OA12368A - Pyrazole derivatives and their use as protein kinase inhibitors. - Google Patents

Pyrazole derivatives and their use as protein kinase inhibitors. Download PDF

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OA12368A
OA12368A OA1200300050A OA1200300050A OA12368A OA 12368 A OA12368 A OA 12368A OA 1200300050 A OA1200300050 A OA 1200300050A OA 1200300050 A OA1200300050 A OA 1200300050A OA 12368 A OA12368 A OA 12368A
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pyrazol
cyclobutyl
phenyl
acetamide
methoxy
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OA1200300050A
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Christopher Blair
Christopher John Helal
Mark Allen Sanner
Travis T Wager
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Pfizer Prod Inc
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Abstract

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

Description

012368
PYRAZOLE DERIVATIVES AND THEIR USE AS PROTEIN KINASE INHIBITORS
Field of the Invention
The subject invention relates to pyrazole dérivatives, pharmaceutical compositions5 comprising such dérivatives and methods of using such dérivatives to treat abnormal cellgrowth and certain diseases and conditions of the centra) nervous System. The compounds ofthe présent invention act as inhibitors of cyclin-dependent protein kinase enzymes cdk5(cyclin-dependant protein kinase 5) and cdk2 (cyclin-dependent protein kinase 2). Thecompounds of the présent invention also are inhibitors of the enzyme GSK-3 (glygocen 10 synthase kinase-3) enzyme.
Background of the Invention
The serine/threonine kinase cdk5 along with its cofactor p25 (or the longer cofactor,p35j has been linked to neurodegenerative disorders, and inhibitors of cdk5/p25 (or cdk5/p35)are therefore usefui for the treatment of neurodegenerative disorders such as Alzheimer’s 15 disease, Parkinson’s disease, stroke, or Huntington’s disease. Treatment of suchneurodegenerative disorders using cdk5 inhibitors is supported by the finding that cdk5 isinvolved in the phosphorylation of tau protein (J. Biochem, 117, 741-749 (1995)). cdk5 alsophosphorylâtes Dopamine and Cyciic AMP-Regulated Phosphorprotein (DARPP-32) atthreonine 75 and is thus indicated in having a rôle in dopaminergic neurotransmission 20 (Nature, 402, 669-671 (1999)).
The serine/threonine kinase cdk2 is essential for normal cell cycling and plays acritical rôle in disorders arising from abnormal cell cycling, a common characteristic of manyoncological disorders. Inhibitors of cdk2 are therefore usefui for the treatment of various typesof cancer and other diseases or conditions related to abnormal cell growth (Meijer, et al., 25 Properties and Potential-applications of Chemical Inhibitors of Cyclin-dependent Kinsases,
Pharmacology &amp; therapeutics, 82 (2-3), 279-284 (1999); Sausvilie, et al., Cyclin-dependentKinases: Initial Approaches to Exploit a Novel Therapeutic Target, Pharmacology &amp;therapeutics 82 (2-3) 285-292 (1999)). GSK-3 is a serine/threonine protein kinase. It is one of severai protein kinases which30 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, a andβ, in vertebrates, reported as having a monomeric structure of 49kD and 47kD respectively.Both isoforms phosphorylate muscle glycogen synthase (Cross, et al., Biochemical Journal303: 21-26 (1994)). The amino acid ïdentity among GSK-3 species homologs has been 35 indicated to be in excess of 98% within the catalytic domain (Plyte, et al., Biochim. Biophys. 012368 -2-
Acta 1114:147-162) (1992)). Due to a remarkably high degree of conservation across thephylogenetic spectrum, a fundamental rôle of GSK-3 in cellular processes is suggested. GSK-3 has been implicated in numerous different disease States and conditions. Forexample, Chen, et al, Diabètes 43: 1234-1241 (1994) hâve suggested that an increase in 5 GSK-3 activity can be important in Type 2 diabètes. Increased GSK-3 expression in diabeticmuscle is also though to contribute to the impaired glycogen synthase activity and skeletalmuscle insulin résistance présent in Type 2 diabètes (Nikoulina, et al., Diabètes 49: 263-271(2000)). Also, a higher activity of a type 1 protein phosphatase measured in immotile spermwas attributed to higher GSK-3 activity and was indicated as responsible for holding the 10 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 thedevelopment and régulation of sperm motility and a possible physiological rôle for a proteinphosphatase 1/inhibitor 2/GSK-3 System. GSK-3 activity has also been associated withAlzheimer's disease and mood disorders such as bipolar disorder (WO 97/41854). Among 15 other conditions, GSK-3 has furthermore been implicated in haïr loss, schizophrenia, andneurodegeneration, including both chronic neurodegenerative diseases (such as Alzheimer's,supra) and neurotrauma, for example stroke, traumatic brain injury, and spinal cord trauma.
Summary of the Invention 20 This invention provides compounds of the formula
H
wherein R1 is a straight chain or branched (C1-C6)alkyl, a straight chain or branched (C2-Ce)alkenyl, a straight chain or branched (C2-Ca)alkynyl, (C3-CB)cycioalkyl, (C4-Ca)cycloalkenyl, (3- 25 8 membered) heterocycloalkyl, (Cs-C^jbicycloalkyl, (Cy-C^jbicycloalkenyl, or (5-11 membered) heterobicycloaikyl; and wherein R1 is optionally substituted with from one to six substituents R5independently 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, - 30 S(=O)R7, -S(=O)2R7, -S(=O)2NR7R8, and R7; R2 is H, F, -CH3, -CN, or -C(=O)OR7; R3 is -C(=O)NR9-, -C(=O)O-, -C(=O)(CR’°R11)n-, or -(CR10R11)n-; 012368 -3- R4 is a straight Chain or a branched (C1-C8)alkyl, a straight chain or a branched (C2-CB)alkenyl, a straight chain or branched (C2-C8 aikynyl), (C3-C8)cycloalkyl, (C4-CB)cycloalkenyl,(3-8 membered) heterocycloalkyl, (C5-C11)bicycloalkyl, (C7-C,,)bicycloalkenyl, (5-11 membered)heterobicycioalkyl, (C6-C14)aryl, or (5-14 membered) heteroaryl; and wherein R4 is optionally 5 substituted with from one to three substitutents R6 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, or R7; each R', R8, and R9 is independently selected from H, straight chain or branched (C,-10 Ce)a)kyl, straight chain or branched (C2-CB)alkenyl, straight chain or branched (C2-CB aikynyl),(C3-CB)cycloalkyl, (C4-C8)cycloalkenyl, (3-8 membered) heterocycloalkyl, (Cs-C^bicycloalkyl,(C7-C11)bicycloalkenyl, (5-11 membered) heterobicycioalkyl, (C6-C14)aryl, and (5-14 membered)heteroaryl, wherein R7, R8, and R9 are each independently optionally substituted with from one tosix substituents independently selected from F, Cl, Br, I, NO2, -CN, -CF3, -NR10R11, 15 -NR10C(=O)R11, -NR10C(=O)OR11, -NR10C(=O)NR11R12, -NR10S(=O)2R11, -NR10S(=O)2NR11R12, -OR10, -OC(=O)R10, -OC(=O)OR10, -OC(=O)NR1ÛR11, -OC(=O)SR10, -SR10, -S(=O)R10,-S(=O)2R10, -S(=O)2NR10R11, -C(=O)R10, -C(=O)OR10, -C(=O)NR10R11, and R10; or, when R7 and R8 are as in NR7R8, they may instead optionally be connected to formwith the nitrogen of NR7R6 to which they are attached a heterocycloalkyl moiety of from three to 20 seven ring members, said heterocycloalkyl moiety optionally comprising one or two furtherheteroatoms independently selected from N, O, and S; each R10, R11, and R12 is independently selected from H, straight chain or branched (C4-C8)alkyl, straight chain or branched (C2-C8)alkenyl, straight chain or branched (C2-Ce aikynyl),(C3-C8)cycloalkyl, (C4-C8)cycloalkenyl, (3-8 membered) heterocycloalkyl, (Cs-C^Jbicycloalkyl, 25 (C^C^bicycloalkenyl, (5-11 membered) heterobicycioalkyl, (C6-C14)aryl, and (5-14 membered)heteroaryl, wherein R10, R’1, and R12 are each independently optionally substituted with from oneto six substituents independently selected from F, Cl, Br, I, NO2, -CN, -CF3, -NR13R14,-NR13C(=O)R14, -NR13C(=O)OR14, -NR13C(=O)NR14R1S, -NR13S(=O)2R14, -NR13S(=O)2NR14R15,-OR13, -OC(=O)R13, -OC(=O)OR13, -OC(=O)NR13R14, -OC(=O)SR13, -SR13, -S(=O)R13. 30 -S(=O)2R13, -S(=O)2NR13R14, -C(=O)R13, -C(=O)OR13, -C(=O)NR13R14, and R13; each R13, R14, and R15 is independently selected from H, straight chain or branched (C4- CB)alkyl, straight chain or branched (C2-C8)alkenyl, straight chain or branched (C2~C8 aikynyl),(C3-C8)cycloalkyl, (C4-C8)cycloalkenyl, (3-8 membered) heterocycloalkyl, (C^QJbicycloalkyl,(C7-Cn)bicycloalkenyl, (5-11 membered) heterobicycioalkyl, (C8-C14)aryl, and (5-14 membered) 35 heteroaryl, wherein R13, R14, and R15 are each independently optionally substituted with from oneto six substituents independently seiected from F, Cl, Br, I, NO2, -CN, -CF3, -NR1BR17, 012368 -4- -NR’6C(=O)R17, -NR16C(=O)OR17, -NR16C(=O)NR17R18, -NR16S(=O)2R17, -NR16S(=O)2NR17R18-OR16, -OC(=O)R16, -OC(=O)OR16, -OC(=O)NR16R17, -OC(=O)SR16, -SR16, -S(=O)R16,-S(=O)2R16, -S(=O)2NR16R17, -C(=O)R16, -C(=O)ORis, -C(=O)NR16R17, and R16 each R16, R17, and R18 is independently selected from H, straight Chain or branched (C,-CB)alkyl, straight chain or branched (C2-C8)alkenyl, straight chain or branched (C2-CB aikynyl),(C3-C8)cycloalkyi, (C4-Ce)cycloalkenyl, (3-8 membered) heterocycloalkyl, (C5-Cn)bicycloalkyl,(CrCu)bicycloalkenyi, (5-11 membered) heterobicycloalkyl, (C6-Ct4)aryl, and (5-14 membered)heteroaryl; n is 0, 1,2, or 3; wherein R10 and R11 in -C(=O)(CR10R11)n- and -(CR10R11)n- are for each itération of ndefined independently as recited above; and pharmaceutically acceptable salts thereof.
Amino-substituted pyrazoles cap exist as mixtures of tautomeric isomers inequilibrium with one another. The présent invention includes ail such tautomers ofcompounds of formula 1, and référencés herein to compounds of formula 1, unless otherwiseindicated, encompass also the tautomers of compounds of formula 1.
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 treatmentof neurodegenerative disorders and other CNS disorders, and of abnormal cell growth,including cancer. The compounds of formula 1 are particularly useful in inhibiting cdk5. Thecompounds of formula 1 are also useful as inhibitors of GSK-3.
The term “alkyl”, as used herein, unless otherwise indicated, includes saturatedmonovalent hydrocarbon radicals having straight or branched moieties. Examples of alkylgroups include, but are not limited to, methyl, ethyl, propyl, isopropyl, and f-butyl.
The term "alkenyl”, as used herein, unless otherwise indicated, includes alkyl moietieshaving at least one carbon-carbon double bond wherein alkyl is as defined above. Examplesof alkenyl include, but are not limited to, ethenyl and propenyl.
The term “aikynyl”, as used herein, unless otherwise indicated, includes alkyl moietieshaving at least one carbon-carbon triple bond wherein alkyl is as defined above. Examples ofaikynyl 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 ofcycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, andcycioheptyl. “Bicycloalkyl” groups are non-aromatic saturated carbocyclic groups consistingof two rings, wherein said rings share one or two carbon atoms. For purposes of the présentinvention, and unless otherwise indicated, bicycloalkyl groups include spiro groups and fused 012368 •‘l -5- 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."Cycioalkenyl” and “bicycloalkenyl” refer to non-aromatic carbocyclic cycloalkyl andbicycloalkyl moieties as defined above, except comprising one or more carbon-carbon doublebonds connecting carbon ring members (an "endocyclic" double bond) and/or one or morecarbon-carbon double bonds connecting a carbon ring member and an adjacent non-ringcarbon (an “exocyclic" double bond). Examples of cycioalkenyl groups include, but are notlimited to, cyclopentenyl and cyclobutenyl, and a non-limiting example of a bicycloalkenylgroup is norbornenyl. Cycloalkyl, cycioalkenyl, bicycloalkyl, and bicycloalkenyl groups alsoinclude groups that are substituted with one or more oxo moieties. Examples of such groupswith oxo moieties are oxocyclopentyl, oxocyclobutyl, oxocyclopentenyl, and norcamphoryl.
The term “aryl", as used herein, unless otherwise indicated, includes an organicradical 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 tonon-aromatic cyclic groups containing one or more heteroatoms, prefereably from one to fourheteroatoms, 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 therings contains a heteroatom (O, S, or N). Heterobicycloalkyl groups for purposes of the présentinvention, and unless otherwise indicated, include spiro groups and fused ring groups. In oneembodiment, each ring in the heterobicycloalkyl contains up to four heteroatoms (i.e. from zéroto four heteroatoms, provided that at least one ring contains at least one heteroatom). Theheterocyclic groups of this invention can also include ring Systems substituted with one or moreoxo moieties. 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, dihydrothienyi, dihydrofuranyl, pyrazolidinyl,imidazolinyl, imidazoiidinyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1 .Ojheptanyl,quinolizinyl, quinuciidinyl, 1,4-dioxaspiro[4.5]decyl, 1,4-dioxaspiro[4.4]nonyi, 1,4-dioxaspiro[4.3]octyl, and 1,4-dioxaspiro[4.2]heptyl. "Heteroaryl”, as used herein, refers to aromatic groups containing one or moreheteroatoms (O, S, or N), preferably from one to four heteroatoms. A multicyclic groupcontaining 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 Systemssubstituted with one or more oxo moieties. Examples of heteroaryl groups are pyridinyl, 012368 -6- pyridazinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, quinolyl, isoquinolyl,tetrazofyl, furyl, thienyl, isoxazolyl, thiazolyf, oxazolyl, isothiazoIyl, pyrrolyl, indolyl,benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, triazinyl,isoindolyl, purinyl, oxadiazolyl, tbiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl,benzotriazolyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl,dihydroquinoly!, tetrahydroquinoiyî, dihydroisoquinolyl, tetrahydroisoquinolyl, benzofuryl,furopyridinyl, pyrolopyrimidinyi, and azaindolyl.
The foregoing groups, as derived from the compounds listed above, may be C-attachedor N-attached where such is possible. For instance, a group derived from pyrroie may be pyrroi- 1-yI (N-attached) or pyrroi-3-yl (C-attached). The terms referring to the groups aiso encompassail possible tautomers.
In one embodiment, this invention provides compounds of formula 1, wherein R3 is-C(=O)NR9- or -C(=O)(CR10R11)n-. In another embodiment, R10 and R11 of -C(=O)(CR10R11)n- areat each itération of n both hydrogen. In another embodiment, R9 of -C(=O)NR9- is hydrogen. Inanother embodiment, R3 is -C(=O)NR9- or -C(=O)(CR10R11)n- and R2 is hydrogen. In anotherembodiment, R3 is -(CR10R11)n-, and n is zéro. In a preferred embodiment R3 is -(CR10R11)n-, n iszéro,' and R4 is (C6-C14)aryl or (5-14 membered) heteroaryl, each optionally substituted as recitedabove.
In another embodiment of the invention, a compound of formula 1 is provided whereinR’ is optionally substituted (C3-CB)cycloaIkyl or optionally substituted (Cs-C1t) bicycloalkyl.Preferred embodiments are wherein R1 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, Ornorbornyl, each optionally substituted as recited above (i.e. optionally with from one to sixsubstituents R5 independentiy selected from F, Cl, Br, I, nitro, cyano, -CF3, -NR7R8,-NR7C(=O)R8, -NR7C(=O)OR8, -NR7C(=O)NR8R9, -NR7S(=O)2Rb, -NR7S(=O)2NR8R9, -OR7,-OC(=O)R7, -0C(=O)0R7, -C(=O)OR7, -C(=O)R7, -C(=O)NR7R8, -OC(=O)NR7RB, -OÇ(=O)SR7,-SR7, -S(=O)R7, -S(=O)2R7, -S(=O)2NR7Rb, and R7). In a more preferred embodiment, R1 is (C3-CB)cycloalkyl or optionally substituted (Cs-C,,) bicycloalkyl, for example cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, or norbornyl, and is optionally substituted with from one to threesubstituents independentiy selected from F, Cl, Br, I, nitro, cyano, -CF3, -NR7R8, -NR7C(=O)R8,-OR7, -C(=O)OR7, -C(=O)R7, and R7. More preferably, R1 is (C3-CB)cycloalkyl or optionallysubstituted (Cg-C,,) bicycloalkyl, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ornorbornyl, and R1 is substituted with -NR7C(=O)R8, (C6-CM)aryl, (3-8 membered)heterocycloalkyl, or (5-14 membered) heteroaryl, and wherein said aryl, heterocycloalkyl, andheteroaryl are each optionally substituted with from one to six substituents independentiyselected from F, Cl, Br, I, NO2, -CN, -CF3, -NR10R”, -NR10C(=O)R1’, -NRWC(=O)OR’1,-NR10C(=O)NR11R12, -NR10S(=O)2R11, -NR10S(=0)2NR1’R12, -OR10, -OC(=O)R’°, -OC(=O)OR10. 012368 -7- -OC(=O)NR’°R", -OC(=O)SR10, -SR’°, -S(=O)R10, -S(=O)2R10, -S(=O)2NR1DR”, -C(=O)R10,-C(=O)OR10, -C(=O)NR’°R11, and R10. In another embodiment of the invention, R1 is bicyclo-[3.1.0]-hexyl and is optionally substituted as recited above (i.e. optionally substituted with fromone to six substituents R5 independently selected from F, Cl, Br, I, nitro, cyano, -CF3, -NR7R®, 5 -NR7C(=O)R8, -NR7C(=O)OR8, -NR7C(=O)NR8R9, -NR7S(=O),Rs, -NR7S(=O)2NRbR3, -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)2NR7R®, and R7.
In another embodiment of the invention, a compound of formula 1 is provided whereinR1 is optionally substituted straight chain or branched (C,-CB)alkyl or optionally substituted 10 straight chain or branched (C2-C8)alkenyl.
In another embodiment of the invention, compounds of formula 1 are provided, but wherein R2 is hydrogen. In a further embodiment, R2 is hydrogen, and R1 is as subdefined in thepreceding paragraphs.
In another embodiment, this invention provides a compound of formula 1 wherein R4 is15 (C6-C14)aryl or (5-14 membered) heteroaryl, each optionally substituted. In a preferredembodiment, R4 is optionally substituted phenyl or optionally substituted pyridyi. In anotherpreferred embodiment, R4 is naphthyl, quinolyl, or isoquinolyl, each optionally substituted. Inanother embodiment, R4 is napthyl, quinolyl, or isoquinolyl, and is unsubstituted. In anotherembodiment, R4 is pyrimidinyl, pyrazinyl, or pyridazyl, and in each case R4 is optionally 20 substituted. in a further embodiment, R4 is pyrimidinyl, pyrazinyl, or pyridazyl, and R4 isunsubstituted.
In another embodiment, compounds of formula 1 are provided, wherein R2 is specificallyhydrogen, and R4 is as subdefined in the preceding paragraph.
Examples of preferred compounds of formula 1 are: 25 (5-cyclobutyl-2H-pyrazol-3-yl)-(3-trifluoromethoxy-phenyl)-amine; N-(5-cyclobutyl-2H-pyrazo!-3-yl)-N',N'-dimethyl-pyridine-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-pyrazo!-3-yl)-naphthalen-2-yl-amine; 30 (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-yi)-N',N'-dimetbyl-pyridine-2,6-diamine; (5-cyclobutyl-2H-pyrazol-3-yl)-(6-trifluoromethyl-pyridin-2-yl)-amine,· (3-benzyioxy-phenyl)-(5-cyclobutyl-2K-pyrazol-3-yl)-amine·, 35 (5-cyclobutyl-2H-pyrazoI-3-yl)-(3-trifIuoromethyl-phenyl)-amine; - N-(5-cyclobutyl-2H-pyrazol-3-yl)-N',N’-dimethyl-benzene-1,3-diamine; 012368 -8-
P (5-cyclobutyl-2H-pyrazol-3-yl)-(3-methoxy-phenyl)-amine; (5-cyciobutyl-2H-pyrazol-3-yl)-(4-nitro-phenyl)-amine; (4-chloro-benzyl)-(5-cyclobutyl-2H-pyrazol-3-yl)-amine; (3-bromo-phenyl)-(5-cyciobutyl-2H-pyrazo!-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-ylJ-cyclopentanone; (5-cyclobutyl-2H-pyrazol-3-yl)-(6-methoxy-4-methyl-quinolin-2-yl)-amine; (5-cyclobutyl-2H-pyrazol-3-yi)-(3-trifluoromethoxy-phenyl)-amine; (2-chloro-4-nitro-phenyl)-(5-cyclobutyl-2H-pyrazol-3-yl)-amine;· 3- irans-[5-(3-trifiuoromethyl-phenylamino)-2H-pyrazol-3-yl]-cyclopentanol;(3,5-bis-trifIuoromethyl-phenyi)-(5-cyclobutyl-2H-pyrazoI-3-yl)-amine;[5-(3-c/s-benzylamino-cyclopeniyl)-1H-pyrazol-3-yi]-(3-trifluoromethyl-phenyl)-amine;{5-[3-c/s-(4-methoxy-benzylamino)-cyclopentyl]-1H-pyrazol-3-yl}-(3-trifIuoromethyl- phenyl)-amine; 4- (5-cyclobutyr-2H-pyrazol-3-ylamino)-benzonitrile;(5-cyclobutyl-2H-pyrazol-3-yl)-(3-fluoro-phenyl)-amine;(5-cycIobutyl-2H-pyrazol-3-yl)-(3,5-dichloro-phenyl)-amine;(2-bromo-phenyl)-(5-cyclobutyl-2H-pyrazol-3-yl)-amine; N-{c/s-3-[5-(3-trifluoromethyl-phenylamino)-2H-pyrazol-3-yl]-cyclopentyl}-acetamide; pyridin-2-yl-{3-irans-[5-(3-trifluoromethyl-phenylamino)-2H-pyrazo!-3-y!]-cyclopentyl}- amine; (5-cyclobutyl-1H-pyrazol-3-yl)-(4-methoxy-phenyl)-amine; pyridine-2-carboxylic acid {3-[5-(3-trifluoromethyl-phenylamino)-2H-pyrazol-3-yI]cyclopentylj-amide; 34rifluoromethyl-N-{3-[5-(3-trifluorornethyl-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-yI]-cyclopentyl}-propionamide; 4-fluoro-N-{3-[5-(3-trifluoromethyl-phenylamino)-2H-pyrazol-3-yl]-cyclopentyl}- benzamide; 2.2.2- trifluoro-N-{3-[5-(3-tnfluoromethyl-phenylamino)-2H-pyrazol-3-yl]-cyclopentyl}-acetamide; 012368 -9- cyclopropanecarboxylic acid {3-(5-(3-trifluorornethyl-phenylarriino)-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-y!]-2-naphthalen-1-yl-acetamide;cyclopropanecarboxylic acid {3-(5-(2-naphthalen-1-y!-acetylamino)-1H-pyrazol-3-yl]· cyclopentyl}-amide; 2-naphthalen-1-yl-N-{5-[3-(2,2,2-trifiuoro-aceiylamino)-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-yi)-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-[(1 S)-(benzooxazol-2-yloxy)-ethyl]-1 H-pyrazol-3-yl}-2-naphthalen-1 -yl- acetamide; N-{5-[( 1 S)-(benzothiazol-2-yloxy)-ethyI]-1 H-pyrazol-3-yl}-2-naphthalen-1 -yl- ..... acetamide; N-[5-(3-hydroxy-1 -methyl-propyl)-1 H-pyrazol-3-yl]-2-naphthalen-1 -yl-acetamide;N-[5-(benzothiazol-2-yloxymethyi)-1H-pyrazol-3-yl]-2-naphthalen-1-yl-acetamide;N-{5-[3-(benzothiazol-2-yloxy)-1 -methyl-propyl]-1 H-pyrazol-3-yl}-2-naphthalen-1 -yl- acetamide; N-[5-(2-hydroxy-(1S)-methyl-ethyl)-2H-pyrazo!-3-yl]-2-naphthalen-1-yl-acetamide; N-{5-((1 R)-(benzothiazol-2-yloxy)-ethyI]-1 H-pyrazol-3-yl}-2-naphthalen-1 -yl- acetamide; N-[5-(3-acetylamino-1 -methyl-propyl)-1 H-pyrazol-3-yl]-2-naphthalen-1 -yl-acetamide; 3- methoxy-N-{c/s-3-[5-(2-naphthalen-1-yl-acetylamino)-2H-pyrazol-3-yl]-cyclobutyl}-benzamide; N-[5-(cis-3-acetylamino-cyclobutyi)-1H-pyrazol-3-yl]-2-naphthalen-1-yl-acetamide; N-{c/s-3-[5-(2-naphthalen-1-yl-acetyiamino)-2H-pyrazol-3-ylJ~cyclobutyl}-benzamide; 2-cyclopropyl-N-{czs-3-[5-(2-naphthalen-1-yl-acetylamino)-2H-pyrazol-3-yl]- cyclobutyl}-acetamide; 6-chloro-pyridine-2-carboxylic acid (czs-3-[5-(2-naphthalen-1 -yl-acetyiamino)-2H-pyrazol-3-y!]-cyclobutyl}-amide; quinoline-2-carboxylic acid {c/s-3-(5-(2-naphthalen-1 -yl-acetylamino)-2H-pyrazoi-3-ylJ-cyclobutyl}-amide; * 012368 1 -10- pyrazine-2-carboxylic acid {c/s-3-[5-(2-naphthalen-1-yl-acetylamino)-2H-pyrazol-3-yi]cyclobutyl}-amide; 4-methoxy-N-{c/s-3-[5-(2-naphthalen-1-yl-acetylamino)-2H-pyrazol-3-yl]-cyclobutyl}- benzamide; N-{c/s-3-[5-(2-naphthalen-1-yl-acetylamino)-2H-pyrazol-3-yl]-cyclobuty!}-3-nitro- benzamide; N-{cz's-3-[5-(2-naphthalen-1-yl-acetylamino)-2H-pyrazol-3-yiJ-cyclobutyl}-3- trifîuoromethyl-benzamide; N-{cz's-3-[5-(2-naphthalen-1-yl-acetylamino)-2H-pyrazol-3-yl]-cyclobutyl}- isobutyramide; 2-phenyl-cyclopropanecarboxylic acid {c/s-3-[5-(2-naphthalen-1-yl-acetylamino)-2Hpyrazol-3-yl]-cyclobutyl}-amide; N-{5-[c/s-3-(benzooxazol-2-yloxy)-cyclobutyl]-1H-pyrazol-3-yl}-2-naphthalen-1-yl- acetamide; 4-dimethylamino-N-{czs-3-[5-(2-naphthalen-1-yl-acetyiamino)-2H-pyrazol-3-yl]- cyclobutylj-benzamide; 3,5-dimethoxy-N-{czs-3-[5-(2-naphthalen-1-yl-aceiylamino)-2H-pyrazol-3-yl]- cyclobutyi}-benzamide; 2-naphthalen-1-yl-N-[5-(c/s-3-phenyl-cyclobutyi)-2H-pyrazol-3-yl]-acetamide; N-{5-[czs-3-(3-methoxy-phenyl)-cyclobutyl]-2H-pyrazol-3-yl}-2-naphthalen-1-yl- acetamide; N-{5-[c/s-3-(2-methoxy-phenyi)-cyclobutyl]-2H-pyrazol-3-yl}-2-naphthaien-1-yl- acetamide; N-{5-[c/s-3-(4-methoxy-phenyl)-cyclobutyl]-2H-pyrazol-3-yl}-2-naphthalen-1-yl- acetamide; 2-naphthalen-1-yl-N-[5-(czs-3-p-tolyl-cyclobutyl)-2H-pyrazol-3-yl]-acetamide; N-{5-[c/s-3-(4-chloro-phenyl)-cyclobutyl]-2H-pyrazol-3-yl}-2-naphthalen-1-yl- acetamide; 2-(4-methoxy-phenyi)-N-{5-(czs-3-(2-methoxy-phenyl)-cyclobutyl]-2H-pyrazol-3-yl}- acetamide; N-{5-[c/s-3-(2-methoxy-phenyl)-cyclobutyl]-2H-pyrazol-3-yl}-2-quinolin-6-yl-acetamide;N-{5-[cfe-3-(2-methoxy-phenyl)-cyclobutyl]-2H-pyrazol-3-yi}-2-phenyl-acetamide;N-{5-(c/s-3-(2-methoxy-phenyl)-cyclobutyl]-2H-pyrazot-3-yl}-2-pyridin-3-yl-acetamide;N-{5-[c/s-3-(4-methoxy-phenyl)-cyclobutyl]-1H-pyrazol-3-yl}-2-quinolin-6-yl-acetamide;2-quinoiin-6-yl-N-[5-(c/s-3-p-tolyl-cyciobutyl)-1 H-pyrazol-3-yl]-acetamide;N-{5-[cis-3-(4-fluoro-phenyl)-cyclobutyi]-1 H-pyrazol-3-yi}-2-quinolin-6-yl-acetamide; 012368 -11- N-{5-[c/'s-3-(4-chioro-phenyl)-cyclobutyl]-1H-pyrazol-3-yI}-2-quinolin-6-yl-acetamide; 2-quinolin-6-yl-N-[5-(c/S'3-/r)-tolyl-cyclobutyl)-1H-pyrazol-3-yl]-acetamide; 4-dimethylamino-N-{c/s-3-[5-(2-naphthaien-1-yl-acetylamino)-2H-pyrazol-3-yl]- cyclobutyl}-benzamide; 2-naphthalen-1-yl-N-{5-[cis-3-(pyridin-2-yloxy)-cyclobiityl]-1H-pyrazol-3-yl}-acetamÎde; 6-methyl-pyridine-2-carboxylic acid {c/s-3-[5-(2-naphthalen-1 -yl-acetylamino)-2H-pyrazol-3-yl]-cyclobutyl}-amide; 2-phenyl-cyclopropanecarboxyIic acid metbyl-{c/s-3-[5-(2-naphthalen-1 -yl-acetylarnino)-2H-pyrazol-3-yl]-cyclobutyl}-amide; N-{5-[c/s-3-(3-methyl-pyrazin-2-yloxy)-cyciobutyl]--1H-pyrazol-3-yi}-2-naphtbalen-1-y!- acetamide; {5-[c/s-3-(2-methoxy-phenyl)-cyclobutyl]-1H-pyrazol-3-yl}-(6-methoxy-pyridin-2-y!)- amine; N-{5-[c/s-3-(3,6-dimethyl-pyrazin-2-yloxy)-cyclobutyl]-1H-pyrazol-3-yI}-2-naphthalen- 1-yl-acetamide; N-{5-[ds-3-(3-methoxy-pyridin-2-yloxy)-cyclobutyl]-1H-pyrazol-3-yl}-'2-naphthaien-1- yl-acetamide; 2-methyl-cyclopropanecarboxylic acid {c/s-3-[5-(2-naphthalen-1 -yl-acetyIamino)-2H-pyrazol-3-yl]-cyclobutyl}-amide; 2-naphthalen-1-yl-N-{5-[c/s-3-(3-trifluoromethyl-pyridin-2-yloxy)-cyclobutyl]-1H- pyrazol-3-yl}-acetamide; 2-naphthalen-1-yl-N-{5-[ci's-3-(3-nitro-pyridin-2-yioxy)-cyclobutyl]- 1H-pyrazol-3-yl}-acetamide; N-{5-[c/s-3-(benzothiazol-2-yloxy)-cyclobutyl]-1H-pyrazol-3-yl}-2-naphthalen-1-yl- acetamide; 2-naphthalen-1 -yl-N-{5-[c/s-3-(4-trifiuoromethyl-pyrimidin-2-yloxy)- cyclobutyl]-1 H- pyrazol-3-yl}-acetamide; 2-naphthalen-1-yl-N-{5-[3-(5-nitro-pyridin-2-yloxy)-cyclobutyl]-1H-pyrazol-3-yl}- acetamide; 2-naphthaien-1-yl-N-{5-[3-(pyrimidin-2-yloxy)-cyclobutyl]-1H-pyrazol-3-yl}-acetamide;2-naphthalen-1 -yl-N-{5-[3-(5-trïfluoromethyl-pyridin-2-yloxy)- cyclobutylj-1 H-pyrazol-3- yl}-acetamide; N-{5-[3-(6-methoxy-pyridazin-3-yloxy)-cycIobutyl]-1H-pyrazol-3-yl}-2-naphthalen-1-yl- acetamide; 2-naphthalen-1-yl-N-{5-(3-(pyrazin-2-yloxy)-cycIobutyl]-1H-pyrazol-3-yl}-acetamide; 012368 V. -12- N-{5-[3-(6-methyl-pyridin-2-yloxy)-cyclobutyl]-1 H-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; 5 N-{5-[3-(6-methoxy-benzothiazol-2-yloxy)-cyclobutyl]-1H-pyrazol-3-yl}-2-naphthalen- 1-yl-acetamide; and pharmaceutically acceptable salts of the foregoing compounds.
