Cyclic amine derivatives and their use as drugs

专利摘要:
A compound represented by the following formula (I), a pharmaceutically acceptable acid addition salt thereof or a pharmaceutically acceptable C 1 -C 6 alkyl addition salt thereof, and medical use thereof: These compounds inhibit the action of chemokines, such as MIP-1α and / or MCP-1 on target cells, thus treating and / or preventing agents for diseases such as atherosclerosis, rheumatoid arthritis, etc., in which blood monocytes and lymphocytes infiltrate tissue. It can be useful as.
公开号:KR20010032253A
申请号:KR1020007005456
申请日:1998-11-17
公开日:2001-04-16
发明作者:시오타다츠키；가타오카겐이치로；이마이미노루；츠츠미다카하루；스도마사키；소가와료；모리타다쿠야；하다다카히코；무로가유미코；다케노우치오사미；후루야모노루；엔도노리아키；타비크리스틴엠.；모리윌너；테그스티븐엘.
申请人:이타가키 히로시；테이진 가부시키가이샤；마이어스 피터 엘.；듀퐁 파마슈티컬즈 리서치 래버러토리즈；
IPC主号:

专利说明:

Cyclic amine derivatives and their use as drugs
Chemokines have a molecular weight of 6-15 kD and are a group of inflammatory / immunogenic polypeptides produced by various cell types such as macrophages, monocytes, eosinophils, neutrophils, fibroblasts, vascular endothelial cells, smooth muscle cells and mammary cells at the inflammatory site. It is an argument. Chemokines can be classified into two major subfamily, CXC chemokines (or α-chemokines) and CC chemokines (or β-chemokines) by differences in the common positions of the four conserved cysteine residues and the chromosomal positions of the genes encoding them. . The first two cysteines of CXC chemokines are separated by one amino acid, and those of CC chemokines are contiguous. For example, IL-8 (abbreviation of interleukin-8) is CXC chemokine, while CC chemokine is MIP-1α / β (abbreviation of macrophage inflammatory protein-1α / β), MCP-1 (monochemistry of chemotactic protein-1). Abbreviations) and RANTES (abbreviations of regulated expression and secreted normal T-cells). There are also chemokines that do not belong to either subfamily. They are C chemokine, a lymphotactin with only two cysteines, and CX ₃ C chemokine, a fractal carine with a chemokine-like domain of mucin structure in which the first two cysteines are separated by three amino acids. to be. These chemokines promote chemotaxis, cell migration, increase expression of cell adhesion molecules such as integrin and thereby cell adhesion, and are intimately involved in the attachment and infiltration of leukocytes into pathogenic sites such as inflammatory tissues. It is thought to be a related protein factor (see, for example, Vaddi, K., et al., The Chemokine Facts Book, Academic Press, 1997; Chemoattractant Ligand and Their Receptors, Horuk, R., Ed., CRC Press, 1996; Ward , GW, et al., Biochem.J., 1998, 333, 457; Luster, AD, New Engl. J. Med., 1998, 338, 436; Baggiolini, M., Nature, 1998, 392, 565; Rollins , Bj, Blood, 1997, 90, 909; Alam, R., J. Allergy Clin.Imunmunol., 1997, 99, 273; Hancock, WW, Am. J. Pathol., 1996, 148, 681; Taub, DD , Cytokine & Growth Factor Rev., 1996, 7, 335; Strieter, RM, et al., J. Immunol., 1996, 156, 3583; Furie, MB, et al., Am. J. Pathol., 1995, 146, 1287 Schall, TJ, et al., Current Opinion in Immunology, 1994, 6, 865; Edginton, SM, Biotechnology, 1993, 11, 676).
For example, MIP-1α causes a transient increase in the level of calcium ion concentrations in cells, T lymphocytes, B lymphocytes (eg, Taub, DD, et al., Science, 1993, 260, 355; Schall, Tj, et al. , J. Exp. Med., 1993, 177, 1821) and eosinophils (see, eg, Rot, A., et al., J. Exp. Med., 1992, 176, 1489), migration of natural killer cells Chemotaxis (see, eg, Maghazachi, AA, et al., J. Immunol., 1994, 153, 4969), expression of integrins (eg, Vaddi, K., et al., J. Immunol., 1994, 153, 4721), and osteoclast differentiation (see, eg, Kukita, T., et al., Lab. Invest., 1997, 76, 399). MIP-1α also enhances IgE and IgG4 production in B cells (see, eg, Kimata, H., et al., J. Exp. Med., 1996, 183, 2397), and hematopoietic stem cells Inhibit proliferation (eg Mayani, H., et al., Exp. Hematol., 1995, 23, 422; Keller, JR, et al., Blood, 1994, 84, 2175; Eaves, CJ, et al. Proc. Natl. Acad. Sci. USA, 1993, 90, 12015; Bodine, DM, et al., Blood, 1991, 78, 914; Broxmeyer, HE, et al., Blood, 1990, 76, 1110). .
Regarding the activity of MIP-1α in vivo and its role in the pathogenesis of disease, it is a rabbit fever factor (see, eg, Davatelis, G., et al., Science, 1989, 243, 1066); Injection of MIP-1α into the paw of mouse results in inflammatory responses such as invasion by neutrophils and monocytes (see, eg, Alam, R., et al., J. Immunol., 1994, 152, 1298); MIP-1α neutralizing antibodies include granulomas (see, eg, Lukacs, NW, et al., J. Exp. Med., 1993, 177, 1551), asthma (eg, Lukacs, NW, et al., Eur. J. Immunol , 1995, 25, 245; Lukacs, NW, et al., J. Immunol., 1997, 158, 4398), multiple sclerosis (e.g., Karpus, WJ, et al., J. Immunol., 1995, 155 , 5003; Karpus, WJ, et al., J. Leukoc. Biol., 1997, 62, 681), idiopathic pulmonary fibrosis (eg, Smith, RE, et al., J. Immunol., 1994, 153, 4704 Smith, RE, Biol. Signals, 1996, 5, 223), acute lung injury (e.g., Shanley, TP, et al., J. Immunol., 1995, 154, 4793; standiford, TJ, et al., J. Immunol., 1995, 155, 1515) and inhibitory or therapeutic effects in animal models of rheumatoid arthritis (see, eg, Kasama, T., et al., T. Clin. Invest., 1995, 95, 2868). Having; That coxsackie virus induced myocarditis and herpes stromal keratitis are inhibited by the MIP-1α gene destroyed in mice (eg Cook, DN et al., Science, 1995, 269, 1583; Tumpey, TM, et al., J. Virology, 1998, 72, 3705); And significant expression of MIP-1α is associated with chronic inflammatory lung disease (see, eg, Standiford, TJ, et al., J. Immunol., 1993, 151, 2852), irritable pneumonia (eg, Denis, M., Am. J. Respir.Crit.Care Med., 1995, 151, 164), rheumatoid arthritis (see, eg, Koch, AE, et al., J. Clin. Invest., 1994, 93, 921), infectious meningitis (e.g., Lahrtz, F., et al., J. Neuroimmunol., 1998, 85, 33) and chronic myositis (see, eg, Adams, EM, et al., Proc. Assoc. Am. Physicians, 1997, 109, 275). It has been reported to be observed in patients with These studies indicate that MIP-1α is deeply involved in local attraction of leukocytes of various subtypes, and initiation, progression, and maintenance of the resulting inflammatory response.
MCP-1 (also known as MCAF (macrophage chemotactic and active factor) or JE) is a CC chemokine produced by monocytes / macrophages, smooth muscle cells, fibroblasts and vascular endothelial cells, and monocytes (eg, Valente, AJ, et al., Blochemistry, 1986, 27, 4162; Matsushima, K., et al., J. Exp. Med., 1989, 169, 1485; Yoshimura, T., et al., J. Immunol., 1989, 142, 1956; Rollins, BJ, et al., Proc. Natl. Acad. Scl. USA, 1988, 85, 3738; Rollins, BJ, et al., Blood, 1991, 78, 1112; Jiang, Y. , et al., J. Immunol., 1992, 148, 2423; Vaddi, K., et al., J. Immunol., 1994, 153, 4721), memory T lymphocytes (eg, Carr, MW, et al. ., Proc. Natl. Acad. Scl. USA, 1994, 91, 3652), T lymphocytes (see, eg, Loetscher, P., et al., FASEB J., 1994, 8, 1055) and natural killer cells ( See, eg, Loetscher, P., et al., J. Immunol., 1996, 156, 322; Allavena, P., et al., Eur. J. Immunol., 1994, 24, 3233). Cause adhesion As well as mediate histamine release by basophils (eg, Alam, R., et al., J. Clin. Invest., 1992, 89, 723; Bischoff, SC, et al., J. Exp. Med., 1992, 175, 1271; Kuna, P., et al., J. Exp. Med., 1992, 175, 489).
Moreover, diseases in which high expression of MCP-1 is thought to accumulate monocyte / macrophage and / or T cells may play a role in the initiation or progression of the disease, such as atherosclerosis (eg Hayes, IM, et al., Arterioscler Thromb. Vasc. Biol., 1998, 18, 397; Takeya, M., et al., Hum. Pathol., 1993, 24, 534; Yla-Herttuala, S., et al., Proc. Natl. Acad. Sci. USA, 1991, 88, 5252; Nelken, NA, J. Clin.Invest., 1991, 88, 1121), rheumatoid arthritis (eg, Koch, AE, et al., J. Clin. Invest. , 1992, 90, 772; Akahoshi, T., et al., Arthritis Rheum., 1993, 36, 762; Robinson, E., et al., Clin.Exp. Immunol., 101, 398), nephritis ( For example, Noris, M., et al., Lab. Invest., 1995, 73, 804; Wada, T., at al., Kidney Int., 1996, 49, 761; Gesualdo, L., et al., Kidney Int., 1997, 51, 155), nephropathy (e.g. Saitoh, A., et al., J. Clin.Lab.Anal., 1996, 12, 1; Yokoyama, H., et al., J Leukoc. Biol., 1998, 63, 493), pulmonary fibrosis , Pulmonary sarcoidosis (see, eg, Sugiyama, Y., et al., Internal.Medicine, 1997, 36, 856), asthma (eg, Karina, M., et al., J. Invest.Allergol.Clin.Immunol. , 1997, 7, 254; Stephene, TH, Am. J. Respir. Crit.Care Med., 1997, 156, 1377; Sousa, A. R., et al., Am. J. Respir. Cell Mol. Biol., 1994, 10, 142), multiple sclerosis (see, eg, McManus, C., et al., J. Neuroimmunol., 1998, 86, 20), psoriasis (eg, Gillitzer, R., et al. , J. Invest. Dermatol., 1993, 101, 127), inflammatory bowel disease (eg, Grimn, MC, et al., J. Leukoc. Biol., 1996, 59, 804; Reinecker, HC, et al., Gastroenterology, 1995, 106, 40), myocarditis (see, eg, Seino, Y., et al., Cytokine, 1995, 7, 301), endometriosis (eg, Jolicoeur, C., et al., Am. J) Pathol., 1998, 152, 125), intraperitoneal attachment (see, eg, Zeyneloglu, HB, et al., Human Reproduction, 1998, 13, 1194), congestive heart failure (eg, Aurust, P., et al. ., Circulation, 1998, 97, 1136), chronic liver disease (e.g. Marra, F., et al., Am. J. Pathol., 1998, 152, 423), viral meningitis (e.g. Lahrtz, F., et al., Eur. J. Immunol., 1997, 27, 2484), Kawasaki disease (see, eg, Wong, M., et al., J. Rheumatol. 1997, 24, 1179) and sepsis ( Yes For, Salkowski, C.A., et al., Infect. Immun., 1998, were reported in 66, 3569). In addition, anti-MCP-1 antibody rheumatoid arthritis (eg, Schimmer, RC, at al., J. Immunol., 1998, 160, 1466; Schrier, DJ, J. Leukoc. Biol., 1998, 63, 359; Ogata, H., et al., J. Pathol., 1997, 182, 106), multiple sclerosis (see, eg, Karpus, WJ, et al., J. Leukoc. Biol., 1997, 62, 681), Nephritis (see, eg, Lloyd, CM, et al., J. Exp. Med., 1997, 185, 1371; Wada, T., et al., FASEB J., 1996, 10, 1418), asthma (eg, Gonzalo, JA, et al., J. Exp. Med. 1998, 188, 157; Lukacs, NW, J. Immunol. 1997, 158, 4398), atherosclerosis (eg, Guzman, LA, et al., Circulation , 1993, 88 (suppl.) I-371), delayed type hypersensitivity (see, eg, Rand, ML, et al., Am. J. Pathol., 1996, 148, 855), pulmonary hypertension (eg, Kimura, H., et al., Lab. Invest., 1998, 78, 571) and intraperitoneal attachment (see, eg, Zeyneloglu, HB, et al., Am. J. Obstet.Gynecol., 1998, 179, 438). Inhibitory effect or treatment in animal models of It has been reported to be effective. In addition, the antagonist of MCP-1, MCP-1 (9-76), has not only been reported to inhibit arthritis in mouse models (see Gong, JH, J. Exp. Med., 1997, 186, 131), MCP- Studies of 1-deficient mice have shown that MCP-1 is essential for monocyte supplementation in vivo (Lu, B., et al., J. Exp. Med., 1998, 187, 601; Gu, L., et al., Moll. Cell, 1998, 2, 275).
These data indicate that chemokines such as MIP-1α and MCP-1 attract monocytes and lymphocytes to the site of disease and mediate their activation, thus atherosclerosis, rheumatoid arthritis, psoriasis, asthma, ulcerative colitis, nephritis (nephrosis) Initiation of diseases deeply involved in monocytes and lymphocytes, such as multiple sclerosis, pulmonary fibrosis, myocarditis, hepatitis, pancreatitis, sarcoidosis, Crohn's disease, endometriosis, congestive heart failure, viral meningitis, cerebral infarction, neuropathy, Kawasaki disease and sepsis , Rovin, BH, et al., Am. J. Kidney. Dis., 1998, 31, 1065; Lloyd, C., et al., Curr. opin.Neprol.Hypertens., 1998, 7, 281; Conti, P., et al., Allergy and Asthma Proc., 1998, 19, 121; Ransohoff, RM, et al., Trends Neurosci., 1998, 21, 154; MacDermott, RP, et al., Inflammatory Bowel Diseases, 1998, 4, 54). Thus, agents that inhibit the action of chemokines on target cells may be effective as agents for the treatment and / or prophylaxis of such diseases.
Genes encoding specific chemokine receptors have been cloned and it is now known that these receptors are G protein-coupled seven-transmembrane receptors present in various leukocyte populations. To date, at least five CXC chemokine receptors (CXCR1-CXCR5) and eight CC chemokine receptors (CCR1-CCR8) have been identified. For example, IL-8 is a ligand of CXCR1 and CXCR2, MIP-1α is a ligand of CCR1 and CCR5, and MCP-1 is a ligand of CCR2A and CCR2B (eg, Holmes, WE, et al., Science 1991, 253, 1278-1280; Murphy PM, et al., Science, 253, 1280-1283; Neote, K. et al., Cell, 1993, 72, 415-425; Charo, IF, et al., Proc. Natl. Acad Sci. USA, 1994, 91, 2752-2756; Yamagami, S., et al., Biochem.Biophys.Res.Commun., 1994, 202, 1156-1162; Combadier, C., et al., The Journal of Biological Chemistry, 1995, 270, 16491-16494, Power, CA, et al., J. Biol. Chem., 1995, 270, 19495-19500; Samson, M., et al., Biochemistry, 1996, 35, 3362-3367; Murphy, PM, Annual Review of immunology, 1994, 12, 592-633). Lung inflammation and granulomatous formation are inhibited in CCR1-deficient mice (Gao, JL, et al., J. Exp. Med., 1997, 185, 1959; Gerard, C., et al., J. Clin.Invest ., 1997, 100, 2022) and that macrophages supplementation and atherosclerosis lesion formation are reduced in CCR2-deficient mice (Boring, L., et al., Nature, 1998, 394, 894; Kuziel, WA). , et al., Proc. Natl. Acad. Sci. USA, 1997, 94, 12053; Kurihara, T., et al., J. Exp. Med., 1997, 186, 1757; Boring, L., et al , J. Clin. Invest., 1997, 100, 2552). Thus, compounds that inhibit the binding of chemokines such as MIP-1α and / or MCP-1 to these receptors, ie chemokine receptor antagonists, inhibit the action of chemokines such as MIP-1α and / or MCP-1 on target cells. It may be useful as a drug to make a drug, but there is no drug known to have such an effect.
The cyclic amine derivatives provided by the present invention are very novel. Recently, diphenylmethane derivatives (WO9724325; Hesselgesser, J., et al., J. Biol. Chem., 1998, 273, 15687), piperidine derivatives (JP9-249566), imidazobenzodiazepine derivatives (JP9- 249570), benzazosine derivatives (JP9-255572), tricyclic compounds with cyclic amino acids (WO9804554), phenothiazine derivatives (Bright, C., et al., Bloorg. Med. Chem. Lett., 1998, 8, 771), piepurazine derivatives (WO9744329), benzimidazole derivatives (WO9806703), distamycin analogs (Howard, OMZ, et al., J. Med. Chem., 1998, 41, 2184), bis -Acridine derivatives (WO9830218), spiro-substituted azacycles (WO9825604; WO9825605), substituted aryl piperazine (WO9825617), aminoquinoline derivatives (WO9827815), 3-arylpiperidine derivatives (WO9831364), hexanoic Amide derivatives (WO9838167) and other small molecules (WO9744329; W09802151; W09804554) antagonist activity of chemokine receptors such as CXCR1, CXCR4, CCR1, CCR2, CCR3 and CCR5 Has been reported. However, these compounds are different from the compounds of the present invention.
The present invention relates to novel cyclic amine derivatives.
The invention also relates to atherosclerosis, rheumatoid arthritis, psoriasis, asthma, ulcerative colitis, nephritis (nephritis), multiple sclerosis, lungs, where tissue infiltration of blood leukocytes such as monocytes and lymphocytes plays a major role in the initiation, progression or maintenance of the disease. Effective chemokine receptors for the treatment and / or prophylaxis of diseases such as fibrosis, myocarditis, hepatitis, pancreatitis, sarcoidosis, Crohn's disease, endometriosis, congestive heart failure, viral meningitis, cerebral infarction, neuropathy, Kawasaki disease and sepsis It is about an antagonist.
Accordingly, it is an object of the present invention to provide small molecule compounds that inhibit the binding of chemokines such as MIP-α and / or MCP-1 to receptors on target cells.
Another object of the present invention is to establish a method of inhibiting the binding of chemokines such as MIP-α and / or MCP-1 to receptors on target cells and / or their effects on target cells.
Another object of the present invention is to propose a method for treating a disease caused by binding of chemokines such as MIP-α and / or MCP-1 to receptors on target cells.
The inventors have studied intensively and found that cyclic amine derivatives having arylalkyl groups, pharmaceutically acceptable C ₁ -C ₆ alkyl addition salts or pharmaceutically acceptable acid addition salts thereof are MIP-α and / or MCP The present invention has been completed by discovering that the chemokine, such as -1, has an excellent activity of inhibiting binding to a receptor on target cells.
That is, the present invention is a compound of formula (I), a pharmaceutically acceptable acid addition salt thereof or a pharmaceutically acceptable C ₁ -C ₆ alkyl addition salt thereof (Invention 1):

Wherein R ¹ is an aromatic heterocyclic group having 1-3 heteroatoms selected from the group consisting of a phenyl group, a C ₃ -C ₈ cycloalkyl group, or an oxygen atom, a sulfur atom, a nitrogen atom or a combination thereof, wherein phenyl or aromatic hetero The cyclic group may be condensed with an aromatic heterocyclic group having 1-3 heteroatoms selected from the group consisting of a benzene ring or an oxygen atom, a sulfur atom, a nitrogen atom, or a combination thereof to form a condensed ring, and a phenyl group, C ₃ − C ₈ cycloalkyl group, aromatic heterocyclic group, or condensed ring is halogen atom, hydroxy group, cyano group, nitro group, carboxyl group, carbamoyl group, C ₁ -C ₆ alkyl group, C ₃ -C ₈ cycloalkyl group, C _2- C ₆ alkenyl groups, C ₁ -C ₆ alkoxy group, C ₁ -C ₆ alkylthio, C ₃ -C ₅ alkylene group, C ₂ -C ₄ alkylene group, a C ₁ -C ₃ alkylenedioxy group, a phenyl group , Phenoxy group, phenylthio group, benzyl group, benzyloxy group, benzo Amino group, C ₂ -C ₇ alkanoyl group, C ₂ -C ₇ alkoxycarbonyl group, C ₂ -C ₇ alkanoyloxy group, C ₂ -C ₇ alkanoylamino group, C ₂ -C ₇ N- alkyl carbamoyl group, C ₄ -C ₉ N-cycloalkylcarbamoyl group, C ₁ -C ₆ alkylsulfonyl group, C ₃ -C ₈ (alkoxycarbonyl) methyl group, N-phenylcarbamoyl group, piperidinocarbonyl group, morpholinocarbonyl group , 1-pyrrolidinylcarbonyl group, divalent represented by formula: -NH (C = O) O-, formula: divalent represented by -NH (C = S) O-, amino group, mono (C ₁ -C ₆ alkyl) amino group, or di (C ₁ -C ₆ alkyl) amino group, where a phenyl group, a C ₃ -C ₈ cycloalkyl group, an aromatic heterocyclic group, or a condensed ring substituent is halogen Optionally substituted with one or more of atoms, hydroxy groups, amino groups, trifluoromethyl groups, C ₁ -C ₆ alkyl groups, or C ₁ -C ₆ alkoxy groups;
R ² is a hydrogen atom, a C ₁ -C ₆ alkyl group, a C ₂ -C ₇ alkoxycarbonyl group, a hydroxy group, or a phenyl group, wherein the C ₁ -C ₆ alkyl or phenyl group is a halogen atom, a hydroxy group, a C ₁ -C ₆ alkyl group, or May be substituted with one or more of C ₁ -C ₆ alkoxy groups, and when j = 0, R ² is not a hydroxy group;
j represents an integer of 0-2;
k represents an integer of 0-2;
m represents an integer of 2-4;
n represents 0 or 1;
R ³ is a hydrogen atom or a C ₁ -C ₆ alkyl group optionally substituted with one or two phenyl groups, and each phenyl group is at least one of a hydrogen atom, a hydroxy group, a C ₁ -C ₆ alkyl group, or a C ₁ -C ₆ alkoxy group May be substituted by;
R ⁴ and R ⁵ may be the same or different and are a hydrogen atom, a hydroxy group, a phenyl group, or a C ₁ -C ₆ alkyl group, wherein the C ₁ -C ₆ alkyl group is a halogen atom, a hydroxy group, a cyano group, a nitro group, a carboxyl group, a carbon carbamoyl group, a mercapto group, a dino-ku no group, C ₃ -C ₈ cycloalkyl, C ₁ -C ₆ alkoxy group, C ₁ -C ₆ alkylthio group, one or more hydrogen atoms, hydroxy groups, C ₁ -C ₆ alkyl group , Phenyl group, phenoxy group, benzyloxy group, benzyloxycarbonyl group, C ₂ -C ₇ alkanoyl group, C ₂ -C ₇ alkoxycarbonyl group, C ₂ -C ₇ optionally substituted with C ₁ -C ₆ alkoxy group or benzyloxy group alkanoyloxy group, C ₂ -C ₇ alkanoylamino group, C ₂ -C ₇ N- alkyl carbamoyl, C ₁ -C ₆ alkylsulfonyl group, an amino group, a mono (C ₁ -C ₆ alkyl) amino group, di ( Aromatic heterocycle having 1-3 heteroatoms selected from the group consisting of a C ₁ -C ₆ alkyl) amino group, or an oxygen atom, a sulfur atom, a nitrogen atom, or a combination thereof Optionally substituted with one or more of the click groups and optionally condensed with a benzene ring, or R ⁴ and R ⁵ together form a 3-6 membered cyclic hydrocarbon;
p represents 0 or 1;
q represents 0 or 1;
G is -CO-, -SO _2- , -CO-O-, -NR ⁷ -CO-, -CO-NR ^7- , -NH-CO-NH-, -NH-CS-NH-, -NR ⁷ A group represented by -SO _2- , -SO ₂ -NR ^7- , -NH-CO-O-, or -O-CO-NH-, wherein R ⁷ is a hydrogen atom or a C ₁ -C ₆ alkyl group, Or R ⁷ together with R ⁵ represent a C ₃ -C ₅ alkylene group;
R ⁶ is an aromatic heterocycle having 1-3 heteroatoms selected from the group consisting of a phenyl group, a C ₃ -C ₈ cycloalkyl group, a C ₃ -C ₈ cycloalkenyl group, a benzyl group, or an oxygen atom, a sulfur atom, a nitrogen atom or a combination thereof Wherein the phenyl, benzyl, or aromatic heterocyclic group is condensed and condensed with an aromatic heterocyclic group having 1-3 heteroatoms selected from the group consisting of benzene rings or oxygen atoms, sulfur atoms, nitrogen atoms or combinations thereof A phenyl group, a C ₃ -C ₈ cycloalkyl group, a C ₃ -C ₈ cycloalkenyl group, a benzyl group, an aromatic heterocyclic group, or a condensed ring may be a halogen atom, a hydroxy group, a mercapto group, a cyano group , Nitro group, thiocyanato group, carboxyl group, carbamoyl group, trifluoromethyl group, C ₁ -C ₆ alkyl group, C ₃ -C ₆ cycloalkyl group, C ₂ -C ₆ alkenyl group, C ₁ -C ₆ alkoxy group , C ₃ -C ₈ cycloalkyloxy group, C ₁ -C ₆ alkylthio group, C ₁ -C ₃ alkylenedioxy group, phenyl group, phenoxy group, phenylamino group, benzyl group, benzoyl group, phenylsulfinyl group, phenylsulfonyl group, 3-phenylureido group, C ₂ -C ₇ alkanoyl group, C ₂ -C ₇ alkoxycarbonyl group, C ₂ -C ₇ alkanoyloxy group, C ₂ -C ₇ alkanoylamino group, C ₂ -C ₇ N- alkyl carbamoyl, C ₁ -C ₆ alkylsulfonyl Nyl group, phenylcarbamoyl group, N, N-di (C ₁ -C ₆ alkyl) sulfamoyl group, amino group, mono (C ₁ -C ₆ alkyl) amino group, di (C ₁ -C ₆ alkyl) amino group, benzylamino group , A C ₂ -C ₇ (alkoxycarbonyl) amino group, a C ₁ -C ₆ (alkylsulfonyl) amino group, or a bis (C ₁ -C ₆ alkylsulfonyl) amino group, which may be substituted with a phenyl group , A C ₃ -C ₈ cycloalkyl group, a C ₃ -C ₈ cycloalkenyl group, a benzyl group, an aromatic heterocyclic group, or a substituent of a condensed ring may be a halogen atom, cyano group, hydroxy group, amino group, trifluoromethyl group, C ₁ - C ₆ alkyl, C ₁ -C ₆ alkoxy group, C ₁ -C ₆ alkylthio group, a mono (C ₁ -C ₆ alkyl) amino, or di (C ₁ -C ₆ alkyl) is optionally substituted with one or more of the amino group .
In addition, the present invention provides a method for treating a target cell on a target cell using a therapeutically effective amount of a compound represented by formula (I), a pharmaceutically acceptable acid addition salt thereof, or a pharmaceutically acceptable C ₁ -C ₆ alkyl addition salt thereof. It is a method that inhibits the binding of chemokines to receptors and / or their action on target cells (invention 2).
The compound represented by the above formula (I) has an activity of inhibiting binding of chemokines such as MIP-1α and / or MCP-1 to receptors of target cells, and chemokines such as MIP-1α and / or MCP-1. It has an activity that inhibits the physiological activity of the cell to be induced.
Description of Preferred Embodiments
(1) Invention 1
In formula (I), R ¹ is an aromatic heterocyclic group having 1-3 heteroatoms selected from the group consisting of a phenyl group, a C ₃ -C ₈ cycloalkyl group, or an oxygen atom, a sulfur atom, a nitrogen atom or a combination thereof, wherein The phenyl or aromatic heterocyclic group may be condensed with an benzene ring or an aromatic heterocyclic group having 1-3 heteroatoms selected from the group consisting of an oxygen atom, a sulfur atom, a nitrogen atom, or a combination thereof to form a condensed ring. , C ₃ -C ₈ cycloalkyl group, aromatic heterocyclic group, or condensed ring is a halogen atom, hydroxy group, cyano group, nitro group, carboxy group, carbamoyl group, C ₁ -C ₆ alkyl group, C ₃ -C ₈ cycloalkyl group , C ₂ -C ₆ alkenyl, C ₁ -C ₆ alkoxy group, C ₁ -C ₆ alkylthio import, C ₃ -C ₅ alkylene group, C ₂ -C ₄ alkyleneoxy group, C ₁ -C ₃ alkylene Deoxy group, phenyl group, phenoxy group, phenylthio group, benzyl group, benzyloxy group, Benzoyl group, C ₂ -C ₇ alkanoyl group, C ₂ -C ₇ alkoxycarbonyl group, C ₂ -C ₇ alkanoyloxy group, C ₂ -C ₇ alkanoylamino group, C ₂ -C ₇ N- alkyl carbamoyl group , C ₄ -C ₉ N-cycloalkylcarbamoyl group, C ₁ -C ₆ alkylsulfonyl group, C ₃ -C ₈ (alkoxycarbonyl) methyl group, N-phenylcarbamoyl group, piperidinocarbonyl group, morpholino Carbonyl group, 1-pyrrolidinylcarbonyl group, divalent group represented by -NH (C = O) O-, formula: divalent group represented by -NH (C = S) O-, amino group, mono (C _1- C ₆ alkyl) amino group, or di (C ₁ -C ₆ alkyl) amino group.
″ C ₃ -C ₈ cycloalkyl group ″ in R ¹ means a cyclic alkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl group, specifically cyclopropyl, cyclopentyl, and And cyclohexyl groups.
″ Aromatic heterocyclic groups having 1-3 heteroatoms selected from the group consisting of an oxygen atom, a sulfur atom, a nitrogen atom, or a combination thereof " in R ¹ are specifically, for example, thienyl, furyl, pyrrolyl, imidazolyl, Pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, triazinyl, triazolyl, oxadiazolyl (furazanyl), thiadiazolyl group, and the like, preferably thienyl , Furyl, pyrrolyl, isoxazolyl, and pyridyl groups.
The ″ condensed ring ″ in R ¹ is an aromatic heterocyclic group having 1-3 heteroatoms selected from the group consisting of a phenyl group or an oxygen atom, a sulfur atom and / or a nitrogen atom at any possible position, and a benzene ring or an oxygen atom, a sulfur atom or a nitrogen atom A ring obtained by condensation with an aromatic heterocyclic group having 1-3 heteroatoms selected from the group, and suitably specifically, for example, naphthyl, indolyl, benzofuranyl, benzothienyl, quinolyl, benz Imidazolyl, benzoxazolyl, benzotriazolyl, benzoxadiazolyl (benzofurazanyl), and benzothiadiazolyl groups.
Among them, a benyl group and an isoxazolyl group may be listed as preferred embodiments of R ¹ .
"Halogen atom" as a substituent of a phenyl group, a C ₃ -C ₈ cycloalkyl group, an aromatic heterocyclic group, or a condensed ring in R ¹ includes a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom, suitably fluorine Atom, chlorine atom, and bromine atom.
″ C ₁ -C ₆ alkyl group ″ as a substituent on R ¹ is methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, isopropyl, isobutyl, sec- C ₁ -C ₆ straight or branched alkyl groups such as butyl, tert-butyl, isopentyl, neopentyl, tert-pentyl, isohexyl, 2-methylpentyl, 1-ethylbutyl group and the like, suitably specifically methyl , Ethyl, propyl, and isopropyl groups.
As the substituent in R ¹ "C ₃ -C ₈ cycloalkyl group" is the same as was defined in the "C ₃ -C ₈ cycloalkyl group" of R ^1, has the same examples as those to be given as a preferred embodiment.
″ C ₂ -C ₆ alkenyl group ″ as the substituent on R ¹ is vinyl, allyl, 1-propenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 4-pentenyl, 5- C ₂ -C ₆ straight or branched alkenyl groups such as hexenyl, 4-methyl-3-pentenyl, and the like, suitably include vinyl and 2-methyl-1-propenyl groups.
″ C ₁ -C ₆ alkoxy group ″ as a substituent in R ¹ means a group consisting of the C ₁ -C ₆ alkyl group and an oxy group, and specifically means, for example, methoxy and ethoxy groups.
″ C ₁ -C ₆ alkylthio group ″ as a substituent in R ¹ means a group consisting of the C ₁ -C ₆ alkyl group and a thio group, and specifically, for example, methylthio and ethylthio group.
In R ¹ "C ₃ -C ₅ alkylene groups" as the substituents are trimethylene, tetramethylene, pentamethylene, and 1-methyltrimethylene group, such as C ₃ -C ₅ 2 mean an alkylene group, and specifically, e.g. , Trimethylene and tetramethylene groups.
″ C ₂ -C ₄ alkyleneoxy group ″ as a substituent on R ¹ is ethyleneoxy (-CH ₂ CH ₂ O-), trimethyleneoxy (-CH ₂ CH ₂ CH ₂ O-), tetramethyleneoxy (-CH ₂ The group consisting of the above C ₂ -C ₄ 2 alkylene and oxy groups such as CH ₂ CH ₂ CH ₂ O-), and 1,1-dimethylethyleneoxy (-CH ₂ C (CH ₃ ) ₂ O-) Specifically, for example, ethyleneoxy and trimethyleneoxy groups are meant.
″ C ₁ -C ₃ alkylenedioxy group ″ as a substituent on R ¹ is methyleneoxy (-OCH ₂ O-), ethylenedioxy (-OCH ₂ CH ₂ O-), trimethylenedioxy (-OCH ₂ CH ₂ C ₁ -C ₃ 2, such as CH ₂ O—), and propylenedioxy (—OCH ₂ CH (CH ₃ ) O—) groups, refers to a group consisting of an alkyllian group and two oxy groups, and specifically, for example, methylene It means a dioxy and ethylenedioxy group.
″ C ₂ -C ₇ alkanoyl groups ″ as substituents on R ¹ are acetyl, propanoyl, butanoyl, pentanoyl, hexanoyl, heptanoyl, isobutyryl, 3-methylbutanoyl, 2-methylbutanoyl, C ₂ -C ₇ straight or branched alkanoyl groups such as pivaloyl, 4-methylpentanoyl, 3,3-dimethylbutanoyl, 5-methylhexanoyl group and the like, and preferred and specific examples include acetyl groups.
″ C ₂ -C ₇ alkoxycarbonyl group ″ as a substituent in R ¹ means a group composed of the C ₂ -C ₇ alkoxy group and a carbonyl group, and preferably means, for example, methoxycarbonyl and ethoxycarbonyl group.
″ C ₂ -C ₇ alkanoyloxy group ″ as a substituent in R ¹ means a group composed of the C ₂ -C ₇ alkanoyl group and an oxy group, and specifically means, for example, an acetyloxy group.
"C ₂ -C ₇ alkanoylamino group" as a substituent in R ¹ means a group composed of the C ₂ -C ₇ alkanoyl group and an amino group, and specifically means, for example, an acetylamino group.
″ C ₂ -C ₇ N-alkylcarbamoyl group ″ as a substituent in R ¹ means a group consisting of the C ₂ -C ₇ alkyl group and a carbamoyl group, and specifically, for example, N-methylcarbamoyl and N -Ethylcarbamoyl group.
″ C ₄ -C ₉ N-cycloalkylcarbamoyl group ″ as a substituent on R ¹ means a group consisting of the C ₃ -C ₈ cycloalkyl group and a carbamoyl group, and specifically, for example, N-methylcarbamoyl And N-ethylcarbamoyl group.
″ C ₁ -C ₆ alkylsulfonyl group ″ as a substituent in R ¹ means a group composed of the C ₁ -C ₆ alkyl group and a sulfonyl group, and specifically, for example, methylsulfonyl group.
″ C ₃ -C ₈ (alkoxycarbonyl) methyl group '' as a substituent in R ¹ means a group consisting of the C ₂ -C ₇ alkoxycarbonyl group and a methyl group, and is preferably, for example, (methoxycarbonyl) methyl and A (epoxycarbonyl) methyl group is meant.
″ Mono (C ₁ -C ₆ alkyl) amino group '' as a substituent in R ¹ means an amino group substituted with one of the C ₁ -C ₆ alkyl groups, and preferably, for example, methylamino and ethylamino groups. .
″ Di (C ₁ -C ₆ alkyl) amino group as a substituent in R ¹ ″ means an amino group substituted with two of the same or different C ₁ -C ₆ alkyl groups, preferably and specifically, for example, dimethylamino, di Ethylamino and N-ethyl-N-methylamino group.
Among them, a halogen atom, a hydroxy group, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₁ -C ₆ alkoxy group, C ₁ -C ₆ alkylthio import, C ₂ -C ₄ alkylene group, a methylene A deoxy group, an N-phenylcarbamoyl group, an amino group, a mono (C ₁ -C ₆ alkyl) amino group, and a di (C ₁ -C ₆ alkyl) amino group are a phenyl group at R ¹ , a C ₃ -C ₈ cycloalkyl group, an aromatic hetero As preferred embodiments of cyclic groups, or substituents on condensed rings.
Moreover, the substituent for the phenyl group, C ₃ -C ₈ cycloalkyl group, aromatic heterocyclic group, or condensed ring in R ¹ may be halogen atom, hydroxy group, amino group, trifluoromethyl group, C ₁ -C ₆ alkyl group, or C ₁ Optionally substituted with one or more of -C ₆ alkoxy groups. A halogen atom, a C ₁ -C ₆ alkyl group, and a C ₁ -C ₆ alkoxy group is as defined in the above substituents for a phenyl group, a C ₃ -C ₈ cycloalkyl group, an aromatic heterocyclic group, or a condensed ring at R ¹ , The same examples can be listed as preferred embodiments.
In formula (I), R ² is a hydrogen atom, a C ₁ -C ₆ alkyl group, a C ₂ -C ₇ alkoxycarbonyl group, a hydroxy group, or a phenyl group, wherein the C ₁ -C ₆ alkyl or phenyl group is a halogen atom, a hydroxy group, C May be substituted with one or more of _1- C ₆ alkyl groups, or C ₁ -C ₆ alkoxy groups, and when j = 0, R ² is not a hydroxy group.
In R ² C ₁ -C ₆ alkyl group and was C ₂ -C ₇ alkoxy carbonyl groups Cobb phenyl group, C ₃ -C ₈ cycloalkyl group, aromatic heterocyclic as defined in the substituent of the cyclic group, or condensed ring in R ¹ The same examples may be listed as preferred embodiments.
In R ² C ₁ -C ₆ a halogen atom as the substituent of an alkyl or phenyl group, C ₁ -C ₆ alkyl, and C ₁ -C ₆ alkoxy group is a phenyl group, C ₃ -C ₈ cycloalkyl group, aromatic heterocyclic group in R ¹ Or as defined in the above substituents of condensed rings, the same examples of which may be listed as preferred embodiments.
Among them, a hydrogen atom is a preferred embodiment of R ² .
In the formula (I), j represents an integer of 0-2. j is particularly preferably 0.
In said formula (I), k represents the integer of 0-2 and m represents the integer of 2-4. Preferably a 2-substituted pyrrolidine in which k is 0 and m is 3, a 3-substituted pyrrolidine in which k is 1 and m is 2, a 3-substituted piperidine in which k is 1 and m is 3, 4-substituted piperidine in which k is 2 and m is 2, or 3-substituted hexahydroazepine in which k is 1 and m is 4.
In the formula (I), n represents 0 or 1.
In particular, 3-amidopyrrolidine, where k is 1, m is 2, n is 0, and 4- (amidomethyl) piperidine, where k is 2, m is 2 and n is 1, is specifically Preferred examples may be listed.
In formula (I), R ³ represents a hydrogen atom or a C ₁ -C ₆ alkyl group optionally substituted with one or two phenyl groups, each phenyl group being a hydrogen atom, a hydroxy group, a C ₁ -C ₆ alkyl group, or C It may be substituted with one or more of _1- C ₆ alkoxy groups.
Was in the C ₁ -C ₆ alkyl group is ³ R group, C ₃ -C ₈ cycloalkyl group, aromatic heterocyclic as defined in the substituent of the cyclic group, or condensed ring in R ^1, specifically, for example, methyl, Ethyl and propyl groups.
In R ³ C ₁ -C ₆ a halogen atom as a substituent a phenyl group of the alkyl group, C ₁ -C ₆ alkyl, and C ₁ -C ₆ alkoxy group on the phenyl group R ^1, C ₃ -C ₈ cycloalkyl group, aromatic heterocyclic As defined in the above substituents on the click group, or condensed ring, the same examples can be listed as preferred embodiments.
Among them, a hydrogen atom is a preferred embodiment of R ³ .
In formula (I), R ⁴ and R ⁵ may be the same or different, and a hydrogen atom, a hydroxy group, a phenyl group, or a C ₁ -C ₆ alkyl group, wherein the C ₁ -C ₆ alkyl group is a halogen atom, a hydroxy group, a cyano group , a nitro group, a carboxy group, a carbamoyl group, a mercapto group, a dino-ku no group, C ₃ -C ₈ cycloalkyl, C ₁ -C ₆ alkoxy group, C ₁ -C ₆ alkylthio group, at least one hydrogen atom, a hydroxy group , Phenyl group, phenoxy group, benzyloxy group, benzyloxycarbonyl group, C ₂ -C ₇ alkanoyl group, C ₂ -C ₇ alkoxy optionally substituted with C ₁ -C ₆ alkyl group, C ₁ -C ₆ alkoxy group or benzyloxy group a carbonyl group, C ₂ -C ₇ alkanoyloxy group, C ₂ -C ₇ alkanoylamino group, C ₂ -C ₇ N- alkyl carbamoyl, C ₁ -C ₆ alkylsulfonyl group, an amino group, a mono (C ₁ -C ₆ alkyl) amino group, di (C ₁ -C ₆ alkyl) amino group, or having 1-3 heteroatoms selected from the group consisting of an oxygen atom, a sulfur atom, a nitrogen atom or a combination thereof Optionally substituted with one or more of aromatic heterocyclic groups and optionally condensed with a benzene ring, or R ⁴ and R ⁵ together form a 3-6 membered cyclic hydrocarbon.
The C ₁ -C ₆ alkyl group in R ⁴ and R ⁵ is as defined in the above substituents of a phenyl group, C ₃ -C ₈ cycloalkyl group, aromatic heterocyclic group, or condensed ring in R ¹ , examples of which Preferred embodiments may be listed.
R ⁴ and R ⁵ on the halogen atom as the substituent of the C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy group, C ₁ -C ₆ alkylthio import, C ₂ -C ₇ alkanoyl group, C ₂ -C ₇ alkoxycarbonyl a carbonyl group, C ₂ -C ₇ alkanoyloxy group, C ₂ -C ₇ alkanoylamino group, C ₂ -C ₇ N- alkyl carbamoyl, C ₁ -C ₆ alkylsulfonyl group, a mono (C ₁ -C ₆ alkyl ) Amino group and di (C ₁ -C ₆ alkyl) amino group are as defined in the above substituents of phenyl group, C ₃ -C ₈ cycloalkyl group, aromatic heterocyclic group, or condensed ring in R ¹ , and the same Examples may be listed as preferred embodiments.
Aromatic heterocyclic groups having 1-3 heteroatoms selected from the group consisting of a C ₃ -C ₈ cycloalkyl group as a substituent of a C ₁ -C ₆ alkyl group at R ⁴ and R ⁵ and an oxygen atom, a sulfur atom, a nitrogen atom, or a combination thereof As defined in the above groups of R ¹ , the same examples may be listed as preferred embodiments.
The halogen atom, C ₁ -C ₆ alkyl group, and C ₁ -C ₆ alkoxy group as a substituent of the phenyl group which is a substituent of the C ₁ -C ₆ alkyl group at R ⁴ and R ⁵ are a phenyl group, a C ₃ -C ₈ cycloalkyl group at R ¹ , Aromatic heterocyclic groups, or as defined in the above substituents on the condensed ring, the same examples can be listed as preferred embodiments.
″ 3-6 membered cyclic hydrocarbons ″ consisting of R ⁴ , R ⁵ and adjacent carbons include cyclopropane, cyclobutane, cyclopentane, and cyclohexane.
Among them, hydrogen atoms and C ₁ -C ₆ alkyl groups may be listed as preferred embodiments of R ⁴ and R ⁵ .
In the formula (I), p represents 0 or 1, q represents 0 or 1. Especially preferably both p and q are zero.
In formula (I), G is -CO-, -SO _2- , -CO-O-, -NR ⁷ -CO-, -CO-NR ^7- , -NH-CO-NH-, -NH-CS -NH-, -NR ⁷ -SO _2- , -SO ₂ -NR ^7- , -NH-CO-O-, or -O-CO-NH- is a group represented by R ⁷ is a hydrogen atom or C _1, or -C ₆ alkyl group, or R ⁷ is C ₃ -C ₅ represents an alkylene group with R ^5.
In the above formula, -CO- means a carbonyl group, -SO ₂ -means a sulfonyl group, and -CS- means a thiocarbonyl group. Preferred G groups are, for example, those represented by the formulas -NR ⁷ -CO- and -NH-CO-NH-.
The C ₁ -C ₆ alkyl group at R ⁷ is as defined in the above substituents of a phenyl group, a C ₃ -C ₈ cycloalkyl group, an aromatic heterocyclic group, or a condensed ring in R ¹ , the same examples of which are preferred embodiments May be enumerated as:
″ C ₂ -C ₅ alkylene group ″ composed of R ⁵ and R ⁷ means methylene, ethylene, propylene, trimethylene, tetramethylene, 1-methyltrimethylene, pentamethylene group, and the like, specifically, ethylene, Trimethylene and tetramethylene groups.
Hydrogen atom is a preferred embodiment of R ⁷ .
In formula (I), R ⁶ is 1- selected from the group consisting of a phenyl group, a C ₃ -C ₈ cycloalkyl group, a C ₃ -C ₈ cycloalkenyl group, a benzyl group, or an oxygen atom, a sulfur atom, a nitrogen atom, or a combination thereof An aromatic heterocyclic group having 3 heteroatoms, wherein the phenyl, benzyl, or aromatic heterocyclic group is an aromatic heterocyclic group having 1-3 heteroatoms selected from the group consisting of a benzene ring or an oxygen atom, a sulfur atom, a nitrogen atom or a combination thereof Can be condensed with a group to form a condensed ring, and a phenyl group, a C ₃ -C ₈ cycloalkyl group, a C ₃ -C ₈ cycloalkenyl group, a benzyl group, an aromatic heterocyclic group, or a condensed ring is a halogen atom, a hydroxyl group , Mercapto group, cyano group, nitro group, thiocyanato group, carboxyl group, carbamoyl group, trifluoromethyl group, C ₁ -C ₆ alkyl group, C ₃ -C ₆ cycloalkyl group, C ₂ -C ₆ alkenyl group, C ₁ -C ₆ alkoxy group, C ₃ -C ₈ Sickle Alkyloxy, C ₁ -C ₆ alkylthio, C ₁ -C ₃ alkylenedioxy group, a phenyl group, a phenoxy group, a phenyl group, a benzyl group, a benzoyl group, phenyl sulfinyl group, phenylsulfonyl group, a 3-phenyl-ureido , C ₂ -C ₇ alkanoyl group, C ₂ -C ₇ alkoxycarbonyl group, C ₂ -C ₇ alkanoyloxy group, C ₂ -C ₇ alkanoylamino group, C ₂ -C ₇ N- alkyl carbamoyl, C _1- C ₆ alkylsulfonyl group, phenylcarbamoyl group, N, N-di (C ₁ -C ₆ alkyl) sulfamoyl group, amino group, mono (C ₁ -C ₆ alkyl) amino group, di (C ₁ -C ₆ Substituted with at least one of an alkyl) amino group, a benzylamino group, a C ₂ -C ₇ (alkoxycarbonyl) amino group, a C ₁ -C ₆ (alkylsulfonyl) amino group, or a bis (C ₁ -C ₆ alkylsulfonyl) amino group Can be.
An aromatic heterocyclic group having 1-3 heteroatoms selected from the group consisting of a C ₃ -C ₈ cycloalkyl group, an oxygen atom, a sulfur atom, a nitrogen atom, or a combination thereof in R ⁶ , and a condensed ring as defined in R ¹ above; And the same examples may be listed as preferred embodiments.
″ C ₃ -C ₈ cycloalkenyl group ″ in R ^{6 means} a cyclic alkenyl group such as cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl group, specifically 1-cyclo Petenyl and 1-cyclohexenyl groups.
Among them, phenyl group, furyl group and thienyl group may be listed as preferred embodiments of R ⁶ .
In the R ⁶ phenyl group, C ₃ -C ₈ cycloalkyl, C ₃ -C ₈ cycloalkenyl group, benzyl group, aromatic heterocyclic group, or condensed halogen atom, C ₁ -C ₆ alkyl group as the substituent of the ring, C ₂ - C ₆ alkenyl groups, C ₁ -C ₆ alkoxy group, C ₁ -C ₆ alkylthio, C ₁ -C ₃ alkylenedioxy group, C ₂ -C ₇ alkanoyl group, C ₂ -C ₇ alkoxycarbonyl group, C ₂ -C ₇ alkanoyloxy group, C ₂ -C ₇ alkanoylamino group, C ₂ -C ₇ N- alkyl carbamoyl, C ₁ -C ₆ alkylsulfonyl group, a mono (C ₁ -C ₆ alkyl) amino group, And di (C ₁ -C ₆ alkyl) amino groups are as defined in the above substituents of a phenyl group, a C ₃ -C ₈ cycloalkyl group, an aromatic heterocyclic group, or a condensed ring at R ¹ , the same examples being preferred May be listed as an embodiment.
As a group groping in R ⁶ "C ₃ -C ₈ cycloalkyl group" is the same as was defined in the above C ₃ -C ₈ cycloalkyl group represented by R ^1, may be the same examples are listed a preferred embodiment and its.
″ C ₃ -C ₈ cycloalkyloxy group ″ as a molar group at R ⁶ means a group consisting of the C ₃ -C ₈ cycloalkyl group and an oxy group, and specifically, for example, cyclopropyloxy, cyclopentyloxy, and cyclo It means a hexyloxy group.
″ N, N-di (C ₁ -C ₆ alkyl) sulfamoyl group ″ as a molar group in R ⁶ means a sulfamoyl group substituted with two of the same or different C ₁ -C ₆ alkyl groups, preferably Examples thereof include N, N-dimethylsulfamoyl, N, N-diethylsulfamoyl, and N-ethyl-N-methylsulfamoyl groups.
″ C ₂ -C ₇ (alkoxycarbonyl) amino group ”as a molar group in R ⁶ means a group composed of the C ₂ -C ₇ alkoxycarbonyl group and an amino group, and specifically includes, for example, (methoxycarbonyl) amino and (Ethoxycarbonyl) means an amino group.
A ″ C ₁ -C ₆ (alkylsulfonyl) amino ″ group as a molar group at R ⁶ means a group consisting of the C ₁ -C ₆ alkylsulfonyl group and amino, and specifically, for example, a (methylsulfonyl) amino group it means.
"Bis (C ₁ -C ₆ alkylsulfonyl) amino" group as a groping in the R ⁶ group stands for the same or different two C ₁ -C ₆ alkyl group-substituted sulfonyl groups, and a preferably specific, e.g. It means a bis (methylsulfonyl) amino group.
Among them, halogen atom, mercapto group, nitro group, thiocyanato group, trifluoromethyl group, C ₁ -C ₆ alkyl group, C ₁ -C ₆ alkoxy group, phenyl group, phenylsulfonyl group, C ₂ -C ₇ alka A noylamino group or amino group may be listed as a preferred embodiment of a substituent for a phenyl group, a C ₃ -C ₈ cycloalkyl group, a C ₃ -C ₈ cycloalkenyl group, a benzyl group, an aromatic heterocyclic group, or a condensed ring at R ⁶ . have.
Moreover, the substituent for the phenyl group, C ₃ -C ₈ cycloalkyl group, C ₃ -C ₈ cycloalkenyl group, benzyl group, aromatic heterocyclic group, or condensed ring in R ⁶ may be a halogen atom, cyano group, hydroxy group, amino group, trifluoromethyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy group, C ₁ -C ₆ alkylthio group, a mono (C ₁ -C ₆ alkyl) amino, or di (C ₁ -C ₆ alkyl) Optionally substituted with one or more of the amino groups.
A halogen atom, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy group, C ₁ -C ₆ alkylthio group, a mono (C ₁ -C ₆ alkyl) amino, or di (C ₁ -C ₆ alkyl) amino group As defined in the above substituents for the phenyl group, C ₃ -C ₈ cycloalkyl group, aromatic heterocyclic group, or condensed ring at R ¹ , the same examples can be listed as preferred embodiments.
(2) invention 2
The compound represented by the formula (I), a pharmaceutically acceptable acid addition salt thereof or a pharmaceutically acceptable C ₁ -C ₆ alkyl addition salt thereof may be prepared by preparing a therapeutically effective amount thereof and a carrier and / or diluent in a pharmaceutical composition. By making a chemokine receptor antagonist formulation of the present invention. Thus, the cyclic amine derivatives shown in (I), pharmaceutically acceptable acid addition salts or pharmaceutically acceptable C ₁ -C ₆ alkyl addition salts thereof can be used orally or parenterally, such as intravenously, It may be administered subcutaneously, intramuscularly, transdermally or rectally.
Oral administration can take the form of tablets, pills, granules, powders, solutions, suspensions, capsules and the like.
Tablets include, for example, excipients such as lactose, starch and crystalline cellulose; Binders such as carboxymethylcellulose, methylcellulose and polyvinylpyrrolidone; Disintegrants such as sodium alginate, sodium bicarbonate and sodium lauryl sulfate, and the like.
Pills, powders and granule formulations may be prepared by standard methods using such excipients. Solutions or suspensions may be prepared by standard methods using glycerin esters such as tricapryline and triacetin or alcohols such as ethanol. Capsules can be made by filling granules, powders or solutions in gelatin and the like.
Subcutaneous, intramuscular or intravenous formulations may be prepared as injections using aqueous or nonaqueous solutions. Aqueous solutions include, for example, isotonic sodium chloride solutions. Non-aqueous solutions include, for example, propylene glycol, polyethylene glycol, olive oil, ethyl oleate, and the like, and optionally preservatives and stabilizers can be added. For injection, it may be stabilized by filtration through a bacterial filter or a combination of disintegrants.
Transdermal administration may be in the form of ointments or creams, and ointments may be prepared by standard methods using castor oil and olive oil, or fatty oils such as petroleum jelly, while creams may be formulated with sorbitan esters of diethylene glycol and fatty acids. It can be prepared using the same emulsifier or fatty oil.
In rectal administration, it can be prepared as a standard suppository using gelatin soft capsules and the like.
Dosages of cyclic amine derivatives, pharmaceutically acceptable acid addition salts or pharmaceutically acceptable C ₁ -C ₆ alkyl addition salts thereof of the present invention may be determined by the type of disease, route of administration, age and sex of the patient, and Depending on the degree, but is preferably 1-500 mg / day for the average adult.
(3) Materials common to Inventions 1 and 2
Preferred embodiments of the cyclic amine compound in the formula (I) include compounds having respective substituents as shown in the following Tables 1.1 to 1.201.
In Tables 1.1 to 1.201, "chirality" refers to the arrangement of asymmetric carbon atoms on cyclic amines. ″ R ″ shows that the subtitle carbon has an R configuration, ″ S ″ shows that the subtitle carbon has an S configuration, and ″-″ indicates that the racemate or compound thereof has a subtitle carbon atom on a nitrogen containing ring. It means not to.


















































































































































































































































































































































































































