HRP20030140A2 - Pyrazole derivatives and their use as protein kinase inhibitors - Google Patents

Description

Field of invention

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

Background of the invention

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

The serine/threonine kinase cdk2 is essential for normal cell cycle and plays a critical role in disorders arising from abnormal cell cycle, a common feature of many oncological disorders. Cdk2 inhibitors are therefore useful for the treatment of various types of cancer and other disorders or conditions associated with abnormal cell growth (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)).

GSK-3 is a serine/threonine protein kinase. It is one of several protein kinases that phosphorylate glycogen synthase (Embi, et al., Eur. J. Biochem. 107: 519-527 (1980); Hemmings, et al., Eur. J. Biochem. 119: 443-451 ( 1982)). In vertebrates, GSK-3 exists in two isoforms α and β, each reported to have a monomeric structure of 49kD and 47kD. Both isoforms phosphorylate muscle glycogen synthases (Cross, et al., Biochemical Journal 303: 21-26 (1994)). Amino acid identity between homologues of GSK-3 species has been shown to be 98% redundant within the catalytic region (Plyte, et al., Biochim. Biophys. Acta 1114: 147-162) (1992)). Due to the remarkably high degree of conservation across the phylogenetic spectrum, a fundamental role of GSK-3 in cellular processes has been suggested.

GSK-3 is associated with a number of different disease states. For example, Chen, et al, Diabetes 43: 1234-1241 (1994) suggest that increased GSK-3 activity may be important in type 2 diabetes. Increased secretion of GSK-3 in diabetic muscle is thought to contribute to decreased glycogen synthase activity and the presence insulin resistance in skeletal muscle in type 2 diabetes (Nikoulina, et al., Diabetes 49: 263-271 (2000)). Also, increased protein phosphatase type 1 activity measured in immotile spermatozoa has been attributed to increased GSK-3 activity and has been shown to be responsible for maintaining sperm motility (Vijayaraghavan, et al. Biology of Reproduction 54: 709-718 (1996)). Vijayaraghavan et al show that such results suggest a biochemical 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 is further implicated in hair loss, schizophrenia and neurodegeneration, including chronic neurodegenerative disease (such as Alzheimer's, see above) and neurotrauma, for example stroke, concussion and spinal cord injury.

The essence of invention

The present invention provides compounds of formula

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wherein R1 is straight or branched (C1-C8) alkyl, straight or branched (C2-C8) alkenyl, straight or branched (C2-C8) alkynyl, (C3-C8) cycloalkyl, (C4-C8) cycloalkenyl, ( three- to eight-membered) heterocycloalkyl, (C5-C11) bicycloalkyl, (C7-C11) bicycloalkenyl, or (five- to eleven-membered) heterobicycloalkyl; and wherein R1 may be substituted with one to six R5 substituents independently selected from F, Cl, Br, I, nitro, cyano, -CF3, -NR7R8, -NR7C (=O)R8, -NR7C(=O)OR8, - NR7C(=O)NR8R9, -NR7S(=O)2R8, -NR7S(=O)2NR8R9, -OR7, -OC(=O)R7, OC(=O)OR7, -C(=O)OR7, - C(=O)R7, -C(=O)NR7R8, -OC(=O)NR7R8, -OC(=O)SR7, -SR7, S(=O)R7, -S(=O)2R7, - S(=O) 2 NR 7 R 8 , and R 7 ;

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

R3 is -C(=O)NR9-, -C(=O)O-, -C(=O)(CR10R11)n-, or -(CR10R11)n-;

R4 straight or branched (C1-C8) alkyl, straight or branched (C2-C8) alkenyl, straight or branched (C2-C8) alkynyl, (C3-C8) cycloalkyl, (C4-C8) cycloalkenyl, (three to eight-membered) heterocycloalkyl, (C5-C11) bicycloalkyl, (C7-C11) bicycloalkenyl, (five- to eleven-membered) heterobicycloalkyl, (C6-C14) aryl or (five- to fourteen-membered) heteroaryl; and wherein R4 may be substituted with one to three R6 substituents independently selected from F, Cl, Br, nitro, cyano, -CF3, -NR7R8, -NR7C(=O)R8, -NR7C(=O)OR8, -NR7C( =O)NR8R9, -NR7S(=O)2R8, -NR7S(=O)2NR8R9, -OR7, -OC(=O)R7, -C(=O)OR7, -C(=O)OR7, -C (=O)R7, -C(=O)NR7R8, -OC(=O)NR7,R8, -OC(=O)SR7, -SR7, -S(=O)R7, -S(=O)2R7 , -S(=O) 2 NR 7 R 8 , or R 7

each R7, R8 and R9 independently selected from H, straight or branched (C1-C8) alkyl, straight or branched (C2-C8) alkenyl, straight or branched (C2-C8) alkynyl, (C3-C8) cycloalkyl, (C4 -C8) cycloalkenyl, (three-membered to eight-membered) heterocycloalkyl, (C5-C11) bicycloalkyl, (C7-C11) bicycloalkenyl, (five- to eleven-membered) heterobicycloalkyl, (C6-C14) aryl, and (five- to fourteen-membered) heteroaryl, where R7 , R8 and R9 may be substituted with one to six substituents independently selected from F, Cl, Br, I, NO2, -CN, -CF3, -NR10R11, -NR10C(=O)R11, -NR10C(=O)OR11, -NR10C(=O)NR11R12, -NR10S(=O)2R11, -NR10S(=O)2NR11R12, -OR10, -OC (=O)R10, -OC(=O)OR10, -OC(=O)NR10R11 , -OC(=O)SR10, -SR10, -S(=O)R10, -S(=O)2R10, -S(=O)2NR10R11, -C(=O)R10, -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 be linked to form with the nitrogen of NR 7 R 8 in which they are incorporated, a heterocycloalkyl unit with three to seven rings, said heterocycloalkyl unit may contain one or two further heteroatoms independently selected from N, O and S;

each R10, R11, and R12 independently selected from H, straight or branched (C1-C8) alkyl, straight or branched (C2-C8) alkenyl, straight or branched (C2-C8 alkynyl), (C3-C8) cycloalkyl, ( C4-C8) cycloalkenyl, (three- to eight-membered) heterocycloalkyl, (C5-C11) bicycloalkyl, (C7-C11) bicycloalkenyl, (five- to eleven-membered) heterobicycloalkyl, (C6-C14) aryl and (five- to fourteen-membered) heteroaryl, where R10 , R11 and R12 can each independently be substituted with one to six substituents independently selected from F, Cl, Br, I, NO2, -CN, -CF3, -NR13R14, -NR13C(=O)R14, -NR13C(=O) OR14, -NR13C(=O)NR14R15 –NR13S(=O)2R14, -NR13S(=O)2NR14R15, -OR13, -OC(=O)R13, -OC(=O)OR13, -OC(=O) NR13R14, -OC(=O)SR13, -SR13, -S(=O)R13, -S(=O)2R13, -S(=O)2NR13R14, -C(=O)R13, -C(=O )OR 13 , -C(=O)NR 13 R 14 and R 13

each R13, R14 and R15 independently selected from H, straight or branched (C1-C8) alkyl, straight or branched (C2-C8) alkenyl, straight or branched (C2-C8 alkynyl), (C3-C8) cycloalkyl, (C4 -C8) cycloalkenyl, (three- to eight-membered) heterocycloalkyl, (C5-C11) bicycloalkyl, (C7-C11) bicycloalkenyl, (five- to eleven-membered) heterobicycloalkyl, (C6-C14) aryl and (five- to fourteen-membered) heteroaryl, where R13, R14 and R15 can each independently be substituted with one to six substituents independently selected from F, Cl, Br, I, NO2, -CN, -CF3, -NR16R17, -NR16C(=O)R17, -NR16C(=O)OR17 , -NR16C(=O)NR17R18, -NR16S(=O)2R17, -NR16S(=O)2NR17R18 –OR16, -OC(=O)R16, -OC(=O)OR16, -OC(=O)NR16R17 , -C(=O)SR16, -SR16, -S(=O)R16, -S(=O)2R16, -S(=O)2NR16R17, -C(=O)R16, -C(=O) OR16, -C(=O)NR16R17 and R16

each R16, R17 and R18 is independently selected from H, straight or branched (C1-C8) alkyl, straight or branched (C2-C8) alkenyl, straight or branched (C2-C8 alkynyl), (C3-C8) cycloalkyl, ( C4-C8) cycloalkenyl, (three- to eight-membered) heterocycloalkyl, (C5-C11) bicycloalkyl, (C7-C11) bicycloalkenyl, (five- to eleven-membered) heterobicycloalkyl, (C6-C14) aryl and (five- to fourteen-membered) heteroaryl;

n 0, 1, 2, or 3;

wherein R 20 and R 11 in -C(=O)(CR 10 R 11 )n- and -(CR 10 R 11 )n- for each repetition of n are defined independently as enumerated above; and their pharmaceutically acceptable salts.

Amino-substituted pyrazoles can exist as a mixture of tautomeric isomers in mutual equilibrium. This invention includes all tautomers of compounds of formula 1, and references herein to compounds of formula 1, unless otherwise indicated, also include tautomers of compounds of formula 1.

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

The term "alkyl", as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight or branched units. 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 units having at least one carbon-carbon double bond, where alkyl is as defined above. Examples of alkenyl include, but are not limited to, ethenyl and propenyl.

The term "alkynyl", as used herein, unless otherwise indicated, includes alkyl units having at least one carbon-carbon triple bond, where 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 units, wherein alkyl is as defined above. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. "Bicycloalkyl" groups are non-aromatic saturated carbocyclic groups consisting of two rings, wherein said rings share one or two carbon atoms. For the purpose of this 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]decyl, spiro[4.4]nonyl, spiro[4.3]octyl, and spiro[4.2]heptyl.

"Cycloalkenyl" and "bicycloalkenyl" refer to non-aromatic carbocyclic cycloalkyl and bicycloalkyl units as described above, except those containing one or more carbon-carbon double bonds connecting carbon ring members ("endocyclic" double bond) and/or one or more carbon-carbon double bonds connecting members of a carbon ring and an 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 bicycloalkenyl groups also include groups substituted with one or more oxo units. Examples of such groups with oxo units are oxocyclopentyl, oxocyclobutyl, oxocyclopentenyl and norcamphoryl.

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 the like, as used herein, mean non-aromatic cyclic groups containing one or more heteroatoms, preferably one to four heteroatoms, each selected from O, S and N. "Heterobicycloalkyl" groups are non-aromatic two-ring cyclic groups, wherein said rings share one or two atoms and wherein at least one of the rings contains a heteroatom (O, S, or N). Heterobicycloalkyl groups for the purpose of this invention, and unless otherwise indicated, include fused ring spiro groups. In one embodiment, each ring in the heterobicycloalkyl contains up to four heteroatoms (for example from none to four heteroatoms, ensuring that at least one ring contains at least one heteroatom). The heterocyclic groups of this invention may also include ring systems substituted with one or more oxo units. Examples of non-aromatic heterocyclic groups are aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, azepinyl, piperazinyl, 1,2,3,6-tetrahydropyridinyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholino, thiomorpholino, thioxanyl, pyrrolinyl, indolinyl. , 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl , quinolizinyl, quinuclidinyl, 1,4-dioxaspiro[4.5]decyl, 1,4-dioxaspiro[4.4]nonyl, 1,4-dioxaspiro [4.3]octyl and 1,4-dioxaspiro[4.2]heptyl.

"Heteroaryl", as used herein, means aromatic groups containing one or more heteroatoms (O, S or N), preferably from one to four heteroatoms. A multicyclic group containing one or more heteroatoms where at least one ring of the group is aromatic is a "heteroaryl" group. Heteroaryl groups of this invention may also include ring systems substituted with one or more oxo units. Examples of heteroaryl groups are pyridinyl, pyridazinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, quinolyl, isoquinolyl, tetrazolyl, furyl, thienyl , isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, indolyl, benzimidazolyl, benzofuranyl, cinolinyl, indazolyl, indolizinyl, phthalazinyl, triazinyl, isoindolyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzotriazolyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl , naphthridinyl, dihydroquinolyl, tetrahydroquinolyl, dihydroisoquinolyl, tetrahydroisoquinolyl, benzofuryl, furopyridines l, pyrrolopyrimidinyl and azaindolyl.

The preceding groups, obtained from the above-mentioned compounds, can be attached through C or N, where possible. For example, a group derived from pyrrole can be pyrrole-1-yl (linked via N) or pyrrole-3-yl (linked via C). The terms relating to the groups also include all possible tautomers.

In one embodiment, the present invention provides compounds of formula 1, wherein R3 is -C(=O)NR9- or -C(=O)(CR10R11)n-. In another embodiment, R 10 and R 11 in -C(=O)(CR 10 R 11 )n- are at each repeat n hydrogen. In another embodiment, R 9 in -C(=O)NR 9 - is hydrogen. In another embodiment, R3 is -C(=O)NR9- or -C(=O)(CR10R11)n- and R2 is hydrogen. In another embodiment, R3 is -(CR10R11)n-, and n is zero. In a preferred embodiment, R 3 is -(CR 10 R 11 )n-, n is zero and R 4 is (C 6 -C 14 )aryl or (5-14 membered) heteroaryl, each of which may be substituted as indicated above.

In another embodiment of the invention, there is provided a compound of formula 1 wherein R 1 may be substituted with (C 3 -C 8 )cycloalkyl or (C 5 -C 11 )bicycloalkyl. Preferred embodiments are where R 1 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or norbornyl, each of which may be substituted as indicated above (ie, may be from one to six substituents independently selected from F, Cl, Br, I, nitro, cyano , -CF3, -NR7R8, -NR7C(=O)R8, -NR7C(=O)OR8, -NR7C(=O)NR8R9, -NR7S(=O)2R8, -NR7S(=O)2NR8R9, -OR7, -OC(=O)R7, -OC(=O)OR7, -C(=O)OR7, -C(=O)R7, -C(=O)NR7R8, -OC(=O)NR7R8, -OC (=O)SR7, -SR7, -S(=O)R7, -S(=O)2R7, -S(=O)2NR7R8, and R7). In a more preferred embodiment, R 1 is (C 3 -C 8 )cycloalkyl or may be substituted (C 5 -C 11 )bicycloalkyl, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or norbornyl, and may be substituted with one to three substituents independently selected from F, Cl, Br,., nitro, cyano, -CF3, -NR7R8, -NR7C(=O)R8, -OR7, -C(=O)OR7, -C(=O)R7 and R7. More preferably, R 1 is (C 3 -C 8 )cycloalkyl or optionally substituted (C 5 -C 11 )bicycloalkyl, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or norbornyl and R 1 is substituted with -NR 7 C(=O)R 8 , (C 6 -C 14 )aryl, (three-membered to eight-membered) heterocycloalkyl or (five-membered to fourteen-membered) heteroaryl, and where indicated the aryl, heterocycloalkyl and heteroaryl may each be substituted with one to six substituents independently selected from F, Cl, Br, I, NO2, -CN , -CF3, -NR10R11, -NR10C(=O)R11, -NR10C(=O)OR11, -NR10C(=O)NR11R12, -NR10S(=O)2R11, -NR10S(=O)2NR11R12, -R10, -OC(=O)R10, -OC(=O)OR10, -OC(=O)NR10R11, -OC(=O)SR10, -SR10,-S(=O)R10, -S(=O)2R10 , -S(=O)2NR10R11, -C(=O)R10, -C(=O)OR10, -C(=O)NR10R11 and R10. In another embodiment of the invention, R 1 is bicyclo[3.1.0]-hexyl and may be substituted as indicated above (for example, may be substituted with one to six R 5 substituents independently selected from F, Cl, Br, I, nitro, cyano , -CF3, -NR7R8, -NR7C(=O)R8, -NR7C(=O)OR8, -NR7C(=O)NR8R9, -NR7S(=O)2R8, -NR7S(=O)2NR8R9, -OR7, -OC(=O)R7, -OC(=O) OR7, -C(=O)OR7, -C(=O)R7, -C(=O)NR7R8, -OC(=O)NR7R8, -OC (=O)SR7, -SR7, -S(=O)R7, -S(=O)2R7, -S(=O)2NR7R8 and R7.

In another embodiment of the invention, a compound of formula 1 is provided where R1 can be substituted by straight-chain or branched (C1-C8) alkyl or can be substituted by straight-chain or branched (C2-C8) alkenyl.

In another embodiment of the invention, compounds of formula 1 are provided, but where R2 is hydrogen. In another embodiment, R 2 is hydrogen and R 1 is as sub-defined in the preceding paragraphs.

In another embodiment, the present invention provides a compound of formula 1 wherein R 4 is (C 6 -C 14 )aryl or (five to fourteen membered) heteroaryl, each optionally substituted. In a preferred embodiment, R 4 may be substituted with phenyl or pyridyl. In another preferred embodiment, R 4 is naphthyl, quinolyl or isoquinolyl, each optionally substituted. In another embodiment, R 4 is naphthyl, quinolyl or isoquinolyl, and is unsubstituted. In another embodiment, R 4 is pyrimidinyl, pyrazinyl or pyridazyl, and in each case R 4 may be substituted. In another embodiment, R 4 is pyrimidinyl, pyrazinyl or pyridazyl and R 4 is unsubstituted.

In another embodiment, compounds of formula 1 are provided, wherein R 2 is specifically hydrogen and R 4 is as sub-defined in the preceding paragraphs.

Examples of preferred compounds of formula 1 are:

(5-cyclobutyl-2H-pyrazol-3-yl)-(3-trifluoromethoxy-phenyl)-amine;

N-(5-cyclobutyl-2H-pyrazol-3-yl)-N',N'-dimethylpyridine-2,6-diamine;

(5-ethyl-2H-pyrazol-3-yl)-(6-methoxy-pyridin-2-yl)-amine;

(5-cyclobutyl-2H-pyrazol-3-yl)-(6-methoxy-pyridin-2-yl)-amine

(5-cyclobutyl-2H-pyrazol-3-yl)-naphthalen-2-yl-amine;

(5-cyclobutyl-2H-pyrazol-3-yl)-naphthalen-1-yl-amine;

N-(5-cyclobutyl-2H-pyrazol-3-yl)-N',N'-dimethyl-naphthalene-1,4-diamine;

N-(5-cyclobutyl-2H-pyrazol-3-yl)-N',N'-dimethyl-pyridine-2,6-diamine;

(5-cyclobutyl-2H-pyrazol-3-yl)-(6-trifluoromethyl-pyridin-2-yl)-amine;

(3-benzyloxy-phenyl)-(5-cyclobutyl-2H-pyrazol-3-yl)-amine;

(5-cyclobutyl-2H-pyrazol-3-yl)-(3-trifluoromethyl-phenyl)-amine;

N-(5-cyclobutyl-2H-pyrazol-3-yl)-N',N'-dimethyl-benzene-1,3-diamine;

(5-cyclobutyl-2H-pyrazol-3-yl)-(3-methoxy-phenyl)-amine;

(5-cyclobutyl-2H-pyrazol-3-yl)-(4-nitro-phenyl)-amine;

(4-chloro-benzyl)-(5-cyclobutyl-2H-pyrazol-3-yl)-amine;

(3-bromo-phenyl)-(5-cyclobutyl-2H-pyrazol-3-yl)-amine;

(5-cyclobutyl-2H-pyrazol-3-yl)-quinolin-2-yl-amine;

[5-(1,4-dioxa-spiro[4.4]non-7-yl)-1H-pyrazol-3-yl]-(3-trifluoromethyl-phenyl)-amine;

(6-chloro-pyridin-2-yl)-(5-cyclobutyl-2H-pyrazol-3-yl)-amine;

3-[5-(3-trifluoromethyl-phenylamino)-2H-pyrazol-3-yl]-cyclopentanones;

(5-cyclobutyl-2H-pyrazol-3-yl)-(6-methoxy-4-methyl-quinolin-2-yl)-amine;

(5-cyclobutyl-2H-pyrazol-3-yl)-(3-trifluoromethoxy-phenyl)-amine;

(2-chloro-4-nitro-phenyl)-(5-cyclobutyl-2H-pyrazol-3-yl)-amine;

3-trans-[5-(3-trifluoromethyl-phenylamino)-2H-pyrazol-3-yl]-cyclopentanol;

(3,5-bis-trifluoromethyl-phenyl)-(5-cyclobutyl-2H-pyrazol-3-yl)-amine;

[5-(3-cis-benzylamino-cyclopentyl)-1H-pyrazol-3-yl-(3-trifluoromethyl-phenyl)-amine;

{5-[3-cis-(4-methoxy-benzylamino)-cyclopentyl]-1H-pyrazol-3-yl}(3-trifluoromethylphenyl)-amine;

4-(5-cyclobutyl-2H-pyrazol-3-ylamino)-benzonitriles;

(5-cyclobutyl-2H-pyrazol-3-yl)-(3-fluoro-phenyl)-amine;

(5-cyclobutyl-2H-pyrazol-3-yl)-(3,5-dichloro-phenyl)-amine;

(2-bromo-phenyl)-(5-cyclobutyl-2H-pyrazol-3-yl)-amine;

N-{cis-3-[5-(3-trifluoromethyl-phenylamino)-2H-pyrazol-3-yl]-cyclopentyl}-acetamide;

pyridin-2-yl-{3-trans-[5-(3-trifluoromethyl-phenylamino)-2H-pyrazol-3-yl]-cyclopentyl}amine;

(5-cyclobutyl-1H-pyrazol-3-yl)-(4-methoxy-phenyl)-amine;

Pyridine-2-carboxylic acid {3-[5-(3-trifluoromethyl-phenylamino)-2H-pyrazol-3-yl]cyclopentyl}-amide;

3-trifluoromethyl-N-{3-[5-(3-trifluoromethyl-phenylamino)-2H-pyrazol-3-yl]-cyclopentyl}-benzamide;

Cyclobutanecarboxylic acid {3-[5-(3-trifluoromethyl-phenylamino)-2H-pyrazol-3-yl[cyclopentyl}-amide;

2,2-dimethyl-N-[3-[5-(3-trifluoromethyl-phenylamino)-2H-pyrazol-3-yl]-cyclopentyl}propionamide;

4-fluoro-N-[3-[5-(3-trifluoromethyl-phenylamino)-2H-pyrazol-3-yl]-cyclopentyl}benzamide;

2,2,2-trifluoro-N-{3-[5-(3-trifluoromethyl-phenylamino)-2H-pyrazol-3-yl]-cyclopentyl}acetamide;

Cyclopropanecarboxylic acid {3-[5-(3-trifluoromethyl-phenylamino)-2H-pyrazol-3-yl]cyclopentyl}-amide;

N-{3-[5-(3-trifluoromethyl-phenylamino)-2H-pyrazol-3-yl]-cyclopentyl}-propionamide;

Cyclohexanecarboxylic acid {3-[5-(3-trifluoromethyl-phenylamino)-2H-pyrazol-3-yl]-cyclopentyl}-amide;

N-[5-(3-acetylamino-cyclopentyl)-2H-pyrazol-3-yl]-2-naphthalen-1-yl-acetamide;

Cyclopropanecarboxylic acid {3-[5-(2-naphthalen-1-yl-acetylamino)-1H-pyrazol-3-yl]cyclopentyl}-amide;

2-naphthalen-1-yl-N-{5-[3-(2,2,2-trifluoro-acetylamino)-cyclopentyl]-2H-pyrazol-3-yl}acetamide;

N-{3-[5-(2-naphthalen-1-yl-acetylamino)-1H-pyrazol-3-yl]-cyclopentyl}-benzamide;

N-(5-hydroxymethyl-1H-pyrazol-3-yl)-2-naphthalen-1-yl-acetamide;

2-Naphthalen-1-yl-N-[5-(thiazol-2-ylaminomethyl)-1H-pyrazol-3-yl]-acetamide;

N-[5-((1S)-hydroxy-ethyl)-2H-pyrazol-3-yl]-2-naphthalen-1-yl-acetamide;

N-{5-[(1S)-(Benzoxazol-2-yloxy)-ethyl]-1H-pyrazol-3-yl}-2-naphthalen-1-yl-acetamide;

N-{5-[(1S)-(Benzothiazol-2-yloxy)-ethyl]-1H-pyrazol-3-yl}-2-naphthalen-1-ylacetamide;

N-[5-(3-hydroxy-1-methyl-propyl)-1H-pyrazol-3-yl]-2-naphthalen-1-yl-acetamide;

N-[5-(Benzothiazol-2-yloxymethyl)-1H-pyrazol-3-yl]-2-naphthalen-1-yl-acetamide;

N-{5-[3-(benzothiazol-2-yloxy)-1-methyl-propyl]-1H-pyrazol-3-yl}-2-naphthalen-1-yl-acetamide;

N-[5-(2-hydroxy-(1S)-methyl-ethyl)-2H-pyrazol-3-yl]-2-naphthalen-1-yl-acetamide;

N-{5-[(1R)-(Benzothiazol-2-yloxy)-ethyl]-1H-pyrazol-3-yl}-2-naphthalen-1-yl-acetamide;

N-[5-(3-acetylamino-1-methyl-propyl)-1H-pyrazol-3-yl]-2-naphthalen-1-yl-acetamide;

3-methoxy-N-{cis-3-[5-(2-naphthalen-1-yl-acetylamino)-2H-pyrazol-3-yl]-cyclobutyl}benzamide;

N-[5-(cis-3-acetylamino-cyclobutyl)-1H-pyrazol-3-yl]-2-naphthalen-1-yl-acetamide;

N-{cis-3-[5-(2-naphthalen-1-yl-acetylamino)-2H-pyrazol-3-yl]-cyclobutyl}-benzamide;

2-cyclopropyl-N-{cis-3-[5-(2-naphthalen-1-yl-acetylamino)-2H-pyrazol-3-yl]-cyclobutyl}-acetamide;

{cis-3-[5-(2-naphthalen-1-yl-acetylamino)-2H-pyrazol-3-yl]-cyclobutyl}-amide-6-chloro-pyridine-2-carboxylic acid;

Quinoline-2-carboxylic acid [cis-3-[5-(2-naphthalen-1-yl-acetylamino)-2H-pyrazol-3-yl]cyclobutyl}-amide;

Pyrazine-2-carboxylic acid {cis-3-[5-(2-naphthalen-1-yl-acetylamino)-2H-pyrazol-3-yl]-cyclobutyl}-amide;

4-methoxy-N-{cis-3-[5-(2-naphthalen-1-yl-acetylamino)-2H-pyrazol-3-yl]-cyclobutyl}-benzamide;

N-{cis-3-[5-(2-naphthalen-1-yl-acetylamino)-2H-pyrazol-3-yl]-cyclobutyl}-3-nitrobenzamide;

N-{cis-3-[5-(2-naphthalen-1-yl-acetylamino)-2H-pyrazol-3-yl]-cyclobutyl}-3-trifluoromethyl-benzamide;

N-{cis-3-[5-(2-naphthalen-1-yl-acetylamino)-2H-pyrazol-3-yl]-cyclobutyl}-isobutyramide;

[cis-3-[5-(2-naphthalen-1-yl-acetylamino)-2H-pyrazol-3-yl]-cyclobutyl}-amide 2-phenyl-cyclopropanecarboxylic acid;

N-{5-[cis-3-(benzooxazol-2-yloxy)-cyclobutyl]-1H-pyrazol-3-yl}-2-naphthalen-1-yl-acetamide;

4-dimethylamino-N-{cis-3-[5-(2-naphthalen-1-yl-acetylamino)-2H-pyrazol-3-yl]-cyclobutyl}-benzamide;

3,5-dimethoxy-N-{cis-3-[5-(2-naphthalen-1-yl-acetylamino)-2H-pyrazol-3-yl]cyclobutyl}-benzamide;

2-Naphthalen-1-yl-N-[5-(cis-3-phenyl-cyclobutyl)-2H-pyrazol-3-yl]-acetamide;

N-{5-[cis-3-(3-methoxy-phenyl)-cyclobutyl]-2H-pyrazol-3-yl-2-naphthalen-1-yl-acetamide;

N-{5-[cis-3-(2-methoxy-phenyl)-cyclobutyl]-2H-pyrazol-3-yl}-2-naphthalen-1-yl-acetamide;

N-{5-[cis-3-(4-methoxy-phenyl)-cyclobutyl]-2H-pyrazol-3-yl}-2-naphthalen-1-yl-acetamide;

2-Naphthalen-1-yl-N-[5-(cis-3-p-tolyl-cyclobutyl)-2H-pyrazol-3-yl]-acetamide;

N-{5-[cis-3-(4-chloro-phenyl)-cyclobutyl]-2H-pyrazol-3-yl}-2-naphthalen-1-yl-acetamide;

2-(4-methoxy-phenyl)-N-{5-[cis-3-(2-methoxy-phenyl)-cyclobutyl]-2H-pyrazol-3-yl}acetamide;

N-5-[cis-3-(2-methoxy-phenyl)-cyclobutyl]-2H-pyrazol-3-yl}-2-quinolin-6-yl-acetamide;

N-{5-[cis-3-(2-methoxy-phenyl)-cyclobutyl]-2H-pyrazol-3-yl]-2-phenyl-acetamide;

N-{5-[cis-3-(2-methoxy-phenyl)-cyclobutyl]-2H-pyrazol-3-yl}-2-pyridin-3-yl-acetamide;

N-{5-[cis-3-(4-methoxy-phenyl)-cyclobutyl]-1H-pyrazol-3-yl}-2-quinolin-6-yl-acetamide;

2-quinolin-6-yl-N-[5-(cis-3-p-tolyl-cyclobutyl)-1H-pyrazol-3-yl]-acetamide;

N-{5-[cis-3-(4-fluoro-phenyl)-cyclobutyl]-1H-pyrazol-3-yl}-2-quinolin-6-yl-acetamide;

N-{5-[cis-3-(4-chloro-phenyl)-cyclobutyl]-1H-pyrazol-3-yl}-2-quinolin-6-yl-acetamide;

2-quinolin-6-yl-N-[5-(cis-3-m-tolyl-cyclobutyl)-1H-pyrazol-3-yl]-acetamide;

4-dimethylamino-N-{cis-3-[5-(2-naphthalen-1-yl-acetylamino)-2H-pyrazol-3-yl]-cyclobutyl}-benzamide;

2-naphthalen-1-yl-N-{5-[cis-3-(pyridin-2-yloxy)-cyclobutyl]-1H-pyrazol-3-yl}-acetamide;

{cis-3-[5-(2-naphthalen-1-yl-acetylamino)-2H-pyrazol-3-yl]-cyclobutyl}-amide-6-methyl-pyridine-2-carboxylic acid;

methyl-{cis-3-[5-(2-naphthalen-1-yl-acetylamino)-2H-pyrazol-3-yl]-cyclobutyl}-amide-2-phenyl cyclopropanecarboxylic acid;

N-{5-[cis-3-(3-methylpyrazin-2-yloxy)-cyclobutyl]-1H-pyrazol-3yl}-2-naphthalen-1-yl-acetamide;

{5-[cis-3-(2-methoxy-phenyl)-cyclobutyl]-1H-pyrazol-3-yl}(6-methoxy-pyridin-2-yl)amine;

N-{5-[cis-3-(3,6-dimethyl-pyrazin-2-yloxy)-cyclobutyl]-1H-pyrazol-3-yl}-2-naphthalen-1-yl-acetamide;

N-{5-[cis-3-(3-methoxy-pyridin-2-yloxy)-cyclobutyl]-1H-pyrazol-3-yl}-2-naphthalen-1-yl-acetamide;

{cis-3-[5-(2-naphthalen-1-yl-acetylamino)-2H-pyrazol-3-yl]-cyclobutyl}-amide-2-methyl-cyclopropanecarboxylic acid;

2-naphthalen-1-yl-N-{5-[cis-3-(3-trifluoromethyl-pyridin-2-yloxy)-cyclobutyl]-1H-pyrazol-3-yl}-acetamide;

2-naphthalen-1-yl-N-{5-[cis-3-(3-nitro-pyridin-2-yloxy)-cyclobutyl]-9H-pyrazol-3-yl}-acetamide;

N-{5-[cis-3-(benzothiazol-2-yloxy)-cyclobutyl]-1H-pyrazol-3-yl}-2-naphthalen-1-yl-acetamide;

2-naphthalen-1-yl-N-{5-[cis-3-(4-trifluoromethyl-pyrimidin-2-yloxy)-cyclobutyl]-1H-pyrazol-3-yl}-acetamide;

2-naphthalen-1-yl-N-{5-[3-(5-nitro-pyridin-2-yloxy)-cyclobutyl]-1H-pyrazol-3-yl}acetamide;

2-naphthalen-1-yl-N-{5-[3-(pyrimidin-2-yloxy)-cyclobutyl]-1H-pyrazol-3-yl}-acetamide;

2-naphthalen-1-yl-N-{5-[3-(5-trifluoromethyl-pyridin-2-yloxy)-cyclobutyl]-1H-pyrazol-3yl}-acetamide;

N-{5-[3-(6-Methoxy-pyridazin-3-yloxy)-cyclobutyl]-1H-pyrazol-3-yl}-2-naphthalen-1-yl-acetamide;

2-naphthalen-1-yl-N-{5-[3-(pyrazin-2-yloxy)-cyclobutyl]-1H-pyrazol-3-yl}-acetamide;

N-{5-[3-(6-methyl-pyridin-2-yloxy)-cyclobutyl]-1H-pyrazol-3-yl}-2-naphthalen-1-yl-acetamide;

N-{5-[3-(6-Chloro-benzothiazol-2-yloxy)-cyclobutyl]-1H-pyrazol-3-yl}-2-naphthalen-1yl-acetamide;

N-{5-[3-(6-Methoxy-benzothiazol-2-yloxy)-cyclobutyl]-1H-pyrazol-3-yl}-2-naphthalen-1-yl-acetamide;

and pharmaceutically acceptable salts of the preceding compounds.

