ZA200300819B - Imidazole derivatives. - Google Patents
Imidazole derivatives. Download PDFInfo
- Publication number
- ZA200300819B ZA200300819B ZA200300819A ZA200300819A ZA200300819B ZA 200300819 B ZA200300819 B ZA 200300819B ZA 200300819 A ZA200300819 A ZA 200300819A ZA 200300819 A ZA200300819 A ZA 200300819A ZA 200300819 B ZA200300819 B ZA 200300819B
- Authority
- ZA
- South Africa
- Prior art keywords
- imidazol
- cyclobutyl
- cis
- acetylamino
- branched
- Prior art date
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- 208000015768 polyposis Diseases 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 108060006633 protein kinase Proteins 0.000 description 1
- 102000006241 protein phosphatase inhibitor-2 Human genes 0.000 description 1
- 108020004098 protein phosphatase inhibitor-2 Proteins 0.000 description 1
- 208000005069 pulmonary fibrosis Diseases 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003072 pyrazolidinyl group Chemical group 0.000 description 1
- 125000002755 pyrazolinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000001422 pyrrolinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
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- 208000037803 restenosis Diseases 0.000 description 1
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- 229960004889 salicylic acid Drugs 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 230000036573 scar formation Effects 0.000 description 1
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- 210000002027 skeletal muscle Anatomy 0.000 description 1
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- 208000000587 small cell lung carcinoma Diseases 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
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- 238000006467 substitution reaction Methods 0.000 description 1
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- 230000015883 synaptic transmission, dopaminergic Effects 0.000 description 1
- 102000013498 tau Proteins Human genes 0.000 description 1
- 108010026424 tau Proteins Proteins 0.000 description 1
- 208000001608 teratocarcinoma Diseases 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000005958 tetrahydrothienyl group Chemical group 0.000 description 1
- 125000004632 tetrahydrothiopyranyl group Chemical group S1C(CCCC1)* 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 238000003354 tissue distribution assay Methods 0.000 description 1
- 238000003325 tomography Methods 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 208000010570 urinary bladder carcinoma Diseases 0.000 description 1
- 230000002485 urinary effect Effects 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
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Description
IMIDAZOLE DERIVATIVES :
Field of the Invention . The subject invention relates to imidazole derivatives, pharmaceutical compositions comprising such derivatives and methods of using such derivatives to treat abnormal cell growth and certain diseases and conditions of the central nervous system. The compounds of the present invention act as inhibitors of cyclin-dependent protein kinase enzymes cdk5 (cyclin-dependent protein kinase 5) and cdk2 (cyclin-dependent protein kinase 2). The compounds of the present invention also are inhibitors of the enzyme GSK-3 (glygocen synthase kinase-3) enzyme.
The serine/threonine kinase cdk5 along with its cofactor p25 (or the longer cofactor, p35) has been linked to neurodegenerative disorders, and inhibitors of cdk5/p25 (or cdk5/p35) are therefore useful for the treatment of neurodegenerative disorders such as
Alzheimer's disease, Parkinson's disease, stroke, or Huntington's disease. Treatment of such neurodegenerative disorders using ¢dk5 inhibitors is supported by the finding that cdk3 is involved in the phosphorylation of tau protein (J. Biochem, 117, 741-749 (1995)). cdkS also phosphorylates Dopamine and Cyclic AMP-Regulated Phosphorprotein {(DARPP-32) at threonine 75 and is thus indicated in having a role in dopaminergic neurotransmission (Nature, 402, 669-671 (1999).
The serine/threonine kinase cdk2 is essential for normal cell cycling and plays a critical role in disorders arising from abnormal cell cycling, a common characteristic of many oncological disorders. Inhibitors of cdk2 are therefore useful for the treatment of various types of cancer and other diseases or conditions related to abnormal cell growth (Meijer, et al.,
Properties and Potential-applications of Chemical Inhibitors of Cyclin-dependent Kinsases,
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. lt is one of several protein kinases which phosphorylate glycogen synthase (Embi, et al., Eur. J. Biochem. 107:519-527 (1980); . Hemmings, et al., Eur. J. Biochem. 119:443-451 (1982)). GSK-3 exists in two isoforms, o and : B, in vertebrates, reported as having a monomeric structure of 49kD and 47kD respectively. v Both isoforms phosphorylate muscle glycogen synthase (Cross, et al., Biochemical Journal 303: 21-26 (1994). The amino acid identity among GSK-3 species homologs has been indicated to be in excess of 98% within the catalytic domain (Plyte, et al., Biochim. Biophys.
Acta 1114:147-162) (1992)). Due to a remarkably high degree of conservation across the . phylogenetic spectrum, a fundamental role of GSK-3 in cellular processes is suggested.
GSK-3 has been implicated in numerous different disease states and conditions. For . example, Chen, et al, Diabetes 43: 1234-1241 (1994) have suggested that an increase in GSK-3 activity can be important in Type 2 diabetes. Increased GSK-3 expression in diabetic muscle is also though to contribute to the impaired glycogen synthase activity and skeletal muscle insulin resistance present in Type 2 diabetes (Nikoulina, et al., Diabetes 49: 263-271 (2000)). Also, a higher activity of a type 1 protein phosphatase measured in immotile sperm was attributed to higher GSK-3 activity and was indicated as responsible for holding the sperm motility in check (Vijayaraghavan, et al. Biology of Reproduction 54: 709-718 (1996).
Vijayaraghavan et al. indicate that such results suggest a biochemical basis for the development and regulation of sperm motility and a possible physiological role for a protein phosphatase 1/inhibitor 2/GSK-3 system. GSK-3 activity has also been associated with
Alzheimer’s disease and mood disorders such as bipolar. disorder (WO 97/41854). Among other conditions, GSK-3 has furthermore been implicated in hair loss, schizophrenia, and neurodegeneration, including both chronic neurodegenerative diseases (such as Alzheimer’s, supra) and neurotrauma, for example stroke, traumatic brain injury, and spinal cord trauma.