The present invention may also use acid addition salts of cyclic amine compounds, wherein the acid is, for example, inorganic acids such as hydrochloric acid, bromic acid, sulfuric acid, phosphoric acid, carboxylic acid, and the like, as well as maleic acid, citric acid, malic acid, tartaric acid, fumaric acid, methane Organic acids such as sulfonic acid, trifluoroacetic acid, formic acid and the like.
Moreover, the invention also relates to cyclic amines such as 1- (4-chlorobenzyl) -1-methyl-4-[{N- (3-trifluoromethylbenzoyl) glycyl} aminomethyl] piperidinium iodide C ₁ -C ₆ alkyl addition salts of the compounds can be used, wherein the alkyl is for example methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, isopropyl , Isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, tert-pentyl, 2-methylpentyl, 1-ethylbutyl and the like, and specifically include methyl and ethyl groups. Preferred embodiments of counter anions of ammonium cations may include halides such as fluoride, chloride, bromide or iodide.
The present invention may also use racemates and all possible optically active forms of the compounds represented by formula (I) above.
The compound represented by said formula (I) can be synthesize | combined by either of the following general manufacturing methods.
(Manufacturing method 1)
Compounds represented by the following formula (II) in the presence or absence of a solvent:

Wherein R ¹ , R ² , R ³ , j, k, m and n are as defined separately in Formula (I) above, and a carboxyl represented by 0.1-10 equivalents of the following Formula (III) mountain:

Wherein R ⁴ , R ⁵ , R ⁶ , G, p and q are as defined separately in formula (I) above or a method of treating with a reactive derivative thereof.
Reactive derivatives of carboxylic acids in the formula (III) include highly reactive carboxylic acid derivatives commonly used in synthetic organic chemistry such as acid hydrides, acid anhydrides, mixed acid anhydrides.
Such reactions include dehydrating agents such as appropriate amounts of molecular sieves, dicyclohexylcarbodiimide (DCC), N-ethyl-N '-(3-dimethylaminopropyl) carbodiimide (EDCI or WSC), carbonyldi Imidazole (CDI), N-hydroxysuccinimide (HOSu), N-hydroxybenzotriazole (HOBt), benzotriazol-1-yloxytris (pyrrolidino) phosphonium hexafluorophosphate (PyBOP ^R ), 2- (1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU), 2- (1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU), 2- (5-norbornene-2,3-dicarboxyimido) -1,1,3,3-terra Methyluronium tetrafluoroborate (TNTU), O- (N-succinimidyl) -1,1,3,3-tetramethyluronium tetrafluoroborate (TSTU), bromotris (pyrrolidino) phosphonium Coupling reages such as hexafluorophosphate (PyBoP ^R ) nt), or inorganic salts such as potassium carbonate, sodium carbonate, sodium hydrogen carbonate, amines such as triethylamine, diisopropylethylamine, pyridine, or the like (piperidinomethyl) polystyrene, (morpholinomethyl) polystyrene, More gentle progress can be made by using a base comprising a polymer supported base such as (diethylaminomethyl) polystyrene, poly (4-vinylpyridine) and the like.
(Manufacturing Method 2)
Alkylating agent represented by one equivalent of the following formula (IV) in the presence or absence of a solvent:

(Wherein R ¹ , R ² , and j are as defined separately in formula (I) above; X represents a halogen atom, an alkylsulfonyloxy group, or an arylsulfonyloxy group)
0.1-10 equivalents of the compound represented by the following formula (V):

Wherein R ³ , R ⁴ , R ⁵ , R ⁶ , G, k, m, n, p and q are as defined separately in Formula (I) above.
Such reactions can be carried out more gently using bases similar to those used in Preparation 1 above. Moreover, these preparations can also be facilitated by iodides such as potassium iodide, sodium iodide and the like.
In said Formula (IV), X represents a halogen atom, an alkylsulfonyloxy group, and an arylsulfonyloxy group. Such halogen atoms preferably include chlorine, bromine, iodine atoms. Suitable examples of alkylsulfonyloxy groups include methylsulfonyloxy, trifluoromethylsulfonyloxy groups, and the like. Preferred embodiments of the arylsulfonyloxy group include an atosyloxy group.
(Manufacturing method 3)
A compound represented by one equivalent of the following formula (VI) or the following formula (VII), in the presence or absence of a solvent under reducing conditions:

Wherein R ¹ and R ² are as defined separately in Formula (I) above; j represents 1 or 2)
R ¹ -CHO (VII)
Wherein R ¹ is as defined in formula (I) above; j represents 0).
Such reactions are generally referred to as reductive amination reactions, and such reducing conditions are complex hydrides, boranes, or electricity such as lithium aluminum hydride, sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, and the like. It can be generated by catalytic hydrogenation using a decomposable reduction or the like and using a catalyst containing a metal such as palladium, platinum, nickel, rhodium and the like.
(Manufacturing method 4)
Compounds represented by the following formula (VIII) in the presence or absence of a solvent:

Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁷ , j, k, m, n, p and q are as defined separately in Formula (I) above. 10 equivalents of carboxylic acid or sulfonic acid represented by the following formula (IX):
HO-AR ⁶ (IX)
(Wherein R ⁶ is as defined in formula (I) above; ″ A ″ represents a carbonyl group or sulfonyl group) or a method for treating with a reactive derivative thereof.
Reactive derivatives of carboxylic acids or sulfonic acids in the formula (IX) include highly reactive carboxylic acid or sulfonic acid derivatives commonly used in synthetic organic chemistry such as acid hydrides, acid anhydrides, mixed acid anhydrides.
Such a reaction can be proceeded more gently by using an appropriate amount of dehydrating agent, binder, or base similar to that used in Preparation 1 above.
(Method 5)
In the presence or absence of a solvent, one equivalent of the compound represented by formula (VIII) is represented by 0.1-10 equivalents of isocyanate or isothiocytate:
Z = C = NR ⁶ (X)
Wherein R ⁶ is as defined in formula (I); Z represents an oxygen atom or a sulfur atom.
(Manufacturing method 6)
Compounds represented by one equivalent of formula (XI), with or without solvent:

Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , j, k, m, n, p and q are as defined separately in Formula (I) above; ″ A ″ is a carbonyl group or Derivatives of an amine represented by the following formula (XII) in 0.1-10 equivalents:
R ⁶ -NH ₂ (XII)
Wherein R ⁶ is as defined in formula (I) above.
In the formula (III), the reactive derivative of carboxylic acid is
Such reaction can be proceeded more gently by using an appropriate amount of dehydrating agent, binder, or base similar to that used in Preparation 1 above.
If the substrate provided in each of these preparations contains substituents which are believed to react under each reaction condition or adversely affect reactions common to synthetic organic chemistry, the functional groups are protected by known suitable protecting groups and then the reaction of the preparation And deprotection using known methods to afford the desired compounds.
Furthermore, the compounds of the present invention can be prepared by further converting the substituent (s) of the compound prepared in Preparation 1-6, using known reactions commonly used in synthetic organic chemistry such as alkylation, acylation, reduction and the like. have.
Each of the above preparations may be selected from the group consisting of halogenated hydrocarbons such as dichloromethane and chloroform, aromatic hydrocarbons such as benzene and toluene, ethers such as diethyl ether and tetrahydrofuran, esters such as ethyl acetate, dimethylformamide, dimethyl sulfoxide and acetonitrile. Reaction solvents including aprotic polar solvents such as methanol, ethanol, isopropyl alcohol and the like can be used.
The reaction temperature of each manufacturing method is -78 degreeC-+150 degreeC, Preferably it is 0 degreeC-100 degreeC. After the reaction is completed, conventional separation and purification processes such as concentration, filtration, extraction, solid phase extraction, recrystallization, chromatography, etc. may be used to separate the desired cyclic amine compound represented by the formula (I). . These can be converted to pharmaceutically acceptable acid addition salts or C ₁ -C ₆ alkyl addition salts by conventional methods.
The invention is further illustrated by the following examples. However, the present invention is not limited to the compounds of these examples. The compound number in these Examples shows the number attached to the compound listed as a preferable example in Table 1.1-1.201.
Reference Example 1: Preparation of 3-amino-1- (4-chlorobenzyl) pyrrolidine dihydrochloride
4-chlorobenzyl chloride (4.15 g, 25.8 mmol) and Pr ₂ NEt (6.67 g, 51.6 mmol) were added 3-{(tert-butoxycarbonyl) amino} pyrrolidine (4.81 g, in DMF (50 mL). 25.8 mmol) in solution. The reaction mixture is stirred for 15 h at 70 ° C. and the solvent is removed under reduced pressure. Recrystallization (CH ₃ CN, 50 mL) gave 3- (tert-butoxycarbonyl) amino-1- (4-chlorobenzyl) pyrrolidine (6.43 g, 80.2%) as a pale yellow solid as the desired material. ¹ H NMR (CDCl ₃ , 300 MHz) δ 1.37 (s, 9H), 1.5-1.7 (br, 1H), 2.1-2.4 (m, 2H), 2.5-2.7 (m, 2H), 2.83 (br , 1H), 3.57 (s, 2H), 4.1-4.3 (br, 1H), 4.9-5.1 (br, 1H), 7.15-7.35 (br, 4H); Purity is determined by RPLC / MS (98%); ESI / MS m / e 311.0 (M ⁺ + H, C ₁₆ H ₂₄ ClN ₂ O ₂ ).
A solution of 3- (tert-butoxycarbonyl) amino-1- (4-chlorobenzyl) pyrrolidine (6.38 g, 20.5 mmol) in CH ₃ OH (80 mL) was diluted with 1 N HCl-Et ₂ O (100). mL) and stir at 25 ° C. for 15 h. The solvent was removed under reduced pressure to give a solid, which was purified by recrystallization (1: 2 CH ₃ OH-CH ₃ CN, 150 mL) to give 3-amino-1- (4-chlorobenzyl) pyrrolidine di as a white powder. Produce hydrochloride (4.939 g, 84.9%): ¹ H NMR (d ₆ -DMSO, 300 MHz) δ 1.35 (s, 1H), 3.3-3.75 (br-m, 4H), 3.9 (br, 1H) , 4.05 (br, 1H), 4.44 (br, 1H), 4.54 (br, 1H), 7.5 (m, 4H), 8.45 (br, 1H), 8.60 (br, 1H); Purity is determined by RPLC / MS (>99%); ESI / MS m / e 211.0 (M ⁺ + H, C ₁₁ H ₁₆ ClN ₂ ).
Optically active (R) -3-amino-1- (4-chlorobenzyl) pyrrolidine dihydrochloride and (S) -3-amino-1- (4-chlorobenzyl) pyrrolidine dihydrochloride are also respectively It is drawn according to the above method using the corresponding reactant. The product shows the same ¹ H NMR as that of racemate.
Example 1: Preparation of 3- (N-benzoylglyciyl) amino-1- (4-chlorobenzyl) pyrrolidine (Compound No. 1)
N-benzoylglycine (9.9 mg, 0.055 mmol), 3-ethyl-1- {3- (dimethylaminopropyl} carbodiimide hydrochloride (EDCI) (10.5 mg) and 1-hydroxybenzotriazole hydrate (NOBt) (7.4 mg) is added to a solution of 3-amino-1- (4-chlorobenzyl0pyrrolidine dihydrochloride (14.2 mg, 0.050 mmol) and Et ₃ N (15.2 mg) in CHCl ₃ (2.5 mL). The reaction mixture is stirred for 16 h at 25 ° C. and washed with 2N aqueous NaOH (2 mL × 2) and brine (1 mL) After filtration through a PTFE membrane filter, the solvent is removed under reduced pressure and pale yellow Provide 3- (N-benzoylglyciyl) amino-1- (4-chlorobenzyl) pyrrolidine (Compound No. 1) (17.7 mg, 95%) as an oil: Purity is determined by RPLC / MS ( 95%); ESI / MS m / e 372.0 (M ⁺ + H, C ₂₀ H ₂₂ ClN ₃ O ₂ ).
Examples 2-32
The compounds of the present invention are synthesized according to the method of Example 1 using the corresponding reactants, respectively. ESI / MS data and yields are summarized in Table 2.
Compound no.Molecular formulaESI / MS m / eYield (mg)Yield (%) Example 22C21 H24 Cl N3 O238616.485 Example 33C19 H21 Cl N4 O237318.7100 Example 44C21 H21 Cl F3 N3 O244057.269 Example 582C22 H23 Cl F3 N3 O24545.611 Example 685C21 H24 Cl N3 O238622.659 Example 786C21 H23 Cl N4 O443121.298 Example 8214C22 H25 Cl N2 O238523.962 Example 9215C23 H27 Cl N2 O341517.484 Example 10216C20 H23 Cl N2 O2 S39121.6quant Example 11217C23 H27 Cl N2 O443115.366 Example 12218C23 H27 Cl N2 O239912.864 Example 13219C22 H24 Cl F N2 O341918.186
Example 14220C22 H25 Cl N2 O238516.485 Example 15221C21 H23 Cl N2 O237114.980 Example 16222C21 H22 Cl2 N2 O240513.365 Example 17223C25 H31 Cl N2 O344318.4 *63 Example 18224C20 H23 Cl N2 O3 S40711.228 Example 19225C22 H26 Cl N3 O240022.7quant Example 20226C23 H28 Cl N3 O343021.098 Example 21227C22 H25 Cl2 N3 O243421.9100 Example 22228C23 H28 Cl N3 O343020.897 Example 23229C25 H32 Cl N3 O246225.4quant Example 24230C26 H31 Cl F N3 O247226.0quant Example 25231C24 H28 Cl N3 O344230.3 *quant Example 26232C22 H32 Cl N3 O24063.919 Example 27233C23 H28 Cl N3 O24148.541 Example 28234C22 H27 Cl N4 O24157.335 Example 29235C24 H29 Cl2 N3 O24629.039 Example 30236C25 H29 Cl N4 O3 S50117.469 Example 31237C21 H24 Cl N3 O340214.271 Example 32238C21 H23 Cl2 N3 O343623.4quant
* Yield of TFA salt
Reference Example 2: Preparation of (R) -3- {N- (tert-butoxycarbonyl) glycyl} amino-1- (4-chlorobenzyl) pyrrolidine
Shake a mixture of (R) -3-amino-1- (4-chlorobenzyl) pyrrolidine dihydrochloride (4.54 g, 16.0 mmol), 2N NaOH solution (80 mL) and ethyl acetate (80 mL) The organic layer is separated and the aqueous layer is extracted with ethyl acetate (80 mL × 2). The combined organic layers are dried over anhydrous sodium sulfate, filtered and evaporated to yield free (R) -3-amino-1- (4-chlorobenzyl) pyrrolidine (3.35 g, 99%).
A solution of (R) -3-amino-1- (4-chlorobenzyl) pyrrolidine (3.35 g, 16 mmol) in CH ₂ Cl ₂ (80 mL) was purified by Et ₃ N (2.5 mL, 17.6 mmol), N treated with -tert-butoxycarbonylglycine (2.79 g, 16.0 mmol), EDCI (3.07 g, 16.0 mmol) and HOBt (2.16 g, 16 mmol). The reaction mixture is stirred for 16 h at 25 ° C., then 2 N NaOH solution (80 mL) is added. The organic layer is separated and the aqueous layer is extracted with dichloromethane (100 mL × 3). The combined organic layers are washed with water (100 mL × 2) and brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated. Column chromatography (SiO ₂ , ethyl acetate) to give the desired (R) -3- {N- (tert-butoxycarbonyl) glycyl} amino-1- (4-globenzyl) pyrrolidine (5.40 g, 92%).
Reference Example 3: Preparation of (R) -1- (4-Chlorobenzyl) -3- (glycylamino) pyrrolidine
To a solution of (R) -3- {N- (tert-butoxycarbonyl) glycyl} amino-1- (4-chlorobenzyl) pyrrolidine (5.39 g, 14.7 mmol) in methanol (60 mL) Add 4 N HCl in oxane (38 mL). The solution is stirred for 2 h at room temperature. The reaction mixture is concentrated and 2N NaOH solution (80 mL) is added. The mixture is extracted with dichloromethane (80 mL × 3) and the combined extracts are dried over sodium sulfate and concentrated. Column chromatography (SiO ₂ , AcOEt / EtOH / Et ₃ N = 90/5/5) gave (R) -3- (glycyl) amino-1- (4-chlorobenzyl) pyrrolidine (3.374 g. 86%): ¹ H NMR (CDCl ₃ , 270 MHz) δ 1.77 (dd, J = 1.3 and 6.9 Hz, 1H), 2.20-3.39 (m, 2H), 2.53 (dd, J = 3.3 and 9.6 Hz, 1H), 2.62 (dd, J = 6.6 and 9.6 Hz, 1H), 2.78-2.87 (m, 1H), 3.31 (s, 2H), 3.57 (s, 2H), 4.38-4.53 (br, 1H) , 7.18-7.32 (m, 4 H), 7.39 (br. S, 1 H).
Other 3-acylamino-1- (4-chlorobenzyl) pyrrolidines are also synthesized according to the methods of Reference Examples 2 and 3 using the corresponding reactants, respectively.
(S) -1- (4-Chlorobenzyl) -3- (glycosylamino) pyrrolidine: 3.45 g, 75% (2 steps).
(R) -3- (β-alanylamino) -1- (4-chlorobenzyl) pyrrolidine: 3.79 g, 85% (2 steps).
(S) -3- (β-alanylamino) -1- (4-chlorobenzyl) pyrrolidine: 3.72 g, 86% (2 steps).
(R) -3-{(S) -alanylamino} -1- (4-chlorobenzyl) pyrrolidine: 368 mg, 65% (2 steps).
(R) -3-{(R) -alanylamino} -1- (4-chlorobenzyl) pyrrolidine: 425 mg, 75% (2 steps).
(R) -3-{(2S) -2-amino-3-thienylpropanol} amino-1- (4-chlorobenzyl) pyrrolidine: 566 mg, 78% (2 steps).
(R) -3-{(2R) -2-amino-3-thienylpropanol} amino-1- (4-chlorobenzyl) pyrrolidine: 585 mg, 81% (2 steps).
(R) -3- (2-amino-2-methylpropanol) amino-1- (4-chlorobenzyl) pyrrolidine: 404 mg, 66% (2 steps).
(R) -3-{(2S) -2-amino-4- (methylsulfonyl) butanol} amino-1- (4-chlorobenzyl) pyrrolidine: 535 mg, 72% (2 steps).
Furthermore, (R) -3- (glysilamino) -1- (4-methylbenzyl) pyrrolidine, (R) -1- (4-bromobenzyl) -3- (glysilamino) pyrrolidine , (R) -1- (2,4-dimethylbenzyl) -3- (glysylamino) pyrrolidine, and (R) -1- (3,5-dimethylisoxazol-4-ylmethyl)- 3- (glysilamino) pyrrolidine is also synthesized according to the methods of Reference Examples 1, 2 and 3 using the corresponding reactants, respectively.
(R) -3- (glysilamino) -1- (4-methylbenzyl) pyrrolidine: 4.65 g, 62% yield from 3-{(tert-butoxycarbonyl) amino} pyrrolidine.
(R) -1- (4-bromobenzyl) -3- (glysilamino) pyrrolidine: 2.55 g, from (R) -3-amino-1- (4-bromobenzyl) pyrrolidine 68% yield: ¹ H NMR (CDCl ₃ , 270 MHz) δ 1.37-1.78 (m, 3H), 2.23-2.39 (m, 2H), 2.50-2.67 (m, 2H), 2.80-2.89 (m, 1H) , 3.32 (s, 2H), 3.58 (s, 2H), 4.39-4.55 (m, 1H), 7.21 (d, J = 6.5 Hz, 2H), 7.45 (d, J = 6.5 Hz, 2H).
(R) -1- (2,4-Dimethylbenzyl) -3- (glycosylamino) pyrrolidine: 1.56 g, 58% yield from 3-{(tert-butoxycarbonyl) amino} pyrrolidine: ¹ H NMR (CDCl ₃ , 270 MHz) δ1.55-1.78 (m, 3H), 2.30 (s, 3H), 2.23-2.31 (m, 2H), 2.33 (s, 3H), 2.51-2.63 (m, 2H ), 2.78-2.87 (m, 1H), 3.30 (s, 2H), 3.55 (s, 2H), 4.38-4.60 (m, 1H), 6.95 (d, J = 7.6 Hz, 1H), 6.97 (s, 1H), 7.13 (d, J = 7.6 Hz, 1H), 7.43 (br-s, 1H).
(R) -1- (3,5-dimethylisoxazol-4-ylmethyl) -3- (glycyamino) pyrrolidine: 3.14 g, 3-{(tert-butoxycarbonyl) amino} py 45% yield from lollidine.
Example 33: (S) -3- [N- {3,5-bis (trifluoromethyl) benzoyl} glycyl] amino-1- (4-chlorobenzyl) pyrrolidine (Compound No. 5) Produce
A solution of 3,5-bis (trifluoromethyl) benzoyl chloride (0.060 mmol) in chloroform (0.4 mL) was added (S) -1- (4-chlorobenzyl) -3- (glycidyl) in chloroform (1.0 mL). To a solution of amino) pyrrolidine (0.050 mmol) and triethylamine (0.070 mmol). The reaction mixture is stirred at room temperature for 2.5 h, then (aminomethyl) polystyrene resin (1.04 mmol / g, 50 mg, 50 mmol) is added and the mixture is stirred at room temperature for 12 h. The reaction mixture is filtered and the resin is washed with dichloromethane (0.5 mL). Combine the filtrate and wash, add dichloromethane (4 mL) and wash the solution with 2 N aqueous NaOH solution (0.5 mL) to give (S) -3- [N- {3,5-bis (trifluoro) Yields methyl) benzoyl} glycyl] amino-1- (4-chlorobenzyl) pyrrolidine (Compound No. 5) (14.4 mg, 57%): purity determined by RPLC / MS (97%); ESI / MS m / e 508.0 (M ⁺ + H, C ₂₂ H ₂₀ ClF ₆ N ₃ O ₂ ).
Examples 34-239
The compounds of the present invention are each synthesized according to the method of Example 33 using the corresponding reactants. ESI / MS data and yields are summarized in Table 3.
Compound no.Molecular formulaESI / MS m / eYield (mg)Yield (%) Example 345C22 H29 Cl F6 N3 O2508.014.457 Example 356C21 H21 Cl F3 N3 O2440.017.077 Example 367C20 H21 Br Cl N3 O2450.017.779 Example 378C20 H21 Cl F N3 O2390.012.765 Example 389C20 H20 Cl3 N3 O2440.039.0quant Example 3910C21 H24 Cl N3 O3402.523.5quant Example 4011C22 H26 Cl N3 O4432.522.4quant Example 4112C22 H26 Cl N3 O4432.515.974 Example 4213C21 H21 Cl F3 N3 O2440.013.160 Example 4314C21 H24 Cl N3 O2386.016.485 Example 4415C20 H21 Cl2 N3 O2406.015.777 Example 4516C21 H24 Cl N3 O2402.028.2quant Example 4617C20 H20 Cl3 N3 O2442.035.6quant Example 4718C21 H21 Cl N4 O2397.522.8quant Example 4819C21 H22 Cl N3 O4416.016.378 Example 4920C21 H20 Cl F4 N3 O2458.024.9quant
Example 5021C21 H20 Cl F4 N3 O2458.017.978 Example 5122C21 H20 Cl F4 N3 O2458.09.441 Example 5223C21 H20 Cl F4 N3 O2458.015.467 Example 5324C21 H21 Cl F3 N3 O3456.020.791 Example 5425C21 H20 Cl F4 N3 O2458.018.581 Example 5526C20 H21 Cl N4 O4417.021.9quant Example 5627C20 H21 Cl N4 O4417.016.881 Example 5728C20 H21 Cl N4 O4417.06.833 Example 5829C22 H20 Cl F6 N3 O2508.020.882 Example 5930C21 H21 Cl F3 N3 O2440.015.269 Example 6031C20 H21 Br Cl N3 O2450.015.669 Example 6132C20 H21 Cl F N3 O2390.011.861 Example 6233C20 H20 Cl3 N3 O2440.015.872 Example 6334C21 H24 Cl N3 O3402.533.8quant Example 6435C22 H26 Cl N3 O4432.556.1quant Example 6536C22 H26 Cl N3 O4432.537.6quant Example 6637C21 H21 Cl F3 N3 O2440.012.657 Example 6738C21 H24 Cl N3 O2386.012.364 Example 6839C20 H21 Cl2 N3 O2406.015.978 Example 6940C21 H24 Cl N3 O2402.011.658 Example 7041C20 H20 Cl3 N3 O2442.017.881 Example 7142C21 H21 Cl N4 O2397.522.4quant Example 7243C21 H22 Cl N3 O4416.030.1quant Example 7344C21 H20 Cl F4 N3 O2458.013.459 Example 7445C21 H20 Cl F4 N3 O2458.013.258 Example 7546C21 H20 Cl F4 N3 O2458.014.463 Example 7647C21 H21 Cl F3 N3 O3456.016.472 Example 7748C21 H20 Cl F4 N3 O245816.572 Example 7849C20 H21 Cl N4 O4417.012.560 Example 7950C21 H20 Cl F4 N3 O2458.026.3quant Example 8051C20 H21 Br Cl N3 O2450.08.638 Example 8152C20 H21 Cl F N3 O2390.54.121 Example 8253C20 H21 Cl2 N3 O2406.05.427 Example 8354C20 H20 Cl3 N3 O2440.08.840 Example 8455C20 H20 Br Cl4 N3 O2440.07.735 Example 8556C21 H24 Cl N3 O2386.04.825 Example 8657C22 H26 Cl N3 O4429.54.923 Example 8758C20 H21 Cl2 N3 O2406.04.120 Example 8859C20 H21 Br Cl N3 O2452.03.516 Example 8960C26 H26 Cl N3 O2448.57.333 Example 9061C21 H21 Cl F3 N3 O2440.07.132 Example 9162C21 H24 Cl N3 O2386.010.454 Example 9263C22 H26 Cl N3 O2400.56.030 Example 9364C21 H21 Cl N3 O2397.07.035 Example 9465C24 H24 Cl N3 O2422.07.736 Example 9566C24 H24 Cl N3 O2422.06.330 Example 9667C20 H20 Cl F2 N3 O2408.04.723 Example 9768C20 H20 Cl F2 N3 O2408.07.838 Example 9869C20 H20 Cl F2 N3 O2408.07.336 Example 9970C20 H20 Cl F2 N3 O2408.09.145 Example 10071C22 H26 Cl N3 O4429.05.626
Example 10172C21 H21 Cl F3 N3 O2456.06.227 Example 10273C21 H21 Cl F3 N3 O2456.516.874 Example 10374C22 H24 Cl N3 O4430.016.476 Example 10475C21 H20 Cl F4 N3 O2458.016.170 Example 10576C21 H20 Cl F4 N3 O2458.017.074 Example 10677C20 H19 Cl F3 N3 O2426.016.276 Example 10778C20 H19 Cl F3 N3 O2426.018.085 Example 10879C22 H20 Cl F6 N3 O2508.018.874 Example 10980C22 H20 Cl F6 N3 O2508.016.465 Example 11081C22 H26 Cl N3 O2400.013.970 Example 11183C20 H21 Cl N4 O4417.016.077 Example 11284C20 H21 Cl N4 O4417.021.6quant Example 11387C23 H22 Cl F6 N3 O2522.017.567 Example 11488C22 H23 Cl F3 N3 O2454.013.961 Example 11589C21 H23 Br Cl N3 O2466.015.466 Example 11690C21 H23 Cl F N3 O2404.010.753 Example 11791C21 H23 Cl3 N3 O2456.013.760 Example 11892C22 H26 Cl N3 O3416.038.4quant Example 11993C23 H28 Cl N3 O4446.025.2quant Example 12094C23 H38 Cl N3 O4446.016.574 Example 12195C22 H23 Cl F3 N3 O2454.016.372 Example 12296C22 H26 Cl N3 O2400.516.784 Example 12397C21 H23 Cl2 N3 O2420.011.253 Example 12498C22 H26 Cl N3 O2416.511.857 Example 12599C21 H22 Cl3 N3 O2454.014.865 Example 126100C22 H23 Cl N4 O2411.09.546 Example 127101C22 H24 Cl N3 O4430.513.261 Example 128102C22 H22 Cl F4 N3 O2472.013.156 Example 129103C22 H22 Cl F4 N3 O2472.036.5quant Example 130104C22 H22 Cl F4 N3 O2472.022.897 Example 131105C22 H22 Cl F4 N3 O2472.020.185 Example 132106C22 H23 Cl F3 N3 O3472.027.4quant Example 133107C22 H22 Cl F4 N3 O2472.018.578 Example 134108C21 H23 Cl N4 O4431.011.955 Example 135109C21 H23 Cl N4 O4431.023.9quant Example 136110C21 H23 Cl N4 O4431.024.4quant Example 137111C23 H22 Cl F6 N3 O2522.09.536 Example 138112C22 H23 Cl F3 N3 O2454.03.917 Example 139113C21 H23 Br Cl N3 O2466.07.532 Example 140114C21 H23 Cl F N3 O2404.06.130 Example 141115C21 H22 Cl3 N3 O2456.06.629 Example 142116C22 H26 Cl N3 O3416.04.823 Example 143117C23 H28 Cl N3 O4446.06.429 Example 144118C23 H28 Cl N3 O4446.024.6quant Example 145119C22 H23 Cl F3 N3 O2454.05.223 Example 146120C22 H26 Cl N3 O2400.54.422 Example 147121C21 H23 Cl2 N3 O2420.07.837 Example 148122C22 H26 Cl N3 O2416.514.168 Example 149123C21 H22 Cl3 N3 O2454.05.424 Example 150124C22 H23 Cl N4 O2411.034.0quant Example 151125C22 H24 Cl N3 O4430.532.0quant
Example 152126C22 H22 Cl F4 N3 O2472.04.619 Example 153127C22 H22 Cl F4 N3 O2472.010.444 Example 154128C22 H22 Cl F4 N3 O2472.07.331 Example 155129C22 H22 Cl F4 N3 O2472.013.557 Example 156130C22 H23 Cl F3 N3 O3470.015.164 Example 157131C22 H22 Cl F4 N3 O2472.08.636 Example 158132C21 H23 Cl N4 O4431.04.420 Example 159133C21 H23 Cl N4 O4431.032.0quant Example 160134C21 H23 Cl N4 O4431.06.932 Example 161135C21 H23 Br Cl N3 O2466.07.834 Example 162136C21 H23 Cl F N3 O2404.013.768 Example 163137C21 H23 Cl2 N3 O2420.514.669 Example 164138C21 H22 Cl3 N3 O2454.017.778 Example 165139C21 H22 Br Cl4 N3 O2454.017.276 Example 166140C22 H26 Cl N3 O2400.015.075 Example 167141C23 H28 Cl N3 O4443.513.962 Example 168142C21 H23 Cl2 N3 O2420.013.765 Example 169143C21 H23 Br Cl N3 O2464.016.169 Example 170144C27 H29 Cl N3 O2462.017.676 Example 171145C22 H23 Cl F3 N3 O2454.016.071 Example 172146C22 H26 Cl N3 O2400.014.975 Example 173147C23 H28 Cl N3 O2414.016.278 Example 174148C22 H23 Cl N4 O2411.014.973 Example 175149C25 H26 Cl N3 O2436.017.178 Example 176150C25 H26 Cl N3 O2436.013.160 Example 177151C21 H22 Cl F2 N3 O2422.014.870 Example 178152C21 H22 Cl F2 N3 O2422.015.373 Example 179153C21 H22 Cl F2 N3 O2422.015.373 Example 180154C21 H22 Cl F2 N3 O2422.016.478 Example 181155C23 H28 Cl N3 O4443.016.976 Example 182156C22 H23 Cl F3 N3 O2470.512.654 Example 183157C22 H23 Cl F3 N3 O2470.020.085 Example 184158C23 H26 Cl N3 O4444.017.478 Example 185159C22 H22 Cl F4 N3 O2472.018.478 Example 186160C22 H22 Cl F4 N3 O2472.019.683 Example 187161C21 H21 Cl F3 N3 O2440.017.077 Example 188162C21 H21 Cl F3 N3 O2440.017.178 Example 189163C23 H22 Cl F6 N3 O2522.020.880 Example 190164C23 H22 Cl F6 N3 O2522.02.710 Example 191165C23 H28 Cl N3 O2414.016.479 Example 192166C22 H23 Cl F3 N3 O2454.08.638 Example 193167C21 H23 Br Cl N3 O2464.011.650 Example 194168C21 H23 Cl2 N3 O2420.011.555 Example 195169C21 H22 Cl3 N3 O2454.010.044 Example 196170C22 H22 Cl F4 N3 O2472.010.444 Example 197171C21 H23 Cl2 N3 O2420.08.942 Example 198172C21 H24 Cl N3 O2386.010.353 Example 199173C21 H23 Cl N4 O4431.014.668 Example 200174C22 H23 Cl F3 N3 O2454.010.446 Example 201175C21 H23 Br Cl N3 O2464.013.458 Example 202176C21 H23 Cl2 N3 O2420.012.760
Example 203177C21 H22 Cl3 N3 O2454.013.258 Example 204178C22 H22 Cl F4 N3 O2472.012.955 Example 205179C21 H23 Cl2 N3 O2420.013.363 Example 206180C21 H24 Cl N3 O2386.024.2quant Example 207181C21 H23 Cl N4 O4431.01.0One Example 208182C23 H25 Cl F3 N3 O2468.015.165 Example 209183C22 H25 Br Cl N3 O2478.018.075 Example 210184C22 H25 Cl2 N3 O2434.016.375 Example 211185C22 H24 Cl3 N3 O2468.018.679 Example 212186C23 H24 Cl F4 N3 O2486.016.568 Example 213187C22 H25 Cl2 N3 O2434.014.466 Example 214188C22 H26 Cl N3 O2400.014.070 Example 215189C22 H25 Cl N4 O4445.016.876 Example 216190C26 H25 Cl F3 N3 O2 S536.017.766 Example 217191C25 H25 Br Cl N3 O2 S546.020.475 Example 218192C25 H25 Cl2 N3 O2 S502.016.967 Example 219193C25 H24 Cl3 N3 O2 S536.018.368 Example 220194C26 H24 Cl F4 N3 O2 S554.019.470 Example 221195C25 H25 Cl2 N3 O2 S502.019.176 Example 222196C25 H26 Cl N3 O2 S468.016.068 Example 223197C25 H25 Cl N4 O4 S513.018.472 Example 224198C26 H25 Cl F3 N3 O2 S536.013.952 Example 225199C25 H25 Br Cl N3 O2 S546.012.947 Example 226200C25 H25 Cl2 N3 O2 S502.015.662 Example 227201C25 H24 Cl3 N3 O2 S536.017.364 Example 228202C26 H24 Cl F4 N3 O2 S554.015.456 Example 229203C25 H25 Cl2 N3 O2 S502.013.554 Example 230204C25 H26 Cl N3 O2 S468.013.759 Example 231205C25 H25 Cl N4 O4 S513.013.954 Example 232206C24 H27 Cl F3 N3 O4 S546.010.037 Example 233207C23 H27 Br Cl N3 O4 S558.017.161 Example 234208C23 H27 Cl2 N3 O4 S512.017.066 Example 235209C23 H26 Cl3 N3 O4 S546.07.327 Example 236210C24 H26 Cl F4 N3 O4 S564.019.268 Example 237211C23 H27 Cl2 N3 O4 S512.07.931 Example 238212C23 H28 Cl N3 O4 S478.013.757 Example 239213C23 H27 Cl N4 O4 S523.05.521
Example 240: (R) -3- [N- {3-fluoro-5- (trifluoromethyl) benzoyl} glycyl] amino-1- (3,5-dimethylisoxazol-4-ylmethyl Preparation of Pyrrolidine (Compound No. 1191)
A solution of 3-fluoro-5- (trifluoromethyl) benzoyl chloride (0.058 mmol) in dichloromethane (1 mL) was added (R) -1- (3) in chloroform (0.2 mL) and dichloromethane (0.75 mL). , 5-dimethylisoxazol-4-ylmethyl) -3- (glyciaminoamino) pyrrolidine (0.050 mmol) and pyreridinomethylpolystyrene (58 mg) are added to the mixture. The reaction mixture is stirred at room temperature for 2 h, then methanol (1.0 mL) is added and the mixture is stirred at room temperature for 30 minutes. The reaction mixture is loaded on a Varian ^™ SCX column and washed with CH ₃ OH (16 mL). The product was eluted with 2N NH ₃ in CH ₃ OH (6 mL) and concentrated to (R) -3- [N- {3-fluoro-5- (trifluoromethyl) benzoyl} glycyl] Amino-1- (3,5-dimethylisoxazol-4-ylmethyl) pyrrolidine (Compound No. 1191) (19.5 mg, 88%) is provided: Purity is determined by RPLC / MS (100% ); ESI / MS m / e 443.2 (M ⁺ + H, C ₂₀ H ₂₂ F ₄ N ₄ O ₃ ).
Examples 241-265
The compounds of the present invention are each synthesized according to the method of Example 240 using the corresponding reactants. ESI / MS data and yields are summarized in Table 4.
Compound no.Molecular formulaESI / MS m / eYield (mg)Yield (%) Example 2411192C20 H22 F4 N4 O3443.219.287 Example 2421193C20 H23 F3 N4 O4441.017.579 Example 2431194C21 H22 F6 N4 O3493.020.483 Example 2441195C19 H23 Br N4 O3435.116.877 Example 2451196C19 H23 N5 O5402.216.281 Example 2461197C20 H22 F4 N4 O3443.217.680 Example 2471198C19 H23 Cl N4 O3391.016.584 Example 2481199C20 H26 N4 O3371.016.187 Example 2491200C19 H22 Cl2 N4 O3425.018.085 Example 2501201C19 H22 F2 N4 O3393.016.685 Example 2511202C20 H22 F4 N4 O3443.216.876 Example 2521203C22 H24 F3 N3 O3436.217.179 Example 2531204C23 H23 F6 N3 O2488.218.174 Example 2541205C21 H24 Br N3 O2430.217.581
Example 2551206C21 H24 N4 O4397.016.282 Example 2561207C22 H23 F4 N3 O2438.217.580 Example 2571208C21 H24 Cl N3 O2386.015.882 Example 2581209C22 H27 N3 O2366.015.786 Example 2591210C21 H23 Cl2 N3 O2420.017.885 Example 2601211C21 H23 F2 N3 O2388.016.384 Example 2611212C22 H23 F4 N3 O2438.217.480 Example 2621213C24 H24 Cl F6 N3 O2536.224.090 Example 2631214C23 H24 Cl F4 N3 O3486.222.291 Example 2641215C22 H24 Cl3 N3 O2469.920.989 Example 2651216C22 H24 Cl F2 N3 O2436.019.389
Example 266: Preparation of (R) -1- (4-chlorobenzyl) -3-[{N- {4- (dimethylamino) benzoyl} glycyl} amino] pyrrolidine (Compound No. 952)
A solution of (R) -1- (4-chlorobenzyl) -3- (glycosylamino) pyrrolidine (13.8 mg, 0.052 mmol) in CHCl ₃ (2 mL) was added Et ₃ N (0.021 mL, 0.15 mmol). , 4- (dimethylamino) benzoic acid (10 mg, 0.061 mmol), EDCI (10.2 mg, 0.053 mmol) and HOBt (7.5 mg, 0.055 mmol). The reaction mixture is stirred for 16 h at room temperature. The solution is washed with 2N NaOH aqueous solution (2 mL × 2) and brine (2 mL) and dried by filtration through PTFE membrane using CH ₂ Cl ₂ (3 mL). Concentration desired compound (Compound No. 952) (24.9 mg, quant): Purity is determined by RPLC / MS (91%); ESI / MS m / e 415.0 (M ⁺ + H, C ₂₂ H ₂₇ ClN ₄ O ₂ ).
Examples 267-347
The compounds of the present invention are each synthesized according to the method of Example 266 using the corresponding reactants. Solid phase extraction (Varian ^™ SCX column) or chromatography (HPLC-C ₁₈ ), if necessary, to provide the desired material. ESI / MS data and yields are summarized in Table 5.
Compound no.Molecular formulaESI / MS m / eYield (mg)Yield (%) Example 267951C22 H24 Cl N3 O4430.026.3quant Example 268953C23 H29 Cl N4 O2429.028.8quant Example 269954C21 H25 Cl N4 O2401.027.9quant Example 270955C22 H27 Cl N4 O2415.026.8quant Example 271956C21 H24 Cl N3 O3402.010.351 Example 272957C20 H22 Cl N3 O3388.01.47 Example 273958C21 H24 Cl N3 O3402.51.26 Example 274959C22 H25 Cl N4 O3429.54.722 Example 275960C23 H27 Cl N4 O3443.010.949 Example 276961C21 H25 Cl N4 O2401.028.4quant Example 277962C22 H27 Cl N4 O2415.024.9quant Example 278963C21 H24 Cl N3 O3402.04.422 Example 279964C22 H24 Cl N3 O4430.029.5quant Example 280965C23 H26 Cl N3 O4444.027.2quant Example 281966C22 H24 Cl N3 O3414.027.0quant Example 282967C23 H26 Cl N3 O3428.027.0quant Example 283968C22 H23 Cl N4 O2411.021.4quant Example 284969C23 H25 Cl N4 O2425.027.6quant Example 285970C22 H27 Cl N4 O2415.028.6quant Example 2869971C23 H29 Cl N4 O2429.027.9quant Example 287972C20 H23 Cl N4 O2387.026.2quant Example 288973C21 H25 Cl N4 O2401.026.8quant Example 289974C20 H23 Cl N4 O2387.026.6quant Example 290975C21 H25 Cl N4 O2401.028.2quant Example 291976C22 H23 Cl N4 O2411.029.2quant Example 292977C23 H25 Cl N4 O2425.029.5quant Example 293978C20 H21 Cl N6 O2413.02.211 Example 294979C21 H23 Cl N6 O2427.010.248 Example 295980C22 H25 Cl N4 O3429.028.8quant Example 296981C23 H27 Cl N4 O3443.011.954 Example 297982C22 H27 Cl N4 O2415.027.4quant Example 298983C23 H29 Cl N4 O2429.528.1quant Example 299984C21 H24 Cl N3 O3402.027.7quant Example 300985C22 H26 Cl N3 O3416.028.6quant Example 3011149C21 H28 N4 O440115.5 *38 Example 3021150C21 H28 N4 O338510.9 *28 Example 3031151C21 H25 F3 N4 O343917.3 *39
Example 3041152C21 H24 F N5 O341512.7 *30 Example 3051153C21 H24 Cl N5 O343017.5 *41 Example 3061154C22 H27 N5 O341020.6 *50 Example 3071155C19 H23 F3 N4 O442913.8 *32 Example 3081156C21 H30 N4 O440317.7 *43 Example 3091157C18 H24 N4 O3 S240912.6 *30 Example 3101158C19 H23 Cl2 N5 O344016.9 *38 Example 3111159C22 H31 N5 O646238.6 *85 Example 3121160C20 H26 Br N5 O346420.445 Example 3131289C20 H27 N5 O44035.8 *14 Example 3141290C21 H29 N5 O34006.9 *17 Example 3151291C24 H28 N4 O24052.468 Example 3161292C22 H27 Br N4 O246123.815 Example 3171293C22 H23 F4 N3 O243820.959 Example 3181294C22 H23 F4 N3 O243820.859 Example 3191295C23 H31 N3 O339817.554 Example 3201296C20 H25 N3 O2 S240418.858 Example 3211297C21 H24 F3 N3 O342418.153 Example 3221388C21 H32 N6 O34177.4 *24 Example 3231389C19 H22 N6 O439915.248 Example 3241401C23 H25 Cl N4 O24258.3 *16 Example 3251402C24 H32 N4 O54578.3 *15 Example 3261403C20 H24 N4 O235314.852 Example 3271404C20 H24 N4 O235317.060 Example 3281405C21 H26 N4 O2 S39917.354 Example 3291407C22 H28 N4 O2 S41319.157 Example 3301410C19 H24 N4 O33579.7 *59 Example 3311769C22 H26 Cl F3 N4 O551911.6 *20 Example 3321770C26 H28 Cl2 N6 O455913.1 *21 Example 3331771C26 H37 N5 O448412.7 *23 Example 3341772C28 H39 N5 O45105.5 *9 Example 3351773C28 H37 N5 O45096.2 *11 Example 3361774C28 H34 N6 O655113.6 *22 Example 3372039C19 H24 N4 O23415.2 *14 Example 3382040C22 H27 N3 O43982.0 *5 Example 3392041C23 H29 N3 O33966.2 *15 Example 3402042C25 H37 N3 O24132.6 *6 Example 3412043C24 H31 N3 O23946.8 *17 Example 3422044C25 H28 N4 O44498.7 *16 Example 3432045C26 H29 Cl N6 O452511.4 *19 Example 3442046C27 H32 N6 O45057.7 *13 Example 3452047C28 H32 N4 O448910.0 *18 Example 3462048C28 H37 N5 O55243.7 *6 Example 3472049C28 H37 N5 O45095.3 *9
* Yield of TFA salt
Example 348: Preparation of (R) -1- (4-chlorobenzyl) -3-[{N- (2-amino-5-chlorobenzoyl) glycyl} amino] pyrrolidine (Compound No. 1084)
(R) -1- (4-Chlorobenzyl) -3- (glycylamino) pyrrolidine (0.050 mmol) in CHCl ₃ (2 mL) was diluted with 2-amino-5-chlorobenzoic acid (0.060 mmol) and diiso. Treated with propylcarbodiimide (0.060 mmol). The reaction mixture is stirred for 15 h at room temperature. The mixture is loaded onto a Varian ^™ SCX column and washed with CH ₃ OH (15 mL). The product was eluted with 2N NH ₃ in CH ₃ OH (5 mL) and concentrated to (R) -1- (4-chlorobenzyl) -3-[{N- (2-amino-5-chlorobenzoyl ) Glycyl} amino] pyrrolidine (Compound No. 1084) (12.7 mg, 60%): Purity is determined by RPLC / MS (87%); ESI / MS m / e 421.0 (M ⁺ + H, C ₂₀ H ₂₂ Cl ₂ N ₄ O ₂ ).
Examples 349-361
Compounds of the invention are each synthesized according to the method of Example 348 using the corresponding reactants. If the starting amine remains, treat with isocyanatomethylated polystyrene (50 mg) in CHCl ₃ (1 mL) at room temperature, filter and concentrate to give the desired material. ESI / MS data and yields are summarized in Table 6.
Compound no.Molecular formulaESI / MS m / eYield (mg)Yield (%) Example 3491085C20 H22 Cl N5 O4432.04.119 Example 3501086C20 H23 Cl N4 O2387.07.941 Example 3511087C22 H23 Cl N4 O2411.015.073 Example 3521088C18 H20 Cl N3 O3362.012.971 Example 3531089C22 H22 Cl F N4 O2429.016.075 Example 3541090C22 H26 Cl N3 O3416.015.876 Example 3551091C21 H24 Cl2 N4 O2435.010.950 Example 3561092C21 H24 Cl N5 O4446.07.935 Example 3571093C21 H25 Cl N4 O2401.09.547 Example 3581094C23 H25 Cl N4 O2425.015.874 Example 3591095C19 H22 Cl N3 O3376.013.572 Example 3601096C23 H24 Cl F N4 O2443.011.853 Example 3611097C23 H28 Cl N3 O3430.015.170
Example 362: Preparation of (R) -1- (4-chlorobenzyl) -3-[{N- (3-bromo-4-methylbenzoyl) glycyl} amino] pyrrolidine (Compound No. 1098)
A solution of (R) -1- (4-chlorobenzyl) -3- (glycyamino) pyrrolidine (0.050 mmol) in CHCl ₃ (1.35 mL) and tert-butanol (0.15 mL) was treated with 3-bromo- Treatment with 4-methylbenzoic acid (0.060 mmol), diisopropylcarbodiimide (0.060 mmol) and HOBt (0.060 mmol). The reaction mixture is stirred for 15 h at room temperature. The mixture is loaded on a Varian ^™ SCX column and washed with CH ₃ OH / CHCl ₃ 1: 1 (12 mL) and CH ₃ OH (12 mL). The product was eluted with 2N NH ₃ in CH ₃ OH (5 mL) and concentrated to (R) -1- (4-chlorobenzyl) -3-[{N- (3-bromo-4-methyl Benzoyl) glysil} amino] pyrrolidine (Compound No. 1098) (11.6 mg, 50%): Purity is determined by RPLC / MS (94%); ESI / MS m / e 466.0 (C ₂₁ H ₂₃ BrClN ₃ O ₂ ).
Examples 363-572
The compounds of the present invention are each synthesized according to the method of Example 362 using the corresponding reactants. If necessary, a preparative TLC is provided to provide the desired material. ESI / MS data and yields are summarized in Table 7.
The following three compounds were each compound No. Obtained as a by-product of 1415, 1416, and 1417.
1419: 7.9 mg, 38% yield; ESI / MS m / e 419.0 (C ₂₀ H ₂₃ ClN ₄ O ₂ S).
1420: 7.1 mg, 36% yield; ESI / MS m / e 399.2 (C ₂₁ H ₂₆ N ₄ O ₂ S).
1421: 7.4 mg, 37% yield; ESI / MS m / e 404.2 (C ₁₉ H ₂₅ N ₅ O 3 S).
Compound no.Molecular formulaESI / MS m / eYield (mg)Yield (%) Example 3631099C20 H20 Br Cl F N3 O2470.03.113 Example 3641100C20 H20 Cl3 F N3 O2424.03.115 Example 3651101C21 H23 Cl I N3 O2512.012.549 Example 3661102C21 H23 Cl N4 O4431.27.736 Example 3671103C22 H26 Br N3 O2446.013.862 Example 3681104C21 H23 Br F N3 O2450.016.574 Example 3691105C21 H23 Cl F N3 O2404.214.773 Example 3701106C22 H26 I N3 O2492.018.575 Example 3711107C22 H26 N4 O4411.215.274 Example 3721108C20 H25 Br N4 O3449.012.857 Example 3731109C19 H22 Br F N4 O3455.016.271 Example 3741110C19 H22 Cl F N4 O3409.214.470 Example 3751111C20 H25 I N4 O3497.017.972 Example 3761112C20 H25 N5 O5416.214.972 Example 3771113C23 H27 Br Cl N3 O2494.016.165 Example 3781114C22 H24 Br Cl F N3 O2498.020.281 Example 3791115C22 H24 Cl2 F N3 O2452.218.682 Example 3801116C23 H27 Cl I N3 O2539.121.981 Example 3811117C23 H27 Cl N4 O4459.218.781 Example 3821171C21 H23 Br Cl N3 O2466.04.921 Example 3831172C22 H23 Cl N4 O3427.216.175 Example 3841173C23 H25 Cl N4 O3441.222.8quant Example 3851174C20 H22 Cl F N4 O2405.221.4quant Example 3861175C22 H26 Br N3 O2446.015.871
Example 3871176C23 H26 N4 O3407.217.687 Example 3881177C24 H28 N4 O3421.220.296 Example 3891178C21 H25 F N4 O2385.016.284 Example 3901179C21 H25 N5 O4412.22.311 Example 3911180C23 H26 N4 O2391.021.6quant Example 3921181C29 H25 Br N4 O3451.020.189 Example 3931182C21 H25 N5 O4412.213.365 Example 3941183C22 H27 N5 O4426.220.998 Example 3951184C19 H24 F N5 O3390.020.0quant Example 3961185C19 H24 N6 O5417.218.287 Example 3971186C21 H25 N5 O3396.217.689 Example 3981187C23 H27 Br Cl N3 O2494.022.190 Example 3991188C24 H27 Cl N4 O3455.217.276 Example 4001189C25 H29 Cl N4 O3469.221.190 Example 4011190C22 H26 Cl F N4 O2433.220.494 Example 4021217C21 H20 Cl2 F3 N3 O2474.038.581 Example 4031218C21 H23 Cl F N3 O2404.235.688 Example 4041219C21 H23 Cl2 N3 O2420.03.79 Example 4051220C20 H22 Cl I N4 O2513.053.0quant Example 4061221C20 H21 Cl F2 N4 O2423.038.792 Example 4071222C19 H23 Cl N4 O2375.233.690 Example 4081223C26 H26 Cl N3 O2 S496.043.788 Example 4091224C20 H21 Cl N4 O5433.040.694 Example 4101225C22 H23 Cl F3 N3 O2454.218.441 Example 4111226C22 H26 F N3 O2384.017.145 Example 4121227C22 H26 Cl N3 O2400.217.544 Example 4131228C21 H25 I N4 O2493.023.347 Example 4141229C21 H24 F2 N4 O2403.218.446 Example 4151230C20 H26 N4 O2355.215.744 Example 4161231C27 H29 N3 O2 S476.020.988 Example 4171232C21 H24 N4 O5413.019.996 Example 4181233C20 H22 Cl F3 N4 O3459.019.485 Example 4191234C20 H25 F N4 O3389.017.892 Example 4201235C20 H25 Cl N4 O3405.218.792 Example 4211236C19 H24 I N5 O3498.023.996 Example 4221237C19 H23 F2 N5 O3408.219.093 Example 4231238C18 H25 N5 O3360.016.391 Example 4241239C25 H28 N4 O3 S481.221.489 Example 4251240C19 H23 N5 O6418.019.995 Example 4261241C23 H24 Cl2 F3 N3 O2502.022.590 Example 4271242C23 H27 Cl F N3 O2432.221.298 Example 4281243C23 H27 Cl2 N3 O2448.021.696 Example 4291244C22 H26 Cl I N4 O2541.026.498 Example 4301245C22 H25 Cl F2 N4 O2451.021.394 Example 4311246C21 H27 Cl N4 O2403.219.496 Example 4321247C28 H30 Cl N3 O2 S524.024.794 Example 4331248C22 H25 Cl N4 O5461.020.790 Example 4341249C20 H20 Cl2 N4 O4451.07.433 Example 4351250C21 H23 Cl N4 O4431.215.572 Example 4361251C19 H22 Cl N5 O5436.022.9quant Example 4371252C23 H28 Cl N3 O2414.217.986
Example 4381253C24 H31 N3 O2394.215.880 Example 4391254C22 H30 N4 O3399.217.387 Example 4401255C20 H22 Br Cl N4 O2467.021.391 Example 4411256C21 H25 Br N4 O2445.020.793 Example 4421257C19 H24 Br N5 O3450.021.897 Example 4431258C21 H25 Cl N4 O2401.218.190 Example 4441259C19 H24 Cl N5 O3406.020.199 Example 4451260C23 H29 N3 O3396.216.885 Example 4461261C23 H30 Cl N3 O3432.219.892 Example 4471262C24 H33 N3 O3412.217.485 Example 4481263C22 H32 N4 O4417.218.790 Example 4491264C25 H26 Cl N3 O3452.229.1quant Example 4501265C26 H29 N3 O3432.218.184 Example 4511266C24 H28 N4 O4437.219.388 Example 4521267C23 H22 Cl F3 N4 O3495.220.683 Example 4531268C21 H23 Cl2 N3 O3436.017.580 Example 4541269C20 H21 Br Cl N3 O3468.019.282 Example 4551270C20 H21 Cl2 N3 O3422.217.382 Example 4561271C20 H20 Cl F N4 O4435.017.179 Example 4571272C24 H25 F3 N4 O3475.221.791 Example 4581273C22 H26 Cl N3 O3416.217.886 Example 4591274C21 H24 Br N3 O3448.019.587 Example 4601275C21 H24 Cl N3 O3402.216.783 Example 4611276C21 H23 F N4 O4415.218.187 Example 4621277C22 H24 F3 N5 O4480.220.385 Example 4631278C20 H25 Cl N4 O4421.218.688 Example 4641279C19 H23 Br N4 O4451.021.394 Example 4651280C19 H23 Cl N4 O4407.219.194 Example 4661281C19 H23 F N4 O4420.219.191 Example 4671282C25 H26 Cl F3 N4 O3523.215.096 Example 4681283C23 H27 Cl2 N3 O3464.212.253 Example 4691284C22 H25 Br Cl N3 O3496.024.197 Example 4701285C22 H25 Cl2 N3 O3450.221.897 Example 4711321C20 H20 Br Cl2 N3 O2486.05.121 Example 4721322C21 H23 Cl2 N3 O2420.010.550 Example 4731323C20 H20 Cl2 I N3 O2532.07.127 Example 4741324C21 H24 Cl N3 O3402.222.2quant Example 4751325C27 H26 Cl N3 O3476.022.293 Example 4761326C20 H21 Cl I N3 O3514.026.9quant Example 4771327C21 H25 Cl N4 O2401.224.2quant Example 4781328C21 H23 Br Cl N3 O2466.023.199 Example 4791329C22 H26 Cl N3 O2400.216.482 Example 4801330C21 H23 Cl I N3 O2512.220.881 Example 4811331C21 H24 N3 O3382.219.6quant Example 4821332C28 H29 N3 O3456.221.193 Example 4831333C21 H24 I N3 O3494.025.3quant Example 4841334C22 H28 N4 O2381.219.0quant Example 4851335C19 H22 Br Cl N4 O3471.025.8quant Example 4861336C20 H25 Cl N4 O3405.218.591 Example 4871337C19 H22 Cl I N4 O3517.023.189 Example 4881338C20 H26 N4 O4387.220.6quant
Example 4891339C26 H28 N4 O4461.223.7quant Example 4901340C19 H23 I N4 O4499.028.2quant Example 4911341C20 H26 N4 O4386.020.5quant Example 4921342C22 H24 Br Cl2 N4 O2514.027.2quant Example 4931343C23 H27 Cl2 N3 O2448.021.495 Example 4941344C22 H24 Cl2 I N3 O2560.027.096 Example 4951345C23 H28 Cl N3 O3430.223.8quant Example 4961346C22 H25 Cl I N3 O3542.029.4quant Example 4971347C19 H22 Cl N3 O2 S392.016.943 Example 4981348C20 H25 N3 O2 S372.26.919 Example 4991349C18 H24 N4 O3 S377.28.143 Example 5001350C21 H26 Cl N3 O2 S420.013.062 Example 5011351C22 H24 Br Cl N4 O3509.25.010 Example 5021352C23 H27 Br N4 O3489.23.615 Example 5031353C21 H26 Br N5 O4494.02.811 Example 5041354C24 H28 Br Cl N4 O3537.25.219 Example 5051355C21 H22 Cl N5 O2412.025.5quant Example 5061356C22 H25 N5 O2392.016.584 Example 5071357C20 H24 N6 O3397.219.9quant Example 5081358C23 H26 Cl N5 O2440.221.899 Example 5091368C21 H20 Cl2 F3 N3 O2474.018.478 Example 5101369C24 H24 Cl F6 I N3 O4568.024.185 Example 5111370C18 H19 Br Cl N3 O2 S458.019.485 Example 5121371C26 H26 Cl N3 O4 S512.222.186 Example 5131372C26 H26 Cl N3 O2448.019.185 Example 5141373C22 H23 Cl F3 N3 O2454.216.271 Example 5151374C25 H27 F6 I N3 O4548.222.181 Example 5161375C19 H22 Br N3 O2 S436.017.178 Example 5171376C27 H29 N3 O4 S492.019.479 Example 5181377C27 H29 N3 O2428.218.185 Example 5191378C20 H22 Cl F3 N4 O3459.017.375 Example 5201379C23 H26 F6 I N4 O5553.221.076 Example 5211380C17 H21 Br N4 O3 S443.016.474 Example 5221381C25 H28 N4 O5 S497.018.474 Example 5231382C25 H28 N4 O3433.217.380 Example 5241383C23 H24 Cl2 F3 N3 O2502.020.080 Example 5251384C20 H23 Br Cl N3 O2 S486.021.087 Example 5261385C28 H30 Cl N3 O4 S540.223.888 Example 5271386C28 H30 Cl N3 O2476.020.084 Example 5281411C22 H24 Cl2 N4 O3463.00.42 Example 5291412C23 H27 Cl N4 O2443.01.36 Example 5301413C21 H26 Cl N5 O4448.01.15 Example 5311414C24 H28 Cl2 N4 O3491.00.83 Example 5321415C21 H22 Cl N5 O2 S444.06.831 Example 5331416C22 H25 N5 O2 S424.04.823 Example 5341417C20 H24 N6 O3 S429.24.521 Example 5351418C23 H26 Cl N5 O2 S472.010.444 Example 5361423C27 H26 Cl N3 O3476.023.9quant Example 5371424C27 H29 N3 O4 S456.228.0quant Example 5381425C26 H28 N4 O4461.222.397 Example 5391426C29 H30 Cl N3 O3504.226.8quant
Example 5401583C21 H22 Cl F3 N4 O2455.014.664 Example 5411584C21 H22 Cl F3 N4 O3471.017.474 Example 5421585C19 H20 Br Cl N4 O2453.015.669 Example 5431586C19 H20 Cl2 N4 O2407.22.311 Example 5441587C26 H26 Cl N3 O3464.015.466 Example 5451588C20 H23 Cl N4 O2387.014.877 Example 5461589C22 H25 F3 N4 O2435.211.151 Example 5471590C20 H25 F3 N4 O3451.216.372 Example 5481591C20 H23 Br N4 O2433.015.471 Example 5491592C20 H23 Cl N4 O2387.015.681 Example 5501593C27 H29 N3 O3444.214.867 Example 5511594C20 H24 F3 N5 O3440.216.274 Example 5521595C20 H24 F3 N5 O4456.215.468 Example 5531596C18 H22 Br N5 O3436.015.672 Example 5541597C18 H22 Cl N5 O3391.814.473 Example 5551598C25 H28 N4 O4449.215.971 Example 5561599C19 H25 N5 O3372.215.885 Example 5571606C21 H21 Cl F3 N3 O2 S472.017.072 Example 5581607C21 H21 Cl F3 N3 O2 S452.215.368 Example 5591608C20 H23 F3 N4 O3 S457.215.970 Example 5601660C21 H22 Br F3 N4 O2501.019.076 Example 5611661C21 H22 Br F3 N4 O3517.016.263 Example 5621662C20 H21 Br F2 N4 O2469.015.165 Example 5631663C20 H22 Br Cl N4 O2467.014.562 Example 5641692C20 H23 Br2 N3 O35147.328 Example 5651693C22 H26 F2 N4 O241716.278 Example 5661694C22 H27 F N4 O239921.8quant Example 5671695C22 H27 Br N4 O245924.5quant Example 5681696C22 H27 I N4 O250727.4quant Example 5691697C22 H27 Cl N4 O241522.1quant Example 5701698C23 H27 F3 N4 O346524.3quant Example 5711699C23 H27 F3 N4 O244925.3quant Example 5721700C22 H25 Br Cl N3 O248017.874
For example, compound No. 1583 shows the following NMR spectra: ¹ H NMR (400 MHz, CD ₃ OD) δ 1.64-1.72 (m, 1H), 2.20-2.30 (m, 1H), 2.41-2.51 (m, 2H), 2.71-2.78 (m, 2H), 3.59 (dd, J = 15.4, 12.9 Hz, 2H), 3.94 (s, 2H), 4.35-4.41 (m, 1H), 6.82 (d, J = 8.6 Hz, 1H), 7.29 ( s, 4H), 7.40 (dd, J = 8.6, 1.7 Hz, 1H), 7.85 (d, J = 0.96 Hz, 1H).
Reference Example 4: Preparation of (S) -3- [N- {3- (trifluoromethyl) benzoyl} glycyl] aminopyrrolidine
(S) -1- (4-chlorobenzyl) -3- [N- {3- (trifluoromethyl) benzoyl} glycyl] aminopyrrolidine (2.93 in 5% HCO ₂ H / methanol (70 mL) g, 6.66 mmol) and a suspension of Pd (OH) ₂ are stirred at 60 ° C. for 3 h. The Pd catalyst is filtered off through Celite and the filtrate is concentrated. To the residue is added 2N aqueous NaOH solution (100 mL) and the mixture is extracted with ethyl acetate (100 mL × 3). The combined extracts are washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. Column chromatography (SiO ₂ , AcOEt / MeOH / Et ₃ N = 85/10 / 5-60 / 30/5) gave (S) -3- [N- {3- (trifluoromethyl) benzoyl as oil. } Glycyl] aminopyrrolidine (1.70 g, 81%): ¹ H NMR (CDCl ₃ , 270 MHz) δ 1.76 (d, J = 7.3 Hz, 1H), 2.07-2.25 (m, 1H), 2.81-1.98 (m, 2H), 3.02-3.11 (m, 2H), 4.12 (s, 2H), 4.41 (br, 1H), 6.90 (br, 1H), 7.45 (br, 1H), 7.58 (dd, J = 7.3 and 7.3 Hz, 1H), 7.77 (d, J = 7.3 Hz, 1H), 8.02 (d, J = 7.3 Hz, 1H), 8.11 (s, 1H); ESI / MS m / e 316.0 (M ⁺ + H, C ₁₄ H ₁₆ F ₃ N ₃ O ₂ ).
(R) -3- [N- {3- (trifluoromethyl) benzoyl} glycyl] aminopyrrolidine is also prepared according to the above method using the corresponding reactant: 1.49 g, 68%; The product shows the same ¹ H NMR and ESI / MS as that of the (S) -isomer.
(R) -3- [N- {2-amino-5- (trifluoromethyl) benzoyl} glycyl] aminopyrrolidine is also prepared according to the above method using the corresponding reactant: 316 mg, 93 %; ESI / MS m / e 331.2 (M ⁺ + H, C ₁₄ H ₁₇ F ₃ N ₄ O _2).
(R) -3- [N- {2- (tert-butoxycarbonylamino) -5- (trifluoromethoxy) benzoyl} glycyl] aminopyrrolidine can also be added to the process using the corresponding reactants. Prepared according to: quant: ¹ H NMR (CDCl ₃ , 400 MHz) δ 1.51 (s, 9H), 1.60-1.70 (m, 2H), 2.10-2.25 (m, 1H), 2.80-2.88 (m, 1H), 2.89-2.98 (m, 1H), 3.04-3.18 (m, 2H), 4.05 (d, J = 4.9 Hz, 2H), 4.43 (br, 1H), 6.15 (br, 1H), 7.03 (br, 1H) , 7.32 (d, J = 9.3 Hz, 1H), 7.38 (s, 1H), 8.42 (d, J = 9.3 Hz, 1H).
Example 573: (R) -3-[{N- (2- (tert-butoxycarbonylamino) -5-trifluoromethylbenzoyl) glycyl} amino] -1- (4-chlorobenzyl) pi Preparation of Lolidine
A solution of (R) -1- (4-chlorobenzyl) -3- (glycyamino) pyrrolidine (5.0 g, 18.7 mmol) in dichloromethane (100 mL) was added Et ₃ N (2.9 mL, 20.5 mmol). , 2- (tert-butoxycarbonylamino) -5- (trifluoromethyl) benzoic acid (6.27 g, 20.5 mmol), EDCI (3.9 g, 20.5 mmol) and HOBt (2.8 g, 20.5 mmol) . The reaction mixture is stirred overnight at room temperature. To the reaction mixture is added 2N aqueous NaOH solution (80 mL) and the mixture is extracted with dichloromethane. The extract is dried over anhydrous Na ₂ S0 ₄ , filtered and evaporated. Column chromatography (SiO ₂ , hexane / ethyl acetate = 1 / 1-1 / 4) was carried out to give (R) -3-[{N- (2- (tert-butoxycarbonylamino) -5 as a white acid amorphous solid. -Trifluoromethylbenzoyl) glyciyl} amino] -1- (4-chlorobenzyl) pyrrolidine (9.41 g, 91%) is provided: ESI / MS m / e 555.2 (M ⁺ + H, C ₂₆ H ₃₀ ClF ₃ N ₄ O ₄ ).
Reference Example 5: Preparation of (R) -3-[{N- (2- (tert-butoxycarbonylamino) -5-trifluoromethylbenzoyl) glycyl} amino] pyrrolidine
(R) -3-[{N- (2- (tert-butoxycarbonylamino) -5-trifluoromethylbenzoyl) glycyl} amino] -1- (4-chlorobenzyl) pyrrolidine (6.3 g, 11.4 mmol), Pd (OH) ₂ (1.68 g), HCO ₂ H (3.7 mL) and methanol (80 mL) are stirred overnight at 50 ° C. After the mixture is cooled to room temperature, the Pd catalyst is filtered off through celite and the filtrate is concentrated. Column chromatography (SiO ₂ , AcOEt, AcOEt / MeOH = 5 / 1-4 / 1) gave (R) -3-[{N- (2- (tert-butoxycarbonylamino) -5 as a white solid. -Trifluoromethylbenzoyl) glyciyl} amino] pyrrolidine (4.42 g, 90%): ¹ H NMR (CDCl ₃ , 400 MHz) δ 1.48 (s, 9H), 2.0-2.4 (m, 2H ), 3.42-3.71 (m, 5H), 4.00-4.22 (m, 2H), 4.56 (br, 1H), 7.48 (d, J = 9.0 Hz, 1H), 7.93 (s, 1H), 8.17 (br, 1H), 8.33 (d, J = 9.0 Hz, 1H), 8.45 (br, 1H).
Example 574: Preparation of (S) -1-benzyl-3- [N- {3- (trifluoromethyl) benzoyl} glycyl] aminopyrrolidine (Compound No. 239)
Solution of (S) -3- [N- {3- (trifluoromethyl) benzoyl} glycyl] aminopyrrolidine (0.060 mmol) in CH ₃ CN (1.1 mL) and (piperidinomethyl) polystyrene ( 2.6-2.8 mmol / g, 30 mg) is added to a solution of benzyl bromide (0.050 mmol) in CH ₃ CN (0.4 mL). The reaction mixture is stirred at 45 ° C. for 5 h. After the mixture is cooled to room temperature, the resin is removed by filtration and the filtrate is concentrated. The residue is dissolved in CH ₃ CN (1.0 mL) and phenyl isocyanate (0.008 mL, 0.05 mmol) is added. The mixture is stirred for 1 h at room temperature, loaded on a Varian ^™ SCX column and washed with CH ₃ OH (15 mL). The product was eluted with 2N NH ₃ in CH ₃ OH (6 mL) and concentrated to give (S) -1-benzyl-3- [N- {3- (trifluoromethyl) benzoyl} gylsil] aminopy. Provides Lolidine (Compound No. 239) (9.0 mg, 44%). Purity is determined by RPLC / MS (99%); ESI / MS m / e 406.0 (M ⁺ + H, C ₂₁ H ₂₂ F ₃ N ₃ O ₂ ).
Example 575: Preparation of (R) -1- (4-butylbenzyl) -3-[{N- (3-trifluoromethylbenzoyl) glycyl} amino] pyrrolidine (Compound No. 1648)
(R) -3- [N- {3- (trifluoromethyl) benzoyl} glycyl] aminopyrrolidine (0.050 mmol), 4-butylbenzaldehyde (0.18 mmol), NaBH ₃ CN (0.23 mmol) and methanol To the mixture of (1.85 mL) is added acetic acid (0.060 mL). The reaction mixture is stirred at 60 ° C. for 12 h. The mixture is cooled to room temperature, loaded on a Varian ^™ SCX column and washed with CH ₃ OH (15 mL). The product was eluted with 2N NH ₃ in CH ₃ OH (5 mL) and concentrated to give (R) -1- (4-butylbenzyl) -3-[{N- (3-trifluoromethylbenzoyl) Lysyl} amino] pyrrolidine (Compound No. 1648) (20.6 mg, 89%): Purity is determined by RPLC / MS (91%); ESI / MS m / e 462.2 (M ⁺ + H, C ₂₅ H ₃₀ F ₃ N ₃ O ₂ ).
Examples 576-738
The compounds of the present invention are synthesized according to the method of Example 574 or 575 using the corresponding reactants respectively. Preparative TLC or chromatography (HPLC-C ₁₈ ), if necessary, to provide the desired material. ESI / MS data and yields are summarized in Table 8.
Compound no.Molecular formulaESI / MS m / eYield (mg)Yield (%) Example 576240C21 H21 F4 N3 O2424.010.248 Example 577241C21 H21 Cl F3 N3 O2440.012.155 Example 578242C21 H20 Cl2 F3 N3 O2474.013.959 Example 579243C21 H20 Cl2 F3 N3 O2474.013.858 Example 580244C22 H24 F3 N3 O2420.013.162 Example 581245C21 H21 F4 N3 O2424.011.956 Example 582246C21 H21 Cl F3 N3 O2440.08.539 Example 583247C21 H20 Cl2 F3 N3 O2474.010.544 Example 584248C22 H4 CF3 N3 O2436.011.051 Example 585249C22 H21 Cl F6 N3 O2474.012.854 Example 586250C22 H24 F3 N3 O2420.011.052 Example 587251C21 H21 F4 N3 O2424.013.564 Example 588252C22 H24 F3 N3 O3436.011.854 Example 589253C22 H24 F3 N3 O2420.011.153 Example 590254C21 H20 Cl F3 N4 O4485.02.410 Example 591255C21 H21 F3 N4 O4451.012.254
Example 592256C21 H21 F3 N4 O4451.011.451 Example 593257C22 H21 F6 N3 O2474.011.147 Example 594258C24 H26 F3 N3 O4478.015.364 Example 595259C22 H23 Cl F3 N3 O2420.06.431 Example 596260C21 H20 Cl2 F3 N3 O2474.012.151 Example 597261C22 H21 Cl F6 N3 O2474.013.657 Example 598262C21 H21 Br F3 N3 O2484.015.263 Example 599263C21 H21 Br F3 N3 O2484.014.560 Example 600264C27 H26 F3 N3 O3498.09.337 Example 601265C21 H21 Br F3 N3 O2484.011.648 Example 602266C22 H22 F3 N3 O4450.08.940 Example 603267C22 H24 F3 N3 O3436.010.347 Example 604268C23 H25 F3 N4 O3463.06.327 Example 605269C22 H24 F3 N3 O4 S484.08.033 Example 606270C23 H24 F3 N3 O4464.08.938 Example 607271C21 H20 F5 N3 O2442.06.128 Example 608272C21 H22 F3 N3 O3422.013.659 Example 609273C22 H21 F3 N4 O2431.012.659 Example 610274C22 H21 F3 N4 O2431.07.736 Example 611275C22 H21 F3 N4 O2431.012.759 Example 612276C21 H20 F5 N3 O2442.011.753 Example 613277C27 H26 F3 N3 O2482.09.539 Example 614278C23 H24 F3 N3 O4464.013.056 Example 615279C22 H21 F6 N3 O3490.010.442 Example 616280C22 H21 F6 N3 O3490.012.049 Example 617281C22 H22 F3 N3 O4450.04.922 Example 618282C25 H30 F3 N3 O2462.0412.052 Example 619283C20 H23 F3 N4 O3425.08.138 Example 620284C27 H25 Cl F3 N3 O2516.04.819 Example 621285C21 H22 F3 N3 O2406.04.824 Example 622286C21 H21 F4 N3 O2424.04.521 Example 623287C21 H21 Cl F3 N3 O2440.05.826 Example 624288C21 H20 Cl2 F3 N3 O2474.08.134 Example 625289C21 H20 Cl2 F3 N3 O2474.08.034 Example 626290C22 H24 F3 N3 O2420.06.029 Example 627291C21 H21 F4 N3 O2424.06.229 Example 628292C21 H21 Cl F3 N3 O2440.04.520 Example 629293C21 H20 Cl2 F3 N3 O2474.05.122 Example 630294C22 H24 CF3 N3 O3436.04.219 Example 631295C22 H21 Cl F6 N3 O2474.06.025 Example 632296C22 H24 F3 N3 O2420.04.321 Example 633297C21 H21 F4 N3 O2424.08.239 Example 634298C22 H24 F3 N3 O3436.012.256 Example 635299C22 H24 F3 N3 O2420.08.139 Example 636300C21 H20 Cl F3 N4 O4485.013.757 Example 637301C21 H21 F3 N4 O4451.015.167 Example 638302C21 H21 F3 N4 O4451.016.674 Example 639303C22 H21 F6 N3 O2474.012.653 Example 640304C24 H26 F3 N3 O4478.014.561 Example 641305C22 H23 Cl F3 N3 O2421.08.437 Example 642306C21 H20 Cl2 F3 N3 O2474.013.557
Example 643307C22 H21 Cl F6 N3 O2474.03.716 Example 644308C21 H21 Br F3 N3 O2484.07.230 Example 645309C21 H21 Br F3 N3 O2484.06.728 Example 646310C27 H26 F3 N3 O3498.04.217 Example 647311C21 H21 Br F3 N3 O2484.06.326 Example 648312C22 H22 F3 N3 O4450.02.411 Example 649313C22 H24 F3 N3 O3436.01.99 Example 650314C23 H25 F3 N4 O3463.05.022 Example 651315C22 H24 F3 N3 O4 S484.02.510 Example 652316C23 H24 F3 N3 O4464.03.314 Example 653317C21 H20 F5 N3 O2442.04.520 Example 654318C21 H22 F3 N3 O3422.07.934 Example 655319C22 H21 F3 N4 O2431.06.530 Example 656320C22 H21 F3 N4 O2431.014.266 Example 657321C22 H21 F3 N4 O2431.014.969 Example 658322C21 H20 F5 N3 O2442.013.662 Example 659323C27 H26 F3 N3 O2482.03.916 Example 660324C23 H24 F3 N3 O4464.015.266 Example 661325C22 H21 F6 N3 O3490.016.166 Example 662326C22 H21 F6 N3 O3490.013.656 Example 663327C22 H22 F3 N3 O4450.05.424 Example 664328C25 H34 F3 N3 O2462.010.947 Example 665329C20 H23 F3 N4 O3425.012.057 Example 666986C27 H25 Cl F3 N3 O2516.01.56 Example 6671118C28 H27 F3 N4 O352521.562 Example 6681119C22 H24 F3 N3 O2 S45216.957 Example 6691120C23 H26 F3 N3 O446620.567 Example 6701121C22 H23 F3 N4 O446516.855 Example 6711122C28 H36 F3 N3 O250421.063 Example 6721123C25 H23 Br F3 N3 O253426.675 Example 6731124C29 H29 F3 N4 O544121.373 Example 6741133C23 H26 F3 N3 O446733.684 Example 6751134C24 H28 F3 N3 O549634.882 Example 6761135C22 H21 F3 N4 O649532.677 Example 6771136C23 H24 F3 N3 O548036.689 Example 6781137C22 H21 Br F3 N3 O452930.869 Example 6791138C24 H26 F3 N3 O244632.786 Example 6801139C22 H24 F3 N3 O242018.651 Example 6811140C21 H20 F3 N5 O649620.549 Example 6821141C25 H24 F3 N3 O245622.558 Example 6831142C25 H24 F3 N3 O245621.655 Example 6841143C35 H34 F3 N3 O461827.353 Example 6851144C23 H26 F3 N3 O446625.564 Example 6861145C23 H25 F3 N4 O651138.088 Example 6871146C28 H28 F3 N3 O351238.389 Example 6881147C23 H25 F3 N4 O346327.162 Example 6891148C27 H26 F3 N3 O248222.457 Example 6901161C22 H24 F3 N3 O445213.558 Example 6911162C24 H28 F3 N3 O346416.770 Example 6921163C22 H23 F4 N3 O345415.868 Example 6931164C23 H26 F3 N3 O345015.768
Example 6941165C23 H24 F3 N3 O446416.368 Example 6951166C22 H23 Br F3 N3 O351315.057 Example 6961168C17 H17 Cl F3 N5 O2 S4486.9 *23 Example 6971169C20 H22 F3 N5 O3 S4701.7 *6 Example 6981170C22 H22 F3 N5 O24462.3 *8 Example 6991286C26 H33 F3 N4 O350725.3 *51 Example 7001287C21 H20 F3 N5 O64964.0 *8 Example 7011288C2 H24 F3 N3 O44523.6 *13 Example 7021298C23 H25 Br F3 N3 O454428.4quant Example 7031299C24 H28 F3 N3 O54961.46 Example 7041300C23 H26 F3 N3 O44667.333 Example 7051301C24 H28 F3 N3 O549612.653 Example 7061302C24 H28 F3 N3 O346424.5quant Example 7071303C23 H25 Br F3 N3 O454422.286 Example 7081304C29 H30 F3 N3 O454228.6quant Example 7091305C26 H26 F3 N3 O348635.4quant Example 7101306C24 H28 F3 N3 O44808.135 Example 7111307C23 H26 F3 N3 O548227.9quant Example 7121308C23 H24 F3 N3 O34485.928 Example 7131309C23 H25 F3 I N3 O459224.085 Example 7141310C22 H24 F3 N3 O44523.416 Example 7151311C22 H22 F3 N3 O44503.416 Example 7161312C21 H21 F2 I N3 O253218.172 Example 7171313C21 H21 Br F3 N3 O248417.476 Example 7181314C19 H19 F3 N4 O4 S45716.877 Example 7191315C20 H22 F3 N3 O341013.670 Example 7201316C22 H20 Cl F6 N3 O250818.677 Example 7211317C21 H20 Cl F2 N4 O448517.074 Example 7221318C21 H20 Cl F4 N3 O245817.078 Example 7231319C21 H20 Cl F4 N3 O245817.681 Example 7241320C21 H20 Br F4 N3 O250218.577 Example 7251390C26 H32 F3 N3 O247616.151 Example 7261391C23 H26 F3 N3 O243420.076 Example 7271392C22 H23 Cl F3 N3 O245420.067 Example 7281393C23 H26 F3 N3 O243420.170 Example 7291394C22 H23 F3 N4 O446518.460 Example 7301395C23 H24 F3 N3 O243221.475 Example 7311396C26 H26 F3 N3 O247010.466 Example 7321397C21 H20 Br2 F3 N3 O256214.554 Example 7331398C22 H22 Cl2 F3 N3 O248810.847 Example 7341399C22 H22 Cl2 F3 N3 O24889.440 Example 7351400C22 H23 Cl F3 N3 O245419.188 Example 7361614C22 H21 F6 N3 S506.024.296 Example 7372050C20 H22 F3 N3 O2 S4266.030 Example 7382051C21 H23 F3 N4 O24216.532
* Yield of TFA salt
Examples 739-748
The compounds of the present invention are each synthesized according to the method of Example 738 using the corresponding reactants. If necessary, preparative TLC is provided to provide the desired material. ESI / MS data and yields are summarized in Table 9.
Compound no.Molecular formulaESI / MS m / eYield (mg)Yield (%) Example 7391650C24 H28 F3 N3 O2448.020.491 Example 7401706C23 H25 F3 N4 O3463.23.711 Example 7411707C22 H25 F3 N4 O2 S467.010.329 Example 7421708C23 H27 F3 N4 O2449.211.434 Example 7431709C24 H29 F3 N4 O2463.215.244 Example 7441775C22 H25 F3 N4 O4467.29.226.3 Example 7451776C22 H25 F3 N4 O4467.28.925.4 Example 7461787C24 H29 F3 N4 O2463.25.616.1 Example 7471802C23 H27 F3 N4 O4481.211.732.5 Example 7481803C22 H25 F3 N4 O3451.29.628.4
Example 749: (R) -3-[{N- (2-amino-5-trifluoromethoxybenzoyl) glycyl} amino] -1- (3-hydroxy-4-methoxybenzyl) pyrrolidine Preparation of (Compound No. 1896)
(R) -3- [N- {2- (tert-butoxycarbonylamino) -5- (trifluoromethoxy) benzoyl} glycyl] aminopyrrolidine (0.050 mmol), 3-hydroxy-4 To a mixture of methoxybenzaldehyde (0.060 mmol), NaBH ₃ CN (0.15 mmol) and methanol (1.3 mL) is added acetic acid (0.050 mL). The reaction mixture is stirred at 60 ° C. for 8 h. The mixture is cooled to room temperature, loaded on a Varian ^™ SCX column and washed with CH ₃ OH (10 mL). The product is eluted with 2N NH ₃ in CH ₃ OH (5 mL) and concentrated. To the resulting material is added 4N HCl in 1,4-dioxane and the solution is stirred overnight at room temperature. Concentrated and preparative TLC to give (R) -3-[{N- (2-amino-5-trifluoromethoxybenzoyl) glyciyl} amino] -1- (3-hydroxy-4-methoxybenzyl) Pyrrolidine (Compound No. 1896) (9.1 mg, 38%) is provided: Purity is determined by RPLC / MS (93%); ESI / MS m / e 483 (M ⁺ + H, C ₂₂ H ₂₅ F ₃ N ₄ O ₅ ).
Examples 750-757
The compounds of the present invention are each synthesized according to the method of Example 749 using the corresponding reactants. ESI / MS data and yields are summarized in Table 10.
Compound no.Molecular formulaESI / MS m / eYield (mg)Yield (%) Example 7501897C22 H25 F3 N4 O3 S48322.794.1 Example 7511898C23 H27 F3 N4 O346512.252.5 Example 7521899C24 H29 F3 N4 O347914.460.2 Example 7531900C22 H25 F3 N4 O54832.610.8 Example 7541901C24 H29 F3 N4 O347914.560.6 Example 7551902C23 H25 F3 N4 O447912.050.2 Example 7561915C23 H27 F3 N4 O5467.22.56.7 Example 7571916C22 H25 F3 N4 O4467.23.18.9
Example 758: (R) -3-[{N- (2-amino-5- (trifluoromethyl) benzoyl) glycyl} amino] -1- (4-vinylbenzyl) pyrrolidine (Compound No. 1701)
(R) -3-[{N- (2-amino-5- (trifluoromethyl) benzoyl) gylsil} amino] pyrrolidine (0.050 mmol), 4-vinylbenzyl chloride (9.9 mg, 0.065 mmol) A mixture of, piperidinomethylpolystyrene (60 mg), acetonitrile (1.0 mL) and chloroform (0.30 mL) is stirred at 50 ° C. for 12 h. The reaction mixture is cooled, loaded on a Varian ^™ SCX column and washed with CH ₃ OH (15 mL). The product was melted using 2N NH ₃ in CH ₃ OH (5 mL) and concentrated to give (R) -3-[{N- (2-amino-5- (trifluoromethyl) benzoyl) glyciyl} amino ] -1- (4-vinylbenzyl) pyrrolidine (Compound No. 1701) (19.6 mg, 88%): Purity is determined by RPLC / MS (92%); ESI / MS m / e 547.2 ( M + + H, C 23 H 25 ClF 3 N 4 O 2).
Examples 759-762
The compounds of the present invention are each synthesized according to the method of Example 758 using the corresponding reactants. If necessary, preparative TLC is provided to provide the desired material. ESI / MS data and yields are summarized in Table 11.
Compound no.Molecular formulaESI / MS m / eYield (mg)Yield (%) Example 7591702C22 H25 F3 N4 O3451.25.324 Example 7601703C22 H23 F3 N4 O4465.25.022 Example 7611704C21 H23 F3 N4 O3437.220.996 Example 7621705C21 H21 Cl2 F3 N4 O2489.29.338
Example 763: (R) -3-[{N- (2-amino-5- (trifluoromethoxy) benzoyl) glycyl} amino] -1- (2,4-dichlorobenzyl) pyrrolidine (compound No. 1905)
(R) -3-[{N- (2-amino-5- (trifluoromethoxy) benzoyl) gylsil} amino] pyrrolidine (0.050 mmol), 2,4-dichlorobenzyl chloride (0.060 mmol), A mixture of piperidinomethylpolystyrene (60 mg), acetonitrile (0.8 mL) and chloroform (0.5 mL) is stirred at 60 ° C. for 12 h. The reaction mixture is cooled, loaded on a Varian ^™ SCX column and washed with 50% CHCl ₃ / CH ₃ OH (10 mL) and CH ₃ OH (10 mL). The product is eluted with 2N NH ₃ in CH ₃ OH (5 mL) and concentrated. To the resulting material is added 4N HCl in 1,4-dioxane (2 mL) and the solution is stirred overnight at room temperature. Concentrate, preparative TLC to give (R) -3-[{N- (2-amino-5- (trifluoromethoxy) benzoyl) glycyl} amino] -1- (2,4-dichlorobenzyl) pyrroli Dean (Compound No. 1905) (17.6 mg, 70%): Purity is determined by RPLC / MS (93%); ESI / MS m / e 505 (M ⁺ + H, C ₂₁ H ₂₁ Cl ₂ F ₃ N ₄ O ₃ ).
Examples 764-770
The compounds of the present invention are each synthesized according to the method of Example 763 using the corresponding reactants. ESI / MS data and yields are summarized in Table 12.
Compound no.Molecular formulaESI / MS m / eYield (mg)Yield (%) Example 7641906C22 H23 F3 N4 O54819.439.1 Example 7651907C21 H23 F3 N4 O44537.533.2 Example 7661908C22 H25 F3 N4 O44677.733.0 Example 7672180C22 H24 Cl F3 N4 O24691.326 Example 7682181C23 H25 F3 N6 O34914.352 Example 7692182C19 H22 F3 N5 O2 S4427.051 Example 7701909C23 H25 F3 N4 O34638.737.6
Example 771: (R) -3-[{N- (2-amino-5-trifluoromethoxybenzoyl) glycyl} amino] -1- (2-amino-4-chlorobenzyl) pyrrolidine (compound No. 1921)
(R) -3-[{N- (2-amino-5-trifluoromethoxybenzoyl) glycyl} amino] pyrrolidine (0.050 mmol), 4-chloro-2-nitrobenzyl chloride (0.050 mmol), A mixture of piperidinomethylpolystyrene (60 mg), acetonitrile (1.0 mL) and chloroform (0.7 mL) is stirred overnight at 50 ° C. The reaction mixture is cooled, loaded on a Varian ^™ SCX column and washed with 50% CHCl ₃ / CH ₃ OH (10 mL) and CH ₃ OH (10 mL). The product is eluted with 2N NH ₃ in CH ₃ OH (5 mL) and concentrated. To the resulting product is added ethanol (3 mL) and 10% Pd-C (15 mg) and the mixture is stirred under H ₂ at room temperature for 1.5 h. Filtration, concentration, preparative TLC gave (R) -3-[{N- (2-amino-5-trifluoromethoxybenzoyl) glyciyl} amino] -1- (2-amino-4-chlorobenzyl ) Pyrrolidine (Compound No. 1921) (2.2 mg, 6%): Purity was determined by RPLC / MS (81%); ESI / MS m / e 486.2 (M ⁺ + H, C ₂₁ H ₂₃ ClF ₃ N ₅ O ₃ ).
Example 772: (R) -3-[{N- (2-amino-5-trifluoromethylbenzoyl) glycyl} amino] -1- (4-bromo-2-fluorobenzyl) pyrrolidine Preparation of (Compound No. 2120)
(R) -3-[{N- (2-amino-5-trifluoromethylbenzoyl) gylsil} amino] pyrrolidine (0.050 mmol), 4-bromo-2-fluorobenzaldehyde (0.15 mmol) To a mixture of, methanol (1.5 mL) and acetic acid (0.016 mL) is added NaBH ₃ CN (0.25 mmol) in methanol (0.50 mL). The reaction mixture is stirred at 50 ° C. overnight. The mixture is cooled to room temperature, loaded on a Varian ^™ SCX column and washed with CH ₃ OH (5 mL × 2). The product is eluted with 2N NH ₃ in CH ₃ OH (5 mL) and concentrated. The residue is dissolved in methanol (0.25 mL) and 4N HCl in dioxane (0.50 mL) is added. The solution is stirred for 5 h at room temperature and concentrated. The residue is dissolved in methanol, loaded on a Varian ^™ SCX column and washed with CH ₃ OH (5 mL × 2). The product is eluted with 2N NH ₃ in CH ₃ OH (5 mL) and concentrated. The resulting material was dissolved in ethyl acetate (0.5 mL), loaded on a Varian ^™ SCX column, eluted with ethyl acetate / methanol = 5: 1 (6 mL) and concentrated to (R) -3- [ {N- (2-amino-5-trifluoromethylbenzoyl) glycidyl} amino] -1- (4-bromo-2-fluorobenzyl) pyrrolidine (Compound No. 2120) (16.0 mg, 31 %): Purity is determined by RPLC / MS (99%); ESI / MS m / e 517.0 ( M + + H, C 21 H 21 BrF 4 N 4 O 2).
Examples 773-793
The compounds of the present invention are each synthesized according to the method of Example 772 using the corresponding reactants. ESI / MS data and yields are summarized in Table 13.
Compound no.Molecular formulaESI / MS m / eYield (mg)Yield (%) Example 7732083C22 H24 Br F3 N4 O4545.22.911 Example 7742084C23 H27 F3 N4 O5497.25.121 Example 7752085C22 H25 F3 N4 O4467.23.113 Example 7762086C21 H22 Cl F3 N4 O3471.04.620 Example 7772087C23 H28 F3 N5 O2464.25.624 Example 7782088C25 H32 F3 N5 O2492.25.924 Example 7792089C21 H21 F5 N4 O2457.24.520 Example 7802090C27 H27 F3 N4 O3513.28.031 Example 7812118C21 H23 F3 N4 O4453.12.712 Example 7822119C21 H23 F3 N4 O4453.14.319 Example 7832121C22 H25 F3 N4 O4467.01.22 Example 7842122C21 H21 Cl F4 N4 O2472.913.128 Example 7852123C22 H22 F3 N5 O6510.113.151 Example 7862124C21 H21 Cl F3 N5 O4500.115.662 Example 7872125C22 H24 F3 N5 O5496.016.065 Example 7882126C22 H24 F3 N5 O4480.115.665 Example 7892137C22 H24 Cl F3 N4 O2469.22.611 Example 7902138C26 H29 F3 N6 O2515.325.198 Example 7912139C20 H24 Cl F3 N6 O2473.225.098 Example 7922149C21 H22 F3 N5 O5482.34.934 Example 7932157C22 H25 F3 N4 O3451.215.570
Example 794: (R) -3-[{N- (2-amino-5-trifluoromethylbenzoyl) glycyl} amino] -1- (2,4-dimethoxypyrimidin-5-ylmethyl Preparation of Pyrrolidine (Compound No. 2175)
(R) -3-[{N- (2-amino-5-trifluoromethylbenzoyl) glycyl} amino] pyrrolidine (17.2 mg, 0.04 mmol) is dissolved in THF (1 mL), 2, 4-dimethoxy-5-pyrimidine carboxyaldehyde (6.7 mg, 0.04 mmol) is added, followed by sodium triacetoxyborohydride (12.7 mg, 0.06 mmol) and glacial acetic acid (2.4 mg, 0.04 mmol). The mixture is stirred for 24 h at room temperature and evaporated. The residue is then dissolved in dichloromethane (1 mL) and washed with 1N NaOH solution (1 mL). The organic phase is recovered, evaporated and treated with 25% trifluoroacetic acid in dichloromethane (1 mL) for 1 h at room temperature and evaporated. The residue was purified using LC / MS to give (R) -3-[{N- (2-amino-5-trifluoromethylbenzoyl) glycyl} amino] -1- (2,4-dimethoxypy Rimidin-5-ylmethyl) pyrrolidine (Compound No. 2175) (18.6 mg, 78%): Purity is determined by RPLC / MS (98%); ESI / MS m / e 483 (M ⁺ + H, C ₂₁ H ₂₅ F ₃ N ₆ O ₄ ).
