US 20090156582A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2009/0156582 A1 Tsukamoto et al. (43) Pub. Date: Jun. 18, 2009

(54) PYRAZOLE COMPOUND Publication Classification (76) Inventors: Tetsuya Tsukamoto, Osaka-shi, (51) Int. Cl. Osaka (JP); Takeshi Yamamoto, A6II 3/55 (2006.01) Osaka-shi,Osaka (JP); Ryosuke A63L/454 (2006.01) Tokunoh, Osaka-shi, Osaka (JP); A63L/462 (2006.01) Tomohiro Kawamoto, Osaka-shi, C07D 403/02 (2006.01) Osaka (JP); Masahiro Okura, Osaka-shi, Osaka (JP); Masakumi (52) U.S. Cl...... 514/217.09: 514/406; 514/326; Kori, Osaka-shi, Osaka (JP); 548/364.1: 548/368.4: 546/211; 540/603 Katsuhito Murase, Osaka-shi, Osaka (JP) (57) ABSTRACT Correspondence Address: The present invention provides a pyrazole compound repre WENDEROTH, LIND & PONACK, L.L.P. sented by the formula (I): 1030 15th Street, N.W., Suite 400 East Washington, DC 20005-1503 (US) b (Io) (21) Appl. No.: 11/884,054 Ra R (22) PCT Filed: Feb. 9, 2006 (86). PCT No.: PCT/UP2006/302686

S371 (c)(1), wherein ring Ao is a pyrazole ring optionally further having 1 (2), (4) Date: Sep. 14, 2007 or 2 substituents; R is a substituted carbamoyl group; and R' (30) Foreign Application Priority Data is an optionally Substituted acylamino group, or a salt thereof or a prodrug thereof, which is useful as an agent for the Feb. 9, 2005 (JP) ...... O333562005 prophylaxis or treatment of GSK-3? related pathology or Dec. 22, 2005 (JP) ...... 3709622005 disease, and a GSK-3? inhibitor including same. US 2009/0156582 A1 Jun. 18, 2009

PYRAZOLE COMPOUND activated during nerve cell death. Accordingly, GSK-3 inhibi tor is expected to not only Suppress neurodegeneration but TECHNICAL FIELD also suppress two major pathological findings of Alzheimer's 0001. The present invention relates to pyrazole com disease. As our own findings, we have clarified that PI3 pounds having a Glycogen Synthase Kinase 3 (GSK-3) kinase-Akt system signal transduction plays a key role in inhibitory activity, which are useful as pharmaceutical neuropoiesis and nerve regeneration and found that inhibition agents, and use thereof. of GSK-3 located downstream thereof can facilitate neu ropoiesis. Considering our new findings in combination, BACKGROUND ART there is a possibility that GSK-3 inhibitor suppresses two major pathological findings of Alzheimer's disease and addi 0002 GSK-3 was found to be a kinase that phosphorylates tionally Suppresses neurodegeneration, induces neuropoiesis and deactivates glycogen synthase. It has been clarified at present that it is involved in the oxidation and synthesis of and achieves regeneration of function. It is assumed that fatty acid, or abnormality in insulin signaling pathway via GSK-3 inhibitor having the above-mentioned properties can phosphates of various protein groups related to metabolism be an ultimate therapeutic drug for Alzheimer's disease, and and signal transduction Such as AcylCoA carboxylase, ATP can also be effective as a therapeutic drug for neurodegenera citrate lyase. Insulin receptor substrate-1 and the like. More tive diseases Such as Parkinson's syndrome and the like, cere over, GSK-3 is known to phosphorylate various structural brovascular disorders and the like. Since a report has recently proteins and regulate functions thereof. Particularly, phos documented that Akt System signal transduction decreases in phorylation of tau protein has been attracting attention in schizophrenia, GSK-3 inhibitor may become a completely relation to the onset of Alzheimer's disease. In addition, new type of therapeutic drug for Schizophrenia. GSK-3 is involved in phosphorylation of various transcrip 0005. The following compounds are known as compounds tion factors, and particularly, activates activator protein-1, having a GSK-3 inhibitory activity. cyclic AMP response element binding protein, nuclear factor (1) Purine, pyrimidine derivatives of activated T cells, heat shock factor-1, b-catenin, Myc. C/EBP, NFK-b or the like. Therefore, its inhibitor is expected The compounds described in WO200220495 such as to be a therapeutic drug for Alzheimer's disease, cerebral apoplexy, manic-depressive illness, Schizophrenia, cancer, type II diabetes and obesity. 0003. In insulin signaling pathway, GSK-3 is negatively H regulated by phosphorylation via Akt (protein kinase B: also C C C described as PKB). In diabetic patients, increased activity of GSK-3 and synthesis of fatty acids and/or insulin resistance S.-->'s H are considered to be synergistically induced by the over Na2 N lapped occurrence of promoted GSK-3 gene expression and insulin dysfunction. Since GSK-3 positively regulates the process of adipocyte differentiation and/or maturation via phosphorylation of C/EBP, increased GSK-3 activity triggers obesity, which in turn aggravates diabetes. In fact, it has been and the like, reported that administration of GSK-3 inhibitor improves the compounds described in EP 1136099-A1 such as insulin resistance of model animals of TYPE II diabetes. We have additionally elucidated as our own findings that GSK-3 inhibitor Suppresses adipocyte differentiation and/or matura R3 tion, expresses an antiobesity effect, as well as promotes Sugar-dependent insulin secretory action of pancreatic re- N1 N cells. Given these findings in combination, GSK-3 is consid ered to be additively and/or synergistically involved in the M l onset of diabetes in the insulin targeting tissues such as liver, (rs1-no skeletal muscle, fat, pancreas and the like, and GSK-3 inhibi N R2 tor can be an effective therapeutic drug for obesity and/or A diabetes because it eliminates these factors. RI 0004 Activation of GSK-3 in Alzheimer's brain has been reported, and therefore, GSK-3 is considered to be involved in neuritic plaque and neurofibrillary change, which are the two major pathological findings in Alzheimer's disease. In the metabolism of amyloid precursor proteins, GSK-3 is linked to Y Secretase to positively regulate the production off amyloid HN protein, a main constituent component of neuritic plaque. As Cl for tau protein, which is a main constituent component of -----, R2 neurofibrillary change, GSK-3 is considered to facilitate R!: R2: H, alkyl phosphorylation of the protein, prevent axonal transport, and R. 2.3 or 4-Py finally induce neurodegeneration. It is also known that R; H, alkyl, halo, halo-alkyl, OH, alkoxy, NO2, CN GSK-3 is located downstream of the PI3 kinase Akt system signal transduction important for the nerve cell Survival, and US 2009/0156582 A1 Jun. 18, 2009

and the like, the compounds described in EP 1136482-A1. EP the compounds described in WO 01/56567-A1 such as 1136483, EP 1136486-A1 and WO2002/18386-A1 such as p–CIOS n E-A N NH2 O

S HN { N NH 2 and the like, and the like. (2) Azole derivatives The compounds described in WO2002057259-A2 such as A: alkylene, CO or bond B: CO, SO, SO2, CFNOR or bond D: OH, halo, CN, NO2, alkoxy, E: alk(en)yl, alkynyl, alkylthio, alkoxy, CO2H, alkoxycarbonyl, subs-Ph, Py, R2 CH R2 e e and the like. NH NH N / N / (3) Maleimide derivatives HN N HN N The compounds described in WO200021927, Rx WO200038675 and WO2001 74771 Such as

ls R1 ls RI H Ry s s1 s s1 O N O and the like, o C the compounds described in WO2003004478 such as

o-Clu Me C and the like, the compounds described in WO2002/10158 such as and the like, the compounds described in WO200224694-A1 and H WO20025.0073-A1 Such as O N O

O

-(RI 21 Sx ( ) (/ NN R N RG-1- Yn N R5 s H H O O N O

21 * CH Y. 3 N N1 N Y: CH or N R': alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, aralkyl, heterocyclyl, R2. aryl or hetroaryl and the like, and the like. US 2009/0156582 A1 Jun. 18, 2009

(4) Other heterocyclic compounds (2) The following compounds have been reported as phos The compounds described in Chemistry & Biology 2000, 7, phodiesterase IV inhibitors (Journal of Computer-Aided 51-63 such as Molecular Design, vol. 15, No. 9, pages 767-785, 2001).

N-(9-methyl-4-oxo-1-phenyl-3,4,6,7-tetrahydro-1,4-diaz epino.6.7.1-hiindol-3-yl)-4-acetylamino-2,5-dimethyl-2H pyrazole-3-carboxamide.

N Me H and the like, Ph the compounds described in WO 01/60374-A1 such as Me NHAC O H N (3) The following compounds have been reported as antibac CC terial agents (Pamazie, Vol. 53, No. 5, pages 346-348, 1998): 0009 (a) N-phenyl-4-benzoylamino-2-ethyl-5-methyl 2H-pyrazole-3-carboxamide, 0010 (b) N-phenyl-2-ethyl-5-methyl-4-(2-nitrobenzoy C lamino)-2H-pyrazole-3-carboxamide, and the like. 0011 (c) N-(4-chlorophenyl)-2-ethyl-5-methyl-4-(4-ni (5) As ATP noncompetitive compounds, the compound trobenzoylamino)-2H-pyrazole-3-carboxamide, and described in J. Med. Chem., 2002,45(6), 1292-1299 which is 0012 (d) N-phenyl-2-ethyl-5-methyl-4-(4-methylben a thiadiazolidinone derivative Zoylamino)-2H-pyrazole-3-carboxamide.

Me 2 N N1 Et -N -Nip. O o N\ f Ph-C-NH -Nin M NY O Me CFO and the like. 0006. On the other hand, the following compounds are known as the pyrazole compounds. (1) The following compounds have been reported as antibac terial agents or antifungal agents (WO02/094793). 0007 (a) N-methyl-2,5-dimethyl-4-2-4-(4-nitrophe noxy)phenyl)acetylamino-2H-pyrazole-3-carboxamide, C and Et O 0008 (b) N-methyl-4-2-4-(4-chlorophenoxy)phenyl 1. C-NH acetylamino-2,5-dimethyl-2H-pyrazole-3-carboxamide.

US 2009/0156582 A1 Jun. 18, 2009

pathology or disease in mammal, which resulted in the -continued completion of the present invention. 0028. Accordingly, the present invention provides the fol y lowing. O N O (1) A compound represented by the formula

C NH O (Io) | Ra Rb Me n N N NH- i -Me \ O NF C-N-Me | O Me wherein Ph ring Ao is a pyrazole ring optionally further having 1 or 2 Substituents; y - Et R" is a Substituted carbamoyl group; and H R’ is an optionally substituted acylamino group or a salt N N O thereof, excluding the following compounds; y ( f a 0029. 1) N-methyl-2,5-dimethyl-4-2-4-(4-nitrophe N N noxy)phenyl)acetylamino-2H-pyrazole-3-carboxamide, Me1 NH H 0030) 2) N-methyl-4-2-4-(4-chlorophenoxy)phenyl O acetylamino-2,5-dimethyl-2H-pyrazole-3-carboxamide, Me -SV 0031. 3) N-(9-methyl-4-oxo-1-phenyl-3,4,6,7-tetrahy O dro-1,4-diazepino.6.7.1-hiindol-3-yl)-4-acetylamino-2, y O 5-dimethyl-2H-pyrazole-3-carboxamide, 0032 4) N-phenyl-4-benzoylamino-2-ethyl-5-methyl / N 2H-pyrazole-3-carboxamide, N f NH \ NH 0033 5) N-phenyl-2-ethyl-5-methyl-4-(2-nitrobenzoy \ lamino)-2H-pyrazole-3-carboxamide, 0034 6) N-(4-chlorophenyl)-2-ethyl-5-methyl-4-(4-ni M-- Ni--M. C O trobenzoylamino)-2H-pyrazole-3-carboxamide, Me O O 0035 7) N-phenyl-2-ethyl-5-methyl-4-(4-methylbenzoy lamino)-2H-pyrazole-3-carboxamide, 0024 However, it has not been known heretofore that 0036 8) N-methyl-N-(2-phenyl-2H-pyrazol-3-yl)-4- these pyrazole compounds have a GSK-3 inhibitory action. acetylamino-2-ethyl-5-methyl-2H-pyrazole-3-carboxam ide, 0037 9) N-methyl-N-(5-methyl-2-phenyl-2H-pyrazol-3- DISCLOSURE OF THE INVENTION yl)-4-acetylamino-2-ethyl-5-methyl-2H-pyrazole-3-car 0025 Conventional compounds having a GSK-3 inhibi boxamide, tory action have some problems to be solved. Such as effec 0038 10) N-methyl-N-(2-methyl-2H-pyrazol-3-yl)-4- tiveness (e.g., insufficient GSK-3 inhibitory action, insuffi acetylamino-2-ethyl-5-methyl-2H-pyrazole-3-carboxam cient selectivity to other kinase inhibitory action and the like), ide, and safety (e.g., possible side effects and the like). In addition, 0039) 11) N-(2,5-dimethyl-2H-pyrazol-3-yl)-N-methyl since they are not sufficient in the property (stability, solubil 4-acetylamino-2-ethyl-5-methyl-2H-pyrazole-3-carboxa ity and the like), oral absorbability, transferability to target mide, organ and the like, practically satisfactory results as a phar 0040 12) N-(4-tert-butylbenzyl)-4-acetylamino-2,5-dim maceutical agent have not been achieved entirely. Thus, the ethyl-2H-pyrazole-3-carboxamide, development of a superior GSK-3 inhibitor effective as a 0041 13) N-(4-tert-butylbenzyl)-4-(2-chloroacety pharmaceutical agent for GSK-3 related pathology or disease lamino)-2,5-dimethyl-2H-pyrazole-3-carboxamide, has been demanded. 0042. 14) N-(4-tert-butylbenzyl)-4-benzoylamino-2,5- 0026. The present invention aims at providing a safe dimethyl-2H-pyrazole-3-carboxamide, GSK-3 inhibitor useful as an agent for the prophylaxis or 0043 15) N,N-dimethyl-4-methanesulfonylamino-1-me treatment of GSK-3 related pathology or disease. thyl-5-1-methyl-2,5-dioxo-4-(1-phenylpropylamino)-2, 0027. The present inventors have conducted intensive 5-dihydro-1H-pyrrol-3-ylamino)-1H-pyrazole-3-car studies and found that the pyrazole compounds represented boxamide, by the following formulas (I) and (I) or salts thereof unex 0044 16) N.N-dimethyl-5-2,5-dioxo-4-(1-phenylpropy pectedly have a superior GSK-3 specific inhibitory activity lamino)-2,5-dihydro-1H-pyrrol-3-ylamino-4-methane based on their specific chemical structures, and further, Supe sulfonylamino-1-methyl-1H-pyrazole-3-carboxamide, rior properties of pharmaceutical product such as stability, 0045. 17) N,N-dimethyl-5-(4-chloro-1-methyl-2,5-di solubility and the like, and can be safe and useful pharmaceu oxo-2,5-dihydro-1H-pyrrol-3-ylamino)-4-methanesulfo tical agents for the prophylaxis or treatment of GSK-3 related nylamino-1-methyl-1H-pyrazole-3-carboxamide, US 2009/0156582 A1 Jun. 18, 2009

0046) 18) N,N-dimethyl-5-(4-chloro-1-methyl-2,5-di (8) mono- or di-Caryl-amino group; oxo-2,5-dihydro-1H-pyrrol-3-ylamino)-4-methanesulfo (9) mono- or di-C7-caralkyl-amino group; nylamino-1-methyl-1H-pyrazole-3-carboxamide. (10) N-Cl alkyl-N-Cl aryl-amino group; (2) The compound of the above-mentioned (1), wherein the (11) N-Cl alkyl-N-(C. alkyl-Caryl)-amino group: compound represented by the formula (Io) is a compound (12) N-Cl alkyl-N-C-7-caralkyl-amino group; represented by the formula: (14) optionally halogenated Calkoxy group: (15) C. alkylthio group optionally Substituted by C. alkoxy group; (I) (18) optionally esterified carboxyl group; R1 O R3 R4 V V A (19) carbamoyl group; N N-X (20) thiocarbamoyl group; A (21) mono- or di-C alkyl-carbamoyl group; R2 (22) mono- or di-Caryl-carbamoyl group; NN A (23) mono- or di-5- to 7-membered heterocycle-carbamoyl group; (24) C. alkyl-carbonylamino group optionally substituted wherein by carboxyl group; R" is an optionally substituted hydrocarbon group or an (25) Caryloxy group optionally substituted by 1 to 3 optionally substituted heterocyclic group, Substituents selected from halogen atom, hydroxy group, R is a hydrogen atom or an optionally substituted hydrocar amino group, nitro group, cyano group, optionally haloge bon group, or nated C. alkyl group, mono- or di-C alkyl-amino group, R" and R form, together with the adjacent nitrogen atom, an C-1 aryl group, mono- or di-Cola aryl-amino group, Cas optionally substituted nitrogen-containing heterocycle; cycloalkyl group, Calkoxy group, Calkoxy-C alkoxy R is a hydrogen atom or an optionally substituted hydrocar group, C- alkylthio group, C- alkylsulfinyl group, C bon group; alkylsulfonyl group, an optionally esterified carboxyl group, R" is an optionally substituted hydrocarbon group, an option carbamoyl group, thiocarbamoyl group, mono- or di-C ally Substituted heterocyclic group, an optionally Substituted alkyl-carbamoyl group, mono- or di-C aryl-carbamoyl hydroxy group, oran optionally Substituted amino group; ring group, Sulfamoyl group, mono- or di-C alkyl-sulfamoyl A is a pyrazole ring represented by the formula: group and mono- or di-Co-1 aryl-sulfamoyl group; (27) heterocyclic oxy group optionally substituted by 1 to 3 Substituents selected from halogen atom, hydroxy group, amino group, nitro group, cyano group, optionally haloge nated C. alkyl group, mono- or di-C alkyl-amino group, C-1 aryl group, mono- or di-Cola aryl-amino group, Cas cycloalkyl group, Calkoxy group, Calkoxy-C alkoxy group, C- alkylthio group, C- alkylsulfinyl group, C alkylsulfonyl group, an optionally esterified carboxyl group, carbamoyl group, thiocarbamoyl group, mono- or di-C alkyl-carbamoyl group, mono- or di-C aryl-carbamoyl wherein R is a hydrogen atom, an optionally substituted group, Sulfamoyl group, mono- or di-C alkyl-sulfamoyl hydrocarbon group or an optionally substituted acyl group; group and mono- or di-Caryl-sulfamoyl group; and R is a hydrogenatom oran optionally substituted hydro (31) a Czaralkyloxy group optionally substituted by 1 to 3 carbon group; and Substituents selected from halogen atom, hydroxy group, X is a carbonyl group or a Sulfonyl group. amino group, nitro group, cyano group, optionally haloge (3) The compound of the above-mentioned (2), wherein R is nated C. alkyl group, mono- or di-C alkyl-amino group, a hydrogen atom. C-1 aryl group, mono- or di-Cola aryl-amino group, Cas (4) The compound of the above-mentioned (2), wherein R' is cycloalkyl group, Calkoxy group, Calkoxy-C alkoxy a C- alkyl group, a C2-alkenyl group or a C2-alkynyl group, C- alkylthio group, C- alkylsulfinyl group, C group, which is optionally substituted by 1 to 5 substituents alkylsulfonyl group, an optionally esterified carboxyl group, selected from halogen atom, optionally Substituted hydroxy carbamoyl group, thiocarbamoyl group, mono- or di-C group, optionally Substituted thio group, optionally Substi alkyl-carbamoyl group, mono- or di-C aryl-carbamoyl tuted Sulfinyl group, optionally Substituted Sulfonyl group, group, Sulfamoyl group, mono- or di-C alkyl-sulfamoyl optionally Substituted amino group, nitro group, cyano group, group and mono- or di-Caryl-sulfamoyl group; and optionally Substituted carbonyl group. (32) C. alkylsulfonyloxy group; (5) The compound of the above-mentioned (2), wherein R' is (33) tri-C alkyl-silyloxy group; a C- alkyl group, a C2-alkenyl group, or a C2-alkynyl (34) nitrogen-containing heterocycle-carbonyl group; group optionally having, at Substitutable positions, 1 to 5 (35) Caryl-carbonyl group: substituents selected from (36) Caryl-thio group; (1) halogen atom; (37) optionally halogenated Caryl-sulfonyl group; (2) hydroxy group; (38) nitrogen-containing heterocycle-Sulfonyl group; and (3) amino group; (39) nitrogen-containing heterocycle-amino group optionally (4) nitro group; Substituted by cyano group. (5) cyano group; (6) The compound of the above-mentioned (2), wherein R' is (7) mono- or di-C alkyl-amino group; a C- alkyl group optionally Substituted by 1 to 5 substituents US 2009/0156582 A1 Jun. 18, 2009 selected from halogen atom, optionally Substituted hydroxy group, Sulfamoyl group, mono- or di-C alkyl-sulfamoyl group, optionally Substituted thio group, optionally Substi group and mono- or di-Caryl-sulfamoyl group; tuted amino group, nitro group, cyano group, and optionally (32) Ce alkylsulfonyloxy group; Substituted carbonyl group. (33) tri-C alkyl-silyloxy group; (7) The compound of the above-mentioned (2) wherein R' is (34) nitrogen-containing heterocycle-carbonyl group; a C- alkyl group optionally having, at substitutable posi (35) Caryl-carbonyl group; tions, 1 to 5 substituents selected from (35) Caryl-thio group: (1) halogen atom; (37) optionally halogenated Caryl-sulfonyl group; (2) hydroxy group; (38) nitrogen-containing heterocycle-Sulfonyl group; and (3) amino group; (39) nitrogen-containing heterocycle-amino group optionally (4) nitro group; Substituted by cyano group. (5) cyano group; (8) The compound of the above-mentioned (2), wherein R is (7) mono- or di-C alkyl-amino group; a hydrogen atom. (8) mono- or di-Caryl-amino group; (9) The compound of the above-mentioned (2), wherein R is (9) mono- or di-C7-caralkyl-amino group; an optionally substituted Caryl group or an optionally (10) N-Cl alkyl-N-C-aryl-amino group: Substituted heterocyclic group. (11) N-Cl alkyl-N-(C. alkyl-Caryl)-amino group; (10) The compound of the above-mentioned (2), wherein R (12) N-Cl alkyl-N-C7 aralkyl-amino group: is a hydrogen atom. (14) optionally halogenated C. alkoxy group; (11) The compound of the above-mentioned (2), wherein R (15) C. alkylthio group optionally Substituted by C. is a hydrogen atom. alkoxy group; (12) The compound of the above-mentioned (2), wherein R (18) optionally esterified carboxyl group; and Rare hydrogen atoms. (19) carbamoyl group; (13) The compound of the above-mentioned (2), wherein X is (20) thiocarbamoyl group; a carbonyl group. (21) mono- or di-C alkyl-carbamoyl group; (14) The compound of the above-mentioned (2), which is (22) mono- or di-Caryl-carbamoyl group; selected from the following: (23) mono- or di-5- to 7-membered heterocycle-carbamoyl 0047 N-(3-(((2-cyanoethyl)amino)carbonyl)-1H-pyra group; Zol-4-yl)pyridine-2-carboxamide; (24) C alkyl-carbonylamino group optionally substituted 0048 N-(3-(((2-cyanoethyl)amino)carbonyl)-1H-pyra by carboxyl group; Zol-4-yl)-6-methylpyridine-2-carboxamide; (25) Caryloxy group optionally Substituted by 1 to 3 0049 N-(3-(((3,3,3-trifluoropropyl)amino)carbonyl)- Substituents selected from halogen atom, hydroxy group, 1H-pyrazol-4-yl)pyridine-2-carboxamide; amino group, nitro group, cyano group, optionally haloge 0050 4-(benzoylamino)-N-(2-cyanoethyl)-1H-pyrazole nated C. alkyl group, mono- or di-C alkyl-amino group. 3-carboxamide: C-1 aryl group, mono- or di-Cola aryl-amino group, Cas 0051 N-(3-(((3-isopropoxypropyl)amino)carbonyl)-1H cycloalkyl group, Calkoxy group, Calkoxy-C alkoxy pyrazol-4-yl)-6-methylpyridine-2-carboxamide; group, C- alkylthio group, C- alkylsulfinyl group, C alkylsulfonyl group, an optionally esterified carboxyl group, 0.052 N-(2-cyanoethyl)-4-(2-furoylamino)-1H-pyrazole carbamoyl group, thiocarbamoyl group, mono- or di-C 3-carboxamide: alkyl-carbamoyl group, mono- or di-C aryl-carbamoyl 0053 N-(3-(((3-hydroxypropyl)amino)carbonyl)-1H group, sulfamoyl group, mono- or di-C alkyl-sulfamoyl pyrazol-4-yl)pyridine-2-carboxamide; group and mono- or di-Caryl-sulfamoyl group; 0054 N-(3-(((2-isopropoxyethyl)amino)carbonyl)-1H (27) heterocyclic oxy group optionally substituted by 1 to 3 pyrazol-4-yl)-6-methylnicotinamide; Substituents selected from halogen atom, hydroxy group, 0055 6-methyl-N-(3-(((2.2.2-trifluoroethyl)amino)car amino group, nitro group, cyano group, optionally haloge bonyl)-1H-pyrazol-4-yl)pyridine-3-carboxamide; and nated C. alkyl group, mono- or di-C alkyl-amino group. 0056 N-(3-(((2-cyanoethyl)amino)carbonyl)-1H-pyra C-1 aryl group, mono- or di-Cola aryl-amino group, Cas Zol-4-yl)-6-methylpyridine-3-carboxamide. cycloalkyl group, Calkoxy group, Calkoxy-C alkoxy (15) A prodrug of the compound of the above-mentioned (1). group, C- alkylthio group, C- alkylsulfinyl group, C (16) A pharmaceutical agent comprising the compound of the alkylsulfonyl group, an optionally esterified carboxyl group, above-mentioned (1) or the prodrug of the above-mentioned carbamoyl group, thiocarbamoyl group, mono- or di-C (15). alkyl-carbamoyl group, mono- or di-C aryl-carbamoyl (17) A GSK-3? inhibitor comprising the compound of the group, sulfamoyl group, mono- or di-C alkyl-sulfamoyl above-mentioned group and mono- or di-Caryl-sulfamoyl group; (1) or the prodrug of the above-mentioned (15). (31) C. aralkyloxy group optionally Substituted by 1 to 3 (18) A neural stem cell differentiation promoter comprising Substituents selected from halogen atom, hydroxy group, the GSK-3? inhibitor of the above-mentioned (17). amino group, nitro group, cyano group, optionally haloge (19) An agent for the prophylaxis or treatment of neurode nated C. alkyl group, mono- or di-C alkyl-amino group. generative disease or diabetes, which comprises the com C-1 aryl group, mono- or di-Cola aryl-amino group, Cas pound of the above-mentioned (1) or the prodrug of the cycloalkyl group, Calkoxy group, Calkoxy-C alkoxy above-mentioned group, C- alkylthio group, C- alkylsulfinyl group, C (15). alkylsulfonyl group, an optionally esterified carboxyl group, (20) A hypoglycemic agent comprising the compound of the carbamoyl group, thiocarbamoyl group, mono- or di-C above-mentioned alkyl-carbamoyl group, mono- or di-C aryl-carbamoyl (1) or the prodrug of the above-mentioned (15). US 2009/0156582 A1 Jun. 18, 2009

(21) A GSK-3? inhibitor comprising a compound represented wherein by the formula: ring Ao is a pyrazole ring optionally further having 1 or 2 (Io) Substituents; Ra Rb R" is substituted carbamoyl; and R’ is optionally substituted acylamino, or a salt thereof or a prodrug thereof to a subject. (28) A method of lowering blood glucose comprising admin istering a compound represented by the formula: wherein ring Ao is a pyrazole ring optionally further having 1 or 2 (Io) Substituents; Ra Rb R" is substituted carbamoyl; and R’ is optionally substituted acylamino, or a salt thereof or a prodrug thereof. (22) A neural stem cell differentiation promoter comprising the GSK-3? inhibitor of the above-mentioned (21). (23) An agent for the prophylaxis or treatment of neurode generative disease or diabetes comprising the GSK-3? inhibi tor of the above-mentioned (21). wherein (24) A hypoglycemic agent comprising the GSK-33 inhibitor ring Ao is a pyrazole ring optionally further having 1 or 2 of the above-mentioned (21). Substituents; (25) A method of inhibiting GSK-3B comprising administer R" is substituted carbamoyl; and ing a compound represented by the formula: R’ is optionally substituted acylamino, (Io) or a salt thereof or a prodrug thereof to a subject. Ra Rb (29) Use of a compound represented by the formula:

b (Io) Ra R wherein ring Ao is a pyrazole ring optionally further having 1 or 2 Substituents; R" is substituted carbamoyl; and R’ is optionally substituted acylamino, or a salt thereof or a prodrug thereof to a subject. (26) A method of promoting neural stem cell differentiation wherein comprising administering a compound represented by the ring Ao is a pyrazole ring optionally further having 1 or 2 formula: Substituents; R" is substituted carbamoyl; and (Io) Ra Rb R’ is optionally substituted acylamino, or a salt thereof or a prodrug thereof for the production of a GSK-3|8 inhibitor. (30) Use of a compound represented by the formula: wherein (Io) ring Ao is a pyrazole ring optionally further having 1 or 2 Ra Rb Substituents; R" is substituted carbamoyl; and R’ is optionally substituted acylamino, or a salt thereof or a prodrug thereof to a subject. (27) A method of preventing or treating a neurodegenerative disease or diabetes comprising administering a compound represented by the formula: wherein (Io) ring Ao is a pyrazole ring optionally further having 1 or 2 Ra Rb Substituents; R" is substituted carbamoyl; and R’ is optionally substituted acylamino, or a salt thereof or a prodrug thereof for the production of a neural stem cell differentiation promoter. US 2009/0156582 A1 Jun. 18, 2009

(31) Use of a compound represented by the formula: cyclooctyl, bicyclo[2.2.1]heptyl, oxobicyclo2.2.1]heptyl, bicyclo[2.2.2]octyl and the like. 0063. In the present specification, examples of the “C. b (Io) aryl group' include, unless otherwise specified, phenyl, Ra R 1-naphthyl 2-naphthyl 2-biphenylyl, 3-biphenylyl, 4-biphe nylyl, 2-anthryl and the like. The C-aryl may be partially saturated, and examples of the partially saturated Caryl include indanyl, tetrahydronaphthyl and the like. 0064. In the present specification, examples of the “C. aralkyl group' include, unless otherwise specified, benzyl, wherein phenethyl, diphenylmethyl, 1-naphthylmethyl 2-naphthylm ring Ao is a pyrazole ring optionally further having 1 or 2 ethyl, 2,2-diphenylethyl, 3-phenylpropyl, 3.3-diphenylpro Substituents; pyl, 4-phenylbutyl, 5-phenylpentyl, 2-biphenylylmethyl, R" is substituted carbamoyl; and 3-biphenylylmethyl, 4-biphenylylmethyl and the like. R’ is optionally substituted acylamino, 0065. In the present specification, examples of the or a salt thereof or a prodrug thereof for the production of an “optionally substituted hydroxy group' include, unless oth agent for the prophylaxis or treatment of a neurodegenerative erwise specified, “hydroxy group”, “optionally substituted disease or diabetes. Coalkoxy group', 'optionally substituted heterocyclic oxy (32) Use of a compound represented by the formula: group”, “optionally Substituted C. aryloxy group'. “optionally substituted C. aralkyloxy group', “tri-Cie alkyl-silyloxy group”, “optionally substituted C. alkylsul (Io) fonyloxy group”, “optionally substituted heterocyclic sulfo Ra Rb nyloxy group' and the like. 0066. In the present specification, examples of the “C. alkoxy group' include, unless otherwise specified, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy and the like. 0067. In the present specification, examples of the “Co wherein alkoxy group' include, in addition to the above-mentioned ring Ao is a pyrazole ring optionally further having 1 or 2 Calkoxy group, heptyloxy, octyloxy, nonyloxy, decyloxy Substituents; and the like. R" is substituted carbamoyl; and 0068. In the present specification, examples of the “C. R’ is optionally substituted acylamino, alkoxy-C alkoxy group” include, unless otherwise speci or a salt thereof or a prodrug thereof for the production of a fied, methoxymethoxy, methoxyethoxy, ethoxymethoxy, hypoglycemic agent. ethoxyethoxy and the like. 0069. In the present specification, examples of the “het BEST MODE FOR EMBODYING THE erocyclic oxy group' include hydroxy group Substituted by INVENTION the below-mentioned "heterocyclic group”. Preferable examples of the heterocyclic oxy group include tetrahydro 0057. In the present specification, examples of the “halo pyranyloxy, thiazolyloxy, pyridyloxy, pyrazolyloxy, gen atom' include, unless otherwise specified, fluorine atom, oxazolyloxy, thienyloxy, furyloxy, tetrahydrothiopyrany chlorine atom, bromine atom and iodine atom. loxy, 1,1-dioxidotetrahydrothiopyranyloxy and the like. 0058. In the present specification, examples of the 0070. In the present specification, examples of the “C. “optionally substituted hydrocarbon group' include, unless aryloxy group' include, unless otherwise specified, phenoxy, otherwise specified, "optionally substituted C. alkyl 1-naphthyloxy, 2-naphthyloxy and the like. group', 'optionally substituted Coalkenyl group', 'option 0071. In the present specification, examples of the “Cz ally substituted C- alkynyl group', 'optionally Substituted aralkyloxy group' include, unless otherwise specified, ben Cs cycloalkyl group', 'optionally substituted C. aryl Zyloxy, phenethyloxy and the like. group”, “optionally Substituted C. aralkyl group' and the 0072. In the present specification, examples of the “tri like. C. alkyl-silyloxy group' include, unless otherwise speci 0059. In the present specification, examples of the “C. fied, trimethylsilyloxy, tert-butyl (dimethyl)silyloxy and the alkyl group' include, unless otherwise specified, methyl, like. ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, 0073. In the present specification, examples of the “C. pentyl, isopentyl, neopentyl, hexyl and the like. alkylsulfonyloxy group' include, unless otherwise specified, 0060. In the present specification, examples of the “C. methylsulfonyloxy, ethylsulfonyloxy and the like. alkenyl group' include, unless otherwise specified, vinyl, 0074. In the present specification, examples of the “het propenyl, isopropenyl, 2-buten-1-yl 4-penten-1-yl, 5-hexen erocyclic Sulfonyloxy group' include Sulfonyloxy group Sub 1-yl and the like. stituted by the below-mentioned "heterocyclic group'. Pref 0061. In the present specification, examples of the “C. erable examples of the heterocyclic Sulfonyloxy group alkynyl group' include, unless otherwise specified, 2-butyn include thienylsulfonyloxy, furylsulfonyloxy and the like. 1-yl 4-pentyn-1-yl, 5-hexyn-1-yl and the like. 0075. In the present specification, examples of the 0062. In the present specification, examples of the “Cs “optionally Substituted mercapto group' include, unless oth cycloalkyl group' include, unless otherwise specified, cyclo erwise specified, “mercapto group”, “optionally substituted propyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, Co alkylthio group', 'optionally substituted heterocyclic US 2009/0156582 A1 Jun. 18, 2009 thio group', 'optionally Substituted Carylthio group'. lidinyl (e.g., 2,5-dioxopyrrolidin-1-yl. 2,5-dioxopyrrolidin “optionally Substituted C7-caralkylthio group' and the like. 3-yl), tetrahydrothiopyranyl (e.g., 2-tetrahydrothiopyranyl. 0076. In the present specification, examples of the “C. 3-tetrahydrothiopyranyl, 4-tetrahydrothiopyranyl), 1,1-di alkylthio group' include, unless otherwise specified, meth oxidotetrahydrothiopyranyl (e.g., 1,1-dioxidotetrahydrothi ylthio, ethylthio, propylthio, isopropylthio, butylthio. Sec opyran-2-yl, 1,1-dioxidotetrahydrothiopyran-3-yl, 1,1-dioxi butylthio, tert-butylthio and the like. In the present specifica dotetrahydrothiopyran-4-yl), dihydrobenzofuranyl (e.g., 2.3- tion, examples of the “Clio alkylthio group” include, in dihydro-1-benzofuran-4-yl, 2,3-dihydro-1-benzofuran-5-yl, addition to the above-mentioned C. alkylthio group, hep 2,3-dihydro-1-benzofuran-6-y1, 2,3-dihydro-1-benzofuran tylthio, octylthio, nonylthio, decylthio and the like. 7-yl) and the like, and the like. 0077. In the present specification, examples of the “het I0081. In the present specification, examples of the erocyclic thio group' include mercapto group Substituted by “optionally substituted sulfinyl group' include, unless other the below-mentioned "heterocyclic group'. Preferable wise specified, “sulfinyl group”, “optionally substituted C examples of the heterocyclic thio group include tetrahydro alkylsulfinyl group”, “optionally substituted heterocyclic pyranylthio, thiazolylthio, pyridylthio, pyrazolylthio. sulfinyl group”, “optionally substituted C. arylsulfinyl oxazolylthio, thienylthio, furylthio, tetrahydrothiopyra group', 'optionally Substituted C7 aralkylsulfinyl group' nylthio, 1,1-dioxidotetrahydrothiopyranylthio and the like. and the like. 0078. In the present specification, examples of the “C. I0082 In the present specification, examples of the arylthio group' include, unless otherwise specified, phe “optionally substituted sulfonyl group” include, unless oth nylthio. 1-naphthylthio. 2-naphthylthio and the like. erwise specified, “sulfonyl group”, “optionally substituted 0079. In the present specification, examples of the “C. C. alkylsulfonyl group', 'optionally Substituted heterocy aralkylthio group' include, unless otherwise specified, ben clic sulfonyl group', 'optionally substituted Carylsulfo Zylthio, phenethylthio and the like. nyl group', 'optionally Substituted C. aralkylsulfonyl 0080. In the present specification, examples of the “het group' and the like. erocyclic group' include, unless otherwise specified, a 5- to I0083. In the present specification, examples of the “C. 14-membered (monocycle, bicyclic or tricyclic) heterocyclic alkylsulfonyl group” include sulfonyl group substituted by group, preferably (i) 5- to 14-membered (preferably 5- to the aforementioned “C. alkyl group'. Preferable examples 10-membered) aromatic heterocyclic group, (ii) 5- to of the C- alkylsulfonyl group include methylsulfonyl, eth 10-membered nonaromatic heterocyclic group containing, as ylsulfonyl and the like. a ring constituting atom besides carbon atom, 1 to 4 hetero I0084. In the present specification, examples of the “C. atoms of 1 or 2 kinds selected from a nitrogen atom, a Sulfur alkylsulfinyl group” include sulfinyl group substituted by the atom and an oxygen atom, and the like. Particularly, 5 or aforementioned “C. alkyl group'. Preferable examples of 6-membered aromatic heterocyclic group is preferable. Spe the C alkylsulfinyl group include methylsulfinyl, ethyl cifically, for example, aromatic heterocyclic groups such as sulfinyl and the like. thienyl (e.g., 2-thienyl, 3-thienyl), furyl (e.g., 2-furyl, 3-fu I0085. In the present specification, examples of the “het ryl), pyridyl (e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl), thiazolyl erocyclic Sulfonyl group' include Sulfonyl group Substituted (e.g., 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), oxazolyl (e.g., by the aforementioned "heterocyclic group'. Preferable 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), quinolyl (e.g., examples of the heterocyclic Sulfonyl group include thienyl 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 8-quinolyl), sulfonyl, furylsulfonyl and the like. isoquinolyl (e.g., 1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, I0086. In the present specification, examples of the “het 5-isoquinolyl), pyrazinyl, pyrimidinyl (e.g., 2-pyrimidinyl, erocyclic sulfinyl group' include Sulfinyl group Substituted 4-pyrimidinyl), pyrrolyl (e.g., 1-pyrrolyl 2-pyrrolyl, 3-pyr by the aforementioned "heterocyclic group'. Preferable rolyl), imidazolyl (e.g., 1-imidazolyl, 2-imidazolyl, 4-imida examples of the heterocyclic Sulfinyl group include thienyl Zolyl), pyrazolyl (e.g., 1-pyrazolyl, 3-pyrazolyl, 4-pyra sulfinyl, furylsulfinyl and the like. Zolyl), pyridaZinyl (e.g., 3-pyridazinyl, 4-pyridaZinyl), isothiazolyl (e.g., 3-isothiazolyl, 4-isothiazolyl, 5-isothiaz I0087. In the present specification, examples of the “C. olyl), isoxazolyl (e.g., 3-isoxazolyl, 4-isoxazolyl, 5-isox arylsulfonyl group' include sulfonyl group substituted by the azolyl), indolyl (e.g., 1-indolyl, 2-indolyl, 3-indolyl), 2-ben aforementioned “Caryl group'. Preferable examples of Zothiazolyl 2-benzooxazolyl, benzoimidazolyl (e.g., the Carylsulfonyl group include phenylsulfonyl, 1-naph 1-benzoimidazolyl, 2-benzoimidazolyl), benzob thienyl thylsulfonyl, 2-naphthylsulfonyl and the like. (e.g., 2-benzob thienyl, 3-benzob thienyl), benzobfura I0088. In the present specification, examples of the “C. nyl (e.g., 2-benzobfuranyl, 3-benzobfuranyl) and the like: arylsulfinyl group' include sulfinyl group substituted by the for example, nonaromatic heterocyclic groups such as pyrro aforementioned "Caryl group”. Preferable examples of lidinyl (e.g., 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl), the Carylsulfinyl group include phenylsulfinyl, 1-naph oxazolidinyl (e.g., 2-oxazolidinyl), imidazolinyl (e.g., 1-imi thylsulfinyl, 2-naphthylsulfinyl and the like. dazolinyl, 2-imidazolinyl, 4-imidazolinyl), piperidinyl (e.g., I0089. In the present specification, examples of the “C. 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl), aralkylsulfonyl group” include sulfonyl group substituted by piperazinyl (e.g., 1-piperazinyl, 2-piperazinyl), morpholinyl the aforementioned “C. aralkyl group”. Preferable (e.g., 2-morpholinyl, 3-morpholinyl, 4-morpholinyl), thio examples of the C-aralkylsulfonyl group include benzyl morpholinyl (e.g., 2-thiomorpholinyl, 3-thiomorpholinyl, sulfonyl, phenethylsulfonyl and the like. 4-thiomorpholinyl), tetrahydropyranyl (e.g., 2-tetrahydropy I0090. In the present specification, examples of the “C. ranyl, 3-tetrahydropyranyl, 4-tetrahydropyranyl), oxetanyl aralkylsulfinyl group” include sulfinyl group substituted by (e.g., 2-oxetanyl, 3-oxetanyl), oxopyrrolidinyl (e.g., 2-ox the aforementioned “C, aralkyl group'. Preferable opyrrolidin-1-yl, 2-oxopyrrolidin-3-yl, 2-oxopyrrolidin-4- examples of the Cz-e aralkylsulfinyl group include benzyl y1, 2-oxopyrrolidin-5-yl, 3-oxopyrrolidin-1-yl), dioxopyrro sulfinyl, phenethylsulfinyl and the like. US 2009/0156582 A1 Jun. 18, 2009