This invention provides compounds of the formula
Nn
RYN Pe
R® 1 wherein R' is a straight chain or branched (C,-Cg)alkyl, a straight chain or branched (C,-
Cg)alkenyl, a straight chain or branched (C,-Cg)alkynyl, (C.-Cg)oycloalkyl, (C,-Cg)cycloalkenyl, (3- 8 membered) heterocycloatkyl, (Cs-C,,)bicycloalkyl, (C,-C,,)bicycioalkenyl, (5-11 membered) heterobicycloalkyl, (CsCy,) aryl, or (5-14 membered) heteroaryl; and wherein R' is optionally substituted with from one to six substituents R® independently selected from F, Cl, Br, |, nitro, cyano, -CF,; -NR'R’, -NR'C(=O)R®, -NR'C(=O)OR®, -NR’C(=O)NR°R®, -NR'S(=0),R®, . NR'S(=0),NRPR?, -OR’, -OC(=O)R’, -OC(=0)OR’, -C(=0)OR’, -C(=O)R’, -C(=O)NR'R®, -OC(=0)NR'RE, -OC(=0)SR’, -SR’, -S(=0)R’, -S(=0),R’, -S(=0),NR'R’, -0-S(=0),R’, -N, and . 30 RR,
R2is H, F, CH, CN, or C(=0)OR’;
Ris -C(=ONR?-, -C(=0)O-, -G(=0)(CRR™),-, ar «(CR R™)-;
R* is a straight chain or a branched (C,-Cg)alkyl, a straight chain or a branched (C»- ' C,)alkeny!, a straight chain or branched (C,-Cq alkynyl), (C5-Cs)cycloalkyl, (C4-Ce)cycloalkenyl, {3-8 membered) heterocycloalkyl, (Cs-C,,)bicycloalkyl, (G+-C,4)bicycloalkenyl, (5-11 membered) . heterobicycloalkyl, (C¢-Ci4)aryl, or (5-14 membered) heteroaryl; and wherein R* is optionally substituted with from one to three substitutents R® independently selected from F, Cl, Br, |, nitro, cyano, -CF;, -NR'R’, -NR'C(=O)R’ -NR’C(=0)OR®, -NR’C(=O)NR®R’, NR’S(=0),R’,
NR’S(=0),NR®R®, -OR?, -OC(=O)R’, -OC(=O)OR’", -C(=0)OR’, -C(=O)R’, -C(=O)NR'R?, -OC(=0)NR’R®, -OC(=0)SR’, -SR’, -S(=Q)R’, -S(=0),R’, -S(=0),NR'R?, or R’; each R7, R®, and R® is independently selected from H, straight chain or branched (Ct Cg)alkyl, straight chain or branched (C,-Ce)alkenyl, straight chain or branched (C,-Cg alkynyl), (C4-Cg)cycloalkyl, (C,-Cg)cycloalkenyl, (3-8 membered) heteracycloalkyl, (Cs-Cyy)bicycloalkyl, (C;-C,4)bicycloalkenyl, (5-11 membered) heterobicycloalkyl, (C¢Cis)aryl, and (5-14 membered) heteroaryl, wherein R7, R?, and R® are each independently optionally substituted with from one to six substituents independently selected from F, Cl, Br, I, NO, -CN, -CFs, -NR'R",
NR™C(=0)R™, -NR™C(=0)OR", -NR"C(=O)NR'"'R'™, -NR'S(=0),R"", -NR"S(=0),NR"R", -OR™, OC(=0)R, -OC(=0)OR", -OC(=O)NR"R", -OC(=0)SR’, -SR™, -S(=O)R™, -S(=0),R", -S(=0),NRPR", -C(=0)R"?, -C(=O)OR', -C(=0)NR"R"’, and Re or, when R7 and R® are as in NR'R?, they may instead optionally be connected to form with the nitrogen of NR'R® to which they are attached a heterocycloalkyl moiety of from three fo seven ring members, said heterocycloalkyl moiety optionally comprising one or two further heteroatoms independently selected from N, O, and S; each R'%, R", and R" is independently selected from H, straight chain or branched (C;-
Cealkyl, straight chain or branched (C,-Cg)alkenyl, straight chain or branched (C,-Cq4 alkynyl), (C4-Cg)eycloalkyl, (C,-Cg)cycloalkenyl, (3-8 membered) heterocycloalkyl, (Cs-Cy)bicycloalkyl, (C,-C,,)bicycloalkenyl, (5-11 membered) heterobicycloalkyl, (Ce-Cyp)aryl, and (5-14 membered) heteroaryl, wherein R*, R", and R* are each independently optionally substituted with from one to six substituents independently selected from F, Cl, Br, I, NO, -CN, CFs, -NRBR™, -NR™¥C(=0)R™, -NR™C(=0)OR™, -NRC(=O)NR"R'S, -NR"S(=0),R", -NR7S(=0),NR"R", .OR™, -OC(=O)R®, -OC(=0)OR®, -OC(=O)NR™R™, -OC(=0)SR", -SR®, -S(=O)R¥, -S(=0),R"™, -S(=0),NR®R™, -C(=0)R™, -C(=0)OR", -C(=O)NR"R", and R"3; . each R', R*, and R* is independently selected from H, straight chain or branched (C,-
Cg)alkyl, straight chain or branched (C,-Cglalkenyl, straight chain or branched (C-Cg alkynyl), . (C,-Cg)cycloalkyl, (C,-Cg)cycloalkenyl, (3-8 membered) heterocycloalkyl, (Cs-C,y)bicycloalkyl, (C,-C,,)bicycloalkenyl, (5-11 membered) heterobicycloalkyl, (Ce-Cyp)aryl, and (5-14 membered) heteroaryl, wherein R™, R", and R'® are each independently optionally substituted with from one to six substituents independently selected from F, Cl, Br, |, NO, -CN, -CF;, -NR'R",
NR*C(=0)R", -NR™C(=0)OR", -NR®C(=O)NR7R', -NR"*S(=0).R", -NR*3(=0),NR""R", . OR, -OC(=O)R', -OC(=O)OR', -OC(=O)NR™R", -OC(=O)SR™, -SR®, -S(=0)R", -S(=0),R, -S(=0),NR™R", -C(=O)R®, -C(=0)OR™, -C(=O)NR'"R"Y, and R"; , each R'®, R", and R™ is independently selected from H, straight chain or branched (C;- Cgalkyl, straight chain or branched (C,-Cg)alkenyl, straight chain or branched (C,-Cg alkynyl), (C5-Cs)cycloalkyl, (C,-Cgcycloatkenyl, (3-8 membered) heterocycloalkyl, (Cs-C,;)bicycloalkyl, (C,-C,1)bicycloalkenyl, (5-11 membered) heterabicycloalkyl, (C-C,4)aryl, and (5-14 membered) heteroaryl; nis0,1,2,0or3; wherein R™ and R" in -C(=0)(CR"R™),- and -(CR"R"),- are for each iteration of n defined independently as recited above; and pharmaceutically acceptable salts thereof.
Compounds of formula 1 of the invention are inhibitors of serine/threonine kinases, especially cyclin-dependent kinases such as cdk5 and cdk2, and are useful for the treatment of neurodegenerative disorders and other CNS disorders, and of abnormal cell growth, including cancer. The compounds of formula 1 are particularly useful in inhibiting cdk5. The compounds of formula 1 are also useful as inhibitors of GSK-3.
The term “alkyl”, as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight or branched moieties. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, and t-butyl.
The term “alkenyl”, as used herein, unless otherwise indicated, includes alkyl moieties having at least one carbon-carbon double bond wherein 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 moieties having at least one carbon-carbon triple bond wherein alkyl is as defined above. Examples of alkynyl groups include, but are not limited to, ethynyl and 2-propynyl.