Example 795 -803
The compounds of the present invention are each synthesized according to the method of Example 794 using the corresponding reactants. ESI / MS data and yields are summarized in Table 14.
Compound no.Molecular formulaESI / MS m / eYield (mg)Yield (%) Example 7952165C18 H21 F3 N6 O24112.027 Example 7962166C18 H20 F3 N5 O2 S4289.966 Example 7972167C24 H25 F3 N6 O248715.173 Example 7982169C24 H29 F3 N4 O24631.224 Example 7992170C26 H25 Cl F3 N5 O25206.040 Example 8002171C19 H23 F3 N6 O242516.888 Example 8012174C23 H24 Br F3 N4 O2 S25915.353 Example 8022178C25 H28 F3 N5 O45185.462 Example 8032179C25 H28 F3 N5 O35026.360
Example 804: (R) -1- (2-amino-4,5-methylenedioxybenzyl) -3-[{N- (2-amino-5-trifluoromethylbenzoyl) glyciyl} amino] py Preparation of Lolidine (Compound No. 2127)
(R) -3-[{N- (2-amino-5-trifluoromethylbenzoyl) glycyl} amino] -1- (4,5-methylenedioxy-2-nitrobenzyl) pyrrolidine (30.5 mg), 10% Pd-activated carbon (6 mg) and methanol (3 mL) are stirred for 10 h at room temperature under hydrogen atmosphere. The Pd catalyst is filtered off through celite and the filtrate is concentrated. (R) -1- (2-amino-4,5-methylenedioxybenzyl) -3-[{N- (2-amino-5-) with solid phase extraction (Bond Elut ^TM SI, 20% methanol / AcOEt) Trifluoromethylbenzoyl) glyciyl} amino] pyrrolidine (Compound No. 2127) (21.9 mg, 76%): Purity is determined by RPLC / MS (95%); ESI / MS m / e 480.1 (M ⁺ + H, C ₂₂ H ₂₄ F ₃ N ₅ O ₄ ).
Examples 805 and 806
The compounds of the present invention are each synthesized according to the method of Example 804 using the corresponding reactants. ESI / MS data and yields are summarized in Table 15.
Compound no.Molecular formulaESI / MS m / eYield (mg)Yield (%) Example 8052128C22 H26 F3 N5 O3466.08.630 Example 8062129C22 H26 F3 N5 O2450.113.137
Example 807: (R) -1- (3-amino-4-chlorobenzyl) -3-[{N- (2-amino-5-trifluoromethylbenzoyl) glycyl) amino] pyrrolidine (compound No. 2132)
(R) -3-[{N- (2-amino-5-trifluoromethylbenzoyl) glycyl) amino] -1- (4-chloro-3-nitrobenzyl) pyrrolidine (32.6 mg), 10 A mixture of% Pd-activated carbon (8 mg), ethyl acetate (2.7 mL) and methanol (0.3 mL) is stirred for 15 h at room temperature under hydrogen atmosphere. The Pd catalyst is filtered off and the filtrate is concentrated. (R) -1- (3-amino-4-chlorobenzyl) -3-[{N- (2-amino-5-trifluoromethyl) with solid phase extraction (Bond Elut ^™ SI, 20% methanol / AcOEt) Benzoyl) gylsil) amino] pyrrolidine (Compound No. 2132) (10.5 mg, 34%): Purity is determined by RPLC / MS (84%); ESI / MS m / e 470.2 (M ⁺ + H, C ₂₁ H ₂₃ ClF ₃ N ₅ O ₂ ).
Example 808: (R) -1- (2-amino-4,5-methylenedioxybenzyl) -3-[{N- (2- (tert-butoxycarbonylamino) -5-trifluoromethyl Preparation of benzoyl) glycyl} amino] pyrrolidine
(R) -3-[{N- (2- (tert-butoxycarbonylamino) -5-trifluoromethylbenzoyl) gylsil} amino] pyrrolidine (0.150 mmol), 4,5-methylenedi To a mixture of oxy-2-nitrobenzaldehyde (0.45 mmol), methanol (4.5 mL) and acetic acid (0.048 mL) is added NaBH ₃ CN (0.75 mmol) in methanol (1.50 mL). The reaction mixture is stirred at 50 ° C. overnight. The mixture is cooled to room temperature, loaded on a Varian ^™ SCX column and washed with CH ₃ OH. The product was eluted with 2N NH ₃ in CH ₃ OH and concentrated to (R) -3-[{N- (2- (tert-butoxycarbonylamino) -5-trifluoromethylbenzoyl) glysil } Amino] -1- (4,5-methylenedioxy-2-nitrobenzyl) pyrrolidine.
(R) -3-[{N- (2- (tert-butoxycarbonylamino) -5-trifluoromethylbenzoyl) glyciyl} amino] -1- (4,5-methylenedioxy, prepared above. A mixture of -2-nitrobenzyl) pyrrolidine, 10% Pd-activated carbon (22 mg) and methanol (3.0 mL) is stirred overnight at room temperature under hydrogen atmosphere. The Pd catalyst was filtered off and the filtrate was concentrated to give (R) -1- (2-amino-4,5-methylenedioxybenzyl) -3-[{N- (2- (tert-butoxycarbonylamino ) -5-trifluoromethylbenzoyl) glyciyl} amino] pyrrolidine (87.1 mg, quant.): No significant by-products were detected in TLC.
(R) -1- (3-amino-4-methoxybenzyl) -3-[{N- (2- (tert-butoxycarbonylamino) -5-trifluoromethylbenzoyl) glyciyl} amino] Pyrrolidine and (R) -1- (3-amino-4-methylbenzyl) -3-[{N- (2- (tert-butoxycarbonylamino) -5-trifluoromethylbenzoyl) glycid } Amino] pyrrolidine is also synthesized according to the method of Example 808 using the corresponding reactants, respectively.
(R) -1- (3-amino-4-methoxybenzyl) -3-[{N- (2- (tert-butoxycarbonylamino) -5-trifluoromethylbenzoyl) glyciyl} amino] Pyrrolidine: 101 mg, quant .; No significant by-products were detected in TLC.
(R) -1- (3-amino-4-methylbenzyl) -3-[{N- (2- (tert-butoxycarbonylamino) -5-trifluoromethylbenzoyl) glyciyl} amino] py Lollidine: 97.2 mg, quant .; No significant by-products were detected in TLC.
Example 809: (R) -1- (3-amino-4-chlorobenzyl) -3-[{N- (2- (tert-butoxycarbonylamino) -5-trifluoromethylbenzoyl) glycyl } Amino] Preparation of Pyrrolidine
(R) -3-[{N- (2- (tert-butoxycarbonylamino) -5-trifluoromethylbenzoyl) glycyl} amino] pyrrolidine (0.150 mmol), 4-chloro-3- To a mixture of nitrobenzaldehyde (0.45 mmol), methanol (4.5 mL) and acetic acid (0.048 mL) is added NaBH ₃ CN (0.75 mmol) in methanol (1.50 mL). The reaction mixture is stirred at 50 ° C. overnight. The mixture is cooled to room temperature, loaded on a Varian ^™ SCX column and washed with CH ₃ OH. The product was eluted with 2N NH ₃ in CH ₃ OH and concentrated to (R) -3-[{N- (2- (tert-butoxycarbonylamino) -5-trifluoromethylbenzoyl) glysil } Amino] -1- (4-chloro-3-nitrobenzyl) pyrrolidine.
(R) -3-[{N- (2- (tert-butoxycarbonylamino) -5-trifluoromethylbenzoyl) glyciyl} amino] -1- (4-chloro-3-nitro, prepared above. A mixture of benzyl) pyrrolidine, 10% Pd-activated carbon (22 mg), ethyl acetate (2.7 mL) and methanol (0.3 mL) is stirred for 15 h at room temperature under hydrogen atmosphere. The Pd catalyst was filtered off and the filtrate was concentrated to give (R) -1- (3-amino-4-chlorobenzyl) -3-[{N- (2- (tert-butoxycarbonylamino) -5- Trifluoromethylbenzoyl) glycyl} amino] pyrrolidine (89.7 mg, quant.): No significant by-products were detected in TLC.
Example 810: (R) -1- (3-amino-4-hydroxybenzyl) 3-[{N- (2-amino-5-trifluoromethylbenzoyl) glycyl} amino] pyrrolidine (compound No. 2187)
(R) -1- (3-amino-4-hydroxybenzyl) 3-[{N- (2- (tert-butoxy) prepared according to the method of Example 808 in 4N HCl in dioxane (2.0 mL) A solution of carbonylamino) -5-trifluoromethylbenzoyl) glycyl} amino] pyrrolidine (20 mg) is stirred overnight at room temperature. After concentrating the solution, and eluting the residue was dissolved in methanol, loaded onto a Varian ^TM SCX column, washed with CH ₃ OH, to use of CH ₃ OH 2N NH _3. Concentrate, preparative TLC (SiO ₂ , AcOEt / MeOH = 4: 1) to give (R) -1- (3-amino-4-hydroxybenzyl) 3-[{N- (2-amino-5-tri Fluoromethylbenzoyl) glysil} amino] pyrrolidine (Compound No. 2187) (9.6 mg, 59%): Purity is determined by RPLC / MS (86%); ESI / MS m / e 452.3 (M ⁺ + H, C ₂₁ H ₂₄ F ₃ N ₅ O ₃ ).
Example 811: (R) -3-[{N- (2-amino-5-trifluoromethylbenzoyl) glycyl} amino] -1- {4-chloro-3- (dimethylamino) benzyl} pyrroli Preparation of Didine (Compound No. 2133)
(R) -1- (3-amino-4-chlorobenzyl) -3-[{N- (2- (tert-butoxycarbonylamino) -5-trifluoromethylbenzoyl) glyciyl} amino] py NaBH ₃ CN (38 mg) is added to a mixture of lollidine (44.9 mg), methanol (0.95 mL), acetic acid (0.05 mL) and 37% aqueous HCHO solution (0.15 mL). The reaction mixture is stirred at 50 ° C. overnight. The mixture is cooled to room temperature and evaporated. 2N NaOH aqueous solution and ethyl acetate are added to the residue, the organic layer is separated, and the aqueous layer is extracted with ethyl acetate. The combined organic layers are dried, concentrated and the residue is loaded on a Varian ^™ SCX column and washed with CH ₃ OH. The product is eluted with 2N NH ₃ in CH ₃ OH and concentrated. The residue is dissolved in 50% concentration HCl / dioxane and the solution is stirred for 1 h at room temperature. The reaction mixture is adjusted to pH 10 with 5N aqueous NaOH solution and extracted with ethyl acetate (twice). The combined extracts are dried over Na ₂ S0 ₄ , filtered and evaporated. Preparative TLC (SiO ₂ , 20% MeOH / AcOEt) gave (R) -3-[{N- (2-amino-5-trifluoromethylbenzoyl) glyciyl} amino] -1- {4-chloro- 3- (dimethylamino) benzyl} pyrrolidine (Compound No. 2133) (10.9 mg, 28%): Purity is determined by RPLC / MS (95%); ESI / MS m / e 498.3 (M ⁺ + H, C ₂₃ H ₂₇ ClF ₃ N ₅ O ₂ ).
Examples 812-814
The compounds of the present invention are each synthesized according to the method of Example 811 using the corresponding reactants. ESI / MS data and yields are summarized in Table 16.
Compound no.Molecular formulaESI / MS m / eYield (mg)Yield (%) Example 8122134C24 H28 F3 N5 O4508.419.050 Example 8132135C24 H30 F3 N5 O3494.421.850 Example 8142136C24 H30 F3 N5 O2478.429.269
Example 815: (R) -3-[{N- (2-amino-5-trifluoromethylbenzoyl) glycyl} amino] -1- (3-methylamino-4-hydroxybenzyl) pyrrolidine Preparation of (Compound No. 2158)
(R) -1- (3-amino-4-hydroxybenzyl) 3-[{N- (2- (tert-butoxycarbonylamino) -5-trifluoromethylbenzoyl) glyciyl} amino] py To a mixture of rollidine (27.3 mg, 0.049 mmol), 37% HCHO solution (4.0 mg, 0.049 mmol), acetic acid (0.10 mL) and methanol (1.3 mL) was added NaBH ₃ CN (9.2 mg) in methanol (0.2 mL). Add. The reaction mixture is stirred overnight at 60 ° C. The mixture is cooled to room temperature, loaded on a Varian ^™ SCX column and washed with CH ₃ OH (5 mL × 2). The product is eluted with 2N NH ₃ in CH ₃ OH (8 mL) and concentrated.
The resulting material is dissolved in methanol (1 mL) and 4N HCl in dioxane (1.0 mL) is added. The solution is stirred for 3 h at room temperature. After concentration of the solution, the residue was dissolved in methanol (1 mL), loaded on a Varian ^™ SCX column, washed with CH ₃ OH (5 mL × 2), 2N NH in CH ₃ OH (8 mL) Elution is carried out using ₃ . Concentrate, preparative TLC (SiO ₂ ) to give (R) -3-[{N- (2-amino-5-trifluoromethylbenzoyl) glyciyl} amino] -1- (3-methylamino-4- Hydroxybenzyl) pyrrolidine (Compound No. 2158) (4.3 mg, 19%): Purity is determined by RPLC / MS (71%); ESI / MS m / e 480.3 (M ⁺ + H, C ₂₂ H ₂₆ F ₃ N ₅ O ₃ ).
Example 816: (R) -1- (3-acetylamino-4-methoxybenzyl) -3-[{N- (2-amino-5-trifluoromethylbenzoyl) glycyl} amino] pyrrolidine Preparation of (Compound No. 2152)
(R) -1- (3-amino-4-methoxybenzyl) -3-[{N- (2- (tert-butoxycarbonylamino) -5-trifluoromethylbenzoyl in pyridine (1 mL) To a solution of glycyl} amino] pyrrolidine (50.5 mg) add acetic anhydride (1 mL). The reaction mixture is stirred overnight at room temperature and methanol is added. The reaction is evaporated and 1N NaOH solution is added. The mixture is eluted with ethyl acetate and the organic layer is concentrated. Preparative TLC gave (R) -1- (3-acetylamino-4-methoxybenzyl) -3-[{N- (2- (tert-butoxycarbonylamino) -5-trifluoromethylbenzoyl) Glycyl} amino] pyrrolidine.
Resultant (R) -1- (3-acetylamino-4-methoxybenzyl) -3-[{N- (2- (tert-butoxycarbonylamino) -5-trifluoromethylbenzoyl) glycid } Amino] pyrrolidine is dissolved in 50% 6N hydrochloric acid in dioxane and the solution is stirred for 2 h at room temperature. The mixture is adjusted to pH 10 with 5M NaOH solution and extracted with ethyl acetate. The organic phase was evaporated and preparative TLC (SiO ₂ , AcOEt / MeOH = 4: 1) gave (R) -1- (3-acetylamino-4-methoxybenzyl) -3-[{N- (2-amino -5-trifluoromethylbenzoyl) glyciyl} amino] pyrrolidine (Compound No. 2152) (3.7 mg, 8%): Purity is determined by RPLC / MS (100%); ESI / MS m / e 508.3 (M ⁺ + H, C ₂₄ H ₂₈ F ₃ N ₅ O ₄ ).
Examples 817-819
The compounds of the present invention are each synthesized according to the method of Example 816 using the corresponding reactants. ESI / MS data and yields are summarized in Table 17.
Compound no.Molecular formulaESI / MS m / eYield (mg)Yield (%) Example 8172150C23 H25 Cl F3 N5 O3512.33.89 Example 8182151C24 H26 F3 N5 O5522.33.18 Example 8192153C24 H28 F3 N5 O3492.34.310
Example 820: (R) -3-[{N- (2-amino-5-trifluoromethylbenzoyl) glycyl} amino] -1- (benz [d] oxazol-5-yl) pyrrolidine Preparation of (Compound No. 2189)
(R) -1- (3-amino-4-hydroxybenzyl) -3-[{N- (2- (tert-butoxycarbonylamino) prepared according to the method of Example 808 in THF (2 mL) A solution of) -5-trifluoromethylbenzoyl) glyciyl} amino] pyrrolidine (20 mg) was added triethyl orthoformate (0.020 mL, 3.3 eq) and pyridinium p-toluenesulfonate (1.2 mg, 0.4 eq). The reaction mixture is stirred overnight at reflux. After cooling to room temperature, the mixture is concentrated. The residue is dissolved in AcOEt, loaded on a BondElut ^™ Si column, eluted with ethyl acetate / methanol = 4/1 and concentrated.
The resulting material is dissolved in AcOEt (1.5 mL) and 4N HCl in dioxane (0.5 mL) is added. The solution is stirred overnight at room temperature, adjusted to pH 10 with 5M aqueous NaOH solution and extracted with AcOEt. The extract was concentrated and purified by PTLC (SiO ₂ , AcOEt / MeOH = 4: 1) to give (R) -3-[{N- (2-amino-5-trifluoromethylbenzoyl) glyciyl} amino]- 1- (benz [d] oxazol-5-yl) pyrrolidine (Compound No. 2189) (0.5 mg, 3%) is provided: Purity is determined by RPLC / MS (97%); ESI / MS m / e 462.3 (M ⁺ + H, C ₂₂ H ₂₂ F ₃ N ₅ O ₃ ).
Example 821: (R) -3-[{N- (2-amino-5-trifluoromethylbenzoyl) glycyl} amino] -1- (benzo [c] thiadiazol-5-yl) pyrroli Preparation of Didine (Compound No. 2183)
Methanesulfonyl chloride (0.0042 mL) in a mixture of 5- (hydroxymethyl) benzo [c] thiadiazole (8.3 mg, 0.050 mmol), (piperidinomethyl) polystyrene (86 mg) and chloroform (1 mL) Is added and the mixture is stirred for 1.5 h at room temperature. Acetonitrile (1 mL) and (R) -3-[{N- (2- (tert-butoxycarbonylamino) -5-trifluoromethylbenzoyl) glyciyl} amino] pyrrolidine (0.060 mmol) Is added and the reaction mixture is stirred at 50 ° C. for 3 h. After cooling to room temperature, phenyl isocyanate (30 mg) is added and the mixture is stirred at room temperature for 1 h, loaded on a Varian ^™ SCX column, and charged with CH ₃ OH (5 mL) and CHCl ₃ (5 mL). Wash. The product is eluted with 2N NH ₃ in CH ₃ OH (3 mL) and concentrated.
The resulting material is dissolved in dichloromethane (1 mL) and 1M chlorotrimethylsilane and 1M phenol in dichloromethane (1 mL) are added. The solution is stirred for 5 h at room temperature, loaded on a Varian ^™ SCX column and washed with CH ₃ OH and dichloromethane. The product is eluted with 2N NH ₃ in CH ₃ OH and concentrated. Preparative TLC (SiO ₂ , AcOEt / MeOH = 3: 1) gave (R) -3-[{N- (2-amino-5-trifluoromethylbenzoyl) glyciyl} amino] -1- (benzo [ c] thiadiazol-5-yl) pyrrolidine (Compound No. 2183) (11.5 mg, 48%): Purity is determined by RPLC / MS (86%); ESI / MS m / e 479,2 (M ⁺ + H, C ₂₁ H ₂₁ F ₃ N ₆ O ₂ S).
Reference Example 6 of 4-[{N- (1- (9-fluorenylmethoxycarbonyl) pyrrolidin-3-yl) carbamoylmethyl} aminomethyl] -3-methoxymethyloxymethyl-polystyrene Produce
Acetic acid (0.3 mL) in a solution of (R) -1- (9-fluorenylmethoxycarbonyl) -3-glycyamino-pyrrolidine hydrochloride (4.38 g, 10 mmol) in DMF (65 mL), Sodium triacetoxyborohydride (1.92 g) and 4-formyl-3- (methoxymethyloxymethyl) polystyrene (1 mmol / g, 200 g) are added. The mixture is shaken for 2 h and filtered. The resin is washed with MeOH, DMF, CH ₂ Cl ₂ and methanol and dried to give the desired material (2.73 g).
Example 822-912: General procedure of solid phase synthesis of 3-aminopyrrolidine
To a mixture of the corresponding acid (1.6 mmol), HBTU (1.6 mmol) and DMF (6 mL) is added diisopropylethylamine (3.6 mmol) and the mixture is shaken for 2 minutes. 4-[{N- (1- (9-Fluorenylmethoxycarbonyl) pyrrolidin-3-yl) carbamoylmethyl} aminomethyl] -3-methoxymethyloxymethyl-polystyrene (400 mg, 0.4 mmol) is added and the mixture is shaken for 1 h and filtered. The resin is rinsed with DMF and CH ₂ Cl ₂ and dried.
The resulting mixture of resin, piperidine (3.2 mL) and DMF (12.8 mL) is shaken for 10 minutes and filtered. The resin is washed with DMF and CH ₂ Cl ₂ and dried.
To dry resin (0.05 mmol) is added a mixture of NaBH (OAc) ₃ (0.25 mmol), AcOH (0.025 mL) and DMF (1 mL). The corresponding aldehyde (2.5 mmol) is added and the mixture is shaken for 2 h, then filtered and washed with CH ₃ OH, 10% diisopropylethylamine in DMF, DMF, CH ₂ Cl ₂ and CH ₃ OH. A mixture of resin, water (0.050 mL) and trifluoroacetic acid (0.95 mL) is shaken for 1 h and filtered. The resin is washed with CH ₂ Cl ₂ and CH ₃ OH. The filtrate and wash are combined and concentrated. Crude material is loaded on a Varian ^™ SCX column and washed with CH ₃ OH (15 mL). The product is eluted with 2N NH ₃ in CH ₃ OH (5 mL) and concentrated. Preparative TLC or HPLC, if necessary, to provide the desired material. ESI / MS data and yields are summarized in Table 18.
Compound no.Molecular formulaESI / MS m / eYield (mg)Yield (%) Example 8221805C21 H21 Br F3 N3 O2 S51613.376 Example 8231806C22 H24 F3 N3 O3 S46812.881 Example 8241807C22 H24 F3 N3 O4 S48413.783 Example 8251808C22 H24 F3 N3 O4 S48414.991 Example 8261809C21 H22 F3 N3 O3 S45412.984 Example 8271810C22 H22 F3 N3 O4 S48212.979 Example 8281811C24 H26 F3 N3 O2 S47812.979 Example 8291812C22 H24 F3 N3 O2 S24845.332 Example 8301813C23 H26 F3 N3 O2 S46612.881 Example 8311814C23 H24 F3 N3 O3 S4809.759 Example 8321815C23 H26 F3 N3 O2 S46612.780 Example 8331816C24 H28 F3 N3 O2 S48014.488 Example 8341817C25 H30 F3 N3 O2 S49414.184 Example 8351818C21 H22 Br F2 N3 O348213.482 Example 8361819C22 H25 F2 N3 O443411.779 Example 8371820C22 H25 F2 N3 O545011.877 Example 8381821C22 H25 F2 N3 O545013.387 Example 8391822C21 H23 F2 N3 O442011.983 Example 8401823C22 H23 F2 N3 O544811.978 Example 8411824C24 H27 F2 N3 O34449.160 Example 8421825C22 H25 F2 N3 O3 S45011.374 Example 8431826C23 H27 F2 N3 O343210.874
Example 8441827C23 H25 F2 N3 O444612.784 Example 8451828C23 H27 F2 N3 O343211.780 Example 8461829C24 H29 F2 N3 O344614.394 Example 8471830C24 H29 F2 N3 O344610.066 Example 8481831C22 H28 Br N3 O34624.831 Example 8491832C23 H31 N3 O441410.474 Example 8501833C23 H31 N3 O543012.183 Example 8511834C23 H31 N3 O543012.082 Example 8521835C22 H29 N3 O44007.958 Example 8531836C23 H29 N3 O542811.176 Example 8541837C25 H33 N3 O342413.392 Example 8551838C23 H31 N3 O3 S4308.760 Example 8561839C24 H33 N3 O341211.381 Example 8571840C24 H31 N3 O442612.989 Example 8581841C24 H33 N3 O341312.891 Example 8591842C24 H33 N3 O34268.760 Example 8601843C25 H35 N3 O342612.284 Example 8611844C26 H37 N3 O344011.376 Example 8621845C31 H37 Br N4 O25776.430 Example 8631846C23 H28 F3 N3 O2 S48012.881 Example 8641847C25 H31 F2 N3 O346012.278 Example 8651848C27 H29 N3 O44606.139 Example 8661849C29 H31 N3 O245415.198 Example 8671850C28 H31 N3 O244212.785 Example 8681851C28 H31 N3 O244214.395 Example 8691852C28 H29 N3 O34563.422 Example 8701853C27 H29 N3 O6 S52415.487 Example 8711854C29 H31 N3 O4 S51815.890 Example 8721855C28 H31 N3 O4 S50617.099 Example 8731856C28 H31 N3 O4 S5063.017 Example 8741857C28 H29 N3 O5 S52010.057 Example 8751858C20 H22 Br2 N4 O25119.3 *37 Example 8761859C21 H25 Br N4 O34616.7 *29 Example 8771860C21 H25 Br N4 O44779.5 *40 Example 8781861C21 H25 Br N4 O447710.0 *42 Example 8791862C20 H23 Br N4 O34477.8 *34 Example 8801863C21 H23 Br N4 O44753.4 *14 Example 8811864C21 H25 Br N4 O2 S4773.9 *16 Example 8821865C22 H25 Br N4 O34736.4 *27 Example 8831866C23 H29 Br N4 O24727.0 *29 Example 8841867C23 H29 Br N4 O24737.6 *32 Example 8851868C24 H31 Br N4 O24879.1 *37 Example 8861869C20 H22 Br I N4 O25578.9 *33 Example 8871870C21 H25 I N4 O35099.2 *37 Example 8881871C21 H25 I N4 O45256.3 *25 Example 8891872C21 H25 I N4 O45255.9 *23 Example 8901873C20 H23 I N4 O34957.7 *31 Example 8911874C21 H23 I N4 O45238.2 *32 Example 8921875C23 H27 I N4 O25196.7 *26 Example 8931876C21 H25 I N4 O25254.3 *17 Example 8941877C22 H27 I N4 O25077.9 *32
Example 8951878C22 H25 I N4 O35218.4 *33 Example 8961879C23 H29 I N4 O25218.2 *32 Example 8971880C23 H29 I N4 O25218.1 *32 Example 8981881C24 H31 I N4 O25358.6 *33 Example 8991882C20 H22 Br N5 O44765.3 *22 Example 9001883C21 H25 N5 O54285.7 *26 Example 9011884C21 H25 N5 O64448.2 *36 Example 9021885C21 H25 N5 O64445.0 *22 Example 9031886C20 H23 N5 O54148.7 *40 Example 9041887C21 H23 N5 O64427.8 *34 Example 9051888C23 H27 N5 O44385.6 *25 Example 9061889C21 H25 N5 O4 S44413.2 *58 Example 9071890C22 H27 N5 O442611.3 *51 Example 9081891C22 H25 N5 O54407.4 *33 Example 9091892C22 H27 N5 O44265.5 *25 Example 9101893C23 H29 N5 O44405.7 *25 Example 9111894C23 H29 N5 O44409.4 *41 Example 9121895C24 H31 N5 O44558.5 *37
* Yield of TFA salt
Reference Example 7: Preparation of 2-carbamoyl-1- (4-chlorobenzyl) pyrrolidine
A solution of dl-prolineamide hydrochloride (2.5 g, 21. 8 mmol) in CH ₃ CN (35 mL) is treated with Et ₃ N (7.45 mL) and 4-chlorobenzyl chloride (3.88 g, 24.1 mmol). The reaction mixture is stirred at 70 ° C. for 4 h and then at 25 ° C. for 16 h. The resulting mixture is diluted with CH ₂ Cl ₂ (20 mL) and washed with water (3 × 30 mL). The organic phase is dried (MgSO ₄ ) and concentrated. Chromatography (SiO ₂ , 1% CH ₃ OH—CH ₂ Cl ₂ ) affords 2-carbamoyl-1- (4-chlorobenzyl) pyrrolidine (5.21 g, 81%).
Reference Example 8: Preparation of 2- (aminomethyl) -1- (4-chlorobenzyl) pyrrolidine
2-Carbamoyl-1- (4-chlorobenzyl) pyrrolidine is dissolved in 1M BH ₃ -THF (9.4 mL) and heated to 70 ° C. After 16 h and 25 h, an additional 0.5 equivalent of 1M BH ₃ -THF is added. After 40 h, 1 N HCl aqueous solution (14 mL) is added, the reaction is heated to reflux for 3 h, 3 N HCl aqueous solution (6 mL) is added, and the reaction is heated for an additional 3 h. The reaction mixture is cooled to 25 ° C., basified with 4N aqueous NaOH solution and extracted with CH ₂ Cl ₂ (4 × 15 mL). Chromatography (SiO ₂ , 8: 1: 1 PrOH-H ₂ O-NH ₄ OH) gave 2- (aminomethyl) -1- (4-chlorobenzyl) pyrrolidine (1.21 g, 86%) do.
Optically active (S) -2- (aminomethyl) -1- (4-chlorobenzyl) pyrrolidine and (R) -2- (aminomethyl) -1- (4-chlorobenzyl) pyrrolidine are also respectively Prepared according to the method using the corresponding reactants.
(S) -2- (aminomethyl) -1- (4-chlorobenzyl) pyrrolidine: ¹ H NMR (CDCl ₃ , 400 MHz) δ 1.40-1.80 (m, 5H), 1.80-1.95 (m, 1H) , 2.12-2.21 (m, 1H), 2.48-2.65 (m, 1H), 2.66-2.78 (m, 2H), 2.85-2.95 (m, 1H), 3.26 (d, J = 13.2 Hz, 1H), 3.93 (d, J = 13.2 Hz, 1H), 7.20-7.40 (m, 4H).
(R) -2- (aminomethyl) -1- (4-chlorobenzyl) pyrrolidine shows the same ¹ H NMR as that of the (S) -isomer.
Example 913: Preparation of 2-{(N-benzoylsilyl) aminomethyl} -1- (4-chlorobenzyl) pyrrolidine (Compound No. 344)
A solution of 2- (aminomethyl) -1- (4-chlorobenzyl) pyrrolidine (22.5 mg, 0.10 mmol) and dl-benzoilucine (0.12 mmol) in CHCl ₃ (1 mL) was diluted with EDCI (23 mg), Treat with HOBt (16.2 mg) and Et ₃ N (15.2 μL) and stir at 25 ° C. for 16 h. The reaction mixture is diluted with CH ₂ Cl ₂ (0.5 mL), washed with 2N aqueous NaOH solution (2 × 0.75 mL), filtered and dried over PTFE membrane and concentrated to 2-{(N-benzoylsilyl) aminomethyl}- 1- (4-chlorobenzyl) pyrrolidine (Compound No. 344) (74 mg, quant): Purity is determined by RPLC / MS (85%); ESI / MS m / e 442 (M ⁺ + H, C ₂₅ H ₃₂ ClN ₃ O ₂ ).
Examples 914-935
The compounds of the present invention are each synthesized according to the method of Example 913 using the corresponding reactants. If necessary, chromatography (HPLC-C ₁₈ , CH ₃ CN / H ₂ O / TFA) gives the desired material as a TFA salt. ESI / MS data and yields are summarized in Table 19. Compound No. 339 and 340 show the following ¹ H NMR spectra, respectively.
Compound no.Molecular formulaESI / MS m / eYield (mg)Yield (%) Example 914330C21 H24 Cl N3 O238675 *quant Example 915331C22 H26 Cl N3 O240044 *70 Example 916332C24 H30 Cl N3 O547657quant Example 917333C20 H23 Cl N4 O238740quant
Example 918334C22 H26 Cl N3 O240068quant Example 919335C21 H23 Cl N4 O443173quant Example 920336C22 H23 Cl F3 N3 O245475quant Example 921337C22 H26 Cl N3 O240068quant Example 922338C22 H26 Cl N3 O240070quant Example 923341C22 H26 Cl N3 O240080 *quant Example 924342C22 H26 Cl N3 O240068quant Example 925343C24 H30 Cl N3 O242863quant Example 926345C23 H27 Cl N2 O239968 *quant Example 927346C23 H26 Cl F N2 O343351quant Example 928347C24 H29 Cl N2 O241347quant Example 929348C23 H27 Cl N2 O239926quant Example 930349C21 H25 Cl N2 O3 S42142quant Example 931350C26 H33 Cl N2 O345712.454 Example 932351C22 H26 Cl N3 O34163481 Example 933352C22 H25 Cl2 N3 O345051quant
* Yield of TFA salt
Example 934. Compound No. 339: 82%; ¹ H NMR (CDCl ₃ ) δ 1.52-1.75 (m, 4H), 1.84-1.95 (m, 1H), 2.10-2.20 (m, 1H), 2.67-2.78 (m, 1H), 2.80-2.90 (m, 1H), 3.10-3.20 (m, 1H), 3.25 (d, J = 13.1, Hz, 1H), 3.50-3.60 (m, 1H), 3.89 (d, J = 13.1 Hz, 1H), 4.28-4.20 ( m, 2H), 7.00-7.05 (m, 1H), 7.12-7.29 (m, 4H), 7.51 9t, J = 7.8 Hz, 1H), 7.74 (d, J = 7.8 Hz, 1H), 7.99 (d, J = 7.8 Hz, 1H), 8.10-8.27 (m, 2H).
Example 935. Compound No. 340: 68%; ¹ H NMR (CDCl ₃ ) δ 1.55-1.73 (m, 4H), 1.86-1.97 (m, 1H), 2.12-2.21 (m, 1H), 2.67-2.76 (m, 1H), 2.86-2.93 (m, 1H), 3.14-3.21 (m, 1H), 3.27 (d, J = 13.1 Hz, 1H), 3.52-3.59 (m, 1H), 3.89 (d, J = 13.1 Hz, 1H), 4.09-4.21 (m , 2H), 7.00-7.07 (m, 1H), 7.12-7.30 (m, 4H), 7.50 (t, J = 7.8 Hz, 1H), 7.73 (d, J = 7.8 Hz, 1H), 8.01 (d, J = 7.8 Hz, 1H), 8.10-8.25 (m, 2H).
Reference Example 9 Preparation of 3- (aminomethyl) -1- (4-chlorobenzyl) pyrrolidine
4-carboxy-1- (4-chlorobenzyl) pyrrolidin-2-one (5.05 g, 20 mmol), EDCI (2.85 g, 22 mmol), HOBt (2.97 g, 22 mmol) and dichloromethane (100 mL To the mixture is added 0.5 M ammonia in dioxane (60 mL, 30 mmol). The reaction mixture is stirred for 15 h at room temperature and washed with 2N HCl (3 times) and 2N NaOH aqueous solution (100 mL × 4). The organic layer is dried over anhydrous magnesium sulfate, filtered and concentrated to give 3-carbamoyl-1- (4-chlorobenzyl) pyrrolidin-2-one (1.49 g) as a colorless solid.
To a solution of 3-carbamoyl-1- (4-chlorobenzyl) pyrrolidin-2-one (1.45 g) in THF (15 mL) is added 1.0N BH ₃ in THF (25 mL). The reaction mixture is stirred at 65 ° C. for 15 h. After cooling to room temperature, the solvent is removed under reduced pressure. Water (30 mL) and concentrated HCl (10 mL) are added and the mixture is stirred at 100 ° C. for 2 h and at room temperature for 1 h. 2N aqueous NaOH solution (100 mL) is added and the mixture is extracted with AcOEt (50 mL × 3). The combined organic layers are dried over K ₂ CO ₃ , filtered and concentrated. 3- (aminomethyl) -1- (4-chlorobenzyl) pyrrolidine (860 mg) as colorless oil by column chromatography (SiO ₂ , 15% CH ₃ OH-5% Et ₃ N in CH ₂ Cl ₂ ). , 19%).
Reference Example 10 Preparation of 1- (4-chlorobenzyl) -3-{(glycyaminoamino) methyl} pyrrolidine
3- (aminomethyl) -1- (4-chlorobenzyl) pyrrolidine (860 mg, 3.8 mmol), Et ₃ N (5.7 mmol), N-tert-butoxycarbonylgylsil (704 mg), EDCI (594 mg), HOBt (673 mg) and dichloromethane (20 mL) are stirred for 15 h at room temperature. Dichloromethane (50 mL) was added and the solution was washed with 2N NaOH solution (50 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated to 3-[{N- (tert-butoxycarbonyl) Glycyl} aminomethyl] -1- (4-chlorobenzyl) pyrrolidine (1.31 g, 90%).
Dioxane in a solution of 3-[{N- (tert-butoxycarbonyl) glyciyl} aminomethyl] -1- (4-chlorobenzyl) pyrrolidine (804 mg, 2.11 mmol) in methanol (10 mL) Add 4N HCl in (5 mL). The solution is stirred for 3.5 h at room temperature. The reaction mixture is concentrated and 1N NaOH solution (20 mL) is added. The mixture was extracted with dichloromethane (20 mL × 3) and the combined extracts were dried over sodium sulfate and concentrated to give the desired 1- (4-chlorobenzyl) -3-{(glycyamino) methyl} pyrrolidine (599 mg , 100%): purity is determined by RPLC / MS (100%); ESI / MS m / e 282.2 (M ⁺ + H, C ₁₄ H ₂₀ ClN ₃ O).
Example 936: Preparation of 3-[{N- (3-trifluoromethylbenzoyl) glycyl) aminomethyl] -1- (4-chlorobenzyl) pyrrolidine (Compound No. 1463)
A solution of 3- (trifluoromethyl) benzoyl chloride (0.058 mmol) in dichloromethane (0.2 mL) was dissolved in chloroform (0.2 mL) and 1- (4-chlorobenzyl) -3- {in dichloromethane (1 mL). To a mixture of glycylamino) methyl} pyrrolidine (0.050 mmol) and piperidinomethylpolystyrene (60 mg). The reaction mixture is stirred for 2.5 h at room temperature, methanol (0.30 mL) is added and the mixture is stirred for 1 h at room temperature. The reaction mixture is loaded on a Varian ^™ SCX column and washed with CH ₃ OH (15 mL). The product was eluted with 2N NH ₃ in Ch ₃ OH (5 mL) and concentrated to 3-[{N- (3-trifluoromethylbenzoyl) glycy) aminomethyl] -1- (4-chlorobenzyl ) Gives pyrrolidine (Compound No. 1463) (22.4 mg, 99%): purity determined by RPLC / MS (97%); ESI / MS m / e 454.2 (M ⁺ + H, C ₂₂ H ₂₃ ClF ₃ N ₃ O ₂ ).
Examples 937-944
The compounds of the present invention are each synthesized according to the method of Example 936 using the corresponding reactants. ESI / MS data and yields are summarized in Table 20.
Compound no.Molecular formulaESI / MS m / eYield (mg)Yield (%) Example 9371464C22 H23 Cl F3 N3 O3470.021.089 Example 9381465C23 H22 Cl F6 N3 O2522.024.594 Example 9391466C21 H23 Br Cl N3 O2466.020.890 Example 9401467C21 H23 Cl2 N3 O2420.019.693 Example 9411468C21 H23 Cl N4 O4431.219.591 Example 9421469C22 H22 Cl F4 N3 O2472.021.892 Example 9431470C21 H22 Cl3 N3 O2456.022.197 Example 9441471C21 H22 Cl F2 N3 O2422.020.999
Example 945: Preparation of 3-[{N- (2-amino-4,5-difluorobenzoyl) glycyl} aminomethyl] -1- (4-chlorobenzyl) pyrrolidine (Compound No. 1506)
A solution of 1- (4-chlorobenzyl) -3-{(glycaminoamino) methyl} pyrrolidine (0.050 mmol) in CHCl ₃ (1.35 mL) and tert-butanol (0.05 mL) was diluted with 2-amino-4, Treatment with 5-difluorobenzoic acid (0.060 mmol), diisopropylcarbodiimide (0.060 mmol) and HOBt (0.060 mmol). The reaction mixture is stirred for 19 h at room temperature. The mixture is loaded on a Varian ^™ SCX column and washed with CH ₃ OH / CHCl ₃ 1: 1 (10 mL) and CH ₃ OH (10 mL). The product was eluted with 2N NH ₃ in CH ₃ OH (5 mL) and concentrated to 3-[{N- (2-amino-4,5-difluorobenzoyl) glycyl} aminomethyl] -1- (4-chlorobenzyl) pyrrolidine (Compound No. 1506) (22.0 mg, quant): Purity is determined by RPLC / MS (92%); ESI / MS m / e 437 (C ₂₁ H ₂₃ ClF ₂ N ₄ O ₂ ).
Examples 946-952
The compounds of the present invention are each synthesized according to the method of Example 945 using the corresponding reactants. ESI / MS data and yields are summarized in Table 21.
Compound no.Molecular formulaESI / MS m / eYield (mg)Yield (%) Example 9461506C21 H24 Br Cl N4 O248120.686 Example 9471507C21 H24 F Cl N4 O241921.7quant Example 9481509C27 H28 Cl N3 O246226.5quant Example 9491510C21 H24 Cl I N4 O252722.084 Example 9501511C29 H21 Br Cl N3 O2 S47223.7quant
Example 9511512C21 H24 Cl2 N4 O243522.3quant Example 9521513C27 H28 Cl N3 O4 S52624.694
Reference Example 11: Preparation of 1- (4-chlorobenzyl) nifecotic acid
4-Chlorobenzyl chloride (6.42 g, 39.9 mmol) and ⁱ Pr ₂ NEt (7.74 g, 40.0 mmol) are added to a solution of ethyl nifekotate (6.29 g, 40.0 mmol) in CH ₃ CN (15 mL). The reaction mixture is stirred at 70 ° C. for 1.5 h. The solvent is removed under reduced pressure. Saturated aqueous NaHCO ₃ (50 mL) is added to the residue and the mixture is extracted with EtOAc (100 mL). The organic phase is washed with saturated aqueous NaHCO ₃ and brine and dried over Na ₂ SO ₄ . The solvent is removed under reduced pressure to give ethyl 1- (4-chlorobenzyl) nifekotate (11.025 g, 97.8%) as red yellow oil which is used without further purification. Purity is determined by RPLC / MS (97%); ESI / MS m / e 382.2 (M ⁺ + H, C ₁₅ H ₂₁ ClNO ₂ ).
A solution of LiOH (1.66 g) in H ₂ O (25 mL) is added to a solution of ethyl 1- (4-chlorobenzyl) nipecotate in THF (60 mL) and CH ₃ OH (20 mL). The reaction mixture is stirred for 15 h at room temperature. The solvent was removed under reduced pressure to give an amorphous solid, which was purified by column chromatography (SiO ₂ , 50% CH ₃ OH-CH ₂ Cl ₂ ) to give 1- (4-chlorobenzyl) nifecotic acid as light yellow amorphous solid. (9.75 g, 98.2%) is obtained. Purity is determined by RPLC / MS (>95%); ESI / MS m / e 254.0 (M ⁺ + H, C ₁₃ H ₁₇ ClNO ₂ ).
Reference Example 12 Preparation of 1- (4-chlorobenzyl) -3-{(tert-butoxycarbonyl) amino} piperidine
A solution of 1- (4-chlorobenzyl) nifecotic acid (7.06 g, 27.8 mmol) in BuOH (500 mL) is treated with Et ₃ N (3.38 g) and activated 3A molecular sieve (30 g). Diphenylphosphoryl azide (8.58 g) is added and the reaction mixture is allowed to reflux for 18 h. Cool the mixture and reflux the solvent for 18 h. The mixture is cooled and the solvent is removed in vacuo. The residue is dissolved in EtOAc (500 mL) and the organic phase is washed with saturated aqueous NaHCO ₃ (2 × 100 mL) and brine (50 mL), dried (Na ₂ SO ₄ ) and concentrated in vacuo. Chromatography (SiO ₂ , 25% EtOAc-hexanes) to give 1- (4-chlorobenzyl) -3-{(tert-butoxycarbonyl) amino} piperidine (2.95 g, 32.6%) as a white crystalline solid. ¹ H NMR (CDCl ₃ , 300 MHz) δ 1.4-1.75 (br, 4H), 2.2-2.7 (br, 4H), 3.5 (br, 2H), 3.8 (br, 1H), 7.3 (br, 4H); Purity is determined by RPLC / MS (>99%); ESI / MS m / e 269.2 (M ⁺ + H-56, C ₁₇ H ₂₆ ClN ₂ O ₂ ).
Reference Example 13: Preparation of 3-amino-1- (4-chlorobenzyl) piperidine
A solution of 1- (4-chlorobenzyl) -3-{(tert-butoxycarbonyl) amino} piperidine (2.55 g, 7.85 mmol) in CH ₃ OH (25 mL) was diluted with 1N HCl-Et ₂ O ( 50 mL). The reaction mixture is stirred at 25 ° C. for 15 h. The solvent is removed under reduced pressure to give 3-amino-1- (4-chlorobenzyl) piperidine (2.49 g, quant) as an amorphous solid. Purity is determined by RPLC / MS (>95%); ESI / MS m / e 225.2 (M ⁺ + H, C ₁₂ H ₁₈ ClN ₂ ).
Example 953: Preparation of 1- (4-chlorobenzyl) -3-[{N- (3-methylbenzoyl) glycyl} amino] piperidine (Compound No. 355)
N- (3-methylbenzoyl) glycine (10.6 mg, 0.055 mmol), EDCI (10.5 mg) and 1-hydroxybenzotriazole hydrate (7.4 mg) in 1- (4-chlorobenzyl in CHCl ₃ (2.5 mL) ) -3-aminopiperidine dihydrochloride (14.9 mg, 0.050 mmol) and Et ₃ N (15.2 mg) are added to a solution. The reaction mixture is stirred for 16 h at 25 ° C. and washed with 2N aqueous NaOH (2 mL × 2) and brine (1 mL). After filtration through a PTFE membrane filter, the solvent was removed under reduced pressure to yield 1- (4-chlorobenzyl) -3-[{N- (3-methylbenzoyl) glyciyl} amino] piperidine (compound as light yellow oil). No. 355) (17.4 mg, 87%): Purity is determined by RPLC / MS (97%); ESI / MS m / e 400.0 (M ⁺ + H, C ₂₂ H ₂₆ ClN ₃ O ₂ ).
Examples 954-982
The compounds of the present invention are each synthesized according to the method of Example 953 using the corresponding reactants. ESI / MS data and yields are summarized in Table 22. Compound No. 358 shows the following ¹ H NMR spectrum.
Compound no.Molecular formulaESI / MS m / eYield (mg)Yield (%) Example 954354C21 H24 Cl N3 O238616.183 Example 955356C20 H23 Cl N4 O238719.4100 Example 956357C22 H26 Cl N3 O240016.884 Example 957359C22 H26 Cl N3 O24008.917 Example 958360C22 H25 Cl N4 O444525.6quant Example 959361C23 H27 Cl N2 O239915.529 Example 960362C24 H29 Cl N2 O342912.458 Example 961363C21 H25 Cl N2 O2 S40522.2quant Example 962364C24 H29 Cl N2 O444520.793 Example 963365C24 H29 Cl N2 O241315.675 Example 964366C23 H26 Cl F N2 O343321.6100 Example 965367C23 H27 Cl N2 O239911.960 Example 966368C22 H25 Cl N2 O238516.083 Example 967369C22 H24 Cl2 N2 O241913.960 Example 968370C26 H33 Cl N2 O345715.954 Example 969371C25 H31 Cl N2 O344319.684 Example 970372C21 H25 Cl N2 O3 S42123.0quant Example 971373C23 H28 Cl N3 O241419.192 Example 972374C24 H30 Cl N3 O344418.684 Example 973375C23 H27 Cl2 N3 O244818.080 Example 974376C24 H30 Cl N3 O344419.688 Example 975377C25 H31 Cl2 N3 O247620.787 Example 976378C27 H33 Cl F N3 O248623.998 Example 977379C25 H30 Cl N3 O345633.3quant Example 978380C24 H30 Cl N3 O24289.846 Example 979381C21 H26 Cl N3 O3 S43610.347 Example 980382C22 H26 Cl N3 O341624.4quant Example 981383C22 H25 Cl2 N3 O345027.5quant
Example 982. Compound No. 358: 88%; ¹ H NMR (CDCl ₃ ) δ 1.53-1.75 (m, 4H), 2.12-2.20 (m, 1H), 2.37-2.50 (m, 2H), 2.53-2.61 (m, 1H), 3.38-3.50 (m, 2H), 2.53-2.61 (m, 1H), 3.38-3.50 (m, 2H), 4.06-4.20 (m, 3H), 7.10-7.13 (m, 1H), 7.18-7.30 (m, 4H), 7.59 ( t, J = 7.8 Hz, 1H), 7.79 (d, J = 7.8 Hz, 1H), 8.01 (d, J = 7.8 Hz, 1H), 8.11 (s, 1H).
Reference Example 14 Preparation of 1-benzyl-4-[{N- (tert-butoxycarbonyl) glycyl} amino] piperidine
A solution of 4-amino-1-benzylpiperidine (3.80 g, 20 mmol) in CH ₂ Cl ₂ (40 mL) was added with N- (tert-butoxycarbonyl) glycine (3.48 g, 20 mmol), EDCI ( 4.02 g, 21 mmol) and HOBt (2.83 g, 21 mmol). The reaction mixture is stirred for 12 h at room temperature and 2N NaOH solution (20 mL) is added. The organic layer is separated and the aqueous layer is extracted with dichloromethane (20 mL × 2). The combined organic layers are washed with water (20 mL) and brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. 1-benzyl-4-[{N- (tert-butoxycarbonyl) glyciyl} amino] piperidine by column chromatography (SiO ₂ , ethyl acetate / MeOH / Et ₃ N = 85/12/3) (6.59 g, 95%).
Reference Example 15 Preparation of 1- (4-Chlorobenzyl) -4- (glycylamino) piperidine
To a solution of 1-benzyl-4- {N- (tert-butoxycarbonyl) glyciyl} aminopiperidine (6.59 g) in methanol (80 mL) is added 4N HCl in dioxane (19 mL). The solution is stirred for 2 h at room temperature. The reaction mixture is concentrated and 2N aqueous NaOH solution (20 mL) is added. The mixture is extracted with dichloromethane (40 mL × 3) and the combined extracts are dried over anhydrous sodium sulfate and concentrated. Column chromatography (SiO ₂ , AcOEt / MeOH / Et ₃ N = 85/12/3) gave 1- (4-chlorobenzyl) -4- (glycyamino) piperidine (3.91 g, 83%). Provides: ¹ H NMR (CDCl ₃ , 400 MHz) d 1.47-1.59 (m, 2H0, 1.59 (br, 2H), 1.76-1.96 (m, 2H), 2.10-2.19 (m, 2H), 2.75-2.87 ( m, 2H), 3.29 (s, 2H), 3.50 (s, 2H), 3.65-3.89 (m, 1H), 7.15-7.23 (m, 1H), 7.23-7.33 (m, 5H).
Other 4-acylamino-1-benzylpiperidines are also synthesized according to the methods of Reference Examples 13 and 14 using the corresponding reactants, respectively.
4- (β-alanylamino) -1-benzylpiperidine: 2.46 g, 51% (step 2).
1-benzyl-4-((S) -lucylamino) piperidine: 1.78 g, 74% (step 2).
1-benzyl-4-((R) -silylamino) piperidine: 1.48 g, 61% (step 2).
Example 983 Preparation of 4- (N-benzoylglyciyl) amino-1-benzylpiperidine (Compound 386)
A solution of benzoyl chloride (0.060 mmol) in chloroform (0.4 mL) was added 1- (4-chlorobenzyl) -4- (glycyamino) piperidine (0.050 mmol) and triethylamine (0.070) in chloroform (1.0 mL). mmol) solution. The reaction mixture is stirred for 2.5 h at room temperature, (aminomethyl) polystyrene resin (1.04 mmol / g, 50 mg, 50 mmol) is added and the mixture is stirred for 12 h at room temperature. The reaction mixture is filtered and the resin is washed with dichloromethane (0.5 mL). The filtrate and washings were combined, dichloromethane (4 mL) was added, and the solution was washed with 2N aqueous NaOH solution (0.5 mL) to 4- (N-benzoylglycyl) amino-1-benzylpiperidine (Compound 386) (11.3 mg, 64%): Purity is determined by RPLC / MS (94%); ESI / MS m / e 352.0 (M ⁺ + H, C ₂₁ H ₂₅ N ₃ O ₂ ).
Examples 984-1034
The compounds of the present invention are each synthesized according to the method of Example 983 using the corresponding reactants. ESI / MS data and yields are summarized in Table 23.
Compound no.Molecular formulaESI / MS m / eYield (mg)Yield (%) Example 984384C22 H26 Cl N3 O240060.0quant Example 985385C21 H23 Cl N4 O443158.791 Example 986387C25 H27 N3 O2402.515.577 Example 987388C21 H24 N4 O4397.016.282 Example 988389C23 H27 N3 O4410.016.279 Example 989390C22 H24 F3 N3 O2420.017.483 Example 990391C22 H23 F4 N3 O2438.018.484 Example 991392C22 H24 F3 N3 O3436.017.179 Example 992393C21 H24 Br N3 O2430.018.084 Example 993394C21 H24 Cl N3 O2386.016.485 Example 994395C21 H24 Br N3 O2430.017.280 Example 995396C21 H23 F2 N3 O2388.015.178 Example 996397C21 H23 Cl2 N3 O2420.011.756 Example 997398C22 H27 N3 O2366.013.172 Example 998399C26 H29 N3 O2416.015.876 Example 999400C22 H26 N4 O4411.017.485 Example 1000401C24 H29 N3 O4424.016.980 Example 1001402C23 H26 F3 N3 O2434.017.782 Example 1002403C23 H25 F4 N3 O2452.018.682 Example 1003404C23 H26 F3 N3 O3450.017.879 Example 1004405C22 H26 Br N3 O2444.017.981 Example 1005406C22 H26 Cl N3 O2400.015.578 Example 1006407C22 H26 Br N3 O2444.017.880 Example 1007408C22 H25 F2 N3 O2402.015.678 Example 1008409C22 H25 Cl2 N3 O2434.017.681 Example 1009410C25 H33 N3 O2408.016.279 Example 1010411C29 H35 N3 O2458.518.882 Example 1011412C25 H32 N4 O4453.019.486 Example 1012413C27 H35 N3 O4466.019.885 Example 1013414C26 H32 F3 N3 O2476.020.285 Example 1014415C26 H31 F4 N3 O2494.020.583
Example 1015416C26 H32 F3 N3 O3492.019.579 Example 1016417C25 H32 Br N3 O2486.019.179 Example 1017418C25 H32 Cl N3 O2442.017.780 Example 1018419C25 H32 Br N3 O2486.020.383 Example 1019420C25 H31 F2 N3 O2444.018.684 Example 1020421C25 H31 Cl2 N3 O2476.019.481 Example 1021422C25 H33 N3 O2408.014.471 Example 1022423C29 H35 N3 O2458.016.472 Example 1023424C25 H32 N4 O4453.018.180 Example 1024425C27 H35 N3 O4466.016.470 Example 1025426C26 H32 F3 N3 O2476.017.373 Example 1026427C26 H31 F4 N3 O2494.018.876 Example 1027428C26 H32 F3 N3 O3492.018.475 Example 1028429C25 H32 Br N3 O2486.017.974 Example 1029430C25 H32 Cl N3 O2442.015.771 Example 1030431C25 H32 Br N3 O2486.017.773 Example 1031432C25 H31 F2 N3 O2444.016.675 Example 1032433C25 H31 Cl2 N3 O2476.018.778 Example 10331016C22 H23 Cl F3 N3 O245432.5 *53 Example 10341017C21 H24 Cl N3 O238655.2 *quant
* Yield of TFA salt
Reference Example 16: Preparation of 3-carbamoyl-1- (4-chlorobenzyl) piperidine
A solution of nifecottamide (6.40 g, 50 mmol) in CH ₃ CN (150 mL) and ethanol (20 mL) was purified by Et ₃ N (7.0 mL, 50 mmol) and 4-chlorobenzyl chloride (8.05 g, 50 mmol). ). The reaction mixture is stirred at 50 ° C. for 16 h. After cooling to room temperature, saturated aqueous NaHCO ₃ (50 mL) and water (150 mL) are added to the reaction mixture. The mixture is extracted with ethyl acetate (150 mL × 3) and the combined organic layers are washed with brine, dried (Na ₂ SO ₄ ) and concentrated to give a light red solid. The crude solid is washed with ether (100 mL) to give 3-carbamoyl-1- (4-chlorobenzyl) piperidine (6.98 g, 54%).
Reference Example 17 Preparation of 3- (aminomethyl) -1- (4-chlorobenzyl) piperidine
3-carbamoyl-1- (4-chlorobenzyl) piperidine (3.80 g, 15 mmol) is dissolved in THF (30 mL) and 1 M BH ₃ -THF (9.4 mL) is added to the solution. The reaction mixture is stirred at 70 ° C. for 15 h. After the mixture was cooled to 0 ° C., 2N HCl aqueous solution (50 mL) was added, the mixture was stirred for an additional 3 h at room temperature, basified with 4N NaOH aqueous solution, extracted with ethyl acetate (100 mL × 3) do. The combined extracts are washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. Column chromatography (SiO ₂ , ethyl acetate / EtOH / Et ₃ N = 80/15/5) gave 3- (aminomethyl) -1- (4-chlorobenzyl) piperidine (2.05 g, 55%). Provides: ¹ H NMR (CDCl ₃ , 400 MHz) δ 1.00-1.09 (m, 1H), 1.50-1.87 (m, 7H), 1.97-2.06 (m, 1H), 2.65-2.77 (m, 2H), 3.16 -3.26 (m, 2H), 3.32 (s, 2H), 3.40 (d, J = 13.3 Hz, 1H), 3.49 (d, J = 13.3 Hz, 1H), 7.22-7.33 (m, 5H).
Example 1035: Preparation of 3-{(N-benzoylglycyl) amino} methyl-1- (4-chlorobenzyl) piperidine (Compound No. 434)
A solution of benzoyl chloride (0.060 mmol) in chloroform (0.4 mL) was added 3- (aminomethyl) -1- (4-chlorobenzyl) piperidine (0.050 mmol) and triethylamine (0.070 mmol) in chloroform (1.0 mL). Is added to the solution. The reaction mixture is stirred for 2.5 h at room temperature, (aminomethyl) polystyrene resin (1.04 mmol / g, 50 mg, 50 mmol) is added and the mixture is stirred for 12 h at room temperature. The reaction mixture is filtered and the resin is washed with dichloromethane (0.5 mL). The filtrates and washes were combined, dichloromethane (4 mL) was added and the solution was washed with 2N aqueous NaOH solution (0.5 mL) to 3-{(N-benzoylglycyl) amino} methyl-1- (4-chlorobenzyl ) Piperidine (Compound No. 434) (14.7 mg, 74%): Purity is determined by RPLC / MS (91%); ESI / MS m / e 400 ( M + + H, C 22 H 26 ClN 3 O 2).
Examples 1036-1058
The compounds of the present invention are each synthesized according to the method of Example 1035 using the corresponding reactants. ESI / MS data and yields are summarized in Table 24.
Compound no.Molecular formulaESI / MS m / eYield (mg)Yield (%) Example 1036435C26 H28 Cl N3 O245016.071 Example 1037436C22 H25 Cl N4 O444518.985 Example 1038437C24 H28 Cl N3 O445818.279 Example 1039438C23 H25 Cl F3 N3 O246819.081 Example 1040439C23 H24 Cl F4 N3 O248620.283 Example 1041440C23 H25 Cl F3 N3 O348418.978 Example 1042441C22 H25 Br Cl N3 O247819.280 Example 1043442C22 H25 Cl2 N3 O243417.380 Example 1044443C22 H25 Br Cl N3 O247818.879 Example 1045444C22 H24 Cl F2 N3 O243616.777 Example 1046445C22 H24 Cl3 N3 O246817.976 Example 1047446C23 H28 Cl N3 O241414.671 Example 1048447C27 H30 Cl N3 O246417.073 Example 1049448C23 H27 Cl N4 O445919.585 Example 1050449C25 H30 Cl N3 O447217.172 Example 1051450C24 H27 Cl F3 N3 O248219.481
Example 1052451C24 H26 Cl F4 N3 O250018.273 Example 1053452C24 H27 Cl F3 N3 O349818.876 Example 1054453C23 H27 Br Cl N3 O249219.479 Example 1055454C23 H27 Cl2 N3 O244816.574 Example 1056455C23 H27 Br Cl N3 O249219.378 Example 1057456C23 H26 Cl F2 N3 O245017.176 Example 1058457C23 H26 Cl3 N3 O248216.970
Reference Example 18 Preparation of 4- (aminomethyl) -1- (4-chlorobenzyl) piperidine
Sequential solution of 4- (aminomethyl) piperidine (7.00 g, 61.3 mmol) in CH ₃ CN (100 mL) with K ₂ CO ₃ (3.02 g) and 4-chlorobenzyl chloride (3.52 g, 21.8 mmol) To be processed. The reaction mixture is heated at 60 ° C. for 16 h, cooled to 25 ° C. and concentrated. The residue is partitioned between CH ₂ Cl ₂ (75 mL) and water (50 mL) and washed with water (2 × 50 mL) and brine (1 × 50 mL). The organic phase is dried (MgSO ₄ ) and concentrated. Chromatography (SiO ₂ , 4% H ₂ O- ⁱ PrOH) gave 4- (aminomethyl) -1- (4-chlorobenzyl) piperidine (3.58 g, 69%).
Example 1059: Preparation of 4-{(N-benzoylglycyl) amino} methyl-1- (4-chlorobenzyl) piperidine (Compound No. 458)
A solution of 4- (aminomethyl) -1- (4-chlorobenzyl) piperidine (50 mg, 0.21 mmol) in CH ₂ Cl ₂ (1 mL) was purified by hippuric acid (38 mg, 0.21 mmol), EDCI ( 48 mg, 0.24 mmol), HOBt (31 mg, 0.23 mmol) and Et ₃ N (38 μL, 0.27 mmol). The reaction mixture is stirred at 25 ° C. for 16 h, diluted with 1 mL of CH ₂ Cl ₂ , washed with 2N aqueous NaOH solution (2 × 0.75 mL), dried (MgSO ₄ ) and concentrated. 4-{(N-benzoylglycyl) amino} methyl-1- (4-chlorobenzyl) piperidine (compound eluted by chromatography (SiO ₂ , 6-8% CH ₃ OH / CH ₂ Cl ₂ gradient elution) No. 458), which is treated with TFA to give a TFA salt (105 mg, 97%): purity is determined by RPLC / MS (85%); ESI / MS m / e 400 ( M + + H, C 22 H 26 ClN 3 O 2).
Examples 1060-1086
The compounds of the present invention are each synthesized according to the method of Example 1059 using the corresponding reactants. ESI / MS data and yields are summarized in Table 25.
Compound no.Molecular formulaESI / MS m / eYield (mg)Yield (%) Example 1060459C23 H28 Cl N3 O241486 *78 Example 1061460C23 H28 Cl N3 O241455quant Example 1062461C23 H25 Cl F3 N3 O246865quant Example 1063462C23 H28 Cl N3 O241461quant Example 1064463C23 H28 Cl N3 O241454quant Example 1065464C25 H32 Cl N3 O549056quant Example 1066465C21 H25 Cl N4 O24013896 Example 1067466C22 H25 Cl N4 O44451534 Example 1068557C23 H28 Cl N3 O241458 *66 Example 1069558C23 H28 Cl N3 O241455quant Example 1070618C25 H32 Cl N3 O244258quant Example 1071686C26 H34 Cl N3 O245662quant Example 1072749C34 H37 Cl N4 O25697.2 *18 Example 1073750C24 H30 Cl N3 O34444.7 *14 Example 1074840C24 H29 Cl N2 O241352 *58 Example 1075841C23 H27 Cl N2 O239952quant
Example 1076842C23 H26 Cl2 N2 O243355quant Example 1077843C25 H31 Cl N2 O242758quant Example 1078844C24 H29 Cl N2 O241356quant Example 1079845C24 H29 Cl N2 O4 S47762quant Example 1080846C29 H31 Cl N2 O34914388 Example 1081847C24 H28 Cl F N2 O344754quant Example 1082848C25 H31 Cl N2 O242747quant Example 1083849C25 H31 Cl N2 O445955quant Example 1084850C22 H27 Cl N2 O3 S43546quant Example 1085873C20 H28 Cl N3 O237844.8quant Example 1086874C23 H27 Cl2 N3 O346451quant
* Yield of TFA salt
Reference Example 19 Preparation of 1- (4-chlorobenzyl) -4- {N- (3,3-diphenylpropyl) aminomethyl} piperidine
4- (aminomethyl) -1- (4-chlorobenzyl) piperidine (120 mg) was added to 3,3-diphenylpropyl methanesulfo in the presence of NaI (2.6 equiv) in CH ₃ CN at 70 ° C. for 16 h. Alkylated with Nate (1.0 equiv). General workup and column chromatography (SiO ₂ ) were carried out to yield 1- (4-chlorobenzyl) -4- {N- (3,3-diphenylpropyl) aminomethyl} piperidine (118 mg, 54%). Provide: Purity is determined by RPLC (98%).
Reference Example 20 Preparation of 1- (4-chlorobenzyl) -4- {N- (2,2-diphenylethyl) aminomethyl} piperidine
4- (aminomethyl) -1- (4-chlorobenzyl) piperidine (120 mg) was polymer-supported borohydride in 2,2-diphenylacetaldehyde (0.66 equiv) and methanol at 25 ° C. for 16 h. Reductive amination with reed followed by normal work-up and column chromatography (SiO ₂ ) to give 1- (4-chlorobenzyl) -4- {N- (2,2-diphenylethyl) aminomethyl} piperidine (70 mg, 49%): Purity is determined by RPLC (98%).
Example 1087 of 4- {N- (N-benzoylglycyl) -N- (2,2-diphenylethyl) aminomethyl} -1- (4-chlorobenzyl) piperidine (Compound No. 524) Produce
A solution of 1- (4-chlorobenzyl) -4- {N- (2,2-diphenylethyl) aminomethyl} piperidine (0.084 mmol) in CH ₂ Cl ₂ was dissolved in hippuric acid (1.1 equiv), HBTU. (1.1 equiv), HOBt (1.1 equiv). The reaction mixture is stirred at 40 ° C. for 24 h. General work-up and preparative TLC (SiO ₂ ) for 4- {N- (N-benzoylglycyl) -N- (2,2-diphenylethyl) aminomethyl} -1- (4-chlorobenzyl) piperi Dean (Compound No. 524) (8.5 mg, 17%): Purity is determined by RPLC / MS (98%); ESI / MS m / e 580 (M ⁺ + H, C ₃₆ H ₃₈ ClN ₃ O ₂ ).
Examples 1088-1090
The compounds of the present invention are each synthesized according to the method of Example 1087 using the corresponding reactants. ESI / MS data and yields are summarized in Table 26.
Compound no.Molecular formulaESI / MS m / eYield (mg)Yield (%) Example 1088521C38 H39 Cl F3 N3 O26625.510 Example 1089522C37 H37 Cl F3 N3 O26488.616 Example 1090523C37 H40 Cl N3 O25944.810
Reference Example 21 Preparation of 1- (4-Chlorobenzyl) -4-{(Valiamino) methyl} Piperidine
A solution of 4- (aminomethyl) -1- (4-chlorobenzyl) piperidine (1.0 g, 4.2 mmol) in CH ₂ Cl ₂ (21 mL) was purified by Et ₃ N (0.76 mL, 5.44 mmol), dl-. Treated with N- (tert-butoxycarbonyl) valine (1.09 g, 5.03 mmol), EDCI (883 mg, 4.61 mmol) and HOBt (623 mg, 4.61 mmol). The reaction mixture is stirred at 25 ° C. for 16 h. The resulting solution is diluted with CH ₂ Cl ₂ (20 mL), washed with 2N NaOH solution (2 × 20 mL), brine (1 × 20 mL) and dried (MgSO ₄ ). Concentrated and chromatographed (SiO ₂ , 3% CH ₃ OH / CH ₂ Cl ₂ ) to give 1- (4-chlorobenzyl) -4-[{(N-Boc-baryl) amino} methyl] as a pale yellow oil. Gives piperidine (1.1 g, 60%): ESI / MS m / e 438 (M ⁺ + H).
1- (4-chlorobenzyl) -4-[{(N-Boc-baryl) amino} methyl] piperidine (1.1 g, 2.51 mmol) is dissolved in 3M HCl-CH ₃ OH solution (25 mL), Stir at 25 ° C. for 1 h. The reaction mixture is concentrated and the resulting salt is dissolved in 3: 1 ^t BuOH-H ₂ O (25 mL). An anion (OH ⁻ ) exchange resin is added until the solution is about base. Filtration and concentration gave 1- (4-chlorobenzyl) -4-{(barylamino) methyl} piperidine (819 mg, 97%), which requires no further purification: RPLC (97% ); ESI / MS m / e 338.1 (M ⁺ + H, C ₁₈ H ₂₈ ClN ₃ O).
Other 4-{(acylamino) methyl} -1- (4-chlorobenzyl) piperidines are each also synthesized according to the method of Reference Example 20 using the corresponding reactants.
1- (4-chlorobenzyl) -4-{(glycosylamino) methyl} piperidine: 0.830 g, 67% (2 steps); ESI / MS 269 (M ⁺ + H).
1- (4-chlorobenzyl) -4-{(serylamino) methyl} piperidine: 0.286 g, 20% (2 steps); ESI / MS 326 (M ⁺ + H).
4-{(alanylamino) methyl} -1- (4-chlorobenzyl) piperidine: 1.20 g, 65% (2 steps); ESI / MS 310 (M ⁺ + H).
1- (4-chlorobenzyl) -4-{(prolylamino) methyl} piperidine: 1.48 g, 86% (2 steps); ESI / MS 336 (M ⁺ + H).
1- (4-chlorobenzyl) -4-{(glutaminylamino) methyl} piperidine: 0.830 g, 27% (2 steps); ESI / MS 367 (M ⁺ + H).
1- (4-chlorobenzyl) -4-{((2-methylalanyl) amino) methyl} piperidine: 2.24 g, 62% (2 steps); ESI / MS 324 (M ⁺ + H).
1- (4-chlorobenzyl) -4-{((O-methylseryl) amino) methyl} piperidine: 0.686 g, 38% (2 steps); ESI / MS 340 (M ⁺ + H).
1- (4-chlorobenzyl) -4-{((1-aminocyclopropylcarbonyl) amino) methyl} piperidine: 2.03 g, 82% (2 steps); ESI / MS 322 (M ⁺ + H).
1- (4-chlorobenzyl) -4-{(rusilamino) methyl} piperidine: 1.30 g, 58% (2 steps); ESI / MS 352 (M ⁺ + H).
1- (4-chlorobenzyl) -4-{((O-benzylseryl) amino) methyl} piperidine: 1.34 g, 56% (2 steps); ESI / MS 416 (M ⁺ + H).
Reference Example 22 Preparation of 1- (tert-butoxycarbonyl) -4-[{N- (9-fluorenylmethyloxycarbonyl) glyciyl} aminomethyl] piperidine
A solution of 4- (aminomethyl) -1- (tert-butoxycarbonyl) piperidine (5.72 g) in CH ₂ Cl ₂ (150 mL) was added with Et ₃ N (3.51 g), N- (9-flu Treated with orenylmethyloxycarbonyl) glycine (7.93 g, 26.7 mmol), EDCI (3.80 g) and HOBt (4.33 g). The reaction mixture is stirred for 5 h at room temperature and the mixture is washed with water (100 mL × 3) and brine (100 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated. Recrystallized from CH ₃ CN / CH ₃ OH (150 mL / 1 mL) at 0 ° C. to yield 1- (tert-butoxycarbonyl) -4-[{N- (9-fluorenylmethyloxy) as light yellow crystals. Carbonyl) glycyl} aminomethyl] piperidine (5.75 g, 44%).
Reference Example 23 Preparation of 4-[{N- (9-fluorenylmethyloxycarbonyl) glycyl} aminomethyl] piperidine
Dioxane (50 mL) in 1- (tert-butoxycarbonyl) -4-[{N- (9-fluorenylmethyloxycarbonyl) glycyl} aminomethyl] piperidine (3.17 g, 6.42 mmol) 4N HCl is added. The solution is stirred for 5 h at room temperature. The reaction mixture is concentrated to give 4-[{N- (9-fluorenylmethyloxycarbonyl) glyciyl} aminomethyl] piperidine (3.85 g) as a white solid. The product is used without further purification.
Reference Example 24 Preparation of 4-[{N- (9-fluorenylmethyloxycarbonyl) gylsil} aminomethyl] -1- (4-methylthiobenzyl) piperidine
4-methylthio in a solution of 4-[{N- (9-fluorenylmethyloxycarbonyl) glycyl} aminomethyl] piperidine (1.00 g, 2.33 mmol) in 1% AcOH / DMF (15 mL). Benzaldehyde (1.24 g) and NaBH (OAc) ₃ (2.56 g) are added. The reaction mixture is stirred for 1 h at 60 ° C., solution (50 mL) is added and the mixture is extracted with AcOEt (50 mL × 2). The combined extracts are dried over anhydrous sodium sulfate, filtered and concentrated. Column chromatography (SiO ₂ , 5% -10% CH ₃ OH / CH ₂ Cl ₂ ) gave 4-[{N- (9-fluorenylmethyloxycarbonyl) glyciyl} aminomethyl]-as a colorless oil. 1- (4-methylthiobenzyl) piperidine (602 mg) is provided.
Reference Example 25 Preparation of 1- (4-ethylbenzyl) -4-[{N- (9-fluorenylmethyloxycarbonyl) glycyl} aminomethyl] piperidine
In a solution of 4-[{N- (9-fluoroenylmethyloxycarbonyl) glycyl} aminomethyl] piperidine (1.00 g, 2.33 mmol) in 2.5% AcOH / CH ₃ OH (80 mL) Ethylbenzaldehyde (1.09 g, 8.16 mmol) and NaBH ₃ CN (6.59 g, 10.5 mmol) are added. The reaction mixture is stirred at 60 ° C. for 13 h. After the mixture is cooled to room temperature, 1N aqueous NaOH solution (50 mL) and dichloromethane (50 mL) are added. The organic layer is separated and the aqueous layer is extracted with dichloromethane (50 mL × 3). The combined organic layers are washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. Column chromatography (SiO ₂ , CH ₃ OH / AcOEt 2: 8) to give 1- (4-ethylbenzyl) -4-[{N- (9-fluorenylmethyloxycarbonyl) glyciyl} aminomethyl] Piperidine (740 mg, 62%).
Reference Example 26 Preparation of 4-{(Glycyaminoamino) methyl} -1- (4-methylthiobenzyl) piperidine
4-[{N- (9-fluorenylmethyloxycarbonyl) glycyl} aminomethyl] -1- (4-methylthiobenzyl) piperidine (590 mg) and piperidine in DMF (4 mL) (1 mL) of solution is stirred for 2 h at room temperature. Concentrate and perform column chromatography (SiO ₂ , Et ₃ N: CH ₃ OH: CH ₂ Cl ₂ = 1: 1: 9) to give 4-{(glycyamino) methyl} -1- (4-methyl as a white solid. Thiobenzyl) piperidine (365 mg) is provided: ¹ H NMR (CDCl ₃ , 270 MHz) δ 1.25 (dd, J = 12 H, 4.1 Hz, 2H), 1.34 (dd, J = 12 Hz, 4.1 Hz, 2H), 1.51 (br-s, 2H), 1.66 (d, J = 12Hz, 2H), 1.77 (d, J = 7.3Hz, 1H), 1.94 (t, J = 9.5Hz, 2H), 2.48 (s , 3H), 2.80 (d, J = 12Hz, 2H), 3.18 (t, J = 6.2Hz, 2H), 3.35 (s, 2H), 3.45 (s, 2H), 7.18-7.29 (m, 4H), 7.35 (br-s, 1 H).
1- (4-ethylbenzyl) -4-{(glysilamino) methyl} piperidine is also synthesized according to the method of Reference Example 25 using the corresponding reactant: 333 mg, 79%.
Reference Example 27 Preparation of 4-{(Glysilamino) methyl} -1- (4-fluorobenzyl) piperidine
4-[{N- (9-fluorenylmethyloxycarbonyl) glycyl} aminomethyl] piperidine (1.50 g, 3.49 mmol) in CH ₃ CN (200 mL), 4-fluorobenzyl bromide (0.478 mL, 3.84 mmol) and a solution of Et ₃ N (1.47 mL, 10.5 mmol) are stirred for 13 h at room temperature and concentrated. Column chromatography (SiO 2, 10% CH ₃ OH / CH ₂ Cl ₂ ) was carried out to give 4-[{N- (9- (fluorenylmethyloxycarbonyl) glyciyl} aminomethyl] -1- (4-fluoro Lobenzyl) piperidine.
4-[{N- (9- (fluorenylmethyloxycarbonyl) glycyl} aminomethyl] -1- (4-fluorobenzyl) piperidine and piperidine (5 mL) in DMF (5 mL) ) Is stirred for 17 h at room temperature, concentrated and subjected to column chromatography (SiO ₂ , Et ₃ N: CH ₃ OH: CH ₂ Cl ₂ = 0.5: 2: 8) to 4-{(glyciamino ) Methyl} -1- (4-fluorobenzyl) piperidine (453 mg, 46%).
REFERENCE EXAMPLE 28 Preparation of 4-{(Glycylamino) methyl} -1- {4- (N-phenylcarbamoyl) benzyl} piperidine
4-[{N- (9-fluorenylmethyloxycarbonyl) glyciyl} aminomethyl] piperidine (1.27 g, 2.96 mmol), Et ₃ N (1.25 mL, 8.88 mmol), KI (50 mg, To a mixture of 0.30 mmol) and CH ₃ CN (200 mL) is added dropwise a solution of 4- (N-phenylcarbamoyl) benzyl chloride (800 mg, 3.26 mmol) in CH ₃ CN (100 mL). The mixture is stirred for 19 h at room temperature and for 5 h at 60 ° C. Concentrate and perform column chromatography (SiO ₂ , 5% CH ₃ OH / CH ₂ Cl ₂ -Et ₃ N: CH ₃ OH: CH ₂ Cl ₂ = 2: 2: 96) to obtain 4-{(glysilamino) Methyl} -1- {4- (N-phenylcarbamoyl) benzyl} piperidine (340 mg, 30%).
Example 1091: Preparation of 1- (4-chlorobenzyl) -4-[{N- (3-cyanobenzyl) valyl} aminomethyl] piperidine (Compound No. 619)
A solution of 1- (4-chlorobenzyl) -4-{(valylamino) methyl} piperidine (20 mg, 0.059 mmol) in CH ₂ Cl ₂ (0.60 mL) was diluted with Et ₃ N (0.011 mL, 0.077 mmol). , m-cyanobenzoic acid (28 mg, 0.071 mmol), EDCI (13 mg, 0.065 mmol) and HOBt (9 mg, 0.065 mmol). The reaction mixture is stirred at 25 ° C. for 16 h. The resulting solution is diluted with CH ₂ Cl ₂ (0.75 mL), washed with 2N aqueous NaOH solution (2 × 0.75 mL) and filtered and dried over PTFE membrane. Concentration gives 1- (4-chlorobenzyl) -4-[{N- (3-cyanobenzyl) valyl} aminomethyl] piperidine (Compound No. 619) (24.2 mg, 88%), which is No further purification is required: purity is determined by RPLC / MS (85%); ESI / MS m / e 467 (M ⁺ + H, C ₂₆ H ₃₁ ClN ₄ O ₂ ).
Examples 1092-1543
The compounds of the present invention are each synthesized according to the method of Example 1091 using the corresponding reactants. ESI / MS data and yields are summarized in Table 27.
Compound no.Molecular formulaESI / MS m / eYield (mg)Yield (%) Example 1092467C22 H25 Br Cl N3 O24781146 Example 1093468C24 H31 Cl N4 O2443941 Example 1094469C23 H28 Cl N3 O34307 *27 Example 1095470C23 H25 Cl N4 O242521quant Example 1096471C24 H28 Cl N3 O4458729 Example 1097472C29 H31 N3 O35045 *21 Example 1098473C24 H28 Cl N3 O34421671 Example 1099474C23 H25 Cl F3 N3 O24681460 Example 1100475C25 H32 Cl N3 O2442522 Example 1101476C22 H25 Cl N4 O4445417 Example 1102477C25 H32 Cl N3 O345810 *36 Example 1103478C21 H27 Cl N4 O2403947 Example 1104479C20 H24 Cl N3 O33901787 Example 1105480C20 H23 Br Cl N3 O347023quant Example 1106481C20 H24 Cl N3 O2 S406733 Example 1107482C21 H26 Cl N3 O2 S420945 Example 1108483C21 H26 Cl N3 O2 S420840 Example 1109484C24 H27 Cl N4 O24399 *34 Example 1110485C24 H24 Cl F6 N3 O25361349 Example 1111486C23 H25 Cl N4 O24251674 Example 1112487C22 H25 Cl2 N3 O2434524 Example 1113488C22 H27 Cl N4 O2415732 Example 1114489C24 H24 Cl F6 N3 O25362178 Example 1115490C24 H30 Cl N3 O3444835 Example 1116491C23 H24 Cl F4 N3 O24861979 Example 1117492C23 H25 Cl F3 N3 O34841876 Example 1118493C23 H24 Cl2 F3 N3 O2502392 Example 1119494C23 H24 Cl F4 N3 O24861979 Example 1120495C23 H24 Cl F4 N3 O24862083 Example 1121496C23 H24 Cl F4 N3 O24861248 Example 1122497C25 H32 Cl N3 O3458416 Example 1123498C23 H26 Cl F3 N4 O24831352 Example 1124499C24 H31 Cl N4 O2443836 Example 1125500C23 H28 Cl N3 O34301048 Example 1126501C22 H24 Br Cl N4 O45231039 Example 1127502C22 H24 Cl F N4 O4463417 Example 1128503C22 H24 Cl2 N4 O44791252 Example 1129504C24 H30 Cl N3 O44601143
Example 1130505C22 H24 Br Cl N4 O452328 Example 1131506C20 H23 Cl N4 O5435210 Example 1132507C21 H26 Cl N3 O3404944 Example 1133508C24 H26 Cl N3 O2 S456One5 Example 1134509C20 H23 Br Cl N3 O2 S4841248 Example 1135510C22 H28 Cl N3 O3418944 Example 1136511C24 H32 Cl N3 O3446940 Example 1137512C25 H29 Cl N4 O24531045 Example 1138513C24 H28 Cl N3 O3442941 Example 1139514C26 H34 Cl N3 O24561149 Example 1140515C23 H28 Cl N3 O3430524 Example 1141525C23 H28 Cl N3 O4 S4782085 Example 1142526C20 H24 Cl N3 O3390631 Example 1143527C20 H24 Cl N3 O2 S406839 Example 1144528C25 H30 Cl F3 N4 O454328.295 Example 1145529C20 H23 Cl N4 O4 S451939 Example 1146530C31 H33 Cl N4 O2529517 Example 1147531C21 H26 Cl N3 O3 S436837 Example 1148532C22 H28 Cl N3 O3418840 Example 1149533C21 H26 Cl N3 O3404632 Example 1150534C21 H25 Cl N4 O5449520 Example 1151535C22 H26 Cl N3 O3 S448837 Example 1152536C23 H31 Cl N4 O2431628 Example 1153537C25 H34 Cl N3 O3460834 Example 1154538C27 H30 Cl N3 O3480936 Example 1155539C22 H25 Cl F3 N3 O34721875 Example 1156540C25 H29 Cl N4 O2453836 Example 1157541C22 H26 Cl N5 O44602.410 Example 1158542C24 H30 Cl N3 O24284.6 *51 Example 1159543C24 H30 Cl N3 O242820.6 *71 Example 1160544C22 H25 Cl F N3 O241815.8 *56 Example 1161545C22 H24 Cl3 N3 O24687.3 *23 Example 1162546C22 H24 Cl3 N3 O246817.4 *55 Example 1163547C22 H24 Cl3 N3 O246814.1 *44 Example 1164548C22 H24 Cl3 N3 O24686.8 *22 Example 1165549C22 H24 Cl2 N4 O44795.7 *18 Example 1166550C22 H24 Cl2 N4 O447918.9 *58 Example 1167551C24 H30 Cl N3 O242814.2 *49 Example 1168552C24 H27 Cl F3 N3 O248230.6 *94 Example 1169553C25 H26 Cl F6 N3 O255038.0 *quant Example 1170554C24 H26 Cl F N4 O24570.9 *3 Example 1171555C24 H26 Cl2 N4 O247311.1 *35 Example 1172556C25 H29 Cl N4 O245312.5 *41 Example 1173559C25 H26 Cl F6 N3 O25501572 Example 1174560C24 H27 Cl N4 O24391268 Example 1175561C23 H27 Br Cl N3 O24941473 Example 1176562C23 H27 Cl2 N3 O24481375 Example 1177563C25 H26 Cl F6 N3 O25501466 Example 1178564C25 H32 Cl N3 O3458528 Example 1179565C24 H26 Cl F4 N3 O25001261 Example 1180566C24 H27 Cl F3 N3 O34981262
