US 20070 197510A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2007/0197510 A1 Ohmoto et al. (43) Pub. Date: Aug. 23, 2007

(54) NITRILES AND MEDICINAL C07D 49/02 (2006.01) COMPOSITIONS CONTAINING THE SAME C07D 487/02 (2006.01) AS THE ACTIVE INGREDIENT C07D 473/02 (2006.01) A6II 3/428 (2006.01) (76) Inventors: Kazuyuki Ohmoto, Mishima-gun (JP); A6II 3/423 (2006.01) Katsuya Hisaichi, Mishima-gun (JP); (52) U.S. Cl...... 514/221; 514/262.1; 514/229.2: Motohiro Okuma, Mishima-gun (JP); 514/259.1: 514/246; 514/367; Makoto Tanaka, Mishima-gun (JP); 514/260.1; 514/258.1: 514/375; Naoki Kawada, Mishima-gun (JP) 514/263.1; 540/562; 544/66; 544/180: 544/262: 544/263; Correspondence Address: 544/256; 544/278; 544/279; SUGHRUE MION, PLLC 548/152; 548/217 2100 PENNSYLVANIA AVENUE, N.W. SUTE 8OO WASHINGTON, DC 20037 (US) (57) ABSTRACT (21) Appl. No.: 10/592,117 The present invention relates to a compound of formula (I) (22) PCT Filed: Mar. 9, 2005

(I) (86). PCT No.: PCT/UP05/04580 S 371(c)(1), (2), (4) Date: Sep. 8, 2006 (30) Foreign Application Priority Data wherein Y and Z each is independently N or C; ring A is a Mar. 10, 2004 (JP)...... 2004-68.212 carbocyclic group or a heterocyclic group; ring B is a heterocyclic group containing at least one nitrogen atom; R Publication Classification is a hydrogen atom, a Substitutent, etc., n is 0, or an integer of from 1 to 10, a salt thereof, a solvate thereof, or an (51) Int. Cl. N-oxide thereof, or a prodrug thereof. The compound of A61K 3I/5513 (2006.01) formula (I), a salt thereof, a solvate thereof, or an N-oxide A61K 31/5383 (2006.01) thereof, or a prodrug thereof has an inhibitory activity A6 IK 3/52 (2006.01) against cysteine protease, and it is useful for the prophylaxis A 6LX 3/59 (2006.01) and/or treatment of a cysteine protease-related disease Such A6 IK 3/53 (2006.01) as osteoporosis, etc. US 2007/019751.0 A1 Aug. 23, 2007

NITRILES AND MEDICINAL COMPOSITIONS tis etc.) and hepatitis C etc.), cancer, collagenosis (systemic CONTAINING THE SAME AS THE ACTIVE lupus erythematosus, rheumatoid arthritis, etc.), autoim INGREDIENT mune diseases (inflammatory bowel diseases, Sjoegren Syn drome, primary biliary cirrhosis, spontaneous thrombocy TECHNICAL FIELD topenic purpura, autoimmune hemolytic anemia, myasthenia 0001. The present invention relates to nitrile derivatives gravis, insulin dependent (type-I) diabetes, etc.), diseases which are useful for the treatment of bone diseases such as accompanied by thrombocytopenia (osteomyelodysplasia osteoporosis, a method for the preparation thereof and use syndrome, periodic thrombocytopenia, aplastic anemia, thereof. spontaneous thrombocytopenia, disseminated intravascular coagulation (DIC), etc.), hepatic diseases such as viral BACKGROUND OF ART hepatitis (C, A, B, F, etc.) or hepatitis medicamentosa and cirrhosis, dementia (Alzheimer's disease, Alzheimer's senile 0002 Cysteine protease is a generic name of proteases dementia, etc.), cerebrovascular injury, nerve degeneration which have a cysteine residue in the activity center and diseases, adult acute respiratory distress syndrome, infec catalyze protein degradation thereat. In animal cells, many tious diseases, prostate hypertrophy, hysteromyoma, bron cysteine proteases are known; for example, cathepsin family, chial asthma, arteriosclerosis, all kinds of lusus naturae, calpain, caspase, etc. Cysteine protease exists in various nephropathy, senile cataract, chronic fatigue syndrome, kinds of cells extensively and plays a basic and essential role myodystrophy, peripheral neuropathy, etc. in the homeostasis, such as conversion of precursor protein into its active form (processing) and degradation of proteins 0005 Moreover, caspase-1 is concerned with various which have become out of use, etc. Until now, its physi inflammatory diseases and those diseases caused by immune ological effects are being vigorously studied, and as the disorders, by means of interleukin-13 (IL-1B) production. A studies progress and characters of the enzymes are revealed, lot of diseases are shown to be involved with caspase-1; for cysteine proteases came to be taken as a cause of really example, inflammatory bowel diseases such as ulcerative colitis, inflammatory diseases and autoimmune disease various kinds of diseases. (insulin-dependent (type-I) diabetes, autoimmune thyroid 0003. It is revealed that cathepsin S (see J. Immunol. diseases, infectious diseases, rejection of an organ trans 161,2731 (1998)), cathepsin L (see J. Exp. Med., 183, 1331 plant, graft versus host diseases, psoriasis, periodontitis (1996)) and cathepsin F (J. Exp. Med., 191, 1177 (2000)) (above, see N. Eng. J. Med., 328, 106 (1993)), pancreatitis play a role in processing of major histocompatibility com (see J. Interferon Cytokine Res., 17, 113 (1997)), hepatitis plex class-II in antigen presenting cells which play an (see J. Leuko. Biol. 58, 90 (1995)), glomerulonephritis (see important role in the early stage of immune responses. In an Kidney Int., 47, 1303 (1995)), endocarditis (see Infect. experimental inflammatory response model induced by anti Immun., 64, 1638 (1996)), myocarditis (see Br. Hearat J., gens, a specific inhibitor of cathepsin S showed an inhibitory 72, 561 (1995)), systemic lupus erythematosus (see Br. J. effect (see J. Clin. Invest., 101, 2351 (1998)). It is also Rheumatol., 34, 107 (1995)), Hashimoto's diseases (see reported that in a leishmania-infected immune response Autoimmunity, 16, 141 (1993)), etc.), etc. Experimentally, it model a cathepsin B inhibitor controlled an immune is reported that in liver injury model induced by lipopolysac response and by means of this effect it inhibited the prolif charide and D-galactosamine, a caspase-1 inhibitor eration of protozoans (see J. Immunol. 161, 2120 (1998)). improved the symptoms, and it is expected that a caspase In vitro, a result is given that a calpain inhibitor and a inhibitor shows an effect in Sepsis, ischemic reperfusion and cysteine protease inhibitor E-64 inhibited apoptosis which is hepatitis gravis (see Am. J. Respir. Crit. Care Med., 159, induced by stimuli on T cell receptors (see J. Exp. Med., 1308 (1999)). 178, 1693 (1993)). And cathepsin W, which is expressed in CD8 T cells and NK cells specifically, is known to increase 0006. It is also shown that cysteine protease is concerned its expression by stimuli of IL-2 by 7 times and so it is with rheumatoid arthritis. IL-1B is shown to be concerned conceived that it is concerned with immune responses (see with this disease (see Arthritis Rheum., 39, 1092 (1996)), J. Immunol. 167, 2172 (2001)). It is also reported that in and in addition, as autoantibody toward calpastatin (endog leukemia patients, gene expression of cathepsin C and enous calpain inhibitor) was found in the serum of the cathepsin W increase and cytotoxic T cells are activated (see patients (see Proc. Natl. Acad. Sci. USA, 92, 7267 (1995)), Int. J. Oncol., 22, 33 (2003)). Therefore, it is conceivable it is thought that increase of calpain activity leads to the that cysteine proteases are much concerned with the cause of diseases. Also, it is reported that cathepsin B and progress of immune responses. cathepsin C activity is increased in leukocyte of patients suffering from rheumatoid arthritis (see Biol. Chem., 383, 0004. It is speculated that caspase or a similar cysteine 865 (2002)). It is reported that in experimental arthritis protease thereto occupies an important position in the model the production of inflammatory cytokine is Sup mechanism of cell death including apoptosis. Therefore it is pressed and affection of arthritis completely in cathepsin C expected for a cysteine protease inhibitor to be used as an knock-out mice, So it is expected that cathepsin C inhibition agent for the prophylaxis and/or treatment of those diseases leads to treatment of rheumatoid arthritis (see J. Clin. concerning apoptosis, Such as infectious diseases, deterio Invest., 109,357 (2002)). ration or Sthenia of immune function and brain function, or tumors etc. Diseases concerning apoptosis include, acquired 0007. It is reported that cathepsin B plays a role in immune deficiency syndrome (AIDS), AIDS-related com decomposing muscular protein in the chronic phase of sepsis plex (ARC), adult T cell leukemia, hairy cell leukemia, (see J. Clin. Invest., 97, 1610 (1996)), and in decomposing spondylopathy, respiratory apparatus disorder, arthritis, muscular protein in myodystrophy model (see Biochem. J., virus-related diseases (HIV, HTLV-1 related diseases (uvei 288, 643 (1992)). At the same time it is reported that calpain US 2007/019751.0 A1 Aug. 23, 2007

decomposes the myocyte cell proteins of myodystrophy leukemia cells (see Clin. Lab. Haematol., 21, 173 (1999)) patients (see J. Biol. Chem., 270, 10909 (1995)). were inhibited by a caspase-1 inhibitor or its receptor 0008. In ischemic reperfusion model, a result is given antagonist, it is expected that caspase-I activity is essential that calpain causes degeneration of brain tissues by means of for the process of proliferation of tumor cells, and that an degradation of protein kinase C-B (see J. Neurochem., 72. inhibitor thereof is effective for these cancers. Also, from the 2556 (1999)) and that a cathepsin B inhibitor inhibits nerve facts that cathepsin B activity increased in colon cancer injury (see Eur. J. Neurosci., 10, 1723 (1998)). metastasis model (see Clin. Exp. Metastasis, 16, 159 (1998)), that cathepsin L activity increased in urine of 0009. In the brain ischemic model, it is known that the bladder cancer patients (see Urology, 59, 308 (2002)), that degradation of spectrin by calpain causes a damage and its cathepsin Z expression was recognized in tumor cells (see J. function disorder in the neurocyte (see Brain Res., 790, 1 (1998)) and it is reported that an IL-1B receptor antagonist Biol. Chem., 273, 16816 (1998)), that cathepsin K protein relieved the symptoms (see Brain Res. Bull., 29, 243 expression recognized in human breast cancer cells proved (1992)). the relationship of cathepsin K and bone metastasis (see Cancer Res., 57, 5386 (1997)), and that a calpain inhibitor 0010. In myocardial ischemic model it is confirmed that Suppressed migration of the cells, which implies that calpain cathepsin B activity increases in the lesion (see Biochem. inhibition might be able to inhibit metastasis of cancer (see Med. Metab. Biol. 45, 6 (1991)). J. Biochem..., 272,32719 (1997)), a cysteine protease inhibi 0011. In the experiment utilizing ischemic liver injury tor is expected to exhibit an inhibitory effect on the metasta model, it proved that necrosis and apoptosis of hepatocyte sis of various malignant tumors. were induced by means of protein-decomposing activity of calpain (see Gastroenterology, 116, 168 (1999)). 0018) As to AIDS (see AIDS, 10, 1349 (1996)) and AIDS-related complex (ARC) (see Arch. Immunol. Ther. 0012. Otherwise, it is known that calpain causes cornea Exp. (Warsz), 41, 147 (1993)), it is implied that IL-1 is turbid by means of degradation of crystalline (see Biol. concerned with the progress of symptoms, and So it is Chem..., 268, 137 (1993)) and that in the lesion of contracted conceivable that cysteine protease inhibition leads to an gut mucosa model it was confirmed that the activity of effective therapy of AIDS and its complication. cathepsin B, H and L increased (see J. Parenter. Enteral. Nutr., 19, 187 (1995)) and it is shown that cysteine protease 0019. Some parasites have cysteine protease activity in is a cause of the diseases resulting from these protein their bodies. Cysteine protease in the phagosome of malaria degradation. It has been revealed that cysteine protease is protozoan is an essential enzyme for Supplying nutrition of concerned with systemic disorders of organs and tissues by the parasites. Its inhibitor show an inhibitory effect of the shock. proliferation of the protozoan (see Blood, 87. 4448 (1996)). Cystein protease inhibitor is thought of as drug for treatment 0013. It is shown that IL-1B is concerned with septic shock and systemic inflammatory response syndrome (see of malaria. Igakuno ayumi, 169,850 (1994)) and besides, it is reported 0020. In Alzheimer type dementia, it is said that adhesion that in endotoxin shock model induced by lipopolysaccha of non-physiological protein called amyloid to brain is ride, a calpain inhibitor prevented circulatory system disor deeply involved with nervous function disorders. Cysteine der, disorders of liver and pancreas and acidosis by means of protease has an activity of generating amyloid by decom inhibitory effect of activation of nuclear factor KB (see Br. posing its precursor protein. Clinically, it is shown that J. Pharmacol., 121, 695 (1997)). cathepsin B possesses a processing activity of amyloid 0014 Since it is reported that calpain is concerned with proteins in the brains of Alzheimer-type dementia patients platelet coagulation process and a calpain inhibitor pre (see Biochem. Biophys. Res. Commun., 177, 377 (1991)). vented platelet coagulation (see Am. J. Physiol., 259, C862 And expressions of cathepsin B protein (see Virchows Arch. (1990)), it is conceivable that a cysteine protease inhibitor is A. Pathol. Anat. Histpathol. 423, 185 (1993)), cathepsin S useful for the disorder of blood coagulation. From the fact protein (see Am. J. Pathol., 146, 848 (1995)) and calpain that calpain activity increased in the serum of the patients of protein (see Proc. Natl. Acad. Sci. USA, 90, 2628 (1993)) purpura (thrombocytopenia) resulting from marrow trans and increase of caspase-1 activity (see J. Neuropathol. Exp. plantation, so it is conceivable that calpain is concerned with Neurol. 58,582 (1999)) were confirmed in the brain lesions. the actual disease symptoms (see Bone Marrow Transplant. And it is implied that cysteine protease is concerned with the 24, 641 (1999)). disease symptoms, by the fact that calpain is concerned with the formation of paired helical filaments which accumulate 0.015 Caspase-1 inhibitor suppressed apoptosis of blood in Alzheimer dementia patients and production of protein vessel endothelial cells, which is seen in the early phase of kinase C which stabilizes the protein (see J. Neurochem. 66, purpura (thrombocytopenia) and is thought to be important 1539 (1996)) and by the knowledge that caspase is con for the progression of the pathology afterwards (see Am. J. cerned with neurocyte death by Bamyloid protein adhesion Hematol. 59, 279 (1998)), so it is expected that a cysteine (see Exp. Cell Res., 234, 507 (1997)). protease inhibitor makes effect on purpura and hemolytic uremic syndrome. 0021. As to Huntington's chorea, cathepsin H activity increased in the patient’s brain (see J. Neurol. Sci., 131, 65 0016. The effect of cysteine protease and its inhibitor is (1995)), and the ratio of activated form of calpain (see J. being investigated in the area of cancer and metastasis of Neurosci., 48, 181 (1997)) increased. In Parkinson's disease, CaCC. the increase of expression of m-calpain was recognized in 0017. Since the proliferations of pancreas cancer cells the mesencephalon in the patients (see Neuroscience, 73. (see Cancer Res., 59, 4551 (1999)) and acute myeloid 979 (1996)) and IL-1B protein was expressed in brain (see US 2007/019751.0 A1 Aug. 23, 2007

Neurosci. Let., 202, 17 (1995)). Therefore, it is speculated tant protein C which is synthesized by type-2 pneumonia that cysteine protease is concerned with the genesis and cells (see Am. J. Respir. Cell Mol. Biol., 26, 659 (2002)). progress of these diseases. 0028. It is pointed out that cysteine protease is also 0022. Otherwise, in the central nervous system, spectrin concerned with diseases concerning bones and cartilages. degradation by calpain is found in the process of injury on Cathepsin K is specifically recognized in osteoclast and it neurocyte observed in the traumatic brain injury model (see has a decomposing activity against bone matrix (see J. Biol. J. Neuropathol. Exp. Neurol. 58, 365 (1999)). Chem., 271, 12517 (1996)), so cathepsin K inhibitor is expected to show an effect in bone diseases where patho 0023. In spinal cord injured model it was recognized that logic bone resorption is recognized, such as osteoporosis, in glia cells calpain messenger RNA increased and its bone fracture, arthritis, rheumatoid arthritis, osteoarthritis, activity increased in the lesion and the possibility was shown hypercalcaemia, osteometastasis of cancer, periodontitis, that calpain had much to do with the degeneration of myelin bone Paget’s disease, etc. Also, since IL-1B is shown to be and actin (see Brain Res., 816, 375 (1999)). And IL-1B was concerned with bone resorption and cartilage degradation, shown to be concerned with the genesis of multiple Sclerosis and a caspase-1 inhibitor and IL-1B receptor antagonist (see Immunol. Today, 14, 260 (1993)). Therefore, it is inhibit the symptoms of bone resorption and arthritis, so it conceivable that a cysteine protease inhibitor is hopeful as is expected that it is effective for arthritis (see Cytokine, 8, an agent for the treatment of these nerve-injured diseases. 377 (1996)) and osteoporosis (see J. Clin. Invest., 93, 1959 0024 Normally, cathepsin S and cathepsin K do not exist (1994)). And it is also reported that IL-1B is concerned with in human arterial walls, but it was confirmed that they osteoarthritis (see Life Sci., 41, 1187 (1987)). expressed in arteriosclerosis lesion and they had an decom posing activity of alveolus elastica (see J. Clin. Invest. 102. 0029. Cysteine protease is involved with production of 576 (1998)) and a calpain inhibitor and antisense of various hormones. Since increase of messenger RNA of m-calpain inhibited the proliferation of human blood vessel cathepsin S was recognized by stimuli of thytropin on Smooth muscle cells and it is shown that m-calpain is thyroid epitheliocyte strains (see J. Biol. Chem., 267, 26038 concerned with the proliferation of smooth muscle (see (1992)), it is conceivable that a cysteine protease inhibitor is Arteioscler. Thromb. Vssc. Biol., 18, 493 (1998)), so it is effective for hyperthyrodism. conceivable that a cysteine protease inhibitor is hopeful for 0030 Since quantity and activity of cathepsin B protein the treatment of blood vessel lesion such as arteriosclerosis, increased in the gingival Sulcus liquid of periodontitis restenosis after percutaneous transluminal coronary angio patients (see J. Clin. Periodontol., 25, 34 (1998)), it is plasty (PTCA) etc. And it is also reported that LDL induces pointed out that cysteine protease is concerned with peri cathepsin H expression in human monocyte and cathepsin H odontitis. Cathepsin G is concerned with abnormal connec is concerned with LDL transformation and it is implied that tive tissue decomposition. LDL is concerned with circulatory disorder (arteriosclerosis) (see Arterioscler. Thromb. Vasc. Biol., 27 (2003)). 0031. Therefore, those compounds which have an inhibi tory activity against cysteine proteases, are useful as agents 0025. It is reported that in liver, cathepsin B is activated for the prophylaxis and/or treatment of inflammatory dis in the process of injuring hepatocyte by bile acid (see J. Clin. eases (periodontitis, arthritis, inflammatory bowel diseases, Invest., 103,137 (1999)) and so it is expected that a cysteine infectious diseases, pancreatitis, hepatitis, glomerulonephri protease inhibitor is useful for cholestatic cirrhosis. tis, endocarditis, myocarditis, ulcerative colitis, etc.), dis 0026. It is reported that in spleen, cathepsin Y is con eases induced by apoptosis (graft versus host diseases, cerned with production of bradykinin potentiating peptide rejection in transplantation, acquired immunodeficiency (BPP) which plays some role in converting kinin into syndrome (AIDS), AIDS-related complex (ARC), adult T bradykinin (see Immunopharmacology, 45, 207 (1999)). cell leukemia, hairy cells leukemia, spondylopathy, disor Therefore, it is expected that cathepsin Y inhibitor has ders of respiratory apparatus, arthritis, HIV or HTLV-1 related diseases (uveitis etc.), virus related diseases (hepa anti-allergy effect. titis C etc.), cancer, collagenosis (systemic lupus erythema 0027. In lungs and respiratory system, it is shown that tosus, rheumatoid arthritis, etc.), ulcerative colitis, Sjoegren cathepsin S is an enzyme that plays a role in elastin syndrome, primary biliary cirrhosis, spontaneous thromb degradation by alveolus macrophages (see J. Biol. Chem. ocytopenic purpura, autoimmune hemolytic anemia, myas 269, 11530 (1994)), so it is probable that cysteine protease thenia gravis, autoimmune diseases (insulin dependent (type is a cause of pulmonary emphysema. In IL-13 transgenic I) diabetes, etc.), diseases accompanied by thrombocytope mice in which COPD-like pathology is recognized, increase nia (myelodysplastic syndrome, cyclic thrombocytopenia, of cathepsin B. S. L., H and K expression is recognized and aplastic anemia, spontaneous thrombocytopenia, dissemi it is also reported that administration of a cysteine protease nated intravascular coagulation (DIC), etc.), viral hepatitis inhibitor Suppresses lung inflammation and lung emphy (A, B, C, F, etc.) or hepatitis medicamentosa and cirrhosis, sema (see J. Clin. Invest., 106, 1081 (2000)). And it is also etc., dementia Such as Alzheimer's disease, Alzheimer-type shown that lung injury (see J. Clin. Invest., 97,963 (1996)), senile dementia, cerebrovascular injury, neurodegenerative lung fibrosis (see Cytokine, 5, 57 (193)) and bronchial disease, adult acute respiratory distress syndrome, infectious asthma (see J. Immunol., 149, 3078 (1992)) are caused by diseases, prostatomegaly, hysteromyoma, bronchial asthma, way of production of IL-13 by caspase-1. It is also shown arteriosclerosis, hyperlipidemia, all kinds of lusus naturae, that blood cathepsin H concentration is increased in asthma nephritis, senile cataract, chronic fatigue syndrome, myod patients, so antiasthma effect by cathepsin H inhibitor is yStrophy, peripheral nerve injury, etc.), diseases induced by expected (see Clin. Chim. Acta, 310, 113 (2001)). It is immune response disorder (graft versus host diseases, rejec known that cathepsin H functions in the excision of Surfac tion in transplantation, allergic diseases (asthmatic bronchi US 2007/019751.0 A1 Aug. 23, 2007 tis, atopic dermatitis, allergic rhinitis, hay fever, diseases by 0035) is known as a compound having an inhibitory house dust, hyperSensitive pneumonia, food allergy, etc.), activity against cathepsin K (see WO03/02721) psoriasis, rheumatoid arthritis, etc.), autoimmune diseases (insulin dependent (type I) diabetes, systemic lupus erythe 0036) The compound of formula (Y) matosus, Hashimoto's diseases, multiple Sclerosis, etc.), diseases induced by decomposition of proteins which com (Y) pose a body (myodystrophy, cataract, periodontitis, hepato RY V cyte injury by bile acid (cholestatic cirrhosis etc.), etc., N CN decomposition of alveolus elastica (emphysema etc.), YY N s ischemic diseases (brain ischemia, brain disorder by Yy-N-N ischemic reperfusion, cardiac infarction, ischemic liver damage, etc.), etc.), shock (septic shock, systemic inflam matory responsive syndrome, endotoxin shock, acidosis, etc.), circulatory disorder (arteriosclerosis, restenosis after PTCA (percutaneous transluminal coronary angioplasty), etc.), disorder of blood coagulation system (thrombocy 0037 wherein all symbols are as defined in the descrip topenic purpura, hemolytic uremic syndrome, etc.), malig tion, nant tumor, acquired immune deficiency syndrome (AIDS, 0038 is known as a compound having an inhibitory AIDS-related complex (ARC), etc.), parasitic diseases activity against cathepsin S (see WOO4/000843). (malaria etc.), neurodegenerative disease (Alzheimer-type senile dementia, Huntington's chorea, Parkinson's disease, DISCLOSURE OF THE INVENTION multiple Sclerosis, traumatic encephalopathy, traumatic spondylopathy, etc.), lung disorder (fibroid lungs, etc.), bone 0039. A task of the present invention is to provide medi diseases (osteoporosis, bone fracture, rheumatoid arthritis, caments which are useful for the prevention and/or treatment arthritis, osteoarthritis, hypercalcaemia, osteometastasis of of bone diseases Such as osteoporosis. cancer, periodontitis, bone Paget’s disease, etc.), endo 0040. The present inventors have energetically investi crinesthenia (hyperthyroidism etc.), etc. gated to find out such compounds having cysteine protease 0032. On the other hand, what is the most important for inhibitory activity, to find out that the nitrile derivative of inhibitors in inhibiting the activity of proteases is, the special formula (I) accomplishes the purpose. reaction site which interacts with the amino acid residues the 0041. The compound in the present invention has an activity center of proteases. The Surrounding structure of the inhibitory activity against cystein protease, for example, reaction sites are represented by -P3P2P1-P1"P2P3'-, cen cathepsin K, so it is useful for the treatment and/or preven tering peptide binding (P1-P1") of the reaction site, and at P1 tion of bone diseases. site there exist amino acid residues which fit the substance specificity of proteases which the inhibitors aim. Some 0042. That is, the present invention relates to reaction sites against cysteine proteases are known, for 1. A compound of formula (I) example, in the specification of WO99/54317, the follow ings are described; P1 position against calpain I, II Such as

norvaline, phenylalanine, etc., P1 position against calpain. I (I) Such as arginine, lysine, tyrosine, Valine, etc., P1 position against papain such as homophenylalanine, arginine, etc., P1 position against cathepsin B-homophenylalanine, phenyla lanine, tyrosine, etc., P1 position against cathepsin S Such as valine, norleucine, phenylalanine, etc., P1 position against cathepsin L. Such as homophenylalanine, lysine, etc., P1 position against cathepsin K Such as arginine, homopheny 0043 wherein ring A is a carbocyclic group or a hetero lalanine, leucine, etc., P1 position against caspase Such as cyclic group, ring B is a heterocyclic group containing at aspartic acid, etc. least one nitrogen atom, ... is a single bond or a double bond, Y and Z each is independently a carbon atom or a 0033. The compound of formula (W) nitrogen atom, n is 0, or an integer of from 1 to 10, R is a hydrogen atom or a substitutent, if R is plural, each of R are the same or different, with the proviso that two of R may form a ring which may have a Substitutent(s) together with an atom to which they bind, a salt thereof, a solvate thereof, or an N-oxide thereof, or a prodrug thereof; 0044) 2. The compound according to the above item 1, wherein ring A is a C5-7 monocyclic carbocyclic group, or a five- to seven-membered monocyclic heterocyclic group, ring B is a five- to seven-membered monocyclic heterocyclic group which contains one nitrogen atom and contains 1 to 2 hetero atom(s) optionally selected from an oxygen atom(s), 0034 wherein all symbols are as defined in the descrip a nitrogen atom(s) and a Sulfur atom(s) which may be tion, oxidized; US 2007/019751.0 A1 Aug. 23, 2007

0045 3. The compound according to the above item 1, wherein ring A is a ring selected from benzene, cyclopen -continued tene, cyclohexene, cycloheptene, pyridine, pyrimidine, pyrazine, tetrahydropyrimidine, dihydropyridazine, T2C TIC pyridazine, dihydropyrimidine, dihydropyrazine, dihydrot riazine, pyrazole, dihydropyrazole, pyrrole, imidazole, tria Zole, thiophene, furan, dihydrofuran, oxadiazine, tetrahy drodiazepine and diazepane; 0049 wherein T', T, T- and Teach is indepen dently a bond or a spacer having from 1 to 10 atoms of the 4. The compound according to the above item 1, wherein principle chain, ring 1, ring1' and ring2' each is indepen ring B is a ring selected from pyrrole, imidazole, pyrazole, dently a cyclic group which may have a substitutent(s), R thiazole, oxazole, pyridine, pyrimidine, dihydrotriazine, is a hydrogen atom or a Substitutent, pyrazine and dihydropyrimidine; 0050 and other symbols have the same meanings as 0046 5. The compound according to the above item 1, described in the above item 1: wherein the compound of formula (I) is 5,6,7,8-tetrahydro 7. The compound according to the above item 6, wherein R' pyrimido-4,5-dipyrimidine-2-carbonitrile, pyrazolo 1.5-all is a branched C1-8 alkyl: pyrimidine-5-carbonitrile, 2,3-dihydro-1H-pyrazolo 3,4-d 0051 8. The compound according to the above item 6. pyrimidine-6-carbonitrile, pyrazolo 1.5-a1.3.5triazine-2- wherein -T^- is -E-E-E'- (wherein E' and E’ each is carbonitrile, 1H-pyrimidoA,5-e1.3.4oxadiazine-7- independently a bond or a divalent C1-5 hydrocarbon group carbonitrile, 1H-pyrazolo 3,4-dpyrimidine-6-carbonitrile, which may have a substitutent(s), E is - O -, - NR' , imidazol-2-alpyrimidine-2-carbonitrile, 1,3-benzothiazol 2-carbonitrile, 6,7,8,9-tetrahydro-5H-pyrimido4.5-e1.4 diazepine-2-carbonitrile, 5H-pyrrolo3.2-dpyrimidine-2- carbonitrile, pyrido 2,3-dipyrimidine-2-carbonitrile, 5,7- R' each is independently a hydrogenatom or a hydrocarbon dihydrofuro3,4-dpyrimidine-2-carbonitrile, 6,7-dihydro group which may have a substitutent(s)), R is a hydrogen 5 H-cyclopentadpyrimidine-2-carbonitrile, 9H-purine-2- atom or a Substitutent containing a nitrogen atom which are carbonitrile, or 1,3-benzoxazole-2-carbonitrile; basic; 0052 9. The compound according to the above item 6. 6. The compound according to the above item 1, which is a wherein -T' is -E-E-E'- (wherein all symbols have the compound of formula (I-A) same meanings as described in the above item 8), ring 1 is (1) C3-10 mono- or bicyclic carbocyclic group which may have a substitutent(s), or (2) three- to ten-membered mono (I-A) or bicyclic heterocyclic group which may have a Substi tutent(s): 0053 10. The compound according to the above item 6. wherein -T' - is -E-E-E'- (wherein all symbols have the same meanings as described in the above item 8), -T- is a bond or a divalent C1-5 hydrocarbon group which may have a substitutent(s), ring 1 and/or ring 2 is (1) C3-10 mono or bicyclic carbocyclic group which may have a Substi tutent(s), or (2) three- to ten-membered mono- or bicyclic heterocyclic group which may have a Substitutent(s): 11. The compound according to the above item 1, which is (I-B) selected from a group that consists of 0054 (1) 8-(2,2-dimethylpropyl)-7-oxo-5,6,7,8-tetrahy dropyrimidoA,5-dipyrimidine-2-carbonitrile, 0055 (2) 1-(2,2-dimethylpropyl)-2-(4-methoxybenzyl)- 3-oxo-2,3-dihydro-1H-pyrazolo 3,4-dipyrimidine-6-car bonitrile, 0056 (3) 1-(2,2-dimethylpropyl)-3-(4-methoxybenzy 1)oxy)-1H-pyrazolo 3,4-dipyrimidine-6-carbonitrile, 0048 wherein R' is a hydrogenatom or a substitutent, n1 is 0, or an integer of from 1 to 3, R is 0057 (4) 4-(2,2-dimethylpropoxy)-1,3-benzothiazol-2- carbonitrile, 0058 (5) 3-(4-biphenylylmethoxy)-1-(2,2-dimethylpro pyl)-1H-pyrazolo 3,4-dipyrimidine-6-carbonitrile, R3-TIA-, TIB-, or 0059 (6) 2-(4-biphenylylmethyl)-1-(2,2-dimethylpro pyl)-3-oxo-2,3-dihydro-1H-pyrazolo 3,4-dpyrimidine-6- carbonitrile, US 2007/019751.0 A1 Aug. 23, 2007