The term “cycloalkyl”, as used herein, unless otherwise indicated, includes non- aromatic saturated cyclic alkyl moieties wherein alkyl is as defined above. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycioheptyl. “Bicycloalkyl” groups are non-aromatic saturated carbocyclic groups consisting . of two rings, wherein said rings share one or two carbon atoms. For purposes of the present invention, and unless otherwise indicated, bicycloalkyl groups include spiro groups and fused . ring groups. Examples of bicycloalkyl groups include, but are not limited to, bicyclo-[3.1.0]- hexyl, norbornyl, spiro[4.5]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 moieties as defined above, except comprising one or more carbon-carbon double bonds connecting carbon ring members (an “endocyclic” double bond) and/or one or more . carbon-carbon double bonds connecting a carbon ring member and an adjacent non-ring carbon (an “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 bicycloalkeny! groups also include groups that are substituted with one or more oxo moieties. Examples of such groups with oxo moieties 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 like terms, as used herein, refer to non-aromatic cyclic groups containing one or more heteroatoms, prefereably from one to four heteroatoms, each selected from O, S and N. “Heterobicycloalkyl” groups are non-aromatic two- ringed cyclic groups, wherein said rings share one or two atoms, and wherein at least one of the rings contains a heteroatom (0, S, or N). Heterobicycloatkyt groups for purposes of the present invention, and unless otherwise indicated, include spiro groups and fused ring groups. In one embodiment, each ring in the heterobicycloalkyl contains up to four heteroatoms (i.e. from zero to four heteroatoms, provided that at least one ring contains at least one heteroatom). The heterocyclic groups of this invention can also include ring systems substituted with one or more oxo moieties. Examples of non-aromatic heterocyclic groups are aziridinyl, azetidinyl, pyrrolidiny!, piperidinyl, azepinyl, piperazinyl, 1,2,3,6-tetrahydropyridinyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholino, thiomorpholino, thioxanyl, pyrrolinyl, indolinyl, 2H-pyranyi, 4H-pyranyl, dioxanyl, 1,3- dioxolanyl, pyrazolinyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, ~~ 3-azabicyclo[3.1.0Jhexanyl, 3-azabicyclof4.1.0lheptanyl, quinoliziny!, quinuclidinyt, 1,4-dioxaspirof4.5]decyl, 1,4-dioxaspiro[4.4]nonyl, 1,4- dioxaspiro[4.3]octy!, and 1,4-dioxaspirof4.2]heptyl. “Heteroaryl’, as used herein, refers to 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 wherein at least one ring of the group is aromatic is a . “heteroaryl” group. The heteroaryl groups of this invention can also include ring systems substituted with one or more oxo moieties. Examples of heteroaryl groups are pyridinyl, pyridazinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, quinolyl, isoguinotyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, indoiyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazotlyl, indolizinyl, phthalazinyl, triazinyl, isoindolyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl,
benzotriazolyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, - naphthyridinyl, . dihydroquinolyl, tetrahydroquinolyl, dihydroisoquinolyl, tetrahydroisoquinolyl, benzofuryl, furopyridinyl, pyrolopyrimidinyl, and azaindolyl. . The foregoing groups, as derived from the compounds listed above, may be C-attached or N-attached where such is possible. For instance, a group derived from pyrrole may be pyrrol- 1-yl (N-attached) or pyrrol-3-yl (C-attached). The terms referring to the groups also encompass all possible tautomers. in one embodiment, this invention provides compounds of formula 1, wherein R3is -
C(=O)NR®- or -C(=0)(CRR'),-. In another embodiment, R™ and R" of -C(=0)(CR™R")- are at each iteration of n both hydrogen. In another embodiment, R® of ~-C(=0)NR®- is hydrogen. In another embodiment, R? is -C(=O)NR®- or -C(=O)(CR"™R""),- and R? is hydrogen.
In another embodiment of the invention, a compound of formula 1 is provided wherein
R' is optionally substitited (C;-Cg)cycloalkyl or optionally substituted (Cs-Cy4) bicycloalkyl.
Preferred embodiments are wherein R' is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or norbornyl, each optionally substituted as recited above (i.e. optionally with from one to six substituents R® independently selected from F, Cl, Br, I, nitro, cyano, -CF, -NR'R® -NR'C(=O)R?, -NR'C(=0)OR?, -NR'C(=O)NR®R®, -NR’S(=0),R®, -NR’S(=0),NR°R®, -OR’, -OC(=O)R’, -OC(=0)OR’, -C(=0)OR’, -C(=0)R’, -C(=O)NR'R®, -OC(=O)NR'R’, -OC(=0)SR’,
SR’, -S(=0)R’, -S(=0),R’, -S(=0),NR'R?, and R"). In a more preferred embodiment, R' is (C4- Cg)cycloalkyl or optionally substituted (Cs-C;,) bicycloalkyl, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or norbornyl, and is optionally substituted with from one to three substituents independently selected from F, Cl, Br, |, nitro, cyano, -CF3, -NR'R?, -NR'C(=0)R®, -OR’, -C(=0)OR’, -C(=O)R’, and R’. More preferably, R' is (C,-Ce)cycloalkyl or optionally substituted (Cs-C,4) bicycloalkyl, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or norbornyl, and R' is substituted with -NR7C(=O)R?, (CeCiaryl, (3-8 membered) heterocycloalkyl, or (5-14 membered) heteroaryl, and wherein said aryl, heterocycloalkyl, and heteroaryl are each optionally substituted with from one to six substituents independently selected from F, Cl, Br, 1, NO, -CN, -CF, -NR™R", -NRYC(=O)R", -NR'C(=O)OR", -NR'°C(=O)NR'"R™, -NR"*S(=0),R", -NR"’S(=0),NR"'"R", -OR'", -OC(=O)R", -OC(=O)OR", -OC(=O)NR™R', -OC(=O)SR™, -SR™, -S(=O)R'", -S(=0),R", -S(=0),NR"R", -C(=O)R", . -C(=0)OR", -C(=O)NR™R", and R™. In another embodiment of the invention, R is bicyclo- [3.1.0]-hexyl and is optionally substituted as recited above (i.e. optionally substituted with from . one to six substituents R® independently selected from F, Cl, Br, |, nitro, cyano, -CF,, -NR'R, -NR’C(=0)R®, -NR’C(=O)OR®, -NR'C(=O)NRPR?, -NR’S(=0),R’, -NR’S(=0),NR°R®, -OR’, -OC(=0)R’, -OC(=0)OR’, -C(=0)OR’, -C(=0)R’, -C(=0)NR'R®, -OC(=O)NR'R®, -OC(=0)SR’, -SR’, -S(=0)R?, -S(=0),R’, -S(=0),NR’R?, and R’).
in another embodiment of the invention, a compound of formula 1 is provided wherein . R' is optionally substituted straight chain or branched (C,-Cg)alky! or optionally substituted straight chain or branched (C,-Cg)alkenyl. . In another embodiment of the invention, compounds of formula 1 are provided, but wherein R?is hydrogen. In a further embodiment, R? is hydrogen, and R! is as subdefined in the preceding paragraphs.
In another embodiment, this invention provides a compound of formula 1 wherein R* is (Ce-Cyg)aryl or (5-14 membered) heteroaryl, each optionally substituted. In a preferred embodiment, R* is optionally substituted phenyl or optionally substituted pyridyl. In another preferred embodiment, R* is naphthyl, quinolyl, or isoquinolyl, each optionally substituted. In another embodiment, R* is napthy!, quinolyl, or isoquinolyl, and is unsubstituted. in another embodiment, compounds of formula 1 are provided, wherein R? is specifically hydrogen, and R* is as subdefined in the preceding paragraph.