Other examples of preferred compounds of formula 1 are:

N-{5-[cis-3-(4-hydroxy-phenyl)-cyclobutyl]-1H-pyrazol-3-yl}-2-quinolin-6-yl-acetamide;

N-{5-[cis-3-(3-hydroxy-phenyl)-cyclobutyl]-1H-pyrazol-3-yl}-2-quinolin-6-yl-acetamide;

2-Naphthalen-1-yl-N-[5-(cis-3-pyridin-3-yl-cyclobutyl)-2H-pyrazol-3-yl]-acetamide;

N-[5-(cis-3-naphthalen-2-yl-cyclobutyl)-2H-pyrazol-3-yl]-2-pyridin-3-yl-acetamide;

N-(5-indan-2-yl-1H-pyrazol-3-yl)-2-quinolin-6-yl-acetamide;

N-[5-(cis-3-pyridin-2-yl-cyclobutyl)-2H-pyrazol-3-yl]-2-quinolin-6-yl-acetamide;

N-[5-(cis-3-pyridin-2-yl-cyclobutyl)-2H-pyrazol-3-yl]-2-quinolin-6-yl-acetamide;

2-(4-methoxy-phenyl)-N-[5-(cis-3-pyridin-4-yl-cyclobutyl)-2H-pyrazol-3-yl]-acetamide;

N-{5-[3-(cis-2-dimethylaminomethyl-phenyl)-cyclobutyl]-2H-pyrazol-3-yl-2-(4-methoxy-phenyl)-acetamide;

N-(5-{cis-3-[3-(2-dimethylamino-ethoxy)-phenyl]-cyclobutyl}-2H-pyrazol-3-yl)-2-(4-methoxy-phenyl)-acetamide;

N-{5-[cis-3-(2-hydroxy-phenyl)-cyclobutyl]-2H-pyrazol-3-yl}-2-(4-methoxy-phenyl)-acetamide;

N-(5-{cis-3-[2-(2-dimethylamino-ethoxy)-phenyl-cyclobutyl}-2H-pyrazol-3-yl)-2-(4-methoxy-phenyl)-acetamide;

2-(4-methoxy-phenyl)-N-[5-(cis-3-phenyl-cyclobutyl)-2H-pyrazol-3-yl]-acetamide;

N-{5-[cis-3-(2-fluoro-phenyl)-cyclobutyl]-2H-pyrazol-3-yl}-2-(4-methoxy-phenyl)acetamide;

N-(5-{cis-3-[4-(azetidin-3-yloxy)-phenyl]-cyclobutyl}-2H-pyrazol-3-yl)-2-(4-methoxy-phenyl)-acetamide;

N-(5-{cis-3-[2-(azetidin-3-yloxy)-phenyl]-cyclobutyl}-2H-pyrazol-3-yl)-2-(4-methoxy-phenyl)-acetamide;

2-(4-methoxy-phenyl)-N-{5-[cis-3-(2-methylsulfanyl-phenyl)-cyclobutyl]-2H-pyrazol-3-yl}-acetamide;

N-{5-[cis-3-(2-amino-phenyl)-cyclobutyl]-2H-pyrazol-3-yl}-2-(4-methoxy-phenyl)-acetamide;

N-{5-[cis-3-(4-cyano-phenyl)-cyclobutyl]-2H-pyrazol-3-yl}-2-(4-methoxy-phenyl)-acetamide;

N-{5-[cis-3-(2-cyano-phenyl)-3-hydroxy-cyclobutyl]-2H-pyrazol-3-yl}-2-(4-methoxy phenyl)-acetamide;

N-{5-[cis-3-(2-hydroxy-ethyl)-cyclobutyl]-1H-pyrazol-3-yl}-2-naphthalen-1-yl-acetamide;

N-{5-[cis-3-(3-cyano-phenyl)-cyclobutyl]-2H-pyrazol-3-yl}-2-(4-methoxy-phenyl)-acetamide;

N-{5-[cis-3-(2-cyano-phenyl)-cyclobutyl]-2H-pyrazol-3-yl}-2-(4-methoxy-phenyl)-acetamide;

N-{5-[cis-3-(3-amino-phenyl)-cyclobutyl]-2H-pyrazol-3-yl}-2-(4-methoxy-phenyl)-acetamide;

Benzoic acid 4-(cis-3-{5-[2-(4-methoxy-phenyl)-acetylamino]-1H-pyrazol-3-yl}-cyclobutyl)-methyl ester;

N-{5-[cis-3-(4-hydroxymethyl-phenyl)-cyclobutyl]-2H-pyrazol-3-yl}-2-(4-methoxy-phenyl)-acetamide;

N-{5-[cis-3-(2-hydroxy-phenyl)-cyclobutyl]-1H-pyrazol-3-yl-2-phenyl-acetamide;

N-{5-[cis-3-(2-hydroxy-phenyl)-cyclobutyl]-1H-pyrazol-3-yl}-2-quinolin-6-yl-acetamide;

N-{5-[cis-3-(2-hydroxy-phenyl)-cyclobutyl]-1H-pyrazol-3-yl}-acetamide;

Cyclopropanecarboxylic acid {5-[cis-3-(2-hydroxy-phenyl)-cyclobutyl]-H-pyrazol-3-yl}-amide

N-{5-[cis-3-(2-hydroxy-phenyl)-cyclobutyl]-1H-pyrazol-3-yl}-isobutyramide;

N-{5-[cis-3-(3-aminomethyl-phenyl)-cyclobutyl]-2H-pyrazol-3-yl-2-(4-methoxy-phenyl)-acetamide;

N-{5-[cis-3-(3-dimethylaminomethyl-phenyl)-cyclobutyl]-2H-pyrazol-3-yl}-2-(4-methoxy-phenyl)-acetamide;

Benzoic acid 3-(cis-3-{5-[2-(4-methoxy-phenyl)-acetylamino]-1H-pyrazol-3-yl}-cyclobutyl)-methyl ester;

N-{5-[cis-3-(3-hydroxymethyl-phenyl)-cyclobutyl]-2H-pyrazol-3-yl]-2-(4-methoxyphenyl)-acetamide;

N-(5-{cis-3-[3-(1-hydroxy-1-methyl-ethyl)-phenyl]-cyclobutyl}-2H-pyrazol-3-yl)-2-(4-methoxy-phenyl)- acetamide;

N-{5-[cis-3-(3-ethylaminomethyl-phenyl)-cyclobutyl]-2H-pyrazol-3-yl}-2-(4-methoxy-phenyl)-acetamide;

N-{5-[cis-3-(3-cyclobutylaminomethyl-phenyl)-cyclobutyl]-2H-pyrazol-3-yl}-2-(4-methoxy-phenyl)-acetamide;

2-(4-methoxy-phenyl)-N-{5-[cis-3-(3-propylaminomethyl-phenyl)-cyclobutyl]-2H-pyrazol-3-yl}-acetamide;

N-5-[cis-3-(3-cyclopentylaminomethyl-phenyl)-cyclobutyl]-2H-pyrazol-3-yl}-2-(4-methoxy-phenyl)-acetamide;

N-(5-{cis-3-[3-(benzylamino-methyl)-phenyl]-cyclobutyl}-2H-pyrazol-3-yl)-2-(4-methoxy-phenyl)-acetamide;

2-(4-methoxy-phenyl)-N-{5-[3-(3-methylaminomethyl-phenyl)-cyclobutyl]-2H-pyrazol-3-yl}-acetamide;

N-{5-[cis-3-(3-cyclopropylaminomethyl-phenyl)-cyclobutyl]-2H-pyrazol-3-yl}-2-(4-methoxy-phenyl)-acetamide;

2-(4-methoxy-phenyl)-N-{5-[cis-3-(3-pyrrolidin-1-ylmethyl-phenyl)-cyclobutyl]-2H-pyrazol-3-yl}-acetamide;

N-{5-[cis-3-(3-diethylaminomethyl-phenyl)-cyclobutyl]-2H-pyrazol-3-yl}-2-(4-methoxy-phenyl)-acetamide;

N-{5-[cis-3-(3-azetidin-1-ylmethyl-phenyl)-cyclobutyl]-2H-pyrazol-3-yl}-2-(4-methoxy-phenyl)-acetamide;

and pharmaceutically acceptable salts of the preceding compounds.

Other specific examples of the compounds of this invention of formula 1 are:

N-[5-(cis-3-pyridin-2-yl-cyclobutyl)-1H-pyrazol-3-yl]-2-quinolin-6-yl-acetamide;

N-[5-(cis-3-pyridin-3-yl-cyclobutyl)-1H-pyrazol-3-yl]-2-quinolin-6-yl-acetamide;

N-[5-(cis-3-pyridin-4-yl-cyclobutyl)-1H-pyrazol-3-yl]-2-quinolin-6-yl-acetamide;

N-[5-(cis-3-pyrazin-2-yl-cyclobutyl)-1H-pyrazol-3-yl]-2-quinolin-6-yl-acetamide;

N-[5-(cis-3-pyrimidin-4-yl-cyclobutyl)-1H-pyrazol-3-yl]-2-quinolin-6-yl-acetamide;

N-{5-[cis-3-(3-methoxy-pyridin-2-yl)-cyclobutyl]-1H-pyrazol-3-yl}-2-quinolin-6-yl-acetamide;

N-{5-[cis-3-(4-methoxy-pyridin-3-yl)-cyclobutyl]-1H-pyrazol-3-yl}-2-quinolin-6-yl-acetamide;

N-{5-[cis-3-(3-methoxy-pyridin-4-yl)-cyclobutyl]-1H-pyrazol-3-yl}-2-quinolin-6-yl-acetamide;

N-[5-[cis-3-(2-methoxy-pyridin-3-yl)-cyclobutyl]-1H-pyrazol-3-yl]-2-quinolin-6-yl-acetamide;

N-{5-[cis-3-(5-methoxy-pyrimidin-4-yl)-cyclobutyl]-1H-pyrazol-3-yl}-2-quinolin-6-yl-acetamide;

N-{5-[cis-3-(1-ethyl-1H-imidazol-2-yl)-cyclobutyl]-1H-pyrazol-3-yl}-2-quinolin-6-yl-acetamide;

N-{5-[cis-3-(1-ethyl-1H-pyrrol-2-yl)-cyclobutyl]-1H-pyrazol-3-yl}-2-quinolin-6-yl-acetamide;

N-{5-[cis-3-(2-aminomethyl-phenyl)-cyclobutyl]-1H-pyrazol-3-yl}-2-quinolin-6-yl-acetamide;

N-[5-[cis-3-(2-pyrrolidin-1-ylmethyl-phenyl)-cyclobutyl]-1H-pyrazol-3-yl}-2-quinolin-6yl-acetamide;

and pharmaceutically acceptable salts of the preceding compounds.

Other specific examples of compounds of formula 1 are:

{4-[(5-cyclobutyl-1H-pyrazol-3-yl-carbamoyl)-methyl]-phenyl}-acetic acid;

N-(5-cyclobutyl-1H-pyrazol-3-yl)-2-(1H-indol-3-yl)-acetamide;

2-(3-chloro-phenyl)-N-(5-cyclobutyl-1H-pyrazol-3-yl)-acetamide;

2-(3-bromo-phenyl)-N-(5-cyclobutyl-1H-pyrazol-3-yl)-acetamide;

2-biphenyl-4-yl-N-(5-cyclobutyl-1H-pyrazol-3-yl)-acetamide;

2-biphenyl-4-yl-N-(5-cyclobutyl-1H-pyrazol-3-yl)-acetamide;

N-(5-cyclobutyl-1H-pyrazol-3-yl)-2-(3,4,5-trimethoxy-phenyl)-acetamide;

{2-[(5-cyclobutyl-1H-pyrazol-3-yl-carbamoyl)-methyl]-phenyl}-acetic acid;

N-(5-cyclobutyl-1H-pyrazol-3-yl)-2-(3,4-dichloro-phenyl)-acetamide;

2-(2-chloro-phenyl)-N-(5-cyclobutyl-1H-pyrazol-3-yl)-acetamide;

N-(5-cyclobutyl-1H-pyrazol-3-yl)-2-(2-fluoro-phenyl)-acetamide;

2-(4-butoxy-phenyl)-N-(5-cyclobutyl-1H-pyrazol-3-yl)-acetamide;

N-(5-cyclobutyl-1H-pyrazol-3-yl)-2-(2,4-difluoro-phenyl)-acetamide;

N-(5-cyclobutyl-1H-pyrazol-3-yl)-2-(2-iodo-phenyl)-acetamide;

N-(5-cyclobutyl-1H-pyrazol-3-yl)-2-(2,3-dimethoxy-phenyl)-acetamide;

N-(5-cyclobutyl-1H-pyrazol-3-yl)-2-(2,5-dihydroxy-phenyl)-acetamide;

N-(5-cyclobutyl-1H-pyrazol-3-yl)-2-(3-hydroxy-4-methoxy-phenyl)-acetamide;

2-(4-acetylamino-phenyl)-N-(5-cyclobutyl-1H-pyrazol-3-yl)-acetamide;

N-(5-cyclobutyl-1H-pyrazol-3-yl)-2-(4-trifluoromethyl-phenyl)-acetamide;

2-(4-chloro-3-nitro-phenyl)-N-(5-cyclobutyl-1H-pyrazol-3-yl)-acetamide;

N-(5-cyclobutyl-1H-pyrazol-3-yl)-2-(4-hydroxy-3,5-dinitro-phenyl)-acetamide;

N-(5-cyclobutyl-1H-pyrazol-3-yl)-2-(3,4-difluoro-phenyl)-acetamide;

2-(2,4-bis-trifluoromethyl-phenyl)-N-(5-cyclobutyl-1H-pyrazol-3-yl)-acetamide;

N-(5-cyclobutyl-1H-pyrazol-3-yl)-2-(3,5-difluoro-phenyl)-acetamide;

N-(5-cyclobutyl-1H-pyrazol-3-yl)-2-(2-fluoro-3-trifluoromethyl-phenyl)-acetamide;

N-(5-cyclobutyl-1H-pyrazol-3-yl)-2-(4-fluoro-3-trifluoromethyl-phenyl)-acetamide;

N-(5-cyclobutyl-1H-pyrazol-3-yl)-2-(2,4,6-trifluoro-phenyl)-acetamide;

N-(5-cyclobutyl-1H-pyrazol-3-yl)-2-(4-methylsulfanyl-phenyl)-acetamide;

N-(5-cyclobutyl-1H-pyrazol-3-yl)-2-(3-hydroxy-phenyl)-acetamide;

N-(5-cyclopentyl-1H-pyrazol-3-yl)-2-phenylacetamide;

2-(4-chloro-phenyl)-N-(5-cyclopentyl-2H-pyrazol-3-yl)-acetamide;

N-(5-cyclopentyl-1H-pyrazol-3-yl)-2-naphthalen-2-yl-acetamide;

N-(5-cyclobutyl-2H-pyrazol-3-yl)-2-(2,4-dichloro-phenyl)-acetamide;

N-(5-cyclobutyl-2H-pyrazol-3-yl)-2-quinolin-6-yl-acetamide;

2-(3-amino-phenyl)-N-(5-cyclobutyl-2H-pyrazol-3-yl)-acetamide;

1-(5-cyclobutyl-1H-pyrazol-3-yl)-3-naphthalen-1-yl-urea;

N-(5-cyclohexyl-1H-pyrazol-3-yl)-2-naphthalen-2-yl-acetamide;

N-(5-cyclohexyl-1H-pyrazol-3-yl)-2-phenylacetamide;

2-(4-chloro-phenyl)-N-(5-cyclohexyl-1H-pyrazol-3-yl)-acetamide;

N-(5-cyclobutyl-1H-pyrazol-3-yl)-2-(4-phenoxy-phenyl)-acetamide;

N-(5-cyclobutyl-1H-pyrazol-3-yl)-2-(4-dimethylamino-phenyl)-acetamide;

N-(5-cyclopentyl-2H-pyrazol-3-yl)-2-(2,3,4-trimethoxy-phenyl)-acetamide;

N-(5-cyclopentyl-2H-pyrazol-3-yl)-2-(4-isopropyl-phenyl)-acetamide;

N-(5-cyclopentyl-2H-pyrazol-3-yl)-2-pyrrolo[2,3-b]pyridin-1-yl-acetamide;

N-(5-cyclobutyl-1H-pyrazol-3-yl)-2-m-tolyl-acetamide;

N-(5-cyclopentyl-2H-pyrazol-3-yl)-2-p-tolyl-acetamide;

N-(5-cyclobutyl-1H-pyrazol-3-yl)-2-(3-trifluoromethoxy-phenyl)-acetamide;

N-[5-(3-benzyloxy-propyl)-1H-pyrazol-3-yl]-2-naphthalen-2-yl-acetamide;

4-[5-(2-naphthalen-2-yl-acetylamino)-1H-pyrazol-3-yl]-piperidine-1-benzyl ester carboxylic acid;

2-naphthalen-2-yl-N-(5-piperidin-4-yl-2H-pyrazol-3-yl)-acetamide;

N-[5-(1-acetyl-piperidin-4-yl)-2H-pyrazol-3-yl]-2-naphthalen-2-yl-acetamide;

N-[5-(1-benzoyl-piperidin-4-yl)-2H-pyrazol-3-yl]-2-naphthalen-2-yl-acetamide;

4-[5-(2-naphthalen-1-yl-acetylamino)-1H-pyrazol-3-yl]-piperidine-1-benzyl ester carboxylic acid;

N-[5-(1-cyclobutanecarbonyl-piperidin-4-yl)-2H-pyrazol-3-yl]-2-naphthalen-2-yl-acetamide;

N-{3-[5-(2-naphthalen-2-yl-acetylamino)-4H-pyrazol-3-yl]-propyl}-benzamide;

N-{3-[5-(2-naphthalen-1-yl-acetylamino)-2H-pyrazol-3-yl]-propyl}-benzamide;

N-{5-[1-(3-methyl-butyl)-piperidin-4-yl]-1H-pyrazol-3-yl}-2-naphthalen-2-yl-acetamide;

N-[3-(5-phenylacetylamino-2H-pyrazol-3-yl)-propyl]-benzamide;

N-{3-[5-(2-m-tolyl-acetylamino)-2H-pyrazol-3-yl]-propyl-benzamide;

N-(3-{5-[2-(3-chloro-phenyl)-acetylamino]-2H-pyrazol-3-yl}-propyl)-benzamide;

{3-[5-(2-Naphthalen-2-yl-acetylamino)-1H-pyrazol-3-yl]-cyclobutyl}-amide-6-methyl-pyridine-2-carboxylic acid;

{3-[5-(2-Naphthalen-2-yl-acetylamino)-1H-pyrazol-3-yl]-cyclobutyl}-amide-6-methyl-pyridine-2-carboxylic acid;

{3-[5-(2-Naphthalen-2-yl-acetylamino)-1H-pyrazol-3-yl]-cyclobutyl}-amide-6-methyl-pyridine-2-carboxylic acid;

N-{5-[3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-cyclobutyl]-2H-pyrazol-3-yl}-2-naphthalen-2-yl-acetamide;

{3-[5-(2-Naphthalen-2-yl-acetylamino)-1H-pyrazol-3-yl]-cyclobutyl}-amide-6-chloro-pyridine-2-carboxylic acid;

N-{3-[5-(2-naphthalen-2-yl-acetylamino)-1H-pyrazol-3-yl]-cyclobutyl}-benzamide;

2-naphthalen-2-yl-N-[5-(2-pyridin-2-yl-ethyl)-2H-pyrazol-3-yl]-acetamide;

2-naphthalen-2-yl-N-[5-(2-pyridin-3-yl-ethyl)-2H-pyrazol-3-yl]-acetamide;

2-naphthalen-2-yl-N-[5-(2-pyridin-4-yl-ethyl)-2H-pyrazol-3-yl]-acetamide;

2-naphthalen-1-yl-N-[5-(2-pyridin-2-yl-ethyl)-2H-pyrazol-3-yl]-acetamide;

2-naphthalen-1-yl-N-[5-(2-pyridin-3-yl-ethyl)-2H-pyrazol-3-yl]-acetamide;

2-naphthalen-1-yl-N-[5-(2-pyridin-4-yl-ethyl)-2H-pyrazol-3-yl]-acetamide;

2-(3-methoxy-phenyl)-N-[5-(2-pyridin-2-yl-ethyl)-2H-pyrazol-3-yl]-acetamide;

2-(3-methoxy-phenyl)-N-[5-(2-pyridin-3-yl-ethyl)-2H-pyrazol-3-yl]-acetamide;

2-(3-methoxy-phenyl)-N-[5-(2-pyridin-2-yl-ethyl)-2H-pyrazol-3-yl]-acetamide;

2-(3-methoxy-phenyl)-N-[5-(2-thiazol-2-yl-ethyl)-2H-pyrazol-3-yl]-acetamide;

2-Naphthalen-1-yl-N-[5-(2-thiazol-2-yl-ethyl)-2H-pyrazol-3-yl]-acetamide;

2-Naphthalen-1-yl-N-[5-(2-thiazol-2-yl-ethyl)-2H-pyrazol-3-yl]-acetamide;

N-[5-(1-benzyl-piperidin-4-yl)-1H-pyrazol-3-yl]-2-naphthalen-2-yl-acetamide;

2-naphthalen-1-yl-N-(5-piperidin-4-yl-1H-pyrazol-3-yl)-acetamide;

2-(4-chloro-phenyl)-N-{3-[5-(2-naphthalen-2-yl-acetylamino)-1H-pyrazol-3-yl]-cyclobutyl}-acetamide;

Pyrazine-2-carboxylic acid {3-[5-(2-naphthalen-2-yl-acetylamino)-1H-pyrazol-3-yl]cyclobutyl}-amide;

2-(3-methoxy-phenyl)-N-{5-[2-(2-trifluoromethyl-phenyl)-ethyl]-2H-pyrazol-3-yl}-acetamide;

2-(3-methoxy-phenyl)-N-{5-[2-(3-trifluoromethyl-phenyl)-ethyl]-2H-pyrazol-3-yl}acetamide;

2-(3-methoxy-phenyl)-N-{5-[2-(4-trifluoromethyl-phenyl)-ethyl]-2H-pyrazol-3-yl}-acetamide;

(3-{5-[2-(3-methoxy-phenyl)-acetylamino]-2H-pyrazol-3-yl}-cyclobutyl)-amide-6-methyl-pyridine-2-carboxylic acid;

(3-{5-[2-(4-methoxy-phenyl)-acetylamino]-2H-pyrazol-3-yl}-cyclobutyl)-amide-6-methyl-pyridine-2-carboxylic acid;

(3-{5-[2-(4-chloro-phenyl)-acetylamino]-2H-pyrazol-3-yl}-cyclobutyl)-amide-6-methyl-pyridine-2-carboxylic acid

and pharmaceutically acceptable salts of said compounds.

Salts of compounds of formula 1 can be obtained by forming salts with any acid or basic group present on the compound of formula 1. Examples of pharmaceutically acceptable salts of compounds of formula 1 are salts of hydrochloric acid, p-toluenesulfonic acid, formic acid, citric acid, succinic acid, salicylic acid , oxalic acid, bromic acid, phosphoric acid, methanesulfonic acid, tartaric acid, maleic acid, di-p-toluyl tartaric acid, acetic acid, sulfuric acid, iodide acid, mandelic acid, and sodium, potassium, magnesium, calcium and lithium salts .

Compounds of formula 1 may have optical centers and therefore may exist in various enantiomeric and other stereoisomeric configurations. The invention includes all enantiomers, diastereomers and other stereoisomers of such compounds of formula 1, as well as their racemic and other mixtures.

The subject of the invention also includes isotope-labeled compounds, identical to those listed in formula 1, wherein one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number commonly found in nature. Examples of isotopes that can be incorporated into the compounds of this invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, iodine and chlorine, such as 3H, 11C, 14C, 18F, 123I and 125I. The compounds of this invention and pharmaceutically acceptable salts of said compounds containing the above-mentioned isotopes and/or other isotopes of other atoms are within the scope of this invention. The isotopically labeled compounds of this invention, for example those incorporating radioactive isotopes such as 3H and 14C, are useful for determining drug and/or substrate tissue distribution. Tritium, i.e., 3H, and carbon-14, i.e., 14C, are particularly preferred isotopes because they are easy to prepare and detect. 11C and 15F isotopes are particularly useful in PET (positron emission tomography) and 125I isotopes are particularly useful in SPECT (single photon emission computerized tomography), both techniques are useful for brain imaging. Furthermore, substitution with heavy isotopes such as deuterium, i.e., 2H, may confer some therapeutic advantages due to greater metabolic stability, for example an increase in half-life in vivo or a reduction in required doses, and may therefore be preferred in some cases. The isotopically labeled compounds of the present invention of Formula 1 may be conveniently prepared according to the procedure disclosed in the Schemes and/or Examples described below, by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.

The present invention also includes compounds of formula I

[image]

where Prot is a protective group; R2 is H, F, -CH3, -CN, or -C (=O)OR'; and n is an integer chosen from 1,2,3, and 4.

Compounds of formula I are used as intermediates for the synthesis of some of the compounds of formula 1 described herein.

It is convenient that n is 1.

Examples of specific protecting groups include, but are not limited to, t-butyl and -CH 2 -Ar, where "Ar" is an aryl or heteroaryl group. An example of the end type of protecting group is para-methoxybenzyl.

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

The present invention also provides a pharmaceutical composition for the treatment of diseases or conditions involving abnormal cell growth in mammals, including humans, comprising a compound of formula 1 in an amount effective to inhibit cdk2 activity and a pharmaceutically acceptable carrier.

The present invention also provides a method of treating a disease or condition involving abnormal cell growth in a mammal, including a human, comprising administering to the mammal a compound of formula 1 in an amount effective to inhibit abnormal cell growth.

The present invention also provides a method of treating a disease or condition involving abnormal cell growth in a mammal, including a human, comprising administering to the mammal a compound of formula 1 in an amount effective to inhibit cdk2 activity.

In a pharmaceutical composition or method of the present invention for treating a disease or condition comprising abnormal cell growth, the disease or condition comprising abnormal cell growth in one aspect is cancer. Cancer can be cancer, for example cancer of the bladder, breast, colon, kidney, liver, lung, for example cancer of the small cell lung, esophagus, gall bladder, ovary, pancreas, stomach, cervix, testicle, prostate, or skin, for example squamous cell carcinoma; a hematopoietic tumor of lymphoid origin, for example leukemia, acute lymphocytic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkins lymphoma, non-Hodgkins lymphoma, hairy cell lymphoma or Burkett's lymphoma; hematopoietic tumor of myeloid origin, for example acute and chronic myeloid leukemia, 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 astrocytoma, neuroblastoma, glioma or schwannoma; melanoma; seminoma; teratocarcinoma; osteosarcoma; xenoderoma pigmentum; keratoctanthoma; cancer of the thyroid follicles; or Kaposi's sarcoma.

In another embodiment, the disease or condition comprising abnormal cell growth is benign. Such diseases and conditions include benign prostatic hyperplasia, familial adenomatous polyposis, neurofibromatosis, inflammatory bowel disease, transplant rejection, fungal infection, and endotoxic shock.

The present invention also provides a pharmaceutical composition for the treatment of a neurodegenerative disease or condition in a mammal, including a human, comprising a compound of formula 1 in an amount effective for the treatment of said disease or condition and a pharmaceutically acceptable carrier.

The present invention also provides a pharmaceutical composition for the treatment of a neurodegenerative disease or condition in a mammal, including a human, comprising a compound of formula 1 in an amount effective to inhibit cdk5 activity and a pharmaceutically acceptable carrier.

The present invention also provides a method for treating a neurodegenerative disease or condition in a mammal, including a human, comprising administering to the mammal a compound of formula 1 in an amount effective to inhibit cdk5 activity.

The present invention also provides a method for the treatment of a neurodegenerative disease or condition in a mammal, including a human, comprising administering to the mammal a compound of formula 1 in an amount effective to treat said disease or condition.

In one embodiment of the invention, the neurodegenerative disease or condition being treated is selected from Huntington's disease, stroke, spinal cord injury, concussion, dementia caused by multiple infarcts, epilepsy, amyotrophic lateral sclerosis, pain, dementia caused by a virus for example dementia caused by AIDS- om, neurodegeneration associated with bacterial infection, migraine, hypoglycemia, urinary incontinence, brain ischemia, multiple sclerosis, Alzheimer's disease, senile dementia of the Alzheimer type, mild cognitive impairment, decline in cognitive abilities caused by aging, emesis, corticobasal degeneration, dementia pugilistica, Down's syndrome, myotonic dystrophy, Niemann-Pick disease, Pick's disease, prion disease with distraction, progressive supranuclear palsy, lower lateral sclerosis and subacute sclerosing panencephalitis.

The present invention also provides a pharmaceutical composition for the treatment of diseases and conditions the treatment of which can be effected or enabled by altering dopamine-mediated neurotransmission in mammals, including humans, comprising a compound of formula 1 in an amount effective for the treatment of said disease or condition and a pharmaceutically acceptable carrier.

The present invention also provides a pharmaceutical composition for the treatment of a disease or condition the treatment of which can be effected or facilitated by altering dopamine-mediated neurotransmission in mammals, including humans, comprising a compound of formula 1 in an amount effective to inhibit cdk5 activity and a pharmaceutically acceptable carrier.

The present invention also provides a method of treating a disease or condition the treatment of which can be effected or facilitated by altering dopamine-mediated neurotransmission in a mammal, including a human, comprising administering to the mammal a compound of formula 1 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 effected or enabled by altering dopamine-mediated neurotransmission in a mammal, including a human, comprising administering to a mammal a compound of formula 1 in an amount effective to treat said disease or condition.

In one embodiment of the invention, the disease or condition whose treatment can be performed or enabled by altering dopamine-mediated neurotransmission is selected from the group consisting of Parkinson's disease; schizophrenia; schizophreniform disorder; schizoaffective disorder, for example hallucinatory or depressive type; hallucinatory disorder; a psychotic disorder induced by chemical substances, for example psychosis induced by alcohol, amphetamine, cannabis, cocaine, hallucinogens, inhalants, opiates or phencyclidine; personality disorders of the paranoid type; personality disorders of the schizoid type; drug addictions, including narcotics (for example heroin, opium and morphine), cocaine and alcoholism; drug withdrawal including narcotics, cocaine and alcohol withdrawal; obsessive compulsive disorder; Tourette syndrome; depression; major depressive episodes, manic or mixed episodes, hypomanic episodes, depressive episodes with atypical features or melancholic features or catatonic features, postpartum depression; post-stroke depression, major depressive disorder, thymus function disorder, minor depressive disorder, premenstrual syndrome, post-psychotic depressive disorder in schizophrenia, major depressive disorder strongly associated with a psychotic disorder such as hallucinations or schizophrenia, bipolar disorder, for example bipolar disorder I, bipolar disorder II, thymus hormone secretion disorder; anxiety; reduced concentration and hyperactivity and attention deficit disorders.

The present invention also provides a pharmaceutical composition for the treatment of a disease or condition, the treatment of which can be carried out or enabled by the reduction of cdk5 activity in mammals, including humans, comprising the administration of a compound of formula 1 to a mammal in an amount effective to inhibit cdk5 activity and a pharmaceutically acceptable carrier.

The present invention also provides a method of treating diseases and conditions the treatment of which can be effected or made possible by reducing cdk5 activity in mammals, including humans, comprising administering to the mammal a compound of formula 1 in an amount effective to inhibit cdk5 activity.

We also found that the compounds of formula 1 possess activity in inhibiting GSK3. Therefore, it can be expected that the compounds of formula 1 will be useful in the treatment of diseases and conditions whose treatment can be carried out or made possible by inhibition of GSK-3. Diseases and conditions that can be treated or facilitated by inhibition of GSK-3 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, amyotrophic lateral sclerosis, multiple sclerosis, stroke, cerebral ischemia, AIDS-related dementia, neurodegeneration associated with bacterial infection , dementia caused by repeated heart attacks, concussion and spinal cord injury. Therefore, the compounds of formula 1 are effective in the treatment of neurodegenerative diseases and conditions based on both cdk5 and GSK-3 activity.

Other disorders and conditions that can be treated or facilitated by inhibition of GSK-3 include psychotic disorders and conditions, for example schizophrenia, schizophreniform disorder; schizoaffective disorder, for example hallucinatory type or depressive type; hallucinatory disorder; chemically induced psychotic disorder, for example psychosis induced by alcohol, amphetamine, cannabis, cocaine, hallucinogens, inhalants, opiates or phencyclidine; paranoid personality disorder and schizoid personality disorder. Treatment of such diseases and conditions may also be accomplished or enabled by altering dopamine-mediated neurotransmission. Therefore, the compounds of formula 1 are effective in the treatment of such disorders and conditions based on both cdk5 activity and GSK-3 activity.

Other disorders and conditions that can be treated or facilitated by GSK-3 inhibition include mood disorders and mood episodes, for example major depressive episode, manic or mixed episode, hypomanic episode, depressive episode with atypical features or with melancholic features or catatonic features, postpartum depression; post-stroke depression, major depressive disorder, thymus function disorder, minor depressive disorder, premenstrual syndrome, post-psychotic depressive disorder in schizophrenia, major depressive disorder strongly associated with a psychotic disorder such as hallucinogenic disorder or schizophrenia, bipolar disorder, for example bipolar disorder I, bipolar disorder II and disorder in the secretion of thymus hormones. Treatment of such mood disorders and episodes, for example depression, may also be effected or facilitated by altering dopamine-mediated neurotransmission. Therefore, the compounds of formula 1 are effective in the treatment of some mood disorders and episodes based on both cdk5 and GSK-3 activity.

Other disorders and conditions whose treatment can be carried out or made possible by inhibition of GSK-3 are male fertility and sperm motility; diabetes mellitus; reduced glucose tolerance; metabolic syndrome or syndrome X; polycystic ovary syndrome; adipose tissue formation and obesity; myogenesis and frailty, for example age-related decline in physical capabilities; acute sarcopenia, for example muscle atrophy and/or cachexia associated with burns, poor rest, limb immobilization or major thoracic, abdominal and/or orthopedic surgery, sepsis; spinal cord injury; hair loss, thinning hair and baldness; immunodeficiency and cancer.

Accordingly, the present invention also provides a pharmaceutical composition for the treatment in mammals, including humans, of diseases or conditions selected from male fertility and sperm motility; diabetes mellitus; reduced glucose tolerance; metabolic syndrome or syndrome X; polycystic ovary syndrome; formation of adipose tissue and obesity; myogenesis and weakness, for example the decline of physical capabilities associated with aging; acute sarcopenia, for example muscle atrophy and/or cachexia associated with burns, poor rest, limb immobilization or major thoracic, abdominal and/or orthopedic surgery, sepsis, spinal cord injury; hair loss, hair thinning and baldness; immunodeficiency and cancer; which contains in its composition a pharmaceutically acceptable carrier and an amount of the compound of formula 1 effective in the treatment of the mentioned diseases and conditions.