0060 (7) 1-(2,2-dimethylpropyl)-3-oxo-2-(2-thienylm tions, anti-RANKL antibody, metalloprotease inhibitors, ethyl)-2,3-dihydro-1H-pyrazolo 3,4-dipyrimidine-6-car prostaglandin derivatives, strontium formulations, anti bonitrile, TNF-C. antibody, anti-IL-6 antibody, HMG-CoA reduc 0061 (8) 1-(2,2-dimethylpropyl)-3-2-(4-morpholi tase inhibitors, steroidal drugs, and antiinflammatory nyl)ethoxy)-1H-pyrazolo 3,4-dpyrimidine-6-carboni drugs; trile, 19. A method for the prophylaxis and/or treatment of a 0062 (9) 9-(2,2-dimethylpropyl)-6-(4-methoxybenzyl)- cysteine protease-related disease in a mammal character 7-oxo-6,7,8,9-tetrahydro-5H-pyrimidoA,5-e1.4diaz ized by administering to a mammal an effective amount of epine-2-carbonitrile, the compound of formula (I) described in the above item 1, a salt thereof, a solvate thereof, or an N-oxide thereof, 0063 (10) 8-(2,2-dimethylpropyl)-6-(4-methoxybenzyl)- or a prodrug thereof, and 7-oxo-5,6,7,8-tetrahydropyrimido4,5-dipyrimidine-2- 20. Use of the compound of formula (I) described in the carbonitrile, above item 1, a salt thereof, a solvate thereof or an 0064 (11) 4-(2,2-dimethylpropyl)aminolpyrido 2,3-d N-oxide thereof, or a prodrug thereof, for the manufacture pyrimidine-2-carbonitrile, of a pharmaceutical preparation for the prophylaxis and/or 0065 (12) 1-(2,2-dimethylpropyl)-3-(4-(4-methyl-1- treatment of a cysteine protease-related disease. piperazinyl)methylphenyl)-1H-pyrimido-4,5-e1,3,4) 0069 Definition of the term in the present invention is oxadiazine-7-carbonitrile, described below. 0.066 (13) 2-6-cyano-1-(2,2-dimethylpropyl)-3-oxo-1, 0070) Examples of a carbocyclic group represented by 3-dihydro-2H-pyrazolo 3,4-dpyrimidin-2-yl)-N-2- ring A include C3-15 mono-, polycyclic (bi- or tricyclic) (dimethylamino)ethylacetamide, carbocyclic group, more concretely, for example, C3-15 0067 (14) 4-(2,2-dimethylpropyl)amino-5,7-dihydro mono-, polycyclic aromatic carbocyclic group, and partially saturated or fully saturated carbocyclic group, polycyclic furo3,4-dpyrimidine-2-carbonitrile, and carbocyclic group having spiro bond, and polycyclic bridged 0068 (15) 4-(2,2-dimethylpropyl)amino-6,7-dihydro carbocyclic group, etc. C3-15 mono-, polycyclic aromatic 5H-cyclopentadpyrimidine-2-carbonitrile; carbocyclic group, partially saturated or fully saturated carbocyclic group includes, for example, cyclopropane, 12. A pharmaceutical composition comprising the com cyclobutane, cyclopentane, cyclohexane, cycloheptane, pound of formula (I) which is described in the above item cyclooctane, cyclononane, cyclodecane, cycloundecane, 1, a salt thereof, a solvate thereof, or an N-oxide thereof, cyclododecane, cyclotridecane, cyclotetradecane, cyclopen or a prodrug thereof as an active ingredient; tadecane, cyclopentene, cyclohexene, cycloheptene, 13. The pharmaceutical composition according to the above cyclooctene, cyclopentadiene, cyclohexadiene, cyclohepta item 12, which is an agent for prevention and/or treatment diene, cyclooctadiene, benzene, pentalene, perhydropental for a cysteine protease-related disease; ene, azulene, perhydroaZulene, indene, perhydroindene, indan, naphthalene, dihydronaphthalene, teterahydronaph 14. The pharmaceutical composition according to the above thalene, perhydronaphthalene, heptalene, perhydroheptal item 13, wherein a cysteine protease-related disease is a ene, biphenylene, as-indacene, S-indacene, acenaphthylene, cathepsin K-related disease; acenaphthene, fluorene, phenalene, phenanthrene, 15. The pharmaceutical composition according to the above anthracene ring, etc. Polycyclic carbocyclic group having item 14, wherein a cathepsin K-related disease is a bone spiro bond, and polycyclic bridged carbocyclic group disease; include, for example, spiro4.4nonane, spiro4.5decane, 16. The pharmaceutical composition according to the above spiro5.5undecane, bicyclo2.2.1]heptane, bicyclo2.2.1 item 15, wherein a bone disease is at least one selected hept-2-ene, bicyclo3.1.1 heptane, bicyclo3.1.1 hept-2- from osteoporosis, bone fracture, arthritis, rheumatoid ene, bicyclo2.2.2]octane, bicyclo2.2.2]oct-2-ene, bicyclo arthritis, osteoarthritis, hypercalcaemia, osteometastasis 3.3.0octane, bicycloak.3.0nonane, bicyclo[4.4.0decane, of cancer, osteosarcoma, periodontitis, and bone Paget’s adamantane and noradamantane ring, etc. disease; 0071 Example of a heterocyclic group represented by ring A includes three- to fifteen-membered mono-, polycy 17. The pharmaceutical composition according to the above clic (bi- or tricyclic) heterocyclic group, more concretely, for item 12, which is a bone resorption inhibitor, example, three- to fifteen-membered mono-, polycyclic aro 18. A drug comprising the compound of formula (I) matic heterocyclic group, and polycyclic heterocyclic group described in the above item 1, a salt thereof, a solvate having spiro bond, and polycyclic bridged heterocyclic thereof, or an N-oxide thereof, or a prodrug thereof, group which contain 1 to 5 hetero atoms selected from an combined with at least one selected from bisphosphonate oxygen atom(s), a nitrogen atom(s) and a Sulfur atom(s) formulations, Vitamin D and its derivatives, Vitamin K which may be oxidized (S, SO, SO), and which may be and its derivatives, calcitonin formulations, C-calcitonin partially saturated or fully saturated, etc. Three- to fifteen gene-related peptide formulations, female hormone for membered mono-, polycyclic aromatic heterocyclic group, mulations, selective estrogen receptor modulators, ipri and polycyclic heterocyclic group having spiro bond, and flavone formulations, calcium formulations, anabolic Ste polycyclic bridged heterocyclic group which contain 1 to 5 roid formulations, parathyroid hormone formulations, hetero atoms selected from an oxygen atom(s), a nitrogen PTHrP derivatives, caspase-1 inhibitors, farnesoid X atom(s) and a Sulfur atom(s) which may be oxidized, and receptor agonists, Bone Morphogenetic Protein formula which may be partially saturated or fully saturated include, US 2007/019751.0 A1 Aug. 23, 2007 for example, pyrrole, imidazole, triazole, tetrazole, pyrazole, drobenzothiazine, pyrazinomorpholine, pyridine, pyrazine, pyrimidine, pyridazine, triazine, azepine, dihydrobenzoxazole, perhydrobenzoxazole, dihydroben diazepine, furan, pyran, oxepine, thiophene, thiopyran, thi Zothiazole, perhydrobenzothiazole, 4,5,6,7-tetrahydrothieno epine, oxazole, isoxazole, thiazole, isothiazole, furazan, 3.2-cpyridine, dihydrobenzimidazole, perhydrobenzimida oxadiazole, oxazine, oxadiazine, oxazepine, oxadiazepine, Zole, dihydrobenzazepine, tetrahydrobenzazepine, thiadiazole, thiazine, thiadiazine, thiazepine, thiadiazepine, dihydrobenzodiazepine, tetrahydrobenzodiazepine, benzo indole, isoindole, indolizine, benzofuran, isobenzofuran, dioxepane, dihydrobenzoxazepine, tetrahydrobenzox benzothiophene, isobenzothiophene, dithianaphthalene, azepine, dihydrocarbazole, tetrahydrocarbazole, perhydro carbazole, dihydroacridine, tetrahydroacridine, indazole, quinoline, isoquinoline, quinolizine, purine, perhydroacridine, dihydrodibenzofuran, dihydrodiben phthalazine, pteridine, naphthyridine, quinoxaline, quinazo Zothiophene, tetrahydrodibenzofuran, tetrahydrodiben line, cinnoline, pyrrolopyridine, benzoxazole, benzothiaz Zothiophene, perhydrodibenzofuran, perhydrodiben ole, thieno3.2-cpyridine, berizimidazole, chromene, ben Zothiophene, tetrahydropyridonaphthyridine, tetrahydro-3- ZOXepine, benzoxazepine, benzoxadiazepine, benzothiepine, carboline, dihydroazepinoindole, hexahydroazepinoindole, benzothiazepine, benzothiadiazepine, benzazepine, benzo tetrahydropyrazoloisoquinoline, tetrahydropyrazolonaph diazepine, benzofurazan, benzothiadiazole, benzotriazole, thyridine, dihydroazepinoindazole, hexahydroazepinoinda carbazole, B-carboline, acridine, phenazine, dibenzofuran, Zole, dihydropyrazolopyridoazepine, hexahydropyrazolopy Xanthene, dibenzothiophene, phenothiazine, phenoxazine, ridoazepine, tetrahydropyrimidoindole, phenoxathiin, thianthrene, phenanthridine, phenanthroline, dihydrothiazinoindole, tetrahydrothiazinoindole, dihy perimidine, pyridonaphthyridine, pyrazoloisoquinoline, drooxazinoindole, tetrahydrooxazinoindole, 2,3-dihydro pyrazolonaphthyridine, pyrimidoindole, aziridine, aZetidine, 1H-benzodelisoquinoline, dioxolane, dioxane, dithiolane, pyrroline, pyrrolidine, imidazoline, imidazolidine, triazo dithiane, benzodioxole, for example, 1,3-benzodioxole, etc., line, triazolidine, tetrazoline, tetrazolidine, dihydropyrazole benzodioxane, chroman, benzodithiolane benzodithiane, (pyrazoline), tetrahydropyrazole (pyrazolidine), dihydropy azaspiro4.4nonane, Oxaazaspiro4.4nonane, oxaazaspiro ridine, tetrahydropyridine, piperidine, dihydropyrazine, tet 2.5octane, dioxaspiro4.4nonane, azaspiro4.5decane, rahydropyrazine, piperazine, dihydropyrimidine, tetrahy thiaspiro4.5decane, dithiaspiro4.5decane, dioxaspiro4. dropyrimidine, perhydropyrimidine, dihydropyridazine, 5decane, oxaazaspiro4.5decane, azaspiro5.5undecane, tetrahydropyridazine, perhydropyridazine, dihydrotriazine, oxaspiro5.5undecane, dioxaspiro5.5undecane, 1.4-di tetrahydrotriazine, perhydrotriazine, dihydroazepine, tet oxa-8-azaspiro4.5undecane, 1.3.8-triazaspiro4.5decane, rahydroazepine, azepane(perhydroazepine), dihydrodiaz azabicyclo2.2.1]heptane, oxabicyclo2.2.1]heptane, azabi epine, tetrahydrodiazepine, diazepane (perhydrodiazepine), cyclo3.1.1 heptane, azabicyclo3.2.1]octane, Oxabicyclo oxirane, oxetane, dihydrofuran, tetrahydrofuran, dihydropy 3.2.1]octane, azabicyclo2.2.2]octane, diazabicyclo2.2.2 ran, tetrahydropyran, dihydrooxepine, tetrahydrooxepine, octane, 2.5-diazabicyclo2.2.1]heptane, 1.3.8-triazaspiro perhydrooxepine, thirane, thietane, dihydrothiophene, tet 4.5 decane, 2.7-diazaspiro4.5decane, 1.4.9-triazaspiro rahydrothiophene, dihydrothiopyran, tetrahydrothiopyran, 5.5undecane, 2,4,6-trioxaspirobicyclo3.3.0octane-3,1'- dihydrothiepine, tetrahydrothiepine, perhydrothiepine, dihy cyclohexane, 1,3-dioxolano.4.5-gchromene, 2-oxabicyclo drooxazole, tetrahydrooxazole (oxazolidine), dihydroisox 2.2.1]heptane, 2.3.4.9-tetrahydrospirof-carboline-1,1'- azole, tetrahydroisoxazole (isoxazolidine), dihydrothiazole, cyclopentanering, etc. tetrahydrothiazole (thiazolidine), dihydroisothiazole, tet rahydroisothiazole (isothiazolidine), dihydrofurazan, tet 0072 Example of “a heterocyclic group containing at rahydrofurazan, dihydrooxadiazole, tetrahydrooxadiazole least one nitrogen atom' represented by ring B include (oxadiazolidine), dihydrooxazine, tetrahydrooxazine, dihy three- to fifteen-membered mono-, polycyclic (bi- or tricy drooxadiazine, tetrahydrooxadiazine, dihydrooxazepine, tet clic) heterocyclic group which contains one nitrogen atom rahydrooxazepine, perhydrooxazepine, dihydrooxadiaz and contains 1 to 4 hetero atoms optionally selected from an epine, tetrahydrooxadiazepine, perhydrooxadiazepine, oxygen atom(s), a nitrogen atom(s) and a Sulfur atom(s) dihydrothiadiazole, tetrahydrothiadiazole (thiadiazolidine), which may be oxidized, more concretely, for example, three dihydrothiazine, tetrahydrothiazine, dihydrothiadiazine, tet to fifteen-membered mono-, polycyclic aromatic heterocy rahydrothiadiazine, dihydrothiazepine, tetrahydrothiaz clic group, and polycyclic heterocyclic group having spiro epine, perhydrothiazepine, dihydrothiadiazepine, tetrahy bond, and polycyclic bridged heterocyclic group which drothiadiazepine, perhydrothiadiazepine, morpholine, contain one nitrogen atom and contain 1 to 4 hetero atoms thiomorpholine, oxathiane, indoline, isoindoline, dihy optionally selected from an oxygen atom(s), a nitrogen drobenzofuran, perhydrobenzofuran, dihydroisobenzofuran, atom(s) and a Sulfur atom(s) which may be oxidized and perhydroisobenzofuran, dihydrobenzothiophene, perhy may be partially saturated or fully saturated. Three- to drobenzothiophene, dihydroisobenzothiophene, perhy fifteen-membered mono-, polycyclic aromatic heterocyclic droisobenzothiophene, dihydroindazole, perhydroindazole, group, and polycyclic heterocyclic group having spiro bond, dihydroquinoline, tetrahydroquinoline, octahydroquinoline, and polycyclic bridged heterocyclic group which contain perhydroquinoline, dihydroisoquinoline, tetrahydroiso one nitrogen atom and contain 1 to 4 hetero atoms optionally quinoline, octahydroisoquinoline, perhydroisoquinoline, selected from an oxygen atom(s), a nitrogen atom(s) and a dihydrophthalazine, tetrahydrophthalazine, perhydro sulfur atom(s) which may be oxidized and may be partially phthalazine, dihydronaphthyridine, tetrahydronaphthyri saturated or fully saturated include, for example, pyrrole, dine, perhydronaphthyridine, dihydroquinoxaline, tetrahyd imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazine, roquinoxaline, perhydroquinoxaline, dihydroquinazoline, pyrimidine, triazine, pyridazine, azepine, diazepine, tetrahydroquinazoline, perhydroquinazoline, tetrahydropyr oxazole, isoxazole, thiazole, isothiazole, furazan, oxadiaz rolopyridine, dihydrocinnoline, tetrahydrocinnoline, perhy ole, oxazine, oxadiazine, oxazepine, oxadiazepine, thiadia drocinnoline, benzoxathiane, dihydrobenzoxazine, dihy Zole, thiazine, thiadiazine, thiazepine, thiadiazepine, indole, US 2007/019751.0 A1 Aug. 23, 2007 isoindole, indazole, quinoline, isoquinoline, purine, phthala ane, 1,3-dioxolano.4.5-gchromene, 2-oxabicyclo2.2.1 Zine, pteridine, naphthyridine, quinoxaline, quinazoline, cin heptane, 2.3.4.9-tetrahydrospiro B-carboline-1,1'- noline, pyrrolopyridine, benzoxazole, benzothiazole, benz cyclopentanering, etc. imidazole, benzoxazepine, benzoxadiazepine, 0073. A substitutent represented by R includes, for benzothiazepine, benzothiadiazepine, benzazepine, benzo example, (1) hydrocarbon group which may have a Substi diazepine, B-carboline, phenanthridine, phenanthroline, tutent(s), (2) carbocyclic group which may have a Substi pyridonaphthyridine, pyrazoloisoquinoline, pyrazolonaph tutent(s), (3) heterocyclic group which may have a Substi thyridine, pyrimidoindole, aZetidine, pyrroline, pyrrolidine, tutent(s), (4) hydroxy which may have a substitutent(s), (5) imidazoline, imidazolidine, triazoline, triazolidine, tetraZo mercapto which may have a Substitutent(s), (6) amino which line, tetrazolidine, pyrazoline, pyrazolidine, dihydropyri may have a substitutent(s), (7) carbamoyl which may have dine, tetrahydropyridine, piperidine, dihydropyrazine, tet a substitutent(s), (8) sulfamoyl which may have a substi rahydropyrazine, piperazine, dihydropyrimidine, tutent(s), (9) carboxy, (10) alkoxycarbonyl (e.g. C1-6 tetrahydropyrimidine, perhydropyrimidine, dihydropy alkoxycarbonyl Such as methoxycarbonyl, ethoxycarbonyl, ridazine, tetrahydropyridazine, perhydropyridazine, dihy tert-butoxycarbonyl, etc.), (11) sulfo, (12) sulfino, (13) drotriazine, tetrahydrotriazine, perhydrotriazine, dihy phosphono, (14) nitro, (15) cyano, (16) amidino, (17) imino, droazepine, tetrahydroazepine, azepane (perhydroazepine), (18) dihydroxyboryl, (19) halogen (fluoro, chloro, bromo, dihydrodiazepine, tetrahydrodiazepine, diazepane (perhy iodo), (20) alkylsulfinyl (e.g. C1-6 alkylsulfinyl such as drodiazepine), dihydroisoxazole, tetrahydroisoxazole (isox methylsulfinyl, ethylsulfinyl, etc.), (21) aromatic ring Sulfi azolidine), dihydrothiazole, tetrahydrothiazole (thiazoli nyl (e.g. C6-10 aromatic ring Sulfinyl such as phenylsulfinyl, dine), dihydroisothiazole, tetrahydroisothiazole etc.), (22) alkylsulfinyl (e.g. C1-6 alkylsulfinyl Such as (isothiazolidine), dihydrofurazan, tetrahydrofurazan, dihy methylsulfonyl, ethylsulfonyl, etc.), (23) aromatic ring Sul drooxazine, tetrahydrooxazine, dihydrooxadiazine, tetrahy fonyl (e.g. C6-10 aromatic ring Sulfonyl Such as phenylsul drooxadiazine, dihydrooxazepine, tetrahydrooxazepine, per fonyl, etc.), (24) oxo, (25) thioxo, (26) (C1-6 alkoxyimi hydrooxazepine, dihydrooxadiazepine, no)methyl (e.g. (methoxyimino)methyl, etc.), (27) acyl, (28) tetrahydrooxadiazepine, perhydrooxadiazepine, dihy formyl, (29) alkyl substituted by hydroxy which may have drothiadiazole, dihydrothiazine, tetrahydrothiazine, dihy a substitutent(s), (30) alkyl substituted by mercapto which drothiadiazine, tetrahydrothiadiazine, dihydrothiazepine, may have a substitutent(s), (31) alkyl substituted by amino tetrahydrothiazepine, perhydrothiazepine, dihydrothiadiaz which may have a substitutent(s), (32) (alkyl which may epine, tetrahydrothiadiazepine, perhydrothiadiazepine, mor have a substitutent(s))oxycarbonyl, (33) HO (CO-amino pholine, thiomorpholine, oxathiane, indoline, isoindoline, acid residue-NH), CO-T"- which may have a substi dihydroindazole, perhydroindazole, dihydroquinoline, tet tutent(s), (34) H-(NH-amino acid residue-CO), O-T"- rahydroquinoline, perhydroquinoline, dihydroisoquinoline, which may have a Substitutent(s), etc. tetrahydroisoquinoline, perhydroisoquinoline, dihydro phthalazine, tetrahydrophthalazine, perhydrophthalazine, 0074) If R is plural, each of R are the same or different. dihydronaphthyridine, tetrahydronaphthyridine, perhy 0075) Hydrocarbon group in "(1) hydrocarbon group dronaphthyridine, dihydroquinoxaline, tetrahydroquinoxa which may have a substitutent(s) includes, for example, line, perhydroquinoxaline, dihydroquinazoline, tetrahydro alkyl, alkenyl, alkynyl, alkylidene, alkenylidene, etc. Alkyl quinazoline, perhydroquinazoline, group includes, for example, straight chain or branched C1-8 tetrahydropyrrolopyridine, dihydrocinnoline, tetrahydrocin alkyl Such as methyl, ethyl, propyl, isopropyl, butyl, isobu noline, perhydrocinnoline, dihydrobenzothiazine, pyrazino tyl, tert-butyl, pentyl, neopentyl, hexyl, heptyl, octyl, etc. morpholine, dihydrobenzoxazole, perhydrobenzoxazole, Alkenyl group includes, for example, straight chain or dihydrobenzothiazole, perhydrobenzothiazole, dihydroben branched C2-8 alkenyl such as ethenyl, propenyl, butenyl, Zimidazole, perhydrobenzimidazole, dihydrobenzazepine, pentenyl, hexenyl, heptenyl, octenyl, etc. Alkynyl group tetrahydrobenzazepine, dihydrobenzodiazepine, tetrahy includes, for example, straight chain or branched C2-8 drobenzodiazepine, dihydrobenzoxazepine, tetrahydroben alkynyl such as ethynyl, propynyl, butynyl, pentynyl, hexy Zoxazepine, tetrahydropyridonaphthyridine, tetrahydro-3- nylheptynyl, octynyl, etc. Alkylidene includes, for example, carboline, dihydroazepinoindole, hexahydroazepinoindole, straight chain or branched C1-8 alkylidene such as meth tetrahydropyrazoloisoquinoline, tetrahydropyrazolonaph ylidene, ethylidene, propylidene, butylidene, pentylidene, thyridine, dihydroazepinoindazole, hexahydroazepinoinda hexylidene, heptylidene, octylidene, etc. Zole, dihydropyrazolopyridoazepine, hexahydropyrazolopy ridoazepine, tetrahydropyrimidoindole, 0076 Alkenylidene includes, for example, straight chain dihydrothiazinoindole, tetrahydrothiazinoindole, azaspiro or branched C2-8 alkenylidene such as ethenylidene, pro 4.4nonane, Oxaazaspiro4.4nonane, oxaazaspiro2.5oc penylidene, butenylidene, pentenylidene, hexenylide, hep tane, dioxaspiro4.4nonane, azaspiro4.5decane, thiaspiro tenylidene, octenylidene, etc. 4.5decane, dithiaspiro4.5decane, dioxaspiro4.5decane, 0077 Substituent in "(1) hydrocarbon group which may oxaazaspiro4.5decane, azaspiro5.5undecane, oxaspiro have a substitutent(s) includes, for example, hydroxy, mer 5.5undecane, dioxaspiro5.5undecane, 1,4-dioxa-8-aza capto, amino, carboxy, nitro, cyano, oxo, mono- or di-C1-6 spiro4.5undecane, 1.3.8-triazaspiro4.5decane, azabicy alkylamino (e.g. methylamino, ethylamino, propylamino, clo2.2.1]heptane, Oxabicyclo2.2.1]heptane, azabicyclo dimethylamino, diethylamino, etc.), N-aromatic ring amino 3.1.1 heptane, azabicyclo3.2.1]octane, oxabicyclo[3.2.1 (e.g. N-phenylamino, etc.), N-aromatic ring-N-alkylamino octane, azabicyclo2.2.2]octane, diazabicyclo2.2.2]octane, (e.g. N-phenyl-N-methylamino, N-phenyl-N-ethylamino, 2,5-diazabicyclo2.2.1]heptane, 1.3.8-triazaspiro4.5de N-phenyl-N-propyl amino, N-phenyl-N-butylamino, N-phe cane, 2.7-diazaspiro4.5decane, 1.4.9-triazaspiro5.5unde nyl-N-pentylamino, N-phenyl-N-hexylamino, etc.), acy cane, 2,4,6-trioxaspirobicyclo3.3.0octane-3,1'-cyclohex lamino, N-acyl-N-alkylamino, C1-6 alkoxy (e.g. methoxy, US 2007/019751.0 A1 Aug. 23, 2007 ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, hexyloxy, straight chain or branched C1-6 alkoxycarbonyl (e.g. meth etc.), C3-7 cycloalkyl-C1-6 alkoxy (e.g. cyclohexylmethy oxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, etc.), tri loxy, cyclopentylethyloxy, etc.), C3-7 cycloalkyloxy (e.g. halomethyl (e.g. trifluoromethyl, etc.), trihalomethoxy (e.g. cyclohexyloxy, etc.), C7-15 aralkyloxy (e.g. benzyloxy, trifluoromethoxy, etc.), trihalomethylthio (trifluorometh phenethyloxy, phenylpropyloxy, naphthylmethyloxy, naph ylthio, etc.), dihalomethylthio (difluoromethylthio, etc.), thylethyloxy, etc.), phenoxy, C1-6 alkoxycarbonyl (e.g. OXO, carbocyclic group (which has the same meaning as the methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, above-described carbocyclic group represented by ring A.), etc.), C1-6 alkylcarbonyloxy (e.g. acetoxy, ethylcarbony heterocyclic group (which has the same meaning as the loxy, etc.), C1-6 alkylthio (e.g. methylthio, ethylthio, pro above-described heterocyclic group represented by ring A), pylthio, butylthio, hexylthio, etc.), halogen (fluoro, chloro, etc. And the 1 to 4 substitutent(s) may exist wherever bromo, iodo), C1-6 alkyl-sulfonyl (e.g. methylsulfonyl, eth possible. ylsulfonyl, propylsulfonyl, butylthio, hexylsulfonyl, etc.), 0080 Heterocyclic group in the “(3) heterocyclic group aromatic ring Sulfonyl (e.g. C6-10 aromatic ring Sulfonyl which may have a Substitutent(s) has the same meaning as Such as phenylsulfonyl, etc.), carbamoyl which may have a the above-described heterocyclic group represented by ring Substitutent(s) (e.g. non-substituted carbamoyl N-mono C1-8 alkylcarbamoyl (N-methylcarbamoyl N-ethylcarbam A. oyl, N-propylcarbamoyl N-isopropylcarbamoyl, N-butyl 0081. Substituent in the “(3) heterocyclic group which carbamoyl, etc.), N,N-di(C1-8 alkyl)carbamoyl (e.g. N.N- may have a substitutent(s) has the same meaning as the dimethylcarbamoyl, N,N-diethylcarbamoyl, N,N- above-described substitutent(s) in the “(2) carbocyclic group dipropylcarbamoyl N,N-dibutylcarbamoyl, etc.), piperidin which may have a substitutent(s)'. 1-ylcarbonyl, piperazin-1-ylcarbonyl, morpholin-4- 0082) Substituent in the “(4) hydroxy which may have a ylcarbonyl, etc.), acyl, carbocyclic group which may have a substitutent(s)”, “(5) mercapto which may have a substi Substitutent(s), heterocyclic group which may have a Sub tutent(s)”, “(6) amino which may have a substitutent(s)'. stitutent(s), —O-(carbocyclic group which may have a Sub “(33) HO-(CO-amino acid residue-NH), CO-T- which stitutent(s)), —O-(heterocyclic group which may have a may have a substitutent(s)', and “(34) H (NH-amino acid substitutent(s)), etc. The 1 to 4 substitutent(s) may exist residue-CO), O-T"- which may have a substitutent(s)" wherever possible. Alkyl in the N-acyl-N-alkylamino includes, for example, hydrocarbon group which may have includes, for example, straight chain or branched C1-6 alkyl a Substitutent(s) (which has the same meaning as the above Such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, described "(1) hydrocarbon group which may have a sub sec-butyl, tert-butyl, pentyl, hexyl, etc. Acyl, acyl in the stitutent(s)'), carbocyclic group which may have a substi acylamino and N-acyl-N-alkylamino have the same mean tutent(s) (which has the same meaning as the above ings as the below-described “(27) acyl. Carbocyclic group described “(2) carbocyclic group which may have a which may have a Substitutent(s) in the "carbocyclic group Substitutent(s)'), heterocyclic group which may have a Sub which may have a substitutent(s), “heterocyclic group stitutent(s) (which has the same meaning as the above which may have a substitutent(s)”, “ O— (carbocyclic described “(3) heterocyclic group which may have a sub group which may have a Substitutent(s)), and heterocyclic stitutent(s)'), alkylsulfonyl (e.g. C1-4 alkylsulfonyl such as group which may have a Substitutent(s) in the -O-(hetero methylsulfonyl, ethylsulfonyl, etc.), aromatic ring Sulfonyl cyclic group which may have a substitutent(s)) have the (e.g. C6-10 aromatic ring Sulfonyl Such as phenylsulfonyl, same meanings as the below-described "(2) carbocyclic etc.), acyl (which has the same meaning as the below group which may have a substitutent(s)', and “(3) hetero described “(27) acyl'), (alkyl which may have a substitutent cyclic group which may have a Substitutent(s), respectively. (s))oxycarbonyl (which has the same meaning as the below 0078 Carbocyclic group in the “(2) carbocyclic group described “(32) (alkyl which may have a which may have a Substitutent(s) has the same meaning as Substitutent(s))oxycarbonyl), etc. A hydrogen atom of the above-described carbocyclic group represented by ring amino in the “(6) amino which may have a substitutent(s) A. may be replaced by one or two substitutent(s). 0079 Substituent in the “(2) carbocyclic group which 0083) “(7) Carbamoyl which may have a substitutent(s) may have a Substitutent(s) includes, for example, straight includes, for example, non-Substituted carbamoyl N-mono chain or branched C1-6 alkyl which may be substituted by C1-6 alkylcarbamoyl (e.g. N-methylcarbamoyl N-ethylcar hydroxy (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobu bamoyl N-propylcarbamoyl N-isopropylcarbamoyl, N-bu tyl, Sec-butyl, tert-butyl, pentyl, hexyl, etc.), straight chain tylcarbamoyl, etc.), N,N-di(C1-6 alkyl)carbamoyl (e.g. or branched C2-6 alkenyl (e.g. ethenyl, propenyl, butenyl, N,N-dimethylcarbamoyl N,N-diethylcarbamoyl N,N- pentenyl, hexenyl, etc.), straight chain or branched C2-6 dipropylcarbamoyl N,N-dibutylcarbamoyl, etc.), piperidin alkynyl (e.g. ethynyl, propynyl, butynyl, pentynyl, hexynyl, 1-ylcarbonyl, piperazin-1-ylcarbonyl, morpholin-4-ylcarbo etc.), hydroxy, straight chain or branched C1-6 alkoxy (e.g. nyl, etc. methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutyloxy, tert-butoxy, pentyloxy, hexyloxy, etc.), mercapto, straight 0084) “(8) Sulfamoyl which may have a substitutent(s) chain or branched C1-6 alkylthio (e.g. methylthio, ethylthio. includes, for example, non-substituted Sulfamoyl N-mono propylthio, isopropylthio, butylthio, isobutylthio, tert-bu C1-6 alkylsulfamoyl (e.g. N-methylsulfamoyl N-ethylsul tylthio, pentylthio, hexylthio, etc.), amino, mono- or di-C1-6 famoyl N-propylsulfamoyl N-isopropylsulfamoyl, N-bu alkylamino (e.g. methylamino, ethylamino, propylamino, tylsulfamoyl, etc.), N,N-di(C1-6 alkyl)sulfamoyl (e.g. N.N- isopropylamino, butylamino, isobutylamino, tert-buty dimethylsulfamoyl, N,N-diethylsulfamoyl, N,N- lamino, pentylamino, hexylamino, dimethylamino, diethy dipropylsulfamoyl N,N-dibutylsulfamoyl, etc.), etc. lamino, dipropylamino, N-methyl-N-ethylamino, etc.), halo 0085 “(27) Acyl' includes, for example, alkylcarbonyl gen (fluoro, chloro, bromo, iodo), cyano, nitro, carboxy, which may have a substitutent(s) (wherein alkyl which may US 2007/019751.0 A1 Aug. 23, 2007