Examples of preferred compounds of formula 1 are: :
N-(1-cyclobutyl-1H-imidazol-4-y!)-2-quinolin-6-yl-acetamide;
N-(1-cyclopentyl-1H-imidazol-4-y!)-2-(4-methoxy-phenyl)-acetamide;
N-[1-(cis-3-phenyl-cyclobuty!)-1 H-imidazol-4-yl]-2-quinolin-6-yl-acetamide;, (1-cyclobutyl-1H-imidazol-4-yt)-carbamic acid phenyl ester; 1-(1-cyclobutyl-1H-imidazol-4-yl)-3-isoquinolin-5-yl-urea;
N-[1-(cis-3-amino-cyclobutyl)-1H-imidazol-4-yl}-2-naphthalen-1 -yl-acetamide, 6-methyl-pyridine-2-carboxylic acid {cis-3-[4-(2-naphthalen-1-yl-acetylamino)- imidazol-1-yll-cyclobutyl}-amide; 1H-imidazole-4-carboxylic acid {cis-3-[4-(2-naphthalen-1-yl-acetylamino)-imidazol-1- yl]-cyclobutyl}-amide; 6-hydroxy-pyridine-2-carboxylic acid {cis-3-[4-(2-naphthalen-1-yl-acetylamino)- imidazol-1-yl]-cyclobutyl}-amide; 3-methyl-pyridine-2-carboxylic acid {cis-3-[4-(2-naphthalen-1-yl-acetylamino)- imidazol-1-yi}-cyclobutyl}-amide; 2-pyridin-3-yl-thiazole-4-carboxylic acid {cis-3-[4-(2-naphthalen-1-yl-acetylamino)- imidazol-1-yl}-cyclobutyl}-amide; . 6-{cis-3-[4-(2-naphthalen-1-yl-acetylamino)-imidazol-1-yl]-cyclobutylcarbamoyl}- nicotinic acid methyl ester; . pyrazine-2-carboxylic acid {cis-3-[4-(2-naphthalen-1-yl-acetylamino)-imidazol-1-yl}- cyclobutyl}-amide;
N-{cis-3-[4-(2-naphthalen-1-yl-acetylamino)-imidazol-1-yl]-cyclobutyl}-benzamide;
5-methyi-pyrazine-2-carboxylic acid {cis-3-[4-(2-naphthalen-1-yl-acetylamino)- . imidazol-1-yl]-cyclobutyl}-amide;
N-{cis-3-[4-(2-naphthalen-1-yl-acetylamino)-imidazol-1 -yl]-cyclobutyl}-isobutyramide; 6-chloro-pyridine-2-carboxylic acid {cis-3-[4-(2-naphthalen-1-yl-acetylamino)-imidazol- 1-yl]-cyclobutyl}-amide; quinoline-2-carboxylic acid {cis-3-[4-(2-naphthalen-1 -yl-acetylamino)-imidazol-1-yl]- cyclobutyl}-amide; 1H-pyrrole-2-carboxylic acid {cis-3-[4-(2-naphthalen-1 -yl-acetylamino)-imidazol-1-yl}- cyclobutyl}-amide;
N-{cis-3-[4-(2-naphthalen-1-yl-acetylamino)-imidazol-1 -yl]-cyclobutyl}-2-m-tolyl- acetamide; pyridine-2-carboxylic acid {cis-3-[4-(2-naphthalen-1 -yl-acetylamino)-imidazol-1-yl}- cyclobutyl}-amide; 2-(3-hydroxy-phenyl)-N-{cis-3-[4-(2-naphthalen-1-yl-acetylamino)-imidazol-1-y]- cyclobutyl}-acetamide; piperidine-4-carboxylic acid {cis-3-[4-(2-naphthalen-1 -yl-acetylamino)-imidazol-1-yl}- cyclobutyl}-amide hydrochloride;
N-[1-(cis-3-acetylamino-cyclobutyl)-1 H-imidazol-4-yl}-2-naphthalen-2-yl-acetamide;
N-{cis-3-{4-(2-isoquinolin-5-yl-acetylamino)-imidazol-1-yl}-cyclobutyl}-benzamide; and pyridine-2-carboxylic acid {cis-3-[4-(2-isoquinolin-5-yl-acetylamino)-imidazol-1-yl}- cyclobutyl}-amide; and pharmaceutically acceptable salts of the foregoing compounds.
Examples of other specific compound of the invention of formula 1 are: cis-N-(1-bicyclof3.1.0}hex-3-yi-1H-imidazol-4-y})-2-quinolin-6-yl-acetamide; cis-N-{1-[trans-6-(pyridine-2-carbonyl)-bicyclo[3.1.0]hex-3-yl}-1H-imidazol-4-yl}-2- quinolin-6-yl-acetamide;
N-{1-[cis-3-(2-methoxy-phenyl)-cyclobutyl]- H-imidazol-4-yi}-2-quinolin-6-yi- acetamide;
N-{1-[cis-3-(2-fluoro-phenyl)-cyclobutyl}-1H-imidazol-4-yl}-2-quinolin-6-yl-acetamide;
N-{1-[cis-3-(4-methoxy-phenyl)-cyclobutyl}-1H-imidazol-4-yi}-2-quinolin-6-yl- \ acetamide; 2-quinolin-6-yl-N-[1-(cis-3-p-tolyl-cyclobutyl)-1H-imidazol-4-yl}-acetamide; . N-{1-[cis-3-(2-ethoxy-phenyl)-cyclobutyl]-1H-imidazol-4-yl}-2-quinolin-6-yl-acetamide;
N-{1-[cis-3-(3-methoxy-phenyl)-cyclobutyl}- 1H-imidazol-4-yl}-2-quinolin-6-yl- acetamide; and pharmaceutically acceptable salts of the foregoing compounds.
Other examples of specific compounds of formula 1 are: . N-{1-[3-(2-hydroxy-phenyl)-cyclobutyl]-1 H-imidazol-4-yl}-2-(4-methoxy-phenyl)- acetamide; . N-{1-[3-(3-hydroxy-phenyl)-cyclobutyl}-1 H-imidazol-4-yl}-2-(4-methoxy-phenyl)- acetamide;
N-{1-[3-(2-amino-phenyl)-cyclobutyl]-1 H-imidazol-4-yl}-2-(4-methoxy-phenyl)- acetamide;
N-{1-[3-(3-amino-phenyl)-cyclobutyl]-1 H-imidazol-4-yl}-2-(4-methoxy-phenyl)- acetamide; .
N-{1-[3-(3-aminomethyl-phenyl)-cyclobutyl]-1 H-imidazol-4-yl}-2-(4-methoxy-phenyl)- acetamide;
N-{1 -[3-(3-dimethylaminomethyi-phenyl)-cyclobutyl]-1 H-imidazol-4-yl}-2-(4-methoxy- phenyl)-acetamide; and 2-(4-methoxy-phenyl)-N-{1-[3-(1-methyl-1 H-pyrazol-3-yl)-cyclobutyl]-1H-imidazol-4- yi}-acetamide; and pharmaceutically acceptable salts of the foregoing compounds.