Other examples of preferred compounds of formula 1 are:N-{5-[c/s-3-(4-Hydroxy-phenyî)-cyclobutyl]-1H-pyrazol-3-yl}-2-quinolin-6-yl-acetamide; 10 N-{5-[c/s-3-(3-Hydroxy-phenyl)-cyclobutyl]-1 H-pyrazol-3-yl}-2-quinoiin-6-yl-acetamide·, 2-Naphthalen-1-yl-N-[5-(c/'s-3-pyridin-3-yl-cyclobutyI)-2H-pyrazol-3-yl]-acetamide;N-[5-(c/s-3-Naphthalen-2-yl-cyclobutyl)-2H-pyrazol-3-yl]-2-pyridin-3-yl-acetamide;N-(5-lndan-2-yl-1 H-pyrazol-3-yl)-2-quinolin-6-yl-acetamide; N-[5-(c/s-3-Pyridin-2-yl-cyclobutyl)-2H-pyrazol-3-yl]-2-quinolin-6-yl-acetamide; 15 N-[5-(cZs-3-Pyridin-2-yl-cycIobutyl)-2H-pyrazol-3-yl}-2-quinolin-6-yl-acetamide; 2-(4-Methoxy-phenyl)-N-[5-(c/s-3-pyridin-4-yl-cyclobutyl)-2H-pyrazol-3-yl]-acetamide; N-{5-[3-(c/s-2-Dimethylaminomethyl-phenyl)-cyclobutyl]-2H-pyrazol-3-yl}-2-{4- methoxy-phenyl)-acetamide; N-(5-{c/s-3-(3-(2-DimethyÎamino-ethoxy)-phenyl]-cyclobutyl}-2H-pyrazoi-3-yl)-2-(4- 20 methoxy-phenyl)-acetamide; N-{5-[c/s-3-(2-Hydroxy-phenyl)-cyclobutyl]-2H-pyrazol-3-yl}-2-(4-methoxy-phenyI)- 'acetamide; N-(5-{cZs-3-[2-(2-Dimethylamino-ethoxy)-phenyl]-cyclobutyl}-2H-pyrazol~3-yl)-2-(4- methoxy-phenyl)-acetamide; 25 2-(4-Methoxy-phenyl)-N-[5-(c/s-3-phenyl-cyclobutyl)-2H-pyrazol-3-yl]-acetamide; N-{5-[c/s-3-(2-Fluoro-phenyl)-cyclobutyl]-2H-pyrazol-3-yl}-2-(4-methoxy-phenyl)- acetamide; N-(5-{c/s-3-[4-(Azetidin-3-yloxy)-phenyl]-cyclobutyl}-2H-pyrazol-3-yt)-2-(4-methoxy- phenyt)-acetamide; 30 N-(5-{c/s-3-[2-(Azetidin-3-yloxy)-phenyl]-cyclobutyl}-2H-pyrazol-3-yl)-2-{4-methoxy- phenyl)-acetamide; 2-(4-Methoxy-phenyl)-N-{5-[c/s-3-(2-methylsulfanyl-phenyl)-cycIobutyl]-2H-pyrazol-3- yl}-acetamide; N-{5-[c/s-3-(2-Amino-phenyl)-cyclobutyl]-2H-pyrazol-3-yl}-2-(4-methoxy-phenyJ)- 35 acetamide; 012368 -13- N-{5-[c/s-3-(4-Cyano-phenyl)-cyclobutyl]-2H-pyrazol-3-yi}-2-(4-methoxy-phenyl)- acetamide; N-{5-[c/s-3-(2-Cyano-phenyl)-3-hydroxy-cyc!obutyl]-2H-pyrazol-3-yl}-2-(4-methoxy- pheny))-acetamide; N-{5-[c/s-3-(2-Hydroxy-ethyl)-cyclobutyl]-1H-pyrazol-3-yl}-2-naphthalen-1-yl- acetamide; N-{5-[c/'s-3-(3-Cyano-phenyl)-cyclobutyl]-2H-pyrazol-3-yl}-2-(4-methoxy-phenyl)- acetamide; N-{5-{c/s-3-(2-Cyano-plienyl)-cyclobutyl]-2H-pyrazol-3-yl}-2-(4-methoxy-phenyl)- acetamide; N-{5-[c/s-3-(3-Amino-phenyl)-cyclobutyl]-2H-pyrazol-3-yl}-2-(4-methoxy-phenyl)- acetamide; 4-{c/s-3-{5-[2-(4-Methoxy-phenyI)-acetylamino]-1H-pyrazol-3-yl}-cyclobutyl)-benzoicacid methyl ester, N-{5-[c/s-3-{4-Hydroxymethyl-phenyl)-cyclobutyi]-2H-pyrazol-3-yl}-2-(4-methoxy- pbenyl)-acetamide; N-{5-[c/s-3-(2-Hydroxy-phenyl)-cyclobutyl]-1H-pyrazol-3-yi}-2-phenyl-acetamide;N-{5-[c/s-3-(2-Hydroxy-phenyl)-cyciobutyl]-1 H-pyrazol-3-yl}-2-quinolin-6-yl-acetamide;N-{5-[c/s-3-(2-Hydroxy-phenyl)-cyclobutyl]-1H-pyrazol-3-yl}-acetamide;
Cyclopropanecarboxylic acid {5-[cfe-3-(2-hydroxy-phenyl)-cyciobutyi]-1 H-pyrazol-3-yl}-amide; N-{5-[c/s-3-(2-Hydroxy-phenyl)-cyclobutyl]-1H-pyrazol-3-yl}-isobutyramide; N-{5-[c/s-3-(3-Aminomethyl-phenyl)-cyclobutyl]-2H-pyrazol-3-yl}-2-(4-methoxy- phenyl)-acetamide; N-{5-[c/s-3-(3-Dimethylaminomethyl-phenyl)-cyclobutyl]-2H-pyrazol-3-yi}-2-(4- methoxy-phenyl)-acetamide; 3-(c/s-3-{5-[2-(4-Methoxy-phenyl)-acetylamino]-1H-pyrazol-3-yl}-cyclobutyi)-benzoicacid methyl ester; N-{5-[c/s-3-(3-Hydroxymethyl-pheny!)-cyciobutyl]-2H-pyrazol-3-yl}-2-(4-methoxy- phenyl)-acetamide; N-(5-{c/s-3-[3-(1-Hydroxy-1-methyl-ethyI)-phenyl]-cyclobutyl}-2H-pyrazol-3-yl)-2-(4- methoxy-phenyl)-acetamide; N-{5-[c/s-3-(3-Ethylaminomethyl-phenyl)-cyclûbutyl]-2H-pyrazoÎ-3-yl}-2-(4-methoxy- phenyl)-acetamide; N-{5-[czs-3-(3-Cyclobutylaminomethyl-phenyi)-cyclobutyI]-2H-pyrazol-3-y1}-2-(4- methoxy-phenyl)-acetamide; 012368 -14- 2-(4-Methoxy-phenyl)-N-{5-[c/s-3-(3-propylaminomethyl-phenyl)-cyclobutyl]-2H-pyrazol-3-yl}-acetamide; N-{5-[c/s-3-(3-Cyclopentylaminomethyl-phenyl)-cyclobutyl]-2H-pyrazol-3-yl}-2-(4- methoxy-phenyl)-acetamide; N-(5-{c/s-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-[c/s-3-(3-Cyclopropylaminomethyl-phenyl)-cyclobutyl]-2H-pyrazol-3-yl}-2-(4- methoxy-phenyl)-acetamide; 2-(4-Methoxy-phenyl)-N-{5-[c/s-3-(3-pyrrolidin-1-ylmethyl-phenyl)-cyclobutyl]-2H- pyrazol-3-yl}-acetamide; N-{5-[c/s-3-(3-Diethylaminomethyl-phenyl)-cycfobutyl]-2H-pyrazol-3-yl}~2-(4-mefhoxy phenyl)-acetamide; N-{5-[czs-3-(3-Azetidin-1-ylmethyl-phenyl)-cyclobutylJ-2H-pyrazol-3-yl}-2-(4-methoxy- phenyl)-acetamide; and pharmaceutically acceptable salts of the foregoing compounds.
Other spécifie examples of compounds of the invention of formula 1 are: N-[5-(c/s-3-pyridin-2-yl-cyclobutyl)-1H-pyrazol-3-yl]-2-quinolin-6-yl-acetamide; N-[5-(c/s-3-pyridin-3-yl-cyclobutyl)-1H-pyrazol-3-yl]-2-quinolin-6-yI-acetamide; N-[5-(czs-3-pyridin-4-yl-cyclobutyl)-1H-pyrazol-3-yl]-2-quinolin-6-yl-acetamide; N-[5-(czs-3-pyrazin-2-yl-cyclobutyl)-1H-pyrazol-3-yl]-2-quinolin-6-yl-acetamide; N-[5-(c/s-3-pyrimidin-4-yl-cyclobutyl)-1H-pyrazol-3-yi]-2-quinolin-6-yl-acetamide; N-{5-[c/s-3-(3-methoxy-pyridin-2-yl)-cyclobutyl]-1H-pyrazol-3-yl}-2-quinolin-6-yl- acetamide; N-{5-[czs-3-(4-methoxy-pyridin-3-yl)-cyclobutyl]-1H-pyrazol-3-yl}-2-quinolin-6-yl- acetamide; N-{5-[czs-3-(3-methoxy-pyridin-4-yl)-cyclobutyl]-1H-pyrazol-3-yl}-2-quinolin-6-yl- acetamide; N-{5-[c/s-3-(2-methoxy-pyridin-3-yl)-cyclobutyl]-1H-pyrazol-3-yl}-2-quinolin-6-yl- acetamide; N-{5-[c/s-3-{5-methoxy-pyrimidin-4-yl)-cyclobutyl]-1 H-pyrazol-3-yl}-2-quinolin-6-yl- acetamide; N-{5-[c/s-3-(1 -ethyl-1 H-imidazol-2-yl)-cyclobutyl]-1 H-pyrazol-3-yi}-2-quinolin-6-yi- acetamlde; 012368 -15- N-{5-[c/s-3-(1-ethyl-1H-pyrrol-2-yl)-cyclobutyl]-1H-pyrazol-3-yl}-2-quinolin-6-yi- acetamide; N-{5-(c/s-3-(2-aminomethyl-phenyl)-cyclobutyl]-1H-pyrazol-3-yl}-2-quinolin-6-yl- acetamide; N-{5-[c/s-3-(2-pyrrolidin-1-ylmethyI-phenyl)-cyclobutyl]-1H-pyrazol-3-yl}-2-quinolin-6- yl-acetamide; and pharmaceutically acceptable salts of the foregoing compounds.
Other spécifie examples of compounds of formula 1 are: {4-[(5-cyclobutyl-1H-pyrazol-3-ylcarbamoyl)-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-1 H-pyrazol-3-yl)-acetamide; 2-biphenyl-4-yl-N-(5-cyclobutyl-1H-pyrazol-3-yl)-acetamide; N-(5-cyclobutyl-1 H-pyrazol-3-yl)-2-(3,4,5-trimethoxy-phenyl)-acetamide;{2-[(5-cyclobutyl-1H-pyrazol-3-ylcarbamoyl)-methyl]-phenyl}-acetic acid;N-(5-cyclobutyl-1 H-pyrazol-3-yl)-2-(3,4-dichloro-phenyl)-aceiamide;2-(2-chloro-phenyl)-N-(5-cyclobutyl-1 H-pyrazo!-3-yl)-acetamide;N-(5-cyclobutyl-1H-pyrazoI-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-1 H-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-cyciobutyl-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-yi)-2-(4-hydroxy-3,5-dinitro-phenyl)-acetamide; N-(5-cyclobutyl-1 H-pyrazoi-3-yl)-2-{3,4-difluoro-phenyl)-acetamide; 2-(2l4-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-trifiuoromethyl-phenyl)-acetamide; N-(5-cyclobutyl-1H-pyrazol-3-yl)-2-(4-fluoro-3-trifiuoromethyl-phenyl)-acetamide; N-(5-cyclobutyl-1H-pyrazo!-3-yl)-2-(2,4,6-trifluoro-phenyl)-acètamide; N-(5-cyclobutyl-1H-pyrazol-3-yl)-2-(4-methylsulfanyl-phenyl)-acetamide; 01236.8 -16- N-(5-cyclobutyl-1H-pyrazol-3-yl)-2-(3-hydroxy-phenyl)-acetamide; N-(5-cyclopentyl-1H-pyrazol-3-yl)-2-phenyl-acetamide; 2-(4-chloro-phenyl)-N-(5-cyclopentyI-2K-pyrazol-3-yl)-acetamide; N-(5-cyclopentyl-1H-pyrazoÎ-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-yi)-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-phenyl-acetamide; 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-yI)-2-pyrrolo[2,3-b]pyridin-1-yl-acetamide;N-(5-cyclobutyl-1 H-pyrazol-3-yl)-2-m-tolyl-acetamide;N-(5-cyclopentyl-2H-pyrazol-3-yl)-2-p-tolyl-acetamide;N-(5-cyclobutyl-1H-pyrazol-3-y!)-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)-1 K-pyrazol-3-yl]-piperidine-1 -carboxylic acid benzyl ester; 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)-1 H-pyrazol-3-yl]-piperidine-1 -carboxylic acid benzyl ester; N-[5-(1-cyclobutanecarbonyl-piperidin-4-yl)-2H-pyrazol-3-yl]-2-naphthalen-2-yl- acetamide; N-{3-[5-(2-naphtha!en-2-yl-acety!amino)-4H-pyrazol-3-yl]-propyl}-benzamide; N-{3-[5-(2-naphthalen-1-yl-acetylamino)-2H-pyrazol-3-yl]-propyl}-benzamide; N-{5-[1-(3-methyI-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)-acetylaminoJ-2H-pyrazol-3'yl}-propyl)-benzamide; 012368
Pf -17- 6-methyl-pyridine-2-carboxylic acid {3-[5-(2-naphthalen-2-yl-acetylamino)-1 H-pyrazol3-ylj-cyclobutyl}-amide; 6-methyl-pyridine-2-carboxylic acid {3-[5-(2-naphthalen-2-yl-acetylamino)-1 H-pyrazol3-yl]-cyclobutyl}-amide; 6-methyl-pyridine-2-carboxylic acid {3-[5-(2-naphthalen-2-yl-acetylamino)-1 H-pyrazol3-ylJ-cyclobutyl}-amide; N-{5-[3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-cyclobutyl]-2H-pyrazol-3-yl}-2- naphthalen-2-yl-acetamide; 6-chloro-pyridine-2-carboxylic acid {3-[5-(2-naphthalen-2-yl-acety!amino)-1 H-pyrazol-3-yl]-cyclobutyl}-amide; 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-yi]-acetamide; 2-naphthalen-1-yl-N-[5-(2-pyridin-2-yl-ethyl)-2H-pyrazol-3-yl]-acetamide; 2-naphthalen-1-yI-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-ylJ-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-4-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-6thyl)-2H-pyrazol-3-yl]-acetamide; 2-naphthalen-2-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-naphthaIen-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]- cyclobutylj-acetamide; pyrazine-2-carboxyIic acid {3-[5-(2-naphthalen-2-yl-acetylamino)-1 H-pyrazol-3-yl]-cyclobutylj-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-pyrazo!-3-yl}- acetamide; 2-{3-methoxy-phenyl)-N-{5-[2-{4-trifluoromethyl-phenyl)-ethyl]-2H-pyrazol-3-yl}- acetamide; 012368 1' -18- 6-methyi-pyridine-2-carboxylic acid (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; and pharmaceuticaily acceptable salts of said compounds.
Salts of compounds of formula 1 can be obtained by forming salts with any acidic orbasic group présent on a compound of formula 1. Examples of pharmaceuticaily acceptablesalts 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, phosphoricacid, methanesulfonic acid, tartaric acid, maleic acid, di-p-toluoyl tartane acid, acetic acid,sulfuric acid, hydroiodic acid, mandelic acid, sodium, potassium, magnésium, calcium, andlithium.
The compounds of formula 1 may hâve optical centers and therefore may occur indifferent enantiomeric and other stereoisomeric configurations. The invention includes ailenantiomers, diastereomers, and other stereoisomers of such compounds of formula 1, aswell as racemic and other mixtures thereof.
The subject invention also includes isotopicaliy-labeled compounds, which areidentical to those recited in formula 1, but for the fact that one or more atoms are replaced byan atom having an atomic mass or mass number different from the atomic mass or massnumber usually found in nature. Examples of isotopes that can be incorporated intocompounds of the invention include isotopes of hydrogen,. carbon, nitrogen, oxygen,phosphorous, fluorine, iodine, and chlorine, such as 3H, 11C, 14C, 18F, 123I and 12SI. Compoundsof the présent invention and pharmaceuticaily acceptable salts of said compounds thatcontain the aforementioned isotopes and/or other isotopes of other atoms are within the scopeof this invention. Isotopicaliy-labeled compounds of the présent invention, for example thoseinto which radioactive isotopes such as 3H and 14C are incorporated, are useful in drug and/orsubstrate tissue distribution assays. Tritiated, i.e., 3H, and carbon-14, i.e., 14C, isotopes areparticularly preferred for their ease of préparation and detectability. 11C and t8F isotopes areparticularly useful in PET (positron émission tomography), and 125l isotopes are particularlyuseful in SPECT (single photon émission computerized tomography), ail useful in brainimaging. Further, substitution with heavier isotopes such as deuterium, i.e., 2H, can affordcertain therapeutic advantages resulting from greater metabolic stability, for exampleincreased in vivo half-life or reduced dosage requirements and, hence, may be preferred insome circumstances. Isotopically labeled compounds of formula 1 of this invention can 012368 generally be prepared by carrying oui 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 includes compounds of the formula
Pt -19-
wherein Prot is a protecting group;
Rz is H, F, -CH3, -CN, or -C(=O)OR7; and n is an integer selected from 1, 2,3, and 4.
Compounds of formula I are useful as intermediates for synthesizing certaincompounds of formula 1 that are described herein.
Preferably, n is 1.
Exemples of spécifie protecting groups include, but are not limited to f-butyi and -CH2-Ar, wherein “Ar” is an aryl or heteroaryl group. An example of the latter type of protectinggroup is para-methoxybenzyl.
This invention also provides a pharmaceutical composition for treating a disease orcondition comprising abnormal ceil growth in a mammal, including a human, comprising acompound of formula 1 in an amount effective in inhibiting abnormal cell growth, and apharmaceutically acceptable carrier.
This invention also provides a pharmaceutical composition for treating a disease orcondition comprising abnormal cell growth in a mammal, including a human, comprising acompound of formula 1 in an amount effective to inhibit cdk2 activity, and a pharmaceuticallyacceptable carrier.
This invention also provides a method for treating a disease or condition comprisingabnormal cell growth in a mammal, including a human, comprising administering to the mammala 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 comprisingabnormal cell growth in a mammal, including a human, comprising administering to themammal 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 orcondition comprising abnormal cell growth, the disease or condition comprising abnormal cellgrowth is in one embodiment canêer. The cancer may be a carcinoma, for example carcinoma 012368 -20- of the bladder, breast, colon, kidney, liver, iung, for example small cell lung cancer, esophagus,gall bladder, ovary, pancréas, stomach, cervix, thyroid, prostate, or skin, for example squamouscell carcinoma; a hematopoietic tumor of lymphoid lineage, for example leukemia, acutelymphocytic leukemia, B-cetl lymphoma, T-cell lymphoma, Hodgkins lymphoma, non-Hodgkins 5 lymphoma, hairy cell lymphoma, or Burkett’s lymphoma; a hematopoietic tumor of myeloidlineage, for example acute and chronic myelogenous leukemias, myelodysplastic syndrome, orpromyelocytic leukemia; a tumor of mesenchymal origin, for example fibrosarcoma orrhabdomyosarcome; a tumor of the central or peripheral nervous system, for exampleastrocytoma, neuroblastoma, glioma or schwannoma; melanoma; seminoma; teratocarcinoma; 10 osteosarcoma; xenoderoma pigmentoum; keratoctanthoma; thyroid foilicular cancer; or Kaposi’ssarcoma.
In another embodiment, the disease or condition comprising abnormal cell growth isbenign. Such diseases and conditions include benign prostate hyperplasia, familialadenomatosis polyposis, neuro-fibromatosis, atherosclerosis, pulmonary fibrosis, arthritis, 15 psoriasis, glomerulonephritis, restenosis, hypertrophie scar formation, inflammatory boweldisease, transplantation rejection, fungal infection, and endotoxic shock.
This invention also provides a pharmaceutical composition for treating aneurodegenerative disease or condition in a mammal, including a human, comprising acompound of formula 1 in an amount effective in treating said disease or condition, and a 20 pharmaceutically acceptable carrier.
This invention also provides a pharmaceutical composition for treating - aneurodegenerative disease or condition in a mammal, including a human, comprising acompound of formula 1 in an amount effective in inhibiting cdk5 activity, and apharmaceutically acceptable carrier. 25 This invention also provides a method for treating a neurodegnerative disease or condition in a mammal, including a human, comprising administering to the mammal acompound of formula 1 in an amount effective in inhibiting cdk5 activity.
This invention also provides a method for treating a neurodegenerative disease orcondition in a mammal, including a human, comprising administering to the mammal a 30 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, traumaticbrain injury, multiinfarct dementia, epilepsy, amyotrophie latéral sclerosis, pain, viral induceddementia for example AIDS induced dementia, neurodegeneration associated with bacterial 35 infection, migraine, hypoglycémie, urinary incontinece, brain ischemia, multiple sclerosis,Alzheimer’s disease, senile dementia of the Alzheimer’s type, mild cognitive impairment, âge- 012368 -21- related cognitive décliné, emesis, corticobasal degeneration, dementia pugilistica, Down’ssyndrome, myotonie dystrophy, Niemann-Pick disease, Pick’s disease, prion disease withtangies, progessive supranuclear palsy, lower latéral sclerosis, and subacute sclerosingpanencephaiistis. 5 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 mediatedneurotransmission in a mammal, inciuding a human, comprising a compound of formula 1 inan amount effective in treating said disease or condition and a pharmaceutically acceptablecarrier. 10 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 mediatedneurotransmission in a mammal, inciuding a human, comprising a compound of formula 1 inan amount effective to inhibit cdk5 and a pharmaceutically acceptable carrier.
This invention also provides a method for treating a disease or condition the treatment 15 of which can be effected or facilitated by altering dopamine mediated neurotransmission in a mammal, inciuding a human, comprising administering to the mammal a compound of formula1 in an amount effective in inhibiting cdk5 activity.
This invention also provides a method for treating a disease or condition the treatmentof which can be effected or facilitated by altering dopamine mediated neurotransmission in a 20 mammal, inciuding a human, comprising administering to the mammal a compound of formula1 in an amount effective in treating said disease or condition.
In one embodiment of the invention, the disease or condition the treatment of whichcan be effected or facilitated by altering dopamine mediated neurotransmission is selectedfrom Parkinson’s disease; schizophrenia; schizophreniform disorder; schizoaffective disorder, 25 for example of the delusional type or the dépressive type; delusional disorder; substance-induced psychotic disorder, for example psychosis induced by alcohol, amphétamine,cannabis, cocaine, hallucinogens, inhalants, opioids, or phencyclidine; personality disorder ofthe paranoid type; personality disorder of the schizoid type; drug addiction, inefuding narcotic(e.g. heroin, opium, and morphine), cocaine and alcohol addiction; drug withdrawal, inciuding 30 narcotic, cocaine and alcohol withdrawal; obsessive compulsive disorder; Tourette’ssyndrome; dépréssion; a major dépressive épisode, a manie or mixed mood épisode, ahypomanie mood épisode, a dépressive épisode with atypical features or with melancholicfeatures or catatonie features, a mood épisode with postpartum onset; post-stroke dépréssion,major dépressive disorder, dysthymie disorder, minor dépressive disorder, premenstrual 35 dysphorie disorder, post-psychotic dépressive disorder of schizophrenia, a major dépressivedisorder superimposed on a psychotic disorder such as delusional disorder or schizophrenia, 012368 -22- a bipolar disorder, for example bipolar i disorder, bipolar II disorder, cyclothymie disorder;anxiety; attention déficit and hyperactivity disorder; and attention déficit disorder.
This invention also provides a pharmaceutical composition for treating a disease orcondition the treatment of which can be effected or facilitated by decreasing cdk5 activity in a 5 mammal, including a human, which composition comprises a compound of formula 1 in anamount effective in inhibiting cdk5 activity and a pharmaceutically acceptable carrier.
This invention also provides a method for treating a disease or condition the treatmentof which can be effected or facilitated by decreasing cdk5 activity in a mammal, including ahuman, which method comprises administering to the mammal a compound of formula 1 in an 10 amount effective in inhibiting cdk5 activity.
We hâve also found that the compounds of formula 1 hâve activity in inhibiting GSK-3. The compounds of formula 1 therefore can be expected to be useful in treating diseasesand 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 15 GSK-3 include neurodegenerative diseases and conditions. Neurodegenerative diseases andconditions are discussed above and include, but are not limited to, for example Alzheimer’sdisease, Parkinson’s disease, Huntington’s disease, amyotrophie latéral sclerosis, multiplesclerosis, stroke, cérébral ischemia, AIDS-related dementia, neurodegeneration associatedwith bacterial infection, multiinfarct dementia, traumatic brain injury, and spinal cord trauma. 20 Therefore, compounds of formula 1 are effective in treating neurodegenerative diseases andconditions based on both cdk5 activity and GSK-3 activity. -
Other diseases and conditions the treatment of which can be effected or facilitated byinhibiting GSK-3 include psychotic disorders and conditions, for example schizophrenia,schizophreniform disorder; schizoaffective disorder, for example of the delusional type or the 25 dépressive type; delusional disorder; substance-induced psychotic disorder, for examplepsychosis induced by alcohol, amphétamine, cannabis, cocaïne, hallucinogène, inhalants,opioids, or phencyclidine; personality disorder of the paranoid type; and personality disorderof the schizoid type. The treatment of such diseases and conditions can also be effected orfacilitated by altering dopamine mediated neurotransmission. Therefore, compounds of 30 formula 1 are effective in treating such disorders and conditions based on both cdk5 activityand GSK-3 activity.
Other disorders and conditions the treatment of which can be effected or facilitated byinhibiting GSK-3 include mood disorders and mood épisodes, for example a major dépressiveépisode, a manie or mixed mood épisode, a hypomanie mood épisode, a dépressive épisode 35 with atypical features or with melancholic features or catatonie features, a mood épisode withpostpartum onset; post-stroke dépréssion, major dépressive disorder, dysthymie disorder, 012368 -23- minor dépressive disorder, premenstrual dysphorie disorder, post-psychotic dépressivedisorder of schizophrenia, a major dépressive disorder superimposed on a psychotic disordersuch as delusional disorder or schizophrenia, a bipoiar disorder, for example bipolar Idisorder, bipolar II disorder, and cyclothymie disorder. The treatment of such mood disordersand épisodes, for example dépression, can also be effected or facilitated by altering dopaminemediated neurotransmission. Therefore, compounds of formula 1 are effective in treatingcertain mood disorders and mood épisodes based on both cdk5 activity and GSK-3 activity.
Other disorders and conditions the treatment of which can be effected or facilitated byinhibiting GSK-3 are male fertility and sperm motility; diabètes mellitus; impaired glucosetolérance; metabolic syndrome or syndrome X; polycystic ovary syndrome; adipogenesis andobesity; myogenesis and frailty, for example age-related décliné in physical performance;acute sarcopenia, for example muscle atrophy and/or cachexia associated with burns, bedrest, limb immobilization, or major thoracic, abdominal, and/or orthopédie surgery; sepsis;spinal cord injury; haïr loss, hair thinning, and balding; immunodeficiency; and cancer.