have a Substitutent(s) has the same meaning as the above described “alkyl which may have a substitutent(s) in the "(1) hydrocarbon group which may have a substitutent(s)'.). (alkenyl which may have a substitutent(s))carbonyl (wherein alkenyl which may have a substitutent(s) has the R3-TIA-, O-it same meaning as the above-described “alkenyl which may have a substitutent(s) in the "(1) hydrocarbon group which may have a substitutent(s)'.). (alkynyl which may have a substitutent(s))carbonyl (wherein alkynyl which may has a -O-- O Substitutent(s) have the same meaning as the above-de scribed “alkynyl which may have a substitutent(s) in the "(1) hydrocarbon group which may have a substitutent(s)'.). (carbocyclic group which may have a substitutent(s))carbo 3. nyl (wherein carbocyclic group which may have a Substi tutent(s) has the same meaning as the above-described "(2) 0090 wherein T., TIP, TC, TIP, T2, TP and TPeach carbocyclic group which may have a Substitutent(s)'.), (het is independently a bond or a spacer having from 1 to 10 erocyclic group which may have a Substitutent(s))carbonyl atoms of the principle chain, ring', ring', ring', ring, (wherein heterocyclic group which may have a substi ring', and ring each is independently a cyclic group tutent(s) has the same meaning as the above-described “(3) which may have a Substitutent(s). heterocyclic group which may have a substitutent(s)'.), etc. 0091 Aspacer having from 1 to 10 atoms of the principle chain represented by T'^, T, T, T'P, T, TP and TP 0.086 Hydroxy which may have a substitutent(s) in the means a space formed by 1 to 10 continued atoms of a main “(29) alkyl substituted by hydroxy which may have a chain. In this case, the “number of atoms as a principle Substitutent(s) has the same meaning as the above-de chain” should be counted Such that atoms as a main chain scribed “(4) hydroxy which may have a substitutent(s)'. become minimum. “A Spacer having from 1 to 10 atoms of mercapto which may have a substitutent(s) in the “(30) alkyl the principle chain' includes, for example, a bivalent group substituted by mercapto which may have a substitutent(s) formed by 1 to 10 continued atoms of a main chain com has the same meaning as the above-described “(5) mercapto prising 1 to 10 selected from —O— —S— —S(O)—, which may have a Substitutent(s)', amino which may have —SO. , —CO—, a nitrogen atom which may have a a substitutent(s) in the “(31) alkyl substituted by amino substitutent(s), and a bivalent C1-10 aliphatic hydrocarbon which may have a Substitutent(s) has the same meaning as group which may have a Substitutent(s), etc. 'A nitrogen the above-described “(6) amino which may have a substi atom which may have a Substitutent(s) includes, an tutent(s)'. Alkyl in the “(29) alkyl substituted by hydroxy —NH in which hydrogen atom is replaced by hydrocar which may have a substitutent(s)”, “(30) alkyl substituted by bon group which may have a substitutent(s) (which has the mercapto which may have a substitutent(s) and “(31) alkyl same meaning as the above-described "(1) hydrocarbon substituted by amino which may have a substitutent(s) group which may have a substitutent(s)'.) besides —NH includes, for example, straight chain or branched C1-6 alkyl and =N-. Such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, 0092 “A divalent C1-10 aliphatic hydrocarbon group' in sec-butyl, tert-butyl, pentyl, hexyl, etc. the “a divalent C1-10 aliphatic hydrocarbon group which may have a substitutent(s) includes, for example, C1-10 0087 Alkyl which may have a substitutent(s) in the “(32) alkylene (e.g. methylene, ethylene, propylene, butylene, (alkyl which may have a substitutent(s))oxycarbonyl has pentylene, hexylene, heptylene, octylene, nonylene, the same meaning as the above-described “alkyl which may decylene, etc.), C2-10 alkenylene (e.g. ethenylene, prope have a substitutent(s) in the "(1) hydrocarbon group which nylene, butenylene, butadienylene, penntenylene, pentadi may have a substitutent(s)'. enylene, hexenylene, hexadienylene, heptenylene, heptadi enylene, octenylene, ocadienylene, nonenylene, 0088 “m” in the “(33) HO-(CO-amino acid residue nonadienylene, decenylene, decadienylene, etc.), C2-10 NH), CO-T- which may have a substitutent(s)', and alkynylene, (e.g. ethynylene, propynylene, butynylene, “(34) H-(NH-amino acid residue-CO), O-T"- which butadiynylene, pentynylene, pentadiynylene, hexynylene, may have a substitutent(s) is an integer of 1 to 3. “Amino hexadiynylene, heptynylene, heptadiynylene, octynylene, acid' means natural amino acid or unusual amino acid, and octadiynylene, nonynylene, nonadiynylene, decynylene, includes, for example, glycine, alanine, Valine, leucine, decadiynylene), etc. “Substituent in the “a divalent C1-10 isoleucine, serine, threonine, cystein, methionine, proline, aliphatic hydrocarbon group which may have a Substi asparagine, glutamine, phenylalanine, tyrosine, tryotophan, tutent(s) has the same meaning as the above-described aspartic acid, glutamic acid, lysine, arginine, histidine, “substitutent in the "(1) hydrocarbon group which may B-alanine, cyStathionine, cystine, homoserine, isoleucine, have a substitutent(s), and the 1 to 4 substitutent(s) may lanthionine, norleucine, norvaline, ornithine, sarcosine, thy exist wherever possible. ronine, etc. T" in the group has the same meaning as the 0093 Ring in the “ring which may have a substitutent(s) below-described T''. represented by ring ring', ring', ring, ring P and ring' 0089. A substitutent represented by Ralso includes group includes, for example, carbocyclic group and heterocyclic described hereinafter; group, etc. This carbocyclic group and heterocyclic group US 2007/019751.0 A1 Aug. 23, 2007 have the same meanings as the above-described carbocyclic 0097 When .... in ring B is single bond, a compound group and heterocyclic group represented by ring A. represented by formula (I) includes a compound represented 0094 Substituent in the “ring which may have a substi by formula described below tutent(s)" represented by ring', ring', ring', ring 'Pring and ring P includes, for example, hydrocarbon group which may have a substitutent(s) (which has the same meaning as (R)na above-described "(1) hydrocarbon group which may have a Substitutent(s)'.), carbocyclic group which may have a Sub stitutent(s) (which has the same meaning as the above described “(2) carbocyclic group which may have a substi tutent(s)'.), heterocyclic group which may have a Substitutent(s) (which has the same meaning as the above 0.098 wherein n2 is 0 or an integer of 1 to 9, other described “(3) heterocyclic group which may have a sub symbols have the same meaning as described above. stitutent(s)'.), hydroxy which may have a substitutent(s) 0099 Preferred as carbocyclic group represented by ring (which has the same meaning as the above-described “(4) A is, for example, C3-10 mono-, or bicyclic carbocyclic hydroxy which may have a Substitutent(s)'.), mercapto group (e.g. C3-10 mono-, or bicyclic aromatic carbocyclic which may have a substitutent(s) (which has the same group and partially Saturated or fully saturated carbocyclic meaning as the above-described “(5) mercapto which may group, etc.). More preferably is, for example, C3-10 mono have a substitutent(s)'.), amino which may have a Substi cyclic carbocyclic group (e.g. C3-10 monocyclic aromatic tutent(s) (which has the same meaning as the above-de carbocyclic group and partially Saturated or fully saturated scribed “(6) amino which may have a substitutent(s)'.), carbocyclic group, etc.), or C5-10 bicyclic carbocyclic carbamoyl which may have a substitutent(s) (which has the group (e.g. C5-10 bicyclic aromatic carbocyclic group and same meaning as the above-described “(7) carbamoyl which partially saturated or fully saturated carbocyclic group, etc.). may have a substitutent(s)'.), Sulfamoyl which may have a More preferred is, for example, a C5-7 monocyclic carbocy Substitutent(s) (which has the same meaning as the above clic group (e.g. C5-7 monocyclic aromatic carbocyclic described “(8) sulfamoyl which may have a substi group and partially Saturated or fully saturated carbocyclic tutent(s)'.), carboxy, alkoxycarbonyl (e.g. C1-6 alkoxycar group, etc.). Most preferred is, for example, cyclopropane, bonyl Such as methoxycarbonyl, ethoxycarbonyl, tert cyclobutane, cyclopentane, cyclohexane, cycloheptane, butoxycarbonyl, etc.), Sulfo, Sulfino, phosphono, nitro, cyclopentene, cyclohexene, cycloheptene, cyclopentadiene, cyano, amidino, imino, dihydroborono, halogen (fluoro, cyclohexadiene, cycloheptadiene, benzene ring. chloro, bromo, iodo), alkylsulfinyl (e.g. C1-6 alkylsulfinyl Such as methylsulfinyl, ethylsulfinyl, etc.), aromatic ring 0.100 Preferred as heterocyclic group represented by ring Sulfinyl (e.g. C6-10 aromatic ring Sulfinyl such as phenyl A is, for example, three- to ten-membered mono-, or bicyclic Sulfinyl, etc.), alkylsulfonyl (e.g. C1-6 alkylsulfonyl such as heterocyclic group (e.g. three- to ten-membered mono-, or methylsulfonyl, ethylsulfonyl, etc.), aromatic ring Sulfonyl bicyclic aromatic heterocyclic group which contains 1 to 5 (e.g. C6-10 aromatic ring Sulfonyl Such as phenylsulfonyl, hetero atoms selected from an oxygen atom(s), a nitrogen etc.), Oxo, thioxo, (C1-6 alkoxyimino)methyl (e.g. (meth atom(s) and a Sulfur atom(s) which may be oxidized, and oxyimino)methyl, etc.), acyl (which has the same meaning which may be partially Saturated or fully saturated, etc.). as the above-described “(27) acyl'.), formyl, alkyl substi More preferably is, for example, three- to ten-membered tuted by hydroxy which may have a substitutent(s) (which monocyclic heterocyclic group (e.g. three- to ten-membered has the same meaning as the above-described “(29) alkyl monocyclic aromatic heterocyclic group which contains 1 to substituted by hydroxy which may have a substitutent(s)'.), 5 hetero atoms selected from an oxygen atom(s), a nitrogen alkyl substituted by mercapto which may have a substi atom(s) and a Sulfur atom(s) which may be oxidized, and tutent(s) (which has the same meaning as the above-de which may be partially saturated or fully Saturated, etc.), or scribed “(30) alkyl substituted by mercapto which may have five- to ten-membered bicyclic heterocyclic group (e.g. five a substitutent(s)'.), alkyl substituted by amino which may to ten-membered bicyclic aromatic heterocyclic group have a Substitutent(s) (which has the same meaning as the which contains 1 to 5 hetero atoms selected from an oxygen above-described “(31) alkyl substituted by amino which atom(s), a nitrogen atom(s) and a sulfur atom(s) which may may have a substitutent(s)'.). (alkyl which may have a be oxidized, and which may be partially saturated or fully Substitutent(s))oxycarbonyl (which has the same meaning as saturated, etc.). More preferred is, for example, a five- to the above-described “(32) (alkyl which may have a substi seven-membered monocyclic heterocyclic group (e.g. five tutent(s))oxycarbonyl.), and the 1 to 5 substitutent(s) may to seven-membered monocyclic aromatic heterocyclic group exist wherever possible. which contains 1 to 3 hetero atoms selected from an oxygen atom(s), a nitrogen atom(s) and a sulfur atom(s) which may 0.095 “A ring which may have a substitutent(s)” formed be oxidized, and which may be partially saturated or fully by two of Rs together with an atom to which they bind has saturated, etc.). Most preferred is, for example, pyridine, the same meaning as the above-described “a ring which may pyrimidine, pyrazine, tetrahydropyrimidine, dihydropy have a substitutent(s)" represented by ring'. ridazine, pyridazine, dihydropyrimidine, dihydropyrazine, 0096 “Substituent” represented by R' or R has the same dihydrotriazine, pyrazole, dihydropyrazole, pyrrole, imida meaning as the above-described Substitutent(s) represented Zole, triazole, thiophene, furan, dihydrofuran, oxadiazine, by R. tetrahydrodiazepine or diazepane ring. US 2007/019751.0 A1 Aug. 23, 2007

0101 Preferred as nitrogen atom and contains 1 to 2 hetero atoms optionally selected from an oxygen atom(s), a nitrogen atom(s) and a Sulfur atom(s) which may be oxidized, and may be partially saturated or fully saturated, etc.). More preferably is, for A example, a three- to ten-membered monocyclic heterocyclic O^n group which contains one nitrogen atom and contains 1 to 2 hetero atoms optionally selected from an oxygen atom(s), a nitrogen atom(s) and a Sulfur atom(s) which may be oxi 0102 wherein the rightward arrow represents a binding dized (e.g. three- to ten-membered monocyclic aromatic position to ring B. heterocyclic group which contains one nitrogen atom and contains 1 to 2 hetero atoms optionally selected from an 0103) is oxygen atom(s), a nitrogen atom(s) and a Sulfur atom(s) which may be oxidized, and may be partially saturated or fully saturated, etc.), or a five- to ten-membered monocyclic heterocyclic group which contains one nitrogen atom and contains 1 to 2 hetero atoms optionally selected from an oxygen atom(s), a nitrogen atom(s) and a Sulfur atom(s) which may be oxidized (e.g. five- to ten-membered bicyclic aromatic heterocyclic group which contains one nitrogen atom and contains 1 to 2 hetero atoms optionally selected from an oxygen atom(s), a nitrogen atom(s) and a Sulfur atom(s) which may be oxidized, and may be partially saturated or fully saturated, etc.). More preferred is, for example, a five- to seven-membered monocyclic heterocy N1 n clic group which contains one nitrogen atom and contains 1 to 2 hetero atoms optionally selected from an oxygen atom(s), a nitrogen atom(s) and a sulfur atom(s) which may be oxidized (e.g. five- to seven-membered monocyclic aro N1N N S O matic heterocyclic group which contains one nitrogen atom H H and contains 1 to 2 hetero atoms optionally selected from an N21 2 oxygen atom(s), a nitrogen atom(s) and a Sulfur atom(s) O s s s which may be oxidized, and may be partially saturated or N S fully saturated, etc.). Most preferred is, for example, pyrrole, imidazole, triazole, pyrazole, thiazole, oxazole, pyridine, N N pyrimidine, dihydrotriazine, pyrazine or dihydropyrimidine r1ng. NSCIC (CCCCs HN 0106 Preferred as in r r ny N Ns NS : B | - “QU

CN- COOa--, --> 0.107 wherein the leftward arrow represents a binding H position to ring A, the rightward arrow represents a binding an 1 H position to cyano, 0108) is

N Yal-N 0104 wherein a hydrogen atom bound to a nitrogen atom may be replaced by R. O) - C - X 0105 Preferred as a heterocyclic group containing at least one nitrogen atom represented by ring B is, for example, a three- to ten-membered monocyclic or bicyclic O-IX-C) - heterocyclic group which contains one nitrogen atom and contains 1 to 2 hetero atoms optionally selected from an N s e s N s oxygen atom(s), a nitrogen atom(s) and a Sulfur atom(s) which may be oxidized (e.g. three- to ten-membered mono-, C - C C1 or bicyclic aromatic heterocyclic group which contains one

US 2007/019751.0 A1 Aug. 23, 2007

0112 More preferred is -continued H N CN, N CN, 21Ne.N. 21 N rr Crs N CN, N CN,

HN rN 2 2N NN-N-N-2N

N N s CN, N H 21Ne.N. 21 N l ODC 2 'CC S X- CN, Nin X CO-CI)-e CN OCN X-CN. CN H OCC-x X- CN, Cs X CN, N N CN, N CN,

N N CN, N CN,

1- N21 O N-- X- N / CN, N 2N 2N

N Sa / CN, N / CN, N- k N N CIC (CI O N-1- X- CN, O)-21 NN -N CN, X- CN N 21NN-N N N 0113 wherein, a hydrogenatom bound to a nitrogenatom may be replaced by). C-s S. CN, CO-N-N CN, 0114. They can also be named as 5,6,7,8-tetrahydropy S O rimido-4,5-dipyrimidine-2-carbonitrile, pyrazolo 1.5-apy CN, CN, rimidine-5-carbonitrile, 2,3-dihydro-1H-pyrazolo 3,4-dpy rimidine-6-carbonitrile, pyrazolo1.5-a1.3.5triazine-2- X- X carbonitrile, 1H-pyrimidoA,5-e1.3.4oxadiazine-7- carbonitrile, 1H-pyrazolo 3,4-dpyrimidine-6-carbonitrile, imidazol-2-alpyrimidine-2-carbonitrile, 1,3-benzothiazole 2-carbonitrile, 6,7,8,9-tetrahydro-5H-pyrimido4.5-e1.4 diazepine-2-carbonitrile, 5H-pyrrolo3.2-dpyrimidine-2- carbonitrile, pyrido 2,3-dipyrimidine-2-carbonitrile, 5,7- dihydrofuro3,4-dpyrimidine-2-carbonitrile, 6,7-dihydro 5 H-cyclopentadpyrimidine-2-carbonitrile, 9H-purine-2- carbonitrile, or 1,3-benzoxazole-2-carbonitrile. 0115) Another preferred as

-N A : B | JuC CN 0111) etc. US 2007/019751.0 A1 Aug. 23, 2007 15 includes, for example, -continued N N CN,

N y - N1 NN A : B | S 2 G : A : B | Z. Nyz YC-CN N CN, ZN-1N-1C-CN, (g) s n 2 A A.: B | G NH N CN, yl/a C-CN, N HN1 n G AYN : B | N1 N Nn CN 2 Z-C CN, S. 2 0116) wherein Y and Z' each is independently a carbon atom or a nitrogen atom, ringG is a ring formed by two RS, N CN, 0117 etc. n 0118 Preferred as 21 H HN-N N CN, G - A B ZU-2A B -CN 2

N CN 0119) is concretely, for example, n s

N N CN, CN,

NS21 o skN N N-N/ H HN -N N CN, CN,

O

CN, CN, Ns CN, / \ / \ O 2 FN CN, s CN,

S 2 S N CN, n US 2007/019751.0 A1 Aug. 23, 2007 16

-continued -continued N CN rN CN, rN CN, Kr s N 2N S 2N S H CN, N \ s Nn CN, N Y2 2N Crs S N CN,

O r2N N N CN,

YSSN 2N 0120 wherein, a hydrogen atom bound to a nitrogen atom may be replaced by R. 0121 etc. 0122) Preferred as

r \ / CN, US 2007/019751.0 A1 Aug. 23, 2007 17

-continued -continued N CN, n CICNN N CN, (ICCN N CN, N-N S

N CN,

N CN, N CN, 7 n N s s o-1'Nea Y-N-N

N CN N CN

? S 2 KH 2

N N CN N N CN HN1 n 21 n N 2 S 2

H H HN-N s CN, N N CN HN N N 21 ()HN 2 C ( C

{ NS N- K N HN H-Ne N Y N-NO c O ( C ( N CN, ( N CN N 2 N 2 H | H 0.124 wherein, a hydrogen atom bound to a nitrogen Nan s atom may be replaced by R. 0.125 etc. US 2007/019751.0 A1 Aug. 23, 2007 18

0126 Preferred as -continued N CN, N

A. G y-z-z-C CN d \ 8. Yl -Z's o o G A B N CN N CN %U-CN N s N s N / \ N / \ \ 0127 is concretely, for example, =/ \, \-( \ NF o N CN, N CN, -(S1 / Y

0.128 wherein, a hydrogen atom bound to a nitrogen atom may be replaced by R. 0129) etc. 0.130) Preferred as a substitutent(s) represented by R' is, for example, branched C1-8 alkyl. More preferably is, for example, isopropyl, 2-methylpropyl, tert-butyl, or 2,2-dim ethylpropyl (neopentyl). 0131 Preferred as a substitutent represented by R is, for example, 1 to 5 substitutent(s) selected from C1-8 alkyl which may be substituted by 1 to 5 R'(s), C2-8 alkenyl which may be substituted by 1 to 5 R'(s), C2-8 alkynyl which may be substituted by 1 to 5 R'(s), C1-8 alkoxy which may be substituted by 1 to 5 R'(s) (wherein C1-8 alkoxy includes, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, Sec-butoxy, tert-butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, etc.), C1-8 alky lthio which may be substituted by 1 to 5 R'(s) (wherein C1-8 alkylthio includes, for example, methylthio, ethylthio. n-propylthio, isopropylthio, n-butylthio, isobutylthio. Sec butylthio, tert-butylthio, pentylthio, hexylthio, heptylthio. octylthio, etc.), carbocyclic group which may have a Sub stitutent(s) (phenyl, naphthyl, etc.), heterocyclic group US 2007/019751.0 A1 Aug. 23, 2007 which may have a substitutent(s) (pyridyl, thienyl, furyl, gen atom which is basic. A substitutent containing a nitrogen etc.), —O-(carbocyclic group (phenyl, naphthyl, etc.)), —O- atom which is basic represented by Rincludes, for example, (heterocyclic group (pyridyl, thienyl, furyl, etc.)), hydroxy, amino which may have a Substitutent(s) or nitrogen-con mercapto, amino, NR'R'', carboxy, C1-6 alkoxycarbonyl, taining heterocyclic group which may have a Substitutent(s). nitro, cyano, halogen, C1-6 acyl (e.g. formyl, ethanoyl, The “amino which may have a substitutent(s) has the same propanoyl, butanoyl, pentanoyl, hexanoyl, etc.), oXo, meaning as the above-described “(6) amino which may have a Substitutent(s)'. "Nitrogen-containing heterocyclic group' has the same meaning as the above-described a heterocyclic group containing at least one nitrogen atom' represented by R 3-TIA-, ring 1B TIB ring B. The "nitrogen-containing heterocyclic group' may O have 1 to 5 substitutent(s), and the substitutent(s) of nitro gen-containing heterocyclic group has the same meaning as the above-described the substitutent(s) in the “(2) carbocy clic group which may have a substitutent(s)". Preferred as R is, for example, C1-8 alkyl, amino, dimethylamino, mor pholin-4-yl, piperidin-4-yl 4-methylpiperazin-1-yl. 0.137 Preferred as T, TP or TP is, for example, a bond, or a C1-5 hydrocarbon group which may have a 3. substitutent(s). 0.138 Preferred as ring in the “ring which may have a 0132) More preferably is, for example, 1 to 5 substi substitutent(s)" represented by ring', ring', ring, tutent(s) selected from methyl, 2-methylpropyl, isopropyl. ring', ring' or ring' is, for example, C3-10 mono-, or 2,2-dimethylpropyl, ethenyl, methoxy, ethoxy, 2,2-dimeth bicyclic carbocyclic group (e.g. C3-10 mono-, or bicyclic ylpropoxy, OXo, aromatic carbocyclic group, and partially saturated or fully saturated carbocyclic group, etc.), or three- to ten-membered mono-, or bicyclic heterocyclic group (e.g. three- to ten membered mono-, or bicyclic aromatic heterocyclic group R 3-TIA , ring 1 TB-, and which contains 1 to 5 hetero atoms selected from an oxygen O atom(s), a nitrogen atom(s) and a sulfur atom(s) which may be oxidized, and which may be partially saturated or fully saturated). More preferably is, for example, C3-10 mono T2 TIC cyclic carbocyclic group (e.g. C3-10 monocyclic aromatic -O- carbocyclic group, and partially Saturated or fully saturated carbocyclic group, etc.), three- to ten-membered monocyclic heterocyclic group (e.g. three- to ten-membered monocyclic 0133) R' includes, for example, hydroxy, halogen, car aromatic heterocyclic group which contains 1 to 5 hetero bocyclic group which may have a Substitutent(s) (phenyl, atoms selected from an oxygen atom(s), a nitrogen atom(s) naphthyl, etc.), heterocyclic group which may have a Sub and a Sulfur atom(s) which may be oxidized, and which may stitutent(s) (pyridyl, thienyl, furyl, etc.). C1-6 alkoxy, —O- be partially saturated or fully saturated, etc.), C5-10 bicyclic (carbocyclic group (phenyl, naphthyl, etc.)), carboxy, C1-6 carbocyclic group (e.g. C5-10 bicyclic aromatic carbocyclic alkoxycarbonyl, -CONR'R'', etc. group, and partially saturated or fully saturated carbocyclic 0134) R' or R' includes, for example, a hydrogenatom, group, etc.), or five- to ten-membered bicyclic heterocyclic C1-6 alkyl, etc. group (e.g. five- to ten-membered bicyclic aromatic hetero cyclic group which contains 1 to 5 hetero atoms selected 0135 Preferred as T', T', T' or T'P is, for example, from an oxygen atom(s), a nitrogen atom(s) and a Sulfur a bond or a divalent C1-5 hydrocarbon group which may atom(s) which may be oxidized, and which may be partially have a substitutent(s), —O-(a divalent C1-5 hydrocarbon saturated or fully saturated, etc.). More preferably is, for group which may have a substitutent(s))-O-, -E-E-E'- example, C5-7 monocyclic carbocyclic group (e.g. C5-7 (wherein E' and E are each independently, a bond or a monocyclic aromatic carbocyclic group, and partially satu divalent C1-5 hydrocarbon group which may have a substi rated or fully saturated carbocyclic group, etc.), or five- to tutent(s), E is O—, NR, S , C(=O) , seven-membered monocyclic heterocyclic group (e.g. five C(=O)NR' , NRC(=O) , SONR' , to seven-membered monocyclic aromatic heterocyclic group NRSO , C(=O)C) , OC(=O) , or which contains 1 to 3 hetero atoms selected from an oxygen -NR'C(=O)NR'-(wherein R'' and R'' are each inde atom(s), a nitrogen atom(s) and a sulfur atom(s) which may pendently a hydrogen atom or hydrocarbon group which be oxidized, and which may be partially saturated or fully may have a substitutent(s).). Preferred as E is saturated, etc.). Most preferably is, for example, cyclopro C(=O)NR' , or NRC(=O) . Preferred as a pane, cyclobutane, cyclopentane, cyclohexane, cyclohep divalent C1-5 hydrocarbon group represented by E' or E is tane, cyclopentene, cyclohexene, cycloheptene, cyclopenta C1-5 alkylene. Preferred as hydrocarbon group which may diene, cyclohexadiene, cycloheptadiene, benzene, have a substitutent(s) represented by R' or R' is C1-8 piperidine, piperazine, morpholine, pyridine, pyrimidine, alkyl. pyrazine, tetrahydropyrimidine, dihydropyridazine, 0136 Preferred as R is, for example, a hydrogen atom, pyridazine, dihydropyrimidine, dihydropyrazine, dihydrot C1-5 hydrocarbon group, a Substitutent containing a nitro riazine, pyrazole, dihydropyrazole, pyrrole, imidazole, tria US 2007/019751.0 A1 Aug. 23, 2007 20