Salts of compounds of formula 1 can be obtained by forming salts with any acidic or basic group present on a compound of formula 1. Examples of pharmaceutically acceptable salts of the compounds of formula 1 are the salts of hydrochloric acid, p-toluenesulfonic acid, fumaric acid, citric acid, succinic acid, salicylic acid, oxalic acid, hydrobromic acid, phosphoric acid, methanesulfonic acid, tartaric acid, maleic acid, di-p-toluoy! tartaric acid, acetic acid, sulfuric acid, hydroiodic acid, mandelic acid, sodium, potassium, magnesium, calcium, and lithium.
The compounds of formula 1 may have optical centers and therefore may occur in different enantiomeric and other stereoisomeric configurations. The invention includes all enantiomers, diastereomers, and other stereoisomers of such compounds of formula 1, as well as racemic and other mixtures thereof.
The subject invention also includes isotopically-labeled compounds, which are identical to those recited in formula 1, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass . number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, . phosphorous, fluorine, iodine, and chlorine, such as *H, "'C, ™C, "°F, "| and '*I. Compounds of the present invention and pharmaceutically acceptable salts of said compounds that contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention. Isotopically-labeled compounds of the present invention, for example those into which radioactive isotopes such as *H and '*C are incorporated, are useful in drug and/or . substrate tissue distribution assays. Tritiated, i.e. °H, and carbon-14, i.e., *C, isotopes are particularly preferred for their ease of preparation and detectability. 1C and "°F isotopes are , particularly useful in PET (positron emission tomography), and 125] isotopes are particularly useful in SPECT (single photon emission computerized tomography), all useful in brain imaging. Further, substitution with heavier isotopes such as deuterium, i.e., 2H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances Isotopically labeled compounds of formula 1 of this invention can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the
Examples below, by substituting a readily available isotopically labeled reagent for a non- isotopically labeled reagent.
This invention also provides a pharmaceutical composition for treating a disease or condition comprising abnormal cell growth in a mammal comprising a compound of formula 1 in an amount effective in inhibiting abnormal cell growth, and a pharmaceutically acceptable carrier.
This invention also provides a pharmaceutical composition for treating a diseases or condition comprising abnormal cell growth in a mammal comprising a compound of formula 1 in an amount effective to inhibit cdk? activity, and a pharmaceutically acceptable carrier.
This invention also provides a method for treating a disease or condition comprising abnormal cell growth in a mammal comprising administering to the mammal a compound of formula 1 in an amount effective in inhibiting abnormal cell growth.
This invention also provides a method for treating a diseases or condition comprising abnormal cell growth in a mammal 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 this invention for treating a disease or condition comprising abnormal cell growth, the disease or condition comprising abnormal cell growth is in one embodiment cancer. The cancer may be a carcinoma, for example carcinoma of the bladder, breast, colon, kidney, liver, lung, for example small cell lung cancer, esophagus, gall bladder, ovary, pancreas, stomach, cervix, thyroid, prostate, or skin, for example squamous } cell carcinoma; a hematopoietic tumor of lymphoid lineage, for example leukemia, acute lymphocytic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkins lymphoma, non-Hodgkins ) lymphoma, hairy cell lymphoma, or Burkett's lymphoma; a hematopoietic tumor of myeloid lineage, for example acute and chronic myelogenous leukemias, myelodysplastic syndrome, or promyelocytic leukemia; a turmor 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 pigmentoum; keratoctanthoma; thyroid follicular cancer; or Kaposi's sarcoma. . in another embodiment, the disease or condition comprising abnormal cell growth is benign. Such diseases and conditions include benign prostate hyperplasia, familial adenomatosis polyposis, neuro-fibromatosis, atherosclerosis, pulmonary fibrosis, arthritis, psoriasis, glomerulonephritis, restenosis, hypertrophic scar formation, inflammatory bowel disease, transplantation rejection, fungal infection, and endotoxic shock.
This invention also provides a pharmaceutical composition for treating a neurodegenerative disease or condition in a mammal comprising a compound of formula 1 in an amount effective in treating said disease or condition, and a pharmaceutically acceptable carrier.
This invention also provides a pharmaceutical composition for treating a neurodegenerative disease or condition in a mammal comprising a compound of formula 1 in an amount effective in inhibiting cdk5 activity, and a pharmaceutically acceptable carrier.
This invention also provides a method for treating a neurodegenerative disease or condition in a mammal comprising administering to the mammal a compound of formula 1 in an amount effective in inhibiting cdks activity.
This invention also provides a method for treating a neurodegenerative disease or condition in a mammal comprising administering to the mammal a compound of formula 1 in an amount effective in treating said disease or condition.
In one embodiment of the invention, the neurodegenerative disease or condition which is treated is selected from Huntington's disease, stroke, spinal cord trauma, traumatic brain injury, multinfarct dementia, epilepsy, amyotrophic lateral sclerosis, pain, viral induced dementia for example AIDS induced dementia, neurodegeneration associated with bacterial infection, migraine, hypoglycemia, urinary incontinece, brain ischemia, multiple sclerosis,
Alzheimer’s disease, senile dementia of the Alzheimer’s type, mild cognitive impairment, age- related cognitive decline, emesis, corticobasal degeneration, dementia pugilistica, Down’s syndrome, myotonic dystrophy, Niemann-Pick disease, Pick’s disease, prion disease with tangles, progessive supranuclear palsy, lower lateral sclerosis, and subacute sclerosing . panencephalistis.
This invention also provides a pharmaceutical composition for treating a disease or ] condition the treatment of which can be effected or facilitated by altering dopamine mediated neurotransmission in a mammal comprising a cdk5 inhibitor in an amount effective in treating said disease or condition and a pharmaceutically acceptable carrier.
This invention also provides a pharmaceutical composition for treating a disease or “ condition the treatment of which can be effected or facilitated by altering dopamine mediated neurotransmission in a mammal comprising a cdk5 inhibitor in an amount effective to inhibit . cdk5 and a pharmaceutically acceptable carrier. )
This invention also provides a method for treating a disease or condition the treatment of which can be effected or facilitated by altering dopamine mediated neurotransmission ina mammal comprising administering to the mammal a cdkd inhibitor in an amount effective in inhibiting cdk5 activity. }
This invention also provides a method for treating a disease ot condition the treatment of which can be effected or facilitated by altering dopamine mediated neurotransmission in a mammal comprising administering to the mammal a cdkS inhibitor in an amount effective in treating said disease or condition. in one embodiment of the invention, the disease or condition the treatment of which can be effected or facilitated by altering dopamine mediated neurotransmission is selected from Parkinson's disease; schizophrenia; schizophreniform disorder; schizoaffective disorder, for example of the delusional type or the depressive type; delusional disorder; substance- induced psychotic disorder, for example psychosis induced by alcohol, amphetamine, cannabis, cocaine, hallucinogens, inhalants, opioids, or phencyclidine; personality disorder of the paranoid type; personality disorder of the schizoid type; drug addiction, including narcotic (e.g. heroin, opium, and morphine), cocaine and alcohol addiction; drug withdrawal, including narcotic, cocaine and alcohol withdrawal, obsessive compulsive disorder; Tourette's syndrome; depression; a major depressive episode, a manic or mixed mood episode, a hypomanic mood episode, a depressive episode with atypical features or with melancholic features or catatonic features, a mood episode with postpartum onset; post-stroke depression, major depressive disorder, dysthymic disorder, minor depressive disorder, premenstrual dysphoric disorder, post-psychotic depressive disorder of schizophrenia, a major depressive disorder superimposed on a psychotic disorder such as delusional disorder or schizophrenia, a bipolar disorder, for example bipolar | disorder, bipolar Il disorder, cyclothymic disorder; anxiety; attention deficit and hyperactivity disorder; and attention deficit disorder.
