ZA200301064B - Pyrazole derivatives and their use as protein kinase inhibitors. - Google Patents
Pyrazole derivatives and their use as protein kinase inhibitors. Download PDFInfo
- Publication number
- ZA200301064B ZA200301064B ZA200301064A ZA200301064A ZA200301064B ZA 200301064 B ZA200301064 B ZA 200301064B ZA 200301064 A ZA200301064 A ZA 200301064A ZA 200301064 A ZA200301064 A ZA 200301064A ZA 200301064 B ZA200301064 B ZA 200301064B
- Authority
- ZA
- South Africa
- Prior art keywords
- pyrazol
- cyclobutyl
- acetamide
- phenyl
- cis
- Prior art date
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- 229940045988 antineoplastic drug protein kinase inhibitors Drugs 0.000 title description 2
- 239000003909 protein kinase inhibitor Substances 0.000 title description 2
- 150000003217 pyrazoles Chemical class 0.000 title description 2
- DLFVBJFMPXGRIB-UHFFFAOYSA-N thioacetamide Natural products CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 59
- 150000001875 compounds Chemical class 0.000 claims description 56
- 125000003118 aryl group Chemical group 0.000 claims description 21
- 150000001602 bicycloalkyls Chemical group 0.000 claims description 19
- 125000001072 heteroaryl group Chemical group 0.000 claims description 19
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 18
- -1 methoxy-phenyl Chemical group 0.000 claims description 18
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 17
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 17
- 229910052731 fluorine Inorganic materials 0.000 claims description 16
- 125000000217 alkyl group Chemical group 0.000 claims description 15
- 201000010099 disease Diseases 0.000 claims description 15
- 125000000304 alkynyl group Chemical group 0.000 claims description 14
- 230000002159 abnormal effect Effects 0.000 claims description 13
- 229910052739 hydrogen Inorganic materials 0.000 claims description 13
- 229910052794 bromium Inorganic materials 0.000 claims description 12
- 229910052799 carbon Inorganic materials 0.000 claims description 12
- 229910052801 chlorine Inorganic materials 0.000 claims description 12
- 150000003839 salts Chemical class 0.000 claims description 12
- 125000001424 substituent group Chemical group 0.000 claims description 12
- 230000010261 cell growth Effects 0.000 claims description 11
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 11
- 125000005842 heteroatom Chemical group 0.000 claims description 11
- 101150053721 Cdk5 gene Proteins 0.000 claims description 10
- 125000003342 alkenyl group Chemical group 0.000 claims description 10
- 229910052740 iodine Inorganic materials 0.000 claims description 10
- 241000124008 Mammalia Species 0.000 claims description 9
- 239000001257 hydrogen Substances 0.000 claims description 9
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 8
- 230000000694 effects Effects 0.000 claims description 8
- 239000003112 inhibitor Substances 0.000 claims description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims description 8
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 7
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 7
- LTUUGSGSUZRPRV-UHFFFAOYSA-N 6-methylpyridine-2-carboxylic acid Chemical compound CC1=CC=CC(C(O)=O)=N1 LTUUGSGSUZRPRV-UHFFFAOYSA-N 0.000 claims description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 6
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 6
- YMGUBTXCNDTFJI-UHFFFAOYSA-N cyclopropanecarboxylic acid Chemical compound OC(=O)C1CC1 YMGUBTXCNDTFJI-UHFFFAOYSA-N 0.000 claims description 6
- 208000015122 neurodegenerative disease Diseases 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- KXDAEFPNCMNJSK-UHFFFAOYSA-N benzene carboxamide Natural products NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 claims description 5
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 5
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 5
- 239000003937 drug carrier Substances 0.000 claims description 5
- 125000002868 norbornyl group Chemical group C12(CCC(CC1)C2)* 0.000 claims description 5
- 229910052760 oxygen Inorganic materials 0.000 claims description 5
- 229910052717 sulfur Inorganic materials 0.000 claims description 5
- AHDDRJBFJBDEPW-UHFFFAOYSA-N 2-phenylcyclopropane-1-carboxylic acid Chemical compound OC(=O)C1CC1C1=CC=CC=C1 AHDDRJBFJBDEPW-UHFFFAOYSA-N 0.000 claims description 4
- NZNMSOFKMUBTKW-UHFFFAOYSA-N cyclohexanecarboxylic acid Chemical compound OC(=O)C1CCCCC1 NZNMSOFKMUBTKW-UHFFFAOYSA-N 0.000 claims description 4
- 206010012601 diabetes mellitus Diseases 0.000 claims description 4
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 claims description 4
- 125000005956 isoquinolyl group Chemical group 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- 229940080818 propionamide Drugs 0.000 claims description 4
- 125000006239 protecting group Chemical group 0.000 claims description 4
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 4
- 125000004289 pyrazol-3-yl group Chemical group [H]N1N=C(*)C([H])=C1[H] 0.000 claims description 4
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 4
- 125000005493 quinolyl group Chemical group 0.000 claims description 4
- 201000004384 Alopecia Diseases 0.000 claims description 3
- METKIMKYRPQLGS-UHFFFAOYSA-N atenolol Chemical compound CC(C)NCC(O)COC1=CC=C(CC(N)=O)C=C1 METKIMKYRPQLGS-UHFFFAOYSA-N 0.000 claims description 3
- 229940047889 isobutyramide Drugs 0.000 claims description 3
- 125000001624 naphthyl group Chemical group 0.000 claims description 3
- 230000004770 neurodegeneration Effects 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- 125000005495 pyridazyl group Chemical group 0.000 claims description 3
- 125000004076 pyridyl group Chemical group 0.000 claims description 3
- 230000019100 sperm motility Effects 0.000 claims description 3
- CZNBBEJUYLPARH-UHFFFAOYSA-N 2-naphthalen-1-yl-n-[5-[3-(5-nitropyridin-2-yl)oxycyclobutyl]-1h-pyrazol-3-yl]acetamide Chemical compound N1=CC([N+](=O)[O-])=CC=C1OC1CC(C=2NN=C(NC(=O)CC=3C4=CC=CC=C4C=CC=3)C=2)C1 CZNBBEJUYLPARH-UHFFFAOYSA-N 0.000 claims description 2
- MMYJHIFAWFHUFJ-UHFFFAOYSA-N 4-[(5-cyclobutyl-1h-pyrazol-3-yl)amino]benzonitrile Chemical compound C1=CC(C#N)=CC=C1NC1=CC(C2CCC2)=NN1 MMYJHIFAWFHUFJ-UHFFFAOYSA-N 0.000 claims description 2
- BMFGAFAVMNOHPA-UHFFFAOYSA-N 5-cyclobutyl-n-(4-methoxyphenyl)-1h-pyrazol-3-amine Chemical compound C1=CC(OC)=CC=C1NC1=NNC(C2CCC2)=C1 BMFGAFAVMNOHPA-UHFFFAOYSA-N 0.000 claims description 2
- AZNRZRAFNYMLPE-UHFFFAOYSA-N 5-cyclobutyl-n-(4-nitrophenyl)-1h-pyrazol-3-amine Chemical compound C1=CC([N+](=O)[O-])=CC=C1NC1=NNC(C2CCC2)=C1 AZNRZRAFNYMLPE-UHFFFAOYSA-N 0.000 claims description 2
- QHEDHOHVFPSPGJ-UHFFFAOYSA-N 5-cyclobutyl-n-naphthalen-1-yl-1h-pyrazol-3-amine Chemical compound C1CCC1C1=NNC(NC=2C3=CC=CC=C3C=CC=2)=C1 QHEDHOHVFPSPGJ-UHFFFAOYSA-N 0.000 claims description 2
- YBRQKXYABHZLBT-UHFFFAOYSA-N 5-cyclobutyl-n-naphthalen-2-yl-1h-pyrazol-3-amine Chemical compound C1CCC1C1=NNC(NC=2C=C3C=CC=CC3=CC=2)=C1 YBRQKXYABHZLBT-UHFFFAOYSA-N 0.000 claims description 2
- ZLKMOIHCHCMSFW-UHFFFAOYSA-N 6-chloropyridine-2-carboxylic acid Chemical compound OC(=O)C1=CC=CC(Cl)=N1 ZLKMOIHCHCMSFW-UHFFFAOYSA-N 0.000 claims description 2
- CJNAMFYYFJDGNQ-KDURUIRLSA-N C1=CC(O)=CC=C1[C@H]1C[C@@H](C=2NN=C(NC(=O)CC=3C=C4C=CC=NC4=CC=3)C=2)C1 Chemical compound C1=CC(O)=CC=C1[C@H]1C[C@@H](C=2NN=C(NC(=O)CC=3C=C4C=CC=NC4=CC=3)C=2)C1 CJNAMFYYFJDGNQ-KDURUIRLSA-N 0.000 claims description 2
- XJDWZCSYFDQADW-OYRHEFFESA-N C1=CC(OC)=CC=C1CC(=O)NC1=CC([C@@H]2C[C@@H](C2)C=2C=C(CN(C)C)C=CC=2)=NN1 Chemical compound C1=CC(OC)=CC=C1CC(=O)NC1=CC([C@@H]2C[C@@H](C2)C=2C=C(CN(C)C)C=CC=2)=NN1 XJDWZCSYFDQADW-OYRHEFFESA-N 0.000 claims description 2
- VCHAAEXLCHTUCS-KDURUIRLSA-N C1=CC(OC)=CC=C1CC(=O)NC1=CC([C@@H]2C[C@@H](C2)C=2C=C(CN)C=CC=2)=NN1 Chemical compound C1=CC(OC)=CC=C1CC(=O)NC1=CC([C@@H]2C[C@@H](C2)C=2C=C(CN)C=CC=2)=NN1 VCHAAEXLCHTUCS-KDURUIRLSA-N 0.000 claims description 2
- IIZBOPVDAGEFES-SZPZYZBQSA-N C1=CC(OC)=CC=C1CC(=O)NC1=CC([C@@H]2C[C@@H](C2)C=2C=C(CN3CCC3)C=CC=2)=NN1 Chemical compound C1=CC(OC)=CC=C1CC(=O)NC1=CC([C@@H]2C[C@@H](C2)C=2C=C(CN3CCC3)C=CC=2)=NN1 IIZBOPVDAGEFES-SZPZYZBQSA-N 0.000 claims description 2
- MPZJSNRIXXDLIV-KDURUIRLSA-N C1=CC(OC)=CC=C1CC(=O)NC1=CC([C@@H]2C[C@@H](C2)C=2C=C(CO)C=CC=2)=NN1 Chemical compound C1=CC(OC)=CC=C1CC(=O)NC1=CC([C@@H]2C[C@@H](C2)C=2C=C(CO)C=CC=2)=NN1 MPZJSNRIXXDLIV-KDURUIRLSA-N 0.000 claims description 2
- JVOCTXRAAATKPV-BGYRXZFFSA-N C1=CC(OC)=CC=C1[C@H]1C[C@@H](C=2NN=C(NC(=O)CC=3C=C4C=CC=NC4=CC=3)C=2)C1 Chemical compound C1=CC(OC)=CC=C1[C@H]1C[C@@H](C=2NN=C(NC(=O)CC=3C=C4C=CC=NC4=CC=3)C=2)C1 JVOCTXRAAATKPV-BGYRXZFFSA-N 0.000 claims description 2
- WFKAJVHLWXSISD-UHFFFAOYSA-N anhydrous dimethyl-acetamide Natural products CC(C)C(N)=O WFKAJVHLWXSISD-UHFFFAOYSA-N 0.000 claims description 2
- TXWOGHSRPAYOML-UHFFFAOYSA-N cyclobutanecarboxylic acid Chemical compound OC(=O)C1CCC1 TXWOGHSRPAYOML-UHFFFAOYSA-N 0.000 claims description 2
- VZFUCHSFHOYXIS-UHFFFAOYSA-N cycloheptane carboxylic acid Natural products OC(=O)C1CCCCCC1 VZFUCHSFHOYXIS-UHFFFAOYSA-N 0.000 claims description 2
- 229960003638 dopamine Drugs 0.000 claims description 2
- 208000024963 hair loss Diseases 0.000 claims description 2
- 230000003676 hair loss Effects 0.000 claims description 2
- GTQPDABHYSLSQS-UHFFFAOYSA-N n-(5-ethyl-1h-pyrazol-3-yl)-6-methoxypyridin-2-amine Chemical compound N1N=C(CC)C=C1NC1=CC=CC(OC)=N1 GTQPDABHYSLSQS-UHFFFAOYSA-N 0.000 claims description 2
- HONMLEQTEHITQP-UHFFFAOYSA-N n-[(4-chlorophenyl)methyl]-5-cyclobutyl-1h-pyrazol-3-amine Chemical compound C1=CC(Cl)=CC=C1CNC1=CC(C2CCC2)=NN1 HONMLEQTEHITQP-UHFFFAOYSA-N 0.000 claims description 2
- QVDBUAZHHAMIOE-UHFFFAOYSA-N n-[3,5-bis(trifluoromethyl)phenyl]-5-cyclobutyl-1h-pyrazol-3-amine Chemical compound FC(F)(F)C1=CC(C(F)(F)F)=CC(NC=2NN=C(C=2)C2CCC2)=C1 QVDBUAZHHAMIOE-UHFFFAOYSA-N 0.000 claims description 2
- QUZWZXFAUSJHEL-UHFFFAOYSA-N n-[5-(2,3-dihydro-1h-inden-2-yl)-1h-pyrazol-3-yl]-2-quinolin-6-ylacetamide Chemical compound C1C2=CC=CC=C2CC1C1=CC(NC(CC=2C=C3C=CC=NC3=CC=2)=O)=NN1 QUZWZXFAUSJHEL-UHFFFAOYSA-N 0.000 claims description 2
- 208000001145 Metabolic Syndrome Diseases 0.000 claims 2
- SIOXPEMLGUPBBT-UHFFFAOYSA-N picolinic acid Chemical compound OC(=O)C1=CC=CC=N1 SIOXPEMLGUPBBT-UHFFFAOYSA-N 0.000 claims 2
- IPPGMQFOEAVJNB-UHFFFAOYSA-N 1-n-(5-cyclobutyl-1h-pyrazol-3-yl)-3-n,3-n-dimethylbenzene-1,3-diamine Chemical compound CN(C)C1=CC=CC(NC=2NN=C(C=2)C2CCC2)=C1 IPPGMQFOEAVJNB-UHFFFAOYSA-N 0.000 claims 1
- AYEGPMGNMOIHDL-UHFFFAOYSA-N 2-methylcyclopropane-1-carboxylic acid Chemical compound CC1CC1C(O)=O AYEGPMGNMOIHDL-UHFFFAOYSA-N 0.000 claims 1
- XLJWJFKYRFPJSD-LZQZEXGQSA-N 3-[2-[(1s,5r,6s)-6-(4-fluorophenyl)-3-azabicyclo[3.2.0]heptan-3-yl]ethyl]-1h-quinazoline-2,4-dione Chemical compound C1=CC(F)=CC=C1[C@@H]1[C@H]2CN(CCN3C(C4=CC=CC=C4NC3=O)=O)C[C@H]2C1 XLJWJFKYRFPJSD-LZQZEXGQSA-N 0.000 claims 1
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims 1
- RMKZQZHBVMJWDU-UHFFFAOYSA-N 5-cyclobutyl-n-(3-fluorophenyl)-1h-pyrazol-3-amine Chemical compound FC1=CC=CC(NC=2NN=C(C=2)C2CCC2)=C1 RMKZQZHBVMJWDU-UHFFFAOYSA-N 0.000 claims 1
- CKKWZMUGVGRYOM-UHFFFAOYSA-N 5-cyclobutyl-n-(3-phenylmethoxyphenyl)-1h-pyrazol-3-amine Chemical compound C=1C=CC=CC=1COC(C=1)=CC=CC=1NC(NN=1)=CC=1C1CCC1 CKKWZMUGVGRYOM-UHFFFAOYSA-N 0.000 claims 1
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- 229940100578 Acetylcholinesterase inhibitor Drugs 0.000 claims 1
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- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Description
PYRAZOLE DERIVATIVES AND THEIR USE AS PROTEIN KINASE INHIBITORS
Field of the Invention i The subject invention relates to pyrazole derivatives, pharmaceutical compositions comprising such derivatives and methods of using such derivatives to treat abnormal cell growth and certain diseases and conditions of the central nervous system. The compounds of the present invention act as inhibitors of cyclin-dependent protein kinase enzymes cdk5 {cyclin-dependent protein kinase 5) and cdk2 (cyclin-dependent protein kinase 2). The compounds of the present invention also are inhibitors of the enzyme GSK-3 (glygocen synthase kinase-3) enzyme.