The present invention also provides a pharmaceutical composition for the treatment in mammals, including humans, of diseases or conditions selected from male fertility and sperm motility; diabetes mellitus; reduced glucose tolerance; metabolic syndrome or syndrome X; polycystic ovary syndrome; formation of adipose tissue and obesity; myogenesis and weakness, for example the decline of physical capabilities associated with aging; acute sarcopenia, for example muscle atrophy and/or cachexia associated with burns, poor rest, limb immobilization or major thoracic, abdominal and/or orthopedic surgery, sepsis; spinal cord injuries; hair loss, hair thinning and balding and immunodeficiency, which contains a pharmaceutically acceptable carrier and an amount of the compound of formula 1 effective in inhibiting GSK-3.

The present invention also provides a method of treating in mammals, including humans, diseases and conditions selected from male fertility and sperm motility; diabetes mellitus; reduced glucose tolerance; metabolic syndrome or syndrome X; polycystic ovary syndrome; formation of adipose tissue and obesity; myogenesis and weakness, for example the decline of physical capabilities associated with aging; acute sarcopenia, for example muscle atrophy and/or cachexia associated with burns, poor rest, limb immobilization or major thoracic, abdominal and/or orthopedic surgery, sepsis; spinal cord injuries; hair loss, hair thinning and baldness and immunodeficiency, which comprises administering to said mammals an amount of the compound of formula 1 effective in the treatment of said diseases and conditions.

The present invention also provides a method of treating in mammals, including humans, diseases or conditions selected from male fertility and sperm motility; diabetes mellitus; reduced glucose tolerance of metabolic syndrome or syndrome X; polycystic ovary syndrome; formation of adipose tissue and obesity; myogenesis and weakness, for example the decline of physical capabilities associated with aging; acute sarcopenia, for example muscle atrophy and/or cachexia associated with burns, poor rest, limb immobilization or major thoracic, abdominal and/or orthopedic surgery, sepsis; spinal cord injuries; hair loss, hair thinning and baldness and immunodeficiency, which comprises administering to said mammals an amount of a compound of formula 1 effective to inhibit GSK-3.

The present invention also provides a method for inhibiting GSK-3 in a mammal, including a human, comprising administering to said mammal an amount of a compound of formula 1 effective in inhibiting GSK-3.

The present invention further provides a pharmaceutical composition for the treatment in mammals, including humans, of disorders selected from Alzheimer's disease, mild cognitive decline, age-related cognitive decline, comprising a compound of formula 1 and a COX-II inhibitor together in an amount effective in the treatment of said disorders and a pharmaceutically acceptable carrier.

The present invention also provides in mammals, including humans, a method of treating disorders selected from Alzheimer's disease, mild cognitive decline, age-related cognitive decline, comprising administering to said mammal a compound of formula 1 and a COX-II inhibitor, wherein the total amounts of the compound are formula 1 and COX-II inhibitors effective in the treatment of the mentioned disorders. The compound of formula 1 and the COX-II inhibitor can be administered to mammals simultaneously and/or separately.

In addition, the compound of formula 1 and the COX-II inhibitor can be administered in a single preparation or in separate preparations.

Furthermore, the compound of formula 1 of the present invention, or a pharmaceutically acceptable salt of the compound of formula 1, can be administered or formulated into a pharmaceutical composition with one or more antidepressants or anxiolytics for the treatment or prevention of depression and anxiety.

Accordingly, the present invention also provides a pharmaceutical composition for the treatment of depression and anxiety in mammals, including humans, comprising a compound of formula 1 and an NK-1 receptor antagonist together in an amount effective for the treatment of depression and anxiety and a pharmaceutically acceptable carrier.

The present invention further provides a method of treating depression and anxiety in a mammal, including a human, which comprises administering a compound of formula 1 and an NK-1 receptor antagonist to said mammal, wherein the total amounts of the compound of formula 1 and the NK-1 receptor antagonist are effective in treating depression and anxiety . The compound of formula 1 and the NK-1 receptor antagonist can be administered to mammals simultaneously and/or at different times. Furthermore, they can be administered together in one pharmaceutical preparation or in separate preparations.

The present invention also provides a pharmaceutical composition for the treatment of depression or anxiety in a mammal including a human, comprising a compound of formula 1 and a 5HT1D receptor antagonist together in an amount effective in the treatment of depression or anxiety and a pharmaceutically acceptable carrier.

The present invention further provides a method of treating depression or anxiety in a mammal, including a human, which comprises administering a compound of formula 1 and a 5HT1D receptor antagonist to said mammal, wherein the total amounts of the compound of formula 1 and the 5HT1D receptor antagonist are effective in treating depression or anxiety. The compound of formula 1 and the 5HT1D receptor antagonist can be administered to mammals simultaneously and/or at different times. Furthermore, they can be administered together in one pharmaceutical preparation or in separate preparations.

The present invention also provides a pharmaceutical composition for the treatment of depression or anxiety in a mammal including a human, comprising a compound of formula 1 and an SSRI together in an amount effective in the treatment of depression or anxiety and a pharmaceutically acceptable carrier.

The present invention further provides a method of treating depression or anxiety in a mammal, including a human, comprising administering a compound of formula 1 and an SSRI to said mammal, wherein the total amounts of the compound of formula 1 and the SSRI are effective in treating depression or anxiety. The compound of formula 1 and the SSRI can be administered to mammals simultaneously and/or at different times. Furthermore, they can be administered together in one pharmaceutical preparation or in separate preparations.

The present invention also provides a pharmaceutical composition for the treatment of schizophrenia in mammals including humans, comprising a compound of formula 1 and an antipsychotic selected from ziprasidone, olanzapine, risperidone, L-745870, sonepiprazole, RP 62203, NGD 941, balaperidone, flesinoxan and gepirone, together in an amount effective in the treatment of schizophrenia and a pharmaceutically acceptable carrier.

The present invention further provides a method of treating schizophrenia in a mammal, including a human, comprising administering to said mammal a compound of formula 1 and an antipsychotic selected from ziprasidone, olanzapine, risperidone, L-745870, sonepiprazole, RP 62203, NGD 941, balaperidone, flesinoxan and gepirone, wherein are the total amounts of the compound of formula 1 and the antipsychotic effective in the treatment of schizophrenia. The compound of formula 1 and the antipsychotic may be administered to mammals simultaneously and/or at different times. Furthermore, they can be administered together in one pharmaceutical preparation or in separate preparations.

The present invention also provides a pharmaceutical composition for the treatment of a disorder selected from Alzheimer's disease, mild cognitive decline and age-related cognitive decline in mammals, including humans, comprising a compound of formula 1 and an acetylcholinesterase inhibitor together in an amount effective for the treatment of said disorders and pharmaceutically acceptable carrier.

The present invention further provides a method of treating, in mammals including humans, a disorder selected from Alzheimer's disease, mild cognitive decline and age-related cognitive decline, comprising administering a compound of formula 1 and an acetylcholinesterase inhibitor to said mammal, wherein the total amounts of the compound of formula 1 and acetylcholinesterase inhibitors effective in the treatment of the aforementioned disorders. The compound of formula 1 and the acetylcholinesterase inhibitor can be administered to mammals simultaneously and/or at different times. Furthermore, they can be administered together in one pharmaceutical preparation or in separate preparations.

The present invention also provides a pharmaceutical composition for the treatment in a mammal of a disease or condition selected from stroke, spinal cord injury, concussion, dementia caused by multiple infarcts, epilepsy, pain, Alzheimer's disease and senile dementia comprising a compound of formula 1 and TPA (tissue tissue activator plasminogen, for example ACTIVASE) together in an amount effective for the treatment of said disorders and a pharmaceutically acceptable carrier.

The present invention further provides a method of treating, in mammals including humans, diseases or conditions selected from stroke, spinal cord injury, concussion, dementia caused by multiple infarcts, epilepsy, pain, Alzheimer's disease and senile dementia, comprising administering to said mammal a compound of the formula 1 and TPA, wherein the total amounts of the compound of formula 1 and TPA are effective in the treatment of depression or anxiety. The compound of formula 1 and TPA can be administered to mammals simultaneously and/or at different times. Furthermore, they can be administered together in one pharmaceutical preparation or in separate preparations.

The present invention also provides a pharmaceutical composition for the treatment of a disease or condition selected from stroke, spinal cord injury, concussion, dementia caused by multiple infarcts, epilepsy, pain, Alzheimer's disease and senile dementia in a mammal including man, comprising a compound of formula 1 and NIF ( neutrophil inhibitory factor) together in an amount effective for the treatment of said disorders and a pharmaceutically acceptable carrier.

The present invention further provides a method of treating, in mammals including humans, diseases or conditions selected from stroke, spinal cord injury, concussion, dementia caused by multiple infarcts, epilepsy, pain, Alzheimer's disease and senile dementia, comprising administering to said mammal a compound of the formula 1 and NIF, wherein the total amounts of the compound of formula 1 and NIF are effective in the treatment of said diseases or conditions. The compound of formula 1 and NIF can be administered to mammals simultaneously and/or at different times. Furthermore, they can be administered together in one pharmaceutical preparation or in separate preparations.

The present invention also provides a pharmaceutical composition for the treatment of diseases or conditions selected from Huntington's disease, stroke, spinal cord injury, concussion, dementia caused by multiple infarcts, epilepsy, amyotrophic lateral sclerosis, pain, dementia caused by a virus for example dementia caused by AIDS, migraines, hypoglycemia, urinary incontinence, brain ischemia, multiple sclerosis, Alzheimer's disease, senile dementia of the Alzheimer type, mild cognitive decline, age-related cognitive decline, emesis, corticobasal degeneration, pugilistic dementia, Down's syndrome, myotonic dystrophy, Niemann-Pick's disease, Pick's disease, prion disorder, progressive supranuclear palsy, lower lateral sclerosis and subacute sclerosing panencephalitis in mammals, including humans, comprising a compound of formula 1 and an NMDA receptor antagonist together in an amount effective for the treatment of disorders and a pharmaceutically acceptable carrier.

The present invention further provides a method of treating in mammals, including humans, diseases or conditions selected from Huntington's disease, stroke, spinal cord injury, concussion, dementia caused by multiple infarcts, epilepsy, amyotrophic lateral sclerosis, pain, dementia caused by a virus for example dementia caused by AIDS -om, migraines, hypoglycemia, urinary incontinence, cerebral ischemia, multiple sclerosis, Alzheimer's disease, senile dementia of the Alzheimer type, mild cognitive decline, age-related cognitive decline, emesis, corticobasal degeneration, pugilistic dementia, Down's syndrome, myotonic dystrophy, Niemann-Pick disease, Pick disease, prion disorder, progressive supranuclear palsy, lower lateral sclerosis and subacute sclerosing panencephalitis, which comprises administering to said mammals a compound of formula 1 and an NMDA receptor antagonist, wherein the total amounts of the compound are ule 1 and NMDA receptor antagonists effective in the treatment of said diseases or conditions. The compound of formula 1 and the NMDA receptor antagonist can be administered to mammals simultaneously and/or at different times. Furthermore, they can be administered together in one pharmaceutical preparation or in separate preparations.

The present invention also provides a pharmaceutical composition for the treatment of a disease or condition selected from stroke, spinal cord injury, concussion, dementia caused by multiple infarcts, epilepsy, pain, Alzheimer's disease and senile dementia in a mammal including a human, comprising a compound of formula 1 and a potassium modulator channels together in an amount effective for the treatment of said disorders and a pharmaceutically acceptable carrier.

The present invention further provides a method of treating in a mammal, including a human, diseases or conditions selected from stroke, spinal cord injury, concussion, dementia caused by multiple infarcts, epilepsy, pain, Alzheimer's disease and senile dementia, comprising administering to said mammal a compound of formula 1 and potassium channel modulators, wherein the total amounts of the compound of formula 1 and the potassium channel modulator are effective in the treatment of said diseases or conditions. The compound of formula 1 and the potassium channel modulator can be administered to mammals simultaneously and/or at different times. Furthermore, they can be administered together in one pharmaceutical preparation or in separate preparations.

The terms "treatment", "treat", and the like refer to the recovery, mitigation or prevention of the progression of the disease or condition to which these terms apply, or one or more symptoms of such disease or condition. As used herein, these terms also include, depending on the patient's condition, preventing the onset of a disease or condition or symptoms associated with the disease or condition, including reducing the frequency of the disease or condition or symptoms associated pre-existing with said disease or condition. Such prevention or reduction before the disease refers to the administration of the compound of this invention to a subject who, at the time of administration, has not yet suffered from the aforementioned diseases or conditions. "Prevention" also includes preventing the return of a disease or condition or associated symptoms.

"Abnormal cell growth", as used herein, refers to cell growth, both malignant (eg, such as cancer) or benign, that is independent of normal regulatory mechanisms (eg, loss of contact inhibition). Examples of benign proliferative disease are psoriasis, benign prostatic hypertrophy, human papillomavirus (HPV) and restenosis.

"Neurodegenerative diseases and conditions", as used herein and unless otherwise indicated, refers to diseases and conditions associated with neuronal degeneration. Conditions and diseases that are neurodegenerative in nature are commonly known to those skilled in the art.

References herein to diseases and conditions "the treatment of which can be effected or made possible by altering dopamine-mediated neurotransmission" mean a disease or condition caused at least in part by dopamine neurotransmission, that is, a disease or condition that results in abnormal dopamine neurotransmission, therefore contributing to the symptoms or manifestation of the disease state.

References herein to diseases and conditions "the treatment of which can be performed or made possible by reduction of cdk5 activity" mean a disease or condition caused at least in part by cdk5 activity, that is, a disease or condition that results in abnormal cdk5 activity that contributes to the symptoms or manifestation of the disease or condition.

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

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

Detailed description of the invention

The above-mentioned compounds of formula 1 and their pharmaceutically acceptable salts can be prepared according to the following reaction schemes and discussion. Unless otherwise indicated R1, R2, R3, and R4 are as defined above."Prot" represents a protecting group. Isolation and purification of products is carried out by standard procedures known to expert chemists.

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

During any subsequent synthetic sequence, it may be necessary and/or desirable to protect sensitive or reactive groups of any molecules involved. This can be accomplished using conventional protecting groups, such as those described in T. W. Greene, Protective Groups in Organic Chemistry, John Wiley & Sons, 1981; and T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Chemistry, John Wiley & Sons, Inc., 1999.

Scheme 1 shows the main methods for preparing compounds of formula 1 where R3 is -(CR10R11)n-, -C(=O)NR9-, -C(=O)O-, or -C(=O)(CR10R11)n- . Treatment of a saturated solution of magnesium chloride in a reaction-inert solvent, preferably acetonitrile, diethyl ether or tetrahydrofuran, at a reaction temperature of -20°C to 40°C, more suitable from about -5°C to 21°C, with a trialkyl amine base, where are preferred triethyl amine or diisopropylethylamine, in the presence of alkyl cyanoacetate and in the presence of acid halides of formula 2, where acid chlorides are preferred, gives intermediate 3a, 2-cyano-3-alkyl-3-oxo-alkyl ester of propionic acid. A preferred alkyl cyanoacetate is ethyl cyanoacetate. Hydrolysis and decarboxylation of 3a to 3 can be achieved by exposing 3a to water in a reaction-inert solvent, preferably dimethylsulfoxide, at a temperature of about 21°C to 200°C, most preferably about 100°C to 118°C.

Reaction of compound 3 in a reaction-inert solvent, such as a lower alcohol, in the presence of hydrazine at a reaction temperature of about 0°C to about 150°C, with a temperature of about 70°C to about 85°C being preferred, affords the corresponding product 4 The hydrazine used can be anhydrous hydrazine or hydrazine hydrate N-alkylhydrazine or N-acyl-hydrazine. Anhydrous hydrazine or alkyl hydrazine, for example 4-methoxy-benzyl-hydrazine, are preferred.

Coupling of compound 4 with an aryl halide or heteroaryl halide to give an intermediate of formula 5, where R3 is -(CR10R11)n- (bond) can be carried out by reaction 4 in a reaction inert solvent, preferably toluene, at a reaction temperature of about 21°C to about 150°C, conveniently at about 100°C to about 110°C, in the presence of a palladium catalyst, a base, more conveniently cesium carbonate or sodium or potassium tert-butoxide, a ligand, where the preferred ligands are 2,2'-bis(diphenylphosphino )-1,1'-binaphthyl, 2-(dicyclohexylphosphino)biphenyl, and 2-(di-tert-butylphosphino)biphenyl, and in the presence of a suitable aryl halide or heteroaryl halide, wherein aryl bromides or chlorides and heteroaryl bromides or chlorides are preferred. The metal catalyst can be a palladium compound, for example palladium chloride, palladium acetate, dichlorobis(acetonitrile) palladium, or derivatives thereof, where palladium acetate is preferred. Removal of the protecting group from compound 5 can be carried out by reacting compound 5 in a reaction-inert solvent, preferably methylene chloride or without solvent, in the presence of an acid, where trifluoroacetic acid is preferred, at a reaction temperature of about 20°C to about 100°C, more conveniently from about 65°C to about 75°C, to give 1a, wherein R3 represents a bond and R4 is as defined above for compounds of formula 1.

The coupling of compound 4 to obtain N-acyl derivatives of compound 6 (where R3 is -C(=O)(CR10R11)n-) can be carried out by reaction 4 in a reaction-inert solvent, preferably methylene chloride, pyridine, tetrahydrofuran or diethyl ether, in the presence of acid chloride ClC(=O)(CH2)nR4, acid anhydride R4(CH2)nC(=O))2O or activated carboxylic acid derivative XC (=O)(CH2)nR4 where X represents an activation group, and in the presence of an amine base , such as triethyl amine or diisopropylethyl amine, where the preferred combination is tripropylphosphonic anhydride and triethylamine, at a temperature of about -78°C to about 40°C. Activated carboxylic acid derivatives can be prepared from a carboxylic acid and a known activating reagent such as polymer coupling agents or coupling agents such as, for example, dicyclohexyl carbodiimide, carbonyl diimidazole, tripropylphosphonic anhydride, alkyl chloroformate, bis(2-oxo- 3-oxazolidinyl)phosphine chloride, benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate, or any other such standard reagent from the literature. Deprotection of 6 can be carried out by reacting 6 in a reaction-inert solvent, where methylene chloride is preferred, or no solvent is used, in the presence of an acid, where trifluoroacetic acid is preferred, at a reaction temperature of about 20°C to about 100° C, preferably from about 65°C to about 75°C. A product of formula 1b was obtained, where R3 represents -C(=O)(CR10R11)n- and R4 is as defined above for compounds of formula 1.

Alternatively, the amine of compound 4 can be treated with a base, such as triethylamine, diisopropylethylamine, pyridine or 2,6-lutidine, and an alkyl, aryl or heteroaryl chloroformate ClC(=O)OR4 (diisopropylethylamine and aryl or heteroaryl chloroformate are in preferred combination) at a temperature of from about -78°C to about 40°C, to give an intermediate where R3 is -C(=O)O- and R4 is as defined above for compounds of formula 1. Deprotection of this intermediate can be achieved as described, i.e. in a reaction-inert solvent, preferably methylene chloride or solvent-free, in the presence of an acid, preferably trifluoroacetic acid, at a reaction temperature of from about 20°C to about 100°C, more preferably from about 65°C to about 75°C. Thus, a carbamate compound of formula 1 is obtained where R3 is -C(=O)O- and R4 is as defined above for compounds of formula 1.

Following treatment of the carbamate of formula 1 obtained in the previous paragraph, with a primary or secondary amine in a solvent such as dioxane, dimethylformamide or acetonitrile, where the preferred mixture is dioxane : dimethylformamide 1:1, at a temperature between 40°C and 90°C, where a preferred temperature of about 70°C, gives the corresponding urea product of formula 1 based on urea where R3 is -C(=O)NR9- and R4 is as defined above for compounds of formula 1.

Compounds of formula 1 where R3 is -(CR10R11)(1-3)- can be prepared from the intermediate product of formula 4 by reacting 4 with an oxo unit (aldehyde or ketone) in a reaction-inert solvent, preferably toluene, tetrahydrofuran or methanol at a reaction temperature of about 0 °C to about 110°C, more preferably about 21°C, in the presence of a reductant, where preferred reductants are sodium triacetoxyborohydride, sodium cyanoborohydride and lithium aluminum hydride to give an intermediate of formula 6 where R3 is -(CR10R11)(1- 3)-. Deprotection of intermediate 6 can be accomplished as described, i.e., in a reaction inert solvent, where trifluoroacetic acid is preferred, at a reaction temperature of about 20°C to about 100°C, more conveniently from about 65°C to about 75° C.

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Scheme 2 shows an alternative method suitable for preparing compounds of formula 1. The method shown in Scheme 2 is preferred when R 4 is an electron-deficient aryl unit, such as 4-nitrophenyl or an electron-deficient heteroaryl unit. The reaction of a ketone having the general structure 8, where R1 and R2 are as defined above for compounds of formula 1, in an inert solvent, wherein the preferred solvents are tetrahydrofuran or diethyl ether, at a reaction temperature of about -116°C to about 50° C, more conveniently at about -78°C to about -65°C, in the presence of a base, a protected amine base is preferred, and also in the presence of an isothiocyanate of general formula 9, wherein R3 is the bond (-(CR10R11)0-) and R4 is aryl or heteroaryl, gives 10. Examples of protected amine bases include lithium diisopropyl amide, potassium bis(trimethylsilyl) amide, lithium bis(trimethylsilyl) amide other such reagents according to the literature. Treatment of compound 10 in a reaction-inert solvent, preferably a lower alcohol, in the presence of an acid, preferably acetic acid, at a reaction temperature of from about 21°C to about 100°C, preferably from about 75°C to about 85°C and in the presence hydrazine, gives a compound of formula 1a, where R 3 is a bond and R 4 is aryl or heteroaryl.

The syntheses of compounds of formula 1 where R1 is substituted with one or more substituents R5 are also shown in scheme 2. The reaction of a compound of formula 10 in an inert solvent, such as lower alcohols, in the presence of an acid, preferably acetic acid, and also in the presence of hydrazine, at at a reaction temperature of from about 0°C to about 150°C, preferably from about 75°C to about 85°C, gives 10a (wherein R3 is a bond, R4 is aryl or heteroaryl, R1 is as defined above and R5 is protected oxo unit (acetal or ketal).

Preferred hydrazines are alkyl hydrazines, for example 4-methoxy-benzyl hydrazines or t-butyl hydrazine.

Removal of the protecting group from the oxo unit R5 can be carried out using well-known conditions found in the literature. For example, treatment of compound 10a in an inert solvent, preferably a lower ketone such as acetone, in the presence of an acid, preferably hydrochloric acid, p-toluenesulfonic acid monohydrate or pyridinium p-toluenesulfonate, at a temperature of from room to about 80°C, preferably about 75° C, gives 10b, where R 5 is an oxo (carbonyl) unit, R 1 is as defined above, R 3 is a bond and R 4 is aryl or heteroaryl.

Reduction of the oxo unit to give an alcohol (R 5 is -OH) can be carried out using well-known chemical procedures. Alternatively, the oxo units of compound 10b can be reacted with an amine, primary and secondary, where the preferred amine is an alkyl amine for example 4-methoxy-benzyl-amine, in a reaction-inert solvent, preferably toluene or tetrahydrofuran, at a reaction temperature of about 21°C to about 150°C, preferably at about 70°C to about 110°C. After 10b is consumed, usually within a period of 12 hours, the reaction mixture is cooled to a temperature of about 21°C to about 50°C and a reductant is added, the preferred reductants being sodium triacetoxyborohydride, sodium cyanoborohydride, and lithium, aluminum hydride to give 10c, where R 1 is as defined above, R 3 is a bond, R 4 is aryl or heteroaryl and R 5 is -NR 7 R 8 . The coupling of 10c to obtain N-acyl derivatives of formula 10d, where R5 is -NR7C(=O)R8, can be carried out by reacting 10c in a reaction-inert solvent, where methylene chloride, pyridine, tetrahydrofuran, diethyl ether are preferred, in the presence of alkyl of chloroformate, hydrochloric acid, acid anhydride or activated carboxylic acid derivatives from -78°C to 40°C. An activated carboxylic acid derivative is prepared from a carboxylic acid and a known activation reagent such as a binding agent on a polymer support or optionally dicyclohexyl carbodiimide, carbonyl diimidazole, thiopropylphosphinic anhydride, alkyl chloroformate, bis(2-xo-3-oxazolidinyl) phosphine -chloride, benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate, or any other reagent according to standard literature, in the presence of a trialkyl amine base, such as triethyl amine or diisopropylethyl amine, where the preferred combination is thiopropylphosphinic anhydride and triethylamine.

The removal of the protecting group on 10b, 10c or 10d can be carried out by reaction in a reaction-inert solvent, where methylene chloride is preferred or without a solvent, in the presence of an acid, preferably trifluoroacetic acid, at a reaction temperature of about 20°C to about 100°C, preferably from about 65°C to about 75°C, to give the corresponding compounds of formula 1, for example 1c, as shown in Scheme 2.

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Scheme 3 shows an alternative method suitable for preparing a compound of formula 1. The method shown in Scheme 3 is preferred when R1 is substituted with R5 selected from -NR7R8, -NR4C(=O)R8, -NR7C(=O)NR8R9, -NR7S(=O )2R8, -NR7S(=O)2NR8R9, -C(=O)R7, -C(=O)OR7 and -C(=O)NR7R8. According to Scheme 3, the reaction of an organolithium base, preferably n-butyl lithium, sec-butyl lithium, phenyl lithium or tert-butyl lithium, at a reaction temperature of about -116°C to about 50°C, preferably at about -78°C to about 45°C, in an inert solvent, especially tetrahydrofuran or diethyl ether, in the presence of an alkylnitrile, preferably acetonitrile, and in the presence of an ester of formula 11, where R1 is as defined above and R5 is a protected oxo unit (specifically ketal or acetal) or is R 5 as defined above gives 3b, where R 5 is the same as in the compound of formula 11.

Conversion of a compound of formula 3b to a compound of formula 1d or formula 1e, where R 3 is -C(=O)(R 10 R 11 )n- or a bond and R 5 is as in the compound of formula 11, can be carried out as indicated in the description of Scheme 1. If R5 is a protected oxo unit, the conversion of such a group to a carbonyl can be carried out at the same time as the removal of the protecting group from the nitrogen in the pyrazole.

Alternatively, the amine of 4a can be treated with a base such as triethylamine, diisopropylethylamine, pyridine or 2,6-lutidine and chloroformate CIC(=O)OR4 (diisopropylethylamine and aryl or heteroaryl chloroformate is the preferred combination) as described above for Scheme 1 to gives the carbamate intermediate 7a where R3 is -C(=O)O- and R4 is as defined above for compounds of formula 1.

Subsequent treatment of 7a obtained in the previous paragraph with a primary or secondary amine in a solvent such as dioxane, dimethylformamide or acetonitrile, where the preferred mixture is dioxane:dimethylformamide 1:1, at a temperature between about 40°C and about 90°C, where the preferred mixture is about 70°C, gives the corresponding urea-based intermediate 7b where R3 is -C(=O)NR9- and R4 is as defined above for compounds of formula 1.

Intermediate 7c where R3 is -(CR10R11)(1-3)- can be prepared from intermediate 4a by reacting 4a with an oxo unit (aldehyde or ketone) in an inert solvent, preferably toluene, tetrahydrofuran or methanol at a reaction temperature of about 0°C to about 110°C, preferably about 21°C, in the presence of a reductant, the preferred reductants being sodium triacetoxyborohydride, sodium cyanoborohydride and lithium, aluminum hydride to give an intermediate of formula 6a where R3 is -(CR10R11)(1-3)- . Deprotection of intermediate 6a can be accomplished as described, i.e., in an inert solvent, preferably trifluoroacetic acid, at a reaction temperature of about 20°C to about 100°C, preferably about 65°C to about 75°C.

Intermediates of formulas 5a, 6a, 7a, 7b or 7c can also be converted to give the following compounds of this invention, as shown in Scheme 3. Scheme 3 shows the use of 5a (where R 3 is a bond) and 6a (where R 3 is -C(= O)(R10R11)n-) as the reactant, therefore the same chemical procedures can be applied to the intermediates of formulas 7a, 7b or 7c to give the analogous products. According to Scheme 3, if R5 in 5a and 6a is a protected oxo (carbonyl) unit (specifically acetal or ketal), deprotection can first be carried out using well-known conditions, which appear in the literature. Treatment of compound 5a or 6a (or 7a, 7b or 7c), in an inert solvent, suitable for a lower ketone, for example acetone, in the presence of acid, where preferred acids are hydrochloric acid, p-toluenesulfonic acid monohydrate, pyridinium p-toluenesulfonate, at temperature which varies between room temperature to about 80°C, conveniently at about 75°C, gives compound 12, where R3 is a bond or 15 where R3 is -C(=O)(CR10R11)n- or if 7a, 7b or 7c used as reactants, compounds analogous to 12 and 15 but where R3 is -C(=O)O-, -C(=O)NR9-, or -(CR10R11)(1-3)-, in each case R5 is oxo (carbonyl) unit.

The oxo unit of the intermediates obtained in the previous paragraph, i.e. compounds 12 and 15, can react with an amine, primary or secondary, where the preferred amines are alkyl amines, for example 4-methoxy-benzyl-amine, in an inert solvent, preferably toluene or tetrahydrofuran, at the reaction at a temperature of about 21°C to about 150°C, preferably at about 70°C to about 110°C. After 12 or 15 is consumed, usually within a 12-hour period, the reaction is cooled to a temperature of about 21°C to about 50°C, and the reductant is added. Preferred reducing agents are sodium triacetoxyborohydride, sodium cyanoborohydride and lithium, aluminum hydride. Such reaction of compounds, for example 12 or 15 gives 13, where R3 is a bond, or 16, where R3 is -C(=O)(CR10R11)n-, individually, in each case R5 is -NR7R5. Analogous compounds to 13 and 16, where R5 is -NR7R8 and R3 is -C(=O)O-, -C(=O)NR9-, or -(CR10R11)(1-3)-, can also be prepared using intermediates analogous to the above-described compounds 12 and 15. Coupling of 13 or 16 or an analogous intermediate to give an N-acyl derivative 14 or 17 or an analogous N-acyl derivative except having R3 as -C(=O)O-, -C(=O )NR9-, or -(CR10R11)(1-3)-, can be carried out by the reaction of 13 or 16 or analogous intermediate products in an inert solvent, where methylene chloride, pyridine, tetrahydrofuran, diethyl ether are preferred, in the presence of acid chloride, of an acid anhydride or activated carboxylic acid derivative, from about -78°C to about 40°C. The activated carboxylic acid can be prepared as described above.

Alternatively, the amine of compound 16 or 13 or an analogous intermediate may additionally be treated with a base, such as triethylamine, diisopropylethylamine, pyridine or 2,6-lutidine, and an alkyl, aryl or heteroaryl chloroformate CIC(=O)2R7 (the preferred combination is diisopropylethylamine and chloroformates) at a temperature of from about -78°C to about 40°C, preferably from about -78°C to about -40°C, to provide compounds of formula 1 wherein R 5 is -NR 7 C(=O)OR 8 . Subsequent treatment of a carbamate of formula 1 with a primary or secondary amine in a solvent such as dioxane, dimethylformamide or acetonitrile, where a 1:1 dioxane:dimethylformamide mixture is preferred, at a temperature of 40°C and 90°C, where 70°C is preferred, gives the corresponding urea-based intermediate where R5 is -NR7C(=O)NR8R9.

The above described deprotection of compounds 12, 13, 14, 15, 16 or 17 or any analogous compound, where R3 and/or R5 is instead of -C(=O)O-, -C(=O)NR9-, or -(CR10R11)(1-3)-, can be carried out by reaction in an inert solvent, preferably methylene chloride or no solvent, in the presence of an acid, preferably trifluoroacetic acid, at a reaction temperature of about 20°C to about 100°C, preferably from about 65°C to about 75°C, giving compounds of formula 1, for example of formula 1c, where R3 is a bond and R5 is -NR7C(=O)R5 or a compound of formula 1f, where R3 is -C (=O)(CR10R11)n- and R5 is -NR7C(=O)R8.

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Schemes 4 and 5 show a preferred method for the preparation of compounds of formula 1, wherein R 1 is optionally substituted with OR 7 or R 7 . Preparation of intermediates 12 and can be carried out as described in Scheme 3.

R3 in intermediate 12 is a bond and R3 in intermediate 15 is -C(=O)(CR10R11)n-. Also, intermediates analogous to intermediates 12 and 15, but where R3 is -C(=O)O-, -C(=O)NR9-, or (CR10R11)(1-3)-, can be used in schemes 4 and 5 In each intermediate (12,15, or analogous intermediates), R 5 is an oxo (carbonyl) unit.

Conversion of the oxo (=O) unit to the hydroxyl unit (-OH), as in 18 and 23, can be accomplished using well-known chemical methods. The preferred method is the reaction of intermediates 12 or 15 or analogous intermediates in an inert solvent, preferably in a tetrahydrofuran/water mixture at a reaction temperature of about -78°C to about 50°C, preferably at 20C, in the presence of a reducing agent, preferably NaBH4 or lithium, aluminum hydride, to obtain compound 18 or 23 or their analogous compounds where R3 is -C(=O)O-, -C(=O)NR9-, or (CR10R11)(1-3)-,

Reaction of compound 18 or 23 or compounds analogous to them where R3 is -C(=O)O-, -C(=O)NR9-, or (CR10R11)(1-3-) in an inert solvent, preferably tetrahydrofuran, at the reaction temperature from about -20°C to about 50°C, preferably at about 20°C, in the presence of an R7-halide, where the preferred R7-halide is R7-Cl, gives compound 19 or 24 or compounds analogous thereto where R3 is -C( =O)O-, -C(=O)NR9-, or (CR10R11)(1-3)-, and in each of the compounds R5 is –OR7 Deprotection of the protecting group can be carried out by reaction in an inert solvent, where it is preferred to use methylene chloride solvent or no solvent is used, in the presence of acids, where trifluoroacetic acid is preferred, at a reaction temperature of from about 20°C to 100°C, preferably from about 65°C to about 75°C, to give the compound of formula 1 g, where R3 is a bond and where R5 = OR7, a compound of formula 1 h, where R3 is -C(=O) (CR10R11)(1-3)-, or an analogous compound where R3 is -C(=O)O -,-C(=O)NR9-, or (CR10R11)(1-3)-,

Alternatively, treating a solution of compound 12 or 15 or an analogous intermediate where R3 is -C(=O)O-, -C(=O)NR9-, or (CR10R11)(1-3)- (in each case R5 is an oxo unit , specifically carbonyl) in an inert solvent, where tetrahydrofuran is preferred, with an organometallic reagent, such as organomagnesium halide, organolithium, organocerium, organotitanium, organozinc, organocopper or organoaluminum, where organomagnesium halide (Grignard reagent) or organolithium reagent is preferred, at a temperature from about -78°C to about 40°C, with -78°C to about 0°C being preferred, gives the alcohol product 21 or 26 or an analogous compound where R3 is -C(=O)O-, -C(= O)NR9- or (CR10R11)(1-3)-, where in each case R1 is hydroxylated and substituted by R7, for example (5-(3-hydroxy,3-phenyl-cyclobutyl)-2-(Prot)- pyrazol-3-yl)-naphthalen-2-yl-amine. The removal of the alcohol was carried out by the reaction of 21 or 26 or an analogous compound in an inert solvent, such as methylene chloride, chloroform or 1,2-dichloroethane or preferably without a solvent, in the presence of an acid, preferably trifluoroacetic acid and in the presence of silane, where triethylsilane and triphenylsilane, at a temperature of from about -10°C to about 50°C, where the preferred temperature is from about 20°C to about 40°C, to obtain a compound of formula 22 or 27 or compounds analogous thereto but where R 3 is -C (=O)O-, -C(=O)NR9-, or (CR10R11)(1-3)-, the intermediate in each case contains R7 attached directly to R1.