0091. In the present specification, examples of the 0101. In the present specification, examples of the “mono “optionally esterified carboxyl group' include, unless other or di-Caryl-carbamoyl group' include, unless otherwise wise specified, carboxyl group, Ce alkoxy-carbonyl group specified, carbamoyl group mono- or di-Substituted by the (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, above-mentioned “C. aryl group”. Examples thereof tert-butoxycarbonyl etc.), Caryloxy-carbonyl group (e.g., include phenylcarbamoyl, 1-naphthylcarbamoyl 2-naphth phenoxycarbonyl etc.), C, aralkyloxy-carbonyl group ylcarbamoyl and the like. (e.g., benzyloxycarbonyl, phenethyloxycarbonyl etc.) and 0102. In the present specification, examples of the “mono the like. or di-5- to 7-membered heterocycle-carbamoyl group' 0092. In the present specification, examples of the include, unless otherwise specified, carbamoyl group mono “optionally halogenated C. alkyl group' include, unless or di-substituted by 5- to 7-membered heterocyclic group. otherwise specified, the above-mentioned “C. alkyl group' Examples of the 5- to 7-membered heterocyclic group optionally substituted by 1 to 5 "halogen atoms” mentioned include heterocyclic group containing, as a ring constituting above. Examples thereof include methyl, ethyl, propyl, iso atom besides carbonatom, 1 to 4 hetero atoms of 1 or 2 kinds propyl, butyl, tert-butyl, isobutyl, trifluoromethyl and the selected from a nitrogen atom, a Sulfur atom and an oxygen like. atom. Preferable examples of the “mono- or di-5- to 7-mem 0093. In the present specification, examples of the bered heterocycle-carbamoyl group' include 2-pyridylcar “optionally halogenated C. alkoxy group' include, unless bamoyl 3-pyridylcarbamoyl, 4-pyridylcarbamoyl, 2-thienyl otherwise specified, the above-mentioned "Ce alkoxy carbamoyl, 3-thienylcarbamoyl and the like. group' optionally substituted by 1 to 5 "halogenatoms’ men 0103) In the present specification, examples of the “mono tioned above. Examples thereof include methoxy, ethoxy, or di-C alkyl-sulfamoyl group' include, unless otherwise isopropoxy, tert-butoxy, trifluoromethoxy and the like. specified, Sulfamoyl group mono- or di-substituted by the 0094. In the present specification, examples of the “mono above-mentioned "Ce alkyl group' and, for example, meth or di-C alkyl-amino group” include, unless otherwise ylsulfamoyl ethylsulfamoyl, dimethylsulfamoyl, diethylsul specified, amino group mono- or di-substituted by the above famoyl and the like can be used. mentioned "Ce alkyl group'. Examples thereof include 0104. In the present specification, examples of the “mono methylamino, ethylamino, propylamino, dimethylamino, or di-Caryl-sulfamoyl group' include, unless otherwise diethylamino and the like. specified, Sulfamoyl group mono- or di-substituted by the 0095. In the present specification, examples of the “mono above-mentioned "Caryl group' and, for example, phe or di-C aryl-amino group” include, unless otherwise nylsulfamoyl, diphenylsulfamoyl, 1-naphthylsulfamoyl, specified, amino group mono- or di-substituted by the above 2-naphthylsulfamoyl and the like can be used. mentioned "Caryl group”. Examples thereof include phe 0105. In the present specification, examples of the nylamino, diphenylamino. 1-naphthylamino, 2-naphthy “optionally substituted C. alkyl group”, “optionally substi lamino and the like. tuted Calkenyl group”, “optionally Substituted C- alky 0096. In the present specification, examples of the “mono nyl group', 'optionally Substituted Co alkoxy group (in or di-C. aralkyl-amino group' include, unless otherwise cluding optionally substituted C. alkoxy group). specified, amino group mono- or di-substituted by the above “optionally Substituted C. alkylsulfonyloxy group' and mentioned “C. aralkyl group”. Examples thereof include “optionally substituted Co alkylthio group (including benzylamino, phenethylamino and the like. optionally Substituted C. alkylthio group) include "Ce 0097. In the present specification, examples of the alkyl group”, “C. alkenyl group”, “C. alkynyl group'. “N-C alkyl-N-Cl aryl-amino group” include, unless “Clio alkoxy group (including Co alkoxy group), “C. otherwise specified, amino group Substituted by the above alkylsulfonyloxy group' and "Coalkylthio group (includ mentioned "Ce alkyl group' and the above-mentioned “C. ing Ce alkylthio group), each optionally having, at Substi 14 aryl group”. Examples thereof include N-methyl-N-phe tutable positions, 1 to 5 substituents selected from (1) halogen nylamino, N-ethyl-N-phenylamino and the like. atom; (2) hydroxy group; (3)amino group; (4) nitro group; (5) 0098. In the present specification, examples of the cyano group; (6) heterocyclic group optionally Substituted by “N-C alkyl-N-C-7. aralkyl-amino group' include, 1 to 3 Substituents selected from halogen atom, hydroxy unless otherwise specified, amino group Substituted by the group, amino group, nitro group, cyano group, optionally above-mentioned “C. alkyl group' and the above-men halogenated C. alkyl group, mono- or di-C alkyl-amino tioned “C. aralkyl group”. Examples thereof include group, C-aryl group, mono- or di-C-aryl-amino group. N-methyl-N-benzylamino, N-ethyl-N-benzylamino and the C-8 cycloalkyl group, Calkoxy group, Co alkoxy-C- like. alkoxy group, Calkylthio group, Calkylsulfinyl group, 0099. In the present specification, examples of the C. alkylsulfonyl group, an optionally esterified carboxyl “N-C alkyl-N-(C. alkyl-carbonyl)-amino group' group, carbamoyl group, thiocarbamoyl group, mono- or include, unless otherwise specified, amino group Substituted di-C alkyl-carbamoyl group, mono- or di-Caryl-car by the aforementioned “C. alkyl group' and C alkyl bamoyl group, Sulfamoyl group, mono- or di-C alkyl-sul carbonyl group (e.g., acetyl, isobutanoyl, isopentanoyl). famoyl group and mono- or di-C aryl-sulfamoyl group Examples thereof include N-acetyl-N-methylamino, (preferably furyl, pyridyl, thienyl, pyrazolyl, thiazolyl, N-acetyl-N-ethylamino and the like. oxazolyl, isoxazolyl, isothiazolyl, oxetanyl, morpholinyl, 0100. In the present specification, examples of the “mono thiomorpholinyl, pyrrolidinyl, oxopyrrolidinyl, dioxopyrro or di-C alkyl-carbamoyl group” include, unless otherwise lidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1,1-dioxi specified, carbamoyl group mono- or di-Substituted by the dotetrahydrothiopyranyl); (7) mono- or di-C alkyl-amino above-mentioned "Ce alkyl group”. Examples thereof group; (8) mono- or di-Caryl-amino group; (9) mono- or include methylcarbamoyl ethylcarbamoyl, dimethylcarbam di-C. aralkyl-amino group; (10) N-Cl alkyl-N-C- oyl, diethylcarbamoyl, ethylmethylcarbamoyl and the like. aryl-amino group; (11) N-Cl alkyl-N-(C. alkyl-C- US 2009/0156582 A1 Jun. 18, 2009 aryl)-amino group; (12) N-Cl alkyl-N-C-7. aralkyl gen-containing heterocycle-carbonyl group (e.g., pyrrolidi amino group: (13)C is cycloalkyl group optionally substi nylcarbonyl, piperidinocarbonyl, morpholinocarbonyl, tuted by C. alkyl group; (14) optionally halogenated C thiomorpholinocarbonyl); (35) Cea aryl-carbonyl group; (36) Caryl-thio group; (37) optionally halogenated C alkoxy group; (15) Calkylthiogroup optionally Substituted aryl-Sulfonyl group; (38) nitrogen-containing heterocycle by Calkoxy group: (16) Calkylsulfinyl group optionally Sulfonyl group (e.g., pyridylsulfonyl); (39) nitrogen-contain Substituted by C. alkoxy group: (17) C. alkylsulfonyl ing heterocycle-amino group optionally Substituted by cyano group optionally Substituted by C. alkoxy group: (18) group (e.g., pyridylamino); (40) nitrogen-containing hetero optionally esterified carboxyl group; (19) carbamoyl group; cycle-thio group; (41) nitrogen-containing heterocycle-Sulfi (20) thiocarbamoyl group; (21) mono- or di-C alkyl-car nyl group; (42) C. aralkylsulfinyl group optionally Substi bamoyl group: (22) mono- or di-Caryl-carbamoyl group: tuted by 1 to 3 substituents selected from halogen atom, (23) mono- or di-5- to 7-membered heterocycle-carbamoyl hydroxy group, amino group, nitro group, cyano group, group; (24)C alkyl-carbonylamino group optionally sub optionally halogenated C. alkyl group, mono- or di-C stituted by carboxyl group (e.g., acetylamino, propiony alkyl-amino group, C-aryl group, mono- or di-Co-1 aryl lamino); (25) a C-14 aryloxy group optionally Substituted by amino group, Css cycloalkyl group. Coalkoxy group, C 1 to 3 Substituents selected from halogen atom, hydroxy alkoxy-C alkoxy group, C- alkylthio group, Co alkyl group, amino group, nitro group, cyano group, optionally Sulfinyl group, Calkylsulfonyl group, optionally esterified halogenated C. alkyl group, mono- or di-C alkyl-amino carboxyl group, carbamoyl group, thiocarbamoyl group, group, C-aryl group, mono- or di-Co-1 aryl-amino group. mono- or di-C alkyl-carbamoyl group, mono- or di-Ca Cs cycloalkyl group, Ce alkoxy group, Ce alkoxy-C aryl-carbamoyl group, Sulfamoyl group, mono- or di-C alkoxy group, Ce alkylthio group, Ce alkylsulfinyl group, alkyl-sulfamoyl group and mono- or di-Caryl-sulfamoyl C. alkylsulfonyl group, optionally esterified carboxyl group; (43) Cz-aralkylsulfonyl group optionally Substituted by 1 to 3 substituents selected from halogen atom, hydroxy group, carbamoyl group, thiocarbamoyl group, mono- or group, amino group, nitro group, cyano group, optionally di-C alkyl-carbamoyl group, mono- or di-Caryl-car halogenated C. alkyl group, mono- or di-C alkyl-amino bamoyl group, sulfamoyl group, mono- or di-C alkyl-sul group, C-aryl group, mono- or di-C-aryl-amino group. famoyl group and mono- or di-Caryl-sulfamoyl group; Cs cycloalkyl group, Calkoxy group, Ce alkoxy-C (26) Caryl group optionally substituted 1 to 3 substituents alkoxy group, Ce alkylthio group, Ce alkylsulfinyl group, selected from halogen atom, hydroxy group, amino group, C. alkylsulfonyl group, an optionally esterified carboxyl nitro group, cyano group, optionally halogenated C. alkyl group, carbamoyl group, thiocarbamoyl group, mono- or group, mono- or di-C alkyl-amino group, Caryl group, di-C alkyl-carbamoyl group, mono- or di-Caryl-car mono- or di-Co-1 aryl-amino group, Cas cycloalkyl group, bamoyl group, Sulfamoyl group, mono- or di-C alkyl-sul Calkoxy group, Calkoxy-C alkoxy group, Ce alky famoyl group and mono- or di-C aryl-sulfamoyl group lthio group, C alkylsulfinyl group, Ce alkylsulfonyl and the like. group, an optionally esterified carboxyl group, carbamoyl 0106. In the present specification, examples of the group, thiocarbamoyl group, mono- or di-C alkyl-carbam “optionally Substituted Cls cycloalkyl group', 'optionally oyl group, mono- or di-C aryl-carbamoyl group, Sulfa Substituted Caryl group”, “optionally substituted Cz moyl group, mono- or di-C alkyl-sulfamoyl group and aralkyl group', 'optionally substituted heterocyclic group'. mono- or di-C aryl-sulfamoyl group; (27) heterocyclic “optionally substituted heterocyclic oxy group”, “optionally oxy group optionally substituted by 1 to 3 substituents Substituted C. aryloxy group', 'optionally Substituted selected from halogen atom, hydroxy group, amino group, Cz-aralkyloxy group”, “optionally substituted heterocyclic nitro group, cyano group, optionally halogenated C. alkyl sulfonyloxy group”, “optionally substituted heterocyclic thio group”, “optionally substituted C. arylthio group' and group, mono- or di-C alkyl-amino group, Caryl group. “optionally Substituted Cz-aralkylthio group' include "Cs mono- or di-Co-1 aryl-amino group, Cas cycloalkyl group, cycloalkyl group”, “Caryl group, "Czaralkyl group'. Calkoxy group, Calkoxy-C alkoxy group, Ce alky "heterocyclic group', 'heterocyclic oxy group', 'Cary lthio group, C alkylsulfinyl group, Ce alkylsulfonyl loxy group”, “C. aralkyloxy group”. “heterocyclic sulfo group, optionally esterified carboxyl group, carbamoyl nyloxy group', 'heterocyclic thio group”, “Cea arylthio group, thiocarbamoyl group, mono- or di-C alkyl-carbam group' and “Cz-aralkylthiogroup, each optionally having, oyl group, mono- or di-C aryl-carbamoyl group, Sulfa at substitutable positions, 1 to 5 substituents selected from (1) moyl group, mono- or di-C alkyl-sulfamoyl group and halogen atom; (2) hydroxy group; (3) amino group; (4) nitro mono- or di-C aryl-Sulfamoyl group; (28) sulfamoyl group; (5) cyano group; (6) optionally substituted C. alkyl group; (29) mono- or di-C alkyl-sulfamoyl group; (30) group; (7) optionally substituted C- alkenyl group; (8) mono- or di-Caryl-sulfamoyl group; (31) C. aralky optionally substituted C-alkynyl group; (9) C-aryl group loxy group optionally substituted by 1 to 3 substituents optionally substituted by 1 to 3 substituents selected from selected from halogen atom, hydroxy group, amino group, halogen atom, hydroxy group, amino group, nitro group, nitro group, cyano group, optionally halogenated C. alkyl cyano group, optionally halogenated C. alkyl group, mono group, mono- or di-C alkyl-amino group, Caryl group. or di-C alkyl-amino group, C-14 aryl group, mono- or mono- or di-Co-1 aryl-amino group, Cas cycloalkyl group, di-C-aryl-amino group, Css cycloalkyl group, Calkoxy Calkoxy group, Calkoxy-C alkoxy group, Ce alky group, Calkoxy-C alkoxy group, Ce alkylthio group. lthio group, C alkylsulfinyl group, Ce alkylsulfonyl C. alkylsulfinyl group, Ce alkylsulfonyl group, optionally group, an optionally esterified carboxyl group, carbamoyl esterified carboxyl group, carbamoyl group, thiocarbamoyl group, thiocarbamoyl group, mono- or di-C alkyl-carbam group, mono- or di-C alkyl-carbamoyl group, mono- or oyl group, mono- or di-C aryl-carbamoyl group, Sulfa di-Caryl-carbamoyl group, Sulfamoyl group, mono- or moyl group, mono- or di-C alkyl-sulfamoyl group and di-C alkyl-sulfamoyl group and mono- or di-C aryl mono- or di-Caryl-sulfamoyl group; (32) C. alkylsul Sulfamoyl group: (10) Caryloxy group optionally substi fonyloxy group; (33) tri-C alkyl-silyloxy group; (34) nitro tuted by 1 to 3 substituents selected from halogen atom, US 2009/0156582 A1 Jun. 18, 2009 hydroxy group, amino group, nitro group, cyano group, group, optionally esterified carboxyl group, carbamoyl optionally halogenated C. alkyl group, mono- or di-C group, thiocarbamoyl group, mono- or di-C alkyl-carbam alkyl-amino group, C-aryl group, mono- or di-Co-1 aryl oyl group, mono- or di-C aryl-carbamoyl group, Sulfa amino group, Css cycloalkyl group, Coalkoxy group, C moyl group, mono- or di-C alkyl-sulfamoyl group and alkoxy-C alkoxy group, Ce alkylthio group, Ce alkyl mono- or di-Caryl-sulfamoyl group; (36) optionally Sub Sulfinyl group, Calkylsulfonyl group, an optionally esteri stituted Calkylenedioxy group (e.g., methylenedioxy, eth fied carboxyl group, carbamoyl group, thiocarbamoyl group, ylenedioxy); (37) C. alkyl-carbonylamino group (e.g., mono- or di-C alkyl-carbamoyl group, mono- or di-Ca acetylamino); (38) N-C-alkyl-N-(Calkyl-carbonyl)- aryl-carbamoyl group, Sulfamoyl group, mono- or di-C amino group (e.g., N-acetyl-N-ethylamino); and the like. alkyl-sulfamoyl group and mono- or di-Caryl-sulfamoyl 0107. In the present specification, examples of the group; (11) C. aralkyloxy group optionally Substituted by “optionally Substituted amino group' include, unless other 1 to 3 Substituents selected from halogen atom, hydroxy wise specified, amino group optionally Substituted by 1 or 2 group, amino group, nitro group, cyano group, optionally substituents selected from (1) optionally substituted C. halogenated C. alkyl group, mono- or di-C alkyl-amino alkyl group; (2) optionally substituted Calkenyl group; (3) group, C-aryl group, mono- or di-Co-1 aryl-amino group. optionally substituted C2-alkynyl group; (4) optionally Sub C-8 cycloalkyl group, Co alkoxy group, Co alkoxy-C- stituted Cls cycloalkyl group; (5) optionally substituted alkoxy group, Ce alkylthio group, Ce alkylsulfinyl group, Caryl group; (6) optionally Substituted Calkoxy group; C. alkylsulfonyl group, optionally esterified carboxyl (7) optionally Substituted acyl group; (8) optionally substi group, carbamoyl group, thiocarbamoyl group, mono- or tuted heterocyclic group (preferably furyl, pyridyl, thienyl, di-C alkyl-carbamoyl group, mono- or di-Caryl-car pyrazolyl, thiazolyl, oxazolyl); (9) Sulfamoyl group; (10) bamoyl group, Sulfamoyl group, mono- or di-C alkyl-sul mono- or di-C alkyl-sulfamoyl group: (11) mono- or di-C- famoyl group and mono- or di-Caryl-sulfamoyl group; 14 aryl-sulfamoyl group and the like. When the “optionally (12) heterocyclic group optionally substituted 1 to 3 substitu Substituted amino group' is amino group Substituted by two ents selected from halogen atom, hydroxy group, amino Substituents, these substituents may form, together with the group, nitro group, cyano group, optionally halogenated C. adjacent nitrogen atom, nitrogen-containing heterocycle. alkyl group, mono- or di-C alkyl-amino group, C-14 aryl Examples of the "nitrogen-containing heterocycle include group, mono- or di-Caryl-amino group, C.s cycloalkyl 5- to 7-membered nitrogen-containing heterocycle contain group. C. alkoxy group, C- alkoxy-C alkoxy group. ing, as a ring constituting atom besides carbon atom, at least C. alkylthio group, Ce alkylsulfinyl group, Ce alkylsul one nitrogen atom, and further optionally containing 1 or 2 fonyl group, optionally esterified carboxyl group, carbamoyl hetero atoms selected from oxygen atom, Sulfur atom and group, thiocarbamoyl group, mono- or di-C alkyl-carbam nitrogen atom. Preferable examples of the nitrogen-contain oyl group, mono- or di-Caryl-carbamoyl group, sulfa ing heterocycle include pyrrolidine, imidazolidine, pyrazoli moyl group, mono- or di-C alkyl-sulfamoyl group and dine, piperidine, piperazine, morpholine, thiomorpholine, mono- or di-C aryl-sulfamoyl group (preferably furyl, thiazolidine, oxazolidine and the like. pyridyl, thienyl, pyrazolyl, thiazolyl, oxazolyl, isoxazolyl, 0108. In the present specification, examples of the isothiazolyl, oxetanyl, morpholinyl, thiomorpholinyl, pyrro “optionally substituted acyl group' include, unless otherwise lidinyl, oxopyrrolidinyl, dioxopyrrolidinyl, tetrahydropyra specified, groups represented by formula: COR, CO nyl, tetrahydrothiopyranyl, 1,1-dioxidotetrahydrothiopyra OR7, SOR7, SOR7, PO(OR7)(OR), CO nyl); (13) mono- or di-C alkyl-amino group: (14) mono- or NR'R'' and CS NR'R' wherein R7 and R are the di-Caryl-amino group; (15) mono- or di-C. aralkyl same or different and each is hydrogenatom, optionally Sub amino group: (16) N-Cl alkyl-N-Cl aryl-amino stituted hydrocarbon group or optionally substituted hetero group; (17) N-Cl alkyl-N-C- aralkyl-amino group; cyclic group, R'' and Rare the same or different and each is (18) Cs cycloalkyl group; (19) optionally substituted C hydrogen atom, optionally Substituted hydrocarbon group or alkoxy group; (20) Calkylthio group optionally substituted optionally substituted heterocyclic group, R" and R* may by Calkoxy group; (21)C alkylsulfinyl group optionally form, together with the adjacent nitrogen atom, optionally Substituted by C. alkoxy group; (22) C. alkylsulfonyl Substituted nitrogen-containing heterocycle, and the like. group optionally Substituted by C. alkoxy group; (23) 0109 Examples of the “nitrogen-containing heterocycle' optionally esterified carboxyl group; (24) carbamoyl group; of the “optionally Substituted nitrogen-containing hetero (25) thiocarbamoyl group; (26) mono- or di-C alkyl-car cycle” formed by R'' and R", together with the adjacent bamoyl group; (27) mono- or di-Caryl-carbamoyl group; nitrogenatom include 5- to 7-membered nitrogen-containing (28) mono- or di-5- to 7-membered heterocycle-carbamoyl heterocycle containing, as a ring constituting atom besides group; (29) sulfamoyl group; (30) mono- or di-C alkyl carbon atom, at least one nitrogen atom, and further option Sulfamoyl group; (31) mono- or di-C aryl-sulfamoyl ally containing 1 or 2 hetero atoms selected from oxygen group; (32) C. alkylsulfonyloxy group; (33) tri-C alkyl atom, Sulfur atom and nitrogen atom. Preferable examples of silyloxy group; (34) nitrogen-containing heterocycle-carbo the nitrogen-containing heterocycle include pyrrolidine, imi nyl group (e.g., pyrrolidinylcarbonyl, piperidinocarbonyl, dazolidine, pyrazolidine, piperidine, piperazine, morpholine, morpholinocarbonyl, thiomorpholinocarbonyl); (35) hetero thiomorpholine, thiazolidine, oxazolidine and the like. cyclic oxy group optionally Substituted by 1 to 3 Substituents 0110. The nitrogen-containing heterocycle optionally has selected from halogen atom, hydroxy group, amino group, 1 or 2 substituents at substitutable positions. Examples of the nitro group, cyano group, optionally halogenated C. alkyl Substituent include hydroxy group, optionally halogenated group, mono- or di-C alkyl-amino group, Caryl group. C1-alkyl group, C-aryl group, C7-caralkyl group and the mono- or di-Co-1 aryl-amino group, Cas cycloalkyl group, like. Coalkoxy group, Calkoxy-C alkoxy group, Co alky 0111 Preferable examples of the “optionally substituted lthio group, C alkylsulfinyl group, Ce alkylsulfonyl acyl group' include formyl group; carboxyl group; carbam US 2009/0156582 A1 Jun. 18, 2009 oyl group: C. alkyl-carbonyl group (e.g., acetyl, isobu pholine, thiomorpholine, azepane, 1,2,3,4-tetrahydroquino tanoyl, isopentanoyl) optionally Substituted by 1 to 3 halogen line, octahydroisoquinoline and the like. atoms; C alkoxy-carbonyl group (e.g., methoxycarbonyl, 0118 Preferable examples of the “substituted carbamoyl ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl) group' include group represented by the formula: optionally Substituted by 1 to 3 halogen atoms; Cs cycloalkyl-carbonyl group (e.g., cyclopentylcarbonyl, cyclo hexylcarbonyl); Cea aryl-carbonyl group (e.g., benzoyl, 1-naphthoyl 2-naphthoyl); C. aralkyl-carbonyl group (e.g., phenylacetyl, 2-phenylpropanoyl); Caryloxy-car bonyl group (e.g., phenyloxycarbonyl, naphthyloxycarbo nyl); C7 aralkyloxy-carbonyl group (e.g., benzyloxycarbo nyl, phenethyloxycarbonyl); mono- or di-C alkyl wherein carbamoyl group; mono- or di-Caryl-carbamoyl group: R" is optionally substituted hydrocarbon group or optionally Cs cycloalkyl-carbamoyl group (e.g., cyclopropylcarbam Substituted heterocyclic group, oyl); C7-caralkyl-carbamoyl group (e.g., benzylcarbamoyl); R’ is hydrogen atom or optionally substituted hydrocarbon Calkylsulfonyl group optionally substituted by 1 to 3 halo group, or R' and R form, together with the adjacent nitrogen gen atoms: C-14 arylsulfonyl group (e.g., phenylsulfonyl) atom, nitrogen-containing heterocycle. optionally Substituted by nitro group: nitrogen-containing I0119) R' in the formula (Io) is optionally substituted acy heterocycle-carbonyl group (e.g., pyrrolidinylcarbonyl, pip lamino group. Examples of the “optionally Substituted acy eridinocarbonyl, morpholinocarbonyl, thiomorpholinocar lamino group' include, unless otherwise specified, the afore bonyl); C alkylsulfinyl group optionally substituted by 1 to mentioned “optionally substituted amino group' substituted 3 halogen atoms; Ca arylsulfinyl group; thiocarbamoyl by 1 or 2 of the aforementioned “optionally substituted acyl group; and the like. groups”. 0112. In the present specification, examples of the “C. I0120 Preferable examples of the “optionally substituted alkylenedioxy group' of the “optionally substituted Ca acylamino group' include group represented by the formula: alkylenedioxy group' include, unless otherwise specified, methylenedioxy, ethylenedioxy, propylenedioxy, tetrafluoro ethylenedioxy and the like. The C alkylenedioxy group optionally has 1 to 3 substituents at substitutable positions. Examples of the Substituent include halogen atom, hydroxy group, amino group, mono- or di-C alkyl-amino group. mono- or di-Co-1 aryl-amino group, mono- or di-C7 aralkyl-amino group, nitro group, cyano group, Co alkoxy wherein R is hydrogenatom or optionally substituted hydro group, Ce alkylthio group and the like. carbon group; 0113. Each symbol in the formulas (I) and (I) is described R" is optionally substituted hydrocarbon group, optionally in detail in the following. Substituted heterocyclic group, optionally Substituted 0114 Ring Ao in the formula (Io) is pyrazole ring option hydroxy group or optionally substituted amino group; ally further having 1 or 2 substituents. The pyrazole ring for X is carbonyl group or Sulfonyl group. ring Ao optionally further has, besides R and R', 1 or 2 I0121 The compound represented by the formula (I) is substituents at substitutable positions. Examples of the “sub preferably the compound represented by the formula (I). stituent include those exemplified as the substituent of the I0122) R' in the formula (I) is optionally substituted hydro aforementioned "optionally substituted Cls cycloalkyl carbon group or optionally Substituted heterocyclic group. It group', with preference given to optionally Substituted is preferably (1) optionally Substituted Calkyl group (more hydrocarbon group (e.g., C alkyl group and the like) and preferably, Substituted C. alkyl group or unsubstituted C. optionally substituted acyl group (e.g., mono- or di-Ca alkyl group), (2) optionally Substituted Coalkenyl group, (3) aryl-carbamoyl group and the like). When the pyrazole ring optionally substituted C. alkynyl group, (4) optionally sub has two substituents, they may be the same or different. stituted Cls cycloalkyl group, (5) optionally Substituted 0115 Ring Ao preferably has no substituent besides R' Caryl group (preferably, phenyl, biphenylylindanyl), (6) and R. optionally substituted C-aralkyl group (preferably, benzyl, 0116 R' in the formula (I) is substituted carbamoyl phenethyl, diphenylmethyl 3-phenylpropyl, 3.3-diphenyl group, preferably carbamoyl group wherein the amino moi propyl), (7) optionally substituted 5- to 14-membered (pref ety is substituted by 1 or 2 substituents selected from (1) erably 5- to 10-membered) aromatic heterocyclic group optionally substituted hydrocarbon group, (2) optionally Sub (preferably, quinolyl), (8) optionally substituted 5- to stituted heterocyclic group and the like. 10-membered nonaromatic heterocyclic group (preferably, 0117. When the amino moiety of carbamoyl group is sub 2-oxo-azepanyl) and the like. stituted by 2 substituents, these substituents may form, (0123 R' in the formula (I) is preferably Calkyl group, together with the adjacent nitrogenatom, nitrogen-containing C2-alkenyl group or C2-alkynyl group (particularly C heterocycle. Examples of the "nitrogen-containing hetero alkyl group), each of which is optionally substituted by 1 to 5 cycle' include 5- to 7-membered nitrogen-containing hetero Substituents selected from halogen atom, optionally substi cycle containing, as a ring constituting atom besides carbon tuted hydroxy group, optionally Substituted thio group, atom, at least one nitrogen atom, and further optionally con optionally Substituted Sulfinyl group, optionally Substituted taining 1 or 2 hetero atoms selected from oxygenatom, Sulfur Sulfonyl group, optionally Substituted amino group, nitro atom and nitrogenatom. Preferable examples of the nitrogen group, cyano group, and optionally Substituted carbonyl containing heterocycle include pyrrolidine, piperidine, mor group. US 2009/0156582 A1 Jun. 18, 2009

I0124) R' in the formula (I) is more preferably C, alkyl (32) Ce alkylsulfonyloxy group; group, C2-alkenyl group or C2-alkynyl group (particularly (33) tri-C alkyl-silyloxy group; C. alkyl group), each of which optionally has, at Substitut (34) nitrogen-containing heterocycle-carbonyl group; able positions, 1 to 5 substituents selected from the follow (35) Caryl-carbonyl group: ings: (36) Caryl-thio group; (1) halogen atom; (37) optionally halogenated Caryl-sulfonyl group; (2) hydroxy group; (38) nitrogen-containing heterocycle-Sulfonyl group; and (3) amino group; (39) nitrogen-containing heterocycle-amino group optionally (4) nitro group; Substituted by cyano group. (5) cyano group; 0.125. When the compound of the formula (I) is used as an (7) mono- or di-C alkyl-amino group; agent for the prophylaxis or treatment of GSK-3 related (8) mono- or di-Caryl-amino group; pathology or disease, R' is more preferably C, alkyl group (9) mono- or di-Czaralkyl-amino group: Substituted by halogen atom (particularly, fluorine atom), (10) N-Cl alkyl-N-Cl aryl-amino group; hydroxy group or cyano group. Particularly, when the GSK-3 (11) N-Cl alkyl-N-(C. alkyl-Caryl)-amino group; related pathology or disease is neurodegenerative disease, R' (12) N-Cl alkyl-N-C7 aralkyl-amino group: is particularly preferably Calkyl group Substituted by fluo (14) optionally halogenated C. alkoxy group; rine atom (particularly, three fluorine atoms). (15) C. alkylthio group optionally Substituted by C. I0126) R' in the formula (I) is hydrogenatom or optionally alkoxy group; Substituted hydrocarbon group, preferably hydrogen atom, (18) optionally esterified carboxyl group; optionally Substituted C. alkyl group and the like, more (19) carbamoyl group; preferably hydrogen atom. (20) thiocarbamoyl group; (O127 R and R in the formula (I) optionally form, (21) mono- or di-C alkyl-carbamoyl group; together with the adjacent nitrogen atom, optionally Substi (22) mono- or di-Caryl-carbamoyl group; tuted nitrogen-containing heterocycle. Preferable examples (23) mono- or di-5- to 7-membered heterocycle-carbamoyl of the nitrogen-containing heterocycle include 5- to 7-mem group; bered nitrogen-containing heterocycle (preferably, pyrroli (24) C. alkyl-carbonylamino group optionally substituted dine, piperidine, morpholine, thiomorpholine, azepane, 1.2, by carboxyl group; 3,4-tetrahydroquinoline, octahydroisoquinoline) and the like, (25) Caryloxy group optionally substituted by 1 to 3 containing at least one nitrogen atom, and further optionally Substituents selected from halogen atom, hydroxy group, containing 1 or 2 hetero atoms selected from oxygen atom, amino group, nitro group, cyano group, optionally haloge Sulfur atom and nitrogen atom. The nitrogen-containing het nated C. alkyl group, mono- or di-C alkyl-amino group. erocycle optionally has 1 or 2 substituents at substitutable C-1 aryl group, mono- or di-Cola aryl-amino group, Cas positions. Examples of the Substituent include those exempli cycloalkyl group, Calkoxy group, Calkoxy-C alkoxy fied as the substituent of the aforementioned “optionally sub group, C- alkylthio group, C- alkylsulfinyl group, C stituted Cls cycloalkyl group'. alkylsulfonyl group, optionally esterified carboxyl group, I0128 R in the formula (I) is hydrogenatom or optionally carbamoyl group, thiocarbamoyl group, mono- or di-C Substituted hydrocarbon group, preferably hydrogen atom. alkyl-carbamoyl group, mono- or di-C aryl-carbamoyl I0129) R' in the formula (I) is optionally substituted hydro group, sulfamoyl group, mono- or di-C alkyl-sulfamoyl carbon group, optionally substituted heterocyclic group, group and mono- or di-Caryl-sulfamoyl group; optionally Substituted hydroxy group or optionally Substi (27) heterocyclic oxy group optionally substituted by 1 to 3 tuted amino group. It is preferably (1) optionally substituted Substituents selected from halogen atom, hydroxy group, C. alkyl group, (2) optionally substituted C. alkenyl amino group, nitro group, cyano group, optionally haloge group, (3) optionally substituted Cls cycloalkyl group, (4) nated C. alkyl group, mono- or di-C alkyl-amino group, optionally Substituted Caryl group (preferably, phenyl, C-1 aryl group, mono- or di-Cola aryl-amino group, Cas biphenylyl), (5) optionally Substituted C. aralkyl group cycloalkyl group, Calkoxy group, Calkoxy-C alkoxy (preferably, benzyl, phenethyl, diphenylmethyl, biphenylm group, C- alkylthio group, C- alkylsulfinyl group, C ethyl), (6) optionally substituted 5- to 14-membered (prefer alkylsulfonyl group, optionally esterified carboxyl group, ably 5- to 10-membered) aromatic heterocyclic group (pref carbamoyl group, thiocarbamoyl group, mono- or di-C erably, 1H-indolyl pyridyl, pyrazinyl, quinolyl), (7) alkyl-carbamoyl group, mono- or di-C aryl-carbamoyl optionally substituted amino group preferably amino group group, sulfamoyl group, mono- or di-C alkyl-sulfamoyl optionally substituted by 1 or 2 substituents selected from group and mono- or di-Caryl-sulfamoyl group; C- alkyl group and C-14 aryl group (e.g., phenyl). (31) Cz-aralkyloxy group optionally substituted by 1 to 3 0.130 Ring A in the formula (I) is pyrazole ring repre Substituents selected from halogen atom, hydroxy group, sented by the formula: amino group, nitro group, cyano group, optionally haloge nated C. alkyl group, mono- or di-C alkyl-amino group, C-1 aryl group, mono- or di-Cola aryl-amino group, Cas cycloalkyl group, Calkoxy group, Calkoxy-C alkoxy group, C- alkylthio group, C- alkylsulfinyl group, C alkylsulfonyl group, optionally esterified carboxyl group, carbamoyl group, thiocarbamoyl group, mono- or di-C alkyl-carbamoyl group, mono- or di-C aryl-carbamoyl group, Sulfamoyl group, mono- or di-C alkyl-sulfamoyl group and mono- or di-Caryl-sulfamoyl group; US 2009/0156582 A1 Jun. 18, 2009

I0131) R' in the formula is hydrogenatom, optionally sub 0.139 R is hydrogen atom; stituted hydrocarbon group or optionally Substituted acyl O140 R is group. It is preferably (1) hydrogen atom, (2) optionally Sub (1) Ce alkyl group optionally Substituted by 1 to 3 Substitu stituted C. alkyl group, (3) mono- or di-Caryl-carbam ents selected from (a) Calkoxy group, (b) Cs cycloalkyl oyl group (preferably, phenylcarbamoyl group) and the like, group optionally Substituted by C. alkyl group(s) (e.g., 7.7- more preferably hydrogen atom. dimethyl-2-oxo-bicyclo2.2.1]heptyl), (c) Co. aryloxy (0132) R' in the formula is hydrogen atom or optionally group (e.g., phenoxy), (d) 5- to 14-membered aromatic het substituted hydrocarbon group. It is preferably (1) hydrogen erocycle (preferably 5- to 10-membered) (e.g., 1H-indole), atom, or (2) optionally substituted C. alkyl group, more and (e) mono- or di-C alkyl-amino group: preferably hydrogen atom. (2) Coalkenyl group optionally substituted by C. aryl 0.133 X in the formula (I) is carbonyl group or sulfonyl group(s): group, preferably carbonyl group. (3) Cs cycloalkyl group: 0134 Preferable examples of the compound represented (4) Caryl group (e.g., phenyl, biphenylyl) optionally Sub by the formula (I) include the following compounds. stituted by 1 to 3 substituents selected from (a) halogen atom, (b) nitro group, (c) cyano group, (d) Calkyl group option Compound IAI ally Substituted by halogenatom(s), (e) Coalkenyl group, (f) 0135 A compound wherein Calkoxy group optionally substituted by halogenatom(s). (g) C-14 aryloxy group (e.g., phenoxy), (h) mono- or di-C- R" is alkyl-sulfamoyl group, and (i) C. alkyl-carbonylamino group (e.g., acetylamino), I0136 (1) C alkyl group optionally substituted by 1 to 3 (5) C. aralkyl group (e.g., benzyl, phenethyl, diphenylm Substituents selected from (a) cyano group, (b) Cs ethyl, biphenylylmethyl) optionally substituted by 1 to 3 sub cycloalkyl group, (c) 5- to 14-membered (preferably 5- to 10-membered) aromatic heterocyclic group (e.g., furanyl. stituents selected from (a) halogen atom, and (b) Coalkoxy pyridyl, 1H-indolyl), (d) 5- to 10-membered nonaromatic group; heterocyclic group (e.g., tetrahydrofuryl, 2-oxo-pyrrolyl), (e) (6) 5- to 14-membered (preferably 5- to 10-membered) aro Coalkoxy group, and (f) Co. alkylthio group: matic heterocyclic group (e.g., 1H-indolyl, pyridyl, pyrazi (2) Css cycloalkyl group: nyl, quinolyl) optionally Substituted by halogen atom(s); or (3) C-1 aryl group (e.g., phenyl, biphenylyl, indanyl) (7) amino group optionally substituted by 1 or 2 substituents optionally substituted by 1 to 3 substituents selected from (a) selected from Co alkyl group and C-14 aryl group (e.g., Calkoxy group optionally substituted by halogen atom(s). phenyl); (b) C. aralkyl group (e.g., benzyl) and (c) C. alkylene 0141 Ring A is pyrazole ring represented by the formula: dioxy group (e.g., ethylenedioxy); (4) C. aralkyl group (e.g., benzyl, phenethyl, diphenylm ethyl, 3-phenylpropyl, 3.3-diphenylpropyl) optionally substi tuted by 1 to 3 Substituents selected from (a) Ce alkyl group optionally Substituted by halogen atom(s), (b) C. alkoxy N \ N group, (c) carboxyl group and (d) C alkylenedioxy group YN R6 or s1 'N 2 R6 (e.g., methylenedioxy); (5) 5- to 14-membered (preferably 5- to 10-membered) aro matic heterocyclic group (e.g., quinolyl); or (6) 5- to 10-membered nonaromatic heterocyclic group (e.g., 2-oxo wherein aZepanyl); R is hydrogen atom, C-alkyl group, or mono- or di-Ca 0137 R’ is hydrogenatom, or Calkyl group optionally aryl-carbamoyl group (e.g., phenylcarbamoyl group); or Substituted by C. alkoxy group(s); or R is hydrogen atom, or C- alkyl group; and 0138) R' and R form, together with the adjacent nitrogen 0.142 X is carbonyl group or Sulfonyl group. atom, 5- to 7-membered nitrogen-containing heterocycle (e.g., pyrrolidine, piperidine, morpholine, thiomorpholine, 0143. Of the compounds represented by the above-men aZepane, 1,2,3,4-tetrahydroquinoline, octahydroisoquino tioned formulas (I) and (I), the following compounds are line) containing at least one nitrogen atom, and further known, but a GSK-3 inhibitory action of these compounds optionally containing 1 or 2 hetero atoms selected from oxy has not been known heretofore. gen atom, Sulfur atom and nitrogen atom and optionally Sub I0144) 1) N-methyl-2,5-dimethyl-4-2-4-(4-nitrophe stituted by 1 to 3 substituents selected from (a) hydroxy noxy)phenyl)acetylamino-2H-pyrazole-3-carboxamide, group, (b) C7-6 aralkyl group (e.g., benzyl), (c) C- alkyl (0145 2) N-methyl-4-2-4-(4-chlorophenoxy)phenyl group optionally substituted by 1 to 3 substituents selected acetylamino-2,5-dimethyl-2H-pyrazole-3-carboxamide, from mono- or di-Caryl-amino group (e.g., 2,6-dimeth 0146 3) N-(9-methyl-4-oxo-1-phenyl-3,4,6,7-tetrahy ylphenylamino) optionally substituted by C. alkyl group(s) dro-1,4-diazepino.6.7.1-hiindol-3-yl)-4-acetylamino-2, and hydroxy group, (d) Caryl group (e.g., phenyl) option 5-dimethyl-2H-pyrazole-3-carboxamide, ally substituted by 1 to 3 substituents selected from halogen 0147 4) N-phenyl-4-benzoylamino-2-ethyl-5-methyl atom, Calkyl group optionally substituted by halogenatom 2H-pyrazole-3-carboxamide, (S), C alkyl-carbonyl group and Co alkoxy group, (e) 0148 5) N-phenyl-2-ethyl-5-methyl-4-(2-nitrobenzoy carbamoyl group, (f) C. alkyl-carbonylamino group (e.g., lamino)-2H-pyrazole-3-carboxamide, acetylamino), and (g) N-Cl alkyl-N-(C. alkyl-carbo 0149 6) N-(4-chlorophenyl)-2-ethyl-5-methyl-4-(4-ni nyl)-amino group (e.g., acetylethylamino); trobenzoylamino)-2H-pyrazole-3-carboxamide, US 2009/0156582 A1 Jun. 18, 2009 17