The serine/threonine kinase cdk5 along with its cofactor p25 (or the longer cofactor, p25) has been linked to neurodegenerative disorders, and inhibitors of cdk&/p25 (or cdk5/p35) are therefore useful for the treatment of neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, stroke, or Huntington's disease. Treatment of such neurodegenerative disorders using cdk5 inhibitors is supported by the finding that cdk5 is involved in the phosphorylation of tau protein (J. Biochem, 117, 741-749 (1995)). cdk5 also phosphorylates Dopamine and Cyclic AMP-Regulated Phosphorprotein (DARPP-32) at threonine 75 and is thus indicated in having a role in dopaminergic neurotransmission (Nature, 402, 669-671 (1999)).
The serine/threonine kinase cdk2 is essential for normal cell cycling and plays a critical role in disorders arising from abnormal cell cycling, a common characteristic of many oncological disorders. Inhibitors of cdk2 are therefore useful for the treatment of various types of cancer and other diseases or conditions related to abnormal cell growth (Meijer, et al.,
Properties and Potential-applications of Chemical Inhibitors of Cyclin-dependent Kinsases,
Pharmacology & therapeutics, 82 (2-3), 279-284 (1999); Sausville, et al., Cyclin-dependent
Kinases: Initial Approaches to Exploit a Novel Therapeutic Target, Pharmacology & therapeutics 82 (2-3) 285-292 (1999)).
GSK-3 is a serine/threonine protein kinase. It is one of several protein kinases which phosphorylate glycogen synthase (Embi, et al., Eur. J. Biochem. 107:519-527 (1980); . Hemmings, et al., Eur. J. Biochem. 119:443-451 (1982)). GSK-3 exists in two isoforms, o and " B, in vertebrates, reported as having a monomeric structure of 49kD and 47kD respectively. . Both isoforms phosphorylate muscle glycogen synthase (Cross, et al., Biochemical Journal 303: 21-26 (1994)). The amino acid identity among GSK-3 species homologs has been indicated to be in excess of 98% within the catalytic domain (Plyte, et al., Biochim. Biophys.
Acta 1114:147-162) (1992)). Due to a remarkably high degree of conservation across the ) phylogenetic spectrum, a fundamental role of GSK-3 in cellular processes is suggested.
GSK-3 has been implicated in numerous different disease states and conditions. For ’ example, Chen, et al, Diabetes 43: 1234-1241 (1994) have suggested that an increase in GSK-3 activity can be important in Type 2 diabetes. Increased GSK-3 expression in diabetic muscle is also though to contribute to the impaired glycogen synthase activity and skeletal muscle insulin resistance present in Type 2 diabetes (Nikoulina, et al., Diabetes 49: 263-271 (2000)). Also, a higher activity of a type 1 protein phosphatase measured in immotile sperm was attributed to higher GSK-3 activity and was indicated as responsible for holding the sperm motility in check (Vijayaraghavan, et al. Biology of Reproduction 54: 709-718 (19986)).
Vijayaraghavan et al. indicate that such resulis suggest a biochemical basis for the development and regulation of sperm motility and a possible physiological role for a protein phosphatase 1/inhibitor 2/GSK-3 system. GSK-3 activity has also been associated with
Alzheimer's disease and mood disorders such as bipolar disorder (WO 97/41854). Among other conditions, GSK-3 has furthermore been implicated in hair loss, schizophrenia, and neurodegeneration, including both chronic neurodegenerative diseases (such as Alzheimer’s, supra) and neurotrauma, for example stroke, traumatic brain injury, and spinal cord trauma.
This invention provides compounds of the formula
H
N- H
AN N—RI—R*
Rr? 1 wherein R' is a straight chain or branched (C,-Cg)alkyl, a straight chain or branched (C,-
Cslalkenyl, a straight chain or branched (C,-Cg)alkynyl, (C5-Cg)cycioalkyl, (C4-Cg)cycloatkenyl, (3- 8 membered) heterocycloalkyl, (Cs-C,,)bicycloalkyl, (C,~C;,)bicycloalkenyl, or (5-11 membered) heterobicycloalkyl; and wherein R' is optionally substituted with from one to six substituents R3 ) independently selected from F, Cl, Br, 1, nitro, cyano, -CF; -NR'R® -NR'C(=O)R® -
NR’C(=0)OR?, -NR’C(=O)NR®R?, -NR’S(=0),R%, -NR’S(=0),NR°R®, -OR’, -OC(=O)R’, - ) OC(=0)OR’, -C(=Q)OR’, -C(=O)R’, -C(=O)NR'R®, -OC(=O)NR’R®, -OC(=0)SR’, -SR’, -
S(=0)R’, -8(=0),R, -S(=0),NR'R?, and R;
R?is H, F, -CH,, -CN, or -C(=0)OR7;
R3? is -C(=0)NR®-, -C(=0)0O-, -C(=O)(CR"R""),-, or -(CRR"), -;
R* is a straight chain or a branched (C,-Cg)alkyl, a straight chain or a branched (C,- : Cylalkenyl, a straight chain or branched (C,-C, alkynyl), (C5-Cg)eycloalkyl, (C,-Cy)eycloalkenyl, (3-8 membered) heterocycloalkyl, (Cs-C,,)bicycloalkyl, (C,-C,,)bicycloalkeny!, (5-11 membered) ' heterobicycloalkyl, (C¢-C,,)aryl, or (5-14 membered) heteroaryl; and wherein R* is optionally substituted with from one to three substitutents R® independently selected from F, Cl, Br, I, nitro, cyano, -CF,; -NR'R®, -NR'C(=O)R?, -NR'C(=O)OR®, -NR'C(=O)NR®R®, -NR’S(=0).,R°, -NR’S(=0),NR®R®, -OR’, -OC(=0)R’, -OC(=0)OR’, -C(=0O)OR’, -C(=0)R’, -C(=O)NR'R?, -OC(=O)NR'R®, -OC(=0)SR’, -SR7, -S(=0)R’, -S(=0),R’, -S(=0),NR'R?, or R’; each R’, R%, and R° is independently selected from H, straight chain or branched (C-
Cgalkyl, straight chain or branched (C,-Cg)alkeny), straight chain or branched (C.-C, alkynyl), (C4-Cy)eycloalkyl, (C,-Cg)cycloalkenyl, (3-8 membered) heterocycloalkyl, (C.-C, )bicycloalkyl, (C,-C,,)bicycloalkenyl, (5-11 membered) heterobicycloalkyl, (C¢C,,)aryl, and (5-14 membered) heteroaryl, wherein R?, R8, and R® are each independently optionally substituted with from one to six substituents independently selected from F, Cl, Br, I, NO, -CN, -CF,; -NR"“R", 156 -NR"C(=O)R'", -NR'C(=O)OR", -NR™C(=O)NR''R", -NR'S(=0),R", -NR"S(=0),NR'"'R", -OR", -OC(=0O)R", -OC(=O)OR™, -OC(=O)NR'R", -OC(=0)SR?, -SRY, -S(=0)RY, -5(=0),R'°, -S(=0),NR"R", -C(=O)R'", -C(=0)OR", -C(=O)NR™R"", and R'’, or, when R” and R® are as in NR'R, they may instead optionally be connected to form with the nitrogen of NR’R® to which they are attached a heterocycloalkyl moiety of from three to seven ring members, said heterocycloalkyl moiety optionally comprising one or two further heteroatoms independently selected from N, O, and S; each RY, R", and R* is independently selected from H, straight chain or branched (C,-
Ce)alkyl, straight chain or branched (C,-Cg)alkenyl, straight chain or branched (C,-Cq alkynyl), (C5-Ce)cycloalkyl, (C,-Cg)cycioalkenyl, (3-8 membered) heterocycloalkyl, (Cs-C,,)bicycloalkyl, (C;-Cyy)bicycloalkenyl, (5-11 membered) heterobicycloalkyl, (C¢-Cy,)aryl, and (5-14 membered) heteroaryl, wherein R', R", and R'? are each independently optionally substituted with from one to six substituents independently selected from F, Ci, Br, I, NO,, -CN, -CF;, -NR™R", -NRPC(=0)R", -NR"C(=0)ORY, -NR“C(=O)NR"R', -NR'S(=0),R", -NR“S(=0).NR"R', -OR"®, -OC(=0)R™, -OC(=0)OR™, -OC(=O)NR¥R", -OC(=O)SR®™, -SR™, -S(=O)R®, -S(=0).R"%, -S(=0),NR®R", -C(=0)R"?, -C(=0)OR", -C(=0)NR™R", and R'*; ’ each R™ R™, and R" is independently selected from H, straight chain or branched (C,-
Cglalkyl, straight chain or branched (C,-Cg)alkenyl, straight chain or branched (C,-Cg alkynyl), * (C3-Ce)cycloalkyl, (C,-Cgloycloalkenyl, (3-8 membered) heterocycloalkyl, (Cs-Cy,)bicycloalkyl, (C;-Cy)bicycloalkenyl, (5-11 membered) heterobicycloalkyl, (C4-C,o)aryl, and (5-14 membered) heteroaryl, wherein R"™, R™, and R"™ are each independently optionally substituted with from one to six substituents independently selected from F, Cl, Br, I, NO,, -CN, -CF,;, -NR"R"
-NR*®C(=0)R", -NR™C(=O)OR", -NR'®C(=0)NR"R'™, -NR"®S(=0),R", -NR®S(=0),NR""R" : -OR'™ -OC(=O)R'™, -OC(=O)OR', -OC{=O)NR™R", -OC(=0)SR'™®, -SR*, -S(=O)R*, -S(=0),R™, -S(=0},NR"R", -C(=0)R'¢, -C(=0)OR'®, -C(=O)NR"*R", and R® ' each R', R", and R" is independently selected from H, straight chain or branched (C:- Cg)alkyl, straight chain or branched (C,-Cg)alkenyl, straight chain or branched (C,-Cq alkynyl), (C4-Cy)eycloalkyl, (C,-Cg)cycloalkenyl, (3-8 membered) heterocycloalkyl, (Cs-C,,)bicycloalky!, (C,-C,,)bicycloalkenyl, (5-11 membered) heterobicycloalkyl, (C4-C,,)aryl, and (5-14 membered) heteroaryl; nis 0, 1,2, or 3; wherein R" and R" in -C(=0)(CR"R"),- and -(CR'R""),- are for each iteration of n defined independently as recited above; and phamaceutically acceptable salts thereof.
Amino-substituted pyrazoles can exist as mixtures of tautomeric isomers in equilibrium with one another. The present invention includes all such tautomers of compounds of formula 1, and references herein to compounds of formula 1, uniess otherwise indicated, 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 treatment of neurodegenerative disorders and other CNS disorders, and of abnormal cell growth, including cancer. The compounds of formula 1 are particularly useful in inhibiting cdk5. The compounds of formula 1 are also useful as inhibitors of GSK-3.