Alternatively, treatment of alcohol products such as 21 or 26 and about one to ten equivalents of base, preferably five equivalents of pyridine or 2,6-lutidine, in an inert solvent, preferably methylene chloride, with a strongly acidic reagent, preferably thionyl chloride, at temperature from about 110°C to about 0°C, where from about 78°C to about -45°C is preferred results in the replacement of alcohol (-OH groups) with chloride. Reductive removal of chloride can be carried out by exposing a mixture of said chloride of compound 21 or 26 and a noble metal catalyst, preferably palladium, to a stream of hydrogen gas at a pressure of about 1 to 100 atmospheres, where the preferred pressure of hydrogen gas is about one to ten atmospheres, to give compound 22 or 27 or a compound analogous thereto, where R3 is -C(=O)O-, -C(=O)NR9-, or (CR10R11)(1-3)-. The metal catalyst can usually be suspended on an inert solid support such as charcoal, in a solvent such as ethyl acetate, tetrahydrofuran, dioxane or a mixture thereof.

In schemes 4 and 5, R5 hydroxy unit of the compound of formula 18 or 23 or analogous compounds where R3 is -C(=O)O-, -C(=O)NR9-or (CR10R11)(1-3)-, can be derivatize using known chemical methods to obtain the corresponding compounds where R5 is -OC(=O)R7, -OC(=O)OR7, -OC(=O)NR7R8 and -OC(=O)SR7, -SR7, -S (=O)R7, -S(=O)2R7 or -S(=O)2NR7R8.

For example, the amine of compound 18 or 23 or compounds analogous thereto where R3 is -C(=O)O-, -C(=O)NR9- or (CR10R11)(1-3)-, can be treated with a base such as triethylamine, diisopropylethylamine, pyridine or 2,6-lutidine, and alkyl, aryl or heteroaryl chloroformate CIC(=O)2R7 (diisopropylethylamine and chloroformates are the preferred combination) at a temperature of from about -78°C to about 40°C, where preferred from -78°C to -40°C to give a carbonate intermediate where R5 is -OC(=O)OR8. Subsequent treatment of the carbonate with a primary or secondary amine in a solvent such as dioxane, dimethylformamide or acetonitrile, where a 1:1 mixture of dioxane and dimethylformamide is preferred, at a temperature between 40°C and 90°C, where about 70°C is preferred gives the corresponding intermediate based on urea where R5 is -OC(=O)NR8R9. The removal of the protecting group of each intermediate can be carried out by reaction in an inert solvent, where the preferred solvent is methylene chloride or without solvent, in the presence of an acid, where the preferred solvent is trifluoroacetic acid, at a reaction temperature of about 20°C to about 100°C, preferably from about 65°C to about 75°C, to give a compound of formula 1, wherein R5 is -OC(=O)OR7 or -OC(=O)NR8R9.

The removal of the protecting group from compounds 22, 27 or derivatives 19 or 24 can be carried out in a reaction-inert solvent, preferably methylene chloride, chloroform, 1,2-dichloroethane or without a solvent, in the presence of an acid, where trifluoroacetic acid is preferred at a reaction temperature of about 20°C to about 100°C, preferably from about 65°C to about 75°C, to give a compound of formula 1i, 1k, or another compound of formula 1.

Compounds of formula 1 as described herein, wherein R 2 is other than hydrogen, may be prepared by transformation of the herein mentioned compounds of formula 1 wherein R is hydrogen, using well known methods. For example, with reference to Scheme 3 above, compounds of formula 1 where R is F, compounds of formula 17, 6a, or 14 can be prepared with N-fluorobenzenesulfonimide in an inert solvent, preferably toluene, dioxane, or xylene, from about room temperature to about 150°C, preferably from about 100°C to 120°C to give the corresponding intermediates where R2 is F. Deprotection of these intermediates can be carried out by reaction in an inert solvent, where methylene chloride is preferred or the solvent is not used, in the presence of an acid where trifluoroacetic acid is preferred at a reaction temperature of from about 20°C to about 100°C, preferably from about 65°C to about 75°C, to give compounds of formula 1 where R2 is F.

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Some of the compounds of formula 1 prepared according to the above processes are obtained as mixtures of isomers or enantiomers. Such mixtures of isomers or enantiomers are within the scope of this invention. Resolution of such a mixture into individual isomers or enantiomers in accordance with conventional techniques is also within the scope of this invention, as are the resolution of isomers and enantiomers.

Pharmaceutically acceptable salts of the compounds of formula 1 can be prepared in the usual manner by treating a solution or suspension of the appropriate free base or acid with one chemical equivalent of a pharmaceutically acceptable acid or base. For the isolation of salts, the usual procedures of concentration or crystallization can be used.

Examples of suitable acids are acetic, lactic, succinic, maleic, tartaric, citric, gluconate, ascorbic, benzoic, cinnamic, formic, sulfate, phosphoric, chloride, bromide, iodide, sulfamate, sulfonic acids such as methanesulfonic, benzene sulfonic, p- toluenesulfonic and related acids. Examples of bases are sodium, potassium and calcium.

A compound of the present invention may be administered alone or in combination with a pharmaceutically acceptable carrier, in single or multiple doses. Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solutions and various organic solvents. Pharmaceutical compositions created by combining a compound of formula 1 with its pharmaceutically acceptable salt can be readily administered in various forms such as tablets, powders, lozenges, syrups, injectable solutions and the like. These pharmaceutical preparations may, if desired, contain additional ingredients such as flavor corrigents, binders, excipients and the like. Therefore, for oral administration, tablets contain various excipients such as sodium citrate, calcium carbonate and calcium phosphate which can be used together with various disintegrants such as starch, methylcellulose, alginic acid and some complex silicates, and together with binders such as polyvinylpyrrolidone, sucrose, gelatin and gum arabic. Additionally, glidants such as magnesium stearate, sodium lauryl sulfate, and talc are often used for tableting. Solid mixtures of a similar type can also be used as fillers in soft and hard gelatin capsules. Preferred substances for this purpose include lactose or galactose and high molecular weight polyethylene glycols. When aqueous suspensions or elixirs are desired for oral administration, the main active ingredient may be combined with sweeteners and flavoring agents, coloring agents or dyes, and if necessary, emulsifiers and suspending agents together with diluents such as water, ethanol, propylene glycol , glycerol and their combinations.

For parenteral administration, solutions containing the compound of this invention or its pharmaceutically acceptable salt in sesame or peanut oil, in an aqueous solution of propylene glycol or in a sterile aqueous solution can be used. Such aqueous solutions should be suitably buffered if necessary and the liquid diluent first made isotonic with sufficient saline or glucose. These special aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. The sterile aqueous agents used are all readily available by standard procedures known in the art.

A compound of formula 1 or a pharmaceutically acceptable salt thereof can be administered orally, transdermally (for example using a patch), parenterally (for example intravenously), rectally or topically. In general, daily dosages for the treatment of neurodegenerative diseases or conditions, or diseases or conditions whose treatment can be carried out or made possible by altering dopamine-mediated neurotransmission, will usually be in the range of about 0.0001 to about 10.0 mg/kg body weight of the patient to be treated. Daily dosages for the treatment of cancer or diseases or conditions involving abnormal growth of cells of a benign nature will usually be in the range of about 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 administered for the treatment of neurodegenerative disorders in adult humans of average weight (about 70 kg) in a dosage range of about 0.01 mg to about 1000 mg per day, preferably from about 0.1 to about 500 mg per day. day, in a single meal or divided (i.e. multiple) meals. Modifications based on the above-mentioned dosage range can be made by a skilled physician taking into account known circumstances such as the weight, age and condition of the person being treated, the frequency of pain and the chosen route of administration.

The compounds of formula 1 and their pharmaceutically acceptable salts may further also be formulated into a pharmaceutical composition with an amount of one or more substances selected from anti-angiogenic agents, signal transduction inhibitors and antiproliferatives, the combined amount of which is effective in inhibiting abnormal cell growth.

Anti-angiogenesis agents, such as MMP-2 (matrix-metalloproteinase 2) inhibitors, MMP-9 (matrix-metalloproteinase 9) inhibitors, and COX-II (cyclooxygenase 11) inhibitors can be used in conjunction with a compound of formula 1 in the methods described herein and pharmaceutical preparations for the treatment of abnormal cell growth, including cancer. Examples of useful COX-II inhibitors include CELEBREXTM (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. 97304971.1 (application filed July 8, 1997), European Patent Application No. 99308617.2 (filed Oct. 29, 1999), Publication WO 98/07697 (published Feb. 26, 1998), WO 98/03516 (published Jan. 29, 1998), WO 98/34918 (published Aug. 13, 1998), WO 98/03516 (published Jan. 29, 1998). /34915 (published August 13, 1998), WO 98/33768 (published August 6, 1998), WO 98/30566 (published July 16, 1998), European Patent Application 606,046 (published July 13, 1994), European Patent Application 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 (application filed July 21, 1998), European Patent p Application No. 99302232.1 (filed Mar. 25, 1999), GB Patent Application No. 9912961.1 (filed Jun. 3, 1999), U.S. Provisional Appl. Patent Application No. 60/148,464 (filed Aug. 12, 1999), U.S. Pat. U.S. Patent 5,863,949 (issued January 26, 1999). Patent 5,861,510 (issued January 19, 1999) and European Patent Publication 780,386 (issued June 26, 1997), all of which are incorporated herein by reference in their entirety. Preferred inhibitors of MMP-2 and MMP-9 are those that have little or no activity in inhibiting MMP-1. Even more preferred are those that selectively inhibit MMP2 and/or MMP-9 relative to other matrix metalloproteinases (ie, 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 in the present invention are AG-3340, RO 32-3555, RS 13-0830 and the compounds listed below:

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

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

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

Carboxylic acid 4-[4-(4-fluoro-phenoxy)-benzenesulfonylamino]-tetrahydro-pyran-4-hydroxyamide;

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

Carboxylic acid 4-[4-(4-chloro-phenoxy)-benzenesulfonylamino]-tetrahydro-pyran-4-hydroxyamide;

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

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

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

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

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

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

(R) carboxylic acid 3-[4-(4-fluoro-phenoxy)-benzenesulfonylamino]-tetrahydro-furan-3-hydroxyamide; and pharmaceutically acceptable salts and solvates of said compounds.

Other anti-angiogenic agents, including other COX-II inhibitors and other MMP inhibitors may also be used in the present invention.

The effective amount of the COX-II inhibitor in combination with the compound of formula 1 is usually determined by the expert. The suggested effective daily dose range for a COX-II inhibitor in combination with a cdk5 inhibitor is from about 0.1 to about 25 mg/kg of body weight. An effective daily amount of a compound of formula 1 will usually be between 0.0001 and 10 mg/kg of body weight. In some cases, the amount of COX-II inhibitor and/or compound of formula 1 in combination may be less than required on an individual amount basis to achieve the same desired effect in inhibiting abnormal cell growth.

The compound of formula 1 can also be used with a signal transduction inhibitor, such as signal transduction agents that inhibit the EGFR (epidermal growth factor receptor) response, such as EGFR antibodies, EGF antibodies, and EGFR inhibitor molecules; a VEGF (vascular endothelial growth factor) inhibitor and an erbB2 receptor inhibitor such as organic molecules or antibodies that bind to the erbB2 receptor, for example, HERCEPTIN (Genentech, Inc. of South San Francisco, California, USA). Such a combination is useful for the treatment and prevention of abnormal cell growth, including cancer, as described herein.

EGFR inhibitors are described in, for example, WO 95/19970 (published July 27, 1995), WO 98/14451 (published April 9, 1998), WO 98/02434 (published January 22, 1998), and US Patent 5,747,498 (published April 5, 1998). . May 1998), and such substances can be used in the present invention as described herein. EGFR inhibitory agents include, but are not limited to, monoclonal antibodies C225 and anti-EGFR 22Mab (ImClone Systems Incorporated of New York, New York, USA), 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, Massachusetts). These and other EGFR inhibitory agents can be used in 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 the compound of formula 1. VEGF inhibitors are described in, for example, publication WO 99/24440 (published 20 May 1999), PCT International Patent Application PCT/IB99/00797 (filed May 3, 1999), in Publication WO 95/21613 (published Aug. 17, 1995), WO 99/61422 (published Dec. 2, 1999), U.S. Pat. Patent 5,834,504 (published Nov. 10, 1998), Publication WO 98/50356 (published Nov. 12, 1998), U.S. Pat. 5,883,113 (issued March 16, 1999), U.S. Pat. 5,886,020 (issued March 23, 1999), U.S. Pat. patent 5,792,783 (published August 11, 1998), publication WO 99/10349 (published March 4, 1999), WO 97/32856 (published September 12, 1997), WO 97/22596 (published June 26, 1997), WO 98/ 54093 (published Dec. 23, 1998), WO 98/02438 (published Jan. 22, 1998), WO 99/16755 (published Apr. 28, 1999), and WO 98/02437 (published Jan. 22, 1998), all of which are incorporated herein by reference. here in its entirety by reference. Other examples of some specific VEGF inhibitors useful in the present invention are IM862 (Cytran Inc. of Kirkland, Washington, USA); anti-VEGF monoclonal antibody from Genentech, Inc. of South San Francisco, California; and angiozyme, a synthetic ribozyme from Ribozyme (Boulder, Colorado) and Chiron (Emeryville, California). These and other VEGF inhibitors can be used in the present invention as described herein.

ErbB2 receptor inhibitors such as GW-282974 (Glaxo Wellcome pic) and monoclonal antibodies AR-209 (Aronex Pharmaceutical inc. of The Woodlands, Texas, USA) and 2B-1 (Chiron) can also be combined with a compound of formula 1, for example those disclosed in WO 98/02434 (published Jan. 22, 1998), WO 99/35146 (published Jul. 15, 1999), WO 99/35132 (published Jul. 15, 1999), WO 98/02437 (published Jul. 15, 1999). Jan. 22, 1998), WO 97/13760 (published Apr. 17, 1997), WO 95/19970 (published Jul. 27, 1995), U.S. 5,587,458 (issued Dec. 24, 1996) and U.S. Pat. patent 5,877,305 (issued March 22, 1999), which are incorporated herein by reference in their entirety. ErbB2 receptor inhibitors useful in the present invention are also described in provisional U.S. Pat. patent application No. 60/117,341, application filed Jan. 27, 1999 and provisional U.S. Pat. patent application No. 60/117,346, application filed Jan. 27, 1999, both of which are incorporated herein by reference in their entirety. Compounds and substances that are inhibitors of the erbB2 receptor are described in the aforementioned PCT patent application, U.S. patents and provisional U.S. patents. patent applications, as well as other compounds and substances that inhibit the erbB2 receptor, can be used with the compound of formula 1, in accordance with the present invention.

A compound of formula 1 may also be used with other agents useful in the treatment of abnormal cell growth or cancer, including but not limited to agents capable of enhancing an antitumor immune response, such as CTLA4 (cytotoxic lymphocyte antigen 4) antibodies and other blocking agents. CTLA4 and anti-proliferative agents such as farnesyl protein transferase inhibitors. Specific CTLA4 antibodies that can be used in the present invention include those described in provisional U.S. Pat. patent application 60/113,647 (published Dec. 23, 1998) which is incorporated by reference in its entirety, therefore other CTLA4 antibodies may be used in the present invention.

The compounds of formula 1 can also be used in a method for inhibiting abnormal growth of cells in mammals in combination with radiation therapy. Techniques for applying radiation therapy are known in the art, and these techniques can be used in the therapeutic combination described here. The use of a compound of the present invention in this therapeutic combination can be determined as described herein.

The compounds of formula 1 may also be administered in combination with a COX-II inhibitor for the treatment of Alzheimer's disease, mild cognitive decline, or age-related cognitive decline. Specific examples of COX-II inhibitors useful in this aspect of the invention are provided above, where the use of a COX-II inhibitor in combination with a compound of formula 1 for the treatment of abnormal cell growth is described. The effective amount of COX-II inhibitor in combination with the compound of formula 1 can be determined by a skilled person. A suggested effective daily dose range for a COX-II inhibitor in combination with a compound of formula 1 is from about 0.1 to about 25 mg/kg of body weight. The daily effective amount of the compound of formula 1 will usually be between 0.0001 and 10 mg/kg of body weight. In some cases, the amount of COX-II inhibitor and/or compound of formula 1 in combination may be less than required on an individual amount basis to achieve the same desired therapeutic effect. Alzheimer's disease, mild cognitive decline or age-related decline in cognitive function.

The compounds of formula 1 can also be administered with an NK-1 receptor antagonist to treat depression or anxiety. An NK-1 receptor antagonist, as defined herein, is a substance capable of antagonizing NK-1 receptors, thereby inhibiting tachykinin-mediated responses, such as substance P-mediated responses. Various NK-1 receptor antagonists are known in the art. , and any such NK-1 receptor antagonist can be used in the present invention as described above in combination with a compound of formula 1. NK-1 receptor antagonists are described in, for example, U.S. Pat. patent number 5,716,965 (issued February 10, 1998); LOUSE. patent number 5,852,038 (issued December 22, 1998); publication WO 90/05729 (international publication date May 31, 1990); LOUSE. patent number 5,807,867 (issued September 15, 1998); LOUSE. patent number 5,886,009 (issued March 23, 1999); LOUSE. patent number 5,939,433 (issued August 17, 1999); LOUSE. patent number 5,773,450 (published June 30, 1998); LOUSE. patent number 5,744,480 (issued April 28, 1998); LOUSE. patent number 5,232,929 (issued August 3, 1993); LOUSE. patent number 5,332,817 (issued July 26, 1994); LOUSE. U.S. Patent No. 5,122,525 (issued June 16, 1992). patent number 5,843,966 (issued December 1, 1998); LOUSE. patent number 5,703,240 (issued December 30, 1997); LOUSE. Patent No. 5,719,147 (issued February 17, 1998) and U.S. Pat. patent number 5,637,699 (issued June 10, 1997). Each of the previous U.S. patent and prior published PCT international patent applications are incorporated by reference in their entirety. Compounds described in the cited references that have activity as NK-1 receptor antagonists can be used in the present invention. Therefore, other NK-1 receptor antagonists can also be used in this invention.

Effective amounts of the NK-1 receptor antagonist in combination with the compound of formula 1 are usually determined by a person skilled in the art. The suggested range of effective daily doses of the NK-1 receptor antagonist in combination with the compound of formula 1 is from about 0.07 to about 21 mg/kg of body weight. An effective amount of the compound of formula 1 will be between 0.0001 and 10 mg/kg of body weight. In some cases, the amount of the NK-1 receptor antagonist and/or the amount of the compound of formula 1 may be less than required on an individual amount basis to achieve the same desired effect in the treatment of depression or anxiety.

The subject of the present invention also provides for combining a compound of formula 1 with a 5HT1D receptor antagonist for the treatment of depression or anxiety. A 5HT1D receptor antagonist, as defined herein, is a substance that antagonizes the 5HT1D subtype of the serotonin receptor. Any such substance can be used in the present invention as described above in combination with a compound of formula 1. Substances having activity as 5HT1D receptor antagonists can be determined by a person skilled in the art. For example, a 5HT1D receptor antagonist is 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); LOUSE. patent number 5,510,350 (issued April 23, 1996); LOUSE. patent number 5,358,948 (published October 25, 1994) and GB patent number 2276162 A (published September 21, 1994). These 5HT1D receptor antagonists, as well as others, can be used in the present invention. The aforementioned published patent applications and patents are incorporated herein by reference in their entirety.

Effective amounts of 5HT1D receptor antagonists in combination with the compound of formula 1 can be determined by a skilled person. The suggested range of effective daily doses of the 5HT1D receptor antagonist in combination with the compound of formula 1 is from about 0.01 to about 40 mg/kg of body weight. Effective daily amounts of a compound of formula 1 will usually be between 0.0001 and 10 mg/kg of body weight. In some cases, the amount of the 5HT1D receptor antagonist and/or the amount of the compound of formula 1 may be less than required on an individual amount basis to achieve the same desired effect in the treatment of depression or anxiety.

The present invention also provides a composition and method for treating depression or anxiety in a mammal comprising a compound of formula 1 and an SSRI. Examples of SSRIs that may be combined in a method or pharmaceutical composition with the 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 the compound of formula 1 or a pharmaceutically acceptable salt thereof. Other antidepressants and/or anxiolytics with which the compound of formula 1 may be combined or administered include WELLBUTRIN, SERZONE and EFFEXOR.

The effective amount of SSRI in combination with the compound of formula 1 can be determined by a skilled person. A suggested range of effective daily doses for an SSRI in combination with a compound of formula 1 is from about 0.01 to about 500 mg/kg of body weight. An effective daily amount of a compound of formula 1 will usually be between 0.0001 to about 10 mg/kg of body weight. In some cases, the amount of the SSRI and/or the amount of the compound of formula 1 may be less than required on an individual amount basis to achieve the same desired effect in the treatment of depression or anxiety.

A compound 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 the treatment of a disease or condition whose treatment may be effected or facilitated by altering dopamine-mediated neurotransmission, such as schizophrenia. Examples of antipsychotics with which a compound of the present invention may be combined include ziprasidone (5-(2-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)ethyl)-6-chloro-1, 3-dihydro- 2H-indol-2-one; U.S. Patent No. 4,831,031 and U.S. Patent No. 5,312,925); olanzapine (2-methyl-4-(4-methyl-1-piperazinyl-10H-thieno (2,3b) (1,5)benzodiazepine; U.S. Patent No. 4,115,574 and U.S. Patent No. 5,229,382); risperidone (3-[2- [4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]6,7,8,9-tetrahydro-2methyl-4H-pyrido[1,2-a]pyrimidin-4 -one; U.S. Patent No. 4,804,663); L-745870 (3-(4-(4-Chlorophenyl)piperazin-1-yl)methyl-1H-pyrrolo(2,3-b)pyridine; U.S. Patent No. 5,432,177); sonepiprazole (S-4-(4-(2-(isochroman-1-yl)ethyl)piperazin-1-yl)benzenesulfonamide; U.S. Patent No. 5,877,317); RP 62203 (phananserin; 2-(3-(4-(4 -fluorophenyl)-1-piperazinyl)propyl)naphtho(1,8-c,d)isothiazole-1,1-dioxide; U.S. Patent No. 5,021,420); NGD 941 (U.S. Patent No. 5,633,376 and U.S. Patent No. 5,428,165); balaperidone ( (1α, 5α, 6α)-3-(2-(6-(4-fluorophenyl)-3-azabicyclo(3.2.0)hept-3-yl)ethyl)-2,4(1H,3H)- quinazolinedione; U.S. Patent No. 5,475,105); flesinoxane ((+)-4-fluoro-N-[2-[4-5-(2-hydroxymethyl-1,4-benzodioxanyl)]-1-piperazinyl]ethyl]benzamide; U.S. Pat. patent number 4,833,142); and gepiron (4,4-dimethyl-1-(4-(4-(2-pyrimidinyl)-1-piperazinyl)butyl)-2,6-piperidinedione; LOUSE. patent number 4,423,049). All of the above-mentioned patents, in this section, are incorporated herein by reference in their entirety. An effective daily amount of a compound of formula 1 will typically be between 0.0001 and 10 mg/kg of body weight. The amount of any of the aforementioned antipsychotic agents contemplated for use in combination with a compound of formula 1 is usually in an amount known in the art to be useful in the treatment of psychotic conditions. Therefore, in some cases, the amount of the antipsychotic and/or the amount of the compound of formula 1 may be less than required on an individual amount basis to achieve the same desired effect in the treatment of depression or anxiety. It is further understood that the present invention also encompasses combining a compound of formula 1 with an antipsychotic or dopaminergic agent other than those listed above.

The suggested amount of sonepiprazole in the combination described above with the compound of formula 1 is from about 0.005 to about 50 mg/kg of the patient's body weight per day. The suggested amount of RP 62203 in such a combination is from about 0.20 to about 6 mg/kg of the patient's body weight per day. The suggested amount of NGD 941 in such a combination is from about 0.1 to about 140 mg/kg of the patient's body weight per day. The suggested amount of balaperidone in such a combination is from about 1 to about 100 mg/kg of body weight per day. The suggested amount of flesinoxan in such a combination is from about 0.02 to about 1.6 mg/kg of body weight per day. The suggested amount of gepirone in such a combination is approx. 01 to about 2 mg/kg of body weight per day. A suggested amount of L-745870 in such a combination is from about 0.01 to about 250 mg/kg of body weight per day, preferably from about 0.05 to about 100 mg/kg of body weight per day. The suggested amount of risperidone in such a combination is from about 0.05 to about 50 mg/kg of body weight per day. The suggested amount of olanzapine in such a combination is from about 0.0005 to about 0.6 mg/kg of body weight per day. The suggested amount of ziprasidone in such a combination is from about 0.05 to about 10 mg/kg of body weight per day. In some cases for each of the previously mentioned combinations, however, the amount of each of the specific ingredients in the combination may be less than required on an individual amount basis to achieve the same desired effect in the treatment of psychotic conditions.

The present invention also provides a pharmaceutical composition and method for treating Alzheimer's disease, mild cognitive decline, or age-related cognitive decline, comprising a compound of formula 1 and an acetylcholinesterase inhibitor. Acetylcholinesterase inhibitors are known in the art, and any acetylcholinesterase inhibitor can be used in the pharmaceutical composition or process described above. Examples of acetylcholinesterase inhibitors that can be used in the present invention are ARICEPT (donepezil; U.S. Patent No. 4,895,841); EXELON (rivastigmine ((S)-[N-ethyl-3-[1-(dimethylamino)ethyl]phenyl carbamate); U.S. Patent No. 5,603,176 and U.S. Patent No. 4,948,807); metrifonate ((2,2,2-trichloro-1-hydroxyethyl)phosphonic acid dimethyl ester; U.S. Patent No. 2,701,225 and U.S. Patent No. 4,950,658); galantamine (U.S. Patent No. 4,663,318); physostigmine (Forest, USA); tacrine (1,2,3,4-tetrahydro-9-acridinamine U.S. Patent No. 4,816,456); huperzine A (5R-(5a,9d,11E))-5-amino-11-ethylidene-5,6,9,10-tetrahydro-7-methyl-5,9-methanecycloocta(b)pyridine-2-(1H )-he); and icopezil (5,7-dihydro-3(2-(1-(phenylmethyl)-4-piperidinyl)ethyl)-6H-pyrrolo(3,2-f)-1,2-benzisoxazol-6-one; U.S. Pat. number 5,750,542 and publication WO 92/17475). The patents and patent applications cited in the paragraph above are hereby incorporated by reference in their entirety.

An effective amount of an acetylcholinesterase inhibitor in combination with a compound of formula 1 can usually be determined by a person skilled in the art. The suggested effective daily dose range for an acetylcholinesterase inhibitor in combination with a compound of formula 1 is from about 0.01 to about 10 mg/kg of body weight. An effective daily amount of a compound of formula 1 will usually be between 0.0001 and 10 mg/kg of body weight. In some cases, the amount of the acetylcholinesterase inhibitor and/or the amount of the compound of formula 1 in combination may be less than required on an individual amount basis to achieve the same desired effect in the treatment of Alzheimer's disease, mild cognitive decline or age-related cognitive decline.

The present invention also provides for combining a compound of formula 1 with a neuroprotector, for example an NMDA receptor antagonist for the treatment of Huntington's disease, stroke, spinal cord injury, concussion, dementia caused by multiple infarcts, epilepsy, amyotrophic lateral sclerosis, pain, dementia caused by a virus for example dementia caused by AIDS, migraine, hypoglycemia, urinary incontinence, brain ischemia, multiple sclerosis, Alzheimer's disease, senile dementia of the Alzheimer type, mild cognitive decline or age-related decline in cognitive function, emesis, corticobasal degeneration, pugilistic dementia, Down's syndrome, myotonic dystrophy, Niemann-Pick disease, Pick disease, prion disease with disorder, progressive supranuclear palsy, lower lateral sclerosis or subacute sclerosing panencephalitis. Examples of NMDA receptor antagonists useful in the present invention include (1S,2S)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidin-1-yl)-1-propanol (U.S. Patent No. 5,272,160 ), eliprodil (U.S. Patent No. 4,690,931), and gavestenel (U.S. Patent No. 5,373,018). Other NMDA receptor antagonists that may also be used in the present invention are described in U.S. Pat. patent number 5,373,018; LOUSE. patent number 4,690,931; LOUSE. patent number 5,272,160; LOUSE. patent number 5,185,343; LOUSE. patent number 5,356,905; LOUSE. patent number 5,744,483; publication 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 U.S. Serial no. 08/292,651 (application filed Aug. 18, 1994). The aforementioned patents and patent applications are incorporated herein by reference in their entirety.

An effective daily amount of a compound of formula 1 in combination with an NMDA receptor antagonist will usually be between 0.0001 and 10 mg/kg of body weight. The amount of an NMDA receptor antagonist intended for use in combination with a compound of formula 1 for the treatment of any of the aforementioned disorders, for example Alzheimer's disease, is usually within the range of about 0.02 mg/kg/day to about 10 mg/kg/day. However, in some cases, the amount of the NMDA antagonist and/or the amount of the compound of formula 1 in combination may be less than required on an individual amount basis to achieve the same desired effect in the treatment of said disorders.

The subject of the invention also provides for combining the compound of formula 1 with some substances capable of treating stroke or concussion, such as TPA, NIF or potassium channel modulators, for example BMS-204352. Such combinations are useful for the treatment of neurodegenerative disorders such as, for example, stroke, spinal cord injury, concussion, dementia caused by multiple infarcts, epilepsy, pain, Alzheimer's disease and senile dementia.

For the combination therapies and pharmaceutical compositions described above, an effective amount of a compound of the present invention and another agent will usually be determined by one skilled in the art, based on the effective amounts of the compounds described herein and those known and described for other agents known in the art, for example the amounts described in the patents listed above and patent applications included herein. Formulations and routes of administration for such therapies and compositions may be based on that described herein for compositions and therapies containing a compound of this invention as the sole active ingredient and on the information provided for the other agent in combination therewith.

For a specific compound of formula 1, the ability to inhibit cdk2, cdk5, or GSK-3 can be determined using biological assay methods known to those skilled in the art, for example by the assay method described below.

The specific activity of a compound of formula 1 to inhibit cdk5 or cdk2 can, for example, be determined by the following assay methods using materials available to those skilled in the art

Enzyme activity can be determined by incorporation of [33P] from gamma phosphate [33P]ATP (Amersham, cat. no. AH-9968) into the biotinylated peptide substrate PKTPKKAKKL. In such an activity determination, the reactions are carried out in a buffer containing 50 mM Tris HCl, pH 8.0; 10mM MgCl2, 0.1mM Na3VO4 and 1mM DTT. The final ATP concentration is about 0.5uM (final specific radioactivity of 4uCi/nmol) and the final substrate concentration is 0.75uM. The reactions, initiated by the addition of either cdk5 and the p25 activator protein or cdk2 and the cyclin E activator, can be carried out at room temperature for about 60 minutes. The reactions are stopped by adding 0.6 volumes of buffer containing (final concentrations): 2.5 mM EDTA, 0.05% Triton-X 100, 100uM ATP and 1.25 mg/ml streptavidin-coated SPA pellets (Amersham cat. no. RPNQ0007). Radioactivity in the pellets was quantified by scintillation counting.

The specific activity of a compound of formula 1 to inhibit GSK-3 can be determined by cell-free and cell-based assays, both of which are described in the art (see, for example, WO 99/65897 ). The cell-free method is usually performed by incubating GSK-3 in a peptide substrate labeled with a radioisotope of ATP (such as, for example, y33P- or y32-P-ATP, both available from Amersham, Arlington Heights , Illinois), magnesium ions and the compound to be determined. The mixture is incubated for a period of time that allows incorporation of the radioisotope-labeled phosphate into the peptide substrate by GSK-3 activity. The reaction mixture is washed to remove residual radiolabeled ATP, typically after first transferring a total or partial amount of the enzyme reaction mixture into a container containing a uniform amount of ligand capable of binding to the peptide substrate. The amount of 33P or 32P remaining in each well after washing is then quantified to determine the amount of radiolabeled phosphate incorporated into the peptide substrate. Inhibition was determined as a reduction, relative to the control, of incorporation of radioisotope-labeled phosphates into the peptide substrate. An example of a suitable GSK-3 peptide substrate for determining the content of the SGSG-linked CREB peptide sequence, derived from the CREB DNA binding protein, is described in Wang, et al., AnaL Biochem., 220: 397-402 (1994). Purified GSK-3 for content determination can, for example, be obtained from cells by transfection with a human GSK-3β expression plasmid as described, for example, in Stambolic, et al., Current Biology 6: 1664-68 (1996). WO 99/65897; Wang, et al., and Stambolic, et al. are incorporated herein by reference in their entirety.