0150 7) N-phenyl-2-ethyl-5-methyl-4-(4-methylbenzoy when compound A has a basic functional group, for example, lamino)-2H-pyrazole-3-carboxamide, a salt with inorganic acid or organic acid is preferable. 0151. 8) N-methyl-N-(2-phenyl-2H-pyrazol-3-yl)-4- 0.165. A prodrug of the compound A or a salt thereof acetylamino-2-ethyl-5-methyl-2H-pyrazole-3-carboxam means a compound which is converted to the compound A ide, with a reaction due to an enzyme, an gastric acid, etc. under 0152 9) N-methyl-N-(5-methyl-2-phenyl-2H-pyrazol-3- the physiological condition in the living body, that is, a com yl)-4-acetylamino-2-ethyl-5-methyl-2H-pyrazole-3-car pound which is converted to the compound A by enzymatic boxamide, oxidation, reduction, hydrolysis, etc.; a compound which is 0153. 10) N-methyl-N-(2-methyl-2H-pyrazol-3-yl)-4- converted to the compound Aby hydrolysis etc. due to gastric acetylamino-2-ethyl-5-methyl-2H-pyrazole-3-carboxam acid, etc. ide, 0154) 11) N-(2,5-dimethyl-2H-pyrazol-3-yl)-N-methyl 0166 A prodrug of compound A may be a compound 4-acetylamino-2-ethyl-5-methyl-2H-pyrazole-3-carboxa obtained by Subjecting an amino group in compound A to an mide, acylation, alkylation or phosphorylation (e.g., a compound 0155 12) N-(4-tert-butylbenzyl)-4-acetylamino-2,5-dim obtained by Subjecting an amino group in compound A to an ethyl-2H-pyrazole-3-carboxamide, eicosanoylation, alanylation, pentylaminocarbonylation, 0156 13) N-(4-tert-butylbenzyl)-4-(2-chloroacety (5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylation, lamino)-2,5-dimethyl-2H-pyrazole-3-carboxamide, tetrahydrofuranylation, pyrrolidylmethylation, pivaloy 0157 14) N-(4-tert-butylbenzyl)-4-benzoylamino-2,5- loxymethylation and tert-butylation, etc.); a compound dimethyl-2H-pyrazole-3-carboxamide, obtained by Subjecting a hydroxy group in compound A to an 0158. 15) N,N-dimethyl-4-methanesulfonylamino-1-me acylation, alkylation, phosphorylation or boration (e.g., a thyl-5-1-methyl-2,5-dioxo-4-(1-phenylpropylamino)-2, compound obtained by Subjecting a hydroxy group in com 5-dihydro-1H-pyrrol-3-ylamino)-1H-pyrazole-3-car pound A to an acetylation, palmitoylation, propanoylation, boxamide, pivaloylation, Succinylation, fumarylation, alanylation, dim 0159) 16) N.N-dimethyl-5-2,5-dioxo-4-(1-phenylpropy ethylaminomethylcarbonylation, etc.); a compound obtained lamino)-2,5-dihydro-1H-pyrrol-3-ylamino-4-methane by Subjecting a carboxyl group in compound A to an esteri sulfonylamino-1-methyl-1H-pyrazole-3-carboxamide, fication or amidation (e.g., a compound obtained by Subject 0160 17) N,N-dimethyl-5-(4-chloro-1-methyl-2,5-di ing a carboxy group in compound A to an C. alkyl esterifi oxo-2,5-dihydro-1H-pyrrol-3-ylamino)-4-methanesulfo cation, phenyl esterification, carboxymethyl esterification, nylamino-1-methyl-1H-pyrazole-3-carboxamide, and dimethylaminomethyl esterification, pivaloyloxymethyl 0161. 18) N,N-dimethyl-5-(4-chloro-1-methyl-2,5-di esterification, ethoxycarbonyloxyethyl esterification, phtha oxo-2,5-dihydro-1H-pyrrol-3-ylamino)-4-methanesulfo lidyl esterification, (5-methyl-2-oxo-1,3-dioxolen-4-yl)me nylamino-1-methyl-1H-pyrazole-3-carboxamide. thyl esterification, cyclohexyloxycarbonylethyl esterification 0162 Examples of salts of compound (I) and compound and methylamidation, etc.) and the like. Of these, a compound (I) of the present invention (unless otherwise specified, these wherein the carboxy group in the compound A is esterified are collectively referred to as compoundA) include metal salt, with a C- alkyl group Such as methyl, ethyl, tert-butyl and ammonium salt, salt with organic base, Salt with inorganic the like is preferably used. Any of these compounds can be acid, salt with organic acid, salt with basic or acidic amino produced from compound Aby a method known per se. acid and the like. 0.167 A prodrug of the compound A may be a compound 0163 Here, preferable examples of the metal salt include that converts to the compound A under physiological condi alkali metal salt Such as Sodium salt, potassium salt and the tions as described in Development of Pharmaceutical Prod like: alkaline earth metal salts such as calcium salt, magne ucts, vol. 7, Molecule Design, 163-198, Hirokawa Shoten sium salt, barium salt and the like, and the like. Preferable (1990). examples of the Salt with organic base include Salts with 0168 Compound A and a salt thereof can be produced by trimethylamine, triethylamine, pyridine, picoline, 2.6-luti the following method and the like. dine, ethanolamine, diethanolamine, triethanolamine, cyclo 0169. For convenience, ring A is defined as hexylamine, dicyclohexylamine, N,N'-dibenzylethylenedi amine and the like. Preferable examples of the salt with inorganic acid include salts with hydrochloric acid, hydro bromic acid, nitric acid, Sulfuric acid, phosphoric acid and the like. Preferable examples of the salt with organic acid include salts with formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, Succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and the in the explanation. As those of ordinary skill in the art will like. Preferable examples of the salt with basic amino acid readily understand, compound A wherein ring A is include salts with arginine, lysine, ornithine and the like, and preferable examples of the salt with acidic amino acid include salts with aspartic acid, glutamic acid and the like. 0164. Of these salts, a pharmaceutically acceptable salt is preferable. For example, when compound A has an acidic R51Y NNN. 2 R6 functional group, metal salts such as alkali metal salt, alkaline earth metal salt and the like; ammonium salt and the like, and can be produced in the same manner. US 2009/0156582 A1 Jun. 18, 2009

0170 In addition, compound A other than compound (I) diisopropylamide, lithium hexamethyldisilazide and the like, can also be produced by a method analogous thereto. metal alkoxides such as sodium methoxide, Sodium ethoxide, 0171 Unless otherwise specified, each symbol of the potassium tert-butoxide and the like, and the like can be used. compounds in the following reaction schemes means the 0.178 As the “acid', for example, methanesulfonic acid, same as mentioned above. The compounds in the reaction p-toluenesulfonic acid, camphorsulfonic acid and the like can schemes include salts and examples of the salts are those be used. defined for compound (I) and the like. The production meth 0179 The amount of the “base' to be use is about 0.1 to 10 ods of compound (I) are now explained. equivalent amount, preferably 0.8 to 2 equivalent amount, 0172 Compound (I) can be produced by reacting com relative to compound (2). pound (2) with compound (3) in, where desired, the presence 0180. The amount of the “acid to be use is about 0.1 to 10 of a base or acid, according to the method described in the equivalent amount, preferably 0.8 to 3 equivalent amount, following reaction scheme 1. relative to compound (2). 0181. This reaction is advantageously carried out without Reaction Scheme 1 Solvent or using a solventinert to the reaction. Such solvent is not particularly limited as long as the reaction proceeds and, RI for example, solvents including ethers such as diethyl ether, O R3 R4 VNH R. R3 R4 tetrahydrofuran, dioxane, 1,2-dimethoxyethane and the like, L Yx ( Y Yx hydrocarbons such as benzene, toluene, cyclohexane, hexane and the like, amides such as N,N-dimethylformamide, N.N- it, R ? dimethylacetamide and the like, halogenated hydrocarbons ( \ ( \ Such as dichloromethane, chloroform, carbon tetrachloride, YN R6 YN R6 1.2-dichloroethane and the like, nitriles Such as acetonitrile, propionitrile and the like, sulfoxides such as dimethylsulfox k ide and the like, nitrogen-containing aromatic hydrocarbons Such as pyridine, lutidine, quinoline and the like, and the like, and a mixed solvent thereof and the like are preferable. The reaction temperature is about -40°C. to 150° C., preferably 0173. In the reaction scheme 1, L is a leaving group, and 0°C. to 100°C. The reaction time is generally 5 minto 24hr. other symbols are as defined above. preferably 10 minto 5 hr. 0.174 Examples of the “leaving group' for L include hydroxy, optionally substituted alkoxy group, optionally Sub 0182. The resultant product (1) obtained as mentioned stituted aryloxy group (e.g., phenyloxy, pyridyloxy, pyrazi above can be used for the next reaction in the form of a nyloxy, N-methylpyridinium oxy), halogen atom (e.g., fluo reaction mixture or a crude product. It can also be isolated rine, chlorine, bromine, iodine etc.), optionally halogenated from the reaction mixture according to a conventional Cs alkylsulfonyloxy (e.g., methanesulfonyloxy, ethane method, and easily purified by a separation means Such as Sulfonyloxy, trichloromethanesulfonyloxy etc.), optionally recrystallization, distillation, chromatography and the like. Substituted Co arylsulfonyloxy and the like. Examples of 0183. As an alternative method replacing the aforemen the “optionally substituted Co arylsulfonyloxy” include tioned reaction, compound (2) and compound (3) may be Co arylsulfonyloxy (e.g., phenylsulfonyloxy, naphthylsul reacted in the presence of a Suitable condensing agent. fonyloxy etc.) optionally having 1 to 3 Substituents selected 0.184 The amount of compound (3) to be used is about 0.8 from C alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, to about 10.0 mol, preferably about 0.8 to about 2.0 mol, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl etc.), C alkoxy relative to 1 mol of compound (2). (e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobu 0185. As the “condensing agent’, for example, N,N'-car toxy, sec-butoxy, pentyloxy, hexyloxy etc.) and nitro and the bodiimides such as N,N'-dicyclohexylcarbodiimide, 1-ethyl like. Specific examples thereof include benzenesulfonyloxy, 3-(3-dimethylaminopropyl)carbodiimide (EDC) hydrochlo m-nitrobenzenesulfonyloxy, p-toluenesulfonyloxy and the ride and the like, azolites such as N,N'-carbonylimidazole and like. the like, dehydrating agents such as N-ethoxycarbonyl-2- 0175 Commercially available products of compound (2) ethoxy-1,2-dihydroquinoline, diethylcyanophosphate, phos and compound (3) can be easily obtained, and these com phorus oxychloride, acetic anhydride and the like, 2-halo pounds can also be produced by a method known perse or a genopyridinium salt such as 2-chloromethylpyridinium method according thereto. iodide, 2-fluoro-1-chloromethylpyridinium iodide and the 0176 The amount of compound (3) to be used is about 1.0 like, and the like are used. to 10 mol, preferably about 1.0 to 2.0 mol, relative to 1 mol of 0186 The amount of the condensing agent to be used is compound (2). about 0.8 to about 5.0 mol, preferably about 1.0 to about 2.0 0177. As the “base', for example, basic salts such as mol, relative to 1 mol of compound (2). Sodium carbonate, potassium carbonate, cesium carbonate, 0187. Where desired, the reaction may be carried out in the Sodium hydrogencarbonate and the like, aromatic amines co-presence of a base together with the condensing agent. As Such as pyridine, lutidine and the like, tertiary amines such as the “base', for example, basic salts such as potassium acetate, triethylamine, tripropylamine, tributylamine, cyclohexy Sodium acetate and the like, tertiary amines such as triethy ldimethylamine, 4-dimethylaminopyridine, N-methylpiperi lamine, tripropylamine, tributylamine, cyclohexyldimethy dine, N-methylpyrrolidine, N-methylmorpholine and the lamine, 4-dimethylaminopyridine, N-methylpiperidine, like, alkali metals such as metal Sodium and the like, alkali N-methylpyrrolidine, N-methylmorpholine and the like, metal hydrides such as Sodium hydride, potassium hydride 1-hydroxy-1H-benzotriazole (HOBt)-monohydrate and the and the like, metal amides Such as Sodium amide, lithium like can be used. US 2009/0156582 A1 Jun. 18, 2009

0188 The amount of the base to be used is about 0.5 to 0196. The amount of compound (5a), compound (5b) or about 5.0 mol, preferably about 1.0 to about 3.0 mol, relative compound (6) to be used is about 0.8 to 10 mol, preferably to 1 mol of compound (2). about 0.8 to 2.0 mol, more preferably about 0.9 to 1.2 mol, 0189 This reaction is advantageously carried out using a relative to 1 mol of compound (4). Solvent inert to the reaction. As such solvent, for example, 0.197 As the “base', for example, basic salts such as Solvents including alcohols such as methanol, ethanol, pro Sodium carbonate, potassium carbonate, cesium carbonate, panol and the like, hydrocarbons such as hexane, cyclohex Sodium hydrogencarbonate and the like, aromatic amines ane, benzene, toluene, Xylene and the like, ethers such as Such as pyridine, lutidine and the like, tertiary amines such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, triethylamine, tripropylamine, tributylamine, cyclohexy 1,2-dimethoxyethane and the like, amides such as N,N-dim ethylformamide, N,N-dimethylacetamide, hexamethylphos ldimethylamine, 4-dimethylaminopyridine, N-methylpiperi phoric triamide and the like, sulfoxides such as dimethylsul dine, N-methylpyrrolidine, N-methylmorpholine and the foxide and the like, halogenated hydrocarbons such as like, alkali metal hydrides such as sodium hydride, potassium dichloromethane, chloroform, carbon tetrachloride, 1,2- hydride and the like, metal amides such as Sodium amide, dichloroethane and the like, nitriles such as acetonitrile, pro lithium diisopropylamide, lithium hexamethyldisilazide and pionitrile and the like, acid anhydrides Such as acetic anhy the like, metal alkoxides such as Sodium methoxide, sodium dride and the like, and the like and a mixed solvent thereofand ethoxide, potassium tert-butoxide and the like and the like can the like are preferable. be mentioned. 0190. The reaction time is generally about 10 minto about 0198 As the “acid', for example, methanesulfonic acid, 72 hr., preferably about 30 minto about 24hr. The reaction p-toluenesulfonic acid, camphorsulfonic acid and the like can temperature is generally about -20° C. to about 150° C. be used. preferably about 0°C. to about 100° C. (0199 The amount of the “base' to be use is about 0.1 to 10 0191 The resultant product can be isolated from the reac equivalent amount, preferably 0.8 to 2 equivalent amount, tion mixture according to a conventional method, and can be relative to compound (4). easily purified by a general separation means (e.g., recrystal 0200. The amount of the “acid to be use is about 0.1 to 10 lization, distillation, chromatography etc.). equivalent amount, preferably 0.8 to 3 equivalent amount, 0.192 Compound (Ia) encompassed in compound (I) can relative to compound (4). also be produced by the method described in the following 0201 This reaction is advantageously carried out without reaction scheme 2. solvent or using a solventinert to the reaction. Such solvent is not particularly limited as long as the reaction proceeds and, for example, solvents including ethers such as diethyl ether, Reaction scheme 2 tetrahydrofuran, dioxane, 1,2-dimethoxyethane and the like, RI O hydrocarbons such as benzene, toluene, cyclohexane, hexane V and the like, amides such as N,N-dimethylformamide, N.N- A. N" R-X-L (R-X);o R-NCO dimethylacetamide and the like, halogenated hydrocarbons R2 f \ (5a) (5b) (6) Such as dichloromethane, chloroform, carbon tetrachloride, N 1.2-dichloroethane and the like, nitrites Such as acetonitrile, YN R6 propionitrile and the like, sulfoxides such as dimethylsulfox ide and the like, nitrogen-containing aromatic hydrocarbons Such as pyridine, lutidine, quinoline and the like, and the like, 4 and a mixed solvent thereof and the like are preferable. The RI O H R4 reaction temperature is about -40°C. to 150° C., preferably V V / N N-X 0°C. to 100°C. The reaction time is generally 5 minto 24hr. A preferably 10 minto 5 hr. R2 W \ 0202 The resultant product (I) obtained as mentioned NS above can be used for the next reaction in the form of a N R6 reaction mixture or a crude product. It can also be isolated from the reaction mixture according to a conventional method, and easily purified by a separation means Such as Ia recrystallization, distillation, chromatography and the like. 0203 As an alternative method replacing the aforemen (0193 In the reaction scheme 2, L is a leaving group, R is tioned reaction, compound (4) and compound (5a) may be a group after removing >NH group from the optionally Sub reacted in the presence of a Suitable condensing agent. stituted amino group for R' (i.e., substituent of the “option 0204 The amount of compound (5a) to be used is about ally substituted amino group” for R'), and other symbols are 0.8 to about 10.0 mol, preferably about 0.8 to about 2.0 mol, as defined above. relative to 1 mol of compound (4). 0194 Compound (Ia) can be produced by reacting com 0205 As the “condensing agent’, for example, N,N'-car pound (4) with compound (5a), compound (5b) or compound bodiimides such as N,N'-dicyclohexylcarbodiimide, 1-ethyl (6) in, where desired, the presence of a base or acid. 3-(3-dimethylaminopropyl)carbodiimide (EDC) hydrochlo 0.195 Commercially available products of compound ride and the like, azolites such as N,N'-carbonylimidazole and (5a), compound (5b) and compound (6) can be easily the like, dehydrating agents such as N-ethoxycarbonyl-2- obtained, and these compounds can also be produced by a ethoxy-1,2-dihydroquinoline, diethylcyanophosphate, phos method known perse or a method according thereto. phorus oxychloride, acetic anhydride and the like, 2-halo US 2009/0156582 A1 Jun. 18, 2009 20 genopyridinium salt such as 2-chloromethylpyridinium 0212. In the reaction scheme 3, L' is a leaving group, and iodide, 2-fluoro-1-chloromethylpyridinium iodide and the other symbols are as defined above. like, and the like are used. 0213. As the “leaving group” for L', for example, halogen 0206. The amount of the condensing agent to be used is about 0.8 to about 5.0 mol, preferably about 1.0 to about 3.0 atom (e.g., fluorine, chlorine, bromine, iodine and the like), mol, relative to 1 mol of compound (4). optionally halogenated Cls alkylsulfonyloxy (e.g., methane 0207. Where desired, the reaction may be carried out in the Sulfonyloxy, ethanesulfonyloxy, trichloromethanesulfony co-presence of a base together with the condensing agent. As loxy etc.), optionally substituted Co arylsulfonyloxy, the “base', for example, basic salts such as potassium acetate, optionally Substituted phenyl group, optionally Substituted Sodium acetate and the like, tertiary amines such as triethy 2-thiobenzothiazole and the like can be used. lamine, tripropylamine, tributylamine, cyclohexyldimethy lamine, 4-dimethylaminopyridine, N-methylpiperidine, 0214 Compound (I) can be produced by reacting com N-methylpyrrolidine, N-methylmorpholine and the like, pound (Ia) with compound (7) in, where desired, the presence 1-hydroxy-1H-benzotriazole (HOBt)-monohydrate and the of a base. like can be used. The amount of the base to be used is about 0215. The amount of compound (7) to be used is about 1.0 0.5 to about 5.0 mol, preferably about 2.0 to about 3.0 mol, to about 10.0 mol, preferably about 1.0 to about 2.0 mol, relative to 1 mol of compound (4). relative to 1 mol of compound (Ia). 0208. This reaction is advantageously carried out using a Solvent inert to the reaction. As such solvent, for example, 0216. As the “base', for example, basic salts such as Solvents including alcohols such as methanol, ethanol, pro Sodium carbonate, potassium carbonate, cesium carbonate, panol and the like, hydrocarbons such as hexane, cyclohex Sodium hydrogencarbonate and the like, aromatic amines ane, benzene, toluene, Xylene and the like, ethers such as Such as pyridine, lutidine and the like, tertiary amines such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, triethylamine, tripropylamine, tributylamine, cyclohexy 1,2-dimethoxyethane and the like, amides such as N,N-dim ethylformamide, N,N-dimethylacetamide, hexamethylphos ldimethylamine, 4-dimethylaminopyridine, N,N-dimethyla phoric triamide and the like, sulfoxides such as dimethylsul niline, N-methylpiperidine, N-methylpyrrolidine, N-methyl foxide and the like, halogenated hydrocarbons such as morpholine and the like, alkali metal hydrides Such as sodium dichloromethane, chloroform, carbon tetrachloride, 1,2- hydride, potassium hydride and the like, metal amides such as dichloroethane and the like, nitrites such as acetonitrile, pro sodium amide, lithium diisopropylamide, lithium hexameth pionitrile and the like, acid anhydrides Such as acetic anhy yldisilaZide and the like, metal alkoxides such as Sodium dride and the like, and the like and a mixed solvent thereofand the like are preferable. methoxide, Sodium ethoxide, potassium tert-butoxide and the 0209. The reaction time is generally about 10 minto about like, and the like can be used. 48 hr, preferably about 30 minto about 24hr. The reaction 0217 The amount of the base to be used is about 1.0 to temperature is generally about -20° C. to about 150° C. about 10.0 mol, preferably about 1.0 to about 2.0 mol, relative preferably about 0°C. to about 100° C. to 1 mol of compound (Ia). 0210. The resultant product can be isolated from the reac 0218. This reaction is advantageously carried out using a tion mixture according to a conventional method, and can be easily purified by a general separation means (e.g., recrystal solvent inert to the reaction. Such solvent is not particularly lization, distillation, chromatography etc.). limited as long as the reaction proceeds and, for example, 0211 When R is an optionally substituted alkyl group, Solvent including alcohols such as methanol, ethanol, pro compound (I) can be produced from compound (Ia) by the panol and the like, ethers such as diethyl ether, tetrahydrofu method described in the following reaction scheme 3. ran, dioxane, 1,2-dimethoxyethane and the like, hydrocar bons such as benzene, toluene, cyclohexane, hexane and the Reaction scheme 3 like, amides such as N,N-dimethylformamide, N,N-dimethy RI O H R4 lacetamide and the like, halogenated hydrocarbons such as V V / dichloromethane, chloroform, carbon tetrachloride, 1,2- N N-X R3-L' dichloroethane and the like, nitriles such as acetonitrile, pro R2 f \ (7) pionitrile and the like, sulfoxides such as dimethylsulfoxide N and the like, and the like and a mixed solvent thereof and the YN R6 like are preferable. R5 0219. The reaction time is generally about 30 minto about Ia 48 hr, preferably about 1 hr to about 24 hr. The reaction RI O R3 R4 temperature is generally about -20° C. to about 200° C. V V / N N-X preferably about 0°C. to about 150° C. M 0220. The resultant product can be isolated from the reac R2 W \ tion mixture according to a conventional method, and can be N easily purified by a general separation means (e.g., recrystal YN R6 lization, distillation, chromatography etc.). R5 0221. In addition, compound (I) can also be produced from compound (Ib) encompassed in compound (I), by the method described in the following reaction scheme 4. US 2009/0156582 A1 Jun. 18, 2009 21

0228. The reaction time is generally about 30 minto about 48 hr, preferably about 1 hr to about 24 hr. The reaction Reaction scheme 4 temperature is generally about -20° C. to about 200° C. RI O R3 R4 preferably about 0°C. to about 150° C. V V / 0229. The resultant product can be used for the next reac , N-X R-L, R-CO-L O R7a-NCO tion in the form of a reaction mixture or a crude product. It can R2 f \ (8) (9) (10) also be isolated from the reaction mixture according to a N conventional method, and can be easily purified by a general YN R6 separation means (e.g., recrystallization, distillation, chroma H tography etc.). Ib 0230. When R is an optionally substituted acyl group, compound (I) can be produced by reacting compound (Ib) RI O R3 R4 with compound (9) or compound (10) in, where desired, the V V / presence of a base or acid. N N-X 0231. The amount of compound (9) or compound (10) to R ? be used is about 1.0 to 5 mol, preferably about 1.0 to 2.0 mol, relative to 1 mol of compound (Ib). ( N ) R6 0232. As the “base', for example, basic salts such as Sodium carbonate, potassium carbonate, cesium carbonate, Sodium hydrogencarbonate and the like, aromatic amines I Such as pyridine, lutidine and the like, tertiary amines such as triethylamine, tripropylamine, tributylamine, cyclohexy ldimethylamine, 4-dimethylaminopyridine, N-methylpiperi dine, N-methylpyrrolidine, N-methylmorpholine and the 0222. In the reaction scheme 4, the symbols are as defined like, alkali metals such as metal sodium and the like, alkali above. metal hydrides such as Sodium hydride, potassium hydride 0223) When R is an optionally substituted alkyl group, and the like, metal amides Such as Sodium amide, lithium compound (I) can be produced by reacting compound (Ib) diisopropylamide, lithium hexamethyldisilazide and the like, with compound (8) in, where desired, the presence of a base. metal alkoxides such as sodium methoxide, Sodium ethoxide, 0224. The amount of compound (8) to be used is about 1.0 potassium tert-butoxide and the like, and the like can be used. to about 10.0 mol, preferably about 1.0 to about 2.0 mol, 0233. As the “acid', for example, methanesulfonic acid, relative to 1 mol of compound (Ib). p-toluenesulfonic acid, camphorsulfonic acid and the like can 0225. As the “base', for example, basic salts such as be used. Sodium carbonate, potassium carbonate, cesium carbonate, 0234. The amount of the “base' to be use is about 0.1 to 10 Sodium hydrogencarbonate and the like, aromatic amines equivalent amount, preferably 0.8 to 2 equivalent amount, Such as pyridine, lutidine and the like, tertiary amines such as relative to compound (Ib). triethylamine, tripropylamine, tributylamine, cyclohexy 0235. The amount of the “acid to be use is about 0.1 to 10 ldimethylamine, 4-dimethylaminopyridine, N,N-dimethyla equivalent amount, preferably 0.8 to 3 equivalent amount, niline, N-methylpiperidine, N-methylpyrrolidine, N-methyl relative to compound (Ib). morpholine and the like, alkali metal hydrides such as sodium 0236. This reaction is advantageously carried out without hydride, potassium hydride and the like, metal amides such as Solvent or using a solventinert to the reaction. Such solvent is Sodium amide, lithium diisopropylamide, lithium hexameth not particularly limited as long as the reaction proceeds and, yldisilaZide and the like, metal alkoxides such as sodium for example, solvents including ethers such as diethyl ether, methoxide, Sodium ethoxide, potassium tert-butoxide and the tetrahydrofuran, dioxane, 1,2-dimethoxyethane and the like, like and the like can be used. hydrocarbons such as benzene, toluene, cyclohexane, hexane 0226. The amount of the base to be used is about 1.0 to and the like, amides such as N,N-dimethylformamide, N.N- about 10.0 mol, preferably about 1.0 to about 2.0 mol, relative dimethylacetamide and the like, halogenated hydrocarbons to 1 mol of compound (Ib). Such as dichloromethane, chloroform, carbon tetrachloride, 0227. This reaction is advantageously carried out using a 1.2-dichloroethane and the like, nitriles Such as acetonitrile, solvent inert to the reaction. Such solvent is not particularly propionitrile and the like, sulfoxides such as dimethylsulfox limited as long as the reaction proceeds and, for example, ide and the like, nitrogen-containing aromatic hydrocarbons Solvents including alcohols such as methanol, ethanol, pro Such as pyridine, lutidine, quinoline and the like, and the like panol and the like, ethers such as diethyl ether, tetrahydrofu and a mixed solvent thereof and the like are preferable. The ran, dioxane, 1,2-dimethoxyethane and the like, hydrocar reaction temperature is about -40 to 150° C., preferably 0 to bons such as benzene, toluene, cyclohexane, hexane and the 100° C. The reaction time is generally 5 minto 24 hr, prefer like, amides such as N,N-dimethylformamide, N,N-dimethy ably 10 minto 5 hr. lacetamide and the like, halogenated hydrocarbons such as 0237. The resultant product (I) obtained as mentioned dichloromethane, chloroform, carbon tetrachloride, 1,2- above can be used for the next reaction in the form of a dichloroethane and the like, nitriles such as acetonitrile, pro reaction mixture or a crude product. It can also be isolated pionitrile and the like, sulfoxides such as dimethylsulfoxide from the reaction mixture according to a conventional and the like, and the like and a mixed solvent thereof and the method, and easily purified by a separation means Such as like are preferable. recrystallization, distillation, chromatography and the like. US 2009/0156582 A1 Jun. 18, 2009 22

0238. As an alternative method replacing the aforemen tioned reaction, compound (Ib) and compound (9) may be reacted in the presence of a Suitable condensing agent. Reaction scheme 5 0239. The amount of compound (9) to be used is about 0.8 RI V to about 10.0 mol, preferably about 0.8 to about 2.0 mol, O NH relative to 1 mol of compound (Ib). L NO ? 0240. As the “condensing agent’, for example, N,N'-di carboimides such as N,N'-dicyclohexylcarbodiimide, W \ (3) 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) N hydrochloride and the like, azolites such as N,N'-carbon YN R6 ylimidazole and the like, dehydrating agents such as N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, diethyl k cyanophosphate, phosphorus oxychloride, acetic anhydride 11 RI O R1 O and the like, 2-halogenopyridinium salt Such as 2-chlorom V V ethylpyridinium iodide, 2-fluoro-1-chloromethylpyridinium N NO2 N NH2 M M iodide and the like, and the like can be used. R2 f \ reduction R2 f \ 0241 The amount of the condensing agent to be used is N N about 0.8 to about 5.0 mol, preferably about 1.0 to about 2.0 YN R6 YN R6 mol, relative to 1 mol of compound (Ib). 0242. Where desired, the reaction may be carried out in the k co-presence of a base together with the condensing agent. As 12 4 the “base', for example, basic salts such as potassium acetate, Sodium acetate and the like, tertiary amines such as triethy 0248 Compound (11) may be a commercially available lamine, tripropylamine, tributylamine, cyclohexyldimethy product, or can be produced by a method known per se, for lamine, 4-dimethylaminopyridine, N-methylpiperidine, example, the method described in Chemistry of Heterocyclic N-methylpyrrolidine, N-methylmorpholine and the like, Compounds, 19, 1326-1330 (1983) or Russian Chemical Bul 1-hydroxy-1H-benzotriazole (HOBt)-monohydrate and the letin (English Translation), 42, 1861-1864 (1993) or a method like can be used. according thereto. Compound (12) can be produced by react 0243 The amount of the base to be used is about 0.5- to ing compound (11) with compound (3) by the method about 5.0 mol, preferably about 1.0 to about 3.0 mol, relative described in reaction scheme 1, from which compound (4) to 1 mol of compound (Ib). can be produced by a reduction reaction. 0249 According to the catalytic reduction method, com 0244. This reaction is advantageously carried out using a pound (4) can be produced by reacting compound (12) with a Solvent inert to the reaction. As such solvent, for example, metal catalyst under a hydrogen atmosphere. Where desired, Solvents including alcohols such as methanol, ethanol, pro a Suitable acid catalyst may be added. panol and the like, hydrocarbons such as hexane, cyclohex 0250) As the “metal catalyst, Raney-nickel, platinum ane, benzene, toluene, Xylene and the like, ethers such as oxide, metal palladium, palladium-activated carbon and the diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, like are used. The amount of the “metal catalyst” to be used is 1,2-dimethoxyethane and the like, amides such as N,N-dim generally about 0.1 to about 1000 wt %, preferably about 1 to ethylformamide, N,N-dimethylacetamide, hexamethylphos about 20 wt %, relative to compound (12). phoric triamide and the like, sulfoxides such as dimethylsul 0251. As the “acid catalyst', organic acids such as formic foxide and the like, halogenated hydrocarbons such as acid, acetic acid, trifluoroacetic acid, p-toluenesulfonic acid dichloromethane, chloroform, carbon tetrachloride, 1,2- and the like, mineral acids such as Sulfuric acid, hydrochloric dichloroethane and the like, nitrites such as acetonitrile, pro acid, hydrobromic acid and the like, and the like can be used. pionitrile and the like, acid anhydrides Such as acetic anhy The amount of the “acid catalyst” to be used is about 0.01 to dride and the like, and the like and a mixed solvent thereofand excess amount, relative to 1 mol of compound (12). the like are preferable. 0252. This reaction is advantageously carried out using a 0245. The reaction time is generally about 10 minto about solvent inert to the reaction. Such solvent is not particularly 72 hr., preferably about 30 minto about 24hr. The reaction limited as long as the reaction proceeds and, for example, temperature is generally about -20° C. to about 150° C. Solvents including alcohols such as methanol, ethanol, pro preferably about 0°C. to about 100° C. panol and the like; ethers such as diethyl ether, tetrahydrofu ran, dioxane, 1,2-dimethoxyethane and the like; hydrocar 0246 The resultant product can be used for the next reac bons such as benzene, toluene, cyclohexane, hexane and the tion in the form of a reaction mixture or a crude product. It can like: amides such as N,N-dimethylformamide, N,N-dimethy also be isolated from the reaction mixture according to a lacetamide and the like; organic acids such as acetic acid and conventional method, and can be easily purified by a general the like; water etc., and the like or a mixed solvent thereof and separation means (e.g., recrystallization, distillation, chroma the like are preferable. The hydrogen pressure is generally tography etc.). about 1 to about 100 atm. preferably about 1 to about 5 atm. 0247 The above-mentioned compound (4) can be pro The reaction time is generally about 30 minto about 48 hr, duced by a method known per se, for example, the method preferably about 1 to 24hr. The reaction temperature is gen described in J. Med. Chem., 35, 917-912 (1992) or the erally about 0°C. to about 120° C., preferably about 20° C. to method described in reaction scheme 5. about 80° C. US 2009/0156582 A1 Jun. 18, 2009