The term “alkyl”, as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight or branched moieties. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, and t-butyl.
The term “alkenyl”, as used herein, unless otherwise indicated, includes alkyl moieties having at least one carbon-carbon double bond wherein alkyl is as defined above. Examples of alkenyl include, but are not limited to, ethenyl and propenyi.
The term “alkynyl”, as used herein, unless otherwise indicated, includes alkyl moieties having at least one carbon-carbon triple bond wherein alkyl is as defined above. Examples of alkynyl groups include, but are not limited to, ethynyl and 2-propynyl. ‘ The term “cycloalkyl”, as used herein, unless otherwise indicated, includes non- aromatic saturated cyclic alkyl moieties wherein alkyl is as defined above. Examples of ‘ cycloalkyl inciude, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. “Bicycloalkyl” groups are non-aromatic saturated carbocyclic groups consisting of two rings, wherein said rings share one or two carbon atoms. For purposes of the present invention, and unless otherwise indicated, bicycloalky! groups include spiro groups and fused ring groups. Examples of bicycloalkyl groups include, but are not limited to, bicyclo-[3.1.0]- ) hexyl, norbornyl, spiro[4.5]decy!, spiro[4.4]nonyl, spiro[4.3Joctyl, and spiro[4.2]heptyl. “Cycloalkenyl” and “bicycloalkenyl” refer to non-aromatic carbocyclic cycloalkyl and * bicycloalkyl moieties as defined above, except comprising one or more carbon-carbon double bonds connecting carbon ring members (an “endocyclic” double bond) and/or one or more carbon-carbon double bonds connecting a carbon ring member and an adjacent non-ring carbon {an “exocyclic” double bond). Examples of cycloalkenyl groups include, but are not limited to, cyclopentenyl and cyciobutenyl, and a non-limiting example of a bicycloalkenyl group is norbornenyl. Cycloalkyl, cycloalkenyl, bicycloalkyl, and bicycloalkenyl groups also include groups that are substituted with one or more oxo moieties. Examples of such groups with oxo moieties are oxocyclopentyl, oxocyclobuty!, oxocyclopentenyl, and norcamphoryl.
The term “aryl”, as used herein, unless otherwise indicated, includes an organic radical derived from an aromatic hydrocarbon by removal of one hydrogen, such as phenyl, naphthyl, indenyl, and fluorenyl.
The terms "heterocyclic", “heterocycloalky!l”, and like terms, as used herein, refer to non-aromatic cyclic groups containing one or more heteroatoms, prefereably from one to four heteroatoms, each selected from O, S and N. “Heterobicycloalkyl” groups are non-aromatic two- ringed cyclic groups, wherein said rings share one or two atoms, and wherein at least one of the rings contains a heteroatom (O, 8, or N). Heterobicycloalkyl groups for purposes of the present invention, and unless otherwise indicated, include spiro groups and fused ring groups. in one embadiment, each ring in the heterabicycloalkyl contains up to four heteroatoms (i.e. from zero to four heteroatoms, provided that at least one ring contains at least one heteroatom). The heterocyclic groups of this invention can also include ring systems substituted with one or more oxo moieties. Examples of non-aromatic heterocyclic groups are aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, azepinyl, piperazinyl, 1,2,3,6-tetrahydropyridiny}, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholino, thiomorpholino, thioxanyl, pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3- dioxolanyl, pyrazolinyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyt, quinoiizinyi, quinuclidinyl, 1,4-dioxaspirof4.5]decy!, 1,4-dioxaspiro[4.4Inonyl, 1,4- } dioxaspiro[4.3]octyl, and 1 ,4-dioxaspiro[4.2]heptyl. “Heteroaryl”, as used herein, refers to aromatic groups containing one or more ” heteroatoms (O, S, or N), preferably from one to four heteroatoms. A multicyclic group containing one or more heteroatoms wherein at least one ring of the group is aromatic is a “heteroaryl” group. The heteroaryl groups of this invention can also include ring systems substituted with one or more oxo moieties. Examples of heteroaryl groups are pyridinyl,
pyridazinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, quinolyl, isoquinolyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyi, isothiazolyl, pyrrolyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, triazinyl, ’ isoindolyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzotriazolyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, dihydroquinoly!, tetrahydroquinolyl, dihydroisoquinolyl, tetrahydroisoquinolyl, benzofuryl, furopyridinyl, pyralopyrimidinyi, and azaindalyl.
The foregoing groups, as derived from the compounds listed above, may be C-attached or N-attached where such is possible. For instance, a group derived from pyrrole may be pyrrol- 1-y! (N-attached) or pyrrol-3-y! (C-attached). The terms referring to the groups also encompass all possible tautomers.
In one embodiment, this invention provides compounds of formula 1, wherein R? is -C(=O)NR°®- or -C(=0)(CR'R"),-. In another embodiment, R'® and R'! of -C(=0)(CR'°R"),- are at each iteration of n both hydrogen. In another embodiment, R® of ~C(=O)NR®- is hydrogen. in another embodiment, R® is -C(=O)NR®- or -C(=O)}(CR"R'"),- and R? is hydrogen. In another embodiment, R? is -(CR™R'"),-, and n is zero. In a preferred embodiment R® is -(CR'°R)-, nis zero, and R* is (C¢-C,)aryl or (5-14 membered) heteroaryl, each optionally substituted as recited above.
In another embodiment of the invention, a compound of formula 1 is provided wherein
R'is optionally substituted (C,Cg)cycloalkyl or optionally substituted (Cs-C,y) bicycloalkyl.
Preferred embodiments are wherein R' is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or norbornyl, each optionally substituted as recited above (i.e. optionally with from one to six substituents R® independently selected from F, Cl, Br, |, nitro, cyano, -CF,; -NR'RS -NR’C(=0)R?, -NR’C(=0)OR® -NR'C(=O)NR°R® -NR’S(=0),R?, -NR’S(=0),NRR®, -OR’, -OC(=0)R’, -OC(=0)OR’, -C(=0)OR’, -C(=0)R’, -C(=ONR'R?, -OC(=0Q)NR’R®, -OC(=0)SR’, -SR’, -8(=0)R’, -S(=0),R’, -S(=0),NR’R®, and R’). In a more preferred embodiment, R' is (C,-
Cs)oycloalkyl or optionally substituted (Cs-C,;) bicycloalkyl, for example cyclopropyl, cyclobutyt, cyclopentyl, cyclohexyl, or norbornyl, and is optionally substituted with from one to three substituents independently selected from F, Cl, Br, 1, nitro, cyano, -CF;, -NR'R®, -NR’C(=0O)R®, -OR’, -C(=0)OR’, -C(=O)R’, and R’. More preferably, R' is (C;-Cg)cycloalkyl or optionally = substituted (Cs-C,,) bicycloalkyl, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or norbornyl, and R' is substituted with -NR'C(=O)R®, (C,C,aryl, (3-8 membered) ~ heterocycloalkyl, or (5-14 membered) heteroaryl, and wherein said aryl, heterocycloalkyl, and heteroaryl are each optionally substituted with from one to six substituents independently selected from F, Cl, Br, I, NO,, -CN, -CF; -NR"R", -NR"C(=O)R", -NR"C(=O)OR', -NR"°C(=0)NR"R", -NR"S(=0),R"", -NR"S(=0),NR''R"?, -OR", -OC(=0)R", -OC(=0)OR",
-OC(=0)NR™R", -OC(=0)SR™, -SR™ -S(=0)R™, -S(=0),R?, -S(=0),NRR", -C(=O)R", } -C(=0)OR", -C(=0O)NR™R", and R™. In another embodiment of the invention, R' is bicyclo- [3.1.0}-hexyl and is optionally substituted as recited above (i.e. optionally substituted with from ’ one to six substituents R® independently selected from F, Cl, Br, I, nitro, cyano, -CF,, -NR'R®, -NR'C(=0)R?, -NR'C(=0)OR®?, -NR’C(=O)NR®R®, -NR'S(=0),R?, -NR’S(=0),NR°R®, -OR’, -OC(=0)R’, -OC(=0)OR’, -C(=0)OR’, -C(=0)R’, -C(=O)NR’R®, -OC(=0)NR'R?, -OC(=0)SR’, -SR’, -S(=0)R’, -8(=0),R’, -S(=0),NR’R’, and R".
In another embodiment of the invention, a compound of formula 1 is provided wherein
R' is optionally substituted straight chain or branched (C.,-Cglalkyl or optionally substituted straight chain or branched (C,-Cg)alkenyl.
In another embodiment of the invention, compounds of formula 1 are provided, but wherein R? is hydrogen. In a further embodiment, R? is hydrogen, and R’ is as subdefined in the preceding paragraphs.
In another embodiment, this invention provides a compound of formula 1 wherein R* is (C-Cilaryl or (5-14 membered) heteroaryl, each optionally substituted. In a preferred embodiment, R* is optionally substituted phenyl or optionally substituted pyridyl. In another preferred embodiment, R* is naphthyl, quinolyl, or isoquinolyl, each optionally substituted. In another embodiment, R* is napthyl, quinolyl, or isoquinolyl, and is unsubstituted. In another embodiment, R* is pyrimidinyl, pyrazinyl, or pyridazyl, and in each case R* is optionally substituted. In a further embodiment, R* is pyrimidinyl, pyrazinyl, or pyridazyl, and R* is unsubstituted.
In another embodiment, compounds of formula 1 are provided, wherein R? is specifically hydrogen, and R* is as subdefined in the preceding paragraph.
Examples of preferred compounds of formula 1 are: (5-cyclobutyl-2H-pyrazol-3-yl)-(3-trifluoromethoxy-phenyl)-amine;