Accordingly, the présent invention also provides a pharmaceutical composition fortreating in a mammal, including a human, a disease or condition selected from maie fertilityand sperm motility; diabètes mellitus; impaired glucose tolérance; metabolic syndrome orsyndrome X; polycystic ovary syndrome; adipogenesis and obesity; myogenesis and frailty,for example age-related décliné in physical performance; acute sarcopenia, for examplemuscle atrophy and/or cachexia associated with burns, bed rest, limb immobilization, or majorthoracic, abdominal, and/or orthopédie surgery; sepsis; hair loss, hair thinning, and balding;and immunodeficiency; which composition comprises a pharmaceutically acceptable carrierand an amount of a compound of formula 1 effective in treating said disease or condition.
The présent invention further provides a pharmaceutical composition for treating in amammal, including a human, a disease or condition selected from male fertility and spermmotility; diabètes mellitus; impaired glucose tolérance; metabolic syndrome or syndrome X;polycystic ovary syndrome; adipogenesis and obesity; myogenesis and frailty, for exampleage-related décliné in physical performance; acute sarcopenia, for example muscle atrophyand/or cachexia associated with burns, bed rest, limb immobilization, or major thoracic,abdominal, and/or orthopédie surgery; sepsis; haïr loss, hair thinning, and balding; andimmunodeficiency; which composition comprises a pharmaceutically acceptable carrier andan amount of a compound of formula 1 effective in inhibiting GSK-3.
The présent invention also provides a method for treating in a mammal, including ahuman, a disease or condition selected from male fertility and sperm motility; diabètesmellitus; impaired glucose tolérance; metabolic syndrome or syndrome X; polycystic ovarysyndrome; adipogenesis and obesity; myogenesis and frailty, for example age-relate,d décliné 012368 -24- in physical performance; acute sarcopenia, for example muscle atrophy and/or cachexiaassociated with burns, .bed rest, limb immobilization, or major thoracic, abdominal, and/ororthopédie surgery; sepsis; haïr loss, hair thînning, and balding; and immunodeficiency; whichmethod comprises administering to said mammal an amount of a compound of formula 1effective in treating said disease or condition.
The présent invention also provides a method for treating in a mammal, including ahuman, a disease or condition selected from male fertiiity and sperm moiility; diabètesmellitus; impaired glucose tolérance; metabolic syndrome or syndrome X; polycystic ovarysyndrome; adipogenesis and obesity; myogenesis and frailty, for example age-reiated déclinéin physical performance; acute sarcopenia, for example muscle atrophy and/or cachexiaassociated with burns, bed rest, limb immobilization, or major thoracic, abdominal, and/ororthopédie surgery; sepsis; hair loss, hair thînning, and balding; and immunodeficiency; whichmethod comprises administering to said mammal an amount of a compound of formula 1effective in inhibiting GSK-3.
The présent invention further provides a method for inhibiting GSK-3 in a mammal,including a human, which method comprises administering to said mammal an amount of acompound of formula 1 effective in inhibiting GSK-3.
The présent invention further provides a pharmaceutical composition for treating in amammal, including a human, a disorder selected from Alzheimer's disease, mild cognitiveimpairment, ' and age-related cognitive décliné comprising a compound of formula 1 and aCOX-II inhibitor together in an amount effective in treating said disorder, andpharmaceutically acceptable carrier.
This invention also provides a method for treating in a mammal, including a human, adisorder selected from Alzheimer’s disease, mild cognitive impariment, and age-relatedcognitive décliné which method comprises administering to said mammal a compound offormula 1 and a COX-ll inhibitor, wherein the combined amounts of the compound of formula 1and the COX-ll inhibitor are effective in treating said disorder. The compound of formula 1 andthe COX-ll inhibitor can be administered to the mammal at the same time and/or separately.Moreover, the compound of formula 1 and the COX-ll inhibitor can be administered in a singlecomposition or in separate compositions.
Moreover, a compound of formula 1 of the invention, or a pharmaceutically acceptablesait of a compound of formula 1, can be administered or formulated into a pharmaceuticalcomposition with one or more anti-depressants or anxiolytic compounds for treatment orprévention of dépréssion and/or anxiety.
Accordingly, this invention also provides a pharmaceutical composition for treating dépréssion or anxiety in a mammal, including a human, comprising a compound of formula 1 012368
Pt -25- and an NK-1 receptor antagonist together in an amount effective in treating dépréssion oranxiety, and a pharmaceutically acceptable carrier.
This invention further provides a method for treating dépréssion or anxiety in amammal, including a human, which method comprises administering to said mammal acompound of formula 1 and an NK-1 receptor antagonist, wherein the combined amounts ofthe compound of formula 1 and the NK-1 receptor antagonist are effective in treatingdépréssion or anxiety. The compound of formula 1 and the NK-1 receptor antagonist can beadministered to the mammal at the same time and/or at different times. Moreover, the may beadministered together in a single pharmaceuticai composition or in separate compositions.
This invention also provides a pharmaceuticai composition for treating dépréssion oranxiety in a mammal, including a human, comprising a compound of formula 1 and a 5HT10receptor antagonist together in an amount effective in treating dépréssion or anxiety, and apharmaceutically acceptable carrier.
This invention further provides a method for treating dépréssion or anxiety in amammal, including a human, which method comprises administering to said mammal acompound of formula 1 and a 5HT1D receptor antagonist, wherein the combined amounts ofthe compound of formula 1 and the 5HT1D receptor antagonist are effective in treatingdépréssion or anxiety. The compound of formula 1 and the 5HT10 receptor antagonist can beadministered to the mammal at the same time and/or at different times. Moreover, they maybe administered together in a single pharmaceuticai composition or in separate compositions.
This invention also provides a pharmaceuticai composition for treating dépréssion oranxiety in a mammal, including a human, comprising a compound of formula 1 and a SSRItogether in an amount effective in treating dépréssion or anxiety, and a pharmaceuticallyacceptable carrier.
This invention further provides a method for treating dépréssion or anxiety in amammal, including a human, which method comprises administering to said mammal acompound of formula 1 and a SSRI, wherein the combined amounts of the compound offormula 1 and the SSRI are effective in treating dépression or anxiety. The compound offormula 1 and the SSRI can be administered to the mammal at the same time and/or atdifferent times. Moreover, they may be administered together in a single pharmaceuticaicomposition or in separate pharmaceuticai compositions.
This invention also provides a pharmaceuticai composition for treating schizophreniain a mammal, including a human, comprising a compound of formula 1 and an antipsychoticselected from ziprasidone, olanzapine, rispéridone, L-745870, sonepiprazole, RP 62203, NGD941, balaperidone, flesinoxan, and gepirone, together in an amount effective in treatingschizophrenia, and a pharmaceutically acceptable carrier. 012368 -26-
This invention further provides a method for treating schizophrenia in a mammai,including a human, which method comprises administering to said mammai a compound offormula 1 and an antipsychotic selected from ziprasidone, olanzapine, rispéridone, L-745870,sonepiprazole, RP 62203, NGD 941, balaperidone, flesinoxan, and gepirone, wherein thecombined amounts of the compound of formula 1 and the antipsychotic are effective in treatingschizophrenia. The compound of formula 1 and the antipsychotic can be administered to themammai at the same time and/or at different times. Moreover, -they may be administeredtogether in a single pharmaceutical composition or in separate pharmaceutical compositions.
This invention also provides a pharmaceutical composition for treating a disorderselected from Alzheimer's disease, mild cognitive impairment, and age-related cognitivedécliné in a mammai, including a human, comprising a compound of formula 1 and anacetylcholinesterase inhibitor together in an amount effective in treating said disorder, and apharmaceutically acceptable carrier.
This invention further provides a method for treating in a mammai, including a human, adisorder selected from Alzheimer’s disease, mild cognitive impairment, and age-related cognitivedécliné, which method comprises administering to said mammai a compound of formula 1 andan acetylcholinesterase inhibitor, wherein the combined amounts of the compound of formula 1and the acetylcholinesterase inhibitor are effective in treating said disorder. The compound offormula 1 and the acetylcholinesterase inhibitor can be administered to the mammai at the sametime and/or at different times. Moreover, they may be administered together in a singlepharmaceutical composition or in separate pharmaceutical compositions. -
This invention also provides a pharmaceutical composition for treating a disease orcondition selected from stroke, spinal cord trauma, traumatic brain injury, multiinfarct dementia,epilepsy, pain, Alzheimer's disease, and senile dementia comprising a compound of formula 1and TPA (tissue plasminogen activator, for example ACTIVASE) together in an amount effectivein treating said disorder, and a pharmaceutically acceptable carrier.
This invention further provides a method for treating in a mammai, including a human, adisease or condition selected from stroke, spinal cord trauma, traumatic brain injury, multiinfarctdementia, epilepsy, pain, Alzheimer’s disease, and senile dementia, which method comprisesadministering to said mammai a compound of formula 1 and TPA, wherein the combinedamounts of the compound of formula 1 and the TPA are effective in treating said disease orcondition. The compound of formula 1 and the TPA can be administered to the mammai at thesame time and/or at different times. Moreover, they may be administered together in a singlepharmaceutical composition or in separate pharmaceutical compositions.
This invention also provides a pharmaceutical composition for treating a disease orcondition selected from stroke, spinal cord trauma, traumatic brain injury, multiinfarct dementia,
PC
01236S -27- epilepsy, pain, Alzheimer’s disease, and senile dementia in a mammal, including a human,comprising a compound of formula 1 and NIF (neutrophil inhibitory factor) together in an amounteffective in treating said disorder, and a pharmaceutically acceptable carrier.
Tbis invention further provides a method for treating in a mammal, including a human, adisease or condition selected from stroke, spinal cord trauma, traumatic brain injury, multiinfarctdementia, epilepsy, pain, Alzheimer’s disease, and senile dementia, which method comprisesadministering to said mammal a compound of formula 1 and NIF, wherein the combinedamounts of the compound of formula 1 and the NIF are effective in treating said disease orcondition. The compound of formula 1 and the NIF can be administered to the mammal at thesame time and/or at different times. Moreover, they may be administered together in a singlepharmaceutical composition or in separate pharmaceutical compositions. ·
This invention also provides a pharmaceutical composition for treating a disease orcondition selected from Huntington’s disease, stroke, spinal cord trauma, traumatic braininjury, multiinfarct dementia, epilepsy, amyotrophie latéral sclerosis, pain, viral induceddementia for example AIDS induced dementia, migraine, hypoglycemia, urinary incontinece,brain ischemia, multiple sclerosis, Alzheimer’s disease, senile dementia of the Alzheimer’stype, mild cognitive impairment, age-related cognitive décliné, emesis, corticobàsâldegeneration, dementia pugilistica, Down’s syndrome, myotonie dystrophy, Niemann-Pickdisease, Pick’s disease, prion disease with tangles, progessive supranuclear palsy, lowerlatéral sclerosis, and subacute sclerosing panencephalistis in a mammal, including a human,comprising a compound of formula 1 and an NMDA receptor antagonist together in an amounteffective in treating said disorder, and a pharmaceutically acceptable carrier.
This invention further provides a method for treating in a mammal, including a human,a disease or condition selected from Huntington’s disease, stroke, spinal cord trauma,traumatic brain injury, multiinfarct dementia, epilepsy, amyotrophie latéral sclerosis, pain, viralinduced dementia for example AIDS induced dementia, migraine, hypoglycemia, urinaryincontinece, brain ischemia, multiple sclerosis, Alzheimer’s disease, senile dementia of theAlzheimer’s type, mild cognitive impairment, age-related cognitive décliné, emesis,corticobasal degeneration, dementia pugilistica, Down’s syndrome, myotonie dystrophy,Niemann-Pick disease, Pick’s disease, prion disease with tangles, progessive supranuclearpalsy, lower latéral sclerosis, and subacute sclerosing panencephalistis, which methodcomprises administering to said mammal a compound of formula 1 and an NMDA receptorantagonist, wherein the combined amounts of the compound of formula 1 and the NMDAreceptor antagonist are effective in treating said disease or condition. The compound offormula 1 and the NMDA receptor antagonist can be administered to the mammal at the same 012363 P' -28- time and/or at different fîmes. Moreover, they may be administered together in a singlepharmaceutical composition or in separate pharmaceutical compositions.
This invention aiso provides a pharmaceutical composition for treating a disease orcondition seiected from stroke, spinal cord trauma, traumatic brain injury, multiinfarctdementia, epilepsy, pain, Alzheimer’s disease, and senile dementia in a mammal, including ahuman, comprising a compound of formula 1 and a potassium channel modulator together inan amount effective in treating said disorder, and a pharmaceutically acceptable carrier.
This invention further provides a method for treating in a mammal, including a human,a disease or condition seiected from stroke, spinal cord trauma, traumatic brain injury,multiinfarct dementia, epilepsy, pain, Alzheimer’s disease, and senile dementia, which methodcomprises administering to said mammal a compound of formula 1 and a potassium channelmodulator, wherein the combined amounts of the compound of formula 1 and the potassiumchannel modulator are effective in treating said disease or condition. The compound offormula 1 and the potassium channel modulator can be administered to the mammal at thesame time and/or at different fîmes. Moreover, they may be administered together in a singlepharmaceutical composition or in separate pharmaceutical compositions.
The terms “treatment”, “treating”, and the like, refers to reversing, alleviating, orinhibiting the progress of the disease or condition to which such term applies, or one or moresymptoms of such disease or condition. As used herein, these terms aiso encompass,depending on the condition of the patient, preventing the onset of a disease or condition or ofsymptoms associated with a disease or condition, including reducing the severity of a diseasemrcondition or symptoms associated therewith prior to affliction with said disease or condition.Such prévention or réduction prior to affliction refers to administration of the compound of theinvention to a subject that is not at the time of administration afflicted with the disease orcondition. “Preventing" aiso encompasses preventing the récurrence of a disease or conditionor of symptoms associated therewith. “Abnormal cell growth”, as used herein, refers to cell growth, either malignant (e.g. asin cancer) or benign, that is independent of normal regulatory mechanisms (e.g., loss ofcontact inhibition). Examples of benign proliférative diseases are psoriasis, benign prostatichypertrophy, human papilloma virus (HPV), and restinosis. “Neurodegenerative diseases and conditions”, as used herein and unless otherwiseindicated, refers to diseases and conditions having associated therewith degeneration ofneurons. Conditions and diseases that are neurodegenerative in nature are generally known tothose of ordinary skill in the art.
References herein to diseases and conditions “the treatment of which can be effected orfacilitated by altering dopamine mediated neurotransmission” mean a disease or condition that is 012368 -29- caused at least in part by dopamine neurotransmission, or a disease or condition that resuit inabnormal dopamine neurotransmission, thus contributing to symptoms or manifestations of thedisease condition. Référencés herein to diseases and conditions “the treatment of which can be effected orfacilitated by decreasing cdk5 activity” mean a disease or condition that is caused at least in partby cdk5 activity, or a disease or condition that results in abnormal cdk5 activity that contributesto symptoms or manifestations of the disease or condition.
An “amount effective to inhibit cdk5” as used herein refers to an amount of acompound sufficient to bind to the enzyme cdk5 with the effect of decreasing cdk5 activity.
An “amount effective to inhibit cdk2 activity” as used herein refers to an amount of acompound sufficient to bind to the enzyme cdk2 with the effect of decreasing cdk2 activity.
Detailed Description of the Invention
Compounds of the formula 1, above, and their pharmaceuticaily acceptable salts, canbe prepared according to the following reaction Schemes and discussion. Unless otherwiseindicated R1, R2, R3, and R4 are as defined above. “Prot” represents a protecting group.Isolation and purification of the products is accomplished by standard procedures which areknown to a chemist of ordinary skill.
As used herein, the expression “reaction inert solvent" refers to a solvent System inwhich the components do not interact with starting matériels, reagents, or intermediates ofproducts in a manner which adversely affects the yield of the desired product
During any of the following synthetic sequences it may be necessary and/or désirableto protect sensitive or reactive groups on any of the molécules concerned. This may beachieved by means of conventional protecting groups, such as those described in T. W.Greene, Protective Groups in Organic Chemistry, John Wiley &amp; Sons, 1981; and T. W.Greene and P. G. M. Wuts, Protective Groups in Organic Chemistry, John Wiley &amp; Sons,Inc., 1999.
Scheme 1 illustrâtes general methods suitable for preparing compounds of formula 1 wherein R3 is -(CR10R11)n-, -C(=O)NR9-, -C(=O)O-, or -C(=O)(CR10R11)n- Treatment of a solution of slurry of magnésium chloride in a reaction inert solvent, preferably acetonitrile, / diethyl ether, or tetrahydrofuran, at a reaction température from -20 °C to 40 °C, preferablyfrom about -5 °C to 21 °C, with a trialkyl amine base, where triethyl amine ordiisopropylethylamine are preferred, in the presence of an alkyl cyano acetate and in thepresence of an acid halide of formula 2, wherein acid chlorides are preferred, affordsintermediate 3a, a 2-cyano-3-alkyl-3-oxo-propionic acid alkyl ester. A preferred alkyl cyanoacetate is ethyl cyano acetate. Hydrolysis and décarboxylation of 3a to 3 may beaccomplished by exposing 3a to water in a réaction inert solvent, preferably dimethylsulfoxide, 012368 tu* -30- at a température from about 21 °C to 200 °C, preferably from about 100 °C to 118 °C.Reaction of 3 in a reaction inert solvent, such as a lower alcohol, in the presence of ahydrazine at a reaction température of from about 0 °C to about 150 °C, where a températureof from about 70 °C to about 85 °C is preferred, affords the corresponding product 4. The 5 hydrazine used may be anhydrous hydrazine or a hydrate form of hydrazine, or N-alkyl-hydrazine or N-acyl-hydrazine. Anhydrous hydrazine or an aikyl hydrazine, for example 4-methoxy-benzyl-hydrazine, are preferred.
Coupling of 4 with an aryl halide or heteroaryl halide to obtain an intermediate offormula 5, wherein R3 is -(CR’°R11)0- (a bond) can be accomplished by reaction of 4 in a 10 reaction inert solvent, preferably toluene, at a reaction température of from about 21 °C toabout 150 °C, preferably at about 100 °C to about 110 °C, in the présence of a palladiumcatalyst, a base, preferably césium carbonate or sodium or potassium tert-butoxide, a ligand,where preferred ligands are 2,2’-bis(diphenylphosphino)-1,1’-binaphythyl, 2-(dicyclohexylphosphino)biphenyl, and 2-(di-tert-butylphosphino)biphenyl, and in the presence 15 of the appropriate aryl halide or heteroaryl halide, where aryl bromides or chlorides andheteroaryl bromides or chlorides are preferred. The métal catalyst may be a palladiumspecies, for example palladium chloride, palladium acetate, dichlorobis(acetonitrile)palladium,or dérivatives thereof, wherein palladium acetate is preferred. Removal of the protectinggroup from 5 can be accomplished by reaction of 5 in a reaction inert solvent, preferably 20 methylene chloride or no solvent, in the presence of an acid, wherein trifluoro acetic acid ispreferred, at a reaction température from about 20 °C to about 100 °C, preferably from aboOt65 °C to about 75 °C, to yield 1a, wherein R3 represents a bond and R4 is as defined above forcompounds of formula 1.
Coupling of 4 to yield N-acyl dérivatives of the nature 6 (wherein R3 is 25 -C(=O)(CR10R11)n-) can be accomplished by reaction of 4 in a reaction inert solvent, preferably methylene chloride, pyridine, tetrahydrofuran, or diethyl ether, in the presence of an acidchloride CIC(=O)(CH2)nR4, acid anhydride R4(CH2)nC(=O))2O, or an activated carboxylic aciddérivative XC(=O)(CH2)„R4 wherein X represents the activating group, and in the presence ofa amine base, such as triethyl amine or diisopropylethyl amine, wherein tripropylphosphonic 30 anhydride and triethylamine are a preferred combination, at a température of from about -78°C to about 40 °C. The activated carboxylic acid dérivative can be prepared from thecarboxylic acid and known activating reagents such as polymer supported coupling agents orcoupling agents such as, for instance, dicyclohexyl carbodiimide, carbonyl diimidazole,tripropylphosphonic anhydride, aikyl chloroformate, bis(2-oxo-3-oxazolidinyl)phosphinic 35 chloride, benzotriazol-1-yloxy-tris(dimethylamino)pbosphoniurn hexafluorophosphate, or any 012368 -31- ’CT/' other such standard literature reagents. Removal of the protecting group on 6 may beaccomplished by reaction 6 in a reaction inert solvent, wherein methylene chloride or nosolvent is preferred, in the presence of an acid, wherein trifluoro acetic acid is preferred, at areaction température from about 20 °C to about 100 °C, preferably from about 65 °C to about75 °C. A product of formula 1b is obtained, wherein R3 represents -C(=O)(CR’°R11)n- and R4is as defined above forcompounds of formula 1.
Aiternatively, the amine of 4 can be treated with a base, such as trieihylamine,diisopropyiethylamine, pyridine, or 2,6-lutidine, and an alkyl, aryl, or heteroaryl chioroformateCIC(=O)OR4 (diisopropyiethylamine and aryl or heteroarly chloroformâtes are a preferredcombination) from a température about -78 °C to about 40 °C, to afford a compound of anintermediate where R3 -C(=O)O- and R4 is as defined above for compounds of formula 1.Removal of the protecting group from this intermediate can be achieved as described, i.e. in areaction inert solvent, wherein methylene chloride or no solvent' is preferred, in the presenceof an acid, wherein trifluoro acetic acid is preferred, at a reaction température from about 20°C to about 100 °C, preferably from about 65 °C to about 75 °C. This affords a carbamatecompound of formula 1 wherein R3 is -C(=O)O- and R4 is as defined above for compounds offormula 1.
Subséquent treatment of the carbamate of the formula 1 formed in the precedingparagraph with a primary or secondary amine in a solvent such as dioxane,dimethylformamide, or acetonitrile, where a 1:1 mixture of dioxane: dimethylformamide ispreferred, at a température between about 40 °C and about 90 °C, where about 70 °C ispreferred, affords the corresponding urea product of formula 1 where R3 is -C(=O)NR9- andR4 is as defined above for compounds of formula 1.
Compounds of formula 1 wherein R3 is -(CR10R11)(1.3)- can be prepared fromintermediates of formula 4 by reaction of 4 with an oxo moiety (aldéhyde or ketone) in areaction inert solvent, preferably toluene, tetrahydrofuran or methanol at a reactiontempérature from about 0 °C to about 110 °C, preferably about 21 °C, in the presence of areducing ragent, where preferred reducing reagents are sodium triacetoxyborohydride,sodium cyanoborohydride, and lithium aluminum hydride to afford an intermediate of formula 6wherein R3 is -(CR10R11)(1.3)-, Removal of the protecting group from this intermediate 6 can beachieved as described, i.e. in a reaction inert solvent, wherein trifluoro acetic acid is preferred,at a reaction température from about 20 °C to about 100 °C, preferably from about 65 °C toabout 75 °C. 012368
P -32-
Scheme 1
Η
Scheme 2 illustrâtes an alternative method suitable for preparing compounds offormula 1. The method depicted in Scheme 2 is preferred when R4 is an électron déficient 5 aryl moiety, such as 4-nitrophenyl, or an électron déficient heteroaryl moiety. Reaction of aketone having the general structure of 8, wherein R1 and R2 are as defined above forcompounds of formula 1, in a reaction inert solvent, wherein tetrahydrofuran or diethyl etherare preferred as solvents, at a réaction température from about -116 °C to about 50 °C,preferably at about -78 °C to about -65 °C, in the presence of a base, a hindered amine base 10 being preferred, and also in the presence of an isothiocyanate of the general formula 9,wherein R3 is a bond (-(CR10R11)0-) and R4 is aryl or heteroaryl, affords 10. Examples ofhindered amine bases include lithium diisopropyl amide, potassium bis(trimethylsilyl) amide,lithium bis(trimethylsilyl) amide, and other such standard literature reagents. Treatment of 10in a reaction inert solvent, a preferred solvent being a lower alcohol, in the presence of an 15 acid, preferably acetic acid, at a reaction température of from about 21 °C to about 100 °C, -33- preferably from about 75 °C to about 85 °C, and in the presence of hydrazine, affords acompound of the formuia 1a, wherein R3 is a bond and R4 is aryl or heteroaryl.
Synthesis of compounds of formula 1 wherein R1 is substituted with one or moresubstituents R5 is also illustrated in Scheme 2. Réaction of a compound of formula 10 in aréaction inert solvent, such as lower alcohols, in the presence of an acid, preferably aceticacid, also in the presence of a hydrazine, at a reaction température of about 0 °C to about 150°C, preferably from about 75 °C to about 85 °C, affords 10a (wherein R3 is a bond, R4 is aryl orheteroaryl, R1 is as defined above, and Rs is a protected oxo moiety (an acetal or ketal).Preferred hydrazines are alkyl hydrazines, for example 4-methoxy-benzyl hydrazine or i-butylhydrazine.
Deprotection of the oxo moiety R5 can be accomplished using weli-known conditions,which appear in the literature. For example, treating compound 10a in a reaction inertsolvent, .preferably a lower ketone for example acetone, in the presence of an acid, preferablyhydrogen chioride, p-toluenesulfonic acid monohydrate, or pyridinium p-toluenesulfonate, at atempérature of from about room température to about 80 °C, preferably about 75 °C, affords10b, wherein R5 is an oxo (carbonyl) moiety, R1 is as defined above, R3 is a bond, and R4 isaryl or heteroaryl. Réduction of the oxo moiety to obtain an aiocohol (R5 is -OH) can be accomplishedusing weli established chemistry. Alternatively, the oxo moiety of 10b can be reacted with anamine, either primary or secondary, wherein the preferred amine is an alkyl amine forexample 4-methoxy-benzyl-amine, in a reaction inert solvent, preferably toluene ortetrahydrofuran, at a reaction température from about 21 °C to about 150 °C, preferably atabout 70 °C to about 110 °C. After 10b is consumed, usually within a 12 hour period, theréaction is cooled to a température of about 21 °C to about 50 °C and a reducing reagent isadded, where preferred reducing reagents are sodium triacetoxyborohydride, sodiumcyanoborohydride and lithium aluminum hydride, to afford 10c, wherein R1 is as definedabove, R3 is a bond’ R4 is aryl or heteroaryl, and R5 is -NR7R8. Coupling of 10c to yield N-acyl dérivatives of the formula 10d, wherein R5 is -NR7C(=O)R8, can be accomplished byreaction of 10c in a réaction inert solvent, wherein methylene chioride, pyridine,tetrahydrofuran, diethyl ether are preferred, in the presence of an alkyl chloroformate, acidchioride, acid anhydride, or an activated carboxylic acid dérivative, from -78 °C to 40 °C. Theactivated carboxylic acid dérivative is prepared from the carboxylic acid and known activatingreagents such as polymer supported coupling agents or alternatively dicyclohexylcarbodiimide. carbonyl diimidazole, tripropyiphosphonic anhydride, alkyl chloroformate, bis(2-oxo-3-oxazolidinyl)phosphinic chioride, benzotriazol-1-yloxy-tris(dimethylamino)phosphonium 012360 η -34- hexafluorophosphate, or any other such standard literature reagents, in the presence of atrialkyl amine base, such as triethyl amine or diisopropylethyl amine, whereintripropylphosphonic anhydride and triethylamine are a preferred combination.
Removal of the protecting group on 10b, 10c, or 10d may be accompiished by5 reaction in a reaction inert solvent, wherein methyiene chloride or no solvent is preferred, inthe presence of an acid, preferably trifiuoro acetic acid, at a reaction température from about20 °C to about 100 °C, preferably from about 65 °C to about 75 °C, to yield the corresponding compounds of formula 1, for example 1c, as depicted in Scheme 2. 012368 -35-
Prot
10d 012368
PC -36-
Scheme 3 illustrâtes an alternative method suitable for the préparation of compoundsof formula 1. The method illustrated in Scheme 3 is preferred when R1 is substituted with R5selected from -NR7R8, -NR7C(=O)R8, -NR7C(=O)NR8R9, -NR7S(=O)2R8, -NR7S(=O)2NR8R9, -C(=O)R7, -C(=O)OR7, and -C(=O)NR7R8. Referring to Scheme 3, reacting an organolithiumbase, preferably n-butyl lithium, sec-butyl lithium, phenyl lithium, or fert-butyl lithium, at areaction température from about -116 °C to about 50 °C, preferably at about -78 °C to about -45 °C, in a reaction inert solvent, especially tetrahydrofuran or diethyl ether, in the presence ofalkylnitrile, preferably acetonitrile, and in the presence of an ester of the formula 11, whereinR1 is as defined above and R5 is a protected oxo moiety (specifically.a ketal or acetal) or R5 isas defined above, gives 3b, wherein R5 is the same as in the compound of formula 11.Processing of a compound with the formula 3b to a compound with the formula 1d or formula1e where R3 is, respectively, -C(=O)(R10R11)n- or a bond and R5 is as in the compound offormula 11 can be accomplished as described in the description of Scheme 1. If R5 is aprotected oxo moiety, conversion of such group to carbonyl, can be accomplished at the sametime as removal of the protecting group from the pyrazole nitrogen.
Alternatively, the amine of 4a can be treated with a base, such as triethylamine,diisopropylethylamine, pyridine, or 2,6-lutidiné, and a chloroformate CIC(=O)OR4(diisopropylethylamine and aryl or heteroarly chloroformâtes are a preferred combination) asdescribed above for scheme 1 to afford a carbamate intermediate 7a where R3-C(=O)O- andR4 is as defined above for compounds of formula 1.
Subséquent treatment of 7a formed in the preceding paragraph with a primary-orsecondary amine in a solvent such as dioxane, dimethylformamide, or acetonitrile, where a1:1 mixture of dioxane: dimethylformamide is preferred, at a température between about 40 °Cand about 90 °C, where about 70 °C is preferred, affords the corresponding urea intermediate7b where R3 is -C(=O)NR9- and R4 is as defined above for compounds of formula 1.
Intermediate 7c wherein R3 is -(CR10R11)(1.3)- can be prepared from intermediate 4a byreaction of 4a with an oxo moiety (aldéhyde or ketone) in a reaction inert solvent, preferablytoluene, tetrahydrofuran or methanol at a reaction température from about 0 °C to about 110°C, preferably about 21 °C, in the presence of a reducing reagent, where preferred reducingreagents are sodium triacetoxyborohydride, sodium cyanoborohydride, and lithium aluminumhydride to afford an intermediate of formula 6a wherein R3 is -{CR10R11){1.3)-. Removal of theprotecting group from this intermediate 6a can be achieved as described, i.e. in a reactioninert solvent, wherein trifluoro acetic acid is preferred, at a reaction température from about 20°C to about 100 °C, preferably from about 65 °C to about 75 °C.