Another example of determination of GSK-3 content, similar to that described in the previous paragraph is as follows: Enzyme activity was determined as incorporation of [33P] from gamma phosphate [33P]ATP (Amersham, cat. No. AH-9968) into the biotinylated peptide substrate PKTPKKAKKL. The reaction is carried out in a buffer containing 50 mM Tris-HCl, pH 8.0; 10mM MgCl2, 0.1mM Na3VO4 and 1mM DTT. The final ATP concentration is 0.5μM (final specific radioactivity of 4μCi/nmol), and the final substrate concentration is 0.75mM. The reactions, started with the addition of enzymes, are carried out at room temperature for about 60 minutes. Reactions are stopped with 0.6 volumes of buffer containing (final concentrations): 2.5mM EDTA, 0.05% Triton-X 100, 100μM ATP and 1.25 mg/ml streptavidin-coated SPA pellets (Amersham cat. No. RPNQ0007). Radioactivity in the pellets was quantified by scintillation counting.

All of the title compounds of the following Examples have an IC50 inhibition of peptide substrate phosphorylation of less than about 50 pM, when assayed for activity in cdk5 inhibition is performed according to the above assay method.

Some of the title compounds of the following examples were assayed for GSK-3 inhibitory activity using the method as described above, and all examples tested had an IC50 for GSK-3β inhibition of less than about 50 μM.

The following Examples illustrate this invention. It should be understood, however, that the invention, as fully described herein and cited in the claims, is not intended to be limited by the details of the following Examples.

In the following Examples, "TFA" stands for "trifluoroacetic acid", "THF" stands for "tetrahydrofuran", "MPLC" stands for "medium pressure liquid chromatography", "TLC" stands for "thin layer chromatography", "KOBut" stands for "potassium-t-butoxide" , "DMSO" is "dimethyl sulfoxide" and "EtOAc" is "ethyl acetate". "MS", such as for example "Powdered 4 A MS" is "molecular sieve".

EXAMPLES

Example 1.

(5-Cyclobutyl-1H-pyrazol-3-yl)-(4-nitro-phenyl)-amine

Step 1. 3-Cyclobutyl-N-(4-nitro-phenyl)-3-oxo-thiopropionamide

A solution of methyl cyclobutyl ketone ( 400 μl, 360 mg, 3.6 mmol) in 10 ml tetrahydrofuran. After 1 hour, 4-nitro-phenyl isothiocyanate (328 mg, 1.8 mmol) was added in one portion. The reactants are allowed to warm to room temperature overnight. After 16 hours, the reaction is terminated with NH4Cl, diluted with CH2Cl2. The layers were separated and the aqueous layer was extracted with CH 2 Cl 2 , dried over MgSO 4 and concentrated under reduced pressure. Purification of the material is carried out by the MPLC technique using the Biotage Flash elution system with a hexane gradient up to 50% EtOAc/hexane. Fractions containing the product were pooled and concentrated to give 3-cyclobutyl-N-(4-nitro-phenyl)-3-oxo-thiopropionamide (266 mg, 53% yield) as a yellow oil. Rf=0.54 (30% acetone/hexane); 1H NMR (400 MHz, CDCl3) δ2.35-1.80 (m, 6H), 3.41 (dddd, J=8.2, 8.2, 7.9, 7.9 Hz, 1H), 4.04 (s, 2H), 7.70 (d, 8.7 Hz, 1H), 8.11 (d, 9.1 Hz, 2H), 8.23 (d, 9.2 Hz, 2H); LRMS m/z (APCI+) 279 (M+1).

Step 2

To a solution of 3-cyclobutyl-N-(4-nitro-phenyl)-3-oxo-thiopropionamide from Step 1 (266 mg, 0.95 mmol) in 2 ml of EtOH, which is being stirred, is added 150 μl of acetic acid, followed by anhydrous hydrazine (283 μl, 306 mg, 9.6 mmol). The reaction mixture was heated to 71°C for 2 hours and then cooled to room temperature. The reaction is quenched with aqueous NaHCO3 solution diluted with EtOAc and then the layers are separated. The organic layer was washed with water and the aqueous layer was re-extracted with CH 2 Cl 2 . The combined organic layers are dried over MgSO4, filtered and concentrated under reduced pressure. Purification of this material was performed. Fractions containing the product were pooled and concentrated to give (5-cyclobutyl-1H-pyrazol-3-yl)-(4-nitro-phenyl)-amine (216 mg, 88%) as a tan solid. Rf 0.36 (30% acetone/hexane); 1H NMR (400 MHz, CDCl3) δ 1.84-2.22 (m, 4H), 2.38-2.42 (m, 2H), 3.50 (dddd, J=8.7, 8.7 , 8.2, 8.2 Hz, 1H), 5.91 (s, 1H), 7.16 (d, J=7.1 Hz, 2H), 8.12 (d, J=7.1Hz, 2H), LRMS m/z (APCI+) 259.3 (M+1).

Example 2.

(5-Cyclobutyl-2H-pyrazol-3-yl)-naphthalen-2-yl-amine

The title compound is prepared in accordance with the procedure for Example 1, using analogous reactants.

1HNMR (400 MHz, CDCl3), δ 1.75-1.98 (m, 2H), 2.04-2.19 (m, 2H), 2.20-2.28 (m, 2H), 3, 26 (dddd, J=8.7, 8.7, 8.3, 8.3 Hz, 1H), 5.96 (s, 1H), 7.18 (dd, J=9.1, 8.7 Hz, 1H), 7.31 (d, J=7.8 Hz, 1H), 7.37 (d, J=7.9 Hz, 1H), 7.53 (s, 1H), 7.61- 7.71 (m, 3H), LRMS m/z (APCI+) 264 (M+1).

Example 3.

(5-Cyclobutyl-2H-pyrazol-3-yl)-naphthalen-1-yl-amine

The title compound is prepared in accordance with the procedure for Example 1, using analogous reactants.

Rf 0.35 (50% EtOAc/hexane), 1H NMR (400 MHz, CDCl 3 ) δ 1.75-1.98 (m, 2H), 2.04-2.19 (m, 2H), 2.20 -2.28 (m, 2H), 3.36-3.44 (dddd, J=8.7, 8.7, 8.7, 8.7 Hz, 1H), 5.92 (s, 1H) , 7.31-7.44 (m, 5H), 7.80 (d, J=8.31 Hz, 1H), 8.98 (d, J=8.72 Hz, 1H), LRMS m/z (APCI+) 264 (M+1).

Example 4.

N-(5-Cyclobutyl-2H-pyrazol-3-yl)-N',N'-dimethyl-naphthalene-1,4-diamine

The title compound is prepared in accordance with the procedure for Example 1, using analogous reactants.

1HNMR (400 MHz, CDCl3), δ 1.73-1.90 (m, 2H), 2.09-2.28 (m, 4H), 2.85 (s, 6H), 3.37 (dddd, J=8.7, 8.7, 8.3, 8.3 Hz, 1H), 5.81 (s, 1H), 7.02 (d, J=8.3 Hz, 1H), 7.36 (d, J=7.8 Hz, 1H), 7.40 (dd, J=6.6, 6.6 Hz, 1H), 7.51 (dd, J=4.8, 4.8 Hz, 1H), 8.04 (d, J=8.3 Hz, 1H), 8.30 (d, J=8.3 Hz, 1H), 13C NMR (100 MHz, CDCl3), δ 153.4, 150 ,2, 145.5, 135.1, 129.9, 127.7, 128.6, 124.7, 122.1, 114.7, 113.4, 91.5, 45.8, 32.3 , 29.5, 18.9, LRMS m/z (APCl+) 307.3 (M+1).

Example 5.

(3-Benzyloxy-phenyl)-(5-cyclobutyl-2H-pyrazol-3-yl)-amine

The title compound is prepared in accordance with the procedure for Example 1, using analogous reactants.

1HNMR (400 MHz, CDCl3), δ 1.82-2.00 (m, 2H), 2.09-2.20 (m, 2H), 2.24-2.32 (m, 2H), 3, 41 (dddd, J=8.7, 8.7, 8.3, 8.3 Hz, 1H), 5.01 (s, 2H), 5.88 (s, 1H), 6.47 (bs, 1H), 6.50 (dd, J=7.5, 1.6 Hz, 1H), 6.67 (dd, J=9.5, 1.6 Hz, 1H), 6.81 (dd, J =2.0, 2.0 Hz, 1H), 7.14 (dd, J=7.9, 8.3 Hz, 1H), 7.31-7.43 (m, 5H), LRMS m/ z (APCl+) 320.4 (M+1).

Example 6.

(4-Chloro-benzyl)-(5-cyclobutyl-2H-pyrazol-3-yl)-amine

The title compound is prepared in accordance with the procedure for Example 1, using analogous reactants.

1HNMR (400 MHz, CDCl3), δ 1.85-2.15 (m, 4H), 2.26-2.32 (m, 2H), 3.39 (dddd, J=8, 7, 8.7 , 8.3, 8.3 Hz, 1H), 4.29 (s, 2H), 5.41 (s, 1H), 5.80 (bs, 2H), 7.26 (7.31 (m, 4H), LRMS m/z (APCI+) 262.3 (M+1).

Example 7.

(3-Bromo-phenyl)-(5-cyclobutyl-2H-pyrazol-3-yl)-amine

The title compound is prepared in accordance with the procedure for Example 1, using analogous reactants.

1HNMR (400 MHz, CDCl3), δ 1.82-1.99 (m, 2H), 2.06-2.17 (m, 2H), 2.21-2.29 (m, 2H), 3, 39 (dddd, J=8.8, 8.8, 8.8, 8.8 Hz, 1H), 5.86 (s, 1H), 6.78 (bs, 1H), 6.98-6, 92 (m, 2H), 7.04 (dd, J=7.9, 7.8 Hz, 1H), 7.24 (s, 1H), 9.80 (bs, 1H), LRMS m/z ( APCI+ 292.3, 294.2 (M+1).

Example 8.

[5-(1,4-Dioxa-spiro[4.4]non-7-yl)-1H-pyrazol-3-yl]-(3-trifluoromethyl-phenyl)-amine

The title compound is prepared in accordance with the procedure for Example 1, using analogous reactants.

1HNMR (400 MHz, CDCl3), δ 1.72-2.16 (m, 5H), 2.25 (ddd, J=13.7, 8.7, 0 Hz, 1H), 3.26 (dddd, J=8.3, 8.2, 8.2, 7.8 Hz, 1H), 3.91-3.97 (m, 4H), 5.83 (s, 1H), 6.71 (bs, 1H), 7.06-7.32 (m, 4H), 9.0 (bs, 1H), LRMS m/z (APCI+) 354.1 (M+1).

Example 9.

(2-Chloro-4-nitro-phenyl)-(5-cyclobutyl-2H-pyrazol-3-yl)-amine

The title compound is prepared in accordance with the procedure for Example 1, using analogous reactants.

Rf 0.35 (30% EtOAc/hexane), 1H NMR (400 MHz, CDCl 3 ), δ 1.90-2.23 (m, 4H), 2.36-2.44 (m, 2H), 3, 48-3.57 (dddd, J=8.3, 8.3, 8.3, 8.3 Hz, 1H), 5.96 (s, 1H), 7.72-7.76 (d, 1H ), 8.05-8.08 (d, 1H), 8.26 (s, 1H), LRMS m/z (APCI+) 293 (M+1).

Example 10.

(3,5-Bis-trifluoromethyl-phenyl)-(5-cyclobutyl-2H-pyrazol-3-yl)-amine

The title compound is prepared in accordance with the procedure for Example 1, using analogous reactants.

Rf 0.35 (30% EtOAc/hexane), 1H NMR (400 MHz, CDCl 3 ), δ 1.80-2.21 (m, 4H), 2.31-2.40 (m, 2H), 3, 47-3.51 (dddd, J=8.7, 8.7, 8.7, 8.7 Hz, 1H), 5.83 (s, 1H), 7.26 (s, 1H), 7, 56 (s, 1H), 7.56 (s, 1H), LRMS m/z (APCI+) 350 (M+1).

Example 11.

4-(5-Cyclobutyl-2H-pyrazol-3-ylamino)-benzonitrile

The title compound is prepared in accordance with the procedure for Example 1, using analogous reactants.

Rf 0.38 (50% EtOAc/hexane), 1H NMR (400 MHz, CD3OD), δ 1.88-2.11 (m, 2H), 2.15-2.25 (m, 2H), 2, 32-2.40 (m, 2H), 3.49-3.57 (dddd, J=8.3, 8.3, 8.3, 8.3 Hz, 1H), 5.85 (s, 1H ), 7.22-7.25 (dd, J=2.5 Hz, 2H), 7.46-7.49 (dd, J=2.5 Hz, 2H), LRMS m/z (APCI+) 239 (M+1).

Example 12.

(5-Cyclobutyl-2H-pyrazol-3-yl)-(3-fluoro-phenyl)-amine

The title compound is prepared in accordance with the procedure for Example 1, using analogous reactants.

Rf 0.30 (50% EtOAc/hexane), 1H NMR (500 MHz, CDCl 3 ), δ 1.86-2.04 (m, 2H), 2.12-2.19 (m, 2H), 2, 30-2.36 (m, 2H), 3.43-3.49 (dddd, J=8.8, 8.8, 8.8, 8.8 Hz, 1H), 5.89 (s, 1H ), 6.53-6.57 (m, 1H), 6.80-6.82 (m, 1H), 6.91-6.94 (m, 1H), 7.14-7.19 (m , 1H), LRMS m/z (APCl+) 232 (M+1).

Example 13.

(2-Bromo-phenyl)-(5-cyclobutyl-2H-pyrazol-3-yl)-amine

The title compound is prepared in accordance with the procedure for Example 1, using analogous reactants.

Rf 0.33 (30% EtOAc/hexane), 1 HNMR (400 MHz, CDCl 3 ), δ 1.90-2.12 (m, 2H), 2.13-2.22 (m, 2H), 2.33 -2.41 (m, 2H), 3.44-3.51 (dddd, J=8.3, 8.3, 8.3, 8.3 Hz, 1H), 5.90 (s, 1H) , 6.69-6.73 (dd, J=6.6, 6.6 Hz, 1H), 7.18-7.22 (dd, J=5.8, 5.8 Hz, 1H), 7 .47-7.49 (d, 1H), 7.598-7.59 (d, 1H), LRMS m/z (APCI+) 292 (M+1).

Example 14.

(5-Cyclobutyl-2H-pyrazol-3-yl)-(3,5-dichloro-phenyl)-amine

The title compound is prepared in accordance with the procedure for Example 1, using analogous reactants.

Rf 0.50 (50% EtOAc/hexane), 1H NMR (CDCl3), δ 1.86-2.07 (m, 2H), 2.09-2.19 (m, 2H), 2.29-2 .38 (m, 2H), 3.42-3.50 (dddd, J=8.5, 8.5, 8.5, 8.5 Hz, 1H), 5.84 (s, 1H), 6 .80 (s, 1H), 6.98 (s, 1H), 6.98 (s, 1H), LRMS m/z (APCl+) 282 (M+1).

Preparation 1.1.

2-Cyano-3-cyclobutyl-3-oxo-ethyl ester of propionic acid

Ethyl cyanoacetate (21.5 g, 0.19 mmol) was added to anhydrous MgCl2 (22.3 g, 0.19 mmol) in 320 mL of CH3CN at 0°C. After 15 min, Et3N (52.0 mL, 38.0 g, 0.37 mmol) was added via syringe. The reaction was allowed to stir for an additional 15 min and then cyclobutane carbonyl chloride (21.0 mL 22.3 g, 0.19 mmol) was added over a period of 5 min. The reaction is allowed to slowly warm to room temperature for 20 hours. The reaction is then cooled to 0°C, quenched with aqueous 0.5 M HCl, and then diluted with 150 mL of Et2O. The aqueous layer was extracted with Et2O (3x150 mL) and the combined organic layers were washed with 150 mL saturated sodium chloride solution, dried over MgSO4, filtered and concentrated to give a yellow-orange oil. This material was purified by vacuum distillation (95-105°C, 2-3 mm) to give the title compound in quantitative yield as a colorless oil.

1H NMR (400 MHz, CDCl3), δ 1.32-1.36 (t, 3H), 1.88-2.09 (m, 2H), 2.21-2.28 (m, 2H), 2 ,32-2.43 (m, 2H), 3.64-3.69 (dddd, J=8.5, 8.5, 8.5, 8.5 Hz, 1H), 4.28-4, 34 (q, 2H), 13.81 (s, 1H).

Preparation 2.1.

Ethyl ester of 2-cyano-3-oxo-pentanoic acid

The title compound is prepared in accordance with the procedure for Preparation 1.1, using analogous reactants.

1H NMR (400 MHz, CDCl3), δ 1.23-1.27 (t, 3H), 1.34-1.37 (t, 3H), 2.61-2.66 (q, 2H), 4 .30-4.35 (q, 2H), 13.70 (s, 1H), LRMS m/z (APCI-) 168 (M-1).

Preparation 1.2.

3-Cyclobutyl-3-oxo-propionitrile

2 mL of H2O is added to a solution of 2-cyano-3-cyclobutyl-3-oxo-ethyl ester of propionic acid (Preparation 1.1) in 40 mL of DMSO, and then the reaction is heated to 118°C. After 35 min, the reaction is cooled in an ice bath and then terminated with saturated NaCI solution. This reaction mixture is then diluted with H2O and CH2Cl2 and the layers are separated. The aqueous layer is extracted with CH2Cl2. The combined organic layers were dried over MgSO 4 , filtered and concentrated under reduced pressure to give the title compound of Preparation 1.2 as a yellow oil. This material is used without further purification.

1H NMR (400 MHz, CDCl3), δ 1.83-2.17 (m, 2H), 2.19-2.30 (m, 2H), 2.31-2.55 (m, 2H), 3 .39 (s, 2H), 3.39-3.43 (dddd, J=8.5, 8.5, 8.5, 8.5 Hz, 1H), LRMS m/z (APCI-) 122 ( M-1).

Preparation 1.3.

5-Cyclobutyl-2-(4-methoxy-benzyl)-2H-pyrazol-3-ylamine

4-Methoxy-benzyl-hydrazine (12.6 g, 82.9 mmol) was added to the crude 3-cyclobutyl-3-oxo-propionitrile prepared above in 515 mL of EtOH, the reaction was heated under reflux (in an oil bath at 85 °C). After 2 hours, the reaction was cooled to room temperature and concentrated under reduced pressure to obtain a viscous oil. Purification of this material is carried out by MPLC technique using a Biotage Flash 45S elution system with a gradient of 10% and 20% EtOAc/hexane. Fractions containing the product were pooled and concentrated under reduced pressure to afford the title compound (10.2 g, 77% yield over 2 steps) as a colorless solid.

Rf 0.3 (40% EtOAc/hexane), 1H NMR (400 MHz, CDCl3), δ 1.85-2.00 (m, 2H), 2.12-2.20 (m, 2H), 2, 25-2.31 (m, 2H), 3.41-3.46 (dddd, J=8.1, 8.1, 8.1, 8.1 Hz, 1H), 3.76 (s, 3H ), 5.07 (s, 2H), 5.46 (s, 1H), 6.82-6.84 (d, J=6.64 Hz, 2H), 7.07-7.09 (d, J=6.64 Hz, 2H), LRMS m/z (APCI+) 258 (M+1).

Preparation 2.3.

5-Ethyl-2-(4-methoxy-benzyl)-2H-pyrazol-3-ylamine

The title compound is prepared according to the procedure for Preparation 1.3, using Preparation 2.1 instead of Preparation 1.1.

Rf 0.4 (50% EtOAc/hexane, 1H NMR (400 MHz, CDCl 3 ), δ 1.16-1.20 (t, 3H), 2.49-2.55 (q, 2H), 3.74 (s, 3H), 5.05 (s, 2H), 5.36 (s, 1H), 6.80-6.82 (d, 2H), 7.06-7.08 (d, 2H), LRMS m/z (APCI+) 232 (M+1).

Preparation 1.4.

[5-Cyclobutyl-2-(4-methoxy-benzyl)-2H-pyrazol-3-yl]-(6-methoxy-pyridin-2-yl)-amine

Procedure A: A dried solution of 5-Cyclobutyl-2-(4-methoxy-benzyl)-2H-pyrazol-3-ylamine (Preparation 1.3, 2.27 g, 8.83 mmol), 2-chloro-6-methoxy pyridine ( 1.06 g, 7.36 mmol), sodium tert-butoxide (1.09 g, 10.3 mmol), 2-(dicyclohexylphosphino)-biphenyl (258 mg, 0.736 mmol) and palladium acetate (165 mg, 0.736 mmol) in toluene is heated at 120°C for one hour and then cooled to room temperature. The reaction mixture was then filtered through a pad of Celite and the filtrate was concentrated and chromatographed using a Biotage Flash 45S eluting system with 20% EtOAc/hexane to give the title compound of Preparation 1.4 as a peach solid (2 g, 74% yield).

Rf 0.25 (20% EtOAc/hexane), 1H NMR (400 MHz, CDCl 3 ), δ 1.82-2.00 (m, 2H), 2.11-2.34 (m, 4H), 3, 45-3.66 (dddd, J=8.7, 8.7, 8.7, 8.7 Hz, 1H), 3.71 (s, 3H), 3.80 (s, 3H), 5, 10 (s, 2H), 6.01-6.03 (d, 1H), 6.07 (s, 1H), 6.14-6.16 (d, 1H), 6.75-6.78 ( d, J=6.65 Hz, 2H), 7.03-7.06 (d, J=8.72 Hz, 2H), 7.29-7.33 (apt, 1 H), LRMS m/z (APCI+) 365 (M+1).

Procedure B. Cesium carbonate (296 mg, 0.454 mmol) was flame-dried in a reaction flask and 3.9 ml of dried toluene was added followed by 200 mg (0.778 mmol) of 5-cyclobutyl-2-(4-methoxy-benzyl)- 2H-pyrazol-3-ylamine (Preparation 1.3). The final mixture was stirred at room temperature for 10 min, and then 2-chloro-6-methoxy pyridine (93.2 mg, 0.648 mmol), 2-(dicyclohexylphosphino)-biphenyl (11.7 mg, 0.0334 mmol) was added. and palladium acetate (3.6 mg, 0.0162 mmol). The mixture is left overnight under reflux under a stream of nitrogen until the reaction is complete. Filtration through Celite, concentration of the filtrate, and chromatography as in Procedure A gave the title compound of Preparation 1.4 (120 mg, 51% yield) as a solid.

Procedure C. To a dried solution (1.95 mol) of 5-Cyclobutyl-2-(4-methoxybenzyl)-2H-pyrazol-3-ylamine (Preparation 1.3, 100 mg, 0.389 mmol) in toluene is added a 1.0 M solution of potassium of t-butoxide (628 μl, 0.628 mmol) at room temperature. After 5 minutes of stirring, 3-bromo-anisole (60 mg, 0.324 mmol), 2-(dicyclohexylphosphino)-biphenyl (23 mg, 0.065 mmol) and palladium acetate (7.5 mg, 0.032 mmol) were added and the reaction was heated. at 105°C for 6 hours, after which the reaction was completed. The reaction mixture was cooled to room temperature, filtered through Celite, and chromatographed as in Procedure A to give the title compound of Preparation 1.4 (72mg, 61% yield) as a viscous gum.

Rf 0.30 (30% EtOAc/hexane), 1 HNMR (400 MHz, CDCl 3 ), δ 1.86-2.04 (m, 2H), 2.12-2.19 (m, 2H), 2.30 -2.36 (m, 2H), 3.54 (dddd, J=8, 8, 8.8, 8.8, 8.8 Hz, 1H), 3.73 (s, 3H), 3.77 (s, 3H), 5.12 (s, 2H), 5.98 (s, 1H), 6.29 (d, J=10.7 Hz, 1H), 6.32-6.35 (m, 1H), 6.40-6.43 (m, 1H), 6.82 (d, J-6.6 Hz, 2H), 7.10 (d, J=8.3 Hz, 2H), 7, 25 (s, 1H), LRMS m/z (APCI+) 364.2 (M+1).

Preparation 2.4.

[5-Ethyl-2-(4-methoxy-benzyl)-2H-pyrazol-3-yl]-(6-methoxy-pyridin-2-yl)-amine

The title compound is prepared according to the procedure for Preparation 1.4, using Preparation 2.3 instead of Preparation 1.3.

Rf 0.28 (25% EtOAc/hexane), 1H NMR (400 MHz, CDCl 3 ), δ 1.22-1.26 (t, 3H), 2.60- 2.66 (q, 2H), 3, 74 (s, 3H), 3.82 (s, 3H), 5.12 (s, 2H), 6.01-6.02 (d, 1H), 6.04 (s, 1H), 6.16 -6.18 (d, 1H), 6.79-6.81 (d, J=6.64 Hz, 2H), 7.07-7.09 (d, J=6.64 Hz, 2H), 7.32-7.36 (apt, 1H), LRMS m/z (APCI+) 339 (M+1).

Example 15.

(5-Cyclobutyl-2H-pyrazol-3-yl)-(3-methoxy-phenyl)-amine

Undiluted trifluoroacetic acid (2 .0 mL) and heat the reaction to 70°C. After 48 hours, the reaction is cooled to room temperature and concentrated under reduced pressure. Purification of this material is carried out by the MPLC technique using the Biotage Flash elution system with 40% EtOAc/hexane. Fractions containing the product were pooled and concentrated to give the title compound (30 mg, 37% yield).

Rf 0.35 (75% EtOAc/hexane), 1H NMR (400 MHz, CDCl3), δ 1.80-2.03 (m, 2H), 2.12-2.17 (m, 2H), 2 ,29-2.33 (m, 2H), 3.40-3.48 (dddd, J=8, 3, 8.3, 8.3, 8.3 Hz, 1H), 3.77 (s, 3H), 5.88 (s, 1H), 6.41-6.43 (d, J=10.4 Hz, 1H), 6.65-6.68 (m, 1H), 6.71-6 .72 (m, 1H), 7.11-7.15 (apt, 1H), LRMS m/z (APCI+) 244 (M+1).

Example 16.

(5-Cyclobutyl-2H-pyrazol-3-yl)-(6-trifluoromethyl-pyridin-2-yl)-amine

The title compound is prepared in accordance with the procedure for Example 15, using analogous reactants.

Rf0, 50 (10% MeOH/CH2Cl2), 1H NMR (400 MHz, CD3OD), δ 1.86-2.19 (m, 2H), 2.21-2.32 (m, 2H), 2.32 -2.39 (m, 2H), 3.51-3.57 (dddd, J=8.7, 8.7, 8.7, 8.7 Hz, 1H), 6.15 (s, 1H) , 7.10 (d, J=9.13 Hz, 1H), 7.73-7.76 (d, J=8.72 Hz, 1H), 8.38 (s, 1H), LRMS m/z (APCI+) 283 (M+1).

Example 17.

(5-Cyclobutyl-2H-pyrazol-3-yl)-(3-trifluoromethyl-phenyl)-amine

The title compound is prepared in accordance with the procedure for Example 15, using analogous reactants.

Rf 0.30 (40% EtOAc/hexane), 1H NMR (400 MHz, CDCl 3 ), δ 1.92-2.26 (m, 4H), 2.38-2.46 (m, 2H), 3, 50-3.58 (dddd, J=8.3, 8.3, 8.3, 8.3 Hz, 1H), 6.01 (s, 1H), 7.31-7.47 (m, 4H ), LRMS m/z (APCl+) 282 (M+1).

Example 18.

N-(5-Cyclobutyl-2H-pyrazol-3-yl)-N',N'-dimethyl-benzene-1,3-diamine

The title compound is prepared in accordance with the procedure for Example 15, using analogous reactants.

Rf 0.50 (5% MeOH/CH2Cl2), 1H NMR (400 Mz, CDCl3), δ 1.91-2.18 (m, 2H), 2.20-2.30 (m, 2H), 2.35-2.43 (m, 2H). 3.11 (s, 6H), 3.48-3.56 (dddd, J=8.3, 8.3, 8.3, 8.3 Hz, 1H), 6.13 (bs, 1H), 6.84-6.95 (m, 2H), 7.13-7.28 (m, 2H) ), 7.31-7.35 (apt, 1H). LRMS m/z (APCl+) 257 (M+1).

Example 19.

(5-Cyclobutyl-2H-pyrazol-3-yl)-quinolin-2-yl-amine

The title compound is prepared in accordance with the procedure for Example 15, using analogous reactants.

Rf 0.35 (70% EtOAc/hexane), 1H NMR (400 MHz, CD3OD), δ 1.92-2.20 (m, 2H), 2.22-2.28 (m, 2H), 2, 41-2.45 (m, 2H), 3.60-3.66 (dddd, J=8.3, 8.3, 8.3, 8.3 Hz, 1H), 6.08 (s, 1H ), 7.26-7.28 (d, J=9.54 Hz, 1H), 7.60-7.64 (m, 1H), 7.87-7.88 (m, 2H), 7, 89-8.00 (d, J=7.46 Hz, 1H), 8.49-8.51 (d, 1H), LRMS m/z (APCl+) 265 (M+1).

Example 20.

(6-Chloro-pyridin-2-yl)-(5-cyclobutyl-2H-pyrazol-3-yl)-amine

The title compound is prepared in accordance with the procedure for Example 15, using analogous reactants.

Rf 0.40 (75% EtOAc/hexane), 1H NMR (400 MHz, CD3OD), δ 1.98-2.21 (m, 2H), 2.24-2.34 (m, 2H), 2, 42-2.49 (m, 2H), 3.62-3.68 (dddd, J=8.8, 8.8, 8.8, 8.8 Hz, 1H), 6.18 (s, 1H ), 6.87-6.89 (d, J=8, 29 Hz, 1H), 7.05-7.07 (d, J=7.47 Hz, 1H), 7.72-7.76 ( apt, 1H), LRMS m/z (APCl+) 249 (M+1).

Example 21.

(5-Cyclobutyl-2H-pyrazol-3-yl)-(6-methoxy-4-methyl-quinolin-2-yl)-amine

The title compound is prepared in accordance with the procedure for Example 15, using analogous reactants.

Rf 0.35 (75% EtOAc/hexane), 1H NMR (400 MHz, CD3OD), δ 1.90-2.18 (m, 2H), 2.19-2.30 (m, 2H), 2, 37-2.47 (m, 2H), 2.78 (s, 3H), 3.60-3.68 (dddd, J=8.7, 8.7, 8.7, 8.7 Hz, 1H ), 3.97 (s, 3H), 6.02 (s, 1H), 7.10 (s, 1H), 7.45 (s, 1H), 7.46 (d, 1H), 7.78 -7.80 (d, 1H), LRMS m/z (APCI+) 309 (M+1).

Example 22.

(5-Cyclobutyl-2H-pyrazol-3-yl)-(3-trifluoromethoxy-phenyl)-amine

The title compound is prepared in accordance with the procedure for Example 15, using analogous reactants.

Rf 0.15 (30% EtOAc/hexane), 1H NMR (400 MHz, CDCl3), δ 1.88-2.07 (m, 2H), 2.10-2.20 (m, 2H), 2, 30-2.38 (m, 2H), 3.42-3.51 (dddd, J=8.3, 8.3, 8.3, 8.3 Hz, 1H), 5.84 (s, 1H ), 6.68-6.70 (d, 1H), 6.99-7.19 (m, 2H), 7.21-7.24 (apt, 1H), LRMS m/z (APCI+) 298 ( M+1).

Example 23.

N-(5-Cyclobutyl-2H-pyrazol-3-yl)-N',N'-dimethyl-pyridin-2, 6-diamine

The title compound is prepared according to the procedure for Example 15, using analogous reactants.

Rf 0.50 (5% MeOH/CH2Cl2), 1H NMR (400 MHz, CDCl3), δ 1.82-2.01 (m, 2H), 2.11-2.21 (m, 2H), 2, 26-2.33 (m, 2H), 3.06 (s, 6H), 3.42-3.48 (dddd, J=8.7, 8.7, 8.7, 8.7 Hz, 1H ), 5.83 (s, 1H), 5.93 (d, J=8.31 Hz, 1H), 6.09 (d, J=7.89 Hz, 1H), 7.29-7.33 (1H, apt), LRMS m/z (APCl+) 258 (M+1).

Example 24.

(5-Ethyl-2H-pyrazol-3-yl)-(6-methoxy-pyridin-2-yl)-amine

The title compound is prepared according to the procedure for Example 15, using analogous reactants.

Rf 0.20 (50% EtOAc/hexane), 1H NMR (400 MHz, CDCl 3 ), δ 1.20-1.28 (m, 3H), 2.60-2.68 (m, 2H), 3, 90-(s, 3H), 6.25-6.27 (d, 1H), 6.45-6.47 (d, 1H), 6.54 (s, 1H), 7.42-7.46 (apt, 1H), LRMS m/z (APCl+) 219 (M+1).

Example 25.

(5-Cyclobutyl-2H-pyrazol-3-yl)-(6-methoxy-pyridin-2-yl)-amine

The title compound is prepared according to the procedure for Example 15, using analogous reactants.

Rf 0.30 (50% EtOAc/hexane), 1H NMR (400 MHz, CDCl 3 ), δ 1.87-2.23 (m, 4H), 2.33-2.41 (m, 2H), 3, 46-3.55 (dddd, J=8.3, 8.3, 8.3, 8.3 Hz, 1H), 3.93 (s, 3H), 6.26-6.28 (d, 1H ), 6.46-6.47 (d, 1H), 6.57 (s, 1H), 7.43-7.47 (apt, 1H), LRMS m/z (APCI+) 245 (M+1) .

Preparation 3.1.

1,4-Dioxa-spiro 4,4]non-7-yl)-ethanone

A solution of methyl magnesium bromide (5.4 mL, 16, 3 mmol, 3.0 M in THF) and then copper (I) bromide (23 mg, 0.16 mmol). The reaction is heated to 65°C. After 20 hours, the reaction is cooled to room temperature and then to 0°C (ice/water bath) and the reaction is stopped with saturated NH4CI solution. The mixture is diluted with methylene chloride (100 mL) and the layers are separated. The aqueous layer was extracted with methylene chloride (100 mL) and the combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. Purification by vacuum distillation (120°C, 2 mm) afforded the title compound (1.39 g, 51% yield) as a clear, colorless oil.

1HNMR (400 MHz, CDCl3), δ 1.79-2.08 (m, 6H), 2.15 (s, 3H), 2.99 (dddd, J=8.3 Hz, 1H), 3, 87-3.94 (m, 4H), LRMS m/z (APCI+) 171 (M+1).

Preparation 3.2.