N-(5-cyclobutyl-2H-pyrazol-3-yt)-N',N'-dimethyl-pyridine-2,6-diamine; (5-ethyl-2H-pyrazol-3-yl)-(6-methoxy-pyridin-2-yl}-amine; (5-cyclobuty!-2H-pyrazol-3-yl)-(6-methoxy-pyridin-2-yl)-amine (5-cyclobutyl-2H-pyrazol-3-yl)-naphthalen-2-yl-amine; (5-cyclobutyl-2H-pyrazol-3-yl)-naphthalen-1-yl-amine;
N-(5-cyclobutyl-2H-pyrazol-3-yl)-N',N'-dimethyl-naphthalene-1,4-diamine;
N-{5-cyclobutyl-2H-pyrazol-3-y1)-N',N'-dimethyl-pyridine-2,6-diamine; : (5-cyclobutyl-2H-pyrazol-3-yl)-(6-trifluoromethyl-pyridin-2-yl}-amine; (3-benzyloxy-phenyi)-(5-cyclobutyl-2H-pyrazol-3-yl}-amine; (5-cyclobutyl-2H-pyrazol-3-yi)-(3-trifluoromethyl-phenyl)-amine,;
N-({5-cyclobutyl-2H-pyrazol-3-y)-N',N'-dimethyl-benzene-1,3-diamine;
(5-cyclobuty!-2H-pyrazol-3-yl)-(3-methoxy-phenyl}-amine; : {5-cyclobutyl-2H-pyrazol-3-yl}-(4-nitro-phenyl}-amine; (4-chloro-benzyl)-{5-cyclobutyl-2H-pyrazol-3-yl)-amine; : {3-bromo-phenyl)-(5-cyclobutyl-2H-pyrazol-3-y!}-amine; (5-cyclobutyl-2H-pyrazol-3-yl)-quinolin-2-yl-amine; [5-(1,4-dioxa-spirof4.4}non-7-yl)-1H-pyrazol-3-yl}-(3-trifluoromethyl-phenyl)-amine; (6-chloro-pyridin-2-y!)-(5-cyclobutyl-2H-pyrazol-3-yi)-amine; 3-[5-(3-trifluoromethyl-phenylamino)-2H-pyrazol-3-yi]-cyclopentanone; (5-cyclobutyl-2H-pyrazol-3-y1})-(6-methoxy-4-methyl-quinolin-2-yl)-amine; (5-cyclobutyl-2H-pyrazol-3-yl)-(3-trifluoromethoxy-phenyl)-amine; (2-chloro-4-nitro-phenyl)-(5-cyclobutyl-2H-pyrazol-3-yi)-amine; 3-trans-[5-(3-trifluoromethyl-phenytamino)-2H-pyrazol-3-yl}-cyclopentanol; (3,5-bis-trifluoromethyl-phenyl)-(5-cyclobutyl-2H-pyrazol-3-yl)-amine; [5-(3-cis-benzylamino-cyclopentyl}-1H-pyrazol-3-yil-(3-trifiuoromethyl-phenyi)-amine; {5-[3-cis-(4-methoxy-benzylamino)-cyclopentyl]-1H-pyrazol-3-yl}-(3-trifluoromethyl- phenyl)-amine; 4-(5-cyclobutyl-2H-pyrazol-3-ylamino)-benzonitrile; (5-cyclobutyl-2H-pyrazol-3-y!)-(3-fluoro-phenyl}-amine; (5-cyclobutyl-2H-pyrazol-3-yl)-(3,5-dichloro-phenyi)-amine; (2-bromo-phenyl)-(5-cyclobutyl-2H-pyrazol-3-yi)-amine;
N-{cis-3-[5-(3-trifluoromethyl-phenylamino)-2H-pyrazol-3-yi]-cyclopentyl}-acetamide; pyridin-2-yl-{3-trans-[5-(3-triflusromethyi-phenylamino)-2H-pyrazol-3-yl}-cyclopentyl}- amine; (5-cyclobutyl-1H-pyrazol-3-yl)-(4-methoxy-phenyl}-amine; pyridine-2-carboxylic acid {3-[5-(3-trifluoromethyl-phenylamino)-2H-pyrazol-3-yl]- cyclopentyl}-amide; 3-triffuoromethyl-N-{3-[5-(3-trifluoromethyl-phenylamino)-2H-pyrazol-3-yl]- cyclopentyl}-benzamide; : cyclobutanecarboxylic acid {3-[5-(3-trifluoromethyl-phenylamino)-2H-pyrazol-3-yi}- 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-trifluoromethyl-phenylamino)-2H-pyrazol-3-yl}-cyclopentyl}- acetamide;
cyclopropanecarboxylic acid {3-[5-(3-trifluoromethyl-phenylamino)-2H-pyrazol-3-yl}- : cyclopentyl}-amide;
N-{3-[5-(3-trifluoromethyl-phenyiamino)-2H-pyrazol-3-yi}-cyclopentyl}-propionamide; : cyclohexanecarboxylic acid {3-[5-(3-trifluoromethyl-phenylamino)-2H-pyrazol-3-yl}- cyclopentyl}-amide;
N-[5-(3-acetylamino-cyclopentyl)-2H-pyrazol-3-yi}-2-naphthalen-1-yl-acetamide; cyclopropanecarboxylic acid {3-[5-(2-naphthalen-1-yl-acetylamino)-1H-pyrazol-3-yl}- cyclopentyl}-amide; 2-naphthalen-1-yl-N-{5-[3-(2,2,2-trifluoro-acetylamino)-cyclopentyl}-2H-pyrazol-3-yl}- acetamide;
N-{3-[5-(2-naphthalen-1-yl-acetylamino)-1H-pyrazol-3-yl}-cyclopentyl}-benzamide;
N-(5-hydroxymethy!-1H-pyrazol-3-yl}-2-naphthalen-1-yl-acetamide; 2-naphthalen-1-yl-N-[5-{thiazol-2-ylaminomethyl)-1H-pyrazol-3-yi]-acetamide;
N-[5-((1S)-hydroxy-ethyl}-2H-pyrazol-3-yl}-2-naphthalen-1-yl-acetamide;
N-{5-[(18)-(benzooxazol-2-yloxy)-ethyl]-1H-pyrazol-3-yl}-2-naphthalen-~1-yl- acetamide;
N-{5-[(1S)-(benzothiazol-2-yloxy)-ethyl]-1H-pyrazol-3-yl}-2-naphthalen-1-yl- acetamide;
N-[5-(3-hydroxy-1-methyl-propyl}-1H-pyrazol-3-yl}-2-naphthalen-1-yl-acetamide;
N-[5-(benzothiazol-2-yloxymethyl)-1H-pyrazol-3-yl}-2-naphthalen-1-yl-acetamide;
N-{5-[3-(benzothiazol-2-yloxy)-1-methyi-propyll-1H-pyrazol-3-yi}-2-naphthalen-1-yl- acetamide;
N-[5-(2-hydroxy-(1S)-methyl-ethyl}-2H-pyrazol-3-yi]-2-naphthalen-1-yl-acetamide;
N-{5-[(1R)-(benzothiazol-2-yloxy)-ethyl}-1H-pyrazol-3-yl}-2-naphthalen-1-y}- acetamide;
N-[5-(3-acetylamino-1-methyl-propyl)-1H-pyrazol-3-yl}-2-naphthalen-1-yl-acetamide; 3-methoxy-N-{cis-3-[5-(2-naphthalen-1-yl-acetylamino)-2H-pyrazol-3-yl}-cyciobutyl}- benzamide;
N-[5-(cis-3-acetylamino-cyciobutyl)-1H-pyrazol-3-yl]-2-naphthalen-1-yi-acetamide;
N-{cis-3-[5-(2-naphthalen-1-yl-acetylamino)-2H-pyrazol-3-yi}-cyclobutyl}-benzamide; : 2-cyclopropyl-N-{¢cis-3-[5-(2-naphthalen-1-yl-acetylamino)-2H-pyrazel-3-yl}- cyclobutyl}-acetamide; - 6-chloro-pyridine-2-carboxylic acid {cis-3-[5-(2-naphthalen-1-yl-acetylamino)-2H- pyrazol-3-yi}-cyclobutyi}-amide; quinoline-2-carboxylic acid {cis-3-[5-(2-naphthalen-1-yl-acetylamino)-2H-pyrazol-3-yl}- cyclobutyl}-amide;
pyrazine-2-carboxylic acid {cis-3-[5-(2-naphthalen-1-yl-acetylamino)-2H-pyrazol-3-yl}- ‘ cyclobutyl}-amide; 4-methoxy-N-{cis-3-[5-(2-naphthalen-1-yl-acetylamino)-2H-pyrazol-3-yl}-cyclobutyl}- : benzamide;
N-{cis-3-[5-(2-naphthalen-1-yl-acetylamino)-2H-pyrazol-3-yi]-cyciobutyl}-3-nitro- benzamide;
N-{cis-3-[5-(2-naphthalen-1-yl-acetylamino)-2H-pyrazol-3-ylj-cyclobutyl}-3- trifftucromethyl-benzamide;
N-{cis-3-[5-(2-naphthalen-1-yl-acetylamino)-2H-pyrazol-3-yl}-cyclobutyl}- isobutyramide; 2-phenyl-cyclopropanecarboxylic acid {cis-3-[5-(2-naphthalen-1-yl-acetylamino)-2H- pyrazol-3-yl]-cyciobutyl}-amide;
N-{5-[cis-3-(benzoaxazol-2-yloxy)-cyclobutyl}-1H-pyrazol-3-yl}-2-naphthalen-1-yl- acetamide; 4-dimethylamino-N-{cis-3-[5-(2-naphthalen-1-yl-acetylamino)-2H-pyrazol-3-yl}- cyclobutyl}-benzamide; 3,5-dimethoxy-N-{cis-3-[5-(2-naphthalen-1-yl-acetylamino)-2H-pyrazol-3-yl}- cyclobutyi}-benzamide; 2-naphthalen-1-y!-N-[5-(cis-3-phenyl-cyclobutyl)-2H-pyrazol-3-yl}-acetamide;
N-{5-[cis-3-(3-methoxy-phenyl)-cyclobutyl]-2H-pyrazol-3-yi}-2-naphthalen-1-yi- acetamide;
N-{5-[cis-3-(2-methoxy-phenyl}-cyclobutyl]-2H-pyrazol-3-yI}-2-naphthalen-1-yl- acetamide;
N-{5-[cis-3-(4-methoxy-phenyl}-cyclobutyl]-2H-pyrazol-3-yi}-2-naphthalen-1-yl- acetamide; 2-naphthalen-1-yl-N-[5-(cis-3-p-tolyl-cyclobutyl)-2H-pyrazal-3-yl}-acetamide;
N-{5-[cis-3-(4-chioro-phenyl)-cyclobutyl]-2H-pyrazol-3-yl}-2-naphthalen-1-yl- acetamide; 2-(4-methoxy-phenyl)-N-{5-[cis-3-(2-methoxy-phenyl)-cyciobutyl]-2H-pyrazol-3-yl}- acetamide; : N-{5-[cis-3-(2-methoxy-phenyl)-cyclobutyl]-2H-pyrazol-3-yl}-2-quinolin-6-yl-acetamide;
N-{5-[cis-3-(2-methoxy-phenyl}-cyclobutyl]-2H-pyrazol-3-yl}-2-phenyl-acetamide; : N-{5-{cis-3-(2-methoxy-phenyl)-cyclobutyl}-2H-pyrazol-3-yl}-2-pyridin-3-yi-acetamide;
N-{5-[cis-3-(4-methoxy-phenyl)-cyclobutyl]-1 H-pyrazol-3-yl}-2-quinolin-6-yl-acetamide; 2-quinolin-6-yI-N-[5-(cis-3-p-tolyl-cyclobutyl)-1H-pyrazol-3-yl}-acetamide;
N-{5-[cis-3-(4-fluoro-phenyl)-cyclobutyl]-1H-pyrazol-3-yi}-2-quinolin-6-yl-acetamide;
N-{5-[cis-3-(4-chloro-phenyl)-cyclobutyl]-1H-pyrazol-3-yi}-2-quinolin-6-yl-acetamide; ' 2-quinolin-6-yl-N-[5-(cis-3-m-tolyl-cyclobutyl)-1H-pyrazol-3-yl}-acetamide; 4-dimethylamino-N-{cis-3-[5-(2-naphthalen-1-yi-acetylamino)-2H-pyrazol-3-yl]- : cyclobutyl}-benzamide; 2-naphthalen-1-yI-N-{5-[cis-3-(pyridin-2-yloxy)-cyciobutyl}-1H-pyrazol-3-yl}-acetamide; 6-methyl-pyridine-2-carboxylic acid {cis-3-[5-(2-naphthalen-1-yl-acetylamino)-2H- pyrazol-3-yl]-cyclobutyl}-amide; 2-phenyl-cyclopropanecarboxylic acid methyi-{cis-3-[5-(2-naphthalen-1-yl- acetylamino)-2H-pyrazol-3-yl}-cyclobutyl}-amide;
N-{5-[cis-3-(3-methyl-pyrazin-2-yloxy)-cyclobutyl}-1H-pyrazol-3-yli}-2-naphthalen-1-yl- acetamide; {5-{cis-3-(2-methoxy-phenyl)-cyclobutyl]- 1H-pyrazol-3-yl}-(6-methoxy-pyridin-2-yl)- amine;
N-{5-[cis-3-(3,6-dimethyl-pyrazin-2-yloxy)-cyciobutyl}-1H-pyrazol-3-yi}-2-naphthalen- 1t-yl-acetamide;
N-{5-[cis-3-(3-methoxy-pyridin-2-yloxy)-cyclobutyl]-1H-pyrazol-3-yl}-2-naphthalen-1- yl-acetamide; 2-methyi-cyclopropanecarboxylic acid {cis-3-[5-(2-naphthalen-1-yl-acetylamino)-2H- pyrazol-3-yl}-cyclobutyl}-amide; 2-naphthalen-1-y}-N-{5-[cis-3~-(3-trifluoromethyl-pyridin-2-yloxy)-cyclobutyl]-1H- pyrazol-3-yl}-acetamide; ’ 2-naphthalen-1-yl-N-{6-[cis-3-(3-nitro-pyridin-2-yloxy)-cyclobutyl]- ~~ 1H-pyrazol-3-yl}- acetamide;
N-{5-[cis-3-(benzothiazol-2-yloxy)-cyciobutyl]-1H-pyrazol-3-yi}-2-naphthalen-1-yl- acetamide; 2-naphthalen-1-yl-N-{5-[cis-3-(4-triflucromethyl-pyrimidin-2-yloxy)- cyclobutyl}-1H- pyrazol-3-yl}-acetamide; 2-naphthalen-1-yl-N-{5-[3-(5-nitro-pyridin-2-yloxy)-cyclobutyl]- 1H-pyrazol-3-yl}- acetamide; 2-naphthalen-1-yl-N-{5-[3-(pyrimidin-2-yloxy)-cyclobutyl}-1H-pyrazoi-3-yl}-acetamide; : 2-naphthalen-1-yi-N-{5-[3-(5-triflucromethyl-pyridin-2-yloxy)- cyclobutyl]-1H-pyrazol-3- yl}-acetamide; : N-{5-[3-(6-methoxy-pyridazin-3-yloxy)-cyclobutyl]-1H-pyrazol-3-yl}-2-naphthalen-1-yl- acetamide; 2-naphthalen-1-yl-N-{5-[3-(pyrazin-2-yloxy)-cyclobutyl}-1H-pyrazol-3-yi}-acetamide;
N-{5-[3-(6-methyl-pyridin-2-yloxy)-cyclobuty!}-1H-pyrazol-3-yl}-2-naphthalen-1-yl- : acetamide;
N-{5-[3-(6-chloro-benzothiazol-2-yloxy)-cyclobutyl]-1H-pyrazol-3-yl}-2-naphthaien-1- ’ yl-acetamide;
N-{5-[3-(6-methoxy-benzothiazol-2-yloxy)-cyclobutyl]-1H-pyrazol-3-yi}-2-naphthalen- 1-yl-acetamide; and pharmaceutically acceptable salts of the foregoing compounds.