0253. After removing the catalyst, the resultant product (0259. In the reaction scheme 6, R' is an optionally sub can also be isolated from the reaction mixture according to a stituted alkyl group, and other symbols are as defined above. conventional method, and can be easily purified by a general 0260 Compound (13) may be a commercially available separation means (e.g., recrystallization, distillation, chroma product, or can be produced by a method known per se, for tography etc.). example, a method according to the description of Indian J. 0254 According to the method using an organic silyl Chem. Sect. B, 28, 56-60 (1989) or Tetrahedron, 3, 209-224 reagent (alkylsilane reagent), compound (4) can be produced (1958). by reacting compound (12) with an alkylsilane reagent and an 0261 Compound (14) can be produced by reducing com acid. pound (13) by the method described in reaction scheme 5. 0255 As the alkylsilane reagent, for example, triethylsi 0262 Compound (15) can be produced by acylating com lane, phenyldimethylsilane and the like can be used. The pound (14) by the methods described in reaction schemes 2 amount of the “alkylsilane reagent” to be used is about 0.8 to and 3. about 20 mol, preferably about 1 to about 5 mol, relative to 1 0263 Compound (2) can be produced by converting the mol of compound (12). ester group of compound (15) to a carboxyl group under basic 0256. As the acid, for example, organic acid such as trif or acidic conditions or by a method generally used. Where luoroacetic acid and the like can be used. The amount of the necessary, for example, compound (2) can be produced by acid is about 0.1 to excess amount, relative to 1 mol of com converting to active ester, acid anhydride, acid halide and the pound (12). like by a method according to the description of Shin Jikken 0257. This reaction is advantageously carried out without Kagaku Koza (New Experimental Chemistry Course), Vol. 14 Solvent or using a solventinert to the reaction. Such solvent is edited by the Chemical Society of Japan and the like. not particularly limited as long as the reaction proceeds and, 0264. The starting compound of the aforementioned com for example, solvents including ethers such as diethyl ether, pound (I) may form a salt and is not particularly limited as tetrahydrofuran, dioxane, 1,2-dimethoxyethane and the like, long as the reaction can be conducted. For example, a salt hydrocarbons such as benzene, toluene, cyclohexane, hexane similar to the salt formed by the aforementioned compound and the like; halogenated hydrocarbons such as dichlo (I) and the like, and the like can be used. romethane, chloroform, carbon tetrachloride, 1,2-dichloroet 0265. When isomerization occurs, the configuration iso hane and the like; organic acids such as acetic acid, trifluo mers (E,Z forms) of compound (I) can be isolated or purified roacetic acid and the like, and the like, or a mixed solvent by, for example, conventional separation means such as thereof and the like are preferable. extraction, recrystallization, distillation, chromatography 0258. The above-mentioned compound (2) can be pro and the like to give a pure compound. It is also possible to duced by a method known per se, for example, a method progress isomerization of a double bond by heating, acid according to the description of Indian J. Chem. Sect. B., 28. catalyst, transition metal complex, metal catalyst, radical spe 782-785 (1989) or Bull. Chem. Soc. Jpn., 52,208-211 (1979) cies catalyst, photoirradiation or strong base catalyst and the or the method described in reaction scheme 6. like according to the method described in Shin Jikken Kagaku Koza (New Experimental Chemistry Course) 14 (edited by Reaction Scheme 6 the Chemical Society of Japan), pages 251-253, Shin Jikken Kagaku Koza (New Experimental Chemistry Course) 19, 4th O Ed. (edited by the Chemical Society of Japan), pages 273-274 R10O NO and a method according thereto to give the corresponding reduction pure isomer. Y \ son 0266 While a stereoisomer occurs depending on the kind N of the substituent of compound (I), both the isomers alone and YN R6 mixtures of each isomers are encompassed in the present R5 invention. 13 0267 Compound (I) may be a hydrate or a non-hydrate. O 0268. In any case, where desired, compound (I) can be synthesized by further using deprotection reaction, acylation R10O NH2 reaction, alkylation reaction, hydrogenation reaction, oxida acylation tion reaction, reduction reaction, carbon chain extension NW \ on reaction and Substituent exchange reaction alone or in a com YN R6 bination of two or more thereof. 0269. When the object product is obtained in a free form R5 by the above-mentioned reactions, the product may be con 14 verted to a salt by a conventional method, and when it is obtained as a salt, the product may be converted to a free form O ,' O R ?' or a different salt by a conventional method. The compound R10O HN-X L N-X (I) thus obtained can be isolated and purified from a reaction mixture by a known means, such as, phase transfer, concen ( \ / \ tration, Solvent extraction, fractionation, crystallization, YN R6 YN R6 recrystallization, chromatography and the like. 0270. When compound (I) is present as a configurational isomer, diastereomer, conformer or the like, each can be 15 2 isolated by the above separation and purification methods on demand. In addition, when compound (I) is in the form of US 2009/0156582 A1 Jun. 18, 2009 24 racemates, they can be separated into d- and 1-forms by any (metabolic) stability and the like. Therefore, it can be used as conventional optical resolution. an agent for the prophylaxis or treatment of GSK-3 related 0271 When, in each of the aforementioned reactions, a pathology or disease, for example, metabolic diseases (e.g., functional group Such as amino group, hydroxy group, car diabetes (type 1 diabetes, type 2 diabetes, gestational diabetes boxy group and the like is present, the compound may be etc.), impaired glucose tolerance, obesity, diabetic neuropa Subjected to the reaction after introducing a protecting group thy, diabetic retinopathy, diabetic nephropathy, lipid metabo generally used in peptide chemistry etc. and the object com lism abnormalities (hypertriglyceridemia, hypercholester pound can be obtained by removing the protecting group as olemia, hypoHDL-emia, postprandial hyperlipemia etc.) and necessary after the reaction. the like), circulatory diseases (e.g., hypertension, cardiac 0272. As the protecting group, for example, formylor C. hypertrophy, angina pectoris, arteriosclerosis and the like), alkyl-carbonyl (e.g., acetyl, propionyl etc.), phenylcarbonyl, inflammatory diseases (e.g., allergy, asthma, rheumatism and Calkoxy-carbonyl (e.g., methoxycarbonyl, ethoxycarbo the like), cirrhosis, alcoholic hepatitis and osteoporosis or an nyl etc.), phenyloxycarbonyl, C7-o aralkyloxy-carbonyl agent for preventing the progress from impaired glucose tol (e.g., benzyloxycarbonyl etc.), trityl, phthaloyl and the like, erance to diabetes. each of which is optionally substituted, can be used. As these 0281. In the area of nervous diseases, the GSK-3 inhibitor Substituents, halogen atom (e.g., fluorine, chlorine, bromine, has a neural stem cell differentiation-stimulated action. iodine etc.), C alkyl-carbonyl (e.g., acetyl, propionyl, Accordingly, the GSK-3 inhibitor can be used as an agent for Valeryl etc.), nitro and the like are used. The number of the the prophylaxis or treatment of neurodegenerative diseases substituents is, for example, about 1 to 3. Such as Alzheimer's disease, mild cognitive impairment 0273. As a method for removing a protecting group, a (MCI), Huntington's chorea, Parkinson's syndrome, epi method known perse or a thereof analogous thereto is used. lepsy, amyotrophic lateral Sclerosis (ALS), multiple Sclero For example, a method of treating with acid, base, ultraviolet sis, cerebellum spinal cord denaturation, Pick disease, rays, hydrazine, phenylhydrazine, sodium N-methyldithio peripheral nerve disorders and the like and mental diseases carbamate, tetrabutylammonium fluoride, palladium acetate Such as Schizophrenia, depression, anxiety, manic depression, and the like, or reduction reaction is used. PTSD (posttraumatic stress disorder; hereinafter sometimes 0274 Compound A obtained in this way, other reaction to be abbreviated to PTSD) and the like. Based on cell pro intermediate and a starting compound thereof can be isolated tection action and/or function regeneration action, it can be and purified from a reaction mixture by a method known per used as an agent for the prophylaxis or treatment of ischemic se, for example, extraction, concentration, neutralization, fil diseases such as cerebral infarction, myocardial infarction tration, distillation, recrystallization, column chromatogra and the like. Particularly preferred is an agent for the prophy phy, thin layer chromatography, preparative high perfor laxis or treatment of diabetes or neurodegenerative disease. mance liquid chromatography (preparative HPLC), 0282 For diagnostic criteria of diabetes, Japan Diabetes moderate-pressure preparative liquid chromatography (mod Society reported new diagnostic criteria in 1999. erate-pressure preparative LC) and the like. 0283 According to this report, diabetes is a condition 0275 A salt of compound A can be produced by a method showing any of a fasting blood glucose level (glucose con known per se. For example, when compound A is a basic centration of intravenous plasma) of not less than 126 mg/dl. compound, it can be produced by adding an inorganic acid or a 75 g oral glucose tolerance test (75 g OGTT) 2 h level organic acid, or when compound A is an acidic compound, by (glucose concentration of intravenous plasma) of not less than adding an organic base or inorganic base. 200 mg/dl., and a non-fasting blood glucose level (glucose 0276. When compound A has an optical isomer, both the concentration of intravenous plasma) of not less than 200 individual optical isomers alone and mixtures thereof are mg/dl. A condition not falling under the above-mentioned naturally encompassed in the present invention. Where diabetes and different from “a condition showing a fasting desired, these isomers can be optically resolved by a method blood glucose level (glucose concentration of intravenous known perse, or individually produced. plasma) of less than 110 mg/dlora 75 g oral glucose tolerance 0277. When compound A is present as a configurational test (75 g OGTT) 2 h level (glucose concentration of intrave isomer, diastereomer, conformer or the like, each can be nous plasma) of less than 140 mg/dl” (normal type) is called isolated by the above separation and purification methods on a “borderline type”. demand. In addition, when compound A is in the form of 0284. In addition, ADA (American Diabetes Association) racemates, they can be separated into S- and R-forms by any reported new diagnostic criteria of diabetes in 1997 and WHO conventional optical resolution method. in 1998. 0278. When compound A includes stereoisomers, both the 0285 According to these reports, diabetes is a condition isomers alone and mixtures of each isomer are encompassed showing a fasting blood glucose level (glucose concentration in the present invention. of intravenous plasma) of not less than 126 mg/dland a 75g 0279 Compound A may be a hydrate, and both hydrate oral glucose tolerance test 2h level (glucose concentration of and non-hydrate are encompassed in the scope of the present intravenous plasma) of not less than 200 mg/dl. invention. Compound A may be labeled with an isotope (e.g., 0286 According to the above-mentioned reports, H, C, S, 'I and the like) or the like. impaired glucose tolerance is a condition showing a fasting 0280 Since the GSK-3 inhibitor of the present invention blood glucose level (glucose concentration of intravenous selectively inhibits GSK-3 and shows low toxicity and a plasma) of less than 126 mg/dland a 75 g oral glucose toler fewer side effects, it is useful as a safe pharmaceutical prod ance test 2 h level (glucose concentration of intravenous uct. The GSK-3 inhibitor of the present invention shows a plasma) of not less than 140 mg/dl and less than 200 mg/dl. superior GSK-3 selective inhibitory action for a mammal According to the report of ADA, a condition showing a fasting (e.g., mouse, rat, hamster, rabbit, cat, dog, bovine, sheep, blood glucose level (glucose concentration of intravenous monkey, human etc.) and is Superior in (oral) absorbability, plasma) of not less than 110 mg/dland less than 126 mg/dl is US 2009/0156582 A1 Jun. 18, 2009 called IFG (Impaired Fasting Glucose). According to the and optically active forms, salts and hydrates, etc. thereof), report of WHO, among the IFG (Impaired Fasting Glucose), antidepressants (e.g., desipramine, amitriptyline, imi a condition showing a 75g oral glucose tolerance test 2h level pramine, tramadol etc.), anticonvulsants (e.g., lamotrigine (glucose concentration of intravenous plasma) of less than etc.), antianxiety drugs (e.g., benzodiazepine etc.), non-ste 140 mg/dl is called IFG (Impaired Fasting Glycemia). roidal anti-inflammatory drugs (e.g., meloxicam, tenoxicam, 0287 Compound A of the present invention can be also indomethacin, ibuprofen, celecoxib, rofecoxib, aspirin, used as an agent for the prophylaxis or treatment of diabetes, indomethacin etc.), disease-modifying anti-rheumatic drugs borderline type, impaired glucose tolerance, IFG (Impaired (DMARDs), anti-cytokine drugs (TNF inhibitor, MAP Fasting Glucose) and IFG (Impaired Fasting Glycemia), as kinase inhibitor and the like), Steroidal drugs (e.g., dexam determined according to the above-mentioned new diagnos ethasone, hexestrol, cortisone acetate etc.), therapeutic agents tic criteria. Moreover, the compound of the present invention for incontinence or frequent urination (e.g., flavoxate hydro can prevent progress of borderline type, impaired glucose chloride, oxybutynin hydrochloride, propiverine hydrochlo tolerance, IFG (Impaired Fasting Glucose) or IFG (Impaired ride etc.), phosphodiesterase inhibitors (e.g., sildenafil (cit Fasting Glycemia) into diabetes. rate) etc.), dopamine agonists (e.g., apomorphine etc.). antiarrhythmics (e.g. mexiletine etc.), sex hormones or 0288 When the compound A of the present invention is derivatives thereof (e.g., progesterone, estradiol, estradiol applied to each of the above-mentioned diseases, it can be benzoate etc.), therapeutic agents for osteoporosis (e.g., alfa used in an appropriate combination with a pharmaceutical calcidol, calcitriol, elcatonin, calcitonin salmon, estriol, ipri agent or a treatment method generally employed for the dis flavone, disodium pamidronate, Sodium alendronate hydrate, ease. For example, acetylcholine esterase inhibitors (e.g., disodium incadronate etc.), parathyroid hormone (PTH), cal donepezil, rivastigmine, galanthamine, Zanapezil (TAK-147) cium receptor antagonists and the like can be mentioned. etc.), antidementia agents (memantine etc.), inhibitors of B Particularly, a combined use with a B secretase inhibitory amyloid protein production, Secretion, accumulation, coagu agent such as 6-(4-biphenylyl)methoxy-2-[2-(N,N-dimethy lation and/or deposition, B secretase inhibitors (e.g., 6-(4- biphenylyl)methoxy-2-[2-(N,N-dimethylamino)ethyltetra lamino)ethyltetralin hydrochloride-monohydrate etc., and lin, 6-(4-biphenylyl)methoxy-2-(N,N-dimethylamino) the like is preferable. methyltetralin, 6-(4-biphenylyl)methoxy-2-(N.N- 0289. In addition, a combined use with a transplantation dipropylamino)methyltetralin, 2-(N,N-dimethylamino) method of neural stem cell or neural precursor cell, or fetal methyl-6-(4-methoxybiphenyl-4-yl)methoxytetralin, 6-(4- neural tissue prepared from embryonic stem cell or nervous biphenylyl)methoxy-2-[2-(N,N-diethylamino)ethyltetralin, tissue, and a combined use with a pharmaceutical agent such 2-2-(N,N-dimethylamino)ethyl-6-(4-methylbiphenyl-4- as an immunosuppressant after the transplantation and the yl)methoxytetralin, 2-2-(N,N-dimethylamino)ethyl-6-(4- like can be mentioned. methoxybiphenyl-4-yl)methoxytetralin, 6-(2',4'-dimethoxy 0290 Examples of therapeutic agent for diabetes include biphenyl-4-yl)methoxy-2-[2-(N,N-dimethylamino)ethyl insulin preparations (e.g., animal insulin preparation tetralin, 6-4-(1,3-benzodioxol-5-yl)phenylmethoxy-2-2- extracted from the pancreas of bovine, Swine; human insulin (N,N-dimethylamino)ethyltetralin, 6-(3',4'- preparation genetically synthesized using Escherichia coli, dimethoxybiphenyl-4-yl)methoxy-2-[2-(N.N- yeast; Zinc insulin; protamine Zinc insulin; insulin fragment dimethylamino)ethyltetralin, an optically active form or derivatives (e.g., INS-1 etc.) and the like), insulin sensitiz thereof, a salt thereofandahydrate thereof, OM99-2 (WO01/ ers e.g., pioglitaZone hydrochloride, troglitaZone, rosiglita 00663)), Y secretase inhibitory agent, B amyloid protein Zone or maleate thereof, GI-262570, JTT-501, MCC-555, coagulation inhibitory agent (e.g., PTI-00703, ALZHEMED YM-440, KRP-297, CS-011, FK-614, compounds described (NC-531), PPI-368 (JP-A-11-5.14333), PPI-558 (JP-A-2001 in WO99/58510 (e.g., (E)-4-4-(5-methyl-2-phenyl-4-ox 500852), SKF-74652 (Biochem. J. (1999), 340(1), azolylmethoxy)benzyloxyimino-4-phenylbutyric acid), 283-289)), Bamyloid vaccine, Bamyloid degrading enzyme N,N-622, AZ-242, BMS-298585, ONO-5816, LM-4156, and the like, cerebral function activators (e.g., aniracetam, BM-13-1258, MBX-102, GW-1536 etc.), C-glucosidase nicergoline etc.), other therapeutic drug for Parkinson's dis inhibitors (e.g., Voglibose, acarbose, miglitol, emiglitate ease (e.g., dopamine receptor agonists (L-DOPA, bro etc.), biguanides (e.g., phenformin, metformin, buformin mocriptine, pergolide, talipexole, pramipexole, Cabergoline, etc.), insulin secretagogues Sulfonylurea (e.g., tolbutamide, adamantadine etc.), monoamine oxidase (MAO) inhibitors glibenclamide, gliclazide, chlorpropamide, tolaZamide, (deprenyl, Selgiline (selegiline), remacemide, riluzole etc.), acetohexamide, glyclopyramide, glimepiride, glipizide, gly anticholinergic agents (e.g., trihexyphenidyl, biperiden etc.), buzole etc.), repaglinide, nateglinide, mitiglinide or calcium COMT inhibitors (e.g., entacapone etc.)), therapeutic drug salt hydrate thereof, GLP-1 etc.), dipeptidyl-peptidase IV for amyotropic lateral Sclerosis (e.g., riluzole etc., neu inhibitors (e.g., NVP-DPP-278, PT-100, NVP-DPP-728, rotrophic factor etc.), therapeutic drug for abnormal behavior, LAF237 etc.), B3 agonists (e.g., CL-316243, SR-58611-A, wandering and the like due to the progress of dementia (e.g., UL-TG-307, SB-226552, AJ-9677, BMS-196085, AZ-40140 sedative drug, antianxiety drug etc.), apoptosis inhibitors etc.), amylin agonists (e.g., pramlintide etc.), phosphoty (e.g., CPI-1189, IDN-6556, CEP-1347 etc.), neuronal differ rosine phosphatase inhibitors (e.g., vanadic acid etc.), gluco entiation or regeneration promoters (e.g., leteprinim, Xalip neogenesis inhibitors (e.g., glycogen phosphorylase inhibi roden (SR-57746-A), SB-216763, Y-128, VX-853, prosap tor, glucose-6-phosphatase inhibitors, glucagon antagonist tide, 5,6-dimethoxy-2-2,2,4,6,7-pentamethyl-3-(4- etc.), SGLUT (sodium-glucose cotransporter) inhibitors methylphenyl)-2,3-dihydro-1-benzofuran-5-ylisoindoline, (e.g., T-1095 etc.) and the like. 5,6-dimethoxy-2-3-(4-isopropylphenyl)-2,2,4,6,7-pentam 0291 Examples of the therapeutic agents for diabetic ethyl-2,3-dihydro-1-benzofuran-5-ylisoindoline, 6-3-(4- complications include aldose reductase inhibitors (e.g., tolr isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-ben estat, epalrestat, Zenarestat, Zopolrestat, minalrestat, fidar Zofuran-5-yl)-6,7-dihydro-5H-1.3dioxolo 4.5-fisoindole estat (SNK-860), CT-112 etc.), neurotrophic factors (e.g., US 2009/0156582 A1 Jun. 18, 2009 26

NGF, NT-3, BDNF etc.), neurotrophic factor production-se poxide and the like. Of these, Furtulon and NeoFurtulon, cretion promoters e.g., neurotrophin production-secretion which are 5-fluorouracil derivatives, and the like are prefer promoters described in WOO1/14372 (e.g., 4-(4-chlorophe able. nyl)-2-(2-methyl-1-imidazolyl)-5-[3-(2-methylphenoxy) 0297 Examples of the immunotherapeutic agents include propyloxazole and the like), PKC inhibitors (e.g., microorganism or bacterial components (e.g., muramyl LY-333531 etc.), AGE inhibitors (e.g., ALT946, pimagedine, dipeptide derivative, Picilbanil etc.), polysaccharides having pyratoxanthine, N-phenacylthiazolium bromide (ALT766), immunity potentiating activity (e.g., lentinan, Schizophyllan, EXO-226 etc.), active oxygen scavengers (e.g., thioctic acid krestin etc.), cytokines obtained by genetic engineering tech etc.), cerebral vasodilators (e.g., tiapuride, mexiletine etc.). niques (e.g., interferon, interleukin (IL) etc.), colony Stimu lating factors (e.g., granulocyte colony stimulating factor, 0292 Examples of the therapeutic agents for hyperlipi erythropoietin etc.) and the like, with preference given to demia include HMG-CoA reductase inhibitors (e.g., pravas interleukins such as IL-1, IL-2, IL-12 and the like. tatin, simvastatin, lovastatin, atorvastatin, fluvastatin, lipantil, cerivastatin, itavastatin, ZD-4522 or a salt thereof 0298 Examples of the antithrombotic agents include hep (e.g., sodium salt etc.) and the like), fibrate compounds (e.g., arin (e.g., heparin Sodium, heparin calcium, dalteparin bezafibrate, beclobrate, binifibrate, ciprofibrate, clinofibrate, Sodium etc.), warfarin (e.g., warfarin potassium etc.), anti clofibrate, clofibric acid, etofibrate, fenofibrate, gemfibrozil, thrombin drugs (e.g., aragatroban etc.), thrombolytic agents nicofibrate, pirifibrate, ronifibrate, simfibrate, theofibrate and (e.g., urokinase, tisokinase, alteplase, nateplase, monteplase, the like), squalene synthase inhibitors (e.g., compounds pamiteplase etc.), platelet aggregation inhibitors (e.g., ticlo described in WO97/10224, for example, N-((3R,5S)-1-(3- pidine hydrochloride, cilostazol, ethyl icosapentate, bera acetoxy-2,2-dimethylpropyl)-7-chloro-5-(2,3-dimethox prost sodium, Sarpogrelate hydrochloride etc.) and the like. yphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzooxazepin-3-yl 0299| Examples of the cachexia improvement pharmaceu acetylpiperidine-4-acetic acid and the like), ACAT inhibitors tical agent include cyclooxygenase inhibitors (e.g., (e.g., avasimibe, eflucimibe and the like), anion exchange indomethacin etc.) Cancer Research, Vol. 49, pages 5935 resins (e.g., colestyramine and the like), probucol, nicotinic 5939, 1989, progesterone derivatives (e.g., megestrol acid drugs (e.g., nicomol, niceritrol and the like), ethyl icosa acetate) Journal of Clinical Oncology, Vol. 12, pages 213 pentate, phytosterol (e.g., Soysterol, Y ory Zanol and the like) 225, 1994, glucosteroids (e.g., dexamethasone etc.), meto and the like. clopramide agents, tetrahydrocannabinol agents (publica 0293 Examples of the antihypertensive agent include tions are all as mentioned above), fat metabolism improving angiotensin converting enzyme inhibitors (e.g., captopril, agents (e.g., eicosapentanoic acid etc.) (British Journal of enalapril, delapril etc.), angiotensin II antagonist (e.g., can Cancer, Vol. 68, pages 314-318, 1993, growth hormones, desartancilexetil, losartan, eprosartan, Valsartan, telmisartan, IGF-1, or antibodies to a cachexia-inducing factor Such as irbesartan, tasosartan etc.), calcium antagonists (e.g., manid TNF-C., LIF, IL-6, oncostatin M and the like. ipine, nifedipine, nicardipine, amlodipine, efonidipine etc.), 0300. It is also possible to apply compound A of the present invention to each of the above-mentioned diseases in potassium channel openers (e.g., levcromakalim, L-27152, combination with a biologic (e.g., antibody, vaccine prepara AL 0671, NIP-121 and the like), clonidine and the like. tion and the like), or as a combination therapy in combination 0294 Examples of the antiobesity agents include antiobe with gene therapy method and the like. Examples of the sity agents acting on the central nervous system (e.g., dexfen antibody and vaccine preparation include vaccine preparation fluramine, fenfluramine, phentermine, sibutramine, anifepra to angiotensin II, vaccine preparation to CETP CETP anti mone, dexamphetamine, mazindol, phenylpropanolamine, body, TNFC. antibody and antibody to other cytokine, amy clobenzoeX etc.), pancreatic lipase inhibitors (e.g., orlistat loid B vaccine preparation, type 1 diabetes vaccine (DIAPEP etc.), B3 agonists (e.g., CL-316243, SR-58611-A, UL-TG 277 manufactured by Peptor Ltd. and the like), anti-HIV 307, SB-226552, AJ-9677, BMS-196085, AZ-40140 etc.), antibody, HIV vaccine preparation and the like, antibody or anorectic peptides (e.g., leptin, CNTF (ciliary neurotrophic vaccine preparation to cytokine, renin-angiotensin enzyme factor) etc.), cholecystokinin agonists (e.g., lintitript, FPL and a product thereof, antibody or vaccine preparation to 15849 etc.) and the like. enzyme or protein involved in blood lipid metabolism, anti 0295 Examples of the diuretics include xanthine deriva body or vaccine to enzyme or protein involved in blood tives (e.g., sodium salicylate and theobromine, calcium sali coagulation or fibrinolytic system, antibody or vaccine prepa cylate and theobromine etc.), thiazide preparations (e.g., ethi ration to protein involved in Saccharometabolism or insulin azide, cyclopenthiazide, trichloromethiazide, resistance and the like. In addition, a combined use with a hydrochlorothiazide, hydroflumethiazide, benzylhydrochlo biological preparation involved in a growth factor Such as rothiazide, penflutizide, polythiazide, methyclothiazide etc.), GH, IGF and the like is possible. Examples of the gene antialdosterone preparations (e.g., spironolactone, triam therapy method include a treatment method using a gene terene etc.), carbonate dehydratase inhibitors (e.g., acetazola relating to cytokine, renin-angiotensin enzyme and a product mide and the like), chlorobenzenesulfonamide preparations thereof, G protein, G protein conjugated receptor and its (e.g., chlortalidone, mefruside, indapamide etc.), azosemide, phosphorylation enzyme, a treatment method using a DNA isosorbide, etacrynic acid, piretanide, bumetanide, furo decoy such as NFKB decoy and the like, a treatment method semide and the like. using an antisense, a treatment method using a gene relating 0296. Examples of the chemotherapeutic agents include to an enzyme or protein involved in blood lipid metabolism alkylating agents (e.g., cyclophosphamide, ifosfamide etc.), (e.g., gene relating to metabolism, excretion or absorption of metabolic antagonists (e.g., methotrexate, 5-fluorouracil or cholesterol or triglyceride or HDL-cholesterol or blood phos derivative thereof etc.), antitumor antibiotics (e.g., mitomy pholipid and the like), a treatment method using a gene relat cin, adriamycin etc.), plant-derived antitumor agents (e.g., ing to an enzyme or protein involved in angiogenesis therapy Vincristine, Vindesine, Taxol etc.), cisplatin, carboplatin, eto targeting obstruction of peripheral vessel and the like (e.g., US 2009/0156582 A1 Jun. 18, 2009 27 growth factors such as HGF, VEGF etc., and the like), a dered glycyrrhiza, mannitol, Sodium hydrogencarbonate, cal treatment method using a gene relating to a protein involved cium phosphate, calcium sulfate and the like. in Saccharometabolism or insulin resistance, an antisense to (0307 Examples of the binder include 5-10 wt % starch cytokine such as TNF and the like, and the like can be men liquid paste, 10-20 wt % gum arabic solution or gelatin solu tioned. In addition, it is possible to use compound A in com tion, 1-5 wt % tragacanth solution, carboxymethyl cellulose bination with various organ regeneration methods utilizing Solution, Sodium alginate Solution, glycerin and the like. heart regeneration, kidney regeneration, pancreas regenera 0308 Examples of the disintegrant include starch, cal tion, blood vessel regeneration and the like or cell transplan cium carbonate and the like. tation therapy utilizing bone marrow cell (myelomonocytic 0309 Examples of the lubricant include magnesium stear cell, myeloid stem cell and the like) or an artificial organ ate, Stearic acid, calcium Stearate, purified talc and the like. utilizing tissue engineering (artificial blood vessel and car 0310. Examples of the Sweetener include glucose, fruc diac muscle cell sheet). tose, invert Sugar, Sorbitol. Xylitol, glycerin, simple syrup and 0301 Compound A of the present invention or a salt the like. thereof can be administered orally or parenterally as it is or 0311 Examples of the surfactant include sodium lauryl after mixing with a pharmacologically acceptable carrier. As sulfate, polysorbate 80, sorbitan monofatty acid ester, poly pharmacologically acceptable carriers, various organic or oxyl 40 stearate and the like. inorganic carrier Substances conventionally used as prepara 0312 Examples of the Suspending agent include gum ara tion materials can be used, and added as excipient, lubricant, bic, Sodium alginate, sodium carboxymethyl cellulose, binder and disintegrant for Solid preparations; or solvent, methyl cellulose, bentonite and the like. Solubilizing agents, Suspending agent, isotonicity agent, 0313 Examples of the emulsifier include gum arabic, buffer, soothing agent and the like for liquid preparation. tragacanth, gelatin, polysorbate 80 and the like. Where necessary, preparation additive such as preservative, 0314. Furthermore, when the compound Aora salt thereof antioxidant, colorant, Sweetening agent and the like can be is produced in the above-mentioned dosage form, a Suitable used. amount of a coloring agent, a preservative, an aromatic, a 0302 For the pharmaceutical agent of the present inven corrigent, a stabilizer, Viscous agents and the like typically tion containing compound Aora salt thereof, the dosage form used in the field of preparation can be added on demand. for oral administration is, for example, tablet (including 0315. The pharmaceutical agent of the present invention Sugar-coated tablet, film-coated tablet), pill, granule, powder, containing compound A or a salt thereof is stable and low capsule (including soft capsule, microcapsule), syrup, emul toxic, and can be used safely. The daily dose varies depending Sion, Suspension and the like, and the dosage form for on the condition and body weight of patients, the kind of parenteral administration is, for example, injection, injecting compound, administration route and the like. For example, in agent, drip infusion, Suppository and the like. In addition, it is the case of oral administration to patients with diabetes, neu effective to make a Sustained release preparation by combin rodegenerative disease and the like, the daily dose to an adult ing with a suitable base (e.g., polymer of butyric acid, poly (body weight about 60 kg) is about 1 to 1000 mg, preferably mer of glycolic acid, copolymer ofbutyric acid-glycolic acid, about 3 to 300 mg, more preferably about 10 to 200 mg, as an a mixture of polymer ofbutyric acid and polymer of glycolic active ingredient (the compound A or a salt thereof), which acid, polyglycerol fatty acid ester etc.). can be given in a single administration or administered in 2 or 0303 While the content of compound A or a salt thereof in 3 portions a day. the pharmaceutical agent of the present invention varies 0316. When the compound A of the present invention or a depending on the form of the pharmaceutical preparation, it is salt thereof is administered parenterally, it is generally admin generally about 2 to 85 wt %, preferably about 5 to 70 wt %, istered in the form of a liquid (e.g., injection). While the dose relative to the whole preparation. varies depending on the Subject of administration, target 0304. As a method for forming compound A or a salt organ, symptom, administration method and the like, it is, for thereof in the above-mentioned dosage form, a known pro example, about 0.01 mg-about 100 mg, preferably about duction method generally used in the pertinent field can be 0.01-about 50 mg, more preferably about 0.01-about 20 mg. applied. When the above-mentioned dosage form is pro in the form of an injection, relative to 1 kg of body weight, duced, various preparation additives such as carrier (e.g., which is preferably given by intravenous injection. As the excipient, binder, disintegrant, lubricant and the like), Sweet injection, intravenous injection as well as Subcutaneous injec ening agent, Surfactant, Suspending agent, emulsifier and the tion, intracutaneous injection, intramuscular injection, instil like generally used in the field of preparation are appropri lation and the like are mentioned, and as a Sustained release ately added in Suitable amounts as necessary for production. preparation, iontophoresis transdermal agent and the like are 0305 When the compound A or a salt thereof is prepared mentioned. Such injections are prepared by methods known in to a tablet, for example, it can be produced by adding an perse, or by dissolving, Suspending or emulsifying the com excipient, a binder, a disintegrant, a lubricant and the like, and pound A of the present invention or a salt thereof in a steril when a pill and a granule are to be prepared, they can be ized aqueous Solution or oily liquid. As an aqueous solution produced by adding an excipient, a binder, a disintegrant and for injection, physiological saline, isotonic Solutions contain the like. When a powder and a capsule are to be prepared, they ing glucose or other auxiliary drugs (e.g., D-Sorbitol, D-man can be produced by adding an excipient and the like, and nitol, sodium chloride and the like) and the like can be men when a syrup is to be prepared, it can be produced by adding tioned, and they can be used in combination with suitable a Sweetener and the like, and when an emulsion or a suspen dissolution aids, such as alcohols (e.g., ethanol), polyalcohols sion is to be prepared, it can be produced by adding a sus (e.g., propylene glycol, polyethylene glycol), nonionic Sur pending agent, a Surfactant, an emulsifier and the like. factants (e.g., polysorbate 80, HCO-50) and the like. As an 0306 Examples of the excipient include lactose, sucrose, oily liquid, Sesame oil, soybean oil and the like can be men glucose, starch, Sucrose, microcrystalline cellulose, pow tioned, which may be used in combination with dissolution US 2009/0156582 A1 Jun. 18, 2009 28 aids (e.g., benzyl benzoate, benzyl alcohol and the like) and q: quartet the like. In addition, buffers (e.g., phosphate buffer, sodium Septet: Septet acetate buffer), Soothing agents (e.g., benzalkonium chloride, m: multiplet procaine hydrochloride and the like), stabilizers (e.g., human br: broad serum albumin, polyethylene glycol and the like), preserva J: coupling constant tives (e.g., benzyl alcohol, phenol and the like) and the like may be added. A prepared injection is generally filled in an HZ: Hertz ampoule. 0321 CDC1: deuterated chloroform 0317. When the compound of the present invention is used DMSO-d: deuterated dimethyl sulfoxide in combination with other pharmaceutical agent, the admin H-NMR: proton nuclear magnetic resonance istration mode of the compound of the present invention and HPLC: high performance liquid chromatography a combination drug is not particularly limited, and the com THF: tetrahydrofuran pound of the present invention and a combination drug only DMF: dimethylformamide need to be combined on administration. Examples of Such HOBt: 1-hydroxybenzotriazole administration mode include the following: WSC: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (1) administration of a single preparation obtained by simul hydrochloride taneously processing the compound of the present invention LC-MS: liquid chromatography-mass spectrometry spec and the concomitant drug, (2) simultaneous administration of trum two kinds of preparations of the compound of the present ESI: electrospray ionization method invention and the concomitant drug, which have been sepa rately produced, by the same administration route, (3) admin Reference Example 1 istration of two kinds of preparations of the compound of the present invention and the concomitant drug, which have been Methyl 4-nitro-1H-pyrazole-3-carboxylate separately produced, by the same administration route in a staggered manner, (4) simultaneous administration of two 0322 Acetyl chloride (9 mL) was added dropwise to kinds of preparations of the compound of the present inven methanol (90 mL), 4-nitro-1H-pyrazole-3-carboxylic acid tion and the concomitant drug, which have been separately (9.00 g, 57.3 mmol) was added to the mixture. The mixture produced, by different administration routes, (5) administra was stirred at room temperature for 16 hr, and concentrated tion of two kinds of preparations of the compound of the under reduced pressure. Methanol was added to the residue, present invention and the concomitant drug, which have been and the mixture was concentrated under reduced pressure, the separately produced, by different administration routes in a operation was twice repeated. The residue was diluted with staggered manner (for example, administration in the order of methanol and ethyl acetate. 5% sodium hydrogencarbonate the compound of the present invention and the concomitant aqueous Solution was added, and the pH was adjusted to 8-9. drug, or in the reverse order) and the like. The dose of the The mixture was extracted with ethyl acetate. The extract was concomitant drug can be appropriately determined based on washed with water, brine, dried over anhydrous magnesium the dose employed in clinical situations. The mixing ratio of Sulfate, and the Solvent was evaporated under reduced pres the compound of the present invention and a concomitant sure to give the title compound (9.83 g, yield 100%). drug can be appropriately determined depending on the 0323 'H-NMR (DMSO-de, 200 MHz): a 3.98 (3H, s), administration Subject, administration route, target disease, 8.28 (1H, s). symptom, combination and the like. When the subject of Reference Example 2 administration is human, for example, a concomitant drug can be used in 0.01-100 parts by weight relative to 1 part by Methyl 4-amino-1H-pyrazole-3-carboxylate weight of the compound of the present invention. 0324. A mixture of methyl 4-nitro-1H-pyrazole-3-car boxylate obtained in Reference Example 1 (9.63 g, 56.3 EXAMPLES mmol), 10% palladium/carbon (1.00 g) and methanol (150 0318. The present invention is explained in detail in the mL) was stirred under hydrogen atmosphere at room tem following by referring to Reference Examples. Examples, perature for 16 hr. The catalyst was filtrated, and the solvent Formulation Examples and Experimental Examples. How was evaporated under reduced pressure to give the title com ever, the examples are mere exemplifications and do not limit pound (7.87 g, yield 99%). the present invention. The present invention may be modified 0325 H-NMR (CDC1): 83.93 (3H, s), 4.08 (2H, brs), without departing from the scope of the invention. 7.25 (1H, s). 0319. The term “room temperature” in the following Ref erence Examples and Examples indicates the range of gener Reference Example 3 ally from about 10° C. to about 35° C. As for “%', the yield is in mol/mol %, the solvent used for chromatography is in 96 by N-isopropyl-4-nitro-1H-pyrazole-3-carboxamide volume and other “%' is in % by weight. OH proton, NH 0326 To a mixture of 4-nitro-1H-pyrazole-3-carboxylic proton etc. that could not be confirmed due to broad peak by acid (6.50 g, 41.4 mmol) and N,N-dimethylformamide (100 proton NMR spectrum are not included in the data. mL), isopropylamine (4.7 mL, 55 mmol), HOBt (6.71 g, 50 0320. The other symbols used herein mean the following: mmol) and (3-dimethylaminopropyl)ethylcarbodiimide s: singlet hydrochloride (9.52g, 50 mmol) were added, and the mixture d: doublet was stirred at room temperature for 16 hr. 5% Aqueous solu dd: doublet of doublets tion of citric acid was added to the reaction mixture, and the dt: doublet of triplets mixture was extracted with ethyl acetate. The extract was t: triplet washed with 5% aqueous solution of citric acid, 5% sodium US 2009/0156582 A1 Jun. 18, 2009 29 hydrogencarbonate aqueous Solution, brine, and dried over 0339 'H-NMR (DMSO-de, 200 MHz): 8 4.46 (2H, d, anhydrous magnesium Sulfate. The solvent was evaporated J=6.0 Hz), 6.32-6.34 (1H, m), 6.41-6.44 (1H, m), 7.61-7.62 under reduced pressure to give the title compound (5.72 g, (1H, m), 8.70-8.90 (1H, brm), 9.15 (1H, brs). yield 70%). 0327 'H-NMR (DMSO-de, 200 MHz): & 1.14 (6H, d, Reference Example 10 J=6.6Hz), 3.91-4.17 (1H, m), 8.45-8.65 (1H, brm), 8.76 (1H, 4-amino-N-methyl-1H-pyrazole-3-carboxamide brs). 0340. A mixture of methyl 4-amino-1H-pyrazole-3-car Reference Example 4 boxylate obtained in Reference Example 2 (5.39 g, 38.2 mmol) and 40% methylamine/methanol solution (25 mL) 4-nitro-3-(pyrrolidin-1-ylcarbonyl)-1H-pyrazole was stirred at room temperature for 2 days. The mixture was concentrated under reduced pressure. Then methanol was 0328. In the same manner as in Reference Example 3, the added to the residue, and the mixture was concentrated under title compound was obtained using pyrrolidine. yield 74%. reduced pressure, the operation was twice repeated. Methanol 0329 "H-NMR (DMSO-d 200 MHz): & 1.79-191 (4H, and activated carbon (4.5 g) were added to the residue. After m), 3.19 (2H, t, J=6.3 Hz), 3.49 (2H, t, J=6.8 Hz), 8.90 (1H, filtration, the solvent was evaporated under reduced pressure brs). to give the title compound (5.31 g, yield 99%). 0341 'H-NMR (DMSO-de, 200 MHz): 8 2.71 (3H, d, Reference Example 5 J=4.8 Hz), 4.58 (2H, brs), 7.09 (1H, s), 7.72-7.86 (1H, brm). N-cyclopentyl-4-nitro-1H-pyrazole-3-carboxamide Reference Example 11 0330. In the same manner as in Reference Example 3, the 4-amino-N-isopropyl-1H-pyrazole-3-carboxamide title compound was obtained using cyclopentylamine. yield 71%. 0342. A mixture of N-isopropyl-4-nitro-1H-pyrazole-3- 0331 'H-NMR (DMSO-d): 81.45-1.67 (6H, m), 1.82-1. carboxamide obtained in Reference Example 3 (5.42 g, 32.2 89 (2H, m), 4.12-4.23 (1H, m), 8.50-8.90 (2H, brm). mmol), 10% palladium carbon (1.0 g) and methanol (200 mL) was stirred under hydrogen atmosphere at room temperature Reference Example 6 for 6 hr. The catalyst was removed by filtration, and the solvent was evaporated under reduced pressure to give the 4-nitro-N-phenyl-1H-pyrazole-3-carboxamide title compound (4.48g, yield 83%). 0343 'H-NMR (DMSO-d): & 1.13 (6H, d, J=6.6 Hz), 0332. In the same manner as in Reference Example 3, the 3.96-4.11 (1H, m), 4.56 (2H, brs), 7.08 (1H, s), 7.46 (1H, brd, title compound was obtained using aniline. yield 88%. J=8.1 Hz). 0333 H-NMR (DMSO-de, 200 MHz): 8 7.14 (1H, t, J=7.3 Hz), 737-7.41 (2H, m), 7.69 (2H, d, J=7.2 Hz), 8.90 Reference Example 12 (1H, brs), 10.70 (1H, brs). 3-(pyrrolidin-1-ylcarbonyl)-1H-pyrazole-4-amine Reference Example 7 0344. In the same manner as in Reference Example 11, the title compound was obtained using 4-nitro-3-(pyrrolidin-1- N-benzyl-4-nitro-1H-pyrazole-3-carboxamide ylcarbonyl)-1H-pyrazole obtained in Reference Example 4. 0334. In the same manner as in Reference Example 3, the yield 92%. title compound was obtained using benzylamine. yield 82%. (0345 H-NMR (DMSO-d 200 MHz): & 1.72-7.97 (4H, 0335 H-NMR (DMSO-d): & 4.47 (2H, d, J=6.0 Hz), m), 3.42 (2H, t, J=7.7 Hz), 3.86 (2H, t, J=6.4 Hz), 4.70 (2H, 7.22-7.35 (5H, m), 8.70-8.90 (1H, brm), 9.17 (1H, brs). brs), 7.11 (1H, s). Reference Example 8 Reference Example 13 4-nitro-N-(2-phenylethyl)-1H-pyrazole-3-carboxam 4-amino-N-cyclopentyl-1H-pyrazole-3-carboxamide ide 0346. In the same manner as in Reference Example 11, the title compound was obtained using N-cyclopentyl-4-nitro 0336. In the same manner as in Reference Example 3, the 1H-pyrazole-3-carboxamide obtained in Reference Example title compound was obtained using 2-phenylethylamine. 5. yield 96%. yield 81%. (0347 'H-NMR (DMSO-d): 81.40-1.95 (8H, m), 4.10-4. 0337 'H-NMR (DMSO-d 200 MHz): 8 2.83 (2H, t, 23 (1H, m), 4.57 (2H, brs), 7.08 (1H, s), 7.55 (1H, brd, J=7.8 J=7.3 Hz), 3.35-3.52 (2H, m), 7.18-7.35 (5H, m), 8.65-8.90 Hz). (2H, brm). Reference Example 14 Reference Example 9 4-amino-N-phenyl-1H-pyrazole-3-carboxamide N-(2-furylmethyl)-4-nitro-1H-pyrazole-3-carboxam ide 0348. In the same manner as in Reference Example 11, the title compound was obtained using 4-nitro-N-phenyl-1H 0338. In the same manner as in Reference Example 3, the pyrazole-3-carboxamide obtained in Reference Example 6. title compound was obtained using furfurylamine. yield 78%. yield 93%. US 2009/0156582 A1 Jun. 18, 2009 30

0349 'H-NMR (DMSO-d): 84.70 (2H, brs), 7.03 (1H, t, with chloroform. The extract was dried over anhydrous J=7.4 Hz), 7.18 (1H, s), 7.26-7.31 (2H, m), 7.79 (2H, d, J=8.4 Sodium sulfate, and the solvent was evaporated under reduced Hz), 9.74 (1H, brs). pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate 4:1-1:1) to Reference Example 15 give the title compound, methyl 1-methyl-4-nitro-1H-pyra 4-amino-N-benzyl-1H-pyrazole-3-carboxamide Zole-3-carboxylate (Rf value 0.43) (0.95 g, yield 44%) and the title compound, methyl 1-methyl-4-nitro-1H-pyrazole-5- 0350. In the same manner as in Reference Example 11, the carboxylate (Rf value 0.71) (0.61 g, yield 28%). title compound was obtained using N-benzyl-4-nitro-1H pyrazole-3-carboxamide obtained in Reference Example 7. Methyl 1-methyl-4-nitro-1H-pyrazole-3-carboxylate yield 98%. 0351 H-NMR (DMSO-de, 200 MHz): 8 4.38 (2H, d, 0359 'H-NMR (CDC1): 83.99 (3H, s), 4.01 (3H, s), 8.13 J=6.2 Hz), 4.59 (2H, brs), 7.11 (1H, s), 7.20-7.31 (5H, m), (1H, s). 8.43 (1H, brt, J=6.2 Hz). Methyl 1-methyl-4-nitro-1H-pyrazole-5-carboxylate Reference Example 16 0360 'H-NMR (CDC1): 84.02 (3H, s), 4.03 (3H, s), 8.01 4-amino-N-(2-phenylethyl)-1H-pyrazole-3-carboxa (1H, s). mide Reference Example 21 0352. In the same manner as in Reference Example 11, the 1-methyl-4-nitro-1H-pyrazole-3-carboxylic acid title compound was obtained using 4-nitro-N-(2-phenyl ethyl)-1H-pyrazole-3-carboxamide obtained in Reference 0361. To a mixture of methyl 1-methyl-4-nitro-1H-pyra Example 8. yield 99%. Zole-3-carboxylate obtained in Reference Example 19 (0.95 0353 'H-NMR (DMSO-d 300 MHz): 8 2.80 (2H, t, g, 5.1 mmol) and THF (25 mL)-methanol (5 mL), 1 Naqueous J–7.4 Hz), 3.40-3.47 (2H, m), 4.59 (2H, brs), 7.08 (1H, s), sodium hydroxide solution (8.0 mL) was added, and the mix 7.16-7.32 (5H, m), 7.80-7.90 (1H, brm). ture was stirred at room temperature for 2 hr. The mixture was acidified with hydrochloric acid, and extracted with ethyl Reference Example 17 acetate. The extract was dried over anhydrous Sodium sulfate, and the solvent was evaporated under reduced pressure to give 4-amino-N-(2-furylmethyl)-1H-pyrazole-3-carboxa the title compound (0.69 g, yield 79%). mide 0362 'H-NMR (CDC1): 84.08 (3H, s), 8.28 (1H, s). 0354. In the same manner as in Reference Example 11, the title compound was obtained using N-(2-furylmethyl)-4-ni Reference Example 22 tro-1H-pyrazole-3-carboxamide obtained in Reference N-cyclopentyl-1-methyl-4-nitro-1H-pyrazole-3-car Example 9. yield 68%. 0355 H-NMR (DMSO-d): & 4.37 (2H, d, J=6.2 Hz), boxamide 4.58 (2H, brs), 6.19 (1H, d. J–3.3 Hz), 6.36-6.37 (1H, m), 0363 A solution of 1-methyl-4-nitro-1H-pyrazole-3-car 7.10 (1H, s), 7.53 (1H, d, J=0.9 Hz), 8.22(1H, brt, J=6.2 Hz). boxylic acid obtained in Reference Example 21 (0.56 g, 3.3 mmol), cyclopentylamine (0.31 g, 3.6 mmol), HOBt (0.53 g, Reference Example 18 3.9 mmol) and WSC (0.75 g, 3.9 mmol) in DMF (10 mL) was Methyl 4-nitro-1H-pyrazole-3-carboxylate stirred at room temperature for 4 hr. The mixture was diluted with water, and extracted with ethyl acetate. The extract was 0356. To a solution of 4-nitro-1H-pyrazole-3-carboxylic washed with Saturated aqueous sodium hydrogencarbonate acid (10.0 g. 63.7 mmol) in methanol (100 mL), thionyl solution, and dried over anhydrous sodium sulfate. The sol chloride (5.1 mL, 70.0 mmol) was added dropwise at 0°C., vent was evaporated under reduced pressure, and the obtained and the mixture was stirred at room temperature for 2 hr. The residue was purified by silica gel column chromatography Solvent was evaporated under reduced pressure, and the (hexane-ethyl acetate 1:1) to give the title compound (0.71 g, obtained residue was dissolved in ethyl acetate. This solution yield 91%). melting point 176-177° C. (ethyl acetate-hex was washed with Saturated aqueous sodium hydrogencarbon ane). ate solution, and dried over anhydrous sodium sulfate. The 0364 'H-NMR (CDC1): 8 1.56-1.75 (6H, m), 2.04-2.08 Solvent was evaporated under reduced pressure to give the (2H, m), 4.00 (3H, s), 4.42-4.48 (1H, m), 8.22 (1H, s). title compound (9.9 g, yield 91%). 0357 'H-NMR (CDC1): 84.06 (3H, s), 8.51 (1H, s). Reference Example 23 4-amino-N-cyclopentyl-1-methyl-1H-pyrazole-3- Reference Example 19 carboxamide Methyl 1-methyl-4-nitro-1H-pyrazole-3-carboxylate 0365. A mixture of N-cyclopentyl-1-methyl-4-nitro-1H Reference Example 20 pyrazole-3-carboxamide obtained in Reference Example 22 Methyl 1-methyl-4-nitro-1H-pyrazole-5-carboxylate (0.61 g, 2.6 mmol), ammonium formate (0.65 g, 10.2 mmol), 10% palladium carbon (200 mg) and ethanol (20 mL) was 0358. A mixture of methyl 4-nitro-1H-pyrazole-3-car stirred under argon atmosphere at 65° C. for 4hr. The catalyst boxylate obtained in Reference Example 18 (2.0 g, 11.7 was removed by filtration, and the filtrate was concentrated mmol), methyl iodide (2.0 g, 14.0 mmol), potassium carbon under reduced pressure. The obtained residue was purified by ate (1.62g, 11.7 mmol) and acetone (60 mL) was stirred at 30° silica gel column chromatography (ethyl acetate) to give the C. for 5 hr. The mixture was diluted with water, and extracted title compound (0.44g, yield 71%). US 2009/0156582 A1 Jun. 18, 2009