Zole, thiophene, furan, dihydrofuran, oxadiazine, tetrahy 0145 wherein R is drodiazepine or diazepane ring. 0139 Preferred as substitutent in the “ring which may have a substitutent(s)" represented by ring', ring", ring, ring', ring P. ring' or ring "P is, for example, 1 to 3 R3-, s substitutent(s) selected from C1-8 alkyl which may be substituted by 1 to 5 R'(s), C2-8 alkenyl which may be substituted by 1 to 5 R'(s), C2-8 alkynyl which may be substituted by 1 to 5 R'(s), C1-8 alkoxy which may be substituted by 1 to 5 R'(s), C1-8 alkylthio which may be O-O- O substituted by 1 to 5 R'(s) carbocyclic group which may have a Substitutent(s) (phenyl, naphthyl, etc.), heterocyclic group which may have a Substitutent(s) (pyridyl, thienyl, furyl, etc.), —O-(carbocyclic group (phenyl, naphthyl, etc.)), —O-(heterocyclic group (pyridyl, thienyl, furyl, etc.)), hydroxy, mercapto, amino, NR'R'', carboxy, C1-6 0146 other symbols have the same meanings as alkoxycarbonyl, nitro, cyano, halogen, C1-6 acyl (e.g. described above, formyl, ethanoyl, propanoyl, butanoyl, pentanoyl, hexanoyl, 0147 formula (I-1-2) etc.) and oxo. 0140. Among compounds of formula (I), a preferred is a compound of formula (I-1) (I-1-2)

(I-1)

0.148 wherein all symbols have the same meanings as described above, 0141 wherein R is 0149 or formula (I-1-3)

R3-TIA-, O-- (I-1-3) -O-- O

TID 0.150 wherein all symbols have the same meanings as 3. -O-r described above, 0151 a salt thereof, a solvate thereof, or an N-oxide 0142 n2 is 0 or an integer of 1 to 9, other symbols have thereof, or a prodrug thereof. the same meanings as described above, 0152 Among compounds of formula (I-1-2), a preferred 0143 a salt thereof, a solvate thereof, or an N-oxide is a compound of formula (I-1-2a) thereof, or a prodrug thereof. 0144. Among compounds of formula (I-1), a preferred is (I-1-2a) a compound of formula (I-1-1)

(I-1-1) (R)2 R-E3-E2-El

0.153 wherein all symbols have the same meanings as described above,

US 2007/019751.0 A1 Aug. 23, 2007

double bond, ring, fused ring (E. Z. cis, trans), isomers by bonylated, (5-methyl-2-oxo-1,3-dioxolene-4-yl)methoxy the presence of asymmetric carbon etc. (R-, S-form, C.-, carbonylated, tetrahydrofuranylated, pyrrolidylmethylated, B-configuration, enantiomer, diastereomer), optical isomers pivaloyloxymethylated, acetoxymethylated, tert-butylated having optical rotation (D, L, d. 1), polars by chromatogra and the like); when the compound of formula (I) has phy separation (more polar compound, less polar com hydroxy group, the hydroxy group of the compound is pound), equilibrium compound, rotamer, a compound of acylated, alkylated, phosphorylated, borated (e.g. the arbitrary ratios of those and racemic mixture. hydroxy group of the compound of formula (I) is acetylated, palmitoylated, propanoylated, pivaloylated, Succinylated, 0294. An optically active compound in the present inven fumarylated, alanylated, dimethylaminomethylcarbonylated tion includes not only 100% optically pure compound and and the like); when the compound of formula (I) has carboxy may include (an)other optical isomer(s) less than 50%. group, the carboxy group of the compounds are ethylesteri 0295) The salt of the compound of formula (I) includes fied, phenylesterified, carboxymethylesterified, dimethy all of the salt which are pharmaceutically acceptable. With laminomethylesterified, pivaloyloxymethylesterified, regard to the pharmaceutically acceptable salts, those which ethoxycarbonyloxyethylesterified, phthalidylesterified, are low-toxic and soluble in water are preferred. Examples (5-methyl-2-oxo-1,3-dioxolene-4-yl)methylesterified, of appropriate salts are salt with alkaline metal (such as cyclohexyloxycarbonylethylesterified, methylamidated and potassium, Sodium and lithium), salt with alkaline earth the like); and the like. These compounds can be manufac metal (Such as calcium and magnesium), ammonium salt tured by the conventional methods per se. In addition, the (such as tetramethylammonium salt and tetrabutylammo prodrugs of the compounds of formula (I) may be solvates. nium salt), salt with organic amine (such as triethylamine, The prodrugs of the compound of formula (I) may be those methylamine, ethylamine, dimethylamine, cyclopenty ones which are converted to a compound of formula (I) in lamine, benzylamine, phenethylamine, piperidine, monoet physiological conditions as described in Molecular Design, hanolamine, diethanolamine, tris(hydroxymethyl)methy as Vol. 7 of Development of pharmaceutical drugs, 1990. lamine, lysine, arginine and N-methyl-D-glucamine) and 163-198, Hirokawa Publishing. acid addition salt such as inorganic acid salt (e.g., hydro chloride, hydrobromide, hydroiodide, sulfate, phosphate and Methods for the Preparation of the Compound of nitrate, etc.) and organic acid salt (e.g., formate, acetate, the Present Invention propionate, trifluoroacetate, lactate, tartrate, oxalate, mal 0301 The compound of the present invention represented onate. Succinate, fumarate, malate, maleate, benzoate, cit by formula (I) can be prepared by methods which properly rate, methanesulfonate, ethanesulfonate, benzenesulfonate, improved and combined known methods, such as methods toluenesulfonate, isethionate, glucuronate, gluconate, aspar described in Comprehensive Organic Transformations: A tate, and glutamate, etc.), etc.). Guide to Functional Group Preparations, 2nd Edition (Rich 0296 An N-oxide of a compound of formula (I) means a ard C. Larock, John Wiley & Sons Inc, 1999), methods compound of formula (I) which nitrogen is oxidized. An described below, or methods described in Examples. In each N-oxide of a compound of formula (I) may also be salt of method described below, a starting material can be used as alkaline (earth) metal, ammonium, organic amine, or acid a salt thereof. An example of the salt includes a pharma addition salt. ceutically acceptable salt of the compound of formula (I) 0297. The salt of a compound of formula (I) includes a described above. quaternary ammonium salt thereof. Aquaternary ammonium 1 A compound represented by formula (I) can be prepared salt means a salt of a compound of formula (I) which by cyanation of a compound represented by formula (II) nitrogen is quaternarized by proper group. Such as alkyl optionally substituted by substitutent(s) (C1-8 alkyl option ally substituted by phenyl, etc.). (II) 0298 The proper solvate of the compound of formula (I) includes, for example, hydarate, alcoholate (ethanolate, etc.), etc. The solvate is preferably non-toxic and water soluble. The solvate of the compound of formula (I) also includes solvates of the above-mentioned alkaline (earth) metal salt thereof (quaternary) ammonium salt thereof, 0302 wherein X is a leaving group, for example, halo organic amine salt thereof, acid addition salt thereof, and gen, mesyloxy, tosyloxy, etc., R has the same meaning as R. N-oxide thereof. With proviso that, carboxy group, hydroxy group, amino 0299 The compounds of formula (I) can be converted to group or mercapto group in R may be protected, if necessary. salts thereof, N-oxide thereof, or solvate thereof by known Other symbols have the same meanings as described above, methods. 0303 and if necessary, followed by removal of the pro tecting group. 0300. The prodrugs of the compound of formula (I) mean the compounds converted into the compound of formula (I) 0304. The cyanation is well known. For example, it may by the reactions of enzymes, gastric acid and the like in an be carried out by reacting a compound represented by organism. As the prodrugs of the compound of formula (I), formula (II) with cyanation reagent (e.g. potassium cyanide, when the compound of formula (I) has amino group, the Sodium cyanide, tetrabutylammonium cyanide, tetraethy amino group of the compound is acylated, alkylated, or lammonium cyanide, etc.) in an organic solvent (e.g. dim phosphorylated, (e.g. the amino group of the compound of ethylsulfoxide, dimethylformamide, dioxane or mixed sol formula (I) is eicosanoylated, alanylated, pentylaminocar vent thereof and water), in the presence of tertiary amine US 2007/019751.0 A1 Aug. 23, 2007 26

(e.g. 1,4-diazabicyclo2.2.2]octane (DABCO), trimethy complex e.g. tetrakistriphenylphosphine palladium (O), bis lamine, dimethylaminopyridine, etc.) at 0 to 150° C. (triphenylphosphine) palladium (II) dichloride, palladium (II) acetate and tris(triphenylphosphine) rhodium (I) chlo 0305 The reaction for removing the protective group for ride, etc. in the presence or absence of a phosphine agent carboxy, hydroxy, amino or mercapto is known and its (e.g. triphenyl phosphine, etc.) in the presence of a trap examples are as follows. reagent (e.g. tributyltin hydride, triethylsilane, dimedone, (1) a deprotection reaction by hydrolyzing reaction with an morpholine, diethylamine, pyrrolidine, etc.), an organic acid alkali; (e.g. acetic acid, formic acid, 2-ethylhexanoic acid, etc.) and/or an organic acid salt (e.g. sodium 2-ethylhexanoate, (2) a deprotection reaction under an acidic condition; potassium 2-ethylhexanoate, etc.) in an organic solvent (e.g. (3) a deprotection reaction by hydrogenolysis; dichloromethane, dimethylformamide, tetrahydrofuran, ethyl acetate, acetonitrile, dioxane, ethanol, etc.), water or a (4) a deprotection reaction of silyl, mixed solvent thereof. (5) a deprotection reaction using a metal; and 0312 Apart from the above, the deprotection may also be (6) a deprotection reaction using metal complex. effected, for example, according to the methods described in T. W. Greene, Protective Groups in Organic Synthesis, 0306 Those methods will be specifically illustrated as Wiley, New York, 1999. follows. 0313 The protective group of carboxyl includes, for 0307 (1) A deprotection reaction using an alkali is car example, methyl, ethyl, allyl, tert-butyl, trichloroethyl, ben ried out, for example, at 0 to 40° C. using a hydroxide of Zyl (Bn) or phenacyl, p-methoxybenzyl, trity1, 2-chlorotrityl alkaline metal (e.g. sodium hydroxide, potassium hydroxide or polymer-Supported group bound thereby, etc. and lithium hydroxide, etc.), a hydroxide of alkaline earth 0314. The protecting group of hydroxy includes, for metal (e.g. barium hydroxide and calcium hydroxide, etc.), example, methyl, trityl, methoxymethyl (MOM), 1-ethoxy a carbonate (e.g. sodium carbonate and potassium carbonate, ethyl (EE), methoxyethoxymethyl (MEM), 2-tetrahydropy etc.), or an aqueous solution thereof or a mixture thereof in ranyl (THP), trimethylsilyl (TMS), triethylsilyl (TES), tert an organic solvent (e.g. methanol, tetrahydrofuran and diox butyldimethylsilyl (TBDMS), tert-butyldiphenylsilyl ane etc.). (TBDPS), acetyl (Ac), pivaloyl, benzoyl, benzyl (Bn), 0308 (2) A deprotection reaction under an acidic condi p-methoxybenzyl, allyloxycarbonyl (Alloc), and 2.2.2- tion is carried out, for example, at 0 to 100° C. in an organic trichloroethoxycarbonyl (Troc), etc. acid (e.g. acetic acid, trifluoroacetic acid, methanesulfonic acid or p-toluenesulfonic acid, etc.), an inorganic acid (e.g. 0315. The protecting group of amino includes, for hydrochloric acid and sulfuric acid, etc.) or a mixture thereof example, benzyloxycarbonyl, tert-butoxycarbonyl, allyloxy (e.g. hydrogen bromidefacetic acid) in an organic solvent carbonyl (Alloc), 1-methyl-1-(4-biphenyl)ethoxycarbonyl (e.g. dichloromethane, chloroform, dioxane, ethyl acetate (Bpoc), trifluoroacetyl, 9-fluorenylmethoxycarbonyl and anisole etc.) in the presence or absence of 2.2.2- (Fmoc), benzyl (Bn), p-methoxybenzyl, benzyloxymethyl trifluoroethanol. (BOM) or 2-(trimethylsilyl)ethoxymethyl (SEM), etc. 0309 (3) A deprotection reaction by hydrogenolysis is 0316 The protective group of mercapto includes, for carried out, for example, at 0 to 200° C. under a hydrogen example, benzyl, methoxybenzyl, methoxymethyl (MOM), atmosphere of ordinary pressure or high pressure or in the 2-tetrahydropyranyl (THP), diphenylmethyl and acetyl (Ac), presence of ammonium formate in the presence of a catalyst etc. (e.g. palladium-carbon, palladium black, palladium hydrox 0317. With regard to the protective group for carboxy, ide-carbon, platinum oxide and Raney nickel, etc.) in a hydroxy, amino and mercapto, there is no particular limita solvent e.g. an ether (e.g. tetrahydrofuran, dioxane, tion to the above ones So far as it is a group which is able dimethoxyethane and diethyl ether, etc.), an alcohol (e.g. to be easily and selectively removed. For example, a depro methanol and ethanol, etc.), a benzene (e.g. benzene and tection reaction may be carried out by a method described in toluene, etc.), a ketone (e.g. acetone and methyl ethyl “T. W. Greene, Protective Groups in Organic Synthesis, ketone, etc.), a nitrile (e.g. acetonitrile, etc.), an amide (e.g. John Wiley & Sons Inc, 1999”. dimethylformamide, etc.), water, ethyl acetate, acetic acid or a mixed solvent comprising two or more thereof. 0318. As persons skilled in the art can easily understand that the aimed compound of the present invention is able to (4) A deprotection reaction of silyl is carried out, for be easily produced by using appropriate ones among those example, at 0 to 40° C. using tetrabutylammonium fluoride deprotection reactions. in an organic solvent miscible with water (e.g. tetrahydro 2 Among a compound represented by formula (I), a furan and acetonitrile etc.). compound represented by formula (IA) 0310 (5) A deprotection reaction using metal is carried out, for example, at 0 to 40°C. with or without ultrasonic

wave in the presence of powdery Zinc in an acidic solvent (IA) (e.g. acetic acid, a buffer of pH 4.2 to 7.2 and a mixed (R)2 Solution of a solution thereof with an organic solvent such as tetrahydrofuran, etc.). 0311 (6) A deprotection reaction using a metal complex is carried out, for example, at 0 to 40° C. using a metal US 2007/019751.0 A1 Aug. 23, 2007 27

0319 wherein all symbols have the same meanings as 0331 Amidation reaction or esterification reaction is described above. known, for example, (1) a method using acid halide; (2) a 0320 can be also prepared by reaction described herein method using mixed anhydride; (3) a method using a con after. densing agent, etc. To explain these methods concretely, (a) Among a compound represented by formula (IA), a 0332 (1) The method using acid halide is carried out, for compound wherein E2 is C(=O)NR' , example, by Subjecting to a reaction carboxylic acid and NR'C(=O) , —C(=O)C) , or - OC(-O) , i.e. a acid-halogenating agent (oxalyl chloride, thionyl chloride, compound represented by formula (IA-1) etc.) in an organic solvent (chloroform, dichloromethane, diethyl ether, tetrahydrofuran, etc.) or without a solvent, at (LA-1) between -20° C. and refluxing temperature, and then sub (R)2 jecting thus obtained acid halide to a reaction with amine or R4-E3-E2-1-El alcohol in the presence of base (pyridine, triethylamine, dimethylaniline, dimethylaminopyridine, diisopropylethy lamine, etc.) in an organic solvent (chloroform, dichlo romethane, diethyl ether, tetrahydrofuran, etc.) at a tempera 0321) wherein E2-1 is C(=O)NR' , ture of 0 to 40° C. Alternatively, it may be carried out by NR'C(=O) –C(=O)C) , or - OC(=O) , and Subjecting acid halide to a reaction with amine or alcohol in other symbols have the same meanings as described above. an organic solvent (dioxane, tetrahydrofuran, etc.) using an 0322 can be prepared by a amidation or esterification of aqueous alkali Solution (an aqueous solution of Sodium a compound represented by formula (III-1) bicarbonate or sodium hydroxide, etc.) at a temperature of 0 to 40° C.

(III-1) 0333 (2) In a method where mixed anhydride is used, for (R)na example, carboxylic acid is subjected to a reaction with acid halide (pivaloyl chloride, tosyl chloride, mesylchloride, etc.) HOOC-E- or acid derivative (ethyl chloroformate, isobutyl chlorofor mate, etc.) in an organic solvent (chloroform, dichlo romethane, diethyl ether, tetrahydrofuran, etc.) or without a 0323 wherein E'' has the same meaning as E'. With Solvent, in the presence of a base (pyridine, triethylamine, proviso that, carboxy group, hydroxy group, amino group or dimethylaniline, dimethylaminopyridine, diisopropylethy mercapto group in E'' may be protected, if necessary. Other lamine, etc.), at a temperature of 0 to 40°C., and then thus symbols have the same meanings as described above, obtained mixed anhydride is subjected to a reaction with amine or alcohol in an organic solvent (chloroform, dichlo 0324 with a compound represented by formula (IV-1) romethane, diethyl ether, tetrahydrofuran, etc.) at a tempera R4-1-E3-1-Rs (IV-1) ture of 0 to 40° C. 0325 wherein E' and R'' have the same meanings as E and R' respectively. With proviso that, carboxy group, 0334 (3) In a method where a condensing agent is used, hydroxy group, amino group or mercapto group in E' and for example, carboxylic acid is subjected to a reaction with R* may be protected, if necessary. R is NHR', or amine or alcohol derivative in an organic solvent (chloro —OH, and other symbols have the same meanings as form, dichloromethane, dimethylformamide, diethyl ether, described above, tetrahydrofuran, etc.) or without a solvent, in the presence or absence of a base (pyridine, triethylamine, dimethylaniline, 0326 or a compound represented by formula (III-2) dimethylaminopyridine, etc.), using a condensing agent (1,3-dicyclohexylcarbodiimide (DCC), 1-ethyl-3-3-(dim ethyl amino)propylcarbodiimide (EDC), 1,1'-carbonyldi

(III-2) (R)2 imidazole (CDI), 2-chloro-1-methylpyridinium iodide, 1-propanephosphonic acid cyclic anhydride (PPA), etc.) in RS- El-l the presence or absence of 1-hydroxybenzotriazole (HOBt) or 1-hydroxy-7-azabenzotriazole (HOAt), at a temperature of 0 to 40° C. 0327 wherein all symbols have the same meanings as 0335 The reactions (1), (2) and (3) are desirably carried described above, out under atmosphere of inert gas (argon, nitrogen, etc.) and 0328 with a compound represented by formula (IV-2) anhydrous conditions. R1-1-E3-1 -COOH (IV-2) 0336. The removal of the protecting group may be carried 0329 wherein all symbols have the same meanings as out by the above described method. described above, (b) Among a compound represented by formula (IA), a 0330) if necessary, followed by removal of the protecting compound wherein E is - SONR' , or - NR'SO , group. i.e. a compound represented by formula (IA-2) US 2007/019751.0 A1 Aug. 23, 2007 28

dine, triethylamine, dimethylaniline, dimethylaminopyri dine, etc.) in an organic Solvent (chloroform, dichlo (IA-2) romethane, diethyl ether, tetrahydrofuran, etc.) at a (R)2 temperature of 0 to 40° C. R-E3-E2-2-El 0348 The removal of the protecting group may be carried out by the above described method. (c) Among a compound represented by formula (IA), a 0337 wherein E is SONR' , or NRSO, , compound wherein E is —O , NR' , or—S , i.e. a and other symbols have the same meanings as described compound represented by formula (IA-3) above, 0338 can be prepared by sulfonamidation of a compound (IA-3) represented by formula (V-1) (R)na R-E-E2-3-El (V-1) (R)2 HOS-E- 0349 wherein E is - O -, - NR' , or - S , and other symbols have the same meanings as described above, 0350 can be prepared by reaction of a compound repre 0339 wherein all symbols have the same meanings as sented by formula (VII-1) described above, 0340 with a compound represented by formula (VI-1) (VII-1) (R)na XI-El-l (VI-1) R-E--- R10 0351 wherein X is a leaving group, for example, halo 0341 wherein all symbols have the same meanings as gen, mesyloxy, tosyloxy, etc., and other symbols have the described above, same meanings as described above, 0342 or a compound represented by formula (V-2) 0352 with a compound represented by formula (VIII-1) R4-1-E3-1-R6 (VIII-1) 0353 wherein R is -OH, -SH or - NHR', and other (V-2) symbols have the same meanings as described above, (R)2 H-N-El 0354 or a compound represented by formula (VII-2) R10

(VII-2) (R)2 0343 wherein all symbols have the same meanings as R6- El-l described above, 0344) with a compound represented by formula (VI-2) R4-1-E-SOH (VI-2) 0345 wherein all symbols have the same meanings as 0355 wherein all symbols have the same meanings as described above, described above, 0346) if necessary, followed by removal of the protecting 0356 with a compound represented by formula (VIII-2) group. 0347 Sulfonamidation reaction is known, for example, 0357 wherein all symbols have the same meanings as by Subjecting to a reaction Sulfonic acid and acid-haloge described above, nating agent (oxalyl chloride, thionyl chloride, phosphorus tetrachloride, phosphorus trichloride, etc.) in an organic 0358) if necessary, followed by removal of the protecting solvent (chloroform, dichloromethane, diethyl ether, tet group. rahydrofuran, methyl tert-butyl ether, etc.) or without a 0359 The reaction is well known. For example, it may be solvent, at between -20° C. and refluxing temperature, and carried out with hydroxide of alkaline metal (sodium then Subjecting thus obtained acid halide to a reaction with hydroxide, potassium hydroxide, lithium hydroxide, etc.), amine in the presence of base (diisopropylethylamine, pyri hydroxide of alkaline earth metal (barium hydroxide, cal US 2007/019751.0 A1 Aug. 23, 2007 29 cium hydroxide, etc.) or carbonate (Sodium carbonate, Edition (Richard C. Larock, John Willey & Sons Inc, 1999) potassium carbonate, etc.), or aqueous Solution thereof, or a or the methods described in Chem. Ber., 96, 1505, 1963: mixture thereof at about 0 to 100° C. in an organic solvent Chem. Ber., 98, 1081, 1965; J. Org. Chem., 53,4137, 1988: (dimethylformaimide, dimethylsulfoxide, chloroform, Bioorg. Med. Chem. Lett., 92, 2569-2572, 1999: Synlett, dichloromethane, diethyl ether, tetrahydrofuran, methyl 2000(6), 829-831; Synthesis, 2001, 55-62; J. Chem. Soc., t-butyl ether, etc.). Perkin Trans 1, 2002, 1847, etc. 0360 The removal of the protecting group may be carried out by the above described method. 0371 For example, among a compound represented by formula (I), a compound represented by formulae (IB), (IC), 0361 Among a compound represented by formula (IA (ID-1), (ID-2), (IE), (IF-1), (IF-2), (IG-1), (IG-2), or (IG-3) 3), a compound wherein E is -O-, i.e. a compound can also be prepared by reaction schemes 1 to 6 described represented by formula (IA-3-1) hereinafter. (0.372) In the reaction schemes, R' represents halogen, (IA-3-1) represents a protective group of amino, Ph represents (R)2 phenyl, TEA represents triethylamine, Me represents R- E3, E2-3-1 -El methyl, Et represents ethyl, Boc represents tert-butoxycar bonyl, R' represents C1-8 alkyl, and other symbols have the same meanings as described above. 0362 wherein E is -O-, and other symbols have the same meanings as described above, Reaction Scheme 1 0363 can be prepared by reaction of a compound repre R101 n R sented by formula (IX) N N1 NR 102 els H (IX) R101 % R101 base (R)2 R10 HO-E-1 N N 2 cyanation R101 NN N R101 R 0364 wherein all symbols have the same meanings as R10 described above, NN H es HeR-s-H 0365 with a compound represented by formula (X) N 2 PdCl2(PPh3)2 R 4-1-E3-I-OH (X) R101 N CN CuI, TEA 0366 wherein all symbols have the same meanings as R described above, 0367) if necessary, followed by removal of the protecting group. Introduction of R group 0368. The reaction is well known. For example, it may be Her carried out with corresponding alcohol compound at about 0 to 60° C. in an organic solvent (dichloromethane, diethyl ether, tetrahydrofuran, acetonitrile, benzene, toluene, etc.) in the presence of azo compound (diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate, 1,1'-(azodicarbon deprotection yl)dipiperidine, 1,1'-azo-bis(N,N-dimethylformamide), etc.) --- and phosphine compound (triphenylphosphine, tribu cyclization tylphosphine, trimethylphosphine, polymer-supported triph Her enylphosphine, etc.). 0369 The removal of the protecting group may be carried out by the above described method. 0370. The compound represented by formulae (II), (III 1), (III-2), (IV-1), (IV-2), (V-1), (V-2), (VI-1), (VI-2), (VII 1), (VII-2), (VIII-1), (VIII-2), (IX), or (X) used as a starting material are known itself, or can be prepared easily by the methods described in examples or the methods per se Such (IB) as the methods described in Comprehensive Organic Trans formations. A Guide to Functional Group Preparations, 2nd US 2007/019751.0 A1 Aug. 23, 2007

-continued Reaction Scheme 2 R10 H HN NN R NN1,N102N n N 1. H als Introduction R101 N1 R101 base N1 N CN of R soup R10 n N R

N- al ---cyclization (IC-1) Ro1 N N R101 R R R N NN N NN deprotection N es 2 He N N R101 R (IC-2) R

Reaction Scheme 3 R R N OH NH, CH3(COEt)2 S1 N NS NaOEt N halogenation M N -N 21 --- N -NH OH R R R N R101 N R N CN NS N Introduction NS n NS n M of R group N cyanation N N-Nna He- N-Nna -- N-Nna

R101 R R (ID-1) R R Pol-C/H.2 N R' cyanation N CN s n s s n N -N 2 N-N 2

R (ID-2)

-continued Reaction Scheme 4 HN n N R K als cyanation i NH2 1)S S On 1. COEt N N R10 | -- s N N 2) NaOH R NH US 2007/019751.0 A1 Aug. 23, 2007 31

-continued -continued R Boc Boc H n 1 N S N s M MeI n N cyanation

i-" N R101 O

N N deprotection N S -- s n YMe 2 M halogenation N CN N NH n N CDI 2 -- N CN

N S n N s n YMe Introduction N N N of R group

R (IF-1)

R’n N S N NN s n Sme N oxidation N N He O1. N els CN

R (IF-2)

N SOMe s n N cyanation N N Ho Reaction Scheme 6

R n N R N1 NR 102 R N ... base Srs R103OC N-N 2N SN Ng || al cyanation

R YN 4. R101 (IE)

deprotection Reaction scheme 5 -- R10 NN R’-NH 8Se. R101 4. R101 st R10 Introduction of R group NN BocNH He RN al ---base US 2007/019751.0 A1 Aug. 23, 2007 32