Other examples of preferred compounds of formula 1 are:
N-{5-[cis-3-(4-Hydroxy-phenyl)-cyclobutyl]-1 H-pyrazol-3-yl}-2-quinolin-6-yl-acetamide;
N-{5-[cis-3-(3-Hydroxy-phenyl)-cyclobutyl]-1 H-pyrazol-3-yi}-2-quinolin-6-yl-acetamide; 2-Naphthalen-1-yI-N-[5-(cis-3-pyridin-3-yl-cyclobutyl)-2H-pyrazol-3-yi}-acetamide;
N-[5-(cis-3-Naphthalen-2-yi-cyciobutyl)-2H-pyrazol-3-yl}-2-pyridin-3-yl-acetamide;
N-(5-Indan-2-yl-1H-pyrazol-3-yl)-2-quinolin-6-yl-acetamide;
N-[5-(cis-3-Pyridin-2-yl-cyclobutyl)-2H-pyrazol-3-yl]-2-quinolin-6-yl-acetamide;
N-[5-(cis-3-Pyridin-2-yl-cyclobutyl)-2H-pyrazol-3-yl]-2-quinolin-6-yl-acetamide; 2-(4-Methoxy-phenyl)-N-[5-(cis-3-pyridin-4-yl-cyclobutyl)-2H-pyrazol-3-yl}-acetamide;
N-{5-[3-(cis-2-Dimethylaminomethyl-phenyl)-cyclobutyt]-2H-pyrazol-3-yl}-2-(4- methoxy-phenyl)-acetamide;
N-(5-{cis-3-[3-(2-Dimethylamino-ethoxy)-phenyl}-cyclobutyl}-2H-pyrazol-3-yl)-2-(4- methoxy-phenyl)-acetamide;
N-{5-{cis-3-(2-Hydroxy-phenyl)-cyclobutyl]-2H-pyrazal-3-yl}-2-(4-methoxy-phenyl)- acetamide;
N-(5-{cis-3-[2-(2-Dimethylamino-ethoxy)-phenyl]-cyclobutyl}-2H-pyrazol-3-yi})-2-(4- methoxy-phenyl)-acetamide; 2-(4-Methoxy-phenyl)-N-[5-(cis-3-phenyi-cyciobutyl)-2H-pyrazol-3-yl]-acetamide;
N-{5-[cis-3-(2-Fluaro-phenyl)-cyclobutyi]-2H-pyrazol-3-yi}-2-{4-methoxy-phenyl)- acetamide;
N-(5-{cis-3-[4-(Azetidin-3-yloxy)-phenyl]-cyclobutyl}-2H-pyrazoi-3-yl)-2-(4-methoxy- phenyl)-acetamide;
N-(5-{cis-3-[2-(Azetidin-3-yloxy)}-phenyl]-cyclobutyl}-2H-pyrazol-3-yi)-2-(4-methoxy- - phenyl)-acetamide; 2-(4-Methoxy-phenyl)-N-{5-[cis-3-(2-methylsulfanyl-phenyl)-cyclobutyl}-2H-pyrazol-3- ’ yl}-acetamide;
N-{5-[cis-3-(2-Amino-phenyl)-cyclobutyl}-2H-pyrazol-3-yi}-2-(4-methoxy-phenyi)- acetamide;
N-{5-{cis-3-(4-Cyano-phenyl)-cyclobutyl]-2H-pyrazol-3-yi}-2-(4-methoxy-phenyl})- ) acetamide;
N-{5-[cis-3-(2-Cyana-phenyl)-3-hydroxy-cyclobutyl]-2H-pyrazol-3-yi}-2-(4-methoxy- : phenyl)-acetamide;
N-{5-[cis-3-(2-Hydroxy-ethyl)-cyclobutyl]-1H-pyrazol-3-yi}-2-naphthalen-1-yl- acetamide;
N-{5-[cis-3-(3-Cyano-phenyl)-cyclobutyl}-2H-pyrazol-3-yl}-2-(4-methoxy-phenyl)- acetamide;
N-{5-[cis-3-(2-Cyano-phenyl)-cyclobutyl]-2H-pyrazol-3-yi}-2-(4-methoxy-phenyl)- acetamide;
N-{5-[cis-3-(3-Amino-phenyl)-cyclobutyl]-2H-pyrazol-3-yl}-2-(4-methoxy-phenyl)- acetamide; 4-(cis-3-{5-[2-(4-Methoxy-phenyl)-acetylamino]-1H-pyrazol-3-yl}-cyclobutyl)-benzoic acid methyl ester;
N-{5-[cis-3-(4-Hydroxymethyl-phenyl}-cyclobutyl]-2H-pyrazol-3-yl}-2-(4-methoxy- phenyl)-acetamide;
N-{5-[cis-3-(2-Hydroxy-pheny!)-cyclobutyl]-1H-pyrazol-3-yl}-2-phenyl-acetamide;
N-{5-{cis-3-(2-Hydroxy-phenyl}-cyclobutyl]- 1 H-pyrazol-3-yl}-2-quinolin-6-yi-acetamide;
N-{5-[cis-3-(2-Hydroxy-phenyl)-cyciobutyl]-1H-pyrazol-3-yl}-acetamide;
Cyclopropanecarboxylic acid {5-[cis-3-(2-hydroxy-phenyl)-cyclobutyl}-1H-pyrazol-3- yl}-amide;
N-{5-[cfs-3-(2-Hydroxy-phenyl)-cyclobutyl}-1H-pyrazol-3-yl}-isobutyramide;
N-{5-[cis-3-(3-Aminomethyl-phenyl}-cyclobutyl]-2H-pyrazol-3-yl}-2-(4-methoxy- phenyl)-acetamide;
N-{5-[cis-3-(3-Dimethylaminomethyl-phenyl)-cyclobutyl]-2H-pyrazol-3-yl}-2-(4- methoxy-phenyl)-acetamide; 3-(cis-3-{5-[2-(4-Methoxy-phenyi}-acetylamino]-1H-pyrazol-3-yl}-cyclobutyl)-benzoic acid methyl! ester;
N-{5-[cis-3-(3-Hydroxymethyl-phenyl)-cyclobutyl]-2H-pyrazol-3-yl}-2-{4-methoxy- phenyl)-acetamide; ’ N-(5-{cis-3-[3-(1-Hydroxy-1-methyl-ethyl)-phenyl]-cyciobutyl}-2H-pyrazol-3-yl)-2-(4- methoxy-phenyt)-acetamide; : N-{5-[cis-3-(3-Ethylaminomethyl-phenyl)-cyclobutyl}-2H-pyrazol-3-yl}-2-(4-methoxy- phenyl}-acetamide;
N-{5-[cis-3-(3-Cyclobutylaminomethyl-phenyl)-cyclobutyi]-2H-pyrazol-3-yl}-2-(4- methoxy-phenyl)-acetamide; :
2-(4-Methoxy-phenyl)-N-{5-[cis-3-(3-propylaminomethyl-phenyl)-cyclobutyl}-2H- ‘ pyrazol-3-yl}-acetamide;
N-{5-{cis-3-(3-Cyclopentylaminomethyl-phenyl)-cyclobutyl}-2H-pyrazol-3-yi}-2-(4- : methoxy-phenyl)-acetamide;
N-(5-{cis-3-[3-(Benzylamino-methyl)-phenyl]-cyciobutyl}-2H-pyrazol-3-yl)-2-(4- methoxy-phenyl)-acetamide; 2-(4-Methoxy-phenyl}-N-{5-[3-(3-methylaminomethyl-phenyl}-cyclobutyl}-2H-pyrazoi- 3-yl}-acetamide;
N-{5-[cis-3-(3-Cyclopropylaminomethyl-phenyl)-cyclobutyl]-2H-pyrazol-3-y(}-2-(4- methoxy-phenyl)-acetamide; 2-(4-Methoxy-phenyl)-N-{5-[cis-3-(3-pyrrolidin-1-yimethyl-phenyl)-cyclobutyl}-2H- pyrazol-3-yl}-acetamide;
N-{5-{cis-3-(3-Diethylaminomethyl-phenyl}-cyclobutyl]-2H-pyrazal-3-yi}-2-(4-methaxy- phenyl)-acetamide;
N-{5-[cis-3-(3-Azetidin-1-ylmethyl-phenyl}-cyclobutyl]-2H-pyrazol-3-yl}-2-(4-methoxy- phenyl)-acetamide; and pharmaceutically acceptable salts of the foregoing compounds.
Other specific examples of compounds of the invention of formula 1 are:
N-[5-(cis-3-pyridin-2-yl-cyclobutyl)-1H-pyrazol-3-yl]-2-quinolin-6-yl-acetamide;
N-{5-(cis-3-pyridin-3-yl-cyclobutyl})-1H-pyrazol-3-yi]-2-quinolin-6-yl-acetamide;
N-{5-(cis-3-pyridin-4-yl-cyclobutyl}-1H-pyrazol-3-yi}-2-quinolin-6-yl-acetamide; :
N-{5-(cis-3-pyrazin-2-yl-cyclobutyl)- 1 H-pyrazol-3-yil-2-quinalin-6-yl-acetamide;
N-[5-(cis-3-pyrimidin-4-yl-cyclobuty!)-1H-pyrazol-3-yi}-2-quinolin-6-yl-acetamide;
N-{5-[cis-3-(3-methoxy-pyridin-2-yl)-cyclobutyi]-1H-pyrazol-3-yl}-2-quinolin-6-yi- acetamide;
N-{5-[cis-3-(4-methoxy-pyridin-3-yl}-cyclobutyl]-1H-pyrazol-3-yl}-2-quinolin-6-yl- acetamide;
N-{5-[cis-3-(3-methoxy-pyridin-4-yl)-cyclobutyl}-1 H-pyrazol-3-yl}-2-quinolin-6-yl- acetamide;
N-{5-[cis-3-(2-methoxy-pyridin-3-yl)-cyclobutyl}- 1 H-pyrazol-3-yl}-2-quinolin-6-yl- ’ acetamide;
N-{5-[cis-3-(5-methoxy-pyrimidin-4-yl)-cyclobutyl}-1H-pyrazol-3-yl}-2-quinolin-6-yl- : acetamide;
N-{5-[cis-3-(1-ethyl-1H-imidazol-2-yl)-cyclobutyl}-1H-pyrazol-3-yi}-2-quinolin-6-yi- acetamide;
N-{5-[cis-3-(1-ethyl-1H-pyrrol-2-yl}-cyclobutyl]- 1H-pyrazol-3-yl}-2-quinalin-6-yi- ‘ acetamide;
N-{5-[cis-3-(2-aminomethyl-phenyl}-cyclobutyi]- 1H-pyrazal-3-yl}-2-quinalin-6-yi- : acetamide;
N-{5-[cis-3-(2-pyrrolidin-1-ylmethyl-phenyl)-cyciobutyl}- 1 H-pyrazol-3-yl}-2-quinolin-6- yi-acetamide; and pharmaceutically acceptable salts of the foregoing compounds.
Other specific 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-yt)-acetamide; 2-biphenyl-4-yl-N-(5-cyclobutyl-1H-pyrazol-3-yl)-acetamide; 2-biphenyl-4-yl-N-(5-cyclobutyl-1H-pyrazol-3-yl}-acetamide;
N-(5-cyclobutyl-1H-pyrazol-3-y1)-2-(3,4,5-trimethoxy-phenyi)-acetamide; {2-[(5-cyclobutyl-1H-pyrazol-3-ylcarbamoyl)-methyl]-phenyl}-acetic acid;
N-(5-cyclobutyl-1H-pyrazol-3-y})-2-(3,4-dichloro-phenyl)-acetamide; 2-(2-chloro-phenyl)-N-(5-cyclobutyl-1H-pyrazol-3-yl)-acetamide;
N-(5-cyclobutyl-1H-pyrazol-3-yl)-2-(2-fluoro-phenyl)-acetamide; 2-(4-butoxy-phenyl)-N-(5-cyclobutyl-1H-pyrazol-3-yl}-acetamide;
N-(5-cyclobutyl-1H-pyrazol-3-yl)-2-(2,4-difluoro-phenyl)-acetamide;
N-(5-cyclobutyl-1H-pyrazol-3-yl}-2-(2-iodo-phenyl)-acetamide;
N-(5-cyclobutyl-1H-pyrazol-3-yl)-2-(2,3-dimethoxy-phenyf)-acetamide;
N-{5-cyclobutyl-1H-pyrazol-3-y1)-2-(2,5-dihydroxy-phenyl)-acetamide;
N-(5-cyclobutyi-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-cyclobuty!-1H-pyrazol-3-yl}-2-(4-trifluoromethyl-phenyl)-acetamide; 2-(4-chloro-3-nitra-phenyl}-N-(5-cyclobutyi- 1H-pyrazol-3-yl)-acetamide;
N-(5-cyclobutyl-1H-pyrazol-3-yl)-2-(4-hydroxy-3,5-dinitro-phenyl)-acetamide;
N-(5-cyclobutyl-1H-pyrazol-3-yl})-2-(3,4-difluoro-phenyl)-acetamide; ) 2-(2,4-bis-triflucromethyi-phenyl)-N-(5-cycliobutyl-1H-pyrazol-3-yt)-acetamide;
N-(5-cyclobutyl-1H-pyrazol-3-yl)-2-(3,5-difluoro-phenyl)-acetamide; : N-(5-cyclobutyl-1H-pyrazol-3-yl}-2-(2-fluoro-3-trifluoromethyl-phenyl)-acetamide;
N-(5-cyclobutyl-1H-pyrazol-3-yl)-2-(4-fluoro-3-trifiuoromethyl-phenyl}-acetamide;
N-(5-cyclobutyl-1H-pyrazol-3-yl}-2-(2 4,6-trifluoro-phenyl)-acetamide;
N-(5-cyclobutyl-1H-pyrazol-3-yl)-2-(4-methylsulfanyl-phenyl!)-acetamide;
N-(5-cyclobutyl-1H-pyrazol-3-yl)-2-(3-hydroxy-phenyl)-acetamide; : N-(5-cyclopentyl-1H-pyrazol-3-yl)-2-phenyl-acetamide; 2-(4-chloro-phenyl)-N-(5-cyclopentyl-2H-pyrazol-3-yl)-acetamide; ) N-(5-cyclopentyi-1H-pyrazoi-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-yi-acetamide; 2-(3-amino-phenyl)-N-(5-cyclobutyl-2H-pyrazol-3-yi)-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-cyciohexyl-1H-pyrazol-3-yi)-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-frimethoxy-phenyl}-acetamide;
N-(5-cyclopentyl-2H-pyrazol-3-yl)-2-(4-isopropyl-pheny!)-acetamide;
N-(5-cyclopentyl-2H-pyrazol-3-yl)-2-pyrrolo[2,3-b]pyridin-1-yl-acetamide;
N-(5-cyclobutyl-1H-pyrazol-3-yl}-2-m-tolyl-acetamide;
N-(5-~cyclopentyl-2H-pyrazol-3-yi)-2-p-tolyl-acetamide;
N-(5-cyclobutyl-1H-pyrazol-3-y!)-2-(3-trifluoromethoxy-phenyl)-acetamide,
N-[5-(3-benzyloxy-propyl}-1H-pyrazol-3-yi]-2-naphthalen-2-yl-acetamide; 4-[5-(2-naphthalen-2-yl-acetylamino)-1H-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-vl}-2-naphthalen-2-yl-acetamide; 4-{5-(2-naphthalen-1-yl-acetylamino)-1H-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-naphthalen-2-yl-acetylamino)-4H-pyrazol-3-ylj-propyl}-benzamide; : ’ N-{3-[5-(2-naphthalen-1-yl-acetylamino)-2H-pyrazol-3-yi]-propyl}-benzamide;
N-{5-[1-(3-methyl-butyl)-piperidin-4-yI}-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-yi]-propyl}-benzamide;
N-(3-{5-[2-(3-chloro-phenyl)-acetylamino]-2H-pyrazol-3-yl}-propyl)-benzamide;
6-methyl-pyridine-2-carboxylic acid {3-[5-(2-naphthalen-2-yl-acetylamino)-1H-pyrazol- ’ 3-yl]-cyciobutyl}-amide; 6-methyl-pyridine-2-carboxylic acid {3-[5-(2-naphthalen-2-yl-acetylamino)-1H-pyrazol- ‘ 3-yl}-cyclobutyl}-amide; 6-methyl-pyridine-2-carboxylic acid {3-[5-(2-naphthalen-2-yl-acetylamino)-1H-pyrazol- 3-yl}-cyclobutyl}-amide;
N-{5-[3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-cyclobutyl}-2H-pyrazol-3-yi}-2- naphthalen-2-yi-acetamide; 6-chloro-pyridine-2-carboxylic acid {3-[5-(2-naphthalen-2-yl-acetylamino)-1H-pyrazol- 3-yll-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-yi-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-yI-N-[5-(2-pyridin-2-yl-ethyl)-2H-pyrazol-3-yl]-acetamide; 2-naphthalen-1-yl-N-[5-(2-pyridin-3-yl-ethyl)-2H-pyrazol-3-yl}-acetamide; 2-naphthalen-1-yl-N-{5-(2-pyridin-4-yl-ethy!)-2H-pyrazol-3-yl}-acetamide; 2-(3-methoxy-pheny)-N-[5-(2-pyridin-2-yl-ethyl)-2H-pyrazol-3-yli}-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-yi-ethyl)-2H-pyrazol-3-yi]-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-ethy!}-2H-pyrazol-3-yl}-acetamide; 2-naphthalen-2-yi-N-[5-(2-thiazol-2-yl-ethyl)-2H-pyrazol-3-yi]-acetamide;
N-[5-(1-benzyl-piperidin-4-yl)-1H-pyrazol-3-yl]-2-naphthalen-2-yl-acetamide; 2-naphthalen-1-yl-N-(5-piperidin-4-yl-1H-pyrazol-3-yl)-acetamide; 2-(4-chloro-phenyl}-N-{3-[5-(2-naphthalen-2-yl-acetylamino)-1H-pyrazol-3-yl}- cyclobutyl}-acetamide; pyrazine-2-carboxylic acid {3-[5-(2-naphthalen-2-yl-acetylamino)-1H-pyrazoi-3-yIl- cyclobutyl}-amide; 2-(3-methoxy-pheny!)-N-{5-[2-(2-trifluoromethyl-phenyi)-ethyl]-2H-pyrazol-3-yl}- ) acetamide; 2-(3-methoxy-phenyl)-N-{5-[2-(3-trifluoromethyl-phenyl)-ethyl)-2H-pyrazol-3-yl}- : acetamide; 2-(3-methoxy-phenyl)-N-{5-[2-(4-trifluoromethyl-phenyl)-ethyl]-2H-pyrazol-3-yi}- acetamide; )
B-methyl-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-yi}-cyclobutyl)-amide; and pharmaceutically acceptable salts of said compounds.