0366 'H-NMR (CDC1): 8 1.47-1.75 (6H, m), 1.98-2.09 0377 'H-NMR (CDC1): 8 3.84 (3H, s), 6.82 (1H, s), (2H, m), 3.78 (3H, s), 4.30-4.37 (1H, m), 6.91 (1H, s). 7.10-7.16 (5H, m), 7.24-7.31 (10H, m). Reference Example 24 Reference Example 29 1-methyl-4-nitro-1H-pyrazole-5-carboxylic acid Methyl 4-((pyrazin-2-ylcarbonyl)amino)-1-trityl-1H pyrazole-3-carboxylate 0367. In the same manner as in Reference Example 21, the title compound was obtained using methyl 1-methyl-4-nitro 0378. A solution of methyl 4-amino-1-trity1-1H-pyrazole 1H-pyrazole-5-carboxylate obtained in Reference Example 3-carboxylate obtained in Reference Example 28 (6.8 g. 17.7 20. yield 95%. mmol), pyrazinecarboxylic acid (2.4 g. 19.4 mmol), HOBt (2.9 g, 21.2 mmol) and WSC (4.1 g, 21.2 mmol) in DMF (115 0368 H-NMR (CDC1): 84.29 (3H, s), 8.21 (1H, s). mL) was stirred at room temperature for 2 hr. The mixture was Reference Example 25 diluted with water, and extracted with ethyl acetate. The extract was washed with Saturated aqueous Sodium hydrogen N-cyclopentyl-1-methyl-4-nitro-1H-pyrazole-5-car carbonate Solution, and dried over anhydrous Sodium sulfate. boxamide The solvent was evaporated under reduced pressure, and the 0369. In the same manner as in Reference Example 22, the obtained residue was washed with diethyl ether to give the title compound was obtained using 1-methyl-4-nitro-1H title compound (7.5 g, yield 87%). pyrazole-5-carboxylic acid obtained in Reference Example 0379 H-NMR (CDC1): 8 3.89 (3H, s), 7.10-7.13 (5H, 24 and cyclopentylamine. yield 47%. m), 7.41-7.46 (10H, m), 8.23 (1H, s), 8.84 (1H, m), 8.96 (1H, 0370 melting point 137-138°C. (ethyl acetate-hexane). d, J=2.4 Hz), 9.25 (1H, s), 11.0 (1H, s). 0371 'H-NMR (CDC1): 8 1.55-1.81 (6H, m), 2.02-2.13 Reference Example 30 (2H, m), 4.18 (3H, s), 4.36-4.45 (1H, m), 8.18 (1H, s). Methyl 4-(methyl(pyrazin-2-ylcarbonyl)amino)-1- Reference Example 26 trity1-1H-pyrazole-3-carboxylate 4-amino-N-cyclopentyl-1-methyl-1H-pyrazole-5- 0380. To a solution of methyl 4-((pyrazin-2-ylcarbonyl) carboxamide amino)-1-trityl-1H-pyrazole-3-carboxylate obtained in Ref erence Example 29 (2.0 g, 4.1 mmol) in DMF (75 mL), 0372. In the same manner as in Reference Example 23, the sodium hydride (60% liquid paraffin dispersion, 0.18 g. 4.5 title compound was obtained using N-cyclopentyl-1-methyl mmol) was added at 0°C., and the mixture was stirred at the 4-nitro-1H-pyrazole-5-carboxamide obtained in Reference same temperature for 20 min, and at room temperature for 15 Example 25. yield 82%. min. This solution was cooled to 0°C. Methyl iodide (0.28 0373) 'H-NMR (CDC1): 8 1.46-1.75 (6H, m), 1.98-2.09 mL, 4.5 mmol) was added, and the mixture was stirred at 60° (2H, m), 4.14 (3H, s), 4.31-4.38 (1H, m), 7.20 (1H, s). C. for one day. The reaction mixture was poured into satu rated aqueous ammonium chloride Solution, and the mixture Reference Example 27 was extracted with ethyl acetate. The extract was washed with Methyl 4-nitro-1-trity1-1H-pyrazole-3-carboxylate water, Saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was evaporated 0374. To a solution of methyl 4-nitro-1H-pyrazole-3-car under reduced pressure, and the obtained residue was purified boxylate obtained in Reference Example 18 (5.0 g, 29.0 by silica gel column chromatography (hexane-ethyl acetate mmol) and triethylamine (4.5 mL, 32.0 mmol) in DMF (50 1:1) to give the title compound (0.91 g, yield 44%). mL), trityl chloride (8.9 g, 32.0 mmol) was added at 0°C., and 0381 H-NMR (CDC1): 8 3.40 (3H, s), 3.82 (3H, s), the mixture was stirred at room temperature for 4 hr. The 6.94-6.97 (5H, m), 723-7.30 (10H, m), 8.30 (1H, dd, J=1.5 mixture was diluted with water, and extracted with ethyl HZ and J=2.4 Hz), 8.49 (1H, d, J-2.4 Hz), 8.78 (1H, d, J–1.5 acetate. The extract was washed with Saturated aqueous Hz). Sodium hydrogencarbonate Solution, and dried over anhy drous sodium sulfate. The solvent was evaporated under Reference Example 31 reduced pressure, and the obtained residue was purified by 4-(methyl(pyrazin-2-ylcarbonyl)amino)-1-trity1-1H silica gel column chromatography (hexane-ethyl acetate 9:1) pyrazole-3-carboxylic acid to give the title compound (7.3 g, yield 61%). 0382. In the same manner as in Reference Example 21, the 0375 H-NMR (CDC1): & 3.28 (3H, s), 7.14-7.19 (5H, title compound was obtained using methyl 4-(methyl m), 7.30-7.35 (10H, m), 8.11 (1H, s). (pyrazin-2-ylcarbonyl)amino)-1-trityl-1H-pyrazole-3-car Reference Example 28 boxylate obtained in Reference Example 30. yield 95%. 0383 'H-NMR (CDC1): 8 3.42 (3H, s), 6.96-6.99 (5H, Methyl 4-amino-1-trity1-1H-pyrazole-3-carboxylate m), 7.26-7.34 (11H, m), 8.32 (1H, d, J=1.2 Hz), 8.50 (1H, d, 0376. A mixture of methyl 4-nitro-1-trity1-1H-pyrazole J=2.4 Hz), 8.88 (1H, s). 3-carboxylate obtained in Reference Example 27 (7.3 g, 17.7 Reference Example 32 mmol), ammonium formate (4.45 g, 70.8 mmol), 10% palla dium carbon (1.8 g) and ethanol (220 mL) was stirred under 4-amino-1-trityl-1H-pyrazole-3-carboxylic acid argon atmosphere at 65°C. for 2 hr. The catalyst was removed 0384. In the same manner as in Reference Example 21, the by filtration, and the solvent of the filtrate was evaporated title compound was obtained using methyl 4-nitro-1-trityl under reduced pressure to give the title compound (6.8 g. 1H-pyrazole-3-carboxylate obtained in Reference Example yield 95%). 27. yield 95%. US 2009/0156582 A1 Jun. 18, 2009 32

0385 'H-NMR (CDC1): 8 7.14-7.19 (5H, m), 7.30-7.35 concentrated under reduced pressure, and the pH was (10H, m), 8.09 (1H, s). adjusted to 6-7 with 1N aqueous hydrochloric acid solution. The resulting white solid was collected by filtration, and this Reference Example 33 was dried under vacuum to give the title compound (1.31 g, N-cyclopentyl-4-nitro-1-trityl-1H-pyrazole-3-car yield 46%). boxamide 0395 H-NMR (DMSO-d): 8 7.67-7.72 (1H, m), 8.09 (1H, dt, J–1.3 Hz and 7.6 Hz), 8.18 (1H, d. J=7.6 Hz), 8.41 0386. In the same manner as in Reference Example 22, the title compound was obtained using 4-amino-1-trityl-1H (1H, s), 8.74 (1H, d, J=4.3 Hz), 11.13 (1H, s), 13.52 (2H, br). pyrazole-3-carboxylic acid obtained in Reference Example 32 and cyclopentylamine. yield 93%. Reference Example 38 (0387 'H-NMR (CDC1): 8 1.44-1.72 (6H, m), 1.98-2.07 6-((2-aminoethyl)amino)nicotinonitrile (2H, m), 4.33-4.40 (1H, m), 7.09-7.13 (6H, m), 7.32-7.41 (10H, m), 8.10 (1H, d. J=1.2 Hz). 0396 6-Chloronicotinonitrile (12.5 g, 90.6 mmol) was Reference Example 34 slowly added to ethylenediamine (182 mL) over 15 min, and the mixture was stirred at room temperature for 2 hr. Potas N-cyclopentyl-N-methyl-4-nitro-1-trity1-1H-pyra sium carbonate (50.1 g, 362 mmol) was added, and the mix Zole-3-carboxamide ture was stirred for additional 30 min. The insoluble material 0388. In the same manner as in Reference Example 30, the was removed by filtration, and the filtrate was concentrated title compound was obtained using N-cyclopentyl-4-nitro-1- under reduced pressure. DMF (100 mL) was added to the trity1-1H-pyrazole-3-carboxamide obtained in Reference residue, and the mixture was further concentrated under Example 33 and methyl iodide. yield 85%. reduced pressure. The obtained white solid was washed with 0389 'H-NMR (CDC1): & 1.35-1.70 (8H, m), 2.96 (3H, ethyl acetate, and dried under vacuum to give the title com s), 3.64-3.75 (1H, m), 7.12-7.18 (5H, m), 7.31-7.39 (10H, m), pound (9.57 g, yield 65%). 8.17 (1H, s). 0397) 'H-NMR (CDC1): 8 2.97 (2H, d, J=6.0 Hz), 3.43 (2H, d. J=6.0 Hz), 6.41 (1H, d, J=8.7 Hz), 7.55 (1H, dd, J–2.4 Reference Example 35 HZ and 8.7 Hz), 8.36 (1H, d, J=2.4 Hz). 4-amino-N-cyclopentyl-N-methyl-1-trity1-1H-pyra Zole-3-carboxamide Reference Example 39 0390. In the same manner as in Reference Example 23, the Methyl 4-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H title compound was obtained using N-cyclopentyl-N-methyl pyrazole-3-carboxylate 4-nitro-1-trityl-1H-pyrazole-3-carboxamide obtained in Ref erence Example 34. yield 95%. 0398. To a solution (275 mL) of methyl 4-nitro-1H-pyra 0391) 'H-NMR (CDC1): 8 1.25-1.74 (8H, m), 2.92 (3H, Zole-3-carboxylate obtained in Reference Example 1 (27.4g, s), 3.64-3.75 (1H, m), 7.13-7.18 (5H, m), 7.26-7.33 (10H, m), 160 mmol) and p-toluenesulfonic acid monohydrate (3.04 g, 6.86 (1H, s). 16 mmol) in chloroform, 2,3-dihydropyran (19.0 mL, 330 mmol) was added at 0°C., and the mixture was warmed to Reference Example 36 room temperature, and stirred for 3 hr. The reaction mixture Methyl 4-((pyridin-2-ylcarbonyl)amino)-1H-pyra was washed with Saturated aqueous sodium hydrogencarbon Zole-3-carboxylate ate solution, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue 0392 A solution of methyl 4-amino-1H-pyrazole-3-car was purified by silica gel column chromatography (hexane boxylate obtained in Reference Example 2 (3.00 g, 21.3 ethyl acetate 2:1) to give the title compound (34.8 g., yield mmol), 2-pyridinecarboxylic acid (2.88 g. 23.4 mmol), HOBt 85%) as pale-yellow oily substance. (3.46g, 25.6 mmol) and WSC (4.91 g, 25.6 mmol) in DMF (75 mL) was stirred at room temperature overnight. The mix 0399 H-NMR (CDC1): & 1.62-1.77 (3H, m), 1.83-2.04 ture was diluted with water, and the resulting white precipi (2H, m), 2.15-2.27 (1H, m), 3.68-3.76 (1H, m), 3.99 (3H, s), tate was collected by filtration. This was dried under vacuum 4.03-4.13 (1H, m), 5.43 (1H, dd, J=2.7 Hz, 9.1 Hz), 8.38 (1H, to give the title compound (3.03 g, yield 58%). S). 0393 H-NMR (DMSO-d): a 3.92 (3H, s), 7.65-7.77 (1H, m), 8.09 (1H, dt, J–1.3 Hz and 7.7 Hz), 8.18 (1H, d, Reference Example 40 J–7.7 Hz), 8.45 (1H, s), 8.76 (1H, d. J–4.8 Hz), 11.20 (1H, s), 13.60 (1H, s). Methyl 4-amino-1-(tetrahydro-2H-pyran-2-yl)-1H pyrazole-3-carboxylate Reference Example 37 4-((pyridin-2-ylcarbonyl)amino)-1H-pyrazole-3- 0400. A mixture of methyl 4-nitro-1-(tetrahydro-2H-py ran-2-yl)-1H-pyrazole-3-carboxylate obtained in Reference carboxylic acid Example 39 (12.8 g. 50 mmol), 10% palladium carbon (con 0394. To a solution of methyl 4-amino-1H-pyrazole-3- taining 50% water, 1.28 g) and ethanol (125 mL) was stirred carboxylate obtained in Reference Example 36 (3.00 g, 12.2 under hydrogen atmosphere at room temperature for 24 hr. mmol) in THF (150 mL)/methanol (30 mL), 1N aqueous The catalyst was removed by filtration, and the filtrate was sodium hydroxide solution (18 mL) was added, and the mix concentrated under reduced pressure to give the title com ture was stirred at 50° C. overnight. The reaction solution was pound as an oil. US 2009/0156582 A1 Jun. 18, 2009

0401 H-NMR (CDC1): 8 1.51-1.66 (3H, m), 1.91-2.01 acetate 1:1) to give the title compound 156 mg (yield 28%) as (3H, m), 3.59-3.68 (1H, m), 3.88 (3H, s), 4.00-4.04 (1H, m), crystals. melting point 163-165° C. 5.29 (1H, d, J=5.7 Hz), 7.16 (1H, s). 0408. 'H-NMR (CDC1): 8 1.50-1.85 (6H, m), 2.20-2.20 (2H, m), 2.60 (3H, s), 4.35-4.50 (1H, m), 9.08 (1H, brs), 11.55 Reference Example 41 (1H, brs). Methyl 4-((3-(acetylamino)benzoyl)amino)-1-(tet rahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxylate Reference Example 45 0402. In the same manner as in Reference Example 36, the N-cyclopentyl-5-ethyl-4-nitro-1H-pyrazole-3-car title compound was obtained using methyl 4-amino-1-(tet boxamide rahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxylate 04.09 To a solution of 5-ethyl-4-nitro-1H-pyrazole-3-car obtained in Reference Example 40 and 3-acetamidobenzoic boxylic acid (0.25 g, 1.35 mmol) and cyclopentylamine (0.17 acid, yield 57%. mL, 1.76 mmol) in DMF (10 mL), WSC (0.39 g, 2.03 mmol) and HOBt (0.31 g, 2.03 mmol) were added, and the mixture Reference Example 42 was stirred at room temperature for 6 hr. The reaction mixture 4-((3-(acetylamino)benzoyl)amino)-1-(tetrahydro was diluted with water, and extracted with ethyl acetate. The 2H-pyran-2-yl)-1H-pyrazole-3-carboxylic acid extract was washed with Saturated aqueous sodium hydrogen carbonate, dried over anhydrous magnesium sulfate, and 0403. To a solution of methyl 4-((3-(acetylamino)ben evaporated under reduced pressure. The residue was purified Zoyl)amino)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3- by silica gel column chromatography (hexane-ethyl acetate carboxylate obtained in Reference Example 41 (10.82g, 28.0 1:1) to give the title compound 96.9 mg (yield 28%) as crys mmol) in THF (70 mL), 2N aqueous sodium hydroxide solu tals. melting point 156-157°C. tion (77 mL) was added, and the mixture was stirred at room 0410 "H-NMR (CDC1,): & 1.31 (3H, t, J–7.5 Hz), 1.50 temperature for 1 hr. The reaction mixture was neutralized 1.90 (6H, m), 2.00-2.20 (2H, m), 3.02 (2H, q, J–7.5 Hz), with 6N hydrochloric acid, and extracted with ethyl acetate. 4.35-4.50 (1H, m), 9.08 (1H, brs), 11.65 (1H, brs). The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated. The Reference Example 46 residue was crystallized from methanol-ethyl acetate to give the title compound (8.07 g., yield 77%). Methyl 4-(((6-methylpyridin-2-yl)carbonyl)amino)- 0404 'H-NMR (DMSO-d): 81.49-1.79 (3H, m), 1.88-2. 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-car 17 (3H, m), 2.08 (3H, s), 3.59-3.75 (1H, m), 3.87-4.01 (1H, boxylate m), 5.54 (1H, dd, J=2.3,9.6Hz), 7.42-7.56 (2H, m), 7.75-7.89 0411 To a mixture of methyl 4-nitro-1-(tetrahydro-2H (1H, m), 8.17 (1H, s), 8.45 (1H, s), 10.00 (1H, s), 10.22 (1H, pyran-2-yl)-1H-pyrazole-3-carboxylate obtained in Refer S). ence Example 39 (9.30 g, 36.5 mmol), ammonium formate Reference Example 43 (10g) and methanol (150 mL), 10% palladium carbon (con taining 50% water, 0.8 g) was added, and the mixture was 4-((3-(acetylamino)benzoyl)amino)-1H-pyrazole-3- stirred for 24hr. The catalyst was removed by filtration, and carboxylic acid p-toluenesulfonic acid the filtrate was evaporated under reduced pressure to give 04.05 To a mixture of 4-((3-(acetylamino)benzoyl) methyl 4-amino-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole amino)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-car 3-carboxylate as an oil. To a solution of this oily substance boxylic acid obtained in Reference Example 42 (7.45 g, 20 and 6-methylpicolinic acid (5.0 g, 36.5 mmol) in DMF (100 mmol) and ethanol (50 mL), p-toluenesulfonic acid monohy mL), WSC (6.88 g. 40 mmol) and HOBt (5.41 g, 40 mmol) were added, and the mixture was stirred at room temperature drate (7.61 g, 40 mmol) was added, and the mixture was for 14 hr. Saturated aqueous Sodium hydrogen carbonate stirred at 60° C. for 3 hr. The crystals were collected by Solution was added to the reaction mixture, and the mixture filtration, and washed with ethanol and ethyl acetate to give was extracted with ethyl acetate. The extract was washed with the title compound (8.05 g, yield 60%). water, dried over anhydrous magnesium sulfate, and evapo 0406 H-NMR (DMSO-d): 8 2.08 (3H, s), 2.29 (3H, s), rated under reduced pressure. The residue was purified by 7.12 (2H, d, J=8.1 Hz), 7.44-7.55 (4H, m), 7.75-7.90 (1H, m), silica gel column chromatography (ethyl acetate) to give the 8.18 (1H, s), 8.29 (1H, s), 9.92 (1H, s), 10.21 (1H, s). title compound (9.02 g, yield 72%) as crystals. melting point Reference Example 44 100-102° C. 0412 'H-NMR (d-DMSO): 81.50-1.80 (3H, m), 1.95-2. N-cyclopentyl-5-methyl-4-nitro-1H-pyrazine-3-car 20 (3H, m), 2.62 (3H, s), 3.60-3.80 (1H, m), 3.95 (3H, s), boxamide 3.90-4.00 (1H, m), 5.57 (1H, d, J=9.6Hz), 7.55-7.65 (1H, m), 04.07 To a solution of 5-methyl-4-nitro-1H-pyrazole-3- 7.95-8.05 (2H, m), 8.56 (1H, s), 11.20 (1H, s). carboxylic acid (0.4g, 2.34 mmol) and cyclopentylamine (0.3 mL, 3.04 mmol) in DMF (10 mL), WSC (0.60 g, 3.51 mmol) Reference Example 47 and HOBt (0.54g, 3.51 mmol) were added, and the mixture 4-(((6-methylpyridin-2-yl)carbonyl)amino)-1-(tet was stirred at room temperature for 15 hr. The reaction mix rahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxylic ture was diluted with water, and extracted with ethyl acetate. acid The extract was washed with Saturated aqueous sodium hydrogen carbonate, dried over anhydrous magnesium Sul 0413 To a solution of methyl 4-(((6-methylpyridin-2-yl) fate, and evaporated under reduced pressure. The residue was carbonyl)amino)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyra purified by silica gel column chromatography (hexane-ethyl Zole-3-carboxylate obtained in Reference Example 46 (8.8 g. US 2009/0156582 A1 Jun. 18, 2009 34

25.6 mmol) in THF-methanol (80-40 mL), 2N aqueous (1H, m), 5.54 (1H, d, J=9.0Hz), 7.55-7.70 (3H, m), 7.88 (2H, sodium hydroxide solution (25.6 mL) was added, and the d, J=8.1 Hz), 8.45 (1H, s), 10.01 (1H, s), 13.50 (1H, s). mixture was stirred at room temperature for 4 hr. The reaction mixture was neutralized with 6N hydrochloric acid (8.53 Reference Example 50 mL), diluted with water, and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magne 4-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3- sium Sulfate, and concentrated under reduced pressure. The carboxylic acid precipitated crystals were collected by filtration to give the title compound (7.75 g, yield 92%). melting point 305-310 0419. To a solution of methyl 4-nitro-1-(tetrahydro-2H C. (decomposition). pyran-2-yl)-1H-pyrazole-3-carboxylate obtained in Refer ence Example 39 (25.5g, 100 mmol) in THF (200 mL), 2N 0414 'H-NMR (d-DMSO): 81.50-1.80 (3H, m), 1.85-2. sodium hydroxide (100 mL) was added at 0°C., and the 15 (3H, m), 3.60-3.75 (1H, m), 3.90-4.00 (1H, m), 5.53 (1H, mixture was warmed to room temperature. The reaction mix d, J–7.2 Hz), 7.53 (1H, t, J=44 Hz), 7.90-8.00 (2H, m), 8.51 ture was stirred at room temperature for 4 hr, cooled to 0°C., (1H, s), 11.31 (1H, s), 13.47 (1H, s). and weakly-acidified with 2N hydrochloric acid. The mixture was extracted with ethyl acetate, and the extract was washed Reference Example 48 with saturated brine, and dried over anhydrous sodium sul Methyl 4-(benzoylamino)-1-(tetrahydro-2H-pyran-2- fate. The solvent was evaporated under reduced pressure, and yl)-1H-pyrazole-3-carboxylate the residue was crystallized from ether-hexane to give the title compound (14.5g, yield 60%). 0415. To a mixture of methyl 4-nitro-1-(tetrahydro-2H 0420 H-NMR (DMSO-d): 81.50-1.77 (3H, m), 1.85-2. pyran-2-yl)-1H-pyrazole-3-carboxylate obtained in Refer 17 (3H, m), 3.62-3.69 (1H, m), 3.91-4.00 (1H, m), 5.53 (1H, ence Example 39 (7.66 g., 30 mmol) and ammonium formate dd, J=2.6 Hz, 9.5 Hz), 9.09 (1H, s). (10 g) in methanol (100 mL), 10% palladium carbon (con taining 50% water, 0.77 g) was added, and the mixture was Reference Example 51 stirred for 14hr. The catalyst was removed by filtration, and the filtrate was evaporated under reduced pressure to give N-(2-cyanoethyl)-4-nitro-1-(tetrahydro-2H-pyran-2- methyl 4-amino-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole yl)-1H-pyrazole-3-carboxamide 3-carboxylate as an oil. To a solution of this oily substance and benzoic acid (3.66 g., 30 mmol) in DMF (70 mL), WSC 0421. To a solution of 4-nitro-1-(tetrahydro-2H-pyran-2- (5.67 g., 33 mmol) and HOBt (4.46g, 33 mmol) were added, yl)-1H-pyrazole-3-carboxylic acid obtained in Reference and the mixture was stirred at room temperature for 4 hr. Example 50 (14.5 g. 60 mmol) and 2-cyanoethylamine (4.87 Water was added to the reaction mixture, and the mixture was mL, 66 mmol) in DMF (145 mL), WSC (13.8 g., 72 mmol) and extracted with ethyl acetate. The extract was washed with HOBt (9.73 g, 72 mmol) were added, and the mixture was saturated aqueous Sodium hydrogen carbonate solution and stirred at room temperature for 4 hr. The reaction mixture was water, dried over anhydrous magnesium sulfate, and evapo diluted with water, and extracted with ethyl acetate. The rated under reduced pressure. The residue was purified by extract was washed with Saturated aqueous sodium hydrogen silica gel column chromatography (hexane-ethyl acetate 1:1) carbonate, dried over anhydrous sodium Sulfate, and evapo to give the title compound (6.69 g, yield 67%) as crystals. rated under reduced pressure. The residue was purified by melting point 124-125° C. silica gel column chromatography (ethyl acetate), and crys 0416) 'H-NMR (d-DMSO): 81.55-1.80 (3H, m), 2.00-3. tallized from ethyl acetate-hexane to give the title compound 20 (3H, m), 3.60-3.80 (1H, m), 4.00 (3H, s), 4.02-4.15 (1H, (14.1 g, yield 80%). m), 5.40-5.50 (1H, m), 7.45-7.60 (3H, m), 7.95 (2H, d, J=8.1 0422 'H-NMR (CDC1): & 1.63-1.79 (3H, m), 1.82-2.05 Hz), 8.59 (1H, s), 9.95 (1H, s). (2H, m), 2.20-2.29 (1H, m), 2.78 (2H, t, J=6.3 Hz), 3.70-3.79 (3H, m), 4.07-4.17 (1H, m), 5.44 (1H, dd, J=2.7,9.1 Hz), 8.04 Reference Example 49 (1H, br), 8.47 (1H, s). 4-(benzoylamino)-1-(tetrahydro-2H-pyran-2-yl)-1H Reference Example 52 pyrazole-3-carboxylic acid 4-amino-N-(2-cyanoethyl)-1-(tetrahydro-2H-pyran 0417. To a solution of methyl 4-(benzoylamino)-1-(tet 2-yl)-1H-pyrazole-3-carboxamide rahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxylate obtained in Reference Example 48 (6.52 g, 19.8 mmol) in 0423. A solution of N-(2-cyanoethyl)-4-nitro-1-(tetrahy THF-methanol (20-50 mL), 2N aqueous sodium hydroxide dro-2H-pyran-2-yl)-1H-pyrazole-3-carboxamide obtained in solution (19.8 mL) was added, and the mixture was stirred at Reference Example 51 (7.33 g, 25 mmol) and 10% palladium room temperature for 2.5 hr. The reaction mixture was neu carbon (containing 50% water, 0.37g) in ethanol (80 mL) was tralized with 6N hydrochloric acid (6.67 mL), diluted with stirred under hydrogen atmosphere at room temperature. The water, and extracted with ethyl acetate. The extract was reaction mixture was stirred for 2 hr, and the catalyst was washed with water, dried over anhydrous magnesium Sulfate, removed by filtration. The filtrate was concentrated under and concentrated under reduced pressure. Diethyl ether was reduced pressure. The residue was dissolved in ethyl acetate, added to the precipitated crystals, and the crystals were col and the mixture was washed with saturated brine, dried over lected by filtration to give the title compound (4.90 g, yield anhydrous Sodium sulfate, and evaporated under reduced 78%). melting point 291-292 C. (decomposition). pressure. The residue was purified by silica gel column chro 0418 H-NMR (d-DMSO): 81.50-1.80 (3H, m), 1.90-2. matography (ethyl acetate), and crystallized from ethyl 00 (2H, m), 2.00-2.20 (1H, m), 3.60-3.80 (1H, m), 3.90-4.00 acetate-hexane to give the title compound (4.98g, yield 76%). US 2009/0156582 A1 Jun. 18, 2009

0424 'H-NMR (CDC1): 8 1.57-1.77 (3H, m), 1.93-2.16 ence Example 39 (8.71 g, 34.1 mmol), ammonium formate (9 (3H, m), 2.69 (2H, t, J=6.6 Hz), 3.61-3.72 (3H, m), 3.98-4.07 g) and methanol (150 ml), 10% palladium carbon (containing (1H, m), 4.13 (2H, br), 5.22 (1H, dd, J=2.6 Hz and 8.9 Hz), 50% water, 0.8 g) was added, and the mixture was stirred for 7.11 (1H, br), 7.14 (1H, s). 29 hr. The catalyst was removed by filtration, and the filtrate was evaporated under reduced pressure. The residue was Reference Example 53 diluted with ethyl acetate, washed with saturated aqueous Methyl 4-(((pyridin-2-yl)carbonyl)amino)-1-(tet Sodium hydrogen carbonate Solution, and evaporated under rahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxylate reduced pressure to give methyl 4-amino-1-(tetrahydro-2H pyran-2-yl)-1H-pyrazole-3-carboxylate as an oil. To a solu 0425 To a mixture of methyl 4-nitro-1-(tetrahydro-2H tion of this oily substance and 6-methyl-3-pyridinecarboxylic pyran-2-yl)-1H-pyrazole-3-carboxylate obtained in Refer acid (4.69 g, 34.1 mmol) in DMF (100ml), WSC (7.04g, 41.0 ence Example 39 (10.2g, 40 mmol), ammonium formate (10 mmol) and HOBt (5.54 g., 41.0 mmol) were added, and the g) and methanol (150 ml), 10% palladium carbon (containing mixture was stirred at room temperature for 24hr. Saturated 50% water, 1.0 g) was added, and the mixture was stirred for aqueous sodium hydrogen carbonate solution was added to 19 hr. The catalyst was removed by filtration, and the filtrate the reaction mixture, and the mixture was extracted with ethyl was evaporated under reduced pressure to give methyl acetate. The extract was washed with water, dried over anhy 4-amino-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-car drous magnesium Sulfate, passed through a small amount of boxylate as an oil. To a solution of this oily Substance and silica gel, and evaporated under reduced pressure. The resi pyridine-2-carboxylic acid (4.92 g, 40 mmol) in DMF (100 due was crystallized from diethyl ether to give the title com ml), WSC (6.88 g, 40 mmol), HOBt (5.41 g, 40 mmol) and pound (7.67g, yield 65%) as crystals. melting point 142-143 triethylamine (5.58 ml, 40 mmol) were added, and the mix C ture was stirred at room temperature for 6 hr. Saturated aque 0430 H-NMR (CDC1): 8 1.50-1.80 (3H, m), 2.00-2.20 ous sodium hydrogen carbonate solution was added to the (3H, m), 2.65 (3H, s), 3.65-3.80 (1H, m), 4.00 (3H, s), 4.08 reaction mixture, and the mixture was extracted with ethyl (1H, d, J=10.5 Hz), 5.45 (1H, t, J=6.3 Hz), 7.28 (1H, d, J=8.1 acetate. The extract was washed with water, dried over anhy Hz), 8.09 (1H, dd, J=8.1, 2.4 Hz), 8.56 (1H, s), 9.08 (1H, d, drous magnesium sulfate, evaporated under reduced pressure, J=1.6 Hz), 9.93 (1H, s). passed through a small amount of silica gel and evaporated under reduced pressure to give the title compound (9.48 g. Reference Example 56 yield 72%) as crystals. melting point 131-132C. 4-(((6-methylpyridin-3-yl)carbonyl)amino)-1-(tet 0426 H-NMR (CDC1): & 1.60- 1.80 (3H, m), 2.00-2.20 rahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxylic (3H, m), 3.65-3.80 (1H, m), 4.03 (3H, s), 405-4.20 (1H, m), 5.46 (1H, t, J=6.2 Hz), 7.20-7.50 (1H, m), 7.85-7.95 (1H, m), acid 8.24 (1H, d, J=9.0Hz), 8.63 (1H, s), 8.70-8.80 (1H, m), 11.35 0431. To a mixture of methyl 4-(((6-methylpyridin-3-yl) (1H, s). carbonyl)amino)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyra Zole-3-carboxylate obtained in Reference Example 55 (7.37 Reference Example 54 g, 21.4 mmol), tetrahydrofuran (100 ml) and methanol (100 4-(((pyridin-2-yl)carbonyl)amino)-1-(tetrahydro-2H ml), 2N aqueous Sodium hydroxide Solution (21.4 ml) was pyran-2-yl)-1H-pyrazole-3-carboxylic acid added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was neutralized with 6N hydrochlo 0427. To a mixture of methyl 4-(((pyridin-2-yl)carbonyl) ric acid (7.13 ml), and diluted with water. The precipitated amino)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-car crystals were collected by filtration to give the title compound boxylate obtained in Reference Example 53 (9.0 g, 27.2 (5.76 g, yield 81%). melting point 304-307°C. (decomposi mmol), tetrahydrofuran (100 ml) and methanol (50 ml), 2N tion). aqueous sodium hydroxide solution (27.2 ml) was added, and 0432 'H-NMR (d-DMSO): 81.50-1.80 (3H, m), 1.90-2. the mixture was stirred at room temperature for 8 hr. The 00 (2H, m), 2.00-2.20 (1H, m), 2.56 (3H, s), 3.60-3.75 (1H, reaction mixture was neutralized with 6N hydrochloric acid m), 3.90-4.00 (1H, m), 5.53 (1H, d, J=6.9 Hz), 7.45 (1H, d, (9.1 ml), diluted with water, and extracted with ethyl acetate. J=8.4 Hz), 8.11 (1H, dd, J–8.4, 1.8 Hz), 8.42 (1H, s), 8.92 The extract was washed with water, dried over anhydrous (1H, d, J=1.8 Hz), 10.01 (1H, s), 13.45 (1H, s). magnesium sulfate, and evaporated under reduced pressure. The precipitated crystals were collected by filtration to give Reference Example 57 the title compound (6.51 g, yield 76%). melting point 300 3.01° C. (decomposition). 3-amino-2,2-dimethylpropanenitrile 0428 H-NMR (d-DMSO): 81.50-1.80 (3H, m), 1.85-2. 1) 3-hydroxy-2,2-dimethylpropanenitrile 20 (2H, m), 3.60-3.80 (1H, m), 3.94 (1H, d, J=12.2 Hz), 5.55 (1H, d, J=9.3 Hz), 7.65-7.80 (1H, m), 8.08 (1H, t, J=7.2 Hz), 0433) To a mixture of ethyl 2-cyano-2-methylpropionate 8.17 (1H, d, J=7.2 Hz), 8.56 (1H, s), 8.70-8.80 (1H, m), 11.18 (5.0 g, 35.4 mmol), tetrahydrofuran (40 ml) and water (100 (1H, s), 13.25 (1H, s). ml), sodium borohydride (4.47 g. 106 mmol) was slowly added, and the mixture was stirred at room temperature for 3 Reference Example 55 hr. 6N hydrochloric acid was added to the reaction mixture to quench the reaction, and the mixture was extracted with ethyl Methyl 4-(((6-methylpyridin-3-yl)carbonyl)amino)- acetate. The extract was washed with water, dried over anhy 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-car drous magnesium Sulfate, passed through a small amount of boxylate silica gel and concentrated under reduced pressure to give the 0429 To a mixture of methyl 4-nitro-1-(tetrahydro-2H title compound (3.4g, yield 97%) as an oil. pyran-2-yl)-1H-pyrazole-3-carboxylate obtained in Refer 0434 H-NMR (CDC1): & 1.36 (6H, s), 3.58 (2H, s). US 2009/0156582 A1 Jun. 18, 2009 36

2) 2-cyano-2-methylpropyl methanesulfonate m), 5.46 (1H, t, J=6.2 Hz), 7.45-7.55 (1H, m), 8.24 (1H, s), 8.60-8.65 (1H, m), 11.29 (1H, s). 0435 To a solution of 3-hydroxy-2,2-dimethylpropaneni trile obtained in 1) (3.3g, 33.3 mmol) in ethyl acetate (50 ml), Reference Example 59 triethylamine (5.10 ml, 36.6 mmol) and methanesulfonyl chloride (2.71 ml, 35.0 mmol) were added, and the mixture 4-(((4-chloropyridin-2-yl)carbonyl)amino)-1-(tet was stirred at room temperature for 2 hr. The reaction mixture rahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxylic was washed with water, dried over anhydrous magnesium acid Sulfate, passed through a small amount of silica gel and con 0443) To a mixture of methyl 4-(((4-chloropyridin-2-yl) centrated under reduced pressure to give the title compound carbonyl)amino)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyra 5.14 g (87%) as an oil. Zole-3-carboxylate obtained in Reference Example 58 (7.1 g, 0436 'H-NMR (CDC1): 81.45 (6H, s), 3.13 (3H, s), 4.12 19.5 mmol), tetrahydrofuran (100 ml) and methanol (100 ml), (2H, s). 2Naqueous sodium hydroxide solution (38.9 ml) was added, and the mixture was stirred at room temperature for 3 hr. The 3) 3-azido-2,2-dimethylpropanenitrile reaction mixture was neutralized with 6N hydrochloric acid (12.9 ml), diluted with water, and extracted with ethyl acetate. 0437. To a solution of 2-cyano-2-methylpropyl methane The extract was washed with water, dried over anhydrous sulfonate obtained in 2) (2.82g, 15.8 mmol) in DMF (20 ml), magnesium sulfate, and evaporated under reduced pressure. sodium azide (2.06 g. 31.6 mmol) was added, and the mixture The precipitated crystals were collected by filtration to give was stirred at 120° C. for 23 hr. The reaction mixture was the title compound (4.95 g, yield 72%). melting point 310 diluted with water, and extracted with ethyl acetate. The 312°C. (decomposition). extract was washed with brine, dried over anhydrous magne 0444 'H-NMR (d-DMSO): 81.50-1.80 (3H, m), 1.90-2. sium Sulfate, and evaporated under reduced pressure to give 00 (2H, m), 2.00-2.20 (1H, m), 3.60-3.75 (1H, m), 3.90-4.05 the title compound (1.62 g, yield 83%) as an oil. (1H, m), 5.56 (1H, d, J=12.0 Hz), 7.80-7.90 (1H, m), 8.16 0438 H-NMR (CDC1): 81.40 (6H, s), 3.40 (2H, s). (1H, s), 8.55 (1H, s), 8.72 (1H, d, J=5.4 Hz), 11.15 (1H, s), 13.28 (1H, s). 4) 3-amino-2,2-dimethylpropanenitrile 0445. In the following Examples, liquid chromatography mass spectrometry spectrum (LC-MS), preparative liquid 0439. To a solution of 3-azido-2,2-dimethylpropanenitrile chromatography and nuclear magnetic resonance spectrum obtained in 3) (1.6 g. 12.9 mmol) in methanol (20 ml), 10% (NMR) were measured under the following conditions. palladium carbon (containing 50% water, 0.4 g) was added, 0446 LC-MS measurement device: Waters Corporation and the mixture was stirred under hydrogen atmosphere for 3 LC-MS system (HPLC part: Agilent Technologies HP1100, days. The catalyst was removed by filtration, and the filtrate MS part: Micromass ZMD), column: CAPCELL PAK was evaporated under reduced pressure to give the title com C18UG120, S-3 um, 1.5x35 mm (Shiseido Co., Ltd.), sol pound (1.2g, yield 95%) as an oil. vent: SOLUTION A; 0.05% trifluoroacetic acid-containing 0440 "H-NMR (CDC1): 81.33 (6H, s), 2.75 (2H, m). water, SOLUTION B: 0.04% trifluoroacetic acid-containing acetonitrile, gradient cycle: 0.00 min (SOLUTIONA/SOLU Reference Example 58 TIONB=90/10), 2.00 min(SOLUTIONA/SOLUTIONB=5/ 95), 2.75 min (SOLUTION A/SOLUTION B=5/95), 2.76 Methyl 4-(((4-chloropyridin-2-yl)carbonyl)amino)-1- min (SOLUTION A/SOLUTION B=90/10), 3.60 min (SO (tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxy LUTION A/SOLUTION B 90/10), injection volume: 2 uL. late flow rate: 0.5 mL/min, detection method: UV 220 nm, MS 0441. To a mixture of methyl 4-nitro-1-(tetrahydro-2H conditions ionization method: ESI pyran-2-yl)-1H-pyrazole-3-carboxylate obtained in Refer 0447 preparative liquid chromatography (preparative ence Example 39 (7.5g, 29.4 mmol), ammonium formate (8 HPLC) instrument: Gilson high throughput purification sys g) and methanol (150 ml), 10% palladium carbon (containing tem, column: YMC CombiPrep ODS-AS-5 um, 50x20 mm 50% water, 0.8 g) was added, and the mixture was stirred for solvent: SOLUTIONA; 0.1% trifluoroacetic acid-containing 24hr. The catalyst was removed by filtration, the filtrate was water, SOLUTION B: 0.1% trifluoroacetic acid-containing evaporated under reduced pressure to give methyl 4-amino acetonitrile, gradient cycle: 0.00 min (SOLUTIONA/SOLU 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxylate as TIONB=95/5), 1.00 min(SOLUTIONA/SOLUTIONB=95/ an oil. To a solution of this oily Substance and 4-chloropi 5), 5.20 min (SOLUTIONA/SOLUTION B=5/95), 6.40 min colinic acid (4.63 g, 29.4 mmol) in DMF (100ml), WSC (6.06 (SOLUTION A/SOLUTION B=5/95), 6.50 min (SOLU g, 35.3 mmol) and HOBt (4.76 g., 35.3 mmol) were added, and TION A/SOLUTION B=95/5), 6.60 min (SOLUTION the mixture was stirred at room temperature for 24hr. Satu A/SOLUTION B=95/5) rated aqueous sodium hydrogen carbonate Solution was flow rate: 20 mL/min, detection method: UV 220 nm. added to the reaction mixture, and the mixture was extracted 0448 NMR measurement device: Varian, Inc. Varian with ethyl acetate. The extract was washed with water, dried gemini 300 (300 MHz), Bruker BioSpin K.K. AVANCE 300. over anhydrous magnesium Sulfate, and evaporated under reduced pressure, passed through a small amount of silica gel Example 1 and evaporated under reduced pressure to give the title com N-isopropyl-4-((phenoxyacetyl)amino)-1H-pyrazole pound (7.44g, yield 69%) as crystals. melting point 201-203° 3-carboxamide C. 0442 'H-NMR (d-DMSO): 81.60-1.80 (3H, m), 2.00-2. 0449 To a solution of 4-amino-N-isopropyl-1H-pyrazole 20 (3H, m), 3.65-3.80 (1H, m), 4.02 (3H, s), 405-4.20 (1H, 3-carboxamide obtained in Reference Example 11 (10.0 mg. US 2009/0156582 A1 Jun. 18, 2009 37