PÇT -37-
Intermediates of formula 5a, 6a, 7a, 7b, or 7c can also be converted to form furthercompounds of the invention, as illustrated in Scheme 3. Scheme 3 depicts use of 5a (whereinR3 is a bond) and 6a (wherein R3 is -C(=O)(R’°R")n-) as reactants, however the samechemistry can be applied to intermediates of formulae 7a, 7b, or 7c to obtain anaiogousProducts. Referring to Scheme 3, if R5 in 5a and 6a is a protected oxo (carbonyi) moiety(specifically acetal or ketal), removal of the protecting group can first be accomplished usingwell-known conditions, which appear in the literature. Treating a compound 5a or 6a (or 7a,7b, or 7c), in a reaction inert solvent, preferably a lower ketone, for example acetone, in thepresence of an acid, where preferred acids are hydrogen chloride, p-toluenesulfonic acidmonohydrate, pyridinium p-toluenesuifonate, at a température varying from about roomtempérature to about 80 °C, préférable at about 75 °C, affords 12, where R3 is a bond, or 15,where R3 is -C(=O)(CR10R11)n-, or, if 7a, 7b, or 7c were used as reactants, compoundsanaiogous to 12 and 15 but wherein R3 is -C(=O)O-, -C'(=O)NR9-, or -(CR^R11)^,-,respectively, in each case R5 being an oxo (carbonyi) moiety.
The oxo moiety of the intermediates produced in the preceding paragraph, such as in12 and 15, can be reacted with an amine, primary or secondary, wherein the preferred aminesare alkyl amine for example 4-methoxy-benzyl-amine, in a reaction inert solvent, preferablytoluene or tetrahydrofuran, at a reaction température from 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 12hour period, the reaction can be cooled to a température of about 21 °C to about 50 °C, and areducing reagent is added. Preferred reducing reagents are sodium triacetoxyborohydride,sodium cyanoborohydride and lithium aluminum hydride. Such reaction of for example 12 or15 affords 13, wherein R3 is a bond, or 16, wherein R3 is -C(=O)(CR10R11)n-, respectively, ineach case R5 being -NR7R8. Anaiogous compounds to 13 and 16, wherein R5 is -NR7R8 andR3 is -C(=O)O-, -C(=O)NR9-, or -(CR10R11){1.3)- can also be prepared, using the intermediatesanaiogous to 12 and 15 described above. Coupling of 13 or 16 or the anaiogousintermediates to yield an N-acyl dérivative 14 or 17 or N-acyl dérivatives anaiogous theretobut having R3 as -C(=O)O-, -C(=O)NR9-, or -(CR10R11)(,.3)-, can be accomplished by reactionof 13 or 16 or the anaiogous intermediates in a réaction inert solvent, wherein methylenechloride, pyridine, tetrahydrofuran, diethyl ether are preferred, in the presence of an acidchloride, acid anhydride, or an activated carboxylic acid dérivative, from about -78 °C to about40 °C. The activated carboxylic acid can be prepared as described above.
Alternatively, the amine of 16 or 13 or the intermediates anaiogous thereto can betreated with a base, such as triethylamine, diisopropylethylamine, pyridine, or 2,6-lutidine, andan alkyl, aryi or heteroaryi chloroformate CIC(=O)2R7 (diisopropylethylamine andchloroformâtes are a preferred combination) from a température of about -78 °C to about 40 012368 P( -38- °C, where from about -78 °C to about -40 °C are preferred, to afford a compounds of formula1 where R5 -NR7C(=O)OR8. Subséquent treatment of the carbamate of the formula 1 with aprimary or secondary amine in a solvent such as dioxane, dimethylformamide, or acetonitrile,where a 1:1 mixture of dioxane: dimethylformamide is preferred, at a température between 40 5 °C and 90 °C, where 70 °C is preferred, affords the corresponding urea intermediate where R5is -NR7C(=O)NR9R9.
Removal of the protecting group on 12, 13, 14, 15, 16, or 17 or any of the analogouscompounds described above wherein R3 and/or R5 is instead -C(=O)O-, -C(=O)NR9-, or -(CR1°R11)(1.3)- may be accomplished by réaction in a reaction inert solvent, wherein methylene 10 chloride or no solvent is preferred, in the presence of an acid, wherein trifluoro acetic acid ispreferred, at a reaction température from about 20 °C to about 100 °C', preferably from about65 °C to about 75 °C, affording respective compounds of formula 1, for example a compoundformula 1c, wherein R3 is a bond and R5 is -NR7C(=O)R8 or a compound of formula 1f,wherein R3 is -C(=O)(CR10R11)n- and R5 is -NR7C(=O)R8. 012368
IV -39-
Schemes 4 and 5 illustrate a preferred method for the préparation of compounds ofthe formula 1, wherein R1 is optionally substituted with OR7 or R7. Préparation of the 5 intermediates 12 and 15 can be accomplished as described in the description of Scheme 3.R3 in intermediate 12 is a bond, and R3 in intermediate 15 is -C(=O)(CR10R11)n-. Also,intermediates anaiogous to 12 and 15, but wherein R3 is -C(=O)O-, -C(=O)NR9-, or -(CR’0Rn)(1.3,-, can be used in Schemes 4 and 5. In each case (12, 15, or anaiogousintermediate), R5 is an oxo (carbonyl) moiety. *· 012368 PC«. -40-
Conversion of the oxo (=0) moiety lo a hydroxyi moiety (-OH), as in 18 and 23, canbe accomplished using well-established chemistry. The preferred method is by reaction of 12or 15 or intermediate analogous thereto in a reaction inert solvent, preferably atetrahydrofuran/water mixture, at a reaction température from about -78 °C to about 50 °C,préférable at about 20 °C, in the presence of a reducing agent, preferably NaBH4 or lithiumaluminum hydride, to afford 18 or 23 or compound analogous thereto wherein R3 is -C(=O)O-,-C(=O)NRS-, or-(CR’°R11)(,.3)-.
Reaction of 18 or 23 or compound analogous thereto wherein R3 is -C(=O)O-,-C(=O)NR9-, or -(CR10R11)(1.3)- in a reaction inert solvent, preferably tetrahydrofuran, at areaction température from about -20 °C to about 50 °C, preferably at about 20 °C, in thepresence of R7-halide, where the preferred R7-halide is R7-CI, affords '19 or 24 or compoundanalogous thereto wherein R3 is -C(=O)O-, -C(=O)NR9-, or -(CR10R11)(1.3,-, in each case R5being -OR7. Removal of the protecting group can be accomplished by reaction in a reactioninert solvent, wherein methylene chloride or no solvent is preferred, in the présents of an acid,wherein trifluoro acetic acid is preferred, at a reaction température from about 20 °C to 100°C, preferably from about 65 °C to about 75 °C, to obtain a compound of formula 1g, whereinR3 is a bond and where R5 = OR7, a compound of formula 1h, wherein R3 is -C(=O)(CR10R11)(0.3)-, or an analogous compound wherein R3 is -C(=O)O-, -C(=O)NR9-, or -(CR10R11)(1.3)-.
Alternatively, treatment of a solution of compound 12 or 15 or analogous intermediatewherein R3 is -C(=O)O-, -C(=O)NR9-, or-(CR’°R11)(,.3)- (in each case R5 being an oxo moiety,specifically carbonyl) in a reaction inert solvent, where tetrahydrofuran is preferred, with anorganometallic reagent, such as an organomagnesium halide, organolithium, organocerium,organotitanium, organozinc, organocopper, or organoaluminum, where the organomagnesiumhaiide (Grignard reagent) or organolithium reagents are preferred, at a température fromabout -78 °C to about 40 °C, where -78 °C to about 0 °C is preferred, affords the alcoholproduct 21 or 26 or analogous compound wherein R3 is -C(=O)O-, -C(=O)NR9-, or -(CR10R11)(1.3)-, wherein in each case R’ is hydroxylated and substituted with R7, for example(5-(3-hydroxy, 3-phenyl-cyclobutyl)-2-(Prot)-pyrazol-3-yl)-naphthalen-2-yl-amine. Removal ofthe alcohol is accomplished by reaction of 21 or 26 or analogous compound in an inertsolvent, such as methylene chloride, chloroform, or 1,2-dichloroethane, or preferably nosolvent, in the presence of an acid, preferably trifluoroacetic acid, and in the presence of asilane, where triethylsilane and triphenyisilane are preferred, at a température from about -10°C to about 50 °C, where about 20 °C to about 40 °C is preferred, obtaining a compound offormula 22 or 27 or compound analogous thereto but wherein R3 is -C(=O)O-, -C(=O)NR9-, or-(CR10Rn)(1.3)-, the intermediate in each case comprising R7 bonded directly to R1. 012368 -41-
Alternatively, treatment of the alcohol products such as 21 or 26 and about one to tenéquivalents of a base, where about five équivalents of pyridine or 2,6-lutidine are preferred, ina reaction inert solvent, preferably methylene chloride, with a strongly acidic reagant,preferably thionyl chloride, at a température from about -110 °C to about 0 °C, where about -78 °C to about -45 °C is preferred, results in replacement of the alcohol (-OH group) withchloride. Reductive removal of the chloride may be accomplished by exposing a mixture ofsaid chloride of 21 or 26 and a noble métal catalyst, palladium being preferred, to anatmosphère of hydrogen gas at a pressure of about 1 to about 100 atmosphères, where apreferred pressure of hydrogen gas is about one to about ten atmosphères, to obtain 22 or 27or a compound analogous thereto wherein R3 is -C(=O)O-, -C(=O)NRS-, or -(CR10R”)(,.3)-.The métal catalyst may be conveniently suspended on an inert solid support such ascharcoal, in a solvent such as ethyl acetate, tetrahydrofuran, dioxane, or a mixture thereof.
In Schemes 4 and 5, the R5 hydroxy moiety of a compound of formula 18 or 23, or ofthe analogous compounds wherein R3 is -C(=O)O-, -C(=O)NR9-, or -(CR10R11)(1.3)-, can bederivatized using chemistry known in the art to obtain corresponding compounds wherein R5is -OC(=O)R7, -OC(=O)OR7, -OC(=O)NR7R8, and -OC(=O)SR7, -SR7, -S(=O)R7, -S(=O)2R7, or-S(=O)ZNR7R8.
For example, the amine of 18 or 23 or a compound analogous thereto wherein 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 an alkyl, aryl or heteroaryl chloroformateCIC(=O)2R7 (diisopropylethylamine and chloroformâtes are a preferred combination) ffom atempérature of about -78 °C to about 40 °C, where from about -78 °C to -40 °C are preferred,to afford a carbonate intermediate where R5 is -OC(=O)OR8. Subséquent treatment of thecarbonate with a primary or secondary amine in a solvent such as dioxane,dimethylformamide, or acetonitrile, where a 1:1 mixture of dioxane: dimethylformamide ispreferred, at a température between about 40 °C and about 90 °C, where about 70 °C ispreferred, affords thé corresponding urea intermediate where R5 is -OC(=O)NR8R9. Removalof the protecting group of either intermediate may be accomplished by reaction in a reaction ofinert solvent, wherein methylene chloride or no solvent is preferred, in the presence of anacid, wherein trifiuoro acetic acid is preferred, at a reaction température from about 20 °C toabout 100 °C, preferably from about 65 °C to about 75 °C, affording a compound of formula 1,where R5 -OC(=O)OR7 or -OC(=O)NR8R9.
Removal of the protecting group of 22, 27, or a dérivative of 19 or 24 can beaccomplished by reaction in a reaction inert solvent, preferably methylene chloride,chloroform, 1,2-dichloroethane, or no solvent, in the presence of an acid, where trifluoroaceticacid is preferred, at a reaction température from about 20 QC to about 100 °C, preferably from 012368 -42- about 65 °C to about 75 °C, affording a compound of formula 1 i, 1k, or other compound offormula 1.
Compounds of formula 1 as described herein wherein R2 is other than hydrogen canbe prepared by transformations of the compounds of formula 1 herein wherein R2 is hydrogen 5 using methods that are well known in the art. For example, referring to Scheme 3, supra,compounds of formula 1 wherein R2 is F can be prepared by treating compounds of formula17, 6a, or 14 with N-fluorobenzenesulfonimide in a reaction of inert solvent, wherein toluene,dioxane, or xylenes are preferred, from about room température to about 150°C, preferablyfrom about 100°C to about 120°C to obtain the corresponding intermediates wherein R2 is F. 10 Removal of the protecting group from these intermediates may be accomplished by reactionin a reaction of inert solvent, wherein methylene chloride or no solvent are preferred, in thepresence of an acid, wherein trifluoro acetic acid is preferred, at a reaction température fromabout 20°C to about 100°C, preferably from about 65°C to about 75°C, thus affordingcompounds of formula 1 wherein R2 is F. 012368 -43-
Scheme 4 Prot
Scheme 5
012368 -44-
Some of the compounds of formula 1 prepared according to the above processes areobtained as a mixture of isomers or enantiomers. Such mixtures of isomers or enantiomersare within the scope of the présent invention. The séparation of such mixtures into the singleisomers or enantiomers according to conventional techniques is also within the scope of theprésent invention, as are the separated isomers and enantiomers themselves.
Pharmaceutically acceptable salts of a compound of formula 1 can be prepared in aconventional manner by treating a solution or suspension of the corresponding free base oracid with one Chemical équivalent of a pharmaceutically acceptable acid or base.Conventional concentration or crystallization techniques can be employed to isolate the salts.Illustrative of suitable acids are acetic, lactic, succinic, maleic, tartaric, citric, gluconic,ascorbic, benzoic, cinnamic, fumaric, sulfuric, phosphoric, hydrochloric, hydrobromic,hydroiodic, sulfamic, sulfonic acids such as methanesulfonic, benzene sulfonic, p-toiuenesulfonic, and related acids, illustrative bases are sodium, potassium, and calcium. A compound of this invention may be administered alone or in combination withpharmaceutically acceptable carriers, in either single or multiple doses. Suitable pharmaceuticalcarriers include inert soiid diluents or fillers, stérile aqueous solutions and various organicsolvents. The pharmaceutical compositions formed by combining a compound of formula 1 or apharmaceutically acceptable sait thereof can then be readily administered in a variety of dosageforms such as tablets, powders, lozenges, syrups, injectable solutions and the like. Thesepharmaceutical compositions can, if desired, contain additional ingrédients such as flavorings,binders, excipients and the like. Thus, for purposes of oral administration, tablets containin&amp;various excipients such as sodium citrate, calcium carbonate and calcium phosphate may beemployed along with various disintegrants such as starch, methylcellulose, alginic acid andcertain complex silicates, together with binding agents such as polyvinylpyrrolidone, sucrose,gelatin and acacia. Additionally, lubricating agents such as magnésium stéarate, sodium laurylsulfate and talc are often useful for tabletting purposes. Solid compositions of a similar type mayalso be employed as fillers in soft and hard filled gelatin capsules. Preferred materials for thisinclude lactose or milk sugar and high molecular weight polyethylene glycols. When aqueoussuspensions or élixirs are desired for oral administration, the essential active ingrédient thereinmay be combined with various sweetening or flavoring agents, coloring matter or dyes and, ifdesired, emulsifying or suspending agents, together with diluents such as water, éthanol,propylene glycol, glycerin and combinations thereof.
For parentéral administration, solutions containing a compound of this invention or apharmaceutically acceptable sait thereof in sesame or peanut oil, aqueous propylene glycol, orin stérile aqueous solution may be employed. Such aqueous solutions should be suitablybuffered if necessary and the liquid diluent first rendered isotonie with suffirent saline or 012368 -45- glucose. These particular aqueous solutions are especially suitable for intravenous,intramuscular, subcutaneous and intraperitoneal administration. The stérile aqueous mediaemployed are ail readily available by standard techniques known to those skilled in the art. A compound of formula 1 or a pharmaceutically acceptable sait thereof can beadministered orally, transdermally (e.g., through the use of a patch), parenterally (e.g.intravenously), rectally, or topically. In general, the daily dosage for treating aneurodegenerative disease or condition or a disease or condition the treatment of which can beeffected or facilitated by altering dopamine mediated neurotransmission will generally range fromabout 0.0001 to about 10.0 mg/kg body weight of the patient to be treated. The daily dosage fortreating cancer or disease or condition involving abnormal cell growth of a benign nature willgenerally range from about 0.0001 to about 500 mg/kg body weight of the patient to be treated.As an example, a compound of the formula 1 or a pharmaceutically acceptable sait thereofcan be administered for treatment of a neurodegenerative disorder to an adult human ofaverage weight (about 70kg) in a dose ranging from about 0.01 mg up to about 1000 mg perday, preferably from about 0.1 to about 500 mg per day, in single or divided (i.e., multiple)portions. Variations based on the aforementioned dosage ranges may be made by aphysician of ordinary skill taking into account known considérations such as the weight, âge,and condition of the person being treated, the severity of the affliction, and the particular routeof administration chosen.
The compounds of formula 1 and their pharmaceutically acceptable salts canfurthermore also be administered or formulated into a pharmaceutical composition with anamount of one or more substances selected from anti-angiogenesis agents, signaltransduction inhibitors, and antiproliférative agents, which amounts are together effective ininhibiting abnormal cell growth.
Anti-angiogenesis agents, such as MMP-2 (matrix-metalloproteinase 2) inhibitors,MMP-9 (matrix-metalloproteinase 9) inhibitors, and COX-II (cyclooxygenase II) inhibitors, canbe used in conjunction with a compound of formula 1 in the methods and pharmaceuticalcompositions described herein for treatment of abnormal cell growth, including cancer.Examples of useful COX-II inhibitors include CELEBREX™ (celecoxib), valdecoxib, androfecoxib. Examples of useful matrix metalloproteinase inhibitors are described in WO96/33172 (published October 24, 1996), WO 96/27583 (published March 7, 1996), EuropeanPatent Application No. 97304971.1 (filed July 8, 1997), European Patent Application No.99308617.2 (filed October 29, 1999), WO 98/07697 (published February 26, 1998), WO98/03516 (published January 29, 1998), WO 98/34918 (published August 13, 1998), WO98/34915 (published August 13,1998), WO 98/33768 (published August 6, 1998), WO 98/30566(published July 16, 1998), European Patent Publication 606,046 (published July 13, 1994), 012368
PCT/IB -46-
European Patent Publication 931,788 (published July 28, 1999), WO 90/05719 (published May331, 1990), WO 99/52910 (published October 21, 1999), WO 99/52889 (published October 21,1999), WO 99/29667 (published June 17, 1999), PCT international Application No.PCT/IB98/01113 (filed July 21, 1998), European Patent Application No. 99302232.1 (filed March25, 1999), Great Britain patent application number 9912961.1 (filed June 3, 1999), United StatesProvisional Application No. 60/148,464 (filed August 12, 1999), United States Patent 5,863,949(issued January 26, 1999), United States Patent 5,861,510 (issued January 19, 1999), andEuropean Patent Publication 780,386 (published June 25, 1997), ail of which are incorporatedherein in their entireties by reference. Preferred MMP-2 and MMP-9. inhibitors are those thathâve little or no activity inhibiting MMP-1. More preferred, are those that selectively inhibit MMP-2 and/or MMP-9 relative to the other matrix-metalloproteinases (i.e. MMP-1, MMP-3, MMP-4,MMP-5, MMP-6, MMP-7, MMP-8, MMP-10, MMP-11, MMP-12, and MMP-13).
Some spécifie exampies of MMP inhibitors useful in the présent invention are AG-3340,RO 32-3555, RS 13-0830, and the compounds recited in the following list: 3-[[4-(4-fluoro-phenoxy)-benzenesulfonyl]-(1-hydroxycarbamoyl-cyclopentyl)-aminoj-propionic acid; 3- exo-3-[4-(4-fiuoro-phenoxy)-benzenesulfonylamino]-8-oxa-bicyclo[3.2.1]octane- 3- carboxylic acid hydroxyamide; (2R, 3R) 1-[4-(2-chloro-4-f!uoro-benzyloxy)-benzenesulfonyl]-3-hydroxy-3-methyl-piperidine-2-carboxylic acid hydroxyamide; 4- [4-(4-fiuoro-phenoxy)-benzenesulfonylamino]-tetrahydro-pyran-4-carboxylic -acid hydroxyamide; 3- [[4-(4-fluoro-phenoxy)-benzenesulfonyl]-(1-hydroxycarbamoyl-cyclobutyl)-aminoj-propionic acid; 4- [4-(4-chloro-phenoxy)-benzenesulfonylamino]-tetrahydro-pyran-4-carboxylicacid hydroxyamide; (R) 3-[4-(4-chloro-phenoxy)-benzenesulfonylamino]-tetrahydro-pyran-3-carboxylicacid hydroxyamide; (2R, 3R) 1 -[4-(4-fluoro-2-methyl-benzyloxy)-benzenesulfonyl]-3-hydroxy-3- methyl-piperidine-2-carboxylic acid hydroxyamide; 3-[[4-(4-fiuoro-phenoxy)-benzenesulfonyl]-(1-hydroxycarbamoyl-1-methyl-ethyl)-aminoj-propionic acid; 3-[[4-(4-fluoro-phenoxy)-benzenesulfonyI]-(4-hydroxycarbamoyl-tetrahydro-pyran- 4- yl)-aminoJ-propionic acid; 3-exo-3-[4-(4-chloro-phenoxy)-benzenesulfonylamino]-8-oxa-bicyclo[3.2.1]octane-3-carboxylic acid hydroxyamide; 012368 -47- 3-endo-3-[4-(4-fluoro-phenoxy)-benzenesulfonylamino]-8-oxa-bicyclo[3.2.1]octane-3-carboxylic acid bydroxyamide; and (R) 3-[4-(4-fluoro-phenoxy)-benzenesulfonylamino]-tetrahydro-furan-3-carboxylicacid hydroxyamide; and pharmaceuticaliy acceptable salts and solvatés of said compounds.
Other anti-angiogenesis agents, including other COX-II Inhibitors and other MMPinhibitors, can also be used in the présent invention.
The effective amount of a COX-ll inhibitor in combination with a compound of formula 1can generally be determined by a person of ordinary skill. A proposed daily effective dose rangefor a COX-ll inhibitor in combination with a cdk5 inhibitor is from about 0.1 to about 25 mg/kgbody weight. The effective daily amount of the compound of formula 1 generally will be betweenabout 0.0001 to about 10 mg/kg body weight. In some instances the amount of COX-ll inhibitorand/or the compound of formula 1 in the combination may be less than would be required on anindividual basis to achieve the same desired effect in inhibiting abnormal cell growth. A compound of formula 1 can also be used with signal transduction inhibitors, such asagents that can inhibit EGFR (epidermal growth factor receptor) responses, such as EGFRantibodies, EGF antibodies, and molécules that are EGFR inhibitors; VEGF (vascularendothélial growth factor) inhibitors; and erbB2 receptor inhibitors, such as organic moléculesor antibodies that bind to the erbB2 receptor, for example, HERCEPTIN™ (Genentech, Inc. ofSouth San Francisco, California, USA). Such combinations are useful for treating andpreventing abnormal cell growth, including cancer, as described herein. EGFR inhibitors are described in, for example in WO 95/19970 (published July 27,1995), WO 98/14451 (published April 9, 1998), WO 98/02434 (published January 22, 1998), andUnited States Patent 5,747,498 (issued May 5, 1998), and such substances can be used in theprésent invention as described herein. EGFR-inhibiting agents include, but are not limited to, themonoclonal antibodies C225 and anti-EGFR 22Mab (ImCIone Systems Incorporated of NewYork, New York, USA), the compounds ZD-1839 (AstraZeneca), BIBX-1382 (BoehringerIngelheim), MDX-447 (Medarex Inc. of Annandale, New Jersey, USA), and OLX-103 (Merck &amp;Co. of Whitehouse Station, New Jersey, USA), VRCTC-310 (Ventech Research) and EGFfusion toxin (Seragen Inc. of Hopkinton, Massachusettes). These and other EGFR-inhibitingagents can be used in the présent invention. VEGF inhibitors, for example SU-5416 and SU-6668 (Sugen Inc. of South SanFrancisco, California, USA), can also be combined with a compound of formula 1. VEGFinhibitors are described in, for example in WO 99/24440 (published May 20, 1999), PCTInternational Application PCT/IB99/00797 (filed May 3, 1999)ξ in WO 95/21613 (publishedAugust 17, 1995), WO 99/61422 (published December2, 1999), United States Patent 5,834,504 012368 -48- (issued November 10, 1998), WO 98/50356 (published November 12, 1998), United StatesPatent 5,883,113 (issued March 16, 1999), United States Patent 5,886,020 (issued March 23,1999), United States Patent 5,792,783 (issued August 11, 1998), WO 99/10349 (publishedMarch 4, 1999), WO 97/32856 (published September 12, 1997), WO 97/22596 (published June26, 1997), WO 98/54093 (published December 3, 1998), WO 98/02438 (published January 22, 1998) , WO 99/16755 (published April 8, 1999), and WO 98/02437 (published January 22, 1998),ail of which are incorporated herein in their entireties by référencé. Other examples of somespécifie VEGF inhibitors useful in the présent invention are 1M862 (Cytran Inc. of Kirkland,Washington, USA); anti-VEGF monoclonal antibody of Genentech, Inc. of South SanFrancisco, California; and angiozyme, a synthetic ribozyme from Ribozyme (Boulder,Colorado) and Chiron (Emeryville, California). These and other VEGF inhibitors can be usedin the présent invention as described herein.
ErbB2 receptor inhibitors, such as GW-282974 (Glaxo Wellcome pic), and themonoclonal antibodies AR-209 (Aronex Pharmaceuticals Inc. of The Woodlands, Texas, USA)and 2B-1 (Chiron), can also be combined with a compound of formula 1, for example thoseindicated in WO 98/02434 (published January 22, 1998), WO 99/35146 (published July 15, 1999) , WO 99/35132 (published July 15, 1999), WO 98/02437 (published January 22, 1998),WO 97/13760 (published April 17,1997), WO 95/19970 (published July 27, 1995), United StatesPatent 5,587,458 (issued December 24, 1996), and United States Patent 5,877,305 (issuedMarch 2,1999), which are ail hereby incorporated herein in their entireties by référencé. ErbB2receptor inhibitors useful in the présent invention are also described in United States ProvisionalApplication No. 60/117,341, filed January 27,1999, and in United States Provisional ApplicationNo. 60/117,346, filed January 27, 1999, both of which are incorporated in their entireties hereinby référencé. The erbB2 receptor inhibitor compounds and substance described in theaforementioned PCT applications, Ü.S. patents, and U.S. provisional applications, as well asother compounds and substances that inhibit the erbB2 receptor, can be used with a compoundof formula 1, in accordance with the présent invention. A compound of formula 1, can also be used with other agents useful in treatingabnormal cell growfh or cancer, including, but not limited to, agents capable of enhaneïngantitumor immune responses, such as CTLA4 (cytotoxic lymphocite antigen 4) antibodies, andother agents capable of blocking CTLA4; and anti-proliferative agents such as farnesyl proteintransferase inhibitors. Spécifie CTLA4 antibodies that can be used in the présent inventioninclude those described in United States Provisional Application 60/113,647 (filed December23, 1998) which is incorporated by référencé in its entirety, however other CTLA4 antibodiescan be used in the présent invention. 012368 -49-
The compounds of formula 1 can also be administered in a method for inhibiting abnormal cell growth in a mammal in combination with radiation therapy. Techniques for administering radiation therapy are known in the art, and these techniques can be used in the combination therapy described herein. The administration of the compound of the invention in 5 this combination therapy can be determined as described herein.
Compounds of formula 1 can also be administered in combination with a COX-IIinhibitor for treating Aizheimer’s disease, miid cognitive impairment, or age-related cognitivedécliné. Spécifie examples of COX-II inhibitors useful in this aspect of the invention areprovided above, wherein use of a COX-II inhibitor in combination with. a compound of formula 10 1 for treatment of abnormal cell growth îs described. The effective amount of a COX-II inhibitor in combination with a compound of formula 1 can generally be determined by a person ofordinary skill. A proposed effective daily dose range for a COX-II inhibitor in combination with acompound of formula 1 is from about 0.1 to about 25 mg/kg body weight. The daily effectiveamount of the compound of formula 1 generally will be between about 0.0001 to about 10 mg/kg 15 body weight. In some instances the amount of COX-II inhibitor and/or the amount of thecompound of formula 1 in the combination may be less than would be required on an individualbasis to achieve the same desired effect in treating Aizheimer’s disease, mild cognitiveimpairment, or age-related cognitive décliné.
Compounds of formula 1 can also be administered in combination with an NK-1 20 receptor antagonist for treatment of dépréssion or anxiety. An NK-1 receptor antagonist, asrecited herein, is a substance that is able to antagonize NK-1 receptors, thereby inhibitingtachykinin-mediated responses, such as responses mediated by substance P. Various NK-1receptor antagonists are known in the art, and any such NK-1 receptor antagonist can beutilized in the présent invention as described above in combination with a compound of 25 formula 1. NK-1 receptor antagonists are described in, for example, United States Patent5,716,965 (issued February 10,1998); United States Patent 5,852,038 (issued December 22, 1998) ; WO 90/05729 (International Publication Date May 31, 1990); United States Patent5,807,867 (issued September 15, 1998); United States Patent 5,886,009 (issued March 23, 1999) ; United States Patent 5,939,433 (issued August 17, 1999); United States Patent 30 5,773,450 (issued June 30, 1998); United States Patent 5,744,480 (issued April 28, 1998);
United States Patent 5,232,929 (issued August 3, 1993); United Stated Patent 5,332,817(issued July 26,1994); United States Patent 5,122,525 (issued June 16,1992), United StatesPatent 5,843,966 (issued December 1, 1998); United States Patent 5,703,240 (issuedDecember 30, 1997); United States Patent 5,719,147 (issued February17, 1998); and United 35 States Patent 5,637,699 (issued June 10, 1997). Each of the foregoing U.S. patents and theforegoing published PCT International Application are inedrporated in their entireties herein by 012368
Pci/ -50- reference. The compounds described in said référencés having NK-1 receptor antagonizingactivity can be used in the présent invention. However, other NK-1 receptor antagonists canalso be used in this invention.
The effective amount of an NK-1 receptor antagonist in combination with a compound offormula 1 can generally be determined by a person of ordinary skill. A proposed effective dailydose range for an NK-1 receptor antagonist in combination with a compound of formula 1 is fromabout 0.07 to about 21 mg/kg body weight. The effective amount of the compound of formula 1will be between about 0.0001 to about 10 mg/kg body weight. In some instances the amount ofNK-1 receptor antagonist and/or the amount of the compound of formula 1 in the combinationmay be less than would be required on an individual basis to achieve the same desired effect intreating dépréssion or anxiety.