Salts of compounds of formula 1 can be obtained by forming salts with any acidic or basic group present on a compound of formula 1. Examples of pharmaceutically acceptable salts of the compounds of formula 1 are the salts of hydrochloric acid, p-toluenesulfonic acid, fumaric acid, citric acid, succinic acid, salicylic acid, oxalic acid, hydrobromic acid, phosphoric acid, methanesulfonic acid, tartaric acid, maleic acid, di-p-toluoyl tartaric acid, acetic acid, sulfuric acid, hydroiodic acid, mandelic acid, sodium, potassium, magnesium, calcium, and lithium.
The compounds of formula 1 may have optical centers and therefore may occur in different enantiomeric and other sterecisomeric configurations. The invention includes all enantiomers, diastereomers, and other stereoisomers of such compounds of formula 1, as well as racemic and other mixtures thereof.
The subject invention also includes isotopically-labeled compounds, which are identical to those recited in formula 1, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, iodine, and chlorine, such as 3H, 'C, C, ®F, '®} and '®I. Compounds of the present invention and pharmaceutically acceptable salts of said compounds that contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention. lsotopically-labeled compounds of the present invention, for example those into which radioactive isotopes such as *H and **C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., *H, and carbon-14, i.e., "*C, isotopes are particularly preferred for their ease of preparation and detectability. ''C and '®F isotopes are ) particularly useful in PET (positron emission tomography), and '#| isotopes are particularly useful in SPECT (single photon emission computerized tomography), all useful in brain ; imaging. Further, substitution with heavier isotopes such as deuterium, i.e., 2H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopically labeled compounds of formula 1 of this invention can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the ' Examples below, by substituting a readily available isotopically labeled reagent for a non- isotopically labeled reagent. ' This invention also includes compounds of the formula
NN Prot
Ve o NH,
Rr?
O— ; wherein Prot is a protecting group;
R?is H, F, -CH,, -CN, or -C(=0)OR’; and n is an integer selected from 1, 2, 3, and 4. } Compounds of formula 1 are useful as intermediates for synthesizing certain compounds of formula 1 that are described herein.
Preferably, nis 1.
Examples of specific protecting groups include, but are not limited to t-butyl and -CH,-
Ar, wherein “Ar” is an aryl or heteroaryl group. An example of the latter type of protecting group is para-methoxybenzyl.
This invention also provides a pharmaceutical composition for treating a disease or condition comprising abnormal cell growth in a mammal, including a human, comprising a compound of formula 1 in an amount effective in inhibiting abnormal celi growth, and a pharmaceutically acceptable carrier.
This invention also provides a pharmaceutical composition for treating a disease ar condition comprising abnormal cell growth in a mammal, including a human, comprising a compound of formula 1 in an amount effective to inhibit cdk2 activity, and a pharmaceutically acceptable carrier.
This invention also provides a method for treating a disease or condition comprising abnormal cell growth in a mammal, including a human, comprising administering to the mammal a compound of formula 1 in an amount effective in inhibiting abnormal cell growth. ) This invention also provides a method for treating a diseases or condition comprising abnormal cell growth in a mammal, including a human, comprising administering to the ) mammal a compound of formula 1 in an amount effective to inhibit cdk2 activity. in a pharmaceutical composition or method of this invention for treating a disease or condition comprising abnormal cell growth, the disease or condition comprising abnormal cell growth is in one embodiment cancer. The cancer may be a carcinoma, for example carcinoma
Claims (14)
1. A compound of the formuia
H
A. H R' AI R? 1 wherein R' is a straight chain or branched (C,-Cy)alkyl, a straight chain or branched (C,- Cg)alkenyl, a straight chain or branched (C,-Cg)alkynyl, (C5-Cg)cycloalkyl, (C,-Cglcycloalkenyl, (3- 8 membered) heterocycloalkyl, (Cs-C,;)bicycloalkyl, (C,-C,;)bicycloalkenyl, or (5-11 membered) heterobicycloalkyl, and wherein R' is optionally substituted with from one to six substituents R® independently selected from F, Cl, Br, I, nitro, cyano, -CF, -NR'R® -NR’C(=O)R®, - -- 10 NRIC{(=0O)OR? -NR'C(=O)NR®R®?, -NR’S(=0),R%, -NR’S(=0),NR°R°, -OR’, -OC(=O)R’, - ~~ ~~ OC(=0)OR?, -C(=O)OR?, -C(=0)R’, -C(=O)NR'R®, -OC(=O)NR'R®, -OC(=O)SR’, -SR’, - S(=0)R’, -S(=0),R’, -S(=0),NR'R®, and R; R?is H, F, -CH,, -CN, or -C(=O)OR’; R¥is -C(=O)NR?-, -C(=0)0O-, -C(=0)(CR"R"),-, or (CRR""),-; R* is a straight chain or a branched (C,-Cg)alkyl, a straight chain or a branched (C,- Cglalkenyl, a straight chain or branched (C.-C; alkynyl), (C5-Cg)cycloalkyl, (C,-Cg)cycloalkenyl, (3-8 membered) heterocycloalkyl, (Cs-C,,)bicycloalkyl, (C,-C;,)bicycloalkenyl, (5-11 membered) heterobicycloalkyl, (C4-C,4)aryl, or (5-14 membered) heteroaryl; and wherein R* is optionally substituted with from one to three substitutents R® independently selected from F, Ct, Br, 1, nitro, cyano, -CF; -NR'R® -NR'C(=O)R?, -NR’C(=0)OR®, -NR'C(=0)NR®R®, -NR’S(=0),R®, - NR’S(=0),NRPR®, -OR’, -OC(=O)R’, -OC(=0)OR’, -C(=0)OR’, -C(=O)R’, -C(=O)NR'R®, - OC(=O)NR'R®, -OC(=0)SR’, -SR’, -8(=0)R, -S(=0),R’, -S(=0),NR'R?, or R’; each R’, R%, and R® is independently selected from H, straight chain or branched (C,- Cs)alkyl, straight chain or branched (C,-Cg)alkenyl, straight chain or branched (C,-Cg alkynyl), (Cs-Cy)cycloalkyl, (C,-Cgcycloalkenyl, (3-8 membered) heterocycloalkyl, (Cs-C,;)bicycloalkyl, ] (C;-Cyq)bicycloalkenyl, (5-11 membered) heterobicycloalkyl, (C¢-C,)aryl, and (5-14 membered) heteroaryl, wherein R’, R®, and R® are each independently optionally substituted with from one to ) six substituents independently selected from F, CI, Br, I, -NO,, -CN, -CF,; -NR'"R" . NR'"C(=O)R", -NR'"C(=O)OR", -NR"C(=O)NR"'R™, -NR'*S(=0),R", -NR"S(=0),NR"'R®2, . OR", -OC(=0)R", -OC(=O)OR', -OC(=O)NR™R'", -OC(=0)SR", -SR™, -S(=0)R", -S(=0),R™ -S(=0),NR"R", -C(=0)R"?, -C(=0)OR'", -C{(=0)NR"R"", and RY;
or, when R” and R® are as in NR’R®, they may instead optionally be connected to form with the nitrogen of NR'R® to which they are attached a heterocycloalkyl moiety of from three to seven ring members, said heterocycloalkyl moiety optionally comprising one or two further ) heteroatoms independently selected from N, O, and S; each R'°, R", and R" is independently selected from H, straight chain or branched (C- Ce)alkyl, straight chain or branched (C,-Cg)alkenyl, straight chain or branched (C,-Cq alkynyl), (C5-Cp)eycloalkyl, (C,-Cg)cycloalkenyl, (3-8 membered) heteracycloalkyt, (Cs-C,;)bicycloalkyl, (C,-Cy,)bicycloalkenyl, (5-11 membered) heterobicycloalkyl, (Ce-Cy4)aryl, and (5-14 membered) heteroaryl, wherein R'™, R"', and R™ are each independently optionally substituted with from one to six substituents independently selected from F, Cl, Br, I, NO, -CN, -CF; -NR"R™, -NR®C(=O)R™, -NR™“C(=0)OR", -NR’C(=O)NR"R', -NR%S(=0),R", -NR"S(=0),NR"R", -OR™, -OC(=0)R®, -OC(=0)OR®, -OC(=O)NR®RY, -OC(=0)SR®, -SR™, -S(=O)R", -S(=0),R™, -S(=0),NR"R", -C(=0)R", -C(=0)OR™, -C(=0)NR™R™, and R", each R%, R", and R" js independently selected from H, straight chain or branched (C,- - -- - Cglalkyl, straight chain or branched (C,-Cg)alkenyl, straight chain or branched (C,-Cg alkynyl), (C5-Cg)eycloalkyl, (C,-Cy)cycloalkenyl, (3-8 membered) heterocycloalkyl, (Cs-Cy;)bicycloalkyl, (C,-C,,)bicycloalkenyl, (5-11 membered) heterobicycloalkyl, (C¢-Cy,)aryl, and (5-14 membered) heteroaryl, wherein R™, R', and R' are each independently optionally substituted with from one to six substituents independently selected from F, Cl, Br, I, NO, -CN, -CF,, -NR"R", -NR'"C(=0)R", -NR'™C(=0)OR", -NR*C(=O)NR"R, -NR"S(=0),R"”, -NR'*S(=0),NR''R' -OR', .OC(=0)R'®, -OC(=0)OR'™, -OC(=O)NR'R', -OC(=O)SR', -SR'®, -S(=O)R', -5(=0),R'®, -8(=0),NR"™R" -C(=0)R", -C(=0)OR’, -C(=O)NR"R", and R™ each R*, R", and R" js independently selected from H, straight chain or branched (C,- Cplalkyl, straight chain or branched (C.,-Cglalkenyl, straight chain or branched (C,-C4 alkynyl), (Cs-Cg)cycloalkyl, (C,-Cgcycloalkenyl, (3-8 membered) heterocycloalkyl, (Cs-C,,)bicycloalkyl, (C;-C,4)bicycloalkenyl, (5-11 membered) heterobicycloalkyl, (CC, aryl, and (5-14 membered) heteroaryt; nis 0, 1,2, or 3; wherein R'* and R" in -C(=0)(CR"™R"),- and -(CR'R"),- are for each iteration of n defined independently as recited above; or a pharmaceutically acceptable salt thereof.