0.06 mmol) in dichloromethane (0.5 mL)-DMF (0.5 mL), phenoxyacetic acid (10.9 mg, 0.072 mmol), diisopropylcar TABLE 1-continued bodiimide (11.3 uL, 0.072 mmol) and HOBt (11.0 mg, 0.072 mmol) were added at room temperature. After 12 hr., the Solvent was evaporated under reduced pressure, and the resi due was dissolved in dimethylsulfoxide (1 mL). The mixture was purified by preparative HPLC to give the title compound 11.1 mg (yield 61%) as amorphous. A-10 0450 LC-MS analysis: purity 97% (retention time: 1.86 min). 0451 MS (ESI+): 303 (M+H). A-11 Examples 2-162 0452 Amine derivative moieties having 8 kinds of pyra Zole skeleton (B-1-B-8) indicated in Table 2, synthesized in Reference Example 10 to Reference Example 17 were reacted with 23 kinds of commercially available carboxylic A-12 acids (R CO.H) shown in Table 1 in the same manner as in Example 1, which was followed by work-up, to give the title compound shown in Table 3-1 to Table 3-11. A-13 TABLE 1. R COOH R= A-1 Me-s-s A-2 A-14

A-3

A-15 eO

A-4 O Cl1N, A-16 A-5 A-17

A-6 in 1. o A-18 A-7

Prn 1 S

A-19 A-8 O- : A-9 A-20

US 2009/0156582 A1 Jun. 18, 2009 46

TABLE 3-1 1-continued RI O R3 V V N N-- A R2 (f \ YN R6 Ex. yield yield retention No. R5 R" compound name MS (M" + 1) (mg) (%) time (min) purity 160 B8 A20 N-(2-furylmethyl)-4-4-(trifluoromethoxy)- 395 12.3 S2.0 2.1 99% benzoylamino-1H-pyrazole-3-carboxamide 161 B8 A21 N-(3-(2-furylmethyl)aminocarbonyl)-1H 350 8.9 42.5 1.8 80% pyrazol-4-yl)-1H-indole-5-carboxamide 162 B8 A23 N-(3-(2-furylmethyl)aminocarbonyl)-1H 313 4.3 23.0 1.7 99% pyrazol-4-yl)pyrazine-2-carboxamide

Example 163 purified by preparative HPLC to give the title compound 6.4 N-(3-((cyclopentylamino)carbonyl)-1-trityl-1H-pyra mg (yield 30%) as amorphous. Zol-4-yl)-N-methylpyrazine-2-carboxamide 0458 LC-MS analysis: purity 96% (retention time: 1.69 min). 0453. In the same manner as in Reference Example 22, the title compound was obtained using 4-(methyl(pyrazin-2-yl 0459 MS (ESI+): 357 (M+H). carbonyl)amino)-1-trityl-1H-pyrazole-3-carboxylic acid 10460 'H-NMR (CDC1): 8 2.90 (3H, s), 6.70 (1H, brs), obtained in Reference Example 31 and cyclopentylamine. 7.28-7.90 (9H, m), 7.79 (1H, s), 8.86 (1H, brs). yield 81%. 0454) 'H-NMR (CDC1): 8 1.26-1.39 (2H, m), 1.57-1.65 Examples 166-336 (4H, m), 1.92-2.00 (2H, m), 3.43 (1H, s), 408-4.26 (1H, m), 6.49 (1H, d, J–7.8 Hz), 6.91-6.94 (5H, m), 7.16 (1H, s), 7.24-7.37 (10H, m), 8.31 (1H, dd, J=1.8 Hz and J=2.4 Hz), 0461 Amine derivative moieties having 8 kinds of pyra 8.49 (1H, d. J=2.4 Hz), 8.80 (1H, d, J=1.8 Hz). Zole skeletons (B-1-B-8) shown in Table 2, synthesized in Reference Example 10 to Reference Example 17, were Example 164 reacted with 23 kinds of commercially available sulfonyl chlorides (R SOCl) shown in Table 4 in the same manner N-(3-((cyclopentyl(methyl)amino)carbonyl)-1-trityl as in Example 165, which was followed by work-up, to give 1H-pyrazol-4-yl)pyrazine-2-carboxamide the title compound shown in Table 5-1 to Table 5-12. 0455. In the same manner as in Reference Example 22, the title compound was obtained using 4-amino-N-cyclopentyl TABLE 4 N-methyl-1-trity1-1H-pyrazole-3-carboxamide obtained in Reference Example 35 and pyrazinecarboxylic acid. yield R SOCI 770%. 0456 'H-NMR (CDC1): 8 1.44-1.71 (6H, m), 1.89-194 (2H, m), 2.96 (3H, s), 5.21-5.31 (1H, m), 7.14-7.19 (5H, m), R= 7.26-7.33 (10H, m), 8.40 (1H, d, J=2.7 Hz), 8.68-8.73 (1H, C-1 m), 9.37 (1H, d, J=1.2 Hz), 11.8 (1H, s). Example 165 4-((biphenyl-4-sulfonyl)amino)-N-methyl-1H-pyra Zole-3-carboxamide : 0457 To a solution of 4-amino-N-methyl-1H-pyrazole-3- C-2 carboxamide obtained in Reference Example 10 (8.4 mg. Me-s: 0.06 mmol) in dichloromethane (0.5 ml)-DMF (0.5 ml), tri ethylamine (0.0125 mL, 0.09 mmol) and biphenyl-4-sulfo C-3 nylchloride (18.2 mg, 0.072 mmol) were added at room tem perature. After stirring for 12 hr. Saturated aqueous sodium Me Me : hydrogencarbonate Solution (2.5 mL) was added, and the mixture was extracted with dichloromethane (2 mL). The extract was washed with saturated brine (2.5 mL), fraction ated by PhaseSep tube (manufactured by Whatman), and concentrated under reduced pressure. The residue was dis solved in dimethylsulfoxide (1 mL), and the mixture was US 2009/0156582 A1 Jun. 18, 2009 47

TABLE 4-continued TABLE 4-continued

C-4 C-15

Me Me :

O

C-5

H C-16

C-6

S C-17 C-7 Me O

C-8 C-18

:

C-9 C-19

: C-10 Me

:

C-11 Me Me Me N C-21 O O NO : C-12 Me1 O N : : \ C-22 C-13 O 1N1\,. C-23 C-14 Me

:

US 2009/0156582 A1 Jun. 18, 2009 60 amino)-1H-pyrazole-3-carboxylic acid p-toluenesulfonate 0539 'H-NMR (DMSO-d): 8 2.08 (3H, s), 3.94-416 obtained in Reference Example 43 and 2-aminoethylisopro (2H, m), 7.44-7.54 (2H, m), 7.78-7.89 (1H, m), 8.12 (1H, s), pylether, yield 89%. 8.37 (1H, s), 9.05-9.17 (1H, m), 10.22 (1H, s), 10.38 (1H, s), 0531 H-NMR (DMSO-d): & 1.09 (6H, d, J=6.0 Hz), 13.49 (1H, s). 2.08 (3H, s), 3.36-3.66 (5H, m), 7.50 (2H, d, J=5.1 Hz), 7.82-7.90 (1H, m), 8.12 (1H, s), 8.28-8.39 (1H, m), 8.32(1H, Example 376 s), 10.22 (1H, s), 10.62 (1H, s), 13.31 (1H, s). 4-((3-(acetylamino)benzoyl)amino)-N-(2-(phe nylthio)ethyl)-1H-pyrazole-3-carboxamide Example 372 0540. In the same manner as in Example 1, the title com 4-((3-(acetylamino)benzoyl)amino)-N-(2-cyanoet pound was obtained using 4-((3-(acetylamino)benzoyl) hyl)-1H-pyrazole-3-carboxamide amino)-1H-pyrazole-3-carboxylic acid p-toluenesulfonate obtained in Reference Example 43 and 2-(phenylthio)ethy 0532. In the same manner as in Example 1, the title com lamine. yield 81%. pound was obtained using 4-((3-(acetylamino)benzoyl) (0541 H-NMR (DMSO-d): 8 2.08 (3H, s), 3.13-3.21 amino)-1H-pyrazole-3-carboxylic acid p-toluenesulfonate (2H, m), 3.43-3.56 (2H, m), 7.16-7.23 (1H, m), 7.30-7.37 obtained in Reference Example 43 and 3-aminopropionitrile. (2H, m), 7.38-7.44 (2H, m), 7.47-7.55 (2H, m), 7.80-7.89 yield 76%. (1H, m), 8.13 (1H, s), 8.33 (1H, s), 8.67-8.80 (1H, m), 10.22 0533 'H-NMR (DMSO-d): 8 2.08 (3H, s), 2.81 (2H, t, (1H, s), 10.60 (1H, s), 13.35 (1H, s). J=6.5 Hz), 3.47-3.59 (2H, m), 7.45-7.54 (2H, m), 7.81-7.90 (1H, m), 8.12 (1H, s), 8.34 (1H, s), 8.77-8.87 (1H, m), 10.22 Example 377 (1H, s), 10.55 (1H, s), 13.40 (1H, s). N-(3-((cyclopentylamino)carbonyl)-5-methyl-1H pyrazol-4-yl)pyrazine-2-carboxamide Example 373 0542. To a solution of N-cyclopentyl-5-methyl-4-nitro 4-((3-(acetylamino)benzoyl)amino)-N-(2-(dimethy 1H-pyrazine-3-carboxamide obtained in Reference Example lamino)ethyl)-1H-pyrazole-3-carboxamide 44 (0.154g, 0.65 mmol) and ammonium formate (300 mg) in ethanol (5 mL), 10% palladium carbon (containing 50% 0534. In the same manner as in Example 1, the title com water, 0.1 g) was added, and the mixture was stirred for 15 hr. pound was obtained using 4-((3-(acetylamino)benzoyl) The catalyst was removed by filtration, and the filtrate was amino)-1H-pyrazole-3-carboxylic acid p-toluenesulfonate evaporated under reduced pressure. The residue was dis obtained in Reference Example 43 and N,N-dimethylethyl solved in ethyl acetate (50 mL), washed with saturated aque enediamine. yield 34%. ous sodium hydrogen carbonate Solution, washed with water, 0535 H-NMR (DMSO-d): 8 2.08 (3H, s), 2.18 (6H, s), dried over anhydrous magnesium Sulfate, and evaporated 2.41 (2H, t, J=6.7 Hz), 3.34-3.44 (2H, m), 7.44-7.55 (2H, m), under reduced pressure. The residue was dissolved in DMF 7.80-7.90 (1H, m), 8.11 (1H, s), 8.25 (1H, t, J=5.8 Hz), 8.32 (10 mL). Pyrazine-2-carboxylic acid (96.3 mg, 0.776 mmol), (1H, s), 10.22 (1H, s), 10.63 (1H, s), 13.30 (1H, s). WSC (167 mg, 0.97 mmol) and HOBt (149 mg, 0.97 mmol) were added, and the mixture was stirred for 4hr. The reaction Example 374 mixture was diluted with water, and extracted with ethyl acetate. The extract was washed with Saturated aqueous 4-((3-(acetylamino)benzoyl)amino)-N-(2-oxo-2- Sodium hydrogen carbonate solution and water, dried over phenylethyl)-1H-pyrazole-3-carboxamide anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chro 0536. In the same manner as in Example 1, the title com matography (dichloromethane-ethyl acetate 1:1) to give the pound was obtained using 4-((3-(acetylamino)benzoyl) title compound (0.15g, yield 74%) as crystals. melting point amino)-1H-pyrazole-3-carboxylic acid p-toluenesulfonate 170-171 O C. obtained in Reference Example 43 and 2-aminoacetophe (0543 'H-NMR (CDC1): 8 1.40-1.80 (6H, m), 2.00-2.20 none. yield 18%. (2H, m), 2.57 (3H, s), 4.35-4.50 (1H, m), 6.84 (1H, brs), 0537 H-NMR (DMSO-d): 8 2.06 (3H, s), 4.83 (2H, d, 8.60-8.70 (1H, m), 8.70-8.80 (1H, m), 9.42(1H, d. J=1.2 Hz), J=5.8 Hz), 7.44-7.51 (2H, m), 7.53-7.63 (2H, m), 7.66-7.74 10.03 (1H, brs), 10.93 (1H, brs). (1H, m), 7.79-7.90 (1H, m), 8.02-8.13 (3H, m), 8.37 (1H, s), 8.68 (1H, t, J=5.8 Hz), 10.20(1H, s), 10.53 (1H,s), 13.41 (1H, Example 378 S). 4-(benzoylylamino)-N-cyclopentyl-5-methyl-1H pyrazole-3-carboxamide Example 375 0544. To a solution of N-cyclopentyl-5-methyl-4-nitro 4-((3-(acetylamino)benzoyl)amino)-N-(2.2.2-trifluo 1H-pyrazine-3-carboxamide obtained in Reference Example roethyl)-1H-pyrazole-3-carboxamide 44 (0.103 g, 0.43 mmol) and ammonium formate (200 mg) in ethanol (5 mL), 10% palladium carbon (containing 50% 0538. In the same manner as in Example 1, the title com water, 0.05 g) was added, and the mixture was stirred for 5 hr. pound was obtained using 4-((3-(acetylamino)benzoyl) The catalyst was removed by filtration, and the filtrate was amino)-1H-pyrazole-3-carboxylic acid p-toluenesulfonate evaporated under reduced pressure. The residue was dis obtained in Reference Example 43 and 2.2.2-trifluoroethy solved in ethyl acetate (50 mL), and the mixture was washed lamine. yield 76%. with Saturated aqueous Sodium hydrogen carbonate solution, US 2009/0156582 A1 Jun. 18, 2009 washed with water, dried over anhydrous magnesium Sulfate, pressure. The residue was purified by silica gel column chro and evaporated under reduced pressure. The residue was dis matography (ethyl acetate) to give the title compound (0.28g. solved in DMF (10 mL), benzoic acid (63.4 mg. 0.52 mmol), yield 86%) as crystals. melting point 255-260° C. (decompo WSC (111 mg, 0.65 mmol) and HOBt (88 mg 0.65 mmol) sition). were added, and the mixture was stirred for 4 hr. The reaction (0549. H-NMR (d-DMSO): 8 2.08 (3H, s), 4.25-440 mixture was diluted with water, and extracted with ethyl (2H, m), 7.52 (1H, s), 7.50-7.60 (1H, m), 7.80-7.90 (1H, m), acetate. The extract was washed with Saturated aqueous 8.14 (1H, s), 8.30 (1H, s), 9.21 (1H, s), 10.24 (1H, s), 10.35 Sodium hydrogen carbonate solution and water, dried over (1H, s), 13.48 (1H, s). anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chro Example 381 matography (hexane-ethyl acetate 1:1) to give the title com pound 70 mg (yield 52%) as non-crystalline powder. 4-((3-(acetylamino)benzoyl)amino)-N-(2-tert-bu (0545 H-NMR (CDC1): 8 1.45-1.80 (6H, m), 1.95-2.15 toxyethyl)-1H-pyrazole-3-carboxamide (2H, m), 2.56 (3H, s), 4.30-4.45 (1H, m), 6.82 (1H, brs), 0550. In the same manner as in Example 380, the title 7.40-7.60 (3H, m), 7.95-8.05 (2H, m), 9.90 (1H, s). compound (0.30 g, yield 77%) was obtained using 4-((3- (acetylamino)benzoyl)amino)-1H-pyrazole-3-carboxylic Example 379 acid p-toluenesulfonate obtained in Reference Example 43 N-(3-((cyclopentylamino)carbonyl)-5-ethyl-1H-pyra and 2-tert-butoxyethylamine as crystals. melting point 124 Zol-4-yl)pyrazine-2-carboxamide 126o C. 0551 H-NMR (d-DMSO): & 1.14 (9H, s), 20.8 (3H, s), 0546. To a solution of N-cyclopentyl-5-ethyl-4-nitro-1H 3.35-3.50 (4H, m), 7.45-7.55 (2H, m), 7.80-7.90 (1H, m), pyrazole-3-carboxamide obtained in Reference Example 45 8.11 (1H, s), 8.22-8.35 (1H, m), 8.33 (1H, s), 10.23 (1H, s), (85 mg, 0.34 mmol) and ammonium formate (150 mg) in 10.62 (1H, s), 13.32 (1H, s). ethanol (5 mL), 10% palladium carbon (containing 50% water, 50mg) was added, and the mixture was stirred for 8 hr. Example 382 The catalyst was removed by filtration, and the filtrate was evaporated under reduced pressure. The residue was dis 4-((3-(acetylamino)benzoyl)amino)-N-(2-(methyl solved in ethyl acetate (50 mL), and the mixture was washed sulfonyl)ethyl)-1H-pyrazole-3-carboxamide with saturated aqueous sodium hydrogen carbonate solution, washed with water, dried over anhydrous magnesium Sulfate, 0552. In the same manner as in Example 380, the title and evaporated under reduced pressure. The residue was dis compound (0.25 g, yield 69%) was obtained using 4-((3- solved in DMF (10 mL). Pyrazine-2-carboxylic acid (50 mg. (acetylamino)benzoyl)amino)-1H-pyrazole-3-carboxylic 0.40 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiim acid p-toluenesulfonate obtained in Reference Example 43 ide hydrochloride (87 mg, 0.505 mmol) and N-hydroxyben and 2-(methylsulfonyl)ethylamine as crystals. melting point Zotriazole (68 mg 0.505 mmol) were added, and the mixture 230-232° C. was stirred for 15 hr. The reaction mixture was diluted with 0553 'H-NMR (d-DMSO): 8 2.06 (3H, s), 3.02 (3H, s), water, and extracted with ethyl acetate. The extract was 3.38 (2H, t, J=6.3 Hz), 3.63-3.80 (2H, m), 7.48 (2H, d, J=5.1 washed with Saturated aqueous Sodium hydrogen carbonate Hz), 7.80-7.90 (1H, m), 8.11 (1H, s), 8.32(1H, s), 10.21 (1H, Solution and water, dried over anhydrous magnesium Sulfate, s), 10.53 (1H, s), 13.38 (1H, s). and evaporated under reduced pressure. The residue was puri fied by silica gel column chromatography (dichloromethane Example 383 ethyl acetate 1:1) to give the title compound (86.7 mg, yield 4-((3-(acetylamino)benzoyl)amino)-N-(2-((4-chlo 78%) as crystals. melting point 175-176° C. rophenyl) sulfonyl)ethyl)-1H-pyrazole-3-carboxam (0547 'H-NMR (CDC1): 8 1.29 (3H, t, J–7.5 Hz), 1.40 ide 1.85 (6H, m), 2.00-2.20 (2H, m), 3.06 (2H, q, J–7.5 Hz), 4.35-4.50 (1H, m), 6.84 (1H, brs), 8.60-8.70 (1H, m), 8.70 0554. In the same manner as in Example 380, the title 8.80 (1H, m), 9.43 (1H, d, J=2.1 Hz), 9.87 (1H, brs), 10.96 compound (0.38 g, yield 84%) was obtained using 4-((3- (1H, brs). (acetylamino)benzoyl)amino)-1H-pyrazole-3-carboxylic acid p-toluenesulfonate obtained in Reference Example 43 Example 380 and 2-((4-chlorophenyl)sulfonyl)ethylamine as crystals. melting point 219–220° C. 4-((3-(acetylamino)benzoyl)amino)-N-(cyanom 0555 H-NMR (d-DMSO): & 2.07 (3H, s), 3.50-3.70 ethyl)-1H-pyrazole-3-carboxamide (4H, m), 7.47 (1H, s), 7.45-7.55 (1H, m), 7.64 (2H, d, J=8.40 0548. To a solution of 4-((3-(acetylamino)benzoyl) Hz), 7.80-7.90 (1H, m), 7.91 (2H, d. J=8.4 Hz), 8.12 (1H, s), amino)-1H-pyrazole-3-carboxylic acid p-toluenesulfonate 8.28 (1H, s), 8.40-8.50 (1H, m), 10.21 (1H, s), 10.42 (1H, s), obtained in Reference Example 43 (0.46g, 1.0 mmol), ami 13.30 (1H, s). noacetonitrile (259 mg, 1.0 mmol) and triethylamine (0.21 mL, 1.2 mmol) in DMF (10 mL), WSC (206 mg, 1.2 mmol) Example 384 and HOBt (162 mg, 1.2 mmol) were added, and the mixture 4-((3-(acetylamino)benzoyl)amino)-N-(2-(pyridin-2- was stirred at room temperature for 4.5 hr. Water was added to ylsulfonyl)ethyl)-1H-pyrazole-3-carboxamide the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with Saturated aqueous 0556. In the same manner as in Example 380, the title Sodium hydrogen carbonate solution and water, dried over compound (0.38 g, yield 90%) was obtained using 4-((3- anhydrous magnesium sulfate, and evaporated under reduced (acetylamino)benzoyl)amino)-1H-pyrazole-3-carboxylic US 2009/0156582 A1 Jun. 18, 2009 62 acid p-toluenesulfonate obtained in Reference Example 43 magnesium Sulfate, passed through a small amount of silica and 2-(pyridin-2-ylsulfonyl)ethylamine as crystals. melting gel and concentrated under reduced pressure. Diethyl ether point 240-241° C. was added to the precipitated crystals, and the crystals were 0557 'H-NMR (d-DMSO): 8 2.09 (3H, s), 3.33 (3H, s), collected by filtration to give the title compound (0.53 g, yield 3.60-3.75 (2H, m), 3.75-3.85 (2H, m), 7.49 (1H, s), 7.45-7.60 97%). melting point 225-227°C. (1H, m), 7.65-7.75 (1H, m), 7.80-7.90 (1H, m), 8.00-8.20 0563 'H-NMR (d-DMSO): 82.61 (3H, s), 2.81 (2H, t, (3H, m), 8.30 (1H, s), 8.50-8.60 (1H, m), 8.75 (1H, d, J=4.0 J=6.2 Hz), 3.55 (2H, q, J=6.2 Hz), 7.50-7.60 (1H, m), 7.90 Hz), 10.23 (1H, s), 10.45 (1H, s), 13.32 (1H, s). 8.00 (2H, m), 8.42(1H, s), 8.69 (1H, t, J=5.8 Hz), 11.52 (1H, s), 13.36 (1H, s). Example 385 4-((3-(acetylamino)benzoyl)amino)-N-(3-isopro Example 388 poxypropyl)-1H-pyrazole-3-carboxamide 6-methyl-N-(1-(tetrahydro-2H-pyran-2-yl)-3-(((2.2, 2-trifluoroethyl)amino)carbonyl)-1H-pyrazol-4-yl) 0558. In the same manner as in Example 380, the title pyridine-2-carboxamide compound (0.36 g, yield 93%) was obtained using 4-((3- (acetylamino)benzoyl)amino)-1H-pyrazole-3-carboxylic 0564) To a solution of 4-(((6-methylpyridin-2-yl)carbo acid p-toluenesulfonate obtained in Reference Example 43 nyl)amino)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3- and 3-isopropoxypropylamine as crystals. melting point 140 carboxylic acid obtained in Reference Example 47 (0.66 g. 1429 C. 2.0 mmol) and 2.2.2-trifluoroethylamine (0.19 mL, 2.4 0559 'H-NMR (d-DMSO): & 1.09 (6H, d, J=6.0 Hz), mmol) in DMF (10 mL), WSC (0.41 g, 2.4 mmol) and HOBt 1.70-182 (2H, m), 2.08 (3H, s), 3.30-3.50 (4H, m), 3.50-3.60 (0.32g, 2.4 mmol) were added, and the mixture was stirred at (1H, m), 7.45-7.55 (2H, m), 7.80-7.90 (1H, m), 8.11 (1H, s), room temperature for 2.5 hr. Saturated aqueous Sodium 8.32 (1H, s), 8.45-8.55 (1H, m), 10.22 (1H, s), 10.69 (1H, s), hydrogen carbonate solution was added to the reaction mix 13.32 (1H, s). ture, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magne Example 386 sium Sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography N-(3-(((2-cyanoethyl)amino)carbonyl)-1-(tetrahy (hexane-ethyl acetate 1:1) to give the title compound (0.77 g. dro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-6-methylpyri yield 94%) as crystals. melting point 184-185°C. dine-2-carboxamide 0565 'H-NMR (CDC1): & 1.60-1.80 (4H, m), 2.07 (2H, 0560. To a solution of 4-(((6-methylpyridin-2-yl)carbo d, J=9.9 Hz), 2.15-2.30 (2H, m), 2.69 (3H, s), 3.65-3.80 (1H, nyl)amino)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3- m), 4.05-4.20(3H, m), 5.38 (1H, dd, J=9.6, 2.4Hz), 7.10-7.20 carboxylic acid obtained in Reference Example 47 (0.66 g. (1H, m), 7.32 (1H, d, J=7.2 Hz), 7.75 (1H, t, J=7.8 Hz), 8.03 2.0 mmol) and 3-aminopropionitrile (0.18 mL, 2.4 mmol) in (1H, d, J–7.2 Hz), 11.51 (1H, s). DMF (15 mL), WSC (0.41 g, 2.4 mmol) and HOBt (0.32g, 2.4 mmol) were added, and the mixture was stirred at room Example 389 temperature for 6 hr. Saturated aqueous sodium hydrogen 6-methyl-N-(3-(((2.2.2-trifluoroethyl)amino)carbo carbonate Solution was added to the reaction mixture, and the nyl)-1H-pyrazol-4-yl)pyridine-2-carboxamide mixture was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium Sulfate, 0566. A mixture of 6-methyl-N-(1-(tetrahydro-2H-pyran and evaporated under reduced pressure. The residue was puri 2-yl)-3-(((2.2.2-trifluoroethyl)amino)carbonyl)-1H-pyrazol fied by silica gel column chromatography (hexane-ethyl 4-yl)pyridine-2-carboxamide obtained in Example 388 (0.72 acetate 1:1) to give the title compound (0.75 g, yield 92%) as g, 1.75 mmol), p-toluenesulfonic acid monohydrate (0.67 g. crystals. melting point 186-187°C. 3.50 mmol) and ethanol (15 mL) was stirred at 60° C. for 3.5 0561 H-NMR (CDC1): & 1.60- 1.80 (3H, m), 2.00-2.15 hr. The reaction mixture was concentrated under reduced (2H, m), 2.15-2.30 (1H, m), 2.70 (3H, s), 2.76 (2H, t, J=6.6 pressure. Saturated aqueous sodium hydrogen carbonate Hz), 3.75 (2H, t, J=6.6Hz), 3.65-3.80 (1H, m), 4.00-4.55 (1H, solution was added, and the mixture was extracted with ethyl m), 5.36 (1H, d, J=7.2 Hz), 7.20-7.30 (1H, m), 7.32 (1H, d, acetate. The extract was washed with water, dried over anhy J=7.2 Hz), 7.75 (1H, t, J=7.7 Hz), 8.03 (1H, d, J=6.9 Hz), 8.58 drous magnesium Sulfate, and evaporated under reduced (1H, s), 11.53 (1H, s). pressure. The residue was purified by silica gel column chro matography (hexane-ethyl acetate 1:1) to give the title com Example 387 pound (0.45 g, yield 79%). melting point 257-258° C. 0567 'H-NMR (d-DMSO): 8 2.61 (3H, s), 4.00-420 N-(3-(((2-cyanoethyl)amino)carbonyl)-1H-pyrazol (2H, m), 7.50-7.60 (1H, m), 7.90-8.00 (2H, m), 8.45 (1H, s), 4-yl)-6-methylpyridine-2-carboxamide 8.90-9.03 (1H, m), 11.44 (1H, s), 13.47 (1H, s). 0562. A mixture of N-3-(((2-cyanoethyl)amino)carbo nyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl-6-me Example 390 thylpyridine-2-carboxamide obtained in Example 386 (0.70 N-(3-(((3-phenoxypropyl)amino)carbonyl)-1-(tet g, 1.83 mmol), p-toluenesulfonic acid monohydrate (0.77 g. rahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)pyridine-2- 4.03 mmol) and ethanol (25 mL) was stirred at 70° C. for 2 hr. carboxamide The reaction mixture was concentrated under reduced pres Sure. Saturated aqueous sodium hydrogen carbonate Solution 0568. To a solution of 4-((pyridin-2-ylcarbonyl)amino)-1- was added, and the mixture was extracted with ethyl acetate. (tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxylic acid The extract was washed with water, dried over anhydrous obtained in Reference Example 54 (0.64g, 2.0 mmol) and US 2009/0156582 A1 Jun. 18, 2009

3-phenoxypropylamine (0.36 g. 2.4 mmol) in DMF (10 mL), crystals, and the crystals were collected by filtration to give WSC (0.41 g, 2.4 mmol) and HOBt (0.32 g, 2.4 mmol) were the title compound (0.56 g, yield 87%) as crystals. melting added, and the mixture was stirred at room temperature for 7 point 144-145° C. hr. Saturated aqueous Sodium hydrogen carbonate Solution (0573 'H-NMR (CDC1): & 1.60-1.80 (3H, m), 2.00-2.15 was added to the reaction mixture, and the mixture was (2H, m), 2.15-2.30 (1H, m), 2.40-2.60 (2H, m), 3.75 (2H, q, extracted with ethyl acetate. The extract was washed with J=6.9 Hz), 3.65-3.80 (1H, m), 4.02-4.15 (1H, m), 5.37 (1H, d, water, dried over anhydrous magnesium sulfate, passed J=9.6 Hz), 7.05-7.20 (1H, m), 7.40-7.50 (1H, m), 7.88 (1H, t, through a small amount of silica gel and concentrated under J–7.8 Hz), 8.23 (1H, d, J–8.1 Hz), 8.58 (1H, s), 11.62(1H, s). reduced pressure. Diethyl ether was added to the precipitated crystals, and the crystals were collected by filtration to give Example 393 the title compound (0.65 g, yield 72%) as crystal. melting N-(3-(((3,3,3-trifluoropropyl)amino)carbonyl)-1H point 106-107° C. pyrazol-4-yl)pyridine-2-carboxamide 0569. H-NMR (CDC1): 81.60- 1.80 (3H, m), 2.15 (2H, t, J=6.3 Hz), 2.00-2.35 (3H, m), 3.71 (2H, q, J=6.3 Hz), 3.65 0574. A mixture of N-(1-(tetrahydro-2H-pyran-2-yl)-3- 3.80 (1H, m), 4.12 (2H, t, J–5.7 Hz), 4.02-4.20(1H, m), 5.37 (((3,3,3-trifluoropropyl)amino)carbonyl)-1H-pyrazol-4-yl) (1H, d, J=9.3 Hz), 6.90-7.02 (3H, m), 7.31 (2H, d, J–7.2 Hz), pyridine-2-carboxamide obtained in Example 392 (0.51 g, 7.45 (1H, dd, J=8.1, 4.8 Hz), 7.87 (1H, t, J=8.4 Hz), 8.28 (1H, 1.24 mmol), p-toluenesulfonic acid monohydrate (0.47 g. d, J=8.1 Hz), 8.58 (1H, s), 8.73 (1H, d, J=4.5 Hz), 11.73 (1H, 2.48 mmol) and ethanol (15 mL) was stirred at 60° C. for 5 hr. S). The reaction mixture was concentrated under reduced pres Sure. Saturated aqueous sodium hydrogen carbonate Solution was added, and the mixture was extracted with ethyl acetate. Example 391 The extract was washed with water, dried over anhydrous N-(3-(((3-phenoxypropyl)amino)carbonyl)-1H-pyra magnesium Sulfate, passed through a small amount of silica Zol-4-yl)pyridine-2-carboxamide gel and evaporated under reduced pressure. Diethyl ether was added to the precipitated crystals, and the crystals were col 0570 A mixture of N-(3-(((3-phenoxypropyl)amino)car lected by filtration to give the title compound (0.32 g, yield bonyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)pyri 79%). melting point 241-243° C. dine-2-carboxamide obtained in Example 390 (0.60 g, 1.33 (0575 H-NMR (d-DMSO): 8 2.50-2.70 (2H, m), 3.54 mmol), p-toluenesulfonic acid monohydrate (0.51 g, 2.67 (2H, q, J–6.7 Hz), 7.65-7.75 (1H, m), 8.00-8.15 (1H, m), 8.16 mmol) and ethanol (15 mL) was stirred at 60° C. for 5 hr. The (1H, d, J=9.6 Hz), 8.42 (1H, s), 8.55-8.70 (1H, m), 8.75-8.80 reaction mixture was concentrated under reduced pressure. (1H, m), 11.58 (1H, s), 13.38 (1H, s). Saturated aqueous Sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The Example 394 extract was washed with water, dried over anhydrous magne N-(3-(((cyanomethyl)amino)carbonyl)-1-(tetrahydro sium Sulfate, passed through a small amount of silica gel and 2H-pyran-2-yl)-1H-pyrazol-4-yl)pyridine-2-carboxa concentrated under reduced pressure. Diethyl ether was mide added to the precipitated crystals, and the crystals were col 0576. To a solution of 4-((pyridin-2-ylcarbonyl)amino)-1- lected by filtration to give the title compound (0.44 g, yield (tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxylic acid 90%). melting point 182-184° C. obtained in Reference Example 54 (0.64g, 2.0 mmol) and 0571 'H-NMR (d-DMSO): 8 1.95-2.10 (2H, m), 3.46 aminoacetonitrile (0.11g, 2.4 mmol) in DMF (10 mL), WSC (2H, q, J=6.8 Hz), 4.04 (2H, t, J=6.8 Hz), 6.90-7.00 (3H, m), (0.41 g, 2.4 mmol), HOBt (0.32 g, 2.4 mmol) and triethy 7.28 (2H, t, J=7.2 Hz), 7.65-7.75 (1H, m), 8.02-8.15 (1H, m), lamine (0.33 mL, 2.4 mmol) were added, and the mixture was 8.15 (1H, d, J–7.0 Hz), 8.41 (1H, s), 8.50-8.60 (1H, m), stirred at room temperature for 6 hr. Saturated aqueous 8.75-8.80 (1H, m), 11.64 (1H, s), 13.33 (1H, s). Sodium hydrogen carbonate solution was added to the reac tion mixture, and the mixture was extracted with ethyl Example 392 acetate. The extract was washed with water, dried over anhy drous magnesium Sulfate, passed through a small amount of N-(1-(tetrahydro-2H-pyran-2-yl)-3-(((3,3,3-trifluoro silica gel and evaporated under reduced pressure. Diethyl propyl)amino)carbonyl)-1H-pyrazol-4-yl)pyridine-2- ether was added to the precipitated crystals, and the crystals carboxamide were collected by filtration to give the title compound (0.54g, yield 76%) as crystals. melting point 213-214°C. 0572 To a solution of 4-((pyridin-2-ylcarbonyl)amino)-1- 0577 'H-NMR (CDC1): & 1.60- 1.80 (3H, m), 2.00-2.15 (tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxylic acid (2H, m), 2.15-2.30 (1H, m), 3.65-3.80 (1H, m), 4.07 (2H, d, obtained in Reference Example 54 (0.50 g, 1.57 mmol) and J=11.4 Hz), 4.42 (2H, d. J=6.0 Hz), 5.38 (1H, dd, J=9.0, 3.0 3,3,3-trifluoropropylamine hydrochloride (0.235 g, 1.57 Hz), 7.17-7.30 (1H, m), 7.40-7.55 (1H, m), 7.80-7.95 (1H, mmol) in DMF (10 mL), WSC (0.32 g, 1.89 mmol), HOBt m), 8.23 (1H, d, J–8.7 Hz), 8.60 (1H, s), 8.70-8.80 (1H, m), (0.26g, 1.89 mmol) and triethylamine (0.44 mL, 3.15 mmol) 11.49 (1H, s). were added, and the mixture was stirred at room temperature for 8 hr. Saturated aqueous sodium hydrogen carbonate solu Example 395 tion was added to the reaction mixture, and the mixture was N-(3-(((cyanomethyl)amino)carbonyl)-1H-pyrazol extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, passed 4-yl)pyridine-2-carboxamide through a small amount of silica gel and concentrated under 0578. A mixture of N-(3-(((cyanomethyl)amino)carbo reduced pressure. Diethyl ether was added to the precipitated nyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)pyri US 2009/0156582 A1 Jun. 18, 2009 64 dine-2-carboxamide obtained in Example 394 (0.50 g, 1.41 (1H, d, J=9.0 Hz), 8.40 (1H, s), 8.60-8.70 (1H, m), 8.70-8.80 mmol), p-toluenesulfonic acid monohydrate (0.54 g, 2.82 (1H, m), 11.64 (1H, s), 13.32 (1H, s). mmol), ethanol (20 mL) and chloroform (10 mL) was stirred at 60° C. for 6 hr. Saturated aqueous sodium hydrogen car Example 398 bonate solution was added to the reaction mixture, and the N-(3-(((2-anilinoethyl)amino)carbonyl)-1-(tetrahy mixture was extracted with ethyl acetate. The extract was dro-2H-pyran-2-yl)-1H-pyrazol-4-yl)pyridine-2- washed with water, dried over anhydrous magnesium Sulfate, passed through a small amount of silica gel and evaporated carboxamide under reduced pressure. Diethyl ether was added to the pre 0584) To a solution of 4-((pyridin-2-ylcarbonyl)amino)-1- cipitated crystals, and the crystals were collected by filtration (tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxylic acid to give the title compound (0.35 g, yield 92%). melting point obtained in Reference Example 54 (0.63 g, 2.0 mmol) and not less than 255° C. (decomposition). N-phenylethylenediamine (0.31 mL, 2.4 mmol) in DMF (10 0579 'H-NMR (d-DMSO): & 4.31 (2H, d, J=4.5 Hz), mL), WSC (0.41 g, 2.4 mmol), HOBt (0.32 g, 2.4 mmol) and 7.65-7.75 (1H, m), 8.08 (1H, t, J=7.5 Hz), 8.16 (1H, d, J=8.1 triethylamine (0.33 mL, 2.4 mmol) were added, and the mix Hz), 8.45 (1H, s), 8.75-9.00 (1H, m), 9.10-9.20 (1H, m), ture was stirred at room temperature for 3 hr. Saturated aque 11.49 (1H, s), 13.47 (1H, s). ous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl Example 396 acetate. The extract was washed with water, dried over anhy drous magnesium Sulfate, passed through a small amount of N-(3-(((2-(pyridin-2-ylamino)ethyl)amino)carbo silica gel and evaporated under reduced pressure. Diethyl nyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl) ether was added to the precipitated crystals, and the crystals pyridine-2-carboxamide were collected by filtration to give the title compound (0.69 g, yield 79%) as crystals. melting point 182-183° C. 0580. To a solution of 4-((pyridin-2-ylcarbonyl)amino)-1- 0585 H-NMR (CDC1): 8 1.55-1.80 (3H, m), 1.95-2.15 (tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxylic acid (2H, m), 2.15-2.30 (1H, m), 3.35-3.50 (2H, m), 3.65-3.80 obtained in Reference Example 54 (0.63 g, 2.0 mmol) and (3H, m), 4.00-4.15 (2H, m), 5.35 (1H, dd, J=9.6 Hz), 6.66 2-pyridylethylenediamine-dihydrochloride (0.50 g, 2.4 (2H, d, J=8.4 Hz), 6.72 (1H, t, J–7.2 Hz), 7.10-7.30 (3H, m), mmol) in DMF (10 mL), WSC (0.41 g, 2.4 mmol), HOBt 7.40-7.50 (1H, m), 7.88 (1H, td, J=7.5, 1.5 Hz), 8.24 (1H, d, (0.32 g, 2.4 mmol) and triethylamine (0.50 mL, 3.6 mmol) J=7.8 Hz), 8.58(1H, s), 8.75 (1H, d, J=4.5 Hz), 11.69 (1H, s). were added, and the mixture was stirred at room temperature for 10 hr. Saturated aqueous Sodium hydrogen carbonate Example 399 Solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with N-(3-(((2-anilinoethyl)amino)carbonyl)-1H-pyrazol water, dried over anhydrous magnesium sulfate, passed 4-yl)pyridine-2-carboxamide through a small amount of silica gel and concentrated under 0586 A mixture of N-(3-(((2-anilinoethyl)amino)carbo reduced pressure. Diethyl ether was added to the precipitated nyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)pyri crystals, and the crystals were collected by filtration to give dine-2-carboxamide obtained in Example 398 (0.64g, 1.47 the title compound (0.62 g, yield 71%) as crystals. melting mmol), p-toluenesulfonic acid monohydrate (0.84 g, 4.42 point 178-180° C. mmol) and ethanol (15 mL) was stirred at 70° C. for 5 hr. 0581 'H-NMR (CDC1): 8 1.55-1.80 (3H, m), 2.00-2.15 Saturated aqueous Sodium hydrogen carbonate Solution was (2H, m), 2.15-2.30 (1H, m), 3.55-3.80 (6H, m), 4.00-4.15 added to the reaction mixture, and the mixture was extracted (1H, m), 4.75-4.85 (1H, m), 5.36 (1H, dd, J=9.6, 1.8 Hz), 6.44 with ethyl acetate. The extract was washed with water, dried (1H, d, J=8.4 Hz), 6.55-6.62(1H, m), 7.35-7.70 (1H, m), 7.85 over anhydrous magnesium Sulfate, passed through a small (1H, t, J=8.4 Hz), 8.10-8.20 (1H, m), 8.23 (1H, d, J=7.8 Hz), amount of silica gel and concentrated under reduced pressure. 8.70-8.80 (1H, m), 11.71 (1H, s). Diethyl ether was added to the precipitated crystals, and the crystals were collected by filtration to give the title compound Example 397 (0.28g, yield 54%). melting point 184-186°C. 0587 H-NMR (d-DMSO): 83.15-3.30 (2H, m), 3.40-3. N-(3-(((2-(pyridin-2-ylamino)ethyl)amino)carbo 60 (2H, m), 5.70-5.80 (1H, m), 6.50-6.60 (1H, m), 6.62 (2H, nyl)-1H-pyrazol-4-yl)pyridine-2-carboxamide d, J=7.2 Hz), 7.00-7.15 (2H, m), 7.63-7.75 (1H, m), 8.00-8.15 (1H, m), 8.16 (1H, d. J=9.0 Hz), 8.42 (1H, s), 8.50-8.60 (1H, 0582. A mixture of N-(3-(((2-(pyridin-2-ylamino)ethyl) m), 8.75-8.80 (1H, m), 11.63 (1H, s), 13.33 (1H, s). amino)carbonyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol 4-yl)pyridine-2-carboxamide obtained in Example 396 (0.58 Example 400 g, 1.33 mmol), p-toluenesulfonic acid monohydrate (0.76 g. N-(3-(((2-hydroxyethyl)amino)carbonyl)-1-(tetrahy 4.00 mmol) and ethanol (15 mL) was stirred at 60° C. for 4 hr. Saturated aqueous sodium hydrogen carbonate Solution (10 dro-2H-pyran-2-yl)-1H-pyrazol-4-yl)pyridine-2- mL) and water (20 mL) were added to the reaction mixture, carboxamide and the precipitated crystals were collected by filtration, 0588 To a solution of 4-((pyridin-2-ylcarbonyl)amino)-1- washed with water, acetone and diethyl ether to give the title (tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxylic acid compound (0.39 g, yield 82%). melting point 260-262°C. obtained in Reference Example 54 (0.63 g, 2.0 mmol) and 0583 'H-NMR (d-DMSO): 83.40-3.60 (4H, m), 6.40-6. 2-aminoethanol (0.14 mL, 2.4 mmol) in DMF (10 mL), WSC 50 (2H, m), 6.60-6.70 (1H, m), 7.37 (1H, t, J=6.8 Hz), 7.60 (0.41 g, 2.4 mmol), HOBt (0.32 g, 2.4 mmol) and triethy 7.75 (1H, m), 7.95-8.03 (1H, m), 8.07 (1H, t, J=6.8 Hz), 8.16 lamine (0.33 mL, 2.4 mmol) were added, and the mixture was US 2009/0156582 A1 Jun. 18, 2009 stirred at room temperature for 10 hr. Saturated aqueous (tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxamide Sodium hydrogen carbonate solution was added to the reac obtained in Reference Example 52 and 2-furancarboxylic tion mixture, and the mixture was extracted with ethyl acid. yield 74%. melting point 157-159° C. (ethyl acetate acetate. The extract was washed with water, dried over anhy hexane). drous magnesium Sulfate, passed through a small amount of 0595 H-NMR (CDC1): & 1.60- 1.80 (3H, m), 2.01-2.12 silica gel and evaporated under reduced pressure. Diethyl (2H, m), 2.13-2.25 (1H, m), 2.74 (2H, t, J=6.6 Hz), 3.65-3.79 ether was added to the precipitated crystals, and the crystals (3H, m), 4.02-4.13 (1H, m), 5.36 (1H, dd, J=2.3 Hz, 9.5 Hz), were collected by filtration to give the title compound (0.53 g, 6.54 (1H, dd, J=1.7 Hz, 3.6 Hz), 720-7.26 (2H, m), 7.55-7.56 yield 73%) as crystals. melting point 214-215° C. (1H, m), 8.45 (1H, s), 10.27(1H, s). 0589 H-NMR (CDC1): & 1.60- 1.80 (3H, m), 2.00-2.15 (2H, m), 2.15-2.30 (1H, m), 3.60-3.80 (3H, m), 3.80-3.90 Example 404 (2H, m), 4.00-4.15 (1H, m), 5.36 (1H, d. J=6.9 Hz), 7.20-7.40 N-(2-cyanoethyl)-4-(3-methylbenzoylamino)-1-(tet (1H, m), 7.40-7.50 (1H, m), 7.87 (1H, t, J=8.0 Hz), 8.22 (1H, rahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxamide d, J–7.8 Hz), 8.57 (1H, s), 8.72 (1H, d, J=5.4 Hz), 11.65 (1H, 0596. In the same manner as in Example 402, the title S). compound was obtained using 4-amino-N-(2-cyanoethyl)-1- Example 401 (tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxamide obtained in Reference Example 52 and 3-methylbenzoic acid. N-(3-(((2-hydroxyethyl)amino)carbonyl)-1H-pyra yield 66%. melting point 113-114°C. (ethyl acetate-hexane). Zol-4-yl)pyridine-2-carboxamide 0597 'H-NMR (CDC1): & 1.60- 1.81 (3H, m), 2.02-2.11 0590. A mixture of N-(3-(((2-hydroxyethyl)amino)carbo (1H, m), 2.13-2.48 (1H, m), 2.44 (3H, s), 2.74 (2H, t, J=6.6 nyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)pyri HZ), 3.67-3.79 (3H, m), 4.03-4.11 (1H, m), 5.36 (1H, dd, dine-2-carboxamide obtained in Example 400 (0.48 g, 1.34 J=2.3 Hz, 9.5 Hz), 7.22-7.30 (1H, m), 7.33-7.40 (2H, m), mmol), p-toluenesulfonic acid monohydrate (0.51 g, 2.67 7.71-7.75 (1H, m), 7.77 (1H, s), 8.54 (1H, s), 10.27(1H, s). mmol) and ethanol (10 mL) was stirred at 60° C. for 3 hr. Saturated aqueous Sodium hydrogen carbonate solution was Example 405 added to the reaction mixture, and the mixture was extracted N-(2-cyanoethyl)-4-(3-methoxybenzoylamino)-1- with ethyl acetate. The extract was washed with water, dried (tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxa over anhydrous magnesium Sulfate, passed through a small mide amount of silica geland concentrated under reduced pressure. Diethyl ether was added to the precipitated crystals, and the 0598. In the same manner as in Example 402, the title crystals were collected by filtration to give the title compound compound was obtained using 4-amino-N-(2-cyanoethyl)-1- (0.32g, yield 87%). melting point 155-156°C. (tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxamide 0591 H-NMR (d-DMSO): 83.30-3.50 (3H, m), 3.50-3. obtained in Reference Example 52 and 3-methoxybenzoic 60 (2H, m), 4.75-485 (1H, m), 7.65-7.75 (1H, m), 8.08 (1H, acid. yield 82%. melting point 118-121 (ethyl acetate-hex t, J=6.0 Hz), 8.16 (1H, d, J=8.1 Hz), 8.20-8.30 (1H, m), 8.41 ane). (1H, s), 8.75 (1H, d, J=4.5 Hz), 11.63 (1H, s), 13.32 (1H, s). 0599) 'H-NMR (CDC1): & 1.60-1.78 (3H, m), 1.99-2.09 (2H, m), 2.12-2.43 (1H, m), 2.74 (2H, t, J=6.6 Hz), 3.67-3.75 Example 402 (3H, m), 3.88 (3H, s), 4.02-4.10 (1H, m), 5.36 (1H, dd, J–2.2 N-(2-cyanoethyl)-4-(cyclopentylcarbonyl)amino)-1- HZ and 9.3 Hz), 705-7.12 (1H, m), 7.22-7.28 (1H, m), 7.39 (tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxa (1H, t, J=7.8 Hz), 7.46-7.50 (1H, m), 7.51-7.55 (1H, m), 8.53 mide (1H, s). 0592 To a solution of 4-amino-N-(2-cyanoethyl)-1-(tet Example 406 rahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxamide N-(2-cyanoethyl)-4-(2,2-dimethylpropanoylamino)- obtained in Reference Example 52 (395 mg, 1.5 mmol) and cyclopentanecarboxylic acid (0.179 mL, 1.65 mmol) in DMF 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-car (5 mL), WSC (345 mg, 1.8 mmol) and HOBt (243 mg, 1.8 boxamide mmol) were added, and the mixture was stirred at room 0600. In the same manner as in Example 402, the title temperature for 4 hr. The reaction mixture was diluted with compound was obtained using 4-amino-N-(2-cyanoethyl)-1- water, and extracted with ethyl acetate. The extract was (tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxamide washed with Saturated aqueous Sodium hydrogen carbonate obtained in Reference Example 52 and pivalic acid. yield Solution, dried over anhydrous Sodium Sulfate, and evapo 82%. yield 87%. oily substance. rated under reduced pressure. The residue was purified by 0601 H-NMR (CDC1): & 1.31 (9H, s), 1.61-1.75 (3H, silica gel column chromatography (ethyl acetate-hexane, 1:1) m), 1.97-2.05 (2H, m), 2.10-2.19 (1H, m), 2.72 (2H, t, J=6.6 to give the title compound 444 mg (yield 75%) as an oil. HZ), 3.63-3.75 (3H, m), 3.99-4.06 (1H, m), 5.31 (1H, dd, 0593) 'H-NMR (CDC1): 8 1.57-2.25 (14H, m), 2.67-2.80 J=2.5 Hz and 9.3 Hz), 7.20-7.28 (1H, m), 8.40 (1H, s), 9.75 (3H, m), 3.63-3.75 (3H, m), 3.97-4.07 (1H, m), 5.27-5.23 (1H, brs). (1H, m), 7.24 (1H, t, J=6.3 Hz), 8.38 (1H, s), 9.39 (1H, s). Example 407 Example 403 N-(2-cyanoethyl)-4-(2-thienylcarbonylamino)-1- N-(2-cyanoethyl)-4-(2-furoylamino)-1-(tetrahydro (tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxa 2H-pyran-2-yl)-1H-pyrazole-3-carboxamide mide 0594. In the same manner as in Example 402, the title 0602. In the same manner as in Example 402, the title compound was obtained using 4-amino-N-(2-cyanoethyl)-1- compound was obtained using 4-amino-N-(2-cyanoethyl)-1-