3-(1,4-Dioxa-spiro[4.4]non-7-yl)-3-oxo-N-(3-trifluoromethyl-phenyl)-thiopropionamide

To a solution of LiHMDS (3.2 mL, 3.2 mmol 1 M in THF) in 20 mL of THF, which is stirred at -78°C (acetone/CO2), a previously cooled solution (-78° C) 1-(1,4-Dioxa-spiro[4.4]non-7-yl)-ethanone (Preparation 3.1, 500 mg, 2.94 mmol in 5 mL of THF). After 30 minutes, 1-isothiocyanato-3-trifluoromethyl-benzene (988 μL, 1.3 g, 6.5 mmol) was added via syringe. The final reaction mixture was slowly warmed to room temperature overnight. The reaction was quenched with NaHCO3 dissolved in EtOAc and the layers separated. Purification of this material is carried out by the MPLC technique using the Biotage Flash 45S elution system with 20% EtOAc/toluene, and then by another MPLC method using the Biotage Flash 45S elution system with 20% acetone/hexane. Fractions containing the product were pooled and concentrated to give the title compound (598 mg, 55% yield) as a yellow viscous gum.

Rf 0.3 (25% acetone/hexane), 1HNMR (400 MHz, CDCl3), δ 1.84-1.87 (m, 2H), 1.95-2.20 (m, 2H), 2.64 -2.70 (m, 1H), 3.28-3.32 (m, 1H), 3.89-4.05 (m, 4H), 3.92 (s, 2H), 7.50-7 .54 (m, 2H), 7.93-7.97 (m, 1H), 8.13-8.15 (m, 1H), LRMS m/z (APCl+) 374 (M+1).

Preparation 3.3.

[5-(1,4-Dioxa-spiro[4.4]non-7-yl)-2-(4-methoxy-benzyl)-2H-pyrazol-3-yl]-(3-trifluoromethyl-phenyl)-amine

In a solution of 3-(1,4-Dioxa-spiro[4.4]non-7-yl)-3-oxo-N-(3-trifluoromethyl-phenyl)-thiopropionamide (Preparation 3.1, 785 mg, 2.1 mmol) in To 21 mL of stirred EtOH was added acetic acid (2.1 mL) followed by 4-methoxy-benzyl-hydrazine (480 mg, 3.2 mmol) and the final mixture was heated to 75°C. After 1 hour, the reaction is cooled to room temperature and quenched with H2O, diluted with EtOAc and the layers are separated. A few drops of concentrated ammonium hydroxide were added to the aqueous layer and then extracted with EtOAc. The combined organic layers are dried over MgSO4, filtered and concentrated under reduced pressure. Purification of the material is carried out by the MPLC technique using a Biotage Flash 45S elution system with 40% EtOAc/hexane. Fractions containing the product were pooled and concentrated under reduced pressure to afford the title compound (788 mg, 79% yield) as a yellow viscous gum.

Rf 0.3 (50% EtOAc/hexane), 1 HNMR (400 MHz, CDCl 3 ), δ 1.78-2.08 (m, 4H), 2.16-2.20 (m, 1H), 2.31 -2.38 (m, 1H), 3.30 (dddd, J=7.9, 9.5, 8.3, 8.7 Hz, 1H), 3.77 (s, 3H), 3.85 -4.00 (m, 4H), 5.14 (s, 2H), 5.95 (s, 1H), 6.81-6.90 (m, 3H), 7.07-7.11 (m , 3H), 7.26-7.29 (m, 2H), LRMS m/z (APCI+) 474 (M+1).

Preparation 3.4.

3-(4-Methoxy-benzyl)-5-(3-trifluoromethyl-phenylamino)-1H-pyrazol-3-yl]-cyclopentanone

In solution [5-(1,4-Dioxa-spiro[4.4]non-7-yl)-2-(4-methoxy-benzyl)-2H-pyrazol-3-yl]-(3-trifluoromethyl-phenyl)- amine (Preparation 3.3, 679 mg, 1.4 mmol) in 14 mL of acetone which is being stirred, 700 μL of H2O is added followed by a catalytic amount of p-toluenesulfonic acid, monohydrate (27.3 mg, 0.14 mmol). The reaction mixture is then heated to 65°C. After 1 hour, the reaction is cooled to room temperature and quenched with H2O, diluted with EtOAc and the layers are separated. The organic layer was dried over MgSO 4 , filtered and concentrated under reduced pressure to give the title compound (617 mg, quantitative yield) as a yellow viscous oil. This material is used without further purification.

Rf 0.28 (50% EtOAc/hexane), 1 HNMR (400 MHz, CDCl 3 ), δ 2.02-2.14 (m, 1H), δ 20-2.30 (m, 1H), 2.36- 2.50 (m, 3H), 2.58-2.63 (m, 1H), 3.45 (dddd, J=6.2, 6.2, 6.2, 6.2 Hz, 1H), 3.76 (s, 3H), 5.11 (s, 2H), 5.94 (s, 1H), 6.79-6.88 (m, 4H), 7.04-7.10 (m, 3H), 7.25-7.29 (m, 1H), LRMS m/z (APCl+) 430 (M+1).

Example 26.

3-Trans-[5-(3-trifluoromethyl-phenylamino)-2H-pyrazol-3-yl]-cyclopentanone

The title compound is prepared according to the procedure for Preparation 3.4, using hydrazine instead of 4-methoxy-benzyl-hydrazine (see synthesis of Preparation 3.3, above).

1HNMR (400 MHz, CDCl3), δ 1.94-1.99 (m, 1H), 2.20-2.48 (m, 4H), 2.62 (ddd, J=18.2, 7.9 , 0 Hz, 1H), 3.38 (dddd, J=9.5, 9.5, 7.5, 6.6 Hz, 1H), 5.85 (s, 1H), 7.09 (d, J=7.4 Hz, 1H), 7.20 (d, J=8.3 Hz, 1 H), 7.26-7.33 (m, 2H), LRMS m/z (APCl+) 310.3 (M+1).

Preparation 3.5.

{2-(4-Methoxy-benzyl)-5-[3-(4-methoxy-benzylamino)-cyclopentyl]-2H-pyrazol-3-yl}(3-trifluoromethyl-phenyl)-amine

To a suspension of 3-[1-(4-Methoxy-benzyl)-5-(3-trifluoromethyl-phenylamino)-1H-pyrazol-3-yl]-cyclopentanone (Preparation 3.4, 3.3 g, 7.6 mmol) in To 76 mL of stirring toluene was added powdered 4 Å MS (16.1 g), followed by 4-methoxybenzyl amine (2.0 g, 15.3 mmol). The final mixture is heated to 110°C overnight. After 12 hours, the reaction was cooled to room temperature and Na(OAc)3BH (3.2 g, 15.3 mmol) was added and stirred for an additional hour before 4 Å MS was filtered off and the final solution was concentrated under reduced pressure. Purification of the material is carried out by the MPLC technique using a Biotage Flash 75S elution system with a gradient of 5% to 8% MeOH/CH2CI2 containing 0.1% NH4OH. Fractions containing the product were pooled and concentrated under reduced pressure to give the title compound (3.9 g, 92% yield) as a yellow viscous oil and a 3:1 mixture of diastereomers.

Rf 0.28 (8% MeOH/CH 2 Cl 2 ), 3:2 cis, trans isomer ratio observed in 1 HNMR spectrum obtained in CD 3 OD, LRMS m/z (APCI+) 551 (M+1).

Examples 27 and 28.

Isomers [5-(3-Benzylamino-cyclopentyl)-1H-pyrazol-3-yl]-(3-trifluoromethyl-phenyl)-amine

The racemate consisting of the cis:trans isomer [5-(3-Benzylamino-cyclopentyl)-1H-pyrazol-3-yl]-(3-trifluoromethyl-phenyl)-amine is prepared according to the procedure for Preparation 3.5, using Example 26 instead of Preparation 3.4. The cis:trans isomers (Examples 27 and 28) were isolated from the mixture by MPLC technique using a Biotage flash 755 elution system with a gradient of 5% to 8% MeOH/CH 2 Cl 2 containing 0.1% NH 4 OH.

Example 27.

1HNMR (400 MHz, CD3COCD3), δ 1.65-1.79 (m, 1H), 1.81-2.07 (m, 4H), 2.25 (m, 1H), 2.50 (dddd, J=7.1, 7.1, 7.1, 7.1 Hz, 1H), 3.24 (dddd, J=2.1, 2.1, 2.1, 2.1 Hz, 1H), 3.80 (s, 2H), 5.70 (s, 1H), 7.01 (d, J=4.3 Hz, 1H), 7.22-7.55 (m, 5H), 7.56 (d, J=2.1 Hz, 1H), 7.98 (s, 1H), 8.01 (s, 1H), LRMS m/z (APCI+) 401.3 (M+1).

Example 28.

1HNMR (400 MHz, CD3COCD3), δ 1.57-1.84 (m, 2H), 1.85-1.99 (m, 1H), 2.04-2.23 (m, 3H), 3, 34-3.42 (m, 2H), 3.80 (s, 2H), 5.70 (s, 1H), 7.00 (d, J=7.9 Hz, 1H), 7.20-7 .55 (m, 5H), 7.56 (d, J=2.0 Hz, 1 H), 7.98 (s, 1H), 8.00 (s, 1H), LRMS m/z (APCI+) 401.3 (M+1).

Example 29.

{5-[cis-3-(4-Methoxy-benzylamino)-cyclopentyl]-1H-pyrazol-3-yl}(3-trifluoromethyl-phenyl)-amine

The title compound is prepared in accordance with preparation procedure 3.5, using the title compound from Example 26 instead of the title compound from Preparation 3.4.

1HNMR (400 MHz, CD3OD), δ 1.47-1.56 (m, 1H), 1.60-1.69 (m, 1H), 1.90-1.97 (m, 2H), 2, 10-2.18 (m, 2H), 3.28-3.31 (m, 2H), 3.67 (s, 2H), 3.75 (s, 3H), 5.72 (s, 1H) , 6.86 (d, J=6.6 Hz, 2H), 6.97 (d, J=7.0 Hz, 1H), 7.25 (d, J=8.7 Hz, 2H), 7 .31-7.35 (m, 2H), 7.48 (s, 1H), LRMS m/z (APCl+) 431.3 (M+1).

Preparation 3.6.

N-(4-Methoxy-benzyl)-N-{3-[1-(4-methoxy-benzyl)-5-(3-trifluoromethyl-phenylamino)-1H-pyrazol-3-yl]-cyclopentyl}-acetamide

In a solution of {2-(4-Methoxy-benzyl)-5-3-(4-methoxy-benzylamino)-cyclopentyl]-2H-pyrazol-3-yl}(3-trifluoromethyl-phenyl)-amine (Preparation 3.5, 109 mg, 0.198 mmol) in 0.5 mL of stirring pyridine, acetic anhydride (94 μL, 0.99 mmol) was added. After 30 min, determine whether the reaction is complete by TLC analysis. The reaction mixture was concentrated under reduced pressure to give N-(4-Methoxy-benzyl)-N-{3-[1-(4-methoxy-benzyl)-5-(3-trifluoromethyl-phenylamino)-1H-pyrazole- 3-yl]-cyclopentyl}-acetamide as a 1:1 ratio of cis, trans isomers determined by 1HNMR, and in foam form. This material is used without further purification.

Rf 0.75 (5% MeOH/CH2Cl2); LRMS m/z (APCI+) 593 (M+1).

Analytical separation of the four isomers of the title compound can be carried out using the following conditions: Column: Chiralcel OD, 5 cm x 10 cm. Mobile phase: 95/5 heptane/EtOH containing 0.025% DEA as modifier. Flow: 75 mL/min. The sample is diluted with a solution of 1: 1 methylene chloride/mobile phase. The retention times of each of the four isomers are 30 min, 37 min, 45 min and 60 min.

Example 30.

N-{cis-3-5-(3-Trifluoromethyl-phenylamino)-2H-pyrazol-3-yl]-cyclopentyl}-acetamide

N-(4-Methoxy-benzyl)-N-{3-[1-(4-methoxy-benzyl)-5-(3-trifluoromethylphenylamino)-1H-pyrazol-3-yl]-cyclopentyl}-acetamide (Preparation 3.6 , 0.20 mmol 140 mg) 2 mL of TFA is added and the reaction is heated to 76°C. After 72 hours, the reaction is cooled to room temperature and concentrated under reduced pressure. Purification of the material is carried out by the MPLC technique using 10 g of filler ISCO in the column with elution with 5% MeOH/CH2CI2. Fractions containing the product were pooled and concentrated to give the title compound (60 mg, 86% yield over two steps).

Rf 0.30 (55 MeOH/CH 2 Cl 2 ); 1HNMR (400 MHz, CD3COCD3), δ 1.55-1.59 (m, 1H), 1.66-1.74 (m, 1H), 1.83 (s, 3H), 1.97-2, 03 (m, 2H), 2.09-2, 20 (m, 2H), 3.32 (dddd, J=8.3, 8.3, 8.3, 8.3 Hz, 1H), 4, 33 (dddd, J=12.9, 7.0, 7.0, 7.0 Hz, 1H), 5.71 (s, 1H), 7.01 (d, J=7.9 Hz, 1H) , 7.16 (bs, 1H), 7.36 (dd, J=7.9, 7.9 Hz, 1H), 7.55 (d, J=8.3 Hz, 1H), 7.99 ( bs, 1H), 8.01 (bs, 1H), LRMS m/z (APCl + ) 353.2 (M+1).

Example 31.

Pyridine-2-carboxylic acid {3-[5-(3-trifluoromethyl-phenylamino)2H-pyrazol-3-yl]-cyclopentyl}-amide

The title compound is prepared according to the procedure of Example 30, using analogous reactants.

Rf 0.33 (5% MeOH/CH2Cl2), 1:1 cis, trans isomer ratio observed in 1HNMR spectrum obtained in CD3OD. LRMS m/z (APCl+) 416 (M+1) melting point 180.1°C (HCl salt)

Example 32.

Pyridine-2-carboxylic acid {3-[5-(3-trifluoromethyl-phenylamino)-2H-pyrazol-3-yl]-cyclopentyl}-amide

The title compound is prepared in accordance with the procedure from Example 30, using analogous reactants.

Rf 0.28 (5% MeOH/CH2Cl2), 1:1 cis, trans isomer ratio observed in 1HNMR spectrum obtained in CD3OD, LRMS m/z (APCl+) 483 (M+1), mp 162.5°C ( HCI salt)

Example 33.

Cyclobutanecarboxylic acid (3-[5-(3-trifluoromethyl-phenylamino)-2H-pyrazol-3-yl]-cyclopentyl}-amide

The title compound is prepared according to the procedure of Example 30, using analogous reactants.

Rf 0.25 (5% MeOH/CH2Cl2), ratio 1:1 cis, trans isomer observed in 1HNMR spectrum obtained in CD3OD, LRMS m/z (APCl+) 393 (M+1), mp 232.4°C ( HCI salt)

Example 34.

2,2-Dimethyl-N-{3-[5-(3-trifluoromethyl-phenylamino)-2H-pyrazol-3yl]-cyclopentyl}-propionamide

The title compound is prepared according to the procedure of Example 30, using analogous reactants.

Rf 0.23 (5% MeOH/CH2Cl2), 1:1 cis, trans isomer ratio observed in 1HNMR spectrum obtained in CD3OD, LRMS m/z (APCl+) 395 (M+1), mp 249.2°C ( HCI salt)

Example 35.

4-Fluoro-N-{3-[5-(3-trifluoromethyl-phenylamino)-2H-pyrazol-3-yl]cyclopentyl}-benzamide

The title compound is prepared according to the procedure of Example 30, using analogous reactants.

Rf 0.30 (5% MeOH/CH 2 Cl 2 ), 1:1 cis, trans isomer ratio observed in 1 HNMR spectrum obtained in CD 3 OD, LRMS m/z (APCl+) 433 (M+1); melting point (dec) does not have a specific melting point.

Example 36.

2,2,2-Trifluoro-N-3-[5-(3-trifluoromethyl-phenylamino)-2H-pyrazol3-yl]-cyclopentyl}-acetamide

The title compound is prepared according to the procedure of Example 30, using analogous reactants.

Rf 0.30 (5% MeOH/CH2Cl2), 3:2 cis, trans isomer ratio observed in 1 HNMR spectrum obtained in CDCl3, LRMS m/z (APCl+) 407 (M+1).

Example 37.

Cyclopropanecarboxylic acid {3-[5-(3-trifluoromethyl-phenylamino)-2H-pyrazol-3-yl]-cyclopentyl}-amide

The title compound is prepared according to the procedure of Example 30, using analogous reactants.

Rf 0.28 (8% MeOH/CH2Cl2), 3:2 cis, trans isomer ratio observed in 1HNMR spectrum obtained in CDCl3. LRMS m/z (APCl+) 379 (M+1).

Example 38.

N-(3-[5-(3-Trifluoromethyl-phenylamino)-2H-pyrazol-3-yl]-cyclopentyl}-propionamide

The title compound is prepared according to the procedure of Example 30, using analogous reactants.

Rf 0.30 (8% MeOH/CH2Cl2), 3:2 ratio of cis, trans isomers observed in 1HNMR obtained in CDCl3. LRMS m/z (APCl+) 367 (M+1).

Example 39

Cyclohexanecarboxylic acid {3-[5-(3-trifluoromethyl-phenylamino)-2H-pyrazol-3-yl]-cyclopentyl}-amide

The title compound is prepared according to the procedure of Example 30, using analogous reactants.

Rf 0.25 (8% MeOH/CH2Cl2), 3:2 cis, trans isomer ratio observed in 1 HNMR spectrum obtained in CDCl3. LRMS m/z (APCI+) 421 (M+1).

Preparation 4.1.

(1,4-Dioxa-spiro[4.4]non-7-yl)-oxo-acetonitrile

nBuLi (3.4 mL, 8.6 mmol, 2.5 M in hexane) was added to 9 mL of THF at -78°C. After equilibration of the reaction temperature (~15 min), acetonitrile (449 μL, 359 mg, 8.6 mmol) was added dropwise. The reaction mixture was allowed to stir for 1 hour before a solution of 1,4-Dioxa-spiro[4.4]nonane-7-methyl ester carboxylic acid (723 mg, 4.3 mmol) was added to the side of the flask. After 1 hour, the reaction is heated to ~45°C (acetonitrile/CO2) and left to stir for 2 hours. The reaction is stopped with cooling by dropwise addition of 2 N HCl (~4.3 mL), pH=7 and then diluted with Et2O. The layers were separated and the organic layer was dried over MgSO4, filtered and concentrated under reduced pressure to give the title compound as a brown oil which crystallized without further purification.

Rf 0.19 (50% EtOAc/hexane); LRMS m/z (APCI+) 196 (M+1).

Preparation 4.2.

5-(1,4-Dioxa-spiro[4.4]non-7-yl)-2-(4-methoxy-benzyl)-2H-pyrazol-3-ylamine

4-Methoxy-benzyl-hydrazine (0.60 g, 4.0 mmol), and the reaction mixture was heated to 65°C. After 2 and a half hours, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. Purification of the material is performed by MPLC technique using a Biotage Flash 40L elution system with a gradient of 50% to 100% EtOAc/hexane, collecting 18 mm fractions. Fractions containing the product were pooled and concentrated under reduced pressure to afford the title compound (0.83 g, 75% yield over two steps).

Rf 0.13 (50% EtOAc/hexane); 1HNMR (400 MHz, CDCl3), δ 2.10-1.72 (m, 5H), 2.23 (dd, J = 13.3, 7.9 Hz, 1H), 3.15 (dddd, J= 7.9, 7.9, 2.5, 2.5 Hz, 1H), 3.39 (br s, 2H), 3.73 (s, 3H), 3.91-3.84 (m, 4H ), 5.03 (s, 2H), 5.34 (s, 1 H), 6.80 (d, J=8.7 Hz, 2H), 7.04 (d, J=8.6 Hz, 2H); 13C NMR (100 Mz, CDCl3) δ 31.4, 36.4, 37.2, 43.1, 51.2, 55.5, 64.3, 64.5, 89.0, 114.4, 117 .9, 128.3, 129.1, 145.2 155.0, 159.3; LRMS m/z (APCI+) 330 (M+1).

Preparation 4.3.

N-[5-(1,4-Dioxa-spiro[4.4]non-7-yl)-2-(4-methoxy-benzyl)-2H-pyrazol-3-yl]-2-naphthalen-1-yl- acetamide

In a solution of 5-(1,4-Dioxa-spiro[4.4]non-7-yl)-2-(4-methoxy-benzyl)-2H-pyrazol-3-ylamine (Preparation 4.2, 0.83 g, 2, 5 mmol) in CH2CI2 (5 mL) which is being stirred, a freshly prepared solution of naphthalen-1-yl-acetyl chloride (1.03 g, 5.0 mmol in CH2CI2) is added and then 1 mL of pyridine is added. After 2 hours, the reaction is stopped with H2O, and 2 mL of NH4OH solution (15%) is added. The mixture is diluted with CH2Cl2 and the layers are separated. The organic layer is dried over MgSO4, filtered and concentrated under reduced pressure. Purification of the material is carried out by the MPLC technique using a Biotage Flash 40L elution system with a gradient of 25% to 50% acetone/hexane, with the collection of 18 mm fractions. Fractions containing the product were pooled and concentrated under reduced pressure to give the title compound (1.2 g, 97% yield) as a light yellow solid.

melting point 162.8°C; 1HNMR (400 MHz, CDCl3), δ 2.09-173 (m, 5H), 2.21 (dd, J=13.3, 7.9 Hz, 1H), 3.18 (dddd, J =7, 5, 5.0 Hz, 1H), 3.68 (s, 3H), 3.89-3.81 (m, 4H), 3.98 (s, 2H), 4.60 (s, 2H), 6.22 (s, 1 H), 6.36 (d, J=8.7 Hz, 2H), 6.51 (d, J=8.7 Hz, 2H), 7.03 (br s, 1 H), 7.23 (d, J=6.7 Hz, 1H), 7.39 (dd, J=7.1, 7.1 Hz, IH), 7.53-7.45 (m, 2H ), 7.88-7.83 (m, 2H), 7.89 (d, J=1.7 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 31.2, 36.4, 37.2, 42.0, 42.9, 51.9, 55.4, 64.3, 64.5, 97.2, 114 ,2, 117.8, 123.7, 125.9, 126.7, 127.4, 127.7, 127.9, 128.7, 129.1, 129.32, 130.2, 132.1 , 134.2, 135.3, 154.9, 159.2, 168.6; LRMS m/z (APCI+) 498 (M+1).

Preparation 4.4.

N-[2-(4-Methoxy-benzyl)-5-(3-oxo-cyclopentyl)-2H-pyrazol-3-yl]-2-naphthalen-1-yl-acetamide

The title compound is synthesized according to the procedure for Preparation 3.4, using as reactant the title compound from Preparation 4.3 instead of the title compound from Preparation 3.3.

1HNMR (400 MHz, CDCl3), δ 1.99-2.18 (m, 1H), 2.21-2.28 (m, 1H), 2.35-2.45 (m, 3H), 2, 53-2.62 (m, 1H), 3.43 (dddd, J=9.5, 6.2, 7.9, 9.5 Hz, 1H), 3.75 (s, 3H), 4, 12 (s, 2H), 4.62 (s, 2H), 6.30 (s, 1H), 6.33 (d, J=9.5 Hz, 1H), 6.55 (d, J=8 .7 Hz, 1H), 7.31-7.33 (m, 1H), 7.45-7.48 (m, 1H), 7.56-7.60 (m, 2H), 7.89 -7.97 (m, 3H), LRMS m/z (APCI+) 454 (M+1).

Preparation 4.5.

N-{2-(4-Methoxy-benzyl)-5-[3-(4-methoxy-benzylamino)-cyclopentyl]-2H-pyrazol-3-yl}-2-naphthalen-1-yl-acetamide

The title compound is prepared according to the procedure for Preparation 3.5, using the title compound from Preparation 4.4 as the reactant instead of the title compound from Preparation 3.4.

Rf 0.25 (8% MeOH/CH2Cl2) (minor), Rf 0.20 (8% MeOH/CH2Cl2) (major), 3:2 cis, trans isomer ratio observed in 1HNMR spectrum obtained in CDCl3. LRMS m/z (APCI+) 575 (M+1).

Preparation 4.6.

N-[5-{3-[Acetyl-(4-methoxy-benzyl)-amino]-cyclopentyl}-2-(4-methoxy-benzyl)-2H-pyrazol-3-yl]-2-naphthalen-1-yl- acetamide

The title compound is synthesized according to the procedure of Preparation 3.6, using as reactant the title compound of Preparation 4.5 instead of the title compound of Preparation 3.5.

Rf 0.30 (80% EtOAc/Toluene), Rf 0.25 (80% EtOAc/Toluene), 1:1 cis, trans isomer ratio observed in 1 HNMR spectrum obtained in CDCl 3 .

Separation of enantiomers of isomers with Rf 0.25 is carried out using the following conditions: Column: Chiralcel OD, 5 cm x 50 cm. Mobile phase: 60/40 heptane/EtOH containing 0.025% DEA as modifier. Flow: 50 mL/min. The sample is diluted with methanol. The retention times of the two enantiomers are 35 min and 45 min. LRMS m/z (APCl+) 617 (M+1).

Preparation 5.1.

Cyclobutanecarboxylic acid (4-methoxy-benzyl)-3-[5-(3-trifluoromethyl-phenylamino)-2H-pyrazol-3-yl]-cyclopentyl}-amide

The title compound is prepared according to the procedure for Preparation 4.6, using analogous reactants.

Rf 0.45 (5% MeOH/CH2Cl2), 1:1 cis, trans isomer ratio observed in 1 HNMR spectrum obtained in CDCl3. LRMS m/z (APCl+) 633 (M+1).

Example 40.

N-[5-(3-Acetylamino-cyclopentyl)-2H-pyrazol-3-yl]-2-naphthalen-1-yl-acetamide

The title compound is synthesized by the procedure of Example 30, using as reactant the compound from Preparation 4.6 instead of Preparation 3.6.

Rf 0.30 (8% MeOH/CH 2 Cl 2 ). a 1:1 ratio of cis, trans isomers observed in the 1HNMR spectrum obtained in CD3OD. LRMS m/z (APCI+) 377 (M+1).

Example 41.

Cyclopropanecarboxylic acid {3-[5-(2-naphthalen-1-yl-acetylamino)-1H-pyrazol-3-yl]-cyclopentyl}-amide

The title compound was synthesized by the same procedure as in Example 30, using analogous reactants.

Rf 0.30 (5% MeOH/CH 2 Cl 2 ). a 1:1 ratio of cis, trans isomers observed in the 1HNMR spectrum obtained in CDCl3. LRMS m/z (APCl+) 403 (M+1).

Example 42.

2-Naphthalen-1-yl-N-{5-[3-(2,2,2-trifluoro-acetylamino)-cyclopentyl]-2H-pyrazol-3-yl}-acetamide

The title compound is synthesized by the procedure of Example 30, using analogous reactants.

Rf 0.30 (5% MeOH/CH 2 Cl 2 ). a 1:1 ratio of cis, trans isomers observed in the 1HNMR spectrum obtained in CD3OD. LRMS m/z (APCI+) 431 (M+1).

Example 43.

N-{3-[5-(2-Naphthalen-1-yl-acetylamino)-1H-pyrazol-3-yl]-cyclopentyl}-benzamide

The title compound is synthesized by the procedure of Example 30, using analogous reactants.

Rf 0.30 (5% MeOH/CH 2 Cl 2 ). a 1:1 ratio of cis, trans isomers observed in the 1HNMR spectrum obtained in CDCl3. LRMS m/z (APCI+) 439 (M+1).

The following title compounds of Examples 44-57 are synthesized by preparing an intermediate analogous to the title compound of Preparation 4.6, using the steps described in "Preparation 4.2" through "Preparation 4.5". In each case, the reactant naphthalen-1-yl acetal chloride, used in the synthesis of the title compound in Preparation 4.3, is used. This intermediate is then treated according to the procedure described for the synthesis of the title compound from Example 30:

Example 44.

3-Methoxy-N-(cis-3-[5-(2-naphthalen-1-yl-acetylamino)-2H-pyrazol-3-yl]-cyclobutyl}-benzamide

Rf 0.33 (10% MeOH/CH 2 Cl 2 ); melting point 124.8°C (mono HCl salt); 1HNMR (400 MHz, CD3OD), δ 2.20 (dd, J=10.2 Hz, 2H), 2.72-2.66 (m, 2H), 3.14 (apt quint, J=8.8 Hz, 1H); 3.75 (s, 3H), 4.12 (s, 2H), 4.40 (apt quint, 8.4 Hz, 1H), 6.31 (s, 1H), 7.03-7.00 ( m, 1H), 7.28 (dd, J=7.8 Hz, 1H), 7.46-7.35 (m, 6H), 7.74 (d, J=7.9 Hz, 1H), 7.81 (d, J=7.0 Hz, 1H), 8.01 (d, J=7.4 Hz, 1H); 13C NMR (100 MHz, CD3OD) δ 170.6, 168.1, 160.0, 149.0, 146.0, 135.5, 134.2, 132.4, 131.3, 129.4, 128 ,6, 128.1, 127.9, 126.2, 125.7, 125.4, 123.7, 119.3, 117.3, 112.5, 93.8, 54.7, 41.5 , 40.2, 36.9, 24.8; LRMS m/z (APCI+) 455.1 (M+1).

Example 45.

N-{cis-3-[5-(2-Naphthalen-1-yl-acetylamino)-2H-pyrazol-3-yl]-cyclobutyl}-trifluoromethyl-benzamide

Rf 0.56 (10% MeOH/CH 2 Cl 2 ); melting point 142.8°C (mono HCl salt); 1HNMR (400 MHz, CD3OD), δ 2.22 (dd, J=9.5, 9.5 Hz, 2H), 2.73 (dd, J=7.4, 7.4 Hz, 2H), 3 .18 (apt quint, J=7.9 Hz, 1H), 4.14 (s, 2H), 4.46 (apt quint, J=7.5 Hz, 1H), 6.40 (s, 1H) , 7.48-4.37 (m, 4H), 7.83 (d, J=4.9 Hz, 1H), 8.03 (s, 1H), 8.05 (s, 1H), 8, 13 (s, 1H); 13C NMR (100 MHz, CD3OD) δ 170.5, 166.4, 148.7, 146.5, 135.2, 134.2, 132.5, 131.5, 130.9, 130.5, 129 ,3, 128.5, 128.0, 127.8, 126.2, 125.6, 125.4, 124.1, 124.0, 123.7, 94.0, 41.6, 40.3 , 36.9, 24.9; LRMS m/z (APCI+) 493.0 (M+1).

Example 46.

N-{cis-3-[5-(2-Naphthalen-1-yl-acetylamino)-2H-pyrazol-3-yl]-cyclobutyl}-isobutyramide

Rf 0.43 (10% MeOH/CH2Cl2 with 0.1% NH4OH in water); melting point 130.6°C (mono HCl salt); 1HNMR (400 MHz, d6 DMSO), δ 0.93 (s, 3H), 0.95 (s, 3H), 1.92 (dd, J=9.9, 9.9 Hz, 2H), 2, 24 (apt fifth, J=6.8 Hz, 1H), 2.54,-2.48 (m, 2H), 3.01 (apt fifth, J=8.3 Hz, 1H), 4.08 ( s, 2H), 4.15-4.08 (m, 1H), 6.32 (s, 1H), 7.54-7.43 (m, 4H), 7.81 (d, J=7, 4 Hz, 1H), 7.94-7.89 (m, 2H), 8.13 (d, J=7.9 Hz, 1H); 13C NMR (100 MHz, d6 DMSO) δ 175.7, 168.7, 147.7, 134.0, 132.6, 129.0, 128.5, 127.8, 126.7, 126.3, 126.2, 125.0, 94.0, 39.6, 38.2, 34.6, 24.5, 20.2; LRMS m/z (APCl+) 391 (M+1).

Example 47.

{cis-3-[5-(2-naphthalen-1-yl-acetylamino)-2H-pyrazol-3-yl]-cyclobutyl}-amide 2-phenyl-cyclopropanecarboxylic acid

Rf 0.56 (10% MeOH/CH2Cl2 with 0.1% NH4OH in water); melting point 139.8°C (mono HCl salt); 1HNMR (400 MHz, d6 DMSO), δ 1.17-1.14 (m, 1H), 1.32-1.28 (m, 1H), 1.75-1.70 (m, 1H), 1 .97-1.89 (dd, J=10.4, 10.4, 2H), 2.20-2.16 (m, 1H), 2.55-2.49 (m, 2H), 3, 02 (apt quint, J=8.2 Hz, 1H), 4.07 (s, 2H), 4.17 (m, 1H), 6.30 (s, 1H), 7.23-7.07 ( m, 5H), 7.54-7.42 (m, 4H), 7.80 (d, J=7.9 Hz, 1 H), 7.90 (d, J=7.9 Hz, 1 H ), 8.12 (d, J=7.8 Hz, 1H), 8.37 (d, J=7.8 Hz, 1H); 13C NMR (100 MHz, d6 DMSO) δ 172.9, 170.8, 152.5, 142.8, 140.8, 134.2, 132.4, 130.3, 129.0, 128.6, 128.3, 126.3, 126.1, 125.9, 125.8, 125.4, 123.6, 92.9, 41.1, 36.5, 25.5, 24.8, 24, 2, 15.1; LRMS m/z (APCl+) 465.0 (M+1).

Example 48.

N-{5-(cis-3-Acetylamino-cyclobutyl)-1H-pyrazol-3-yl]-2-naphthalen-1-yl-acetamide

Rf 0.50 (10% MeOH/CH2Cl2), 1HNMR (400 MHz, CD3OD), δ 1.86 (s, 3H), 1.97-2.05 (m, 2H), 2.59-2.66 (m, 2H), 3.07 (apt quint, J=8.0 Hz, 1H), 4.13 (s, 2H), 4.20 (apt quint, J=7.8 Hz, 1H), 6 .25 (s, 1H), 7.37-7.48 (m, 4H), 7.77 (d, J=7.9 Hz, 1H), 7.81-7.85 (m, 1H), 8.01-8.03 (m, 1H), 13C-NMR: 21.37, 24.64, 37.09, 40.20, 40.78, 93.59, 93.65, 123.71, 125 ,41, 125.70, 126.22, 127.88, 128.04, 128.58, 131.36, 132.45, 134.18, 146.36, 148.68, 170.53, 171.31 ,), MS LRMS m/z (APCl+) 363 (M+1), mp 209.4°C (HCl salt).

Example 49.