2. A compound according to claim 1, wherein R® is -(CR"R")_, ) -C(=O)NH- or -C(=O)(CR'"R"),-.
3. A compound according to claim 1, wherein R' is optionally substituted (C;-Cg)cycloalkyt or optionally substituted (Cs-C,,) bicycloalkyl.
:
4. A compound according to claim 3, wherein R' is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl, or bicyclo-[3.1.0]-hexyl, each optionally substituted.
’ 5. A compound according to claim 1, wherein R' is optionally substituted straight chain or branched (C,-Cg)alky! or optionally substituted straight chain or branched (C,- Caglalkenyl.
6. A compound according to claim 1, wherein R* is (C.-C, )aryl or (5-14 membered) heteroaryl, each optionally substituted.
7. A compound according to claim 6, wherein R* is phenyl, pyridyl, naphthyl, quinolyl, isoquinolyl, pyrimidinyl, pyrazinyl, or pyridazyl, each optionally substituted.
8 A compound according to any of claims 1-7, wherein RZ is hydrogen.
9. A compound of claim 1, selected from the group consisting of: (5-ethyl-2H-pyrazol-3-yl)-(6-methoxy-pyridin-2-yl)-amine; (5-cyclobutyl-2H-pyrazol-3-yl)-(6-methoxy-pyridin-2-yi)-amine Ce eee oo 15 (5-cyclobutyl-2H-pyrazol-3-yl)-naphthalen-2-yl-amine; (5-cyclobutyl-2H-pyrazol-3-yl)-naphthalen-1-yl-amine; N-(5-cyclobutyl-2H-pyrazol-3-yI)-N',N'-dimethyl-naphthalene-1,4-diamine; N-(5-cyclobutyl-2H-pyrazol-3-y)-N',N'-dimethyl-pyridine-2,6-diamine; (5-cyclobutyl-2H-pyrazol-3-yl}-(8-trifluoromethyl-pyridin-2-yl)-amine; (3-benzyloxy-phenyl)-(5-cyclobutyl-2H-pyrazol-3-yl)-amine; (5-cyclobutyl-2H-pyrazol-3-yl)-(3-triftuoromethyl-phenyl)-amine; N-(5-cyclobutyl-2H-pyrazol-3-yl)-N',N'-dimethyl-benzene-1,3-diamine; (5-cyclobutyl-2H-pyrazol-3-yl)-(3-methoxy-phenyi)-amine; (5-cyclobutyl-2H-pyrazol-3-yl)-(4-nitro-phenyl)-amine; (4-chloro-benzyl)-(5-cyclobutyl-2H-pyrazol-3-yl)-amine; (3-bromo-phenyl)-(5-cyclobutyl-2H-pyrazol-3-yl)-amine; (5-cyclobutyl-2H-pyrazol-3-yi)-quinolin-2-yl-amine; {5-(1,4-dioxa-spirof4.4]non-7-yl)-1H-pyrazol-3-yi]-(3-trifluoromethyl-phenyl}-amine; (6-chloro-pyridin-2-yl)-(5-cyclobutyl-2H-pyrazol-3-yl)-amine; 3-[5-(3-trifluoromethyl-phenylamino)-2H-pyrazoi-3-yl]-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; B (2-chloro-4-nitro-phenyl)-(5-cyclobutyl-2H-pyrazol-3-yl)-amine; 3-trans-[5-(3-trifluoromethyl-phenylamino)-2H-pyrazol-3-yl]-cyclopentanol; (3,5-bis-trifluoromethyl-phenyl}-(5-cyclobutyl-2H-pyrazol-3-yl}-amine; [5-(3-cis-benzylamino-cyclopentyl)-1H-pyrazol-3-yi}-(3-trifluoromethyl-phenyl)-amine;
{5-[3-cis-(4-methoxy-benzylamino)-cyclopentyll-1H-pyrazol-3-yi}-(3-trifluoromethyl- phenyl)-amine; 4-(5-cyclobutyl-2H-pyrazol-3-ylamino)-benzonitrile; ) (5-cyclobutyl-2H-pyrazol-3-yl)-(3-fluoro-phenyl)-amine;
(5-cyclobutyl-2H-pyrazol-3-yh-(3,5-dichloro-phenyl)-amine; (2-broma-pheny!)-(5-cyclobutyl-2H-pyrazol-3-yi}-amine; N-{cis-3-[5-(3-trifluoromethyl-phenylamino)-2H-pyrazol-3-yl}-cyclopentyl}-acetamide; pyridin-2-yl-{3-trans-[5-(3-trifluoromethyl-phenylamino)-2H-pyrazol-3-yl]-cyclopentyl}-
amine,
{5-cyclobutyl-1H-pyrazol-3-yl)-(4-methoxy-phenyl)-amine; pyridine-2-carboxylic acid . {3-[5-(3-trifluoromethyl-phenylamino)-2H-pyrazol-3-yl}-
cyclopentyl}-amide; 3-triftuoromethy!-N-{3-[5-(3-trifluoromethyl-phenylamino)-2H-pyrazol-3-yl]- cyclopentyl}-benzamide; oo. oo 15 : cyclobutanecarboxylic acid {3-[5-(3-trifluoromethyi-phenytamino)-2H-pyrazol-3-ylj- cyclopentyl}-amide; 2 ,2-dimethyl-N-{3-[5-(3-trifluoromethyl-phenylamino)-2H-pyrazol-3-yi}-cyclopentyt}- propionamide; 4-fluoro-N-{3-[5-(3-trifluoromethyl-phenylamino)-2H-pyrazol-3-yl}-cyclopenty!}- benzamide; 2,2,2-trifluoro-N-{3-[5-(3-trifluoromethyi-phenylamino)-2H-pyrazoi-3-yil-cyclopentyl}- acetamide; cyclopropanecarboxylic acid {3-[5-(3-triflucromethyl-phenylaminc)-2H-pyrazol-3-ylj- cyciopentyl}-amide; N-{3-[5-(3-trifluoromethyl-phenylamino)-2H-pyrazol-3-yi]-cyclopentyl}-propionamide; cyclohexanecarboxylic acid {3-[5-(3-trifluoromethyl-phenylamino)-2H-pyrazol-3-yi}- cyclopentyl}-amide; N-[5-(3-acetylamino-cyclopentyl)-2H-pyrazol-3-yl]-2-naphthalen-1-yl-acetamide; cyclopropanecarboxylic acid {3-[5-(2-naphthalen-1-yl-acetylamino)-1H-pyrazol-3-yi}- cyclopentyl}-amide; ’ 2-naphthalen-1-yl-N-{5-[3-(2,2,2-trifluoro-acetylamino)-cyclopentyi]-2H-pyrazol-3-yl}- acetamide; ) N-{3-[5-(2-naphthalen-1-yl-acetylamino)- 1H-pyrazol-3-ylj-cyciopentyl}-benzamide; N-(5-hydroxymethyl-1H-pyrazol-3-yl)-2-naphthalen-1-yl-acetamide; 2-naphthalen-1-ylI-N-{5-(thiazol-2-ylaminomethy!)- 1H-pyrazol-3-yl}-acetamide; N-[5-((1S)-hydroxy-ethyl)-2H-pyrazol-3-yl}-2-naphthalen- 1-yl-acetamide;
N-{5-[(1S)~(benzooxazoal-2-yloxy)-ethyl]-1H-pyrazol-3-yi}-2-naphthalen-1-yi- ) acetamide; N-{5-[(1S)-(benzothiazol-2-yioxy)-ethyl]-1H-pyrazol-3-yl}-2-naphthalen-1-yl- i acetamide;
N-[5-(3-hydroxy-1-methyl-propyl)-1H-pyrazol-3-yl]-2-naphthalen-1-yl-acetamide; N-[5-(benzothiazol-2-yloxymethyl)-1H-pyrazol-3-yl}-2-naphthalen-1-yl-acetamide; N-{5-[3-(benzothiazol-2-yloxy)-1-methyl-propyl]-1H-pyrazol-3-yl}-2-naphthalen-1-yl-
acetamide; N-[5-(2-hydroxy-(1S)-methyi-ethyl)-2H-pyrazol-3-yl}-2-naphthalen-1-yl-acetamide; N-{5-](1R)-(benzathiazol-2-yloxy)-ethyi]-1H-pyrazol-3-yi}-2-naphthalen-1-yl- acetamide; N-[5-(3-acetylamino-1-methyl-propyl)-1H-pyrazol-3-yl}-2-naphthalen-1-yl-acetamide; 3-methoxy-N-{cis-3-[5-(2-naphthalen-1-yl-acetylamino)-2H-pyrazol-3-yll-cyclobutyl}- benzamide; oo N-{5-(cis-3-acetylamino-cyclobutyl)-1H-pyrazol-3-yl]-2-naphthalen-1-yl-acetamide; N-{cis-3-[5-(2-naphthalen-1-yl-acetylamino)-2H-pyrazol-3-yl}-cyclobutyl}-benzamide; 2-cyclopropyl-N-{cis-3-[5-(2-naphthalen-1-yl-acetylamino)-2H-pyrazol-3-yl}- cyclobutyl}-acetamide; 6-chloro-pyridine-2-carboxylic acid {cis-3-[5-(2-naphthalen-1-yl-acetylamino)-2H- pyrazol-3-yl}-cyclobutyl}-amide; quinoline-2-carboxylic acid {cis-3-[5-(2-naphthalen-1-yl-acetylamino)-2H-pyrazol-3-yl]- cyclobutyl}-amide; pyrazine-2-carboxylic acid {cis-3-[5-(2-naphthalen-1-yl-acetylamino)-2H-pyrazol-3-yl]- cyclobutyl}-amide; 4-methoxy-N-{cis-3-[5-(2-naphthalen-1-yl-acetylamino)-2H-pyrazol-3-yl]-cyclobutyl}- benzamide; N-{cis-3-[5-(2-naphthalen-1-yl-acetylamino)-2H-pyrazol-3-yl]-cyclobutyl}-3-nitro- benzamide; N-{cis-3-[5-(2-naphthalen-1-yl-acetylamino)-2H-pyrazol-3-yi}-cyclobutyl}-3- trifluoromethyl-benzamide; i N-{cis-3-[5-(2-naphthalen-1-yl-acetylamino}-2H-pyrazol-3-yl}-cyclobutyl}- isobutyramide; ' 2-phenyl-cyclopropanecarboxylic acid {cis-3-[5-(2-naphthalen-1-yl-acetylamino)-2H- pyrazol-3-vylil-cyclobutyl}-amide; N-{5-[cis-3-(benzooxazol-2-yloxy)-cyclobutyi}-1H-pyrazol-3-yl}-2-naphthalen-1-yl- acetamide;
4-dimethylamino-N-{cis-3-[5-(2-naphthalen-1-yl-acetylamino)-2H-pyrazol-3-yl}- cyclobutyl}-benzamide; 3,5-dimethoxy-N-{cis-3-[5-(2-naphthalen-1-yl-acetylamino)-2H-pyrazol-3-yl]- ) cyclobutyl}-benzamide; 2-naphthalen-1-yI-N-[5-(cis-3-phenyl-cyclobutyl})-2H-pyrazol-3-yl]-acetamide; N-{5-[cis-3-(3-methoxy-phenyl)-cyclobutyi]-2H-pyrazol-3-yl}-2-naphthalen-1-yl- acetamide; N-{5-[cis-3-(2-methoxy-phenyl)-cyclobutyl]-2H-pyrazol-3-yl}-2-naphthalen-1-yl- acetamide; N-{5-[cis-3-(4-methoxy-phenyl)-cyclobutyl]-2H-pyrazol-3-yl}-2-naphthalen-1-yl- acetamide; 2-naphthalen-1-yl-N-[5-(cis-3-p-tolyl-cyclobutyl)-2H-pyrazol-3-yl]-acetamide; N-{5-[cis-3-(4-chloro-phenyl)-cyclobutyl]-2H-pyrazol-3-yl}-2-naphthalen-1-yi- acetamide; oo oo 15 2-(4-methoxy-phenyl)-N-{5-[cis-3-(2-methoxy-phenyl)-cyclobutyl}-2H-pyrazol-3-yi}- acetamide; N-{5-[cis-3-(2-methoxy-phenyl)-cyclobutyl}-2H-pyrazol-3-yl}-2-quinolin-6-yl-acetamide; N-{5-[cis-3-(2-methoxy-phenyl)-cyclobutyl}-2H-pyrazol-3-y1}-2-phenyl-acetamide; N-{5-[cis-3-(2-methoxy-phenyl)-cyclobutyl}-2H-pyrazol-3-yi}-2-pyridin-3-yl-acetamide; N-{5-[cis-3-(4-methoxy-phenyl)-cyclobutyl]-1H-pyrazol-3-yl}-2-quinolin-6-yl-acetamide; 2-quinolin-6-yI-N-[5-(cis-3-p-tolyl-cyclobutyl)-1H-pyrazol-3-yl]-acetamide; N-{5-[cis-3-(4-fiuoro-phenyl)-cyclobutyil-1H-pyrazol-3-yl}-2-quinolin-6-yl-acetamide; N-{5-[cis-3-(4-chloro-phenyl)-cyclobutyl}-1H-pyrazol-3-yl}-2-quinolin-6-yl-acetamide; 2-quinolin-6-yl-N-[5-(cis-3-m-tolyl-cyclobutyl)-1H-pyrazol-3-yl}-acetamide; 4-dimethylamino-N-{cis-3-[5-(2-naphthalen- 1 -yl-acetylamino)-2H-pyrazol-3-yl]- cyclobutyl}-benzamide; 2-naphthalen-1-yl-N-{5-{cis-3-(pyridin-2-yloxy)-cyclobutyl]-1H-pyrazol-3-yl}-acetamide; 6-methyl-pyridine-2-carboxylic acid {cis-3-[5-{2-naphthalen-1-yl-acetylamino)-2H- pyrazol-3-yl]-cyciobutyl}-amide; 2-phenyl-cyclopropanecarboxylic acid methyl-{cis-3-[5-(2-naphthalen-1-yl- i acetylamino)-2H-pyrazol-3-yi}-cyclobutyl}-amide; N-{5-[cis-3-(3-methyl-pyrazin-2-yloxy)-cyclobutyl]- 1 H-pyrazol-3-yl}-2-naphthalen-1-yi- ) acetamide; {5-[cis-3-(2-methoxy-phenyl)-cyclobutyl}-1H-pyrazol-3-yl}-(6-methoxy-pyridin-2-yl)- amine;