US 2009/0156582 A1 Jun. 18, 2009 72

4-yl)pyridine-2-carboxamide obtained in Example 452 (0.25 0701 'H-NMR (d-DMSO): & 1.15 (9H, s), 1.65-180 g, 0.55 mmol), p-toluenesulfonic acid monohydrate (0.32 g, (2H, m), 3.30-3.50 (4H, m), 7.60-7.75 (1H, m), 8.06 (1H, d, 1.66 mmol) and ethanol (10 ml) was stirred at 60°C. for 3 hr. J=7.8 Hz), 8.15 (1H, d, J=7.8 Hz), 8.30-8.40 (1H, m), 8.38 Saturated aqueous Sodium hydrogen carbonate solution was (1H, s), 8.74 (1H, d, J=6.0 Hz), 11.62 (1H, s), 13.27 (1H, s). added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried Example 456 over anhydrous magnesium Sulfate, passed through a small amount of silica gel and evaporated under reduced pressure. N-(3-(((cyanopropyl)amino)carbonyl)-1-(tetrahydro Diethyl ether was added to the precipitated crystals, and the 2H-pyran-2-yl)-1H-pyrazol-4-yl)pyridine-2-carboxa crystals were collected by filtration to give the title compound mide (0.16g, yield 88%). melting point 162-163°C. 0702. To a solution of 4-((pyridin-2-ylcarbonyl)amino)-1- 0697) 'H-NMR (d-DMSO): 8 3.37 (2H, t, J=74 Hz), (tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxylic acid 3.55-3.65 (2H, m), 7.10-7.20 (1H, m), 7.36 (1H, d, J=7.8 Hz), obtained in Reference Example 54 (0.64g, 2.0 mmol) and 7.60-7.75 (2H, m), 8.07 (1H, t, J=7.4 Hz), 8.15 (1H, d, J=7.8 4-aminobutyronitrile hydrochloride (0.347 g, 2.88 mmol) in Hz), 8.41 (1H, s), 8.42-8.50 (1H, m), 8.65-8.80 (2H, m), DMF (10 ml), WSC (0.41 g, 2.4 mmol), HOBt (0.32 g, 2.4 11.60 (1H, s), 13.33 (1H, s). mmol) and triethylamine (0.54 ml, 3.9 mmol) were added, and the mixture was stirred at room temperature for 5 hr. Example 454 Saturated aqueous Sodium hydrogen carbonate Solution was added to the reaction mixture, and the mixture was extracted N-(3-(((3-tert-butoxypropyl)amino)carbonyl)-1-(tet with ethyl acetate. The extract was washed with water, dried rahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)pyridine-2- over anhydrous magnesium Sulfate, and evaporated under carboxamide reduced pressure. The residue was purified by silica gel col umn chromatography (hexane:ethyl acetate 1:1-1:2). 0698. To a solution of 4-((pyridin-2-ylcarbonyl)amino)-1- Diethyl ether was added to the precipitated crystals, and the (tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxylic acid crystals were collected by filtration to give the title compound obtained in Reference Example 54 (0.63 g, 2.0 mmol) and (0.31 g, yield 41%) as crystals. melting point 155-157°C. 3-tert-butoxypropylamine hydrochloride (0.40g, 2.4 mmol) 0703 H-NMR (CDC1): & 1.60- 1.80 (3H, m), 2.00 (2H, in DMF (10 ml), WSC (0.41 g, 2.4 mmol), HOBt (0.32g, 2.4 q, J=6.9 Hz), 2.00-2.15 (2H, m), 2.15-2.30 (1H, m), 2.48 (2H, mmol) and triethylamine (0.33 ml, 2.4 mmol) were added, t, J–7.2 Hz), 3.59 (2H, q, J=6.9 Hz), 3.65-3.80 (1H, m), and the mixture was stirred at room temperature for 3 hr. 4.05-4.15 (1H, m), 5.37 (1H, dd, J=9.6, 1.8 Hz), 7.00-7.10 Saturated aqueous Sodium hydrogen carbonate solution was (1H, m), 7.40-7.50 (1H, m), 7.87 (1H, td, J=7.8, 1.8 Hz), 8.23 added to the reaction mixture, and the mixture was extracted (1H, d. J–8.1 Hz), 8.58 (1H, s), 8.70-8.80 (1H, m), 11.61 (1H, with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium Sulfate, passed through a small S). amount of silica gel and evaporated under reduced pressure. Example 457 Diethyl ether was added to the precipitated crystals, and the crystals were collected by filtration to give the title compound N-(3-(((cyanopropyl)amino)carbonyl)-1H-pyrazol-4- (0.76g, yield 87%) as crystals. melting point 101-103°C. yl)pyridine-2-carboxamide (0699) 'H-NMR (CDC1): 8 1.25 (9H, s), 1.60-1.80 (3H, 0704. A mixture of N-(3-(((cyanopropyl)amino)carbo m), 1.80-1.95 (2H, m), 2.00-2.15 (1H, m), 2.15-2.30 (1H, m), nyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)pyri 3.53 (2H, t, J=5.7 Hz), 3.59 (2H, q, J=5.7 Hz), 3.60-3.80 (1H, dine-2-carboxamide obtained in Example 456 (0.27 g. 0.71 m), 4.05 (1H, d. J=11.4 Hz), 5.33 (1H, dd, J=9.3, 2.4 Hz), mmol), p-toluenesulfonic acid monohydrate (0.27 g, 1.41 7.40-7.50 (1H, m), 7.50-7.60 (1H, m), 7.85 (1H, td, J=7.8, 1.8 mmol) and ethanol (15 ml) was stirred at 60° C. for 4 hr. Hz), 8.21 (1H, d, J=7.8 Hz), 8.54 (1H, s), 8.70-8.80 (1H, m), Saturated aqueous Sodium hydrogen carbonate Solution was 11.77 (1H, s). added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried Example 455 over anhydrous magnesium Sulfate, passed through a small amount of silica gel and evaporated under reduced pressure. N-(3-(((3-tert-butoxypropyl)amino)carbonyl)-1H Diethyl ether was added to the precipitated crystals, and the pyrazol-4-yl)pyridine-2-carboxamide crystals were collected by filtration to give the title compound 0700. A mixture of N-(3-(((3-tert-butoxypropyl)amino) (0.20 g, yield 95%). melting point 231-233°C. carbonyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl) (0705 H-NMR (d-DMSO): & 1.80-1.95 (2H, m), 2.53 pyridine-2-carboxamide obtained in Example 454 (0.71 g, (2H, q, J–7.5 Hz), 3.37 (2H, q, J=6.9 Hz), 7.65-7.75 (1H, m), 1.65 mmol), p-toluenesulfonic acid monohydrate (0.31 g, 8.07 (1H, t, J=7.6 Hz), 8.16 (1H, d, J=7.6 Hz), 8.41 (1H, s), 1.65 mmol) and ethanol (20 ml) was stirred at 50° C. for 8 hr. 8.55-8.75 (1H, m), 8.76 (1H, d, J=4.5 Hz), 11.61 (1H, s), Saturated aqueous Sodium hydrogen carbonate solution was 13.32 (1H, s). added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried Example 458 over anhydrous magnesium Sulfate, and evaporated under N-(3-(((2-cyano-2-methylpropyl)amino)carbonyl)-1- reduced pressure. The residue was purified by silica gel col (tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-pyri umn chromatography (hexane:ethyl acetate 1:1-1:2). dine-2-carboxamide Diethyl ether was added to the precipitated crystals, and the crystals were collected by filtration to give the title compound 0706 To a solution of 4-((pyridin-2-ylcarbonyl)amino)-1- (0.42g, yield 74%). melting point 193-194°C. (tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxylic acid US 2009/0156582 A1 Jun. 18, 2009 obtained in Reference Example 54 (0.63 g, 2.0 mmol) and 0711 H-NMR (CDC1): 8 1.25 (3H, s), 1.60- 1.80 (3H, 2-cyano-2-methylpropylamine obtained in Reference m), 2.00-2.15 (2H, m), 2.15-2.30 (1H, m), 2.83 (1H, d, J–13.5 Example 57 (0.40 g, 4.0 mmol) in DMF (10 ml), WSC (0.41 Hz), 3.05 (1H, d, J=13.5 Hz), 3.60-3.85 (3H, m), 405-4.20 g, 2.4 mmol) and HOBt (0.32 g, 2.4 mmol) were added, and (1H, m), 5.39 (1H, d, J=7.2 Hz), 7.25-7.40 (5H, m), 7.40-7.50 the mixture was stirred at room temperature for 24hr. Satu (1H, m), 7.87 (1H, t, J=7.7 Hz), 8.27 (1H, d, J=8.1 Hz), 8.59 rated aqueous sodium hydrogen carbonate Solution was (1H, s), 8.72 (1H, d, J–3.9 Hz), 11.55 (1H, s). added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried Example 461 over anhydrous magnesium Sulfate, passed through a small N-(3-(((2-cyano-2-methyl-3-phenylpropyl)amino) amount of silica geland concentrated under reduced pressure. carbonyl)-1H-pyrazol-4-yl)pyridine-2-carboxamide Diethyl ether was added to the precipitated crystals, and the crystals were collected by filtration to give the title compound 0712. To a solution of N-(3-(((2-cyano-2-methyl-3-phe (0.63 g, yield 79%) as crystals. melting point 138-140°C. nylpropyl)amino)carbonyl)-1-(tetrahydro-2H-pyran-2-yl)- (0707 'H-NMR (CDC1): 8 1.44 (6H, s), 1.60-1.80 (3H, 1H-pyrazol-4-yl)pyridine-2-carboxamide obtained in m), 2.00-2.15 (2H, m), 2.15-2.30 (1H, m), 3.65 (2H, d. J=6.9 Example 460 (0.86 g, 1.82 mmol) in ethanol-chloroform Hz), 3.70-3.80 (1H, m), 405-4.20(1H, m), 5.39 (1H, d, J=9.3 (15-15 ml), p-toluenesulfonic acid monohydrate (0.69 g, 3.64 Hz), 720-7.30 (1H, m), 7.40-7.50 (1H, m), 7.88 (1H, t, J=7.8 mmol) was added, and the mixture was stirred at 60° C. for 7 Hz), 8.23 (1H, d, J=7.8 Hz), 8.61 (1H, s), 8.70-8.80 (1H, m), hr. The reaction mixture was diluted with Saturated aqueous 11.56 (1H, s). Sodium hydrogen carbonate Solution, and the mixture was extracted with ethyl acetate. The extract was washed with Example 459 water, dried over anhydrous magnesium sulfate, passed through a small amount of silica gel and concentrated under N-(3-(((2-cyano-2-methylpropyl)amino)carbonyl)- reduced pressure. Diethyl ether was added to the precipitated 1H-pyrazol-4-yl)pyridine-2-carboxamide crystals, and the crystals were collected by filtration to give the title compound (0.54g, yield 76%) as crystals. melting 0708. A mixture of N-(3-(((2-cyano-2-methylpropyl) point 196-197° C. amino)carbonyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol 0713 'H-NMR (CDC1): 8 1.26 (3H, s), 2.84 (1H, d, 4-yl)-pyridine-2-carboxamide obtained in Example 458 J=12.5 Hz), 3.03 (1H, d, J=12.5 Hz), 3.50-3.60 (1H, m), (0.59 g, 1.49 mmol), p-toluenesulfonic acid monohydrate 3.60-3.75 (1H, m), 7.25-7.40 (5H, m), 7.60-7.70 (1H, m), (0.57g, 2.98 mmol) and ethanol (20 ml) was stirred at 60° C. 8.05-8.15 (1H, m), 8.15 (1H, d, J–7.2 Hz), 8.45 (1H, s), for 12 hr. Saturated aqueous Sodium hydrogen carbonate 8.70-8.80 (2H, m), 11.54 (1H, s), 13.43 (1H, s). Solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with Example 462 water, dried over anhydrous magnesium sulfate, evaporated under reduced pressure, passed through a small amount of Ethyl 4-(((4-((pyridin-2-ylcarbonyl)amino)-1-(tet silica gel and concentrated under reduced pressure. Diethyl rahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)carbonyl) ether was added to the precipitated crystals, and the crystals amino)butanoate were collected by filtration to give the title compound (0.29 g, 0714 To a solution of 4-((pyridin-2-ylcarbonyl)amino)-1- yield 62%). melting point 238-240°C. (tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxylic acid 0709 'H-NMR (d-DMSO): & 1.34 (6H, s), 3.50 (2H, t, obtained in Reference Example 54 (1.27 g. 4.0 mmol) and J=6.6 Hz), 7.60-7.70 (1H, m), 8.07 (1H, t, J=8.0 Hz), 8.15 ethyl 4-aminobutanoate-hydrochloride (0.74g, 4.4 mmol) in (1H, d, J=7.4 Hz), 8.44 (1H, s), 8.65-8.75 (1H, m), 8.75 (1H, DMF (20 ml), WSC (0.825 g, 4.8 mmol) and HOBt (0.65 g, d, J=5.0 Hz), 11.54 (1H, s), 13.41 (1H, s). 4.8 mmol) were added, and the mixture was stirred at room temperature for 24 hr. Saturated aqueous Sodium hydrogen Example 460 carbonate Solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was N-(3-(((2-cyano-2-methyl-3-phenylpropyl)amino) washed with water, dried over anhydrous magnesium sulfate, carbonyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol and evaporated under reduced pressure. The residue was puri 4-yl)pyridine-2-carboxamide fied by silica gel column chromatography (hexane:ethyl acetate=1:1) to give the title compound (0.88 g, yield 4.6%) as 0710. To a solution of 4-((pyridin-2-ylcarbonyl)amino)-1- crystals. melting point 114-115° C. (tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxylic acid 0715 H-NMR (CDC1): 8 1.25 (3H, t, J=7.2 Hz), 1.60 obtained in Reference Example 54 (0.63 g, 2.0 mmol) and 1.80 (3H, m), 1.95-2.05 (2H, m), 2.05-2.15 (2H, m), 2.15-2. 3-amino-2-benzyl-2-methylpropanenitrile (0.52 g, 3.0 30 (1H, m), 2.42 (2H, t, J–7.2 Hz), 3.52 (2H, d, J=6.6 Hz), mmol) in DMF (10 ml), WSC (0.41 g, 2.4 mmol) and HOBt 3.65-3.80 (1H, m), 4.13 (2H, q, J–7.2 Hz), 4.00-4.15 (1H, m), (0.32g, 2.4 mmol) were added, and the mixture was stirred at 5.35-5.40 (1H, m), 6.95-7.05 (1H, m), 7.40-7.50 (1H, m), room temperature for 3 hr. Saturated aqueous sodium hydro 7.86 (1H, td, J-7.5, 1.8 Hz), 8.21 (1H, t, J=7.8 Hz), 8.56 (1H, gen carbonate solution was added to the reaction mixture, and s), 8.71 (1H, d, J–4.0 Hz), 11.69 (1H, s). the mixture was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium Sulfate, Example 463 passed through a small amount of silica gel and concentrated under reduced pressure. Diethyl ether was added to the pre Ethyl 4-(((4-((pyridin-2-ylcarbonyl)amino)-1H-pyra cipitated crystals, and the crystals were collected by filtration Zol-3-yl)carbonyl)amino)butanoate to give the title compound (0.90 g, yield 95%) as crystals. 0716. A mixture of ethyl 4-(((4-((pyridin-2-ylcarbonyl) melting point 187-190° C. amino)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)car US 2009/0156582 A1 Jun. 18, 2009 74 bonyl)amino)butanoate obtained in Example 462 (0.84 g. 50 (1H, m), 7.87 (1H, td, J=7.8, 1.5 Hz), 8.22 (1H, d, J=9.0 1.96 mmol), p-toluenesulfonic acid monohydrate (0.74 g, Hz), 8.59 (1H, s), 8.70-8.80 (1H, m), 11.54 (1H, s). 3.91 mmol) and ethanol (20 ml) was stirred at 60°C. for 4 hr. Saturated aqueous Sodium hydrogen carbonate solution was Example 466 added to the reaction mixture, and the mixture was extracted N-(3-(((2-hydroxy-1,1-dimethylethyl)amino)carbo with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium Sulfate, and evaporated under nyl)-1H-pyrazol-4-yl)pyridine-2-carboxamide reduced pressure. The residue was purified by silica gel col 0722. A mixture of N-3-(((2-hydroxy-1,1-dimethylethyl) umn chromatography (hexane:ethyl acetate 1:1-1:2). amino)carbonyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol Diethyl ether was added to the precipitated crystals, and the 4-yl)pyridine-2-carboxamide obtained in Example 465 (0.54 crystals were collected by filtration to give the title compound g, 1.39 mmol), p-toluenesulfonic acid monohydrate (0.53 g, (0.55g, yield 81%). melting point 179-180° C. 2.79 mmol) and ethanol (10 ml) was stirred at 60°C. for 5 hr. 0717 'H-NMR (d-DMSO): & 1.17 (3H, t, J=7.2 Hz), Saturated aqueous Sodium hydrogen carbonate Solution was 1.75-190 (2H, m), 2.34 (2H, t, J=7.2 Hz), 3.29 (2H, t, J=6.9 added to the reaction mixture, and the mixture was extracted Hz), 4.04 (2H, q, J=7.2 Hz), 7.60-7.70 (1H, m), 8.06 (1H, t, with ethyl acetate. The extract was washed with water, dried J=7.7 Hz), 8.15 (1H, d, J=7.2 Hz), 8.40 (1H, s), 8.40-8.55 over anhydrous magnesium-Sulfate, and evaporated under (1H, m), 8.75 (1H, d. J=3.6 Hz), 11.62 (1H, s), 13.30 (1H, s). reduced pressure. The residue was purified by silica gel col umn chromatography (hexane:ethyl acetate-1:2-1:4) to give Example 464 the title compound (0.27g, yield 64%). melting point 193 195o C. 4-(((4-((pyridin-2-ylcarbonyl)amino)-1H-pyrazol-3- 0723 'H-NMR (d-DMSO): & 1.37 (6H, s), 3.45 (2H, d, yl)carbonyl)amino)butanoic acid J=5.1 Hz), 5.10-5.22(1H, m), 7.36 (1H, s), 7.60-7.75 (1H, m), 0718 To a mixture of ethyl 4-(((4-((pyridin-2-ylcarbonyl) 8.07 (1H, t, J=7.8 Hz), 8.16 (1H, d, J=7.8 Hz), 8.41 (1H, s), amino)-1H-pyrazol-3-yl)carbonyl)amino)butanoate 8.78 (1H, d, J=4.5 Hz), 11.50 (1H, s), 13.27 (1H, s). obtained in Example 463 (0.40 g, 1.16 mmol), ethanol (5 ml) Example 467 and tetrahydrofuran (3 ml), 1N aqueous sodium hydroxide solution (4.63 ml, 4.63 mmol) was added, and the mixture N-(3-(((3-hydroxypropyl)amino)carbonyl)-1-(tet was stirred at room temperature for 4.5 hr. The reaction mix rahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)pyridine-2- ture was neutralized with 1N hydrochloric acid (4.63 ml), and carboxamide concentrated under reduced pressure. Water was added to the 0724. To a solution of 4-((pyridin-2-ylcarbonyl)amino)-1- precipitated crystals, and the crystals were collected by fil (tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxylic acid tration to give the title compound (0.36g, yield 98%). melting obtained in Reference Example 54 (0.63 g, 2.0 mmol) and point 227-228°C. 3-hydroxypropylamine (0.15 ml, 2.4 mmol) in DMF (10 ml), 0719 'H-NMR (d-DMSO): & 1.70-190 (2H, m), 2.27 WSC (0.41 g, 2.4 mmol) and HOBt (0.32 g, 2.4 mmol) were (2H, t, J–74 Hz), 3.29 (2H, t, J=6.6 Hz), 7.67 (1H, t, J=6.0 added, and the mixture was stirred at room temperature for 24 Hz), 8.06 (1H, t, J=7.5 Hz), 8.15 (1H, d, J–7.5 Hz), 8.39 (1H, hr. Saturated aqueous Sodium hydrogen carbonate Solution s), 8.40-8.55 (1H, m), 8.75 (1H, d. J–4.5 Hz), 11.62 (1H, s), was added to the reaction mixture, and the mixture was 12.06 (1H, s), 13.30 (1H, s). extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, passed Example 465 through a small amount of silica gel and evaporated under N-(3-(((2-hydroxy-1,1-dimethylethyl)amino)carbo reduced pressure. Diethyl ether was added to the precipitated nyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl) crystals, and the crystals were collected by filtration to give pyridine-2-carboxamide the title compound (0.74g, yield 99%) as crystals. melting point 139-140° C. 0720. To a solution of 4-((pyridin-2-ylcarbonyl)amino)-1- 0725 H-NMR (CDC1): 8 1.50-1.90 (5H, m), 2.00-2.15 (tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxylic acid (2H, m), 2.15-2.30 (1H, m), 3.10-3.20 (1H, m), 3.64 (2H, q, obtained in Reference Example 54 (0.63 g, 2.0 mmol) and J=6.0Hz), 3.65-3.80 (2H, m), 4.00-4.20(1H, m), 5.36 (1H, d, 2-amino-2-methylpropanol (0.21 g, 2.4 mmol) in DMF (10 J=9.3 Hz), 7.10-725 (1H, m), 7.45 (1H, dd, J=11.1, 6.3 Hz), ml), WSC (0.41 g, 2.4 mmol) and HOBt (0.32 g, 2.4 mmol) 7.86 (1H, t, J=8.8 Hz), 8.21 (1H, d, J=7.5 Hz), 8.58 (1H, s), were added, and the mixture was stirred at room temperature 8.71 (1H, d. J=3.9 Hz), 11.62 (1H, s). for 17 hr. Saturated aqueous Sodium hydrogen carbonate Solution was added to the reaction mixture, and the mixture Example 468 was extracted with ethyl acetate. The extract was washed with N-(3-(((3-hydroxypropyl)amino)carbonyl)-1H-pyra water, dried over anhydrous magnesium sulfate, passed Zol-4-yl)pyridine-2-carboxamide through a small amount of silica gel and evaporated under reduced pressure. Diethyl ether was added to the precipitated 0726. A mixture of N-(3-(((3-hydroxypropyl)amino)car crystals, and the crystals were collected by filtration to give bonyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)pyri the title compound (0.53 g, yield 75%) as crystals. melting dine-2-carboxamide obtained in Example 467 (0.70 g, 1.87 point 194-195° C. mmol), p-toluenesulfonic acid monohydrate (0.71 g, 3.75 0721 'H-NMR (CDC1): 8 1.43 (6H, s), 1.60- 1.80 (3H, mmol) and ethanol (15 ml) was stirred at 60° C. for 5 hr. m), 2.00-2.15 (2H, m), 2.15-2.30 (1H, m), 3.73 (2H, d. J=6.3 Saturated aqueous Sodium hydrogen carbonate Solution was HZ), 3.65-3.80 (1H, m), 4.10 (1H, d, J=10.5 Hz), 4.95 (1H, t, added to the reaction mixture, and the mixture was extracted J=6.5 Hz), 5.35 (1H, dd, J=9.9, 1.6 Hz), 6.96 (1H, s), 7.40-7. with ethyl acetate. The extract was washed with water, dried US 2009/0156582 A1 Jun. 18, 2009

over anhydrous magnesium Sulfate, passed through a small obtained in Reference Example 54 (0.63 g, 2.0 mmol) and amount of silica geland concentrated under reduced pressure. 2-hydroxybutylamine (0.23 ml, 2.4 mmol) in DMF (10 ml), The precipitated crystals were recrystallized from ethyl WSC (0.41 g, 2.4 mmol) and HOBt (0.32 g, 2.4 mmol) were acetate to give the title compound (0.42g, yield 77%). melt added, and the mixture was stirred at room temperature for 24 ing point 209-211° C. hr. Saturated aqueous Sodium hydrogen carbonate Solution 0727 'H-NMR (d-DMSO): 81.60-1.80 (2H, m), 3.30-3. was added to the reaction mixture, and the mixture was 40 (2H, m), 3.40-3.55 (2H, m), 4.50-4.60 (1H, m), 7.60-7.70 extracted with ethyl acetate. The extract was washed with (1H, m), 8.06 (1H, td, J–7.8, 1.2 Hz), 8.15 (1H, d, J=1.2 Hz), water, dried over anhydrous magnesium sulfate, passed 8.39 (1H, s), 8.35-8.50 (1H, m), 8.74 (1H, d, J=8.4 Hz), 11.63 through a small amount of silica gel and evaporated under (1H, s), 13.28 (1H, s). reduced pressure. Diethyl ether was added to the precipitated Example 469 crystals, and the crystals were collected by filtration to give N-(3-(((3-hydroxy-2,2-dimethylpropyl)amino)carbo the title compound (0.76 g, yield 98%) as crystals. melting nyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl) point 160-161° C. pyridine-2-carboxamide (0733 H-NMR (CDC1): & 1.01 (3H, t, J–7.5 Hz), 1.50 0728. To a solution of 4-((pyridin-2-ylcarbonyl)amino)-1- 1.80 (5H, m), 2.00-2.15 (2H, m), 2.15-2.30 (1H, m), 2.55-2. (tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxylic acid 65 (1H, m), 3.30-340 (1H, m), 3.60-3.85 (3H, m), 5.36 (1H, obtained in Reference Example 54 (0.63 g, 2.0 mmol) and d, J=9.6Hz), 7.20-7.35 (1H, m), 7.44 (1H, dd, J=7.5, 4.8 Hz), 3-amino-2,2-dimethylpropanol (0.25 g, 2.4 mmol) in DMF 7.87 (1H, td, J–7.8, 0.9 Hz), 8.22(1H, d, J=7.8 Hz), 8.57 (1H, (10 ml), WSC (0.41 g, 2.4 mmol) and HOBt (0.32 g, 2.4 d, J=4.8 Hz), 11.65 (1H, s). mmol) were added, and the mixture was stirred at room temperature for 21 hr. Saturated aqueous Sodium hydrogen Example 472 carbonate Solution was added to the reaction mixture, and the N-(3-(((2-hydroxybutyl)amino)carbonyl)-1H-pyra mixture was extracted with ethyl acetate. The extract was Zol-4-yl)pyridine-2-carboxamide washed with water, dried over anhydrous magnesium Sulfate, passed through a small amount of silica gel and evaporated 0734. A mixture of N-(3-(((2-hydroxybutyl)amino)carbo under reduced pressure. Diethyl ether was added to the pre nyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)pyri cipitated crystals, and the crystals were collected by filtration dine-2-carboxamide obtained in Example 471 (0.72 g, 1.86 to give the title compound (0.69 g, yield 86%) as crystals. mmol), p-toluenesulfonic acid monohydrate (0.71 g, 3.69 melting point 189-190° C. mmol) and ethanol (15 ml) was stirred at 60° C. for 3.5 hr. 0729) 'H-NMR (CDC1): 8 0.96 (6H, s), 1.60-1.80 (3H, Saturated aqueous Sodium hydrogen carbonate Solution was m), 2.00-2.15 (2H, m), 2.15-2.30 (1H, m), 3.25 (2H, d. J–7.2 added to the reaction mixture, and the mixture was extracted Hz), 3.31 (2H, d, J=7.2 Hz), 3.65-3.80 (1H, m), 4.00-4.15 with ethyl acetate. The extract was washed with water, dried (2H, m), 5.37 (1H, dd, J=9.3, 2.4 Hz), 7.20-7.30 (1H, m), over anhydrous magnesium Sulfate, passed through a small 7.40-7.50 (1H, m), 7.86 (1H, td, J=7.8, 1.8 Hz), 8.21 (1H, d, amount of silica gel and concentrated under reduced pressure. J=8.1 Hz), 8.59 (1H, s), 8.65-8.75 (1H, m), 11.57 (1H, s). The precipitated crystals were recrystallized from ethyl Example 470 acetate to give the title compound (0.41 g, yield 73%). melt N-(3-(((3-hydroxy-2,2-dimethylpropyl)amino)carbo ing point 202-203°C. nyl)-1H-pyrazol-4-yl)pyridine-2-carboxamide (0735. H-NMR (d-DMSO): 8 0.91 (3H, t, J=6.9 Hz), 2.15-2.55 (2H, m), 3.30-345 (2H, m), 3.50-3.65 (1H, m), 0730. A mixture of N-(3-(((3-hydroxy-2,2-dimethylpro 4.79 (1H, d, J=4.8 Hz), 7.60-7.70 (1H, m), 8.00-8.20 (3H, m), pyl)amino)carbonyl)-1-(tetrahydro-2H-pyran-2-yl)-1H 8.41 (1H, s), 8.74 (1H, d, J=5.7 Hz), 11.60 (1H, s), 13.31 (1H, pyrazol-4-yl)pyridine-2-carboxamide obtained in Example S). 469 (0.64g, 1.59 mmol), p-toluenesulfonic acid monohydrate (0.61 g, 3.19 mmol) and ethanol (20 ml) was stirred at 60°C. Example 473 for 5 hr. Saturated aqueous sodium hydrogen carbonate solu tion was added to the reaction mixture, and the mixture was N-(3-(((2-hydroxy-3-phenylpropyl)amino)carbonyl)- extracted with ethyl acetate. The extract was washed with 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)pyri water, dried over anhydrous magnesium sulfate, and evapo dine-2-carboxamide rated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate-1: 0736. To a solution of 4-((pyridin-2-ylcarbonyl)amino)-1- 1-1:3). Diethyl ether was added to the precipitated crystals, (tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxylic acid and the crystals were collected by filtration to give the title obtained in Reference Example 54 (0.63 g, 2.0 mmol) and compound (0.36 g, yield 71%). melting point 217-218°C. 2-hydroxy-3-phenylpropylamine (0.36 g, 2.4 mmol) in DMF 0731 'H-NMR (d-DMSO): 8 0.84 (6H, s), 3.10-3.30 (10 ml), WSC (0.41 g, 2.4 mmol) and HOBt (0.32 g, 2.4 (4H, m), 4.77 (1H, t, J=5.3 Hz), 7.67 (1H, t, J=6.0 Hz), 8.06 mmol) were added, and the mixture was stirred at room (1H, d, J=7.8 Hz), 8.15 (1H, d, J=7.8 Hz), 8.41 (1H, s), 8.75 temperature for 5 hr. Saturated aqueous sodium hydrogen (1H, d, J–4.2 Hz), 11.57 (1H, s), 13.31 (1H, s). carbonate Solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was Example 471 washed with water, dried over anhydrous magnesium sulfate, N-(3-(((2-hydroxybutyl)amino)carbonyl)-1-(tetrahy passed through a small amount of silica gel and evaporated dro-2H-pyran-2-yl)-1H-pyrazol-4-yl)pyridine-2- under reduced pressure. Diethyl ether was added to the pre carboxamide cipitated crystals, and the crystals were collected by filtration 0732. To a solution of 4-((pyridin-2-ylcarbonyl)amino)-1- to give the title compound (0.88 g, yield 98%) as crystals. (tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxylic acid melting point 132-134°C. US 2009/0156582 A1 Jun. 18, 2009 76