N-{cis-3-[5-(2-Naphthalen-1-yl-acetylamino)-2H-pyrazol-3-yl]-cyclobutyl}-benzamide

Rf 0.50 (10% MeOH/CH2Cl2), 1HNMR (400 MHz, CD3OD), δ 2.20-2.30 (m, 2H), 2.70-2.80 (m, 2H), 3.20 (apt fifth, J=8.0 Hz, 1H), 4.18 (s, 2H), 4.48 (apt fifth, J=7.8 Hz, 1H), 6.24 (bs, 1H), 7 ,38-7.50 (m, 7H), 7.75-7.88 (m, 4H), 8.00-8.05 (m, 1H), 13C-NMR: 24.68, 36.92, 40.12, 41.47, 93.54, 123.68, 125.39, 125.72, 126.25, 127.20, 127.96, 128.12, 128.35, 128.59, 131, 17, 131.56, 132.44, 134.20, 145.86, 149.19, 168.39, 170.60, MS LRMS m/z (APCl+) 425 (M+1), mp 194.0 °C (HCl salt).

Example 50.

2-Cyclopropyl-N-{cis-3-[5-(2-naphthalen-1-yl-acetylamino)-2H-pyrazol-3-yl]-cyclobutyl}-acetamide

Rf 0.60 (10% MeOH/CH2Cl2), 1HNMR (400 MHz, CD3OD), δ 0.93 (t, J=7.5 Hz, 2H), 1.34 (d, J=6.2 Hz, 1H), 1.65 (d, J=5.0 Hz, 1H), 1.70-1.78 (m, 2H), 2.01-2.15 (m, 2H), 2.55-2 .58 (m, 1H), 2.62-2.68 (m, 2H), 3.20 (apt quint, J=7.8 Hz, 1H), 4.20 (s, 2H), 5.40 (apt quint, J=6.2 Hz, 1H), 6.22 (bs, 1H), 7.40-7.56 (m, 4H), 7.78-7.88 (m, 2H), 8 .02-8.08 (m, 1H), 13C NMR: 8.27, 24.52, 26.64, 36.63, 36.85, 36.96, 39.47, 40.12, 40.77 , 77.66, 93.27, 112.50, 123.67, 125.38, 125.73, 126.24, 127.95, 128.14, 128.59, 132.45, 134.21, 146 .71, 169.62, 170.63, MS LRMS m/z (APCl+) 403 (M+1), mp 93.2°C (HCl salt).

Example 51.

6-Chloro-pyridine-2-carboxylic acid {cis-3-[5-(2-naphthalen-1-yl-acetylamino)-2H-pyrazol-3-yl]-cyclobutyl}-amide

Rf 0.50 (10% MeOH/CH2Cl2), 1HNMR (400 MHz, CD3OD), δ 2.25-2.42 (m, 2H), 2.76-2.82 (m, 2H), 3.30 (apt quint, J=7.9 Hz, 1 H), 4.22 (s, 2H), 4.54 (apt quint, J=7.5 Hz, 1H), 6.35 (s, 1H), 7.42-7.64 (m, 5H), 7.81-7.89 (m, 2H), 7.93-8.11 (m, 3H), 13C-NMR: 24.58, 36.65 , 40.17, 41.06, 77.50, 93.77, 121.03, 122.58, 123.67, 123.82, 124.50, 125.40, 125.72, 126.24, 127 .37, 128.01, 128.11, 128.59, 134.20, 140.63, 140.70, 144.41, 150.36, 170.70, 182.15, MS LRMS m/z (APCI+ ) 460 (M+1), mp (dec) (HCl salt).

Example 52.

Quinoline-2-carboxylic acid {cis-3-[5-(2-naphthalen-1-yl-acetylamino)-2H-pyrazol-3-yl]-cyclobutyl}-amide

Rf 0.30 (5% MeOH/CH2Cl2), 1HNMR (400 MHz, CD3OD), δ 2.25-2.38 (m, 2H), 2.76-2.78 (m, 2H), 3.25 (apt fifth, J=8.3 Hz, 1H), 4.16 (s, 2H), 4.56 (apt fifth, 8.7 Hz, 1H), 6.36 (bs, 1H), 7.38 -7.49 (m, 4H), 7.60-7.64 (m, 1H), 7.71-7.99 (m, 4H), 8.02-8.13 (m, 3H), 8 ,36 (d, J=8.7 Hz, 1H), 13C-NMR: 24.80, 37.08, 40.22, 41.08, 53.50, 94.03, 118.41, 123.70 , 124.50, 125.39, 125.70, 126.22, 127.25, 127.82, 128.15, 128.57, 129.42, 129.54, 130.34, 132.43, 134 ,18, 137.70, 137.80, 146.02, 146.73, 148.93, 149.60, 164.89, 170.57, MS LRMS m/z (APCl+) 476 (M+1), melting point 200.3°C (HCl salt).

Example 53.

Pyrazine-2-carboxylic acid {cis-3-[5-(2-naphthalen-1-yl-acetylamino)-2H-pyrazol-3-yl]-cyclobutyl}-amide

Rf 0.30 (5% MeOH/CH2Cl2), 1HNMR (400 MHz, CD3OD), δ 2.25-2.38 (m, 2H), 2.75-2.84 (m, 2H), 3.26 (apt quint, J=8.7 Hz, 1H), 4.21 (s, 2H), 4.55 (apt quint, J=8.7 Hz, 1H), 6.28 (s, 1H), 7 .42-7.54 (m, 4H), 7.81-7.89 (m, 2H), 8.03-8.07 (m, 1H), 8.66 (d, J=2.5 Hz , 1H), 8.75 (d, J=2.5 Hz, 1H), 9.20 (s, 1H), MS LRMS m/z (APCI+) 427 (M+1).

Example 54.

4-Methoxy-N-{cis-3-[5-(2-naphthalen-1-yl-acetylamino)-2H-pyrazol-3-yl]-cyclobutyl}-benzamide

Rf 0.35 (5% MeOH/CH2Cl2), 1HNMR (400 MHz, CD3OD), δ 2.17-2.25 (m, 2H), 2.68-2.75 (m, 2H), 3.18 (apt fifth, J=8.3 Hz, 1H), 3.79 (s, 3H), 4.15 (s, 2H), 4.44 (apt fifth, J=7.8 Hz, 1H), 6 .33 (s, 1H), 6.91 (d, J=5.0 Hz, 2H), 7.37-7.49 (m, 4H), 7.77 (d, J=5.0 Hz, 2H), 7.82-7.84 (m, 1H), 7.96-8.04 (m, 2H), 13C-NMR: 24.80, 37.02, 40.22, 41.46, 54 .71, 54.76, 93.90, 113.50, 123.72, 125.41, 125.70, 126.22, 127.24, 127.88, 128.08, 128.58, 129.09 , 131.36, 132.44, 134.17, 142.17, 146.03, 146.21, 149.14, 162.76, 167.93, 170.56, MS LRMS m/z (APCl+) 455 (M+1), melting point 175.6°C (HCl salt).

Example 55.

N-{cis-3-[5-(2-Naphthalen-1-yl-acetylamino)-2H-pyrazol-3-yl]-cyclobutyl}-3-nitro-benzamide

Rf 0.35 (5% MeOH/CH2Cl2), 1HNMR (400 MHz, CD3OD), δ 2.26-2.34 (m, 2H), 2.74-2.79 (m, 2H), 3.25 (apt fifth, J=8.7 Hz, 1H), 4.19 (bs, 2H), 4.50 (apt fifth, J=8.3 Hz, 1H), 6.31 (bs, 1H), 7 .37-7.49 (m, 4H), 7.63-7.80 (m, 3H), 8.19-8.33 (m, 2H), 8.58-8.65 (m, 2H) , 13C NMR: 24.82, 36.80, 40.10, 41.73, 93.87, 115.43, 118.34, 122.22, 122.28, 123.81, 125.87, 126, 27, 127.38, 127.87, 128.56, 129.81, 131.39, 132.40, 133.22, 134.06, 135.89, 141.96, 142.04, 146.50, 161.89, 165.60, MS LRMS m/z (APCl+) 470 (M+1), mp 123.5°C (HCl salt).

Example 56.

3,5-Dimethoxy-N-{cis-3-[5-(2-naphthalen-1-yl-acetylamino)-2H-pyrazol-3-yl]-cyclobutyl}-benzamide

Rf 0.50 (10% MeOH/CH2Cl2), 1HNMR (400 MHz, CD3OD), δ 2.23-2.30 (, 2H), 2.73-2.79 (m, 2H), 3.23 ( apt fifth, J=8.3 Hz, 1H), 3.78 (s, 6H), 4.19 (bs, 2H), 4.47 (apt fifth, J=8.3 Hz, 1H), 6, 30 (bs, 1H), 6.62 (s, 1H), 6.97 (s, 2H), 7.41-7.52 (m, 4H), 7.85 (m, 2H), 8.03 -8.08 (m, 1H), MS LRMS m/z (APCI+) 485 (M+1)

Example 57.

4-Dimethylamino-N-{cis-3-[5-(2-naphthalen-1-yl-acetylamino)-2H-pyrazol-3-yl]-cyclobutyl}-benzamide

Rf 0.45 (10% MeOH/CH2Cl2), 1HNMR (400 MHz, CD3OD), δ 2.18-2.28 (m, 2H), 2.70-2.80 (m, 2H), 2.99 (s, 6H), 3.20 (apt quint, J=8.2 Hz, 1H), 4.18 (bs, 2H), 4.46 (apt quint, J=8.3 Hz, 1H), 6 .31 (bs, 1H), 6.69 (d, J=8.7 Hz, 2H), 7.42-7.53 (m, 4H), 7.71 (d, J=9.1 Hz, 2H), 7.80-7.88 (m, 2H), 8.06 (d, J=8.3 Hz, 1H), MS LRMS m/z (APCI+) 485 (M+1).

Example 58.

N-[5-((1S)-Hydroxy-ethyl)-2H-pyrazol-3-yl]-2-naphthalen-1-yl-acetamide

The synthesis of the title compound is carried out by the procedure for the title compound from Preparation 4.3, using a reactant analogous to naphthalen-1-yl-acetyl chloride. This is followed by the removal of the protective group. The final intermediate is treated according to the procedure for Example 30.

Rf 0.50 (10% MeOH/CH2Cl2), 1HNMR (400 MHz, CDCl3), δ 1.64 (d, J=6.6 Hz, 3H), 4.12 (s, 2H), 5.97 ( dd, J=6.6, 6.6 Hz, 1 H), 6.47 (s, 1H), 7.34-7.40 (m, 2H), 7.42-7.50 (m, 2H ), 7.74-7.87 (m, 3H), LRMS m/z (APCl+) 296 (M+1); melting point 101.3°C (HCl salt).

Example 59.

N-[5-(2-Hydroxy-(1S)-methyl-ethyl)-2H-pyrazol-3-yl]-2-naphthalen-1-yl-acetamide

The synthesis of the title compound is carried out by the procedure for the title compound from Preparation 4.3, using a reactant analogous to naphthalen-1-yl-acetyl chloride. This is followed by the removal of the protective group. The final intermediate is treated according to the procedure for Example 30.

1HNMR (400 MHz, CD3OD), δ 1.25 (d, J=7.1 Hz, 3H), 2.92-3.01 (m, 1H), 3.58-3.62 (m, 2H) , 4.20 (bs, 2H), 6.22 (bs, 1H), 7.40-7.58 (m, 4H), 7.80 (d, J=7.0 Hz, 1H), 7, 88 (d, J=7.1 Hz, 1H), 8.06 (d, J=7.0 Hz, 1H), LRMS m/z (APCl+) 310 (M+1), mp 117.6° C (HCl salt).

Preparation 6.1.

N-[5-[1-(Benzothiazol-2-yloxy)-ethyl]-2-(4-methoxy-benzyl)-2H-pyrazol-3-yl]-2-naphthalen-1-yl-acetamide

In a solution of N-[5-(1-Hydroxy-ethyl)-2-(4-methoxy-benzyl)-2H-pyrazol-3-yl]2-naphthalen-1-yl-acetamide (300 mg, 0.72 mmol ) in 7.2 mL of stirring THF was added 2-chlorobenzthiozole (104 μL, 0.79 mmol, 135 mg) followed by a solution of KOBut (1.4 mL, 1.4 mmol, 1.0 M in THF) drop by drop. After 2 the reaction is quenched with NH4Cl and then diluted with EtOAc. The layers are separated and the organic layer is dried with MgSO4, filtered and concentrated under reduced pressure. Purification of the material is carried out by the MPLC technique using a cartridge with 10 g of ISCO on a Biotage elution system with 30% EtOAc/hexane, with the collection of 8 mm fractions. Fractions containing the product were pooled and concentrated under reduced pressure to give the title compound (100 mg, 25% yield) as a yellow viscous oil.

Rf 0.50 (50% EtOAc/hexane), 1 HNMR (400 MHz, CDCl 3 ), δ 1.82 (d, J=7.5 Hz, 3H), 3.74 (s, 3H), 4.06 ( d, J=4.6 Hz, 2H), 4.65 (dd, J=15.8, 15.8 Hz, 2H), 6.02 (dd, J=7.1, 7.1 Hz, 1 H), 6.27 (s, 1H), 6.29 (d, J=8.7 Hz, 2H), 6.51 (d, J=8.7 Hz, 2H), 6.99-7, 06 (m, 3H), 7.27-7.29 (m, 1H), 7.30-7.38 (m, 1H), 7.40-7.43 (m, 1H), 7.50- 7.60 (m, 2H), 7.87-7.95 (m, 3H), LRMS m/z (APCI+) 549 (M+1).

Example 60.

N-[5-[(1S)-(Benzothiazol-2-yloxy)-ethyl]-1H-pyrazol-3-yl}-2-naphthalen-1-yl-acetamide

The title compound is synthesized using Preparation 6.1 according to the procedure for Example 15.

Rf 0.41 (5% MeOH/CH2Cl2), 1HNMR (400 MHz, CDCl3), δ 1.81 (d, J=7.1 Hz, 3H), 4.17 (s, 2H), 5.84 ( dd, 6.7, 6.7 Hz, 1H), 6.68 (s, 1H), 6.85 (d, J=7.9 Hz, 1H), 7.10-7.20 (m, 2H ), 7.32-7.57 (m, 5H), 7.79-7.86 (m, 2H), 7.97-7.99 (m, 1H), LRMS m/z (APCl+) 429 ( M+1).

Example 61.

N-[5-(Benzothiazol-2-yloxymethyl)-1H-pyrazol-3-yl]-2-naphthalen-1-yl-acetamide

The title compound is synthesized according to the procedure of Example 60, using analogous reactants.

Rf 0.50 (5% MeOH/CH2Cl2), 1HNMR (400 MHz, CD3OD), δ 4.20 (s, 2H), 5.38 (s, 2H), 6.46 (s, 1H), 7, 40-7.58 (m, 5H), 7.80-7.90 (m, 4H), 8.06-8.08 (m, 2H), LRMS m/z (APCI-) 412 (M-1 ).

Example 62.

N-{5-[(1R)-(Benzothiazol-2-yloxy)-ethyl]-1H-pyrazol-3-yl}-2-naphthalen-1-yl-acetamide

The title compound is synthesized according to the procedure of Example 60, using analogous reactants.

Rf 0.41 (5% MeOH/CH2Cl2), 1HNMR (400 MHz, CDCl3), δ 1.85 (d, J=7.1 Hz, 3H), 4.20 (s, 2H), 5.88 ( dd, J=7.1, 7.1 Hz, 1H), 6.68 (s, 1H), 6.91 (d, J=7.9 Hz, 1H), 7.15-7.26 (m , 2H), 7.38-7.60 (m, 5H), 7.78-7.95 (m, 3H), LRMS m/z (APCI+) 429 (M+1).

Example 63.

N-{5-[cis-3-(Benzoxazol-2-yloxy)-cyclobutyl]-1H-pyrazol-3-yl}-2-naphthalen-1-yl-acetamide

The title compound is synthesized according to the procedure of Example 60, using analogous reactants.

Rf 0.24 (10% MeOH/CH 2 Cl 2 ); melting point 142.0°C (mono HCl salt); 1HNMR (400 MHz, CDCl3) δ 2.43-2.17 (m, 2H), 3.01-2.94 (m, 2H), 3.18 (apt quint, J=8.3 Hz, 1H) , 4.12 (s, 2H), 5.21 (apt quint, J=7.3 Hz, 1H), 6.59 (s, 1H), 7.54-7.31 (m, 8H), 7 .72 (dd, J=7.9 Hz, 1H), 7.77 (dd, 7.5 Hz, 1H), 7.94 (d, J=8.3 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 170.3, 162.0, 151.5, 148.4, 143.2, 140.5, 134.0, 132.2, 129.7, 129.0, 128 ,8, 126.9, 125.8, 125.7, 124.7, 123.8, 123.5, 123.4, 118.1, 110.1, 94.9, 71.3, 41.5 , 36.7, 22.8 (m, 3H), LRMS m/z (APCI+) 439.1 (M+1).

Preparation 7.1.

N-[5-(cis-3-hydroxy-3-phenyl-cyclobutyl)-2-(4-methoxy-benzyl)-2H-pyrazol-3-yl]-2-naphthalen-1-yl-acetamide

The preparation of the initial ketone N-[2-(4-methoxy-benzyl)-5-(3-oxo-cyclobutyl)-2H-pyrazol-3-yl]-2-naphthalen-1-yl-acetamide is carried out using a procedure analogous to the described for Preparation 4.4 (including syntheses in Preparations 4.1-4.3).

A solution of the ketone (50 mg, 0.11 mmol) in tetrahydrofuran (5 mL) cooled to -30°C was treated with dropwise addition of phenyl magnesium bromide (500 μL, 0.5 mmol, 1 M solution in THF). After the addition is complete, the reaction mixture is stirred for 40 min at ~30°C, then a saturated ammonium chloride solution is added and the mixture is warmed to room temperature. The THF was removed under vacuum and the residue dissolved in methylene chloride which was washed with water and saturated sodium chloride solution. The dissolved residue is then dried and filtered. The crude material was purified by chromatography on silica gel (50:1 chloroform-methanol) to give 54 mg (80% yield) of the title compound.

1H NMR (400 MHz, CDCl 3 ) δ 7.9 (m, 3H), 7.55 (m, 4H), 7.46 (m, 1H), 7.35 (m, 3H), 7.21 (m , 1H), 6.90 (m, 1H), 6.80 (dd, J=0.8, 8.7 Hz, 1 H), 6.54 (d, J=8.7 Hz, 2H), 6.37 (d, J=8.7 Hz, 2H), 6.34 (s, 1H), 4.65 (s, 2H), 4.12 (s, 2H), 3.74 (s, 3H ), 3.20 (m, 1H), 3.01 (m, 2H), 2.55 (m, 2H); MS (AP/Cl): 518.2 (M+H) + .

Preparation 7.2

N-[2-(4-methoxy-benzyl)-5-(cis-3-phenyl-cyclobutyl)-2H-pyrazol-3-yl]-2-naphthalen-1-yl-acetamide

A solution of N-[5-(3-hydroxy-3-phenyl-cyclobutyl)-2-(4-methoxy-benzyl)-2H-pyrazol-3-yl]-2-naphthalen-1-yl-acetamide (Preparation 7.1, 54 mg, 0.10 mmol) in a mixture of 1:1 methylene chloride-trifluoroacetic acid (4 mL) is treated with triethylsilane (1.2 mL) at 23°C. After stirring for 16 h, the solvent was removed under vacuum and the residue was purified by silica gel chromatography (100:1 chloroform-methanol) to give 39 mg (78% yield) of the title compound as a 10:1 mixture of cis-trans isomers.

1H NMR (400 MHz, CDCl3): δ 7.90 (m, 3H), 7.56 (m, 2H), 7.45 (dd, J=7.1, 8.3 Hz, 1H), 7, 30 (m, 3H), 7.25 (m, 1H), 7.18 (m, 1H), 6.78 (s, 1H), 6.55 (d, J=8.7 Hz, 2H), 6.36 (m, 3H), 4.63 (s, 2H), 4.10 (s, 2H), 3.74 (s, 3H), 3.44 (m, 2H), 2.73 (m , 2H), 2.30 (m, 2H); MS (AP/Cl): 502.2 (M+H) + ; isomer with a smaller proportion, characteristic signals in the 1H NMR spectrum: δ 4.66 (s), 4.12 (s), 2.60 (m).

Example 64.

2-Naphthalen-1-yl-N-[5-(cis-3-phenyl-cyclobutyl)-1H-pyrazol-3-yl]-acetamide

A solution of N-[2-(4-methoxy-benzyl)-5-(3-phenyl-cyclobutyl)-2H-pyrazol-3-yl]-2-naphthalen-1-yl-acetamide (Preparation 7.2, 38 mg, 0.076 mmol) in trifluoroacetic acid (5 mL) at room temperature is treated with anisole (165 μL, 1.5 mmol). The solution is heated to 70°C for 5 hours. The solvent was removed under vacuum and the residue was purified by chromatography on silica gel (40:1 chloroform-methanol) to give 27 mg (89% yield) of the title compound as a mixture of 94:6 cis-trans isomers. The product is dissolved in ethyl acetate and treated with hydrochloric acid in diethyl ether to give the HCl salt.

1H NMR (400 MHz, CD3OD): δ 8.04 (d, J=8.3 Hz, 1H), 7.88 (d, J=7.5 Hz, 1H), 7.82 (d, J= 7.9 Hz, 1H), 7.50 (m, 4H), 7.28 (m, 4H), 7.17 (m, 1H), 6.26 (s, 1H), 4.27 (s, 2H), 3.59 (m, 2H), 2.82 (m, 2H), 2.30 (m, 2H); MS (AP/Cl): 382.3 (M+H) +.

The title compounds of the following Examples 65-71 are synthesized as in Example 64, including the synthesis of Preparations 7.1 and 7.2, using the analogous starting ketone:

Example 65.

N-{5-[cis-3-(2-Methoxy-phenyl)-cyclobutyl]-2H-pyrazol-3-yl}-2-quinolin-6-yl-acetamide

1H NMR (400 MHz, CDCl3): δ 9.23 (s, 1 H), 8.80 (dd, J=1.7, 4.1 Hz, 1H), 7.93 (m, 2H), 7 .54 (d, J=1.7 Hz, 1H), 7.47 (dd, J=2.1, 8.7 Hz, 1H), 7.27 (q, J=4.1 Hz, 1H) , 7.15 (m, 1H), 7.08 (d, J=7.5 Hz, 1H), 6.87 (td, J=0.8, 7.5 Hz, 1H), 6.78 ( d, J=7.9 Hz, 1H), 6.57 (s, 1H), 3.76 (s, 3H), 3.73 (s, 2H), 3.61 (m, 1H), 3, 38 (m, 1H), 2.68 (m, 2H), 2.22 (m, 2H); MS (AP/Cl): 413.2 (M+H) + .

Example 66.

N-{5-[cis-3-(2-Methoxy-phenyl)-cyclobutyl]-2H-pyrazol-3-yl}-2-pyridin-3-yl-acetamide

1H NMR (400 MHz, CD3OD): δ 8.95 (s, 1H), 8.82 (d, J=5.8 Hz, 1H), 8.67 (d, J=8.3 Hz, 1H) , 8.11 (m, 1H), 7.17 (m, 2H), 6.89 (m, 2H), 6.32 (s, 1H), 4.21 (s, 2H), 3.81 ( s, 3H), 3.76 (m, 1H), 3.62 (m, 1H), 2.82 (m, 2H), 2.34 (m, 2H); MS (AP/Cl): 363.2.

Example 67.

N{5-[cis-3-(2-Methoxy-phenyl)-cyclobutyl]-2H-pyrazol-3-yl}-2-naphthalen-1-yl-acetamide hydrochloride

1H NMR (400 MHz, CD3OD): δ 8.03 (d, J=7.9 Hz, 1H), 7.89 (d, J=7.5 Hz, 1H), 7.83 (d, J= 7.5 Hz, 1H), 7.5 (m, 4H), 7.17 (m, 2H), 6.91 (m, 2H), 6.22 (s, 1H), 4.27 (s, 2H), 3.80 (s, 3H), 3.75 (m, 1H), 3.60 (m, 1H), 2.81 (m, 2H), 2.32 (m, 2H); MS (AP/Cl): 412.2.

Example 68.

N-{5-[cis-3-(4-Methoxy-phenyl)-cyclobutyl]-2H-pyrazol-3-yl}-2-naphthalen-1-yl-acetamide

1H NMR (400 MHz, CDCl3): δ 7.97 (m, 2H), 7.83 (d, J=7.5 Hz, 1H), 7.77 (m, 1H), 7.49 (m, 2H), 7.40 (m, 2H), 7.11 (d, J=8.3 Hz, 2H), 6.84 (d, J=8.7 Hz, 2H), 6.51 (s, 1H), 4.08 (s, 2H), 3.78 (s, 3H), 3.4 (m, 2H), 2.69 (m, 2H), 2.18 (m, 2H); MS (AP/CI): 412.2; isomer with a smaller proportion, characteristic signals in the 1H NMR spectrum: 6.65 (s), 2.51 (m).

Example 69.

N-{5-[cis-3-(4-Chloro-phenyl)-cyclobutyl]-2H-pyrazol-3-yl}-2-naphthalen-1-yl-acetamide

1H NMR (400 MHz, CDCl3): δ 7.96 (d, J=7.5Hz, 1H), 7.85 (m, 2H), 7.74 (s, 1H), 7.51 (m, 2H ), 7.42 (m, 2H), 7.26 (m, 1H), 7.12 (d, J=8.3 Hz, 2H), 6.49 (s, 1H), 4.12 (s , 2H), 3.40 (m, 2H), 2.72 (m, 2H), 2.20 (m, 2H); MS (AP/Cl): 416.1, 418.1 (M+H) + ; isomer with a smaller proportion, characteristic signals in the 1H NMR spectrum: δ 6.65 (s), 2.55 (m).

Example 70.

2-Naphthalen-1-yl-N-[5-(cis-3-p-tolyl-cyclobutyl)-2H-pyrazol-3-yl]acetamide

1H NMR (400 MHz, CDCl 3 ): δ 8.04 (s, 1H), 7.95 (d, J=7.9 Hz, 1H), 7.81 (d, J=8.3 Hz, 1H) , 7.75 (m, 1H), 7.47 (m, 2H), 7.36 (m, 2H), 7.10 (m, 3H), 6.52 (s, 1H), 4.06 ( s, 2H), 3.38 (m, 2H), 2.70 (m, 2H), 2.32 (s, 3H), 2.20 (m, 2H); MS (AP/CI) : 396.2; isomer with a smaller proportion, characteristic signals in the 1H NMR spectrum: δ 6.65 (s), 3.65 (m), 2.51 (m).

Example 71.

2-(4-Methoxy-phenyl)-N-{5-[cis-3-(2-methoxy-phenyl)-cyclobutyl]2H-pyrazol-3-yl}-acetamide

1H NMR (400 MHz, CD3OD): δ 7.23 (d, J=8.7 Hz, 2H), 7.16 (d, J=7.5 Hz, 2H), 6.89 (m, 4H) , 6.21 (s, 1H), 3.80 (s, 3H), 3.76 (s, 3H), 3.7 (m, 1H), 3.67 (s, 2H), 3.59 ( m, 1H), 2.79 (m, 2H), 2.29 (m, 2H); MS (AP/Cl): 392.2 (M+H) + .

The following additional Examples of compounds of the invention were synthesized as described herein:

N-{5-[cis-3-(4-hydroxy-phenyl)-cyclobutyl]-1H-pyrazol-3-yl}-2-quinolin-6-yl-acetamide;

N-{5-[cis-3-(4-hydroxy-phenyl)-cyclobutyl]-1H-pyrazol-3-yl}-2-quinolin-6-yl-acetamide;

2-Naphthalen-1-yl-N-[5-(cis-3-pyridin-3-yl-cyclobutyl)-2H-pyrazol-3-yl]-acetamide;

N-[5-(cis-3-naphthalen-2-yl-cyclobutyl)-2H-pyrazol-3-yl]-2-pyridin-3-yl-acetamide;

N-(5-indan-2-yl-1H-pyrazol-3-yl)-2-quinolin-6-yl-acetamide;

N-[5-(cis-3-pyridin-2-yl-cyclobutyl)-2H-pyrazol-3-yl]-2-quinolin-6-yl-acetamide;

N-[5-(cis-3-pyridin-2-yl-cyclobutyl)-2H-pyrazol-3-yl]-2-quinolin-6-yl-acetamide;

2-(4-methoxy-phenyl)-N-[5-(cis-3-pyridin-4-yl-cyclobutyl)-2H-pyrazol-3-yl]-acetamide;

N-{5-[3-(cis-2-dimethylaminomethyl-phenyl)-cyclobutyl]-2H-pyrazol-3-yl]-2-(4-methoxy-phenyl)-acetamide;

N-(5-{cis-3-[3-(2-dimethylamino-ethoxy)-phenyl]-cyclobutyl}-2H-pyrazol-3-yl)-2-(4-methoxy-phenyl)-acetamide;

N-{5-[cis-3-(4-hydroxy-phenyl)-cyclobutyl]-1H-pyrazol-3-yl}-2-(4-methoxy-phenyl)acetamide;

N-(5-{cis-3-[2-(2-dimethylamino-ethoxy)-phenyl]-cyclobutyl}-2H-pyrazol-3-yl)-2-(4-methoxy-phenyl)-acetamide;

2-(4-methoxy-phenyl)-N-[5-(cis-3-phenyl-cyclobutyl)-2H-pyrazol-3-yl]-acetamide;

N-{5-[cis-3-(2-fluoro-phenyl)-cyclobutyl]-2H-pyrazol-3-yl}-2-(4-methoxy-phenyl)-acetamide;

N-(5-{cis-3-[4-(azetidin-3-yloxy)-phenyl]-cyclobutyl}-2H-pyrazol-3-yl)-2-(4-methoxy-phenyl)-acetamide;

N-(5-{cis-3-[2-(azetidin-3-yloxy)-phenyl]-cyclobutyl}-2H-pyrazol-3-yl)-2-(4-methoxy-phenyl)-acetamide;

2-(4-methoxy-phenyl)-N-{5-[cis-3-(2-methylsulfanyl-phenyl)-cyclobutyl]-2H-pyrazol-3-yl}-acetamide;

N-{5-[cis-3-(2-amino-phenyl)-cyclobutyl]-2H-pyrazol-3-yl}-2-(4-methoxy-phenyl)-acetamide;

N-{5-[cis-3-(4-cyano-phenyl)-cyclobutyl]-2H-pyrazol-3-yl}-2-(4-methoxy-phenyl)-acetamide;

N-{5-[cis-3-(2-cyano-phenyl)-3-hydroxy-cyclobutyl]-2H-pyrazol-3-yl}-2-(4-methoxy-phenyl)-acetamide;

N-{5-[cis-3-(2-hydroxy-ethyl)-cyclobutyl]-1H-pyrazol-3-yl}-2-naphthalen-1-yl-acetamide;

N-{5-[cis-3-(3-cyano-phenyl)-cyclobutyl]-2H-pyrazol-3-yl}-2-(4-methoxy-phenyl)-acetamide;

N-{5-[cis-3-(2-cyano-phenyl)-cyclobutyl]-2H-pyrazol-3-yl}-2-(4-methoxy-phenyl)-acetamide;

N-{5-[cis-3-(3-amino-phenyl)-cyclobutyl]-2H-pyrazol-3-yl}-2-(4-methoxy-phenyl)-acetamide;

Benzoic acid 4-(cis-3-[5-[2-(4-methoxy-phenyl)-acetylamino]-1H-pyrazol-3-yl}-cyclobutyl)-methyl ester;

N-{5-[cis-3-(4-hydroxymethyl-phenyl)-cyclobutyl]-2H-pyrazol-3-yl]-2-(4-methoxy-phenyl)-acetamide;

N-{5-[cis-3-(2-hydroxy-phenyl)-cyclobutyl]-1H-pyrazol-3-yl}-2-phenyl-acetamide;

N-{5-[cis-3-(2-hydroxy-phenyl)-cyclobutyl]-1H-pyrazol-3-yl}-2-quinolin-6-yl-acetamide;

N-[5-[cis-3-(2-hydroxy-phenyl)-cyclobutyl]-1H-pyrazol-3-yl}-acetamide;

Cyclopropanecarboxylic acid {5-[cis-3-(2-hydroxy-phenyl)-cyclobutyl]-1H-pyrazol-3-yl}-amide;

N-{5-[cis-3-(2-hydroxy-phenyl)-cyclobutyl]-1H-pyrazol-3-yl-isobutyramide;

N-[5-[cis-3-(3-aminomethyl-phenyl)-cyclobutyl]-2H-pyrazol-3-yl}-2-(4-methoxy-phenyl)-acetamide;

N-{5-[cis-3-(3-dimethylaminomethyl-phenyl)-cyclobutyl]-2H-pyrazol-3-yl}-2-(4-methoxy-phenyl)-acetamide;

Benzoic acid 3-(cis-3-{5-[2-(4-methoxy-phenyl)-acetylamino]-1H-pyrazol-3-yl}-cyclobutyl)-methyl ester;

N-{5-[cis-3-(3-hydroxymethyl-phenyl)-cyclobutyl]-2H-pyrazol-3-yl}-2-(4-methoxy-phenyl)-acetamide;

N-(5-{cis-3-[3-(1-hydroxy-1-methyl-ethyl)-phenyl]-cyclobutyl}-2H-pyrazol-3-yl)-2-(4-methoxy-phenyl)- acetamide;

N-{5-[cis-3-(3-ethylaminomethyl-phenyl)-cyclobutyl]-2H-pyrazol-3-yl}-2-(4-methoxy-phenyl)-acetamide;

N-{5-[cis-3-(3-cyclobutylaminomethyl-phenyl)-cyclobutyl]-2H-pyrazol-3-yl}-2-(4-methoxy-phenyl)-acetamide;

2-(4-methoxy-phenyl)-N-{5-[cis-3-(3-propylaminomethyl-phenyl)-cyclobutyl]-2H-pyrazol-3-yl}-acetamide;

N-{5-[cis-3-(3-cyclopentylaminomethyl-phenyl)-cyclobutyl]-2H-pyrazol-3-yl}-2-(4-methoxy-phenyl)-acetamide;

N-(5-{cis-3-[3-(benzylamino-methyl)-phenyl]-cyclobutyl}-2H-pyrazol-3-yl)-2-(4-methoxy-phenyl)-acetamide;

2-(4-methoxy-phenyl)-N-{5-[3-(3-methylaminomethyl-phenyl)-cyclobutyl]-2H-pyrazol-3-yl}-acetamide;

N-{5-[cis-3-(3-cyclopropylaminomethyl-phenyl)-cyclobutyl]-2H-pyrazol-3-yl}-2-(4-methoxy-phenyl)-acetamide;

2-(4-methoxy-phenyl)-N-{5-[cis-3-(3-pyrrolidin-1-ylmethyl-phenyl)-cyclobutyl]-2H-pyrazol-3-yl}-acetamide;

N-{5-[cis-3-(3-diethylaminomethyl-phenyl)-cyclobutyl]-2H-pyrazol-3-yl}-2-(4-methoxy-phenyl)-acetamide; and

N-{5-[cis-3-(3-azetidin-1-ylmethyl-phenyl)-cyclobutyl]-2H-pyrazol-3-yl}-2-(4-methoxy-phenyl)-acetamide.