Example 1181567C24 H26 Cl2 F3 N3 O25161261 Example 1182568C24 H26 Cl F4 N3 O25001577 Example 1183569C24 H26 Cl F4 N3 O25001159 Example 1184570C24 H26 Cl F4 N3 O25001684 Example 1185571C26 H34 Cl N3 O34721477 Example 1186572C24 H28 Cl F3 N4 O24971155 Example 1187573C21 H25 Br Cl N3 O2 S5001264 Example 1188574C21 H25 Br Cl N3 O2 S5001575 Example 1189575C25 H34 Cl N3 O34601687 Example 1190576C22 H28 Cl N3 O2 S4661371 Example 1191577C22 H28 Cl N3 O34181272 Example 1192578C25 H28 Cl N3 O2 S4701581 Example 1193579C25 H29 Cl N4 O24531794 Example 1194580C22 H28 Cl N3 O2 S4341591 Example 1195581C21 H26 Cl N3 O2 S4201380 Example 1196582C22 H28 Cl N3 O2 S4341059 Example 1197583C26 H31 Cl N4 O2467631 Example 1198584C30 H32 Cl N3 O35181892 Example 1199585C24 H27 Cl N4 O24391485 Example 1200586C23 H27 Cl2 N3 O24481797 Example 1201587C24 H27 Cl F3 N3 O24821791 Example 1202588C23 H29 Cl N4 O2429529 Example 1203589C27 H36 Cl N3 O2470424 Example 1204590C26 H34 Cl N3 O2456636 Example 1205591C25 H33 Cl N4 O2457738 Example 1206592C24 H30 Cl N3 O3444420 Example 1207593C24 H30 Cl N3 O3444214 Example 1208594C23 H28 Cl N3 O3430425 Example 1209595C25 H30 Cl N3 O4472738 Example 1210596C25 H30 Cl N3 O3456740 Example 1211597C25 H30 Cl N3 O34561585 Example 1212598C21 H26 Cl N3 O34041594 Example 1213599C22 H29 Cl N4 O2417530 Example 1214600C21 H25 Br Cl N3 O3484634 Example 1215601C24 H30 Cl N3 O3444528 Example 1216602C25 H33 Cl N4 O2457528 Example 1217603C23 H29 Cl N4 O2429422 Example 1218604C21 H27 Cl N4 O2403958 Example 1219605C21 H26 Cl N3 O34041787 Example 1220606C21 H26 Cl N3 O2 S4201574 Example 1221607C22 H28 Cl N3 O3 S45031quant Example 1222608C23 H30 Cl N3 O34321780 Example 1223609C22 H28 Cl N3 O34181889 Example 1224610C23 H28 Cl N3 O3 S4622086 Example 1225611C26 H36 Cl N3 O34742190 Example 1226612C28 H32 Cl N3 O34942084 Example 1227613C23 H27 Cl F3 N3 O34861981 Example 1228614C24 H33 Cl N4 O244523quant Example 1229615C25 H29 Cl N4 O2453420 Example 1230616C32 H35 Cl N4 O25431140
Example 1231617C25 H27 Cl F3 N3 O24826.737 Example 1232620C25 H31 Br Cl N3 O25201549 Example 1233621C25 H31 Cl2 N3 O24761864 Example 1234622C27 H37 Cl N4 O24851450 Example 1235623C26 H34 Cl N3 O34721969 Example 1236624C25 H31 Cl N4 O44872173 Example 1237625C25 H33 Cl N4 O24571969 Example 1238626C27 H30 Cl F6 N3 O2578825 Example 1239627C27 H36 Cl N3 O34861655 Example 1240628C27 H34 Cl N3 O45002480 Example 1241629C26 H30 Cl F4 N3 O25281856 Example 1242630C26 H31 Cl F3 N3 O35262168 Example 1243631C26 H30 Cl2 F3 N3 O25441548 Example 1244632C26 H30 Cl F4 N3 O25281341 Example 1245633C26 H30 Cl F4 N3 O25282063 Example 1246634C26 H30 Cl F4 N3 O25281962 Example 1247635C28 H38 Cl N3 O35001136 Example 1248636C26 H34 Cl N3 O24562189 Example 1249637C26 H31 Cl F3 N3 O25102095 Example 1250638C26 H31 Cl N4 O24671554 Example 1251639C27 H37 Cl N4 O24851966 Example 1252640C26 H34 Cl N3 O34721656 Example 1253641C27 H34 Cl N3 O45001859 Example 1254642C32 H36 Cl N3 O35462473 Example 1255643C26 H31 Cl F3 N3 O25101654 Example 1256644C29 H40 Cl N3 O24981861 Example 1257645C25 H33 Cl N4 O24572278 Example 1258646C26 H34 Cl N3 O34721347 Example 1259647C27 H34 Cl N3 O35001346 Example 1260648C28 H38 Cl N3 O24841760 Example 1261649C28 H38 Cl N3 O350012.542 Example 1262650C32 H36 Cl N3 O3546One*2 Example 1263651C28 H35 Cl N4 O24954*12 Example 1264652C25 H31 Cl N4 O44875 *14 Example 1265653C30 H42 Cl N3 O3528One*3 Example 1266654C27 H34 Cl N3 O34847 *21 Example 1267655C26 H32 Cl F3 N4 O25256 *16 Example 1268656C23 H30 Cl N3 O34326 *18 Example 1269657C23 H30 Cl N3 O2 S4484*13 Example 1270658C27 H33 Cl N4 O248One*4 Example 1271659C23 H29 Cl N4 O4 S4934*10 Example 1272660C34 H39 Cl N4 O25713 *7 Example 1273661C24 H32 Cl N3 O3 S4783 *7 Example 1274662C25 H34 Cl N3 O34602*6 Example 1275663C24 H32 Cl N3 O34462*5 Example 1276664C24 H31 Cl N4 O54912*5 Example 1277665C25 H32 Cl N3 O3 S490One*3 Example 1278666C26 H37 Cl N4 O24733 *7 Example 1279667C30 H36 Cl N3 O35223 *7 Example 1280668C25 H31 Cl F3 N3 O35142*6 Example 1281669C24 H33 Cl N4 O244515 *45
Example 1282670C23 H29 Br Cl N3 O35103 *7 Example 1283671C23 H29 Cl N4 O54772*5 Example 1284672C23 H31 Cl N4 O24312*7 Example 1285673C23 H30 Cl N3 O2 S4482*6 Example 1286674C24 H31 Cl N3 O2 S4623 *9 Example 1287675C24 H31 Cl N3 O2 S462One*4 Example 1288676C27 H33 Cl N4 O24822*6 Example 1289677C28 H35 Cl N4 O24952*6 Example 1290678C24 H31 Cl N3 O34463 *9 Example 1291679C27 H31 Cl N3 O2 S498One*3 Example 1292680C23 H29 Br Cl N3 O2 S5262*6 Example 1293681C25 H34 Cl N3 O34602*5 Example 1294682C27 H38 Cl N3 O34882*4 Example 1295683C24 H32 Cl N3 O2 S2494One*4 Example 1296684C26 H36 Cl N3 O4 S25542*5 Example 1297685C24 H31 Cl N3 O4 S25263 *7 Example 1298687C25 H30 Cl N3 O244024quant Example 1299688C27 H28 Cl F6 N3 O25762898 Example 1300689C26 H29 Cl N4 O24652399 Example 1301690C25 H29 Br Cl N3 O25182699 Example 1302691C27 H35 Cl N4 O24832497 Example 1303692C26 H32 Cl N3 O347024quant Example 1304693C27 H28 Cl F6 N3 O25761655 Example 1305694C27 H34 Cl N3 O348425quant Example 1306695C27 H32 Cl N3 O44981247 Example 1307696C26 H29 Cl F3 N3 O35242595 Example 1308697C26 H29 Cl N4 O24651564 Example 1309698C27 H35 Cl N4 O248324quant Example 1310699C26 H32 Cl N3 O347026quant Example 1311700C27 H32 Cl N3 O44981562 Example 1312701C27 H32 Cl N3 O34821144 Example 1313702C26 H29 Cl F3 N3 O25082394 Example 1314703C28 H36 Cl N3 O248226quant Example 1315704C25 H29 Cl N4 O44851143 Example 1316705C24 H30 Cl N3 O2 S46025quant Example 1317706C24 H30 Cl N3 O2 S46025quant Example 1318707C26 H29 Cl F3 N3 O25081555 Example 1319708C23 H27 Br Cl N3 O2 S5262592 Example 1320709C24 H30 Cl N3 O2 S249226quant Example 1321710C23 H27 Br Cl N3 O2 S5262594 Example 1322711C25 H32 Cl N3 O345826quant Example 1323712C27 H30 Cl N3 O2 S49626quant Example 1324713C24 H30 Cl N3 O344426quant Example 1325714C28 H33 Cl N4 O24931250 Example 1326715C23 H28 Cl N3 O2 S44624quant Example 1327716C27 H31 Cl N4 O247932quant Example 1328717C23 H27 Cl N4 O54752395 Example 1329718C23 H29 Cl N4 O242924quant Example 1330719C23 H28 Cl N3 O343024quant Example 1331720C23 H27 Br Cl N3 O35102495 Example 1332721C24 H31 Cl N4 O24432298
Example 1333722C26 H32 Cl N3 O3470937 Example 1334723C25 H31 Cl N4 O24551044 Example 1335724C29 H38 Cl N3 O249628quant Example 1336725C32 H34 Cl N3 O35442695 Example 1337726C27 H33 Cl N4 O3497311 Example 1338727C25 H29 Cl2 N3 O247425quant Example 1339728C25 H31 Cl N4 O24552192 Example 1340729C25 H29 Cl N4 O448526quant Example 1341730C25 H29 Cl2 N3 O24742190 Example 1342731C27 H32 Cl N3 O34821041 Example 1343732C26 H28 Cl F4 N3 O252627quant Example 1344733C28 H36 Cl N3 O34982289 Example 1345734C26 H28 Cl F4 N3 O25262594 Example 1346735C26 H28 Cl F4 N3 O25262387 Example 1347736C26 H30 Cl F3 N4 O25232478 Example 1348737C26 H28 Cl F4 N3 O25262166 Example 1349738C25 H32 Cl N3 O34582384 Example 1350739C27 H31 Cl N4 O24791966 Example 1351740C24 H31 Cl N4 O54892377 Example 1352741C23 H27 Cl N4 O4 S4912688 Example 1353742C24 H30 Cl N3 O3 S4762382 Example 1354743C23 H28 Cl N3 O34302181 Example 1355744C26 H32 Cl N3 O24542591 Example 1356745C27 H36 Cl N3 O34862380 Example 1357746C26 H35 Cl N4 O24712796 Example 1358747C25 H29 Cl F3 N3 O35122374 Example 1359748C23 H28 Cl N3 O2 S4462282 Example 1360751C24 H30 Cl N3 O3444311 Example 1361752C25 H26 Cl F6 N3 O3566720 Example 1362753C24 H27 Cl N4 O3455622 Example 1363754C23 H27 Cl2 N3 O3464829 Example 1364755C24 H30 Cl N3 O4460622 Example 1365756C23 H27 Cl N4 O5475518 Example 1366757C25 H32 Cl N3 O4474518 Example 1367758C25 H30 Cl N3 O5488518 Example 1368759C24 H27 Cl F3 N3 O4514620 Example 1369760C24 H26 Cl F4 N3 O3516618 Example 1370761C24 H26 Cl F4 N3 O3516310 Example 1371762C24 H27 Cl F3 N3 O3498295 Example 1372763C23 H28 Cl N3 O3430495 Example 1373764C24 H30 Cl N3 O2428942 Example 1374765C25 H32 Cl N3 O24421047 Example 1375766C25 H29 Cl F3 N3 O24961042 Example 1376767C25 H32 Cl N3 O4 S506832 Example 1377768C24 H29 Br Cl N3 O2506935 Example 1378769C25 H29 Cl F3 N3 O3512622 Example 1379770C25 H28 Cl F4 N3 O2514310 Example 1380771C25 H28 Cl F4 N3 O25141037 Example 1381772C25 H29 Cl F3 N3 O2496833 Example 1382773C26 H36 Cl N3 O34741041 Example 1383774C23 H30 Cl N3 O2 S24801250
Example 1384775C27 H38 Cl N3 O34881457 Example 1385776C29 H34 Cl N3 O35081249 Example 1386777C24 H29 Cl F3 N3 O35002287 Example 1387778C24 H28 Cl2 N4 O4507622 Example 1388779C24 H29 Cl2 N3 O24621046 Example 1389780C24 H29 Cl N4 O44731565 Example 1390781C26 H31 Cl N4 O24677 *20 Example 1391782C25 H32 Cl N3 O34588*23 Example 1392783C26 H34 Cl N3 O34727 *19 Example 1393784C26 H31 Cl F3 N3 O25107 *17 Example 1394785C26 H34 Cl N3 O44886 *17 Example 1395786C24 H28 Cl N3 O2426229 Example 1396787C25 H30 Cl N3 O24402194 Example 1397788C25 H27 Cl F3 N3 O24944*14 Example 1398789C25 H30 Cl N3 O4 S504935 Example 1399790C24 H27 Cl2 N3 O24605 *16 Example 1400791C24 H27 Cl N4 O44713 *10 Example 1401792C25 H27 Cl F3 N3 O35105 *16 Example 1402793C25 H26 Cl F4 N3 O25115 *16 Example 1403794C25 H26 Cl F4 N3 O25125 *16 Example 1404795C25 H27 Cl F3 N3 O24946 *21 Example 1405796C23 H28 Cl N3 O2 S24784*14 Example 1406797C27 H36 Cl N3 O34867 *29 Example 1407798C29 H32 Cl N3 O3506313 Example 1408799C24 H27 Cl F3 N3 O34983 *11 Example 1409800C24 H26 Cl2 N4 O45055 *15 Example 1410801C26 H29 Cl N4 O24651241 Example 1411802C25 H30 Cl N3 O34565 *15 Example 1412803C26 H32 Cl N3 O34706 *16 Example 1413804C26 H29 Cl F3 N3 O25088*20 Example 1414805C26 H32 Cl N3 O44866 *15 Example 1415806C24 H27 Br Cl N3 O25065 *14 Example 1416807C27 H32 Cl N5 O351029.7quant Example 1417808C26 H33 Cl N4 O348529.9quant Example 1418809C25 H30 Cl2 N4 O350530.2quant Example 1419810C30 H35 Cl N4 O455131.0quant Example 1420811C25 H29 Cl2 N5 O555030.4quant Example 1421812C24 H31 Cl N4 O3 S252325.088 Example 1422813C26 H30 Cl F3 N4 O353920.570 Example 1423814C26 H30 Cl F3 N4 O455522.775 Example 1424815C26 H29 Cl F4 N4 O355725.885 Example 1425816C26 H30 Cl F3 N4 O353925.386 Example 1426817C26 H29 Cl F4 N4 O355726.888 Example 1427818C25 H30 Br Cl N4 O355127.190 Example 1428819C27 H29 Cl F6 N4 O360713.942 Example 1429820C25 H30 Cl N5 O551614.151 Example 1430821C24 H28 Cl2 N4 O55234086 Example 1431822C23 H30 Cl N3 O3 S24964193 Example 1432823C26 H31 Cl N4 O348343quant Example 1433824C27 H38 Cl N3 O45033783 Example 1434825C29 H34 Cl N3 O45242861
Example 1435826C24 H29 Cl F3 N3 O45164087 Example 1436827C26 H31 Cl N4 O34833172 Example 1437828C25 H29 Cl F3 N3 O45284086 Example 1438829C25 H28 Cl F4 N3 O35304597 Example 1439830C25 H28 Cl F4 N3 O35303574 Example 1440831C24 H29 Br Cl N3 O35234598 Example 1441832C24 H29 Cl2 N3 O34783891 Example 1442833C24 H29 Cl N4 O54883887 Example 1443834C25 H29 Cl F3 N3 O35124293 Example 1444835C24 H30 Cl N3 O344443quant Example 1445836C25 H32 Cl N3 O34583791 Example 1446837C25 H29 Cl F3 N3 O35124191 Example 1447838C26 H34 Cl N3 O44883478 Example 1448839C27 H36 Cl N3 O65343771 Example 1449942C27 H30 Cl F6 N3 O25781748 Example 1450997C26 H34 Cl N3 O24567.6 *23 Example 1451998C27 H33 Cl F3 N3 O2524615 Example 1452999C27 H36 Cl N3 O2470824 Example 14531000C27 H36 Cl N3 O3486924 Example 14541001C28 H38 Cl N3 O3500410 Example 14551002C27 H33 Cl F3 N3 O3540923 Example 14561003C28 H38 Cl N3 O2484721 Example 14571004C28 H38 Cl N3 O45161130 Example 14581005C29 H40 Cl N3 O5547923 Example 14591006C30 H42 Cl N3 O4544821 Example 14601007C32 H46 Cl N3 O5589717 Example 14611008C25 H31 Cl N4 O34712579 Example 14621009C26 H33 Cl N4 O45013597 Example 14631010C27 H35 Cl N4 O4515359 Example 14641011C27 H35 Cl N4 O34993254 Example 14651012C27 H35 Cl N4 O55312777 Example 14661013C28 H37 Cl N4 O65611437 Example 14671014C29 H39 Cl N4 O55592466 Example 14681015C31 H43 Cl N4 O66032565 Example 14691018C26 H34 Cl N3 O448813.0 *39 Example 14701019C28 H38 Cl N3 O553213.4 *37 Example 14711020C25 H32 Cl N3 O447412.7 *40 Example 14721021C26 H28 Cl F6 N3 O459613.8 *34 Example 14731022C25 H32 Cl N3 O447414.2 *37 Example 14741023C25 H32 Cl N3 O244311.5 *32 Example 14751024C26 H34 Cl N3 O550412.0 *30 Example 14761025C27 H36 Cl N3 O450214.7 *37 Example 14771026C29 H40 Cl N3 O554613.5 *32 Example 14781027C26 H34 Cl N3 O448811.9 *31 Example 14791028C27 H30 Cl F6 N3 O461014.6 *31 Example 14801029C25 H32 Cl N3 O345814.0 *38 Example 14811030C24 H27 Cl F3 N3 O349814.0 *35 Example 14821031C24 H30 Cl N3 O344410.4 *29 Example 14831032C25 H32 Cl N3 O447414.9 *39 Example 14841033C25 H32 Cl N3 O244213.3 *37 Example 14851034C26 H34 Cl N3 O550413.7 *34
Example 14861035C27 H36 Cl N3 O450216.7 *42 Example 14871036C29 H40 Cl N3 O554715.5 *36 Example 14881037C26 H34 Cl N3 O448814.1 *36 Example 14891038C27 H30 Cl F6 N3 O461017.5 *37 Example 14901039C25 H32 Cl N3 O345815.1 *41 Example 14911040C24 H27 Cl F3 N3 O349815.4 *39 Example 14921041C24 H30 Cl N3 O344412.7 *35 Example 14931042C22 H26 Br Cl N4 O249510.4 *25 Example 14941043C22 H26 Cl2 N4 O244911.1 *29 Example 14951044C23 H29 Cl N4 O24295.2 *14 Example 14961045C23 H29 Cl N4 O344512.4 *33 Example 14971046C22 H25 Cl3 N4 O248310.0 *25 Example 14981047C24 H31 Cl N4 O244312.1 *32 Example 14991048C25 H33 Cl N4 O550516.1 *39 Example 15001049C23 H28 Br Cl N4 O250712.0 *29 Example 15011050C28 H38 Cl N3 O451639.2 *quant Example 15021051C28 H38 Cl N3 O248434.0 *quant Example 15031052C29 H40 Cl N3 O554614.5 *39 Example 15041053C30 H42 Cl N3 O454411.8 *32 Example 15051054C32 H46 Cl N3 O558812.2 *31 Example 15061055C29 H40 Cl N3 O453044.5 *quant Example 15071056C30 H36 Cl F6 N3 O465246.0 *quant Example 15081057C28 H38 Cl N3 O350011.2 *32 Example 15091058C27 H36 Cl N3 O348635.5 *quant Example 15101059C27 H33 Cl F3 N3 O354041.4 *quant Example 15111060C29 H40 Cl N3 O453013.6 *37 Example 15121061C30 H36 Cl F6 N3 O465244.2 *quant Example 15131062C28 H38 Cl N3 O350039.9 *quant Example 15141063C27 H36 Cl N3 O348612.0 *35 Example 15151064C27 H33 Cl F3 N3 O354037.8 *quant Example 15161065C28 H38 Cl N3 O451612.3 *34 Example 15171066C28 H38 Cl N3 O248430.7 *90 Example 15181067C29 H40 Cl N3 O554613.8 *37 Example 15191068C30 H42 Cl N3 O454413.1 *35 Example 15201069C32 H46 Cl N3 O558914.1 *35 Example 15211070C29 H34 Cl N3 O3 S257238.393 Example 15221071C32 H35 Cl N4 O355939.698 Example 15231072C33 H42 Cl N3 O458040.998 Example 15241073C35 H38 Cl N3 O460040.594 Example 15251074C30 H33 Cl F3 N3 O459238.791 Example 15261075C31 H33 Cl F3 N3 O46043887 Example 15271076C30 H33 Cl N4 O556538.594 Example 15281077C31 H33 Cl F3 N3 O358835.884 Example 15291078C30 H34 Cl N3 O352034.793 Example 15301079C31 H36 Cl N3 O353438.4quant Example 15311080C32 H38 Cl N3 O456439.397 Example 15321081C33 H40 Cl N3 O661045.5quant Example 15331082C28 H36 Cl N3 O34984.1 *10 Example 15341083C28 H36 Cl N3 O34986.4 *16 Example 15351125C30 H32 Cl2 N4 O55993.4 *8 Example 15361126C30 H32 Br Cl N4 O56443.4 *7
Example 15371127C32 H35 Cl N4 O35591.6 *4 Example 15381128C31 H32 Cl F4 N3 O36064.3 *10 Example 15391129C31 H32 Cl F4 N3 O36065.9 *14 Example 15401130C30 H33 Br Cl N3 O35995.7 *13 Example 15411131C30 H33 Cl2 N3 O35546.4 *16 Example 15421132C31 H33 Cl F3 N3 O35886.3 *15 Example 15431167C27 H34 Cl N3 O34841.8 *4
* Yield of TFA salt
Example 1544: Preparation of 1- (4-chlorobenzyl) -4-[{N- (3,5-bis (trifluoromethyl) benzoyl) glycyl} aminomethyl] piperidine (Compound No. 1213)
A solution of 3,5-bis (trifluoromethyl) benzoyl chloride (0.058 mmol) in dichloromethane (1 mL) was added to 1- (4-chlorobenzyl) -4 in chloroform (0.2 mL) and dichloromethane (0.75 mL). Add to a mixture of-{(glysilamino) methyl} piperidine (0.050 mmol) and piperidinomethylpolystyrene (58 mg). The reaction mixture is stirred at room temperature for 2 h, then methanol (1.0 mL) is added and the mixture is stirred at room temperature for 30 minutes. The reaction mixture is loaded on a Varian ^™ SCX column and washed with CH ₃ OH (16 mL). The product was eluted with 2N NH ₃ in CH ₃ OH (6 mL) and concentrated to 1- (4-chlorobenzyl) -4-[{N- (3,5-bis (trifluoromethyl) benzoyl) Glycyl} aminomethyl] piperidine (Compound No. 1213) (24.0 mg, 90%): Purity is determined by RPLC / MS (100%); ESI / MS m / e 536.2 (M ⁺ + H, C ₂₄ H ₃₄ ClF ₆ N ₃ O ₂ ).
Examples 1545-1547
The compounds of the present invention are each synthesized according to the method of Example 1544 using the corresponding reactants. ESI / MS data and yields are summarized in Table 28.
Compound no.Molecular formulaESI / MS m / eYield (mg)Yield (%) Example 15451214C23 H24 Cl F4 N3 O2486.222.291 Example 15461215C22 H24 Cl3 N3 O2467.920.989 Example 15471216C22 H24 Cl F2 N3 O2436.019.389
Example 1548: Preparation of 4-[{N- (3-bromo-4-methylbenzoyl) glycyl} aminomethyl] -1- (4-chlorobenzyl) piperidine (Compound No. 1113)
A solution of 1- (4-chlorobenzyl) -4-{(glycaminoamino) methyl} piperidine (0.050 mmol) in CHCl ₃ (1.35 mL) and tert-butanol (0.15 mL) was treated with 3-bromo-4 Treatment with methylbenzoic acid (0.060 mmol), diisopropylcarbodiimide (0.060 mmol) and HOBt (0.060 mmol). The reaction mixture is stirred for 15 h at room temperature. The mixture is loaded on a Varian ^™ SCX column and washed with CH ₃ OH / CHCl ₃ 1: 1 (12 mL) and CH ₃ OH (12 mL). The product was eluted with 2N NH ₃ in CH ₃ OH (5 mL) and concentrated to 4-[{N- (3-bromo-4-methylbenzoyl) glyciyl} aminomethyl] -1- (4- Chlorobenzyl) piperidine (Compound No. 1113) (16.1 mg, 65%): Purity is determined by RPLC / MS (95%); ESI / MS m / e 494.0 (M ⁺ + H, C ₂₃ H ₂₇ ClN ₃ O ₂ ).
Examples 1549-1619
The compounds of the present invention are each synthesized according to the method of Example 1548 using the corresponding reactants. If necessary, preparative TLC is used to provide the desired material. ESI / MS data and yields are summarized in Table 29.
Compound no. 1422 is Compound No. Obtained as a by-product of 1418: 5.6 mg, 25% yield; ESI / MS m / e 447.2 (C ₂₂ H ₂₇ ClN ₄ O ₂ S).
Compound no.Molecular formulaESI / MS m / eYield (mg)Yield (%) Example 15491114C22 H24 Br Cl F N3 O2498.020.281 Example 15501115C22 H24 Cl2 F N3 O2452.218.682 Example 15511116C23 H27 Cl I N3 O2539.121.981 Example 15521117C23 H27 Cl N4 O4459.218.781 Example 15531187C23 H27 Br Cl N3 O2494.022.190 Example 15541188C24 H27 Cl N4 O3455.217.276 Example 15551189C25 H29 Cl N4 O3469.221.190 Example 15561190C22 H26 Cl F N4 O2433.220.494 Example 15571241C23 H24 Cl2 F3 N3 O2502.022.590 Example 15581242C23 H27 Cl F N3 O2432.221.298 Example 15591243C23 H27 Cl2 N3 O2448.021.696 Example 15601244C22 H26 Cl I N4 O2541.026.498 Example 15611245C22 H25 Cl F2 N4 O2451.021.394 Example 15621246C21 H27 Cl N4 O2403.219.496 Example 15631247C28 H30 Cl N3 O2 S524.024.794 Example 15641248C22 H25 Cl N4 O5461.020.790 Example 15651282C25 H26 Cl F3 N4 O3523.225.096 Example 15661283C23 H27 Cl2 N3 O3464.212.253 Example 15671284C22 H25 Br Cl N3 O3496.024.197 Example 15681285C22 H25 Cl2 N3 O3450.221.897 Example 15691342C22 H24 Br Cl2 N3 O2514.027.2quant Example 15701343C23 H27 Cl2 N3 O2448.021.495 Example 15711344C22 H24 Cl2 I N3 O2560.027.096 Example 15721345C23 H28 Cl N3 O2430.223.8quant Example 15731346C22 H25 Cl I N3 O3542.029.4quant Example 15741350C21 H26 Cl N3 O2 S420.013.062 Example 15751354C24 H28 Br Cl N4 O3537.25.219 Example 15761358C23 H26 Cl N5 O2440.221.899
Example 15771383C23 H24 Cl2 F3 N3 O2502.020.080 Example 15781384C20 H23 Br Cl N3 O2 S486.021.087 Example 15791385C28 H30 Cl N3 O4 S540.223.888 Example 15801386C28 H30 Cl N3 O2476.020.084 Example 15811414C24 H28 Cl2 N4 O3491.00.83 Example 15821418C23 H26 Cl N5 O2 S472.010.444 Example 15831436C29 H30 Cl N3 O3504.226.8quant Example 15841600C23 H26 Cl F3 N4 O2483.216.568 Example 15851601C23 H26 Cl F3 N4 O3499.020.080 Example 15861602C21 H24 Br Cl N4 O2481.018.175 Example 15871603C21 H24 Cl2 N4 O2435.05.525 Example 15881604C27 H30 Cl N3 O3492.018.676 Example 15891605C21 H27 Cl N4 O2415.218.187 Example 15901609C23 H25 N3 O2 S500.018.373 Example 15911659C22 H26 Cl2 N4 O2449.0366.083 Example 15921664C24 H29 F3 N4 O2 S495.213.755 Example 15931665C24 H29 F3 N4 O3 S511.214.958 Example 15941666C23 H28 F2 N4 O2 S463.212.956 Example 15951667C22 H27 Br2 N3 O354226.196 Example 15961668C24 H30 F2 N4 O244522.9quant Example 15971669C24 H31 F N4 O242724.0quant Example 15981670C24 H31 I N4 O253528.1quant Example 15991671C25 H31 F3 N4 O349326.8quant Example 16001672C25 H31 F3 N4 O247824.7quant Example 16011673C24 H29 Br Cl N3 O250824.998 Example 16021674C20 H22 Br2 F N3 O353225.696 Example 16031675C22 H25 F3 N4 O243521.599 Example 16041676C22 H26 F2 N4 O241721.4quant Example 16051677C22 H26 Br F N4 O247923.498 Example 16061678C22 H26 F I N4 O252527.4quant Example 16071679C22 H26 Cl F N4 O243322.4quant Example 16081680C23 H26 F4 N4 O348325.5quant Example 16091681C23 H26 F4 N4 O246723.299 Example 16101682C23 H26 Br Cl N3 O49824.298 Example 16111683C27 H28 Br2 N4 O463331.8quant Example 16121684C29 H31 F2 N5 O353628.3quant Example 16131685C29 H32 F N5 O351831.1quant Example 16141686C29 H32 Br N5 O357829.6quant Example 16151687C29 H31 I N5 O362632.4quant Example 16161688C29 H32 Cl N5 O353428.2quant Example 16171689C30 H32 F3 N5 O458431.7quant Example 16181690C30 H32 F3 N5 O356830.6quant Example 16191691C29 H30 Br Cl N4 O359931.4quant
For example, compounds 1245 and 1600 show the following NMR spectra.
Compound no. 1245: ¹ H NMR (270 MHz, CDCl ₃ ) δ 1.20-1.97 (m, 7H), 2.80-2.86 (m, 2H), 3.19 (t, J = 6.5 Hz, 2H), 3.43 (s, 2H), 4.02 (d, J = 5.3 Hz, 2H), 5.52 (br s, 2H), 6.44 (d, J = 11.9, 6.6 Hz, 1H), 7.02 (br s, 1H), 7.21-7.32 (m, 5H).
Compound no. 1600: ¹ H NMR (270 MHz, CDCl ₃ ) δ 1.25-1.97 (m, 9H), 2.82-2.87 (m, 2H), 3.21 (t, J = 6.5 Hz, 2H), 3.44 (s, 2H), 4.06 (d, J = 5.1 Hz, 2H), 5.98 (br s, 1H), 6.71 (d, J = 8.3 Hz, 1H), 6.87 (br s, 1H), 7.26 (s, 4H), 7.43 (dd, J = 5.9 Hz, 1 H), 7.64 (s, 1 H).
Example 1620: Preparation of 1- (4-chlorobenzyl) -4-[{N- (4-isopropylphenylsulfonyl) glycyl} aminomethyl] piperidine (Compound No. 869)
A solution of 1- (4-chlorobenzyl) -4-{(glycylamino) methyl} piperidine (14.8 mg, 0.05 mmol) in CHCl ₃ (2 mL) was dissolved in (piperidinomethyl) polystyrene resin (28 mg , 2.8 mmol / g), 4-isopropylbenzenesulfonyl chloride (1.5 equiv) and stir at 25 ° C. for 16 h. (Aminomethyl) polystyrene is added to remove residual sulfonyl chloride and the reaction mixture is stirred at 25 ° C. for 16 h. Filtration and concentration afforded 1- (4-chlorobenzyl) -4-[{N- (4-isopropylphenylsulfonyl) glycyl} aminomethyl] piperidine (Compound No. 869) (22.1 mg, 92%) Purity is determined by RPLC / MS (86%); ESI / MS m / e 478 (M ⁺ + H, C ₂₄ H ₃₂ ClN ₃ O ₃ S).
Examples 1621-1627
The compounds of the present invention are each synthesized according to the method of Example 1620 using the corresponding reactants. ESI / MS data and yields are summarized in Table 30.
Compound no.Molecular formulaESI / MS m / eYield (mg)Yield (%) Example 1621865C22 H28 Cl N3 O3 S45016.272 Example 1622866C22 H25 Cl F3 N3 O3 S5048.835 Example 1623867C23 H24 Cl F6 N3 O3 S5728.028 Example 1624868C23 H30 Cl N3 O3 S4649.641 Example 1625870C22 H28 Cl N3 O3 S4508.839 Example 1626871C25 H34 Cl N3 O3 S49211.145 Example 1627872C21 H26 Cl N3 O3 S4369.644
Example 1628: Preparation of 1- (4-chlorobenzyl) -4-[{2- (3- (4-trifluoromethylphenyl) ureido) acetylamino} methyl] piperidine (Compound No. 852)
A solution of 1- (4-chlorobenzyl) -4-{(glycylamino) methyl} piperidine (14.8 mg, 0.05 mmol) in CHCl ₃ (2 mL) was dissolved in (piperidinomethyl) polystyrene resin (28 mg , 2.8 mmol / g), 3- (trifluoromethyl) phenyl isocyanate (1.3 equiv) and stir at 25 ° C. for 16 h. (Aminomethyl) polystyrene is added to remove residual isocyanates and the reaction mixture is stirred at 25 ° C. for 16 h. Filtration and concentration afforded 1- (4-chlorobenzyl) -4-[{2- (3- (4-trifluoromethylphenyl) ureido) acetylamino} methyl] piperidine (Compound No. 852) (19 mg , 78%): purity is determined by RPLC / MS (92%); ESI / MS m / e 483 (M ⁺ + H, C ₂₃ H ₂₆ ClF ₃ N ₄ O ₂ ).
Examples 1629-1641
The compounds of the present invention are each synthesized according to the method of Example 1628 using the corresponding reactants. ESI / MS data and yields are summarized in Table 31.
Compound no.Molecular formulaESI / MS m / eYield (mg)Yield (%) Example 1629851C23 H26 Cl F3 N4 O248312.255 Example 1630853C22 H27 Cl N4 O24168.5 *32 Example 1631854C23 H29 Cl N4 O242911.4 *42 Example 1632855C23 H29 Cl N4 O242910.1 *37 Example 1633856C24 H29 Cl N4 O345710.3 *36 Example 1634857C23 H29 Cl N4 O344510.9 *39 Example 1635858C23 H29 Cl N4 O34458.6 *31 Example 1636859C22 H26 Cl2 N4 O244911.0 *39 Example 1637860C23 H26 Cl N5 O24409.2 *33 Example 1638861C22 H27 Cl N4 O S43113.362 Example 1639862C23 H29 Cl N4 O S44515.369 Example 1640863C23 H29 Cl N4 O2 S46114.764 Example 1641864C23 H29 Cl N4 O2 S46113.157
Yield of TFA salt
Example 1642: Preparation of 1- (4-chlorobenzyl) -4-[{N- (3-ethoxybenzoyl) -D-phenylalanyl} aminomethyl] piperidine (Compound No. 2091)
A solution of 1- (4-chlorobenzyl) -4- (aminomethyl) piperidine (100 mg) in CHCl ₃ (3 mL) was added Et ₃ N (0.090 mL), N- (tert-butoxycarbonyl) Treatment with -D-phenylalanine (122 mg), EDCI (89 mg) and HOBt (62 mg). The reaction mixture is stirred for 17 h at room temperature. The reaction mixture is washed with 1N aqueous NaOH solution (2 mL × 2) and brine (2 mL). The organic layer is dried and concentrated to give 1- (4-chlorobenzyl) -4-[{N- (tert-butoxycarbonyl) -D-phenylalanyl} aminomethyl] piperidine.
The resulting 1- (4-chlorobenzyl) -4-[{N- (tert-butoxycarbonyl) -D-phenylalanyl} aminomethyl] piperidine is dissolved in methanol (5 mL) and dioxane Add 4N HCl in (1.5 mL). The solution is stirred for 19 h at room temperature and concentrated.
The resulting material and a solution of _3- ethoxybenzoic acid (80 mg, 0.48 mmol) in CHCl ₃ (1 mL) are treated with Et ₃ N (0.090 mL), EDCI (90 mg) and HOBt (68 mg). The reaction mixture is stirred for 11 h at room temperature. The reaction mixture is washed with 1N aqueous NaOH solution (1.5 mL × 2) and brine (1.5 mL). The organic layer is dried and concentrated. Column chromatography (SiO ₂ , CH ₂ Cl ₂ / MeOH = 95: 5) gave 1- (4-chlorobenzyl) -4-[{N- (3-ethoxybenzoyl) -D-phenylalanyl} amino Methyl] piperidine (Compound No. 2091) (183.5 mg, 82%): Purity is determined by RPLC / MS (99%); ESI / MS m / e 534.0 (M ⁺ + H, C ₃₁ H ₃₆ ClN ₃ O ₃ ).
Examples 1643-1657
The compounds of the present invention are each synthesized according to the method of Example 1642 using the corresponding reactants. ESI / MS data and yields are summarized in Table 32.
Compound no.Molecular formulaESI / MS m / eYield (mg)Yield (%) Example 16432092C33 H37 Cl N4 O3572.8152.964 Example 16442093C27 H36 Cl N3 O3 S518.0177.482
Example 16452094C29 H34 Cl N3 O3 S539.9164.473 Example 16462095C28 H38 Cl N3 O3500.0139.166 Example 16472096C31 H42 Cl N3 O3540.0161.771 Example 16482097C27 H36 Cl N3 O3485.8157.878 Example 16492098C31 H35 Cl2 N3 O3567.9172.272 Example 16502099C30 H34 Cl N3 O3519.8144.766 Example 16512100C32 H38 Cl N3 O4564.0181.577 Example 16522101C38 H42 Cl N3 O4639.9192.372 Example 16532103C33 H40 Cl N3 O4577.8159.966 Example 16542104C28 H36 Cl N3 O5530.199.745 Example 16552115C27 H36 Cl N3 O3486.2122.960 Example 16562116C28 H38 Cl N3 O3500.1118.357 Example 16572117C28 H34 Cl N5 O3524.198.345
Reference Example 29 Preparation of 1- (tert-butoxycarbonyl) -4-[{N- (3- (trifluoromethyl) benzoyl) glyciyl} aminomethyl] piperidine
N- {3- (trifluoromethyl) benzoyl} glycine (4.22 g, 17.0 mmol), EDCI (4.25 g, 22.1 mmol), 1-hydroxybenzotriazole hydrate (2.99 g, 22.1 mmol) and Et ₃ N (1.72 g) is added to a solution of 1- (tert-butoxycarbonyl) -4- (aminomethyl) piperidine (4.03 g) in dry CH ₂ Cl ₂ (200 mL). The reaction mixture is stirred at 25 ° C. for 20 h. H ₂ O (100 mL) is added to the reaction mixture and the mixture is extracted with CH ₂ Cl ₂ (2 × 50 mL). The combined extracts are washed with H ₂ O (2 × 50 mL), brine (50 mL) and dried (MgSO ₄ ). The solvent was removed under reduced pressure to give a yellow oil which was subjected to column chromatography (SiO ₂ , 70% EtOAc-hexane) to give 1- (tert-butoxycarbonyl) -4-[{N- (3 as a white solid). -(Trifluoromethyl) benzoyl) glycyl} aminomethyl] piperidine (6.39 g, 85%): ¹ H-NMR (CDCl ₃ , 300 MHz) δ 1.4 (s, 9H), 1.0-1.8 (m, 5H), 2.6-2.8 (m, 2H), 3.15-3.3 (m, 2H), 4.0-4.3 (m, 4H), 6.6-6.7 (m, 1H), 7.64 (s, 1H), 7.60 (dd, 1H, J = 7.2, 7.2 Hz), 7.79 (d, 1H, J = 7.2 Hz), 8.0 (d, 1H, J = 7.2 Hz), 8.11 (s, 1H): Purity is RPLC / MS Determined (97%); ESI / MS m / e 444.3 (M ⁺ + H, C ₂₁ H ₂₈ F ₃ N ₃ O ₄ ).
Reference Example 30: Preparation of 4-[{N- (3-trifluoromethyl) benzoyl) glycyl} aminomethyl] piperidine
1- (tert-butoxycarbonyl) -4-[{N- (3- (trifluoromethyl) benzoyl) glycyl} aminomethyl] piperidine in CH ₃ OH (40 mL) (2.29 g, 5.16 mmol) is treated with 1N HCl-Et ₂ O (55 mL). The reaction mixture is stirred at 25 ° C. for 15 h and the solvent is removed under reduced pressure. 2N aqueous NaOH solution (100 mL) is added to the reaction mixture, and the mixture is extracted with EtOAc (3 × 100 mL). The combined extracts are washed with brine and dried (K ₂ CO ₃ ). The solvent was removed under reduced pressure to give a white solid, which was subjected to column chromatography (SiO ₂ , CH ₃ OH / CH ₂ Cl ₂ / Et ₃ N = 7/6/1) to give 4-[{N- (3-trifluoromethyl) benzoyl) gylsil} aminomethyl] piperidine (1.27 g, 72%) is provided: Purity is determined by RPLC / MS (98%); ESI / MS m / e 344.1 (M ⁺ + H, C ₁₆ H ₂₀ F ₃ N ₃ O ₃ ).
Example 1658: 1- {3- (trifluoromethyl) benzyl} -4-[{N- (3- (trifluoromethyl) benzoyl) gylsil) aminomethyl} piperidine (Compound No. 927) Manufacture
Solution of 4-[{N- (3- (trifluoromethyl) benzoyl) glyciyl} aminomethyl] piperidine (19.9 mg, 0.058 mmol) in CH ₃ CN (1.0 mL) and (piperidinomethyl) Polystyrene (55 mg, 2.7 mmol base / g resin) is added to a solution of 3- (trifluoromethoxy) benzyl bromide (12.3 mg, 0.048 mmol) in CH ₃ CN (1.0 mL). The reaction mixture is stirred at 60 ° C. for 2.5 h. Phenyl isocyanate (6.9 mg, 0.048 mmol) is added to the cooled reaction mixture and the mixture is stirred at 25 ° C. for 1 h. The reaction mixture is loaded on a Varian ^™ SCX column and washed with CH ₃ OH (20 mL). The product was eluted with 2N NH ₃ in CH ₃ OH (6 mL) and concentrated to give 1- {3- (trifluoromethyl) benzyl} -4-[{N- (3- (tri Fluoromethyl) benzoyl) glycyl) aminomethyl} piperidine (Compound No. 927) (22.8 mg, 91%): Purity is determined by RPLC / MS (99%); ESI / MS m / e 518.1 (M ⁺ + H, C ₂₄ H ₂₅ F ₆ N ₃ O ₃ ).
Examples 1659-1710
The compounds of the present invention are each synthesized according to the method of Example 1658 using the corresponding reactants. ESI / MS data and yields are summarized in Table 33.
Compound no.Molecular formulaESI / MS m / eYield (mg)Yield (%) Example 1659875C23 H26 F3 N3 O24346.340 Example 1660876C23 H25 Br F3 N3 O25124.323
Example 1661877C24 H25 F3 N4 O245911.368 Example 1662878C23 H25 F3 N4 O44798.348 Example 1663884C25 H29 F3 N4 O349110.861 Example 1664885C24 H28 F3 N3 O4 S5129.049 Example 1665886C23 H25 F4 N3 O245212.778 Example 1666887C24 H25 F6 N3 O250213.977 Example 1667888C23 H26 F3 N3 O345011.571 Example 1668889C29 H30 F3 N3 O251012.468 Example 1669890C27 H28 F3 N3 O248412.069 Example 1670891C23 H24 Cl2 F3 N3 O250211.463 Example 1671892C24 H28 F3 N3 O346411.770 Example 1672893C24 H26 F3 N5 O552213.974 Example 1673894C26 H32 F3 N3 O349211.364 Example 1674895C24 H28 F3 N3 O24484.830 Example 1675896C24 H25 F3 N4 O245917.5quant Example 1676897C24 H26 F3 N3 O44789.257 Example 1677898C24 H26 F3 N3 O44788.955 Example 1678899C24 H28 F3 N3 O346413.782 Example 1679900C25 H28 F3 N3 O449218.6quant Example 1680901C29 H30 F3 N3 O251013.775 Example 1681902C23 H24 F3 N5 O652412.667 Example 1682903C25 H30 F3 N3 O449414.079 Example 1683906C25 H30 F3 N3 O246211.267 Example 1684907C31 H34 F3 N3 O253819.675 Example 1685908C30 H31 F3 N4 O355330.476 Example 1686909C20 H31 F3 N4 O355312.663 Example 1687910C23 H24 Cl2 F3 N3 O250211.061 Example 1688911C23 H25 Cl F3 N3 O246820.289 Example 1689912C23 H24 Br2 F3 N3 O259020.295 Example 1690913C24 H28 F3 N3 O346412.676 Example 1691914C30 H32 F3 N3 O354013.972 Example 1692915C24 H28 F3 N3 O34648.325 Example 1693916C22 H25 F3 N4 O24352.58 Example 1694917C22 H25 F3 N4 O24352.79 Example 1695918C26 H30 F3 N3 O45063.922 Example 1696919C24 H28 F3 N3 O244815.999 Example 1697920C24 H25 F6 N3 O351820.381 Example 1698921C27 H28 F3 N3 O248415.589 Example 1699922C20 H26 F3 N3 O23987.351 Example 1700923C29 H29 Cl F3 N3 O254412.548 Example 1701928C24 H25 F6 N3 O351821.486 Example 1702929C24 H28 F3 N3 O2 S48023.7quant Example 1703930C24 H28 F3 N3 O244821.399 Example 1704931C24 H25 F3 N4 O245921.497 Example 1705932C23 H24 Cl F3 N4 O451315.663 Example 1706933C24 H28 F3 N3 O244816.677 Example 1707934C22 H25 F3 N4 O243518.043 Example 1708935C23 H25 F3 N4 O447915.165 Example 1709936C23 H25 F3 N4 O447915.467 Example 17101615C24 H25 F6 N3 O2 S534.226.399
Example 1711: Preparation of 1- {4- (dimethylamino) benzyl} -4-[{N- (3- (trifluoromethyl) benzoyl) glycyl} aminomethyl] piperidine (Compound No. 937)
Of 4-[{N- (3- (trifluoromethyl) benzoyl) glycyl} aminomethyl] piperidine (20.0 mg, 0.058 mmol) in NaBH ₃ CN (16.5 mg) and CH ₃ OH (1.0 mL). The solution is added to a solution of 4- (dimethylamino) benzaldehyde (30.4 mg, 0.204 mmol) in 5% CH ₃ COOH / CH ₃ OH (1.0 mL). The reaction mixture is stirred at 60 ° C. for 19 h. The solvent is evaporated to give a solid. CH ₃ CN (2.0 mL) and phenyl isocyanate (6.9 mg, 0.048 mmol) are added to the solid and the mixture is stirred at 25 ° C. for 1 h. The reaction mixture is loaded on a Varian ^™ SCX column and washed with CH ₃ OH (20 mL). The product was eluted with 2N NH ₃ -CH ₃ OH (6 mL), and the eluate was concentrated to give 1- {4- (dimethylamino) benzyl} -4-[{N- (3- (tri (tri-tri) as a pale yellow oil. Fluoromethyl) benzoyl) glycyl} aminomethyl] piperidine (Compound No. 937) (13.5 mg, 49%): Purity is determined by RPLC / MS (87%); ESI / MS m / e 477.3 (M ⁺ + H, C ₂₅ H ₃₁ F ₃ N ₄ O ₂ ).
Examples 1712-1729
Compounds of the invention are each synthesized according to the method of Example 1711 using the corresponding reactants. Preparative TLC (SiO ₂ ), if necessary, to provide the desired material. ESI / MS data and yields are summarized in Table 34.
Compound no.Molecular formulaESI / MS m / eYield (mg)Yield (%) Example 1712879C24 H26 F3 N3 O447813.062 Example 1713880C24 H26 F3 N3 O447816.378 Example 1714881C23 H15 Br F3 N3 O251211.451 Example 1715882C29 H30 F3 N3 O352613.458 Example 1716883C23 H25 Cl F3 N3 O24687.939 Example 1717904C23 H26 F3 N3 O34503.317 Example 1718905C21 H23 F3 N4 O4 S48527.798 Example 1719938C23 H24 Cl F4 N3 O24868.630 Example 1720939C23 H24 Cl F3 N4 O451311.037 Example 1721940C23 H26 F3 N3 O34505.521 Example 1722941C24 H24 Cl F6 N3 O253611.236 Example 1723987C30 H32 F3 N3 O252417.576 Example 17241449C25 H30 F3 N3 O246221.680 Example 17251450C26 H32 F3 N3 O247623.585 Example 17261452C27 H35 F3 N4 O25055.117 Example 17271453C26 H32 F3 N3 O349222.077 Example 17281454C25 H30 F3 N3 O347821.477 Example 17291456C25 H28 F3 N3 O449223.883
Example 1730: 1- (3-hydroxy-4-methoxybenzyl) -4-[{N- (3- (trifluoromethyl) benzoyl) glycyl} aminomethyl] piperidine (Compound No. 1452 Manufacturing
4-[{N- (3- (trifluoromethyl) benzoyl) glycyl} aminomethyl] piperidine (20.0 mg, 0.058 mmol) and 3- in 5% CH ₃ COOH / CH ₃ OH (1.0 mL) To a solution of hydroxy-4-methoxybenzaldehyde (33 mg) is added NaBH ₃ CN (16.5 mg) in 5% CH ₃ COOH / CH ₃ OH (1.0 mL). The reaction mixture is stirred at 60 ° C. for 15 h. The reaction mixture is loaded on a Varian ^™ SCX column and washed with CH ₃ OH (15 mL). The product was eluted with 2N NH ₃ -CH ₃ OH (5 mL) and the eluate was concentrated to 1- (3-hydroxy-4-methoxybenzyl) -4-[{N- (3- (trifluoro Romethyl) benzoyl) glyciyl} aminomethyl] piperidine (Compound No. 1452) (25.8 mg, 92%): Purity is determined by RPLC / MS (91%); ESI / MS m / e 480 (M ⁺ + H, C ₂₄ H ₂₈ F ₃ N ₃ O ₄ ).
Examples 1731-1733
The compounds of the present invention are each synthesized according to the method of Example 1730 using the corresponding reactants. ESI / MS data and yields are summarized in Table 35.
Compound no.Molecular formulaESI / MS m / eYield (mg)Yield (%) Example 17311455C24 H28 F3 N3 O448024.086 Example 17321647C27 H34 F3 N3 O2490.223.696 Example 17331649C26 H32 F3 N3 O2476.223.197
Example 1734: Preparation of 1- (4-benzylbenzyl) -4-[{N- (3- (trifluoromethyl) benzoyl) glycyl} aminomethyl] piperidine (Compound No. 926)
Of (piperidino-methyl) polystyrene (54 mg, 2.7 mmol base / g resin) and CHCl ₃ (1.0 mL) of methanesulfonyl chloride _{(4.2 mg, 0.037 mmol) 3} (1.0 mL) CHCl A solution of 4- ( Benzyl) benzyl alcohol (8.7 mg, 0.044 mmol) is added. The reaction mixture is stirred at 25 ° C. for 15 h. A solution of 4-[{N- (3- (trifluoromethyl) benzoyl) glycyl} aminomethyl] piperidine (15.1 mg, 0.044 mmol) in KI (2 mg) and CH ₃ CN (1.0 mL) Add to the reaction mixture and stir the mixture at 65 ° C. for 5 h. Phenyl isocyanate (5.2 mg) is added to the cooled reaction mixture and the mixture is stirred at 25 ° C. for 1 h. The reaction mixture is loaded on a Varian ^™ SCX column and washed with CH ₃ OH (20 mL). The product was eluted with 2N NH ₃ in CH ₃ OH (6 mL) and concentrated to give 1- (4-benzylbenzyl) -4-[{N- (3- (trifluoromethyl) benzoyl as light yellow oil. ) Glycyl} aminomethyl] piperidine (Compound No. 926) (5.6 mg, 29%): Purity determined by RPLC / MS (94%); ESI / MS m / e 524.1 (M ⁺ + H, C ₃₀ H ₃₂ F ₃ N ₃ O ₂ ).
Reference Example 31 Preparation of 4-[{N- (benzyloxycarbonyl) gylsil) amino} methyl] -1- (tert-butoxycarbonyl) piperidine
A solution of 4- (aminomethyl) -1- (tert-butoxycarbonyl) piperidine (3.54 g, 16.5 mmol) in CH ₂ Cl ₂ (80 mL) was diluted with Et ₃ N (2.8 mL, 20 mmol), Treated with N- (benzyloxycarbonyl) glycine (3.77 g, 18 mmol), EDCI (3.45 g, 18 mmol) and HOBt (2.43 g, 18 mmol). The reaction mixture is stirred for 15 h at room temperature and 2N NaOH aqueous solution (100 mL) is added. The organic layer is separated and the aqueous layer is extracted with dichloromethane (100 mL × 3). The combined organic layers are dried over anhydrous sodium sulfate, filtered and concentrated. Column chromatography (SiO ₂ , ethyl acetate) to give the desired 4-[{N- (benzyloxycarbonyl) glyciyl) amino} methyl] -1- (tert-butoxycarbonyl) piperidine ( 6.27 g, 94%).
Reference Example 32: Preparation of 4-{(glycylamino) methyl} -1- (tert-butoxycarbonyl) piperidine
A solution of 4-[{(N- (benzyloxycarbonyl) glyciyl) amino} methyl] -1- (tert-butoxycarbonyl) piperidine (6.26 g, 15.4 mmol) in methanol (100 mL) Hydrogenate at 1 atmosphere in the presence of 5% palladium on charcoal (620 mg) at room temperature for 7 h. The catalyst was removed by filtration through celite and the combined filtrates were concentrated to give 4-{(glycyaminoamino) methyl} -1- (tert-butoxycarbonyl) piperidine (3.84 g, 92% as a solid). ).
Reference Example 33 Preparation of 4-[{(N- (2-amino-5-chlorobenzoyl) glycyl) amino} methyl] -1- (tert-butoxycarbonyl) piperidine
A solution of 4-{(glysilamino) methyl} -1- (tert-butoxycarbonyl) piperidine (1.33 g, 4.90 mmol) in CH ₂ Cl ₂ (25 mL) was purified with Et ₃ N (0.75 mL, 5.4 mmol), 2-amino-5-chlorobenzoic acid (840 mg, 4.9 mmol), EDCI (940 g, 4.9 mmol) and HOBt (660 g, 4.9 mmol). The reaction mixture is stirred for 3 h at room temperature and 2N NaOH aqueous solution (20 mL) is added. The organic layer is separated and the aqueous layer is extracted with dichloromethane (20 mL × 3). The combined organic layers are dried over anhydrous sodium sulfate, filtered and concentrated. Column chromatography (SiO ₂ , ethyl acetate) was carried out to give the desired 4-[{(N- (2-amino-5-chlorobenzoyl) gylsil) amino} methyl] -1- (tert-butoxycarbonyl) as a solid. Piperidine (1.63 g, 78%).
Reference Example 34 Preparation of 4-[{N- (2-amino-5-chlorobenzoyl) glycyl) amino} methyl] piperidine
4-[{N- (2-amino-5-chlorobenzoyl) gylsil) amino} methyl] -1- (tert-butoxycarbonyl) piperidine (1.63 g, 3.84 mmol) in methanol (20 mL) To a solution of is added 4N HCl in dioxane (9.5 mL). The solution is stirred for 6 h at room temperature. The reaction mixture is concentrated and 2N aqueous NaOH solution (20 mL) is added. The mixture was extracted with dichloromethane (20 mL × 3) and the combined extracts were dried over sodium sulfate, filtered and concentrated to 4-[{N- (2-amino-5-chlorobenzoyl) glyciyl) amino} methyl] Gives piperidine (1.19 g, 95%): ¹ H NMR (CDCl ₃ , 270 MHz) δ 1.10-1.76 (m, 4H), 2.55 (td, J = 2.4 and 12.2 Hz, H), 3.00-3.10 (m, 2H), 3.17 (t, J = 6.2 Hz, 2H), 3.48 (s, 2H), 4.03 (d, J = 4.9 Hz, 2H), 5.50 (br. s, 2H), 6.11-6.23 ( m, 1H), 6.60 (d, J = 8.8 Hz, 1H), 6.85-7.02 (m, 1H), 7.15 (dd, J = 2.7 and 8.8 Hz, 1H), 7.38 (d, J = 2.4 Hz, 1H ); ESI / MS m / e 325.2 (C ₁₅ H ₂₁ ClN ₄ O ₂ ).
4-[{(N- (2-amino-5-boromobenzoyl) glyciyl) amino} methyl] piperidine is also synthesized according to the methods of Reference Examples 32 and 33 using the corresponding reactants: 951 mg , 64% (step 2). ESI / MS m / e 369.2 (C ₁₅ H ₂₁ BN ₄ O ₂ ).
Example 1735: 4-[{(N- (2- (tert-butoxycarbonylamino) -4,5-difluorobenzoyl) gylsil) amino} methyl] -1- (4-chlorobenzyl) pi Preparation of Ferridine
A solution of 1- (4-chlorobenzyl) -4-{(glyciaminoamino) methyl} piperidine dihydrochloride (738 mg, 2 mmol) in CH ₂ Cl ₂ (20 mL) was diluted with Et ₃ N (1.1 mL). , 8 mmol), 2- (tert-butoxycarbonylamino) -4,5-difluorobenzoic acid (607 mg, 2.2 mmol), EDCI (422 mg, 2.2 mmol) and HOBt (337 mg, 2.2 mmol) To be processed. The reaction mixture is stirred for 14 h at room temperature, 0.6 N aqueous NaOH solution (50 mL) is added and the mixture is extracted with dichloromethane (3 times). The combined organic layers are dried over anhydrous sodium sulfate, filtered and concentrated. Column chromatography (SiO ₂ , ethyl acetate followed by ethyl acetate / methanol = 92/8) was used to produce the desired 4-[{(N- (2- (tert-butoxycarbonylamino) -4,5-difluorobenzoyl ) Glycyl) amino} methyl] -1- (4-chlorobenzyl) piperidine (1.01 g, 92%) is provided: ESI / MS m / e 551.3 (M ⁺ + H, C ₂₇ H ₃₃ ClF ₂ N ₄ O ₄ ).
4-[{(N- (2- (tert-butoxycarbonylamino) -5-trifluoromethylbenzoyl) glycyl) amino} methyl] -1- (4-chlorobenzyl) piperidine also corresponds Prepared according to the above method using a reactant: 3.03 g, 82%; ESI / MS m / e 583.2 (M ⁺ + H, C ₂₈ H ₃₄ ClF ₃ N ₄ O ₄ ).
Reference Example 35 Preparation of 4-[{(N- (2-amino-5-trifluoromethylbenzoyl) gylsil) amino} methyl] piperidine
1- (4-chlorobenzyl) -4-[{(N- (2-amino-5-trifluoromethylbenzoyl) glycyl) amino} methyl] piperi in 5% HCO ₂ H / methanol (10 mL) A suspension of Dean (447 mg, 0.93 mmol) and Pd (OH) ₂ (60 mg, 0.23 mmol) is stirred at 50 ° C. for 14 h. The Pd catalyst is filtered through celite and the filtrate is concentrated. To the residue is added 1N NaOH aqueous solution (15 mL) and the mixture is extracted with ethyl acetate (30 mL × 3). The combined extracts are dried over anhydrous sodium sulfate, filtered and concentrated. Column chromatography (SiO ₂ , AcOEt / MeOH / Et ₃ N = 70/25/5) to give 4-[{(N- (2-amino-5-trifluoromethylbenzoyl) glycy) amino} methyl] piperidine provides (284 mg, 86%): ESI / MS m / e 359.0 (m + + H, C 16 H 21 F 3 N 4 O 2).
4-[{(N- (2-amino-4,5-difluorobenzoyl) glycyl) amino} methyl] piperidine, 4-[{N- (2- (tert-butoxycarbonylamino) -5-trifluoromethoxybenzoyl) glyciyl} aminomethyl] piperidine, 4-[{(N- (2- (tert-butoxycarbonylamino) -4,5-difluorobenzoyl) glycid ) Glysyl) amino} methyl] piperidine, and 4-[{(N- (2- (tert-butoxycarbonylamino) -5-trifluoromethylbenzyl) glycyl) amino} methyl] piperi Deans are also prepared according to the above method using the corresponding reactants, respectively.
4-[{(N- (2-amino-4,5-difluorobenzoyl) glycy) amino} methyl] piperidine: 564 mg, 89%; ESI / MS m / e 327.2 ( M + + H, C 15 H 20 F 2 N 4 O 2).
4-[{N- (2- (tert-butoxycarbonylamino) -5-trifluoromethoxybenzoyl) glycyl} aminomethyl] piperidine: quant; ¹ H NMR (CDCl ₃ , 400 MHz) δ 1.10-1.25 (m, 2H), 1.45-1.73 (m, 3H), 1.51 (s, 9H), 2.53-2.64 (M, 2H), 3.04-3.13 (m , 2H), 3.22 (t, J = 6.3 Hz, 2H), 4.09 (d, J = 4.6 Hz, 2H), 5.91 (br. S, 1H), 7.08 (br. S., 1H), 7.32 (d , J = 9.0 Hz, 1H), 7.38 (s, 1H), 8.43 (d, J = 9.0 Hz, 1H).
4-[{(N- (2- (tert-butoxycarbonylamino) -4,5-difluorobenzoyl) gylsil) gylsil) amino} methyl] piperidine: 310 mg, 40%; ESI / MS m / e 427.3 (M ⁺ + H, C ₂₀ H ₂₈ F ₂ N ₄ O ₄ ).
4-[{(N- (2- (tert-butoxycarbonylamino) -5-trifluoromethylbenzyl) gylsil) amino} methyl] piperidine: 1.35 g, 57%; ESI / MS m / e 459.3 (M ⁺ + H, C ₂₁ H ₂₉ F ₃ N ₄ O ₄ ).
Example 1736: 4-[{(N- (2-amino-5-chlorobenzoyl) glycyl} aminomethyl] -1- (4-ethoxybenzyl) piperidine (Compound No. 1429) and 1- ( Preparation of 4-ethoxybenzyl) -4-[{N- (2- (4-ethoxybenzyl) amino-5-chlorobenzoyl) glycyl} aminomethyl] piperidine (Compound No. 1433)
Sodium cyanoborohydride (140 mmol) in methanol (0.4 mL) was added to 4-[{N- (2-amino-5-chlorobenzoyl) glycyl} aminomethyl] piperidine (0.10 mmol), 4- To a mixture of oxybenzaldehyde (0.10 mmol), acetic acid (0.050 mL) and methanol (1.6 mL). The reaction mixture is stirred at 60 ° C. for 14 h. The reaction mixture is loaded on a Varian ^™ SCX column and washed with CH ₃ OH (20 mL). The product is eluted with 2N NH ₃ in CH ₃ OH (6 mL) and concentrated. Preparative TLC (SiO 2, AcOEt / CH ₃ OH 5: 1) was used to obtain 4-[{(N- (2-amino-5-chlorobenzoyl) glyciyl} aminomethyl] -1- (4-ethoxybenzyl) pi Ferridine (Compound No. 1429) and 1- (4-ethoxybenzyl) -4-[{N- (2- (4-ethoxybenzyl) amino-5-chlorobenzoyl) glycyl} aminomethyl] piperi Dean (Compound No. 1433) is provided.
Compound no. 1429: 4.5 mg, 20%: Purity was determined by RPLC / MS (95%); ESI / MS m / e 459.2 (M ⁺ + H, C ₂₄ H ₃₁ ClN ₄ O 3).
Compound no. 1433: 8.4 mg, 28%: Purity determined by RPLC / MS (98%); ESI / MS m / e 593.2 (M ⁺ + H, C ₃₃ H ₄₁ ClN ₄ O ₄ ).
Example 1737-1779
The compounds of the present invention are each synthesized according to the method of Example 1736 using the corresponding reactants. ESI / MS data and yields are summarized in Table 36.
Compound no.Molecular formulaESI / MS m / eYield (mg)Yield (%) Example 17371430C24 H29 Cl N4 O4473.03.113 Example 17381431C24 H31 Br N4 O3505.25.823 Example 17391432C24 H29 Br N4 O4517.04.116 Example 17401434C33 H41 Br N4 O6637.29.730 Example 17411435C24 H31 Cl N4 O2443.29.744 Example 17421436C25 H33 Cl N4 O2457.212.555 Example 17431437C25 H33 Cl N4 O3473.29.440 Example 17441438C24 H31 Br N4 O2489.25.924 Example 17451439C25 H33 Br N4 O2503.215.261 Example 17461440C25 H33 Br N4 O3519.211.043 Example 17471441C23 H29 Br N4 O2 S507.29.337
Example 17481442C33 H41 Cl N4 O2561.46.824 Example 17491443C35 H45 Cl N4 O4589.49.833 Example 17501444C35 H45 Cl N4 O4621.49.430 Example 17511445C33 H41 Br N4 O2605.26.521 Example 17521446C35 H45 Br N4 O2635.210.734 Example 17531447C35 H45 Br N4 O4665.412.437 Example 17541448C31 H37 Br N4 O2 S2643.27.624 Example 17551457C24 H32 Cl N5 O2458.24.520 Example 17561458C23 H29 Cl N4 O4461.26.026 Example 17571459C24 H32 Br N5 O2504.06.827 Example 17581460C23 H29 Br N4 O4505.08.032 Example 17591461C31 H37 Cl N4 O6597.25.920 Example 17601462C31 H37 Br N4 O6643.26.019 Example 17611514C26 H36 Cl N5 O2486.25.523 Example 17621515C23 H29 Cl N4 O4463.05.825 Example 17631516C26 H36 Br N5 O2530.24.216 Example 17641517C23 H29 Br N4 O4505.06.526 Example 17651518C31 H37 Cl N4 O6597.24.314 Example 17661519C31 H37 Br N4 O6641.25.317 Example 17671570C23 H29 Cl N4 O2 S461.02.712 Example 17681571C31 H37 Cl N4 O2 S2597.24.916 Example 17691651C37 H49 Br N4 O2663.25.517 Example 17701652C26 H35 Br N4 O2515.26.023 Example 17711653C35 H45 Br N4 O2633.25.016 Example 17721654C26 H33 Br N4 O2501.06.225 Example 17731655C37 H49 Cl N4 O2617.45.618 Example 17741656C26 H35 Cl N4 O2471.25.925 Example 17751657C35 H45 Cl N4 O2589.24.616 Example 17761658C25 H33 Cl N4 O2457.25.323 Example 17771785C26 H33 F3 N4 O2491.24.712.8 Example 17781786C25 H29 F3 N4 O3491.23.710.1 Example 17791804C25 H32 F2 N4 O2459.23.39.6
Example 1780: Preparation of 4-[{N- (2-amino-5-trifluoromethoxybenzoyl) glycyl} aminomethyl] -1- (4-isopropylbenzyl) piperidine (Compound No. 1903)
4-[{N- (2- (tert-butoxycarbonylamino) -5-trifluoromethoxy) benzoylglycyl} aminomethyl] piperidine (0.050 mmol), 4-isopropylbenzaldehyde (0.060 mmol) To a mixture of, NaBH ₃ CN (0.15 mmol), and methanol (1.3 mL) is added acetic acid (0.050 mL). The reaction mixture is stirred at 60 ° C. for 8 h. The mixture is cooled to room temperature, loaded on a Varian ^™ SCX column and washed with CH ₃ OH (10 mL). The product is eluted with 2N NH ₃ in CH ₃ OH (5 mL) and concentrated. To the resulting material is added 4N HCl in 1,4-dioxane (2 mL) and the solution is stirred overnight at room temperature. Concentrated and preparative TLC gave 4-[{N- (2-amino-5-trifluoromethoxybenzoyl) glycyl} aminomethyl] -1- (4-isopropylbenzyl) piperidine (Compound No. 1903) (6.6 mg, 26%): Purity is determined by RPLC / MS (93%); ESI / MS m / e 507 (M ⁺ + H, C ₂₆ H ₃₃ F ₃ N ₄ O ₃ ).
Examples 1781-1783
The compounds of the present invention are each synthesized according to the method of Example 1780 using the corresponding reactants. ESI / MS data and yields are summarized in Table 37.
Compound no.Molecular formulaESI / MS m / eYield (mg)Yield (%) Example 17811904C26 H33 F3 N4 O35079.637.9 Example 17821917C25 H31 F3 N4 O5525.21.23.1 Example 17831918C24 H29 F3 N4 O4495.22.87.5
Example 1784: 4 [{N- (2-amino-4,5-difluorobenzoyl) glycyl} aminomethyl] -1- (5-bromo-2-ethoxybenzyl) piperidine (Compound No Manufacture of 2052
4-[{N- (2- (tert-butoxycarbonylamino) -4,5-difluorobenzoyl) glycyl} aminomethyl] piperidine (0.050 mmol), 5-bromo-2-e To a mixture of oxybenzaldehyde (0.15 mmol), methanol (1.2 mL), and acetic acid (0.030 mL) is added NaBH ₃ CN (0.25 mmol) in methanol (0.50 mL). The reaction mixture is stirred at 50 ° C. for 13 h. The mixture is cooled to room temperature, loaded on a Varian ^™ SCX column and washed with CH ₃ OH (5 mL × 3). The product is eluted with 2N NH ₃ in CH ₃ OH (5 mL) and concentrated. Dichloromethane (1 mL) and trifluoroacetic acid (TFA) (0.50 mL) are added to the resulting material and the solution is stirred for 10 minutes at room temperature. The reaction mixture is concentrated, the residue is dissolved in methanol, loaded on a Varian ^™ SCX column and washed with CH ₃ OH (5 mL × 2). The product is eluted with 2N NH ₃ in CH ₃ OH (5 mL) and concentrated. Preparative TLC (SiO2, ethylacetate / methanol = 10/1) was used to obtain 4 [{N- (2-amino-4,5-difluorobenzoyl) glyciyl} aminomethyl] -1- (5-bromo- 2-ethoxybenzyl) piperidine (Compound No. 2052) (10.2 mg, 38%) is provided: Purity is determined by RPLC / MS (96%); ESI / MS m / e 539.2 (M ⁺ + H, C ₂₄ H ₂₉ BrF ₂ N ₄ O ₃ ).
Examples 1785-1792
The compounds of the present invention are each synthesized according to the method of Example 1784 using the corresponding reactants. ESI / MS data and yields are summarized in Table 38.
Compound no.Molecular formulaESI / MS m / eYield (mg)Yield (%) Example 17852053C30 H34 F2 N4 O4553.412.746 Example 17862054C27 H30 F2 N4 O3497.213.755 Example 17872055C23 H28 F2 N4 O4463.210.144 Example 17882056C22 H24 Br F3 N4 O2515.27.730 Example 17892057C23 H27 Br F2 N4 O3527.08.633 Example 17902058C24 H30 F2 N4 O4477.26.427 Example 17912059C28 H30 F2 N4 O3509.46.726 Example 17922060C25 H32 F2 N4 O5507.27.228
Example 1793: 4-[{N- (2-amino-4,5-difluorobenzoyl) gylsil} aminomethyl] -1- (3,4-diethoxybenzyl) piperidine (Compound No. 2065 Manufacturing
4-[{N- (2- (tert-butoxycarbonylamino) -4,5-difluorobenzoyl) glycyl} aminomethyl] piperidine (0.050 mmol), 3,4-diethoxybenzaldehyde ( 0.15 mmol), methanol (1.2 mL), and acetic acid (0.050 mL) are added NaBH ₃ CN (0.25 mmol) in methanol (0.50 mL). The reaction mixture is stirred at 50 ° C. overnight. The mixture is cooled to room temperature, loaded on a Varian ^™ SCX column and washed with CH ₃ OH (5 mL × 2). The product is eluted with 2N NH ₃ in CH ₃ OH (5 mL) and concentrated. To the resulting material was added dichloromethane (2 mL) and phenyl isocyanate (0.10 mL) and the solution was stirred for 1 h at room temperature, loaded on a Varian ^TM SCX column and loaded with CH ₃ OH (5 mL × 2). Wash. The product is eluted with 2N NH ₃ in CH ₃ OH (5 mL) and concentrated. The residue is dissolved in methanol (0.25 mL) and 4N HCl in dioxane (0.125 mL) is added. The solution is stirred overnight at room temperature and concentrated. The residue is dissolved in methanol, loaded on a Varian ^™ SCX column and washed with CH ₃ OH (5 mL × 2). The product was eluted with 2N NH ₃ in CH ₃ OH (5 mL) and concentrated to 4-[{N- (2-amino-4,5-difluorobenzoyl) glycyl} aminomethyl] -1- (3,4-diethoxybenzyl) piperidine (Compound No. 2065) (21.2 mg, 84%) is provided: Purity is determined by RPLC / MS (97%); ESI / MS m / e 505.2 (M ⁺ + H, C ₂₆ H ₃₄ F ₂ N ₄ O ₄ ).
Examples 1794-1808
The compounds of the present invention are each synthesized according to the method of Example 1793 using the corresponding reactants. ESI / MS data and yields are summarized in Table 39.
Compound no.Molecular formulaESI / MS m / eYield (mg)Yield (%) Example 17942061C23 H27 F3 N4 O2449.212.656 Example 17952062C23 H27 F3 N4 O3465.219.785 Example 17962063C25 H32 F2 N4 O4491.219.881 Example 17972064C22 H24 Br F3 N4 O2515.217.568 Example 17982066C29 H32 F2 N4 O3523.218.069 Example 17992067C26 H34 F2 N4 O2473.221.993 Example 18002068C22 H24 Cl F3 N4 O2469.211.248 Example 18012069C24 H30 F2 N4 O3461.420.288 Example 18022070C23 H27 Br F2 N4 O3527.217.767 Example 18032071C24 H30 F2 N4 O4477.210.946 Example 18042072C25 H32 F2 N4 O3475.219.381 Example 18052073C29 H32 F2 N4 O3523.222.887 Example 18062074C29 H32 F2 N4 O4539.222.584 Example 18072075C23 H27 F3 N4 O3465.214.964 Example 18082076C22 H24 F4 N4 O2453.221.997
Example 1809: 4-[{N- (2-amino-4,5-difluorobenzoyl) gylsil} aminofetyl] -1- (2-hydroxy-3-methylbenzyl) piperidine (Compound No. 2106) Preparation
4-[{N- (2- (tert-butoxycarbonylamino) -4,5-difluorobenzoyl) glycyl} aminomethyl] piperidine (0.050 mmol), 2-hydroxy-3-methyl To a mixture of benzaldehyde (0.25 mmol), methanol (1.0 mL), and acetic acid (0.040 mL) is added NaBH ₃ CN (0.40 mmol) in methanol (0.50 mL). The reaction mixture is stirred at 50 ° C. overnight. The mixture is cooled to room temperature, loaded on a Varian ^™ SCX column and washed with CH ₃ OH (5 mL × 2). The product is eluted with 2N NH ₃ in CH ₃ OH (5 mL) and concentrated. The resulting material is dissolved into ethyl acetate / methanol = 5: 1 (1 mL), loaded onto a Varian ^™ Si column, eluted with ethyl acetate / methanol = 5: 1 (5 mL) and concentrated. The residue is dissolved in methanol (2 mL) and 4N HCl in dioxane (0.50 mL) is added. The solution is stirred overnight at room temperature and concentrated. The residue is dissolved in methanol, loaded on a Varian ^™ SCX column and washed with CH ₃ OH (5 mL × 2). The product is eluted with 2N NH ₃ in CH ₃ OH (5 mL) and concentrated. Preparative TLC gave 4-[{N- (2-amino-4,5-difluorobenzoyl) glycyl} aminofetyl] -1- (2-hydroxy-3-methylbenzyl) piperidine (Compound No. 2106): purity is determined by RPLC / MS (97%); ESI / MS m / e 447.0 (M ⁺ + H, C ₂₃ H ₂₈ F ₂ N ₄ O ₃ ).
Examples 1810-1823
The compounds of the present invention are each synthesized according to the method of Example 1809 using the corresponding reactants. ESI / MS data and yields are summarized in Table 40.
Compound no.Molecular formulaESI / MS m / eYield (mg)Yield (%) Example 18102077C22 H25 Cl F2 N4 O3467.23.716 Example 18112078C24 H30 F2 N4 O4477.21.98 Example 18122079C30 H34 F2 N4 O4553.44.817 Example 18132080C22 H25 Cl F2 N4 O3467.213.558 Example 18142081C22 H25 Cl F2 N4 O3467.213.859 Example 18152082C23 H28 F2 N4 O4463.29.642 Example 18162105C23 H28 F2 N4 O4463.2NDND Example 18172106C23 H28 F2 N4 O3447.0NDND Example 18182107C20 H23 Br F2 N4 O2 S503.1NDND Example 18192108C25 H28 F2 N4 O2 S487.2NDND Example 18202109C20 H23 Br F2 N4 O3487.0NDND Example 18212110C22 H28 F2 N4 O3435.1NDND Example 18222111C22 H24 Cl F3 N4 O2469.0NDND Example 18232112C24 H29 Br F2 N4 O4557.0NDND
ND: Not determined.
Example 1824: 4-[{N- (2-amino-4,5-difluorobenzoyl) gylsil} aminomethyl] -1- (3-amino-4-methylbenzyl) piperidine (Compound No. 2114)
4-[{N- (2- (tert-butoxycarbonylamino) -4,5-difluorobenzoyl) glycyl} aminomethyl] piperidine (0.050 mmol), 4-methyl-3-nitrobenzaldehyde (0.25 mmol), methanol (1.2 mL), and acetic acid (0.050 mL) are added NaBH ₃ CN (0.50 mmol) in methanol (1.0 mL). The reaction mixture is stirred at 50 ° C. overnight. The mixture is cooled to room temperature, loaded on a Varian ^™ SCX column and washed with CH ₃ OH (5 mL × 2). The product is eluted with 2N NH ₃ in CH ₃ OH (5 mL) and concentrated. The resulting material is dissolved into ethyl acetate / methanol = 2: 1 (2 mL), loaded on a Varian ^™ Si column, eluted with ethyl acetate / methanol = 2: 1 (6 mL) and concentrated. The residue is dissolved in methanol (1 mL) and 4N HCl in dioxane (0.50 mL) is added. The solution is stirred overnight at room temperature and concentrated. The residue is dissolved in methanol, loaded on a Varian ^™ SCX column, washed with CH ₃ OH (5 mL × 2) and eluted with 2N NH ₃ in CH ₃ OH (5 mL). Concentration gives 4-[{N- (2-amino-4,5-difluorobenzoyl) glyciyl} aminomethyl] -1- (4-methyl-3-nitrobenzyl) piperidine.
4-[{N- (2-amino-4,5-difluorobenzoyl) glycyl} aminomethyl] -1- (4-methyl-3-nitrobenzyl) piperidine, 5% palladium- A mixture of activated carbon (15 mg) and methanol (2 mL) is stirred for 4 h at room temperature under hydrogen atmosphere. The Pd catalyst is filtered off through celite and the filtrate is concentrated. Preparative TLC (SiO ₂ , ethyl acetate / MeOH = 3/1) was used to produce 4-[{N- (2-amino-4,5-difluorobenzoyl) glyciyl} aminomethyl] -1- (3-amino 4-methylbenzyl) piperidine (Compound No. 2114) (2.9 mg, 13%) is provided: Purity is determined by RPLC / MS (100%); ESI / MS m / e 446.1 (M ⁺ + H, C ₂₃ H ₂₉ F ₂ N ₅ O ₂ ).
Example 1825: 4-[{N- (2-amino-4,5-difluorobenzoyl) gylsil} aminomethyl] -1- (3-amino-4-methoxybenzyl) piperidine (Compound No. 2113)
Title compound, 4-[{N- (2-amino-4,5-difluorobenzoyl) glycyl} aminomethyl] -1- (3-amino-4-methoxybenzyl) piperidine (Compound No. 2113) is synthesized according to the method of Example 1824 using the corresponding reactant: 4.6 mg, 20% yield; ESI / MS m / e 462.2 (M ⁺ + H, C ₂₃ H ₂₉ F ₂ N ₅ O ₃ ).
Example 1826: 1- (3-Amino-4-hydroxybenzyl) -4-[{N- (2- (tert-butoxycarbonylamino) -4,5-difluorobenzoyl) glyciyl} amino Preparation of Methyl] piperidine
4-[{N- (2- (tert-butoxycarbonylamino) -4,5-difluorobenzoyl) glycyl} aminomethyl] piperidine (0.35 mmol), 4-hydroxy-3-nitro To a mixture of benzaldehyde (1.22 mmol), methanol (3.8 mL), and acetic acid (0.175 mL) is added NaBH ₃ CN (1.58 mmol) in methanol (3.2 mL). The reaction mixture is stirred at 50 ° C. overnight. The mixture is cooled to room temperature, loaded on a Varian ^™ SCX column and washed with CH ₃ OH. The product is eluted with 2N NH ₃ in CH ₃ OH and concentrated. The resulting material was dissolved in ethyl acetate / methanol = 5: 1, loaded on a Varian ^TM Si column, eluted with ethyl acetate / methanol = 5: 1 (10 mL), concentrated to 4-[{N -(2- (tert-butoxycarbonylamino) -4,5-difluorobenzoyl) gylsil} aminomethyl] -1- (4-hydroxy-3-nitrobenzyl) piperidine (175 mg, 87%).
4-[{N- (2- (tert-butoxycarbonylamino) -4,5-difluorobenzoyl) glycyl} aminomethyl] -1- (4-hydroxy-3-nitrobenzyl prepared above A mixture of piperidine, 10% palladium-activated carbon (45 mg), and methanol (5 mL) is stirred for 2 h at room temperature under a hydrogen atmosphere. The Pd catalyst was filtered off and the filtrate was concentrated to give 1- (3-amino-4-hydroxybenzyl) -4-[{N- (2- (tert-butoxycarbonylamino) -4,5-di Fluorobenzoyl) glycyl} aminomethyl] piperidine (100 mg, 60%).
Example 1827: 4-[{N- (2-amino-4,5-difluorobenzoyl) glycyl} aminomethyl] -1- (3-amino-4-hydroxybenzyl) piperidine (Compound No. 2141) Preparation
1- (3-amino-4-hydroxybenzyl) -4-[{N- (2- (tert-butoxycarbonylamino) -4,5-difluorobenzoyl) glycyl in methanol (1 mL) To a solution of aminomethyl] piperidine (20.0 mg, 0.035 mmol) is added 4N HCl in dioxane (0.50 mL) and the solution is stirred overnight at room temperature. After concentration of the solution, the residue was dissolved in methanol, loaded on a Varian ^™ SCX column, washed with CH ₃ OH (5 mL × 2) and using 2N NH ₃ in CH ₃ OH (5 mL). Elute. Concentrate to 4-[{N- (2-amino-4,5-difluorobenzoyl) glycyl} aminomethyl] -1- (3-amino-4-hydroxybenzyl) piperidine (Compound No. 2141 ) (17.6 mg, quant.): Purity is determined by RPLC / MS (85%); ESI / MS m / e 448.3 (M ⁺ + H, C ₂₂ H ₂₇ F ₂ N ₅ O ₃ ).
Examples 1828-1831
Compounds of the invention are synthesized according to the methods of Examples 1826 and 1827 using the corresponding reactants, respectively. Preparative TLC (SiO ₂ ), if necessary, to provide the desired material. ESI / MS data and final step yields are summarized in Table 41.
Compound no.Molecular formulaESI / MS m / eYield (mg)Yield (%) Example 18282140C23 H27 F2 N5 O4476.36.728.4 Example 18292144C24 H30 F3 N5 O3393.218.782.0 Example 18302145C23 H28 F3 N5 O3480.319.863.7 Example 18312146C24 H28 F3 N5 O4508.313.581.7
Example 1832 1- (3-amino-4-chlorobenzyl) -4-[{N- (2- (tert-butoxycarbonylamino) -4,5-difluorobenzoyl) glyciyl} aminomethyl ] Preparation of Piperidine
4-[{N- (2- (tert-butoxycarbonylamino) -4,5-difluorobenzoyl) glycyl} aminomethyl] piperidine (0.14 mmol), 4-chloro-3-nitrobenzaldehyde (0.50 mmol), methanol (1.5 mL), and acetic acid (0.070 mL) are added NaBH ₃ CN (0.63 mmol) in methanol (1.3 mL). The reaction mixture is stirred at 50 ° C. overnight. The mixture is cooled to room temperature, loaded on a Varian ^™ SCX column and washed with CH ₃ OH. The product is eluted with 2N NH ₃ in CH ₃ OH and concentrated. The resulting material was dissolved into ethyl acetate / methanol = 5: 1, loaded on a Varian ^TM Si column, eluted with ethyl acetate / methanol = 5: 1 (6 mL), concentrated to 4-[{N -(2- (tert-butoxycarbonylamino) -4,5-difluorobenzoyl) gylsil} aminomethyl] -1- (4-chloro-3-nitrobenzyl) piperidine (44 mg, 53 %): ESI / MS m / e 596.3 (M ⁺ + H).
4-[{N- (2- (tert-butoxycarbonylamino) -4,5-difluorobenzoyl) glycyl} aminomethyl] -1- (4-chloro-3-nitrobenzyl) A mixture of piperidine (121 mg, 0.20 mmol), 10% palladium-activated carbon (85 mg), ethyl acetate (10 mL) and methanol (1 mL) is stirred for 19 h at room temperature under hydrogen atmosphere. The Pd catalyst was filtered off and the filtrate was concentrated to give 1- (3-amino-4-chlorobenzyl) -4-[{N- (2- (tert-butoxycarbonylamino) -4,5-difluoro Robenzoyl) glycyl} aminomethyl] piperidine (78 mg, 68%).
Example 1833 1- (3-amino-4-chlorobenzyl) -4-[{N- (2-amino-4,5-difluorobenzoyl) glycyl} aminomethyl] piperidine (Compound No. 2142)
Title compound, 1- (3-amino-4-chlorobenzyl) -4-[{N- (2-amino-4,5-difluorobenzoyl) glycyl} aminomethyl] piperidine (Compound No. 2142 ) Is synthesized according to the method of example 1832 using the corresponding reactant: 13.7 mg, 98%; Purity is determined by RPLC / MS (83%); ESI / MS m / e 466.2 (M ⁺ + H, C ₂₂ H ₂₆ ClF ₂ N ₅ O ₂ ).
Example 1834: 1- (3-acetylamino-4-hydroxybenzyl) -4-[{N- (2-amino-4,5-difluorobenzoyl) glycyl} aminomethyl] piperidine (compound No. 2148)
1- (3-amino-4-hydroxybenzyl) -4-[{N- (2- (tert-butoxycarbonylamino) -4,5-difluorobenzoyl) glyciyl} aminomethyl] piperi Acetic anhydride (0.12) in dichloromethane (0.12 mL) to a mixture of dine (27 mg, 0.049 mmol), (piperidinomethyl) polystyrene (2.7 mmol / g, 60 mg, 0.15 mmol) and dichloromethane (2 mL) mmol) is added. The reaction mixture is stirred for 3 h at room temperature. The mixture is loaded on a Varian ^™ SCX column and washed with CH ₃ OH. The product was eluted with 2N NH ₃ in CH ₃ OH and concentrated to 1- (3-acetylamino-4-hydroxybenzyl) -4-[{N- (2- (tert-butoxycarbonylamino) 4,5-difluoro-benzoyl) provides glycyl} aminomethyl] piperidine (30 mg, quant):. ESI / MS m / e 590.4 (m + + H, C 29 H 37 F 2 N ₅ O ₆ ).