In another embodiment, the cdk5 inhibitor in the method or composition for treating a . disease or condition the treatment of which can be effected or facilitated by altering dopamine mediated neurotransmission is a compound of formula 1 or a pharmaceutically-acceptable ; salt thereof.
This invention also provides a pharmaceutical composition for treating a disease or condition facilitated by cdk5 activity in a mammal which composition comprises a compound of formula 1 in an amount effective in inhibiting cdk5 activity and a pharmaceutically . acceptable carrier.
This invention also provides a method for treating a disease or condition facilitated by . cdk5 activity in a mammal which method comprises administering to the mammal a compound of formula 1 in an amount effective in inhibiting cdk5 activity.
We have also found that the compounds of formula 1 have activity in inhibiting GSK- 3. The compounds of formula 1 therefore can be expected to be useful in treating diseases and conditions the treatment of which can be effected or facilitated by inhibition of GSK-3.
Diseases and conditions the treatment of which can be effected or facilitated by inhibiting 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, multiinfarct dementia, traumatic brain injury, and spinal cord trauma.
Therefore, compounds of formula 1 are effective in treating neurodegenerative diseases and conditions based on both cdk5 activity and GSK-3 activity.
Other diseases and conditions the treatment of which can be effected or facilitated by inhibiting GSK-3 include psychotic disorders and conditions, for example schizophrenia, schizophreniform disorder; schizoaffective disorder, for example of the delusional type or the depressive type; delusional disorder; substance-induced psychotic disorder, for example psychosis induced by alcohol, amphetamine, cannabis, cocaine, hallucinogens, inhalants, opioids, or phencyclidine; personality disorder of the paranoid type; and personality disorder of the schizoid type. The treatment of such diseases and conditions can also be effected or facilitated by altering dopamine mediated neurotransmission. Therefore, compounds of formula 1 are effective in treating such disorders and conditions based on both cdk5 activity and GSK-3 activity.
Other disorders and conditions the treatment of which can be effected or facilitated by inhibiting GSK-3 include mood disorders and mood episodes, for example a major depressive episode, a manic or mixed mood episode, a hypomanic mood episode, a depressive episode with atypical features or with melancholic features or catatonic features, a mood episode with . postpartum onset; post-stroke depression, major depressive disorder, dysthymic disorder, minor depressive disorder, premenstrual dysphoric disorder, post-psychotic depressive . disorder of schizophrenia, a major depressive disorder superimposed on a psychotic disorder such as delusional disorder or schizophrenia, a bipolar disorder, for example bipolar disorder, bipolar H disorder, and cyclothymic disorder. The treatment of such mood disorders and episodes, for example depression, can also be effected or facilitated by altering dopamine mediated neurotransmission. Therefore, compounds of formula 1 are effective in treating . certain mood disorders and mood episodes based on both cdk5 activity and GSK-3 activity.
Other disorders and conditions the treatment of which can be effected or facilitated by . inhibiting GSK-3 are male fertility and sperm motility; diabetes mellitus; impaired glucose tolerance; metabolic syndrome or syndrome X; polycystic ovary syndrome; adipogenesis and obesity; myogenesis and frailty, for example age-related decline in physical performance; acute sarcopenia, for example muscle atrophy and/or cachexia associated with burns, bed rest, limb immobilization, or major thoracic, abdominal, and/or orthopedic surgery; sepsis; spinal cord injury; hair loss, hair thinning, and balding; immunodeficiency; and cancer.
Accordingly, the present invention also provides a pharmaceutical composition for treating in a mammal, including a human, a disease or condition selected from male fertility and sperm motility; diabetes mellitus; impaired glucose tolerance; metabolic syndrome or syndrome X; polycystic ovary syndrome; adipogenesis and obesity; myogenesis and frailty, for example age-related decline in physical performance; acute sarcopenia, for example muscle atrophy and/or cachexia associated with burns, bed rest, limb immobilization, or major thoracic, abdominal, and/or orthopedic surgery; sepsis; hair loss, hair thinning, and balding; and immunodeficiency; which composition comprises a pharmaceutically acceptable carrier and an amount of a compound of formula 1 effective in treating said disease or condition.
The present invention further provides a pharmaceutical composition for treating in a mammal, including a human, a disease or condition selected from male fertility and sperm motility; diabetes mellitus; impaired glucose tolerance; metabolic syndrome or syndrome X; polycystic ovary syndrome; adipogenesis and obesity; myogenesis and frailty, for example age-related decline in physical performance; acute sarcopenia, for example muscle atrophy and/or cachexia associated with burns, bed rest, limb immobilization, or major thoracic, abdominal, and/or orthopedic surgery; sepsis; hair loss, hair thinning, and balding; and immunodeficiency; which composition comprises a pharmaceutically acceptable carrier and an amount of a compound of formula 1 effective in inhibiting GSK-3.
The present invention also provides a method for treating in a mammal, including a human, a disease or condition selected from male fertility and sperm motility; diabetes mellitus; impaired glucose tolerance; metabolic syndrome or syndrome X; polycystic ovary syndrome; adipogenesis and obesity, myogenesis and frailty, for example age-related decline in physical performance; acute sarcopenia, for example muscle atrophy and/or cachexia ) associated with burns, bed rest, limb immobilization, or major thoracic, abdominal, and/or orthopedic surgery; sepsis; hair loss, hair thinning, and balding; and immunodeficiency; which method comprises administering to said mammal an amount of a compound of formula 1 effective in treating said disease or condition.