Claims (14)

1. Compound formula, [image] indicated that R1 is straight or branched (C1-C8) alkyl, straight or branched (C2-C8) alkenyl, straight or branched (C2-C8) alkynyl, (C3-C8) cycloalkyl, (C4-C8) cycloalkenyl, (three- to eight-membered) heterocycloalkyl, (C5-C11) bicycloalkyl, (C7-C11) bicycloalkenyl, or (five- to eleven-membered) heterobicycloalkyl; and wherein R1 may be substituted with one to six R5 substituents independently selected from F, Cl, Br, I, nitro, cyano, -CF3, -NR7R8, -NR7C (=O)R8, -NR7C(=O)OR8, - NR7C(=O)NR8R9, -NR7S(=O)2R8, -NR7S(=O)2NR8R9, -OR7, -OC(=O)R7, OC(=O)OR7, -C(=O)OR7, - C(=O)R7, -C(=O)NR7R8, -OC(=O)NR7R8, -OC(=O)SR7, -SR7, S(=O)R7, -S(=O)2R7, - S(=O) 2 NR 7 R 8 , and R 7 ; R 2 is H, F, -CH 3 , -CN, or -C(=O)OR 7 ; R3 is -C(=O)NR9-, -C(=O)O-, -C(=O)(CR10R11)n-, or -(CR10R11)n-; R4 straight or branched (C1-C8) alkyl, straight or branched (C2-C8) alkenyl, straight or branched (C2-C8) alkynyl, (C3-C8) cycloalkyl, (C4-C8) cycloalkenyl, (three to eight-membered) heterocycloalkyl, (C5-C11) bicycloalkyl, (C7-C11) bicycloalkenyl, (five- to eleven-membered) heterobicycloalkyl, (C6-C14) aryl or (five- to fourteen-membered) heteroaryl; and wherein R4 may be substituted with one to three R6 substituents independently selected from F, Cl, Br, nitro, cyano, -CF3, -NR7R8, -NR7C(=O)R8, -NR7C(=O)OR8, -NR7C( =O)NR8R9, -NR7S(=O)2R8, -NR7S(=O)2NR8R9, -OR7, -OC(=O)R7, -C(=O)OR7, -C(=O)OR7, -C (=O)R7, -C(=O)NR7R8, -OC(=O)NR7,R8, -OC(=O)SR7, -SR7, -S(=O)R7, -S(=O)2R7 , -S(=O) 2 NR 7 R 8 , or R 7 each R7, R8 and R9 independently selected from H, straight or branched (C1-C8) alkyl, straight or branched (C2-C8) alkenyl, straight or branched (C2-C8) alkynyl, (C3-C8) cycloalkyl, (C4 -C8) cycloalkenyl, (three- to eight-membered) heterocycloalkyl, (C5-C11) bicycloalkyl, (C7-C11) bicycloalkenyl, (five- to eleven-membered) heterobicycloalkyl, (C6-C14) aryl, and (five- to fourteen-membered) heteroaryl, where R7 , R8 and R9 may be substituted with one to six substituents independently selected from F, Cl, Br, I, NO2, -CN, -CF3, -NR10R11, -NR10C(=O)R11, -NR10C(=O)OR11, -NR10C(=O)NR11R12, -NR10S(=O)2R11, -NR10S(=O)2NR11R12, -OR10, -OC(=O)R10, -OC(=O)OR10, -OC(=O)NR10R11 , -OC(=O)SR10, -SR10, -S(=O)R10, -S(=O)2R10, -S(=O)2NR10R11, -C(=O)R10, -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 be linked to form with the nitrogen of NR 7 R 8 in which they are incorporated, a heterocycloalkyl unit with three to seven rings, said heterocycloalkyl unit may contain one or two further heteroatoms independently selected from N, O and S; each R10, R11, and R12 independently selected from H, straight or branched (C1-C8) alkyl, straight or branched (C2-C8) alkenyl, straight or branched (C2-C8 alkynyl), (C3-C8) cycloalkyl, ( C4-C8) cycloalkenyl, (three- to eight-membered) heterocycloalkyl, (C5-C11) bicycloalkyl, (C7-C11) bicycloalkenyl, (five- to eleven-membered) heterobicycloalkyl, (C6-C14) aryl and (five- to fourteen-membered) heteroaryl, where R10 , R11 and R12 can each independently be substituted with one to six substituents independently selected from F, Cl, Br, I, NO2, -CN, -CF3, -NR13R14, -NR13C(=O)R14, -NR13C(=O) OR14, -NR13C(=O)NR14R15 –NR13S(=O)2R14, -NR13S(=O)2NR14R15, -OR13, -OC(=O)R13, -OC(=O)OR13, -OC(=O) NR13R14, -OC(=O)SR13, -SR13, -S(=O)R13, -S(=O)2R13, -S(=O)2NR13R14, -C(=O)R13, -C(=O )OR 13 , -C(=O)NR 13 R 14 and R 13 each R13, R14 and R15 independently selected from H, straight or branched (C1-C8) alkyl, straight or branched (C2-C8) alkenyl, straight or branched (C2-C8 alkynyl), (C3-C8) cycloalkyl, (C4 -C8) cycloalkenyl, (three- to eight-membered) heterocycloalkyl, (C5-C11) bicycloalkyl, (C7-C11) bicycloalkenyl, (five- to eleven-membered) heterobicycloalkyl, (C6-C14) aryl and (five- to fourteen-membered) heteroaryl, where R13, R14 and R15 can each independently be substituted with one to six substituents independently selected from F, Cl, Br, I, NO2, -CN, -CF3, -NR16R17, -NR16C(=O)R17, -NR16C(=O)OR17 , -NR16C(=O)NR17R18, -NR16S(=O)2R17, -NR16S(=O)2NR17R18 –OR16, -OC(=O)R16, -OC(=O)OR16, -OC(=O)NR16R17 , -C(=O)SR16, -SR16, -S(=O)R16, -S(=O)2R16, -S(=O)2NR16R17, -C(=O)R16, -C(=O) OR16, -C(=O)NR16R17 and R16 each R16, R17 and R18 is independently selected from H, straight or branched (C1-C8) alkyl, straight or branched (C2-C8) alkenyl, straight or branched (C2-C8 alkynyl), (C3-C8) cycloalkyl, ( C4-C8) cycloalkenyl, (three- to eight-membered) heterocycloalkyl, (C5-C11) bicycloalkyl, (C7-C11) bicycloalkenyl, (five- to eleven-membered) heterobicycloalkyl, (C6-C14) aryl and (five- to fourteen-membered) heteroaryl; n 0, 1, 2, or 3; where R 20 and R 11 in -C(=O)(CR 10 R 11 )n- and -(CR 10 R 11 )n- for each repetition of n are defined independently as cited above; or pharmaceutically acceptable salts thereof. 2. Compound according to claim 1, characterized in that R3 is -(CR10R11)n-, -C(=O)NH- or -C(=O)(CR10R11)n-. 3. Compound according to claim 1, characterized in that R1 is optionally substituted by (C3-C8) cycloalkyl or (C5-C11) bicycloalkyl. 4. A compound according to claim 3, characterized in that R1 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl, or bicyclo-[3.1.0]-hexyl, each optionally substituted. 5. Compound according to claim 1, characterized in that R1 is optionally substituted straight-chain or branched (C2-C8) alkyl or optionally substituted straight-chain or branched (C2-C8) alkenyl. 6. The compound according to claim 1 characterized in that R4 is (C6-C14) aryl or (five- to fourteen-membered) heteroaryl, each optionally substituted. 7. A compound according to claim 6, characterized in that R4 is phenyl, pyridinyl, naphthyl, quinolyl, isoquinolyl, pyrimidinyl, pyrazinyl or pyridazyl, each optionally substituted. 8. A compound according to any one of claims 1-7, characterized in that R is hydrogen. 9. Compound according to claim 1, characterized in that it is selected from the group consisting of: (5-ethyl-2H-pyrazol-3-yl)-(6-methoxy-pyridin-2-yl)-amine; (5-cyclobutyl-2H-pyrazol-3-yl)-(6-methoxy-pyridin-2-yl)-amine (5-cyclobutyl-2H-pyrazol-3-yl)-naphthalen-2-yl-amine; (5-cyclobutyl-2H-pyrazol-3-yl)-naphthalen-1-yl-amine; N-(5-cyclobutyl-2H-pyrazol-3-yl)-N',N'-dimethyl-naphthalene-1,4-diamine; N-(5-cyclobutyl-2H-pyrazol-3-yl)-N',N'-dimethyl-pyridine-2,6-diamine; (5-cyclobutyl-2H-pyrazol-3-yl)-(6-trifluoromethyl-pyridin-2-yl)-amine; (3-benzyloxy-phenyl)-(5-cyclobutyl-2H-pyrazol-3-yl)-amine; (5-cyclobutyl-2H-pyrazol-3-yl)-(3-trifluoromethyl-phenyl)-amine; N-(5-cyclobutyl-2H-pyrazol-3-yl)-N',N'-dimethyl-benzene-1,3-diamine; (5-cyclobutyl-2H-pyrazol-3-yl)-(3-methoxy-phenyl)-amine; (5-cyclobutyl-2H-pyrazol-3-yl)-(4-nitro-phenyl)-amine; (4-chloro-benzyl)-(5-cyclobutyl-2H-pyrazol-3-yl)-amine; (3-bromo-phenyl)-(5-cyclobutyl-2H-pyrazol-3-yl)-amine; (5-cyclobutyl-2H-pyrazol-3-yl)-quinolin-2-yl-amine; [5-(1,4-dioxa-spiro[4.4]non-7-yl)-1H-pyrazol-3-yl]-(3-trifluoromethyl-phenyl)-amine; (6-chloro-pyridin-2-yl)-(5-cyclobutyl-2H-pyrazol-3-yl)-amine; 3-[5-(3-trifluoromethyl-phenylamino)-2H-pyrazol-3-yl]-cyclopentanone; (5-cyclobutyl-2H-pyrazol-3-yl)-(6-methoxy-4-methyl-quinolin-2-yl)-amine; (5-cyclobutyl-2H-pyrazol-3-yl)-(3-trifluoromethoxy-phenyl)-amine; (2-chloro-4-nitro-phenyl)-(5-cyclobutyl-2H-pyrazol-3-yl)-amine; 3-trans-[5-(3-trifluoromethyl-phenylamino)-2H-pyrazol-3-yl]-cyclopentanol; (3,5-bis-trifluoromethyl-phenyl)-(5-cyclobutyl-2H-pyrazol-3-yl)-amine; [5-(3-cis-benzylamino-cyclopentyl)-1H-pyrazol-3-yl]-(3-trifluoromethyl-phenyl)-amine; {5-[3-cis-(4-methoxy-benzylamino)-cyclopentyl]-1H-pyrazol-3-yl}(3-trifluoromethylphenyl)-amine; 4-(5-cyclobutyl-2H-pyrazol-3-ylamino)-benzonitrile; (5-cyclobutyl-2H-pyrazol-3-yl)-(3-fluoro-phenyl)-amine; (5-cyclobutyl-2H-pyrazol-3-yl)-(3,5-dichloro-phenyl)-amine; (2-bromo-phenyl)-(5-cyclobutyl-2H-pyrazol-3-yl)-amine; N-{cis-3-[5-(3-trifluoromethyl-phenylamino)-2H-pyrazol-3-yl]-cyclopentyl}-acetamide; pyridin-2-yl-{3-trans-[5-(3-trifluoromethyl-phenylamino)-2H-pyrazol-3-yl]-cyclopentyl}-amine; (5-cyclobutyl-1H-pyrazol-3-yl)-(4-methoxy-phenyl)-amine; Pyridine-2-carboxylic acid {3-[5-(3-trifluoromethyl-phenylamino)-2H-pyrazol-3-yl]cyclopentyl}-amide; 3-trifluoromethyl-N-{3-[5-(3-trifluoromethyl-phenylamino)-2H-pyrazol-3-yl]cyclopentyl}-benzamide; Cyclobutane carboxylic acid {3-[5-(3-trifluoromethyl-phenylamino)-2H-pyrazol-3-yl]-cyclopentyl}-amide; 2,2-dimethyl-N-{3-[5-(3-trifluoromethyl-phenylamino)-2H-pyrazol-3-yl]-cyclopentyl}propionamide; 4-fluoro-N-{3-[5-(3-trifluoromethyl-phenylamino)-2H-pyrazol-3-yl]-cyclopentyl}-benzamide; 2,2,2-trifluoro-N-{3-[5-(3-trifluoromethyl-phenylamino)-2H-pyrazol-3-yl]-cyclopentyl}acetamide; Cyclopropanecarboxylic acid [3-[5-(3-trifluoromethyl-phenylamino)-2H-pyrazol-3-yl]cyclopentyl}-amide; N-{3-[5-(3-trifluoromethyl-phenylamino)-2H-pyrazol-3-yl]-cyclopentyl}-propionamide; Cyclohexanecarboxylic acid {3-[5-(3-trifluoromethyl-phenylamino)-2H-pyrazol-3-yl]cyclopentyl)-amide; N-[5-(3-acetylamino-cyclopentyl)-2H-pyrazol-3-yl]-2-naphthalen-1-yl-acetamide; Cyclopropanecarboxylic acid [3-[5-(2-naphthalen-1-yl-acetylamino)-1H-pyrazol-3-yl]cyclopentyl}-amide; 2-naphthalen-1-yl-N-{5-[3-(2,2,2-trifluoro-acetylamino)-cyclopentyl]-2H-pyrazol-3-yl}acetamide; N-{3-[5-(2-naphthalen-1-yl-acetylamino)-1H-pyrazol-3-yl]-cyclopentyl}-benzamide; N-(5-hydroxymethyl-1H-pyrazol-3-yl)-2-naphthalen-1-yl-acetamide; 2-Naphthalen-1-yl-N-[5-(thiazol-2-ylaminomethyl)-1H-pyrazol-3-yl]-acetamide; N-[5-((1S)-hydroxy-ethyl)-2H-pyrazol-3-yl]-2-naphthalen-1-yl-acetamide; N-{5-[(1S)-(Benzoxazol-2-yloxy)-ethyl]-1H-pyrazol-3-yl}-2-naphthalen-1-yl-acetamide; N-{5-[(1S)-(Benzothiazol-2-yloxy)-ethyl]-1H-pyrazol-3-yl}-2-naphthalen-1-yl-acetamide; N-[5-(3-hydroxy-1-methyl-propyl)-1H-pyrazol-3-yl]-2-naphthalen-1-yl-acetamide; N-[5-(Benzothiazol-2-yloxymethyl)-1H-pyrazol-3-yl]-2-naphthalen-1-yl-acetamide; N-{5-[3-(benzothiazol-2-yloxy)-1-methyl-propyl]-1H-pyrazol-3-yl}-2-naphthalen-1-yl-acetamide; N-[5-(2-hydroxy-(1S)-methyl-ethyl)-2H-pyrazol-3-yl]-2-naphthalen-1-yl-acetamide; N-{5-[(1R)-(Benzothiazol-2-yloxy)-ethyl]-1H-pyrazol-3-yl}-2-naphthalen-1-yl-acetamide; N-[5-(3-acetylamino-1-methyl-propyl)-1H-pyrazol-3-yl]-2-naphthalen-1-yl-acetamide; 3-methoxy-N-{cis-3-[5-(2-naphthalen-1-yl-acetylamino)-2H-pyrazol-3-yl]-cyclobutyl}-benzamide; N-[5-(cis-3-acetylamino-cyclobutyl)-1H-pyrazol-3-yl]-2-naphthalen-1-yl-acetamide; N-{cis-3-[5-(2-naphthalen-1-yl-acetylamino)-2H-pyrazol-3-yl]-cyclobutyl}-benzamide; 2-cyclopropyl-N-{cis-3-[5-(2-naphthalen-1-yl-acetylamino)-2H-pyrazol-3-yl]-cyclobutyl}-acetamide; 6-Chloro-pyridine-2-carboxylic acid {cis-3-[5-(2-naphthalen-1-yl-acetylamino)-2H-pyrazol-3-yl]-cyclobutyl}-amide; Quinoline-2-carboxylic acid {cis-3-[5-(2-naphthalen-1-yl-acetylamino)-2H-pyrazol-3-yl]-cyclobutyl}-amide; Pyrazine-2-carboxylic acid {cis-3-[5-(2-naphthalen-1-yl-acetylamino)-2H-pyrazol-3-yl]-cyclobutyl}-amide; 4-methoxy-N-{cis-3-[5-(2-naphthalen-1-yl-acetylamino)-2H-pyrazol-3-yl]-cyclobutyl}-benzamide; N-{cis-3-[5-(2-naphthalen-1-yl-acetylamino)-2H-pyrazol-3-yl]-cyclobutyl}-3-nitrobenzamide; N-{cis-3-[5-(2-naphthalen-1-yl-acetylamino)-2H-pyrazol-3-yl]-cyclobutyl}-3-trifluoromethyl-benzamide; N-{cis-3-[5-(2-naphthalen-1-yl-acetylamino)-2H-pyrazol-3-yl]-cyclobutyl}-isobutyramide; 2-phenyl-cyclopropanecarboxylic acid {cis-3-[5-(2-naphthalen-1-yl-acetylamino)-2H-pyrazol-3-yl]-cyclobutyl}-amide; N-{5-[cis-3-(benzoxazol-2-yloxy)-cyclobutyl]-1H-pyrazol-3-yl}-2-naphthalen-1-ylacetamide; 4-dimethylamino-N-{cis-3-[5-(2-naphthalen-1-yl-acetylamino)-2H-pyrazol-3-yl]-cyclobutyl}-benzamide; 3,5-dimethoxy-N-{cis-3-[5-(2-naphthalen-1-yl-acetylamino)-2H-pyrazol-3-yl]-cyclobutyl}-benzamide; 2-Naphthalen-1-yl-N-[5-(cis-3-phenyl-cyclobutyl)-2H-pyrazol-3-yl]-acetamide; N-{5-[cis-3-(3-methoxy-phenyl)-cyclobutyl]-2H-pyrazol-3-yl}-2-naphthalen-1-yl-acetamide; N-{5-[cis-3-(2-methoxy-phenyl)-cyclobutyl]-2H-pyrazol-3-yl}-2-naphthalen-1-yl-acetamide; N-{5-[cis-3-(4-methoxy-phenyl)-cyclobutyl]-2H-pyrazol-3-yl)-2-naphthalen-1-yl-acetamide; 2-Naphthalen-1-yl-N-[5-(cis-3-p-tolyl-cyclobutyl)-2H-pyrazol-3-yl]-acetamide; N-{5-cis-3-(4-chloro-phenyl)-cyclobutyl]-2H-pyrazol-3-yl}-2-naphthalen-1-ylacetamide; 2-(4-methoxy-phenyl)-N-{5-[cis-3-(2-methoxy-phenyl)-cyclobutyl]-2H-pyrazol-3-yl}acetamide; N-{5-[cis-3-(2-methoxy-phenyl)-cyclobutyl]-2H-pyrazol-3-yl}-2-quinolin-6-yl-acetamide; N-{5-[cis-3-(2-methoxy-phenyl)-cyclobutyl]-2H-pyrazol-3-yl)-2-phenyl-acetamide; N-{5-[cis-3-(2-methoxy-phenyl)-cyclobutyl]-2H-pyrazol-3-yl}-2-pyridin-3-yl-acetamide; N-{5-[cis-3-(4-methoxy-phenyl)-cyclobutyl]-1H-pyrazol-3-yl}-2-quinolin-6-yl-acetamide; 2-quinolin-6-yl-N-[5-(cis-3-p-tolyl-cyclobutyl)-1H-pyrazol-3-yl]-acetamide; N-{5-[cis-3-(4-fluoro-phenyl)-cyclobutyl]-1H-pyrazol-3-yl}-2-quinolin-6-yl-acetamide; N-{5-[cis-3-(4-chloro-phenyl)-cyclobutyl]-1H-pyrazol-3-yl}-2-quinolin-6-yl-acetamide; 2-quinolin-6-yl-N-[5-(cis-3-m-tolyl-cyclobutyl)-1H-pyrazol-3-yl]-acetamide; 4-dimethylamino-N-{cis-3-[5-(2-naphthalen-1-yl-acetylamino)-2H-pyrazol-3-yl]-cyclobutyl}-benzamide; 2-Naphthalen-1-yl-N-{5-[cis-3-(pyridin-2-yloxy)-cyclobutyl-1H-pyrazol-3-yl}-acetamide; 6-methyl-pyridine-2-carboxylic acid {cis-3-[5-(2-naphthalen-1-yl-acetylamino)-2H-pyrazol-3-yl]-cyclobutyl}-amide; 2-phenyl-cyclopropane carboxylic acid methyl-{cis-3-[5-(2-naphthalen-1-yl-acetylamino)-2H-pyrazol-3-yl]-cyclobutyl}-amide; N-[5-[cis-3-(3-methyl-pyrazin-2-yloxy)-cyclobutyl]-1H-pyrazol-3-yl}-2-naphthalen-1-ylacetamide; {5-[cis-3-(2-methoxy-phenyl)-cyclobutyl]-1H-pyrazol-3-yl}(6-methoxy-pyridin-2-yl)amine; N-{5-[cis-3-(3,6-dimethyl-pyrazin-2-yloxy)-cyclobutyl]-1H-pyrazol-3-yl}-2-naphthalen-1-yl-acetamide; N-{5-[cis-3-(3-methoxy-pyridin-2-yloxy)-cyclobutyl]-1H-pyrazol-3-yl}-2-naphthalen-1-yl-acetamide; 2-methyl-cyclopropanecarboxylic acid {cis-3-{5-(2-naphthalen-1-yl-acetylamino)-2H-pyrazol-3-yl]-cyclobutyl}-amide; 2-naphthalen-1-yl-N-{5-[cis-3-(3-trifluoromethyl-pyridin-2-yloxy)-cyclobutyl]-1H-pyrazol-3-yl}-acetamide; 2-naphthalen-1-yl-N-{5-[cis-3-(3-nitro-pyridin-2-yloxy)-cyclobutyl]-1H-pyrazol-3-yl}acetamide; N-{5-[cis-3-(benzothiazol-2-yloxy)-cyclobutyl]-1H-pyrazol-3-yl}-2-naphthalen-1-yl-acetamide; 2-naphthalen-1-yl-N-{5-[cis-3-(4-trifluoromethyl-pyrimidin-2-yloxy)-cyclobutyl]-1H-pyrazol-3-yl}-acetamide; 2-naphthalen-1-yl-N-{5-[3-(5-nitro-pyridin-2-yloxy)-cyclobutyl]-1H-pyrazol-3-yl}-acetamide; 2-naphthalen-1-yl-N-{5-[3-(pyrimidin-2-yloxy)-cyclobutyl]-1H-pyrazol-3-yl}-acetamide; 2-naphthalen-1-yl-N-{5-[3-(5-trifluoromethyl-pyridin-2-yloxy)-cyclobutyl]-1H-pyrazol-3-yl}-acetamide; N-{5-[3-(6-Methoxy-pyridazin-3-yloxy)-cyclobutyl]-1H-pyrazol-3-yl}-2-naphthalen-1-yl-acetamide; 2-naphthalen-1-yl-N-[5-[3-(pyrazin-2-yloxy)-cyclobutyl]-1H-pyrazol-3-yl}-acetamide; N-{5-[3-(6-methyl-pyridin-2-yloxy)-cyclobutyl]-1H-pyrazol-3-yl}-2-naphthalen-1-yl-acetamide; N-{5-[3-(6-chloro-benzothiazol-2-yloxy)-cyclobutyl]-1H-pyrazol-3-yl)-2-naphthalen-1-yl-acetamide; N-{5-[3-(6-Methoxy-benzothiazol-2-yloxy)-cyclobutyl]-1H-pyrazol-3-yl}-2-naphthalen-1-yl-acetamide; N-{5-[cis-3-(4-hydroxy-phenyl)-cyclobutyl]-1H-pyrazol-3-yl}-2-quinolin-6-yl-acetamide; N-{5-[cis-3-(3-hydroxy-phenyl)-cyclobutyl]-1H-pyrazol-3-yl}-2-quinolin-6-yl-acetamide; 2-Naphthalen-1-yl-N-[5-(cis-3-pyridin-3-yl-cyclobutyl)-2H-pyrazol-3-yl]-acetamide; N-[5-(cis-3-naphthalen-2-yl-cyclobutyl)-2H-pyrazol-3-yl]-2-pyridin-3-yl-acetamide; N-(5-indan-2-yl-1H-pyrazol-3-yl)-2-quinolin-6-yl-acetamide; N-[5-(cis-3-pyridin-2-yl-cyclobutyl)-2H-pyrazol-3-yl]-2-quinolin-6-yl-acetamide; N-[5-(cis-3-pyridin-2-yl-cyclobutyl)-2H-pyrazol-3-yl]-2-quinolin-6-yl-acetamide; 2-(4-methoxy-phenyl)-N-[5-(cis-3-pyridin-4-yl-cyclobutyl)-2H-pyrazol-3-yl]-acetamide; N-{5-[3-(cis-2-dimethylaminomethyl-phenyl)-cyclobutyl]-2H-pyrazol-3-yl}-2-(4-methoxy-phenyl)-acetamide; N-(5-{cis-3-[3-(2-dimethylamino-ethoxy)-phenyl]-cyclobutyl-2H-pyrazol-3-yl)-2-(4-methoxy-phenyl)-acetamide; N-{5-[cis-3-(2-hydroxy-phenyl)-cyclobutyl]-2H-pyrazol-3-yl}-2-(4-methoxy-phenyl)-acetamide; N-(5-{cis-3-[2-(2-dimethylamino-ethoxy)-phenyl]-cyclobutyl}-2H-pyrazol-3-yl)-2-(4-methoxy-phenyl)-acetamide; 2-(4-methoxy-phenyl)-N-[5-(cis-3-phenyl-cyclobutyl)-2H-pyrazol-3-yl]-acetamide; N-{5-[cis-3-(2-fluoro-phenyl)-cyclobutyl]-2H-pyrazol-3-yl-2-(4-methoxy-phenyl)acetamide; N-(5-{cis-3-[4-(azetidin-3-yloxy)-phenyl]-cyclobutyl}-2H-pyrazol-3-yl)-2-(4-methoxyphenyl)-acetamide; N-(5-{cis-3-[2-(azetidin-3-yloxy)-phenyl]-cyclobutyl}-2H-pyrazol-3-yl)-2-(4-methoxyphenyl)-acetamide; 2-(4-methoxy-phenyl)-N-{5-[cis-3-(2-methylsulfanyl-phenyl)-cyclobutyl]-2H-pyrazol-3-yl}-acetamide; N-{5-[cis-3-(2-amino-phenyl)-cyclobutyl]-2H-pyrazol-3-yl}-2-(4-methoxy-phenyl)-acetamide; N-{5-[cis-3-(4-cyano-phenyl)-cyclobutyl]-2H-pyrazol-3-yl}-2-(4-methoxy-phenyl)-acetamide; N-{5-[cis-3-(2-cyano-phenyl)-3-hydroxy-cyclobutyl]-2H-pyrazol-3-yl}-2-(4-methoxy-phenyl)-acetamide; N-{5-[cis-3-(2-hydroxy-ethyl)-cyclobutyl]-1H-pyrazol-3-yl}-2-naphthalen-1-yl-acetamide; N-{5-[cis-3-(3-cyano-phenyl)-cyclobutyl]-2H-pyrazol-3-yl}-2-(4-methoxy-phenyl)-acetamide; N-{5-[cis-3-(2-cyano-phenyl)-cyclobutyl]-2H-pyrazol-3-yl}-2-(4-methoxy-phenyl)-acetamide; N-{5-[cis-3-(3-amino-phenyl)-cyclobutyl]-2H-pyrazol-3-yl}-2-(4-methoxy-phenyl)-acetamide; Benzoic acid 4-(cis-3-{5-[2-(4-methoxy-phenyl)-acetylamino]-1H-pyrazol-3-yl}-cyclobutyl)-methyl ester; N-{5-[cis-3-(4-hydroxymethyl-phenyl)-cyclobutyl]-2H-pyrazol-3-yl}-2-(4-methoxy-phenyl)-acetamide; N-{5-[cis-3-(2-hydroxy-phenyl)-cyclobutyl]-1H-pyrazol-3-yl}-2-phenyl-acetamide; N-{5-[cis-3-(2-hydroxy-phenyl)-cyclobutyl]-1H-pyrazol-3-yl}-2-quinolin-6-yl-acetamide; N-{5-[cis-3-(2-hydroxy-phenyl)-cyclobutyl]-1H-pyrazol-3-yl}-acetamide; Cyclopropane carboxylic acid {5-[cis-3-(2-hydroxy-phenyl)-cyclobutyl]-1H-pyrazol-3yl}-amide; N-{5-[cis-3-(2-hydroxy-phenyl)-cyclobutyl]-1H-pyrazol-3-yl}-isobutyramide; N-{5-[cis-3-(3-aminomethyl-phenyl)-cyclobutyl]-2H-pyrazol-3-yl}-2-(4-methoxy-phenyl)-acetamide; N-{5-[cis-3-(3-dimethylaminomethyl-phenyl)-cyclobutyl]-2H-pyrazol-3-yl}-2-(4-methoxy-phenyl)-acetamide; Benzoic acid 3-(cis-3-{5-[2-(4-methoxy-phenyl)-acetylamino]-1H-pyrazol-3-yl}-cyclobutyl)-methyl ester; N-{5-[cis-3-(3-hydroxymethyl-phenyl)-cyclobutyl]-2H-pyrazol-3-yl}-2-(4-methoxyphenyl)-acetamide; N-(5-{cis-3-[3-(1-hydroxy-1-methyl-ethyl)-phenyl]-cyclobutyl}-2H-pyrazol-3-yl)-2-(4-methoxy-phenyl)- acetamide; N-{5-[cis-3-(3-ethylaminomethyl-phenyl)-cyclobutyl]-2H-pyrazol-3-yl}-2-(4-methoxyphenyl)-acetamide; N-{5-[cis-3-(3-cyclobutylaminomethyl-phenyl)-cyclobutyl]-2H-pyrazol-3-yl}-2-(4-methoxy-phenyl)-acetamide; 2-(4-methoxy-phenyl)-N-[5-[cis-3-(3-propylaminomethyl-phenyl)-cyclobutyl]-2H-pyrazol-3-yl}-acetamide; N-{5-[cis-3-(3-cyclopentylaminomethyl-phenyl)-cyclobutyl]-2H-pyrazol-3-yl}-2-(4-methoxy-phenyl)-acetamide; N-(5-{cis-3-[3-(benzylamino-methyl)-phenyl]-cyclobutyl}-2H-pyrazol-3-yl)-2-(4-methoxy-phenyl)-acetamide; 2-(4-methoxy-phenyl)-N-{5-[3-(3-methylaminomethyl-phenyl)-cyclobutyl]-2H-pyrazol-3-yl}-acetamide; N-{5-[cis-3-(3-cyclopentylaminomethyl-phenyl)-cyclobutyl]-2H-pyrazol-3-yl}-2-(4-methoxy-phenyl)-acetamide; 2-(4-methoxy-phenyl)-N-{5-[cis-3-(3-pyrrolidin-1-ylmethyl-phenyl)-cyclobutyl]-2H-pyrazol-3-yl}-acetamide; N-{5-[cis-3-(3-diethylaminomethyl-phenyl)-cyclobutyl]-2H-pyrazol-3-yl}-2-(4-methoxy-phenyl)-acetamide; N-{5-[cis-3-(3-azetidin-1-ylmethyl-phenyl)-cyclobutyl]-2H-pyrazol-3-yl}-2-(4-methoxy-phenyl)-acetamide; and pharmaceutically acceptable salts of the above-mentioned compounds. 10. A pharmaceutical preparation for the treatment of diseases or conditions involving abnormal cell growth or neurodegenerative diseases or conditions in mammals, characterized in that it contains the compound of claim 1 in an amount effective for the treatment of said diseases or conditions and a pharmaceutically acceptable carrier. 11. Pharmaceutical preparation for the treatment of diseases or conditions in mammals, the treatment of which can be carried out or made possible by changing dopamine-mediated neurotransmission, characterized in that it contains the compound from claim 1 in an amount effective for inhibiting cdk5 activity and a pharmaceutically acceptable carrier. 12. Pharmaceutical preparation for the treatment in mammals of diseases or conditions selected from male fertility and sperm motility; diabetes mellitus; reduced glucose tolerance; metabolic syndrome or syndrome X; polycystic ovary syndrome; formation of adipose tissue and obesity; myogenesis and weakness, for example the decline of physical capabilities associated with aging; acute sarcopenia, for example muscle atrophy and/or cachexia associated with burns, poor rest, limb immobilization or major thoracic, abdominal and/or orthopedic surgery, sepsis; spinal cord injury; hair loss, hair thinning and baldness and immunodeficiency, characterized in that it contains the compound of claim 1 in an amount effective for the treatment of said diseases or conditions, and a pharmaceutically acceptable carrier. 13. Pharmaceutical preparation containing the compound according to claim 1 and another ingredient selected from the group consisting of SSRIs, NK-1 receptor antagonists, 5HT1D antagonists, ziprasidone, olanzapine, risperidone, L-745870, sonepiprazole, RP 62203, NGD 941, balaperidone . 14. Compound formula [image] indicated that Prot is a protecting group; that R is H, F, -CH3, -CN, or -C(=O)OR7; and that n is an integer chosen from 1,2,3, and 4.