The subject invention also provides combining a compound of formula 1 with a 5HT10receptor antagonist for treatment of dépréssion or anxiety. A 5HT10 receptor antagonist, asrecited herein, is a substance that antagonizes the 5HT,0 subtype of serotonin receptor. Anysuch substance can be used in the présent invention as described above in combination with acompound of formula 1. Substances having 5HT10 receptor antagonizing activity can bedetermined by those of ordinary skill in the art. For example, 5HT10 receptor antagonists aredescribed in WO 98/14433 (International Publication Date April 9, 1998); WO 97/36867(International Publication Date October9, 1997); WO 94/21619 (International Publication DateSeptember 29, 1994); United States Patent 5,510,350 (issued April 23, 1996); United StatesPatent 5,358,948 (issued October 25, 1994); and GB 2276162 A (published September 2.1,1994). These 5HT1D receptor antagonists, as well as others, can be used in the présentinvention. The aforementioned published patent applications and patents are incorporatedherein by référencé in their entireties.
The effective amount of a 5HT1D receptor antagonist in combination with a compound offormula 1 can generally be determined by a person of ordinary skill. A proposed effective dailydose range for a 5HT1D receptor antagonist in combination with a compound of formula 1 is ffomabout 0.01 to about 40 mg/kg body weight. The effective daily amount of the compound offormula 1 generally will be between about 0.0001 to about 10 mg/kg body weight. In someinstances the amount of 5HT1D receptor antagonist and/or the amount of compound of formula 1in the combination may be less than would be required on an individual basis to achieve thesame desired effect in treating dépression or anxiety.
This invention also provides a pharmaceutical composition and method for treatingdépression or anxiety in a mammal comprising a compound of formula 1 and a SSRI.Examples of SSRIs that can be combined in a method or pharmaceutical composition withcompounds of formula 1 and their pharmaceuticaily acceptable salts inciude, but are not 012368 -51- limited to, fluoxetine, paroxetine, sertraline, and fluvoxamine. Other SSRIs may be combinedor administered in combination with a compound of formula 1 or a pharmaceuticailyacceptable sait thereof. Other antidepressants and/or anxiolytic agents with which acompound of formula 1 may be combined or administered include WELLBUTRIN, SERZONEand EFFEXOR.
The effective amount of a SSRI in combination with a compound of formula 1 cangenerally be determined by a person of ordinary skill. A proposed effective daily dose range fora SSRI in combination with a compound of formula 1 is fram about 0.01 to about 500 mg/kgbody weight. The effective daily amount of the compound of formula 1 generally will be betweenabout 0.0001 to about 10 mg/kg body weight. In some.instances the amount of SSRI and/or theamount of the compound of formula 1 in the combination may be less than would be required onan individual basis to achieve the same desired effect in treating dépréssion or anxiety. A compound of formula 1, or a pharmaceuticaily acceptable sait thereof, can also becombined with one or more antipsychotic agents, for example a dopaminergic agent, for thetreatment of diseases or conditions the treatment of which can be effected or facilitated byaltering dopamine neurotransmission, such as schizophrenia. Examples of antipsychoticswith Which a compound of the invention can 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. Patent4,831,031 and U.S. Patent 5,312,925); olanzapine (2-methyl-4-(4-methyl-1-piperazinyl-10H-thieno (2,3b) (1,5)benzodiazepine; U.S Patent 4,115,574 and U.S. Patent 5,229,382);rispéridone (3-[2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl}6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one;. U.S. Patent 4,804,663); L-745870 (3-(4-(4- chlorophenyl)piperazin-1-yl)methyl-1H-pyrrolo(2,3-b)pyridine; U.S. Patent 5,432,177);sonepiprazole (S-4-(4-(2-(isochroman-1-yl)ethyl)piperazin-1-yI)benzenesulfonamide; U.S.Patent 5,877,317); RP 62203 (fananserin; 2-(3-(4-{4-fluorophenyl)-1-piperazinyl)propyl)naphtho(1,8-c,d)isothiazole-1,1-dioxide; U.S. Patent 5,021,420); NGD 941(U.S. Patent 5,633,376 and U.S. Patent 5,428,165); baiaperidone ((1α,5α,6α)-3-(2-(6-(4-fluorophenyl)-3-azabicycio(3.2.0)hept-3-yl)ethyl)-2,4(1 H,3H)-quinazolinedione; U.S. Patent5,475,105); flesinoxan ((+)-4-fluoro-N-[2-[4-5-(2-hydroxymethyl-1,4-benzodioxanyl)]-1-piperazinyljethyljbenzamide; U.S. Patent 4,833,142); and gepirone (4,4-dimethyl-1 -(4-(4-(2-pÿrimidinyl)-1-piperazinyl)butyl)-2,6-piperidinedione; U.S. Patent 4,423,049). The patentsrecited above in this paragraph are each incorporated herein by reference in their entireties.The effective daily amount of the compound of formula 1 will typically be between about 0.0001to about 10 mg/kg body weight. The amount of any of the aforementioned antipsychoticagents contemplated for use in combination with a compound of formula 1 is generally theamount known in the art to be useful for treating psychotic conditions. However, in some 012368 -52- instances, the amount of the antipsychotic and/or the amount of the compound of formula 1 inthe combination may be less than would be required on an individual basis to achieve the samedesired effect in treating dépréssion or anxiety. It is furthermore to be understood that theprésent invention also encompasses combining a compound of formula 1 with antipsychotic ordopaminergic other than those in the aforementioned list. A proposed amount for sonepiprazole in the above-described combination with acompound of formula 1, is from about 0.005 to about 50 mg/kg body weight of the patient perday. A proposed amount of RP 62203 in such combination is from about 0.20 to about 6 mg/kgbody weight of the patient per day. A proposed amount of NGD 941 in such combination is fromabout 0.1 to about 140 mg/kg of body weight per day. A proposed amount of balaperidone insuch combination is from about 1 to about 100 mg/kg body weight per day. A proposed amountof flesinoxan in such combination is from about 0.02 to about 1.6 mg/kg body weight per day. Aproposed amount for gepirone in such combination is from about .01 to about 2 mg/kg bodyweight per day. A proposed amount of L-745870 in such combination is from about 0.01 toabout 250 mg/kg body weight per day, preferably from about 0.05 to about 100 mg/kg bodyweight per day. A proposed amount of rispéridone in such combination is from about 0.05 toabout 50 mg/kg body weight per day. A proposed amount of olanzapine in such combination isfrom about 0.0005 to about 0.6 mg/kg body weight per day. A proposed amount of ziprasidonein such combination is from about 0.05 to about 10 mg/kg body weight per day. In someinstances for each of the aforementioned combinations, however, the amount of each spécifieingrédient in the combination may be less than would be required on an individual basis toachieve the same desired effect in treating a psychotic condition.
This invention also provides a pharmaceutical composition and method for treatingAlzheimer’s disease, mild cognitive impairment, or age-related cognitive décliné comprising acompound of formula 1 and an acetylcholinesterase inhibitor. Acetylcholinesterase inhibitorsare known in the art, and any such acetylcholinesterase inhibitor can be used in the above-described pharmaceutical composition or method. Examples of acetylcholinesterase inhibitorsthat can be used in this invention are ARICEPT (donepezil; U.S. Patent 4,895,841); EXELON(rivastigmine ((S)-[N-ethyl-3-[1-(dimethylamino)ethyl]phenyl carbamate); U.S. Patent5,603,176 and U.S. Patent 4,948,807); metrifonate ((2,2,2-trichloro-1-hydroxyethyl)phosphonicacid dimethyi ester; U.S. Patent 2,701,225 and U.S. Patent 4,950,658); galantamine (U.S.Patent 4,663,318); physostigmine (Forest, USA); tacrine (1,2,3,4-tetrahydro-9-acridinamine;U.S. Patent 4,816,456); huperzine A (5R-(5a,90,11E))-5-amino-11-ethylidene-5,6,9,10-tetrahydro-7-methyl-5,9-methaneocycloocta(b)pyridin-2-(1H)-one); and icopezil (5,7-dihydro-3-(2-(1 -(phenylmethyl)-4-piperidinyl)ethyl)-6H-pyrrolo(3,2-f)-1,2-benzisoxazol-6-one; U.S. Patent "Μ 2368 -53- 5,750,542 and WO 92/17475). The patents and patent applications recited above in thisparagraph are herein incorporated by référencé in their entireties.
The effective amount of an acetylchoiinesterase inhibitor in combination with acompound of formula 1 can generally be determined by a person of ordinary skill. A proposedeffective daily dose range for an acetylchoiinesterase inhibitor in combination with a compoundof formula 1 is from about 0.01 to about 10 mg/kg body weight. The effective daily amount of thecompound of formula 1 generally will be between about 0.0001 to about 10 mg/kg body weight.In some instances the amount of acetylchoiinesterase inhibitor and/or the amount of thecompound of formula 1 in the combination may be less than would be required on an individualbasis to achieve the same desired effect in treating Alzheimer’s disease, mild cognitiveimpairment, or age-related cognitive décliné.
The présent invention also provides for combining a compound of formula 1 withneuroprotectants, for example NMDA receptor antagoniste, for treatment of Kuntington’sdisease, stroke, spinal cord trauma, traumatic brain injury, multiinfarct dementia, epilepsy,amyotrophie latéral sclerosis, pain, viral induced dementia for example AIDS induceddementia, migraine, hypoglycemia, urinary incontinece, brain ischemia, multiple sclerosis,Alzheimer’s disease, senile dementia of the Alzheimer’s type, mild cognitive impairment, age-related cognitive décliné, emesis, corticobasal degeneration, dementia pugiiistica, Down’ssyndrome, myotonie dystrophy, Niemann-Pick disease, Pick’s disease, priori disease withtangles, progessive supranuclear palsy, lower latéral sclerosis, or subacute sclerosingpanencephalistis. Examples of NMDA receptor antagoniste that can be used in the présentinvention include ( 1 S,2S)-1 -(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidin-1 -yl )-1 - propanol (U.S. Patent 5,272,160), eliprodil (U.S. Patent 4,690,931), and gavestenel (U.S.Patent 5,373,018). Other NMDA receptor antagonists, which can also be used in the présentinvention, are described in U.S. Patent 5,373,018; U.S. Patent 4,690,931; U.S. Patent5,272,160; U.S. Patent 5,185,343; U.S. Patent 5,356,905; U.S. Patent 5,744,483; WO97/23216; WO 97/23215; WO 97/23214; WO 96/37222; WO 96/06081; WO 97/23458; WO97/32581; WO 98/18793; WO 97/23202; and U.S. Serial No. 08/292,651 (filed August 18,1994). The aforementioned patents and patent applications are each hereby incorporated byréférencé in their entireties.
The effective daily amount of the compound of formula 1 in the combination with anNMDA receptor antagonist generally will be between about 0.0001 to about 10 mg/kg bodyweight. The amount of the NMDA receptor antagonist contemplated for use in combinationwith a compound of formula 1 for treatment of any of the aforementioned disorders, forexample Alzheimer’s disease, is generally within the range of from about 0.02 mg/kg/day toabout 10 mg/kg/day. However, in some instances, the amount of the NMDA antagonist and/or 012368 -54- the amount of the compound of formula 1 in the combination may be less than would be requiredon an individual basis to achieve the same desired effect in treating said disorders.
The subject invention also provides for combining a compound of'formula 1 withcertain substances capable of treating a stroke or traumatic brain injury, such as TPA, NIF, orpotassium channel modulators, for example BMS-204352. Such combinations are useful fortreating neurodegenerative disorders such as stroke, spinal cord trauma, traumatic braininjury, multiinfarct dementia, epilepsy, pain, Alzheimer’s disease, and senile dementia, forexample.
For the above-described combination thérapies and pharmaceutical compositions, theeffective amounts of the compound of the invention and of the other agent can generally bedetermined by those of ordinary skill in the art, based on the effective amounts for thecompounds described herein and those known or described for the other agent known in theart, for example the amounts described in the above-recited patents and patent applicationincorporated herein. The formulations and routes of administration for such thérapies andcompositions can be based on the information described herein for compositions andthérapies comprising a compound of the invention as the sole active agent and on informationprovided for the other agent in combination therewith. A spécifie compound of formula 1 can be determined to inhibit cdk2, cdk5, or GSK-3using biological assays known to those of ordinary skill in the art, for example the assaysdescribed bélow.
The spécifie activity of a compound of formula 1 for inhibition of cdk5 or cdk2 can, forexample, be ascertained by means of the following assays using materials available to those ofordinary skill in the art:
Enzyme activities can be assayed as the incorporation .of [33P] from the gammaphosphate of [33PJATP (Amersham, cat. no. AH-9968) into biotinylated peptide substratePKTPKKAKKL. In such an assay, reactions are carried out in a buffer containing 50mM Tris-KCI, pH 8.0; 10mM MgCI2, 0.1 mM Na3VO4, and 1mM DTT. The final concentration of ATP isabout 0.5uM (final spécifie radioactivity of 4uCi/nmol), and the final concentration of substrate0.75uM. Reactions, initiated by the addition of either cdk5 and activator protein p25 or cdk2and activator cyclin E, may be carried out at room température for about 60 minutes.Reactions are stopped by addition of 0.6 volume of buffer containing (final concentrations):2.5mM EDTA, 0.05%Triton-X 100, 100uM ATP, and 1.25 mg/ml streptavidin coated SPAbeads (Amersham cat. no. RPNQ0007). Radioactivity associated with the beads is quantifiedby scintillation counting.
The spécifie activity of a compound of formula 1 for inhibition of GSK-3 can bedetermined in both cell-fee and cell-based assays, both of which are described in the art (see, 012368 -55- for example, WO 99/65897). A cell-free assay can be carried out in general by incubating« GSK-3 with a peptide substrate, radiolabeled ATP (such as, for example, γ33Ρ- or γ32-Ρ-ΑΤΡ,both available from Amersham, Arlington Heights, Illinois), magnésium ions, and thecompound to be assayed. The mixture is incubated for a period of time to aüow incorporation 5 of radiolabeld phosphate into the peptide substrate by GSK-3 activity. The reaction mixture iswashed to remove unreacted radiolabeled ATP, typically after first transferring ail or a portionof the enzyme reaction mixture to a wel! that confains a uniform amount of a ligand that iscapable of binding to the peptide substrate. The amount of 33P or 32P remaining in each wellafter washing is then quantified to détermine the amount of radiolabeled phosphate 10 incorporated into the peptide substrate. Inhibition is observed as a réduction, relative to acontrol, in the incorporation of radiolabeled phosphate into the peptide substrate. An exampleof a suitable GSK-3 peptide substrate for an assay is the SGSG-linked CREB peptidesequence, derived from the CREB DNA binding protein, described in Wang, et al., Anal.Biochem., 220:397-402 (1994). Purified GSK-3 for an assay may, for example, be obtained 15 from cells transfected with a human GSK-3p expression plasmid as described in, for exampleStambolic, et al., Current Biology 6:1664-68 (1996). WO 99/65897; Wang, et al., andStambolic, et al. are incorporated in their entireties herein by reference.
Another example of a GSK-3 assay, similar to the one described in the precedingparagraph is as follows: Enzyme activifies are assayed as the incorporation of [33P] from 20 gamma phosphate of [33PJATP (Amersham, cat. No. AH-9968) into biotinylated peptidesubstrate PKTPKKAKKL. Reactions are carried out in a buffer containing 50mM Tris-HCI, pH8.0; 10mM MgCI2, 0.1mM Na3VO4, and 1mM DTT. The final concentration of ATP is 0.5μΜ(final spécifie radioactivity of 4pCi/nmol), and the final concentration of substrate is 0.75μΜ.Réactions, initiated by the addition of enzyme, are carried out at room température for about 25 60 minutes. Reactions are stopped by addition of 0.6 volume of buffer containing (final concentrations): 2.5mM EDTA, 0.05%Triton-X 100, 100μΜ ATP, and 1.25 mg/ml streptavidincoated SPA beads (Amersham cat. No. RPNQ0007). Radioactivity associated with the beadsis quantified by scintillation counting.
Ail of the title compounds of the following Examples had an IC a, inhibiting peptide 30 substrate phosphorylation of less than about 50 μΜ when assayed for cdk5 inhibition accordingto the preceding assay.
Several of the title compounds of the following Examples were assayed for GSK-3inhibition using an assay such as that described above, and ali tested had an ICr, for inhibition ofGSK-3P of less than about 50 μΜ . 012368 -56-
The following Examples illustrate the présent invention. It is to be understood, however,that the invention, as fully described herein and as recited in the daims, is not intended to belimited by the details of the following Examples.
In the following Examples “TFA” indicates “trifluoroacetic acid", “THF” indicates“tetrahydrofuran", “MPLC" indicates “medium pressure liquid chromatography”, “TLC" indicates“thin iayer chromatography”, “KOBu1" indicates “potassium-f-butoxide”, “DMSO" is “dimethylsulfoxide”, and “EtOAc” is “ethyl acetate”. “MS", as in, for example, “Powdered 4 Â MS" is“molecular sieve".
EXAMPLES
Example 1. (5-Cyclobutyl-1 H-pyrazol-3-yl)-(4-nitro-phenyl)-amine
Step 1. 3-Cyclobutyl-N-(4-nitro-phenyl)-3-oxo-thiopropionamide
To a stirring solution of lithium bis(trimethylsilyl)amide (3.6 mL, 3.6 mmol, 1.0 M intetrahydrofuran) in tetrahydrofuran at -78 °C (acetone/CO2 bath) was added a solution ofmethyl cyclobutyl ketone (400 uL, 360 mg, 3.6 mmol) in 10 mL of tetrahydrofuran. After 1 hr4-nitro-phenyl isothiocyanate (328 mg, 1.8 mmol) was added in one portion. The reactant wasaliowed to slowly warm to rt overnight. After 16 hr the reaction was quenched with NH4CI,diluted with CH2CI2. The layers were separated and the aqueous Iayer was extracted withCHzCI2, dried over MgSO4 and concentrated under reduced pressure. Purification of thismaterial was accomplished by MPLC using the Biotage Flash System eluting with a gradientof hexanes through 50 % EtOAcZ hexanes. The product-containing fractions were collectedand concentrated to give 3-cyclobutyl-N-(4-nitro-phenyI)-3-oxo-thiopropionamide (266 mg, J53% yield) as a yellow oil. Rf = 0.54 (30% acetone/hexanes); ’H NMR (400 MHz, CDCI3) δ 2.35-1.80 (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 stirring solution of 3-Cyclobutyl-N-(4-nitro-phenyl)-3-oxo-thiopropionamide fromStep 1 (266 mg, 0.95 mmol) in 2 mL of EtOH was added 150 uL of acetic acid follow byanhydrous hydrazine (283 uL, 306 mg, 9.6 mmol). The reaction was heated to 71 °C for 2 hrand then cooled to rt. The reaction was then quenched with aqueous NaHCO3 diluted withEtOAc and then the layers were separated. The organic Iayer was washed with water and theaqueous Iayer was back extracted with CH2CI2. The combined organic layers were dried overMgSO4, filtered and concentrated under reduced pressure. Purification of this material wasaccomplished by MP LC using the Biotage Flash System eluting with a gradient of hexanesthrough 50 % acetone/ hexanes. The product containing fractions were collected andconcentrated to give (5-cyciobutyl-1H-pyrazol-3-yl)-(4-nitro-phenyl)-amine (216 mg, 88%) as atan solid. R, 0.36 (30% acetone/hexanes); 1H NMR (400 MHz, CDCI3) δ 1.84-2.22 (m, 4H), 012368 -57- 2.38-2.42 (m, 2H), 3,50 (dddd, J=8.7, 8.7, 8.2, 8.2Hz, 1H), 5.91 (s, 1H), 7.16 (d, J=7.1Hz, 2H),8.12 (d, J=7.1 Hz, 2H). LRMS m/z (APCE) 259.3 (M+1).
Example 2. (5-Cyclobutyl-2H-pyrazol-3-yl)-naphthalen-2-yl-amine
The title compound was prepared according to the method for Example 1, usinganalogous reactants. ’HNMR (400MHz, CDCI3), 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, 8.3Hz, 1H), 5.96 (s, 1H), 7.18 (dd, J=9.1, 8.7Hz, 1H), 7.31 (d,J=7.8Hz, 1H), 7.37 (d, J=7.9Hz, 1H), 7.53 (s, 1H), 7.61-7.71 (m, 3H). LRMS m/z (APCE) 264(M+1).
Example 3. (5-Cyclobutyl-2H-pyrazol-3-yl)-naphthalen-1-yl-amine
The title compound was prepared according to the method for Example 1, usinganalogous reactants.
Rf 0.35 (50% EtOAc/Hexane), 1H NMR (400MHz, CDCI3) 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, 8.7Hz, 1H), 5.92 (s, 1H),7.31-7.44 (m, 5H), 7.80 (d, J=8.31 Hz, 1H), 8.98 (d, 3=8.72 Hz, 1H). LRMS m/z (APCE) 264(M+1).
Example 4. N-(5-Cyclobutyl-2H-pyrazol-3-yl)-N',N'-dimethyl-naphthalene-1,4- diamine
The title compound was prepared according to the method for Example 1, usinganalogous reactants. ’HNMR (400MHz, CDCI3), 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, 8.3Hz, 1H), 5.81 (s, 1H), 7.02 (d, J=8.3Hz, 1H), 7.36 (d, J=7.8Hz, 1H), 7.40 (dd, J=6.6, 6.6Hz, 1H), 7.51 (dd, J=4.8, 4.8Hz, 1H), 8.04 (d, J=8.3Hz, 1H), 8.30 (d,J=8.3Hz, 1H). 13C NMR (100MHz, CDCI3), 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 (APCI+) 307.3 (M+1 ).
Example 5. (3-Benzyloxy-phenyl)-(5-cyclobutyl-2H-pyrazoI-3-yl)-amine
The title compound was prepared according to the method for Example 1, usinganalogous reactants. ’HNMR (400MHz, CDCI3), 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, 8.3Hz, 1H), 5.01 (s, 2H), 5.88 (s, 1H), 6.47 (bs, 1H), 6.50 (dd,J=7.5, 1.6Hz, 1H), 6.67 (dd, J=9.5, 1.6Hz, 1H), 6.81 (dd, J=2.0, 2.0Hz, 1H), 7.14 (dd, J=7.9,8.3Hz, 1H), 7.31-7.43 (m, 5H). LRMS m/z (APCE) 320.4 (M+1).
Example 6. (4-Chloro-benzyl)-(5-cyclobutyl-2H-pyrazol-3-yl)-amine
The title compound was prepared according to the method for Example 1, usinganalogous reactants. ο 12368 -58- ’HNMR (400MHz, CDCI3), δ 1.85-2.15 (m, 4H), 2.26-2.32 (m, 2H), 3.39 (dddd, J=8.7,8.7, 8.3, 8.3Hz, 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)-amine5 The title compound was prepared according to the method for Example 1, using analogous reactants. ’HNMR (400MHz, CDCI3), 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, 8.8Hz, 1H), 5.86 (s, 1H), 6.78 (bs, 1H), 6.98-6.92 (m, 2H), 7.04(dd, J=7.9, 7.8Hz, 1 H), 7.24 (s, 1 H), 9.80 (bs, 1 H). LRMS m/z (APCI+) 292.3, 294.2 (M+1 ). 10 Example 8. [5-(1,4-Dioxa-spiro[4.4]non-7-yl)-1 H-pyrazol-3-yl]-(3-trifluoromethyl- phenyl)-amine
The title compound was prepared according to the method for Example 1, usinganalogous reactants. 1HNMR (400MHz, CDCI3), δ 1.72-2.16 (m, 5H), 2.25 (ddd, J=13.7, 8.7, 0 Hz, 1H), 3.2615 (dddd, J=8.3, 8.2, 8.2, 7.8Hz, 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 was prepared according to the method for Example 1, usinganalogous reactants. 20 R, 0.35 (30% EtOAc/Hexane), 1H NMR (400MHz, CDCI3), 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, 8.3Hz, 1H), 5.96 (s, 1H), 7.72-7.76 (d, 1H),8.05-8.08 (d, 1H), 8.26 (s, 1H). LRMS m/z (ΑΡΟΓ) 293 (M+1).
Example 10. (3,5-Bis-trifluoromethyl-phenyl)-(5-cyclobutyl-2H-pyrazol-3-yl)- amine 25 The title compound was prepared according to the method for Example 1, using analogous reactants. R, 0.35 (30% EtOAc/Hexane), 1H NMR (400MHz, CDCI3), 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, 8.7Hz, 1H), 5.83 (s, 1H), 7.26 (s, 1H), 7.56 (s, 1 H), 7.56 (s, 1 H). LRMS m/z (APCI+) 350 (M+1 ). 30 Example 11. 4-(5-Cyclobutyl-2H-pyrazol-3-ylamino)-benzonitrile
The title compound was prepared according to the method for Example 1, using analogous reactants. R, 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, 8.3Hz, 1H), 5.85 (s, 35 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 012368 -59- (M+1).
Example 12. (5-Cyclobutyl-2H-pyrazol-3-yl)-(3-fluoro-phenyl)-amine
The title compound was prepared according to the method for Example 1, using analogous reactants. 5 R, 0.30 (50% EtOAc/ Hexane), 1H NMR (500 MHz, CDCI3), 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, 8.8Hz, 1H), 5.89 (s, 1H),6.53-6.57 (m, 1H), 6.80-6.82 (m, 1 H). 6.91-6.94 (m, 1H), 7.14-7.19 (m, 1H). LRMS m/z(APCI+) 232 (M+1).
Example 13. (2-Bromo-phenyl)-(5-cyclobutyl-2H-pyrazol-3-yl)-amine10 The title compound was prepared according to the method for Example 1, using analogous reactants. R, 0.33 (30% EtOAc/ Hexane). 1HNMR (400 MHz, CDCI3), 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, 8.3Hz, 1H), 5.90 (s, 1H),6.69-6.73 (dd, J=6.6, 6.6Hz, 1H), 7.18-7.22 (dd, J=5.8, 5.8Hz, 1H), 7.47-7.49 (d, 1H), 7.598- 15 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 was prepared according to the method for Example 1, using analogous reactants.
Rf 0.50 (50% EtOAc/ Hexane), <H NMR (CDCI3), δ 1.86-2.07 (m, 2H), 2.09-2.19 (m,20 2H), 2.29-2.38 (m, 2H), 3.42-3.50 (dddd, J=8.5, 8.5, 8.5, 8.5Hz, 1H), 5.84 (s, 1H), 6.80 (s, 1H), 6.98 (s, 1H), 6.98 (s, 1H). LRMS m/z (APCE) 282 (M+1).
Préparation 1.1. 2-Cyano-3-cyclobutyl-3-oxo-propionic acid ethyl ester
To anhydrous MgCl2 (22.3 g, 0.19 mmol) in 320 mL of CH3CN at 0 °C was addedethyl cyanoacetate (21.5 g, 0.19 mmol). After 15 min Et3N (52.0 mL, 38.0 g, 0.37 mmol) was 25 added via syringe. The reaction was allowed to stir an additional 15 min and thencyclobutane carbonyl chloride (21.0 mL 22.3 g, 0.19 mmol) was added over a five min period.The reaction was allowed to slowly warm to rt over 20 hr. The reaction was then cooled to 0°C, quenched with aqueous 0.5 M HCl, and then diluted with 150 mL of Et2O. The aqueouslayer was extracted with Et2O (3x150 mL) and then the combined organic layers were washed 30 with 150 mL of brine, dried over MgSO„, filtered and concentrated to give a yellow-orange oil.This matériel was purified by vacuum distillation (95-105 °C, 2-3 mm) to give the titlecompound in a quantitative yield and as a colorless oil. 1H NMR (400MHz, CDCI3), 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, 8.5Hz, 1H), 4.28-4.34 (q, 2H), 13.81 (s, 35 1H). 012368 PCT. -60-
Preparation 2.1. 2-Cyano-3-oxo-pentanoic acid ethyl ester
The title compound was prepared according to the method for Préparation 1.1, usinganalogous reactants. 1H NMR (400MHz, CDCI3), 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, 1 H). LRMS m/z (APCl') 168 (M-1 ).
Préparation 1.2. 3-Cyclobutyl-3-oxo-propionitrile
To 2-cyano-3-cyclobutyl-3-oxo-propionic acid ethyl ester (Préparation 1.1) in 40 mL ofDMSO was added 2 mL of HZO and then the reaction was heated to 118 °C. After 35 min thereaction was cooled in an ice water bath and then quenched with a saturated solution of NaCI.This reaction mixture was further diluted with H2O and CH2CI2 and the layers were separated.The aqueous layer was extracted with CH2CI2. The combined organic layers were dried overMgSO4, filtered and concentrated under reduced pressure to give the title compound ofPréparation 1.2 as a yellow oil. This material was used without further purification. 1H NMR (400MHz, CDCI3), 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, 8.5Hz, 1H). LRMS m/z (APCl') 122 (M-1).
Préparation 1.3. 5-Cyclobutyl-2-(4-methoxy-benzyi)-2H-pyrazol-3-ylamine
To crüde 3-cyclobutyl-3-oxo-propionitrile prepared above in 515 mL of EtOH wasadded 4-methoxy-benzyl-hydrazine (12.6 g, 82.9 mmol) and the reaction was heated to reflux(oil bath at 85 ° C). After 2 hr the reaction was cooled to rt and concentrated under reducedpressure to give a viscous oil. Purified of this material was accomplished by MPLC using theBiotage Flash 45S System eluting with a gradient of 10% and 20% EtOAc/ hexanes. Theproduct containing fractions were collected and concentrated to give the title compound (10.2g, 77% yield over 2 steps) as a colorless solid. R, 0.3 (40% EtOAc/Hexane), 1H NMR (400MHz, CDCI3), 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, 8.1Hz, 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). LRMSm/z (ΑΡΟΓ) 258 (M+1).
Préparation 2.3. 5-Ethyl-2-(4-methoxy-benzyl)-2H-pyrazol-3-ylamine
The title compound was prepared according to the method for Préparation 1.3, usingPréparation 2.1 instead of Préparation 1.1. R, 0.4 (50% EtOAc/Hexane, Ή NMR (400MHz, CDCI3), 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). LRMSm/z (APCL) 232 (M+1).