0381 5 ul of Synthesized substrate (carbobenzoxy-L- -continued phenylalanyl-L-arguine-4-methylchromanyl-7-amide O R-O L-prolyl-L-phenylalanyl-L-arginine-4-methylchromanyl-7- amide) solution and 5 ul of cysteine protease inhibitor 7N1SN Solution of several concentrations, 80 ul of cathepsin L 2 enzyme reaction buffer (400 mmol/L of acetic acid, 4 N N es CN mmol/L of EDTA, 8 mmol/L of DTT are mixed to adjust to pH 5.5) and 10 ul of cathepsin L enzyme solution are mixed R and the increase of fluorescence intensity is measured (weX (IG-2) (IG-3) (excitation wavelength)=355 nm, wem (fluorescence wave length)=460 nm) when reacted at 37° C. 0373 All reactions in each reaction scheme is well (4) Measurement of Calpain Inhibitory Activity known. All starting materials and reagents in the reaction schemes are known compounds, or can be prepared easily by 0382. The activity is measured according to the method known methods. described in Calcium-depending protease, Seibutsukagaku Jikkenhou (Biochemistry Experimental Method) Tampa 0374. In each reaction of the present specification, reac kubunkaikouso (Protease) 1, 57 (1993). tion products may be purified by conventional techniques, for example, distillation under atmospheric or reduced pres (5) Measurement of Caspase-1 Inhibitory Activity Sure, high performance liquid chromatography, thin layer 0383 Caspase-1 inhibitory activity can be measured in chromatography or column chromatography using silica gel or magnesium silicate, washing or recrystallization, etc. the way prescribed hereinafter. Purification may be carried out after each reaction, or after 0384 50 ul of caspase-1 enzyme reaction solution (20 a series of reactions. mmol/L of 4-(2-hydroxyethyl)-1-piperazinethanesulfonate sodium hydroxide buffer (pH 7.4), 10 mmol/L of potassium Pharmacological activities of the compounds of the present chloride, 1.5 mmol/L of magnesium chloride, 0.1 mmol/L invention: EDTA, 10% glycerol) and 50 ul of cysteine protease inhibi 0375. The following methods can be used as pharmaco tor Solution of several concentrations, 50 ul of caspase-1 logical test besides the methods described in “Biological enzyme solution and 100 ul of synthesized substrate (acetyl Examples.” L-tyrosinyl-L-valinyl-L-alanyl-L-aspartic acid-4-methyl chromanyl-7-amide) solution of several concentrations are (1) Measurement of Cathepsin B Inhibitory Activity reacted at 37°C. and the fluorescence intensity is measured 0376 Cathepsin B inhibitory activity can be measured in (vex (excitation wavelength)=355 nm, wem (fluorescence the way prescribed hereinafter. wavelength)=460 nm). 0377 10 uI of synthesized substrate (carbobenzoxy-L- (6) Investigation in Bone Resorption Inhibitory Activity arginyl-L-arginine-4-methyl-chromanyl-7-amide or car Using Mouse Calvaria Cultivation System bobenzoxy-L-phenylalanyl-L-arginine-4-methyl-chroma 0385 Mouse neonatal calvaria is cultured in D-minimum nyl-7-amide) solution of several concentrations, 10 uL of essential medium containing cysteine protease inhibitor cysteine protease inhibitor Solution of several concentra (mixture of Penicillin G potassium (final concentration 100 tions, 70 ul of cathepsin B enzyme reaction buffer (mixture U/ml), Streptomycin Sulfate (final concentration 0.1 mg/ml), of 400 mmol/L of acetic acid, 4 mmol/L of EDTA, 8 mmol/L bovine serum albumin (final concentration 0.1%), glutamine of DDT to adjust to pH 5.5) and 10 ul of cathepsin Benzyme (final concentration 0.3 mg/ml) in D-minimal essential Solution are mixed and the increase of fluorescence intensity medium) with incitant (parathyroid hormone (PTH) or aro is measured (Wex (excitation wavelength)=355 nm, Wem tinoid) at 37° C. and the calcium concentration in the culture (fluorescence wavelength)=460 nm) when reacted at 37°C. medium is measured. (2) Measurement of Cathepsin S Inhibitory Activity (7) Bone Resorption Pit Formation Test Using Rabbit Osteo 0378 Cathepsin S inhibitory activity can be measured in clast Cells the way prescribed hereinafter. 0386 Osteoclast cells collected from rabbit bones are 0379 10 ul of synthesized substrate (carbobenzoxy-L- sowed over slices of bovine cortical bone, dentine or teeth leucyl-L-leucyl-L-arguinine-4-methyl-chromanyl-7-amide) of toothed whale and are cultured at 37° C. in C-minimal solution and 5 ul of cysteine protease inhibitor solution of essential medium containing final concentration 5% of fetal several concentrations, 75ul of cathepsin S enzyme reaction bovine serum and various concentrations of cysteine pro buffer (100 mmol/L of sodium phosphate, 2 mmol/L of tease inhibitor. The pits form on the slices by the osteoclast EDTA, 2 mmol/L of DTT are mixed to adjust to pH 6.5) and cells are observed and at the same time type-I collagen 10 ul of cathepsin S enzyme solution are mixed and the C-terminal telopeptide (CTx) concentration in culture increase of fluorescence intensity is measured (weX(excita medium can be measured. tion wavelength)=355 nm, wem (fluorescence wavelength)= (8) Investigation of Immune Reaction Inhibitory Effect 460 nm) when reacted at 37° C. Using Antigen-Sensitized Mouse Spleen Cells (3) Measurement of Cathepsin L. Inhibitory Activity 0387 Spleen cells are collected from mice sensitized by 0380 Cathepsin Linhibitory activity can be measured in ovalbumin (OVA) several times. Inhibitory effect of cysteine the way prescribed hereinafter. protease inhibitors against immune response induced by US 2007/019751.0 A1 Aug. 23, 2007

OVA stimulus can be investigated, using cytokine concen spontaneous thrombocytopenia, disseminated intravascular tration and immunoglobulin concentration in culture solu coagulation (DIC), etc.), viral hepatitis (A, B, C, F, etc.) or tion as indicators. hepatitis medicamentosa and cirrhosis, etc., dementia Such as Alzheimer's disease, Alzheimer-type senile dementia, (9) Investigation in Inhibitory Effect Against Bone Resorp cerebrovascular injury, neurodegenerative disease, adult tion Using the Rat PTH Hypercalcemia Model acute respiratory distress syndrome, infectious diseases, 0388. The effect of cysteine protease inhibitor (compul prostatomegaly, hysteromyoma, bronchial asthma, arterio sory oral administration, intraperitoneal administration) on Sclerosis, hyperlipidemia, all kinds of lusus naturae, nephri bone resorption which is promoted by intravenous admin tis, senile cataract, chronic fatigue syndrome, myodystro istration of parathyroid hormone (PTH) solution (30 g/ml) phy, peripheral nerve injury, etc.), diseases induced by can be investigated in rats, using calcium concentration in immune response disorder (graft versus host diseases, rejec blood as an indicator. tion in transplantation, allergic diseases (asthmatic bronchi tis, atopic dermatitis, allergic rhinitis, hay fever, diseases by (10) Studies on Bone Resorption Inhibitory Effect Using house dust, hyperSensitive pneumonia, food allergy, etc.), TPTx rat PTHrP-Induced Hypercalcemia Model psoriasis, rheumatoid arthritis, etc.), autoimmune diseases 0389. The effect of cysteine protease inhibitor (compul (insulin dependent (type I) diabetes, systemic lupus erythe sory oral administration, intraperitoneal administration) on matosus, Hashimoto's diseases, multiple Sclerosis, etc.), bone resorption, promoted by Subcutaneous administration diseases induced by decomposition of proteins which com of parathyroid hormone related peptide (PTHrP) to a fasting pose a body (myodystrophy, cataract, periodontitis, hepato rat (thyroparathyroidectomized; TPTX) can be investigated, cyte injury by bile acid (cholestatic cirrhosis etc.), etc., using calcium concentration in blood as an indicator. decomposition of alveolus elastica (emphysema etc.), ischemic diseases (brain ischemia, brain disorder by (11) Measurement of Cathepsin H Inhibitory Activity ischemic reperfusion, cardiac infarction, ischemic liver 0390. Using Arg-MCA aminomethylcoumarin as syn damage, etc.), etc.), shock (septic shock, systemic inflam thetic substrate, according to the method described in FEBS matory responsive syndrome, endotoxin shock, acidosis, Lett. 280(2), 307-310/1991, Methods Enzymol. 80, 535 etc.), circulatory disorder (arteriosclerosis, restenosis after 561/1981, the activity can be measured. PTCA (percutaneous transluminal coronary angioplasty), etc.), disorder of blood coagulation system (thrombocy (12) Measurement of Cathepsin C Inhibitory Activity topenic purpura, hemolytic uremic syndrome, etc.), malig 0391) Using Gly-Phe-CHN as synthetic substrate, nant tumor, acquired immune deficiency syndrome (AIDS, AIDS-related complex (ARC), etc.), parasitic diseases according to the method described in J. Immunol. 150, (malaria etc.), neurodegenerative disease (Alzheimer-type 4733–4742, 1993, the activity can be measured. senile dementia, Huntington's chorea, Parkinson's disease, Toxicity: multiple Sclerosis, traumatic encephalopathy, traumatic spondylopathy, etc.), lung disorder (fibroid lungs, etc.), bone 0392 The toxicity of the compound of formula (I), a salt diseases (osteoporosis, bone fracture, rheumatoid arthritis, thereof, a solvate thereof, or an N-oxide thereof, or a arthritis, osteoarthritis, hypercalcaemia, osteometastasis of prodrug thereof was very low, so the compound is safe cancer, periodontitis, bone Paget’s disease, etc.), endo enough for pharmaceutical use. crinesthenia (hyperthyroidism etc.), etc. As the compound of Application to Pharmaceuticals: formula (I) has an inhibitory activity against cystein pro 0393. The compound represented by formula (I), a salt tease, it is also useful as a bone resorption inhibitor. thereof, a solvate thereof, or an N-oxide thereof, or a 0394 Cysteine protease which the compound of formula prodrug thereof (hereinafter referred to as “the compound of (I) inhibits is all preferable, for example, cathepsin K. formula (I)) has an inhibitory activity against cysteine cathepsin L. cathepsin S, cathepsin B, cathepsin H. cathe proteases (cathepsins such as K, L, S. B. F. H. C. V. O. W. psin F, cathepsin Y, cathepsin C, calpain, caspase-1, etc. Z. etc., caspases such as caspase-1, calpains such as calpain, Among them, cathepsin K is most preferred. Of course, etc.), and therefore it is useful as an agent for the prophylaxis cysteine proteases other than them are included in the scope and/or treatment of inflammatory diseases (periodontitis, of the present invention and naturally so are those cysteine arthritis, inflammatory bowel diseases, infectious diseases, proteases to be discovered in the future. pancreatitis, hepatitis, glomerulonephritis, endocarditis, myocarditis, ulcerative colitis, etc.), diseases induced by 0395. The compound of formula (I) may also be admin apoptosis (graft versus host diseases, rejection in transplan istered as a concomitant agent in combination with other tation, acquired immunodeficiency syndrome (AIDS). agents for AIDS-related complex (ARC), adult T cell leukemia, hairy 1) supplement and/or reinforcement of preventive and/or cells leukemia, spondylopathy, disorders of respiratory treating effect(s) of the compound of formula (I), apparatus, arthritis, HIV or HTLV-1 related diseases (uveitis etc.), virus related diseases (hepatitis C etc.), cancer, col 2) improvement in kinetics and absorption of the compound lagenosis (systemic lupus erythematosus, rheumatoid arthri of formula (I) and reduction of dose and/or tis, etc.), ulcerative colitis, Sjoegren syndrome, primary biliary cirrhosis, spontaneous thrombocytopenic purpura, 3) reduction of side effect of the compound of formula (I). autoimmune hemolytic anemia, myasthenia gravis, autoim 0396 A concomitant agent of the compound of formula mune diseases (insulin dependent (type I) diabetes, etc.), (I) with other agents may be administered in a mode of diseases accompanied by thrombocytopenia (myelodysplas compounded agent in which both components are com tic syndrome, cyclic thrombocytopenia, aplastic anemia, pounded in a single preparation or in a mode of separate US 2007/019751.0 A1 Aug. 23, 2007 34 preparations. When administration is conducted using sepa 04.01 Vitamin D derivatives include, for example, alfa rate preparations, a simultaneous administration and admin calcidol, falecalcitriol, calcitriol, 1C.25-dihydroxycholecal istrations with time difference is included. In the case of ciferol, dihydrotaxisterol, ST-630, KDR, ST-630, ED-71, administrations with time difference, the compound of for rocaltrol (Ro44-7.190), tacalcitol, maxacalcitol, etc. mula (I) may be firstly administered and then other drug may be administered, or the other drug may be firstly adminis 0402 Vitamin K and its derivatives include, for example, tered and then the compound of formula (I) may be admin vitamin K, (phytonadione), vitamin K (menatetrenone), etc. istered. Each of the methods for the administration may be 0403 Calcitonin formulations include, for example, cal the same or different. citonin salmon (STH-32, SMC20-51), calcitonin chicken 0397) There is no particular limitation for the diseases for (MCI-536), secalciferol, elcatonin, TJN-135, etc. which the above-mentioned concomitant agent achieves the 0404 Female hormone formulations include, for preventive and/or the treating effect but any disease will be example, estrogen preparations, progesterone preparations, acceptable so far as it Supplements and/or enforces the etc. Estrogen preparations include, for example, estrogen, preventive and/or treating effect of the compound of formula estradiol, estradiol benzoate, estradiol cypionate, estradiol (I). dipropionate, estradiol enannthate, estradiol hexahydroben Zoate, estradiol phenylpropionate, estradiol undecanoate, 0398. For example, examples of the other drug for estradiol Valerate, estrone, ethinylestradiol, mestranol, Supplement and/or reinforcing the preventive and/or treating estriol, chlormadinone acetate, norethisterone. Progesterone effect of the compound of formula (I) to bone diseases preparations include, for example, progesterone, hydrox include, for example, bisphosphonate formulations, Vitamin yprogesterone caproate, medroxyprogesterone acetate, tri D and its derivatives, Vitamin K and its derivatives, calci megestone, etc. tonin formulations, C-calcitonin gene-related peptide formu lations, female hormone formulations, selective estrogen 04.05 Selective estrogen receptor modulators (SERM) receptor modulators (SERM), ipriflavone formulations, cal include, for example, tamoxifen, lasofoxifene tartrate, ral cium formulations, anabolic steroid formulations, parathy oxifene hydrochloride, baZedoxifene acetate, PSK-3471. roid hormone (PTH) formulations, PTHrP derivatives, etc. caspase-1 inhibitors, farnesoid X receptor agonists, Bone Morphogenetic Protein (BMP) formulations, anti-RANKL 0406 Ipriflavone formulations include, for example, ipri (receptor activator of NF-kappa B ligand) antibody, metal flavone, etc. loprotease inhibitors, prostaglandin derivatives, strontium 0407 Calcium formulations include, for example, cal formulations, anti TNF-C. antibody, anti-IL-6 antibody, cium chloride, calcium gluconate, calcium glycerophos HMG-CoA reductase inhibitors, steroidal drugs, and antiin phate, calcium lactate, calcium L-aspartate, calcium hydro flammatory drugs, etc. Nonsteroidal antiinflammatory agent, gen phosphate, etc. local anesthetic agent and/or muscle-relaxing drug can also 0408 Anabolic steroid formulations include, for be used together for the purpose of redress of pain accom example, nandrolone decanoate, nandrolone phenylpropi panied by bone fracture and osteoporosis. onate, nandrolone cyclohexylpropionate, metenolone enan 0399 Bisphosphonate formulations include, for example, thate, mestanolone, stanozolol, oxymetholone, etc. minodronic acid (1-hydroxy-2-(imidazol-2-apyridin-3-yl )ethylidenebisphosphonic acid, salt thereof, or hydrate 04.09 Parathyroid hormone (PTH) formulations include, thereof), alendronate (4-amino-1-hydroxybutylidene-1,1- for example, PTH, teriparatide acetate, MBRI-93.02, bisphosphonic acid (alendronic acid), or Sodium salt thereof, Ostabolin-C, etc. or trihydrate thereof), incadronate (cycloheptylaminometh 0410) PTHrP derivatives include, for example, ylene-1,1-diphosphoric acid (incadronic acid), or disodium RS-66271, hPTHrP, etc. salt thereof, hydrate thereof), clodronate (1,1-dichlorometh ylene-1,1-diphosphoric acid (clodronic acid), or disodium 0411 Caspase-1 inhibitors include, for example, pralna salt thereof), tiludronate ((4-chlorophenyl)thiomethylene-1, casan, nitroflubiprofen, etc. 1-diphosphoric acid (tiludronic acid), or disodium salt 0412 Farnesoid X receptor agonists include, for thereof), etidronate (1-hydroxy-1,1-diphosphoric acid example, SR-45023A, etc. (etidronic acid), or disodium salt thereof), ibandronate (1-hydroxy-3-(N-methyl-N-pentylamino)propylidene-1,1- 0413 Anti-RANKL antibody includes, for example, bisphosphonic acid), risedronate (1-hydroxy-2-pyridine-3- AMG162, etc. ylethylidenediphosphoric acid (risedronic acid), or sodium 0414 Metalloprotease inhibitors include, for example, salt thereof, sester hydrate thereof), piridronate (2-(2-py minocycline hydrochloride, etc. ridinyl)ethylidene-1,1-bisphosphonic acid), pamidronate (3-amino-1-hydroxypropylidene-1,1-bisphosphonic acid 0415 Prostaglandin derivatives include, for example, (pamidronic acid), or disodium salt thereof, or pentahydrate EP2 agonist, EP4 agonist, EP4 antagonist, for example, thereof), Zoledronate (1-hydroxy-2-(1H-imidazol-1-yl)eth ONO-4819, nitroflurbiprofen, etc. ylidene-1,1-bisphosphonic acid, or hydrate thereof), olpad ronate (3-(dimethylamino)-1-hydroxypropylidene-1,1-bis 0416) Strontium formulations include, for example, phosphonic acid), neridronate (6-amino-1- strontium ranelate, etc. hydroxyhexylidene-1,1-bisphosphonic acid), etc. 0417 Anti TNF-C. antibody include, for example, inflix imab, etanercept, etc. 0400 Vitamin D include, for example, Vitamin D. (ergo calciferol), Vitamin D (cholecalciferol), etc. 0418 Anti-IL-6 antibody include, for example, A, etc. US 2007/019751.0 A1 Aug. 23, 2007

0419 HMG-CoA reductase inhibitors include, for 0430. In such solid compositions, one or more of the example, pravastatin, simvastatin, lovastatin, fluvastatin, active compound(s) may be admixed with vehicles (such as atorvastatin, pitavastatin, rosuvastatin, etc. lactose, mannitol, glucose, microcrystalline cellulose or starch), binders (such as hydroxypropyl cellulose, polyvi 0420 Steroidal drugs include, for example, KB-889 nylpyrrolidone or magnesium metasilicate aluminate), dis (OD14, tibolone), Hipros (TZP-4238), etc. integrants (such as cellulose calcium glycolate), lubricants 0421) Antiinflammatory drugs include, for example, (such as magnesium Stearate), stabilizing agents, and solu sasapyrine, sodium salicylate, aspirin, aspirin dialuminate tion adjuvants (such as glutamic acid or aspartic acid) and formulation, diflunisal, indomethacin, Suprofen, ufenamate, prepared according to methods well known in normal phar dimethylisopropyl azulen, bufexamac, felbinac, diclofenac, maceutical practice. The Solid forms may, if desired, be tolimetin Sodium, Clinoril, fenbufen, napmetone, proglu coated with coating agents (such as Sugar, gelatin, hydrox metacin, indomethacin farnesil, acemetacin, proglumetacin ypropyl cellulose or hydroxypropylmethyl cellulose phtha maleate, amfenac sodium, mofeZolac, etodolac, ibuprofen, late), or be coated with two or more films. And further, ibuprofen piconol, naproxen, flurbiprofen, flurbiprofen coating may include containment within capsules of absorb aXethyl, ketoprofen, fenoprofen calcium, tiaprofenen, able materials such as gelatin. oxaprozin, pranoprofen, loxoprofen Sodium, aluminoprofen, 0431 Liquid compositions for oral administration Zaltoprofen, mefenamic acid, aluminum mefenamate, tolfe include pharmaceutically acceptable solutions, Suspensions, namic acid, floctafenine, ketophenylbutaZone, oxyfenbuta emulsions, syrups and elixirs. In Such forms, one or more of Zone, piroXicam, tenoxicam, anpiroXicam, napageln cream, the active compound(s) may be dissolved, Suspended or epirizole, tiaramide hydrochloride, tinoridine hydrochloride, emulized into diluent(s) commonly used in the art (Such as emorfaZone, Sulpyrine, Migrenin, Saridon, Sedes G, Ami purified water, ethanol or a mixture thereof). Besides such pylo N. Sorbon, pyrine system antipyretics, acetaminophen, liquid forms may also comprise some additives, such as phenacetin, dimethothiazine mesylate, simetride formula Wetting agents, Suspending agents, emulsifying agents, tion, or antipyrine system antipyretics, etc. Sweetening agents, flavoring agents, aroma, preservative or 0422 There is no limitation for the ratio by weight of the buffering agent. compound of formula (I) to other agents. 0432. Injections for parenteral administration in the present invention include Solutions, Suspensions and emul 0423. With regard to other agents, two or more agents sions, and also solid injections which are to be dissolved or may be administered in combination. Suspended in Solvents upon use. Such an injection is pre 0424 Such other agents which supplement and/or rein pared by dissolving, Suspending or emulsifying one or more force the preventive and/or treating effect of the compound active Substances in a solvent and then put to use. Examples of formula (I) include not only those which have been found of the solvent include distilled water for injection, physi on the basis of the above-mentioned mechanism but also ological Saline, plant oil, alcohols such as propylene glycol, those which will be found in future. polyethylene glycol and ethanol, and combinations thereof. Further, the injection may contain a stabilizer, a solubilizing 0425 The pharmaceutical composition comprising the auxiliary agent such as glutamic acid, aspartic acid and compound of formula (I), a combination of the compound of POLYSORBATE 80 (registered trade mark) etc.), suspend formula (I) and other drug as an active ingredient is gener ing agent, emulsifying agent, soothing agent, buffering ally administered systemically or topically and orally or agent, preservative agent and the like. The injection may be parenterally when it is used for the above objects. sterilized in the final step of the preparation process or the 0426. The dosages are determined depending on age, whole preparation process may be operated under sterile body weight, symptom, therapeutic effect, administration conditions. Alternatively, the sterile product, for example a route, duration of the treatment and the like. Generally, 1 mg sterile freeze-dried product may be prepared, and upon use, to 1000 mg per adult is orally administered once to several the product may be dissolved in sterilized or aseptic distilled times per day, or 0.1 mg to 100 mg per adult is parenterally water for injection or other sterilized or aseptic solvents. administered (preferably by intravenous administration) 0433. Other compositions for parenteral administration once to several times per day, or continuously administered include liquids for external use, ointments, endemic lini from vein for 1 to 24 hours per day. ments, inhalants, spray compositions, suppositories for intrarectal administration, and pessaries for intravaginal 0427 Since the dose changes depending on various con administration and the like containing one or more active ditions as described above, there are cases in which doses compound(s) which can be prepared by known methods. lower than or greater than the above ranges may be used. 0434 Spray compositions may contain stabilizing agents 0428 The pharmaceutical composition comprising the Such as Sodium hydrogen Sulfate, buffering agents to give compound of formula (I), a concomitant agent of the com isotonicity, isotonic solutions such as sodium chloride, pound of formula (I) and other drug as an active ingredient sodium citrate or citric acid, in addition to inert diluents. For may be administered in the form of Solid compositions, preparation of Such spray compositions, for example, the liquid compositions and other compositions for oral admin method described in the U.S. Pat. Nos. 2,868,691 and istration, and injections, external preparations, Supposito 3.095,355. ries, and the like for parenteral administration. EFFECT OF THE INVENTION 0429 Solid compositions for oral administration include 0435 The compounds of the present invention have the tablets, pills, capsules, dispersible powders, granules and the inhibitory activity against cathepsin K. So they are useful for like. Capsules include hard capsules and Soft capsules. preventing and/or treating cathepsin K-related diseases. US 2007/019751.0 A1 Aug. 23, 2007 36

BEST MODE FOR CARRYING OUT THE Example 3 INVENTION tert-butyl({2-cyano-4-(2,2-dimethylpropyl)amino 0436 The following Examples are intended to illustrate 5-pyrimidinyl)methyl)carbamate the present invention, but the present invention is not limited thereto. 0443 To a solution of the compound prepared in Example 2 (200 mg) in dimethylsulfoxide (2 mL) were 0437. In chromatographic separations and TLC, the sol added potassium cyanide (61 mg), 1,4-diazabicyclo2.2.2 vents in parenthesis show the eluting and developing Sol octane (16 mg) and water (0.3 mL), then the mixture was vents and the ratios of the solvents used are by volume. The stirred for 2 hours at 80°C., 4 hours at 100° C., refluxed for solvents in the parentheses in NMR show the solvents for 19 hours at 110°C. The reaction mixture was cooled to room measurement. temperature, poured into water, extracted with ethyl acetate. 0438 All the compounds described in the present speci The extract washed with brine, dried over anhydrous sodium fication were named by using ACD/Name (registered trade sulfate, concentrated. The obtained residue was purified by mark, Advanced Chemistry Development Inc.) or ACD/ column chromatography on silica gel (hexane:ethyl acetate= Name Batch (registered trademark, Advanced Chemistry 5:2) to give the title compound (75 mg; yellow crystals) Development Inc.), which is a computer Software that gen having the following physical data. erally names the compound according to IUPAC nomencla ture system, or directly named according to IUPAC nomen 0444 TLC: Rf 0.39 (hexane:ethyl acetate=2:1). clature system. Example 4 Example 1 5-(aminomethyl)-4-(2,2-dimethylpropyl)amino-2- 2-chloro-5-(chloromethyl)-N-(2,2-dimethylpropyl)- pyrimidinecarbonitrile 4-pyrimidineamine 0445. To a solution of the compound prepared in 0439 Under atmosphere of argon, 2,4-dichloro-5-(chlo Example 3 (67 mg) in dichloromethane (1 mL) on ice bath romethyl)pyrimidine (3.95 g) was dissolved to tetrahydro was added trifluoroacetic acid (0.1 mL). After the reaction furan (34 mL), and the mixture was cooled to -5°C. To the mixture was stirred for 30 minutes, trifluoroacetic acid (0.1 reaction mixture was added triethylamine (3.37 mL), and mL) was added thereto, then the mixture was stirred for 1 neopentylamine (2.36 mL) was dropped thereto, then the hour at room temperature. To the reaction mixture was mixture was stirred for 3.5 hours with temperature rising added trifluoroacetic acid (0.05 mL), then the mixture was little by little. The reaction mixture was diluted by ethyl stirred for 1 hour at room temperature. The reaction mixture acetate, added by brine and water, then separated. The water was concentrated, then the obtained residue was dissolved to layer was extracted with ethyl acetate. The combined ethyl acetate. The Solution was poured into Saturated aque organic layer washed with a small amount of Saturated ous solution of Sodium hydrogen carbonate, extracted with aqueous solution of Sodium hydrogen carbonate and brine, ethyl acetate. The extract was washed with a small amount dried over anhydrous sodium sulfate, then concentrated. To of brine, dried over anhydrous sodium sulfate, concentrated the residue was added tert-butyl methyl ether, and an to give the title compound (45 mg) having the following insoluble powder was removed by filtration to give the title physical data. compound (872 mg; white powder). The filtrate was con centrated. The obtained residue was purified by column 0446 TLC: Rf 0.51 (dichloromethane:methanol=10:1). chromatography on silica gel (hexane:ethyl acetate=5:1-> 4:1) to give the title compound (1.19 g) having the following Example 5 physical data. 8-(2,2-dimethylpropyl)-7-oxo-5,6,7,8-tetrahydropy 0440 TLC: Rf 0.44 (hexane:ethyl acetate=2:1). rimidoA,5-dipyrimidine-2-carbonitrile Example 2 0447) di-tert-butyl({2-chloro-4-(2,2-dimethylpropy l)amino-5-pyrimidinyl)methyl)imidodicarbonate 0441 To a solution of di-tert-butyl imidodicarbonate (798 mg) in dimethylformamide (7 mL) on ice bath were added sodium hydride (147 mg: 60%) and dimethylforma mide (3 mL), then the mixture was stirred for 20 minutes. To the reaction mixture was added a solution of the compound prepared in Example 1 (870 mg) in dimethylformamide (4 mL), then the mixture was stirred for 30 minutes at 0°C. The reaction mixture was added by iced water, extracted with ethyl acetate. The organic layer washed with brine, dried over anhydrous sodium sulfate, concentrated The obtained 0448. To a solution of carbodiimidazole (31 mg; CDI) in residue was purified by column chromatography on silica dioxane (0.5 mL) was dropped a solution of the compound gel (hexane:ethyl acetate=5:1) to give the title compound prepared in Example 4 (42 mg) in dioxane (0.5 mL), the (429 mg) having the following physical data. mixture was stirred for 30 minutes at room temperature. CDI (10 mg) was added thereto, then the mixture was stirred for 0442.) TLC: Rf 0.40 (hexane:ethyl acetate=4:1). 1 hour at room temperature, refluxed for 6.5 hours at 100° US 2007/019751.0 A1 Aug. 23, 2007 37

C. The reaction mixture was cooled to room temperature, drazinecarboxylate instead of neopentylamine in the step then concentrated. To the residue was added ethyl acetate, corresponding to Example 1, the title compound having the the solution washed with brine, dried over anhydrous following physical data was obtained. Sodium sulfate, concentrated. The obtained residue was purified by column chromatography on silica gel (hexane 0457 TLC: Rf 0.47 (dichloromethane:methanol=10:1); :ethyl acetate=1:1) to give the title compound (35 mg) 0458 H NMR (CDC1): 8 1.05 (s, 9H), 4.16 (s, 2H), having the following physical data. 9.20 (s, 1H). 0449) TLC: Rf 0.57 (dichloromethane:methanol=10:1); Example 8 0450 "H NMR (CDC1): 8 0.95 (s, 9H), 4.07 (s. 2H), 4.51 (s. 2H), 5.52-5.66 (m. 1H), 8.31 (t, J=1.01 Hz, 1H). 3-(4-biphenylylmethoxy)-1-(2,2-dimethylpropyl)- 1H-pyrazolo 3,4-dipyrimidine-6-carbonitrile (com Example 6 pound 8A), and 2-(4-biphenylylmethyl)-1-(2,2-dim ethylpropyl)-3-oxo-2,3-dihydro-1H-pyrazolo 3,4-d 7-(2,2-dimethylpropyl)aminol-6-methylpyrazolol. pyrimidine-6-carbonitrile (compound 8B) 5-apyrimidine-5-carbonitrile 0459) 0451

Compound 8 A CH H3C CH3

HN 7 N N CH 3

Ol N 2 CN

0452. By the same procedures as described in Example 1->Example 3, using 5,7-dichloro-6-methylpyrazolo1.5-all pyrimidine instead of 2,4-dichloro-5-(chloromethyl)pyrimi dine in the step corresponding to Example 1, the title compound having the following physical data was obtained. 0453 TLC: Rf 0.39 (hexane:ethyl acetate=4:1); Compound 8 B 0454) H NMR (CDC1): 8 1.08 (s, 9H), 2.67 (s, 3H), 3.59 (d. J=5.86 Hz, 2H), 6.60 (d. J=2.38 Hz, 1H), 6.75-6.90 (m. 1H), 8.06 (d. J=2.38 Hz, 1H).