0737 'H-NMR (CDC1): & 1.60- 1.80 (3H, m), 2.00-2.15 2.99 mmol) and ethanol (10 ml) was stirred at 60°C. for 6 hr. (2H, m), 2.15-2.30 (1H, m), 2.70 (1H, brs), 2.81 (1H, dd, Saturated aqueous Sodium hydrogen carbonate Solution was J=13.5, 8.1 Hz), 2.90 (1H, dd, J=13.5, 5.4 Hz), 3.35-3.50 (1H, added to the reaction mixture, and the mixture was extracted m), 3.65-3.85 (2H, m), 4.00-4.20 (2H, m), 5.35 (1H, d. J=9.6 with ethyl acetate. The extract was washed with water, dried Hz), 7.20-7.40 (5H, m), 7.40-7.50 (1H, m), 7.86 (1H, td, over anhydrous magnesium Sulfate, passed through a small amount of silica gel and concentrated under reduced pressure. J=7.7, 1.8 Hz), 8.22(1H, d, J=8.1 Hz), 8.57 (1H, s), 8.71 (1H, The precipitated crystals were recrystallized from ethyl d, J–4.2 Hz), 11.64 (1H, s). acetate to give the title compound (0.37g, yield 80%). melt ing point 193-194° C. Example 474 0743 H-NMR (d-DMSO): & 1.15 (6H, s), 1.65 (2H, t, N-(3-(((2-hydroxy-3-phenylpropyl)amino)carbonyl)- J=7.7 Hz), 3.30-3.50 (2H, m), 4.44 (1H, s), 7.65-7.75 (1H, m), 1H-pyrazol-4-yl)pyridine-2-carboxamide 8.06 (1H, t, J=7.5 Hz), 8.15 (1H, d, J=8.1 Hz), 8.39 (1H, s), 0738. A mixture of N-(3-(((2-hydroxy-3-phenylpropyl) 8.35-8.45 (1H, m), 8.74 (1H, d. J=5.1 Hz), 11.63 (1H, s), amino)carbonyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol 13.27 (1H, s). 4-yl)pyridine-2-carboxamide obtained in Example 473 (0.83 Example 477 g, 1.85 mmol), p-toluenesulfonic acid monohydrate (0.70 g, N-(3-(((2-isopropoxyethyl)amino)carbonyl)-1-(tet 3.69 mmol) and ethanol (20 ml) was stirred at 60°C. for 3 hr. rahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-6-meth Saturated aqueous Sodium hydrogen carbonate solution was ylnicotinamide added to the reaction mixture, and the mixture was extracted 0744. To a solution of 4-(((6-methylpyridin-3-yl)carbo with ethyl acetate. The extract was washed with water, dried nyl)amino)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3- over anhydrous magnesium Sulfate, passed through a small carboxylic acid obtained in Reference Example 56 (0.66 g. amount of silica geland concentrated under reduced pressure. 2.0 mmol) and 2-(2-isopropyl)ethylamine (0.29 ml, 2.4 Diethyl ether was added to the precipitated crystals, and the mmol) in DMF (10 ml), WSC (0.41 g, 2.4 mmol) and HOBt crystals were collected by filtration to give the title compound (0.32g, 2.4 mmol) were added, and the mixture was stirred at (0.55g, yield 82%). melting point 180-181° C. room temperature for 24hr. Saturated aqueous Sodium hydro gen carbonate Solution was added to the reaction mixture, and 0739 H-NMR (d-DMSO): 82.60-2.70 (1H, m), 2.70-2. the mixture was extracted with ethyl acetate. The extract was 80 (1H, m), 3.20-3.30 (1H, m), 3.35-3.50 (1H, m), 3.80-4.00 washed with water, dried over anhydrous magnesium sulfate, (1H, m), 4.99 (1H, d, J=4.5 Hz), 7.15-7.40 (5H, m), 7.60-7.70 passed through a small amount of silica gel and evaporated (1H, m), 8.06 (1H, t, J=6.3 Hz), 8.15-8.20 (2H, m), 8.41 (1H, under reduced pressure to give the title compound (0.80 g, s), 8.70-8.80 (1H, m), 11.59 (1H, s), 13.32 (1H, s). yield 96%) as an oil. Example 475 0745 H-NMR (CDC1): 8 1.20 (6H, d, J=6.0 Hz), 1.55 1.80 (3H, m), 2.00-2.15 (2H, m), 2.15-2.30 (1H, m), 3.60(3H, N-(3-(((3-hydroxy-3-methylbutyl)amino)carbonyl)- s), 3.65-3.80 (1H, m), 4.06 (1H, d. J=10.5 Hz), 5.37 (1H, dd, 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)pyri J=9.0 Hz), 7.25 (1H, d, J–7.8 Hz), 8.08 (1H, dd, J=7.8, 2.4 dine-2-carboxamide Hz), 8.49 (1H, s), 9.11 (1H, s), 10.58 (1H, s). 0740. To a solution of 4-((pyridin-2-ylcarbonyl)amino)-1- Example 478 (tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxylic acid N-(3-(((2-isopropoxyethyl)amino)carbonyl)-1H obtained in Reference Example 54 (0.63 g, 2.0 mmol) and pyrazol-4-yl)-6-methylnicotinamide 4-amino-2-methylbutan-2-ol (0.31 g, 3.0 mmol) in DMF (10 0746. A mixture of N-3-(((2-isopropoxyethyl)amino) ml), WSC (0.41 g, 2.4 mmol) and HOBt (0.32 g, 2.4 mmol) carbonyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)- were added, and the mixture was stirred at room temperature 6-methylnicotinamide obtained in Example 477 (0.80g, 1.93 for 16 hr. Saturated aqueous Sodium hydrogen carbonate mmol), p-toluenesulfonic acid monohydrate (0.73 g, 3.85 Solution was added to the reaction mixture, and the mixture mmol) and ethanol (15 ml) was stirred at 60°C. for 3 hr. The was extracted with ethyl acetate. The extract was washed with reaction mixture was concentrated under reduced pressure. water, dried over anhydrous magnesium Sulfate, and purified Saturated aqueous Sodium hydrogen carbonate Solution was by silica gel column chromatography (hexane:ethyl added, and the mixture was extracted with ethyl acetate. The acetate=1:1-1:5) to give the title compound (0.65 g, yield extract was washed with water, dried over anhydrous magne 81%) as crystals. melting point 138-139° C. sium Sulfate, and evaporated under reduced pressure. The 0741 'H-NMR (CDC1): & 1.31 (6H, s), 1.60-1.80 (3H, residue was purified by silica gel column chromatography m), 1.82 (2H, t, J=6.9 Hz), 2.00-2.15 (1H, m), 3.64 (2H, q, (hexane:ethyl acetate=1:3-ethyl acetate) to give the title com J=6.4 Hz), 3.70-3.80 (1H, m), 4.00-4.15 (1H, m), 5.35 (1H, d, pound (0.48g, yield 75%). melting point 168-169°C. J=7.5 Hz), 7.40-7.50 (2H, m), 7.86 (1H, t, J=7.7 Hz), 8.21 0747 'H-NMR (d-DMSO): & 1.08 (6H, d, J=7.5 Hz), (1H, d, J=7.5 Hz), 8.55 (1H, s), 8.71 (1H, d, J–3.9 Hz), 11.73 2.56 (3H, s), 3.40-3.50 (2H, m), 3.50-3.55 (2H, m), 3.55-3.65 (1H, s). (1H, m), 7.45 (1H, d, J=8.1 Hz), 8.05-8.15 (1H, m), 8.30 (1H, s), 8.30-8.40 (1H, m), 8.92 (1H, s), 10.67 (1H, s), 13.31 (1H, Example 476 S). N-(3-(((3-hydroxy-3-methylbutyl)amino)carbonyl)- Example 479 1H-pyrazol-4-yl)pyridine-2-carboxamide 6-methyl-N-(1-(tetrahydro-2H-pyran-2-yl)-3-(((2.2, 0742 A mixture of N-(3-(((3-hydroxy-3-methylbutyl) 2-trifluoroethyl)amino)carbonyl)-1H-pyrazol-4-yl) amino)carbonyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol pyridine-3-carboxamide 4-yl)pyridine-2-carboxamide obtained in Example 475 (0.60 0748. To the solution 4-(((6-methylpyridin-3-yl)carbonyl) g, 1.49 mmol), p-toluenesulfonic acid monohydrate (0.57 g. amino)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-car US 2009/0156582 A1 Jun. 18, 2009 77 boxylic acid obtained in Reference Example 56 (0.66 g, 2.0 3.70 (2H, q, J=6.3 Hz), 4.00-4.15 (1H, m), 5.30-5.40 (1H, m), mmol) and 2.2.2-trifluoroethylamine (0.19 ml, 2.4 mmol) in 7.05-7.20 (1H, m), 7.26 (1H, d, J=8.1 Hz), 8.07 (1H, dd, DMF (10 ml), WSC (0.41 g, 2.4 mmol) and HOBt (0.32g, 2.4 J=8.1, 2.3 Hz), 8.50 (1H, s), 9.10 (1H, s), 10.42 (1H, s). mmol) were added, and the mixture was stirred at room temperature for 2.5 hr. Saturated aqueous sodium hydrogen Example 482 carbonate Solution was added to the reaction mixture, and the 6-methyl-N-(3-(((3,3,3-trifluoropropyl)amino)carbo mixture was extracted with ethyl acetate. The extract was nyl)-1H-pyrazol-4-yl)nicotinamide washed with water, dried over anhydrous magnesium Sulfate, passed through a small amount of silica gel and evaporated 0754. A mixture of 6-methyl-N-(1-(tetrahydro-2H-pyran under reduced pressure. Diethyl ether was added to the pre 2-yl)-3-(((3,3,3-trifluoropropyl)amino)carbonyl)-1H-pyra cipitated crystals, and the crystals were collected by filtration Zol-4-yl)nicotinamide obtained in Example 481 (0.41 g, 0.96 to give the title compound (0.51 g, yield 62%) as crystals. mmol), p-toluenesulfonic acid monohydrate (0.37 g, 1.93 melting point 132-133°C. mmol) and ethanol (20 ml) was stirred at 60° C. for 5 hr. 0749 H-NMR (CDC1): & 1.60- 1.80 (3H, m), 2.00-2.15 Saturated aqueous Sodium hydrogen carbonate Solution was (1H, m), 2.15-2.30 (1H, m), 2.64 (3H, s), 3.65-3.80 (1H, m), added to the reaction mixture, and the mixture was extracted 4.00-420 (2H, m), 5.37 (1H, dd, J=9.6, 2.7 Hz), 7.10-7.20 with ethyl acetate. The extract was washed with water, dried (1H, m), 7.26 (1H, d, J=6.3 Hz), 8.07 (1H, dd, J–8.4, 2.7 Hz), over anhydrous magnesium Sulfate, passed through a small 8.52 (1H, s), 9.09 (1H, d, J=2.7 Hz), 10.27(1H, s). amount of silica gel and concentrated under reduced pressure. Diethyl ether was added to the precipitated crystals, and the Example 480 crystals were collected by filtration to give the title compound 6-methyl-N-(3-(((2.2.2-trifluoroethyl)amino)carbo (0.30 g, yield 93%). melting point 196-197°C. nyl)-1H-pyrazol-4-yl)pyridine-3-carboxamide (0755 'H-NMR (d-DMSO): 8 2.56 (3H, s), 2.50-2.70 (2H, m), 3.53 (2H, q, J=5.4 Hz), 7.46 (1H, d, J–7.8 Hz), 8.09 0750 A mixture of 6-methyl-N-(1-(tetrahydro-2H-pyran (1H, d, J=7.5 Hz), 8.31 (1H, s), 8.70-8.80 (1H, m), 8.92 (1H, 2-yl)-3-(((2.2.2-trifluoroethyl)amino)carbonyl)-1H-pyrazol s), 10.61 (1H, s), 13.37 (1H, s). 4-yl)pyridine-3-carboxamide obtained in Example 479 (0.48 g, 1.17 mmol), p-toluenesulfonic acid monohydrate (0.44 g. Example 483 2.33 mmol) and ethanol (20 ml) was stirred at 60°C. for 5 hr. N-(3-(((2-cyanoethyl)amino)carbonyl)-1-(tetrahy The reaction mixture was concentrated under reduced pres dro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-6-methylpyri Sure. Saturated aqueous sodium hydrogen carbonate Solution was added, and the mixture was extracted with ethyl acetate. dine-3-carboxamide The extract was washed with water, dried over anhydrous 0756. To a solution of 4-(((6-methylpyridin-3-yl)carbo magnesium sulfate, and evaporated under reduced pressure. nyl)amino)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3- The residue was purified by silica gel column chromatogra carboxylic acid obtained in Reference Example 56 (0.66 g. phy (hexane:ethyl acetate=1:1-1:4) to give the title compound 2.0 mmol) and 3-aminopropionitrile (0.18 ml, 2.4 mmol) in (0.30 g, yield 79%). melting point 218-219°C. DMF (15 ml), WSC (0.41 g, 2.4 mmol) and HOBt (0.32g, 2.4 0751 H-NMR (d-DMSO): 8 2.57 (3H, s), 4.00-420 mmol) were added, and the mixture was stirred at room (2H, m), 7.46 (1H, d, J=7.8 Hz), 8.09 (1H, d, J=7.8 Hz), 8.34 temperature for 24 hr. Saturated aqueous Sodium hydrogen (1H, s), 8.92 (1H, s), 9.00-9.20 (1H, m), 10.41 (1H, s), 13.34 carbonate Solution was added to the reaction mixture, and the (1H, s). mixture was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, Example 481 passed through a small amount of silica gel and evaporated under reduced pressure. Diethyl ether was added to the pre 6-methyl-N-(1-(tetrahydro-2H-pyran-2-yl)-3-(((3.3, cipitated crystals, and the crystals were collected by filtration 3-trifluoropropyl)amino)carbonyl)-1H-pyrazol-4-yl) to give the title compound (0.60 g, yield 86%) as crystals. nicotinamide melting point 118-120° C. 0752 To a solution of 4-(((6-methylpyridin-3-yl)carbo (0757 'H-NMR (CDC1): & 1.55-1.80 (3H, m), 2.00-2.15 nyl)amino)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3- (2H, m), 2.15-2.30 (1H, m), 2.64 (3H, s), 2.74 (2H, t, J=6.6 carboxylic acid obtained in Reference Example 56 (0.50 g, HZ), 3.65-3.80 (3H, m), 4.00-4.15 (1H, m), 5.36 (1H, dd, 1.5 mmol) and 3,3,3-trifluoropropylamine hydrochloride J=9.3, 2.1 Hz), 7.26 (1H, d, J=7.5 Hz), 7.20-7.30 (1H, m), (0.22g, 1.5 mmol) in DMF (10 ml), WSC (0.31 g, 1.8 mmol), 8.07 (1H, dd, J=8.4, 2.7 Hz), 8.50 (1H, s), 9.09 (1H, d, J=2.7 HOBt (0.24 g, 1.8 mmol) and triethylamine (0.42 ml, 3.0 Hz), 10.34 (1H, s). mmol) were added, and the mixture was stirred at room temperature for 24 hr. Saturated aqueous Sodium hydrogen Example 484 carbonate Solution was added to the reaction mixture, and the N-(3-(((2-cyanoethyl)amino)carbonyl)-1H-pyrazol mixture was extracted with ethyl acetate. The extract was 4-yl)-6-methylpyridine-3-carboxamide washed with water, dried over anhydrous magnesium Sulfate, passed through a small amount of silica gel and evaporated 0758. A mixture of N-(3-(((2-cyanoethyl)amino)carbo under reduced pressure. Hexane-diethyl ether was added to nyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-6-me the precipitated crystals, and the crystals were collected by thylpyridine-3-carboxamide obtained in Example 483 (0.62 filtration to give the title compound (0.45 g, yield 71%) as g, 1.62 mmol), p-toluenesulfonic acid monohydrate (0.62g, crystals. melting point 147-148° C. 3.24 mmol) and ethanol (20 ml) was stirred at 60°C. for 8 hr. 0753 H-NMR (CDC1): & 1.60- 1.80 (3H, m), 2.00-2.15 The reaction mixture was concentrated under reduced pres (2H, m), 2.15-2.30 (1H, m), 2.40-2.60 (2H, m), 2.64 (3H, s), Sure. Saturated aqueous sodium hydrogen carbonate Solution US 2009/0156582 A1 Jun. 18, 2009

was added, and the mixture was extracted with ethyl acetate. boxylic acid obtained in Reference Example 59 (0.70g, 2.0 The extract was washed with water, dried over anhydrous mmol) and 3-aminopropionitrile (0.18 ml, 2.4 mmol) in DMF magnesium sulfate, and evaporated under reduced pressure. (10 ml), WSC (0.41 g, 2.4 mmol) and HOBt (0.32 g, 2.4 The residue was purified by silica gel column chromatogra mmol) were added, and the mixture was stirred at room phy (hexane:ethyl acetate=1:5-ethyl acetate) to give the title temperature for 24 hr. Saturated aqueous Sodium hydrogen compound (0.34g, yield 70%). melting point 201-203°C. carbonate Solution was added to the reaction mixture, and the 0759 H-NMR (d-DMSO): 8 2.56 (3H, s), 2.81 (2H, t, mixture was extracted with ethyl acetate. The extract was J=6.6 Hz), 3.53 (2H, q, J=6.1 Hz), 7.46 (1H, d, J–7.8 Hz), washed with water, dried over anhydrous magnesium sulfate, 8.05-8.15 (1H, m), 8.32 (1H, s), 8.78-8.90 (1H, m), 8.92 (1H, evaporated under reduced pressure, passed through a small s), 10.58 (1H, s), 13.37 (1H, s). amount of silica gel and evaporated under reduced pressure to give the title compound (0.58 g, yield 72%) as crystals. melt Example 485 ing point 218-219°C. N-(3-(((2-hydroxyethyl)amino)carbonyl)-1-(tetrahy 0765 'H-NMR (CDC1): & 1.60-1.95 (3H, m), 2.00-2.15 dro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-6-methylnico (2H, m), 2.15-2.30 (1H, m), 2.75 (2H, t, J=6.5 Hz), 3.75 (2H, tinamide qJ=6.6Hz), 3.70-3.80 (1H, m), 4.00-4.15 (1H, m), 5.35-5.40 0760. To a solution of 4-(((6-methylpyridin-3-yl)carbo (1H, m), 7.20-7.35 (1H, m), 7.40-7.50 (1H, m), 8.22 (1H, s), nyl)amino)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3- 8.55 (1H, s), 8.62 (1H, d. J=5.1 Hz), 11.51 (1H, s). carboxylic acid obtained in Reference Example 56 (0.66 g. 2.0 mmol) and 2-aminoethanol (0.14 ml, 2.4 mmol) in DMF Example 488 (10 ml), WSC (0.41 g, 2.4 mmol) and HOBt (0.32 g, 2.4 4-chloro-N-(3-(((2-cyanoethyl)amino)carbonyl)-1H mmol) were added, and the mixture was stirred at room pyrazol-4-yl)pyridine-2-carboxamide temperature for 5 hr. Saturated aqueous sodium hydrogen carbonate Solution was added to the reaction mixture, and the 0766. A mixture of 4-chloro-N-(3-(((2-cyanoethyl) mixture was extracted with ethyl acetate. The extract was amino)carbonyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol washed with water, dried over anhydrous magnesium Sulfate, 4-yl)-pyridine-2-carboxamide obtained in Example 487 passed through a small amount of silica gel and evaporated (0.55 g, 1.37 mmol), p-toluenesulfonic acid monohydrate under reduced pressure. Diethyl ether was added to the pre (0.52g, 2.74 mmol) and ethanol (20 ml) was stirred at 60°C. cipitated crystals, and the crystals were collected by filtration for 8 hr. The reaction mixture was concentrated under to give the title compound (0.70 g, yield 94%) as crystals. reduced pressure. Saturated aqueous sodium hydrogen car melting point 140-140°C. bonate Solution was added, and the mixture was extracted 0761 H-NMR (CDC1): & 1.60- 1.80 (3H, m), 2.00-2.15 with ethyl acetate. The extract was washed with water, dried (2H, m), 2.15-2.30 (1H, m), 2.64 (3H, s), 3.62 (2H, q, J=5.1 over anhydrous magnesium Sulfate, passed through a small HZ), 3.65-4.80 (1H, m), 3.80-3.90 (1H, m), 4.00-4.10 (1H, amount of silica gel and evaporated under reduced pressure. m), 5.35 (1H, d, J=9.3 Hz), 7.20-7.40 (2H, m), 8.00-8.10 (1H, The precipitated crystals were recrystallized from ethanol to m), 8.49 (1H, s), 9.09 (1H, s), 10.48 (1H, s). give the title compound (0.40 g, yield 92%). melting point 261-263° C. Example 486 0767 H-NMR (d-DMSO): 82.81 (2H, t, J–7.2 Hz), 3.53 N-(3-(((2-hydroxyethyl)amino)carbonyl)-1H-pyra (2H, q, J–7.2 Hz), 7.85 (1H, d, J=5.1 Hz), 8.14 (1H, s), 8.42 Zol-4-yl)-6-methylnicotinamide (1H, s), 8.74 (1H, t, J=6.6 Hz), 8.75-8.85 (1H, m), 11.56 (1H, 0762. A mixture of N-(3-(((2-hydroxyethyl)amino)carbo s), 13.40 (1H, s). nyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-6-me thylnicotinamide obtained in Example 485 (0.65 g, 1.74 Example 489 mmol), p-toluenesulfonic acid monohydrate (0.66 g, 3.48 mmol) and ethanol (20 ml) was stirred at 60° C. for 6 hr. N-(2-cyanoethyl)-4-(4-methoxybenzoylamino)-1H Saturated aqueous Sodium hydrogen carbonate solution was pyrazole-3-carboxamide added to the reaction mixture, and the mixture was extracted 0768. In the same manner as in Example 401, the title with ethyl acetate. The extract was washed with water, dried compound was obtained using N-(2-cyanoethyl)-4-(4-meth over anhydrous magnesium Sulfate, passed through a small oxybenzoylamino)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyra amount of silica geland concentrated under reduced pressure. The precipitated crystals were recrystallized from ethyl Zole-3-carboxamide obtained in Example 410. yield 75%. acetate to give the title compound (0.39 g, yield 77%). melt melting point 199-200° C. (ethyl acetate-hexane). ing point 233-235° C. 0769 'H-NMR (CDC1): 8 2.81 (2H, t, J=6.6 Hz), 3.54 0763 'H-NMR (d-DMSO): 8 2.56 (3H, s), 3.36 (2H, q, (2H, q, J=6.6 Hz), 3.85 (3H, s), 7.12 (2H, d, J=9.1 Hz), 7.84 J=6.0 Hz), 3.52 (2H, q, J=5.4 Hz), 4.75-4.85 (1H, m), 7.46 (2H, d, J=9.1 Hz), 8.31 (1H, s), 8.83 (1H, t, J=6.0 Hz), 10.54 (1H, d, J–7.8 Hz), 8.09 (1H, d, J–8.1 Hz), 8.30 (1H, s), (1H, s), 13.36 (1H, s). 8.30-8.40 (1H, m), 8.91 (1H, s), 10.71 (1H, s), 13.31 (1H, s). Example 490 Example 487 N-(2-cyanoethyl)-1-(tetrahydro-2H-pyran-2-yl)-4- 4-chloro-N-(3-(((2-cyanoethyl)amino)carbonyl)-1- ((4-(trifluoromethyl)benzoyl)amino)-1H-pyrazole-3- (tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-pyri carboxamide dine-2-carboxamide 0764. To a solution of 4-(((4-chloropyridin-2-yl)carbonyl) 0770. In the same manner as in Example 402, the title amino)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-car compound was obtained using 4-amino-N-(2-cyanoethyl)-1-

US 2009/0156582 A1 Jun. 18, 2009 84

0808 PCR was done according to the protocol attached to TABLE 6-12-continued KOD plus DNA polymerase (Toyo Boseki Kabushiki Kai sha). The obtained PCR product was electrophoresed on aga Ex. R1 R2 R3 X R4 RS R6 rose gel (1%), and 1.2kb of DNA fragment including GSK3f 492 NCCH2CH2 H H CO 4-CF3P H H gene was collected from the gel and then digested with 493 NCCH2CH2 H H CO 3-CF3Ph H H restriction enzymes EcoRI and Sal I. The restriction enzyme 494 NCCH2CH2 H H CO 5-Br-2-furyl THP H treated DNA was electrophoresed on agarose gel (1%). The 495 NCCH2CH2 H H CO 5-Me-2-furyl THP H 496 NCCH2CH2 H H CO 5-Br-2-furyl H H obtained DNA fragment was collected, and ligated to the 497 NCCH2CH2 H H CO 5-Me-2-furyl H H plasmid pFASTBAC 1 (Invitrogen), which had been digested 498 NCCH2CH2 H H CO 3-AcPh THP H with restriction enzyme EcoRI and Sal I, to produce expres sion plasmid pFB-GSK3B. The base sequence of insertion fragment was confirmed to find that it corresponded to the 499 NCCH2CH2 H H CO CO? THP H objective sequence. In addition, virus stock BAC-GSK3B of O recombinant Baculovirus was prepared using BAC-TO-BAC Baculovirus Expression System (Invitrogen). SOO NCCH2CH2 H H CO 3-furyl THP H SO1 NCCH2CH2 H H CO 3-AcPh H H Preparation of Recombinant GSK3f Enzyme (0809. Sf21 cells (Invitrogen) were seeded on Sf-900 II SO2 NCCH2CH2 H H CO CO? H H SFM medium (Invitrogen) (150 ml) containing 10% fetal calf O serum at 1x10° cells/ml, and cultured at 27°C. for 24hr. The virus stock BAC-IKKB obtained above of recombinant Bacu SO3 NCCH2CH2 H H CO 3-furyl H H lovirus was added by 150 ul to the obtained culture medium, and the cells were cultured for another 60 hr. The culture medium was centrifuged (3000 rpm, 10 min) to separate the cells, and the cells were washed once with PBS. The cells TABLE 6-13 were suspended in 10 ml of cell lysis buffer (25 mM HEPES Ex. R1 R2 R3 X R4 RS R6 (pH 7.5), 1% Triton X, 130 mM sodium chloride, 1 mM EDTA, 1 mM Dithiothreitol, 25 mM f-glycerophosphate, SO4 NCCH2CH2 H H CO 5-Ph-2-furyl THP H Protease inhibitor Complete (Boehringer), 1 mM Sodium SOS NCCH2CH2 H H CO / THP H orthovanadate), treated 4 times using a homogenizer (POLY TRON) at 20000 rpm for 30 sec to disrupt the cells. The disrupted solution of cells was centrifuged (40000 rpm, 45 c min.), and GSK3? was purified from the obtained supernatant using Anti-FLAG M2 Affinity Gel (Sigma Ltd.). SO6 NCCH2CH2 H H CO / H H c b) Experimental Method Measurement of GSK3f Inhibitory Activity SO7 NCCH2CH2 H H CO 5-Ph-2-furyl H H 0810. To a reaction solution (25 mM HEPES (pH 7.5), 10 mM magnesium acetate, 1 mM DTT, 0.01% bovine serum albumin (Wako Pure Chemical Industries, Ltd.)) (37.5 ul) Experimental Example 1 containing recombinant GSK3f enzyme (100 ng) obtained above and a matrix peptide from glycogen synthase (YR a) Test Material RAAVPPSPSLSRHSSPHQpSEDEEE (SEQ ID NO:3), pS shows phosphorylated serine) (100 ng) was added a test com Cloning of Human GSK3f Gene and Preparation of Recom pound (2.5 ul) dissolved in DMSO, and the mixture was binant Baculovirus incubated at room temperature for 5 min. 10 ul of ATP solu (0807 Human GSK3 Bgene was cloned by a PCR method tion (2.5uMATP) was added to the obtained mixture, and the using a primer set: mixture was reacted at room temperature for 30 min. Kinase Glo Reagent (Promega) (50 ul) was added to the reaction Solution to stop the reaction. After reaction at room tempera GSK3b-U: ture for 10 min, the luminescent intensity was measured using (SEQ ID NO: 1) ARVO multilabel counter (PerkinElmer Life Sciences). The 5'-AAAGAATTCACCATGGACTACAAGGACGACGATGACAAGTCAGGGCG concentrations of the test compounds needed for 50% inhi GCCCAGAACCACCTCCTT-3' bition of luminescent intensity (ICso value) were calculated and by PRISM3.0 (GraphPad Software). The results are shown in Table 7. GSK3b-L: (SEQ ID NO: 2) 5'-AAAAGTCGACT CAGGTGGAGTTGGAAGCTGATGCAGAAG-3' TABLE 7 prepared using human brain cDNA (Clontech; trade name: Ex. No. IC50 (nM) QUICK-Clone cDNA) as a template and in reference to the OO1 267 base sequence of GSK3 gene registered in GenBank under OO3 &1OO Accession Number NM 002093.

US 2009/0156582 A1 Jun. 18, 2009 86

TABLE 7-continued TABLE 8 Ex. No. IC50 (nM) Example number IC50 value (nM) 395 &100 79 70 397 &100 98 440 399 &100 401 &100 411 &100 412 &100 Experimental Example 3 413 &100 414 &100 Measurement of Sugar Release Suppressive Action 415 &100 Using Cultured Hepatocyte 416 &100 417 &100 0812 H4IIE-C3 cells (from rat liver) were seeded on 24 418 &100 420 &100 well or 96 well collagen coated plate (manufactured by Fal 422 &100 con), and cultured in Dulbecco's Modified Eagle Medium 424 &100 (DMEM: manufactured by GIBCO) containing 10% FBS, 25 426 &100 mM Glucose until the cells became sub-confluent. Then, the 428 &100 cells were starvation treated with DMEM containing 0% FBS and 5.6 mM glucose. The medium was exchanged to DMEM containing test compound adjusted to 10 LM and Sugar pro Experimental Example 2 duction stimulant (Dexamethasone (500 nM), 8CPT-cAMP (0.1 mM)), and the cells were pretreated for 5 hr. After wash Measurement of Nerve Cell Death Suppressive ing with PBS, the cells were cultured in Phenol Red-free, Activity Glucose-free DMEM containing the test compound and sugar production stimulant for 3 hr, and the glucose content released in the medium was measured. A glucose measure 0811. The cerebral cortex was taken from fetus of TP-14 ment kit (A-22 189) manufactured by Molecular Probes was pregnant SD rat (CLEA Japan, Inc.), and nerve cell was used for the glucose measurement. The obtained results of prepared using nerve cell culture system (SUMITOMO Sugar release suppression activity are shown in the following. BAKELITE). The cerebral cortex was placed in enzymatic The Sugar release Suppressive activity is shown in a relative solution of cell dispersion solution kit (SUMITOMO value when the released glucose content of a GSK3? inhibitor BAKELITE), and incubated at 37° C. for 30 min. The cells free group is 100%. were suspended by pipetting, and collected by centrifugation at 1000 rpm for 5 min. The supernatant was removed, and cell dispersion solution (SUMITOMO BAKELITE) was added. The cells were suspended by pipetting. The cell Suspension Example 387 69% Example 412 74% was placed on removing solution (SUMITOMO Example 413 64% BAKELITE), and the cells were collected by centrifugation Example 416 62% at 1000 rpm for 5 min. The supernatant was removed, and the Example 420 62% cells were suspended in nerve cell culture medium (SUMI Example 426 55% Example 430 76% TOMOBAKELITE). 100 ul of the suspension was seeded on Example 455 79% a poly D lysinelaminin 96 well plate (Becton, Dickinson and Example 470 75% Company) at 1x10 cells/well. Then, the plate was cultured in Example 480 69% a carbon dioxide gas incubator at 37° C. for 4 days. A test compound (50 ul) was added on the 96 well plate, and 50 uL/well of LY294.002 was added at 50 uM of the final con INDUSTRIAL APPLICABILITY centration. Then, the plate was cultured in a carbon dioxide gas incubator for 24hr. The medium (100 ul) was sampled, 0813 The pyrazole compound of the present invention is and 100 ul of Cell Titer Glo solution (Promega) was added to useful as an agent for the prophylaxis or treatment of GSK-3? count the viable cell number. The concentration of the test related pathology or disease. compound needed for 50% inhibition of nerve cell death 0814. This application is based on application Nos. 2005 (ICs value) was calculated by PRISM 3.0 (GraphPad Soft 033356 and 2005-370962 filed in Japan, the contents of ware). The results are shown in Table 8. which are incorporated hereinto by reference.

SEQUENCE LISTING

<16 Oc NUMBER OF SEO ID NOS: 3

SEO ID NO 1 LENGTH: 65 TYPE: DNA ORGANISM: Artificial

US 2009/0156582 A1 Jun. 18, 2009

18) N,N-dimethyl-5-(4-chloromethyl-2,5-dioxo-2,5-dihy (5) cyano group; dro-1H-pyrrol-3-ylamino)-4-methanesulfonylamino-1-me (7) mono- or di-C alkyl-amino group; thyl-1H-pyrazole-3-carboxamide. (8) mono- or di-Caryl-amino group; 2. The compound of claim 1, wherein the compound rep (9) mono- or di-Czaralkyl-amino group: resented by the formula (Io) is a compound represented by the (10) N-Cl alkyl-N-Cl aryl-amino group; formula: (11) N-Cl alkyl-N-(C. alkyl-C aryl)-amino group; (12) N-Cl alkyl-N-C-7-caralkyl-amino group; (I) (14) optionally halogenated Calkoxy group: RI O R3 R4 V V M (15) C. alkylthio group optionally substituted by C. N N-X alkoxy group; A (18) optionally esterified carboxyl group; R2 (19) carbamoyl group; NS A (20) thiocarbamoyl group; (21) mono- or di-C alkyl-carbamoyl group; (22) mono- or di-Caryl-carbamoyl group; wherein (23) mono- or di-5- to 7-membered heterocycle-carbamoyl R" is an optionally substituted hydrocarbon group or an group; optionally substituted heterocyclic group, (24) C. alkyl-carbonylamino group optionally substi R is a hydrogen atom or an optionally substituted hydro tuted by carboxyl group; carbon group, or (25) Caryloxy group optionally substituted by 1 to 3 R" and R form, together with the adjacent nitrogenatom, Substituents selected from halogen atom, hydroxy an optionally Substituted nitrogen-containing hetero group, amino group, nitro group, cyano group, option cycle; ally halogenated C. alkyl group, mono- or di-C R is a hydrogen atom or an optionally substituted hydro alkyl-amino group, C-14 aryl group, mono- or di-Ca carbon group; aryl-amino group, C.s cycloalkyl group, Ce alkoxy R" is an optionally substituted hydrocarbon group, an group, C- alkoxy-C alkoxy group, Co alkylthio optionally substituted heterocyclic group, group, Ce alkylsulfinyl group, Ce alkylsulfonyl an optionally substituted hydroxy group, or an optionally group, an optionally esterified carboxyl group, carbam Substituted amino group; oyl group, thiocarbamoyl group, mono- or di-C alkyl ring A is a pyrazole ring represented by the formula: carbamoyl group, mono- or di-C aryl-carbamoyl group, Sulfamoyl group, mono- or di-C alkyl-sulfa moyl group and mono- or di-Caryl-sulfamoyl group: (27) heterocyclic oxy group optionally substituted by 1 to 3 Substituents selected from halogen atom, hydroxy group, amino group, nitro group, cyano group, option ally halogenated C. alkyl group, mono- or di-C alkyl-amino group, Caryl group, mono- or di-Ca aryl-amino group, Css cycloalkyl group, Co alkoxy group, C alkoxy-C alkoxy group, Ce alkylthio group, Ce alkylsulfinyl group, Ce alkylsulfonyl wherein R is a hydrogen atom, an optionally substituted group, an optionally esterified carboxyl group, carbam hydrocarbon group or an optionally Substituted acyl oyl group, thiocarbamoyl group, mono- or di-C alkyl group; and R is a hydrogen atom or an optionally sub carbamoyl group, mono- or di-C aryl-carbamoyl stituted hydrocarbon group; and group, sulfamoyl group, mono- or di-C alkyl-sulfa X is a carbonyl group or a sulfonyl group. moyl group and mono- or di-Caryl-sulfamoyl group; 3. The compound of claim 2, wherein R is a hydrogen (31) a C-caralkyloxy group optionally substituted by 1 to atOm. 3 Substituents selected from halogen atom, hydroxy 4. The compound of claim 2, wherein R' is a C- alkyl group, amino group, nitro group, cyano group, option group, a C- alkenyl group or a C- alkynyl group, which is ally halogenated C. alkyl group, mono- or di-C optionally substituted by 1 to 5 substituents selected from alkyl-amino group, C-14 aryl group, mono- or di-Ca halogen atom, optionally Substituted hydroxy group, option aryl-amino group, C.s cycloalkyl group, Ce alkoxy ally substituted thio group, optionally substituted sulfinyl group, C- alkoxy-C alkoxy group, Co alkylthio group, optionally substituted Sulfonyl group, optionally Sub group, Ce alkylsulfinyl group, Ce alkylsulfonyl stituted amino group, nitro group, cyano group, and option group, an optionally esterified carboxyl group, carbam ally Substituted carbonyl group. oyl group, thiocarbamoyl group, mono- or di-C alkyl 5. The compound of claim 2, wherein R' is a C- alkyl carbamoyl group, mono- or di-C aryl-carbamoyl group, a C2-alkenyl group, or a C2-alkynyl group optionally group, Sulfamoyl group, mono- or di-C alkyl-sulfa having, at Substitutable positions, 1 to 5 substituents selected moyl group and mono- or di-Caryl-sulfamoyl group: from (32) C. alkylsulfonyloxy group; (1) halogen atom; (33) tri-C alkyl-silyloxy group; (2) hydroxy group; (34) nitrogen-containing heterocycle-carbonyl group; (3) amino group; (35) Caryl-carbonyl group; (4) nitro group; (36) Caryl-thio group; US 2009/0156582 A1 Jun. 18, 2009 89

(37) optionally halogenated Caryl-sulfonyl group; (31) C7-caralkyloxy group optionally Substituted by 1 to 3 (38) nitrogen-containing heterocycle-Sulfonyl group; and Substituents selected from halogen atom, hydroxy (39) nitrogen-containing heterocycle-amino group option- group, amino group, nitro group, cyano group, option ally Substituted by cyano group. ally halogenated C. alkyl group, mono- or di-C 6. The compound of claim 2, wherein R' is a C- alkyl alkyl-amino group, C-14 aryl group, mono- or di-Ca group optionally substituted by 1 to 5 substituents selected aryl-amino group, C.s cycloalkyl group, Ce alkoxy from halogen atom, optionally Substituted hydroxy group, group, C- alkoxy-C alkoxy group, Co alkylthio optionally substituted thio group, optionally Substituted group, Ce alkylsulfinyl group, Ce alkylsulfonyl amino group, nitro group, cyano group, and optionally Sub- group, an optionally esterified carboxyl group, carbam stituted carbonyl group. oyl group, thiocarbamoyl group, mono- or di-C alkyl 7. The compound of claim 2 wherein R' is a C alkyl carbamoyl group, mono- or di-C aryl-carbamoyl group optionally having, at Substitutable positions, 1 to 5 group, Sulfamoyl group, mono- or di-C alkyl-sulfa substituents selected from moyl group and mono- or di-Caryl-sulfamoyl group: (1) halogen atom; (32) C. alkylsulfonyloxy group; (2) hydroxy group; (33) tri-C alkyl-silyloxy group; (3) amino group; (34) nitrogen-containing heterocycle-carbonyl group; (4) nitro group; (35) Caryl-carbonyl group; (5) cyano group; (36) Caryl-thio group: (7) mono- or di-C alkyl-amino group; (37) optionally halogenated Caryl-sulfonyl group; (8) mono- or di-Caryl-amino group; (38) nitrogen-containing heterocycle-Sulfonyl group; and (9) mono- or di-C7-caralkyl-amino group; (39) nitrogen-containing heterocycle-amino group option (10) N-Cl alkyl-N-Cl aryl-amino group; ally Substituted by cyano group. (11) N-Cl alkyl-N-(C. alkyl-C aryl)-amino 8. The compound of claim 2, wherein R is a hydrogen group; atOm. (12) N-Cl alkyl-N-C-7 aralkyl-amino group: 9. The compound of claim 2, wherein R is an optionally (14) optionally halogenated C 16 alkoxy group; Substituted Caryl group or an optionally Substituted het (15) C. alkylthio group optionally substituted by C. erocyclic group. alkoxy group; 10. The compound of claim 2, wherein R is a hydrogen (18) optionally esterified carboxyl group; atOm. (19) carbamoyl group; 11. The compound of claim 2, wherein R is a hydrogen (20) thiocarbamoyl group; atOm. (21) mono- or di-C alkyl-carbamoyl group; 12. The compound of claim 2, wherein R and R are (22) mono- or di-Caryl-carbamoyl group; hydrogen atoms. 13. The compound of claim 2, wherein X is a carbonyl (23) mono- or di-5- to 7-membered heterocycle-carbamoyl group. group; - 0 (24) C. alkyl-carbonylamino group optionally substi- following:14. The compound of claim 2, which is selected from the tuted by carboxyl group; N-(3-(((2-cyanoethyl)amino)carbonyl)-1H-pyrazol-4-yl) (25) Caryloxy group optionally substituted by 1 to 3 pyridine-2-carboxamide; Substituents selected from halogen atom, hydroxy group, amino group, nitro group, cyano group, option N-(3-(((2-cyanoethyl)amino)carbonyl)-1H-pyrazol-4-yl)- ally halogenated C. alkyl group, mono- or di-C 6-methylpyridine-2-carboxamide; alkyl-amino group, C-14 aryl group, mono- or di-Ca N-(3-(((3,3,3-trifluoropropyl)amino)carbonyl)-1H-pyra aryl-amino group, Css cycloalkyl group, Co alkoxy Zol-4-yl)pyridine-2-carboxamide; group, C- alkoxy-C alkoxy group, Co alkylthio 4-(benzoylamino)-N-(2-cyanoethyl)-1H-pyrazole-3-car group, Ce alkylsulfinyl group, Ce alkylsulfonyl boxamide; group, an optionally esterified carboxyl group, carbam N-(3-(((3-isopropoxypropyl)amino)carbonyl)-1H-pyra oyl group, thiocarbamoyl group, mono- or di-C alkyl Zol-4-yl)-6-methylpyridine-2-carboxamide; carbamoyl group, mono- or di-C aryl-carbamoyl N-(2-cyanoethyl)-4-(2-furoylamino)-1H-pyrazole-3-car group, Sulfamoyl group, mono- or di-C alkyl-sulfa boxamide: moyl group and mono- or di-Caryl-sulfamoyl group; N-(3-(((3-hydroxypropyl)amino)carbonyl)-1H-pyrazol (27) heterocyclic oxy group optionally substituted by 1 to 4-yl)pyridine-2-carboxamide: 3 Substituents selected from halogen atom, hydroxy N-(3-(((2-isopropoxyethyl)amino)carbonyl)-1H-pyrazol group, amino group, nitro group, cyano group, option 4-yl)-6-methylnicotinamide; ally halogenated C. alkyl group, mono- or di-C 6-methyl-N-(3-(((2.2.2-trifluoroethyl)amino)carbonyl)- alkyl-amino group, C-14 aryl group, mono- or di-Ca 1H-pyrazol-4-yl)pyridine-3-carboxamide; and aryl-amino group, Css cycloalkyl group, Co alkoxy N-(3-(((2-cyanoethyl)amino)carbonyl)-1H-pyrazol-4-yl)- group, C- alkoxy-C alkoxy group, Co alkylthio 6-methylpyridine-3-carboxamide. group, C alkylsulfinyl group, C alkylsulfonyl 15. A prodrug of the compound of claim 1. group, an optionally esterified carboxyl group, carbam- 16. A pharmaceutical agent comprising the compound of oyl group, thiocarbamoyl group, mono- or di-C alkyl- claim 1. carbamoyl group, mono- or di-C aryl-carbamoyl 17. A GSK-3? inhibitor comprising the compound of claim group, Sulfamoyl group, mono- or di-C alkyl-sulfa- 1. moyl group and mono- or di-Ca-aryl-sulfamoyl 18. A neural stem cell differentiation promoter comprising group; the GSK-3 B inhibitor of claim 17. US 2009/0156582 A1 Jun. 18, 2009 90

19. An agent for the prophylaxis or treatment of neurode wherein generative disease or diabetes, which comprises the com ring A is a pyrazole ring optionally further having 1 or 2 pound of claim 1. Substituents; 20. A hypoglycemic agent comprising the compound of R" is substituted carbamoyl; and claim 1. 21. A GSK-3? inhibitor comprising a compound repre R’ is optionally substituted acylamino, sented by the formula: or a salt thereof or a prodrug thereof to a subject. 27. A method of preventing or treating a neurodegenerative (Io) disease or diabetes comprising administering a compound Ra Rb represented by the formula:

Ny. (Io) N Ra Rb wherein ring A is a pyrazole ring optionally further having 1 or 2 Substituents; R" is substituted carbamoyl; and R’ is optionally substituted acylamino, or a salt thereof or a prodrug thereof. wherein 22. A neural stem cell differentiation promoter comprising ring A is a pyrazole ring optionally further having 1 or 2 the GSK-3 B inhibitor of claim 21. Substituents; 23. An agent for the prophylaxis or treatment of neurode R" is substituted carbamoyl; and generative disease or diabetes comprising the GSK-3? inhibi tor of claim 21. R’ is optionally substituted acylamino, 24. A hypoglycemic agent comprising the GSK-3B inhibi or a salt thereof or a prodrug thereof to a subject. tor of claim 21. 28. A method of lowering blood glucose comprising 25. A method of inhibiting GSK-3? comprising adminis administering a compound represented by the formula: tering a compound represented by the formula: (Io) (Io) Ra Rb Ra Rb

NNA0 N wherein wherein ring Ao is a pyrazole ring optionally further having 1 or 2 ring Ao is a pyrazole ring optionally further having 1 or 2 Substituents; Substituents; R" is substituted carbamoyl; and R" is substituted carbamoyl; and R’ is optionally substituted acylamino, R’ is optionally substituted acylamino, or a salt thereof or a prodrug thereof to a subject. or a salt thereof or a prodrug thereof to a subject. 26. A method of promoting neural stem cell differentiation 29-32. (canceled) comprising administering a compound represented by the 33. A pharmaceutical agent comprising the prodrug of formula: claim 15. 34. A GSK-3? inhibitor comprising the prodrug of claim (Io) 15. Ra Rb 35. An agent for the prophylaxis or treatment of neurode generative disease or diabetes which comprises the prodrug of claim 15. 36. A hypoglycemic agent comprising the prodrug of claim 15.