Préparation 1.4._[5-Cyclobutyl-2-(4-methoxy-benzyl)-2H-pyrazol-3-yl]-(6- methoxy-pyridin-2-yi)-amine 012368 -61-
Procedure A: A dry toluene solution of 5-Cyclobutyl-2-(4-methoxy-benzyl)-2H-pyrazol-3-ylamine (Préparation 1.3, 2.27g, 8.83mmol), 2-chloro-6-methoxy pyridine (1.06g,7.36mmol), sodium tert-butoxide (1.09g, 10.3mmol), 2-(dicyclohexylphosphino)-biphenyl(258mg, 0.736mmol), and palladium acetate (165mg, 0.736mmol), was heated to 120 °C foran hour and then cooled to rt. The reaction was then filtered through Celite pad and thefiltrate was concentrated down and chromatographed using the Biotage Flash 45S systemeluting with 20% EtOAc/hexanes to give the title compound of Préparation 1.4 as a peachcolored solid (2g, 74% yield).
Rf 0.25 (20% EtOAc/Hexane), ’H NMR (400MHz, CDCI3), 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, 8.7Hz, 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=6i65 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. Césium carbonate (296mg, 0.454mmol) Vvas fiame dried in a réactionflask and 3.9ml of dry toluene was then transferred followed by 200mg (0.778mmol) of 5-Cyclobutyl-2-(4-methoxy-benzyl)-2H-pyrazo!-3-ylamine (Préparation 1.3). The resultingmixture was stirred at rt for 10min followed by the additions of 2-chloro-6-methoxy pyridine(93.2mg, 0.648mmol), 2-(dicyclohexylphosphino)-biphenyl (11.7mg, 0.0334mmol) andpalladium acetate (3.6mg, 0.0162mmol). Refluxing under nitrogen overnight took the réactionto completion. Filtration through Celite, concentration of the filtrate, and chromatography as inprocedure A yielded the title compound of Préparation 1.4 (120mg, 51 % yield) as a solid.
Procedure C. To a dry toluene (1.95ml) solution of 5-Cyclobutyl-2-(4-methoxy-benzyl)-2H-pyrazol-3-ylamine (Préparation 1.3, 100mg, 0.389mmol) was added 1.0Mpotassium t-butoxide (628μΙ, 0.628mmol) at rt. After 5min stirring, 3-bromo-anisole (60mg,0.324mmol), 2-(dicyclohexylphosphino)-biphenyl (23mg, 0.065mmol), and palladium acetate(7.5mg, 0.032mmol) were added and the reaction was heated to 105 °C for 6 hours when thereaction went to completion. The reaction was cooled to rt, filtered through Celite, andchromatographed as in the procedure A to give the title compound of Préparation 1.4 (72mg,61 % yield) as a viscous gum. R, 0.30 (30% EtOAc/hexanes), ’HNMR (400MHz, CDCI3), 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, 8.8Hz, 1H), 3.73 (s, 3H), 3.77 (s,3H), 5.12 (s, 2H), 5.98 (s, 1H), 6.29 (d, J=10.7Hz, 1H), 6.32-6.35 (m, 1H), 6.40-6.43 (m, 1H),6.82 (d, J-6.6HZ, 2H), 7.10 (d, J=8.3Hz, 2H), 7.25 (s, 1H). LRMS m/z (APCI+) 364.2 (M+1).
Préparation 2.4. [5-Ethyl-2- (4-methoxy-benzyl)-2H-pyrazol-3-yl]-(6-methoxy- pyridin-2-yl)-amine
The title compound was prepared according to the method for Préparation 1.4, usingPréparation 2.3 instead of Préparation 1.3. 012368 PCT/ -62- R, 0.28 (25% EtOAc/Hexane), 1H NMR (400MHz, CDCI3), 8 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 (APCP) 339 (M+1). 5 Example 15. (5-Cyclobutyl-2H-pyrazol-3-yl)-(3-methoxy-phenyl)-amine
To [5-Cyclobutyl-2-(4-methoxy-benzyl)-2H-pyrazol-3-ylJ-(3-methoxy-phenyl)-amine(Préparation 1.4, 120 mg, 0.331 mmol) was added neat trifluoro acetic acid (2.0 ml_) and thereaction was heated to 70 °C. After 48 hr the reaction was cooled to rt and concentratedunder reduced pressure. Purification of this material was accomplished by MPLC using the 10 Biotage Flash System eluting with 40% EtOAc/hexanes. The product-containing fractionswere collected and concentrated to give the title compound (30 mg, 37 % yield). R, 0.35 (75% EtOAc/Hexane), 1H NMR (400MHz, CDCI3), 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, 8.3Hz, 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 15 (apt, 1 H). LRMS m/z (APCI+) 244 (M+1 ).
Example 16. (5-Cyclobutyl-2H-pyrazol-3-yl)-(6-trifluoromethyl-pyridin-2-yl)- amine
The title compound was made according to the method for Example 15, usinganalogous reactants. 20 R, 0.50 (10% MeOH/CH2CI2), ’H NMR (400MHz, 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, 8.7Hz, 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 25 The title compound was made according to the method for Example 15, using analogous reactants. R, 0.30 (40% EtOAc/Hexane), 1H NMR (400MHz, CDCI3), 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, 8.3Hz, 1H), 6.01 (s, 1H), 7.31-7.47 (m, 4H).LRMS m/z (APCF) 282 (M+1). 30 Example 18. N-(5-Cyclobutyl-2H-pyrazol-3-yl)-N',N'-dimethyl-benzene-1,3- diamine
The title compound was made according to the method for Example 15, usinganalogous reactants.
RtO.50 (5% MeOH/CH2Clz), 1H NMR (400Mz, CDCI3), δ 1.91-2.18 (m, 2H), 2.20-2.3035 (m, 2H), 2.35-2.43 (m, 2H). 3.11 (s, 6H), 3.48-3.56 (dddd, J=8.3, 8.3, 8.3, 8.3Hz, 1H), 6.13 072368 -63- (bs, 1 H), 6.84-6.95 (m, 2H), 7.13-7.28 (m, 2H), 7.31-7.35 (apt, 1H). LRMS m/z (APCI+) 257(M+1).
Example 19. (5-Cyclobutyl-2H-pyrazol-3-yl)-quinolin-2-yl-amine
The title compound was made according to the method for Example 15, usinganalogous reactants. R, 0.35 (70% EtOAc/Hexane), Ή NMR (400MHz, 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, 8.3Hz, 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,1 H), 8.49-8.51 (d, 1 H). LRMS m/z (ΑΡΟΓ) 265 (M+1 ).
Example 20. (6-Chloro-pyridin-2-yl)-(5-cyclobutyl-2H-pyrazol-3-yl)-amine
The title compound was made according to the method for' Example 15, usinganalogous reactants. R, 0.40 (75% EtOAc/Hexane), ’H NMR (400MHz, 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, 8.8Hz, 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(APCI+) 249 (M+1).
Example 21. (5-Cyclobutyl-2H-pyrazol-3-yl)-(6-methoxy-4-methyl-quinolin-2-yl)- amine
The title compound was made according to the method for Example 15, usinganalogous reactants. R, 0.35 (75% EtOAc/Hexane), 1H NMR (400MHz, 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, 8.7Hz, 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). LRMSm/z (APCI+) 309 (M+1).
Example 22. (5-Cyclobutyl-2H-pyrazol-3-yl)-(3-trifluoromethoxy-phenyl)-amine
The title compound was made according to the method for Example 15, usinganalogous reactants. · R, 0.15 (30% EtOAc/Hexane), 1H NMR (400MHz, CDCI3), 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, 8.3Hz, 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-pyridine-2,6- diamine
The title compound was made according to the method for Example 15, usinganalogous reactants. R, 0.50 (5% MeOH/CH2CI2), 1H NMR (400MHz, CDCI3), δ 1.82-2.01 (tn, 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, 8.7Hz, 1H), 012368 -64- 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(APCF) 258 (M+1).
Example 24. (5-Ethyl-2H-pyrazol-3-yl)-(6-methoxy-pyridin-2-yl)-amine
The title compound was made according to the method for Example 15, usinganalogous reactants. R, 0.20 (50% EtOAc/Hexane), Ή NMR (400MHz, CDCI3), 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 (APCE) 219 (M+1).
Example 25. (5-Cyclobutyl-2H-pyrazol-3-yl)-(6-methoxy-pyridin-2-yl)-amine
The title compound was made according to the method for Example 15, usinganalogous reactants. R, 0.30 (50%EtOAc/Hexane), 1H NMR (400MHz, CDCI3), 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, 8.3Hz, 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).
Préparation 3.1. 1,4-Dioxa-spiro[4.4]non-7-yi)-ethanone
To a stirring solution of known nitrile (1.25 g, 8.17g)((Aust.-J. Chem. 1994, 47, 1833)in tetrahydrofuran at rt was added a solution of methyl magnésium bromide (5.4 mL, 16.3mmol, 3.0M in THF) followed by copper (I) bromide (23 mg, 0,16 mmol). The reaction wasthen heated to 65 °C. After 20 hr the reaction cooied to rt and then to 0 °C (ice/water bath)and quenched with a saturated solution of NH4CI. This mixture was diluted with methylenechloride (100 mL) and the layers separated. The aqueous layer was extracted with methylenechloride (100 mL) and the combined organic layers were dried over MgSO4, filtered andconcentrated under reduced pressure. Purification was accomplished by vacuum distillation(120 °C, 2 mm) to give the title compound (1.39 g, 51% yield) as a clear colorless oil. 1HNMR (400MHz, CDCI3), δ 1.79-2.08 (m. 6H), 2.15 (s, 3H), 2.99 (dddd, J=8.3Hz,1H), 3.87-3.94 (m, 4H). LRMS m/z (APCI+) 171 (M+1).
Préparation 3.2. 3-(1,4-Dioxa-spiro[4.4]non-7-yl)-3-oxo-N-(3-trifluoromethyl- phenyl)-thiopropionamide
To a stirring solution of LiHMDS( 3.2 mL, 3.2 mmol 1 M in THF) in 20 mL of THF at-78 °C (acetone/CO2) was a precooled solution (-78 °C) of 1-(1,4-Dioxa-spiro[4.4]non-7-yl)-ethanone (Préparation 3.1, 500 mg, 2.94 mmol in 5 mL of THF) via cannula down the side ofthe flask. After 30 minutes, 1-isothiocyanato-3-trifluoromethyl-benzene (988 uL, 1.3 g, 6.5mmol) was added dropwise via syringe. The resulting réaction was slowly allowed to warm tort overnight. The reaction was then quenched with NaHCO3, diluted with EtOAc and thelayers were separated. Purification of this material was accomplished by MPLC using the 012368 -65-
Biotage Flash 45S System eluting with 20% EtOAc/toluene, followed by a second MPLC usingthe Biotage Flash 45S system eluting with 20% acetone/bexanes. The product-containingfractions were collected and concentrated to give the title compound (598 mg, 55% yield) as ayellow viscous gum. • R, 0.3 (25% Acetone/ Hexanes). ’HNMR (400MHz, CDCI3), 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, 1 H), 8.13-8.15 (m, 1H). LRMS m/z (APCE) 374 (M+1).
Préparation 3.3. [5-(1,4-Dioxa-spiro[4.4]non-7-yl)-2-(4-methoxy-benzyl)-2H- pyrazoi-3-yl]-(3-trifluoromethyl-phenyl)-amine
To a stirring solution of 3-(1,4-Dioxa-spiro[4.4]non-7-yl)-3-oxo-N-(3-trifluoromethyl- phenyl)-thiopropionamide (Préparation 3.1, 785 mg, 2.1 mmol) in 21 mL of EtOH was addedacetic acid (2.1 mL) followed by 4-methoxy-benzyI-hydrazine (480 mg, 3.2 mmol) and theresulting mixture was heated to 75 °C. After 1 hr the reaction was cooled to rt quenched withH2O, diluted with EtOAc and the layers were separated. To the aqueous layer was added afew drops of concentrated ammonium hydroxide and then extracted with EtOAc. Thecombined organic layers were dried over MgSO4, filtered and concentrated under reducedpressure. Purification of this material was accomplished by MPLC using the Biotage Flash45S system eluting with 40% EtOAc/hexanes. The product-containing fractions werecollected and concentrated under reduced pressure to give the title compound (788 mg, 79%yield) as a yellow viscous gum. R, 0.3 (50% EtOAc/Hexanes). 1HNMR (400MHz, CDCl3), 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, 8.7Hz, 1H), 3.77 (s, 3H), 3.85-4.00 (m, 4K), 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 (APCE) 474 (M+1 ).
Préparation 3.4. 3-[1 -(4-Methoxy-benzyl)-5-(3-trifluoromethyl-phenytamino)-1 H- pyrazol-3-yl]-cyclopentanone
To a stirring solution of [5-(1,4-Dioxa-spiro[4.4]non-7-yl)-2-(4-methoxy-benzyl)-2H-pyrazol-3-yl]-(3-trifluoromethyl-phenyl)-amine (Préparation 3.3, 679 mg, 1.4 mmol) in 14 mL ofacetone was added 700 uL H2O followed by a cataiytic amount of p-toluenesulfonic acidmonohydrate (27.3 mg, 0.14 mmol). The reaction mixture was then heated to 65 °C. After 1hr the reaction was cooled to rt and quenched with H2O, diluted with EtOAc and the layerswere separated. The organic layer was dried over MgSO4, filtered and concentrated underreduced pressure to give the title compound (617 mg, quantitative yield) as a yellow viscousoil. This material was used without further purification. R, 0.28 (50% EtOAc/Hexanes). ’HNMR (400MHz, CDCI3), δ 2.02-2.14 (m, 1H), 2.20-2.30 (m, 1H), 2.36-2.50 (m, 3H), 2.58-2.63 (m, 1H), 3.45 (dddd, J=6.2, 6.2, 6.2, 6.2Hz, 1H), 012368 -66- 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 (APCP) 430 (M+1).
Example 26._3-Tra/7S-[5-(3-trifluoromethyl-phenylamino)-2H-pyrazol-3-yl]- cyclopentanone
The title compound was prepared according to the method for Préparation 3.4, usinghydrazine instead of 4-methoxy-benzyl-hydrazine (see synthesis of Préparation 3.3, supra}. ’HNMR (400MHz, CDCI3), δ 1.94-1.99 (m, 1H), 2.20-2.48 (m, 4H). 2.62 (ddd, J=18.2,7.9, 0Hz, 1H), 3.38 (dddd, J=9.5, 9.5, 7.5, 6.6Hz, 1H), 5.85 (s, 1H), 7.09 (d, J=7.4Hz, 1H), 7.20 (d, J=8.3Hz, 1H), 7.26-7.33 (m, 2H). LRMS m/z (APCF) 310.3 (M+1).
Préparation 3.5._{2-(4-Methoxy-benzyl)-5-[3-(4-methoxy-benzylamino)- cyclopentyl]-2H-pyrazol-3-yl}-(3-trifluoromethyl-phenyl)-amine
To a stirring slurry of 3-[1-(4-Methoxy-benzyl)-5-(3-trifluoromethyl-phenylamino)-1H-pyrazol-3-yl]-cyclopentanone (Préparation 3.4, 3.3 g, 7.6 mmol) in 76 mL of toluene wasadded, powdered 4 A MS (16.1 g), followed by 4-methoxybenzyl amine (2.0 g, 15.3 mmol).The resulting mixture was heated to 110 °C overnight. After 12 hr the reaction was cooled tort and Na(OAc)3BH (3.2g, 15.3 mmol) was added and stirred for an additional hr before 4 AMS were filtered off and the resulting solution was concentrated under reduced pressure.Purification of this material was accomplished by MPLC using the Biotage Flash 75S Systemeluting with a gradient of 5% through 8% MeOH/CH2CI2 containing 0.1% NH4OH. Theproduct-containing fraction was collected and concentrated under reduced pressure to givethe title compound (3.9 g, 92% yield) as a yellow viscous oil and a 3:1 mixture Ofdiastereomers. R( 0.28 (8% MeOH/CH2CI2), 3:2 ratio of c/s, trans isomers seen in the ’HNMRobtained in CD3OD. LRMS m/z (APCP) 551 (M+1).
Examples 27 and 28. Isomers of [5-(3-Benzylamino-cyclopentyl)-1H-pyrazol-3- yl]-(3-trifluoromethyl-phenyl)-amine A racemate comprising cis:trans isomers of [5-(3-Benzylamino-cyclopentyl)-1H-pyrazol-3-yl]-(3-trifluoromethyl-phenyl)-amine was prepared according to the method forPréparation 3.5, using Example 26 instead of Préparation 3.4. Cis:trans isomers (Examples27 and 28) were isolated from the mixture by MPLC using the Biotage flash 755 Systemeluting with a gradient of 5% through 8% MeOH/CH2CI2 containing 0.1% NH4OH.
Exampie 27. ’HNMR (400MHz, 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, 7.1Hz, 1H), 3.24 (dddd, J=2.1, 2.1. 2.1, 2.1Hz, 1H), 3.80 (s, 2H), 5.70 (s, 1H), 7.01 (d, J=4.3Hz, 1H), 7.22-7.55 (m, 5H), 7.56 (d, J=2.1Hz, 1H), 7.98 (s, 1H), 8.01 (s, 1H). LRMS m/z (APCI+) 401.3 (M+1).
PCT -67-
Example 28. ’HNMR (400MHz, 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=7.9Hz, 1H), 7.20-7.55 (m, 5H),7.56 (d, J=2.0Hz, 1H), 7.98 (s, 1H), 8.00 (s, 1H). LRMS m/z (APCF) 401.3 (M+1).
Example 29. {5-[c/'s-3-(4-Methoxy-benzylamino)-cyclopentyl}-1 H-pyrazol-3-yl}-(3- trifluoromethyl-phenyl)-amine
The title compound was prepared according ίο the method for preparaiion 3.5, usingthe title compound of Example 26 instead of the title compound of Préparation 3.4. ’HNMR (400MHz, 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=6.6Hz, 2H), 6.97 (d, J=7.0Hz, 1H), 7.25 (d, J=8.7Hz, 2H), 7.31-7.35'(m, 2H), 7.48 (s, 1H).LRMS m/z (APCI+) 431.3 (M+1 ).
Préparation 3.6._N-(4-Methoxy-benzyl)-N-{3-[1-(4-methoxy-benzyl)-5-(3- trifluoromethyl-phenylamino)-1H-pyrazol-3-ylI-cyciopentyl}-acetamide
To a stirring solution of {2-(4-Methoxy-benzyl)-5-{3-(4-methoxy-benzylamino)-cyclopentyl]-2H-pyrazol-3-yl}-(3-trifluoromethyl-phenyl)-amine (Préparation 3.5, 109 mg, 0.198mmol) in 0.5 mL of pyridine was added acetic anhydride (94 uL, 0.99 mmol). After 30 min thereaction was determined to be complété by TLC analysis. This reaction mixture wasconcentrated under reduced pressure to give N-(4-Methoxy-benzyl)-N-{3-(1-(4-methoxy-benzyl)-5-(3-trifluoromethyl-phenylamino)-1H-pyrazol-3-yi]-cyclopentyl}-acetamide as a 1:1ratio of cis, trans isomers determined by ’HNMR and as a foam. This material was usedwithout further purification. R, 0.75 (5% MeOH/ CH2CI2); LRMS m/z (APCF) 593 (M+1).
Analytical séparation of the four isomers of the title compound was accomplishedusing the following conditions: Column: Chiralcel OD, 5cm x 10cm. Mobile phase: 95/5heptane/EtOH containing 0.025% DEA as a modifier. Flow rate: 75 mL/min. The sample wasloaded using 1:1 Methylene chloride/mobile phase. The rétention times for the four isomèrewere 30 min, 37 min, 45min, and 60 min, respectively.
Example 30. N-{c/s-3-[5-(3-Trifluoromethyl-phenylamino)-2H-pyrazol-3-yI}- cyclopentylj-acetamide
To N-(4-Methoxy-benzyl)-N-{3-[1-(4-methoxy-benzyl)-5-(3-trifluoromethyl- phenyiamino)-1H-pyrazol-3-yl]-cycIopentyl}-acetamide (Préparation 3.6, 0.20 mmol 140 mg)was added 2 mL of TFA and reaction was heated to 76 °C. After 72 h the reaction cooled to rtand concentrated under reduced pressure. Purification of this material was accomplished byMPLC using a 10 g ISCO™ column elufing with 5% MeOH/CH2Cf2. The product-containingfractions were collected and concentrated to give/the title compound (60 mg, 86% yield over wp 012368 -68- two steps). R/0.30 (55 MeOH/CH2CI2); ’HNMR (400MHz, 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, 8.3,8.3Hz, 1H), 4.33 (dddd, J=12.9, 7.0, 7.0, 7.0Hz, 1H), 5.71 (s, 1H), 7.01 (d, J=7.9Hz, 1H), 7.16 5 (bs,-1H), 7.36 (dd, J=7.9, 7.9Hz, 1H), 7.55 (d, J=8.3Hz, 1H), 7.99 (bs, 1H), 8.01 (bs, 1H).LRMS m/z (APCI*) 353.2 (M+1).
Example 31. Pyridine-2-carboxylic acid {3-[5-(3-trifluoromethyl-phenylamino)- 2H-pyrazol-3-ylj-cyclopentyl}-amide
The title compound was prepared according to the method for Example 30, using10 analogous reactants. R, 0.33 (5% MeOH/ CH2CI2), 1:1 ratio of c/s, trans isomers seerï in ’HNMR obtained inCD3OD. LRMS m/z (APCI*) 416 (M+1), mp 180.1 °C (HCl sait)
Example 32. Pyridine-2-carboxylic acid {3-[5-(3-trifluoromethyl-phenylamino)-2H- pyrazol-3-ylJ-cyclopentyl}-amide 15 The title compound was prepared according to the method for Example 30, using analogous reactants. R, 0.28 (5% MeOH/ CH2CI2), 1:1 ratio of c/s, frans isomers seen in ’HNMR obtained inCD3OD. LRMS m/z (APCI+) 483 (M+1), mp 162.5 °C (HCl sait)
Example 33. Cyctobutanecarboxylic acid {3-[5-(3-trifluoromethyl-phenylamino)-20 2H-pyrazol-3-yl]-cyclopentyl}-amide
The title compound was prepared according to the method for Example 30, usinganalogous reactants.
Rf 0.25 (5% MeOH/ CH2CI2), 1:1 ratio of c/s, trans isomers seen in ’HNMR obtained inCD3OD. LRMS m/z (APCI*) 393 (M+1), mp 232.4 ‘C (HCI sait) 25 Example 34. 2,2-Dimethyl-N-{3-[5-(3-trifluoromethy^-pheπy^am^no)-2H-pyrazol·3- ylî-cyclopentyl}-propionamide
The title compound was prepared according to the method for Example 30, usinganalogous reactants.
Rf 0.23 (5% MeOH/ CH2CI2), 1:1 ratio of c/s, trans isomers seen in ’HNMR obtained in30 CD3OD. LRMS m/z (APCI*) 395 (M+1 ), mp 249.2 'C (HCl sait)
Example 35. 4-Fluoro-N-{3-[5-(3-trifiuoromethyl-phenylami'no)-2H-pyrazol-3-yl]- cyclopentyl}-benzamide
The title compound was prepared according to the method for Example 30, using analogous reactants. 35 R, 0.30 (5% MeOH/ CH2CI2), 1:1 ratio of c/s, trans isomers seen in ’HNM R obtained in CD3OD. LRMS m/z (APCI*) 433 (M+1 ); mp (dec)· no distinct meiting point. 012368 -69-
Example 36. 2,2,2-Trifluoro-N-{3-[5-(3-trifiuoromethyl-phenylamino)-2H-pyrazol- 3-yl]-cyclopentyl}-acetamide
The title compound was prepared according to the method for Example 30, usinganalogous reactants. R, 0.30 (5% MeOH/ CH2CI2), 3:2 ratio of cis, trans isomers seen in 1HNMR obtained inCDCI3. LRMS m/z (APCE) 407 (M+1 ).
Example 37._Cyclopropanecarboxylic acid {3-[5-(3-trifluoromethyl- phenylamino)-2H-pyra2ol-3-yl]-cyclopentyl}-amide
The title compound was prepared according to the method for Example 30, using analogous reactants. R, 0.28 (8% MeOH/ CH2CI2), 3:2 ratio of cis, trans isomers seen in 1HNMR obtained inCDCI3. LRMS m/z (APCI+) 379 (M+1).
Exampie 38._N-{3-[5-(3-Trifluoromethyl-phenylamino)-2H-pyrazoi-3-yl]- cyclopentyl}-propionamide
The title compound was prepared according to the method for Example 30, usinganalogous reactants.
Rf 0.30 (8% MeOH/ CH2CI2), 3:2 ratio of cis, trans isomers seen in 1HNMR obtained inCDCI3. LRMS m/z (APCI+) 367 (M+1).
Example 39. Cyclohexanecarboxylic acid {3-[5-(3-trifluoromethyl-phenylamino)- 2H-pyrazol-3-yl]-cyclopentyl)-amide
The title compound was prepared according to the method for Example 30, usinganalogous reactants. R, 025 (8% MeOH/ CH2CI2), 3:2 ratio of cis, trans isomers seen in 1HNMR obtained inCDCI3. LRMS m/z (APCI+) 421 (M+1 ).
Préparation 4.1. (1,4-Dioxa-spiro[4.4]non-7-yl)-oxo-acetonitrile
To 9 mL of THF at -78 °C was added nBuLi (3.4 mL, 8.6 mmol, 2.5 M in hexanes).
After réaction température equilibrated (-15 min), acetonitrile (449 uL, 359 mg, 8.6 mmol) wasadded dropwise. Reaction was allowed to stir 1 hr before a solution of 1,4-Dioxa-spiro[4.4]nonane-7-carboxylic acid methyl ester (723 mg, 4.3 mmol) was added down the sideof the flask. After 1 hr the reaction was warmed to -45 °C (acetonitrile/CO2) and allowed tostir for 2 hr. Reaction was quenched cold by the 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 driedover MgSO4, filtered and concentrated under reduced pressure to yield the title compound asa brown oil that was used without further purification. R, 0.19 (50 % EtOAc/hexanes); LRMS m/z (APCI+) 196 (M+1).
Préparation 4.2. 5-{1 >4-Dioxa-spiro[4.4]non-7-y|)~-2-(4-methoxy-benzyl)-2H- 012368 -70- pyrazol-3-ylamine Το crude (1,4-Dioxa-spiro[4.4]non-7-yl)-oxo-acetonitrile (Préparation 4.1) in EtOH (6.8mL) was added 4-methoxy-benzyl-hydrazine (0.60 g. 4.0 mmol), and then the reaction washeated to 65 °C. After 2 1/2 hr the reaction was cooled to rt and concentrated under reducedpressure. Purification of this material was accomplished by MPLC using the Biotage Flash40L System eluting with a gradient of 50% through 100% EtOAc/hexanes, collecting 18 mmfractions. The product containing-fraction was collected and concentrated under reducedpressure to give the titie compound (0.83 g, 75% yield over 2 steps). R, 0.13 (50% EtOAc/hexanes); 1HNMR (400MHz, CDCI3), 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, 1H), 6.80 (d, J = 8.7 Hz, 2H), 7.04 (d, J = 8.6 Hz,2H); 13C NMR (100 Mz, CDCI3) 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).
Préparation 4.3. N-[5-(1,4-Dioxa-spiro[4.43non-7-yl)-2-(4-methoxy-benzyl)-2H- pyrazol-3-yn-2-naphthalen-1-yl-acetamide
To a stirring solution of 5-(1,4-Dioxa-spiro[4.4]non-7-yl)-2-(4-methoxy-benzyl)-2H-pyrazol-3-ylamine (Préparation 4.2, 0.83 g, 2.5 mmol) in CH2CI2 (5 mL) was added a freshlyprepared solution of naphthalen-1-yl-acetyl chloride (1.03 g, 5.0 mmol in CH2CI2) followed bythe addition of 1 mL of pyridine. After 2 hr, the reaction was quenched with H2O, and 2 mL.ofa solution of NH4OH (15%) was added. This mixture was diluted with CH2CI2 and the layerswere separated. The organic layer was dried over MgSO4, filtered and concentrated underreduced pressure. Purification of this material was accomplished by MPLC using the BiotageFlash 40L system eluting with a gradient of 25% through 50% acetone/hexanes, collecting 18mm fractions. The product-containing fraction was collected and concentrated under reducedpressure to give the titie compound (1.2 g, 97% yield) as a light yellow solid. mp 162.8 °C; ’HNMR (400MHz, CDCI3), δ 2.09-173 (m, 5H), 2.21 (dd, J = 13.3, 7.9Hz, 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, 1H), 6.36 (d, J = 8.7 Hz, 2H), 6.51 (d, J = 8.7 Hz, 2H), 7.03 (br s, 1H), 7.23 (d, J= 6.7 Hz, 1H), 7.39 (dd, J = 7.1,7.1 Hz, 1 H), 7.53-7.45 (m, 2H), 7.88-7.83 (m, 2H), 7.89 (d, J = 1.7 Hz, 1H); 13C NMR (100 Mz, CDCI3) 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).
Préparation 4.4. N-[2-(4-Methoxy-benzyl)-5-(3-oxo-cyclopentyl)-2H-pyrazol-3-yl]- 2-naphthalen-1 -yl-acetamide
The titie compound was synthesized according to the method for Préparation 3.4,using the titie compound of Préparation 4.3 instead of the titie compound of Préparation 3.3 as 012368 -71- a reactant. ’HNMR (400MHz, CDC!3), 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, 9.5Hz, 1H), 3.75 (s, 3H), 4.12 (s, 2H), 4.62 (s,2H), 6.30 (s, 1H), 6.33 (d, J=9.5Hz, 1H), 6.55 (d, J=8.7Hz, 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 (APCP) 454 (M+1).
Préparation 4.5._N-{2-(4-Methoxy-benzyt)-5-(3-(4-methoxy-benzyÎamino)- cyclopentyl]-2H-pyrazol-3-yl}-2-naphthalen-1 -yl-acetamide
The title compound was prepared according to the method for Préparation 3.5, usingthe title compound of Préparation 4.4 as a reactant instead ofthe title compound ofPréparation 3.4. R, 0.25 (8% MeOH/ CH2CI2) (minor), Rf 0.20 (8% MeOH/ CH2C12) (major), 3:2 ratio ofcis, trans isomers seen in ’HNMR obtained in CDCI3. LRMS m/z (APCi+) 575 (M+1).
Préparation 4.6. N-[5-{3-[Acetyl-(4-methoxy-benzÿl)-amino]-cyclopentyl}-2-(4- methoxy-benzyl)-2H-pyrazol-3-yl]-2-naphthalen-1-yl-acetamide
The title compound was synthesized according to the method for Préparation 3.6,using the title compound of Préparation 4.5 instead ofthe title compound of Préparation 3.5 asa reactant. R, 0.30 (80% EtOAc/ Toluene), Rf 0.25 (80% EtOAc/ Toluene), 1:1 ratio of cis, transisomers seen in ’HNMR obtained in CDCI3.