N-{5-[cis-3-(3,8-dimethyl-pyrazin-2-yloxy)-cyclobutyl]-1H-pyrazol-3-yl}-2-naphthaien- 1-yl-acetamide; N-{5-[cis-3-(3-methoxy-pyridin-2-yloxy)-cyclobutyl]-1H-pyrazol-3-yl}-2-naphthalen-1- ’ yl-acetamide; 2-methyl-cyclopropanecarboxylic acid {cis-3-[5-(2-naphthalen-1-yl-acetylamino)-2H- pyrazol-3-yl}-cyclobutyl}-amide; 2-naphthaien-1-yl-N-{5-[cis-3-(3-trifluoromethyl-pyridin-2-yloxy)-cyclobutyi]- 1H- pyrazol-3-yl}-acetamide; 2-naphthalen-1-yl-N-{5-[cis-3-(3-nitro-pyridin-2-yloxy)-cyclobuty!}- ~~ 1H-pyrazol-3-yl}- acetamide; N-{5-[cis-3-(benzathiazol-2-yloxy)-cyclobutyl}-1H-pyrazol-3-yi}-2-naphthalen-1-yl- acetamide; 2-naphthalen-1-yl-N-{5-[cis-3-(4-trifluoromethyl-pyrimidin-2-yloxy)- cyclobutyl]-1H- pyrazol-3-yl}-acetamide; - oo 15 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-yf}-acetamide; 2-naphthaien-1-yl-N-{5-{3-(5-trifluoromethyl-pyridin-2-yloxy)- cyclobutyl}-1H-pyrazol-3- yl}-acetamide; N-{5-[3-(6-methoxy-pyridazin-3-yloxy)-cyclobutyl]-1H-pyrazol-3-yi}-2-naphthalen-1-yl- acetamide; 2-naphthalen-1 -yl-N-{5-[3-(pyrazin-2-yloxy)-cyclobutyi}-1 H-pyrazol-3-yl}-acetamide; N-{5-[3-(6-methyl-pyridin-2-yloxy)-cyclobutyl]-1H-pyrazol-3-yl}-2-naphthalen-1-yl- acetamide; N-{5-[3-(6-chloro-benzothiazol-2-yloxy)-cyclobutyl}-1H-pyrazol-3-yl}-2-naphthalen-1- yl-acetamide; N-{5-[3-(6-methoxy-benzothiazol-2-yloxy)-cyclobutyl]-1H-pyrazoi-3-yi}-2-naphthalen- 1-yl-acetamide; N-{5-[cis-3-(4-Hydroxy-phenyl)-cyclobutyl]-1H-pyrazol-3-yl}-2-quinolin-6-yl-acetamide; N-{5-[cis-3-(3-Hydroxy-phenyl)-cyclobutyl}-1H-pyrazol-3-yl}-2-quinolin-6-yl-acetamide; . 2-Naphthalen-1 -yl-N-[5-(cis-3-pyridin-3-yl-cyclobutyl)-2H-pyrazol-3-yl]-acetamide; N-[5-(cis-3-Naphthalen-2-yl-cyclobutyl)-2H-pyrazol-3-yl]-2-pyridin-3-yl-acetamide; ’ N-(5-indan-2-yl-1H-pyrazol-3-yl)-2-quinolin-6-yl-acetamide; N-[5-(cis-3-Pyridin-2-yl-cyclobutyl)-2H-pyrazot-3-yl}-2-quinolin-6-yl-acetamide; N-[5-(cis-3-Pyridin-2-yl-cyclobutyl)-2H-pyrazol-3-yl}-2-quinolin-6-yl-acetamide; 2~(4-Methoxy-phenyl)-N-[5-(cis-3-pyridin-4-yl-cyclobutyl)-2H-pyrazol-3-yl}-acetamide;
N-{5-[3-(cis-2-Dimethylaminomethyl-phenyl)-cyclobutyl}-2H-pyrazol-3-yl}-2-(4- methoxy-phenyl)-acetamide; N-(5-{cis-3-[3-(2-Dimethylamino-ethoxy)-phenyl]-cyclobutyl}-2H-pyrazol-3-yl)-2-(4- ’ methoxy-phenyl)-acetamide; N-{5-{cis-3-(2-Hydroxy-pheny!)-cyciobutyl}-2H-pyrazol-3-yi}-2-(4-methoxy-phenyl)- acetamide; N-(5-{cis-3-[2-(2-Dimethylamino-ethoxy)-phenyl}-cyclobutyl}-2H-pyrazol-3-yl)-2-(4- methoxy-phenyl)-acetamide; 2-(4-Methoxy-phenyl)-N-[5-(cis-3-phenyl-cyclobutyl)-2H-pyrazol-3-yl]-acetamide; N-{5-[cis-3-(2-Fluoro-phenyl)-cyclobutyl]-2H-pyrazol-3-yl}-2-(4-methoxy-pheny!)- acetamide; N-(5-{cis-3-[4-(Azetidin-3-yloxy)-phenyl}-cyclobutyl}-2H-pyrazol-3-yl)-2-(4-methoxy- phenyl)-acetamide; N-(5-{cis-3-[2-(Azetidin-3-yloxy}-phenyl]-cyclobutyl}-2H-pyrazol-3-yl)-2-(4-methoxy~ . . E 15 phenyl)-acetamide: 2-(4-Methoxy-phenyl)-N-{5-[cis-3-(2-methylsulfanyl-phenyl)-cyclobuty!]-2H-pyrazol-3- yi}-acetamide; N-{5-[cis-3-(2-Amino-phenyl)-cyclobutyl]-2H-pyrazol-3-yl}-2-(4-methoxy-phenyl)- acetamide; N-{5-[cis-3-(4-Cyano-phenyl}-cyclobutyl}-2H-pyrazol-3-yl}-2-(4-methoxy-phenyl)- acetamide; N-{5-[cis-3-(2-Cyano-phenyl)-3-hydroxy-cyclobuty!}-2H-pyrazoi-3-yi}-2-(4-methoxy- phenyl)-acetamide; N-{5-[cis-3-(2-Hydroxy-ethyl)-cyclobutyl]-1H-pyrazol-3-yl}-2-naphthalen-1-yi- acetamide; N-{5-[cis-3-(3-Cyano-phenyl)-cyclobutyl}-2H-pyrazol-3-yi}-2-(4-methoxy-phenyi)- acetamide; N-{5-[cis-3-(2-Cyano-phenyl)-cyclobutyl]-2H-pyrazol-3-yl}-2-(4-methoxy-phenyil)- acetamide; . N-{5-[cis-3-(3-Amino-phenyl)-cyclobutyl]-2H-pyrazol-3-yl}-2-(4-methoxy-phenyl)- ’ acetamide; 4-~(cis-3-{5-[2-(4-Methoxy-phenyl)-acetylamino}-1H-pyrazol-3-yl}-cyclobutyl)-benzoic ' acid methyl ester; N-{5-[cis-3-(4-Hydroxymethyl-pheny!)-cyclobutyl]-2H-pyrazol-3-y1}-2-(4-methoxy- phenyl}-acetamide; N-{5-[cis-3-(2-Hydroxy-phenyl)-cyclobutyl}-1H-pyrazol-3-yl}-2-phenyl-acetamide;
N-{5-[cis-3-(2-Hydroxy-pheny!)-cyclobutyl}-1H-pyrazol-3-yl}-2-quinolin-6-yl-acetamide; N-{5-[cis-3-(2-Hydroxy-phenyl)-cyclobutyl]-1H-pyrazol-3-yl}-acetamide; Cyclopropanecarboxylic acid {5-[cis-3-(2-hydroxy-phenyl)-cyclobutyl}-1H-pyrazol-3- ’ yl}-amide; 5} N-{5-[cis-3-(2-Hydroxy-phenyl)-cyclobutyl]-1H-pyrazol-3-yl}-isobutyramide; N-{5-[cis-3-(3-Aminomethyl-phenyl)-cyclobutyl]-2H-pyrazol-3-yl}-2-(4-methoxy- phenyl)-acetamide; N-{5-[cis-3-(3-Dimethylaminomethyl-phenyl)-cyclobutyl]-2H-pyrazol-3-yl}-2-(4- methoxy-phenyl)-acetamide; 3-(cis-3-{5-[2-(4-Methoxy-phenyl)-acetylamino]-1H-pyrazol-3-yl}-cyclobutyl)-benzoic acid methyl ester; N-{5-[cis-3-(3-Hydroxymethyl-phenyl)-cyclobutyl]-2H-pyrazol-3-yl}-2-(4-methoxy- phenyl}-acetamide; N-(5-{cis-3-[3-(1-Hydroxy-1-methyl-ethyl)-phenyl]-cyclobutyl}-2H-pyrazol-3-yl)-2-(4- EE : methoxy-phenyl)-acetamide; N-{5-[cis-3-(3-Ethylaminomethyl-phenyl)-cyclobutyi}-2H-pyrazol-3-yi}-2-(4-methoxy- phenyl)-acetamide; N-{5-[cis-3-(3-Cyclobutylaminomethyl-phenyl)-cyclobutyl]-2H-pyrazol-3-yi}-2-(4- methoxy-phenyl)-acetamide; 2-(4-Methoxy-phenyl)-N-{5-[cis-3-(3-propylaminomethyl-phenyl)-cyclobutyl]-2H- pyrazol-3-yl}-acetamide; N-{5-[cis-3-(3-Cyclopentylaminomethyl-phenyl)-cyclobutyl}-2H-pyrazol-3-yl}-2-(4- methoxy-phenyl)-acetamide; N-(5-{cis-3-[3-(Benzylamino-methyl)-phenyl]-cyclobutyl}-2H-pyrazol-3-yl)-2-(4- methoxy-phenyl)-acetamide; 2-(4-Methoxy-phenyl)-N-{5-{3-(3-methylaminomethyi-phenyl)-cyclobutyl}-2H-pyrazol- 3-yl}-acetamide; N-{5-[cis-3-(3-Cyclopropylaminomethyl-phenyl)-cyclobutyl}-2H-pyrazol-3-yl}-2-(4- methoxy-phenyl)-acetamide; 2-(4-Methoxy-phenyl)-N-{5-[cis-3-(3-pyrrolidin-1-yimethyl-phenyl)-cyclobutyl]-2H- ’ pyrazol-3-yl}-acetamide; N-{5-[cis-3-(3-Diethylaminomethyl-pheny!)-cyclobutyl]-2H-pyrazol-3-yl}-2-(4-methoxy- : phenyl)-acetamide; N-{5-[cis-3-(3-Azetidin-1-ylmethyl-phenyl)-cyclobutyl]-2 H-pyrazol-3-yl}-2-(4-methoxy- phenyl)-acetamide; and pharmaceutically acceptable salts of the foregoing compounds.
-g2-
10. A pharmaceutical composition for treating a disease or condition comprising ) abnormal cell growth or a neurodegenerative disease or condition in a mammal comprising a compound of claim 1 in an amount effective in treating said disease or condition, and a ’ pharmaceutically acceptable carrier.
11. A pharmaceutical composition for treating a disease or condition in a mammal the treatment of which can be effected or facilitated by altering dopamine mediated neurotransmission comprising a compound of claim 1 in an amount effective in treating said disease ar condition or in an amount effective to inhibit cdk5 activity, and a pharmaceuticaily acceptable carrier.
12. A pharmaceutical composition for treating in a mammal a disease or condition selected from male fertility and sperm motility; diabetes mellitus; impaired glucose tolerance; metabolic syndrome or syndrome X; polycystic ovary syndrome; adipogenesis and obesity; myogenesis and frailty, for example age-related decline in physical performance; acute sarcopenia, for example muscle atrophy and/or cachexia associated with burns, bed rest, limb SL a. 15 immobilization, or major thoracic, abdominal, and/or orthopedic surgery; sepsis; hair loss, hair thinning, and balding; and immunodeficiency, comprising a compound of claim 1 in an amount effective in treating said disease or condition, and a pharmaceutically acceptable carrier.
13. A pharmaceutical composition comprising a compound according to claim 1 and a second member selected from the group consisting of an SSRI, an NK-1 receptor antagonist, a 5HT,, antagonist, - ziprasidone, olanzapine, risperidone, L-745870, sonepiprazole, RP 62203, NGD 941, balaperidone, flesinoxan, gepirone, an acetylcholinesterase inhibitor, TPA, NIF, a potassium channel modulator such as BMS- 204352, and an NMDA receptor antagonist, wherein the cdk5 inhibitor and the second member are together in an effective amount, and a pharmaceutically acceptable carrier.
14. A compound of the formula Ne Prot Te 0 NH, R? O— l : wherein Prot is a protecting group; i R?is H, F, -CH,, -CN, or -C(=O)OR’; and n is an integer selected from 1, 2, 3, and 4.
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US6613776B2 (en) | 2000-09-15 | 2003-09-02 | Vertex Pharmaceuticals Incorporated | Pyrazole compounds useful as protein kinase inhibitors |
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