Example 7 1-(2,2-dimethylpropyl)-3-oxo-2,3-dihydro-1H-pyra Zolo 3,4-dpyrimidine-6-carbonitrile 0455)

0460 Under atmosphere of argon, to a solution of the compound prepared in Example 7 (60 mg) in tetrahydrofu ran (1 mL) were added triphenylphosphine (68 mg) and 4-biphenylylmethanol (48 mg), diethyl azodicarboxylate (2.2M toluene solution, 118 LL) was dropped thereinto, the reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated. The obtained resi 0456 By the same procedures as described in Example due was purified by column chromatography on silica gel 1->Example 3 Example 4, using methyl 2,4-dichloropyri (hexane:ethyl acetate=9:1->4:1) to give the title compound midine-5-carboxylate instead of 2,4-dichloro-5-(chlorom 8A (60 mg) and compound 8B (6 mg) having the following ethyl)pyrimidine and tert-butyl 2-(2,2-dimethylpropyl)hy physical data. US 2007/019751.0 A1 Aug. 23, 2007

Compound 8A: Example 8(4) 0461) TLC: Rf 0.63 (hexane:ethyl acetate=4:1); 1-(2,2-dimethylpropyl)-3-(2-phenoxyethoxy)-1H 0462) H NMR (CDC1): 8 1.01 (s, 9 T), 4.15 (s, 2H), pyrazolo 3,4-dpyrimidine-6-carbonitrile 5.48 (s. 2H), 7.30-7.41 (m, 1H), 7.40-7.51 (m, 2H), 7.51 7.72 (m, 6H), 9.07 (s, 1H). 0474) TLC: Rf 0.49 (hexane:ethyl acetate=4:1); Compound 8B: 0475 H NMR (CDC1): 8 1.01 (s, 9H), 4.14 (s. 2H), 0463) TLC: Rf 0.43 (hexane:ethyl acetate=2:1); 4.35-4.47 (m, 2H), 4.70-4.84 (m, 2 H), 6.88-7.05 (m, 3H), 7.27-7.39 (m, 2H), 9.08 (s, 1H). 0464) "H NMR (CDC1): 8 1.00 (s, 9H), 3.94 (s. 2H), 5.32 (s. 2H), 7.16 (d. J=8.23 Hz, 2H), 7.29-7.48 (m, 3H), Example 8(5) 747-7.58 (m, 4H), 9.13 (s, 1H). 1-(2,2-dimethylpropyl)-3-2-(4-morpholi Example 8(1)-Example 8(5) nyl)ethoxy)-1H-pyrazolo 3,4-dpyrimidine-6-carbo 0465 By the same procedures as described in Example 8. nitrile using corresponding alcohol compound instead of 4-biphe 0476 TLC: Rf 0.33 (hexane:ethyl acetate=1:3); nylylmethanol, the following compounds were obtained. In Example 8(2), using 2-thienylmethanol instead of 4-biphe 0477 H NMR (CDC1): 8 1.00 (s, 9H), 2.50-2.68 (m, nylylmethanol, the compound 8(2A) and the compound 4H), 2.88 (t, J=5.76 Hz, 2H), 3.66-3.83(m, 4H), 4.12(s, 2H), 8(2B) were obtained. 4.55(t, J=5.76 Hz, 2H), 9.06(s, 1H). Example 8(1) Example 9 1-(2,2-dimethylpropyl)-3-(3-pyridinylmethoxy)-1H 8-(2,2-dimethylpropyl)-2-(methylthio)pyrazolo 1.5- pyrazolo 3,4-dpyrimidine-6-carbonitrile a 1.3.5triazin-4(1H)-one 0466 TLC: Rf 0.36 (hexane:ethyl acetate=1:1); Step (9-A): 0467 H NMR (CDC1): 8 1.00 (s, 9H), 4.14 (s. 2H), 0478. To a suspension of molecular sieves 4A powder 5.47 (s. 2H), 7.30-7.43 (m, 1H), 7.79-7.92 (m, 1H), 8.63 (dd, (MS4A, 2.0 g) in toluene (40 mL) were added piperidine J=4.76, 1.70 Hz, 1H), 8.78 (d. J=1.70 Hz, 1H), 9.07 (s, 1H). (1.19 mL) and acetic acid (0.69 mL), then the mixture was stirred for 10 minutes, methyl cyanoacetate (3.53 mL) and Example 8(2) pivalaldehyde (4.77 mL) were added thereto, the mixture was stirred for 5 hours at 80° C. The reaction mixture was 1-(2,2-dimethylpropyl)-3-(2-thienylmethoxy)-1H cooled to room temperature, added by ethyl acetate and pyrazolo 3,4-dpyrimidine-6-carbonitrile (compound water. After MS4A was separated by filtration, the filtrate 8(2A)), and 1-(2,2-dimethylpropyl)-3-oxo-2-(2-thie was extracted by ethyl acetate. The organic layer washed nylmethyl)-2,3-dihydro-1H-pyrazolo 3,4-dpyrimi with brine, dried over anhydrous sodium sulfate, concen dine-6-carbonitrile (compound 8(2B)) trated. The obtained residue was purified by column chro matography on silica gel (ethyl acetate hexane=1:20-> 1:10) Compound 8(2A): to give methyl 2-cyano-4,4-dimethyl-2-pentenoate (4.72 g). 0468 TLC: Rf 0.67 (hexane:ethyl acetate=4:1); Step (9-B) 0469 H NMR (CDC1): 8 1.03 (s, 9H), 4.15 (s, 2H), 0479. Under atmosphere of argon, to a solution of the 5.61 (s. 2H), 7.03 (dd, J=5.10, 3.48 Hz, 1H), 7.20-7.25 (m, compound prepared in step (9-A) (3.79 g) in ethyl acetate 1H), 7.38 (dd, J=5.10, 1.19 Hz, 1H), 9.04 (s, 1H). (76 mL) was added 5% palladium on carbon (192 mg). Compound 8(2B): Under atmosphere of hydrogen, the reaction mixture was stirred for 40 minutes. The atmosphere of reaction mixture 0470 TLC: Rf 0.20 (hexane:ethyl acetate=4:1); was replaced by argon, the mixture was filtrated by cerite 0471 'H NMR (CDC1): 8 0.99 (s, 9H), 4.03 (s. 2H), (trademark), the filtrate was concentrated to give methyl 5.37 (d. J=0.80 Hz, 2H), 6.92 (dd, J=5.12, 3.48 Hz, 1H), 2-cyano-4,4-dimethylpentanoate (3.69 g). 6.96-7.04 (m, 1H), 7.22 (dd, J=5.12, 1.28 Hz, 1H), 9.06 (s, 1H). Step (9-C): 0480 Under atmosphere of argon, to a solution of the Example 8(3) compound prepared in step (9-B) (1.68 g) in tetrahydrofuran (20 mL) was dropped diisobutylaluminum hydride (1.0 M 1-(2,2-dimethylpropyl)-3-(2-phenylethoxy)-1H toluene solution, 10.0 mL) at -74°C., then the mixture was pyrazolo 3,4-dpyrimidine-6-carbonitrile stirred for 2.5 hours at -75° C. The temperature of reaction mixture was raised to -42°C. little by little, the mixture was 0472 TLC: Rf 0.36 (hexane:ethyl acetate=9:1); added by methanol (1.5 mL) and 1N hydrochloric acid, then 0473 H NMR (CDC1) & 1.00 (s, 9H), 3.19 (t, J=7.14 extracted with ethyl acetate. The organic layer washed with Hz, 2H), 4.12 (s. 2H), 4.62 (t, J=7.14 Hz., 2H), 7.21-7.40 (m, brine, dried over anhydrous sodium Sulfate, concentrated to 5H), 9.02 (s, 1H). give crude 2-formyl-4,4-dimethylpentanenitrile (1.61 g). US 2007/019751.0 A1 Aug. 23, 2007 39

Step (9-D): triethylamine (0.056 mL) and (2.2-dimethylpropyl)amine 0481 To a solution of the compound prepared in step (0.047 mL), the mixture was stirred overnight at room (9-C) (1.42 g) in ethanol (28 mL) was added hydrazine temperature. The reaction mixture was poured into water, monohydrate (0.428 mL), then the mixture was refluxed for extracted with ethyl acetate. The organic layer washed with 1 day. The reaction mixture was cooled to room temperature, water, dried over anhydrous sodium Sulfate, concentrated. concentrated. To the residue were added water, ethyl acetate The obtained residue was purified by column chromatogra and 1N hydrochloric acid, then separated. The water layer phy on silica gel (ethyl acetate:hexane=5:95->15:85-> washed with ethyl acetate, neutralized by Saturated aqueous 100:0) to give the title compound (68 mg) having the Solution of sodium hydrogen carbonate, then extracted with following physical data. ethyl acetate. The organic layer was washed with brine, 0489) TLC: Rf 0.39 (hexane:ethyl acetate=9:1). dried over anhydrous sodium Sulfate, concentrated to give 4-(2,2-dimethylpropyl)-1H-pyrazol-5-amine (530 mg). Example 12 Step (9-E): 0482 To a solution of the compound prepared in step N.8-bis(2,2-dimethylpropyl)-2-(methylsulfo (9-D) (210 mg) in a mixed solvent of ethyl acetate (4 mL) nyl)pyrazolo 1.5-a1.3.5triazine-4-amine and benzene (15 mL) on ice bath was dropped a solution of 0490. To a solution of the compound prepared in ethyl isothiocyanatoformate (180 mg) in benzene (5 mL), Example 11 (65 mg) in dichloromethane (3 mL) on ice bath then the mixture was stirred for 1 hour on ice bath, 2 hours was added m-chloroperbenzoic acid (128 mg), and the at room temperature. The reaction mixture was concen mixture was stirred for 1 hour on ice bath, 1.5 hours at room trated. The residue washed with a mixed solvent of ethyl temperature. The reaction mixture was poured into Saturated acetate and hexane to give ethyl({4-(2,2-dimethylpropyl)- aqueous solution of Sodium hydrogen carbonate, extracted 1H-pyrazol-5-yl)aminocarbonothioyl)carbamate (207 mg). with ethyl acetate. The organic layer washed with water, Step (9-F): dried over anhydrous sodium sulfate, concentrated. The 0483 The compound prepared in step (9-E) (200 mg) residue was purified by column chromatography on silica was dissolved to 2N aqueous solution of sodium hydroxide gel (parallel preparative purifier system). The obtained solid (1.5 mL), then stirred for 1 hour at room temperature. The was dissolved to ethyl acetate, the solution washed with reaction mixture was added by 2N aqueous solution of saturated aqueous solution of Sodium sulfite and brine Sulfuric acid to make pH of solution 1, then stirred for 1 sequentially, dried over anhydrous sodium sulfate, concen hour. The precipitates was collected, then dried to give trated to give the title compound (65 mg) having the 8-(2,2-dimethylpropyl)-2-thioxo-2,3-dihydropyrazolo 1.5- following physical data. a 1.3.5triazin-4(1H)-one (135 mg). 0491) TLC: Rf 0.33 (hexane:ethyl acetate=3:1). Step (9-G): 0484) To a solution the compound prepared in step (9-F) Example 13 (115 mg) in ethanol (2 mL) was added 2N aqueous solution of sodium hydroxide (0.48 mL), then methyl iodide (0.03 8-(2,2-dimethylpropyl)-4-(2,2-dimethylpropy mL) was added thereto at room temperature, the mixture was l)aminolpyrazolo 1.5-a 1.3.5triazine-2-carbonitrile stirred for 20 minutes. The reaction mixture was concen trated. After the obtained solid was washed with diisopropyl 0492 ether, it was dissolved to water (23 mL), added by 2N aqueous solution of sulfuric acid (0.5 mL). The obtained CH solid was collected, dried to give the title compound (102 HN mg) having the following physical data. CH3 0485 TLC: Rf 0.47 (dichloromethane:methanol=9:1). N NN1 NN CH 3 Example 10 4-chloro-8-(2,2-dimethylpropyl)-2-(methylthio)pyra S-l-lN CN Zolo15-a1.3.5triazine HC 0486 To phosphorus oxychloride (1.9 g) were added the compound prepared in Example 9 (94.5 mg) and N.N- dimethylaniline (3 drops), the mixture was stirred for 3 hours at 120° C. The reaction mixture was poured into iced water, extracted with ethyl acetate. The organic layer 0493 To a solution of the compound prepared in washed with water and brine, dried over anhydrous sodium Example 12 (58 mg) in dimethylsulfoxide (1 mL) were Sulfate, concentrated to give the title compound (109 mg) added 1,4-diazabicyclo2.2.2]octane (18 mg), potassium having the following physical data. cyanide (30 mg) and water (0.1 mL), then the mixture was 0487 TLC: Rf 0.39 (hexane:ethyl acetate=9:1). stirred for 4 hours at 50° C. The reaction mixture was poured Example 11 into water, extracted with ethyl acetate. The organic layer washed with water, dried over anhydrous sodium sulfate, N.8-bis(2,2-dimethylpropyl)-2-(methylthio)pyrazolo concentrated. The obtained residue was purified by column 1.5-a 1.3.5triazine-4-amine chromatography on silica gel (parallel preparative purifier 0488 To a solution of the compound prepared in system) to give the title compound (44.4 mg) having the Example 10 (98 mg) in tetrahydrofuran (2 mL) were added following physical data. US 2007/019751.0 A1 Aug. 23, 2007 40

0494 TLC: Rf 0.50 (hexane:ethyl acetate=4:1); dried over anhydrous sodium sulfate, concentrated. The 0495 H NMR (CDC1): 8 0.94 (s, 9H), 1.05 (s, 9H), obtained residue was purified by column chromatography on 2.61 (s. 2H), 3.52 (d. J=6.59 Hz, 2H), 6.69-6.82 (m, 1H), silica gel (hexane:ethyl acetate=70:30-60:40) to give the title 7.91 (s, 1H). compound (230 mg) having the following physical data. Example 14 0504) TLC: Rf 0.25 (hexane:ethyl acetate=6:4): 4-(2,2-dimethylpropyl)aminolpyrazolo 1.5-a1.3.5 0505 H NMR (CDC1): 8 1.05 (s, 9H), 1.26 (t, J=7.14 triazine-2-carbonitrile Hz, 3H), 1.33 (s.9H), 2.43-2.59 (m, 4H), 2.60-2.81 (m, 2H), 3.22-3.38(m, 1H), 3.45(d. J=14 Hz, 1H), 3.71 (t, J=4.67 Hz, 0496) 4H), 3.73-3.86 (m, 1H), 4.02 (d. J=14 Hz, 1H), 4.23-4.49 (m, 2H), 8.33 (s, 1H). Example 17 1-(2,2-dimethylpropyl)-2-[2-(4-morpholinyl)ethyl 3-oxo-2,3-dihydro-1H-pyrazolo 3,4-dipyrimidine-6- carbonitrile 4-methylbenzenesulfonate 0506) 0497. By the same procedures as described in the step

(9-G) in Example 9 Example 10->Example 11->Example 12->Example 13, using 2-thioxo-2,3-dihydropyrazolo 1.5- a 1.3.5triazin-4(1H)-one instead of the compound pre pared in the step (9-F) in the corresponding step of the step (9-G) in Example 9, the title compound having the following physical data was obtained. 0498 TLC: Rf 0.48 (hexane:ethyl acetate=2:1); 0499) 'H NMR (CDC1): 8 1.05 (s, 9H), 3.53 (d. J=6.59 Hz, 2H), 6.62 (d. J=2.20 Hz, 1H), 6.76-6.93 (m, 1H), 8.08 (d. J=2.20 Hz, 1H). Example 15 ethyl 4-2-(tert-butoxycarbonyl)-1-(2,2-dimethylpro ac-K)-so pyl)hydrazino-2-cyano-5-pyrimidinecarboxylate 0500 By the same procedures as described in Example 1 Example 12 Example 13, using ethyl 4-chloro-2-(meth 0507 To a solution of the compound prepared in ylthio)-5-pyrimidinecarboxylate instead of 2,4-dichloro-5- Example 16 (203 mg) in isopropylamine (2 mL) was added (chloromethyl)pyrimidine, and tert-butyl 2-(2,2-dimethyl p-toluenesulfonic acid monohydrate (157 mg), then the propyl)hydrazinecarboxylate instead of neopentylamine in mixture was stirred for 3.5 hours at 90° C. The reaction the step corresponding to Example 1, the title compound mixture was cooled to room temperature, the precipitated having the following physical data was obtained. solid was collected. The solid washed with isopropylamine 0501) TLC: Rf 0.64 (hexane:ethyl acetate=2:1); (1 mL), dried to give the title compound (169 mg) having the 0502) H NMR (CDC1): 8 1.00 (s, 9H), 1.16-1.53 (m, following physical data. 12H), 2.57-3.03 (m, 1H), 4.24-4.54 (m, 2H), 4.58-4.99 (m, 1H), 6.18-7.12 (m, 1H), 8.59 (s, 1H). 0508 TLC: Rf 0.15 (hexane:ethyl acetate=1:1); Example 16 0509 H NMR (DMSO-d): 8 0.90 (s, 9H), 2.28 (s, 3H), 2.95-3.77 (m, 8H), 3.87-4.05 (m, 2H), 4.08(s, 2H), 4.32-4.50 ethyl 4-2-(tert-butoxycarbonyl)-1-(2,2-dimethyl ((m, 2H), 7.11(d. J=7.68 Hz, 2H), 7.46(d. J=8.05 Hz, 2H), propyl)-2-[2-(4-morpholinyl)ethylhydrazino-2- 9.25 (s, 1H), 9.58 (s, 1H). cyano-5-pyrimidinecarboxylate 0503) To a solution of the compound prepared in Example 18(1)-Example 18(2) Example 15 (189 mg) and 4-(2-chloroethyl) morpholine hydrochloride (186 mg) in dimethylformamide (1 mL) was 0510) By the same procedures as described in Example added potassium carbonate (207 mg), then the mixture was 16->Example 17, using corresponding halide compound stirred for 14 hours at 90°C. The reaction mixture was added instead of 4-(2-chloroethyl)morpholine hydrochloride in the by ethyl acetate and water, extracted with ethyl acetate. The step corresponding to Example 16, the title compound organic layer washed with water and brine sequentially, having the following physical data was obtained. US 2007/019751.0 A1 Aug. 23, 2007

Example 18(1) Example 21 1-(2,2-dimethylpropyl)-2-(4-methoxybenzyl)-3-oxo 1-(2,2-dimethylpropyl)-3-(4-(4-methyl-1-piperazi 2,3-dihydro-1H-pyrazolo 3,4-dpyrimidine-6-carbo nyl)methylphenyl)-1H-pyrimido-4,5-e1.3.4loxa nitrile diazine-7-carbonitrile 0511) TLC: Rf 0.51 (hexane:ethyl acetate 1:1); 0522) 0512) H NMR (CDC1): 8 0.97 (s, 9H), 3.76 (s, 3H), 3.91 (s. 2H), 5.21 (s. 2H), 6.81 (d. J=8.70 Hz, 2H), 7.04 (d. J=8.70 Hz, 2H), 9.09 (s, 1H). Example 18(2) 6-cyano-1-(2,2-dimethylpropyl)-3-oxo-1,3-dihydro 2H-pyrazolo 3,4-dpyrimidin-2-yl)acetic acid 0513) TLC: Rf 0.43 (dichloromethane:methanol:acetic acid=20:2:1); 0514) H NMR (CDC1): 8 0.98 (s, 9H), 3.94 (s, 2H), 4.82 (s. 2H), 7.98 (s, 1H), 9.09 (s, 1H). Example 19 0523 To a solution of the compound prepared in Example 20 (50 mg) and 4-(4 methyl-1-piperazinyl)m- 1-(2,2-dimethylpropyl)-3-ethoxy-1H-pyrazolo 3,4-d ethylbenzoic acid dihydrochloride (135 mg) in dimethyl pyrimidine-6-carbonitrile formamide (1.8 mL) were added triethylamine (184 uL), 0515) 1-hydroxy-7-azabenzotriazole (HOAt, 60 mg) and 1-ethyl 3-(3-dimethylaminopropyl)carbodiimide hydrochloride (84 mg), then the mixture was stirred for 19 hours at 40°C., 7 hours at 50° C. The reaction mixture was cooled to room temperature, then added by water, extracted with ethyl acetate. The organic layer washed with brine, dried over anhydrous sodium sulfate, concentrated. The obtained resi due was purified by column chromatography on silica gel (ethyl acetate->ethyl acetate:methanol=10: 1->dichlo romethane:methanol=10:1), then by preparative thin-layer chromatography (dichloromethane:methanol=9:1) to give the title compound (7 mg) having the following physical data. 0516 By the same procedures as described in Example 0524) TLC: Rf 0.37 (dichloromethane:methanol=10:1); 17, using the compound prepared in Example 15 instead of 0525 H NMR (CDC1): 8 1.05 (s, 9H), 2.30 (s, 3H), the compound prepared in Example 16, the title compound 2.34-2.73 (m, 8H), 3.46 (s. 2H), 3.54 (s. 2H), 7.37 (d. J=8.42 having the following physical data was obtained. Hz, 2H), 7.51 (s, 1H), 7.67 (d. J=8.42 Hz, 2H). 0517 TLC: Rf 0.69 (hexane:ethyl acetate=4:1); 0518 H NMR (CDC1): 8 1.00 (s, 9H), 1.50 (t, J=7.10 Example 21(1)-Example 21(2) Hz, 2H), 4.12 (s. 2H), 4.47 (q, J=7.10 Hz, 2H), 9.04 (s, 1H). 0526. By the same procedures as described in Example 21, using corresponding carboxylic acid compound instead Example 20 of 4-(4-methyl-1-piperazinyl)methylbenzoic acid dihydro chloride, the title compound was obtained. 5-bromo-4-1-(2,2-dimethylpropyl)hydrazino-2- pyrimidinecarbonitrile Example 21 (1) 0519. By the same procedures as described in Example 1->Example 3->Example 17, using 5-bromo-2,4-dichloro 1-(2,2-dimethylpropyl)-3-(4-1-(2-methoxyethyl)-4- pyrimidine instead of 2,4-dichloro-5-(chloromethyl)pyrimi piperidinylphenyl)-1H-pyrimido-4,5-e1.3.4loxa dine and tert-butyl 2-(2,2-dimethylpropyl)hydrazinecar diazine-7-carbonitrile boxylate instead of neopentylamine in the step corresponding to Example 1, the title compound having the 0527 TLC: Rf 0.51 (dichloromethane:methanol=10:1); following physical data was obtained. 0528) "H NMR (CDC1): 8 1.04 (s, 9H, 1.71-1.96 (m, 4H), 1.98-2.23 (m, 2H), 2.46-2.59 (m, 1H), 2.62 (t, J=5.58 0520 TLC: Rf 0.57 (hexane:ethyl acetate=2:1); Hz, 2H), 3.00-3.20 (m, 2H), 3.37 (s.3H), 3.45 (s. 2H), 3.55 0521 'H NMR (DMSO-d): 8 0.94 (s, 9H), 3.68 (s. 2H), (t, J=5.58 Hz, 2H), 7.27 (d. J=8.30 Hz, 2H), 7.50 (s, 1H), 5.07 (s. 2H), 8.45 (s, 1H). 7.66 (d. J=8.30 Hz, 2H). US 2007/019751.0 A1 Aug. 23, 2007 42

Example 21(2) Example 24 1-(2,2-dimethylpropyl)-3-vinyl-1H-pyrimidoA,5-e 9-(2,2-dimethylpropyl)-6-(4-methoxybenzyl)-7-oxo 6,7,8,9-tetrahydro-5H-pyrimidoA.5-e1.4diaz 1.3.4oxadiazine-7-carbonitrile epine-2-carbonitrile 0529) TLC: Rf 0.54 (hexane:ethyl acetate=4:1); 0537) 0530 "H NMR (CDC1): 8 0.99 (s, 9H), 3.38 (s. 2H), 5.61 (dd, J=9.60, 2.10 Hz, 1H), 5.88 (dd, J=17.40, 2.10 Hz, 1H), 5.97 (dd, J=17.40, 9.60 Hz, 1H), 7.47 (s, 1H). Example 22 2-chloro-N-(2,2-dimethylpropyl)-5-(4-methoxy benzyl)aminomethyl-4-pyrimidineamine 0531. To a solution of (4-methoxybenzyl)amine (137 mg) in tetrahydrofuran (3 mL) on ice bath was added diisopro pylethylamine (192 LL), then the mixture was dropped by a Solution of the compound prepared in Example 1 (248 mg) 0538 To a solution of the compound prepared in in tetrahydrofuran (2 mL), stirred for 30 minutes at room Example 23 (34 mg) in tetrahydrofuran (0.5 mL) on ice bath was added diisopropylethylamine (35 LL), the mixture was temperature, 2.5 hours at 50° C., then 4 hours at 60°C. The added by a solution of chloroacetyl chloride (12 mg) in reaction mixture was added by (4-methoxybenzyl)amine tetrahydrofuran (0.5 mL), stirred for 1 hour at room tem (137 mg) and diisopropylethylamine (192 uL), stirred for 9 perature. To the reaction mixture were added potassium hours at 65° C. The reaction mixture was concentrated. The carbonate (28 mg), potassium iodide (33 mg) and dimeth ylformamide (0.2 mL), then the mixture was stirred for 2 obtained residue was diluted with ethyl acetate, washed with hours at 55° C., 5 hours at 80°C. The reaction mixture was water, Saturated aqueous Solution of sodium hydrogen car cooled to room temperature, poured into water, extracted bonate and brine sequentially, dried over anhydrous sodium with ethyl acetate. The organic layer washed with water and brine sequentially, dried over anhydrous Sodium sulfate, sulfate, concentrated. The obtained residue was purified by concentrated. The obtained residue was purified by column column chromatography on silica gel (hexane:ethyl acetate= chromatography on silica gel (hexane:ethyl acetate=1:2) to 3:1) to give the title compound (300 mg) having the fol give the title compound (19 mg) having the following lowing physical data. physical data. 0539 TLC: Rf 0.53 (hexane:ethyl acetate=1:3); 0532 TLC: Rf 0.29 (hexane:ethyl acetate=2:1); 0540 "H NMR (CDC1): 8 1.02 (s, 9H), 3.68 (s, 2H), 3.79 (s.3H), 4.35 (s. 2H), 4.47 (s. 2H), 4.61 (s. 2H), 6.81 (d. 0533 H NMR (CDC1) & 0.96 (s, 9H), 3.31 (d. J=5.85 J=8.70 Hz, 2H), 7.12(d, J=8.70 Hz, 2H), 7.54(s, 1H). Hz, 2H), 3.64-3.72 (m, 4H), 3.80 (s.3H), 6.87 (d. J=8.70 Hz, 2H), 7.18 (d. J=8.70 Hz, 2H), 7.69 (s, 1H), 7.73-7.89 (m, Example 25 1H). 8-(2,2-dimethylpropyl)-6-(4-methoxybenzyl)-7-oxo 5,6,7,8-tetrahydropyrimidoA,5-dipyrimidine-2-car Example 23 bonitrile 4-(2,2-dimethylpropyl)amino-5-(4-methoxyben 0541) Zyl)aminomethyl)-2-pyrimidinecarbonitrile 0534. By the same procedures as described in Example 3, using the compound prepared in Example 22 instead of the compound prepared in Example 2, the title compound hav HC3 No O1. N Nals CN ing the following physical data was obtained. HC 0535 TLC: Rf 0.29 (hexane:ethyl acetate=2:1); H3C CH 0536) "H NMR (CDC1): 8 0.96 (s, 9H), 3.31 (d. J=6.04 Hz, 2H), 3.68 (s. 2H), 3.74 (s. 2H), 3.81 (s, 3H), 6.87 (d. 0542. To a solution of tetrahydrofuran (0.5 mL) in tri J=8.70 Hz, 2H), 7.15 (d. J=8.70 Hz, 2H), 7.85 (s, 1H), ethylamine (42 mL) on ice bath was dropped a solution of 7.90-8.08 (m, 1H). triphosgene (10 mg) in tetrahydrofuran (0.3 mL). To the US 2007/019751.0 A1 Aug. 23, 2007 reaction mixture was dropped a solution of the compound 0549) TLC: Rf 0.42 (hexane:ethyl acetate=9:1); prepared in Example 23 (34 mg) in tetrahydrofuran (0.4 mL), the reaction mixture was stirred for 1 hour at room 0550 "H NMR (CDC1): 8 1.14 (s, 9H), 3.88 (s. 2H), temperature. To the reaction mixture were added triethy 7.00 (dd, J-7.32, 1.65 Hz, 1H), 7.46-7.56 (m, 2H). lamine (42 mL) and triphosgene (8 mg), the mixture was Example 28(1)-Example 28(4) stirred for 5 minutes at room temperature, 30 minutes at 50° 0551. By the same procedures as described in Example 1 C., 21 hours at 70° C. The reaction mixture was cooled to Example 3, using 5,7-dichloropyrazolo 1.5-apyrimidine or room temperature, poured into water, extracted with ethyl 2,4-dichloropyrido 2,3-dipyrimidine instead of 2,4- acetate. The organic layer was washed with brine, dried over dichloro-5-(chloromethyl)pyrimidine, and (4-methoxyben anhydrous Sodium sulfate, concentrated. The obtained resi Zyl)amine instead of neopentylamine in the step correspond due was purified by column chromatography on silica gel ing to Example 1, the following compounds are obtained. (hexane:ethyl acetate=4:1->2:1) to give the title compound (20 mg) having the following physical data. Example 28(1) 0543) TLC: Rf 0.34 (hexane:ethyl acetate=2:1); 7-(4-methoxybenzyl)aminolpyrazolo 1.5-apyrimi 0544 H NMR (CDC1): 8 0.94 (s, 9H), 3.81 (s, 3H), dine-5-carbonitrile 4.14 (s. 2H), 4.25 (s. 2H), 4.43-4.80 (m, 2H), 6.79-6.94 (m, 0552) TLC: Rf 0.38 (hexane:ethyl acetate=2:1); 2H), 7.20-7.27 (m, 2H), 8.19 (s, 1H). 0553 "H NMR (CDC1): 83.82 (s, 3H), 4.57 (d. J=5.67 Hz, 2H), 6.25 (s, 1H), 6.66 (d. J=2.20 Hz, 1H), 6.86-6.97 (m, Example 26 1H), 6.92 (d. J=8.78 Hz, 2H), 7.28 (d. J=8.78 Hz, 2H), 8.09 (d. J=2.20 Hz, 1H). N-(5Z)-4-chloro-5H-1,2,3-dithiazol-5-ylidene-2-(2, 2-dimethylpropoxy)aniline Example 28(2) 7-(4-methoxybenzyl)amino-2-methylpyrazolo 1.5- 0545) To a solution of 2-(2,2-dimethylpropoxy)phenyl apyrimidine-5-carbonitrile amine (529 mg) in dichloromethane (20 mL) was added 4,5-dichloro-1,2,3-dithiazol-1-ium chloride (679 mg, this 0554) TLC: Rf 0.43 (hexane:ethyl acetate=2:1); compound is described in Chem. Ber. 118, 1632-1643 0555 H NMR (CDC1): 8 2.49 (s, 3H), 3.83 (s, 3H), (1985)) at room temperature, then the mixture was stirred 4.55 (d. J=5.68 Hz, 2H), 6.19 (s, 1H), 6.44 (s, 1H), 6.77-6.87 overnight at room temperature. The reaction mixture was (m. 1H), 6.93 (d. J=8.60 Hz, 2H), 7.29 (d. J=8.60 Hz, 2H). added by water and ethyl acetate, extracted with ethyl acetate. The organic layer washed with water and brine, Example 28(3) dried over anhydrous sodium sulfate, concentrated. The 7-(2,2-dimethylpropyl)aminolpyrazolo 1.5-apyri obtained residue was purified by column chromatography on midine-5-carbonitrile silica gel (hexane:ethyl acetate=1:20) to give the title com pound (86.8 mg) having the following physical data. 0556 TLC: Rf 0.44 (hexane:ethyl acetate=3:1); 0557 "H NMR (CDC1): 8 1.09 (s.9H), 3.22 (d. J=6.59 0546) TLC: Rf 0.74 (hexane:ethyl acetate=4:1). Hz, 2H), 6.26 (s, 1H), 6.66 (d. J=2.38 Hz, 1H), 6.64-6.78 (m, Example 27 1H), 8.10(d. J=2.38 Hz, 1H). Example 28(4) 4-(2,2-dimethylpropoxy)-1,3-benzothiazol-2-carbo 4-(2,2-dimethylpropyl)aminolpyrido2.3-dpyrimi nitrile dine-2-carbonitrile 0547 0558 TLC: Rf 0.49 (hexane:ethyl acetate=1:4): 0559) 'H NMR (CDC1): 8 1.06 (s, 9H), 3.60 (d. J=6.22 Hz, 2H), 5.99-6.23 (m, 1H), 7.56 (dd, J=8.32, 4.30 Hz, 1H), X-CN 8.16 (dd, J=8.42, 1.83 Hz, 1H), 9.16 (dd, J=4.39, 1.83 Hz, CH N 1H).