Enantiomeric séparation of the isomer with the R, 0.25 was accomplished using thefollowing conditions: Column: Chiralcel OD, 5cm x 50cm. Mobile phase: 60/40Heptane/EtOH containing 0.025% DEA as a modifier. Flow rate: 50 mL/min. The sample wasloaded using methanol. The rétention times for the two enantiomers were 35 min and 45 min.LRMS m/z (ΑΡΟΓ) 617 (M+1).
Préparation 5.1. Cyclobutanecarboxylic acid (4-methoxy-benzyl)-{3-[5-(3- trifluoromethyl-phenylamino)-2H-pyrazol-3-yl]-cyclopentyl}-amide
The title compound was prepared according to the method for Préparation 4.6, usinganalogous reactants. R, 0.45 (5% MeOH/ CK2CI2), 1:1 ratio of cis, trans isomers seen in *HNMR obtained inCDCI3. LRMS m/z (ΑΡΟΓ) 633 (M+1 ).
Example 40. N-[5-(3-Acetylamino-cyclopentyl)-2H-pyrazol-3-yl]-2-riaphthalen-1 - yl-acetamide
The title compound was synthesized by the method for Example 30, usingPréparation 4.6 as a reactant instead of Préparation 3.6. R, 0.30 (8% MeOH/ CH2CI2). 1:1 ratio of cis, trans isomers was seen in the 1HNMRobtained in CD3OD. LRMS m/z (ΑΡΟΓ) 377 (M+1). 012368
PC -72-
Example 41._Cyclopropanecarboxylic acid {3-[5-(2-naphthalen-1-yl- acetylamino)-1H-pyrazol-3-yl]-cyclopentyl}-amide
The titie compound was synthesized by the method for Example 30, using analogousreactants. R, 0.30 (5% MeOH/ CH2CI2). 1:1 ratio of cis, trans isomers was seen in the ’HNMRobtained in CDCI3. LRMS m/z (APCE) 403 (M+1 ).
Example 42._2-Naphthalen-1-yl-N-{5-[3-(2,2,2-trifluoro-acetylamino)- cyclopentylj-2H-pyrazol-3-yl}-acetamide
The titie compound was synthesized by the method for Example 30, using analogousreactants. R, 0.30 (5% MeOH/ CH2CI2). 1:1 ratio of cis, trans isomers was seen in the ’HNMRobtained in CD3OD. LRMS m/z (APCE) 431 (M+1).
Example 43._N-{3-[5-(2-Naphthalen-t-yi-aeetylamino)-1H-pyrazol-3-yl]- cyclopentyl}-benzamide
The titie compound was synthesized by the method for Example 30, using analogousreactants. R, 0.30 (5% MeOH/ CH2CI2). 1:1 ratio of cis, trans isomers was seen in the 1HNMRobtained in CDCI3. LRMS m/z (APCE) 439 (M+1).
The following titie compounds of Examples 44-57 were synthesized by preparing anintermediate analogous to the titie compound of Préparation 4.6, using the steps described in"Préparation 4.2” through “Préparation 4.5”. In each case, a reactant analogous lonaphthalen-1 -yl acetal chloride used in synthesis of the titie compound of Préparation 4.3 wasused. This intermediate was than treated according to the method described for synthesis ofthe titie compound of Example 30:
Example 44. 3-Methoxy-N-{c/s-3-[5-(2-naphthalen-1 -yl-acetylamino)-2H-pyrazol- 3-yl]-cyclobutyl}-benzamide
Rf 0.33 (10% MeOH/CH2CI2); mp 124.8 °C (mono HCl sait); ’HNMR (400MHz,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, 1 H); ’3C NMR (100 Mz, 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 (APCE) 455.1 (M+1).
Example 45. N-{cfs-3-[5-(2-Naphthalen-1-yl-acetylamino)-2H-pyrazol-3-yl]- cyclobutyl}-3-trifluoromethyl-benzamide R, 0.56 (10% MeOH/CH2CI2); mp 142.8 °C (mono HCl sait); ’HNMR (400MHz, 012368 -73- 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,· 1 H), 4.14 (s, 2H), 4.46 (apt quint, J=7.5 Hz, 1 H), 6.40 (s, 1 H), 7.48-4.37 (m , 4H), 7.83(d, J = 4.9Hz, 1H), 8.03 (s, 1H), 8.05 (s, 1H), 8.13 (s, 1H); ’3C NMR (100 Mz, 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, 5 126.2, 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-{c/'s-3-[5-(2-Naphthalen-1 -yl-acetylamino)-2H-pyrazol-3-yl]- cyclobutylj-isobutyramide R, 0.43 (10% MeOH/CH2CI2 with 0.1% ΝΗ,ΟΗ aq); mp 130.6 °C (mono HCI sait); 10 ’HNMR (400MHz, d6 DMSO), δ 0.93 (s, 3H), 0.95 (s, 3H), 1.92 (dd, J = 9.9, 9.9 Hz, 2H), 2.24(apt quint, J = 6.8 Hz, 1H), 2.54,-2.48 (m, 2H), 3.01 (apt quint, 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, 1 H); ); 13C NMR (100 Mz, 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; 15 LRMS m/z (APCI+) 391 (M+1 ).
Example 47. 2-Phenyl-cyclopropanecarboxyIic acid {c/s-3-(5-(2-naphthalen-1-yl- acetylamino)-2H-pyrazol-3-yl3-cyclobutyl}-amide
Rf 0.56 (10% MeOH/CH2CI2 with 0.1% NH4OH aq); mp 139.8 °C (mono HCl sait); 1HNMR (400MHz, d6 DMSO), δ 1.17-1.14 (m, 1H), 1.32-1.28 (m, 1H), 1.75-1.70 (m, 1H), 20 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, 1H), 7.90 (d, J= 7.9 Hz, 1H), 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, 25 24.2, 15.1; LRMS m/z (APCI+) 465.0 (M+1).
Example 48. N-[5-(c/s-3-Acetylamino-cyclobutyl)-1H-pyrazol-3-yl]-2-naphthalen- 1-yl-acetamide R, 0.50 (10% MeOH/ CH2CI2). ’HNMR (400MHz, CD3OD), δ 1.86 (s, 3H), 1.97-2.05(m, 2H), 2.59-2.66 (m, 2H), 3.07 (apt quint, J=8.0Hz, 1H), 4.13 (s, 2H), 4.20 (apt quint, 30 J=7.8Hz, 1H), 6.25 (s, 1H), 7.37-7.48 (m, 4H), 7.77 (d, J=7.9Hz, 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 (APCI+) 363 (M+1), mp 209.4 °C (HCl sait).
Example 49. N-{c/s-3-[5-(2-Naphthalen-1 -yl-acetylamino)-2H-pyrazol-3-yl]- 35 cyclobutyl}-benzamide 012368 -74- R(0.50 (10% MeOH/ CH2CI2). ’HNMR (400MHz, CD3OD), δ 2.20-2.30 (m, 2H), 2.70- 2.80 (m, 2H), 3.20 (apt quint, J=8.0Hz, 1H), 4.18 (s, 2H), 4.48 (apt quint, J=7.8Hz, 1H), 6.24(bs, 1H), 7.38-7.50 (m, 7H), 7.75-7.88 (m, 4H), 8.00-8.05 (m, 1H). ’3C-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 (APCP) 425(M+1), mp 194.0°C(HCI sait).
Example 50. 2-Cyclopropyl-N-{c/s-3-[5-(2-naphthalen-1 -yl-acetylamino)-2H- pyrazol-3-yl]-cyclobutyl}-acetamide
Rf0.60 (10% MeOH/ CH2CI2). ’HNMR (400MHz, CD3OD), δ 0.93 (t, J=7.5Hz, 2H),1.34 (d, J=6.2Hz, 1H), 1.65 (d, J=5.0Hz, 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=7.8Hz, 1H), 4.20 (s/2H), 5.40 (apt quint,J=6.2Hz, 1H), 6.22 (bs. 1H), 7.40-7.56 (m, 4H), 7.78-7.88 (m, 2H), 8.02-8.08 (m, 1H). ’3C-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 (APCI+) 403 (M+1 ), mp 93.2 °C (HCl sait).
Example 51. 6-Chforo-pyridine-2-carboxylic acid {cfe-3-[5-(2-naphthalen-1-yl- acetylamino)-2H-pyrazol-3-yl]-cyclobutyl}-amide R, 0.50 (10% MeOH/ CH2Cl2). ’HNMR (400MHz, CD3OD), δ 2.25-2.42 (m, 2H), 2.76- 2.82 (m, 2H), 3.30 (apt quint, J=7.9Hz, 1H), 4.22 (s, 2H), 4.54 (apt quint, J=7.5Hz, 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. MSLRMS m/z (APCP) 460 (M+1), mp (dec) (HCl sait).
Example 52. Quinoline-2-carboxylic acid {c/s-3-[5-(2-naphthalen-1-yl- acetylamino)-2H-pyrazol-3-yl]-cyclobutyl}-amide R, 0.30 (5% MeOH/ CH2CI2). ’HNMR (400MHz, CD3OD), δ 2.25-2.38 (m, 2H), 2.76- 2.78 (m, 2H), 3.25 (apt quint, J=8.3Hz, 1H), 4.16 (s, 2H), 4.56 (apt quint, 8.7Hz, 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=8.7Hz, 1H)..’3C-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(APCP) 476 (M+1), mp 200.3 °C (HCl sait).
Example 53. Pyrazine-2-carboxylic acid {c/s-3-[5-(2-naphthalen-1-yl- acetylamino)-2H-pyrazol-3-yl]-cyclobutyl}-amide R,0.30 (5% MeOH/ CH2CI2). ’HNMR (400MHz, CD3OD), δ 2.25-2.38 (m, 2H), 2.75-2.84 (m, 2H), 3.26 (apt quint, J=8.7Hz, 1H), 4.21 (s, 2H), 4.55 (apt quint, J=8.7Hz, 1H), 6.28 012368 1’(. ' -75- (s, 1H), 7.42-7.54 (m, 4H), 7.81-7.89 (m, 2H), 8.03-8.07 (m, 1 H), 8.66 (d, J=2.5Hz, 1H), 8.75(d, J=2.5Hz, 1H), 9.20 (s, 1H). MS LRMS m/z (APCI*) 427 (M+1).
Example 54. 4-Methoxy-N-(c/s-3-[5-(2-naphthalen-1 -yl-acetylamino)-2H-pyrazol- 3-yl]-cycl°butyl}-benzamide R, 0.35 (5% MeOH/ CH2CI2). ’HNMR (400MHz, CD3OD), δ 2.17-2.25 (m, 2H), 2.68-2.75 (m, 2H), 3.18 (apt quint, J=8.3Hz, 1H), 3.79 (s, 3H), 4.15 {s, 2H), 4.44 (apt quint,J=7.8Hz, 1H), 6.33 (s, 1H), 6.91 (d, J=5.0Hz, 2H), 7.37-7.49 (m, 4H), 7.77 (d, J=5.0Hz, 2H),7.82-7.84 (m, 1H), 7.96-8.04 (m, 2H). ’3C-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 LRMSm/z (APCP) 455 (M+1 ), mp 175.6 °C (HCl sait).
Example 55. N-{c/s-3-[5-(2-Naphthalen-1-yI-acetylamino)-2H-pyrazol-3-yl]- cyclobutyl}-3-nitro-benzamide R, 0.35 (5% MeOH/ CH2CI2). ’HNMR (400MHz, CD3OD), δ 2.26-2.34 (m, 2H), 2.74- 2.79 (m, 2H), 3.25 (apt quint, J=8.7Hz, 1H), 4.19 (bs, 2H), 4.50 (apt quint, J=8.3Hz, 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 (APCP)470 (M+1), mp 123.5 °C (HCl sait).
Example 56. 3,5-Dimethoxy-N-{c/s-3-I5-{2-naphthalen-1 -yl-acetylamino)-2H- pyrazol-3-yl]-cyclobutyl}-benzamide R, 0.50 (10% MeOH/ CH2CI2). ’HNMR (400MHz, CD3OD), δ 2.23-2.30 (, 2H), 2.73- 2.79 (m, 2H), 3.23 (apt quint, J=8.3Hz, 1H), 3.78 (s, 6H), 4.19 (bs, 2H), 4.47 (apt quint,J=8.3Hz, 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-{c/s-3-[5-(2-naphthalen-1 -yl-acetylamino)-2H- pyrazol-3-yl]-cyclobutyl}-benzamide
Rf0.45 (10% MeOH/ CH2CI2). ’HNMR (400MHz, CD3OD), δ 2.18-2.28 (m, 2H), 2.70- 2.80 (m, 2H), 2.99 (s, 6H), 3.20 (apt quint, J=8.2Hz, 1H), 4.18 (bs, 2H), 4.46 (apt quint,J=8.3Hz, 1H), 6.31 (bs, 1H), 6.69 (d, J=8.7Hz, 2H), 7.42-7.53 (m, 4H), 7.71 (d, J=9.1Hz, 2H),7.80-7.88 (m, 2H), 8.06 (d, J=8.3Hz, 1H). MS LRMS m/z (APCI+) 485 (M+1).
Example 58. N-(5-((1 S)-Hydroxy-ethyl)-2H-pyrazoI-3-ylI-2-naphthalen-1 -yl- acetamide
Synthesis of the title compound was accomplished by the method for the titlecompound of Préparation 4.3, using a reactant analogous to naphtbalen-1-yl-acetyl chloride.This was followed by deprotectiop. The resulting intermediate was treated according to the 012368 .
I V -76- method for Example 30. R, 0.50 (10%MeOH/ CH2CI2). ’HNMR (400MHz, CDCI3), δ 1.64 (d, J=6.6Hz, 3H), 4.12(s, 2H), 5.97 (dd, J=6.6, 6.6Hz, 1H), 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 (APCP) 296 (M+1); mp 101.3 °C (HCl sait).
Example 59. N-[5-(2-Hydroxy-(1S)-methyl-ethyl)-2H-pyrazol-3-yl)-2-naphthalen- 1- yl-acetamide
Synthesis of the title compound was accomplished by the method for Préparation 4.3,using a reactant analogous to naphthalen-1-yl-acetyl chloride. This was followed bydeprotection. The resulting intermediate was treated according to the.method for Example 30. ’HNMR (400MHz, CD3OD), δ 1.25 (d, J=7.1Hz, 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=7.0Hz,’1H), 7.88 (d, J=7.1Hz,1H), 8.06 (d, J=7.0Hz, 1H). LRMS m/z (APCP) 310 (M+1), mp 117.6 °C (HCl sait).
Préparation 6.1. N-[5-[1-(Benzothiazol-2-yloxy)-ethyl]-2-(4-methoxy-benzyl)-2H- pyrazol-3-yl]-2-naphthalen-1-yl-acetamide
To a stirring 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 THF was added 2-chiorobenzthiozole (104 uL, 0.79 mmol, 135 mg) followed by a solution of KOBu* (1.4 mL, 1.4mmol, 1.0 M in THF) dropwise. After 2 hrs the reaction was quenched with NH4CI and thendiluted with EtOAc. The layers were separated and the organic layer was dried of MgSO4,filtered and concentrated under reduced pressure. Purification of this material wasaccomplished by MPLC using a 10 g ISCO cartridge on a Biotage System eluting with 30%EtOAc/hexanes, collecting 8 mm fractions. The product-containing fraction was collected andconcentrated under reduced pressure to give the title compound (100 mg, 25% yield) as ayellow viscous oil.
Rf0.50 (50% EtOAc/Hexanes). ’HNMR (400MHz, CDCI3), δ 1.82 (d, J=7.5Hz, 3H),3.74 (s, 3H), 4.06 (d, J=4.6Hz, 2H), 4.65 (dd, J=15.8, 15.8Hz, 2H), 6.02 (dd, J=7.1, 7.1Hz,1H), 6.27 (s, 1H), 6.29 (d, J=8.7Hz, 2H), 6.51 (d, J=8.7Hz, 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). LRMSm/z (APCP) 549 (M+1).
Example 60._N-{5-[(1S)-(Benzothiazol-2-yloxy)-ethyl3-1H-pyrazol-3-yl}-2- naphthalen-1 -yl-acetamide
The title compound was synthesized using Préparation 6.1 according to the methodfor Example 15. R{0.41 (5% MeOH/ CH2CI2). ’HNMR (400MHz; CDCI3), δ 1.81 (d, J=7.1Hz, 3H), 4.17(s, 2H), 5.84 (dd, 6.7, 6.7Hz, 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 (APCP) 429 (M+1). 012368 -77-
Example 61. N-[5-(Benzothi3zol-2-yloxymethyl)-1H-pyrazol-3-ylj-2-naphthalen- 1-yl-acetamide
The title compound was synthesized according to the method for Example 60, usinganalogous reactants. R, 0.50 (5% MeOH/ CH2CI2). ’HNMR (400MHz, 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 (APCL) 412(M-1).
Example 62._N-{5-[(1 R)-(Benzothiazol-2-yloxy)-ethyl]-1 H-pyrazol-3-yl}-2- naphthalen-1 -yl-acetamide
The tille compound was synthesized according to the method for Example 60, usinganalogous reactants. R,0.41 (5% MeOH/ CH2CI2). ’HNMR (400MHz, CDCI3), δ 1.85 (d, J=7.1Hz, 3H), 4.20(s, 2H), 5.88 (dd, J=7.1, 7.1Hz, 1H), 6.68 (s, 1H), 6.91 (d, J=7.9Hz, 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-[c/s-3-(Benzooxazol-2-yloxy)-cyclobutyl]-1 H-pyrazol-3-yl}-2- naphthalen-1 -yl-acetamide
The title compound was synthesized according to the method for Example 60, usinganalogous reactants. R, 0.24 (10% MeOH/CH2CI2); mp 142.0 °C (mono HCl sait); 1HNMR (400MHz, CDCI3)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 (aptquint, J = 7.3Hz, 1H), 6.59 (s, 1H), 7.54-7.31 (m, 8H), 7.72 (dd, J = 7.9 Hz, 1H), 7.77 (dd, 7.5Hz, 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 (APCP) 439.1 (M+1).
Préparation 7.1. N-[5-(c<s-3-hydroxy-3-phenyl-cyclobutyl)-2-(4-methoxy-benzyl)- 2H-pyrazol-3-yl]-2-naphthaien-1-yl-acetamide
Préparation' of the starting ketone N-[2-(4-methoxy-benzyl)-5-(3-oxo-cyclobutyl)-2H-pyrazol-3-yi]-2-naphthalen-1-yl-acetamide was accomplished using a method analogous tothat described for Préparation 4.4 (including synthesis of Préparations 4.1-4.3). A solution of the ketone (50 mg, 0.11 mmol) in tetrahydrofuran (5 mL) cooled to -30°C was treated dropwise with phenyl magnésium bromide (500 uL, 0.5 mmol, 1M solution inTHF). Upon completion of addition, the réaction mixture was stirred for 40 min at -30 °C, thensaturated aqueous ammonium chloride solution was added and the mixture was warmed toroom température. THF was removed in vacuo, and the residue was diluted with methylenechloride which was washed with water and brine. The diluted residue was then dried andfiltered. The crude matériel was purified by sîlica gel chromatography (50:1 chloroform- 012368. -78- PC' methanol) to afford 54 mg (80% yield) of the title comopund. 1H NMR (400 MHz, CDCI3) 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, 1H), 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/CI): 518.2 (M+H)+.
Préparation 7.2 N-[2-(4-methoxy-benzyl)-5-(c/s-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-pyrazoi- 3-yl]-2-naphthalen-1-yl-acetamide (Préparation 7.1, 54 mg, 0.10 mmol) in 1:1 methylenechloride-trifluoroacetic acid (4 mL) was treated with triethyisilane (1.2 mL) at 23 °C. Afterstirring for 16 h, the solvent was removed in vacuo and the residue wâs purified by silica gelchromatography (100:1 chloroform-methanol) to afford 39 mg (78% yield) of the titlecompound as a 10:1 mixture of cis - trans isomers. 1H NMR (400 MHz, CDCI3): 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/CI): 502.2 (M+H)+; minor isomer, characteristic 1H NMR signais: δ 4.66 (s), 4.12 (s),2.60 (m).
Example 64. 2-naphthalen-1-yl-N-[5-(cfs-3-phenyl-cyclobutyl)-1H-pyrazol-3-yl3- acetamide A solution of N-[2-(4-methoxy-benzyl)-5-(3-phenyl-cyclobutyl)-2H-pyrazol-3-yl]-2-naphthalen-1-yl-acetamide (Préparation 7.2, 38 mg, 0.076 mmol) in trifluoroacetic acid (5 mL)at room température was treated with anisole (165 uL, 1.5 mmol). The solution was heated at70 °C for 5 h. The solvent was removed in vacuo and the residue was purified by silica gelchromatography (40:1 chloroform-methanol) to afford 27 mg (89% yield) of the title compoundas a 94:6 mixture of cis - trans isomers. The product was dissolved in ethyl acetate andtreated with hydrogen chloride in diethyl ether to afford the HCl sait. 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/CI): 382.3 (M+H)+.
The title compounds of the following Examples 65-71 were synthesized as in Example64, including synthesis of Préparations 7.1 and 7.2, using an analogous starting ketone:
Example 65. N-{5-[c/s-3-(2-Methoxy-phenyI)-cyclobutyl]-2H-pyrazol-3-yl}-2- quinolin-6-yl-acetamide 1H NMR (400 MHz, CDCI3): δ 9.23 (s, 1H), 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. 012368 -79- 1 H), 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/CI): 413.2 (M+H)+.
Example 66. N-f5-[c/s-3-(2-Methoxy-phenyl)-cyclobutylj-2H-pyrazol-3-yl}-2-5 pyridin-3-yl-acetamide 1H NMR (400 MHz, CD3OD): δ 8.95 (s, 1 H), 8.82 (d, J = 5.8 Hz, 1 H), 8.67 (d, J = 8.3Hz, 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/CI): 363.2.
Example 67. N-{5-[c/s-3-(2-Methoxy-phenyl)-cyclobutyl]-2H-pyrazol-3-yl}-2-10 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/CI): 412.2.
Example 68. N-{5-[c/s-3-(4-Methoxy-phenyl)-cyclobutyl]-2H-pyrazol-3-yl}-2-15 naphthalen-1 -yl-acetamide 1H NMR (400 MHz, CDCI3): 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; minorisomer, characteristic 1H NMR signais: 6.65 (s), 2.51 (m). 20 Example 69._N-{5-[c/s-3-(4-Chloro-phenyl)-cyclobutyl]-2H-pyrazol-3-yl}-2- naphthalen-1-yl-acetamide 1H NMR (400 MHz, CDCI3): d 7.96 (d, J = 7.5 Hz, 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/CI): 416.1, 418.1 (M+H)+; minor isomer, 25 characteristic 1H NMR signais: δ 6.65 (s), 2.55 (m).
Example 70. 2-Naphthalen-1-yl-N-[5-(c/s-3-p-tolyl-cyclobutyl)-2H-pyrazol-3-yl]- acetamide 1H NMR (400 MHz, CDCI3): d 8.04 (s, 1H), 7.95 (d, J = 7.9 Hz, 1H), 7.81 (d, J = 8.3Hz, 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), 30 3.38 (m, 2H), 2.70 (m, 2H), 2.32 (s, 3H), 2.20 (m, 2H); MS (AP/CI): 396.2; minor isomer, characteristic 1H NMR signais: δ 6.65 (s), 3.65 (m), 2.51 (m).
Example 71. 2-(4-Methoxy-phenyl)-N-{5-[c/s-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).35 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),
01236Q -80- 2.79 (m, 2H). 2.29 (m, 2H); MS (AP/CI): 392.2 (M+H)+.
The following additional Examples of compounds of the invention were synthesized as described herein: N-{5-[c;s-3-(4-Hydroxy-phenyl)-cyclobutylJ-1H-pyrazol-3-yl}-2-quinolin-6-yl-acetamide;N-{5-fc/'s-3-(3-Hydroxy-phenyl)-cyclobutyl]-1 H-pyrazol-3-yl}-2-quinolin-6-yl-acetamide;2-Naphthalen-1-yl-N-[5-(c/s-3-pyridin-3-yl-cyclobutyl)-2H-pyrazol-3-yl]-acetamide;N-[5-(c/s-3-Naphthalen-2-yl-cyclobuty!)-2H-pyrazol-3-yl]-2-pyridin-3-yi-acetamide;N-(5-lndan-2-yl-1H-pyrazol-3-yl)-2-quinolin-6-yl-acetamide; N-[5-(c/s-3-Pyridin-2-yl-cyclobutyl)-2H-pyrazol-3-yI]-2-quinolin-6-yl-acetamide; N-[5-(c/s-3-Pyridin-2-yl-cyclobutyl)-2H-pyrazoi-3-yl]-2-quinolin-6-yl-acetamide; 2-(4-Methoxy-phenyl)-N-[5-(c/s-3-pyridin-4-yl-cyclobutyl)-2H-pyrazol-3-yl]-acetamide; N-{5-[3-{cÂs-2-Dimethylaminomethyl-phenyl)-cyclobutyl]-2H-pyrazol-3-yI}-2-(4- methoxy-phenyl)-acetamide; N-(5-{c/s-3-[3-(2-Dimethylamino-ethoxy)-phenyl]-cyclobuty!}-2H-pyrazol-3-yl)-2-(4- methoxy-phenyl)-acetamide; N-{5-[c/s-3-(2-Hydroxy-phenyl)-cyclobutyl]-2H-pyrazol-3-yl}-2-(4-methoxy-phenyl)- acetamide; N-(5-{c/s-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-y!]-acetamide; N-{5-[c/s-3-(2-Fluoro-phenyl)-cyclobutyl]-2H-pyrazol-3-yl}-2-(4-methoxy-phenyl)- acetamide; N-(5-{c/s-3-[4-(Azetidin-3-yloxy)-phenyl]-cyclobutyl}-2H-pyrazol-3-yl)-2-(4-methoxy- phenyl)-acetamide; N-{5-{c/s-3-[2-(Azetidin-3-yloxy)-phenyl]-cyclobutyl}-2H-pyrazol-3-yl)-2-(4-methoxy- phenyl)-acetamide; 2-(4-Methoxy-phenyl)-N-{5-[c/s-3-(2-methylsulfanyl-phenyl)-cyclobutyl]-2H-pyrazol-3- yl}-acetamide; N-{5-[c/s-3-(2-Amino-phenyl)-cyclobutyl]-2H-pyrazol-3-yl}-2-(4-methoxy-phenyl)- acetamide; N-{5-[c/s-3-(4-Cyano-phenyl)-cyclobutyl]-2H-pyrazol-3-yl}-2-(4-methoxy-phenyl)- acetamide; N-{5-[c/s-3-(2-Cyano-phenyl)-3-hydroxy-cyclobutyl]-2H-pyrazol-3-yl}-2-(4-methoxy- phenyl)-acetamide; N-{5-[c/s-3-(2-Hydroxy-ethyl)-cyclobutyl]-1H-pyrazol-3-yl}-2-naphthalen-1-yl- acetamide; 012368 -81- N-{5-[c/s-3-(3-Cyano-phenyl)-cyclobutyl]-2H-pyrazol-3-yl}-2-(4-methoxy-phenyl)- acetamide; N-{5-[c/s-3-(2-Cyano-phenyl)-cyclobutyl]-2H-pyrazol-3-yl}-2-(4-methoxy-phenyl)- acetamide; N-{5-[c/s-3-(3-Amino-phenyl)-cyclobuty[]-2H-pyrazol-3-yl}-2-(4-methoxy-phenyl)- acetamide; 4-(c/s-3-{5-[2-(4-Methoxy-phenyl)-acetylamino]-1H-pyrazol-3-yl}-cyclobutyl)-benzoicacid methyl ester; N-{5-[c/s-3-(4-HydroxymethyI-phenyl)-cyclobutyl]-2H-pyrazol-3-yl}-2-(4-methoxy- phenyi)-acetamide; N-{5-[c/s-3-(2-Hydroxy-phenyl)-cyclobutyl]-1H-pyrazol-3-yl}-2-phenyl-acetamide·, N-{5-[c/s-3-(2-Hydroxy-phenyl)-cyclobutyI]-1H-pyrazo!-3-yl}-2-quinolin-6-yl-acetamide; N-{5-[cfe-3-(2-Hydroxy-phenyl)-cyclobutyi]-1H-pyrazol-3-yl}-acetamide;
Cyclopropanecarboxylic acid {5-[c/s-3-(2-hydroxy-phenyl)-cyclobutyl]-1 H-pyrazol-3-yl}-amide; N-{5-[c/s-3-(2-Hydroxy-phenyl)-cyclobutyl]-1 H-pyrazoi-3-yl}-isobutyramide;N-{5-[c/s-3-(3-Aminomethyl-phenyl)-cyclobutyl]-2H-pyrazol-3-yl}-2-(4-methoxy- pheny!)-acetamide; N-{5-[c/s-3-(3-Dimethyiaminomethyl-phenyl)-cyclobutyl]-2H-pyrazol-3-yl}-2-(4- methoxy-phenyl)-acetamide; 3-(c/s-3-{5-[2-(4-Methoxy-phenyl)-acetylamino]-1H-pyrazol-3-yl}-cyclobutyl)-benzoicacid methyl ester; N-{5-[c/s-3-(3-Hydroxymethy(-phenyl)-cyclobutyl]-2H-pyrazol-3-yi}-2-(4-methoxy-pheny! )-acetamide; N-(5-{c/s-3-[3-(1-Hydroxy-1-methyl-ethyl)-phenyl]-cyclobiityl}-2H~pyrazol-3-yl)-2-(4- methoxy-phenyl)-acetamide; N-{5-[c/s-3-(3-Ethylaminomethyl-phenyl)-cyclobutyIJ-2H-pyrazol-3-yI}-2-(4-methoxy- phenyl)-acetamide; N-{5-[c/s-3-(3-Cyclobutylaminomethyl-phenyl)-cyclobutyl]-2H-pyrazoI-3-yl}-2-(4- methoxy-phenyt)-acetamide; 2-{4-Methoxy-phenyl)-N-{5-[c/s-3-(3-propylaminomethyl-phenyl)-cyclobutyl]-2H- pyrazol-3-yl}-acetamide; N-{5-[c/s-3-(3-Cyclopentylaminomethyl-phenyl)-cyclobutyl]-2H-pyrazol-3-yl}-2-(4- methoxy-phenyi)-acetamide; N-(5-{c/s-3-[3-(Benzylarnino-methyl)-phenyl]-cyclobutyl}-2H-pyrazol-3-yl)-2-(4- methoxy-phenyl)-acetamide; 012368 -82- 2-(4-Mefhoxy-pheny()-N-{5-[3-(3-methylaminomethyl-phenyl)-cyciobutyi]-2H-pyrazol- 3-yl}-acetamide; N-{5-[c/s-3-(3-Cyclopropylaminomethyl-phenyi)-cyclobutyî]-2H-pyrazol-3-yl}-2-(4- methoxy-phenyl)-acetamide; 5 2-(4-Methoxy-phenyl)-N-{5-[c/s-3-(3-pyrroiidin-1-ylmethyl-phenyi)-cyclobutyl]-2H- pyrazol-3-yl}-acetamide; N-{5-[c/s-3-(3-Diethy]aminomethyl-phenyl)-cyclobutyl]-2H-pyrazol-3-yl}-2-(4-methoxyphenyl)-acetamide; and N-{5-[cZs-3-(3-Azetidin-1-ylmethyl-phenyl)-cyclobutyl]-2H-pyrazoI-3-yl}-2-(4-methoxy-10 phenyl)-acetamide.