1- (3-acetylamino-4-hydroxybenzyl) -4-[{N- (2- (tert-butoxycarbonylamino) -4,5-difluoro obtained above in methanol (1 mL) To a solution of benzoyl) glycyl} aminomethyl] piperidine is added 4N HCl in dioxane (0.50 mL) and the solution is stirred overnight at room temperature. After concentration of the solution, the residue was dissolved in methanol, loaded on a Varian ^™ SCX column, washed with CH ₃ OH (5 mL × 2) and using 2N NH ₃ in CH ₃ OH (5 mL). Elute. Concentrated and preparative TLC (SiO ₂ , AcOEt / MeOH = 3: 2) to give 1- (3-acetylamino-4-hydroxybenzyl) -4-[{N- (2-amino-4,5-di Fluorobenzoyl) glycyl} aminomethyl] piperidine (Compound No. 2148) (2.3 mg, 9.2%): Purity is determined by RPLC / MS (98%); ESI / MS m / e 490.3 (M ⁺ + H, C ₂₄ H ₂₉ F ₂ N ₅ O ₄ ).
Examples 1835-1839
Compounds of the present invention are synthesized according to the methods of Examples 1826 and 1834 using the corresponding reactants, respectively. ESI / MS data and yields are summarized in Table 42.
Compound no.Molecular formulaESI / MS m / eYield (mg)Yield (%) Example 18352143C25 H29 F2 N5 O5518.34.845 Example 18362147C25 H31 F2 N5 O4504.33.023 Example 18372154C26 H32 F3 N5 O4536.44.166 Example 18382155C25 H30 F3 N5 O4522.35.571 Example 18392156C26 H30 F3 N5 O5550.37.078
Example 1840 4-[{N- (2-amino-4,5-difluorobenzoyl) gylsil} aminomethyl] -1- (3-methylamino-4-hydroxybenzyl) piperidine (compound No. 2160)
4-[{N- (2- (tert-butoxycarbonylamino) -4,5-difluorobenzoyl) glycyl} aminomethyl] -1- (3-amino-4-hydroxybenzyl) piperi To a mixture of dine (20.4 mg, 0.037 mmol), 37% HCHO solution (3.0 mg, 0.037 mmol), acetic acid (0.10 mL) and methanol (1.3 mL) was added NaBH ₃ CN (7.0 mg) in methanol (0.2 mL). do. The reaction mixture is stirred overnight at 60 ° C. The mixture is cooled to room temperature, loaded on a Varian ^™ SCX column and washed with CH ₃ OH (5 mL × 2). The product was eluted with 2N NH ₃ in CH ₃ OH (8 mL) and concentrated to 4-[{N- (2- (tert-butoxycarbonylamino) -4,5-difluorobenzoyl) Lysyl} aminomethyl] -1- (3-methylamino-4-hydroxybenzyl) piperidine is provided.
4-[{N- (2- (tert-butoxycarbonylamino) -4,5-difluorobenzoyl) glyciyl} aminomethyl] -1- (3-methyl obtained above in methanol (1.0 mL) To a solution of amino-4-hydroxybenzyl) piperidine is added 4N HCl in dioxane (1.0 mL) and the solution is stirred for 3 h at room temperature. After concentration of the solution, the residue was dissolved in methanol (1 mL), loaded on a Varian ^™ SCX column, washed with CH ₃ OH (5 mL × 2), 2N NH in CH ₃ OH (8 mL) Elution is carried out using ₃ . Concentrated, preparative TLC (SiO ₂ ) to give 4-[{N- (2-amino-4,5-difluorobenzoyl) glycyl} aminomethyl] -1- (3-methylamino-4-hydroxy Benzyl) piperidine (Compound No. 2160) (3.4 mg, 20%): Purity is determined by RPLC / MS (96%); ESI / MS m / e 462.4 (M ⁺ + H, C ₂₃ H ₂₉ F ₂ N ₅ O ₃ ).
Examples 1841-1844
Compounds of the invention are synthesized according to the methods of Examples 1826 and 1840 using the corresponding reactants, respectively. ESI / MS data and yields are summarized in Table 43.
Compound no.Molecular formulaESI / MS m / eYield (mg)Yield (%) Example 18412159C24 H31 F2 N5 O3476.37.648 Example 18422161C23 H28 Cl F2 N5 O2480.37.345 Example 18432162C25 H32 F3 N5 O3508.46.024 Example 18442163C24 H30 F3 N5 O3494.34.315
Example 1845: 4-[{N- (2-amino-4,5-difluorobenzoyl) glycyl} aminomethyl] -1- (benzo [c] furazan-5-yl) piperidine (compound No. 2130)
4-[{N- (2- (tert-butoxycarbonylamino) -4,5-difluorobenzoyl) glycyl] aminomethyl] piperidine (0.050 mmol), 5- (bromomethyl) benzo [c] Furazan (0.75 mmol), (piperidinomethyl) polystyrene (2.6-2.8 mmol / g, 60 mg, 0.15 mmol), methanol (0.2 mL), acetonitrile (1.0 mL), and chloroform (0.50 mL ) Is stirred overnight at 50 ° C. The mixture is cooled to room temperature, loaded on a Varian ^™ SCX column and washed with CH ₃ OH (5 mL × 2). The product is eluted with 2N NH ₃ in CH ₃ OH (5 mL) and concentrated. To the resulting material is added chloroform (1.5 mL) and phenyl isocyanate (0.075 mL), the solution is stirred for 1 h at room temperature, loaded on a Varian ^TM SCX column, washed with CH ₃ OH (5 mL × 2) do. The product is eluted with 2N NH ₃ in CH ₃ OH (5 mL) and concentrated. The residue is dissolved in methanol (1 mL) and 4N HCl in dioxane (0.50 mL) is added. The solution is stirred overnight at room temperature and concentrated. The residue is dissolved in methanol, loaded on a Varian ^™ SCX column, washed with CH ₃ OH (5 mL × 2) and eluted with 2N NH ₃ in CH ₃ OH (5 mL). Concentrate and preparative TLC (SiO ₂ , ethyl acetate / MeOH = 5/1) to give 4-[{N- (2-amino-4,5-difluorobenzoyl) glyciyl} aminomethyl] -1- (benzo [c] furazan-5-yl) piperidine (Compound No. 2130) (3.6 mg, 16%): Purity is determined by RPLC / MS (87%); ESI / MS m / e 459.3 (M ⁺ + H, C ₂₂ H ₂₄ F ₂ N ₆ O ₃ ).
Example 1846: 4-[{N- (2-amino-4,5-difluorobenzoyl) gylsil} aminomethyl] -1- (3,5-dimethylisoxazol-4-yl) piperidine Preparation of (Compound No. 2131)
Title compound, 4-[{N- (2-amino-4,5-difluorobenzoyl) glycyl} aminomethyl] -1- (3,5-dimethylisoxazol-4-yl) piperidine ( compound No. 2131) is synthesized according to the methods of example 1845 using the corresponding reactant: 3.8 mg, 18% yield; ESI / MS m / e 436.2 (m + + H, C 21 H 27 F 2 N 5 O ₃ ).
Example 1847: 4-[{N- (2-amino-5-chlorobenzoyl) glycyl} aminomethyl] -1- {4- (trifluoromethylthio) benzyl} piperidine (Compound No. 1616) Manufacture
4-[{N- (2-amino-5-chlorobenzoyl) glycyl} aminomethyl] piperidine (16.2 mg, 0.050 mmol), 4- (trifluoromethylthio) benzyl bromide (20.3 mg, 0.075 mmol ), Piperidinomethylpolystyrene (60 mg), acetonitrile (1.0 mL) and chloroform (0.50 mL) are stirred at 60 ° C. for 15 h. The reaction mixture is cooled, loaded on a Varian ^™ SCX column and washed with CH ₃ OH (15 mL). The product was eluted with 2N NH ₃ in CH ₃ OH (5 mL) and concentrated to 4-[{N- (2-amino-5-chlorobenzoyl) glycyl} aminomethyl] -1- {4- ( Trifluoromethylthio) benzyl} piperidine (Compound No. 1616) (21.9 mg, 85%): Purity is determined by RPLC / MS (96%); ESI / MS m / e 545.2 (M ⁺ + H, C ₂₃ H ₂₆ ClF ₃ N ₄ O ₂ S).
Examples 1848-1868
The compounds of the present invention are each synthesized according to the method of Example 1847 using the corresponding reactants. If necessary, preparative TLC is provided to provide the desired material. ESI / MS data and yields are summarized in Table 44.
Compound no.Molecular formulaESI / MS m / eYield (mg)Yield (%) Example 18481617C23 H26 Br F3 N4 O2 S559.021.075 Example 18491777C23 H25 Cl2 F3 N4 O2517.016.363.0 Example 18501778C24 H29 F3 N4 O2463.29.541.1 Example 18511779C24 H27 F3 N4 O4493.212.751.6 Example 18521780C23 H26 Br F3 N4 O2527.016.462.2 Example 18531781C23 H27 F3 N4 O3465.210.028.7 Example 18541782C25 H29 F3 N4 O2475.212.234.3 Example 18551783C24 H26 F3 N5 O2474.217.248.4 Example 18561784C23 H27 F3 N4 O2449.211.333.6 Example 18571788C25 H31 F3 N4 O2477.210.042.0 Example 18581789C24 H29 F3 N4 O3479.210.027.9 Example 18591792C24 H30 F2 N4 O2445.25.926.5 Example 18601793C22 H24 Cl2 F2 N4 O2485.29.237.9 Example 18611794C23 H28 F2 N4 O2431.25.726.5 Example 18621795C23 H26 F2 N4 O4461.26.026.1 Example 18631796C22 H25 Br F2 N4 O2497.010.542.4 Example 18641797C22 H26 F2 N4 O3433.23.516.2 Example 18651798C23 H28 F2 N4 O3447.25.625.1 Example 18661799C24 H28 F2 N4 O2443.25.524.9 Example 18671800C23 H25 F2 N5 O2442.29.442.6 Example 18681801C22 H26 F2 N4 O2417.26.531.2
Example 1869 Preparation of 4-[{N- (2-amino-5-trifluoromethoxybenzoyl) gylsil} aminomethyl] -1- (4-bromobenzyl) piperidine (Compound No. 1910)
4-[{N- (2- (tert-butoxycarbonylamino) -5-trifluoromethoxybenzoyl) glycyl} aminomethyl] piperidine (0.050 mmol), 4-bromobenzyl bromide (0.060 mmol ), Piperidinomethylpolystyrene (60 mg), acetonitrile (0.8 mL) and chloroform (0.5 mL) are stirred for 12 h at 60 ° C. The reaction mixture is cooled, loaded on a Varian ^™ SCX column and washed with 50% CHCl ₃ / CH ₃ OH (10 mL) and CH ₃ OH (10 mL). The product is eluted with 2N NH ₃ in CH ₃ OH (5 mL) and concentrated. To the resulting material is added 4N HCl in 1,4-dioxane (2 mL) and the solution is stirred overnight at room temperature. Concentrated, preparative TLC gave 4-[{N- (2-amino-5-trifluoromethoxybenzoyl) glycyl} aminomethyl] -1- (4-bromobenzyl) piperidine (Compound No. 1910 ) (6.5 mg, 24%): Purity is determined by RPLC / MS (96%); ESI / MS m / e 545 (M ⁺ + H, C ₂₃ H ₂₆ BrF ₃ N ₄ O ₃ ).
Examples 1870-1873
The compounds of the present invention are each synthesized according to the method of Example 1869 using the corresponding reactants. ESI / MS data and yields are summarized in Table 45.
Compound no.Molecular formulaESI / MS m / eYield (mg)Yield (%) Example 18701911C23 H25 Cl2 F3 N4 O353310.639.7 Example 18711912C23 H27 F3 N4 O448112.552.0 Example 18721913C25 H31 F3 N4 O34937.530.5 Example 18731914C24 H29 F3 N4 O347911.046.0
Example 1874: 4-[{N- (2-amino-5-trifluoromethylbenzoyl) gylsil} aminomethyl] -1- (benz [d] imidazol-5-yl) piperidine (Compound No 2186) Preparation
4-[{N- (2- (tert-butoxycarbonylamino) -5-trifluoromethylbenzoyl) glycyl} aminomethyl] piperidine (0.060 mmol), 1- (tert-butoxycarbonyl A mixture of) -6- (bromomethyl) benz [d] ididazole (15.6 mg, 0.050 mmol), (piperidinomethyl) polystyrene (86 mg) and acetonitrile (2 mL) at 50 ° C. for 3 h. Stir. Cool to room temperature, add phenyl isocyanate (30 mg) and stir the mixture for 1 h at room temperature, load on a Varian ^™ SCX column, wash with CH ₃ OH (5 mL) and CHCl ₃ (5 mL) do. The product is eluted with 2N NH ₃ in CH ₃ OH (3 mL) and concentrated.
The resulting material is dissolved in methanol (1 mL) and 4N HCl in dioxane (1 mL) is added. The solution is stirred overnight at room temperature, loaded on a Varian ^™ SCX column and washed with CH ₃ OH and dichloromethane. The product is eluted with 2N NH ₃ in CH ₃ OH and concentrated. Preparative TLC (SiO ₂ , AcOEt / MeOH = 3: 1) gave 4-[{N- (2-amino-5-trifluoromethylbenzoyl) glycylic} aminomethyl] -1- (benz [d] imide Dazol-5-yl) piperidine (Compound No. 2186) (1.9 mg, 7.8%): Purity is determined by RPLC / MS (100%); ESI / MS m / e 489.4 (M ⁺ + H, C ₂₄ H ₂₇ F ₃ N ₆ O ₂ ).
Example 1875: 4-[{N- (2-amino-4,5-difluorobenzoyl) glycyl} aminomethyl] -1- (benzo [c] thiadiazol-5-yl) piperidine ( Preparation of Compound No. 2184
Methanesulfonyl chloride (0.0042 mL) in a mixture of 5- (hydroxymethyl) benzo [c] thiadiazole (8.3 mg, 0.050 mmol), (piperidinomethyl) polystyrene (86 mg), and chloroform (1 mL). ) Is added and the mixture is stirred for 1.5 h at room temperature. Acetonitrile (1 mL) and 4-[{N- (2- (tert-butoxycarbonylamino) -4,5-difluorobenzoyl) glycyl} aminomethyl] piperidine (0.060 mmol) are added And the reaction mixture is stirred at 50 ° C. for 3 h. After cooling to room temperature, phenyl isocyanate (30 mg) is added and the mixture is stirred at room temperature for 1 h, loaded on a Varian ^™ SCX column, and charged with CH ₃ OH (5 mL) and CHCl ₃ (5 mL). Wash. The product is eluted with 2N NH ₃ in CH ₃ OH (3 mL) and concentrated.
The resulting material is dissolved in dichloromethane (1 mL) and 1M chlorotrimethylsilane and 1M phenol in dichloromethane (1 mL) are added. The solution is stirred for 5 h at room temperature, loaded on a Varian ^™ SCX column and washed with CH ₃ OH and dichloromethane. The product is eluted with 2N NH ₃ in CH ₃ OH and concentrated. Preparative TLC (SiO ₂ , AcOEt / MeOH = 3: 1) to give 4-[{N- (2-amino-4,5-difluorobenzoyl) glyciyl} aminomethyl] -1- (benzo [c] Thiadiazol-5-yl) piperidine (Compound No. 2184) (1.3 mg, 5.5%) is provided: Purity is determined by RPLC / MS (100%); ESI / MS m / e 475.2 (M ⁺ + H, C ₂₂ H ₂₄ F ₂ N ₆ O ₂ S).
Example 1876: 4-[{N- (2-amino-5-trifluoromethylbenzoyl) gylsil} aminomethyl] -1- (benzo [c] thiadiazol-5-yl) piperidine (compound No. 2185)
Title compound, 4-[{N- (2-amino-5-trifluoromethylbenzoyl) glycyl} aminomethyl] -1- (benzo [c] thiadiazol-5-yl) piperidine (Compound No 2185) is synthesized using the method of Example 1875 using the corresponding reactant: 7.2 mg, 28% yield; ESI / MS m / e 507.4 (M ⁺ + H, C ₂₃ H ₂₅ F ₃ N ₆ O ₂ S).
Example 1877: 4-[{N- (2-amino-5-trifluoromethylbenzoyl) glycyl} aminomethyl] -1- (2-amino-4-chlorobenzyl) piperidine (Compound No. 1919 Manufacturing
4-[{N- (2-amino-5-trifluoromethylbenzoyl) glyciyl} aminomethyl] piperidine (0.050 mmol), 4-chloro-2-nitrobenzyl chloride (0.050 mmol), piperidino A mixture of methylpolystyrene (60 mg), acetonitrile (1.0 mL) and chloroform (0.7 mL) is stirred at 50 ° C. overnight. The reaction mixture is cooled, loaded on a Varian ^™ SCX column and washed with 50% CHCl ₃ / CH ₃ OH (10 mL) and CH ₃ OH (10 mL). The product is eluted with 2N NH ₃ in CH ₃ OH (5 mL) and concentrated. To the resulting material is added ethanol (3 mL) and 10 Pd-C (15 mg) and the mixture is stirred under H ₂ at room temperature for 1.5 h. Filtration, concentration, preparative TLC gave 4-[{N- (2-amino-5-trifluoromethylbenzoyl) glycyl} aminomethyl] -1- (2-amino-4-chlorobenzyl) piperi Dean (Compound No. 1919) (5.1 mg, 14%): Purity is determined by RPLC / MS (90%); ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.09-1.32 (m, 4H), 1.41-1.59 (m, 1H), 1.66 (d, J = 12.5 Hz, 2H), 1.88 (t, J = 11.5 Hz, 2H ), 2.82 (d, J = 11.5 Hz, 2H), 3.17 (t, J = 6.5 Hz, 2H), 3.42 (s, 2H), 4.05 (d, J = 5.5 Hz, 2H), 4.85 (br s, 1H), 5.92 (br s, 2H), 6.25-6.36 (m, 1H), 6.55-6.66 (M, 1H), 6.70 (d, J = 8.5 Hz, 1H), 6.85 (d, J = 8.5 Hz, 1H), 7.26 (s, 1 H), 7.42 (d, J = 8.5 Hz, 1 H), 7.68 (s, 1 H); ESI / MS m / e 498.2 (M ⁺ + H, C ₂₃ H ₂₇ ClF ₃ N ₅ O ₂ ).
Examples 1878 and 1879
The compounds of the present invention are each synthesized according to the method of Example 1877 using the corresponding reactants. ESI / MS data and yields are summarized in Table 46.
Compound no.Molecular formulaESI / MS m / eYield (mg)Yield (%) Example 18781920C22 H26 Cl F2 N5 O2466.23.510.0 Example 18791922C23 H27 Cl F3 N4 O3514.21.23.1
Example 1880: 4-[{N- (2-amino-5-trifluoromethylbenzoyl) glycyl} aminomethyl] -1- (benz [d] oxazol-5-yl) piperidine (Compound No 2188)
1- (3-amino-4-hydroxybenzyl) -4-[{N- (2- (tert-butoxycarbonylamino) -5-, prepared according to the method of Example 1826 in THF (2 mL) A solution of trifluoromethylbenzoyl) glyciyl} aminomethyl] piperidine (34.8 mg, 0.060 mmol) was added to triethyl orthoformate (0.033 mL, 3.3 equiv) and pyridinium p-toluenesulfonate (2 mg, 0.4 Equivalent weight). The reaction mixture is stirred overnight at reflux. After cooling to room temperature, the mixture is concentrated. The residue is dissolved in AcOEt, loaded on a BondElut ^™ Si column, eluted with ethyl acetate / methanol = 4/1 and concentrated.
The resulting material is dissolved in AcOEt (1.5 mL) and 4N HCl in dioxane (0.5 mL) is added. The solution is stirred overnight at room temperature, adjusted to pH 10 with 5M aqueous NaOH solution and extracted with AcOEt. The extract was purified by PTLC (SiO ₂ , AcOEt / MeOH = 4: 1) to give 4-[{N- (2-amino-5-trifluoromethylbenzoyl) glyciyl} aminomethyl] -1- (benz [d ] Oxazol-5-yl) piperidine (Compound No. 2188) (1.6 mg, 5%): Purity was RPLC / MS (94%); ESI / MS m / e 490.3 (M ⁺ + H, C ₂₄ H ₂₆ F ₃ N ₅ O ₃ ).
Example 1881: 4-[{N- (2-amino-4,5-difluorobenzoyl) gylsil} aminomethyl] -1- (2-oxo-2,3-dihydro-1,3-benz Preparation of Oxazol-5-yl) piperidine (Compound No. 2190)
1- (3-amino-4-hydroxy) -4-[{N- (2- (tert-butoxycarbonylamino) -4,5-difluorobenzoyl) glycyl] aminomethyl] piperidine To a mixture of (22 mg, 0.040 mmol), NaHCO ₃ (0.040 mmol), water (0.7 mL) and methanol (1.5 mL) is added phenyl chloroformate (0.046 mmol) and the mixture is stirred for 3 h at room temperature. . 1N NaOH solution (0.040 mL) is added and the reaction mixture is stirred for an additional 1.5 h. The mixture is extracted with ethyl acetate and evaporated. The residue is dissolved in methanol, loaded on a Varian ^™ SCX column and washed with CH ₃ OH (5 mL × 2). The product is eluted with 2N NH ₃ in CH ₃ OH (5 mL) and concentrated.
To the resulting material is added 1M chlorotrimethylsilane and 1M phenol in dichloromethane (2 mL). The solution is stirred for 2 h at room temperature and evaporated. The residue is dissolved in methanol, loaded on a Varian ^™ SCX column and washed with CH ₃ OH (5 mL × 2). The product is eluted with 2N NH ₃ in CH ₃ OH (5 mL) and concentrated. Preparative TLC (SiO ₂ , AcOEt / MeOH = 5: 2) to give 4-[{N- (2-amino-4,5-difluorobenzoyl) glyciyl} aminomethyl] -1- (2-oxo- 2,3-dihydro-1,3-benzoxazol-5-yl) piperidine (Compound No. 2190) (4.1 mg, 22%) is provided: Purity is determined by RPLC / MS (100% ); ESI / MS m / e 474.2 (M ⁺ + H, C ₂₃ H ₂₅ F ₂ N ₅ O ₄ ).
Examples 1882-1884
The compounds of the present invention are each synthesized according to the method of Example 1881 using the corresponding reactants (phenyl chlorothioinoformate is used instead of phenyl chloroformate for the preparation of compounds No. 2192 and 2193). ESI / MS data and yields are summarized in Table 47.
Compound no.Molecular formulaESI / MS m / eYield (mg)Yield (%) Example 18822191C24 H26 F3 N5 O4506.33.110 Example 18832192C23 H25 F2 N5 O3 S490.26.935 Example 18842193C24 H26 F3 N5 O3 S522.23.611
Reference Example 36 4-[{N- (1- (9-Fluorenylmethoxycarbonyl) piperidin-4-ylmethyl) carbamoylmethyl} aminomethyl] -3-methoxyphenyloxymethyl-polystyrene Manufacture
To a solution of 1- (9-fluorenylmethoxycarbonyl) -4- (glycyaminomethyl) piperidine hydrochloride (10 mmol) in DMF (65 mL) acetic acid (0.3 mL), sodium triacetoxybo Lohydride (1.92 g) and 4-formyl-3- (methoxyphenyloxymethyl) -polystyrene (1 mmol / g, 200 g) are added. The mixture is shaken for 2 h and filtered. The resin is washed with MeOH, DMF, CH ₂ Cl ₂ , and methanol and dried to give the desired material.
Example 1885-2000: General procedure for solid phase synthesis of 4-aminomethylpiperidine
To a mixture of the corresponding acid (1.6 mmol), HBTU (1.6 mmol) and DMF (6 mL) is added diisopropylethylamine (3.6 mmol) and the mixture is shaken for 2 minutes. 4-[{N- (1- (9-fluorenylmethoxycarbonyl) piperidin-4-ylmethyl) carbamoylmethyl} aminomethyl] -3-methoxyphenyloxymethyl-polystyrene (0.4 mmol ) Is added and the mixture is shaken for 1 h and filtered. The resin is rinsed with DMF and CH ₂ Cl ₂ and dried.
The resulting mixture of resin, piperidine (3.2 mL) and DMF (12.8 mL) is shaken for 10 minutes and filtered. The resin is washed with DMF and CH ₂ Cl ₂ and dried.
To dry resin (0.05 mmol) is added a mixture of NaBH (OAc) ₃ (0.25 mmol), AcOH (0.025 mL) and DMF (1 mL). The corresponding aldehyde (2.5 mmol) is added and the mixture is shaken for 2 h, then filtered and washed with CH ₃ OH, 10% diisopropylethylamine in DMF, DMF, CH ₂ Cl ₂ and CH ₃ OH. . A mixture of resin, water (0.050 mL) and trifluoroacetic acid (0.95 mL) is shaken for 1 h and filtered. The resin is washed with CH ₂ Cl ₂ and CH ₃ OH. The filtrate and wash are combined and concentrated. The crude material is loaded on a Varian ^™ SCX column and washed with CH ₃ OH (15 mL). The product is eluted with 2N NH ₃ in CH ₃ OH (5 mL) and concentrated. Preparative TLC or HPLC, if necessary, to provide the desired material. ESI / MS data and yields are summarized in Table 48.
Compound no.Molecular formulaESI / MS m / eYield (mg)Yield (%) Example 18851923C23 H25 Br F3 N3 O2 S54415.787 Example 18861924C24 H28 F3 N3 O3 S49614.689 Example 18871925C23 H25 F4 N3 O2 S48411.773 Example 18881926C23 H24 F5 N3 O2 S50213.984 Example 18891927C23 H26 F3 N3 O3 S48210.767 Example 18901928C24 H26 F3 N3 O4 S51014.385 Example 18911929C26 H30 F3 N3 O2 S50614.788 Example 18921930C24 H28 F3 N3 O2 S251214.485 Example 18931931C25 H30 F3 N3 O2 S49414.388
Example 18941932C25 H28 F3 N3 O3 S5097.1 *35 Example 18951933C25 H30 F3 N3 O2 S49414.388 Example 18961934C26 H32 F3 N3 O2 S50914.486 Example 18971935C23 H25 F3 N4 O4 S51114.988 Example 18981936C24 H28 F3 N3 O2 S48013.384 Example 18991937C26 H32 F3 N3 O2 S50911.166 Example 19001938C23 H27 Br2 N3 O25385.3 *25 Example 19011939C24 H30 Br N3 O34885.0 *25 Example 19021940C23 H27 Br F N3 O24764.9 *25 Example 19031941C23 H26 Br F2 N3 O24946.1 *30 Example 19041942C23 H28 Br N3 O34741.7 *9 Example 19051943C24 H28 Br N3 O45026.6 *32 Example 19061944C26 H32 Br N3 O24987.0 *35 Example 19071945C24 H30 Br N3 O250411.167 Example 19081946C25 H32 Br N3 O24883.2 *16 Example 19091947C25 H30 Br N3 O35005.735 Example 19101948C25 H32 Br N3 O24864.9 *25 Example 19111949C26 H34 Br N3 O25006.7 *33 Example 19121950C23 H27 Br N4 O45035.0 *25 Example 19131951C24 H30 Br N3 O24725.1 *26 Example 19141952C22 H24 Br2 F N3 O254214.983 Example 19151953C23 H27 Br F N3 O349213.986 Example 19161954C22 H24 Br F2 N3 O248012.579 Example 19171955C22 H23 Br F3 N3 O249813.280 Example 19181956C22 H25 Br F N3 O34787.044 Example 19191957C23 H25 Br F N3 O45064.0 *20 Example 19201958C25 H29 Br F N3 O250214.688 Example 19211959C23 H27 Br F N3 O2 S50813.178 Example 19221960C24 H29 Br F N3 O249013.885 Example 19231961C24 H27 Br F N3 O35042.7 *13 Example 19241962C24 H29 Br F N3 O249012.778 Example 19251963C25 H31 Br F N3 O250413.581 Example 19261964C22 H24 Br F N4 O450714.888 Example 19271965C23 H27 Br F N3 O247612.177 Example 19281966C25 H31 Br F N3 O250413.480 Example 19291967C22 H26 Br F N4 O24774.7 *20 Example 19301968C23 H29 F N4 O34296.9 *32 Example 19311969C22 H27 F N4 O34153.7 *17 Example 19321970C23 H27 F N4 O44435.4 *24 Example 19331971C25 H31 F N4 O24394.3 *20 Example 19341972C23 H29 F N4 O2 S4456.2 *28 Example 19351973C24 H31 F N4 O24276.3 *29 Example 19361974C24 H31 F N4 O24274.9 *23 Example 19371975C22 H26 F N5 O44445.9 *27 Example 19381976C23 H29 F N4 O24136.7 *32 Example 19391977C23 H26 F N5 O24245.1 *24 Example 19401978C25 H33 F N4 O24416.3 *29 Example 19411979C25 H30 F2 N4 O24578.0 *35 Example 19421980C24 H28 F2 N4 O34596.0 *26 Example 19431981C22 H25 F2 N5 O44629.3 *41 Example 19441982C23 H25 F2 N5 O24426.0 *27
Example 19451983C25 H32 F2 N4 O24598.3 *37 Example 19461984C22 H26 Br I N4 O25859.7 *36 Example 19471985C23 H29 I N4 O35379.2 *36 Example 19481986C22 H27 I N4 O35235.8 *23 Example 19491987C23 H27 I N4 O45518.2 *32 Example 19501988C25 H31 I N4 O25476.7 *26 Example 19511989C23 H29 I N4 O2 S5536.4 *25 Example 19521990C24 H31 I N4 O25357.2 *29 Example 19531991C24 H29 I N4 O35495.6 *22 Example 19541992C24 H31 I N4 O25356.2 *25 Example 19551993C22 H26 I N5 O455210.2 *40 Example 19561994C23 H29 I N4 O25217.5 *30 Example 19571995C23 H26 I N5 O25326.8 *27 Example 19581996C25 H33 I N4 O25497.1 *28 Example 19591997C25 H33 I N4 O25493.0 *12 Example 19601998C22 H25 Br Cl N3 O24787.6 *39 Example 19611999C23 H28 Cl N3 O34307.0 *39 Example 19622000C22 H25 Cl F N3 O241814.1102 Example 19632001C22 H26 Cl N3 O34166.3 *36 Example 19642002C23 H26 Cl N3 O44447.1 *39 Example 19652003C25 H30 Cl N3 O244015.3105 Example 19662004C23 H28 Cl N3 O2 S4468.4 *45 Example 19672005C24 H30 Cl N3 O24287.4 *41 Example 19682006C24 H30 Cl N3 O242813.898 Example 19692007C22 H25 Cl N4 O444516.0109 Example 19702008C23 H28 Cl N3 O241414.1103 Example 19712009C23 H25 Cl N4 O242514.8106 Example 19722010C25 H32 Cl N3 O244214.599 Example 19732011C25 H32 Cl N3 O244214.599 Example 19742012C22 H24 Br2 Cl N3 O255812.8 *58 Example 19752013C23 H27 Br Cl N3 O35088.6 *42 Example 19762014C22 H25 Br Cl N3 O34946.0 *30 Example 19772015C23 H25 Br Cl N3 O45228.4 *40 Example 19782016C25 H29 Br Cl N3 O251817.6103 Example 19792017C23 H27 Br Cl N3 O2 S52417.199 Example 19802018C24 H29 Br Cl N3 O250614.788 Example 19812019C24 H27 Br Cl N3 O35208.0 *38 Example 19822020C24 H29 Br Cl N3 O250614.788 Example 19832021C22 H24 Br Cl N4 O452312.0 *57 Example 19842022C23 H27 Br Cl N3 O24928.5 *42 Example 19852023C23 H24 Br Cl N4 O25036.3 *31 Example 19862024C25 H31 Br Cl N3 O25209.6 *46 Example 19872025C25 H31 Br Cl N3 O252015.087 Example 19882026C22 H23 Br Cl F2 N3 O251415.893 Example 19892027C22 H26 Br2 N4 O253710.7 *42 Example 19902028C23 H29 Br N4 O34898.5 *36 Example 19912029C22 H27 Br N4 O34757.5 *32 Example 19922030C23 H27 Br N4 O45036.8 *28 Example 19932031C25 H31 Br N4 O24996.2 *26 Example 19942032C24 H29 Br N4 O35018.9 *37 Example 19952033C24 H31 Br N4 O24879.1 *39
Example 19962034C22 H26 Br N5 O45046.4 *26 Example 19972035C23 H29 Br N4 O24736.5 *28 Example 19982036C23 H26 Br N5 O24846.3 *27 Example 19992037C25 H33 Br N4 O25015.4 *22 Example 20002038C22 H25 Br F2 N4 O24955.4 *23
* Yield of TFA salt
Example 2001: Preparation of 1- (3-carbamoylbenzyl) -4-[{N- (3- (trifluoromethyl) benzoyl) glycyl} aminomethyl] piperidine (Compound No. 924)
EDCI (10.7 mg), 1-hydroxybenzotriazole hydrate (7.5 mg), Et ₃ N (15.4 mg), 0.5 M NH ₃ and DMF (0.5 mL) in dioxane (0.1 mL, 0.05 mmol) were converted to CHCl ₃ To a solution of 1- (3-carboxybenzyl) -4-[{N- (3- (trifluoromethyl) benzoyl) glycyl} aminomethyl] piperidine (19.4 mg, 0.041 mmol) in (2.5 mL) Add. The reaction mixture is stirred for 20 h at 25 ° C. and washed with 2N NaOH (2 × 2 mL) and brine (1 mL). After filtration through a PTFE membrane filter, the solvent was removed under reduced pressure to yield 1- (3-carbamoylbenzyl) -4-[{N- (3- (trifluoromethyl) benzoyl) glycile} as a pale yellow solid. Aminomethyl] piperidine (Compound No. 924) (17.9 mg, 92%): Purity is determined by RPLC / MS (89%); ESI / MS m / e 447.3 (M ⁺ + H, C ₂₄ H ₂₇ F ₃ N ₄ O ₃ ).
Example 2002: Preparation of 1- (4-carbamoylbenzyl) -4-[{N- (3- (trifluoromethyl) benzoyl) glycyl} aminomethyl] piperidine (Compound No. 925)
Compound no. 925 is synthesized according to the method of Example 2001 using the corresponding reactant: 14.2 mg, 72%; Purity is determined by RPLC / MS (86%); ESI / MS m / e 447 (M ⁺ + H, C ₂₄ H ₂₇ F ₃ N ₄ O ₃ ).
Example 2003 Preparation of 1- (4-aminobenzyl) -4-[{N- (3- (trifluoromethyl) benzoyl) glycyl} aminomethyl] piperidine (Compound No. 516)
A solution of 1- (4-nitrobenzyl) -4-[{N- (3- (trifluoromethyl) benzoyl) glycyl} aminomethyl] piperidine (22.4 mg, 0.047 mmol) in EtOH (3 mL) Is hydrogenated at 25 ° C. at 1 atmosphere in the presence of charcoal (10 mg) 5% palladium for 1 h. The catalyst is removed by filtration and washed with EtOH (5 mL). The collected filtrate was evaporated to give 1- (4-aminobenzyl) -4-[{N- (3- (trifluoromethyl) benzoyl) glycidyl} aminomethyl] piperidine as light yellow solid (Compound No. 516 ) (20.1 mg, 96%). Purity is determined by RPLC / MS (99%); ESI / MS m / e 449.1 (M ⁺ + H, C ₂₃ H ₂₇ F ₃ N ₄ O ₂ ).
Examples 2004 and 2005
Compound no. 517 and 518 are each synthesized according to the method of Example 2003 using the corresponding reactants. ESI / MS data and yields are summarized in Table 49.
Compound no.Molecular formulaESI / MS m / eYield (mg)Yield (%) Example 2004517C23 H27 F3 N4 O244926.578 Example 2005518C23 H27 F3 N4 O244925.371
Example 2006: Preparation of 1- {4- (benzoylamino) benzyl) -4-[{N- (3- (trifluoromethyl) benzoyl) glycyl} aminomethyl] piperidine (Compound No. 519)
EDCI (4.7 mg), 1-hydroxybenzotriazole hydrate (3.3 mg), Et ₃ N (2.5 mg) and benzoic acid (3.0 mL) were converted to 1- (4-aminobenzyl) in CH ₂ Cl ₂ (2.5 mL). To a solution of -4-[{N- (3- (trifluoromethyl) benzoyl) glycyl} aminomethyl] piperidine (10.1 mg, 0.023 mmol). The reaction mixture is stirred for 16 h at 25 ° C. and washed with 2N NaOH (2 × 2 mL) and brine (1 mL). After filtration through a PTFE membrane filter, the solvent was removed under reduced pressure to give a yellow oil which was subjected to preparative TLC (SiO ₂ , 10% CH ₃ OH-CH ₂ Cl ₂ ) to give 1- {4- ( Benzoylamino) benzyl) -4-[{N- (3- (trifluoromethyl) benzoyl) glycyl} aminomethyl] piperidine (Compound No. 519) (4.6 mg, 36%) is provided: Purity Is determined by RPLC / MS (99%); ESI / MS m / e 553.2 (M ⁺ + H, C ₃₀ H ₃₁ F ₃ N ₄ O ₃ ).
Example 2007: 1- {4- (piperidinocarbonyl) benzyl} -4-[{N- (3- (trifluoromethyl) benzoyl) glycyl} aminomethyl] piperidine (Compound No. 1572 Manufacturing
Piperidine (0.048 mmol), diisopropylcarbodiimide (0.45 mmol) in DMF (0.15 mL), 1-hydroxybenzotriazole hydrate (0.45 mmol) in DMF (0.15 mL) in DMF (1.0 mL) To a solution of 1- (4-carboxybenzyl) -4-[{N- (3- (trifluoromethyl) benzoyl) glyciyl} aminomethyl] piperidine (0.040 mmol). The reaction mixture is stirred for 17 h at room temperature, loaded on a Varian ^™ SCX column and washed with CHCl ₃ / CH ₃ OH 1: 1 (5 mL) and CH ₃ OH (5 mL). The product was eluted with 2N NH ₃ in CH ₃ OH (5 mL) and concentrated to 1- {4- (piperidinocarbonyl) benzyl} -4-[{N- (3- (trifluoromethyl ) Benzoyl) glycyl} aminomethyl] piperidine (Compound No. 1572) (14.3 mg, 66%): Purity is determined by RPLC / MS (99%); ESI / MS m / e 545 (M ⁺ + H, C ₂₉ H ₃₅ F ₃ N ₄ O ₃ ).
Example 2008-2015
The compounds of the present invention are each synthesized according to the method of Example 2007 using the corresponding reactants. ESI / MS data and yields are summarized in Table 50.
Compound no.Molecular formulaESI / MS m / eYield (mg)Yield (%) Example 20081573C31 H33 F3 N4 O458317.676 Example 20091574C21 H33 F3 N4 O356718.883 Example 20101575C30 H30 Cl F3 N4 O35873.214 Example 20111576C28 H33 F3 N4 O454721.197 Example 20121577C26 H31 F3 N4 O45215.124 Example 20131578C31 H33 F3 N4 O356716.975 Example 20141579C31 H33 F3 N4 O35676.026 Example 20151580C29 H35 F3 N4 O354515.169
Example 2016: Preparation of 1- [4- (chloroformyl) benzyl] -4-[{N- (3- (trifluoromethyl) benzoyl) glycyl} aminomethyl] piperidine
A mixture of 1- (4-carboxybenzyl) -4-[{N- (3- (trifluoromethyl) benzoyl) glycyl} aminomethyl] piperidine (240 mg) and thionyl chloride (1 mL) Stir at room temperature for 12 h, remove excess thionyl chloride under reduced pressure to afford the desired 1- [4- (chloroformyl) benzyl] -4-[{N- (3- (trifluoromethyl) benzoyl) Glycyl} aminomethyl] piperidine is provided. Acid chloride is used without further purification.
Example 2017: 1- [4- {N- (2-methoxyethyl) carbamoyl} benzyl] -4-[{N- (3- (trifluoromethyl) benzoyl) glycyl} aminomethyl] pi Preparation of Ferridine (Compound No. 1612)
1- [4- (chloroformyl) benzyl] -4-[{N- (3- (trifluoromethyl) benzoyl) glycyl} aminomethyl] piperidine (0.042 mmol), 2-methoxyethylamine (3.8 mg, 0.050 mmol), piperidinomethylpolystyrene (46 mg) and dichloromethane (1.5 mL) are stirred for 17 h at room temperature. Water (0.020 mL) is added and the mixture is stirred for 30 minutes. Methanol (1 mL) is added and the mixture is loaded on a Varian ^™ SCX column and washed with CH ₃ OH (10 mL). The product was eluted with 2N NH ₃ in CH ₃ OH (5 mL) and concentrated to 1- [4 {N- (2-methoxyethyl) carbamoyl} benzyl] -4-[{N- (3 -(Trifluoromethyl) benzoyl) glyciyl} aminomethyl] piperidine (Compound No. 1612) (26.7 mg, 100%): Purity is determined by RPLC / MS (92%); ESI / MS m / e 535.2 (M ⁺ + H, C ₂₇ H ₃₃ F ₃ N ₄ O ₄ ).
Example 2018-2020
The compounds of the present invention are each synthesized according to the method of Example 2017 using the corresponding reactants. If necessary, preparative TLC is provided to provide the desired material. ESI / MS data and yields are summarized in Table 51.
Compound no.Molecular formulaESI / MS m / eYield (mg)Yield (%) Example 20181610C31 H30 F6 N4 O3621.24.414 Example 20191611C30 H29 Cl2 F3 N4 O3621.235.7quant Example 20201613C31 H35 F3 N4 O3581.229.9quant
Example 2021 Preparation of 4- [N- {5-bromo-2- (methylamino) benzoyl} glycyl] aminomethyl-1- (4-chlorobenzyl) piperidine (Compound No. 1427)
4- {N- (2-amino-5-bromobenzoyl) glycyl} aminomethyl-1- (4-chlorobenzyl) piperidine (Compound N. 1042) in triethylorthoformate (6.5 mL) ( 50 mg, 0.10 mmol) is stirred at 150 ° C. for 17 h. Concentrate to give a yellow solid. To a solution of a yellow solid in ethanol (3 mL) is added sodium borohydride (7.6 mg, 0.2 mmol) and the mixture is stirred for 14 h at room temperature. The resulting white precipitate is dissolved in dichloromethane and the solution is washed with 1N aqueous NaOH (2 mL). The organic layer is separated, dried over K ₂ CO ₃ , filtered and evaporated. Column chromatography (SiO ₂ , 20% MeOH / CHCl ₃ ) to give 4- [N- {5-bromo-2- (methylamino) benzoyl} glycyl] aminomethyl-1- (4-chlorobenzyl) pi Ferridine (Compound No. 1427) (40 mg, 80%) is provided: Purity is determined by RPLC / MS (100%); ESI / MS m / e 505 (C ₂₃ H ₂₈ BrClF ₆ N ₄ O ₂ ).
Example 2022 Preparation of 4- [N- {5-bromo-2- (dimethylamino) benzoyl} glycyl] aminomethyl-1- (4-chlorobenzyl) piperidine (Compound No. 1428)
Sodium cyanoborohydride (26 mg, 0.42 mmol) and acetic acid (14 μL) were added 4- {N- (2-amino-5-bromobenzoyl) glycyl} aminomethyl-1- (4-chlorobenzyl) To the mixture of piperidine (Compound No. 1042) (67 mg, 0.14 mmol), 37% aqueous formaldehyde solution (0.112 mL, 1.4 mmol), acetonitrile (2 mL) and methanol (1.5 mL) are added sequentially. The solution is stirred at 50 ° C. for 30 h, then 1N aqueous NaOH and dichloromethane are added. The aqueous layer is separated and the organic layer is dried over K ₂ CO ₃ , filtered and evaporated. 4- [N- {5-bromo-2- (dimethylamino) benzoyl} glycyl] aminomethyl-1- (4-chlorobenzyl) piperi by column chromatography (SiO ₂ , 20% MeOH / AcOEt) Dean (Compound No. 1428) (60 mg, 82%) is provided: Purity is determined by RPLC / MS (100%); ESI / MS m / e 523 (C ₂₄ H ₃₀ BrClF ₆ N ₄ O ₂ ).
Example 2023: 4-[{N- (5-bromo-2- (methylsulfonylamino) benzoyl) glycyl} aminomethyl] -1- (4-chlorobenzyl) piperidine (Compound No. 1581) Manufacture
4-[{N- (2-amino-5-bromobenzoyl) glycyl} aminomethyl] -1- (4-chlorobenzyl) piperidine (25 mg, 0.05 mmol), methanolsulfonyl chloride (0.0045 mL ), Triethylamine (0.026 mL) and a mixture of dichloromethane (2 mL) are stirred for 17 h at room temperature. The reaction mixture is subjected to column chromatography (SiO ₂ ), loaded on a Varian ^™ SAX column and washed with CH ₃ OH (5 mL). The product was eluted with 0.1 N HCl in CH ₃ OH (5 mL) and concentrated to 4-[{N- (5-bromo-2- (methylsulfonylamino) benzoyl) glyciyl} aminomethyl]- Provides 1- (4-Chlorobenzyl) piperidine (Compound No. 1581) (5.4 mg, 19%): ESI / MS m / e 573.0 (M ⁺ + H, C ₂₃ H ₂₈ BrClN ₄ O ₄ S ).
Example 2024: 4-[{N- (5-bromo-2- (bis (methylsulfonyl) amino) benzoyl) gylsil} aminomethyl] -1- (4-chlorobenzyl) piperidine (Compound No 1582) Preparation
1- (4-chlorobenzyl) -4-[{N- (2-amino-5-bromobenzoyl) glycyl} aminomethyl] piperidine (57 mg, 0.10 mmol), methanesulfonyl chloride (0.018 mL , 0.24 mmol), triethylamine (0.068 mL) and dichloromethane (2 mL) are stirred for 8 h at room temperature. 1N aqueous NaOH solution (1 mL) is added and the mixture is extracted with dichloromethane (2 mL × 3). The combined extracts are dried over K ₂ CO ₃ , filtered and evaporated. Column chromatography (SiO ₂ ) undertakes 4-[{N- (5-bromo-2- (bis (methylsulfonyl) amino) benzoyl) glyciyl} aminomethyl] -1- (4-chlorobenzyl) pi Ferridine (Compound No. 1582) (40 mg, 62%) is provided: ESI / MS m / e 651 (M ⁺ + H, C ₂₄ H ₃₀ BrClN ₄ O ₆ S ₂ ).
Example 2025 1- (4-chlorobenzyl) -1-methyl-4-[{N- (3- (trifluoromethyl) benzoyl) glycidyl} aminomethyl] piperidine iodide (Compound No. 461 methylammonium iodide)
(Piperidinomethyl) polystyrene (80 mg, 2.7 mmol base / g resin) and 4-[{N- (3- (trifluoromethyl) benzoyl) glyciyl} aminomethyl] in CH ₃ CN (1.0 mL) A solution of piperidine (30 mg, 0.087 mmol) is added to a solution of 4-chlorobenzyl chloride (11.7 mg, 0.073 mmol) in CH ₃ CN (1.0 mL). The reaction mixture is stirred at 60 ° C. for 2 h. Phenyl isocyanate (10.4 mg, 0.087 mmol) is added to the cooled reaction mixture and the mixture is stirred at 25 ° C. for 1 h. The reaction mixture is loaded on a Varian ^™ SCX column and washed with CH ₃ OH (20 mL). The product was eluted with 2N NH ₃ in CH ₃ OH (6 mL) and concentrated to give 1- (4-chlorobenzyl) -4-[{N- (3- (trifluoro) as colorless oil which was used without purification. Methyl) benzoyl) glycyl} aminomethyl] piperidine. Iodomethane (28 mg, 0.20 mmol) was diluted with 1- (4-chlorobenzyl) -4-[{N- (3- (trifluoromethyl) benzoyl) glyciyl} aminomethyl in CH ₃ CN (2.0 mL). ] Add to solution of piperidine and stir the reaction mixture at 70 ° C. for 4 h. Solvent was removed under reduced pressure to yield 1- (4-chlorobenzyl) -1-methyl-4-[{N- (3- (trifluoromethyl) benzoyl) glyci} aminomethyl] piperidine yole as light yellow oil. Odide (31.7 mg, 71%) is provided: Purity is determined by RPLC / MS (99%); ESI / MS m / e 482.1 (M ⁺ , C ₂₄ H ₂₈ ClF ₃ N ₃ O ₂ ).
Example 2026 1- {4-chlorobenzyl} -4- [N-methyl-N- {N- (3- (trifluoromethyl) benzoyl) glycidyl} aminomethyl] piperidine (Compound No. 520 Manufacturing
Formaldehyde (108 mg, 1.33 mmol, 37% wt solution in H ₂ O) was diluted with 1- (4-chlorobenzyl) -4- (aminomethyl) piperi in 10% CH ₃ COOH / CH ₃ OH (3 mL). To a solution of Dean (318 mg, 1.33 mmol) and NaBH ₃ CN (668 mg). The reaction mixture is stirred at 25 ° C. for 1 h. The reaction mixture is loaded onto a DOWEX ^™ 50W × 2 column (10 mL) and washed with CH ₃ OH (100 mL). The product was eluted with 2N NH ₃ in CH ₃ OH (100 mL), concentrated to give crude 1- (4-chlorobenzyl) -4-{(methylamino) methyl} piperidine as a colorless oil that was used without purification. Provide 173 mg.
EDCI (85 mg), 1-hydroxybenzotriazole hydrate (60 mg) was added 1- (4-chlorobenzyl) -4-{(methylamino) methyl} piperidine in CH ₂ Cl ₂ (4 mL). 111 mg, 0.44 mmol) is added to the solution. The reaction mixture is stirred at 25 ° C. for 1 h and then washed with 1N aqueous NaOH (2 mL × 2) and brine (1 mL). After filtration through a PTFE membrane filter, the solvent was removed under reduced pressure to give a yellow oil, which was subjected to preparative TLC (SiO ₂ , 5% CH ₃ OH / CH ₂ Cl ₂ ) as light yellow oil. Chlorobenzyl} -4- [N-methyl-N- {N- (3- (trifluoromethyl) benzoyl) glycyl} aminomethyl] piperidine (Compound No. 520) (14.0 mg, 3.4%) to provide. Purity is determined by RPLC / MS (99%); ESI / MS m / e 482.1 ( M + + H, C 24 H 27 ClF 3 N 3 O 2).
Reference Example 37: Preparation of 3-Amino Homopiperidine
A solution of DL-α-amino-ε-caprolactam (2 g, 16 mmol) in THF (70 mL) is treated with 1M BH ₃ -THF solution (80 mL) and heated to reflux for 3 h. 2N aqueous HCl solution (50 mL) is added and the reaction is heated to reflux for an additional 1 h and then cooled to 25 ° C. The reaction is basified by addition of 4N NaOH solution (pH 10) and extracted with EtOAc (3 × 200 mL). The combined organic phases are washed with saturated aqueous NaHCO ₃ , dried (MgSO ₄ ) and concentrated to give the desired material (990 mg, 54%) which is used without further purification.
Reference Example 38: Preparation of 3-amino-1- (4-chlorobenzyl) homopiperidine
A solution of 3-aminohomopiperidine (1.71 g, 15 mmol) in CH ₃ CN (45 mL) with p-chlorobenzyl chloride (463 mg, 2.9 mmol) and K ₂ CO ₃ (828 g, 6 mmol) Treat and heat to 70 ° C. for 9 h. The reaction mixture is cooled to 25 ° C. and concentrated to give a yellow solid. The residue is partitioned between H ₂ O (5 mL) and EtOAc (50 mL) and extracted with EtOAc (2 × 50 mL). The combined organic extracts are washed with brine (20 mL), dried (Na ₂ SO ₄ ) and concentrated. The resulting yellow oil is purified by chromatography (SiO ₂ , 5-20% CH ₃ OH-CH ₂ Cl ₂ gradient elution) to give the desired product (639 mg, 93%) as a yellow oil.
Example 2027 Preparation of 1- (4-chlorobenzyl) -3-{(4-benzoylbutyryl) amino} homopiperidine (Compound No. 994)
A solution of 3-amino-1- (4-chlorobenzyl) homopiperidine (24 mg, 0.10 mmol) and 4-benzoylbutyric acid (1.2 equiv) in CHCl ₃ (1 mL) was diluted with EDCI (23 mg), HOBt ( 16.2 mg) and Et ₃ N (15.2 μL) and stir at 25 ° C. for 16 h. The reaction mixture is diluted with CH ₂ Cl ₂ (0.5 mL), washed with 2N aqueous NaOH solution (2 × 0.75 mL), filtered and dried over PTFE membrane and concentrated to 1- (4-chlorobenzyl) -3-{( 4-benzoylbutyryl) amino} homopiperidine (Compound No. 994) (43 mg, 99%): Purity is determined by RPLC / MS (98%); ESI / MS m / e 413 (M ⁺ + H, C ₂₄ H ₂₉ ClN ₂ O ₂ ).
Examples 2028-2042
The compounds of the present invention are each synthesized according to the method of Example 2027 using the corresponding reactants. Chromatography (HPLC-C18), if necessary, to provide the desired material as a TFA salt. ESI / MS data and yields are summarized in Table 52.
Compound no.Molecular formulaESI / MS m / eYield (mg)Yield (%) Example 2028943C23 H25 Cl F3 N3 O2468628 Example 2029944C23 H28 Cl N3 O2414529 Example 2030945C22 H25 Cl N4 O4445630 Example 2031946C23 H27 Cl N4 O4459524 Example 2032947C25 H31 Cl N2 O4459420 Example 2033948C24 H29 Cl2 N3 O2462632 Example 2034949C25 H32 Cl N3 O2442631 Example 2035988C23 H25 Cl F3 N3 O24684592 Example 2036989C23 H28 Cl N3 O34304497 Example 2037990C22 H26 Cl N3 O24004199 Example 2038991C23 H27 Cl N2 O23994197 Example 2039992C25 H31 Cl N2 O44594798 Example 2040993C25 H31 Cl N2 O24274498 Example 2041995C25 H31 Cl N2 O34434495 Example 2042996C24 H31 Cl N4 O24435 *11
* Yield of TFA salt
Example 2043 Measurement of Inhibition of MIP-1α Binding to THP-1 Cells by Test Compounds
Human monocyte leukemia cell line THR-1 was suspended in measuring buffer (RPI-1640 (Gibco-BRL Co.) containing 0.1% BSA and 25 mM HEPES adjusted to pH 7.4) at a concentration of 1 × 10 ⁷ cells / mL Obtain a suspension. The test compound is diluted in the measurement buffer and used as the test compound solution. Iodineylated human MIP-1α (DuPont NEN Co.) is diluted to 250 nCi / mL in the measurement buffer and used as a labeled ligand solution. In a 96 well filter plate (Millipore Co.), 25 μL of test compound solution, 25 μL of labeled ligand solution and 50 μL of cell suspension are aliquoted into each well in this order, stirred (total reaction volume 100 μL), Incubate at 18 ° C. for 1 h.
After the reaction, the reaction solution is filtered and the filter is washed twice with 200 μL of cold PBS (200 μL of cold PBS is added and then filtered). The filter is air-dried and 25 μL of liquid scintillator is added to each well. Radioactivity retained in the cells on the filter is measured using TopCount (Packard Instrument Co.).
Non-specificity determined by adding 100 ng of unlabeled human MIP-1α (Peprotech Co.) in place of the test compound to calculate the ability of the test compound to inhibit human MIP-1α binding to THP-1 cells. Redeem is subtracted and the score without test compound added is 100%.
Inhibition (%) = {1-(A-B) / (C-B)} × 100
(A, score of test compound added; B, score of 100 ng of added unlabeled human MIP-1α; C, score of added [ ¹²⁵ I] -labeled human MIP-1α)
In determining inhibition by cyclic amine derivatives of the invention, for example, the following compounds showed 20-50%, 50-80% and> 80% inhibitory activity at 2 μM or 10 μM, respectively. These compounds are
20% -50% inhibitory activity at 10 μM: compound no. 29, 37, 41, 45, 46, 47, 50, 82, 85, 107, 120, 134, 214, 217, 218, 220, 222, 225, 226, 227, 228, 229, 230, 231, 233, 234, 236, 237, 238, 333, 334, 335, 336, 338, 340, 342, 347, 348, 349, 350, 352, 357, 359, 361, 366, 372, 374, 375, 376, 380, 382, 383, 385, 470, 471, 472, 473, 474, 483, 484, 488, 489, 491, 497, 499, 500, 502, 506, 508, 510, 514, 515, 518, 524, 543, 553, 554, 555, 556, 563, 571, 575, 576, 578, 579, 580, 583, 586, 587, 588, 590, 591, 592, 595, 596, 598, 603, 610, 611, 612, 614, 624, 625, 626, 629, 635, 638, 639, 640, 641, 642, 643, 644, 646, 647, 648, 649, 652, 653, 658, 659, 660, 665, 666, 669, 671, 675, 677, 679, 681, 682, 684, 691, 695, 696, 700, 702, 704, 706, 711, 712, 714, 717, 721, 723, 724, 726, 727, 728, 729, 731, 737, 739, 740, 741, 742, 744, 746, 765, 767, 772, 773, 774, 775, 776, 780, 781, 785, 786, 787, 788, 790, 791, 792, 793, 795, 796, 797, 798, 805, 806, 807, 810, 813 820, 821, 822, 824, 825, 827, 829, 830, 833, 834, 837, 838, 844, 853, 855, 873, 877 , 878, 880, 882, 887, 888, 891, 894, 901, 903, 904, 905, 911, 929, 932, 933, 935, 938, 940, 948, 993, 996, 1006, 1018, 1026, 1028, 1035, 1048, 1053, 1054, 1055, 1056, 1068, 1070, 1071, 1072, 1073, 1075, 1076, 1081, 1763, 1764.
50% -80% inhibitory activity at 10 μM: compound no. 1, 2, 3, 4, 7, 13, 22, 23, 24, 25, 27, 31, 32, 38, 48, 83, 119, 121, 123, 131, 215, 216, 221, 235, 337, 351, 354, 358, 362, 363, 365, 367, 368, 369, 373, 378, 381, 384, 458, 459, 463, 465, 466, 467, 468, 478, 479, 480, 482, 485, 486, 487, 492, 493, 494, 495, 496, 498, 501, 503, 504, 507, 511, 512, 513, 520, 523, 527, 529, 530, 531, 532, 533, 534, 535, 536, 537, 538, 539, 540, 541, 542, 545, 546, 547, 548, 549, 550, 551, 552, 558, 559, 560, 561, 562, 565, 567, 568, 569, 570, 572, 573, 574, 577, 581, 582, 594, 597, 599, 600, 602, 604, 606, 607, 608, 609, 613, 615, 616, 618, 619, 620, 621, 628, 630, 631, 632, 633, 634, 636, 637, 645, 651, 654, 655, 657, 661, 662, 664, 673, 674, 676, 678, 680, 683, 685, 687, 688, 689, 693, 703, 705, 707, 708, 709, 710, 713, 716, 718, 719, 720, 725, 730, 732, 733, 734, 735, 736, 749, 750, 751, 752, 753, 754, 756, 758, 760, 762, 763, 764, 766, 768, 769, 770, 771, 777, 778, 779, 784, 794, 799, 800, 802, 804, 808, 809, 811, 812, 815, 816, 819, 828, 831, 832, 835, 836, 839, 840, 845, 846, 847, 848, 850, 851, 854, 857, 858, 859, 860, 861, 862, 863, 865, 866, 867, 868, 872, 874, 876, 886, 899, 910, 942, 998, 1004, 1005, 1007, 1013, 1015, 1016, 1017, 1019, 1020, 1021, 1022, 1024, 1030, 1037, 1042, 1043, 1044, 1045, 1046, 1047, 1049, 1050, 1052, 1059, 1060, I061, 1067, 1069, 1074, 1078, 1079, 1080, 1766.
> 80% inhibitory activity at 10 μM: compound no. 461, 464, 469, 481, 490, 505, 509, 521, 526, 528, 544, 564, 566, 601, 605, 617, 622, 623, 627, 650, 656, 663, 668, 672, 686, 690, 692, 694, 715, 743, 747, 748, 755, 757, 759, 761, 782, 783, 803, 814, 817, 818, 826, 849, 856, 864, 869, 870, 871, 999, 1000, 1001, 1002, 1003, 1008, 1009, 1010, 1011, 1012, 1023, 1029, 1031, 1032, 1033, 1034, 1036, 1038, 1039, 1040, 1041, 1051, 1057, 1058, 1062, 1063, 1064, 1065, 1066, 1082, 1083.
20% -50% inhibitory activity at 2 μM: compound no. 1042, 1043, 1244, 1245, 1416, 1435, 1436, 1438, 1441, 1480, 1570, 1583, 1584, 1589, 1590, 1594, 1595, 1601, 1660, 1672, 1687, 1724, 1779, 1780, 1787, 1795, 1796, 1798, 1799, 1802, 1893, 1894, 1898, 1900, 1915, 1919, 1920, 2092, 2096, 2098, 2100.
50% -80% inhibitory activity at 2 μM: compound no. 1190, 1414, 1600, 2091, 2094, 2095.
> 80% inhibitory activity at 2 μM: compound no. 2093, 2097, 2099, 2103, 2104.
Example 2044 Measurement of Inhibition of MCP-1 Binding to THP-1 Cells
1. Construction of recombinant baculovirus carrying the human MCP-1 gene
Two synthetic DNA primers flanked with restriction enzyme sites based on already published human MCP-1 gene sequences (e.g., T. Yoshimura et al., FEBS Lett., 1989, 244, 487-493) 5'-CACTCTAGACTCCAGCATGA-3 'and 5'-TAGCTGCAGATTCTTGGGTTG-3') are used to amplify DNA fragments in cDNA derived from human endothelial cells (manufactured by Kurabow Co.); The amplified fragments were cleaved with restriction enzymes (PstI and XbaI), ligated into delivery vector pVL1393 (Invitrogen Co.), and the resulting vector co-transfected with Sac-9 insect cells with infectious baculovirus and The supernatant is plaque analyzed to obtain human MCP-1 gene baculovirus recombinant.
2. Synthesis of [ ¹²⁵ I] -labeled human MCP-1 expressed in baculovirus
Using the method of K. Ishii et al. (Biochem Biophys Research Communication, 1995, 206, 955-961), 5 × 10 ⁶ Sf-6 insect cells were treated with 5 × 10 ⁷ PFU (plaque forming units) of the human MCP. Infected with -1 recombinant baculovirus and incubated for 7 days in Ex-Cell 401 medium. The culture supernatant is affinity purified using a Heparin Sepharose column (Pharmacia Co.) and then further purified using reversed phase HPLC (Vydac C18 column) to prepare purified human MCP-1. Purified human MCP-1 was protein labeled using the Bolton Hunter method to express human MCP-1 (inactive 2000 Ci / mmol) in [ ¹²⁵ I] -labeled baculovirus.
3-1. Determination of Inhibition of Binding of [ ¹²⁵ I] -labeled Baculovirus Expressed Human MCP-1 to THP-1 Cells (Method 1)
Human monocyte leukemia cell line THP-1 was suspended in measurement buffer (RPI-1640 (Gibco-BRL Co.) containing 0.1% BSA adjusted to pH 7.4 and 25 mM HEPES) at a concentration of 1 × 10 ⁷ cells / mL Make a suspension. The test compound is diluted in the measurement buffer and used as the test compound solution. The [ ¹²⁵ I] -labeled human MCP-1 is diluted to 1 mCi / mL in the measurement buffer and used as a labeled ligand solution. In a 96 well filter plate (Millipore Co.), 25 μL of test compound solution, 25 μL of labeled ligand solution and 50 μL of cell suspension are aliquoted into each well in this order, stirred (total reaction volume 100 μL), Incubate at 18 ° C. for 1 h.
After the reaction, the reaction solution is filtered and the filter is washed twice with 200 μL of cold PBS (200 μL of cold PBS is added and then filtered). The filter is air-dried and 25 μL of liquid scintillator is added to each well. Radioactivity retained in the cells on the filter is measured using TopCount (Packard Instrument Co.).
To calculate the ability of a test compound to inhibit the binding of human MCP-1 to THP-1 cells, subtract non-specific binding determined by adding 100 ng of unlabeled human MCP-1 in place of the test compound and The test compound is scored 100%.
Inhibition (%) = {1-(A-B) / (C-B)} × 100
(A, score of added test compound; B, score of 100 ng of added unlabeled human MCP-1; C, score of added [ ¹²⁵ I] -labeled human MCP-1)
In measuring inhibition by the cyclic amine derivatives of the invention, for example, the following compounds showed 20-50%, 50-80% and> 80% inhibitory activity at 1 μM, 10 μM or 100 μM, respectively. These compounds are
20% -50% inhibitory activity at 100 μM: compound no. 3, 6, 11, 15, 16, 19, 28, 44, 88, 92, 94, 104, 111, 112, 124, 125, 133, 219, 220, 224, 228, 236, 338, 343, 346, 347, 348, 349, 362, 363, 367, 368, 371, 373, 381, 618, 847, 849, 850, 866, 867, 869, 870, 871, 872, 873.
50% -80% inhibitory activity at 100 μM: compound no. 1, 8, 10, 12, 18, 21, 26, 30, 33, 35, 39, 84, 89, 90, 91, 96, 97, 98, 99, 100, 101, 103, 106, 108, 109, 110, 116, 122, 126, 216, 218, 221, 225, 226, 231, 330, 332, 333, 334, 337, 341, 342, 350, 352, 354, 356, 359, 360, 361, 364, 366, 374, 375, 379, 382, 462, 463, 464, 557, 686, 840, 841, 842, 843, 844, 845, 846, 848, 862, 863, 864, 865, 868.
> 80% inhibitory activity at 100 μM: compound no. 2, 4, 5, .7, 13, 14, 17, 20, 22, 23, 24, 25, 27, 29, 31, 32, 34, 36, 38, 40, 41, 42, 43, 45, 46 , 47, 48, 49, 50, 83, 85, 86, 95, 102, 105, 107, 113, 114, 115, 119, 120, 121, 123, 127, 128, 129, 130, 131, 132, 134 , 214, 215, 217, 227, 237, 238, 331, 335, 336, 339, 340, 345, 351, 355, 357, 358, 383, 458, 459, 460, 466, 558, 851, 852, 861 , 874.
20% -50% inhibitory activity at 10 μM: compound no. 12, 18, 30, 34, 40, 42, 43, 51, 52, 53, 54, 55, 56, 57, 59, 60, 64, 66, 75, 76, 77, 78, 79, 82, 89, 90, 97, 98, 102, 103, 116, 127, 128, 129, 130, 132, 135, 136, 140, 141, 144, 156, 157, 159, 160, 161, 162, 163, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 178, 179, 190, 191, 192, 195, 197, 200, 202, 203, 204, 205, 208, 233, 234, 235, 239, 240, 241, 242, 243, 245, 247, 249, 250, 255, 263, 264, 269, 274, 278, 279, 282, 306, 316, 317, 323, 324, 380, 404, 409, 433, 446, 448, 449, 451, 470, 471, 473, 476, 479, 486, 488, 489, 497, 498, 499, 501, 504, 507, 508, 509, 510, 512, 514, 516, 519, 527, 530, 532, 542, 545, 560, 563, 564, 565, 566, 568, 569, 572, 573, 574, 575, 578, 583, 584, 586, 587, 589, 590, 599, 600, 601, 603, 606, 612, 613, 620, 621, 622, 624, 625, 627, 629, 630, 632, 634, 636, 637, 640, 641, 642, 643, 644, 645, 646, 647, 648, 649, 658, 678, 682, 687, 692, 694, 764, 775, 856, 857, 860, 881, 882, 883, 884, 890, 892, 899, 900, 903, 905, 907, 908, 911, 912, 916, 917, 921 , 922, 923, 925, 927, 931, 932, 935, 939, 940, 968, 986, 1039, 1041, 1045, 1047, 1062, 1063, 1083.
50% -80% inhibitory activity at 10 μM: compound no. 7, 32, 36, 61, 62, 63, 65, 67, 69, 70, 71, 72, 73, 74, 81, 91, 105, 114, 121, 123, 134, 137, 138, 139, 146, 147, 148, 149, 151, 154, 165, 177, 232, 244, 248, 251, 252, 253, 256, 259, 261, 266, 267, 276, 286, 292, 293, 295, 301, 305, 307, 310, 314, 315, 320, 322, 328, 434, 435, 436, 437, 439, 440, 443, 447, 450, 452, 453, 454, 455, 456, 468, 469, 472, 474, 475, 477, 478, 480, 481, 482, 483, 485, 490, 493, 494, 500, 505, 511, 517, 520, 529, 534, 540, 543, 544, 548, 555, 556, 561, 562, 570, 576, 579, 611, 617, 853, 854, 855, 858, 859, 875, 877, 879, 880, 885, 886, 887, 888, 891, 894, 895, 904, 906, 909, 910, 913, 914, 918, 928, 930, 933, 937, 938, 945, 970, 1040, 1044, 1046.
> 80% inhibitory activity at 10 μM: compound no. 31, 45, 46, 48, 58, 68, 80, 83, 113, 115, 142, 143, 145, 150, 152, 265, 268, 272, 275, 283, 285, 287, 288, 290, 291, 294, 296, 297, 302, 308, 309, 313, 321, 325, 326, 358, 438, 441, 442, 444, 445, 457, 466, 467, 484, 487, 491, 492, 495, 496, 503, 518, 537, 538, 547, 554, 876, 878, 919, 929, 943.
20% -50% inhibitory activity at 1 μM: compound no. 1118, 1121, 1136, 1143, 1146, 1158, 1159, 1167, 1170, 1359, 1361, 1362, 1363.
50% -80% inhibitory activity at 1 μM: compound no. 1133, 1134, 1137, 1141, 1156, 1161, 1162, 1163, 1164, 1166.
> 80% inhibitory activity at 1 μM: compound no. 1147.
3-2. Determination of the Inhibition of Binding of [ ¹²⁵ I] -labeled Baculovirus Expressed Human MCP-1 to THP-1 Cells (Method 2)
Human monocyte leukemia cell line THP-1 is suspended in measurement buffer (50 mM HEPES, pH 7.4, 1.0 mM CaCl ₂ , 5.0 mM MgCl ₂ , 0.5% BSA) to make a cell suspension at a concentration of 1 × 10 ⁷ cells / mL. The test compound is diluted in the measurement buffer and used as the test compound solution. The [ ¹²⁵ I] -labeled human MCP-1 is diluted to 1 mCi / mL in the measurement buffer and used as a labeled ligand solution. In a 96 well filter plate (Millipore Co.), 25 μL of test compound solution, 25 μL of labeled ligand solution and 50 μL of cell suspension are aliquoted into each well in this order, stirred (total reaction volume 100 μL), Incubate at 18 ° C. for 1 h.
After the reaction, the reaction solution is filtered and the filter is washed twice with 200 μL of cold PBS (200 μL of cold PBS is added and then filtered). The filter is air-dried and 25 μL of liquid scintillator is added to each well. Radioactivity retained in the cells on the filter is measured using TopCount (Packard Instrument Co.).
To calculate the ability of a test compound to inhibit the binding of human MCP-1 to THP-1 cells, subtract non-specific binding determined by adding 100 ng of unlabeled human MCP-1 in place of the test compound and The test compound is scored 100%.
Inhibition (%) = {1-(A-B) / (C-B)} × 100
(A, score of added test compound; B, score of 100 ng of added unlabeled human MCP-1; C, score of added [ ¹²⁵ I] -labeled human MCP-1)
In measuring inhibition by cyclic amine derivatives of the invention, for example, the following compounds showed 20-50%, 50-80% and> 80% inhibitory activity at 0.2 μM, 1 μM or 10 μM, respectively. These compounds are
20-50% inhibitory activity at 10 μM: compound no. 1560.
50-80% inhibitory activity at 10 μM: compound no. 1550.
> 80% inhibitory activity at 10 μM: compound no. 541, 1042, 1043, 1559.
20-50% inhibitory activity at 1 μM: compound no. 1098, 1100, 1101, 1104, 1105, 1109, 1110, 1116, 1174, 1175, 1176, 1178, 1187, 1188, 1189, 1197, 1198, 1199, 1200, 1201, 1202, 1209, 1210, 1211, 1212, 1222, 1225, 1229, 1230, 1237, 1238, 1243, 1250, 1259, 1261, 1265, 1266, 1272, 1277, 1282, 1294, 1299, 1302, 1307, 1315, 1318, 1319, 1320, 1329, 1330, 1335, 1336, 1337, 1343, 1344, 1353, 1355, 1356, 1357, 1358, 1368, 1372, 1385, 1386, 1392, 1400, 1413, 1422, 1423, 1425, 1426, 1429, 1430, 1432, 1437, 1440, 1445, 1446, 1447, 1448, 1450, 1452, 1453, 1455, 1458, 1459, 1461, 1463, 1464, 1466, 1468, 1469, 1470, 1471, 1474, 1419, 1482, 1485, 1507, 1508, 1510, 1511, 1512, 1513, 1514, 1515, 1516, 1518, 1519, 1521, 1522, 1524, 1535, 1538, 1540, 1542, 1544, 1571, 1573, 1574, 1575, 1576, 1577, 1578, 1579, 1580, 1581, 1582, 1585, 1587, 1598, 1602, 1603, 1604, 1609, 1611, 1612, 1613, 1614, 1615, 1616, 1617, 1618, 1622, 1627, 1630, 1643, 1646, 1662, 1669, 1716, 1717, 1723, 1728, 1731, 1733, 1736, 1739, 1740, 1747, 1750, 1755, 1757, 1758, 1759, 1760, 1761 , 1762, 1769, 1770, 1771, 1772, 1773, 1774, 1777, 1783, 1784, 1785, 1791, 1793, 1904, 1911, 1917, 2057, 2061, 2063, 2064, 2065, 2066, 2067, 2068, 2069 , 2071, 2072, 2073, 2074, 2075, 2076, 2080, 2081, 2082, 2110, 2112, 2123, 2130, 2131, 2139.
50-80% inhibitory activity at 1 μM: compound no. 37, 298, 318, 1084, 1091, 1113, 1106, 1108, 1111, 1113, 1114, 1115, 1138, 1142, 1165, 1179, 1190, 1192, 1193, 1195, 1196, 1204, 1205, 1206, 1207, 1208, 1245, 1246, 1255, 1257, 1258, 1262, 1263, 1293, 1300, 1342, 1351, 1352, 1354, 1370, 1371, 1373, 1375, 1377, 1378, 1380, 1381, 1383, 1384, 1391, 1411, 1412, 1414, 1417, 1418, 1419, 1421, 1424, 1431, 1436, 1439, 1449, 1454, 1456, 1457, 1460, 1462, 1472, 1473, 1487, 1502, 1504, 1506, 1517, 1525, 1526, 1527, 1529, 1530, 1531, 1532, 1533, 1534, 1536, 1537, 1539, 1541, 1545, 1593, 1600, 1601, 1606, 1608, 1619, 1620, 1621, 1623, 1624, 1625, 1626, 1628, 1629, 1645, 1650, 1654, 1658, 1663, 1664, 1665, 1670, 1671, 1672, 1673, 1675, 1678, 1679, 1681, 1684, 1687, 1688, 1689, 1690, 1711, 1712, 1714, 1718, 1722, 1725, 1726, 1727, 1729, 1730, 1732, 1734, 1735, 1737, 1741, 1742, 1743, 1744, 1745, 1746, 1748, 1751, 1753, 1754, 1756, 1779, 1781, 1782, 1786, 1788, 1789, 1790, 1792, 1795, 1797, 1798, 1800, 1801, 1804, 1848, 1862, 1883, 1885, 1886, 1887, 18 89, 1893, 1894, 1903, 1905, 1910, 1912, 1913, 1914, 1918, 1922, 1976, 1985, 2027, 2035, 2062, 2083, 2084, 2088, 2089, 2090, 2111, 2124, 2125, 2126, 2135.
> 80% inhibitory activity at 1 μM: compound no. 299, 311, 312, 329, 1042, 1043, 1085, 1119, 1191, 1203, 1220, 1228, 1236, 1244, 1256, 1288, 1295, 1308, 1310, 1376, 1382, 1393, 1395, 1415, 1416, 1420, 1435, 1438, 1441, 1480, 1481, 1570, 1583, 1584, 1589, 1590, 1594, 1595, 1607, 1634, 1660, 1661, 1666, 1668, 1695, 1696, 1697, 1698, 1699, 1701, 1702, 1703, 1704, 1705, 1706, 1707, 1708, 1709, 1713, 1724, 1749, 1752, 1775, 1776, 1778, 1780, 1787, 1794, 1796, 1799, 1802, 1803, 1841, 1869, 1870, 1871, 1872, 1876, 1877, 1892, 1896, 1897, 1898, 1899, 1900, 1901, 1902, 1906, 1907, 1908, 1909, 1915, 1916, 1919, 1920, 1921, 2085, 2086, 2087, 2113, 2114, 2118, 2119, 2120, 2121, 2122, 2127, 2128, 2129, 2132, 2133, 2136, 2137, 2138, 2159, 2161, 2162, 2187, 2189, 2193.
20-50% inhibitory activity at 0.2 μM: compound no. 1680, 1682, 1686, 1691, 1694, 1700, 1805, 1810, 1811, 1812, 1813, 1815, 1816, 1817, 1818, 1819, 1820, 1824, 1825, 1826, 1827, 1828, 1832, 1833, 1834, 1835, 1836, 1839, 1840, 1842, 1843, 1851, 1852, 1853, 1854, 1855, 1856, 1858, 1859, 1860, 1863, 1864, 1865, 1866, 1868, 1874, 1878, 1879, 1880, 1888, 1890, 1891, 1895, 1926, 1927, 1928, 1929, 1930, 1934, 1935, 1937, 1945, 1946, 1951, 1952, 1953, 1954, 1959, 1960, 1961, 1962, 1966, 1969, 1970, 1971, 1972, 1973, 1977, 1978, 1979, 1980, 1981, 1985, 2014, 2027, 2028, 2033, 2035, 2039, 2040, 2041, 2042, 2044, 2045, 2046.
50-80% inhibitory activity at 0.2 μM: compound no. 1677, 1678, 1679, 1681, 1687, 1688, 1689, 1690, 1695, 1697, 1808, 1809, 1841, 1848, 1861, 1862, 1869, 1870, 1871, 1872, 1873, 1876, 1877, 1883, 1884, 1885, 1886, 1887, 1889, 1893, 3894, 1976.
> 80% inhibitory activity at 0.2 μM: compound no. 1696, 1892.
Example 2045 Measurement of Inhibition of Binding of [ ¹²⁵ I] -labeled Human MCP-1 to Cells Expressing MCP-1 Receptor
1. Induction of cells expressing MCP-1 receptor
The plasmid obtained by cloning the cDNA fragment containing the MCP-a receptor (reported in S. Yamagami et al., Biochemical Biophysical Research Communications 1994, 02, 1156-1162) into the NotI site into the expression plasmid pCEP4 (Invitrogen Co.). Is transfected into human kidney epithelial cell line 293-EBNA using lipofectamine reagent (Gibco-BRL Co.). Cells are cultured in the presence of a selective reagent (Hygromycin) and a transfected strain that stably expresses is obtained. Expression of the receptor is confirmed by binding of [ ¹²⁵ I] -labeled human MCP-1.
2. Measurement of inhibition of binding of [ ¹²⁵ I] -labeled baculovirus expressed human MCP-1 to MCP-1 receptor expressing cells
MCP-1 receptor expressing cells on a tissue culture dish were scraped using a cell scraper and loaded with D-MEM (Gibco-BRL Co. Ltd. containing 0.1% BSA and 25 mM HEPES adjusted to pH 7.4). Suspension at)) yields a cell suspension at a concentration of 6 x 10 ⁶ cells / mL. The test compound is diluted in the measurement buffer. The rest of the procedure is as described in Example 2044.
In measuring inhibition by some exemplary compounds of the invention, the inhibitory activity was substantially the same as those of Example 2044, respectively.
Example 2046 Measurement of Inhibition of Cell Chemotaxis
To measure inhibition of cellular chemotaxis by the compounds of the present invention, Fall et al. Cell chemotaxis induced by monocyte chemotactic factor MCP-1 was measured using the human monocyte leukemia cell line THP-1 as a chemotactic cell according to the method (J. Immunol. Methods, 190, 33, 239-247). 2 × 10 ⁶ cells / mL of THP-1 cells (suspended in RPMI-1640 (Flow Laboratories Co.) + 10% FCS) were placed in an upper chamber (200) in a 96 well micro-chemotaxis chamber (Neuroprobe®). μL), human recombinant MCP-1 in copper solution (Peprotech Co.) at a final concentration of 20 ng / mL was placed in the lower chamber, and the polycarbonate filter (PVP-free, Neuroprobe®) was placed in two chambers. Position it in between. They are incubated at 37 ° C. for 2 h in 5% CO ₂ .
Remove the filter, fix the cells transferred to the bottom of the filter, stain using Diff Quick (Kokusai Shiyaku Co.), and quantify using a plate reader (Molecular Device Co.) at a wavelength of 550 nm. Determine cell migration rate as a means of wells. In addition, test compounds are placed in the upper and lower chambers together with THP-1 and MCP-1, respectively, to determine inhibition of cell migration (inhibition IC ₅₀ (μM)). Inhibition is defined as {(MCP-1 induced cell migration without test compound in the upper and lower chambers)-(cell migration without addition of MCP-1 to the lower chamber) = 100%), the concentration of the test compound giving 50% inhibition. Denotes IC ₅₀ .
When inhibition by the cyclic amine derivative of the invention was measured, for example, the 50% inhibitory concentration (IC ₅₀ ) for the following compounds was IC ₅₀ <0.1 μM.
IC ₅₀ <0.1 μM: Compound No. 4, 37, 298, 299, 311, 312, 318, 329, 461, 886, 909, 1042, 1043, 1085, 1119, 1138, 1142, 1165, 1179, 1191, 1203, 1205, 1220, 1228, 1236, 1244, 1245, 1256, 1288, 1293, 1295, 1308, 1310, 1352, 1376, 1382, 1393, 1395, 1416, 1420, 1435, 1436, 1438, 1441, 1480, 1531, 1532, 1570, 1583, 1584, 1589, 1590, 1594, 1595, 1600, 1601, 1607, 1660, 1661, 1664, 1666, 1668, 1698, 1699, 1701, 1702, 1703, 1704, 1706, 1707, 1708, 1709, 1713, 1775, 1776, 1778, 1779, 1787, 1794, 1796, 1799, 1802, 1803, 1896, 1898, 1899, 1900, 1901, 1902, 1906, 1907, 1908, 1909, 1915, 1916, 1919, 1920, 1921, 2087, 2114, 2128, 2129, 2132, 2137, 2141, 2144, 2157, 2158, 2189.
Chemokine receptor antagonists containing a cyclic amine compound of the present invention, a pharmaceutically acceptable acid addition salt or a pharmaceutically acceptable C ₁ -C ₆ alkyl addition salt thereof, contain MIP-1α and / or MCP on target cells. Inhibits chemokines, such as -1, such as atherosclerosis, rheumatoid arthritis, psoriasis, asthma, ulcerative colitis, and nephritis, where tissue infiltration such as blood monocytes and lymphocytes plays a major role in the initiation, progression, or maintenance of the disease. Nephropathy), therapeutic agents and / or prophylactic agents for diseases such as multiple sclerosis, pulmonary fibrosis, myocarditis, hepatitis, pancreatitis, sarcoidosis, Crohn's disease, endometriosis, congestive heart failure, viral meningitis, cerebral infarction, neuropathy, kawasaki disease and sepsis Useful as