O Example 29 HCDN 1-(2,2-dimethylpropyl)-3-(4-methoxybenzyl)oxy 1H-pyrazolo 3,4-dpyrimidine-6-carbonitrile 0548. The compound prepared in Example 26 (199 mg) 0560) was dissolved to N-methylmorpholine (2 mL), then the mixture was microwaved for 1 minutes (max temperature: 150° C., 90W). The reaction mixture was cooled to room temperature, added by water and ethyl acetate, extracted with ethyl acetate. The organic layer was washed with water and brine sequentially, dried over anhydrous sodium sulfate, concentrated. The obtained residue was purified by column chromatography on silica gel (hexane:ethyl acetate=1:20), HC-O HC then by preparative thin-layer chromatography (hexane :ethyl acetate=1:9) to give the title compound (24.8 mg) having the following physical data. US 2007/019751.0 A1 Aug. 23, 2007 44

0561. To a solution of the compound prepared in pounds instead of N,N-dimethyl-1,2-ethanediamine, the fol Example 7 (10 mg) in dimethylformamide (0.2 mL) was lowing compounds were obtained. added potassium carbonate (6.6 mg), then the mixture was stirred for 10 minutes at room temperature. To the reaction Example 30(1) mixture was added a solution of p-methoxybenzyl chloride (6.8 mg) in dimethylformamide (0.2 mL), the mixture was isopropylo-cyano-1-(2,2-dimethylpropyl)-3-oxo-1, stirred for 2 hours at 60°C. The reaction mixture was cooled 3-dihydro-2H-pyrazolo 3,4-dpyrimidin-2-yl)acetate to room temperature, added by water and 1N hydrochloric 0569. TLC: Rf 0.50 (hexane:ethyl acetate=6:4): acid, extracted with tert-butyl methyl ether. The organic layer washed with water and brine sequentially, dried over 0570 "H NMR (CDC1): 8 0.98 (s, 9H), 1.22 (d. J=6.22 anhydrous Sodium sulfate, concentrated. The obtained resi HZ, 6H), 3.76-3.94 (m, 2H), 4.65-4.82 (m, 2H), 4.91-5.12 due was purified by column chromatography on silica gel (m. 1H), 8.90-9.33 (m, 1H). (hexane:ethyl acetate=9:1) to give the title compound (14 mg) having the following physical data. Example 30(2) 0562) TLC: Rf 0.52 (hexane:ethyl acetate=4:1); tert-butyl G-cyano-1-(2,2-dimethylpropyl)-3-oxo-1, 3-dihydro-2H-pyrazolo 3,4-dpyrimidin-2-yl)acetate 0563 "H NMR (CDC1): 8 1.01 (s, 9H), 3.83 (s, 3H), 4.14 (s. 2H), 5.37 (s. 2H), 6.93 (d. J=8.60 Hz, 2H), 7.44(d. 0571 TLC: Rf 0.37 (hexane:ethyl acetate=7:3); J=8.60 Hz, 2H), 9.02(s, 1H). 0572) H NMR (CDC1): 8 0.99 (s, 9H), 1.40 (s, 9H), 3.87 (s. 2H), 4.65 (s. 2H), 9.07 (s, 1H). Example 30 0573. Example 30(3) 2-6-cyano-1-(2,2-dimethylpropyl)-3-oxo-1,3-dihy dro-2H-pyrazolo 3,4-dpyrimidin-2-yl)-N-2-(dim ethyl G-cyano-1-(2,2-dimethylpropyl)-3-oxo-1,3- ethylamino)ethylacetamide dihydro-2H-pyrazolo 3,4-dipyrimidin-2-yl)acetate 0564) 0574) TLC: Rf 0.20 (hexane:ethyl acetate=7:3); 7.14 Hz, 2H), 4.75(s, 2H), 9.08(s, 1H). Example 30(4) O O 2-6-cyano-1-(2,2-dimethylpropyl)-3-oxo-1,3-dihy - N dro-2H-pyrazolo 3,4-dipyrimidin-2-yl)-N-5-(dim ethylamino)pentyl)acetamide He-y/ NullN 4. CN 0575 TLC: Rf 0.50 (dichloromethane:methanol:acetic CH HC acid=10:2:1); 0576) "H NMR (CDC1): 8 0.99 (s, 9H), 1.23-138 (m, 2H), 1.38-1.57 (m, 4H), 2.20 (s, 6H), 2.21-2.28 (m, 2H), 3.12-3.29 (1, 2H), 4.05 (s. 2H), 4.69 (s. 2H), 6.55-6.69 (m, 0565) To a solution of the compound prepared in 1H), 9.08 (s, 1H). Example 18(2) (58 mg) and N,N-dimethyl-1,2-ethanedi Example 30(5) amine (21 mg) in dimethylformamide (1 mL) were added 1-hydroxybenzotriazole (HOBt, 30 mg) and 1-ethyl-3-(3- 2-6-cyano-1-(2,2-dimethylpropyl)-3-oxo-1,3-dihy dimethylaminopropyl)carbodiimide hydrochloride (46 mg), dro-2H-pyrazolo 3,4-dipyrimidin-2-yl)-N-4-(dim then the mixture was stirred for 17 hours at room tempera ethylamino)butylacetamide ture. The reaction mixture was added by ethyl acetate, water and Saturated aqueous solution of Sodium hydrogen carbon 0577 TLC: Rf 0.50 (dichloromethane:methanol:acetic ate, extracted with ethyl acetate. The organic layer washed acid=10:2:1); with brine, dried over anhydrous Sodium sulfate, concen 0578 "H NMR (CDC1): 8 0.99 (s, 9H), 1.48-1.62 (m, trated. The residue washed with tert-butyl methyl ether, 4H), 2.26 (s, 6H), 2.27-2.34 (m, 2H), 3.13-3.29(m, 2H), 4.03 dried to give the title compound (41.9 mg) having the following physical data. (s. 2H), 4.66 (s. 2H), 8.06-8.20(m, 1H), 9.06 (s, 1H). 0566 TLC: Rf 0.50 (dichloromethane:methanol:acetic Example 30(6) acid=10:2:1); 2-6-cyano-1-(2,2-dimethylpropyl)-3-oxo-1,3-dihy 0567 "H NMR (CDC1): 8 0.98 (s, 9H), 2.16 (s, 6H), dro-2H-pyrazolo 3,4-dipyrimidin-2-yl)-N-3-(dim 2.31-2.44 (m, 2H), 3.23-3.30 (m, 2H), 4.01 (s. 2H), 4.68 (s, ethylamino)propyl)acetamide 2H), 6.32-6.48 (m. 1H), 9.08 (s, 1H). 0579) TLC: Rf 0.50 (dichloromethane:methanol:acetic Example 30(1)-Example 30(7) acid=10:2:1); 0580 "H NMR (CDC1): 8 0.99 (s, 9H), 1.49-1.77 (m, 0568. By the same procedures as described in Example 2H), 2.13 (s, 6H), 2.30-2.50 (m, 2H), 3.27-3.37 (, 2H), 4.01 30, using corresponding amine compounds or alcohol com (s. 2H), 4.66 (s. 2H), 7.85-8.08 (m, 1H), 9.07 (s, 1H). US 2007/019751.0 A1 Aug. 23, 2007 45

Example 30(7) Solution of Sodium hydrogen carbonate and brine sequen tially, dried over anhydrous Sodium Sulfate, concentrated. 2-6-cyano-1-(2,2-dimethylpropyl)-3-oxo-1,3-dihy The obtained residue was purified by column chromatogra dro-2H-pyrazolo 3,4-dpyrimidin-2-yl)-N-(4-fluo phy on silica gel (ethyl acetate:hexane=1:2-> 1:1) to give the rophenyl)acetamide title compound (94 mg) having the following physical data. 0581) TLC: Rf 0.20 (dichloromethane:ethyl acetate=1:1): 0590 TLC: Rf 0.28 (ethyl acetate:hexane=1:1); 0582) H NMR (CDC1): 8 0.99 (s, 9H), 4.02 (s. 2H), 0591) H NMR (CDC1): 8 0.99 (s, 9H), 2.51 (s, 3H), 4.90 (s. 2H), 7.10-7.20 (m, 2H), 7.48-7.58 (m, 2H), 9.23 (s, 3.38 (s. 2H), 3.58-3.71 (m, 4H), 5.75-5.83 (m. 1H), 8.82 1H), 10.41 (s, 1H). 8.84(m, J=0.73 Hz, 1H). Example 31 Example 34 ethyl 4-(2-aminoethyl)(2,2-dimethylpropyl)amino 9-(2,2-dimethylpropyl)-5-oxo-6,7,8,9-tetrahydro-5H 2-(methylthio)-5-pyrimidinecarboxylate 4-methyl pyrimido4.5-e1.4diazepine-2-carbonitrile benzenesulfonate 0583. By the same procedures as described in Example 0592) 1->Example 17, using ethyl 4-chloro-2-(methylthio)-5-py rimidinecarboxylate instead of 2,4-dichloro-5-(chlorometh yl)pyrimidine, and tert-butyl 2-(2,2-dimethylpropy O l)aminolethylcarbamate instead of neopentylamine in the step corresponding to Example 1, the title compound having HN the following physical data was obtained. r 0584) TLC: Rf 0.46 (ethyl acetate:methanol=9:1): N Nals CN 0585 H NMR (CDC1): 8 0.98 (s.9H), 1.33 (t, J=6.9 Hz, H3C 3H), 2.35 (s.3H, 2.58 (s.3H), 2.70-2.80 (m, 2H), 3.31-3.46 (m. 2H), 4.12-4.25 (m. 2H), 4.32 (q, J=6.9 Hz, 2H), 7.16 (d. H3C J=8.4 Hz, 2S, 7.73 (d. J=8.4 Hz, 2S, 8.41-8.59 (m, 2H), 8.64 CH3 (s, 1H, 9.10-9.30 (m. 1H). Example 32 0593. By the same procedures as described in Example 12 Example 13, using the compound prepared in Example Disodium 4-(2-aminoethyl)(2,2-dimethylpropy 33 instead of the compound prepared in Example 11 in the l)amino-2-(methylthio)-5-pyrimidinecarboxylate step corresponding to Example 12, the title compound 4-methylbenzenesulfonate having the following physical data was obtained. 0586 To a solution of the compound prepared in 0594) TLC: Rf 0.60 (hexane:ethyl acetate=1:2): Example 31 (226 mg) in dioxane (4 mL) were added 1N aqueous solution of sodium hydroxide (1.2 mL) and ethanol 0595 H NMR (CDC1): 8 1.00 (s, 9H), 3.41 (s. 2H), (1 mL), then the mixture was stirred for 3 hours at 80° C. 3.66-3.73 (m, 4H), 6.05-6.14 (m, 1H), 8.98-9.00 (m, 1H). The reaction mixture was concentrated. The obtained resi due was azeotroped with ethanol to give the title compound Example 35 (282 mg) having the following physical data. ethyl 7-chloro-5-methylimidazo 1,2-apyrimidin-2- 0587 TLC: Rf 0.20 (ethyl acetate:methanol:acetic acid= carboxylate 8:1:1): 0596) To a solution of 4-chloro-6-methyl-2-pyrim 0588 H NMR (DMSO-d): 8 0.84 (s, 9H), 2.28 (s, 3H), idineamine (2.87 g) in tetrahydrofuran (50 mL) was added 2.40 (s.3H), 2.62-2.74 (m, 2H), 3.20-3.50 (m, 4H), 7.10 (d. ethyl 3-bromo-2-oxopropanoate (2.51 mL), then the mixture J=8.1 Hz, 2H), 7.46 (d. J=8.1 Hz, 2H), 8.29 (s, 1H). was stirred for 3 hours at room temperature, then refluxed for 6 hours. The reaction mixture was added by ethyl acetate Example 33 and Saturated aqueous solution of Sodium hydrogen carbon ate, extracted with ethyl acetate. The organic layer washed 9-(2,2-dimethylpropyl)-2-(methylthio)-6,7,8,9-tet with water and brine sequentially, dried over anhydrous rahydro-5H-pyrimidoA,5-e1.4diazepin-5-one Sodium sulfate, concentrated. The obtained residue was 0589 To a solution of the compound prepared in purified by column chromatography on silica gel (ethyl Example 32 (275 mg) and 1-hydroxybenzotriazole (88.8 acetate:hexane=1:1->2:1->3:1). The obtained compound mg) in dimethylformamide (7 mL) on ice bath was added washed with a mixed solvent of ethyl acetate and hexane to 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydro give the title compound (1.65 g) having the following chloride (116 mg), then the reaction mixture was stirred for physical data. overnight with rising to room temperature. The reaction mixture was added by ethyl acetate and Saturated aqueous 0597 TLC: Rf 0.29 (ethyl acetate:hexane=2:1); Solution of sodium hydrogen carbonate, extracted with ethyl 0598 H NMR (CDC1): 8 1.44 (t, J=7.14 Hz, 3H), 2.68 acetate. The organic layer washed with Saturated aqueous (s, 3H), 4.47 (t, J=7.14 Hz, 2H), 6.83 (s, 1H), 8.06 (s, 1H). US 2007/019751.0 A1 Aug. 23, 2007 46

Example 36 aqueous solution of Sodium hydrogen carbonate, extracted with ethyl acetate. The organic layer washed with saturated Sodium 7-(2,2-dimethylpropyl)amino-5-meth aqueous solution of sodium hydrogen carbonate and brine, ylimidazol-2-alpyrimidin-2-carboxylate dried over anhydrous sodium sulfate, concentrated. The obtained residue was purified by column chromatography on 0599. By the same procedures as described in Example silica gel (ethyl acetate:hexane=1:1->2:1), then the obtained 1->Example 32, using the compound prepared in Example compound was dissolved to methanol, then concentrated to 35 instead of 2,4-dichloro-5-(chloromethyl)pyrimidine in give the title compound (52.6 mg) having the following the step corresponding to Example 1, the title compound physical data. having the following physical data was obtained. 0607 TLC: Rf 0.42 (hexane:ethyl acetate=1:2): 0600 TLC: Rf 0.07 (dichloromethane:methanol=9:1); 0608 H NMR (CDC1): 8 0.97 (s, 9H), 2.49 (d. J=0.91 0601) "H NMR (CDOD): 8 0.88-1.00 (m, 9H), 2.50 (s, Hz, 3H), 3.27-3.47 (m, 2H), 4.80-5.14(m, 1H), 6.03-6.11(m, 3H), 3.16-3.29 (m, 2H), 6.23-6.30 (m, 1H), 7.59-7.67 (m, 1H), 7.59(s, 1H). 1H). Example 39 Example 37 methyl 3-amino-4-(2,2-dimethylpropyl)-1H-pyrrole 2-carboxylate 7-(2,2-dimethylpropyl)amino-5-methylimidazol, 0609 Under atmosphere of argon, methyl 2-cyano-4.4- 2-apyrimidin-2-carboxamide dimethylpentanoate (1.61 g) was dissolved to dry tetrahy 0602) To a solution of the compound prepared in drofuran (20 mL), the mixture was cooled to -70° C. Example 36 (297 mg) in dimethylformamide (1 mL) on ice disobutylaluminum hydride (1.01M toluene solution, 9.42 bath were added 1-hydroxybenzotriazole (157 mg) and mL) was slowly dropped thereto, the mixture was stirred for 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydro 2 hours at -70° C., then stirred for 1.5 hours with rising to chloride (210 mg), the mixture was stirred for 5 hours with -34°C. The reaction mixture was added by methanol (0.77 rising to room temperature. The reaction mixture was added mL), and 1N hydrochloric acid, extracted with ethyl acetate. by 28% aqueous solution of ammonia (10 mL), stirred for a The organic layer washed with 1N hydrochloric acid and while, added by ethyl acetate and water, then extracted with brine sequentially, dried over anhydrous Sodium sulfate, ethyl acetate. The organic layer was washed with saturated concentrated to give crude 2-formyl-4,4-dimethylpentaneni aqueous solution of Sodium hydrogen carbonate and brine trile (1.58 g). sequentially, dried over anhydrous sodium Sulfate, concen 0610 Under atmosphere of argon, to a solution of trated. The residue was washed with a mixed solvent of ethyl 2-formyl-4,4-dimethylpentanenitrile (1.58 g) in methanol acetate and hexane to give the title compound (83 mg) (50 mL) were added dimethylaminomalonate hydrochloride having the following physical data. (2.62 g) and a solution of sodium acetate (1.17 g) in water (10 ml) at room temperature, then the mixture was stirred 0603) TLC: Rf 0.36 (dichloromethane:methanol=9:1); overnight at room temperature. The reaction mixture was 0604 H NMR (CDC1): 8 0.98 (s, 9H), 2.48 (s, 3H), concentrated, added by ethyl acetate and water, extracted 3.34-3.44 (m, 2H), 4.76-4.93 (m, 1H), 5.41-5.55 (m, 1H), with ethyl acetate. The organic layer washed with water and brine sequentially, dried over anhydrous Sodium sulfate, 5.99-6.02 (m, 1H), 7.21-7.38 (m, 1H), 7.76 (s, 1H). concentrated to give crude dimethyl (1Z)-2-cyano-4.4- Example 38 dimethyl-1-penten-1-yl)aminomalonate (2.09 g). To a solu tion of dimethyl (1Z)-2-cyano-4,4-dimethyl-1-penten-1- 7-(2,2-dimethylpropyl)amino-5-methylimidazol, yl)aminomalonate (2.08 g) in methanol (50 mL) was added 2-alpyrimidine-2-carbonitrile sodium methoxide (28% methanol solution, 91.6 mg), the mixture was stirred for 2 hours at room temperature, then 0605) refluxed for 30 minutes. The reaction mixture was cooled to room temperature, concentrated. The obtained residue was added by diisopropylether and water, extracted with diiso CH3 propylether. The organic layer washed with water and brine sequentially, dried over anhydrous Sodium sulfate, concen 21 NN trated. The obtained residue was purified by column chro matography on silica gel (ethyl acetate:hexane=1:4) to give N S. the title compound (518 mg) having the following physical HN N D)-csN data. H3C 0611) TLC: Rf 0.47 (ethyl acetate:hexane=1:2): HC 0612) H NMR (CDC1): 8 0.92 (s, 9H), 2.21 (s. 2H), CH3 3.83 (s, 3H), 4.00-4.55 (m, 2H), 6.42-6.64 (m. 1H), 7.75 8.32 (m, 1H). Example 40 0606 To a solution of the compound prepared in Example 37 (68 mg) in dichloromethane (8 mL) on ice bath methyl 3-(tert-butoxycarbonyl)amino-4-(2,2-dim were added pyridine (63 uL) and trifluoroacetic anhydride ethylpropyl)-1H-pyrrole-2-carboxylate (74 uL), then the mixture was stirred for 3 hours at room 0613 Under atmosphere of argon, to the compound pre temperature. The reaction mixture was added by saturated pared in Example 39 (373 mg) was added a solution of US 2007/019751.0 A1 Aug. 23, 2007 47 di-tert-butyl dicarbonate (635 mg) in dioxane (4.5 mL), the 0622 TLC: Rf 0.56 (ethyl acetate:methanol=9:1): mixture was stirred for 11.5 hours at 90° C. The reaction mixture was cooled to room temperature, then concentrated. 0623 H NMR (CDC1): 8 0.91 (s, 9H), 2.22 (s. 2H), The obtained residue was purified by column chromatogra 2.60-3.60 (m, 2H), 3.86 (s.3H), 6.37 (s, 1H), 6.40-6.66 (m, phy on silica gel (ethyl acetate:hexane=1:4-> 1:3) to give the 2H). title compound (401 mg) having the following physical data. Example 44 0614 TLC: Rf 0.18 (ethyl acetate:hexane=1:4): 7-(2,2-dimethylpropyl)-5-methyl-2-thioxo-1,2,3,5- 0615) 'H NMR (CDC1): 8 0.86 (s, 9H), 1.47-1.52 (m, tetrahydro-4H-pyrrolo3.2-dpyrimidin-4-one 9H), 2.47 (s. 2H), 3.84 (s, 3H), 6.44-6.86 (m, H), 6.63 (d. J=3.11 Hz, 1H), 8.52-8.78 (m, 1H). 0624. To a solution of the compound prepared in Example 43 (8.7 mg) in dimethylformamide (0.3 mL) were Example 41 added carbon disulfide (2.5 LL) and sodium hydroxide (1.9 mg), then the mixture was stirred for 1 day at room tem methyl 3-(tert-butoxycarbonyl)amino-4-(2,2-dim perature. The reaction mixture was added by diluted hydro ethylpropyl)-1-methyl-1H-pyrrole-2-carboxylate chloric acid and brine, extracted with ethyl acetate. The 0616) To a solution of the compound prepared in organic layer washed with brine, dried over anhydrous Example 40 (299 mg) in dimethylformamide (2 mL) were Sodium sulfate, concentrated to give the title compound added potassium carbonate (173 mg) and methyl iodide (78 (11.0 mg) having the following physical data. LL), then the mixture was stirred overnight at room tem 0625 TLC: Rf 0.61 (ethyl acetate:hexane=1:1); perature. The reaction mixture was concentrated. The obtained residue was added by ethyl acetate and water, 0626) "H NMR (CDC1): 8 0.93 (s, 9H), 2.30 (s. 2H), extracted with ethyl acetate. The organic layer washed with 3.97 (s, 3H), 6.73 (s, 1H), 8.78-9.07 (m, 2H). water and brine sequentially, dried over anhydrous sodium sulfate, concentrated. The obtained residue was purified by Example 45 column chromatography on silica gel (ethyl acetate:hexane= 1:4-> 1:3) to give the title compound (246 mg) having the 7-(2,2-dimethylpropyl)-4-methoxy-5-methyl-2-(me following physical data. TLC: Rf 0.36 (ethyl acetate:hex thylthio)-5H-pyrrolo3.2-dpyrimidine ane=1:4); 0627 To a solution of the compound prepared in Example 44 (11.0 mg) in dimethylformamide (0.3 mL) were 0617 H NMR (CDC1): 8 0.86 (s, 9H), 1.48 (s, 9H), added potassium carbonate (13.2 mg) and methyl iodide (5.7 2.41 (s. 2H), 3.81 (s, 3H), 3.83 (s, 3H), 6.47 (s, 1H), uL), then the mixture was stirred for 3 hours at room 6.55-6.95 (m, 1H). temperature. The reaction mixture was added by 1N hydro chloric acid and brine, extracted with ethyl acetate. The Example 42 organic layer washed with brine, dried over anhydrous tert-butyl 2-(aminocarbonyl)-4-(2,2-dimethylpro Sodium sulfate, concentrated to give the crude title com pyl)-1-methyl-1H-pyrrol-3-yl)carbamate pound having the following physical data. 0618. By the same procedures as described in Example 0628 TLC: Rf 0.61 (ethyl acetate:hexane=1:3); 32->Example 37, using the compound prepared in Example 0629 H NMR (CDC1): 8 0.91 (s, 9H), 2.51 (s. 2H), 41 instead of the compound prepared in Example 31 in the 2.60 (s, 3H), 3.55 (s, 3H), 4.03 (s, 3H), 6.75 (s, 1H). step corresponding to Example 32, the title compound having the following physical data was obtained. Example 46 0619) TLC: Rf 0.38 (ethyl acetate:hexane=1:1); 7-(2,2-dimethylpropyl)-4-methoxy-5-methyl-5H 0620 "H NMR (DMSO-d): 8 0.81 (s, 9H), 1.40 (s, 9H), pyrrolo3.2-dpyrimidine-2-carbonitrile 2.13 (s. 2H), 3.68 (s, 3H), 6.58 (s, 1H), 6.70-7.30 (m, 2H), 8.12-8.26 (m, 1H). 0630

Example 43 3-amino-4-(2,2-dimethylpropyl)-1-methyl-1H-pyr role-2-carboxamide 0621. To a solution of the compound prepared in Example 42 (13.4 mg) in dichloromethane (0.3 mL) was added trifluoroacetic acid (0.1 mL), then the mixture was stirred for 1.5 hours at room temperature. The reaction HC mixture was concentrated. The obtained residue was added by ethyl acetate and saturated aqueous solution of sodium hydrogen carbonate, extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous Sodium sulfate, concentrated to give the title compound 0631 By the same procedures as described in Example (13.4 mg) having the following physical data. 12->Example 13, using the compound prepared in Example US 2007/019751.0 A1 Aug. 23, 2007 48

45 instead of the compound prepared in Example 11 in the for 4 hours at room temperature. The reaction mixture was step corresponding Example 12, the title compound having added by trityl chloride (77 mg), stirred for 30 minutes at the following physical data was obtained. 50° C. The reaction mixture was cooled to room tempera ture, poured into water, extracted with chloroform. The 0632) TLC: Rf 0.32 (hexane:ethyl acetate=4:1); organic layer washed with brine, dried over anhydrous 0633 H NMR (CDC1): 8 0.91 (s, 9H), 2.56 (s, 2H), Sodium sulfate, concentrated. The residue was azeotroped 3.78 (s, 3H), 4.10 (s, 3H), 6.91 (s, 1H). with toluene, washed with tert-butyl methyl ether to give the title compound (558 mg) having the following physical data. Example 47 0641) TLC: Rf 0.65 (hexane:ethyl acetate=1:1). 7-(2,2-dimethylpropyl)-4-(2,2-dimethylpropy l)amino-5-methyl-5H-pyrrolo3.2-dpyrimidine-2- Example 50 carbonitrile 6-(2,2-dimethylpropyl)amino-H-purine-2-carbonitrile 0634) 0642)

CH3 HN CH3 CH N n 3 N

2 {llN N CN

0.643. To a suspension of the compound prepared in Example 49 (200 mg) in dimethylsulfoxide (1.5 mL) were added potassium cyanide (54 mg), 1,4-diazabicyclo2.2.2 octane (14 mg) and water, then the mixture was stirred for 0635. By the same procedures as described in step (9-G) 3.5 hours at 150° C. The reaction mixture was poured into of Example 9->Example 10->Example 11->Example water, extracted with ethyl acetate. The organic layer 12->Example 13, using the compound prepared in Example washed with brine, dried over anhydrous sodium sulfate, 44 instead of the compound prepared in step (9-F) in the step concentrated. The residue washed with tert-butyl methyl corresponding to the step (9-G) of Example 9, the title ether to give the title compound (45 mg) having the follow compound having the following physical data was obtained. ing physical data. 0636 TLC: Rf 0.48 (hexane:ethyl acetate=2:1); 0644) TLC: Rf 0.66 (chloroform:methanol=5:1). 0637 H NMR (CDC1): 8 0.91 (s, 9H), 1.02 (s, 9H), 2.61 (s. 2H), 3.48 (d. J=5.85 Hz, 2H), 4.08 (s.3H), 5.01-5.17 Example 51 (m. 1H), 6.90 (s, 1H). 6-(2,2-dimethylpropyl)amino-9-trity1-9H-purine-2- Example 48 carbonitrile 2-chloro-N-(2,2-dimethylpropyl)-1H-purine-6-amine 0645) 0638. To a suspension of 2,6-dichloropurine (700 mg) in butanol (10 mL) was added neopentylamine (0.96 mL), then CH the mixture was stirred for 1 hour at 100° C. The reaction HN CH mixture was cooled to room temperature, the precipitate was CH collected. The obtained crystals were washed with tert-butyl N n 3 methyl ether to give the title compound (565 mg) having the following physical data. 2 N N CN 0639 TLC: Rf 0.66 (chloroform:methanol=5:1). Example 49 2-chloro-N-(2,2-dimethylpropyl)-9-trity1-9H-purine 6-amine 0640 The compound prepared in Example 48 (300 mg) and potassium carbonate (190 mg) were suspended to dim ethylformamide (4 mL), the mixture was stirred for 30 minutes at room temperature. To the reaction mixture was 0646 By the same procedures as described in Example added trityl chloride (384 mg), then the mixture was stirred 49, using the compound prepared in Example 50 instead of US 2007/019751.0 A1 Aug. 23, 2007 49 the compound prepared in Example 48, the title compound Example 53(1) having the following physical data was obtained. 6-(4-biphenylylmethyl)-8-(2,2-dimethylpropyl)-7- 0647 TLC: Rf 0.29 (hexane:ethyl acetate:methanol= oxo-5,6,7,8-tetrahydropyrimidoA,5-dipyrimidine-2- 6:2:0.1). carbonitrile Example 52 0655) 6-(2,2-dimethylpropyl)amino-9-methyl-9H-purine 2-carbonitrile O 1.N NNals 0648) O H3CO N N CN HC CH3 CH N n 3 0656 By the same procedures as described in Example 53, using biphenylylmethyl bromide instead of tert-butyl 2 bromoacetate, the title compound having the following N N CN physical data was obtained. 0657 TLC: Rf 0.24 (ethyl acetate:hexane=1:3); 0658 H NMR (CDC1): 8 0.96 (s, 9H), 4.13-4.20 (m, 0649. By the same procedures as described in Example 2H), 4.30-4.37 (m, 2H), 4.68-4.79 (m, 2H), 7.29-7.49 (m, 49->Example 50, using methyl iodide instead of trityl 5H), 7.52-7.64 (m, 4H), 8.23 (s, 1H). chloride in the step corresponding to Example 49, the title compound having the following physical data was obtained. Example 54 0650 TLC: Rf 0.59 (chloroform:methanol=9:1). 7-cyano-1-(2,2-dimethylpropyl)-2-cyano-l-(2,2-dimethylpropyl)-2-oxo-l,4-dihydro 1,4-dihydr pyrimido4,5-dipyrimidin-3 (2H)-yl)acetic acid Example 53 0659 tert-butyl 7-cyano-1-(2,2-dimethylpropyl)-2-oxo-1, HO 4-dihydropyrimido4,5-dipyrimidin-3 (2H)-yl)acetate 0651) r O O1. N Nals CN

HC O N NN H3C CH, O 2 O N N CN 0660 To a solution of the compound prepared in HC Example 53 (58.0 mg) in tert-butanol (1-mL) was added p-toluenesulfonic acid monohydrate (46 mg), then the mix ture was stirred for 2 days at 80° C. The reaction mixture was cooled to room temperature, concentrated. The obtained residue washed with diisopropyl ether to give the crude title 0652. Under atmosphere of argon, to a solution of the compound (63.4 mg). The obtained residue (51 mg) was compound prepared in Example 5 (53.8 mg) in dimethyl purified by column chromatography on silica gel (ethyl formamide (0.5 mL) were added potassium carbonate (207 acetate:methanol:acetic acid=50:1:1) to give the title com mg) and tert-butyl bromoacetate (38 LL), then the mixture pound (34.7 mg) having the following physical data. was stirred overnight at room temperature. The reaction 0661 TLC: Rf 0.38 (ethyl acetate:methanol:acetic acid= mixture was added by ethyl acetate and water, extracted with 18:1:1); ethyl acetate. The organic layer washed with water and brine, dried over anhydrous Sodium sulfate, concentrated. 0662) H NMR (CDC1): 8 0.92 (s, 9H), 3.98-4.37 (m, The obtained residue was purified by column chromatogra 4H), 4.41-4.70 (m, 2H), 8.31 (s, 1H). phy on silica gel (ethyl acetate:hexane=1:4-> 1:3-> 1:2) to give the title compound (74.3 mg) having the following Example 55(1)-Example 55(16) physical data. 0663 By the same procedures as described in Example 30, using the compound prepared in Example 54 instead of 0653) TLC: Rf 0.57 (ethyl acetate:hexane=1:2): the compound prepared in Example 18(2), N,N-dimethyl-1, 0654) H NMR (CDC1): 8 0.93 (s, 9H), 1.48 (s, 9H), 2-ethanediamine or corresponding amine compound instead 3.95-4.22 (m, 4H), 4.43-4.68 (m, 2H), 8.28-8.30 (m, 1H). of it, the following compounds were obtained.