Claims (14)

012368 -83- CLAIMS What is claimed is:
1. A compound of the formula
2-Naphthalen-1-yl-N-[5-(c/s-3-pyridin-3-yl-cyclobutyl)-2H-pyrazol-3-yl]-acetamide; N-[5-(c/s-3-Naphthalen-2-yl-cyclabiityl)-2H-pyrazol-3-yl]-2-pyridin-3-yl-acetamide; N-(5-lndan-2-yl-1H-pyrazol-3-yl)-2-quinolin-6-yl-acetamide; N-[5-(c/s-3-Pyridin-2-yl-cyclobutyl)-2H-pyrazol-3-yl]-2-quinoIin-6-yl-acetamide; N-[5-(c/s-3-Pyridin-2-yl-cyclobutyl)-2H-pyrazo!-3-yl]-2-quinolin-6-yl-acetamide; 2-(4-Methoxy-phenyl)-N-[5-(c/s-3-pyridin-4-yl-cyclobutyl)-2H-pyrazol-3-yl]-acetamide; 012368 -90- N-{5-[3-(c/s-2-Dimethylaminomethyl-phenyl)-cyclobutyl]-2H-pyrazol-3-yl}-2-(4- methoxy-phenyl)-acetamide; N-(5-{c/s-3-[3-(2-Dimethylamino-ethoxy)-phenyI]-cyclobutyl}-2H-pyrazol-3-yl)-2-(4- methoxy-phenyl)-acetamide; N-{5-[c/s-3-(2-Hydroxy-phenyl)-cyclobutylJ-2H-pyrazol-3-yl}-2-(4-methoxy-phenyl)- acetamide; N-(5-{c/s-3-[2-(2-Dimethylamino-ethoxy)-phenyl]-cyclobutyl}-2H-pyrazol-3-yl)-2-(4- methoxy-pheny!)-acetamide; 2-(4-Methoxy-phenyl)-N-[5-(c/s-3-phenyl-cyclobutyl)-2H-pyrazpl-3-yl]-acetamide; N-{5-[c/s-3-(2-Fluoro-phenyl)-cyclobutyl]-2H-pyrazol-3-yl}-2-(4-methoxy-phenyI)- acetamide; N-(5-{c/s-3-[4-(Azetidin~3-yloxy)-phenyl]-cyc!obutyl}-2H-pyrazoI-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-[c/s-3-(2-methylsuifanyl-phenyl)-cyclobutylJ-2H-pyrazol-3 yi}-acetamide; N-{5-[c/s-3-(2-Amino-phenyl)-cyclobutyl]-2H-pyrazol-3-yl}-2-(4-methoxy-phenyl)- acetamide; N-{5-[c/s-3-(4-Cyano-phenyl)-cyclobutyl]-2H-pyrazol-3-yl}-2-(4-methoxy-phenyl)- acetamide; N-{5-[c/s-3-(2-Cyano-phenyl)-3-hydroxy-cyclobutyl]-2H-pyrazol-3-yl}-2-(4-methoxy- phenyl)-acetamide; N-{5-[c/s-3-(2-Hydroxy-ethyl)-cyclobutyl]-1H-pyrazol-3-yi}-2-naphthaien-1-yl- acetamide; N-{5-[c/s-3-(3-Cyano-phenyl)-cyciobutyl]-2H-pyrazol-3-yl}-2-(4-methoxy-phenyl}- acetamide; N-{5-[c/s-3-(2-Cyano-phenyl)-cyclobutyl]-2H-pyrazol-3-yl}-2-(4-methoxy-phenyl)- acetamide; N-{5-[c/s-3-(3-Amino-phenyl)-cyclobutyl]-2H'pyrazol-3-yl}-2-(4-methoxy-phenyl)- acetamide; 4-(c/s-3-{5-[2-(4-Methoxy-phenyl)-acetylamino]-1H-pyrazol-3-yl}-cyclobutyl)-benzoicacid methyl ester; N-{5-[c/s-3-(4-Hydroxymethyl-phenyl)-cyclobutyl]-2H-pyrazol-3-yl}-2-(4-methoxy- phenyl)-acetamide; N-{5-[c/s-3-(2-Hydroxy-phenyl)-cyciobutyl]-1H-pyrazol-3-yl}-2-phenyl-acetamide; 012368 -91- N-{5-[c/s-3-{2-Hydroxy-phenyl)-cyclobutyl]-1H-pyrazol-3-yt}-2-quinolin-6-yi-acetamide;N-{5-[c/s-3-(2-Hydroxy-phenyl)-cyciobutyl]-1H-pyrazol-3-yl}-acetamide;Cyclopropanecarboxylic acid {5-[cis-3-(2-hydroxy-phenyl)-cyclobutyl]-1 H-pyrazol-3- yl}-amide; N-{5-ic/s-3-(2-Hydroxy-phenyl)-cyclobutyi]-1H-pyrazol-3-yl}-isobutyramide; N-{5-[c/s-3-(3-Aminomethyl-phenyl)-cyclobutyl]-2H-pyrazol-3-yl}-2-(4-methoxy- phenyi)-acetamide; N-{5-[c/s-3-(3-Dimethyfarninomethyl-phenyi)-cyclobutylJ-2H-pyrazol-3-yl}-2-(4- methoxy-phenyi)-acetamide; 3-(c/s-3-{5-[2-(4-Methoxy-phenyl)-acetylamino]-1H-pyrazol-3-yl}-cyclobutyl)-benzoicacid methyl ester; N-{5-[c/s-3-(3-Hydroxymethyl-phenyl)-cyclobutylJ-2H-pyrazo(-3-yl}-2-(4-methoxy- phenyl)-acetamïde; N-(5-{cfe-3-£3-(1-Hydroxy-1-methyl-ethyl)-phenyl]-cyclobutyl}-2H-pyrazoI-3-yl)-2-(4- methoxy-phenyl)-acetamide; N-{5-[cZs-3-(3-Ethylaminomethyl-phenyl)-cyclobutylJ-2H-pyrazol-3-yl}-2-(4-methoxy-phenyl)-acetamide; - ' N-{5-[c/s-3-(3-Cyclobutylaminomethyl-phenyl)-cyclobutyl]-2H-pyrazoi-3-yl}-2-(4- methoxy-phenyl)-acetamide; 2-(4-Methoxy-phenyl)-N-{5-[c/s-3-(3-propylarninornethyI-phenyl)-cyclobutyl]-2H- pyrazol-3-yl}-acetamide; N-{5-[c/s-3-(3-Cyclopentylaminomethyl~phenyl)-cyclobutyl]-2H-pyrazol-3-yl}-2-(4- methoxy-phenyl)-acetamide; N-(5-{c/s-3-[3-(Benzylamino-methyl)-phenyl]-cyclobutyl}-2H-pyrazol-3-yl)-2-(4- methoxy-pbenyl)-acetamide; 2-(4-Methoxy-phenyl)-N-{5-[3-(3-methylaminomethyl-phenyl)-cyclobutyi]-2H-pyrazol- 3-yl}-acetamide; N-{5-[c/s-3-(3-Cyclopropylaminomethyl-phenyl)-cyclobutyl]-2H-pyrazol-3-yl}-2-(4- methoxy-phenyl)-acetamide; 2-(4-Metboxy-phenyl)-N-{5-(c/s-3-(3-pyrrolidin-1-ylmethyl-phenyl)-cyclobutyI]-2H- pyrazol-3-yl}-acetamide; N-{5-£c/s-3-(3-Diethylaminomethyl-phenyl)-cyciobutyl]-2H-pyrazol-3-yl}-2-(4-methoxy- phenyl)-acetamide; N-{5-(c/s-3-(3-Azetidin-1-ylmethyl-phenyl)-cyclobutyl]-2H-pyrazol-3-yl}-2-(4-methoxy-phenyl)-acetamrde; and pharmaceutically acceptable salts of the foregoing compounds. 012368 -92-
2. A compound according to claim 1, wherein R3 is -(CR’°R”)n-,-C(=O)NH- or -C(=O)(CR’°R”)n-.
3. A compound according to claim 1, wherein R’ is optionally substituted(C3-Ce)cycloalkyl or optionally substituted (Cs-C.,,) bicycloalkyl. •v 012368 -85-
4. A compound according to claim 3, wherein R’ is cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, norbornyl, or bicyclo-[3.1.0]-hexyl, each optionallysubstituted.
5. A compound according to claim 1, wherein R1 is optionally substituted5 straight chain or branched (C,-C0)alkyl or optionally substituted straight Chain or branched (C2- C8)alkenyl.
6. A compound according to claim 1, wherein R4 is (C6-C,4)aryl or (5-14membered) heteroaryl, each optionally substituted.
7. A compound according to claim 6, wherein R4 is phenyl, pyridyl,10 naphthyl, quinolyl, isoquinolyl, pyrimidinyl, pyrazinyl, or pyridazyl, each optionally substituted.
8 A compound according to any of ciaims 1-7, wherein R2 is hydrogen.
9. A compound of claim 1, selected from the group consisting of:(5-ethyl-2H-pyrazol-3-yl)-(6-methoxy-pyridin-2-yI)-amïne;(5-cyclobutyl-2H-pyrazol-3-yl)-(6-methoxy-pyridin-2-yl)-amine 15 (5-cyclobutyl-2H-pyrazol-3-yl)-naphthalen-2-yl-amine; (5-cyclobutyl-2H-pyrazol-3-yl)-naphthalen-1 -yl-amine;N-ÎS-cyclobutyl^H-pyrazol-S-yO-N’.N'-dimethyl-naphthalene-M-diamine;N-(5-cyclobutyl-2H-pyrazol-3-yl)-N',N'-dimethyl-pyridine-2,6-diamine;(5-cyclobutyl-2H-pyrazoI-3-yl)-(6-trifluoromethyl-pyridin-2-yl)-amine; 20 (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-yI)-N',N’-dimethyl-benzene-1,3-diamine; (5-cyclobutyl-2H-pyrazol-3-yl)-(3-methoxy-phenyl)-amine; (5-cyclobutyI-2H-pyrazol-3-yl)-(4-nitro-phenyl)-amine; 25 (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; 30 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-cyciobutyl-2H-pyrazol-3-yl)-(3-trifluoromethoxy-phenyl)-amine; (2-chloro-4-nitro-phenyl)-(5-cyclobutyl-2H-pyrazol-3-yl)-amine; 3-frans-[5-(3-trifiuoromethyl-phenylamino)-2H-pyrazol-3-yI]-cyclopentanoi; 35 (3,5-bis-trifiuoromethyl-phenyI)-(5-cyclobutyl-2H-pyrazol-3-yl)-amine; (5-(3-c/s-benzylamino-cyclopentyl)-1H-pyrazol-3-yl]-(3-trifluoromethyl-phenyl)-amine; 012368 Λ ' -86- {5-[3-c/s-(4-methoxy-benzylamino)-cyclopentyl]-1K-pyrazol-3-yl}-(3-trifluoromethyl- phenyl)-amine; 4-(5-cyclobutyl-2H-pyrazol-3-ylamino)-benzonitrile; (5-cyclobutyl-2H-pyrazol-3-yl)-(3-fluoro-phenyl)-amine; 5 (5-cyclobutyl-2H-pyrazol-3-yl)-(3,5-dichloro-phenyl)-amine; (2-bromo-phenyl)-(5-cyclobutyl-2H-pyrazol-3-yl)-amine; N-{c/s-3-[5-(3-trifluoromethyl-pheny!amino)-2H-pyrazol-3-yl]-cyclopentyl}-acetamide; pyridin-2-yl-{3-irans-[5-(3-trifluoromethyl-phenylamino)-2H-pyrazol-3-yl]-cyclopentyl}- amine; 10 (5-cyclobutyl-1 H-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; 15 cyclobutanecarboxylic acid {3-[5-(3-trifluoromethyl-phenylamino)-2H-pyrazol-3-yl]- cyclopentyl}-amide; 2.2- dimethyl-N-{3-[5-(3-trifluoromethyl-phenyiamino)-2H-pyrazol-3-yl]-cyclopentyl}-propionamide; 4- fluoro-N-{3-[5-(3-trtfluoromethy(-phenylamino)-2H-pyrazol-3-yl]-cyclopentyl}-20 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; 25 N-{3-[5-(3-trifluoromethyl-phenylamino)-2H-pyrazol-3-yl]-cyclopentyl}-propionamide; cyclohexanecarboxylic acid {3-[5-(3-trifluoromethyl-phenylamino)-2H-pyrazol-3-yl]- cyclopentylj-amide; N-[5-(3-acetylamino-cyclopentyl)-2H-pyrazol-3-yl]-2-naphthalen-1-yl-acetamide;cyclopropanecarboxylic acid {3-[5-(2-naphthalen-1 -yl-acetylamino)-1 H-pyrazol-3-yI]- 30 cyclopentylj-amide; 2-naphthalen-1-yl-N-{5-[3-(2,2I2-trifluoro-acetylamino)-cyclopentyl3-2H-pyrazol-3-yl}- acetamide; N-{3-[5-(2-naphthalen-1-yl-acetylamino)-1H-pyrazol-3-yl]-cyclopentyI}-benzamide; N-(5-hydroxymethyl-1H-pyrazol-3-yl)-2-naphthalen-1-yl-acetamide; 2-naphthalen-1 -yl-N-[5-(thiazol-2-ylarninomethyl)-1 H-pyrazol-3-yl]-acetamide; N-[5-({1S)-hydroxy-ethyl}-2H-pyrazo!-3-yl]-2-napbthalen-1-yl-acetamide; 012368 PC’ -37- N-{5-[(1S)-(benzooxazo(-2-yloxy)-eihyf]-'!H-pyrazol-3-yl}-2-naphihalen-1-yl- acetamide; N-{5-[(1S)-(benzothiazol-2-yloxy)-ethyl]-1H-pyrazol-3-y.l}-2-naphthalen-1-yi- 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-(benzothiazot-2-yloxy)-1 -methyl-propyl]-1 H-pyrazol-3-yl}-2-naphtha!en-1 -yl- acetamide; N-[5-(2-hydroxy-(1S)-methyl-ethyi)-2H-pyrazol-3-yl]-2-naphthalen-1-yl-acetamide; N-{5-[(1R)-(benzothiazol-2-yioxy)-ethyl]-1H-pyrazol-3-yl}-2-naphthalen-1-yl- acetamide; N-[5-(3-acetylamino-1-methyl-propyl)-1 H-pyrazol~3-yl]-2-naphthalen-1-yl-acetamide; 3- methoxy-N-{c/s-3-[5-(2-naphthalen-1-yi-acetylamino)-2H-pyrazol-3-yl]-cyclobutyI}-benzamide; N-[5-(c/s-3-acetylamino-cyciobutyl)-1H-pyrazol-3-yI]-2-naphthalen-1-yl-acetamide;N-{c/s-3-[5-(2-naphthalen-1-yl-acetylamino)-2H-pyrazol-3-yl]-cyclobutyl}-benzamide;2-cyclopropyl-N-{c/s-3-[5-(2-naphthalen-1 -yl-acetylamino)-2H-pyrazol-3-yl]- cyclobutyl}-acetamide; 6-chloro-pyridine-2-carboxylic acid {c/s-3-[5-(2-naphthalen-1 -yl-acetylamino)-2H pyrazol-3-yl]-cyclobutyl}-amide; quinoiine-2-carboxylic acid {c/s-3-[5-(2-naphthalen-1 -yl-acetylamino)-2H-pyrazo!-3-yl]cyciobutyij-amide; pyrazine-2-carboxylic acid {c/s-3-[5-(2-naphthalen-1-yl-acetylamino)-2H-pyrazol-3-yl]cyclobutyl}-amide; 4- methoxy-N-{cfs-3-[5-(2-naphthalen-1-yl-acetyiamino)-2H-pyrazol-3-yI]-cyclobutyl}-benzamide; N-{c/s-3-[5-(2-naphthalen-1-yl-acetylamino)-2H-pyrazol-3-yl]-cyclobutyl}-3-nitro- benzamide; N-{cfs-3-[5-(2-naphthalen-1-yl-acetylamino)-2H-pyrazol-3-yl]-cyclobutyl}-3- trifluoromethyl-benzamide; N-{c/s-3-[5-(2-naphthalen-1-yl-acetylamino)-2H-pyrazol-3-yl]-cyclobutyi}- isobutyramide; 2-phenyl-cyclopropanecarboxylic acid {c/s-3-[5-(2-naphthalen-1 -yl-acetylamino)-2HpyrazoI-3-yl]-cyclobutyl}-amide; N-{5-[c/'s-3-(benzooxazol-2-yloxy)-cyclobutyl]-1H-pyrazol-3-yJ}-2-naphthalen-1-yl- acetamide; 012368 -88- 4-dimethylamino-N-{cfs-3-[5-(2-naphthalen-1-yl-acetylamino)-2H-pyrazol-3-yl]- cyclobutyl}-benzamide; 3l5-dimethoxy-N-{c/'s-3-[5-(2-naphthalen-1-yl-acetylamino)-2H-pyrazol-3-yl]- cyclobutylj-benzamide; 2-naphtha!en-1-yl-N-[5-(c/s-3-phenyl-cyclobutyl)-2H-pyrazol-3-yl]-acetamide; N-{5-[cfs-3-(3-metboxy-phenyl)-cyclobutyi]-2H-pyrazol-3-yl}-2-naphthalen-1-yl- aœtamide; N-{5-[c/s-3-(2-methoxy-phenyl)-cyclobutyl]-2H-pyrazol-3-yl}-2-naphthalen-1-yl- acetamide; N-{5-[c/s-3-(4-methoxy-phenyl)-cyclobutyl]-2H-pyrazol-3-yl}-2-naphthalen~1-yi- acetamide; 2-naphthalen-1-yl-N-[5-(c/s-3-p-toIyl-cyclobutyl)-2H-pyrazol-3-yl]-acetamide; N-{5-[c/s-3-(4-chloro-phenyl)-cyclobutyl]-2H-pyrazol-3-yl}-2-naphthalen-1-yl- acetamide; 2-(4-methoxy-phenyl)-N-{5-[c/s-3-(2-methoxy-phenyi)-cyclobutyl]-2H-pyrazol-3-yl}- acetamide; N-{5-[c/s-3-(2-methoxy-phenyl)-cyclobutyl]-2H-pyrazol-3-yl}-2-quinolin-6-yi-acetamide; N-{5-[c/s-3-(2-methoxy-phenyl)-cyclobutyl]-2H-pyrazol-3-yl}-2-phenyl-acetamide; N-{5-[cjs-3-(2-methoxy-phenyl)-cyclobutyi]-2H-pyrazol-3-yl}-2-pyridin-3-yl-acetamide; N-{5-[c/s-3-(4-methoxy-phenyi)-cyclobutyi]-1H-pyrazol-3-yl}-2-quinolin-6-yl-acetamide; 2-quinoiin-6-yl-N-[5-(c/s-3-p-tolyl-cyclobutyl)-1H-pyrazol-3-yl]-acetamide; N-{5-[c/s-3-(4-fIuoro-pheny[)-cyclobutyl]-1H-pyrazoi-3-y(}-2-quinolin-6-yl-acetamide; N-{5-[c/s-3-(4-chloro-phenyl)-cyclobutyl]-1H-pyrazoi-3-yl}-2-quinolin-6-yl-acetamide; 2-quinolin-6-yl-N-[5-(c/s-3-m-tolyl-cyclobutyl)-1H-pyrazol-3-yl]-acetamide; 4-dimethylamino-N-{c/s-3-[5-(2-naphthalen-1-yl-acetylamino)-2H-pyrazol-3-yl]- cyclobutylj-benzamide; 2-naphthalen-1-yl-N-{5-[c/s-3-(pyridin-2-yloxy)-cyciobutyl]-1H-pyrazol-3-yl}-acetamide;6-methyl-pyridine-2-carboxylic acid {c/s-3-[5-(2-naphthalen-1 -yl-acetylamino)-2H- pyrazol-3-yl]-cyclobutyl}-amïde; 2-phenyl-cyclopropanecarboxylic acid methyl-{c/s-3-[5-(2-naphthalen-1 -yl-acetylamino)-2H-pyrazol-3-yl]-cyclobutyl}-amide; N-{5-[cZs-3-(3-methyl-pyrazin-2-yloxy)-cyclobutyl]-1H-pyrazol-3-yl}-2-naphthalen-1-yl- acetamide; {5-[c/s-3-(2-methoxy-phenyl)-cyciobutyl]-1H-pyrazol-3-yl}-(6-methoxy-pyridin-2-yl)- amine; 012368 -89- N-{5-[ciS-3-(3,6-dimethyl-pyrazin-2-yloxy)-cyclobutyl]-1H-pyrazol-3-yl}-2-napbthalen- 1-yl-acetamide; N-{5-[c/s-3-(3-methoxy-pyridin-2-yloxy)-cyclobutyl}-1 H-pyrazol-3-yl}-2-naphthalen-1-yl-acetamide; 2-methyl-cyclopropanecarboxylic acid {c/s-3-[5-(2-naphthalen-1 -yl-acetylamino)-2Hpyrazol-3-y!J-cyclobutyl}-amide; 2-naphihalen-1-yl-N-{5-[c/s-3-(3-trifluoromethyl-pyridin-2-yloxy)-cyclobuiy(]-1H- pyrazol-3-yl}-acetamide; 2-naphthalen-1 -yl-N-{5-[c/'s-3-(3-nitro-pyridin-2-yioxy)-cyclobutyl)- 1 H-pyrazol-3-yl} acetamide; N-{5-[c/s-3-(benzothiazol-2-yloxy)-cyclobutyl]-1H-pyrazol-3-yl}-2-naphthalen- 1-yl-acetamide; 2-naphthalen-1-yl-N-{5-[c/s-3-(4-trifluoromethyl-pyrimidin-2“yloxy)- cyclobutyl]-1 H·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]-1 H-pyrazol-3- yl}-acetamide; N-{5-[3-(6-methoxy-pyridazin-3-yloxy)-cyclobutyl]-1H-pyrazol-3-yl}-2-naphthalen-1-yI- 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-chioro-benzothiazol-2-yloxy)-cyclobiityl]-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-[c/s-3-(4-Hydroxy-phenyl)-cyclobutyl]-1H-pyrazol-3-yl}-2-quinoIin-6-yl-acetamide; N-{5-[c/s-3-(3-Hydroxy-phenyl)-cyclobutyl]-1H-pyrazol-3-yl}-2-quinolin-6-yl-acetamide;
10. A pharmaceutical composition for treating a disease or condition comprisingabnormal cell growth or a neurodegenerative disease or condition in a mammal comprising acompound of claim 1 in an amount effective in treating said disease or condition, and apharmaceutically acceptable carrier.
10 15 20 25 wherein R1 is a straight Chain or branched (C,-C8)alkyl, a straight chain or branched (C2-C8)alkenyl, a straight chain or branched (C2-C8)alkynyl, (C3-C8)cycioalkyl, (C4-C8)cycloalkenyl, (3-8 membered) heterocycloalkyl, (C5-Cn)bicycloalkyl, (C7-C„)bicycloalkenyj, or (5-11 membered)heterobicycloalkyl, and wherein R1 is optionally substituted with from one to six substituents Rsindependently 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)2NR7Rb, and R7; R2 is H, F, -CH3, -CN, or -C(=O)OR7; R3 is -C(=O)NR9-, -C(=O)O-, -C(=O)(CR10R11)„-, or -(CR10R11)„-; R4 is a straight chain or a branched (C^^lkyl, a straight chain or a branched (C2-C8)alkenyl, a straight chain or branched (C2-C8 alkynyl), (C3-C8)cycloalkyl, (C4-C8)cycloalkenyl,(3-8 membered) heterocycloalkyl, (C5-Cn)bicycloalkyl, (C7-C11)bicycloalkenyl, (5-11 membered)heterobicycloalkyl, (C6-C14)aryl, or (5-14 membered) heteroaryl; and wherein R4 is optionallysubstituted with from one to three substitutents R6 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(=0)NR7R8, -OC(=O)SR7, -SR7, -S(=O)R7, -S(=O)2R7, -S(=O)2NR7R8, or R7; each R7, R8, and R9 is independently selected from H, straight chain or branched (C,-C8)alkyl, straight chain or branched (C2-C8)alkenyl, straight chain or branched (C2-C8 alkynyl),(C3-C8)cycloalkyl, (C4-C8)cycloalkenyl, (3-8 membered) heterocycloalkyl, (C5-C„)bicycloalkyl,(C7-C11)bicycloalkenyl, (5-11 membered) heterobicycloalkyl, (C6-C14)aryl, and (5-14 membered)heteroaryl, wherein R7, R8, and R9 are each independently optionally substituted with from one tosix 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)OR’°, -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; 30 0.12368 -84- or, when R7 and R8 are as in NR7RB, they may instead optionally be connected to formwith the nitrogen of NR7R8 to which they are attached a heterocycloalkyl moiety of from three toseven ring members, said heterocycloalkyl moiety optionally comprising one or two furtherheteroatoms independently selected from N, O, and S; each R10, R11, and R12 is independently selected from H, straight chain or branched (C,-Ce)alkyl, straight chain or branched (C2-Cs)alkenyl, straight chain or branched (C2-C8 alkynyl),(C3-Ca)cycloalkyl, (C4-C8)cycloalkenyl, (3-8 membered) heterocycloalkyl, (Cs-CjJbicycloalkyl,(Cj-CuJbicycloalkenyl, (5-11 membered) heterobicycloalkyi, (C6-C14)aryl, and (5-14 membered)heteroaryl, wherein R10, R11, and R12 are each independently optionally substituted with from oneto six substituents independently selected from F, Cl, Br, l, NO2, -CN, -CF3, -NR’3R'4,-NR’3C(=O)R’4, -NR’3C(=O)OR’4, -NR’3C(=O)NR’4R’s, -NR’3S(=O)2R’4; -NR’3S(=O)2NR’4R’s,-OR’3, -OC(=O)R’3, -OC(=O)OR13, -OC(=O)NR’3R’4, -OC(=O)SR13, -SR’3, -S(=O)R13,-S(=O)2R’3, -S(=O)2NR’3R’4, -C(=O)R’3, -C(=O)OR’3, -C(=O)NR’3R14, and R’3; each R13, R’4, and R’5 is independently selected from H, straight chain or branched (C,-C8)alkyl, straight chain or branched (C2-C8)alkenyl, straight chain or branched (C2-C8 alkynyl),(C3-C8)cycloalkyl, (C4-CB)cycloalkenyl, (3-8 membered) heterocycloalkyl, (Cs-CuJbicycloalkyl,(C7-Cn)bicycloalkenyl, (5-11 membered) heterobicycloalkyi, (C6-C14)aryl, and (5-14 membered)heteroaryl, wherein R’3, R’4, and R’5 are each independently optionally substituted with from oneto six substituents independently selected from F, Cl, Br, i, NO2, -CN, -CF3, -NR’6R’7,-NR16C(=O)R’7, -NR’6C(=O)OR’7, -NR16C(=O)NR’7R’8, -NR’6S(=O)2R’7, -NR’6S(=O)2NR17R’8-OR’6, -OC(=O)R’6, -OC(=O)OR’6, -OC(=O)NR’6R’7, -OC(=O)SR’6, -SR16, -S(=O)R(Ü, -S(=O)2R16, -S(=O)2NR’6R’7, -C(=O)R’6, -C(=O)OR1B, -C(=O)NR’6R’7, and R’6 each R16, R’7, and R18 fs independently selected from H, straight chain or branched (C,-C8)alkyl, straight chain or branched (C2-C8)alkenyl, straight chain or branched (C2-C8 alkynyl),(C3-CB)cycloalkyl, (C4-C8)cycloalkenyl, (3-8 membered) heterocycloalkyl, (C5-CI1)bicycloalkyl,(C7-Cn)bicycloalkenyl, (5-11 membered) heterobicycloalkyi, (C6-C14)aryl, and (5-14 membered)heteroaryl; n is 0,1,2, or 3; wherein R’° and R” in -C(=O)(CR’°R”)n- and -(CR’°R”)n- are for each itération of ndefined independently as recited above; or a pharmaceutically acceptable sait thereof.
11. A pharmaceutical composition for treating a disease or condition in a mammalthe treatment of which can be effected or facilitàted by altering dopamine mediatedneurotransmission comprising a compound of claim 1 in an amount effective in treating saiddisease or condition or in an amount effective to inhibit cdk5 activity, and a pharmaceuticallyacceptable carrier.
12. A pharmaceutical composition for tre.ating in a mammal a disease or conditionselected from male fertility and sperm.motility; diabètes mellitus; impaired glucose tolérance;metabolic syndrome or syndrome X; polycystic ovary syndrome; adipogenesis and obesily;myogenesis and frailty, for example age-related décliné in physical performance; acutesarcopenia, for example muscle atrophy and/or cachexia associated with burns, bed rest, limbimmobilization, or major thoracic, abdominal, and/or orthopédie surgery; sepsis; hair loss, hairthinning, and balding; and immunodeficiency, comprising a compound of claim 1 in an amounteffective in treating said disease or condition, and a pharmaceutically acceptable carrier.
13. A pharmaceutical composition comprising a compound according to claim 1and a second member selected from the group consisting of an SSRI, an NK-1 receptorantagonist, a 5HT1D antagonist, ziprasidone, olanzapine, rispéridone, L-745870,sonepiprazole, RP 62203, NGD 941, balaperidone, flesinoxan, gepirone, anacetylcholinesterase inhibitor, TPA, NIF, a potassium channel modulator such as BMS-204352, and an NMDA receptor antagonist, wherein the cdk5 inhibitor and the secondmember are together in an effective amount, and a pharmaceutically acceptable carrier.
14. A compound of the formula
wherein Prot is a protecting group; R2 is H, F, -CH3, -CN, or -C(=O)OR7; and n is an integer selected from 1, 2, 3, and 4.
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