Claims (1)
- . CLAIMS What is claimed is:, 1. A compound of the formula A 0 RY—N ana SX 1 wherein R' is a straight chain or branched (C,-Cg)alkyl, a straight chain or branched (C.- Cg)alkenyl, a straight chain or branched (C,-Cg)alkynyl, (C,-Cg)cycloalkyl, (C,-Cg)cycloalkenyl, (3- 8 membered) heterocycloalkyl, (Cs-C,,)bicycloalkyl, (C,-C,;)bicycloalkenyl, (5-11 membered) heterobicycloalkyl, (C4-Cys) aryl, or (5-14 membered) heteroaryl; and wherein R' is optionally substituted with from one to six substituents R% independently selected from F, Cl, Br, 1, nitro, cyano, -CF, -NR7R®, -NR'C(=O)R®, -NR'C(=0)OR’, -NR’C(=0)NRIR?, -NR’S(=0),R%, - NR’S(=0),NRER?, -OR’, -OC(=O)R’, -OC(=O)OR’, -C(=0)OR’, -C(=O)R’, -C(=O)NR'R®, -OC(=0)NRR?, -OC(=0)SR’, -SR’, -S(=O)R’, -S(=0),R’, -5(=0),NRR?, -O-S(=0),R’, -N;, and RR’ R?is H, F, -CH,, -CN, or -C(=0O)OR’; : R? is -C(=O)NR®-, -C(=0)O-, -C(=0)(CR"R"),-, or (CR"’R"").-; R'is a straight chain or a branched (C;-Cg)alkyl, a straight chain or a branched (C.- Cgalkeny), a straight chain or branched (C,-Cq alkynyl), (Ca-Cg)eycloalkyl, (C,-Cg)cycloalkenyl, (3-8 membered) heterocycloalkyl, (Cs-C4;)bicycloalkyl, (C,~C4,)bicycloatkenyl, (5-11 membered) heterobicycloalkyl, (Ce-Cis)aryl, or (5-14 membered) heteroaryl; and wherein R* is optionally substituted with from one to three substitutents R® independently selected from F, Cl, Br, |, nitro, ‘ cyano, -CF, -NR'R’, -NR'C(=O)R’, -NR'C(=O)OR’ -NR’C(=0)NR°R®, -NR’S(=0),R®, NR’S(=0),NR®R’, -OR’, -OC(=O)R’, -OC(=0)OR’, -C(=0)OR’, -C(=O)R’, -C(=O)NR'R®, -OC(=O)NR'R?, -OC(=0)SR’, -SR’, -S(=0)R’, -§(=0),R’, -S(=0),NR'R®, or R’; each R’, R®, and R® is independently selected from H, straight chain or branched (C,- Co)alkyl, straight chain or branched (C,-Cg)alkenyl, straight chain or branched (C.-C; alkynyl), ] (Cs-Cs)eycloalkyl, (C,-Cgleycloalkenyl, (3-8 membered) heterocycloalkyl, (Cs-Cyq)bicycloalkyl, (C,-C,4)bicycloalkenyl, (5-11 membered) heterobicycloalkyl, (Ce-Cus)aryl, and (5-14 membered) ] 30 heteroaryl, wherein R’, R?, and R® are each independently optionally substituted with from one to six substituents independently selected from F, Cl, Br, |, NO; -CN, -CF,, -NR"R" -NR™C(=0)R"", -NRC(=O)OR", -NRC(=O)NR''R", -NR°S(=0),R", -NR™S(=0),NR''R?,Ful 1 lBUV YY 4 VY HOOD LOR", -OC(=O)R®, -OC(=0)OR™, -OC(=OJNR"R", -OC(=O)SR', -SR, -S(=0)R™, - -$(=0),R", -S(=0),NR"R", -C(=0)R"°, -C(=0)OR", -C(=O)NR™R", and R'; or, when R” and RE are as in NR'R?, they may instead optionally be connected to form . with the nitrogen of NRR® to which they are attached a heterocycloalkyl moiety of from three to seven ring members, said heterocycloalkyl moiety optionally comprising one or two further heteroatoms independently selected from N, O, and S; each RR" and R%is independently selected from H, straight chain or branched (C+- Ce)alkyl, straight chain or branched (C,-Cg)alkenyl, straight chain or branched (C,-Cq alkynyl), (C-Cg)cycloalkyl, (C,-Cg)cycloalkenyl, (3-8 membered) heterocycioalkyl, (C.-C; )bicycloalkyl, (C,-C,,)bicycloalkenyl, (5-11 membered) heterobicycloalkyl, (C¢-Cy,)aryl, and (5-14 membered) heteroaryl, wherein R™, R"!, and R' are each independently optionally substituted with from one to six substituents independently selected from F, Cl, Br, I, -NO,, -CN, -CF;, -NR®R™, NRBC(=0)R™, -NR™C(=0)OR", -NRPC(=O)NR"R, NRPS(=0),R", -NRPS(=0),NR"R", -OR®, -OC(=0)R™, -OC(=0)OR®, -OC(=0)NR™R", -OC(=0)SR™, -SR", -S5(=0)R", -S(=0),R™, -S(=0),NRPR", -C(=O)R", -C(=0)OR", -C(=O)NR™R™, and R™, each R%, R*, and R'is independently selected from H, straight chain or branched (C;- Cg)alkyl, straight chain or branched (C,-Cg)alkenyl, straight chain or branched (C.-C, alkynyl), (Cs-Ce)cycloalkyl, (C4-Cg)cycloalkenyl, (3-8 membered) heterocycloalkyl, (Cs-Cy4)bicycloalkyl, (C,-C,,)bicycloalkeny!, (5-11 membered) heterobicycloalkyl, (C&-Cys)aryl, and (5-14 membered) heteroaryl, wherein R®, R", and R' are each independently optionally substituted with from one to six substituents independently selected from F, Cl, Br, I, -NO, -CN, CF, -NR"R", -NR"®C(=0)R", -NR'"C(=0)OR", -NR'®C(=O)NR''R'®, -NR'"S(=0),R", -NR"*S(=0),NR"R, OR", -OC(=O)R®™, -OC(=0)OR'™, -OC(=O)NR™RY, -OC(=O)SR’™, -SR® -S(=O)R', -S(=0),R", -S(=0),NR"®*R", -C(=O)R', -C(=0)OR", -C(=0)NR™R", and R'S; each R', R'7, and R" is independently selected from H, straight chain or branched (C,- Ce)alkyl, straight chain or branched (C,-Cg)alkenyl, straight chain or branched (C.-C alkynyl), (C,-Ce)cycloalkyl, (C,-Cg)cycloalkenyl, (3-8 membered) heterocycloalkyl, (Cs-C,4)bicycloalkyl, (C,-C,4)bicycloalkenyl, (5-11 membered) heterobicycloalkyl, (C4s-Cia)aryl, and (5-12 membered) heteroaryl; nis 0, 1,2, or 3; . wherein R'* and R" in -C(=0)(CR'R"),- and -(CR"R"),- are for each iteration of n defined independently as recited above; . or a pharmaceutically acceptable salt thereof.2. A compound according to claim 1, wherein R® is -C(=O)NH- or - C(=O)}CR™R").-.3. A compound according to claim 1, wherein R' is optionally substituted . (C+-Cs)cycloalkyl or optionally substituted (C¢-C,,) bicycloalkyl. 