US 2007/019751.0 A1 Aug. 23, 2007 51

Example 55(13) Example 57 2-7-cyano-1-(2,2-dimethylpropyl)-2-oxo-1,4-dihy 2-(2-methyl-2-propen-1-yl)-6-nitrophenol dropyrimido4,5-dipyrimidin-3(2H)-yl)-N-(3-phe 0.699) Under atmosphere of argon, the compound pre nylpropyl)acetamide pared in Example 56 (3.09 g) was warmed on oil bath (190° C.) without solvent, then stirred for 6 hours. The reaction 0688 TLC: Rf 0.23 (ethyl acetate:hexane=2:1); mixture was cooled to room temperature. The obtained 0689 H NMR (CDC1): 8 0.92 (s, 9H), 1.74-1.94 (m, residue was purified by column chromatography on silica 2H), 2.56-2.72 (m, 2H), 3.21-3.38 (m, 2H), 3.88-4.20 (m, gel (ethyl acetate:hexane=1: 30-1: 10) to give the title com 4H), 4.48-4.66 (m, 2H), 5.90-6.03 (m, 1H), 7.09-7.35 (m, pound (1.64 g) having the following physical data. 5H), 8.28 (s, 1H). 0700 TLC: Rf 0.69 (ethyl acetate:hexane=1:9); Example 55(14) 0701) "H NMR (CDC1): 8 1.74-1.77 (m, 3H), 3.44 (s, 2H), 4.67-4.70 (m, 1H), 4.85-4.89 (m. 1H), 6.93 (dd, J=8.60, 8-(2,2-dimethylpropyl)-6-2-(4-methyl-1-piperazi 7.32 Hz, 1H), 7.44-7.49 (m. 1H), 8.01 (dd, J=8.60, 1.74 Hz, nyl)-2-oxoethyl-7-oxo-5,6,7,8-tetrahydropyrimido 1H), 10.95 (s, 1H). 4,5-dipyrimidine-2-carbonitrile Example 58 0690 TLC: Rf 0.22 (dichloromethane:methanol:acetic acid=8:1:1); 2-amino-6-isobutylphenol 0691) H NMR (CDC1): 8 0.93 (s, 9H), 2.32 (s, 3H), 0702 Under atmosphere of argon, the compound pre 2.35-2.50 (m, 4H), 3.43-3.51 (m, 2H), 3.59-3.67 (m, 2H), pared in Example 57 (1.35 g) was dissolved to methanol 3.96-4.36(m, 4H), 4.42-4.71 (m, 2H), 8.25(s, 1H). (13.5 mL), the mixture was degassed, then 10% palladium on carbon (50% wet, 138 mg) was added thereto. Under Example 55(15) atmosphere of hydrogen, the mixture was stirred for 4 hours at room temperature. After the hydrogen was replaced to 6-2-(4-benzyl-1-piperazinyl)-2-oxoethyl-8-(2,2- argon, the reaction mixture was filtrated with cerite (trade dimethylpropyl)-7-oxo-5,6,7,8-tetrahydropyrimido mark), filtrate was concentrated to give the title compound 4,5-dipyrimidine-2-carbonitrile (1.15 g) having the following physical data. 0692 TLC: Rf 0.66 (dichloromethane:methanol:acetic 0703) TLC: Rf 0.63 (ethyl acetate:hexane=1:1); acid=8:1:1); 0704 H NMR (CDC1): 8 0.94 (d. J=6.59 Hz, 5H), 0693) 'H NMR (CDC1): 8 0.93 (s, 9H), 2.34-2.57 (m, 1.82-1.98 (m, 1H), 2.44 (d. J=7.14 Hz, 2H), 3.02-4.45 (m 4H), 3.38-3.49 (m, 2H), 3.53 (s. 2H), 3.57-3.68 (m, 2H), 2H), 6.53-6.79 (m, 3H). 3.97-4.42 (m, 4H), 4.40-4.74 (m, 2H), 7.19-7.38 (m, 5H), Example 59 8.25 (s, 1H). 7-isobutyl-1,3-benzoxazole-2-carbonitrile Example 55(16) 0705) 2-7-cyano-1-(2,2-dimethylpropyl)-2-oxo-1,4-dihy dropyrimidoA,5-dipyrimidin-3 (2H)-yl)-N-(2,2-dim ethylpropyl)acetamide 0694) TLC: Rf 0.29 (ethyl acetate:hexane=2:1); 0695 H NMR (CDC1): 8 0.90 (s, 9H), 0.92 (s, 9H), 3.08 (d. J=6.40 Hz, 2H), 3.93-4.22 (m, 4H), 4.53-4.71 (m, 2H), 5.99-6.16 (m. 1H), 8.31 (s, 1H). Example 56 1-(2-methyl-2-propen-1-yl)oxy-2-nitrobenzene 0706 By the same procedures as described in Example 0696 Under atmosphere of argon, to a solution of 2-ni 26->Example 27, using the compound prepared in Example trophenol (2.78 g) in dimethylformamide (10 mL) were 58 instead of 2-(2,2-dimethylpropoxy)phenyl)amine in the added 3-bromo-2-methyl-1-propene (2.12 mL) and potas step corresponding to Example 26, the title compound sium carbonate (3.04 g), then the mixture was stirred over having the following physical data was obtained. night at room temperature. The reaction mixture was added by ethyl acetate and water, extracted with ethyl acetate. The 0707 TLC: Rf 0.18 (dichloromethane:hexane=1:9); organic layer washed with water and brine sequentially, 0708 H NMR (CDC1): 8 0.95 (d. J=6.59 Hz, 6H), dried over anhydrous sodium Sulfate, concentrated to give 1.99-2.16 (m, 1H), 2.79 (d, J-7.32 Hz, 2H), 7.33-7.37 (m, the title compound (3.94 g) having the following physical 1H), 7.43 (dd, J=7.78 Hz, 1H), 7.68-7.74 (m, 1H). data. Example 60 0697 TLC: Rf 0.36 (ethyl acetate:hexane=1:9); 0698 H NMR (CDC1): 8 1.84-1.86 (m, 3H), 4.57 (s, 2-(ethylthio)-5,7-dihydrofuro3,4-dipyrimidin-4-ol 2H), 5.01-5.05 (m. 1H), 5.14-5.17 (m, 1H), 6.98-7.09 (m, 0709) To a solution of ethyl imidothiocarbamate hydro 2H), 7.46-7.54 (m, 1H), 7.81-7.87 (m. 1H). bromide (2.59 g) in water (25 mL) were added sodium US 2007/019751.0 A1 Aug. 23, 2007 52 carbonate (1.48 g) and methyl 4-oxotetrahydro-3-furancar Example 63 boxylate (1.44g), then the mixture was stirred for 3.5 hours at room temperature, 18 hours at 70° C., then 4 hours at 80° 4-(2,2-dimethylpropyl)amino-6,7-dihydro-5H-cy C. The reaction mixture was cooled to room temperature, the clopentadpyrimidine-2-carbonitrile precipitate was collected, washed with water and diisopro 0719) pyl ether sequentially to give the title compound (744 mg) having the following physical data. The former water layer washed with ethyl acetate, extracted with dichloromethane. CH The organic layer washed with brine, dried over anhydrous HN CH3 Sodium sulfate, concentrated. The obtained residue was CH added by diisopropyl ether, the precipitated solid was col n N lected to give the title compound (139 mg) having the following physical data. N CN 07.10 TLC: Rf 0.65 (ethyl acetate): 0711 H NMR (CDC1): 81.38 (t, J=7.36 Hz, 3H), 3.20 0720. By the same procedures as described in Example (q, J=7.36 Hz, 2H), 4.80-4.97 (m, 2H), 4.98-5.15(m, 2H), 10->Example 1->Example 3, using 6,7-dihydro-1H-cyclo 11.62-12.25(m. 1H). pentadpyrimidin-2,4(3H,5H)-dione instead of the com pound prepared in Example 9 in the step corresponding to Example 61 Example 10, the title compound having the following physi 4-chloro-2-(ethylthio)-5,7-dihydrofuro3,4-dpyrimi cal data was obtained. dine 0721 TLC: Rf 0.36 (hexane:ethyl acetate=2:1); 0712. To a suspension of the compound prepared in 0722) H NMR (CDC1): 8 0.96 (s, 9H), 2.09-2.27 (m, Example 60 (50mg) in thionyl chloride (148 uL) was added 2H), 2.71 (t, J=7.50 Hz, 2H), 2.94 (t, J=7.50 Hz, 2H), 3.38 dimethylformamide (20 uL), then the mixture was stirred for (d. J=6.40 Hz, 2H), 4.51-4.74 (m, 1H). 5 minutes at 45° C. The reaction mixture was cooled to room temperature, poured into iced water, extracted with ethyl BIOLOGICAL, EXAMPLES acetate. The organic layer washed with brine, dried over Pharmacological Activities of the Compounds of the Present anhydrous sodium Sulfate, concentrated to give the title Invention: compound (49 mg) having the following physical data. 0723. It was confirmed by the following experiments that 0713) TLC: Rf 0.68 (hexane:ethyl acetate=4:1); the compound of formula (I) of the present invention has an 07.14 'H NMR (CDC1): 81.40 (t, J-7.35 Hz, 3H), 3.17 inhibitory activity against cystein protease. (q, J=7.35 Hz, 2H), 5.00 (m, 2H), 5.10 (m, 2H). (i) Measurement of Cathepsin k Inhibitory Activity 0724 65 uL of Cathepsin K Enzyme Reaction Buffer (50 Example 62 Mmol/L of 2-(N-morpholino)ethanesulfonate, 2 mmol/L of 4-(2,2-dimethylpropyl)amino-5,7-dihydrofuro3,4- ethylenediaminetetraacetate (EDTA) and 4 mmol/L of dpyrimidine-2-carbonitrile dithiothreitol (DTT) were mixed to adjust to pH 5.5), 5 LL of cysteine protease inhibitor Solution of several concentra 0715) tions, 20 uL of synthesized substrate (t-butyloxycarbonyl L-alanyl-glycyl-L-prolyl-L-arginine-4-methylchromanyl-7-

amide) solution of several concentrations and 10 uL of cathepsin Kenzyme solution were mixed and the increase of fluorescence intensity when reacted at 37°C. was measured (vex (excitation wavelength)=355 nm, wem (fluorescence wavelength)=460 nm). As to the substrate and the compound of the present invention, enzyme reactions were carried out in combination of several appropriate concentrations and Dixon plotting was prepared to define the absolute value of X-coordinate of the intersection point of the graph as Ki value. 0716 By the same procedures as described in Example 0725. It was confirmed that the compound of formula (I) 1->Example 12->Example 13, using the compound pre of the present invention showed strong inhibitory activity, pared in Example 61 instead of 2,4-dichloro-5-(chlorometh i.e. the ICso value is under 10 uM. For example, the ICso yl)pyrimidine in the step corresponding to Example 1, the value of the compound 8(2B) prepared in example 8 was 2.9 title compound having the following physical data was nM, that of the compound prepared in example 55(14) was obtained. 12 nM. 0717 TLC: Rf 0.34 (hexane:ethyl acetate=3:2): Formulation Example 1 0718 H NMR (CDC1): 8 0.97 (s, 9H), 3.14-3.55 (m, 0726. The following components were admixed in a 2H), 4.40-4.82 (m. 1H), 4.96 (t, J=2.74 Hz, 2H), 5.00-5.15 conventional method and punched out to give 10,000 tablets (m. 2H). each containing 10 mg of the active ingredient. US 2007/019751.0 A1 Aug. 23, 2007

8-(2,2-Dimethylpropyl)-7-oxo-5,6,7,8-tetrahydropyrimido ischemic diseases (brain ischemia, brain disorder by 4,5-dipyrimidine-2-carbonitrile (100 g), ischemic reperfusion, cardiac infarction, ischemic liver damage, etc.), etc.), shock (septic shock, systemic inflam Carboxymethylcellulose calcium (disintegrating agent) matory responsive syndrome, endotoxin shock, acidosis, (20.0 g), etc.), circulatory disorder (arteriosclerosis, restenosis after Magnesium Stearate (lubricant) (10.0 g), PTCA (percutaneous transluminal coronary angioplasty), etc.), disorder of blood coagulation system (thrombocy Microcrystalline cellulose (870 g). topenic purpura, hemolytic uremic syndrome, etc.), malig nant tumor, acquired immune deficiency syndrome (AIDS, Formulation Example 2 AIDS-related complex (ARC), etc.), parasitic diseases 0727 The following components were admixed in a (malaria etc.), neurodegenerative disease (Alzheimer-type conventional method, and the Solution was filtered through senile dementia, Huntington's chorea, Parkinson's disease, a dustproofing filter, and then 5 ml aliquots were charged multiple Sclerosis, traumatic encephalopathy, traumatic into ampoules, which were autoclaved to give 10,000 spondylopathy, etc.), lung disorder (fibroid lungs, etc.), bone ampoules each containing 20 mg of the active ingredient. diseases (osteoporosis, bone fracture, rheumatoid arthritis, arthritis, osteoarthritis, hypercalcaemia, osteometastasis of 8-(2,2-Dimethylpropyl)-7-oxo-5,6,7,8-tetrahydropyrimido cancer, periodontitis, bone Paget’s disease, etc.), endo 4,5-dipyrimidine-2-carbonitrile (200g), crinesthenia (hyperthyroidism etc.), etc. Mannitol (2 kg), 1. A compound of formula (I) Distilled water (50 L).

INDUSTRIAL APPLICABILITY (I) 0728. A compound of formula (I) in the present invention has an inhibitory activity against cysteine proteases, espe cially cathepsin K, and therefore it is useful as an agent for the prophylaxis and/or treatment of inflammatory diseases (periodontitis, arthritis, inflammatory bowel diseases, infec wherein ring A is a carbocyclic group or a heterocyclic tious diseases, pancreatitis, hepatitis, glomerulonephritis, group; ring B is a heterocyclic group containing at least endocarditis, myocarditis, ulcerative colitis, etc.), diseases one nitrogen atom; .... is a single bond or a double induced by apoptosis (graft versus host diseases, rejection in bond; Y and Z each is independently a carbon atom or transplantation, acquired immunodeficiency syndrome a nitrogen atom; n is 0, or an integer of from 1 to 10; (AIDS), AIDS-related complex (ARC), adult T cell leuke R is a hydrogen atom or a Substitutent, if R is plural, mia, hairy cells leukemia, spondylopathy, disorders of res each of R are the same or different, in which two of R piratory apparatus, arthritis, HIV or HTLV-1 related diseases may form a ring which may have a Substitutent(s) (uveitis etc.), virus related diseases (hepatitis C etc.), cancer, collagenosis (systemic lupus erythematosus, rheumatoid together with an atom to which they bind, arthritis, etc.), ulcerative colitis, Sjoegren syndrome, pri a salt thereof, a solvate thereof, or an N-oxide thereof, or mary biliary cirrhosis, spontaneous thrombocytopenic pur a prodrug thereof. pura, autoimmune hemolytic anemia, myasthenia gravis, 2. The compound according to claim 1, wherein ring A is autoimmune diseases (insulin dependent (type I) diabetes, a C5-7 monocyclic carbocyclic group, or a five- to seven etc.), diseases accompanied by thrombocytopenia (myelod membered monocyclic heterocyclic group; and ring B is a ysplastic syndrome, cyclic thrombocytopenia, aplastic ane five- to seven-membered monocyclic heterocyclic group mia, spontaneous thrombocytopenia, disseminated intravas which contains one nitrogen atom and contains 1 to 2 hetero cular coagulation (DIC), etc.), viral hepatitis (A, B, C, F, atom(s) selected from an oxygenatom(s), a nitrogenatom(s) etc.) or hepatitis medicamentosa and cirrhosis, etc., demen and a Sulfur atom(s) which may be oxidized. tia Such as Alzheimer's disease, Alzheimer-type senile 3. The compound according to claim 1, wherein ring A is dementia, cerebrovascular injury, neurodegenerative dis a ring selected from benzene, cyclopentene, cyclohexene, ease, adult acute respiratory distress syndrome, infectious cycloheptene, pyridine, pyrimidine, pyrazine, tetrahydropy diseases, prostatomegaly, hysteromyoma, bronchial asthma, rimidine, dihydropyridazine, pyridazine, dihydropyrimi arteriosclerosis, hyperlipidemia, all kinds of lusus naturae, dine, dihydropyrazine, dihydrotriazine, pyrazole, dihydro nephritis, senile cataract, chronic fatigue syndrome, myod pyrazole, pyrrole, imidazole, triazole, thiophene, furan, yStrophy, peripheral nerve injury, etc.), diseases induced by dihydrofuran, oxadiazine, tetrahydrodiazepine and diaz immune response disorder (graft versus host diseases, rejec epane. tion in transplantation, allergic diseases (asthmatic bronchi 4. The compound according to claim 1, wherein ring B is tis, atopic dermatitis, allergic rhinitis, hay fever, diseases by a ring selected from pyrrole, imidazole, pyrazole, thiazole, house dust, hyperSensitive pneumonia, food allergy, etc.), oxazole, pyridine, pyrimidine, dihydrotriazine, pyrazine and psoriasis, rheumatoid arthritis, etc.), autoimmune diseases dihydropyrimidine. (insulin dependent (type I) diabetes, systemic lupus erythe 5. The compound according to claim 1, wherein the matosus, Hashimoto's diseases, multiple Sclerosis, etc.), compound of formula (I) is 5,6,7,8-tetrahydropyrimidoA,5- diseases induced by decomposition of proteins which com dpyrimidine-2-carbonitrile, pyrazolo 1.5-apyrimidine-5- pose a body (myodystrophy, cataract, periodontitis, hepato carbonitrile, 2,3-dihydro-1H-pyrazolo 3,4-dipyrimidine-6- cyte injury by bile acid (cholestatic cirrhosis etc.), etc., carbonitrile, pyrazolo 1.5-a1.3.5triazine-2-carbonitrile, decomposition of alveolus elastica (emphysema etc.), 1H-pyrimidoA.5-e 1,3,4oxadiazine-7-carbonitrile, US 2007/019751.0 A1 Aug. 23, 2007 54

1H-pyrazolo 3,4-dipyrimidine-6-carbonitrile, imidazol-2- 9. The compound according to claim 6, wherein -T'- is apyrimidine-2-carbonitrile, 1,3-benzothiazol-2-carboni -E'-E-E'-in which E' and E’ each is independently a bond trile, 6,7,8,9-tetrahydro-5H-pyrimidoA,5-e1.4diazepine or a divalent C1-5 hydrocarbon group which may have a 2-carbonitrile, 5H-pyrrolo3.2-dpyrimidine-2-carbonitrile, substitutent(s), and E is —O , NR' , —S , pyrido 2,3-dipyrimidine-2-carbonitrile, 5,7-dihydrofuro3, C(=O) , C(=O)NR' , NRC(=O) , 4-dipyrimidine-2-carbonitrile, 6,7-dihydro-5H-cyclopenta - SONR , NRSO, , —C(=O)C) , dpyrimidine-2-carbonitrile, 9H-purine-2-carbonitrile, or OC(=O) , or NR'C(=O)NR'' in which R'' and 1,3-benzoxazole-2-carbonitrile. R' each is independently a hydrogenatom or a hydrocarbon 6. The compound according to claim 1, which is a group which may have a substitutent(s); and ring 1 is (1) compound of formula (I-A) C3-10 mono- or bicyclic carbocyclic group which may have a Substitutent(s), or (2) three- to ten-membered monocyclic or bicyclic heterocyclic group which may have a Substi (I-A) tutent(s). 10. The compound according to claim 6, wherein -T"- is -E-E-E'-in which E' and E’ each is independently a bond or a divalent C1-5 hydrocarbon group which may have a substitutent(s), and E is - O -, - NR' , —S , C(=O) C(=O)NR' , NRC(=O) , - SONR' , NRSO , —C(=O)C) , OC(=O) , or NR'C(=O)NR'' in which R'' and R' each is independently a hydrogenatom or a hydrocarbon group which may have a substitutent(s): -T- is a bond or a divalent C1-5 hydrocarbon group which may have a

(I-B) substitutent(s): and ring 1 and/or ring 2 is (1) C3-10 mono- or bicyclic carbocyclic group which may have a Substitutent(s), or (2) three- to ten-membered monocyclic or bicyclic heterocyclic group which may have a Substi tutent(s). 11. The compound according to claim 1, which is selected from the group consisting of: (1) 8-(2,2-dimethylpropyl)-7-oxo-5,6,7,8-tetrahydropy rimidoA,5-dipyrimidine-2-carbonitrile, wherein R' is a hydrogen atom or a substitutent; n1 is 0, or an integer of from 1 to 3; and R is (2) 1-(2,2-dimethylpropyl)-2-(4-methoxybenzyl)-3-oxo 2,3-dihydro-1H-pyrazolo 3,4-dpyrimidine-6-carboni trile, (3) 1-(2,2-dimethylpropyl)-3-(4-methoxybenzyl)oxy R3-TIA-, G)-it- O 1H-pyrazolo 3,4-dpyrimidine-6-carbonitrile, (4) 4-(2,2-dimethylpropoxy)-1,3-benzothiazol-2-carboni trile, (5) 3-(4-biphenylylmethoxy)-1-(2,2-dimethylpropyl)-1H pyrazolo 3,4-dpyrimidine-6-carbonitrile, wherein T'', T', T' and Teach is independently a bond or a spacer having from 1 to 10 atoms of the (6) 2-(4-biphenylylmethyl)-1-(2,2-dimethylpropyl)-3- principle chain: ring 1, ring1' and ring2 each is oxo-2,3-dihydro-1H-pyrazolo 3,4-dipyrimidine-6-car independently a cyclic group which may have a Sub bonitrile, stitutent(s); and R is a hydrogen atom or a substitutent, (7) 1-(2,2-dimethylpropyl)-3-oxo-2-(2-thienylmethyl)-2, and other symbols have the same meanings as described 3-dihydro-1H-pyrazolo 3,4-dpyrimidine-6-carboni in claim 1. 7. The compound according to claim 6, wherein R' is a trile, branched C1-8 alkyl. (8) 1-(2,2-dimethylpropyl)-3-2-(4-morpholinyl)ethoxy 8. The compound according to claim 6, wherein -T"- is 1H-pyrazolo 3,4-dpyrimidine-6-carbonitrile, -E-E-E'-in which E' and E’ each is independently a bond or a divalent C1-5 hydrocarbon group which may have a (9) 9-(2,2-dimethylpropyl)-6-(4-methoxybenzyl)-7-oxo substitutent(s), and E is —O , —NR' , —S , 6,7,8,9-tetrahydro-5H-pyrimidoA.5-e1.4diazepine C(=O) , C(=O)NR' , NRC(=O) , 2-carbonitrile, –SONR , NRSO, , - C(=O)C) , (10) 8-(2,2-dimethylpropyl)-6-(4-methoxybenzyl)-7-oxo OC(=O) , or NR'C(=O)NR'' in which R'' and 5,6,7,8-tetrahydropyrimidoA,5-dipyrimidine-2-carbo R' each is independently a hydrogenatom or a hydrocarbon group which may have a substitutent(s); and R is a hydro nitrile, gen atom or a Substitutent containing a nitrogen atom which (11) 4-(2,2-dimethylpropyl)aminolpyrido2,3-dipyrimi is basic. dine-2-carbonitrile, US 2007/019751.0 A1 Aug. 23, 2007

(12) 1-(2,2-dimethylpropyl)-3-(4-(4-methyl-1-piperazi 17. The pharmaceutical composition according to claim nyl)methylphenyl)-1H-pyrimido-4,5-e1,3,4 oxadi 12, which is a bone resorption inhibitor. azine-7-carbonitrile, 18. A drug comprising the compound of formula (I) (13) 2-6-cyano-1-(2,2-dimethylpropyl)-3-oxo-1,3-dihy described in claim 1, a salt thereof, a solvate thereof, or an dro-2H-pyrazolo 3,4-dipyrimidin-2-yl)-N-2-(dim N-oxide thereof, or a prodrug thereof, combined with at least ethylamino)ethylacetamide, one selected from bisphosphonate formulations, Vitamin D (14) 4-(2,2-dimethylpropyl)amino-5,7-dihydrofuro3,4- and its derivatives, Vitamin Kand its derivatives, calcitonin dpyrimidine-2-carbonitrile, and formulations, C-calcitonin gene-related peptide formula (15) 4-(2,2-dimethylpropyl)amino-6,7-dihydro-5H-cy tions, female hormone formulations, selective estrogen clopentadpyrimidine-2-carbonitrile. receptor modulators, ipriflavone formulations, calcium for 12. A pharmaceutical composition comprising the com mulations, anabolic steroid formulations, parathyroid hor pound of formula (I) which is described in claim 1, a salt mone formulations, PTHrP derivatives, caspase-1 inhibitors, thereof, a solvate thereof, or an N-oxide thereof, or a farnesoid X receptor agonists, Bone Morphogenetic Protein prodrug thereof as an active ingredient, and a pharmaceu formulations, anti-RANKL antibody, metalloprotease tically acceptable carrier and/or diluent. inhibitors, prostaglandin derivatives, strontium formula 13. The pharmaceutical composition according to claim tions, anti TNF-C. antibody, anti-IL-6 antibody, HMG-CoA 12, which is an agent for prevention and/or treatment for a reductase inhibitors, steroidal drugs, and antiinflammatory cysteine protease-related disease. drugs. 14. The pharmaceutical composition according to claim 19. A method for the prophylaxis and/or treatment of a 13, wherein a cysteine protease-related disease is a cathepsin cysteine protease-related disease in a mammal, which com K-related disease. 15. The pharmaceutical composition according to claim prises administering to a mammal an effective amount of the 14, wherein a cathepsin K-related disease is a bone disease. compound of formula (I) described in claim 1, a salt thereof, 16. The pharmaceutical composition according to claim a solvate thereof, or an N-oxide thereof, or a prodrug 15, wherein a bone disease is at least one selected from thereof. osteoporosis, bone fracture, arthritis, rheumatoid arthritis, 20. (canceled) osteoarthritis, hypercalcaemia, osteometastasis of cancer, osteosarcoma, periodontitis, and bone Paget’s disease.