-1-yl-acetylamino) -imidazol-1-yl] -cyclobutylcarbamoyl} -nicotinic acid methyl ester; Pyrazine-2-carboxylic acid {cis-3- [4- (2-naphthalen-1-yl-acetylamino) -imidazol-1-yl] -cyclobutyl} -amide; N- {cis-3- [4- (2-naphthalen-1-yl-acetylamino) -imidazol-1-yl] -cyclobutyl} benzamide; 5-methyl-pyrazine-2-carboxylic acid {cis-3- [4- (2-naphthalen-1-yl-acetylamino) -imidazol-1-yl] -cyclobutyl} -amide; N- {cis-3- [4- (2-naphthalen-1-yl-acetylamino) -imidazol-1-yl] -cyclobutyl} -isobutyramide; 6-chloro-pyridine-2-carboxylic acid {cis-3- [4- (2-naphthalen-1-yl-acetylamino) -imidazol-1-yl] -cyclobutyl} amide; quinoline-2-carboxylic acid (cis-3- [4- (2-naphthalen-1-yl-acetylamino) -imidazol-1-yl] -cyclobutyl} -amide; 1H-pyrrole-2-carboxylic acid {cis-3- [4- (2-naphthalene- 1-yl-acetylamino) -imidazol-1-yl] -cyclobutyl} -amide; N- {cis-3- [4- (2-naphthalen-1-yl-acetylamino) -imidazol-1-yl] -cyclobutyl} -2-t-tolyl-acetamide; Pyridine-2-carboxylic acid {cis-3- [4- (2-naphthalen-1-yl-acetylamino) -imidazol-1-yl] -cyclobutyl} -amide; 2- (3-hydroxy-phenyl) -N- {cis-3- [4- (2-naphthalen-1-ylacetylamino) -imidazol-1-yl] -cyclobutyl} -acetamide; piperidine-4-carboxylic acid {cis-3- [4- (2-naphthalen-yl-acetylamino) -imidazol-1-yl] -cyclobutyl} -amide hydrochloride; N- [1- (cis-3-acetylamino-cyclobutyl) -1H-imidazol-4-yl] - 2- naphthalen-2-yl-acetamide; 113 • · N- {cis-3- [4- (2-isoquinolin-5-yl-acetylamino) -imidazol-1-yl] -cycobutyl} -benzamide; and pyridine-2-carboxylic acid {cis-3- [4- (2-isoquinolin-5-yl-acetylamino) -imidazol-1-yl] -cyclobutyl} -amide; and pharmaceutically acceptable salts of the above compounds. A pharmaceutical composition for treating a disease or condition consisting of abnormal cell growth, or a neurodegenerative disease, or condition in a mammal, characterized in that it contains a compound according to claim 1 in an amount effective for treating said disease, or a condition, and a pharmaceutically acceptable carrier. A pharmaceutical composition for treating a disease or condition in mammals whose treatment may be effective or facilitated by altering a dopamine mediated neurotransmission, characterized in that it contains a cdk5 inhibitor in an amount effective for treating said disease, or condition, or amount, effectively inhibiting cdk5 activity, and a pharmaceutically acceptable carrier. A pharmaceutical composition for the treatment in a mammal of a disease or condition selected from the group consisting of male infertility and sperm motility; diabetic melitus; impaired glucose tolerance; metabolic syndrome, or syndrome X; polycystic ovarian syndrome; adipogenesis and obesity; myogenesis and fragility, for example, age-related decline in physical characteristics; acute sarcopenia, for example, muscle atrophy and / or cachexia associated with burning, poor support, limb immobilization, or 114 major thoracic, abdominal, and / or orthopedic surgery; sepsis; hair loss, thinning hair, and baldness; and an immune deficiency characterized in that it contains a compound of claim 1 in an amount effective to treat said disease or condition, and a pharmaceutically acceptable carrier. 13.. A pharmaceutical composition comprising a cdk5 inhibitor and a second member selected from the group consisting of SSRI antagonist and NK receptor, 5HT ₁₀ antagonist, cyprasidone, olanzapine, risperidone, L-745870, sonepiprazole, RP 62203, NGD 9413, NGD balaperidone, flesinoxane, gepirone, an acetylcholinesterase inhibitor, TPA, NIF, a calcium channel modulator such as BMS-204352, and an NMDA receptor antagonist, characterized in that the cdk5 inhibitor and the second member are together in an effective amount, and pharmaceutically acceptable