4, A compound according to claim 4, wherein R' is cyclopropyl, \ cyclobutyl, cyclopentyl, cyclohexyl, norbormnyl, or bicyclo-[3.1.0)-hexyl, each optionally substituted.5. A compound according to claim 1, wherein R’ is optionally substituted straight chain or branched (C,-C,)alkyl or optionally substituted straight chain or branched (C,- Cg)alkenyl. )8. A compound according to claim 1, wherein R* is (Cs-Cy,)aryl or (5-14 membered) heteroaryl, each optionally substituted.7. A compound according to claim 6, wherein R* is phenyl, pyridyl, naphthyl, quinolyl, or isoquinolyl, each optionally substituted.8. A compound according to any of claims 1-7, wherein R? is hydrogen.9. A compound of claim 1, selected from the group consisting of: N-(1-cyclobutyl-1H-imidazol-4-yl)-2-quinolin-6-yl-acetamide; N-(1-cyclopentyl-1H-imidazol-4-yl)-2-(4-methoxy-phenyl)-acetamide; N-[1-(cis-3-phenyl-cyclobutyl)-1H-imidazol-4-yl]-2-quinolin-6-yl-acetamide; (1-cyclobutyl-1H-imidazol-4-yl)-carbamic acid phenyl ester; 1-(1-cyclobutyl-1H-imidazol-4-yl)-3-isoquinolin-5-yl-urea; N-[1-(cis-3-amino-cyclobutyl)-1H-imidazol-4-yl}-2-naphthalen-1-yl-acetamide; 6-methyl-pyridine-2-carboxylic acid {cis-3-[4-(2-naphthalen-1-yl-acetylamino)- imidazol-1-yl}-cyclobutyl}-amide; 1H-imidazole-4-carboxylic acid {cis-3-[4-(2-naphthalen-1-yl-acetylamino)-imidazol-1- yi}-cyclobutyl}-amide; 6-hydroxy-pyridine-2-carboxylic acid {cis-3-[4-(2-naphthalen-1-yl-acetylamino)- imidazot-1-yl]-cyclobutyl}-amide; 3-methyil-pyridine-2-carboxylic acid {cis-3-[4-(2-naphthalen-1-yl-acetylamino)- imidazol-1-yll-cyclobutyl}-amide; 2-pyridin-3-yl-thiazole-4-carboxylic acid {cis-3-[4-(2-naphthalen-1-yl-acetylamino)- imidazol-1-ylj-cyclobutyl}-amide; } 6-{cis-3-[4-(2-naphthalen-1-yl-acetylamino)-imidazol-1-yl]-cyclobutylcarbamoyl}- nicotinic acid methyl ester; pyrazine-2-carboxylic acid {cis-3-[4-(2-naphthalen-1-yl-acetylamino)-imidazol-1-yi]- cyclobutyl}-amide; N-{cis-3-[4-(2-naphthalen-1-yl-acetylamino)-imidazol-1-yl]-cyclobutyl}-benzamide;5-methyl-pyrazine-2-carboxylic acid {cis-3-[4-(2-naphthalen-1 -yl-acetylamino)- - imidazol-1-yi}-cyclobutyl}-amide; N-{cis-3-[4-(2-naphthalen-1-yl-acetylamino)-imidazol-1 -yl]-cyclobutyl}-isobutyramide; . 6-chloro-pyridine-2-carboxylic acid {cis-3-[4-(2-naphthalen-1-yl-acetylamino)-imidazol- 1-yi}-cyclobutyl}-amide; quinoline-2-carboxylic acid {cis-3-{4-(2-naphthalen-1-yl-acetylamino)-imidazol-1 yi cyclobutyl}-amide; 1H-pyrrole-2-carboxylic acid {cis-3-[4-(2-naphthalen-1-yl-acetylamino)-imidazol-1-yl}- cyclobutyi}-amide; N-{cis-3-[4-(2-naphthalen-1-yl-acetylamino)-imidazol-1 -yll-cyclobutyl}-2-m-tolyl- acetamide; pyridine-2-carboxylic acid {cis-3-[4-(2-naphthalen-1-yl-acetylamino)-imidazol-1-y]- cyclobutyl}-amide; 2-(3-hydroxy-phenyl)-N-{cis-3-[4-(2-naphthalen-1 -yl-acetylamino)-imidazol-1-yl}- cyclobutyl}-acetamide; piperidine-4-carboxylic acid {cis-3-[4-(2-naphthalen-1-yl-acetylamino)-imidazol-1-yl}- cyclobutyl}-amide hydrochloride; N-[1-(cis-3-acetylamino-cyclobutyl)-1 H-imidazol-4-yl]-2-naphthalen-2-yl-acetamide; N-{cis-3-[4-(2-isoquinolin-5-yl-acetylamino)-imidazol-1 -yll-cyclobutyli}-benzamide; and pyridine-2-carboxylic acid {cis-3-[4-(2-isoquinolin-5-yl-acetylamino)-imidazol-1-yl]- cyclobutyl}-amide; and pharmaceutically acceptable salts of the foregoing compounds.10. A pharmaceutical composition for treating a disease or condition comprising abnormal cell growth or a neurodegenerative disease or condition in a mammal comprising a compound of claim 1 in an amount effective in treating said disease or condition, and a pharmaceutically acceptable carrier.11. A pharmaceutical composition for treating a disease or condition in a mammal the treatment of which can be effected or facilitated by altering dopamine mediated neurotransmission comprising a cdk5 inhibitor in an amount effective in treating said disease or condition or in an amount effective to inhibit cdk5 activity, and a pharmaceutically. acceptable carrier.12. A pharmaceutical composition for treating in a mammal a disease or . condition selected from male fertility and sperm motility; diabetes mellitus; impaired glucose tolerance; metabolic syndrome or syndrome X; polycystic ovary syndrome; adipogenesis and obesity; myogenesis and frailty, for example age-related decline in physical performance; acute sarcopenia, for example muscle atrophy and/or cachexia associated with burns, bed rest, limb immobilization, or major thoracic, abdominal, and/or orthopedic surgery; sepsis; hair . loss, hair thinning, and balding; and immunodeficiency, comprising a compound of claim 1 in an amount effective in treating said disease or condition, and a pharmaceutically acceptable } carrier.13. A pharmaceutical composition comprising a cdk5 inhibitor and a second member selected from the group consisting of an SSRI, an NK-1 receptor antagonist, a 5HTp antagonist, ziprasidone, olanzapine, risperidone, L-745870, sonepiprazole, RP 62203, NGD 941, balaperidone, flesinoxan, gepirone, an acetylcholinesterase inhibitor, TPA, NIF, a . potassium channel modulator such as BMS-204352, and an NMDA receptor antagonist, wherein the cdk5 inhibitor and the second member are together in an effective amount, and a pharmaceutically acceptable carrier.
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| US5401851A (en) * | 1992-06-03 | 1995-03-28 | Eli Lilly And Company | Angiotensin II antagonists |
| US5760246A (en) * | 1996-12-17 | 1998-06-02 | Biller; Scott A. | Conformationally restricted aromatic inhibitors of microsomal triglyceride transfer protein and method |
| ZA987385B (en) * | 1997-08-19 | 2000-04-18 | Lilly Co Eli | Growth hormone secretagogues. |
| ZA987383B (en) * | 1997-08-19 | 2000-02-17 | Lilly Co Eli | Treatment of congestive heart failure with growth hormone secretagogues. |
| KR100581199B1 (en) * | 1998-06-19 | 2006-05-17 | 카이론 코포레이션 | Inhibitors of Glycogen Synthase Kinase 3 |
| WO2000021550A2 (en) * | 1998-10-13 | 2000-04-20 | President And Fellows Of Harvard College | Methods and compositions for treating neurodegenerative diseases |
| CO5160260A1 (en) * | 1999-02-19 | 2002-05-30 | Lilly Co Eli | SECRETAGOGOS OF THE HORMONE OF GROWTH DERIVED FROM IMI- DAZOL 1,4- SUBSTITUTED |
| DE69912808T2 (en) * | 1999-12-08 | 2004-09-30 | Centre National De La Recherche Scientifique (C.N.R.S.) | Use of hymenialdisine and its derivatives for the preparation of therapeutic agents |
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