权利要求:
Claims (54)
[1" claim-type="Currently amended] A compound of formula (I), a pharmaceutically acceptable acid addition salt thereof or a pharmaceutically acceptable C ₁ -C ₆ alkyl addition salt thereof:

Wherein R ¹ is an aromatic heterocyclic group having 1-3 heteroatoms selected from the group consisting of a phenyl group, a C ₃ -C ₈ cycloalkyl group, or an oxygen atom, a sulfur atom, a nitrogen atom or a combination thereof, wherein phenyl or aromatic hetero The cyclic group may be condensed with an aromatic heterocyclic group having 1-3 heteroatoms selected from the group consisting of a benzene ring or an oxygen atom, a sulfur atom, a nitrogen atom, or a combination thereof to form a condensed ring, and a phenyl group, C ₃ − C ₈ cycloalkyl group, aromatic heterocyclic group, or condensed ring is halogen atom, hydroxy group, cyano group, nitro group, carboxyl group, carbamoyl group, C ₁ -C ₆ alkyl group, C ₃ -C ₈ cycloalkyl group, C _2- C ₆ alkenyl groups, C ₁ -C ₆ alkoxy group, C ₁ -C ₆ alkylthio, C ₃ -C ₅ alkylene group, C ₂ -C ₄ alkylene group, a C ₁ -C ₃ alkylenedioxy group, a phenyl group , Phenoxy group, phenylthio group, benzyl group, benzyloxy group, benzo Amino group, C ₂ -C ₇ alkanoyl group, C ₂ -C ₇ alkoxycarbonyl group, C ₂ -C ₇ alkanoyloxy group, C ₂ -C ₇ alkanoylamino group, C ₂ -C ₇ N- alkyl carbamoyl group, C ₄ -C ₉ N-cycloalkylcarbamoyl group, C ₁ -C ₆ alkylsulfonyl group, C ₃ -C ₈ (alkoxycarbonyl) methyl group, N-phenylcarbamoyl group, piperidinocarbonyl group, morpholinocarbonyl group , 1-pyrrolidinylcarbonyl group, divalent represented by formula: -NH (C = O) O-, formula: divalent represented by -NH (C = S) O-, amino group, mono (C ₁ -C ₆ alkyl) amino group, or di (C ₁ -C ₆ alkyl) amino group, where a phenyl group, a C ₃ -C ₈ cycloalkyl group, an aromatic heterocyclic group, or a condensed ring substituent is halogen Optionally substituted with one or more of atoms, hydroxy groups, amino groups, trifluoromethyl groups, C ₁ -C ₆ alkyl groups, or C ₁ -C ₆ alkoxy groups;
R ² is a hydrogen atom, a C ₁ -C ₆ alkyl group, a C ₂ -C ₇ alkoxycarbonyl group, a hydroxy group, or a phenyl group, wherein the C ₁ -C ₆ alkyl or phenyl group is a halogen atom, a hydroxy group, a C ₁ -C ₆ alkyl group, or May be substituted with one or more of C ₁ -C ₆ alkoxy groups, and when j = 0, R ² is not a hydroxy group;
j represents an integer of 0-2;
k represents an integer of 0-2;
m represents an integer of 2-4;
n represents 0 or 1;
R ³ is a hydrogen atom or a C ₁ -C ₆ alkyl group optionally substituted with one or two phenyl groups, and each phenyl group is at least one of a hydrogen atom, a hydroxy group, a C ₁ -C ₆ alkyl group, or a C ₁ -C ₆ alkoxy group May be substituted by;
R ⁴ and R ⁵ may be the same or different and are a hydrogen atom, a hydroxy group, a phenyl group, or a C ₁ -C ₆ alkyl group, wherein the C ₁ -C ₆ alkyl group is a halogen atom, a hydroxy group, a cyano group, a nitro group, a carboxyl group, a carbon carbamoyl group, a mercapto group, a dino-ku no group, C ₃ -C ₈ cycloalkyl, C ₁ -C ₆ alkoxy group, C ₁ -C ₆ alkylthio group, one or more hydrogen atoms, hydroxy groups, C ₁ -C ₆ alkyl group , Phenyl group, phenoxy group, benzyloxy group, benzyloxycarbonyl group, C ₂ -C ₇ alkanoyl group, C ₂ -C ₇ alkoxycarbonyl group, C ₂ -C ₇ optionally substituted with C ₁ -C ₆ alkoxy group or benzyloxy group alkanoyloxy group, C ₂ -C ₇ alkanoylamino group, C ₂ -C ₇ N- alkyl carbamoyl, C ₁ -C ₆ alkylsulfonyl group, an amino group, a mono (C ₁ -C ₆ alkyl) amino group, di ( Aromatic heterocycle having 1-3 heteroatoms selected from the group consisting of a C ₁ -C ₆ alkyl) amino group, or an oxygen atom, a sulfur atom, a nitrogen atom, or a combination thereof Optionally substituted with one or more of the click groups and optionally condensed with a benzene ring, or R ⁴ and R ⁵ together form a 3-6 membered cyclic hydrocarbon;
p represents 0 or 1;
q represents 0 or 1;
G is -CO-, -SO _2- , -CO-O-, -NR ⁷ -CO-, -CO-NR ^7- , -NH-CO-NH-, -NH-CS-NH-, -NR ⁷ A group represented by -SO _2- , -SO ₂ -NR ^7- , -NH-CO-O-, or -O-CO-NH-, wherein R ⁷ is a hydrogen atom or a C ₁ -C ₆ alkyl group, Or R ⁷ together with R ⁵ represent a C ₃ -C ₅ alkylene group;
R ⁶ is an aromatic heterocycle having 1-3 heteroatoms selected from the group consisting of a phenyl group, a C ₃ -C ₈ cycloalkyl group, a C ₃ -C ₈ cycloalkenyl group, a benzyl group, or an oxygen atom, a sulfur atom, a nitrogen atom or a combination thereof Wherein the phenyl, benzyl, or aromatic heterocyclic group is condensed and condensed with an aromatic heterocyclic group having 1-3 heteroatoms selected from the group consisting of benzene rings or oxygen atoms, sulfur atoms, nitrogen atoms or combinations thereof A phenyl group, a C ₃ -C ₈ cycloalkyl group, a C ₃ -C ₈ cycloalkenyl group, a benzyl group, an aromatic heterocyclic group, or a condensed ring may be a halogen atom, a hydroxy group, a mercapto group, a cyano group , Nitro group, thiocyanato group, carboxyl group, carbamoyl group, trifluoromethyl group, C ₁ -C ₆ alkyl group, C ₃ -C ₆ cycloalkyl group, C ₂ -C ₆ alkenyl group, C ₁ -C ₆ alkoxy group , C ₃ -C ₈ cycloalkyloxy group, C ₁ -C ₆ alkylthio group, C ₁ -C ₃ alkylenedioxy group, phenyl group, phenoxy group, phenylamino group, benzyl group, benzoyl group, phenylsulfinyl group, phenylsulfonyl group, 3-phenylureido group, C ₂ -C ₇ alkanoyl group, C ₂ -C ₇ alkoxycarbonyl group, C ₂ -C ₇ alkanoyloxy group, C ₂ -C ₇ alkanoylamino group, C ₂ -C ₇ N- alkyl carbamoyl, C ₁ -C ₆ alkylsulfonyl Nyl group, phenylcarbamoyl group, N, N-di (C ₁ -C ₆ alkyl) sulfamoyl group, amino group, mono (C ₁ -C ₆ alkyl) amino group, di (C ₁ -C ₆ alkyl) amino group, benzylamino group , A C ₂ -C ₇ (alkoxycarbonyl) amino group, a C ₁ -C ₆ (alkylsulfonyl) amino group, or a bis (C ₁ -C ₆ alkylsulfonyl) amino group, which may be substituted with a phenyl group , A C ₃ -C ₈ cycloalkyl group, a C ₃ -C ₈ cycloalkenyl group, a benzyl group, an aromatic heterocyclic group, or a substituent of a condensed ring may be a halogen atom, cyano group, hydroxy group, amino group, trifluoromethyl group, C ₁ - C ₆ alkyl, C ₁ -C ₆ alkoxy group, C ₁ -C ₆ alkylthio group, a mono (C ₁ -C ₆ alkyl) amino, or di (C ₁ -C ₆ alkyl) is optionally substituted with one or more of the amino group Provided that when k = 2, m = 2, n = 0 and the phenyl group of R ¹ is not substituted, a phenyl group of R ⁶ , a C ₃ -C ₈ cycloalkyl group, a C ₃ -C ₈ cycloalkenyl group, a benzyl group, The C ₁ -C ₆ alkyl group as a substituent to the aromatic heterocyclic group or the condensed ring is not substituted with an amino group, and R ⁶ is not a benzyl group.
[2" claim-type="Currently amended] 2. A compound, a pharmaceutically acceptable acid addition salt thereof, or a pharmaceutically acceptable C ₁ -C ₆ alkyl addition thereof, according to claim 1 wherein k = 1 and m = 2 in formula (I) salt.
[3" claim-type="Currently amended] 3. A compound, a pharmaceutically acceptable acid addition salt thereof, or a pharmaceutically acceptable C ₁ -C ₆ alkyl addition salt thereof, according to claim 2, wherein n = 0 in the formula (I).
[4" claim-type="Currently amended] 2. A compound, a pharmaceutically acceptable acid addition salt thereof or a pharmaceutically acceptable C ₁ -C thereof according to claim 1, wherein k = 0, m = 3 and n = 1 in formula (I) ₆ alkyl addition salts.
[5" claim-type="Currently amended] A compound according to claim 1, wherein k = 1 and m = 3 in formula (I), a pharmaceutically acceptable acid addition salt thereof or a pharmaceutically acceptable C ₁ -C ₆ alkyl addition thereof salt.
[6" claim-type="Currently amended] A compound according to claim 1, wherein k = 2 and m = 2 in formula (I), a pharmaceutically acceptable acid addition salt thereof or a pharmaceutically acceptable C ₁ -C ₆ alkyl addition thereof salt.
[7" claim-type="Currently amended] 7. A compound, a pharmaceutically acceptable acid addition salt thereof or a pharmaceutically acceptable C ₁ -C ₆ alkyl addition salt thereof according to claim 6, wherein n = 1 in formula (I).
[8" claim-type="Currently amended] A compound according to claim 1, wherein k = 1 and m = 4 in formula (I), a pharmaceutically acceptable acid addition salt thereof or a pharmaceutically acceptable C ₁ -C ₆ alkyl addition thereof salt.
[9" claim-type="Currently amended] 2. A compound, a pharmaceutically acceptable acid addition salt thereof, or a pharmaceutically acceptable C ₁ -C ₆ alkyl addition salt thereof, according to claim 1, wherein j = 0 in Formula (I).
[10" claim-type="Currently amended] A compound according to claim 1, wherein p is 0, q is 0, and G is a group represented by -NR ⁷ -CO-, a pharmaceutically acceptable acid addition salt thereof or Pharmaceutically acceptable C ₁ -C ₆ alkyl addition salts.
[11" claim-type="Currently amended] The compound according to claim 1, wherein R ² is a hydrogen atom, R ³ is a hydrogen atom, and R ⁷ is a hydrogen atom in formula (I), a pharmaceutically acceptable acid addition salt thereof or a pharmaceutical thereof Acceptable C ₁ -C ₆ alkyl addition salts.
[12" claim-type="Currently amended] The substituent according to claim 1, wherein the substituent for the phenyl group, C ₃ -C ₈ cycloalkyl group, aromatic heterocyclic group or condensed ring in R ¹ is at least one halogen atom, hydroxy group, C ₁ -C ₆ alkyl group , C ₂ -C ₆ alkenyl, C ₁ -C ₆ alkoxy group, C ₁ -C ₆ alkylthio, C ₂ -C ₄ alkylene group, a methylene-dioxide group, N- phenyl-carbamoyl group, amino group, mono ( C ₁ -C ₆ alkyl) amino group, or a di (C ₁ -C ₆ alkyl) amino group, a pharmaceutically acceptable acid addition salt thereof or a pharmaceutically acceptable C ₁ -C ₆ alkyl addition salt.
[13" claim-type="Currently amended] 2. The method of claim 1, wherein expression of the R ⁶ group in (I), C ₃ -C ₈ cycloalkyl, C ₃ -C ₈ cycloalkenyl group, a benzyl group, a substituent on the aromatic heterocyclic group or the condensed ring or more halogen atoms, a nitrogen atom, a trifluoromethyl group, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy group, a phenyl sulfonyl group, a compound, its characterized in that the C ₂ -C ₇ alkanoylamino group, or an amino group Pharmaceutically acceptable acid addition salts or pharmaceutically acceptable C ₁ -C ₆ alkyl addition salts thereof.
[14" claim-type="Currently amended] 2. A compound according to claim 1, wherein R ¹ in formula (I) is a phenyl group or isoxazolyl group, a pharmaceutically acceptable acid addition salt thereof or a pharmaceutically acceptable C ₁ -C ₆ alkyl addition thereof salt.
[15" claim-type="Currently amended] The compound according to claim 1, wherein R ⁶ in formula (I) is a phenyl group, a furyl group, or a thienyl group, a pharmaceutically acceptable acid addition salt thereof, or a pharmaceutically acceptable C ₁ -C thereof ₆ alkyl addition salts.
[16" claim-type="Currently amended] Of chemokines to receptors on target cells using a therapeutically effective amount of a compound represented by formula (I), a pharmaceutically acceptable acid addition salt thereof, or a pharmaceutically acceptable C ₁ -C ₆ alkyl addition salt thereof Methods of Inhibiting Binding and / or Their Action on Target Cells:

Wherein R ¹ is an aromatic heterocyclic group having 1-3 heteroatoms selected from the group consisting of a phenyl group, a C ₃ -C ₈ cycloalkyl group, or an oxygen atom, a sulfur atom, a nitrogen atom or a combination thereof, wherein phenyl or aromatic hetero The cyclic group may be condensed with an aromatic heterocyclic group having 1-3 heteroatoms selected from the group consisting of a benzene ring or an oxygen atom, a sulfur atom, a nitrogen atom, or a combination thereof to form a condensed ring, and a phenyl group, C ₃ − C ₈ cycloalkyl group, aromatic heterocyclic group, or condensed ring is halogen atom, hydroxy group, cyano group, nitro group, carboxyl group, carbamoyl group, C ₁ -C ₆ alkyl group, C ₃ -C ₈ cycloalkyl group, C _2- C ₆ alkenyl groups, C ₁ -C ₆ alkoxy group, C ₁ -C ₆ alkylthio, C ₃ -C ₅ alkylene group, C ₂ -C ₄ alkylene group, a C ₁ -C ₃ alkylenedioxy group, a phenyl group , Phenoxy group, phenylthio group, benzyl group, benzyloxy group, benzo Amino group, C ₂ -C ₇ alkanoyl group, C ₂ -C ₇ alkoxycarbonyl group, C ₂ -C ₇ alkanoyloxy group, C ₂ -C ₇ alkanoylamino group, C ₂ -C ₇ N- alkyl carbamoyl group, C ₄ -C ₉ N-cycloalkylcarbamoyl group, C ₁ -C ₆ alkylsulfonyl group, C ₃ -C ₈ (alkoxycarbonyl) methyl group, N-phenylcarbamoyl group, piperidinocarbonyl group, morpholinocarbonyl group , 1-pyrrolidinylcarbonyl group, divalent represented by formula: -NH (C = O) O-, formula: divalent represented by -NH (C = S) O-, amino group, mono (C ₁ -C ₆ alkyl) amino group, or di (C ₁ -C ₆ alkyl) amino group, where a phenyl group, a C ₃ -C ₈ cycloalkyl group, an aromatic heterocyclic group, or a condensed ring substituent is halogen Optionally substituted with one or more of atoms, hydroxy groups, amino groups, trifluoromethyl groups, C ₁ -C ₆ alkyl groups, or C ₁ -C ₆ alkoxy groups;
R ² is a hydrogen atom, a C ₁ -C ₆ alkyl group, a C ₂ -C ₇ alkoxycarbonyl group, a hydroxy group, or a phenyl group, wherein the C ₁ -C ₆ alkyl or phenyl group is a halogen atom, a hydroxy group, a C ₁ -C ₆ alkyl group, or May be substituted with one or more of C ₁ -C ₆ alkoxy groups, and when j = 0, R ² is not a hydroxy group;
j represents an integer of 0-2;
k represents an integer of 0-2;
m represents an integer of 2-4;
n represents 0 or 1;
R ³ is a hydrogen atom or a C ₁ -C ₆ alkyl group optionally substituted with one or two phenyl groups, and each phenyl group is at least one of a hydrogen atom, a hydroxy group, a C ₁ -C ₆ alkyl group, or a C ₁ -C ₆ alkoxy group May be substituted by;
R ⁴ and R ⁵ may be the same or different and are a hydrogen atom, a hydroxy group, a phenyl group, or a C ₁ -C ₆ alkyl group, wherein the C ₁ -C ₆ alkyl group is a halogen atom, a hydroxy group, a cyano group, a nitro group, a carboxyl group, a carbon carbamoyl group, a mercapto group, a dino-ku no group, C ₃ -C ₈ cycloalkyl, C ₁ -C ₆ alkoxy group, C ₁ -C ₆ alkylthio group, one or more hydrogen atoms, hydroxy groups, C ₁ -C ₆ alkyl group , Phenyl group, phenoxy group, benzyloxy group, benzyloxycarbonyl group, C ₂ -C ₇ alkanoyl group, C ₂ -C ₇ alkoxycarbonyl group, C ₂ -C ₇ optionally substituted with C ₁ -C ₆ alkoxy group or benzyloxy group alkanoyloxy group, C ₂ -C ₇ alkanoylamino group, C ₂ -C ₇ N- alkyl carbamoyl, C ₁ -C ₆ alkylsulfonyl group, an amino group, a mono (C ₁ -C ₆ alkyl) amino group, di ( Aromatic heterocycle having 1-3 heteroatoms selected from the group consisting of a C ₁ -C ₆ alkyl) amino group, or an oxygen atom, a sulfur atom, a nitrogen atom, or a combination thereof Optionally substituted with one or more of the click groups and optionally condensed with a benzene ring, or R ⁴ and R ⁵ together form a 3-6 membered cyclic hydrocarbon;
p represents 0 or 1;
q represents 0 or 1;
G is -CO-, -SO _2- , -CO-O-, -NR ⁷ -CO-, -CO-NR ^7- , -NH-CO-NH-, -NH-CS-NH-, -NR ⁷ A group represented by -SO _2- , -SO ₂ -NR ^7- , -NH-CO-O-, or -O-CO-NH-, wherein R ⁷ is a hydrogen atom or a C ₁ -C ₆ alkyl group, Or R ⁷ together with R ⁵ represent a C ₃ -C ₅ alkylene group;
R ⁶ is an aromatic heterocycle having 1-3 heteroatoms selected from the group consisting of a phenyl group, a C ₃ -C ₈ cycloalkyl group, a C ₃ -C ₈ cycloalkenyl group, a benzyl group, or an oxygen atom, a sulfur atom, a nitrogen atom or a combination thereof Wherein the phenyl, benzyl, or aromatic heterocyclic group is condensed and condensed with an aromatic heterocyclic group having 1-3 heteroatoms selected from the group consisting of benzene rings or oxygen atoms, sulfur atoms, nitrogen atoms or combinations thereof A phenyl group, a C ₃ -C ₈ cycloalkyl group, a C ₃ -C ₈ cycloalkenyl group, a benzyl group, an aromatic heterocyclic group, or a condensed ring may be a halogen atom, a hydroxy group, a mercapto group, a cyano group , Nitro group, thiocyanato group, carboxyl group, carbamoyl group, trifluoromethyl group, C ₁ -C ₆ alkyl group, C ₃ -C ₆ cycloalkyl group, C ₂ -C ₆ alkenyl group, C ₁ -C ₆ alkoxy group , C ₃ -C ₈ cycloalkyloxy group, C ₁ -C ₆ alkylthio group, C ₁ -C ₃ alkylenedioxy group, phenyl group, phenoxy group, phenylamino group, benzyl group, benzoyl group, phenylsulfinyl group, phenylsulfonyl group, 3-phenylureido group, C ₂ -C ₇ alkanoyl group, C ₂ -C ₇ alkoxycarbonyl group, C ₂ -C ₇ alkanoyloxy group, C ₂ -C ₇ alkanoylamino group, C ₂ -C ₇ N- alkyl carbamoyl, C ₁ -C ₆ alkylsulfonyl Nyl group, phenylcarbamoyl group, N, N-di (C ₁ -C ₆ alkyl) sulfamoyl group, amino group, mono (C ₁ -C ₆ alkyl) amino group, di (C ₁ -C ₆ alkyl) amino group, benzylamino group , A C ₂ -C ₇ (alkoxycarbonyl) amino group, a C ₁ -C ₆ (alkylsulfonyl) amino group, or a bis (C ₁ -C ₆ alkylsulfonyl) amino group, which may be substituted with a phenyl group , A C ₃ -C ₈ cycloalkyl group, a C ₃ -C ₈ cycloalkenyl group, a benzyl group, an aromatic heterocyclic group, or a substituent of a condensed ring may be a halogen atom, cyano group, hydroxy group, amino group, trifluoromethyl group, C ₁ - C ₆ alkyl, C ₁ -C ₆ alkoxy group, C ₁ -C ₆ alkylthio group, a mono (C ₁ -C ₆ alkyl) amino, or di (C ₁ -C ₆ alkyl) is optionally substituted with one or more of the amino group .
[17" claim-type="Currently amended] 17. The method of claim 16, wherein k = 1 and m = 2 in formula (I), wherein the chemokine binds to the receptor on the target cell and / or inhibits its action on the target cell.
[18" claim-type="Currently amended] 18. The method of claim 17, wherein n = 0 in Formula (I), wherein the chemokine binds to the receptor on the target cell and / or inhibits its action on the target cell.
[19" claim-type="Currently amended] 17. The method according to claim 16, wherein in the formula (I) k = 0, m = 3 and n = 1 inhibits the binding of chemokine to the receptor on the target cell and / or its action on the target cell Way.
[20" claim-type="Currently amended] 17. The method of claim 16, wherein k = 1 and m = 3 in formula (I), wherein the chemokine binds to the receptor on the target cell and / or inhibits its action on the target cell.
[21" claim-type="Currently amended] 17. The method of claim 16, wherein k = 2 and m = 2 in formula (I), wherein the chemokine binds to the receptor on the target cell and / or inhibits its action on the target cell.
[22" claim-type="Currently amended] 22. The method of claim 21, wherein n = 1 in formula (I), wherein the chemokine binds to the receptor on the target cell and / or inhibits its action on the target cell.
[23" claim-type="Currently amended] 17. The method of claim 16, wherein k = 1 and m = 4 in formula (I) to inhibit chemokine binding to receptors on target cells and / or their action on target cells.
[24" claim-type="Currently amended] 17. The method of claim 16, wherein j = 0 in Formula (I), wherein the chemokine binds to the receptor on the target cell and / or inhibits its action on the target cell.
[25" claim-type="Currently amended] 17. The chemokine binding and / or target of the receptor on the target cell according to claim 16, wherein p = 0, q = 0 in Formula (I), and G is a group represented by -NR ⁷ -CO-. A method of inhibiting its action on the cell.
[26" claim-type="Currently amended] 17. The chemokine binding to the receptor on the target cell and / or the target cell phase according to claim 16, wherein in formula (I), R ² is a hydrogen atom, R ³ is a hydrogen atom, and R ⁷ is a hydrogen atom. How to inhibit its action on.
[27" claim-type="Currently amended] 17. A substituent according to claim 16, wherein the substituent for the phenyl group, C ₃ -C ₈ cycloalkyl group, aromatic heterocyclic group or condensed ring in R ¹ is at least one halogen atom, hydroxy group, C ₁ -C ₆ alkyl group , C ₂ -C ₆ alkenyl, C ₁ -C ₆ alkoxy group, C ₁ -C ₆ alkylthio, C ₂ -C ₄ alkylene group, a methylene-dioxide group, N- phenyl-carbamoyl group, amino group, mono ( A method for inhibiting chemokine binding to receptors on target cells and / or their action on target cells, characterized in that it is a C ₁ -C ₆ alkyl) amino group, or a di (C ₁ -C ₆ alkyl) amino group.
[28" claim-type="Currently amended] 17. The method of claim 16, wherein expression of the R ⁶ group in (I), C ₃ -C ₈ cycloalkyl, C ₃ -C ₈ cycloalkenyl group, a benzyl group, a substituent on the aromatic heterocyclic group or the condensed ring The target cell on the target cell, characterized in that the halogen atom, nitrogen atom, trifluoromethyl group, C ₁ -C ₆ alkyl group, C ₁ -C ₆ alkoxy group, phenylsulfonyl group, C ₂ -C ₇ alkanoylamino group, or amino group A method of inhibiting chemokine binding to a receptor and / or its action on target cells.
[29" claim-type="Currently amended] 17. The method of claim 16, wherein R ¹ in formula (I) is a phenyl group or isoxazolyl group, wherein the chemokine binds to the receptor on the target cell and / or inhibits its action on the target cell.
[30" claim-type="Currently amended] 17. The method according to claim 16, wherein R ⁶ in formula (I) is a phenyl group, a furyl group, or a thienyl group, which inhibits the binding of chemokines to receptors on target cells and / or their action on target cells. Way.
[31" claim-type="Currently amended] The method of claim 16, wherein the chemokine is MIP-1α. 17. The method of claim 16, wherein the chemokine is MIP-1α.
[32" claim-type="Currently amended] The method of claim 16, wherein the chemokine is MCP-1. 17. The method of claim 16, wherein the chemokine is MCP-1.
[33" claim-type="Currently amended] The method of claim 16, wherein the chemokine receptor is CCR1. 18. The method of claim 16, wherein the chemokine receptor binds to the receptor on the target cell and / or its action on the target cell.
[34" claim-type="Currently amended] The method of claim 16, wherein the chemokine receptor is CCR2A or CCR2B. 17. The method of claim 16, wherein the chemokine binds to the receptor on the target cell and / or inhibits its action on the target cell.
[35" claim-type="Currently amended] 2. A compound according to claim 1, wherein the compound is 4-[{N- (2-amino-5-chlorobenzoyl) glycyl} aminomethyl] -1- (4-chlorobenzyl) piperidine Pharmaceutically acceptable acid addition salts or pharmaceutically acceptable C ₁ -C ₆ alkyl addition salts thereof.
[36" claim-type="Currently amended] A compound according to claim 1, wherein the compound is 4-[{N- (2-amino-4,5-difluorobenzoyl) glycyl} aminomethyl] -1- (4-chlorobenzyl) piperidine Compound, a pharmaceutically acceptable acid addition salt thereof or a pharmaceutically acceptable C ₁ -C ₆ alkyl addition salt thereof.
[37" claim-type="Currently amended] A compound according to claim 1, wherein the compound is 4-[{N- (2-amino-5-trifluoromethylbenzoyl) glycyl} aminomethyl] -1- (4-chlorobenzyl) piperidine Compounds, pharmaceutically acceptable acid addition salts thereof or pharmaceutically acceptable C ₁ -C ₆ alkyl addition salts thereof.
[38" claim-type="Currently amended] A compound according to claim 1, wherein the compound is 4-[{N- (2-amino-5-trifluoromethoxybenzoyl) glycyl} aminomethyl] -1- (4-chlorobenzyl) piperidine Compounds, pharmaceutically acceptable acid addition salts thereof or pharmaceutically acceptable C ₁ -C ₆ alkyl addition salts thereof.
[39" claim-type="Currently amended] The compound of claim 1, wherein the compound is 4-[{N- (2-amino-4,5-difluorobenzoyl) glycyl} aminomethyl] -1- (4-bromobenzyl) piperidine Compounds thereof, pharmaceutically acceptable acid addition salts thereof or pharmaceutically acceptable C ₁ -C ₆ alkyl addition salts thereof.
[40" claim-type="Currently amended] The compound of claim 1, wherein the compound is 1- (2-amino-4-chlorobenzyl) -4-[{N- (2-amino-5-trifluoromethylbenzoyl) glycyl} aminomethyl] piperidine Compounds, pharmaceutically acceptable acid addition salts thereof or pharmaceutically acceptable C ₁ -C ₆ alkyl addition salts thereof.
[41" claim-type="Currently amended] The compound of claim 1, wherein the compound is 1- (3-amino-4-methoxybenzyl) -4-[{N- (2-amino-4,5-difluorobenzoyl) glycyl} aminomethyl] piperi A compound, a pharmaceutically acceptable acid addition salt thereof, or a pharmaceutically acceptable C ₁ -C ₆ alkyl addition salt thereof.
[42" claim-type="Currently amended] The compound of claim 1, wherein the compound is 4-[{N- (2-amino-4,5-difluorobenzoyl) glycyl} aminomethyl] -1- {4-chloro-3- (methylamino) benzyl} A compound characterized in that it is piperidine, a pharmaceutically acceptable acid addition salt thereof or a pharmaceutically acceptable C ₁ -C ₆ alkyl addition salt thereof.
[43" claim-type="Currently amended] The compound of claim 1, wherein the compound is 4-[{N- (2-amino-5-trifluoromethylbenzoyl) glycyl} aminomethyl] -1- (2-thioxo-2,3-dihydro-1 , 3-benzoxazol-5-ylmethyl) piperidine, a pharmaceutically acceptable acid addition salt thereof or a pharmaceutically acceptable C ₁ -C ₆ alkyl addition salt thereof.
[44" claim-type="Currently amended] A compound according to claim 1, wherein the compound is 3-[{N- (2-amino-5-trifluoromethylbenzoyl) glycidyl} amino] -1- (4-chlorobenzyl) pyrrolidine , Pharmaceutically acceptable acid addition salts thereof or pharmaceutically acceptable C ₁ -C ₆ alkyl addition salts thereof.
[45" claim-type="Currently amended] A compound according to claim 1, wherein the compound is 3-[{N- (2-amino-5-trifluoromethylbenzoyl) glycyl} amino] -1- (4-methoxybenzyl) pyrrolidine Compounds, pharmaceutically acceptable acid addition salts thereof or pharmaceutically acceptable C ₁ -C ₆ alkyl addition salts thereof.
[46" claim-type="Currently amended] The compound of claim 1, wherein the compound is 3-[{N- (2-amino-5-trifluoromethylbenzoyl) glycyl} amino] -1- (3,4-methylenedioxybenzyl) pyrrolidine A compound characterized by a pharmaceutically acceptable acid addition salt thereof or a pharmaceutically acceptable C ₁ -C ₆ alkyl addition salt thereof.
[47" claim-type="Currently amended] The compound of claim 1, wherein the compound is 3-[{N- (2-amino-5-trifluoromethylbenzoyl) glycyl} amino] -1- (2,3-dihydro-1-benzofuran-5- Monomethyl) pyrrolidine, a pharmaceutically acceptable acid addition salt thereof or a pharmaceutically acceptable C ₁ -C ₆ alkyl addition salt thereof.
[48" claim-type="Currently amended] A compound according to claim 1, wherein the compound is 3-[{N- (2-amino-5-trifluoromethylbenzoyl) glycyl} amino] -1- (4-methylthiobenzyl) pyrrolidine Compounds, pharmaceutically acceptable acid addition salts thereof or pharmaceutically acceptable C ₁ -C ₆ alkyl addition salts thereof.
[49" claim-type="Currently amended] A compound according to claim 1, wherein the compound is 3-[{N- (2-amino-5-trifluoromethylbenzoyl) glycyl} amino] -1- (4-ethylbenzyl) pyrrolidine , Pharmaceutically acceptable acid addition salts thereof or pharmaceutically acceptable C ₁ -C ₆ alkyl addition salts thereof.
[50" claim-type="Currently amended] A compound according to claim 1, wherein the compound is 3-[{N- (2-amino-5-trifluoromethoxybenzoyl) glycyl} amino] -1- (4-ethylbenzyl) pyrrolidine , Pharmaceutically acceptable acid addition salts thereof or pharmaceutically acceptable C ₁ -C ₆ alkyl addition salts thereof.
[51" claim-type="Currently amended] The compound of claim 1, wherein the compound is 1- (3-amino-4-methoxybenzyl) -3-[{N- (2-amino-5-trifluoromethylbenzoyl) glyciyl} amino] pyrrolidine Compounds, pharmaceutically acceptable acid addition salts thereof or pharmaceutically acceptable C ₁ -C ₆ alkyl addition salts thereof.
[52" claim-type="Currently amended] The compound of claim 1, wherein the compound is 3-[{N- (2-amino-5-trifluoromethylbenzoyl) glycyl} amino] -1- (4-chloro-3-methylbenzyl) pyrrolidine A compound characterized by a pharmaceutically acceptable acid addition salt thereof or a pharmaceutically acceptable C ₁ -C ₆ alkyl addition salt thereof.
[53" claim-type="Currently amended] The compound of claim 1, wherein the compound is 3-[{N- (2-amino-5-trifluoromethylbenzoyl) glycyl} amino] -1- {4-hydroxy-3- (methylamino) benzyl} pi A compound characterized in that it is lollidine, a pharmaceutically acceptable acid addition salt thereof or a pharmaceutically acceptable C ₁ -C ₆ alkyl addition salt thereof.
[54" claim-type="Currently amended] The compound of claim 1, wherein the compound is 3-[{N- (2-amino-5-trifluoromethylbenzoyl) glycyl} amino] -1- (1,3-benzoxazol-5-ylmethyl) pi A compound characterized in that it is lollidine, a pharmaceutically acceptable acid addition salt thereof or a pharmaceutically acceptable C ₁ -C ₆ alkyl addition salt thereof.

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引用文献:

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公开号 | 申请日 | 公开日 | 申请人 | 专利标题

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法律状态:
1997-11-18|Priority to US97248497A

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1997-11-18|Priority to US8/972,484

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1998-04-06|Priority to US5528598A

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1998-04-06|Priority to US9/055,285

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1998-08-13|Priority to US9/133,434

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1998-08-13|Priority to US13343498A

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1998-11-17|Application filed by 이타가키 히로시, 테이진 가부시키가이샤, 마이어스 피터 엘., 듀퐁 파마슈티컬즈 리서치 래버러토리즈

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1998-11-17|Priority to PCT/US1998/023254

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2001-04-16|Publication of KR20010032253A

优先权:

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申请号 | 申请日 | 专利标题

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US97248497A| true| 1997-11-18|1997-11-18|

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US8/972,484|1997-11-18|

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US5528598A| true| 1998-04-06|1998-04-06|

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US9/055,285|1998-04-06|

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US13343498A| true| 1998-08-13|1998-08-13|

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US9/133,434|1998-08-13|

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PCT/US1998/023254|WO1999025686A1|1997-11-18|1998-11-17|Cyclic amine derivatives and their use as drugs|